Side Effects of Drugs Annual, Volume 33: A worldwide yearly survey of new data in adverse drug reactions

Side Effects of Drugs Annual 33 HONORARY EDITOR Prof. M.N.G. Dukes, Oslo, Norway

ADVISORY EDITORIAL BOARD Prof. F. Bochner, Adelaide, Australia Prof. I.R. Edwards, Uppsala, Sweden Prof. G.P. Velo, Verona, Italy

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Contributors M.C. ALLWOOD, BPHARM, PHD Pharmacy Academic Practice Unit, School of Biological, Forensic and Pharmaceutical Sciences, University of Derby, Mickleover, Derby, UK. E-mail: [email protected]. LUIS H. MARTÍN ARIAS, MD, PHD Instituto de Farmacoepidemiología, Facultad de Medicina, 47005 Valladolid, Spain. E-mail: [email protected]. J.K. ARONSON, MA, MBCHB, DPHIL, FRCP, FBPHARMACOLS, FFPM(HON) University of Oxford Department of Primary Health Care, 23–38 Hythe Bridge Street, Oxford OX1 2ET. E-mail: [email protected]. V.V. BANU REKHA Tuberculosis Research Centre, Mayor VR Ramanathan Road, Chetpet, Chennai 600031, India. E-mail: [email protected]. ANDREAS J. BIRCHER Allergy Unit, Department of Dermatology, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland. E-mail: [email protected]. CORRADO BLANDIZZI, MD, PHD Division of Pharmacology & Chemotherapy, Department of Internal Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy. E-mail: [email protected]. KRISTIEN BOELAERT, MD, PHD, MRCP School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, IBR Building 2nd floor, University of Birmingham, Birmingham B15 2TT, UK. E-mail: [email protected]. ALFONSO CARVAJAL, MD, PHD, Instituto de Farmacoepidemiología, Facultad de Medicina, 47005 Valladolid, Spain. E-mail: [email protected]. K. CHAN PHD, DSC, FIBIOL, FCP, FRPHARMS, FRSM Faculty of Pharmacy, The University of Sydney and Centre for Complementary Medicine Research, University of Western Sydney, Locked Bag 1797, Penrith South DC NSW 2751, Australia. E-mail: [email protected]. N.H. CHOULIS, MD, PHD LAVIPHARM Research Laboratories, Agias Marinas Street, 19002 Peania, Attika, Greece. E-mail: [email protected].

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Contributors

JAMIE J. COLEMAN, MBCHB, MA (MED ED), MD, MRCP(UK) Department of Clinical Pharmacology, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. E-mail: [email protected]. NATASCIA CORTI, MD University Hospital Zurich, Department of Medicine, Division of Infectious Diseases and Hospital Epidemiology, Rämistrasse 100, CH-8091 Zürich, Switzerland. E-mail: [email protected]. J. COSTA, MD Clinical Pharmacology Department, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Ctra. de Canyet s/n, 08916 Badalona, Spain. E-mail: [email protected]. NICHOLAS J. COWLEY, MBCHB, MRCP(UK), FRCA School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Email: [email protected]. ANTHONY R. COX, PHD Pharmacy Practice Group, School of Pharmacy, Aston University, Birmingham, B4 7ET, UK. Email: [email protected]. STEPHEN CURRAN, BSC, MBCHB, MMEDSC, MRCPSYCH, PHD Fieldhead Hospital, South West Yorkshire Mental Health NHS Trust, Ouchthorpe Lane, Wakefield, WF1 3SP, UK. E-mail: [email protected]. GWYNETH A. DAVIES, MD, MRCP Senior Clinical Lecturer, Asthma & Allergy, School of Medicine, Swansea University, Swansea, Wales, UK. E-mail: [email protected]. S. DITTMANN, MD, DSCMED 19 Hatzenporter Weg, 12681 Berlin, Germany. E-mail: [email protected]. IDA DUARTE Santa Casa de São Paulo Medical School, São Paulo, Brazil. E-mail: [email protected]. M.N.G. DUKES, MD, MA, LLM Trosterudveien 19, 0778 Oslo, Norway. E-mail: [email protected]. RIF S. EL-MALLAKH, MD Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, MedCenter One, 501 E Broadway, Suite 340, Louisville, Kentucky 40202, USA. E-mail: [email protected]. M. FARRÉ, MD Human Pharmacology and Neurosciences, Institut de Recerca Hospital del Mar (IMIM) – Parc de Salut Mar, Universitat Autònoma de Barcelona, Doctor Aiguader 88, 08003 Barcelona, Spain. E-mail: [email protected].

Contributors

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A. FINZI, MD Istituto di Ricerche Farmacologiche M. Negri,via G La Masa 19, 20156 Milan, Italy. E-mail: andrea.fi[email protected]. M.G. FRANZOSI, PHD Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche “Mario Negri”, Via Eritrea 62, 20157 Milan, Italy. E-mail: [email protected]. S. GALEA, MD, MRCPSYCH, MSC (ADDICTIVE BEHAVIOUR), DIP (FORENSIC MENTAL HEALTH) Auckland Community Alcohol & Drugs Services, 50 Pitman House, Carrington Road, Point Chevalier, Auckland, New Zealand, & Centre for Addiction Studies, St George's Hospital Medical School, 6th Floor, Hunter Wing, Cranmer Terrace, London SW17 0RE, UK. E-mail: [email protected]. YONGLIN GAO, MD Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, MedCenter One, 501 E Broadway, Suite 340, Louisville, Kentucky 40202, USA. E-mail: [email protected]. A.H. GHODSE, MD, PHD, DSC, FFPH, FRCP, FRCPE, FRCPSYCH International Centre for Drug Policy, St George's University of London, 6th Floor, Hunter Wing, Cranmer Terrace, London SW17 0RE, UK. E-mail: [email protected]. ANDREAS H. GROLL, MD Infectious Disease Research Program, Center for Bone Marrow Transplantation and Department of Hematology/Oncology, University Children's Hospital, AlbertSchweitzer-Strasse 33, 48129 Muenster, Germany. E-mail: [email protected]. AVINASH GUPTA, MBBS, BSC, MRCP University of Oxford, Department of Medical Oncology, Churchill Hospital, Oxford OX3 7LJ, UK. E-mail: [email protected]. ALISON HALL, BSC, MBCHB, FRCA School of Clinical Science, University of Liverpool, The Duncan Building, Daulby Street, Liverpool, L69 3GA, UK. E-mail: [email protected]. ALEXANDER IMHOF, MD University Hospital Zurich, Department of Medicine, Division of Infectious Diseases and Hospital Epidemiology, Rämistrasse 100, CH-8091 Zürich, Switzerland. E-mail: [email protected]. M.S. JAWAHAR, MD, MSC, DLSHTM Tuberculosis Research Centre, Chennai 600031, India. E-mail: [email protected]. NATALIA JIMENO, MD, PHD Instituto de Farmacoepidemiología, Facultad de Medicina, 47005 Valladolid, Spain. E-mail: [email protected].

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Contributors

CLARICE KOBATA Santa Casa de São Paulo Medical School, São Paulo, Brazil. E-mail: [email protected]. SARAH LANGENFELD, MD University of Massachusetts Medical School, Department of Psychiatry, 361 Plantation Street, Worcester, MA 01605, USA. E-mail: [email protected]. M. LARTEY, MBCHB, MSC, FWACP Department of Medicine & Therapeutics, University of Ghana Medical School, PO Box 4236, Accra, Ghana. E-mail: [email protected]. R. LATINI, MD Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche “Mario Negri”, Via Eritrea 62, 20157 Milan, Italy. E-mail [email protected]. ROSANA LAZZARINI Santa Casa de São Paulo Medical School, São Paulo, Brazil. E-mail: [email protected]. M. LEUWER, MD School of Clinical Science, University of Liverpool, The Duncan Building, Daulby Street, Liverpool, L69 3GA, UK. E-mail: [email protected]. Z.X. LIN, BSC, PHD School of Chinese Medicine, Faculty of Science, 1/F Sino Building, The Chinese University of Hong Kong, Shatin NT, Hong Kong SAR, PR China. E-mail: linzx@cuhk. edu.hk. PAM MAGEE, BSC, MSC, MRPHARMS Fillongley, Coventry, UK. Email: [email protected]. R.H.B. MEYBOOM, MD, PHD Department of Pharmacoepidemiology and Pharmacotherapy, Faculty of Pharmacy, Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands. E-mail: [email protected]. MARK MIDDLETON, PHD, FRCP University of Oxford, Department of Medical Oncology, Churchill Hospital, Oxford OX3 7LJ, UK. E-mail: [email protected]. TORE MIDTVEDT, MD, PHD Department of Microbiology, Tumor and Cell Biology (MTC), Von Eulers v. 5, Karolinska Institutet, Box 60 400, S-171 77 Stockholm, Sweden. E-mail: [email protected]. PHILIP B. MITCHELL, AM, MBBS, MD, FRANZCP, FRCPSYCH University of New South Wales School of Psychiatry, Prince of Wales Hospital, Randwick, NSW 2031, Australia. E-mail: [email protected].

Contributors

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SHABIR MUSA, MBCHB, MRCPSYCH Fieldhead Hospital, South West Yorkshire Mental Health NHS Trust, Ouchthorpe Lane, Wakefield, WF1 3SP, UK. E-mail: [email protected]. PAUL NESTEL, MD, FRACP Baker Heart & Diabetes Institute, PO Box 6492, St Kilda Road Central, Melbourne, Victoria 8008, Australia. E-mail: [email protected]. JULIE OLLIFF, MBCHB, MRCP, FRCR Imaging Department, Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Edgbaston, Birmingham, B15 2WB, UK. E-mail: [email protected]. R.C.L. PAGE, MD, FRCP, MA(ED) Endocrine Unit, Dundee House, City Hospital, Hucknall Road, Nottingham NG5 1PB, UK. Email: [email protected]; [email protected]. JAYENDRA K. PATEL, MD University of Massachusetts Medical School, Department of Psychiatry, 361 Plantation Street, Worcester, MA 01605, and Lake Area Psychiatry, 333 Dr. Michael DeBakey Drive, Lake Charles, LA 70601, USA. E-mail: [email protected]. MIKE PYNN, MRCP Clinical Lecturer, School of Medicine, Swansea University, Swansea, Wales, UK. E-mail: [email protected]. ALEXANDER RAYMANN, MD, DESA (DEAA) Department of Anaesthesiology, Intensive Care and Pain Medicine, Klinikum Region Hannover Nordstadt, Hannover, Germany. E-mail: [email protected]. PETER RILEY, MBCHB, MRCP, FRCR Imaging Department, Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Edgbaston, Birmingham, B15 2WB, UK. E-mail: [email protected]. ANITA ROTTER Clinic of Dermatology, Santa Casa de São Paulo, São Paulo, Brazil. E-mail: [email protected]. CARMELO SCARPIGNATO, MD, DSC, PHARMD, FRCP, FCP, FACG Laboratory of Clinical Pharmacology, School of Medicine & Dentistry, University of Parma, Via Volturno, 39–43125 Parma, Italy. E-mail: [email protected]. MICHAEL SCHACHTER, MD Department of Clinical Pharmacology, National Heart and Lung Institute, Imperial College, St Mary's Hospital, London W2 1NY, UK. E-mail: [email protected]. J.S.A.G. SCHOUTEN, MD Department of Ophthalmology, Maastricht University Hospital, PO Box 5800, 6202 AZ Maastricht, The Netherlands. E-mail: [email protected].

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Contributors

DOMINIK SCHREY, MD Infectious Disease Research Program, Center for Bone Marrow Transplantation and Department of Hematology/Oncology, University Children's Hospital, Albert-Schweitzer-Strasse 33, 48129 Muenster, Germany. E-mail: [email protected]. STEPHAN A. SCHUG, MD, FANZCA, FFPMANZCA Level 2, MRF Building G Block, Royal Perth Hospital, GPO Box X2213, Perth, WA 6847, Australia. E-mail: [email protected]. REGINALD P. SEQUEIRA, PHD, FCP Department of Pharmacology & Therapeutics, College of Medicine & Medical Sciences, Arabian Gulf University, PO Box 22979, Manama, Bahrain. E-mail: [email protected]. OSCAR OZMUND SIMOOYA, BSC, MBCHB, MSC The Copper belt University, Health Services Division, PO Box 21692, Kitwe, Zambia, Central Africa. E-mail: [email protected]. REBECCA SPENCER Fieldhead Hospital, South West Yorkshire Mental Health NHS Trust, Ouchthorpe Lane, Wakefield, WF1 3SP, UK. E-mail: [email protected]. D. SPOERL Allergy Unit, Department of Dermatology, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland. E-mail: [email protected]. SEBASTIAN STRAUBE, BMBCH, MA, DPHIL Department of Occupational, Social and Environmental Medicine, University Medical Center Göttingen, Waldweg 37 B, D-37073 Göttingen, Germany. E-mail: sebastian. [email protected]. P.F.W. STRENGERS, MD Sanquin Blood Supply Foundation, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. E-mail: [email protected]. ANNE TAEGTMEYER, MD University Hospital Zurich, Department of Medicine, Division of Infectious Diseases and Hospital Epidemiology, Rämistrasse 100, CH-8091 Zürich, Switzerland. E-mail: [email protected]. K. TORPEY, MD, PHD, MPH Family Health International, 4401 Wilson Boulevard, Suite 700, Arlington, VA 22203, USA. E-mail: [email protected]. LUCIANA TRAMACERE U.O. Neurologia, Ospedale S Giovanni di Dio, Via Torregalli 3, 50143 Firenze, Italy. E-mail: [email protected]. GIJSBERT B. VAN DER VOET, PHD, ERT Health Council of The Netherlands, Parnassusplein 5 (C709)—2511 VX The Hague, The Netherlands. E-mail: [email protected].

Contributors

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P.J.J. VAN GENDEREN, MD, PHD Department of Internal Medicine, Harbour Hospital and Institute of Tropical Diseases, Haringvliet 2, 3011 TD Rotterdam, The Netherlands. E-mail: [email protected]. K.J. VELTHOVE, PHARMD, PHD Sanquin Blood Supply Foundation, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. E-mail: [email protected]. P. VERHAMME, MD Vascular Medicine and Haemostasis, University of Leuven, Herestraat, 49, 3000 Leuven, Belgium. E-mail: [email protected]. GARRY M. WALSH, MSC, PHD School of Medicine, Institute of Medical Sciences Building, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK. E-mail: [email protected]. THOMAS J. WALSH, MD Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Weill Cornell Medical College of Cornell University, New York, New York, USA. E-mail: [email protected]. MANUEL WENK, MD Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, Perth, Australia & Department of Anesthesiology and Intensive Care, University Hospital Muenster, Albert-Schweitzer-Str. 33, 48149 Muenster, Germany. E-mail: [email protected]. C. WILLIAMS, BSC, MBCHB, FRCA Department of Anaesthesia, 12th Floor, Royal Liverpool University Hospital, Prescot Street, Liverpool, L7 8XP, UK. E-mail: [email protected]. EILEEN WONG, MD Harvard Medical School, Massachusetts Mental Health Center, Department of Psychiatry, Jamaica Plain, MA 02130, USA. E-mail: [email protected]. GAETANO ZACCARA, MD U.O. Neurologia, Ospedale S Giovanni di Dio, Via Torregalli, 50100 Firenze, Italy. E-mail: [email protected]. H.W. ZHANG, BSC, MPHIL, PHD School of Chinese Medicine, Faculty of Science, 1/F Sino Building, The Chinese University of Hong Kong, Shatin NT, Hong Kong SAR, PR China. E-mail: [email protected].

Special reviews SSRIs and emergent suicidal ideation Antidepressants in pregnancy The uses of lithium Adulteration of street drugs with clenbuterol Flumazenil Typical versus atypical antipsychotic drugs Weight gain and diabetes mellitus due to antipsychotic drugs Suicidality and antiepileptic drugs Lacosamide Visual impairment and vigabatrin An update on adverse events in patients taking COX-2 selective and non-selective NSAIDs Urinary tract dysfunction after recreational use of ketamine Cartilage toxicity from local anesthetics Tetrabenazine Stress cardiomyopathy and catecholamines Inhaled glucocorticoids and the risk of pneumonia Inhaled glucocorticoids and skeletal adverse effects Long-term safety of long-acting beta2-adrenoceptor agonists (LABAs)—an update Cardiovascular risks of inhaled anticholinergic drugs More about amiodarone-induced thyrotoxicosis and its management Dronedarone Nervous system adverse effects of triptans Antihypertensive drugs and their adverse effects in the perioperative period Thimerosal and neurodevelopment in infants Titanium allergy Pro-oxidant effects of deferiprone Disinfectants and bacterial resistance Triphenylmethane dyes Carbapenems and seizures Tetracyclines and the environment Drug-drug interactions with antifungal azoles Adverse metabolic effects of antiretroviral drugs Amantadine and corneal edema Multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis Antituberculosis drug treatment in transplant recipients Problems in interpreting interaction studies with protease inhibitors in patients co-infected with tuberculosis and AIDS Dapsone-induced hematological abnormalities and their management Pandemic influenza H1N1 vaccines Autism and vaccines The risks of infections from transfusions Vitamin A supplementation in infants at times of immunization Aprotinin and renal function xvi

26 27 39 53 79 89 94 127 139 178 241 268 281 305 313 353 355 357 364 382 386 408 413 453 456 468 479 481 491 497 545 582 602 623 627 628 630 659 661 669 691 724

Special reviews

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Cross-reactivity between thiopurines Attitudes to the use of hormone replacement therapy Can HRT activate latent breast cancer? Intrauterine administration of levonorgestrel Abuse of anabolic steroids and the justification of control measures Is there an increased risk of cancer in patients using insulin? Taxanes and other microtubule stabilizing agents Use of carboxypeptidase in the treatment of methotrexate toxicity Cardiotoxicity of “mad honey”

824 853 856 865 869 890 935 950 996

Cumulative indexes of special reviews, Annuals 11–32 1. Index of drugs Note: the format 32.609 refers to SEDA-32, p. 609. Abetimus, drug development, 29.460 ACE inhibitors acetylsalicylic acid, interaction, 28.124 angioedema, 22.225, 29.207, 31.352, 32.380 cough, 19.211 indications, 24.233 Acetaminophen, see Paracetamol Acetylsalicylic acid, 21.100 ACE inhibitors, interaction, 28.124 antithrombotic effectiveness, 12.74 benefit to harm balance in preventing strokes and heart attacks, 27.109 co-medication, 26.423 gastrointestinal effects, 17.95, 18.90 Reye's syndrome, 11.79, 15.85 rhinosinusitis/asthma, 17.94 respiratory disease, 31.193 sensitivity, 12.75 Acupuncture incidence of adverse effects, 29.589 traumatic effects, 29.590 Adenosine, dyspnea and bronchospasm, 32.337 Adrenaline, myocardial infarction and vasospasm, 31.259 Aerosols, delivery, 27.172 Albumin, human, anaphylaxis, 14.296 Alcohol, 31.757 vitamin A, beta-carotene, interaction, 24.442 Aldosterone antagonists, in heart failure, 24.246 Alkylating drugs, 31.721 Aluminium in albumin solutions, 23.359 toxicity in children, 12.185 tumorigenicity, 31.383 Aminoglycoside antibiotics, 17.304 contact dermatitis, 13.225 dosage regimens, 20.234, 21.265, 23.264 nephrotoxicity, 15.268, 17.305 ototoxicity, 14.222, 18.268 xviii

and ribostamycin, 15.270 Amiodarone, dysrhythmias, 25.211 eryptosis, 32.339 respiratory toxicity, 15.168 thyroid disease, 27.192, 31.327 Amphetamines, 29.3 Amphotericin, liposomal, 17.319 nephrotoxicity, 13. 231, 14.229, 27.276 Anabolic steroids abuse, 29.508, 32.751 Analgesics agranulocytosis and aplastic anemia, 11.87 choice of drug and dose, 12.63 headache, 21.95 headaches in children, 23.114 nephropathy, 21.98 Androgens, in women, 24.477 Anesthesia, dental, safety of, 16.122 Anesthetics halogenated, renal damage, 20.106 local, and lipid emulsion, 32.261 local, combinations, 20.121 local, lipid rescue, 31.231 local, neurotoxicity, 21.129, 25.152 ocular, 17.542 Angiotensin II receptor antagonists, angioedema 30.238 Anisoylated plasminogen-streptokinase activator complex (APSAC), 12.313 Anorectic drugs cardiac valvulopathy 22.3, 23.2, 24.4, 25.5 primary pulmonary hypertension, 18.7, 21.2, 23.2, 25.5 Anthracyclines, 25.533 Antiallergic drugs, ocular treatment, 11.420 Antibacterial drugs, resistance, 31.413, 32.445 intrapartum, 32.446 Anticancer antimetabolites, 29.531 Anticholinergic drugs, 22.507, 31.273 cardiovascular risks, 32.318 Anticoagulants, oral, skin necrosis, 29.358

Cumulative indexes of special reviews, Annuals 11–32 Anticonvulsants, see Antiepileptic drugs Antidepressants, see also individual agents during and after pregnancy, 21.17 and emergent suicidality, 32.29 mania, 29.18 overdose, 28.14 pregnancy, 32.31 relative risks, 11.16 Antidysrhythmic drugs in atrial fibrillation, 24.197 prodysrhythmic effects, 17.218, 23.196 Antiepileptic drugs bone loss, 27.74 comparison, 25.78 death, 23.83 overdosage, 22.84 psychiatric effects, 22.82, 27.72 Antiestrogens, genotoxicity and tumorigenicity, 27.429 Antifungal drugs drug interactions (azoles), 24.318, 28.299, 29.282, 30.320, 31.459, 32.497 Pneumocystis jiroveci (carinii) pneumonia, 18.289 Antihelminthic drugs Mazzotti reaction, 31.507 pharmacovigilance in developing countries, 32.571 Antihistamines cardiovascular adverse effects, 17.196, 22.176, 25.183, 26.180 drowsiness/sedation, 21.170, 23.171, 26.182 Antihypertensive drugs, 19.209 in diabetes mellitus, 28.226 fixed-dose combinations, 22.224 individualizing therapy, 17.246 quality of life, 32.375 Antimalarial drugs, 14.237, 17.325, 20.257 adjunctive treatments, 24.330 prophylaxis, 13.239, 23.304 Antimicrobial drugs, see also different types allergic reactions, 23.251 coagulation disorders, 18.258 colitis, 12.216, 17.303 intestinal motility, 13.220 male fertility, 16.262 new, 13.210 new, with adjuvants, 17.296 the pill and pregnancy, 24, 274 policies and politics, 16.273 pregnancy, 11.231 prescribing, 15.254 preterm infants, 21.258 prudent use, 25.279 , 27.242, 28. 265 resistance, 12.206, 13.210, 19.237, 20.228, 21.257, 22.265, 23.250, 24.273, 29.244, 31.413

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seizures, 18.261 side chains, 16.264 Antioxidant vitamins, 20.363 Antiprotozoal drugs African trypanosomiasis, 18.293 toxoplasmosis, 20.262 Antipsychotic drugs comparisons of different types 25.53, 27.50 deaths, 32.89 diabetes mellitus, 28.60 use in conditions other than schizophrenia, 27.49 use in elderly patients, 30.59 weight gain, 26.56 Antiretroviral drugs, metabolic complications, 28.329 Antischistosomal drugs, 12.261 Antithyroid drugs, pregnancy, 13.377 Antituberculosis drugs, 16.341, 31.500 children, 32.557 genetic susceptibility, 28.342 hepatotoxicity, 25.363, 26.339, 31.495, 32.555 Mycobacterium avium–complex infection, 20.278 transplant recipients, 32.559 Appetite suppressants cardiac valvulopathies, 22.3, 23.2, 24.4, 25.5 primary pulmonary hypertension, 18.7, 21.2, 23.2, 25.5 Aprotinin, market withdrawal, 32.642 Aripiprazole, 31.70 Arylpropionic acids, stereoisomers 32.229 Aspirin, see Acetylsalicylic acid Asthma medications, exacerbation of asthma, 20.165 Atovaquone, 19.266 Avoparcin lessons from, 27.242 resistance, 29.244 Azathioprine, see Thiopurines Azoles, see Antifungal drugs Baclofen, withdrawal syndrome, 26.152 Bambuterol, cardiac failure, 23.181 Benzodiazepines brain damage, 14.36 dependence, 12.41 depression, 17.43 medicolegal aspects, 13.33 Beta2-adrenoceptor agonists, 18.159 asthma, 19.178, 21.179 asthma deaths, 17.164 long-acting, respiratory adverse effects, 30.198, 31.309 long-acting, genetic susceptibility factors, 30.199, 31.310

xx Beta-adrenoceptor antagonists arthralgia, 11.164 sexual function, 15.188 Beta-carotene, see also Vitamin A alcohol, vitamin A, interaction, 24.442 tumorigenicity, 25.454 Beta-lactam antibiotics effects on eukaryotic cells, 13.212 immediate hypersensitivity reactions, 14.211 pregnancy, 25.280 Blood, see Transfusions Botulinum toxin A, use in primary axillary hyperhidrosis, 27.161 Budesonide, children, susceptibility factors, 30.194 Calcium antagonists, long-term safety, 20.185, 21.208, 22.214 Carbamazepine, skin reactions, 32.129 Carnitine, 13.269 Carotenoids, tumorigenicity, 25.454 Ceftriaxone, 15.258 nephrolithiasis, 29.246 Cephalosporins immunological reactions, 28.267 hypersensitivity reactions, cross-reactivity with penicillins, 30.280 and vitamin K, 12.210 Charcoal, activated, in digitalis overdose, 24.201 Chinese medicines, injectable formulations, 32.880 Chloramphenicol, children, 15.267 Chloroquine, 15.286 Chondroprotective agents, 14.439 Chymopapain, 11.279, 14.264 Ciclesonide, 30.196 Ciclosporin, urinary system, 19.348 Clozapine, 15.50 agranulocytosis, 22.1359 Cocaine cardiovascular reactions, 18.5 fetotoxicity, 29.41, 30.35 prenatal exposure and perinatal effects, 27.1 second-generation effects, 20.24 Cocamidopropylbetaine, allergy, 19.151 Codeine, breast feeding, 31.154 Complementary and alternative therapies, indirect risks, 27.521 esophagus, adverse effects on, 14.442 Contrast media adverse reactions, 13.431, 24.525 anaphylactoid and allergic reactions, 20.422 delayed reactions, 26.513 in magnetic resonance imaging, 20.419 nephrotoxicity, 27.500, 28.556, 29.575, 31.731, 31.735, 32. 846 sialadenitis, 32.845

Cumulative indexes of special reviews, Annuals 11–32

systemic fibrosis, 32.852 Corticosteroids, see Glucocorticoids Cosmetics adverse reactions, 13/117 contact allergy, 11.142, 16.150, 19.151 ingredient labeling 22.159 Co-trimoxazole, hypersensitivity reactions, 20.264 COX-2 inhibitors, 24.115, 25.126, 26.116 cardiovascular disease, 29.116, 32.225 gastrointestinal adverse reactions, 32.225 Danaparoid sodium, 32.631 Daptomycin, muscle damage, 30.309 Deferiprone, cardiac siderosis, 29.235 Deferoxamine, 16.247 bone dysplasia, 23.241 cardiac siderosis, 29.235 bone dysplasia, 23.241 cardiac siderosis, 29.235 yersiniosis, 11.215 Diamorphine, progressive spongiform leukoencephalopathy, 24.40 Diclofenac, liver damage, 20.91 Diethylstilbestrol, transgenerational effects, 31.657 Digitalis, in atrial fibrillation, 24.197 Digoxin, compared with other drugs in heart failure in sinus rhythm, 14.141 compared with other drugs in chronic uncomplicated atrial fibrillation, 14.144 in atrial fibrillation, 32.333 in heart failure in sinus rhythm, 18.196 Dimethylfumarate, 32.295 Dipeptidyl peptidase IV inhibitors, 30.498 Diuretics diabetes mellitus, electrolyte abnormalities, and the ALLHAT trial, 27.219 hyponatremia, 29.219 interactions with NSAIDs, 12.80 renal cell carcinoma, 23.225 renal insufficiency, 25.250 thiamine deficiency, 32. 401 DNA alkylating drugs, 31.721 Dofetilide, 26.208 Dopamine receptor agonists pathological gambling, 30.174 sleep disorders, 26.160, 27.149 Doxylamine, overdose and rhabdomyolysis, 31.298 Drotrecogin alfa (activated), 32.591 Ecstasy, see MDMA EDTA, pseudothrombocytopenia, 21.250 Endothelin receptor antagonists, in hypertension, 26.233 Enzyme inhibitors, 15.337

Cumulative indexes of special reviews, Annuals 11–32 Epinephrine, see Adrenaline Erythromycin, versus the new macrolides, 21.269 Erythropoietin, pure red cell aplasia, 27.348 status and safety, 16.400 Ethambutol, optic neuropathy, 30.358 Ethylene oxide, dialyser hypersensitivity, 11.219 Etomidate, adrenal suppression, 32.249 Etoposide, 27.477 Etretinate, ossification, 12.127 Euxyl K 400, contact allergy, 16.150 Fat emulsions, priapism, 11.313 Felbamate aplastic anemia, 19.68, 22.86 risk/benefit ratio, 23.86 Fenfluramine cardiac valvulopathies, 22.3, 23.2, 24.4, 25.5 primary pulmonary hypertension, 18.7, 21.2, 23.2, 25.5 Fenoterol, safety in severe asthma, 23.182 Fentanyl, buccal and transdermal administration, 20.77 Fertility drugs malignant melanoma, 26.434 ovarian cancer, 24.474 Finasteride, 30.480 Fish oil, 13.460 Flecainide, in supraventricular dysrhythmias, 21.200 Fluoroquinolones, 12.250, 18.271 Fluorouracil, adverse reactions, 23.476 Folic acid, dietary supplementation, 19.369 safety aspects, 27.407 Formoterol, tolerance, 24.187 Fragrances, contact allergy, 20.149 Gadolinium salts, nephrotoxicity, 28.561, 31.735, 32.852 General anesthetics, see Anesthetics Germanium, 16.545 Glucocorticoids bone, 16.447, 22.182, 25.195 contact allergy, 15.139, 21.158 effective dose and therapeutic ratio, 23.175 and eyes, 29.481 and growth, 14.335 inhaled, children, risks in, 27.174 inhaled, effects on mouth and throat, 29.168 inhaled, effects on skin, 29.169 inhaled, fracture risk, 31.307 inhaled, growth inhibition, 26.186 inhaled, hypothalamic–pituitary–adrenal gland function, 31.305 inhaled, pneumonia risk, 32.311 inhaled, systemic availability, 24.185, 26.187

xxi

musculoskeletal adverse reactions, 21.417, 32.312 osteoporosis and osteonecrosis, 16.447, 19.377, 20.374, 21.417, 22.182, 28.473 preterm infants, 17.445 Glucose solutions, hypophosphatemia, 11.312 Grapefruit juice, drug interactions 23.519 Growth hormone adults, 16.501 Creutzfeldt–Jakob disease, 11.371 insulin resistance, 24.504 malignancy, 23.468 Heparin low-molecular-weight, 12.311 thrombocytopenia, 30.404, 32.626 Hepatitis B vaccine, demyelinating diseases, 21.331, 22.346, 24.374 Herbal medicines, warfarin, interactions, 30.400 Heroin, see Diamorphine Histamine (H2) receptor antagonists, 13.330, 15.393 HIV-protease inhibitors insulin resistance, 22.317 lipodystrophy, 22.317 HMG Co-A reductase inhibitors, interactions, 25.530, 30.517 Hormone replacement therapy cardiovascular reactions, 31.659 ovarian cancer, 32.740 Hormones, sex breast cancer 11.346 tumors, 22.465 HRT, see Hormone replacement therapy 5-HT, see Serotonin Hydrochlorothiazide, non-cardiogenic pulmonary edema, 31.373 Hypnotics, 20.30 avoiding adverse reactions, 21.37 Hypoglycemic drugs, combinations of, 27.458, 28.521 Immunization adverse reactions, 24.364 and autoimmune disease, 27.336 bioterrorism, 25.378, 26.354 multiple, 27.334 surveillance after, 15.340, 22.333, 23.335, 24.364, 25.376, 26.353, 27.334 Immunotherapy, in leishmaniasis, 15.299 Incretin mimetics, 29.528 Indacaterol, 32.317 Indometacin, fetal and neonatal complications, 18.102 Influenza vaccine, 29.332 Inhalations, 11.151

xxii Insulin edema, 11.364 human, and hypoglycemia, 15.452 inhalation, 30.495 modes of administration, 26.464 resistance, and growth hormone, 24.504 synthetic analogues, 24.489 Interferon þ ribavirin, 30.344 Interferons, psychological and psychiatric reactions, 29.384 Interleukin-2, 14.325 Ipecacuanha, myopathy, 11.422 Irinotecan, 27.477 Iodine, radioactive, 11.358 Iron chelators, combinations, 31.399 Isoniazid genetic susceptibility factors, 12.257 prophylactic, toxicity, 24.352 KathonÒ CG, 31.134 Kava kava liver damage, 27.518 adverse reactions, 28.579 Ketoconazole, hepatotoxicity, 12.229 Ketorolac, risk of adverse reactions, 17.110 Khat, 30.43 Lamotrigine, skin rashes, 20.62, 24.88 Latex, allergy, 31.761 Laxatives, abuse, 13.336 Leflunomide, 29.435 Leukotriene receptor antagonists, Churg–Strauss syndrome, 24.183, 27.177, 29.174 Levacetylmethadol, 32.193 Levodopa, and malignant melanoma, 31.267 Lipid-lowering drugs, 13.402, 15.479 Lithium adverse reactions, prevention and treatment, 13.17, 17.28 beneficial uses other than in bipolar disorder, 27.19 efficacy, comparisons with other agents, 30.23 interactions, 16.13, 18.30 intoxication, prevention and treatment, 17.29 monitoring therapy, 11.24, 18.25 mortality, 19.14 neuroprotection, 32.41 urinary system, 14.18, 19.16 thyroid, 12.26 Local anesthetics, see Anesthetics Loop diuretics, see Diuretics Lorenzo's oil, 27.475 Lyme disease vaccine, autoimmune disease, 24.366

Cumulative indexes of special reviews, Annuals 11–32

Macrolides, drug interactions, 14.220 intestinal motility, 18.269 Malaria vaccines, 22.306 Mannitol, 28.236 MAO inhibitors, see Monoamine oxidase inhibitors MDMA (ecstasy) cognitive reactions, 26.32, 32.63 deaths, 24.32 epidemiology of use, 30.37 Measles immunization, see also MMR autism, 23.350 Crohn's disease, 23.350 neurological adverse reactions, 23.348 subacute sclerosing panencephalitis, 29.335 Mebendazole, hypersensitivity reactions, 12.263 Melatonin, 25.523 Mercaptopurine, see Thiopurines Metamfetamine, 29.3 Metformin contraindications, 28.515 lactic acidosis, 23.459, 29.526 Methyldibromoglutaronitrile, contact allergy, 16.150, 19.151 Methylphenidate, effects at different ages, 31.6 Methylthiotetrazole, 11.226 Mibefradil, drug interactions, 23.210 Midazolam, 15.112 Midodrine, 26.159 Milrinone, intravenous, acute heart failure, 21.196 MMR immunization autism, 23.350, 25.387, 28.363 Crohn's disease, 23.350, 25.387 Mometasone furoate, 30.197 Monoamine oxidase inhibitors, 12.8, 13.6, 17.361 Monofunctional alkylating agents, 32.827 Morphine, managing adverse reactions, 26.98 Muscle relaxants emergency medicine, 20.133 eyes, 21.145 hypersensitivity reactions, 27.138 intensive care, 19.140 Neuromuscular blocking agents, anaphylaxis, 29.145 non-depolarizing neuromuscular blockers, 15.127 recovery in intensive care, 12.114 residual paralysis, 27.139 Niacin, extended-release, 16.440 N-Lost derivatives, 31.721 Nomifensine, 11.15 NSAIDs, see also COX-2 inhibitors acute renal insufficiency, 28.122 blood pressure, 19.92, 27.102 cardiovascular adverse reactions, 32.225

Cumulative indexes of special reviews, Annuals 11–32 children, 19.96 current controversies, 17.102 COX-2 inhibitors, 24.115, 25.126, 26.116 dyspepsia, 28.120 gastrointestinal adverse reactions, 14.79, 17.95, 18.90, 18.99, 20.86, 21.96, 22.108, 23.114, 32.225 gastrointestinal damage, role of Helicobacter pylori, 27.105 gastrointestinal damage, reducing, 30.125 gastrointestinal toxicity, prevention, 19.93 inflammatory bowel disease, 25.131 inhibiting cardioprotective effects of acetylsalicylic acid, 28.118 interactions with diuretics, 12.80 intracerebral hemorrhage, 28.119 necrotizing fasciitis, 28.121 nephrotoxicity, 11.82, 18.100, 20.89, 24.120, 26.111 osteoarthritis, 11.87 skin reactions, 13.72 topical, 18.163 Ocular drugs allergic reactions, 21.486 geriatric patients, 16.542 risk factors for adverse reactions, 22.507 Omeprazole, tumors, 16.423 Opioids abuse, 29. 44 adverse reactions, frequency, 32.183 adverse reactions, prevention, 24.100 death, 25.37 obstetric use, 24.102 routes of administration, 30.106 tolerance in neonates, 23.97 Oral contraceptives antimicrobial drugs, and pregnancy, 24.274 and breast cancer, 15.426 formulations, 24.472 third-generation, 25.484, 26.442 venous thromboembolism, 23.442 Orlistat, 30.429 Oxymorphone, 32.203 Paclitaxel, adverse reactions, 21.463 Pancreatic enzyme supplements, fibrosing colonopathy, 20.322 Paracetamol asthma, 30.129 hepatotoxicity in alcoholism, 12.76 liver damage, 17.98, 18.94 overdose, 13.68, 23.117 Parenteral nutrition bone reactions, 22.378 cholestasis, 22.376

xxiii

infections 22.379 Penicillins acute desensitization, 23.252 hypersensitivity reactions, cross-reactivity with cephalosporins, 30.280 immunological reactions, 28.267 Peritoneal dialysis fluids, effects on peritoneum, 22.381 Peroxisome proliferator-activated receptors, see also Thiazolidinediones dual agonists, 32.782 Pertussis vaccine, 11.284, 11.285 Phentermine, cardiac valvulopathies, 24.4 Pholcodine, 32.206 Photodynamic therapy, cancers 32.832 Phytoestrogens, in foodstuffs, 31.655 Pilsicainide, 32.348 Piroxicam gastrointestinal reactions, 11.97, 12.91 Pivalic acid, and carnitine, 12.209 Platinum compounds, 26.490 Polio vaccine, AIDS, 23.352 Polyaspartic acid, protective against nephrotoxicity, 17.305 Polyethylene glycol, electrolyte, mineral, metal, and fluid balance, 29.376 Polystyrene sulfonates, 25.271 Polyvinylpyrrolidone, storage disease, 22.522 PPAR, see Peroxisome proliferator-activated receptors Pregabalin, 30.86 Propofol infusion syndrome, 26.135 prevention of pain, 30.143 Propolis, allergy, 17.181 Proton pump inhibitors, tumors, 23.383 Psilocybin, 31.49 PUVA, malignant melanoma, 22.166 Pyrazinamide, in latent pulmonary tuberculosis, 27.323 Pyrimethamine þ sulfadoxine, prevention of malaria, 32.523 Quinidine, versus quinine, 15.295 Quinine, versus quinidine, 15.295 Rasagiline, 31.270 Rasburicase, 31.203 Renin inhibitors, 30.242 Rhesus anti-D, prophylaxis, 13.297 Ribavirin þ interferon, 30.344 Ribostamycin, and aminoglycosides, 15.270 Rocuronium, allergic reactions, 26.150 and pholcodine, 31.249 Rotashield, intussusception, 23.354 Rotavirus vaccine, Kawasaki disease, 31.522 Rubella vaccine, joints, 11.295

xxiv Salbutamol, adrenoceptor genotypes, 29.173 Salmeterol, tolerance, 24.187 Sapropterin, 32.609 Sedatives, 29.128 Sex hormones, tumors, 22.465 Serotonin receptor antagonists, 15.391 selective serotonin reuptake inhibitors, drug interactions, 22.13 selective serotonin reuptake inhibitors, gastrointestinal bleeding, 32.33 selective serotonin reuptake inhibitors, suicidal behavior, 29.19, 31.18 Smallpox vaccination, 27.339 Somatostatin, 15.468 Spinal manipulation, adverse reactions, 29.591 SSRIs, see Serotonin Statins, see HMG Co-A reductase inhibitors Steroids, see Glucocorticoids Stimulants, in ADHD, 31.4 Sugammadex, 32.275 Sulfonamide derivatives, hypersensitivity reactions, 30.252 Sumatriptan, 17.171 Suprofen, nephrotoxicity, 12.88 Suramin, patients with prostate cancer, 20.283 Surgam, gastric reactions, 12.89 Suxamethonium, postoperative myalgia, 28.155 Tamoxifen, versus aromatase inhibitors, 30.475 Teniposide, 27.477 Tetracyclines adverse reactions, 12.212, 26.268 chemically modified, 31.419 comparative toxicity, 22.268 and metalloproteinases, 26.266 non-antimicrobial properties, 30.288 in pregnancy, 25.280 in rheumatology, 23.255 therapeutic effects, 24.278 Tetrahydrobiopterin, 32.609 TGN 1412, 32.642 Theophylline, asthma, 17.2, 18.1, 18.2 Thiazides, see Diuretics Thiazolidinediones cardiovascular reactions, 31.697 musculoskeletal reactions, 32.779 peripheral edema, 29.531 Thiomersal, in vaccines, 28.357 Thiopurines, genetic susceptibility, 31.634 Thyroid hormones, 29.464 Thyroxine, drug interactions, 24.484 Tiaprofenic acid, cystitis, 18.106 TNF, see tumor necrosis factor Tolcapone, 32.289

Cumulative indexes of special reviews, Annuals 11–32

Topiramate, cognitive reactions, 26.81 Topoisomerase inhibitors, 27.477 Topotecan, 27.477 Trocetrapib, 32.816 Transfusions AIDS, 12.298 complications, 12.300 Tretinoin, topical, teratogenicity, 18.164 Triazolam, 16.33 Tricyclic antidepressants endocrine reactions, 11.12 mania, 13.8 L-tryptophan, eosinophilia–myalgia syndrome, 15.514 Tumor necrosis factor antagonists, infection risk, 29.395, 31.594 Tyrosine kinase inhibitors, 30.520 Vaccines, see also individual agents adjuvants, 32.577 autism, 31.516 combinations, 29.327, 30.369 Guillain–Barré syndrome, 31.515 HIV-infected individuals, 12.269 Kawasaki disease, 31.522 national compensation systems, 12.271 poliomyelitis, 22.352 thiomersal in, 28.357 Valproate, overdose, 32.157 polycystic ovary syndrome, 26.81 Vancomycin lessons from, 27.242 resistance, 29.244 Vigabatrin psychosis and abnormal behavior, 18.71 visual field defects, 21.78, 24.95, 25.98, 26.82 Vinca alkaloids, 28.538 Vitamin A, 17.436 alcohol, beta-carotene, interaction, 24.442 hypervitaminosis, 15.411 in pregnancy, 21.405 and prostate cancer, 13.346 Vitamin B6, debate, 23.420 Vitamin E, co-medication, 26.423 Vitamin K cancer, 23.424 skin reactions, 25.461 Vitamins, in old age, 22.431 Warfarin, herbal medicines, interactions, 30.400 Ximelagatran, hepatotoxicity, 30.411 Zidovudine, 13.246 Zileuton, 32.322

Cumulative indexes of special reviews, Annuals 11–32

2. Index of adverse reactions Cardiovascular anticholinergic drugs, 32.318 atrial fibrillation, antidysrhythmic drugs, 24.197 atrial fibrillation, digitalis, 24.197 cardiac failure, aldosterone antagonists, 24.246 cardiac failure, bambuterol, 23.181 cardiac siderosis, deferoxamine/deferiprone, 29.235 cardiotoxicity, antihistamines, 17.196, 25.183, 26.180 cardiotoxicity, calcium antagonists, 20.185 cardiotoxicity, cocaine, 18.5 cardiotoxicity, coxibs, 29.116 cardiotoxicity, hormone replacement therapy, 31.659 cardiotoxicity, propofol, 26.135 cardiotoxicity, thiazolidinediones, 31.697 dysrhythmias, antihistamines, 22.176 dysrhythmias, amiodarone, 25.211 hypertension, NSAIDs, 19.92, 27.102 myocardial infarction, acetylsalicylic acid, 27.109 myocardial infarction, adrenaline, 31.259 NSAIDs, 32.225 prodysrhythmic reactions, antidysrhythmic drugs, 17.218, 23.196 QT interval prolongation, 24.54 valvulopathies, fenfluramine, 22.3, 23.2, 24.4, 25.5 valvulopathies, phentermine, 24.4, 25.5 vasospasm, adrenaline, 31.259 venous thromboembolism, oral contraceptives, 23.442 Respiratory amiodarone, 15.168 asthma, acetylsalicylic acid, 17.94, 31.193 asthma, fenoterol, 23.182 asthma, paracetamol, 30.129 asthma, in pregnancy, 28.186 asthma deaths, beta2-adrenoceptor agonists, 17.164 asthma exacerbation, asthma medications, 20.165 beta2-adrenoceptor agonists, long-acting, 30.198 bronchoconstriction, paradoxical, nebulizer solutions, 13.134 bronchospasm, adenosine, 32.337 Churg–Strauss syndrome, leukotriene receptor antagonists, 24.183, 27.177, 29.174 cough, ACE inhibitors, 19.211

xxv

dyspnea, adenosine, 32.337 long-acting beta2-adrenoeceptor agonists, 31.309 pneumonia, glucocorticoids, 32.311 primary pulmonary hypertension, appetite suppressants, 18.7, 21.2, 23.2, 25.5 pulmonary edema, non-cardiogenic, hydrochlorothiazide, 31.373 rhinosinusitis, acetylsalicylic acid, 17.94 Ear, nose, throat glucocorticoids, inhaled, 29.168 Nervous system anticholinergic effects, 31.273 brain damage, benzodiazepines, 14.36 Creutzfeldt–Jakob disease, growth hormone, 11.371 demyelinating diseases, hepatitis B vaccine, 21.331, 22.346, 24.374 drowsiness/sedation, antihistamines, 21.170, 23.171, 26.182 Guillain–Barré syndrome, vaccines 31.515 headache, analgesics, 21.95, 23.114 intracerebral hemorrhage, NSAIDs, 28.119 neuroleptic malignant syndrome, 11.47, 20.41 neurotoxicity, anesthetics, local, 21.129 neurotoxicity, measles immunization, 23.348 overdosage, antiepileptic drugs, 22.84 pain, propofol, 30.143 poliomyelitis, vaccines, 22.352 progressive spongiform leukoencephalopathy, diamorphine, 24.40 seizures, antimicrobial drugs, 18.261 sleep disorders, dopamine receptor agonists, 26.160, 27.149 strokes, acetylsalicylic acid, 27.109 strokes, risperidone, 28.76 subacute sclerosing panencephalitis, measles vaccine, 29.335 tardive dyskinesia, 14.47, 20.38 tardive syndromes, 17.54 transient symptoms, intrathecal anesthetics, 25.152 Neuromuscular residual paralysis, neuromuscular blocking drugs, 27.139 Sensory systems eye reactions, drug abuse, 12.33 eye reactions, glucocorticoids, 29. 481 eye reactions, muscle relaxants, 21.145 optic neuropathy, ethambutol, 30.358 ototoxicity, aminoglycosides, 14.222, 18.268 visual field defects, vigabatrin, 21.78, 24.95, 25.98, 26.82 Psychological cognitive reactions, MDMA, 26.32, 32.63 cognitive reactions, metamfetamine, 29.3 cognitive reactions, topiramate, 26.78

xxvi Psychological (cont) gambling, dopamine receptor agonists, 30.174 interferons, 29.384 Psychiatric antiepileptic drugs, 22.82, 27.72 autism, MMR/measles immunization, 23.350, 25.387, 28.363, 31.516 depression, benzodiazepines, 17.43 mania, antidepressants, 13.8, 29.18 interferons, 29.384 psychosis and abnormal behavior, vigabatrin, 18.71 suicidal behavior, antidepressants, 32. 29 suicidal behavior, SSRIs, 29.19, 31.18 Endocrine Adrenal suppression, etomidate, 32.249 diabetes mellitus, antihypertensive drugs, 28.226 diabetes mellitus, antipsychotic drugs, 28.60 diabetes mellitus, diuretics, 27.219 hypothalamic–pituitary–adrenal gland function, inhaled glucocorticoids, 31.305 insulin resistance, growth hormone, 24.504 insulin resistance, HIV-protease inhibitors, 22.317 ovarian hyperstimulation syndrome, valproate, 26.477 polycystic ovary syndrome, valproate, 26.81 thyroid disease, amiodarone, 27.192, 31.310 thyroid disease, lithium, 12.26 tricyclic antidepressants, 11.12 Metabolism antiretroviral drugs, 28.329 hyperlactatemia, 29.302 hypoglycemia, insulin, 15.452 lactic acidosis, metformin, 23.459, 29.526 lipoatrophy, 29.302 lipodystrophy, HIV-protease inhibitors, 22.317 metabolic acidosis, propofol, 26.135 mitochondrial toxicity, 29.302 polyvinylpyrrolidone storage disease, 22.522 weight gain, antipsychotic drugs, 26.56 Nutrition thiamine deficiency, diuretics, 32.401 Electroyte balance electrolyte abnormalities, diuretics, 27.219, 29.219 polyethylene glycol, 29.376 Mineral balance hypophosphatemia, glucose solutions, 11.312 polyethylene glycol, 29.376 Metal balance polyethylene glycol, 29.376 Fluid balance edema, insulin, 11.364 edema, thiazolidinediones, 29.531

Cumulative indexes of special reviews, Annuals 11–32

polyethylene glycol, 29.376 Hematologic agranulocytosis, analegsics, 11.89 agranulocytosis, clozapine, 22.59 aplastic anemia, analegsics, 11.89 aplastic anemia, felbamate, 19.68, 22.86 coagulation disorders, beta-lactam antibiotics, 18.258 eosinophilia–myalgia syndrome, tryptophan, 15.514 hemolytic disease of the newborn, anti-D prophylaxis, 12.293 hemostasis, cephalosporins, 12.210 pseudothrombocytopenia, EDTA, 21.250 pure red cell aplasia, erythropoietin, 27.348 thrombocytopenia, heparin, 30.404, 32.626 Mouth Glucocoricoids, inhaled, 29.168 Salivary glands sialadenitis, iodinated contrast media, 32.845 Gastrointestinal bleeding, acetylsalicylic acid, 17.95, 18.90 cholestasis, total parenteral nutrition, 22.376 colitis, antimicrobial drugs, 12.216, 17.303 Crohn's disease, MMR/measles immunization, 23.350, 25.387 dyspepsia, NSAIDs, 28.120 fibrosing colonopathy, pancreatic enzyme supplements, 20.322 inflammatory bowel disease, NSAIDs, 25.131 intestinal motility, antimicrobial drugs, 13.220 intestinal motility, macrolides, 18.269 intussusception, Rotashield, 23.354 NSAIDs, 32.225 piroxicam, 12.91 SSRIs, 32.33 Surgam, 12.89 ulceration, bleeding and perforation, NSAIDs, 11.97, 14.79, 16.103, 17.95, 18.90, 18.99, 19.93, 20.86, 21.96, 22.108, 23.114, 27.105, 30.125 Liver hepatotoxicity, alcohol/vitamin A/betacarotene, 24.442 hepatotoxicity, antituberculosis drugs, 25.363, 26.339, 31.495, 32.555 hepatotoxicity, diclofenac, 20.91 hepatotoxicity, kava kava, 27.518 hepatotoxicity, ketoconazole, 12.229 hepatotoxicity, paracetamol, 12.76, 17.98, 18.94 hepatotoxicity, ximelagatran, 30.411 Reye's syndrome, acetylsalicylic acid, 11.79, 15.85 Urinary tract acute renal insufficiency, NSAIDs, 28.122 cystitis, tiaprofenic acid, 18.106

Cumulative indexes of special reviews, Annuals 11–32 nephrolithiasis, ceftriaxone, 29.246 nephrotoxicity, aminoglycosides, 15.268, 17.305 nephrotoxicity, amphotericin, 13.231, 14.229, 27.276 nephrotoxicity, analgesics, 21.98 nephrotoxicity, anesthetics, halogenated, 20.106 nephrotoxicity, ciclosporin, 19.348 nephrotoxicity, contrast media, 27.500, 28.556, 29.575, 31.731, 31.735, 32.846 nephrotoxicity, gadolinium salts, 28.561 nephrotoxicity, lithium, 14.18, 19.16 nephrotoxicity, NSAIDs, 11.82, 18.100, 20.89, 24.120, 26.111 nephrotoxicity, suprofen, 12.88 renal cell carcinoma, diuretics, 23.225 renal insufficiency, diuretics, 25.250 Skin contact allergy, 23.160 contact allergy, glucocorticoids, 15.139 contact dermatitis, aminoglycosides, 13.225 cutaneous reactions, NSAIDs, 13.72 glucocorticoids, inhaled, 29.169 necrosis, oral anticoagulation, 29.358 rashes, lamotrigine, 20.62, 24.88 serious reactions, carbamazepine, 32.129 systemic fibrosis, contrast media, 32.852 vitamin K1, 25.461 Serosae peritoneum, peritoneal dialysis, 22.381 pleurodesis, 25.189 Musculoskeletal arthralgia, beta-adrenoceptor antagonists, 11.164 arthralgia, rubella vaccination, 11.295 bone, total parenteral nutrition, 22.378 bone dysplasia, deferoxamine, 23.241 bone loss, antiepileptic drugs, 27.74 bone mineral density, glucocorticoids, 25.195 eosinophilia–myalgia syndrome, tryptophan, 15.514 fractures, inhaled glucocorticoids, 31.307, 32.312 fractures, thiazolidinediones, 32.779 growth in children, inhaled glucocorticoids, 26.186 growth in children, oral glucocorticoids, 14.335 growth in children, stimulants, 31.4 muscle damage, daptomycin, 30.309 myopathy, ipecacuanha, 11.422 ossification, etretinate, 12.127 osteoarthritis, NSAIDs, 1187 osteoporosis and osteonecrosis, glucocorticoids, 16.447, 19.377, 20.374, 21.417, 22.182, 28.473

xxvii

rhabdomyolysis, doxylamine overdose, 31.298 rhabdomyolysis, propofol, 26.135 postoperative myalgia, suxamethonium, 28.155 Sexual function beta-adrenoceptor antagonists, 15.188 priapism, fat emulsions, 11.313 Immunologic allergic reactions, antimicrobial drugs, 23.251 allergic reactions, contact allergy, cosmetics, 11.142 allergic reactions, contact allergy, KathonÒ CG, 11.134 allergic reactions, latex, 31.761 allergic reactions, rocuronium, 26.150 allergy testing, chymopapain, 11.279 anaphylaxis, human albumin, 14.296 anaphylaxis, neuromuscular blocking agents, 29.145 angioedema, ACE inhibitors, 22.225, 29.207 aspirin sensitivity, 12.75 autoimmune disease, immunizations, 27.336 autoimmune disease, Lyme disease vaccine, 24.366 cocamidopropylbetaine, 19.151 contrast agents, 20.422 cosmetics, 16.150, 19.151 co-trimoxazole, 20.264 desensitization, penicillin, 23.252 Euxyl K 400, 16.150 fragrances, 20.149 glucocorticoids, 21.158 hypersensitivity reactions, beta-lactam antibiotics, 14.211, 30.280 hypersensitivity reactions, ethylene oxide, 11.219 hypersensitivity reactions, muscle relaxants, 27.138 hypersensitivity reactions, mebendazole, 12.263 hypersensitivity reactions, rocuronium, 31.249 hypersensitivity reactions, sulfonamide derivatives, 30.252 immune reconstitution disease, 29.315 Kawasaki disease, rotavirus vaccine, 31.522 Mazzotti reaction, antihelminthic drugs, 31.507 methyldibromoglutaronitrile, 16.150, 19.151 ocular drugs, 21.486 propolis, 17.181 red man syndrome, 17.312 Autacoids angioedema, angiotensin converting enzyme inhibitors, 31.352, 32. 380 angioedema, angiotensin II receptor antagonists, 30.238

xxviii Infection risk AIDS, polio vaccine, 23.352 AIDS, transfusions, 12.298 necrotizing fasciitis, NSAIDs, 28.121 total parenteral nutrition, 22.379 tumor necrosis factor antagonists, 29.395, 31.594 yersiniosis, deferoxamine, 11.215 Body temperature malignant hyperthermia, 18.112 Trauma acupuncture, 29.590 Death antiepileptic drugs, 23.83 antipsychotic drugs, 32.89 calcium antagonists, 22.214 digoxin, 32.333 ecstasy, 24.32 lithium, 19.14 opiates, 25.37, 29.44 Drug abuse anabolic steroids, 29.508, 32.751 Drug tolerance antimicrobial drug resistance, 11.223, 12.208, 19.237, 20.228, 21.257, 22.265, 23.250, 24.273, 25.279, 29.244, 31.413, 32.445 opioids in neonates, 23.97 Drug dependence benzodiazepines, 12.41 Drug withdrawal baclofen, 26.152 Genotoxicity antiestrogens, 27.429 Tumorigenicity alcohol/vitamin A/beta-carotene, 24.442 aluminium, 31.383 antiestrogens, 27.429 beta-carotene, 25.454 carotenoids, 25.454 fertility drugs, 24.474, 26.434 growth hormone, 23.468 hormone replacement therapy, 32.740 levodopa, 31.267 omeprazole, 16.423 oral contraceptives, 11.346, 15.426 proton pump inhibitors, 23.383 PUVA, malignant melanoma, 22.166 sex hormones, 22.465 vitamin K, 23.424 Fertility fertility, male, antimicrobial drugs, 16.262 Pregnancy affective disorders in, 21.17 antibiotics, 11.231, 32.446 antidepressants, 32.31 antimicrobial drugs and the pill, 24.274 antithyroid drugs, 13.377

Cumulative indexes of special reviews, Annuals 11–32

asthma, 28.186 beta-lactams, 25.280 cocaine, 27.1 opioids, 24.102 tetracyclines, 25.280 vitamin A, 21.405 Teratogenicity antibiotics, 11.231 tretinoin, topical, 18.164 Fetotoxicity cocaine, 20.24, 27.1, 29.41, 30.35 diethylstilbestrol, transgenerational reactions, 31.657 indometacin, 18.102 Lactation cocaine, 31.154 Susceptibility factors age, methylphenidate, 31.6 children, aluminium, 12.185 children, antituberculosis drugs, 32.557 children, budesonide, 30.194 children, inhaled glucocorticoids 27.174 children, NSAIDs, 19.96 elderly patients, antipsychotic drugs, 30.59 genetic susceptibility, antituberculosis drugs, 28.342 genetic susceptibility, beta-adrenoceptor agonists, 29.173, 30.199, 31.310 genetic susceptibility, isoniazid, 12.257 genetic susceptibility, thiopurine toxicity, 31.634 HIV infection, immunization, 12.269 intensive care, muscle relaxants, 19.140 neonatal complications, indometacin, 18.102 ocular drugs, 22.507 old age, vitamins, 22.431 preterm infants, beta-lactam antibiotics, 21.258 transplant recipients, antituberculosis drugs, 32.559 Drug administration delivery of aerosols, 27.172 dosage regimens, aminoglycosides, 23.264 errors, 28.587, 29.596 formulations, oral contraceptives, 24.472 inhaled glucocorticoids, systemic availability, 24.185 inhaled insulin, 30.495 intravitreal and parabulbar injection, 29.581 labeling problems, cosmetics, 22.159 opioids, 30.106 Drug overdose antidepressants, 28.14 digitalis, charcoal, 24.201 paracetamol, 23.117 valproate, 32.157

Cumulative indexes of special reviews, Annuals 11–32 Drug formulations enantiomers and racemates, 13.442 Drug–drug interactions acetylsalicylic acid/ACE inhibitor, 28.124 acetylsalicylic acid/NSAIDs, 28.118 alcohol/vitamin A/beta-carotene, 24.442 antimicrobial drugs/the pill, 24.274 antifungal azoles, 24.318, 28.299, 29.282, 30.320, 31.459, 32.497 diuretics/NSAIDs, 12.80 grapefruit juice, 23.519 herbal medicines/warfarin, 30.400 HMG Co-A reductase inhibitors, 25.530, 30.517 lithium, 16.13 lithium/selective serotonin reuptake inhibitors, 18.30 macrolides, 14.220 mibefradil, 23.210

xxix

monoamine oxidase inhibitors/foods, 13.6 NSAIDs/ACE inhibitors, 28.122 paracetamol, 13.68 selective serotonin reuptake inhibitors, 22.13 thyroxine, 24.484 Management of adverse drug reactions local anesthetics, lipid emulsion, 32.261 Methods ethnopharmacology, 14.429 eukaryotic cells, effects of beta-lactams, 13.212 hemolytic disease of the newborn, prophylaxis, 13.297 lithium, monitoring, 11.24 local anesthetic toxicity, lipid rescue, 31.231 onchocerciasis, treatment, 14.261 post-marketing surveillance, 14.210, 15.266, 24.274

Table of Essays, Annuals 1–32 SEDA Author 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

19 20 21

22 23 24 25 26 26 27 27 28 29 30 31 32

xxx

M.N.G. Dukes K.H. Kimbel L. Lasagna

Country

Title

The Netherlands The moments of truth Germany Drug monitoring: why care? USA Wanted and unwanted drug effects: the need for perspective M.N.G. Dukes The Netherlands The van der Kroef syndrome J.P. Griffin, P.F. D'Arcy UK Adverse reactions to drugs—the information lag I. Bayer Hungary Science vs practice and/or practice vs science E. Napke Canada Adverse reactions: some pitfalls and postulates M.N.G. Dukes Denmark The seven pillars of foolishness W.H.W. Inman UK Let's get our act together S. Van Hauen Denmark Integrated medicine, safer medicine and “AIDS” M.N.G. Dukes Denmark Hark, hark, the fictitious dogs do bark M.C. Cone Switzerland Both sides of the fence C. Medawar UK On our side of the fence M.N.G. Dukes, E. Helsing Denmark The great cholesterol carousel P. Tyrer UK The nocebo effect—poorly known but getting stronger M.N.G. Dukes Denmark Good enough for Iganga? M.N.G. Dukes Denmark The mists of tomorrow R.D. Mann UK Databases, privacy, and confidentiality—the effect of proposed legislation on pharmacoepidemiology and drug safety monitoring A. Herxheimer UK Side effects: freedom of information and the communication of doubt E. Ernst UK Complementary/alternative medicine: what should we do about it? H. Jick USA Thirty years of the Boston Collaborative Drug Surveillance Program in relation to principles and methods of drug safety research J.K. Aronson, RE Ferner UK Errors in prescribing, preparing, and giving medicines: definition, classification, and prevention K.Y. Hartigan-Go, Philippines Inclusion of therapeutic failures as adverse drug J.Q. Wong reactions I. Palmlund UK Secrecy hiding harm: case histories from the past that inform the future L. Marks UK The pill: untangling the adverse effects of a drug D.J. Finney UK From thalidomide to pharmacovigilance: a personal account L.L. Iversen UK How safe is cannabis? J.K. Aronson UK Louis Lewin—Meyler's predecessor H. Jick USA The General Practice Research Database J.K. Aronson UK Classifying adverse drug reactions in the 21st century M. Hauben, A. Bate USA/Sweden Data mining in drug safety J.K. Aronson UK Drug withdrawals because of adverse effects J. Harrison, P. Mozzicato USA MedDRAÒ: the Tale of a Terminology K. Chan Australia Regulating complementary and alternative medicines

Mechanistic and clinical descriptions of adverse drug reactions Adverse drug reactions are described in the Side Effects of Drugs Annuals using two complementary systems, EIDOS and DoTS [1–3]. These two systems are illustrated in Figures 1 and 2. Examples of their use have been discussed elsewhere [4–8].

1. EIDOS The EIDOS mechanistic description of adverse drug reactions [3] has five elements:

• • • • •

the the the the the

Extrinsic species that initiates the reaction (Table 1); Intrinsic species that it affects; Distribution of these species in the body; (physiological or pathological) Outcome (Table 2), which is the adverse effect; Sequela, which is the adverse reaction.

Extrinsic species This can be the parent compound, an excipient, a contaminant or adulterant, a degradation product, or a derivative of any of these (e.g. a metabolite) (for examples see Table 1). Intrinsic species This is usually the endogenous molecule with which the extrinsic species interacts; this can be a nucleic acid, an enzyme, a receptor, an ion channel or transporter, or some other protein. Distribution A drug will not produce an adverse effect if it is not distributed to the same site as the target species that mediates the adverse effect. Thus, the pharmacokinetics of the extrinsic species can affect the occurrence of adverse reactions. Outcome Interactions between extrinsic and intrinsic species in the production of an adverse effect can result in physiological or pathological changes (for examples see Table 2). Physiological changes can involve either increased actions (e.g. clotting due to tranexamic acid) or decreased actions (e.g. bradycardia due to beta-adrenoceptor antagonists). Pathological changes can involve cellular adaptations (atrophy, hypertrophy, hyperplasia, metaplasia, and neoplasia), altered cell function (e.g. mast cell degranulation in IgE-mediated anaphylactic reactions), or cell damage (e.g. cell lysis, necrosis, or apoptosis). Sequela The sequela of the changes induced by a drug describes the clinically recognizable adverse drug reaction, of which there may be more than one. Sequelae can be classified using the DoTS system.

xxxi

Mechanistic and clinical descriptions of adverse drug reactions

xxxii

1. EIDOS: a mechanistic description

2. DoTS: a clinical description

Drug

Dose-relatedness Drug

Dis

trib

u ti on

Extrinsic

Intrinsic

Patient

Outcome

Patient

Adverse reaction

Adverse reaction

Susceptibility factors

Figure 1. The EIDOS and DoTS systems of describing adverse drug reactions.

Dose-relation (benefit:harm)

Drug

Dis

trib uti

on

Extrinsic

Outcome

Sequela

Intrinsic Patient

Adverse reaction

Susceptibility Figure 2. How the EIDOS and DoTS systems relate to each other.

Time course

Time course

Mechanistic and clinical descriptions of adverse drug reactions

xxxiii

Table 1 The EIDOS mechanistic description of adverse drug effects and reactions Feature

Varieties

Examples

E.

1. The parent compound 2. An excipient 3. A contaminant

Insulin Polyoxyl 35 castor oil 1,1-Ethylidenebis [L-tryptophan] Lead in herbal medicines Outdated tetracycline

Extrinsic species

4. An adulterant 5. A degradation product formed before the drug enters the body 6. A derivative of any of these (e.g. a metabolite) I.

The intrinsic species and the nature of its interaction with the extrinsic species (a) Molecular

1. Nucleic acids
DNA
RNA 2. Enzymes
Reversible effect
Irreversible effect 3. Receptors
Reversible effect
Irreversible effect 4. Ion channels/transporters 5. Other proteins
Immunological proteins
Tissue proteins

(b) Extracellular

(c) Physical or physicochemical

1. 2. 3. 1. 2.

Water Hydrogen ions (pH) Other ions Direct tissue damage Altered physicochemical nature of the extrinsic species

D.

Distribution

1. Where in the body the extrinsic and intrinsic species occur (affected by pharmacokinetics)

O.

Outcome (physiological or pathological change) Sequela

The adverse effect (see Table 2)

S.

The adverse reaction (use the Dose, Time, Susceptibility [DoTS] descriptive system)

Acrolein (from cyclophosphamide)

Melphalan Mitoxantrone Edrophonium Malathion Prazosin Phenoxybenzamine Calcium channel blockers; digoxin and Naþ/Kþ-ATPase Penicilloyl residue hapten N-acetyl-p-benzoquinoneimine (paracetamol [acetaminophen]) Dextrose 5% Sodium bicarbonate Sodium ticarcillin Intrathecal vincristine Sulindac precipitation

Antihistamines cause drowsiness only if they affect histamine H1 receptors in the brain – –

Mechanistic and clinical descriptions of adverse drug reactions

xxxiv

Table 2 Examples of physiological and pathological changes in adverse drug effects (some categories can be broken down further) Type of change 1. Physiological changes (a) Increased actions (b) Decreased actions 2. Cellular adaptations (a) Atrophy (b) Hypertrophy (c) Hyperplasia (d) Metaplasia (e) Neoplasia
Benign
Malignant j Hormonal j Genotoxic j Immune suppression 3. Altered cell function 4. Cell damage (a) Acute reversible damage
Chemical damage
Immunological reactions (b) Irreversible injury
Cell lysis
Necrosis
Apoptosis 5. Intracellular accumulations (a) Calcification (b) Drug deposition

Examples

Hypertension (monoamine oxidase inhibitors); clotting (tranexamic acid) Bradycardia (beta-adrenoceptor antagonists); QT interval prolongation (antiarrhythmic drugs) Lipoatrophy (subcutaneous insulin); glucocorticosteroid-induced myopathy Gynecomastia (spironolactone) Pulmonary fibrosis (busulfan); retroperitoneal fibrosis (methysergide) Lacrimal canalicular squamous metaplasia (fluorouracil) Hepatoma (anabolic steroids) Vaginal adenocarcinoma (diethylstilbestrol) Transitional cell carcinoma of bladder (cyclophosphamide) Lymphoproliferative tumors (ciclosporin) IgE-mediated mast cell degranulation (class I immunological reactions)

Periodontitis (local application of methylenedioxymetamfetamine [MDMA, ‘ecstasy’]) Class III immunological reactions

Class II immunological reactions Class IV immunological reactions; hepatotoxicity (paracetamol, after apoptosis) Liver damage (troglitazone)

Milk-alkali syndrome Crystal-storing histiocytosis (clofazimine) Skin pigmentation (amiodarone)

2. DOTS In the DoTS system (SEDA-28, xxvii–xxxiii; 1,2) adverse drug reactions are described according to the Dose at which they usually occur, the Time course over which they occur, and the Susceptibility factors that make them more likely, as follows:

•

Relation to dose
Toxic reactions (reactions that occur at supratherapeutic doses)
Collateral reactions (reactions that occur at standard therapeutic doses)
Hypersusceptibility reactions (reactions that occur at subtherapeutic doses in susceptible individuals)

Mechanistic and clinical descriptions of adverse drug reactions

•

•

xxxv

Time course
Time-independent reactions (reactions that occur at any time)
Time-dependent reactions j Immediate or rapid reactions (reactions that occur only when a drug is administered too rapidly) j First-dose reactions (reactions that occur after the first dose of a course of treatment and not necessarily thereafter) j Early reactions (reactions that occur early in treatment and then either abate with continuing treatment, owing to tolerance, early tolerant, or persist, early persistent) j Intermediate reactions (reactions that occur after some delay but with less risk during longer term therapy, owing to the “healthy survivor” effect) j Late reactions (reactions the risk of which increases with continued or repeated exposure) j Withdrawal reactions (reactions that occur when, after prolonged treatment, a drug is withdrawn or its effective dose is reduced) j Delayed reactions (reactions that occur at some time after exposure, even if the drug is withdrawn before the reaction appears) Susceptibility factors
Genetic
Age
Sex
Physiological variation (e.g. weight, pregnancy)
Exogenous factors (for example, the effects of other drugs, devices, surgical procedures, food, smoking)
Diseases

The following reactions are described in SEDA-33 using the EIDOS and DoTS systems: ACE inhibitors: angioedema Adrenaline: ischemic tissue damage Angiotensin II receptor antagonists: angioedema Antipsychotic drugs: weight gain and diabetes mellitus Benzocaine: methemoglobinemia Bisphosphonates: osteonecrosis of the jaw Catecholamines: takotsubo cardiomyopathy Cocaine: ischemic cardiac events Contrast media: nephrotoxicity Dapsone: hemolytic anemia and/or methemoglobinemia Diuretics, loop and thiazide: hyponatremia and hypokalemia Dopamine receptor agonists: pathological gambling Dopamine receptor agonists: sleep attacks Ephedrine: ischemic heart disease Ergot-derived dopamine receptor agonists: fibrotic reactions Ethambutol: optic neuropathy Gadolinium salts: systemic fibrosis Glucocorticoids: osteoporosis Glucocorticoids, inhaled in COPD: pneumonia Heparin: type II thrombocytopenia Incretin mimetics: nausea and vomiting Iodides: sialadenitis Nitrofurantoin: lung disease Statins: myopathy, myalgia, and rhabdomyolysis Thiazolidinediones: reduced bone density and increased risk of fractures Thionamides: agranulocytosis Vigabatrin: visual field loss

417 315 418 94 289 1009 313 58 965 630 439 322 322 317 321 634 969 843 353 714 896 965 524 925 899 884 178

xxxvi

Mechanistic and clinical descriptions of adverse drug reactions

The following reactions have also been described in previous editions of SEDA using the DoTS system: Adrenaline: hypertension Anticoagulants, oral: skin necrosis Antituberculosis drugs: hepatotoxicity Pseudoephedrine: toxic epidermal necrolysis SSRIs: suicidal behavior Statins: acute pancreatitis Ximelagatran: liver damage

30.170 29.358 31.495 30.172 29.19 31.715 30.411

References 1. Aronson JK, Ferner RE. Joining the DoTS. New approach to classifying adverse drug reactions. BMJ 2003; 327: 1222–5. 2. Aronson JK, Ferner RE. Clarification of terminology in drug safety. Drug Saf 2005; 28(10): 851–70. 3. Ferner RE, Aronson JK. EIDOS: A mechanistic classification of adverse drug effects. Drug Saf 2010; 33(1): 13–23. 4. Callréus T. Use of the dose, time, susceptibility (DoTS) classification scheme for adverse drug reactions in pharmacovigilance planning. Drug Saf 2006; 29(7): 557–66. 5. Aronson JK, Price D, Ferner RE. A strategy for regulatory action when new adverse effects of a licensed product emerge. Drug Saf 2009; 32(2): 91–8. 6. Calderón-Ospina C, Bustamante-Rojas C. The DoTS classification is a useful way to classify adverse drug reactions: a preliminary study in hospitalized patients. Int J Pharm Pract 2010; 18(4): 230–5. 7. Ferner RE, Aronson JK. Preventability of drug-related harms. Part 1: A systematic review. Drug Saf 2010; 33(11): 985–94. 8. Aronson JK, Ferner RE. Preventability of drug-related harms. Part 2: Proposed criteria, based on frameworks that classify adverse drug reactions. Drug Saf 2010; 33(11): 995–1002.

How to use this book THE SCOPE OF THE SIDE EFFECTS OF DRUGS ANNUALS Volumes in the Side Effects of Drugs Annual (SEDA) series have been published since 1977. The series is designed to provide a critical account of new information relating to adverse drug reactions and interactions. It complements the standard encyclopedic work in this field, Meyler's Side Effects of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interactions, the 15th edition of which was published in 2006.

PERIOD COVERED The present Annual reviews all reports that presented significant new information on adverse reactions to drugs during the second half of 2008 and the whole of 2009; the next volume (SEDA-34) will cover 2010. During the production of this Annual, some more recent papers have also been included; older literature has also been cited when it is relevant. Special reviews (see below) often cover a much wider range of literature.

SELECTION OF MATERIAL In compiling the Side Effects of Drugs Annual particular attention is devoted to publications that provide essentially new information or throw a new light on problems already recognized. Some confirmatory reports are also described. In addition, some authoritative new reviews are listed. Publications that do not meet these criteria are omitted. Readers anxious to trace all references on a particular topic, including those that duplicate earlier work, or to cross-check an electronic search, are advised to consult Adverse Reactions Titles, a monthly bibliography of titles from about 3400 biomedical journals published throughout the world, compiled by the Excerpta Medica International Abstracting Service.

Special reviews The special reviews deal in more detail with selected topics, often interpreting conflicting evidence, providing the reader with clear guidance. They are not restricted to literature published in the period covered by the volume and are identified by the traditional prescription symbol and are printed in italics. This volume includes a Cumulative Index of the Special Reviews that were published in SEDA-11 to SEDA-32 and a list of the Special Reviews that appear in the current Annual.

CLASSIFICATION OF DRUGS Drugs are classified according to their main field of use or the properties for which they are most generally recognized. In some cases a drug is included in more than one chapter (for example, lidocaine is mentioned in Chapter 11 as a local anesthetic and in Chapter 17 as an antidysrhythmic drug). Fixed combinations of drugs are dealt with according to their most characteristic component or as a combination product. xxxvii

xxxviii

How to use this book

NAMES OF DRUGS AND CHEMICALS Drugs are usually called by their recommended or proposed International Non-proprietary Names (rINN or pINN); when these are not available, chemical names have been used. If a fixed combination has a generic combination British Approved Name (e.g. “co-trimoxazole” for trimethoprim þ sulfamethoxazole) that name has been used; in some cases brand names have been used instead. When the plus symbol (þ) is used to link drug names (for example, “lopinavir þ ritonavir”), it implies that the two drugs are administered either in one formulation or in conjunction with one another; otherwise the word “plus” is used. Chemicals are named according to the rules of the International Union of Pure and Applied Chemistry (IUPAC; http://www.iupac.org); for example, we use “aluminium”, not “aluminum”.

SYSTEM OF TAGGING REFERENCES References in the text are tagged using the following system, which was introduced in SEDA-24: M A R r C c H E S

A meta-analysis or other form of systematic review. An anecdote or set of anecdotes (i.e. case histories). A major review, including non-systematic statistical analyses of published studies. A brief commentary (e.g. in an editorial or a letter). A major randomized controlled trial or observational study. A minor randomized controlled trial or observational study or a non-randomized study. A hypothesis article. An experimental study (animal or in vitro). A statement from an official body (e.g. Governments, WHO), a manufacturer, or a guidelines group, or a statement about a forthcoming clinical trial.

The various editions of Meyler's Side Effects of Drugs are cited in the text as SED-l4, SED-15, etc; the Side Effects of Drugs Annuals 1–32 are cited as SEDA-1, SEDA-2, etc. References are cited in the bibliography to each chapter using the Vancouver method. Titles of articles in [square brackets] are English translations of original titles.

INDEXES Index of drugs: this index provides a complete listing of all references to a drug for which adverse reactions and/or drug interactions are described. Index of adverse reactions: this index is necessarily selective, since a particular adverse reaction may be caused by very large numbers of compounds; the index is therefore mainly directed to adverse reactions that are particularly serious or frequent, or are discussed in special detail. For indexing purposes American spelling has, with a few exceptions, been used, e.g. “anemia” and “estrogen” rather than “anaemia” and “oestrogen”.

Abbreviations The following abbreviations are used throughout the book: ADP APACHE ASA AUC AUC0!x AUCt bd BMI CAPD CD [4, 8, etc]

CI Cmax Cmin COX-1 and COX-2 CT CYP [e.g. CYP2D6, CYP3A4] eGFR ESR FDA FEV1 G6PD HbA1c HDL, LDL, VLDL HR IGF INR IQ [range] MAC MIC MIM MRI NNT, NNTB, NNTH NSAIDs

adenosine diphosphate acute physiology and chronic health evaluation [score] American Society of Anesthesiologists the area under the concentration versus time curve from zero to infinity the area under the concentration versus time curve from zero to time x the area under the concentration versus time curve during a dosage interval twice a day (bis in die) body mass index continuous ambulatory peritoneal dialysis cluster of differentiation (describing various glycoproteins that are expressed on the surfaces of T cells, B cells, and other cells, with varying functions) confidence interval maximum (peak) concentration after a dose minimum (trough) concentration after a dose cyclo-oxygenase enzyme isoforms 1 and 2 computed tomography cytochrome P450 isoenzymes estimated glomerular filtration rate erythrocyte sedimentation rate [US] Food and Drug Administration forced expiratory volume in 1 second glucose-6-phosphate dehydrogenase hemoglobin A1c high-density lipoprotein, low-density lipoprotein, and very low density lipoprotein [cholesterol] hazard ratio insulin-like growth factor international normalized ratio interquartile [range] minimum alveolar concentration minimum inhibitory concentration Mendelian Inheritance in Man (see http://www.ncbi.nlm.nih.gov/ omim/607686) magnetic resonance imaging number needed to treat [for benefit, for harm] non-steroidal anti-inflammatory drugs xxxix

Abbreviations

xl

od OR PCR PPAR RR SNP tds tmax Vmax

once a day (omne die) odds ratio polymerase chain reaction peroxisome proliferator-activated receptor risk ratio or relative risk single nucleotide polymorphism three times a day (ter die summendum) the time at which Cmax is reached maximum velocity [of a reaction]

Graham Dukes* SIDE EFFECTS OF DRUGS ESSAY

Third-generation oral contraceptives: time to look again? “It is difficult to say what an essay is . . .. Remembering its French origin in essai, perhaps one may call the essay simply an attempt to open out a subject.” Chambers and King [1]

The history of the oral contraceptives and their association with thromboembolic complications has been repeatedly reviewed in these volumes, and with good reason. No apology is needed for considering the issue anew, since concerns persist, and it seems that there is remarkably little solid evidence—perhaps none at all—to allay them. That, surely, is sufficient reason to broach the subject once more in an essay, in the hope that others will now take a much closer look and succeed in penetrating to the truth of the matter.

THREE GENERATIONS The first generation of the oral contraceptive products, introduced in around 1960, *Professor M. N. G. Dukes is a physician and international lawyer who has worked in pharmaceutical research management, public health, and development aid. He edited Meyler's Side Effects of Drugs from 1975 to 2000 and the Side Effects of Drugs Annuals from 1977 to 1992. He is currently External Professor of Drug Policy Studies at the University of Oslo, Norway.

was widely and properly welcomed as constituting a breakthrough in family planning. The method was simpler and considerably more reliable than anything that had preceded it. However, within a few years it became unhappily evident that these products—typically comprising up to 5 mg of a progestogen (such as norethinodrel, norethisterone, levonorgestrel, or lynestrenol) and 150 micrograms of the estrogen mestranol—were associated with a significant incidence of thromboembolic complications. The response to the problem took time, but it ultimately became clear that considerable reductions in the doses of both components were both feasible and necessary. The dose of progestogen was lowered to 2.5 mg and thereafter typically to 1 mg or less; mestranol was replaced by the more potent ethinylestradiol, and the dose of the latter was reduced markedly, in some cases to a mere 30 micrograms. These changes proved to be possible without any loss of contraceptive effect. The resulting products were not all of identical composition, but the risk of thromboembolic complications had clearly been contained, or at least reduced to a tolerable level. As a group, the reformulated products became known as the second generation of oral contraceptives. So it was in the 1980s, and so it might well have remained, but for one element: the expiry of patents. The estrogen mestranol enjoyed no patent protection, but xli

xlii

Third-generation oral contraceptives: time to look again?

norethinodrel had been patented in the USA as early as 1954, norethisterone in 1956, and lynestrenol in 1958, while levonorgestrel was patented in Britain in 1961 [2]. Two decades further on such protection would expire, and manufacturers of generic products would then be at liberty to use these substances freely, marketing unbranded products at substantially lower costs. By all accounts, therefore, researchbased firms with interests in the field set about searching for new progestogenic molecules that would replace their older congeners and earn patents of later date, enjoying protection for a further period. In due course, several such newly synthesized substances, eligible to play this role, emerged. Desogestrel had been developed by the Organon company, and patent applications that were lodged in Germany in 1973 [3] and in the Netherlands in 1974 [4] were duly granted. It was introduced in Britain as MarvelonÒ (containing 150 micrograms of desogestrel with 30 micrograms of ethinylestradiol) and MercilonÒ (with a lower dose of the estrogen). Similarly, the Schering company developed the progestogen gestodene: it introduced it as a component of FemodeneÒ (FemovanÒ), which contained 75 micrograms of the progestogen and 30 micrograms of ethinylestradiol. Other combinations that included gestodene were marketed under licence by the Wyeth company. As a group these reformulated products became known as the third generation of oral contraceptives. Even more recently, a further series of progestogens (such as drospirenone) have emerged, which some workers have regarded as comprising a fourth generation [5, 6], a matter to which we shall return shortly.

RENEWED CONCERN During the years that followed the marketing of the third generation of products, a series of publications appeared in the

medical literature, voicing the fear that with their appearance the risk of thromboembolic complications had once more increased. In October 1995 the UK regulatory authorities informed all physicians and pharmacists of three new (and at the time still unpublished) epidemiological studies that suggested that combined oral contraceptives of the third generation caused an approximately twofold increase in the risk of venous thromboembolism; a series of precautions with regard to the use of these products was set out and the data sheets were revised accordingly [7]. Although the regulatory authorities of the European Union did not follow the British lead, considering that further evidence was still needed, matters in Britain came to a head in court. Civil actions were brought against the companies owned in the United Kingdom by Schering, Organon, and Wyeth on behalf of a series of women or their families who claimed to have suffered the ill effects of the third generation of products in the form of serious (and in some instances fatal) episodes of venous thromboembolism. The litigation, before Mr. Justice Mackay in the High Court in London, was considered in detail in SED-15 (pp. 1651–2). As anyone who was present in court can attest, the hearings were marked by a series of direct and sharp conflicts between medical statisticians giving evidence for the plaintiffs or the defendants. Having considered the evidence, the learned judge issued on 29 July 2002 an extensive judgement on a series of lead cases [8]. Following a critical consideration of the facts, the contradictions, and the uncertainties, and the sometimes defective quality of the evidence, he came to the conclusion that the products of the third generation did indeed carry a greater risk of complications than those of the second generation. As he put it, “The most likely figure to represent the relative risk is around 1.7.” Since the parties had agreed in advance that the plaintiffs’ cases should be allowed only if the risk was at least doubled, the claims for damages failed. Not surprisingly,

Third-generation oral contraceptives: time to look again?

the subsequent press releases by defendants to the media stressed the failure of the claims, rather than the judge's finding that with the introduction of the third-generation products the risk had indeed been increased, apparently by some 70%. Here one must pause for a moment to reflect on what this means. If the learned judge was right in his assessment, then among the millions of women using “the pill” the proportion of users likely to suffer clinically manifest (and sometimes fatal) thromboembolic events must have risen by some two-thirds once they started to take the third-generation products rather than those of the second generation. One must also realize that no clear added benefit appeared to have been demonstrated with the new products, such as might have outweighed the added risk. In theory they might have a beneficial effect on the lipid profile, but even in large case–control studies one has seen no reduced incidence of stroke or myocardial infarction [9, 10]. It would seem that the move to the third generation was a matter of patents, prices, and profits, no more than that.

PROFILING THE RISK In the continuing debate about the third generation of oral contraceptives one relevant consideration sometimes appears to have received too little attention. That is the possibility—and even the extreme likelihood—that the thromboembolic risks of the oral contraceptives are particularly pronounced in a subgroup of users who are identifiable in advance and can thus be excluded from exposure to products that carry a relatively high risk. In the mid1990s, a team at Leiden University in The Netherlands advanced evidence that such a well-defined subpopulation of individuals at particular risk did indeed exist; it comprised carriers of the thrombogenic factor V Leiden mutation [11]. When 126 women of fertile age who had had episodes of deep

xliii

vein thrombosis were compared with 259 control subjects, the highest age-adjusted relative risk for thrombosis (with a mean of 8.7) was associated with a third-generation product based on desogestrel; lower relative risks (ranging from 2.2 to 3.8) were found for all other types of oral contraceptive. However, the most striking finding was that among carriers of the factor V Leiden mutation the risk of deep vein thrombosis with desogestrel-based products was almost 50 times higher than in non-carriers who were not using an oral contraceptive. The risk of using desogestrel products was also higher, as one might have expected, in women with a family history of deep vein thrombosis. The numbers of women in the study population using other third-generation products were too small to draw conclusions. Two years later complementary evidence was provided by a group working elsewhere in the Netherlands on thrombin formation [12]. Their findings were at the time concisely summarized under three headings in a commentary by Vandenbroucke and Rosendaal in The Lancet [13]. To quote them literally, “One, third-generation oral contraceptives induce a resistance to the blood's natural anticoagulation system (APCresistance) of almost the same magnitude as the resistance induced by a mutation in coagulation factor V (factor V Leiden); two, second-generation contraceptives show only part of this effect—in that users of second-generation pills can be clearly demarcated both from women not on oral contraceptives and from women on thirdgeneration pills; three, in women heterozygous for the factor V Leiden mutation who take oral contraceptives, APC-resistance is as high as that among homozygotes for the mutation.” To put it simply, this work further delineated the nature of the thromboembolic risk associated with oral contraceptives as a whole, defined more clearly the susceptible groups, and also underlined the particular problem attached to products of the third generation.

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Third-generation oral contraceptives: time to look again?

A FOURTH GENERATION? Of the progestogens that have emerged still more recently from the laboratory (the socalled fourth generation), drospirenone has been the most prominent, having been developed for contraceptive purposes in a series of combinations with an estrogen. One of these, which contains 3 mg of drospirenone plus 30 micrograms of ethinylestradiol, has been marketed under the name YasminÒ, with a variant known as YazÒ. These products have given rise to various controversies of their own [14], but again thromboembolism has come to the fore. In 2003 the suspicion was voiced that drosperidone-based contraceptives might be just as likely to cause thromboembolism as products of the third generation [15]; 1 year later, an inter-university study group in The Netherlands showed that the combination did indeed increase APCresistance, just as the products of the third generation had done. Not unexpectedly, a subsequent case–control study in that same country showed that the thrombotic risk was at least as high with drospirenone combinations as with the third generation, and perhaps rather higher [16]. Almost simultaneously, a national follow-up study in Denmark independently confirmed these findings [17], and as we shall see, there was more to come. One might add that, in both of these studies and others, similar findings were reported for another product in which the progestogen used was cyproterone.

THE DEFENDERS However concerned one may be, it is only fair to examine whatever arguments have been advanced by those who continue to champion either the products of the third generation or those that have emerged still later. When, at a drug policy meeting organized by Healthy Skepticism in Amsterdam in October 2010, a speaker pointed to persisting concerns about thromboembolism, a medical spokesman for a pharmaceutical

company stood up to assure the audience that the industry was now aware of substantial evidence for the safety of the third-generation products. To date, unfortunately, it remains unclear where satisfactory evidence to this effect is to be found. The most widely cited sources for such a view appear to be two papers—from 2007 and 2010 respectively—commissioned or financed by Bayer Schering Pharma and published from Berlin. The first of these reported a “European Active Surveillance study on Oral Contraceptives”, commissioned by the manufacturer of drospirenone. It was primarily concerned with that drug, although it also involved a series of others and extended to issues beyond thromboembolism. Summarizing 142 475 women-years of observations [18] its authors concluded in so many words that “. . . Risks of adverse cardiovascular and other serious events in users of a drospirenone-containing oral contraceptive are similar to those associated with the use of other oral contraceptives.” At first sight the discrepancy between this comfortable conclusion and the solidly incriminating findings of the drospirenone studies in the Netherlands and Denmark seem puzzling, but a closer look provides a series of explanations. First, the work related to a whole series of adverse events, of which venous thromboembolism was only one; secondly, although a comparison with levonorgestrel-based products of the second generation was properly included, the formulations in use varied, the estrogen content being either less than 30 micrograms or more than 30 micrograms in half the subjects involved, while a sixth of this group were using a sequential rather than a monophasic formulation; thirdly, the reassuring general conclusion related to a comparison of drospirenone formulations with all others, the latter even including thirdgeneration products. Similarly, one experiences certain doubts regarding the second of the industry-sponsored Berlin studies, which centred on gestodene and was published in 2010 [19]. To their credit, the authors themselves expressed a series of reservations, because of the constraints under which their work,

Third-generation oral contraceptives: time to look again?

in Austria, had been performed. Nevertheless, to quote their cautious conclusion, this case–control study “does not suggest that there is an increased risk of venous thromboembolism for users of oral contraceptives containing gestodene compared with users of second-generation oral contraceptives”. Findings in earlier studies may indeed, as these investigators argued, have been influenced to some extent by the time factor; users of second-generation products had commonly taken them for 8 years or more at a time when their experiences were compared with those of women taking thirdgeneration contraceptives, who tended to be in an earlier phase of treatment. Since, in the view of the Berlin group, the risk of thromboembolic complications may be higher during the early months of use, this could have adversely affected the adverse effects data in the third-generation group. Arguments such as these merit consideration, although the question remains whether they could possibly attenuate the impressive and incriminating evidence derived from earlier laboratory and case–control studies.

THE VIEW TODAY Two decades have elapsed since the earliest expressions of concern that the oral contraceptives of the third generation might be less safe than their predecessors. Many more grounds for worry have appeared in print as the years have gone by. Authoritative recent studies only seem to have confirmed that the risks are at least as great as was estimated in the 1990s; independent reviews appear to have underlined that conclusion [20, 21]. Defence of these products has at times been vigorous but (perhaps inevitably) flawed, with every shot from the ramparts promptly challenged by new assaults. At the moment of writing that is most clearly the case where the drospirenone-based products are concerned. The Berlin studies in their defence have been

xlv

followed by the appearance of two large nested case–control studies from Susan Jick's group, which have further emphasized the degree of risk attached to the drospirenone products, contrasted with second-generation levonorgestrel combinations that contain 30 micrograms of estrogen. The first study [22], built around 186 American cases of thromboembolism, points to a mean relative risk of no less than 2.8 (2.1–3.8). The second study [23], based on 61 British cases plus controls, similarly showed a relative risk of 2.7 (1.5–4.7), contrasted with the levonorgestrel product. Differences between the treatment and control groups, including age, duration of contraceptive use, or pre-existing susceptibility factors, were examined, but none sufficed to explain the striking differences in the risks associated with the two products. In retrospect, one is bound to wonder whether the originators of drospirenone tested in the early stages its effect in the APC-resistance test; that would have provided in good time a pointer to its apparent potential for thrombogenesis.

CONCLUSIONS The battle around drospirenone is not the first to be fought in the field of oral contraception, and it seems unlikely to be the last. However, over a longer period one sees that such dramatic skirmishes have alternated with an uneasy calm, during which the regulators and experts step aside to deal with other conundrums; at some moments one senses a vague belief and hope that, given time, the thromboembolism problem will simply go away. Regulators have been heard justifying their inaction in the matter, on the grounds that society has a duty to demand absolute proof of a problem before taking restrictive action; but if that were true, would we not still be hopefully treating dyspepsia with Mother Seigel's Syrup, which consisted primarily of hydrochloric acid and treacle [24]

xlvi

Third-generation oral contraceptives: time to look again?

and consuming a range of quack medicines contained conventional treatments (such as opium and ipecacuanha in Dover's powder), poisons (such as hemlock), or nothing of value whatsoever [25]? And here and there a faintly protesting voice still argues that the “pill” is no more risky than pregnancy. Is that true? And if it is indeed so, is that a sufficient reason to tolerate the imposition of risks on healthy women, when they can be avoided or reduced? It is surely time for patients and prescribers, regulators and lawyers to demand greater clarity in these matters. Issues of public health are rarely black and white, but that is no reason to ignore shades of grey. One cannot leave vital questions

unanswered and important business unfinished. This is an area in which we have much reason to believe that unnecessary harm has been done and may continue to be done unless proper action is taken. If we are wrong in that belief, so be it. At the very least, society should now try to penetrate to the truth and accept whatever consequences that truth may bring with it.

Acknowledgements The author would like to express his indebtedness to senior members of the staff of the University of Leiden, who critically reviewed an early draft of this essay.

References [1] Chambers R, King C. A book of essays. Preface. Toronto: Macmillan of Canada; 1963. [2] Patent data are as cited by Kleemann A, Engel J. Sostanze Farmmaceutiche: Sintesi, Brevetti, Applicazioni Milano: OEMF; 1988. [3] Deutsches Bundespatent. DBP 2.361.120. [4] Netherlands Patent 7.411.607. [5] Sitruk-Ware R. New progestagens: a review of their effects in premenopausal and postmenopausal women. Drugs Aging 2004; 21 (13): 865–83. [6] Anonymous. Progestin. Wikipedia. Last accessed 28 April 2011. [7] Rawlins MD. Dear Doctor/Pharmacist letter. Combined oral contraceptives and thromboembolism. London: Committee on Safety of Medicines; 18 October 1995. [8] High Court: XYZ (Claimants) and others versus (1) Schering Health Care Limited (2) Organon Laboratories Limited, and (3) John Wyeth and Brother Limited. Judgement by the Hon. Mr. Justice Mackay. Case No. 0002638. Neutral Citation No. (2002) EWHC 1420 (QB). London. [9] Heinemann LAJ, Lewis MA, Thorogood M, Spitzer WO, GuggenmoosHolzmann I, Bruppacher R. Case–control

[10]

[11]

[12]

[13]

study of oral contraceptives and risk of thromboembolic stroke: results from International Study on Oral Contraceptives and Health of Young Women. BMJ 1997; 315 (7121): 1502–4. Dunn N, Thorogood M, Faragher B, de Caestecker L, MacDonald TM, McCollum C, Thomas S, Mann R. Oral contraceptives and myocardial infarction: results of the MICA case–control study. BMJ 1999; 318(7198): 1579–83. Bloemenkamp KW, Rosendaal FR, Helmerhorst FM, Büller HR, Vandenbroucke JP. Enhancement by factor V Leiden mutation of risk of deep vein thrombosis associated with oral contraceptives containing a third-generation progestagen. Lancet 1995; 346(8990): 1593–6. Rosing J, Tans G, Nicolaes GAF, Thomassen MC, van Oerle R, van der Ploeg PM, Heijnen P, Hamulyak K, Hemker HC. Oral contraceptives and venous thrombosis: different sensitivities to activated protein C in women using second and third generation oral contraceptives. Br J Haematol 1997; 97(1): 233–8. Vandenbroucke JP, Rosendaal FR. End of the line for “third-generation-pill” controversy. Lancet 1997; 349(9059): 1113–4.

Third-generation oral contraceptives: time to look again? [14] Singer N. Health concerns over popular contraceptives. New York Times; 25 September 2009. http://www.nytimes.com/2009/ 09/26/health/26contracept.html?pagewanted=all (last accessed 28 April 2011). [15] Van Grootheest K, Vrieling T. Thromboembolism associated with the new contraceptive Yasmin. BMJ 2003; 326(7383): 257. [16] van Hylckama Vlieg A, Helmerhorst FM, Vanderbroucke JP, Doggen CJM, Rosendaal FR. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case–control study. BMJ 2009; 339: b2921. [17] Lidegaard , Lkkegaard E, Svendsen AL, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ 2009; 339: b2890. [18] Dinger JC, Heinemann LAJ, KühlHabich D. The safety of a drospirenonecontaining oral contraceptive: final results from the European Active Surveillance study on Oral Contraceptives based on 142,475 women-years of observation. Contraception 2007; 75(5): 344–54. [19] Heinemann LAJ, Dinger JC, Assmann A, Minh TD. Use of oral contraceptives containing gestodene and risk of venous

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[24]

[25]

xlvii thromboembolism: outlook 10 years after the third-generation “pill scare” Contraception 2010; 81(5): 401–7. Martinez F, Avecilla A. Combined hormonal contraception and venous thromboembolism. Eur J Contracept Reprod Health Care 2007; 12: 97–106. Amy J-J, Tripathi V. Contraception for women: an evidence based overview. BMJ 2009; 339: b2895. Jick SS, Hernandez RK. Risk of non-fatal thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case– control study using United States claims data. BMJ 2011; 342: d2151. Parkin L, Sharples K, Hernandez RK. Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: nested case–control study based on UK General Practice Research Database. BMJ 2011; 342: d2139. British Medical Association. Mother Seigel's curative syrup. In: Secret remedies: what they cost and what they contain. London: British Medical Association, 1909; 176–7. Aronson JK. Patent medicines and secret remedies. BMJ 2009; 339: b5415.

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1

Central nervous system stimulants and drugs that suppress appetite

[SED-15, 180; SEDA-30, 1; SEDA-31, 1; SEDA-32, 1]

AMPHETAMINES

Note on spelling In International Nonproprietary Names (INNs) the digraph -phis usually replaced by -f-, although usage is not consistent, and -ph- is used at the beginnings of some drug names (for example, compare fenfluramine and phentermine) or when a name that begins with a ph- is modified by a prefix (for example, chlorphentermine). For the amphetamines the spellings that are used in SEDA are as follows: amfetamine, benzfetamine,dexamfetamine,metamfetamine (methylamphetamine), and methylenedioxymetamfetamine (ecstasy); however, for the general term for the group of drugs the more common spelling “amphetamines” is used.

Amfetamine and dexamfetamine [SEDA-30, 1; SEDA-32, 1] Systematic reviews A search of 2187 articles and 9 grey literature sources identified 72 studies of amfetamine-related mortality, seven of which provided data from cohort studies of users. The estimated crude mortality rates ranged from 0 in Australia to 2.95 Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00001-5 # 2011 Elsevier B.V. All rights reserved.

(CI ¼ 1.45, 4.59) in Thailand. The Czech cohort reported only the standardized mortality rate, which was 6.22 overall [1C]. This variation in death rate suggests that mortality among amfetamine users varies geographically in important ways. The low mortality rate in the Czech cohort may have been explained by the absence of AIDSrelated deaths [2c]. The high death rates in the Dutch cohort were not consistent with data that suggest that access to both harm reduction (needle and syringe programs) and treatment services for general health care were high during the period of study [3C]. There is evidence that injection of amphetamines was associated with a higher mortality than other primary routes of administration [4C]. This is consistent with the well-documented increased risks in intravenous users of HIV and hepatitis C infections, both of which cause substantial morbidity and mortality [5c]. There was evidence that length of amfetamine use was associated with a high mortality rate in those who had been users for 5 years or more. It is unclear how mortality among amfetamine users varies with age. Cardiovascular There is no evidence at present to support the use of amfetamine to enhance recovery after stroke. Despite a trend to improved motor function, doubts remain over its safety and it has significant hemodynamic adverse effects, the consequences of which are unknown. Furthermore, there are insufficient data from which to draw conclusions regarding the effects of 1

2

amfetamine on mood or communication or quality of life [6M]. Both raised blood pressure and raised heart rate are associated with poor outcomes after stroke [7C], as is impaired baroreceptor sensitivity with increased cardiac events and dysrhythmias [8C]. Despite concerns regarding increasing heart rate and blood pressure, up to a fifth of patients with acute strokes have low blood pressure, and hypotension is associated with a poor outcome [9M]. Cardiomyopathy due to a toxic effect of Adderall, intermediate in onset, with uncertain susceptibility factors such as preexisting coronary artery disease and possibly drug–drug interactions, has been reported [10A]. • A 33-year-old man treated with Adderall (dexamfetamine þ amfetamine) for ADHD. Adderall was started initially at 20 mg daily and two months later increased to 40 mg, and fluoxetine 20 mg/day was added as a mood stabilizer. Seven months later the daily dosage of both drugs doubled, and a month later Adderall was again increased to 80 mg bd. On the higher dose of Adderall, the patient experienced increased hyperactivity and irritability. Two months later, he developed symptoms of abdominal pain, vomiting, and cough that lasted a month. He was diagnosed as having a cardiomyopathy and underwent a successful cardiac transplant. Microscopic examination of heart tissue revealed (a) focally severe coronary atherosclerosis of the proximal right coronary artery; (b) cardiomyopathy, mild cardiomegaly, with biventricular myocyte hypertrophy; (c) mild focal nonspecific interstitial myocarditis suggestive of hypersensitivity; and (d) fatty infiltration on the right ventricular myocardium. The contribution of coronary artery atherosclerosis to the development of cardiomyopathy was uncertain.

There have been eight previously reported cases of cardiomyopathy associated with Adderall. Whether an interaction between Adderall and fluoxetine would have contributed to the cardiomyopathy in this patient is uncertain. Death In a matched case–control study, mortality data from 1985 to 1996 were used to identify 564 cases of sudden death at ages 7–19 years across the USA, and a

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Reginald P. Sequeira

matched group of 564 young people who died as passengers in motor vehicle traffic accidents [11C]. There was a significant association of stimulant use with sudden unexplained death. The primary exposure measure was the presence of amfetamine, dexamfetamine, metamfetamine, or methylphenidate, according to informant reports or as noted in medical examiner records, toxicology results, or death certificates. In 10 of the sudden unexplained deaths (1.8%) the youths had taken stimulants, specifically methylphenidate; in contrast, only two subjects in the motor vehicle accident comparison group (0.4%) had used stimulants, and only one case involved methylphenidate. As a result of this study, the US Food and Drug Administration issued a safety communication, stating that given the limitation of this study, it was unable to conclude that these data affect the overall benefit to harm profile of stimulant medications used to treat ADHD in children [12S]. The FDA advised health-care professionals to follow the current prescribing information, including taking a medical history for cardiovascular disease and performing a physical examination focusing on the cardiovascular system. Susceptibility factors Genetic Further evidence that genetic variants in the SLC6A2 gene are involved in acute responses to amfetamine, which may progress to amfetamine abuse, has been reported [13C]. In a three-session, double-blind, crossover study, 162 healthy Caucasians (90 men), aged 18–35 years took either a placebo or oral dexamfetamine (10 or 20 mg). The associations between the degrees of selfreported elation and vigor after amfetamine and single nucleotide polymorphisms (SNPs) and SNP haplotypes in SLC6A2 were determined. SNPs rs36017 and rs1861647 were associated with significantly higher ratings of elation and vigor after amfetamine 20 mg. Ratings of vigor after amfetamine 20 mg were also associated with a two-SNP haplotype formed with rs1861647 and rs5569 and a three haplotype formed

Central nervous system stimulants and drugs that suppress appetite

with rs36017, rs10521329, and rs3785155. The authors postulated that people with genotype C/C at rs36017 or with genotype A/A at rs1861647 would experience more profound increases in feelings of vigor and elation after taking amfetamine and would therefore be more inclined to use amfetamine again. It is unclear whether the highly linked polymorphisms are in linkage dysequilibrium with a functional variant that has not been identified yet or whether these polymorphisms directly influence mRNA processing, stability, or splicing. Nevertheless, these findings add to a growing literature on the genetic determinants of responses to amphetamines. Such studies are important because acute differences in responses to a drug may contribute to variability in the risk of abuse and drug dependence.

Drug overdose Outcomes after accidental amfetamine ingestion in children under 7 years have been evaluated in a retrospective chart review over 4 years (January 2003 to December 2007) in 118 patients, average age 3.1 years (range 8 months to 7 years), of whom 90 (76%) were naïve to the medication and accidentally ingested amfetamine prescribed for siblings [14c]. In all, 28 took a “double dose” of their normally prescribed medication, of whom 25 were observed at home and developed no or minimal symptoms; three were referred to an emergency department with headache or mild agitation but were subsequently discharged. In all, 76 developed symptoms and were evaluated at a health-care facility; 15 received benzodiazepines for agitation and 16 were observed for more than 12 hours. All the patients had favorable outcomes. Although toxic exposure in this study resulted in mild to moderate symptoms, amfetamine exposure has the potential to cause severe adverse effects. Therefore, toxic exposure should be evaluated and treated individually based on the symptoms each patient has.

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3

Ecstasy (3,4methylenedioxymetamfetamine, MDMA) See Chapter 4.

Metamfetamine [SEDA-30, 2; SEDA-31, 1; SEDA-32, 3] Cardiovascular It is generally presumed that in patients who develop chest pain after using amfetamine the risk of acute myocardial infarction is increased [15c]. However, in a systematic review, although there was a high incidence of acute coronary syndrome in patients with chest pain after metamfetamine ingestion, there was no evidence that the incidence of acute myocardial infarction was increased [16R]. Evolving diagnostic criteria [17C] were used: acute coronary syndrome diagnosis was based on measurement of myocardial creatine kinase (CK-MB) and also included unstable angina, which is diagnosed in patients with angina and a normal CKMB relative index and evidence of myocardial ischemia on non-invasive cardiac stress testing or significant coronary artery disease by coronary angiography. The prevalence of self-reported illicit use of cocaine and/or metamfetamine in patients with acute decompensated heart failure has been studied, using a multicenter observational registry, in 11 258 patients, of whom 594 (5%) had previously used cocaine (96%) and/or metamfetamine (5%) [18C]. Users had a median age of 50 years compared with 76 years in non-users. As there were disproportionately more young African–American men with hypertension, left ventricular systolic dysfunction, and markedly raised B-type natriuretic peptide concentrations, the authors speculated that the severity of cardiac dysfunction in these young patients would probably result in higher morbidity, mortality, and health costs. Although these patients had a greater degree of left ventricular dysfunction (ejection fraction <40%), they did not have a greater risk-adjusted mortality.

4

In a case–control chart review, 107 metamfetamine users and 114 controls were identified [19C]. The two groups had similar sex distribution, length of hospital stay, prevalence of coronary artery disease, diabetes mellitus, hypertension, cigarette smoking, and alcohol, marijuana, and cocaine abuse. The cases were older than the controls (mean age 38 versus 35 years), had higher values of BMI (37 versus 30 kg/m2), and had a higher prevalence of renal insufficiency (13% versus 4.4%). Metamfetamine users had a 3.7-fold higher odds ratio for cardiomyopathy, after adjusting for age, BMI, and renal insufficiency. LVEF was significantly lower in cardiomyopathy patients with metamfetamine use. Nervous system Use of metamfetamine is associated with ischemic stroke, intracerebroventricular hemorrhage, and subarachnoid hemorrhage, especially among young individuals. All cases of subarachnoid hemorrhage were aneurysmal, and most were located in the anterior circulation, as were most of the strokes. Although in many cases imaging confirmed arterial stenosis in the vascular distribution of the stroke, there was no evidence that the ischemic stroke associated with the use of metamfetamine was due to an inflammatory cause rather than a process of accelerated atherosclerosis [20C]. These conclusions were based on a retrospective chart review of admissions to a tertiary care neurovascular service from January 2003 to July 2007; there were 30 cases out of 1574 patients who had used metamfetamine, documented by history or urine toxicology screening. There was an apparent selection bias in this study: neither the duration nor the severity of substance use was estimated. Nevertheless, metamfetamine is a susceptibility factor for stroke in young adults, consistent with previous reports [21c, 22c]. It is likely that various stroke subtypes are related to metamfetamine-induced hypertensionrelated vascular pathology rather than vasculitis, as has been suggested before [23R, 24c]. In 20 adults with a confirmed history of metamfetamine use and dependence, currently engaged in rehabilitation and confirmed to have been abstinent for an average of

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Reginald P. Sequeira

6 months, there was memory impairment compared with 20 metamfetamine-naive participants [25c]. These memory deficits did not vary as a function of specific memory task demands. Of all the cognitive measures, cognitive inhibition shared greatest variance with group effects on the prospective memory measure. Periventricular leukomalacia has been reported after prenatal metamfetamine exposure [26A]. • A 23-year-old woman gave birth to a male infant weighing 1080 g at 30 weeks of gestation. She reported using metamfetamine and marijuana once 3 days before delivery and denied any other drug use during pregnancy. After cesarean section the infant's Apgar scores were 6 at 1 minute and 7 at 5 minutes. The initial capillary pH was 7.27, with a PaCO2 of 6.9 kPa and a base deficit of 4 mmol/l. A drug screen of meconium was positive for metamfetamine (850 ng/g) and tetrahydrocannabinol (54 ng/ g). Cranial ultrasound at 1 week was unremarkable, but at 6 weeks it was highly abnormal, with multiple small cysts bilaterally in the subependymal white matter anterior to the lateral ventricle consistent with periventricular leukomalacia. Ophthalmology was normal. At 24 months he had severe developmental delay, with spastic quadriplegic cerebral palsy.

The authors thought that this patient had no risk factors for periventricular leukomalacia, except for prematurity. They also thought that the cranial ultrasound results at weeks 1 and 6 were consistent with a history of metamfetamine exposure at 3 days before birth. They postulated that metamfetamine had caused cerebral ischemia and subsequent destruction of white matter and cyst formation 6 weeks later. However, they acknowledged that other factors could have contributed to the pathophysiology, including contamination of metamfetamine. Gastrointestinal Occult metamfetamine abuse should be considered when young patients present with signs and symptoms suggestive of ischemic colitis. • A 44-year-old man developed ischemic colitis after abusing crystalline metamfetamine [27A]. Although a direct causal relation was not established, the temporality in this case,

Central nervous system stimulants and drugs that suppress appetite with the absence of classic susceptibility factors, made metamfetamine the presumptive etiology.

Drug abuse In the York Region in Toronto, Canada, a new strategy has been developed to curb metamfetamine use, modeling on Vancouver's four-pillar drug strategy (prevention, treatment, harm reduction, and enforcement) [28S]. However, more than 70% of Vancouver's street-involved youth have used metamfetamine and metamfetamine use increased significantly in intravenous drug users, from 2% to 15% in 8 years, despite Vancouver's four-pillar strategy [29r]. It may therefore be unjustifiably optimistic to anticipating that the supply of metamfetamine can be suppressed, as, unlike other drugs, metamfetamine can be inexpensively produced locally, and the likelihood that law enforcement can successfully curbing the growth in the supply of metamfetamine is exceedingly small. There is also pessimism about the benefits of antidrug media campaigns and Drug Abuse Resistance Education (DARE) programs. It has been suggested that Dmetamfetamine hydrochloride, or crystal meth, is more likely to cause dependency than other forms of metamfetamine [30r]. When smoked or injected it causes an almost immediate “rush”, compared with 20 minutes after oral ingestion. It is used rectally as well as snorted. The authors also stated that when ‘compared with cocaine, crystal meth . . . can keep the user “up” for 12 hours. A user binging in crystal meth (on a “run”) may stay awake for 10 days’. Prolonged use can lead to “tweaking” or psychosis with extreme paranoia and result in body scabs from picking at imaginary bugs crawling on or under the skin. About 25 million people worldwide may have used amphetamine and metamfetamine in 12 months, making it the most widely used illicit drug after cannabis. Although the authors appreciated the reported decline in the use of amphetamines among school students, they did not believe that it is enough. The reasons for using crystal meth among women may include a desire to lose

Chapter 1

5

weight; in men it often improved sex performance. Self-identified gay/bisexual students were 26 times more likely to have used crystal meth in the previous year. Street youth reportedly used crystal meth as a coping strategy against negative emotions and circumstances. The authors acknowledged that pharmacological treatment is challenging, as there is no effective medication for amphetamine abuse; nonpharmacological treatments, although effective, may not have enduring effects. Bellemare reacted to this article by raising unique child protection concerns that are associated with the use and production of crystal meth, which are not relevant to other drugs [31r]. The specific concerns were about children who live in places where metamfetamine is produced. Besides neglect of child care by those who are actively engaged in metamfetamine production, these laboratories can explode, expose children to strangers and drug users, and expose them to drug seeking behaviors, including hypersexuality and sexual abuse. The author strongly urged clinicians to exercise their legal and moral duty to protect these children by calling the child welfare authorities as appropriate. Teratogenicity In 29 children, aged 3–4 years, who had been exposed to metamfetamine in utero, and 37 unexposed children, fractional anisotropy and apparent diffusion coefficients were determined in various parts of the brain [32c]. There were alterations in white matter maturation, involving more compact axons or greater dendritic density. The findings of this study were confounded by incomplete drug histories from some subjects, which could have minimized or exaggerated the effects of metamfetamine. In addition, genetic and environmental influences cannot be ruled out as a source of lower white matter diffusion. It is also not known whether the diffusion changes observed in metamfetamineexposed children remain low, normalize, or become higher with age. The molecular mechanisms that might be responsible for metamfetamine neurotoxicity include oxidative stress, activation of

6

transcription factors, DNA damage, excitotoxicity, blood–brain barrier breakdown, and various apoptotic pathways [33ER]. Congenital cataract with triangular morphology has been reported in association with prenatal metamfetamine exposure [34A]. Although this association was probably coincidental, the morphology of the cataract and the specific timing of prenatal exposure (6–7 weeks of gestation) suggested that further studies would be worthwhile. Maternal depressive symptoms are associated with neurodevelopmental patterns of reduced arousal and increased stress. Among 13 808 screened subjects from Honolulu, 1632 were eligible and 176 mothers were enrolled; prenatal metamfetamine exposure combined with maternal depression was not associated with any additional neurodevelopmental differences [35C]. When adjusted for co-variates, metamfetamine exposure was associated with lower arousal and higher lethargy scores. Only 136 biological mothers with child custody (50 of whom had used metamfetamine) had the Addiction Severity Index (ASI) administered at 1 month. The NICU Network Neurobehavioral Scale (NNNS) was administered to the neonate within the first 5 days of life by an examiner blinded to metamfetamine exposure. There were several limitations to this study. The severity of depression in the mothers was assessed not at the neonatal visit but after 1 month. Since only the biological mothers were included in the study, the sample size was limited, because several infants who had been exposed to metamfetamine were placed in foster care or the care of relatives, so that data from their biological mothers was not assessed.

Fenfluramines

[SED-15, 1333; SEDA-30, 7; SEDA-32, 7] Cardiovascular A wide range of drugs, including those used for migraine prophylaxis (ergotamine, methysergide), appetite suppressants (fenfluramine and dexfenfluramine), dopamine receptor agonists (pergolide and cabergoline), and ecstasy

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Reginald P. Sequeira

(methylenedioxymetamfetamine, MDMA) [36A] have been implicated in drug-induced fibrotic valvular disease [37R]. 5HT2B receptor activity through activation of protein kinase and potentiation of the effect of transforming growth factor b is thought to result in mitogenesis of cardiac valves [38r, 39r]. Investigations into individual susceptibility need to establish which clinical and demographic factors predict patients at greatest risk of druginduced valvular heart disease, and the role of genetic polymorphisms. It is also important that new drugs that interact with the serotonin pathways and 5HT2B receptors should be assessed at the clinical trials stage, in order to establish the risk of valvular heart disease before they are used in clinical practice. Hematologic In a cross-sectional study, platelet counts in 47 patients with pulmonary arterial hypertension (PAH) receiving intravenous epoprostenol were compared with platelet counts in 44 patients who were taking oral agents [40C]. Idiopathic PAH accounted for 69% of cases; the rest were associated with fenfluramine (18%), connective tissue disease (10%), or congenital heart disease (2%). There was thrombocytopenia in 34% of the patients who were treated with epoprostenol compared with 15% of those who took oral therapy (OR ¼ 2.9). Higher doses of epoprostenol were associated with lower platelet counts than lower doses. The effects of hemodynamics and epoprostenol were independent and additive, with the highest rates of thrombocytopenia seen among patients with both severe hemodynamic abnormalities and use of epoprostenol. Treatment options for thrombocytopenia in PAH are limited, owing to incomplete understanding of its pathophysiology; withdrawal of epoprostenol is rarely recommended.

Atomoxetine Observational studies In an open study of the use of atomoxetine for over 4 years in 384 adults with ADHD, the adverse events

Central nervous system stimulants and drugs that suppress appetite

were mainly related to the expected noradrenergic effects of the drug [41c]. Systematic reviews In a systematic review of data from 13 double-blind, placebocontrolled trials and three open extension studies in 714 children and adolescents with ADHD treated with atomoxetine for at least 3 years, under 6% had aggressive/hostile behavior and under 1.6% reported suicidal ideation/behavior; there were no clinically significant effects on growth rate, vital signs, or electrocardiography [42M]. Cardiovascular In children, adolescents, and adults there was a small but significant prolongation of the QT interval in electrocardiogram when Bazett's correction was used but not when the Fridericia formula was used [43c]. The effects of atomoxetine on hERG potassium channels have been studied in human embryonic kidney cells [44E]. Atomoxetine inhibited hERG current with an IC50 of 6.3 mmol/l. The effect occurred quickly and was washed out quickly. Channel activation and inactivation were not affected. Inhibition was state-dependent, suggesting open channel blockade. Use dependence was not observed. Nervous system In a cohort study of 21 606 patients with ADHD treated with atomoxetine and 21 606 treated with other medications, the rate ratios were 1.38 (95% CI ¼ 0.42, 4.54) for the risk of stroke and 0.31 (95% CI ¼ 0.04, 2.63) for the risk of a transient ischemic attack (TIA) [45C]. There was an increased risk of TIA when those with ADHD treated with any medications were compared with the general population (HR ¼ 3.44; 95% CI ¼ 1.13, 11), but no increased risk of stroke. Sensory systems Mydriasis has been reported in a 15-year-old girl who took atomoxetine for ADHD [46A]. Psychiatric A report of aggression in a boy taking atomoxetine has again raised the question of whether this is an adverse effect of the drug [47AM].

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• A 13-year-old boy with ADHD was given atomoxetine and 5 weeks later developed changed behavior, disorientation, irrelevant speech, and self-harming behavior. He was very aggressive and hostile towards other children and adults. No organic cause was found. The boy improved after withdrawal of atomoxetine.

In an extensive review of the literature the authors found no evidence of other reports of such an effect. However, in one unpublished study four subjects stopped taking the drug because of irritability or aggression [48S]. This could be a rare adverse effect that has not been noticed in trials, although a previous meta-analysis was negative (SEDA-32, 8). Acute agitation and suicidal ideation occurred in an 11-year-old boy after he started to take atomoxetine [49A]. However, a previous meta-analysis was negative (SEDA-32, 8). Teeth Nocturnal bruxism worsened in a 12-year-old boy with ADHD when he was given atomoxetine, improved after withdrawal, and recurred after rechallenge; it responded to the addition of buspirone [50A]. Drug–drug interactions Methylphenidate In an open study in children aged 6–17 years the addition of OROS methylphenidate increased the rates of insomnia, irritability, and loss of appetite compared with atomoxetine alone [51c]. Susceptibility factors Alcohol abuse and dependence increase the risk of atomoxetine-related adverse events [52C].

Methylphenidate [SED-15, 2307; SEDA-30, 4; SEDA-3, 3; SEDA-32, 10] Observational studies Treatment with relatively high doses (up to 1.5 mg/kg/day) of OROS methylphenidate in 114 adolescents with ADHD was associated with small but statistically significant mean increases in

8

blood pressure and heart rate, primarily during the first 6 weeks of treatment, without clinically important ECG changes [53C]. Only 57 subjects had completed 6 months of treatment and 19 dropped out because of non-cardiovascular adverse events: reduced appetite/weight loss (n ¼ 6), reduced appetite/weight loss and irritability (n ¼ 3), mood changes (n ¼ 3), stomach ache (n ¼ 1), headache (n ¼ 1), light-headedness (n ¼ 1), and excessive sweating (n ¼ 1). One subject discontinued medication because of recurrent bouts of palpitation during the first 6 weeks of treatment. Being an open study, there was no comparison of the cardiovascular end-points with a placebo or active comparator. Also, since most of the visits occurred at 7–10 hours after the morning dose of medication, the timing of blood pressure measurement may not have coincided with the peak action of the medication. Comparative studies Exposure to methylphenidate and amfetamine salts carried similar risks for cardiac emergency department visits in a retrospective cohort study of claims data from the Florida Medical data on 2 131 953 children and adolescents, between 1994 and 2004, with a diagnosis of ADHD [54C]. However, emergency department visits may reflect parent concern rather than acute cardiac adverse events. The drug dosages were not considered, because treatment recommendations included dosage titration according to patient response and the occurrence of adverse effects. In a study based on the UK General Practice Research Database (GPRD) in patients with ADHD, aged 2–21 years, from 1993 to 2006 with prescriptions for methylphenidate, dexamfetamine, or atomoxetine, there was no increase in the risk of sudden death but there was an increased risk of suicide [55C]. Seven patients died in a cohort of 18 637 patientyears, and cause of death was obtained in six; none was deemed to be a case of sudden death (incident rate ratio 1.63; 95% CI ¼ 0.04, 9.71). The standardized mortality ratios for suicide were 162 (95% CI ¼ 20, 585) in patients aged 11–14 years and

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1.84 (95% CI ¼ 0.05, 10) in patients aged 15–21 years. Although the medications may have contributed to the increased risk of suicide, other factors that can also predispose to suicide, such as depression and antisocial behavior, frequently co-exist with ADHD [56c, 57R]. Placebo-controlled trials In a randomized, double-blind, placebo-controlled crossover trial of methylphenidate in 13 patients with apathetic Alzheimer's disease stabilized on a cholinesterase inhibitor, methylphenidate produced significant benefit [58c]. There was a positive relation between the acute effects of dexamfetamine and the response to methylphenidate, implicating a role for dopaminergic dysfunction in the development and treatment of apathy in Alzheimer's disease. A significantly higher proportion of patients had at least one adverse event with methylphenidate compared with placebo; two had serious adverse events while taking methylphenidate, consisting of delusions, agitation, anger, irritability, and insomnia, which resolved on withdrawal of methylphenidate. Systematic reviews In 26 placebo-controlled trials in 811 adults with ADHD, methylphenidate was well tolerated in the short-term and produced no serious adverse effects [59M]. However, there is little information on the long-term safety of methylphenidate in adults, although the number of serious adverse effects reported has so far been low. Methylphenidate is associated with modest increases in blood pressure and heart rate. Surveys of the use of stimulants in US universities have shown that misuse of prescribed medications, for recreation or to enhance the ability to study, is fairly common, although the magnitude of harm that arises from such practices is unclear. Warnings from the FDA and scientific debate surrounding the potential of psychostimulants to exacerbate tics have created clinical uncertainty for practitioners treating ADHD in children with comorbid tics. A meta-analysis of nine studies involving 477 subjects has suggested that among six medications used in ADHD

Central nervous system stimulants and drugs that suppress appetite

(the alpha-adrenoceptor agonists clonidine and guanfacine, atomoxetine, desipramine, dexamfetamine, methylphenidate, and selegiline), methylphenidate seems to offer the greatest and most immediate improvement in the symptoms of ADHD and does not seem to worsen tics [60M]. Alpha agonists offer the best combined improvement in both tics and symptoms of ADHD. Atomoxetine and desipramine offer additional evidence-based treatments for ADHD in children with comorbid tics; supratherapeutic doses of dexamfetamine should be avoided. However, it is important to note that effect size of medications in trials is influenced by many factors besides the efficacy of the medication, including differences in the precision of rating scales. This difference may have been particularly influential in measures of efficacy in treating ADHD and the inattention and hyperactivity/impulsive symptom subtypes, because multiple rating scales and raters were used. The trials in this meta-analysis included primarily male subjects and it is not known how well the results would apply to girls with ADHD and comorbid tics. For several outcomes, there was significant heterogeneity between studies, suggesting that differences in trial design may have influenced effect sizes. Such differences in trial design include the type of rating scale and dose and duration of treatment. With a relatively smaller number of studies contributing to this meta-analysis, it is not possible to determine which of these hypothesized factors contributed to heterogeneity. Methylphenidate is considered safe for children who are seizure free. However, a few reports of seizure aggravation in methylphenidate-treated children with uncontrolled epilepsy have raised concerns about its use in this group [61R]. Psychiatric Psychosis is an important but unpredictable adverse effect of stimulant medications and can mimic the symptoms of ADHD. Four cases of stimulant-induced psychosis (three with methylphenidate and one with ConcertaÒ XL) resolved spontaneously on withdrawal of medication and

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recurred on rechallenge [62A]. It is important to screen and identify psychotic symptoms during stimulant drug treatment, because they could be mistaken for deterioration in the symptoms of ADHD and result in dosage titration upwards, with serious implications. Urinary tract A possible association of methylphenidate and enuresis has been reported [63A]. • An 11-year-old boy with ADHD was given methylphenidate and after the daily dosage had been titrated to 20 mg enuresis started to occur. After 2 months, the medication was withdrawn and the enuresis stopped immediately. About 1 month later, methylphenidate was restarted and the enuresis reoccurred when the dose reached 20 mg/day. It continued for about 3 months but immediately stopped when the medication was withdrawn. Another rechallenge after 2 months, followed by withdrawal of methylphenidate, replicated the response. Other causes of enuresis were excluded and the patient never had daytime urinary incontinence.

In previous reports methylphenidate was reportedly effective in controlling giggle incontinence [64A, 65A]. Skin The potential for vasculopathy in patients with ADHD taking stimulants has been reported in four patients, two of whom were taking methylphenidate and two dexamfetamine [66A]. They developed acral cyanosis, livedo reticularis, or Raynaud's syndrome. Two (one each taking methylphenidate and dexamfetamine) had positive antinuclear antibody titers and one (taking dexamfetamine) had histological evidence of stratum malpigian necrosis with perivascular lymphocytic infiltration on skin biopsy. Both of the patients who were taking methylphenidate had antihistone antibodies. One patient improved after withdrawal of dexamfetamine and her medication for ADHD was changed to bupropion; others had worsening of their symptoms on higher doses of medication. Genotoxicity Recent studies have added to the accumulating evidence that therapeutic

10

concentrations of methylphenidate do not cause cytogenetic damage in humans [67C]. In 109 children with ADHD taking methylphenidate (starting dose 10 mg/day to a maximum of 60 mg/day) for a total duration of 84 days, cytogenetic anomalies were investigated, including chromosomal aberrations, micronuclei, and sister chromatid exchanges in peripheral blood lymphocytes in culture. None was significantly affected by methylphenidate. Since dosage titration was used in the study design, both the daily dose administered and the total cumulative dose over the course of this study differed according to the needs of the patients. These results are in marked contrast to previous findings of significant increases in all three end-points with a similar study design but with a smaller sample size and a behavior therapy only control group [68c]. Other mutational end-points are consistent with the human and animal cytogenetic data on methylphenidate [69ER]. Taken together, these findings show a high degree of consistency and confirm that methylphenidate does not induce chromosomal aberrations or other type of genetic damage in children with ADHD [70C]. It is important to note that an epidemiological study of the risk of cancer among 35 400 methylphenidatetreated patients with ADHD, who take this medication before age 20, showed no moderate or strong association [71c]. Susceptibility factors Genetic There has been considerable interest in the evaluation of genetic determinants of the response to methylphenidate in ADHD. Preliminary studies have suggested that dopaminergic genes [72C] and noradrenergic and possibly glutaminergic genes [73C] may be involved. Juvenile Huntington disease with acute onset of motor symptoms coincident with initiation of treatment with methylphenidate has been reported [74A]. • An 8-year-old boy, otherwise healthy, with symptoms of ADHD was given methylphenidate and within 4 weeks had a rapid decline in fine motor skills, with dysarthria, intention tremor, motor impersistence, and diffusely increased tone. His symptoms persisted

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despite withdrawal of methylphenidate. There was a paternal history of Huntington disease and a molecular analysis suggested juvenile Huntington disease.

This report suggests the possibility that methylphenidate (a dopamine receptor agonist) in patients with a family history of Huntington disease may lead to clinical exacerbation of motor symptoms and/or an unwitting diagnosis in an unprepared family. Many children who develop the juvenile form of Huntington disease are initially misdiagnosed as having ADHD [75A], and one-quarter of those with juvenile Huntington disease have attention deficits [76A]. Thus, a child with an unrecognized family history of Huntington disease presenting with isolated cognitive symptoms may be treated with stimulants, and this association may therefore have been coincidental. Drug–drug interactions Fluoxetine Tactile and visual hallucinations with the combination of methylphenidate and fluoxetine have been reported [77A]. • A 10-year-old boy with ADHD, oppositional defiant disorder, and generalized and separation anxiety disorders started taking OROS methylphenidate 18 mg/day and fluoxetine 10 mg/day. Four days later, he had an acute episode of intense hallucinations 3 hours after taking the medications. His mother reported that the visual hallucinations lasted about 1 hour and the tactile hallucinations more than 2 hours. Two days later he had a similar episode. His mother withdrew the medications for 10 days, during which time he was symptom free. When OROS methylphenidate 18 mg/day monotherapy was restarted he did not report any hallucinations. Mirtazapine 15 mg/day was added for symptoms of anxiety and sleep disturbances. During the next 2 months his condition improved and he had no further hallucinations.

There has been a previous report of treatment-related hallucinations with the combination of methylphenidate and fluoxetine in a 14-year-old girl with ADHD depressive disorder [78A]. The mechanism whereby methylphenidate þ fluoxetine might cause hallucinations is unclear.

Central nervous system stimulants and drugs that suppress appetite

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Modafinil

[SED-15, 2369; SEDA-30, 6; SEDA-31, 7; SEDA-32, 6]

Other adverse effects reported at higher doses, such as diarrhea and dyspepsia, were not seen.

Observational studies Armodafinil, the R-isomer of modafinil, produces consistently higher plasma concentrations late in the day than modafinil, when compared milligram for milligram. In two multipledose pharmacokinetic studies in healthy men aged 18–50 years adverse events were studied in subjects who completed 7 days of once-daily armodafinil (n ¼ 34) or modafinil (n ¼ 18) [79c]. The most common adverse events were headache, palpitation, nausea, and dizziness with armodafinil, and headache, palpitation, insomnia, and anxiety with modafinil. With both drugs, adverse events were mild or moderate in intensity. While the adverse events were similar at lower doses, they were more frequent with higher doses, requiring withdrawal of the 400 mg dose of armodafinil and the 800 mg dose of modafinil after 7 and 3 days respectively. Two subjects who took armodafinil 400 mg/day had events that led to withdrawal, one with multiple events (headache, abdominal pain, pharyngitis, hypertonia, vasodilatation, nausea, insomnia, anorexia, conjunctivitis, anxiety, emotional liability, confusion, and weakness) and one with mild nausea and moderate amblyopia. There were clinically significant cardiovascular changes, including sustained hypertension in one subject, in those who took modafinil 800 mg/day. There were no serious adverse events with armodafinil, while two adverse events were reported after administration of modafinil. Both of the subjects with serious adverse event required hospitalization for monitoring and evaluation. There were electrocardiographic abnormalities in one subject taking 400 mg/day and anxiety/tachycardia in one taking 800 mg/day. In patients with primary biliary cirrhosis the dosage of modafinil was limited to 200 mg/day because of the possibility of reduced drug metabolism in this population [80c]. Despite the low dosage, some patients had adverse effects, including nausea, insomnia, headache, and nervousness.

Placebo-controlled studies There was reduced appetite in patients with ADHD treated with modafinil [81c]. Gastrointestinal adverse events, such as nausea and dry mouth, were more common compared with placebo in cocaine dependent subjects who took modafinil 200 mg/ day, and one of 70 subjects had an abnormal electrocardiogram, hypertension, chest discomfort, a bitter taste sensation, irritability, agitation, anxiety, and tension, and there were two instances of insomnia, one instance of sweaty palms, and one case of upper lip swelling in those who took 400 mg/day [82c]. There was exacerbation of psychosis in five of 83 patients with schizophrenia who took modafinil compared with two of 70 who took placebo [83R]. Psychiatric Long-term modafinil treatment can rarely cause psychotic symptoms [84A]. • A 25-year-old woman with a history of narcolepsy took modafinil, titrated up to 300 mg/ day, and had dry mouth and tachycardia. After 5 days, she continued to take 300 mg/ day without any apparent adverse effects. About 6 months later she had visual and auditory hallucinations and delusions of reference. Modafinil was withdrawn and her psychotic symptoms resolved. After restarting modafinil on alternate days occasional hallucinations recurred.

There have been other reports of modafinil-associated psychosis in patients with narcolepsy [85A, 86A, 87A].

METHYLXANTHINES Caffeine [SED-15, 588; SEDA-30, 5; SEDA-31, 8; SEDA-32, 14] Teratogenicity Adenosine receptors are among the first receptors to be expressed in the embryonic brain, and modulation

12

potentially affects axon formation [88E]. Intrauterine exposure to 10 or more cups of coffee per day was associated with a threefold increased risk of hyperkinetic disorder and ADHD [89C]. After adjustment for a number of confounding factors, such as smoking, alcohol intake, sex of the child, maternal age, a family history of psychopathology and parental socio-economic factors, the risk fell and became statistically insignificant (RR ¼ 2.3; 95% CI ¼ 0.9, 5.9). This study was based on Aarhus Birth Cohort data in Denmark and included 24 068 singletons delivered between 1990 and 1998. Linkage was performed with three Danish longitudinal registers: the Psychiatric Central Register, the Integrated Database for Labor Market Research, and the Danish Civil Registration System. Information about coffee consumption during pregnancy was obtained at 16 weeks of gestation from a self-administered questionnaire. A methodological strength of this study was the community-based sample and disentangling of confounding effects using Cox regression analysis. It is important to pursue a synergistic effect of intrauterine exposure to caffeine and cigarette smoke on the risk of hyperkinetic disorder and ADHD. A randomized, controlled trial has shown that the effect of caffeine on fetal growth was found only among smokers [90C]. Moreover, the implications of reduced maternal metabolism of caffeine during the third trimester [91c] need to be considered. In the National Birth Defects Prevention Study in the USA, a population-based, case–control study of major birth defects, excluding infants with single-gene disorders and chromosomal abnormalities, there was no association between maternal dietary caffeine intake and orofacial clefts [92C]. This analysis included 1531 infants with cleft lip with or without cleft palate, 813 infants with cleft palate only, and 5711 infants with no major birth defects as controls. Maternal caffeine intake was selfreported. Dietary caffeine intake may have changed during pregnancy, making exposure assessment during the critical period for orofacial development difficult.

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Drug overdose Hemodynamic instability and hypotension after massive caffeine overdose improved with loading doses followed by continuous infusions of both phenylephrine and lidocaine [93A]. Hypotension in caffeine overdose is multifactorial: b2-adrenoceptor agonism causes peripheral vasodilatation and b1-adrenoceptor stimulation leads to profound tachycardia with incomplete diastolic filling. The authors suggested that both phenylephrine and lidocaine should be considered in the treatment of cardiovascular collapse secondary to methylxanthine poisoning. Lactic acidosis has been reported in caffeine poisoning [94A]. • A 17-year-old woman was admitted to the emergency department 30 minutes after taking 12 g of caffeine (266 mg/kg) in a suicide attempt. She had constant nausea with repeated vomiting, tremor, anxiety, and hyperventilation, hypokalemia of 2.4 mmol/l, and a blood lactate concentration of 3.1 mmol/l. The lactate concentration rose to 7.0 mmol/l at 9 hours after ingestion, and no other cause besides caffeine poisoning was identified. She was given ondansetron and midazolam intravenously for nausea and anxiety, and the hypokalemia was cautiously corrected. She was also given propranolol.

Excessive sympathetic stimulation with increased glycogenolysis and lipolysis and a secondary rise in pyruvate could explain lactic acidosis in caffeine poisoning.

Theophylline [SED-15, 3361; SEDA-30, 5; SEDA-31, 8; SEDA-32, 15] Nervous system Status epilepticus has been attributed to theophylline in two cases. • A 5-year-old boy with no history of convulsions had a generalized tonic–clonic seizure after taking oral theophylline for 2 days followed by non-convulsive status epilepticus [95A]. The serum theophylline concentration was 19.7 mg/l. An intravenous bolus dose of midazolam 0.26 mg/kg largely restricted seizure activity to the right hemisphere and another 0.24 mg/kg followed by a continuous infusion of 0.20 mg/kg/hour completely abolished the electrical status.

Central nervous system stimulants and drugs that suppress appetite • An 8-month-old boy who had been given oral modified-release theophylline and additional aminophylline suppositories developed convulsive status epilepticus [96A]. A combination of diazepam, lidocaine, and thiopental was required to stop the convulsion. A pharmacokinetic study showed that the use of the modified-release formula would have given a plasma concentration of no more than 15 mg/ l, but that the addition of aminophylline would have increased it to over 20 mg/l.

Drug overdose Acute pancreatitis has been reported after severe theophylline overdose [97A].

DRUGS THAT SUPPRESS APPETITE [SEDA-30, 7; SEDA-31, 9; SEDA-32, 16] The need for studies of the long-term safety and efficacy of antiobesity drugs [98R] and the regulatory challenges for new drugs to treat obesity with comorbid metabolic disorders [99R, 100R, 101C] have been reviewed. New central targets for the treatment of obesity are being explored [102R].

Phentermine

[SED-15, 2804; SEDA-31,

9; SEDA-32, 17] Cardiovascular Ventricular tachycardia/ fibrillation in an otherwise healthy 48-yearold woman who was taking no medications other than phentermine was attributed to sympathetic activation [103A]. The cardiac safety concern of phentermine suggested by these authors has been debated [104r].

Sibutramine

[SED-15, 3131; SEDA-30, 7; SEDA-31, 9; SEDA-32, 17] Cardiovascular Acute myocardial infarction in a 24-year-old man with a low risk of atherosclerosis, possibly associated with sibutramine, has been reported [105A]. Other causes were ruled out, including

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cocaine abuse, viral myocarditis, aortic dissection, hypercoagulable states, and autoimmune vasculitis. Susceptibility factors Genetic Patient selection based on candidate genes may enhance the response to sibutramine in obesity [106C].

Rimonabant

[SEDA-32, 19]

Rimonabant has been withdrawn because of psychiatric adverse effects [107r, 108r, 109r], including, in one case, a major depressive episode with melancholic features that resolved after withdrawal of rimonabant [110A]. In a placebo-controlled trial in obesity there was an excess risk of psychiatric reactions (43% versus 28%) [111C]. Systematic reviews In a systematic review of 28 randomized placebo-controlled trials lasting 12–24 months in adults using licensed doses of orlistat (16 trials), sibutramine (7 trials), and rimonabant (5 trials), the risk ratios (RRs) for withdrawal because of adverse events were significantly increased for rimonabant (2.00; CI ¼ 1.66, 2.41) and orlistat (1.59; 1.21, 2.08), but not sibutramine (0.98; 0.68, 1.41) [112M]. Compared with placebo, the risk difference for rimonabant was 7% (NNTH 14) and for orlistat 3% (NNTH 39). The most common adverse events that led to withdrawal were gastrointestinal with orlistat (40%) and psychiatric with rimonabant (47%). In another systematic review of nine published randomized placebo-controlled trials of rimonabant in 9635 adults, rimonabant 20 mg/day was associated with increased risks of adverse events (RR ¼ 1.35; 95% CI ¼ 1.17, 1.56), withdrawal (RR ¼ 1.79; 95% CI ¼ 1.35, 2.38), psychiatric adverse events (RR ¼ 2.35; 95% CI ¼ 1.66, 3.34), and nervous system adverse events (RR ¼ 2.35; 95% CI ¼ 1.49, 3.70); the NNTH for psychiatric adverse events was 30 [113M].

14

Cardiovascular Atrial fibrillation has been attributed to rimonabant in two cases [114A]. • A man who took rimonabant for 5 weeks developed palpitation, fatigue, and exertional dyspnea. He had atrial fibrillation with a ventricular rate of 98–135/minute. No other cause of atrial fibrillation was found and rimonabant was withdrawn. After 2 weeks his rhythm had reverted to sinus rhythm. The patient refused re-challenge and 9 months later was still in sinus rhythm. • After taking rimonabant for 3 weeks a man developed dizziness, palpitation, and exertional dyspnea. He had atrial fibrillation, for which no other causes were found. Rimonabant was withdrawn and 10 days later the rhythm had reverted to sinus rhythm with first-degree atrioventricular block.

Nervous system Rimonabant has been reported to cause partial seizures in a patient with a history of generalized epilepsy [115A] • A 52-year-old obese man with hypertension, diabetes mellitus, and a history of absences and two generalized tonic–clonic seizures at ages 4–15 years, but who had been seizure free for over 20 years took rimonabant 20 mg/day and 2 months later started to have nocturnal partial seizures consisting of a stereotypical feeling of falling into a deep hole, often followed by right leg jerks lasting 3 minutes on average. These seizures were totally different from the generalized seizures he had had in his youth. After withdrawal of rimonabant the seizures disappeared. A few weeks later he restarted rimonabant and 3 days later his partial seizures returned. Routine and sleep-deprivation electroencephalography showed frequent epileptiform paroxysms, consisting of generalized irregular slow waves intermingled with frontal and temporal spikes and focal epileptiform abnormalities in the left temporal lobe, as in previous recordings over 20 years before. The seizures again resolved immediately after rimonabant withdrawal, and 3 months later sleep-deprived electroencephalography showed mainly focal (left > right) temporal epileptiform discharges and generalized irregular slow-wave paroxysms.

A proconvulsant effect of rimonabant is not unexpected, since cannabinoids have anticonvulsant properties in animals. Psychological In a double-blind, placebocontrolled study in 30 healthy adults, a single dose of rimonabant 20 mg did not alter

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subjective mood but did reduce incidental recall of positive self-relevant adjectives, an effect opposite to that seen with antidepressants [116c]. Rimonabant did not affect other measures of emotional processing. Drug–drug interactions Ciclosporin The interaction of rimonabant with ciclosporin (n ¼ 10) and tacrolimus (n ¼ 8) has been assessed in stable renal transplant recipients [117c]. Rimonabant increased the AUC0!12 of ciclosporin by 20%. The authors concluded that this effect was probably of marginal clinical relevance since trough concentrations were unaltered. Tacrolimus pharmacokinetics were unaffected by rimonabant.

Tesofensine Tesofensine is an inhibitor of neuronal reuptake of dopamine, noradrenaline, and serotonin. There has been considerable interest in this investigational drug for weight reduction as an adjunct to energy restriction. Placebo-controlled studies In a phase II clinical trial of tesofensine in Denmark there was a significant reduction in body weight compared with placebo [118C]. The common adverse events were dry mouth, nausea, constipation, diarrhea, and insomnia. After 24 weeks, tesofensine 0.25 and 0.5 mg/day had no significant effect on systolic and diastolic blood pressures compared with placebo, but heart rate increased by 7.4/minute. However, there is a reduction in blood pressure of 3–5 mmHg systolic and 2–3 mmHg diastolic with weight losses of 4–5 kg, and increases of 1 mmHg in systolic pressure and 2–3 mmHg in diastolic pressure among participants taking tesofensine 0.5 mg compared with controls seem to suggest that tesofensine can increase blood pressure [119r]. Drug development in the field of weight reduction has regularly faced pharmacovigilance hurdles, because anorexigenic drugs affect various neurotransmitter systems and can lead to serious adverse

Central nervous system stimulants and drugs that suppress appetite

effects. It has been suggested that the bar should be set high when new drugs are introduced for obesity, in order to avoid repetition of drug scandals related to antiobesity drugs [120r].

DRUGS USED IN ALZHEIMER'S DISEASE [SEDA-30, 8; SEDA-31, 10; SEDA-32, 19] Observational study In an open study in patients with ADHD rivastigmine produced sustained inhibition of acetylcholinesterase and butyrylcholinesterase, whereas donepezil and galantamine did not inhibit butyrylcholinesterase and were associated with increases in CSF acetylcholinesterase [121c]. The clinical implications of these findings require evaluation. Smell identification function could be useful as a clinical measure for assessing treatment response in Alzheimer's disease [122c]. Improved olfaction with donepezil correlated strongly with improvement in Clinician Interview Based Impression of Change plus Caregiver Input (CIBIC-plus), and predicted global improvement better than other measures, such as cognition. These findings are biologically plausible, because olfaction depends on brain regions that are primarily affected by Alzheimer's disease.

Donepezil [SED-15, 1179; SEDA-30, 8; SEDA-31, 10; SEDA-32, 19] Observational studies Donepezil improved cognitive dysfunction in patients with Alzheimer's disease, but also ameliorated behavioral and psychological symptoms of dementia (BPSD), including hallucinations/ delusions, wandering, and aggression [123c]. Donepezil also alleviated the burden on care-givers for about 60% of patients. There were 30 reports of adverse drug

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reactions from 23 of 289 patients, an incidence rate of 8%. The major adverse reactions were five cases of upper abdominal discomfort (1.73%) and two each of anemia, insomnia, delusions, dizziness, and gait disorder (0.69%). Serious reactions were one case each of anemia, anorexia, dizziness, upper abdominal discomfort, and gait disorder. In a study of the effect of donepezil 10 mg/ day the progression of cognitive dysfunction was slowed [124c]. The incidence of adverse events was 11.5% lower than the rate of 40% or higher recorded during previous clinical trials. The incidence of adverse events was 12%, lower than the rate of 40% or higher that has been recorded during previous trials in Japan. Seven of the 61 patients enrolled in this study were forced to withdraw because of adverse events that occurred within 1 month of treatment with donepezil 10 mg/day. If longer-term donepezil treatment is planned, it is appropriate to start with a dose of 5 mg/day and then increase to 10 mg/day to minimize the adverse effects, particularly those that occur at the start of treatment Placebo-controlled studies In a 6-month, randomized, double-blind, placebo-controlled study of 189 Japanese patients, 68 were given placebo, 69 were given donepezil 5 mg/day, and 52 were given donepezil 10 mg/day [125c]. Those who took donepezil 10 mg/day with little or no interruption achieved the best long-term outcome. Overall, 177 patients (93.7%) had at least one adverse event. There were severe adverse events in 15 patients (7.9%) and serious adverse events in 33 (17.5%). Since altered expression of central muscarinic and nicotinic acetylcholine receptors in hippocampal and cortical regions might contribute to cognitive impairment in patients with schizophrenia, increasing cholinergic activity might help improve cognition in these patients. With this in mind, donepezil, a cholinesterase inhibitor, has been examined in a 12-week, multicenter, placebo-controlled, double-blind, parallel-group study in 250 patients with schizophrenia or schizoaffective disorder

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who were clinically stabilized on aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone, alone or in combination [126C]. They were randomized to cotreatment with donepezil (5 mg/day for 6 weeks and then 10 mg/day for 6 weeks; mean age 41 years; n ¼ 121) or with placebo (mean age 40 years; n ¼ 124). Adjunctive donepezil therapy did not significantly improve cognitive impairment in moderately ill patients with schizophrenia or schizoaffective disorder maintained on antipsychotic drugs. Treatment-emergent adverse events were reported by 55% of those who took donepezil and 61% of those who took placebo; the frequency of severe adverse events was similar in the two groups (8.3% and 8.9% respectively) as were serious adverse events (5.8% and 5.6%). There were no differences in the frequency of dosage reduction or temporary study drug withdrawal because of adverse events (donepezil, n ¼ 3; placebo n ¼ 2) or in the frequency of adverse event-related withdrawal (donepezil n ¼ 10; placebo, n ¼ 13). The most common adverse events were headache and those affecting the digestive and nervous systems; treatment groups were comparable with regard to changes in vital signs and laboratory analyses throughout the study.

Huperzine Huperzine, an alkaloid from the plant Huperzia serrata, is a potent and highly selective, reversible acetylcholinesterase inhibitor. Systematic reviews In a meta-analysis of the efficacy and safety of huperzine-A 300–500 micrograms/day in Alzheimer's disease, the estimated effect size on the Mini-Mental State Examination (MMSE) and Activity of Daily Living (ADL) increased over the treatment time. Most of the adverse effects were cholinergic and there were no serious adverse events [127M]. The meta-analysis included four double-blind, randomized, placebo-controlled trials, with more than 20 participants

Reginald P. Sequeira

in each arm. All were carried out in China. In all, 474 patients were included, 235 in the huperzine group and 237 in the control group. The trial durations ranged from 8 to 24 weeks; the longer duration resulted in better efficacy on MMSE scores. Adverse symptoms included tachycardia, low energy, dry mouth, and hypertension at multiple-dose ranges; bradycardia, headache, and intense dreams at a dose of 400 micrograms bd; muscle cramps at 400 micrograms bd; arthralgia at 300–400 micrograms bd; and nausea, drowsiness, and diarrhea. A meta-analysis has shown that most clinical studies of huperzine showed promising results in Alzheimer's disease; however, most of the studies were found to have methodological shortcomings [128M], further confirmed recently [129R].

Memantine

[SED-15, 2250;

SEDA-32, 20] The efficacy and adverse effects of memantine have been reviewed [130R]. The following adverse effects occur in more than 2% of patients: fatigue, pain, hypertension, dizziness, headache, constipation, vomiting, back pain, confusion, somnolence, hallucinations, coughing, dyspnea, agitation, falls, injuries, urinary incontinence, diarrhea, bronchitis, insomnia, urinary tract infection, influenza-like symptoms, abnormal gait, depression, upper respiratory tract infections, anxiety, peripheral edema, nausea, anorexia, and arthralgia. Memantine undergoes both hepatic and renal elimination. In patients with severe liver or kidney impairment lower dosages are required, but in patients with mild to moderate renal impairment, no adjustment is necessary.

Rivastigmine

[SED-15, 3072; SEDA-30, 10; SEDA-31, 11; SEDA-32, 20] Observational studies In a multicenter study of a transdermal rivastigmine patch

Central nervous system stimulants and drugs that suppress appetite

(9.5 mg/day) for up to 1 year, 870 of 1195 patients completed the double-blind phase and entered the open extension [131c]. Nausea and vomiting (16% and 14% respectively) were the most frequent adverse effects. Skin tolerability at the site of application was generally good, with no, slight, or mild irritation as the most common application site reaction. Erythema (7.7%) and pruritus (5.6%) were moderate or severe reactions to rivastigmine, and 3.7% withdrew owing to reactions at the site of application. There was also a trend towards an increase in adverse skin reactions over time. Rivastigmine was withdrawn in 73 patients (8.4%) during the extension phase because of reactions at the site of application (3.6%) or gastrointestinal disorders (2.9%). In a prospective, non-interventional, postmarketing observational study in Taiwan, rivastigmine 3–6 mg/day was well tolerated by patients with Alzheimer's disease [132C]. In 261 patients, the mean duration of rivastigmine exposure was 151 days. Of 253 patients, 155 (61%) reported at least one adverse event, the most frequent of which were psychiatric (9.1%) and gastrointestinal (8.3%). The most common adverse events were mild dizziness (5.5%), insomnia (5.1%), anorexia (4.0%), constipation (4%), vomiting (4%), and nausea (3.6%). In all, 12 patients (4.7%) reported 16 serious adverse events, including two deaths, one case of syncope with head trauma, one peptic ulcer, and six other hospitalizations. None was reported to be related to rivastigmine. The authors stressed the importance of starting with a low dose of rivastigmine and gradually increasing the dosage. Systematic reviews There is evidence that a lower dose small transdermal patch is associated with fewer adverse effects than capsules or a higher dose larger patch, with efficacy comparable to both [133M]. Liver Hepatotoxicity associated with transdermal rivastigmine use has been reported [134A].

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17

• Two months after starting to use a rivastigmine transdermal patch (4.6 mg/day, increased to 9.5 mg/day 1 month later), an 84-year-old woman developed fatigue, weakness, abdominal bloating, yellowish eyes, dark urine, and a transient rash. Her other medications included aspirin, ramipril, and valproic acid. She had a raised total bilirubin concentration with a conjugated fraction of 36 mmol/l, raised aminotransferases, alkaline phosphatase, and gamma-glutamyl transpeptidase activities, and an eosinophilia. Tests for hepatic virus markers and autoantibodies were negative. Ultrasonography showed a normal echogenic liver and no bile duct or gall bladder abnormalities. Rivastigmine was withdrawn, and the signs and symptoms of hepatitis gradually improved. She continued taking other medications, and 5 weeks after withdrawal of rivastigmine her liver function tests were normal.

The explanation of liver toxicity in this patient is uncertain, but a hypersensitivity reaction was possible. Drug overdose An 80-year-old woman with Alzheimer's disease had an overdose when she used nine 5 cm2 transdermal patches of rivastigmine [135A]. She had fasciculation of her gastrocnemius and quadriceps muscles bilaterally. The patches were removed and the underlying skin was cleansed with soap and water. Although the working diagnosis was rivastigmine overdose, due to minimal pulmonary muscarinic findings, atropine was not used. She was instead given pralidoxime 1 g intravenously. Within 30 minutes of the end of the infusion her sweating and miosis had improved and her fasciculation had resolved. Although the use of pralidoxime is debated, a clinical trial has confirmed a significant advantage for oxime therapy in organophosphate poisoning [136C]. In poisoning with carbamates (such as rivastigmine), the clinical course tends to be mild and self-limiting, because carbamate-induced cholinesterase inhibition tends to be mild and spontaneously reversible. This case of apparently safe and effective pralidoxime administration without the use of atropine in a patient with transdermal rivastigmine toxicity reinforces recent data demonstrating the potential safety of pralidoxime in carbamate poisoning.

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hemodialysis. Am J Emerg Med 2009; 27 (253): e3–6. [94] Schmidt A, Karlson-Stiber C. Caffeine poisoning and lactate rise: an overlooked toxic effect? Acta Anaesth Scand 2008; 52: 1012–4. [95] Nobutoki T, Takahashi JY, Ihara T. A 5year-old boy with nonconvulsive status epilepticus induced by theophylline treatment. No To Hattatsu 2008; 40(4): 328–32. [96] Kato Z, Yamagishi A, Nakamura M, Kondo N. Theophylline-associated status epilepticus in an infant: pharmacokinetics and the risk of suppository use. World J Pediatr 2009; 5(4): 316–8. [97] Liu PH, Lee BJ, Wang CY, Hung DZ. Acute pancreatitis after severe theophylline overdose. Clin Toxicol (Phila) 2008; 46(10): 1103. [98] Li M, Cheung BMY. Pharmacotherapy of obesity. Br J Clin Pharmacol 2009; 68: 804–10. [99] Heal DJ, Gosden J, Smith SL. Regulatory challenges for new drugs to treat obesity and comorbid metabolic disorders. Br J Clin Pharmacol 2009; 68: 861–74. [100] McGill JB, Haffner S, Rees TJ, Sowers JR, Tershakovec AM, Weber M. Progress and controversies: treating obesity and insulin resistance in the context of hypertension. J Clin Hypertens 2009; 11: 36–41. [101] Willemen MJC, Mantel-Teeuwisse AK, Straus SMJM, Leufkens HGM, Egberts ACG, Sturkenboom MCJM. Cardiovascular and psychiatric risk profile and patterns of use in patients starting anti-obesity drugs. Pharmacoepidemiol Drug Saf 2009; 18: 631–8. [102] Sargent BJ, Moore NA. New central targets for the treatment of obesity. Br J Clin Pharmacol 2009; 68: 852–60. [103] Makaryus JN, Makaryus AN. Cardiac arrest in the setting of diet pill consumption. Am J Emerg Med 2008; 26(732): e1–3. [104] Rothman RB, Hendricks EJ. Phentermine cardiovascular safety. Am J Emerg Med 2009; 27: 1010–3. [105] Eroglu E, Gemici G, Bayrak F, Kalkan AK, Degertekiin M. Acute myocardial infarction in a 24 year-old man possibly associated with sibutramine use. Int J Cardiol 2009; 137: e43–5.

Central nervous system stimulants and drugs that suppress appetite [106] Grudell ABM, Sweetser S, Camilleri M, Eckert DJ, Vazquez-Rocque MI, Carlson PJ, Burton DD, Braddock AE, Clark MM, Graszer KM, Kalsy SA, Zinsmeister AR. A controlled pharmacogenetic trial of sibutramine on weight loss and body composition in obese and overweight adults. Gastroenterology 2008; 135: 1142–54. [107] Stapleton JA. Trial comes too late as psychiatric side effects end hope for rimonabant. Addiction 2009; 104(2): 277–8. [108] Taylor D. Withdrawal of rimonabant— walking the tightrope of 21st century pharmaceutical regulation? Curr Drug Saf 2009; 4(1): 2–4. [109] Anonymous. Rimonabant: depression and suicide. Prescrire Int 2009; 18(99): 24. [110] de Mattos Viana B, Prais HA, Daker MV. Melancholic features related to rimonabant. Gen Hosp Psychiatry 2009; 31(6): 583–5. [111] Nissen SE, Nicholls SJ, Wolski K, RodésCabau J, Cannon CP, Deanfield JE, Després JP, Kastelein JJ, Steinhubl SR, Kapadia S, Yasin M, Ruzyllo W, Gaudin C, Job B, Hu B, Bhatt DL, Lincoff AM, Tuzcu EM. STRADIVARIUS investigators. Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: the STRADIVARIUS randomized controlled trial. JAMA 2008; 299(13): 1547–60. [112] Johansson K, Neovius K, DeSantis SM, Rössner S, Neovius M. Discontinuation due to adverse events in randomized trials of orlistat, sibutramine and rimonabant: a meta-analysis. Obes Rev 2009; 10(5): 564–75. [113] Chavez-Tapia NC, Tellez-Avila FI, Bedogni G, Crocè LS, Masutti F, Tiribelli C. Systematic review and metaanalysis on the adverse events of rimonabant treatment: considerations for its potential use in hepatology. BMC Gastroenterol 2009; 9: 75. [114] Cocco G, Chu D. Rimonabant may induce atrial fibrillation. BMJ 2009; 338: b1061. [115] Braakman HM, van Oostenbrugge RJ, van Kranen-Mastenbroek VH, de Krom MC. Rimonabant induces partial seizures in a patient with a history of

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generalized epilepsy. Epilepsia 2009; 50 (9): 2171–2. Horder J, Cowen PJ, Di Simplicio M, Browning M, Harmer CJ. Acute administration of the cannabinoid CB1 antagonist rimonabant impairs positive affective memory in healthy volunteers. Psychopharmacology (Berl) 2009; 205(1): 85–91. Amundsen R, Asberg A, Robertsen I, Vethe NT, Bergan S, Hartmann A, Midtvedt K. Rimonabant affects cyclosporine a, but not tacrolimus pharmacokinetics in renal transplant recipients. Transplantation 2009; 87(8): 1221–4. Astrup A, Madsbad S, Breum L, Jensen TJ, Kroustrup JP, Larsen TM. Effect of tesofensine on body weight loss, body composition, and quality of life in obese patients: a randomized, doubleblind, placebo-controlled trial. Lancet 2008; 372: 1906–13. Tsai AG. Tesofensine and weight loss. Lancet 2009; 373: 719. Sommet A, Pathak A, Montastruc J-L. Tesofensine and weight loss. Lancet 2009; 373: 719. Nordberg A, Darreh-Shori T, Peskind E, Soininen H, Mousawi M, Eagle G, Lane R. Different cholinesterase inhibitor effects on CSF cholinesterase in Alzheimer's patients. Curr Alzheimer Res 2009; 6: 4–14. Velayudhan L, Lovestone S. Smell identification test as a treatment response marker in patients with Alzheimer's disease receiving donepezil. J Clin Psychoparmacol 2009; 29: 387–90. Tanaka T, Kauzi H, Morihara T, Sadik G, Kudo T, Takeda M. Post-marketing survey of donepezil hydrochloride in Japanese patients with Alzheimer's disease with behavioral and psychological symptoms of dementia (BPSD). Psychogeriatrics 2008; 114–23. Nozawa M, Ichimiya Y, Nozawa E, Utumi Y, Sugiyama H, Murayama N, Iseki E, Arai H. Clinical effects of high oral dose of donepezil for patients with Alzheimer's disease in Japan. Psychogeriatrics 2009; 9: 50–5. Homma A, Imai Y, Tago H, Asada T, Shigeta M, Iwamoto T, Takita M,

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Arimoto I, Koma H, Takase T, Ohbayashi T. Long-term safety and efficacy of donepezil in patients with severe Alzheimer's disease: results from a 52week, open-lable, multicenter, extension study in Japan. Dement Geriatr Cogn Disord 2009; 27: 232–9. Keefe RS, Malhotra AK, Meltzer HY, Kane JM, Buchanan RW, Murthy A, Sovel M, Li C, Goldman R. Efficacy and safety of donepezil in patients with schizophrenia or schizoaffective disorder: significant placebo/practice effects in a 12-week, randomized, double-blind, placebocontrolled trial. Neuropsychopharmacology 2008; 33(6): 1217–28. Wang B-S, Wang H, Wei Z-H, Song Y-Y, Chen H-Z. Efficacy and safety of natural acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer's disease: an updated meta-analysis. J Neural Transm 2009; 116: 457–65. Li J, Wu HM, Zhou RL, Liu GJ, Dong BR. Huperzine A for Alzheimer's disease. Cochrane Database Syst Rev 2008; 2: CD005592. Desilets AR, Gickas JJ, Dunican KC. Role of huperzine A in the treatment of Alzheimer's disease. Ann Pharmacother 2009; 43: 514–8. Thomas SJ, Grossberg GT. Memantine: a review of studies into its safety and efficacy in treating Alzheimer's disease and other dementias. Clin Interv Aging 2009; 4: 367–77.

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[131] Grossberg G, Sadowsky C, Forstl H, Frolich L, Nagel J, Tekin S, Zechner S, Ros J, Orgogozo J-M. Safety and tolerability of the rivastigmine patch. Results of a 28-week open-label extension. Alzheimer Dis Disord 2009; 23: 158–64. [132] Chiu P-Y, Dai D-E, Hsu H-P, Lee C, Lin J-J, Kuo H-C, Huang Y-C, Liu Y-C, Tsai C-P. Safety/tolerability and efficacy of rivastigmine in Taiwanese patients with Alzheimer's disease. A prospective postmarketing surveillance study. Clin Drug Invest 2009; 29: 729–38. [133] Birks J, Grimley Evans J, Lakovidou V, Tsolaki M, Holt FE. Rivastigmine for Alzheimer's disease. Cochrane Database Syst Rev 2009; 2: CD001191. [134] Mumoli N, Carmignani G, Luschi R, Cei M, Chiavistelli P. Hepatitis with cholestasis caused by rivastigmine transdermal patch. Am J Gastroenterol 2009; 104: 2859–60. [135] Hoffman RS, Manini AF, RussellHaders AL, Felberbaum M, MercurioZappala M. Use of pralidoxime without atropine in rivastigmine (carbamate) toxicity. Hum Exp Toxicol 2009; 28: 599–602. [136] Pawar KS, Bhoite RR, Pillay CP, Chavan SC, Malshikare DS, Garad SG. Continuous pralidoxime infusion versus repeated bolus injection to treat organophosphorus pesticide poisoning: a randomized controlled trial. Lancet 2006; 368: 2136–41.

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2

Antidepressant drugs

GENERAL Comparative rates of adverse effects with different antidepressants One limitation of meta-analyses is that they depend on the particular head-to-head comparisons chosen by the researchers, be they industry-based or academic-based. Multiple-treatments meta-analysis is a statistical technique that was developed to extract data from multiple randomized controlled trials to test for comparative efficacy and tolerability of agents that were not compared in individual reports. The relative efficacy and tolerability of 12 different antidepressants have been studied in a multiple-treatments meta-analysis, which showed that escitalopram, sertraline, bupropion, and citalopram were better tolerated than the other antidepressants studied [1M]. The cumulative probabilities of being among the most acceptable four treatments were: escitalopram (28%), sertraline (27%), bupropion (19%), citalopram (19%), milnacipram (7%), mirtazapine (4%), fluoxetine (3%), venlafaxine (1%), duloxetine (1%), fluvoxamine (0.4%), paroxetine (0.2%), and reboxetine (0.1%). Susceptibility factors Cardiac disease In a comprehensive review of all (old and new) antidepressant medications and cardiovascular disease, it was concluded that tricyclic

Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00002-7 # 2011 Elsevier B.V. All rights reserved.

antidepressants should be avoided in those with or at risk of cardiovascular disease; that reboxetine, duloxetine, and venlafaxine increase the blood pressure; and that there is a dearth or absence of data about the use of many antidepressants in patients with cardiac disease [2R].

MONOAMINE OXIDASE INHIBITORS [SED-15, 2371; SEDA-32, 32]

Moclobemide Drug–drug interactions Carbamazepine and valproate The mood stabilizers carbamazepine and valproate are often used in combination with antidepressants in patients with unipolar or bipolar affective disorder. The effects of valproate and carbamazepine on the steady-state pharmacokinetics of moclobemide and two metabolites have been studied in a non-randomized crossover study in 21 patients with unipolar depression [3c]. Valproate had no effect, but carbamazepine was associated with a 35% reduction in moclobemide AUC, a 28% reduction in Cmax, and a 41% reduction in clearance after 4 weeks of co-administration. These changes were interpreted as being due to induction carbamazepine of the metabolism of moclobemide and its main metabolite. However, there was no concurrent loss of efficacy, throwing into doubt the clinical significance of these significant kinetic effects. 25

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SELECTIVE SEROTONIN RE-UPTAKE INHIBITORS (SSRIS) [SED-15, 3109; SEDA-30, 16; SEDA-31, 18; SEDA-32, 33] Cardiovascular Carotidynia, a focal cervical pain that involves the anatomical territory of the affected carotid artery and often radiates to the ipsilateral side of the face or ear, has been attributed to fluoxetine and citalopram [4A]. • After taking fluoxetine 20 mg for 5 months, a 43-year-old man developed left intercostal pain, which became bilateral, steadier, episodic, and stabbing on deep breathing and movement of the trunk. Two weeks later, he noted a tender swollen mass at the level of the right carotid bifurcation, accompanied by a severe pulsating pain, which radiated to the ipsilateral jaw on contralateral head movement. Cervical magnetic resonance and angiomagnetic resonance studies showed abnormal soft tissue thickening of the right common carotid and its bifurcation. Fluoxetine was withdrawn and the carotidynia and intercostal pain resolved completely. Fluoxetine was restarted on two further occasions, and the pain recurred within 4 weeks and resolved on withdrawal. The same symptoms recurred after challenge with citalopram on two occasions.

SSRIs and emergent suicidal ideation Further data have clarified the highly controversial relation between SSRI antidepressants and emergent suicidality. Prior studies have suggested that this adverse effect may be more likely to occur in children, adolescents, and young people than in older adults (SEDA31, 18; SEDA-32, 29). The findings of three prospective trials of depressed or anxious children and adolescents have thrown new light on this question. Results have been reported from the Treatment of Adolescents with Depression Study (TADS) [5C, 6C], in which 439 adolescents were randomly allocated to 12 weeks of fluoxetine, cognitive behavioral therapy, the combination of these, or clinical

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management with placebo. Those allocated initially to placebo received open active treatment as clinically indicated after 12 weeks, and all subjects were followed for 36 weeks. There were no differences between the groups in the rates of suicidal events (suicide attempts, preparation for suicidal behavior, or suicidal ideation) during either the initial 12-week double-blind phase or the 36-week open treatment phase. There were no suicides in either group. In the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study [7C], 334 depressed adolescents, who had not responded to a previous trial with an SSRI antidepressant, were randomized to either another SSRI or venlafaxine, with or without cognitive behavioral therapy. There were no significant differences between the groups in the rates of suicidal and non-suicidal self-injury, although the significance of this was limited by the lack of a placebo comparison group [8r]. In 488 children and adolescents (aged 7–17 years) with an anxiety disorder who were randomized to 12 weeks of sertraline up to 200 mg/day, cognitive behavioral therapy, the combination of these, or placebo, suicidal and homicidal ideation were no more common with sertraline than placebo; no child attempted suicide [9C]. Combining the findings of these childhood and adolescent studies, the two large placebo-controlled trials [5C, 9C] were consistent in not demonstrating an increased rate of suicidal thoughts or behavior with SSRI antidepressants compared with placebo, while Brent et al. [7C] found no difference between an SSRI and venlafaxine. Interpreting these controlled studies conservatively, the data suggest either that these agents do not increase the risk of suicidal thoughts or behavior in depressed or anxious children and adolescents, or that such outcomes are uncommon. With respect to the adult literature, a pooled analysis, by Pfizer-employed staff, of sertraline placebo-controlled trials, using the FDA-defined search method, showed no evidence of an increase in the risk of suicidality compared with placebo in those who took sertraline. In the open citalopram

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phase of the STAR*D depression trial [10C] 74% of the 1909 subjects with baseline suicidal ideation (i.e. before they started to take citalopram) improved by the final visit, while 4% worsened [11M]. Of 1721 without baseline suicidal ideation, 7% experienced emergence of such thoughts by the first post-baseline visit, but 63% of these had no suicidal ideation at their final visit. Finally, the effect of the warning issued by the UK Medicines and Healthcare products Regulatory Authority (MHRA) in December 2003, not to prescribe SSRI antidepressants, except fluoxetine, for those younger than 18 years, has been examined [12C]. Prescriptions fell significantly (by 51%) during 2000–2006. However, there were no changes in the rates of non-fatal self-harm or self-poisoning. Skin SSRI-induced photosensitivity is uncommon. Three cases have been reported, in association with sertraline [13A] and with fluvoxamine and paroxetine [14A]. Sexual function SSRIs can cause sexual dysfunction, particularly reduced libido, impaired orgasm in women, and inhibition of ejaculation or erectile difficulties in men. There have been two reports of unusual male sexual dysfunction. In two cases of spermatorrhea (excessive emission of semen without orgasm or erection) in men taking fluvoxamine, the problem resolved on drug withdrawal [15A]. Spontaneous ejaculations occurred daily in a 27-yearold man after he had taken citalopram for 2 weeks [16A]. They were unrelated to sexual fantasies, arousal, erection, or any sensation of orgasm and resolved on drug withdrawal. They did not recur when he took paroxetine. There have been two reports of the management of SSRI-induced sexual adverse effects. First, in an 8-week prospective double-blind placebo-controlled trial of sildenafil 50–100 mg/day in 98 previously sexually functioning premenopausal women whose major depression had remitted on SSRIs, but who were also experiencing sexual dysfunction, sildenafil was associated

27

with a significant reduction in adverse sexual effects [17C]. Secondly, in an 8-week open study, mirtazapine produced significant reductions in SSRI-induced sexual dysfunction in 49 outpatients (men and women) [18c].

Antidepressants in pregnancy [SEDA-30, 16; SEDA-31, 19; SEDA-32, 31] Intense interest in the potential for SSRI antidepressants to have teratogenic and adverse pregnancy outcomes continues, and four further major data-based reports have appeared [19C, 20C, 21C, 22C], as well as a report on the management of depression in pregnancy from two leading US professional bodies [23S] and three leading editorials or commentaries [24r, 25r, 26r]. Previous reports had suggested that SSRIs can cause cardiovascular abnormalities, and the strongest evidence related to paroxetine. However, the relative contributions of these medications and the effect of depressive illness have remained uncertain. In a prospective study of pregnant women who had contacted teratology information services in Israel, Italy, and Germany because of first-trimester exposure to fluoxetine (n ¼ 346) or paroxetine (n ¼ 463), compared with a control group (n ¼ 1467) who had contacted these services regarding exposure to non-teratogenic agents during the same time period, miscarriage rates were higher after exposure to fluoxetine, but this was not significantly different from controls after accounting for other factors such as smoking rates and maternal age [19C]. After exclusion of genetic and cytogenetic anomalies, there were higher rates of major anomalies after exposure to fluoxetine (4.7%) and paroxetine (5.2%) than in controls (2.5%), and most of this was related to cardiovascular anomalies (fluoxetine 2.8%; paroxetine 2.0%; controls 0.6%). After accounting for relevant confounders, fluoxetine remained significantly associated with higher rates of cardiovascular anomalies (OR ¼ 4.47; 95% CI ¼ 1.31, 15).

28

In a prospective observational study the separate effects of SSRI antidepressants and depression in 238 women were assessed at 20, 30, and 36 weeks of gestation, and neonatal outcomes were determined on blinded review of delivery records and infant examinations [20C]. The women were categorized into three exposure groups: (i) no SSRIs, no depression (n ¼ 131); (ii) SSRI exposure, either continuous (n ¼ 48) or partial (i.e. at some point during the pregnancy; n ¼ 23); and (iii) no SSRI exposure, but depression that was either continuous (n ¼ 14) or partial (i.e. at some point during the pregnancy; n ¼ 22). Infants who were exposed to either SSRIs (RR ¼ 3.56; 95% CI ¼ 1.40, 9.01) or continuous depression (RR ¼ 4.25; 95% CI ¼ 1.06, 15) throughout the pregnancy were more likely to be born before term than infants with no exposure to SSRIs or depression. However, after controlling for maternal age and race, only continuous SSRI exposure remained significantly related to the risk of preterm delivery (RR ¼ 5.43; 95% CI ¼ 1.98, 15). Neither exposure to an SSRI nor depression increased the risk of minor physical abnormalities. In a study of a Danish population-based cohort of 493 113 children, in which four nationwide registers were linked (births; medicinal products; fertility; and hospital diagnoses), redemptions for SSRIs during early pregnancy (defined as up to 112 days of gestation) were not associated with major anomalies overall, but were associated with a greater risk of septal heart defects (OR ¼ 1.99; 95% CI ¼ 1.13, 3.53) [21C]. This was significant for sertraline (OR ¼ 3.25; 95% CI ¼ 1.21, 8.75) and citalopram (OR ¼ 2.52; 95% CI ¼ 1.04, 6.10), but not for paroxetine or fluoxetine. Rates were also higher when there had been redemptions for more than one type of SSRI (OR ¼ 4.70; 95% CI ¼ 1.74, 13). However, absolute increases in rates of septal heart defects were low: 0.5% in unexposed children; 0.9% in those whose mothers redeemed one SSRI; and 2.1% in those whose mothers redeemed more than one type of SSRI. In a second Danish study, this time focusing on outcomes in women who were receiving prenatal care at Aarhus University

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Hospital, the relation between in utero exposure to SSRIs (at any stage during the pregnancy) and pregnancy outcome was examined [22C]. The researchers compared outcomes in 329 women exposed to SSRIs, 4902 with a history of psychiatric illness but no SSRIs during pregnancy, and 51 770 women with no history of psychiatric illness or SSRI exposure during pregnancy. There was a greater likelihood of preterm birth in those exposed to SSRIs compared with women with no history of psychiatric illness (OR ¼ 2.0; 95% CI ¼ 1.3, 3.2). Neonates who had been exposed to SSRIs were also more likely than those with no psychiatric history to be admitted to a neonatal intensive care unit (OR ¼ 2.4; 95% CI ¼ 1.7, 3.4) and to have a low Apgar score (<8) (OR ¼ 4.4; 95% CI ¼ 2.6, 7.6). There were similar differences in the exposed group compared with those with a psychiatric history but who had not been exposed to these medications. What conclusions can be drawn from these four studies? First, the reports of Diav-Citrin et al [19C] and Pedersen et al [21C] confirm prior reports of increased rates of cardiovascular anomalies with SSRIs, suggesting that this is a class effect rather than specific to paroxetine, as some previous studies had suggested. The report of Diav-Citrin highlights the importance of accounting for other potential confounders, such as smoking and maternal age, while that of Pedersen et al suggests that the main anomaly is that of septal heart defects and that the use of multiple SSRIs may further increase risk. Second, the studies of Wisner et al [20C] and Lund et al [22C] are consistent in demonstrating higher rates of preterm deliveries in neonates exposed to SSRIs. Wisner et al examined for the effect of depression, but found no convincing statistical evidence for an additional effect of depression independent of SSRI exposure. Lund et al extended the findings of higher rates of premature delivery, demonstrating the greater rates of poor physical health in exposed neonates, who had higher rates of low Apgar scores and neonatal intensive care admissions. While they could not examine the effect of

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depression during pregnancy, Lund et al found no evidence of an effect of pre-existing psychiatric diagnosis. In a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists, based on a comprehensive review of the literature before the publication of the above four studies, the authors concluded that while there had been reports linking antidepressants to both fetal anomalies and neonatal dysfunction, the effect of confounding factors such as depressive symptoms during pregnancy had not been adequately investigated [23S]. The recent studies of Wisner et al and Lund et al suggest that the effect of SSRI antidepressants is unrelated to current depression or preexisting psychiatric illness. Susceptibility factors Genetic There has been a growing number of reports of attempts to identify genetic predictors of the adverse effects of SSRIs, largely arising out of two large effectiveness trials, the US STAR*D [27R, 28R] and the European GENDEP project. Using the STAR*D dataset, Perlis et al looked for genetic predictors of sexual dysfunction in depressed patients taking citalopram, and found an association with the glutamatergic genes GR1A1, GR1A3, GR1K2, and GR1N3A [29C]. Perroud et al. from the GENDEP project, looked for genetic predictors of treatment-emergent suicidal ideation during treatment with escitalopram or nortriptyline [30C]. Polymorphisms in BDNF (the gene for brain-derived neurotrophic factor) were significantly associated with an increase in suicidal ideation. While they are of substantial interest, both of these reports should be regarded as preliminary, in the absence of replication in independent datasets.

Citalopram and escitalopram Cardiovascular Long QT syndrome is associated with an increased risk of life-threatening cardiac dysrhythmias. Torsade de pointes has been attributed to citalopram [31A].

29 • An 81-year-old man with hypertension, diabetes, end-stage renal disease, and depression, became dizzy and had an episode of torsade de pointes, with a prolonged QT interval of 572 ms (QTc 695 ms). An ECG recorded 1 month before he started to take citalopram had shown a normal QT interval.

The citalopram was withdrawn and the QT interval normalized. Infection risk In two cases Herpes zoster infection occurred within 6 weeks of treatment with citalopram [32A]. There have been no previous reports of such an association with any SSRI, and there is no definite effect of these agents on immune function. The association should therefore be regarded as provisional. Drug overdose Seizures are a recognized, albeit uncommon, complication of overdose with a number of SSRI antidepressants, but the susceptibility factors have not been elucidated. Of 241 patients who presented with overdose of citalopram, 7.5% had generalized seizures [33C]. Co-ingested venlafaxine or tricyclic antidepressants increased the risk substantially (OR ¼ 15). In the absence of co-ingested drugs, the minimum citalopram dose associated with seizures was 400 mg, with an increase in the odds ratio for seizures of 1.1 for every 100 mg increment in citalopram dose. Drug–drug interactions Propafenone A possible interaction of citalopram and the class 1C antidysrhythmic drug propafenone (which is metabolized by CYP2D6) has been reported [34A]. • An 80-year-old white woman took propafenone 900 mg/day for more than 10 years for paroxysmal atrial fibrillation without adverse effects. She then took citalopram 20 mg/day for 3 months for “anxiety attacks” and began to have episodes of chest tightness and dizziness, which became more frequent during the following months, causing several falls and requiring visits to the emergency department. However, no coronary event was diagnosed. The dose of propafenone was then halved while the citalopram was continued. She recovered and had no further symptoms 1 year later.

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Paroxetine Psychological There has been continuing debate within professional circles and the public about the effect of the newer antidepressants on personality, though there have been few data to throw light on this contentious issue. In one of the few controlled studies, personality (as measured by neuroticism and extraversion on the NEO Five-factor inventory) was examined in a placebo-controlled study of paroxetine for depression [35C], in which 120 subjects were randomized to paroxetine, 60 to placebo, and 60 to cognitive therapy. There was “normalization” of personality measures, i.e. reduced neuroticism and increased extraversion, with paroxetine compared with placebo (after statistically accounting for changes in degrees of depression). These findings suggest that SSRIs may have a pharmacological effect on personality distinct from their antidepressant action. There was no evidence of any pathological effect on personality. Susceptibility factors Genetic Impaired platelet function due to SSRIs has been well-documented, and is associated with clinical evidence of an increased bleeding tendency. The mechanism is related to the effect of SSRIs on the serotonin transporter (5-HTTLPR) in the platelet membrane, which leads to reduced platelet serotonin concentrations; however, there have been no studies of the relation of genetic polymorphisms of 5-HTTLPR to this pharmacological action. In a prospective pre–post trial of paroxetine, the effect of paroxetine was most pronounced in patients with no LA alleles or only a single allele, and was most marked in those with the S/S genotype [36C]. Drug–drug interactions Flecainide Flecainide, a class 1C antidysrhythmic agent, is metabolized by CYP2D6. In a study of the interaction of the CYP2D6*10 allele and paroxetine in an open crossover study in healthy Korean subjects, paroxetine significantly increased the AUC of flecainide and

Philip B. Mitchell

reduced its clearance in heterozygotes but had no effects in homozygotes [37C]. The CYP2D6*10 allele is one of the most common intermediate metabolism alleles in East Asians. Delirium occurred in a 69-year-old woman who had been taking paroxetine regularly for 5 years after she took flecainide for atrial fibrillation for 2 weeks; her serum flecainide concentration was markedly raised and the delirium resolved 3 days after flecainide withdrawal [38A].

Sertraline Musculoskeletal Rhabdomyolysis has again been attributed to sertraline [39A]. • A 71-year-old woman took sertraline 50 mg/day for depression and 2 months later was found to have markedly increased creatine kinase, lactate dehydrogenase, and aspartate aminotransferase activities and serum myoglobin concentration. These abnormalities resolved within 1 week of sertraline withdrawal, but recurred dramatically 2 weeks after re-introduction of sertraline. Once again, everything resolved after withdrawal of sertraline. She was successfully treated with escitalopram without recurrence of the biochemical disturbances.

Liver Hepatotoxicity has again been attributed to sertraline (SEDA-30, 16) [40A]. In this case report, it presented within 6 months of treatment in a 17-year-old boy with no other demonstrable explanation.

SEROTONIN AND NORADRENALINE RE-UPTAKE INHIBITORS (SNRIS) Psychiatric Mania and hypomania due to SNRIs have been reviewed in the light of a case of duloxetine-induced hypomania in a non-bipolar patient [41Ar]. The data suggest that SNRIs, especially venlafaxine,

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can induce mood switching in patients with bipolar depression and in certain patients with unipolar depression, and that duloxetine and milnacipran can also cause manic or hypomanic symptoms. The authors suggested starting treatment with a low dose and titrating upwards as required.

Duloxetine

[SEDA-32, 34]

Placebo-controlled studies In a placebocontrolled study of 1491 patients nausea was more frequent in those who took duloxetine (30% versus 7.1%) and weight loss was significantly greater; all of those who withdrew because of an adverse event were taking duloxetine (22%) [42C]. Systematic reviews In a systematic review of 36 experimental and observational studies duloxetine caused nausea, vomiting, and dry mouth more often than comparator drugs, but these differences did not lead to higher withdrawal rates than in patients taking SSRIs [43M]. Cardiovascular Symptomatic tachycardia has been attributed to duloxetine 20 mg/day in a 26-year-old man; it resolved on withdrawal and recurred after rechallenge; it responded to treatment with propranolol while the duloxetine was continued [44A]. An apical cardiomyopathy has also been attributed to duloxetine [45A]. Nervous system Shock-like sensations in the head (encephalastrapy [46r]) have occasionally been reported in association with antidepressants, and particularly after withdrawal of venlafaxine [47Ar]. Another report has now implicated withdrawal of duloxetine [48A]. Serotonin syndrome has been attributed to duloxetine [49A, 50A]. Psychiatric Binge eating has been attributed to duloxetine 90 mg/day in a 37-yearold woman; the behavior resolved when the dosage was reduced to 60 mg/day

31

[51A]. Such behavior might be related to altered serotonin function. Electrolyte balance Hyponatremia been attributed to duloxetine [52A].

has

• An 85-year-old woman with major depression was given duloxetine 30 mg/day and within 6 days developed an unstable gait and reduced vigilance. Her serum sodium concentration was 110 mmol/l, the serum osmolality 234 mOsm/kg, and urine osmolality (310 mOsm/kg), suggesting the syndrome of inappropriate antidiuretic hormone secretion (SIADH). She recovered after withdrawal of duloxetine.

Sexual function Increased sexual desire has been attributed to duloxetine [53A]. • A 36 year-old man who had had a right parietal lobe stroke took duloxetine 30 mg/day for 1 week and developed mild nausea and sedation were mentioned. The dose was increased to 60 mg/day and he started to have increased sexual desires and masturbated 3–4 times a day, even in front of his children or wife. There were no other hypomanic, manic, or obsessive–compulsive symptoms.

Drug overdose Overdose with duloxetine has been described in a 38-year-old man who had become suicidal within 4 days after having switched from escitalopram 20 mg/day to duloxetine 30 mg/day [54A]. He was unconscious and severely hypotensive but recovered after treatment in intensive care. The authors discussed the possibility that duloxetine had made him feel suicidal, although such an effect has not emerged in clinical trials. A 30-year-old woman with major depression and multiple sclerosis took duloxetine 1680 mg, pipamperone 380 mg, amitriptyline 250 mg and became unconscious, had a seizure, and became delirious with agitation and hallucinations; her plasma duloxetine concentration was >2000 ng/ml and the CSF concentration was 15 ng/ml [55A]. Despite the very high plasma concentration, she survived. The authors suggested that active transporters (the “blood–brain barrier”) had protected the brain.

32

Pregnancy and lactation A 29-year-old woman took duloxetine for depression during the second half of an otherwise uncomplicated pregnancy, gave birth at term to a healthy girl, and breastfed her without incident while continuing to take duloxetine [56A]. Drug–drug interactions Warfarin In 15 healthy subjects taking warfarin 2–9 mg/ day with a stable international normalized ratio (INR) of 1.5–2.0, duloxetine 60 mg for 14 days or 60 mg for 4 days then 120 mg for 10 days had no clinically or statistically significant effect on the steadystate pharmacodynamics or pharmacokinetics of warfarin [57C].

Venlafaxine and desvenlafaxine [SED-15, 3614; SEDA-30, 19; SEDA-31, 22; SEDA-32, 35] Desvenlafaxine, the major active metabolite of venlafaxine, has been relatively recently introduced as an antidepressant [58R]. It has been approved for marketing in the USA but not Europe. Placebo-controlled studies In an 8-week placebo-controlled flexible-dose (200–400 mg/day) study in 235 subjects with major depressive disorder treatment-emergent adverse effects were reported by 96% of those taking desvenlafaxine and 86% of those taking placebo; 12% of those taking desvenlafaxine withdrew because of adverse effects, nausea being the most common [59C]. Adverse effects reported by at least 5% and at a frequency of at least twice that of the placebo control group were: nausea (36%), dry mouth (31%), hyperhidrosis (20%), insomnia (16%), somnolence (15%), reduced appetite (15%), tremor (11%), blurred vision (10%), yawning (9%), sedation (9%), vomiting (9%), mydriasis (9%), middle insomnia (8%), initial insomnia (6%), erectile dysfunction (6%), constipation (6%), feeling jittery (5%), and dyspepsia (5%). In an 8-week, randomized, placebocontrolled comparison of desvenlafaxine (50 or 100 mg/day) and duloxetine in 638

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Philip B. Mitchell

subjects with major depressive disorder, 7% of those taking desvenlafaxine 100 mg/ day withdrew because of adverse events [60C]. The most frequent adverse effects were: nausea (23%), insomnia (14%), somnolence (11%), fatigue (10%), reduced appetite (9%), constipation (7%), hyperhidrosis (6%), blurred vision (5%), vomiting (4%), abnormal dreams (2%), and yawning (1%). On withdrawal by tapering at the end of the study, 27% described withdrawal symptoms, the most common being dizziness (10%), headache (5%), and nausea (5%). Liver Fulminant hepatic failure has been attributed to a combination of venlafaxine and trazodone [61A]. • A 48-year-old woman with normal liver function took venlafaxine 75 mg/day and trazodone 200 mg/day for depression and 4 months later developed increasing jaundice and encephalopathy. She had markedly raised transaminases and bilirubin. There were no other explanations for her hepatic failure, and she received an urgent liver transplantation. The pathology showed severe acute hepatitis compatible with toxic acute liver failure. She recovered fully, and had normal liver function tests 1 year later.

Drug overdose There has been growing awareness of the cardiac adverse effects of venlafaxine (SEDA-32, 35). A 51-yearold woman with no known risk factors for coronary artery disease had an episode of non-ST-elevation myocardial infarction in association with an overdose of venlafaxine [62A]. However, in a case series of 273 patients who took an overdose of venlafaxine, overdose caused only minor abnormalities in the QT and QRS intervals, and was unlikely to be associated with major dysrhythmias, except possibly with large doses (> 8 g) [63C]. The commonest cardiovascular effects were tachycardia (54% of patients) and mild hypertension (40%). Drug–drug interactions Desvenlafaxine has been reported to have minimal effect on CYP2D6 in a comparison with duloxetine, a moderate inhibitor of CYP2D6, in a randomized, open, crossover study in healthy

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subjects, in which desvenlafaxine had a minimal effect on desipramine pharmacokinetics [64C].

OTHER ANTIDEPRESSANTS Agomelatine Agomelatine is an agonist at melatonin (MT1/MT2) receptors and an antagonist at 5-HT2C receptors; it shares the latter action with other antidepressants, such as mirtazapine [65R, 66R]. Comparative studies In a 12-week randomized controlled trial in 276 depressed patients allocated to agomelatine 50 mg/ day or venlafaxine (titrated to a target dose of 150 mg/day), of those randomized to agomelatine 20% reported treatment-emergent adverse effects, the most common being nausea (12%), headache (10%), and upper respiratory tract infections (7%); 2% withdrew because of adverse effects [67C]. The rate of treatment-emergent sexual dysfunction (reduced libido in males and impaired orgasm in females) was lower than in those who took venlafaxine. Placebo-controlled studies In a 24-week placebo-controlled study in 339 patients with major depressive disorder there was a withdrawal rate of 2%; most of the adverse events were of mild to moderate intensity [68C]. The most common adverse effects of agomelatine, which occurred more frequently than with placebo, were headache (8%), back pain (6%), neck pain (2%), constipation (2%), dyspepsia (2%), and initial insomnia (2%). There were no symptoms associated with abrupt withdrawal.

Bupropion (amfebutamone) [SED-15, 108; SEDA-30, 20; SEDA-31, 22; SEDA-32, 35] Observational studies In a study of 698 000 individuals using the French Pharmacovigilance Database 2001–2004, the use of

33

bupropion during the first 3 years of its marketing in France was associated with 475 serious adverse reactions (SARs), including 21 deaths [69C]. The most common SARs were cutaneous or allergic reactions (31% of SARs), including angioedema and serum sickness-like reactions. Serious neurological reactions were frequent (23% of SARs), mostly comprising seizures. Drug overdose The incidence and nature of seizures after overdoses of bupropion XL have been reported in a study of 117 patients who presented to five poison centers in the USA [70C]. Seizures occurred in 32%, and the median dose of those who had a seizure was 4350 mg, compared with 2400 mg in those who did not. Onethird had delayed initial convulsions, defined as occurring more than 8 hours after the overdose. This suggests the need for a minimum observation period of 24 hours after overdosage with bupropion. Drug–drug interactions The inhibitory effect of bupropion on CYP2D6 metabolism has been previously demonstrated in vivo, for example by inhibition of dextromethorphan metabolism (SEDA-30, 20). An in vitro study using desipramine as substrate has suggested that this effect is due to the metabolites erythrohydrobupropion and threohydrobupropion, which were much more potent inhibitors of CYP2D6 than hydroxybupropion or bupropion itself [71E].

Mirtazapine

[SED-15, 2356;

SEDA-32, 36] Nervous system There have been two reports of movement disorders induced by mirtazapine. Most of a case series of 14 patients with restless legs syndrome presented within a few days of starting treatment, and the symptom occurred more often in those who also took tramadol or dopamine receptor antagonists, such as antiemetics [72c]. In one case, severe akathisia developed within 4 hours of a first

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34

dose of mirtazapine and required treatment with intravenous diazepam [73A]. Somnambulism [74A] and severe nightmares [75A] have been attributed to mirtazapine. Electrolyte balance Mirtazapine can cause hyponatremia (SEDA-32, 37) and many reports of antidepressant-induced hyponatremia have been in elderly patients. A 76-year-old man developed delayed onset of hyponatremia, and developed worsening lethargy and confusion after taking mirtazapine for 2 months [76A]. Skin Stevens–Johnson syndrome has been attributed to mirtazapine [77A]. • A 29-year-old man developed a disseminated pruritic eruption with confluent red macules and bullous lesions after taking mirtazapine 15 mg/day for 3 weeks. The lesions involved 10–15% of his body and there were severe oral and genital erosions. He became generally unwell and lost 5 kg. The lesions improved after withdrawal of mirtazapine and treatment with topical glucocorticoids for 1 week.

Philip B. Mitchell

Trazodone Drug–drug interactions Clarithromycin Trazodone is predominantly metabolized by CYP3A4, which is inhibited by clarithromycin. In a double-blind crossover study in healthy volunteers, co-administration of clarithromycin increased the AUC of trazodone, prolonged its half-life, increased its Cmax, and reduced its oral clearance [78C]. There was a concomitant increase in self- and observer-rated sedation and ratings of feeling “spacey”, suggesting that this kinetic effect was clinically significant. Declaration of potential conflicts of interest Philip Mitchell has received remuneration for lectures or advisory board membership from AstraZeneca, Eli Lilly & Co, Janssen-Cilag, and Lundbeck in the last 5 years. He has not been a member of an industry advisory board since late 2007 and has accepted no remuneration from industry since early 2009.

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Philip B. Mitchell

[41] Peritogiannis V, Antoniou K, Mouka V, Mavreas V, Hyphantis TN. Duloxetineinduced hypomania: case report and brief review of the literature on SNRIs-induced mood switching. J Psychopharmacol 2009; 23(5): 592–6. [42] Davidson J, Allgulander C, Pollack MH, Hartford J, Erickson JS, Russell JM, Perahia D, Wohlreich MM, Carlson J, Raskin J. Efficacy and tolerability of duloxetine in elderly patients with generalized anxiety disorder: a pooled analysis of four randomized, double-blind, placebo-controlled studies. Hum Psychopharmacol 2008; 23(6): 519–26. [43] Gartlehner G, Thaler K, Hansen RA, Gaynes BN. The general and comparative efficacy and safety of duloxetine in major depressive disorder: a systematic review and meta-analysis. Drug Saf 2009; 32(12): 1159–73. [44] Stevens DL. Duloxetine-associated tachycardia. Ann Pharmacother 2008; 42(10): 1511–3. [45] Bergman BR, Reynolds HR, Skolnick AH, Castillo D. A case of apical ballooning cardiomyopathy associated with duloxetine. Ann Intern Med 2008; 149(3): 218–9. [46] Aronson JK, When I. Use a word . . . bottled lightning. BMJ 2005; 331: 824. [47] Reeves RR, Mack JE, Beddingfield J. shock-like sensations during venlafaxine withdrawal. Pharmacotherapy 2003; 23(5): 678–81. [48] Pitchot W, Ansseau M. Shock-like sensations associated with duloxetine discontinuation. Ann Clin Psychiatry 2008; 20 (3): 175. [49] Hadikusumo B, Ng B. Serotonin syndrome induced by duloxetine. Aust N Z J Psychiatry 2009; 43(6): 581–2. [50] Liu PT, Argento V, Skudlarska B, Blagodatny M. Serotonin syndrome in an octogenarian after switch from fluoxetine to duloxetine. J Am Geriatr Soc 2009; 57 (12): 2384. [51] Lai CH. Duloxetine related binge eating behaviors: a case report. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33(8): 1581–2. [52] Müssig K, Mörike K, Häring HU. Severe and symptomatic hyponatremia following

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37 [64] Patroneva A, Connolly SM, Fatato P, Pedersen R, Jiang Q, Paul J. An assessment of drug-drug interactions: the effect of desvenlafaxine and duloxetine on the pharmacokinetics of the CYP2D6 probe desipramine in healthy subjects. Drug Metab Dispos 2008; 36(12): 2484–91. [65] San L, Arranz B. Agomelatine: a novel mechanism of antidepressant action involving the melatonergic and the serotonergic system. Eur Psychiatry 2008; 23(6): 396–402. [66] Dolder CR, Nelson M, Snider M. Agomelatine treatment of major depressive disorder. Ann Pharmacother 2008; 42(12): 1822–31. [67] Kennedy SH, Rizvi S, Fulton K, Rasmussen J. A double-blind comparison of sexual functioning, antidepressant efficacy, and tolerability between agomelatine and venlafaxine XR. J Clin Psychopharmacol 2008; 28(3): 329–33. [68] Goodwin GM, Emsley R, Rembry S, Rouillon F. Agomelatine prevents relapse in patients with major depressive disorder without evidence of a discontinuation syndrome: a 24-week randomized, doubleblind, placebo-controlled trial. J Clin Psychiatry 2009; 70(8): 1128–37. [69] Beyens MN, Guy C, Mounier G, Laporte S, Ollagnier M. Serious adverse reactions of bupropion for smoking cessation: analysis of the French Pharmacovigilance Database from 2001 to 2004. Drug Saf 2008; 31(11): 1017–26. [70] Starr P, Klein-Schwartz W, Spiller H, Kern P, Ekleberry SE, Kunkel S. Incidence and onset of delayed seizures after overdoses of extended-release bupropion. Am J Emerg Med 2009; 27(8): 911–5. [71] Reese MJ, Wurm RM, Muir KT, Generaux GT, St John-Williams L, McConn DJ. An in vitro mechanistic study to elucidate the desipramine/bupropion clinical drug-drug interaction. Drug Metab Dispos 2008; 36(7): 1198–201. [72] Kim SW, Shin IS, Kim JM, Park KH, Youn T, Yoon JS. Factors potentiating the risk of mirtazapine-associated restless legs syndrome. Hum Psychopharmacol 2008; 23 (7): 615–20. [73] Gulsun M, Doruk A. Mirtazapine-induced akathisia. J Clin Psychopharmacol 2008; 28 (4): 467.

38 [74] Yeh YW, Chen CH, Feng HM, Wang SC, Kuo SC, Chen CK. New onset somnambulism associated with different dosage of mirtazapine: a case report. Clin Neuropharmacol 2009; 32(4): 232–3. [75] Dang A, Garg G, Rataboli PV. Mirtazapine induced nightmares in an adult male. Br J Clin Pharmacol 2009; 67(1): 135–6. [76] Famularo G, Gasbarrone L, De Virgilio A, Minisola G. Mirtazapine-associated hyponatremia in an elderly patient. Ann Pharmacother 2009; 43(6): 1144–5.

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Rif S. El-Mallakh and Yonglin Gao

3 The uses of lithium Acute mania In a review of 60 years of data examining lithium use in bipolar disorder, Grof and Muller-Oerlinghausen noted that despite being the psychotropic drug with the best demonstrated efficacy, lithium is also the most contested [1R]. Many studies continue to demonstrate its efficacy and superiority or equivalence to alternative agents. In a 12-month retrospective clinical audit of two adult psychiatric units in Auckland, New Zealand, lithium was the drug of choice in 33% of acutely manic patients [2C]. In clinical practice in the treatment of bipolar disorder, many agents are used. Comparative or adjunctive efficacy are important considerations. In an open 12-week, randomized assignment study valproate was compared with lithium in 300 patients with acute mania [3C]. Overall the two drugs reduced manic symptoms equally well, but valproate was superior to lithium in the number of subjects who achieved remission (72% versus 66%, defined as a Young Mania Rating Scale score of less than 12). Both drugs were associated with a 44% adverse effect rate. Similarly, the authors of a review of published randomized comparisons of lithium and carbamazepine concluded that the two drugs are equivalent in both acute and prophylactic efficacy [4M]. Carbamazepine was associated with fewer withdrawals due to adverse effects in acute mania, while with lithium there were fewer discontinuations during maintenance treatment. Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00003-9 # 2011 Elsevier B.V. All rights reserved.

Lithium Antipsychotic drugs are more often used in the treatment of bipolar illness. Lithium was equivalent to aripiprazole, and both were superior to placebo, in a 3-week, double-blind, randomized, placebo-controlled study of acutely manic patients [5C]. The improvement was maintained for an additional 9 weeks (a total of 12 weeks), with a 12.7 point drop in Young Mania Rating Scale score for lithium and a 14.5 point drop for aripiprazole. The most common adverse events with aripiprazole were headache, nausea, akathisia, sedation, and constipation and with lithium nausea, headache, constipation, and tremor. In a 4-week randomized, double-blind study of 50 patients with acute mania, lithium and verapamil produced equivalent significant improvement in mania versus baseline [6c]. Combined treatment approaches are becoming the standard of care, but these approaches are only now being examined. In a 6-month augmentation study, lithium alone was equivalent to lithium þ divalproex in the prevention of mood recurrence in rapidly cycling patients with type I and II bipolar affective disorder with co-morbid substance abuse [7C]. Of 149 patients, most withdrew early (79%: poor adherence 42%, nonresponse 26%; adverse effects 10%). Of the 31 who remained in the study 55% relapsed into an abnormal mood state. A more novel approach has been examined in a 4-week double-blind, randomized, placebo-controlled study of lithium alone (n ¼ 60) or lithium þ allopurinol (n ¼ 60) [8C]. Lithium reduced manic symptoms, but the combination was more effective. The improvement in allopurinol-treated patients correlated positively with a reduction in plasma uric acid concentrations. 39

40

Animal models of mania help explain the mechanisms of lithium action. Positron emission tomography (PET) was used to study glucose utilization (using 18 F-fluorodeoxyglucose) in the ouabain animal model of mania [9E]. Motor hyperactivity induced by intracerebroventricularly administered ouabain was associated with reduced cerebral glucose utilization. Lithium administration normalized glucose uptake. In the D-amphetamine model of mania, hyperactivity is associated with lipid peroxidation and DNA damage. Treatment with either lithium or valproate ameliorated both the lipid peroxidation and DNA damage [10E]. Bipolar depression The acute efficacy of lithium has been compared with that of other agents in three studies in bipolar depression. In a 12-week, open study of 83 depressed patients with type II illness who were randomized to either venlafaxine (n ¼ 43) or lithium (n ¼ 40), improvement in depressive symptoms was significantly greater with venlafaxine [11C]. The rate of mood switches was not different between treatments in either rapid cycling or non-rapid cycling patients. Therapy was prematurely discontinued in 26 patients, 11 because of lack of efficacy, 13 because of adverse events, two because of non-compliance; another seven were lost to follow-up. There was one serious adverse event, an increase in suicidal ideation, during lithium therapy, judged to be unrelated to the drug. Polydipsia, polyuria, and tremor were the most common adverse events during lithium therapy. In a double-blind, placebo-controlled, multicenter trial of type I and II depressed patients treated with either lithium alone (plus placebo) or lithium plus lamotrigine, improvement was greater with combination treatment [12C]. In a randomized, blind-rater 16-week comparison in 90 patients, lithium and lamotrigine were associated with similar significant improvements over baseline, but the early drop-out rate was high at 42% [13C]. Adverse events were more common in those taking lithium than in those taking lamotrigine (Table 1).

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Rif S. El-Mallakh and Yonglin Gao

Table 1 Patients reporting adverse reactions in cases in which there were significant between group differences (% of 45 patients in each group) [13C] Adverse reaction

Lithium

Lamotrigine

Dry mouth Thirst Nausea/vomiting “Upset stomach” Tremor Increased urinary frequency Dizziness/ lightheadedness Drowsiness/panic Increased appetite Cognitive slowing Word finding Increased weight Impaired memory “Feeling dull” Reduced sexual interest Ringing in ears

53 49 47 43 41 33

20 7.3 24 20 9.8 2.4

31

7.3

31 29 27 25 23 20 18 16

9.8 4.9 7.3 4.9 4.9 0 2.4 2.4

12

0

Unipolar depression In an open randomized study in 46 subjects with unipolar depression examined over 3 weeks lithium augmented mirtazapine successfully (n ¼ 13), but carbamazepine was ineffective when added to mirtazapine (n ¼ 10) compared with mirtazapine alone (n ¼ 23) [14C]. Lithium augmentation in treatment-resistant depression remains among the best studied successful interventions [15C]. Prevention of recurrence of affective disorder Insight into how best to use lithium to reduce the recurrence of new mood episodes continues to accrue. In long-term prospective study in five centers, the International Group for the Study of Lithium-Treated Patients examined the relative stability of patients with predominantly atypical features (n ¼ 100; e.g. mixed states or rapid cycling) or more typical bipolar features (n ¼ 142) over a mean of 10 years [16C]. There were no differences in the overall measures of morbidity in the two groups. This was not consistent with the results of another study in which 100 patients were

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studied retrospectively over 3 years of use of life charting [17C]. Atypical features, such as mixed episodes and rapid cycling, were less likely to be associated with remission and more predictive of greater severity of duration of episodes. In a 2-year randomized double-blind study of the comparative efficacy of a mood stabilizer alone (lithium or valproate plus placebo) or a mood stabilizer added to quetiapine in 628 bipolar subjects, combination treatment resulted in fewer mood episodes (20%) versus a mood stabilizer alone (52%), and mania and depression were prevented to an equal degree [18C]. Serum lithium concentrations may be related to the polarity of recurrence. In an 18-month maintenance trial, relapses or recurrences of depressive episodes were preceded by serum concentrations above the mean, both when evaluated individually or across the entire study population [19C]. The authors concluded that lower concentrations were adequate for preventing depression, and that higher concentrations prevented episodes of mania and hypomania. However, the data can also be interpreted in the opposite manner—that higher lithium concentrations are required to prevent depression. Dementia Lithium has neuroprotective properties in vivo. In human endothelial cell and rat cortical astrocyte cultures, lithium 0.2 mmol/l increased phosphorylation of GSK-3b (inactivation of GSK-3b) and promoted secretion of vascular endothelial growth factor (VEGF) [20E]. The effect on GSK-3b may be more general, since lithium also reduced GSK-3b concentrations in primary cultures of rat cortical and hippocampal cells [21E] and in neural precursor cells [22E]. This effect on GSK-3b expression and activity is probably related to the observation that lithium treatment of primary culture cortical cells reduces both tau protein concentrations and tau phosphorylation (tau is phosphorylated by GSK-3b) [23E]. Similarly, in PC12 cells, lithium 1.2 mmol/l reduced morphine-induced apoptosis by down-regulating the BAX, which is pro-

41

apoptotic and up-regulating BCL-2, which is protective [24E]. At the organ level, lithium has been associated with an increase in cortical grey matter as examined using structural magnetic resonance imaging (MRI) [25R] and an increase in N-acetyl-aspartate, a derivative of aspartic acid, which is a marker of neuronal health, measured by magnetic resonance spectroscopy [26C]. These neuroprotective characteristics of lithium may reduce the risk of dementia. In an observational cohort study using national medical databases in Denmark, patients who had received a prescription for lithium at least once (n ¼ 16 238) had a higher rate of subsequent dementia than those who had never used lithium (n ¼ 1 487 177) (RR ¼ 1.47; 95% CI ¼ 1.22, 1.76), but long-term use of lithium was associated with a dramatic reduction in the likelihood of eventual dementia [27C]. By contrast, the use of anticonvulsants was associated with a significantly increased risk of dementia and the risk increased with long-term use. For all these reasons, it is not surprising that lithium has independently been proposed in Alzheimer's disease as a potential agent for prevention [28R] and treatment [29R]. The effects of lithium have been studied for up to 1 year in 22 patients with Alzheimer's disease, of whom 14 stopped the study early, in three cases because of adverse effects [30R]. The Mini-Mental State Exam (MMSE) score did not change in those who took lithium compared with the controls. In a 10-week, randomized, placebo-controlled study of lithium in 71 subjects with mild dementia (MMSE 21–26; 38 placebo, 33 lithium) there was no change in cognition, mood, GSK-3b activity in lymphocytes, or phosphorylated tau concentrations in the cerebrospinal fluid [31C]. Amyotrophic lateral sclerosis The neuroprotective effects of lithium suggest that it might be useful in other neurodegenerative or neurodestructive conditions. Amyotrophic lateral sclerosis (ALS), a disease of wasting of the motor neurons of the spinal cord, is of particular interest. In a mouse

Au1

42

model of ALS, the combination of lithium and valproate was more effective in delaying disease onset and reducing neurological deficits than either lithium or valproate alone [32E]. HIV infection Imaging was used in an open study for 10 weeks in 15 subjects with human immunodeficiency virus (HIV) and evidence of cognitive decline; there was no evidence of improvement in either cognition or mood [33C]. Multiple sclerosis Lithium was effective in a mouse model of experimental autoimmune encephalomyelitis (a model of multiple sclerosis). It reduced neurological symptoms if administered both before and after induction of the illness and the animals rapidly relapsed if lithium was withdrawn [34E]. Cerebral ischemia Lithium was efficacious in a rat model of cerebral ischemia; given alone or in combination with prostaglandin E1 it reduced infarct size and cerebral edema [35E]. Use in children The Collaborative Lithium Trials (CoLT) is a large multicenter study that has been initiated at seven sites to examine the best practices in using lithium in children with mania [36r]. Data are currently being gathered and analysed. The first randomized, double-blind, placebo-controlled trial of severe mood dysregulation (SMD) in youths has been performed. SMD is a proposed disorder that distinguishes children who have persistent severe irritability and hyperarousal and who do not fit the criteria for current disorders [37R]. Children aged 7–17 years were assigned to lithium (n ¼ 14) or placebo (n ¼ 11) after a 2-week single-blind placebo run-in phase and were followed for 6 weeks [38C]. Nearly half (45%) of the children improved during the 2-week placebo period and were not randomized. Among the remaining 25 subjects, lithium was not different from placebo in reducing the patients’ mood or behavior symptoms. In a retrospective study of the effectiveness of lithium in 60 youths with a similar

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Rif S. El-Mallakh and Yonglin Gao

symptom complex—conduct disorder—who were followed for an average of 8.4 months, 29 had at least a 50% reduction in the Modified Overt Aggression Scale score or were rated as ‘much improved’ or ‘very much improved’ on the Clinical Global Impression scale [39C]. Ten took lithium alone and 19 took a concomitant atypical antipsychotic drug. Less severely affected children generally did better. Cardiovascular Lithium generally does not have significant cardiac effects. However, lithium toxicity has been associated with transient electrocardiographic changes. • In a 46-year-old man who had had confusion and ataxia for 2 days the serum lithium concentration was 4.69 mmol/l [40A]. The electrocardiogram was normal but there was ST segment elevation in the anterior leads and biphasic T waves. Although these changes suggested ischemia, the cardiac enzymes were normal as was echocardiography. The patient was hemodialysed and the electrocardiographic normalized over several days. • In a 39-year-old woman with signs of lithium toxicity, the serum lithium concentration was 2.96 mmol/l and the potassium 2.72 mmol/l [41A]. Her electrocardiographic showed ST segment depression in leads V2 and V3, widespread T wave inversion, and prolongation of the P wave (180 msec), QRS complex (120 msec), QT interval (640 msec), and PR interval (320 msec). She improved rapidly and the electrocardiographic with normalized after hemodialysis reduced her serum lithium concentration to 0.57 mmol/l and normalized the potassium.

While lithium may have played a role in the second case, the significant hypokalemia may have been responsible. Lithium can also be associated with changes in cardiac conduction [42A]. • A 57-year-old woman developed acute mental status changes. Her serum lithium concentration was 2.2 mmol/l and the creatinine 187 mmol/l. She was hypotensive (70/ 45 mmHg) and bradycardic (37/minute). An electrocardiogram showed complete atrioventricular block. Her hemodynamic status normalized when she cleared the lithium.

While the AV block in this case may seem to have been related to lithium toxicity,

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the presentation was more consistent with a rise in the serum lithium concentration due to reduced renal clearance after the onset of heart block. Nervous system In 16 patients with acute lithium intoxication treated on a toxicological unit, intensity was mild in 25%, moderate in 50%, and severe in 25% [43C]. Over one-third required hemodialysis. Mean length of hospitalization was 16 days, of which 4.8 were spent in acute care and 11.2 in recovery. There was long-lasting ataxia in two subjects. Severe lithium toxicity is associated with seizures. In two cases, seizures were associated with high lithium concentrations (4.86 mmol/l in a 25-year-old woman and 2.5 mmol/l in a 48-year-old man) [44A]. A third case occurred in a 20-year-old man whose lithium concentration was only 0.8 mmol/l [45A]. Status epilepticus that lasted 45 minutes occurred in a middleaged woman undergoing electroconvulsive therapy (ECT) while she had therapeutic serum concentrations of lithium and was also taking agents that reduce the seizure threshold (clomipramine and quetiapine) [46A]. It has been previously proposed that ECT can cause the intracellular concentration of lithium to rise without a concomitant rise in serum concentration [47H]. In three cases lithium was associated with nervous system toxicity. • A 24-year-old woman who was 24 weeks pregnant and had pregnancy-related hyponatremia and mood symptoms was given lithium and developed diabetes insipidus, which rapidly corrected her hyponatremia and caused central pontine and extrapontine myelinolysis [48A]. • An 11-year-old boy who had taken lithium for 6 months developed pseudotumor cerebri with secondary visual field loss [49A]. • A 42-year-old woman developed dementia in the setting of atrophy and multiple diffuse areas of brain calcification when she took lithium for antidepressant drug-associated mania [50A]. She became semi-comatose, with dysarthria and right-sided dystonia. Her serum lithium concentration was only 0.57 mmol/l, but her neurological signs resolved when lithium was discontinued.

43

A complicated case of thyroiditis and Hashimoto's encephalopathy has been associated with lithium [51A]. • A 61-year-old woman with type II bipolar illness, who was taking levothyroxine for thyroiditis, developed an encephalopathy within 40 days of starting to take lithium. Her serum antithyroid antibodies were raised and antithyroid antibodies were detectable in the cerebrospinal fluid. She improved with a course of methylprednisolone.

The authors suggested that lithium-induced antibodies can have a shared target in both the thyroid and the brain, although how an ion can induce such antibodies is not clear. Lithium can affect peripheral nerves, but deleterious consequences are rare. • A 73-year-old man taking lithium for bipolar II disorder (serum concentration 0.8 mmol/l) developed confusion, dysarthria, gait disturbance, muscle stiffness, and twitching [52A]. A brain CT scan was consistent with vascular encephalopathy. Peripheral electromyography (EMG) showed many intermittent spontaneous motor unit discharges in doublets, triplets, and multiplets, consistent with peripheral nerve hyperexcitability. The EMG normalized after withdrawal of lithium.

Severe lithium toxicity can have permanent or long-lived sequelae. This has been called the syndrome of irreversible lithiumeffectuated neurotoxicity (SILENT) [53A]. • A 44-year-old woman continued to have dyscoordination 1 year after an overdose of lithium 6 g (lithium concentration not stated). • In another case a maximum lithium concentration 1.9 mmol/l was associated with dysmetria and unsteady gait, which persisted for 3 years after the episode of toxicity, and 2 years later a brain MRI scan showed prominent cerebellar atrophy [54A].

Psychological The effect of lithium on cognition remains unclear. Most studies have found minimal drug-related cognitive deficits. When 40 euthymic bipolar I patients were compared with 40 healthy controls, the only neuropsychological abnormalities were in patients who were taking antipsychotic drugs; they had reduced semantic fluency, verbal learning, recognition memory,

44

and planning abilities [55C]. Patients who were taking only mood stabilizers (including lithium, n ¼ 14) were not affected. Similarly, in 44 patients with bipolar I disorder, 22 of whom were drug free, all the cognitive symptoms that were noted (delayed verbal recall and perseverations during the five-point test) became insignificant after control of residual depressive symptoms [56C]. Finally, in 33 patients with bipolar depression taking lithium or valproate, 32 taking no medication, and 52 controls, those taking the medications had greater response latency and made more errors in tasks of sustained attention [57C]. In a meta-analysis of 12 studies (539 subjects, of whom 276 took lithium for an average of 3.9 years), in which patients were comparable for medication, mood state, educational level, cognitive abilities, and medications, lithium was associated with reduced immediate verbal learning, reduced verbal memory, and reduced creativity [58M]. Longer duration of lithium treatment was associated with reduced psychomotor performance. Many aspects were unaffected, including delayed verbal memory, visual memory, attention, executive function, and processing speed. Endocrine Thyroid A woman with thyroid carcinoma who was taking lithium for bipolar disorder discontinued her thyroid hormone replacement in preparation for radioactive iodine (131I) treatment [59A]. Within 3 weeks she developed severe lithium toxicity, which the authors attributed to renal insufficiency associated with hypothyroidism [60R]. Lithium was not withdrawn in this patient, because of an earlier suggestion that lithium can be used as an adjunct in 131I treatment [61R]. In an in vitro study using follicular thyroid carcinoma cell lines, lithium 10–20 mmol/l induced expression of NR4A1 and FOSB, genes whose underexpression is associated with malignancy [62E]. Parathyroid In some individuals lithium can increase serum calcium and parathyroid hormone concentrations [63M]. In a

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retrospective study of patients who had taken lithium for at least 1 year, laboratory personnel monitored the frequency of serum calcium determinations [64C]. Of 100 patients, 43 had had at least one serum calcium concentration measurement. Of these, five had raised calcium concentrations. However, lithium also increases bone density [65C] and reduces the risk of bone fracture [66C] (see Musculoskeletal). In six cases of lithium-associated hyperparathyroidism, four had parathyroid adenomas [67A, 68A]. The authors suggested that lithium can help uncover pre-existing parathyroid disease, although there does appear to be an increased incidence of multiglandular or multiadenomatous disease in patients taking lithium. Surgical treatment is often curative when adenomas are discovered. When hypercalcemia persists, cinacalcet, a calcimimetic can be used effectively. Diabetes insipidus In a retrospective chart review of 116 subjects taking lithium, in whom 24-hour urine collections had been performed, 46 had polyuria; 12 of these were also taking serotonergic antidepressants, compared with only 10 of the 70 subjects who did not have polyuria, a significant difference (OR ¼ 2.86; 95% CI ¼ 1.00, 8.21) [69C]. When diabetes insipidus occurs, amiloride can be an effective treatment. In 87 subjects (45 taking lithium and 42 taking other psychotropic drugs) there was impaired urinary concentrating ability and reduced urinary excretion of aquaporin 2 and cyclic AMP; 11 were given amiloride 10 mg/day for 6 weeks in a double-blind, crossover design, and when they were then given 40 micrograms of desmopressin (dDAVP), amiloride was associated with an increase in urinary osmolality and aquaporin 2 excretion [70C]. The authors concluded that this effect was mediated by increased responsiveness to the ability of desmopressin to increase translocation of aquaporin 2 to the apical membrane in principal cells of the collecting duct.

Lithium

Chapter 3

Hematologic Lithium increases bone marrow neutrophil production, protects bone marrow hemopoietic stem cells after exposure to anticancer drugs or radiation, and increases platelet count [71R]. These effects suggest several potential uses in medicine, such as concomitant use in patients who have clozapine-induced neutropenia. • A 26-year-old African–Brazilian man with paranoid schizophrenia improved with clozapine 400 mg/day, but his absolute neutrophil count fell to 600  106/l; coadministration of lithium (serum concentration 0.6 mmol/l) allowed clozapine to be used in a dose of 600 mg/day while maintaining an absolute neutrophil count of 2.5–3.0  109/l [72A].

Gastrointestinal In the acetic acid-induced colitis rat model for inflammatory bowel disease, lithium 20 mg/kg given 1 hour before the acetic acid ameliorated the macroscopic and microscopic gut abnormalities, including reduced neutrophil infiltration, reduced myeloperoxidase activity, and reduced lipid peroxidation [73E]. Urinary tract The association of lithium with renal dysfunction has again been confirmed in a retrospective record review of 59 out-patients [74C]. There was a positive association between duration of lithium treatment and serum creatinine concentration, but the duration of treatment was also greater in older patients (14.2 years for those over 65 years of age and 6.9 years for those under 65 years of age). Lithium was associated with an increased incidence of kidney microcysts (1–2 mm diameter) in patients taking lithium, in both the cortex and medulla of the kidneys and more prevalent in areas of atrophy or fibrosis [75r]. Skin Lithium is associated with an increased risk of psoriasis [76R, 77R]. In a 10-year database study using the UK-based General Practice Research Database (GPRD) 36 702 subjects with psoriasis were compared with an equivalent matched group without psoriasis; long-term use of lithium (five or more prescriptions) was

45

associated with an increased risk of psoriasis (OR ¼ 1.68; 95% CI ¼ 1.18, 2.39) [78C]. Musculoskeletal Lithium is associated with increased bone density. In 75 patients with mood disorders taking lithium and 75 without mood disorders and no lithium exposure, mean bone density was an average of 4.5–7.5% higher in those taking lithium [66C]. Furthermore, in a 10-year administrative database study in which subjects older than 50 years in Manitoba 15 792 subjects with bone fractures were compared with a matched sample of 47 289 without fractures, there was a significantly reduced risk of fractures in those taking lithium (OR ¼ 0.63; 95% CI ¼ 0.43, 0.93). By contrast, antidepressant drug treatment increased the risk (OR ¼ 1.15; 95% CI ¼ 1.07, 1.24; serotonin reuptake inhibitors had the highest risk: OR ¼ 1.45; 95% CI ¼ 1.32, 1.59) as did benzodiazepines (OR ¼ 1.10; 95% CI ¼ 1.04, 1.16). Drug withdrawal Lithium withdrawal can cause neurological adverse effects. Recurrent night-time headaches are frequently referred to as alarm clock headaches or hypnic headaches, and this has now been reported after lithium withdrawal [79A]. • A 54-year-old woman with bipolar disorder who had taken lithium for 6 years (600–900 mg/day with serum, concentrations of 0.8–1.5 mmol/l) stopped taking lithium because of renal dysfunction. About 1 month after withdrawal she began to have nocturnal headaches about 4 hours after going to sleep. They were of mild to moderate intensity, lasted for 3–4 hours, and resolved spontaneously. The headaches persisted for 1 month and then ended without treatment.

Sudden lithium withdrawal also causes mood disorders to recur. A retrospective review of 310 charts yielded 53 cases of withdrawal [80C]. Recurrence of a mood episode after lithium withdrawal was highest at 86% within 3 months. Withdrawal of antipsychotic drugs (64%) and antidepressants (58%) were associated with lower rates of recurrence. More than half of these episodes required hospitalization.

46

Chapter 3

Teratogenicity In a review of all English language literature published between 1969 and 2005, a total of 24 pregnancies in women taking lithium were reported, but only eight included women who took only lithium. The most common findings were larger infant size, transient lithium toxicity with concentrations in the infants higher than in their mothers, and two cases of congenital heart abnormalities (Ebstein's anomaly and patent ductus arteriosus) [81R]. Similarly, registry data (n ¼ 225) had also reported an increased risk of cardiovascular defects (8%, n ¼ 18) among the 25 (11%) with any congenital defect, an increased risk of prematurity (36%), and increased size for gestational age (37%). However, prospective studies that do not pick reporting due to outcome (as is the case for published reports and registry data) have generally shown no change in the risk of malformations compared with controls (2.7% in lithium-treated mothers, n ¼ 377, versus 3.2% in controls). Lithium is not benign in pregnancy, but the risk of teratogenicity may have been exaggerated.

lithium concentration had fallen to 0.84 mmol/l. This was followed by continuous veno-venous hemofiltration, which prevented rebound, and the lithium concentration continued to fall over the next 14 hours to 0.3 mmol/l. Some of her neurological symptoms improved quickly, but her lethargy did not clear for a further 3 weeks.

Drug overdose Treatment of lithium overdose must be individualized to the clinical condition. Three case reports have highlighted the number of options that are available to clinicians. • A 47-year-old woman with somnolence and a serum lithium concentration of 3.5 mmol/l was treated with an infusion of isotonic saline 200 ml/hour [82A]. Over the next 25 hours her concentration fell to 0.9 mmol/l and her mental status normalized; intravenous fluids were withdrawn. After 48 hours her lithium concentration had fallen to 0.3 mmol/l. • A 47-year-old woman took an overdose of lithium [83A]. Her initial serum lithium concentration was 1.62 mmol/l, but it rose to 2.77 mmol/l 8 hours later, despite intravenous fluids, and she was lethargic and nauseated. She was given sustained low-efficiency hemodialysis for 8 hours. The lithium concentration fell quickly and remained at under 1.0 mmol/l for the duration of her course. • An 80-year-old woman became obtunded after slowly deteriorating over the previous week. Her serum lithium concentration was 3.4 mmol/l and her creatinine was 125 mmol/l [84A]. Because of poor diuresis (10 ml/hour) she was hemodialysed for 4 hours until her

Rif S. El-Mallakh and Yonglin Gao

In the first case, a young, otherwise healthy woman, with normal renal function, conservative treatment was adequate. In the second case, with rapidly rising concentrations hemodialysis produced recovery within 4 hours, since lithium had not had an opportunity to accumulate in the intracellular compartment. The third patient required aggressive treatment because of her age and the slow onset of toxicity, which conspired to slow her recovery. Drug–drug interactions Angiotensin converting enzyme (ACE) inhibitors ACE inhibitors can increase lithium concentrations, and in one case this combination caused dyspnea and bradycardia [85A]. In another case the addition of a loop diuretic and an ACE inhibitor precipitated lithium toxicity within 3 days [86A]. Non-steroidal anti-inflammatory drugs Non-steroidal anti-inflammatory drugs can reduce lithium renal clearance and increase lithium concentrations. • A 76-year-old woman took lithium 1000 mg/ day and several over-the-counter pain medications [87A]. Diclofenac 75 mg bd was added, and after 1 week, she developed a confusional state, a raised serum creatinine, and a serum lithium concentration of 2.43 mmol/l. She recovered completely 4 days after withdrawal of lithium and diclofenac and then tolerated reintroduction of lithium at a lower dosage (400 mg/day).

Management of adverse drug reactions Guidelines, 19 in all from seven countries, for treating toxicity have been evaluated using the Appraisal of Guidelines Research and Evaluation (AGREE) instrument; there were deficiencies in nearly every single guideline [88M]. Many had missing information. For example, none highlighted

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Chapter 3

the importance of taking a psychiatric history and only one suggested psychiatric evaluation. Only two provided information regarding monitoring during hemodialysis and only five provided information about discharge. In more general terms, 60% provided information regarding supportive care, 53% regarding diagnosis, 76% regarding appropriate treatment, and 20% regarding discharge and follow-up. The authors recommended frequent updating of treatment guidelines to improve their utility. Monitoring therapy One of the predictors of lithium clearance, and consequently lithium toxicity, is creatinine clearance [89c], and lithium concentrations are closely associated with its adverse effects. In a study of 186 patients who were followed between 1973 and 2000 (an average of 5.7 years/patient) in which nine specific adverse effects were recorded monthly in a standardized manner (diarrhea, nausea, vomiting, stomach ache, tiredness, concentration deficits, tremor, polyuria, and polydipsia), the frequency of adverse effects increased as a function of lithium concentration as did their intensity [90C]. The mean number of adverse effects increased from 3.3 at a concentration of 0.6 mmol/l to 3.8 in patients with a concentration of 1.2 mmol/l. However, there was also a relation between mood state and adverse effects. Patients with manic symptoms had fewer adverse effects (an average of 2.0),

47

while patients with depression had more (an average of 4.6) compared with euthymic patients (an average of 3.3). However, measuring lithium concentrations can be problematic. In neonates, an inadequate sample of blood can lead to a falsely high lithium concentration [91A]. Alternatively, there may simply be laboratory error [92A], suggesting that the clinical presentation is important. Lithium concentrations appear to have seasonal variation. In a retrospective chart review of 101 patients, there was 25% variability in lithium concentrations over the seasons; plasma concentrations (anticoagulant not specified) were highest in the summer (about 0.55 mmol/l) and lowest in the autumn and winter (about 0.42 mmol/l), although doses did not vary [93c]. Measuring erythrocyte lithium concentrations does not appear to offer any advantages over serum lithium determinations in the management of lithium toxicity [94R]. One would expect that brain lithium concentrations might be related to effects of lithium. When brain lithium concentrations were measured with 7Li magnetic resonance spectroscopy, in older subjects (>50 years) brain concentrations correlated with higher somatic symptoms on the Hamilton Depression rating scale and frontal lobe dysfunction [95C].

References [1] Groff P, Müller-Oerlinghausen B. A critical appraisal of lithium's efficacy and effectiveness: the last 60 years. Bipolar Disord 2009; 11(Suppl 2): 10–9. [2] Wheeler A, Robinson G, Fraser A. Mood stabilizer loading versus titration in acute mania: audit of clinical practice. Aust N Z J Psychiatry 2008; 42(11): 955–62. [3] Bowden C, Gögüs A, Grunze H, Häggström L, Rybakowski J, Vieta E. A 12-week, open, randomized trial comparing sodium valproate to lithium in patients with

bipolar I disorder suffering from a manic episode. Int Clin Psychopharmacol 2008; 23(5): 254–62. [4] Ceron-Litvoc D, Soares BC, Geddes J, Litvoc J, de Lima MS. Comparison of carbamazepine and lithium in treatment of bipolar disorder: a systematic review of randomized controlled trials. Hum Psychopharmacol 2009; 24: 19–28. [5] Keck PE, Orsulak PJ, Cutler AJ, Sanchez R, Torbeyns A, Marcus RN, McQuade RD, Carson WH. CN138-135

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[6]

[7]

[8]

[9]

[10]

[11]

[12]

Study Group. Aripiprazole monotherapy in the treatment of acute bipolar I mania: a randomized, double-blind, placebo- and lithium-controlled study. J Affect Disord 2009; 112(1–3): 36–49. Pal Singh G. A double-blind comparative study of clinical efficacy of verapamil versus lithium in acute mania. Int J Psychiatry Clin Pract 2008; 12(4): 303–8. Kemp DE, Gao K, Ganocy SJ, Elhaj O, Bilali SR, Conroy C, Findling RL, Calabrese JR. A 6-month, double-blind, maintenance trial of lithium monotherapy versus combination of lithium and divalproex for rapid-cycling bipolar disorder and co-occurring substance abuse or dependence. J Clin Psychiatry 2009; 70(1): 113–21. Machado-Vieira R, Soares JC, Lara DR, Luckenbaugh DA, Busnello JV, Marca G, Cunha A, Souza DO, Zarate Jr. CA, Kapczinski F. A double-blind, randomized, placebo-controlled 4-week study on the efficacy and safety of the purinergic agents allopurinol and dipyridamole adjunctive to lithium in acute bipolar mania. J Clin Psychiatry 2008; 69(8): 1237–45. Hougland MT, Gao Y, Herman L, Ng CK, Lei Z, El-Mallakh RS. Positron emission tomography with fluorodeoxyglucose-F18 in an animal model of mania. Psychiatry Res Neuroimaging 2008; 164(2): 166–71. Andreazza AC, Kauer-Sant'Anna M, Frey BN, Stertz L, Zanotto C, Ribeiro L, Giasson K, Valvassori SS, Réus GZ, Salvador M, Quevedo J, Gonçalves CA, Kapczincki F. Effects of mood stabilizers on DNA damage in an animal model of mania. J Psychiatry Neurosci 2008; 33(6): 516–24. Amsterdam JD, Wang CH, Shwarz M, Shults J. Venlafaxine versus lithium monotherapy of rapid and non-rapid cycling patients with bipolar II major depressive episode: a randomized, parallel group, open-label trial. J Affect Disord 2009; 112: 219–30. Van der Loos MI, Mulder PG, Hartong EG, Blom MB, Vergouwen AC, de Keyzer HJ, Notten PJ, Luteijen ML, Timmermans MA, Vieta E, Nolen WA. LanLit Study Group. Efficacy and safety

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[48] Bejot Y, Depierre P, Osseby GV, Troisgros O, Moreau T, Giroud M. Central pontine and extra-pontine myelinolysis: a complication of lithium toxicity in a pregnant woman. Clin Neurol Neurosurg 2008; 110(8): 852–4. [49] Kelly SJ, O'Donnell T, Fleming JC, Einhaus S. Pseudotumor cerebri associated with lithium in an 11 year-old boy. J Am Assoc Pediatr Ophthalmol Strabismus 2009; 13(2): 204–6. [50] Kim JH, Ha K. Hypersensitive neurological response to lithium in a patient with organic bipolar disorder secondary to idiopathic basal ganglia calcification. Aust N Z J Psychiatry 2008; 42(7): 646. [51] Nagamine M, Yoshino A, Ishii M, Ogawa T, Kurauchi S, Yoshida T, Shigemura J, Kodera T, Tanaka Y, Nomura S. Lithium-induced Hashimoto's encephalopathy: a case report. Bipolar Disord 2008; 10(7): 846–8. [52] Bolamperti L, Mula M, Varrasi C, Tarletti R, Cavanna A, Monaco F, Cantello R. Generalized peripheral nerve hyperexcitability associated with lithium. J Neuropsychiatry Clin Neurosci 2009; 21(3): 346–7. [53] Porto FH, Leite MA, Fontenelle LF, Marrocos RP, Szczerback NF, de Freitas MR. The Syndrome of Irreversible Lithium-Effectuated NeuroToxicity (SILENT): one-year follow-up of a single case. J Neurol Sci 2009; 277(1–2): 172–3. [54] Rodrigues de Cerqueira AC, Costa dos Reis M, Novis FD, Bezerra JMF, Canedo de Magalhães G. Cerebellar degeneration secondary to acute lithium carbonate intoxication. Arq Neuropsiquiatr 2008; 66(3-A): 578–80. [55] Jamrozinski K, Gruber O, Kemmer C, Falkai P, Scherk H. Neurocognitive functions in euthymic bipolar patients. Acta Psychiatr Scand 2009; 119(5): 365–74. [56] Goswami U, Sharma A, Varma A, Gulrajani C, Ferrier IN, Young AH, Gallagher P, Thompson JM, Moore PB. The neurocognitive performance of drugfree and medicated euthymic bipolar patients do not differ. Acta Psychiatr Scand 2009; 120(6): 456–63.

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[57] Holmes MK, Erickson K, Luckenbaugh DA, Drevets WC, Bain EE, Cannon DM, Snow J, Sahakian BJ, Manji HK, Zarate CA. Acomparison of cognitive functioning in medicated and unmedicated subjects with bipolar depression. Bipolar Disord 2008; 10(7): 806–15. [58] Wingo AP, Wingo TS, Harvey PD, Baldessarini RJ. Effects of lithium on cognitive performance: a meta-analysis. J Clin Psychiatry 2009; 70(11): 1588–97. [59] Phillips BD, Gopalakrishnan G, Gohh R, Hennessey JV. Lithium toxicity precipitated by profound hypothyroidism. Thyroid 2008; 18(6): 651–4. [60] van Hoek I, Daminet S. Interactions between thyroid and kidney function in pathological conditions of these organ systems: a review. Gen Comp Endocrinol 2009; 160(3): 205–15. [61] Gershengorn MC, Izumi M, Robbins J. Use of lithium as an adjunct to radioiodine therapy of thyroid carcinoma. J Clin Endocrinol Metab 1976; 42(1): 105–11. [62] Camacho CP, Latini FR, Oler G, Hojaij FC, Maciel RM, Riggins GJ, Cerutti JM. Downregulation of NR4A1 in follicular thyroid carcinomas is restored following lithium treatment. Clin Endocrionol (Oxf) 2009; 70(3): 475–83. [63] Saunders BD, Saunders EFH, Gauger PG. Lithium therapy and hyperparathyroidism: an evidence-based assessment. World J Surg 2009; 33(11): 2314–23. [64] Jones BJ, Twomey PJ. Requesting patterns of serum calcium concentration in patients on long-term lithium therapy. Int J Clin Pract 2009; 63(1): 170–2. [65] Zamani A, Omrani GR, Nasab MM. Lithium's effect on bone mineral density. Bone 2009; 44(2): 331–4. [66] Bolton JM, Metge C, Lix L, Prior H, Sareen J, Leslie WD. Fracture risk from psychotropic medications: a populationbased analysis. J Clin Psychopharmacol 2008; 28(4): 384–91. [67] Perera N, Gluch L, Crawford BA. Misleading parathyroid sestamibi scan in lithium users. Int J Med 2009; 39: 556–7. [68] Szalat A, Mazch H, Freund HR. Lithiumassociated hyperparathyroidism: report of

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long-term lithium treatment: a case report. Cephalalgia 2009; 29(4): 484–6. Franks MA, Macritchie KA, Mahmood T, Young AH. Bouncing back: is the bipolar rebound phenomenon peculiar to lithium? A retrospective naturalistic study. J Psychopharmacol 2008; 22(4): 452–6. Yacobi S, Ornoy A. Is lithium a real teratogen? What can we conclude from the prospective versus retrospective studies? A review. Isr J Psychiatry Relat Sci 2008; 45 (2): 95–106. Boltan DD, Fenves AZ. Effectiveness of normal saline dieresis in treating lithium overdose. Proc Bayl Univ Med Cent 2008; 21(3): 261–3. Fiaccadori E, Maggiore U, Parenti E, Greco P, Cacassi A. Sustained low-efficiency dialysis (SLED) for acute lithium intoxication. NDT Plus 2008; 1(5): 329–32. Meertens JH, Jagernath DR, Eleveld DJ, Zijlstra JG, Franssen CF. Hsemodialysis followed by continuous veno-venous haemodiafiltration in lithium intoxication; a model and a case. Eur J Intern Med 2009; 20(3): e70–3. Ide N, Gotou S, Mori M. Hospital pharmacists prevented advance of lithium intoxication through pharmaceutical interventions. Yakugaku Zasshi 2009; 129(8): 1007–11. Fiegler K, Liechti ME, Bodmer M, Bruggisser M. Intoxication with lithium. Praxis (Bern 1994) 2009; 98(13): 685–90. Faaij RA, Ziere G, Zietse R, Van der Cammen TJ. Delirium due to a drug-drug interaction of lithium and an NSAID. J Nutr Health Aging 2009; 13(3): 275–6. Wilting I, Egberts AC, Heerdink ER, Ververs TF, Meulenbelt J, Nolen WA. Evaluation of available treatment guidelines for the management of lithium

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intoxication. Ther Drug Monit 2009; 31(2): 247–60. ElDesoky ES, Kumar V, Alorainy MS, Hamidi MM, Derendorf H. Estimation of lithium clearance from routine clinical data in Egyptian bipolar patients. A population pharmacokinetic approach. Int J Clin Pharmacol 2008; 46(12): 617–26. Wilting I, Heerdink ER, Mersch PPA, Den Boer JA, Johannes A, Egberts ACG, Nolen WA. Association between lithium serum levels, mood state, and patientreported adverse drug reactions during long-term lithium treatment: a naturalistic follow-up study. Bipolar Disord 2009; 11 (4): 434–40. Tanaka T, Moretti ME, Verjee ZH, Shupak M, Ivanyi KE, Ito S. A pitfall of measuring lithium levels in neonates. Ther Drug Monit 2008; 30(6): 752–4. Parker G. Alert: inaccurate lithium assay results. Aust N Z J Psychiatry 2008; 42(7): 643–5. Medhl B, Prakash O, Jose VM, Pradhan B, Chakrabarty S, Pandhi P. Seasonal variation in plasma levels of lithium in the Indian population: is there a need to modify the dose? Singapore Med J 2008; 49(9): 724–7. El Balkhi S, Megarbane B, Poupon J, Baud FJ, Galliot-Guilley M. Lithium poisoning: is determination of the red blood cell lithium concentration useful? Clin Toxicol (Phila) 2009; 47(1): 8–13. Forester BP, Streeter CC, Berlow YA, Tian H, Wardrop M, Finn CT, Harper D, Renshaw PF, Moore CM. Brain lithium levels and effects on cognition and mood in geriatric bipolar disorder: a lithium-7 magnetic resonance spectroscopy study. Am J Geriatr Psychiatry 2009; 17(1): 13–23.

Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong

4 Adulteration of street drugs with clenbuterol Street drugs are often modified by substitution, dilution, contamination, or adulteration [1rc]. • Substitution involves complete replacement of one drug by another one. • Dilution involves the addition of pharmacologically inert or dissimilar compounds to reduce the content of active drug in the product. Typical diluents used are sugars, starches, talc, and quinine. • Contamination involves unintentional inclusion of a foreign substance, often a by-product of the process of synthesis. • Adulteration involves the intentional addition of a pharmacologically active substance in an attempt to use less of the intended product without making the user aware.

These changes may go unnoticed or can on occasion cause morbidity and/or mortality. From 28 January to 2 February 2005, nine cases of atypical reactions to heroin were reported from a county in New Jersey, USA. The patients had nausea, chest pain, palpitation, agitation, anxiety, tachycardia, hypotension, hyperglycemia, hypokalemia, and metabolic acidosis with increased lactate concentrations. Cyanide poisoning was suspected, but cyanide was not found and specific treatment was ineffective. However, clenbuterol was identified as an adulterant in a sample of heroin obtained by the police. A public health alert was issued using the USA Centers for Disease Control and Prevention's EPI-X system Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00004-0 # 2011 Elsevier B.V. All rights reserved.

Drugs of abuse which included a request to report all potentially exposed cases to regional poison centers. There were 34 patients from five centers in USA that met the case definitions or “probable” clenbuterol poisoning over a period of 6 months. Thirteen cases met criteria for “confirmed” exposure. The initial nine cases or the index cases were listed with the 21 “probable” exposures, even though they tested positive for clenbuterol, as the test was done by the law officers. The mean age of the patients was 34 years, and 31 were men. The results of a urine drug screen were reported in 27 of the 34 cases, and eight were positive for cocaine. All the patients survived and were discharged. Clenbuterol is a potent, long-acting b2adrenoceptor agonist with unique b3adrenoceptor agonist effects. It is often used illegally by ranchers to increase the lean mass of cattle and by body builders for its anabolic effects. The authors suggested that as clenbuterol causes excessive stimulation of badrenoceptors, it can cause hypokalemia and hyperglycemia. As this was often observed in these cases, the authors suggested a possible diagnostic value to these observations. Cardiac markers were documented in 14 of 34 patients; six had evidence of myocardial injury, as evidenced by increased troponin concentrations. Two of these also had metabolites of cocaine in the urine. The authors cited previous reports of clenbuterol-associated myocardial infarction. The clinicians used b-adrenoceptor antagonists to treat 10 patients before clenbuterol was identified or suspected in these cases; no adverse events were reported. Thus, adulteration of heroin by clenbuterol was associated with sympathomimetic effects, metabolic acidosis, and myocardial injury. However, collaborative efforts among the 53

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poison control centers using the CDC Epi-X system rapidly led to identification of the disease outbreak. In another paper, with some of the same authors involved in the report mentioned above, a small epidemic of an atypical neuromuscular syndrome in five individuals who had used clenbuterol-tainted heroin has been described [2cr]. • A 47-year-old man injected heroin and developed diffuse muscle cramping that progressed over 16 hours. He had severe pain, agitation, sweating, and opisthotonos. His mental status was clear with no focal motor deficits. Limited physical examination was unremarkable. His potassium was 3.3 mmol/l, glucose 7.2 mmol/l, creatine kinase 5539 U/l; troponin concentrations and the cerebrospinal fluid were normal. To achieve adequate sedation, he required endotracheal intubation, and after sedation had intermittent spasms of his legs, hyperreflexia, and clonus. Strychnine poisoning and tetanus were suspected. He was intubated for 8 days and recovered completely. However, his urine and blood were negative for strychnine. Subsequent testing revealed clenbuterol in urine, blood, and CSF. • A 40-year-old opioid-dependent man currently taking methadone maintenance treatment developed nausea, vomiting, and bilateral spasmodic leg pain. He had insufflated heroin 3 days before admission and reported symptoms within 2 hours of drug use followed by diffuse crampy muscle aches and right flank pain. He reported that friends who had used the same heroin had had similar symptoms. He was in moderate distress, with akathisia, muscular spasm of both hamstrings, hyper-reflexia throughout, and clonus in the knees and ankles. The creatine kinase activity was 9734 U/l. He was treated with midazolam, ketorolac, lorazepam, and ondansetron and subsequently admitted to intensive care. His condition improved 24 hours later and the creatine kinase fell to 2398 U/l. He was discharged 36 hours after admission and later his urine was found to be negative for strychnine but positive for clenbuterol. Heroin metabolites were absent. • A 35-year-old woman with a history of mild asthma and substance abuse insufflated heroin and rapidly developed diffuse muscular pain and spasms involving the face, neck, arms, and chest. She reported that other friends had had similar experiences. She had mild physical distress, was anxious, and had hyper-reflexia without clonus. Her creatine kinase activity was 395 U/l. She received 1 liter of isotonic saline and intravenous lorazepam and improved symptomatically. She was discharged. Her urine was negative for strychnine but positive for clenbuterol, morphine, 6-MAM, and codeine.

Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong

• A 33-year-old man who both sold and was known to have used the same heroin as patients 2 and 3 above reported palpitation, shaking, and muscle tightness involving the face, neck, and shoulders within minutes of insufflating heroin. He had mild resting tremor in the arms and hyper-reflexia without clonus. He refused serum laboratory studies but agreed to a urine drug test. He was given lorazepam and left. His urine was negative for strychnine but positive for morphine, 6-MAM, and clenbuterol. • A 45-year-old man developed nausea, vomiting, and leg shaking within 5 minutes of insufflating heroin. He had mild distress, anxiety, hyper-reflexia, and ankle clonus. His potassium was 5.8 mmol/l and creatine kinase activity 296 U/ml. Urine testing was negative for strychnine but positive for clenbuterol, morphine, 6-MAM, and codeine.

The authors reported that these patients had an unusual neuromuscular syndrome (which has not previously been described), characterized by muscle spasms and hyperreflexia that lasted between 2 and 8 days. They reported that though clenbuterol toxicity has been reported to cause muscle tremors and myalgia, previous patients did not have tetany, muscle spasms, or hyper-reflexia. None of the drug screens detected strychnine, which is a common contaminant of heroin. They concluded that this novel neuromuscular syndrome was probably due to clenbuterol-adulterated heroin, but acknowledged that there could be other possible explanations/contaminations that were not detected.

Benzylpiperazine and related compounds [SEDA-32, 55] Placebo-controlled studies In a randomized, double-blind, placebo-controlled study in 27 healthy, right-handed, nonsmoking women, mean age 22 years, benzylpiperazine increased blood pressure and heart rate, euphoria, and dysphoria, and sociability and drug liking [3c].

Nervous system In 178 individuals who were reviewed in hospital after having

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taken benzylpiperazine, 69% had also taken other substances, most commonly ethanol [4c]. In those who took benzylpiperazine alone, increased plasma benzylpiperazine concentrations were associated with increased seizure frequency. Ethanol coingestion reduced the incidence of seizures, but significantly increased the likelihood of confusion and agitation. Drug–drug interactions Benzylpiperazine and its analogue 3-trifluoromethylphenylpiperazine are often used in combination [5c], mimicking the effects of ecstasy. The combination can cause dissociative-type symptoms, nausea, and signs consistent with sympathomimetic toxicity [6A]. Both compounds inhibit CYP2D6, CYP1A2, and CYP3A4 [7E, 8E], and mutual inhibition of metabolism occurred when the two compounds were co-administered in seven healthy volunteers, with reduced production of their metabolites, 3-hydroxybenzylpiperazine and hydroxytrifluoromethylphenylpiperazine [9c].

[SED-15, 614; SEDA-30, 31; SEDA-31, 33; SEDA-32, 55]

CANNABINOIDS

Systematic reviews Serious and non-serious adverse events associated with medical cannabinoids in 321 reports, as reported during the last 40 years, have been systematically reviewed [10M]. Those that focused on recreational cannabis were excluded, and 23 randomized controlled studies and eight observational studies, describing 4779 adverse events, were included. Serious events were defined as those that were lifethreatening or resulted in death, or required admission to a hospital or prolonged a current admission, or resulted in persistent or significant disability or incapacity, or were congenital malformations. Of the adverse events, 4615 (96%) were not serious. Of the

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164 serious events, 21 (13%) were relapses of multiple sclerosis, 16 (9.8%) were vomiting, and 15 (9.1%) were urinary tract infections. The rate of non-serious adverse events was higher among those randomized to cannabinoids versus controls (RR ¼ 1.86; 95% CI ¼ 1.57, 2.21); there was no difference in serious adverse events between the two groups. The most common non-serious adverse event (714 events, 15.5%) was dizziness. The median exposure time was 2 weeks (range 8 hours to 12 months). The authors concluded that while the short-term use of medical cannabinoids increases the risk of non-serious adverse events, it does not seem to increase the risk of serious events. They found little information about long-term risks of exposure. Others have commented that these findings support the use of cannabinoids to treat acute medical conditions such as pain, but for longer term use more data is needed [11r]. They also noted that none of the trials involved smoked cannabis, which may have its own set of adverse effects. They also drew attention to the need to examine the risks as they apply to older adults, for example, risks of cardiovascular disease, cancer, and any differences in the risk of dependence. In another systematic review of the evidence for using cannabinoids in the management of chemotherapy-induced nausea and vomiting in patients with cancer, nabilone, dronabinol, and levonantradol was superior to placebo and neuroleptic drugs [12M]. However, the cannabinoids caused adverse effects in some patients, even when they were given orally and their use was limited to 24 hours. Some untoward reactions occurred almost exclusively in patients who were exposed to them: paranoid delusions (5%), hallucinations (6%), and dysphoria and/or depression (13%). Although the patients had more adverse effects and greater intensity of symptoms during treatment with cannabinoids, most of the dropouts, which were responsible for almost 30% of the nearly 400 dropouts in all the studies included in the systematic review, were probably not due to cannabinoid toxicity.

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Cardiovascular Preliminary results from a cohort study in adults recruited after hospitalization for myocardial infarction have suggested that cannabis use may increase the risk of death among people with coronary heart disease [13R]. Of 1913 patients, 52 reported cannabis use during the previous year. During the mean follow-up time of 3.8 years, 317 died. Compared with those who did not report cannabis use, those who had used it at least weekly had a hazard ratio of 4.2 (95% CI ¼ 1.2, 14). The ageand sex-adjusted risk for any use was greater for both cardiovascular mortality (HR ¼ 1.9; 95% CI ¼ 0.6, 6.3) and mortality from non-cardiovascular causes (HR ¼ 4.9; 95% CI ¼ 1.6, 15). The authors suggested that the effects of cannabis that may affect the cardiovascular risk include: increased heart rate and blood pressure, reduced oxygen uptake (due to carbon monoxide exposure) at a time when increased heart rate increases oxygen demand. However, they also noted the increased risk of mortality from noncardiac causes. They cautioned that these results should be viewed as preliminary, given, for example, the small proportion of cannabis users in the study and the wide confidence intervals; additionally, although they controlled for important clinical characteristics, such as alcohol and nicotine use, there may have been more complex confounders from lifestyle or other factors. Nervous system Both cannabis use and schizophrenia have been linked to progressive loss of gray matter and cannabis use has also been associated with poorer clinical outcomes in people with schizophrenia. From the results of a longitudinal MRI study in 51 patients with recent-onset schizophrenia and 31 sex- and age-matched healthy subjects, the authors hypothesized that loss of gray matter volume in people with schizophrenia who use cannabis may be greater than in non-users [14Cr]. Of the 51 subjects with schizophrenia, 19 used cannabis over the 5-year study period and 32 did not. Cannabis use was assessed using the Composite Diagnostic Interview (CIDI) and random urine toxicology

Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong

screens throughout the study. The Positive and Negative Symptom Scale (PANSS) was used to assess symptoms. The cannabis-using patients had a larger gray matter volume loss than the healthy controls and non-cannabis-using patients. Non-cannabis-using patients also experienced some, but less, volume loss than the healthy controls. The cannabis-using patients also had more marked enlargement of both the third ventricle and the lateral ventricles than the controls and the non-cannabis-using patients. There was no difference in overall positive and negative symptoms between those who did or did not use cannabis, nor any difference in the overall cumulative length of hospitalization, but those who did not use cannabis had a slightly greater improvement in their positive and negative symptoms. Increased ventricular size correlated with a greater need for help with daily functioning and with a lower GAF score; however, there was no apparent direct correlation with cannabis use. The authors provided several potential explanatory mechanisms, not directly demonstrated in this study: cannabis might augment vulnerability to the gray matter changes that are associated with schizophrenia by direct effects, by heightening psychotic symptoms (which in turn might facilitate loss of gray matter volume), or by reducing adherence to medications that would otherwise attenuate the brain changes. Limitations of this study included the relatively small number of patients, the lack of a cannabis-using otherwise healthy control group, and difficulty in quantifying the amount of cannabis exposure (since amounts were based on patient and family recall and since there are differences in the amount of tetrahydrocannabinol in cannabis preparations). Psychological The cerebellum contains the highest density of cannabinoid receptors in the brain, but little is known about the effects of cannabis on cerebellar-dependent learning. The long-term effects of cannabinoids on the cerebellum have been assessed based on Eyeblink conditioning, an associated motor learning task that pairs a conditioned stimulus (tone) to an

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unconditioned stimulus (a puff of air), leading to a conditioned eye blink; the cerebellum is critically involved in this process. Current cannabis users (n ¼ 14) and healthy drug-naive controls (n ¼ 10) were evaluated [15C]. The cannabis users had used cannabis at least once a week in the past month, had a positive urine toxicology screen, and had used no other illicit drugs in the past 6 months. The cannabis users had fewer conditioned responses and their conditioned responses were poorly timed; however, they had normal unconditioned responses, and the problem seems specific to acquisition of the conditioned response. Limitations of this study included the small sample size and the lack of information about whether or not a period of abstinence could improve these effects. Cannabis use may worsen cognitive function among patients with multiple sclerosis and may affect emotional functioning. Cognitive impairment, most commonly impaired attention and slower processing, is an important predictor of quality of life for both patients and families. Of 140 consecutive community patients with multiple sclerosis, 10 (7.7%) were current cannabis users (using at least once a month) and had a slower mean processing time [16c]. While the cannabis users were younger, there were no significant differences between the users and non-users in sex, education, disease course or duration, or physical disability (as measured by the Expanded Disability Status Scale). Because age could affect cognitive status independent of cannabis use, the 10 cannabis users were each age-matched to four subjects who did not use cannabis. Using the Structured Clinical Interview IV, there were no differences in the percentages of patients who met current criteria for any diagnosis, although the cannabis users had a higher rate of lifetime psychiatric diagnoses. The subjects were assessed using the Neuropsychological Battery for multiple sclerosis (NPBMS), which includes the Selective Reminding Test, the 7/24 Spatial Learning Test, the Paced Auditory Serial Addition Task, and the Controlled Oral Word Association Test. The NPBMS was

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supplemented with a computerized version of the Symbol Digit Modalities Test, which tests processing speed and working memory. Among cognitive variables, the cannabis users performed less well in the measure of performance time for visual working memory. The authors noted that direction of causality could not be determined and pointed out that differences may not be direct differences due to cannabis use, if, for example, cannabis use is a marker for some other risk factor. The limitations of the study included the small sample size, self-reporting of cannabis use, and lack of urine toxicology confirmations, but it has provided information about an area not previously examined. Teeth An association between cannabis use and periodontal disease has been reported from a prospective cohort study of 903 individuals born in Dunedin, New Zealand, between 1972 and 1973 [17c]. Cannabis use data were collected at ages 18, 21, 26, and 32 and dental examinations were done at ages 26 and 32. After controlling for tobacco smoking, sex, irregular use of dental services, and dental plaque, the cannabis users had a higher relative risk of periodontal combined attachment loss: 1.6 (95% CI ¼ 1.2, 2.2) for having one site or more with 4 mm or greater combined attachment loss; 3.1 (95% CI ¼ 1.5, 6.4) for having one site or more with 5 mm or greater combined attachment loss; and 2.2 (95% CI ¼ 1.2, 3.9) for having incident attachment loss (compared with those who had never smoked cannabis). There was a dose–response relation. Liver Daily cannabis use may be a susceptibility factor for steatosis in chronic hepatitis C, an important consideration, since steatosis has been reported to increase fibrosis and reduce the rate of viral eradication. In 315 consecutive patients with chronic hepatitis C undergoing liver biopsy collected, the patients were categorized as non-users (64%), occasional users (12%), and daily users (24%) [18c]. After alcohol intake and viral genotype were controlled for, marked steatosis (at least 30% of

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hepatocytes with cytoplasmic fat vacuoles) was more frequent in daily cannabis users than in non-users (OR ¼ 2.1; 95% CI ¼ 1.01, 4.50). Infection risk A 56-year-old woman with underlying COPD, a past cigarette smoker and current cannabis smoker, had multiple pulmonary nodules seen in a routine chest X-ray [19A]. Biopsy of the nodules showed cavitary lesions and invasive pulmonary aspergillosis. Aspergillus can be found in samples of marijuana and chronic cannabis use probably predisposed her, perhaps owing to impairment in mucociliary activity and alveolar macrophages function. While prior reports of invasive pulmonary aspergillosis have been documented in immunocompromised individuals who use cannabis, she was not immunocompromised.

[SED-15, 848; SEDA-30, 31; SEDA-31, 37; SEDA-32, 58]

COCAINE

Cardiovascular Ischemic cardiac events due to cocaine EIDOS classification: Extrinsic moiety: Cocaine Intrinsic moiety: Alpha-adrenoceptors Distribution: Myocardium and platelets Outcome: Vasospasm and increased platelet aggregability Sequela: Ischemic cardiac events due to cocaine DoTS classification: Dose-relation: Toxic Time-course: Time independent Susceptibility factors: Not known In the USA, cocaine is the illicit recreational drug that leads to the most emergency room visits and chest pain is the most common complaint. The American Heart Association has reviewed the current

Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong

literature on cocaine-associated chest pain and myocardial infarction and has provided guidance on diagnosis and clinical management [20R]. Cardiovascular toxicity due to cocaine abuse forms a spectrum of adverse medical conditions. The pathophysiology of cardiovascular events has been reviewed [21R]. Ischemia and vasospasm are adrenergically mediated and there is a prothrombotic effect due to increased platelet aggregability. In the setting of hypoxia, intracoronary thrombosis can occur. In the acute setting of cocaine-induced chest pain, assessment includes the possible diagnosis of acute myocardial infarction. However, cocaine may independently affect cardiac biomarkers [22r]. Recent cocaine use may alter the specificity of measurement of serum creatine kinase and its MB fraction. Among cocaine users, increased serum creatine kinase activities and increased mean myoglobin concentrations are common. Increased skeletal muscle activity and rhabdomyolysis are often present, possibly because of cocaine-induced hyperthermia. Troponin I concentrations are more reliable cardiac biomarkers for detecting cocaineinduced myocardial infarction and are associated with a poor prognosis. Aortic dissection is an uncommon cardiovascular complication of cocaine use. In a retrospective chart review of 164 patients with acute aortic dissection [23c] 16 (9.8%) had used cocaine or crack cocaine within 24 hours before the onset of symptoms and 148 (90%) had no history of cocaine use. In the cocaine group, 11 had inhaled intranasally and five had smoked crack cocaine. The length of time between cocaine use and the onset of aortic dissection was 4–24 (mean 13) hours. The cocaine users were younger, were more often men, and had more co-morbid polysubstance abuse. In those who had surgery there was a higher rate of pulmonary complications in the cocaine users. The authors suggested that this may have been due to lung impairment caused by smoking cocaine; many cocaine users were also cigarette smokers. Painless aortic dissection has been attributed to cocaine use [24A].

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• A 48-year-old man had sudden paralysis of his legs with loss of bowel control. His medical history included hypertension, post-traumatic stress disorder, depression, and cigarette smoking. His blood pressure was 60/40 mmHg and his pulse 56/minute. His muscle strength was 0/5, and there was areflexia in the legs. From the umbilicus down there was loss of sensation to touch. Rectal tone was absent. The serum creatinine was 186 mmol/l, lactic acid 9.5 mmol/l, and serum alcohol 78 mmol/l, and a urine screen was positive for cocaine. The electrocardiogram showed sinus bradycardia at 60/minute. A chest X-ray showed a widened mediastinum. There was a moderate pericardial effusion with right ventricular collapse, severe aortic regurgitation, and extensive aortic dissection starting from the aortic valve. After cardiac surgery he developed spinal cord damage.

Severe gangrene of all four limbs due to cocaine-associated peripheral vasospasm has been reported [25A]. • A 43-year-old woman developed reduced mental responsiveness after using crack cocaine the previous night and repeatedly in previous weeks. Her hands and legs were cyanotic. She developed bilateral hand compartment syndrome and required emergency fasciotomy and carpal tunnel release. Despite anticoagulant and antithrombotic therapy her condition deteriorated and she developed dry gangrene of eight digits and the legs below the knees, requiring digital and above-knee amputations. There was no evidence of autoimmune disorders or vasculitis.

The authors suggested that cocaine-induced peripheral vasospasm with associated delayed and persistent vasospasm was a probable mechanism for this outcome. The vasospastic action of cocaine peaks at 1 hour after use and correlates with an increased serum concentration of cocaine (benzoylmethylecgonine). Delayed and persistent vasospasm can occur, as the major metabolites of cocaine, benzyolecgonine and ecgonine methyl ester, can also reportedly cause vasospasm [26r]. Respiratory Cocaine use is associated with various pulmonary complications. Pneumothorax, lung cavitation, and pleural empyema have been reported [27A]. • A 32-year-old chronic cocaine user developed a cough, shortness of breath, fever, and

59 left-sided chest pain. The white blood cell count was 14.7 109/l, a chest X-ray showed a left-sided pneumothorax, and a CT scan showed five cavities in the right lower lung lobe, the largest being 5 cm in diameter. Gram stain of the sputum showed Staphylococcus aureus. The diseased lobe was excised and histology showed diffuse alveolar damage, pneumonic infiltration, thrombosis in subsegmental arteries, areas of pulmonary infarction, and fibrinopurulent material in the pleura.

Cocaine powder has a direct effect on the lungs and there is an indirect effect via vasoconstriction. Barotrauma was the most likely cause for the pneumothorax and pneumomediastinum in this case. An uncommon pulmonary infiltrate called exogenous lipoid pneumonia occurs secondary to aspiration or inhalation of fat-like substances, such as oil-based laxatives. Exogenous lipoid pneumonia has been attributed to inhalation of crack cocaine mixed with petroleum jelly [28A]. • A 42-year-old African–American man with paranoid schizophrenia who smoked crack cocaine mixed with petroleum jelly and cigarettes developed progressive shortness of breath. His medications included fluticasone, ipratropium, and salbutamol inhalers, haloperidol, quetiapine, trihexyphenidyl, and celecoxib. His oxygen saturation fell from 93% on room air to 88% after 1 minute of walking. There were fine inspiratory crackles in both lung bases. A chest X-ray showed diffuse reticular infiltrates. Pulmonary function tests showed a combined restrictive and obstructive ventilatory defect with a reduced diffusion capacity. A course of high-dose glucocorticoids was ineffective. A wedge biopsy showed exogenous lipoid pneumonia, with lipid vacuoles surrounded by inflammatory infiltrates.

The prevalence of self-reported illicit use of cocaine and/or metamfetamine in patients with acute decompensated heart failure has been studied, using a multicenter observational registry, in 11 258 patients, of whom 594 (5%) had previously used cocaine (96%) and/or metamfetamine (5%) [29C]. Users had a median age of 50 years compared with 76 years in nonusers. As there were disproportionately more young African–American men with hypertension, left ventricular systolic dysfunction, and markedly raised B-type

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natriuretic peptide concentrations, the authors speculated that the severity of cardiac dysfunction in these young patients would probably result in higher morbidity, mortality, and health costs. Although these patients had a greater degree of left ventricular dysfunction (ejection fraction < 40%), they did not have a greater risk-adjusted mortality. Musculoskeletal Osteonecrosis of the calcaneus following cocaine injection in the foot has been reported [30A]. • A 49-year-old man developed pain, redness, and swelling in his left foot 3 days after having injected cocaine into veins on the top of his left foot. He had a fever of 39.4 C, edema, and erythema of the lower third of the left leg, with superficial blisters and skin excoriation. The white blood cell count was 24  109/l and an X-ray and MRI scan showed sclerosis of the navicular bone, suggestive of osteonecrosis, soft tissue swelling around the ankle, consistent with cellulitis, and osteoarthritis of the talonavicular joint, with a subchondral cyst at the head of the talus. The fever and ankle swelling persisted despite intravenous antibiotics, and aspiration of the ankle joint yielded a purulent fluid. As blood cultures were positive for meticillin resistant Staphylococcus aureus (MRSA), he was given intravenous vancomycin. The wound and ankle joint were debrided and irrigated several times. Bone histology showed focal areas of necrotic bone with calcification surrounded by vascularized fibrous tissue in the bone marrow, consistent with healing of infarcted bone.

The calcaneus has a rich vascular supply and is an uncommon site of infarction. Endocrine Panhypopituitarism with positive autoimmune serology secondary to cocaine use has been reported [31A]. • A 41-year-old man who habitually inhaled cocaine developed severe fatigue, cold intolerance, anorexia, and weight loss of 20 kg over 6 months. He had low serum concentrations of TSH, free thyroxine, and free triiodothyronine, FSH, LH, ACTH, cortisol, prolactin, and testosterone. MRI and CT scans showed a normal sized pituitary gland within a dense, edematous, contrast-enhancing mass. The nasal septum was destroyed, and there were no conchae and severely eroded sinus walls.

Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong

A transnasal biopsy showed a non-specific, non-granulomatous inflammation and colonization with Staphylococcus aureus. There was a strongly positive C-ANCA titer (320 U/l) with specificity for human neutrophil elastase-specific anti-neutrophil cytoplasmic antibodies (HNEANCA); PR3-ANCA was negative. These results ruled out Wegener's granulomatosis and a diagnosis of cocaine-induced HNEANCA associated panhypopituitarism was made. He stopped using cocaine and 2 years later the ANCA titers were repeatedly negative.

Skin The adverse effects of cocaine on the skin include vasculitides, purpura, urticarial, and non-specific eruptions. The delusion of parasitosis or formication, the false belief that insects are crawling underneath the skin, has also been described. Two other reactions have been described in a review [32Ar]. • A 37-year-old woman developed numerous discrete papular erythematous excoriations with overlying crusts on the lower legs, thighs, and forearms. She also had worsened dental caries and unexplained weight loss of 18 kg. A urine test was positive for benzoylecgonine. • A 39-year-old man had itchy skin and weight loss of 14–18 kg over 3 months and described a whitish, hairy substance that protruded from burning skin lesions. He had erythematous, excoriated papules on the arms, legs, the front of the trunk, and buttocks. A urine test was positive for cocaine.

The authors recommended that when a patient presents with chronic skin lesions, a vague medical history, negative findings during previous examinations, labile affect, and delusional behavior, a drug screen should be obtained to check for cocaine use. Fetotoxicity Cocaine exposure in utero may have a direct effect on autonomic nervous system regulation, cardiac control mechanisms, and cardiovascular functioning in neonates [33C]. In 21 prenatally cocaineexposed infants and 23 non-exposed controls, studied within 120 hours of birth, there was a positive interaction between prenatal cocaine exposure and orthostatic stress. Whereas both exposed and non-exposed infants had increased heart rates and heart rate variability, the responses of the exposed

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infants to orthostatic stress were both delayed and prolonged. The responses of the non-exposed infants were immediate but transient. The authors suggested that cocaine exposure in utero may alter development of the sympathetic and parasympathetic systems and thus lead to altered neonatal cardiovascular function. Cocaine exposure in utero and its possible effect on language development has been studied in a prospective, longitudinal study in 398 children (209 cocaine-exposed and 189 non-exposed), who were evaluated at birth, 1, 2, 4, and 6 years of age [34C]. Cocaine exposure had a negative effect on all language domains during the first 6 years of life. Over time, the cocaine-exposed group showed stable language growth but did not catch up in the areas of linguistic deficits. The authors also mentioned that the cumulative risk of language deficits is also based on other variables, such as other toxic exposures and environmental, genetic, and social factors. The effect of cocaine exposure in utero on subsequent growth has been studied by enrolling mothers from a prenatal clinic and interviewing them at the end of each trimester about their use of cocaine and other substances; follow-up assessments of the offspring were done at 1, 3, 7, and 10 years [35C]. This study was the first to conduct longitudinal growth-curve analysis using four time-points and to extend into childhood. The offspring who were exposed to cocaine during the first trimester grew at a slower rate than non-exposed controls. At 7 and 10 years, but not at 1 or 3 years, children with prenatal cocaine exposure were smaller on all growth parameters than the children who had not been exposed. There have been two radiological studies of the effect of in utero cocaine exposure on neurocognitive development in older offspring. In the first study, 24 cocaineexposed adolescents and 25 matched noncocaine-exposed controls underwent structural and perfusion functional MRI during resting states [36C]. The cocaine-exposed adolescents had significantly reduced global cerebral blood flow. The affected areas

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were mainly in the posterior and inferior brain regions, including the occipital cortex and thalamus. In addition, the cocaineexposed group had increased relative cerebral blood flow in the anterior and superior brain regions, such as the prefrontal, cingulate, insular, amygdala, and superior parietal cortex. These findings suggest that there may be compensatory mechanisms for reduced global cerebral blood flow due to a prenatal cocaine effect during neural ontogeny. In the second study volumetric MRI data of brains were collected in 35 children, mean age 12 years, with intrauterine exposure to cocaine, alcohol, tobacco, and marijuana (14 cocaine-exposed and 21 noncocaine-exposed) [37c]. The children with cocaine exposure had lower mean cortical gray matter, total parenchymal volumes, and smaller mean head circumference. As the number of exposures to prenatal substances grew, these specific measured areas showed further reductions in size. Even though the sample size was small, this study has provided relevant information on the adverse effect of prenatal drug exposure among older children. Fibromuscular dysplasia has been reported in a child with in utero cocaine exposure [38A]. • A 21-month-old boy began vomiting daily. He had been exposed to cocaine in utero. His symptoms improved initially and then deteriorated, with loss of consciousness. He developed pneumonia, a dilated cardiomyopathy, and presumptive myocarditis, had a respiratory arrest and renal failure and died. Postmortem findings were consistent with dilated cardiomyopathy and the major coronary arteries had moderate luminal narrowing by intimal fibroplasia. Histology showed changes of intimal fibroplasia diffusely present in the intramyocardial coronary artery branches, consistent with intimal fibroplasia, a rare variant of fibromuscular dysplasia. There was no evidence of myocarditis.

Fibromuscular dysplasia is an idiopathic disease of small and medium sized arteries. The authors postulated that cocaine had altered transforming growth factor beta, which had caused intimal fibroplasia.

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Ecstasy (3,4-methylenedioxymetamfetamine, MDMA) [SED-15, 180; SEDA-30, 37; SEDA-31, 41; SEDA-32, 61; for other amphetamines see Chapter 1] Cardiovascular Based on reports that in vitro MDMA can cause proliferation of cardiac valvular interstitial cells, the authors of a study recruited 29 subjects who were using or had used MDMA, mean age 24 years, and 29 sex- and age-matched controls to evaluate the occurrence of cardiac valvular disease in Belgium from December 2004 to February 2006 [39c]. Subjects who had used drugs that could cause valvulopathy and subjects with any current or past cardiac disease were excluded. Eight users had abnormal echocardiograms using the US FDA criteria for appetite suppressant-induced valvular heart disease, compared with none in the control group. Users with valvular regurgitation of  2/4 for mitral and tricuspid valves or any aortic regurgitation had used on average higher cumulative doses of MDMA than those with lower grades of regurgitation. Six had mitral regurgitation of 1/4 and four of 2/4, compared with none in the control group. Tricuspid regurgitation of  2/4 was present in 13 MDMA users and absent in the controls. Four MDMA users had mild aortic regurgitation. There were valvular strands, defined as thin, mobile, filamentous projections attached to the valvular leaflets, in six MDMA users and none in the controls. The authors described these strands as “witnesses” of an abnormal underlying valvular structure. They observed that this was the first time valvulopathy in young adults using MDMA has been reported. They speculated that the possible mechanism may be activation of serotonin 5HT2B receptors and induction of mitogenic responses in human valvular interstitial cells. They proposed that this might explain the fact that intermittent use in these young patients could give rise to cardiac valvulopathy. They were also concerned that valvular strands are associated with ischemic stroke in young individuals.

Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong

Sensory systems Vision Acute bilateral angle closure and transient myopia has been attributed to MDMA [40A]. • A previously emmetropic 39-year-old healthy man developed bilateral angle closure and transient myopia after using MDMA for 2 weeks. He had painless progressive reduction in vision in both eyes over 2 days, bilateral myopic refraction, and an intraocular pressure of 40–41 mmHg in both eyes, with bilateral ciliochoroidal effusions. Bilateral neodymium-doped yttrium aluminium garnet peripheral iridotomy was performed, but the intraocular pressures remained high. His vision improved following treatment with brimonidine 0.2% and timolol maleate 0.5% topically and then oral acetazolamide for 4 days.

The authors suggested that fluid movement in choroidal effusion could have been related to drug-induced membrane potential changes or a possible idiosyncratic reaction. The acute myopia was probably due to forward displacement of the lens caused by superciliary effusion, although ciliary body swelling and lens thickening could also have played a role. They also postulated that the ciliary effusion in this case could have been due to the serotonergic effects of MDMA.

Psychological The effects of four different single intranasal doses of metamfetamine (0, 12, 25, and 50 mg/70 kg) on a broad range of behavioral and physiological measures have been studied in 11 non-treatment seeking metamfetamine abusers in a double-blind study [41c]. Metamfetamine concentrations rose progressively for 4 hours after administration. The cardiovascular and subjective effects increased and peaked about 5–15 minutes after administration. Cognitive performance and less complicated tasks improved on all active doses, whereas performance in more complicated tasks was improved only by the intermediate doses. The authors proposed that the rapid action on subjective well-being probably contributes to increased abuse liability, as may the performance enhancing effect. However, they were puzzled by the rapidity of the subjective

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effects and the effects on performance, which occurred before the plasma concentrations had peaked. They quoted previous data that suggest that metamfetamine is commonly abused in multiple dose cycles, with an interdose interval of 0.5–3 hours and may continue for several days, suggesting that binging may result in for very high, potentially toxic, plasma concentrations of amphetamines. They further contrasted the effects of cocaine and metamfetamine: the cardiovascular effects of cocaine last 30–50 minutes while those of metamfetamine last more than 240 minutes, making metamfetamine potentially more toxic. Prospective memory, which involves remembering future intentions, has been reported to be negatively affected by MDMA in a double-blind, placebo-controlled, two-way crossover study of a single dose of MDMA 75 mg in 12 recreational MDMA users [42C]. A single dose of MDMA increased the number of prospective memory failures, which correlated with plasma MDMA concentration. Functional imaging showed that MDMA decreased BOLD activation in the left thalamus, left putamen, left precuneus, and the bilateral inferior parietal lobules. The authors concluded that loss of deactivation in the inferior parietal lobules may account for increments in memory failures observed during MDMA intoxication. The effect of MDMA on memory was small. The detrimental effect of MDMA did not correlate with lifetime use. There was a threefold intersubject variability in plasma concentrations of MDMA, implying that pharmacokinetic variables may play an important part in these effects. The authors speculated that MDMA suppresses brain processes that are normally involved in prospective memory. Prospective memory has been assessed in 20 adults with amfetamine abuse/dependence who were abstinent for an average period of 6 months and 20 metamfetamine-naive participants using “Virtual Week”, a laboratory measure that closely approximates the type of prospective memory tasks that actually occur in everyday life [43c]. Metamfetamine users were significantly impaired, and the deficits

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did not vary as a function of specific prospective memory task demands. The authors suggested that these deficits were not secondary to the effects of other illicit drug use. They found prospective memory impairment in those who had used metamfetamine but had been abstinent on average for 6 months, suggesting that the neurocognitive deficits were not transient. The authors made the case that failure to respond was the most common type of error made by both groups, but across all tasks. The metamfetamine users had significant impairment of retrospective memory and executive functioning. However, the cross-sectional design, small sample size, and other factors limited their conclusions. In a comparison of 29 current MDMA users, 10 previous users, and 46 non-users, using tests of working memory MDMA users performed worse than non-MDMA users in a letter comparison task, although the overall difference was not significant [44c]. Current MDMA users made significantly more errors in pattern recognition task than the other groups. When the results were combined, current MDMA users made significantly more errors than non-users. Working memory deficits were significantly greater in both MDMA groups compared with the controls. Although MDMA users made more errors in information processing speed and in letter comparison tasks at all levels of complexity compared with non-MDMA users, the differences were not statistically significant. The authors suggested that age-related impairment of information processing is more global in nature and is characterized by more global slowing, compared with the MDMA-related impairment, which appears to be more specific and localized, perhaps reflecting some kind of attentional deficit among current users. They acknowledged that MDMA users had used a range of other drugs, making it difficult to attribute the results unambiguously to MDMA alone. MDMA has been suggested to alter cognitive function and impulsivity, but the data have often been tainted by the concurrent use of other drugs of abuse. Decision-making, self-reported impulsivity, and drug use have been studied in 22 abstinent MDMA users,

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30 other drug users, and 29 healthy non-drug controls [45c]. Users of MDMA and other drugs had comparable patterns of decisionmaking and impulsivity. However, both drug groups had poorer decision-making and impulsivity than controls. Poorer decisionmaking was related to heavier drug use in the past year, heavier weekly alcohol use, and lifetime substance use disorder, while increased impulsivity was associated with heavier drug use, heavier weekly alcohol use, more lifetime substance use disorders, and more self-reported depression. MDMA users had heavier patterns of drug use in general, making a specific role of MDMA use in reward-related decision-making and impulsivity questionable. No particular drug class emerged as being most strongly associated with decision-making deficits. Immunologic Death from a possible anaphylactic reaction to MDMA has been reported [46A]. • A healthy 13-year-old girl took MDMA and had swelling of her lips. A few weeks later she took 1½ tablets of MDMA and soon after complained of nausea and took an antiemetic containing zingerone, without much effect. After about 4 hours she became apneic, comatose, hypothermic (33 C), hypotensive, and tachycardic. She died 30 hours after ingestion. Autopsy showed massive brain edema with tonsillor and transtentorial herniations and anoxic/ischemic encephalopathy. Her lungs were congested and she had laryngeal edema. There was zingerone in the urine and MDMA blood concentrations were too low to explain death by acute intoxication alone. Concomitant intoxication from alcohol and other drugs was excluded. There was no evidence of disseminated intravascular coagulopathy, rhabdomyolysis, hyponatremia, acute renal or liver failure, or water intoxication. A friend had taken a similar formulation of MDMA and had had no reaction.

The authors concluded that this was most probably a case of anaphylactic reaction to MDMA or an adulterant or contaminant and did not find any other similar published reports. Susceptibility factors Sex Sex differences associated with the effects of MDMA as reported in 28 studies have been reviewed

Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong

[47M]. The preclinical and clinical data suggest that adult women are more susceptible than men to the acute and subacute psychological and physical adverse effects of MDMA. However, men appear to be more sensitive to the physiological effects of MDMA. The authors suggested that these data are consistent with what has been reported with amphetamines and cocaine. They also commented on the relevance of these data to the preponderance of mood disorders, especially depression, in women. Specifically, they raised concerns that women who use MDMA and have a history of depression may be at greater risk of future psychological difficulties, such as relapse of depression. As MDMA consumption occurs at dance parties, and can be associated with unprotected sexual activity, they expressed the concern that users are at increased risk of accidental gestation, since gestational exposure to MDMA can increase the risk of abnormal neurodevelopment. They acknowledged that there is much that is not known about why there are sex differences in responses to MDMA. They postulated that the reasons for these differences are: (1) regulation by MDMA of gonadal hormone responses in women by altered serotonin and dopamine neurotransmission or by regulation of gene expression; (2) sex-based pharmacokinetic variables affecting the systemic availability and distribution of MDMA; (3) sex differences in brain structures, which may afford different vulnerability.

Gamma-hydroxybutyric acid (sodium oxybate) and analogues [SED-30, 1479; SEDA-32, 68] Systematic reviews The tolerability and abuse liability of gamma-hydroxybutyric acid (GHB) have been reviewed [48M]. GHB is abused by a small percentage of people (<1%) as a “club drug” and is commonly associated with enhanced sexual experiences (65%), euphoria (41%), somnolence (71%), and confusion (24%).

Drugs of abuse

Chapter 4

Although it can be associated with serious coma, there have been few reported deaths. Formal studies of its abuse liability do not suggest that it has a high abuse propensity, mainly because oversedation and dizziness at high doses are unpleasant. Years of clinical use in narcolepsy do not support the development of tolerance or withdrawal symptoms in the absence of substance dependence. Nervous system Fixed, dilated, asymmetric pupils developed in two patients during continuous intravenous therapy with gamma-hydroxybutyrate, in the absence of cerebral herniation [49A]. Drug abuse The incidence of craving for and abuse of gamma-hydroxybutyric acid has been studied in four groups of patients: pure alcoholics, alcoholics with a sustained full remission from cocaine dependence, alcoholics with a sustained full remission from heroin dependence, and alcoholics in a methadone maintenance treatment program [50c]. All were given oral gammahydroxybutyric acid 50 mg/kg tds for 3 months. There was significantly more craving for gamma-hydroxybutyric acid in those in remission from cocaine dependence than in the pure alcoholics and in those in remission from heroin dependence than in those taking methadone. The authors recommended that gammahydroxybutyric acid should not be used in alcoholics with sustained full remission from heroin or cocaine dependence. Drug overdose Two deaths and one nonfatal intoxication following ingestion of gamma-butyrolactone, a precursor of gamma-hydroxybutyric acid, have been reported; in another case a 36-year-old woman obtained gamma-butyrolactone from nail polish remover pads [51A]. A 25-year-old drug addict died from an overdose of gamma-butyrolactone after mistaking it for water in preparing a dilution [52A].

65

Khat [SEDA-30, 43; SEDA-31, 48; SEDA-32, 69] The experimental and clinical pharmacology of khat, models of addiction, and its adverse effects have been thoroughly reviewed [53R]. In a special edition of the journal Substance Use and Misuse the moral, political, cultural, and economic influences of khat in Kenyan society have been reviewed, dealing with the complex question of whether khat should be considered an illicit drug [54c]. Other articles included a review of the impact of khat on women's economic independence and moral standing in East Africa [55A], a case study of a London neighborhood's response to the use of khat [56c], and an analysis of the public discourse regarding the role of khat in Ethiopia [57c]. Cardiovascular Perioperative considerations specific to habitual khat chewers have been reviewed [58c]. Given the sympathomimetic effects of khat and its potential for cardiac toxicity, the author recommended vigilant monitoring of perioperative cardiovascular function and the selection of anesthetics with fewer sympathomimetic or cardiovascular effects. Acute use of khat (within 4 hours before surgery) can lead to increased anesthetic requirements, whereas chronic users, if their catecholamines are depleted, may need less anesthesia and are at risk of perioperative hypotension. Psychiatric Susceptibility factors, including use of khat, associated with violent expression have been studied among 1294 male college students in Ethiopia [59c]. A selfadministered survey asked for numbers of violent acts, defined as an intentional act of physical force or power, threatened or actual, against another, with a high likelihood of resultant physical or psychological harm. The authors collected sociodemographic information and asked about hypothesized susceptibility factors, including the style of anger expression (measured by the Spielberger Anger-Out Expression

66

Chapter 4

Scale), negative life events, and substance use (whether or not the person labelled themselves as a user of khat, alcohol, and/ or tobacco). They found that 54% of the students surveyed had committed at least one violent act in the past academic year. While alcohol and cigarette use did not increase the risk of violence, the use of khat increased the risk significantly (OR ¼ 1.46; 95% CI ¼ 1.02, 2.08). Having a moderate or high level of anger expression and having more than four negative life events in the past year was more highly associated with violent acts. This study was limited by the lack of details about any immediate temporal relation between violence and the use of khat, the amount or frequency used, and the use of any substances other than khat, alcohol, or tobacco. The authors suggested that schools should implement screening for violence and prevention programs that target the susceptibility factors of stress, anger management, and substance use. Pregnancy In an analysis of data from the 1997 Yemen Demographic and Maternal Health Survey (7343 women who had at least one live birth in past 5 years), 41% of the women surveyed answered “yes” when asked if they had smoked khat while pregnant [60c]. There were associations between khat smoking during pregnancy and lack of education, poverty, and living in a rural area. The authors did not comment on how this pattern may have changed over the years since that 1997 survey. Drug overdose Hagigat, which contains 200 mg of cathinone (one of the components of khat leaves), approximately equivalent to 555 g of khat, are marketed in Israel in capsules as a natural stimulant. Reports to Israel's poison control center of exposure to hagigat have been analysed [61c]. During the 10-month data collection period, there were 34 reports about patients aged 16–54 (median 25) years, 24 men and 10 women. In two cases the drug was inhaled. Myocardial ischemia was

Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong

reported in three cases, pulmonary edema in two, and intracerebral hemorrhage in one. Common adverse effects were headache, nausea, vomiting, hypertension, tachycardia, chest pain, and myalgia. There was no association between the number of capsules ingested and the intensity of the poisoning; however, this might have been due to the small number of cases. The authors estimated that a typical khat session involves 100–200 g of leaves (about 36–72 mg of cathinone); this difference in amount ingested, as well as the faster absorption of hagigat, probably modifies the clinical effects.

OPIOID ANALGESICS See Chapter 8, in which both therapeutic and abuse aspects of the opioids are covered.

Psilocybin

[SEDA-31, 49; SEDA-32, 69]

Drug overdose A 28-year-old man with a history of drug and alcohol abuse came to hospital on several occasions during 2 months with a variety of symptoms, including altered mental status, vomiting, sweating, and mydriasis, which resolved spontaneously on each occasion; each time he required a high level of care [62A]. He later admitted using mushrooms. Of 742 patients with acute intentional exposures to mushrooms, 59 (7.9%) were admitted to hospital, 17 of whom required admission to a critical care unit and four required in-patient psychiatric admission [63c]. Their average age was 21 years and there was a male-to-female predominance of 3.3:1. The actual mushroom was identified in 11 cases, 10 of which involved psilocybin. The most common symptoms were vomiting (n ¼ 34), nausea (n ¼ 19), altered mental status (n ¼ 17), abdominal pain (n ¼ 13), and diarrhea (n ¼ 10).

Drugs of abuse

Chapter 4

67

References [1] Hoffman RS, Kirrane BM, Marcus SM. The Clenbuterol Study Investigators. A descriptive study of an outbreak of clenbuterolcontaining heroin. Ann Emerg Med 2008; 52: 548–53. [2] Manini A, Labinson RM, Kirrane RS, Hoffman RS, Rao R, Stajic M, Nelson LS. A novel neuromuscular syndrome associated with clenbuterol-tainted heroin. Clin Toxicol 2008; 46: 1088–92. [3] Lin JC, Bangs N, Lee H, Kydd RR, Russell BR. Determining the subjective and physiological effects of BZP on human females. Psychopharmacology (Berl) 2009; 207(3): 439–46. [4] Gee P, Gilbert M, Richardson S, Moore G, Paterson S, Graham P. Toxicity from the recreational use of 1-benzylpiperazine. Clin Toxicol (Phila) 2008; 46(9): 802–7. [5] Wilkins C, Sweetsur P, Girling M. Patterns of benzylpiperazine/trifluoromethylphenylpiperazine party pill use and adverse effects in a population sample in New Zealand. Drug Alcohol Rev 2008; 27(6): 633–9. [6] Wood DM, Button J, Lidder S, Ramsey J, Holt DW, Dargan PI. Dissociative and sympathomimetic toxicity associated with recreational use of 1-(3-trifluoromethylphenyl) piperazine (TFMPP) and 1-benzylpiperzine (BZP). J Med Toxicol 2008; 4(4): 254–7. [7] Murphy M, Antia U, Chang HY, Han JY, Ibrahim U, Tingle M, Russell B. Party pills and drug-drug interactions. N Z Med J 2009; 122(1293): 3564. [8] Antia U, Tingle MD, Russell BR. Metabolic interactions with piperazine-based 'party pill' drugs. J Pharm Pharmacol 2009; 61(7): 877–82. [9] Antia U, Tingle MD, Russell BR. In vivo interactions between BZP and TFMPP (party pill drugs). N Z Med J 2009; 122 (1303): 29–38. [10] Wang T, Collet J, Shapiro S, Ware MA. Adverse effects of medical cannabinoids: a systematic review. CMAJ 2008; 178(13): 1669–78. [11] Degenhardt L, Hall WD. The adverse effects of cannabinoids: implications for

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use of medical marijuana. CMAJ 2008; 178 (3): 1685–6. Machado Rocha FC, Stéfano SC, De Cássia Haiek R, Rosa Oliveira LM, Da Silveira DX. Therapeutic use of Cannabis sativa on chemotherapy-induced nausea and vomiting among cancer patients: systematic review and meta-analysis. Eur J Cancer Care (Engl) 2008; 17: 431–43. Mukamal KJ, Maclure M, Muller JE, Mittleman MA. An exploratory prospective study of marijuana use and mortality following acute myocardial infarction. Am Heart J 2008; 155(3): 465–70. Rais M, Cahn W, Van Haren N, Schnack H, Caspers E, Hulshoff Pol H, Kahn R. Excessive brain volume loss over time in cannabis-using first-episode schizophrenia patients. Am J Psychiatry 2008; 165(4): 490–6. Skosnik PD, Edwards CR, O'Donnell BF, Steffen A, Steinmetz JE, Hetrick WP. Cannabis use disrupts eyeblink conditioning: evidence for cannabinoid modulation of cerebellar-dependent learning. Neuropsychopharmacology 2008; 33: 1432–40. Ghaffar O, Feinstein A. Multiple sclerosis and cannabis: a cognitive and psychiatric study. Neurology 2008; 71: 164–9. Thomson WM, Poulton R, Broadbent JM, Moffitt TE, Caspi A, Beck JD, Welch D, Hancox RJ. Cannabis smoking and periodontal disease among young adults. JAMA 2008; 299(5): 525–31. Kunos G, Gao B. Endocannabinoids, CB1 receptors and liver disease: hitting more than one bird with the same stone. Gastroenterology 2008; 134(2): 623–5. Sakkour A, Wang T, Tashkin D. A 56-yearold woman with COPD and multiple pulmonary nodules. Chest 2008; 133: 566–9. McCord J, Jneid H, Hollander JE, de Lemos JA, Cercek B, Hsue P, Gibler WB, Ohman M, Drew B, Philippides G, Newby LK. Management of cocaine-associated chest pain and myocardial infarction. A scientific statement from the American Heart Association Acute Cardiac Care

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Committee of the Council on Clinical Cardiology. Circulation 2008; 117: 1897–907. Afonso L, Mohammad T, Thatai D. Crack whips the heart: a review of the cardiovascular toxicity of cocaine. Am J Cardiol 2007; 100: 1040–3. Kapoor JR. Effect of cocaine on cardiac biomarkers. Am J Cardiol 2008; 101: 744. Daniel JC, Huynh TT, Zhou W, Kougias P, El Sayed HF, Huh J, Coselli JS, Lin PH. Acute aortic dissection associated with use of cocaine. J Vasc Surg 2007; 46: 427–33. Johnson JA, Callison C, Miller AN. A 48year-old man with paralysis and hypotension. Chest 2008; 134: 862–5. Dhawan SS, Wang BWE. Four-extremity gangrene associated with crack cocaine abuse. Ann Emerg Med 2007; 49: 186–9. Mittleman MA, Mintzer D, Maclure M. Triggering of myocardial infarction by cocaine. Circulation 1999; 99: 2737–41. Solini L, Gourgiotis S, Salemis NS, Koukis I. Bilateral pneumothorax, lung cavitations, and pleural empyema in a cocaine addict. Gen Thorac Cardiovasc Surg 2008; 56: 610–2. Turner BJ, St Michel D, Tang S. Exogenous lipoid pneumonia: an unexpected complication of substance abuse. Ann Intern Med 2008; 149: 364–5. Diercks DB, Fonarow GC, Kirk D, JoisBilowich P, Hollander JE, Weber JE, Wynne J, Mills RM, Yancy C, Peacock WF. ADHERE Scientific Advisory Committee and Investigators. Illicit stimulant use in a United States heart failure population presenting to the emergency department (from the Acute Decompensated Heart Failure National Registry Emergency Module). Am J Cardiol 2008; 102: 1216–9. Panchbhavi VK, Leontaritis NM. A case report of atypical magnetic resonance images of the hindfoot following cocaine injection in the foot and a review of osteonecrosis in calcaneus. Foot Ankle Surg 2008; 14: 215–20. De Lange TE, Simsek S, Kramer MH, Nanayakkara PWB. A case of cocaineinduced panhypopituitarism with human neutrophil elastase-specific anti-neutrophil cytoplasmic antibodies. Eur J Endocrinol 2009; 160: 499–502.

Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong

[32] Brewer JD, Meves A, Bostwick M, Hamacher KL, Pittelkow MR. Cocaine abuse: dermatologic manifestations and therapeutic approaches. J Am Acad Dermatol 2008; 59: 483–7. [33] John V, Dai HY, Talati A, Charnigo RJ, Neuman M, Bada HS. Autonomic alterations in cocaine-exposed neonates following orthostatic stress. Pediatr Res 2007; 61: 251–6. [34] Lewis BA, Kirchner LK, Short EJ, Minnes S, Weishampel P, Satayathum S, Singer LT. Prenatal cocaine and tobacco effects on children's language trajectories. Pediatrics 2007; 120: e78–85. [35] Richardson GA, Goldschmidt L, Larkby C. Effects of prenatal cocaine exposure on growth: a longitudinal analysis. Pediatrics 2007; 120: e1017–27. [36] Rao H, Wang J, Giannetta J, Korczykowski M, Shera D, Avants B, Gee J, Detre JA, Hurt H. Altered resting cerebral blood flow in adolescents within utero cocaine exposure revealed by perfusion functional MRI. Pediatrics 2007; 120: e1245–54. [37] Rivkin MJ, Davis PE, Lemaster JL, Cabral HJ, Warfield SK, Mulkern RV, Robson CD, Rose-Jacobs R, Frank D. Volumetric MRI study of brain in children with intrauterine exposure to cocaine, alcohol, tobacco and marijuana. Pediatrics 2008; 121: 741–50. [38] Thomas KR, Thomas SP, HewanLowe KO, Pestaner JP. Fibromuscular dysplasia in association with intrauterine cocaine exposure. Cardiovasc Pathol 2007; 16: 313–6. [39] Droogmans S, Cosyns B, D'haenen H, Creeten E, Weytjens C, Franken PR, Scott B, Schoors D, Kemdem A, Close L, Vandenbossche JL, Bechet S, Van Camp G. Possible association between 3,4methylenedioxymethamphetamine abuse and valvular heart disease. Am J Cardiol 2007; 100: 1442–5. [40] Kumar RS, Grigg J, Fairnelli AC. Ecstasy induced acute bilateral angle closure and transient myopia. Br J Ophthalmol 2007; 91: 693–5. [41] Hart CL, Gunderson EW, Perez A, Kirkpatrick MG, Thurmond A, Comer SD,

Drugs of abuse

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[43]

[44]

[45]

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[47]

[48]

[49]

[50]

Chapter 4

Foltin RW. Acute physiological and behavioral effects of intranasal methamphetamine in humans. Neuropsychopharmacology 2008; 33: 1847–55. Ramaekers JG, Kuypers KPC, Wingen M, Heinecke A, Formisano E. Involvement of inferior parietal lobules in prospective memory impairment during acute MDMA (ecstasy) intoxication: an event-related fMRI study. Neuropsychopharmacology 2009; 34: 1641–8. Rendell PG, Mazur M, Henry JD. Prospective memory impairment in former users of methamphetamine. Psychopharmacology 2009; 203: 609–16. Wareing M, Fisk JE, Montgomery C, Murphy PN, Chandler MD. Information processing speed in ecstasy (MDMA) users. Hum Psychopharmacol Clin Exp 2007; 22: 81–8. Hanson KL, Luciana M, Sullwold K. Reward-related decision-making deficits and elevated impulsivity among MDMA and other drug users. Drug Alcohol Depend 2008; 96(1–2): 99–110. Sauvageau A. Death from a possible anaphylactic reaction to ecstasy. Clin Toxicol 2008; 46: 156. Allot K, Redman J. Are there sex differences associated with the effects of ecstasy/3,4methylenedioxymethamphetamine (MDMA)? Neurosci Behav Rev 2007; 31: 327–47. Kantrowitz JT, Citrome L, Javitt DC. A review of tolerability and abuse liability of gamma-hydroxybutyric acid for insomnia in patients with schizophrenia. Clin Ther 2009; 31(Pt 1): 1360–73. Klein M, Remi J, Pfister HW, Straube A, Rupprecht TA, Weckbach S, Pfefferkorn T. Mimicking of cerebral herniation through gamma-hydroxybutyric acid therapy. Am J Crit Care 2008; 17(6): 593–5 596. Caputo F, Francini S, Stoppo M, Lorenzini F, Vignoli T, Del Re A, Comaschi C, Leggio L, Addolorato G, Zoli G, Bernardi M. Incidence of craving for and abuse of gamma-hydroxybutyric acid (GHB) in different populations of treated alcoholics: an open comparative

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[51]

[52]

[53]

[54]

[55]

[56]

[57]

[58]

[59]

[60]

study. J Psychopharmacol 2009; 23(8): 883–90. Lenz D, Rothschild MA, Kröner L. Intoxications due to ingestion of gammabutyrolactone: organ distribution of gammahydroxybutyric acid and gammabutyrolactone. Ther Drug Monit 2008; 30(6): 755–61. Fieguth A, Albrecht K, Weller JP, Kühnle R, Teske J. Erster Todesfall durch GammaHydroxybuttersäure (GHB) nach Aufnahme von Gamma-Butyrolacton (GBL) in Niedersachsen. [First report of lethal gammahydroxybutyrate (GHB) intoxication after consumption of gamma-butyrolactone (GBL) in Lower Saxony]. Arch Kriminol 2009; 223(1–2): 45–51. Graziani M, Milella MS, Nencini P. Khat chewing from the pharmacological point of view: an update. Subst Use Misuse 2008; 43(6): 762–83. Carrier N. Is miraa a drug? Categorizing Kenyan khat. Subst Use Misuse 2008; 43 (6): 803–18. Beckerleg S. Khat in East Africa: taking women into or out of sex work? Subst Use Misuse 2008; 43(8–9): 1170–85. Klein A. Khat in the neighbourhood—local government responses to khat use in a London community. Subst Use Misuse 2008; 43 (6): 819–31. Gebissa E. Scourge of life or an economic lifeline? Public discourses on khat (Catha edulis) in Ethiopia. Subst Use Misuse 2008; 43(6): 784–802. Bamgbade OA. The perioperative implications of khat use. Eur J Anaesthesiol 2008; 25(2): 170–2. Gelaye B, Philpart M, Goshu M, Berhane Y, Fitzpatrick AL, Williams MA. Anger expression, negative life events and violent behaviour among male college students in Ethiopia. Scand J Public Health 2008; 36: 538. Khawaja M, Al-Nsour M, Saad G. Khat (Catha edulis) chewing during pregnancy in Yemen: findings from a national population survey. Matern Child Health J 2008; 12 (3): 308–12.

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[61] Bentur Y, Bloom-Krasik A, RaikhlinEisenkraft B. Illicit cathinone (“hagigat”) poisoning. Clin Toxicol 2008; 46(3): 206–10. [62] McClintock RL, Watts DJ, Melanson S. Unrecognized magic mushroom abuse in a 28-year-old man. Am J Emerg Med 2008; 26(8): 972.e3–4.

Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong

[63] Barbee G, Berry-Cabán C, Barry J, Borys D, Ward J, Salyer S. Analysis of mushroom exposures in Texas requiring hospitalization, 2005–2006. J Med Toxicol 2009; 5(2): 59–62.

Rebecca Spencer, Stephen Curran, and Shabir Musa

5

Hypnosedatives and anxiolytics

Comparative studies Experience and perceptions of using Z drugs (zaleplon, zolpidem, and zopiclone) and benzodiazepine hypnotics in the community have been studied in a cross-sectional survey of general practice patients [1c]. Patients who had received at least one prescription for a Z drug or a benzodiazepine in the previous 6 months were sent a postal questionnaire. Of 1600 surveys posted, 935 responses (58%) were received, of which 705 (75%) were from patients taking drugs for insomnia. Of those 705 patients, 88% first received a prescription for a hypnotic from their GP, and 95% had taken a sleeping tablet for 4 weeks or more. At least one adverse effect was reported in 42%; 19% wanted to stop taking the hypnotic; and 49% had tried to stop. Compared with those taking benzodiazepines patients who were taking Z drugs were more likely to express a wish to stop (23% versus 12%; OR ¼ 1.67; 95% CI ¼ 1.13, 2.49), or to have attempted to stop (52% versus 41%; OR ¼ 1.54; 95% CI ¼ 1.12, 2.12). The two groups did not differ significantly in respect of benefits or adverse effects. There were no significant differences in patients’ perceptions of efficacy or adverse effects. Adverse effects were commonly reported, which may have contributed to a high proportion of responders, particularly patients taking Z drugs who wanted to stop or who had previously tried to stop taking the medication.

Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00005-2 # 2011 Elsevier B.V. All rights reserved.

Reported prescribing practices were often at variance with the licence for short-term use.

AZASPIRONES

[SEDA-28, 52;

SEDA-32, 75]

Buspirone

[SED-15, 575; SEDA-32, 75]

Placebo-controlled studies In a placebocontrolled study of the use of buspirone (maximum 60 mg/day for 12 weeks) and motivational interviewing in 50 subjects with marijuana dependence, all the adverse events were mild to moderate in intensity [2C]. Most of those who took buspirone (96%) had at least one adverse event compared with 78% of those who took placebo. Dizziness was more common with buspirone (RR ¼ 3.52; 95% CI ¼ 1.08, 11). Dry mouth (RR ¼ 2.35), flushing/sweating (RR ¼ 2.93), and cold-like symptoms (RR ¼ 2.35) were also more common with buspirone than placebo, but not significantly so.

[SED-15, 429; SEDA-30, 49; SEDA-31, 57; SEDA-32, 75]

BENZODIAZEPINES

Nervous system In a study of the relation between the blood concentration of benzodiazepines and their effects on performance 71

Chapter 5

Rebecca Spencer, Stephen Curran, and Shabir Musa

in field sobriety tests, a retrospective case file evaluation was conducted to select 171 drivers who had been tested positive for benzodiazepines only in the period from January 1999 to December 2004 [3c]. Drivers were grouped into those with subtherapeutic, therapeutic, or high concentrations. The outcomes of the tests (walking, walking after turning, nystagmus, Romberg's test, behavior, pupils, and orientation) were binomial. Observations of behavior (n ¼ 137), walking (n ¼ 109), walking after turning (n ¼ 89), and Romberg's test (n ¼ 88) were significantly related to the benzodiazepine concentration. There was no significant relation between benzodiazepine concentration and pupil size, nystagmus, or orientation. These results suggest a relation between the concentration of benzodiazepines and the results of some performance tests. The authors concluded that more effort is needed to standardize the tests and to determine their sensitivity and specificity.

ventricular and atrial septal defects, were recorded in the infants of mothers who had used an SSRI alone, a benzodiazepine alone, or the combination, and were compared with outcomes after no exposure. The risk of a major congenital anomaly or congenital heart disease increased after combined SSRI þ benzodiazepine exposure compared with no exposure. However, using a weighted regression model, controlling for maternal illness characteristics, combination therapy risk was significantly associated only with congenital heart disease. The risk of an atrial septal defect was higher after SSRI monotherapy compared with no exposure, after adjustment for maternal covariates. Daily dose was not associated with an increased risk. Infants who had been exposed to prenatal SSRIs in combination with benzodiazepines had a higher incidence of congenital heart disease compared with no exposure, even after controlling for maternal illness characteristics. SSRI monotherapy was not associated with an increased risk of major congenital anomalies, but was associated with an increased incidence of atrial septal defect.

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Psychiatric In a prospective study of the use of benzodiazepines or opioids in relation to the incidence and duration of delirium in 304 admissions to an intensive care unit, 72% of patients had delirium on their first day of admission and lasting a median of 3 days [4c]. After controlling for baseline dementia, use of haloperidol, and health status, the use of either a benzodiazepine or an opioid within 48 hours was associated with the duration of delirium and in those without pre-existing dementia, there was a 142% increase in the rate of delirium. Teratogenicity The incidence of congenital anomalies after prenatal exposure to selective serotonin reuptake inhibitor antidepressants (SSRIs) used alone and in combination with benzodiazepines has been studied [5C] by linking population health data, maternal health, and prenatal prescription records to neonatal records, representing all live births (British Columbia, Canada, n ¼ 119 547) during 39 months (1998–2001). The incidence and risk differences (RD) for major congenital anomalies and congenital heart disease, including

Clobazam

[SED-15, 806]

Skin Stevens–Johnson syndrome has been reported in a patient taking a combination of clobazam, lamotrigine, and valproic acid [6A].

Clonazepam

[SED-15, 815]

Psychological The relation between clonazepam plasma concentrations after a single oral dose of 4 mg and impairment of psychomotor performance has been studied in 23 healthy volunteers [7c]. Clonazepam reduced psychomotor performance by up to 72% at 1.5–4 hours after administration and there was time-dependent tolerance. However, there was too much interindividual variation to allow individual prediction of these effects.

Hypnosedatives and anxiolytics

Chapter 5

73

Hair Hair loss has been reported in association with clonazepam [8A].

Diazepam

Drug withdrawal Withdrawal of benzodiazepines is associated with a risk of features such as rebound insomnia, anxiety, perceptual changes, convulsions, or delirium [9A]. Malignant catatonia has also rarely been reported, as another case illustrates.

Drug resistance P glycoprotein can confer drug resistance on cells by allowing them to export drugs. In a study of the binding of some benzodiazepines (bromazepam, chlordiazepoxide, diazepam, and flurazepam) to P glycoprotein in proteoliposomes and their effects on its transport function and ATPase activity in the human cancer cell line, KBV1, the toxicity of the benzodiazepines towards the KB-V1 cells was first evaluated and the non-toxic drug concentrations were used to assess drug efflux and ATPase activity [12E]. Using flow cytometry, accumulation and efflux of daunorubicin were studied by measuring the daunorubicin-associated geometric mean fluorescence intensity. Vanadate was used as a comparative inhibitor. Flurazepam inhibited daunorubicin efflux in 80%. ATPase activity showed that flurazepam inhibits P glycoprotein-linked enzyme activity, indicating coupling between drug transport and ATP hydrolysis. Bromazepam, chlordiazepoxide, and diazepam activated P glycoprotein-linked ATPase activity, suggesting a role as transported substrates, but they did not interfere with daunorubicin transport.

• A 60-year-old man developed acute confusion, grimacing, stereotypy, refusal of food and water, muscle rigidity, mutism, and extreme negativism after abruptly discontinuing all psychotropic medications. He was given lorazepam and then clonazepam was re-started. His catatonic symptoms and autonomic instability resolved completely.

The mechanism by which catatonia is precipitated by benzodiazepine withdrawal is not known; the authors speculated that it may involve a rapid reduction in GABA transmission. Drug abuse Clonazepam is often used as a drug of abuse and to treat drug addicts. In cases referred to the Section of Forensic Chemistry at the University of Copenhagen in 2002–2007 clonazepam and its metabolite 7-aminoclonazepam were detected in 297 cases after traffic accidents (median 0.067 mg/kg), in 92 perpetrators or victims of a crime (median 0.071 mg/kg), and in 140 postmortem cases (median 0.115 mg/kg) [10c]. In 27 of the postmortem cases with high concentrations other drugs had been taken, but clonazepam was thought to have been the primary cause of death in five (concentrations 0.26–0.54 mg/kg). The extent of abuse of clonazepam has been assessed in a French study, in which deliveries of clonazepam to individuals who had had a prescription reimbursed were monitored for 9 months [11c]. There was an increase of 82% in participants who had a delivery of clonazepam between 2001 and 2006, and some deviant participants were identified; they included a higher proportion of men, benzodiazepine users, and buprenorphine users. The proportion of deviant participants increased between 2001 and 2006 from 0.86% to 1.38%.

[SED-15, 1103; SEDA-30, 50; SEDA-31, 57; SEDA-32, 75]

Drug administration route Intranasal and intravenous diazepam have been compared [13A]. The tmax and half-life were similar after 5 and 10 mg intranasally and the systemic availability was 75%. There were no adverse events, although many subjects reported swallowing much of the preparation. All reported transient pain and watery eyes.

Flunitrazepam

[SED-15, 1394;

SEDA-31, 58] Cardiovascular Accidental injection of flunitrazepam tablets dissolved in tap water into the left femoral artery by a 22-year-old drug abuser caused acute ischemia of the leg with severe rhabdomyolysis within 5 hours [14A]. There was acute occlusion

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Chapter 5

of the posterior tibial artery, which resolved with intra-arterial urokinase and prostaglandins and intravenous anticoagulation. Nervous system The risk of road traffic accidents in individuals who have filled a prescription for flunitrazepam, nitrazepam, zolpidem, or zopiclone has been studied [15c]. All Norwegians aged 18–69 years (3.1 million) were followed from January 2004 until the end of September 2006. Information on prescriptions, road traffic accidents, and emigration/death was obtained from three Norwegian population-based registries. The first week after the hypnotics had been dispensed was considered to be the exposure period. Standardized incidence ratios (SIRs) were calculated by comparing the incidence of accidents in the exposed person-time to the incidence of accidents in the unexposed person-time. During exposure, 129 accidents were registered for zopiclone, 21 for zolpidem, 27 for nitrazepam, and 18 for flunitrazepam. The SIRs were: Z hypnotics (zopiclone þ zolpidem) 2.3; nitrazepam 2.7; and flunitrazepam 4.0. The highest SIRs were found among the youngest users for all hypnotics. Thus, users of hypnotics had a clearly increased risk of road traffic accidents, and the risk for flunitrazepam was particularly high.

Flurazepam Nervous system The residual effects of gaboxadol 10 mg and flurazepam 30 mg on the day after bedtime administration have been compared in a crossover, double-blind, randomized, placebo-controlled study in 25 healthy elderly subjects [16c]. Flurazepam significantly impaired choice reaction time, the threshold for critical flicker fusion, digit symbol substitution, and speed of compensatory tracking, but did not alter immediate or delayed word recall or the eyes-closed endpoint of the body sway test. Gaboxadol had no deleterious effects.

Rebecca Spencer, Stephen Curran, and Shabir Musa

Lorazepam [SED-15, 2163; SEDA-30, 51; SEDA-31, 58; SEDA-32, 76] Sexual function Greatly enhanced sexual desire has been attributed to lorazepam [17A]. • A 62-year-old married woman with carcinoma of the breast was given lorazepam 1 mg at bedtime for insomnia. At her next follow-up appointment, she reported with some embarrassment how she felt after taking the first dose. Over the next hour, she had developed a strangely intense sexual desire, an overwhelming pleasant sensation climbing over her inner thighs, progressing to the genitalia, followed by the sensation of having sexual intercourse, which she repressed before getting an orgasm. She said that for the first time in some years she had seriously thought about waking up her husband to initiate intercourse. “I had not felt like this in years. It was like having sexual intercourse without wanting it. I could not help myself feeling an intense but unwanted pleasure”. The sensations faded gradually over the next few hours. The symptoms were repeated when she took a dose on the next evening.

The authors suggested that this could have been explained by inhibition of the action of serotonin in the septal and amygdaline nuclei. Drug formulations Propylene glycol is used as a solvent for many liquid formulations of drugs, including lorazepam. There is a high risk of propylene glycol toxicity during the administration of large doses of lorazepam intravenously, as has been reported in critically ill adults [18c]. This has been studied in 35 adults who received any dose of parenteral lorazepam and in 14 patients who received lorazepam in doses of 1 mg/kg/ day or more [19c]. The osmolar gap (measured serum osmolality minus calculated osmolarity) was used as a measure of toxicity. The serum propylene glycol concentration was measured when the osmolar gap exceeded 10. In phase 1, 35 patients were monitored for 186 patient-days; 10 developed an osmolar gap greater than 10, but only one had a propylene glycol concentration over 180 mg/l. In phase 2, 14 patients received lorazepam in a median dose of

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Chapter 5

631 mg (interquartile range 437–972 mg) over a median of 5.5 days. Nine patients had propylene glycol concentrations over 180 mg/l and six of them developed transient acute kidney injury, metabolic acidosis, or both. There was a correlation between the osmolar gap and the propylene glycol concentration. An osmolar gap of 10 or greater had a likelihood ratio of 4.4 to predict a propylene glycol concentration over 180 mg/l; an osmolar gap of 12 or greater had a likelihood ratio of 2.7 to predict the development of propylene glycol toxicity. The authors concluded that the osmolar gap may be helpful in screening for propylene glycol toxicity in patients who are receiving intravenous lorazepam in doses of 1 mg/kg/day or more. Drug–herb interactions The dangers of herbal medicines have been highlighted by the case of a man who self-medicated with Valeriana officinalis and Passiflora incarnata while he was also taking lorazepam and developed shaking hands, dizziness, throbbing, and muscle fatigue [20A]. The authors suggested that the active principles in valerian and passionflower might increase the inhibitory effects of benzodiazepines.

Lormetazepam

[SED-15, 2167;

SEDA-32, 77] Drug overdose Although benzodiazepine overdose is rarely fatal, a very large overdose can be [21A]. • A 34-year-old woman was found dead in her bed with evident traces of vomit and feces. No medicinal products or drugs of abuse were found around the body and there was no evidence of injury or trauma. At the autopsy, 3 days later, external examination was unremarkable and there were no signs of chronic drug abuse. Internal examination showed pulmonary edema and severe vascular congestion in all internal organs. Toxicological analysis of blood, urine, and bile samples showed the presence of lormetazepam and its metabolite lorazepam in traces. This, together with the absence of other drugs or alcohol, strongly suggested that death was due to acute overdose of lormetazepam only.

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Midazolam

[SED-15, 2337; SEDA-30, 51; SEDA-31, 59; SEDA-32, 77]

Observational studies In a prospective study of 516 children undergoing CT scans, who received midazolam 0.212 mg/kg, there was adequate sedation in 5.9 minutes and only a few patients required additional boluses [22c]. There were adverse effects in 9.1% of patients, including desaturation in 6.9%, all of whom were treated successfully with oxygen, hiccups in 1.4%, and agitation in 0.79%. All the adverse effects were self-limiting. In 41 adults undergoing transesophageal echocardiography, who received midazolam either alone (2.5 mg bolus plus 1 mg increments as required) or in combination with remifentanil (midazolam 0.5 mg þ remifentanil 0.08 micrograms/kg/ minute), the median time to an acceptable Aldrete score (a measurement of readiness for discharge) was much slower after midazolam than remifentanil þ midazolam (30 versus 5 minutes) [23c]. There were significant reductions in blood pressure but not heart rate in both groups and there were no adverse respiratory events. In a study of sedation during local anesthesia for bone marrow aspiration, 46 adults were randomized to midazolam 2 mg every 2 minutes (n ¼ 21) until conscious sedation was achieved or Entonox (n ¼ 25) delivered by the patient [24c]. Amnesia was induced by midazolam in 55% compared to 4% with Entonox. There was greater pain and dizziness with Entonox, but midazolam caused desaturation in 19% of patients. Midazolam reversal was required in 10 patients for either desaturation or prolonged sedation (after a mean dose of 0.08 mg/kg). Respiratory The effect of oral midazolam 0.3 mg/kg on respiratory function has been studied in 18 children (median age 78 months) without cardiorespiratory disease undergoing elective surgery [25c]. There was a reduction in tidal and minute volume but not respiratory rate or expiratory times. There was a 6.5% reduction in functional residual capacity and corresponding

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increases in LCI, respiratory resistance, and elastance (7.8%, 7.4%, and 9.2% respectively) 20 minutes after pre-medication. There were no episodes of desaturation.

10 minutes at both intranasal doses and the systemic availability was 60%. The maximum concentration was dose-dependent but half-life was not affected by dose or route of administration. The most common adverse events were pharyngitis (n ¼ 11), rhinitis (14), and taste disturbances (11), but all were transient and lasted only 2–14 minutes. There were no serious adverse events or changes in endoscopic nasal examination.

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Nervous system Extrapyramidal adverse effects have been attributed to midazolam [26A] and hypothesized to have been due to inhibition of firing in the substantia nigra secondary to an effect on a3-containing GABAA receptors [27r]. Acid–base balance A severe hyperchloremic metabolic acidosis with a normal anion gap occurred in a 9-year-old girl who was given a high-dose continuous intravenous infusion of midazolam for refractory status epilepticus and resolved within 5 hours of withdrawal [28A]. The authors suggested that it was due to the use of hydrochloric acid in the parenteral formulation. Drug administration route Intranasal midazolam is used widely and successfully as pre-medication, particularly in children, avoiding first-pass metabolism and increasing systemic availability [29A]. In a double-blind, crossover, randomized trial in 10 healthy volunteers midazolam 0.2 mg/kg was given by nebulizer and liquid instillation nasally 5 days apart [30c]. Plasma concentrations were greater after intranasal midazolam. Nasal instillation caused increased sedation but no difference in the time to sedation. There were no respiratory adverse events. Blood pressure and oxygen saturation fell in both groups (peak reduction at 15 minutes) but none required extra oxygen. Mean heart rate and diastolic pressure were increased. The incidence of unpleasant adverse effects was greater after intranasal midazolam, and nasal stinging, eye irritation, hiccups, and excessive secretions were common. One patient with asthma became wheezy after intranasal administration. Intranasal midazolam 2.5 and 5 mg have been compared with intravenous midazolam 2.5 mg in a crossover study in 18 healthy volunteers [31c]. The tmax was

Drug–drug interactions Antifungal azoles Posaconazole inhibits CYP3A4, by which midazolam is metabolized. The effects of oral posaconazole 200 mg bd for 7 days and ketoconazole 400 mg od for 7 days on the pharmacokinetics of oral and intravenous midazolam have been studied in 12 healthy volunteers [32c]. Both azoles reduced the clearance and prolonged the half-life of midazolam, ketoconazole more so than posaconazole. Seven subjects reported at least one adverse event during the study (five with posaconazole alone and four with posaconazole þ midazolam). The most common adverse events were diarrhea (n ¼ 3 with posaconazole alone, two with ketoconazole alone, and one with posaconazole þ midazolam) and flatulence (one with posaconazole alone and one with midazolam alone). Opioids Drug–drug interactions with midazolam have been studied in 7431 patients in a Brazilian hospital (28% of all the patients who had been admitted to the hospital) [33c]. Flumazenil was given to 26 patients within 24 hours after midazolam and there were clinically significant drug–drug interactions resulting from prescriptions of drugs preceding the use of flumazenil in 23 cases. The most common interactions were related to central nervous system depressants (22 cases), mainly opioid agonists. Protease inhibitors The effects of multiple doses of ritonavir-boosted saquinavir (100 mg þ 1000 mg bd for 2 weeks) on the pharmacokinetics of a single oral dose

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Chapter 5

of midazolam 7.5 mg have been studied in 18 healthy volunteers [34c]. Saquinavir þ ritonavir increased the Cmax of midazolam 4.3-fold and the AUC 12.4-fold; the half-life was prolonged from 4.7 to 15 hours. The Cmax and AUC of 10 -hydroxymidazolam were reduced by about sevenfold and twofold respectively. The combination resulted in prolonged sedation. Drug overdose Between November 2004 and November 2008, UK health-care staff reported 498 dosing errors for midazolam to the National Patient Safety Agency (NPSA); there were three deaths [35S]. The following problems were reported: • drawing up part content of a high-strength injection ampoule (10 mg in 2 ml or 10 mg in 5 ml) or giving the whole ampoule by mistake; • failing to titrate the dose to the needs of the individual patient; • not understanding the risks of combining midazolam with other drugs, such as opioids; • widespread use of, and possible over-reliance on, the reversing agent, flumazenil.

The Agency made recommendations:

the

following

• remove high-strength midazolam from all but defined clinical areas (such as general anesthesia, intensive care, and palliative care) and replace with low-strength alternatives; • review training needs; • identify a lead (usually an anesthetist) for sedation policy and auditing the use of flumazenil locally; • routinely use the safer 1 mg/ml strength (in 2 ml or 5 ml ampoules) rather than highstrength midazolam in general areas—for example, where outpatient diagnostic procedures are performed; • do not use part-ampoules or part-phials of high-strength midazolam; • do not rely on flumazenil to reverse oversedation by midazolam, but aim to prevent oversedation in the first place; however, if you need to use flumazenil, audit its use; • continue to use high-strength midazolam for general anesthesia and intensive care sedation, and for palliative care when syringe drivers are used; in the latter case undertake a formal risk assessment, especially when different strengths of midazolam are stocked for different indications in a single clinical area.

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Drug–herb interactions Interactions of midazolam with herbal medicines have been reviewed [36R].

Temazepam

[SED-15, 3312;

SEDA-30, 52] Susceptibility factors Age Temazepam 15 mg and diphenhydramine 50 mg for 14 nights have been compared in elderly individuals with insomnia (mean age 74, range 70–89 years) in a randomized, placebo-controlled, crossover study [37c]. Primary outcome measures were subjective assessments of sleep recorded on sleep diaries. Secondary measures were the morning-after psychomotor impairment, using the digital symbol substitution task and the manual tracking task, and the morning-after memory impairment, using a free-recall procedure. Temazepam improved sleep quality, total sleep time, number of awakenings, and sleep-onset latency compared with placebo. Diphenhydramine improved the number of awakenings only. The numbers of adverse events were similar after all treatments, although there was one fall during temazepam treatment. This suggests that temazepam is more effective than diphenhydramine, although this advantage is mitigated by the risk of falls. The choice of agent to use in elderly people must consider these relative benefits and harms.

Triazolam

[SED-15, 3486; SEDA-31, 60; SEDA-32, 79] Nervous system The effects of triazolam 0.375 mg, and zolpidem 10 mg, two GABAA allosteric activators, on sleepdependent motor skill memory consolidation have been studied in a placebo-controlled study in 12 healthy men [38C]. Triazolam was associated with longer total sleep time and increased stage 2 sleep. Both zolpidem and triazolam were associated with an increased latency to rapid eye

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movement (REM) sleep. Overnight motor learning correlated with total sleep time after placebo but not after triazolam or zolpidem. Motor performance was significantly impaired overnight by triazolam only.

tabulated. Combining controlled trials for the four drugs, there were 6190 participants who had taken hypnotics and 2535 who had taken placebo in parallel. There were eight mentions of incident non-melanoma skin cancers among participants who took hypnotics but no comparable mentions of cancers among those receiving placebo. There were also four mentions of incident tumors of uncertain malignancy among those who took hypnotics but none among those who took placebo. FDA files showed that all four of the new hypnotics were associated with cancers in rodents. Three had been shown to be clastogenic. Together with epidemiological data and laboratory studies, the available evidence suggests that new hypnotics may increase the risk of cancers.

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Drug overdose A 76-year-old woman died after taking a combination of triazolam and promazine in overdose [39A]. Post-mortem triazolam and promazine concentrations were respectively: blood 1100 and 3450 ng/ml; gastric contents 1300 and 5800 ng/ml.

BENZODIAZEPINE-LIKE DRUGS Zaleplon

[SED-15, 3710; SEDA-29, 57]

Psychiatric Perceptual disturbances have been attributed to zaleplon [40A]. • A 20-year-old Caucasian woman with DSMIV diagnoses of major depressive disorder and borderline personality disorder reported insomnia characterized by difficulty falling asleep, but no difficulty maintaining sleep, for 6 months. She was given zaleplon 10 mg capsules and advised to take one at bedtime as needed. She was also taking fluoxetine 60 mg od, ziprasidone 40 mg/day, and the oral contraceptive AlesseÒ. When her insomnia persisted the dose of zaleplon was increased to 20 mg and she took it about six times during the next month. On three of those occasions she had had some unusual perceptual experiences, including seeing tree branches moving closer to her, seeing movements of water and fire in a painting on a wall, and seeing people moving and talking to her on another picture. After each episode, she had fallen asleep and wakened the next morning with no unwanted after-effects.

Tumorigenicity Data from controlled trials have been analysed to determine whether hypnotics can cause cancer [41M]. The US Food and Drug Administration (FDA) Approval History and Documents were accessed for zaleplon, eszopiclone, zolpidem, and ramelteon. Incident cancers that occurred during randomized administration or placebo administration were

Drug overdose A case of zaleplon overdose has been described [42A]. • A 24-year-old woman took 28 or so tablets of zaleplon. The time of ingestion was undetermined but it was probably more than 4 hours earlier. She was confused and sleepy. She looked pale and her mouth and lips were stained blue-green. Soon after arrival she vomited dark blue-green stomach contents. Although a complete neurological examination was difficult to perform, there were no major abnormalities. Her blood pressure was low but responded to 20 ml/kg of isotonic saline. The electrocardiogram showed sinus tachycardia. A urine sample was strongly blue-green in color and a urine drug screen for opioids, benzodiazepines, cocaine, amphetamines, barbiturates, methadone, and cannabinoids was negative. She subsequently became restless, was confused, and had visual hallucinations and intermittent myoclonus. The next day she was alert and cooperative and a complete examination was normal.

The authors concluded that the blue-greenish discoloration of the vomit and urine could be an important sign of zaleplon overdose.

Zolpidem

[SED-15, 3723; SEDA-30, 53; SEDA-31, 61; SEDA-32, 80]

Nervous system Sleep walking has been attributed to zolpidem [43r].

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• A 51-year-old, white, married woman experienced two episodes of somnambulism with amnesia while taking zolpidem 10 mg at bedtime. During these episodes, she walked down the steps from her second-storey bedroom to the kitchen and ate normal amounts of food. She stopped taking zolpidem and had no further problems.

Cases of sleep driving associated with the use of non-benzodiazepine hypnotics reported to the US Food and Drug Administration (FDA) Adverse Events Reporting System have been summarized [44c]. On 1 March 2006, the FDA Adverse Events Reporting System was searched for postmarketing reports of sleep driving associated with zolpidem, zaleplon, and eszopiclone. Each identified case was evaluated to ensure that it met the general requirements for sleep driving. There were 14 cases, 13 of which involved zolpidem. Of these 13, eight involved concomitant use of a psychotropic drug (benzodiazepine, alcohol, or a narcotic). Zolpidem was the most commonly implicated drug in sleep driving, but it is unclear whether this is attributable to a greater risk of sleep driving with zolpidem, more widespread use of the drug, or other factors. Concomitant use of other psychotropic drugs could have potentiated the effect of zolpidem.

Zopiclone [SED-15, 3710; SEDA-31, 62] Nervous system The residual effects at 10–11 hours after evening doses of temazepam 20 mg and zopiclone 7.5 mg on driving performance in a standardized highway driving test have been evaluated in 18 healthy elderly drivers in a double-blind, three-way, placebo-controlled crossover study [45C]. Driving performance did not differ between temazepam and placebo but was significantly impaired after zopiclone. The magnitude of the impairment was comparable with that found before in younger volunteers.

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BENZODIAZEPINE ANTAGONISTS Flumazenil Flumazenil is a benzodiazepine antagonist used to reverse the effects of benzodiazepines in the treatment of poisoning or in anesthesia [46c, 47R, 48R, 49A]. It reduces the risks of complications from drug overdose, obviating the need for invasive interventions such as mechanical ventilation and invasive hemodynamic monitoring [50c]. However, it is not effective in reversing the amnesic effects of midazolam [51A]. It has also been used to reverse the effects of zaleplon [52A], zolpidem [53A, 54A, 55C], zopiclone [56A, 57A], antihistamines such as promethazine [58A, 59A], baclofen [60A], cannabis [61A], carisoprodol [62A], chloral hydrate [63A], chlorzoxazone [64A], carbamazepine [65A], gabapentin [66A], paclitaxel [67A], propofol [68C], and thiopental [69C]. Guidelines for its use have been summarized [70R]. The problems in using flumazenil are those of dose adjustment, the risks of panic anxiety, seizures, or other signs of excessively rapid benzodiazepine withdrawal. Its use is also commonly associated with vomiting and headache, and rarely with psychosis or sudden cardiac death [71A], especially in mixed overdoses. It can occasionally cause a benzodiazepine withdrawal reaction [72C]. In 17 patients who were given flumazenil to reverse the effect of midazolam after upper gastrointestinal endoscopy, it reversed the sedative effects in under 2 minutes but did not affect the ventilatory effects [73c]. However, in a randomized, double-blind, placebo-controlled crossover study in 12 healthy volunteers intravenous flumazenil 1.0 mg restored respiratory function within 3 minutes [74C]. Since flumazenil has a short half-life (about 1 hour) compared with the longer half-lives of most benzodiazepines, its beneficial effects can wear off before the effects of the benzodiazepines [75R]. Re-sedation occurs in about

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65% of patients, usually within 0.5–3 hours after the first dose, the shorter interval being associated with poisoning with combinations of drugs; repeated doses of flumazenil, sometimes followed by continuous infusion are effective [76M]. In 50 patients who were given intravenous placebo or flumazenil 15 minutes after injection of flunitrazepam 0.03 mg/kg in a randomized, double-blind study, flumazenil promptly reversed sedation for 30 minutes, hypotonia for 45 minutes, and anterograde amnesia for 60 minutes, and improved orientation and collaboration for 60 minutes; however, anterograde amnesia recurred after 60 minutes and sedation after 90 minutes [77C]. In a placebo-controlled study in 30 patients who had received midazolam followed by intravenous flumazenil, subcutaneous flumazenil did not prevent the rebound sedation that occurred after 90 min; adverse effects included nausea and vomiting [78C]. However, a continuous infusion of flumazenil 0.5 mg/hour can prevent re-sedation [79C]. Paradoxical adverse effects of benzodiazepines, such as aggressive behavior, can occur [80r] and can be reversed by flumazenil [81A, 82A, 83A, 84A, 85A]. In 58 patients undergoing surgery under spinal or epidural anesthesia, flumazenil 0.1 mg over 10 seconds abolished the agitation without reversing sedation (total dose range 0.1–0.5 mg) [86cr]. In 30 patients who had been given midazolam, flumazenil 0.15–0.5 mg resulted in cessation of the agitation without reversal of sedation [87A]. Adverse effects of flumazenil were not reported in these studies. Flumazenil has been used as a non-specific treatment in patients with hepatic encephalopathy [88c, 89R]. However, it was effective in only some subjects in a double-blind, placebo-controlled, crossover study in 527 patients with cirrhosis and hepatic encephalopathy grade III and IVa, of whom 265 received flumazenil and 262 received placebo [90C]. There was improvement of the neurological score in 18% of the patients with grade III encephalopathy and in 15% of those with grade IVa compared with 3.8% and 2.7% respectively of those who received placebo; electroencephalography improved in 28% and 22% compared with

5% and 3.3%. Similar results were obtained in a study of 236 patients with grade IVa hepatic encephalopathy [91C]. In a single-dose, crossover, double-blind, placebo-controlled study of flumazenil and placebo in 16 subjects with Parkinson's disease, scores on the Unified Parkinson's Disease Rating Scale tended to improve, but the effect was not significant; the most common adverse events were light-headedness or dizziness [92C]. Flumazenil is not anxiolytic after alcohol withdrawal [93C]. It is not generally helpful to measure benzodiazepine plasma concentrations, but they can assist in the diagnosis of overdose and thus guide the use of antagonists [94c].

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Placebo-controlled studies In a doubleblind, randomized, placebo-controlled study in 105 unconscious adults with suspected drug overdose, 73 of whom had taken benzodiazepines, flumazenil caused adverse effects in nine cases: agitation (n ¼ 3), a depressive mood (n ¼ 3), nausea and vomiting (n ¼ 1), shivering (n ¼ 1), and one severe adverse reaction—a sudden fall in blood pressure in a 28-year-old woman in deep coma after combined poisoning with benzodiazepines and maprotiline [95C]. In a multicenter, double-blind, placebocontrolled study of the effects of intravenous flumazenil 0.7 mg in reversing the effects of midazolam, 82% of 131 flumazenil-treated patients had complete reversal of sedation, compared with 15% of 65 placebo-treated patients. However, flumazenil reversed midazolam-induced amnesia in only 60% of patients. Dizziness (10%) and nausea (9%) were the most common adverse effects [96C]. Similar results were obtained in a double-blind, placebo-controlled study in patients who had been given midazolam plus an opioid (fentanyl, pethidine, or morphine) [97C], intravenous diazepam [98C], or diazepam plus an opioid [99C]. Cardiovascular Multifocal ventricular extra beats with short runs of ventricular tachycardia occurred within seconds after the administration of flumazenil to reverse oxazepam

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toxicity in a 30-year-old woman [100A]. She had also taken chloral hydrate, which may have sensitized the heart. Ventricular fibrillation has also been reported in a 60-year-old man [101A]. In another case co-administration of a tricyclic antidepressant may also have increased the risk of dysrhythmias [102A]. • A 57-year-old woman took an overdose of lorazepam and amitriptyline and became deeply unconscious. She had a nodal rhythm and frequent multifocal ventricular extra beats, ventricular couplets and triplets, and salvos of ventricular tachycardia. She was given intravenous flumazenil in divided doses to a total of 500 micrograms. Her respiratory rate increased to 20/minute and after 5 minutes she had generalized tonic–clonic convulsions, followed in 15 seconds by ventricular tachycardia, with no cardiac output, which reverted to sinus rhythm with direct current cardioversion. The convulsion ended spontaneously after 30 seconds but recurred within 2 minutes, again followed by sustained ventricular tachycardia. This pattern of events recurred and nine cardioversions were required. The convulsions eventually resolved with intravenous diazepam and thiopental.

Complete heart block occurred when flumazenil was given to a woman who had taken an overdose of paracetamol and temazepam [103A]. Nervous system Seizures have been attributed to flumazenil [104A, 105A, 106A, 107A, 108A, 109A, 110A, 111R], including status epilepticus [112A, 113A], which can be fatal. However, it has been suggested that seizures are not a toxic effect of flumazenil, but are in many cases instead due to unmasking of the anticonvulsant effect of the benzodiazepine or to a severe benzodiazepine-withdrawal syndrome; furthermore, in some cases they may be due to other drugs taken at the same time, such as tricyclic antidepressants [114c]. Thus, it has been recommended that flumazenil should not be given to patients who have used benzodiazepines for seizure disorders or to patients who have taken other drugs that increase the risk of seizures (e.g. bupropion, ciclosporin, cocaine, cyclic antidepressants, isoniazid, lithium, methylxanthines, monoamine oxidase inhibitors, and propoxyphene).

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Opisthotonos after flumazenil has been reported [115A]. • A healthy 17-year-old man received an interscalene brachial plexus block using mepivacaine 600 mg and bupivacaine 150 mg. He became disorientated and showed signs of local anesthetic toxicity, for which he was given midazolam 5 mg. Flumazenil 0.5 mg was given 23 minutes after the end of the procedure, causing opisthotonos.

Ballismus has also been reported [116A]. Psychiatric Oral flumazenil was used in a woman who had had several episodes of hepatic encephalopathy, in an attempt to prevent deterioration into coma, but after 2 days she had an acute psychosis; the symptoms resolving rapidly when flumazenil was withdrawn [117c]. Endocrine The effects of flumazenil and midazolam on adrenocorticotrophic hormone and cortisol responses to a corticotrophin-releasing hormone challenge have been assessed in eight healthy men [118c]. Flumazenil significantly caused reduced adrenocorticotrophic responses compared with midazolam or placebo, but had no effects on cortisol secretion. The authors suggested that this agonist effect of flumazenil on the pituitary-adrenal axis might account for the anxiolytic activity of flumazenil, which has been observed during simulated stress. Susceptibility factors Age The usefulness and relative safety of midazolam in children have been reviewed [119R]. Myoclonic-like movements associated with midazolam in three full-term newborns were reversed by flumazenil [120A]. The pharmacokinetics of flumazenil are not altered in elderly people [121c]. Drug withdrawal In individuals who have taken long-term benzodiazepines, flumazenil can provoke acute withdrawal reactions [122C, 123C] and extreme anxiety [124A]. Duration of exposure to the benzodiazepine does not affect the intensity of withdrawal beyond the first week of exposure [125C].

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In a placebo-controlled study in 34 chronic users of diazepam 5–20 mg/day for 5–28 years, a single-dose of flumazenil caused anxiety reactions; in nine of 15 subjects with a history of panic attacks, panic attacks were precipitated [126C].

cause excitation; a case has been reported with chloral hydrate [129A].

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Drug administration route In six patients undergoing elective surgery during general anesthesia endotracheal flumazenil 1.0 mg in 10 ml of saline therapeutic blood concentrations were rapidly achieved [127c]. In 11 patients aged 2–6 years undergoing general anesthesia for dental surgery intranasal drops of flumazenil resulted in plasma concentrations similar to those reported after intravenous administration [128c].

OTHER HYPNOSEDATIVES Chloral hydrate [SED-15, 705; SEDA30, 52; SEDA-31, 60; SEDA-32, 79] Nervous system Paradoxical reactions to hypnosedatives occur occasionally and can

Drug overdose Unintentional administration of a 10-fold dose of chloral hydrate (667 mg/kg) in a 3-month-old girl resulted in respiratory depression, requiring intubation and ventilation [130A]. There were also esophagitis and gastric ulcers. The serum trichloroethanol concentration was 89 mg/l 6 hours later and fell to 20 mg/l within 24 hours and dialysis was not required.

Ramelteon

[SEDA-32, 79]

On 8 September 2008 the European Medicines Agency announced that Takeda, the manufacturers of ramelteon, had withdrawn its application for marketing authorization for ramelteon for the treatment of primary insomnia in patients over the age of 18 years with a view to extending its clinical programme to address outstanding questions on the benefit to harm balance; this followed a negative recommendation from the regulators in June 2008 [131r].

References [1] Siriwardena AN, Qureshi MZ, Dyas JV, Middleton H, Orner R. Magic bullets for insomnia? Patients’ use and experiences of newer (Z drugs) versus older (benzodiazepine) hypnotics for sleep problems in primary care. Br J Gen Pract 2008; 58(551): 417–22. [2] McRae-Clark AL, Carter RE, Killeen TK, Carpenter MJ, Wahlquist AE, Simpson SA, Brady KT. A placebo-controlled trial of buspirone for the treatment of marijuana dependence. Drug Alcohol Depend 2009; 105(1–2): 132–8. [3] Smink BE, Lusthof KJ, de Gier JJ, Uges DRA, Egberts ACG. The relation between the blood benzodiazepine concentration and performance in suspected impaired drivers. J Forensic Legal Med 2008; 15: 483–8.

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88

Alfonso Carvajal, Luis H. Martín Arias, and Natalia Jimeno

6 GENERAL

Antipsychotic drugs [SED-15, 2438;

SEDA-32, 83]

Typical versus atypical antipsychotic drugs Data from two major government-funded studies of comparative antipsychotic drug effectiveness in schizophrenia contradict the widely prevalent belief that the newer second-generation medications are vastly superior to the older first-generation drugs [SEDA-30, 56; SEDA-31, 65]. The World Psychiatry Association Section on Pharmacopsychiatry has reviewed the literature on the comparative effectiveness of different antipsychotic drug treatments for schizophrenia and has issued a statement [1R]. They reported that antipsychotic drugs are very heterogeneous, with substantial differences in adverse effects profiles from drug to drug. Second-generation antipsychotic drugs were also found to be inconsistently more effective than first-generation agents in alleviating negative, cognitive, and depressive symptoms, and were less likely to cause tardive dyskinesia; these modest benefits were principally driven by the ability of second-generation antipsychotics to provide equivalent improvement in positive symptoms along with a lower risk of causing extrapyramidal adverse effects. Clozapine was shown to be more efficacious than other agents in treatment-refractory schizophrenia. Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00006-4 # 2011 Elsevier B.V. All rights reserved.

Dosage was a key variable in optimizing effectiveness of both first- and second-generation antipsychotic drugs. In contrast to their relatively similar efficacy in treating positive symptoms, there were substantial differences between first- and second-generation antipsychotic agents with regard to their propensity to cause extrapyramidal, metabolic, and other adverse effects: second-generation agents are less likely to cause acute extrapyramidal symptoms and tardive dyskinesia but have a tendency to cause greater metabolic adverse effects than first-generation agents.

Observational studies Psychiatrists’ attitudes to and actual practices in using typical and atypical antipsychotic drugs in elderly people have been audited in 321 patients (mean age 76 years) in 18 old-age psychiatry units across Australia, in which the attitudes of a sample of 57 prescribing doctors (mean age 46 years) were assessed [2c]. Over 96% of the doctors reported that adverse events were obstacles to prescribing typical antipsychotic drugs; the most common concerns with typical drugs were related to acute extrapyramidal symptoms (86%), tardive dyskinesia (80%), sedation (35%), hyperprolactinemia (18%), and weight gain (18%). With regard to atypical drugs, 33% of the doctors reported that weight gain was an obstacle to prescribing, and they were concerned about olanzapine (91%), clozapine (60%), oral risperidone (32%), and quetiapine (25%). Despite these concerns, psychiatrists used the full repertoire of antipsychotic drugs for a range of mental illness in elderly people, including more than 20% of off-label indications. Antipsychotic 89

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drugs are currently used off-label in dementia [SEDA-31, 65]. Antipsychotic drug-induced short-term serious events have been assessed in a retrospective cohort study in older adults with dementia [3C]. A serious event was a composite outcome defined as an event serious enough to lead to an acute care hospital admission or death within 30 days of starting therapy. Older adults with dementia, some living in the community (n ¼ 20 682) and others living in a nursing home (n ¼ 20 559) were identified. Propensity-based matching was used to balance differences between the drug exposure groups in each setting. Among 6894 community-dwelling older adults taking atypical antipsychotic drugs, 960 (14%) were classified as having had any serious event; of those, 186 (2.7%) died. Relative to community-dwelling older adults with dementia who did not receive a prescription for antipsychotic drugs (n ¼ 6894), similar older adults who did receive atypical antipsychotic drugs (n ¼ 6894) were 3 times more likely (adjusted OR ¼ 3.2; 95% CI ¼ 2.8, 3.7), and those who received a conventional antipsychotic drug (n ¼ 6894) 3.8 times more likely, to have a serious adverse event within 30 days of starting therapy (adjusted OR ¼ 3.8; 95% CI ¼ 3.3, 4.4). The pattern of serious events was similar but less pronounced among older adults living in a nursing home. In a survey, only two of six published randomized controlled trials of antipsychotic drug therapy for dementia gave data on any adverse event [4c]; in two of these trials there was no information about deaths. The risk of death in elderly users of antipsychotic drugs has previously been reviewed [5C]. The incidence rates for six categories of adverse events of antipsychotic drug use have been compared in a retrospective cohort study of 4140 children and adolescents (mean age 10 years) and 4500 children (mean age 7.2 years) with similar service encounters but not treated with psychotropic drugs [6c]. Six atypical and two conventional antipsychotic drugs were studied. The overall incidence/prevalence rates in the control and treated groups differed dramatically in obesity/weight gain (8.6% versus 20%), type 2 diabetes (1.9% versus

5.2%), dyslipidemia (11% versus 4.2%), cardiovascular conditions (3.4% versus 14.2%), neurological/sensory symptoms (14% versus 65%), and digestive/urogenital problems (71% versus 93%); the odds of obesity/excessive weight gain, type 2 diabetes and dyslipidemia, digestive/urogenital problems, and neurological/sensory symptoms were higher in girls and those for whom multiple antipsychotic drugs had been prescribed. Multiple antipsychotic drugs were prescribed in 42% of the treated cohort, in whom the adjusted OR was 2.6 (95% CI ¼ 1.5, 4.7) for metabolic adverse events and 1.7 (95% CI ¼ 1.1–2.7) for cardiovascular conditions. Metabolic and cardiovascular adverse events were further studied by the same authors in the same sample of children and adolescents [7C]. Compared with the controls, the treated cohort had a higher prevalence of obesity (OR ¼ 2.1), type 2 diabetes mellitus (OR ¼ 3.2), cardiovascular conditions (OR ¼ 2.7), and orthostatic hypotension (OR ¼ 1.6). In the treated cohort, those who had been exposed to multiple antipsychotic drugs had a significantly higher risk of incident obesity/weight gain (OR ¼ 2.3), type 2 diabetes mellitus (OR ¼ 2.4), and dyslipidemia (OR ¼ 5.3). Incident cardiovascular events were more likely with the use of conventional antipsychotic drugs (OR ¼ 4.3) and mood stabilizers (OR ¼ 1.3). Incident orthostatic hypotension was more prevalent in those co-prescribed selective serotonin reuptake inhibitors (OR ¼ 1.8) and mood stabilizers (OR ¼ 1.3). People with schizophrenia have substantially increased rates of mortality than the general population because of chronic illness, particularly cardiovascular disease [8M]. In an 11-year follow-up study of mortality in patients with schizophrenia (n ¼ 66 881), the gap in life expectancy between patients with schizophrenia and the general population in Finland did not widen between 1996 (25 years) and 2006 (23 years) [9C, 10r]. During that time, the proportion of use of second-generation antipsychotic drugs rose from 13% to 64%. Compared with current use of perphenazine, the highest risk of overall mortality was recorded for

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quetiapine (adjusted HR ¼ 1.4; 95% CI ¼ 1.1, 1.8) followed by haloperidol (HR ¼ 1.4; 95% CI ¼ 1.1, 1.7) and risperidone (HR ¼ 1.3; 1.1, 1.6), and the lowest risk for clozapine (HR ¼ 0.7; 95% CI ¼ 0.6, 0.9). Long-term cumulative exposure (7–11 years) to any antipsychotic drug was associated with a lower mortality than with no drug use (HR ¼ 0.8; 95% CI ¼ 0.77, 0.84). It is said that the difference in mortality between clozapine and other antipsychotic drugs might be attributable to more intensive monitoring during clozapine treatment, the greater effectiveness of clozapine, the poor safety of other drugs, or all these causes. According to the authors, current results raise the question of whether clozapine should be used as a first-line treatment, because it seems to be the safest antipsychotic drug in terms of mortality and is also the most effective. Comparative studies First- and secondgeneration antipsychotic drugs have been compared in 119 children and adolescents (aged 8–19 years) with early-onset schizophrenia and schizoaffective disorder [11C], who were randomized to olanzapine 2.5–20 mg/day, risperidone 0.5–6 mg/day, or molindone 10–140 mg/day, plus benzatropine 1 mg/day for 8 weeks; some subjects were excluded because of a previous history of non-response to a study drug. There were no significant differences among the treatment groups in response rates, which were low in all three groups (molindone: 50%, n ¼ 40; olanzapine: 34%, n ¼ 35; risperidone: 46%, n ¼ 41) or in the magnitude of symptom reduction. Olanzapine and risperidone were associated with significantly greater weight gain. Olanzapine had the greatest risk of weight gain (average 6.1 kg) and significant increases in fasting cholesterol, low density lipoprotein, insulin, and liver transaminases. Akathisia led to treatment discontinuation in two participants taking molindone and in one taking risperidone. In an open randomized study in patients with schizophrenia, supported by the marketing authorization holders of some of the antipsychotic drugs studied, AstraZeneca,

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Pfizer, and Sanofi-Aventis, there were no differences between atypical antipsychotic drugs and haloperidol after 1 year [12c]. More of those who took haloperidol had signs of parkinsonism than those who took an atypical antipsychotic drug; in contrast, the proportion of patients who were overweight was higher with olanzapine than with haloperidol. With haloperidol 72% of patients discontinued treatment for any cause within the 12 months (dose range 1–4 mg/day; n ¼ 103), with amisulpride 40% (dose range 200–800 mg/day; n ¼ 104), with olanzapine 22% (5–20 mg/day; n ¼ 105), with quetiapine 53% (200–750 mg/day; n ¼ 104), and with ziprasidone 45% (40–160 mg/day; n ¼ 82). Rates of admission to hospital were 7–23% and did not differ significantly between treatments. Since the study was open, the psychiatrists’ expectations could have led to haloperidol being withdrawn more often. The authors stated that it cannot be concluded that second-generation antipsychotic drugs are more efficacious than haloperidol in the treatment of these patients. Placebo-controlled studies In a study of the effect of long-term treatment with neuroleptic drugs on global cognitive decline and neuropsychiatric symptoms in patients with Alzheimer's disease, 64 patients were randomized to continue treatment with thioridazine, chlorpromazine, haloperidol, trifluoperazine, or risperidone and 64 to placebo [13c]. There was no significant difference in global cognitive functioning or neuropsychiatric symptoms between the groups after 6 months. There was a higher risk of parkinsonism in the treated patients, but the differences were not significant. Systematic reviews First-generation and second-generation antipsychotic drugs in patients with schizophrenia have been compared in a meta-analysis [14M] (for an indepth review, see SEDA-27, 50). The study included 150 double-blind, mostly shortterm, randomized clinical trials with 21 533 participants. Four second-generation antipsychotic drugs (amisulpride, clozapine, olanzapine, and risperidone) were better than first-generation ones for overall

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efficacy, with small to medium effect sizes, which is similar to the results of a previous meta-analysis [15M]. The overall results are not consistent with the view that second-generation drugs improve negative symptoms, depression, and quality of life. Second-generation antipsychotic drugs caused fewer extrapyramidal adverse effects than haloperidol (even at low doses), but only clozapine, olanzapine, and risperidone caused fewer extrapyramidal adverse effects than lowpotency first-generation antipsychotic drugs. With the exception of aripiprazole and ziprasidone, second-generation antipsychotic drugs produced more weight gain, in various degrees, than haloperidol but not than low-potency first-generation drugs. The authors concluded that second-generation antipsychotic drugs differ in many properties and are not a homogeneous class. They also suggested that public institutions could save costs by funding studies to define selected old compounds accurately, because they were not rigorously studied at the time they were introduced. This meta-analysis merited an editorial, in which some points were further emphasized [16r]; thus, the name “second-generation antipsychotic drugs” would be inaccurate, as this group of drugs is in fact a heterogeneous mixture of compounds, some being superior to others. Accordingly, the spurious invention of the atypical drugs can be regarded as an invention, cleverly manipulated by drug companies for marketing purposes. The authors mentioned that using an inadequate comparator (haloperidol) favors the atypical drugs. Different second-generation antipsychotic drugs have been compared in another meta-analysis [17M]. The primary outcome measure was the change in total score on the Positive and Negative Syndrome Scale (PANSS); secondary outcome measures were subscores for positive and negative symptoms and rates of dropout because of inefficacy. The analysis included 78 randomized studies, at least single-blind, with 167 relevant arms and 13 558 participants; 49 studies were mainly sponsored by pharmaceutical companies, 22 were publicly funded, and in seven funding was uncertain.

Olanzapine was superior to aripiprazole, quetiapine, risperidone, and ziprasidone, and its efficacy was similar to that of amisulpride and clozapine; risperidone was more efficacious than quetiapine and ziprasidone. Clozapine and olanzapine, followed by quetiapine and then risperidone, were the most likely to cause weight gain and glucose and lipid abnormalities. Amisulpride and risperidone carried a risk of extrapyramidal symptoms and substantial increases in prolactin concentrations. The effect sizes ranged between 1.9 (olanzapine versus risperidone) and 8.3 (olanzapine versus ziprasidone) PANSS points, and the clinical relevance of the difference between olanzapine and risperidone (1.9 PANSS points) based on a large sample size (n ¼ 2404) is particularly doubtful. For perspective, the average difference between second-generation antipsychotic drugs and placebo in another meta-analysis was only 10 PANSS points [18M]. A sensitivity analysis was also performed with sponsor, dose, study quality, treatment resistance, study origin, and trial duration as moderators, and there were only a few differences; excluding studies sponsored by pharmaceutical companies did not change the result. This is similar to the result of another meta-analysis of the effects of several potentially biasing factors (e.g. industry support, extrapyramidal adverse effects) on drug efficacy in comparison of second-generation and first-generation antipsychotic drugs [19M]. The effectiveness of second-generation antipsychotic drugs has been addressed in a systematic review of 16 randomized head-to-head comparisons of second-generation antipsychotic drugs [20M]. The trials were categorized as effectiveness studies if there was a statement from the authors that a naturalistic, pragmatic, practical, or reallife study design was used, or if the methods section was presented in corresponding terms. There were differences in sample sizes, inclusion criteria, follow-up periods, and sources of funding. In acute episodes and first episodes there were no differences between the second-generation antipsychotic drugs in relief of symptoms; during longterm treatment those who used olanzapine

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had longer times to discontinuation of treatment and better treatment adherence compared with those who used other atypical drugs. Olanzapine was associated with more metabolic adverse effects than other second-generation antipsychotic drugs. Cardiovascular Extensive data link the typical antipsychotic drugs with an increased risk of sudden cardiac death [SEDA-24, 54; SEDA-30, 56]. The adjusted incidence of sudden cardiac death among current users of single antipsychotic drugs has been estimated in a retrospective cohort of Tennessee Medicaid enrolees [21C]. Current users of both typical drugs (n ¼ 44 218) and atypical drugs (n ¼ 46 089) had greater rates of sudden cardiac death than non-users (n ¼ 186 600), with adjusted incidence-rate ratios for use of 2.0 (95% CI ¼ 1.7, 2.3) and 2.3 (1.9, 2.7) respectively. For typical antipsychotic drugs the risk increased from 1.3 (1.0, 1.8) for low doses to 2.4 (1.9, 3.1) for high doses; for atypical agents the risk increased from 1.6 (1.0, 2.5) for low doses to 2.9 (2.2, 3.6) for high doses. The incidence-rate ratios for atypical versus typical antipsychotic drugs was 1.1 (0.3, 1.4). The authors suggested that antipsychotic drugs increase the risk of serious ventricular dysrhythmias, probably through blockade of potassium channels and prolongation of cardiac repolarization. Changes in the 10-year risk of coronary heart disease have been compared between treatment groups in 1125 patients followed for 18 months or until treatment discontinuation in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) in schizophrenia [22C]. The mean change in 10-year coronary heart disease risk differed significantly between treatments. Olanzapine was associated with a 0.5% increase and quetiapine with a 0.3% increase, while the risk fell in patients who used perphenazine (0.5%), risperidone ( 0.6%), and ziprasidone (0.6%). The difference in 10-year coronary heart disease risk between olanzapine and risperidone was statistically significant.

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Nervous system A re-analysis of the CATIE study (n ¼ 1443) has been performed in order to compare the incidence of treatment-emergent extrapyramidal effects between second-generation antipsychotic drugs and perphenazine in people with schizophrenia [23R]. There were no significant differences in the incidence of parkinsonism, dystonia, akathisia, or tardive dyskinesia. The probabilities of tardive dyskinesia event within 1 year in people with no tardive dyskinesia at baseline, with adjustment for baseline co-variates, were: olanzapine 0.01 (95% CI ¼ 0.002, 0.03); perphenazine 0.03 (95% CI ¼ 0.01, 0.07); quetiapine 0.02 (95% CI ¼ 0.001, 0.06); and risperidone 0.01 (95% CI ¼ 0.004, 0.04). There were greater rates of concomitant antiparkinsonian medication among individuals taking risperidone and lower rates among individuals taking quetiapine; there were lower rates of withdrawal because of parkinsonism among people taking quetiapine or ziprasidone. There was a trend to a greater likelihood of concomitant medications for akathisia among individuals taking risperidone and perphenazine. The authors suggested that previous reports of a relatively lower incidence of extrapyramidal symptoms with second-generation antipsychotic drugs were likely to be related to the use of higher dosages of the highpotency first-generation antipsychotic drug, haloperidol. One of the limitations pointed out in the study was the relatively short duration of exposure. Neurological adverse events associated with antipsychotic drug use in children and adolescents have been studied retrospectively using medical and pharmacy claims from one state's Medicaid program [24C]. The incidence rates for these events in 4140 children who were taking antipsychotic drugs (mean age 10 years) and an untreated sample of 4500 children (mean age 7.2 years) were compared. The treated cohort had a higher prevalence of involuntary movements (OR ¼ 6.2; 95% CI ¼ 4.5, 8.3), sedation (OR ¼ 1.8; 95% CI ¼ 1.2, 2.3), and seizures (OR ¼ 6.2; 95% CI ¼ 5.3, 7.7). The odds of incident involuntary movements were significantly

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higher in those taking aripiprazole, risperidone, haloperidol, and multiple antipsychotic drugs; the odds of incident seizures were greater for those taking risperidone and multiple antipsychotic drugs; the odds of incident sedation were greater for those taking ziprasidone, risperidone, quetiapine, and multiple antipsychotic drugs. Exposure to risperidone and multiple antipsychotic drugs consistently confers a higher risk of a range of neurological adverse events in young patients, especially those with pre-existing central nervous system or cardiovascular disorders or mental retardation. Levetiracetam, the levorotary stereoisomer of an ethylated congener of piracetam, was effective in the treatment of tardive dyskinesia in a randomized, doubleblind, placebo-controlled study [25c]. The levetiracetam/placebo difference reached a trend level by week 4 and was statistically significant at weeks 6, 9, and 12; at week 12 the AIMS total score model-estimated marginal mean in the levetiracetam group dropped 44% from baseline, and the placebo group estimated mean fell 19%. Overall adverse effects were similar in the two groups; since there have been reports of leukopenia, neutropenia, pancytopenia, and thrombocytopenia in patients taking levetiracetam, particular attention was given to these reactions: in no patient did the white blood cell count fall below 2.8  109/l, the neutrophil count below 1.0  109/l, or the platelet count below 75  109/l. Sensory systems Typical antipsychotic drugs, mainly phenothiazines, have been associated with cataract formation [SEDA24, 57]. There were lenticular opacities in 21 of 52 patients who used typical antipsychotic drugs and in 5 of 28 patients who used atypical antipsychotic drugs [26c]. Patients who used typical antipsychotic drugs had earlier mental illness onset, had used antipsychotic drugs for longer periods, had used higher doses, and were older. No pigment deposition was found, neither in the cornea nor in the retina of these patients.

Weight gain and diabetes mellitus due to antipsychotic drugs EIDOS classification: Extrinsic moiety Antipsychotic drugs Intrinsic moiety [?]H1, M3, and 5-HT2C receptors Distribution Adipocytes and other cells Outcome Altered physiology (leptin secretion, insulin resistance, impaired glucose tolerance) Sequela Weight gain and diabetes mellitus due to antipsychotic drugs DoTS classification: Dose-relation Collateral reaction Time-course Intermediate Susceptibility factors Genetic (African–American origin; the 102T allele of HTR2A, the 825T allele of GNB3, the 23Cys allele of HTR2C, and the 64Arg/Arg genotype of ADRB3; see Table 1); sex (male) The potential interactions between atypical antipsychotic drugs and several hormones that affect appetite regulation and carbohydrate metabolism have been reviewed [27r]. The effects of atypical antipsychotic drugs on carbohydrate intolerance and the development of diabetes show that they produce abnormalities in glucose tolerance by altering appetite regulation, insulin secretion and action, and the release of insulin counter-regulatory hormones, in particular leptin and ghrelin; high concentrations of those hormones have been observed in patients taking atypical antipsychotic drugs. Receptor-binding profiles of different antipsychotic drugs may also help explain the occurrence of some metabolic adverse effects associated with each drug [28r]. Thus, drug affinity at histamine H1 receptors is linked to weight gain; this is consistent with data demonstrating that histamine H1 receptor antagonism promotes feeding in rodents and that H1 knockout mice are susceptible to weight gain. It has also been observed that atypical orexigenic antipsychotic drugs

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reverse the actions of leptin, an anorexigenic hormone. Drug affinity for H1, M3, and 5-HT2C receptors correlates with an increased risk of diabetes. The receptorbinding profiles that correlate with antipsychotic drug-associated dyslipemia are not well understood; however, it has been suggested that peroxisome proliferator-activated receptor (PPAR) agonists may convey therapeutic benefit. Metabolic syndrome The metabolic syndrome is highly prevalent among patients with schizophrenia, due in part to medications. The metabolic syndrome is a cluster of metabolic abnormalities (glucose intolerance, hypertension, obesity) in a single subject. These abnormalities define a continuum of risk, and those who have more features of this syndrome appear to be more predisposed to type 2 diabetes mellitus and cardiovascular disease. The finding of differential metabolic profiles for atypical antipsychotic drugs has been confirmed in numerous prospective studies [29R]; accordingly, the parameters that are most influenced by treatment with metabolically offending medications are weight, serum triglycerides, and measures of glycemic control, with substantially less effect on serum HDL cholesterol or blood pressure. The change in the proportion of subjects with the metabolic syndrome and individual criteria has been compared between antipsychotic drugs, along with mean changes for individual criteria in phase 1 of the CATIE schizophrenia study [30C]. Among all subjects whose metabolic syndrome status could be determined at 3 months (n ¼ 660), the prevalence of the metabolic syndrome increased for olanzapine (from 35% to 44%), but decreased for ziprasidone (from 38% to 30%). Although effect sizes varied across subgroups, at 3 months olanzapine and quetiapine had the largest mean increases in waist circumference (0.7 inches for both) followed by risperidone (0.4 inches), compared with no change for ziprasidone and a reduction in waist circumference for perphenazine (0.4 inches). Olanzapine also had significant effects on fasting triglycerides at 3 months

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(þ 0.25 mmol/l) compared with ziprasidone ( 0.35 mmol/l). Consistent results were found in a study carried out in India, in which all consecutive drug-naïve patients with a first episode of schizophrenia (n ¼ 99) were recruited into a randomized, double-blind, controlled study; the prevalence of metabolic syndrome after 6 months (10% and 18% as assessed by ATPIA and International Diabetes Federation criteria respectively) was five times as high compared with the matched healthy control group [31c]. Olanzapine had a maximum prevalence of metabolic syndrome at 20–25% (n ¼ 35), followed by risperidone at 9–24% (n ¼ 33) and haloperidol at 0–3% (n ¼ 31). In a prospective study, fasting serum and anthropometric measures were obtained from 45 patients with first-episode psychosis and 41 healthy adults of similar age, ethnicity, and sex [32c]. At baseline, the distributions of cardiovascular risk markers were similar and the percentages of young patients with first-episode psychosis and healthy controls who were overweight/obese, dyslipidemic, hyperglycemic, and hyperinsulinemic did not differ. At 24 weeks, compared with baseline, 16 of the patients with psychosis who continued to take the same antipsychotic medication had statistically significant increases in BMI, glucose, insulin, cholesterol, leptin, and E-selectin, and a reduction in adiponectin. Patients with bipolar disorder and schizophrenia who are treated with second-generation antipsychotic drugs had similar high rates of the metabolic syndrome in a retrospective comparison of different metabolic parameters [33c]. The prevalence of metabolic syndrome in a matched and randomly selected sample was 43% in bipolar disorder (n ¼ 74) and 46% in schizophrenia (n ¼ 111). Diabetes mellitus [SEDA 28, 60; SEDA-30, 58; SEDA-31, 67; SEDA-32, 87] The prevalence of detected diabetes in the general population is around 3–4%; type 2 diabetes accounts for 85–90% of all cases and results from a combination of insulin resistance and

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relative insulin deficiency. The prevalence of type 2 diabetes in patients with schizophrenia has been estimated at 9% [34C]. Atypical antipsychotic drugs have been linked to a higher risk of glucose intolerance, and consequently development of type 2 diabetes mellitus. The acute effects of oral administration of olanzapine and ziprasidone on wholebody insulin sensitivity in healthy subjects have been investigated [35c] using the standardized hyperinsulinemic euglycemic clamp technique in 29 healthy male volunteers who took either olanzapine 10 mg/day (n ¼ 14) or ziprasidone 80 mg/day (n ¼ 15) for 10 days. Olanzapine caused a significant reduction in mean whole-body insulin sensitivity from 5.7 ml/hour/kg at baseline to 4.7 ml/hour/kg; ziprasidone had no effect (5.2 ml/hour/kg versus 5.1 ml/hour/kg). In another study, medication-naïve patients with schizophrenia were randomized to olanzapine (n ¼ 35), risperidone (n ¼ 33), or haloperidol (n ¼ 31) [36c]. After 6 weeks, there were significant increases in weight, fasting blood sugar, and 2-hour postprandial blood sugar between the matched healthy control group (n ¼ 51; mean age, 28 years) and the treatment group as a whole (n ¼ 99; mean age 26 years). There was also a significant increase in the incidence of diabetes mellitus at end-point by the WHO criteria (10%; olanzapine, n ¼ 3; risperidone, n ¼ 3; haloperidol, n ¼ 3). The risks of diabetes with different antipsychotic drugs have been compared in a meta-analysis of 11 studies in people with schizophrenia or related disorders, including cross-sectional studies, case–control studies, cohort studies, and controlled trials [37M]. The relative risk of diabetes in patients with schizophrenia taking one of the second-generation versus first-generation antipsychotic drugs was 1.3 (95% CI ¼ 1.1, 1.5). According to the authors, there were methodological limitations in most of the studies, leading to heterogeneity and difficulty in interpreting the data; they pointed out that one residual confounder not reported in any of the studies was whether an increased amount of screening occurred in those

taking second-generation antipsychotic drugs, owing to greater clinical awareness. Triglycerides Atypical antipsychotic drugs have been linked to hyperlipidemia [SEDA30, 58]. Taking advantage of the data gathered in the CATIE study [SEDA-30, 56], the effects of antipsychotic drugs on triglycerides have been explored [38R]. In 246 subjects there were significant treatment differences in the 3-month change from baseline; the greatest increases in median and adjusted mean non-fasting triglycerides concentrations were seen among those randomized to quetiapine (mean þ0.62 mmol/l) and olanzapine (mean þ0.26 mmol/l). Ziprasidone had no effect. There were reductions with risperidone (mean 0.21 mmol/l) and perphenazine (mean 0.1 mmol/l). Raised triglycerides due to olanzapine usually involve weight gain accompanied by insulin resistance. However, serum triglyceride concentrations can rise without weight gain or abnormal glucose metabolism [39A, 40A]. Weight gain [SEDA-32, 87] In the CATIE study (see SEDA-30, 56), there was weight gain of 7% or more in 30% of patients with schizophrenia taking olanzapine 7.5–30 mg/ day; the amount of weight gain induced by olanzapine was much greater than that induced by quetiapine, risperidone, or ziprasidone. There were statistically significant differences in weight gain at 3 months with olanzapine, risperidone, and haloperidol in a randomized study of drug-naïve patients [41C]. At 3 months there were increases of 3.8 kg for haloperidol (n ¼ 46), 5.9 kg for risperidone (n ¼ 52), and 8.4 kg for olanzapine (n ¼ 49); after 1 year, the difference in weight gain had disappeared: 9.7 kg for haloperidol (n ¼ 24), 8.9 kg for risperidone (n ¼ 35), and 10.9 kg for olanzapine (n ¼ 36). The findings, contrary to those reported in other studies, were explained by the authors as being due to differences in follow-up periods. The effects of antipsychotic drugs (haloperidol, olanzapine, and risperidone) on peptides involved in energy balance (insulin,

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ghrelin, leptin, adiponectin, visfatin, and resistin) have been studied in 70 drug-naïve patients with a first episode of psychosis [42C]. There were significant increases in weight (10.2 kg), body mass index (3.56 kg/ m2), and fasting plasma insulin (3.93 mU/ ml), leptin (6.76 ng/ml), and ghrelin (15.47 fmol/ml) concentrations. The increments in insulin and leptin concentrations correlated with the increments in weight and body mass index and seem to have been a consequence of higher fat stores; the three antipsychotic drugs had similar effects on all the parameters evaluated. The authors suggested that the unexpected increase in ghrelin concentrations might have been causally related to weight gain from antipsychotic drugs. Prescription of second-generation antipsychotic drugs has increased dramatically in recent years in children [SEDA-31, 66], in whom metabolic effects, and weight gain in particular, are supposed to be greater than in adults. The metabolic and hormonal adverse effects in children and adolescents (mean age 15 years) after 6 months of treatment have been evaluated [43c]. After 6 months, BMI increased significantly in those taking olanzapine (baseline 22.7 kg; change 3.7 kg; n ¼ 20) and risperidone (baseline 21.8 kg; change 1.4 kg; n ¼ 22), but not in those taking quetiapine (baseline 21.5 kg; change 0.9 kg; n ¼ 24). Mean total cholesterol concentrations increased significantly in patients receiving olanzapine (baseline 4.1 mmol/l; change 0.27) and quetiapine (baseline 4.2; change, 0.38). Susceptibility factors Genetic factors associated with olanzapine-induced weight have been studied in Japan [44C]. Patients with schizophrenia (n ¼ 164) took olanzapine (mean dose 15.5 mg/day) for 8–24 weeks. BMI rose by a mean of 4.3%. Olanzapineinduced weight gain correlated negatively with baseline BMI and positively with clinical global improvement and the length of olanzapine treatment, but did not correlate with the daily dose of olanzapine, concomitant antipsychotic drugs, sex, age, or smoking. Among 21 polymorphisms examined, four genetic variants, the 102T allele of HTR2A, the 825T allele of GNB3, the

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23Cys allele of HTR2C, and the 64Arg/Arg genotype of ADRB3, were significantly associated with olanzapine-induced weight gain. Stepwise regression analysis showed that the baseline BMI predicted 13% of the weight gain, and the two latter genetic factors added 6.8%. The patients with double and triple genetic risk factors had 5.1% and 8.8% increases in BMI respectively; the patients with a single or no risk factor had about a 1% increase. In a review of the use of pharmacogenetic testing to predict the likelihood of some adverse drug reactions the authors emphasized that the mechanisms of olanzapineinduced weight gain may involve the gene for 5-HT2C receptors; other candidate genes that may be associated with olanzapineinduced weight gain include CYP2D6, the synaptosomal-associated protein of 25 kDa (SNAP25), G-protein beta 3 subunit gene (GNB3), the alpha2a-adrenergic receptor (ADRA2A), leptin (LEP), and the leptin receptor (LEPR) [45R]. For a summary of other genetic factors that have been investigated in relation to antipsychotic druginduced metabolic reactions, see Table 1. Management The effects of lifestyle intervention and metformin, alone and in combination, for antipsychotic-induced weight gain and abnormalities in insulin sensitivity, have been evaluated in a randomized controlled trial in adult Chinese patients with schizophrenia [53c]. Those who gained more than 10% of their predrug weight within the first year of treatment with clozapine, olanzapine, risperidone, or sulpiride were assigned to one of four groups, in which patients continued their antipsychotic drug treatment and were randomly assigned for 12 weeks to placebo (n ¼ 32), 750 mg/ day of metformin alone (n ¼ 32), 750 mg/ day of metformin and lifestyle intervention (n ¼ 32), or lifestyle intervention only (n ¼ 32). All patients with first-episode schizophrenia maintained relatively stable psychiatric improvement. The lifestyle-plusmetformin group had a mean reduction in BMI of 1.8 (95% CI ¼ 1.3, 2.3), the metformin-alone group had a mean reduction in BMI of 1.2 (95% CI ¼ 0.9, 1.5), and the

Table 1 Genetic factors and antipsychotic drug-induced metabolic reactions Antipsychotic drug/reaction Several antipsychotic drugs/weight gain Olanzapine/weight gain Olanzapine/weight gain Clozapine/weight gain Olanzapine/weight gain Olanzapine/weight gain

Genetic factor

No.

Comments

Ref.

5-HT2C receptors

123

Conflicting results

SEDA-27, 53

11 42 91 62 67

Association Possible protective effect of the T allele GG associated with a higher risk G allele associated with a higher risk Weight profiles significantly associated

SEDA-27, SEDA-30, SEDA-30, SEDA-31, SEDA-32,

94

S SERTPR allelic variant and SS genotype was associated with significantly higher weight gain

SEDA-32, 103

Association

[44c]

Weight gain was significantly higher for patients with the AG genotype than for those with the AA genotype (Korean patients) LEPR Q223R polymorphism may be associated with obesity in women with a psychotic disorder treated with atypical antipsychotic drugs Higher risk in those carrying the leptin –2548A/G allele within the “high risk” group carrying the 5-HT2C receptor gene –759C/CC These genes may be promising candidates for studies of the direct effects of some antipsychotic drugs on hyperlipidemia MTHFR 677C/T variant may predispose patients to metabolic complications Strong association between three markers localized within or near the INSIG2 gene (rs17587100, rs10490624, and rs17047764) and antipsychotic drugrelated weight gain The results do not support a major role of alpha1Aadrenoceptor genetic variants in obesity

[46c]

Olanzapine/weight gain

CYP2D6 5-HT2C receptors (759C/T) ADRA2A (1291C/G) ADRA2A (1291C/G) Apolipoproteins E and A4 and scavenger receptor class B, member 1 L/S promoter (SERTPR) and l/s intron 2 (SERTin2) genetic variants of serotonin transporter (SERT) polymorphisms 102T allele of HTR2; 825T allele of GNB3, the 23Cys allele of HTR2C; 64Arg/Arg genotype of ADRB3 Leptin gene (LEP) (AG 2548)

Olanzapine/weight gain

LEP- and LEPR

200

Atypical drugs/metabolic disturbances

5-HT2C receptors (759C/T) and leptin (2548A/G)

134

Several atypical drugs/ hyperlipidemia, direct effects Atypical drugs/metabolic syndrome Clozapine/weight gain

Acetyl-coenzyme A carboxylase alpha SNP (rs4072032); neuropeptide Y (rs1468271); ACCbeta (rs2241220) MTHFR 677C/T and 1298A/C genotype

357

Genes involved in the SREBP activation of fatty acids and cholesterol production (SREBF1, SREBF2, SCAP, INSIG1, and INSIG2)

160

Alpha1A-adrenoceptor gene (563–C/T, –4155–G/C, and 4884–A/G)

427

Olanzapine/weight gain

Olanzapine/weight gain

Several antipsychotic drugs/obesity

164 74

58

[47c]

[48c]

[49c]

[50c] [51c]

[52c]

61 66 63 85 103

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lifestyle-plus-placebo group had a mean reduction in BMI of 0.5 (95% CI ¼ 0.3, 0.8); however, the placebo group had a mean increase in BMI of 1.2 (95% CI ¼ 0.9, 1.5). There were no significant differences in the frequencies and types of adverse effects among the groups. The beneficial effect of metformin alone had already been seen in a previous double-blind study by the same authors [54c], in which 40 in-patients with schizophrenia were randomized for 12 weeks to olanzapine 15 mg/day plus metformin 750 mg/day (n ¼ 20) or olanzapine 15 mg/ day plus placebo (n ¼ 20). Of the 40 patients, 37 completed treatment; all had a restricted diet. Metformin attenuated the increases in weight (0.5 kg versus 5.4 kg), BMI (0.1 versus 1.8), waist circumference (0.3 cm versus 1.2 cm), and waist-to-hip ratios (0.003 versus 0.184). In a meta-analysis of randomized controlled trials adjunctive non-pharmacological interventions, either individual or group interventions or cognitive-behavioral therapy, and nutritional counselling were similarly effective in reducing or attenuating antipsychotic druginduced weight gain and treatment effects were maintained during follow-up [55M]. Urinary tract Drug-induced urinary retention has been reviewed, emphasizing the anticholinergic activity of some antipsychotic drugs [56r]. Sexual dysfunction Ischemic priapism, painful and persistent penile erection unrelated to sexual desire or stimulation, has been described in association with antipsychotic drugs [SEDA-24, 59; SEDA-28, 64]. Four men aged 25–55 years developed priapism while taking antipsychotic drugs (amisulpride, clozapine, levomepromazine, olanzapine, pipotiazine, risperidone, or zuclopenthixol) [57A]; they were treated with aspiration and irrigation of the corpora cavernosa with sympathomimetic drugs, followed in one case by a surgical distal cavernoglandular shunt; all cases resolved.

99

INDIVIDUAL DRUGS Amisulpride [SED-15, 173; SEDA-31, 69; SEDA-32, 92] Observational studies In an open study, 29 patients were treated with a wide range of doses of amisulpride (50–1200 mg/day) [58c]. After 2 weeks, brain single photon emission tomography scans were performed 2 hours after intravenous injection of 185 MBq of (123I)IBZM iodobenzamide. D2 receptor blockade correlated with doses and plasma concentrations of amisulpride; there was no correlation between the clinical response and striatal D2 occupancy. There were extrapyramidal adverse effects, which had to be treated with biperiden, in 31% of the patients.

Aripiprazole [SEDA-30, 61; SEDA-31, 70; SEDA-32, 93] Placebo-controlled studies In a 6-week multicenter, double-blind, randomized, placebo-controlled study, patients aged 13–17 years with schizophrenia were assigned to aripiprazole (10 mg/day, n¼ 100; 30 mg/day, n ¼ 102) or placebo (n ¼ 100) [59C]. At the end of the study, both doses of aripiprazole significantly reduced PANSS total scores. Adverse events that occurred in more than 5% of subjects in either aripiprazole group and with a combined incidence at least twice the rate for placebo were extrapyramidal disorders, somnolence, and tremor. Mean changes in prolactin concentrations were 8.5, –12, and 15 ng/ml for placebo and for 10 and 30 mg of aripiprazole respectively. Mean body weight changes were 0.8, 0.0, and 0.2 kg for placebo and for 10 and 30 mg of aripiprazole respectively. Aripiprazole has been previously compared with placebo in patients with bipolar I disorder [SEDA-31, 74]. Now the results of several studies in such patients have emerged. In a 100-week, double-blind, placebo-controlled study in 28 patients with

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rapid-cycling bipolar disorder the most common adverse reactions to aripiprazole ( 10% incidence and twice the placebo rate) were anxiety (n ¼ 4), sinusitis (n ¼ 4), depression (n ¼ 3), and upper respiratory infection (n ¼ 3) [60C]. One patient withdrew because of akathisia. There were no significant between-group differences in mean changes in weight or metabolic parameters. However, the results of this study were seriously limited by the fact that only 12 patients completed the initial 26week treatment period and only three completed the 100-week double-blind period. Re-analyses of the results of two randomized, 3-week, flexible-dose, double-blind, placebo-controlled trials in subpopulations of patients with acute mania or mixed episodes of bipolar I disorder have been performed [61C]. Aripiprazole significantly reduced mean Young Mania Rating Scale (YMRS) total scores at end-point compared with placebo and in three subgroups stratified by baseline severity of depressive symptoms using the Montgomery-Asberg Depression Rating Scale (MADRS). In the overall population, the most common adverse reactions to aripiprazole (n ¼ 263), which occurred in  5% of patients and were at least twice the rate of the placebo group (n ¼ 260) were somnolence (aripiprazole 21% versus placebo 8%), dyspepsia (19% versus 9), akathisia (14% versus 5%), and accidental injury (9% versus 2%). In a multicenter study, out-patients were randomly adjunctive assigned to aripiprazole (15 or 30 mg/day; n ¼ 253) or placebo (n ¼ 131) for 6 weeks [62C]. They had had a manic or mixed episode (with or without psychotic features) with partial non-response to lithium/valproate monotherapy and with target serum concentrations of lithium (0.6–1.0 mmol/l) or valproate (50–125 mg/l). Improvement was significantly greater with aripiprazole than with placebo. Withdrawal rates due to adverse reactions were higher with aripiprazole than with placebo (9% versus 5% respectively). Akathisia was the most frequently reported extrapyramidal symptomrelated adverse reaction, and it occurred

significantly more frequently among those taking aripiprazole (19%) than among those taking placebo (5.4%). There were no significant differences between treatments in weight changes. The efficacy and safety of adjunctive aripiprazole added to standard antidepressant therapy in 736 patients with major depressive disorder with anxious/atypical features at baseline have been evaluated [63C]. Data from two identical 14-week studies (an 8-week prospective antidepressant treatment phase and a 6-week randomized, double-blind phase) were used. Patients who took aripiprazole had significantly greater improvement in Montgomery-Asberg Depression Rating Scale (MADRS) total scores than patients taking placebo. Treatment-emergent adverse effects that occurred in 5% of patients were akathisia (25% aripiprazole; 4% placebo), restlessness (12% versus 2%), fatigue (8% versus 4%), insomnia (8% versus 2%), and blurred vision (6% versus 1%). An analysis of weight change over the course of double-blind treatment showed that the increase was greater with aripiprazole (1.61–1.83 kg) than placebo (0.22–0.48 kg). In a 12-week, multicenter, randomized, double-blind, placebo-controlled trial of aripiprazole in the treatment of alcoholism in 295 subjects, aripiprazole produced more positive subjective effects and less overall severity of alcohol dependence than placebo, although there was no difference between aripiprazole and placebo on the primary end-point, possibly because of doserelated attrition (treatment was started at 2 mg/day and titrated to a maximum of 30 mg/day at day 28). Withdrawals (40% versus 27%) and treatment-related adverse effects (83% versus 64%) were more common with aripiprazole. The most common treatment-related adverse events that differed significantly between aripiprazole and placebo were: fatigue, insomnia, restlessness, somnolence, anxiety, and altered attention; serious adverse reactions attributed to aripiprazole were chest pain, cellulitis, migraine, and thrombosis; extrapyramidal adverse reactions attributed

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to aripiprazole were akathisia (6%), tremor (3.4%), and dyskinesias (1.4%). Observational studies In a 6-week, prospective, unrandomized, open study in 20 patients with acute bipolar depression, aripiprazole up to a maximum of 30 mg/ day improved Montgomery-Asberg Depression Rating Scale (MADRS) and Mania Rating Scale (MRS) scores significantly [64c]. The most frequent adverse reactions were nausea and akathisia; two patients withdrew because of akathisia. In an open 16-week study of the efficacy and tolerability of aripiprazole in 85 patients with bipolar disorder and acute depression inadequately responsive to a mood stabilizer there were significant reductions in mean MADRS and Clinical Global Impression-Severity (CGI-S) scales [65c]. Three patients withdrew because of adverse reactions, the most common of which was akathisia, which occurred in 21% of subjects; there was also a statistically non-significant weight gain (0.9 kg). The effectiveness and cognitive effects of aripiprazole (mean dose 6.7 mg/day) have been assessed in a 6-week, open study in 23 children with attention-deficit/hyperactivity disorder [66c]. There was overall significant improvement from baseline on attention-deficit/hyperactivity disorder and functional outcome measures. The most common adverse events were sedation (n ¼ 18), headache (n ¼ 11), nausea (n ¼ 7), increased appetite (n ¼ 6), musculoskeletal pain (n ¼ 6), stomach ache (n ¼ 5), hiccups (n ¼ 4), and flu-like symptoms (n ¼ 4). There was a significant increase in weight, with an increase from a mean of 37.6 kg at baseline to a mean of 39.6 kg at end of the study. Nervous system Aripiprazole has been previously associated with neuroleptic malignant syndrome but with doubts about the validity of the diagnoses. However, postmarketing pharmacovigilance schemes in Australia have collected a higher proportion of cases of neuroleptic malignant syndrome with aripiprazole compared with the total number of reports received for

101

other antipsychotic drugs [SEDA-31, 76]. In a new case, neuroleptic malignant syndrome occurred when aripiprazole was added to olanzapine [67A]. • In a 33-year-old man taking olanzapine 10 mg/ day aripiprazole and benzatropine were added; after 2 weeks the dose of aripiprazole was increased from 5 to 10 mg/day and shortly afterwards the patient developed sweating, a raised temperature, tachycardia, and muscle rigidity, with raised alanine aminotransferase, aspartate aminotransferase, and creatine phosphokinase (peak 3210 U/l).

Reduced choreiform movements have been reported when a 47-year-old man with Huntington's disease was given aripiprazole 20 mg/day for 2 weeks; his gait became stable, enabling him to walk smoothly without assistance [68A]. Endocrine Aripiprazole is said to stabilize the dopaminergic system and thus ameliorate schizophrenic symptoms without increasing serum prolactin [SEDA-31, 76]. Prolactin concentrations and sexual function in schizophrenic patients have been evaluated in an open, 26-week, multicenter study, in which 555 patients were randomized to aripiprazole (n ¼ 284) or standard care (olanzapine, quetiapine, or risperidone; n ¼ 271) [69C]. At 8 weeks, those who took aripiprazole reported significantly greater improvement in sexual function. Baseline mean serum prolactin concentrations were similar in the two groups (434 and 423 mg/l respectively); however, at week 26, the mean fall in serum prolactin was 342 mg/l with aripiprazole compared with 133 mg/l with the other treatments. Susceptibility factors Hepatic or renal impairment Two open, single-dose studies have been conducted to investigate whether the pharmacokinetics of aripiprazole are altered in individuals with hepatic or renal impairment [70c]. In study 1, six subjects with normal hepatic function and 19 with hepatic impairment (mild, n ¼ 8; moderate, n ¼ 8; severe, n ¼ 3) received a single dose of aripiprazole 15 mg. The same dose was used in study 2, in seven patients with normal

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renal function and six with severe renal impairment. There were no differences in aripiprazole pharmacokinetics in either study. Drug–drug interactions Cocaine Six cocaine-dependent subjects were given aripiprazole 15 mg/day and placebo for 10 days in counterbalanced order before assessment of the physiological and subject-rated effects of intranasal cocaine [71c]. Intranasal cocaine produced prototypical stimulant-like effects (for example, increased blood pressure and heart rate, increased subject ratings of Like Drug and Stimulated) and aripiprazole enhanced these effects. The authors concluded that although these results suggest that aripiprazole is safe and tolerable when combined with cocaine, enhancement of the effects of cocaine during maintenance is not desirable. Metamfetamine The results of a doubleblind study of potential interactions of intravenous metamfetamine (15 and 30 mg) with oral aripiprazole (15 mg) have been published [72C]. The effects of aripiprazole on abstinence-related craving and cue-induced craving were also evaluated. Participants included non-treatmentseeking metamfetamine-dependent patients who took aripiprazole (n ¼ 8) or placebo (n ¼ 8) for 2 weeks. Aripiprazole had no effect on cue-induced metamfetamine craving, but was associated with increased craving independent of metamfetamine dose, euphoria, and amphetamine-like effects after metamfetamine. Aripiprazole reduced the increase in systolic blood pressure after metamfetamine, but it had no other effects on cardiovascular responses to metamfetamine. Aripiprazole did not alter the pharmacokinetics of metamfetamine. The adverse events tended to be equally distributed between the two groups, except for tremor (n ¼ 4) and restlessness (n ¼ 3), which were more common in those who took aripiprazole.

Clozapine

[SED-15, 823; SEDA-30, 61; SEDA-31, 78; SEDA-32, 94]

Comparative studies Clozapine and olanzapine The efficacy and safety of clozapine (300 mg/day; n ¼ 18) and olanzapine (up to 30 mg/day; n ¼ 21) have been evaluated in a 12-week double-blind study of treatment-refractory children and adolescents with schizophrenia aged 10–18 years [73C]. Significantly more clozapine-treated adolescents met response criteria (66%) compared with the olanzapine-treated subjects (33%); clozapine was also superior to olanzapine in terms of reductions in the psychosis cluster scores and negative symptoms from baseline to end-point. Significant weight gain and metabolic abnormalities were major problems associated with both treatments. Five of 39 subjects (three taking clozapine and two taking olanzapine) gained more than 7% of their baseline body weight, and nine (four taking clozapine and five taking olanzapine) had newly emergent fasting triglyceride concentrations over 1.24 mmol/l. Furthermore, five patients, all taking clozapine, had serious adverse events and/or discontinued treatment because of adverse reactions neutropenia, upper bowel obstruction, increased thirst and polyuria, weight gain (3.2 kg), and drug-induced diabetes (glucose 8.0 mmol/l). Subsequently, 33 patients (14 taking clozapine and 19 taking olanzapine) were available for a 12-week open extension study [74c]. The incidence of hypertriglyceridemia, defined as fasting triglycerides over 1.41 mmol/l (10/14), and the incidence of prediabetes, defined as a fasting blood glucose of 5.5 mmol/l or more (4/ 14 ¼ 29%), at week 24 in the clozapinetreated subjects were high. However, 7 of 10 young patients with schizophrenia who failed treatment with olanzapine responded in a 12week, open trial of clozapine. Clozapine, olanzapine, and haloperidol In a randomized, double-blind, parallel-group, 12 week study, 100 physically aggressive in-patients with schizophrenia were given clozapine (n ¼ 33), olanzapine, (n ¼ 34),

Antipsychotic drugs

Chapter 6

or haloperidol (n ¼ 33) [75C]. Olanzapine was associated with better cognitive function relative to haloperidol and clozapine, and this improvement was associated with a reduction in aggressive behavior. There were no differences among the groups in adverse effects, including sedation and extrapyramidal effects; however, those who took haloperidol were also given benzatropine. Cardiovascular Clozapine has been associated with venous thromboembolism. The mortality rate associated with pulmonary embolism has been estimated to be about 28 times higher than in the general population of similar age and sex; it is not clear whether pulmonary embolism can be attributed to clozapine or some characteristic of its users [SEDA-28, 65]. A new case of pulmonary embolism has been reported [76A]. • A 45-year-old man became acutely confused after taking an overdose of clozapine, which he had previously been taking for 6 months. He had acute dyspnea due to bilateral pulmonary emboli. He was not overweight, but was a heavy smoker; plasma concentrations of clozapine are lower in smokers than in nonsmokers [SEDA-31, 81].

Hematologic Agranulocytosis, leukopenia, and neutropenia associated with clozapine have been extensively studied and discussed [SED-15, 829; SEDA-32, 97]. • A 55-year-old man developed neutropenia after taking clozapine 750–800 mg/day for 12 years [77A]. Valproic acid 1500 mg/day had been added 2 years before. When donepezil was added his white blood cell and neutrophil counts fell.

Of 26 Korean children and adolescents with refractory early-onset schizophrenia (mean age 14 years) nine developed neutropenia; there was no agranulocytosis [78c]. Drug–drug interactions Benzodiazepines In 152 patients who concomitantly took clozapine and benzodiazepines from 2001 to 2006 there were no reports of deaths [79c].

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Iloperidone Iloperidone is a novel antipsychotic drug which is a mixed dopamine D2/serotonin 5-HT2A receptor antagonist. In 2008, the US Food and Drug Administration required Vanda Pharmaceuticals, the manufacturers, to carry out a comparison of iloperidone with placebo and an active comparator such as olanzapine or risperidone [80S]. It was finally approved in the USA in May 2009. Comparative studies Iloperidone has been compared with haloperidol in patients with schizophrenia using data from three prospective multicenter studies, each with a 6-week stabilization period followed by a 46-week, double-blind, maintenance phase [81M]. In all, 1644 patients were randomized to iloperidone 4–16 mg/day or haloperidol 5–20 mg/day; of the 1326 patients who completed the 6-week phase and who improved, only 473 (iloperidone, n ¼ 359; haloperidol, n ¼ 114) were included in the long-term efficacy analysis; mean doses at end-point were 12.5 mg/day in both groups. Mean time to relapse was 90 (median 50) days with iloperidone and 102 (median 78) days with haloperidol; relapse rates were slightly higher with iloperidone than with haloperidol (44% and 41% respectively). The adjusted mean change from baseline to end-point in PANSS-T score (last observation carried forward) was  16.1 for iloperidone and 17.4 for haloperidol. For the safety analysis, a total of 489 patients (iloperidone, n ¼ 371, mean age 35 years, 64.4% men; haloperidol, n ¼ 118, mean age, 35 years, 60.2% men) were included. In the maintenance phase, serious adverse events were reported by 18% of patients who took iloperidone and by 16% of those who took haloperidol; exacerbation of psychotic symptoms was the most frequent adverse event (iloperidone, 11%; haloperidol, 5.9%). Of all the patients who were evaluated, 224 (18%) of those who took iloperidone were hospitalized, and there were four deaths (0.3%); two other patients treated with iloperidone died in the first month after

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the study ended. Of those who took haloperidol, 56 (14%) were hospitalized; there was one death (0.2%). The most common adverse events in the maintenance phase were insomnia (18%), anxiety (11%), and aggravated schizophrenia (8.9%) with iloperidone; and insomnia (17%), akathisia (14%), tremor (13%), and muscle rigidity (13%) with haloperidol. Mean changes in Fridericia's QTc interval at end-point were 10.3 ms for iloperidone and 9.4 ms for haloperidol; metabolic changes were minimal in both groups. Placebo-controlled studies In a randomized, placebo-controlled, multicenter study, with a 1-week titration period and a 3-week double-blind maintenance period, 593 patients with acute exacerbations of schizophrenia were randomized to iloperidone 24 mg/day, ziprasidone 160 mg/day as an active control, or placebo [82C]. Like ziprasidone, iloperidone produced significant improvement compared with placebo. Iloperidone was associated with higher rates of weight gain, tachycardia, orthostatic hypotension, dizziness, and nasal congestion. There was similar QT interval prolongation with both active treatments, although no patient had a treatment-emergent corrected QT interval of 500 ms or greater. The incidence of clinically relevant changes in laboratory parameters was comparable between iloperidone and ziprasidone. Iloperidone was associated with a low incidence of extrapyramidal symptoms.

Olanzapine [SED-15, 2598; SEDA-30, 64; SEDA-31, 81; SEDA-32, 99] Observational studies The use of antipsychotic drugs in children and adolescents is of particular concern. In a 24-week, multicenter, open study supported by Eli-Lilly, the marketing authorization holder, 96 adolescents with schizophrenic disorder (mean age 16 years; 68% boys) were given olanzapine 10 mg/day [83c]. BPRS scores fell from baseline to week 6 by a mean of 17. The most common adverse events were weight gain and increased prolactin. Weight

gain was observed in 29 patients; mean weight gain from baseline to week 6 was 5.1 kg (n ¼ 76) and from baseline to 24 weeks 11.7 kg (n ¼ 32); the mean BMI rose from 21.2 at baseline to 22.8 at week 6 and to 25.0 at week 24; 24 patients had a 7% or greater weight gain. There were higher-than-normal prolactin concentrations (boys 16 mg/l; girls 29 mg/l) in 28% at baseline, 82% at week 2, and 59% at week 6; there was a similar pattern of prolactin concentrations, with a peak of 27 mg/l at week 4 in the boys (n ¼ 58) and 45 mg/l in the girls (n ¼ 26). One patient discontinued treatment because of weight gain and one girl because of galactorrhea. In a prospective open trial in 40 boys with autism (mean age 12 years) who took olanzapine (mean dose 7.5, range 5–10 mg/ day) for 13 weeks, there were significant improvements in scores on the Aberrant Behavior Checklist scale [84c]. Extrapyramidal symptoms and dyskinetic symptoms did not change from baseline to end-point. There were no significant increases in hepatic enzymes or any serum chemistry. There were transient mild adverse reactions such as drowsiness and sedation, when treatment was begun (13% of patients). Mean body weight was 52.5 kg before treatment and 52.8 kg after treatment. In an open 6-week trial mean weight increased by 4.1 kg (range 1.1–7.7 kg) in 12 children and adolescents with Tourette's syndrome (age range 7–14 years; 11 boys) [85c]. Of 278 adults (mean age 36 years, 180 men) with acute psychosis and agitation, 148 took oral olanzapine monotherapy (mean dose 12 mg/day); only mild adverse events were observed, including bradycardia, dry mouth, sedation, hypertension, hypotension, and orthostatic hypertension (one case each) [86c]. Comparative studies Olanzapine and clozapine The efficacy and safety of clozapine (300 mg/day; n ¼ 18) and olanzapine (up to 30 mg/day; n ¼ 21) have been evaluated in a 12-week double-blind study of treatmentrefractory children and adolescents with schizophrenia aged 10–18 years [73C].

Antipsychotic drugs

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105

in measures of efficacy, nausea, or akathisia [89c].

Significantly more clozapine-treated adolescents met response criteria (66%) compared with the olanzapine-treated subjects (33%); clozapine was also superior to olanzapine in terms of reductions in the psychosis cluster scores and negative symptoms from baseline to end-point. Significant weight gain and metabolic abnormalities were major problems associated with both treatments. Five of 39 subjects (three taking clozapine and two taking olanzapine) gained more than 7% of their baseline body weight, and nine (four taking clozapine and five taking olanzapine) had newly emergent fasting triglyceride concentrations over 1.24 mmol/l. Furthermore, five patients, all taking clozapine, had serious adverse events and/or discontinued treatment because of adverse effects: neutropenia, upper bowel obstruction, increased thirst and polyuria, weight gain (3.2 kg), and drug-induced diabetes (glucose 8.0 mmol/l). Subsequently, 33 patients (14 taking clozapine and 19 taking olanzapine) were available for a 12-week open extension study [87C]. The incidence of hypertriglyceridemia, defined as fasting triglycerides over 1.41 mmol/l (10/14), and the incidence of prediabetes, defined as a fasting blood glucose of 5.5 mmol/l or more (4/14 ¼ 29%), at week 24 in the clozapinetreated subjects were high. However, 7 of 10 young patients with schizophrenia who failed treatment with olanzapine responded in a 12-week, open trial of clozapine. Olanzapine and clozapine were effective in a 6-month, double-blind study in treatment-resistant schizophrenia patients [88c] who were randomized to olanzapine mean dose 34 mg/day (n ¼ 19) or clozapine mean dose 564 mg/day (n ¼ 21). Mean weight gain was 1.6 kg in patients taking clozapine and 7.2 kg in those on olanzapine; there was no significant relationship between olanzapine dose and change in weight.

Olanzapine and lithium Chinese patients with bipolar manic or mixed episodes were randomized to olanzapine (mean daily dose 18 mg/day; mean age 31 years; n ¼ 69) or lithium carbonate (mean daily dose 1110 mg/day; mean age 34 years; n ¼ 71) for 4 weeks in a multicenter, double-blind, controlled study [90c]. Patients in both groups improved in different psychopathological assessments. Treatment-emergent adverse events during the study occurred in 55% with olanzapine and 42.3% with lithium; the most common events with olanzapine were constipation (13%), nausea (7.2%), and somnolence (7.2%); with lithium they were nausea (13%) and nasopharyngitis (5.6%). More of those who took olanzapine reported adverse events relating to the following MedDRA system organ classes: metabolism and nutrition disorders (olanzapine 5.8%; lithium 1.4%), nervous system disorders (olanzapine 13%; lithium 5.6%), and psychiatric disorders (olanzapine 5.8%; lithium 0.0%). There were no serious adverse events or deaths during this study; one patient taking lithium withdrew because of abnormal hepatic function. Mean weight increased during the 4-week study in both groups but was significantly higher with olanzapine (1.85 kg versus 0.73 kg). In addition, significantly more of those who took olanzapine had a clinically significant weight increase (7% of baseline weight) compared with lithium (16% versus 2.9%). The blood glucose concentration increased in one patient taking olanzapine (baseline: 5.6 mmol/l; end-point: 10.8 mmol/l) and total cholesterol increased in four patients (three taking olanzapine and one taking lithium).

Olanzapine and droperidol In a randomized non-blinded clinical trial, patients attending an emergency department for primary headache were given either intramuscular droperidol 5 mg (n ¼ 42) or off-label olanzapine 10 mg (n ¼ 45). There were no significant differences between the groups

Olanzapine, quetiapine, and risperidone In two studies olanzapine, quetiapine, and risperidone had similar efficacies in patients with psychoses but differed in adverse effects. In a comparative study, 75 in-patients with schizophrenia were randomized to

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olanzapine (mean dose at end-point 15 mg/ day; mean age 35 years; n ¼ 25), quetiapine (mean dose at end-point 590 mg/day; mean age 39 years; n ¼ 25), or risperidone (mean dose at study endpoint 5.1 mg/day; mean age 43 years; n ¼ 25) [91c]. After 8 weeks, there were significant clinical improvements in all treatment arms, with no significant differences. There were 14 withdrawals: five on olanzapine, four on quetiapine, and five on risperidone. At the final visit there was a 7% increase in baseline body weight in 8%, 8%, and 29% with quetiapine, risperidone, and olanzapine respectively. Extrapyramidal symptoms were significantly worse with risperidone than both olanzapine and quetiapine at week 3 and compared with quetiapine thereafter. In the Child and Adolescent First-Episode Psychosis Study (CAFEPS), a longitudinal multicenter study, 110 patients aged 9–17 years were treated for a first psychotic episode [92c]. Only patients who received one antipsychotic drug from baseline to 6 months of follow-up were included in the safety analysis (risperidone, n ¼ 50; quetiapine, n ¼ 18; olanzapine, n ¼ 16). Using the baseline score as a co-variate, there were no significant differences in the reductions in any of the four clinical scales in patients who took risperidone, quetiapine, or olanzapine for 6 months. As expected, olanzapine caused significantly greater gains in weight and BMI than the other two drugs (mean body weight gain 12 kg for olanzapine versus 6.0 kg for quetiapine and 6.1 kg for risperidone; mean BMI increase 3.9 for olanzapine versus 1.4 for quetiapine and 1.9 for risperidone), even after controlling for initial weight or BMI. The percentage of patients with hypokinesia/akinesia was significantly higher with risperidone than with olanzapine or quetiapine (50% versus 15% and 13%); there was dystonia in one patient taking risperidone. Olanzapine and risperidone Atypical antipsychotic drugs are occasionally used off-label for obsessive symptoms. From an initial sample of 96 Italian patients with

obsessive–compulsive disorder who underwent a 16-week first phase of treatment with SSRIs, 50 were judged to be resistant and were randomized to additional risperidone (mean age 36 years; mean daily dose 2.1 mg; n ¼ 25) or olanzapine (mean age 34 years; mean daily dose 5.3 mg; n ¼ 25) in an 8-week, singleblind, second phase [93c]. Adverse experiences were reported by 52% of those who took additional risperidone and 64% of those who took olanzapine; adverse events motivated withdrawal in two patients taking olanzapine (reduced sexual desire and weight gain). Placebo-controlled studies Subjects with borderline personality disorder (n ¼ 314) have been treated off-label with olanzapine (modal dose 7.1 mg/day) in a 12-week randomized, double-blind, placebo-controlled trial [94C]. Olanzapine and placebo produced similar significant improvements, but time to response was significantly shorter with olanzapine. Withdrawal rates because of adverse events were 11% for both olanzapine and placebo. Increased appetite and weight gain were significantly greater with olanzapine (mean weight gain 2.8 kg versus  0.4 kg); olanzapine also produced significantly larger increases in fasting total cholesterol, fasting LDL cholesterol, total and direct bilirubin, hepatic enzymes, and prolactin. There were serious adverse events in 15 patients: six taking olanzapine (suicidal ideation, n ¼ 4; aggression, agitation, alcoholism, drug misuse, impulsive behavior, self-mutilation, and self-injurious ideation, n ¼ 1 each) and nine taking placebo (suicidal ideation, n ¼ 4; aggression, anxiety, exacerbation of borderline personality disorder symptoms, n ¼ 2 each; and depressed mood, fatigue, and weight reduction, n ¼ 1 each). Increased appetite and significantly more weight gain (2.7 kg versus 0.1 kg) were also found in 42 patients with pathological gambling who were randomized in a 12-week study to olanzapine (mean dose 8.9 mg/ day) or placebo [95c].

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In a double-blind, placebo-controlled study, 34 patients with anorexia nervosa were randomly assigned to either olanzapine plus day-hospital treatment (n ¼ 16) or placebo plus day-hospital treatment (n ¼ 18) [96c]. At 10 weeks, body weight had increased in both groups, although the achievement of target body mass index was greater and earlier in those who took olanzapine. Cardiovascular Clozapine, which is close related to olanzapine, has been implicated as an independent susceptibility factor for pulmonary embolism [SEDA-28, 65]. A possible association between olanzapine and pulmonary thromboembolism has also been described [SEDA-32, 102]. New cases have been reported [97A, 98A]. • A 47-year-old woman with schizophrenia was found dead in her apartment. She had been taking lithium and olanzapine. Autopsy showed an acute pulmonary embolus in the left main pulmonary artery, with extension into the lobar branches and an adherent thrombus in the left popliteal vein. There was no evidence of other pathology. Postmortem toxicology confirmed the presence of olanzapine and showed no other substances. There were no other risk factors, such as obesity, a sedentary lifestyle, a history of smoking, recent trauma or immobilization, use of estrogens, or a family history of thrombotic events; factor V Leiden and prothrombin mutations were negative.

In previous cases, identified by specific searching, one subject had two known risk factors for pulmonary embolism (obesity and a recent ankle fracture), one had one risk factor (obesity), and three had none. • A 23-year-old man, not overweight, a smoker of 1 pack/day, with an early-onset schizoaffective disorder was given olanzapine 20 mg/day, paroxetine 20 mg/day, and valproate 2000 mg/ day. After 12 weeks, he suddenly developed back pain radiating to the left anterosuperior part of the thorax; over the next few hours he became dyspneic and had an episode of hemoptysis. Arterial blood gases were normal. Bilateral pulmonary embolism was confirmed by a CT scan. Olanzapine was withdrawn and oral anticoagulation was given for 6 months. As his psychotic symptoms recurred 12 weeks later, he was given risperidone 3 mg/day and

107 3 weeks later had a second episode of pulmonary embolism, which was attributed to nonadherence to the anticoagulant treatment. However, 16 weeks later he had a third episode; following exhaustive investigations, antipsychotic drugs (olanzapine and risperidone) remained the most probable causal factor. He improved with anticoagulation and amisulpride 400 mg/day. Paroxetine 20 mg/day and valproate 2 g/day were maintained throughout these episodes.

Nervous system Abnormality of P300 waveforms of event-related potentials has been suggested to represent an aspect of the pathophysiology of schizophrenia; low resolution electromagnetic tomography analysis (LORETA) has been used to obtain current density images of P300 in 16 patients with schizophrenia taking olanzapine and 16 healthy controls [99c]. The patients had significantly smaller LORETA values in several brain regions on the left side, particularly in the superior temporal gyrus, middle frontal gyrus, and precentral gyrus, than control subjects. After treatment for 6 months with olanzapine the P300 source density increased significantly only in the left superior temporal gyrus, suggesting positive changes in cortical activity; however, the small sample size precluded firm conclusions. Drug withdrawal Switching patients from one antipsychotic drug to another is a common practice; three strategies for changing olanzapine to risperidone have been assessed in a 6-week, randomized, open study in 123 patients with schizophrenia or schizoaffective disorder: (i) an abrupt strategy, in which olanzapine was withdrawn when risperidone was started; (ii) a gradual strategy, in which olanzapine was given at 50% entry dose for 1 week after risperidone was started and then discontinued; and (iii) a very gradual strategy, in which olanzapine was given at 100% entry dose for 1 week, then at 50% in the second week, and then withdrawn [100c]. All-cause treatment withdrawal was lowest (12%) in those with the slowest olanzapine dosage reduction; adverse events accounted for withdrawal in 5% of patients on the abrupt

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and very gradual strategies, and in 15% of those on the gradual strategy. Management of adverse drug reactions In a second phase of the previous study, 71 patients with a BMI over 26 kg/m2 were enrolled in a weight-loss program while taking risperidone and randomly assigned to 14 weeks of a behavioral treatment program for weight reduction (n ¼ 34) or usual care (risperidone modal dose 4.5 mg/day; n ¼ 37), there was significant weight loss in both treatment groups after 14 weeks: mean changes were 2.0 kg in the subjects enrolled in the behavioral program and 1.1 kg in the control group [100c]. The authors concluded that specific weight-loss behavioral programs might prevent weight gain associated to olanzapine.

Paliperidone Paliperidone, or 9-hydroxyrisperidone, is the major active metabolite of risperidone. It binds to both dopamine D2 and serotonin 5-HT2A receptors, and antagonism at these receptors is thought to account for its therapeutic activity in schizophrenia. It was approved by the US Food and Drug Administration in 2007 for acute and maintenance treatment of schizophrenia; it is available in modified-release tablets. The available literature on the pharmacodynamics, pharmacokinetics, clinical efficacy, and tolerability of paliperidone has been extensively reviewed [101R]. Placebo-controlled studies Paliperidone modified-release, quetiapine, and placebo have been compared in patients with recently exacerbated schizophrenia requiring hospitalization in a 6-week double-blind study [102C]. In-patients were randomly assigned to paliperidone modified-release (n ¼ 160), quetiapine (n ¼ 159), or placebo (n ¼ 80). A 2-week monotherapy phase was followed by a 4-week additivetherapy phase; target doses were at the

upper end of the recommended ranges: paliperidone modified-release, 9 or 12 mg/ day, and quetiapine, 600 or 800 mg/day. Six-week completion rates were 78% with paliperidone modified-release, 67% with quetiapine, and 64% with placebo. Improvement in mean PANSS total change score was greater with paliperidone modified-release than with quetiapine from day 5 (11 versus 8.2) to the monotherapy phase end-point (23.4 versus 17.1). At the 6-week end-point, there was significantly greater improvement with paliperidone than quetiapine or placebo, despite similar use of additive therapy (predominantly other antipsychotic drugs). Over the entire study period, serious adverse events were reported by 13 (8.2%) patients taking paliperidone, 7 (4.4%) taking quetiapine, and 2 (2.5%) taking placebo; the most common adverse event was schizophrenia (3.8%, 1.9%, and 0.0% respectively). There were significantly higher values for changes in prolactin with paliperidone; the values at end-point were 32, –6.7, and 4.5 ng/ml respectively. Elderly patients with schizophrenia (mean age 70 years; n ¼ 114) who took paliperidone in a 6-week double-blind, placebo-controlled study followed by a 24week open extension with paliperidone (mean doses 7.4 and 8.5 mg/day respectively) treatment-emergent adverse events were similar (71% with placebo and 67% with paliperidone), as were withdrawal rates because of adverse events (8% and 7% respectively) [103c]. There were serious adverse events in three patients taking placebo and in two taking paliperidone (acute coronary syndrome and mania, n ¼ 1 each); there was also an age-related increase in the incidence of somnolence. There was a higher incidence of tachycardia with paliperidone in both phases, increases being more pronounced in patients aged 70–75 years compared with those aged 64–69. There was prolongation of the QTc interval to over 500 ms in the first phase, leading to discontinuation (n ¼ 2), and in the second phase (n ¼ 1); these three patients had histories of QT interval

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prolongation. In the double-blind phase, there were raised prolactin concentrations in 45% of the men and 49% of the women taking paliperidone, but they returned to normal at the end of the study; prolactin concentrations also rose in patients taking paliperidone who had previously taken placebo. The incidence of extrapyramidal symptoms was low throughout the study; during the second phase, medication for treatment of this effect was used in 27% and 22% respectively. In a re-analysis of different short-term studies, the efficacy and tolerability of modified-release paliperidone have been assessed in patients with acute schizophrenia [104M]. Patients were randomly allocated to paliperidone 3 mg/day (n ¼ 123), 6 mg/day (n ¼ 234), 9 mg/day (n ¼ 245), 12 mg/day (n ¼ 240), 15 mg/day (n ¼ 113), or placebo (n ¼ 351); mean ages were 36–39 years. All doses of paliperidone were significantly better than placebo. There were treatmentemergent adverse events in 66–77% in those who took paliperidone and in 6% of those who took placebo; serious adverse events occurred in 5–6% of patients in all groups, the most common being exacerbation of psychotic symptoms. Orthostatic hypotension occurred from 1% at 6 mg/day to 4% at 12 mg/day. A higher proportion of patients assigned to paliperidone above 6 mg/day had extrapyramidal symptoms; one patient with a previous history of tardive dyskinesia with clozapine had an episode after taking paliperidone for 4 days. Glucose-related adverse events were reported in both groups (paliperidone, 1%; placebo, 1%). Mean body weight increased by 0.6 kg with paliperidone 3 mg/day and 1.9 kg with 15 mg/day, and fell by 0.4 kg with placebo. Median prolactin concentration increases were larger among women (81 ng/ml) than men (24 ng/ml) when all paliperidone groups were combined; the magnitude of this effect increased with increasing drug doses and there were prolactin-related adverse events in 1–2% of patients taking paliperidone 3–12 mg and 4% of those taking 15 mg. There were no deaths, cases of

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neuroleptic malignant syndrome, or other severe symptoms. Cardiovascular Paliperidone has been associated with seizures and atrial fibrillation [105A]. • A 46-year old man with bipolar disorder, diabetes mellitus, hypertension, hyperlipidemia, and tobacco use took metformin hydrochloride 2 g/day, insulin glargine 64 units/day, insulin lispro 44 units/day, simvastatin 20 mg/ day, enalapril maleate 5 mg/day, escitalopram 30 mg/day, lamotrigine 200 mg/day, and clonazepam 2 mg as needed. Owing to stress at work, he was given paliperidone 3 mg orally on day 1 and 6 mg/day thereafter. After 4 days he had a possible tonic–clonic seizure, a headache, palpitation, and mild dyspnea. An electrocardiogram showed atrial fibrillation, a ventricular rate of 151/minute, a QTc interval of 461 ms, and no significant changes in the ST segment or T wave. Sinus rhythm recurred after the administration of single oral doses of potassium chloride 20 mmol and diltiazem 10 mg. The heart rate and QTc interval normalized to 68/minute and 392 ms.

In this case pharmacogenetic testing revealed CYP2D6 alleles *4 and *10 and CYP3A4 alleles *16B and *1F, which are associated with poor-to-intermediate CYP2D6 activity and reduced CYP3A4 activity in vitro. Drug–drug interactions In September 2008, the FDA Center for Drug Evaluation and Research changed the information in the section included in the safety labelling of paliperidone [106S], as follows: • Potential for Invega (paliperidone) to affect other drugs Paliperidone is a weak inhibitor of P-glycoprotein at high concentrations. No in vivo data are available and the clinical relevance is unknown. • Potential for other drugs to affect Invega In vitro studies have shown that paliperidone is a P-glycoprotein substrate.

Co-administration of Invega 6 mg once daily with carbamazepine 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state Cmax and AUC of paliperidone.

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Quetiapine

[SED-15, 2995; SEDA-30, 67; SEDA-31, 87; SEDA-32, 104]

Quetiapine has been approved in the USA for the treatment of schizophrenia in adolescents aged 13–17 years, bipolar mania in children and adolescents aged 10–17 years, and as adjunctive therapy for treatment of major depressive disorder [107S]. Observational studies In 477 patients with schizophrenia (mean age 38 years), who were switched from their medication to quetiapine (mean median dose 575 mg/ day) because of insufficient efficacy (66%) or insufficient tolerability (34%) in a 12week, multicenter, open-label study supported by AstraZeneca, the marketing authorization holder of quetiapine common adverse events included somnolence (18%), sedation (15%), and dizziness and dry mouth (14% each), and extrapyramidal symptoms (8.0%) [108C]. There were higher glucose concentrations both at baseline (n ¼ 8) and end-point (n ¼ 12). The mean body weight change was 1.0 kg. In a 12-week, open, flexible-dose study of quetiapine in 40 out-patients with generalized anxiety disorder who had not achieved remission after at least 8 weeks of adequate doses of standard therapy, the most common adverse reactions were sedation (n ¼ 29), dry mouth (n ¼ 12), and sexual dysfunction (n ¼ 10) [109c]. Mean total weight gain from pre-treatment to week 12 was about 0.5 kg and 14% of patients had a 7% weight gain. Seven patients withdrew because of adverse events: sedation (n ¼ 5), panic attacks (n ¼ 1), and bilateral iritis (n ¼ 1). Adverse reactions to quetiapine have been studied in 13 children aged 10–12 years, 14 adolescents aged 13–17 years, and 29 adults, mean age 37 years, with a psychotic disorder, in a study that was supported by AstraZeneca, the marketing authorization holder; quetiapine was titrated up to 400 mg/day over 12 days [110c]. None of the children withdrew because of adverse events, two

had dyskinesias, dizziness, and somnolence and required dosage reduction. The most common adverse events were somnolence (26%), orthostatic hypotension (22%), dizziness (15%), and sedation (7.4%); the heart rate increased by more than 145/ minute in four patients. One of the adults withdrew because of agitation, and there were treatment-related adverse events in 19, including orthostatic hypotension (about 50%), dizziness (45%), anxiety (24%), lethargy (21%), and dry mouth and insomnia (both 17%); the heart rate increased by more than 120/minute in 17 patients; all hematological tests were within the reference ranges. Quetiapine has been used in very small numbers of patients for off-label indications: prevention of migraine (75 mg/day; mean age 39 years; n ¼ 34) [111c] and cocaine dependence (mean dose 429 mg/day; mean age 47 years; n ¼ 22) [112c]. In the first study the most common adverse events, which occurred in nine patients, were worsening headache, drowsiness, somnolence, increased appetite, weight gain, and nausea. In the second study, all the subjects had sedation at some time during treatment, and several dropped out because of it; weight increased significantly and other reactions were dry mouth, orthostatic faintness, and constipation. Comparative studies Quetiapine and lithium In a 4-week, multicenter, double-blind study, Chinese patients with bipolar mania were randomized to quetiapine (mean dose, 648 mg/day; mean age, 33 years; n ¼ 77) or lithium (mean serum concentration 0.80 mmol/l; mean age 34 years; n ¼ 77) [113c]. The proportion of patients with at least one adverse event during the study was higher with quetiapine (78%) than lithium (69%). The most common (5%) adverse events with quetiapine were constipation (35%), dizziness (15%), diarrhea (10%), increased alanine aminotransferase (9.0%), bouts of palpitation (9.0%), increased aspartate aminotransferase (7.7%), pharyngolaryngeal pain (6.4%), upper respiratory tract infections (6.4%), and dry mouth

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(5.1%). In those who took lithium the most common adverse events were nausea (17%), constipation (13%), vomiting (13%), nasopharyngitis (12%), dizziness (6.5%), diarrhea (6.5%), and upper respiratory tract infections (6.5%); one patient had bone marrow depression and three had adverse events (pruritus, vomiting, and depressed level of consciousness and dizziness) that led to withdrawal. Tachycardia, bradycardia, and minor conduction block occurred in both groups. There were transient increases in hepatic enzyme activities in five patients taking quetiapine and in two taking lithium. There were high blood glucose concentrations in three patients in each group. Mean weight gain was 1.5 kg with quetiapine and 0.3 kg with lithium. Extrapyramidal symptoms (dystonia, akathisia, tremor, and extrapyramidal disorder) were similar with quetiapine (5.1%) and lithium (6.5%). Quetiapine and risperidone In a 12-month multicenter, non-randomized study in patients with acute schizophrenia who were given quetiapine (mean age 37 years; mean dose 719 mg/day; n ¼ 367) or risperidone (mean age 36 years; mean dose 7.0 mg/ day; n ¼ 125), serious adverse events with quetiapine (n ¼ 3) were death by suicide, tachycardia, and dystonia; and with risperidone (n ¼ 3), severe rigidity/dysphagia, sedation, and acute dystonia [114C]. Orthostatic hypotension was more frequent with quetiapine than with risperidone (14% versus 6.7%); male sexual dysfunction (loss of libido 22% versus 11%; erectile dysfunction 21% versus 9.4%; and impaired ejaculation 18% versus 6.9%) were more common with risperidone. Extrapyramidal symptoms (including rigidity and hypokinesia) occurred in 33% and there were no significant differences between the two groups in female sexual dysfunction, somnolence, constipation, reduced salivation, headache, dyspepsia, tachycardia, or weight gain. Quetiapine and valproate In a 12-month comparison of quetiapine (mean dose 465 mg/day; n ¼ 22) and valproate (mean dose 720 mg/day; n ¼ 16) in patients with rapid-cycling bipolar disorder, orthostatic

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dysregulation (59% versus 19%) and sedation (50% versus 6%) were the most frequent adverse events [115c]. Other effects were dry mouth (27% versus 13%) and headache (23% versus 19%). Adverse events were the most frequent reason for discontinuation only in the quetiapine group. Adverse events leading to withdrawal in patients taking quetiapine included abnormal electroencephalographic signs of arousal, suicide attempt, and lymphedema (one each), and body weight changes (mean 4.5 kg in patients taking quetiapine and 2.7 kg in those taking valproate). Drug abuse [SEDA-30, 68; SEDA-32, 107] Quetiapine abuse has again been described [116A]. • A 29-year-old man reported that the local police were disturbing his sleep by “electronically monitoring” his testicles; he also said he had schizophrenia and was being treated with quetiapine 600 mg nightly. He received his “usual” dose and slept soundly. The next morning he was still somnolent without thought or mood disturbance. His urine toxicology screen was negative. A pharmacy review revealed that he had received different and excessive amounts of quetiapine from several sources during the past few months. On confrontation, he admitted both excessive use and sale of quetiapine.

Risperidone

[SED-15, 3052; SEDA-30, 69; SEDA-31, 90; SEDA-32, 107] In a review of the use of risperidone in autistic disorder in children and adolescents it was stressed that somnolence, increased appetite, increased prolactin concentrations, and fatigue were the most common adverse events [117R].

Observational studies In an open study, 232 children and adolescents (mean age 11 years) with disruptive behavioral disorders were followed during 1 year in an extension period with risperidone, having been previously randomized to risperidone

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or placebo in a double-blind, 6-month withdrawal study [118C]. Weight gain and extrapyramidal symptoms (most frequently dystonia, n ¼ 7) were each reported by 10 subjects. Prolactin concentration increased with risperidone; median prolactin concentrations at baseline were 237 mU/l in women and 175 mU/l in men; at end-point the values were 356 and 238 mU/l respectively. There was gynecomastia in two men and transient dysmenorrhea in one woman. Twenty had serious adverse events, including psychiatric aggravation in 10. In a retrospective study of male delinquents, mean age 16 years, with childhood onset and persistent conduct disorder treated either with psychosocial treatment and risperidone (mean dose 2.5 mg/day; n ¼ 60) or cognitive-behavioral treatment alone (n ¼ 69), the most common adverse events in the patients taking risperidone were somnolence (26%), weight gain (18%), increased appetite (17%), and constipation (14%); mean body weight increased by 6.8 kg during a mean time of 9 months [119c]. Comparative studies Risperidone and divalproex In a retrospective study of 28 patients aged 5–14 years with bipolar disorder who had been treated with risperidone (n ¼ 16) or divalproex (n ¼ 12), risperidone was associated with faster clinical improvement and significantly more weight gain than divalproex (mean changes 2.46 kg versus 0.43 kg); however, the small sample size precluded definitive conclusions [120c]. Risperidone and haloperidol In a 24-week study (12-week double-blind and 12-week open), 28 children and adolescents with autistic disorder were treated either with risperidone (mean age 10 years; n ¼ 13) or haloperidol (mean age 11 years; n ¼ 15), both in doses of 0.01–0.08 mg/kg/day [121c]. There were significant mean weight gains from baseline to end-point (4.2 kg with risperidone and 6.3 kg with haloperidol). However, there were no significant differences in weight and prolactin concentrations between the two groups at end-point.

Other common events were constipation (risperidone 29%; haloperidol 23.1%) and nocturnal enuresis (20% and 23% respectively). There were greater increases in prolactin concentrations with risperidone in a 12week, double-blind study, in which children and adolescents with autistic disorder were assigned to either risperidone (mean age 10 years; n ¼ 15) or haloperidol (mean age 11 years; n ¼ 15); the mean doses were 2.6 mg/day for both drugs [122c]. Combination studies Herbal preparations are occasionally used as adjunctive treatments to antipsychotic drugs. In an 8-week, randomized, double-blind, placebo-controlled study of warm-supplementing kidney yang capsule 2.7 g/day added to risperidone in 200 patients with schizophrenia [123c]. Performance on the Wisconsin Card Sorting Test was significantly higher in the group of patients taking the combination than in those taking placebo; there were no significant differences in adverse events; tremor, akathisia, weight gain, and insomnia occurred in more than 10% of patients in both groups. Placebo-controlled studies In 86 nonpsychotic patients who presented with aggressive challenging behavior from 10 centers in England and Wales and one in Queensland, Australia, who were randomly assigned to haloperidol (n ¼28), risperidone (n ¼ 29), or placebo (n ¼ 29), aggression was substantially reduced by all three treatments after 4 weeks; the placebo group showed the greatest change (a median reduction in the modified overt aggression scale score) after 4 weeks of 9 for placebo (79% from baseline); 7 for risperidone (58% from baseline); and 6.5 for haloperidol (65% from baseline) [124c]. There were no important differences between the treatments, including adverse effects; patients who took placebo had no evidence at any time of a worse response than patients who had been assigned to either of the antipsychotic drugs. The authors suggested that antipsychotic drugs should no longer be regarded as acceptable in the routine

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treatment for aggressive challenging behavior in people with intellectual disabilities. The authors of an accompanying editorial pointed out that the sample size in this study was impressive, in view of the practical, legal, and cultural problems associated with recruitment for such research [125r]. Off-label uses of risperidone have been assessed in two studies. In a double-blind study, elderly patients with depression resistant to citalopram, who had previously responded to adjunctive therapy with risperidone, where randomly allocated to continue with adjunctive therapy with risperidone (modal dose 0.8 mg/day; n ¼ 32) or to receive placebo (n ¼ 31) [126c]. Three patients taking risperidone reported headache. In a 12-week, double-blind study, cocaine-dependent men were randomized to risperidone (n ¼ 16) or placebo (n ¼ 15); mean weight changes were 2.9 kg and 0.2 kg respectively, one patient taking risperidone withdrew because of tardive dyskinesia [127c]. Nervous system Impaired sensorimotor function was observed in 33 antipsychotic drug-naïve patients with schizophrenia after they were given risperidone (n ¼ 29) or olanzapine (n ¼ 4); mean doses at 6 and 26 weeks were 3.9 and 3.2 mg/day for risperidone and 11.3 and 15 mg/day for olanzapine [128c]. Drug formulations Long-acting injectable risperidone is commonly used in patients with psychoses. There have been two studies sponsored by Janssen Cilag, the risperidone marketing authorization holder. In the first, an observational study in 842 individuals (mean age 41 years), 27% had withdrawn after 6 months because of adverse events (mean dose at end-point 36 mg) [129c]. In the second study, which lasted 2 years, long-acting injectable risperidone (n ¼ 50) was compared with oral risperidone (n ¼ 47) and haloperidol (n ¼ 47) [130c]. Prolactin-related adverse events occurred in four of those who received injectable risperidone (galactorrhea in one; amenorrhea

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and galactorrhea in two; amenorrhea and delayed menses in one); there was one case of menorrhagia with haloperidol and one case of gynecomastia with oral risperidone. The percentage of dropouts for any reason was 20% for injectable risperidone compared with 49% for the oral medications. In 529 patients (mean age 39 years) treated with long-lasting injectable risperidone (modal dose 25 mg), the median time to discontinuation was 16 months [131C]. A total of 13% (n ¼ 69) withdrew because of an adverse event, including disease exacerbation and delirium (n ¼ 4 each); mean body weight increased by 1.0 kg from baseline to end-point; glucose-related events were reported by four patients. The most common treatment adverse events were anxiety (24%), insomnia (19%), weight increase (14%), depression (11%), exacerbation of disease (10%), headache (7.7%), relapse (7.4%), tremor (6.0%), and weight reduction (5.5%); 94 patients gained >7% of their body weight and six reported pain or injection-site reactions. In 50 patients with newly diagnosed schizophrenia (mean age 25 years) who were treated with injectable risperidone 25–50 mg every 2 weeks for 2 years [132c], prolactin concentrations increased in 18 patients, four of whom reported possible prolactin-related adverse events (amenorrhea in one; galactorrhea in one; amenorrhea and galactorrhea in one; amenorrhea and delayed menses in one). Mean increase in body mass index was 4.8 kg/m2; 10 subjects required anticholinergic medication, and one developed persistent dyskinesia. Management of adverse reactions The herbal Peony-Glycyrrhiza preparation Decoction 45 g/day for 4 weeks increased the efficacy of bromocriptine 5 mg/day in reducing risperidone-induced hyperprolactinemia in 20 women with hyperprolactinemia (serum prolactin concentration >50 mg/l), who were currently experiencing oligomenorrhea or amenorrhea; one patient withdrew after taking bromocriptine for 5 days because of worsening of facial acne [133c].

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Sertindole [SED-15, 3120; SEDA-30, 72; SEDA-32, 110] Cardiovascular Sertindole has been associated with prolongation of the QT interval in clinical trials; it was withdrawn from the market because of an excessive relative reporting rate of sudden deaths in 1998 and then re-introduced in 2001 in Europe under certain restrictions [SEDA-26, 66]. Some re-analyses, sponsored by H Lundbeck A/S, the marketing authorization holder, have been published [134c, 135c]; they have not added any substantial information to that already published from the European Sertindole Safety and Exposure Survey [SEDA-32, 110].

Ziprasidone

[SED-15, 3721; SEDA-30, 72; SEDA-31, 94; SEDA-32, 111]

Observational studies Numerous open studies of ziprasidone promoted by Pfizer, the marketing authorization holder, have previously been published [SEDA-32, 111] and further studies, similarly promoted, have emerged. Of 185 subjects who were switched from olanzapine or risperidone to ziprasidone, 72 completed a 1-year extension study [136c]. The most common adverse effects were insomnia (23%) and somnolence (11%); no patient had a corrected QT interval over 500 ms at any time during the study. In 63 subjects aged 10–17 years in an open study of oral ziprasidone, consisting of a 3-week fixed-dose period and a subsequent 24-week flexible-dose period, adverse effects occurred mostly during dose titration and in the high-dose (160 mg/day) group [137c]. The most common adverse effects during the first period were sedation (32%), somnolence (30%), and nausea (25%), and during the flexible-dose period sedation (30%), somnolence (30%), and headache (25%). The incidences of movement disorders were 22% and 16% during the first and second periods. Adverse effects caused withdrawal in 6% during the fixed-dose period and in 20% in the flexible-dose period. One-third

gained 7% of their baseline weight. There were no changes in Fridericiacorrected QT intervals by more than 60 ms from baseline. In 70 patients with schizophrenia and persistent symptoms or troublesome adverse effects who were assigned to a flexible dosage (40–160 mg/day) in a 12-month open trial of ziprasidone looking for cognitive improvement, there were significant improvements in executive functions, attention, and information processing domains, but the effect sizes were moderate [138c].

Cardiovascular It is unknown to what extent QT interval prolongation due to ziprasidone increases cardiovascular risk; particular attention has been devoted to sudden death [SEDA-31, 95]. In an open, randomized, postmarketing study (the Ziprasidone Observational Study of Cardiac Outcomes–ZODIAC), whose primary outcome measure was the rate of mortality, 18 094 patients with schizophrenia were randomly assigned to either ziprasidone or olanzapine [139c]. Baseline data suggested that this population had a substantial prevalence of cardiovascular risk factors, and concomitant medications were often used, but no other data were released.

Zotepine Sexual function Spontaneous ejaculation related to zotepine therapy has been reported, supposedly for the first time [140c]. • A 38-year-old man with schizophrenia was given a combination of zotepine 100 mg/day and haloperidol ester 100 mg every 2 weeks and complained of spontaneous ejaculation, which became more severe when the dosage of zotepine was increased to 150 mg/day. Zotepine was discontinued and the spontaneous ejaculation no longer occurred with haloperidol monotherapy. A combination of haloperidol 100 mg every 2 weeks and quetiapine was then used, and spontaneous ejaculation did not recur.

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Zuclopenthixol

[SED-15, 3722;

SEDA-32, 112] Placebo-controlled studies The effects of zuclopenthixol on aggressive behavior in patients with intellectual disabilities have previously been investigated [SEDA-32, 112], and a secondary parameter analysis of the results of this study has been published [141R]. After open treatment with

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zuclopenthixol (n ¼ 49), responders were randomly assigned to continue (n ¼ 19) or discontinue (n ¼ 20) zuclopenthixol during a 12-week, double-blind, placebo-controlled period. Zuclopenthixol was superior to placebo. In the placebo-controlled period, one patient in each group withdrew because of adverse events; adverse effects were reported by six patients taking zuclopenthixol group and by five patients taking placebo.

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J Child Adolesc Psychopharmacol 2008; 18 (4): 327–36. Maina G, Pessina E, Albert U, Bogetto F. 8-week, single-blind, randomized trial comparing risperidone versus olanzapine augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder. Eur Neuropsychopharmacol 2008; 18(5): 364–72. Schulz SC, Zanarini MC, Bateman A, Bohus M, Detke HC, Trzaskoma Q, Tanaka Y, Lin D, Deberdt W, Corya S. Olanzapine for the treatment of borderline personality disorder: variable dose 12-week randomised double-blind placebo-controlled study. Br J Psychiatry 2008; 193(6): 485–92. McElroy SL, Nelson EB, Welge JA, Kaehler L, Keck Jr. PE. Olanzapine in the treatment of pathological gambling: a negative randomized placebo-controlled trial. J Clin Psychiatry 2008; 69(3): 433–40. Bissada H, Tasca GA, Barber AM, Bradwejn J. Olanzapine in the treatment of low body weight and obsessive thinking in women with anorexia nervosa: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry 2008; 165(10): 1281–8. Kannan R, Molina DK. Olanzapine: a new risk factor for pulmonary embolus? Am J Forensic Med Pathol 2008; 29(4): 368–70. Borras L, Eytan A, de Timary P, Constant EL, Huguelet P, Hermans C. Pulmonary thromboembolism associated with olanzapine and risperidone. J Emerg Med 2008; 35(2): 159–61. Higuchi Y, Sumiyoshi T, Kawasaki Y, Matsui M, Arai H, Kurachi M. Electrophysiological basis for the ability of olanzapine to improve verbal memory and functional outcome in patients with schizophrenia: a LORETA analysis of P300. Schizophr Res 2008; 101(1–3): 320–30. Ganguli R, Brar JS, Mahmoud R, Berry SA, Pandina GJ. Assessment of strategies for switching patients from olanzapine to risperidone: a randomized, open-label, rater-blinded study. BMC Med 2008; 6: 17. Fowler JA, Bettinger TL, Argo TR. Paliperidone extended-release tablets for

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the acute and maintenance treatment of schizophrenia. Clin Ther 2008; 30(2): 231–48. Canuso CM, Dirks B, Carothers J, KosikGonzalez C, Bossie CA, Zhu Y, Damaraju CV, Kalali AH, Mahmoud R. Randomized, double-blind, placebo-controlled study of paliperidone extendedrelease and quetiapine in inpatients with recently exacerbated schizophrenia. Am J Psychiatry 2009; 166(6): 691–701. Tzimos A, Samokhvalov V, Kramer M, Ford L, Gassmann-Mayer C, Lim P, Eerdekens M. Safety and tolerability of oral paliperidone extended-release tablets in elderly patients with schizophrenia: a double-blind, placebo-controlled study with six-month open-label extension. Am J Geriatr Psychiatry 2008; 16(1): 31–43. Meltzer HY, Bobo WV, Nuamah IF, Lane R, Hough D, Kramer M, Eerdekens M. Efficacy and tolerability of oral paliperidone extended-release tablets in the treatment of acute schizophrenia: pooled data from three 6-week, placebocontrolled studies. J Clin Psychiatry 2008; 69(5): 817–29. Schneider RA, Lizer MH. Apparent seizure and atrial fibrillation associated with paliperidone. Am J Health Syst Pharm 2008; 65(22): 2122–5. Food and Drug Administration. Invega (paliperidone) extended-release tablets, http:/ /www.fda.gov/Safety/MedWatch / SafetyInformation/Safety-RelatedDrug LabelingChanges/ucm119318.htm September. Food and Drug Administration. New Drug Application (NDA) Efficacy Supplements Calendar Year Approvals, http://www.fda. gov/Drugs/DevelopmentApprovalProcess/ HowDrugsareDevelopedandApproved/ Drugan dBiologicAppro v a l R e p o r ts/ EfficacySupplementApprovals/ucm215927. htm 31 December. Ganesan S, Agambaram V, Randeree F, Eggens I, Huizar K, Meulien D. Study 147 Investigators. Switching from other antipsychotics to once-daily extended release quetiapine fumarate in patients with schizophrenia. Curr Med Res Opin 2008; 24(1): 21–32.

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[109] Katzman MA, Vermani M, Jacobs L, Marcus M, Kong B, Lessard S, Galarraga W, Struzik L, Gendron A. Quetiapine as an adjunctive pharmacotherapy for the treatment of non-remitting generalized anxiety disorder: a flexibledose, open-label pilot trial. J Anxiety Disord 2008; 22(8): 1480–6. [110] Winter HR, Earley WR, HamerMaansson JE, Davis PC, Smith MA. Steady-state pharmacokinetic, safety, and tolerability profiles of quetiapine, norquetiapine, and other quetiapine metabolites in pediatric and adult patients with psychotic disorders. J Child Adolesc Psychopharmacol 2008; 18(1): 81–98. [111] Krymchantowski AV, Jevoux C. Quetiapine for the prevention of migraine refractory to the combination of atenolol þ nortriptyline þ flunarizine: an open pilot study. Arq Neuropsiquiatr 2008; 66(3B): 615–8. [112] Kennedy A, Wood AE, Saxon AJ, Malte C, Harvey M, Jurik J, Kilzieh N, Lofgreen C, Tapp A. Quetiapine for the treatment of cocaine dependence: an open-label trial. J Clin Psychopharmacol 2008; 28(2): 221–4. [113] Li H, Ma C, Wang G, Zhu X, Peng M, Gu N. Response and remission rates in Chinese patients with bipolar mania treated for 4 weeks with either quetiapine or lithium: a randomized and double-blind study. Curr Med Res Opin 2008; 24(1): 1–10. [114] Perez V, Canas F, Tafalla M. A 12-month, open-label, comparative study of quetiapine and risperidone in the acute and long-term treatment of schizophrenia. Int Clin Psychopharmacol 2008; 23(3): 138–49. [115] Langosch JM, Drieling T, Biedermann NC, Born C, Sasse J, Bauer H, Walden J, Bauer M, Grunze H. Efficacy of quetiapine monotherapy in rapid-cycling bipolar disorder in comparison with sodium valproate. J Clin Psychopharmacol 2008; 28(5): 555–60. [116] Murphy D, Bailey K, Stone M, Wirshing WC. Addictive potential of quetiapine. Am J Psychiatry 2008; 165(7): 918. [117] Scott LJ, Dhillon S. Spotlight on risperidone in irritability associated with autistic

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disorder in children and adolescents. CNS Drugs 2008; 22(3): 259–62. Haas M, Karcher K, Pandina GJ. Treating disruptive behavior disorders with risperidone: a 1-year, open-label safety study in children and adolescents. J Child Adolesc Psychopharmacol 2008; 18(4): 337–45. Caldwell MF, Malterer M, Umstead D, McCormick DJ. A retrospective evaluation of adjunctive risperidone treatment in severely behaviorally disordered boys receiving psychosocial treatment. J Child Adolesc Psychopharmacol 2008; 18(1): 34–43. MacMillan CM, Withney JE, Korndörfer SR, Tilley CA, Mrakotsky C, Gonzalez-Heydrich JM. Comparative clinical responses to risperidone and divalproex in patients with pediatric bipolar disorder. J Psychiatr Pract 2008; 14(3): 160–9. Gencer O, Emiroglu FN, Miral S, Baykara B, Baykara A, Dirik E. Comparison of long-term efficacy and safety of risperidone and haloperidol in children and adolescents with autistic disorder. An open label maintenance study. Eur Child Adolesc Psychiatry 2008; 17(4): 217–25. Miral S, Gencer O, Inal-Emiroglu FN, Baykara B, Baykara A, Dirik E. Risperidone versus haloperidol in children and adolescents with AD: a randomized, controlled, double-blind trial. Eur Child Adolesc Psychiatry 2008; 17(1): 1–8. Chen ZH, Wang GH, Wang XP, Chen RY, Wang HL, Yang MH, Huo YX, Mei HB. Effects of warmsupplementing kidney yang (WSKY) capsule added on risperidone on cognition in chronic schizophrenic patients: a randomized, double-blind, placebo-controlled, multi-center clinical trial. Hum Psychopharmacol 2008; 23(6): 465–70. Tyrer P, Oliver-Africano PC, Ahmed Z, Bouras N, Cooray S, Deb S, Murphy D, Hare M, Meade M, Reece B, Kramo K, Bhaumik S, Harley D, Regan A, Thomas D, Rao B, North B, Eliahoo J, Karatela S, Soni A, Crawford M. Risperidone, haloperidol, and placebo in the treatment of aggressive challenging behaviour

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in patients with intellectual disability: a randomised controlled trial. Lancet 2008; 371(9606): 57–63. Matson JL, Wilkins J. Antipsychotic drugs for aggression in intellectual disability. Lancet 2008; 371(9606): 9–10. Alexopoulos GS, Canuso CM, Gharabawi GM, Bossie CA, Greenspan A, Turkoz I, Reynolds 3rd C. Placebo-controlled study of relapse prevention with risperidone augmentation in older patients with resistant depression. Am J Geriatr Psychiatry 2008; 16(1): 21–30. Loebl T, Angarita GA, Pachas GN, Huang KL, Lee SH, Nino J, Logvinenko T, Culhane MA, Evins AE. A randomized, double-blind, placebo-controlled trial of long-acting risperidone in cocaine-dependent men. J Clin Psychiatry 2008; 69(3): 480–6. Lencer R, Sprenger A, Harris MS, Reilly JL, Keshavan MS, Sweeney JA. Effects of second-generation antipsychotic medication on smooth pursuit performance in antipsychotic-naive schizophrenia. Arch Gen Psychiatry 2008; 65(10): 1146–54. Curtis VA, Katsafouros K, Möller HJ, Medori R, Sacchetti E. Long-acting risperidone improves negative symptoms in stable psychotic patients. J Psychopharmacol 2008; 22(3): 254–61. Emsley R, Oosthuizen P, Koen L, Niehaus DJ, Medori R, Rabinowitz J. Oral versus injectable antipsychotic treatment in early psychosis: post hoc comparison of two studies. Clin Ther 2008; 30(12): 2378–86. Llorca PM, Sacchetti E, Lloyd K, Kissling W, Medori R. Long-term remission in schizophrenia and related psychoses with long-acting risperidone: results obtained in an open-label study with an observation period of 18 months. Int J Clin Pharmacol Ther 2008; 46(1): 14–22. Emsley R, Medori R, Koen L, Oosthuizen PP, Niehaus DJ, Rabinowitz J. Long-acting injectable risperidone in the treatment of subjects with recent-onset psychosis: a preliminary study. J Clin Psychopharmacol 2008; 28(2): 210–3. Yuan HN, Wang CY, Sze CW, Tong Y, Tan QR, Feng XJ, Liu RM, Zhang JZ, Zhang YB, Zhang ZJ. A randomized,

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crossover comparison of herbal medicine and bromocriptine against risperidone-induced hyperprolactinemia in patients with schizophrenia. J Clin Psychopharmacol 2008; 28(3): 264–370. Lançon C, Toumi M, Sapin C, Hansen K. The Sertindole Safety Survey: a retrospective analysis under a named patient use programme in Europe. BMC Psychiatry 2008; 8: 57. Azorin JM, Murteira S, Hansen K, Toumi M. Evaluation of patients on sertindole treatment after failure of other antipsychotics: a retrospective analysis. BMC Psychiatry 2008; 8: 16. Simpson GM, O'Gorman CJ, Loebel A, Yang R. Long-term improvement in efficacy and safety after switching to ziprasidone in stable outpatients with schizophrenia. CNS Spectr 2008; 13(10): 898–905. DelBello MP, Versavel M, Ice K, Keller D, Miceli J. Tolerability of oral ziprasidone in children and adolescents with bipolar mania, schizophrenia, or schizoaffective disorder. J Child Adolesc Psychopharmacol 2008; 18(5): 491–9. Gibel A, Ritsner MS. Neurocognitive effects of ziprasidone and related factors in patients with chronic schizophrenia undergoing usual care: a 12-month, openlabel, flexible-dose, naturalistic observational trial. Clin Neuropharmacol 2008; 31(4): 204–20. Strom BL, Faich GA, Reynolds RF, Eng SM, D'Agostino RB, Ruskin JN, Kane JM. The Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC): design and baseline subject characteristics. J Clin Psychiatry 2008; 69(1): 114–21. Wang PW, Wang SY, Huang CJ. Zotepine-induced spontaneous ejaculation. Int J Clin Pharmacol Ther 2008; 46 (11): 571–3. Hässler F, Glaser T, Pap AF, Beneke M, Diefenbacher A, Reis O. Zuclopenthixol Disruptive Behavior Study Group. A double-blind placebo-controlled discontinuation study of zuclopenthixol for the treatment of aggressive disruptive behaviours in adults with mental retardation—secondary parameter analyses. Pharmacopsychiatry 2008; 41(6): 232–9.

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Antiepileptic drugs

GENERAL Clinicians have only recently realized that chronic adverse effects of antiepileptic drugs, mainly those involving central nervous system, may be more disabling to the patient than the seizures themselves. Up to a few years ago, the historical belief that seizure frequency is the major determinant of health-related quality of life and that adverse reactions are merely a secondary end-point was the prevalent opinion. It has been shown that changes in seizure rate among patients with drug-resistant epilepsy are only modestly correlated with quality of life, while adverse reactions and depression are critical determinants of subjective health status [1C]. Observational studies In an attempt to define specific patterns of adverse reactions and their clinical relevance to subjective health status, 200 subjects with epilepsy completed validated self-report health assessments, including the Adverse Event Profile and Quality of Life in Epilepsy Inventory (QOLIE)-89 [sic] [2C]. The mean number of adverse reactions per subject was 6.5. Factor analysis segregated all adverse reactions into five classes: • • • • •

cognition/coordination; mood/emotion; sleep; weight/cephalalgia; tegument/mucosa.

Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00007-6 # 2011 Elsevier B.V. All rights reserved.

Higher scores in each adverse reaction class were associated with lower QOLIE-89 scores, and Cognition/Coordination scores were the strongest predictor. A subgroup of 62 subjects met criteria for a prospective randomized trial on the value of using the Adverse Event Profile score in clinical management. They were randomly assigned to a group in which treating physicians had access to adverse events profile scores at each visit or to another group in which these data were not made available. Improvements in Cognition/Coordination, Mood/Emotion, and Tegument/Mucosa scores were associated with improvements in QOLIE-89 scores and improved Cognition/Coordination was the only predictor of improved QOLIE-89. Using a questionnaire to assess complaints of adverse reactions to antiepileptic drugs, an active intervention policy has been studied in a randomized controlled study in 111 adults with epilepsy who had had moderate to severe complaints [3C]. Drug therapy was either continued unchanged (n ¼ 58) or adjusted by reducing the dose or switching to other antiepileptic drug (n ¼ 53). After 7 months, the relative chance of improvement in quality of life was 1.80 (1.04–3.12) for the intervention group compared with the controls and the relative chance of a reduction in the number of complaints was 1.34 (0.88– 2.05). Different strategies for detecting adverse effects have been compared in a cross-sectional epidemiological study in standard clinical practice in 579 patients: spontaneous reporting by the patient and a checklist of possible treatment-related adverse reactions completed by the patient—34% reported adverse reactions spontaneously 125

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and 65% did so through the checklist [4C]. Significant adverse reactions were an important reason for modifying treatment in patients who reported higher degrees of discomfort. In an open, long-term, observational study, retention in the study, the percentage of patients who withdrew because of adverse events, and the percentage of patients who achieved seizure freedom were assessed in 1066 epileptic patients taking lamotrigine (n ¼ 336), levetiracetam (n ¼ 301), or topiramate (n ¼ 429) in a single epilepsy center [5C]. Two-year retention rates were 69%, 46%, and 38% respectively. Seizure freedom rates were lowest for lamotrigine and highest for levetiracetam. The numbers of patients who withdrew because of adverse events were 154/429 (36%) with topiramate, 52/336 (15%) with lamotrigine, and 68/301 (23%) with levetiracetam. The technique of event symmetry analysis has been used to identify adverse reactions from a population of 479 000 subjects [6C]. All prescription data from the Odense University Pharmacoepidemiological Database for the period August 1990 to December 2006 and diagnoses from the County Hospital register for the period 1994 to 2006 were used. The method assesses the distribution of disease entities and prescription of other drugs, before and after antiepileptic treatment, as asymmetry in these distributions may indicate adverse reactions to antiepileptic drugs. All incident antiepileptic drug users during the study period (n ¼ 24 882) were identified. Known adverse events (for example, constipation, nausea, hyponatremia, and osteoporosis) were detected. Unanticipated signals from analysis without any preselection of drugs and diagnoses were the association of topiramate with dopaminergic agents, of gabapentin with glaucoma, and of valproic acid with hypothyroidism. Studies of the contribution of specific adverse reactions to impaired health-related quality of life have been reviewed [7R]. Cardiovascular Major atherogenic risk factors among epileptic children, including altered metabolism of homocysteine,

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disordered lipid profiles, and increased lipoprotein(a) serum concentrations, as well as thyroid hormone deficiency, with particular emphasis on the clinical implications, have been reviewed [8R]. Measurement of intima media thickness at the wall of the common carotid artery by B mode ultrasonography has been performed in 195 patients taking long-term antiepileptic drugs and 195 healthy age- and sex-matched control subjects [9C]. The intima media thickness was significantly increased in patients with epilepsy, more in men than in women. Furthermore, whereas body mass index, homocysteine, C-reactive protein, and thiobarbituric acid reactive substances were significantly raised, folic acid and thiols were significantly reduced in the patients with epilepsy. In addition, the log-transformed common carotid artery intima media thickness increased linearly with duration of antiepileptic drug therapy after adjustments for age, sex, and thiobarbituric acid reactive substance concentration. Total plasma homocysteine concentrations and other cardiovascular risk factors have been evaluated in 60 children taking long-term carbamazepine or valproate [10c]. Plasma total homocysteine, urine methylmalonic acid, and lipoprotein(a) were significantly higher in children taking these drugs than in controls. Lower serum vitamin B12, serum folate, and ApoB were also found in children taking antiepileptic drugs. High homocysteine concentrations were significantly associated with urine methylmalonic acid. Psychological Children with new-onset, idiopathic epilepsy have been evaluated at baseline and at 6 months (n ¼ 45) and 12 months (n ¼ 31) after starting antiepileptic drug therapy [11c]. Cognitive functioning after 12 months of treatment was significantly improved. However, there was a transient drop in performance of children with generalized seizures after the 6 months, which may have been caused by persistent seizures or by the drug used (mainly ethosuximide). There was also worsening of reaction time and reaction

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time variability in those with focal seizures at 12 months, which was attributed to the medications used, mainly carbamazepine. The clinical aspects of the cognitive adverse effects of antiepileptic drugs have been reviewed [12R]. In an overview of studies that highlighted cognitive evaluation in adults and children with epilepsy, it emerged that although aspects of cognitive dysfunction, risk factors, and consequences have been investigated in many studies, the mechanisms of contribution of epilepsy-related variables, including antiepileptic drugs, to patients’ cognition have largely been unexplored [13R]. The differential effect of antiepileptic drugs on mature and immature brains and the mechanisms that underlie epilepsy and the adverse effects of antiepileptic drugs on cognition are discussed.

Suicidality and antiepileptic drugs Up to a few years ago, the association between the risk of suicidal ideation and behavior and the use of antiepileptic drugs had been explored in very few studies. In an observational study of 517 consecutive patients taking levetiracetam, four (0.7%) reported suicidal ideation [14C]. The incidence of suicidal ideation and behavior resulting from antiepileptic drug exposure in clinical trials is unknown, because most published data group all psychiatric adverse events together rather than reporting suicidality by itself [15R, 16R, 17R]. In 2005, in a sponsor's report of a doubleblind study, there was a slightly higher risk of suicidality in the antiepileptic drug-treated patients compared with those taking placebo and there were also reports of suicidality related to the branded formulation of gabapentin [18r]. These data prompted the US Food and Drug Administration (FDA) to reanalyse all data on the risk of suicide in controlled studies of antiepileptic drugs.

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In January 2008, the FDA issued an alert that a meta-analysis had shown a significantly increased risk of suicidality associated with all antiepileptic drugs. Suicidality occurred in 4.3 per 1000 patients taking antiepileptic drugs in the active arm compared with 2.2 per 1000 patients in the comparison arm [19S]. This represents a risk difference of 2.1 per 1000 (95% CI ¼ 0.7, 4.2). This analysis had grouped data from 199 randomized clinical trials, including 43 892 patients with epilepsy, psychiatric disorders and other disorders, predominantly pain. Eleven drugs had been evaluated: carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide. For many clinicians, the FDA alert was particularly surprising, because antiepileptic drugs were considered to be a class (defined as all drugs that share the ability to reduce the frequency of seizures) despite their different mechanisms of action, and consequently all of them were considered to be associated with this risk. This procedure has been criticized. In fact, analyses for single antiepileptic drugs were also done and showed a significant protective effect on suicidality for carbamazepine and divalproex while all other antiepileptic drugs had odds ratios greater than 1, indicating an increased risk, although the increase reached statistical significance only with lamotrigine (OR ¼ 2.08; 95% CI ¼ 1.03, 4.40) and topiramate (OR ¼ 2.53; 95% CI ¼ 1.21, 5.85). Other methodological problems should be considered. For example, the FDA included only 33% of these trials in the main analysis, because trials without reports of suicidality were excluded. It has also been considered that although the question of suicidality with these drugs is controversial, the adverse effects of failing to control epilepsy are not. If antiepileptic drugs are less frequently prescribed or taken, seizure control may worsen, with associated increases in accidents and mortality, or sudden unexplained death from seizures [20R]. In a large study of people with epilepsy it has been reported that 21% had an accident

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during the study, of which 24% were seizurerelated [21C]. Sudden unexpected death in epilepsy (SUDEP) occurs in 0.35–2.7 per 1000 people with epilepsy in populationbased studies [22R] and is more common in people with uncontrolled seizures [23R]. Even if the FDA analysis is correct, the risk of suicidality, predominantly suicidal ideation, is only 3.4/1000 in people with epilepsy taking the 11 antiepileptic drugs. The rate of completed suicides in the general population is 12.0/100 000 [24C], with a marked predominance in men [25C], while the lifetime prevalence of suicide attempts is 0.6–4.9% overall [26C], with a preponderance in women. Epilepsy is comorbid with suicidality [27C] and with major depression [28C]. After a diagnosis of epilepsy, the risk of completed suicide increases: the overall standardized mortality ratio ranges from 3.5 to 5.0 and is higher in the presence of a known psychiatric diagnosis [29C]. In addition, suicidal ideation and behavior have been identified as psychiatric phenomena in patients with drug-resistant epilepsy [30C]. After the FDA alert, several reviews analysed data on the association between suicidality and psychiatric compliance in patients with epilepsy, and hypotheses have been proposed. For example, it has been suggested that forced normalization, although rare, may be an epilepsy-related process that could result in increased suicidality [31C]. It consists of the development of depressive or psychotic episodes in patients who become seizure-free after having suffered chronic drug-resistant epilepsy [32C]. This alert can be expected to cause concern among patients and family members. Accordingly, clinicians should provide a comprehensive explanation of the alert, describing this drug-“related” suicidality risk in the context of the complexity of suicidality in this disease [33R, 34r, 35r]. It is likely that in the future a prospective investigation of suicidality in every regulatory trial will be required, and it is also possible that patients will need to be screened for suicidality, depression, and anxiety before randomization [36R].

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The reaction of neurologists to the FDA alert concerning suicidal ideation or behavior and antiepileptic drugs has been explored in a study of 175 of 780 participants who answered a questionnaire via email on the approach to suicidality and depression in patients with epilepsy [37c]. Although 98% warned about behavioral adverse effects when starting antiepileptic drugs, only 44% warned specifically about suicidal ideation or behavior. More than half were not aware of patients who attempted to commit suicide or who had committed suicide. In 47 918 patients with bipolar disorder suicide attempt rates were studied before and after treatment with antiepileptic drugs and the results were compared with a medication-free control group [38C]. There was no significant difference in suicide attempt rates in patients taking an antiepileptic drug (13 per 1000 person-years) compared with patients not taking an antiepileptic drug or lithium (13 per 1000 person-years). In antiepileptic drug-treated subjects, the rate of suicide attempts was significantly higher before treatment (72 per 1000 person-years) than after treatment (13 per 1000 personyears). In patients taking no concomitant treatment with an antidepressant or an antipsychotic drug, antiepileptic drugs were significantly protective relative to no drug treatment (3 per 1000 versus 15 per 1000 person-years). The authors concluded that in this population of patients, the use of antiepileptic drugs reduces suicide attempt rates. There has been a longitudinal, retrospective cohort study of all individuals who obtained anticonvulsants (valproic acid, carbamazepine, oxcarbazepine, or lamotrigine; n ¼ 9952) or lithium (n ¼ 6693) from 1995 to 2001, and who also obtained antipsychotic drugs at least once [39C]. Among the patients who obtained an antipsychotic drug at least once during the study period, more consistent purchasing of anticonvulsants (at least 6 prescriptions) was associated with a substantial reduction in the risk of suicide compared with individuals who received only a single anticonvulsant prescription.

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Metabolism The relation between weight gain and the homeostatic hormones leptin and insulin has been explored in 70 treated and 20 untreated patients with epilepsy [40C]. Body mass index, serum leptin, and serum insulin were significantly raised in patients taking valproate compared with untreated patients and those taking carbamazepine or lamotrigine. In those taking valproate, serum insulin correlated with body mass index, leptin, treatment duration, and drug dosage, and serum leptin correlated with age, body mass index, serum insulin, treatment duration, and drug and valproate dosage. Liver The pathogenesis and clinical characteristics of drug-induced liver injury associated with antiepileptic drugs has been reviewed [41R]. Reactive metabolites can, in some cases, lead to direct cytotoxicity and liver cell necrosis, whereas in other cases they can cause neoantigen formation, inducing immunoallergic mechanisms. In fact, hypersensitivity features are found in more than 70% of patients with phenytoin-induced liver injury, whereas this is only observed in 30% of carbamazepineassociated hepatotoxicity and very rarely with valproate-induced liver injury. No specific therapy is of proven value in these cases. However, carnitine, which is an important co-factor in mitochondrial betaoxidation of fatty acids, is recommended in valproate-associated liver injury, and Nacetylcysteine is an appropriate treatment in patients with liver injury due to phenytoin and carbamazepine. Liver transplantation may be required for patients with the most severe liver reactions. Skin The clinical and laboratory findings of anticonvulsant hypersensitivity syndrome have been retrospectively evaluated using the medical records of 31 patients over a 12year period [42C]. The syndrome was related to carbamazepine in 48% of all cases, phenytoin in 35%, and lamotrigine in 9.6%, and in co-treatment with lamotrigine and valproic acid in 6.5% of cases. Symptoms appeared at 2–86 (mean: 36) days after the start of treatment. The rashes were

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maculopapular and/or erythrodermic in 77% of patients, bullous in 19%, and erythematopustular in 3.2%. Fever and peripheral lymphadenopathy were detected in 61% and 55% of cases respectively. Hepatic enzymes were raised in 71% and there was a leukocytosis in 43% and a peripheral eosinophilia in 64%. Musculoskeletal Hip bone mineral density was measured in 4222 older communitydwelling men at baseline and at an average of 4.6 years later, of whom 62 were taking enzyme-inducing antiepileptic drugs, 100 were taking non-enzyme-inducing antiepileptic drugs, and 4060 were taking no antiepileptic drugs [43C]. The average rate of change in total hip bone mineral density was  0.35%/year among non-users compared with  0.53%/year among users of non-enzyme-inducing antiepileptic drugs and 0.46%/year among users of enzymeinducing antiepileptic drugs. In these old people, the use of non-enzyme-inducing antiepileptic drugs was independently associated with increased rates of hip bone loss. Bone mineral density has been assessed in 96 children with epilepsy taking antiepileptic drugs and in 63 healthy children and adolescents [44c]. There was abnormal bone mineral density in 56, with values documenting osteopenia in 42 and osteoporosis in 14. There was a significant difference between patients with epilepsy and controls. Lack of autonomous gait, severe mental retardation, a long duration of antiepileptic drug treatment, topiramate adjunctive therapy, and less physical activity correlated significantly with abnormal bone mineral density. In a case–control study using data from a hip fracture register of a US county with a population of almost 500 000 inhabitants, 7557 patients were admitted to county hospitals with a hip fracture [45C]. Controls (n ¼ 27 575) were frequency matched by age and sex. Fracture risk was increased with ever use of any antiepileptic drug. The risk was also increased in those who used only enzyme-inducing drugs, and not in those who used non-inducing antiepileptic drugs.

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Fracture risk was higher with recent use and high daily dosages. The adverse effects on bone caused by chronic anticonvulsant drug therapy have been reviewed [46R]. Bone mineral density at the left femoral neck and spine has been measured in 130 Thai patients with epilepsy who had been taking long-term antiepileptic drugs, either as monotherapy (n ¼ 79) or polytherapy (n ¼ 51) [47c]. Bone mineral density at the femoral neck had a mean Z-score of 0.15 and at the lumbar spine 0.56. There was osteopenia in the spine in 31 patients and in the femoral neck in 30. Three patients had osteoporosis of the spine and one had osteoporosis of the femoral neck. In a cross-sectional observational study of the effects of antiepileptic drug treatment on vitamin D status and markers of bone turnover in 38 children with epilepsy, the results were compared with those obtained in 44 healthy controls [48c]. More than 75% of the patients were vitamin D deficient and 21% had insufficient vitamin D. Serum concentrations of osteocalcin and bone alkaline phosphatase were significantly raised, but the concentrations of C terminal telopeptide of type I collagen were significantly reduced. There were significantly lower concentrations of vitamin D and C terminal telopeptide of type I collagen and higher activities of bone alkaline phosphatase in those taking polytherapy.

Sexual function The effects of oxcarbazepine monotherapy on sexual function have been studied in 673 men with partial epilepsy [49C]. In 181 (79%) of 228 patients with pre-existing impairment, sexual function improved; 23 had no impairment at the final visit. The improvements were most marked in patients who stopped taking enzyme-inducing antiepileptic drugs after starting to take oxcarbazepine. The authors suggested that enzyme induction has negative effects on sexual function and that substitution with less inducing drugs may be beneficial.

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Teratogenicity The mental and motor developmental quotients of 395 infants of mothers with epilepsy have been prospectively evaluated [50C]. Infants not exposed to antiepileptic drugs (n ¼ 32) had a higher mental developmental quotient (mean 92; 95% CI ¼ 81, 103) and motor developmental quotient (mean 95; 95% CI ¼ 85, 105) than those who had been exposed to antiepileptic drugs (mean 89; 95% CI ¼ 86, 92 and mean 90; 95% CI ¼ 87, 93 respectively). Those exposed to polytherapy had significantly lower developmental quotients than those exposed to monotherapy. On multiple regression analysis, polytherapy was a stronger predictor of lower developmental quotients than dosage. Valproate monotherapy was associated with significantly lower mental and motor developmental quotients. All births delivered in Norway from 1999 to 2005 (n ¼ 372 128) have been analysed, and 2805 pregnancies in women with a current or past history of epilepsy (0.8%) and 362 302 pregnancies in women without a history of epilepsy were selected [51C]. Women with epilepsy had an increased risk of mild pre-eclampsia and delivery before week 34. Antiepileptic drugs were used in 233 of the pregnant women with epilepsy (94%). These patients had an increased risk of mild pre-eclampsia, gestational hypertension, vaginal bleeding late in pregnancy, and delivery before 34 weeks of gestation. There was no significant increase in the risk of these complications in women with epilepsy who were not using antiepileptic drugs. All 2861 deliveries by women with epilepsy recorded in Norway in a certain period were compared to all 369 267 non-epilepsy deliveries observed in the same period [52C]. Most of those with epilepsy (n ¼ 1900) did not use antiepileptic drugs during pregnancy, while in 961 pregnancies there was exposure. Compared with non-epilepsy controls, antiepileptic drug-exposed infants were significantly more often preterm and more often had low birth weights (<2500 g), low head circumferences (< 2.5 percentile), and low Apgar scores. The frequency of major congenital malformations was 2.8% (n ¼ 81) in the

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epilepsy group versus 2.5% in the controls. An increased risk of major malformations could be demonstrated only for exposure to valproate (5.6%) and polytherapy (6.1%). Cesarean section was performed more often in maternal epilepsy, regardless of drug exposure. The use of antiepileptic drugs in 4798 pregnancies in women with epilepsy has been prospectively studied using data from 38 countries. Exposure to second-generation antiepileptic drugs ranged from 3.5% in India and 7.3% in Italy to 75% in Denmark. The use of second-generation drugs has increased over time (for lamotrigine, from 9.9% of all pregnancies before 2001 to 30% after 2003) [53C]. In an interim analysis of cognitive outcomes at 3 years of age in 309 children whose mothers who took a single antiepileptic agent (carbamazepine, lamotrigine, phenytoin, or valproate) during pregnancy in the USA and the UK, children who had been exposed to valproate had significantly lower IQ scores than those who had been exposed to other antiepileptic drugs [54C]. After adjustment for maternal IQ, maternal age, antiepileptic drug dosage, gestational age at birth, and maternal preconception use of folate, the mean IQ was 101 in children exposed to lamotrigine, 99 in those exposed to phenytoin, 98 in those exposed to carbamazepine, and 92 in those exposed to valproate. The association between valproate use and IQ was dose-related. This finding supports a recommendation that valproate should not be used as a first-choice drug in women of childbearing potential. The consequences of exposing fetuses to antiepileptic drugs during pregnancy have been discussed in several reviews and correspondences [55R, 56r, 57R, 58R, 59R, 60R]. All new information on the teratogenic effects of the most frequently used antiepileptic drugs has been reviewed [61R]. The prevalence of major congenital malformations associated with exposure to carbamazepine or lamotrigine was only marginally increased from expected, while malformation rates with valproate have been reported to be 2–4 times higher. This adverse outcome appears to be dose-related.

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Furthermore, exposure to valproate in utero seems to be associated with poorer postnatal cognitive development. The available evidence on the management of women with epilepsy during pregnancy, including the risk of pregnancyassociated complications or other medical problems, have been discussed by a committee of the American Academy of Neurology [62S, 63S]. For women with epilepsy taking antiepileptic drugs, there is probably no substantially increased risk of cesarean delivery or late pregnancy bleeding, and probably no moderately increased risk of premature contractions or premature labor and delivery. However, smoking may increase the risk. Seizure freedom for at least 9 months before pregnancy is probably associated with a high likelihood (84–92%) of remaining seizure-free during pregnancy. Preconceptional folic acid supplementation was possibly effective in preventing major congenital malformations in the children of women with epilepsy taking antiepileptic drugs [64S, 65S]. Supplementation with vitamin K was not considered useful, because there is no evidence of an increased risk of hemorrhagic complications. Lactation Concerning transfer of antiepileptic into breast milk, it was judged that primidone and levetiracetam transfer into breast milk in clinically important amounts, and that valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred in clinically important amounts [64S, 65S]. During pregnancy, there is an increase in the clearance of lamotrigine, phenytoin, and to a lesser extent carbamazepine, and possibly reduced concentrations of levetiracetam and of the active metabolite of oxcarbazepine. Supplementing with at least 0.4 mg of folic acid before pregnancy and monitoring lamotrigine, carbamazepine, and phenytoin concentrations and probably also levetiracetam and the monohydroxy derivative of oxcarbazepine is recommended. Susceptibility factors Genetic Genetic predictors of susceptibility to adverse reactions

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to antiepileptic drugs and their molecular mechanisms have been reviewed [66R]. Drug overdose Of 16 796 toxic exposures to antiepileptic drugs (phenytoin, valproic acid, and carbamazepine) in the USA in 2006, 12 resulted in death, as reported by the US Toxic Surveillance System [67c]. Some specific problems determined by overdose of some old and new antiepileptic drugs have been briefly reviewed. For example, topiramate can cause a significant metabolic acidosis, lamotrigine Stevens–Johnson syndrome, oxcarbazepine hyponatremia, and levetiracetam psychosis. Possible adoption of guidelines for critical care management of overdose are discussed. Drug–drug interactions In a pharmacoepidemiological study, the likelihood of relevant drug interactions of antiepileptic drugs with other drugs has been analysed through inspection of a medical and pharmaceutical claims database. All the data of adults with epilepsy and taking any antiepileptic drug during the period from 1 July 2001 to 31 December 2004 were extracted and analysed for concomitant non-antiepileptic drugs used after the start of antiepileptic drug therapy. Concomitant medications were used in every age group and use increased with age in both men and women. Polypharmacy with non-antiepileptic drug medications was common in both men and women and was not unique to elderly patients with epilepsy. These findings suggest that clinicians must be mindful of potential interactions of antiepileptic and non-antiepileptic drugs in patients of all age groups [68C]. Interactions of antiepileptic drugs with drugs that are usually prescribed in the postsurgical care of transplant recipients have been reviewed [69R]. The possible adverse consequences of CYP isoenzyme induction have been reviewed and the authors suggested that new treatment for epilepsy be started with non-inducing antiepileptic drugs unless there is a clear indication for one of the inducing drugs [70R].

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Management of adverse drug reactions The clinical characteristics and treatment of the anticonvulsant hypersensitivity syndrome have been reviewed. Treatment with N-acetylcysteine and intravenous immunoglobulin is suggested. The rationale for this relies on the scavenging properties of Nacetylcysteine and on modulation of the over-reactive immune system by immunoglobulin [71R].

Carbamazepine [SED-15, 627; SEDA30, 78; SEDA-31, 107; SEDA-32, 126] Observational studies In a long-term, open, observational study, the long-term retention rate and adverse effects of carbamazepine (n ¼ 105) were evaluated and compared with topiramate (n ¼ 41) in infants and toddlers with epilepsy [72c]. After 6 months, 73% of those who had been treated with topiramate and 63% of those who had been treated with carbamazepine were improved. Topiramate was withdrawn because of adverse effects in only one case (2.4%), whereas carbamazepine was withdrawn because of adverse effects in 6.7% of patients. Comparative studies Carbamazepine and oxcarbazepine as adjunctive therapy in 52 patients with bipolar I and bipolar II affective disorder taking lithium maintenance treatment have been compared in an 8week, double-blind, randomized, parallelgroup, single-center study [73c]. Several adverse events were significantly more frequent with carbamazepine: sedation (n ¼ 16), increased appetite (n ¼ 13), weight gain (n ¼ 11), tremor (n ¼ 5), constipation (n ¼ 3), nausea/vomiting (n ¼ 3), dry mouth (n ¼ 2), and insomnia (n ¼ 2). Hyponatremia, hypertension, tachycardia, diplopia, rush, and electrocardiographic abnormalities were not observed. Systematic reviews A systematic analysis of seven randomized controlled trials assessing the comparative efficacy of

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carbamazepine and lithium in the treatment of acute mania and in the maintenance phase of bipolar disorder has been performed [74M]. In three acute studies withdrawals due to adverse effects and the numbers of subjects with at least one adverse effect were not different between carbamazepine and lithium. In four studies of maintenance treatment the number of withdrawals because of adverse effects was significantly higher with carbamazepine. Cardiovascular A retrospective electrocardiographic study in elderly patients (>65 year old) with newly diagnosed epilepsy and randomized to sustained-release carbamazepine or lamotrigine in 108 patients who had been previously included in an international randomized double-blind, 40week trial, excluding patients with significant unpaced atrioventricular conduction defects, there were no significant changes in QRS duration or QT intervals between baseline and treatment visit, but heart rate fell and PQ intervals increased slightly with both treatments. There were no differences between the groups in changes from baseline to treatment visit and no relations between individual electrocardiographic changes and serum drug concentrations, except for QTc intervals, which shortened slightly with increasing carbamazepine concentrations. Respiratory Acute interstitial pneumonitis with atypical features has been attributed to carbamazepine in a patient with postherpetic neuralgia [75A]. Nervous system Drug-resistant hypertension with leukoencephalopathy might have been due to carbamazepine [76A]. • A 21-year-old man who took carbamazepine for idiopathic trigeminal neuralgia for several days developed arterial hypertension (from 110/60 to 170/126 mmHg) followed by disturbance of consciousness. An MRI scan showed transient hyperintense lesions in the bilateral fronto-parieto-occipital subcortical white matter, suggesting the presence of vasogenic edema caused by hypertension. Despite the administration of various antihypertensive

133 drugs, the blood pressure improved only after withdrawal of carbamazepine.

A lesion in the splenium of the corpus callosum occurred 10 days after sudden carbamazepine withdrawal and resolved 2 months later; this could have been coincidental [77A]. Endocrine The effects of long-term carbamazepine (n ¼ 18) and valproate (n ¼ 14) on thyroid function in newly diagnosed children with epilepsy have been evaluated in a prospective open comparison with 32 sex- and age-matched controls [78c]. At baseline evaluation, thyroid function was normal. At the 3rd, 6th, and 12th month evaluations, patients taking carbamazepine had serum thyroxine (T4) and free thyroxine (fT4) concentrations significantly lower than baseline and control subjects; valproate had no such effect. In a prospective, randomized study of thyroid function in 160 men and women with epilepsy both before and after double-blind withdrawal of antiepileptic drug monotherapy, serum samples were obtained from 130 [79C]. After drug withdrawal, there were significant increases in free thyroxine serum concentrations in those who had taken carbamazepine. Metabolism A role of carbamazepine in the pathogenesis of hyperammonemia was suspected in a 26-year-old man with bipolar disorder [80A]. • A 26-year-old man with bipolar disorder, seizures, and mild mental retardation, who had started taking carbamazepine for aggression and seizure control 3 weeks before, developed severe agitation and aggressive behavior. Other medications, which had been stable for at least 6 months, included topiramate, olanzapine, quetiapine, guanfacine, and desmopressin acetate. All laboratory examinations and vital signs were normal. The serum carbamazepine concentration was 3.9 mg/l and serum ammonia 127 (reference range 19–60) mg/l. Carbamazepine was withdrawn and he was given oral lactulose. His serum ammonia concentration returned to normal after 4 days. This patient had previously a raised serum ammonia concentrations while taking valproic acid.

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Serum leptin and insulin concentrations have been measured in 56 epileptic patients who had been on monotherapy with carbamazepine for at least 6 months and in 42 control healthy subjects [81c]. Body mass index and leptin and insulin concentrations were not different in those taking carbamazepine compared with controls. Hematologic It has been suggested that carbamazepine may have caused a fatal case of anaplastic large cell lymphoma in a 73-year-old man with diabetic neuropathy and rapidly progressive erythematous skin lesions [82A]. Skin Drug reactions with eosinophilia and systemic symptoms (DRESS) in patients taking carbamazepine have been reported [83A]. Involvement of internal organs was often characterized by liver injury [84A, 85Ar]. In four cases drug hypersensitivity syndrome was triggered by carbamazepine in the presence of concomitant active human herpesvirus (HHV-6), demonstrated by positive PCR for viral DNA and an increased anti-HHV-6 IgG titer. In one of these patients, drug-specific lymphocytes were detected by a lymphocyte transformation test when the virus was active. Furthermore, two genetic factors previously associated with intolerance to carbamazepine were detected: the allele HLA-A*3101 (a genetic variant of human leukocyte antigen) and a homozygous variant allele of SNP rs1051740 of the peroxide hydrolase gene [86c]. One patient with carbamazepine hypersensitivity syndrome had a strongly positive prick and patch skin tests 6 weeks after complete recovery. The usefulness of skin tests in diagnosing carbamazepine-induced DRESS has been emphasized [87A]. • A 34-year-old man with epilepsy who was taking valproic acid and phenobarbital was also given carbamazepine and 34 days later developed hyperthermia and cervical lymphadenopathy and subsequently a generalized cutaneous eruption (exfoliative confluent macules and papules) [88A]. The white cell count

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was raised, with an eosinophilia, and there was liver dysfunction. On day 21 after the start of symptoms anti-HHV6 IgM was detected. About 1 month later, the skin eruption, fever, lymphadenopathy, liver dysfunction, and eosinophilia progressively disappeared.

A patient who had had carbamazepineinduced DRESS presented with the same clinical picture after taking lamotrigine for 52 days. The authors discussed cross-reactivity between carbamazepine and lamotrigine, which are aromatic and non-aromatic anticonvulsants [89A]. HLA allele B*1502 is a marker for an increased risk of carbamazepine-induced Stevens–Johnson syndrome and toxic epidermal necrolysis in Han Chinese. The FDA has therefore changed the carbamazepine label, recommending genotyping in all Asians [90S]. Carbamazepine-induced toxic epidermal necrolysis has been reported in a child [91A]. The possible association between HLAB*1502 and carbamazepine- or phenytoininduced Stevens–Johnson syndrome or maculopapular eruptions has been explored in 31 Thai subjects who had these antiepileptic drug-induced complications between 1994 and 2007 and in 50 antiepileptic drug-tolerant controls [92c]. There was a strong association between HLA-B*1502 and phenytoin- and carbamazepineinduced Stevens–Johnson syndrome. However, some patients with HLA-B*1502 had had carbamazepine-induced Stevens–Johnson syndrome and were tolerant of phenytoin and vice versa, which suggests that other factors contribute to this adverse reaction. The association between HLA-B*1502 and carbamazepine-induced Stevens– Johnson syndrome and toxic epidermal necrolysis has been investigated in eight Indian patients, of whom six had the HLAB*1502 allele, confirming the association in Indian patients [93c]. The risk of erythema multiforme, Stevens– Johnson syndrome, or toxic epidermal necrolysis in 72 patients with bipolar disorder taking carbamazepine, valproate, or other medications has been analysed using a large

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database [94C]. Both carbamazepine (OR ¼ 3.7; 95% CI ¼ 2.0, 6.8) and valproate (OR ¼ 2.2; 95% CI ¼ 1.2, 4.2) were associated. In a young patient with carbamazepineinduced toxic epidermal necrolysis, blister fluid was analysed for protein, chemical, and mineral contents [95A]. There was a threefold increase in albumin and protein compared with burns blisters. Musculoskeletal In a young patient a tendon sheath abscess was considered a possible complication of severe carbamazepine hypersensitivity [96A]. Sexual function Sexual function has been investigated in patients with epilepsy (aged 18–45 years) taking carbamazepine (63 men/30 women), lamotrigine (37 men/40 women), or levetiracetam (30 men/26 women) monotherapy and in healthy controls (36 men/44 women) [97c]. In women using carbamazepine, steroid hormonebinding globulin concentrations were higher and progesterone concentrations lower. Arizona Sexual Experience Scale scores suggested that women taking lamotrigine and levetiracetam have better sexual function than those taking carbamazepine and controls. In men, carbamazepine was associated with lower free androgen indices and dehydroepiandrosterone sulfate concentrations and higher concentrations of steroid hormone-binding globulin, folliclestimulating hormone, and luteinizing hormone. Arizona Sexual Experience Scale scores for men were similar in all groups. Susceptibility factors Genetic Polymorphic variants in various genes involved in the pharmacokinetics and pharmacodynamics of carbamazepine have been investigated in 70 patients with epilepsy who had benefited from carbamazepine monotherapy [98C]. Known variants in drug-metabolizing enzyme genes and a sodium channel polymorphism in SCN2A were screened using polymerase chain reaction-restriction fragment length polymorphism or direct sequencing. No single genetic variable was of sufficient power to influence carbamazepine dosing requirements independently.

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However, a multivariate model, incorporating age and specific genotypes of the EPHX1 gene encoding microsomal epoxide hydrolase, showed a significant association with the maintenance dose of carbamazepine. Drug formulations In a 3-month, randomized, blinded study in patients with type I or type II bipolar affective disorder, who were already taking carbamazepine or who were starting to take it, immediaterelease or extended-release carbamazepine capsules were substituted. Autonomic and gastrointestinal adverse events were significantly less common in those who took the extended-release formulation [99C]. Drug overdose In 115 of 130 poisoned patients aged 14–59 years plasma carbamazepine concentrations were above the usual target range [100C]. There was acute pulmonary failure in three cases. There was a positive correlation between plasma carbamazepine concentrations and both systolic blood pressure and heart rate. Drug–drug interactions Aripiprazole The pharmacokinetic interaction of carbamazepine with aripiprazole has been studied in 18 in-patients with schizophrenia [101c]. One week after co-administration of carbamazepine 400 mg/day plasma concentrations of aripiprazole and its metabolite dehydroaripiprazole fell by 64% and 68% respectively. Paracetamol A pharmacokinetic interaction was suspected in a 34-year-old man taking carbamazepine for complex partial seizures, who developed acute liver and renal failure after taking less than 2.5 g a day of paracetamol [102A]. Tacrolimus The metabolism of tacrolimus is largely via CYP3A4, and all agents that induce or inhibit this enzyme can change its blood concentration. The interaction of tacrolimus with carbamazepine has been studied in a patient who underwent heart transplantation [103A]. The dose-corrected AUC0!12h of tacrolimus 11 days after

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carbamazepine treatment was about 50% of the value before carbamazepine, and about 70% after 3 months.

Ethosuximide Immunologic Systemic lupus erythematosus with an increase in anti-double-strand DNA antibodies has been attributed to ethosuximide [104A]. • A woman with refractory absence epilepsy at age 8 years developed arthritis with an increase in anti-double-strand DNA antibodies while taking ethosuximide and carbamazepine. Both drugs were withdrawn and the symptoms were ascribed to carbamazepine. At age 24, because of numerous absence seizures, ethosuximide 1000 mg/day was again prescribed and 1 month later she had arthralgia and fever and the antinuclear antibody concentration was were 80 UI/ml. Ethosuximide was continued and 3 weeks later the antinuclear antibodies were 640 UI/ml and the anti-double-strand DNA antibodies were 33 IU/ml. Ethosuximide was withdrawn and the antibodies normalized and the arthralgia and fever abated.

This case was unusual, since drug-induced lupus is usually associated with antibodies to single-stranded, not double-stranded, DNA.

Felbamate

[SED-15, 1328]

Observational studies In a retrospective chart review study of felbamate in 53 children under 4 years, 16 reported at least one adverse event while taking felbamate and none required drug withdrawal [105c]. The events were somnolence (n ¼ 7), loss of appetite (n ¼ 6), sleep disturbance (n ¼ 5), behavioral changes (n ¼ 4), and vomiting (n ¼ 1). There were no serious adverse effects during the study and no significant laboratory changes in liver or renal function or hematology.

Gaetano Zaccara and Luciana Tramacere

Gabapentin

[SED-15, 1465; SEDA-30, 80; SEDA-31, 110; SEDA-32, 131] Observational studies In an open study in 75 patients with chemotherapy-induced neuropathic pain, gabapentin monotherapy 800 mg/day caused mild somnolence in about 25%, but none stopped taking the drug [106c].

Comparative studies In a 6-week, doubleblind, double-dummy, crossover trial in 56 patients with diabetic polyneuropathy or post-herpetic neuralgia, daily oral gabapentin, nortriptyline, and their combination were compared and drug doses were titrated to the maximum tolerated dose [107C]. There was less pain with combination treatment than with gabapentin or nortriptyline alone. During dose titration, moderate or severe dry mouth was significantly more frequent with nortriptyline or combination treatment than with gabapentin, whereas an inability to concentrate was significantly more frequent with gabapentin. At the maximum tolerated dose, moderate or severe dry mouth was significantly more frequent with nortriptyline or combination treatment than with gabapentin. There were no serious adverse events. Gabapentin and lorazepam have been compared in the treatment of alcohol withdrawal symptoms in a double-blind study in 100 patients, who were randomized to two doses of gabapentin (900 mg/day tapering to 600 mg/day or 1200 mg/day tapering to 800 mg/day) or lorazepam (6 mg/day tapering to 4 mg/day) for 4 days [108C]. There was a tendency for lorazepam to cause more sedation and for gabapentin more pruritus. One patient who used gabapentin was withdrawn because of urticaria. Two participants who stopped taking gabapentin 600 mg had probable withdrawal seizures and one had a syncopal event. No patients had delirium tremens. In a double-blind, 4-week, placebo-controlled trial, 214 men with hot flushes, on a stable androgen deprivation therapy program for prostate cancer, were randomized to placebo or gabapentin at target doses of

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300, 600, or 900 mg/day, without benefit [109C]. The only adverse effects that were significantly different between the combined gabapentin arms and the placebo arm were loss of appetite and constipation, which were more common with placebo. Gabapentin and controlled-release oxycodone have been used for acute pain in 87 patients with herpes zoster in a 28-day, double-blind, placebo-controlled trial, starting within 6 days from the onset of the rash, with only modest benefit from gabapentin during the first week [110C]. There were significantly more withdrawals among those taking oxycodone. Four of those who took gabapentin did not complete the study because of adverse effects or serious adverse effects (two with imbalance and dizziness, one with tremulousness and dizziness, and one with fever). The NNTH for withdrawal because of adverse effects or serious adverse effects was 5.8 for controlled-release oxycodone and 9.7 for gabapentin. Systematic reviews In a systematic review of four randomized placebo-controlled studies of gabapentin in women with hot flushes after natural or tamoxifen-induced menopause, dropouts due to adverse events were more frequent in those who took gabapentin, particularly two adverse effects, dizziness/unsteadiness and fatigue/ somnolence [111M]. Nervous system Bilateral ballismus has been observed in a woman with Parkinson's disease after the administration of gabapentin; it resolved fully after drug withdrawal [112A]. • An 83-year-old woman with Parkinson's disease was given gabapentin for neuropathic pain and after 5 days developed generalized dyskinetic movements involving all four limbs, which were so severe that they prevented her from standing. Her mental function was normal and she had no other neurological signs. A CT scan of the brain and laboratory tests were normal. Gabapentin was withdrawn and within 4 weeks the involuntary movements resolved completely.

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Gabapentin-induced myoclonus occurred in an elderly patient with no other medical conditions that could have caused it [113A]. A patient with end-stage renal disease developed an encephalopathy a few days after taking gabapentin in usual adult doses. Gabapentin is excreted unchanged in the urine and its half-life, normally 5–9 hours, increases to up to 132 hours in anuria [114A]. Chorea in an elderly patient with anxiety resolved completely after gabapentin was withdrawn [115A]. • A 75-year-old man with anxiety disorder developed choreiform movements involving the neck, trunk, upper and lower limbs, and tongue after taking gabapentin 300 mg three times a day (tds) for 1 month. He had no family history of Huntington's disease or other conditions that might have caused chorea. The symptoms resolved within 2 days of gabapentin withdrawal.

In a retrospective study in 162 patients with epilepsy taking gabapentin, pre-existing myoclonus was worsened in two cases within 2 weeks of starting gabapentin; in another case it occurred de novo [116c]. Withdrawal of gabapentin or clonazepam add-on treatment resulted in resolution of myoclonus with no serious sequelae in all three cases. Sensory systems Hearing loss was attributed to high concentrations of gabapentin in a patient with renal insufficiency [117A]. • A 46-year-old woman with a 6-year history of diabetes mellitus and previously normal renal function developed anuria, hearing loss, myoclonus, and confusion with hallucinations. She was taking lisinopril, hydrochlorothiazide, furosemide, atorvastatin, omeprazole, salmeterol/fluticasone and salbutamol by inhalation, metformin, insulin, oxycodone, alprazolam, venlafaxine, and gabapentin 300 mg tds. The gabapentin blood concentration was 17.6 mg/l. All her symptoms improved after one session of hemodialysis and had resolved at the time of discharge 4 days later.

Skin A fixed drug eruption has been associated with gabapentin [118A]. • A 44-year-old man with post-herpetic neuralgia was given amitriptyline and gabapentin

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300 mg tds. After 2 days he developed a mildly itchy and painful bullous eruption in the mouth; it soon ruptured leaving an erosion. Gabapentin was withdrawn. The lesion healed slowly in 8–10 days. He was subsequently treated with pregabalin which was well tolerated. Repeated patch testing was always negative. However, oral provocation with gabapentin 300 mg produced the same bullous lesion at the same site after 4 hours.

1847 U/l (240–480 U/l), and the serum potassium concentration was 6.3 mmol/l (3.5–5.5 mmol/l). There was myoglobin in the urine. Electromyography confirmed a myopathy. She underwent emergency hemodialysis. A muscle biopsy showed changes of myopathy. Gabapentin was withheld. She was given parenteral fluids and furosemide and gradually improved.

An urticarial rash has been attributed to gabapentin [119A].

Susceptibility factors Renal disease Unrecognized gabapentin toxicity, mainly characterized by a significant deterioration in consciousness, occurred in a patient with acute renal impairment [123A]. During episodes of acute renal insufficiency the dose of gabapentin should be reduced.

Hair Acute alopecia developed in a patient who took gabapentin for neuropathic pain [120A]. • A 28-year-old woman took gabapentin 1800 mg/day for a continuous sharp pain and a burning sensation with allodynia and hyperalgesia in her right shoulder blade. After 1 week she noticed significant hair loss with patchy areas of alopecia among areas of normal hair growth. Hematological tests, plasma electrolytes, blood iron and ferritin concentrations, thyroid hormones, cortisol, and adrenocorticotropic hormone were all within normal limits. Pregnancy, fever, malnutrition, dermatological problems, and autoimmune disorders such as systemic lupus erythematosus were excluded. Gabapentin was withdrawn, and hair shedding stopped 2 months later, followed by gradual regrowth.

Psychiatric A 38-year-old male physician developed delirium and gabapentin dependence after high self-administered doses [121A]. Musculoskeletal Gabapentin can rarely cause a myopathy and rhabdomyolysis. Myoglobinuria, causing acute renal insufficiency, has been described in a patient with painful diabetic neuropathy [122A]. • A 63-year-old woman took gabapentin for painful diabetic neuropathy and after 3 weeks developed fatigue, gait instability, diffuse muscle pain, muscle weakness in her legs, and reduced urine output with a reddish color. She was taking insulin, irbesartan, and gabapentin 900 mg/day. She had proximal muscle tenderness and weakness. The ankle reflexes were both absent and vibration sensation was reduced in both feet. There was acute renal insufficiency (creatinine concentration 700 mmol/l). Creatine kinase activity was 75 680 U/l (26–167 U/l), lactate dehydrogenase activity

Drug formulations Gabapentin has a short half-life and a saturable mechanism of absorption, with consequent lack of proportionality between doses and concentrations. New formulations have therefore been developed. An extended-release formulation may overcome the problems of saturable absorption and short half-life. When administered with a meal, this formulation gradually expands and releases the drug to the upper gastrointestinal tract over an extended period of time. This enables it to be taken once or twice a day compared with three times a day or more for immediate-release gabapentin. In a double-blind, placebo-controlled study of extended-release gabapentin in 147 patients with painful diabetic neuropathy, the patients were randomized to placebo or gabapentin 3000 mg, either as a single evening daily dose or as two divided doses (1200 mg in the morning and 1800 mg in the evening) for 4 weeks. The incidence of adverse events was low: dizziness in 17%, 12%, and 0% and somnolence in 13%, 4.1%, and 0% of patients in the gabapentin extended single-dose, divided-dose, and placebo groups respectively [124C]. Gabapentin enacarbil is another attempt to overcome the problem of gabapentin saturable absorption. It is a prodrug that is actively transported and provides predictable dose-proportional gabapentin exposure and oral availability of about 70%.

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Lacosamide

In a randomized, double-blind, placebocontrolled, crossover study, extendedrelease gabapentin enacarbil 600 mg tablets were given as single oral doses of 2400, 3600, 4800, or 6000 mg to 32 healthy volunteers. Gabapentin exposure in blood was proportional to the dose of gabapentin enacarbil over the range 2400–6000 mg (equivalent to 1250–3125 mg of gabapentin). Blood concentrations of intact gabapentin enacarbil were low and transient. The most commonly reported adverse effects, mild to moderate in intensity, were dizziness and nausea (50% and 25% of subjects respectively). Two subjects had treatment-emergent adverse effects rated as severe: psychomotor retardation, vertigo, and sedation (after a dose of 4800 mg) and somnolence (after 6000 mg). There were no clinically significant changes in laboratory parameters, vital signs, or electrocardiography; QTc intervals did not exceed 480 ms or change from baseline by more than 30 ms at any dose of gabapentin enacarbil [125C]. In a 14-day, double-blind, controlled trial, 96 subjects with restless legs syndrome were randomized to the prodrug gabapentin enacarbil 1200 or 600 mg/day or placebo, with benefit by day 14 [126C]. The most common treatment-emergent adverse events were somnolence (gabapentin enacarbil: 1200 mg, 36% and 600 mg, 14%; placebo, 15%) and dizziness (18%, 14%, 3%), most of which were rated mild or moderate in intensity.

The antiepileptic drug lacosamide, a functionalized amino acid, has a novel mechanism of action—selective enhancement of slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes [128R]. In August 2008, lacosamide was granted market authorization by the European Commission as an adjunctive therapy for partial-onset seizures with or without secondary generalization. It was approved by the FDA as an adjunctive therapy for partial-onset seizures in October 2008 [129r]. It is also effective against neuropathic pain attributed to distal diabetic neuropathy [130R]. It is available as oral or intravenous formulations. The apparent lack of sedative effects makes lacosamide attractive for patients who are likely to develop somnolence with other antiepileptic drugs. Reports of potential electrocardiographic changes with lacosamide suggest that caution is needed before using it in patients with pre-existing cardiac disease and in those taking class I antidysrhythmic drugs or drugs that cause PR interval prolongation. When used as short-term replacement for oral lacosamide, intravenous lacosamide is well tolerated when administered as a 15-, 30-, or 60minute infusion.

Drug overdose Patients with impaired driving who were positive for gabapentin and were submitted to a Toxicology Laboratory between 2003 and 2007 have been reviewed [127c]. The concentrations of gabapentin in blood in 137 cases ranged from <2.0 to 24.7 mg/l, with a mean of 8.4 mg/l. In four cases gabapentin was the only drug detected as a possible cause of driving impairment. The subjects had characteristic clinical symptoms (horizontal gaze nystagmus, poor performance on standardized field sobriety tests, dilated pupils, low body temperature, and increased heart rate and blood pressure).

Observational studies In a 6-month, open study, lacosamide was given to 25 patients with drug-resistant focal epilepsy [131c]. One patient became seizure-free for 5 months and two for 1 and 4 months. Eight patients reported a greater than 50% reduction in seizure frequency. Thirteen patients reported adverse effects during the titration period. In five patients the adverse effects disappeared during the maintenance phase and/or with dosage reduction. Most frequently observed were fatigue (n ¼ 6), double vision (n ¼ 5), depression (n ¼ 5), dizziness (n ¼ 4), nausea (n ¼ 3), irritability (n ¼ 2), word-finding difficulties (n ¼ 2), tremor (n ¼ 2), and coordination problems

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(n ¼ 2). Two patients lost more than 10% of their body weight. In an open study of lacosamide in 69 patients with painful diabetic neuropathy the initial dose was followed by escalation by 100 mg/day up to a maximum of 400 mg/day [132c]. Patients then entered a 20week maintenance period after which they could opt to continue for up to about 2.5 years. The most commonly reported adverse events that were considered possibly related to the trial medication were headache (7%), dizziness (7%), tremor (4%), fatigue (6%), and diarrhea and nausea (4%). The adverse events occurred most often during the titration period. Seven patients withdrew because of adverse effects—electrocardiographic changes (n ¼ 2), dizziness and nausea (n ¼ 1), chest pain and nausea (n ¼ 1), dizziness, fatigue, and tinnitus (n ¼ 1), possible stroke and convulsion (n ¼ 1, this was considered a serious adverse event), accidental overdose (n ¼ 1). Placebo-controlled studies Lacosamide 200, 400, or 600 mg/day has been studied in three randomized, placebo-controlled trials with a 12-week maintenance period, in which about 1300 patients with partial-onset seizures were included [133M]. There was a statistically significant reduction in 28-day seizure frequency compared with placebo. Lacosamide was generally well tolerated in adult patients with partial-onset seizures, and most treatment-emergent adverse events were of mild or moderate intensity. Dizziness was the most common treatment-related adverse event [134R]. In a double-blind, randomized, placebocontrolled trial, oral lacosamide (200, 400, and 600 mg/day) was given to 654 patients with painful diabetic neuropathy for 12 weeks after a 6-week dose titration period [135C]. The proportions of patients with treatment-emergent adverse effects that were considered to be at least possibly related to the trial medication were 31% for placebo, 39% for lacosamide 200 mg/day, 53% at 400 mg/day, and 68% at 600 mg/day. The most common included dizziness (n ¼ 3, 8, 27, and 39 in those treated with placebo, lacosamide 200, 400, and 600 mg/day

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respectively) nausea (n ¼ 4, 14, 9, and 25), and headache (n ¼ 8, 14, 10, and 18). Vertigo was reported in eight patients and blurred vision in seven of those taking 600 mg/day. Other neurological adverse events, such as somnolence and behavioral or cognitive effects, were relatively uncommon. Nine subjects in the placebo group (n ¼ 65), 17 in the lacosamide 200 mg/day group (n ¼ 141), 30 in the 400 mg/day group (n ¼ 125), and 58 in the 600 mg/day group (n ¼ 137) withdrew because of an adverse event, the most common of which were dizziness and nausea. One patient in the lacosamide 600 mg group died in cardiac arrest. However, this was considered unlikely to have been related to the trial medication rather than pre-existing cardiac disease. There were changes in laboratory measurements, weight gain, and peripheral edema in very few subjects. Lacosamide had no effect on the QT interval, but there was a small prolongation in the mean PR interval (mean change 5.1 milliseconds in the lacosamide 200 mg/day group, 13 milliseconds in the 400 mg/day group, and 12 milliseconds in the 600 mg/ day group, compared with 2.3 milliseconds in the placebo group). There was a slight prolongation in mean QRS duration in patients taking lacosamide. First-degree atrioventricular block (PR interval > 200 ms) was reported in under 2% of patients in any treatment group. There was one case of second-degree atrioventricular block in a patient with a normal baseline PR interval in the lacosamide 600 mg/day group 5 days after the last dose. In a multicenter, randomized, placebocontrolled, double-blind trial in 495 patients with painful diabetic neuropathy who took lacosamide 200, 400, or 600 mg/day for 12 weeks after a 6-week titration phase, the lacosamide 400 mg/day group had significant improvement in the primary efficacy measure [136C]. The most common treatment-emergent adverse events included dizziness, nausea, fatigue, headache, and tremor and all appeared to be dose-related. For example, the incidence of dizziness was 5% at 400 mg/day and 22% at 600 mg/day. There was nausea in 5% of patients taking 400 mg/day and 12% of those taking

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600 mg/day. Fatigue was present in 2% and 7% of patients respectively, and tremor in 2% and 6%. Other central nervous system adverse effects, specifically somnolence and behavioral or cognitive effects, were relatively uncommon. For example, somnolence occurred in 3% and memory impairment in 2%. There were 8, 8, 21, and 37 withdrawals in patients treated with placebo, 200, 400, or 600 mg lacosamide respectively, and most occurred early in the study. Dizziness, nausea, and disordered balance were the most common adverse events that led to drug withdrawal. The incidence of edema was low (3% with lacosamide, 4% with placebo). There were no effects on laboratory measurements attributable to the experimental drug. There were no effects on heart rate or QT interval; the placebo-subtracted mean maximum change from baseline in PR interval was 6.1 milliseconds with lacosamide 200 mg/day, 8.3 milliseconds with 400 mg/day, and 9.8 milliseconds with 600 mg/day. The incidence of first degree atrioventricular block was similar in all the groups and there were no reports of second-degree atrioventricular block. Lacosamide 200 and 400 mg/day as addon therapy in 485 patients with uncontrolled partial-onset seizures has been studied in a multicenter, double-blind, placebo-controlled trial, which consisted of an 8-week baseline, a 4-week titration period, and a 12-week maintenance period [137C]. The median percentage reduction in seizure frequency was 21% for placebo, 35% for lacosamide 200 mg/day, and 36% for 400 mg/ day. The most clearly dose-related treatment-emergent adverse events included dizziness (17 and 25 patients randomized to 200 or 400 mg of lacosamide respectively), nausea (9 and 13 patients), and vomiting (5 and 9 patients). Diplopia (13 and 16 patients) did not appear to be dose-related. The incidence of somnolence was low (4.3%, 3.8%, and 3.7% in patients randomized to lacosamide 200 mg, 400 mg, and placebo respectively). The experimental drug was withdrawn in 42 patients because of adverse effects; eight had been randomized to placebo, 10 to lacosamide 200 mg/day, and 24 to 400 mg/day. The adverse effects

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that most often led to withdrawal were diplopia (2.2%), vertigo (1.6%), and vomiting (1.2%). There were no effects on QT interval or QRS duration. Lacosamide was associated with a dose-related increase in mean PR interval (4.6 msec at the end of maintenance with 400 mg/day). Laboratory analyses were not affected and body weight did not change.

Lamotrigine

[SED-15, 1990; SEDA-30, 80; SEDA-31, 113; SEDA-32, 134] Observational studies Lamotrigine has been evaluated in a study that included an open, 1-week screening phase, a 20-week escalation phase, and a 12-week maintenance phase in 54 children aged under 13 years who had newly diagnosed absence epilepsy and had not previously been treated with antiepileptic drugs [138c]. Rash was reported in six patients (11%), urticaria in one patient (2%), and pruritus in two patients (4%). None of these events was serious or resulted in premature withdrawal. Three patients had adverse events that led to premature withdrawal: increased seizure activity in one, tremor in one, and vomiting and dizziness in one patient. In a retrospective study of lamotrigine monotherapy for seizure control in 72 children and adolescents with epilepsy, the mean follow-up period was 33 months [139c]. In six patients lamotrigine was withdrawn because of adverse events (rash 4, low white cell count 1, severe sleepiness 1). Rashes occurred 2–3 weeks after the start of therapy in four patients. In 204 infants (aged 1–24 months) with partial seizures who had been previously given lamotrigine in a randomized, double-blind, placebo-controlled study and who were followed in a long-term study for at least 24 weeks, the only adverse event that was thought to be attributable to the drug was irritability (n ¼ 10) [140c]. There were no cases of serious rash. Lamotrigine has been assessed in 196 patients with bipolar disorder for a mean

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duration of 434 days and a mean final dosage of 236 mg/day without valproate and 169 mg/day with valproate [141c]. Lamotrigine was withdrawn in about one-quarter of cases after a mean of 255 days, most often because of inefficacy and seldom because of adverse effects. In only 3.5% of cases (7/200) was lamotrigine withdrawn because of rashes. Ratings for central nervous system adverse effects (tremor, sedation, headache, memory problems, akathisia, and other extra pyramidal symptoms) and gastrointestinal adverse effects (nausea, vomiting, diarrhea, and constipation), dry mouth, sexual dysfunction, and increased appetite did not change significantly between baseline and the last visit. Some patients had reduced weight, which correlated with impaired appetite. The pharmacodynamic interaction between lamotrigine and valproic acid has been evaluated retrospectively in 35 patients with drug-resistant epilepsy [142c]. Median follow-up was 42 months. With lamotrigine þ valproate, 18 patients became seizure-free, 4 improved, and 13 did not improve. Of the 22 patients who improved, 11 had previously failed lamotrigine and valproate monotherapy. Of the 13 patients who did not respond, 5 stopped taking the combination, primarily because of adverse effects—tremor (n ¼ 4), weight gain (n ¼ 3), dizziness (n ¼ 2), and insomnia (n ¼ 2). Of the 22 patients who improved with the combination, 16 had some adverse effect, which resolved after the dosage of either lamotrigine or valproate was reduced. Comparative studies Lamotrigine versus divalproex sodium In a 12-week, doubleblind, randomized, placebo-controlled comparison of lamotrigine and divalproex sodium in 25 patients with schizophrenia or schizoaffective disorders stabilized on an antipsychotic drug, there were no differences in any outcome measure [143C]. Very few patients reported adverse effects. Two patients randomized to divalproex sodium and placebo reported depression and suicidal thought or tremors respectively. Two patients (one taking lamotrigine and one

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taking divalproex sodium) reported small weight gains. Lamotrigine versus levetiracetam Adjunctive lamotrigine (n ¼ 132) and adjunctive levetiracetam (n ¼ 136) have been compared in an 8-week, randomized, doubleblind, parallel-group escalation phase and a 12-week maintenance phase adults with partial seizures [144C]. Adverse events that led to withdrawal were reported in 11% of those who took lamotrigine and 18% of those who took levetiracetam. Non-serious rashes were reported as adverse events in eight of those who took lamotrigine and nine of those who took levetiracetam. The most common adverse events with lamotrigine were headache (n ¼ 42), dizziness (n ¼ 17), nausea (n ¼ 14), fatigue (n ¼ 10), and somnolence (n ¼ 7). Lamotrigine versus lithium Lamotrigine (up to 200 mg/day) and lithium (up to 900 mg/day) have been compared in a 16-week, open, randomized study in 98 patients with bipolar II disorders [145c]. The mean number of adverse effects in those taking lamotrigine was 4.2 and the mean number of adverse effects in those taking lithium was 9.2. The most common adverse effects in those taking lamotrigine were nausea/ vomiting (24%), upset stomach (20%), dry mouth (20%), tremor (9.8%), and drowsiness/panic (9.8%). Placebo-controlled studies In a 16-week, double-blind, placebo-controlled, flexibledose study of lamotrigine in binge-eating disorder associated with obesity, 51 outpatients were randomized to either lamotrigine (n ¼ 26) or placebo (n ¼ 25) [146c]. Four patients withdrew because of adverse events (lamotrigine, n ¼ 3; placebo, n ¼ 1), the most common of which were headache (35% versus 28%), insomnia (35% versus 20%), somnolence (27% versus 8%), rash (15% versus 12%), and dry mouth (15% versus 0%). Systematic reviews In a systematic review of five randomized, placebo-controlled

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studies in 161 patients, in which lamotrigine or placebo had been administered to patients with psychoses who were already taking clozapine, the dropout rate did not differ between lamotrigine and placebo. [147M]. Three patients had severe adverse events from lamotrigine (psychiatric symptoms in three, facial pain and gingival infection in one), and two among those who took placebo (psychiatric symptoms). Rashes were reported in four patients during lamotrigine therapy and in two during placebo. Cardiovascular In a subcohort (n ¼ 108) of a 40-week, randomized, double-blind comparison of lamotrigine and sustainedrelease carbamazepine in patients aged 65 and over with newly diagnosed epilepsy, target drug maintenance doses were 400 mg/day for carbamazepine and 100 mg/day for lamotrigine, with adjustments based on clinical response [148C]. Resting 12-lead electrocardiograms were recorded under standardized conditions at baseline and at 40 weeks. Of the 108 patients randomized, 60 (carbamazepine n ¼ 29; lamotrigine n ¼ 30) were evaluated. There were no significant changes recorded between baseline and final visit in QRS duration and QT intervals, but heart rate fell and the PQ interval was slightly prolonged by both treatments. However, there were no differences between the groups in the changes from baseline to final visit and no significant relations between individual electrocardiographic changes and serum drug concentrations. Nervous system Two cases of lamotrigineassociated aseptic meningitis recurred after rechallenge [149A, 150A]. • A 25-year-old woman developed meningism, vomiting, conjunctivitis, and myalgia 8 days after starting lamotrigine 25 mg/day. She had generalized epilepsy, peptic ulcer disease, and celiac disease, and her medications were phenytoin, rabeprazole, and levonorgestrel/ ethinylestradiol. Cerebrospinal fluid values were protein 1.14 g/l, glucose 3.4 mmol/l, erythrocytes 22  106/l, leukocytes 112  106/l (67% neutrophils, 32% mononuclear cells). Cerebrospinal fluid and blood cultures for

143 bacteria, mycobacteria, fungi, and viruses were negative and a CT scan was normal. Lamotrigine was withdrawn and she was discharged on day 4 with a diagnosis of presumed viral meningitis. She took lamotrigine again and 15 days later she developed a severe headache, photophobia, neck stiffness, vomiting, dysesthesia, and fever. All tests were again negative and an MRI scan was normal. Lamotrigine was again withdrawn and her fever and meningism rapidly resolved.

Psychiatric Psychiatric problems that can occur in patients using lamotrigine for mental disorders (mainly bipolar disorder) or epilepsy have been reviewed [151R]. The main features of these psychiatric adverse effects are affective switches, full acute psychotic episodes, and hallucinations. Obsessive symptoms occurred in a patient taking lamotrigine 100 mg/day and improved after dosage reduction and then withdrawal [152A]. Lamotrigine-induced mania has been reported in a child with autism spectrum disorder and epilepsy [153A]. • A 10-year-old boy suddenly developed behavioral changes (frequent laughing without any reason, increased hyperactivity, a reduced need for sleep, increased irritability, and aggressive behavior). He was hyperactive and distractible but had no psychotic symptoms. His mother had noted this behavior when lamotrigine, which had been substituted for carbamazepine for epilepsy, had reached a dosage of 100 mg/day. Lamotrigine was gradually withdrawn and his manic symptoms gradually subsided.

Endocrine Polycystic ovary syndrome, hyperandrogenism, or ovulatory dysfunction in women with epilepsy after starting to take valproate or lamotrigine have been prospectively studied in patients with epilepsy, who were randomized to valproate (n ¼ 225) or lamotrigine (n ¼ 222) for 12 months [154C]. More of those who took valproate group developed ovulatory dysfunction or polycystic ovary syndrome. Hyperandrogenism was more frequent with valproate among those who started treatment at ages under 26 years but was similar if treatment was started at age 26 years or over. Similar percentages of patients had adverse effects between those randomized

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to lamotrigine or valproate. Tremor, vomiting, nausea, alopecia, and weight gain were reported more often with valproate. Rashes caused withdrawal in five patients taking lamotrigine and none taking valproate. The proportion of participants who withdrew because of an adverse event was similar between the groups (4%). Salivary glands Sjögren's syndrome has been attributed to lamotrigine [155A]. Liver Three cases of anticonvulsant hypersensitivity syndrome or drug-related rash with eosinophilia and systemic symptoms (DRESS) have been described in conjunction with lamotrigine-associated hepatitis; two recovered after withdrawal of lamotrigine [156A, 157A], but the third required liver transplantation [158A]. • A 43-year-old woman taking oxcarbazepine for depression was given lamotrigine and after 2 weeks developed nausea, a generalized macular rash, and abnormal liver function tests (AsT 6079 IU/l; AlT 6900 IU/l; total bilirubin 67 mmol/l; alkaline phosphatase 149 IU/l). There were no intraoral lesions, lymphadenopathy, or hepatosplenomegaly and no signs of encephalopathy. All drugs were withdrawn and management included intravenous hydration and supportive care. After 3 days her liver enzymes improved substantially and 1 month later were in the reference range.

Skin Stevens–Johnson syndrome [159A] and anticonvulsant hypersensitivity syndrome [160A] have been described in patients taking lamotrigine. Possible cross-reactivity between carbamazepine and lamotrigine, which are aromatic and nonaromatic anticonvulsants, has been illustrated [89A]. • A 14-year-boy developed erythroderma, fever, and interstitial pneumonitis after taking carbamazepine for 44 days and had a positive patch test to carbamazepine 6 weeks after recovery. He developed a similar clinical and biological picture after taking lamotrigine for 52 days.

Cutaneous adverse drug reactions to psychotropic drugs have been studied using a database of 208 401 psychiatric in-patients

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monitored in a multicenter drug safety surveillance project [161C]. There were 214 cases of clinically relevant cutaneous drug reactions, of which seven were life-threatening. Substances with the highest and statistically significant risk were antiepileptic drugs, particularly lamotrigine and carbamazepine. In a prospective study, the incidence of rash was calculated in 237 patients who were taking lamotrigine for bipolar I disorder in Korea, of whom 30 developed a rash at a median time of onset of 16 days [162c]. In two cases the rash was serious, but none developed Stevens–Johnson syndrome or toxic epidermal necrolysis. Lamotrigine-induced rash and rechallenge have been systematically reviewed, 44 papers being retrieved [163M]. In 39 cases, rechallenge was attempted and rash recurred in only five cases. Thus, many patients who develop benign rashes from lamotrigine can be rechallenged without adverse consequences. However, very slow titration of lamotrigine is of crucial importance for reducing the rate of recurrence. Sexual function Reproductive and sexual function have been investigated in patients with epilepsy aged 18–45 taking lamotrigine (37 men/40 women), levetiracetam (30 men/ 26 women), or carbamazepine (63 men/30 women) monotherapy and in healthy controls (36 men/44 women) [97c]. Dehydroepiandrosterone sulfate concentrations were higher and androstenedione concentrations lower in lamotrigine-treated women. In women, Arizona Sexual Experience Scale scores were significantly lower in those using lamotrigine or levetiracetam, suggesting that they have better sexual function than carbamazepine users and controls. Men in all treatment groups had lower androstenedione and free testosterone concentrations. Arizona Sexual Experience Scale scores for men were similar in all groups. Drug withdrawal The potential for withdrawal symptoms during treatment with lamotrigine has been investigated retrospectively [164c]. Six patients with epilepsy were identified who reported transient psychological symptoms during stable, chronic

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lamotrigine monotherapy. These consisted largely of irritability, in addition to complaints of anxiety, difficulty in thinking, and weakness, and they occurred in the 1–2 hours before the patients were due to take their next dose of medication. However, some patients were also taking other psychoactive medications, including benzodiazepines, and the hypothesis that these are an end-of-dose phenomenon should be further explored. Pregnancy In 20 women with epilepsy who took lamotrigine during pregnancy [165c] all the pregnancies and births were normal, but three gave birth to healthy twins, two had vanished twin syndromes, and one had a miscarriage. The authors suggested that lamotrigine might induce twin pregnancy. Teratogenicity Data from the North American antiepileptic drug Pregnancy Registry have shown an unexpectedly high prevalence of isolated orofacial clefts in infants exposed to lamotrigine monotherapy during the first trimester of pregnancy, with a rate of 8.9 per 1000 [166C]. To verify this, a population-based case–control study with malformed controls based on EUROCAT congenital anomaly registers (which covers 3.9 million births) has been performed [167C]. The odd ratios for lamotrigine monotherapy versus no antiepileptic drug use were 0.67 (95% CI ¼ 0.10, 2.34) for orofacial clefts relative to other malformations, 0.80 (95% CI ¼ 0.11, 2.85) for isolated orofacial clefts, 0.79 (95% CI ¼ 0.03, 4.35) for cleft palate, and 1.01 (95% CI ¼ 0.03, 5.57) for isolated cleft palate. There was no evidence of a specific increased risk of isolated orofacial clefts relative to other malformations due to lamotrigine monotherapy. However, the finding of an increased risk of oral clefts in offspring exposed to lamotrigine during pregnancy has been questioned by other workers [168r]. Data from the UK Epilepsy & Pregnancy Register, another independent prospective registration and follow-up study (a total of 1229 pregnancies exposed to lamotrigine monotherapy resulting in 1151 live births), have not confirmed the finding. Suggested possible

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explanations for these different results are an improbable difference for oral clefts between the populations studied in the USA and the UK or some bias associated with the design of the studies. A literature search for congenital malformations after the use of lamotrigine during pregnancy yielded 10 studies and birth registers; the risk of a major congenital malformation due to lamotrigine was 1–4% [169M]. A female infant was born with micrognathia, low-set ears, facial dysmorphism, and unilateral radius aplasia to a mother who used lamotrigine 100 mg/day and oxcarbazepine 1200 mg/day during pregnancy for seizures [170A]. Fetotoxicity A 3-day-old full-term newborn had from series of tonic-clonic and myoclonic seizures [171A]. The authors speculated that these seizures were caused by the drop in lamotrigine concentrations in his blood after delivery. Susceptibility factors Genetic High-resolution HLA genotyping has also been performed in 65 patients of European ancestry taking lamotrigine (22 cases with lamotrigine-induced severe cutaneous drug reactions and 43 controls taking lamotrigine without such symptoms) and the association of HLA genetic variants with these adverse reactions was evaluated by contrasting allele frequencies between the cases and the controls for each of 112 HLA four-digit alleles [172C]. Five alleles were found with higher frequencies in the cases compared with the treated controls, although none of the associations identified was statistically significant; they included B*580, previously reported to be associated with allopurinol-induced serious cutaneous adverse reactions. Marginal association evidence was also observed for alleles Cw*0718 and DQB1*0609, both of which were strongly correlated with B*5801. Other alleles identified were A*6801and DRB1*1301. None of the cases carried B*1502. Thus, there is suggestive evidence for some associations, but no single major HLA-related genetic factor has been

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identified for lamotrigine-induced severe cutaneous drug reactions in patients of European origin. Drug overdose Lamotrigine overdose with life-threatening consequences has been reported [173A]. • A 23-year-old woman took an intentional overdose of lamotrigine 9.2 g, chlorphenamine 56 mg, and citalopram 220 mg while intoxicated with alcohol. Her heart rate was 107/ minute, blood pressure 140/73 mmHg, and respiratory rate 36/minute with an oxygen saturation of 97%. Her temperature was 38.5  C and she had a partially compensated metabolic acidosis. She was agitated with a reduced conscious level, tremor, and bilateral horizontal nystagmus. Electrocardiography showed sinus tachycardia, a widened QRS complex (>120 msec), and a prolonged QTc interval (>470 msec). She was intubated and ventilated and given intravenous magnesium and sodium bicarbonate. The next morning the electrocardiographic changes had resolved.

Drug–drug interactions Lamotrigine Polypharmacy with enzyme inducers is an important susceptibility factor for valproate encephalopathy. Valproic acid-induced hyperammonemic encephalopathy developed exclusively during concomitant treatment with lamotrigine þ valproate in a psychiatric setting [174A]. • A 72-year-old woman with bipolar I disorder, who was taking a combination of valproic acid and clozapine, was admitted with acute mania and psychosis following 2 months of poor drug compliance. Lamotrigine was added initially in a dosage of 12.5 mg/day and increased by 12.5 mg every 3 days up to final dose of 75 mg/day after 2 weeks. She developed weakness, hand tremor, lethargy, and asterixis after 3 weeks and electroencephalography showed typical triphasic waves. The ammonia concentration rose to 59 mmol/l (reference range 9–30 mmol/l), the valproate concentration was 86 mg/l, and liver enzymes were in the reference range. Valproate was withdrawn and the hyperammonemia and symptoms resolved during the next week.

Oral contraceptives Serum antiepileptic drug concentrations of lamotrigine and valproate were measured at two times during a single menstrual cycle in four groups

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of 12 women with epilepsy [175C]. Both valproate and lamotrigine concentrations were significantly reduced by the oral contraceptive (median reductions of 23% for valproate and 33% for lamotrigine). Serum lamotrigine concentrations fell non-significantly by 31% during the midluteal phase compared with the early-mid follicular phase in the absence of oral contraception. Raltegravir In 12 healthy volunteers, the AUC, Cmax, and the mean ratio of the AUCs of lamotrigine-2N-glucuronide to lamotrigine have been measured after a single dose of lamotrigine 100 mg during treatment with raltegravir 400 mg twice a day (bd) and after a washout period [176c]. There were no significant effects. Management of adverse reactions Intravenous immunoglobulin was successfully given to a patient with epilepsy and toxic epidermal necrolysis, which appeared after 2 weeks of treatment with lamotrigine and valproate [177A].

Levetiracetam

[SED-15, 2035; SEDA30, 82; SEDA-31, 116; SEDA-32, 137]

Observational studies Levetiracetam monotherapy has been investigated in 35 patients with late-onset post-stroke seizures in a prospective open study [178c]. At a mean follow-up period of 18 months, 27 patients had achieved seizure freedom. Four of 35 patients stopped taking levetiracetam because of severe adverse events: drowsiness with gait disturbance and aggressive behavior in two cases, and severe psychomotor agitation with aggressive behavior in the other two patients. The use, safety, and efficacy of levetiracetam in 51 patients in intensive care unit have been retrospectively analysed [179c]. Nineteen patients first received levetiracetam intravenously formulation before receiving it orally, 18 received the

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intravenous formulation only, and the other 14 the oral doses only. The most common maintenance dose was 500 mg bd and the average duration of therapy was 13 days. There were no cases of adverse hemodynamic events or cardiac dysrhythmias. In a prospective multicenter, open, addon study, 33 children aged 4–16 years with refractory epilepsy were given levetiracetam in addition to their previous treatment regimen [180c]. The retention rate was 70% after 26 weeks, with a median levetiracetam dosage of 22 mg/kg/day. Most reported adverse effects were hyperactivity (49%), somnolence (36%), irritability (33%), and aggressive behavior (27%).

Comparative studies Levetiracetam versus phenytoin Levetiracetam monotherapy has been compared with phenytoin for postoperative control of glioma-related seizures in a randomized pilot study [181c]. Over 13 months, 29 patients were randomized in a 2:1 ratio to start levetiracetam within 24 hours of surgery or to continue phenytoin therapy. Similar percentages of patients were seizure-free after 6 months of treatment. Reported adverse effects at 6 months were: dizziness (0% levetiracetam, 14% phenytoin), difficulty with coordination (0% versus 29%), depression (7% versus 14%), lack of energy or strength (20% versus 43%), insomnia (40% versus 43%), and mood instability (7% versus 0%). No adverse effect resulted in hospitalization or withdrawal from the study. Levetiracetam and phenytoin have been retrospectively compared in the prophylaxis of early and late postoperative seizures in 315 patients [182c]. Levetiracetam (n ¼ 105) was at least as effective as phenytoin (n ¼ 210) and significantly better tolerated. Adverse effects that prompted a change in antiepileptic drug therapy occurred in one patient taking levetiracetam, who had visual hallucinations, compared with 38 patients taking phenytoin (18%). In patients who were followed for at least 1 year and developed epilepsy, levetiracetam also had a higher retention rate.

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Placebo-controlled studies The effect of levetiracetam as adjunctive therapy in Chinese patients with refractory partial seizures has been evaluated in a 4-week titration and 12-week maintenance period, randomized, placebo-controlled trial in 56 patients [183c]. There were adverse events in 23 patients taking levetiracetam and 22 taking placebo. These were generally moderate and no patient withdrew. Levetiracetam was associated with somnolence, dizziness, and agitation in more than 10% of patients. There were no treatment-emergent serious adverse events. Levetiracetam has been evaluated as add-on therapy in Chinese patients with refractory partial-onset seizures in a multicenter, 4 week titration and 12-week maintenance, double-blind, placebo-controlled trial, in which 206 patients aged 16–70 years were randomized to levetiracetam (n ¼ 103) or placebo (n ¼ 103) [184C]. Levetiracetam significantly reduced the weekly partial-onset seizure frequency over placebo by 27%. Adverse events, which were of mild-to-moderate intensity, were reported by 65 patients taking levetiracetam and 62 taking placebo. The most common were somnolence (18% levetiracetam and placebo), reduced platelet counts (9.7% versus 9.7%), dizziness (7.8% versus 14%), and headache (3.9% versus 8.7%). Cardiovascular Maintaining adequate cerebral perfusion pressure is key in the management of patients with acute cerebral symptoms. For this reason, data from 148 consecutive patients with acute cerebral symptoms who received intravenous infusions of a single dose of 750 mg or more of either fosphenytoin (n ¼ 78) or levetiracetam (n ¼ 71) and had blood pressures documented in the 2 hours before and the 2 hours after their intravenous infusion have been retrospectively analysed [185c]. Following the infusion, there was a more than a 10 mmHg fall in systolic, diastolic, and mean blood pressures in those who were given fosphenytoin, while there were only very slight changes in these values in patients who received levetiracetam. This

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difference was statistically significant after adjusting for age and clinical presentation. Nervous system In a retrospective analysis of 207 patients treated with levetiracetam, there was a paradoxical increase in seizure frequency or more severe seizures, including generalized tonic-clonic seizures, in 14% of patients [186c]. Of the 30 patients in the paradoxical effect group, 15 were mentally retarded compared with a much lower percentage of mentally retarded patients in the rest of the group (16/177 ¼ 9%). A metabolic encephalopathy with triphasic waves and myoclonus has been associated with levetiracetam intoxication in a patient with chronic renal insufficiency [187A]. • An 80-year-old woman developed status myoclonicus combined with a moderate confusional state. Electroencephalography showed diffuse theta-delta slowing with prominent multifocal triphasic waves. She was taking levetiracetam 2000 mg/day for post-stroke symptomatic seizures, in addition to verapamil, propranolol, metformin, oxazepam, escitalopram and co-beneldopa. Standard laboratory tests showed stable renal insufficiency. The serum levetiracetam concentration was 184 mmol/l and the dose was reduced to 500 mg/day. Three days later, the myoclonic jerks had disappeared, cognitive function was normal, and electroencephalography showed normal background activity.

Psychological In a prospective, open, noninterventional study, objective and subjective cognitive measures were evaluated in 401 patients with epilepsy before and 3 and 6 months after introducing levetiracetam [188c]. Very good tolerance was reported by 68% and cognitive improvement by 58%. Objective improvement was significant in one-quarter of the patients, while 5–6% deteriorated. Adverse events were reported in 28 patients. Psychotropic effects were reported by 1.5%, tiredness by 0.7%, vegetative symptoms by 1.7%, and increased seizure frequency by 0.7% of patients. In a double-blind, placebo-controlled, non-inferiority study, 99 children with

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inadequately controlled partial-onset seizures were randomized (2:1) to adjunctive levetiracetam or placebo for 12 weeks [189c]. Adverse events were reported by 89% of those who took levetiracetam and 85% of those who took placebo. Those reported more often with levetiracetam were headache (27%), nasopharyngitis (17%), fatigue (14%), vomiting (14%), somnolence (14%), and aggression (13%). Psychiatric When 288 consecutive patients with epilepsy who had taken levetiracetam (90% polytherapy, mean dose 2689 mg) and 135 of their relatives were asked whether levetiracetam had caused positive or negative behavioral changes, 59% reported a behavioral change that they explicitly attributed to the drug, which was very negative (12%), negative (25%), positive (16%), or very positive (6%), compared with only 9% of 43 control patients who took other antiepileptic drugs [190C]. Negative ratings were due to loss of selfcontrol, restlessness, sleeping problems, and aggression. Positive ratings were due to increased energy, vigilance, and activation. These changes were not related to the type of epilepsy, co-therapy, dose, drug load, or psychiatric history, even though the negative effects were associated with poorer seizure control and mental retardation. Depression has been described in both elderly epileptic patients [191A] and a child with epilepsy [192A], probably caused by levetiracetam. • A 73-year-old black man with stage 4 kidney disease was given levetiracetam 500 mg bd for treatment of partial seizures. After 5 months he developed new-onset depression, with low mood, weight loss, and fatigue. Levetiracetam was withdrawn and 4 weeks later the depressive symptoms had nearly completely resolved.

Negative behavioral effects of levetiracetam have been reported to have been mitigated by pyridoxine [193A]. In a randomized, double-blind, parallelgroup study in adults with partial seizures, including an 8-week escalation phase and a 12-week double-blind maintenance phase,

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lamotrigine adjunctive therapy (n ¼ 132) and levetiracetam adjunctive therapy (n ¼ 136) have been compared [144C]. Lamotrigine was more efficacious than levetiracetam in relieving symptoms of anger and hostility, depression and dejection, fatigue, and confusion and bewilderment. Hematologic Thrombocytopenia has been reported in a child [194A] and an adult with epilepsy [195A] during treatment with levetiracetam, in one case requiring blood transfusion. The adverse effect occurred within days or weeks and quickly resolved after withdrawal. Altered platelet function probably caused by levetiracetam has been reported in a 75-year-old man with focal epilepsy [196A]. Platelet aggregation profile normalized 3 weeks after drug discontinuation. Pancytopenia has been described in two elderly patients who took levetiracetam for seizures [197A, 198A]. • A 76-year-old woman with seizures secondary to ischemic stroke developed status epilepticus despite treatment with clonazepam. She was given intravenous levetiracetam 1000 mg/day and 2 days later developed pancytopenia, with a hemoglobin concentration of 9.8 g/dl, a platelet count of 83  109/l, and a white blood cell count of 5.7  106/l. These changes worsened during the next 4 days and she required blood transfusion. Levetiracetam was withdrawn and 2 days later the blood cell count improved. When rechallenge with oral levetiracetam 0.5 g/day 1 year later pancytopenia rapidly recurred.

Liver Fulminant liver failure has been reported, with rapid recurrence after rechallenge [199A]. • A 21-year-old man took levetiracetam for partial seizures for 1 month, and had a generalized seizure preceded by a 6-day history of pale stools, dark urine, and jaundice. The serum bilirubin was 591 mmol/l, alanine aminotransferase 1610 U/l, alkaline phosphatase 246 U/l, and the international normalized ratio (INR) 3.6. A liver biopsy showed massive confluent hepatocyte necrosis with no evidence of pre-existing liver disease. Levetiracetam was withdrawn but the liver failure continued to deteriorate and he subsequently required liver transplantation. Postoperatively levetiracetam

149 was restarted, but his liver function tests rapid deteriorated during the next few days. After 4 days levetiracetam was again withdrawn, with immediate improvement. A liver biopsy performed 2 days later showed a limited acute resolving insult.

Urinary tract A 17-year-old patient with epilepsy and normal renal function developed interstitial nephritis and renal failure while taking levetiracetam [200A]. • A 17-year-old girl took levetiracetam 250 mg bd for generalized tonic-clonic seizures and 10 days later developed intermittent vomiting, abdominal pain, and loose stools. She had a high serum creatinine concentration (290 mmol/l) and the urine was positive for protein and blood. A renal biopsy confirmed subacute allergic interstitial nephritis with multifocal tubular degeneration, interstitial edema, early fibrosis, and infiltration with lymphocytes and eosinophils. There were no interstitial granulomas, vasculitis, or glomerulopathy, and glomerular and tubular immunoglobulins and complement were not identified. Viral particles were not seen at electron microscopy. The serum creatinine rose further to 680 mmol/l. Levetiracetam was withdrawn and oral glucocorticoids were administered. He made a complete and rapid recovery.

Pregnancy Levetiracetam clearance increases in pregnancy. Levetiracetam plasma concentrations have been prospectively monitored in five women during pregnancy and 2 and 12 months after delivery [201c]. Without change in the dosage of levetiracetam, the mean levetiracetam concentrations during the third trimester were 62% of the 12-month postpartum concentrations, but only 47% of the 2-month postpartum concentrations. The authors concluded that if the 2-month postpartum concentrations are considered as baseline, as is usually the case in prospective studies on antiepileptic drug pharmacokinetics during pregnancy, the gestational fall in levetiracetam concentration throughout pregnancy would be overestimated. In three other patients who took lamotrigine, baseline late postpartum levetiracetam clearance was 63%, as in the second trimester. In these patients, the number of seizures was not changed once the dosage of lamotrigine was increased and none of the

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women had adverse effects during the puerperium. The mean umbilical cord/maternal levetiracetam plasma concentration ratio was 1.21 and none of the neonates had malformations; they were normal for their gestational age. A woman developed status epilepticus during the first trimester of pregnancy, which might have been caused by a fall in her levetiracetam blood concentrations [202A]. The clearance of levetiracetam increases during pregnancy, particularly during the third trimester, probably due to increased renal blood flow.

Teratogenicity Of 147 patients 2% had children with a major congenital malformation and 4.8% had a minor anomaly; in all these patients, levetiracetam was associated with the use of other antiepileptic drugs [203M].

Drug formulations Extended-release levetiracetam Once-daily extended-release levetiracetam as add-on therapy in refractory partial-onset seizures has been evaluated in a 12 week, double-blind, randomized, placebo-controlled trial in 158 patients [204C]. There were adverse events in 41 (53%) of those who used extended-release leve-tiracetam and in 43 (54%) of those who used placebo; the most common were somnolence, influenza, irritability, nasopharyngitis, dizziness, and nausea. Once-daily adjunctive extended-release levetiracetam 1000 mg/day (n ¼ 70) and adjunctive immediate-release levetiracetam 500 mg bd (n ¼ 204) have been compared in a meta-analysis of three randomized, placebo-controlled, phase III trials in 555 patients aged over 16 years with partialonset seizures [205M]. After adjustment for placebo-associated adverse events, immediate-release levetiracetam was associated with statistically more treatment-emergent adverse effects than extended-release levetiracetam across nervous system disorders (risk difference ¼ 18%), psychiatric disorders (risk difference ¼ 11%), and

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disorders of metabolism and nutrition (risk difference ¼ 3%). Intravenous levetiracetam The safety of rapid intravenous loading doses (20, 40, and 60 mg/kg; corresponding to maximum doses of 1000, 2000, and 3000 mg) of levetiracetam has been prospectively evaluated in healthy subjects and patients with epilepsy [206C]. There were no significant effects on blood pressure or electrocardiography and no local infusion site reactions. In a retrospective analysis of 118 intravenous infusions of levetiracetam in 15 children with epilepsy, most of whom were aged under 4 years, the following adverse effects were noted during the post-infusion period: lethargy (n ¼ 2), agitation (1), irritability (1), mild tremors (1), and ataxia (1); no adverse effects required drug withdrawal [207c]. Three patients had reductions in white blood cell counts within the first 4 days after administration of the first dose of levetiracetam. In 12 adults with status epilepticus, intravenous levetiracetam 2500 mg was added as soon as possible to a standardized regimen of intravenous clonazepam and/or rectal diazepam as needed followed by phenytoin or valproic acid; no serious adverse effects could be related directly to the administration of levetiracetam [208c]. In a retrospective analysis of 36 patients who received intravenous levetiracetam for refractory status epilepticus [209c] a median dose of 3000 mg/day (range 1000– 9000) was used as a loading bolus or by continuous pump infusion. Status epilepticus was terminated in 69% of patients. None had cardiac dysrhythmias or significantly reduced blood pressure, or required an increase in the dose of catecholamines. Two patients had nausea and vomiting during levetiracetam loading, leading to aspiration pneumonia in one. In a retrospective study of 32 patients who had been given intravenous levetiracetam for status epilepticus, there was arterial hypotension after intravenous levetiracetam in four patients during co administration of propofol and during rapid infusion of phenytoin in one patient [210c]. There

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were no cardiac dysrhythmias and no impairment of respiration or oxygenation. There was sedation after drug administration in six patients, but only in those who had previously received benzodiazepines. Nausea and vomiting occurred in one patient and another had raised liver enzymes. There were no signs of local irritation at injection sites. In a retrospective study in 43 patients with various forms of status epilepticus after ineffective treatment with benzodiazepines, intravenous levetiracetam was given as a short infusion of 1000 or 2000 mg [211c]. Status epilepticus was terminated in 19. There were no severe adverse reactions. Among patients aged over 80, somnolence was reported, which could have been due to benzodiazepines, and/or post-seizure twilight state. There were no metabolic disturbances or interactions. In a retrospective chart study of 34 patients with status epilepticus who were given intravenous levetiracetam, the median loading dose of levetiracetam was 1000 mg and the maintenance dosage was 500–1500 mg/12 hours (median 1000 mg/12 hours) [212c]. Status epilepticus stopped in a clear temporal relation to drug infusion in 71% of patients and there were no serious adverse events. Management of adverse drug reactions The possible benefit of pyridoxine (vitamin B6) in the treatment of levetiracetaminduced behavioral adverse effects has been explored in a questionnaire study in 90 children with epilepsy, 22 of whom started taking pyridoxine after having been taking levetiracetam [213c]. There was behavioral improvement in nine, no effect in eight, deterioration in four, and an uncertain effect in one.

Oxcarbazepine [SED-15, 2646; SEDA30, 83; SEDA-31, 118; SEDA-32, 141] Observational studies In a prospective open study in 147 patients with newly diagnosed epilepsy, followed for a median of

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18 months, 92 became seizure-free [214c]. Overall, 13 (8.8%) stopped taking oxcarbazepine because of intolerable adverse effects: nausea, and vomiting with low serum sodium concentrations (5); Stevens– Johnson syndrome (n ¼ 2); fatigue and drowsiness (2); dizziness, nausea, and vomiting (2); and severe headache, dizziness, and raised serum gamma-glutamyl transferase activity (1 each). Only one elderly patient had hyponatremia with mild symptoms, which responded to fluid restriction and did not require drug withdrawal. In 36 children with newly diagnosed partial epilepsy who were given oxcarbazepine monotherapy (average dose 22, range 10– 35 mg/kg) and were followed for 36 months, 18% had adverse effects (fatigue, headache, sedation, memory deficit, agitation) after 1 year, but during the second year only one patient still had an adverse effect (headache) and during the third one had reduced vigilance [215c]. There were no cases of hyponatremia or hepatic dysfunctions. Oxcarbazepine was withdrawn because of sedation in one patient. Comparative studies Oxcarbazepine has been compared with traditional antiepileptic drugs in 35 patients with brain tumor-related epilepsy in a retrospective observational study [216c]. Oxcarbazepine and traditional antiepileptic drugs had similar efficacy but different patterns of adverse effects. Significantly fewer of those who took oxcarbazepine dropped out and in relation to serious adverse effects, only three of those who took oxcarbazepine compared with 13 of those who took other drugs had to stop treatment. As regards the total incidence of adverse effects, four patients had adverse effects during oxcarbazepine treatment compared with 15 of those who took other drugs. In a retrospective study of the medical records of 26 children and adolescents with epilepsy who had been rapidly switched from carbamazepine to oxcarbazepine (dose conversion ratios 1.0–1.5), the transition was well tolerated; three patients had adverse events (rashes) [217c].

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Oxcarbazepine and carbamazepine have been compared for 8 weeks in 52 patients with bipolar disorders already taking lithium [73c]. Both drugs reduced bipolar scores; 14 patients taking oxcarbazepine and 15 taking carbamazepine reported at least one adverse event. Oxcarbazepine (1000–2400 mg/day) and divalproex sodium (750–2000 mg/day) have been compared in a 12 week, randomized, double-blind pilot study in 60 patients with acute mania [218c]. The median time to symptomatic remission of and the relapse rate did not differ. There were 22 adverse events in those who took oxcarbazepine group compared with 56 in those who took divalproex. The most common adverse events with oxcarbazepine were nausea (n ¼ 5), dizziness (3), vomiting (4), sedation (3), and dyspepsia (3). Systematic reviews Oxcarbazepine is claimed to be better tolerated than carbamazepine. In a meta-analysis of blinded and unblinded randomized controlled trials (723 participants) of carbamazepine versus oxcarbazepine monotherapy for partial-onset seizures, the most common adverse events were allergic rash, dizziness or vertigo, and headache; there were no significant differences between the two drugs [219M]. There was a trend towards a clinical advantage of oxcarbazepine in the occurrence of fatigue/drowsiness/sedation, and there were significantly more episodes of nausea, vomiting, or both among those who used oxcarbazepine. Nervous system Parkinsonism has been attributed to oxcarbazepine [220A]. • A 38-year-old woman with trigeminal neuralgia was given oxcarbazepine 900 mg/day and after 1 week developed slowing of body movements, monotonous speech, gait abnormality, and tremor in her hands. There was facial hypomimia, bilateral bradykinesia, cogwheel rigidity, postural instability and a slight intermittent rest tremor in the hands. Cranial MRI, MR angiography, and laboratory examinations were normal. Oxcarbazepine was

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withdrawn and 2 weeks later all the extrapyramidal symptoms had resolved.

Neuroleptic malignant syndrome without fever occurred when oxcarbazepine was given in addition to long-term administration of amisulpride [221A]. • A 31-year-old man who was already taking amisulpride 400 mg bd for chronic schizophrenia took oxcarbazepine up to a maintenance dose of 1200 mg/day. After a few days he developed altered consciousness, tremor, rigidity, slow movements, a wooden appearance, sweating, a high blood pressure (165/95 mmHg), and a fluctuating pulse rate. His temperature was 37  C. He had a mild leukocytosis, raised serum AST and ALT activities, and markedly raised creatine kinase and lactate dehydrogenase activities (3038 and 727 U/l respectively). Other laboratory results were normal. A brain CT scan was normal and there was no evidence of infection or thyroid disease. A diagnosis of neuroleptic malignant syndrome was made. Amisulpride was withdrawn and the dose of oxcarbazepine was reduced to 600 mg/day. Amantadine and levodopa were added and the serum creatine kinase, which peaked (4019 U/L) on the second day, fell thereafter and become normal after 10 days. The syndrome resolved completely after 7 days.

The association between oxcarbazepine was not clear in this case. Hematologic Reversible leukopenia and hyponatremia have been attributed to high-dose oxcarbazepine [222A]. • A 38-year-old man with partial epilepsy taking a stable regimen of levetiracetam (3000 mg/ day), clonazepam (4 mg/day), and oxcarbazepine (1800 mg/day) increased the dosage of oxcarbazepine to 2400 mg/day because of partial seizures with secondary generalization. He developed hyponatremia (125 mmol/l) and leukopenia (total white cell count 2.8  109/l; 50% neutrophils). The dosage of oxcarbazepine was reduced to 1800 mg/day and a few days later the white cell count was 3.8  109/l with a parallel increase in sodium concentration to 132 mmol/l. The dosage of oxcarbazepine was again increased to 2400 mg/day, and after 2 more days both the white cell count and serum sodium fell (to 3.2  109/l and 125 mmol/l respectively). Oxcarbazepine was withdrawn and replaced by topiramate; 2 days

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later the white cell count was 4.8  109/l and the serum sodium concentration was normal.

Skin Oxcarbazepine is considered to be much less likely than carbamazepine to cause skin reactions, owing to its different metabolic pathway. Oxcarbazepine-associated Stevens–Johnson syndrome has been described in two Chinese patients with epilepsy, one of whom was positive for HLAB*1502 [223A, 224A]. • A 53-year-old man, who was taking enalapril maleate, amlodipine besylate, and aspirin, had several seizures and was given first phenobarbital, then valproic acid, and then oxcarbazepine. After 20 days he developed a generalized skin rash and oral ulceration followed by a high fever. He had widespread confluent erythematous macules and papules and numerous flat atypical target lesions with central dusky discoloration on the face, neck, trunk, and proximal arms. Genotyping showed the presence of an HLA-B*1502 allele.

A 13-year-old boy developed a severe rash and systemic symptoms after starting to take oxcarbazepine [225A]. Musculoskeletal The effect of oxcarbazepine on bone metabolism has been investigated in two studies, with slightly different results. In a cross-sectional study in 28 adults with epilepsy who took oxcarbazepine monotherapy for 1 year and 28 healthy volunteers, [226c] although alkaline phosphatase and vitamin D3 concentrations were significantly different, calcium, phosphate, alkaline phosphatase, and bone densitometry were not different from baseline after 1 year. In a second study, the effect of oxcarbazepine monotherapy for 18 months on bone turnover was longitudinally explored in 34 newly diagnosed prepubertal and pubertal children [227c]. The serum concentrations of 25-hydroxycolecalciferol were significantly reduced by oxcarbazepine, while osteocalcin and gamma-glutamyl transferase activity were significantly increased compared with baseline values. Phosphorus, parathyroid hormone, and calcitonin concentrations and alkaline phosphatase activity increased nonsignificantly. In three patients who had

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T scores of bone mineral density worse than 1.5 before treatment, there was osteopenia after oxcarbazepine treatment (T scores worse than 2.0). Immunologic A lupus-like syndrome occurred in a young boy who took oxcarbazepine and valproic acid [228A]. • A 7-year-old boy with epilepsy, who was taking oxcarbazepine, developed a fever, anorexia, diffuse arthralgias, myalgias, weight loss, and swelling of the finger and toe joints. He had a raised erythrocyte sedimentation rate and Creactive protein and antinuclear antibodies were positive (1/160). Since he was having recurrent seizures, valproic acid and levetiracetam were added and the dosage of oxcarbazepine was reduced. After 45 days he was still symptomatic. He had generalized lymphadenopathy, hepatosplenomegaly, and arthritis in the proximal interphalangeal joints of the hands, wrists, and ankles. The main laboratory findings were strongly positive Coombs’ test and antinuclear antibody (1/1000) and positive anti-histone and anti-nucleosome antibodies. Oxcarbazepine and valproic acid were withdrawn and glucocorticoid treatment was started. The syndrome resolved after 2 days and the laboratory tests gradually normalized.

Teratogenicity A female infant was born with micrognathia, low-set ears, facial dysmorphism, and unilateral radius aplasia to a mother who had used lamotrigine 100 mg/day and oxcarbazepine 1200 mg/day during pregnancy for seizures [170A]. Drug formulations Extended-release oxcarbazepine should cause fewer adverse effects because of the less marked peak serum oxcarbazepine concentration before metabolism to its active monohydroxy derivate. In an open study, 27 patients with difficult-to-treat localization-related epilepsies who had been taking immediate-release oxcarbazepine were abruptly switched to extended-release oxcarbazepine in identical dosages and the concentrations of oxcarbazepine and its active metabolite were measured before and after the switch [229c]. The new formulation was associated with significantly fewer adverse effects and better quality of life, and this was explained by lower peak oxcarbazepine concentrations.

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Drug overdose Oxcarbazepine overdose has been described in a child [230A]. • A 13-year-old boy with autism spectrum disorder taking risperidone accidentally ingested oxcarbazepine suspension 15 g after it was added in a dosage of 300 mg bd to treat persistent aggression. He had normal vital signs and was somnolent but rousable to painful stimuli. Neurological examination, electrocardiography, and laboratory tests were normal. He was given activated charcoal by nasogastric tube and remained hemodynamically stable and did not need ventilatory support. His somnolence progressively improved over the next 12 hours.

Phenobarbital and primidone [SED-15, 2798; SEDA-30, 85; SEDA-32, 145] Observational studies When patients with partial epilepsy who were taking carbamazepine were randomized to either valproate (n ¼ 68) or primidone (n ¼ 68) in an open study, significantly more of those who took valproate achieved a greater than 50% seizure reduction [231c]. Of those taking primidone, three withdrew because of dizziness, three because of drowsiness, and one because of gastrointestinal complaints. Nervous system An infant with drugresistant epilepsy associated with bilateral Sturge–Weber syndrome became comatose after taking high-dose phenobarbital for a few months and regained consciousness as the serum phenobarbital concentration fell to below 40 mg/ml. The authors suggested that patients with severe cerebrovascular diseases are more susceptible to the sedative effects of phenobarbital [232A]. A 13-year-old girl with acute intermittent porphyria had several attacks of the disease and developed an acute severe axonal motor neuropathy after taking porphyrinogenic medications, including phenobarbital, for 3 weeks [233A]. Skin Seven children aged 2–11 years developed severe skin reactions (erythema

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multiforme, Stevens–Johnson syndrome, and toxic epidermal necrolysis) while taking barbiturates [234A] and another case of toxic epidermal necrolysis has been described [235A]. A 3-year-old boy who had had an anticonvulsant hypersensitivity syndrome developed alopecia areata universalis while convalescent [236A]. Skin histology showed perifollicular, peribulbar, and suprabulbar lymphocyte infiltration. Recurrent plantar fibromatosis, also known as Ledderhose syndrome, occurred in a patient who had taken phenobarbital for a long time [237A]. Teratogenicity The teratogenic potential of high doses of phenobarbital has been studied, in a comparison of the number of congenital anomalies observed in exposed children born to pregnant patients who attempted suicide with phenobarbital during pregnancy with the number observed in unexposed children born to the same patients [238c]. Of 1044 self-poisoned pregnant women, 88 took phenobarbital 400–3000 mg in a suicide attempt and delivered live babies; 12 (14%) of the 88 exposed children and 8 (10%) of their 78 siblings had congenital abnormalities; 34 of the 88 exposed children were born to mothers who attempted suicide with phenobarbital between the 3rd and 12th post-conceptional weeks, the critical period for most congenital abnormalities. The authors concluded that the use of phenobarbital once but in extremely large doses in non-epileptic pregnant women does not seem to be associated with an increased risk of congenital abnormalities. Drug withdrawal Seizures have been reported after withdrawal of phenobarbital, despite very slow tapering [239A]. • A 51-year-old woman, who had been seizurefree for 3 years after the removal of a cavernous angioma in her right anterolateral temporal lobe, and who had taken phenobarbital 150 mg/day for 11 years, started reducing the dose and replacing it with lamotrigine. When the dose of phenobarbital reached 60 mg/day (blood concentration 7 mg/ml) with lamotrigine 25 mg bd, complex partial seizures occurred.

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Her dose of phenobarbital was increased to 90 mg/day and she again became seizure-free. Lamotrigine had to be withdrawn because of a rash. Levetiracetam was started and at a dose of 500 mg bd the dose of phenobarbital was tapered again at a slower rate. However, she had complex partial seizures again when she was taking phenobarbital 30 mg/day and levetiracetam 750 mg bd. The dose of levetiracetam was increased to 1000 mg bd, but complex partial seizures continued while the dose of phenobarbital was being tapered and for 3 weeks after withdrawal. No further seizures occurred during the next 24 months.

The authors suggested that molecular changes in the GABA system probably accounted for many of the effects of phenobarbital withdrawal. Drug overdose A man who was dependent on phenobarbital committed suicide by taking twenty 60-mg tablets [240A].

Phenytoin and fosphenytoin

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Cardiovascular Life-threatening junctional bradycardia occurred in a patient with a high serum phenytoin concentration (91 mg/l, 23 mmol/l). The authors suggested that in this case severe cardiotoxicity had been caused by the high concentration of phenytoin and the presence of predisposing factors that enhanced drug toxicity [242A]. Fulminant myopericarditis occurred in a patient with drug-induced lupus from chronic use of phenytoin [243A]. Respiratory Pneumonitis has been attributed to phenytoin [244A]. • A 48-year-old woman who had taken phenytoin for 30 years developed a dry cough and a low-grade fever and was given various antibiotics for 1.5 years, without effect. A chest X-ray and a CT scan showed diffuse reticular ground glass opacities in both lung fields. A drug lymphocyte stimulation test for phenytoin was positive. A lung biopsy showed predominant lymphocytic infiltration of the lung parenchyma, compatible with drug-induced pneumonitis. Phenytoin was withdrawn and oral prednisolone was given. The symptoms and X-ray improved.

[SED-15, 2813; SEDA-30, 85; SEDA-31, 120; SEDA-32, 145]

Neuromuscular function Phenytoin toxicity masquerading as motor neuron disease has been described [245A].

Comparative studies Phenytoin and levetiracetam Phenytoin has been compared retrospectively with levetiracetam for prophylaxis of early and late postoperative seizures in 315 patients [182c]. Adverse effects prompting a change in antiepileptic drug therapy in only one patient taking levetiracetam, who had visual hallucinations, but in 38 (18%) of those who took phenytoin. In patients who were followed for at least 1 year and developed epilepsy, levetiracetam had also a higher retention rate.

• A middle-aged lady who was taking phenytoin 600 mg/day, sodium valproate 1000 mg/day, and clonazepam 1 mg/day developed progressive difficulty in walking, dysarthria, dysphagia, and weight loss. She had diplopia and motor weakness greater on the right, with hyper-reflexia and fasciculation. Electromyography and nerve conduction studies showed chronic denervation with signs of re-innervation. She was hypoalbuminemic and had a high serum phenytoin concentration (237 mmol/l). Phenytoin was withdrawn and when the concentration fell, her motor power, respiratory function, and bulbar weakness became normal.

Phenytoin and valproate Phenytoin (n ¼ 25) by infusion and intravenous valproate (n ¼ 49) have been compared in status epilepticus or acute repetitive seizures in 74 patients [241c]. There were no adverse effects with valproate but three patients who received phenytoin had adverse effects (cardiac dysrhythmias, vertigo, and hyponatremia).

Endocrine A 48-year-old woman with epilepsy and hypothyroidism had an episode of phenytoin intoxication and was found to be profoundly hypothyroid, despite adequate thyroid replacement therapy; normalization of the phenytoin concentration was associated with reversion to euthyroidism [246A].

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Metabolism Of 30 patients with epilepsy who were taking long-term phenytoin, 10 had osteoporosis and 17 had osteopenia, affecting predominantly the femur, without any significant reduction in bone mineral density in the lumbar spine [247cE]. There were small changes calcium and phosphate metabolism with trends towards hypocalcemia and secondary hyperparathyroidism, which were not due to vitamin D deficiency, as the serum vitamin concentrations were normal. Hematologic Agranulocytosis has been observed as an unexpected progression from a phenytoin-associated antiepileptic drug hypersensitivity syndrome [248A]. • A 5-year-old boy with a drug-resistant form of epilepsy received intravenous phenytoin because of very frequent focal and generalized seizures. His seizure frequency improved. Phenytoin was continued orally, and 12 days later he suddenly developed a high fever, a diffuse erythematous maculopapular rash involving the face and trunk, bilateral cervical lymphadenopathy, and increased serum transaminase activities, consistent with drug hypersensitivity syndrome. Phenytoin was immediately withdrawn and high-dose intravenous methylprednisolone pulse therapy was introduced. The fever abated within 2 days, the skin rash gradually resolved, and the transaminases normalized. However, on the 8th day after defervescence, the high fever reappeared without any other symptoms or localized signs. On the same day, he had neutrophil were barely detected in a peripheral blood film. He was given granulocyte colonystimulating factor, cefepime, and intravenous immunoglobulin and recovered completely within 1 week.

Urinary tract Fibrillary glomerulonephritis, a rare form of glomerulopathy with immunoglobulin deposition, has been associated with phenytoin in a patient with epilepsy [249A]. Granulomatous interstitial nephritis has been reported in a 25-year-old man who had been taking phenytoin 300 mg/day [250A]. Urolithiasis due to phenytoin has been reported [251A].

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• A 79-year-old woman, who had been taking phenytoin for 10 years, developed a fever and seizures and was found to have a right pelvic kidney with hydronephrosis and multiple large calcifications. Urinary stones were removed by percutaneous nephrolithotomy and contained the phenytoin metabolite 5-(para-hydroxyphenyl)-5-phenylhydantoin (35%) and proteinaceous material (65%).

This was a between-the-eyes adverse reaction of type 1a [252H]. In this patient, the average total serum phenytoin concentration in the previous year was in the usual target range. The authors concluded that a metabolite of phenytoin can cause urolithiasis. Skin A woman developed localized skin necrosis after intravenous administration of phenytoin for generalized convulsive status epilepticus. The authors consequently made some recommendations for the intravenous administration of phenytoin: a dedicated intravenous cannula should be inserted in a large peripheral vein; the rate of administration should not exceed 50 mg/minute; the cannula should be periodically flushed with saline after each bolus; continuous monitoring for signs of extravasation, hypotension, and bradycardia should be performed [253A]. Phenytoin has been implicated in two cases of drug rash with eosinophilia and systemic symptoms (DRESS) in children [254A]. Susceptibility factors Genetic Phenytoin is metabolized principally by CYP2C9 and less so by CYP2C19. There is conflicting evidence about the potential role of P glycoprotein (coded by the adenosine triphosphatebinding cassette subfamily B member 1; ABCB1) in transporting phenytoin out of the central nervous system. The association between common genetic variants in the exons of the genes for cytochrome CYP2C9, CYP2C19, and ABCB1 and the risk of acute nervous system toxicity has been retrospectively explored in 14 patients with epilepsy receiving phenytoin, who had acute phenytoin intoxication [255c]. The adjusted OR for the CYP2C9*1/*3 genotype was 8.91 (95% CI ¼ 0.79, 100). The adjusted OR for the CYP2C9*2/*2 genotype was 9.48

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(95% CI ¼ 0.79, 115). The adjusted OR for the CYP2C19*1/*3 genotype was 4.21 (95% CI ¼ 0.58, 31). All of the other odds ratios were close to unity. However, these data were not statistically significant, and it is not clear whether these putative genetic associations are important in determining the adverse effects of phenytoin. The possible association between HLAB*1502 and carbamazepine- or phenytoininduced Stevens–Johnson syndrome or maculopapular eruptions has been explored in 31 Thai subjects who had these antiepileptic drug-induced complications between 1994 and 2007 and in 50 subjects who had no such reactions [92c]. There was a strong association between HLA-B*1502 and phenytoin- and carbamazepine-induced Stevens–Johnson syndrome. However, some patients with the allelic variant HLA-B*1502 had Stevens– Johnson syndrome while taking carbamazepine but not while taking phenytoin and vice versa, which suggests that other factors contribute to this adverse reaction. A 53-year-old Asian woman took phenytoin for 4 days and became lethargic, with a high unbound concentration 4.4 mg/l. She was a CYP2C9 poor metabolizer [256A]. Gastrointestinal disease A patient with epilepsy taking phenytoin had intestinal obstruction and developed status epilepticus as a result of phenytoin intoxication, which was caused by altered absorption due to paralytic ileus [257A]. • A19-year-old woman with cerebral palsy and epilepsy had her convulsions well controlled by phenytoin, phenobarbital, and nitrazepam. She developed a diagnosis of paralytic ileus related to acute gastroenteritis, and was given intravenous infusions in lieu of eating and drinking. The antiepileptic drugs were given orally as before. After 7 days she developed status epilepticus. Diazepam failed to control the convulsions, and she was intubated and pentobarbital was given; the convulsions stopped. The serum phenytoin concentration 3 days later was 69 mg/l (17 mmol/l).

Prolonged stasis of phenytoin in the obstructed intestinal tract was believed to have delayed drug absorption and finally increased the serum concentration,

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causing phenytoin intoxication and status epilepticus. Drug–drug interactions Clozapine Phenytoin intoxication occurred after the intravenous administration of a loading dose of phenytoin in a patient with clozapinerelated seizures; phenytoin intoxication was supposed to have been due to inhibition of CYP2C9 by clozapine [258A]. TS-1 A patient who took phenytoin and TS-1, a combination formulation of tegafur, gimeracil, and oteracil potassium, for 1 month became lightheaded and had repeated falls associated with a serum phenytoin concentration of 34 mg/l (8.6 mmol/l). The authors suggested that the time between the start of combined treatment and the onset of the adverse symptoms suggested an indirect mechanism, rather than direct inhibition of phenytoin-metabolizing enzymes by TS-1 [259A]. Management of adverse drug reactions Several methods have been proposed to enhance the elimination of phenytoin after overdose, and the effectiveness of hemoperfusion is debated. A woman with severe iatrogenic phenytoin overdosage, with a peak plasma concentration of 117 mg/l (29 mmol/l) benefited substantially from three sessions of a 4-hour long combination of activated charcoal hemoperfusion and high-flux hemodialysis; these procedures considerably shortened the half-life of phenytoin from 40–100 hours to 7–13 hours [260A].

Pregabalin

[SEDA-30, 86; SEDA-32, 146]

Observational studies In 15 patients with familial dysautonomia, pregabalin up to a dose of 6 mg/kg/day gave good results in the treatment of nausea and dysautonomic crises [261c]. Adverse effects included peripheral edema in one patient who

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stopped taking pregabalin, weight gain in four, and worsened balance in seven. In a prospective open pilot study, 16 patients with multiple sclerosis and painful paroxysmal symptoms were treated with pregabalin 75–300 mg/day for at least 3 months [262c]. Three dropped out of the study because of adverse effects: one with dizziness, two with difficulty in concentration and general malaise. In an open study, 30 children, who had been treated for solid tumors and leukemia and had developed a painful peripheral neuropathy, were given pregabalin 150– 300 mg/day for 8 weeks [263c]. There was significant long-lasting pain relief in 25 them. There were mild or moderate adverse effects (nausea and drowsiness in the titration phase) in four patients; drug withdrawal was not required. Long-term persistence with pregabalin treatment has been retrospectively evaluated in 402 patients with epilepsy, of whom 15 stopped taking it within 1 week (all reported either adverse effects or worsening of seizures) [264C]. At last follow-up, 168 patients (42%) continued to take pregabalin. Adverse effects were reported by 220 patients, of whom 162 withdrew. The most frequent adverse effects were nervous system-related, including lethargy, tiredness, headaches, blurred vision, double vision, unsteadiness, and ataxia, which were reported by 141 patients. Weight gain was reported by 48 patients (30 withdrew). Psychiatric adverse effects were observed in 26 patients (12 reported depression, low mood, or mood swings, and 24 withdrew). Woman were more likely to report adverse effects than men, but not more likely to report weight gain. Comparative studies Pregabalin and 5% lidocaine in a medicated plaster have been compared in a randomized, open, multicenter, non-inferiority study in 96 patients with post-herpetic neuralgia and 204 with painful diabetic polyneuropathy [265C]. Overall, 66% of those who used the lidocaine plaster and 62% of those who used pregabalin were considered to have responded. There

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were fewer adverse effects from lidocaine than pregabalin (5.8% versus 41%). In an open study 409 patients with neuropathic pain were given pregabalin þ controlled-release oxycodone (n ¼ 169) or monotherapy with either oxycodone (n ¼ 106) or pregabalin (n ¼ 134) [266C]. The combination of controlled-release oxycodone þ pregabalin and controlled-release oxycodone monotherapy were both more effective in alleviating neuropathic pain than pregabalin monotherapy. Combination therapy had a better safety profile than monotherapy with either drug, with a dropout rate due to adverse events of 5.9% compared with 10% and 19% respectively. The most frequently reported adverse events with pregabalin were somnolence and peripheral edema. Combination therapy was most often associated with constipation. Overall, the combination of controlled-release oxycodone and pregabalin resulted in an improved adverse events profile compared with pregabalin monotherapy. Pregabalin and celecoxib, alone and in combination, have been evaluated in the treatment of chronic low-back pain in 36 patients in a 12-week, randomized, crossover study [267c]. The combination was more effective than either monotherapy. Adverse effects were recorded in 16 patients and four patients withdrew as a result. Five patients reported nausea or dizziness during treatment with pregabalin and seven had similar symptoms during treatment with celecoxib þ pregabalin. Placebo-controlled studies Pregabalin has been compared with amitriptyline in alleviating pain associated with diabetic peripheral neuropathy in a randomized, doubleblind, crossover, active-control, 5-week maintenance trial with variable dose titration in 51 [268c] subjects, who were randomized to pregabalin (starting at 75 mg/ day and increasing to 150 and 300 mg bd after 1 and 2 weeks) or amitriptyline (starting at 10 mg/day and increasing to 25 and 50 mg at night-time). There was no significant difference between the treatments. There were 34 treatment-emergent adverse

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events with amitriptyline and 18 with pregabalin. Amongst pregabalin users, three patients developed daytime somnolence, three developed dizziness, three had constipation, two developed peripheral edema, and one developed flu-like symptoms. Six patients withdrew as a result of adverse events (three with somnolence, two with peripheral edema, and one with constipation). Of 20 patients with essential tremor who were randomized to pregabalin 150–600 mg/day or placebo in a double-blind, crossover study four withdrew during pregabalin treatment because of postural instability, nausea, and dizziness (two cases) [269c]. Other adverse effects were mild to moderate in intensity. More common during pregabalin versus placebo were drowsiness (pregabalin 5 versus placebo 3), dizziness (4 versus 1), and fatigue (3 versus 0). Systematic reviews A systematic review and meta-analysis of randomized, doubleblind studies of the analgesic effect of pregabalin in acute and chronic neuropathic pain conditions showed no clear evidence of beneficial effects in acute postoperative pain [270M]. Pregabalin 300, 450, and 600 mg/day was effective in patients with postherpetic neuralgia, painful diabetic neuropathy, central neuropathic pain, and fibromyalgia. The number of patients with a serious adverse event during pregabalin treatment was the same as in those who took placebo. Treatment was withdrawn because of adverse events in 18–28% of subjects. Daytime somnolence typically occurred in 15– 25% and dizziness occurred in 27–46% at a pregabalin dose of 600 mg/day.

159 confused and drowsy, had visual hallucinations, and developed large-amplitude myoclonic jerks that prevented ambulation. Noises provoked startle responses. Pregabalin was withdrawn, and 90 hours later (16 dialysates), the myoclonus and other symptoms had resolved.

This patient previously had similar reversible confusion and myoclonus while taking gabapentin 300 mg tds. Parkinsonism has been associated with pregabalin [272A]. • A 64-year-old woman with a diabetic sensorimotor polyneuropathy for which she was taking gabapentin 300 mg/day þ amitriptyline 25 mg/day was given pregabalin 75 mg bd in addition to her usual medications, and 3 months later developed a resting chin tremor that resolved with speech, impaired writing with micrographia, general slowness, and difficulty in executing certain activities of daily living. The diagnosis was parkinsonism, with axial symptoms, bilateral symmetrical postural tremor, bradykinesia, and rigidity. Pregabalin was withdrawn and 6 months later she had almost completely recovered.

Two patients with multiple sclerosis, who were taking pregabalin for pain, developed acute delirium and delusions [273A]. • A 65-year-old woman with multiple sclerosis, spastic paraparesis, and chronic pain, who had previously taken gabapentin, lamotrigine, and amitriptyline, with partial pain relief, was given pregabalin 75 mg/day; after 3 days she developed slurred speech, delusions, and insomnia. Pregabalin was withdrawn, and she recovered her normal cognitive function.

Demyelinating lesions throughout the CNS may have facilitated this unusual effect of pregabalin.

Nervous system Pregabalin-associated myoclonus and confusion has been described in a patient with chronic renal insufficiency [271A].

Electrolyte balance Severe clinical confusion secondary to hyponatremia has been associated with pregabalin and attributed to pregabalin-induced sodium wasting nephropathy [274A].

• A 47-year-old man with chronic renal insufficiency (baseline urea and creatinine concentrations of 22 mmol/l and 359 mmol/l respectively) secondary to insulin-dependent diabetes mellitus and self-administered peritoneal dialysis started to take pregabalin 75 mg bd for distal neuropathic pain and 2 days later became

• A 74-year-old man with type II diabetes mellitus and an ischemic cardiomyopathy with congestive heart failure had a below-knee amputation because of chronic osteomyelitis and was given pregabalin for neuropathic pain. After several weeks he became weak and confused. There were no signs of

160 peripheral edema or pulmonary congestion. The serum sodium was 110 mmol/l, potassium 4.40 mmol/l, and osmolarity 232 mOsm/kg. Pregabalin was withdrawn, followed by fluid restriction and isotonic saline. The sodium concentration rose to 125 mmol/l and the confusion resolved. On day 4 the sodium concentration had risen to 130 mmol/l.

Urinary tract Pregabalin toxicity in a hemodialysis patient has been successfully treated with hemodialysis [275A].

Rufinamide Rufinamide is a novel anticonvulsant that prolongs the inactivated state of voltagegated sodium channels. It was approved for use in Europe in January 2007 and by the Food and Drug Administration in the USA in January 2009 as add-on therapy for seizures in patients aged 4 years and older with Lennox–Gastaut syndrome. Somnolence and vomiting are common adverse effects, as are headache, dizziness, fatigue, nausea, diplopia, and tremor. Electrocardiography shows that rufinamide shortens the QT interval, which seems to be free of risk, but it should be avoided in patients with familial short QT syndrome, and caution must be exercised when using it with other medications that can shorten the QT interval [276S]. Observational studies Non-blinded studies have suggested beneficial effects in patient with myoclonic and absence seizures [277c]. Rufinamide has been studied in 409 children with epilepsy in the double-blind placebo-controlled studies and in 391 patients receiving rufinamide in double-blind and/ or open extensions. Somnolence, vomiting, and headache were the most common adverse events. There was no change in hematology or body weight [278C]. In a retrospective analysis of all data from patients taking rufinamide in Germany and Austria, 45 children and 15 adults were identified with various severe and inadequately controlled epilepsy syndromes. The response rate (at least a 50%

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seizure reduction) was 47% (28 of 60 patients); 35 (58%) had at least one adverse event during rufinamide treatment. The most common adverse events were fatigue in 11 patients, vomiting in eight, loss of appetite in six, and behavioral disturbances in five. Tremor, sleep disturbances, exhaustion, unstable gait, and dizziness were reported in three patients, and headache, depression, and increased appetite in two. Four patients withdrew because of adverse events, depression, fatigue, and vomiting. Placebo-controlled studies The efficacy of rufinamide in Lennox–Gastaut syndrome has been demonstrated in a randomized double-blind clinical trial in 138 patients with highly refractory epilepsy [279C]. Rufinamide 3200 mg/day as adjunctive therapy was also more effective than placebo in a multicenter trial of refractory partial seizures [280C].

Stiripentol

[SED-15, 3182]

Stiripentol inhibits GABA reuptake and produces barbiturate-like positive allosteric modulation of GABAA receptors [281E]. It has non-linear pharmacokinetics, with a marked reduction in clearance with increased dosages [282c, 283c]. Stiripentol is highly (>99%) protein bound, which probably limits its clearance by dialysis. Stiripentol was given marketing authorization in the European Union on 4 January 2007 for use in conjunction with clobazam and valproate as adjunctive therapy of refractory generalized tonic–clonic seizures in patients with severe myoclonic epilepsy in infancy (Dravet's syndrome) whose seizures are not adequately controlled with clobazam and valproate [284R]. Observational studies In an open study in 25 young patients with severe myoclonic epilepsy (Dravet's syndrome) who were already taking at least one conventional antiepileptic drug and who had more than four tonic–clonic seizures per month, 14

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had a more than 50% reduction in seizures [285c]. During titration, the most common adverse effects were loss of appetite (n ¼ 8), sleep disturbance (2), hyperactivity or irritability (6), and ataxia (5). These effects required dosage modification of stiripentol or other antiepileptic drugs. One patient stopped taking stiripentol in the later phase of the study because of loss of appetite. Drug–drug interactions Care must be taken in using stiripentol as add-on therapy with carbamazepine, clobazam, phenobarbital, phenytoin, and valproate, because stiripentol inhibits the metabolism of these drugs and/or their metabolites [286c].

Tiagabine

[SED-15, 3419; SEDA-30, 89; SEDA-31, 123; SEDA-32, 148] The efficacy and tolerability of tiagabine have been reviewed [287R].

Observational studies Almost 2000 patients have been recruited in an open prospective study in which tiagabine was added to a previous unsatisfactory antiepileptic treatment in patients with partial seizures [288c]. At the second month of treatment, adverse effects were reported by 13% of patients and after 4 months by 8.6%. The most frequent were somnolence/fatigue, headache/nausea, and anxiety/ mood disorders. No serious adverse events were reported. Patients who withdrew because of adverse effects in three trials of tiagabine for the treatment of generalized anxiety disorder have been briefly described [289r]. Patients taking tiagabine were significantly more likely than placebo-treated patients to discontinue the experimental dug during flexible-dose trials. In one fixed-dose trial, there was a trend for a higher adverse event dropout rate among those who took 8 or 12 mg/day relative to placebo; in those who took 4 mg/day, there was no such trend.

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Drug–drug interactions Gemfibrozil An interaction between gemfibrozil and tiagabine has been described [290A]. • A 39-year-old man who was taking oral tiagabine 16 mg tds and oral carbamazepine 500 mg bd for complex partial seizures secondary to mesial temporal sclerosis and had type IV hypertriglyceridemia was given gemfibrozil, soon after a single 600 mg dose of which he reported severe confusion and altered consciousness. A further single dose of gemfibrozil 300 mg resulted in lightheadedness and led to 59% and 75% increases in total serum tiagabine concentrations at 2 and 5 hours respectively, without significant changes in carbamazepine concentrations.

Monitoring therapy The evidence for tiagabine drug concentration monitoring has been reviewed. There are large intra- and inter-individual variations in serum concentrations and hepatic insufficiency requires dosage adaptation. In patients taking therapeutic doses, target serum concentrations are 20–100 mg/l (50–250 nmol/l) and the importance of this for drug monitoring has yet to be assessed [291R].

Topiramate [SED-15, 3447; SEDA-30, 89; SEDA-31, 124; SEDA-32, 148] Observational studies Topiramate has been retrospectively evaluated in 227 patients with symptomatic epilepsy, of whom 12 withdrew because of adverse effects [292c]. The incidence of adverse effects was 36% and the most common were weight loss, memory impairment, paresthesia, headache, and dizziness; most were mild to moderate in intensity and transient. In a multicenter, open, single-arm, noninterventional study in 147 patients aged 12 years and over with epilepsy, in whom valproate was poorly tolerated or was not effective, topiramate was added at a starting dose of 25 mg/day and titrated up at 25 mg/day increments every 1–2 weeks to a final maintenance dose of 50–200

162

mg/day. Average duration of follow-up was 20 weeks and the overall discontinuation rate was 16%, mainly because of adverse effects (in 8.2% of 147 patients). The most frequent adverse effects were weight loss (4.8%), paresthesia and fatigue (4.1% each), and speech disorders and headaches (2.7% each). Topiramate monotherapy has been studied in a 24-week, multicenter, open trial in 244 patients with epilepsy [293c]. The mean stabilized daily dose of topiramate over the last 28 days of treatment was significantly lower in patients who reported 1–3 seizures (n ¼ 147) than in those who reported more than three seizures (n ¼ 66) during a 3-month retrospective baseline period (191 versus 239 mg/day). The incidences of drug-related treatment-emergent adverse effects were similar in the two groups, but there was a lower frequency of serious adverse effects in in the low-seizure-frequency group (12/259, 4.6%) than in those in the high-seizure-frequency group (8/131, 6.1%). In addition, more patients in the high-seizure-frequency group withdrew because of adverse effects and the incidence of cognitive effects was higher (26% versus 24%). The other most common adverse effects were paresthesia (25%), fatigue (12%), anorexia (11%), dizziness (11%), somnolence (10%), headache (9.7%), and hypesthesia (9.7%). In a prospective open study in 21 intellectually disabled patients who were given topiramate for epilepsy there were 57 treatment-emergent adverse events, 23 of which (40%) were at least possibly related to treatment; during topiramate therapy, there were two sudden, unexpected deaths [294c]. Comparative studies In a 26-week, multicenter, randomized, double-blind, doubledummy, parallel-group non-inferiority comparison of topiramate and amitriptyline in the prophylaxis of episodic migraine in 331 subjects (172 topiramate, 159 amitriptyline) there were no significant differences between the groups in any of the outcome measures [295C]. There were treatment-

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emergent adverse effects in 152 (86%) of the 177 who took topiramate and 150 (89%) of the 169 who took amitriptyline. The most common effects of topiramate were paresthesia (30%), fatigue (17%), somnolence (12%), hypesthesia (11%), and nausea (10%) and the most frequent adverse effects leading to study withdrawal were fatigue (3.4%), dizziness (1.7%), hypesthesia (1. 7%), anxiety (1.7%), and confusion (1.7%). In a single-center, 8-week titration and 4-week maintenance period, double-blind, randomized study of topiramate or amitriptyline, alone or in combination, in 73 patients with migraine with or without aura all the treatments resulted in significant improvements in all efficacy measures [296c]. Discontinuation rates due to adverse events were 8.3%, 14%, and 4.3% with topiramate, amitriptyline, and the combination respectively. The most common adverse effects in the topiramate group were paresthesia (35% at 8 weeks and 40% at 12 weeks), weight loss (25% and 35% respectively), and memory impairment (10% and 15%, respectively). Two dosages of topiramate have been compared in 38 elderly patients (aged over 60 years) with non-controlled partial-onset seizures in a pilot, 24-week, double-blind, randomized, parallel-group study [297c]. They were randomized to topiramate 50 or 200 mg/day, either as monotherapy or added to previous monotherapy. The overall incidence of adverse events was similar for the two dosages (66% with 50 mg/day and 62% with 200 mg/day). The most common adverse events were somnolence (13% with 50 mg/day and 8% with 200 mg/day), dizziness (13% versus 8%), and headache (13% versus 5%). There were adverse cognitive effects in six patients taking 50 mg/day and in four taking 200 mg/day. A total of 14 patients (seven in each group) stopped taking topiramate because of adverse events. In 62 patients who were randomized to low-dose topiramate or propranolol for migraine prophylaxis in a randomized, 8-week, double-blind trial both drugs significantly reduced the frequency, intensity,

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and duration of attacks [298c]. The most common adverse effects of topiramate were paresthesia (n ¼ 7), weight loss (5), somnolence (4), and dizziness (3); all were of mild to moderate intensity. In a double-blind, randomized, placebocontrolled study, in which 103 adolescents with at least a 6-month history of migraine were assigned to daily topiramate (50 or 100 mg/day) or placebo for 16 weeks [299c]. 29 of the 35 who took topiramate 50 mg/ day, 30 of the 35 who took topiramate 100 mg/day, and 26 of the 33 who took placebo completed double-blind treatment. Topiramate 100 mg/day, but not 50 mg/day, resulted in a statistically significant reduction in the monthly migraine attack rate. Six subjects had treatment-emergent adverse events that led to withdrawal from the study. Of those who took topiramate 50 mg/day, three withdrew because of fatigue (n ¼ 1), nervousness (1), and headache/emotional lability/ depression (1). Of those who took topiramate 100 mg/day, two withdrew because of treatment-emergent fatigue (n ¼ 1), renal calculus (1) or epistaxis (1). There was doserelated weight loss of at least 10% from baseline in 22% of the placebo group, 28% in the 50 mg/day topiramate group, and 48% in the 100 mg/day topiramate group. Systematic reviews A meta-analysis of the efficacy and safety of topiramate when used as add-on treatment in drug-resistant partial epilepsy has been updated [300M]. Ten trials that included 1312 randomized participants were analysed. The risk ratios of the commonest adverse effects were: ataxia 1.95 (99% CI ¼ 1.04, 3.65); dizziness 1.55 (99% CI ¼ 1.08, 2.22); fatigue 2.19 (99% CI ¼ 1.43, 3.35); nausea 2.35 (99% CI ¼ 1.28, 4.29); somnolence 2.18 (99% CI ¼ 1.47, 3.21) and “thinking abnormally” 5.77 (99% CI ¼ 2.50, 13.35). The risk ratio for withdrawal for any reason was 2.26 (95% CI ¼ 1.55, 3.31). A comparison of adverse drug reactions to topiramate in different diseases has been systematically reviewed [301M]. All published randomized controlled trials that compared topiramate monotherapy with other drugs in epilepsy and migraine were analysed. Four

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randomized clinical trials in patients with epilepsy (n ¼ 1179 treated with topiramate) and six randomized trials in patients with migraine (n ¼ 1723 treated with topiramate) were included. The risk ratios for paresthesia in migraine versus epilepsy trials were 2.5 (99% CI ¼ 1.66, 3.77) for 50 mg/day, 2.7 (99% CI ¼ 1.80, 3.97) for 100 mg/day, and 3.0 (99% CI ¼ 1.95, 4.56) for 200 mg/day. For dropouts related to adverse effects in migraine versus epilepsy trials, the risk ratio was 2.5 (95% CI ¼ 2.03, 2.98) for 50 mg but there were no differences for the other doses. Behavioral adverse drug reactions and headache were found only in the case of epilepsy, whereas cognitive complaints and altered taste were found only in the case of migraine. The authors concluded that at equal doses of topiramate, migraineurs have a different pattern of adverse effects than patients with epilepsy and are more likely to drop out because of adverse effects. All the available evidence for the use of topiramate as monotherapy in patients with newly or recently diagnosed epilepsy has been examined in a systematic review of three randomized, double-blind, controlled trials which recruited more than 1000 patients [302M]. The most common adverse events associated with topiramate 50–500 mg/day generally occurred early in the course of treatment and were nervous system-related effects: headache (15–25%), dizziness (12–19%), fatigue (11–23%), somnolence (10–17%), anorexia (8–10%), insomnia (7–10%), and hyperesthesia (5– 10%). Adverse events that were likely to have been related to the carbonic-anhydrase activity of topiramate (e.g. paresthesia, changes in serum bicarbonate) were frequent (13–35%) but were not usually considered clinically relevant. Renal calculi occurred infrequently (1%). The most frequent adverse events during maintenance therapy were headache (20%), reduced appetite (11%), and weight loss (11%). Nervous system A woman with familial hemiplegic migraine experienced worsening of her symptoms after repeated doses of topiramate [303A].

164 • A 33-year-old woman with familial hemiplegic migraine was given topiramate 25 mg/day for monthly attacks of migraine. She had never had status migrainosus. After a week she developed dysphasia, disorientation, and prolonged severe right-sided weakness complicating a migraine attack and lasting about 4 days. She had right-sided weakness involving the arm and leg and cortical sensory loss. All blood tests were normal and a brain MRI scan was unremarkable. Topiramate was withdrawn and her symptoms resolved within 48 hours. Six months later she took topiramate again and after 5 days had a new severe attack. Topiramate was immediately tapered off, with prompt resolution of the symptoms.

A 42-year-old woman developed tremor and myoclonus after topiramate 50 mg/day was added to fluvoxamine 300 mg/day as an antimigraine agent [304A]. Two cases of restless legs syndrome have been attributed to topiramate [305A]. Sensory systems There have been several cases of angle-closure glaucoma and/or acute myopia associated with topiramate [306A, 307A, 308A]. One patient who developed impaired vision while taking topiramate for symptomatic epilepsy had signs of a maculopathy [309A]. The topiramate was withdrawn, but vision failed to improve significantly over 6 months of follow-up. The authors speculated that topiramate, like vigabatrin, may cause persistent visual impairment through direct retinal toxicity. A 3-year-old boy with idiopathic generalized epilepsy lost his ability to detect and recognize taste and smell during treatment with topiramate, and improved after drug withdrawal [310A]. Psychological The cognitive effects of topiramate have been explored in two small studies. In an open, prospective study of 35 patients with migraine aged over 18 years topiramate was started at 25 mg/day and increased by 25 mg/day each week, until the maximum dose of 50 mg bd was reached in the fourth week [311c]. Only 22 patients completed the 3-month study. Although 41% complained of cognitive

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effects, neuropsychological evaluation, which was performed using the Wechsler memory scale, showed significant changes only in the visual memory section. There was a non-significant increase in the latency of P300, especially in the frontal and central areas, while P300 amplitude did not change significantly. The cognitive effects of levetiracetam and topiramate have also been evaluated in a blinded but non-randomized study in 79 patients with intractable epilepsy [312c]. Assessments were done at baseline and after 1 year of treatment using the Cognitive Abilities Screening Instrument. There were no relevant differences between the two drugs. Psychiatric A patient with migraine developed reversible, dose-related, auditory hallucinations during topiramate therapy [313A]. • A 27-year-old woman took topiramate 25 mg/ day for migraine prophylaxis, and the dose was gradually increased to 100 mg/day, at which point she reported frightening auditory hallucinations. Psychiatric examination was normal. Laboratory findings, electroencephalography, brain-stem auditory-evoked potentials, audiometry, and a cranial MRI scan were normal. The auditory hallucinations disappeared after the dosage of topiramate was gradually reduced to 50 mg/day.

Metabolism Valproate reduces free and total carnitine concentrations in children. In a cross-sectional study in 91 children, the effects of some new antiepileptic drugs (vigabatrin, n ¼ 24; lamotrigine, n ¼ 28; and topiramate) on serum carnitine concentrations have been studied; 18 children taking valproate served as positive controls [314c]. Carnitine concentrations were unaffected by the new drugs. Uric acid, cholesterol, and lipoprotein serum concentrations have been measured in 53 patients with migraine taking topiramate and 44 age- and sex-matched controls. Topiramate significantly increased uric acid concentrations [315c]. Valproic acid-induced hyperammonemic encephalopathy is characterized by confusion and possible exacerbation of an

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underlying psychiatric disorder; it can be difficult to diagnose. In one case co-administration of topiramate with valproate may have triggered this complication. The authors speculated that this synergistic effect of topiramate may relate to its ability to inhibit carbonic anhydrase, with consequent alteration of some enzymes in the urea cycle whose first step uses HCO– in the synthesis of carbamoylphosphate [316A]. Nutrition Vitamin B12 deficiency has been attributed to topiramate [317A]. Acid–base balance In some patients topiramate can cause metabolic acidosis, whose susceptibility factors, underlying mechanisms, and clinical effects have been reviewed [318R]. Topiramate impairs both the normal reabsorption of filtered HCO– by the proximal renal tubule and the excretion of Hþ by the distal renal tubule. This combination of defects is termed mixed renal tubular acidosis. The mechanism involves inhibition of carbonic anhydrase. This mechanism can make patients acutely ill, and chronically can lead to nephrolithiasis, osteoporosis, and in children growth retardation. The usefulness of monitoring HCO– concentrations has not been proven and is not routine. Hence, there is no proven method for predicting or preventing the effect of topiramate on acid–base balance. However, patients with a history of renal calculi or known mixed renal tubular acidosis should not receive topiramate. Another case of topiramate-induced metabolic acidosis has been discussed [319A]. Hematologic A patient who took topiramate 100 mg/day for migraine had epistaxis, without a history of nosebleeds; laboratory parameters were within the reference ranges [320A]. The epistaxis resolved within 12 hours of drug withdrawal. The authors discussed the possible antiplatelet activity of topiramate.

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Urinary tract The susceptibility factors for topiramate-induced renal stones have been studied in six subjects [321c]. After 5 days treatment there was a 31% reduction in mean calcium and a 40% reduction in mean citrate urinary concentrations. Dose escalation was associated with a further reduction in citrate concentration. The authors concluded that topiramate causes a profound reduction in urinary citrate concentrations, equivalent to the changes seen in distal renal tubular acidosis. In a retrospective study of non-ambulatory and neurologically impaired individuals in a long-term care facility, 13 of 24 who were taking topiramate monotherapy or polytherapy developed clinical evidence of urolithiasis after a mean treatment duration of 36 months [322c]. Sweat glands The pathogenesis of hypohidrosis, a rare and reversible adverse effect of topiramate that is often associated with hyperthermia, has been studied in two children [323A]. Sympathetic skin responses were recorded during topiramate treatment and after withdrawal. Electrophysiology showed normal function of both beta and delta sensory fibers and absent sympathetic skin responses, which recovered to normal after topiramate withdrawal. The authors concluded that topiramate may cause transient specific inhibition of carbonic anhydrase in sweat glands, without involvement of peripheral nervous system. Topiramate-associated blue pseudochromhidrosis has been described [324A]. Chromhidrosis is a rare skin disorder, in which the apocrine glands excrete sweat that contains lipofuscin pigments. Pseudochromhidrosis is a term used when the eccrine sweat is colored on the surface of the skin as a result of the deposit of extrinsic dyes or paints. Since some carbonic anhydrase isoenzymes are expressed in the sudoral eccrine glands, the hypothesized mechanism of this adverse effect was inhibition of this enzyme by topiramate. Sexual function Sexual dysfunction in response to new antiepileptic drugs has rarely been described. Reversible erectile

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dysfunction has been described in a man taking topiramate, in which other possible pathogenic mechanisms were excluded [325A]. Body temperature Several post-marketing reports have suggested that topiramate can be associated with hypothermia, which is defined as a fall in body core temperature to less than 35 C. The US Food and Drug Administration's Adverse Events Reporting System database has been searched for reports of hypothermia in association with the use of topiramate [326c]. Attention was focused on the possible association between the concomitant use of topiramate and valproic acid and the induction of hypothermia. There were 22 unduplicated reports of hypothermia in patients exposed to topiramate. More than one antiepileptic drug had been used in most reports; valproic acid was mentioned in seven and topiramate in four, which was seven times more often in the database as a cause of hypothermia than would be statistically expected when considering all other drugs. Hypothermia has also been found in association with concomitant administration of topiramate and valproic acid in patients who tolerated either drug alone. Teratogenicity The UK Epilepsy and Pregnancy Register is a prospective pregnancy register set up to determine the relative safety of all antiepileptic drugs taken in pregnancy. Suitable cases of women with epilepsy who become pregnant while taking topiramate either singly or together with other antiepileptic drugs have been analysed [327c]. Full outcome data were available on 203 pregnancies. Of these, 178 resulted in live births; 16 (9.0%) had a major congenital malformation, four of which were oral clefts and four of which were cases of hypospadias. Three of these complications (4.8%) were observed in 70 monotherapy exposures and 13 (11%) in cases exposed to topiramate as part of a polytherapy regimen. The authors asserted that the rate of oral clefts observed was 11 times the background rate. Although these data should be interpreted with caution, they raise some concerns about the potential teratogenic effects of topiramate.

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Experimental data in support of a teratogenic effect of topiramate have been briefly reviewed [328r]. Topiramate inhibits histone deacetylases and may cause low birth weight and teratogenic effects. Susceptibility factors Genetic Three single nucleotide polymorphisms of the glutamate receptor GluR5 gene (GRIK1) have been studied as possible predictors of topiramate-induced adverse effects in 51 heavy drinkers who completed a 5-week dose escalation schedule to a target dose of either 200 or 300 mg/day or matched placebo [329c]. A SNP in intron 9 of the GRIK1 gene (rs2832407) was associated with the intensity of topiramate-induced adverse effects and with serum concentrations of topiramate. Drug dosage regimens Several studies have shown that high starting doses and/or fast titration influence the tolerability of topiramate. In a retrospective study of fast titration in 423 epileptic patients taking topiramate, 42 developed depression [330c]. Rapid titration was associated with a fivefold increased risk of depression. This risk further increased in the presence of other risk factors (13-fold when rapid titration was associated with febrile seizures, 23-fold when associated with a previous history of depression, and 7.6-fold in the presence of hippocampal sclerosis). In one case serious adverse effects, such as seizures and polymyoclonus, were probably caused by a high initial dose and the fast rate of increase in dosage [331A]. • A 26-month-old girl, who was given topiramate 6 mg/kg/day for 2 weeks developed seizures and myoclonus. Topiramate had been started in a dosage of 1 mg/kg/day and increased to 6 mg/ kg/day by increments at 3-day intervals. The advised topiramate initial dose is 1–3 mg/kg/ day, which is normally increased at 1- or 2-week intervals by increments of 1–3 mg/kg/day. The drug was withdrawn and after 3 days her myoclonus had resolved.

In a prospective, observational study of rapid oral initiation of topiramate in 19 multiply handicapped children with resistant epilepsy who were given a mean initial dose of

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topiramate of 1.1 (range 0.66–2.67) mg/kg/ day following rapid titration, the mean final dose was 3.3 mg/kg/day [332c]. Six patients withdrew because of adverse events (behavioral disturbances in three, fatigue in one, vomiting in one, and hyperkinesias in one). There was at least one adverse event in 17 patients; the most common was fatigue, followed by reduced appetite and unspecified psychiatric disorders. Drug overdose Seven cases of acute topiramate toxicity observed in two clinical units of poison centers have been described [333A]. The doses of topiramate were 11– 218 mg/kg. Somnolence was characteristic and vertigo, agitation, and mydriasis were less common. There was a metabolic acidosis in four cases. One patient who had not previously taken topiramate and who had taken 31 mg/kg had three secondarily generalized tonic–clonic seizures. All recovered without sequelae and were discharged after 4–8 days. Drug–drug interactions Glucocorticoids Topiramate is a weak inducer of CYP3A4, which is involved in steroid metabolism. In one case a modest dose of topiramate accelerated the metabolic clearance of dexamethasone and fludrocortisone and caused hypoadrenalism [334A]. According to the authors, this effect of topiramate can occur in any patient who is taking a fixed-dose of a glucocorticoid. • A 35-year-old woman who was taking dexamethasone and fludrocortisone replacement for congenital adrenal hyperplasia and with biochemical evidence of good control started to take topiramate 100 mg/day for atypical seizures. Within a few weeks she complained of tiredness, nausea, weight loss, and muscle aches. A diagnosis of hypoadrenalism was supported by raised plasma 17-hydroxyprogesterone, adrenocorticotrophin, and plasma renin activity.

Posaconazole Posaconazole inhibits CYP3A4, which can increase topiramate concentrations [335A]. • A 48-year-old man with long-standing epilepsy, stabilized with valproate 700 mg bd and

167 topiramate 100 mg bd, underwent partial pneumonectomy for invasive aspergillosis and was given posaconazole. After 2 weeks he developed progressive stupor, daytime somnolence, anorexia, and weight loss. Topiramate toxicity, secondary to a drug interaction with posaconazole, was suspected. Posaconazole was replaced with intravenous amphotericin, and topiramate was continued. His stupor and appetite gradually improved over 10 days. The topiramate plasma concentration was 27 mmol/l on admission and 12 mmol/l 11 days after withdrawal of posaconazole.

Management of adverse drug reactions Five patients with topiramate associated bilateral acute angle-closure glaucoma unresponsive to ocular hypotensive therapy and drug discontinuation were effectively treated with argon laser peripheral iridoplasty [336A, 337A].

Valproate sodium and semisodium (divalproex)

[SED-15, 3579; SEDA-30, 92; SEDA-31, 126; SEDA32, 153] Observational studies In a phase III, open, multicenter study, 169 children with partial seizures were treated with divalproex sodium sprinkle capsules as monotherapy or add-on treatment [338c]. The most common treatment-emergent adverse events were vomiting (14%), tremor (9%), somnolence (8%), and diarrhea (8%). Patients had similar overall adverse event incidence rates whether they received polytherapy at any time during the study or monotherapy (83% and 80% respectively). However, patients taking polytherapy were more likely to have gastrointestinal disorders (36% versus 21%), diarrhea (11% versus 5%), vomiting (17% versus 10%), and increased weight (4% versus 2%). Nine patients (5.3%) prematurely withdrew because of an adverse event. Ammonia concentrations were increased in 31 patients and there was a mean increase in uric acid concentrations and fall in

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platelets, although these changes were asymptomatic in most cases. Divalproex sodium extended-release has been evaluated in a 12-month, open extension of a 3-month, double-blind, placebocontrolled, multicenter study in 112 adolescents with migraine [339C]. The most common symptomatic adverse events were weight gain (15%), nausea (14%), somnolence (12%), upper respiratory tract infection (11%), and sinusitis (8%). Five subjects had serious adverse events, and 15 prematurely withdrew because of an adverse event. Plasma ammonia concentrations were increased in 8% but there were no other clinically significant changes in laboratory values, vital signs, or electrocardiography. In a 6-month open study of divalproex sodium extended-release (15 mg/kg/day on day 1 with increases allowed to a maximum of 35 mg/kg) in 226 children and adolescents with acute mania associated with bipolar I disorder the most common adverse events were weight gain (16%), nausea (9%), and increased appetite (8%); raised plasma ammonia concentrations were non-symptomatic in all cases [340c]. Comparative studies In an open prospective comparison of valproate and primidone in 136 patients with partial epilepsy unresponsive to carbamazepine significantly more of those who took valproate (51%) achieved a greater than 50% seizure reduction than those who took primidone (34%) [231c]. One patient withdrew from valproate because of dizziness and three because of nausea. Of those who took primidone, three withdrew because of dizziness, three patients because of drowsiness, and one because of gastrointestinal complaints. Adverse effects in other patients were mild and gradually disappeared during treatment. Long-term valproate (starting dose 20 mg/kg/day) and lithium (starting dose 400 mg/day) have been compared in 300 patients with bipolar I disorder presenting with acute mania in a 12-week open study [341c]. Remission rates were 66% for those who took lithium and 72% for those who

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took valproate. The most frequently reported treatment-related adverse events were nausea (14 treated with lithium versus 16 treated with valproate), tremor (25 versus 2), weight gain (6 versus 13), and fatigue (2 versus 9). Tremor was significantly more common with lithium and fatigue with valproate. Treatment was discontinued because of an adverse event in 14 patients who took lithium and in five who took valproate. Placebo-controlled studies Valproic acid is a histone deacetylase inhibitor which has antioxidative and antiapoptotic properties and reduced glutamate toxicity in preclinical studies. It has therefore been evaluated in a double-blind, placebo-controlled study in 163 patients with amyotrophic lateral sclerosis, who were randomized to valproate 1500 mg/day or placebo [342C]. Valproate did not affect survival or the rate of decline of functional status. The most frequent adverse events were diarrhea (n ¼ 16 versus 14 with placebo), nausea (15 versus 12), vomiting (0 versus 3), abdominal pain (14 versus 15), increased appetite (19 versus 17), reduced appetite (17 versus 20), weight gain (20 versus 19), and tremor (39 versus 40). One patient taking valproate withdrew because of severe cognitive impairment. In a 3-week double-blind study patients with mild to moderate mania were randomized to divalproex (n ¼ 201; 500–2500 mg/ day), olanzapine (n ¼ 205; 5–20 mg/day), or placebo (n ¼ 105) [343C]. Those who completed the first part of the study continued with a 9-week double-blind extension. Olanzapine was significantly more efficacious than placebo at 3 weeks and significantly more efficacious than divalproex at 12 weeks. Adverse effects caused withdrawal from the study in 13% (28/215) of those who took olanzapine and 9.5% (19/ 201) of those who took divalproex. Significantly more of those who took olanzapine reported weight increase and somnolence compared with divalproex or placebo. Significantly more of those who took divalproex reported nausea and insomnia compared with olanzapine. Those who took

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olanzapine also had significantly greater increases in concentrations of glucose, cholesterol, triglycerides, uric acid, and prolactin than those who took divalproex. In a 28-day, double-blind, placebo-controlled study, followed by a 6-month open extension study of divalproex extendedrelease in 150 children and adolescents with bipolar disorders, there were no significant differences in efficacy [344C]. Four of those who took divalproex extended-release and three of those who took placebo withdrew because of adverse effects. Mean plasma ammonia concentrations increased with divalproex extended-release, but only one patient was symptomatic. In the 6-month open extension study, the most common adverse events were headache and vomiting. Systematic reviews In an updated systematic review of all randomized, placebo-controlled trials of the use of valproate to control agitation in patients with dementia, valproate did not produce improvement [345M]. There were more adverse events (falls, infection, gastrointestinal disorders) among those who took valproate. Cardiovascular Carotid artery intima media thickness and serum lipids have been measured in 44 children with epilepsy taking valproic acid and 40 healthy children. Although there was no difference in serum lipid profiles, the intima media of the common carotid artery was significantly thicker in those who took valproic acid [346c]. This finding has uncertain significance and may be due to epilepsy and not to the drug. Hyperhomocysteinemia occurred in a 23year-old patient with the 677C/T polymorphism in the MTHFR gene taking valproate who had an ischemic stroke in the left temporo-parieto-occipital region [347A]. Respiratory Eosinophilic pleural effusion (defined as more than 10% eosinophils), which can sometimes be caused by drugs, was suspected to have been due to valproate in two cases [348A, 349A].

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Nervous system Encephalopathy There have been several further reports of valproate-induced hyperammonemic encephalopathy [350A, 351A, 352A, 353A]. In one case it was associated with central pontine myelinolysis and coma in a patient with Sjögren's syndrome who had taken long-term valproic acid for a psychotic disorder [354A]. Encephalopathy has been studied in 63 adults who had taken valproate for a minimum of at least 2 years in a retrospective analysis [355c]. Long duration of valproate treatment did not correlate with the risk of encephalopathy. In seven cases, temporary administration of lactulose alone was effective and valproate was not withdrawn. The authors also concluded that this complication is relatively common. In one patient there was a possible synergistic interaction of valproic acid and topiramate with respect to the emergence of hyperammonemic encephalopathy [316A]. The authors speculated that inhibition of carbonic anhydrase by topiramate might be the basis of this, since HCO– is used in the synthesis of carbamoylphosphate in the urea cycle. In a young child valproate-induced stupor was unusually associated with an electroencephalographic pattern of increased fast activity [356A]. The authors speculated that this effect of valproate was related to an interaction of valproate with GABA metabolism and GABA neuronal networks. Parkinsonism Parkinsonism has been attributed to valproate [357A], in one case associated with cognitive impairment [358A]. One patient with Huntington's disease developed both parkinsonism and Pisa syndrome secondary to valproic acid [359A]. Pisa syndrome is an uncommon type of truncal dystonia manifested by persistent lateral flexion of the trunk. • A 67-year-old man with Huntington's disease (CAG expanded repeat of 41 triplets) and clear symptoms of the disease (hypotonia, dysarthria, generalized chorea, facial grimacing,

170 slow saccadic eye movements, and impaired cognitive functions) was initially given olanzapine 10 mg/day, sertraline 50 mg/day, and clonazepam 1 mg/day, followed by valproic acid 500 mg bd because of progression of the cognitive impairment and psychiatric symptoms. Some days later, he developed worsening of gait impairment and a resting tremor in both arms, mild bilateral rigidity, marked bradykinesia, and anterior and right flexion of the trunk. Valproic acid was withdrawn and 1 week later his trunk posture improved dramatically, the right flexion disappeared, and he was able to walk without aid. His parkinsonian symptoms improved slightly and completely resolved within 2 months.

A 45-year-old man with a 10-year history of post-traumatic stress disorder and alcoholism started stuttering after taking divalproex sodium 600 mg/day for 4 days [360A]. Psychological The effects of lithium and valproate on the risk of being involved in traffic accidents have been studied using three population-based registries [361C]. Exposure consisted of receiving prescriptions for either lithium or valproate. Standardized incidence ratios were calculated by comparing the incidence of motor vehicle accidents during time exposed with the incidence during the time not exposed. During the study period, more than 20 000 road accidents occurred, including 36 during exposure to lithium and 31 during exposure to valproate. The overall risk of an accident was not increased, with the exception of a three-fold increase in risk among younger female drivers taking lithium. Psychiatric Confusion, delirium, and dementia Using the French Pharmacovigilance database, 272 cases (153 women and 119 men) of confusion associated with valproic acid were selected [362c]. This adverse reaction mostly occurred in patients aged 61–80 years and in 40% was observed during the first 2 weeks of valproic acid exposure. It was labeled as serious in almost 63% and its outcome was favorable in 82%. Worsening of cognitive symptoms and delirium has been reported after

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the use of valproate in a patient with dementia [363A]. • A 75-year-old woman with Alzheimer's dementia developed moderate cognitive impairment associated with aggression, agitation, and severe insomnia. She had been taking galantamine, promazine, acetylsalicylic acid, and pantoprazole. Valproate 500 mg/ day for the first week and then twice a day was prescribed. After 16 days she suddenly developed hyperactive delirium characterized by worsening of insomnia and agitation, severe confusion, delusions, and visual hallucinations. She also became ataxic and completely dependent in activities of daily living. Organic and metabolic abnormalities were excluded. Valproate was withdrawn and haloperidol 5 mg and intravenous saline were given. She recovered after 1 week.

Dementia has been attributed to valproic acid after 1 year in an elderly fragile patient who had had a convulsive crisis after an ischemic stroke [364A]. Endocrine In a prospective, randomized study of thyroid function in 160 men and women with epilepsy, both before and after double-blind withdrawal of antiepileptic drug monotherapy, serum samples were obtained from 130 patients [79C]. Following antiepileptic drug withdrawal, there were significant increases in free thyroxine serum concentrations in those who were taking carbamazepine while in women taking valproate serum concentrations of free triiodothyronine (T3) fell significantly compared with the non-withdrawal group. The effect was reversed by withdrawal. However, in another comparison of carbamazepine (n ¼ 18) and valproate (n ¼ 14) on thyroid function in newly diagnosed children with epilepsy, valproate had no effect on serum thyroxine (T4) and free thyroxine (fT4) concentrations [78c]. Metabolism Ammonia Asymptomatic hyperammonemia occurred after an intravenous loading dose of valproate in 30 of 40 participants at 1 hour after infusion of valproate (20 or 30 mg/kg at a rate of 6 or 10 mg/kg/minute) and usually fell over the following 24 hours [365c]. Multivariable

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repeated-measures analysis suggested that age, time since dosing, and co-therapy with enzyme-inducing antiepileptic drugs were significant predictors of changes in ammonia concentrations. Valproate dose, concentrations, infusion rate, and sex made no contribution. Carnitine In 60 children with primary epilepsy free of neurological or nutritional problems who took valproate for at least 1 year, mean total carnitine and free carnitine concentrations were significantly lower compared with pre-treatment and control concentrations, while ammonia, acylcarnitine, and the acylcarnitine/free carnitine ratio were significantly higher [366c]. Total carnitine and free carnitine were negatively associated with ammonia concentration. These results confirm previous findings of an interaction between the metabolism of valproate and carnitine. Weight The effect of valproate on body weight and hormones has been studied in 52 healthy adults who were randomized to valproate or placebo in a double-blind protocol [367C]. Weight increased significantly with valproate but not placebo. Those who took valproate also had increased cravings for fast food and reduced glucose concentrations compared with placebo. Physical activity, hunger, binge eating, depression, and GLP-1 were increased by valproate. The authors concluded that valproate-associated weight gain is probably due to reduced glucose concentrations and an increased motivation to eat. Insulin resistance, components of the metabolic syndrome, and adiponectin concentrations in 60 overweight bipolar patients taking sodium valproate have been compared with those observed in 60 nonpsychiatric overweight control subjects [368c]. There was a high frequency of the metabolic syndrome in the two groups (50% and 32% respectively) and similar frequencies of insulin resistance, abdominal obesity, hypertriglyceridemia, hypertension, and fasting hyperglycemia were found in both groups. High-density lipoprotein cholesterol concentrations were lower,

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while adiponectin was unexpectedly higher in patients taking valproate. Weight gain in children has been specifically investigated in three studies. In a retrospective study weight gain associated with valproic acid (n ¼ 31) or carbamazepine (n ¼ 49) monotherapy was studied in children with epilepsy, aged over 12 years [369c]. With valproic acid there was no gain in body mass index over time, but there was a significant gain with carbamazepine. Of 94 children taking valproate, 23 had a greater than 0.25 SD/year weight gain and 12 had a greater than 0.5 SD/year gain [370c]. There was a negative correlation between duration of treatment and weight gain. The results of these two studies suggest that children are less likely than adults to gain weight when taking valproate. The relationships between valproateinduced obesity in children and concomitant metabolic changes, such as hyperinsulinemia and insulin resistance, hyperleptinemia and leptin resistance, and an increase in the availability of long-chain free fatty acids, have been reviewed [371R]. The authors concluded that, although mechanisms of hyperinsulinemia in valproate-induced weight gain are unclear, it is likely that obesity is the cause of hyperinsulinemia and all related metabolic changes. Hematologic In a prospective study in 24 children with newly diagnosed epilepsy, valproate caused an early reduction in platelet counts and concentrations of factor VII, factor VIII, protein C, and fibrinogen, and increased lipoprotein (a) concentrations [372c]. In a prospective study of 23 children several coagulation disorders were associated with valproate: thrombocytopenia (n ¼ 2), acquired von Willebrand's disease (6), a significant fall in fibrinogen concentrations (12), and a reduction in factor XIII (4) [373c]. Thrombelastography showed altered platelet function in 11 and prothrombin time was significantly prolonged, with many other coagulation defects. Susceptibility factors for thrombophilia have been investigated in 21 children with

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newly diagnosed epilepsy taking valproic acid monotherapy [374c]. After 9–12 months there was a statistically significant increase in lipoprotein(a) concentrations and a reduction in fibrinogen. In 50 children taking valproate there were significant changes in fibrinogen, platelet count, and von Willebrand factor, but no patient developed the laboratory changes that are typical of von Willebrand's syndrome [375c]. Neutropenia occurred in a patient who had taken stable therapy with delayedrelease divalproex sodium for almost 8 years; despite the delay, a causal relation was considered probable [376A]. The incidences of leukopenia and neutropenia have been evaluated retrospectively in 131 children and adolescents taking valproate, quetiapine, or the combination [377c]. The combined incidences of neutropenia and/or leukopenia were 44%, 26%, and 6% with the combination, valproate monotherapy, and quetiapine monotherapy respectively. There were statistically significant differences in the incidences of neutropenia and/or leukopenia between quetiapine and valproate and between quetiapine alone and the combination. Leukopenia and neutropenia induced by valproate and quetiapine co administration are not rare and patients taking a combination of these drugs should be monitored. Liver Reversible non-alcoholic fatty liver disease occurred in a child who developed obesity while taking valproate [378A]. Acute cholestatic hepatitis with hepatic failure occurred in 48-year-old patient with a glioblastoma taking long-term valproate when temozolomide and the integrin inhibitor cilengitide were added [379A]. Valproate was withdrawn and the liver tests normalized. Pancreas Acute pancreatitis has been described in a 7-year-old girl who took valproate 15 mg/kg/day for generalized epilepsy [380A]. Skin A severe psoriasiform eruption has been reported in a 14-year-old boy patient

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taking sodium valproate [381A]. Histology of the skin showed hyperkeratosis, parakeratosis, loss of the granular layer, irregular acanthosis in the epidermis, and a perivascular infiltrate (mononuclear cells in the upper dermis). Valproate was withdrawn and the eruption completely disappeared in 4 months. Onychomadesis, complete separation and subsequent shedding of the nail plate, beginning at the proximal nail fold (unlike onycholysis, which begins distally), has been attributed to valproate [382A]. Onychomadesis of both the thumbnails and two toenails developed after 4 years of treatment and gradually resolved after valproate withdrawal. In a large database study, treatment with valproic acid was significantly associated with erythema multiforme, Stevens–Johnson syndrome, or toxic epidermal necrolysis among patients with bipolar disorder [94C] (see “Carbamazepine” for details). Hair In 32 children, hair and serum zinc concentrations and serum biotinidase activity were measured before valproate and after 3 and 6 months. Mean serum and hair zinc concentrations were reduced at 3 and 6 months, and the mean serum biotinidase activity was lower than the pre-treatment values at 3 months but returned to initial values by 6 months. The authors suggested that hair loss in patients taking valproate can be attributed to zinc and biotinidase depletion, but the differences were not statistically significant and so the conclusion is unwarranted [383c]. Musculoskeletal Myopathy has been associated with valproate in an elderly patient with a schizoaffective disorder [384A]. • An 85-year-old woman with a schizoaffective disorder was given valproate 600 mg/day and after 4 days complained of muscle pain and weakness. Other medications were quetiapine 200 mg/day, nifedipine 10 mg/day, torsemide 10 mg/day, levothyroxine 75 micrograms/day, and acetylsalicylic acid 100 mg/day. There was a fivefold increase in myoglobin concentration (292 mg/l), a sixfold increase in creatine kinase activity (14 mmol/l), and slightly increased liver enzyme activities. The serum

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concentration of valproate was 46 (target range 30–100) mg/l. Valproate and quetiapine were withdrawn and torsemide was replaced by furosemide 10 mg/day. After 15 days the myoglobin concentration and creatine kinase activity returned to normal. Reintroduction of quetiapine caused no deterioration in muscle symptoms and laboratory measures.

Reproductive system Polycystic ovary syndrome, hyperandrogenism, or ovulatory dysfunction in women with epilepsy taking valproate or lamotrigine have been prospectively studied in patients with epilepsy, who were randomized for 12 months to valproate (n ¼ 225) or lamotrigine (n ¼ 222) [154C]. More women taking valproate developed ovulatory dysfunction or polycystic ovary syndrome. Hyperandrogenism was more frequent with valproate than lamotrigine among those who were younger than 26 years at the start of treatment but similar in older women. Tremor, vomiting, nausea, alopecia, and weight gain were more common with valproate. Rashes caused withdrawal from the study in five patients taking lamotrigine and none taking valproate. The proportion of participants who withdrew because of an adverse event was 4% in each group. Polycystic ovarian syndrome and menstrual irregularities were more prevalent in those taking valproate within a population of 71 women with epilepsy who had taken antiepileptic drugs for a minimum of 2 years [385c]. There was no correlation between dose and duration of treatment and the probabilities of such complications. The increased prevalence of polycystic ovary syndrome associated with valproate has been reviewed [386R]. The risk seems to be higher in women with epilepsy than in women with bipolar disorders, and this might be due to underlying neuroendocrine dysfunction related to the seizure disorder. Immunologic Rowell's syndrome is the association of a lupus-like syndrome (systemic, subacute cutaneous, or discoid) together with erythema multiforme (including toxic epidermal necrolysis) and evidence of antinuclear antibodies and other

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immunological markers. Exposure to some medications can cause this syndrome, which has been reported with valproate [387A]. • A 51-year-old woman, who had taken valproate, sertraline, and olanzapine for severe depression over 5 months, developed erythematous erosive skin lesions affecting large areas of skin, associated with a sensation of burning in the skin, arthralgia, general fatigue, and subclinical fever. There were many erythematous lesions on the face, neck, arms, and trunk and elsewhere generalized erythroderma-like skin inflammation, with involvement of the oral mucosa. There were also leukopenia, anemia, and thrombocytopenia, with increased erythrocyte sedimentation rate, serum aminotransferases, and creatine kinase, hypergammaglobulinemia and a positive rheumatoid factor. Echocardiography showed pericarditis. Serum immunofluorescence showed a speckled pattern of antinuclear antibodies. Immunoenzymatic assay showed titers of 1:5000 for SS-A, SS-B, and Ro-52. Direct immunofluorescence of skin samples showed granular deposits of IgG and IgA at the epidermodermal junction. Histopathology showed features consistent with lupus erythematosus. Valproate was withdrawn and prednisolone was started; 2 weeks later the titer of antinuclear antibodies had fallen to 1: 3200. After 4 months of clinical remission, sodium valproate was again introduced and the symptoms recurred.

A lupus-like syndrome occurred in a small boy taking oxcarbazepine and valproic acid [228A] (see “Oxcarbazepine”). Body temperature In an analysis performed using the US Food and Drug Administration's Adverse Events Reporting System database, hypothermia was associated with concomitant administration of topiramate and valproic acid in patients who tolerated either drug alone (see also “Topiramate”) [326c]. Teratogenicity In an analysis of the medical records of 284 valproate-exposed pregnancies in the North American Antiepileptic Drug Pregnancy Registry 30 (11.0%) were associated with malformations [388c]. There were 15/126 (12%) malformations in patients with idiopathic generalized epilepsy, 4/28 (14%) in patients with partial epilepsy, 9/105 (9%) in those

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with non-classifiable epilepsy, and 2/25 (8%) in non-epileptic patients. This confirms that valproate, and not the underlying syndrome, is associated with an increased risk of malformations in drug-exposed fetuses. There was a trend toward an increased risk of malformations at higher doses of valproate. A newborn girl had right fibular aplasia and an absent fifth toe [389A]. Exposure of fetuses to valproate uncommonly results in pulmonary anomalies, as in a newborn boy with unilateral lung agenesis [390A]. A newborn girl who was exposed in utero to antiepileptic drugs, especially valproate, had craniosynostosis, trigonocephaly, right radius aplasia, a hypoplastic thumb, and cardiac and renal malformations; her brother, who was similarly exposed had Baller–Gerold syndrome phenotype, trigonocephaly, polymastia, and hypospadias [391A]. Four cases of fetal valproate syndrome, characterized by major and minor malformations in association with developmental delay, have been reported [392A]. The mothers were screened for the 677C-T mutation but only one was heterozygous for this mutation. Further cases of fetal valproate syndrome with unusual characteristics have been described [393A, 394A]. A review of the evidence has suggested that there is a longer-term risk of impaired cognitive and behavioral development of children who have been exposed in utero to sodium valproate [59R]. The effects of fetal exposure to carbamazepine, lamotrigine, and valproate on cognitive fluency and flexibility have been investigated prospectively in 54 children; fluency and originality were significantly worse after exposure to valproate than after lamotrigine and carbamazepine [395c]. Drug formulations In seven healthy men who took an oral dose of conventional and slow-release formulations of valproate 800 mg on two separate days, blood samples were taken for determination of

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valproate and its monounsaturated (2-en, 3-en, and 4-en) and hydroxylated (3-OH, 4-OH, and 5-OH) metabolites [396c]. After the slow-release formulation there was a reduced Cmax, a prolonged tmax, and a reduced AUC of the metabolites that are produced by microsomal oxidation (4-en, 4-OH, and 5-OH). In contrast, the kinetics of the beta-oxidative metabolites (2-en, 3en, and 3-OH) were unchanged irrespective of formulation. The slow-release formulation may be safer, because of reduced formation of 4-en valproate, the most toxic metabolite, together with reduced peak concentrations of the parent compound. The pharmacokinetics of valproate have been studied in 27 patients with focal or generalized epilepsy taking a single daily dose of prolonged-release valproate given in the evening [397c]. In about 60% of the patients the serum concentration measured at 0900 h corresponded to the peak value. In another 33% the peak concentration was reached at either 2400 h or at 0300 h. The pharmacokinetics of single oral doses of magnesium valproate solution, suspension, and enteric-coated tablets have been studied in 24 healthy volunteers; the three formulations met the regulatory criteria for bioequivalence [398c]. In a prospective evaluation of 41 consecutive adult out-patients who were followed for 6 months after switching overnight from immediate-release to extended-release divalproex sodium, seizure frequency and the adverse effects profile did not change significantly after switching drug formulations, but there was a significant subjective improvement in tremor with the extendedrelease formulation [399c]. Overnight versus gradual switching to extended-release divalproex sodium have been compared in adults with intellectual and developmental disabilities taking divalproex sodium for epilepsy (n ¼ 9) or for comorbid bipolar disorder (n ¼ 7) [400c]. There were no major differences. One subject in the overnight group had sedation, seizures, worsening of tremor, or gastrointestinal adverse events and one had acute diarrhea and vomiting, followed by a very brief tonic leg seizure 6 days later.

Antiepileptic drugs

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The effect of intravenous valproate when given for the treatment of status epilepticus has been studied in small retrospective case series. In 32 patients who received intravenous valproate for status epilepticus as first or second line therapy there were no serious cardiovascular complications; the only adverse events reported were initial leukocytosis and hypotension [401c]. In a prospective study of 48 patients with status epilepticus refractory to benzodiazepines, intravenous valproate (30 mg/ kg, 6 mg/kg per hour was not associated with systemic or local adverse effects [402c]. In a comparison of intravenous valproate (n ¼ 49) and phenytoin infusion (n ¼ 25) in 74 patients with status epilepticus or acute repetitive seizures, the two drugs were equally effective but there were adverse effects in none of those given valproate and in three of those who were given phenytoin (cardiac dysrhythmia, vertigo, and hyponatremia) [241c]. Drug overdose Valproate overdose can mimic brain death [403A]. • A 19-year-old man developed severe confusion and rapidly became deeply comatose. All brain-stem reflexes were absent, including missing pupillary responses to light. The serum valproic acid concentration was 12 430 mmol/L (usual target range 350–700) and there was severe hyperammonemia (500 mmol/l; normal <30). Brain edema was ruled out by CT scan. He was given L-carnitine and continuous venovenous hemodiafiltration and made a full clinical recovery.

A patient with schizophrenia developed a confusional state and was initially treated for non-convulsive seizures until the serum valproic acid concentration test showed acute intoxication [404A]. Guidelines have been published on the conditions for emergency department referral and prehospital care for patients who have ingested toxic amounts of valproate immediate-release or extended-release dosage forms [405S]. Drug–drug interactions Aspirin A 59-yearold white woman with moderate mental

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retardation and a schizoaffective disorder developed confusion, dizziness, lethargy, and tremor of the hands after starting low-dose valproate treatment [406A]. The valproate unbound fraction was increased, which may have been due to displacement by aspirin and other drugs. Carbapenems An old Chinese man with epilepsy had seizures when meropenem was added to treatment with valproate [407A]. In a retrospective study of six critically ill patients taking valproate who concurrently received meropenem (n ¼ 4), imipenem (n ¼ 1), or ertapenem (n ¼ 1) mean plasma valproate trough concentrations fell by 58% and estimated mean valproate clearance increased by 191% compared with values obtained while they were not receiving a carbapenem; five patients had generalized seizures during concurrent valproate þ carbapenem treatment, including two with no prior history of seizures [408A]. Meropenem is an enzyme inducer. Because of this pharmacokinetic interaction, concurrent use of these medications should be avoided. Chitosan Two cases of a probable interaction of valproate with chitosan, a substance available to help weight loss, have been reported; chitosan may reduce the absorption of valproate [409A]. • A 35-year-old woman taking valproate 500 mg bd and phenobarbital 75 mg/day for idiopathic generalized epilepsy who had been seizurefree for 3 years had a recurrence of myoclonic jerks, absences, and a tonic-clonic seizure a few days after taking a dietary supplementation that contained chitosan 500 mg bd for weight loss. The seizures remitted after chitosan was stopped. Three months later she restarted chitosan and within 5 days once more had seizures. Serum valproate was undetectable. Chitosan was withdrawn, the seizures remitted, and the valproate concentration returned to baseline (50 mg/l) within 4 days.

Oral contraceptives Serum concentrations of lamotrigine and valproate were measured twice during a single menstrual cycle in four groups of 12 women with epilepsy [175C]. Both valproate and lamotrigine

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concentrations were significantly reduced by the oral contraceptive (median reductions of 23% for valproate and 33% for lamotrigine). Serum lamotrigine concentrations fell non-significantly by 31% during the mid-luteal phase compared with the early-mid follicular phase in the absence of oral contraception. Oxcarbazepine An interaction of oxcarbazepine with valproate resulted in an increase in both total valproate and a disproportionately larger increase in the unbound fraction, which may have been due to both inhibition of valproate metabolism and displacement from protein binding sites; the authors also hypothesized that oxcarbazepine had inhibited protein-mediated valproate transport into the site of metabolism in hepatocytes [410A]. Quetiapine One patient taking long-term valproate developed edema in both legs 7 days after the addition of quetiapine, which promptly resolved after drug withdrawal [411A]. Valproate inhibits quetiapine metabolism and increases its plasma concentration by about 77%. Management of adverse drug reactions Two identical cases of life-threatening valproate overdose which were treated with two different approaches have been described [412A]. One patient was treated with supportive therapy alone until cerebral edema and seizures developed; the other was treated with immediate extended hemodialysis followed by high-volume hemodiafiltration. The first patient remained critically ill with high valproate and ammonia concentrations, seizures, and life-threatening cerebral edema. The second patient's valproate and ammonia concentrations rapidly fell with hemodialysis and hemodiafiltration and he improved rapidly. In another patient severe valproate overdose associated with a serum valproate concentration of 1320 mg/l resulted in coma

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but consciousness was regained after three sessions of hemodialysis [413A]. The advantages of using carnitine in patients with valproate overdose or valproate-induced hepatotoxicity and hyperammonemic encephalopathy have been discussed [414R]. Carnitine supplementation may increase the beta-oxidation of valproate, thereby limiting cytosolic omega-oxidation and the production of toxic metabolites that are involved in liver toxicity and ammonia accumulation. In a systematic literature search, 31 reports have been identified of the use of extracorporeal elimination in acute valproate poisoning [415M]. Even though there have been no controlled comparisons of the clinical outcomes with or without extracorporeal elimination in valproate poisoning, extracorporeal methods of elimination should be considered in patients with features of severe valproate poisoning (coma or hemodynamic compromise) and plasma valproate concentrations over 850 mg/l, particularly if severe hyperammonemia and electrolyte and acid–base disturbances are present. Hemodialysis appears to be the extracorporeal method of choice to enhance valproate elimination in acute poisoning, and several case reports have consistently shown that during hemodialysis the half-life of valproate can be reduced to around 2 hours and that enhanced clearance is often associated with clinical improvement.

Vigabatrin [SED-15, 3623; SEDA-30, 98; SEDA-31, 136; SEDA-32, 160] The pharmacokinetics, mechanism of action, and toxicology of vigabatrin have been reviewed [416R]. Another review focused on clinical problems [417R]. Observational studies In a retrospective review of 84 children who were taking

Antiepileptic drugs

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vigabatrin for infantile spasms and partial epilepsies related to tuberous sclerosis complex and other etiologies, control of infantile spasms was achieved in 73% of those with tuberous sclerosis complex and 27% of those with other etiologies [418c]. Partial onset seizures were controlled in 34% of all the children; there were adverse events in 13%. Electroretinography and/or behavioral visual field testing was done in 52% and the drug was withdrawn in one case because of an abnormal result. Placebo-controlled studies Vigabatrin has been evaluated in cocaine-dependent individuals, who were randomly assigned to vigabatrin (n ¼ 50) or placebo (n ¼ 53) in a 9-week double-blind trial and a 4-week follow-up assessment [419C]. Twelve of those who took vigabatrin and two of those who took placebo maintained abstinence through the follow-up period. The retention rate was 62% with vigabatrin arm versus 42% with placebo. The rates of adverse events were the same in the two groups. Early somnolence was the most common complaint among those taking vigabatrin (n ¼ 12) and those taking placebo (n ¼ 8). There was transient hypertension in two subjects taking placebo and four taking vigabatrin. There were visual abnormalities in three patients taking vigabatrin and in one taking placebo. Systematic reviews The use of vigabatrin in partial epilepsy has been evaluated in a systematic review and meta-analysis of 11 short-term, randomized, placebo-controlled trials, testing doses of 1000–6000 mg, [420M]. There were 982 observations in the primary intention-to-treat analysis of efficacy. Patients who took vigabatrin were significantly more likely to obtain a 50% or greater reduction in seizure frequency than those who took placebo (RR ¼ 2.58; 95% CI ¼ 1.87, 3.57). Those who took vigabatrin were also significantly more likely to have treatment withdrawn (RR ¼ 2.49; 95% CI ¼ 1.05, 5.88), and more likely to

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experience a number of adverse effects, significantly so for fatigue or drowsiness. Nervous system There was white matter vacuolation and intramyelinic edema in the brain of a child with quadriparetic cerebral palsy secondary to hypoxic brain injury following premature birth, who died 3 weeks after the start of a course of vigabatrin [421A]. This increases concerns about the use of vigabatrin in individuals with preexisting abnormalities of myelin. In 8 of 23 patients there were MRI abnormalities attributable to vigabatrin and characterized by new-onset and reversible T2weighted hyperintensities and restricted diffusion in thalami, globus pallidus, dentate nuclei, brainstem, or corpus callosum [422c]. Diffusion-weighted imaging was positive, and apparent diffusion coefficient maps demonstrated restricted diffusion. Young age and relatively high doses were susceptibility factors. All the findings reversed after drug withdrawal. The frequency of transient MRI abnormalities in children taking vigabatrin has been retrospectively reviewed in 205 infants with infantile spasms (332 cranial images) and 668 children and adults with partial epilepsies (2074 images) [423c]. Among infants with infantile spasms, the prevalence of prespecified MRI abnormalities was significantly higher among vigabatrin-treated versus vigabatrin-naive subjects (22% versus 4%). Of nine subjects in the prevalent population with at least one subsequent MRI scan, there was resolution of abnormalities in six. Among adults and children who took vigabatrin for partial seizures, there was no statistically significant difference in the incidence or prevalence of prespecified MRI abnormalities between vigabatrin-exposed and vigabatrinnaive subjects. The authors concluded that vigabatrin is associated with transient, asymptomatic magnetic resonance imaging abnormalities in infants treated for infantile spasms and that most of these abnormalities resolve, even in subjects who continue to take the drug.

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Visual impairment and vigabatrin EIDOS classification: Extrinsic moiety Vigabatrin Intrinsic moiety Not known Distribution Nerve fibers in the retina Outcome Atrophy Sequela Visual field loss from vigabatrin DoTS classification: Dose-relation Collateral reaction Time-course Late Susceptibility factors Age (more common in adults)

Vigabatrin-induced ocular adverse effects have been reviewed [424R]. In 734 patients with refractory partial epilepsy, divided into three groups and stratified by age (8–12 years; >12 years) and exposure to vigabatrin, the frequencies of visual field loss differed across the groups [425c]. The three groups were: patients who had taken vigabatrin for at least 6 months (current users); patients who had previously taken vigabatrin for at least 6 months but who had not taken it for at least 6 months (prior users); patients who had never taken vigabatrin (never users). The results are shown in Table 1. Since the probability of vigabatrin-associated visual field loss is positively associated with treatment duration, careful assessment of the balance of benefit to harm in continuing treatment with vigabatrin is recommended in patients who are currently taking it. In those who continue to take it, visual field examination at least every 6 months is recommended. In 204 patients with epilepsy, grouped on the basis of antiepileptic drug therapy (current, previous, or no exposure to vigabatrin), there was bilateral visual field constriction in 59% of current users, 43% of prior users, and 24% of never users [426c]. Assessment of retinal function showed abnormal responses in 48% of current users and 22% of prior users, but in none of the never users.

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In eight patients with visual field constriction, who were examined 4–6 years after they had stopped taking vigabatrin visual field constriction was unchanged [427c]. The amplitude of the 30 Hz flicker response was still reduced. The authors concluded that vigabatrin causes permanent retinal damage. Persistence of visual loss after vigabatrin therapy has also been studied in 16 schoolage children who had taken vigabatrin in infancy for infantile spasms, and who were examined by Goldmann kinetic perimetry at age 6–12 years [428c]. Vigabatrin had been started at a mean age of 7.6 (range 3.2–20) months and the mean duration of therapy was 21 (9.3–30 months) with a cumulative dose of 655 (209–1109) g. Fifteen children had normal visual fields. There was mild visual field loss in one child who had taken vigabatrin for 19 months to a cumulative dose of 572 g. The authors concluded that the risk of visual loss may be lower in children who are given vigabatrin in infancy. In a retrospective study of charts from 47 children with infantile spasms who were given vigabatrin as a first-line drug and charts from 15 children at the age of at least 6 years without neurological or cognitive deficits, who had taken vigabatrin for at least 6 months during infancy, only one patient had visual field defects after at least two examinations [429c]. These results confirm that this adverse effect plays a minor role in young children and that treatment of infantile spasms for 3–6 months with vigabatrin seems to carry minimal risk.

Table 1 Frequencies of visual loss in different groups of patients taking vigabatrin Frequency Group Current users Prior users Never users

Age 8–12 years

Age >12 years

10/38 (26%)

65/150 (43%)

7/47 (15%) 1/186

37/151 (25%)

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In 42 children with infantile spasms, all of whom had been exposed to vigabatrin for a minimum of 1 month, and in whom contrast sensitivity and grating acuity were measured using sweep visual evoked potential testing, grating acuity was significantly reduced in children with evidence of retinal toxicity based on 30-Hz flicker amplitude reductions on fullfield electroretinography [430c]. There were no differences in contrast sensitivity between children with and without retinal toxicity. In 28 of 31 young children with epilepsy who were taking vigabatrin binocular white sphere kinetic perimetry was used to test peripheral visual fields; their median visual field extents were smaller than in controls [431c]. In eight of these subjects, binocular field extents were smaller than the minimum in the controls. Monocular white sphere kinetic perimetry did not differ between the two groups. In nine patients who were tested with both this new technique and Goldmann kinetic perimetry, visual field extents did not differ between tests. Screening procedures that have been recommended before and during treatment with vigabatrin have been reviewed [432R]. As a rule, a complete ophthalmological examination, including perimetry and retinal electrophysiology, should be performed every 6 months. However, it may be necessary to rely on retinal electrophysiology, since some patients may not be able to undergo perimetry. Until now, the incidence of vigabatrin-associated retinal toxicity in Asian populations has not been studied. In 18 Chinese patients, 8 men and 10 women, who had taken vigabatrin for 13 months to 5 years, mean dosage 1581 mg/day, there were significant bilateral visual field defects in 20 eyes, and 80% showed a concentric pattern, compared with none in the control group [433c]. Impairment of visual processing due to vigabatrin (not simply visual field loss) has been studied using a spatial attention task [434c]. Performance was tested at eccentricities varying from 30 degrees to 60 degrees on a panoramic screen covering 180 degrees. Participants were patients with epilepsy taking vigabatrin, patients taking other antiepileptic drugs, and healthy controls. Nine patients in the vigabatrin group had mild visual field constriction. In those taking

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vigabatrin there was a general slowing down of response times, which could only be explained by an alteration in the photoreceptors not yet detected by perimetry. The slowing down of visual processing at large eccentricity for flashed stimuli suggested that patients taking vigabatrin might have impaired ability to detect moving objects in the periphery before visual field restriction. Four children who had been exposed to vigabatrin in utero all had normal visual fields and retinal nerve fiber layer thicknesses, suggesting that vigabatrin does not cause visual toxicity in children exposed to vigabatrin prenatally [435c]. Metabolism The effects of vigabatrin (n ¼ 24), topiramate (n ¼ 21), and lamotrigine (n ¼ 28) on serum carnitine concentrations have been investigated in 91 children and compared with those obtained from 18 children taking valproate [314c]. The new drugs did not alter carnitine concentrations. Drug–drug interactions Metamfetamine Treatment of metamfetamine dependence with vigabatrin has been suggested. Possible cardiovascular adverse effects induced by the co-administration of these substances and the possible interaction between vigabatrin and metamfetamine have been evaluated in a double-blind, placebo-controlled, parallel-group study in healthy volunteers [436c]. Vigabatrin did not alter metamfetamine or amfetamine plasma concentrations or toxicity. There were no serious adverse events and the total number of adverse effects was similar in the two groups. There were no significant differences in systolic or diastolic blood pressures or heart rate.

Zonisamide

[SED-15, 3728; SEDA-30, 99; SEDA-31, 137; SEDA-32, 161] Observational studies In an open prospective study in 13 patients with idiopathic generalized epilepsies who were taking zonisamide mean dosage 319 mg/day, 12 continued to take zonisamide at month 6

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and 11 at month 12 [437c]. Seven patients were seizure-free and four had adverse events—loss of appetite and weight loss in three and headache, somnolence, and irritability in the other. Two patients withdrew because of adverse events. In a retrospective study of 74 patients with epilepsy taking zonisamide mean dosage 368 mg/day, of whom 34 continued to take zonisamide for 12 months after the start of therapy, 11 had at least a 50% reduction in seizure frequency [438c]. There were adverse effects in 45, which led to drug withdrawal in 24. In a prospective, add-on, open study in 82 patients, aged 3–34 years, with partial (n ¼ 47) or generalized (n ¼ 35) refractory epilepsy, zonisamide was started in a dosage of 1 mg/kg/day and increased by 2 mg/kg every 1–2 weeks over a period of 3 months up to a maximum dose of 12 mg/kg/day [439c]. After 12 months the mean dosage was 5.7 mg/kg/day and nine patients were seizure-free. There were adverse effects in 22 patients. The most common treatmentemergent adverse effects were nervous system irritability (n ¼ 9), weakness (n ¼ 5), reduced appetite (n ¼ 3), drowsiness (n ¼ 2), and insomnia (n ¼ 2). One patient developed a rash 10 days after starting zonisamide, which required drug withdrawal; when zonisamide was tried again, the rash recurred. In 317 patients with refractory partial epilepsy who had completed a fixed-dose, randomized, double-blind, add-on trial with zonisamide, and were recruited into an open extension study, retention rates at 1, 2, and 3 years were 65%, 45%, and 29% respectively [440c]. Adverse effects were reported by 89% of patients, the most commonly reported being dizziness (12%), somnolence (12%), and weight loss (11%). Serious adverse effects were reported in 52 patients (16%) and convulsions were the most common. The overall withdrawal rate due to adverse effects was 22%. In 17 children with infantile spasms who were given zonisamide at a starting dose of 2–8 mg/kg/day, the dose was increased by 2–5 mg/kg/day every 3–4 days until the seizures disappeared or the dose reached 30 mg/kg/day [441c]. Adverse reactions

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included irritability in four patients and reduced appetite in two. Of 109 children with epilepsy prospectively treated with zonisamide at a starting dose of 1 mg/kg/day, and increased by 2 mg/kg/day every 1–2 weeks to an initial maximum dose of 12 mg/kg/day, 52 completed 15 months of treatment [442c]. The most common treatment-related adverse effects were somnolence (n ¼ 22), reduced appetite (n ¼ 20), hostility (n ¼ 9), nervousness (n ¼ 9), reduced sweating (n ¼ 8), emotional lability (n ¼ 6), weakness (n ¼ 5), abnormal thoughts (n ¼ 5), and dizziness (n ¼ 4). Seven patients withdrew from the study because of adverse effects; these included increases in drugmetabolizing enzymes (n ¼ 3), hostility (n ¼ 2), and rash, pancreatitis, and nervousness (1 each). Analysis of adverse events according to use of concomitant enzyme-inducing drugs showed no significant differences between the groups. The patient who withdrew because of severe pancreatitis was taking zonisamide 6.1 mg/kg and was also taking valproate. Zonisamide has been evaluated as addon therapy in six patients with epilepsy due to brain tumors [443c]. Two patients had adverse effects: one had sexual dysfunction and one had drowsiness. Zonisamide has been assessed in 63 patients with migraine refractory to topiramate [444c]. The initial dosage was 50 mg/ day, with gradual titration to 400 mg/day. After 2 and 6 months there was a statistically significant improvement in the number of migraine attacks, headache severity, and reduced use of acute medication. There were adverse effects in 15 patients. The most common were difficulty in concentrating (n ¼ 9), fatigue (n ¼ 7), and paresthesia (n ¼ 6). Four patients stopped taking zonisamide because of adverse effects (three because of difficulty in concentrating and one because of restless legs syndrome). In 12 subjects with isolated head tremor who were given either zonisamide or propranolol in a randomized, crossover pilot study, zonisamide was more effective than propranolol [445c]. There were adverse effects in eight, mild sedative effects in five and gastrointestinal problems, such as diarrhea and abdominal discomfort, in three.

Antiepileptic drugs

Chapter 7

Metabolism Possible zonisamide-induced hyperammonemia occurred in a child with citrullinemia [446A]. Inhibition of carbonic anhydrase by zonisamide, which in turn reduces the availability of bicarbonate ions for carbamylphosphate synthesis, was the suggested mechanism. Immunologic Patients who develop an anticonvulsant hypersensitivity syndrome after taking an aromatic antiepileptic drug are more likely to develop a similar complication after taking other aromatic antiepileptic drugs. Cross-reactivity between zonisamide and other anticonvulsants and/or sulfonamides and prediction using the lymphocyte toxicity assay have been studied in 40 adults who had had clinical hypersensitivity syndrome reactions to sulfamethoxazole (n ¼ 20) or anticonvulsant drugs (n ¼ 20) [447c]. Patients with sulfamethoxazole-related but not anticonvulsant drug-related hypersensitivity syndrome reactions showed crossreactivity to zonisamide. The lymphocyte toxicity assay predicted a possible reaction to zonisamide only in those who were sensitive to sulfamethoxazole.

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Drug formulations The bioequivalence of oral dispersible tablets of zonisamide 100 and 300 mg and immediate-release reference capsules has been assessed in two open, randomized-sequence, single-dose, two-period, two-treatment, crossover studies; the test formulation met regulatory criteria for bioequivalence [448c]. In the first study, 25 subjects had treatment-emergent adverse effects. Those that were considered to be possibly or probably related to zonisamide were fatigue (n ¼ 2), abdominal pain (n ¼ 2), and weakness, dry lips, nausea, anorexia, oral paresthesia, and back pain (one each). In the second study, 21 subjects had treatment-emergent adverse effects and those that were considered to be possibly or probably related to zonisamide were dizziness (n ¼ 3), nausea (n ¼ 2), increased serum creatinine (n ¼ 2), and abdominal pain/discomfort, glossodynia, vomiting, blurred vision, lethargy/fatigue, nervousness, and generalized pruritus (one each). In neither of the two studies were there clear differences between the formulations in the reported adverse events.

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Villanueva V, Porcel J. Strategies to detect adverse effects of antiepileptic drugs in clinical practice. Epilepsy Behav 2008; 13(1): 178–83. [5] Bootsma HP, Ricker L, Hekster YA, Hulsman J, Lambrechts D, Majoie M, Schellekens A, de Krom M, Aldenkamp AP. The impact of side effects on long-term retention in three new antiepileptic drugs. Seizure 2009; 18(5): 327–31. [6] Tsiropoulos I, Andersen M, Hallas J. Adverse events with use of antiepileptic drugs: a prescription and event symmetry analysis. Pharmacoepidemiol Drug Saf 2009; 18(6): 483–91. [7] Perucca P, Gilliam FG, Schmitz B. Epilepsy treatment as a predeterminant of psychosocial ill health. Epilepsy Behav 2009; 15(Suppl 1): S46–50.

182 [8] Jakubus T, Michalska-Jakubus M, Lukawski K, Janowska A, Czuczwar SJ. Atherosclerotic risk among children taking antiepileptic drugs. Pharmacol Rep 2009; 61(3): 411–23. [9] Tan TY, Lu CH, Chuang HY, Lin TK, Liou CW, Chang WN, Chuang YC. Long-term antiepileptic drug therapy contributes to the acceleration of atherosclerosis. Epilepsia 2009; 50(6): 1579–86. [10] Aydemir G, Meral C, Suleymanoglu S, Karademir F. Long-term effects of antiepileptic therapy on cardiovascular risk factors in children. Neurol India 2009; 57(4): 504. [11] Mandelbaum DE, Burack GD, Bhise VV. Impact of antiepileptic drugs on cognition, behavior, and motor skills in children with new-onset, idiopathic epilepsy. Epilepsy Behav 2009; 16(2): 341–4. [12] Mula M, Trimble MR. Antiepileptic druginduced cognitive adverse effects: potential mechanisms and contributing factors. CNS Drugs 2009; 23(2): 121–37. [13] Hamed SA. The aspects and mechanisms of cognitive alterations in epilepsy: the role of antiepileptic medications. CNS Neurosci Ther 2009; 15(2): 134–56. [14] Mula M, Sander JW. Suicidal ideation in epilepsy and levetiracetam therapy. Epilep Behav 2007; 11: 130–2. [15] Mula M, Trimble MR, Yuen A, Liu RS, Sander JW. Psychiatric adverse events during levetiracetam therapy. Neurology 2003; 61: 704–6. [16] Cramer JA, De Rue K, Devinsky O, Edrich P, Trimble MR. A systematic review of the behavioral effects of levetiracetam in adults with epilepsy, cognitive disorders, or an anxiety disorder during clinical trials. Epilep Behav 2004; 4: 123–34. [17] Hesdorffer DC, Kanner AM. The FDA alert on suicidality and antiepileptic drugs: fire or false alarm? Epilepsia 2009; 50(5): 978–86. [18] Rosack J. FDA wants reanalysis of data on seizure drug's suicide risk. Psychiatric News 2005; 40: 12. [19] US Department of Health and Human Services, Food and Drug Administration,

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effect of valproic acid medication? Pediatr Dermatol 2009; 26(6): 749–50. Yilmaz Y, Tasdemir HA, Paksu MS. The influence of valproic acid treatment on hair and serum zinc levels and serum biotinidase activity. Eur J Paediatr Neurol 2009; 13(5): 439–43. Reiche I, Tröger U, Postel SC, Wolf R, Bode-Böger SM. Valproic acid-induced myopathy in a patient with schizoaffective disorder. J Clin Psychopharmacol 2009; 29 (4): 402–3. Gorkemli H, Genc BO, Dogan EA, Genc E, Ozdemir S. Long-term effects of valproic acid on reproductive endocrine functions in Turkish women with epilepsy. Gynecol Obstet Invest 2009; 67(4): 223–7. Bilo L, Meo R. Polycystic ovary syndrome in women using valproate: a review. Gynecol Endocrinol 2008; 24(10): 562–70. Kacalak-Rzepka A, Kiedrowicz M, Bielecka-Grzela S, Ratajczak-Stefanska V, Maleszka R, Mikulska D. Rowell's syndrome in the course of treatment with sodium valproate: a case report and review of the literature data. Clin Exp Dermatol 2009; 34(6): 702–4. Bromfield EB, Dworetzky BA, Wyszynski DF, Smith CR, Baldwin EJ, Holmes LB. Valproate teratogenicity and epilepsy syndrome. Epilepsia 2008; 49 (12): 2122–4. Cole RL, Van Ross ER, Clayton-Smith J. Fibular aplasia in a child exposed to sodium valproate in pregnancy. Clin Dysmorphol 2009; 18(1): 37–9. Trivedi A, Halliday R, Waters K, Levison J. Unilateral lung agenesis: coincidence or association with maternal valproate therapy? J Paediatr Child Health 2009; 45(10): 622–3. Ozdemir OM, Kiliç I, Ozsari T, Kiliç BA, Faivre L, Aral B, Gürses D, Semerci CN. Fetal sodium valproate exposure causes Baller-Gerold syndrome phenotype: both phenotypes in the same family. Turk J Pediatr 2009; 51(6): 631–6. Sabers A, Larsen K, Blichfeldt S, Sahlholdt L, Rasmussen JO. Valproate treatment during pregnancy: description of four cases with foetal valproate

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syndrome. Ugeskr Laeger 2009; 171(4): 221–5. Seidahmed MZ, Miqdad AM, AlDohami HS, Shareefi OM. A case of fetal valproate syndrome with new features expanding the phenotype. Saudi Med J 2009; 30(2): 288–91. Al-Mendalawi MD, Seidahmed MZ. A case of fetal valproate syndrome with new features expanding the phenotype. Saudi Med J 2009; 30(7): 977. McVearry KM, Gaillard WD, VanMeter J, Meador KJ. A prospective study of cognitive fluency and originality in children exposed in utero to carbamazepine, lamotrigine, or valproate monotherapy. Epilepsy Behav 2009; 16(4): 609–16. Nagai G, Ono S, Yasui-Furukori N, Nakamura A, Mihara K, Kondo T. Formulations of valproate alter valproate metabolism: a single oral dose kinetic study. Ther Drug Monit 2009; 31(5): 592–6. Graf W, Fraunberger B, Yang T, Kerling F, Pauli E, Stefan H. Once daily monotherapy with prolonged-release valproate minitablets given in the evening—a chronopharmacological study. Int J Clin Pharmacol Ther 2009; 47(7): 439–43. Marcelín-Jiménez G, AngelesMoreno AP, Contreras-Zavala L, Morales-Martínez M, Rivera-Espinosa L. A single-dose, three-period, six-sequence crossover study comparing the bioavailability of solution, suspension, and enteric-coated tablets of magnesium valproate in healthy Mexican volunteers under fasting conditions. Clin Ther 2009; 31(9): 2002–11. Pierre-Louis SJ, Brannegan RT, Evans AT. Seizure control and side-effect profile after switching adult epileptic patients from standard to extendedrelease divalproex sodium. Clin Neurol Neurosurg 2009; 111(5): 437–41. Hellings JA, Barth FX, Logan M, CookWiens G, Osorio I, Reed RC. Overnight versus progressive conversion of multiple daily-dose divalproex to once-daily divalproex extended release: which strategy is better tolerated by adults with intellectual

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disabilities? J Clin Psychopharmacol 2009; 29(5): 492–5. Tiamkao S, Sawanyawisuth K. Predictors and prognosis of status epilepticus treated with intravenous sodium valproate. Epileptic Disord 2009; 11(3): 228–31. Chen L, Feng P, Wang J, Liu L, Zhou D. Intravenous sodium valproate in mainland China for the treatment of diazepam refractory convulsive status epilepticus. J Clin Neurosci 2009; 16(4): 524–6. Auinger K, Müller V, Rudiger A, Maggiorini M. Valproic acid intoxication imitating brain death. Am J Emerg Med 2009; 27(9): 1177 e5-e6. Hurdle AC, Moss RD. Unrecognized valproic acid intoxication. Am J Emerg Med 2009; 27(2): 250 e1-2. Manoguerra AS, Erdman AR, Woolf AD, Chyka PA, Caravati EM, Scharman EJ, Booze LL, Christianson G, Nelson LS, Cobaugh DJ, Troutman WG. American Association of Poison Control Centers. Valproic acid poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 2008; 46(7): 661–76. de Leon J, Kiesel JL, Fleming MW, Strobl B. Valproic acid toxicity associated with low dose of aspirin and low total valproic acid levels: a case report. J Clin Psychopharmacol 2009; 29(5): 509–11. Gu J, Huang Y. Effect of concomitant administration of meropenem and valproic acid in an elderly Chinese patient. Am J Geriatr Pharmacother 2009; 7(1): 26–33. Tobin JK, Golightly LK, Kick SD, Jones MA. Valproic acid-carbapenem interaction: report of six cases and a review of the literature. Drug Metabol Drug Interact 2009; 24(2–4): 153–82. Striano P, Zara F, Minetti C, Striano S. Chitosan may decrease serum valproate and increase the risk of seizure reappearance. BMJ 2009; 339: b3751. Xiong GL, Ferranti J, Leamon MH. Toxic interaction between valproate and oxcarbazepine: a case detected by the free valproate level. J Clin Psychopharmacol 2008; 28(4): 472–3. Chen CY, Yeh YW, Kuo SC, Shiah IS, Liu PY, Chen CL. Pedal edema associated

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with addition of low-dose quetiapine to valproate treatment in bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33(8): 1551–2. Licari E, Calzavacca P, Warrillow SJ, Bellomo R. Life-threatening sodium valproate overdose: a comparison of two approaches to treatment. Crit Care Med 2009; 37(12): 3161–4. Mestrović J, Filipović T, Polić B, Stricević L, Omazić A, KuzmanićSamija R, Markić J. Life-threatening valproate overdose successfully treated with haemodialysis. Arh Hig Rada Toksikol 2008; 59(4): 295–8. Lheureux PE, Hantson P. Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila) 2009; 47(2): 101–11. Thanacoody RH. Extracorporeal elimination in acute valproic acid poisoning. Clin Toxicol (Phila) 2009; 47(7): 609–16. Tolman JA, Faulkner MA. Vigabatrin: a comprehensive review of drug properties including clinical updates following recent FDA approval. Expert Opin Pharmacother 2009; 10(18): 3077–89. Willmore LJ, Abelson MB, BenMenachem E, Pellock JM, Shields WD. Vigabatrin: 2008 update. Epilepsia 2009; 50(2): 163–73. Camposano SE, Major P, Halpern E, Thiele EA. Vigabatrin in the treatment of childhood epilepsy: a retrospective chart review of efficacy and safety profile. Epilepsia 2008; 49(7): 1186–91. Brodie JD, Case BG, Figueroa E, Dewey SL, Robinson JA, Wanderling JA, Laska EM. Randomized, double-blind, placebo-controlled trial of vigabatrin for the treatment of cocaine dependence in Mexican parolees. Am J Psychiatry 2009; 166(11): 1269–77. Hemming K, Maguire MJ, Hutton JL, Marson AG. Vigabatrin for refractory partial epilepsy. Cochrane Database Syst Rev 2008;(3): CD007302. Horton M, Rafay M, Del Bigio MR. Pathological evidence of vacuolar myelinopathy in a child following vigabatrin administration. J Child Neurol 2009; 24 (12): 1543–6.

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[422] Pearl PL, Vezina LG, Saneto RP, McCarter R, Molloy-Wells E, Heffron A, Trzcinski S, McClintock WM, Conry JA, Elling NJ, Goodkin HP, de Menezes MS, Ferri R, Gilles E, Kadom N, Gaillard WD. Cerebral MRI abnormalities associated with vigabatrin therapy. Epilepsia 2009; 50(2): 184–94. [423] Wheless JW, Carmant L, Bebin M, Conry JA, Chiron C, Elterman RD, Frost M, Donald Shields W, Paolicchi JM, Thiele EA, Zupanc ML, Collins SD. Magnetic resonance imaging abnormalities associated with vigabatrin in patients with epilepsy. Epilepsia 2009; 50(2): 195–205. [424] Hawker MJ, Astbury NJ. The ocular side effects of vigabatrin (Sabril): information and guidance for screening. Eye (Lond) 2008; 22(9): 1097–8. [425] Wild JM, Chiron C, Ahn H, Baulac M, Bursztyn J, Gandolfo E, Goldberg I, Goñi FJ, Mercier F, Nordmann JP, Safran AB, Schiefer U, Perucca E. Visual field loss in patients with refractory partial epilepsy treated with vigabatrin: final results from an open-label, observational, multicentre study. CNS Drugs 2009; 23 (11): 965–82. [426] Gonzalez P, Sills GJ, Parks S, Kelly K, Stephen LJ, Keating D, Dutton GN, Brodie MJ. Binasal visual field defects are not specific to vigabatrin. Epilepsy Behav 2009; 16(3): 521–6. [427] Kjellström U, Lövestam-Adrian M, Andréasson S, Ponjavic V. Full-field ERG and visual fields in patients 5 years after discontinuing vigabatrin therapy. Doc Ophthalmol 2008; 117(2): 93–101. [428] Gaily E, Jonsson H, Lappi M. Visual fields at school-age in children treated with vigabatrin in infancy. Epilepsia 2009; 50(2): 206–16. [429] Wohlrab G, Leiba H, Kästle R, Ramelli G, Schmitt-Mechelke T, Schmitt B, Landau K. Vigabatrin therapy in infantile spasms: solving one problem and inducing another? Epilepsia 2009; 50 (8): 2006–8. [430] Durbin S, Mirabella G, Buncic JR, Westall CA. Reduced grating acuity associated with retinal toxicity in children with

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infantile spasms on vigabatrin therapy. Invest Ophthalmol Vis Sci 2009; 50(8): 4011–6. Agrawal S, Mayer DL, Hansen RM, Fulton AB. Visual fields in young children treated with vigabatrin. Optom Vis Sci 2009; 86(6): 767–73. Ingster-Moati I, Orssaud C. Protocole de surveillance ophtalmologique des patients traités par antipaludéens de synthèse ou par vigabatrin au long cours. [Ophthalmological monitoring protocol for patients treated with long-term antimalarials or vigabatrin.] J Fr Ophtalmol 2009; 32(1): 83–8. Hui AC, Liu DT, Wong KK, Man BL, Leung T, Lam PT, Lam DS. Vigabatrininduced visual dysfunction in Chinese patients with refractory epilepsy. Eur J Ophthalmol 2008; 18(4): 624–7. Naili F, Boucart M, Derambure P, Arndt C. Visual impairment at large eccentricity in participants treated by vigabatrin: visual, attentional or recognition deficit? Epilepsy Res 2009; 87(2–3): 213–22. Lawthom C, Smith PE, Wild JM. In utero exposure to vigabatrin: no indication of visual field loss. Epilepsia 2009; 50(2): 318–21. De La Garza 2nd R, Zorick T, Heinzerling KG, Nusinowitz S, London ED, Shoptaw S, Moody DE, Newton TF. The cardiovascular and subjective effects of methamphetamine combined with gamma-vinyl-gamma-aminobutyric acid (GVG) in non-treatment seeking methamphetamine-dependent volunteers. Pharmacol Biochem Behav 2009; 94(1): 186–93. Marinas A, Villanueva V, Giráldez BG, Molins A, Salas-Puig J, Serratosa JM. Efficacy and tolerability of zonisamide in idiopathic generalized epilepsy. Epileptic Disord 2009; 11(1): 61–6. Wellmer S, Wellmer J, Bauer J. Zonisamide as add-on treatment for focal epilepsies. An outcome analysis of 74 patients. Nervenarzt 2008; 79(12): 1416, 1418–23. Coppola G, Grosso S, Verrotti A, Parisi P, Luchetti A, Franzoni E, Mangano S, Pelliccia A, Operto FF, Iannetti P,

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Curatolo P, Balestri P, Pascotto A. Zonisamide in children and young adults with refractory epilepsy: an open label, multicenter Italian study. Epilepsy Res 2009; 83(2–3): 112–6. Wroe SJ, Yeates AB, Marshall A. Longterm safety and efficacy of zonisamide in patients with refractory partial-onset epilepsy. Acta Neurol Scand 2008; 118(2): 87–93. Yum MS, Ko TS. Zonisamide in West syndrome: an open label study. Epileptic Disord 2009; 11(4): 339–44. Shinnar S, Pellock JM, Conry JA. Openlabel, long-term safety study of zonisamide administered to children and adolescents with epilepsy. Eur J Paediatr Neurol 2009; 13(1): 3–9. Maschio M, Dinapoli L, Saveriano F, Pompili A, Carapella CM, Vidiri A, Jandolo B. Efficacy and tolerability of zonisamide as add-on in brain tumorrelated epilepsy: preliminary report. Acta Neurol Scand 2009; 120(3): 210–2. Bermejo PE, Dorado R. Zonisamide for migraine prophylaxis in patients refractory

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to topiramate. Clin Neuropharmacol 2009; 32(2): 103–6. Song IU, Kim JS, Lee SB, Ryu SY, An JY, Kim HT, Kim YI, Lee KS. Effects of zonisamide on isolated head tremor. Eur J Neurol 2008; 15(11): 1212–5. Shaikh AY, Muranjan MN, Gogtay NJ, Lahiri KR. Possible mechanism for zonisamide-induced hyperammonemia in a child with citrullinemia type 1. Indian J Med Sci 2009; 63(5): 203–6. Neuman MG, Shear NH, Malkiewicz IM, Kessas M, Lee AW, Cohen L. Predicting possible zonisamide hypersensitivity syndrome. Exp Dermatol 2008; 17(12): 1045–51. Maanen R, Bentley D. Bioequivalence of zonisamide orally dispersible tablet and immediate-release capsule formulations: results from two open-label, randomizedsequence, single-dose, two-period, twotreatment crossover studies in healthy male volunteers. Clin Ther 2009; 31(6): 1244–55.

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Opioid analgesics and narcotic antagonists

Note on receptor nomenclature: Opioid receptors, originally called d, k, and m receptors, are also referred to as OP1, OP2, and OP3 receptors, or DOR, KOR, and MOR receptors respectively.

GENERAL Observational studies Tincture of opium is a preparation of powdered opium, which contains morphine, codeine, papaverine, and alcohol. It is used as an antidiarrheal agent, to treat neonatal abstinence syndrome, in the management of pain, and traditionally for the management of opioid dependency in some Asian countries. In an open study, opium-dependent subjects were allocated to three different doses of tincture of opium twice a day: 10 ml (6.66 mg morphine equivalents; n ¼ 13), 20 ml (13.3 mg morphine equivalents; n ¼ 8), and 30 ml (20 mg morphine equivalents; n ¼ 11) [1c]. In all the subjects tincture of opium effectively suppressed withdrawal symptoms without causing significant adverse effects. Nervous system Opioid-related sleep disorders are increasingly being recognized as a Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00008-8 # 2011 Elsevier B.V. All rights reserved.

common cause for concern. Of 98 patients with chronic pain, long-term opioid therapy was associated with obstructive, central, and combined sleep apnea in 83 [2c]. Of six patients with central sleep apnea, who were receiving opioids (morphine equivalent doses of 120–420 mg/day) for chronic pain, four achieved symptomatic improvement when treated with bi-level ventilation, correcting nocturnal hypoxemia and reducing sleep fragmentation [3A]. Three cases of central sleep apnea induced by acute ingestion of opioids have been described [4A]. In the first case, ingestion of unknown quantities of oxycodone was associated with an increase in the apnea–hypopnea index from 3.3 to 93 and an increase in the central apnea index from 0 to 76. In the second case, oxycodone 15 mg was associated with an increase in the apnea–hypopnea index from 0.6 to 28 and an increase in the central apnea index from 0 to 28. In the third case, extendedrelease morphine 120 mg was associated with an increase in the apnea–hypopnea index from 38 to 120 and an increase in the central apnea index from 2.1 to 76. Respiratory Practice guidelines have been proposed to reduce the incidence and severity of neuraxial opioid-related respiratory depression, improving the quality of anesthetic care and patient safety [5R]. The authors suggested guidelines for the identification of patients at increased risk, the prevention of respiratory depression after administration, the detection of respiratory depression, and management. 205

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Psychological The cognitive effects of long-term opioid treatment for management of cancer pain has been reviewed, highlighting the paucity of studies and the fact that existing studies only showed minor cognitive deficits, such as reaction time, attention, balance, and memory. Cognitive impairment was also associated with dosage increases and short-acting opioid supplementation [6R]. The cognitive effects of fentanyl given by intravenous patient-controlled analgesia and patient-controlled epidural analgesia have been compared in patients who were randomized to intravenous administration (n ¼ 30), epidural administration (n ¼ 30), or no treatment (n ¼ 20) [7C]. The intravenous group had impairment of attention, sustained attention, attention span and memory, and processing speed ability. The epidural group had only impaired processing speed ability, which is regarded as a very sensitive measure, even after minor neurological insults. Opioids are associated with a longer duration of a first episode of delirium, which was associated with opioids, including morphine and fentanyl, often combined with benzodiazepines in an older population of 304 patients admitted for intensive care treatment [8C]. Endocrine Reduced cortisol concentrations were reported in 44 newly admitted critical care patients. Cortisol concentrations were lower after parenteral opioid administration in opioid-naïve patients (n ¼ 33) but not in patients with a recent history of long-term opioid use [9c]. Gastrointestinal Narcotic bowel syndrome, defined as chronic and/or frequent recurring abdominal pain aggravated by use of narcotics, has been investigated in a random cohort of 4898 people in the community. Narcotic bowel syndrome was rare (n ¼ 5), but those who used narcotics reported more gastrointestinal symptoms and tended to use more laxatives [10C]. The effects of long-term treatment with oral sustained-release hydromorphone, transdermal fentanyl, and transdermal

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buprenorphine on nausea, vomiting, and constipation, have been prospectively explored in 174 patients with cancer pain [11C]. There was constipation in 15% and nausea and vomiting in 21%. There was a higher incidence of 72 hours stool-free periods among those who used transdermal opioids, suggesting that transdermal opioids do not offer much benefit with gastrointestinal adverse effects. Sexual function Sexual behavior and sexual dysfunction have been explored in 60 patients taking buprenorphine (n ¼ 30) or methadone maintenance treatment (n ¼ 30). Those who took methadone had more problems with sexual excitation (33% versus 3.3%) and difficulty in reaching orgasm (40% versus 10%) than those who took buprenorphine. Sexual satisfaction was also significantly greater in those who used buprenorphine (90% versus 63%) [12r]. There was sexual dysfunction in 47 women who used sustained-action oral or transdermal opioids for non-malignant pain [13c]. Concentrations of testosterone, estradiol, and dehydroepiandrosterone were 48–57% lower than concentrations in the control group (n ¼ 68). Luteinizing hormone and follicle-stimulating hormone concentrations were also lower in both premenopausal and postmenopausal women. Oophorectomized women also had 39% lower concentrations of free testosterone. These findings suggested hypogonadotrophic hypogonadism and reduced adrenal androgen production. Similar findings have been found in both men and women in a systematic review [14M]. The authors recommended routine screening of patients taking long-term opioids and management of opioid-induced hypogonadism by opioid rotation, non-opioid pain management, or sex hormone supplementation. Death Lack of consensus and disparities in clinical practice are seen as common contributors to deaths related to prescription opioids [15r]. The main sources of diverted prescription opioids are patients for whom

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opiates are prescribed for pain, elderly patients, “doctor shoppers”, and pill brokers. Education of physicians and patients could address these concerns [16r, 17c]. Drug abuse In body packing, multiple packets of substances are packed generally in the bowel. A 45-year-old man developed miosis and respiratory depression; he had multiple packets in the bowel, seen on abdominal radiography [18A]. Safety concerns related to medication adherence have been explored in 91 methadone-maintained patients attending community pharmacies [19C]. There was nonadherence to prescribing recommendations in 42% of cases. Non-adherent behaviors included splitting of the dose, storage of the dosage form, missed pick up, formulation given away, sold, or exchanged, and formulation stolen or lost. The authors suggested that medication adherence should be regularly reviewed. Oxycodone, hydrocodone, and hydromorphone have been compared with regards to abuse liability. They did not differ substantially from one another, suggesting that analgesic potencies did not reflect relative differences in abuse liability [20c]. In an epidemiological study of pain and attendant psychopathology in opioid analgesic abusers, 60–70% of all those started on a legitimate prescription of opioids for pain later misused opioids [21C]. In an exploratory qualitative study of 25 street drug users in Toronto, Canada, 14 had a history of fentanyl use in at least the past 3 months [22c]. Abuse practices included extracting fentanyl from its matrix patch with vinegar and water; sharing the extracted fentanyl with other users by loading syringes from one container, hence increasing the risk of infection with bloodborne viruses; and overdosing because of difficulty in gauging the concentration of fentanyl in the extract. Hence, fentanyl patches on the street pose a significant public health risk. The abuse potential of opioids is evident through the experience of withdrawal symptoms. In a prospective study, 79 children receiving midazolam and/or opioids

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for more than 5 days, and were followed up for withdrawal symptoms [23c]. Most of them (73 out of 79) received both medications and withdrawal symptoms were attributable to both. Agitation, anxiety, muscle tension, sleep difficulties, diarrhea, fever, sweating, and tachypnea were the most common symptoms. In a cross-sectional study of abuse and dependence of drugs used for self-medication over 2 months, among those who had used codeine in the previous month (n ¼ 53), there was misuse by 15%, abuse by 7.5%, and lack of control and dependence in 7.5% [24C]. In a randomized study, the abuse potential of ALO-01 extended-release capsules containing morphine sulfate and naltrexone was studied with regards to pharmacodynamic effects, including drug-liking and euphoria [25C]. Participants were randomized to either two 60-mg capsules, two 60-mg capsules crushed, morphine sulfate 120 mg, or placebo. There was reduced desirability associated with ALO-01, whether whole or crushed. Fetotoxicity Exposure to opioids in utero can lead to the development of the neonatal abstinence syndrome, especially in infants born to mothers who have misused these drugs. Neonatal abstinence syndrome in neonates born to mothers taking treatment has been investigated in 68 neonates. Pre-delivery higher doses of maternal methadone were associated with an increased incidence of treatment for withdrawal and with longer episodes of neonatal abstinence syndrome. There was a dose–response relationship— for every 1 mg increase in last maternal methadone dosage before delivery, an extra 0.18 days of infant treatment for neonatal abstinence syndrome were required; furthermore, breastfeeding reduced the duration of neonatal abstinence syndrome by 7.76 days [26c]. In a similar study, involving 450 singleton pregnancies in drug misusing women taking methadone, 46% of the neonates developed the neonatal abstinence syndrome [27C]. Breastfeeding was associated with amelioration of symptoms. Admissions to

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the neonatal unit were necessary in 48%, 40% being due to neonatal abstinence syndrome. Infants born to poly-drug misusing women, compared with those only taking prescribed methadone, were more vulnerable, and required longer hospital stays (11 versus 8 days), and used more health-care resources. Infants born to mothers who had misused drugs accounted for 2.9% of all births but disproportionately used 18% of neonatal unit days. In a prospective study, the neonatal abstinence syndrome has also been described in 58 infants who had been exposed to buprenorphine in utero. There was neonatal abstinence syndrome in 38 infants, most of whom had been hospitalized for around 28 days. There was a positive correlation between urinary norbuprenorphine concentrations over the first 3 days of life and the duration of morphine treatment and length of hospital stay. The authors also studied social problems, which were evident in all infants and contributed to the length of hospital stay [28c]. Sublingual buprenorphine has been proposed as an effective and well-tolerated treatment for neonatal abstinence syndrome. In a randomized trial, infants with neonatal abstinence syndrome, who had been born to mothers taking maintenance methadone, were randomized to either sublingual buprenorphine 13–39 micrograms/ kg per day (n ¼ 13) or standard-of-care oral neonatal opium solution (n ¼ 13) [29C]. Buprenorphine administration was associated with a 31% reduction in length of treatment and a 29% reduction in the length of hospital stay. One infant had seizures after buprenorphine, but it was not clear whether buprenorphine was causal. Susceptibility factors Age Susceptibility to adverse effects in patients with chronic non-malignant pain has been reviewed [30R]. Opioid prescribing in the elderly is indicated for severe pain that has not responded to non-opioid drugs. Slow titration of the dose until adequate benefit is achieved. Opioids to be avoided in such patients include pethidine, because of the

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risk of seizures; pentazocine, because of associated neuropsychiatric toxicity; dextropropoxyphene, because of neural and cardiac toxicity; and methadone, because of its long half-life. Combinations of drugs should also be avoided. Critically ill patients Management of pain in critically ill patients has been reviewed [31R]. Opioids remain the mainstay of treatment in intensive care units. The benefit–harm balance of opioid analgesics requires continued assessment. The choice of opioid and dosage regimen should take into account the evidence base, as well as the physicochemical, pharmacokinetic, and pharmacodynamic characteristics of the drugs. The potential and actual development of adverse effects needs to be monitored and doses titrated accordingly. Lean rather than total body weight should be used when calculating weight-based dosing regimens. The determination of effective equianalgesic alternative doses or routes of administration is complex, and factors such as age, comorbidities, and tolerance need to be considered. Opioid adjuncts need to be considered case by case. The authors also supported the use of non-pharmacological interventions, such as music and relaxation techniques. Adjunct techniques can provide opioidsparing effects, reducing the incidence of opioid-related adverse effects. According to the results of a meta-analysis, adjunctive acupuncture reduced the consumption of opioid-related adverse effects such as nausea, dizziness, sedation, pruritus, and urinary retention [32M]. Of 2169 patients who received palliative care in 95 general practices in the Netherlands during the 3 months before their death, a significant proportion (16%) were given strong opioids before a trial of weak opioids; in 48% of all patients who were given opioids, laxatives were not prescribed and antiemetics were prescribed in 29% [33C]. Pharmacological tolerance of analgesic effects, symptoms of withdrawal, opioidinduced hyperalgesia, and psychological factors have been reported as contributing

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to analgesic failure, giving rise to controversy around the efficacy of long-term opioids. The increased risk of abuse and diversion necessitates monitoring, taking into consideration reliable predictors, such as a history of prior substance use, younger age, depression, and anxiety. Opioidinduced hyperalgesia presents another challenge, which, if recognized, could affect the efficacy of opioids in the management of pain [34r, 35R, 36R, 37R]. Management of adverse drug reactions The translation of knowledge about drug safety into clinical practice has been studied through the creation of a “Patient-orientated Prescription for Analgesia”, which contained evidence-based medical knowledge at the point of prescribing [38C]. Such a method of prescribing was shown to reduce the occurrence of opioid-associated severe/fatal adverse events.

OPIOID RECEPTOR AGONISTS Alfentanil

[SED-15, 72; SEDA-31, 153; SEDA-32, 187] Observational studies In a study involving 50 patients with osteoporotic vertebral fractures, scheduled for percutaneous vertebroplasty, an infusion of alfentanil 1.05 mg/hour was effective for intraoperative pain relief; transient apnea of less than 10 seconds occurred in only two patients and nausea and vomiting in three [39c].

Nervous system Emergence agitation has again been described in a randomized placebo-controlled study in 105 children having adenotonsillectomy, who were given alfentanil 10 or 20 micrograms/kg after loss of the eyelash reflex. Induction and maintenance was with sevoflurane 1.5–2.5% [40C]. Emergence delirium was measured using Aono's scale and the pediatric anesthesia emergence delirium (PAED) scale.

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The incidence of severe agitation postoperatively was significantly lower with alfentanil than placebo, but there were no differences between the two doses of alfentanil. Adverse events were rare, but significantly more children given 20 micrograms/ kg of alfentanil became hypotensive on induction. There was no difference in respiratory adverse effects or recovery times. Higher doses of alfentanil can cause respiratory adverse effects, and therefore a dose of 10 micrograms/kg should have the most benefit in reducing emergence delirium and fewer adverse effects.

Codeine [SED-15, 880; SEDA-31, 156; SEDA-32, 187] Lactation Breastfeeding by mothers taking codeine may be ill-advised, particularly if they are ultrarapid metabolizers of codeine, in whom morphine is formed in large amounts, because of the risk of adverse effects on the baby [SEDA-31, 154]. Reports of this association continue to appear. For example, a baby died after its breastfeeding mother took codeine and paracetamol, although the death could not be directly linked to codeine [41A]. It is important to consider interindividual variations in drug response, such as genotypes linked with increased opioid concentrations, the dose–response relation to drug toxicity, and the susceptibility of the very young or premature infant whose drug-excretory mechanisms are underdeveloped [42r]. In a case–control study, neonatal CNS depression was reported in 24% of breastfed infants whose mothers used codeine [43C]. The mothers of these infants had consumed 59% more codeine than mothers whose infants did not experience toxicity. Toxicity also occurred in some babies whose mothers had taken low doses (mean 0.63 mg/kg/day), highlighting increased sensitivity of infants to the CNS depressant effects of opioids. Susceptibility factors Genetic The use of codeine as an antitussive in children can be associated with severe and even fatal

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adverse effects. When 3-year-old twins were given 10 drops of codeine per day for 6 days for an upper respiratory tract infection, one was found lying in vomit and apneic, and required mechanical ventilation and the other died following aspiration of gastric contents [44A]. Blood codeine concentrations were high (total codeine 489 ng/ml and 645 ng/ml). Both were extensive metabolizers by CYP2D6. These cases also highlight the danger posed by inaccurate dosing when giving codeine “by drops” [45R]. • A healthy 2-year-old boy with a history of sleep apnea was given 10–12.5 mg codeine orally every 4–6 hours after elective adenotonsillectomy [46A]. After 2 days, he developed fever and wheezing due to bronchopneumonia and the next day had absent vital signs. The blood concentration of codeine was 0.70 mg/l and of morphine 32 ng/ml. He was an ultrarapid metabolizer.

Dextromethorphan [SED-15, 1088; SEDA-30, 109; SEDA-31, 158; SEDA-32, 187] Comparative studies In 90 children undergoing adenotonsillectomy who were randomized to placebo, dextromethorphan cough syrup (1 mg/kg), or tramadol syrup pre-operatively plus intravenous tramadol 1 mg/kg during induction of anesthesia, the incidence of nausea and vomiting was highest in the tramadol group (10% compared to 5.5% with dextromethorphan group and 6.6% with placebo); however, significantly fewer patients (6.6% versus 40%) who received tramadol required supplementary pethidine [47c]. Psychiatric A 60-year-old lady developed agitation, paranoia, and psychosis after taking dextromethorphan, propoxyphene, and hydrocodone [48A]. She had no history of previous mental illness. She had taken propoxyphene and hydrocodone þ paracetamol for pain and dextromethorphan for cough in higher than recommended doses associated with a respiratory tract infection.

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Dextropropoxyphene [SED-15, 1092; SEDA-30, 109; SEDA-31, 156] Death Co-proxamol, a combination of dextropropoxyphene and paracetamol, was gradually withdrawn from the UK market following a change in legislation in 2005. In a retrospective observational study of mortality data in Scotland over the period 2000–2006, the change in legislation was associated with a reduction in co-proxamol-related deaths, without a compensatory rise in mortality from other analgesics [49C].

Diamorphine (heroin) [SED-15, 1096; SEDA-30, 110; SEDA-31, 158; SEDA-32, 188] Comparative studies In a randomized comparison of injectable diamorphine (mean dose 392 mg/day; n ¼ 115), oral methadone (mean dose 96 mg/day; n ¼ 111), and injectable hydromorphone (n ¼ 25) in patients with opioid dependence refractory to treatment, those who received diamorphine had more adverse events (51 events) than those who received methadone (18 events) or hydromorphone (10 events) [50C]. The most serious events were seizures (seven events with diamorphine in six patients) and overdose (11 events with diamorphine and two with hydromorphone). However, outcome measures were more favorable with diamorphine. The authors suggested that although diamorphine was beneficial it should be delivered in settings where prompt medical intervention could be provided. Cardiovascular In 21 diamorphine-related deaths, myocarditis was found at autopsy [51c]. There was a fivefold increase in inflammatory cells in the myocardial interstitium. The effect of potential contaminants was unclear. • A 29-year-old with a history of substance abuse presented with cardiac arrest and coma [52A]. Toxicology showed that he had used

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benzodiazepines and opiates. He received therapeutic hypothermia, maintaining his core temperature at 32–34 C. He eventually recovered fully.

Nervous system Heroin-associated spongiform leukoencephalopathy has been described in a 36-year-old heroin abuser who had a 3-day history of lethargy and increasing unresponsiveness [53A]. A CT scan showed scattered small foci of hemorrhage and an MRI scan showed injury in the bilateral subcortical white matter consistent with restricted diffusion and T2 hyperintense lesions 3 months later. Psychiatric Hallucinations occurred in a patient who had received diamorphine by subcutaneous infusion for several months; they resolved when he switched to oxycodone [54Ar]. Musculoskeletal A 21-year-old man who had recently used heroin and cocaine developed atraumatic rhabdomyolysis, with extensive swelling of his left leg, drowsiness, and agitation [55A]. He had a high creatine kinase activity and myoglobinuria, and methadone, heroin, and benzodiazepines were found in his urine. The rhabdomyolysis was attributed to the coma, rather than a direct effect of the drugs. Drug dependence The prescribing of diamorphine for the management of dependence has been reviewed [56R]. In one survey, adverse reactions to diamorphine included pruritus, sweating, reddening of the skin, dry mouth, nausea, vomiting, constipation, dizziness, impaired vision, headache, muscle twitching, fatigue, impaired concentration and memory, and impaired sex drive [57C]. However, these were not necessarily solely related to diamorphine, since most of the patients were using other substances or medications. More severe adverse reactions included death, seizures, and respiratory depression. The authors mentioned the importance of ensuring adequately supervised treatment models to reduce the potential risk of diversion.

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Drug overdose The prevalence, characteristics, and outcomes of non-fatal diamorphine overdoses presenting to a large hospital in Western Australia over 12 months have been studied prospectively [58C]. Of all emergency department presentations, 249 (0.5%) were for non-fatal diamorphine overdose. Individuals had a mean age of 19 years and 61% were men. The highest proportion of overdoses occurred on Wednesdays, and most had used the heroin in the presence of others. There was a trend to an increasing frequency in teenage girls and repeat overdosing was common. Other substances were commonly used: benzodiazepines 27%, alcohol 16%, cannabis 11%, amphetamines 5.8%, hallucinogens 1.3%, and other drugs 4%. In a community hospital in the USA, there was a significant increase in diamorphine overdoses over a 1-month period (June–July 2006) [59r]. There were 30 overdoses in this period and nine of these reported having used “blue bag” heroin, diamorphine laced with fentanyl. During a similar period in the previous year, only six overdoses had been due to diamorphine. The authors suggest that fentanyllaced heroin may have contributed to the increased increase.

Dihydrocodeine

[SED-15, 1125;

SEDA-32, 190] Nervous system Generalized convulsions and a mixed acidosis have been attributed to intoxication with an over-the-counter antitussive medication containing dihydrocodeine and chlorphenamine (SS Bron); however, the effects were attributed to the chlorphenamine [60A].

Fentanyl

[SED-15, 1346; SEDA-30, 110; SEDA-31, 159; SEDA-32, 191] Comparative studies In a comparison of fentanyl 0.5 micrograms/kg and remifentanil 0.5 micrograms/kg in patients undergoing gastroscopy, those who received intravenous

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fentanyl (n ¼ 99) took significantly longer to recover (8.7 minutes) compared with those who received remifentanil (n ¼ 100; 7.6 minutes). The latter required less propofol, which contributed to the faster recovery time [61C]. In a randomized blind comparison, patients undergoing sedation for emergency procedures received either ketamine 0.3 mg/kg or fentanyl 1.5 micrograms/kg followed by intravenous propofol 0.4 mg/ kg bolus [62c]. All five severe events were in those who received fentanyl and fentanyl caused more mild (OR ¼ 5.9), moderate (OR ¼ 3.8), and severe (OR ¼ 12.3) adverse events. Desaturation was the main contributor to this difference. Fentanyl was 5.1 times more likely to cause sedation than ketamine, and this persisted after adjustment for age, weight, procedure type, and pre-procedure pain (OR ¼ 4.6). Cardiovascular In patients undergoing orthopedic reduction or abscess drainage who were randomized to ketamine 0.3 mg/ kg (n ¼ 32) or fentanyl 1.5 micrograms/kg (n ¼ 31) intravenously, the latter had significantly more cardiorespiratory events (5.1 times the odds for serious events); only 16% did not experience any cardiorespiratory events, compared with 53% of those who received ketamine [63c]. Of those who received fentanyl, 32% reported mild cardiorespiratory events, 36% moderate, and 16% severe. In those who received ketamine, the incidences were 25%, 22%, and 0% respectively. Fentanyl enhances vagal tone and can cause bradycardia. In 27 children undergoing catheter ablation under propofol anesthesia, which has minimal effect on the sinus node, electrophysiological stimulation was performed before and after a bolus dose of fentanyl 2 micrograms/kg and a subsequent infusion of 0.075 micrograms/kg/minute [64c]. There was an increase in calculated sinus node recovery time but no change in sinoatrial conduction time after fentanyl, suggesting that fentanyl þ propofol impairs sinus node recovery and therefore

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reduces automaticity without affecting conduction time. Respiratory The incidence of fentanylinduced cough has been investigated and correlated with the speed and dose of injection in 476 non-smoking patients free from respiratory tract infections and bronchial hyper-reactivity undergoing elective surgery [65C]. They received fentanyl 1.5 micrograms/kg over 2 seconds (n ¼ 120), over 5 seconds (n ¼ 118), or over 10 seconds (n ¼ 119); 119 received placebo. The incidences of cough within 5 minutes after injection were similar in all the groups, at 3–6%. Upper respiratory tract events and postoperative hypoxemia were more common in 18 children undergoing elective orchidopexy who received intravenous fentanyl than in 18 who received caudal analgesia in a randomized comparison (seven versus one) [66c]. Nervous system In a 58-year-old man with a history of Parkinson's disease, fentanyl as an anesthetic and for postoperative analgesia was associated with severe bradykinesia and rigidity [67A]. The mechanism was unclear but probably resulted from an effect on the dopaminergic nigrostriatal system. Endocrine Secondary adrenal insufficiency was reported in a 64-year-old man with a history of diffuse large B cell lymphoma after he was given transdermal fentanyl 75 micrograms/hour for multifactorial pain [68A]. Adrenal insufficiency recurred when he was re-started on fentanyl by his general practitioner. Musculoskeletal Muscle rigidity resulting in reduced thoracic wall compliance occurred intraoperatively in a 2-year-old child soon after fentanyl administration, although the dose was low (1 microgram/kg) [69A]. Immunologic A 46-year-old woman developed generalized erythema, bronchospasm, and hypotension 4 hours after exposure to

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transdermal fentanyl [70A]. She had had a previous allergic reaction to fentanyl. The delayed onset was thought to have been due to the cutaneous route of administration. Susceptibility factors Age In a comparison of 30 elderly patients (>75 years) undergoing cardiac surgery and 20 younger ones (< 60 years), the former had higher fentanyl plasma concentrations (mean 5.7 versus 3.8 ng/ml) 2 hours postoperatively [71C]. Concentrations of oxycodone were similar, but the elderly patients had less pain, with longer intervals between dose requirements, and were more sedated. Drug administration route Transdermal The efficacy and safety of a fentanyl iontophoretic transdermal system have been explored in a meta-analysis of six trials [72M]. In comparisons of the fentanyl transdermal system and morphine in patientcontrolled analgesia, fewer of those who received fentanyl withdrew because of adverse effects, fewer had nausea and pruritus, and none had respiratory depression; however, more had headaches. Nebulizer Nebulized fentanyl has been studied in children with suspected limb fractures who were randomized to nebulized fentanyl 4 micrograms/kg (n ¼ 36) or intravenous morphine 0.1 mg/kg (n ¼ 37) [73c]. There were no reported adverse effects in those who received nebulized fentanyl, but one patient was withdrawn from the study because of inadequate analgesia. Drug–drug interactions Paroxetine Serotonin syndrome in a 49-year-old woman after cardiac surgery was linked to an interaction of paroxetine 40 mg/day with perioperative fentanyl 5 micrograms/kg [74A]. Ropivacaine In 108 children who were given epidural fentanyl (0.2 micrograms/ kg/hour) in combination with ropivacaine (1.25 or 1.5 mg/ml) for postoperative analgesia after hypospadias repair, adverse effects were more common in those who

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received the combination than in those who received ropivacaine alone [75c]. Management of adverse drug reactions 5HT3 receptor antagonists The addition of ondansetron and ketorolac to fentanyl was associated with less nausea and vomiting and dizziness in 135 patients undergoing thyroid surgery [76c]. In a prospective, randomized, doubleblind comparison of ramosetron or ondansetron in the management of opioidinduced postoperative nausea and vomiting, 94 patients received fentanyl 25 micrograms/kg in a total volume of 100 ml at a rate of 2 ml/hour and 0.5 ml per demand with a 15-minute lockout period [77c]. Ramosetron was superior to ondansetron in preventing vomiting and reducing the severity of nausea. Ketamine In 202 adults, low-dose ketamine (1 mg/kg þ 42 and 83 micrograms/kg/hour for 24 hours) improved the analgesic effects of fentanyl (0.5 micrograms/kg basal and 0.5 micrograms/kg on demand with 6 minutes lockout for 48 hours) and was associated with lower incidence of postoperative nausea and vomiting [78C]. In contrast, in women who underwent abdominal hysterectomy, the use of ketamine and fentanyl (infusion of ketamine 15 micrograms/kg/min þ three boluses of fentanyl 1 microgram/kg) was associated with hallucinations (in seven out of 15 patients) during and after surgery [79c]. Those who received ketamine alone also had hallucinations (in nine out of 15 cases). Propofol In a randomized study in 60 children who underwent interventional radiology and were allocated to propofol 0.5 mg/kg þ fentanyl 1 microgram/kg þ ketamine 0.5 mg/kg (n ¼ 30) or propofol 0.5 mg/kg þ fentanyl 1 microgram/kg þ saline 0.9% (n ¼ 30) intravenously, there was oxygen desaturation in three of those who received ketamine and nine of those who did not [80c]. Those who received ketamine also had agitation (n ¼ 2) and tachycardia (n ¼ 1), which did not occur in the other group. Nystagmus was also a common adverse reaction (19 cases versus

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one). The addition of low-dose ketamine reduced the risk of desaturation.

Hydromorphone [SED-15, 1703; SEDA-31, 162; SEDA-32, 193] Observational studies In 223 patients who were given intravenous hydromorphone 1 mg followed by an optional 1 mg 15 minutes later, there was oxygen desaturation in 5%, bradycardia in 10%, nausea in 13%, vomiting in 7%, and pruritus in 5%; no serious adverse events were reported [81c]. Comparative studies A fixed dose of intravenous hydromorphone 1 mg followed by an optional 1 mg 15 minutes later (n ¼ 112) has been compared with analgesia provided at the discretion of the clinician (n ¼ 112) in patients who presented to an emergency department [82C]. There was adequate analgesia in both groups and the adverse effects profiles were similar. Adverse events in those who received hydromorphone included oxygen desaturation (5%), nausea (17%), vomiting (4.7%), and pruritus (6.5%). In a randomized controlled comparison of hydromorphone and morphine in patientcontrolled analgesia, 50 patients were randomized to either hydromorphone 0.2 mg/ ml or morphine 1 mg /ml; there was no difference in the adverse reactions profile between the two regimens [83c].

Levacetylmethadol (levo-aacetylmethadol, LAAM) [SEDA-32, 193] Cardiovascular The effects of levacetylmethadol (n ¼ 31) on the QT interval have been studied in a randomized controlled comparison with racemic methadone (n ¼ 22) [84C]. After 24 weeks, levacetylmethadol caused significant prolongation of the QTc interval (0.409 versus 0.418 seconds), while methadone had no effect. There was no statistically significant change in QT dispersion in either group. There were more patients with

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borderline prolonged and prolonged QTc intervals among those who received levacetylmethadol (seven versus one). The authors recommended careful electrocardiographic monitoring in patients receiving levacetylmethadol.

Methadone [SED-15, 2270; SEDA-30, 112; SEDA-31, 163; SEDA-32, 196] Observational studies The adverse effects profile of methadone has been compared with that of morphine [95c]. Methadone was associated with fewer adverse events, because it is more lipophilic and has no active metabolites. Symptoms due to methadone overdose generally occur within 9 hours of ingestion with a mean onset of symptoms at 3.2 hours. In an open study in 21 opioid-tolerant patients with severe cancer pain who were switched to methadone, the switch was generally well tolerated; only one patient required treatment withdrawal, because of respiratory depression [85c]. Drowsiness was one of the most frequent adverse effects (in six patients) but it was of moderate intensity and responded to dosage reduction. Constipation was problematic in six. Other effects included nausea and vomiting (n ¼ 2), sweating (n ¼ 2), and confusion (n ¼ 1). Cardiovascular A 56-year-old man was successfully switched from methadone 100 mg/day to buprenorphine after methadone-induced torsade de pointes [86A]. Morphine was used to counteract withdrawal symptoms. The QT interval normalized over the 3 days and remained normal even 12 months later. The factors that predispose to methadone-induced QT interval prolongation have been reviewed [87R]. It was associated with female sex, hypokalemia, high-dose methadone, drug interactions (for example, with medications that inhibit the metabolism of methadone or with protein-bound drugs), underlying cardiac problems or congenital unrecognized QT prolongation, and

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DNA polymorphisms. The authors suggested that despite the risk of mortality associated with methadone-induced QT prolongation, the high mortality in untreated drug users tips the balance in favor of methadone. In 10 of 109 patients receiving methadone maintenance treatment in whom the QTc interval was prolonged (>400 ms), the susceptibility factors were older age, higher methadone dose, and the use of antidepressants (trazodone and mirtazapine) [88C]. Sensory systems Acute bilateral sensorineural hearing loss followed methadone overdose (75 mg) in an opioid-naïve individual; there was gradual improvement in hearing over 10 days [89A]. Skin Necrolytic migratory erythema has been attributed to methadone [90A]. • An 18-year-old woman presented with severe symptoms of thick scales, pustules, and hair loss suggestive of seborrheic dermatitis in the scalp area. Descaling measures, antifungal agents, potent topical steroids, and systematic antibiotics produced limited benefit. Over the next 12 months she developed an erythematous, scaly, weepy rash in the axillae and toe webs, which waxed and waned. Skin scrapings were repeatedly negative for fungi. She was then lost to follow up for 2 years. When she returned, her seborrheic dermatitis had become much worse, having spread to the groin and perianal area. She admitted to using heroin, underwent detoxification, and was enrolled into a methadone maintenance program. Her symptoms were difficult to control after 6 months of additional treatment and she was admitted with septicemia secondary to cutaneous herpes simplex and staphylococcal infection of the groin. Recurrent viral and bacterial infections of the groin area remained a problem. Immunodeficiency was ruled out. Some symptom control was achieved with prophylactic systemic antiviral drugs, antibiotics, systemic and topical steroids, antifungal drugs, and antibiotics. Glucagonoma syndrome and zinc deficiency were ruled out. A biopsy from the groin area showed a combination of parakeratosis and keratinocyte vacuolar changes, supporting a diagnosis of necrolytic migratory erythema. This was considered to be secondary to

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opiates. After patient was off methadone for 4 months, the rash cleared and the hair completely regrew. The rash returned when she restarted methadone.

Necrolytic migratory erythema is usually part of the glucagonoma syndrome, which is characterized by an alpha cell tumor of the pancreas, leading to adult onset diabetes mellitus, weight loss, and glossitis. It is often mistaken for intertrigo or seborrheic dermatitis. Its pathogenesis is not well understood. The role of opiates in this case was not clear, but it was not due to poor nutrition or poor absorption of nutrients. The authors speculated that opiates had had a direct effect on epidermal metabolism. Death Mortality from a naltrexone implant (n ¼ 376) and methadone (n ¼ 658) have been compared in opioid-dependent individuals [91C]. Methadone was associated with increased mortality during the induction period. Fetotoxicity Visual evoked potentials, indicators of the integrity and maturity of the visual pathway, were recorded within 4 days from birth of 21 full-term infants of mothers who had taken methadone [92c]. The drugexposed infants had small-amplitude or non-detectable immature waveforms compared with 20 controls. This suggests that maternal methadone and other illicit drugs altered on visual development in infants. Pregnancy Preterm births were reported as being more prevalent in 258 opiateaddicted pregnant women who were taking methadone in a retrospective cohort study [93C]. The preterm rate was 29% (almost 3 times the national average of 11%). The higher rate was not affected by medical or infectious co-morbidity, but there was a correlation between preterm birth and the use of more than one substance. Susceptibility factors HIV infection A 36year-old woman with advanced HIV infection and taking methadone 70 mg/day and diazepam 20 mg/day had recurrent attacks

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of syncope due to prolongation of the QT interval (QTc 540 ms) and torsade de pointes [94A]. The authors postulated that she had acquired HIV-induced long QT syndrome. Drug–drug interactions The use of methadone in treating cancer pain is limited by its potential for interactions and its adverse effects profile [95R]. Some drugs (for example, antifungal azoles, quinolones, macrolides, selective serotonin reuptake inhibitors) can inhibit the metabolism of methadone, increasing the risk of QT interval prolongation, respiratory depression, or other adverse effects; others (such as anticonvulsants, antituberculosis drugs, antiretroviral drugs, high doses of glucocorticoids, risperidone, St John's wort, fusidic acid, spironolactone, alcohol consumption, and cigarette smoking) increase the speed of methadone metabolism, potentiating withdrawal effects. Conversely, methadone can reportedly inhibit the metabolism of other drugs (for example, tricyclic antidepressants), increasing the risk of QT interval prolongation, NSAIDs (affecting analgesia), or benzodiazepines (causing nervous system toxicity). Of the selective serotonin re-uptake inhibitors, fluvoxamine, fluoxetine, and paroxetine significantly inhibit methadone metabolism, whereas with sertraline and citalopram the effect is minimal; the interaction with venlafaxine is unclear. Antiretroviral drugs In 12 healthy HIVnegative volunteers, nelfinavir reduced plasma methadone concentrations by 40–50%, increased its renal clearance, and increased hepatic metabolism, extraction, and clearance [96c]. Nevirapine and efavirenz increase the R/S enantiomer concentration ratio, hence increasing the therapeutic effects of methadone, which are almost exclusively mediated by the R enantiomer, as has been shown in five patients taking nevirapine and nine taking efavirenz [97c]. These interactions are thought to be mediated by induction of CYP2B.

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Cannabis The combination of cannabis with methadone has been studied in 77 Australian and 74 Swiss methadone maintenance patients [98c]. There were lower 24-hour dose-corrected trough plasma concentrations of both (R)-methadone and (S)-methadone; there was no effect of sex, alcohol, tobacco smoking, or duration of methadone treatment. Nicotine In 40 patients taking methadone maintenance treatment, nicotine enhanced opioid withdrawal suppression and methadone attenuated nicotine withdrawal [99C]. The interaction of nicotine with methadone increased ratings of euphoria and drug liking and reduced restlessness, irritability, and depression. Non-pharmacological effects were also reported, with experiences of positive effects and reduced negative effects. These findings could explain the high prevalence of smoking among patients who take methadone.

Morphine

[SED-15, 2386; SEDA-30, 113; SEDA-31, 164; SEDA-32, 199]

Comparative studies An evaluation of the use of postoperative intravenous patientcontrolled analgesia across a decade highlighted that this method of administration has become more popular and is associated with reduction in morphine consumption and respiratory depression; however, there are significant risks of nausea (47%) and vomiting (19%) [100C]. In the emergency treatment of acute severe pain, intravenous morphine titration (median 0.16 mg/kg with three boluses) was associated with adverse effects in 11% of patients (67 events) [101c]. Nausea and vomiting were the most common events, followed by dizziness, urinary retention, respiratory depression (not severe), pruritus, and allergy. Intrathecal morphine (400 micrograms) combined with intravenous patient-controlled analgesia using fentanyl has been compared with intravenous patientcontrolled analgesia alone in 40 patients

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undergoing liver surgery [102c]. The incidences of adverse effects were comparable except for pruritus, which was significantly more common in those who received intrathecal morphine. Epidural morphine 4 mg has been compared with epidural morphine 5 mg as patient-controlled analgesia for postoperative analgesia in women after cesarean section; the latter had more nausea and vomiting (16% versus 72%) and more pruritus (29% versus 82%) [103c]. In a comparison of oral sustained-release morphine (mean 94 mg/day) and hydromorphone (138 or 206 mg/day) with regard to nausea, vomiting, and constipation, in patients receiving opioids for cancer pain, morphine provided better pain relief at lower doses (after accounting for dose conversion) but was associated with more nausea, constipation, and higher consumption of antiemetic and gastroprotective drugs [104C]. Morphine (mean dose 112 mg) and mexiletine (mean dose 933 mg) have been compared in the management of postamputation pain in a double-blind, randomized, placebo-controlled, crossover study in 60 patients [105c]. Morphine was associated with a higher rate of adverse effects, mainly constipation (17 versus two), drowsiness (nine versus four), and nausea (four versus zero). Systematic reviews In a meta-analysis of the benefits and harms associated with intrathecal morphine without local anesthetic in patients undergoing major surgery, morphine was associated with respiratory depression; the NNTH was 84 [106M]. The authors also reported that the NNTH was worse (15) when only the data from three studies that specifically reported respiratory depression were used. The NNTH for pruritus was 6. The incidence of urinary retention was 12% (compared with 8.5% in controls). There was no difference in the incidence of nausea and vomiting. Respiratory The safety of intravenous morphine 0.05–0.1 mg/kg has been explored in 43 non-intubated neonates undergoing central line placement. Five

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had respiratory depression compared with none of the 43 controls; however, these infants had underlying respiratory insufficiency and two of them were given an overdose of morphine [107c]. Morphine should be used with caution in this population. • A 38-year-old woman undergoing laparotomy with removal of intra-abdominal abscess following a duodenectomy developed acute lung injury after switching from sufentanil to morphine 0.1 mg/kg/hour; her symptoms developed within 3–4 hours and resolved after withdrawal of morphine [108A].

Nervous system A 74-year-old man developed downbeat nystagmus after receiving epidural morphine 3 mg every 12 hours for postoperative pain (total dose 12 mg over 48 hours) [109A]. The nystagmus resolved 36 hours after morphine withdrawal. A 50-year-old woman who was given intrathecal morphine 0.5 mg in conjunction with general anesthesia for lung surgery did not regain consciousness postoperatively [110A]. A brain scan showed cortical and subcortical increased fluid-attenuated inversion recovery intensities in the occipitoparietal and upper frontal regions, effacement of sulci, and cortical and leptomeningeal enhancement. She gradually recovered over the next few days. This presentation suggested posterior reversible encephalopathy syndrome, which the authors suggested might have been caused by intrathecal morphine. Gastrointestinal Postoperative nausea due to morphine is associated with genetic variation at position 118 of the m opioid receptor. In 270 women who received intrathecal morphine 0.1 mg as postoperative analgesia, those who were homozygous for the A118G polymorphism had a higher incidence of nausea and vomiting [111C]. Musculoskeletal Muscle rigidity, laryngospasm, and respiratory compromise occurred twice in a 2-day-old full-term neonate, first after a bolus dose of morphine 100 micrograms/kg and then after a continuous infusion of 4.4 micrograms/kg/hour [112A].

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Drug administration route The effects of intravenous morphine 10 mg given to 38 patients with moderate pain after surgery have been compared with those of intramuscular morphine 10 mg [113c]. There was quicker analgesia with intravenous morphine, without serious respiratory depression. The level of sedation was greater after intravenous morphine, but this lasted for only 5 minutes. Intranasal morphine 7.5 mg (n ¼ 45) or 15 mg (n ¼ 45) has been compared with intravenous morphine 7.5 mg (n ¼ 45) and oral morphine 60 mg (n ¼ 45) in a placebo-controlled study in 225 patients with moderate to severe pain after third molar extraction [114C]. Intranasal morphine 15 mg had similar efficacy to intravenous morphine and caused typical systemic opioid effects. The highest incidence of adverse events was experienced by those who received oral morphine. Nasal irritation was most common in those who received intranasal morphine 15 mg (11%). Drug–drug interactions Itraconazole Itraconazole 200 mg/day for 4 days increased the absorption and plasma concentrations of oral morphine by 20–30% in 12 healthy volunteers; the pharmacodynamic effects of morphine were not enhanced [115c]. Oprelvekin An interaction of oprelvekin (50 micrograms/kg/day) with morphine (120 mg orally bd) was suggested as the probable cause of respiratory depression and sedation in a 20-year-old woman with thrombocytopenia associated with chemotherapy [116A]. Oprelvekin was thought to have reduced the renal excretion of morphine metabolites. Management of adverse drug reactions Dexmedetomidine Combining dexmedetomidine 5 micrograms/ml and morphine 1 mg/ml in intravenous patient-controlled analgesia resulted in better analgesia, reduced morphine consumption, and a reduced incidence of nausea and vomiting

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in a double-blind randomized study in 100 women undergoing hysterectomy [117c]. In a similar study, 64 patients undergoing laminectomy received morphine 0.15 mg/kg and were later randomized to receive morphine alone (0.02 mg/kg intravenous with 15 minutes lockout time) or morphine and dexmedetomidine (0.02 mg/kg intravenous morphine þ 0.1 microgram/kg dexmedetomidine, lock out interval 15 minutes); the combination treatment produced higher sedation scores but a lower incidence of nausea [118c]. 5HT receptor antagonists In a systematic review of nine randomized controlled studies, serotonin receptor antagonists significantly reduced the severity of pruritus and the need for treatment, but did not affect its incidence; the incidence of postoperative nausea and vomiting was reduced [119M]. Gabapentin Preoperative gabapentin 1200 mg reduced the incidence and severity of morphine-induced pruritus and delayed its time of onset compared with placebo (48% versus 78%) in 86 patients who received preservative-free morphine 0.2 mg intrathecally [120c]. Ketamine In 81 patients undergoing abdominal surgery, who were randomized to intraoperative and postoperative ketamine (0.5 mg/kg bolus þ 2 micrograms/kg/minute for 48 hours), intraoperative ketamine only (0.5 mg/kg bolus þ 2 micrograms/kg/ minute), or placebo, ketamine significantly reduced morphine requirements and the frequency of nausea [121c]. The addition of ketamine as an opiate sparer, 1.5 or 5 mg per bolus morphine dose, has been studied in 58 patients undergoing transthoracic heart and lung surgery, a procedure that is associated with severe pain [122c]. Those who took ketamine used 50% less morphine and required less rescue diclofenac for pain control. Pain scores were consistently lower with ketamine, despite reduced amounts of morphine administered. Respiratory parameters were much better with ketamine: none compared with seven patients requiring oxygen for hypoxia. The

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morphine group had increased postoperative nausea and vomiting, but the difference did not reach significance and there were no psychotomimetic adverse effects with ketamine. Although small in numbers this wellpowered study suggests a significant morphine-sparing effect of ketamine, accompanied by fewer adverse effects. In another study, postoperative ketamine as an adjuvant to morphine (1 mg morphine þ 5 mg ketamine with a 7minute lock out time) was associated with fewer adverse effects; one patient who received the combination regimen reported lightheadedness, which resolved spontaneously [123c]. In 75 patients who were randomly assigned to placebo, ketamine, or nefopam, those in the two treatment groups consistently required less morphine at all times compared with placebo (59, 39, and 39 mg in the placebo, nefopam, and ketamine groups respectively) and had a longer time to first analgesia during recovery [124c]. There were no differences in the two treatment groups with regard to morphine consumption at any time. There was significantly more postoperative nausea and vomiting after placebo, but there were no other differences in the incidence of adverse effects. Mirtazapine In a placebo-controlled study, 110 patients undergoing lower limb surgery, who received morphine 0.2 mg as spinal anesthesia, were randomized to preoperative placebo or mirtazapine 30 mg [125C]. The incidence of pruritus was significantly reduced by mirtazapine (52% versus 75%) and the period of onset was longer (7.2 versus 3.2 hours). Nalbuphine The combination of morphine þ nalbuphine reduced the incidence of morphine-induced pruritus [126C]. Patients undergoing gynecological operations were randomly allocated to five groups, each of which received varying ratios of the combination regimen: 1. morphine 1 mg/ml (n ¼ 65)—ratio 1:0; 2. morphine 0.75 mg/ml þ nalbuphine 0.25 mg/ ml (n ¼ 65)—ratio 1:3;

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3. morphine 0.5 mg/ml and nalbuphine 0.5 mg/ ml (n ¼ 59)—ratio 1:1; 4. morphine 0.25 mg/ml and nalbuphine 0.75 mg/ml (n ¼ 63)—ratio 3:1; 5. nalbuphine 1 mg/ml (n ¼ 59)—ratio 0:1.

The incidence of pruritus gradually fell from group 1 to 5 showing that the beneficial effect of nalbuphine was ratio-dependent. Naloxone Co-infusion of morphine (median dose 1.14 mg/kg on day 1; 1.50 mg/kg on day 2) with low-dose naloxone (0.25 micrograms/ kg/hour) and high-dose naloxone (1 micrograms/kg/hour) for amelioration of pruritus has been studied in 18 children with sickle cell pain crises [127c]. Pruritus was rated as less severe in the high-dose group. The combination treatment was feasible and acceptable. However, one patient was withdrawn from the trial because of excessive somnolence; nausea and vomiting were also reported. In 15 male volunteers, naloxone-3-glucuronide 0.16 mg/kg reversed constipation due to morphine without altering its analgesic effects; colonic transit time was delayed with the addition of naloxone-3glucuronide [128c]. In infants treated with continuous morphine infusion (0.04 mg/ml), those who were also given oral naloxone hydrochloride (3 micrograms/kg qds) had improved mean stool frequency and mean total food intake [129c]. Ondansetron In a randomized, double-blind study in 150 patients undergoing abdominal surgery with patient-controlled analgesia using morphine 1.5 mg, the combination of ondansetron 30 mg and prochlorperazine 20 mg reduced postoperative nausea and vomiting in the first 24 hours after surgery but not during the next 24 hours [130c].

Oxycodone [SED-15, 2651; SEDA-30, 115; SEDA-31, 167; SEDA-32, 202] The use of oxycodone has been reviewed, highlighting the importance of hepatic and renal dysfunction [131R]. In severe hepatic impairment the clearance of oxycodone falls by 75% and the volume of distribution

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increases by 50%; renal impairment also reduces clearance. Rifampicin increases the clearance of oxycodone, reducing exposure by 85%, and hence providing inadequate analgesia. Observational studies In patients with moderate to severe cancer pain taking OxyContinÒ (controlled-release oxycodone hydrochloride), adverse reactions occurred in 25% in the first week and the incidence gradually fell with time, to 12% in the 8th week [132C]. The most common adverse effects reported in the first week were constipation (26%), nausea (13%), vomiting (6.2%), dizziness (5%), and lethargy (3.7%). Other effects included dysuria, fatigue, headache, pruritus, and thirst. There was a similar pattern at 8 weeks. Five patients had delusions after dosage reduction or withdrawal, and another had delirium on days 2 and 3. The authors suggested that the adverse effects of OxyContinÒ could be reduced with preventive medication. In 236 patients taking OxyContinÒ for moderate to severe postherpetic neuralgia adverse effects abated with time on treatment; they included nausea (18%), constipation (10%), dizziness (10%), and somnolence (5.1%) [133C]. In 67 patients with malignant or nonmalignant neuropathic pain, dizziness and nausea were reported under 5%; respiratory depression and excessive sedation were not reported [134c]. Comparative studies In 14 patients using controlled-release oxycodone for postoperative pain and nine using patient-controlled morphine, there was a lower incidence of postoperative nausea and vomiting with oxycodone (14% versus 20%) [135c]. There was no somnolence, respiratory depression, confusion, or pruritus in either group. In a comparison of controlled-release oxycodone 20 mg and controlled-release tramadol 200 mg in the management of postoperative pain after surgery for breast cancer in 54 patients, there were no significant differences in adverse events [136c].

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The effects of oxycodone, methadone, morphine, and tramadol on the QT interval and HERG channels involved have been studied in 100 patients taking opioids for chronic non-malignant pain [137C]. Oxycodone and methadone caused prolongation of the QT interval, while morphine and tramadol did not; oxycodone blocked HERG channels in vitro. An increase in oxycodone dose of 100 mg was associated with a 10 msec increase in QTc interval. Gastrointestinal In a randomized study, 87 patients with pain due to herpes zoster infection taking famciclovir were allocated to controlled-release oxycodone, gabapentin, or placebo; eight patients withdrew, in four cases because of constipation, and of the others, 15 also had constipation [138c, 139r]. Drug–drug interactions Rifampicin Rifampicin reduced the therapeutic effect of oxycodone by inducting CYP3A in 12 healthy volunteers [140c]. Voriconazole Voriconazole markedly caused a 3.6-fold increase in plasma oxycodone concentrations after oral oxycodone in 12 healthy subjects, by inhibiting CYP3Amediated N-demethylation of oxycodone [141c]. Eight subjects reported adverse events, but none was severe. Management of adverse drug reactions Naloxone The combination of rectal oxycodone 40, 60, or 80 mg/day and rectal naloxone 10, 20, or 40 mg/day has been studied in a randomized, placebo-controlled 202 patients with chronic pain [142c]. The addition of naloxone reduced opioid-induced constipation. The combination of prolonged-release oxycodone 40, 60, or 80 mg/day and prolonged-release naloxone has been studied in 202 patients with chronic pain [143C, 144r]. Naloxone 20 and 40 mg significantly improved bowel function. A 2:1 oxycodone: naloxone combination ratio was identified as most suitable and there were no unexpected adverse events. With the higher doses

Opioid analgesics and narcotic antagonists

Chapter 8

of naloxone there was a tendency to an increased incidence of diarrhea. Pregabalin The combination of controlledrelease oxycodone with pregabalin reduced the incidence of somnolence associated with oxycodone in 169 patients compared with 106 on oxycodone alone [145c].

Oxymorphone

[SED-15, 2270;

SEDA-32, 203] Systematic reviews In a review of nine trials of oxymorphone alone or compared with placebo or other active agents, concentrating on its use in elderly patients, there were few adverse events [146M]. The authors suggested that oxymorphone should be considered appropriate for use in elderly, particularly those in whom there is concern about interactions with drugs that are metabolized by CYP isoenzymes, which oxymorphone does not inhibit. Death Two opiate abusers using oxymorphone by inhalation died; the post-mortem blood concentrations were 50 and 120 mg/l [147A].

Papaverine [SED-15, 2678; SEDA- 30, 115; SEDA-31, 168; SEDA-32, 205] Nervous system In a 67-year-old woman who had had a subarachnoid hemorrhage, intra-arterial papaverine was associated with development of a lesion in the left mesencephalon without a significant mass effect [148A]. The authors postulated that the papaverine had disrupted the blood–brain barrier, causing extravasation of blood and radiographic contrast agents, possibly facilitated by secondary hyperperfusion. Sensory systems Ears Topical papaverine for the treatment of vasospasm in neurosurgery was associated with transient disturbance for neurophysiological function of the ascending auditory pathway [149c].

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There was a temporal relation between papaverine and changes in brainstem auditory evoked potentials, leading to waveform loss. Other cases have been reported, as have patients with focal seizures [150r]. Sexual function In penile smooth muscle cells, endothelial cells, and fibroblasts intracavernosal injection of papaverine causes dose-dependent cytotoxicity and muscle hypertrophy and fibrosis [151r]. However, these effects tend to be limited to minor structural changes at the injection site and no significant effects on penile architecture. The incidence of fibrotic changes was low. Drug administration route Intracavernosal papaverine has been studied in 60 patients with normal Doppler studies of the penis. Injecting on one side of the penis affected the sinusoids and cavernosal artery on that side more than on the other side; five patients had priapism [152c]. The authors suggested dividing the dose and injecting both sides.

Pentazocine

[SED-15, 2777; SEDA-30, 115; SEDA-31, 168; SEDA-32, 205]

Skin A 54-year-old man developed deep punched-out ulcers with yellowish exudates and hyperpigmented and sclerotic surrounding skin on both thighs after using subcutaneous and intramuscular pentazocine for paraplegia and chronic back pain [153A]. A few months before the appearance of the ulcers he had increased the dosage to 30 mg up to 20 times a day. The lesions improved with a local antibiotic cream under occlusion.

Pethidine (meperidine) [SED-15, 2791; SEDA-30, 115; SEDA-31, 168; SEDA-32, 206] Systematic reviews Pethidine has been compared with dihydroergotamine, antiemetics, and ketorolac in acute migraine [154M]. Pethidine caused more dizziness and sedation and was less efficacious than the antiemetics, although they were associated with akathisia. There were no

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differences in efficacy or adverse effects between pethidine and ketorolac.

Remifentanil

Nervous system Pethidine is not recommended in the management of chronic pain because its active metabolite, norpethidine (normeperidine), is excitatory and can cause seizures [155R].

Observational studies When remifentanil was given by intravenous infusion pump at a rate of 0.1–0.15 micrograms/kg/minute to 186 patients undergoing percutaneous transhepatic biliary drainage (mean total dose 116 micrograms), 10% had transient bradycardia and 2% had respiratory depression [160C].

• A 27-year-old pregnant woman underwent cesarean section under epidural anesthesia and was given patient-controlled epidural analgesia, resulting in a total dose of 180 mg of pethidine over 9 hours; she had a tonic–clonic seizure, thought to be secondary to a high CSF concentration of norpethidine [156A].

Piritramide Respiratory When piritramide (mean dose 64 micrograms/kg) was given to 39 neonates and infants for postoperative analgesia, respiratory depression occurred in one case [157c].

Pholcodine

[SEDA-32, 206]

Immunologic Anaphylactic reactions have been attributed to the use of a cough syrup containing pholcodine, explaining the difference in risk between Norway and Sweden, and leading to the withdrawal of pholcodine from the Norwegian market and to examination of the role of pholcodine-containing products in other countries [158R]. In a multinational study of the effect of pholcodine-containing cough mixtures on the prevalence of IgE antibodies to various drugs, using the United Nations International Narcotics Control Board (INCB) database, there was a significant positive association between pholcodine consumption and the prevalence of IgE sensitization to pholcodine and morphine, but not to suxamethonium and p-aminophenyl-phosphoryl choline [159C]. This could be associated with an increased risk of allergic reactions.

[SED-15, 3030; SEDA-30, 116; SEDA-31, 168; SEDA-32, 207]

Comparative studies In a randomized study, 30 ASA I and II patients undergoing hysteroscopy were given propofol, mean dosage 90 micrograms/kg/minute) and either fentanyl 1 microgram/kg followed by boluses of 0.5 micrograms/kg if there were signs of insufficient analgesia or remifentanil 0.5 micrograms/kg followed by an infusion of 0.05 micrograms/kg/minute [161c]. Remifentanil was associated with a significantly lower mean arterial pressure after 1 minute but other adverse events (hypotension, respiratory depression) were similar between the two groups and all were successfully remedied by improving airway patency and reducing the dose. When intravenous remifentanil 2 micrograms/kg was compared with fentanyl 2 micrograms/kg and sufentanil 0.2 micrograms/kg in 315 patients undergoing elective abdominal surgery, there was a higher incidence of cough with remifentanil (54% versus 33% with fentanyl and 31% with sufentanil); the severity of cough was also greater with remifentanil [162C]. Cardiovascular In 132 patients undergoing elective craniotomy, remifentanil was in 12 different doses (0.10–0.21 micrograms/kg/ minute) was associated with hypotension at a median dose of 0.13 micrograms/kg/minute and bradycardia at 0.17 micrograms/kg/ minute [163c]. Respiratory In a comparison of remifentanil 1 microgram/kg and alfentanil 10 micrograms/kg in preventing withdrawal movements after rocuronium injection in 115 adults undergoing elective surgery,

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remifentanil was associated with a higher frequency of cough (24% versus 2%); one patient who received remifentanil developed apnea [164c]. Bolus remifentanil can be associated with thoracic muscle rigidity and consequent difficulty in mask or pressure-controlled ventilation [166R]. Drug tolerance Tolerance to remifentanil has been studied after short-term administration of remifentanil to 36 healthy volunteers [165C]. After a 3-hour infusion its analgesic potency fell by 5–24%, the risk of respiratory depression fell by 20–48%, and the risk of sedative effects fell by 32%. The authors concluded that short-term clinically useful doses of remifentanil were not associated with significant tolerance. Drug withdrawal A withdrawal syndrome has been described after the use of remifentanil by infusion in intensive care units [166R]. Within 10 minutes of withdrawal, patients experienced tachycardia, hypertension, sweating, mydriasis, and myoclonus. These symptoms persisted despite the use of morphine and clonidine and only resolved on readministration of remifentanil. Gradual tapering of remifentanil reduces the incidence of withdrawal symptoms. Susceptibility factors Intensive care The use of remifentanil in intensive care has been reviewed [167R]. Remifentanil is metabolized by unspecific blood and tissue esterases and its clearance is independent of organ insufficiency. The most commonly reported adverse events in mechanically ventilated critically ill patients include hypotension, bradycardia, and nausea. Thoracic and muscle rigidity and shivering have been reported with higher doses. Other reported concerns include tolerance and withdrawal pain. Drug administration route Remifentanil by manually controlled continuous infusion (0.125 micrograms/kg/minute for 2 minutes þ a continuous infusion of 0.05 micrograms/ kg/minute) has been compared with

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target-controlled infusion [168c]. In targetcontrolled infusion, the amount of medication received is the amount required to achieve the target. When 57 patients were given manually controlled continuous infusion remifentanil, target-controlled infusion remifentanil, or placebo, fewer of those who received the target-controlled infusion had bradypnea (five versus eight), apnea (two versus eight), or drowsiness (two versus five) compared with those who received manually controlled continuous infusion. Drug–drug interactions Morphine In a randomized double-blind study in 40 children undergoing surgical correction of idiopathic scoliosis, pre-treatment with morphine 150 micrograms/kg did not attenuate remifentanil-induced hyperalgesia, and there were trends to the use of more opioid after surgery and an increase in opioid-related adverse effects [169c].

Sufentanil

[SED-15, 3210; SEDA-31, 169; SEDA-32, 208] Comparative studies In a comparison of epidural sufentanil 0.015 micrograms/kg and fentanyl 0.1 micrograms/kg in children undergoing urological surgery, the former was associated with a higher incidence of pruritus (in six out of 32 compared with none) [170c].

Drug–drug interactions Midazolam A combination of midazolam (5 mg initially followed by 2.5 mg) and sufentanil 15 micrograms was given to a 3-year-old 14-kg girl as sedation for a dental procedure [171A]. She developed laryngospasm, airway obstruction, and deep sedation. She was given positive pressure ventilation, 0.4 mg naloxone intranasally, and two doses of flumazenil 100 micrograms intranasally. She recovered rapidly.

Tilidine Tilidine is a low to medium potency analgesic. It undergoes rapid first-pass metabolism

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to its active metabolites, nortilidine and bisnortilidine. Its analgesic activity is largely exerted through nortilidine which is a potent agonist at m opioid receptors. Drug–drug interactions Voriconazole In 16 volunteers, there was an interaction of tilidine with voriconazole, resulting in a 20fold increase in tilidine exposure [172c]. Voriconazole inhibits the metabolism of tilidine, resulting in increased exposure to the active metabolite nortilidine. This interaction was associated with an increased incidence of adverse drug reactions (from 40 to 79). The adverse reactions included dizziness (94%), nausea (75%), headache (56%), visual disturbances/photophobia (50%), vomiting (38%), and pruritus (31%).

Tramadol

[SED-15, 3469; SEDA-30, 117; SEDA-31, 170; SEDA-32, 208]

Comparative studies In 90 children undergoing adenotonsillectomy who were randomized to placebo, dextromethorphan cough syrup 1 mg/kg, or tramadol syrup pre-operatively plus intravenous tramadol 1 mg/kg during induction of anesthesia, the incidence of nausea and vomiting was highest in the tramadol group (10% compared to 5.5% with dextromethorphan group and 6.6% with placebo); however, significantly fewer patients (6.6% versus 40%) who received tramadol required supplementary pethidine [47c]. Tramadol 100 mg/day has been compared with ibuprofen and pregabalin in 20 healthy volunteers [173c]. Tramadol was associated with mild adverse effects, mainly fatigue/drowsiness (eight episodes), nausea/ vomiting (seven), dizziness/headache/difficulty in concentrating (seven). The NNTH for tramadol was 1.6. Placebo-controlled studies In a placebocontrolled study of the use of tramadol 50 mg tds in 35 patients with neuropathic pain due to spinal cord injuries adverse effects were substantial and resulted in withdrawal in 43% of patients compared

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with 17% of those on placebo [174c]. Adverse events were experienced by 91%; the common events included tiredness (74%), dry mouth (52%), dizziness (52%), sweating (39%), nausea (39%), and constipation (35%). Respiratory Respiratory depression is rare after the use of tramadol. A 66-year-old man developed respiratory depression after being given tramadol for postoperative pain [175A]. He responded to assisted mask ventilation and intravenous naloxone 0.4 mg. He had renal impairment and was an ultrarapid CYP2D6 metabolizer of tramadol, which has an active metabolite Odesmethyltramadol. Nervous system A 74-year-old man with Parkinson's disease was given tramadol 100 mg qds and his tremor worsened after 2 weeks, causing significant functional impairment [176A]. There was rapid improvement within 2 weeks of tramadol withdrawal. The authors speculated that the mechanism of this adverse effect might be related to effects on serotonergic pathways. Gastrointestinal In a randomized prospective comparison of lornoxicam 16 mg and tramadol 1 mg/kg every 6 hours for 24 hours for postoperative pain after inguinal hernia repair, tramadol caused nausea in 10% [177C]. Multiorgan failure Acute respiratory distress and multiple organ dysfunction occurred in a 19-year-old with a 6-month history of tramadol abuse; the blood tramadol concentration was 9.5 mg/l, which is well above the lethal blood concentration of 2 mg/l [178A]. Drug withdrawal A withdrawal syndrome has been described in a neonate born to a mother who was taking tramadol 400 mg/ day for chronic low back pain [179A]. During the last weeks of pregnancy, the dose was reduced to 200 mg/day. At 35 hours of age, the neonate had signs of severe withdrawal. The symptoms occurred earlier

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and lasted for a shorter time than symptoms after withdrawal of methadone or buprenorphine. The authors suggested that the shorter course was related to the half-life of the tramadol metabolite, O-demethyl-tramadol hydrochloride. Drug overdose Tramadol intoxication was responsible for 4.9% of admissions to an Iranian poisoning ward over a 2-month period (114 patients) [180c]. Most were men and the most common age group was 21–30 years. The most common adverse effects of tramadol toxicity were nausea, vomiting, nervous system depression, tachycardia, and seizures. Most of the toxic effects resolved within 24 hours. Patients who did not survive were reported to have taken high doses, ranging from 5000 to 8200 mg.

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respiratory depression with buprenorphine is lower than with other opioids and it is not associated with immunosuppression. Older age and severe impairment of renal function do not alter buprenorphine pharmacokinetics. There is a relatively low incidence of adverse effects, such as nervous system effects and constipation with transdermal buprenorphine, making it suitable for administration to at-risk patients, such as those requiring hemodialysis. Observational studies The role of buprenorphine in the treatment of non-psychotic major depression has been explored in six treatment-resistant patients with severe non-psychotic depression [183c]. They received buprenorphine 0.8–2 mg/day and their depressive symptoms improved within 1 week. In the initial days, they had adverse effects such as nausea, constipation, sedation, dizziness, and sweating.

Drug–drug interactions Paracetamol The synergistic effects and associated adverse effects of tramadol and paracetamol have been compared with those of codeine þ paracetamol (co-codamol) and dextropropoxyphene þ paracetamol (co-proxamol) [181C]. The combination of tramadol þ paracetamol was associated with the highest reporting rate and seriousness of adverse events. The most common adverse events were gastrointestinal, vascular, neurological, psychiatric, and cutaneous. There were fewer hepatobiliary events.

Respiratory Buprenorphine-induced respiratory depression has been studied in 24 subjects who received buprenorphine 0.2 mg and increasing doses of naloxone [184c]. Reversal of buprenorphine-induced respiratory depression required high doses of naloxone (over 2 mg) and further increases in naloxone dose (to over 4 mg) resulted in recurrent respiratory depression.

PARTIAL OPIOID RECEPTOR AGONISTS

• A 33-year-old man with a history of heroin addiction, alcohol abuse, and hepatitis C infection, developed hepatic and renal failure after switching from methadone to buprenorphine 20 mg/day. Investigations excluded the possibility of hepatitis reactivation.

Buprenorphine

[SED-15, 571; SEDA30, 118; SEDA-31, 171; SEDA-32, 209]

The safety of transdermal buprenorphine has been reviewed [182R]. Buprenorphine can be effectively and safely combined with full m receptor agonists, and switching between buprenorphine and other opioids at equianalgesic doses is not associated with inadequate analgesic efficacy. The risk of

Liver Therapeutic doses of buprenorphine have been linked to acute hepatitis and renal failure [185A].

The authors highlighted the need for liver function monitoring in the first few weeks of buprenorphine treatment in susceptible patients, such as those with hepatitis, alcohol abuse, or concomitant use of drugs that cause mitochondrial toxicity. Two patients developed acute hepatitis that occurred after abuse of buprenorphine intravenously [186A]. Both were taking

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sublingual buprenorphine 8 mg/day and were hepatitis C virus carriers. The authors stressed that buprenorphine had been the probable cause of the acute hepatitis and that the main mechanism was mitochondrial toxicity, exacerbated by other factors, such as concomitant use of alcohol. In both cases, acute hepatitis was followed by disappearance of hepatitis C RNA, suggesting clearance of the virus. Death The susceptibility factors that are associated with mortality among opioiddependent people taking buprenorphine or methadone treatment have been explored in an epidemiological study [187C]. Drug overdose and trauma were the major contributors to increased mortality. Periods of higher risk included the induction period on to methadone (but not on to buprenorphine) and at times of treatment withdrawal, which tend to be associated with a risk of relapse and an increased risk of suicide. Buprenorphine and methadone have similar standardized mortality ratios. The authors postulated that although buprenorphine induction was not associated with an increased risk, treatment with buprenorphine was linked to shorter periods of treatment, balancing the increased mortality rate. During the study period (1985–2006), the treatment program reduced mortality by 29%. Drug dependence Buprenorphine is suitable for treating opioid withdrawal. In a systematic review, buprenorphine was associated with low rates of full abstinence from drugs after opioid detoxification, and although detoxification with buprenorphine occurred over a shorter period, this was not associated with shifts in abstinence rates [188M]. Drug withdrawal Withdrawal symptoms have been described in a 2-year-old girl, who had been given regular buprenorphine tablets by her mother [189A]. She developed irritability, agitation, crying, yawning, piloerection, dilated pupils, a high pulse

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rate, and a blood pressure of 89/43 mmHg. Her symptoms resolved over 5 weeks after administration of morphine and then methadone. Pregnancy The roles of buprenorphine and methadone in the clinical management of opioid dependence during pregnancy and breast feeding have been reviewed [190R]. The dosages must be tailored to the needs of each opioid-dependent pregnant woman. Drug formulations A novel implant of buprenorphine (ProbuphineÒ) with sustained-release technology has been evaluated in 12 subjects with opioid dependence maintained on sublingual buprenorphine [191c]. Most of them (92%) had at least one adverse event and 58% had events related to the insertion or removal of the implant. Other adverse events were experienced by 42% and included dizziness, constipation, abdominal pain, implant site reactions, flushing, and pallor. There were no serious events. Drug administration route Transdermal buprenorphine has been studied in children with cancer pain in three case studies. An adverse event occurred in only one case— erythema and pruritus at the patch site [192A]. In 30 elderly patients over the age of 65 adverse events were comparable to those experienced by younger patients; however, 23% of elderly patients withdrew prematurely from the study owing to adverse events [193c]. In 30 adults, transdermal buprenorphine 35 micrograms/hour produced adequate pain relief, but there was a high incidence of adverse events: patients developed constipation (n ¼ 3), hypotension (3), urinary retention (2), or paradoxical hyperalgia (1); nine discontinued treatment mostly because of nausea and daytime sleepiness [194c]. Drug overdose During November 2002 to December 2005 there were 96 reports of unintentional buprenorphine overdose in children under 6 years of age from US

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poison centers to the Research Abuse, Diversion & Addiction-Related Surveillance System; 10 patients were excluded because they did not meet the inclusion criteria—seven were lost to follow-up and three had taken multiple substances [195c]. Of the others, 32 had no symptoms after overdose, 48 had minor reactions, and six had severe reactions. The mean time of onset of the adverse reactions was 64 minutes and they lasted 2–8 hours in most cases. There was significant central nervous system and respiratory depression in 7%. The clinical implications of this are that generally buprenorphine overdose is well tolerated, but any child under 2 years of age and any child who has taken more than 2 mg would require observation for a minimum of 6 hours.

Butorphanol [SED-15, 582; SEDA-31, 172; SEDA-32, 210] Comparative studies When patients with suspected biliary colic were randomized to intravenous ketorolac 30 mg (n ¼ 21) or intravenous butorphanol 1 mg (n ¼ 25), the former had more nausea (24% versus 4%) and vomiting (5% versus none); the latter had more sedation (36% versus 5%), dizziness (28% versus none), and rashes (4% versus none) [196c]. When butorphanol 4 micrograms/kg/hour was compared with fentanyl 0.4 micrograms/ kg/hour as intravenous patient-controlled analgesia for postoperative pain after abdominal hysterectomy in 100 patients, there were few adverse reactions [197c]. Respiratory rate was reduced by butorphanol 1 hour after the start of treatment. Drug withdrawal A 58-year-old man, who took midazolam 1.2 mg and butorphanol 0.12 mg/hour for 12 hours for insomnia over 2 weeks, had an acute withdrawal syndrome during tracheotomy; accumulation of butorphanol triggered withdrawal when remifentanil was used during the operation [198A].

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OPIOID RECEPTOR ANTAGONISTS Methylnaltrexone

[SED-15, 2307;

SEDA-32, 211] Methylnaltrexone has been widely used to manage opioid induced constipation and acts by blocking the entry of opioids into cells [199r]. The common adverse effects include abdominal pain, gas, nausea, dizziness, and diarrhea. The FDA has recommended that patients should stop taking methylnaltrexone if it causes severe diarrhea, vomiting, nausea, or abdominal pain. Placebo-controlled studies In a doubleblind, randomized, placebo-controlled trial in 154 patients with advanced illness and opioid induced constipation a single subcutaneous injection of methylnaltrexone 0.15 or 0.3 mg/kg was compared with placebo [200C]. The most common adverse events were abdominal pain and flatulence, and three patients had serious adverse events attributed to methylnaltrexone.

Nalmefene

[SED-15, 2420; SEDA-30, 119; SEDA-32, 211]

Placebo-controlled studies The effect of nalmefene on gambling symptoms and urges has been investigated using three doses of nalmefene (25, 50, and 100 mg) [201R]. Those who took 25 mg improved overall; those who took 50 and 100 mg did not, perhaps because of the frequency of adverse effects.

Naloxone

[SED-15, 2421; SEDA-30, 119; SEDA-31, 172] Cardiovascular Cardiac arrest occurred in a preterm neonate (gestation 27 weeks) after a bolus of naloxone (100 micrograms/kg) for the treatment of a 10-fold morphine

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overdose [202A]. Profound bradycardia and asystole occurred immediately after naloxone administration, the immediacy suggesting a causal relationship. Biliary tract Pruritus due to cholestasis in a 73-year-old man was treated with naloxone 2 nanograms/kg/minute, doubled every 12 hours up to 200 nanograms/kg/minute [203A]. The pruritus improved after 2 days but on the third day he had pain from metastases. The authors suggested caution in using opioid antagonists for pruritus, because of the possibility of unmasking pain.

Naltrexone

[SED-15, 2423; SEDA-30, 120; SEDA-31, 172; SEDA-32, 211]

The adverse reactions associated with the use of naltrexone in patients with alcohol dependence tend to be mild gastrointestinal reactions (nausea, vomiting, and abdominal pain or discomfort) and they occur early in treatment [204R]. Hepatotoxicity has been reported with high doses (100–300 mg/ day) and especially in obese individuals. Naltrexone can also precipitate opioid withdrawal and may not be suitable for those requiring future opioids, such as those requiring surgery. In 12 subjects with kleptomania the most common adverse reaction to naltrexone 50–150 mg/day was nausea (in five subjects, one of whom withdrew as a result) [205c]. Other events included dry mouth and

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insomnia. The events were mild to moderate and usually occurred in the first week of treatment. Observational studies In 30 drinkers the magnitude of naltrexone-induced aversion correlated with the amount of ethanol consumed during naltrexone treatment [206c]. The level of aversion also predicts future reduction in consumption. Placebo-controlled studies In a doubleblind, randomized, placebo-controlled trial in 80 patients with amfetamine dependence, naltrexone 50 mg/day was given for 12 weeks [207C]. There were adverse reactions in 14 patients and they were rated as mild. The most frequent reactions were nausea, gastrointestinal discomfort, headache, and fatigue. Drug–drug interactions Sertraline The combination of naltrexone 50 mg and sertraline 100 mg has been studied in patients with alcohol dependence in rural settings [208c]. The combination did not result in improved abstinence rates. Adverse events were more common in those who took naltrexone and sertraline (n ¼ 33) than those who took naltrexone alone (n ¼ 34) or placebo (n ¼ 34). There was nausea in 78% (compared with 59% and 47% respectively); dry mouth in 72% (47% and 47%); sleepiness in 69% (35% and 26%); and dizziness in 47% (24% and 21%).

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[121] Zakine J, Samarcq D, Lorne E, Moubarak M, Montravers P, Beloucif S, Dupont H. Postoperative ketamine administration decreases morphine consumption in major abdominal surgery: a prospective, randomized, double-blind, controlled study. Anesth Analg 2008; 106(6): 1856–61. [122] Nesher N, Serovian I, Marouani N, Chazan S, Weinbroum AA. Ketamine spares morphine consumption after transthoracic lung and heart surgery without adverse hemodynamic effects. Pharmacol Res 2008; 58(1): 38–44. [123] Nesher N, Ekstein MP, Paz Y, Marouani N, Chazan S, Weinbroum AA. Morphine with adjuvant ketamine versus higher dose of morphine alone for immediate postthoracotomy analgesia. Chest 2009; 136(1): 245–52. [124] Aveline C, Gautier JF, Vautier P, Cognet F, Hetet HL, Attali JY, Leconte V, Leborgne P, Bonnet F. Postoperative analgesia and early rehabilitation after total knee replacement: a comparison of continuous low-dose intravenous ketamine versus nefopam. Eur J Pain 2009; 13(6): 613–9. [125] Sheen MJ, Ho S-T, Lee C-H, Tsung Y-C, Chang F-L, Huang S-T. Prophylactic mirtazapine reduces intrathecal morphineinduced pruritus. Br J Anaesth 2008; 101 (5): 711–5. [126] Yeh Y-C, Lin T-F, Lin F-S, Wang Y-P, Lin C-J, Sun W-Z. Combination of opioid agonist and agonist-antagonist: patientcontrolled analgesia requirement and adverse events among different-ratio morphine and nalbuphine admixtures for postoperative pain. Br J Anaesth 2008; 101(4): 542–8. [127] Koch J, Manworren R, Clark L, Quinn CT, Buchanan GR, Rogers ZR. Pilot study of continuous co-infusion of morphine and naloxone in children with sickle cell pain crisis. Am J Hematol 2008; 83(9): 728–31. [128] Netzer P, Sendensky A, Wissmeyer MP, Baumeler S, Batista C, Scheurer U, Krause T, Reber P, Brenneisen R. The effect of naloxone-3-glucuronide on colonic transit time in healthy men after acute morphine administration: a

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[168] Moerman AT, Herregods LL, De Vos MM, Mortier EP, Struys MMRF. Manual versus target-controlled infusion remifentanil administration in spontaneously breathing patients. Anesth Analg 2009; 108(3): 828–34. [169] McDonnell C, Zaarour C, Hull R, Thalayasingam P, Pehora C, Ahier J, Crawford MW. Pre-treatment with morphine does not prevent the development of remifentanil-induced hyperalgesia. Can J Anaesth 2008; 55(12): 813–8. [170] Cho JE, Kim JY, Kim JE, Chun DH, Jun NH, Kil HK. Epidural sufentanil provides better analgesia from 24 h after surgery compared with epidural fentanyl in children. Acta Anaesthesiol Scand 2008; 52(10): 1360–3. [171] Heard C, Creighton P, Lerman J. Intranasal flumazenil and naloxone to reverse over-sedation in a child undergoing dental restorations. Pediatr Anesth 2009; 19(8): 795–9. [172] Grun B, Krautter S, Riedel K-D, Mikus G. Inhibition of the active principle of the weak opioid tilidine by the triazole antifungal voriconazole. Br J Clin Pharmacol 2009; 68(5): 712–20. [173] Altis K, Schmidtko A, Angioni C, Kuczka K, Schmidt H, Geisslinger G, Lotsch J, Tegeder I. Analgesic efficacy of tramadol, pregabalin and ibuprofen in menthol-evoked cold hyperalgesia. Pain 2009; 147: 116–21. [174] Norrbrink C, Lundeberg T. Tramadol in neuropathic pain after spinal cord injury a randomized, double-blind, placebo-controlled trial. Clin J Pain 2009; 25(3): 177–84. [175] Stamer UM, Stuber F, Muders T, Musshoff F. Respiratory depression with tramadol in a patient with renal impairment and CYP2D6 gene duplication. Anesth Analg 2008; 107(3): 926–9. [176] Mellor K, Ahmed A, Thomson A. Tramadol hydrochloride use and acute deterioration in Parkinson's disease tremor. Mov Disord 2009; 24(4): 622–3. [177] Mentes O, Bagci M. Postoperative pain management after inguinal hernia repair: lornoxicam versus tramadol. Hernia 2009; 13(4): 427–30.

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238 [178] Wang S-Q, Li C-S, Song Y-G. Multiply organ dysfunction syndrome due to tramadol intoxication alone. Am J Emerg Med 2009; 27(7): 903.e5–7. [179] Willaschek C, Wolter E, Buchhorn R. Tramadol withdrawal in a neonate after longterm analgesic treatment of the mother. Eur J Clin Pharmacol 2009; 65(4): 429–30. [180] Shadnia S, Soltaninejad K, Heydari K, Sasanian G, Abdollahi M. Tramadol intoxication: a review of 114 cases. Hum Exp Toxicol 2008; 27(3): 201–5. [181] Tavassoli N, Lapeyre-Mestre M, Sommet A, Montastruc J-L. Reporting rate of adverse drug reactions to the French pharmacovigilance system with three step 2 analgesic drugs: dextropropoxyphene, tramadol and codeine (in combination with paracetamol). Br J Clin Pharmacol 2009; 68 (3): 422–6. [182] Kress HG. Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine. Eur J Pain 2009; 13(3): 219–30. [183] Nyhuis PW, Gastpar M, Scherbaum N. Opiate treatment in depression refractory to antidepressants and electroconvulsive therapy. J Clin Psychopharmacol 2008; 28 (5): 593–5. [184] Sarton E, Teppema L, Dahan A. Naloxone reversal of opioid-induced respiratory depression with special emphasis on the partial agonist/antagonist buprenorphine. Adv Exp Med Biol 2008; 605: 486–91. [185] Zuin M, Giorgini A, Selmi C, Battezzati PM, Cocchi CA, Crosignani A, Benetti A, Invernizzi P, Podda M. Acute liver and renal failure during treatment with buprenorphine at therapeutic dose. Dig Liver Dis 2009; 41(7): e8–10. [186] Peyriere H, Tatem L, Bories C, Pageaux G-P, Blayac J-P, Larrey D. Hepatitis after intravenous injection of sublingual buprenorphine in acute hepatitis C carriers: report of two cases of disappearance of viral replication after acute hepatitis. Ann Pharmacother 2009; 43(5): 973–7. [187] Degenhardt L, Randall D, Hall W, Law M, Butler T, Burns L. Mortality among clients of a state-wide opioid pharmacotherapy program over 20 years: risk

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Anti-inflammatory and antipyretic analgesics and drugs used in gout

An update on adverse events in patients taking COX-2 selective and non-selective NSAIDs Cyclo-oxygenase-2 (COX-2) selective inhibitors (coxibs) were developed because of reduced gastrointestinal adverse reactions compared with traditional non-selective NSAIDs, but later evidence suggested an increased cardiovascular risk [1R, 2R]. More information has recently been published about adverse events in patients taking COX-2 selective and non-selective NSAIDs.

1. Gastrointestinal adverse events A lower gastrointestinal risk with coxibs was confirmed in a retrospective case–control study of the incidence of peptic ulcer bleeding and perforation in users of COX-2 selective and non-selective NSAIDs [3C]. The study was based on 2.2 million adults taking celecoxib, diclofenac, ibuprofen, naproxen, rofecoxib, or valdecoxib. Adjusted odds ratios (OR) compared with naproxen were: ibuprofen 0.86 (95% CI ¼ 0.68, 1.09), rofecoxib 0.79 (0.62, 1.02), diclofenac 0.66 (0.47, 0.94), valdecoxib 0.50 (0.26, 0.97), and celecoxib 0.45 (0.35, 0.58). The overall Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00009-X # 2011 Elsevier B.V. All rights reserved.

OR for peptic ulcer bleeding and perforation of non-selective NSAIDs compared with coxibs was 1.51 (95% CI ¼ 1.26, 1.98). A meta-analysis of 21 randomized controlled trials of celecoxib and non-selective NSAIDs included 7797 patients taking celecoxib 200 mg/day, 6653 taking celecoxib 400 mg/day, 2953 taking naproxen, 499 taking ibuprofen, and 5643 taking diclofenac [4M]. Gastrointestinal adverse events were reported by fewer patients taking celecoxib (16%) than patients taking naproxen (24%), ibuprofen (24%), or diclofenac (20%). In a review of coxibs for osteoarthritis based on 17 studies with over 10 000 patients the relative risk (RR) of gastroduodenal ulcers while taking a coxib compared with taking a non-selective NSAID was 0.26 (95% CI ¼ 0.23, 0.30) [5M]. A study in 23 504 patients with osteoarthritis or rheumatoid arthritis, the MEDAL (Multinational Etoricoxib and Diclofenac Arthritis Long-term) study, confirmed lower gastrointestinal/liver adverse event discontinuation rates for etoricoxib versus diclofenac; the hazard ratios (HR) were 0.46 (95% CI ¼ 0.39, 0.54), 0.52 (0.42, 0.63), and 0.49 (0.39, 0.62) for etoricoxib 60 mg/day versus diclofenac 150 mg/day in osteoarthritis, etoricoxib 90 mg/day versus diclofenac 150 mg/day in osteoarthritis, and etoricoxib 90 mg/day versus diclofenac 150 mg/day in rheumatoid arthritis respectively [6C]. While lower rates of upper gastrointestinal events with coxibs versus non-selective NSAIDs are now well established, there 241

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seems to be little difference with regard to lower gastrointestinal adverse events, at least when etoricoxib and diclofenac are compared. In an analysis of 34 701 patients with osteoarthritis or rheumatoid arthritis randomized to etoricoxib (60 or 90 mg/day) or diclofenac (150 mg/day) from the MEDAL study, the EDGE (Etoricoxib versus Diclofenac Sodium Gastrointestinal Tolerability and Effectiveness) study, and the EDGE II study, there was no reduction in lower gastrointestinal clinical events (including perforation, obstruction requiring hospitalization, and bleeding) with etoricoxib compared with diclofenac [7C]. Rates of lower gastrointestinal clinical events were 0.32 and 0.38 per 100 patient-years for etoricoxib and diclofenac respectively (HR ¼ 0.84; 95% CI ¼ 0.63, 1.13).

2. Cardiovascular adverse events Several studies have suggested that regular use of coxibs increases the risk of myocardial infarction. New analyses have confirmed this view. In a retrospective cohort study (n ¼ 38 258 patients; 26 376 patientyears), the odds of acute myocardial infarction during exposure to etodolac, naproxen, celecoxib, or rofecoxib were reported. Compared with naproxen, there was no significantly increased risk with etodolac, whereas with celecoxib (OR ¼ 2.18; 95% CI ¼ 1.09, 4.35) and rofecoxib (OR ¼ 2.16; 95% CI ¼ 1.04, 4.46) there was an increased risk [8C]. However, some non-selective NSAIDs other than naproxen may also increase cardiovascular risk. Coxibs cause more cardiovascular adverse events than naproxen but do not seem to increase cardiovascular risk compared with some other non-selective NSAIDs [5M, 9M]. For example, data from the MEDAL study (n ¼ 23 504 patients, see above) showed that the thrombotic cardiovascular risk hazard ratio of etoricoxib versus diclofenac was 0.96 (95% CI ¼ 0.81, 1.15), suggesting that etoricoxib was not more dangerous than diclofenac [6C]. A meta-analysis has shown that after noncardiac surgery, valdecoxib and its prodrug parecoxib did not increase the risk of

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Sebastian Straube

cardiovascular adverse events [10M]. This contrasts with coronary artery bypass graft surgery, after which an increased incidence of cardiovascular adverse events has been reported [11C]. Recent analyses have allowed a more precise estimation of the increased cardiovascular risk associated with regular use of coxibs or non-selective NSAIDs. The 5-year efficacy and safety analysis of the Adenoma Prevention with Celecoxib Trial (2035 patients receiving placebo, celecoxib 200 mg bd, or celecoxib 400 mg bd) showed that for cardiovascular and thrombotic adverse events, the RR compared with placebo was 1.6 (95% CI ¼ 1.0, 2.5) for patients taking celecoxib 200 mg bd and 1.9 (95% CI ¼ 1.2, 3.1) for patients taking celecoxib 400 mg bd [12C]. The final analysis of the Adenomatous Polyp Prevention on Vioxx (APPROVe) study (n ¼ 2587 patients; rofecoxib 25 mg, n ¼ 1287; and placebo, n ¼ 1300) included the combined incidence of non-fatal myocardial infarction, non-fatal stroke, and death from cardiovascular, hemorrhagic, and unknown causes (Antiplatelet Trialists' Collaboration, APTC, combined end-point) and found that 59 individuals had an APTC combined end-point in the rofecoxib 25 mg group versus 34 in the placebo group (HR ¼ 1.79; 95% CI ¼ 1.17, 2.73) [13C]. In a case–control study using drug-dispensing and hospitalization data from more than 2 million residents in The Netherlands, subjects with a first hospitalization for acute myocardial infarction, cardiovascular and gastrointestinal events were identified [14C]. Use of coxibs and non-selective NSAIDs was classified into remote, recent, and current use. Compared with remote use, the risk of acute myocardial infarction was increased in current users of all coxibs (adjusted OR ¼ 1.73; 95% CI ¼ 1.37, 2.19) and all non-selective NSAIDs (adjusted OR ¼ 1.41; 95% CI ¼ 1.23, 1.61). Analysis by separate agents showed that the risk of acute myocardial infarction was increased with celecoxib (OR ¼ 2.53; 95% CI ¼ 1.53, 4.18), rofecoxib (OR ¼ 1.60; 95% CI ¼ 1.22, 2.10), ibuprofen (OR ¼ 1.56; 95% CI ¼ 1.19, 2.05), and diclofenac (OR ¼ 1.51; 95% CI ¼ 1.22, 1.87), but not with naproxen (OR ¼ 1.21; 95% CI ¼ 0.87, 1.68).

Anti-inflammatory and antipyretic analgesics and drugs used in gout

The cardiovascular risk with coxibs and non-selective NSAIDs seems to depend not only on which drug is used, but also on patient characteristics and past medical history. In a cohort study of beneficiaries of US Medicare and a drug benefit program (Pharmaceutical Assistance Contract for the Elderly in Pennsylvania), 76 082 new users of coxibs, 53 014 new users of nonselective NSAIDs, and 46 558 non-users were identified [15C]. Compared with nonusers, the adjusted RR of cardiovascular disease events for new users of coxibs and nonselective NSAIDs varied between agents; for example it was increased for rofecoxib (1.22; 95% CI ¼ 1.14, 1.30), not significantly different for ibuprofen (0.96; 95% CI ¼ 0.83, 1.10), and reduced for celecoxib (0.89; 95% CI ¼ 0.83, 0.94) and naproxen (0.79; 95% CI ¼ 0.67, 0.93). The authors went on to determine the cardiovascular disease event rates for different NSAIDs in various patient subgroups and observed increased event rates with certain agents in certain patients. For example, among those aged 80 years or over, patients taking rofecoxib had 4.8 more cardiovascular disease events per 100 person-years and patients taking ibuprofen had 3.4 more events compared with non-users. For patients with a prior myocardial infarction, those taking rofecoxib had 9.4 more cardiovascular disease events and those taking ibuprofen had 11.4 more events per 100 person-years than non-users. In a retrospective cohort study patients with osteoarthritis (6580 patients chronically exposed to celecoxib, 9800 to rofecoxib, 2907 to naproxen, and 51 539 non-chronically exposed controls, either non-chronic users or non-users) were investigated. Comparing the risk of hospitalization for acute myocardial infarction or ischemic stroke with the non-chronic users as the reference group, there was an increased risk with rofecoxib (adjusted HR ¼ 1.25; 95% CI ¼ 1.04, 1.50) but no significantly increased risk with celecoxib or naproxen. Furthermore, the risk of hospitalization for acute myocardial infarction or ischemic stroke varied considerably with patient characteristics: the excess risk attributable to rofecoxib

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(comparison with non-chronic NSAID users) varied from three per 1000 personyears in those under 65 years old with no previous ischemic stroke to 19 per 1000 personyears for patients aged 65 or over and with a history of ischemic stroke [16C]. In patients with chronic heart failure, coxibs and non-selective NSAIDs, including naproxen, were associated with increased mortality and cardiovascular morbidity. In a Danish study of 107 092 patients who survived their first hospitalization because of heart failure between 1995 and 2004 and their subsequent use of NSAIDs, the hazard ratios for death associated with rofecoxib, celecoxib, ibuprofen, diclofenac, naproxen, and other NSAIDs were 1.70 (95% CI ¼ 1.58, 1.82), 1.75 (95% CI ¼ 1.63, 1.88), 1.31 (95% CI ¼ 1.25, 1.37), 2.08 (95% CI ¼ 1.95, 2.21), 1.22 (95% CI ¼ 1.07, 1.39), and 1.28 (95% CI ¼ 1.21, 1.35) respectively [17C].

3. Gastrointestinal The question of whether coxibs can exacerbate inflammatory bowel disease has been addressed in a systematic review, which found only two randomized placebo-controlled trials including 363 patients [18M]. There was no significant difference in the relapse rate between coxibs and placebo. The authors concluded that there were insufficient data to determine the effect of coxibs on exacerbations of inflammatory bowel disease.

4. Urinary tract The association between COX-2 selective and non-selective NSAIDs and acute kidney injury has been investigated in 183 446 Medicare beneficiaries [19C]. There was acute kidney injury in 870 (0.47%) users of non-selective NSAIDs or coxibs. Compared with celecoxib there was a significantly higher risk with indometacin (RR ¼ 2.23; 95% CI ¼ 1.70, 2.93), ibuprofen (RR ¼ 1.73; 95% CI ¼ 1.36, 2.19), and

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rofecoxib (RR ¼ 1.52; 95% CI ¼ 1.26, 1.83). Overall, acute kidney injury requiring hospitalization was a relatively rare adverse event in users of non-selective NSAIDs or coxibs.

Sebastian Straube

The magnitude of the cardiovascular risk with COX-2 selective and non-selective NSAIDs depends on patient characteristics and past medical (especially cardiovascular) history. The choice of the best NSAID should take account of individual patient characteristics.

5. Liver In a pooled analysis of 41 randomized trials of the hepatic safety of celecoxib and nonselective NSAIDs there were fewer hepatobiliary adverse events with celecoxib (1.1%) than diclofenac (4.2%). For ibuprofen (1.5%) and placebo (0.89%) the incidence of adverse events was comparable to that with celecoxib. The incidence of serious hepatic adverse events was low: 0.05% among 24 933 celecoxib-treated patients, and 0.21% among 7639 diclofenac-treated patients [20M]. However, rare cases of celecoxib-induced liver failure requiring transplantation have been reported [21A].

6. Respiratory While the use of coxibs as an alternative to other NSAIDs has been suggested for patients with aspirin-induced asthma, there have been case reports of asthmatic reactions to coxibs in patients with aspirin-sensitive asthma [22A, 23A]; so caution is necessary.

Conclusions Recent evidence has confirmed the lower risk of upper (but not lower) gastrointestinal adverse events with coxibs compared with traditional NSAIDs and also the increased cardiovascular risk with regular use of coxibs compared with placebo. However, the evidence now suggests that there may also be an increased cardiovascular risk for some (non-naproxen) non-selective NSAIDs. Postoperative use of coxibs after non-cardiac surgery seems not to be associated with an increased cardiac risk, in contrast to coronary artery bypass graft surgery.

AMIDOPYRINE AND RELATED COMPOUNDS Metamizole (dipyrone) [SED-15, 2268] Nervous system A series of 28 cases of post-injection injuries after intragluteal injections recorded over 8 years in an electroneuromyography laboratory has been reported [24c]. A complete history was available in 26 cases. They all had sudden pain and subsequent radiation of pain and numbness in the distribution of the sciatic nerve. In 23 cases the injected drug was known; it was metamizole (dipyrone) in 11.

ANILINE DERIVATIVES [SED-15, 2679; SEDA-30, 129]

Paracetamol (acetaminophen) Respiratory More evidence has been published about the possible association between paracetamol and asthma. In a multicenter case–control study of 521 patients with asthma and 507 controls, weekly use of paracetamol, compared with less frequent use, was associated with asthma [25C]. A study of 19 349 adult twins enrolled in the nationwide Danish Twin Registry showed a higher prevalence of asthma in subjects with frequent intake of paracetamol (OR ¼ 2.16; 95% CI ¼ 1.03, 4.53) after adjusting for confounders [26C]. Furthermore, a study of 205 487 children aged 6–7 years showed that paracetamol use for fever in the first year of life was associated with a higher risk of asthma

Anti-inflammatory and antipyretic analgesics and drugs used in gout

symptoms at age 6–7 (OR ¼ 1.46; 95% CI ¼ 1.36, 1.56) [27C]. Current use of paracetamol was also associated with a higher risk of asthma symptoms. Moreover, paracetamol use, both in infancy and at age 6–7 years, was associated with rhinoconjunctivitis and eczema. Skin A vulval fixed drug eruption has been attributed to paracetamol [28A]. Immunologic Two cases of paracetamolassociated anaphylaxis and angioedema have been reported [29A, 30A].

ANTHRANILIC ACID DERIVATIVES Etofenamate Skin A series of 14 cases of allergic and photoallergic contact dermatitis induced by etofenamate has been reported [31c]. According to the authors, about 20 previous cases have been described in the English language literature.

Mefenamic acid

[SED-15, 2230]

Sensory systems A 30-year-old man developed bilateral transient myopia, secondary angle closure glaucoma, and choroidal detachment while taking mefenamic acid [32A]. He was successfully managed by stopping the medication and symptomatic treatment.

ARYLALKANOIC ACID DERIVATIVES [SED-15, 2555; SEDA-31, 186; SEDA-32, 229]

Bufexamac Skin Pigmented purpuric dermatosis has been attributed to bufexamac [33A]. • Four days after using a bufexamac-containing cream for hemorrhoids a 56-year-old man

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developed mostly non-palpable purpura beginning on the trunk and generalizing within a few days. There was moderate itch, especially perianally. Pervious patch testing had shown sensitization to bufexamac. The clinical and histological picture was of a pigmented purpuric eruption.

Acute generalized exanthematous pustulosis has been attributed to bufexamac [34A]. • A 3-year-old girl used topical bufexamac twice a day for mild eczema of the cheeks and after 2 days developed erythematous and pustular lesions, at first on the face and then rapidly spreading to the rest of the body, associated with a fever. Acute generalized exanthematous pustulosis was confirmed by skin biopsy.

Diclofenac Cardiovascular Kounis syndrome (acute myocardial infarction occurring during the course of an allergic reaction) has been attributed to diclofenac [35A]. Gastrointestinal In a retrospective case– control study of 75 patients undergoing laparoscopic colorectal resection with primary anastomosis, there was a higher rate of anastomotic leakages in patients who took oral diclofenac for postoperative analgesia (seven of 33 patients) compared with patients who received opioid analgesia (one of 42 patients) [36c]. Liver In 17 289 patients who had used diclofenac for a mean of 18 months there were rises in aminotransferases to more than three times the upper limit of normal in 527 cases (3.1%) and to more than 10 times the upper limit of normal in 86 (0.5%); there were liver-related hospitalizations in four (0.023%) [37C]. Skin Allergic contact dermatitis [38A] and photoallergic contact dermatitis [39A] have been attributed to topical diclofenac. In the two cases with photoallergic contact dermatitis, there was cross-reactivity with aceclofenac.

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Musculoskeletal Bleeding outside the gastrointestinal tract due to diclofenac, a rare event, has been reported [40A]. • A 60-year-old woman developed a spontaneous thigh hematoma after taking diclofenac 100 mg/day for osteoarthritis for 9 days. On the ninth day a severe sharp pain developed in her right thigh and was followed 2 days later by extensive bruising of her right leg.

Flurbiprofen Skin A fixed drug eruption in association with a drug-induced myocarditis has been attributed to flurbiprofen [41A]. • Α 23-year-old man with chest pain noted skin eruptions on his hands, lips, mouth, and penis 24–36 hours after he had taken flurbiprofen (dose not stated). The electrocardiogram showed widespread ST elevation and cardiac markers (troponin I, creatine kinase) were raised.

Ibuprofen

Sebastian Straube

Ketoprofen Skin Erythema multiforme induced by photocontact dermatitis occurred in a patient taking ketoprofen [45A]. • A 74-year-old man developed erythema multiforme on his left elbow where a ketoprofen-containing tape had been applied and exposed to sunlight. The eruption subsequently spread to the limbs and trunk. Lymphocyte stimulation tests showed lymphocytes reactive with a photohaptenic moiety of ketoprofen.

Ketorolac Respiratory Acute asthma with a fatal outcome has been attributed to ketorolac in a woman with a history of asthma [46A]. • A 45-year-old woman with a history of asthma collapsed and died within a few minutes after an intramuscular injection of ketorolac tromethamine. Autopsy confirmed a recent asthma attack. Based on the timing of the collapse after ketorolac tromethamine injection, her death was attributed to an adverse reaction to ketorolac tromethamine, resulting in acute bronchospasm and cardiac arrest.

Gastrointestinal Esophageal perforation has been attributed to ibuprofen [42A].

Loxoprofen

• An 18-year-old man developed sudden onset, severe, retrosternal pain, dysphagia, and odynophagia after taking ibuprofen capsules. An X-ray and CT scan showed esophageal perforation.

Liver A 36-year-old woman developed progressive intrahepatic cholestasis after a 5-day course of loxoprofen 180 mg/day for menstrual pain [47A].

Liver Ibuprofen has been linked with hyperbilirubinemia in preterm neonates. In a retrospective comparison of 418 preterm infants receiving ibuprofen prophylaxis of patent ductus arteriosus and 288 infants who were not treated with ibuprofen those who received ibuprofen had a higher peak serum bilirubin concentration, needed more phototherapy, and had a longer duration of phototherapy [43C]. Skin A 64-year-old woman who had taken ibuprofen 400 mg for toothache developed multiple pustular lesions and underlying erythema of the cheeks and chin due to acute localized exanthematous pustulosis [44A].

COX-2 SELECTIVE INHIBITORS [SEDA-30,

130; SEDA-31, 190; SEDA-32, 232]

Celecoxib

[SED-15, 685; SEDA-31, 190; SEDA-32, 233] Immunologic Celecoxib-associated anaphylaxis has been described in a patient who had previously tolerated it [48A].

Drug overdose In 177 cases of pediatric celecoxib ingestion reported to Texas poison control centers during 2000–2007, the dose

Anti-inflammatory and antipyretic analgesics and drugs used in gout

was reported in 92; the mean dose was 306 mg (range 10–2300 mg) [49C]. Specific effects were rash, abdominal pain, vomiting, agitation/irritability, and drowsiness (reported in one case each). None of the ingestions resulted in more than minor effects. Drug–drug interactions Docetaxel Celecoxib may enhance the marrow toxicity of docetaxel [50c]. In patients (24 enrolled, 20 treated) with non-small cell lung cancers celecoxib 400 mg orally bd was started 7 days before the first cycle of docetaxel and continued without interruption. Docetaxel 75 mg/ m2 was administered intravenously on a 21day cycle. Frequent neutropenia (14 patients, 58%) and neutropenic fever (5 patients, 21%) resulted in early closure of the trial.

Rofecoxib [SED-15, 3076; SEDA-31, 191; SEDA-32, 233] Observational studies In postmarketing surveillance of serious adverse events associated with the use of rofecoxib from 1999 to 2002 there were 31 024 reports of serious adverse events, and the drug was considered the primary suspect in 97.8% of reports [51C]. There were 3915, 3677, 1653, 1917, and 233 reports of hemorrhage, edema, death, thrombosis, and embolism respectively. The authors argued that, in addition to the risk of myocardial infarction and stroke, rofecoxib use might be associated with an increased risk of hemorrhage. A limitation of this analysis was that the data may have contained multiple reports from the same individual.

INDOLEACETIC ACIDS [SEDA-25, 134]

Indometacin

[SED-15, 1739]

Observational studies In 105 preterm infants randomized to receive an extended 3-day course of either low-dose indometacin (0.1 mg/kg/day) or higher-dose indometacin (0.2 or 0.5 mg/kg/day) for persistent patent ductus arteriosus, increasing

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indometacin concentrations above those achieved with a conventional dosing regimen was associated with higher rates of moderate or severe retinopathy of prematurity and raised serum creatinine [52c].

[SEDA-15, 2555; SEDA-28, 128; SEDA-30, 132; SEDA-32, 233]

OXICAMS

Meloxicam

[SEDA-15, 2248; SEDA-31, 192]

Drug–drug interactions Antifungal azoles In a crossover study in 12 healthy volunteers who took meloxicam 15 mg without pretreatment (controls), after pretreatment with voriconazole (an inhibitor of CYP2C9 and CYP3A4), and after pretreatment with itraconazole (an inhibitor of CYP3A4), voriconazole increased the AUC0!72h of meloxicam by 47% and itraconazole reduced it by 37% [53c]. The lower plasma meloxicam concentrations during the itraconazole phase were associated with a reduced effect of meloxicam, as demonstrated by weaker inhibition of thromboxane B2 synthesis.

Piroxicam

[SED-15, 2843; SEDA-31, 192]

Skin A fixed drug eruption with mucosal involvement has been attributed to piroxicam; the authors referred to 11 previous similar reports, two of which had mucosal involvement [54A].

PYRAZOLONE DERIVATIVES (PHENYLBUTAZONE AND RELATED COMPOUNDS) [SEDA-27, 111]

Phenylbutazone

[SEDA-15, 2805]

Skin Drug rash with eosinophilia and systemic symptoms (DRESS) has been attributed to phenylbutazone [55A].

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248 • A 57-year-old woman developed a drug rash with eosinophilia and systemic symptoms after taking phenylbutazone for 15 days. She had a skin eruption, hypereosinophilia, and liver involvement and made a full recovery after drug withdrawal.

Another case was reported of Sweet's syndrome with sialadenitis induced by phenylbutazone [56A]. Interference with diagnostic tests Factitious rises in serum testosterone (DPCÒ RIA, Los Angeles, CA, USA) in five patients taking phenylbutazone have previously been described [57A] and six further cases using other assays (DSLÒ RIA, Webster, TX, USA; and BRAHMSÒ TRACE on KRYPTORÒ, Berlin, Germany) have been reported [58A].

SALICYLATES

[SED-15, 15;

SEDA-30, 128]

Acetylsalicylic acid (aspirin) Respiratory More genetic determinants of aspirin-intolerant asthma have been identified. Interleukin-10 (IL-10), transforming growth factor b-1 (TGF-b1) [59C], angiotensin I-converting enzyme (ACE) [60C], and high-affinity IgE receptor (FceR1) promoter polymorphisms [61C] have been associated with aspirin-intolerant asthma, as have polymorphisms in the genes for indoleaminepyrrole 2,3 dioxygenase (INDO) and the interleukin 1 receptor, type II (IL1R2) [62C]. Nervous system A spontaneous spinal epidural hematoma in a 62-year-old man taking aspirin 100 mg/day caused low back pain, progressive bilateral lower limb weakness and numbness, and urinary retention [63A]. He subsequently developed paraplegia with a sensory level at L1, lax anal tone, and reduced perianal sensation. Emergency decompression laminectomy was followed by recovery.

Sebastian Straube

Gastrointestinal Hypertriglyceridemia may be a susceptibility factor for peptic ulceration caused by aspirin. In 137 patients newly diagnosed with gastroduodenal ulcers and 274 controls, high serum triglycerides were associated with aspirin-related peptic ulceration [64C]. In patients with high serum triglycerides not taking aspirin the risk of peptic ulceration was not increased. Skin Genetic determinants of aspirininduced urticaria and aspirin-intolerant chronic urticaria have been identified. Two tumor necrosis factor a (TNF-a) promoter polymorphisms and a leukotriene C4 synthase promoter polymorphism are associated with aspirin-induced urticaria [65C, 66C]. A transforming growth factor b-1 (TGFb1) promoter polymorphism is associated with aspirin-intolerant chronic urticaria [67C]. Drug rash with eosinophilia and systemic symptoms (DRESS) occurred in a 2-yearold boy with Kawasaki disease taking aspirin 80 mg/kg/day [68A]. Reproductive system Recurrent hematospermia has been attributed to aspirin (dose not stated) [69A]. Death In a registry-based study of 58 465 Swedish patients with diabetes aspirin significantly increased the risk of death in those without cardiovascular disease (previous or acute myocardial infarction, angina pectoris, ischemic stroke, transient ischemic attack, intermittent claudication, previous coronary artery bypass graft surgery, or percutaneous coronary intervention) by 17% (95% CI ¼ 1, 36) at age 50 years and by 29% (95% CI ¼ 16, 43) at age 85 years [70C]. In elderly patients with diabetes with cardiovascular disease who used aspirin there was a non-significant trend towards reduced mortality, by 11% at age 85 years. The risk of serious bleeding was also increased by aspirin in those without cardiovascular disease and reduced by aspirin in those with cardiovascular disease.

Anti-inflammatory and antipyretic analgesics and drugs used in gout

Drug overdose A report of salicylate intoxication has shown that salicylate absorption and metabolism after a large overdose can be unpredictable and that there is a risk of delayed toxicity [71A]. • A 53-year-old man attempted suicide by taking about 200 aspirin tablets (325 mg each). The serum salicylate concentration 7 hours after admission was 0.96 mmol/l and after 17 hours 3.5 mmol/l, when he was sweating, tachypneic, and unresponsive to questioning. He died 20 hours after the initial admission despite intensive treatment.

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adverse events in the diacerein arm, most commonly yellow discoloration of the urine and soft stools [74c].

Flupirtine

[SEDA-15, 1425]

Nervous system Abuse of flupirtine can cause nervous system symptoms [75A]. • A 17-year-old girl developed a headache, blurred vision, confusion, ataxia, and syncope. A urine sample was green in color and contained a high concentration of flupirtine (which had caused the green coloration). Her symptoms resolved in 24 hours. Because she did not admit to having taken flupirtine, the ingested dose was unclear.

MISCELLANEOUS DRUGS Benzydamine (benzindamine) [SEDA-15, 443] Drug abuse Benzydamine is used as a hallucinogen in Brazil. Of 2807 street youths aged 10–18 years 78 reported lifetime recreational benzydamine use in a survey [72c]. Unwanted effects were reported by 21 of 30 recent users, including nausea and vomiting in six. Drug overdose In a retrospective study of ingestions of benzydamine-containing vaginal irrigation products reported to the Spanish Poison Control Centre (1991–2003) there were 724 reports [73c]. When present, signs and symptoms were largely gastrointestinal (48% of symptomatic patients), neurological (31%), or both (21%). The most frequent symptoms were nausea (33% of symptomatic patients), vomiting (28%), dizziness (20%), hallucinations (15%), abdominal pain (13%), esophageal irritation (11%), and agitation (11%). Six of 68 children had hallucinations and a 4-year-old developed convulsions.

Nimesulide

[SED-15, 2524]

Liver Nimesulide-induced hepatotoxicity can occur, with serious and potentially fatal outcomes. Three cases of liver failure related to nimesulide have been reported [76A, 77A, 78A]. In a retrospective analysis from the Irish national liver transplant unit all recipients of a liver transplant for fulminant hepatic failure of unknown cause (1994–2007) were evaluated [79c]. There were 32 patients with seronegative, non-paracetamol-induced liver failure. Nimesulide had been started within 6 months in six patients and was assessed as probably associated with liver injury in all of these cases. Skin Two cases of fixed drug eruptions associated with nimesulide have been reported [80A, 81A]. Fetotoxicity The use of cyclo-oxygenase inhibitors in pregnancy is associated with a risk of premature closure of the ductus arteriosus, as occurred after maternal selfmedication with nimesulide for low back pain at 39 weeks of gestation [82A].

Diacerein (diacetylrhein) [SEDA-15, 1094] Placebo-controlled studies In a placebocontrolled trial of diacerein in osteoarthritis (n ¼ 64) there were significantly more

Phenazopyridine

[SED-15, 2795]

Hematologic Two new cases of cyanosis (acrocyanosis and purple hands) associated

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with sulfhemoglobinemia and methemoglobinemia after phenazopyridine have been reported [83A, 84A].

DRUGS USED IN THE TREATMENT OF GOUT Allopurinol [SEDA-15, 80; SEDA-31, 201] Skin Allopurinol has commonly been implicated in Stevens–Johnson syndrome and toxic epidermal necrolysis [85C]. This association has been confirmed by an analysis from Singapore. Of 85 cases of Stevens–Johnson syndrome and toxic epidermal necrolysis managed in Singapore from 2003 to 2007, allopurinol was implicated in 13 cases [86c]. The HLA-B*5801 allele is associated with severe cutaneous adverse reactions caused by allopurinol in the Han Chinese population [87c]. The association between allopurinol-related Stevens–Johnson syndrome and toxic epidermal necrolysis and HLA-B*5801 has also been confirmed in Thai and Japanese patients [88c, 89c]. Two more cases of drug rash with eosinophilia and systemic symptoms (DRESS) associated with allopurinol have been reported [90A, 91A]. Oral ulceration has been attributed to allopurinol; the authors found a total of six reported cases of allopurinol-induced oral mucosal ulcers including the new case [92A].

Sebastian Straube

Colchicine [SEDA-28, 133; SEDA-30, 133; SEDA-31, 202] Drug–drug interactions Colchicine is metabolized by CYP3A4 and transported by P glycoprotein. It can therefore accumulate and have toxic effects during concomitant therapy with inhibitors of CYP3A4 and P glycoprotein, such as clarithromycin, disulfiram, and ciclosporin. Three such cases have been described [93A, 94A, 95A].

Febuxostat

[SEDA-32, 235]

Comparative studies In a double-blind, randomized, controlled comparison (n ¼ 1072) of febuxostat (80, 120, or 240 mg/day) with allopurinol and placebo, the proportions of patients with any adverse event or serious adverse events were similar across the groups. However, diarrhea and dizziness were more frequent in those who took febuxostat 240 mg compared with those who took the lower doses of febuxostat [96C].

Rasburicase

[SEDA-31, 203; SEDA-32,

236] Hematologic When rasburicase (recombinant urate oxidase) converts uric acid into soluble allantoin, which is eliminated by the kidneys, a high concentration of hydrogen peroxide is generated. This hydrogen peroxide can cause hemolysis and methemoglobinemia in patients with glucose-6-phosphate-dehydrogenase and catalase deficiencies [97r].

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[38]

Sebastian Straube

Three of the ISAAC programme. Lancet 2008; 372(9643): 1039–48. Drummond C, Fischer G. Vulval fixed drug eruption due to paracetamol. Australas J Dermatol 2009; 50(2): 118–20. Ho MH, Tung JY, Lee TL, Tsoi NS, Lau YL. Anaphylaxis to paracetamol. J Paediatr Child Health 2008; 44(12): 746–7. Panchabhai TS, Gogtay NJ, Bavdekar SB. Paracetamol induced angioedema. Indian J Med Sci 2008; 62(10): 420–2. Goday Buján JJ, Pérez Varela L, Piñeyro Molina F, Díaz Román T, Fonseca E. Allergic and photoallergic contact dermatitis from etofenamate: study of 14 cases. Contact Dermatitis 2009; 61(2): 118–20. Vishwakarma P, Raman GV, Sathyan P. Mefenamic acid-induced bilateral transient myopia, secondary angle closure glaucoma and choroidal detachment. Indian J Ophthalmol 2009; 57(5): 398–400. Waltermann K, Marsch WCh, Kreft B. Kontaktallergie durch Bufexamac unter dem Bild einer chronischen Pigmentpurpura. [Bufexamac-induced pigmented purpuric eruption.] Hautarzt 2009; 60(5): 424–7. Belhadjali H, Ghannouchi N, Njim L, Mohamed M, Moussa A, Bayou F, Chakroun M, Zakhama A, Zili J. Acute generalized exanthematous pustulosis induced by bufexamac in an atopic girl. Contact Dermatitis 2008; 58(4): 247–8. de Groot JW, Gosselink AT, Ottervanger JP. Acute ST-segment elevation myocardial infarction associated with diclofenac-induced anaphylaxis: case report. Am J Crit Care 2009; 18(4): 386–7 388. Klein M, Andersen LP, Harvald T, Rosenberg J, Gogenur I. Increased risk of anastomotic leakage with diclofenac treatment after laparoscopic colorectal surgery. Dig Surg 2009; 26(1): 27–30. Laine L, Goldkind L, Curtis SP, Connors LG, Yanqiong Z, Cannon CP. How common is diclofenac-associated liver injury? Analysis of 17,289 arthritis patients in a long-term prospective clinical trial. Am J Gastroenterol 2009; 104(2): 356–62. Lynde CB, Pierscianowski TA, Pratt MD. Allergic contact dermatitis caused by diclofenac cream. CMAJ 2009; 181(12): 925–6.

Anti-inflammatory and antipyretic analgesics and drugs used in gout [39] Fernández-Jorge B, Goday-Buján JJ, Murga M, Molina FP, Pérez-Varela L, Fonseca E. Photoallergic contact dermatitis due to diclofenac with cross-reaction to aceclofenac: two case reports. Contact Dermatitis 2009; 61(4): 236–7. [40] Salemis NS. Spontaneous thigh hematoma associated with diclofenac. Am J Emerg Med 2009; 27(1): 129.e1–2. [41] Uzkeser M, Emet M, Aslan S, Cakir Z, Turkyilmaz S, Aksakal E, Seven B. Myocarditis due to oral flurbiprofen use. Am J Emerg Med 2009; 27(1): 132.e3–5. [42] Singh NP, Rizk JG. Oesophageal perforation following ingestion of over-the-counter ibuprofen capsules. J Laryngol Otol 2008; 122(8): 864–6. [43] Zecca E, Romagnoli C, De Carolis MP, Costa S, Marra R, De Luca D. Does ibuprofen increase neonatal hyperbilirubinemia? Pediatrics 2009; 124(2): 480–4. [44] Rastogi S, Modi M, Dhawan V. Acute localized exanthematous pustulosis (ALEP) caused by ibuprofen. A case report. Br J Oral Maxillofac Surg 2009; 47(2): 132–4. [45] Izu K, Hino R, Isoda H, Nakashima D, Kabashima K, Tokura Y. Photocontact dermatitis to ketoprofen presenting with erythema multiforme. Eur J Dermatol 2008; 18(6): 710–3. [46] Campobasso CP, Procacci R, Caligara M. Fatal adverse reaction to ketorolac tromethamine in asthmatic patient. Am J Forensic Med Pathol 2008; 29(4): 358–63. [47] Ichikawa T, Sato H, Kaira K, Oh-I S, Kakizaki S, Sato K, Takagi H, Mori M. Prolonged intrahepatic cholestasis after exposure to loxoprofen. Clin Ther 2008; 30 (12): 2402–6. [48] Chamberlin KW, Silverman AR. Celecoxib-associated anaphylaxis. Ann Pharmacother 2009; 43(4): 777–81. [49] Forrester MB. Cases of pediatric ingestion of celecoxib reported to Texas poison control centers in 2000–2007. Hum Exp Toxicol 2009; 28(4): 191–4. [50] Schneider BJ, Kalemkerian GP, Kraut MJ, Wozniak AJ, Worden FP, Smith DW, Chen W, Gadgeel SM. Phase II study of celecoxib and docetaxel in non-small cell lung cancer (NSCLC) patients with progression after platinum-based therapy. J Thorac Oncol 2008; 3(12): 1454–9.

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[51] Bottone FG, Barry WT. Postmarketing surveillance of serious adverse events associated with the use of rofecoxib from 1999–2002. Curr Med Res Opin 2009; 25 (6): 1535–50. [52] Jegatheesan P, Ianus V, Buchh B, Yoon G, Chorne N, Ewig A, Lin E, Fields S, MoonGrady A, Tacy T, Milstein J, Schreiber M, Padbury J, Clyman R. Increased indomethacin dosing for persistent patent ductus arteriosus in preterm infants: a multicenter, randomized, controlled trial. J Pediatr 2008; 153(2): 183–9. [53] Hynninen VV, Olkkola KT, Bertilsson L, Kurkinen KJ, Korhonen T, Neuvonen PJ, Laine K. Voriconazole increases while itraconazole decreases plasma meloxicam concentrations. Antimicrob Agents Chemother 2009; 53(2): 587–92. [54] Fernández-Jorge B, Goday JJ, Almagro M, Fonseca E. Exantema fijo medicamentoso por piroxicam. [Fixed drug eruption due to piroxicam.]. Actas Dermosifiliogr 2008; 99 (3): 239–40. [55] Valade S, Toledano C, Tiev K, Gain M, Josselin L, Cabane J, Kettaneh A. Dress syndrome à la phénylbutazone. [DRESS syndrome caused by phenylbutazone]. Rev Med Interne 2009; 30(8): 708–10. [56] Levang J, Muller P, Girardin P, Humbert P. Syndrome de Sweet et sialadénite à la phénylbutazone. [Sweet's syndrome and phenylbutazone-induced sialadenitis.] Ann Dermatol Venereol 2008; 135(4): 291–4. [57] Giltay EJ, Popp-Snijders C, van Denderen JC, van Schaardenburg D, Gooren LJ, Dijkmans BA. Phenylbutazone can spuriously elevate unextracted testosterone assay results in patients with ankylosing spondylitis. J Clin Endocrinol Metab 2000; 85(12): 4923–4. [58] Uzzan B, Dumont-Fischer D, Lahlou N, Bihan H, Boissier MC, Alvarez JC, Perret GY, Cohen R. Factitious increases in serum testosterone concentrations related to phenylbutazone therapy. Fundam Clin Pharmacol 2008; 22(2): 159–60. [59] Kim SH, Yang EM, Lee HN, Cho BY, Ye YM, Park HS. Combined effect of IL-10 and TGF-beta1 promoter polymorphisms as a risk factor for aspirin-intolerant asthma and rhinosinusitis. Allergy 2009; 64(8): 1221–5.

254 [60] Kim TH, Chang HS, Park SM, Nam BY, Park JS, Rhim T, Park HS, Kim MK, Choi IS, Cho SH, Chung IY, Park BL, Park CS, Shin HD. Association of angiotensin I-converting enzyme gene polymorphisms with aspirin intolerance in asthmatics. Clin Exp Allergy 2008; 38(11): 1727–37. [61] Palikhe NS, Kim SH, Cho BY, Ye YM, Hur GY, Park HS. Association of three sets of high-affinity IgE receptor (FceR1) polymorphisms with aspirin-intolerant asthma. Respir Med 2008; 102(8): 1132–9. [62] Sekigawa T, Tajima A, Hasegawa T, Hasegawa Y, Inoue H, Sano Y, Matsune S, Kurono Y, Inoue I. Geneexpression profiles in human nasal polyp tissues and identification of genetic susceptibility in aspirin-intolerant asthma. Clin Exp Allergy 2009; 39(7): 972–81. [63] Oh JY, Lingaraj K, Rahmat R. Spontaneous spinal epidural haematoma associated with aspirin intake. Singapore Med J 2008; 49(12): e353–5. [64] Fujii T, Nakabayashi T, Hashimoto S, Kuwano H. Correlation between serum triglycerides and gastro-duodenal ulcer associated with low-dose aspirin. Hepatogastroenterology 2009; 56(93): 1241–4. [65] Choi JH, Kim SH, Cho BY, Lee SK, Kim SH, Suh CH, Park HS. Association of TNF-alpha promoter polymorphisms with aspirin-induced urticaria. J Clin Pharm Ther 2009; 34(2): 231–8. [66] Sánchez-Borges M, Acevedo N, Vergara C, Jiménez S, Zabner-Oziel P, Monzón A, Caraballo L. The A-444C polymorphism in the leukotriene C4 synthase gene is associated with aspirin-induced urticaria. J Investig Allergol Clin Immunol 2009; 19(5): 375–82. [67] Park HJ, Ye YM, Hur GY, Kim SH, Park HS. Association between a TGFb1 promoter polymorphism and the phenotype of aspirin-intolerant chronic urticaria in a Korean population. J Clin Pharm Ther 2008; 33(6): 691–7. [68] Kawakami T, Fujita A, Takeuchi S, Muto S, Soma Y. Drug-induced hypersensitivity syndrome: drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome induced by aspirin treatment of Kawasaki disease. J Am Acad Dermatol 2009; 60(1): 146–9.

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[69] Najafi L, Noohi AH. Recurrent hematospermia due to aspirin. Indian J Med Sci 2009; 63(6): 259–60. [70] Welin L, Wilhelmsen L, Björnberg A, Odén A. Aspirin increases mortality in diabetic patients without cardiovascular disease: a Swedish record linkage study. Pharmacoepidemiol Drug Saf 2009; 18(12): 1143–9. [71] Herres J, Ryan D, Salzman M. Delayed salicylate toxicity with undetectable initial levels after large-dose aspirin ingestion. Am J Emerg Med 2009; 27(9): 1173. e1–1173.e3. [72] Opaleye ES, Noto AR, Sanchez ZM, Moura YG, Galduróz JC, Carlini EA. Recreational use of benzydamine as a hallucinogen among street youth in Brazil. Rev Bras Psiquiatr 2009; 31(3): 208–13. [73] Ballesteros S, Ramón MF, MartínezArrieta R. Ingestions of benzydaminecontaining vaginal preparations. Clin Toxicol (Phila) 2009; 47(2): 145–9. [74] Brahmachari B, Chatterjee S, Ghosh A. Efficacy and safety of diacerein in early knee osteoarthritis: a randomized placebocontrolled trial. Clin Rheumatol 2009; 28 (10): 1193–8. [75] Hufschmidt A, Krisch A, Peschen I. A girl with headache, confusion and green urine. J Neurol 2009; 256(7): 1169–70. [76] Betrosian AP, Flevari K, Andrianakis I, Boudouri I, Douzinas EE. Severe hemolytic anemia and fatal hepatic failure associated with nimesulide. Dig Liver Dis 2009; 41(1): 80. [77] Page M, Christin F, Hayi-Slayman D, Baillon JJ, Ber CE, Delafosse B, Dumortier J, Rimmelé T. Hépatite fulminante liée à un traitement par nimésulide: encore un cas et revue de la littérature. [Acute liver failure due to a treatment by nimesulide: another case and review.] Ann Fr Anesth Reanim 2008; 27(9): 742–6. [78] Lukić S, Krstić M, Damjanov N, Boricić I, Popović D, Djuranović S, Kovacević N, Tomanović N. Cholestatic hepatitis associated with nimesulide—a case report. Srp Arh Celok Lek 2009; 137(9–10): 550–3. [79] Walker SL, Kennedy F, Niamh N, McCormick PA. Nimesulide associated fulminant hepatic failure. Pharmacoepidemiol Drug Saf 2008; 17(11): 1108–12.

Anti-inflammatory and antipyretic analgesics and drugs used in gout [80] Katoulis AC, Bozi E, Kanelleas A, Makris M, Alevizou A, Panagiotides I, Stavrianeas NG. Psoriasiform fixed drug eruption caused by nimesulide. Clin Exp Dermatol 2009; 34(7): e360–1. [81] Rallis E, Stavropoulou E, Paraskevopoulos I. Nimesulide-induced, multifocal, urticarial fixed drug eruption confirmed by oral provocation test. Indian J Dermatol Venereol Leprol 2008; 74(4): 403–4. [82] Prefumo F, Marasini M, De Biasio P, Venturini PL. Acute premature constriction of the ductus arteriosus after maternal selfmedication with nimesulide. Fetal Diagn Ther 2008; 24(1): 35–8. [83] Kermani TA, Pislaru SV, Osborn TG. Acrocyanosis from phenazopyridineinduced sulfhemoglobinemia mistaken for Raynaud phenomenon. J Clin Rheumatol 2009; 15(3): 127–9. [84] Singh NK, Mirza N. Elderly woman with orange urine and purple hands. Mayo Clin Proc 2008; 83(7): 744. [85] Halevy S, Ghislain PD, Mockenhaupt M, Fagot JP, Bouwes Bavinck JN, Sidoroff A, Naldi L, Dunant A, Viboud C, Roujeau JC. EuroSCAR Study Group. Allopurinol is the most common cause of Stevens–Johnson syndrome and toxic epidermal necrolysis in Europe and Israel. J Am Acad Dermatol 2008; 58(1): 25–32. [86] Lee HY, Pang SM, Thamotharampillai T. Allopurinol-induced Stevens–Johnson syndrome and toxic epidermal necrolysis. J Am Acad Dermatol 2008; 59(2): 352–3. [87] Hung SI, Chung WH, Liou LB, Chu CC, Lin M, Huang HP, Lin YL, Lan JL, Yang LC, Hong HS, Chen MJ, Lai PC, Wu MS, Chu CY, Wang KH, Chen CH, Fann CS, Wu JY, Chen YT. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci USA 2005; 102(11): 4134–9. [88] Tassaneeyakul W, Jantararoungtong T, Chen P, Lin PY, Tiamkao S, Khunarkornsiri U, Chucherd P, Konyoung P, Vannaprasaht S, Choonhakarn C, Pisuttimarn P, Sangviroon A, Tassaneeyakul W. Strong association between HLA-B*5801 and allopurinol-induced Stevens–Johnson syndrome and toxic

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[97]

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epidermal necrolysis in a Thai population. Pharmacogenet Genomics 2009; 19(9): 704–9. Kaniwa N, Saito Y, Aihara M, Matsunaga K, Tohkin M, Kurose K, Sawada J, Furuya H, Takahashi Y, Muramatsu M, Kinoshita S, Abe M, Ikeda H, Kashiwagi M, Song Y, Ueta M, Sotozono C, Ikezawa Z, Hasegawa R. JSAR research group. HLA-B locus in Japanese patients with anti-epileptics and allopurinol-related Stevens–Johnson syndrome and toxic epidermal necrolysis. Pharmacogenomics 2008; 9(11): 1617–22. Calogiuri GF, Satriano F, Muratore L, Valacca A, Nettis E, Di Leo E, Vacca A. Therapeutic alternatives in a patient with DRESS syndrome induced by allopurinol. J Investig Allergol Clin Immunol 2009; 19 (4): 333–4. Sackesen C, Dut R, Gucer S, Soyer OU, Adalioglu G. Allopurinol-induced DRESS syndrome in a 13-year-old girl. J Investig Allergol Clin Immunol 2009; 19(1): 65–7. Sato C, Nomura J, Matsumura Y, Watanabe Y, Shimizu K, Tagawa T. A case of gingival ulcer thought to be caused by allopurinol. J Oral Maxillofac Surg 2009; 67(11): 2510–3. Chen SC, Huang MC, Fan CC. Potentially fatal interaction between colchicine and disulfiram. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33(7): 1281. McKinnell J, Tayek JA. Short term treatment with clarithromycin resulting in colchicine-induced rhabdomyolysis. J Clin Rheumatol 2009; 15(6): 303–5. Eleftheriou G, Bacis G, Fiocchi R, Sebastiano R. Colchicine-induced toxicity in a heart transplant patient with chronic renal failure. Clin Toxicol (Phila) 2008; 46 (9): 827–30. Schumacher Jr. HR, Becker MA, Wortmann RL, Macdonald PA, Hunt B, Streit J, Lademacher C, Joseph-Ridge N. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum 2008; 59(11): 1540–8. Góth L. Rasburicase therapy may cause hydrogen peroxide shock.. Orv Hetil 2008; 149(34): 1587–90.

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General anesthetics and therapeutic gases

ANESTHETIC VAPORS [SEDA-30, 137; SEDA-31, 217; SEDA-32, 243]

carbon monoxide; and metabolism via the glutathione pathway, yielding carbon dioxide and a glutathione conjugate, similar to paracetamol overdose.

HALOGENATED VAPORS

Chloroform

[SED-15, 721]

Chloroform is a halogenated hydrocarbon used previously as an anesthetic agent and a general industrial solvent. Short-term exposure has adverse health effects, such as hepatitis, dysrhythmias, and carbon monoxide poisoning [1A]. • A 23-year-old man attempted suicide by ingesting 100 ml chloroform and dichloromethane. His Glasgow Coma Score was 9/15 and his pupils were mildly dilated but responsive. Initial hemodynamic variables and blood and radiology investigations were normal. The carbon monoxide concentration was 8.9% (reference range 0–1.9%) and he was treated with activated charcoal. On day 3 he developed nausea, vomiting, abdominal pain, and jaundice and on days 4 and 5 aminotransferase activities peaked (AsT 1617 IU/l and AlT 2677 IU/l). A CT scan showed severe fatty infiltration of the liver parenchyma. Four weeks later the liver enzymes returned to normal and ultrasonography of the liver was normal 6 months after the event.

The mechanism of hepatic injury in this case had two potential mechanisms: oxidative metabolism, producing phosgene (a hepatotoxin), hydrochloric acid, and Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00010-6 # 2011 Elsevier B.V. All rights reserved.

Halothane

[SED-15, 1581]

Liver Halothane hepatitis has again been described [2A]. Susceptibility factors are increasing age, female sex, obesity, autoimmune disease, and previous exposure to hepatotoxic drugs such as isoniazid or rifampicin. • A 4-year-old obese (36-kg) Hispanic girl underwent adenotonsillectomy using halothane general anesthesia, during which there were no perioperative adverse events. She was discharged on the same day. She had been treated with isoniazid and rifampicin 4 years previously, because of a positive Mantoux test. On day 10 she developed a fever, vomiting, and malaise and had raised liver enzymes. On day 12 she was lethargic with an all-over body rash, hepatomegaly (AsT 7876 IU/l, AlT 6090 IU/l), and a raised white cell count (14
109/l). She had renal insufficiency (blood urea nitrogen 23 mmol/l and creatinine 274 mmol/l) and a coagulopathy. Hepatitis serology and an autoimmune screen were normal and Epstein–Barr virus serology showed previous but not current infection. She was treated with fluids, clotting products, antibiotics, and N-acetylcysteine. She did not require ventilator or inotropic support and on day 21 was discharged home. One month later, her liver and renal function and coagulation were normal. Subsequent analysis showed IgG autoantibodies to a 58 kDa endoplasmic reticulum protein, ERp58, and CYP2E1 and trifluoroacetylated IgG4 antibodies. 257

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This child developed halothane hepatitis after her first vapor anesthetic but she had susceptibility factors of obesity, female sex, and previous exposure to isoniazid and rifampicin, albeit 4 years before. Isoniazid induces CYP2E1 and therefore increases the metabolism of halothane, perhaps placing her at increased risk. Although there is no defined diagnostic test for halothane hepatitis, most experts feel that the presence of hepatitis, eosinophilia, CYP2E1 or ERp58 autoantibodies, or trifluoroacetyl chloride specific IgG antibodies after the exclusion of infection increases the probability.

Isoflurane

[SED-15, 1921; SEDA-30, 138; SEDA-31, 218; SEDA-32, 244]

Psychological Isoflurane can be used for sedation in intensive care units (ICUs). In a retrospective chart review, 335 patients who received isoflurane for more than 12 hours were investigated for psychomotor dysfunction [3c]. In 12 cases, there was generalized tremor, facial tremor, generalized chorea, or hallucinations. There were no significant differences in MAC-hours or the use of adjuncts to isoflurane (midazolam, morphine, fentanyl, glucocorticoids, or aminophylline) between patients with and without psychomotor dysfunction. Regression analysis showed that age under 4 years and duration of isoflurane (but not MAC-hours) correlated with the occurrence of psychomotor dysfunction. Psychomotor dysfunction was significantly less if duration of isoflurane inhalation was less than 24 hours (0% versus 7.1%). Inhalation for more than 24 hours made no further difference. The limitations of this study were that the conclusions were drawn from 10 patients who developed symptoms; when they were further divided into groups according to age and duration of exposure, there were fewer than four patients per group. Also, as some of the described symptoms were very mild and short lived, it is possible that some were missed. There was no mention of whether the study was conducted retrospectively or prospectively,

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which will almost certainly have affected the quantity of missing data.

Methoxyflurane

[SED-15, 2290;

SEDA-32, 244] Systematic reviews A review of all articles concerning the use of methoxyflurane in the emergency and pre-hospital setting yielded 48 relevant articles; all except one were from case series [4M]. Six articles investigated the analgesic efficacy of methoxyflurane, using doses of less than 0.5%. Most described an absolute pain reduction of 1–4 points on a 10-point scale with variable patient satisfaction. One prospective observational study described a lack of success with methoxyflurane in patients who were unable to achieve a sufficient degree of analgesia before a painful stimulus; the authors hypothesized that pre-empting the painful stimulus may increase the success of procedural management. In pre-hospital use, two large case series (105 children and 83 adults) describe no serious adverse effects. Minor adverse effects of hallucinations, vomiting, dizziness, cough, and headache have been described. Comparative data with other agents are minimal. Urinary tract Methoxyflurane can cause dose-dependent renal toxicity in anesthetic doses. There have been no cases of renal toxicity using the current analgesic dosage recommendations (one 3 ml cartridge used to deliver up to 0.7% using a penthrox inhaler). However, there have been reports of renal and hepatic dysfunction when methoxyflurane has been used as a drug of abuse and in obstetric practice, although the doses used were not described.

Sevoflurane

[SED-15, 3123; SEDA-30, 138; SEDA-31, 218; SEDA-32, 245] Comparative studies In a prospective single-blind trial in 125 randomized patients

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who received a standardized general anesthetic and then either propofol (2 mg/kg/ hour) or sevoflurane (0.5–1%), all other postoperative management was standardized [5c]. The duration of postoperative sedation was comparable in the two groups. Although length of stay in the Intensive Care Unit (ICU) did not differ, ventilated time and length of stay in the hospital were significantly shorter with sevoflurane. Postoperative adverse effects (nausea and vomiting, agitation and delirium) were similar in the two groups. Inorganic fluoride ions were significantly increased by sevoflurane. Concentrations of alpha-glutathione-S-transferase (alpha-GST, a cytosolic protein highly specific to cells in the proximal tubules, used for predicting toxicity) were significantly raised in both groups at 24 and 48 hours from baseline with no differences between the groups. There was no correlation between inorganic fluoride concentrations and alpha-GST or serum creatinine concentrations. The activity of N-acetyl-glucosaminidase (NAG, a lysosymal enzyme released into the urine in tubular injury) was unchanged in both study arms. This study suggests that short-term sedation with sevoflurane does not affect renal integrity, even in the presence of increased inorganic fluoride concentrations. The effects of desflurane or sevoflurane on immediate recovery and return to normal function have been studied in 130 patients who were randomized to sevoflurane or desflurane (approximately 0.8 MAC) as maintenance anesthesia for superficial, non-cavitational surgery [6c]. Early recovery end-points (eye opening, obeying commands, and orientation) were significantly shorter with desflurane but there were no differences in the times to sitting, tolerating fluids, or length of stay in the post-anesthesia care unit. Normal activities of daily living were resumed on the first postoperative day by 60% of those who had received desflurane and 48% of those who had received sevoflurane, a non-significant difference. Over 95% of both groups were satisfied with their overall experience. The incidences of coughing were similar in the two groups during

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induction, maintenance, and emergence, but in the overall period those who received desflurane had a higher incidence of coughing, although all the episodes were short lasting and none resulted in laryngospasm. There were no differences in the incidences of postoperative sore throat, pain, or nausea and vomiting between the two groups. Composite end-points were used to achieve statistical significance in the incidence of coughing, but as none resulted in a clinically significant airway event, the clinical relevance is debatable. The anesthetist was not blinded but was instructed to maintain a “minimally acceptable level of anesthesia, to prevent movement and achieve rapid wake up”, which may have biased the results. In a double-blind randomized study, 179 children undergoing day-case dental surgery received either sevoflurane (2%) or propofol (250 micrograms/kg/minute with additional boluses of 1 mg/kg as required). Rescue analgesia was provided using boluses of fentanyl and emergence delirium was measured using the pediatric anesthesia emergence delirium (PAED) score [7C]. There were no differences in premedication, duration of procedure, or dose of intraoperative fentanyl between the groups. There were no significant differences in the PAED scores. Patients who required more postoperative rescue analgesia had a higher PAED score, perhaps suggesting confusion between pain and delirium. The incidence of postoperative nausea and vomiting was higher with sevoflurane (odds ratio, OR ¼ 5.3) and more nursing interventions were also required in the recovery room. It may be that patients with postoperative pain in this study were defined as having emergence delirium, and this may have influenced the outcome of the study. Also, patients in the propofol group received sevoflurane for induction. Although this is a common anesthetic technique in children, it may have affected the results. Systematic reviews In a meta-analysis of 23 prospective randomized studies of the incidence of emergence delirium in children under 12 years of age anesthetized with

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sevoflurane (n ¼ 1252) or halothane (n ¼ 1111) the pooled OR of the incidence of emergence delirium with sevoflurane was 2.21 [8M]. In all subgroup analyses (better quality-rated studies, children under 7 years, inguinal or minor urological surgery, and myringotomy surgery), the higher OR for sevoflurane-induced emergence delirium remained significant. There is no widely used definition of emergence delirium, which made these studies heterogeneous, but tests for heterogeneity in this study showed no differences. No study used a validated tool for emergence delirium, such as the PAED score, and blinding was variable. Emergence delirium is difficult to define and often, especially in younger children, difficult to distinguish from pain. The authors of this study claimed to show that sevoflurane still has a greater incidence of emergence delirium if a pain strategy is provided, but there were no comparisons of pain scores to assess the adequacy of the analgesic strategies used. Cardiovascular Sevoflurane is a drug with minimal cardiovascular adverse effects, although cardiac rhythm disturbances have been recorded [9A]. • A 4-year-old boy underwent repair of a gastrocutaneous fistula. After inhalational induction, anesthesia was maintained at 2% sevoflurane with 66% N2O and 30 minutes later he developed third-degree heart block. Sevoflurane was withdrawn and replaced with propofol; 5 minutes later he reverted spontaneously to sinus rhythm. A postoperative 12-lead electrocardiogram was normal with borderline prolongation of the QTc interval to 466 ms.

Sevoflurane prolongs cardiac conduction and the QTc interval by inhibiting voltagegated sodium and L-type calcium channels. Body temperature Sevoflurane has once again been linked to malignant hyperthermia, in a 37-year-old man in whom the genetic link was found in the ryanodine receptor [10A]. The current recommendations of the European Malignant Hyperthermia Group are to perform open muscle biopsy followed by an in vitro contracture test and molecular

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testing for families known to carry causative mutations.

OTHER VAPORS Nitric oxide

[SED-15, 2538]

Observational studies In 11 patients with severe pulmonary hypertension, six due to primary pulmonary arterial hypertension and four due to chronic thromboembolic disease, inhaled nitric oxide was used either alone or combined with a phosphodiesterase type 5 inhibitor [11c]. After 6 months of treatment, seven patients had clinical deterioration that was reversed on adding a phosphodiesterase type 5 inhibitor. One died after 8 months and another underwent pulmonary transplantation after 9 months.

Nitrous oxide [SED-15, 2550; SEDA30, 140; SEDA-31, 221; SEDA-32, 247] Observational studies In a prospective observational study of the analgesic efficacy of N2O for procedural sedation, children aged 1–17 years underwent predominantly orthopedic procedures and laceration repairs under 50–70% N2O, delivered either by a demand valve or a continuousflow device; 94% of the patients had mild to moderate sedation and only two patients, who had both received 70% N2O, were deeply sedated [12c]. Parental satisfaction scores were generally very high (over 92%). No patients had a serious adverse event. Pre-procedural and peri-procedural pain scores were very different, depending on the presenting condition, and ranged from 2 to 10 cm on a 10-cm visual analogue scale. Only 124 of the initial 220 children enrolled had complete data sets, which may have biased the results. In a prospective study of the effects of different concentrations of N2O (50% and 70%) on sedation and incidence of adverse

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events in 762 children, there was a significant increase in the degree of sedation with 70% N2O [13c]. There were adverse events in 8.3% (vomiting 5.7%, agitation 1.3%, and nausea 0.9%, with individual cases of other minor adverse effects), although there were no differences between the two groups. Two patients had serious adverse events, both of whom received 70% N2O: one developed chest pain associated with normal vital signs, which was resolved with oral antacids, and one developed repeated episodes of hypoxia, which resolved with oxygen. There were no episodes of aspiration or laryngospasm. Documentation of adverse events in this study relied on accurate charts, and there may be a tendency to under-report minor adverse effects. Comparative studies In a study of the role of either EMLA cream or N2O to alleviate pain induced by intramuscular palivizumab injections in children aged under 24 months in a crossover study, 55 children were randomized to EMLA plus air inhalation or N2O (50/50) plus placebo cream, or both at each of three injections over a course of 3 months [14c]. Baseline behavioral and pain scores were similar with the three interventions. The EMLA þ N2O combination had significantly reduced behavioral and pain scores than EMLA or N2O alone. There was no effect of gestational age, sex, or birth weight. Parental pain assessment mirrored this and was assessed as being significantly lower in the combination group. All the adverse effects were minor and self-limiting (one episode of vomiting in the combination group) and there were no cases of drowsiness. There were no differences in the incidences of skin reactions (7–8% in each group, including placebo cream). A complete placebo group, although acknowledged to have been omitted, was considered unethical, as EMLA cream has already been shown to be efficacious. Placebo-controlled studies In a doubleblind, randomized, placebo-controlled study of the efficacy of N2O þ enteral midazolam for botulinum toxin injections, children with cerebral palsy received midazolam 0.35–0.5

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mg/kg either orally or rectally or nitrous oxide 0–70% in oxygen delivered using a continuous-flow device [15c]. Children who were randomized to midazolam received 100% oxygen via the continuous-flow device and those who were randomized to N2O received the same volume of isotonic saline enterally. There were no differences in the maximal levels of sedation achieved, but sedation scores at discharge were higher in the midazolam group. Pain scores in the children who received N2O were significantly lower. Nine children had adverse events, one in the midazolam group (hypoxia resolved with extra oxygen) and eight in the N2O group (one each of nausea and headache, two with brief hypoxia resolved with extra oxygen, and four with vomiting). There were no episodes of airway obstruction or apnea. The small numbers made it difficult to draw conclusions concerning adverse events, because although N2O appears to have increased the numbers of adverse events when combined, individual types of event are rare. In this group of children, who often have problems with secretions and gastroesophageal reflux disease, it is hard to draw firm conclusions. Nervous system N2O can interfere with methionine synthesis by inactivating methylcobalamin. This can result in demyelination of the nervous system and cause a polyneuropathy [16A]. • A 19-year-old girl with a history of recreational N2O use developed progressive weakness of the legs and a gait disturbance and was unable to walk without assistance. Nerve conduction studies showed a demyelinating polyneuropathy, and somatosensory evoked potentials suggested a central pathway lesion. A magnetic resonance imaging (MRI) scan showed high-intensity signals involving the posterior columns of the cervical and thoracic spinal cord. N2O-induced subacute degeneration of the cord was diagnosed, and she was given vitamin B12. After 1 week, there was improvement, and after 2 months neurological function was normal.

Medsafe in New Zealand has reminded prescribers that prolonged use of nitrous oxide has been associated with neurological and hematological adverse effects such as

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megaloblastic anemia and myelopathy, due to inactivation of vitamin B12 [17S]. Neurological symptoms can occur without any other hematological changes. Prescribers are also advised to check vitamin B12 concentrations in those with risk factors for vitamin B12 deficiency before using N2O and to seek specialist advice, if necessary. N2O should not be used continuously for more than 24 hours or more often than every 4 days without clinical supervision and hematological monitoring. Gastrointestinal N2O causes postoperative nausea and vomiting by several mechanisms, such as increased middle ear pressure, bowel distension, and activation of the dopaminergic system in the chemoreceptor trigger zone. In 147 patients undergoing gynecological laparoscopic surgery, who were randomized to 30% O2 in air, 50% O2 þ 50% N2O, or 70% N2O þ 30% O2 after a standardized general anesthetic with no prophylaxis of nausea and vomiting, there was a significant difference at 24 hours between 70% N2O and 0% N2O with respect to postoperative nausea and vomiting (62% versus 33%) and nausea (56% versus 26%) [18c]. There were no differences between 0% and 50% N2O and 50% and 70% N2O. Severe vomiting rates (more than two episodes within 30 minutes or more than three in 24 hours) were similar between the groups. There were no differences in opiate or rescue antiemetic drug use. In a large prospective, multicenter randomized trial the incidence of severe postoperative nausea and vomiting was investigated in 2050 patients undergoing general anesthesia expected to exceed 2 hours, who received either 70% N2O with O2 or 80% O2 with air after airway instrumentation until completion of surgery [19C]. Overall 17% had nausea and vomiting in the first 24 hours after surgery. Age over 55 years, female sex, abdominal surgery, N2O administration, absence of bispectral index (BIS) monitoring, and longer duration of anesthesia were predictors of severe nausea and vomiting. The presence or absence of BIS monitoring is an

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interesting predictor in this study and is consistent with other studies, probably mediated via a reduction in the amount of anesthesia required. The investigators did not record a past history of postoperative nausea and vomiting, motion sickness, or postoperative opioids, which may have significantly affected these results. This identifies a potential problem with post hoc data analysis of other than primary endpoints. Genotoxicity DNA damage by N2O has been studied in 84 medical staff who had had occupational exposure to N2O and halogenated hydrocarbons for at least 5 years [20c]. The control group consisted of 83 staff members working outside the theatre environment. DNA damage in peripheral blood leukocytes was measured, and the exposed subjects had a significantly higher DNA damage score. N2O and vapor concentrations were measured in the operating theatres and were consistently higher than the recommended national guidelines. Further, single regression analysis showed a significant correlation between N2O exposure and DNA damage. After adjusting for age, sex, smoking, and hospital location, DNA damage score was still significantly associated with N2O concentrations. In contrast, there was no significant correlation between DNA damage score and concentrations of halogenated hydrocarbons.

INTRAVENOUS AGENTS: NON-BARBITURATE ANESTHETICS Etomidate [SED-15, 1302; SEDA-30, 140; SEDA-31, 221; SEDA-32, 248] Comparative studies In a randomized controlled multicenter trial of the effect of etomidate versus ketamine in emergency intubation, 655 patients were randomized to either etomidate 0.3 mg/kg or ketamine 2 mg/kg [21C]. Maximum SOFA (Sequential

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Organ Failure Assessment) scores and its components did not differ between the groups during the first 3 days of admission. Basal cortisol concentrations were significantly lower in those who received etomidate (441 versus 690 nmol/l) as was the percentage of non-responders to a standard ACTH stimulation test (93% versus 49%). This resulted in a higher incidence of adrenal insufficiency in those who received etomidate (OR ¼ 6.7). There were no differences in mortality between either the ketamine/ etomidate groups or responders and nonresponders to ACTH stimulation. There were no differences in the duration of catecholamine use, duration of weaning from respiratory support or length of stay in the ICU. There were no serious adverse events in either group. Endocrine Etomidate can cause adrenal suppression, which has been linked to increased mortality in critically ill patients requiring anesthesia for ventilation after injury or illness. This retrospective database review was undertaken to assess any association between the use of etomidate and outcomes after trauma that resulted in hypotension in 97 patients [22c]. Stepwise multivariate regression analysis, adjusted for confounding variables (hypertonic saline and blood transfusion, APACHE II score and Injury Severity Score, ISS) showed that those who received etomidate there was a trend in towards a significant increase in adult respiratory distress syndrome (ARDS; 40% versus 20%) and multiple-organ dysfunction syndrome (MODS; 46% versus 25%). This corresponded to a significant increase in the number of ventilated days and length of stay in the ICU in those who received etomidate. As these data were not collected primarily to look at this outcome, it is difficult to assess for missing data and the effect of both differences in practice between anesthetists and the use of etomidate in sicker patients, owing to its inherent lack of cardiovascular adverse effects. Despite this, there was good homogeneity between the two groups with respect to physiological and injury

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severity scores and the comparison may therefore be valid.

Ketamine

[SEDA-32, 250]

Observational studies In a small retrospective review of 65 children and adolescents who received intravenous ketamine for elective percutaneous solid organ biopsies under radiological guidance the patients received 2 mg/kg followed by an infusion of up to 150 micrograms/kg/minute (median 70 micrograms/kg/minute) [23c]. Median recovery time was 60 minutes. There were two adverse effects during sedation: agitation and hypertension in a patient with poorly controlled pre-operative hypertension. In the recovery period, there were eight adverse events, most of which were nausea and vomiting. Patient and parent satisfaction was high (92%). This small trial has added to the evidence that ketamine can maintain cardiovascular stability and is suitable for procedural sedation in selected groups of patients. There is some prior evidence that the use of ketamine during emergency care correlates with sustained post-traumatic stress disorder symptoms in trauma victims. In a prospective non-randomized study in 50 adults who had had mild to moderate trauma without loss of consciousness 13, 24, and 13 received ketamine, opioids, and non-opioid analgesics in weight-related doses [24c]. On the third day after admission, questionnaires were completed investigating dissociation, re-experiencing, avoidance, and hyperarousal. Previous traumatic experiences were also investigated using the traumatic life event questionnaire. Patients who were given ketamine had consistently higher scores than the other two groups, with specifically higher incidences of re-experiencing, avoidance, and hyperarousal. Doses were not reported and the numbers were small, but this study has shown a strong and consistent increase in symptoms of post-traumatic stress disorder in patients treated with racemic ketamine.

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In 82 children undergoing tonsillectomy who were randomized to morphine 0.1 mg/kg alone or in combination with ketamine 0.25 mg/kg after sevoflurane induction, there were no differences in the duration of anesthesia, surgery, or recovery between the two groups [25c]. There were no differences in pain scores or total morphine consumption, but the ketamine group required less rescue morphine during recovery. There were no episodes of hallucinations after ketamine. However, the incidence of vomiting was 7.5% with morphine and 2.3% with ketamine. Ketamine has also been studied as an adjuvant to lidocaine intravenous regional anesthesia for hand surgery in 40 patients who received ketamine 0.1 mg/kg either as an adjuvant to the lidocaine or as an intravenous injection [26c]. There were no significant differences in tourniquet pain or opiate requirements, either intraoperatively or during the recovery period. There were no difference in the incidence of psychotomimetic effects and satisfaction was high in both groups. The authors felt that it would be unethical to include a control group, as ketamine has already been shown to be superior to placebo. However, this makes the conclusions hard to interpret. In a prospective analysis of 92 adults who underwent procedural sedation using intravenous ketamine (mean dose 0.7 mg/kg) for almost exclusively orthopedic procedures, 91 achieved adequate sedation as defined by their physician, but heart rate and blood pressure increased by 21% and 18% respectively [27c]. There were adverse events in 21%, including recovery agitation (13%), vomiting (4%), and clonic movements (4%). Seven of 12 patients with recovery agitation required intravenous midazolam. There were no episodes of laryngospasm. There were no standard criteria for the diagnosis of recovery agitation or clonic movements in this study. In a retrospective database review of 1030 adults, 1.6% received pre-hospital ketamine for induction of anesthesia and the rest for sedation (dose 0.5–1.0 mg/kg) [28c]. In no case was an airway manoeuvre required and no patient required intubation. About

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90% of the patients had midazolam coadministered, usually in a dose of 1–2 mg. In some cases there were emergence phenomena, but missing data cannot be accounted for. In a prospective observational study of the effectiveness of ketamine 10 mg and midazolam 0.5 mg delivered as a bolus by patient-controlled administration as analgesia for changing burns dressings, 44 patients underwent 95 treatments, each requiring an average of 9.4 ml (94 mg ketamine and 4.7 mg midazolam) over a mean of 78 minutes [29c]. Average effectiveness scores were 8.5 out of 10 for both staff and patients. There were 23 adverse events in 15 patients, the most common being hallucinations (11/23) and desaturation <95% (5/23). There was no difference in total drug dose in those with and without adverse events. Many of the patients received preprocedure opioids (morphine and oxycodone) in varying amounts, which may have affected pain scores, depending on the dose and timing of the adjunctive analgesia. Comparative studies Sevoflurane and ketamine have been prospectively compared in induction of anesthesia in 50 children with congenital heart disease [30c]. After premedication, they were given either intramuscular ketamine 5 mg/kg with high-flow oxygen or incremental doses of sevoflurane (up to 8%) via a face mask. Following intravenous cannulation, all the children received a standardized anesthetic induction, and there were no differences between the groups with regard to loss of eyelash reflex, time to intravenous access or intubation, and heart rate or oxygen saturation (SpO2). Systolic blood pressure was significantly lower after sevoflurane at all times but only transiently, and no vasopressors were required. There were 17 respiratory events: breath holding (n ¼ 13), coughing (3), and hiccups (1) after sevoflurane, and none resulted in a serious adverse event, such as laryngospasm. There was excessive salivation in 16% after ketamine. These data imply that ketamine is a safe and hemodynamically stable alternative to

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inhalational induction for children with congenital heart disease. In a prospective analysis, 210 patients who required emergency procedural sedation and who were given midazolam (51%), ketamine (40%), and propofol (9%) were used as primary agents; median doses were 5, 65, and 100 mg respectively, and 64% also received opioid analgesia [31c]. The time to full orientation was longer after midazolam and ketamine than propofol (30 and 25 versus 10 minutes). Significantly more of those who were given midazolam had recall of the procedure. There was also a significant association between the administration of ketamine and re-emergence phenomena, although there was no standardized description of these symptoms and those affected were much younger, both factors that could have biased this result. Overall, 16% had an adverse event and there was no significant association between an agent and adverse events. However, there was apnea or hypoxia (desaturation <94%) in 17% and 12% after propofol and midazolam respectively compared with 1% after ketamine. The highest incidence of adverse events occurred when patients were sedated to a “no response” level, although the authors did not elaborate on which type of adverse events. When patients were oversedated with midazolam, there was a significant increase in adverse reactions, which was not seen at the same level of sedation with ketamine. There was no mention of the use of adjunctive opioids or adverse events that may have contributed to respiratory episodes. This study gives further evidence of the safety and perhaps superiority of ketamine over midazolam in emergency procedures. The number of patients in this study who received propofol was very small, and it is therefore difficult to draw conclusions. In a prospective non-randomized observational study of behavioral changes and vomiting after discharge in 554 children who had undergone procedural sedation with ketamine alone (66%), ketamine þ midazolam (19%), or midazolam þ fentanyl (15%) questionnaires were collected

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from parents [32c]. Those who received fentanyl þ midazolam had a significantly higher risk of maladaptive behavior than those who received ketamine þ midazolam. Post Hospital Behavior Questionnaire (PHBQ) scores increased by 0.4 per increase in fentanyl dose by 1 microgram/ kg and by 0.6 per 1 mg/kg increase in ketamine dose. There was vomiting during the procedure in 5.9%, 11%, and 3.7% after ketamine, ketamine þ midazolam, and fentanyl þ midazolam respectively. Vomiting after discharge occurred in 20% and 14% of those that had received ketamine and fentanyl þ midazolam. After controlling for age, sex, fasting status, duration and type of procedure, and the presence of a parent, the choice of sedation agent did not affect the odds of vomiting after discharge. Not all eligible children were enrolled in this study and a significant number of missed cases may have biased the results. Nonblinding of the parents and reliance on parental questioning without face-to-face interviews may have introduce further bias. Combination studies The addition of ketamine to fentanyl has also been studied in a randomized placebo-controlled study in 200 patients undergoing cervical spine surgery [33c]. All received non-steroidal antiinflammatory drugs (NSAIDs) at the end of surgery and for rescue analgesia. After cervical surgery, visual analogue scores were significantly lower in the high-dose ketamine group for 48 hours and in the low-dose ketamine for 24 hours. Fentanyl and NSAID requirements were significantly lower after high-dose ketamine. Low-dose ketamine provided improved pain scores at rest but not on movement. Postoperative nausea and vomiting was significantly less common in the high-dose ketamine group, presumably because of the lower doses of opiate required. Placebo-controlled studies In a doubleblind randomized study of propofol (0.5 mg/kg) þ fentanyl (1 microgram/kg) with or without the addition of ketamine 0.5 mg/kg in 60 children undergoing interventional radiological procedures, the addition

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of ketamine provided superior sedation, and significantly fewer children required extra doses of propofol [34c]. There were fewer respiratory complications with ketamine (10% versus 30%) but no patient required intubation. There were no other differences with respect to adverse events (agitation and tachycardia) between the two groups, with the exception of a significant increase in nystagmus with ketamine. This study provides further evidence that ketamine is suitable for out-patient radiology procedures in children. Regional anesthesia causes shivering by effects on the thermoregulatory system, causing hypothermia. Patients who were having a spinal anesthetic with bupivacaine 15 mg were randomized in a double-blind study to saline, midazolam 75 micrograms/ kg, ketamine 0.5 mg, or midazolam 0.25 mg þ ketamine 37.5 micrograms/kg [35c]. At 15 minutes, the incidences of shivering were 60, 50, 23, and 3.3% in the four groups respectively. There were significantly more patients with a higher shivering score among the controls compared with the others. Axillary body temperature increased significantly in all the groups compared with controls. There were no significant differences in the incidences of hypotension, nausea and vomiting, or hallucinations between the groups. Although there was a relatively high incidence of hypotension, all responded to ephedrine and all were hemodynamically stable by 30 minutes after spinal anesthesia. The authors concluded that combinations of very low doses of midazolam and ketamine are most effective in shivering induced by regional anesthesia. The postulated mechanisms are that ketamine induces nonshivering thermogenesis by an action on the hypothalamus or that an effect of noradrenaline and midazolam reduces core body temperature by inhibiting tonic thermoregulatory vasoconstriction. Ketamine has been investigated in the prevention of chronic pain after thoracotomy in 86 patients who were randomized to ketamine or placebo after a standardized general anesthetic using propofol or etomidate [36c]. The treatment group received

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ketamine 1 mg/kg at induction, 1 mg/kg/ hour perioperatively, and 1 mg/kg infused over the first 24 hours postoperatively in addition to a 1 mg/bolus of morphine. Significantly, more patients had a pain score of more than 3/10 in the first 24 hours in the placebo groups, and there was a trend towards reduced morphine consumption after ketamine (37 versus 41 mg). There were no differences in adverse events (bradycardia, hypotension, hypoxia, bradypnea, vomiting, dizziness, or oversedation) attributable to either drug, and naloxone was not required. At 6 weeks and 4 months, there were no differences in the incidences of chronic pain between the groups. More than 50% of all patients had symptoms of neuropathic pain at 4 months. The role of ketamine in the treatment of chronic pain has been studied in 60 patients who were randomized to S-ketamine or placebo over 4.2 days starting at 1.2 micrograms/kg/minute and increasing if pain control was insufficient to a maximum of 7.2 micrograms/kg/minute or placebo [37c]. The two groups differed significantly in depression and anxiety scores, but below the threshold for psychopathology. Baseline pain scores were 7.2 and 6.8 out of 10 for ketamine and placebo respectively. Ketamine improved pain scores over the 11-week follow-up period but lost significance at week 12. Univariate analysis showed that baseline pain scores predicted pain at week 1. Most patient had adverse effects during the treatment period: those who were given ketamine had higher incidences of nausea (63% versus 17%), vomiting (47% versus 10%), and psychotomimetic effects (drug high and hallucinations) (93% versus 17%); headache was present in about one-third of both groups. Although powered to show a reduction in pain scores, the differences in depression and anxiety scoring may have biased the results. Systematic reviews The authors of a review of all published studies of low-dose ketamine for procedural sedation concluded that the drug confers a high degree of safety with minimal cardiovascular adverse

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effects [38M]. They also commented that ketamine is a respiratory stimulant and that patients retain their pharyngeal reflexes; however, reports of apnea are not uncommon, and those who administer ketamine should have airway skills. Reports of psychiatric adverse effects on emergence were variable, with variable end-points. For ketamine monotherapy they quoted an incidence of 10–20%, but this is difficult to interpret because of the variable and surrogate outcomes used. There was vomiting in 5–15% of cases. Nervous system In a double-blind, randomized placebo-controlled trial the incidence of unpleasant dreams after subanesthetic doses of ketamine was investigated in 30 healthy volunteers using home nightmare frequency [39c]. They received either low-dose ketamine (plasma concentration 115 ng/ml), high-dose ketamine (plasma concentration 219 ng/ml), or placebo. There were no significant differences between high-dose and low-dose ketamine, and the groups were therefore combined to increase the sample size. Ketamine resulted in the same number of unpleasant dreams as placebo, but the dreams were significantly more unpleasant. This was due to a lack of positive dream emotions rather than an increase in negativity. A possible explanation may be that the effect of ketamine on the electroencephalogram was similar to that of sleep deprivation, with increases in non-rapid eye movement (non-REM) sleep followed by a rebound increase in REM sleep over the 12 hours after ketamine, suggested to cause intensification of dream imagery. Psychological The incidences of different types of emergence phenomena after intravenous ketamine, mean dose 1.15 mg/kg, for procedural sedation have been investigated in children [40c]. Of 745 patients, 93 (13%) cried on awakening from sedation, of whom 84 were consoled by their parents. The rest were defined as having emergence delirium. Another seven children were

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recorded as having emergence delirium, but there was no standard definition of this. Emergence delirium was not associated with age or sex. At least one nightmare occurred in 3.4% in the weeks after sedation. There were pleasant visual hallucinations in 47%, facial distortion and double vision being the most common. It is difficult to assess very young patients; with no standard definition, what might perhaps have been disorientation on waking may have been interpreted as emergence delirium. It would be interesting to define these events and to distinguish between emergence phenomena, some of which may be pleasant experiences, and emergence delirium and other unpleasant psychological experiences. Salivary glands Ketamine has traditionally been co-administered with atropine to counteract increased salivation and oropharyngeal secretions. In a prospective observational study in 1090 children, excessive salivation was assessed on a 10-cm visual analogue scale [41c]. The mean total dose of ketamine was 2.1 mg/kg and only 0.5% received adjunctive atropine; 92% were assigned as having salivation rates of zero and only 1.3% of cases had scores over 50 mm. There was one brief episode of desaturation attributed to laryngospasm from excessive salivation, which was treated with brief assisted ventilation. There was vomiting during sedation or recovery in 7.5%, and agitation, crying, and hallucination scores were all low, with under 1.5% patients scoring over 5 cm on the 10-cm scale in each group. Although this was an unblinded observational study, with subjective end-points, the numbers were large and this suggests that excessive salivation may not be a problem with this dose of ketamine for procedural sedation. Biliary tract In three ketamine abusers with recurrent epigastric pain the common bile ducts were dilated, mimicking choledochal cysts on imaging [42A].

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Urinary tract dysfunction after recreational use of ketamine Urinary tract dysfunction has been associated with recreational use of ketamine [43R]. It was first described in a series of nine patients, all of whom were daily ketamine users, who presented with severe dysuria, frequency, urgency, and gross hematuria [44c]. The urine cultures were sterile in all cases. CT scans showed marked thickening of the bladder wall, a small capacity, and perivesicular stranding, consistent with severe inflammation. All had severe ulcerative cystitis. Biopsies in four patients showed epithelial denudation and inflammation with a mild eosinophilic infiltrate. Withdrawal of ketamine, and treatment with pentosan polysulfate, gave symptomatic relief. In a retrospective chart review of 233 abusers of ketamine aged 13–60 (median 22) years, there were lower urinary tract symptoms in 12% [45c]. The cause of this complication is not known. One postulated mechanism is direct damage to the urinary tract mucosa from metabolites of ketamine causing submucosal inflammation and eventually edema and fibrosis; microvascular changes may compromise the intrinsic microcirculation, causing neovascularization. The preponderance of abnormalities in the lower urinary tract may be due to increased time spent in contact with ketamine metabolites. The clinical features could be secondary to bladder ischemia and an autoimmune reaction to the bladder urothelium and submucosa triggered by the drug and metabolites. Case reports There have been several individual case reports [46A, 47A, 48A, 49A, 50A, 51r], including the following. • A 26-year-old man, a known ketamine user, collapsed. He had previously had severe urinary tract dysfunction treated with antibiotics [52A]. A CT scan of the abdomen showed bilateral hydronephrosis and cystoscopy showed a significantly reduced bladder capacity without ureteric obstruction. He was hypotensive, acidotic, and in acute renal failure and

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required invasive respiratory support, hemofiltration, and inotropic support. Bilateral nephrostomies released gelatinous debris from the left pelvicalyceal system, which contained ketamine, cannabinoid, and lidocaine metabolites. His urine output returned and although he required intermittent renal support for 24 days, his renal function began to recover and follow-up ultrasonography showed resolution of the hydronephroses.

The presence of ketamine in the renal pelvis in this case suggests a between-the-eyes adverse reaction of type 1a [53H]. However, ketamine does not usually precipitate in the renal pelvis and therefore the added presence of the cannabinoid metabolites may have been crucial to the presentation in this case. • A 27-year-old man, a regular ketamine user, developed severe suprapubic pain, increased urinary frequency, and hematuria [54A]. All investigations, including renal function, urinalysis, and culture, were normal. Cystoscopy showed a small erythematous bladder. Biopsies showed ulcerative hemorrhagic cystitis. His symptoms did not respond to drug withdrawal, opioids, antispasmodics, and anticholinergic drugs. He underwent cystoprostatectomy with new bladder formation and recovered. • A 26-year-old man developed increased urinary frequency, nocturia, dysuria, and hematuria which lasted for 7 months after he started to use recreational ketamine weekly [55A]. Antibiotics and anticholinergic drugs were ineffective. Urinalysis and culture were normal. Ultrasonography showed a thickened bladder wall with a small capacity, and cystoscopy showed mild inflammatory changes. Bladder biopsies were negative, although they were not taken at a time an active episode of cystitis.

The last patient may have mild disease, as he had used ketamine only weekly rather than daily. He benefitted symptomatically from drug withdrawal. • A 16-year-old girl who took oral ketamine 8 mg/kg/day for 9 days for neuropathic pain developed dysuria, increased frequency, urgency, and incontinence [56A]. Urinalysis was normal and urine culture was negative. The symptoms abated when the dose of ketamine was reduced to 6 mg/kg/day and completely disappeared at 2 mg/kg/day. When ketamine was reintroduced the urinary symptoms reappeared at a dose of 5 mg/kg/day.

This case shows that ketamine-associated cystitis may not be limited to drug abusers.

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• A 19-year-old woman who had abused ketamine daily for 3 years developed severe lower urinary tract symptoms [57A]. Her symptoms resolved after she took duloxetine 60 mg/day for 2 weeks.

Case series Seven men and three women, aged 20–30 (mean 25) years, who had all abused ketamine for 1–4 years, developed dysuria, increased frequency (having to void once every 15 minutes), urgency, urge incontinence, and painful hematuria [58c]. None had positive urine cultures. Functional bladder capacities were 30–100 ml. Urodynamic tests showed detrusor overactivity, with urinary leakage when the bladder was filled to a capacity of 30–50 ml. There was bilateral reflux in one case and unilateral reflux in two; seven had bilateral hydronephrosis. [The title of this paper is confusing, since “street ketamine” is a term that is used to refer to phencyclidine; however, in the paper the authors refer to ketamine.] In 11 patients with severe urinary tract symptoms after recreational use of ketamine, renal function was normal in all cases and urinalysis showed non-bacterial pyuria negative for tuberculosis [59c]. Urodynamic studies in patients who tolerated the procedure showed a small bladder capacity and detrusor overactivity. Five patients underwent bladder wall biopsy, which showed eosinophilia and mast cells in high concentrations. Their symptoms slightly improved after drug withdrawal, but six patients were given intravesical instillations of hyaluronan, a heparin-like substance used to increase the growth of the glycosaminoglycan layer of the damaged urothelium. In 17 patients with ketamine-associated cystitis, who underwent urinary tract biopsies, the characteristic histopathological features were ulceration, eosinophilia, and atypical urothelium [60c]. Urine cytology in four patients showed hypercellularity and cellular atypia. Immunohistochemistry in 10 patients showed a high expression of p53 (9/10) and Ki67 (6/10) and no expression of CK20. Two had metaplastic changes. These markers are expressed in most cases of bladder carcinoma in situ, which

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ketamine-induced urinary tract destruction may therefore mimic. A syndrome of cystitis and contracted bladder has been described in a retrospective analysis of 59 ketamine abusers in Hong Kong, all had moderate to severe lower urinary tract symptoms, with increased frequency, urgency, dysuria, urge incontinence, and occasionally painful hematuria [61c]. Average micturition frequency was 20–200 ml every 15–90 minutes. At cystoscopy in 42 patients there were various degrees of epithelial inflammation similar to that seen in chronic interstitial cystitis. All of 12 bladder biopsies had histological features resembling interstitial cystitis. Urodynamically, there was detrusor overactivity or reduced bladder compliance with or without vesicoureteric reflux in 47 patients who were studied. There was unilateral or bilateral hydronephrosis on renal ultrasonography in 30 patients, and four had features suggestive of papillary necrosis on radiological imaging. Eight patients had a raised serum creatinine concentration. The radiological findings of this adverse reaction have been described in 23 patients, all with a history of ketamine abuse, who had severe lower urinary tract symptoms [62c]. Ultrasonography showed a small bladder volume and wall thickening. CT scans showed marked generalized bladder wall thickening, mucosal enhancement, and perivesical inflammation; ureteric wall thickening and enhancement were also observed. In advanced cases, CT scans and urography showed ureteric narrowing and strictures. Drug administration route Ketamine can be associated with long recovery periods and potential psychiatric adverse events. All patients who had received ketamine for out-patient emergency procedural sedation at a tertiary children's hospital were entered into a sedation registry and retrospectively identified [63c]. Of 229 patients 48% received ketamine intramuscularly and 52% intravenously. The mean doses were higher in the former (3.7 versus 1.5 mg). Adverse events occurred in 35% of

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the former and 20% of the latter; the most common were excess salivation (11% versus 1.7%) and emesis. There were five episodes of desaturation in each group all treated with simple airway manoeuvres and oxygen. No patient required intubation or admission. Those who received intramuscular ketamine had a significantly longer length of stay in hospital after sedation (2.9 versus 2.2 hours). This was a small single-center retrospective study, and missing data cannot be accounted for. In addition, the attending physicians may have unknowingly biased the results depending on personal preference of administration and the individual patient. Management of adverse drug reactions The use of ketamine and dexmedetomidine sedation combined with caudal anesthesia for incarcerated inguinal hernia repair has been described in three high-risk infants with bronchiolitis [64A]. All had congenital heart disease with associated acute viral bronchiolitis, making them at high risk for general anesthesia. Although the documented adverse effects of dexmedetomidine include bradycardia, hypotension, tachycardia, fever, and nausea, in this case series the authors reported no effect on respiratory rate, endtidal CO2, or cardiovascular function. The addition of ketamine may have prevented the bradycardia and hypotension associated with dexmedetomidine and vice versa for the hypertension, tachycardia, and emergence phenomena associated with ketamine.

Propofol

[SED-15, 2945; SEDA-30, 142; SEDA-31, 222; SEDA-32, 252] Observational studies In a study of relocation of hip prostheses, 98 adults received intravenous morphine titrated to relieve pain and then a bolus of propofol 1 mg/kg 60 seconds before the procedure [65c]. Fracture reduction was successful in 94 patients, but 41 required additional doses of propofol because of inadequate sedation or a prolonged reduction time. Eight had

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desaturation, which responded to either airway repositioning or brief supplementary ventilation. Four had hypotension, and all responded to a-adrenoceptor agonists. The doses of propofol that were associated with adverse events were not mentioned. In 500 infants undergoing MRI scans, sedation was induced using intravenous nalbuphine 0.1 mg/kg and propofol 1 mg/ kg mixed with lidocaine 0.25 mg/ml [66c]. Extra doses of propofol 0.5 mg/kg were given as required, followed by a maintenance dose of 5 mg/kg/hour. Induction time and recovery were longest in infants, although the duration of the procedure was similar at all ages. Sedation was adequate in all but nine children, who required one extra dose of propofol and an increase in the rate of infusion to 6 mg/kg/hour. There was hypoxia (SpO2 <92%) in five cases. Three had partial airway obstruction, which resolved after repositioning, and two required brief additional ventilation. There were no cardiovascular adverse events and all recovered uneventfully. In a pediatric sedation database (PSRC) from 37 centers, 88 672 records were retrospectively reviewed, of which 49 836 involved propofol as the sole or primary sedative for a selection of procedures, most of which were radiological [67C]. Desaturation (716/10 000), airway obstruction (432/ 10 000), cough interrupting the procedure (356/10 000), and secretions requiring suction (341/10 000) were the most common respiratory adverse events. There were changes in hemodynamic variables of >30% in 282/10 000. Other adverse events were rare. There were two cases of cardiac arrest requiring resuscitation, in a child with a tracheoesophageal fistula who developed laryngospasm, hypoxia, bradycardia, and asystole, which resolved with adrenaline, and in a healthy 16-year-old who received a large dose of propofol (195 mg) and became apneic and hypotensive, resulting in asystole for about 30 seconds. There were four episodes of aspiration after vomiting, followed by deterioration in respiratory function; all had significant desaturation but all resolved with positive pressure ventilation. Susceptibility factors

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for adverse pulmonary events included higher ASA status, age over 6 months, inadequate nutrition, and use of adjunctive opiates. Comparative studies Propofol and pentobarbital have been compared for radiological imaging in two studies in children. In a retrospective study using the PSRC database, 7079 cases were identified, 5072 involving propofol and 2007 pentobarbital [68c]. Significantly more children received adjunctive midazolam after pentobarbital than propofol (73% versus 24%). Complication rates in the two groups were 6.83% and 4.99% with propofol and pentobarbital respectively, but individual complication rates were below 1%. Multivariate analysis, controlling for age, sex, weight, and ASA grading, showed an association between pentobarbital and increased adverse events, specifically inadequate sedation, prolonged recovery, allergic complications, and vomiting; however, controlling for adjunctive midazolam only inadequate sedation and vomiting remained statistically significant. There were no significant differences in respiratory or airway events and there were no episodes of aspiration. In another study, in which parents chose propofol or pentobarbital for their child's sedation during CT scanning, there were conflicting results [69c]. Pentobarbital 1–2 mg/kg as a bolus dose was followed by further boluses as required to a maximum of 6 mg/kg. Propofol 1–2 mg/kg as a bolus dose was followed by further 1 mg/kg boluses to achieve adequate sedation, followed by an infusion of 150–200 micrograms/kg/minute. Although overall adverse events in the two groups were similar (12% versus 4% for propofol and pentobarbital respectively), there were higher incidences of airway events (23% versus 0%) and respiratory events (12% versus 0%) with propofol. Study times were significantly longer with propofol, perhaps due to the increased incidence of airway and respiratory events, whereas recovery times were significantly longer with pentobarbital (100 versus 34 minutes). Parent

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choice may have significantly biased the results. Sedation rather than general anesthesia is required for some forms of middle ear surgery in which it is desirable to test hearing. In a prospective study, 70 patients aged 16–70 years were randomized to propofol 1–1.5 mg/kg followed by an infusion of 1–2 mg/kg/hour or midazolam 0.02–0.05 mg/kg, and a maintenance dose of 0.01–0.02 mg/kg titrated to a bispectral index (BIS) score of 70–80 [70c]. Surgery and sedation times and recovery times were significantly longer after midazolam. Pain and sedation scores were similar, but BIS scores were lower after propofol at the start of sedation (71 versus 80). Patient and surgeon satisfaction was greater with propofol. There were few adverse events (three after propofol and none after midazolam groups), but the study was not powered to look at adverse events, and it is difficult to draw any useful conclusions from this. Placebo-controlled studies Sedation for lumbar puncture on 44 occasions in 22 children has been investigated in a doubleblind, crossover, randomized trial [71c]. They received propofol 1–2 mg/kg/minute with or without fentanyl 1 microgram/kg 5 minutes before. The mean total doses of propofol were 3 and 5 mg/kg when given with and without fentanyl. Adverse events occurred in 18% and 50% of patients with and without fentanyl. Hypotension was the most common adverse event, but it occurred in the two groups equally. There were no episodes of airway obstruction in the propofol þ fentanyl group, but there were three episodes in those who received propofol alone. In this small study the anesthetizing physician was not blinded, and along with the low incidence of adverse events this makes it difficult to draw any significant conclusions from the composite end-point of all adverse events. In another similar double-blind, crossover, randomized, placebo-controlled study of 22 children with acute leukemia, mean age 6.4 years, on 44 occasions, there were adverse events in 11 patients after propofol

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and four after propofol þ fentanyl [72c]. Average recovery times were 37 versus 26 minutes. Most of the families preferred propofol þ fentanyl. Propofol infusion syndrome Propofol infusion syndrome has been reported in children and adults after short-term high-dose propofol. It presents with variations of severe metabolic acidosis, rhabdomyolysis, myoglobinuria, cardiac failure, and death. The pathophysiology is unknown, but genetic predisposition, mitochondrial inhibition, and increases in serum free fatty acids are believed to play a role. Catecholamines and corticosteroids may act as triggering agents. • A 67-year-old man underwent anesthesia for coronary artery bypass grafts induced with midazolam, thiopental, fentanyl, and vecuronium [73A]. He had a mild lactic acidosis before general anesthesia. Anesthesia was maintained using isoflurane and propofol 0.8 mg/kg/hour, increasing to 5.2 mg/kg/hour during cardiopulmonary bypass (total 79 minutes). During the operation, there was a worsening metabolic acidosis, and he required intravenous adrenaline postoperatively. Propofol was stopped on wound closure but the acidosis continued to worsen, with a peak serum lactate of 13 mmol/l. His urine became weakly positive for myoglobin and hemoglobin but was negative for ketones. The serum creatine kinase activity was increased (260 mmol/l) with predominantly CK-MM, but liver function tests and troponin were normal. Propofol was withdrawn and the metabolic parameters recovered within 6 hours.

In an analysis of 1139 patients with suspected propofol infusion syndrome in adults (mean age 52 years) and children (mean age 9 years), the presenting symptoms included cardiac (43%), hypotension (34%), rhabdomyolysis (27%), hepatic (24%), renal (24%), metabolic acidosis (20%), hypoxia (18%), and hyperthermia (12%) [74M]. Propofol infusion ranges exceeded 5 mg/kg/hour in 129 cases in which the dose was reported. Regrettably, two important variables with respect to the propofol infusion syndrome, dosage and timing of propofol infusion, were not recorded in about 90% of papers. Multivariate logistic regression analysis identified

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age over 18 years, male sex, propofol administration for over 48 hours, and concomitant treatment with catecholamines as independent susceptibility factors for death. Cardiac failure was independently associated with death. Rhabdomyolysis, renal failure, and hypotension were cumulative susceptibility factors. In a retrospective review of patients admitted with head trauma who were given propofol by infusion for sedation, propofol infusion syndrome was defined by unexplained acidosis, a raised creatine kinase activity unrelated to trauma, and electrocardiographic changes [75cA]. Of 50 patients, 30 had received concomitant vasopressors; only three developed propofol infusion syndrome. The dose of propofol used in these cases was higher than the recommended 5 mg/kg/hour (83 micrograms/kg/minute) and it was given for longer than the recommended time (48 hours). The authors concluded that concomitant use of vasopressors confers an odds ratio of 29 for propofol infusion syndrome, although the sample size was too small for this to be calculated accurately. Two cases of propofol infusion syndrome in children undergoing cardiac surgery have been reported after short infusions of average doses of propofol. The diagnosis was based on the absence of other causes and abrupt resolution on drug withdrawal. A possible cause in this case was the combination of propofol with an inadequate carbohydrate intake to suppress fat metabolism [76A]. Respiratory In a non-blinded prospective study in adults undergoing sedation for emergency procedures 146 patients were randomized to propofol 1 mg/kg followed by 0.5 mg/kg every 3 minutes, with or without alfentanil 10 micrograms/kg; all received intravenous morphine before sedation [77c]. There was a high incidence of adverse respiratory effects in both groups, as judged by the need for extra oxygen (propofol 34%, alfentanil 44%) and either airway adjuncts (9.5% and 17%) or repositioning (18% and 28%); these differences were not significant, but significantly more of those who received alfentanil

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required stimulation to induce breathing (28% versus 15%) and had an absent trace detected on the end-tidal CO2 monitor. The addition of morphine did not improve pain relief but did increase the incidence of respiratory depression. Nervous system Although propofol has anticonvulsant action it can rarely cause seizures [78A]. • A 50-year-old man with no previous history of seizures was anesthetized with fentanyl 100 micrograms and propofol 100 mg. Within 30 seconds of receiving the propofol, he developed tonic-clonic seizures over the trunk and lower body. Despite thiopental 125 mg the seizures recurred and required further boluses of thiopental and midazolam. Surgery continued uneventfully and postoperative recovery was unremarkable. A CT scan of the brain was normal.

Propofol has previously been associated with tonic-clonic seizures and jerky movements, many of which go unreported. The pathophysiology is unknown, but spontaneous movements induced by propofol are probably not related to cortical activity but potentially to subcortical activity. In high doses, propofol depresses both the cortex and subcortex, thus acting as an anticonvulsant. In low doses, it may inhibit the subcortex only, resulting in cortical hyperactivity. Propofol-induced hiccups have been reported [79A]. • A 3½-year-old girl was repeatedly sedated with propofol for radiotherapy, and during the first and fifth episodes developed hiccups rapidly after propofol induction. The first episode passed uneventfully, but the second was complicated by laryngospasm. This was managed by bag and mask ventilation and recovery was uneventful. She had two further similar episodes, both of which were treated with lidocaine.

The reported incidence of hiccups after propofol is under 1%. Propofol is often given with lidocaine to prevent pain during injection, which may mask the hiccups; thus, the incidence may have been underestimated. In this case lidocaine was not used, as there was a tunnelled Hickman line in

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situ. The dose of propofol was not mentioned. Functional magnetic resonance imaging (fMRI) scanning to visualize brain activity relies primarily on the blood oxygen level dependent (BOLD) signal, an indirect measurement of cerebral blood flow associated with neuronal activity. In a prospective study of fMRI, 14 children were randomized to propofol 1 mg/kg by bolus injection followed either by propofol 4 mg/kg/hour or by midazolam 0.6 mg/kg/hour [80c]. There were no differences in MRI time, and all studies were completed without movement or adverse events. The children in both groups required further boluses of sedation, and there were no differences in recovery time. Midazolam temporally affected neuronal activity and vascular response leading to a delay in functional response whereas propofol produced a similar activation pattern to non-sedated adults. Pain Propofol can reportedly cause hypotension and pain on injection. In 156 patients who were randomized to lidocaine 1%, ephedrine 15 mg, or ephedrine 30 mg per 20 ml of propofol, there was no significant difference in the distribution of pain on injection [81c]. However, six of 51 patients who were given lidocaine required rescue medication for hypotension compared with no patients in either ephedrine group. The authors suggested that ephedrine is therefore as good as lidocaine in preventing pain on injection. However, in the absence of control group these results must be interpreted with caution. Pain on injection with propofol is thought to be more common and more difficult to avoid in children. An emulsion containing medium-chain and long-chain triglycerides (mct/lct) has been introduced as a solvent that is suggested to cause less pain on injection than standard long-chain triglyceride propofol. In a double-blind, randomized, placebo-controlled trial study in 160 preschool children comparing both propofol emulsions with and without added lidocaine, there were significant reductions

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in pain scores in those who received the new solvent plus lidocaine [82C]. There was no correlation of pain with the size and site of the cannula. In a prospective double-blind study in 120 children who were randomized to alfentanil 15 micrograms/kg 90 seconds before propofol 3 mg/kg or to propofol 3 mg/kg mixed with 0.1% lidocaine, or both, the incidence of injection pain was significantly lower in the combined group (2.6%) than either of the other two groups (38% and 30% respectively). Endocrine Transient diabetes insipidus has been attributed to propofol [83A]. • A 13-year-old boy with hyperparathyroidism and multiple endocrine neoplasia type I was due to have elective parathyroidectomy. He was known to be susceptible to malignant hyperthermia and so general anesthesia was performed with propofol 100–200 micrograms/ kg/minute and remifentanil 0.05–0.15 micrograms/kg/minute. After 1 hour his urine output was 1000 ml despite only 400 ml input. Urine specific gravity was low, with high plasma osmolality and serum sodium. Desmopressin postoperatively restored normal urine output.

Either remifentanil or propofol could have been responsible in this case. Remifentanil is a pure m opioid receptor agonist, which inhibits vasopressin release from the posterior pituitary; however, this patient had previously had a hypophysectomy. Propofol reversibly inhibits the action of antidiuretic hormone in rat hypothalamus, and this could have formed the basis of transient diabetes insipidus. Acid-base balance The incidence of metabolic acidosis has been studied in patients undergoing elective intracranial surgery using either propofol by target-controlled infusion (2–3.5 micrograms/ml) or sevoflurane 1–2.5% þ remifentanil 0.1–0.5 micrograms/kg/minute [84c]. There were no significant differences between the two groups with respect to duration of anesthesia, dose of remifentanil, or amount of intravenous fluid resuscitation. The pH values were similar, but the anion gap was significantly higher in those who received

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propofol. There was a metabolic acidosis in seven of the patients who were given propofol compared with one of those who were given sevoflurane. The lowest base excess measured correlated with the lactate concentration, the total dose of propofol, and the length of the procedure. There were high lactate concentrations in those who were given sevoflurane, but they did not correlate with acidosis. Interventions to treat hypotension and tachycardia were significantly more common in those who received propofol (13 versus 1) but hypotension and bradycardia were more common with sevoflurane (22 versus 12). The mild to moderate metabolic acidosis associated with increases in lactate concentration may have been evidence of early propofol infusion syndrome. Mannitol may have contributed, as there was a trend towards greater use of mannitol in those who received propofol. Liver In a prospective study of the effects of propofol infusion on hepatic and pancreatic enzymes in 30 children undergoing elective craniotomy who had taken phenytoin for at least 1 week the total dose of propofol was 2200 mg (about 75 mg/kg) for a mean duration of 4.9 hours [85c]. Serum aminotranferases, alkaline phosphate, and gamma-glutamyl transferase rose and peaked on the first postoperative day and returned to baseline within 3–7 days. Serum amylase activity and triglyceride concentrations were significantly higher for 5 days, but no child had symptoms of pancreatitis. There was no correlation between total propofol dose and peak enzyme activities on day 1. Although the changes were statistically significant, all the values remained within the reference ranges and may be of little clinical significance. Pancreas Propofol can reportedly cause pancreatitis, perhaps because of alterations in lipid metabolism, leading to hypertriglyceridemia, release of free fatty acids, and chylomicron plugging of pancreatic capillaries. In a retrospective case note review of 479 children with acute leukemia who underwent general anesthesia for a

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diagnostic procedure, five developed acute pancreatitis [86c]. However, none of the cases occurred within 24 hours of administration of propofol, and all occurred sooner after the administration of other drugs, including cytosine arabinoside, mercaptopurine, and L-asparaginase, any one of which could have been responsible. Urinary tract There have been two reports of propofol-associated green urine [87A, 88A]. • A 53-year-old man with liver cirrhosis had a large upper gastrointestinal hemorrhage and was given propofol 100 mg for induction of anesthesia; 1 hour later he was noted to have green urine. No other medications or recent food could have caused this. • A 40-year-old man who was given a propofol infusion after trauma developed green urine after 4 days; his urine returned to normal within 24 hours of propofol withdrawal.

Green discoloration of the urine due to propofol probably occurs from the production of a phenolic green chromophore which is conjugated in the liver and excreted in the urine. Other causes include ingestion of methylthioninium chloride (methylene blue) or food coloring, pigment from Pseudomonas urine infection, or biliverdin.

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INTRAVENOUS AGENTS: BARBITURATE ANESTHETICS Thiopental sodium [SED-15, 3395; SEDA-30, 146; SEDA-31, 226; SEDA-32, 255] Comparative studies In a randomized controlled trial of thiopental and pentobarbital in the control of refractory intracranial hypertension in 44 patients with severe traumatic brain injuries the former was more efficacious in reducing refractory intracranial pressure (OR ¼ 5.1) [90c]. There were no differences in adverse effects with respect to infections or the SOFA score before or maximum score attained between the two groups; almost all of the patients had hypotension on at least one occasion. Gastrointestinal There have been two reports of bowel ischemia after barbiturate coma treatment for refractory status epilepticus [91A].

• A 35-year-old woman, scheduled for an emergency cesarean section, was anesthetized with propofol 2 mg/kg and rocuronium 0.9 mg/kg and maintained with sevoflurane. About 15 minutes before the end of the operation she became tachycardic, difficult to ventilate, and hypoxic despite 70% oxygen. After a second dose of propofol for reintubation, she again became hypotensive and profoundly hypoxic and required inotropic support. Pulmonary edema was diagnosed. Afterwards, a skin test showed a strong weal and flare reaction to propofol.

• A 72-year-old man was given thiopental 303 mg/kg over 48 hours and 36 hours later developed abdominal tenderness, peritonism, and hyperlactatemia (11 mmol/l). At emergency laparotomy there was extensive fresh necrosis of the terminal ileum extending to the retrosigmoid junction. Histology showed no vascular or inflammatory changes. He developed septic shock and died 12 hours postoperatively. • A 21-year-old woman with complex partial seizures followed by secondary generalized status epilepticus, refractory to burst suppression with various agents, including propofol, ketamine, and thiopental for more than 2 months, was then given thiopental 840 mg/kg over 150 hours combined with hypothermia (34 C). On day 6, while normothermic, she developed ileus and hyperlactatemia (5.6 mmol/l). At laparotomy she had megacolon with focal cecal necrosis. Histology showed no signs of vascular or inflammatory change.

Anaphylactic reactions usually occur seconds to minutes after antigen administration, but late onset anaphylaxis can also occur, as in this case.

The postulated mechanism in these cases was ileus, a known rare complication of high-dose barbiturates, possibly complicated by hypothermia in the second case.

Immunologic Anaphylaxis with pulmonary edema has been described after the use of propofol at cesarean section [89A].

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Electrolyte balance Disturbances of potassium homeostasis rarely complicate therapeutic barbiturate coma [92A]. • A 14-year-old girl with a severe traumatic brain injury developed a raised intracranial pressure, which was treated with 2900 mg of thiopental over 42 hours. Before the infusion she had hypokalemia (2.5 mmol/l), which was corrected, but it persisted despite potassium replacement of 200 mmol. She suddenly developed tachycardia, anterior ST segment changes, and atrial fibrillation 7 hours after the end of the infusion. Her serum potassium peaked at 7.0 mmol/l and hyperkalemia persisted for 36 hours.

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The postulated mechanisms in this case were (a) a concentration-dependent reversible inhibition of neuronal potassium currents, leading to an extracellular shift or (b) inhibition of phosphofructokinase, leading to a reduction in intracellular lactate and pyruvate production and increases in intracellular pH and potassium concentration. Hypokalemia before the administration of thiopental was possibly secondary to treatment with insulin and positive inotropes. The authors recommended that abrupt withdrawal of thiopental should be avoided and that a tapering strategy should be used.

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[40] Treston G, Bell A, Cardwell R, Fincher G, Chand D, Cashion G. What is the nature of the emergence phenomenon when using intravenous or intramuscular ketamine for paediatric procedural sedation? Emerg Med Australas 2009; 21(4): 315–22. [41] Brown L, Christian-Kopp S, Sherwin TS, Khan A, Barcega B, Denmark TK, Moynihan JA, Kim GJ, Stewart G, Green SM. Adjunctive atropine is unnecessary during ketamine sedation in children. Acad Emerg Med 2008; 15(4): 314–8. [42] Wong SW, Lee KF, Wong J, Ng WW, Cheung YS, Lai PB. Dilated common bile ducts mimicking choledochal cysts in ketamine abusers. Hong Kong Med J 2009; 15 (1): 53–6. [43] Middela S, Pearce I. Ketamine-induced vesicopathy: a literature review. Int J Clin Pract 2011; 65(1): 27–30. [44] Shahani R, Streutker C, Dickson B, Stewart RJ. Ketamine-associated ulcerative cystitis: a new clinical entity. Urology 2007; 69(5): 810–2. [45] Ng SH, Tse ML, Ng HW, Lau FL. Emergency department presentation of ketamine abusers in Hong Kong: a review of 233 cases. Hong Kong Med J 2010; 16 (1): 6–11. [46] Tsai JH, Tsai KB, Jang MY. Ulcerative cystitis associated with ketamine. Am J Addict 2008; 17(5): 453. [47] Hoskins R. Ketamine associated cystitis—a case report. Int Emerg Nurs 2009; 17(1): 69–71. [48] Chiew YW, Yang CS. Disabling frequent urination in a young adult. Ketamine-associated ulcerative cystitis. Kidney Int 2009; 76(1): 123–4. [49] Storr TM, Quibell R. Can ketamine prescribed for pain cause damage to the urinary tract? Palliat Med 2009; 23(7): 670–2. [50] Noorzurani R, Vicknasingam B, Narayanan S. Illicit ketamine induced frequency of micturition in a young Malay woman. Drug Alcohol Rev 2010; 29(3): 334–6. [51] Chen KT, Foo NP, Lin HJ. Frequent visits with urinary symptoms: subtle signs of ketamine abuse. Am J Emerg Med 2008; 26(9): 1061–2.

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[52] Chu PS, Ma WK, Wong SC, Chu RW, Cheng CH, Wong S, Tse JM, Lau FL, Yiu MK, Man CW. The destruction of the lower urinary tract by ketamine abuse: a new syndrome? BJU Int 2008; 102(11): 1616–22. [53] Aronson JK, Hauben M. Anecdotes that provide definitive evidence. BMJ 2006; 333 (7581): 1267–9. [54] Dhillon BS, Nuttall MC, Coull N, O'Brien TS. Minerva. BMJ 2008; 336: 898. [55] Colebunders B, Van Erps P. Cystitis due to the use of ketamine as a recreational drug: a case report. J Med Case Reports 2008; 2: 219. [56] Grégoire MC, MacLellan DL, Finley GA. A pediatric case of ketamine-associated cystitis. (Letter-to-the-Editor re: Shahani R, Streutker C, Dickson B, et al: Ketamine-associated ulcerative cystitis: a new clinical entity. Urology 69: 810–812, 2007) Urology 2008; 71(6): 1232–3. [57] Chao JY, Shai HA. Duloxetine treatment of long-term ketamine abuse-related lower urinary tract symptoms: a case report. Gen Hosp Psychiatry 2010; 32(6): 647.e5–6. [58] Chu PS, Kwok SC, Lam KM, Chu TY, Chan SW, Man CW, Ma WK, Chui KL, Yiu MK, Chan YC, Tse ML, Lau FL. “Street ketamine”-associated bladder dysfunction: a report of ten cases. Hong Kong Med J 2007; 13(4): 311–3. [59] Tsai TH, Cha TL, Lin CM, Tsao CW, Tang SH, Chuang FP, Wu ST, Sun GH, Yu DS, Chang SY. Ketamine-associated bladder dysfunction. Int J Urol 2009; 16(10): 826–9. [60] Oxley JD, Cottrell AM, Adams S, Gillatt D. Ketamine cystitis as a mimic of carcinoma in situ. Histopathology 2009; 55 (6): 705–8. [61] Chu PS, Ma WK, Wong SC, Chu RW, Cheng CH, Wong S, Tse JM, Lau FL, Yiu MK, Man CW. The destruction of the lower urinary tract by ketamine abuse: a new syndrome? BJU Int 2008; 102(11): 1616–22. [62] Mason K, Cottrell AM, Corrigan AG, Gillatt DA, Mitchelmore AE. Ketamineassociated lower urinary tract destruction: a new radiological challenge. Clin Radiol 2010; 65(10): 795–800. [63] Ramaswamy P, Babl FE, Deasy C, Sharwood LN. Pediatric procedural

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279 sedation with ketamine: time to discharge after intramuscular versus intravenous administration. Acad Emerg Med 2009; 16 (2): 101–7. Bozdogan N, Sener M, Caliskan E, Kocum A, Aribogan A. A combination of ketamine and dexmedetomidine sedation with caudal anesthesia during incarcerated inguinal hernia repair in three high-risk infants. Paediatr Anaesth 2008; 18(10): 1009–11. Mathieu N, Jones L, Harris A, Hudson A, McLauchlan C, Riou P, Lloyd G. Is propofol a safe and effective sedative for relocating hip prostheses? Emerg Med J 2009; 26 (1): 37–8. Machata AM, Willschke H, Kabon B, Kettner SC, Marhofer P. Propofol-based sedation regimen for infants and children undergoing ambulatory magnetic resonance imaging. Br J Anaesth 2008; 101(2): 239–43. Cravero JP, Beach ML, Blike GT, Gallagher SM, Hertzog JH. The incidence and nature of adverse events during pediatric sedation/anesthesia with propofol for procedures outside the operating room: a report from the Pediatric Sedation Research Consortium. Anesth Analg 2009; 108(3): 795–804. Mallory MD, Baxter AL, Kost SI. Propofol vs. pentobarbital for sedation of children undergoing magnetic resonance imaging: results from the Pediatric Sedation Research Consortium. Paediatr Anaesth 2009; 19(6): 601–11. Zgleszewski SE, Zurakowski D, Fontaine PJ, D'Angelo M, Mason KP. Is propofol a safe alternative to pentobarbital for sedation during pediatric diagnostic CT? Radiology 2008; 247(2): 528–34. Benedik J, Manohin A. Sedation for middle ear surgery: prospective clinical trial comparing propofol and midazolam. Central Eur J Med 2008; 3(4): 487–93. Hollman GA, Schultz MM, Eickhoff JC, Christenson DK. Propofol-fentanyl versus propofol alone for lumbar puncture sedation in children with acute hematologic malignancies: propofol dosing and adverse events. Pediatr Crit Care Med 2008; 9(6): 616–22. Cechvala MM, Christenson D, Eickhoff JC, Hollman GA. Sedative preference of

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families for lumbar punctures in children with acute leukemia: propofol alone or propofol and fentanyl. J Pediatr Hematol Oncol 2008; 30(2): 142–7. Ilyas MI, Balacumaraswami L, Palin C, Ratnatunga C. Propofol infusion syndrome in adult cardiac surgery. Ann Thorac Surg 2009; 87(1): e1–3. Fong JJ, Sylvia L, Ruthazer R, Schumaker G, Kcomt M, Devlin JW. Predictors of mortality in patients with suspected propofol infusion syndrome. Crit Care Med 2008; 36(8): 2281–7. Smith H, Sinson G, Varelas P. Vasopressors and propofol infusion syndrome in severe head trauma. Neurocrit Care 2009; 10(2): 166–72. Laquay N, Pouard P, Silicani MA, Vaccaroni L, Orliaguet G. Early stages of propofol infusion syndrome in paediatric cardiac surgery: two cases in adolescent girls. Br J Anaesth 2008; 101(6): 880–1. Miner JR, Gray RO, Stephens D, Biros MH. Randomized clinical trial of propofol with and without alfentanil for deep procedural sedation in the emergency department. Acad Emerg Med 2009; 16(9): 825–34. Garg R, Dehran M. Convulsions with propofol: a rare adverse event. J Postgrad Med 2009; 55(1): 69–71. Landers C, Turner D, Makin C, Zaglul H, Brown R. Propofol associated hiccups and treatment with lidocaine. Anesth Analg 2008; 107(5): 1757–8. Gemma M, de Vitis A, Baldoli C, Calvi MR, Blasi V, Scola E, Nobile L, Iadanza A, Scotti G, Beretta L. Functional magnetic resonance imaging (fMRI) in children sedated with propofol or midazolam. J Neurosurg Anesthesiol 2009; 21(3): 253–8. Austin JD, Parke TJ. Admixture of ephedrine to offset side effects of propofol: a randomized, controlled trial. J Clin Anesth 2009; 21(1): 44–9. Rochette A, Hocquet AF, Dadure C, Boufroukh D, Raux O, Lubrano JF, Bringuier S, Capdevila X. Avoiding propofol injection pain in children: a prospective, randomized, double-blinded, placebo-

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controlled study. Br J Anaesth 2008; 101 (3): 390–4. Kassebaum N, Hairr J, Goldsmith W, Barwise J, Pandharipande P. Diabetes insipidus associated with propofol anesthesia. J Clin Anesth 2008; 20(6): 466–8. Bonhomme V, Demoitie J, Schaub I, Hans P. Acid-base status and hemodynamic stability during propofol and sevofluranebased anesthesia in patients undergoing uncomplicated intracranial surgery. J Neurosurg Anesthesiol 2009; 21(2): 112–9. Ture H, Mercan A, Koner O, Aykac B, Ture U. The effects of propofol infusion on hepatic and pancreatic function and acid-base status in children undergoing craniotomy and receiving phenytoin. Anesth Analg 2009; 109(2): 366–71. Crawford MW, Pehora C, Lopez AV. Drug-induced acute pancreatitis in children receiving chemotherapy for acute leukemia: does propofol increase the risk? Anesth Analg 2009; 109(2): 379–81. Tan CK, Lai CC, Cheng KC. Propofolrelated green urine. Kidney Int 2008; 74 (7): 978. Leclercq P, Loly C, Delanaye P, Garweg C, Lambermont B. Green urine. Lancet 2009; 373(9673): 1462. Inal MT, Memis D, Vatan I, Cakir U, Yildiz B. Late-onset pulmonary edema due to propofol. Acta Anaesthesiol Scand 2008; 52(7): 1015–7. Pérez-Bárcena J, Llompart-Pou JA, Homar J, Abadal JM, Raurich JM, Frontera G, Brell M, Ibáñez J, Ibáñez J. Pentobarbital versus thiopental in the treatment of refractory intracranial hypertension in patients with traumatic brain injury: a randomized controlled trial. Crit Care 2008; 12(4): R112. Cereda C, Berger MM, Rossetti AO. Bowel ischemia: a rare complication of thiopental treatment for status epilepticus. Neurocrit Care 2009; 10(3): 355–8. Neil MJ, Dale MC. Hypokalaemia with severe rebound hyperkalaemia after therapeutic barbiturate coma. Anesth Analg 2009; 108(6): 1867–8.

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11

Local anesthetics

GENERAL Nervous system Horner's syndrome, the triad of miosis, ptosis, and enophthalmos, is a common complication of regional blockade of the brachial plexus, following disruption of sympathetic nerve input from the cervical sympathetic ganglia [1A]. In rare cases it has been witnessed after intercostal regional anesthesia. It has also been reported in connection with thoracic epidural anesthesia [2A, 3A] and extrapleural regional anesthesia [4A]. Although it can be disconcerting for the awake patient, Horner's syndrome is generally well tolerated. Permanent lesions have been reported, but in the vast majority of cases the symptoms disappear after discontinuation of the regional anesthesia. It is advisable to inform patients having the above procedures of the possibility of Horner's syndrome and its generally benign course, in order to avoid distress and subsequent refusal of regional anesthesia. In a retrospective analysis of 334 patients with a history of seizure disorder undergoing 411 regional blocks, local anesthesia was implicated in seizure activity in only five of 24 seizures, judging by the time-course of the events [5R]. There was no proof that the local anesthetic had caused the seizure. Depending on the classification of these five cases, the authors estimated the incidence of

Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00011-8 # 2011 Elsevier B.V. All rights reserved.

seizures after regional blockade in patients with a history of seizure disorder at 0–120 per 10 000 (95% CI 0–280 per 10 000). They concluded that a pre-existing seizure disorder does not contraindicate the use of regional anesthesia, but should always trigger precautions for potential perioperative seizures.

Cartilage toxicity from local anesthetics Intra-articular injection of local anesthetics for pain relief after surgical procedures is an offlabel use of these compounds, but is commonly practised and widely published. Although its effectiveness is questionable and inferior to other modes of pain relief, such as peripheral regional blockade [6C, 7c], intraarticular injection is still widely used in various settings, possibly because of ease of administration. However, a growing body of evidence from laboratory data, animals, and case series in humans has emerged, raising concerns about the safety of intra-articular injection of local anesthetics. The direct toxic effects of local anesthetics on cartilage have been widely discussed. Animal studies After injection of saline, bupivacaine, or neostigmine into 45 knee joints in rabbits, there were no histopathological changes with saline, but significant changes with bupivacaine and neostigmine [8E]. In a study of the long-term effects of continuous intra-articular infusion of bupivacaine 0.25%, 36 rabbits were randomized into three 281

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groups and given an infusion of saline, bupivacaine, or bupivacaine þ adrenaline over 48 hours into the glenohumeral joint [9E]. Histopathological examination after 3 months showed no permanent impairment of cartilage function, suggesting that cartilage can recover from exposure to bupivacaine. Whether these results can be extrapolated to human chondrocytes is unclear. In vitro studies A direct toxic effect of 0.5% bupivacaine solution on bovine articular chondrocytes in vitro has been reported [10E]. Even a short exposure of 15–30 minutes was associated with up to 42% dead chondrocytes, and the rate was even higher (72%) when the articular surface was removed. Similar results were obtained in a study in which bovine articular chondrocytes were exposed to lidocaine 1% or 2% solution [11E]. There was a dose-dependent cytotoxic effect on chondrocytes that was less prominent than with bupivacaine, but still significant, suggesting that local anesthetics as a class (rather than a specific compound) may adversely affect cartilage metabolism. The effects of the common practice of injecting local anesthetics in combination with methylprednisolone have been investigated in vitro [12E]. Chondrocyte viability fell significantly with increasing doses and time of exposure to clinically relevant doses. The first studies involving human articular chondrocytes were published in 2008. In a study of the effect of bupivacaine in different concentrations for various exposure times on human and bovine chondrocytes longer exposure resulted in higher chondrotoxicity [13E]. The chondrotoxic effects of bupivacaine 0.5% and ropivacaine 0.5% have been studied in an in vitro model using human articular cartilage [14E]. Ropivacaine was significantly less toxic than bupivacaine, and the effects of ropivacaine on chondrocytes were comparable to those of saline. Chondrocytes isolated from human articular cartilage harvested during total knee replacement have been cultured for 24, 48, and 72 hours in artificial synovial fluid and continuously perfused with differing concentrations of lidocaine and bupivacaine in

combination with or without adrenaline [15E]. Bupivacaine 0.25% and 0.5% caused only minimal chondrocyte necrosis within the first 48 hours, but bupivacaine 0.5% caused significant chondrotoxic effects after 72 hours. All combinations of local anesthetics with adrenaline caused significant chondrotoxicity. Human reports As of now, only case reports have been published, no controlled studies. Having retrospectively reviewed 12 cases of postoperative chondrolysis, all of which involved the use of a high-flow intra-articular infusion of bupivacaine 0.25% with adrenaline, the authors recommended that intra-articular infusions of local anesthetics combined with adrenaline should not be used until more data are available [16c]. Of 23 patients with post-arthroscopic glenohumeral chondrolysis, all of whom had received a 20 ml intra-articular bolus injection of bupivacaine 0.25% with adrenaline, 14 occurred in patients after labral repair using a bioabsorbable device and seven had involved a thermal probe; four occurred in shoulders in which fixation anchors, pain pumps, and thermal probes had not been used [17A]. The authors stated that they had not seen any cases of chondrolysis before they started to infiltrate local anesthetics into the glenohumeral joint. Mechanism of action The mechanisms of chondrotoxicity due to local anesthetics are not well understood and remain speculative. One mechanism could be related to the pro-inflammatory effects of bupivacaine and lidocaine. Bupivacaine potentiates nitric oxide synthase-2 (NOS2) activity in rat glial cells, stimulating inflammation through the production of nitric oxide [18E] and lidocaine selectively upregulates pro-inflammatory proteins [19E]. This might not be a class effect of local anesthetics, as newer local anesthetics, such as ropivacaine, do not promote inflammatory processes [20E, 21E, 22E]. Clinical implications In view of the mounting evidence of the chondrotoxicity of local anesthetics in general, or at least some

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local anesthetics, several authors have recommended that until better data become available, only newer local anesthetics, such as ropivacaine, should be used intra-articularly [23r] or that injection of local anesthetics into joints should be completely avoided [24r]. These recommendations are in line with a warning by the FDA against the intra-articular infusion of local anesthetics after reviewing 35 reports of chondrolysis given continuous intra-articular infusions of local anesthetics with elastomeric infusion devices to control post-surgical pain [25S]. Chondrolysis was diagnosed within a median of 8.5 months after the infusion. Almost all of the reported cases occurred after shoulder surgery. Joint pain, stiffness, and loss of motion occurred as early as the second month after infusion. In more than half of these reports, the patients required additional surgery, including arthroscopy or arthroplasty. The FDA noted that chondrolysis in these cases was multifactorial and could have been related to the local anesthetics, the device materials, and/or other sources, and that single intra-articular injections of local anesthetics in orthopedic procedures have been used for many years without any reports of chondrolysis. Based on these reports, the FDA has required drug manufacturers to update their product labels to warn health-care professionals about this potential serious adverse effect and has required the manufacturers of pumps that may be used to infuse local anesthetics, including elastomeric infusion devices, to include similar warnings with their products.

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100 mg and lidocaine 400 mg [1A]. It occurred 30 minutes after the block and resolved after 2 hours. There was no respiratory compromise and surgery was completed without further complications. Delayed quadriparesis occurred after an interscalene brachial plexus block with Winnie's technique [26A]. • A 71-year-old woman scheduled for arthroscopic rotator cuff repair of the right shoulder received an interscalene brachial plexus block with ropivacaine 75 mg and mepivacaine 150 mg. After 15 minutes she had complete motor blockade of the right arm. She was anesthetized and the operation was performed, taking 80 minutes. She was transferred to the recovery room, and 2 hours later she noted weakness in both legs when she tried to walk. The right arm had complete sensory and motor block and the left arm had motor weakness (III/V) and reduced thermoanalgesic sensitivity. She had bilateral ptosis. Electromyography of the arms and legs and craniocervical T1–2 MRI showed no pathology. The symptoms resolved without treatment 72 hours after brachial plexus blockade. She was hemodynamically stable through the entire episode, and required no ventilatory assistance.

The onset and duration of the symptoms in this case could not be satisfactorily explained by a local anesthetic effect; whether the interscalene blockade caused the quadriparesis was not proven but could not be ruled out.

CAUDAL, EPIDURAL, AND SPINAL ANESTHESIA EFFECTS RELATED TO MODES OF USE [SED-15, 2121; SEDA-30, 152; SEDA-31, 233; SEDA-32, 262]

Brachial plexus anesthesia Nervous system Horner's syndrome occurred in a patient who received a sagittal infraclavicular block with levobupivacaine

Epidural anesthesia Nervous system Three cases of Horner's syndrome have been reported with the use of thoracic epidural catheters. This adverse effect is considered to be due to either high epidural or inadvertent subdural catheter placement. • A 13-year-old boy had a thoracic epidural at T7/8 plus general anesthesia for left thoracotomy using levobupivacaine 0.125% [2A]. After 72 hours of continuous infusion at a rate of

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6–8 ml/hour he developed miosis and ptosis on the right side and 4 hours after the end of the epidural infusion the symptoms resolved. • Two patients developed unilateral Horner's syndrome 20 minutes after a test dose of 3 ml of 1.5% lidocaine with adrenaline 1:200 000 in an epidural catheter at level T4/5 and T5/6 respectively [3A]. In both cases epidural positioning of the catheter was demonstrated by CT epidurography. The symptoms resolved after 90 minutes and did not return after using the epidural catheter in theatre and postoperatively with bupivacaine 0.125% plus fentanyl 3 micrograms/ ml at an infusion rate of 6–9 ml/hour.

The authors argued that an anatomical change might have occurred between the injection and the infusion; the different pressure applied when injecting the local anesthetic during testing and then infusing it may have led to the reported effect. Prolonged leg pain after insertion of an epidural catheter into the thoracic subarachnoid space has been reported [27A]. • In a 31-year-old woman scheduled for laparoscopic myomectomy a thoracic epidural catheter was placed at T12/L1 and elicited pain in the leg. The catheter was drawn back 3 cm. The pain subsided, no blood or CSF was aspirated, and a test dose of 2 ml of lidocaine 2% was injected. Within minutes she developed symptoms of spinal analgesia and a second aspiration proved that the catheter was in the intrathecal position. Therefore, only 20 micrograms of fentanyl in 2 ml of saline were given, and the catheter was removed afterwards. After an uncomplicated perioperative period, she developed severe pain extending from the left buttock to the tips of the toes in a radicular distribution from L2 to L5. It was treated with a lumbar epidural infusion for the first 13 days and afterwards with carbamazepine and amitriptyline for 12 more days. The pain and allodynia abated by 25 days after insertion of the catheter. An MRI scan showed a small area of high intensity in the ipsilateral dorsal column.

The authors assumed that a small spinal cord lesion had caused this transient episode of neuropathic pain. Acute transient hiccups after epidural injection of levobupivacaine have been described [28A]. • A 30-year-old primigravida with a twin pregnancy received an epidural catheter at L3/4

for pain relief. Within minutes of a loading dose of 5 ml of levobupivacaine 0.125% she developed hiccups. Epidural analgesia was continued with levobupivacaine 0.1% plus alfentanil 40 micrograms/ml at a rate of 10 ml/hour. The hiccups continued for 1 hour and then resolved spontaneously. Minutes after a second bolus to treat breakthrough pain the hiccups returned for 2 hours before resolving again.

Hiccups have been associated with administration of glucocorticoids into the epidural space [29A, 30A]. Their cause is not understood. They are usually transient and self-limiting, and reassurance is often the only treatment needed.

Spinal (intrathecal) anesthesia Cardiovascular Hypotension during surgery for femoral neck fracture in elderly patients is common. In a retrospective comparison of the incidence of hypotension between general anesthesia, single injection spinal anesthesia, and continuous spinal anesthesia, with bolus injections of either 2.5 or 5 mg as needed in 333 patients hypotension was rare in those who received continuous spinal anesthesia with 2.5 mg (4%), compared with 83%, 68%, and 34% in the other groups [31C]. In a prospective study in 32 elderly patients, ASA grades 1–3, who received spinal anesthesia with bupivacaine 10–17.5 mg, baseline blood pressure variability and nearinfrared spectroscopy reduction predicted hypotension with high sensitivity (0.73 and 0.90 respectively) and specificity (0.78 and 0.64, respectively) [32C]. However, heart rate, systemic vascular resistance index, baroreceptor sensitivity, and heart rate variability were of limited predictive value. Respiratory The risk of postoperative spells of apnea in preterm infants has promoted the use of spinal anesthesia, because of improved safety. However, high spinal anesthesia has been associated with respiratory failure in a preterm infant [33A]. The authors concluded that the cephalad spread of spinal anesthesia is less

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predictable in preterm infants and that caution is warranted. Since high spinal anesthesia after using an adequate weight-adjusted dose of local anesthetic is very rare it is still a safe alternative to general anesthesia in preterm infants. Nervous system A Cochrane review of 16 trials has compared the risk of transient neurological symptoms after spinal anesthesia with lidocaine versus other local anesthetics [34R]. There were 1467 patients, of whom 125 developed transient neurological symptoms, i.e. slight to severe pain in the buttocks and legs after full recovery from the spinal anesthesia. The symptoms usually develop 2–24 hours after intrathecal injection and last 1–2 days. There is no evidence that this painful condition is associated with nervous system damage. The symptoms disappeared spontaneously by the fifth postoperative day in all patients. The relative risk of transient neurological symptoms after spinal anesthesia with lidocaine compared with other local anesthetics (bupivacaine, levobupivacaine, prilocaine, procaine, ropivacaine, or 2-chloroprocaine) was 7.3 (95% CI ¼ 4.2, 13). Mepivacaine gave similar results to lidocaine. The authors concluded that since the risk of transient neurological symptoms is significantly higher when lidocaine or mepivacaine are used for spinal anesthesia, alternative local anesthetics should be used. Microradiculopathy after spinal anesthesia with bupivacaine has been reported [35A]. • A 48-year-old man underwent uneventful spinal anesthesia at L3/4 with 3 ml of 0.5% hyperbaric bupivacaine solution for varicose vein surgery of the lower limb. Postoperatively, the left leg recovered adequately but the right leg had persistent lower limb motor deficits and absent patellar and Achilles reflexes but a normal plantar reflex and a sensory hypesthesia below T10. A thoracolumbar MRI scan was unremarkable, but electromyography showed normal sensory action potentials and acute motor denervation in right L4–S5 (severe) and left L5–S1 (moderate), indicative of multiradiculopathy. The motor and sensory deficits remained unchanged during 2 years of follow-up.

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The asymmetrical presentation in this case differs from previous reports [36A], but in the absence of any other reasonable explanation this injury was attributed to bupivacaine. Persistent cauda equina syndrome has been reported after spinal anesthesia with procaine [37A]. • A 52-year-old woman underwent uneventful spinal anesthesia at L3/4 with 1.5 ml procaine 10% for elective knee arthroscopy. Postoperatively, her sensory levels decreased adequately and she was discharged. However, she became unable to urinate, was intermittently incontinent of urine, and noticed pelvic numbness from the right perineum to the perianal region. Later, she developed parasacral burning and throbbing with an intermittent shooting right thigh pain. She was unable to defecate for a week until she was given laxatives. MRI scans were normal. Detailed neurological examinations were consistent with cauda equina syndrome. After 1 year the neurological findings were essentially unchanged.

This is the first report of cauda equina syndrome induced by procaine. The relative risk compared with other local anesthetics needs to be established. Spinal anesthesia with intrathecal bupivacaine has been associated with spinal myoclonus [38A]. • A 52-year-old woman developed spinal myoclonus 60 minutes after receiving 60 mg of hyperbaric prilocaine 5%. She had involuntary, asymmetrical, brief movements of the legs at a frequency of 10–20/minute. Treatment with intravenous diazepam 5 mg blunted the symptoms but did not abolish them; they resolved completely 60 minutes after full recovery from spinal anesthesia. There were no residual signs of neurological impairment.

Spinal myoclonus is postulated to be caused by reduced activity of inhibitory pathways at the level of motor neurons or interneurons. It is a rare self-limiting adverse event and has so far been evoked by bupivacaine and prilocaine. Diazepam has been reported to be effective in the past, but did not convince in this case. Spinal anesthesia with intrathecal bupivacaine has also been associated with

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propriospinal myoclonus [39A], a rare involuntary rhythmic movement of muscles of one myelomere, spreading to rostral and caudal myotomes. It originates in the spinal cord with no pathological findings in the electroencephalogram corresponding to abnormal movement. It is elicited by tumors, trauma, neurodegenerative disease, spinal compression, and drugs. Propriospinal myoclonus has previously been described after intrathecal application of bupivacaine (plain and hyperbaric). In the case described here the myoclonus started after 24 hours and lasted for 3 days, although valproate and clonazepam were started early on. In previous reports the symptoms often began within 3 hours of spinal administration and the myoclonus ceased after the effect of the local anesthetic ended. It remains unclear if this case was an unusual example of delayed myoclonus evoked by spinal administration of bupivacaine or propriospinal myoclonus of unknown cause. A subdural hematoma occurred after spinal anesthesia for cesarean section [40A]. • Spinal anesthesia was performed with a 25gauge Quincke needle in a 31-year-old woman who had no hemostatic susceptibility factors or bleeding disorders. Her symptoms started 48 hours after surgery, with right retro-orbital pain and persistent, moderate right headache. After 2 hours she became drowsy, her Glasgow Coma Scale score fell to 8, she had anisocoric pupils (right > left) and marked right hemiparesis, and a CT scan showed a right temporoparietal subdural hematoma with midline displacement.

The authors explained the ipsilateral hemiparesis by invoking the Kernohan–Woltman notch phenomenon, in which intracranial mass lesions compress the cerebral peduncle on the opposite side against the tentorial notch, interrupting the fibers of the cerebrospinal tract. The subdural hematoma was aspirated and she was discharged with minimal weakness of the right leg. Chemical meningitis has been reported in four patients undergoing spinal anesthesia for different procedures [41A]. All developed meningitis on the first postoperative day. In each case cerebrospinal fluid

analysis suggested bacterial meningitis, but all blood cultures taken before antibiotic treatment were negative. Their symptoms improved with antibiotics and dexamethasone within 24 hours. Further investigations showed that all patients had received the local anesthetic bupivacaine chloral hydrate in a generic formulation called TradinolTM (“lot 001”), produced by a local pharmaceutical company in Brazil. The national health surveillance agency was notified and published a resolution to suspend the distribution and sale of the product, mentioning another eight similar cases in other Brazilian states. Death Fatal cardiac arrest following bladder catheterization for urinary retention after spinal anesthesia has been reported [42A]. • A 16-year-old girl underwent appendectomy with spinal anesthesia and 6 hours after surgery developed abdominal pain due to a distended bladder. When she was catheterized, she went into cardiopulmonary arrest. Despite immediate resuscitation, she died.

The proposed reason for cardiovascular arrest in this case was urinary syncope, which can follow rapid loss of tension in the bladder. Care has to be taken to avoid rapid emptying of a distended bladder, although the fatal outcome is difficult to understand.

Infiltration anesthesia Nervous system Pain on injection is a very common adverse reaction to local anesthetics when used for infiltration. A review of the efficacy of bicarbonate in reducing pain on intradermal injection of local anesthetic agents showed a significant advantage of the buffered solution [43R]. When bicarbonate was added to the local anesthetic pain scores on a visual analogue scale were reduced by 12% (95% CI ¼ 6.7, 17).

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Dental anesthesia

Ocular anesthesia

Nervous system Mandibular nerve block with articaine has been associated with possible precipitation of multiple sclerosis [44A].

Cardiovascular Three cases of central retinal artery occlusion after surgery with peribulbar anesthesia have been reported [47A]. In two cases ropivacaine 0.75% (17 and 13 ml) was used; in the third case the block was done with 14 ml of 2% mepivacaine. The authors suggested that these cases might be related to raised intraocular pressure due to the block or vasoconstriction caused by the local anesthetics.

• A 30-year-old man developed an isolated left abducens nerve palsy 1 day after removal of the mandibular right second and third molars under mandibular nerve block with 1.8 ml of articaine with 1:100 000 adrenaline. Multiple sclerosis was diagnosed because of the sudden onset of the symptom and the presence of typical MRI abnormalities. The symptoms subsided 20 days after starting glucocorticoid therapy.

However, the association of the mandibular block or the agent articaine with the onset of multiple sclerosis was not proven and does not seem likely.

Extrapleural anesthesia Nervous system Horner's syndrome has been reported after extrapleural infusion of bupivacaine. • After extrapleural infusion of bupivacaine 0.5% (3 ml/hour) via a catheter with multiple side holes, ipsilateral Horner's syndrome was diagnosed on the first postoperative day [4A]. After discontinuing the infusion the symptoms resolved without further complications.

Horner's syndrome due to extrapleural infusions is a rare complication, thought to indicate local anesthetic spread from the thoracic paravertebral to the cervical region [45r].

Intravenous regional anesthesia In a review of the literature on adverse events associated with intravenous regional anesthesia the author concluded that Bier's block is safe when anesthetic doses are kept low [46R]. Seizures have been reported at doses as low as 1.4 mg/kg of lidocaine, 4 mg/kg of prilocaine, and 1.6 mg/kg of bupivacaine. Serious cardiac events have only been reported with lidocaine and bupivacaine.

Sensory systems Eyes Photorefractive keratectomy is a widely performed procedure for improving visual acuity. There are various regimens of medication for postoperative pain management, including the use of oral medications, topical non-steroidal antiinflammatory drugs, and local anesthetic solutions. The risk associated with long-term use of topical local anesthetic solutions has been highlighted [48A]. • A 51-year-old woman underwent photorefractive keratectomy and 7 days later developed epithelial basement membrane dystrophy in both corneas. After repeat keratectomy and antibiotic treatment she returned on day 3 with impaired vision, large epithelial defects, and corneal infiltrates in both eyes. Cultures were negative. She had continued to instill non-prescribed “comfort drops” made up of a 0.05% tetracaine solution every 30 minutes in both eyes from the initial surgery. She was asked to stop using the drops, and 2 weeks later the eyes had fully reepithelialized, the infiltrates had begun to clear, and vision improved.

While pain after photorefractive keratectomy needs to be treated effectively, the non-prescribed long-term misuse of local anesthetics can lead to impaired wound healing. Postulated mechanisms include inhibition of corneal epithelial migration and adhesion and toxic effects on stromal keratocytes [49E, 50E].

Peripheral nerve block Nervous system In an analysis of closed claims by the American Society of Anesthesiologists concerning complications

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associated with eye blocks and peripheral nerve blocks 6894 claims filed in the years 1980–2000 were identified [51R]. Only 159 claims were associated with peripheral nerve blocks. Most of these were due to temporary injuries (56%), while 36% related to permanent injuries and 8% were due to death or brain damage. Permanent injuries were mainly at the level of the brachial plexus and were associated with axillary and interscalene brachial blocks. However, median nerve and ulnar nerve injuries were also common. Unintentional intravascular injection of local anesthetic with systemic local anesthetic toxicity was the cause in 7 of 19 cases that resulted in death or brain damage. Of the total, 97 were associated with eye blocks. An anesthetist provided the block in 59 cases and in 38 the anesthetist only provided monitored anesthesia care. Claims with eye blocks had a significantly higher rate of payments to the plaintiff mainly because of permanent nerve damage due to needle trauma.

Topical anesthesia Observational studies Topical anesthetic exposure in children younger than 6 years old has been reviewed, including 8576 cases of exposure to topical anesthetics reported to the American Association of Poison Control Centers from 1983 to 2003 [52R]. There were seven deaths due to local anesthetic toxicity, mainly because of aspiration or ingestion of topical anesthetics. These rare serious events are alarming, because many topical anesthetics are available over-the-counter. Placebo-controlled studies In a randomized, double-blind, placebo-controlled study of the effect of 4 mg/kg of nebulized lidocaine 2% before insertion of a nasogastric tube in children no adverse events were reported [53c]. Although pain scores were significantly lower in the treatment arm in the period after insertion of the nasogastric tube, the intervention did not seem to be useful because the nebulization itself was very distressing.

Cardiovascular Ingested lidocaine meant for gargling before direct laryngoscopy led to cardiac arrest [54A]. • A 50-year-old woman received 20 ml of lidocaine 5% as a gargling solution before direct laryngoscopy and accidently swallowed the solution; 20 minutes later she had a cardiac arrest and was successfully resuscitated. Plasma lidocaine concentrations were not measured.

Lidocaine has a systemic availability of 30–35% after ingestion and the use of such a high oral dose (1000 mg, 20 mg/kg) is dangerous. • A 48-year-old man sprayed an unknown amount of lidocaine on to his penis before sexual activity and developed chest tightness and bradycardia for 2 days [55A]. Cardiac enzymes were normal and an electrocardiogram showed sinus bradycardia without ST segment changes. The symptoms resolved after several hours of observation without any treatment.

The authors proposed that the chest tightness might have been caused by systemic intoxication by the local anesthetic. Unfortunately the amount of lidocaine used, the exact timing between use and onset of symptoms, and serum lidocaine concentration were not reported. A history of concomitant use of other medications was also missing. The duration of the symptoms (2 days) was rather long for an effect of lidocaine, although its toxic metabolites have quite long half-lives.

Nervous system A patient who used lidocaine 5% and phenylephrine 0.5% as a nasal decongestant for left sinus surgery developed an ipsilateral fixed dilated pupil [56A]. The consensual pupillary light reflex in the right eye was normal, suggesting that the optic nerve was not damaged. The eye returned to normal after 4 hours, suggesting that the dilated pupil was a drug effect of either lidocaine interacting with the short ciliary nerve or direct stimulation of the sympathetic fibers of the eye by phenylephrine. Since papillary status is used to find out early about intraocular

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complications in sinus surgery, care should be taken to avoid spillage of decongestant agents into the eyes. Immunologic Allergic reactions to lidocaine for fiberoptic bronchoscopy have been reviewed [57R]. The authors concluded that lidocaine is safe in bronchoscopy, provided that care is taken to limit the dose. In suspected local anesthetic allergy they suggested patch testing before the use of any topical anesthesia. The combination of lidocaine 7% þ tetracaine 7% (“LT peel”) is a novel topical anesthetic cream formulation mainly used in dermatological procedures, such as laser treatment [58R]. An allergic reaction has been reported [59A]. • A 26-year-old woman with no history of atopy developed erythema and edema of the face and angioedema of the lips 15 minutes after applying LT peel to her entire face before laser surgery. She reported mild pruritus, burning, and tingling of the face. The cream was removed, she was given a single oral dose of diphenhydramine 50 mg, and the symptoms resolved within 30 minutes.

Whether the allergic reaction was directly due to one of the local anesthetic components of the cream or an immunogenic metabolite (such as p-aminobenzoic acid) was not further investigated.

INDIVIDUAL COMPOUNDS Benzocaine [SED-15, 427; SEDA-30, 158; SEDA-31, 239; SEDA-32, 266] Hematologic Methemoglobinema EIDOS classification: Extrinsic moiety Benzocaine Intrinsic moiety Hemoglobin Distribution Erythrocytes Outcome Oxidation of iron in hemoglobin

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Sequela Methemoglobinemia due to benzocaine DoTS classification: Dose-relation Hypersusceptibility Time-course Immediate Susceptibility factors Sepsis, anemia Methemoglobinemia related to local anesthetics has been reviewed [60R]. Benzocaine has reportedly caused methemoglobinemia after as little as a single spray, and rebound symptoms have occurred 18 hours after treatment of benzocaine-induced methemoglobinemia with methylthioninium chloride (methylene blue). The author concluded that benzocaine should not be used anymore. An accompanying editorial underlined the importance of avoiding benzocaine, because of an “inability to predict potentially fatal events relating to the use of this drug” [61r]. This statement has been supported by the continuing flow of case reports on hematological adverse effects of benzocaine. For example, a 3-year-old child developed marked cyanosis after ingesting benzocaine 330 mg in a falsely mixed “magic mouth wash” [62A]. Several cases of methemoglobinemia have followed the use of marketed formulations of benzocaine, such as Baby OrajelTM (which contains benzocaine 7.5%) and CetacaineTM (14% benzocaine þ 2% tetracaine). • A 6-year-old boy was treated with an unknown amount of a benzocaine gel for toothache and developed cyanosis, vomiting, and lethargy 3 hours later [63A]. Methemoglobinemia (70%, a potentially fatal concentration) was immediately treated with methylthioninium chloride 1 mg/kg. The symptoms resolved within the next hour. • A 15-month-old 6.8 kg girl had general anesthesia for rigid bronchoscopy to rule out a recurrent tracheoesophageal fistula after tracheoesophageal fistula repair, fundoplication, and gastrostomy in the past [64A]. Because she had residual tracheomalacia and recurrent aspiration she was brought to ICU postoperatively for weaning and extubation. Extubation was uneventful, but her mother attributed crying to teething pain and used Baby OrajelTM for pain relief. Shortly afterwards the baby desaturated, which was attributed to atelectasis; it responded

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after several hours to oxygen. This sequence was repeated three times. After the fourth application of a pea-sized drop of benzocaine 7.5% the baby developed profound cyanosis and tachycardia, and an arterial blood gas showed methemoglobinemia of 43%. She was treated with methylthioninium chloride 1 mg/ kg and her symptoms improved promptly. The methemoglobin concentration was 0.9% 2 hours later. • A 69-year-old woman had CetacaineTM (14% benzocaine þ 2% tetracaine) sprayed into the oropharynx before awake fiberoptic intubation [65A]. The exact amount of spray was not reported. After an hour her SaO2 fell to 85% and her skin appeared dusky. Methemoglobinemia was diagnosed and she was given methylthioninium chloride 2 mg/kg, after which the symptoms resolved within 1 hour.

These cases stress the importance of keeping methemoglobinemia in mind when desaturation occurs after the use of local anesthetics. Skin Contact dermatitis has occurred after the use of benzocaine 5% in a condom [66A]. • A 22-year-old man developed recurrent erythematous–edematous dermatitis of the shaft of the penis a few hours after sexual intercourse using condoms. Tests for latex protein hypersensitivity were negative. A patch test established the diagnosis of contact allergy to benzocaine.

Bupivacaine

[SED-15, 568; SEDA-30, 159; SEDA-31, 239; SEDA-32, 267] Cardiovascular A bupivacaine infusion caused a significant dysrhythmia in an elderly patient [67A].

• A 78-year-old woman received a femoral nerve block with 30 ml of bupivacaine 0.5% for total knee replacement. After surgery an infusion of bupivacaine 0.25% (8 ml/hour) was given via a femoral nerve catheter. She developed complete heart block 9 hours later. A preoperative electrocardiogram had shown sinus rhythm and electrolytes were normal. Sinus rhythm resumed 6 hours after the end of the infusion. There was no other cardiac pathology, and the authors assumed that bupivacaine had caused the dysrhythmia.

Cardiac arrest has been reported after femoral nerve block [68A]. • A 17-year-old patient had seizures directly after receiving 20 ml of bupivacaine 0.5% over 2–3 minutes for femoral nerve blockade; aspiration tests every 5 ml were negative. He was bag-ventilated and given 3 mg of midazolam intravenously, followed by Intralipid 20%; 1–2 minutes later he went into cardiac arrest with ventricular fibrillation. He was successfully resuscitated.

It is not clear that it was the bupivacaine that was responsible in this case.

Dibucaine Drug overdose Dibucaine has been withdrawn from the market as an injectable spinal anesthetic, because of its adverse reactions profile, but it remains available as an over-the-counter topical formulation. Ingestion of a potentially lethal dose of dibucaine in a child has been reported [69A]. • An 18-month-old girl weighing 15 kg ingested an estimated 150 mg (12.5 mg/kg) of dibucaine from a tube of sunburn medication that contained 1% dibucaine. Within 30 minutes she became unresponsive and cyanotic and had intermittent generalized tonic–clonic seizures for about 10 minutes. She was given diazepam 5 mg rectally and was intubated. The electrocardiogram showed a wide-complex bradycardia with frequent paroxysmal ventricular extra beats and later atrioventricular nodal block with a QRS complex duration of 200 ms, a QT interval of 513 ms, and frequent transient episodes of ventricular tachycardia. She was given sodium bicarbonate, magnesium sulfate, and intermittent intravenous diazepam. She remained in sinus rhythm with subsequent narrowing of the QRS complex, was extubated 12 hours after presentation, and recovered without sequelae.

Lidocaine

[SED-15, 2051; SEDA-30, 160; SEDA-31, 240; SEDA-32, 267] Cardiovascular The ECG manifestations of Brugada syndrome are often concealed but can be unmasked by sodium channel

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blockers with slow dissociation kinetics. Lidocaine has rapid dissociation kinetics and thus has little or no effect on the ST segment in patients with Brugada syndrome. However, a novel mutation of the sodium channel has been described in a patient in whom lidocaine precipitated the Brugada syndrome [70A]. • A 45-year-old man with no history of cardiac disease had a seizure. His electrocardiogram was normal. He then suddenly developed a monomorphic wide-complex ventricular tachycardia for which he was given lidocaine 70 mg followed by a continuous infusion of 1 mg/minute. This led to ST segment elevation in leads V1–3, which persisted even 1 year later. There was no evidence of myocardial infarction and he had no chest pain. He was genotyped and the sodium channel mutation was discovered.

Nervous system Possible central nervous system toxicity after low-dose lidocaine has been reported [71A]. • A 26-year-old woman weighing 50 kg had a subdural hematoma and was scheduled for elective percutaneous dilatational tracheostomy. While the skin above the trachea was being infiltrated with 1 ml of lidocaine 2% she developed generalized convulsions. Aspiration confirmed intravascular placement and the convulsions stopped after intravenous thiopental 100 mg. An MRI scan showed an aberrant carotid artery overlying the trachea.

The authors assumed that injection of as little as 20 mg of lidocaine into the carotid artery had caused the convulsions. Although this possibility cannot be excluded, it should be noted that early postoperative convulsions after brain surgery for epidural and subdural hematomas are common, and these convulsions may have been independent of the lidocaine. Respiratory Intravenous lidocaine is commonly used as part of anesthetic induction, especially in children, to prevent reflex bronchoconstriction caused by endotracheal intubation. Intravenous lidocaine significantly improves intubating conditions when it is used as part of inhalational induction. However, intravenous lidocaine can cause reduced airway diameter in

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asthmatics, as has been illustrated in a child with asthma [72A]. • A 17-month-old girl weighing 9 kg underwent anesthesia for elective upper gastrointestinal endoscopy. She had a history of seasonal allergies and intermittent mild episodes of asthma. Induction of anesthesia with a volatile anesthetic was initially uneventful. After venous access had been established she was given intravenous lidocaine 1.5 mg/kg and immediately developed bilateral expiratory wheezes and a marked increase in inspiratory peak pressure. There were no rashes and no other signs of an allergic reaction. The wheezing resolved over 5 minutes without any further interventions and the trachea was later intubated without any problems. There were no further respiratory symptoms during the operation or postoperatively.

The mechanism of action in this case was not fully understood. A central mechanism of action of lidocaine may have reduced activity of the noradrenergic non-cholinergic bronchodilatory system [73c]. Immunologic Type IV allergic reactions to lidocaine are rare. However, cross-reactivity to the amide local anesthetics has been described [74A]. • A 54-year-old woman, who had used lidocaine cream intermittently for over 1 year for hemorrhoids, suddenly developed a severe perianal bullous eczematous type IV reaction a few days after applying the cream again. Subsequent patch testing with a local anesthetic series showed cross-reactivity to the amide local anesthetics lidocaine, bupivacaine, mepivacaine, and prilocaine. There was no cross-reactivity with an ester-type anesthetic.

Prilocaine and EMLAÒ (prilocaine þ lidocaine)

[SED-15, 2916; SEDA-31, 240; SEDA-32, 268]

Hematologic Methemoglobinemia related to local anesthetics has been reviewed [60R]. Plain prilocaine can cause methemoglobinemia in the following doses: • patients taking other oxidizing drugs—doses over 1.3 mg/kg;

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• children under 6 months of age—doses over 2.5 mg/kg; • renal insufficiency—doses over 3.2 mg/kg; • healthy adults—doses over 5 mg/kg.

Several case reports have substantiated the opinions in this review. • An otherwise healthy 32-year-old woman received prilocaine 60 mg for removal of a gluteal abscess and developed symptoms of suspected methemoglobinemia, with dizziness, fever, and headache 1 hour after surgery and peripheral cyanosis and tachycardia 3 hours later [75A]. She was given 5 ml of methylthioninium chloride 1% and her symptoms resolved within 30 minutes. Erythrocyte glucose-6-phosphatedehydrogenase activity was normal.

The weight of this patient was not reported; however, the dose that she was given was very low for the development of methemoglobinemia in an otherwise healthy patient. So far only benzocaine had been reported to cause cyanosis in very low doses. • A 42-day-old boy received prilocaine 40 mg during circumcision [76A]. The route of administration was not reported. He developed cyanosis 1 hour later. The methemoglobin concentration was 45%. Because methylthioninium chloride was unavailable, he was given intravenous ascorbic acid 300 mg/kg and his symptoms abated after 30 minutes and disappeared after 2 hours.

The authors suggested that high-dose ascorbic acid can be used as an alternative in methemoglobinemia if methylthioninium chloride cannot be used. • A 19-month-old boy received EMLA cream 60 g for analgesia on 250 cm² of skin with second-degree burns [77A] and 5 hours later became cyanosed during induction of general anesthesia for wound debridement. The methemoglobin concentration was 16%. After surgery he had a seizure while recovering from anesthesia and was given intravenous midazolam 2 mg. Plasma concentrations of prilocaine and lidocaine were 4.4 and 12.5 mg/l respectively. He was given no specific treatment, and after 9 hours the methemoglobin concentration was normal.

The maximum dose of EMLA cream for children aged 1–5 years is 10 g on 100 cm² of intact skin. This was therefore a case of overdose with the additional problem of unpredictable

absorption of the agent through compromised skin. Neurological sequelae are expected at plasma prilocaine and lidocaine concentrations of 50–100 mg/l, but the two agents may have had additive or synergistic neurological toxicity or the seizure may not have been due to the local anesthetics. Immunologic Tumescent local anesthesia is widely used for liposuction as well as phlebectomy procedures and can cause severe adverse effects including fatal complications [78A]. An allergic reaction to prilocaine has been reported. • A 55-year-old woman underwent varicose surgery on her right leg using tumescent local anesthesia with 883 ml of prilocaine 0.065% þ adrenaline 1:1 000 000. Surgery was uneventful, but 1 week later she developed erythema and swelling in the groin spreading to the distal injection sites. When initial broad spectrum antibiotics failed and papulovesicles developed, an allergic reaction was suspected and confirmed by patch testing, which was positive with prilocaine and lidocaine. Oral prednisolone 20 mg/day led to rapid improvement.

An immediate allergic reaction prilocaine has been reported [79A].

to

• A 60-year-old women underwent intravenous regional anesthesia with 3 mg/kg of prilocaine 0.5% diluted with saline to a total of 40 ml for surgical treatment of carpal tunnel syndrome and 3 minutes after injection developed severe erythema and edema in the limb below the tourniquet. Intravenous hydrocortisone was started and the tourniquet was released after 20 minutes. All the skin signs disappeared within 1 hour and there were no systemic reactions after release of the tourniquet. A skin prick test later confirmed allergy to prilocaine.

Another report has stressed the rare atopic potential of amide local anesthetics [80A]. • An 80-year-old woman with persistent leftthoracic pain after an episode of herpes zoster used EMLA daily for pain relief and after 10 days developed erythema and inflammation at the site of administration. There were no systemic effects and the lesions resolved with local glucocorticoids. Patch tests confirmed hypersensitivity to both lidocaine and prilocaine.

A rare adverse effect of EMLA on blood vessels has been reported [81A].

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• A 3-year-old boy with molluscum contagiosum was scheduled for curettage and EMLA cream was applied 60 minutes before the procedure and covered with plastic film. When the plastic film was removed, petechial and purpuric macules were seen. Surgery proceeded. There was no excessive bleeding and a platelet count was normal. After 1 week the purpuric lesions disappeared.

Patch testing was not performed. The pathogenesis in this case was not known. The authors discussed the possible association between atopic dermatitis and purpura after the application of EMLA, although the patient did not have a family or personal history of atopic dermatitis.

Propitocaine Skin A fixed drug eruption after propitocaine has been reported [82A]. • A 50-year-old Japanese man received propitocaine hydrochloride and felypressin for dental treatment and 1 day later developed slate-colored, well-circumscribed, round erythematous lesions on the face and upper arms and on the oral and genital mucosae. He had had macular erythema after a nerve block 1 year earlier using mepivacaine and after dental treatment involving lidocaine. The symptoms resolved after treatment for 9 days with oral prednisolone. Patch tests showed reactions to the amide local anesthetics, lidocaine, propitocaine, and mepivacaine.

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Ropivacaine [SED-15, 3078; SEDA-30, 161; SEDA-31, 240; SEDA-32, 269] Nervous system High doses of ropivacaine can lead to seizures [83A]. • An 18-year-old man with a history of childhood febrile convulsions received a combined axillary/interscalene brachial plexus block with two doses of ropivacaine 150 mg 15 minutes apart, and 2 minutes after the second dose developed generalized tonic–clonic seizure, which were successfully treated with oxygen, ventilation, and intravenous midazolam. The arterial plasma concentration ropivacaine at the time of the convulsions was only 2.1 mg/l.

The authors hypothesized that the history of febrile convulsions in this patient might have been a susceptibility factor for seizures provoked by local anesthetics. However, this is contradicted by the study quoted above, which showed that a history of seizure disorder is only a minor susceptibility factor for postoperative seizures after regional blockade, even if there was recent seizure activity [5R]. Since the febrile convulsions were very long ago in the case reported here, the seizure might have been due to nervous system toxicity after a rather high dose of 5 mg/kg ropivacaine, despite the low concentration later found [84r].

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in hip surgery: a case report. Minerva Anestesiol 2010; 76(4): 290–3. Ramos-Aparici R, Segura-Pastor D, EdoCebollada L, Vila-Sánchez M. Acute subdural hematoma after spinal anesthesia in an obstetric patient. J Clin Anesth 2008; 20(5): 376–8. Santos MC, de Albuquerque BC, Monte RL, Filho GG, Alecrim MG. Outbreak of chemical meningitis following spinal anesthesia caused by chemically related bupivacaine. Infect Control Hosp Epidemiol 2009; 30(9): 922–4. Mandal K, Ranjan P, Mathur S. Urinary syncope following spinal anesthesia leading to cardio respiratory arrest and death. Acta Anesthesiol Scand 2008; 52(8): 1169. Hanna MN, Elhassan A, Veloso PM, Lesley M, Lissauer J, Richman JM, Wu CL. Efficacy of bicarbonate in decreasing pain on intradermal injection of local anesthetics: a meta-analysis. Reg Anesth Pain Med 2009; 34(2): 122–5. Kocer B, Ergan S, Nazliel B. Isolated abducens nerve palsy following mandibular block articaine anesthesia, a first manifestation of multiple sclerosis: a case report. Quintessence Int 2009; 40(3): 251–6. Aniteye EA, Edwin F, Tettey MM, Frimpong-Boateng K. Post-thoracotomy Horner syndrome associated with extrapleural infusion of bupivacaine. Interact Cardiovasc Thorac Surg 2009; 9(2): 310. Guay J. Adverse events associated with intravenous regional anesthesia (Bier block): a systematic review of complications. J Clin Anesth 2009; 21(8): 585–94. Calenda E, Rey N, Compere V, Muraine M. Peribulbar anesthesia leading to central retinal artery occlusion. J Clin Anesth 2009; 21(4): 311–2. Lee JK, Stark WJ. Anesthetic keratopathy after photorefractive keratectomy. J Cataract Refract Surg 2008; 34(10): 1803–5. Dass BA, Soong HK, Lee B. Effects of proparacaine on actin cytoskeleton of corneal epithelium. J Ocul Pharmacol 1988; 4 (3): 187–94. Moreira LB, Kasetsuwan N, Sanchez D, Shah SS, LaBree L, McDonnell PJ. Toxicity of topical anesthetic agents to human keratocytes in vivo. J Cataract Refract Surg 1999; 25(7): 975–80.

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[51] Lee LA, Posner KL, Cheney FW, Caplan RA, Domino KB. Complications associated with eye blocks and peripheral nerve blocks: an American Society of Anesthesiologists closed claims analysis. Reg Anesth Pain Med 2008; 33(5): 416–22. [52] Curtis LA, Dolan TS, Seibert HE. Are one or two dangerous? Lidocaine and topical anesthetic exposures in children. J Emerg Med 2009; 37(1): 32–9. [53] Babl FE, Goldfinch C, Mandrawa C, Crellin D, O'Sullivan R, Donath S. Does nebulized lidocaine reduce the pain and distress of nasogastric tube insertion in young children? A randomized, double-blind, placebo-controlled trial. Pediatrics 2009; 123(6): 1548–55. [54] Doumiri M, Moussaoui A, Maazouzi W. Cardiac arrest after gargling and oral ingestion of 5% lidocaine. Can J Anaesth 2008; 55(12): 882–3. [55] Lin F, Chang W-H, Su Y-J, Tsai C-H. Cardiovascular complications resulting from topical lidocaine application. Int J Gerontol 2008; 2(4): 229–32. [56] Jindal M, Sharma N, Parekh N. Intraoperative dilated pupil during nasal polypectomy. Eur Arch Otorhinolaryngol 2009; 266(7): 1035–7. [57] Bose AA, Colt HG. Lidocaine in bronchoscopy: practical use and allergic reactions. J Bronchol Intervent Pulmonol 2008; 15 (3): 163–6. [58] Alster TS. The lidocaine/tetracaine peel: a novel topical anesthetic for dermatologic procedures in adult patients. Dermatol Surg 2007; 33(9): 1073–81. [59] Channual J, Wu JJ, Zachary CB. Localized contact urticaria caused by lidocaine/tetracaine peel. Arch Dermatol 2009; 145(4): 499–500. [60] Guay J. Methemoglobinemia related to local anesthetics: a summary of 242 episodes. Anesth Analg 2009; 108(3): 837–45. [61] Weinberg GL. Banning benzocaine: of bananas, bureaucrats, and blue men. Anesth Analg 2009; 108(3): 699–701. [62] Kreshak AA, Ly BT, Edwards WC, Carson SH. A 3-year-old boy with fever and oral lesions. Diagnosis: methemoglobinemia. Pediatr Ann 2009; 38(11): 613–6. [63] Chung NY, Batra R, Itzkevitch M, Boruchov D, Baldauf M. Severe

[64]

[65]

[66]

[67]

[68]

[69]

[70]

[71]

[72]

[73]

[74]

methemoglobinemia linked to gel-type topical benzocaine use: a case report. J Emerg Med 2010; 38(5): 601–6. Bong CL, Hilliard J, Seefelder C. Severe methemoglobinemia from topical benzocaine 7.5% (Baby Orajel) use for teething pain in a toddler. Clin Pediatr (Phila) 2009; 48(2): 209–11. Annabi EH, Barker SJ. Severe methemoglobinemia detected by pulse oximetry. Anesth Analg 2009; 108(3): 898–9. Muratore L, Calogiuri G, Foti C, Nettis E, Di Leo E, Vacca A. Contact allergy to benzocaine in a condom. Contact Dermatitis 2008; 59(3): 173–4. Hay DC, Mayle Jr. RE, Goodman SB. Third-degree heart block associated with bupivacaine infusion following total knee arthroplasty. A case report. J Bone Joint Surg Am 2009; 91(9): 2238–40. Markowitz S, Neal JM. Immediate lipid emulsion therapy in the successful treatment of bupivacaine systemic toxicity. Reg Anesth Pain Med 2009; 34(3): 276. Nelsen J, Holland M, Dougherty M, Bernad J, Stork C, Marraffa J. Severe central nervous system and cardiovascular toxicity in a pediatric patient after ingestion of an over-the-counter local anesthetic. Pediatr Emerg Care 2009; 25(10): 670–3. Barajas-Martinez HM, Hu D, Cordeiro JM, Wu Y, Kovacs RJ, Meltser H, Kui H, Elena B, Brugada R, Antzelevitch C, Dumaine R. Lidocaine-induced Brugada syndrome phenotype linked to a novel double mutation in the cardiac sodium channel. Circ Res 2008; 103(4): 396–404. Sharma R, Goel N, Kumar A, Panda A. Central nervous system toxicity with a 1 ml lidocaine injection in the aberrant carotid artery overlying the trachea. Acta Anaesthesiol Scand 2008; 52(10): 1436. Burches Jr. BR, Warner DO. Bronchospasm after intravenous lidocaine. Anesth Analg 2008; 107(4): 1260–2. Chang HY, Togias A, Brown RH. The effects of systemic lidocaine on airway tone and pulmonary function in asthmatic subjects. Anesth Analg 2007; 104(5): 1109–15, tables of contents. Yuen WY, Schuttelaar ML, Barkema LW, Coenraads PJ. Bullous allergic contact

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[76]

[77]

[78]

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[80]

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dermatitis to lidocaine. Contact Dermatitis 2009; 61(5): 300–1. Gaigl Z, Seitz CS, Trautmann A. Methemoglobinemia due to local anesthesia with low-dose prilocaine. Dermatol Surg 2009 Jan; 35(1): 168–9. Boran P, Tokuc G, Yegin Z. Methemoglobinemia due to application of prilocaine during circumcision and the effect of ascorbic acid. J Pediatr Urol 2008; 4(6): 475–6. Book A, Fehlandt C, Krija M, Radke M, Pappert D. Methemoglobin intoxication by prilocaine in EMLA. Accidental intoxication of an infant with scald injuries. Anaesthesist 2009; 58(4): 370–4. Martinez MA, Ballesteros S, Segura LJ, Garcia M. Reporting a fatality during tumescent liposuction. Forensic Sci Int 2008; 178(1): e11–6. Dogramaci Y, Dogramaci AC, Esen E, Korkmaz T. Severe allergic reactions to prilocaine during intravenous regional anesthesia. Eur J Dermatol 2008; 18(4): 462–3. Timmermans MW, Bruynzeel DP, Rustemeyer T. Allergic contact dermatitis

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from EMLA cream: concomitant sensitization to both local anesthetics lidocaine and prilocaine. J Dtsch Dermatol Ges 2009; 7(3): 237–8. Roldan-Marin R, de-la-Barreda Becerril F. Petechial and purpuric eruption induced by lidocaine/prilocaine cream: a rare adverse effect. J Drugs Dermatol 2009; 8(3): 287–8. Takahama H. A fixed drug eruption that developed cross-sensitivity among amide local anaesthetics, including mepivacaine hydrochloride, lidocaine hydrochloride and propitocaine hydrochloride. J Eur Acad Dermatol Venereol 2008; 22(11): 1400–1. Satsumae T, Tanaka M, Saito S, Inomata S. Convulsions after ropivacaine 300 mg for brachial plexus block. Br J Anaesth 2008; 101(6): 860–2. Marri S, Coventry D. Convulsions associated with ropivacaine 300 mg for brachial plexus block. Br J Anaesth 2009; 102(4): 562–3.

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Neuromuscular blocking agents and skeletal muscle relaxants

DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS Suxamethonium

[SED-15, 2489; SEDA-31, 247; SEDA-32, 273] Systematic reviews The place of suxamethonium in pediatric practice has been reviewed [1r]. It has significant adverse effects, some of which can be life-threatening. This is particularly relevant in pediatric anesthesia, because the spectrum of childhood diseases may expose susceptible individuals to an increased chance of adverse events compared with adults. The authors suggested that the rapidity of onset and offset of suxamethonium encourages its use by practitioners with only occasional experience of pediatric anesthesia. Rocuronium has a similar onset of action at a dose of 1.2 mg/kg, but sugammadex (a reversal agent specific to rocuronium) does not have a product licence for immediate reversal of neuromuscular blockade in children.

Cardiovascular Tako-Tsubo syndrome is transient left ventricular apical ballooning, very similar to acute myocardial infarction,

Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00012-X # 2011 Elsevier B.V. All rights reserved.

but with an excellent short-term prognosis, has been reported after physical or emotional stress. It has also been reported after anaphylaxis caused by suxamethonium [2A]. Musculoskeletal Spontaneous subluxation of the temporomandibular joint has been reported in a 39-year-old woman with primary hyperparathyroidism and a normal airway after induction of anesthesia and the administration of suxamethonium [3A]. Her mouth could not be opened, and direct laryngoscopy was not possible. Her trachea was intubated with a TrachlightTM device and the temporomandibular joint was reduced after surgery. Thiopental can reduce muscle fasciculation associated with suxamethonium. In 300 ASA I and II patients, who were randomized to suxamethonium immediately after thiopental or 30 seconds later the onset of fasciculation was earlier in the former and the duration of fasciculation was shorter [4c]. In addition, there was moderate to severe fasciculation in the latter. The relation between fasciculations and postoperative myalgia has not been well defined. The authors did not comment on the incidence and severity of myalgia after surgery, which has greater clinical relevance. Immunologic Refractory shock from anaphylaxis can occur after induction of general anesthesia [5A]. 299

300 • A 74-year-old woman with acute appendicitis was scheduled for emergency surgery. She had no history of atopy or pre-existing allergy. Anesthesia was induced with propofol 2 mg/kg and suxamethonium 1 mg/kg and 4 minutes later she developed severe bronchospasm with high airway pressure, a reduced end-tidal CO2 from 32 to 15 mmHg, undetectable oxygen saturation, hypotension (40/28 mm Hg), and bradycardia (40/minute). Despite the absence of any cutaneous signs, anaphylactic shock was immediately suspected and cardiopulmonary resuscitation was started without delay. After 60 minutes of unsuccessful resuscitation, she was given two boluses of terlipressin 1 mg at 5-minute intervals without benefit. She died after 90 minutes. After 70 minutes the serum tryptase concentration was more than 200 mg/l (threshold 13.5 mg/l) and a specific IgE for suxamethonium confirming the diagnosis of anaphylactic shock. The allergic reaction was confirmed by quaternary ammonium fixation of 4.44% (> 3% confirms an allergic reaction) and inhibition by suxamethonium of 92% (> 20% confirms an allergic reaction). • A 49-year-old man, scheduled for emergency appendectomy, had general anesthesia induced with propofol 2 mg/kg and suxamethonium 1 mg/kg. He immediately developed a low end-tidal CO2 (25 mm Hg) and extensive erythema with piloerection. After 15 min of CPR, including cardioversion and IV amiodarone 300 mg, two boluses of 1 mg terlipressin at 5-min intervals were administered. Emergency circulatory support was instituted after 75 min of cardiopulmonary resuscitation; using extracorporeal membrane oxygenation his systolic blood pressure remained low at 60 mm Hg and he died 12 hours later from refractory shock and multiple organ failure. Blood tests 50 minutes after the onset of the reaction showed a serum tryptase concentration over 200 mg/l and specific IgE against suxamethonium confirming the diagnosis of anaphylactic shock.

Raised serum tryptase concentrations and immunoglobin E to suxamethonium confirmed anaphylaxis to suxamethonium in these two patients. Hypotension was refractory to terlipressin in both cases and to extracorporeal membrane oxygenation in one. However, both interventions were instituted after a prolonged period of resuscitation. Methythioninium chloride, glucagon, and a1-adrenoceptor agonists have been proposed as alternative therapeutic options in

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adrenaline-resistant anaphylactic shock. Direct myocardial injury has been suggested in anaphylaxis with early cardiac arrest. Myocardial injury could be related to a high degree of myocardial mast cell infiltration in these patients. In these two patients the degree of cardiac mast cell infiltration could not be investigated because autopsies were refused. Body temperature Malignant hyperthermia occurred 3 hours after the start of an operation for esophageal resection in an 82-yearold man after anesthesia induced with propofol and suxamethonium and maintained with sevoflurane [6A]. Masseter spasm was not a feature. End-tidal CO2 rose to 55 mmHg and body temperature exceeded 39.0
C. The patient responded promptly to dantrolene. Reports of malignant hyperthermia in patients over the age of 80 years are unusual. Both suxamethonium and sevoflurane are potent triggers. Susceptibility factors Bariatric surgery A 34-year-old obese woman who received suxamethonium while undergoing laparoscopic Roux-en-Y gastric bypass later developed suxamethonium myalgia leading to a prolonged stay in hospital and subsequent pneumonia [7A]. The authors concluded that in the presence of suitable alternative paralytic agents, suxamethonium should be avoided in patients undergoing bariatric surgery. However obese patients are at greater risk of aspiration pneumonia, and rapid-sequence induction of anesthesia with suxamethonium is standard practice. Pneumoperitoneum is also associated with atelectasis and postoperative pneumonia. Drug–drug interactions Carbamate An 18year-old woman took an intentional overdose of N-methyl carbamate, an insecticide [8A]. She was uneventfully intubated using propofol and extubated after 10 days, but required emergency re-intubation due to respiratory failure. Propofol 150 mg and suxamethonium were used to facilitate intubation. Masseter muscle spasm led to difficulty in intubation and ventilation.

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Hypoxic cardiac arrest occurred before her airway was secured and she died of hypoxic brain injury 3 days later. The authors proposed that masseter muscle spasm may be associated with suxamethonium even late in the setting of carbamate poisoning. However masseter muscle spasm commonly occurs after suxamethonium and is occasionally life-threatening [9A]. Distigmine A patient taking the anticholinesterase distigmine bromide for urinary retention underwent ECT facilitated by suxamethonium 1 mg/kg [10A]. Paralysis after administration of suxamethonium lasted 30 minutes and plasma cholinesterase activity was below the reference range. Reduced plasma cholinesterase activity leads to reduced clearance of suxamethonium and prolonged action, a predictable interaction.

NON-DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS [SED-15, 2489; SEDA-31, 248; SEDA-32, 274]

Rocuronium [SED-15, 3073; SEDA-31, 248; SEDA-32, 274] Systematic reviews Because of its fast onset of action, rocuronium is a potential alternative to suxamethonium for rapid-sequence intubation in patients with an increased risk of aspiration. Four relevant studies considering the use of suxamethonium and rocuronium in emergency departments were selected from an evidence search and a structured review performed [11r]. For the outcomes of clinically acceptable intubation conditions and time to onset, the two agents were not statistically significantly different. Suxamethonium seems to produce conditions that have higher satisfaction scores. The authors concluded that suxamethonium remains the drug of choice for emergency department rapid-sequence induction, unless there is a contraindication.

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This is a slightly different conclusion from that reached in a Cochrane review of rocuronium versus suxamethonium for rapidsequence intubation, which was that suxamethonium creates excellent intubation conditions more reliably than rocuronium [12R]. However, the ability of sugammadex to reverse deep neuromuscular blockade under rocuronium may alter the benefit to harm balance in comparison with suxamethonium.

Sugammadex

[SEDA-32, 275]

There have been many reviews of the pharmacology and uses of sugammadex [13R, 14R, 15R, 16R, 17R, 18R, 19R, 20R, 21R]. Observational studies In an open, randomized dose–response study of sugammadex for reversal of deep neuromuscular blockade induced by rocuronium or vecuronium during anesthesia with propofol followed by sevoflurane, in 102 patients aged 20–65 years, a single bolus dose of sugammadex 0.5, 1.0, 2.0, 4.0, or 8.0 mg/kg was given for reversal of neuromuscular blockade [22C]. There was a dose-related effect on the mean time to recovery of the T4/T1 ratio to 0.9 with increasing doses of sugammadex. There was recurrent neuromuscular blockade in five patients, all of whom had received rocuronium (two given sugammadex 0.5 mg/kg and three given 1.0 mg/kg), but there were no accompanying clinical events. Comparative studies In a multicenter, randomized, controlled comparison, sugammadex was associated with significantly faster reversal of vecuronium-induced neuromuscular blockade than neostigmine; there were no serious or unexpected adverse events [23C]. Placebo-controlled studies In a randomized, assessor-blinded, placebo-controlled study of sugammadex 2 or 4 mg/kg in 116 patients with underlying cardiovascular disease (New York Heart Association class II–III) undergoing non-cardiac surgery, sugammadex had no

302

overall adverse effects on the QTc (Fridericia) interval [24C]. There were three serious adverse events, one in each treatment group. Blood pressure and heart rate fell after the start of anesthesia, but blood pressure was significantly higher after both doses of sugammadex at 30 minutes. The fall in heart rate from baseline was significantly greater with sugammadex 2 mg/kg and at both doses the increase at 30 minutes was greater than with placebo. Both doses of sugammadex resulted in a considerably shorter time to recovery of the T4/ T1 ratio to 0.9. In a multicenter, double-blind, randomized study in 20 ASA 1–3 patients aged 18–69 years and scheduled for elective surgery lasting at least 120 minutes, anesthesia was induced with remifentanil and rocuronium and maintained with sevoflurane or propofol; remifentanil was used for analgesia and rocuronium to maintain a block of greater than 90% [25C]. After surgery, sugammadex was used for reversal of neuromuscular blockade. There were no signs of recurarization or associated adverse effects. The authors concluded that interaction of neuromuscular blocking agents with sevoflurane appears not to affect the reversal time after sugammadex. Systematic reviews In a systematic review of 18 randomized controlled trials in which sugammadex was compared with placebo or other medications or in which different doses of sugammadex were compared with each other in a total of 1321 adults, sugammadex reversed rocuronium-induced neuromuscular blockade, regardless of the depth of the block, more rapidly than placebo or neostigmine [26C]. There were serious adverse events in under 1% of patients and no significant difference between sugammadex and either placebo or neostigmine. Cardiovascular In 176 adults who were randomized to sugammadex (2, 4, 8, 12, or 16 mg/kg) or placebo at 3 or 15 minutes after high-dose rocuronium (1.0 or 1.2 mg/ kg) during propofol anesthesia, there was no evidence of recurrent neuromuscular

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blockade or residual neuromuscular blockade [27C]. There was prolongation of the corrected QT interval, which was possibly related to sugammadex, in one patient and another two had markedly abnormal arterial blood pressure lasting about 15 minutes after sugammadex. Susceptibility factors Age In a placebo-controlled comparison of infants (28 days to 23 months; n ¼ 8), children (2–11 years; n ¼ 22), adolescents (12–17 years; n ¼ 28), and adults (18–65 years; n ¼ 26), sugammadex satisfactorily reversed neuromuscular blockade dose-relatedly [28C]. There was no evidence of recurrence of blockade, inadequate reversal, significant QT prolongation, or other abnormalities. Renal disease Sugammadex is primarily cleared by the kidneys. In 15 adults with end-stage renal failure and 15 controls, anesthesia was induced and maintained using intravenous opiates and propofol [29C]. There was no significant difference in the time from administration of sugammadex to recovery, no evidence of recurrence of neuromuscular blockade, and no sugammadex-related serious adverse events.

SKELETAL MUSCLE RELAXANTS Baclofen

[SED-15, 408; SEDA-30, 164; SEDA-31, 250; SEDA-32, 276] Systematic reviews The use of baclofen has been reviewed [30r] and specifically in adults with cerebral palsy [31r].

Observational studies In a multicenter study of baclofen 60 mg/day for abstinence initiation in severe cocaine-dependent individuals there was no effect on cocaine use after 8 weeks [32c]. In a retrospective questionnaire study of overall satisfaction among caregivers with intrathecal baclofen in six children and

Neuromuscular blocking agents and skeletal muscle relaxants

adolescents with progressive neurological disorders causing spasticity, most were overall satisfied with the effects of treatment [33c]. Reported adverse reactions were increased drooling, increased swallowing difficulties, reduced head balance, abdominal discomfort, constipation, back pain due to worsening scoliosis, and increased tolerance of baclofen, requiring frequent pump adjustments. In a prospective study of the efficacy at 12 months and safety up to 24 months of intrathecal baclofen in 17 children with spastic cerebral palsy, there were 80 adverse events; eight of which were serious but not life-threatening [34c]. In a prospective multicenter study of long-term outcomes in 115 adults who were given a continuous infusion of intrathecal baclofen over 12 months, 66 had no adverse events. The reported adverse events were wound complications (22%), catheter problems (36%), cerebrospinal fluid leakage (25%), and other complications (17%) [35C]. In a single-blind, placebo-run-in, doseescalation study in 36 patients with complex regional pain syndrome, followed for 12 months, there were substantial improvements in patient and assessor-rated dystonia scores, pain, disability, and quality-oflife [36C]. There were 89 adverse events in 26 patients; they were related to baclofen (n ¼ 19) or pump/catheter system defects (n ¼ 52) or could not be specified (n ¼ 18). Placebo-controlled studies In a doubleblind, placebo-controlled smoking reduction study in 60 smokers titrated upwards to baclofen 20 mg qds, the most common adverse effect during baclofen treatment was transient drowsiness; however, there were no differences between the groups in mild, moderate, or severe sedation [37c]. Nervous system In a study of the usefulness of intrathecal baclofen in severe spastic hemiparesis following stroke in eight patients, six had functional deterioration and weakening of their paretic side, with walking disability [38c].

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Psychiatric In a retrospective study based on a review of the clinical histories of all patients with an intrathecal baclofen infusion system in a neurorehabilitation hospital, 12 (9.5%) of 126 patients developed delirium related to baclofen [39c]. Eight cases were due to intoxication and four to withdrawal. There were no deaths. Gastrointestinal Intrathecal baclofen can affect peristalsis, and constipation is a commonly reported adverse effect. In severe cases paralytic ileus can result [40A]. • A 62-year-old woman with myelitis and treated with intrathecal baclofen developed vomiting, epigastric pain, and absent peristalsis 7 months after implantation of the intrathecal device. Her last bowel evacuation had occurred 24 days before. She died from complications after surgery.

Infection risk Infection of an intrathecal baclofen delivery device with Mycobacterium fortuitum with associated meningitis was successfully treated by removing the device and giving prolonged antibiotic therapy [41A]. Pregnancy In a review of neonatal inpatient medical records from four pregnancies in three women receiving intrathecal baclofen for spasticity two of the infants were born preterm, one by urgent cesarean delivery for maternal pre-eclampsia and the other a spontaneous vaginal delivery [42A]. Both preterm infants were of appropriate size and weight for preterm gestational age; the two full-term infants were small and large for gestational age. The authors concluded that it was not possible to draw conclusions about pregnancy outcomes in patients with intrathecal baclofen from these few cases. Drug tolerance In a retrospective study in 37 patients treated with intrathecal baclofen, the dose increased in the first 18 months after implantation and then stabilized around a mean dose of 350 micrograms/ day [43c]. Eight patients developed tolerance, defined as a dose increase of over

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100 micrograms/year. No predictive factors for the development of tolerance could be determined. Pulsatile bolus infusion (n ¼ 1) and a drug holiday (n ¼ 2) were both effective in reducing the daily dose of baclofen. Patients who needed surgical revision of the pump system because of mechanical failures (n ¼ 11) had a significant dose reduction during the first month after revision.

• a boxed warning highlighting the possibility of experiencing potentially life-threatening distant spread of toxin effect from the injection site after local injection. • the issue of a medication guide to help patients understand the risks and benefits of botulinum toxin products.

Drug administration route An obstructed catheter connection pin discovered during intrathecal baclofen pump exchange caused increased intrathecal drug dosage requirements and eventual oral baclofen was required [44A]. In a retrospective clinical and radiographic review of complications related to intrathecal baclofen and posterior spine fusion in patients with cerebral palsy, the dosage of baclofen did not increase despite the operation [45c].

The established drug names have also been changed, in order to reinforce individual potencies and prevent medication errors. The new name to replace “botulinum toxin type A” is OnabotulinumtoxinA (marketed as Botox and Botox Cosmetic). The name that replaces to “botulinum toxin type B” is RimabotulinumtoxinB (marketed as Myobloc). The FDA has also approved another botulinum toxin product in this class, AbobotulinumtoxinA (marketed as Dysport), and this product also includes boxed warnings.

Drug–drug interactions Alcohol An acute interaction of baclofen in combination with intoxicating doses of alcohol in 18 heavy social drinkers was well tolerated [46c].

Uses The uses of botulinum toxin in Parkinson's disease [48r], anal fissure [49r], and women with chronic pain [50r] have been reviewed.

Botulinum toxins

Comparative studies In a randomized blinded comparison of botulinum toxin with isosorbide dinitrate in the treatment of chronic anal fissure, adverse effects were similar in the two groups [51c].

[SED-15, 551; SEDA-30, 165; SEDA-31, 252; SEDA-32, 276]

Nomenclature Although botulinum toxin is commonly known as “botox”, that name is in fact only one of the brand names of formulations in which botulinum toxins are available. For example, in the UK, the following branded formulations are available: • botulinum toxin type A: Bocouture (50-unit vials), Vistabel (50-unit vials), Xeomin (100unit vials); • botulinum toxin type A–hemagglutinin complex: Azzalure (125-unit vials), Botox (50-unit vials), Dysport (500-unit vials); • botulinum toxin type B: Neurobloc (5000 units/ml in vials containing 0.5, 1, or 2 ml).

This can cause considerable confusion. In July 2009 the US Food and Drug Administration approved the following

revisions to the prescribing information of botulinum toxin products (Botox, Botox Cosmetic, and Myobloc) [47S]:

Neuromuscular function Long-term data on the use of botulinum toxin type A in the treatment of hyperhidrosis are required in order for the implications to be fully appreciated. Muscle weakness has been reported during long-term therapy [52A]. • A 14-year-old girl with excessive sweating of the hands, feet, and axillae was given a trial course of botulinum toxin type A (DysportÒ, Speywood, UK). The dose was no greater than 500 IU to each palm, which is well within recommended guidelines. She reported successful symptom control, and injections were continued every 9 month to a total of five treatments. However, 2 years after the first course of injections, she complained of

Neuromuscular blocking agents and skeletal muscle relaxants functionally debilitating weakness in both hands, with increasing difficulty in performing manoeuvres such as buttoning clothing and opening packaged foods. There was mild atrophy of the muscles of the thenar eminence bilaterally. There was no weakness in the feet, which had also been treated. Nerve conduction studies showed reduced responses in the hands. After starting a rehabilitation program the amplitude in all the nerves studied improved, as did the atrophy, although there was residual weakness in the thenar and hypothenar eminences and in the interossei.

Maximum bite force has been measured in 30 subjects who had an injection of botulinum toxin to treat masseter muscle hypertrophy, followed by a booster injection in 14 patients after 18 weeks [53c]. Mean maximum bite force was about 20% lower at 2 weeks than before the injection, gradually recovered after 4 weeks, and returned to the pre-injection level at 12 weeks.

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Drug–drug interactions Escitalopram A 27-year-old woman taking the selective serotonin reuptake inhibitor escitalopram took an intentional overdose of cyclobenzaprine and developed the serotonin syndrome, which was successfully treated with supportive measures and cyproheptadine [57A]. This case was complicated by a positive opiate screen, as opiates can precipitate the serotonin syndrome.

Dantrolene sodium

[SED-15, 1023]

Neuromuscular function Torticollis, responsive to intravenous biperiden, presented as an extrapyramidal adverse effect of cyclobenzaprine in a patient with liver impairment [54A]. Drug dosage regimens In a double-blind, randomized, two-period crossover study in 16 healthy volunteers single oral doses of cyclobenzaprine extended-release 15 and 30 mg were compared [55C]. Cyclobenzaprine 15 mg was associated with adverse events in five subjects: headache, dizziness, musculoskeletal pain, dermatitis, and glossodynia; cyclobenzaprine 30 mg was associated with adverse events in two subjects: somnolence and dysmenorrhea. All the adverse events were mild in intensity. In a randomized, open, two-period crossover comparison of once-daily cyclobenzaprine extended-release 30 mg versus cyclobenzaprine immediate release 10 mg tds in 18 healthy young adults all adverse events were mild in intensity; the most common was somnolence [56C].

[SED-15, 1048]

Skin A severe acneiform eruption exacerbated by dantrolene sodium has been reported [58A].

Tetrabenazine Cyclobenzaprine

305

[SEDA-32, 277]

Tetrabenazine, a benzoquinolizine derivative, inhibits vesicular monoamine transporter 2, leading to depletion of dopamine and other monoamines in the central nervous system. It was licensed in 2008 by the US Food and Drug Administration for use in the treatment of chorea associated with Huntingdon's disease. It is also used in the treatment of hemiballismus, tardive dyskinesia, and Tourette syndrome. Tetrabenazine was synthesized in the 1950s as part of research into compounds with reserpine-like activity and was initially used in the treatment of schizophrenia. Its common reversible adverse effects include drowsiness/sedation, weakness, parkinsonism, depression, and acute akathisia. The pharmacology of tetrabenazine has been reviewed [59R, 60R, 61R]. Observational studies In a randomized placebo-controlled study in 84 ambulatory patients with Huntington's disease who took tetrabenazine (n ¼ 54) or placebo (n ¼ 30) for 12 weeks, there were five serious adverse events in four subjects who took tetrabenazine (suicide by drowning, a complicated fall, restlessness/suicidal ideation, and breast

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cancer) compared with one withdrawal and no serious adverse events with placebo [62C]. The same group has reported an open extension study in 75 participants, designed to assess the long-term safety and effectiveness of tetrabenazine for chorea in Huntington's disease for up to 80 week [63c]. Three participants withdrew because of adverse events, including depression, delusions with associated previous suicidal behavior, and vocal tics. When mild and unrelated adverse events were excluded, the most commonly reported adverse events were sedation/somnolence (n ¼ 18), depressed mood (17), anxiety (13), insomnia (10), and akathisia (9). Parkinsonism and dysphagia scores were significantly increased at week 80 compared with baseline. In 68 patients with Huntington's disease treated with tetrabenazine for a mean period of 34 (range 3–104) months, there were two withdrawals because of adverse effects; 34 patients reported at least one adverse effect [64c]. In a prospective evaluation of 19 patients (12 women), mean age 56 (range 37–76) years, with Huntington's disease [65c] 18 patients completed the study and were rated after an average of 5.9 (range 2–11) months at a final mean tetrabenazine dose of 63 (range 25–150) mg/day. Adverse events included akathisia, insomnia, constipation, depression, drooling, and subjective weakness. In a retrospective chart review of 448 patients who had used tetrabenazine between 1997 and 2004 (mean age at onset of the movement disorder, 43 years; 42% men) for a variety of hyperkinesias, including tardive dyskinesia (n ¼ 149), dystonia (n ¼ 132), chorea (n ¼ 98), tics (n ¼ 92), and myoclonus (n ¼ 19), treatment lasted for a mean of 2.3 years and efficacy was sustained in most cases [66c]. Common adverse effects included drowsiness (25%), parkinsonism (15%), depression (7.6%), and akathisia (7.6%). Comparative studies In six patients with Huntington's disease, in whom aripiprazole and tetrabenazine were compared, aripiprazole caused less sedation and sleepiness [67c].

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Nervous system Tetrabenazine inhibits vesicular monoamine transporter 2, leading to depletion of dopamine and other monoamines in the central nervous system. In a retrospective chart review, 448 patients who had used tetrabenazine between 1997 and 2004 (mean age at onset of the movement disorder, 43 years; 42% men) were treated for a variety of hyperkinesias, including tardive dyskinesia (n ¼ 149), dystonia (n ¼ 132), chorea (n ¼ 98), tics (n ¼ 92), and myoclonus (n ¼ 19) [68c]. They took treatment for a mean of 2.3 years and efficacy was sustained in most cases. Common adverse effects included drowsiness (25%), parkinsonism (15%), depression (7.6%), and akathisia (7.6%). Although it has repeatedly been observed that tetrabenazine alleviates hyperkinetic movements, it can worsen parkinsonism [69R]. Psychiatric In a retrospective review of the charts of 518 patients treated with tetrabenazine, 246 had no history of depression, of whom 28 (11%) developed depression [70c]. Of 272 patients with a documented history of depression had a significantly higher rate of worsening in 50 cases (18%). Metabolism Weight gain over time has been compared in 32 boys with tics taking tetrabenazine (mean age 13 years) and an agematched group of 41 patients (33 boys) with tics taking only antipsychotic drugs (mean age 12 years) [71c]. Weight gain with tetrabenazine was 0.36 kg/month (mean follow-up duration 25 months) and with antipsychotic drugs 0.75 kg/month (mean follow-up duration 19 months). Body temperature Neuroleptic malignant syndrome has been attributed to tetrabenazine [72A, 73A]. • In a patient with Huntington's disease neuroleptic malignant syndrome followed abrupt introduction of tetrabenazine and discontinuation of haloperidol, which may have contributed [74A]. Recovery was uneventful, and rechallenge with tetrabenazine in conventional doses and slow upward titration was not followed by recurrence.

Neuromuscular blocking agents and skeletal muscle relaxants • A 45-year-old patient developed severe hyperthermia (rectal temperature above 41
C), with intense rhabdomyolysis and liver cytolysis during tetrabenazine therapy for neuroleptic tardive dyskinesia [75A]. There was a good response to parenteral sodium dantrolene and oral bromocriptine. In addition to tetrabenazine, this patient took lorazepam and two antidepressant drugs: clomipramine and mianserin.

Susceptibility factors Age In a review of tetrabenazine therapy in 31 children with hyperkinetic movement disorders refractory to other medications, adverse effects were similar to those in adults; however, the children had a lower incidence of drug-induced parkinsonism [76c].

Tizanidine [SED-15, 3436; SEDA-28, 157; SEDA-32, 278] Comparative studies Oral baclofen has been compared retrospectively with tizanidine as adjuvant therapy to botulinum toxin type A in the management of spasticity in children [77c]. In 30 children with gastrocnemius spasticity, of whom 17 were treated with adjuvant oral baclofen and 13 received tizanidine, the mean Gross Motor Functional Measurement scores (77 versus 68) and caregiver questionnaire scores (70 versus 67) were higher with tizanidine than baclofen. The authors suggested that the combination of botulinum toxin type A with tizanidine is more effective and causes fewer adverse reactions than the combination of botulinum toxin type A and oral

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baclofen in spastic cerebral palsy. These findings were limited by the non-randomized retrospective nature of the study. Placebo-controlled studies In a doubleblind, randomized, placebo-controlled comparison of an injection of botulinum toxin type A into spastic upper limb muscles and oral tizanidine in 60 subjects with upper limb spasticity due to stroke or traumatic brain, the incidence of adverse effects was higher with tizanidine than botulinum toxin and placebo [78C]. Systematic reviews In a systematic review tizanidine was found to be very useful in patients with spasticity caused by multiple sclerosis, acquired brain injury, or spinal cord injury [79M]. It can also be helpful in patients with chronic neck and/or lower back pain who have a myofascial component to their pain. Doses should be gradually titrated upwards. Drug formulations In a single-dose, open, randomized, two-way, crossover study in 28 fasted healthy adults a capsule formulation of tizanidine hydrochloride was compared with the capsule contents administered in applesauce; they were not bioequivalent [80c]. The drug was more available (90% CI ¼ 103–134%) when the contents were sprinkled on to apple sauce. A total of 31 adverse events were reported by 17 of the 28 subjects; 15 who took the intact capsule reported 18 events and 11 who took the contents reported 13 events. There were no serious adverse events.

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[34] Hoving MA, van Raak EP, Spincemaille GH, van KranenMastenbroek VH, van Kleef M, Gorter JW, Vles JS. Dutch Study Group on Child Spasticity. Safety and one-year efficacy of intrathecal baclofen therapy in children with intractable spastic cerebral palsy. Eur J Paediatr Neurol 2009; 13(3): 247–56. [35] Delhaas EM, Beersen N, Redekop WK, Klazinga NS. Long-term outcomes of continuous intrathecal baclofen infusion for treatment of spasticity: a prospective multicenter follow-up study. Neuromodulation 2008; 11(3): 227–36. [36] van Rijn MA, Munts AG, Marinus J, Voormolen JH, de Boer KS, TeepeTwiss IM, van Dasselaar NT, Delhaas EM, van Hilten JJ. Intrathecal baclofen for dystonia of complex regional pain syndrome. Pain 2009; 143(1–2): 41–7. [37] Franklin TR, Harper D, Kampman K, Kildea-McCrea S, Jens W, Lynch KG, O'Brien CP, Childress AR. The GABAB agonist baclofen reduces cigarette consumption in a preliminary double-blind placebocontrolled smoking reduction study. Drug Alcohol Depend 2009; 103(1–2): 30–6. [38] Kofler M, Quirbach E, Schauer R, Singer M, Saltuari L. Limitations of intrathecal baclofen for spastic hemiparesis following stroke. Neurorehabil Neural Repair 2009; 23(1): 26–31. [39] Castaño B, Benito J, Pires F, Ferreira S, Lopez R, Vidal J. Delirium secondary to intrathecal baclofen. Spinal Cord 2009; 47 (6): 477–80. [40] Patti F, Pappalardo A, Lo Fermo S, Cimino V, Castiglione A, Zappia M. Lifethreatening constipation induced by intrathecal baclofen therapy. Eur Neurol 2008; 60(2): 95–6. [41] Aliabadi H, Osenbach RK. Intrathecal drug delivery device infection and meningitis due to Mycobacterium fortuitum: a case report. Neuromodulation 2008; 11(4): 311–4. [42] Morton CM, Rosenow J, Wong C, Kirschner KL. Intrathecal baclofen administration during pregnancy: a case series and focused clinical review. PMR 2009; 1 (11): 1025–9. [43] Heetla HW, Staal MJ, Kliphuis C, van Laar T. The incidence and management of

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Neuromuscular blocking agents and skeletal muscle relaxants [67] Brusa L, Orlacchio A, Moschella V, Iani C, Bernardi G, Mercuri NB. Treatment of the symptoms of Huntington's disease: preliminary results comparing aripiprazole and tetrabenazine. Mov Disord 2009; 24(1): 126–9. [68] Kenney C, Hunter C, Davidson A, Jankovic J. Short-term effects of tetrabenazine on chorea associated with Huntington's disease. Mov Disord 2007; 22: 10–3. [69] Morgan JC, Sethi KD. Drug-induced tremors. Lancet Neurol 2005; 4: 866–76. [70] Kenney C, Hunter C, Mejia N, Jankovic J. Is history of depression a contraindication to treatment with tetrabenazine? Clin Neuropharmacol 2006; 29(5): 259–64. [71] Ondo WG, Jong D, Davis A. Comparison of weight gain in treatments for Tourette syndrome: tetrabenazine versus neuroleptic drugs. J Child Neurol 2008; 23(4): 435–7. [72] Ossemann M, Sindic CJ, Laterre C. Tetrabenazine as a cause of neuroleptic malignant syndrome. Mov Disord 1996; 11(1): 95. [73] Petzinger GM, Bressman SB. A case of tetrabenazine-induced neuroleptic malignant syndrome after prolonged treatment. Mov Disord 1997; 12(2): 246–8. [74] Mateo D, Muñoz-Blanco JL, GiménezRoldán S. Neuroleptic malignant syndrome related to tetrabenazine introduction and haloperidol discontinuation in Huntington's disease. Clin Neuropharmacol 1992; 15(1): 63–8.

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[75] Stevens E, Roman A, Houa M, Razavi D, Jaspar N. Severe hyperthermia during tetrabenazine therapy for tardive dyskinesia. Intensive Care Med 1998; 24(4): 369–71. [76] Jain S, Greene PE, Frucht SJ. Tetrabenazine therapy of pediatric hyperkinetic movement disorders. Mov Disord 2006; 21 (11): 1966–72. [77] Dai AI, Wasay M, Awan S. Botulinum toxin type A with oral baclofen versus oral tizanidine: a nonrandomized pilot comparison in patients with cerebral palsy and spastic equinus foot deformity. J Child Neurol 2008; 23(12): 1464–6. [78] Simpson DM, Gracies JM, Yablon SA, Barbano R, Brashear A. Botulinum neurotoxin versus tizanidine in upper limb spasticity: a placebo-controlled study. J Neurol Neurosurg Psychiatry 2009; 80(4): 380–5. [79] Malanga G, Reiter RD, Garay E. Update on tizanidine for muscle spasticity and emerging indications. Expert Opin Pharmacother 2008; 9(12): 2209–15. [80] Henney 3rd HR, Fitzpatrick A, Stewart J, Runyan JD. Relative bioavailability of tizanidine hydrochloride capsule formulation compared with capsule contents administered in applesauce: a single-dose, openlabel, randomized, two-way, crossover study in fasted healthy adult subjects. Clin Ther 2008; 30(12): 2263–71.

Michael Schachter

13 Drugs that affect autonomic functions or the extrapyramidal system DRUGS THAT STIMULATE BOTH ALPHA- AND BETAADRENOCEPTORS [SEDA-30, 170; SEDA-31, 259; SEDA-32, 281]

Stress cardiomyopathy and catecholamines Stress cardiomyopathy (takotsubo cardiomyopathy, “broken heart syndrome”, or “gebrochenes Herz Syndrom”) was first described in Japan in the early 1990s [1c] and has been reviewed [2M]. “Tako tsubo” means “octopus trap” in Japanese. EIDOS classification: Extrinsic moiety Catecholamines Intrinsic moiety? Adrenoceptors Distribution Myocardium Outcome Takotsubo cardiomyopathy Sequela Takotsubo cardiomyopathy due to catecholamines DoTS classification: Dose-relation Toxic Time-course Time-independent Susceptibility factors Sex (postmenopausal women); diseases (pre-existing ischemia)

Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00013-1 # 2011 Elsevier B.V. All rights reserved.

Mechanism In various observational studies of this type of cardiomyopathy there was an association with raised catecholamine concentrations [3A, 4c, 5M]. There have also been several reports following severe emotional stress [6A, 7A], in patients with pheochromocytomas, both adrenal [8A, 9A, 10c, 11A] and extra-adrenal [12A, 13A, 14A], and in patients who have been given catecholamines [15c, 16A, 17A, 18A, 19A, 20A]. In five consecutive patients with takotsubo-like left ventricular dysfunction there was local release of noradrenaline from the heart as measured in blood taken from the aortic root and coronary sinus [21c]. Indirect effects of drugs on catecholamines have also resulted in takotsubo syndrome. In one case there was transient typical ballooning of the left ventricular apex during systole following the use of cocaine, thought to have been due to inhibition of catecholamine reuptake [22A]. A 43-year-old woman who took an overdose of venlafaxine, an inhibitor of serotonin and noradrenaline reuptake, developed a takotsubo cardiomyopathy and there was an increase in urinary normetadrenaline (normetanephrine) concentration [23A]. Irukandji syndrome, which follows a sting from the jellyfish called Carukia barnesi, found in Far North Queensland, Australia, presents with sympathetic overdrive, with direct pressor effects and tachycardia secondary to sudden release of endogenous noradrenaline and adrenaline; it can include stress cardiomyopathy [24A]. Cases of takotsubo cardiomyopathy reported after anaphylaxis [25A, 26A, 27A] 313

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may in fact have been, at least in part, due to catecholamines given as part of treatment [28A]. Catecholamines do not improve function in the apical ballooning syndrome and may make it worse. In 11 patients an infusion of low-dose dobutamine did not improve the akinetic wall motion, despite the hypercontractile basal left ventricular wall, and despite the fact that the syndrome is reversible [29c]. In other cases, takotsubo syndrome was worsened by infusion of catecholamines (in one case adrenaline, dobutamine, and noradrenaline and in another dopamine) and improved when the catecholamines were withdrawn [30A, 31A]; beta-blockade was beneficial. The mechanism is presumed to be mediated by adrenoceptors, since in animals the reaction is significantly attenuated by pretreatment with alpha- and beta-adrenoceptor antagonists. It has been hypothesized that high concentrations of circulating adrenaline, by an action on beta2-adrenoceptors, trigger a switch in intracellular signal trafficking in ventricular cardiomyocytes, from G(s) protein to G(i) protein signalling [32H]. Although G(i) protein signalling protects against the apoptotic effects of intense activation of beta1-adrenoceptors, it is also negatively inotropic. This effect is greatest in the apical myocardium, in which the beta-adrenoceptor density is greatest. It is not known what role vasospasm plays. Most cases occur in postmenopausal women, for reasons that are not understood. However, there have also been reports in younger patients [33A, 34c], particularly after catecholamine overdose [35A, 36A, 37A]. Diagnosis The diagnosis depends on four criteria [38M]: 1. ST segment changes or T wave inversion. 2. Transient wall motion abnormalities that are often inconsistent with coronary anatomy. 3. Absence of obstructive coronary artery disease or evidence of acute plaque rupture. 4. Absence of significant head trauma, intracranial hemorrhage, pheochromocytoma, or other causes of myocardial dysfunction.

Myocardial edema with consequent regional wall thickening has been seen using magnetic resonance imaging [39A].

Chapter 13

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Varieties There are three main types: left ventricular apical ballooning (classical takotsubo cardiomyopathy), an inverted or reverse variant (basal akinesis with a hyperdynamic apex, also called “the artichoke heart”), and a midventricular variant. Reports Stress cardiomyopathy has been described in six patients after infusion of adrenaline and in three patients after infusion of dobutamine [40c]. No obstructive coronary artery disease was demonstrated in any patient and follow-up was uneventful, with return to normal hemodynamics and echocardiography. A 27-year-old man also developed transient left ventricular dysfunction resembling takotsubo syndrome after self-injection of adrenaline [41A] and a 41year-old woman developed takotsubo syndrome after receiving two doses of intravenous adrenaline 500 micrograms for an anaphylactic reaction to a bee sting [42A]. Takotsubo cardiomyopathy was also reported in a 62-year-old man with nontopic severe persistent asthma and chronic obstructive disease, who received repeated subcutaneous injections of adrenaline (300 micrograms 8 times in 4 hours) for severe asthma [43A]. Reverse takotsubo cardiomyopathy has also been attributed to adrenaline in a 24year-old woman with no previous history of cardiac disease [44Ar]. Reversible severe left ventricular systolic dysfunction with apical ballooning has also been reported during dobutamine stress echocardiography [45A, 46A, 47A, 48A, 49A, 50A, 51A, 52A, 53A, 54A] and also in one case after recovery from stress echocardiography [55A]. In one case it occurred in a patient with previous orthotopic heart transplantation [56A]. In another case it occurred in a patient who had had a subarachnoid haemorrhage [57A], in which sympathetic nervous system activity is increased and in which acute myocardial infarction can also occur. Almost all cases after exposure to catecholamines have occurred acutely. However, in one case a dilated cardiomyopathy was attributed to chronic overexposure to inhaled adrenaline [58A].

Drugs that affect autonomic functions or the extrapyramidal system • A 44-year-old man, who had had asthma since childhood, and who was taking Franol (ephedrine hydrochloride 11 mg þ phenobarbital 8 mg þ theophylline 120 mg) three times a day and using a Brovon inhalant spray (0.5% adrenaline þ 0.14% atropine methonitrate þ 0.88% papaverine hydrochloride) as required, developed a dilated cardiomyopathy. He had been using the inhaler up to 40 times a day and had done so for 20 years. The inhaler and tablets were withdrawn and he improved with conventional management of asthma and heart failure.

Adrenaline (epinephrine) [SED-15, 41; SEDA-30, 170; SEDA-31, 259; SEDA32, 281] Cardiovascular The incidences of intraoperative critical dysrhythmias related to adrenaline in patients who have received inhalational anesthesia with halogenated agents have been analysed in a retrospective questionnaire study of Japanese Anesthesiologists in 583 institutions; critical dysrhythmias were recorded in 1.2 case per 100 000 cases [59c]. Isolated atrial fibrillation, which resolved spontaneously, has been attributed to local anesthesia with adrenaline during a dental procedure in an anxious patient [60A]. Often one of the earliest therapeutic principles a medical student learns is that adrenaline is key in the treatment of anaphylaxis. A very unusual case from Glasgow suggests that this life-saving use of the drug can produce late thrombosis in a drug-eluting coronary stent [61A]. • A 78-year-old man developed anaphylaxis after exposure to peanuts and was given intramuscular adrenaline 0.5 mg with very good response. However, very shortly afterwards he became sweaty and nauseated, without chest pain, but with a tachycardia of 107/ minute and ST segment elevation in the anterior chest leads of the electrocardiogram. He had has a stent inserted for established coronary artery disease in the left anterior descending artery 4 years earlier. Cardiac catheterization showed occlusion of the same artery, without apparent restenosis.

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The authors concluded that this complication had occurred because of platelet activation by the exogenous adrenaline. If so, it would be the first such case, causing very late stent thrombosis (more than 1 year after intervention), which seems unlikely; other cases have been described, mostly associated with the withdrawal of antiplatelet drug therapy. Vasoconstriction Reports of acute myocardial infarction attributed to adrenaline continue to appear, as in the cases occurred in two elderly women with pre-existing coronary artery disease after the use of intramuscular adrenaline 0.5 mg to treat acute anaphylaxis [62A]. EIDOS classification: Extrinsic moiety Adrenaline Intrinsic moiety Alpha-adrenoceptors Distribution Blood vessels (for example myocardial) Outcome Vasoconstriction Sequela Ischemic tissue damage disease due to adrenaline DoTS classification: Dose-relation Toxic Time-course Time-independent Susceptibility factors Diseases (pre-existing ischemia)

In a 61-year-old man topical endobronchial administration of adrenaline (3 ml of a 1:10 000 solution) resulted in chest pain, ST segment elevation, and ventricular extra beats; the chest pain with sublingual glyceryl trinitrate resolved, as did the ST segment abnormalities [63A]. Cardiac catheterization showed that he had mild coronary artery disease. Myocardial damage can also occur in patients who do not have pre-existing coronary artery disease, particularly if large doses are used. • A 37-year-old woman with an acute anaphylactic reaction to amoxicillin was given two intravenous bolus doses of adrenaline 500 micrograms (diluted 1:10 000) 5 minutes apart; her blood pressure remained low and she was given another intravenous dose of 1 mg,

316 which was accidentally infused undiluted (1:1000). The blood pressure rose but immediately afterwards she developed chest tightness and ST segment depression. The symptoms disappeared spontaneously after 20 minutes. Serum troponin T and creatine kinase MB fraction rose during the next 24 hours.

Although this reaction could have been due to adrenaline toxicity, the authors also discussed the possibility that it was part of the so-called Kounis syndrome or “allergic angina”, which is the occurrence of chest pain after an allergic reaction, accompanied by clinical and laboratory findings of classic angina pectoris or acute myocardial infarction, caused by inflammatory mediators [64Ar]. In another case of possible Kounis syndrome, anaphylaxis and adrenaline treatment were accompanied by transient left ventricular dysfunction, similar to the takotsubo syndrome [65A]. Splenic infarction and abscess has been reported in a 68-year-old woman who had received two injections of a solution of hypertonic saline plus adrenaline 1 day apart during endoscopy on separate occasions for a bleeding gastric ulcer [66A]. The authors recommended the use of adhesive agents, small amounts of sclerosants, and a slow injection speed for endoscopic injection therapy. The vasoconstrictor effect of adrenaline should cause hypertension. However, paradoxical hypotension has been reported in three patients with massive quetiapine overdose, in whom the blood pressure fell dramatically after infusion of adrenaline; hemodynamic stability was restored when noradrenaline was substituted for adrenaline [67A]. Sensory systems Vision Acute macular neuroretinopathy has been attributed to adrenaline [68A]. • A 21-year-old woman was given adrenaline, in an unspecified dose, for a severe generalized urticarial reaction of unknown cause. Very soon after she developed blurred vision in both eyes and 6 days later developed persistent visual impairment, like looking through black spots. The visual acuity was 20/40 in the right eye and 20/30 in the left. Slit lamp examination of the eyes was normal, but there were bilateral central visual field defects and reddish-brown petal-shaped lesions in both

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maculae. Electroretinography was consistent with bilateral maculopathy, which was confirmed by optical coherence tomography, which was abnormal in the outer retina. After a year she had recovered normal visual acuity.

Acute macular neuroretinopathy, a condition of uncertain cause and variable prognosis, occurs mostly in young women. Viral, autoimmune, and ischemic causes have been proposed, and the last might be the mechanism in the cases that have been ascribed to adrenaline. No treatment is available. A 66-year-old Chinese man developed corneal endothelial decompensation after intraocular lens repositioning using intracameral adrenaline, attributed to prolonged, direct exposure of the corneal endothelium to relatively high concentrations of adrenaline [69A]. The authors recommended that intracameral epinephrine should not be used for intraoperative mydriasis in procedures in which high concentrations of adrenaline are likely to result. Nervous system Cervical cord injuries effectively inactivate most of the sympathetic nervous system, leading to denervation hypersensitivity to exogenous catecholamines. The potential consequences of this have been demonstrated in two cases [70A]. • A 63-year-old man with paralysis below C4 developed chest pain but had no positive evidence of myocardial infarction. His pulse rate suddenly fell to 24/minute and he collapsed. He was given intravenous adrenaline 1 mg and atropine 0.4 mg, after which he developed a supraventricular tachycardia at 156/minute followed very soon after by ventricular tachycardia and then fibrillation. Resuscitation was unsuccessful. • A 60-year-old man with an injury at C6 had a cardiac arrest while being prepared for surgery; the rhythm was not mentioned. He responded to intravenous adrenaline in a dose of only 0.1 mg and recovered fully.

The authors pointed out the difference in outcomes in these two cases and suggested that the standard dose of adrenaline given to the first patient was in effect excessive, because of denervation hypersensitivity, while the low dose given in the second case was effective and safe.

Drugs that affect autonomic functions or the extrapyramidal system

Drug administration route Intracavernous instillation of adrenaline for acute priapism does not usually cause systemic effects. However, a 39-year-old man, who was given three injections of adrenaline 100 micrograms þ lidocaine 9 mg 20 minutes apart, developed hypertension (blood pressure 221/124 mmHg) and a sinus tachycardia (heart rate 108/minute without extra beats) [71A]. He recovered after being given oral aspirin 325 mg, sublingual glyceryl trinitrate 0.4 mg, and intravenous labetalol 10 mg. There was no evidence of myocardial damage. The risks of unintentional injection of adrenaline in autoinjectors used in the first aid treatment of anaphylaxis have been the subject of a systematic review of 26 reports detailing 69 cases (58% women); 42% were injured in the home and 91% sustained injury to a finger or thumb; 45 were evaluated in an emergency department and nine were not treated or were only observed [72M]. The injured part was warmed in 25% of cases, glyceryl trinitrate paste was used in 9%, local injections of phentolamine and/or lidocaine in 22%, and other treatments in 20%. There were no permanent sequelae. The authors concluded that people who are at risk of anaphylaxis need regular coaching in how to use adrenaline autoinjectors correctly and safely and that improved autoinjector design would address the problems that they had identified.

Ephedra and ephedrine

[SED-15, 1221; SEDA-30, 171; SEDA-31, 262; SEDA-32, 282] Cardiovascular Myocardial infarction EIDOS classification: Extrinsic moiety Ephedrine Intrinsic moiety Alpha-adrenoceptors Distribution Myocardial blood vessels Outcome Vasospasm Sequela Ischemic heart disease due to ephedrine DoTS classification: Dose-relation Toxic

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Time-course Time-independent Susceptibility factors Diseases (preexisting ischemic heart disease)

Another case of acute myocardial infarction has been attributed to ephedrine abuse in a young athlete in whom an intracoronary thrombus was found in the left anterior descending coronary artery at urgent angiography and was successfully removed; there was an underlying non-obstructive atherosclerotic plaque but no evidence of plaquerupture; the authors suggested that this event had been precipitated by vasoconstriction [73A]. In another case, a 29-year-old man, who had at various times used Ma Huang, Xenadrine RFX, and Hydroxycut, had an acute myocardial infarction secondary to coronary artery aneurysms and thrombosis; with the analogy of cocaine, the authors suggested that chronic use of ephedrine may have led to coronary artery aneurysms, perhaps due to recurrent vasospasm [74A]. A 31-year-old woman with no risk factors for cardiac disease had a perioperative myocardial infarction during spinal anesthesia, attributed to coronary artery vasospasm secondary to ephedrine and/or metaraminol [75AR]. Teratogenicity An association between periconceptional use of weight loss products and certain birth defects has been reported [76C]. Mothers of infants with birth defects (case infants) and a random selection of live births (control infants) born during the period 1998–2003 in the USA participated in the National Birth Defects Prevention Study. Mothers of control infants (2.4%) and 2.6% of mothers of case infants reported using ephedrine-containing weight loss products. The use of any weight loss product was associated with anencephaly (adjusted OR ¼ 2.6; 95% CI ¼1.3, 5.3), transposition of the great arteries (adjusted OR ¼ 2.1; 95% CI ¼1.1, 4.3), and aortic stenosis (adjusted OR ¼ 3.4; 95% CI¼1.5, 7.9). The use of products containing ephedra was associated with an increased risk of anencephaly (adjusted OR ¼ 2.8; 95% CI ¼ 1.0, 7.3) while other

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weight loss products were associated with transposition of the great arteries (adjusted OR ¼ 1.8; 95% CI ¼1.2, 2.7) and aortic stenosis (adjusted OR ¼ 2.1; 95% CI ¼ 1.3, 3.5). This study had several strengths: consistent case definition (both the specific period of use and the product used), detailed information on potential confounders from the maternal interview, and a large sample size. The limitations were that there was no specific question on dieting, and a more general question on herbal products that included use of weight loss products; because this was a hypothesis generating, rather than a hypothesis testing, study, no corrections were made for multiple testing, resulting in an increased probability of false-positive associations. Notwithstanding these caveats, the American College of Obstetrics and Gynecology has recommended that women refrain from attempting to lose weight during pregnancy, unless they are advised to do so by their physicians [77S].

Drug overdose Of children aged under 2 years who presented to the pediatric emergency department of a large, urban, tertiarycare children's hospital with signs and symptoms of an apparent life-threatening event, a substantial number had a positive toxicology screen [78c]. In particular, several had been given an over-the-counter (OTC) cold medication. Of 596 children, 274 (46%) had a toxicology screen performed, of which 50 were considered true positives (18%) and 23 positive results were considered clinically significant (8.4%); 13 were positive for an OTC formulation (4.7%), mostly ephedrine and pseudoephedrine, antihistamines, and antitussives. No parents or caregivers admitted to having given their child an OTC cold medication. The authors speculated that infants could have received these medications either inadvertently, through breastfeeding, or deliberately, in a misguided attempt to treat the symptoms of a cold and congestion. A previous report from the Centers for Disease Control and Prevention suggested that OTC cold medications are more widely used in infants than suspected [79CS].

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Pseudoephedrine

[SED-15, 1221; SEDA-30, 171; SEDA-31, 263; SEDA-32, 282]

Cardiovascular A 45-year-old man had signs of an inferior myocardial infarction after taking pseudoephedrine; metoprolol reversed the signs and symptoms and coronary angiography showed normal coronary arteries [80A]. A similar case was reported in a 33-year-old man [81A]. Skin A 30-year-old woman took ActifedÒ (pseudoephedrine þ triprolidine) for 5 days and developed a generalized, maculopapular, pruriginous dermatitis with facial edema, malaise, and fever [82A]. Patch tests with Actifed and pseudoephedrine alone were both positive; tests with ephedrine and phenylephrine were negative; triprolidine was not tested. Drug overdose A 16-year-old girl took 25 tablets of Sudafed, each containing pseudoephedrine 60 mg [83A]. She complained of nausea and headache and had a fine tremor of the fingers and a tachycardia of 140/ minute. The serum creatine kinase activity and myoglobin were increased. In another case accidental overdose of a modifiedrelease formulation of pseudoephedrine was associated with a hypertensive crisis and a non-ST-elevation myocardial infarction [84A].

DRUGS THAT PREDOMINANTLY STIMULATE ALPHA 1 ADRENOCEPTORS [SEDA-27, 147; SEDA-30, 172; SEDA-31, 264; SEDA-32, 283]

Phenylephrine [SED-15, 2808; SEDA30, 172; SEDA-31, 264; SEDA-32, 283] Cardiovascular Although phenylephrine might be expected to produce an increased

Drugs that affect autonomic functions or the extrapyramidal system

blood pressure, reports of such an effect are very rare, certainly with oral formulations. A report from Spain appears to be the first to describe hypertension in a child attributable to phenylephrine [85A]. • A 5-year-old girl was found by chance to have a blood pressure of 135/80 mmHg, confirmed by ambulatory monitoring. She had taken a cold remedy containing phenylephrine (total dose 7.5 mg in 24 hours) for 4 days before the blood pressure measurement. No other cause for the raised blood pressure was found and the readings returned to normal (109/66 mmHg) 1 week after withdrawal.

This effect was attributed to phenylephrine; the other components of the remedy did not have the potential to increase the blood pressure.

DRUGS THAT STIMULATE BETA 1 -ADRENOCEPTORS [SEDA-30, 173; SEDA-31, 265; SEDA-32, 284]

Dobutamine [SED-15, 1169; SEDA-30, 173; SEDA-31, 265; SEDA-32, 285] Cardiovascular Dobutamine may cause coronary artery spasm. Cardiologists from France and Tunisia reviewed over 6000 patients who underwent dobutamine stress echocardiography over a 4-year period [86C]. Of these, nearly 600 had an abnormal result and 471 underwent coronary angiography; 20 had apparently structurally normal coronary arteries, but two of those had spontaneous vasospasm. The rest had vasospasm in response to intracoronary methylergometrine 0.2 mg. The vessels involved corresponded to the territories with abnormal wall movements during stress echocardiography, and the authors concluded that in this small proportion of cases dobutamine actually caused vasospasm, as of course did the methylergometrine. The authors considered the possibility of false negatives, in whom

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dobutamine did not cause spasm and who were therefore not given the provocation test. A case of acute myocardial infarction has been reported during dobutamine stress echocardiography [87A].As the pain did not resolve with intravenous nitrates, thrombolysis was given. A subsequent coronary angiography showed only mild atheroma and no stenoses. In another case, there was 10-mm ST segment elevation during dobutamine stress echocardiographyin a patient in whom there was no significant coronary stenosis [88A]. This effect was attributed to dobutamineinduced coronary artery spasm. Complete heart block is also a potential risk of dobutamine, although it is uncommon. • A 50-year-old woman with chest pain underwent stress testing with dobutamine sestamibi 20 micrograms/kg/minute [89A]. Shortly afterwards she felt faint, her pulse rate fell to 50/ minute, and she became hypotensive. Shortly thereafter she developed third-degree heart block and the dobutamine was withheld. After being placed in the Trendelenburg position her systolic blood pressure rose to 220 mmHg, but it fell to 180 mmHg after sublingual glyceryl trinitrate. She recovered rapidly, and a subsequent electrocardiogram and serum troponin measurements were normal.

The authors thought that this was the first recorded case of complete heart block associated with dobutamine, although there have been a few case reports of bradycardia with second-degree heart block. A more widely recognized complication of diagnostic dobutamine administration is the so-called empty ventricle syndrome, characterized by outflow or midcavity obstruction and symptomatic hypotension. The possibility that this could be avoided or mitigated by concurrent infusion of isotonic saline based on some positive animal experiments has been investigated in 100 patients, mean age 66 years, who were randomized to dobutamine 10–50 micrograms/kg/minute with atropine 0.6–1 mg if the target heart rate was not achieved, with or without saline 800 ml/hour during the test [90C]. The patients were asked to rate their symptoms on a scale from 1 to 10 and echocardiography was performed to document end-systolic volume and to delineate

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the left ventricular outflow tract before the procedure and at the peak dose. There were no significant differences in symptom scores (3.5 with saline vs. 3.0), end-systolic volume at peak (18 vs. 16), maximal left ventricular outflow tract gradient (16 mmHg vs. 14 mmHg), or change in systolic blood pressure (0.7 mmHg vs. 0.9 mmHg). The authors concluded that this approach is not worth pursuing. Death due to rupture of a splenic artery aneurysm occurred during dobutamine þ atropine stress echocardiography in a 55year-old man [91A]. Stress cardiomyopathy—see under “Adrenaline”. Nervous system A 68-year-old woman who underwent routine stress echocardiography with dobutamine þ atropine, which was negative as regards coronary disease, immediately developed transient global amnesia, which recovered in about 5 hours [92A]. CT and MRI scans and electroencephalography were normal. The mechanism was not clear, although atropine may have had a greater role than dobutamine, given the effects of anticholinergic drugs on memory. Piloerection, which occurred in 92 (42%) of 218 consecutive patients who underwent dobutamine stress echocardiography, correlated with the age of the patients and was present in 73% of patients aged 50 years or younger [93c]. Piloerection is a frequent adverse effect of dobutamine infusion, particularly in patients aged 50 years or less, and it occurs most often at a dose of 10 micrograms/kg/minute. It usually precedes the increase in heart rate caused by dobutamine, and is therefore an early and clear indication that the intravenous infusion is working properly.

Levodopa [SED-15, 2039; SEDA-28, 162; SEDA-30, 174; SEDA-31, 266; SEDA-32, 285] Nervous system Severe hiccups have been attributed to levodopa [94A].

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• An 81-year-old man with probable Parkinson's disease was given increasing doses of levodopa combined with benserazide. When the dose reached a total of 500 mg/day of levodopa he developed hiccups, which lasted for 3 days. He took no further levodopa and the hiccups stopped. On restarting at a dose of 100 mg the hiccups returned, though only for 1 hour. However, this was enough for the patient to refuse all follow-up and treatment.

The authors thought that this was only the second report of levodopa-induced hiccups, but they noted that dopamine receptor antagonists have been used to treat hiccups due to other causes. Ever since the introduction of levodopa there have been concerns that it may be neurotoxic, particularly towards neurons in the substantia nigra, which are in any case depleted in Parkinson's disease. There is a plausible mechanism for this, through generation of free radicals. The evidence from cell culture studies, animal studies, and clinical data has been reviewed, and the authors concluded that the culture experiments are confounded by lack of ascorbate in the medium, which would act as an important protective agent, as it appears to do in vivo in animals, notably in primates [95R]. The clinical data have failed to support the idea that levodopa accelerates striatal neuronal loss. However, the evidence is contradictory, and it seems unlikely that even after 50 years we shall get a definitive answer. Mouth A rare and rather bizarre adverse effect of levodopa is so-called serpentine tongue [96A]. • A 60-year-old man with early Parkinson's disease who was given co-careldopa 200/20 mg daily developed involuntary but not wholly uncontrollable movements of his tongue, which greatly interfered with his speech. He had repetitive twisting and turning movements of the tongue, which ceased on protrusion. The levodopa was replaced by ropinirole, with resolution of the abnormal movements.

The authors drew attention to the occurrence of levodopa-associated involuntary movements even in early Parkinson's disease, and to the possibility that these may take very atypical forms.

Drugs that affect autonomic functions or the extrapyramidal system

Dopamine receptor agonists Cardiovascular Syncope due to cardiac pauses on four occasions has been described in a 51-year-old woman taking ropinirole 0.5 mg/daily for restless legs [97A]. During 24-hour electrocardiography she had two further episodes without warning, and the recording showed 15-second pauses. An adverse reaction to ropinirole was suspected and the drug was withdrawn. There were no subsequent episodes and repeat electrocardiography was normal. Although a possible association between ropinirole and syncope has been suggested, this appears to be the first detailed case report. Fibrotic reactions The literature on dopamine agonists and fibrotic heart valve disease continues to grow. EIDOS classification: Extrinsic moiety Dopamine receptor agonists (especially pergolide and cabergoline) Intrinsic moiety 5HT2B receptors Distribution Serosae, cardiac valves Outcome Hyperplasia (fibrosis) Sequela Fibrotic reactions due to some ergot-derived dopamine receptor agonists DoTS classification: Dose-relation Collateral Time-course Late Susceptibility factors Unknown Of 33 patients (mean age 62 years, 26 men) who had taken pergolide (mean dosage 2.8 mg/day) for a median duration of 5.1 years [98c]. Seven had detectable structural changes, of whom two had valvular regurgitation, which was considered to be not clinically significant. The authors noted that according to some reports similar rates of non-significant valvular anomalies are seen in control populations, and that total abandonment of pergolide may be unwarranted, as the non-ergot dopamine agonists appear to have less efficacy.

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Bromocriptine has received less attention than pergolide in this controversy, but is the subject of a paper from Singapore [99c]. In patients with Parkinson's disease, of whom 72 were taking bromocriptine, 21 were taking pergolide, and 47 were taking neither of these drugs, the odds ratio (OR) for valvular regurgitation was 3.32 with bromocriptine and 3.66 with pergolide, compared with the patients who had not been exposed to dopamine receptor agonists. In the patients taking bromocriptine the risk of valve lesions was related to the cumulative dose. The severity of the lesions was greater in general among the pergolidetreated patients. The three groups were not ideally comparable: the mean ages were similar (59–61 years), but the control group contained fewer women, had shorter durations of illness, and had less motor disability. However, it is not clear that these differences had any effect on the results. The authors speculated that Asian patients may be particularly susceptible to this type of adverse reaction, as the dose of bromocriptine was modest compared with those used in clinical trials: 19 mg/ day rather than 24–52 mg/day. It is clearly important to consider who might be at particular risk of this adverse reaction. In 223 patients (mean age 70 years, 132 women) the incidences of aortic, mitral, and tricuspid regurgitation were 27%, 16%, and 25% respectively [100c]. The details of drug usage are difficult to summarize, as there was a great deal of switching between drugs, but at the time of analysis the numbers taking cabergoline, pergolide, and bromocriptine were respectively 90, 57, and 38. Bromocriptine was not associated with valvular lesions, although the other two ergotderived drugs were. For these drugs, age 70 years and over and hypertension were associated with a striking increase in the risk of aortic and mitral regurgitation, with an odds ratio of 95 compared with normotensive younger patients. The authors also concluded that low doses of both agents (cabergoline 0.9 mg/day, pergolide 1.1 mg/ day) were still associated with an increased risk, raising the question of differential ethnic susceptibility compared with Caucasians, in whom the risk is generally associated with considerably higher doses.

322 • A 49-year-old woman who took low-dose pergolide (0.625 mg/day) daily for 5 years for restless legs syndrome developed chronic and then acute heart failure and had moderate to severe aortic and mitral regurgitation, requiring replacement of both valves [101A].

This is very unusual at such a low dose of pergolide. Cabergoline, rather than pergolide, is the dopamine receptor agonist that is most often used in patients with prolactinoma. There have been several studies, in the UK, Italy, and Belgium, of whether the lower doses of drug used in this condition, as opposed to those used in Parkinson's disease, are associated with valve abnormalities [102c, 103c, 104c, 105c]. Nearly 400 patients have been described, with treatment durations of 1–13 years and cumulative doses of 300–400 mg, although in a few cases this was greatly exceeded. All four groups of investigators concluded that in these circumstances cabergoline is not implicated as a cause of clinically significant valvelesions, though in one report [102c] there was an increased incidence of clinically non-significant right-sided valvular regurgitation. The Dutch authors of a report on patients with prolactinoma arrived at a broadly similar conclusion [106c]. Of 78 patients, 47 were treated for up to 8 years (mean 5.2 years) with a mean cumulative dose of 363 mg. There was mild tricuspid regurgitation in 41% of cabergoline treated subjects (vs. 26% of controls), and aortic calcification in 40% (vs. 18%). However, none of these abnormalities was regarded as clinically relevant. One can therefore be reasonably confident of the safety of lowdose cabergoline in endocrine disease, but not with any complacency. Nervous system Sleep attacks Sleep attacks attributable to dopamine receptor agonists continue to be reported. EIDOS classification: Extrinsic moiety Dopamine receptor agonists, particularly ergot-related compounds

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Intrinsic moiety Dopamine (?D2) receptors Distribution Brain Outcome Altered cell function (nature unknown) Sequela Sleep attacks due to dopamine receptor agonists DoTS classification: Dose-relation Collateral Time-course Time-independent Susceptibility factors Not known

• An 86-year-old woman with restless legs took cabergoline 0.5 mg/day for 6 weeks and had five episodes of sleep attacks associated with amnesia [107A]. Cabergoline was withdrawn and the sleep attacks ceased within 72 hours. She later took ropinirole 0.25 mg at night for 4 weeks increasing to 0.5 mg at night and had no sleep attacks.

Psychiatric Panic attacks have occasionally been attributed to levodopa therapy and to pramipexole, and ropinirole may also be implicated [108A]. • A 73-year-old woman, with a 9-year history of Parkinson's disease, developed attacks of acute anxiety, crying, tachypnea, and hypertension after each of three daily doses of ropinirole 1 mg. These episodes lasted up to 2 hours. Rotigotine was substituted, at an eventual dose of 8 mg/day, and the attacks ceased: it had earlier been shown that ropinirole withdrawal also led to cessation of the attacks.

Compulsive behaviors Disorders of impulse control, including compulsive gambling, can occur with all dopamine receptor agonists. EIDOS classification: Extrinsic moiety Dopamine receptor agonists Intrinsic moiety Dopamine (?D1/D3) receptors Distribution Brain Outcome Altered cell function (nature unknown)

Drugs that affect autonomic functions or the extrapyramidal system

Sequela Pathological gambling due to dopamine receptor agonists (particularly pramipexole) and other compulsive behaviors DoTS classification: Dose-relation Collateral Time-course Intermediate Susceptibility factors Genetic (dopamine D1 receptor gene allele DRD1-800 T/C), age (younger age of onset of Parkinson's disease), sex (male), drugs (combined therapy with levodopa) Hypersexuality and compulsive gambling have been reported with the relatively new drug rotigotine, which is delivered by transdermal patch, in three patients with Parkinson's disease, all of whom were also taking levodopa [109A]. • A 44-year-old man took rotigotine 18 mg/day and developed symptoms of hypersexuality, which persisted for several months but resolved when the drug was withdrawn. • A 58-year-old woman started to gamble compulsively while taking rotigotine 22.5 mg/day; she had gambled for many years but never to the same extent. This behavior ceased when the dosage was reduced to 9 mg/day. • A 48-year-old man developed hypersexuality and compulsive gambling, in the process losing over $100 000. He also had punding behavior, including daily mowing the lawn. Normal behavior resumed after he stopped taking rotigotine.

Although the authors did not mention it, it is striking that all three affected patients were young in terms of the general population with Parkinson's disease. • A 64-year-old woman had compulsive behaviors due to pramipexole, which were greatly improved by replacement with rotigotine [110A]. While taking pramipexole 4.5 mg/day she developed several compulsions, including constant snacking, gambling, and playing computer games. The latter in particular greatly interfered with her daily life. After changing to rotigotine 6 mg/day all the compulsive behaviors ceased.

Clearly there is still a great deal to be learned about the mechanisms of these extraordinary effects. A functional MRI study

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in 12 women has supported the hypothesis that chronic ventral striatal activation is a key part of the process, although the practical implications of this are not clear at the moment [111c].

DRUGS THAT STIMULATE BETA 2 -ADRENOCEPTORS For inhaled beta2-adrenoceptor agonists see Chapter 16.

Clenbuterol Drug adulteration Adulteration of heroin with clenbuterol is frequently reported [112A]. In 13 confirmed cases of exposure to clenbuterol in this way, clenbuterol was identified in the blood and or urine of 12 [113c]. Symptoms included nausea, chest pain, palpitation, dyspnea, and tremor. The physical findings included significant tachycardia and hypotension, and there was laboratory evidence of hyperglycemia, hypokalemia, and increased lactate concentrations; six patients had biochemical evidence of myocardial injury. Ten were given beta-adrenoceptor antagonists without adverse effects. Clenbuterol was detected in 12 of 106 postmortem cases in the USA in which the cause of death was attributed to illicit drug use [114c]. In each case heroin use was either confirmed by the presence of 6-acetylmorphine or strongly suspected by the presence of morphine with a history of heroin abuse. The authors suggested that one should test for clenbuterol when treating a suspected heroin user with an atypical presentation. A novel neuromuscular syndrome, characterized by muscle spasm, tremor, hyperreflexia, and raised serum creatine kinase activity, has been described in five heroin users and attributed to clenbuterol adulteration [115c].

Ritodrine Musculoskeletal Rhabdomyolysis with severe generalized weakness and muscle pain occurred when a pregnant woman without a history was given ritodrine hydrochloride;

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the creatine kinase was raised and there was myoglobinuria [116A]. Electromyography showed a typical myogenic pattern and diffuse denervation activity. Muscular biopsy ruled out inflammatory and metabolic myopathies.

OTHER DRUGS THAT INCREASE DOPAMINE ACTIVITY Catechol-O-methyl transferase inhibitors [SED-15, 1219;

SEDA-32, 289]

Tolcapone Monitoring therapy Monitoring for abnormal liver function tests is mandatory in patients taking tolcapone. However, [117c] of 21 patients only five fully complied with the monitoring regimen in the first 6 months after starting therapy and this fell further in the next half-year. The authors noted that post-marketing surveillance may be very different in reality from that intended by regulatory bodies and manufacturers. In this case no problems arose during the period of observation.

DRUGS THAT AFFECT THE CHOLINERGIC SYSTEM [SEDA-30, 177; SEDA-31, 272; SEDA-32, 290]

Anticholinergic drugs [SED-15, 264; SEDA-30, 153; SEDA-31, 273; SEDA-32, 290] Nervous system In 54 patients (39 women), with a history of migraine, intramuscular hyoscine butylbromide 20 mg/kg, used as premedication for gastroduodenal imaging, caused severe migrainous headaches

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Michael Schachter

accompanied by nausea and vomiting [118c]. There was no preceding aura, and the headache started 20–30 minutes after the injection and lasted 6–18 hours. In contrast, of 1865 non-migraineurs only one experienced a mild headache. The authors cited a report that suggested that the cholinesterase inhibitor donepezil appeared to be effective in migraine prophylaxis, more so than propranolol, although this appears to have been published in abstract form only [119r]. Psychological Most anticholinergic drug use today is intended to have a peripheral autonomic effect, especially on the bladder. Drugs designed for this purpose have poor central nervous system penetration, in order to minimize cognitive and behavioral effects. However, as authors from the US FDA have noted, this is not always successful, especially in children [120c]. They identified 27 children and 143 adults in whom central anticholinergic effects were reported during treatment with oxybutynin. The median age of the children was 6 years, and the most common indication was enuresis, followed by neurogenic bladder. About 30% of the children were aged under 5 years, Hallucinations, sedation, and confusion were the commonest events (each 21–22% of the total), followed by agitation, anxiety, and insomnia (7–8% each). The authors stated that the incidence of central nervous system adverse effects in proportion to all reports is considerably higher in children than adults, although from the way the data were presented it was difficult to quantify this. Certainly, stimulant adverse effects are much more common in children, as opposed to more frequent sedation in adults. However, it has long been known that anticholinergic drugs have marked cognitive effects at the other end of the age range. In a cross-sectional study of 750 subjects aged 65 years or over (median age 74 years, 61% women) exposed to anticholinergic drugs, cognitive and functional performance was assessed by the Mini-Mental State Examination and the Global

Drugs that affect autonomic functions or the extrapyramidal system

Deterioration Scale [121C]. The authors concluded that those taking anticholinergic drugs (about 20% of the total) were significantly more likely to have cognitive impairment than the other (OR ¼ 2.3, after adjustment for possible confounding variables). Although this was not surprising, the range of drugs they classified as anticholinergic was surprisingly wide, including

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cimetidine, codeine, digoxin, and nifedipine, and even warfarin, none of which has anticholinergic activity. Of course, more widely recognized anticholinergic drugs, such as amitriptyline, were also included, although only one person was taking oxybutynin. It is therefore difficult to assess the quantitative significance of these observations.

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in 3 patients treated with rotigotine. Clin Neuropharmacol 2009; 32(2): 59–62. Claassen DO, Josephs KA. Pramipexole induced compulsive behaviors abate after initiation of rotigotine. Movement Dis 2009; 24(7): 1090–1. Abler B, Hahlbrock R, Unrath A, Grön G, Kassubek J. At-risk for pathological gambling: imaging neural reward processing under chronic dopamine agonists. Brain 2009; 132(Pt 9): 2396–402. Dimaano JQ, Burda AM, Korah JE, Wahl M. Street drugs possibly tainted with clenbuterol. J Emerg Nurs 2008; 34(6): 582–3. Hoffman RS, Kirrane BM, Marcus SM. A descriptive study of an outbreak of clenbuterol-containing heroin. Ann Emerg Med 2008; 52(5): 548–53. Wingert WE, Mundy LA, Nelson L, Wong SC, Curtis J. Detection of clenbuterol in heroin users in twelve postmortem cases at the Philadelphia medical examiner's office. J Anal Toxicol 2008; 32(7): 522–8. Manini A, Labinson RM, Kirrane B, Hoffman RS, Rao R, Stajic M, Nelson LS. A novel neuromuscular syndrome associated with clenbuterol-tainted heroin. Clin Toxicol (Phila) 2008; 46(10): 1088–92. Verriello L, D'Amico D, Pauletto G, Gigli GL, Bergonzi P. Rhabdomyolysis caused by tocolytic therapy with ritodrine

[117]

[118]

[119]

[120]

[121]

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hydrochloride. Neuromuscul Disord 2009; 19(10): 718–20. Unger M, Reese JP, Oertel WH, Eggert KM. Real-life evaluations of compliance with mandatory drug safety monitoring exemplified with tolcapone in Parkinson's disease. Eur Neurol 2008; 60 (3): 122–6. Ikeda K, Kawase Y, Takazawa T, Iwamoto K, Ito H, Murata K, Sato R, Nagaoka T, Sekine T, Nagata R, Nakamura Y, Hirayama T, Ishikawa Y, Miura K, Yoshii Y, Iwasaki Y. Scopolamine-induced migraine like headache. Intern Med 2009; 48(9): 681–5. Klapper J, Mathew NT, Abu-Shakra S. Donepezil vs. propranolol for migraine prevention: results of a randomized controlled, double-blind, double-dummy clinical trial. Neurology 2005; 64(1): A335. Gish P, Mosholder AD, Truffa M, JohannLiang R. Spectrum of central anticholinergic adverse effects associated with oxybutynin: comparison of pediatric and adult cases. J Pediatr 2009; 155(3): 432–4. Cancelli I, Gigli GL, Piani A, Zanchettin B, Janes F, Rinaldi A, Valente M. Drugs with anticholinergic properties as a risk factor for cognitive impairment in elderly people. A population-based study. J Clin Psychopharmacol 2008; 28(6): 654–9.

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14

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Editor's note: The adverse effects of many drugs that are used to treat some skin diseases are covered in other chapters; for example, monoclonal antibodies in Chapter 37 and non-topical corticosteroids in Chapter 39. Vitamin A carotenoids are covered in Chapter 34. Many adverse effects of other drugs on the skin are covered in their relevant chapters.

Contact dermatitis Further reviews of systemic contact dermatitis have appeared, including descriptions of common allergens and some insights into the possible mechanisms of action [1r]. It is a cutaneous eruption that occurs in response to systemic exposure to allergens. The exact pathological mechanism is uncertain. The broad spectrum of presentations, which are often non-specific, can make it difficult for clinicians to suspect the diagnosis, but it is an important diagnosis to consider in the case of recalcitrant, widespread, or recurrent dermatitis, in which patch testing often reveals allergies. Diagnosis and appropriate management can be life-altering for affected patients. Systemic contact dermatitis can occur after many routes of exposure, such as Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00014-3 # 2011 Elsevier B.V.

transdermal, subcutaneous, intravenous, intramuscular, inhalation, and oral ingestion [2r]. However, the most important factor to consider is the time-course of exposure to possible allergens and the development of symptoms, because contact dermatitis can have a latency period of a few hours to a few days after systemic exposure [3r]. Allergic contact dermatitis is commonly defined by two phases: a sensitization phase, in which the patient remains asymptomatic, and an elicitation phase, in which cutaneous inflammation occurs mediated by the immune system [4r]. Various metals, medicaments, foods, botanicals, and chemicals have been implicated as causative agents. For example, nickel allergy is one of the most common causes of allergic contact dermatitis and its incidence is thought to be increasing; other common metal allergens include cobalt, gold, mercury, and copper. A broad range of drugs has also been implicated, including allopurinol, ampicillin, benzocaine, erythromycin, methylsalicylate, naproxen, neomycin, and streptomycin.

Camphor

[SED-15, 612]

Nervous system Isolated cases of camphorinduced seizures have been reported in young children after gastrointestinal, dermal, and inhalational exposure. In 1982, after a series of unintentional ingestions of camphor products, the US Food and Drug 333

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Administration restricted the camphor content to less than 11% in some products intended for medicinal use, and in May 2010 warned consumers not to purchase or use various products that contained methyl salicylate and camphor [5S]. Three cases of seizures have been associated with imported, illegally sold camphor in children aged 15–36 months who presented to a large, urban children's hospital during a 2-week period [6c]. Two had ingested camphor, and one had been exposed through repetitive rubbing of camphor on her skin. All three required pharmacological interventions to terminate the seizures. One required bag-valve-mask ventilation for transient respiratory depression. All three patients had leukocytosis and two patients had hyperglycemia. Exposure occurred as a result of using camphor for spiritual purposes, as a cold remedy, or for pest control.

Coal tar Lactation Ointments that contain coal tar contain genotoxic polycyclic aromatic hydrocarbons [7A]. • A woman with atopic dermatitis used ointments containing coal tar. Over a period of 50 days the accumulated dose of different such ointments corresponded to 993 mg of pyrene and 464 mg of benz[a]pyrene. During this time, she gave breast milk to her 3-monthold daughter. Analysis of urine samples from the breast-fed child showed high concentrations of a metabolite of pyrene (1-hydroxypyrene, 1-OHP), in the same range as urinary concentrations of this metabolite in the mother's urine.

As no pyrene was observed in the breast milk at a limit of detection of 0.0035 mmol/ l, transfer of pyrene from mother to child via breast milk was not likely. Furthermore, the concentration of 1-hydroxypyrene observed in the mother's milk was too low to not account for the observed urinary excretion in the child. The authors therefore assumed that pyrene was transferred

from mother to child via another route, presumably direct skin-to-skin or skin-tomouth contact.

COSMETICS Acetaldehyde mouthwashes Tumorigenicity Increasing evidence suggests that acetaldehyde, the first metabolite of ethanol, mediates the carcinogenicity of alcoholic beverages. Ethanol is also found in a number of mouthwashes at a typical concentration of 5–27% (v/v). It has been suggested that there may be an increased risk of oral cancer in users of such mouthwashes, but the epidemiological evidence has been inconclusive. Acetaldehyde concentrations in saliva have been measured after the use of 13 alcohol-containing mouthwashes, which were rinsed in the mouth by four healthy, non-smoking volunteers (n ¼ 4) as directed by the manufacturers (20 ml for 30 seconds) [8C]. Saliva was collected at 0.5, 2, 5, and 10 minutes afterwards and analysed using headspace gas chromatography. The concentrations were significantly above endogenous concentrations and corresponding to concentrations normally found after consumption of alcoholic beverages. Using alcohol-containing mouthwashes twice a day leads to systemic acetaldehyde exposure of 0.26 micrograms/kg/day on average, which corresponds to a lifetime cancer risk of 3  10–6, a low public health concern. However, the acetaldehyde concentrations in the saliva are those that are associated with DNA adduct formation and sister chromatid exchange in vitro, raising concerns about local carcinogenic effects in the oral cavity.

Mascara Sensory systems Eyes Mascara is associated with eye pathology, such as blepharitis, madarosis, and contact dermatitis. Its ocular adverse effects include secondary allergic

Dermatological drugs, topical agents, and cosmetics

conjunctivitis, Pseudomonas-induced corneal ulcers, and a conjunctival mass (a “mascaroma”). Three cases of eye problems secondary to long-term mascara use have been reported [9cr]. Two patients had multiple pigmented conjunctival lesions. One had a history of melanoma of the hand. Conjunctival biopsy showed non-melanocytic pigment granules in conjunctival stroma cells in both cases. The other patient had a history of dry eyes, and also had pigment clumping around a punctal plug. The third patient had canalicular obstruction from a mascara-laden dacryolith (a “dacryomascaralith”).

DERMAL FILLERS Hydroxyethylmethacrylate and ethylmethacrylate Skin DermaliveÒ is a mixture of 60% of a biodegradable fluid-cross-linked hyaluronic acid, which is obtained through bacterial fermentation, and 40% non-biodegradable soft hydroxyethylmethacrylate and ethylmethacrylate particles. This has been used as an injectable filler for nearly a decade. Data from the Berlin registry for adverse reactions to injectable fillers have been analysed [10C]. Of 118 registered patients, 34 had been treated with this filler. Of 95 treated areas, 87 had responded with a reaction. The most common adverse events were nodules (n ¼ 85) in 87 affected areas, discoloration (n ¼ 39), erythema or inflammation (n ¼ 32), and swelling (n ¼ 24). Most of the nodular reactions were rated as severe. The mean latency period for these mostly severe reactions was nearly 2 years. Adverse reactions to injectable fillers may be due to the material itself (e.g. the irregularly shaped surface), the patient, or the technique used by the physician. Based on the frequency and severity of these reactions, the use of this filler is not advisable.

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Non-animal stabilized hyaluronic acid (NASHA) Skin Non-permanent biodegradable dermal fillers, including non-animal stabilized hyaluronic acid (NASHA), have been considered to be non-toxic and non-immunogenic, although recent evidence shows that these statements can no longer be supported. Studies of localized and generalized hypersensitivity reactions, formation of immunemediated granulomas, and sarcoidosis-like disease have been published. The ability of hyaluronic acid analogues to cause immune-mediated reactions is a matter of discussion. Theoretically, hyaluronic acid obtained biosynthetically by bacterial fermentation (NASHA) has the advantage of being free from the risk of transmitting diseases between species or of eliciting allergic reactions in patients who are sensitive to foods such as beef, chicken, and eggs. Although more than 99% of NASHA is protein-free, it may contain small amounts of hyaluroninassociated proteins, and there is therefore a theoretical risk of adverse reactions. The protein load in RestylaneÒ is about 120–170 ng/l. On the other hand, NASHA uses cross-linking compounds, mainly butanediol diglicidileter, which is not NASHA specific. This cross-linker could play a role in the adverse effects related to these compounds. Vasculitis has been reported [11A]. • A 45-year-old woman developed acute urticaria and purpura about 3 weeks after RestylaneÒ (Q-Med, Uppsala, Sweden) had been injected to correct facial wrinkles. Vasculitis was later confirmed histologically. A second bout of vasculitis occurred, supposedly related to new exposure to hyaluronic acid.

The authors analysed the possible relation between vasculitis and the use of hyaluronic acid and NASHA (RestylaneÒ) compounds. Although hyaluronic acid is a universal polysaccharide in living organisms and is considered inert, glycosaminoglycans can be immunogenic and may provoke humoral and cellular responses. The prevalence of delayed adverse reactions related to hyaluronic acid is not

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known, because doctors tend not to communicate negative events. According to published data in Europe, the prevalence ranges from 0.06% to 8.2% [12c, 13C, 14C].

Dimethylfumarate

[SEDA-32, 295]

Skin More cases of contact dermatitis attributed to dimethylfumarate in armchairs have been reported [15A, 16A], and other cases affecting the feet have been reported, owing to its use in shoes [17A, 18A, 19A].

the use of agents such as monobenzyl ether of hydroquinone, phenol, and catechol derivatives. The short time interval in this case suggested a direct toxic effect of paraphenylenediamine or some other chemical ingredient of the henna paste in these tattoos. Contact leukoderma can persist for up to 2 years. Three patients used paint-on henna tattoos and about 1 week later developed localized hypertrichosis over the same area as the tattoo, which resolved spontaneously within 34 months [21A].

Hair dyes [SEDA-15, 1573; SEDA-30, 182; SEDA-31, 288; SEDA-32, 296]

DYESTUFFS

Henna

[SEDA-32, 296]

Skin Temporary henna tattoos have become increasingly popular. The active dyestuff in henna is 2-hydroxy-1,4-naphthoquinone (Lawsone). Contact allergy and immediate hypersensitivity reactions to henna are rare events, as traditionally henna is used as a pure dye prepared from the stems and the leaves of the plant, with the addition of coffee or tea for enhancing the color. The growing practice of mixing in various chemical dyes, such as paraphenylenediamine (PPD; a chemical sensitizer), to enhance the properties of henna has resulted in an increase in the number of adverse allergic reactions caused by these tattoos. Contact leukoderma has been attributed to henna [20A].

[SEDA-32, 296]

Tumorigenicity Previous studies have suggested an association between the use of hair dyes and some cancers [SEDA-15, 1573; SEDA-30, 182, SEDA-31, 288]. Hair dyes are among the chemicals most extensively used and they contain aromatic amine derivates, many of which are mutagenic, and which are associated with a risk of basal cell carcinoma. In a cohort study of hairdressers, there was an increased risk of in situ skin cancers. In this case–control study, patients with basal cell carcinomas on the head and neck were matched with controls to assess the relation with the use of hair dyes [22C]. Patients without a history of known susceptibility factors for basal cell carcinoma were asked about the details of their use of hair dyes. Of 100 women with basal cell carcinomas, 64 had used hair dyes, compared with 54 of 117 controls. The patients with basal cell carcinomas also tended to use darker hair dyes and used dyes more frequently than those without basal cell carcinomas.

• An 8-year-old Indian girl developed an area of depigmentation over the site of a henna tattoo which had been applied 3 days before. Leukoderma caused by the paraphenylenediamine in the henna paste was considered the most probable cause.

FRAGRANCES

Allergic contact dermatitis to black henna has rarely been reported in children. Contact leukoderma has been described after

Skin Fragrance chemicals included in topical medications have been implicated as offending agents in leg ulcers, especially in

Geraniol

Dermatological drugs, topical agents, and cosmetics

patients of advanced age, through allergic contact dermatitis. Geraniol is usually found in cosmetics and household products. However, it is one of the less potent contact allergens of the eight compounds comprising the fragrance mix [23A]. • A man developed an allergic contact dermatitis on his leg with secondary spread after using a topical medication containing geraniol and lavender essence for 3 weeks. He was patch-tested with the Spanish standard series, fragrance series (Chemotechnique, Malmo, Sweden), Blastoestimulina cream, and Betadine. There were positive results with Blastoestimulina (þþ), fragrance mix (þþ), potassium dichromate (þþ), cobalt chloride (þþ), nickel (þ/ þþ), geraniol (þþ), Bulgarian rose oil (þþ), geranium oil bourbon (þþ), and geranium essence (þþ). The ingredients of Blastoestimulina were patch-tested, yielding positive reactions to geraniol (þþ), lavender essence (þ/ þþ), and neomycin sulfate (þ/þþ).

There have been very few cases of sensitization to geraniol and lavender in relation to excipients of topical medications. The authors emphasized the importance of regulating the presence of potent fragrance allergens contained in topical drugs to reduce the frequency of this problem.

Lyral (hydroxyisohexyl 3-cyclohexene carboxaldehyde) Skin Lyral was created and introduced in 1960 by the International Flavors and Fragrances Company. It is an aromatic chemical that is formed through the reaction of myrcenol with acrolein and it is found with high frequency in fragrances and deodorants. Repeated exposure may be required for eventual sensitization. It is estimated to have a reactivity rate of 2.7% in the general population. Contact dermatitis has been reported in a 65-year-old man with recurrent axillary dermatitis, who had a þþ reaction to Lyral 5% in petrolatum; Lyral was found in his deodorant, Brut Deodorant Spray (by Helen of Troy LP, Idelle Labs, EI Paso, Texas) [24A].

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Fumaric acid esters

337

[SED-15, 1453]

Tumorigenicity Fumaric acid esters have been used in the treatment of psoriasis since 1959, after Schweckendiek's description. They induce a shift from the T-helper 1 (Th-1) cytokine response to a Th-2 cytokine response and subsequent lymphopenia with low CD3 and CD4 counts. Low CD4 counts reflect the degree of immunosuppression and, in organ transplant recipients increase the risk of skin cancers, such as squamous cell carcinoma [25A]. • A 49-year-old man with psoriasis, who had been treated with PUVA, sun exposure, methotrexate, and ciclosporin for extensive disease covering 90% of his body surface area, and had actinic damage to his face, with multiple actinic keratoses, was given a fumaric acid ester (FumadermÒ); after 6 weeks the psoriasis was well controlled. However, he developed two tender 1-cm erythematous nodules on his right calf and left thigh, which were squamous cell carcinomas. A month later, a third, rapidly growing nodule was excised and was found to be an infiltrating squamous cell carcinoma. The total lymphocyte count during this period was low (290  106/l) and he had low CD4, CD8, and CD19 counts, the CD4 count being significantly reduced (104  106/l).

This patient had had high UV exposure over his lifetime, including both PUVA and sunlight, which would have put him at high risk of skin cancer. In addition, he had lymphopenia and a reduction in CD subsets after taking a fumaric acid ester, resulting in profound immunosuppression.

Immunomodulators, topical [SEDA-32, 297]

Pimecrolimus and tacrolimus Skin Pimecrolimus and tacrolimus can be used for prolonged periods, avoiding the adverse effects that are related to long-term use of topical glucocorticoids. Although atrophy, telangiectasia, and tachyphylaxis have not been described, topical tacrolimus

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and pimecrolimus can cause transient adverse reactions, generally of mild to moderate intensity, such as burning, a feeling of warmth, smarting, pain, soreness, and rosaceiform dermatitis at the site of application. Drug–drug interactions Alcohol Several cases of an asymptomatic red flushing of the face after moderate alcohol ingestion in tacrolimus-treated patients have been described. Erythematous flushing of the face occurred after ingestion of a small amount of alcohol in seven patients during treatment of their facial vitiligo with topical calcineurin inhibitors [26A]. When 25 patients with chronic stable localized vitiligo were instructed to apply the calcineurin inhibitors to lesions on the face twice daily for 24 weeks, a facial flush occurred in two of 13 who had used pimecrolimus 1% cream and in five of 12 who had used tacrolimus 0.1% ointment after they drank small quantities of beer or wine. They reported sudden onset of an itching–burning sensation quickly followed by flushing. The facial reaction occurred within 5–10 minutes after alcohol ingestion and at 2–4 weeks after the start of treatment. The facial flushing disappeared after 20–30 minutes. After the end of the treatment, the flushing reaction did not recur, even after alcohol intake. The association between flushing of the face and alcohol consumption occurs in 6–7% of patients who use topical tacrolimus. The pathophysiological mechanism is not known, but there are four hypotheses. 1. Both ethanol and calcineurin inhibitors can release neuropeptides, leading to extreme vasodilatation. 2. Calcineurin inhibitors inhibit aldehydedehydrogenase in the areas to which they are applied, and subsequent accumulation of acetaldehyde could lead to vasodilatation after alcohol consumption, as in patients who take disulfiram. 3. There may be an interaction of the two drugs on the calcineurin–calmodulin–calcium complex, on which both alcohol and tacrolimus/ pimecrolimus are known to act. 4. Demodex mites has been observed in abundance in patients with flares of rosacea during topical treatment with tacrolimus and pimecrolimus; it is possible that treatment

with calcineurin inhibitors leads to incipient rosacea with flares after alcohol consumption.

Facial flushing should be recognized as an adverse effect of topical calcineurin inhibitors, both pimecrolimus and tacrolimus, independently from the skin disease.

Minoxidil

[SEDA-32, 2997]

See Chapter 20.

PHOTOTHERAPY AND PHOTOCHEMOTHERAPY [SED-15, 2823; SEDA-32, 297]

Aminolevulinic acid

[SEDA-32, 297]

Nervous system Pain during photodynamic therapy with topical aminolevulinic acid limits its use. In a systematic review of trials (2000–2008) in which aminolevulinic acid or methylaminolevulinic acid were used in at least 10 patients per trial, and in which a semiquantitative pain scale was used, 43 articles were identified [27M]. Pain intensity was associated with lesion size and location and was severe in some diagnoses, such as plaque-type psoriasis. There were results inconsistent for correlations of pain with the light source, the wavelength of light, fluence rate, and the total light dose. GABA receptors, cold/menthol receptors (transient receptor potential cation channel, subfamily M, member 8), and vanilloid/capsaicin receptors (transient receptor potential cation channel, subfamily V, member 1) may be involved in pain perception during photodynamic therapy with aminolevulinic acid and are therefore worth further investigation. Skin Erosive pustular dermatosis of the scalp is a rare inflammatory disease of unknown cause that usually occurs in elderly people. It is characterized by sterile pustules, chronic crusted erosions, cicatricial alopecia, and skin atrophy [28A].

Dermatological drugs, topical agents, and cosmetics • A 93-year-old woman with long standing female-type androgenetic alopecia had actinic keratoses on the scalp that were treated with two sessions of topical methylaminolevulinate photodynamic therapy, with improvement. However, 28 days after the first treatment, she developed burning erosions, which extended slowly but progressively, and areas of scarring alopecia. The clinical and histopathological features were consistent with a diagnosis of erosive pustular dermatosis. She was treated with oral methylprednisolone (16 mg/day with progressive tapering) in combination with topical gentamicin þ betamethasone cream, resulting in marked improvement of the lesions and partial resolution of the cutaneous atrophy after 3 months, but with residual scarring alopecia.

Severe phototoxic reactions occurred in four patients undergoing methylaminolevulinate photodynamic therapy for histologically confirmed basal cell carcinomas or actinic keratosis on the nose [29c]. All complained of severe discomfort, burning, and a stinging sensation during irradiation. They also developed severe phototoxic reactions, with erythema, edema, and crust formation, which spread widely outside the clinically affected areas. After topical mupirocin there was complete healing within 7 days with excellent cosmetic results.

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had received PUVA had a lower percentage of patients with a history of basal cell carcinoma before the decade in which they were studied. Those who had started PUVA treatment by the age of 25 years and were 40 years old in the 1990s had a significantly higher risk. When each tumor was counted, the incidence of tumors was far higher after PUVA. The incidence of basal cell carcinomas was significantly higher in patients with more than 200 PUVA treatments than those with fewer treatments. The greatest increase in risk was among those who started PUVA before the age of 25 years. The average number of tumors per patient who developed at least one basal cell carcinoma was about three times higher in those who received PUVA patients than in the Australian cohort.

VITAMIN A (RETINOIDS) [SED-15, 3653; SEDA-30, 185; SEDA-32, 298; for vitamin a carotenoids see chapter 34]

Acitretin PUVA (psorsalens þ UVA light) Tumorigenicity Exposure to cutaneous carcinogens in young people results in a greater risk of basal cell carcinoma than comparable exposure in older people. A prospective cohort study of the incidence of basal cell carcinomas in a subtropical Australian population [30C] provided a population with which North American patients treated with PUVA could be compared [31c]. During a 10-year period 1380 patients were enrolled and 692 were followed for the entire decade. Of the rest, 254 had died and 88 were lost to follow-up. Complete data (up to death) were available for 92%. Those who had received PUVA were older, a higher proportion were men (64%), and fewer patients were fair-skinned (30% of skin types 1 and 2). Although they were older, those who

339

[SEDA-32, 298]

Hair A 70-year-old woman with psoriasis developed darkening of her previously white hair, which also became curly after taking acitretin for 6 months [32A]. Pregnancy Pregnancy outcomes have been assessed in nine women who inadvertently received transfusions of potentially acitretin-contaminated blood products in South Korea, matched with 18 women by age, gravidity, and singleton- or twin-pregnancy, and who had received transfusions that were not so contaminated [33c]. There were no differences between cases and controls in gestational age at delivery, birth weight, rate of pre-term deliveries, or rate of low birth weight. There were no cases of malformations or neurological abnormalities in either group. Inadvertent exposure to acitretin-contaminated blood products was not associated with adverse pregnancy

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outcomes, perhaps because acitretin and etretinate were removed during the manufacturing process. Drug overdose Fulminant hepatic failure occurred after an intentional overdose of acitretin 600 mg [34A]. The patient fulfilled the King's College Hospital poor prognostic criteria by 66 hours after overdose, but rapidly improved thereafter and did not require liver transplantation.

Isotretinoin

[SEDA-32, 298]

Cardiovascular A 17-year-old boy with minimal pre-existing risk for thromboses had a central retinal vein occlusion in one eye while taking isotretinoin for acne [35A]. DNA testing showed that he was a heterozygous carrier of the G20210A mutation of the prothrombin gene. Despite the fact that this mutation is thought to represent only a minor susceptibility factor for thrombosis, it is possible that isotretinoin greatly increased the risk of a vaso-occlusive incident in this patient. Gastrointestinal A systematic search for case reports, case series, and clinical studies of the association between isotretinoin and inflammatory bowel disease yielded 12 case reports and one case series of such an association, to which the Bradford Hill guidelines to evaluate causality [36H] were applied [37c]. The cases occurred in seven countries over 23 years and differed with respect to isotretinoin dose, duration of treatment before development of the disease, whether the disease developed on or off medication, and the clinical presentation. There have been no prospective or retrospective studies. An estimated 59 coincident cases of inflammatory bowel disease would be expected in isotretinoin users each year, assuming no increased risk. The current evidence is insufficient to confirm or refute a causal association. Panenteritis has been attributed to isotretinoin [38A].

• A 22-year-old man who had taken isotretinoin 20 mg bd for 5 days for nodular acne developed melena. Upper gastrointestinal endoscopy showed edema and hyperemia of the gastric mucosa of the body and antrum. Flexible sigmoidoscopy showed edema and hyperemia of the mucosa of the rectum and sigmoid colon, with numerous erosions. To exclude the possibility of small bowel involvement, he underwent video capsule endoscopy, which showed diffuse and extensive intestinal inflammation with aphthae and multiple linear, irregular-shaped jejunal ulcers. Isotretinoin was withdrawn and he had a complete resolution.

Metabolism In a prospective controlled study in 74 patients taking isotretinoin for cystic acne, blood concentrations of homocysteine, vitamin B12, and folate were assessed before and after 45 days of isotretinoin therapy [39C]. The control group consisted of 80 individuals. Homocysteine concentrations were significantly higher in those who took isotretinoin. The vitamins were unaffected, but serum lipids and liver enzymes increased significantly. These effects may have been due to inhibition of cystathionine-beta-synthase, an enzyme required for the metabolism of homocysteine by either the drug or liver dysfunction. Daily supplementation with vitamin B12 and folate can lower plasma concentrations of homocysteine, and the authors therefore recommended the use of these vitamins in patients taking isotretinoin. Sensory systems Eyes Conjunctival epithelial cells, basal tear secretion, and tear quality were markedly affected in patients during treatment with isotretinoin 0.8 mg/ kg [40c]. Ocular adverse effects of isotretinoin are generally not serious and resolve after withdrawal. Corneal steepening occurred in a patient after systemic treatment with isotretinoin for 7 weeks [41A]. There was significant impairment of visual acuity, which could not be explained by the change in refractive error. All the signs and symptoms resolved within 7 weeks after withdrawal. Skin In a retrospective study, five patients who took isotretinoin developed, during

Dermatological drugs, topical agents, and cosmetics

or after treatment, a peculiar facial eruption resembling seborrheic dermatitis [42c]. The pathogenesis of this effect probably involves a minimal toxic retinoid effect on epidermal differentiation, with overgrowth of commensal micro-organisms in susceptible individuals.

Tretinoin (all-trans retinoic acid, ATRA) [SEDA-30, 186; SEDA-32, 301] Skin Of four prospective, randomized, controlled trials in healthy volunteers at two independent research facilities, two examined phototoxicity after 24 hours of drug exposure under occlusion (combined n ¼ 51), and two examined photoallergenicity after a 3-week, six-dose induction phase (combined n ¼ 72) followed by challenge [43M]. There were no phototoxic or photoallergic reactions with tretinoin 0.05% in a new gel formulation. These findings are

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consistent with previous studies of tretinoin in various formulations, and support the conclusion that tretinoin appears to be neither phototoxic nor photoallergenic in vivo.

VITAMIN D ANALOGUES, TOPICAL [SED-15, 594; SEDA-31, 293; SEDA-32, 301; for oral vitamin d analogues see chapter 34]

Tacalcitol

[SEDA-32, 301]

Placebo-controlled studies In a doubleblind, randomized, vehicle-controlled study of tacalcitol in 80 patients with non-segmental vitiligo there was no significant effect on repigmentation or reduction in the size of the lesions; nor were there any serious adverse reactions [44C].

References [1] Nijhawan RI, Molenda M, Zirvas MJ, Jacob SE. Systemic contact dermatitis. Clin Dermatol 2009; 27(3): 355–64. [2] Veien NK. Ingested food in systemic allergic contact dermatitis. Clin Dermatol 1997; 15(4): 547–55. [3] Thyssen JP, Maibach HI. Drug-elicited systemic allergic (contact) dermatitis—update and possible pathomechanisms. Contact Dermatitis 2008; 59(4): 195–202. [4] Saint-Mazard P, Berard F, Dubois B. The role of CD4þ and CD8þ T cells in contact hypersensitivity and allergic contact dermatitis. Eur J Dermatol 2004; 14(3): 131–8. [5] US Food and Drug Administration. FDA warning: consumers advised not to use Arrow Brand Medicated Oil & Embrocation, Aceite Medicinal La Flecha, or “箭嘜驅風油”, http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm213596.htm.

[6] Khine H, Weiss D, Graber N, Hoffman RS, Esteban-Cruciani N, Avner JR. A cluster of children with seizures caused by camphor poisoning. Pediatrics 2009; 123(5): 1269–72. [7] Scheepers PTJ, Van Houtum JLM, Anzion RBM, Harder R, Bos RP, Van Der Valk PGM. Uptake of pyrene in a breastfed child of a mother treated with coal tar. Pediatr Dermatol 2009; 26(2): 184–7. [8] Lachenmeier DW, Gumbel-Mako S, Sohnius E-M, Keck-Wilhelm A, Kratz E, Mildau G. Salivary acetaldehyde increase due to alcohol-containing mouthwash use: a risk factor for oral cancer. Int J Cancer 2009; 125(3): 730–5. [9] Ciolino JB, Mills DM, Meyer DR. Ocular manifestations of long-term mascara use. Ophthal Plast Reconstr Surg 2009; 25(4): 339–41.

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Ida Duarte, Rosana Lazzarini, Anita Rotter, and Clarice Kobata

[10] Rossner M, Rossner F, Bachmann F, Wiest L, Rzany B. Risk of severe adverse reactions to an injectable filler based on a fixed combination of hydroxyethylmethacrylate and ethylmethacrylate with hyaluronic acid. Dermatol Surg 2009; 25(1): 367–74. [11] Alijotas-Reig J. Recurrent urticarial vasculitis related to nonanimal hyaluronic acid skin filler injection. Dermatol Surg 2009; 35(1): 395–7. [12] Duranti F, Salti G, Bovani B, Calandra M, Rosati ML. Injectable hyaluronic acid gel for soft tissue augmentation. Dermatol Surg 1998; 24(12): 1317–25. [13] Friedman PM, Mafong EA, Kauvar ANB. Safety data of injectable nonanimal stabilized hyaluronic acid gel for soft tissue augmentation. Dermatol Surg 2002; 28(6): 491–4. [14] André P. Evaluation of the safety of a nonanimal stabilized hyaluronic acid (NASHA) in European countries: a retrospective study from 1997 to 2001. J Eur Acad Dermatol Venereol 2004; 18(4): 422–8. [15] Mercader P, Serra-Baldrich E, Alomar A. Contact dermatitis to dimethylfumarate in armchairs. Allergy 2009; 64(5): 818–9. [16] Guillet G, Coindre M, Levillain P, Guillet GH. Dermite lichénoïde par hypersensibilité au diméthylfumarate: présentation atypique du “syndrome du fauteuil chinois”. [Lichenoid dermatitis resulting from sensitization to dimethylfumarate: atypical presentation of “Chinese sofa dermatitis”.] Ann Dermatol Venereol 2009; 136(3): 279–81. [17] Vigan M, Biver C, Bourrain JL, Pelletier F, Girardin P, Aubin F, Humbert P. Eczema aigu d'un pied au dimethylfumarate. [Acute dimethylfumarate-induced eczema on the foot.]. Ann Dermatol Venereol 2009; 136 (3): 281–3. [18] Matía Cubillo AC, Emilio Huertes García JJ, De Juana Izquierdo FJ. Dermatitis alergica de contacto por calzado con dimetilfumarato. [Allergic contact dermatitis due to shoes with dimethylfumarate.] Med Clin (Barc) 2010; 135(3): 138–9. [19] Santiago F, Andrade P, Gonçalo M, Mascarenhas R, Figueiredo A. Allergic contact dermatitis to shoes induced by

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dimethylfumarate: a new allergen imported from China. Dermatol Online J 2010; 16(3): 3. Mendiratta V. Acquired leucoderma after henna tattoo in an Indian girl. J Eur Acad Dermatol Venereol 2009; 23(5): 582–3. Kartal Durmazlar SP, Tatlican S, Eskioglu F. Localized hypertrichosis due to temporary henna tattoos: report of three cases. J Dermatolog Treat 2009; 20(6): 371–3. Feizy V, Toosi S. Relation of basal cell carcinoma to hair dye use. J Am Acad Dermatol 2009; 61(3): 532–3. Juarez A, Goiriz R, Sanchez-Perez J, Garcia-Diez A. Disseminated allergic contact dermatitis after exposure to a topical medication containing geraniol. Dermatitis 2008; 19(3): 163. Jacob SE. Allergic contact dermatitis from Lyral in an aerosol deodorant. Dermatitis 2008; 19(4): 216–7. Jennings L, Murphy GM. Squamous cell carcinoma as a complication of fumaric acid ester immunosuppression. J Eur Acad Dermatol Venereol 2009; 23(12): 1445–69. Stinco G, Piccirillo F, Sallustio M, Patrone P. Facial flush reaction after alcohol ingestion during topical pimecrolimus and tacrolimus treatment. Dermatology 2009; 218(1): 71–2. Warren CB, Karai LJ, Vidimos A, Maytin EV. Pain associated with aminolevulinic acid-photodynamic therapy of skin disease. J Am Acad Dermatol 2009; 61(6): 1033–43. Guarneri C, Vaccaro M. Erosive pustular dermatosis of the scalp following topical methylaminolaevulinate photodynamic therapy. J Am Acad Dermatol 2009; 60(3): 521–2. Toll A, Parera ME, Vélez M, Pujol RM. Photodynamic therapy with methyl aminolevulinate induces phototoxic reactions on areas of the nose adjacent to basal cell carcinomas and actinic keratoses. Dermatol Surg 2008; 34(8): 1145–7. Richmond-Sinclair NM, Pandeya N, Ware RS, Neale RE, Williams GM, van der Pols JC, Green AC. Incidence of basal cell carcinoma multiplicity and detailed anatomic distribution: longitudinal study of an Australian population. J Invest Dermatol 2009; 129(2): 323–8.

Dermatological drugs, topical agents, and cosmetics [31] Stern RS. Putting iatrogenic risk in perspective: basal cell cancer in PUVA patients and Australians. J Invest Dermatol 2009; 129: 2315–6. [32] Seckin D, Yildiz A. Repigmentation and curling of hair after acitretin therapy. Australas J Dermatol 2009; 50(3): 214–6. [33] Han JY, Choi JS, Chun JM, Park HD, Lee SY, Kim CH, Park Q, NavaOcampo AA, Koren G. Pregnancy outcome of women transfused during pregnancy with blood products inadvertently obtained from donors treated with acitretin. J Obstet Gynaecol 2009; 29(8): 694–7. [34] Leithead JA, Simpson KJ, MacGilchrist AJ. Fulminant hepatic failure following overdose of the vitamin A metabolite acitretin. Eur J Gastroenterol Hepatol 2009; 21(2): 230–2. [35] Labiris G, Katsanos A, Karapetsa M, Mpanaka I, Chatzoulis D. Association between isotretinoin use and central retinal vein occlusion in an adolescent with minor predisposition for thrombotic incidents: a case report. J Med Case Reports 2009; 3: 58. [36] Howick J, Glasziou P, Aronson JK. The evolution of evidence hierarchies: what can Bradford Hill's ‘guidelines for causation’ contribute? J R Soc Med 2009; 102: 186–94. [37] Crockett SD, Gulati A, Sandler RS, Kappelman MD. A causal association between isotretinoin and inflammatory bowel disease has yet to be established. Am J Gastroenterol 2009; 104: 2387–93. [38] Spada C, Riccioni ME, Marchese M, Familiari P, Costamagna G. Isotretinoin-

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associated panenteritis. J Clin Gastroenterol 2008; 42(8): 923–5. Polat M, Lenk N, Bingöl S, Oztaş P, Ilhan MN, Artüz F, Alli N. Plasma homocysteine level is elevated in patients on isotretinoin therapy for cystic acne: a prospective controlled study. J Dermatolog Treat 2008; 19(4): 229–32. Karalezli A, Borazan M, Altinors DD, Dursun R, Kiyici H, Akova YA. Conjunctival impression cytology, ocular surface, and tear-film changes in patients treated with systemic isotretinoin. Cornea 2009; 28(1): 46–50. Santodomingo-Rubido J, BarradoNavascues E, Rubido-Crespo M-J. Druginduced ocular side-effects with isotretinoin. Ophthalmic Physiol Opt 2008; 28(5): 497–501. Barzila A, David M, Trau H, Hodak E. Seborrheic dermatitis-like eruption in patients taking isotretinoin therapy for acne: retrospective study of five patients. Am J Clin Dermatol 2008; 9: 255–61. Slade HB, Shroot B, Feldman SR, Cargill DI, Stanfield J. Reappraising the phototoxicity of tretinoin: a report of four controlled clinical trials. Photodermatol Photoimmunol Photomed 2009; 25(3): 146–52. Rodríguez-Martín M, García Bustínduy M, Sáez Rodríguez M, Noda Cabrera A. Randomized, double-blind clinical trial to evaluate the efficacy of topical tacalcitol and sunlight exposure in the treatment of adult nonsegmental vitiligo. Br J Dermatol 2009; 160(2): 409–14.

Garry M. Walsh

15

Antihistamines (H1 receptor antagonists)

Antihistamines, or H1 receptor antagonists, have an established and valued place in the symptomatic treatment of the manifestations of allergic disease and can be administered orally, nasally, or as eye drops. The H1 histamine receptor is a heptahelical transmembrane molecule that transduces extracellular signals to intracellular second messenger systems via G proteins. H1 antihistamines act as inverse agonists that combine with the H1 receptor, stabilizing it in the inactive form and shifting the equilibrium toward the inactive state [1R].

Cetirizine

[SED-15, 702; SEDA-30, 189; SEDA-31, 297; SEDA-32, 305] Nervous system Acute dystonia has been attributed to cetirizine [2A].

• A 6-year-old boy developed an involuntary deviation of his jaw to the left and an inability to swallow after taking cetirizine 5 mg/day for 3 days for allergic rhinitis. The acute dystonic reaction responded to intramuscular biperiden 5 mg within 1 hour.

Dystonic movements are thought to be due to imbalances in cholinergic stimulation. Cetirizine is a piperazine derivative and the authors postulated that the dystonia may have been due to its dopamine receptor blocking properties. Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00015-5 # 2011 Elsevier B.V. All rights reserved.

Immunologic Anaphylactic shock has been attributed to cetirizine. • A 30-year-old woman with chronic idiopathic urticaria took a single oral dose of cetirizine 10 mg and about 15 minutes later developed widespread severe pruritus and urticarial eruptions, severe breathlessness, and an inability to speak. She became restless and disoriented and lost consciousness. Her respiration was very shallow and her pulse and blood pressure were unrecordable.

This was her first exposure to cetirizine or any other piperazine derivative, and on recovery she reported no previous history of allergic drug reactions or concomitant use of any other medication or alcohol [3A]. Although fixed drug eruptions have been previously reported with both cetirizine and levocetirizine [SEDA-31, 30] anaphylaxis caused by systemic antihistamines is very rare, particularly in the absence of known previous exposure. The authors speculated that the potential antigenic nature of the piperazine ring may have been a factor [4A]. Teratogenicity In a prospective cohort study in 196 pregnant women who had taken cetirizine during the first trimester and 1686 controls who had not been exposed to potential teratogens there was no evidence of teratogenicity [5C].

Chlorphenamine Nervous system A generalized convulsion has been attributed to acute intoxication with chlorphenamine [6C]. 345

346 • A 35-year-old man developed generalized convulsions and a mixed acidosis attributed to abuse of SS Bron tablets, an over-the-counter antitussive medication sold in Japan that contains chlorphenamine. He was confused, with bilateral pinpoint pupils. The blood pressure was 143/94 mmHg, the heart rate 113/minute, and the respiratory rate 16/minute. There was a metabolic acidosis and the blood lactate concentration was 300 mg/l. He had generalized convulsions that were treated with diazepam 20 mg. Midazolam was continuously administered intravenously for sedation and 12 hours later he recovered consciousness and became alert with no further convulsions. The serum concentration of chlorphenamine on admission was 0.43 mg/l, i.e. more than 20 times greater than the mean peak concentration after a single dose (4–17 mg/l).

Others later speculated that the toxicity of chlorphenamine had been due to inhibition of serotonin reuptake and postsynaptic 5HT1A receptor agonism [7r]. Immunologic Contact dermatitis has been attributed to chlorphenamine in combination with other compounds [8A]. • An 89-year-old man who had used over-thecounter topical antiseptics developed pruritic lesions over his left knee after using a topical medication containing benzalkonium chloride, dibucaine hydrochloride, chlorphenamine maleate, naphazoline hydrochloride, and a mixture of fragrance ingredients. There were pruritic erythematous papules and vesicles over the knee, and linear extensions down the lower leg appeared the next day. The dermatitis was successfully treated with topical glucocorticoids. Subsequent patch testing of the over-the-counter antiseptic was positive.

The authors diagnosed allergic contact dermatitis to dibucaine hydrochloride, chlorphenamine maleate, and naphazoline hydrochloride, although none of these was patch tested in isolation. They speculated that sensitization to these three agents had occurred sequentially during previous exposures to the topical antiseptic.

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Garry M. Walsh

in general practice in England desloratadine was well tolerated [9C]. Mouth Oral ulceration occurred when a tablet of desloratadine was allowed to dissolve under the tongue [10A] • A 53-year-old woman with a history of hypertension, mild psoriasis, and allergic rhinitis developed acute, painful, irregular, non-indurated yellow-based ulcers on the floor of the mouth with more superficial but more extensive ulceration on the inner side of the tongue. There was no prior history of chronic oral aphthosis and no lesions present anywhere else. She had taken one tablet of desloratadine about 30 minutes before the ulceration occurred. However, rather than swallowing the tablet with water, she had kept it under the tongue, as she had previously done for homeopathic treatments, and after 30 minutes felt pain and inflammation at the application site; the painful oral ulcers were present the next morning. She had taken desloratadine before for allergic rhinitis without any cutaneous or systemic adverse effects, ruling out hypersensitivity.

This was a between-the-eyes adverse reaction of type 2 [11H]. Skin A fixed drug eruption has been attributed to desloratadine [12A]. • A 22-year-old man with a history of fixed drug eruptions, seasonal rhinitis, and mild atopic dermatitis took one tablet of desloratadine and on the next day developed generalized eczema. Patch tests performed 2 months later were strongly positive and were followed during the next 24 hours by a relapse of the pruriginous eczematous lesions spreading on the trunk.

The authors further investigated the incidence of false-positive fixed drug eruptions in healthy volunteers and concluded that these can be avoided by using 1% desloratadine diluted with petrolatum.

Desloratadine

[SED-15, 1074; SEDA30, 189; SEDA-31, 298; SEDA-32, 306]

Diphenhydramine [SED-15, 1134; SEDA-30, 189; SEDA-31, 298; SEDA-32, 307]

Observational studies In a post-marketing study using prescription event monitoring

Skin Allergic contact dermatitis has been attributed to diphenhydramine [13A].

Antihistamines (H1 receptor antagonists)

Chapter 15

• A 45-year-old woman developed an acute, itchy, vesicular, erythematous eruption around the mouth associated with treatment of a previous rosacea with an anti-allergic cream composed of chlorophyll, kamillosan, erythromycin, metronidazole, and diphenhydramine (concentrations not recorded). Within 10 days of discontinuing the cream and applying a topical corticosteroid the lesions cleared. Subsequent patch testing with the anti-allergic cream was positive, and patch tests with the individual ingredients were positive for diphenhydramine and metronidazole. Ultraviolet A irradiation before patch testing with diphenhydramine was positive, while patch tests in 12 healthy patients were negative.

The authors concluded that the patient had had allergic contact dermatitis due to both metronidazole and diphenhydramine. Drug overdose Misuse of diphenhydramine appears to be associated with elevated mood, increased energy, and in some cases hallucinogenic effects [14A]. Diphenhydramine overdose is therefore relatively common, but although it is considered to be relatively non-toxic, serious adverse effects and even death have been reported in adults [15A]. • A 39-year-old man with no significant previous medical history was found in a lethargic state after taking an over-the-counter antiemetic that contained diphenhydramine salicylate 40 mg per tablet. The number of tablets and time of ingestion were not stated, and he denied taking any other medication. He became unresponsive and developed dry skin and increased muscle tone in the limbs. His pupils were 4.5 mm in diameter and sluggishly reactive to light. The blood pressure was 83/ 40 mmHg, heart rate 150/minute, and respiratory rate 30/minute. Circulatory collapse with severe dehydration and metabolic acidosis induced by diphenhydramine toxicity was diagnosed. Repeated intravenous administration of sodium bicarbonate was necessary to maintain the pH above 7.20. He then developed status epilepticus and was given intravenous diazepam 10 mg followed by a continuous infusion of midazolam 3–8 mg/hour. The systolic blood pressure fell below 60 mmHg, and he was intubated and given mechanical ventilatory assistance, intravenous catecholamines, and volume resuscitation. Despite intravenous dopamine (20 micrograms/kg/minute) and noradrenaline (1 microgram/kg/minute), his systolic blood pressure fell further, to less than 40 mmHg. He gradually became edematous,

347 and foamy sputum began to appear. A chest Xray showed a diffuse infiltrate. The metabolic acidosis worsened and continuous hemodialysis was initiated for renal support and maintenance of acid–base balance. He developed severe pulmonary edema and died. Ingestion of diphenhydramine was confirmed by toxicological analysis.

The authors reported that the clinical manifestations of coma, status epilepticus, cardiogenic shock, metabolic acidosis, and pulmonary edema were compatible with previously reported fatal cases of acute diphenhydramine poisoning. Opsoclonus and rhabdomyolysis have been reported after diphenhydramine overdose [16A]. • A 22-year-old man took 3.3 g of diphenhydramine in a suicide attempt was found unconscious in bed and soon afterwards had a generalized seizure. He was unresponsive to painful stimuli. His pupils were dilated and sluggishly reactive to direct light. He had rapid conjugate oscillations of the eyes in the horizontal, vertical, and rotatory planes, interpreted as opsoclonus. The white blood cell count was 22.9
109/l, pH 6.84, anion gap 33 mmol/l, serum creatinine 1.32 mg/dl, and creatine kinase 292 IU/l. Several hours later his serum creatine kinase rose to 72 312 IU/l and he developed oliguric acute renal failure. The serum diphenhydramine concentration was 26 mg/l 10 hours after ingestion. There were no benzodiazepines or tricyclic antidepressants or their metabolites in the urine. Electroencephalography showed diffuse beta waves without epileptiform activity. A brain MRI scan and lumbar puncture were normal.

In healthy subjects, the mean Cmax after oral diphenhydramine 50 mg was 0.66 mg/l [17C]. Opsoclonus is most usually associated with viral or paraneoplastic encephalitis. The authors speculated that the anticholinergic activity of diphenhydramine had been responsible in this patient.

Hydroxyzine

[SED-15, 1705]

Cardiovascular Like some other antihistamines, hydroxyzine can cause prolongation of the QT interval [18A].

Chapter 15

348 • A 34-year-old woman took hydroxyzine 75 mg/ day for chronic prurigo and 3 days later had repetitive syncope. An electrocardiogram showed marked QT interval prolongation (640 ms, QTc ¼ 630 ms). She reported no prior family history, but she had had a presyncopal attack of unknown origin several years before. Hydroxyzine was withdrawn immediately and she had no more attacks of syncope. The QT interval gradually shortened to 460 ms (QTc ¼ 464 ms) 3 weeks after the episode.

The authors concluded that hydroxyzine had caused extreme prolongation of the QT interval. However, because the QT interval remained slightly prolonged after withdrawal of hydroxyzine, they conducted genetic testing and identified a heterozygous missense HERG mutation, A614V, causing a substitution of alanine at codon 614 to valine that resulted in a dominant negative effect on HERG expression.

Promethazine

[SED-15, 2938]

Cardiovascular In a double-blind study of the effect of promethazine on ventricular repolarization (QT interval and transmural dispersion of repolarization) in patients undergoing elective surgical procedures who had no cardiovascular disorders, promethazine caused significant prolongation of the QTc interval. However, the authors also concluded that the lack of simultaneous changes in transmural dispersion of repolarization reduced the risk of ventricular dysrhythmias [19C]. There have been two reports of intraarterial promethazine injection that led to digital necrosis; both eventually led to amputations [20A]. • A 43-year-old woman was given accidently an injection of promethazine into the brachial artery of the left arm. Immediately after the injection, she had burning pain from the left antecubital fossa to the hand. Vasospasm occurred in the left hand, which subsequently became erythematous. She was discharged, but 5 days later returned complaining of pain and discoloration of the left index and ring fingers and purple discoloration of the thumb and little finger. The radial pulse was intact and she was given an analgesic, but 5 days

Garry M. Walsh

later the thumb and digits of her left hand were cyanotic distal to the proximal segments, with a palpable radial pulse. Angiography showed an occluded ulnar artery from its origin, with occlusion of multiple distal digital arteries. After treatment with intra-arterial lidocaine, papaverine, and alteplase for 24 hours angiography showed a patent radial artery, an occluded ulnar artery with some collateral flow, a patent arch, and occlusion of the distal digital arteries to the thumb and fingers. She subsequently developed necrosis of the left hand and required amputations of all five digits 6 weeks after the initial event. Histopathology showed coagulation necrosis. • A 26-year-old woman was accidentally given intra-arterial injections of isotonic saline, pethidine 50 mg, and promethazine 12.5 mg through a catheter in the anatomical snuffbox in the left wrist. She reported pain, swelling, and discoloration of her left hand, which was grossly edematous with second digit cyanosis distal to the proximal interphalangeal joint. Stellate ganglion block was performed in an effort to relieve vasospasm and anticoagulation with heparin and later coumadin was started. However, 2 weeks later, there was demarcation of the terminal segment of the left index finger. The left thumb was involved, with focal ischemia and cyanosis along the ventral aspect of the terminal pulp. There was also cephalic vein thrombosis extending from the left mid-forearm to the level of the first carpometocarpal joint. Arteriography showed normal blood flow to the level of the left wrist, but occlusion of the radial artery in the anatomical snuffbox, with segmental occlusion of multiple distal digital arteries. The left index finger was amputated 3 weeks after the initial injury, with no further progression in the left thumb. Microscopy of the amputated digit showed intimal hyperplasia with occlusion of the small vessel muscular arteries.

The authors pointed out that inadvertent intra-arterial administration of promethazine leads to ischemia and tissue necrosis. They further suggested that hand surgeons must be aware of this complication and consider the diagnosis of intra-arterial promethazine administration when evaluating patients with digital and hand ischemia who have recently had intravenous injection of medications. Pregnancy Self-poisoning with large doses of promethazine during pregnancy does not appear to result in teratogenic, fetotoxic, or neurotoxic effects in the children born to these mothers [21C].

Antihistamines (H1 receptor antagonists)

Chapter 15

Drug overdose Promethazine is a phenothiazine derivative first-generation H1 receptor antagonist but is also an antagonist at muscarinic (M1) and dopamine (D2) receptors. Adverse effects associated with therapeutic use of promethazine include dystonic reactions, psychosis in the absence of other anticholinergic symptoms or signs, and neuroleptic malignant syndrome. The principal effects of promethazine overdose are central nervous system depression and anticholinergic effects, including delirium, agitation, and hallucinations. In an analysis of a series of cases of promethazine overdose in a prospective database of poisoning admissions to an Australian regional toxicology service, the main feature of promethazine toxicity was delirium, the probability of which was related to dose [22C]. Administration of activated charcoal reduced the probability of delirium.

Rupatadine

[SEDA-32, 308]

Rupatadine is both an H1 receptor antagonist and a potent antagonist of the pro-inflammatory lipid mediator, platelet activating factor (PAF); it has been used to treat allergic rhinitis [23C, 24R]. Cardiovascular Rupatadine can cause prolongation of the QT interval [25A]. • A 73-year-old man with diabetes, dyslipidemia, intermittent claudication, and adenocarcinoma of the prostate took rupatadine 10 mg/day for 1 week for cold symptoms and had presyncopal episodes accompanied by sweating and dizziness and one syncopal episode that resolved

349 within a few seconds. After admission he had further syncopal episodes with torsade de pointes. An electrocardiogram showed sinus bradycardia with left bundle-branch block, QT interval prolongation (QTc 680 ms), and twophase T waves in the precordial leads. Echocardiography showed a normal left ventricle with no valve disease. Electroencephalography and a CT scan 6 months before had been normal results and the QTc interval had been 547 ms. Rupatadine was withdrawn. He was advised to avoid QT interval-prolonging drugs and was supplied with a cardioverter defibrillator. He was asymptomatic 9 months later, with a QTc interval of 460 ms.

The authors stressed that the summary of product characteristics for this drug did not mention the potential for cardiovascular adverse effects and that a 400-fold greater dose of rupatadine than that used in clinical practice is required to block potassium channels in vitro [26E], suggesting that the risk should be low. However, a case-series study using Portuguese and Spanish pharmacovigilance databases reported five cases of cardiac rhythm disturbances associated with rupatadine. The reporting rate was two cases per 100 000 patients treated per year. In all cases the reaction started after exposure and resolved when rupatadine was withdrawn and in two cases rupatadine was the only medication taken [27C]. The authors concluded that the summary of product characteristics for rupatadine should be amended to indicate a possible association with cardiotoxicity. Furthermore, rupatadine should be avoided in patients with hereditary long-QT syndrome, kidney or liver impairment, or taking CYP3A4 inhibitors.

References [1] Leurs R, Church MK, Taglialatela M. H1-antihistamines: inverse agonism, antiinflammatory actions and cardiac effects. Clin Exp Allergy 2002; 32: 489–98. [2] Esen I, Demirpence S, Yis U, Kurul S. Cetirizine-induced dystonic reaction in a 6-year old boy. Pediatr Emerg Care 2008; 24: 627–8.

[3] Afonso N, Shetgaonkar P, Dang A, Rataboli PV. Cetirizine-induced anaphylaxis: a rare adverse drug reaction. Br J Clin Pharmacol 2009; 67(5): 577–8. [4] Fisher M, Baldo BA. Anaphylaxis during anaesthesia: current aspects of diagnosis and prevention. Eur J Anaesthesiol 1994; 11: 263–84.

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350 [5] Weber-Schoendorfer C, Schaefer C. The safety of cetirizine during pregnancy: a prospective observational cohort study. Reprod Toxicol 2008; 26(1): 19–23. [6] Murao S, Manabe H, Yamashita T, Sekikawa T. Itoxication with over-thecounter antitussive medication containing dihydrocodeine and chlorpheniramine causes generalized convulsion and mixed acidosis. Intern Med 2008; 47: 1013–5. [7] Karamanakos PN. Intoxication with overthe-counter antitussive medication containing dihydrocodeine and chlorpheniramine causes generalized convulsion and mixed acidosis. Intern Med 2008; 47(20): 1821. [8] Yamadori Y, Oiso N, Hirao A, Kawara S, Kawada A. Allergic contact dermatitis from dibucaine hydrochloride, chlorpheniramine maleate, and naphazoline hydrochloride in an over-the-counter topical antiseptic. Contact Dermatitis 2009; 61: 52–3. [9] Layton D, Wilton L, Shakir SA. Examining the tolerability of the non-sedating antihistamine desloratadine: a prescriptionevent monitoring study in England. Drug Saf 2009; 32(2): 169–79. [10] Kluger N. Oral ulcerations caused by incorrect administration of desloratadine. J Eur Acad Dermatol Venereol 2009; 23: 169–243. [11] Aronson JK, Hauben M. Anecdotes that provide definitive evidence. BMJ 2006; 332: 1267–9. [12] Barbaud A, Bursztejn AC, Schmutz JL, Trechot P. Patch tests with desloratadine at10% induce false-positive results: test at 1%. J Eur Acad Dermatol Venereol 2008; 22: 1497–524. [13] Fernández-Jorge B, Goday J, Buja N, Fernández-Torres R, Rodrıguez-Lojo R, Fonseca E. Concomitant allergic contact dermatitis from diphenhydramine and metronidazole. Contact Dermatitis 2008; 59: 115–6. [14] Thomas A, Nallur DG, Jones N, Deslandes PN. Diphenhydramine abuse and detoxification: a brief review and case report. J Psychopharmacol 2009; 23(1): 101–5. [15] Kamijo Y, Soma K, Sato C, Kurihara K. Fatal diphenhydramine poisoning with increased vascular permeability including late pulmonary congestion refractory to

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[24]

Garry M. Walsh

percutaneous cardiovascular support. Clin Toxicol 2008; 46: 864–8. Irioka T, Yamanami A, Uchida N, Iwase M, Yasuhara H, Mizusawa H. Opsoclonus caused by diphenhydramine self-poisoning. J Neuroopthalmol 2009; 29: 72–3. Blyden GT, Greenblatt DJ, Scavone JM, Shader RI. Pharmacokinetics of diphenhydramine and a demethylated metabolite following intravenous and oral administration. J Clin Pharmacol 1986; 26(7): 529–33. Sakaguchi T, Itoh H, Ding WG, Tsuji K, Nagaoka I, Oka Y, Ashihara T, Ito M, Yumoto Y, Zenda N, Higashi Y, Takeyama Y, Matsuura H, Horie M. Hydroxyzine, a first generation H1-receptor antagonist, inhibits human ether-a-go-gorelated gene (HERG) current and causes syncope in a patient with the HERG mutation. J Pharmacol Sci 2008; 108: 462–71. Owczuk R, Twardowski P, DylczykSommer A, Wujtewicz MA, Sawicka W, Drogoszewska B, Wujtewicz M. Influence of promethazine on cardiac repolarisation: a double-blind, midazolam-controlled study. Anaesthesia 2009; 64(6): 609–14. Foret AL, Bozeman AP, Floyd 3rd WE. Necrosis caused by intra-arterial injection of promethazine: case report. J Hand Surg Am 2009; 34(5): 919–23. Petik D, Ács N, Bánhidy F, Czeizel AE. A study of the potential teratogenic effect of large doses of promethazine used for a suicide attempt by 32 pregnant women. Toxicol Ind Health 2008; 24: 87–96. Page CB, Duffull SB, Whyte IM, Isbister GK. Promethazine overdose: clinical effects, predicting delirium and the effect of charcoal. Q J Med 2009; 102(2): 123–31. Valero A, de la Torre F, Castillo JA, Rivas P, del Cuvillo A, Antépara I, Borja J, Donado E, Molà O, Izquierdo I. Safety of rupatadine administered over a period of 1 year in the treatment of persistent allergic rhinitis: a multicentre, openlabel study in Spain. Drug Saf 2009; 32(1): 33–42. Katiyar S, Prakash S. Pharmacological profile, efficacy and safety of rupatadine in allergic rhinitis. Prim Care Respir J 2009; 18(2): 57–68.

Antihistamines (H1 receptor antagonists)

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[25] Nombela-Franco L, Ruiz-Antoran B, Toquero-Ramos J, Silva-Melchor L. Torsades de pointes associated with rupatadine. Rev Esp Cardiol 2008; 61(3): 327–33. [26] Caballero R, Valenzuela C, Longobardo M. Effects of rupatadine, a new dual antagonist of histamine and platelet-activating factor receptors, on human cardiac Kv1.5 channels. Br J Pharmacol 1999; 128: 1071–81.

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[27] Carvajal A, Macías D, Salado I, Sáinz M, Ortega S, Campo C, García del Pozo J, Martín Arias LH, Velasco A, Gonçalves S, Pombal R, Carmona R. Heart rhythm disturbances associated with rupatadine: a case series from the Spanish and Portuguese pharmacovigilance systems. Clin Pharmacol Ther 2009; 85(5): 481–4.

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INHALED GLUCOCORTICOIDS [SEDA-30, 193; SEDA-31, 305; SEDA-32, 311]

Inhaled glucocorticoids and the risk of pneumonia EIDOS classification: Extrinsic species Glucocorticoids Intrinsic species Not known Distribution Lungs Outcome Not known Sequela Pneumonia from inhaled glucocorticoids in COPD DoTS classification: Dose-relation Collateral reaction Time-course Early Susceptibility factors Age (over 55 years); physiological changes (low body mass index); diseases (severe COPD) The association between the use of inhaled glucocorticoids and pneumonia in patients with chronic obstructive pulmonary disease (COPD) was reviewed in SEDA-32 (p. 311). More data have appeared. A meta-analysis of 11 randomized controlled trials that lasted at least 6 months, involving Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00016-7 # 2011 Elsevier B.V. All rights reserved.

14 426 patients with COPD compared different inhaled glucocorticoid subclasses without and without long-acting betaadrenoceptor agonists (LABAs) versus bronchodilators or placebo [1M]. Seven of the trials (10 776 patients) examined pneumonia as one of their outcomes, and a pooled analysis showed a higher risk in those who used inhaled glucocorticoids (RR ¼ 1.34; CI ¼ 1.03, 1.75). Subgroup analysis showed that the risk of pneumonia increased with the dose of inhaled glucocorticoid, the severity of COPD, and concomitant use of a LABA. In a meta-analysis of 18 randomized controlled trials involving 16 996 patients with COPD who were followed up for 24–156 weeks inhaled glucocorticoids with or without a LABA were compared with either placebo or a LABA alone [2M]. Most of the studies included high-dose inhaled glucocorticoids (2 mg beclometasone equivalents). Inhaled glucocorticoids were associated with an increased incidence of pneumonia (RR ¼ 1.60; CI ¼ 1.33, 1.92), including serious pneumonia (life-threatening, requiring hospitalization, or leading to death or disability) (RR ¼ 1.71; CI ¼ 1.46, 1.99). However, this was not associated with an increased risk of pneumonia-related mortality. The number needed to harm (NNTH) was 47. In a systematic review of 18 randomized controlled trials the combination of inhaled glucocorticoids þ a LABA was compared with a LABA alone in 12 446 patients with COPD; the studies lasted 12–156 weeks [3M]. There was a significantly increased risk of pneumonia (RR ¼ 1.63; CI ¼ 1.35, 353

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1.98) with an NNTH of 40 for those who used inhaled glucocorticoids þ a LABA. In a post-hoc analysis of data from the TORCH study the risk of pneumonia was examined in patients with moderate to severe COPD using inhaled glucocorticoids [4c]. In the original study, 6184 patients were randomized to one of four treatment arms (fluticasone, salmeterol, fluticasone þ salmeterol, or placebo). Inhaled glucocorticoids were associated with a significantly increased incidence of pneumonia, 84 and 88/1000 patient-years for fluticasone and fluticasone þ salmeterol respectively versus 52/1000 patient-years for salmeterol or placebo. For pneumonia as a serious adverse event there was a similar trend, with an NNTH of 47. Death due to pneumonia occurred in under 1% of participants, and therefore the numbers of events were too small to detect any difference between the groups. Susceptibility factors for pneumonia in this group were increasing age (over 65 years), a low FEV1 (under 30%), COPD exacerbations within the last year, a high MRC dyspnea score (categories 4 and 5), and a low BMI. The meta-analyses highlighted so far have involved trials with any subclass of inhaled glucocorticoids. In a meta-analysis of data on 7042 patients from seven studies of budesonide (dosage range 320–1280 micrograms/day) with or without formoterol versus control treatment (placebo or formoterol), in which the authors also adjusted for baseline characteristics, there was no significant difference in the incidence of pneumonia in those who used inhaled glucocorticoids (OR ¼ 1.05; CI ¼ 0.81, 1.37) [5M]. Proposed explanations for this contradictory finding included different pharmacokinetics of budesonide and fluticasone (faster clearance from the lungs) and different pharmacodynamics (reduced potency). An updated meta-analysis of 24 randomized controlled trials in 23 096 patients with COPD showed that inhaled glucocorticoids were associated with a risk of pneumonia (RR ¼ 1.57; CI ¼ 1.41, 1.75) [6M]. However, subgroup analysis showed that although inhaled fluticasone and mometasone were significantly associated with pneumonia, the data on budesonide

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showed only a non-significant trend towards an increased risk. Conclusions Overall, most of the published data suggest an increased risk of pneumonia in patients with COPD who use inhaled glucocorticoids, but without an increased risk of related mortality. However, all the metaanalyses have weaknesses, which limit their interpretation. Pneumonia was not a primary outcome in any of the included studies and the criteria used to make a diagnosis were not stringent, with no requirement for radiological confirmation. Furthermore, it has been argued [7r] that many of the analyses did not have access to adequate baseline patient data, leading to difficulties in excluding potential confounders. Whether there are differences in the risk of pneumonia between various subclasses of inhaled glucocorticoids remains to be determined. Large long-term studies with stringent criteria for the diagnosis of pneumonia and measurement of the risk of pneumonia as a primary outcome are required, including analyses of potential differences between inhaled glucocorticoids.

Ear, nose, throat In a study of the risk of pharyngitis in 55 patients who used inhaled glucocorticoids (controls and asthmatics), inhaled glucocorticoids were associated with throat irritation, sore throat, weakness of voice/hoarseness, and clinical pharyngitis. However, the clinical appearances of pharyngitis in these individuals did not correlate with cellular markers of inflammation. A post-marketing study of 158 patients using inhaled steroids and LABAs for asthma or COPD showed that throat symptoms were the most common adverse effects related to glucocorticoid therapy, including sore throat (54%), dry throat (52%), and oral thrush (11%); there was skin bruising in 35% [8c]. In a systematic review there was an increased risk of oropharyngeal candidiasis in 12 446 patients (RR ¼ 1.59; CI ¼ 1.07, 2.37; NNTH ¼ 22) [3M].

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Sensory systems Vision In a systematic review of four case–control studies in nearly 200 000 patients, there was a significant relation between cataracts and the dose of inhaled glucocorticoid; the random-effects pooled odds ratio for the risk of cataracts per 1000 micrograms increase in daily beclomethasone dipropionate dose was 1.25 [9M]. Endocrine The effects of inhaled glucocorticoids on the hypothalamic–pituitary– adrenal axis in adults and children were reviewed in SEDA-31 (p. 305). In summary, at low doses inhaled glucocorticoids have little effect, but at high doses (2000 micrograms beclometasone equivalents) adrenal suppression can occur. In a French survey of 11 783 hospital specialists combined with a pharmacovigilance database, there were 46 cases of adrenal insufficiency attributable to inhaled corticosteroids at doses of over 500 micrograms beclometasone equivalents in children and over 1000 micrograms beclometasone equivalents in adults; 12 cases were associated with concomitant use of enzyme inhibitors [10C]. In a cohort study in 50 patients with bronchiectasis, basal cortisol and a short Synacthen test were used to study adrenal gland function [11c]. There was adrenal suppression in 24% of these patients not using glucocorticoids, but it was significantly more likely in those who used inhaled glucocorticoids (49%). This was associated with symptoms of adrenal suppression and worse quality of life. The effect was not related to the dose of inhaled glucocorticoids, the use of other topical glucocorticoids, or the use of oral glucocorticoids in the preceding year. In contrast, in a randomized controlled trial in 645 patients with moderate asthma uncontrolled by regular inhaled glucocorticoids compared with combined beclometasone diproprionate and formoterol, there was no evidence of adrenal suppression [12C]. This may suggest that the doses of glucocorticoids were too low. In 41 patients aged 8–18 years with asthma, using fluticasone 200–300 micrograms/day (400–660 micrograms

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beclometasone equivalents) there was no evidence of adrenal suppression or differences between dosage regimens during follow-up for 10 weeks [13c]. In a review of the literature published to date in this area the authors concluded that at higher than recommended doses inhaled glucocorticoids can precipitate adrenal crises in children and adults [14R]. They cited observational data that suggest a more prominent effect of fluticasone propionate, but acknowledged that study designs are open to bias. Furthermore, the authors of a previous Cochrane review of fluticasone versus beclomethasone and budesonide concluded that although there were concerns about the risk of adrenal suppression in children using fluticasone (in doses over 400 micrograms) the randomized controlled trials analysed did not provide sufficient data to address this question [15M]. Musculoskeletal A link between high-dose inhaled corticosteroids and Achilles tendonitis, an adverse effect seen with oral steroids, has been suggested [16A].

Inhaled glucocorticoids and skeletal adverse effects Children Several randomized controlled trials have shown an association between the use of inhaled corticosteroids and reduced growth velocity in the first year of treatment in pre-pubertal children, although in trials in which these individuals have been followed for longer (up to 10 years) this effect appears to diminish (SEDA-32, 312). More recently the effects of inhaled budesonide (200 micrograms bd), nedocromil, and placebo have been studied in the Childhood Asthma Management Programme (CAMP), in children with mild to moderate asthma, conducted over 4.3 years [17C]. At the end of the trial the children who had used budesonide were a mean of 1.1 cm shorter than those in the other treatment arms. In a follow-up study of the long-term benefits and harms 4.8 years

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after the end of the study, in the 941 children from the original cohort, growth suppression, while less during follow-up, nevertheless persisted (0.9 cm in the treatment group versus placebo) [18C]. The effect was more pronounced in girls (1.7 cm) than in boys (0.3 cm), which differs from previous findings of a greater effect in boys [19C]. It should be noted that 54% of the boys and 25% of the girls had not reached their full adult height at the end of the study. Bone mineral density was also examined in this cohort [20C]. In the 531 boys and 346 girls followed for a median of 7 years there was an association between reduced bone mineral accretion with oral glucocorticoid use, which was dose-related, but only in boys. With regards to the use of inhaled glucocorticoids, this was associated with a statistically significant reduction in bone mineral accretion in boys but not in girls. The effect did not appear to be dose-related. Inhaled glucocorticoids, unlike their oral counterparts, did not increase the risk of osteopenia or fractures. The authors argued that inhaled glucocorticoids appeared to be much safer in terms of effects on bone mineral density than bursts of oral glucocorticoids and that therefore the ability of regular inhaled glucocorticoids to reduce the need for oral glucocorticoids outweighed the small risks. In 2978 children with cystic fibrosis inhaled glucocorticoids caused a small but significant reduction in height for age and increased use of oral hypoglycemic drugs [21C]. The authors of two reviews have concluded that overall treatment with inhaled glucocorticoids can cause slowing of growth velocity in the early stages of treatment, although previous long-term studies have shown that the children will eventually reach their anticipated adult heights [22R]. Adults Previous observational data have suggested that inhaled glucocorticoids reduce bone mineral density and increase the risk of fractures (SEDA-31, 307; SEDA-32, 313). An analysis of a subset of 685 patients using inhaled glucocorticoids in the TORCH study, and excluding patients taking oral

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glucocorticoids, showed no changes in bone mineral density from a baseline in which 30% of women had osteoporosis and 41% osteopenia (overall prevalence 65%) density [23C]. There was a low incidence of fractures (5.1–6.3%). While recognizing the limitations of this study, including the short follow-up time and high drop-out rate, the authors suggested that the frequencies of osteopenia and osteoporosis in patients with COPD are high, but that there is no evidence to suggest a significant link between inhaled glucocorticoids and low bone mineral density. In a meta-analysis of 13 observational and randomized controlled trials there was no overall increased risk of fractures associated with inhaled glucocorticoids (RR ¼ 1.02; CI ¼ 0.96, 1.08) even when the analysis was restricted to the four randomized controlled trials [24M]. However when stratified by the dose of inhaled glucocorticoid there was a small increased risk of fractures amongst those taking high doses (RR ¼ 1.30; CI ¼ 1.07, 1.58). In contrast, another meta-analysis of three double-blind randomized controlled trials, including TORCH, in a total of 8131 patients, showed no increased risk of fractures (OR ¼ 1.09; CI ¼ 0.89, 1.33) despite the use of high-dose inhaled glucocorticoids (beclomethasone 800 micrograms, fluticasone 1000 micrograms) [1M]. In a more recent review of the literature, including trial and observational data, the authors concluded that inhaled glucocorticoids may produce a modest reduction in bone mineral density and a small associated increase in the risk of fracture, which appears to be dose-related [22R]. However, it has been argued that most of this evidence comes from observational data, with risks of bias (recall and confounding) and that adequately powered randomized controlled trials are needed to clarify this risk and quantify it accurately [25R]. In the meantime, physicians need to be aware of this potential adverse effect, and, certainly in the case of asthma, try to maintain patients on the lowest dose of inhaled glucocorticoids required to control their disease.

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BETA 2 -ADRENOCEPTOR AGONISTS [SEDA-30, 198; SEDA-31, 308; SEDA-32, 314] For non-respiratory uses of b2-adrenoceptor agonists, see Chapter 13.

Long-term safety of long-acting beta2-adrenoceptor agonists (LABAs)—an update Concerns have been raised about the longterm safety of LABAs; the overall and respiratory adverse effects were reviewed in SEDA-30 (p. 198) and SEDA-31 (p. 309). Meta-analysis, using data from 33 826 patients with asthma, has shown that LABAs are associated with an increased risk of exacerbations requiring hospitalization (OR ¼ 2.6; 95% CI ¼ 1.6, 4.3), life-threatening exacerbations (OR ¼ 1.8; 95% CI ¼ 1.1, 3.9), and death from asthma (OR ¼ 3.5; 95% CI ¼ 1.3, 9.3) in a small subgroup of patients [26M, 27M]. Potential publication bias was a limitation of the meta-analysis; furthermore, the Salmeterol Multicenter Asthma Research Trial (SMART) provided 80% of the data and accounted for most of the asthma-related deaths [28r]. The authors of a Cochrane review (n ¼ 42 333) concluded that there were potential safety problems associated with LABAs, particularly in patients who are not taking inhaled glucocorticoids [29M]. In December 2008, the US Food and Drug Administration (FDA) concluded that the benefits of single-agent LABAs did not outweigh the risks and removed the asthma indication for single-agent salmeterol and formoterol [30r]. The revised label was informed mainly by data from the Serevent Nationwide Surveillance (SNS) study and the SMART study, and a 2008 meta-analysis conducted by the FDA. In a systematic review comparing LABAs and placebo and LABAs þ inhaled glucocorticoids and inhaled glucocorticoids alone for at least 12 weeks (n ¼ 36 588), LABAs were associated with an increase in catastrophic

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events (asthma-related intubations and deaths) (OR ¼ 2.10; 95% CI ¼ 1.37, 3.22) [31M]. This was significant for LABAs þ variable doses of glucocorticoids versus placebo (OR ¼ 1.83; 95% CI, 1.14–2.95) and for a LABA þ an inhaled glucocorticoid versus an inhaled glucocorticoid alone (OR ¼ 3.65; 95% CI ¼ 1.39, 9.55). There were similar increases in risk for variable and concomitant inhaled glucocorticoids, salmeterol and formoterol, and in children and adults. In the analysis of patients using concomitant inhaled glucocorticoids, there remained an association with increased numbers of catastrophic events compared with inhaled glucocorticoids alone (OR ¼ 8.19; 95% CI ¼ 1.10, 61), but studies without catastrophic events were excluded. Cochrane reviewers have sought to address serious adverse events associated with the use of regular LABAs combined with inhaled glucocorticoids for asthma. In one review (n ¼ 15 155; 1155 children, 14 000 adults) the combination of a LABA þ an inhaled glucocorticoid was compared with higher doses of inhaled glucocorticoids [32M]. In adolescents and adults, a LABA þ an inhaled glucocorticoid was modestly more effective at reducing exacerbations. LABAs led to an increased frequency of tremor (RR ¼ 1.84; CI ¼ 1.20, 2.82) and less oral candidiasis, but adverse effects associated with long-term inhaled glucocorticoids were rarely monitored. In children, combination therapy was associated with a non-significant trend towards an increased risk of oral glucocorticoid-treated exacerbations and hospital admissions. The authors therefore raised concerns about the safety of combination therapy, in view of the modest improvement in children under the age of 12 years. However, a larger Cochrane review in children, in which the addition of a LABA to an inhaled glucocorticoid was compared with the same or an increased dose of inhaled glucocorticoid (n ¼ 5572), showed no difference in the risk of overall adverse effects. While there was no difference in the number of exacerbations requiring systemic glucocorticoids, LABAs were associated with improved lung function and short-term growth [33M]. In another Cochrane review (n ¼ 21 248; 4625 children, 16 623 adults) the addition of

358

a LABA to the same dose of an inhaled glucocorticoid was studied [34M]. There was no significant difference in serious adverse events with the LABAs (RR ¼ 1.06; CI ¼ 0.87, 1.30), but the confidence intervals were wide. In adults, add-on LABA therapy reduced the rate of exacerbations requiring oral glucocorticoids, improved lung function and symptoms, and modestly reduced the use of SABAs. In a meta-analysis of about 96 000 patients, the combination of a LABA þ an inhaled glucocorticoid reduced asthmarelated hospitalizations and/or emergency visits compared with inhaled glucocorticoids alone (OR ¼ 0.82; CI ¼ 0.72, 0.94) [35M]. In a meta-analysis of the effect of at least 12 weeks of treatment with a LABA on asthma-related and total morbidity and mortality in patients who were concomitantly using inhaled glucocorticoids (n ¼ 29 401 patients; over 8200 patient-years) there were 14 deaths in those using a LABA and eight in controls; there were three asthma-related deaths and two asthma-related non-fatal intubations, all in those using a LABA (n ¼ 15 710) [36M]. The OR for total mortality was 1.26 (CI ¼ 0.58, 2.74). Asthma-related deaths and intubations were few and there was insufficient power to draw conclusions about the effect of LABAs on these outcomes. In a Cochrane review the combination of a LABA þ an inhaled glucocorticoid was compared with the glucocorticoid alone in 8050 glucocorticoid-naive adults and children with asthma [37M]. There was no significant difference in the risk of serious adverse events or any adverse events. While the addition of a LABA significantly improved lung function, reduced symptoms, and marginally reduced the need for rescue SABAs, a higher dose of inhaled glucocorticoids was more effective in reducing the risk of exacerbations that required rescue systemic corticosteroids, and the risk of withdrawals, than combination therapy. Small numbers of children precluded firm conclusions in that group. In a systematic review the addition of a LABA to inhaled glucocorticoids significantly reduced the risk of exacerbations compared with a similar dose of inhaled

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glucocorticoids [38M]. There was significantly more tremor with the LABA þ inhaled glucocorticoid combination (NNTH ¼ 21) and compared with higher doses of inhaled glucocorticoids (NNTH ¼ 74). The authors concluded that benefit to harm balance favors the addition of a LABA to an inhaled glucocorticoid in adults with symptomatic asthma. In a large observational study (n ¼ 507 966) patients who had recently started asthma medication (SABA, LABA, inhaled glucocorticoids) were at an initial increased risk of myocardial infarction, particularly in the first 3 months, which then fell; there was no significant difference in the risk between treatments (RRs: SABA ¼ 2.4, LABA ¼ 1.5, inhaled glucocorticoids ¼ 1.5) [39C]. Heavy long-term use (more than 13 prescriptions in 1 year) of an inhaled glucocorticoid and a SABA was also associated with an increased risk of myocardial infarction. Limitations of this study included potential confounders and the possibility that inhalers are sometimes incorrectly given for cardiac asthma (i.e. pulmonary edema). Comparative studies Adrenoceptor agonists versus glucocorticoids Add-on LABA therapy (n ¼ 17 418) has been compared with high-dose inhaled glucocorticoids (n ¼ 46 930) in a 12-month observational study in patients with asthma [40C]. The use of rescue bronchodilators was lower in those taking LABAs, but higher usage of inhaled glucocorticoids was associated with a lower risk of severe exacerbations and hospitalizations. However, a post-hoc analysis (with its inherent limitations) of the Formoterol and Corticosteroid Establishing Therapy study (n ¼ 852 treated) showed that add-on formoterol increased the duration of well-controlled asthma, compared with a fourfold increase in budesonide [41C]. In a 3-year comparison of salmeterol, fluticasone, and salmeterol þ fluticasone, the frequencies of adverse events were similar across the groups [42C]. Hoarseness/ dysphonia was the most common adverse event that the investigator considered to be drug-related; it occurred in 15% of

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patients using salmeterol, in 5% of those using fluticasone, and 9% of those using salmeterol þ fluticasone. In children with persistent asthma in the VIAPAED study, adding salmeterol to fluticasone in a single inhaler was more effective than doubling the dose of inhaled glucocorticoids [43C]. In a similar study in adults with COPD, salmeterol þ fluticasone was associated with a higher incidence of pneumonia [44C]. Formoterol versus salmeterol In a randomized controlled trial in patients with COPD, formoterol had a faster onset of action with no significant difference in treatment-associated adverse events (5.8% versus 1.5% with salmeterol) [45C]. Headache was the most common adverse event with formoterol (3.6%); bronchitis and upper respiratory tract infections were the most common adverse events with salmeterol (2.3% each). Levosalbutamol versus racemic salbutamol In 49 patients, mean heart rate and plasma (R)-salbutamol concentrations were higher with racemic salbutamol than levosalbutamol, with similar improvements in FEV1 [46c]. Combination studies Asthma guidelines recommend adding long-acting beta2adrenoceptor agonists (LABAs) to inhaled glucocorticoids at step 3 in adults and adolescents, before increasing the dose of beclometasone or other glucocorticoids above 400 microgram equivalents and certainly before increasing above 800 micrograms [47S, 48S]. LABAs and combination therapy are licensed for children over 5 years, but have not yet been adequately evaluated in younger children. LABAs should not be used as monotherapy in asthma but as add-on therapy to inhaled glucocorticoids [49S]. Cardiovascular In a randomized placebocontrolled study of nebulized arformoterol 15/25 micrograms bd or 50 micrograms/

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day or salmeterol 42 micrograms bd in 1429 patients with COPD the risk of atrial tachycardia was increased by 2–5% [50C]. More serious dysrhythmias (atrial fibrillation/flutter, non-sustained/sustained ventricular tachycardia) were uncommon and were not increased by LABAs. LABAs did not increase the mean heart rate. Musculoskeletal In an observational study in 158 patients minor adverse reactions were common in association with LABAs (studied in combination with inhaled glucocorticoids) and the reactions were dose-related [51c]. Of those taking LABAs, 72% reported potential adverse reactions, the commonest being muscle cramps (62%) and muscle twisting (39%). Teratogenicity Beta2-adrenoceptor agonists can cause functional and behavioral teratogenic effects and have been associated with increases in autism spectrum disorders, psychiatric disorders, poor cognitive and motor function, poor school performance, and changes in blood pressure in the offspring [52R]. It should be emphasized that risks of untreated disease to the mother and fetus are greater than the risk of using a beta2adrenoceptor agonist but that the drugs should only be used when clearly indicated. In a comparison of 502 infants with cardiac anomalies (Congenital Malformations Registry) with matched controls, the offspring of women with asthma who had used bronchodilators were at increased risk of any heart defect (OR ¼ 2.20; 95% CI ¼ 1.05, 4.61) and specifically obstructive defects (OR ¼ 4.49; CI ¼ 2.03, 9.94), which remained significant when looking at only salbutamol (OR ¼ 4.62; CI ¼ 1.66, 12.85) [53C]. Unfortunately, there was no information on frequency or dosing of medications, and multiple medications were also associated with a risk of cardiac defects. The authors suggested that both maternal asthma status (control; severity) and use of asthma medications, particularly bronchodilators, may play a role in cardiac malformations in their offspring.

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In 24 children with major congenital malformations, there was no increased risk of malformations with gestational exposures to short- or long-acting betaadrenoceptor agonists [54C]. Susceptibility factors Genetic The LARGE study showed a significant B16 genotypespecific difference in methacholine responsiveness but no difference in salmeterol response between Arg/Arg (n ¼ 42) or Gly/Gly (n ¼ 45) in individuals with asthma [55c]. Post-hoc subgroup analyses in African–Americans showed significant changes in peak expiratory flow (PEF) in the eight Gly/Gly subjects but not in the nine Arg/Arg subjects, but the numbers were small. Minor adverse events were mainly nasopharyngitis/pharyngitis.

Formoterol

[SED-15, 1443;

SEDA-32, 316] Combination studies Formoterol versus/ plus tiotropium See under “Tiotropium”. Formoterol added to an inhaled glucocorticoid In a review of the use of formoterol in adults and adolescents (n ¼ 8028) and children (n ¼ 2788) there were four adult deaths among 6594 people randomized to inhaled glucocorticoids þ formoterol and none in those who used inhaled glucocorticoids alone; one death was reported to be asthma-related but the difference was not statistically significant [56M]. There were no significant differences in non-fatal serious adverse events from any cause in adults, and a non-significant increase in events in children who used formoterol was not statistically significant. Asthma-related serious adverse events in adults using formoterol were less common (OR ¼ 0.53; CI ¼ 0.28, 1.00), with a non-significant higher trend in children. In children, the number of events was too small to assess whether the increase in all-cause non-fatal serious adverse events found in a previous meta-analysis of regular formoterol alone was abolished by the additional use of inhaled glucocorticoids. The

Gwyneth A. Davies and Mike Pynn

review was inconclusive regarding definite evidence of harm/no harm relating to the use of formoterol þ inhaled glucocorticoids. Only one asthma-related death was reported with formoterol over 3000 patient-years. In a systematic review of asthma-related mortality in patients using formoterol compared with those not using formoterol, including all AstraZeneca parallel-group randomized controlled trials lasting 3–12 months, there were eight asthma-related deaths (0.34 per 1000 person-years) in 49 906 patients using formoterol (92% also using inhaled glucocorticoids), and two (0.22 per 1000 personyears) in 18 098 patients (83% also using inhaled glucocorticoids) not randomized to formoterol; this was a non-significant difference [57M]. Asthma-related serious adverse events (over 90% of which were associated with hospitalization) were significantly fewer in those who used formoterol (0.75% versus 1.10%). Increased daily doses of formoterol caused no increase in asthma-related serious adverse events. There was no significant difference in cardiac mortality, non-cardiac non-asthma-related mortality, nor all-cause mortality in those who used formoterol. Among those who were given an inhaled glucocorticoid at baseline, there were seven asthma-related deaths (0.32 per 1000 person-years) in 46 003 patients randomized to formoterol and one (0.14 per 1000 personyears) in 13 905 patients not randomized to formoterol; this was also non-significant. There were few asthma-related or cardiacrelated deaths among patients randomized to formoterol, and all the differences were non-significant. However, despite over 68 000 patients, there was insufficient power to conclude that there was no increased mortality with formoterol. Cardiac-related serious adverse events were not increased, and asthma-related serious adverse events were significantly reduced in those who used formoterol. Formoterol þ budesonide as maintenance and reliever therapy Budesonide þ formoterol (Symbicort) for maintenance and reliever therapy (Symbicort SMART) has been evaluated in a Cochrane review of five trials (n ¼ 5378) compared with

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inhaled glucocorticoids for maintenance þ a separate reliever inhaler [58M]. There was no significant difference in fatal/nonfatal serious adverse events. Single inhaler therapy was associated with a reduced mean total daily dose of inhaled glucocorticoids (mean reduction from 107 to 267 micrograms/day; results not combined owing to heterogeneity) and reduced asthma exacerbations requiring oral glucocorticoids, with no significant reduction in hospitalization. In 224 children, single inhaler therapy was associated with a reduced need for inhaled glucocorticoids and oral corticosteroids, and the annual height gain was 1 cm greater in this group (CI ¼ 0.3, 1.7 cm). Single inhaler therapy is not currently licensed for children under 18 years of age in the UK. In a meta-analysis of eight trials the SMART approach reduced the risk of severe exacerbations and severe exacerbations requiring hospitalization or emergency treatment, with no increase in adverse events [59M]. However, there was heterogeneity among these trials. Data relating to budesonide þ formoterol therapy from six randomized controlled trials of at least 6 months (n ¼ 14 346) have been analysed [60M]. SMART therapy was well tolerated compared with fixed-dose alternatives, and there was no increased risk of death or cardiac-related serious adverse events or withdrawals because of adverse events; asthma-related serious adverse events and withdrawals were significantly reduced. Limitations of the randomized controlled trials were noted, particularly exclusion of patients with co-morbidities, necessitating continuing surveillance. A pooled analysis of six 6-month, randomized, open studies showed that serious adverse events were uncommon, with comparable incidences in the two treatment groups [61M]. Higher eosinophil counts were associated with maintenance and reliever therapy compared with fixed-dose combination treatment containing a fourfold higher maintenance dose of budesonide, but these remained within the range associated with stable control [62C]. There were no

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significant differences in adverse events, exacerbation rates, or lung function. A 12-month open study in primary care showed no clinically important differences in adverse events between flexible and fixed dosing of budesonide þ formoterol. Maintenance and reliever therapy was associated with a significantly lower daily dose of budesonide and direct cost savings, with at least equivalent efficacy [63C]; there were similar findings in other studies [64C]. Route of administration Nebulized versus inhaled formoterol Dose-ranging and PK/ PD studies have shown that 20 micrograms of a nebulized formoterol fumarate inhalation solution was comparable to 12 micrograms of formoterol fumarate dry powder in patients with COPD [65c]. The former transiently reduced the mean serum potassium concentration and increased the mean serum glucose in a dose-related manner. There were no clinically significant electrocardiographic changes, but mean heart rate increased by up to 6/minute after a total dose of nebulized formoterol of 244 micrograms. In a 12-month open study of the long-term safety of nebulized formoterol [66C] there was no significant difference between twicedaily nebulized formoterol 20 micrograms bd compared with formoterol fumarate dry powder 12 micrograms. There were exacerbations of COPD in 16% and 18% respectively. Deaths, serious adverse events, and withdrawals because of adverse events occurred in 1.3%, 16%, and 5.4% with nebulized formoterol compared with 1.9%, 18%, and 7.5% with inhaled formoterol. There were no clinically important changes in serum potassium or glucose, and no treatmentrelated increases in cardiac dysrhythmias, heart rate, or QTc interval.

Indacaterol

[SEDA-32, 317]

Comparative studies Indacaterol versus formoterol In a comparison of once-daily indacaterol and twice-daily formoterol in patients with COPD, indacaterol had a

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greater effect on inspiratory capacity [67c]. Cough was the commonest adverse event; it occurred most frequently with indacaterol (20%) compared with placebo (3.3%) and formoterol (none).

Salmeterol

[SED-15, 3099; SEDA-30,

202] Combination studies Salmeterol þ an inhaled glucocorticoid In a meta-analysis of asthma-related deaths in patients taking salmeterol compared with those taking nonLABA comparators, there were 35 deaths in 106 575 subjects [68M]. Two studies (SMART and SNS) contributed 30 of these deaths and therefore dominated the metaanalysis. The odds ratio for asthma mortality with salmeterol was 2.7 (CI ¼ 1.4, 5.3). The relative risk of death from asthma in patients who had not used inhaled glucocorticoids was 7.3 (CI ¼ 1.8, 29.4). In patients who had used inhaled glucocorticoids, the relative risk of death was 2.1 (CI ¼ 0.6, 7.9). In 63 studies in which patients were randomized to salmeterol þ fluticasone or inhaled glucocorticoids, there were no asthma deaths in 22 600 patients. The authors concluded that salmeterol monotherapy in asthma increases the risk of asthma mortality and that the risk is reduced by concomitant use of an inhaled glucocorticoid. There is no evidence that salmeterol þ fluticasone is associated with increased asthma mortality, although the statistical power of available studies was low. In a Cochrane review of salmeterol for at least 12 weeks added to inhaled glucocorticoids versus inhaled glucocorticoids alone in 10 873 adults and 1173 children, there were no significant differences in fatal or non-fatal serious adverse events in those who used salmeterol þ an inhaled glucocorticoid and there were no asthma-related deaths [69M]. The number of adverse events was too small to assess whether the increase in all-cause non-fatal serious adverse events found in previous metaanalysis of regular salmeterol alone is abolished by additional use of inhaled

Gwyneth A. Davies and Mike Pynn

glucocorticoids. The GSK website, comparing salmeterol with placebo in 14 studies (n ¼ 14 983), has reported deaths in only two adult studies [28C, 70C]. There were 44 deaths with salmeterol compared with 33 with placebo. The pooled OR was not statistically significant (1.33; CI ¼ 0.85, 2.10). The results of a systematic review (n ¼ 74 092) have reinforced the view that LABAs cannot be prescribed as monotherapy: although serious exacerbations were reduced, there was a contrasting increase in asthma-related deaths (RR ¼ 3.83; CI ¼ 1.21, 12) [71M]. A LABA þ an inhaled glucocorticoid reduced exacerbations and hospitalizations and was equivalent to inhaled glucocorticoids in terms of life-threatening episodes and asthmarelated deaths. However, despite the protective effect of inhaled glucocorticoids, children and those who used salmeterol had an increased risk of non-fatal serious adverse events. In a meta-analysis of trials lasting over 12 weeks (n ¼ 20 966) there was no evidence of increased serious adverse events with salmeterol [72M]. There was a reduced risk of severe exacerbations and no increased risk of asthma-related hospitalization. Asthmarelated deaths and intubations were too few (one of each in those taking a LABA alone) to draw conclusions. In 18 patients with mild allergic asthma, salmeterol increased serum and platelet concentrations of neurotrophin brain-derived neurotrophic factor (BDNF), which may underlie the adverse effects of monotherapy on airway responsiveness in asthma [73c]. In summary, salmeterol monotherapy in asthma increases the risk of asthma mortality, and this risk is reduced by concomitant use of an inhaled glucocorticoid. There is no evidence that combination salmeterol þ fluticasone in adults is associated with increased risks of serious adverse events or asthma mortality, although the latter conclusion is limited by low statistical power in the available studies. There may be an increased risk of non-fatal serious adverse events in children using salmeterol.

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A lack of large, well-designed, prospective, controlled studies of the asthma-related risks associated with LABAs makes it difficult to reach a consensus regarding their best use in asthma [74R]. Further data are needed in relation to fatal or near-fatal events. Clinical judgement is needed to weigh the symptomatic benefits of add-on LABAs to inhaled glucocorticoids in the context of persistent uncertainty regarding potential adverse effects. Combination of a LABA þ an inhaled glucocorticoid remains a mainstay of asthma treatment (step 3); LABA monotherapy is contraindicated.

ANTICHOLINERGIC DRUGS [SEDA-30, 203; SEDA-31, 311; SEDA-32, 318]

Tiotropium bromide [SED-15, 3433; SEDA-30, 203, SEDA-31, 311; SEDA-32, 319] Combination studies In a randomized study in 225 patients who were given tiotropium, formoterol, or the combination over 12 weeks, there was no difference in adverse events with the addition of a LABA [75c]. There were no significant differences in the numbers of adverse events, including cardiovascular events, between the groups. In a comparison of tiotropium þ formoterol versus salmeterol þ fluticasone in 605 long-term smokers with chronic obstructive pulmonary disease (COPD) aged over 40 years, adverse events were not significantly different between the groups [76C]. Placebo-controlled studies In a randomized placebo-controlled study of tiotropium, formoterol, or the combination for 6 months in 847 patients with COPD aged over 40 years, adverse events were no different between the groups; combination therapy did not appear to confer any additional risk [77C]. In a placebo-controlled comparison of tiotropium administered by two different

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devices (Handihaler and Respimat) in 207 patients with COPD over 30 weeks, there were more withdrawals because of adverse events with placebo (8.2% versus 1.6–2.1%); adverse reactions were comparable between the inhaler devices [78C]. Systematic reviews Inhaled tiotropium has gained widespread acceptance in the treatment of COPD and is now recommended by the UK National Institute for Health and Clinical Excellence (NICE) as a therapeutic option for those who are still symptomatic despite the use of short-acting bronchodilators. In 2009 a large metaanalysis of 20 phase III and IV placebocontrolled studies of the tiotropium Handihaler in 17 041 patients updated the evidence in this area [79M]. Inclusion criteria were duration of treatment over 4 weeks, patients aged over 40 years with more than a 10 pack-year smoking history, and a diagnosis of COPD evidenced by airway obstruction on spirometry. Other respiratory medications were permitted. Overall there was a lower incidence of adverse events in the active treatment group versus placebo, expressed as a rate difference (RD) per 100 patient-years at risk and 95% confidence intervals (17; 22,  12) with a non-significant reduction in serious adverse events (1.41;  2.8, 0.0) and a significant reduction in fatal events (0.63;  1.14, 0.12). This included a lower risk of respiratory events ( 14;  17,  12) and major adverse cardiovascular events (0.45; 0.85, 0.05). Typical anticholinergic drug effects were highlighted and included increased risks of dry mouth (1.68; 1.28, 2.03), constipation (0.34; 0.04, 0.64), gastrointestinal obstruction (0.15; 0.01, 0.28), and pharyngitis (0.73; 0.06, 1.4). Urinary symptoms were also more likely in those taking tiotropium, including dysuria (0.016; 0.05, 0.27). However, unlike in previous studies, although there was a trend towards an increased risk of urinary retention it was not statistically significant. In a meta-analysis of 11 randomized controlled trials in a total of 1006 Chinese

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patients with COPD who had taken treatment for at least 4 weeks compared with either placebo or ipratropium, the most common adverse effects were anticholinergic, including dry mouth and urinary retention [80M]. Although there was a trend to an overall increased risk of adverse events with tiotropium, it did not reach significance (RR ¼ 1.16; 0.76, 1.77).

Cardiovascular risks of inhaled anticholinergic drugs The risk of adverse cardiovascular events during the use of inhaled anticholinergic drugs was reviewed in SEDA-32 (p. 318). Further information has come to light in this controversial area. Ipratropium bromide The Lung Health Study was the first randomized controlled trial to suggest an increased risk of adverse cardiovascular outcomes with anticholinergic drugs [81C]. Conducted over 5 years, it examined the benefits of ipratropium bromide and smoking cessation versus placebo and noted a higher risk of supraventricular tachycardia and cardiovascular morbidity and mortality in smokers randomized to the anticholinergic drug. However, it has been argued that the cardiovascular mortality outcomes were not adjusted for multiple end-points. Nor was a dose–response relation established. Furthermore, post-hoc analysis of adherence to inhaler therapy showed that although the risk of supraventricular tachycardia and subsequent hospitalization was strongest in those who were most compliant with therapy, overall cardiovascular morbidity and mortality appeared to be centred on patients who were noncompliant [82r]. In a case–control study of 2242 patients discharged from hospital with asthma, treatment with ipratropium bromide at discharge was associated with an increased risk of death, specifically related to cardiovascular events [83C].

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In a nested case–control study in US Veterans with COPD identified by the National Veterans Affairs database who were followed up between 1999 and 2004, the relation between the use of various respiratory medications and cause of death was examined [84C]. There was an association between all-cause mortality and ipratropium bromide and more specifically cardiovascular deaths (OR ¼ 1.34; CI ¼ 1.22, 1.47); however, the study lacked critical baseline data, including lung function and smoking status. Later, a subset of the same cohort was examined to look at the effects of ipratropium on all cardiovascular events [85C]. The primary end-point was the time to first hospitalization because of a cardiac dysrhythmia, heart failure, or acute coronary syndrome. Of 82 717 veterans with COPD, 6234 had a cardiovascular event during the follow-up period, and this was significantly higher in those who had used ipratropium in the previous 6 months (HR ¼ 1.40; CI ¼ 1.30, 151). In those who had used ipratropium more than 6 months before there was no difference. This study had several limitations, including a lack of baseline data on other cardiovascular risk factors and data on COPD disease severity, including spirometry. Tiotropium A potential association with cardiovascular risk has been suggested for long-acting anticholinergic drugs. In a 2year randomized controlled study of the benefits of tiotropium versus fluticasone and salmeterol in 1323 patients with severe COPD, tiotropium was associated with significantly increased mortality (3% versus 6%), with an increase in cardiac events [86C]. However, in a case series that specifically studied stroke in relation to tiotropium, there was no association [87c]. In a large meta-analysis in 2008, in which data from 17 randomized controlled trials of either ipratropium bromide or tiotropium in 13 654 patients were pooled, further concerns arose [88M]. Placebo-controlled and alternative treatment studies were included and patients were followed up for 6 weeks to 5 years. The primary end-point was combined

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cardiovascular deaths, myocardial infarctions, and stroke. It was higher in those who had used anticholinergic drugs: 1.9% versus 1.2% on control therapy (RR ¼ 1.60; CI ¼ 1.22, 2.10). This appeared to be due to a significantly increased incidence of cardiovascular death or myocardial infarction, without a significantly increased risk of stroke. Most of the data on increased cardiovascular events came from the Lung Health Study (weight 51%), with the problems already highlighted above. It has been suggested that the contradiction between this study and that of subsequent meta-analyses could be explained first by the inclusion of ipratropium bromide trials [89r] and secondly by the inclusion of trials that compared tiotropium with inhaled glucocorticoids, which may reduce cardiovascular events [90C]. Some have argued that the study did not take into account differential drop-out rates: patients tended to drop out earlier from the placebo group and were therefore followed up for different periods of time, during which adverse events could have been reported. Methodological problems were also highlighted, including the double inclusion of 1000 patients (from the original study and a subsequent meta-analysis) [91r]. In a large randomized, placebo-controlled trial of tiotropium in 5994 subjects over 4 years, Understanding Potential Long Term Impacts on Function and Tiotropium (UPLIFT) [92C], a post-hoc analysis [93C] examined mortality and observed 792 deaths; there was a lower risk with tiotropium than with placebo (HR ¼ 0.84; CI ¼ 0.73, 0.97). In contrast to the previous meta-analysis, this included a reduction in cardiac mortality (HR ¼ 0.86; CI ¼ 0.75, 0.99). The meta-analysis of Chinese patients mentioned above found no increased risk of cardiovascular events in this population, but it included relatively small numbers and follow-up for only 6 months [80M]. In another meta-analysis of the cardiovascular effects of tiotropium, 19 randomized controlled trials in 18 111 participants were pooled to look at the primary end-point of major adverse cardiovascular events, cardiovascular deaths, non-fatal myocardial infarctions, or strokes [94M]. All the studies included tiotropium in one treatment arm,

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15 compared with placebo, two with combination therapy of salmeterol and fluticasone, and two with salmeterol. All the studies involved adults with COPD of varying degrees of severity who had used treatment for more than 4 weeks and for up to 4 years. Overall there was no difference in cardiovascular end-points (0.96; CI ¼ 0.82, 1.12). However, the authors noted an apparent modification of this risk with increasing smoking history, with a trend towards increased cardiovascular risk in patients with a greater than 55 pack-year history. They concluded that overall tiotropium does not appear to increase the risk of cardiovascular events or related mortality but that the potential interaction with other risk factors should be noted and caution exercised. In a meta-analysis of 30 placebo-controlled trials of duration 4 weeks to 4 years, the analysis involved 19 545 individuals who were randomized to tiotropium (n ¼ 10 846) as a dry powder inhaler (Handihaler) or a soft mist generating inhaler (Respimat) [95M]. There was lower all-cause mortality in the tiotropium group (RR ¼ 0.88; CI ¼ 0.77, 1.0). The main cardiovascular end-point was combined cardiovascular deaths, non-fatal myocardial infarctions, non-fatal strokes, and deaths (sudden death, sudden cardiac death, or cardiac death). The incidence of cardiovascular events was 2.15 per 100 patient-years in the treatment group versus 2.67 in the placebo group. The apparent reduction in events with tiotropium was significant (RR ¼ 0.83; CI ¼ 0.71, 0.98). The risk of myocardial infarction, cardiac failure, or stroke showed a trend towards reduction with tiotropium. There are conflicting data on the risk of adverse cardiovascular reactions to inhaled anticholinergic drugs. Some have argued that adverse reactions are seen more consistently in studies of short-acting drugs. Certainly, the more recent data on the longacting counterparts seems more reassuring. Adequately powered randomized control trials with cardiovascular safety as their primary end-point are needed. Urinary tract In 25 patients with COPD and co-existing benign prostatic

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hyperplasia, tiotropium had no adverse effects on lower urinary tract function [96c].

LEUKOTRIENE MODIFIERS [SEDA-30, 203; SEDA-31, 312; SEDA-32, 319]

Montelukast

[SED-15, 2384; SEDA-32,

319] Comparative studies Montelukast versus fluticasone and/or fluticasone þ salmeterol In a randomized controlled trial in preschool children with asthma-like symptoms fluticasone had a beneficial effect on symptoms and montelukast on blood eosinophils compared with placebo [97c]. There were more upper respiratory tract infections in both active treatment groups compared with placebo, and concomitant medication, such as antibiotics, was also more common in the active treatment groups. Placebo-controlled studies In a randomized placebo-controlled study of montelukast 4 or 8 mg in infants aged 3–24 months with symptoms of post-respiratory syncytial virus bronchiolitis over 20 months there was no benefit and no significant differences in clinical or laboratory adverse events compared with placebo [98C]. There were no significant differences in adverse events or suspected adverse reactions between montelukast 5 or 10 mg and placebo in Japanese patients with seasonal allergic rhinitis [99C]. Similar findings were reported in children with allergic rhinitis [100c]. Systematic reviews Montelukast has been examined in seven randomized controlled trials and their open extensions in 2751 children [101M]. Montelukast had a clinical and laboratory safety profile similar to placebo or active control/usual care therapies, which did not change with long-term use. Clinical/laboratory adverse events were generally mild and transient. The commonest adverse events included upper

Gwyneth A. Davies and Mike Pynn

respiratory infections, worsening asthma, pharyngitis, and fever in all groups. Respiratory Churg–Strauss syndrome There has been controversy regarding the association between leukotriene receptor antagonists and Churg–Strauss syndrome, and it has been unclear whether the association is causal or a result of unmasking as glucocorticoid therapy is withdrawn. Churg–Strauss syndrome was reported in a woman with a background of asthma and eczema, not on oral glucocorticoids, 5 weeks after starting montelukast therapy [102A]. Cutaneous leukocytoclastic vasculitis and eosinophilia completely resolved within 4 weeks of withdrawal. The relation between montelukast and the onset of Churg–Strauss syndrome has been examined in a retrospective casecrossover study in 78 patients. The odds ratios for Churg–Strauss syndrome were 4.5 (CI ¼ 1.5, 14) for montelukast, 3.0 (CI ¼ 0.8, 11) for LABAs, 1.7 (CI ¼ 0.5, 5.4) for inhaled glucocorticoids, and 4.0 (CI ¼ 1.3, 12.5) for oral glucocorticoids. However, positive estimates associated with asthma medications suggested potential confounding by a general escalation of asthma therapy before the onset of Churg–Strauss syndrome. The apparent association between montelukast and Churg–Strauss syndrome could also have been explained by the increasing use of this medication over time [103c]. In a systematic review 62 patients with Churg–Strauss syndrome were distinguished in terms of glucocorticoid use (nil/ unchanged/reduced) [104M]. Most of the patients in each group showed a clear temporal relationship between the start of leukotriene antagonist drug therapy and the onset of Churg–Strauss syndrome, with no evidence of pre-existing disease, suggesting that the association may be causal. Psychiatric The US FDA has stated that post-marketing cases of neuropsychiatric events have been reported for montelukast and zafirlukast [105S]. The events included agitation, aggression, anxiousness, dream abnormalities, hallucinations, depression,

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insomnia, irritability, restlessness, suicidal thinking and behavior, and tremor. The FDA recommended that patients should be informed of the potential for these events and requested a review of reports of suicidality in clinical trials of montelukast amidst their examination of several drug classes in this regard. The reviewers found no reports of completed suicide, and reports of possibly suicidalityrelated adverse events (PSRAEs) were rare on montelukast and similar to controls [106M]. As reported under conflicts of interest, employees of Merck and Co Inc were authors of this study, and a further retrospective analysis of Merck data in 11 673 adults and children taking montelukast showed that behavior-related adverse experiences (BRAEs) were infrequent in clinical trials of montelukast. The frequencies of patients with one or more behaviorrelated adverse experience were 2.73% and 2.27% in the montelukast and placebo groups respectively. The odds ratio for montelukast versus placebo was 1.12 (CI ¼ 0.93, 1.36). Serious events, including those that led to withdrawal, were rare. A further review of three randomized controlled trials showed no evidence of a negative effect of montelukast on emotional wellbeing, using quality of life rather than indices of depression [107R]. However, the studies that were included in these reviews were not originally designed to assess suicidality or behavior-related adverse events. The authors also pointed out that sufferers of asthma and atopy have a higher than usual incidence of psychological morbidity, and that such reports are not unexpected. Autacoids Possible montelukast-induced angioedema has been reported in a woman who had four such episodes over a month, with onset 5 days after starting montelukast [108A]. Given the history of severe allergies in this case, causality was uncertain. Pregnancy Outcomes in infants born to women who took montelukast during pregnancy have been compared with outcomes in the infants of disease-matched controls who used inhalers for a similar indication

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and women who did not have asthma and had not been exposed to any known teratogens in a prospective multicenter study [109C]. Of 180 montelukast-exposed pregnancies, there were 160 live births, 20 spontaneous abortions, and one major malformation. Birth weight was lower (304 g) in the babies of women who had taken montelukast, which was attributed to the severity of maternal asthma. Montelukast did not appear to increase the baseline rate of major malformations.

Pranlukast

[SED-15, 2908]

Comparative studies Pranlukast versus fexofenadine No clinically important adverse effects were seen in a comparison of pranlukast 60 mg bd and fexofenadine 120 mg bd (þ mequitazine in both groups) in non-asthmatic patients with Japanese cedar pollinosis, but the numbers were small [110c]. Pranlukast appeared to inhibit airway hyperresponsiveness whereas fexofenadine did not. Pranlukast versus montelukast There was no significant difference in adverse events between pranlukast 450 mg and montelukast 5 or 10 mg in a double-blind non-inferiority study in seasonal allergic rhinitis [111C]. Diarrhea, thirst, and somnolence were suspected adverse reactions that occurred in over 1% in any of the three groups. One patient in each montelukast group withdrew because of diarrhea, which was considered a serious adverse event and which resolved on withdrawal.

PHOSPHODIESTERASE TYPE IV INHIBITORS [SEDA29, 174; SEDA-30, 203; SEDA-31, 313; SEDA-32, 321]

Cilomilast

[SEDA-30, 203; SEDA-31, 313; SEDA-32, 321] Placebo-controlled studies In five phase III double-blind, randomized, placebo-controlled,

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parallel-group studies in patients with resistant asthma who were randomized to oral cilomilast 15 mg (n ¼ 2088) or placebo (n ¼ 1408) twice daily for 24 weeks, the mean change from baseline in FEV1 in those who took cilomilast was greater than that with placebo in all the studies (range 24–44 ml) [112R]. The effect on exacerbations of COPD was variable. And there were no significant changes in the primary end-points of the anti-inflammatory studies, although some anti-inflammatory activity was detected, including a reduction in tissue CD8þ T lymphocytes and CD68þ macrophages in airway biopsies. There was no consistent effect of cilomilast on hyperinflation. In all studies, gastrointestinal adverse events were reported more often in those who took cilomilast and they mostly occurred in the first 2 weeks. There were no serious adverse reactions. However, subsequent phase III studies failed to confirm the earlier results, and the development of cilomilast was terminated.

Roflumilast [SEDA-30, 203; SEDA-31, 313; SEDA-32, 321] Roflumilast has received approval from the European Medicines Agency (EMA) for use as maintenance treatment in severe COPD associated with chronic bronchitis with frequent exacerbations, as an add-on to bronchodilator therapy. In a pooled analysis of two identical multicenter randomized placebo-controlled trials, roflumilast (n ¼ 1537) and placebo (n ¼ 1534) were compared in patients with severe COPD with a chronic bronchitis phenotype and at least one exacerbation requiring glucocorticoids treatment in the previous year [113C]. Inhaled glucocorticoids, tiotropium, and theophylline were not allowed. Treatment with roflumilast increased the pre-bronchodilator FEV1 and reduced the rate of exacerbations. However, adverse events were more common in the intervention group (67% versus 62%), and withdrawal secondary to these effects; including headaches, nausea, and diarrhea,

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was more likely (14% versus 11%). The probability of withdrawal was higher during the first 12 weeks. There was weight loss in those who took roflumilast (mean 2.1 kg), whereas placebo treatment was associated with slight weight gain (0.08 kg). Weight reduction occurred in the first 6 months and was more marked in those who reported gastrointestinal adverse reactions or headache or in obese individuals. In two randomized controlled trials published simultaneously the benefits of roflumilast, in addition to the long-acting bronchodilators tiotropium (HELIOS trial, n ¼ 934) [114C] and salmeterol (EOS trial, n ¼ 744), were compared with placebo. The patients had moderate to severe COPD and did not require a history of recent exacerbation for inclusion. The addition of roflumilast to long-acting bronchodilators improved FEV1. In both studies roflumilast was associated with higher withdrawal rates and this was statistically significant in the EOS trial. The incidence of adverse events thought to be drug-related was also highest in the roflumilast treatment arms (18% and 12% when it was combined with salmeterol and tiotropium respectively versus 3% and 2% in the two placebo arms.) The main adverse reactions were diarrhea, nausea, and weight loss, 2 kg in the EOS trial and 1.8 kg in the HELIOS trial after 24 weeks. In contrast to the previous study, weight loss was not influenced by baseline BMI but was more common in those with adverse gastrointestinal effects. The trials to date suggest a NNT of 5 to prevent one exacerbation; however, such benefits have to be weighed against the significant adverse effects, although it has been argued that the adverse events that have led to withdrawal were transient and occurred early on in treatment. Weight loss in the 6-month trial was of similar magnitude to that in the 1-year trial suggesting that this is an early phenomenon. However, this adverse effect is of concern, especially in COPD, in which a low BMI is associated with a worse prognosis. On the other hand, this adverse effect has been suggested to be of some benefit and has been associated

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with a possible reduction in both blood glucose and glycosylated haemoglobin [115c]. Whether roflumilast is more efficacious than inhaled glucocorticoids in preventing exacerbations has yet to be determined, but currently clinicians have to weigh the adverse effects profile against the increased apparent risk of pneumonia with inhaled glucocorticoids [116r].

LIPOXYGENASE INHIBITORS Zileuton

[SEDA-15, 3717; SEDA-32, 322]

Psychiatric The US FDA has stated that post-marketing cases of neuropsychiatric events have been reported in patients taking zileuton [105S]. However, to date neuropsychiatric events in patients taking zileuton have not been specifically studied. It should be noted that patients with asthma have more psychological co-morbidity. Combination studies Add-on zileuton 600 mg qds has been evaluated in patients with asthma using fluticasone 250 micrograms þ salmeterol 50 micrograms in a pilot non-randomized, non-placebo, single-blind study [117c]. Three of 22 patients stopped taking zileuton because of headache and/or nausea. There were small increases in lung function with zileuton but no changes in symptoms or nitric oxide.

MUCOLYTICS

[SEDA-32, 325]

Systematic reviews In a Cochrane review of 28 trials in 7042 patients with COPD, oral mucolytic treatment was not associated with an increase in adverse events compared with placebo [118M]. In fact, the meta-analysis showed a significant effect in favor of the mucolytic drugs (OR ¼ 0.81;

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CI ¼ 0.70, 0.94) but this did not include data from several large studies, and the authors concluded that there is probably no difference from placebo. In a meta-analysis of 15 randomized controlled studies of erdosteine with various comparators, including placebo and other mucolytic drugs, in 1046 patients, 54 patients (10%) reported adverse events with erdosteine compared with 57 (11%) in the reference groups [119M]. Some of the trials were not double-blind. The most common adverse events were gastrointestinal complaints, namely nausea, epigastric pain or heartburn, and diarrhea. One patient reported taste loss with erdosteine. Equal numbers experienced allergic reactions (three in each group).

Non-prescription cough and cold medicines [SEDA-31, 314; SEDA-32, 326] Death All 90 unexpected infant deaths that occurred in Arizona in 2006 have been reviewed by the Arizona Child Fatality Program, in order to determine whether there was an association of death with over-the-counter cough and cold medications [120R]. There were 10 unexpected infant deaths associated with use of cold medications. The infants were aged 17 days to 10 months. Post-mortem toxicology found evidence of recent administration of pseudoephedrine, antihistamines, dextromethorphan, and/or other ingredients of cold medications. The families who had used these medications had sociodemographic risk factors, and 50% of them had limited English proficiency. Only four of the infants had received medical care for their current illness before death, and only one had had the over-the-counter medication prescribed by a clinician. This study has raised concerns regarding the role of the over-the-counter cough and cold medications in deaths and supports the recommendation that such medications should not be given to infants, and certainly not without consulting a clinician.

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17 Positive inotropic drugs and drugs used in dysrhythmias CARDIAC GLYCOSIDES [SED-15, 648; SEDA-30, 209; SEDA-31, 321; SEDA-32, 333] Placebo-controlled trials A new post-hoc analysis of the Digoxin Investigation Group (DIG) study has examined the effect of digoxin on mortality and hospitalization during the first year of follow-up in patients with chronic heart failure randomized to digoxin or placebo (3889 and 3899 respectively) [1C]. The rationale was that the median dose of digoxin (0.25 mg/day) and the target serum digoxin concentration (0.8–2.5 ng/ml) were higher than currently recommended, which in part may explain the lack of long-term mortality benefit of digoxin in the DIG trial. At 1 year all-cause mortality was 392 and 448 patients with digoxin and placebo respectively (HR in favour of digoxin ¼ 0.87; 95% CI ¼ 0.76, 0.995). Respective hazard ratios for cardiovascular and heart failure deaths were 0.87 (95% CI ¼ 0.76, 1.01) and 0.66 (95% CI ¼ 0.52, 0.85). All-cause hospitalization occurred in 1411 and 1529 patients taking digoxin and placebo respectively (HR ¼ 0.89; 95% CI ¼ 0.83, 0.96). Hospitalizations included a larger number of suspected cases of digoxin toxicity in those taking digoxin compared with those taking placebo (120 versus 36) and of atrioventricular block Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00017-9 # 2011 Elsevier B.V. All rights reserved.

or bradydysrhythmias (30 versus 5). Respective hazard ratios for cardiovascular and heart failure hospitalizations were 0.82 (95% CI ¼ 0.75, 0.89) and 0.59 (95% CI ¼ 0.52, 0.66). Thus, digoxin reduced 1-year mortality and hospitalization in patients with chronic heart failure taking angiotensin-converting enzyme inhibitors and diuretics. The authors’ hypothesis was not confirmed, as the serum digoxin concentration was not a strong predictor of adverse outcomes. However, the conclusions of this study were limited by the fact that the patients were relatively young and in sinus rhythm. Drug–drug interactions Eslicarbazepine In a double-blind, placebo-controlled, crossover trial in healthy volunteers, co-administration of eslicarbazepine, a blocker of voltage-gated sodium channels, which has been used in the treatment of epilepsy, had no clinically relevant effect on systemic exposure to digoxin; there was no significant effect on digoxin Cmax or steady-state plasma concentrations [2c]. Etoricoxib In a double-blind, randomized, placebo-controlled trial of the effects of etoricoxib 120 mg/day on the steady-state pharmacokinetics of digoxin 0.25 mg/day, etoricoxib increased digoxin Cmax by 33%, but did not affect steady-state digoxin concentration [3c]. There were no serious adverse effects. However, this study was carried out in 14 healthy volunteers aged 21–35, who are not representative of the real-world users of these drugs. 377

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Macrolides The interaction of digoxin with macrolide antibiotics in patients with digitalis toxicity has been investigated in two recent studies. The association between hospitalization for digoxin toxicity and recent exposure to individual macrolide antibiotics has been investigated in a 15year, population-based, nested case–control study [4c]. Clarithromycin was associated with the highest risk of digoxin toxicity (OR ¼ 15; 95% CI ¼ 7.9, 28), whereas erythromycin and azithromycin were associated with much lower risks. In another retrospective populationbased case-control study, data from the National Health Insurance Research Database were scrutinized in a search for patients with heart failure newly treated with digoxin between January 2001 and December 2004 who were hospitalized for digitalis toxicity; they were compared with the matched controls for use of clarithromycin [5c]. Prescription of clarithromycin before the index date was associated with increased risk of hospitalization for digoxin intoxication; the relative risks were 4.36 at 7 days (95% CI ¼ 1.28, 15), 5.07 at 14 days (95% CI ¼ 2.36, 11), and 2.98 at 30 days (95% CI ¼ 1.59, 5.63). The effect was dose related. Varenicline The effects of varenicline on the multiple-dose pharmacokinetics of digoxin have been investigated in 18 smokers who were randomized to digoxin 0.2 mg with varenicline 1 mg bd or placebo for 14 days [6c]. There were no adverse effects, and the authors suggested that digoxin can be safely administered with varenicline without the need for dosage adjustment. Management of adverse drug reactions As there are no evidence-based guidelines for treating patients with digoxin toxicity, differences among specialists in the use of digoxinspecific antibody fragments and the decision to admit these patients have been evaluated by asking cardiologists, emergency physicians, and medical toxicologists about their practices [7c]. There were significant differences among clinicians in various specialties regarding the treatment of chronic digoxin

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toxicity, which may reflect diverse perspectives or knowledge gaps and may translate into excess costs or less than ideal care. The efficacy and safety of a step-by-step fixed dose protocol for digoxin-specific Fab fragments in the management of digoxin toxicity has been investigated in an open uncontrolled prospective study in 20 elderly patients with acute or chronic digoxin intoxication [8c]. Two vials of specific antidigoxin antibody Fab fragments were administered on admission and repeated if after 1 hour the electrocardiographic signs of toxicity had not resolved. As 70% of patients needed only the first dose, the authors suggested that this protocol is as effective as an equimolar dose of Fab fragments, with significant cost reduction. Although hyperkalemia is often treated with intravenous calcium, this is traditionally contraindicated in digoxin toxicity, although this dogma has been questioned (SEDA-32, 335). In a retrospective analysis of the records of patients who were given intravenous calcium while suffering from digoxin toxicity, there were no life-threatening dysrhythmias within 1 hour of calcium administration and mortality was similar among those who did not receive calcium (27/136, 20%) and those who did (5/23, 22%) [9c]. This confirms that in acute digoxin intoxication intravenous calcium does not seem to cause malignant dysrhythmias or increase mortality.

OTHER POSITIVE INOTROPIC DRUGS

[SED-15, 2822; SEDA-30, 212; SEDA-31, 323; SEDA-32, 336]

Milrinone

[SED-15, 2346; SEDA-30, 212; SEDA-31, 323; SEDA-32, 336] Cardiovascular Atrial fibrillation Postoperative atrial fibrillation is a frequent complication after cardiac surgery. Inotropic drugs are commonly used perioperatively

Positive inotropic drugs and drugs used in dysrhythmias

to support ventricular function. In a retrospective analysis of 232 patients who underwent cardiac surgery, the use of milrinone was associated with a significantly increased risk of postoperative atrial fibrillation (58% versus 26% in non-users) [10C]. Older age (63 versus 57 years), hypertension, a lower preoperative ejection fraction, mitral valve surgery, right ventricular dysfunction, and a higher mean pulmonary artery pressure (27 versus 22 mmHg) were also associated with postoperative atrial fibrillation. A multivariable logistic regression analysis showed that age, ejection fraction, and use of milrinone (OR ¼ 4.86; 95% CI ¼ 2.31, 10) independently predicted postoperative atrial fibrillation. Ventricular dysrhythmias and hypotension In a retrospective study of 60 patients listed for cardiac transplantation, pre-treatment at home with intravenous milrinone was an effective strategy as a bridge to transplant if the waiting time was short (mean 60, range 9–257 days) [11C]. There were adverse effects potentially due to milrinone in two cases: syncopal episodes and discharge of an automated implantable cardioverter defibrillator.

ANTIDYSRHYTHMIC DRUGS ADENOSINE AND ANALOGUES [SED-15, 36; SEDA-30, 212; SEDA-31, 323; SEDA-32, 337]

Cardiovascular Atrial fibrillation is an infrequent complication of adenosine treatment of supraventricular dysrhythmias, but is rare when it is used for diagnostic purposes. In a series of adenosine stress tests, atrial fibrillation occurred in 8 (0.41%) of 1948 patients and lasted from 15 seconds to 6 hours; there was spontaneously reversion to sinus rhythm in all cases [12c]. Ventricular extra beats and/or ventricular tachycardia are prodysrhythmic effects

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of adenosine in terminating supraventricular tachycardia. In 46 patients ventricular tachycardia occurred in 8 (17%); it was always polymorphic, short-lived, and selfterminating [13c].

Respiratory The safety of adenosine in myocardial perfusion testing as an alternative to dipyridamole, which is contraindicated in patients with obstructive airways disease, has been examined in 46 consecutive patients who received intravenous adenosine 140 mg/kg/minute for 4 minutes; only 14 complained of chest discomfort and nine had dyspnea; none required intravenous aminophylline or resuscitation [14c].

Gastrointestinal Adenosine can cause reduced esophageal distensibility and visceral hyperalgesia, producing symptoms similar to those described in patients with functional esophageal noncardiac chest pain. In 14 healthy volunteers who were studied by stepwise graded esophageal balloon distension with impedance planimetry before and after receiving placebomatched intravenous adenosine 100 mg/kg/ minute, adenosine significantly lowered the thresholds for first perception, discomfort, and pain; the cross-sectional area of the esophagus increased and the esophageal wall became stiffer after adenosine [15c].

Adenosine receptor agonists [SEDA-30, 213; SEDA-31, 324; SEDA-32, 337]

Binodenoson Placebo-controlled studies In a doseescalating, double-blind, placebo-controlled study, young adults with mild intermittent

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asthma were randomly assigned to either binodenoson 1.5 micrograms/kg (n ¼ 41) or placebo (n ¼ 22) [16C]. Binodenoson caused no clinically significant bronchoconstriction or alterations in pulmonary function and transiently increased heart rate and systolic blood pressure. The most common treatment-emergent adverse events were tachycardia, dizziness, and flushing.

Regadenoson Observational studies The effects of age, sex, body mass index, and diabetes on the effects of regadenoson stress myocardial perfusion imaging have been studied on an analysis of a database of 2015 patients [17c]. Compared with adenosine, regadenoson had a lower combined symptom score and less chest pain, flushing, and throat, neck, or jaw pain, but more headache and gastrointestinal discomfort. Cardiovascular Patients who required myocardial perfusion imaging were randomized double-blind to low-level exercise with bolus intravenous injection of regadenoson (n ¼ 39) or placebo (n ¼ 21); there were adverse events in 77% and 33% respectively [18C]. Peak heart rate was 13/minute higher after exercise with regadenoson. There were no differences in changes in blood pressure, and no cases of second-degree or higher AV block. Respiratory In a double-blind, randomized, placebo-controlled, crossover study of regadenoson in 38 patients with moderate chronic obstructive pulmonary disease (COPD) and 11 with severe COPD, 18 of whom had dyspnea during activities of daily living, there were no differences between regadenoson and placebo on lung function; there was new-onset wheezing in 6% and 12% respectively, but none of the patients required acute treatment with bronchodilators or oxygen [19C]. The effects of regadenoson on airway resistance have been investigated in a doubleblind, randomized, placebo-controlled,

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crossover trial in patients with asthma and a positive adenosine monophosphate challenge test [20C]. The mean ratio of the FEV1 at each time tested relative to the baseline FEV1 was significantly higher after treatment with regadenoson than with placebo from 10 to 60 minutes after treatment. One patient had a 36% asymptomatic reduction in FEV1 after regadenoson, with spontaneous reversion. The most common adverse events with regadenoson were tachycardia (66%), dizziness (53%), headache (45%), and dyspnea (34%); mean heart rate increased significantly, up to a maximum of 10/minute.

Amiodarone [SED-15, 148; SEDA-30, 213; SEDA-31, 324; SEDA-32, 339] Observational studies In a 10-year prospective study of the effects of the timing of the introduction of amiodarone after corrective surgery for congenital heart defects, 71 of 2651 patients (2885 procedures, 2106 cardiopulmonary bypass procedures) received amiodarone for newly detected postoperative atrial tachydysrhythmias (n ¼ 70) or ventricular tachydysrhythmias (n ¼ 7) as “early treatment” (i.e. within 60 minutes from detection; n ¼ 29) or “late treatment” (i.e. after 60 minutes from detection; n ¼ 42) [21C]. There were significant benefits of early treatment for time to rate and rhythm control, reduction in the dose needed to obtain rate control, and reduction of pediatric cardiac intensive care stay. No adverse events in either group required additional catecholamine therapy, additional fluids, or resuscitation. In a randomized study of treatment with amiodarone for 6 days after pulmonary resection in 65 patients and 65 controls who received no amiodarone, there was a significant reduction in the frequency of atrial fibrillation in treated patients (14% versus 32%); there were no significant differences in the incidences of pulmonary complications or amiodarone-related adverse effects between treated and control patients (bradycardia in 4 versus 1 and QTc interval prolongation in 1 versus 0 respectively) [22c].

Positive inotropic drugs and drugs used in dysrhythmias

Systematic reviews In a systematic review of 15 randomized studies in 8422 patients, amiodarone reduced the risk of sudden cardiac death (7.1% versus 9.7%) and cardiovascular death (14% versus 16%) [23M]. Amiodarone increased the risk of pulmonary toxicity (2.9% versus 1.5%; OR ¼ 1.97) and thyroid toxicity (3.6% versus 0.4%; OR ¼ 5.68). Cardiovascular Amiodarone-induced torsade de pointes has been reported in a patient with Wolff–Parkinson–White syndrome who had been given intravenous amiodarone for a wide-complex tachycardia [24A]. Aas sinus rhythm was restored, QT interval prolongation and T wave alternans occurred, followed by symptomatic torsade de pointes. The dysrhythmia spontaneously terminated after discontinuation of intravenous amiodarone. Amiodarone-induced torsade de pointes occurred in a woman with decompensated liver cirrhosis, ischemic heart disease, and prolongation of the QT interval, who developed atrial fibrillation. After DC cardioversion and restoration of sinus rhythm, a new episode of atrial fibrillation was successfully treated with intravenous metoprolol, and the QT interval normalized [25A]. In a retrospective study of the potential for major adverse cardiovascular events in 57 patients with amiodarone-induced thyrotoxicosis compared with 224 euthyroid patients for a mean of 49 months, the patients with thyrotoxicosis had a higher rate of events (32% versus 11%), mostly driven by a higher rate of ventricular tachydysrhythmias requiring admission (7.0% versus 1.3%); overall, there was a 2.7 times increased risk [26c]. Thyrotoxicosis (HR ¼ 2.68) and a left ventricular ejection fraction below 45% (HR ¼ 2.52) were independent predictors of major adverse cardiovascular events. Acute cardiogenic shock with profound hypotension has been reported in a neonate who was given intravenous amiodarone for paroxysmal supraventricular tachycardia [27A]. • A 4-day-old neonate was given an intravenous loading dose of amiodarone erroneously prescribed at the oral dose (1200 mg/m2 ¼ 47 mg/kg).

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During the first 24 hours he developed acute cardiogenic shock, profound hypotension, myocardial ischemia, a severe encephalopathy, and multiple organ failure, with acute hepatic and renal insufficiency, which recovered within a few days.

The hypothesis that the two excipients, benzyl alcohol and polysorbate 80, precipitated cardiogenic shock seems plausible, particularly because the plasma concentrations of amiodarone and desethylamiodarone never reached toxic concentrations. Respiratory Amiodarone pulmonary toxicity has been described after lung transplantation [28A]. • A 61-year-old man with idiopathic pulmonary fibrosis underwent lung transplantation and received intravenous and oral amiodarone for recurrent postoperative atrial fibrillation. After 2 months he developed a bilateral pleural effusions and lung consolidation. There was high attenuation of the liver parenchyma, compatible with amiodarone deposition. Because of possible acute allograft rejection, he was given glucocorticoids. Bronchoscopy and bronchoalveolar lavage showed a white blood cell count of 36  106/l, with 52% neutrophils, 39% lymphocytes, 8% monocytes and no eosinophils. Blood cultures were negative. Transbronchial biopsies showed no evidence of rejection but there were intra-alveolar foamy macrophages. Right thoracentesis confirmed the presence of a sterile exudative pleural effusion. Withdrawal of amiodarone led to complete resolution of the pleural effusions and lung consolidation within 8 weeks.

In another case a post-mortem lung mass was found to be due to lymphoplasmacytic infiltrates in the alveolar walls and intraalveolar accumulation of foamy macrophages containing myelinoid bodies, suggesting that it was due to amiodarone [29A]. Amiodarone lung toxicity, exceedingly rare in children, has been described in a child with supraventricular tachycardia after repair of a transposition of the great vessels, who developed acute amiodaroneinduced pulmonary toxicity [30A]. Recent cardiac surgery, a high concentration of inspired oxygen during mechanical ventilation, and chest trauma were considered associated susceptibility factors.

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As interferon gamma (IFN-g: Th1 cytokine) inhibits pulmonary fibroblast proliferation, whereas interleukin-4 (IL-4: Th2 cytokine) augments fibroblast growth and collagen production, it has been hypothesized that amiodarone-induced lung toxicity is related to the balance of Th1/Th2. In 26 Japanese patients, six with and 20 without radiological signs of amiodarone lung toxicity, the Th1/Th2 balance was investigated by measuring the ratio of IFNg and IL-4 produced by activated peripheral CD4þ T cells [31cH]. The Th1/Th2 balance was significantly different and was the most powerful indicator of amiodarone-induced subclinical lung toxicity. Nervous system In a retrospective study of the medical records of 707 patients treated with amiodarone over 151 months, there was a cumulative incidence of probable amiodarone-induced neurotoxic effects in 2.8%, 1.6% being referred to a neurology department. The neurological problems included tremor, gait ataxia, peripheral neuropathy, and cognitive impairment. The primary susceptibility factor for amiodaronerelated toxicity was duration of treatment, not age, dose, sex, or indication. However, the higher incidence of neurotoxic effects that was observed when amiodarone was first introduced may have been related to a much higher daily dose [32C]. Amiodarone-associated neurotoxicity has been reported [33A]. • A 76-year-old man developed ataxia after taking amiodarone hydrochloride 400 mg orally tds for more than 2 months, intended as a loading dosage. The ataxia lessened over the first 2 weeks after the amiodarone was withdrawn and resolved completely within 5 months.

This case emphasizes the need for strict monitoring of patient adherence to the scheduled loading dose period. Sensory systems Cornea verticillata has been studied in 22 patients with Fabry disease and in 11 patients taking amiodarone, comparing the corneal microstructure in both types [34c]. Confocal laser-scanning

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microscopy showed the same pattern of hyper-reflective deposits in the basal cell layer of corneal epithelium in both sets of patients. Microdot changes in the anterior stroma were more prevalent in those who were taking amiodarone.

More about amiodarone-induced thyrotoxicosis and its management Diagnosis Amiodarone-induced thyrotoxicosis occurred in a patient with an autonomously functioning nodular goiter [35A]. • A 64-year-old woman with atrial fibrillation and a nodular goiter developed overt thyrotoxicosis after taking amiodarone 200 mg/day for less than 12 weeks. A thyroid scan showed a hyperfunctioning nodule in the left lobe, and the thyroid-stimulating hormone (TSH) receptor antibody titer was transiently raised. Amiodarone was withdrawn and she was given propylthiouracil 100 mg tds, but developed a severe generalized rash, a fever, and leukocytosis after 4 weeks. Thyroidectomy was performed, and histopathology was compatible with type 1 amiodarone-induced thyrotoxicosis.

Differentiating between the two types of thyrotoxicosis is difficult but important for implementation of the correct therapeutic strategy. Amiodarone should be avoided in patients with toxic nodular goiters and subtotal thyroidectomy may be the treatment of choice. A patient taking amiodarone for atrial fibrillation developed hyperthyroxinemia, which led to a diagnosis of thyroid hormone resistance syndrome [36A]. Although thyroid hormone resistance is not a complication of amiodarone treatment, hyperproduction of hormone, accompanied by high concentrations of thyroid hormone without TSH suppression, is a rare genetic disorder that is worth being aware of. Presentation Atrial fibrillation can be induced by amiodarone-induced thyrotoxicosis even some time after drug withdrawal, as has been described in a patient who had taken oral amiodarone for 2.5 years for ventricular dysrhythmias, in whom it had been withdrawn 6 months before [37A].

Positive inotropic drugs and drugs used in dysrhythmias

Pathophysiology Concentrations of amiodarone and desethylamiodarone were measured simultaneously in plasma and fat in 30 patients who had taken amiodarone for 3 months to 12 years [38c]. Amiodarone concentrations in fat were 4–226 (mean 55) times higher than in plasma, and correlated with plasma concentrations (r ¼ 0.68). Nine of 12 patients who had taken amiodarone for at least 2 years developed clinically important adverse reactions, predominantly hypothyroidism (n ¼ 6), compared with two of 18 patients who had taken it for less time (RR ¼ 6.75; 95% CI ¼ 1.8, 26). The risk of adverse reactions did not correlate with amiodarone concentrations in plasma or fat. Management Glucocorticoids are the firstline treatment in type 2 amiodarone-induced thyrotoxicosis, and thionamides play no role. In a matched retrospective cohort comparison of the efficacy of a thionamide (methimazole) or a glucocorticoid (prednisone) for 40 days in type 2 amiodaroneinduced thyrotoxicosis, in 42 patients, 23% of those who took prednisone were still thyrotoxic, compared with 86% of those who took methimazole [39C]. When those who had taken methimazole were then given prednisone, 94% achieved euthyroidism within another 40 days. The American Thyroid Association has investigated how North American thyroidologists assess and treat amiodarone-induced thyrotoxicosis and has compared the results with those of a survey using the same questionnaire previously carried out among European thyroidologists [40C]. Most of the respondents (91% versus 68% in Europe) see under 10 new cases of amiodaroneinduced thyrotoxicosis per year, which seems to be less common than amiodarone-induced hypothyroidism in North America (34% and 66% of amiodarone-induced thyroid dysfunction respectively, compared with 75% and 25% in Europe). When thyrotoxicosis is suspected in North America hormonal assessment is mostly based on measurements of serum-free T4 and TSH, while serum-free T3 determination is requested less often than

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in Europe; thyroid autoimmunity is included in the initial assessment less than in Europe. Withdrawal of amiodarone is more often considered unnecessary by North American thyroidologists in type 1 amiodaroneinduced thyrotoxicosis (which occurs in patients with latent disease, due to the iodine contained in amiodarone) than in type 2 amiodarone-induced thyrotoxicosis (which is due to destructive thyroiditis in a previously normal gland): 21% versus 10% in Europe in type 1; 34% versus 20% in type 2. In type 1 thyrotoxicosis thionamides represent the treatment of choice in North America and Europe, but as monotherapy in 65% compared with 51%; European thyroidologists more often consider potassium perchlorate as a useful addition (31% versus 15%). Glucocorticoids are the selected treatment for type 2 thyrotoxicosis, either alone (62% vs. 46% in Europe) or in association with thionamides (16% versus 25%). After restoration of euthyroidism, thyroid ablation in the absence of recurrent thyrotoxicosis is recommended in type 1 less often in North America. If amiodarone needs to be restarted, prophylactic thyroid ablation is advised by 76% in type 1 thyrotoxicosis, while a wait-and-see strategy is adopted by 61% in type 2, as in Europe. This survey shows differences in therapeutic attitudes, which reflect the frequent uncertainty of the underlying mechanism that leads to amiodarone-induced thyrotoxicosis. Liver In a Bayesian approach, linking information from clinical trials with hepatotoxicity from published case reports, the maximum number of expected cases of hepatotoxicity in patients taking amiodarone or placebo was calculated using a Poisson distribution [41H]. The calculated odds ratio was used as a prior for the subsequent quantification of the likelihood of amiodarone-induced hepatotoxicity in individuals. The prior odds of amiodaroneinduced hepatotoxicity was 0.48. The Bayesian model combined information about the latency period and the period of remission, together with analytical parameters that properly defined the toxicity

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profile reported in a series of 39 cases. The analytical pattern defined by this model was different from that expected if liver injury in published cases had been due to other causes. This method deserves further evaluation using a larger database. Amiodarone has been associated with steatohepatitis with advanced fibrosis, presenting with hepatic decompensation and portal hypertension, with ascites and recurrent hemorrhage from esophageal varices [42A]. There was marked histological similarity between amiodarone-induced liver disease and alcoholic and non-alcoholic steatohepatitis. Immunologic Amiodarone is contraindicated in patients with hypersensitivity to intravenous contrast media. Three patients with previous reactions to contrast media had no adverse reactions during prolonged amiodarone treatment 100–200 mg/day [43A]. Poor absorption of oral amiodarone and reactions to other components of contrast media besides iodine, causing histamine release, could explain this lack of cross-reactivity. Drug dosage regimens In a randomized study of the major events that occurred in 209 patients who received episodic or continuous amiodarone for prevention of atrial fibrillation after electrical cardioversion following amiodarone loading, with a median follow-up of 2.1 years, only 48% of the patients who took episodic treatment were in sinus rhythm, compared with 64% of those on continuous treatment [44C]. The causes of amiodarone withdrawal were not significantly different (20/106 during episodic treatment and 25/103 during continuous treatment). Hyperthyroidism and hypothyroidism were the most frequent adverse effects (in 11 and 10 patients respectively). Thus, episodic treatment with amiodarone appears to be less effective in the prevention of atrial fibrillation recurrences without any advantage in terms of adverse effects. Drug–drug interactions Enalapril In a study of the combined use of amiodarone

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100–200 mg/day with enalapril 5 mg/day in 58 patients with paroxysmal atrial fibrillation, adverse reactions to amiodarone that required drug withdrawal included only interstitial pneumonia in two subjects (3.4%) and a rash in one (1.7%) [45c]. Haloperidol In a series of 381 patients there was a small, potentially significant prolongation of the QTc interval in 49 of them who were taking amiodarone and haloperidol, but there were no tachydysrhythmias; in 138 other patients who were taking at least one other drug that prolongs the QT interval, there was no apparent effect [46c]. Monitoring therapy In a retrospective chart review of antidysrhythmic drug therapy in patients taking class I or class III antidysrhythmic drugs, adherence to monitoring protocols was assessed, and the type and frequency of pharmacist-identified events and interventions were determined [47c]. In all, 134 patients were studied, including 58 taking amiodarone, 40 taking sotalol, 28 taking dofetilide, and 8 taking propafenone. Amiodarone was associated with the highest rate of adverse events (23% of patient visits). A change in the antiarrhythmic medication regimen was recommended for nine patients and resulted in drug withdrawal in three.

Bepridil

[SED-15, 445; SEDA-31, 329]

Respiratory Three cases of interstitial pneumonia have been described in Japanese patients during treatment with bepridil. In one case, exertional dyspnea developed over 8 months and transbronchial lung biopsy specimens showed moderate lymphocytic infiltration; glucocorticoid therapy led to resolution in 3 weeks [48A]. The other two patients developed pneumonia after 20 and 60 days; one required glucocorticoid treatment and the other was discharged having improved after bepridil withdrawal [49A].

Positive inotropic drugs and drugs used in dysrhythmias

Cibenzoline

[SED-15, 740; SEDA-30, 217; SEDA-31, 330; SEDA-32, 347]

Nervous system Acute myasthenia has been reported in a Japanese patient with chronic renal dysfunction [50A]. • A woman in her late 60s with chronic kidney disease was given cibenzoline 300 mg/day for atrial fibrillation. After 3 days, she developed blepharoptosis. Anti-acetylcholine receptor antibodies were not found and an edrophonium test was negative. She developed pneumonia with a pleural effusion and diarrhea, and her renal function worsened. At the same time, her blepharoptosis worsened and she developed a dull headache, weakness, and difficulty in chewing. Dyspnea was accompanied by hypercapnia. Cibenzoline was withdrawn. Her condition improved and she was taken off the respirator on day 35. Repetitive stimulation of 5 Hz was applied to her right facial nerve along with evoked electromyography on days 2 and 11 after withdrawal of cibenzoline. On day 2, electromyography showed a waning phenomenon, whereas no such phenomenon was seen on day 11. The blood concentration of cibenzoline immediately after withdrawal was extremely high (2448 ng/ml).

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50–60%. However, when both drugs were applied together, the KATP channels were almost completely closed. Dramatic inhibition of KATP channels is sufficient to cause membrane depolarization in the pancreatic beta cells and stimulate insulin secretion. Monitoring therapy The relation between the anticholinergic effects of disopyramide and serum concentrations of disopyramide or its metabolite mono-N-dealkyldisopyramide have been studied in 141 in-patients [53c]. There was no correlation of creatinine clearance and the ratio of the serum concentration to the dose of disopyramide, but a significant inverse correlation between creatinine clearance and the concentration to dose ratio of the metabolite. There was no significant difference in disopyramide concentration between patients with and without anticholinergic adverse effects, but there were significant differences in the metabolite concentration, creatinine clearance, and the ratio of metabolite to parent. The authors recommended that when the serum concentration of the metabolite is over 1 mg/l, disopyramide should be discontinued or the dose reduced.

Disopyramide

[SED-15, 1145; SEDA-30, 217; SEDA-32, 347]

Musculoskeletal Myasthenia gravis, in a patient with pre-existing disease, was exacerbated after the use of disopyramide for atrial fibrillation, followed by a takotsubo-shaped cardiomyopathy, QT interval prolongation, and torsade de pointes [51A]. Drug–drug interactions Sulfonylureas Severe hypoglycemia occurred in a 62-year-old woman with type 2 diabetes taking lowdose glimepiride after disopyramide was introduced; she had no further episodes occurred after withdrawal of disopyramide [52AE]. Current recordings of KATP channels expressed in Xenopus oocytes showed that at concentrations that are associated with clinical benefit, disopyramide and glimepiride both inhibited KATP channels by

Dofetilide

[SED-15, 1173; SEDA-30, 217; SEDA-32, 347]

Cardiovascular One case of torsade de pointes was observed in a series of 160 patients taking dofetilide, mean dose 428 mg/dose, for chemical cardioversion of atrial fibrillation or flutter, 50 of whom were also taking magnesium sulfate in an attempt to improve the chance of success [54c]. The addition of magnesium sulfate resulted in a 107% increase in success rate. However, the patient with the dysrhythmia did not receive magnesium sulfate. In another efficacy study in 36 patients accepted for ablation of atrial fibrillation who started taking dofetilide before the procedure and 91 who were given dofetilide after ablation, six stopped taking it

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because of QT interval prolongation without dysrhythmias [55c].

Dronedarone Many amiodarone congeners have been developed over a long period in the hope of overcoming its frequent, often severe, multiorgan adverse effects. Among them, dronedarone has been the most promising. It is a non-iodinated benzofuran derivative, characterized, in comparison with amiodarone, by deletion of the two atoms of iodine and the addition of a methylsulfonyl group [56R]. Dronedarone shares most of its electrophysiological and pharmacological properties with amiodarone, prolonging the action potential duration by blocking Naþ and Ca2þ channels. It has a nonspecific sympatholytic effect and slows the sinus rate by inhibiting spontaneous phase 4 depolarization. Dronedarone has a serum half-life of about 24 hours, compared with 50 days or longer of amiodarone. The active metabolite of amiodarone, desethylamiodarone, accumulates in tissues, whereas debutyldronedarone, the principal metabolite of dronedarone, does not accumulate significantly in plasma or tissues. Desethylamiodarone has a strong inhibitory effect on the triiodothyronine (T3) receptor, whereas debutyldronedarone has a weak effect [57C]. In two randomized, controlled trials in 1237 patients with atrial fibrillation or flutter, the European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm (EURIDIS, NCT00259428) and the American–Australian–African Trial with Dronedarone in Atrial Fibrillation or Flutter Patients for the Maintenance of Sinus Rhythm (ADONIS NCT00259376), dronedarone was more effective than placebo in maintaining sinus rhythm and in controlling the ventricular rate during recurrences of atrial fibrillation [58M]. At 12 months of follow-up, the rates of pulmonary, thyroid, and hepatic adverse effects were not significantly greater with dronedarone than with placebo; there was a higher incidence of raised serum creatinine

Chapter 17

A. Finzi

with dronedarone than with placebo (2.4% versus 0.2%). However, another study of dronedarone in patients with advanced symptomatic congestive heart failure, but without atrial fibrillation, was prematurely terminated because of an excess number of deaths among those taking dronedarone [59C]. Adverse effects of dronedarone were not responsible for this outcome, and an increased serum creatinine concentration in eight patients versus none in the placebo group was the only significant difference between the treated and untreated patients. The ATHENA trial was a placebo-controlled, double-blind, parallel-arm trial to assess the efficacy of dronedarone 400 mg bd for the prevention of cardiovascular hospitalization or death from any cause in patients with atrial fibrillation/atrial flutter [60C]. Treatment was prematurely withdrawn in 696 of the 2301 patients (30%) taking dronedarone, compared with 716 of the 2327 (30.8%) taking placebo. The main reasons were treatment-emergent adverse events (in 13% of those taking dronedarone versus 8.1% of those taking placebo), gastrointestinal events (26% versus 22%), skin related events (10% versus 7.6%), raised serum creatinine (4.7% versus 1.3%), and QT interval prolongation (1.7% versus 0.6%). In a meta-analysis of randomized controlled studies of dronedarone and amiodarone for prevention of recurrent atrial fibrillation, four placebo-controlled trials of dronedarone, four placebo-controlled trials of amiodarone, and one trial of dronedarone versus amiodarone were compared [61M]. Amiodarone was superior to dronedarone in preventing recurrent atrial fibrillation, but there was a trend towards greater all-cause mortality (OR ¼ 1.61; 95% CI ¼ 0.97, 2.68) and more overall adverse events requiring drug withdrawal with amiodarone than with dronedarone (OR ¼ 1.81; 95% CI ¼ 1.33, 2.46). Among adverse reactions, thyroid toxicity was more frequent with amiodarone (7.5% versus 4.0%) whereas increased serum creatinine was more frequent with dronedarone (4.0% versus 0%). For every 1000 patients treated with dronedarone instead of amiodarone, the authors estimated that there were about

Positive inotropic drugs and drugs used in dysrhythmias

228 more recurrences of atrial fibrillation in exchange for 9.6 fewer deaths and 62 fewer adverse events requiring drug withdrawal. This meta-analysis prompted comments and criticisms with regard to the imbalance in the number of trials with amiodarone and dronedarone and their patient populations [62r]. However, although further confirmation from direct comparisons is needed, dronedarone does seem to be somewhat less efficacious but possibly safer than amiodarone. In conclusion, based on the results of an adequate series of clinical trials, dronedarone may be a useful alternative to amiodarone, with similar or slightly less antidysrhythmic efficacy, but significantly better tolerability. It is noteworthy that it seems to have no prodysrhythmic effects and has definitely no thyrotoxic effect. Among its non-cardiac adverse effects, only a raised serum creatinine seems to be clinically relevant and deserves careful monitoring, particularly in patients with impaired renal function.

Flecainide [SED-15, 1370; SEDA-30, 217; SEDA-31, 330; SEDA-32, 348] Cardiovascular Flecainide is used diagnostically to uncover latent Brugada syndrome in patients with the SCN5A mutation. However, sporadically it can accidentally reveal a Brugada pattern when used for therapeutic purposes in other dysrhythmias, and caution is recommended when selecting it for their treatment. In one case intravenous flecainide for atrial fibrillation induced a transient Brugada-like syndrome, sinus arrest, and total atrioventricular block; an SCN5A mutation was subsequently identified [63A]. Electrolyte balance Severe flecainide-induced hyponatremia has been described [64A]. • A 67-year-old woman with symptomatic paroxysmal atrial tachycardia was given oral flecainide 100 mg bd. After 1 month, she developed dizziness, generalized malaise, and

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387

weakness. She had hyponatremia with a fall in serum sodium concentration from 136 mmol/l before flecainide to 122 mmol/l. There were no signs or symptoms of volume overload or volume depletion. The random urine osmolality was 242 mOsm/kg, suggesting an inability to excrete a dilute urine. Serum osmolality was 282 mOsm/kg (reference range 275–290 mOsm/kg), which ruled out the syndrome of inappropriate antidiuretic hormone secretion. The urine random sodium concentration was 41 mmol/l (reference range < 30 mmol/l), indicative of increased urinary sodium loss, which was puzzling as the patient showed no signs of volume depletion. Renal function was normal. After fluid restriction, the sodium concentration rose to 130 mmol/l and her symptoms abated. Flecainide was continued, and 5 days later, she again developed dizziness, generalized malaise, and weakness. Once again, the serum sodium concentrations had fallen to 127 mmol/l. In addition to fluid restriction, flecainide was withdrawn. Her symptoms improved and the serum sodium concentration normalized. No further episodes of hyponatremia occurred over the next 12 months.

In this case, hyponatremia was precipitated by flecainide and recovered after drug withdrawal. The authors postulated that the mechanism was direct inhibition of renal and intestinal epithelial sodium channels, leading to reduced sodium reabsorption. Skin There have been several reports of various cutaneous adverse effects of flecainide, such as urticaria, flushing, pruritus, and psoriasis. There has now been a report of a fixed drug eruption [65A]. • A 69-year-old man developed a recurrent foot blister several weeks after starting oral flecainide. The clinical suspicion of a fixed drug eruption was confirmed histologically. The patient was given clobetasol ointment and advised to continue taking flecainide despite the eruption, given the importance of the medication in treating his dysrhythmia.

Drug overdose Deliberate overdose with flecainide has been described [66A]. • A 37-year-old man took flecainide 1500 mg over a few minutes and developed chest discomfort, dyspnea, and a ventricular tachycardia, which resolved spontaneously. In sinus rhythm, a Brugada pattern on the electrocardiogram became evident, with right bundle branch block and

Chapter 17

388 typical ST segment elevation in the right precordial leads. Hypotension, which occurred after some hours, was treated with intravenous fluids, and a mild acidosis required sodium bicarbonate. He recovered after 2 days.

Accidental flecainide intoxication, due to a medication error, occurred in a 2-year-old toddler who was given intravenous flecainide 4.8 mg/kg/day and nadolol for persistent junctional reciprocating tachycardia [67A]. Cardiogenic shock with absence of vital signs required emergency treatment, and ventricular tachycardia was treated with sodium bicarbonate; recovery was uneventful. The serum flecainide concentration was 0.67 mg/l. Drug–drug interactions Paroxetine An interaction of flecainide with paroxetine has been described. • A 67-year-old patient taking paroxetine 40 mg/ day developed confusion and paranoia after taking flecainide 200 mg/day for 2 weeks. The plasma flecainide concentration was 1360 mg/l (usual target range 200–1000); the symptoms subsided after paroxetine was withdrawn and the dose of flecainide was reduced [68A].

Paroxetine is a CYP2D6 inhibitor, which could have explained this interaction. The effects of CYP2D6 genetic polymorphisms on the pharmacokinetics of a single oral dose of flecainide and on the extent of its interaction with paroxetine have been investigated in an open study in 21 healthy Korean volunteers [69c]. The AUC, terminal half-life, and mean residence time increased significantly after paroxetine in those with the CYP2D6*10 allele, which is common among Asians.

A. Finzi

led to ST segment elevation in leads V1–3. The tachycardia was hemodynamically destabilizing and was quickly converted electrically.

Lidocaine-induced ST segment elevation and the fact that the patient had a malignant dysrhythmia and ST segment elevation unmasked by the Na channel blocker led to a diagnosis of Brugada syndrome. Because of the unique characteristics of the case, he was referred for genotyping to look for a channelopathy. He had a double mutation in the SCN5A gene, capable of altering the interaction of lidocaine with the sodium channels, conferring class Ic activity on this class Ib drug, with potent use-dependent blockade of the sodium channel; there was an additive effect of the two missense mutations in sensitizing the sodium channel to lidocaine. Cardiac arrest occurred after 20 minutes a 52-year-old woman gargled and accidentally swallowed 20 ml of a 5% lidocaine solution before laryngoscopy [71A]. She developed somnolence, bradypnea, hypotension, and eventual cardiac arrest, which necessitated external cardiac massage, intubation, and adrenaline infusion. Recovery was uneventful. Prolonged use of topical lidocaine can result in systemic and specifically cardiovascular toxicity [72A]. • A healthy 48-year-old man sprayed lidocaine solution on his glans penis on several occasions before having sex over a period of 2 weeks and developed chest discomfort and profound bradycardia, which resolved with conservative treatment.

Respiratory Topical lidocaine can cause bronchospasm and airways obstruction in asthmatics [73R] as can intravenous lidocaine [74A].

has

• A 17-month-old child was given intravenous lidocaine 1.5 mg/kg to facilitate endotracheal intubation and immediately developed bronchospasm, which resolved uneventfully after 5 minutes.

• A 45-year-old black man with no history of cardiac disease had a seizure associated with a monomorphic broad-complex ventricular tachycardia. He was given lidocaine 70 mg followed by a continuous infusion of 1 mg/minute, which

Nervous system Nervous system adverse effects have been reported during treatment with different lidocaine formulations for analgesia. Intravenous lidocaine in doses titrated between 1 and 4 mg/minute

Lidocaine

[SED-15, 1370; SEDA-30, 217; SEDA-31, 330]

Cardiovascular Brugada syndrome been attributed to lidocaine [70A].

Positive inotropic drugs and drugs used in dysrhythmias

was investigated in 68 patients with intractable daily headache for an average of 8.5 days: 25% obtained complete remission and 57% partial remission. The more frequent adverse effects were nausea and vomiting (n ¼ 14) and hallucinations (n ¼ 8); none led to drug withdrawal [75c]. In a comparison with ropivacaine 5 mg/ ml for out-patient knee arthroscopy in 30 patients, lidocaine 10 mg/ml caused pain and dysalgesia in the buttocks, thighs, or legs in 40% [76c]. Central nervous system toxicity from local anesthetics has previously been described. Lidocaine is usually considered to be safe up to a total intravenous dose of 3 mg/kg. However, although the total dose of the local anesthetic is important, lidocaine injected directly into the arterial circulation close to the central nervous system can produce toxicity in small doses [77A]. • A 26-year-old patient undergoing percutaneous dilatation tracheostomy was given lidocaine accidentally into an aberrant carotid artery underlying the trachea. Generalized convulsions immediately occurred, which resolved after injection of thiopental and extra oxygen.

Mexiletine [SED-15, 1370; SEDA-30, 217; SEDA-31, 330] Nervous system Mexiletine 600–1500 mg/ day has been investigated in nine patients with refractory chronic headache. Although it was “much more effective” or “more effective” than previous medications, adverse effects such as nausea, fatigue, tremor, dizziness, incoordination, and, to a lesser extent, palpitation led to withdrawal in most patients [78c].

Pilsicainide

[SEDA-32, 348]

Drug overdose A young woman ingested many tablets of pilsicainide and atenolol; her pilsicainide and atenolol plasma concentrations were 7.83 and 4.94 mg/l

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389

respectively, far above the usual target concentrations [79A].

Procainamide

[SED-15, 2923;

SEDA-30, 219] Cardiovascular Intravenous procainamide had a prodysrhythmic effect when it was given as a single 1000 mg bolus during an electrophysiological study in a patient with myotonic dystrophy type 1 [80A]. During ventricular pacing, ventricular tachycardia and fibrillation occurred and required DC cardioversion. By slowing cardiac conduction, procainamide, as do other sodium channel blockers, worsens abnormalities already present in the hearts of patients with myotonic dystrophy type 1.

Propafenone

[SED-15, 2939; SEDA-30, 218; SEDA-31, 331; SEDA-32, 351] Cardiovascular Propafenone, like all class I antidysrhythmic agents, can increase the heart rate in patients with atrial tachydysrhythmias, because of its vagolytic effect, which leads to enhancement of atrioventricular nodal conduction. A case of propafenone-mediated 1:1 atrial tachycardia has been reported [81A].

• A 58-year-old man developed sudden onset rapid palpitation and significant presyncope while walking on the flat. The previous day he had undergone DC cardioversion for atrial fibrillation, which had been initially successful. However, 6 hours after cardioversion he became aware of an intermittently fast but regular heartbeat. He was well with no hemodynamic compromise. An electrocardiogram showed an atrial tachycardia instead of atrial fibrillation. He had been taking propafenone 300 mg bd, bisoprolol 5 mg at night, and warfarin. The dose of bisoprolol was increased to 5 mg bd and he was discharged with a plan for out-patient ablation. He collapsed in the hospital car park with rapid palpitation, chest tightness, and vagal symptoms. He was

390 hypotensive with a heart rate of 200/minute. An electrocardiogram showed an atrial tachycardia with 1:1 atrioventricular conduction, which promptly improved after intravenous atenolol.

Immunologic A lupus-like syndrome has been reported in a patient taking propafenone [82A]. • A 73-year-old woman developed weakness and erythematous plaques on the trunk and limbs after taking propafenone for 2 months. She had a neutropenia with a predominance of immature cells in the bone marrow. Skin biopsy was compatible with subacute cutaneous lupus erythematosus. After withdrawal of all drugs there was complete clinical and analytical recovery. Her medications were then sequentially re-introduced, with the exception of propafenone. After 6 months she remained asymptomatic.

Drug overdose Deliberate propafenone overdose has been reported [83A]. • A 17-year-old man took about 20 tablets of propafenone (total 6000 mg) and 24 tablets of trimethoprim (total 1920 mg) þ sulfamethoxazole (total 9600 mg) with suicidal intent. Within 1 hour, he started vomiting, and had nausea, loss of consciousness, cyanosis, mild acidosis, and eventually cardiorespiratory arrest. He was resuscitated and sinus rhythm was restored at a rate of 55/minute, with a blood pressure of 70/45 mmHg. An electrocardiogram showed sinus bradycardia, extreme widening of the QRS complex (260 msec), and a right bundle branch block pattern. He was given intravenous saline, bicarbonate, and dopamine, and respiration was supported mechanically, which resulted in rapid restoration of sinus rhythm and improved hemodynamic parameters and acidosis. A subsequent electrocardiogram showed shortening of the QRS duration (230 msec).

Drug–drug interactions Carvedilol An interaction of propafenone with carvedilol has been reported [84A]. • A 76-year-old woman who was taking carvedilol for hypertension and paroxysmal supraventricular dysrhythmias had an attack of transient syncope after taking a single dose of propafenone 600 mg. Her blood pressure was 110/60 mmHg, heart rate 68/minute, and an electrocardiogram showed left bundle branch block and first degree atrioventricular

Chapter 17

A. Finzi

block. Her electrocardiogram normalized over the next few hours.

Others later commented that since propafenone and carvedilol are both metabolized by CYP2D6, inhibition of propafenone metabolism by carvedilol may have caused the syncope reported in this case [85H]. Citalopram An interaction of propafenone with citalopram reportedly caused adverse effects attributable to propafenone, mimicked coronary artery disease [86A]. • An 80-year-old woman with mild cognitive impairment, who had taken propafenone 900 mg/day for over 10 years for paroxysmal atrial fibrillation without adverse effects, was given citalopram, and 3 months later had episodes of chest tightness and dizziness, which became more frequent, causing several falls but no acute coronary event. She was given amlodipine 2.5 mg/day, a glyceryl trinitrate patch 0.4 mg/hour, and warfarin 5 mg/day. After one fall, she became delirious. Amlodipine and glyceryl trinitrate were withdrawn and the dose of propafenone was reduced to 450 mg/day; citalopram 20 mg/day was continued. She recovered, both cognitively and physically, and did not have any further symptoms after 1 year of follow-up. Coronary investigations were negative.

Quinidine and derivatives [SED-15, 2997; SEDA-30, 219; SEDA-31, 332; SEDA-32, 352] Observational studies In a retrospective study of oral quinidine for termination of atrial fibrillation in 501 consecutive patients (mean age 66 years, 32% women), quinidine 200–400 mg was given every 6 hours until cardioversion or for a maximum of 48 hours [87C]. Quinidine did not have to be withdrawn because of adverse drug reactions and there was no significant QT interval prolongation and no life-threatening ventricular dysrhythmias. The mean total dose of quinidine was 617 mg and 92% of the patients received verapamil or a beta-blocker to slow the ventricular rate to below 100/minute. Cardioversion was successful in 84%. All adverse drug

Positive inotropic drugs and drugs used in dysrhythmias

reactions were minor and transient (diarrhea in 13%, first degree atrioventricular block in 4%, symptomatic hypotension in 2%, supraventricular and ventricular extra beats and nausea in 1% respectively; there was a rash in one patient). Multivariate analysis showed that female sex (OR ¼ 2.62; CI ¼ 1.61, 4.26) and an ejection fraction

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391

of 45–54% (OR ¼ 1.97; CI ¼ 1.15, 3.36) were independent susceptibility factors for adverse drug reactions. Based on these data the authors concluded that quinidine for pharmacological cardioversion of atrial fibrillation is safe and well tolerated in this subset of patients.

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[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

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[50]

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differences between North American and European thyroidologists. Clin Endocrinol (Oxf) 2008; 69(5): 812–8. Llanos L, Moreu R, Peiro AM, Pascual S, Frances R, Such J, Horga JF, PerezMateo M, Zapater P. Causality assessment of liver injury after chronic oral amiodarone intake. Pharmacoepidemiol Drug Saf 2009; 18(4): 291–300. Raja K, Thung SN, Fiel MI, Chang C. Drug-induced steatohepatitis leading to cirrhosis: long-term toxicity of amiodarone use. Semin Liver Dis 2009; 29(4): 423–8. Snider M, Boyd M, Carnes CA. Amiodarone use in patients with documented hypersensitivity to intravenous contrast dye. Ann Pharmacother 2008; 42(9): 1349–50. Ahmed S, Rienstra M, Crijns HJ, Links TP, Wiesfeld AC, Hillege HL, Bosker HA, Lok DJ, Van Veldhuisen DJ, Van Gelder IC, CONVERT Investigators. Continuous vs episodic prophylactic treatment with amiodarone for the prevention of atrial fibrillation: a randomized trial. JAMA 2008; 300(15): 1784–92. Komatsu T, Ozawa M, Tachibana H, Sato Y, Orii M, Kunugida F, Nakamura M. Combination therapy with amiodarone and enalapril in patients with paroxysmal atrial fibrillation prevents the development of structural atrial remodelling. Int Heart J 2008; 49(4): 435–47. Bush SE, Hatton RC, Winterstein AG, Thomson MR, Woo GW. Effects of concomitant amiodarone and haloperidol on QTc interval. Am J Health Syst Pharm 2008; 65(23): 2232–6. Snider M, Kalbfleisch S, Carnes CA. Initial experience with antiarrhythmic medication monitoring by clinical pharmacists in an outpatient setting: a retrospective review. Clin Ther 2009; 31(6): 1209–18. Suzuki T, Hanaoka M, Yokoyama T, Koizumi T, Kubo K. Gradual progression of interstitial pneumonia induced by bepridil. Intern Med 2009; 48(23): 2033–5. Watanabe M, Takata Y, Fukasawa S, Sakota K, Abe T, Goseki Y, Setoguchi Y, Chikamori T, Yamashina A. Two patients with bepridil-induced interstitial pneumonia. Circ J 2009; 73(7): 1352–5. Kawasaki H, Yahata K, Okamoto C, Imamaki H, Seta K, Sugawara A.

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Myasthenia-like syndrome induced by cibenzoline overdose in a patient with chronic kidney disease. Nippon Jinzo Gakkai Shi 2008; 50(7): 942–7. Hirose K, Yamaguchi H, Oshima Y, Choraku M, Hirono A, Takamori N, Tamura K. Severe respiratory failure and torsades de pointes induced by disopyramide in a patient with myasthenia gravis. Intern Med 2008; 47(19): 1703–8. Negishi M, Shimomura K, Proks P, Mori M, Shimomura Y. Mechanism of disopyramide-induced hypoglycaemia in a patient with type 2 diabetes. Diabet Med 2009; 26 (1): 76–8. Tsuchishita Y, Fukumoto K, Kusumoto M, Ueno K. Effects of serum concentrations of disopyramide and its metabolite monoN-dealkyldisopyramide on the anticholinergic side effects associated with disopyramide. Biol Pharm Bull 2008; 31(7): 1368–70. Coleman CI, Sood N, Chawla D, Talati R, Ghatak A, Kluger J. Intravenous magnesium sulfate enhances the ability of dofetilide to successfully cardiovert atrial fibrillation or flutter: results of the Dofetilide and Intravenous Magnesium Evaluation. Europace 2009; 11(7): 892–5. Shamiss Y, Khaykin Y, Oosthuizen R, Tunney D, Sarak B, Beardsall M, Seabrook C, Frost L, Wulffhart Z, Tsang B, Verma A. Dofetilide is safe and effective in preventing atrial fibrillation recurrences in patients accepted for catheter ablation. Europace 2009; 11(11): 1448–55. Singh BN. Amiodarone as a paradigm for developing new drugs for atrial fibrillation. J Cardiovasc Pharmacol 2008; 52(4): 300–5. Sun W, Sarma JS, Singh BN. Chronic and acute effects of dronedarone on the action potential of rabbit atrial muscle preparations: comparison with amiodarone. J Cardiovasc Pharmacol 2002; 39: 677–84. Singh BN, Connolly SJ, Crijns HJ, Roy D, Kowey PR, Capucci A, Radzik D, Aliot EM, Hohnloser SH, for the EURIDIS and ADONIS Investigators. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med 2007; 357(10): 987–99.

A. Finzi

[59] Kber L, Torp-Pedersen C, McMurray JJV, Gtzsche O, Lévy S, Crijns H, Amlie J, Carlsen J, for the Dronedarone Study Group. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med 2008; 358(25): 2678–87. [60] Hohnloser SH, Crijns HJGM, van Eickels M, Gaudin C, Page RL, TorpPedersen C, Connolly SJ, for the ATHENA Investigators. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009; 360(7): 668–78. [61] Piccini JP, Hasselblad V, Peterson ED, Washam JB, Califf RM, Kong DF. Comparative efficacy of dronedarone and amiodarone for the maintenance of sinus rhythm in patients with atrial fibrillation. J Am Coll Cardiol 2009; 54(12): 1089–95. [62] Chan PS, Nallamothu BK, Oral H. Amiodarone or dronedarone for atrial fibrillation: too early to know the winner? J Am Coll Cardiol 2009; 54(12): 1096–8. [63] Van Opstal JM, Volders PGA, Crijns HJGM. Provocation of silence. Europace 2009; 11(3): 385–7. [64] Ahmed M, Sra J, Akhtar M, Mortada ME. A case of flecainide-induced hyponatremia. J Cardiovasc Electrophysiol 2009; 20(10): 1170–2. [65] Knapp III CF, Cooke ER, Sheehan DJ. Bullous fixed drug eruption caused by flecainide. J Am Acad Dermatol 2009; 60(2): e3. [66] Soni S, Gandhi S. Flecainide overdose causing Brugada-type pattern on electrocardiogram in a previously well patient. Am J Emerg Med 2009; 27(3): 373–5.e3. [67] D'Alessandro LC, Rieder MJ, Gloor J, Freeman D, Buffo-Sequiera I. Life-threatening flecainide intoxication in a young child secondary to medication error. Ann Pharmacother 2009; 43(9): 1522–7. [68] Tsao YY, Gugger JJ. Delirium in a patient with toxic flecainide plasma concentrations: the role of a pharmacokinetic drug interaction with paroxetine. Ann Pharmacother 2009; 43(7): 1366–9. [69] Lim KS, Cho J-Y, Jang I-J, Kim B-H, Kim J, Jeon J-Y, Tae Y-M, Yi S, Eum S, Shin S-G, Yu K-S. Pharmacokinetic interaction of flecainide and paroxetine in relation to the

Positive inotropic drugs and drugs used in dysrhythmias

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CYP2D6*10 allele in healthy Korean subjects. Br J Clin Pharmacol 2008; 66(5) 660–6, 749. Barajas-Martinez HM, Hu D, Cordeiro JM, Wu Y, Kovacs RJ, Meltser H, Kui H, Elena B, Brugada R, Antzelevitch C, Dumaine R. Lidocaine-induced Brugada syndrome phenotype linked to a novel double mutation in the cardiac sodium channel. Circ Res 2008; 103: 396–404. Doumiri M, Moussaoui A, Maazouzi W. Cardiac arrest after gargling and oral ingestion of 5% lidocaine. Can J Anaesth 2008; 55(12): 882–3. Lin F, Chang W-H, Su Y-J, Tsai C-H. Cardiovascular complication resulting from topical lidocaine. Int J Gerontol 2008; 2 (4): 229–32. Bose AA, Colt HG. Lidocaine in bronchoscopy: practical use and allergic reactions. J Bronchol 2008; 15(3): 163–6. Burches Jr. BR, Warner DO. Bronchospasm after intravenous lidocaine. Anesth Analg 2008; 107(4): 1260–2. Marmura M, Rosen N, Fanelli G, Danelli G, Zasa M, Baciarello M, Di Cianni S, Leone S. Intrathecal ropivacaine 5 mg/ml for outpatient knee arthroscopy: a comparison with lidocaine 10 mg/ml. Acta Anaesthesiol Scand 2009; 53(1): 109–15. Abbas M, Silberstein S. Intravenous lidocaine in the treatment of refractory headache: a retrospective case series. Headache 2009; 49(2): 286–91. Sharma R, Goel N, Kumar A, Panda A. Central nervous system toxicity with a 1 ml lidocaine injection in the aberrant carotid artery overlying the trachea. Acta Anaesthesiol Scand 2008; 52(10): 1436. Marmura MJ, Passero Jr. FC, Young WB. Mexiletine for refractory chronic daily headache. A report of nine cases. Headache 2008; 48(10): 1506–10.

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[79] Hikiji W, Kudo K, Nishida N, Ishida T, Usumoto Y, Tsuji A, Ikeda N. Acute fatal poisoning with pilsicainide and atenolol. Int J Legal Med 2008; 122(6): 503–6. [80] Otten RF, Scherschel JA, Lopshire JC, Bhakta D, Pascuzzi RM, Groh WJ. Arrhythmia exacerbation after sodium channel blockade in myotonic dystrophy type 1. Muscle Nerve 2009; 40(5): 901–2. [81] Khavandi A, Walker SK. Atrial tachycardia with 1:1 atrioventricular conduction precipitated by propafenone. Emerg Med J 2009; 26(12): 904–5. [82] Couto N, Ferreira M, Reis E. Neutropenia and cutaneous lesions secondary to propafenone. Eur J Dermatol 2009; 19(4): 365–7. [83] Ardiç I, Günebakmaz O, Yarlioglues M, Kaya MG. Acute intoxication with propafenone and trimethoprim–sulfamethoxazole in a case of suicide attempt. Turk Kardiyol Dern Ars 2009; 37(6): 410–3. [84] Patanè S, Marte F, Di Bella G. Transient syncope, left bundle branch block and first degree atrioventricular block after “pill-inthe-pocket” administration. Int J Cardiol 2008; 126: e19–21. [85] Boriani G, Biffi M, Diemberger I, Domenichini G, Marziali A, Martignani C. Atrial fibrillation: adverse effects of “pillin-the-pocket” treatment and propafenonecarvedilol interaction. Int J Cardiol 2010; 140(2): 242–3. [86] Garcia A. Adverse effects of propafenone after long-term therapy with the addition of citalopram. Am J Geriatr Pharmacother 2008; 6(2): 96–9. [87] Schwaab B, Katalinic A, Böge UM, Loh J, Blank P, Kölzow T, Poppe D, Bonnemeier H. Quinidine for pharmacologic cardioversion of atrial fibrillation: a retrospective analysis in 501 consecutive patients. Ann Noninvasive Electrocardiol 2009; 14(2): 128–36.

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18

Beta-adrenoceptor antagonists and antianginal drugs

BETA-ADRENOCEPTOR ANTAGONISTS [SED-15, 452; SEDA-30, 223; SEDA-31, 339; SEDA32, 363] Sexual function Beta-blockers can cause erectile dysfunction in men. However, cardiovascular diseases and thiazide diuretics can do the same and psychosocial factors can contribute. Thus, the assumption that beta-blockers can cause erectile dysfunction in a large number of treated men needs to be verified. In a randomized study of 114 hypertensive men (mean age 57 years) without erectile dysfunction, all were given metoprolol 100 mg/day; however, one group were fully informed of the risk of erectile dysfunction with beta-blockers, another group were partially informed, and a third group were not informed at all [1c]. After 60 days of therapy with metoprolol, the incidences of erectile dysfunction were 32% in group 1, 13% in group 2, and 8% in group 3. All those who reported erectile dysfunction were randomized to tadalafil 20 mg/day or placebo in a crossover study with 4-week treatment periods and 1 week of washout between each. Metoprolol was continued in the same dosage.

At the time of final evaluation, tadalafil and placebo were equally effective in reducing erectile dysfunction. These results confirm that knowledge about the possibility of erectile dysfunction influences its occurrence, and questions the use of phosphodiesterase-5 inhibitors to correct erectile dysfunction in patients taking beta-blockers.

Atenolol

[SED-15, 366; SEDA-31, 339]

Drug–drug interactions Thalidomide A 76year-old Japanese man with hypertension and multiple myeloma who was taking atenolol developed syncope and sinus bradycardia after thalidomide was added; his heart rate fell from 70 to 30/minute [2A]. The heart rate rose to 70/minute a few days after stopping atenolol. Either drug alone did not cause bradycardia, but the combination caused a profound reduction in sinus heart rate. If thalidomide is given to patients who are already taking a beta-blocker, the heart rate should be carefully monitored.

Betaxolol Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00018-0 # 2011 Elsevier B.V. All rights reserved.

[SEDA-32, 363]

Comparative studies In 105 children aged under 6 years who were randomized for 12 weeks to betaxolol suspension (n ¼ 34) or timolol maleate ophthalmic gel-forming 397

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solution 0.25% (n ¼ 35) or 0.5% (n ¼ 36) for glaucoma, both drugs produced statistically significant mean reductions in intraocular pressure [3C]. Adverse events were predominantly non-serious and those attributed to betaxolol were hyperemia, discomfort, and irritation in the eyes; there was one case of bradycardia and one of hypotension.

Bisoprolol

[SED-15, 522]

Respiratory Although selective beta1adrenoceptor antagonists may be better tolerated than non-selective ones, adverse respiratory reactions have been reported. In the absence of randomized trials, 27 patients with heart failure and moderate or severe COPD were randomized to the highly selective beta-blocker bisoprolol or placebo over 4 months. There was a significant reduction in FEV1 in those who took bisoprolol, although the number of exacerbations of COPD, symptoms, and quality of life were similar in the two groups [4c]. Larger randomized controlled trials are needed addressing the issue of beta-blockade in this large and often ignored population of patients with heart failure and COPD.

Carvedilol

[SED-15, 676; SEDA-32, 363]

Sexual function Peyronie's disease has been attributed to carvedilol [5A]. However, the association of beta-blockers with Peyronie's disease is not convincing [SED-15, 463]. Drug overdose An 84-year-old man took total of 60 (6.25 mg) tablets and rapidly developed hypotension (systolic blood pressure 70 mmHg), bradycardia (45/ minute), and a junctional rhythm [6A]. He was given intravenous glucagon and dopamine infusion and recovered after 14 hours. The carvedilol serum concentration was 472 mg/l, compared with a predicted steady-state concentration of 8.5 mg/l during treatment with 6.25 mg bd.

M.G. Franzosi and R. Latini

Drug–drug interactions Propafenone An interaction of carvedilol with propafenone has been reported [7A]. • A 76-year-old woman who was taking carvedilol for hypertension and paroxysmal supraventricular dysrhythmias had an attack of transient syncope after taking a single dose of propafenone 600 mg. Her blood pressure was 110/60 mmHg, heart rate 68/minute, and an electrocardiogram showed left bundle branch block and first degree atrioventricular block. Her electrocardiogram normalized over the next few hours.

Others later commented that since propafenone and carvedilol are both metabolized by CYP2D6, inhibition of propafenone metabolism by carvedilol may have caused the syncope reported in this case [8H].

Celiprolol

[SED-15, 687]

Respiratory Even non-asthmatic patients should be carefully monitored for respiratory adverse effects when they are first given cardioselective beta-blockers. A 79-year-old man developed a wheeze without dyspnea or cough. After withdrawal of celiprolol, which he had taken for 7 years before the onset of the wheeze and for 3 years after, his peak expiratory flow rate improved as did his respiratory symptoms [9A].

Esmolol

[SED-15, 1252]

Comparative studies Blood pressure control is important after repair of coarctation of the aorta. In a multicenter trial in 116 children under 6 years of age, esmolol, 125 micrograms/kg (n ¼ 36), 250 micrograms/kg (n ¼ 43), and 500 micrograms/kg (n ¼ 37), was effective in reducing systolic blood pressure [10C]. The three dose groups had similar incidences of adverse events, the most common being postoperative pain (n ¼ 90), postoperative agitation (24), postoperative anemia (22), hypokalemia (32), and metabolic acidosis (33). In 17 cases in which adverse events were attributable to esmolol, the reactions were hypotension (n ¼ 10), bradycardia (1), wheezing (3), and a reaction at the injection site (1).

Beta-adrenoceptor antagonists and antianginal drugs

Labetalol

[SED-15, 1985; SEDA-32, 364]

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Drug overdose Death has been attributed to labetalol overdose.

chest pressure and new ST segment elevation in the anterior electrocardiographic leads 6 days after metoprolol had been withdrawn because of symptomatic bradycardia. After myocardial infarction had been excluded, takotsubo cardiomyopathy was diagnosed, based on chest radiography and echocardiography. Metoprolol was restarted and her symptoms completely regressed, as did the left ventricular dilatation.

• A 44-year-old woman with a history of depression and alcoholism was found dead at home [12A]. An autopsy showed non-specific abnormalities (alveolar edema, hepatic steatosis, and interstitial nephritis). Because several boxes of medicines had been found near the body, a toxicological analysis was carried out on peripheral blood and urine samples. Ethanol (1.24 g/l in blood, 2.63 g/l in urine, and 1.33 g/kg in gastric content), meprobamate (14 mg/l in blood), nordiazepam (0.12 mg/l in blood), and labetalol (1.7 mg/l in blood and 20 mg/l in urine) were found. Labetalol concentrations in samples of viscera (liver, heart, kidney, and lung) and gastric contents were also high (14, 7.8, 5.4, 5.2, and 31 micrograms/g respectively).

Susceptibility factors Genetic Metoprolol plasma concentrations in CYP2D6 poor metabolizers are higher than in extensive metabolizers. The effect of this polymorphism on metoprolol concentrations and effects has been assessed in a prospective, double-blind study. Metoprolol caused significantly and persistently greater reductions in heart rate, diastolic blood pressure, and mean arterial pressure in poor metabolizers than in extensive metabolizers. CYP2D6 therefore has an effect on interindividual differences in response to metoprolol [15c].

Metoprolol

Sotalol [SED-15, 3170; SEDA-28, 218; SEDA-29, 195]

Body temperature Fever has been attributed to labetalol [11A].

[SED-15, 2321; SEDA-32,

364] Nervous system Sleepwalking is as a rare adverse effect of metoprolol, possibly facilitated by a history of childhood somnambulism [13A]. • A 66-year-old woman was referred to the sleep laboratory because of unusual sleep behavior shortly after she started to take metoprolol 50 mg/day for hypertension. Her somnambulism completely resolved within 2–3 weeks after ramipril was substituted for metoprolol.

Drug withdrawal Transient left ventricular ballooning syndrome (takotsubo cardiomyopathy) occurs mostly in post-menopausal women in response to stressful events and beta-blockers are used to treat it. Abrupt withdrawal of beta-blockade can result in a hyperadrenergic syndrome that can lead to takotsubo cardiomyopathy, even in the absence of a stressful precipitating event [14A]. • A 59-year-old woman with hypertension and left ventricular hypertrophy developed

Cardiovascular Sotalol can increase the risk of torsade de pointes, and in all case series the risk has been reported to be significantly higher in women than in men. This difference suggests that sex hormones play a role; testosterone may protect men from QT prolongation [16R].

Timolol

[SED-15, 3428; SEDA-32, 365]

Skin Contact dermatitis of the eyelids has been attributed to timolol eye-drops in a 40year-old man, confirmed by patch tests [17A]. Susceptibility factors Genetic The relation between the effects of timolol and CYP2D6 Arg296Cys and Ser486Thr genotypes has been studied in 73 patients with primary open-angle glaucoma [18c]. Topical timolol significantly reduced intraocular pressure and heart rate in all the subjects. There was no significant difference in intraocular pressure in those with different CYP2D6

400

Arg296Cys or Ser486Thr genotypes. However, timolol had different effects on heart rate: bradycardia tended to occur in those with the Arg296Cys CT and TT genotypes than in those with the CC genotype. Drug–drug interactions Bevacizumab The effect of timolol þ dorzolamide eye-drops, which reduces aqueous outflow from the eye, on the activity of intravitreal bevacizumab has been studied in 38 patients with macular edema after retinal vein obstruction [19c]. Mean central retinal thickness was used as a surrogate for the activity of bevacizumab. Mean central retinal thickness was significantly reduced by bevacizumab, and after 5 weeks the effect was enhanced by timolol þ dorzolamide but not after 9 weeks. The authors suggested that timolol þ dorzolamide eye-drops had reduced the clearance of intravitreal bevacizumab. However, this needs to be confirmed. If it is a real effect, it remains to be seen whether it improves the efficacy of bevacizumab or increases the risk of adverse effects.

POTASSIUM CHANNEL ACTIVATORS Nicorandil [SED-15, 2505; SEDA-31, 340; SEDA-32, 365] Skin Perianal and other mucosal ulcers have been reported with chronic use of nicorandil. Inguinal ulcers have been attributed to nicorandil without any associated mucosal ulcers [20A]. • An 85-year-old man who had taken nicorandil 20 mg/day for 4–5 years developed inguinal ulcers, which did not respond to topical or systemic agents. Near complete healing occurred 8 weeks after withdrawal of nicorandil.

It is important to recognize not only mucosal, but also cutaneous isolated ulcers with nicorandil and to stop treatment as soon as possible.

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Ulceration of the oral mucosa, perianal skin, and peristomal skin with nicorandil has been more often reported than lesions of the vaginal mucosa. Two elderly women developed large painful ulcers of the vulva, which healed in a few days after withdrawal of nicorandil, which had been prescribed for angina pectoris [21A]. The mechanisms of this adverse reaction are unknown. Similar findings have been reported in a series of five elderly women [22c], stressing the importance of taking a careful drug history in patients with such ulcers. Prompt resolution after stopping nicorandil is typical.

NITRATES, ORGANIC [SEDA-15, 2529; SEDA-30, 225; SEDA-32, 366] Cardiovascular Local application of exogenous nitric oxide donors, such as glyceryl trinitrate or isosorbide dinitrate, promotes healing of chronic anal fissures by reducing anal resting pressure and improving anodermal blood flow. However, headache, due to vasodilatation, which occurs in as many as 40% of the patients, is a major factor that limits their use. In any case, nitrates are barely superior to placebo in producing complete healing. In an attempt to circumvent this adverse reaction, 15 patients with chronic anal fissures were treated topically for at least 12 weeks with a gel containing arginine. There was complete healing after 18 weeks of treatment in 62% of the patients, and headaches did not occur [23c]. Placebo-controlled studies are needed to establish whether arginine is a better alternative to NO donors in the treatment of chronic anal fissures.

Glyceryl trinitrate (nitroglycerin) Nervous system Transdermal glyceryl trinitrate has been advocated in the treatment of peripheral vascular disease and

Beta-adrenoceptor antagonists and antianginal drugs

frostbite. A 49-year-old elite mountaineer applied a 10 mg glyceryl trinitrate patch to each leg in order to prevent frostbite [24A]. During his last ascent above 8000 meters he developed neurological symptoms suggestive of acute mountain sickness, which he had never had before. His symptoms were relieved shortly after he removed the patches during the return trip. The use of glyceryl trinitrate at high altitude should be strongly discouraged. Hematologic Methemoglobinemia is a wellknown complication of intravenous glyceryl trinitrate therapy and has been reported again in an unusual case [25A]. • A 45-year-old man was injured by an exploding bomb and, apart from burns and various lesions, had a peak of plasma concentration of methemoglobin of 42%, because of extensive transcutaneous absorption of glyceryl trinitrate from non-combusted particles attached to his skin. He was given methylthioninium chloride (methylene blue) serially over 6 days and the hemoglobin normalized.

Drug formulations Nitrates are often prescribed for Raynaud's phenomenon, but their use is limited by adverse effects such as headache, dizziness, and skin irritation. A new gel formulation of glyceryl trinitrate (MQX-503) has been tested in 219 patients with Raynaud's phenomenon, in a doubleblind, randomized, placebo-controlled trial. MQX-503 was significantly more effective than placebo, and had comparable adverse effects [26c].

CALCIUM CHANNEL BLOCKERS [SED-15, 598;

SEDA30, 225; SEDA-31, 340; SEDA-32, 366]

Mouth Gingival enlargement is often associated with calcium channel blockers and ciclosporin. In 93 renal transplant recipients who had taken ciclosporin (n ¼ 31), ciclosporin þ nifedipine (n ¼ 31), or ciclosporin þ amlodipine (n ¼ 31), more

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of those who took ciclosporin þ nifedipine (90%) had gingival enlargement than those who took ciclosporin þ amlodipine (58%) or ciclosporin alone (52%) [27c]. More of those who took ciclosporin þ nifedipine had severe gingival enlargement (23%) compared with ciclosporin þ amlodipine (16%) or ciclosporin alone (0%). This suggests that these combinations should be avoided, or that amlodipine should be used instead of nifedipine if a calcium channel blocker is required in a patient taking ciclosporin. However, the study was not randomized and the authors did not report the reason for the use of calcium channel blockers in these patients.

Amlodipine

[SED-15, 175; SEDA-30, 225; SEDA-31, 340; SEDA-32, 367] Autacoids The calcium channel blockers verapamil, diltiazem, and nifedipine have been associated with angioedema, and a case has also now been reported in a patient taking amlodipine [28A].

• A 50-year-old African–American woman had a left-sided stroke, with hemiplegia. Her blood pressure was 214/125 mmHg and she was given a continuous infusion of labetalol and hemodialysis, but remained hypertensive. The blood pressure stabilized with intravenous nicardipine which was switched to oral amlodipine 10 mg/day. After about 24 hours she developed swelling of the face and tongue. Fosphenytoin and famotidine were withdrawn, but there was still massive edema of the tongue, causing it to protrude from the mouth. Amlodipine was withdrawn and about 24 hours later the oropharyngeal and tongue edema had reduced significantly. The angioedema completely resolved after 10 days.

Nicardipine and amlodipine could have caused this patient's angioedema; however, the symptoms continued for 4 days after the withdrawal of nicardipine. Amlodipine was started 24 hours before the onset, and the symptoms began to improve 24 hours after withdrawal. Skin Drug hypersensitivity reactions can cause an atypical lymphoid cell infiltrate

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ranging from a benign condition to a malignant lymphoma. There have been a few reports of CD30-positive drug-induced pseudolymphoma in patients taking amlodipine. Skin infiltration of atypical lymphoid cells mimicking mycosis fungoides has now been reported during amlodipine therapy [29A]. • A 74-year-old man developed red solid papules and erythematous plaques on his abdomen, chest, the inner aspect of the arms, and the lower legs after taking amlodipine 5 mg/day and naftopidil 50 mg/day for 2 months for hypertension. Histology of the skin lesions after 10 months showed massive infiltration of small lymphocytes and large atypical lymphocytes in the upper dermis. Large atypical cells were positive for CD30. The eruption was initially diagnosed as lymphomatoid papulosis, but the papular lesions evolved into scaly erythematous plaques resembling mycosis fungoides. He was given intramuscular interferon-gamma and ultraviolet B in combination, but the eruption and pruritus worsened. The eruption was therefore suspected to be a peculiar form of drug eruption rather than a cutaneous T-cell lymphoma. A lymphocyte stimulation test for amlodipine and naftopidil was strongly positive for amlodipine and negative for naftopidil. The eruption resolved within 2 months of withdrawal of amlodipine.

Lercanidipine

[SED-15, 2024;

SEDA-30, 226] Serosae Calcium channel blockers have been rarely associated with chylous ascites in patients taking peritoneal dialysis. The mechanism is unknown. Chylous ascites has been attributed to lercanidipine [30A]. • A 41-year-old uremic woman who had taken lercanidipine 10 mg/day for 3 days developed a painless peritoneal effluent. She had been undergoing continuous ambulatory peritoneal dialysis for 2 weeks for end-stage nephropathy. The only physical finding was mild epigastric tenderness. The turbid peritoneal effluent contained a high triglyceride concentration without evidence of micro-organisms or cellular components, suggestive of chylous ascites. Lercanidipine was withdrawn and the dialysis effluent cleared within 24 hours. Re-challenge with lercanidipine provoked the same adverse reaction within 16 hours.

M.G. Franzosi and R. Latini

Nicardipine [SED-15, 2502; SEDA-30, 227; SEDA-32, 367] Liver Raised liver enzymes have been associated with nicardipine [31A]. • A 61-year-old man with hypertension had a right middle cerebral artery infarction and an evolving stroke, followed by a cerebral hemorrhage during angiography and stent placement. After neurosurgery he was given hypertonic saline, mannitol for cerebral edema, and a nicardipine infusion for blood pressure control. After 4 days he developed a fever with progressively rising liver enzymes. Other medications included metoprolol and heparin. The white blood cell count was 13  109/l and there was no evidence of infection. The liver enzymes continued to rise without changes in protein or bilirubin. Nicardipine was withdrawn and labetalol substituted. The fever resolved and the liver enzymes normalized.

Nifedipine [SED-15, 2516; SEDA-30, 227; SEDA-31, 341] Susceptibility factors Sex There are differences in blood pressure between the sexes, the mechanisms of which are unknown; furthermore, it is not known whether sex can influence the response to antihypertensive therapy. In a prospective study 3535 untreated hypertensive Chinese patients were randomized to atenolol, sustainedrelease nifedipine, captopril, or hydrochlorothiazide for 8 weeks [32c]. Women had significantly better pressure responses, but more adverse effects with sustainedrelease nifedipine and captopril than men. The authors suggested that sex should be taken into account when selecting antihypertensive drugs. Drug–drug interactions Voriconazole A clinically relevant drug interaction between voriconazole and nifedipine þ eplerenone has been reported [33A]. • A 48-year-old man with myelodysplastic syndrome underwent bone marrow transplantation from an unrelated donor and took

Beta-adrenoceptor antagonists and antianginal drugs ciclosporin and methylprednisolone for acute graft-versus-host disease. He had taken regular candesartan, nifedipine, and eplerenone for hypertension. He was given intravenous voriconazole for prophylaxis of fungal infections. His blood pressure fell to 76/48 mmHg after 2 days, without evidence of hypovolemia, acute blood loss, or septicemia. Candesartan, nifedipine, and eplerenone were withdrawn and his blood pressure rose after 1 day; at 5 days it was 180/80 mmHg. Candesartan and nifedipine were started again, with a reduction in the dose of nifedipine, and eplerenone was no longer needed to control the hypertension.

Both nifedipine and eplerenone are metabolized by CYP3A4, which is inhibited by voriconazole. Other azoles, such as fluconazole, reportedly also interact with nifedipine, but such an interaction has not been demonstrated with eplerenone.

Nimodipine

[SED-15, 2526; SEDA-29,

199]

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intracellular calcium. In a prospective population-based study, the Rotterdam Study, the presence of two single nucleotide polymorphisms (SNPs) in the NOS1AP gene, rs10494366 T > G and rs10918594 C > G, modified the QTc interval-prolonging effect of calcium channel blockers [35C]. The study included 16 603 electrocardiograms from 7565 participants, after exclusion of patients with left ventricular hypertrophy and left and right bundle branch block, and those with pacemakers. The use of verapamil was associated with significant QTc interval prolongation (6.0 ms; 95% CI ¼ 1.7, 10) compared with non-users. Furthermore, users of verapamil with the rs10494366 GG genotype had significantly more QTc prolongation than users with the TT genotype (25.4 ms; 95% CI ¼ 5.9, 45). In other words, the minor alleles of both NOS1AP SNPs significantly potentiated the QTc interval-prolonging effect of verapamil. Amlodipine, isradipine, nifedipine, and diltiazem did not prolong the QT interval.

Nervous system Familial hemiplegic migraine is an autosomal dominant form of migraine. A prolonged attack of hemiplegic migraine was worsened by intravenous nimodipine in a Norwegian family with four members affected over three generations. The family had a point mutation in the ATP1A2 gene that caused a change in valine to methionine (V628M). One of the affected individuals, a 16-year-old boy, had prolonged attacks of migraine and a single generalized clonic–tonic seizure, which was possibly provoked by intravenous nimodipine [34A]. The authors concluded that nimodipine is contraindicated in the management of prolonged attacks of familial hemiplegic migraine.

Drug overdose In a case of attempted suicide with 7.2 g of sustained-release verapamil, with extremely high initial plasma concentrations (3600 mg/l 1.5 hours after ingestion), there was a very long period of toxicity, with a surprising sudden escalation of symptoms on the third day, characterized by extreme hypotension, bradycardia, and loss of consciousness [36A]. Massive bowel irrigation, prolonged cardiac pacing, and invasive hemodynamic monitoring are advisable when treating toxicity from sustained-release verapamil. Repeated doses of activated charcoal have also been suggested, especially after overdose with modified-release formulations [37A]. Two patients with serious calcium channel blocker overdose gradually improved after being given levosimendan [38A].

Verapamil

• A 47-year-old woman who had taken 16 g of verapamil 1 hour before was given activated charcoal 50 g orally, a noradrenaline infusion, and boluses of calcium and atropine. She had a cardiac arrest and was given boluses of calcium, glucagon, and adrenaline. Because of refractory shock she was also given levosimendan, and after 6 hours the doses of vasopressors were reduced. She gained full

[SED-15, 3618; SEDA-30, 228; SEDA-31, 342; SEDA-32, 367] Susceptibility factors Genetic The NOS1AP gene has been associated with variation in the duration of the QT interval in several large populations. NOS1 is presumed to influence

404 consciousness 24 hours after the cardiac arrest and was sedated with propofol. The infusion of levosimendan was continued for 30 hours and sinus rhythm was restored on day 2. • A 38-year-old man was found in his bed deeply comatose and it was suspected that he had taken amlodipine 630 mg, zopiclone 300 mg, and uncertain amounts of citalopram and paracetamol at least 4 hours earlier. He was given activated charcoal, intravenous boluses of glucagon and calcium, and dopamine by infusion, followed by noradrenaline by infusion. Because of persistent hypotension and heart failure he was given levosimendan and the dobutamine was withdrawn. After 90 minutes his cardiac function had improved. The dose of levosimendan was increased and continued for 24 hours, when his lactic acidosis resolved.

These two cases cannot be considered as providing direct evidence of a beneficial effect of levosimendan. Both patients received intensive conventional treatment

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for severe calcium channel blocker overdose, but their circulatory state and tissue perfusion remained unsatisfactory. The addition of levosimendan was associated with improvement and stabilization of hemodynamics and both patients survived after near-fatal overdoses. Verapamil is a lipophilic phenylalkylamine. Intravenous fat emulsion (IntralipidÒ) is composed of triglycerides and a phospholipid emulsifier. In case reports and animal experiments, it attenuated the cardiotoxic effects of some lipophilic drugs and has been used in a case of verapamil overdose [39A]. • A 32-year-old man developed shock after overdosing on sustained-release verapamil 13.44 g and was given 100 ml of IntralipidÒ 20% over 20 minutes plus an infusion of 0.5 ml/kg/hour for 24 hours. He became hemodynamically stable and was soon weaned from pressor amines and glucagon.

References [1] Cocco G. Erectile dysfunction after therapy with metoprolol: the Hawthorne effect. Cardiology 2009; 112: 174–7. [2] Yamaguchi T. Syncope and sinus bradycardia from combined use of thalidomide and b-blocker. Pharmacoepidemiol Drug Saf 2008; 17: 1033–5. [3] Plager DA, Whitson JT, Netland PA, Vijaya L, Sathyan P, Sood D, Krishnadas SR, Robin AL, Gross RD, Scheib SA, Scott H, Dickerson JE. BETOPTIC S Pediatric Study Group. Betaxolol hydrochloride ophthalmic suspension 0.25% and timolol gel-forming solution 0.25% and 0.5% in pediatric glaucoma: a randomized clinical trial. J AAPOS 2009; 13(4): 384–90. [4] Hawkins NM, MacDonald MR, Petrie MC, Chalmers GW, Carter R, Dunn FG, McMurray JJV. Bisoprolol in patients with heart failure and moderate to severe chronic obstructive pulmonary disease: a randomized controlled trial. Eur J Heart Fail 2009; 11: 684–90. [5] Bell DS. Peyronie disease in association with carvedilol: a case report. South Med J 2008; 101(11): 1157–8.

[6] Bouchard NC, Forde J, Hoffman RS. Carvedilol overdose with quantitative confirmation. Basic Clin Pharmacol Toxicol 2008; 103(1): 102–3. [7] Patanè S, Marte F, Di Bella G. Transient syncope, left bundle branch block and first degree atrioventricular block after “pill-inthe-pocket” administration. Int J Cardiol 2008; 126: e19–21. [8] Boriani G, Biffi M, Diemberger I, Domenichini G, Marziali A, Martignani C. Atrial fibrillation: adverse effects of “pill-inthe-pocket” treatment and propafenonecarvedilol interaction. Int J Cardiol 2010; 140 (2): 242–3. [9] Rubab A, Branley HM. Reversible bronchospasm with the cardio-selective betablocker celiprolol in a non-asthmatic subject. Respir Med CME 2009; 2: 141–3. [10] Tabbutt S, Nicolson SC, Adamson PC, Zhang X, Hoffman ML, Wells W, Backer CL, McGowan FX, Tweddell JS, Bokesch P, Schreiner M. The safety, efficacy, and pharmacokinetics of esmolol for blood pressure control immediately after repair of coarctation of the aorta in infants and

Beta-adrenoceptor antagonists and antianginal drugs

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[15]

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[17]

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[20]

[21]

children: a multicenter, double-blind, randomized trial. J Thorac Cardiovasc Surg 2008; 136: 321–8. Kamel J, Spain L, Jellis C, Hunter A, Peel T. Drug fever due to labetalol. Intern Med J 2008; 38(11): 871–2. Grassin Delyle S, Duverneuil-Mayer C, Abe E, Mathieu B, Lorin De La Grandmaison G, Charlier P, Alvarez JC. Fatal intoxication with labetalol (Trandate). Forensic Sci Int 2008; 178(2–3): e19–21. Hensel J, Pillmann F. Late-life somnambulism after therapy with metoprolol. Clin Neuropharmacol 2008; 31: 248–50. Jefic D, Koul D, Boguszewski A, Martini W. Transient left ventricular apical ballooning syndrome caused by abrupt metoprolol withdrawal. Int J Cardiol 2008; 131: e35–7. Rau T, Wuttke H, Michels LM, Werner U, Bergmann K, Kreft M, Fromm MF, Eschenhagen T. Impact of the CYP2D6 genotype on the clinical effects of metoprolol: a prospective longitudinal study. Clin Pharmacol Ther 2009; 85: 269–72. Coker SJ. Drugs for men and women—how important is gender as a risk factor for TdP? Pharmacol Ther 2008; 119: 186–94. Buquicchio R, Foti C, Cassano N, Ventura M, Vena GA. Allergic contact dermatitis from timolol complicating choroidal melanoma-related glaucoma. Eur J Dermatol 2009; 19(1): 74–5. Yang Y, Wu K, Yuan H, Yu M. Cytochrome oxidase 2D6 gene polymorphism in primary open-angle glaucoma with various effects to ophthalmic timolol. J Ocul Pharmacol Ther 2009; 25(2): 163–71. Byeon SH, Kwon OW, Song JH, Kim SE, Park YS. Prolongation of activity of single intravitreal bevacizumab by adjuvant topical aqueous depressant (timolol–dorzolamide). Graefes Arch Clin Exp Ophthalmol 2009; 247(1): 35–42. Heil M, Hubiche T, Beltran C, Taieb A, Miremont-Salamé G, Milpied B. Isolated cutaneous inguinal ulcerations induced by nicorandil. J Eur Acad Dermatol Venereol 2008; 22: 1120–56. Chan SK, Harris MD, Baldwin PJW, Sterlinga JC. Vulvovaginal ulceration during prolonged treatment with nicorandil.

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BJOG Int J Obstet Gynaecol 2009; 116: 1403–5. Fraser SJ, Pinion SB, Adamson B, Allana SJR. Vulval ulceration induced by the potassium channel activator nicorandil: a case series of five patients. BJOG Int J Obstet Gynaecol 2009; 116: 1400–2. Gosselink MP, Darby M, Zimmerman DDE, Gruss HJ, Schouten WR. Treatment of chronic anal fissure by application of L-arginine gel: a phase II study in 15 patients. Dis Colon Rectum 2005; 48: 832–7. Mazzuero G, Mazzuero A, Pascariello A. Severe acute mountain sickness and suspected high altitude cerebral edema related to nitroglycerin use. High Alt Med Biol 2008; 9: 241–3. Badii F, Maghelli S, Costa N, Borreggine D, Zoccali G, Durì D. Acute methemoglobinemia after nitroglycerine transcutaneous absorption after bomb explosion: a case report. J Trauma 2009; 66: 936–7. Chung L, Shapiro L, Fiorentino D, Baron M, Shanahan J, Sule S, Hsu V, Rothfield N, Steen V, Martin RW, Smith E, Mayes M, Simms R, Pope J, Kahaleh B, Csuka ME, Gruber B, Collier D, Sweiss N, Gilbert A, Dechow FJ, Gregory J, Wigley FM. MQX503, a novel formulation of nitroglycerin, improves the severity of Raynaud's phenomenon. Arthritis Rheum 2009; 60: 870–7. López-Pintor RM, Hernández G, de Arriba L, Morales JM, Jiménez C, de Andrés A. Amlodipine and nifedipine used with cyclosporine induce different effects on gingival enlargement. Transplant Proc 2009; 41: 2351–3. Southward J, Irvine E, Rabinovich M. Probable amlodipine-induced angioedema. Ann Pharmacother 2009; 43: 772–6. Kabashima R, Orimo H, Hino R, Nakashima D, Kabashima K, Tokura Y. CD30-positive T-cell pseudolymphoma induced by amlodipine. J Eur Acad Dermatol Venereol 2008; 22: 1522–4. Tsao YT, Chen WL. Calcium channel blocker-induced chylous ascites in peritoneal dialysis. Kidney Int 2009; 75: 868. Chaudhry M, Maqsood A, Diab-Agha S, Rosenberg J. Nicardipine-induced acute

Au1

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[35]

hepatitis in an intensive care unit patient. Am J Ther 2009; 16: 71–3. Fan XH, Han Y, Sun K, Wang Y, Xin Y, Bai Y, Li W, Yang T, Song X, Wang H, Fu C, Chen J, Shi Y, Zhou XL, Wu H, Hui R. Sex differences in blood pressure response to antihypertensive therapy in Chinese patients with hypertension. Ann Pharmacother 2008; 42: 1772–81. Kato J, Mori T, Nakamura Y, Sakurai M, Aisa Y, Ikeda Y, Okamoto S. Hypotension due to the drug interaction of voriconazole with eplerenone and nifedipine. Eur J Clin Pharmacol 2009; 65: 323–4. Mjaset C, Russell MB. Intravenous nimodipine worsening prolonged attack of familial hemiplegic migraine. J Headache Pain 2008; 9: 381–4. van Noord C, Aarnoudse AJLHJ, Eijgelsheim M, Sturkenboom MCJM, Straus SMJM, Hofman A, Kors JA,

[36]

[37]

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Newton-Cheh C, Witteman JCM, Stricker BHC. Calcium channel blockers, NOS1AP, and heart-rate-corrected QT prolongation. Pharmacogenet Genomics 2009; 19: 260–6. Tuka V, Ricarova B, Janota T, Malik J, Kotrlikova E. Surprisingly delayed escalation of severe verapamil poisoning. Eur J Emerg Med 2009; 16(2): 100–2. Buckley CD, Aronson JK. Prolonged halflife of verapamil in a case of overdose: implications for therapy. Br J Clin Pharmacol 1995; 39(6): 680–3. Varpula T, Rapola J, Sallisalmi M, Kurola J. Treatment of serious calcium channel blocker overdose with levosimendan, a calcium sensitizer. Anesth Analg 2009; 108: 790–2. Young AC, Velez LI, Kleinschmidt KC. Intravenous fat emulsion therapy for intentional sustained-release verapamil overdose. Resuscitation 2009; 80(5): 591–3.

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Drugs acting on the cerebral and peripheral circulations

DRUGS USED IN THE TREATMENT OF ARTERIAL DISORDERS OF THE BRAIN AND LIMBS Buflomedil

[SED-15, 566; SEDA-29, 202; SEDA-32, 371]

Death Data on the efficacy of buflomedil in intermittent claudication were retrieved from a Cochrane systematic review, and data on safety were obtained by comparing the number of reports of serious adverse events and deaths published in the literature with those reported in postmarketing surveillance databases [1M]. The authors concluded that the evidence that buflomedil is beneficial is undermined by documented publication bias. They also concluded that there is bias in reporting adverse events to international safety databases, illustrated by the discrepancy between the number of published drugrelated deaths (20), deaths recorded in the WHO database that were potentially drug related (20), and deaths that were attributed to buflomedil in the database of the international marketing authorization holder (11).

Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00019-2 # 2011 Elsevier B.V. All rights reserved.

Cilostazol

[SED-15, 773; SEDA-29, 202; SEDA-30, 231; SEDA-32, 371]

Hematologic A spinal epidural hematoma in the region of T12 to L3 occurred in a 90-yearold man after removal of an epidural catheter while he was taking cilostazol, which was attributed to reduced platelet function [2A]. Drug withdrawal Thrombosis occurred in a drug-eluting stent 3 days after withdrawal of cilostazol and after colonoscopic polypectomy in the presence of a colorectal adenocarcinoma in a 78-year-old man; aspirin and clopidogrel had been continued [3A]. Thrombosis in this case may have been at least partly due to reduced platelet aggregation secondary to loss of the therapeutic effect of cilostazol and it is also possible that there was rebound hyperaggregability of platelets; the contribution of hypercoagulability because of the presence of a cancer could not be assessed. Drug–drug interactions Glycirrhizin Pseudoaldosteronism occurred after cilostazol was added to treatment in a 65-year-old man who had taken glycyrrhizin for 10 years without problems [4A]. His serum potassium concentration, which had been over 4 mmol/l, gradually fell to 2.5 mmol/l during the next 7 months. He had also taken imidapril and olmesartan for over 1 year, and plasma renin activity and aldosterone were suppressed. Urinary potassium excretion was increased, even when there was severe hypokalemia. Glycyrrhizin was withdrawn and he was given oral potassium and spironolactone. The serum 407

408

potassium concentration normalized after 2 weeks, even though the cilostazol was continued. The mechanism was suggested to be displacement by cilostazol from albumin binding sites of glycyrrhizin or its metabolites, glycyrrhetic acid and 3b-monoglucuronyl glycyrrhetic acid, the second of which is thought to be responsible for the potassiumwasting effects of licorice.

Naftidrofuryl Systematic reviews Naftidrofuryl is still being marketed in a number of countries for the symptomatic treatment of intermittent claudication. In a meta-analysis based on individual patient data provided by the manufacturers seven randomized controlled trials published between 1984 and 2001 were reanalysed [5M, 6M]. Naftidrofuryl significantly improved walking distance. There were no significant differences in serious adverse events, but naftidrofuryl led to significantly poorer gastrointestinal tolerance. The safety data were confirmed by the individual data analysis. Drug overdose A 52-year-old man was found dead in his bed [7A]. Autopsy showed no structural cause of death. Analysis of post-mortem blood detected valproic acid in the usual target range and disulfiram above the usual target range, but in each case far below the lethal concentration. However, naftidrofuryl was present in a very high concentration (7500 mg/l) and was thought to have been the cause of death.

DRUGS USED IN THE TREATMENT OF MIGRAINE Triptans [SED-15, 3525; SEDA-31, 346; SEDA-32, 372] Cardiovascular Cases of myocardial infarction in patients taking triptans have been

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P. Verhamme

reviewed in the light of a 54-year-old woman with no history of coronary artery disease who had an acute myocardial infarction 30 minutes after using subcutaneous sumatriptan 6 mg; coronary angiography was normal [8AR].

Nervous system adverse effects of triptans The nervous system adverse effects of triptans have been reviewed in light of the question of whether they can enter the brain [9R]. Some patients complain of sleepiness/ tiredness, difficulty in thinking, and dizziness after sumatriptan [10C], and in a meta-analysis, sumatriptan 100 mg caused 6% more nervous system adverse events than placebo, and zolmitriptan 2.5 mg caused 9% more [11M]. In one large randomized controlled trial [12C] any nervous system adverse events were more frequent after sumatriptan 100 mg (30%; n ¼ 386) than after rizatriptan 10 mg (23%; n ¼ 385) [13C] despite the fact that the two drugs were equally efficacious. In a placebo-controlled study in healthy women triptans had adverse nervous system effects, mainly mild sedative effects, which were less than sedation after temazepam 20 mg; sumatriptan, but not rizatriptan, also caused a significant increase in the electroencephalographic alpha power compared with placebo [14C]. Zolmitriptan 5 and 10 mg, but not sumatriptan 100 mg, had an effect on cortical auditory-evoked potential in humans [15C]. In a placebo-controlled study in men with a history of substance abuse, subcutaneous sumatriptan 8 and 16 mg reduced euphoria dose relatedly and increased apathetic sedation and disliking [16C]. There have also been rare cases of central nervous system effects after subcutaneous and oral sumatriptan, including akathisia [17A], acute dystonia [18A], and pathological laughter [19A]. A seizure has been attributed to almotriptan [20A].

Drugs acting on the cerebral and peripheral circulations • A 37-year-old woman with a history of migraine and a strong family history of migraine, in one case associated with hemiparesis, had a focal left motor seizure with secondary generalization and postictal left hemiparesis 20 minutes after taking almotriptan 12.5 mg for a headache. Six months later she took ergotamine tartrate 2 mg and 1 hour later developed weakness in the left arm for 5 minutes followed 18 hours later by two generalized tonic–clonic seizures.

The authors invoked two mechanisms for this: drug-induced vasoconstriction and a genetic susceptibility, since there are gene mutations (CACNA1A, ATP1A2, SCN1A) that are associated with familial forms of migraine with or without aura, hemiplegic migraine, and epileptic syndromes. However, the nervous system effects of triptans can be partly ascribed to unmasking of the symptoms of migraine, since responders to eletriptan had more nervous system adverse events than non-responders [21C].

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monoamine oxidase inhibitors and the use of sumatriptan within 2 weeks after discontinuation of therapy with monoamine oxidase inhibitors” [23S]. The systemic availability of subcutaneous sumatriptan is nearly 100% and metabolism by monoamine oxidase type A (MAOA) leads to about 40% of the dose appearing in the urine as indole acetic acid, which is inactive. In a survey of summary pharmacokinetic data taken from the literature and from GlaxoSmithKline's study C92-050, a pharmacokinetic compartmental model was used to generate predicted kinetic parameters after the perturbation that would be expected to occur after inhibition by the MAOA inhibitor moclobemide [24H]. The analysis suggested that inhibition of MAOA would be expected to have a trivial effect on the pharmacokinetics of a 6-mg subcutaneous dose of sumatriptan. However, these findings should not be extrapolated to other routes of administration.

Gastrointestinal Acute-on-chronic ischemic colitis has been attributed to rizatriptan [22A]. • A 50-year-old woman with migraine developed abdominal pain and hematochezia after taking rizatriptan intermittently for 3 weeks, not exceeding a total dose of 30 mg/day. She had severe progressive continuous lower abdominal pain with nausea and bloody diarrhea, having had similar milder intermittent abdominal pain for the past few months. Her temperature was 37.7 C, pulse 95/minute, and there was severe tenderness in the lower abdomen without rebound tenderness. There was bright blood in the rectum. Colonoscopy showed moderate to severe colitis in the sigmoid colon, the descending colon, and the transverse colon, with patchy erythema in the rectum and ascending colon, and biopsies showed mild acute and chronic ischemic changes, with acute inflammation, glandular atrophy, and fibrosis in the lamina propria; the terminal ileum was normal as were biopsies from the terminal ileum. The erythrocyte sedimentation rate (ESR) was normal and ANA, ASCA, and pANCA were negative. Rizatriptan was withdrawn and her symptoms gradually improved.

Drug–drug interactions Moclobemide The summary of product characteristics for sumatriptan, under the heading “contraindication”, states “concomitant use of

OTHER PERIPHERAL VASODILATORS Inhibitors of phosphodiesterase type V [SED-15, 3133; SEDA-30, 232; SEDA-31, 346; SEDA-32, 372] Respiratory Vasodilatation induced by PDE-5 inhibitors is responsible for common undesired effects, such as headache, flushing, and nasal congestion. The effect of sildenafil on nasal airways has been measured in 11 young normally potent volunteers using a double-blind crossover design [25C]. Endonasal volume measured with a nasal telescope fell significantly after a dose of sildenafil, as has previously been shown with another technique in a few patients. Nervous system Cerebral vasodilatation, increasing blood flow, is suspected to have increased the risk of intracerebral hemorrhage in a 62-year-old man 2 hours after a first dose of sildenafil 50 mg and before

410

any sexual activity; however, a fortuitous association could not be ruled out [26A]. Sensory systems Adverse effects of PDE-5 inhibitors on the eyes have repeatedly been reported, but it is unclear whether these events are coincidental or related to drugrelated effects on the ocular circulation or on other structures in the eye [27R]. In a multicenter study 244 subjects were randomized to tadalafil 5 mg/day, sildenafil 50 mg/day, or placebo for 6 months [28C]. There was one case of retinal artery occlusion in a patient taking placebo and there were no abnormalities in electroretinography or visual function and no treatmentrelated findings suggestive of drug toxicity. Hematologic Sildenafil has been associated with thrombocytopenia [29A]. • A 53-year-old woman with multiple pathology was admitted to the intensive care unit in respiratory distress. Sildenafil was added empirically to her extensive drug regimen, because of pulmonary hypertension. Her platelet count fell after 1 week. Heparin was first suspected and withdrawn, without effect. Sildenafil was then withdrawn and the platelet count started to rise. Two rechallenges with

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sildenafil because of worsening respiratory function led each time to a new pronounced fall in platelet count. Complete withdrawal of sildenafil resulted in sustained recovery.

The mechanism of this effect in this patient is not known. Drug–drug interactions The use of phosphodiesterase-5 inhibitors with concomitant medications has been reviewed from literature published in 1998–2007 [30R]. Concomitant use of nitrates is completely contraindicated, and the authors suggested that precautions be taken with concomitant use of either alpha-blocking drugs or potent inhibitors of CYP3A. Bosentan The pharmacokinetic interaction of sildenafil and the dual endothelin receptor antagonist bosentan, both of which are marketed for the treatment of pulmonary arterial hypertension, has been studied in 55 healthy men [31C]. Bosentan reduced the Cmax and AUCt of sildenafil, and sildenafil increased the corresponding values of bosentan. The clinical implications for combined therapy are not known.

References [1] De Backer TL, Vander Stichele RH, Van Bortel LM. Bias in benefit-risk appraisal in older products: the case of buflomedil for intermittent claudication. Drug Saf 2009; 32(4): 283–91. [2] Kaneda T, Urimoto G, Suzuki T. Spinal epidural hematoma following epidural catheter removal during antiplatelet therapy with cilostazol. J Anesth 2008; 22(3): 290–3. [3] Im E, Lee SH, Kim JS, Choi D, Jang Y. Drug-eluting stent thrombosis after cilostazol withdrawal in a patient previously treated with triple antiplatelet therapy. Int J Cardiol 2009; 135(2): e55–7. [4] Maeda Y, Inaba N, Aoyagi M, Tanase T, Shiigai T. Pseudoaldosteronism caused by combined administration of cilostazol and glycyrrhizin. Intern Med 2008; 47(14): 1345–8.

[5] De Backer TL, Vander Stichele R, Lehert P, Van Bortel L. Naftidrofuryl for intermittent claudication. Cochrane Database Syst Rev 2008; 2: CD001368. [6] De Backer TL, Vander Stichele R, Lehert P, Van Bortel L. Naftidrofuryl for intermittent claudication: meta-analysis based on individual patient data. BMJ 2009; 338: b603. [7] Koller MF, Schmid M, Iten PX, Vonlanthen B, Bär W. Fatal intoxication with naftidrofuryl. Leg Med (Tokyo) 2009; 11(5): 229–33. [8] Chalaupka FD. Acute myocardial infarction with sumatriptan: a case report and review of the literature. Headache 2009; 49(5): 762–4. [9] Tfelt-Hansen PC. Does sumatriptan cross the blood-brain barrier in animals and man? J Headache Pain 2010; 11(1): 5–12.

Drugs acting on the cerebral and peripheral circulations [10] Gallagher RM, Kunkel R. Migraine patient concerns affecting compliance: results from the NHF survey. Headache 2003; 43: 36–43. [11] Ferrari MD, Goadsby PJ, Roon KI, Lipton RB. Triptans (serotonin, 5-HT1B/1D agonists) in migraine: detailed results and methods of a meta-analysis of 53 trials. Cephalalgia 2002; 22: 633–58. [12] Tfelt-Hansen P, Teall J, Rodriguez F, Giacovazzo M, Paz J, Malbecq W, Block GA, Reines SA, Visser WH. On behalf of the Rizatriptan 030 study Group. Oral rizatriptan versus oral sumatriptan: a direct comparative study in the acute treatment of migraine. Headache 1998; 38: 748–55. [13] Silberstein SD, Diener H-C, McCarrolll KA, Lines CR. CNS effects of sumatriptan and rizatriptan. Cephalalgia 2004; 24: 78–9. [14] van der Post J, Schram MT, Schoemaker RC, Pieters MS, Fuseau E, Pereira A, Baggen S, Cohen AF, van Gerven JM. CNS effects of sumatriptan an rizatriptan in healthy female volunteers. Cephalalgia 2002; 22: 271–81. [15] Proieletti-Cecchini P, Afra J, Schoenen J. Intensity dependence of cortical auditory evoked potential as a surrogate marker of central nervous system serotonin transmission in man: demonstration of a central effect for the 5HT1B/1D agonist zolmitriptan (311C90, Zomig). Cephalalgia 1997; 17: 849–54. [16] Sullivan JT, Preston KL, Testa MP, Busch M, Jasinski DR. Psychoactivity and abuse potential of sumatriptan. Clin Pharmacol Ther 1992; 52: 635–42. [17] López-Alemany M, Ferrer-Tuset C, Bernácer-Alpera B. Akathisia and acute dystonia induced by sumatriptan. J Neurol 1997; 244: 131–3. [18] Oterino A, Pascual J. Sumatriptan-induced axial dystonia in a patient with cluster headache. Cephalalgia 1998; 18: 360–1. [19] Barbanti P, Fabbrini G, Berardelli A. Acute pathological laughter induced by sumatriptan. Cephalalgia 2008; 28: 92–3. [20] Mazzoleni R, Kreisler A, Lucas C, Kwiatkowski A, Gautier S, Destee A, Defebvre L. Seizure after use of almotriptan. Clin Neurol Neurosurg 2008; 110(8): 850–1.

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[21] Goadsby PJ, Dodick D, Almas M, Diener H-C, Tfelt-Hansen P, Lipton RB, Parsson B. Treatment emergent CNS symptoms following triptan therapy are part of the migraine attack. Cephalalgia 2007; 27: 254–62. [22] Alkhatib AA, Gangotena F, Peterson KA. Rizatriptan induced acute on top of chronic ischemic colitis. Am J Gastroenterol 2009; 104(10): 2643–4. [23] Aurobindo Pharma Ltd. Sumatriptan 50 mg Tablets. http://www.medicines.org.uk/EMC/ medicine /23027/SPC/Sumatriptanþ50mgþ Tablets. [24] Fox AW. Subcutaneous sumatriptan pharmacokinetics: delimiting the monoamine oxidase inhibitor effect. Headache 2010; 50 (2): 249–55. [25] Trimarchi M, Salonia A, Bondi S, Montorsi F, Bussi M. Nasal congestion after visual sexual stimulation with and without sildenafil (Viagra): a randomized placebo-controlled study. Eur Arch Otorhinolaryngol 2008; 265(3): 303–6. [26] Alpsan MH, Bebek N, Ciftci FD, Coban O, Bahar S, Tuncay R. Intracerebral hemorrhage associated with sildenafil use: a case report. J Neurol 2008; 255: 932–3. [27] Laties AM. Vision disorders and phosphodiesterase type 5 inhibitors: a review of the evidence to date. Drug Saf 2009; 32: 1–18. [28] Cordell WH, Maturi RK, Costigan TM, Marmor MF, Weleber RG, Coupland SG, Danis RP, McGettigan JW, Antoszyk AN, Klise S, Sides GD, for the ERG testing during chronic PDE5 inhibitor administration (ERG-PDE5i) consortium. Retinal effects of 6 months of daily use of tadalafil or sildenafil. Arch Ophthalmol 2009; 127: 367–73. [29] Philip A, Ramchandani S, Dorrance K, Dorrance C. Sildenafil-induced thrombocytopenia. Ann Intern Med 2008; 149: 437–9. [30] Corona G, Razzolli E, Forti G, Maggi M. The use of phosphodiesterase 5 inhibitors with concomitant medications. J Endocrinol Invest 2008; 31: 799–808. [31] Burgess G, Hoogkamer H, Collings L, Dingemanse J. Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil. Eur J Clin Pharmacol 2008; 64: 43–50.

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Antihypertensive drugs

Antihypertensive drugs and their adverse effects in the perioperative period Introduction A number of risk factors have been identified for perioperative cardiovascular complications, and are used for risk stratification of patients for surgery. These include a history of ischemic heart disease, myocardial dysfunction, or a history of compensated heart failure, a history of cerebrovascular disease, diabetes mellitus, and renal insufficiency. Patients in these risk categories are very likely to be taking one or more antihypertensive medications, both to control arterial hypertension and as therapy for other underlying diseases. Preoperative evaluation is an opportunity to optimize control of cardiovascular risk factors and review medication requirements. The rationale for perioperative antihypertensive medication It is clear that perioperative morbidity and mortality figures for patients with one or more of these risk factors are higher than for those without, in particular for high-risk surgical procedures, including vascular surgery. Current data show rates of 2.7% for perioperative mortality and 4.4% for non-fatal myocardial infarction in patients with cardiovascular risk factors [1C]. During the perioperative period, there is a catecholamine surge, leading to increased myocardial oxygen consumption. The Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00020-9 # 2011 Elsevier B.V. All rights reserved.

rationale for the use of pharmacological therapy in these patients is to reduce this myocardial stress. However, adverse drug effects may act to offset this benefit, making evaluation of net benefit difficult. Although arterial hypertension is not itself an independent risk factor for cardiovascular complications in non-cardiac surgery, the presence of a raised blood pressure should facilitate the identification of patients who are at risk of associated cardiovascular pathology, and prompt a search to be undertaken. In patients with mild to moderate (grade 1 or 2) hypertension, there is no evidence that preoperative optimization is beneficial in the short term, although antihypertensive medications already prescribed should be continued during the perioperative period [2S]. Guidelines also suggest that patients with a systolic blood pressure over 180 mmHg or a diastolic blood pressure over 110 mmHg are at increased perioperative risk, and elective surgery should be deferred until control is achieved. Control over a period of weeks allows cardiovascular risk to be minimized, although rapid control is preferable if the benefit to harm balance favors early surgery [3C]. Perioperative beta-blockers There is a continuing debate about the administration of antihypertensive medications in the perioperative period. Particular focus has been directed at perioperative beta-blockers because they can reduce the incidence of perioperative cardiovascular adverse events. Randomized studies have shown that betaadrenoceptor antagonists can reduce perioperative myocardial ischemia, as assessed by continuous ST-segment monitoring [4C]. 413

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In order to establish whether this confers any clinical benefit, several multicenter randomized controlled trials have been published [1C,5C,6C,7C,8C,9C,10C]. Half of these trials included patients at high risk of perioperative complications, and half did not require the presence of risk factors. Trials that did not identify high-risk categories for surgery did not identify clear benefit from perioperative beta-blockade [5C,6C,9C]. The first trial, in 200 high-risk patients who underwent non-cardiac surgery under general anesthesia using atenolol as the study drug, showed a significantly reduced mortality for up to 2 years of follow up [7C]. Another study, the Dutch Echographic Cardiac Risk Evaulation Applying Stress Echo (DECREASE) trial, selected 112 patients undergoing vascular surgery, carefully selected for high risk with positive dopamine stress echo testing, to receive standard care or bisoprolol, started 1 week before surgery, and titrated to heart rate [8C]. There was an impressive 89% reduction in cardiac mortality/myocardial infarction in the treatment group (3.4% versus 34%), sustained up to 3 years. In by far the largest trial, POISE (PeriOperative ISchaemic Evaluation trial) 8351 patients with cardiovascular risk factors, undergoing non-cardiac surgery, were randomly assigned to metoprolol succinate or placebo 2–4 hours before surgery and to continue for 30 days [1C]. This resulted in a 17% reduction in the composite end-point of death, myocardial infarction, or non-fatal cardiac arrest at 30 days (5.8% versus 6.9%). However, the reduction in non-fatal myocardial infarction was offset by an increase in total mortality (3.1% versus 2.3%) and double the numbers of strokes (1% versus 0.5%). There was more hypotension in the therapy group, and a post-hoc analysis identified this population at most risk of death and stroke. The most recent meta-analysis, pooling the available data, did not identify any significant reduction in all cause or cardiovascular mortality, but confirmed a reduction in non-fatal myocardial infarction and myocardial ischemia at the expense of an increased risk of stroke [11M]. Safety outcomes included a high risk of perioperative bradycardia and hypotension requiring treatment. However, it should be

borne in mind that two-thirds of the pooled data arose from the POISE trial. It is possible that the benefit of the beta-blockade in this group was offset by the method of administration, with introduction of high-dose metoprolol immediately before surgery, leading to postoperative problems with heart rate and blood pressure control. Fixed-dose strategies, used in the majority of trials, do not account for variations in response to medication within populations, leading to inadequate dosing in some patients and too much in others. A more tailored strategy of titration to response is likely to lead to fewer postoperative adverse events. Current advice for using perioperative beta-blockade With this evidence in mind, the current advice is to use beta-blockers in high-risk patients without contraindications during high risk, usually vascular, surgery [12S]. Those with intermediate cardiovascular risk may also benefit [13C]. Beta-blockade should be titrated to achieve a heart rate of 60–70/minute. In order to reduce the morbidity and mortality associated with postoperative hypotension and bradycardia, it is important that beta-blockade is started optimally 1 week to 1 month preoperatively, in order to achieve safe dosage titration. Treatment with a selective beta1-adrenoceptor antagonist without intrinsic sympathomimetic activity is favored. The duration of therapy has not been adequately determined, although the risk of postoperative cardiovascular events continues for several months. Preoperative identification of indications for long-term beta-blockade should lead to consideration of life-long treatment. Beta-blockade as long-term therapy When beta-blockers have been appropriately titrated to effect for indications other than surgery, and a maintenance phase has been achieved, the advice is to continue treatment perioperatively in all groups of patients and all surgical risk categories. When betablockers are prescribed for hypertension, the absence of evidence of perioperative cardioprotective effects of other agents does not support a change in therapy. Higher mortality rates have been observed after beta-blocker withdrawal in observational studies, and so

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this is not advised [14c,15c]. Certainly, when beta-blockers are prescribed for patients with ischemic heart disease, stable heart failure, or dysrhythmias; they should not be discontinued, as these patients fit into high-risk categories for surgery. Beta-blockers should not be continued if there are independent indications to withdraw treatment, such as decompensated heart failure or hypotension [12S]. Drugs acting on the renin-angiotensin system (RAS) It is possible that perioperative treatment with angiotensin converting enzyme (ACE) inhibitors may have beneficial effects on postoperative outcome. This supposition stems from information about longer term benefits independent of blood pressure control, including anti-inflammatory actions, improvements in endothelial function, and end-organ preservation. Evidence from the placebo-controlled QUO VADIS study in patients undergoing cardiac surgery showed fewer postoperative cardiovascular events in those who were randomized to quinapril starting 1 month before surgery and continuing for 1 year [16C]. However, the prolonged duration of treatment may have influenced the results, and a more recent systematic review has questioned these findings [17M]. Intraoperative hypotension attributed to drugs acting on the renin-angiotensin system A complication is the risk that ACE inhibitors can cause severe hypotension during anesthesia [18c,19R], as can the angiotensin receptor blockers (ARBs) [20c], which can also impair the response to standard vasopressors used intraoperatively. This problem can be minimized by drug withdrawal the day before surgery. However, treatment should be resumed as soon as practicable postoperatively, assuming stabilized intravascular volume. Patients at high risk of perioperative cardiovascular risk, in particular those with stable left ventricular dysfunction, may benefit from continued ACE inhibition, although there is still a risk of intraoperative hypotension [12S,21c]. A more informed choice may be possible after the publication of a larger trial, currently recruiting, in which continued ACE inhibition is

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being compared with a short period of withdrawal preoperatively [22S]. Other specific considerations of perioperative use of ACE inhibitors The risk of angioedema with ACE inhibitors is a susceptibility factor in dental and maxillofacial surgery, during which orofacial manipulation can lead to localized angioedema. This adverse effect must be recognized when edema of the face, lips, oral cavity, or larynx occurs perioperatively in patients taking ACE inhibitors. Calcium channel blocking drugs Most of the work on perioperative outcomes has focused on reducing myocardial oxygen demand using beta-blockade. Calcium channel blockers may be suitable alternatives in high-risk patients with contraindications to beta-adrenoceptor antagonists. However, the dihydropyridines do not offer the protection that those with heart-rate lowering properties offer, and may even worsen outcome [23C]. Other antihypertensive agents There is little direct evidence to support the use of other antihypertensive agents perioperatively, although advice is to continue drugs already prescribed. Although diuretics are usually used in low doses compared with those used in heart failure, the possibility of electrolyte disturbances should be remembered, as potassium imbalance can increase the risk of perioperative dysrhythmias and worsen outcomes [24c]. The use of perioperative alpha2 adrenoceptor agonists may improve outcomes in high-risk patients, but most of the supportive evidence is confined to vascular surgery [25M]. However, a randomized trial of moxonidine in patients undergoing major vascular surgery showed no evidence of a beneficial effect on mortality or perioperative myocardial ischemia [26C]. Conclusion The current evidence does not support the need to treat moderate arterial hypertension aggressively perioperatively, but supports continued medication when possible unless clinical circumstances dictate otherwise. Most of the evidence for starting antihypertensive drug treatment relates to risk modification in patients at high cardiovascular risk. Many

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high-risk patients will have arterial hypertension, and this should prompt a cardiovascular risk assessment and drug therapy when there is a sound evidence base.

ANGIOTENSIN CONVERTING ENZYME INHIBITORS [SED-15, 226; SEDA-30, 234; SEDA-31, 350; SEDA-32, 379] Combination studies There is continued interest in the use of drug combinations involving angiotensin converting enzyme (ACE) inhibitors and other inhibitors of the renin–angiotensin–aldosterone system (RAAS). While attempts are being made to quantify the beneficial clinical effects of such combinations, there are clear concerns about the potential for renal impairment and electrolyte imbalance, including hyperkalemia. The efficacy and safety of adding another RAAS inhibitor or blocker to an ACE inhibitor or an angiotensin II receptor antagonist plus a beta-adrenoceptor antagonist in heart failure secondary to left ventricular systolic dysfunction has been discussed [27r]. It is difficult to know how much RAAS blockade is too much in such cases, in view of uncertain benefits and significant increases in adverse effects. The combined use of ACE inhibitors and angiotensin II receptor antagonists is also considered to carry limited benefits and evidence of renal adverse effects [28r]. In an analysis of the Valsartan in Heart Failure Trial (Val-HeFT), focusing on chronic kidney disease, the benefits and harms of dual blockade of the RAAS have been explored [29C]. Compared with the addition of placebo to ACE inhibition, the addition of valsartan led to higher rates of discontinuation and hyperkalemia in those with chronic kidney disease at baseline. However, the authors argued that the overall benefits of combined therapy would outweigh the risks even in those with chronic kidney disease.

In a large industry-sponsored randomized study, the ONTARGET trial (Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial), the effects of telmisartan, ramipril, alone or in combination were examined in patients without heart failure [30C]. Telmisartan and ramipril both increased the risks of renal impairment, as measured by the primary renal end-points of first occurrence of dialysis, renal transplantation, doubling of serum creatinine, or death [31C]. However, combination therapy, while associated with a lower rate of proteinuria, was associated with a significant increase in the primary renal outcomes. One hypothesis for the poorer renal outcomes with combination therapy compared with single therapy is a greater reduction in glomerular filtration rate in those with unknown renal artery stenosis. In an open, randomized, crossover trial in 18 patients with chronic non-diabetic proteinuric kidney disease, double blockade with telmisartan and cilazapril plus hydrochlorothiazide was compared with triple blockade (the addition of spironolactone) [32c]. Plasma renin activity and proteinuria were reduced, but the risk of hyperkalemia increased. Respiratory In 199 patients with heart failure taking enalapril there was a higher incidence of cough in those with non-severe heart failure (classes I or II) than in those with classes III and IV [33c]. An ejection fraction over 40% or a brain natriuretic peptide (BNP) concentration under 3000 ng/l predicted the risk of cough. The authors suggested that cough may be a marker of non-severe heart failure and that the highly activated renin–angiotensin system in severe congestive heart failure might prevent bradykinin buildup, even in the presence of ACE inhibition. The problems of multiple prescribing in the elderly have been discussed in the context of a case of enalapril-associated dry cough misdiagnosed as pneumonia [34A]. The prescribed antibiotics caused pseudomembranous colitis and an opioidbased syrup contributed to delirium. The authors drew attention to the effect of the “prescribing cascade” that can occur following the failure to identify an adverse drug reaction.

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It has been hypothesized that the combination of ACE inhibitors and aliskiren may reduce the rate of cough associated with ACE inhibitors [35H]. The theoretical mechanism suggested is that aliskiren reduces renin activity and plasma concentrations of angiotensin I, leaving more uninhibited ACE free to metabolize bradykinin. However, this hypothesis is based on a non-statistically significant difference in cough rates between ramipril and ramipril þ aliskiren in a trial that was not primarily designed to ascertain differences in rates of cough. Metabolism Hypoglycemia associated with ACE inhibitors has been a concern, particularly given their benefits in hypertension in diabetes mellitus. In a systematic review of drug-induced hypoglycemia, ACE inhibitors emerged as one of the most common groups of drugs associated with hypoglycemia [36M]. However, the evidence base was considered to be of low quality. Autacoids There have been many studies of the association of ACE inhibitors with angioedema (SEDA-29, 207; SEDA-31, 352; SEDA-32, 380). EIDOS classification: Extrinsic moiety ACE inhibitors Intrinsic moiety Tissues affected by bradykinin Distribution Areas of production of bradykinin Outcome Tissue swelling (lips and tongue, larynx and pharynx) Sequela Angioedema from ACE inhibitors DoTS classification: Dose-relation Hypersusceptibility reaction Time-course Intermediate Susceptibility factors Genetic (blacks; dipeptidyl peptidase IV deficiency); sex (female); exogenous factors (drugs— NSAIDs, vaccines, immunosuppressants; surgery—dental and maxillofacial procedures; devices—polyacrylonitrile membranes in hemodialysis); diseases

417

(a history of angioedema; acquired dipeptidyl peptidase IV deficiency)

The incidence of ACE inhibitor-induced angioedema has been investigated in a retrospective study of admissions to an emergency admissions unit [37c]. In a randomized trial of ramipril 5 mg/day (n ¼ 505) versus placebo (n ¼ 503) in patients with hypertension there was no difference in the frequency and types of adverse events and serious adverse events [38C]. However, cough was more common with ramipril (4.8%) than placebo (0.4%). Diagnosis of angioedema can sometimes be difficult. In a 59-year-old woman taking long-term enalapril CT and MR, imaging showed a right peritonsillar/pharyngeal mass like lesion, suggesting a differential diagnosis of infection or a tumor [39A]. However, 1 day later, a contrast-enhanced MR image showed no focal mass and the tonsils and pharynx were normal. Enalapril was withdrawn and her symptoms subsided. The authors advised that clinicians and radiologists should be aware of the unexpected focal nature of angioedema. Cerebral angioedema has been associated with enalapril [40A]. • A 28-year-old woman with systemic lupus erythematosus developed angioedema of the face and lip without airways involvement after taking enalapril for 2 weeks. Several hours later she had tonic-clonic seizures, which were controlled with diazepam and phenytoin. A CT scan showed extensive cerebral edema involving white matter. Enalapril was withdrawn and she received supportive treatment and intravenous dexamethasone 10 mg every 12 hours.

Susceptibility factors Hyperkalemia associated with ACE inhibitors is often associated with drug–drug interactions, in particular with aldosterone antagonists such as spironolactone. In a prospective observational cohort study of cardiac patients taking ACE inhibitors with interacting drugs [41C], one in 10 patients had hyperkalemia suspected to be associated with a drug–drug interaction. Predictive susceptibility factors for hyperkalemia

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included advanced age, renal disease, hepatic disease, and polypharmacy. The authors argued that susceptibility factors should trigger more frequent monitoring. Using the African American Study of Kidney Disease and Hypertension (AASK) database, non-diabetic adults were randomly assigned to ACE inhibitors, beta adrenoceptor antagonists, or calcium channel blockers [42C]. Hyperkalemia was associated with a reduced glomerular filtration rate (below 41 ml/minute/1.73 m2). Hyperkalemia was also significantly more common with ACE inhibitors. The use of a potassium-wasting diuretic was associated with a 59% reduction in the risk of hyperkalemia.

Enalapril [SED-15,1210; SEDA-30, 235; SEDA-31, 355; SEDA-32, 384] Musculoskeletal Pseudopolymyalgia been associated with enalapril [46A].

has

• A 72-year-old man developed myalgia, morning stiffness, and polyarthritis after taking enalapril 10 mg/day for 3 months. There were no laboratory changes and no changes on CT scan; the symptoms disappeared within 3 months of withdrawal.

Lisinopril [SED-15, 2071; SEDA-30, 237; SEDA-31, 357; SEDA-32, 385]

Benazepril [SED-15, 420; SEDA-29, 209]

Skin Erythroderma associated with lisinopril has been reported [47A].

Liver A 32-year-old woman with type 2 diabetes and hypertension who had taken benazepril for 14 weeks developed jaundice; a liver biopsy showed marked cholestasis with necrosis and inflammatory changes [43A].

ANGIOTENSIN II RECEPTOR ANTAGONISTS

Captopril [SED-15, 625; SEDA-31, 355; SEDA-32, 384] Electrolyte balance Hyperkalemia (6.0 mmol/l) has been reported in an 18-monthold child who had received long-term captopril after an elective operation on a type 1 truncus arteriosus defect [44A]. The child also had anemia, presumed to be due to erythroid hypoplasia. Skin Contact dermatitis associated with captopril has been reported on the hands and eyelids of a 35-year-old mother who was giving captopril syrup to her child [45A]. Patch testing isolated captopril as the causative agent, and the authors suggested that the thiol (sulfhydryl) component was the cause. Exposure to captopril was thought to have occurred during both administration of the drug and exposure to unmetabolized captopril in the urine of the child when changing nappies.

[SED-15, 223; SEDA-30, 238; SEDA31, 358; SEDA-32, 387] Autacoids Angioedema attributed to angiotensin receptor blockers continues to be reported [48c]. EIDOS classification: Extrinsic moiety Angiotensin II receptor antagonists Intrinsic moiety Tissues affected by bradykinin Distribution Areas of production of bradykinin Outcome Tissue swelling (lips and tongue, larynx and pharynx) Sequela Angioedema DoTS classification: Dose-relation? Collateral Time-course Time independent Susceptibility factors Previous angioedema with an ACE inhibitor

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A meta-analysis of the risk of angioedema associated with angiotensin II receptor blockers in patients with previous angioedema associated with ACE inhibitors has suggested that the risk of subsequent angioedema is 2–17% for any subsequent angioedema and 0–9.2% for confirmed angioedema [49M]. Teratogenicity In a retrospective analysis of 26 735 pregnant women with hypertension, only five had used angiotensin II receptor antagonists [50c]. In all five cases the angiotensin II receptor antagonist was withdrawn when pregnancy was confirmed (between weeks 5 and 23). There were two deliveries of healthy babies at term and one full-term baby had an additional finger and toe. The other two pregnancies were complicated by oligohydramnios, ending in pre-term delivery.

Candesartan [SED-15, 612; SEDA-30, 241; SEDA-31, 358; SEDA-32, 386] Teratogenicity A woman who took candesartan 8 mg for 2 years before and throughout her pregnancy for idiopathic hypertension delivered a boy by cesarean section at 34 weeks who subsequently died following respiratory difficulties [51A]. The autopsy showed hypoplasia, renal dysplasia, and calvarial hypoplasia with brain malformation. The authors noted that the known risk of fetal toxicity associated with candesartan may be ignored by prescribers.

Losartan

[SED-15, 2168; SEDA-30, 242; SEDA-31, 359; SEDA-32, 000]

Comparative studies In a double-blind comparison of losartan 50 and 150 mg/day in patients with heart failure, high-dose losartan had a beneficial effect on mortality and hospital admissions with heart failure [52C]. However, hyperkalemia, hypotension, renal impairment, and angioedema were more common in the high-dose group.

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Cardiovascular A woman taking losartan 25 mg/day and carbamazepine was admitted to hospital with head trauma secondary to syncope; her heart rate was 30/minute and her serum potassium concentration 6.7 mmol/l [53A]. It was suspected that the hyperkalemia was associated with losartan, leading to third-degree sinoatrial block or complete sinus arrest. Sensory systems Taste Dysgeusia in a 78year-old woman occurred after losartan was added to her antihypertensive treatment [54A]. She described a constant unpleasant taste, which resolved within 2 weeks after replacement of losartan by amlodipine.

Olmesartan

[SEDA-32, 387]

Nervous system In a non-interventional study of olmesartan, with 6 weeks followup, dizziness was the most frequent adverse reaction (0.19%) [55c]. Fetotoxicity Olmesartan given in the last month of pregnancy was associated with oligohydramnios [56A]. The neonate developed severe renal failure and died at 45 days. A post-mortem showed tubal dysgenesis in the kidneys, alveolar damage, pulmonary hemorrhage, and focal pneumonia. An association with olmesartan in this case seems unlikely, given its late introduction in pregnancy.

Telmisartan

[SED-15, 3311; SEDA-30, 242; SEDA-31, 360; SEDA-32, 388]

Drug–drug interactions Mycophenolate mofetil In a pharmacokinetic study of telmisartan, valsartan, and candesartan in combination with mycophenolate mofetil in renal transplant patients, telmisartan increased the elimination of mycophenolic acid; there was no interaction with valsartan or candesartan [57c]. It was suggested that this was due to activation by

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telmisartan of PPAR-g, leading to increased glucuronidation of mycophenolate. The authors suggested periodic monitoring of mycophenolate concentrations during co-administration with telmisartan.

Valsartan [SED-15, 3593; SEDA-30, 242; SEDA-31, 360; SEDA-32, 388] Observational studies In an open singledose study of valsartan in children and adolescents with hypertension, only minor adverse effects (such as headache) were recorded; there were no serious adverse events or clinically significant laboratory results [58c]. Placebo-controlled studies In a doubleblind randomized trial of valsartan in 90 children, with an open follow-up arm, there were no changes in linear growth, weight gain, or head circumference, or developmental disorders; drug-related adverse events were similar with placebo and valsartan [59c]. Cardiovascular Prolonged hypotension followed an intentional overdose of amlodipine and valsartan [60A].

DIRECT RENIN INHIBITORS [SEDA-30,

242; SEDA-31, 360; SEDA-32, 000] NON-PEPTIDE INHIBITORS

Aliskiren [SEDA-30, 242; SEDA-32, 388] Systematic reviews Several reviews of aliskiren have included information on its adverse effects [61R,62R,63R]. In addition, a Cochrane systematic review and metaanalysis has been conducted, for which the authors reviewed six trials in 3684 patients [64M]. Adverse events reported in these

trials included headache, nasopharyngitis, diarrhea, and back pain; but the rates of these events were similar between placebo and all doses of aliskiren. Cardiovascular Prolongation of the QT interval and resultant torsade de pointes and cardiac arrest has been attributed to aliskiren [65A]. The patient had multiple co-morbidities and was taking several cardioactive drugs, including sotalol, which prolongs the QT interval. However, the QT intervals measured while the patient was taking sotalol but before aliskiren was added led the authors to suggest that aliskiren had caused the dysrhythmia. The potential weaknesses in attributing causality to this adverse reaction, especially given the absence of evidence in other post-marketing data were highlighted in an accompanying editorial, which concluded with prudent advice: “it is not possible to implicate aliskiren as a sole cause of QT prolongation in this patient, but it may suggest that patients on sotalol should be monitored when starting aliskiren” [66r]. Furthermore, a study of aliskiren (at up to four times the normal dosing limit) in nearly 300 healthy volunteers has also shown no adverse effects on cardiac conduction and repolarization [67c]. Urinary tract Acute renal insufficiency with hyperkalemia has been reported in a 76year-old hypertensive woman taking both aliskiren and spironolactone [68A]. Preexisting renal impairment and concomitant use of an aldosterone receptor antagonist were predisposing factors, and it is not surprising that the same pattern of adverse effects is seen in cases like this as have been seen with ACE inhibitors and angiotensin receptor blockers before. Drug overdose An accidental single ingestion of aliskiren 300 mg in a 12-year-old child led to falls in systolic and diastolic pressures of 63 and 40 mmHg respectively without any permanent adverse consequences [69A]. Drug–drug interactions Several industrysponsored interaction studies of aliskiren

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have been conducted in healthy volunteers [70c,71c,72c,73c]. These studies have shown that it is safe to co-administer aliskiren with acenocoumarol, atorvastatin, digoxin, fenofibrate, ketoconazole, metformin, pioglitazone, and modified-release isosorbide mononitrate. The only co-administered drug whose exposure was reduced was furosemide, although the clinical significance of this interaction is uncertain.

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The clinical pharmacology, use, and adverse effects of ambrisentan in the management of pulmonary artery hypertension have been reviewed [75R]. The adverse effects of ambrisentan include peripheral edema, nasal congestion, palpitation, flushing, nasopharyngitis, and sinusitis. In placebo-controlled trials lasting up to 12 weeks the incidence of liver enzyme function abnormalities is lower with ambrisentan than with placebo.

propionic acid-based compound rather than a sulfonamide, and its adverse hepatic effects are known to be different. Previous short-term studies have suggested that ambrisentan may be associated with a lower risk of aminotransferase abnormalities. This study supports this view, as none of the 36 patient had serum transaminase activities more than three times the upper limit of normal, although one had a transient rise that resolved after temporary dosage reduction. Most of the other adverse effects were similar to those in studies of other endothelin receptor antagonists, including peripheral edema, flushing, and headache. However, the results of longerterm studies have shown that ambrisentan can cause liver abnormalities and can lead to treatment withdrawal; at present it is possible that the differences in reporting rates of liver enzyme adverse effects with different agents can be attributed to different rates of exposure. A long-term extension study—ARIES-E (Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies)—of the original 12 week randomized trials (ARIES-1 and ARIES-2) has been reported [77c]. From the original 383 patients, 261 patients were still taking ambrisentan after 2 years, during which time 42 had died and 22 had withdrawn because of adverse events, most of which were consistent with disease progression. The annual incidence of aminotransferase abnormalities was about 2%, and although this rate is low, 12 patients had enzyme rises to more than 3 times the upper limit of normal and two withdrew as a result. Monitoring of liver function is therefore still advised.

Liver The availability of ambrisentan in patients with pulmonary artery hypertension who have previously discontinued other endothelin receptor antagonists because of liver function abnormalities provides an important option for patients who have had adverse reactions to bosentan or sitaxsentan [76c]. Ambrisentan is a

Drug–drug interactions Tadalafil The interaction of ambrisentan with tadalafil has been investigated in a crossover study in 26 healthy adults [78c]. In contrast to bosentan, there was no interaction, and dosage adjustment is not necessary during combination therapy.

ENDOTHELIN RECEPTOR ANTAGONISTS [SED-15, 1215; SEDA-30, 245; SEDA-31, 360; SEDA32, 389] The biological basis and clinical data underlying the practical use of endothelin receptor antagonists (ERAs) in the field of pulmonary hypertension have been reviewed [74R].

Ambrisentan

[SEDA-30, 245; SEDA-31, 361; SEDA-32, 389]

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Warfarin In a crossover study in 22 healthy subjects multiple doses of ambrisentan had no clinically relevant effects on the pharmacokinetics and pharmacodynamics of a single dose of warfarin [79c].

(such as dyspnea and pneumonia) were not uncommon but were not judged to be related to bosentan by the investigators; withdrawals most often involved worse dyspnea (6%), general deterioration in physical health (6%), and liver enzyme increases (6%).

Bosentan [SED-15, 549; SEDA-30, 245; SEDA-31, 361; SEDA-32, 389]

Placebo-controlled studies In a randomized placebo-controlled trial of bosentan in 30 patients with severe chronic obstructive pulmonary disease (COPD) without evidence of severe pulmonary hypertension at rest there was no evidence of improved exercise capacity; in fact, hypoxemia and functional status deteriorated [84c]. The use of bosentan in patients with mildly symptomatic pulmonary arterial hypertension has been studied in a multicenter, double-blind, randomized, placebo-controlled trial (the EARLY study) [85C]. Patients over 12 years of age (n ¼ 185) with less functional compromise (WHO functional class 2) were randomized to bosentan or placebo and followed for 6 months double-blind, followed by an open extension period. Adverse events were common in both groups and included nasopharyngitis and abnormal liver enzymes in the bosentan arm. Laboratory tests identified increases in aminotransferases of more than three times the upper limit of normal in 12 (13%) patients taking bosentan compared with two (2%) patients taking placebo. Liver enzyme abnormalities invariably resolved on dose reduction or drug withdrawal.

Observational studies Experience with bosentan in the European postmarketing surveillance program in children has been described [80c]. The analysis compared older (12 years and over) and younger children, most of whom had idiopathic pulmonary hypertension or secondary to congenital heart disease. Hepatic aminotransferase activities were increased in fewer younger children (2.7% versus 7.8%) and withdrawal rates were also lower in those under 12 years. As well as confirming the value of monthly liver function monitoring, this industry-sponsored analysis may suggest that bosentan is better tolerated in children than in adults. The use of endothelin receptor antagonists for pulmonary hypertension has been examined in 14 high-risk adults with sickle cell disease [81c]. Most were taking bosentan and three were taking ambrisentan. There were similar adverse effects as in previous studies, including rises in serum alanine aminotransferase (n ¼ 2), peripheral edema (4), rash (1), headache (3), and reduced hemoglobin (2), none of which required drug withdrawal. In unselected patients with HIV-associated pulmonary hypertension bosentan was safe in combination with highly active antiretroviral therapy; there were no adverse effects on the control of HIV infection [82c]. In a study of the long-term effects of bosentan in pulmonary hypertension associated with connective tissue disorders over a follow-up period of 48 weeks in 53 patients [83c] there were frequent adverse events, such as peripheral edema, nausea, and worse dyspnea; serious adverse events

Immunologic Delayed hypersensitivity in a patient taking bosentan has been described [86A]. • A 44-year-old Hispanic woman with pulmonary hypertension secondary to scleroderma, but no previous allergic disorders, had a generalized maculopapular rashafter taking bosentan for 18 days. Her symptoms subsided with oral betamethasone for 10 days and 1 month later she underwent skin tests, patch tests, lymphocyte transformation tests (all of which were also performed in three controls who had scleroderma and who had tolerated bosentan), and a controlled oral provocation test. The skin and patch tests were negative

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in both the patient and controls, but the lymphocyte transformation test was positive only in the patient. In the oral provocation test, bosentan at 1% of the therapeutic dose provoked pruritus, erythema, angioedema, fever, rash, bronchospasm, eosinophilia, and hepatic/renal abnormalities within 24 hours, consistent with drug rash with eosinophilia and systemic symptoms (DRESS).

Extensive investigation in this case confirmed cell-mediated hypersensitivity to bosentan.

Sitaxsentan [SEDA-30, 245; SEDA-31, 362; SEDA-32, 390] Observational studies STRIDE-2X is the 1-year open extension study of the 18 week STRIDE-2 (Sitaxsentan To Relieve ImpaireD Exercise) investigation that followed patients taking sitaxsentan or bosentan for pulmonary artery hypertension [87C]. As well as efficacy measures, the researchers included time to withdrawal because of adverse events and time to rises in hepatic aminotransferases in the outcome measures. For the analysis population, the risk of raised aminotransferases to more than 3 times the upper limit of normal at 1 year was 6% with sitaxsentan 100 mg/day and 14% with bosentan. The cumulative risk of withdrawal at 1 year with raised aminotransferases was 3% with sitaxsentan 100 mg/day and 9% with bosentan. Other adverse events were peripheral edema, nasopharyngitis, dyspnea, and cough, consistent with previous trials in pulmonary artery hypertension. The overall withdrawal rates at 1 year were 15% with sitaxsentan 100 mg/ day and 30% with bosentan. Sitaxsentan therefore seems to have similar efficacy to bosentan and from this evidence may have the advantage of causing fewer hepatic adverse events in longer-term treatment (but see below). Liver In addition to the trial evidence, case studies of sitaxsentan and hepatic dysfunction have been reported. Liver damage associated with sitaxsentan progressed

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despite drug withdrawal, but eventually responded to glucocorticoid therapy [88A]. A liver biopsy was not obtained in this case, but the authors surmised that the pattern of adverse features and response to glucocorticoids suggested an immune-mediated mechanism. Two other cases of severe liver dysfunction have been attributed to sitaxsentan within 12 weeks of treatment [89A]. In both patients the aminotransferase activities peaked at up to 30 times the upper limit of normal and both had protracted periods of jaundice. Only the first was symptomatic at presentation, whereas the second was detected on routine liver function test monitoring. These three cases have been discussed in the light of an earlier study of two cases and an unreported case of severe hepatitis [90r]. The author discussed the atypical presentations and also suggested that these cases were much more serious (severe progressive liver dysfunction despite drug withdrawal) than previous cases of hepatotoxicity during therapy with endothelin receptor antagonists. Therefore although there is direct comparative evidence from trial data of possible benefits of sitaxsentan compared with bosentan, it is possible that despite fewer cases of raised aminotransferases, there may be a greater potential for severe and possibly fatal liver toxicity from sitaxsentan.

Drug–drug interactions Acenocoumarol Endothelin receptor antagonists and oral anticoagulants are commonly used in patients with pulmonary artery hypertension, and their interaction has been examined [91c] in a subgroup analysis of patients who were enrolled in the STRIDE-3 trial. There were increases in INR up to 4.0 or more in 26 of 51 patients taking acenocoumarol, but no significant bleeding events, suggesting that with close dosage adjustment co-administration of sitaxsentan with acenocoumarol should be manageable.

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DRUGS THAT ACT ON THE SYMPATHETIC NERVOUS SYSTEM [SEDA-30, 245; SEDA-31, 362; SEDA-32, 391] PRESYNAPTIC ALPHAADRENOCEPTOR AGONISTS

Clonidine

[SED-15, 817; SEDA-30, 245; SEDA-31, 362; SEDA-32, 391] Cardiovascular In a phase II dose-ranging study of clonidine in the treatment of acute organophosphorus poisoning there was a significantly higher incidence of hypotension in the higher dosage group, which required temporary withdrawal of treatment in several cases [92A].

Nervous system Clonidine has been successfully used for impulsive and oppositional behavior in attention-deficit hyperactivity disorder as well as for its centrally mediated sedative action when taken late in the day. A child who took clonidine for this indication had night terrors shortly after initial therapy, insomnia during attempts at drug withdrawal, and depression when the drug was finally tapered and stopped [93A]. Body temperature Fever has been associated with clonidine [94A]. • A 66-year-old woman with Alzheimer's disease, morbid obesity, hypertension, and depression, who was taking memantine, donepezil, duloxetine, metoprolol, amlodipine, and clonidine 100 micrograms tds, had a nonST segment elevation myocardial infarction and was given aspirin, atorvastatin, and clopidogrel. The dose of clonidine was doubled to optimize blood pressure control, after which she developed a high fluctuating fever. Clinical and laboratory examinations did not reveal a source for the fever, which settled only after the clonidine dosage reduction and withdrawal.

Whether it was the increased dose of clonidine alone or interactions with the previous or new medicines is unclear, but the temporal relation suggested a probable association with clonidine.

Drug overdose A systems error related to incorrect pharmaceutical preparation of an epidural solution containing bupivacaine, adrenaline, and clonidine led to a 100-fold overdose of the clonidine component in three infants undergoing surgery [95A]. All three had prolonged sedation postoperatively but none required medical interventions or had any lasting sequelae. The authors suggested that this overdosing error offered some indication of the margin of safety for epidural clonidine dosing in healthy children. Drug–drug interactions Escitalopram An interaction of clonidine with escitalopram has been reported [96A]. • Clonidine was given to a 66-year-old critically ill patient to control agitation, after which her regular medications including escitalopram were started 1 day later. Over 3 days she became more sedated to the level of near unconsciousness. This resolved when the escitalopram was withdrawn.

Combinations of centrally acting drugs with possible sedative effects should be used cautiously in critically ill patients.

Methyldopa

[SED-15, 2291; SEDA-31, 363; SEDA-32, 391] Hematologic Methyldopa-induced hemolytic anemia has been described in a young woman with hypertension [97A].

• A 26-year-old woman taking a combined oral contraceptive took methyldopa for hypertension as she was planning a pregnancy in the near future. She developed a hemolytic anemia. The methyldopa was withdrawn and the anemia resolved within 6 weeks.

Liver Two independent case reports have described acute hepatitis in pregnancy related to methyldopa [98A,99A]. Each presented with jaundice and dark urine; one in the first trimester and one in the second trimester. In both cases the hepatitis resolved quickly, although in one case prednisolone was given.

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Fetotoxicity A positive antiglobulin test in a neonate investigated for jaundice was related to her mother's use of methyldopa during pregnancy [100A]. The authors correctly pointed out that the presence of a positive direct antiglobulin test in the absence of blood group incompatibility should prompt a search for a drug-related cause. Drug overdose A mixed overdose of methyldopa, theophylline, indapamide, and paracetamol led to prolonged severe hypotension in an 89-year-old man, who required vigorous intravenous fluid replacement and several days of intravenous noradrenaline to maintain his vital signs [101A].

POSTSYNAPTIC a-ADRENOCEPTOR ANTAGONISTS [SEDA-30,

246;

SEDA-31, 363; SEDA-32, 391] The use of postsynaptic a-adrenoceptor antagonists in older patients with benign prostatic hyperplasia has been reviewed [102R]. Cardiovascular Postsynaptic a-adrenoceptor antagonists cause vasodilatation, and therefore, while they are useful as antihypertensive agents, they are associated with adverse effects such as dizziness, presyncope, and syncope. These adverse effects are particularly important for patients with benign prostatic hyperplasia, who are not hypertensive. A meta-analysis has shown that the use of postsynaptic a-adrenoceptor antagonists (including alfuzosin, terazosin, doxazosin, and doxazosin GITS) for benign prostatic hyperplasia confers an added risk of vascular-related adverse events compared with placebo [103M]. Tamsulosin was associated with a non-statistically significant trend toward a higher incidence of such events; vasodilatory adverse effects are likely to be related to the selectivity profiles of individual drugs.

Sensory systems Intraoperative floppy iris syndrome (IFIS) in cataract surgery is associated with a-adrenoceptor antagonists, especially tamsulosin. The factors associated with IFIS have been explored in a comparative case series [104c]. When standard criteria for identifying IFIS were used, 4.1% of 660 patients undergoing routine cataract surgery were affected. The use of tamsulosin or other a-adrenoceptor antagonists correlated with the syndrome. The association has already been fairly clearly verified; however, this analysis also showed that 8 out of 9 patients with IFIS but without evidence of current or past a-adrenoceptor antagonist exposure had hypertension. Given the current evidence it is impossible to ascertain whether hypertension is an independent susceptibility factor for IFIS. Musculoskeletal The association of aadrenoceptor antagonists with fractures has been studied in a Korean case–control study using a health insurance database [105c]. After adjustment for the use of other agents (5a-reductase inhibitors, antidepressants, antipsychotic drugs, benzodiazepines, and calcium channel blockers) there was an increased risk of fractures in patients taking doxazosin or tamsulosin, but not terazosin or alfuzosin. Sexual function There was a clear association between a-adrenoceptor antagonists and ejaculatory dysfunction (pain/discomfort) in an observational study in Spanish men with benign prostatic hyperplasia and/or lower urinary tract symptoms [106c]. The presence and severity of symptoms were assessed using the male sexual health questionnaire; there was an 83% prevalence of ejaculatory dysfunction in patients taking a-adrenoceptor antagonists. Most cases of ejaculatory dysfunction were mild and severe dysfunction occurred in only 4% of cases. Although the adverse effects on sexual function were seen with all of the a-adrenoceptor antagonists, alfuzosin was associated with better ejaculatory function than tamsulosin, terazosin, or doxazosin.

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Doxazosin [SED-15, 1188; SEDA-30, 246; SEDA-31, 363; SEDA-32, 392]

Tamsulosin [SED-15, 3303; SEDA-30, 246; SEDA-31, 364; SEDA-32, 392]

Observational studies In a retrospective review of 97 patients with hypertension, doxazosin was usually added as a fifth agent in doses of 2–16 mg/day [107c]. Adverse effects related to doxazosin were rare and drug withdrawal was necessary in only five patients.

Sensory systems Eyes The association between tamsulosin and adverse ophthalmic events related to cataract surgery has been examined in two non-randomized studies. In the first, patients undergoing cataract surgery in Turkey were prospectively examined; 15 patients developed IFIS, 12 of whom were taking systemic tamsulosin [111c]. The second study was a nested case-control analysis which used Canadian linked health-care databases to assess the risk of adverse events after cataract surgery [112C]. There were serious adverse ophthalmic events up to 14 days after surgery, including retinal detachment, lost lens or lens fragment, and endophthalmitis. Adverse events were significantly more common among patients with recent tamsulosin exposure (adjusted OR ¼ 2.33; 95% CI ¼ 1.22, 4.43). Recent exposure to other a-adrenoceptor antagonists or prior exposure to tamsulosin was not significantly associated with the same events. Because of the nature of this research, it is not possible to link the adverse outcomes definitively to episodes of IFIS, but this study is set apart from previous work as it has linked tamsulosin exposure to clinically important postoperative complications, which one can surmise relate to more common drug-induced intra-operative complications.

Sexual function Retrograde ejaculation has been described in a young man with a pheochromocytoma who took doxazosin for preoperative blood pressure control [108A].

Indoramin

[SED-15, 1746]

Drug overdose Cardiovascular collapse and prolongation of the QT interval with torsade de pointes was been reported in two cases of self-poisoning with large doses of indoramin [109A]. The risk of indoraminassociated cardiotoxicity and torsade de pointes appears to be high when the dose is more than 750 mg.

Prazosin

[SED-15, 2915; SEDA-32, 392]

Cardiovascular Prazosin, used to treat the symptoms of sleep-related post-traumatic stress disorder (PTSD), has been linked to chest pain [110A]. • A 25-year-old male veteran developed PTSD after deployment in Iraq and was given prazosin 1 mg at night for sleep disturbance. After only a few doses he developed acute, intermittent, left-sided chest pain. No alternative cause could be found for the pain and he had minimal cardiac risk factors. The pain resolved completely within 1 week after drug withdrawal.

Causality was not discussed, but while an adverse reaction to the drug was possible, there could have been other explanations.

Sexual function Partial priapism (partial segmental thrombosis of the corpus cavernosum) has been associated with tamsulosin [113A]. • A 59-year-old man developed a perineal mass 2 hours after taking a second dose of tamsulosin for lower urinary tract symptoms. The proximal part of the penis shaft was stiff, consistent with partial priapism. Ultrasound examination showed no flow in the cavernosal artery and MR imaging showed edema towards the base of the penis. Surgical exploration allowed blood to be aspirated from the thrombotic segment and a shunt to be inserted in the corpus cavernosum spongiosum. Postoperatively normal sexual function was restored within 3 months.

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Priapism has also been described in a 47year-old man taking tamsulosin 400 micrograms/day as a smooth muscle relaxant for the off-label indication of a distal urethral stone [114A]. Sexual function While ejaculatory disorders have been attributed to a-adrenoceptor antagonists; it is less clear whether they affect semen. In a randomized, doubleblind, placebo-controlled 3-way crossover study of sperm in 48 healthy men after exposure to tamsulosin, alfuzosin, and placebo for 5 days each tamsulosin was associated with negative effects on ejaculate volume, sperm concentration, total sperm count, semen viscosity, and sperm motility compared with placebo; alfuzosin was comparable to placebo [115c]. Post-ejaculate urine sperm concentrations were comparatively normal between all agents, suggesting that retrograde ejaculation is not responsible for the ejaculatory dysfunction. There was complete absence of ejaculation in 17 of the 48 men (35%) during treatment with tamsulosin compared with none in the other groups.

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427

sleepiness and headache then convulsions—and a paradoxical increase in blood pressure [117A]. Symptomatic treatment with anticonvulsants and mannitol resulted in a full recovery. Although moxonidine is an a2-adrenoceptor antagonist, the authors postulated that during acute overdose the blood concentration may be high enough to allow non-selective activation of peripheral a1-adrenoceptors on blood vessels.

OTHER CENTRALLY ACTING DRUGS Reserpine (and Rauwolfia alkaloids) [SED-15, 3034] In a Cochrane systematic review of four randomized controlled trials (all conducted over three decades ago) reserpine was effective in reducing systolic blood pressure as a first-line agent [118M]. The number of patients included in these trials was small (237), and none of the trials reported withdrawals because of adverse reactions.

[SEDA-32, 393]

Fetotoxicity Transient respiratory depression occurred in a neonate after the mother had received intravenous urapidil for uncontrolled hypertension in pregnancy [116A]. The neonate required artificial ventilation for a period of 24 hours but recovered fully. Urapidil was found in very high amounts in the urine.

IMIDAZOLINE RECEPTOR AGONISTS Moxonidine

[SED-15, 2395; SEDA-30,

247] Drug overdose Acute moxonidine overdose in a 17-year-old woman resulted in central nervous system reactions—initial

DIRECT VASODILATORS Diazoxide

[SED-15, 1188;SEDA-32,

393] Multiorgan damage An infant with persistent hyperinsulinemic hypoglycemia received diazoxide and developed pulmonary hypertension, heart failure, and neutropenia [119A]. • A girl with macrosomia, who was delivered by cesarean section at 34 weeks, developed seizures and hypoglycemia in the first days of life due to hyperinsulinemia and was given octreotide and diazoxide. After 10 days she became short of breath with signs of heart failure and had evidence of pulmonary hypertension on echocardiography and cardiac catheterization. There was also neutropenia. Her respiratory

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and hemodynamic status improved after drug withdrawal, as did the neutrophil count.

The exact mechanism of the pulmonary hypertension, heart failure, and neutropenia was unclear, but it was probably mediated by direct toxic effects on the pulmonary vascular resistance, myocardium, and bone marrow.

Hydralazine and dimethylhydralazine

[SED-15, 1701; SEDA-31, 365; SEDA-32, 393] Liver Hydralazine-induced cholestatic jaundice has been reported [120A]. • A 63-year-old African–American woman with hypertension and end-stage renal disease on hemodialysis developed epigastric pain and jaundice, having taken hydralazine 75 mg tds. Abdominal ultrasound and CT and MRI imaging showed no evidence of biliary obstruction. There was complete clinical and biochemical recovery after 4 weeks when the drug was withdrawn.

Immunologic A 50-year-old woman taking hydralazine for hypertension developed alveolar hemorrhage and anti-neutrophil cytoplasmic antibody (ANCA)-positive pauci-immune glomerulonephritis; despite the absence of full criteria for drug-induced

lupus, the presence of antihistone antibodies and recovery on drug withdrawal were consistent with a drug-induced cause [121A]. Two other patients with hydralazineinduced vasculitis have been reported, in one case a pulmonary–renal syndrome was accompanied by digital gangrene, associated with histopathological evidence of a leukocytoplasmic vasculitis and there was a hypercoagulable state related to the presence of antiphospholipid antibodies and the factor V Leiden mutation [122R]. The authors reviewed other published cases.

Minoxidil [SED-15, 2354; SEDA-30, 183; SEDA-32, 297] Skin Oral minoxidil for hypertension has been associated with fatal toxic epidermal necrolysis [123A]. • A 69-year-old African-American woman with a stroke and hypertension was given minoxidil 2.5 mg/day and 11 days later developed a maculopapular rash with target lesions, which progressed through a vesicular stage over 8 days to frank bullae and skin necrosis. Histological findings were consistent with Stevens–Johnson syndrome. Epidermal necrolysis with resultant skin sloughing led to 30% loss of skin, and she deteriorated and died despite critical care support.

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429 [7] Mangano DT, Layug EL, Wallace A, Tateo I. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med 1996; 335(23): 1713–20. [8] Poldermans D, Boersma E, Bax JJ, Thomson IR, van de Ven LL, Blankensteijn JD, Baars HF, Yo TI, Trocino G, Vigna C, Roelandt JR, van Urk H. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med 1999; 341(24): 1789–94. [9] Yang H, Raymer K, Butler R, Parlow J, Roberts R. The effects of perioperative beta-blockade: results of the Metoprolol after Vascular Surgery (MaVS) study, a randomized controlled trial. Am Heart J 2006; 152(5): 983–90. [10] Zaugg M, Bestmann L, Wacker J, Lucchinetti E, Boltres A, Schulz C, Hersberger M, Kalin G, Furrer L, Hofer C, Blumenthal S, Muller A, Zollinger A, Spahn DR, Borgeat A. Adrenergic receptor genotype but not perioperative bisoprolol therapy may determine cardiovascular outcome in atrisk patients undergoing surgery with spinal block: the Swiss Beta Blocker in Spinal Anesthesia (BBSA) study: a doubleblinded, placebo-controlled, multicenter trial with 1-year follow-up. Anesthesiology 2007; 107(1): 33–44. [11] Bangalore S, Wetterslev J, Pranesh S, Sawhney S, Gluud C, Messerli FH. Perioperative beta blockers in patients having non-cardiac surgery: a meta-analysis. Lancet 2008; 372(9654): 1962–76. [12] Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJV, Ponikowski P, PooleWilson PA, Stromberg A, van Veldhuisen DJ, Atar D, Hoes AW, Keren A, Mebazaa A, Nieminen M, Priori SG, Swedberg K. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008. Eur Heart J 2008; 29(19): 2388–442.

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Jeffrey K. Aronson

21 CARBONIC ANHYDRASE INHIBITORS [SED-15, 643; SEDA-30, 254; SEDA-31, 371; SEDA-32, 403]

Acetazolamide Nervous system Glyceryl trinitrate dilates cephalic arteries without increasing cerebral blood flow, while acetazolamide increases cerebral blood flow without dilating cerebral arteries. The hypothesis that acetazolamide, by dilating cerebral arterioles but not arteries and thereby reducing pulsatile stretching of the wall of the large arteries and their perivascular sensory nerves, would reduce or prevent headache due to glyceryl trinitrate has been tested in 14 healthy volunteers in a randomized, double-blind, crossover study [1C]. However, acetazolamide combined with glyceryl trinitrate caused a more delayed headache than glyceryl trinitrate alone. Furthermore, in three volunteers a migraine-like headache occurred after the combination and not with glyceryl trinitrate alone. The authors suggested that the triggering of migraine in individuals with no previous attacks could be genetically determined. Because of its effects on regional cerebral blood volume, acetazolamide has been used to study cerebral hemodynamics. In two men, aged 60 and 72 years, with strokes due to unilateral internal carotid artery occlusion, an acetazolamide challenge resulted in enlargement of the cerebral Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00021-0 # 2011 Elsevier B.V. All rights reserved.

Diuretics infarction; the authors suggested that dehydration may have been the precipitating factor [2A]. Sensory systems Myopia has been attributed to acetazolamide [3A]. • A 27-year-old man developed loss of visual acuity after treating himself with acetazolamide for acute mountain sickness. His distance vision deteriorated after a single dose of acetazolamide 250 mg. Fundoscopy was normal, but there was bilateral reduced acuity for distance vision, while near vision was unaffected. His visual acuity returned to normal within 48 hours.

A change in refraction at high altitude, and thus transient myopia, can occur through osmotically altered vitreous volume or altered curvature of the lens secondary to edema or ciliary muscle spasm. The authors pointed out that altitude-related hypoxia (causing corneal swelling) and dehydration (associated with both exercise and inadequate fluid intake) could have contributed in this case. Drugs that can cause transient myopia include aspirin [4A], chlortalidone [5A], co-trimoxazole [6A, 7A], dapsone [8A], hydrochlorothiazide [9A], metronidazole [10A, 11A], prochlorperazine [12A], quinine [13A], sulfonamides [14A, 15R], tetracyclines [16A], topiramate [17c, 18A, 19A], triamterene [20A, 21A], and carbonic anhydrase inhibitors, particularly acetazolamide [22A, 23A, 24A, 25c]. The mechanism may be an allergic reaction in the ciliary body [26A]. Acid–base balance Acetazolamide causes a metabolic acidosis, which is usually mild, but can be associated with hypokalemia. In nine subjects who took acetazolamide 250 mg or placebo every 8 hours for 3 days in a double-blind, randomized, crossover 437

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design, metabolic acidosis due to acetazolamide was accompanied by a rise in ventilation, a substantial fall in PaCO2, and a parallel leftward shift of the ventilatory CO2 response curve [27c]. Acetazolamide shifted the concentration–effect curve relating hypoxic sensitivity to arterial hydrogen ion concentration to the left, without altering its slope, showing that it did not affect the interaction of O2 and CO2. There was no specific inhibitory effect of acetazolamide on hypoxic sensitivity. • In a 9-year-old girl recombinant human growth hormone 6 mg/week caused idiopathic intracranial hypertension (pseudotumor cerebri), which was treated with acetazolA amide [28 ]. After 4 days the dose was increased to 30 mg/kg/day, and 2 days later she developed a severe metabolic acidosis, with a pH of 7.29.

There has been a previous report of metabolic acidosis in a 1-year-old girl who took 500–1250 mg of acetazolamide [29A]. Gastrointestinal Adynamic ileus has been attributed to acetazolamide [30A]. • A 75-year-old-man developed abdominal cramps and constipation after taking acetazolamide 125 mg bd and prednisone 25 mg/day for 2 days. He stopped taking the acetazolamide, and the symptoms resolved in 3 days. Later he started to take acetazolamide again in a dosage of 250 mg/day, and within 24 hours the symptoms returned. Acetazolamide was withdrawn and the symptoms resolved within 48 hours.

Skin Acetazolamide has been implicated in worsening of pemphigus in a 52-year-old woman with pre-existing disease who took the drug for 1 month; however, relapse could have been coincidental [31A].

Dorzolamide Sensory systems Choroidal detachment has been attributed to dorzolamide [32A],

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Jeffrey K. Aronson

adding to previous reports of this rare reaction [33A, 34A, 35A]. • A 75-year-old woman developed bilateral ocular irritation, swollen eyelids, and reduced visual acuity after using dorzolamide 2% eyedrops tds for 2 days, in addition to long-term latanoprost þ timolol. Her best-corrected visual acuity deteriorated from 6/9 right and left, to 6/12 and 6/18 respectively. The eyelids were erythematous and there was bilateral conjunctival injection. The anterior chambers were deep and the intraocular pressure was 22 mmHg in both eyes, with no intraocular inflammation. Fundoscopy showed extensive bilateral choroidal detachment. Dorzolamide was withdrawn and the problem resolved within 2 weeks.

Drug–drug interactions Bevacizumab The effect of timolol þ dorzolamide eye-drops, which reduces aqueous outflow from the eye, on the activity of intravitreal bevacizumab has been studied in 38 patients with macular edema after retinal vein obstruction [36c]. Mean central retinal thickness was used as a surrogate for the activity of bevacizumab. Mean central retinal thickness was significantly reduced by bevacizumab, and after 5 weeks the effect was enhanced by timolol þ dorzolamide but not after 9 weeks. The authors suggested that timolol þ dorzolamide eye-drops had reduced the clearance of intravitreal bevacizumab. However, this needs to be confirmed. If it is a real effect, it remains to be seen whether it improves the efficacy of bevacizumab or increases the risk of adverse effects.

THIAZIDE AND THIAZIDELIKE DIURETICS [SED-15, 3375; SEDA-30, 256; SEDA-31, 372; SEDA-32, 405] Electrolyte balance Cases of hyponatremia and hypokalemia continue to be reported in patients taking thiazide and thiazide-like diuretics [37A].

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Chapter 21

EIDOS classification: Extrinsic moiety Loop, thiazide, and thiazide-like diuretics Intrinsic moiety Na/K/Cl cotransporters (loop diuretics) or Na/Cl co-transporters (thiazides) Distribution Nephrons: loop of Henle (loop diuretics) or distal convoluted tubule (thiazides) Outcome Altered physiology (excess natriuresis and kaliuresis) Sequela Hyponatremia and hypokalemia DoTS classification: Dose-relation Collateral Time-course Time independent, but typically occurs within weeks of starting therapy Susceptibility factors Age; sex (female); physiological factors (reduced solute intake); drugs (e.g. licorice derivatives)

An unusual interaction of hydrochlorothiazide with a herbal tea, resulting in hyponatremia and rhabdomyolysis, has been reported [38A]. • A 45-year-old woman developed muscle weakness, restlessness, and blurred vision while taking hydrochlorothiazide 25 mg/day, having drunk 7 liters of a herbal tea during a single day. She had severe hyponatremia (108 mmol/l), hypokalemia, and reduced plasma and urine osmolality. Creatine kinase and myoglobin were markedly increased.

In 10 healthy volunteers who took licorice 32 g alone or in combination with hydrochlorothiazide 25 mg/day for 2 weeks in an open, randomized crossover study, licorice alone had no effects on plasma potassium, sodium, creatinine, renin activity, serum aldosterone, blood pressure, or heart rate [39C]. However, when licorice and hydrochlorothiazide were combined, the plasma potassium fell by 0.32 mmol/l, plasma renin activity rose by 1.6 mg/l/hour, and weight fell by 0.9 kg; in two subjects there was hypokalemia, which

439

developed during the first week of combined treatment.

Hydrochlorothiazide Sensory systems Retinal phototoxicity with macular damage immediately after exposure to UV light in a 40-year-old myopic woman was attributed to the UV light, compounded by the photosensitizing effect of hydrochlorothiazide; it gradually improved over 1 year after withdrawal [40A]. Metabolic In 22 non-diabetic, abdominally obese, hypertensive patients in a multicenter, three-way, crossover trial who were given candesartan 16 or 32 mg, hydrochlorothiazide 25 or 50 mg, or placebo followed by intravenous glucose tolerance tests and euglycemic hyperinsulinemic clamps, insulin sensitivity was reduced by hydrochlorothiazide, liver fat content was increased, the subcutaneous to visceral abdominal adipose tissue ratio was reduced, and aminotransferase activities and concentrations of glycosylated hemoglobin and high-sensitivity C-reactive protein were higher [41C]. The authors suggested that these findings could partly explain the diabetogenic potential of thiazides. Skin After developing contact dermatitis on the eyelids to para-phenylenediamine in a hair dye, a 52-year-old African–American woman with atopy had a similar rash while taking hydrochlorothiazide for hypertension [42A]. A lichenoid eruption has been associated with hydrochlorothiazide; there was possible cross-reactivity to furosemide [43A]. Immunologic Hydrochlorothiazide was associated with an allergic reaction that mimicked septic shock on three separate occasions in a 78-year-old woman; on the third occasion it started almost immediately after a single dose of hydrochlorothiazide [44A]. She had previously had allergic reactions to sulfonamides and penicillin.

440

[SED-15, 567, 1454; SEDA-30, 258; SEDA-31, 375; SEDA-32, 408]

LOOP DIURETICS

Furosemide Endocrine Diuretics are sometimes used in an attempt to accelerate the elimination of unbound radioiodine in patients who are given therapeutic radioiodine. However, in 23 patients with differentiated thyroid cancer who were given 131I, furosemide 20 mg 3 hours later and then 8-hourly for 3 days, combined with potassium chloride, significantly reduced radioiodine excretion compared with 20 patients who were not given furosemide [45c]. Urinary tract Susceptibility factors for nephrocalcinosis have been studied in 55 neonates born before 32 weeks of gestation [46c]. The strongest independent factor was furosemide therapy above a cumulative dose of 10 mg/kg, with a 48-fold increased risk (CI ¼ 4, 585). The risk of nephrocalcinosis was 1.65 (1.07, 2.56) times higher per 100 g lower body weight and 4.5 (1.14, 18) times higher per mmol/l of urinary calcium concentration. Many other susceptibility factors were significant only in univariate analysis (gestational age, mechanical ventilation, infection, bronchopulmonary dysplasia, blood transfusions, intraventricular hemorrhage, surfactant therapy, vasopressors, phenobarbital or caffeine, duration of hospital stay), suggesting indirect effects only. The authors suggested that if furosemide is prescribed for preterm infants, it should be given with caution and close monitoring of calcium excretion; in infants with respiratory distress syndrome calcium-sparing thiazide diuretics may be preferred.

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Jeffrey K. Aronson

C-terminal domain of BP180 (Brunsting-Perry type). Furosemide was withdrawn and he was given oral prednisolone 10 mg/day. The eruptions resolved leaving superficial scars.

The authors suggested that photosensitivity caused by furosemide may have contributed to the induction and exacerbation of these lesions. Body temperature Repeated bouts of hyperthermia with skin blisters occurred in an 18-year-old girl with a severe Mycoplasma pneumoniae infection during hemodialysis and continuous infusion of furosemide and other drugs [48A]. When the medications were withdrawn, the hyperthermia resolved within 2 days. After rechallenge with two intravenous doses of furosemide 5 mg, there was an almost simultaneous increase in heart rate and temperature and the blisters reappeared. Management of adverse drug reactions Desensitization to drugs is increasingly being described by the use of initially tiny doses, gradually increasing to therapeutic doses, sometimes over very short periods of time [SEDA-30, 416; SEDA-33, 494]. A rapid oral desensitization protocol for furosemide has been described (Table 1) and used successfully in a 44-year-old woman who developed urticaria while taking furosemide [49A]. Previous protocols have involved rapid intravenous administration (Table 2) [50A] or oral administration over 3 days (Table 3) [51A].

ALDOSTERONE RECEPTOR ANTAGONISTS

Skin Localized bullous pemphigoid has been associated with furosemide [47A].

Spironolactone [SED-15, 3176; SEDA30, 259; SEDA-31, 375; SEDA-32, 409]

• A 56-year-old man with chronic renal insufficiency developed irregular atrophic erythematous plaques on his forehead, cheeks, and ear lobes after taking furosemide for 4 years. Histology showed localized bullous pemphigoid with IgG class autoantibodies to the

Observational studies Of 134 patients with heart failure, 76 were currently taking spironolactone or had previously taken it; spironolactone was withdrawn in 19 mainly because of hyperkalemia, deterioration in

Diuretics

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441

Table 1 A rapid oral desensitization protocol for patients with furosemide hypersensitivity Time (minutes)

Dose (as oral solution)

0 20 40 60 80 100 120 140 160 180 200 220

1 microgram 3 micrograms 10 micrograms 30 micrograms 100 micrograms 300 micrograms 1 mg 3 mg 10 mg 40 mg 100 mg 100 mg (tablet)

Table 2 An intravenous desensitization protocol for patients with furosemide hypersensitivity Time (minutes)

Dose (as oral solution)

0 20 40 60 80 100 120 140 160 180

1 microgram 3 micrograms 10 micrograms 30 micrograms 100 micrograms 300 micrograms 1 mg 3 mg 10 mg 40 mg

Table 3 A 3-day oral desensitization protocol for patients with furosemide hypersensitivity Time (hours) Day 1 0 3 6 9 Day 2 0 3 6 Day 3 0 3 6 9 12 15

Dose (as oral solution)

5 micrograms 10 micrograms 30 micrograms 1000 micrograms 100 micrograms 300 micrograms 1 mg 1 mg 1 mg 3 mg 3 mg 100 mg 100 mg

442

renal function, and gynecomastia [52c]. The authors concluded that the adverse effects of spironolactone are more common than have been reported in clinical trials. Metabolism In a prospective study in 27 hirsute women (20 with polycystic ovary syndrome and seven with idiopathic hirsutism), mean age 23 years, spironolactone 100 mg/ day for 3 months was associated with a small but significant fall in mean HDL cholesterol by 0.19 mmol/l and a significant rise in mean LDL cholesterol by 0.72 mmol/l [53cr]. There were no significant changes in total cholesterol, triglycerides, or fasting blood glucose. Serum concentrations of testosterone, dehydroepiandrosterone, and prolactin fell significantly. Other studies have yielded conflicting results of the effects of spironolactone on serum lipids. Some have shown no effects [54c, 55c]; others have variously shown increased triglycerides [56C, 57c], reduced triglycerides and HDL cholesterol [58c], reduced triglycerides [59c], and increased HDL cholesterol [60c].

OSMOTIC DIURETICS Mannitol [SED-15, 2203; SEDA-30, 260; SEDA-32, 409] Respiratory Inhaled mannitol as a dry powder has been used to treat patients with cystic fibrosis, since it increases mucociliary clearance by rehydrating the airways. In 39 children with cystic fibrosis, aged 8–18 years, a bronchial provocation

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Jeffrey K. Aronson

challenge with incrementally increasing doses of dry powder mannitol up to a maximum cumulative dose of 475 mg produced a positive challenge (a fall in FEV1 of at least 15% from baseline) in nine, and commonly caused cough [61c]. In 48 patients with asthma, aged 18–73 years, of whom 21 used inhaled corticosteroids and 23 had atopy, two pairs of bronchial challenges were performed with mannitol and methacholine in a random order on two separate days [62c]. The airway response to mannitol was attenuated when mannitol was given after methacholine compared with the other way round, but the response to methacholine was not affected by order of administration. The authors concluded that bronchial challenge with inhaled mannitol and methacholine could be performed on the same day if the mannitol was given first. Fluid balance In two patients undergoing transurethral resection, the bladder was irrigated with large volumes of mannitol 5%, which was absorbed and caused pulmonary edema and severe hyponatremia (serum sodium 99 and 97 mmol/l) [63A]. Hypertonic saline increased the serum sodium concentration and plasma volume expansion corrected hypotension; one patient also required positive-pressure ventilation and intravenous noradrenaline. Both recovered completely. In a 51-year-old woman, absorption of a solution containing mannitol and sorbitol after irrigation during hysteroscopy led to hypocalcemia and hyponatremia; hyperglycemia and lactic acidosis also occurred, because of metabolism of sorbitol [64A].

References [1] Daugaard D, Thomsen LL, Iversen HK, Olesen J. Delayed migraine-like headache in healthy volunteers after a combination of acetazolamide and glyceryl trinitrate. Cephalalgia 2009; 29(12): 1294–300.

[2] Meguro T, Tanabe T, Muraoka K, Terada K, Hirotsune N, Nishino S. Enlargement of cerebral infarction after CBF study with acetazolamide challenge: two case report. No Shinkei Geka 2009; 37(2): 183–8.

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[3] Szawarski P, Hall-Thompson B. Acetazolamide-induced myopia at altitude. Wilderness Environ Med 2009; 20(3): 300–1. [4] Sandford-Smith JH. Transient myopia after aspirin. Br J Ophthalmol 1974; 58(7): 698–700. [5] Michaelson JJ. Transient myopia due to Hygroton. Am J Ophthalmol 1962; 54: 1146–7. [6] Bovino JA, Marcus DF. The mechanism of transient myopia induced by sulfonamide therapy. Am J Ophthalmol 1982; 94(1): 99–102. [7] Postel EA, Assalian A, Epstein DL. Druginduced transient myopia and angle-closure glaucoma associated with supraciliary choroidal effusion. Am J Ophthalmol 1996; 122(1): 110–2. [8] Gopalani VV, More AS. Dapsone-induced acute myopia. Indian J Dermatol Venereol Leprol 2006; 72(6): 455–6. [9] Beasley FJ. Transient myopia and retinal edema during hydrochlorothiazide (Hydrodiuril) therapy. Arch Ophthalmol 1961; 65: 212–3. [10] Grinbaum A, Ashkenazi I, Avni I. Drug induced myopia associated with treatment for gynecological problems. Eur J Ophthalmol 1995; 5: 136–8. [11] Grinbaum A, Ashkenazi I, Avni I, Blumenthal M. Transient myopia following metronidazole treatment for Trichomonas vaginalis. JAMA 1992; 267(4): 511–2. [12] Yasuna E. Acute myopia associated with prochlorperazine (Compazine) therapy. Am J Ophthalmol 1962; 54: 793–6. [13] Segal A, Aisemberg A, Ducasse A. Quinine, myopie transitoire et glaucome par fermeture de l'angle. [Quinine, transient myopia and angle-closure glaucoma.] Bull Soc Ophtalmol Fr 1983; 83(2): 247–9. [14] Maddalena MA. Transient myopia associated with acute glaucoma and retinal edema following vaginal administration of sulfanilamide. Arch Ophthalmol 1968; 80 (2): 186–8. [15] Mattsson R. Transient myopia following the use of sulphonamides. Acta Ophthalmol (Copenh) 1952; 30(4): 385–98.

443 [16] Edwards TS. Transient myopia due to tetracycline. JAMA 1963; 186: 69–70. [17] Cereza G, Pedrós C, Garcia N. Topiramate in nonapproved indications and acute myopia or angle closure glaucoma. Br J Clin Pharmacol 2005; 60(5): 578–9. [18] Chen TC, Chao CW, Sorkin JA. Topiramate induced myopic shift and angle closure glaucoma. Br J Ophthalmol 2003; 87(5): 648–9. [19] Desai CM, Ramchandani SJ, Bhopale SG, Ramchandani SS. Acute myopia and angle closure caused by topiramate, a drug used for prophylaxis of migraine. Indian J Ophthalmol 2006; 54(3): 195–7. [20] Soylev MF, Green RL, Feldon SE. Choroidal effusion as a mechanism for transient myopia induced by hydrochlorthiazide and triamterene. Am J Ophthalmol 1995; 120 (3): 395–7. [21] Cristiansson J. Transient myopia after the administration of Diamox. Acta Ophthalmol (Copenh) 1958; 36(2): 356–7. [22] Kronning E. Transient myopia following the use of acetazolamide. Acta Ophthalmol (Copenh) 1957; 35(5): 478–84. [23] Binder SS. Acute transient myopia associated with the use of acetazolamide (Diamox). J Am Med Assoc 1957; 165(2): 154–5. [24] Garland MA, Sholk A, Guenter KE. Acetazolamide-induced myopia. Am J Obst Gynecol 1962; 84: 69–71. [25] Muirhead JF, Scheie HG. Transient myopia after acetazolamide. Arch Ophthalmol 1960; 63: 315–8. [26] Galin MA, Baras I, Zweifach P. Diamoxinduced myopia. Am J Ophthalmol 1962; 54: 237–40. [27] Teppema LJ, van Dorp EL, Dahan A. Arterial [Hþ] and the ventilatory response to hypoxia in humans: influence of acetazolamide-induced metabolic acidosis. Am J Physiol Lung Cell Mol Physiol 2010; 298 (1): L89–95. [28] Tornese G, Tonini G, Patarino F, Parentin F, Marchetti F. Double adverse drug reaction: recombinant human growth hormone and idiopathic intracranial

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hypertension—acetazolamide and metabolic acidosis: a case report. Cases J 2009; 2: 6534. Baer E, Reith DM. Acetazolamide poisoning in a toddler. J Paediatr Child Health 2001; 37(4): 411–2. Gallerani M, Coletti M, Ferri M, Napolitano N, Boari B. Acetazolamideinduced adynamic ileus. Intern Emerg Med 2009; 4(6): 527–9. Lo Schiavo A, Sangiuliano S, Puca RV, Brunetti G, Ruocco E. Pemphigus relapse and acetazolamide, a drug with an active amide group: a casual or causal relationship? J Eur Acad Dermatol Venereol 2009; 23(6): 716–7. Doherty MD, Wride NK, Birch MK, Figueiredo FC. Choroidal detachment in association with topical dorzolamide: is hypotony always the cause? Clin Experiment Ophthalmol 2009; 37(7): 750–2. Fineman MS, Katz LJ, Wilson RP. Topical dorzolamide-induced hypotony and ciliochoroidal detachment in patients with previous filtration surgery. Arch Ophthalmol 1996; 114(8): 1031. Davani S, Delbosc B, Royer B, Kantelip J-P. Choroidal detachment induced by dorzolamide 20 years after cataract surgery. Br J Ophthalmol 2002; 86(12): 1457–8. Goldberg S, Gallily R, Bishara S, Blumenthal EZ. Dorzolamide-induced choroidal detachment in a surgically untreated eye. Am J Ophthalmol 2004; 138(2): 285–6. Byeon SH, Kwon OW, Song JH, Kim SE, Park YS. Prolongation of activity of single intravitreal bevacizumab by adjuvant topical aqueous depressant (timolol– dorzolamide). Graefes Arch Clin Exp Ophthalmol 2009; 247(1): 35–42. Nicolás Sánchez FJ, Sarrat Nuevo RM, Soler Rosell T, Gort Oromí AM. Hipopotasemia de larga duración asociada a clortalidona. [Long term hypopotassaemia associated with chlorthalidone.] Nefrologia 2009; 29(4): 377–8. Fritzsch J, Eckrich K. Hyponatriämie, Rhabdomyolyse und Enzephalopathie nach Einnahme von Hydrochlorothiazid und Tee. [Hyponatremia, rhabdomyolysis and encephalopathy after taking hydrochlorothiazide

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Jeffrey K. Aronson

and drinking tea.] Dtsch Med Wochenschr 2009; 134(14): 683–5. Hukkanen J, Ukkola O, Savolainen MJ. Effects of low-dose liquorice alone or in combination with hydrochlorothiazide on the plasma potassium in healthy volunteers. Blood Press 2009; 18(4): 192–5. Costagliola C, Menzione M, Chiosi F, Romano MR, Della Corte M, Rinaldi M. Retinal phototoxicity induced by hydrochlorothiazide after exposure to a UV tanning device. Photochem Photobiol 2008; 84 (5): 1294–7. Eriksson JW, Jansson PA, Carlberg B, Hägg A, Kurland L, Svensson MK, Ahlström H, Ström C, Lönn L, Ojbrandt K, Johansson L, Lind L. Hydrochlorothiazide, but not candesartan, aggravates insulin resistance and causes visceral and hepatic fat accumulation: The Mechanisms for the Diabetes Preventing Effect of Candesartan (MEDICA) Study. Hypertension 2008; 52(6): 1030–7. Jacob SE, Zapolanski T, Chayavichitsilp P. Sensitivity to para-phenylenediamine and intolerance to hydrochlorothiazide. Dermatitis 2008; 19(6): E44–5. Aouam K, Ali HB, Youssef M, Chaabane A, Hamdi MH, Boughattas NA, Zili JE. Lichenoid eruption associated with hydrochlorothiazide and possible cross reactivity to furosemide. Therapie 2009; 64 (5): 344–7. Mineo MC, Cheng EY. Severe allergic reaction to hydrochlorothiazide mimicking septic shock. Pharmacotherapy 2009; 29 (3): 357–61. Matovic MD, Jankovic SM, Jeremic M, Tasic Z, Vlajkovic M. Unexpected effect of furosemide on radioiodine urinary excretion in patients with differentiated thyroid carcinomas treated with iodine 131. Thyroid 2009; 19(8): 843–8. Gimpel C, Krause A, Franck P, Krueger M, von Schnakenburg C. Exposure to furosemide as the strongest risk factor for nephrocalcinosis in preterm infants. Pediatr Int 2010; 52(1): 51–6. Takeichi S, Kubo Y, Arase S, Hashimoto T, Ansai S. Brunsting–Perry type localized bullous pemphigoid, possibly induced by

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[53]

[54]

[55]

[56]

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furosemide administration and sun exposure. Eur J Dermatol 2009; 19(5): 500–3. Ebdrup L, Pedersen CM, Andersen MH, Storgaard M. Prolonged hyperthermia from furosemide infusion—a case report. Eur J Clin Pharmacol 2010; 66(2): 215–6. Alim N, Patel JY. Rapid oral desensitization to furosemide. Ann Allergy Asthma Immunol 2009; 103(6): 538. Shteinberg M, Karkabi B, Cohen S. Desensitization therapy in a patient with furosemide allergy. Eur J Intern Med 2007; 18 (1): 69–70. Juang P, Page RL, Zolty R. A successful rapid desensitization protocol in a loop diuretic allergic patient. J Card Fail 2005; 11 (6): 481. Lopes RJ, Lourenço AP, Mascarenhas J, Azevedo A, Bettencourt P. Safety of spironolactone use in ambulatory heart failure patients. Clin Cardiol 2008; 31(11): 509–13. Nakhjavani M, Hamidi S, Esteghamati A, Abbasi M, Nosratian-Jahromi S, Pasalar P. Short term effects of spironolactone on blood lipid profile: a 3-month study on a cohort of young women with hirsutism. Br J Clin Pharmacol 2009; 68(4): 634–7. Garcá Puig J, Miranda ME, Mateos F, Herrero E, Lavilla P, Gil A. Hydrochlorothiazide versus spironolactone: long-term metabolic modifications in patients with essential hypertension. J Clin Pharmacol 1991; 31(5): 455–61. Wild RA, Demers LM, ApplebaumBowden D, Lenker R. Hirsutism: metabolic effects of two commonly used oral contraceptives and spironolactone. Contraception 1991; 44(2): 113–24. Scherstén B, Thulin T, Kuylenstierna J, Engström M, Karlberg BE, Tolagen K, Nordlander S, Nilsson G. Clinical and biochemical effects of spironolactone

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administered once daily in primary hypertension. Multicenter Sweden study. Hypertension 1980; 2(5): 672–9. Jeunemaitre X, Chatellier G, Kreft-Jais C, Charru A, DeVries C, Plouin PF, Corvol P, Menard J. Efficacy and tolerance of spironolactone in essential hypertension. Am J Cardiol 1987; 60(10): 820–5. Falch DK, Schreiner A. The effect of spironolactone on lipid, glucose and uric acid levels in blood during long-term administration to hypertensives. Acta Med Scand 1983; 213(1): 27–30. Zulian E, Sartorato P, Benedini S, Baro G, Armanini D, Mantero F, Scaroni C. Spironolactone in the treatment of polycystic ovary syndrome: effects on clinical features, insulin sensitivity and lipid profile. J Endocrinol Invest 2005; 28(1): 49–53. Gökmen O, Senöz S, Gülekli B, Işik AZ. Comparison of four different treatment regimes in hirsutism related to polycystic ovary syndrome. Gynecol Endocrinol 1996; 10(4): 249–55. Minasian C, Wallis C, Metcalfe C, Bush A. Bronchial provocation testing with dry powder mannitol in children with cystic fibrosis. Pediatr Pulmonol 2008; 43(11): 1078–84. Gade E, Thomsen SF, Porsbjerg C, Backer V. The bronchial response to mannitol is attenuated by a previous methacholine test: but not vice versa. Clin Exp Allergy 2009; 39(7): 966–71. Wang JH, He Q, Liu YL, Hahn RG. Pulmonary edema in the transurethral resection syndrome induced with mannitol 5%. Acta Anaesthesiol Scand 2009; 53(8): 1094–6. Lee GY, Han JI, Heo HJ. Severe hypocalcemia caused by absorption of sorbitolmannitol solution during hysteroscopy. J Korean Med Sci 2009; 24(3): 532–4.

Gijsbert B. van der Voet

22

Metals

Aluminium [SED-15, 97; SEDA-30, 262; SEDA-31, 383; SEDA-32, 413]

parenteral nutrition solutions had reduced neurodevelopmental scores [3R].

Although agents that contain aluminium are highly efficient as phosphate binders, they are no longer widely used because of proven neurotoxicity and osteotoxicity. They are gradually being replaced by safer calcium-based salts, or calcium-free compounds, such as sevelamer hydrochloride and lanthanum carbonate [1R].

Psychiatric The controversial role of aluminium in Alzheimer's disease has recently been re-evaluated [4R].

Nervous system Neurotoxic effects of aluminium are regularly reported as a result of intravesical treatment of hemorrhagic cystitis, as a pediatric case illustrates [2A]. • A 9-year-old girl with acute lymphoblastic leukemia and a bone marrow transplant developed hemorrhagic cystitis and clot retention. Her bladder was irrigated with 1% alum (aluminium ammonium sulfate) for 5 days, during which time she received 15 liters of alum solution at a rate of 250 ml/hour alternating with 250 ml of isotonic saline. In total, her bladder mucosa was exposed to 22.5 g of elemental aluminium. Within 3 days she became very agitated and confused and over the next 48 hours became violent. The alum was withheld after 5 days. The maximum serum aluminium concentration was 27 mg/l (normal < 0.6 mg/l). She was given two doses of intravenous deferoxamine mesylate 10 mg/kg on days 8 and 9 and by the next day her psychotic symptoms had improved.

In a randomized study, preterm infants who had been exposed to aluminium in

Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00022-2 # 2011 Elsevier B.V. All rights reserved.

Musculoskeletal Bone area and bone mineral content in lumbar spine, hip, and whole body were measured with dual radiograph absorptiometry in 59 children aged 13–15 who had been born preterm and randomly assigned standard or aluminium-depleted parenteral nutrition solutions during the neonatal period. Those who had been randomly assigned to standard parenteral nutrition solutions had lower lumbar spine bone mineral content, apparently explained by a reduction in bone size. In nonrandomized analyses, children who were exposed as neonates to aluminium above the median (55 micrograms/kg) had lower hip bone mineral content, independent of bone or body size. The authors concluded that neonates who are exposed to parenteral aluminium may have reduced lumbar spine and hip bone mass during adolescence, potential risk factors for later osteoporosis, and hip fracture. It has been suggested that macrophagic myofasciitis and chronic fatigue syndrome may be caused by adverse reactions to alumina-containing adjuvants in vaccines. Both conditions are characterized by aberrant immune responses, have a number of prominent symptoms in common, and coincide in many individuals. Vaccine-associated chronic fatigue syndrome and macrophagic myofasciitis have been described in an adult with aluminium overload [5c]. 447

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Tumorigenicity In 4316 male aluminium smelters, who were followed during 1983– 2002, cumulative inhalation of dust, cumulative fluoride exposure, and cumulative benzo(a)pyrene exposure were linked to the risk of respiratory cancers, after adjustment for smoking [6c]. Susceptibility factors Renal disease The determination of toxic elements in human biological samples is an important clinical screening procedure. In 100 men, aged 25– 55, with chronic renal insufficiency on maintenance hemodialysis and 150 healthy volunteers in the same age range, the concentrations of aluminium, cadmium, and lead were determined in blood samples before and after hemodialysis and the concentrations in urine were determined once, before hemodialysis [7c]. The blood concentrations in the patients before hemodialysis were higher than after dialysis. In the controls the blood concentrations were significantly lower than in the patients with chronic renal insufficiency. Aluminium toxicity has been studied retrospectively in 36 hospitalized adults who had a serum creatinine concentration at least 1.5 times greater than on the first day of parenteral nutrition; 12 were undergoing hemodialysis [8c]. Mean aluminium exposure was 3.8 µg/kg/day in the 36 patients, of whom 29 had safe calculated exposures (5 µg/kg/day) and also significantly higher serum creatinine concentrations than those with high aluminium exposure. The authors suggested that most patients with acute kidney disease who require parenteral nutrition do not receive excessive exposure to aluminium.

Antimony

[SED-15, 316; SEDA-30, 263; SEDA-31, 384; SEDA-32, 414] The adverse effects of the pentavalent antimonial compounds, sodium stibogluconate and meglumine antimoniate, that are widely used to treat leishmaniasis have been reviewed; they include nausea,

Gijsbert B. van der Voet

vomiting, weakness and myalgia, abdominal colic, diarrhea, rashes, hepatotoxicity, and cardiotoxicity [9R]. Resistance to antimonials is important in the treatment of this disease. Skin Drug rash with eosinophilia and systemic symptoms (DRESS) has been associated with antimonial drugs in a 40-year-old man with cutaneous and mucosal leishmaniasis [10A].

Arsenic

[SED-15, 339; SEDA-30, 263; SEDA-31, 385; SEDA-32, 414] Arsenic trioxide continues to be used in the chemotherapy of acute promyelocytic leukemia. A novel organic arsenic derivative S-dimethylarsinoglutathione (Darinaparsin) shows promise for the treatment of a wider spectrum of hematological malignancies and solid tumors than arsenic trioxide [11R,12R].

Sensory systems Vision In 100 patients with acute promyelocytic leukemia taking oral arsenic trioxide, there were two cases of serious visual problems, both in patients in complete remission with normal platelet counts [13A]. • A 25-year-old man with acute promyelocytic leukemia in first complete remission took oral arsenic trioxide 10 mg/day and all-trans retinoic acid (ATRA) 45 mg/m2/day for 2 weeks every 2 months over 2 years. After completion of maintenance, the vision in his right eye deteriorated to light perception only, after a basketball injury sustained during the last course of oral treatment. Fundoscopy showed a large retinal tear with total rhegmatogenous detachment. Posterior vitrectomy, lensectomy, retinectomy, endolaser photocoagulation, and silicone oil injection did not affect visual recovery. The concentrations of elemental arsenic in the plasma, aqueous humor, and vitreous humor were 115, 35, and 57 nmol/l respectively. • A 35-year-old man with acute promyelocytic leukemia in relapse achieved a second remission with oral arsenic trioxide 10 mg/day for 30 days, followed by idarubicin 9 mg/day for 5 days. He was a chronic smoker (3 packs/

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Chapter 22

day) with a history of right amaurosis fugax. Two days after chemotherapy, he developed sudden blindness in the right eye, due to central retinal artery occlusion. No sources of cardiac or carotid embolization were found. He was treated with anterior chamber paracentesis, acetazolamide, and timolol eyedrops, but optic atrophy ensued.

Both patients had clear anatomical causes for blindness, and unilateral (rather than bilateral) blindness suggested a limited role for systemic arsenic toxicity. Nevertheless, a weak contribution of ocular arsenic toxicity should not be ruled out. Both arsenic trioxide and all-trans retinoic acid can increase intracranial pressure, resulting in pseudotumor cerebri and a secondary increase in intraocular pressure, which may augment retinal injury. Also, arsenic trioxide can cause vasoconstriction and worsen retinal artery occlusion. Finally, elemental arsenic was detected in the eyes at 30–50% of the plasma concentration, a ratio comparable to that in cerebrospinal fluid. This may have direct retinal toxicity, especially with the high peak concentrations associated with intravenous arsenic trioxide. Full ophthalmic evaluation is recommended in patients receiving longterm or intravenous arsenic trioxide. Teeth Toothache occurred in a 45-year-old man taking arsenic trioxide [14A]. The pain was mainly in the upper right and left cheeks, but radiated to become more severe in the lower anterior region. It increased in intensity, occurred after eating, and awoke him from sleep. Opioid analgesia was required for pain relief. Two days after a cycle of arsenic trioxide the pain diminished, and after 4 days it had completely resolved. The total cumulative dose of arsenic trioxide was 1590 mg.

449

were attributed to bismuth iodoform paraffin paste; blood and urine bismuth concentrations were 340 and 2800 mg/l respectively [15A]. The symptoms responded to chelation therapy with intravenous 2,3dimercapto-1-propanesulfonic acid (DMPS) for 27 days followed by oral therapy to a total of 51 days.

Calcium salts

[SED-15, 610;

SEDA-28, 245] Calcium is the most abundant essential mineral in the human body, 99% being located in the bones and teeth. Calcium salts have been used therapeutically in many conditions, such as lactose intolerance, osteoporosis, premenstrual syndrome, colorectal cancer, kidney stones, and multiple sclerosis. Calcium supplementation has long been regarded as a fundamental part of the prevention and treatment of postmenopausal bone loss. Several other health benefits have also been suggested, including improvements in blood pressure and serum cholesterol. Its adverse effects include constipation, bloating, and gas [16r], as well as interference with the absorption of phosphate [17r].

Bismuth [SED-15, 518; SEDA-30, 264; SEDA-31, 385; SEDA-32, 414]

Cardiovascular The effects of calcium supplementation on vascular disease have been studied in a large, randomized, controlled trial in healthy postmenopausal women over 5 years [18C]. There was a substantial increase in rates of vascular events, particularly myocardial infarction, in women who were randomized to calcium. These effects were more marked in those who were highly compliant with treatment. Calcium supplementation also appears to accelerate vascular disease in patients with renal impairment, including those not yet requiring hemodialysis.

Nervous system In a 67-year-old man, acute confusion, disorientation, delusions, verbal aggression, and myoclonic jerks with intermittent episodes of drowsiness

Mineral metabolism Under steady-state conditions, urinary calcium excretion corresponds to the calcium load in healthy subjects. However, in patients on chronic

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450

hemodialysis reliable data are not available. In these patients, calcium-containing phosphate binders are suspected to play a role in the progression of arteriosclerosis. The effects of calcium carbonate 500 mg qds and the calcium-free phosphate binder sevelamer hydrochloride 800 mg qds on serum calcium and urinary calcium excretion have been evaluated in 12 healthy men in a randomized, single-blind, placebo-controlled, three-way crossover phase I study for 6 days on each treatment [19c]. Mean daily urinary phosphorus excretion was significantly lower in those who took sevelamer compared with placebo. Mean daily total urinary excretion of calcium was significantly higher in those who took calcium carbonate compared with placebo.

Chromium

[SED-15, 737; SEDA-30, 264; SEDA-31, 386; SEDA-32, 414] Urinary tract There are major concerns about infusion of excess chromium during parenteral nutrition, because of potential nephrotoxicity [20R].

Cobalt

[SED-15, 847; SEDA-30, 264; SEDA-31, 386; SEDA-32, 415] Chromium–cobalt alloys are being increasingly used in medical implants, and metalon-metal hip resurfacing arthroplasty can cause the release of large amounts of very small wear particles and metal ions [21R]. The long-term biological consequences of exposure to these chromium–cobalt particles are largely unknown.

Immunologic An aseptic lymphocyte-dominated-vasculitis-associated lesion (ALVAL) was reported in a patient in whom cobalt sensitization developed after insertion of a chromium–cobalt prosthesis [22A]. • Allergy to metal components was suspected in a 71-year-old woman after bilateral total hip

Gijsbert B. van der Voet

arthroplasty with femoral heads made of cobalt and chromium. Groin pain soon after surgery was treated with prednisolone, but when it was withdrawn the pain recurred and a swelling in the left groin was noted. A CT scan showed a cystic collection of fluid anterior to the left iliopsoas muscle and probably communicating with the hip joint. A large periprosthetic cystic mass was removed. Histology showed fibrinoid necrosis, a chronic inflammatory infiltrate with lymphocytes and macrophages, and capillary proliferation. Patch testing with nickel, cobalt chloride 1%, and potassium dichromate was positive with cobalt.

Copper

[SED-15, 901; SEDA-30, 265; SEDA-31, 387; SEDA-32, 415] Wilson's disease in children has been reviewed again [23R].

Reproductive system Intrauterine contraceptive devices (IUCDs) can migrate to unusual locations in the body. Ovarian penetration by a copper-based device has again been reported [24AR]. • A 22-year-old nulliparous woman developed lower abdominal pain, severe dysmenorrhea, and dyspareunia. A T-shaped IUCD (copper T) that had been inserted 7 years before was seen in a 2.0
1.4
2.3-cm cyst in the right ovary and was removed laparoscopically.

Gallium [SED-15, 1477; SEDA-30, 265; SEDA-32, 416] The medical applications of gallium compounds have been reviewed [25R]. Radiogallium compounds continue to be used for tumor imaging. Gallium compounds (gallium nitrate, gallium maltolate) are used as antineoplastic agents in non-Hodgkin's lymphoma and bladder cancer. Gallium compounds may have immunosuppressive and anti-inflammatory activity.

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Chapter 22

Gold and gold salts

[SED-15, 1520; SEDA-30, 265; SEDA-31, 387; SEDA-32, 416]

The clinical pharmacology and adverse effects of gold compounds have again been reviewed [26R]. Their mechanism of action in rheumatoid arthritis has not been elucidated. The experimental pharmacology of the auranocyanide anion, a human metabolite of several anti-rheumatic gold complexes, has also been reviewed [27R].

451

may also be safe among patients who are allergic to or intolerant of iron dextran. Infection risk Current evidence on the role of intravenous iron in increasing the incidence of infection and oxidative stress deserves special consideration, but the clinical data are conflicting. Oxidative stress should not be considered as a barrier to the administration of intravenous iron.

Lanthanum carbonate Iron salts [SED-15, 1911; SEDA-30, 265; SEDA-31, 387; SEDA-32, 417] Immunologic The frequency of adverse drug events associated with four different iron formulations (high and low molecular weight iron dextran, iron sucrose, and sodium ferric gluconate complex) in the management of anemia in chronic kidney disease has been reviewed [28MR]. In general, with the exception of high molecular weight iron dextran (as Imferon, which is no longer available, and Dexferrum, which is not recommended), serious or life-threatening adverse events are rare. The Revised European Best Practice Guidelines do not recommend the use of iron dextran formulations. Iron sucrose, ferric gluconate, and low molecular weight iron dextran can be given without significant risk of anaphylaxis, but only the last can be given as a total-dose infusion. Iron sucrose has the least reported number of adverse events and high molecular weight iron dextran the highest; low molecular weight iron dextran and ferric gluconate fall between these two. Comparisons of iron sucrose or iron gluconate with low molecular weight iron dextran show no difference in toxicity or efficacy but greater ease of administration with low molecular weight iron dextran. Low molecular weight iron dextran (InFed) is relatively safe and substantially less costly than either iron sucrose or iron gluconate. Ferric gluconate and iron sucrose

[SEDA-31,

389; SEDA-32, 417] Lanthanum carbonate is an aluminiumfree, calcium-free, phosphate-binding agent used to control phosphate concentrations in patients with renal insufficiency [29R]. Lanthanum carbonate was generally well tolerated in short- and long-term clinical studies; the most common adverse events were gastrointestinal (for example nausea, vomiting, diarrhea, abdominal pain, and constipation) and they occurred with a similar incidence to other phosphate binders (including sevelamer hydrochloride and calciumbased binders). These adverse events were minimized by taking lanthanum carbonate with food, and generally abated over time with continued administration. The incidence of treatment-related adverse events did not increase with increased exposure to lanthanum carbonate, and no new or unexpected adverse events were reported in an extension study in which patients with end-stage renal failure took treatment for up to 6 years. Lanthanum carbonate was associated with fewer episodes of hypercalcemia than calcium carbonate. With up to 6 years of lanthanum carbonate treatment, the incidence of fractures was low (4.3%). Nervous system Nervous system effects of lanthanum have been reported [30A]. • A 75-year-old woman undergoing hemodialysis for end-stage renal disease developed abdominal pain and dizziness and became confused. Among her numerous medications was lanthanum carbonate 750 mg bd.

452 Abdominal radiography showed multiple diffuse calcium-like deposits throughout the digestive tract, especially in the rectosigmoid region. Sigmoidoscopy showed diverticular disease, with mucous membrane inflammation and off-white foreign bodies on the bowel wall, which were found to be lanthanum carbonate tablet residues. Her confusion resolved after withdrawal of lanthanum, and plasma lanthanum concentrations fell at the same time from 2.13 mg/l on the day after withdrawal to 1.05 mg/l on day 4 and 0.25 mg/l on day 7.

The authors tentatively suggested a role for lanthanum tablets in aggravating diverticular disease and causing confusion. However, these suggestions were convincingly rebutted by others [31r].

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Gijsbert B. van der Voet

• A 39-year-old woman developed vomiting, massive watery diarrhea, and carpopedal spasm 4 hours after taking a handful of magnesium hydroxide tablets (estimated dose 10 g) in a suicide attempt [33A]. The serum potassium concentration was 3.5 mmol/l, ionized calcium 1.15 mmol/l, and magnesium 0.95 mmol/l, which is near the lower limit of the reference range. A few hours later she developed a tingling sensation and muscle spasm in the arms. The serum ionized calcium concentration was 0.87 mmol/l and magnesium 0.8 mmol/l. She was given calcium gluconate 1 g intravenously and the diarrhea improved. After 3 days she was asymptomatic.

Manganese [SED-15, 2200; SEDA-30, 267; SEDA-32, 418] Magnesium salts

[SED-15, 2196; SEDA-30, 266; SEDA-31, 390; SEDA-32, 417]

Placebo-controlled studies In a randomized, double-blind study of the preventive analgesic efficacy of adding magnesium to a multimodal regimen of patient-controlled epidural analgesia, 90 patients undergoing abdominal hysterectomy were randomly assigned to (a) a bolus of magnesium 50 mg epidurally before induction of anesthesia followed by infusion at 10 ml/hour until the end of surgery, (b) epidural saline followed by a bolus of epidural magnesium 50 mg at the end of surgery, and (c) epidural saline during all three periods [32C]. There was significantly less pain at rest or during movement in those who were pretreated with magnesium. The authors concluded that continuous epidural magnesium started before anesthesia provided preventive analgesia and an analgesic-sparing effect, improving postoperative analgesia without increasing the incidence of adverse effects. Metal metabolism Excessive ingestion of magnesium can cause hypermagnesemia without kidney dysfunction. In one case hypomagnesemia paradoxically resulted from excessive ingestion of magnesium hydroxide.

Fetotoxicity Little is known about the effects of manganese deficiency or excess on the human fetus [34R]. In two studies lower maternal blood manganese concentrations were associated with fetal intrauterine growth retardation [35C] and lower birth weights [36C]. In the first of these, the relation between blood concentrations of manganese and intrauterine growth restriction was assessed in 410 apparently healthy mothers (aged 18–35 years) and their neonates. Whole blood manganese concentrations in the mothers were significantly lower when there was intrauterine growth retardation than in cases in which the baby was appropriate for gestational age (mean 17 versus 19 mg/l respectively). Conversely, umbilical cord blood manganese concentrations were significantly higher in neonates with intrauterine growth restriction than in those who were appropriate for gestational age (45 versus 38 mg/l respectively). There was a significant relation between maternal whole blood and umbilical cord blood manganese concentrations in cases with intrauterine growth retardation. In the second study the association between maternal and umbilical cord blood manganese concentrations and birth weight was studied in 470 mother–infant pairs born at term. Non-linear spline and quadratic

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regression models were used to test the hypothesis of an inverted U-shaped relation between manganese concentrations and birth weight. The mean concentrations of manganese were 24 mg/l in maternal blood and 42 mg/l in cord blood. Umbilical cord manganese was not associated with birth weight. There was a non-linear relation between maternal manganese and birth weight after adjusting for potential confounders. Birth weight increased with manganese concentrations up to 3.1 mg/l, with a slight reduction in weight at higher concentrations. These findings suggest that manganese may affect fetal growth.

Mercury and mercurial salts [SED-15, 2259; SEDA-30, 268; SEDA-31, 391; SEDA-32, 419]

Thimerosal and neurodevelopment in infants The debate about the relation between autism and mercury (as thimerosal) in vaccines continues, without useful conclusions [37R]. In a population-based study of the pharmacokinetics of mercury after immunization of 72 premature infants weighing 2000–3000 g at birth, the mean maximal blood mercury concentration was 3.6 mg/l, and it occurred at 1 day after immunization; the maximal mean stool mercury concentration was 35 ng/g, and it occurred on day 5; urine mercury was almost undetectable [38C]. The blood mercury half-life was 6.3 (95% CI ¼ 3.9–8.8) days, and mercury concentrations returned to prevaccination values by day 30. The blood half-life of intramuscular ethyl mercury from thimerosal in vaccines given to premature infants is substantially shorter than that of oral methyl mercury in adults. Because of the differing pharmacokinetics, exposure guidelines based on oral methyl mercury in adults may not be accurate for children who receive thimerosal-containing vaccines. In a study based on the automated Vaccine Safety Datalink 278 624 subjects who

453

had received their first oral polio immunization by 3 months of age, the association between the prevalence of outcomes and doses of mercury from thimerosalcontaining vaccines was modelled using Poisson regression analysis [39c]. There were consistent significantly increased rate ratios for autism, autism spectrum disorders, tics, attention deficit disorder, and emotional disturbances with mercury exposure; in contrast, none of the controls had significantly increased rate ratios. The authors discussed the several limitations of this study, including possible bias due to incompleteness of the records and the potential for confounding. In a comparison of two groups of 1403 children who had been exposed randomly to different amounts of thimerosal through immunization (cumulative dose of ethylmercury 62.5 or 137.5 micrograms), 10 years later 24 neuropsychological outcomes were evaluated and only two were significantly associated with thimerosal exposure, a result that could have arisen by chance [40c]. In a study of neurodevelopment in infants at 6 months who had been exposed in utero to thimerosal in tetanus–diphtheria vaccines during pregnancy there were no differences from infants who had not been exposed [41c]. Although there was a significant correlation between the concentration of mercury in the hair of the mothers and the hair of the neonates, there was no correlation between the degree of in utero exposure to ethylmercury and mercury concentrations in neonatal hair.

Nickel

[SED-15, 2502; SEDA-30, 268; SEDA-31, 392; SEDA-32, 419] Cardiovascular Nickel hypersensitivity has been associated with a pericardial effusion after cardiac surgery [42A].

• A 52-year-old woman underwent percutaneous closure of a patent foramen ovale with a septal occluder device, and on the next morning noted severe, burning, left-sided chest pain

454 near the anterior axillary line, after which she had daily chest pain and occasional episodic bouts of palpitation. A transesophageal echocardiogram 18 months later showed a small, hemodynamically insignificant pericardial fluid collection posterior to the left atrium in the transverse pericardial sinus. She also reported a history of a reaction to inexpensive jewelry, raising the possibility of previously unrecognized nickel allergy. Skin patch testing showed an allergic contact dermatitis to nickel, with an unusual pustular reaction. The septal occluder was removed and the foramen ovale was closed with a pericardial patch.

Selenium [SED-15, 3119; SEDA-30, 269; SEDA-31, 392; SEDA-32, 420] Selenium availability from various foodstuffs has been reviewed [43R], as has its role in the management of cancers [44R]. Hair and nails Incidental cases reflecting the use of nutritional supplements that escape regulation and quality control have been reported; in two cases there were signs consistent with selenium poisoning after use of a dietary supplement called “Total Body Formula” [45A]. • A 45-year-old woman developed a diffuse erythematous, pruritic, exfoliative eruption on the scalp and progressive hair loss. She also had discoloration of the nails, dizziness, fatigue, amenorrhea, and dental caries. The hair loss had started 7 days after she began taking a nutritional supplement, “Total Body Formula”, but she continued to take it for about 30 days and nearly finished a 0.95-liter container. She had seborrhea-like scaling with some acneiform papules on the scalp. There was hair loss, and pulled hairs were predominantly in the anagen phase. There was a grayish-white discoloration in transverse bands in most of her fingernails 2–4-mm distal to the cuticle. Serum and urine selenium concentrations 5 weeks after the last dose were within the reference ranges. However, the concentration of selenium in the hair 6 weeks after the last dose was high, at 3.2 mg/g (reference range 0.4–1.4 mg/g). The hair and nails began to improve 5 weeks after the last dose, and most of her symptoms resolved completely after 6 months.

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Gijsbert B. van der Voet

• A 56-year old woman developed hair loss, discolored nails, metatarsal cramping, fatigue, and malaise. She had diffuse alopecia, and pulled hairs were in the anagen phase: the nails were thickened and yellow distally. The serum selenium concentration was 166 mg/l (reference range 110–160) 7 weeks after the last dose of “Total Body Formula”. The hair and nails began to improve 2 months after the last dose and were completely normal after 7 months.

Susceptibility factors Renal disease Plasma copper, selenium, and zinc concentrations and antioxidant metalloenzymes, glutathione peroxidase (GPX) and superoxide dismutase (SOD), were studied in 17 patients on maintenance hemodialysis, 14 uremic patients, and 14 healthy subjects [46C]. Plasma selenium concentrations and erythrocyte GPX were significantly lower in those on hemodialysis, and the two were correlated. There was also a correlation between reduced plasma zinc and erythrocyte SOD activity.

Silver salts and derivatives [SED-15, 3140; SEDA-30, 269; SEDA-31, 393; SEDA-32, 420] Skin Argyria has again been reported [47A,48A]. • A 73-year-old man developed slate-gray pigmentation on the face after using colloidal silver on occasion for at least 5 years, the total amount of ingested colloidal silver having been 0.2 g. Histology of a skin biopsy from the forehead showed upper dermal mild perivascular lymphocyte infiltration and brown-black extracellular granules in the upper dermis and between collagen bundles. Silver concentrations were 13 mg/l in the urine, 29 mg/l in blood, 36 mg/g in skin tissue. He stopped taking silver and was encouraged to use sun protection to help prevent further skin discoloration, after which he improved rapidly. • A 25-year-old woman developed severe generalized dystrophic epidermolysis bullosa having used a topical silver sulfadiazine 1% cream under occlusive dressings as an antimicrobial agent since early childhood. Over the course of many years her skin had turned a metallic slate-grey and she had developed loss of proprioception, a tingling sensation in her limbs,

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455

and impaired coordination. Her serum silver concentration was markedly raised at 2645 nmol/l. Silver granules were seen in a previously excised squamous cell carcinoma.

Skin Toxic epidermal necrolysis has been attributed to strontium ranelate 2 g/day in a 72-year-old Chinese woman with postmenopausal osteoporosis. The lesions resolved after treatment with intravenous immunoglobulin 1 g/kg/day for 3 days [53A].

• venous thromboembolism—1.1 (95% CI ¼ 0.2, 5.0); • memory loss—1.8 (0.2, 14); • minor skin complaints—2.0 (1.3, 3.1); • gastrointestinal disturbances—3.0 (2.3, 3.8).

• A 56-year-old woman developed a severe generalized rash consisting of erythematous to violaceous tender confluent papules, symmetrically distributed on the face, trunk, and limbs after taking strontium ranelate for 2 months [54A]. There was neither fever nor malaise. A skin biopsy showed papillary edema, a perivascular mixed infiltrate with eosinophils, and mild epidermal spongiosis with necrotic keratinocytes. After withdrawal of strontium ranelate and treatment with oral and topical glucocorticoids and oral diphenhydramine, severe hypopigmentation and patchy alopecia developed on the scalp, but the other lesions resolved, leaving brown-gray postinflammatory hyperpigmentation.

There were no cases of osteonecrosis of the jaw, toxic epidermal necrosis, Stevens–Johnson syndrome, or drug rash with eosinophilia and systemic symptoms (DRESS).

Drug rash with eosinophilia and systemic symptoms (DRESS) has been attributed to strontium ranelate several reports [55A,56A], including a case with a bullous eruption [57A].

Strontium salts

[SEDA-32, 420]

Observational studies In a survey of the adverse effects of strontium ranelate using the UK General Practice Research Database (GPRD), age-adjusted rate ratios for certain adverse reactions were [49c]:

Mineral metabolism Strontium is handled similarly in the body to calcium [50c,51c], but there have been few reports of altered calcium balance in patients who have received strontium salts. Symptomatic hypocalcemia occurred in a 32-year-old man after he was given radioactive 89SrCl (4 mCi, dose of strontium not stated) [52AH]. He also had vitamin D deficiency and hypoparathyroidism, the latter being attributed by the authors to strontium. They hypothesized that strontium stimulates calcium-sensing receptors in the parathyroid glands, kidneys, and bones, suppressing parathyroid hormone production, increasing urinary excretion of calcium, reducing production of 1,25dihydroxycolecalciferol by the kidneys, inhibiting of calcium release from bones, and reducing calcium absorption from the intestines; strontium may also have direct effects on the kidneys and bones by stimulating calcium-sensing receptors.

Hair Strontium hydroxide has been used as a depilatory [58c], and it is not therefore surprising that there have been reports of alopecia in patients taking strontium ranelate. In a series of five cases reported to the Spanish pharmacovigilance system [59Ac], the odds ratios (95% CI) for the risks of alopecia in postmenopausal women taking various drugs were: • • • • •

strontium ranelate 14 (5.4, 37); acitretin 92 (22, 387); methotrexate 4.7 (1.7, 13); doxorubicin 3.0 (0.4, 22); valproic acid 2.4 (0.3, 17).

Genotoxicity and cytotoxicity Incinerated industrial waste in Taiwan contains strontium, which was genotoxic in green monkey kidney cells (Vero cells) [60E]. However, in in vitro studies on human periodontal ligament fibroblasts from healthy human third molars strontium ranelate 2.5 mg/ml was not cytotoxic [61E].

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Titanium [SED-15, 3434; SEDA-30, 270; SEDA-31, 394; SEDA-32, 420] Sensory systems Eyes and vision In 10 patients, orbital adherence syndrome developed after orbital fracture repair with titanium mesh along an orbital wall and/or a titanium plate over the orbital rim [62c]. Six of the patients had cicatricial eyelid retraction and nine had restriction of extraocular movements, resulting in diplopia. There was fibrotic adherence between the titanium implant and orbital or periorbital tissues. The diplopia improved after removal of the titanium and replacement with nylon implants. Musculoskeletal In two cases of osteolysis in hips with third-generation alumina ceramic-on-ceramic couplings, periarticular tissue contained titanium wear debris (from impingement of the neck of the titanium femoral component against the rim of the titanium shell) and ceramic debris (from edge loading wear of the ceramic) [63A]. The authors could not decide whether the titanium debris, the ceramic debris, or both had caused the osteolysis.

Titanium allergy Allergic reactions to titanium are reported from time to time [64A]. Frequency Allergic skin reactions to titanium are rare. In 445 patients who had received bone-anchored skin-penetrating titanium implants for anchorage of facial prostheses or bone-conducting hearing aids, nine had adverse skin reactions around the titanium implants; none had delayed hypersensitivity to titanium [65c]. In these and other cases [66A] skin reactions have been attributed to infections with Staphylococcus aureus. In some cases allergy may be due not to titanium but to a contaminant, such as nickel [67A,68E], chromium or cobalt [69A], palladium [70A], or an epoxy resin [71A].

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Gijsbert B. van der Voet

Clinical diagnosis Patch tests are often negative, in which case a positive lymphocyte transformation test may give the diagnosis [72AR]. In 54 patients who had received titanium-based dental or endoprosthetic implants a lymphocyte transformation test against 10 metals was positive, with titanium in 21 cases, ambiguous in 16, and negative in 19 [73c]. All had negative patch tests. Removal of the implants produced marked clinical improvement and in 15 who were retested lymphocyte reactivity normalized. It has been suggested that a 0.1% solution of titanium tetrachloride may be preferable as a patch test reagent for titanium allergy [74c]. Different titanium containing compounds have different degrees of immunogenicity; the in vitro effects of different titanium salts on the proliferation of cultured human peripheral blood mononuclear cells and cytokine release, titanium dioxide was not immunogenic, titanium oxalate was markedly so; titanocene selectively increased cytokine release but did not affect cell proliferation, and titanium ascorbate altered the release of TNF-alpha but not interferongamma [75E]. Histology In 54 patients who had fractures of the long bones stabilized with limitedcontact dynamic compression plates made of titanium samples of the soft tissue layer covering the plate were recovered after 18 months [76c]. The plates were covered by a connective tissue layer 2 mm thick on average. In patients with local pain there were significantly more round cells and macrophages, consistent with chronic granulomatous inflammation. In subepithelial soft tissue and bone specimens from 19 patients in whom implants (14 stainless steel and 5 titanium) had been in situ for more than 6 months, there were scattered T lymphocyte clusters, small numbers of macrophages, and abundant expression of HLA-DR in the soft tissue adjacent to both types of implant [77c]. There were immunocompetent cells in the connective tissue lining the periphery of the screw holes and metal particles in the soft tissues and bone.

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Biopsy specimens from 17 mandibular fracture sites treated by open reduction with titanium in 12 patients showed doublelayered connective tissue, which consisted of dense fibrous connective tissue and relatively loose connective tissue containing proliferated blood vessels with hypertrophied endothelial cells [78c]. The vascular endothelial cells expressed HLA-DR, CD54, and CD62P antigens; in some cases they were CD62E-positive. CD68-positive, and CD11c-positive round or spindle-shaped macrophages had infiltrated around the small vessels and contained fine cytoplasmic titanium particles. In some cases CD4þ and CD8þ T lymphocytes had infiltrated around venules. Sources Dental and bone implants Inflammatory reactions and contact sensitivity have been reported after insertion of titanium implants. Osseointegration of the implant tends to occur, but around the area there can be an intense inflammatory reaction and persistent irritation of soft tissues [79A]. Titanium allergy can reportedly cause failure of dental implants [80A,81A] and interfere with the implant/restoration process in artificial joints [82A]. • A 49-year old woman had severe reactions to all six titanium implants that were placed in her mandible between the left and right mental foramen. Three types of implants were used, an LIBB compression implant, a cylindrical implant, and a Brånemark-like implant. The tissue reactions were severe enough to warrant removal of all the implants and the surrounding soft tissues showed chronic inflammation with fibrosis around all the implants and foreign-body giant-cell reactions around two. She recuperated and the soft and hard tissues healed satisfactorily. • A 64-year-old man underwent a total hip arthroplasty for severe osteoarthritis of his left hip following avascular osteonecrosis. An SEM3 type (Science et Médecine, Montrouge, France) cementless forged Ti Al6-4V alloy, with femoral stem size 12, coated with hydroxyapatite on the proximal third, with a metallic head of a diameter 28 mm, and an ultra-high molecular weight polyethylene (UHMWPE) insert (liner) with a metal acetabular cup (50 mm) was inserted. Four years after the operation, he developed severe pain in the left

457 hip while walking and inability to bear weight. An X-ray showed a fracture of the femoral neck without bone loss in the proximal femur and he underwent a revision of the total hip arthroplasty. There was an extensive amount of bone adherent to the device, and the fractured implant was well fixed.

Dental implants have been studied in 35 patients, of whom 16 had had symptoms of allergy after implantation or unexplained implantation failure and 19 had a history of other allergies, or were heavily exposed to titanium during implantation surgery, or had implantation failure for which the cause was known [83c]. Nine patients had positive reactions to titanium allergy tests: eight in the first group, in five of whom there had been unexplained implant failures, and one in the other group. None of 35 controls had positive reactions. In one case, facial eczema occurred after titanium dental implantation, with complete remission after removal [84A]. In another case, drug rash with eosinophilia and systemic symptoms (DRESS) occurred in a previously healthy 19-year-old man after insertion of a titanium bioprosthesis for a spinal fracture [85A]. Gingival hyperplasia surrounding the transmucosal portions of titanium implants has been attributed to titanium allergy [86A]. In two cases exposure to titanium in dental implants caused reactive lesions in the peri-implant mucosa, diagnosed as epulis, in which metal-like particles were observed histologically [87A]. One involved a pyogenic granuloma and the other a peripheral giant cell granuloma. Tissues from five patients who underwent revision operations for failed total hip replacements contained large quantities of particulate titanium, abundant macrophages and T-lymphocytes, and no B-lymphocytes [88c]. In four cases the titanium had come from alloy screws. Skin patch tests with dilute solutions of titanium salts were negative, but two of the patients had a positive skin test to a titanium-containing ointment. Inhaled dust In a furnace feeder for an aluminium smelting company, granulomatous lung disease was associated with pulmonary

458

deposition of various metallic particles [89A]. The relation between the metallic dust and the granulomatous process was investigated by lymphocyte transformation tests to aluminium sulfate, titanium chloride, beryllium sulfate, and nickel sulfate were. There was a positive lymphocyte proliferative response to titanium chloride on two separate occasions and no reactions to the other metals, consistent with hypersensitivity to titanium. Pacemakers Dermatitis due to titanium hypersensitivity has occasionally been reported after insertion of a pacemaker [90A,91A,92A,93A,94A]. Surgical clips Exacerbation of atopic dermatitis has been attributed to titanium in surgical clips [95A]. Ear piercing A 68-year-old man developed a granulomatous dermatitis after piercing his ears. There were titanium, aluminium, and vanadium particles within macrophages in the lesions [96A]. Topical solutions Contact allergy has been attributed to topical ammonium titanium lactate 10% [97A].

Zinc

[SED-15, 3717; SEDA-30, 270; SEDA-31, 394; SEDA-32, 420] Nervous system Denture adhesives and creams are a source of zinc and can cause hyperzincemia and hypocupremia [98A].

• A 47-year-old woman developed progressive knee and back pain, weakness, paresthesia, sensory loss, ataxia, and falls. Physical, neurological, and neurophysiological examinations, T2-weighted MRI scans of the brain and spine, cerebrospinal fluid analysis, and serum concentration measurements showed that she had a myeloneuropathy with anemia, due to copper deficiency, secondary to zinc overload associated with long-term use of denture cream with a high zinc content, which she

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Gijsbert B. van der Voet

had used for many years. Change to a low-zinc denture cream and oral copper replacement resulted in clinical improvement.

Sensory systems Olfaction Zinc nasal sprays can cause loss of the sense of smell in animals and humans, and the FDA has warned consumers and healthcare professionals to stop using zinccontaining nasal products sold over-thecounter as cold remedies (Zicam Nasal Gel and Nasal Swab), because they are associated with long-lasting or permanent loss of the sense of smell [99S]. The FDA has received over 130 reports of anosmia associated with the use of these products. Many have stated that loss of the sense of smell occurred with the first dose of the product, while others have reported that it happened after later doses. According to the FDA, these products have not been shown to be effective in reducing the duration or severity of cold symptoms. This advice does not relate to oral zinc tablets and lozenges. Hematologic Zinc supplementation has proven beneficial in the treatment of acute child diarrhea and appears to enhance linear growth. However, there is a theoretical risk of anemia, due to inhibition of iron transport because of reduced copper absorption. Although many zinc supplementation trials have included hematological measures, the effect of zinc on these outcomes has not been comprehensively reviewed. In a systematic review of 21 randomized studies of the effect of zinc supplementation on hemoglobin concentrations in 3869 apparently healthy children aged 0–15 years, the duration of treatment was 4–15 months and dosages were typically 10– 20 mg/day [100M]. Zinc supplementation did not cause changes in hemoglobin concentration. There was no evidence of effects of age, zinc dosage, duration of treatment, type of control, baseline hemoglobin, geographical or health-care setting, or quality of the studies.

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461 [53] Lee HY, Lie D, Lim KS, Thirumoorthy T, Pang SM. Strontium ranelate-induced toxic epidermal necrolysis in a patient with post-menopausal osteoporosis. Osteoporos Int 2009; 20(1): 161–2. [54] Boada A, Carrascosa JM, Leal L, Ferrándiz C. Generalized cutaneous drug eruption due to strontium ranelate. J Eur Acad Dermatol Venereol 2009; 23(3): 321–2. [55] Jonville-Béra AP, Crickx B, Aaron L, Hartingh I, Autret-Leca E. Strontium ranelate-induced DRESS syndrome: first two case reports. Allergy 2009; 64(4): 658–9. [56] Iyer D, Buggy Y, O'Reilly K, Searle M. Strontium ranelate as a cause of acute renal failure and DRESS syndrome. Nephrology (Carlton) 2009; 14(6): 624. [57] Kramkimel N, Sibon C, Le Beller C, Saiag P, Mahé E. Bullous DRESS in a patient on strontium ranelate. Clin Exp Dermatol 2009; 34(7): e349–50. [58] Powis SJA, Waterworth TA, Arkell DG. Preoperative skin preparation: clinical evaluation of depilatory cream. BMJ 1976; 2: 1166–8. [59] Sainz M, del Pozo JG, Arias LH, Carvajal A. Strontium ranelate may cause alopecia. BMJ 2009; 338: b1494. [60] Huang WJ, Tang HC, Lin KL, Liao MH. An emerging pollutant contributing to the cytotoxicity of MSWI ash wastes: strontium. J Hazard Mater 2010; 173(1– 3): 597–604. [61] Er K, Polat ZA, Ozan F, Taşdemir T, Sezer U, Siso SH. Cytotoxicity analysis of strontium ranelate on cultured human periodontal ligament fibroblasts: a preliminary report. J Formos Med Assoc 2008; 107(8): 609–15. [62] Lee HB, Nunery WR. Orbital adherence syndrome secondary to titanium implant material. Ophthal Plast Reconstr Surg 2009; 25(1): 33–6. [63] Murali R, Bonar SF, Kirsh G, Walter WK, Walter WL. Osteolysis in third-generation alumina ceramic-on-ceramic hip bearings with severe impingement and titanium metallosis. J Arthroplasty 2008; 23(8): 1240e13–9. [64] Farronato G, Tirafili C, Alicino C, Santoro F. Titanium appliances for allergic

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[86] Mitchell DL, Synnott SA, VanDercreek JA. Tissue reaction involving an intraoral skin graft and CP titanium abutments: a clinical report. Int J Oral Maxillofac Implants 1990; 5(1): 79–84. [87] Olmedo DG, Paparella ML, Brandizzi D, Cabrini RL. Reactive lesions of periimplant mucosa associated with titanium dental implants: a report of 2 cases. Int J Oral Maxillofac Surg 2010; 39(5): 503–7. [88] Lalor PA, Revell PA, Gray AB, Wright S, Railton GT, Freeman MA. Sensitivity to titanium. A cause of implant failure? J Bone Joint Surg Br 1991; 73(1): 25–8. [89] Redline S, Barna BP, Tomashefski Jr. JF, Abraham JL. Granulomatous disease associated with pulmonary deposition of titanium. Br J Ind Med 1986; 43(10): 652–6. [90] Brun R, Hunziker N. Pacemaker dermatitis. Contact Dermatitis 1980; 6(3): 212–3. [91] Verbov J. Pacemaker contact sensitivity. Contact Dermatitis 1985; 12(3): 173. [92] Peters MS, Schroeter AL, Van Hale HM, Broadbent JC. Pacemaker contact sensitivity. Contact Dermatitis 1984; 11(4): 214–8. [93] Viraben R, Boulinguez S, Alba C. Granulomatous dermatitis after implantation of a titanium containing pace maker. Contact Dermatitis 1995; 33(6): 437.

463 [94] Yamauchi R, Morita A, Tsuji T. Pacemaker dermatitis from titanium. Contact Dermatitis 2000; 42(1): 52–3. [95] Tamai K, Mitsumori M, Fujishiro S, Kokubo M, Ooya N, Nagata Y, Sasai K, Hiraoka M, Inamoto T. A case of allergic reaction to surgical metal clips inserted for postoperative boost irradiation in a patient undergoing breast conserving therapy. Breast Cancer 2001; 8(1): 90–2. [96] High WA, Ayers RA, Adams JR, Chang A, Fitzpatrick JE. Granulomatous reaction to titanium alloy: an unusual reaction to ear piercing. J Am Acad Dermatol 2006; 55(4): 716–20. [97] Basketter DA, Whittle E, Monk B. Possible allergy to complex titanium salt. Contact Dermatitis 2000; 42(5): 310–1. [98] Spain RI, Leist TP, De Sousa EA. When metals compete: a case of copper-deficiency myeloneuropathy and anemia. Nat Clin Pract Neurol 2009; 5(2): 106–11. [99] Anonymous. Zinc-containing intranasal products: loss of sense of smell. WHO Newsl 2009; 4: 4. [100] Dekker LH, Villamor E. Zinc supplementation in children is not associated with decreases in hemoglobin concentrations. J Nutr 2010; 140(5): 1035–40.

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23

Metal antagonists

IRON CHELATORS The effectiveness of iron chelators is illustrated by the tremendous improvements in both life expectancy and quality of life in patients with thalassemia, thanks to structured and rigorous diagnosis and treatment schemes, as for example in Cyprus. At the same time, the chronic use of chelators continues to pose major challenges, concerns regarding their best use, and scientific assessment of their long-term benefits and harms [1R, 2R]. The use of iron chelators has been reviewed [3R] and some articles have provided a practical summary comparison of today's leading chelating drugs [4R, 5R] (see Table 1). The use of combinations of these drugs may lessen some problems or create others [SEDA 31, 399]. In a review of the current outlook of transfusional iron overload in Latin America, an expert panel formulated a number of recommendations [5R], which are relevant to the safe and rational use of iron chelators, including • patient education—the key to gaining acceptance of the need for therapy and in emphasizing the importance of ensuring adherence to the dosing schedule; • education of health authorities and physicians responsible for treating hematological disorders—needed to ensure that iron chelation therapy is available to all patients who need it and that it is prescribed at the recommended doses;

Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00023-4 # 2011 Elsevier B.V. All rights reserved.

• education of different social security systems and health authorities on the importance of providing iron chelation medication; • inclusion of iron chelation treatments on the official lists of medicines approved by Medicines Boards.

Suggestions for future studies include the incidence of hemochromatosis in different Latin American countries, the efficacy and safety of iron chelation therapy, and pharmacoeconomic studies. Several papers have also illustrated that bthalassemia is itself directly or indirectly associated with a wide variety of pathologies, for example skin disorders [6R], infections, hearing loss, osteoporosis, and cholelithiasis. This needs to be given due attention in attributing adverse effects to the drugs used in these patients, while some of these complications may become more frequent during the use of a chelator. New compounds There is a series of new iron chelators in development. DP-b99 is an experimental membrane-activated lipophilic chelator of iron, calcium, and zinc [7r]. In a double-blind, placebo-controlled, randomized multicenter trial in 150 patients with strokes, the primary end-point of a change in the clinical neurological scale score (NIHSS) from baseline to 90 days was not met. Secondary end-points, on the other hand, were significantly improved after 90 days. There were no clinically significant differences between the groups in vital signs and there were no major safety problems. CP94 (1,2-diethyl-3hydroxypyridin-4-one HCl) has been used in an open controlled study in a mixed topical formulation together with 5-aminolevulinic acid to enhance topical photodynamic therapy in six patients with basal cell carcinomas, without causing any adverse reactions [8c]. 465

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Table 1 Summary comparison of three iron chelators [4R, 5R]

Compound

Description/ pharmacokinetics

Deferasirox

Tridentate chelator; molecular mass 373 362; half-life 8–16 hours; excretion fecal

Deferiprone

Bidentate chelator; molecular mass 139 152 g/m; half-life 2– 3 hours; excretion urinary

Deferoxamine

Hexadentate chelator; molecular mass 560 684 g/mol; half-life 6 hours; excretion urinary and fecal

Dose

Monitoring

20 mg/kg/day orally as a single dose; dose in increments of 5 or 10 mg/kg every 3–6 months according to serum ferritin; maximum 30 mg/kg/day 50–100 mg/kg/day orally in 2–3 divided doses

Monthly: renal and hepatic values Yearly: ophthalmic review (color vision, cataract visual fields, fundus); audiometry Every visit: total and differential cell counts, joint complaints (stiffness, pain, swelling) Three-monthly: dose, ferritin, AlT Three-monthly: mean daily dosesa; serum ferritin and creatinine; therapeutic serum indexb; compliance indexc; vision

20–40 mg/kg/day as a subcutaneous night-time infusion over 8–10 hours of a 10% solution, 5–7 nights/ week

a

Therapeutic index: mean daily dose (in mg/kg)/serum ferritin (keep below 0.025). Mean daily dose (over a week): actual daily dose administered
7. Compliance index: the number of factual administrations over the year/prescribed number of daily treatments.

b c

Cardiovascular Iron-induced cardiac injury is a major cause of morbidity and mortality in all transfusion-dependent diseases. The complex processes that determine the entry, storage, toxicity, and detoxification of iron in the heart have been reviewed [9R]. Direct measurement of cardiac iron, using T2weighted magnetic resonance imaging rather than indirect methods, such as measuring serum ferritin concentrations or liver iron concentrations, has contributed to earlier recognition of myocardial iron loading and the prevention of cardiac injury. Cardiac T2-weighted MRI predominantly reflects safely stored cardiac iron, which explains how patients can have abnormal values in association with normal cardiac function. However, this safely stored iron pool is in dynamic equilibrium with labile myocyte iron, leading to a higher risk of cardiac decompensation at low values. The short half-life of deferoxamine limits its suppression of non-transferrin-bound serum iron (NTBI) to the hours of drug administration, so that effective cardiac iron chelation requires continuous or near-

continuous administration. Deferiprone is a relatively small molecule and readily enters myocytes and intracellular compartments. It is an effective cardiac iron chelator when used alone or in combination with deferoxamine. Cardiac iron, cardiac function, and patient survival all appear to improve with deferiprone. In vitro evidence shows that intracellular sites of labile cardiac iron accumulation are accessed more rapidly by deferasirox and deferiprone than by deferoxamine. In addition, deferasirox restored the contractility of rat cardiac myocytes after iron loading. All three chelators can remove labile iron from plasma. Animal experiments also suggest that deferasirox and deferiprone have comparable access to intracardiac iron.

Deferasirox

[SEDA-30, 273; SEDA-31, 401; SEDA-32, 426] In patients with bone marrow failure requiring hemopoietic stem cell transplantation,

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prior iron chelation may improve survival [10c], and early deferasirox treatment may result in long-term reduction in transfusion requirements [11c]. Cost-effectiveness There is uncertainty about the risk of serious adverse reactions to deferasirox, the associated susceptibility factors, and resultant cost-effectiveness [12R, 13R]. In a cost-utility multiple appraisal of deferasirox and deferoxamine, the former was concluded to be cost-effective, with an incremental cost-effectiveness ratio (ICER) below £20 000–30 000 per QALY gained [14r]. The rates of serious adverse events were thought not to be different, and serious adverse events, but their costs were not specified or included in the assessment. In a cost-utility multiple appraisal of deferasirox, deferoxamine, and deferiprone, it was concluded that in the short term there is little clinical difference between any of the three chelators in terms of removing iron from the blood and the liver, and that deferasirox may be costeffective compared with deferoxamine but not compared with deferiprone [15R]. The authors emphasized that the primary focus for future research should be on the longterm benefits of chelation therapy, including adverse reactions and adherence. Observational studies In a retrospective study of dose escalation of deferasirox to above 30 mg/kg/day in 264 heavily ironloaded patients, gastrointestinal hemorrhage and lenticular opacities developed as suspected adverse reactions in one patient each, but no details were given [16c]. There was no worsening of renal or hepatic function. Hematologic While blood dyscrasias may not be established adverse reactions to deferasirox, the recently revised data sheet of Exjade reads “There have been postmarketing reports (both spontaneous and from clinical trials) of cytopenias, including agranulocytosis, neutropenia and thrombocytopenia, in patients treated with Exjade. Some of these patients died. The relationship of these episodes to treatment with Exjade is uncertain. Most of these

467

patients had pre-existing hematologic disorders that are frequently associated with bone marrow failure. Monitor blood counts regularly. Consider interrupting treatment with Exjade in patients who develop unexplained cytopenia. Reintroduction of therapy with Exjade may be considered, once the cause of the cytopenia has been elucidated” [17R]. Gastrointestinal The data sheet for ExjadeÒ (deferasirox, Novartis) has been revised and a boxed warning has been added that gastrointestinal hemorrhage can occur and that deaths have occurred [17S, 18R]. Liver The data sheet for ExjadeÒ (deferasirox, Novartis) has been revised and a boxed warning has been added that hepatic failure can occur and that deaths have occurred [17S, 18S]. The results of a prospective, multicenter, 1year, open study (ESCALATOR) in the Middle East of the use of daily deferasirox in heavily iron-overloaded patients with b-thalassemia have been reviewed [19cr]. Of 237 patients (162 children and 55 adults) 233 completed 1 year of treatment. The starting dosage was 10–20 mg/kg/day and the dosage was increased to 25 or 30 mg/day in most patients. Adverse events were reported by 180 patients and were judged to be drug related in 105 (44%). Serious events occurred in 17 (7.3%), of which only one (obstructive jaundice) was thought to be drug related. There were no withdrawals because of adverse events that were considered to be drug related. Metal metabolism Symptomatic hypocalcemia has been attributed to deferasirox in a patient with end-stage renal disease undergoing peritoneal dialysis [20CR]. • A 43-year-old woman with sickle cell nephropathy and hypertension, who had undergone peritoneal dialysis for 1 year, had been given repeated blood transfusions and erythropoietin, leading to severe iron overload. She was given deferasirox 20 mg/kg/day, and her other medications included allopurinol, amlodipine, atenolol, darbepoetin alfa, folic acid, lanthanum carbonate, lisinopril, and losartan. The

Chapter 23

468 peritoneal dialysate solutions contained ionized calcium 2.5 mmol/l. The serum calcium fell to 1.47 mmol/l (ionized calcium 1.5 mmol/l), without a change in parathyroid hormone concentration. Despite paricalcitol, oral calcium, and addition of calcium to the dialysate solution, the serum calcium continued to fall and she developed periorbital paresthesia and mental slowing. The serum calcium concentration normalized with intravenous calcium. Deferasirox was withdrawn but later restarted. The serum calcium again fell. Deferasirox was again withdrawn and the calcium concentration again increased.

The authors hypothesized that chelation by deferasirox of iron from bone tissue had led to increased calcium uptake, the “hungry bone syndrome”, and they suggested that if deferasirox is used in patients on dialysis, serum calcium should be checked routinely. Hypocalcemia has previously been described in connection with deferoxamine in an 8-month-old infant with aluminium overload related to parenteral nutrition, without increased urinary calcium excretion, suggesting bone uptake of calcium after chelation of aluminium [21A]. A similar hypocalcemic effect has been observed in two patients with dialysis-related aluminium-induced osteomalacia treated with deferoxamine [22A]. Urinary tract The data sheet of Exjade has been revised and a boxed warning added that renal impairment and failure may occur and that deaths have occurred [17S, 18S]. While increases in serum creatinine due to deferasirox are usually benign, in one of 14 patients with excess iron storage due to myelodysplasia, deferasirox (dose not specified) had to be withdrawn after 1 month because of impaired renal function [23c]. Acute interstitial nephritis and renal failure have been attributed to deferasirox [24CR]. • A 62-year-old man with myelodysplastic syndrome, who had received multiple erythrocyte transfusions, was given oral deferasirox 2 g/ day. He was not taking NSAIDs or other nephrotoxic drugs, but 2 months later his serum creatinine had risen from 141 to 194 mmol/l. When it rose to 265 mmol/l, a renal biopsy was taken. The glomeruli were unremarkable, but there was a diffuse interstitial mononuclear infiltrate with neutrophils

R.H.B. Meyboom

and increased numbers of eosinophils, interstitial edema, and interstitial fibrosis with proportional tubular atrophy. Stains for IgG, IgA, IgM, C3, C1q, k and l light chains, and fibrinogen were negative. The diagnosis was acute interstitial nephritis due to drug hypersensitivity on a background of chronic interstitial nephritis. Deferasirox was withdrawn and the creatinine concentration fell to 115 mmol/l.

Fanconi syndrome has been attributed to deferasirox [25Cr]. • A 78-year-old man with sideroblastic anemia and chronic lymphocytic leukemia took deferasirox 24 mg/kg/day for transfusional iron overload. He also had diabetes mellitus without microangiopathy and was also taking glibenclamide, metformin, and perindopril. Before deferasirox the serum creatinine was 82 mmol/l and eGFR was 84 ml/minute, without proteinuria or electrolyte abnormalities. Within 1 month the serum creatinine rose to 122 mmol/l and the eGFR fell to 35 ml/minute. There was proximal tubular dysfunction, with hypophosphatemia, low plasma uric acid, a metabolic acidosis, glycosuria, and increased urinary b2microglobulin. There was no monoclonal gammopathy, and Doppler ultrasonography showed normal kidneys. Deferasirox and perindopril were withdrawn, and within 1 month the serum creatinine fell to 107 mmol/l and the proximal tubulopathy resolved.

Infection risk The potential therapeutic role of iron chelation in mucormycosis was initially obscured by the apparently increased risk of mucormycosis during the use of deferoxamine [SEDA-31, 403]. In an open study in eight patients with biopsy-proven mucormycosis, deferasirox (5–20 mg/kg/day for an average of 14 days) was a safe adjunctive therapy [26cr].

Deferiprone

[SED-15, 1054; SEDA-30, 273; SEDA-31, 402; SEDA-32, 427]

Pro-oxidant effects of deferiprone At sufficiently high concentrations deferiprone forms a stable water-soluble 3:1 complex with Fe3þ, with a binding constant of 37, and has antioxidant activity. At lower concentrations, on the other hand, incomplete 1:1 and 1:2 chelator–iron complexes

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form and the unoccupied coordination sites of these complexes can paradoxically catalyse the formation of hydroxyl radicals and other reactive oxygen species. For some time it has been suspected that the mechanism underlying the development of characteristic adverse reactions to deferiprone, such as agranulocytosis, arthritis, and perhaps heart failure, is related to this paradoxical pro-oxidant action of deferiprone. The potential for free radical formation has been studied after a single oral dose of deferiprone 25 mg/kg in 21 patients with beta thalassemia or hemoglobin E [27R]. None of the patients had received a blood transfusion in the preceding month. In the presence of tert-butylhydroperoxide and ascorbic acid, free radicals were assessed by electron paramagnetic resonance (EPR) spectroscopy spin trapping technique, using 5,5-dimethyl-1-pyrrolineN-oxide (DMPO). Shortly after administration of deferiprone, the EPR signal intensities fell. However, a pro-oxidant activity was later observed in the sera of several patients, as indicated by an enhanced EPR signal, notably at 300, 360, and 480 minutes after dosing. Most of these patients had severe iron load and had serum molar deferiprone/iron ratios below 3. Although iron status could also have determined free radical formation; there were significant correlations between NTBI and the deferiprone/ iron ratio. On the other hand, in almost all of the patients, a higher ratio was associated with antioxidant activity throughout the study. This study has shown for the first time in vivo a paradoxical pro-oxidant action of deferiprone. In order to avoid adverse effects, a dosage regimen should be designed that is based on the iron status of the patient and aimed at maintaining a sufficiently high ratio of the serum chelator-to-iron concentration. A possible advance in this respect is the development of “pro-chelators”, chelators that bind iron only when activated by oxidative stress [28E]. Cardiovascular A severe cardiomyopathy with congestive heart failure has been reported after withdrawal of deferiprone for severe arthritis [29c].

469 • A 40-year-old man with sideroblastic anemia, who had had regular erythrocyte transfusions for 4 years, was given nightly subcutaneous infusions of deferoxamine subcutaneously 3 g/ day on 5 days/week. After 22 months he developed vestibular toxicity and deferoxamine was replaced by oral deferiprone 75 mg/kg/day. Cardiac ultrasonography was normal and there were no signs of pulmonary hypertension or right ventricle dysfunction. After 6 weeks he suddenly developed severe arthralgia and swelling of the knees and deferiprone was withdrawn. During the next few days he developed severe dyspnea and 2 weeks later congestive heart failure. The ventricular ejection fraction had fallen to 30% and there was a dilated hypokinetic cardiomyopathy. No other causes were found and he died 3 months later.

Heart failure is a common cause of death in end-stage b-thalassemia, which might have contributed in this patient. In previous studies of deferiprone, heart failure occurred in four out of 51 patients [30C] and nine out of 532 patients [31C], but most of them had had left ventricular dysfunction before administration of deferiprone. The mechanism and precipitating factors of deferiprone-induced cardiotoxicity are uncertain. It could be due to a direct toxic effect or to an increase in non-transferrin-bound iron. The heart selectively takes up labile iron species, and labile plasma iron can generate reactive oxygen species and is thought to play a major role in ironrelated heart failure [32c]. The short half-life of deferiprone may also be influential. The observation in these two patients that cardiotoxicity happened after stopping is of particular interest, in the light of the recent observation that in a single-dose study prooxidant effects of deferiprone were mainly observed at the end of the study period, when deferiprone blood concentrations had fallen. Hematologic In a 5-year randomized study in 213 patients with b-thalassemia, deferiprone monotherapy 75 mg/kg/day was compared with deferiprone 75 mg/kg/day on 3 days/week alternating with deferoxamine 50 mg/kg/day on 3 days/week [33C]. While neutropenia was equally frequent in the two groups (11 and 15 patients), there was agranulocytosis in three of the patients who received deferiprone monotherapy and none in the other group. This may be related to the

470

pro-oxidant action of deferiprone and raises the question of whether combined use of deferiprone with deferoxamine reduces the risk of agranulocytosis. Nervous system Two patients with neurological reactions during the use of excessive doses of deferiprone, as referred to in the Ferriprox Dear Dr letter of July 2006, have been described in more detail [34CR]. These observations suggest that deferiprone should not be used in dosages exceeding 100 mg/kg/day. • In a 9-year-old boy who used deferiprone 119 mg/kg/day for 2 years (indication not specified) the dose was increased to 238 mg/kg/ day. During the next 16 months he developed a cerebellar syndrome, with dizziness, axial hypotonia, nystagmus, and diplopia, together with obsessive–compulsive behavior. Neurological investigations were normal and there were no infections, inflammation, or immunological disorders. He started to improve 3 weeks after stopping deferiprone and he recovered within 1 year. • A 7-year-old girl took deferiprone 232 mg/kg/ day and 2 months later developed a cerebellar syndrome, with inability to walk in a straight line, impaired motor coordination, nystagmus, and dystonia. The symptoms disappeared 1 month after drug withdrawal.

Musculoskeletal Symptoms of arthropathy are reported to occur in 13–20% of patients who take deferiprone and to require withdrawal in about 2%. It typically affects the knees, but the ankles, wrists, elbows, shoulders, and other joints may be affected. It is more frequent with a high iron load, high serum ferritin concentrations, and high deferiprone doses and less common after the first year of use [35R]. Arthroscopy has shown excess iron in the synovium and cartilage, but no deferiprone. Synovial biopsy has shown iron deposition and proliferation of the synovial lining without inflammatory reactions. The changes in epiphyseal cartilage and subchondral bone are unique to deferiprone-related arthropathy. The mechanism is uncertain, but it is thought that deferiprone-related shifts of iron to the synovium may increase free

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radical formation and local tissue injury during incomplete complexation of iron. There are usually no antibodies, rheumatoid factor, or antinuclear or anti-DNA antibodies detectable in the serum. The radiographic and MRI findings in deferiprone arthropathy have been characterized [36A]. • An 8-year-old boy, who had been receiving regular blood transfusions since he was 3 months, was given deferiprone 40–80 mg/kg/ day at irregular intervals according to serum ferritin concentrations. He developed pain in both knees at the age of 4 years. Plain radiographs showed mild irregular subchondral flattening of the femoral condyles and beaking of the patellae. MRI scans showed irregular thickening of the cartilage with subchondral erosions and cartilage intrusions in the subchondral defects. Joint effusion was minimal, but there were hypo-intense bands in the infrapatellar fat. Except for hemosiderin deposition the metaphysis and the epiphyseal plate were grossly normal. The bone marrow appeared black because of hemosiderin deposition.

Most patients with joint symptoms due to deferiprone are able to continue taking it, with or without NSAIDs. In 60 patients taking deferiprone, arthropathy occurred in only two, one of whom was described in detail, illustrating that deferiprone-induced arthritis can be severe and disabling [37Ar]. • A 29-year-old man with b-thalassemia took deferiprone for 4 years, initially in a dosage of 75 mg/kg/day, later increased to 100 mg/ kg/day. He developed bilateral arthritis of the knees, with swelling and pain particularly in the right knee. There were no infections, osteoarthrosis, or other abnormalities of the bone, cartilage, or surrounding soft tissues and tests for immunological abnormalities were negative. T2-weighted signals were low in the bone marrow, because of iron disposition. Arthritic fluid culture was negative. Triamcinolone was injected into the right knee joint, deferiprone was replaced by deferoxamine, and NSAIDs were given. There was a complete resolution of the arthritis. Deferiprone was not reintroduced.

Another patient, with suspected deferiprone-related heart failure, had acute severe bilateral arthritis of the knees 6 weeks after starting deferiprone, necessitating drug withdrawal [29C].

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Deferoxamine

[SED-15, 1058; SEDA30, 274; SEDA-31, 402; SEDA-32, 429]

Sensory systems Vision Deferoxamine in high dose has been linked to retinal damage, thought to be due to retinal pigment epithelium iron deficiency. The relation between iron and pathology of the eye (for example, in age related macular degeneration) and the possible therapeutic use of chelators has been reviewed, illustrating the difficulty in distinguishing between spontaneous ocular adverse events and reactions to chelating drugs [38r]. The prevalence of ocular toxicity of deferoxamine has been evaluated retrospectively in 84 children, average age 13 years, who had received deferoxamine for an average of 6.6 years for transfusion-related hemochromatosis in b-thalassemia, E/b-thalassemia, or a-thalassemia [39cr]. The standard dosage was 25–50 mg/kg/day, given subcutaneously over 10 hours on 5–7 nights a week; three patients received short-term intravenous deferoxamine at some time during the study. Baseline ophthalmic screening was followed by yearly reviews (a total of 421 examinations; average five per patient). As a rule electroretinography and fluorescein angiography were carried out only when the ophthalmic history or physical examination was abnormal. Only one patient had abnormal findings, with central blurring, retinal pigmentary changes, and a reduced central response on electroretinography. This patient (age not mentioned) had a 3-year history of poor adherence and was temporarily receiving intravenous deferoxamine 50 mg/kg/day as a continuous 24-hour infusion; all symptoms promptly recovered after changing to subcutaneous administration. The authors recommended ophthalmic screening only in patients receiving high doses or intravenous deferoxamine or in the case of visual symptoms. Auditory function In a cross-sectional study of the frequency of sensorineural hearing loss in 67 patients (minimum age 5, maximum 24 years) receiving regular deferoxamine by subcutaneous pump infusion for b-thalassemia the mean dose was 50 mg/kg/day on a

471

mean of 5.5 days/week; the mean duration of treatment was 11 (range 1–21) years [40CR]. In five cases (three girls, two boys) there was sensorineural hearing loss, which may have been due to deferoxamine and was otherwise unexplained. In three patients chelation treatment was changed, but on follow-up there was no improvement. There were no substantial differences between these children and those with normal hearing (for example, age, sex, dose and duration of drug use, disease parameters). Although in these five cases the mean exposure time to deferoxamine of 15 years was longer than in the patients without hearing loss (10 years) the difference was not statistically significant. It is not always correct to attribute hearing loss to deferoxamine or other chelators [41A]. • A 6-year-old boy with transfusion-dependent b-thalassemia developed unilateral hearing loss shortly after low-dose deferoxamine (dose not specified). Ototoxicity was assumed, but the deficit was later found to be conductive and due to bone marrow proliferation within the ossicular chain as a consequence of the disease.

Musculoskeletal In a retrospective series of 84 children receiving deferoxamine for transfusion-related hemochromatosis (b-thalassemia, E/b-thalassemia, or a-thalassemia) bone dysplasia occurred in 17 [39c]. The standard dose was 25–50 mg/kg/day subcutaneously over 10 hours on 5–7 nights a week; three patients received short-term intravenous deferoxamine at some point during the study.

Combinations of iron chelators [SEDA 31, 399; SEDA 32, 426] Infection risk Reactivation of hepatitis B infection may have been caused by the combined use of deferiprone and deferoxamine [42A]. • A 29-year-old man with b-thalassemia (CD39IVSH-1), who had received deferoxamine for 19 years, developed co-existent cholelithiasis, moderate spleen enlargement, and chronic HBV hepatitis (HBsAg positive, HBeAg negative, HBV-DNA

472 2.1
103 copies/ml, normal baseline alanine aminotransferase). Deferiprone 50 mg/kg/day was added to deferoxamine 30 mg/kg on 3– 5 days/week and the alanine aminotransferase activity increased. Deferiprone was withdrawn and the enzyme activity fell. Deferiprone was reintroduced and there was a new sustained rise in aminotransferase activity to about twice baseline. There were 139
103 copies/ml of HBV-DNA. Extensive testing did not identify autoantibodies. Deferiprone was withdrawn again and the HBV-DNA cleared partly within 8 weeks and alanine aminotransferase activity returned to normal. Later, deferiprone was reintroduced in the same dosage and there was no relapse of hepatitis after 24 months.

This patient received regular transfusions, and the episode of hepatitis activation cannot be attributed with certainty to the combined administration of deferiprone and deferoxamine. The first rechallenge with deferiprone was followed by prompt relapse, but the second was not. Iron storage and iron chelators both have immunomodulating effects [43c], and this report suggests that combined use of deferiprone and deferoxamine may affect the immune system. Patients with pre-existing viral hepatitis should be monitored, but hepatitis reactivation should not necessarily be mistaken for drug-induced liver damage.

PENICILLAMINE AND RELATED DRUGS [SED-15, 2729; SEDA-30, 274; SEDA-31, 403; SEDA-32, 430]

Penicillamine Effective as penicillamine is in excreting copper, it can also seriously worsen neurological symptoms early in the treatment of Wilson's disease. Unfortunately, there is still a lack of high-quality evidence regarding the best initial treatment in this disease, and early diagnosis can also be difficult [44M, 45R]. Since zinc is effective and has negligible adverse effects, it is probably the best choice in the initial treatment of

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presymptomatic patients as well as in patients with neurological involvement, although in patients with acute hepatic disease zinc may act too slowly and penicillamine may be needed. Neither trientine nor tetrathiomolybdate has been studied widely enough to decide about the best use of these drugs in the initial treatment of Wilson's disease. Observational studies In a retrospective chart study of 11 children with cystinuria, penicillamine (goal dose 20 mg/kg) was effective [46CR]. During a total of 1203 patient-months several patients had minor transient adverse events, such as arthralgia, which did not require withdrawal; there were serious adverse reactions in two patients. A 7-year-old boy developed generalized amino-aciduria after 3 years; it resolved on drug withdrawal. Penicillamine was reintroduced later and there was a second episode of amino-aciduria, which resolved after penicillamine withdrawal. A 22-year-old woman developed elastosis perforans serpiginosa after taking penicillamine for 15 years. Respiratory Hypersensitivity pneumonitis has been attributed to penicillamine [47A]. • A 50-year-old woman with Wilson's disease and hepatic cirrhosis was given penicillamine 1 g/day and pyridoxine 50 mg/day and after 6 weeks developed acute dyspnea. She had a respiratory rate of 20/minute, a temperature of 37.5 C, and reduced breath sounds in both lung bases, with diffuse end-inspiratory crackles. Oxygen saturation was 93% at rest. A chest radiograph showed increased interstitial markings and a CT scan showed diffuse changes in both lungs with ground-glass opacities and thickening of intralobular and interlobular septa. There were 42% lymphocytes, 48% macrophages, and 9% eosinophils in bronchial lavage fluid. When penicillamine was withdrawn and replaced by trientine her symptoms improved and the chest radiograph returned to normal.

Endocrine In pregnant women with Wilson's disease chelation therapy is needed throughout pregnancy. The connection between maternal use of penicillamine

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Chapter 23

and transient goitrous hypothyroidism in the neonate has been evaluated [48A]. • A mother with Wilson's disease gave birth at 35 weeks to a boy weighing 2.4 kg with a palpable goiter. Neonatal screening and thyroid function tests at 18 days showed hypothyroidism without TSH receptor antibodies. He was given levothyroxine 25 micrograms/day and the goiter resolved within 5 months; levothyroxine was continued for 4 years. The mother had used penicillamine 1.5 g/day for 15 years and during pregnancy the dose had been increased to 2 g/ day; no other drugs were taken. There was no family history of thyroid disease. • The same mother gave birth at term to a second son, weighing 3.1 kg. The perinatal course was uneventful, but neonatal screening showed severe hypothyroidism; serum thyroglobulin concentrations were extremely high and a thyroid scan showed a diffusely enlarged gland. Levothyroxine was effective within 2 months and was withdrawn after 7 months.

After parturition the mother's thyroid function tests were normal, as were thyroglobulin and thyroperoxidase; TSH receptor antibodies were undetectable. Her thyroid was not palpable, but a scan showed diffuse enlargement and 131I uptake was increased. She developed a multinodular goiter 4 years later, but free thyroxine and TSH concentrations remained normal. Three more children born to mothers using penicillamine all had subclinical hypothyroidism. The authors hypothesized that penicillamine inhibits thyroid hormone iodination and coupling reactions catalysed by thyroid peroxidase, and concluded that in utero exposure to penicillamine may cause congenital goitrous hypothyroidism and persistent subclinical hypothyroidism in older children. Skin Elastosis of the lip has been described as a possible late sequel of the use of penicillamine [49Ar]. • A 45-year-old man with Wilson's disease developed two 1- to 2-cm annular atrophic plaques on the mucosa of the lower lip with a mildly raised hyperkeratotic rim. Histology showed irregular acanthotic and atrophic epithelium without perforation. There were markedly increased elastic fibers with a bramble-bush morphology, as is typically seen in penicillamine dermopathy. During previous

473 treatment with penicillamine he had had elastosis perforans serpiginosa of the skin of the axillae, leading to withdrawal of penicillamine and replacement by zinc acetate and trientine. Bilateral hyperpigmented atrophic plaques with annular slightly raised borders were still present in the axillae. The patient was also known to chew tobacco.

Another case of bullous pemphigoid has been described in a patient taking penicillamine [50A]. • A 47-year-old man with Wilson's disease, who had taken penicillamine 1.5 g/day for about 20 years, developed marked pruritus, large tense blisters on an erythematous base, erythematous papules, and small plaques on the trunk and arms. A biopsy of a bullous lesion showed a subepidermal blister with eosinophils and lymphocytes in the blister cavity. Direct immunofluorescence showed linear deposits of C3, IgG, and IgA. There were IgG deposits on the epidermal roof of the artificially induced separation. The bullous lesions responded to topical clobetasol and betamethasone, but new lesions continued to appear. Penicillamine was replaced by zinc sulfate, and the rash improved promptly. When penicillamine was reintroduced, the pruritus and tense blisters recurred within a few days.

OTHER CHELATORS DMPS (2,3-dimercapto-1propanesulfonic acid) Skin Stevens–Johnson syndrome occurred in a patient with chronic mercury poisoning who was given DMPS [51Cr]. • An 11-year-old boy with chronic non-symptomatic mercury poisoning was treated with oral DMPS 600 mg/day, and after 1 week started to feel unwell, with a mild fever and painful gums; 1 week later he developed a disseminated cutaneous eruption of red pruritic macules on the chest and back. He was given levocetirizine 5 mg/day, and 3 days later the rash had spread all over the body, the macules had become confluent, and there were erosions and crusts on the lips and blisters in the oral mucosa. There were no blisters on the skin or genitals and no corneal lesions. There were no signs of infection, and serological tests for Herpes simplex and Yersinia were negative. DMPS was withdrawn and the lesions gradually resolved.

474

Edetic acid (ethylene diamine tetra-acetic acid, EDTA) [SED-15, 1300; SEDA-30, 276; SEDA-31 405; SEDA32, 431] Placebo-controlled studies In a doubleblind, randomized, placebo-controlled study (40 cases, 40 controls), mesotherapy with disodium edetate (subcutaneous injections of a 15% solution þ procaine 1%) in combination with pulse-mode 1 MHz phonotherapy phonophoresis was highly effective in calcific tendinitis of the shoulder; there were no injection-site reactions or other adverse events [52cr]. Mineral metabolism Errors causing serious intoxication continue to be reported, because of confusion between disodium edetate (which has a strong affinity for calcium) and calcium disodium edetate (which can be used in lead poisoning) [53A]. If chelation therapy is required in children, calcium disodium edetate, not disodium edetate, should be used, because of the risk of hypocalcemia.

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R.H.B. Meyboom

• A 43-year-old man with Wilson's disease was given zinc acetate 400 mg/day, trientine 900 mg/day, and olanzapine 15 mg/day. He had persistent stable neutropenia 0.94
109 and then developed distal weakness in the hands and feet. Electrophysiological tests showed a length-dependent sensorimotor axonal peripheral neuropathy. Compound muscle and sensory nerve action potentials were reduced in amplitude. There were fibrillation potentials and large motor unit potentials with reduced recruitment in the distal limb muscles. The peroneus brevis muscle showed neurogenic atrophy and the superficial peroneal nerve axonal degeneration. Total serum copper and ceruloplasmin were markedly reduced and serum zinc was raised. There was a reduced copper concentration in the cerebrospinal fluid. Zinc acetate was withdrawn and the dose of trientine temporarily reduced to 300 mg/day. The neutrophil count normalized, but there was only mild neurological improvement.

Copper is an essential co-factor for various redox enzymes that prevent free radical formation. Copper deficiency is an established cause of reduced hemopoiesis. Hypercupremia and paradoxically also hypocupremia can both cause neuropathy.

Skin Edetic acid can cause hypersensitivity reactions, including contact eczema [54A]. • A 75-year-old man with several malignant epithelial tumors used UriageTM SPF50þ cream as a sunscreen, and 10 months later developed eczematous areas where the cream had been applied on the face, neck, and the backs of the hands. A patch test with the cream was positive after 4 days; of the 24 components of the product provided by the manufacturer only tetrasodium edetate (0.2% in water) was positive; tetrasodium edetate produced no reactions in five control subjects.

Trientine [SED-15, 3508; SEDA-32, 431] Metal metabolism A sensorimotor axonal peripheral neuropathy and mild bone marrow suppression occurred as probable complications of copper deficiency, secondary to treatment with trientine and zinc acetate [55A].

POLYSTYRENE SULFONATES [SED-15,

2894; SEDA-30, 275; SEDA-32, 433] Gastrointestinal Ischemic colitis [56A], colonic necrosis [57A, 58A, 59A], colonic perforation [60A], and ileal perforation [61A] have again been reported in patients taking sodium polystyrene sulfonate. In a review of all gastrointestinal specimens reported as containing crystals of sodium polystyrene sulfonate from December 1998 to June 2007, 29 patients were identified; nine were excluded as incidental findings with normal mucosa and nine were excluded as having had symptoms administration of sodium polystyrene sulfonate or because an alternative cause was identified [62c]. Eleven patients had confirmed intestinal necrosis and a temporal relation to the administration sodium polystyrene

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Chapter 23

sulfonate suggestive of drug-induced necrosis. Only two were postoperative and only four had end-stage renal disease. All had had hyperkalemia, had used oral sodium

475

polystyrene sulfonate, and had developed symptoms of intestinal injury between 3 hours and 11 days after administration. Four died.

References [1] Kolnagou A, Kontoghiorghes GJ. Advances in the prevention and treatment are changing thalassemia from a fatal to a chronic disease. Experience from a Cyprus model and its use as a paradigm for future applications. Hemoglobin 2009; 33(5): 287–95. [2] Cappellini MD, Piga A. Current status in iron chelation in hemoglobinopathies. Curr Mol Med 2008; 8(7): 663–74. [3] Cappellini MD, Pattoneri P. Oral iron chelators. Annu Rev Med 2009; 60: 25–38. [4] Dubey AP, Parakh A, Dublish S. Current trends in the management of beta thalassemia. Indian J Pediatr 2008; 75(7): 739–43. [5] Araújo A, Drelichman G, Cançado RD, Watman N, Magalhães SM, Duhalde M, Marfil J, Feliú A, Clementina L, Linares Ballesteros A, Di Stefano M. Latin American Experts Panel. Management of transfusional iron overload in Latin America: current outlook and expert panel recommendations. Hematology 2009; 14(1): 22–32. [6] Dogramaci AC, Savas N, Ozer B, Duran N. Skin diseases in patients with beta-thalassemia major. Int J Dermatol 2009; 48(10): 1057–61. [7] Diener H-C, Schneider D, Lampl Y, Bornstein NM, Kozak A, Rosenberg G. DP-b99, a membrane-activated metal ion chelator, as neuroprotective therapy in ischemic stroke. Stroke 2008; 39(6): 1774–8. [8] Campbell SM, Morton CA, Alyahya R, Horton S, Pye A, Curnow A. Clinical investigation of the novel iron-chelating agent, CP94, to enhance topical photodynamic therapy of nodular basal cell carcinoma. Br J Dermatol 2008; 159(2): 387–93. [9] Wood JC. Cardiac iron across different transfusion-dependent diseases. Blood Rev 2008; 22(Suppl 2): S14–21.

[10] Lee JW. Iron chelation therapy in the myelodysplastic syndromes and aplastic anemia: a review of experience in SouthKorea. Int J Hematol 2008; 88: 16–23. [11] Capalbo S, Spinosa G, Franzese MG, Palumbo G. Early deferasirox treatment in a patient with myelodysplastic syndrome results in a long-term reduction in transfusion requirements. Acta Haematol 2009; 121(1): 19–20. [12] Kontoghiorghes GJ. Transparency and access to full information for the fatal or serious toxicity risks, low efficacy and high price of deferasirox, could increase the prospect of improved iron chelation therapy worldwide. Hemoglobin 2008; 32(6): 608–15. [13] Porter JB, Taher AT, Cappellini MD, Vichinsky EP. Ethical issues and risk/benefit assessment of iron chelation therapy: advances with deferiprone/deferoxamine combinations and concerns about the safety, efficacy and costs of deferasirox [Kontoghiorghes GJ, Hemoglobin 2008; 32 (1–2):1–15]. Hemoglobin 2008; 32(6): 601–7. [14] Karnon J, Tolley K, Oyee J, Jewitt K, Ossa D, Akehurst R. Cost-utility analysis of deferasirox compared to standard therapy with desferrioxamine for patients requiring iron chelation therapy in the United Kingdom. Curr Med Res Opin 2008; 24(6): 1609–21. [15] McLeod C, Fleeman N, Bagust A, Boland A, Chu P, Dickson R, Dundar Y, Greenhalgh J, Modell B, Olujohhungbe A, Telfer P, Walley T. Deferasirox for the treatment of iron overload associated with regular blood transfusions (transfusional haemosiderosis) in patients suffering with chronic anaemia: a systematic review and economic evaluation. Health Technol Assess 2009; 13(1) iii–iv, ix–xi, 1–121.

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476 [16] Taher A, Cappellini MD, Vichinsky E, Galanello R, Piga A, Lawniczek T, Clark J, Habr D, Porter JB. Efficacy and safety of deferasirox doses of > 30 mg/kg per d in patients with transfusion-dependent anaemia and iron overload. Eur J Haematol 2009; 82 (6): 752–9. [17] Exjade Data Sheet. http://www.accessdata. fda.gov/drugsatfda_docs/label/2010/021882s 010lbl.pdf. [18] USA Food and Drug Administration. Exjade (deferasirox): Boxed Warning. 18 February 2010. http://www.fda.gov/Safety/ MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm200850.htm. [19] Taher A, El-Beshlawy A, Elalfy MS, Al Zir K, Daar S, Habr D, KriemlerKrahn U, Hmissi A, Al Jefri A. Efficacy and safety of deferasirox, an oral iron chelator, in heavily iron-overloaded patients with beta-thalassaemia: the ESCALATOR study. Eur J Haematol 2009; 82(6): 458–65. [20] Yusuf B, McPhedran P, Brewster UC. Hypocalcemia in a dialysis patient treated with deferasirox for iron overload. Am J Kidney Dis 2008; 52(3): 587–90. [21] Klein GL, Snodgrass WR, Griffin MP, Miller NL, Alfrey AC. Hypocalcemia complicating deferoxamine therapy in an infant with parenteral nutrition-associated aluminum overload: evidence for a role of aluminum in the bone disease of infants. J Pediatr Gastroenterol Nutr 1989; 9: 400–3. [22] Brown DJ, Dawborn JK, Ham KN, Xipell JM. Treatment of dialysis osteomalacia with desferrioxamine. Lancet 1982; 2 (8294): 343–5. [23] Wimazal F, Nosslinger T, Baumgartner C, Sperr WR, Pfeilstocker M, Valent P. Deferasirox induces regression of iron overload in patients with myelodysplastic syndromes. Eur J Clin Invest 2009; 39(5): 406–11. [24] Brosnahan G, Gokden N, Swaminathan S. Acute interstitial nephritis due to deferasirox: a case report. Nephrol Dial Transplant 2008; 23(10): 3356–8. [25] Rafat C, Fakhouri F, Ribeil J-A, Delarue R, Le Quintrec M. Fanconi syndrome due to deferasirox. Am J Kidney Dis 2009; 54(5): 931–4. [26] Spellberg B, Walsh TJ, Kontoyiannis DP, Edwards Jr. JJ, Ibrahim AS. Recent

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

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advances in the management of mucormycosis: from bench to bedside. Clin Infect Dis 2009; 48(12): 1743–51. Jirasomprasert T, Morales NP, Limenta LMG, Sirijaroonwong S, Yamanont P, Wilairat P, Fucharoen S, Chantharaksri U. Pharmaco/ ferrokinetic-related pro-oxidant activity of deferiprone in beta-thalassemia. Free Radic Res 2009; 43(5): 485–91. Charkoudian L, Pham D, Franz K. A prochelator triggered by hydrogen peroxide inhibits iron-promoted hydroxyl radical formation. J Am Chem Soc 2006; 128: 12424–5. Aqodad N, Loréal O, Erdtman L, Brissot P, Guyader D. Fatal congestive heart failure with deferiprone. Gastroenterol Clin Biol 2008; 32(6–7): 656–7. Hoffbrand AV, Al-Refaie F, Davis B, Siritanakatkul N, Jackson BF, Cochrane J, Prescott E, Wonke B. Long-term trial of deferiprone in 51 transfusion-dependent iron overloaded patients. Blood 1998; 91(1): 295–300. Ceci A, Baiardi P, Felisi M, Cappellini MD, Carnelli V, De Sanctis V, Galanello R, Maggio A, Masera G, Piga A, Schettini F, Stefàno I, Tricta F. The safety and effectiveness of deferiprone in a large-scale 3-year study in Italian patients. Br J Haematol 2002; 118(1): 330–6. Esposito BP, Breuer W, Sirankapracha P, Pootrakul P, Hershko C, Cabantchik ZI. Labile plasma iron in iron overload: redox activity and susceptibility to chelation. Blood 2003; 102: 2670–7. Maggio A, Vitrano A, Capra M, Cuccia L, Gagliardotto F, Filosa A, Romeo MA, Magnano C, Caruso V, Argento C, Gerardi C, Campisi S, Violi P, Malizia R, Cianciulli P, Rizzo M, D'Ascola DG, Quota A, Prossomariti L, Fidone C, Rigano P, Pepe A, D'Amico G, Morabito A, Gluud C. Long-term sequential deferiprone– deferoxamine versus deferiprone alone for thalassaemia major patients: a randomized clinical trial. Br J Haematol 2009; 145(2): 245–54. Beau-Salinas F, Guitteny MA, Donadieu J, Jonville-Bera AP, Autret-Leca E. High doses of deferiprone may be associated with cerebellar syndrome. BMJ 2009; 338: a2319.

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[35] Galanello R, Campus S. Deferiprone chelation therapy for thalassemia major. Acta Haematol 2009; 122(2): 155–64. [36] Chand G, Chowdhury V, Manchanda A, Singh S. Deferiprone-induced arthropathy in thalassemia: MRI findings in a case. Indian J Radiol Imaging 2009; 19(2): 155–7. [37] Vlachaki E, Tselios K, Perifanis V, Tsatra I, Tsayas I. Deferiprone-related arthropathy of the knee in a thalassemic patient: report of a case and review of the literature. Clin Rheumatol 2008; 27(11): 1459–61. [38] Loh A, Hadziahmetovic M, Dunaief JL. Iron homeostasis and eye disease. Biochim Biophys Acta 2009; 1790(7): 637–49. [39] Baath JS, Lam W-C, Kirby M, Chun A. Deferoxamine-related ocular toxicity: incidence and outcome in a pediatric population. Retina 2008; 28(6): 894–9. [40] Shamsian BS, Aminasnafi A, Moghadassian H, Gachkar L, Arzanian MT, Alavi S, Esfehani H, Garallahi F, Amini R. Sensory neural hearing loss in beta-thalassemia major patients treated with deferoxamine. Pediatr Hematol Oncol 2008; 25(6): 502–8. [41] Thio D, Prasad V, Anslow P, Lennox P. Marrow proliferation as a cause of hearing loss in beta-thalassaemia major. J Laryngol Otol 2008; 122(11): 1253–6. [42] Ricchi P, Cinque P, Lanza Galeota A, Di Matola T, Ammirabile M, Prossomariti L. Hepatitis B virus reactivation during combined therapy with deferiprone and desferioxamine in a hepatitis B surface antigen thalassemic carrier. Int J Hematol 2009; 89(2): 135–8. [43] Pradhan V, Badakere S, Ghosh K. Antihistone and other autoantibodies in beta-thalassemia major patients receiving iron chelators. Acta Haematol 2003; 109(1): 35–9. [44] Wiggelinkhuizen M, Tilanus MEC, Bollen CW, Houwen RHJ. Systematic review: clinical efficacy of chelator agents and zinc in the initial treatment of Wilson disease. Aliment Pharmacol Ther 2009; 29(9): 947–58. [45] Manolaki N, Nikolopoulou G, Daikos GL, Panagiotakaki E, Tzetis M, Roma E, Kanavakis E, Syriopoulou VP. Wilson disease in children: analysis of 57 cases. J Pediatr Gastroenterol Nutr 2009; 48(1): 72–7.

477 [46] DeBerardinis RJ, Coughlin II CR, Kaplan P. Penicillamine therapy for pediatric cystinuria: experience from a cohort of American children. J Urol 2008; 180(6): 2620–3. [47] Seo JY, Kim S-Y, Choi W-C. Hypersensitivity pneumonitis induced by penicillamine. J Gastroenterol Hepatol 2009; 24(4): 700. [48] Hanukoglu A, Curiel B, Berkowitz D, Levine A, Sack J, Lorberboym M. Hypothyroidism and dyshormonogenesis induced by d-penicillamine in children with Wilson's disease and healthy infants born to a mother with Wilson's disease. J Pediatr 2008; 153(6): 864–6. [49] Lewis BKH, Chern PL, Stone MS. Penicillamine-induced elastosis of the mucosal lip. J Am Acad Dermatol 2009; 60(4): 700–3. [50] Popadic S, Skiljevic D, Medenica L. Bullous pemphigoid induced by penicillamine in a patient with Wilson disease. Am J Clin Dermatol 2009; 10(1): 36–8. [51] van der Linde AA, Pillen S, Gerrits GP, Bouwes Bavinck JN. Stevens–Johnson syndrome in a child with chronic mercury exposure and 2,3-dimercaptopropane-1sulfonate (DMPS) therapy. Clin Toxicol (Phila) 2008; 46(5): 479–81. [52] Cacchio A, De Blasis E, Desiati P, Spacca G, Santilli V, De Paulis F. Effectiveness of treatment of calcific tendinitis of the shoulder by disodium EDTA. Arthritis Rheum 2009; 61(1): 84–91. [53] Baxter AJ, Krenzelok EP. Pediatric fatality secondary to EDTA chelation. Clin Toxicol 2008; 46(10): 1083–4. [54] Sanchez-Pedreno P, Garcia-Bravo B, FriasIniesta J. Contact allergy to tetrasodium EDTA in a sunscreen. Contact Dermatitis 2009; 61(2): 125–6. [55] Foubert-Samier A, Kazadi A, Rouanet M, Vital A, Lagueny A, Tison F, Meissner W. Axonal sensory motor neuropathy in copper-deficient Wilson's disease. Muscle Nerve 2009; 40(2): 294–6. [56] Tapia C, Schneider T, Manz M. From hyperkalemia to ischemic colitis: a resinous way. Clin Gastroenterol Hepatol 2009; 7(8): e46–7. [57] Thomas A, James BR, Landsberg D. Colonic necrosis due to oral Kayexalate in

478 a critically-ill patient. Am J Med Sci 2009; 337(4): 305–6. [58] Bomback AS, Woosley JT, Kshirsagar AV. Colonic necrosis due to sodium polystyrene sulfate (Kayexalate). Am J Emerg Med 2009; 27(6): 753.e1–2. [59] Joo M, Bae WK, Kim NH, Han SR. Colonic mucosal necrosis following administration of calcium polystryrene sulfonate (Kalimate) in a uremic patient. J Korean Med Sci 2009; 24(6): 1207–11. [60] Montagnac R, Méhaut S, Schillinger F. Complications digestives du polystyrène sulfonate de sodium (KayexalateÒ) (KXL)

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chez le dialysé [Digestive adverse effects due to sodium polystyrene sulfonate (KayexalateÒ) in dialysis patients.] Nephrol Ther 2009; 5(3): 214–6. [61] Trottier V, Drolet S, Morcos MW. Ileocolic perforation secondary to sodium polystyrene sulfonate in sorbitol use: a case report. Can J Gastroenterol 2009; 23(10): 689–90. [62] McGowan CE, Saha S, Chu G, Resnick MB, Moss SF. Intestinal necrosis due to sodium polystyrene sulfonate (Kayexalate) in sorbitol. South Med J 2009; 102(5): 493–7.

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Antiseptic drugs and disinfectants

Disinfectants and bacterial resistance The first observations to suggest that some quaternary ammonium compounds, such as benzalkonium chloride, stearalkonium chloride, and cetylpyridine chloride, have antimicrobial activity were made in as early as 1916, but their full potential was first realized in the 1930s [1E, 2R]. Since then their uses have steadily increased and include many industrial purposes, water treatment, and antifungal treatment in horticulture, as well as inclusion in pharmaceutical and everyday consumer products. For example, benzalkonium chloride, the most commonly used, is found in products such as eye drops, artificial tears, decongestion nose drops, facial moistures, facial cleansers, acne treatments, sun protection creams and lotions, body lotions, moisturizers, pain relievers, and hand sanitizers [3R]. Very often good reasons for their use are lacking and claims are limited to assertions that they are “bug-killers”. The quaternary ammonium compounds can be looked upon as “hard antibacterial agents”. They are poorly metabolized and irrespective of use will reach the environment via water. Although there are considerable variations in their biodegradability, their environmental half-lives are weeks to months. Consequently, bacterial resistance has to be expected. The authors of an extensive

Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00024-6 # 2011 Elsevier B.V. All rights reserved.

survey, covering 142 references, concluded that the development of resistance to quaternary ammonium compounds in both pathogenic and non-pathogenic bacteria, related to practical applications in human medicine and the food industry, has been well documented [4R]. The key point is that increasing evidence for co-resistance and cross-resistance between quaternary ammonium compounds and most antibiotics on the market (such as beta-lactams, chloramphenicol, fusidic acid, macrolides, quinolones, tetracyclines) has been found in many pathogenic bacteria, such as Escherichia coli, Listeria monocytogenes, Salmonella spp., and Pseudomonas aeruginosa. It seems reasonable to assume that resistance may also be present in many more species. The efflux pumps that confer resistance in these organisms can be encoded in plasmids or chromosomally. Co-resistance and cross-resistance may also develop with most other disinfectants. Taken together, unnecessary use of disinfectants may contribute to the persistence and spread of antibiotic resistance, limiting our treatment options for bacterial infections. This is important because resistance is the most serious adverse effect of all antibiotics.

[SED-15, 1439, 1513; SEDA-31, 409; SEDA-32, 437]

ALDEHYDES Formaldehyde

Tumorigenicity The most recent evaluation by the International Agency for Research 479

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on Cancer classified the sterilizing and preservative agent formaldehyde as a known human carcinogen. It concluded that there is strong evidence that formaldehyde causes nasopharyngeal cancer, strong but not sufficient evidence for leukemia, and limited evidence for sinonasal cancer. However this classification has been debated [SEDA-32, 438]. Excess mortality from lymphohemopoietic malignancies, in particular myeloid leukemia, and brain tumors, has been found in surveys of anatomists, pathologists, and funeral workers, all of whom may have worked with formaldehyde. The risk of cancers in the funeral industry has been investigated by studying the relation of mortality to work practices and formaldehyde exposure [5C]. Professionals employed in the funeral industry who died between 1960 and 1986 from lymphohemopoietic malignancies or brain tumors were compared with deceased matched controls with regard to work practices and to estimated levels of formaldehyde exposure. Mortality from myeloid leukemia increased significantly with increasing number of years of embalming and with increasing peak formaldehyde exposure. These exposures were not related to other lymphohemopoietic malignancies or to brain cancer. The biological monitoring of occupational exposure to formaldehyde is useful both for investigating genetic damage and in epidemiological studies of tumorigenicity. To verify the relation between formaldehyde human serum albumin conjugate (FA-HAS), a biological marker of exposure, and markers of effect, namely chromosome aberrations, micronuclei, sister chromatid exchanges, laboratory workers who had been exposed to high concentrations of formaldehyde were compared with a reduced exposure group [6C]. There was a significant relation between occupational exposure to formaldehyde and the biological marker of exposure (FA-HAS). The markers of effect did not indicate the presence of genetic damage.

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Glutaral (glutaraldehyde) Gastrointestinal Ischemic colitis has been attributed to glutaral [7A]. • A 50-year-old woman underwent colonoscopy and 2 hours later developed pain in the lower abdomen and left iliac fossa. There was rectal bleeding and patchy erythema and ulceration in the upper rectum, and more striking changes in the distal sigmoid colon, with diffuse inflammation and areas of necrosis and spontaneous bleeding. She was treated symptomatically and recovered over 2–3 days.

This episode was attributed to inadequate rinsing after immersion of the endoscope in a solution of glutaral. Other similar cases have been reported [8A]. In a review of the medical records of patients with acute rectocolitis after endoscopy, seven patients were identified [9c]. All developed a self-limiting syndrome of abdominal pain and bloody diarrhea within 48 hours of uncomplicated endoscopy. Glutaral-induced colitis was diagnosed and attributed to a defect in the procedure for cleaning the endoscopes. Skin A 26-year-old applied topical glutaral to a plantar wart for 5 months and developed deep ulceration [10A].

BISBIGUANIDES Chlorhexidine

[SED-15, 714; SEDA-30, 278; SEDA-31, 410; SEDA-32, 439]

Observational studies The use of chlorhexidine in bathing patients has been studied in an evaluation of the effects on the rates of infections associated with central venous catheters in patients in coronary care units [11c]. On one 70-bedded unit all consecutive patients admitted during 9 months received daily baths with 2% chlorhexidine. Infections in central venous catheters were compared with infections before and after

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the intervention period. Despite the limitations of this study, infections were significantly less common during the intervention period, and patients tolerated the chlorhexidine solution well, although the wound care team observed that about 1% had increased dryness of the skin. This study also evaluated the effect of the chlorhexidine bath on the rates of ventilator-associated pneumonia and observed no change during the pre-intervention and intervention periods. Comparative studies In a multicenter randomized controlled comparison of chlorhexidine impregnated sponges and standard dressings in 1653 patients, patients with a history of allergy to chlorhexidine or the transparent dressing were excluded [12C]. The chlorhexidine impregnated sponges significantly reduced the rates of catheter colonization and catheter-related bloodstream infections. There was severe contact dermatitis, leading to permanent removal of the chlorhexidine sponge, in eight patients (11% of patients and 5.3% of catheters). There were no systemic adverse reactions to chlorhexidine. Skin allergy to the transparent dressing occurred in two patients. Although the incidence of skin lesions was low, contact dermatitis will occur occasionally and requires prompt removal of the chlorhexidine sponge. Ventilation-associated pneumonia continues to be a common and costly complication of critical care [13c]. It develops after aspiration of bacteria from the oropharynx into the lung and subsequent failure of host defences to clear the bacteria. Dental plaque biofilms are colonized by respiratory pathogens in ventilated patients. Thus, improvements in oral hygiene in these patients may prevent pneumonia. In a randomized study of the minimum frequency of application of chlorhexidine gluconate necessary to reduce oral colonization by pathogens in 175 intubated patients, decontamination of the oral cavity did not reduce the total amount of potential respiratory pathogens. However the chlorhexidine oral rinse did reduce the number of Staphylococcus aureus organisms in the dental

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plaque and there was a non-significant reduction in pneumonia rates. There was no evidence of resistance to chlorhexidine and no adverse effects.

CATIONIC SURFACTANTS Benzalkonium compounds [SED-15, 421; SEDA-28, 261; SEDA-32, 440] Immunologic In a 31-year-old woman episodes of flushing, itching, burning and red eyes, difficulty in breathing, and pain after the use of epinastine eye drops turned out to be due to benzalkonium chloride as a preservative [14A].

DYESTUFFS Triphenylmethane dyes [SEDA-28, 262] Triphenylmethane is a hydrocarbon, (C6H5)3CH, from which synthetic dyestuffs are derived, including brilliant blue, brilliant green, bromocresol green, fuchsine, gentian violet, and malachite green (Figure 1). They are intensely colored and poorly resistance to light and chemical bleaches. They have industrial uses in copying papers and printing inks and in textile applications for which light-fastness is not important. Of the triphenylmethane derivatives, gentian violet has been most often used in medical applications. It is a purple dye, so-called because its color resembles that of the gentian flower; it has nothing to do with Gentiana species. It is a mixture of crystal violet (hexamethyl-para-rosaniline) 96% and methyl violet (tetramethyl- and pentamethylpara-rosaniline). Methyl violet was first synthesized by Lauth in 1861 [15E] after Perkins’ discovery of aniline dyes [16R]. Gentian violet has been used in medicine for over 100 years: as an antiseptic for

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Cl– +

N

N

Triphenylmethane

Malachite green

N

Br

Br

OH

HO Br

Cl–

Br O N+

N Gentian violet

S O O Bromocresol green

Figure 1 Structures of triphenylmethane, malachite green, gentian violet, and bromocresol green.

external use, by local application to treat oral and vaginal candidiasis and to prepare the vagina for gynecological operations, as an antihelminthic agent by oral administration, as a blood additive to prevent transmission of Chagas’ disease [17E, 18E, 19ER, 20ER, 21E] and toxoplasmosis [22E], and in the management of chronic obstructive parotitis [23c]. Although its use is now restricted in many countries, because of concerns about its mutagenic and carcinogenic effects, it remains first-line medication for oral candidiasis in some countries, such as South Africa. However, in those with HIV/AIDS it is not preferred, because the visible purple staining of the mouth leads them to be stigmatized as HIV-positive. Financial constraints have also limited the use of gentian violet, and lemon juice applied directly in the mouth or as a lemon juice infusion is widely used. In a randomized study in 90 patients with oral candidiasis in HIV/AIDS both lemon juice and lemon grass were more effective than gentian violet [24c]. Furthermore, because of mucosal staining, adherence to therapy with gentian violet was poor.

Brilliant blue has been used to assist internal limiting membrane peeling during surgery for macular holes and epiretinal membranes, without adverse reactions [25c, 26c, 27c]. Pararosaniline pamoate has been used in the treatment of schistosomiasis in the Philippines in children, and there were few adverse reactions [28c]. Respiratory Mucosal ulceration and airways obstruction can occur with application of gentian violet, and occlusive laryngotracheitis requiring orotracheal intubation has been reported [29A]. • Mucosal lesions consistent with oral candidiasis developed in a previously healthy, full-term, exclusively breast-fed, 2-week-old girl. She was treated with oral nystatin, resulting in an initial reduction in the severity of the lesions. After a few days, the thrush became more prominent. At 4 weeks of age, 1% aqueous gentian violet was prescribed and the day after she developed a cough and difficulty in feeding. There was no nasal congestion, fever, or rhinorrhea. Over the next 7 days her cough and feeding difficulties became progressively

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worse, and she developed a hoarse cry and stridor. Nasal washings for respiratory syncytial virus were negative. Intravenous fluconazole and ceftriaxone were given for presumed sepsis and fungal tracheitis. Lateral neck radiographs showed an absence of air in the cervical trachea. She was intubated with a 3.5 mm oral endotracheal tube for airway management, and then had direct laryngoscopy under general anesthesia. The supraglottic, glottic, and subglottic structures were very edematous, but the vocal cords were mobile. Blood cultures on the day of admission failed to grow bacteria or fungi. There were no fungi in the supraglottic exudate. Nasopharyngeal samples were negative in viral cultures.

Sensory systems Gentian violet has been used as a corneal stain; there were only minor adverse effects in 112 patients and in 40 healthy eyes [30c]. However, corneal and conjunctival abrasions have been described [31A], and in one case bilateral keratoconjunctivitis followed instillation of a 1% aqueous solution of gentian violet and was complicated by a secondary uveitis and Gram-negative conjunctivitis [32A]. Keratoconjunctivitis sicca has also been described after inadvertent instillation of gentian violet 1% in both eyes in a 60-yearold man; in rabbits gentian violet caused variable thinning of the epithelial lining of the conjunctivae, with total loss of goblet cells and subepithelial capillary congestion with neutrophil infiltration [33AE]. Use of a low concentration of gentian violet to stain the anterior lens capsule during surgery caused no adverse effects [34c]. Hematologic Methemoglobinemia occurred in a 3-year-old girl after acute ingestion of malachite green from a commercial aquarium product [35A]. Mouth There have been reports of irritation in patients who have used gentian violet in the mouth [36A, 37A, 38A, 39A, 40A, 41r]. Urinary tract Chemical cystitis due to intravesical installation of gentian violet is rare. Cases have occurred in adult women when an undiluted solution was used. Cystitis has been reported in a child after bladder

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instillation of diluted gentian violet [42A] and in a woman after accidental instillation [43A]. • A 16-month-old boy developed painful gross hematuria after a herniorrhaphy. During the operation, gentian violet solution diluted to 0.1% had been instilled into the bladder to rule out bladder injury, and hematuria developed several hours later. There was no pyuria. Ultrasonography showed multiseptate structures resulting from edema and hematoma in the bladder and bilateral hydronephrosis. The hematuria responded to intravenous hydration, and follow-up ultrasonography showed bladder wall thickening with resolution of the strictures and less hydronephrosis. • A 32-year-old woman was given gentian violet to inject into her vagina, but accidentally injected it into the urethra. Within a few seconds she developed burning pain in the lower abdomen, followed by urinary frequency and urgency and dysuria. Cystoscopy showed gross inflammation and edema on the left side of the bladder with acute ulceration of the overlying mucosa.

Skin Contact sensitization to brilliant green, gentian violet, and malachite green has been described in 11 patients with eczema mainly on the legs [44c]. There was sensitization to brilliant green in all 11, with simultaneous sensitivity to gentian violet in eight and to malachite green in six; triphenylmethane and para-rosaniline produced negative reactions. The authors suggested that the probable determinants of sensitization are the N(CH3)2 or the N(C2H5)2 moieties in the para position of the benzene ring structure and that cross-reactivity is limited to substances with amino groups substituted with at least two alkyl groups (see Figure 1). There are several other anecdotal reports of contact reactions to gentian violet, particularly in older literature [45A, 46A, 47A], and to brilliant green [48A]. In one case there was co-existent nickel sensitivity [49A]. Even recently, contact dermatitis has been attributed to gentian violet in a 28-year-old Chinese woman without a history of allergy [50A]. Necrotic skin lesions have also been described [51A, 52A, 53A]. Skin necrosis occurred in a child after the application of 2% gentian violet to the gluteal fold; the authors recommended using concentrations below 1% for the treatment of intertrigo [54A].

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Musculoskeletal In two patients, injection of a low concentration of gentian violet into the glenohumeral joint, in order to visualize a rotator cuff tear during surgery, resulted in chondrolysis [55A]. Immunologic An allergic reaction, with urticaria, edema of the eyelids and lips, and hypotension, occurred after the use of Patent Blue Violet dye for lymphangiography [56A]. Tumorigenicity In the Rosenkranz bacterial assay gentian violet caused reparable DNA damage but it was not mutagenic in the Ames assay [57E]. In experiments in a DNA polymerase-deficient strain of E. coli the triphenylmethane dyes inhibited growth in the following order of potency: gentian violet > crystal violet > malachite green > methyl violet [58E]. Chronic oral administration of gentian violet to mice caused a dose-related increased risk of hepatocellular carcinoma after 18–24 months [59E]. In rats there was an increased risk of follicular cell adenocarcinoma of the thyroid gland and hepatocellular adenomas; in females the risk of mononuclear cell leukemia was also increased [60E]. However, in another study in rats there was a reduced incidence of mononuclear cell leukemia in rats fed malachite green [61E]. The tumorigenic effects of gentian violet in animals are probably mediated through a metabolite. It is demethylated in the liver and is reduced to leukogentian violet by intestinal microflora. Complete demethylation produces leukopararosaniline, which is carcinogenic in rats. A free-radical derivative is also formed in the liver, but its toxicity is not clear; N-demethylation by peroxidases and cyclo-oxygenase are other routes of metabolism [62R]. However, since there is no evidence that the phenylmethane dyes are carcinogenic in man, it has been suggested that they are safe to use [63r].

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HALOGENS Hypochlorous acid Observational studies Hypochlorite is very unstable, but hypochlorous acid is stable and is highly microbicidal, active against bacteria, viruses, and fungi. It has been used in 30 patients to treat venous leg ulcers that had not healed with conventional treatment; 10 achieved a 44% ulcer reduction after 3 weeks [64c]. The other 20 patients were then treated for 12 weeks; in nine cases there was full healing and in five the ulcers were reduced in size by over 60%. All the patients became free of pain. Adverse effects were not reported.

Sodium hypochlorite

[SED-15, 3157;

SEDA-28, 262] Respiratory Dilute hypochlorite solutions are currently the most common bleaching products used in private households around the world. Acute exposure to chlorine gas, which is released during the use of hypochlorite, can cause acute respiratory effects. Furthermore, the low concentrations of hypochlorite that are used in cleaning can affect pulmonary function [SEDA-26, 259]. It has been proposed that chloramines, which are typically released during cleaning activities when hypochlorite reacts with organic matter, may be allergens in a form of irritant-induced asthma. However, hypochlorite is effective as a cleaning agent in the inactivation of cat and other indoor allergens. The association of household use of hypochlorite with atopic sensitization, allergic disease, and respiratory health status has been assessed in 3626 participants in the European Community Respiratory Health Survey II. Specific serum IgE to four environmental allergens was available and all the participants did the cleaning in their own homes [65C]. The use of

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hypochlorite was associated with less atopic sensitization. This association was apparent for specific IgE to both indoor (cat) and outdoor (grass) allergens and was consistent in various subgroups, including those without a history of respiratory problems. There were dose–response relations for the frequency of hypochlorite use and sensitization rates. Lower respiratory tract symptoms, but not allergic symptoms, were more prevalent among those who used hypochlorite on four or more days per week. The use of hypochlorite was not associated with indoor allergen concentrations. The authors therefore concluded that people who clean their homes with hypochlorite are less likely to be atopic but are more likely to have respiratory symptoms.

[SEDA-15, 1896; SEDA-30, 279; SEDA-31, 411; SEDA-32, 440]

IODOPHORS

Iodine Although povidone iodine is now more commonly used as an antiseptic, iodine has traditionally been used as a powerful bactericidal agent. Owing to the problems associated with the emergence of drug-resistant pathogens, new strategies in the design of antimicrobial agents are investigating the properties of iodine in novel ways. An ideal antimicrobial agent should be non-toxic and possess broad-spectrum antiviral, antibacterial, and antifungal activity and exclude resistance. This has led to the design of a combination agent, iodine–lithium–alpha-dextran [66R]. This uses the non-specific antimicrobial action of molecular and ionized iodine and the systemic immunomodulatory effects of the polysaccharide complex of iodine and lithium. This new agent has been assessed by parenteral administration in HIV-infected patients. The adverse effects of phlebitis of punctured small veins and subfebrile fever,

485

transient headache, malaise, and sweating did not lead to withdrawal of therapy. Hepatitis was a serious adverse effect and occurred in 0.11% of subjects with viral hepatitis.

Polyvinylpyrrolidone (povidone) and povidone-iodine Endocrine Hypothyroidism and altered metabolism of thyroid hormones have been reported as adverse events in neonates and children, resulting from the use of antiseptics containing povidone-iodine [SED-15, 1896; SEDA-30, 279; SEDA-31, 411; SEDA-32, 440]. Because of concerns about possible iodine excess, chlorhexidine-based antiseptics have replaced povidone-iodine in some clinical settings. However, this may not be advantageous for infants and children who are receiving total parenteral nutrition (TPN) as iodine is not routinely added to TPN solutions. Previously, iodine deficiency was considered unlikely in patients receiving TPN, because of adsorption from iodine-containing skin disinfectants and other adventitious sources [67r, 68R]. Immunologic Severe systemic reactions to povidone-iodine are rare [SEDA-32, 441] and are more often reported with lavage or instillation into wounds or body cavities, although there are individual case reports of anaphylaxis when povidone-iodine has been applied vaginally [SEDA-20, 226] and rectally [69A].

PHENOLIC COMPOUNDS [SED-15, 2800, SEDA-32, 441]

Pentachlorophenol Observational studies Pentachlorophenol is a chlorinated aromatic compound that has been used extensively as a fungicide.

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From the 1950s to the late 1980s pentachlorophenol-based fungicides were widely used in the New Zealand sawmill industry, and there were persistent claims of longterm adverse effects on health. In a crosssectional study of the surviving members of a cohort gathered to study mortality in sawmill workers employed from 1970 to 1990, only 116 of the 293 participants had been exposed to pentachlorophenol and all but 10% had low or short-term exposures. However, pentachlorophenol exposure was associated with a number of physical and neuropsychological health effects, which persisted long after exposure had ceased [70c]. Tumorigenicity Pentachlorophenol was first registered as a wood preservative in the USA in 1936, and has also been used in ropes, paints, adhesives, canvas, insulation, and brick walls. Use by the general public was restricted in 1984, and the use of pentachlorophenol was limited to industrial areas. In 1990 the International Agency for Research on Cancer classified pentachlorophenol as a possible human carcinogen, based on sufficient information in animal assays but limited data in humans. More recently, case reports and

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case studies have raised concerns about the risk of hemopoietic tumors, non-Hodgkin's lymphoma, and soft tissue sarcoma. In a systematic review of published studies pertaining to cancer risk in relation to pentachlorophenol, there were associations between hemopoietic cancers and data on the risks of other cancers and risks associated with other types of chlorophenols [71M].

Phenol Nervous system In addition to its uses as an antiseptic and disinfectant, phenol is now more commonly used by injection as a sclerosant, local anesthetic, and analgesic. Pain and edema at the injection site are well documented, and dysesthesia has been reported [SEDA-26, 260]. In a retrospective study of single and multilevel injections of phenol, botulinum toxin, or both in children with chronic muscle spasticity, the local adverse effects were comparable with other previously reported studies. However, in contrast to previous studies, rare cases of dysesthesia (0.4%) were reported with phenol injections [72r].

References [1] Rahn O, van Eseltine WP. Quaternary ammonium compounds. Annu Rev Microbiol 1947; 1: 173–92. [2] Gilbert P, Moore LE. Cationic antiseptics: diversity of action under a common epithet. J Appl Microbiol 2005; 99(4): 703–15. [3] Thorsteinsson T, Loftsson T, Masson M. Soft antibacterial agents. Curr Med Chem 2003; 10(13): 1129–36. [4] Hegstad K, Langsrud S, Lunestad BT, Scheie AA, Sunde M, Yazdankhah SP. Does the wide use of quaternary ammonium compounds enhance the selection and spread of antimicrobial resistance and thus threaten our health? Microb Drug Resist 2010; 16(2): 91–104.

[5] Hauptmann M, Stewart PA, Lubin JH, Beane Freeman LE, Hornung RW, Herrick RF, Hoover RN, Fraumeni JF, Blair A, Hayes RB. Mortality from lymphohematopoietic malignancies and brain cancer among embalmers exposed to formaldehyde. J Natl Cancer Inst 2009; 101(24): 1696–708. [6] Pala M, Ugilon P, Ceppi M, Rizzo F, Maiorana L, Bolognesi C, Schiliro T, Gill G, Bigatti P, Bono R, Vecchio D. Occupational exposure to formaldehyde and biological monitoring of research institute workers. Cancer Detect Prev 2008; 32(2): 121–6. [7] Tsai MS, Chiu HH, Li JH. Education and imaging. Gastrointestinal: glutaraldehyde

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proctocolitis. J Gastroenterol Hepatol 2008; 23(9): 1460. Kurdaş OO, Sezikli M, Cetinkaya ZA, Güzelbulut F, Yaşar B, Coşgun S, Değirmenci AS. Glutaraldehyde-induced colitis: three case reports. Indian J Gastroenterol 2009; 28(6): 221–3. Hsu CW, Lin CH, Wang JH, Wang HT, Ou WC, King TM. Acute rectocolitis following endoscopy in health check-up patients—glutaraldehyde colitis or ischemic colitis? Int J Colorectal Dis 2009; 24(10): 1193–200. Fujisawa Y, Furuta J, Kawachi Y, Otsuka F. Deep plantaris ulceration secondary to the topical treatment of wart with glutaraldehyde. J Dermatol 2009; 36(11): 618–9. Munoz-Price LS, Hota B, Stemer A, Weinstein RA. Prevention of bloodstream infections by use of daily chlorhexidine baths for patients at a long-term acute care hospital. Infect Control Hosp Epidemiol 2009; 30(11): 1031–5. Timsit JF, Schwebel C, Bouadma L, Geffroy A, Garrouste-Orgeas M, Pease S, Herault MC, Haounche H, CalvinoGunther S, Gestin B, Armand-Lefevre L, Leflon V, Chaplaen C, Benali A, Francais A, Adrie C, Zahar JR, Thuong M, Arrault X, Croize J, Lucet JC. Chlorhexidine impregnated sponges and less frequent dressing changes for prevention of catheter-related infections in critically ill patients. JAMA 2009; 301(12): 1231–41. Scannapieco FA, Yu J, Raghavendran K, Vacanti A, Owens SI, Wood K, Mylotte JM. A randomized trial of chlorhexidine gluconate on oral bacterial pathogens in mechanically ventilated patients. Crit Care 2009; 13(4): R117–28. Anderson D, Faltay B, Haller NA. Anaphylaxis with use of eye-drops containing benzalkonium chloride preservative. Clin Exp Optom 2009; 92(5): 444–6. Lauth C. On the new aniline dye, “Violet de Paris”. Laboratory 1867; 1: 138–9. Garfield S. Mauve: How One Man Invented a Colour That Changed the World. London: Faber and Faber, 2000. Moraes-Souza H, Kerbauy J, Barretto OC, Pühler GM, Nonoyama K, Juliano Y.

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Metabolism and preservation of fresh and stored erythrocytes in blood treated with gentian violet. Braz J Med Biol Res 1988; 21(2): 241–6. Celentano AM, González Cappa SM. Enfermedad de Chagas y transfusion sanguinea: actividad tripanocida del clorhidrato de maprotilina y del violeta de genciana. [Chagas’ disease and blood transfusion: trypanocidal activity of maprotiline hydrochloride and gentian violet.] Medicina (B Aires) 1988; 48(3): 265–8. Moreno SN. Metabolism and mode of action of gentian violet. Mem Inst Oswaldo Cru 1988; 83(Suppl 1): 308–20. Docampo R, Moreno SN, Gadelha FR, de Souza W, Cruz FS. Prevention of Chagas’ disease resulting from blood transfusion by treatment of blood: toxicity and mode of action of gentian violet. Biomed Environ Sci 1988; 1(4): 406–13. Ramirez LE, Lages-Silva E, Pianetti GM, Rabelo RM, Bordin JO, Moraes-Souza H. Prevention of transfusion-associated Chagas’ disease by sterilization of Trypanosoma cruzi-infected blood with gentian violet, ascorbic acid, and light. Transfusion 1995; 35(3): 226–30. Pinto PL, Amato Neto V, Duarte MI, Cotrim JX, Moreira AA, de Sant'ana EJ, Campos R. Estudo experimental sobre possivel atividade da violeta de genciana na profilaxia da transmissao da toxoplasmose por transfusao de sangue. [Experimental study of the possible activity of gentian violet in preventing the transmission of toxoplasmosis due to blood transfusion.] Rev Inst Med Trop Sao Paulo 1985; 27(2): 89–94. Wang S, Li J, Zhu X, Zhao Z, Sun T, Dong H, Zhang Y. Gland atrophy following retrograde injection of methyl violet as a treatment in chronic obstructive parotitis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998; 85(3): 276–81. Wright SC, Maree JE, Sibanyoni M. Treatment of oral thrush in HIV/AIDS patients with lemon juice and lemon grass and gentian violet. Phytomedicine 2009; 16: 118–24.

488 [25] Enaida H, Hisatomi T, Hata Y, Ueno A, Goto Y, Yamada T, Kubota T, Ishibashi T. Brilliant blue G selectively stains the internal limiting membrane/brilliant blue G-assisted membrane peeling. Retina 2006; 26(6): 631–6. [26] Wirbelauer C, Häberle H, Pham DT, Klin Monbl Augenheilkd. Klinische Erfahrungen zur Färbung der Netzhautoberfläche mit Brilliant blau G. [Clinical experience with brilliant blue G staining of the retinal surface.] Klin Monbl Augenheilkd 2011; 228 (1): 62–5. [27] Naithani P, Vashisht N, Khanduja S, Sinha S, Garg S. Brilliant blue G-assisted peeling of the internal limiting membrane in macular hole surgery. Indian J Ophthalmol 2011; 59(2): 158–60. [28] Pesigan TP, Banzon TC, Santos AT, Noseñas J, Zabala RG. Pararosaniline pamoate (CI-403-A) in the treatment of Schistosoma japonicum infection in the Philippines. Bull World Health Organ 1967; 36(2): 263–74. [29] Baca DJ, Drexler C, Cullen E. Obstructive laryngotracheitis secondary to gentian violet exposure. Clin Pediatr 2001; 40(4): 233–5. [30] Islam A, Khan A, Rahman ZA. Corneal vital staining with gentian violet. Bangladesh Med Res Counc Bull 1990; 16(2): 70–4. [31] Pessah A, Ofosu JR, Klein BL. Conjunctival staining and corneal and conjunctival abrasions caused by 2% aqueous gentian violet solution. Pediatr Emerg Care 1998; 14(4): 285–6. [32] Parker WT, Binder PS. Gentian violet keratoconjunctivitis. Am J Ophthalmol 1979; 87(3): 340–3. [33] Dhir SP, Sharma SK, Munjal VP, Gupa A. Keratoconjunctivitis sicca following instillation of gentian violet. Indian J Ophthalmol 1982; 30(1): 21–2. [34] Unlü K, Askünger A, Söker S, Kilinç N, Karaca C, Erdinc M. Gentian violet solution for staining the anterior capsule. J Cataract Refract Surg 2000; 26(8): 1228–32. [35] Spiller H, Rodgers G, Willias D, Bosse G, Sullivan J. Methemoglobinemia due to malachite green ingestion in a child. Clin Toxicol (Phila) 2008; 46(4): 320–1.

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[36] Horsfield P, Logan FA, Newey JA. Oral irritation with gentian violet. Br Med J 1976; 2(6034): 529. [37] Slotkowski EL. Formation of mucous membrane lesions secondary to prolonged use of one per cent aqueous gentian violet. J Pediatr 1957; 51(6): 652–4. [38] Slotkowski EL, Redondo D. Mucosal irritation following use of gentian violet. Am J Dis Child 1966; 112(1): 40–2. [39] John RW. Necrosis of oral mucosa after local application of crystal violet. Br Med J 1968; 1(5585): 157–8. [40] Horsfield P, Logan FA, Newey JA. Oral irritation with gentian violet. Br Med J 1976; 2(6034): 529. [41] Verbov J. Oral irritation with gentian violet. Br Med J 1976; 2(6036): 639. [42] Kim SJ, Koh H, Park JS, Ahn HS, Choi JB, Kim YS. Hemorrhagic cystitis due to intravesical instillation of gentian violet completely recovered with conservative management. Yonsei Med J 2003; 44(1): 163–5. [43] Walsh C, Walsh A. Haemorrhagic cystitis due to gentian violet. Br Med J (Clin Res Ed) 1986; 293(6549): 732. [44] Bielicky T, Novák M. Contact-group sensitization to triphenylmethane dyes. Gentian violet, brilliant green, and malachite green. Arch Dermatol 1969; 100(5): 540–3. [45] Michel PJ, Buyer R, Delorme G. Accidents géneraux (cyanose, collapsus cardiovasculaire) par sensibilisation à une solution aqueuse de violet de gentiane et vert de méthyle en application locales. [Generalized reactions (cyanosis, cardiovascular collapse) caused by sensitization to an aqueous solution of gentian violet and methyl green applied locally.] Bull Soc Fr Dermatol Syphiligr 1958; 65(2): 183. [46] Epstein S. Dermal contact dermatitis; sensitivity to rivanol and gentian violet. Dermatologica 1958; 117(5): 287–96. [47] Schoppelrey HP, Mily H, Agathos M, Breit R. Allergic contact dermatitis from pyoctanin. Contact Dermatitis 1997; 36(4): 221–4. [48] Shehade SA, Foulds IS. Allergic contact dermatitis to brilliant green. Contact Dermatitis 1986; 14(3): 186–7.

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[49] Lawrence CM, Smith AG. Ampliative medicament allergy: concomitant sensitivity to multiple medicaments including yellow soft paraffin, white soft paraffin, gentian violet and Span 20. Contact Dermatitis 1982; 8(4): 240–5. [50] Torres JA, Sastre J, de las Heras M, Requena L, del Haro R, Cazorla A. Irritative contact dermatitis due to gentian violet (methylrosaniline chloride) in an airplane passenger: a case report. J Investig Allergol Clin Immunol 2009; 19(1): 67–8. [51] Björnberg A, Mobacken H. Necrotic skin reactions caused by 1 per cent gentian violet and brilliant green. Acta Derm Venereol 1972; 52(1): 55–60. [52] Meurer M, Konz B. Hautnekrosen nach Anwendung. 2%iger Pyoaktinlosung. [Skin necroses following the use of a 2-per-cent Pyoctanin solution.] Hautarzt 1977; 28(2): 94–5. [53] Zabala Egurrola JA, Pertusa Peña C, Arruza Echevarría A, Llarena Ibarguren R, Arregui-Erbina P, Olartecoechea Errasti G. Necrosis de glande secundaria al violeta de genciana. [Glans penis necrosis secondary to gentian violet treatment.] Arch Esp Urol 1989; 42(8): 800–2. [54] Meurer M, Konz B. Hautnekrosen nach Anwendung 2%iger Pyoktaninlosung. [Skin necrosis following the use of a 2-per-cent Pyoctanin solution.] Hautarzt 1977; 28(2): 94–5. [55] Shibata Y, Midorikawa K, Koga T, Honjo N, Naito M. Chondrolysis of the glenohumeral joint following a color test using gentian violet. Int Orthop 2001; 25 (6): 401–3. [56] Hietala SO, Hirsch JI, Faunce HF. Allergic reaction to Patent Blue Violet during lymphography. Lymphology 1977; 10(3): 158–60. [57] Au W, Butler MA, Bloom SE, Matney TS. Further study of the genetic toxicity of gentian violet. Mutat Res 1979; 66(2): 103–12. [58] Rosenkranz HS, Carr HS. Possible hazard in use of gentian violet. Br Med J 1971; 3 (5776): 702–3. [59] Littlefield NA, Blackwell BN, Hewitt CC, Gaylor DW. Chronic toxicity and carcinogenicity studies of gentian violet in mice. Fundam Appl Toxicol 1985; 5(5): 902–12.

489 [60] Littlefield NA, Gaylor DW, Blackwell BN, Allen RR. Chronic toxicity/carcinogenicity studies of gentian violet in Fischer 344 rats: two-generation exposure. Food Chem Toxicol 1989; 27(4): 239–47. [61] Culp SJ, Mellick PW, Trotter RW, Greenlees KJ, Kodell RL, Beland FA. Carcinogenicity of malachite green chloride and leucomalachite green in B6C3F1 mice and F344 rats. Food Chem Toxicol 2006; 44(8): 1204–12. [62] Docampo R, Moreno SN. The metabolism and mode of action of gentian violet. Drug Metab Rev 1990; 22(2–3): 161–78. [63] Arbiser JL. Gentian violet is safe. J Am Acad Dermatol 2009; 61(2): 359. [64] Selkon JB, Cherry GW, Wilson JM, Hughes MA. Evaluation of hypochlorous acid washes in the treatment of chronic venous leg ulcers. J Wound Care 2006; 15 (1): 33–7. [65] Zock JP, Plana E, Anto JM, Benke G, Blanc PD, Carosso A, DahlmanHogland A, Heinrich J, Jarvis D, Kromhout H, Lillienberg L, Mirabilli MC, Norback D, Olivier M, Ponzio M, Radon K, Soon A, van Sprundel M, Sunyer J, Svanes C, Toren K, Verlato G, Villani S, Kogevinas M. Domestic use of hypochlorite bleach, atopic sensitisation and respiratory symptoms in adults. J Allergy Clin Immunol 2009; 124(4): 731–8. [66] Davtyan TK, Mkhitaryan LM, Gabrielyan ES. Design of iodine–lithium–alpha-dextrin liquid crystals with potent antimicrobial and anti-inflammatory properties. Curr Pharm Des 2009; 15(11): 1172–86. [67] Zimmermann MB. Iodine: it's important in patients who require parenteral nutrition. Gastroenterology 2009; 137(5 Suppl): S36–46. [68] Zimmermann MB. Iodine deficiency. Endocrinol Rev 2009; 30(4): 376–408. [69] Palobart C, Cros J, Orsel I, Nathan N. Anaphylactic shock to iodinated povidone. Ann Fr Anesth Reanim 2009; 28(2): 168–70. [70] McLean D, Eng M, Dryson E, Walls G, Harding E, Wong KC, Cheng S, Mannetje A, Ellison-Loschmann L, Slater T, Shoemack P, Pearce N. Morbidity in former sawmill workers exposed to

490 pentachlorophenol: a cross-sectional study in New Zealand. Am J Ind Med 2009; 52 (4): 271–81. [71] Cooper GS, Jones S. Pentachlorophenol and cancer risk: focusing the lens on specific chlorophenols and contaminants. Environ Health Perspect 2008; 116(8): 1001–8.

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[72] Kolaski K, Ajizian SJ, Passmore L, Pasutharnchat N, Koman LA, Smith BP. Safety profile of multilevel chemical denervation procedures using phenol or botulinum toxin or both in a paediatric population. Am J Phys Med Rehabil 2008; 87(7): 556–66.

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25

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines

BETA-LACTAM ANTIBIOTICS [SED-15,

478; SEDA-30, 280; SEDA-31, 420; SEDA-32, 447] CARBAPENEMS [SED-15, 638; SEDA-30, 246; SEDA-31, 420; SEDA-32, 448]

Carbapenems and seizures Like other beta-lactam antibiotics, the carbapenems can cause seizures, which have been reported in association with imipenem þ cilastatin [1A, 2A, 3A, 4A, 5A, 6A, 7A], doripenem [8R, 9R], ertapenem [10R, 11A], and panipenem [12A]. Mechanisms The mechanisms by which carbapenems provoke seizures are unclear. One mechanism might be competitive inhibition of the inhibitory neurotransmitter gammaaminobutyric acid (GABA), resulting in reduced suppression of epileptogenic discharges [13R]. Binding of GABA is antagonized to various degrees by different carbapenems, resulting in some cases in nervous system excitation and convulsions [14R]. There may also be interactions with receptors for excitatory amino acid neurotransmitters, Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00025-8 # 2011 Elsevier B.V.

such as a-amino-3-hydroxy-5-methyl-isoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA) [15E, 16E]. Animal studies In rabbits imipenem þ cilastatin and another carbapenems were more neurotoxic than benzylpenicillin [17E]. In mice, ataxia and seizures were seen, with much lower blood concentrations of imipenem than cefotaxime or benzylpenicillin (1900 mg/ml versus 3400 mg/ml and 5800 mg/ml) [18E]. In mice imipenem also lowered the convulsive threshold of pentetrazol (pentylenetetrazole) more than cefazolin and two other carbapenems [19E]. In rats, phenytoin and phenobarbital both suppressed imipenem-induced seizures dose dependently, but only phenobarbital reduced electroencephalographic epileptiform discharges [20E]. In rats imipenem þ cilastin provoked convulsions dose dependently, with characteristic electroencephalographic changes [21E]. Audiogenic stimulation did not by itself provoke seizures in untreated rats but did after pretreatment with imipenem; however, these seizures were not accompanied by electroencephalographic changes. The authors proposed that imipenem-induced seizures involve neuronal networks in the cortex whereas audiogenic seizures involve networks in the brainstem. In various types of animals meropenem [22E] and other carbapenems [23E, 24E] were less epileptogenic than imipenem. Cilastatin alone was not proconvulsant, but it increased the effects of co-administered imipenem. In dogs, intraventricular injection of imipenem, panipenem, and meropenem caused 491

492

seizures, but doripenem had no effect on the electroencephalogram and behavior [25E]. There was a similar discrepancy between the doripenem and the other carbapenems in mice and rats. In in vitro studies, imipenem, meropenem, and panipenem inhibited the binding of muscimol to GABA receptors in mouse brain homogenates, while doripenem did not. In addition, doripenem had no effect on the anticonvulsive action of valproic acid in the pentylenetetrazole- or bicuculine-induced convulsive models. Frequency Doripenem Doripenem has now been on the market for about 5 years. Of 263 patients with nosocomial pneumonia 10 had seizures. In patients with seizure-predisposing conditions, seizures occurred during treatment in two of 193 receiving doripenem and in six of 116 receiving imipenem þ cilastatin [26R]. Ertapenem Ertapenem came on to the market around 10 years ago. Of 30 patients taking ertapenem three had seizures [27c]. All had moderate renal insufficiency (creatinine clearances 44, 54, and 56 ml/minute) and all had received intravenous ertapenem 1 g/day. All three had some kind of nervous system disorder, but only one had previously had seizures. Two were given prophylactic antiepileptic drugs. Imipenem Imipenem is a more common cause of seizures than other beta-lactam antibiotics, particularly when high doses are given [28C, 29AR]. Since imipenem þ cilastatin came on the market about 25 years ago seizure rates as high as 6% have been reported, especially when dosing with respect to renal function is not carefully monitored and adjusted. In a review of 1754 patients there was a similar incidence of seizures with imipenem þ cilastatin as with other antibiotic regimens usually containing another beta-lactam [30c]. In another study, seven of 21 children developed seizure activity while receiving imipenem þ cilastatin for bacterial meningitis [31c]. However, computer-assisted monitoring of imipenem þ cilastatin dosages in relation to renal function resulted in a reduced incidence of seizures [32C]. Of 82 children with various malignancies who received imipenem þ cilastatin 143

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times for neutropenic fever, three had convulsions attributed to the drug [33c]. In a meta-analysis of 37 papers published between 1984 and 1999 the seizure rate was 1.4% among 6000 adults taking imipenem þ cilastatin [34M]. Meropenem In 403 children there was no meropenem-associated neurotoxicity [35C] and meropenem was well tolerated in children with bacterial meningitis [36C]. In a meta-analysis of studies in more than 5000 patients receiving meropenem and more than 1880 receiving imipenem þ cilastatin, the incidence of drug-related seizures was 0.8% for meropenem and 2.8% for imipenem þ cilastatin, despite the fact that patients with nervous system disorders, including seizures, were excluded [37M]. A similar low rate of neurotoxicity with meropenem was observed in a more recent review [38R]. In summary, a larger dose range of meropenem than imipenem appears to be tolerated, but when strictly observing known risk factors for seizure propensity the difference between the two compounds is very small [39R, 40R]. Susceptibility factors The proconvulsant activity of the carbapenems, particularly imipenem, has limited their usefulness in patients at high risk of seizures, such as patients with nervous system infections, especially meningitis, chronic or acute nervous system damage, and more generally in patients with compromised renal function and a reduced threshold for seizure activity. The risk of seizures due to carbapenems is increased by renal insufficiency [41Ac, 42A] and a previous stroke [43A] and may be increased by prior intrathecal methotrexate therapy [44A] and concomitant treatment with theophylline [45A]. Meropenem reduces plasma valproate concentrations, affording two mechanisms for an increased risk of seizures in patients with epilepsy, epileptogenic effect of meropenem, and loss of antiepileptic action of valproate [46A, 47A, 48A, 49A, 50A, 51A, 52c]. In 39 patients who took valproate and meropenem valproate plasma concentrations fell in all patients within 24 hours by an average of 66% [53A].

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines

Meropenem Hematologic Acute intravascular hemolysis, occurring as a result of drug administration, is assumed to arise through one of two mechanisms [54R]. Red cell antibodies can develop in response to some drugs; recovery depends on clearance of the autoantibody from the circulation and can take several weeks. However, most cases of drug-induced hemolysis arise through a mechanism in which the drug acts as a hapten, resulting in complement-mediated intravascular hemolysis. This may have been the mechanism in the following case [55A]. • A 64-year-old man with dialysis-dependent renal insufficiency underwent surgery for cecal perforation. He had a history of a rash after penicillin. Postoperatively he received cefuroxime, gentamicin, and metronidazole (doses not reported) with no adverse reactions. On postoperative day 7 he developed peritonitis and septic shock. A mixture of cephalosporin-resistant bacteria was found in his peritoneal fluid and he was given meropenem 1 g bd. After the first dose the hemoglobin concentration fell from 8.1 to 5.4 g/dl over 12 hours. Laboratory tests were consistent with intravascular hemolysis, including a blood film with spherocytes and fragments. During continuous venovenous hemofiltration the hemofiltrate developed a red-brown discoloration. Meropenem was withdrawn and the hemolysis resolved about 6 hours later.

The authors suggested that the rapid onset of symptoms, the results of laboratory tests, and the rapid resolution of symptoms after withdrawal of meropenem all pointed to a hapten-mediated mechanism.

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patient due to more than one drug is rare. However, as second- and third-generation cephalosporins are often implicated [58R], this might be of importance if switching from one cephalosporin to another. One such case has been reported [59A]. • A 49-year-old woman with extensive skin damage after a traffic accident was given cefotiame for 19 days and then cefoperazone for 15 days (doses not reported). Her hemoglobin fell to 5.7 g/dl, with a reticulocyte count of 4.8%. She was given intravenous ceftizoxime 1 g bd and then intravenous cefoperazone þ sulbactam (cefobactam) 1 g tds instead. However, the hemoglobin did not increase. Ceftizoxime- and cefobactam-dependent antibodies were found in her blood. Cephalosporins were withdrawn and the hemoglobin increased.

The authors proposed that for the prompt diagnosis of drug-induced hemolytic anemia, tests for all causative drugs should be conducted by two methods.

Cefotaxime Biliary tract Inspissated bile syndrome has been attributed to cefotaxime in a neonate [60A]. Skin Acute generalized exanthematous pustulosis has been attributed to cefotaxime after 12 days in a 30-year-old woman and confirmed by a positive patch test [61A].

Ceftriaxone [SED-15, 688; SEDA-30, 284; SEDA-31, 422; SEDA-32, 448]

CEPHALOSPORINS

Immunologic Drug-induced hemolytic anemia can be due to many drugs, but is often not properly diagnosed [56R, 57R], because when clinicians suspect it they simply withdraw possible causative agents and switch to other drugs. Hemolytic anemia in the same

Nervous system Encephalopathy with generalized triphasic waves occurred in a patient with pre-existing cerebrovascular disease who was given ceftriaxone for a urinary tract infection [62A]. Hematologic Further cases of hemolytic anemia have been attributed to ceftriaxone [63A]. In a 6-year-old girl with sickle cell disease it resulted in a hemoglobin concentration of 0.4 g/dl and extensive

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neurological sequelae; serology confirmed the presence of ceftriaxone antibodies [64A]. Biliary tract Biliary pseudolithiasis has been attributed to intravenous ceftriaxone in a 64-year-old man [65A]. Pancreas Acute pancreatitis has been attributed to ceftriaxone in a Japanese adult [66A]. Management of adverse drug reactions Desensitization to drugs is increasingly being implemented, by the use of initially tiny doses, gradually increasing to therapeutic doses, sometimes over very short periods of time [67A; SEDA-30, 416; SEDA-33, 441]. Desensitization to ceftriaxone has been reported in a 60-year-old woman with Lyme disease in whom doxycycline treatment had failed [68A]. After administration of intravenous ceftriaxone 1 g/day for 8 days she developed a rash on the palms, feet, and neck, which resolved spontaneously after the infusion was stopped. Treatment was re-started 1 day later, and after 8 days she developed pharyngeal, plantar, and palmar pruritus, a rash, nausea, and abdominal cramps. Because no other drug was suitable she was desensitized, starting with 0.001 mg and increasing the dose 10-fold every 20 minutes on the first day. The full regimen is shown in Table 1; the total dose of 1 g/day was achieved on day 3, without any adverse reactions, and continued thereafter. Drug–drug interactions Calcium salts The FDA's warning that calcium-containing solutions should not be given simultaneously with ceftriaxone or within 48 hours of the last dose, because of a risk of calcium deposition in the lungs and kidneys [69R], has been reinforced in a review, whose authors concluded that ceftriaxone should be avoided or used in very low doses in neonates, and especially in those concomitantly receiving intravenous calcium solutions and those with hyperbilirubinemia, and should potentially be restricted in elderly people who are concomitantly receiving intravenous calcium [70R].

Tore Midtvedt

Table 1 An intravenous desensitization protocol for ceftriaxone hypersensitivity

Time (minutes)

Dose (as intravenous solution) (mg)

Day 1 0 20 40 60

0.001 0.01 0.1 1

Day 2 0 20 40 60 Day 3 0 20 40 Days 4–30

1 5 10 50 100 250 550 1000

MONOBACTAMS AND MONOCARBAMS [SED-15, 2378; SEDA-30, 286; SEDA-31, 423; SEDA-32, 450]

Chemically modified monobactams and their nonantimicrobial properties The monobactams have a single beta-lactam ring structure. The only clinically used monobactam is aztreonam. Replacement of the 1-sulfonic acids residue in monobactam with an N-sulphonylated carbonyl amino moiety yields monocarbams [71R, 72R]. So far, however, no monocarbam derivative is on the market, probably because their antimicrobial moiety is not optimal. Since micro-organisms need iron for growth, some siderophore-conjugated monocarbams are now under evaluation [73E]. It is reasonable to assume that it will take some time until they are marketed. One of the many problems not yet solved is the in vivo fate of the siderophore itself, since it may create some new adverse effects of its own.

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines

Aztreonam Immunologic Prospective studies of hypersensitivity reactions have suggested that the incidence of cross-reactivity between penicillins and carbapenems, judged by skin tests, is around 1%. It is generally thought that there is little risk of cross-reactivity between aztreonam and other beta-lactams in allergic patients, although ceftazidime and aztreonam have similar side chains. In a systematic review of the English-language literature on the subject of cross-sensitivity to penicillins, carbapenems, and monobactams, the authors concluded that the use of aztreonam in a patient with ceftazidime hypersensitivity may carry an increased risk of type I reactions and should be undertaken cautiously [74M]. They also re-emphasized the importance of obtaining a thorough history about the previous allergic event. Drug formulations In February 2010, a solution of aztreonam for inhalation, formulated with lysine, was approved by the US FDA for the treatment of respiratory symptoms in patients with cystic fibrosis and infected with Pseudomonas aeruginosa [75E], a bacterium that has always been difficult to treat with antibiotics, especially when it grows in biofilm, as is the case in the airways. So far, no new types of adverse effects have been found [76R]. A key problem will be the development of resistance to this new formulation [77R]. Drug–drug interactions Telavancin In a randomized crossover study in healthy participants, telavancin 10 mg/kg did not alter the pharmacokinetics of intravenous aztreonam 2 g [78C].

[SED-15, 2756; SEDA-30, 286; SEDA-31, 424; SEDA32, 450]

PENICILLINS

Immunologic The Jarisch–Herxheimer reaction is a series of transient systemic

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events, including tachycardia, fever, chills, arthralgia, and headache; it is common during treatment of spirochete infections with penicillins, but can occur after the use of other antibiotics and in other infections, such as toxoplasmosis [79R]. For example, of 1415 cases of tick-borne relapsing fever due to borreliosis in Iran, 0.8% had a Jarisch–Herxheimer reaction during treatment [80c]. During pregnancy 40% or more of women with syphilis who take penicillin have symptoms of a Jarisch–Herxheimer reaction [81R, 82R]; they can also have uterine contractions, reduced fetal movements, and an altered fetal heart rate pattern, including late decelerations. The Jarisch–Herxheimer reaction was triggered by intrapartum ampicillin in a pregnant woman with undiagnosed secondary syphilis [83A]. • A 24-year-old Hispanic woman developed uterine contractions at 34 weeks gestation, having had vaginal ulcers due to herpes infection during pregnancy. She was given intravenous ampicillin 2 g 6-hourly for prevention of group B streptococcal infection during preterm labor, and about 6 hours after the first dose began to have fever and chills and a tachycardia. At the same time, the fetal heart rate rose from 120 to 150/minute and began to show late decelerations. Cesarean section was undertaken, and she delivered a boy weighing 2.2 kg with Apgar scores of 8 and 9 at 1 and 5 minutes but with respiratory difficulties. On the next day a diagnosis of secondary syphilis was established, and she was given one dose of benzathine penicillin G intramuscularly. The neonate had congenital syphilis and was treated with high doses of penicillin G intravenously for 19 days.

The mechanisms of the Jarisch–Herxheimer reaction are not known, but some believe that it occurs as a result of a rapid killing of spirochetes, resulting in an acute inflammatory response caused by release of lipoproteins, or from an increase in prostaglandins [84A]. Whatever the mechanism(s), the bottom line in this case is that both the patient and her son tolerated another beta-lactam antibiotic when the first reaction was over. In another case there was MRI evidence of cerebral inflammation after the use of penicillin in a patient with tertiary syphilis, in the absence of systemic symptoms of a Jarisch–Herxheimer reaction [85A].

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In one patient with neurosyphilis, dementia, and a Jarisch–Herxheimer reaction after intravenous penicillin improved with olanzapine [86A]. In another similar case a Jarisch–Herxheimer reaction was accompanied by a Hoigné reaction after the use of high-dose intravenous penicillin [87A].

Tore Midtvedt

Allergic reactions to penicillins are usually of classes I and III, but class IV reactions can also occur, as illustrated by a reaction in a patient with systemic lupus erythematosus after the use of amoxicillin [94A].

Ampicillin Amoxicillin Teeth The hypothesis that the use of antibiotics in early childhood may cause molar incisor hypomineralization has been tested in a retrospective study of 141 school children, 23 of whom were affected; the risk was greater among those who had taken, during the first year of life, either amoxicillin (OR ¼ 2.06; 95% CI ¼ 1.01, 4.17) or erythromycin (OR ¼ 4.14; 95% CI ¼ 1.05, 16) than in children who had not received treatment [88cE]. In in vitro experiments in mouse E18 teeth, amoxicillin increased the thickness of the enamel but not dentine. Skin The increased risk of a maculopapular rash after the use of amoxicillin in patients with infectious mononucleosis has been illustrated by the case of a 24-yearold woman who developed such a rash after a single dose of amoxicillin 500 mg [89A]. Reactivation of human herpesvirus 6 may also lead to skin reactions, as suggested by a series of seven cases of amoxicillininduced flares in patients with drug reactions with eosinophilia and systemic symptoms (DRESS) due to other drugs; in in vitro studies in a human T lymphoblastoid MT4 cell line, amoxicillin increased replication of human herpesvirus 6 [90cE]. Immunologic The association of an allergic reaction with angina pectoris (the Kounis syndrome) has been discussed in the light of a case in which three episodes of vasospastic angina, two of them related to amoxicillin, could have been due to other causes [91A, 92r]. Another case has been described in a 13-year-old boy, who developed chest pain 30 minutes after taking an oral dose of co-amoxiclav [93A].

Hematologic Ampicillin dose dependently causes impaired platelet function by both reversible and irreversible mechanisms and moderately prolongs the bleeding time by 60–90 seconds. The effect usually takes 24 hours to start. Bleeding time and platelet function were measured in 15 neonates (gestation 33–41 weeks, weights 1760–3835 g) who had not been exposed to maternal beta-lactam antibiotics during labor and who were given ampicillin 50–100 mg/kg every 12 hours [95c]. The first dose of ampicillin had no effect, but after the third (n ¼ 5) and fourth (n ¼ 4) doses, bleeding times were prolonged by an average of 60 (95% CI ¼ 37, 83) seconds and time to platelet aggregation by a non-significant average of 20 (20, 60) seconds.

Co-amoxiclav and clavulanic acid Psychiatric An acute psychosis, with visual hallucinations, persecutory delusions, and disordered speech, has been attributed to co-amoxiclav in a 55-year-old woman [96A, 97A]. Skin A fixed drug eruption has been attributed to co-amoxiclav [98A], as has a linear IgA bullous eruption [99Ar], acute generalized exanthematous pustulosis (AGEP) [100A], and contact dermatitis [101Ar]. Immunologic Urticaria and angioedema, a class I reaction, after the use of co-amoxiclav in 10 children aged 4–12 years were attributed to allergy to clavulanic acid, on the basis of the IgE response to an oral challenge and negative skin tests with penicillins [102c].

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines

Flucloxacillin Liver The risk of flucloxacillin-associated cholestatic liver disease has been assessed in a study of 346 072 first-time users of flucloxacillin, of whom 21 developed cholestatic hepatitis within 1–45 days after a prescription; the incidence estimate was 6.1 per 100 000 users (95% CI ¼ 3.8, 9.3) [103C]. In comparison, there were four cases out of 1 179 360 first-time users of penicillin V, an incidence estimate of 0.3 per 100 000 users (95% CI ¼ 0.1, 0.9). Immunologic Acute interstitial nephritis, a class III reaction, with acute renal failure has been attributed to flucloxacillin [104A].

Piperacillin þ tazobactam Psychiatric Adverse psychiatric effects have been attributed to piperacillin [105A]. • An 87-year-old man who was given piperacillin þ tazobactam 2 g þ 250 mg every 12 hours after hemodialysis developed auditory and visual hallucinations, bizarre behavior, disorientation, and progressive mental confusion 2 hours after the sixth dose. Piperacillin þ tazobactam was withdrawn, and he recovered within 6 hours. The serum piperacillin concentration was 56 mg/l.

Electrolytic balance Severe hypokalemia secondary to short-term use of piperacillin þ tazobactam occurred in a patient with normal renal function and a normal serum potassium concentration before antibiotic therapy; the electrolyte abnormality resolved after piperacillin þ tazobactam had been withdrawn [106A]. Hematologic Cases of penicillin-induced hemolytic anemia continue to be reported [107A]. The risk appears to be especially high in patients with cystic fibrosis, which might be explained by the frequent use of penicillins, including piperacillin, combined with a hyperimmune state. More cases have been reported [108A, 109A].

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The nature of the interaction of piperacillin antibodies with erythrocytes has been studied in the context of six cases of piperacillininduced hemolytic anemia [110A]. The authors suggested that a diagnosis of piperacillin-induced hemolytic anemia should not be made solely on the reactivity of a patient's plasma or serum with piperacillin- or piperacillin/tazobactam-coated erythrocytes and that testing in the presence of piperacillin is more reliable. Others have made the point that adequate interpretation of a positive direct antibody test requires knowledge of the clinical history, including the drug history [111A]. Skin Piperacillin and piperacillin þ tazobactam can cause petechial rashes or purpura by causing thrombocytopenia [112C]. However, a non-thrombocytopenic petechial rash has also been reported [113A]. • A 64-year-old African American woman was given piperacillin þ tazobactam 2.25 g qds for 5 days and developed a petechial rash on the legs; there was no fever, change in bowel movements, nausea, vomiting, or shortness of breath. Prothrombin time and partial thromboplastin time were normal. A skin biopsy showed a superficial perivascular mixed dermatitis with lymphocyte and neutrophil infiltration. The rash resolved after 3 days.

The patient fulfilled all the criteria of the American Association for Rheumatology for a diagnosis of a hypersensitivity vasculitis [114R]. Acute generalized exanthematous pustulosis (AGEP) has also been reported [115A].

TETRACYCLINES AND GLYCYLCYCLINES [SED-15, 3330; SEDA-30, 288; SEDA-31, 419; SEDA-32, 451]

Tetracyclines and the environment Some pharmaceuticals, such as antibiotics, should be recognized as ubiquitous persistent environmental contaminants.

498

Antibiotics have been and still are extensively used in animal farms and fish farming for disease control and sometimes also for growth promotion. Once administered to animals or fishes, the antibiotic or its metabolites—which may also have antimicrobial properties—can be present in urine and/or feces and thereby reach the environment. The use of farm manure and fishpond sediment as organic fertilizers has a long history in agriculture. In the history of the use of antibiotics, some attention has been paid to the spread of micro-organisms that are resistant to antimicrobial drugs in this way. Unlike other environmental pollutants, such as heavy metals and pesticides, the behavior and fate of antibiotics in the environment have been far less well studied. In fact, there is limited information on the effects of antibiotics on soil ecosystems. In soil, micro-organisms and plants have very close functional relations and constitute a holistic system; therefore, any disturbance to the equilibria among soil micro-organisms and between micro-organisms and plants may adversely affect the stability and productivity of soil ecosystems. In fact, studies of the influence of antibiotics on the environment have been more focused on the spreading of genes that code for resistance than on the more direct effects of these compounds on environmental ecosystems. However, now the trend is switching to investigations in which the more direct impact of antibiotics on soil microbiology and productivity are being studied, including some recent reports from China, which is ranked first in the world in terms of annual production of at least two of the most commonly used tetracycline derivatives [116R], and where these compounds are widely used. For example, Chinese shrimps and prawns have been banned in Europe and the USA, because of their high content of antibiotics, such as tetracyclines [117R], reflecting extensive use of antibiotics that may have environmental consequences in China. A recent Chinese study was designed to provide better understanding of the interactions among tetracyclines, soil microbes,

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and plants, with an emphasis on the effects of tetracyclines on soil microbes and their environmental fate [118E]. Here I highlight some of the many interesting results. First, tetracycline was slowly degraded in soil, about 30% being degraded after 60 days. Many factors can affect this degradation, including temperature and the presence of tetracycline-degrading microbes in the soil, but the message is clear: tetracyclines are slowly degraded. The most serious interaction was that the “plant biomass” was adversely affected by tetracyclines, especially plant roots, with a reduction of 40% compared with controls. Exposure to various concentrations of tetracycline resulted in significant suppression of the growth of wheat roots and shoots. The authors concluded that the agricultural use of animal manure and fishpond sediment containing considerable amounts of antibiotics may give rise to ecological risks. Who can—or should—act? The answer is simple: regulatory agencies. The time has come for them to strengthen the rules for pharmaceutical companies intending to bring new compounds on the market and also to scrutinize more closely compounds that are already in use. Antibiotic-induced adverse environmental effects are serious and could be reduced by more adequate antibiotics policies.

Tetracyclines and glycylcyclines and their non-antimicrobial properties [SEDA-32, 451] Reports of the non-antimicrobial effects of tetracyclines continue to appear, and the clinical uses of non-antimicrobial tetracyclines in dermatology have been highlighted [119R]. In general, when these drugs are used for non-infectious conditions, adverse reactions seem to be of same types and frequencies as when they are used as antimicrobial agents. However, the adverse effects profiles of the chemically modified tetracyclines have still not been properly elucidated.

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines

Doxycycline Liver Hepatitis has been attributed to doxycycline in a 37-year-old man with a strong family history of autoimmune diseases [120A]. Pancreas Pancreatitis has been attributed to doxycycline in a 75-year-old woman [121A]. Skin Drug rash with eosinophilia and systemic symptoms (DRESS) is relatively common in patients taking minocycline, but seems to be much less so in patients taking doxycycline. However, a report has appeared in a 25-year-old woman of African origin who had been taking doxycycline for malaria prophylaxis for 3 weeks [122A]. Sweet's syndrome has been reported in a 41-year-old woman with acne who took doxycycline for almost 2 weeks [123A]. Immunologic A Jarisch–Herxheimer reaction occurred four times in a 36-year-old man with Q fever pneumonia after treatment with doxycycline, with an acute rise in temperature, tachycardia, tachypnea, hypoxia, hypotension, and temporary deterioration of the chest x-ray; on each occasion the reaction lasted for 6 hours [124A].

Minocycline Observational studies Tetracyclines, especially minocycline, inhibit the matrix metalloproteinases (MMPs), and this has been studied in patients with the so-called fragile X syndrome (MIM 300624), an inherited form of intellectual disability and autism, with an estimated prevalence of about 1 in 4000 [125C]. The gene responsible is located on the X chromosome (Xq27.3) and is called Fragile X Mental Retardation-1 (FMR1; MIM 309550) [126E]. Minocycline improved behavioral performance and reduced anxiety in a FMRI knockout mouse [127E], and has been studied in an open trial in 20 patients with the fragile X syndrome, aged 13–32 years [128c]. The

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hypothesis was based on the facts that matrix metalloproteinase activities are increased in fragile X syndrome, that doxycycline can reduce serum and tissue concentrations of MMP-9 (as has been shown, for example, in women using a levonorgestrel-releasing subcutaneous implant [129c]), and that the benefits seen in FMR1 knockout mice may have come about through a reduction in excess activity of MMP-9 [130H]. The only treatment-related adverse effects were diarrhea in three cases and seroconversion to a positive antinuclear antibody in another two, both with a 1/80 titer and a nuclear profile. These results pave the way for the discovery of more specific inhibitors of human MMP-9, preferably without antimicrobial activity, rather than using minocycline in all patients with the fragile X syndrome. Cardiovascular In a 63-year-old man with aortic regurgitation and a 6.0-cm ascending aortic aneurysm the aortic valve was tricuspid and patulous and there was dark discoloration of the left ventricular outflow tract, aortic valve leaflets, and sinuses of Valsalva [131A]. Histology showed black granular pigment in the body of the leaflets within macrophages and in the ground substance of the leaflet. The damage to the aortic valve was attributed to long-term minocycline therapy. Respiratory Acute eosinophilic pneumonia with marked neutrophilia has been attributed to minocycline [132A, 133Ar]. Nervous system Benign intracranial hypertension has been reported in a 26-year-old woman who was taking doxycycline for malaria prophylaxis [134A]. Endocrine Black discoloration of the thyroid gland occurred in a 31-year-old woman who had taken minocycline for 18 months before presenting with hyperthyroidism and a palpable thyroid nodule; a concurrent papillary microcarcinoma was probably coincidental [135A].

500

Mouth Tetracyclines can stain body tissues, particularly cartilage and bone and there have been reports of blue discoloration of a palatal torus in a 91-year-old woman who had taken minocycline for 3.5 years [136A] and of staining over the whole of the palate [137A, 138A]. In one case minocycline-induced pigmentation caused a bluish black discoloration over the medial and lateral aspects of the left ankle following an avulsion fracture, mimicking persistent ecchymosis [139A]. Liver Autoimmune hepatitis has been reported in a 20-year-old woman who had taken minocycline for 1 year [140A], in a 17-year-old-woman who had taken minocycline 50 mg/day and an oral contraceptive for about 2 years [141A], and in three other patients [142A]. Skin Skin pigmentation due to minocycline has been reviewed [143R]. There are three distinct types: • type I—blue-black/grey pigment on the face in areas of scarring or inflammation associated with acne; stains for iron and melanin extracellularly and in macrophages in the dermis; resolves slowly over time; • type II—blue-grey pigment on normal skin on the shins and forearms; stains for iron and melanin extracellularly and in macrophages in the dermis; resolves slowly over time; • type III—diffuse muddy-brown discoloration in areas of sun exposure; shows non-specifically increased melanin in basal keratinocytes and dermal melanophages staining for melanin only; persists indefinitely.

Immunologic An anaphylactic reaction to minocycline, a rare adverse reaction has again been reported [144A]. • A 56-year-old woman had three episodes of anaphylaxis during 1 year and within 4 minutes of an oral challenge with minocycline 50 mg developed an itching and burning sensation in her face and forearms, followed by orbital and lip swelling. Within 10 minutes her symptoms had worsened, her heart rate was 55/ minute, respiratory rate 24/minute, and blood pressure 70/50 mmHg.

The pathogenesis of minocycline-induced hypersensitivity is unknown. Although it is not known for certain that minocycline has

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reactive metabolites, it may generate an iminoquinine derivative. Neither tetracyclines nor doxycycline contain the amino acid side-chain that has the potential to form such a metabolite, and therefore hypersensitivity may be specific to minocycline. A lupus-like syndrome with neutropenia has been associated with minocycline in an 18-year-old man [145A]. Drug hypersensitivity syndrome has been attributed to minocycline in a 15-year-old girl after treatment for acne vulgaris for 4 week; 7 weeks later she developed autoimmune hyperthyroidism (Graves’ disease), and 7 months after discontinuing minocycline she developed autoimmune type 1 diabetes mellitus [146A]. She also developed raised titers of several markers of systemic autoimmune disease, including antinuclear, anti-Sjögren syndrome A, and anti-Smith antibodies. The authors suggested that drug hypersensitivity syndrome may be associated with other autoimmune phenomena. In another case DRESS was accompanied by myocarditis [147A]. Susceptibility factors Genetic A hypersensitivity reaction with marked eosinophilia occurred in a 62-year-old man with CD30positive lymphomatoid papulosis after he took minocycline 100 mg/day for 3 weeks [148A]. The authors suggested that he may have been particularly susceptible because of a deletion on chromosome 4 (4q12), resulting in a fusion tyrosine kinase, FIP1L1/PDGFRA (Fip1-like 1/plateletderived growth factor a; MIM 607686), since there have been reports of the presence of this fusion gene in patients with lymphomatoid papulosis who have developed eosinophilia, because skin infiltration by CD30þ cells from lymphomatoid papulosis has a Th2 cytokine profile and produces interleukin 5, which stimulates eosinophil differentiation and proliferation. Drug–drug interactions Dapsone Relapse of toxoplasmic encephalitis in an HIVinfected patient was attributed to a possible interaction between dapsone and minocycline [149A].

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines

Management of adverse drug reactions Fractional photothermolysis has been used to treat blue minocycline-associated pigmentation of the face [150A].

Tetracycline Management of adverse effects Teeth discolored from exposure to tetracycline in a 32-year-old Japanese man have been successfully bleached using a KTP laser, a type of neodymium-doped yttrium aluminium garnet (Nd:YAG) laser [151A].

Tigecycline

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coagulation disorder, with hypofibrinogenemia, associated with the use of tigecycline [152A]. The authors concluded that monitoring the international normalized ratio (INR), activated partial thromboplastin time (aPTT), and fibrinogen should be considered in all patients taking tigecycline, especially if treatment is long-term. However, this seems excessive at present; more information is needed before making such a firm recommendation. Pancreas Pancreatitis occurred in a 64year-old woman who took tigecycline 100 mg/day for 14 days [153A] and in a 69year-old woman who took tigecycline for 7 days [154A].

Hematologic A 54-year-old woman undergoing hemodialysis developed a severe

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treatments in autism. Neurotherapeutics 2010; 7(3): 264–74. Belcher E, Soni M, Azeem F, Sheppard MN, Petrou M. Minocyclineinduced pigmentation of the aortic valve and sinuses of Valsalva. Ann Thorac Surg 2009; 88(5): 1704. Yamasawa H, Ohno S, Nakaya T, Ishii Y, Hosono T, Tsujita A, Bando M, Sugiyama Y. Case of minocycline-induced acute eosinophilic pneumonia accompanied by marked neutrophilia in the peripheral blood. Nihon Kokyuki Gakkai Zasshi 2008; 46(10): 820–4. Klerkx S, Pat K, Wuyts W. Minocycline induced eosinophilic pneumonia: case report and review of literature. Acta Clin Belg 2009; 64(4): 349–54. Roux X, Sallansonnet-Froment M, De Greslan T, Bounolleau P, Ouologuem M, Tereygeol M, Taillia H, Renard JL. Hypertension intracrânienne bénigne secondaire à la prise de doxycycline. [Idiopathic intracranial hypertension as a side effect of doxycycline] Rev Med Interne 2009; 30(12): 1058–60. Tacon L, Tan CT, Alvarado R, Gill AJ, Sywak M, Fulcher G. Drug-induced thyroiditis and papillary carcinoma in a minocycline-pigmented black thyroid gland. Thyroid 2008; 18(7): 795–7. Buddula A. Staining of palatal torus secondary to long term minocycline therapy. J Indian Soc Periodontol 2009; 13(1): 48–9. Noonan VL, Kabani S, Wu J. Minocycline-induced staining of the oral cavity. J Mass Dent Soc 2009; 57(4): 42. Noonan V, Kabani S. Medication-induced hyperpigmentation of the oral mucosa. J Mass Dent Soc 2010; 58(4): 40. Youssef S, Langevin KK, Young LC. Minocycline-induced pigmentation mimicking persistent ecchymosis. Cutis 2009; 84(1): 22–6. Ford TJ, Dillon JF. Minocycline hepatitis. Eur J Gastroenterol Hepatol 2008; 20(8): 796–9. Healy J, Alexander B, Eapen C, RobertsThomson IC. Minocycline-induced autoimmune hepatitis. Intern Med J 2009; 39 (7): 487–8.

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508 [142] Ramakrishna J, Johnson AR, Banner BF. Long-term minocycline use for acne in healthy adolescents can cause severe autoimmune hepatitis. J Clin Gastroenterol 2009; 43(8): 787–90. [143] Geria AN, Tajirian AL, Kihiczak G, Schwartz RA. Minocycline-induced skin pigmentation: an update. Acta Dermatovenerol Croat 2009; 17(2): 123–6. [144] Jang JW, Bae YJ, Kim YG, Jin YJ, Park KS, Cho YS, Moon HB, Kim TB. A case of anaphylaxis to oral minocycline. J Korean Med Sci 2010; 25(8): 1231–3. [145] Ahmed F, Kelsey PR, Shariff N. Lupus syndrome with neutropenia following minocycline therapy—a case report. Int J Lab Hematol 2008; 30(6): 543–5. [146] Brown RJ, Rother KI, Artman H, Mercurio MG, Wang R, Looney RJ, Cowen EW. Minocycline-induced drug hypersensitivity syndrome followed by multiple autoimmune sequelae. Arch Dermatol 2009; 145(1): 63–6. [147] Shaughnessy KK, Bouchard SM, Mohr MR, Herre JM, Salkey KS. Minocycline-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome with persistent myocarditis. J Am Acad Dermatol 2010; 62(2): 315–8. [148] Talsania N, O'Toole EA. Severe hypersensitivity reaction to minocycline in

[149]

[150]

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[152]

[153]

[154]

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association with lymphomatoid papulosis. Clin Exp Dermatol 2009; 34(7): e397–8. Gallien S, Bigé N, Kitzis MD, Longuet P, Gervais A, Leport C. Drug-to-drug interaction between dapsone and minocycline: an unusual cause of relapse of toxoplasmic encephalitis in an HIV-infected patient. Scand J Infect Dis 2009; 41(9): 700–2. Izikson L, Anderson RR. Resolution of blue minocycline pigmentation of the face after fractional photothermolysis. Lasers Surg Med 2008; 40(6): 399–401. Kinoshita J, Jafarzadeh H, Forghani M. Vital bleaching of tetracycline-stained teeth by using KTP laser: a case report. Eur J Dent 2009; 3(3): 229–32. Pieringer H, Scmekal B, Biesenbach G, Pohanka E. Severe coagulation disorder with hypofibrinogenemia associated with the use of tigecycline. Ann Hematol 2010; 89: 1063–4. Lipshitz J, Kruh J, Cheung P, Cassagnol M. Tigecycline-induced pancreatitis. J Clin Gastroenterol 2009; 43(1): 93. Hung WY, Kogelman L, Volpe G, Iafrati M, Davidson L. Tigecyclineinduced acute pancreatitis: case report and literature review. Int J Antimicrob Agents 2009; 34(5): 486–9.

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26

Miscellaneous antibacterial drugs

AMINOGLYCOSIDE ANTIBIOTICS [SED-15,

118; SEDA-30, 297; SEDA-31, 427; SEDA-32, 461] Sensory systems Auditory and vestibular function The evidence that ototoxicity due to aminoglycoside antibiotics is synergistic with ototoxicity due to noise exposure (as occurs commonly, for example, on neonatal intensive care units) has been reviewed [1R]. The authors concluded that prevention of ototoxic synergy of noise with aminoglycosides is best achieved by using non-ototoxic bactericidal drugs and by attenuating perceived noise intensity when lifesaving aminoglycoside therapy is required. Data on the mechanisms of vestibular toxicity and its development in association with aminoglycoside exposure have been extracted from the MEDLINE database and summarized [2M]. For similarly designed studies the pooled incidence of vestibular toxicity was 11% for gentamicin, 7.4% for amikacin, 3.5% for tobramycin, and 1.1% for netilmicin. The underlying mechanism appears to be excessive production of oxidative free radicals, a timedependent mechanism, but not apparently related to dose or serum concentration. Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00026-X # 2011 Elsevier B.V. All rights reserved.

The authors concluded that care should be taken to minimize the duration of exposure to aminoglycosides, in order to reduce the risk ototoxicity. A survey of prescribing practices in 27 cystic fibrosis units in Australia showed an increase in the use of once-daily aminoglycoside dosing and an increase in the reports of both ototoxicity and renal toxicity since 1999 (27–75% and 19–65% respectively) [3c]. Tobramycin was the aminoglycoside of choice in all units. Exact details of these adverse effects were not given. Electrolyte balance Aminoglycosides cause fluid, electrolyte, and acid–base disorders by altering renal tubular function in several ways, leading to hypokalemia and acidosis or alkalosis. Stimulation of the calcium-sensing receptor has been reported to cause a Bartter-like syndrome (hypokalemic metabolic alkalosis, hypomagnesemia, hypocalcemia, and normal serum creatinine concentrations). More rarely, a proximal renal tubular acidosis (Fanconi syndrome: non-anion gap metabolic acidosis) can develop. The mechanisms have been summarized [4R]. Urinary tract In 306 consecutive patients starting aminoglycoside therapy in an ITU-independent susceptibility factors for aminoglycoside-associated nephrotoxicity were a baseline estimated glomerular filtration rate (eGFR) under 60 ml/minute/ 1.73 m2, diabetes mellitus, treatment with other nephrotoxic drugs or iodinated contrast agents, and hypotension [5C]. 509

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Amikacin

[SED-15, 111; SEDA-31, 427; SEDA-32, 461]

Sensory systems Vestibular function Measurement of vestibular function in infants who had received amikacin, using vestibular evoked myogenic potentials in 28 infants and healthy controls, showed that the vestibular organ was damaged by amikacin more often than the cochlea (6 versus 0 abnormal findings) [6c]. Mineral balance Type 5 Bartter-like syndrome with severe hypocalcemia has been attributed to amikacin [7A]. • A 39-year-old man with suspected urinary tract infection received amikacin and after 4 days he developed severe renal tubular dysfunction resulting in refractory hypokalemia, hypocalcemia, hypomagnesemia, metabolic alkalosis, and polyuria. This constellation of biochemical abnormalities mimic Type 5 Bartter's syndrome (activating mutation of the calcium sensing receptor in the thick ascending loop of Henle and the distal tubule). Laboratory values returned to normal 15 days after discontinuation of amikacin

Urinary tract The prevalence of gentamicin- and amikacin-induced nephrotoxicity has been studied in patients with normal baseline renal function; eight of 49 patients receiving amikacin developed nephrotoxicity [8c]. Amikacin-induced nephrotoxicity did not significantly depend on dosing frequency (see also “Gentamicin”). The effect of sex on the development of aminoglycoside-induced nephrotoxicity has been studied in men and women receiving either amikacin or gentamicin. Women treated with amikacin were much more likely to develop nephrotoxicity than their male counterparts (32% versus 6%). However, the study did not include other susceptibility factors for nephrotoxicity. Thus it is not known whether sex is an independent susceptibility factor for nephrotoxicity due to amikacin [9c]. Skin Two children (aged 3 and 6 years) developed localized lipoatrophy 4 and 2 months respectively after single intramuscular

Natascia Corti, Anne Taegtmeyer, and Alexander Imhof

injections of amikacin [10A]. In both cases the lipoatrophy showed signs of resolution with conservative management at follow-up 2 months later. Susceptibility factors Age In a retrospective cohort study in 161 children during the first day of life, there was a correlation between lower gestational age and/or birth weight z score and lower amikacin clearance [11c]. Diagnosis of adverse drug reactions Urinary N-acetyl-beta-D-glucosaminidase (NAG) concentrations and lactate dehydrogenase and alkaline phosphatase activities were measured in 32 children aged 2 months to 2 years treated with amikacin or gentamicin for suspected infections [12c]. There was a significant increase in NAG on day 5 compared with the values before amikacin treatment (n ¼ 18). Although serum creatinine and urea rose, there were no significant differences compared with baseline values. The authors concluded that urinary NAG is an index of nephrotoxicity and should be developed as a single test for the diagnosis and monitoring of drug-induced nephrotoxicity.

Gentamicin [SED-15, 1500; SEDA-30, 297; SEDA-31, 427; SEDA-32, 461] Sensory systems Vision A 75-year-old diabetic woman with glaucoma, diabetic retinopathy, and an epiretinal membrane in the left eye underwent transconjunctival sutureless 25-gauge vitrectomy of the left eye and was given subconjunctival gentamicin sulfate 0.4 mg/ml [13A]. One month after surgery, when visual acuity had not recovered, fluorescein angiography showed occlusion of perifoveal capillaries, causing macular infarction. The authors warned against using gentamicin when it can gain access to the inside of the eye, through thinned sclera or sutureless sclerotomy, as in the case here.

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Vestibular function Impairment of evoked vestibulo-ocular reflexes (eVOR) in gentamicin vestibulotoxicity in 12 patients with gentamicin vestibulotoxicity and 13 healthy controls suggests that vestibular hair cells, activated by electrical stimulation, mediate the eVOR; abnormalities of eVOR, especially the phasic component, might be a marker of vestibular injury in gentamicin vestibulotoxicity [14c]. Mineral balance A 45-year-old woman developed symptomatic hypocalcemia, with metabolic alkalosis, hypokalemia, and hypomagnesemia (Bartter-like syndrome), several days after a 10-day course of gentamicin for a urinary tract infection [15A]. Comorbidities included ovarian cancer treated with intraperitoneal cisplatin (in a dose not thought to cause renal tubular dysfunction). Recovery took 6 weeks, and sustained highdose electrolyte replacement was required to counteract persistent urinary potassium and calcium losses. The authors suggested that a polyvalent toxin of gentamicin had caused multiple renal tubular abnormalities. Urinary tract In a retrospective crosssectional study of the incidence of gentamicin-associated acute kidney damage in 228 patients receiving gentamicin, the RIFLE criteria were used to stage renal damage according to serum creatinine concentration and urine output pattern using the following groups: “at Risk”, “Injury”, “Failure”, “Loss”, “End-stage renal disease” [16c]. The incidence of acute kidney damage was 24% (any RIFLE category); 18% developed “risk”, 4.3% developed “injury”, 2.4% developed “failure”, and none developed end-stage renal disease. Independent predictors were the number of gentamicin concentration measurements over 2 mg/l and higher baseline serum creatinine concentration, but there was no effect of gentamicin dose. Patients who developed acute kidney damage had higher mortality in hospital. Initial low-dose gentamicin for Staphylococcus aureus bacteremia and endocarditis and the incidence of a clinically significant

511

reduction in creatinine clearance have been studied in 137 patients, based on the results of a prospective cohort study of safety data from a randomized, controlled trial in 236 patients from 44 hospitals in four countries [17C]. They were randomized to either standard therapy with antistaphylococcal penicillin, or vancomycin plus initial low-dose gentamicin, or daptomycin monotherapy. There was a reduced creatinine clearance in 8% of daptomycin recipients, 22% of those who received vancomycin plus lowdose gentamicin, and 25% of those who received antistaphylococcal penicillin plus low-dose gentamicin. Independent predictors of a clinically significant reduction in creatinine clearance (by 20 ml/minute or more if the baseline creatinine clearance was above 50 ml/minute or by 10 ml/minute or more if the baseline creatinine clearance was below 50 ml/minute) were age above 64 years and any initial low-dose gentamicin. On the basis of these findings, the authors concluded that initial low-dose gentamicin as part of therapy for S. aureus bacteremia and native valve infective endocarditis is nephrotoxic and should not be used routinely. However, concern about the design of this study has thrown the validity of these conclusions into question, as patients not randomized to gentamicin had in fact received gentamicin before enrolment [18r]. Also, the study did not adequately investigate the potential nephrotoxic effects of vancomycin. The severity of nephrotoxicity of gentamicin has been assessed in a prospective observational cohort study in 373 patients with infective endocarditis [19C]. Gentamicin was given to 77% (n ¼ 287, median duration 14 days) and eGFR fell by 8.6%, compared with a 2.3% increase in those who were not given gentamicin. The reduction in renal function correlated with the duration of gentamicin treatment, with a reduction of 0.55 ml/minute/1.73 m2 in estimated endogenous creatinine clearance per day of gentamicin treatment. However, renal impairment during hospitalization was not related to post-discharge mortality (mean duration of follow-up 562 days). The authors concluded that these findings do not imply

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that gentamicin should not be used to treat infective endocarditis. Patients undergoing hemodialysis were included in the study (21 in the non-gentamicin group and 10 in the gentamicin group), although it is not clear how their data were handled for the purposes of renal function analysis; they were excluded from the mortality analysis. Skin A 74-year-old woman underwent left knee replacement, which included the use of gentamicin-loaded bone cement (PalacosÒ), and developed a spreading pruritic eczematous rash on her left leg 3 days later [20A]. Subsequent patch tests were positive to gentamicin. Immunologic An endotoxin-like reaction occurred in a 92-year-old man who received antibiotic prophylaxis with gentamicin 200 mg and teicoplanin before surgery for a fractured neck of femur [21A]. The patient was allergic to penicillin. Soon after uneventful surgery he developed rigors and hyperthermia (maximum temperature 40 C) requiring active cooling, which the authors attribute to the single dose of gentamicin. Serum myoglobin concentration and creatine kinase activity were not measured. Drug formulations A patient with an eGFR of 65 ml/minute/1.73 m2 and multiple comorbidities had 120 gentamicin beads implanted near an infected hip joint during drainage and irrigation and 10 days later suddenly developed severe hearing loss [22A]. The serum gentamicin concentration was 0.7 mg/l. The beads were changed 4 days later and a high gentamicin concentration was again noted. Gentamicin was detectable for 4 weeks and the concentration was above 0.5 mg/l for 3 weeks. Ordinarily, gentamicin–polymethylmethacrylate beads release gentamicin locally at initially high concentrations, followed by a period of constant release for up to about 80 days. Systemically, only extremely low concentrations are detectable (below 0.1 mg/l), because of a blood–bone barrier. The authors speculated that disruption of the barrier and/or

Natascia Corti, Anne Taegtmeyer, and Alexander Imhof

increased blood flow at the site of the wound had caused altered gentamicin pharmacokinetics. However, moderate renal impairment may also have contributed in this case. In 42 patients who underwent two-stage revision hip arthroplasty for periprosthetic infection and were managed with an interim cement spacer loaded with liquid gentamicin (480 mg per 10 ml pack of cement monomer), with or without vancomycin, none had detectable gentamicin in the blood during the first week [23c]. Drug overdose After massive gentamicin overdose in a 14-month-old girl, who received gentamicin 56 mg/kg for empirical treatment of fever, the peak serum gentamicin concentration was 89 mg/l [24A]. She was treated with 4 hours of hemodialysis 4 hours after the overdose; her renal function remained stable throughout and there was no evidence of renal or hearing impairment 3 months later. Diagnosis of adverse drug reactions Urinary lipocalin-type prostaglandin D synthase (L-PGDS) has been used as a biomarker for the early phase of gentamicininduced renal impairment in a prospective study in six patients with endocarditis who were given long-term intravenous gentamicin plus a beta-lactam/carbapenem antibiotic or vancomycin [25c]. Lipocalin-type prostaglandin D synthase, beta 2 microglobulin, and NAG were measured within 10 days of the start of therapy and later. Systemic clearance of gentamicin was reduced by 10% in the late treatment phase compared to the early phase and urinary excretion of lipocalin-type prostaglandin D synthase increased. In contrast there were no significant changes in the other two markers. Serum creatinine and eGFR remained unchanged throughout. The authors pointed out the limitations of the study, the small sample size, and lack of controls. The clinical usefulness of lipocalin-type prostaglandin D synthase as a biomarker of gentamicininduced nephrotoxicity is also limited by wide interindividual variability.

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Urinary N-acetyl-beta-D-glucosaminidase (NAG), lactate dehydrogenase, and alkaline phosphatase activities were measured in 32 children aged 2 months to 2 years treated with gentamicin or amikacin for suspected infections [12c]. All three rose significantly on day 5 was found compared. Serum creatinine and urea also rose, but there were no significant differences from baseline. The authors concluded that urinary NAG activity is an index of nephrotoxicity and should be developed as a single test for the diagnosis and monitoring of drug-induced nephrotoxicity.

Neomycin

513

range) in 6% and 6.3% of patients treated with systemic paromomycin 11 mg/kg/day for 14 and 21 days respectively, and 15% and 17% rises in aspartate aminotransferase activity [28C]. However, at baseline 21% and 20% had grade 1 rises in alanine aminotransferase activity (up to 2.5 times the upper limit of the reference range). Four patients with baseline grade 1 hepatic enzyme rises who received paromomycin for 14 days developed grade 3 rises (5.1–20 times the upper limit of the reference range), necessitating drug withdrawal.

Tobramycin [SEDA-30, 297; SEDA-32,

462] Skin “Recall dermatitis” has been reported in a 61-year-old man who underwent patch testing with neomycin; localized allergic contact dermatitis developed at previous neomycin-treated sites [26A]. Immunologic A 52-year-old man who had treated recurrent nasal scabs with a nasal ointment containing bacitracin, neomycin, prednisolone, and carrying agents for 10 years had an immediate allergic reaction to topical nasal neomycin [27A]. On the previous two occasions on which he had used the ointment he had developed acute facial swelling; pruritus of the eyes, nose, ears, and throat; and generalized urticaria within 3 minutes. Skin prick tests confirmed sensitivity to neomycin sulfate, with negative responses to tobramycin and gentamicin.

Paromomycin

[SEDA-32, 463]

Nervous system Injection site pain was the most common adverse event (44%) in a study of intravenous paromomycin given for 14 or 21 days (n ¼ 217 and 112 respectively) for visceral leishmaniasis [28c]. Liver There were grade 2 or greater rises in alanine aminotransferase activity (>2.5 times the upper limit of the reference

[SED-15, 3437; SEDA-30, 297; SEDA-31, 428; SEDA-32, 463]

Sensory systems Vestibular function Vestibulotoxicity was assessed in 23 patients with cystic fibrosis who had received at least one dose of systemic tobramycin [29c]. There was peripheral loss of vestibular function in 30% of patients and central loss in one. Symptoms of dizziness did not correlate with objective measures of vestibular loss. The authors concluded that their results support vestibular function screening in patients with cystic fibrosis during or after tobramycin exposure, although prospective longitudinal investigation would be required before a more specific evidence-based proposal could be made. Skin Recurrent transient aquagenic wrinkling of the palms has been reported in a 28-year-old woman receiving intravenous or inhalational tobramycin for management of cystic fibrosis [30A]. The palmar eruption occurred consistently within 1–2 days of each dose of tobramycin and typically persisted for 7–14 days before gradually resolving. Water exposure severely exacerbated the eruption, but it persisted in the absence of exposure. Eruptions were restricted to the palms. The patient had previously noted pronounced wrinkling in the absence of tobramycin, and the authors suspected an inherent predisposition, exacerbated by tobramycin.

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CHLORAMPHENICOL AND RELATED DRUGS [SED-15, 706; SEDA-30, 298; SEDA-31, 429; SEDA-32, 464] Liver Hepatitis was attributed to conjunctival administration of 0.5% chloramphenicol eye drops in a 37-year-old male engineer with conjunctivitis [31A].

FLUOROQUINOLONES [SED-15, 1396; SEDA-30, 298; SEDA-31, 429; SEDA-32, 464] Sensory systems Vision Pharmacovigilance databases (the National Registry of DrugInduced Ocular Side Effects, and databases of the World Health Organization and the Food and Drug Administration) have been interrogated to investigate a possible association between diplopia and fluoroquinolones [32c]. There were 171 cases. The median time from the start of therapy to the appearance of the adverse drug reaction was 9.6 days (range 1 day to 5 months) and 17 subjects had concomitant tendinitis. There were 53 positive cases of dechallenge and five of positive rechallenge. The authors concluded that according to the World Health Organization criteria, there is a possible relation between fluoroquinolones and diplopia. Tendinitis of the extraocular muscles is a plausible mechanism. Susceptibility factors Children The evidence for quinolone-induced arthropathy in children has been reviewed [33R]. Data from animal studies and case reports, including tendon-related adverse reactions seen in adults, support a policy of restricting the use of fluoroquinolones in children and adolescents. The emergence of fluoroquinolone-resistant pneumococci is another reason for restricting their use. The authors cited statements from the American Academy of Pediatrics on cases in which

Natascia Corti, Anne Taegtmeyer, and Alexander Imhof

treatment with quinolones in children may be considered. These are for the treatment of exacerbations of pulmonary disease in patients with cystic fibrosis, complicated urinary tract infections, enteritis (transmitted by multiresistant Salmonella or Shigella species), chronic otitis media (caused by Pseudomonas aeruginosa), prophylaxis of anthrax, and other severe potentially lifethreatening diseases. Teratogenicity In a meta-analysis of the safety of quinolones in the first trimester of pregnancy five studies were included, representing 984 quinolone exposures, 318 of which were exposures to fluoroquinolones [34M]. The summary odds ratio was 1.05 (95% CI ¼ 0.9, 1.22) for major malformations, 2.6 (0.36, 19) for stillbirth, 1.15 (0.69, 1.91) for preterm birth, and 0.73 (0.57, 2.2) for low birth weight. The authors concluded that fears of teratogenicity from quinolones are not justified. Drug–drug interactions Warfarin In a nested case–control and case–crossover study using US Medicaid data, seeking interactions between warfarin and fluoroquinolones (ciprofloxacin, levofloxacin, gatifloxacin), there was an increased risk of hospitalization for gastrointestinal bleeding in all warfarin users (308 100 warfarin users and 11 444 warfarin users hospitalized with gastrointestinal bleeding) [35M], but no increased risk in those who took warfarin with fluoroquinolones.

Ciprofloxacin [SED-15, 783; SEDA-30, 298; SEDA-31, 429; SEDA-32, 465] Cardiovascular Long QT syndrome and torsade de pointes occurred postpartum in a woman with heart failure who was taking ciprofloxacin for a urinary tract infection. Other causative factors included hypokalemia and hypomagnesemia [36A]. The electrolyte disturbances were corrected, a pacemaker was implanted, and she was

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given propranolol, but the QT interval remained prolonged at 490 msec. Nervous system Hemibalismus and altered mental status occurred in a 59-year-old patient with cirrhosis who took a prolonged course of ciprofloxacin for a renal abscess [37A]. Hematologic A 30-year-old man took oral ciprofloxacin 1 g/day for 3 days for a suspected urinary tract infection and developed a rapidly fatal hemolytic anemia and severe thrombocytopenia [38A]. The authors attributed the hemolysis and thrombocytopenia to ciprofloxacin, but a non-drug cause could not be ruled, since hematuria preceded exposure to ciprofloxacin. A 76-year-old man developed severe thrombocytopenia after taking ciprofloxacin on two occasions for a community-acquired pneumonia [39A]. The authors concluded that ciprofloxacin had probably been causative, since there was improvement on dechallenge, a positive rechallenge, and detectable platelet-reactive antibodies against glycoprotein IIb/IIIa. According to WHO causality criteria, this constellation fits the definition of a certain reaction. Liver A 66-year-old man developed acute cholestatic hepatitis after receiving intravenous ciprofloxacin for 3 days for gastroenteritis; all other cause of hepatitis were excluded and alkaline phosphatase and gamma-glutamyl transferase activities returned to normal within 3 months of ciprofloxacin withdrawal [40A]. Skin A 63-year-old man who took ciprofloxacin for a urinary tract infection for 7 days developed photoinduced acute exanthematous pustulosis after 6 hours of direct sunlight exposure; withdrawal of the quinolone and treatment with corticosteroids led to rapid clinical improvement [41A]. A 66-year-old woman developed Stevens–Johnson syndrome, confirmed by skin biopsy, after taking oral ciprofloxacin for acute pyelonephritis for 10 days [42A]. She

515

was also taking levothyroxine 150 micrograms/day and was biochemically hyperthyroid. The authors postulated that excess levothyroxine had caused increased ciprofloxacin concentrations through inhibition of cytochrome P450 enzymes. Musculoskeletal Two cases of Achilles’ tendinitis [43A, 44A] and one case of Achilles’ tendon rupture [45A] were reported in patients who had taken ciprofloxacin for less than a week and another case of Achilles’ tendon rupture 1 week after a 1-week course of ciprofloxacin [46A]. The cases of Achilles’ tendon rupture occurred during exercise and were not preceded by symptoms of tendinitis. Ciprofloxacin-induced severe myalgia necessitating emergency care treatment with opiate analgesia and a benzodiazepine occurred within 2 hours of a dose of ciprofloxacin in a patient who was taking it for the third time, having had mild myalgia on the second occasion [47A]. Creatine kinase activity was not raised and the symptoms disappeared within 24 hours. Immunologic Two cases of ciprofloxacininduced hemorrhagic vasculitis have been reported in two patients with diabetes and infected ischemic foot ulcers after treatment with ciprofloxacin plus clindamycin for 4 and 6 days [48A]. The vasculitis resolved completely 2 weeks after withdrawal in one case, but progressive infection and gangrene necessitated below-knee amputation in the other. A further two cases of cutaneous vasculitis developed in association with ciprofloxacin therapy for 7 and 8 days; the lesions all regressed on ciprofloxacin [49A] withdrawal. Drug formulations Ciprofloxacin extendedrelease (Ciprofloxacin XR) 1000 mg/day has been compared with ciprofloxacin 500 mg bd in 103 and 109 patients respectively for complicated urinary tract infections; there were single episodes of headache, glycosuria, erythema, and raised gamma-glutamyl transferase activity in the former [50C].

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Drug–drug interactions Clozapine In two cases ciprofloxacin caused a rise in serum clozapine concentrations to twice the upper end of the usual target range; one patient developed rhabdomyolysis [51A]. The authors recommended avoiding the concomitant use of CYP1A2 and CYP3A4 inhibitors, such as ciprofloxacin, with clozapine or to monitor serum clozapine concentrations and reduce the dose accordingly. Diclofenac The interaction of ciprofloxacin 500 mg with diclofenac 50 mg had been investigated in a single-dose, two-period, crossover study in 12 healthy men [52c]. The Cmax of ciprofloxacin increased from 2.48 to 3.91 mg/l when it was co-administered with diclofenac. The tmax was reduced from 1.5 to 2.0 hours. There were significant increases in AUC and half-life and a significant reduction in total body clearance. The clinical consequences of this interaction are unknown. We disagree with the authors’ recommendation that this combination be avoided or continued only after dosage adjustments, since we do not believe that the data from this study in 12 healthy men allows such a sweeping conclusion. Simvastatin Rhabdomyolysis occurred in a 77-year-old woman taking simvastatin 40 mg/day when she also took ciprofloxacin for a urinary tract infection [53A]. The symptoms began after the second dose of ciprofloxacin, and 3 days later the creatine kinase activity was 28 980 U/l. After withdrawal of ciprofloxacin and simvastatin, the creatine kinase activity returned to normal within 14 days and functional activity improved by day 23. The author speculated that simvastatin toxicity had been caused by the addition of ciprofloxacin, although the mechanism is unclear, as ciprofloxacin is only a weak inhibitor of CYP3A4, of which simvastatin is a substrate. Venlafaxine Inhibition of CYP3A4 by ciprofloxacin in a 61-year-old man taking methadone and venlafaxine was thought to have caused serotonin syndrome after 2 weeks therapy [54A].

Natascia Corti, Anne Taegtmeyer, and Alexander Imhof

Gemifloxacin

[SED-15, 1487]

Nervous system A 67-year-old woman became febrile, dysphasic, uncooperative, and agitated 24 hours after taking a single dose of gemifloxacin 320 mg for a mild upper respiratory infection [55A]. Electroencephalography showed generalized slowing. Her symptoms resolved within 2 days without definitive treatment. The authors speculated that she may have had a prodromal convulsive episode and concluded that gemifloxacin had been responsible. Drug–drug interactions Probenecid The interaction of gemifloxacin with probenecid, an inhibitor of renal organic anion and organic cation transport, has been studied in 17 healthy volunteers [56c]. Probenecid increased plasma concentrations of gemifloxacin, reduced its urinary excretion, reduced its total clearance by 31%, and prolonged its half-life from 8.1 to 9.5 hours. Modelling showed that competitive inhibition of renal tubular secretion of gemifloxacin by probenecid was the most likely mechanism.

Levofloxacin

[SED-15, 2047; SEDA-30, 299; SEDA-31, 432; SEDA-32, 467]

Observational studies In a multicenter trial of levofloxacin in 4888 Chinese patients gastrointestinal disorders occurred in 193 patients (3.9%) and local irritation at the infusion site in 84 [57C]. Comparative studies In a prospective, double-blind, non-inferiority phase 3 trial of tigecycline versus levofloxacin for community-acquired pneumonia, the following adverse events were reported in 212 patients who took levofloxacin: headache in four (1.9%); hypokalemia in eight (3.8%); leukocytosis and thrombocythemia in two and four (0.9% and 1.9%); diarrhea, nausea, and vomiting in 17, 18, and 14 (8, 8.5, and 6.6); and raised aminotransferase activities in 16 (7.5%) [58C].

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In a phase 3 comparison study of intravenous levofloxacin with intravenous tigecycline, the following adverse events were reported in 210 patients who took levofloxacin: headache in 10 (4.8%); diarrhea, nausea, and vomiting in 9, 12, and 4 (4.3%, 5.7%, and 1.9%); anemia and eosinophilia in 7 and 11 (3.3% and 5.2%); raised aminotransferase activities in 21 (10%); and raised alkaline phosphatase activity in 3.8%. [59C]. Nervous system A 58-year-old woman who was taking mirtazapine and metoclopramide started to take levofloxacin; 1 day later she had an episode of loss of consciousness associated with urinary incontinence and on the following day two tonic–clonic seizures [60A]. Levofloxacin and mirtazapine were withdrawn and the seizure activity stopped. No other cause for her seizures was found. The authors concluded that levofloxacin is epileptogenic and had also, by inhibiting CYP1A2, increased the serum concentrations of mirtazapine and metoclopramide, drugs that also have epileptogenic effects. A 15-year-old boy developed benign intracranial hypertension after taking levofloxacin for 3 weeks [61A]. Headache, diplopia, and papilledema resolved within 1 week of levofloxacin withdrawal. Psychiatric An 83-year-old man developed delirium after taking levofloxacin for 3 days for a right lower lobe pneumonia [62A]. The delirium resolved within 2 days of levofloxacin withdrawal. The authors proposed that the underlying mechanism may be an agonist action at GABA receptors. Metabolism A 65-year-old woman with type 2 diabetes, chronic obstructive pulmonary disease, and renal impairment, taking glipizide [63A], was given intravenous levofloxacin 250 mg/day and had several episodes of severe treatment-refractory hypoglycemia on the next day, despite withdrawal of glipizide. Hypoglycemic episodes (two requiring glucagon in addition to intravenous dextrose) continued for 6 days (until 2 days after levofloxacin was withdrawn). Insulin was not suppressed, in keeping with

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data from animal studies that have shown that fluoroquinolones directly stimulate insulin secretion from pancreatic beta cells. The risks of severe hypoglycemia and hyperglycemia have been studied in patients taking levofloxacin, gatifloxacin, ciprofloxacin, or azithromycin [64C]. Levofloxacin was associated with a frequency of hypoglycemia of 0.19 per 1000 patients and of hyperglycemia of 0.18 per 1000 patients, compared with 0.07 and 0.1 respectively among patients taking azithromycin. Skin A localized phototoxic reaction and increased stool frequency occurred in a 63-year-old man with prostate cancer who had taken two courses of levofloxacin during the 90 days before radiotherapy [65A]. The low dose of radiation and the lack of concomitant chemotherapy made a purely radiation-associated reaction unlikely. The authors pointed out that photon beam radiation and fluoroquinolones can both inhibit cell growth via free radical production, and postulated an interaction. Musculoskeletal A previously healthy 91year-old man was given levofloxacin for presumed bacterial pneumonitis and developed bilateral heel pain within 4 days and bilateral complete Achilles’ tendon rupture after 4 weeks [66A]. In a study of levofloxacin plus metronidazole in uncomplicated pelvic inflammatory disease there was a single case of myalgia and Achilles tendonitis among 40 participants; the symptoms developed 4 days after treatment began and levofloxacin and metronidazole were withdrawn [67c]. In 117 men who took oral levofloxacin 500 mg/day for chronic bacterial prostatitis there were six cases of musculoskeletal and connective tissue disorders (5.1%) [68C]. Immunologic Cutaneous vasculitis has been reported in a 65-year-old man who took oral levofloxacin and rifampicin for an epidural abscess [49A]. Palpable purpura appeared on his skin after 3 days and disappeared rapidly when levofloxacin was

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withdrawn. Histology showed a leukocytoclastic small-vessel vasculitis. Drug-drug interactions Warfarin In a retrospective study of 21 patients taking warfarin, levofloxacin significantly increased the international normalized ratio (INR) [69c]. In some cases there was concomitant renal failure, which would have raised serum levofloxacin concentrations. Three patients had episodes of bleeding. The authors proposed that levofloxacin had displaced of warfarin from protein binding sites, reduced in vitamin K production by gut bacteria, and inhibited CYP2C9-mediated warfarin metabolism. They advised careful INR monitoring when warfarin and levofloxacin are coadministered.

Moxifloxacin

[SED-15, 2392; SEDA-30, 300; SEDA-31, 434; SEDA-32, 468]

Systematic reviews The adverse effects of moxifloxacin, other fluoroquinolones, and other antibacterial classes have been compared [70M]. Data were extracted from published clinical trials, meta-analyses, postmarketing studies, spontaneous report systems, and case reports for rare effects published before March 2009. Global analysis did not show significantly more drug-related adverse effects than with comparators. Tendon rupture was infrequent and severe cutaneous reactions and allergies were very rare. Nervous system adverse effects and phototoxicity were less common than with other fluoroquinolones. Severe cardiac toxicity was not reported, although there was a 4–7 msec prolongation of the QT interval. Hepatotoxicity was not different from that observed for other fluoroquinolones (excluding trovafloxacin) and was less frequent than reported with co-amoxiclav and telithromycin. Cardiovascular QT prolongation and torsade de pointes have been reported in a 71-year-old man who received intravenous moxifloxacin for pneumonia [71A]. The QTc interval, which was 434 msec before

Natascia Corti, Anne Taegtmeyer, and Alexander Imhof

moxifloxacin, was prolonged to 565 msec within hours. He subsequently developed torsade des pointes, which self-terminated. After withdrawal of moxifloxacin no further dysrhythmias occurred and the QTc interval returned to normal over the next few days. The effect of moxifloxacin on the QT interval has been studied in 20 healthy subjects who received either moxifloxacin 400 mg (route not specified, although mean time to maximum concentration was 2.3 hours, implying an oral dose) or placebo [72c]. A pharmacokinetic–pharmacodyamic model estimated a 3.9-msec increase in the QTc interval for every 1 mg/l increase in moxifloxacin concentration. The mean peak moxifloxacin concentration was 2.24 mg/l. An early increase in QTc interval reverted almost to baseline values at 5–6 hours after the dose, and then increased again and remained above the predose baseline for up to 48 hours after the dose. The authors attributed the fall in QTc interval at 5–6 hours to artifact. Gastrointestinal Four patients developed fatal pseudomembranous colitis after receiving moxifloxacin for pulmonary infections [73A]. The delay between therapy with moxifloxacin and the development of Clostridium difficile-associated disease was 5–26 days. All had significant comorbidities. Liver In a prospective, randomized, open, parallel-group, multinational comparison of sequential intravenous/oral moxifloxacin 400 mg/day and sequential intravenous/oral co-amoxiclav 100 mg/200 mg tds for complicated skin and skin structure infections 406 patients were given moxifloxacin, of whom one had a transient increase in aminotransferase activity from 35 U/l before treatment to 448 U/l on day 13 [74c]. Skin Linear immunoglobulin A bullous dermatosis occurred in a 72-year-old man who took moxifloxacin for 7 days [75A]. Moxifloxacin was withdrawn, systemic steroids were given, and the skin lesions completely resolved within 3 weeks.

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Acute generalized exanthematous pustulosis has been reported after oral moxifloxacin in a 76-year-old woman [76A]. Moxifloxacin-induced drug hypersensitivity syndrome with features of toxic epidermal necrolysis has been reported in a 44-year-old Asian man after he had taken moxifloxacin for 1 week [77A].

Trovafloxacin

[SED-15, 46]

Liver Trovafloxacin was withdrawn from the European market because of liver toxicity and acute liver failure in 1999, but it is still available under very strong restrictions in the USA. In experiments in isolated human hepatocytes trovafloxacin inhibited expression of hepatic nuclear factor-4a (HNF-4a), which in turn suppressed the function of a network of genes that govern major metabolic processes, lipid and carbohydrate metabolism, and mitochondrial biology [78E]. The author concluded that this is the probable underlying mechanism of trovafloxacin-induced hepatotoxicity.

GLYCOPEPTIDES

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primary outcome of “all-cause mortality”, teicoplanin caused significantly fewer adverse events than vancomycin expressed as per patient episodes (RR ¼ 0.61; 95% CI ¼ 0.50, 0.74) and significantly less nephrotoxicity (RR ¼ 0.44; 95% CI ¼ 0.32, 0.61); significantly fewer events required withdrawal of teicoplanin (RR ¼ 0.57; 95% CI ¼ 0.33, 0.8) [80M]. Severe nephrotoxicity requiring hemodialysis and red man syndrome was reported only with vancomycin; rashes were not significantly different. Immunologic Vancomycin- and teicoplanininduced drug rash with eosinophilia and systemic symptoms (DRESS) was diagnosed in a 38-year-old woman who had had an emergency aortic valve replacement because of acute endocarditis [81A]. Vancomycin 500 mg tds had to be withdrawn on day 43 because of rapid-onset neutropenia, and treatment was continued with rifampicin and teicoplanin. Severe DRESS with persistent fever, multiorgan failure, nodal enlargement, eosinophilia, and upper body erythema developed and she recovered only after withdrawal of antibiotics and high-dose intravenous glucocorticoid therapy.

[SEDA-30,

435; SEDA-32, 469] Observational studies In a retrospective review of medical charts in a Taiwan hospital, there were 117 patients whose vancomycin treatment had to be stopped because of drug-induced fever (n ¼ 24), rash (n ¼ 77), fever and rash (n ¼ 8), or neutropenia (n ¼ 8) [79c]. After treatment was switched to teicoplanin, only 10% (112 patients) had a recurrence of the drug-induced adverse event; four of the eight patients who had had vancomycininduced neutropenia had neutropenia with teicoplanin. Systematic reviews In a systematic review of randomized controlled trials with the

Teicoplanin

[SED-15, 3305; SEDA-30, 301; SEDA-32, 469] Skin A 10-year-old girl developed a pigmented eruption around the mouth 48 hours after the start of an infusion of teicoplanin; she had had a similar episode after teicoplanin administration a few years before [82A].

Drug dosage regimens In 36 out-patients with osteomyelitis and prosthetic infections who were given teicoplanin either daily or three times weekly for 60–360 days, trough and peak concentrations were similar in the two groups and six patients had mild liver toxicity. The authors conclude that three times weekly teicoplanin seems a valuable option [83A].

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Telavancin There have been several reviews of telavancin (VibativÒ), which was approved in November 2009 by the FDA [84R, 85R, 86R, 87R, 88R]. Telavancin is a rapidly bactericidal lipoglycopeptide, which is active against Gram-positive organisms, including meticillin-resistant and vancomycin-resistant S. aureus, multidrug-resistant Streptococcus pneumoniae, and glycopeptide-resistant enterococci. As telavancin is eliminated mostly by the kidneys, dosage adjustment in renal insufficiency is needed. The most common adverse effects are nausea and vomiting. QT interval prolongation is more common with telavancin than with comparator agents and there was renal impairment in trials in 3.1%. Caution is advised when QT intervalprolonging agents or nephrotoxic drugs are used concomitantly.

Vancomycin

[SED-15, 3593; SEDA-30, 301; SEDA-32, 470] Respiratory Occupational asthma occurred in a pharmaceutical employee who worked for 10 months as a production worker with vancomycin powder [89A]. After 5 months he complained of rhinitis, cough, dyspnea, and chest discomfort. Vancomycin-associated occupational asthma was diagnosed. An intradermal test was positive and there was a significant increase in histamine release capacity, but specific IgE or IgG antibodies were not identified. Direct histamine release by vancomycin was suggested as the possible mechanism. Neuromuscular function Neuralgic amyotrophy with bilateral shoulder pain and stiffness developed in a 22-year-old man with cystic fibrosis taking vancomycin, tobramycin, and piperacillin/tazobactam; the symptoms persisted for 2 months and recurred when the same antibiotics were given 8 months later [90A]. Hematologic Possible vancomycin-induced thrombocytopenia occurred within 15 hours of treatment with vancomycin in a 61-year-

Natascia Corti, Anne Taegtmeyer, and Alexander Imhof

old man [91A] and vancomycin-dependent IgG and IgM platelet antibodies were detected within 7 days in a neonate [92A]. Vancomycin was withdrawn and the platelet counts recovered after 4–10 days. Urinary tract Treatment with tenofovir in combination with prolonged administration of vancomycin caused renal insufficiency in two HIV-positive patients [93A]. In a retrospective cohort study of 80 patients received vancomycin given either as an intermittent infusion or as a continuous infusion with a similar cumulative dose; the prevalence of nephrotoxicity was similar in the two groups (16%) [94c]. When continuous vancomycin in 119 patients was compared with intermittent administration in 30 patients after elective cardiac surgery, renal function deteriorated in 28% and 37% respectively [95c]. Skin Several cases of skin reactions after vancomycin have been reported. In an 82year-old woman with chronic renal insufficiency oral vancomycin 250 mg qds caused a pruritic rash similar to red man syndrome; the rash abated after vancomycin withdrawal and treatment with antihistamines [96A]. In an elderly woman, who had already had a maculopapular rash after intravenous vancomycin in combination with piperacillin/tazobactam and metronidazole, a pruritic rash developed after exposure to oral vancomycin for C. difficile infection [97A]. A 76-year-old woman with penicillin and sulfa allergy was given vancomycin for a pacemaker infection with meticillin-sensitive S. aureus [98A]. On day 4 she developed a worsening papular rash and a skin biopsy confirmed a severe leukocytoclastic necrotizing vasculitis, which resolved 5 days after vancomycin withdrawal. A 60-year-old woman with polyarthritis taking sulfasalazine developed a drug rash with eosinophilia and systemic symptoms (DRESS) with acute liver failure after taking vancomycin for 2 days [99A]. After liver transplantation and initial recovery, hepatitis recurred. Lymphocytes and eosinophils were detected post-mortem in the

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transplanted liver. The relation between sulfonamide hypersensitivity and intolerance to vancomycin is unclear; cross reactivity has not been described and vancomycin is structurally not related to the sulfonamides. Immunologic An elderly woman who received intravenous vancomycin for endophthalmitis developed oral ulcers, fever, and a diffuse erythematous body rash after 1 week. Double-stranded DNA and antihistone antibodies suggested a lupus-like syndrome [100A]. The symptoms improved dramatically after withdrawal of antibiotics and treatment with oral prednisone. Autacoids In an 11-day-old baby red man syndrome and stridor developed postoperatively after intravenous infusion of vancomycin 45 mg (15 mg/kg) [101A]. Drug formulations MRSA bacteremia in a liver transplant patient did not respond to generic vancomycin (Vancomycin Abbott), despite treatment for 10 days in appropriate doses but resolved after switching to the original product (Vancomycin Lilly) [102AE]. The generic vancomycin product had significantly lower activity against S. aureus in a neutropenic mouse model, compared with the original product. The authors warned that pharmacokinetic bioequivalence might not predict therapeutic equivalence in antimicrobials. Drug administration In two cases gastrointestinal disease led to unexpected high vancomycin concentrations after oral administration. In a 65-year-old man with severe colitis and renal insufficiency a vancomycin serum concentration of 50 mg/l was associated with oral vancomycin 0.5 g 6-hourly [103A]. In another patient with severe gastrointestinal graft versus host disease (GVHD) potentially toxic serum concentrations were found during treatment with oral vancomycin [104A]. Monitoring of vancomycin concentrations should be considered in patients with impaired gastrointestinal mucosa.

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Drug–drug interactions Furosemide A 77year-old woman who was given intravenous vancomycin 1 g bd and oral furosemide 20 mg/day developed severe hypokalemia (1.7 mmol/l) with pulseless ventricular tachycardia, necessitating cardioversion [105A]. The potassium concentration remained stable only after withdrawal of vancomycin. She had previously taken furosemide 40 mg/day without hypokalemia. Monitoring therapy A consensus statement of the American Society of Health-System Pharmacists (ASHP), the Infectious Diseases Society of America (IDSA), and the Society of Infectious Diseases Pharmacists (SIDP) concerning vancomycin monitoring and dosing recommendations for adult has been published [106S]. A higher trough vancomycin serum concentration of 15–20 mg/l is recommended in complicated infections, such as bacteremia, endocarditis, osteomyelitis, meningitis, and hospital-acquired pneumonias. However, the safety of higher trough concentrations over a prolonged period has not been studied and there are few data suggesting a direct relation between toxicity and specific serum concentrations. Combining vancomycin with other nephrotoxic drugs (for example aminoglycosides) increases the risk of nephrotoxicity and would be expected to alter the concentration–effect relation. Close monitoring of renal function and vancomycin trough concentrations is recommended with higher serum vancomycin concentrations.

KETOLIDES [SED-15, 1976; SEDA-30, 301; SEDA-31, 436; SEDA-32, 471] Telithromycin

[SEDA-32, 471]

Liver In a retrospective analysis of 42 cases of hepatotoxicity attributed to telithromycin, there were four deaths and one liver transplantation; typical clinical features were short latency (median, 10 days) and abrupt onset of fever, abdominal pain, and jaundice,

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sometimes with ascites, even in cases that resolved [107c]. Drug–drug interactions Oxycodone In 11 healthy subjects telithromycin clearly reduced the N-demethylation of oxycodone to noroxycodone by inhibiting CYP3A4 [108c]. Thus, telithromycin may increase the risk of opioid adverse effects in patients taking multiple doses of oxycodone for pain relief; it may be appropriate to reduce the dose of oxycodone by 25–50%, followed by readjustment according to clinical response.

[SED-15, 2063; SEDA-30, 302; SEDA-31, 437; SEDA-32, 472]

LINCOSAMIDES

Clindamycin Gastrointestinal In a retrospective study in 34 patients who took oral rifampicin 600 mg/day and clindamycin 600 mg/day for 10 weeks, the most frequent adverse event was diarrhea [109c]. Observational studies In a retrospective study in 70 patients with bone and joint infections, prolonged, continuous, intravenous clindamycin therapy (600 mg as a loading dose infused over 60 minutes, followed immediately by a continuous infusion of 30–40 mg/kg/day) one patient developed cytolytic hepatitis and one had an allergic rash; both resolved after clindamycin withdrawal [110c].

MACROLIDE ANTIBIOTICS [SED-15, 2183; SEDA-30, 302; SEDA-31, 437; SEDA-32, 472] Susceptibility factors Breast-feeding infants Treatment of infants with macrolides has been associated with hypertrophic pyloric stenosis, causing projectile vomiting,

Natascia Corti, Anne Taegtmeyer, and Alexander Imhof

dehydration, electrolyte abnormalities, and in rare cases death, possibly via an interaction of macrolides with gastric motilin receptors. Large population-based cohorts have suggested that exposure to macrolides via breast milk may also be associated with pyloric stenosis. However, in a prospective controlled observational study in 55 infants exposed to macrolide antibiotics in breast milk compared with 36 infants who were exposed to amoxicillin, seven of the former had compared with three of the latter (OR ¼ 1.6; 95% CI ¼ 0.38, 6.7) [111c]. The adverse reactions in the infants exposed to macrolides were rash, diarrhea, loss of appetite, and somnolence. Drug–drug interactions Digoxin In a 15year, population-based, nested case–control study of the association between hospitalization for digoxin toxicity and recent exposure to individual macrolide antibiotics, clarithromycin was associated with the highest risk of digoxin toxicity (adjusted OR ¼ 15; 95% CI ¼ 8, 28), whereas there were much lower risks with erythromycin (adjusted OR ¼ 3.7; 95% CI ¼ 1.7, 7.9) and azithromycin (adjusted OR ¼ 3.7; 95% CI ¼ 1.1, 13) [112c].

Azithromycin [SED-15, 389; SEDA-30, 302; SEDA-31, 437; SEDA-32, 472] Cardiovascular Fulminant myocarditis can rarely result from a hypersensitivity reaction to azithromycin, as in the case of a 48-year-old man [113A]. Respiratory Recurrent alveolar hemorrhage was attributed to azithromycin in a 78-year-old man who took azithromycin for an upper respiratory tract infection [114A]. Nervous system There are anecdotal reports of exacerbation of myasthenia gravis with azithromycin. In a 13-year-old boy with myasthenia gravis in whom a single intravenous dose of azithromycin, 500 mg infused over 1 hour, caused sudden worsening of motor symptoms necessitating

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endotracheal intubation, the respiratory weakness and limb power improved within a few minutes of intravenous calcium gluconate [115A]. Such rapid reversal suggests that azithromycin probably acts presynaptically, by suppressing acetylcholine release. Hematologic Although leukopenia is the one of the most frequent azithromycinrelated laboratory abnormalities in children, agranulocytosis has not been reported in adults. However, an 81-year-old man who took azithromycin for acute otitis media developed febrile neutropenia, and was given granulocyte colony-stimulating factor and cefepime; his symptoms and neutrophil count recovered within 7 days after azithromycin withdrawal [116A]. Liver Vanishing bile duct syndrome has been reported in a 62-year-old man who had had Stevens–Johnson syndrome 1 month before, after taking azithromycin 500 mg/day for 3 days; liver transplantation was performed 7 months later [117A]. Drug–drug interactions Statins In a systematic screening of the World Health Organization's adverse drug reactions database, 53 cases of rhabdomyolysis with azithromycin and statins were investigated retrospectively [118c]. Rhabdomyolysis occurred shortly after initial treatment with azithromycin in 23% of cases. In 11 patients an interaction was suggested. With the exception of one patient, the statins were prescribed at the recommended daily doses.

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Biliary tract Erythromycin can induce postprandial biliary colic [120c].

Clarithromycin

[SED-15, 799; SEDA30, 302; SEDA-31, 438; SEDA-32, 473]

Comparative studies Clarithromycin and ciprofloxacin have been compared as third-line drugs added after 2 years of treatment with rifampicin and ethambutol for pulmonary disease caused by Mycobacterium avium-intracellulare (MAC; n ¼ 170), Mycobacterium malmoense (n ¼ 167), and Mycobacterium xenopi (n ¼ 34); an optional comparison of immunotherapy with Mycobacterium vaccae versus no immunotherapy was also performed [121C]. Progress was monitored annually during the 2 years of treatment and for 3 years thereafter. If the patient did not improve by 1 year, the regimen was supplemented by the addition of the drug that had not been used in the original allocation. The study included 371 patients, of whom 186 received clarithromycin and 185 ciprofloxacin. Overall, 20% in each group were unable to tolerate treatment. Ciprofloxacin was associated with more unwanted effects than clarithromycin (16% versus 9%).

Erythromycin [SED-15, 1237; SEDA30, 302; SEDA-31, 438; SEDA-32, 474]

Psychiatric Visual hallucinations associated with clarithromycin have been reported in two children who took clarithromycin in therapeutic dosages; the symptoms gradually disappeared after clarithromycin withdrawal [122A]. Mania is an extremely rare psychiatric adverse drug reaction but has been reported in a child who took clarithromycin [123A].

Gastrointestinal In 264 (28%) of 942 respondents who took oral erythromycin 1000 mg/ day for 10 days as prophylaxis for pertussis infection, there were some form adverse effects, of which the most common involved gastrointestinal symptoms, for example, diarrhea (16%), stomach ache (7.5%), nausea (3.6%), epigastric distress (2.1%), and abdominal distention (1.8%) [119c].

Gastrointestinal In a double-blind, randomized, placebo-controlled study of the effect of clarithromycin on cardiovascular events and mortality in patients with chronic coronary artery disease in 2172 patients who took clarithromycin 500 mg/ day and 2200 who took matching placebo for 14 days, there was at least one nonserious adverse event in 40% of the former

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compared with 25% of the latter [124C]. Gastrointestinal adverse reactions were reported 950 times by 697 patients taking clarithromycin (32%) compared with 485 times by 390 patients taking placebo (18%). There were no significant differences in other non-serious or serious adverse events during the first month. Liver Liver impairment was reported in patient with systemic sclerosis after concomitant administration of bosentan and clarithromycin [125A], Hoigné syndrome in a patient who took clarithromycin for rosacea [126A], and cholestatic hepatitis in a 64year-old patient who took clarithromycin for Helicobacter pylori eradication [127A]. Musculoskeletal Rhabdomyolysis has been attributed to clarithromycin without concurrent use of other medications [128A]. Immunologic An anaphylactic reaction occurred in a child after treatment with clarithromycin [129A]. Drug–drug interactions Colchicine Rhabdomyolysis occurred in a 48-year-old African-American man with hypertension and chronic gout, who was taking colchicine 0.6 mg/day and who took clarithromycin 500 mg bd for 3 days for a communityacquired pneumonia [130A]. The serum aminotransferases rose and the serum creatine kinase activity was 22 996 U/l; the urine contained myoglobin. Withdrawal of colchicine and clarithromycin resulted in clinical and biochemical resolution. Simvastatin Rhabdomyolysis after combined therapy with simvastatin 80 mg/day and clarithromycin has been recently reported in two women; they recovered rapidly, after simvastatin withdrawal [131A, 132A]. The interacting mechanism was probably inhibition of CYP3A4; inhibition of P glycoprotein transport of simvastatin may also have contributed.

Natascia Corti, Anne Taegtmeyer, and Alexander Imhof

Roxithromycin Placebo-controlled studies In a doubleblind study, 31 adults with early rheumatoid arthritis who had not previously received disease-modifying antirheumatic drugs were randomized to oral roxithromycin 300 mg/day or placebo for 3 months [133C]. There were adverse events in 11 who took roxithromycin and seven who took placebo. The most common adverse events (>5%) were nausea, abdominal pain, headache, and dry mouth. There were no dose-limiting adverse effects. One patient taking roxithromycin withdrew because of severe emesis.

[SED-15, 2542; SEDA-30, 303; SEDA-31, 439; SEDA-32, 476]

NITROFURANTOIN

Respiratory Lung disease after long-term nitrofurantoin therapy has again been described in [134A, 135A, 136A, 137A]. In two cases there was bronchiolitis obliterans and in two cases interstitial lung disease with pneumonitis, one with fatal lung fibrosis. There was complete or partial resolution of symptoms after treatment with glucocorticoids. EIDOS classification: Extrinsic species Nitrofurantoin Intrinsic species Cells involved in allergic reactions (lymphocytes, eosinophils), fibroblasts, pneumocytes Distribution Lungs Outcome Fibrosis or inflammation Sequela Nitrofurantoin-induced lung disease DoTS classification: Dose-relation Hypersusceptibility reaction Time-course Late Susceptibility factors Female sex

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Liver Acute toxic hepatitis was associated with nitrofurantoin for a urinary tract infection in a pregnant woman at 36 weeks of gestation [138A]. After induced delivery because of hypertension, the liver enzymes normalized only after nitrofurantoin withdrawal. Urinary tract Acute renal insufficiency due to granulomatous interstitial nephritis associated with long-term prophylactic nitrofurantoin improved after nitrofurantoin withdrawal [139A]. Immunologic Hypersensitivity reactions to nitrofurantoin have been reported. • Diffuse target-shaped lesions of the skin eosinophilia and multiorgan involvement (DRESS) occurred after 4 days of treatment with nitrofurantoin for a urinary tract infection in a 77year-old woman; she recovered after high-dose glucocorticoid treatment [140A]. • A 57-year-old woman developed a fever after taking nitrofurantoin for 4 days for a urinary tract infection. Creatinine, creatine kinase, and liver enzymes were raised and there was an eosinophilia; she recovered after nitrofurantoin withdrawal [141A]. • A 77-year-old woman with a penicillin allergy had a recurrent fever, malaise, rigor, chills, and a leukocytosis after several exposures to nitrofurantoin; no further inflammatory episodes occurred after nitrofurantoin withdrawal [142A].

[SED-15, 2645; SEDA-30, 304; SEDA-31, 439]

OXAZOLIDINONES

Adverse reactions to linezolid have been reviewed based on data from several phase II and phase III studies and from prospective comparative postmarketing studies [143R, 144R]. Trials were restricted to 28 days. With the continuing emergence of resistant Grampositive organisms, against which it is highly effective, linezolid has been increasingly used for off-label indications, such as endocarditis. These indications necessitate

525

prolonged administration, which predisposes to serious adverse events. Common adverse events in phase III studies were gastrointestinal complaints and abnormal liver function tests, which led to discontinuation in some patients. Depending on the study and on the time of administration hematological adverse events, such as anemia, leukopenia, and thrombocytopenia, were seen in up to 46%. Pre-existing hematological abnormalities and prolonged treatment are risk factors for myelosuppression. There have been more than 40 cases of only partially reversible peripheral neuropathy and fully reversible optic neuropathy, and one case of reversible Bell's palsy, in most cases with treatment for more than 28 days. Mitochondrial disturbance may be the causative mechanism. More than 13 cases of lactic acidosis have been reported; the risk is higher in older patients and during prolonged treatment. Nephrotoxicity has occurred in trials. Observational studies In a retrospective study in South Korea of linezolid in combination with other second-line drugs in 11 patients with intractable multidrug resistant tuberculosis, nine had serious adverse events [145c]. Eight patients developed a peripheral neuropathy in the legs after a median of 4 months; linezolid was withdrawn in these cases. Three patients developed an optic neuropathy, including two who had a peripheral neuropathy, after a median of 4 months. Two patients developed anemia requiring blood transfusion. Nervous system A 41-year-old patient with a history of alcohol abuse and heart failure developed an encephalopathy after taking linezolid for 2 days, becoming mute and akinetic and recovering 48 hours after linezolid withdrawal [146A]. A 12-year-old girl developed a peripheral neuropathy after taking linezolid for 4 months for chronic vertebral osteomyelitis, with reduced sensation with painful burning paresthesia in both legs; there was

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nearly complete resolution 10 months after linezolid withdrawal [147A]. Linezolid-associated seizures occurred in two patients with a history of epilepsy [148A, 149A]. One developed recurrent complex partial seizures, which ended only after switching linezolid to teicoplanin. The other, a 45-year-old woman with intractable seizures, had a significant rise in daily seizure frequency and finally almost constant seizure activity after three doses of linezolid for a wound infection; 3 days later her seizures regained their usual frequency and became more frequent again when linezolid was restarted. Sensory systems Vision A patient with ocular sarcoidosis developed reduced vision with optic disc hyperemia after long-term treatment with linezolid for osteomyelitis. Vision improved and the hyperemia disappeared after linezolid withdrawal [150A]. Auditory function Auditory nerve neuropathy in a neonate has been associated with linezolid [151A]. Although the neonate had been treated with an aminoglycoside before switching to linezolid, the authors speculated that linezolid had been the causative agent. The hearing loss did not recover and the baby was assessed for cochlear implants. Hematologic Anemia has been attributed to linezolid in two cases. In a patient with laryngeal cancer the hemoglobin concentration fell from 12.5 to 5.9 g/dl over 2 months of linezolid therapy; there were ringed sideroblasts in the bone marrow and the hemoglobin slowly increased after linezolid withdrawal [152A]. A 2-year-old boy with infective endocarditis took linezolid for 4 weeks and his hemoglobin concentration fell to 6.5 g/dl with markedly reduced erythropoiesis; he recovered 19 days after linezolid withdrawal [153A]. In a retrospective chart review the susceptibility factors for linezolid-associated thrombocytopenia were a dose over 22 mg/ kg, a low baseline platelet count, and renal impairment (creatinine clearance below 30 ml/minute) [154c].

Natascia Corti, Anne Taegtmeyer, and Alexander Imhof

In 33 patients who received linezolid, creatinine clearance and platelet count ratio before and after linezolid were linearly correlated [155c]. A patient undergoing chronic hemodialysis developed severe thrombocytopenia after taking linezolid for 7 days; it resolved after linezolid withdrawal [156A]. Metabolism Four cases of linezolid-associated lactic acidosis have been described. One patient developed pancytopenia, deteriorating renal function, and lactic acidosis (pH 6.93, blood lactate 61 mmol/l) after 34 days; he recovered fully after switching to imipenem [157A]. Two patients with tuberculosis took linezolid in combination with other antituberculosis drugs and developed symptomatic lactic acidosis [158A, 159A]. One patient died despite linezolid withdrawal. A renal transplant recipient developed lactic acidosis after a short course of linezolid [160A]. Liver Severe hyperbilirubinemia developed in a patient with decompensated liver cirrhosis after linezolid therapy for 5 days; after linezolid withdrawal the bilirubin continued to rise, but then gradually improved over 10 days [161A]. Urinary tract A 21-year-old drug abuser developed acute interstitial nephritis with a pruritic maculopapular rash and fever shortly after starting to take linezolid for osteomyelitis; renal function gradually improved after 8 days of glucocorticoid treatment [162A]. Skin An 88-year-old woman developed a drug rash with eosinophilia and systemic symptoms (DRESS), with severe pruritus, a maculopapular rash, an eosinophilia, liver enzyme rises, and acute renal insufficiency, after taking linezolid for 7 days; a renal biopsy showed a tubulointerstitial nephritis with eosinophils; recovery followed linezolid withdrawal [163A]. A 64-year-old man developed confluent non-blanching petechiae and purpura over the entire body after taking linezolid for 9 days for a retroperitoneal abscess; despite linezolid withdrawal he died [164A].

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Musculoskeletal Creatine kinase activity rose in a 79-year-old man after switching from vancomycin to linezolid; only after linezolid withdrawal did creatine kinase activity return to baseline [165A]. Drug–drug interactions Linezolid is primarily metabolized by oxidation of the morpholine ring, resulting in two inactive ring-opened carboxylic acid metabolites; it is not metabolized by CYP enzymes and does not inhibit their activities. Rifampicin In eight healthy men intravenous rifampicin 600 mg reduced serum linezolid concentrations after a single intravenous dose of 600 mg; after 6 hours, the concentration was 90% of expected, after 9 hours, it was 80%, and after 12 hours, it was 65% [166c]. The authors suggested that this effect might be due to up-regulation of linezolid intestinal secretion. A similar reduction has been seen in a critically ill patient who was receiving linezolid and rifampicin [167A]. The effect of rifampicin on the steady-state pharmacokinetics of linezolid has also been evaluated in an open, multiple-dose, crossover study in 16 healthy subjects [168cE]. Rifampicin reduced the AUC of linezolid by 32% and the Cmax by 21%, but the tmax and apparent volume of distribution were unaffected. The apparent oral clearance was increased and the half-life shortened. Parallel studies in human hepatocytes showed that rifampicin increased the metabolism of linezolid by about 50% compared with a 19- to 40-fold increase in testosterone metabolism. These increases were about 50% inhibited by ketoconazole. Modelling of these data using Simcyp suggested that rifampicin-inducible drug metabolizing enzymes play a very minor role in linezolid clearance. Serotonin reuptake inhibitors Linezolid is a reversible inhibitor of monoamine oxidase and can cause drug–drug interactions when it is combined with monoamine oxidase inhibitors, monoamines such as adrenaline and noradrenaline, tyramine-containing foods, and other serotonergic agents. Several cases of serotonin syndrome have been reported

527

with co-administration of serotonin reuptake inhibitors, including venlafaxine [169A]. Linezolid associated serotonin syndrome has been reviewed. Combination with an SSRI increases the risk. Of 29 reports of serotonin syndrome in the FDA database, the most common co-medications were SSRIs, and in 17 published case reports of serotonin syndrome linezolid was combined with an SSRI. The time to onset was <24 hours to 3 weeks and the symptoms resolved at 1–5 days. In a retrospective chart review the incidence of serotonin toxicity in patients taking linezolid and SSRIs was 3%. No conclusions about incidence can be drawn from this small review, but the authors suggested that the combination of linezolid and an SSRI should be administered based on an analysis of the benefit to harm balance [170R]. In four other cases linezolid caused serotonin syndrome when it was combined with serotonergic drugs, such as SSRIs [171A, 172A, 173A], and in one case metoclopramide plus enteral administration of tryptophan-rich nutrition [174A]. Sympathomimetic drugs Reversible hypertension has been observed in patients taking linezolid with sympathomimetic drugs, such as pseudoephedrine and phenylpropanolamine [175c].

[SED-15, 2891; SEDA-31, 441; SEDA-32, 476]

POLYMYXINS Colistin

Urinary tract The nephrotoxicity of polymyxins has been reviewed and is the major limiting factor in their use [176R]. It has been speculated that the mechanism is the content of D-aminobutyric acid and fatty acids, which increase the permeability of tubular cells and cause edema, lysis, and tubular necrosis. Most studies have been observational, with limited patient numbers (up to 82) and mostly in patients in ICU given colistimethate

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sodium or polymyxin B. These reports show nephrotoxicity rates of 15–55%. There are higher prevalence rates in older patients, in patients with pre-existing renal insufficiency, and at higher doses. As other causes might have caused renal failure in patients in ICU, the rates of nephrotoxicity associated with the single polymyxins might be lower. Intravenous and nebulized colistin in the treatment of multidrug resistant Gram-negative infections have been analysed in two retrospective chart reviews of 115 and 121 treatments [177c, 178c]. There was nephrotoxicity in 8.3% and 14% respectively, and chronic renal insufficiency, diabetes mellitus, and aminoglycoside use were associated susceptibility factors. Four patients experienced neurotoxicity in one study. In a retrospective study of 66 active soldiers without previous renal replacement therapy receiving colistin mostly intravenously, 45% had some degree of renal dysfunction and 21% stopped treatment because of nephrotoxicity. The authors concluded that the probability of renal toxicity increases with cumulative dose and duration of treatment (a fourfold increase with treatment for more than 14 days) [179c]. In a retrospectively assessment of renal function before and after treatment with intravenous colistin for Acinetobacter infection in 54 mainly critically ill patients, there was a clinically significant increase in serum creatinine concentration in six patients, all of whom had normal renal function at baseline, but other causes of nephrotoxicity could not be ruled out; there were no differences in patients with pre-existing renal impairment [180c].

[SED-15, 3182; SEDA-28, 285; SEDA-30, 307; SEDA-31, 442]

STREPTOGRAMINS

Pristinamycin Immunologic Leukocytoclastic vasculitis has been reported in association with pristinamycin [181A].

Natascia Corti, Anne Taegtmeyer, and Alexander Imhof

SULFONAMIDES, TRIMETHOPRIM, AND CO-TRIMOXAZOLE [SED-15, 3216, 3510; SEDA-30, 308; SEDA-31, 442; SEDA-32, 477]

Sulfadiazine Observational studies The safety of topical silver sulfadiazine has been reviewed and the adverse effects of the silver and sulfadiazine components discussed [182R]. Allergic reactions with cross-sensitivity to antibiotic sulfonamides can occur, but there have been no reports of severe allergic reactions. Hemolytic anemia in G6PD-deficient patients can occur. Methemoglobinemia occurred in a 3-year-old child with burns and a dominant beta thalassemia trait treated with silver sulfadiazine. Urinary tract Bilateral flank pain and progressive oliguria developed over 3 weeks in a 47-year-old woman who took sulfadiazine for toxoplasmosis retinitis [183A]. Only in a second CT scan (an unenhanced helical scan with very low attenuation for stones) was urolithiasis detected; sulfonamide crystals were found in the urine.

Trimethoprim and co-trimoxazole Nervous system An 82-year-old man developed a higher level gait disorder and nocturnal delirium after taking co-trimoxazole (trimethoprim 800 mg þ sulfamethoxazole 160 mg bd) for 37 day; 3 days after cotrimoxazole withdrawal his gait returned to normal [184A]. Liver The treatment of Pneumocystis jirovecii pneumonia remains a challenge in HIV-infected individuals. The drug of choice in severe cases, co-trimoxazole, must be given in high doses for effective outcomes. Adverse effects such as hepatotoxicity, rash, anemia, thrombocytopenia, and neutropenia are therefore common and a hindrance to successful therapy. Two

Miscellaneous antibacterial drugs

Chapter 26

patients developed liver toxicity and focal lesions mimicking liver abscesses [185A]. Urinary tract Acute allograft dysfunction, with features of allergic acute interstitial nephritis, occurred in 11 renal transplant patients who were taking co-trimoxazole for prophylaxis of Pneumocystis pneumonia. All occurred within 1 month after transplantation, and renal function improved immediately after co-trimoxazole withdrawal [186A]. Skin Sweet's syndrome has been attributed to co-trimoxazole in two cases. A 67-yearold man with mesothelioma and an empyema developed tender erythematous nodules on his arms, hands, and face, with arthralgia after taking co-trimoxazole for 1 day; a skin biopsy showed neutrophilic infiltrates and the symptoms resolved 48 hours after withdrawal [187A]. A 7year-old boy developed diffuse painful papulonecrotic lesions after taking co-trimoxazole for a gastrointestinal infection; histology showed a neutrophilic infiltrate without vasculitis; systemic glucocorticoid and antibiotic therapy led to complete healing [188A]. Erythrodermic psoriasis, a severe disabling variant of psoriasis, which most commonly evolves from pre-existing chronic plaque-type psoriasis, has been associated with co-trimoxazole [189A]. Other reported skin reactions include a fixed drug eruption in a 47-year-old man [190A] and a case of Stevens–Johnson syndrome and toxic epidermal necrolysis [191A]. In a retrospective chart review of 50 patients with Stevens–Johnson syndrome and toxic epidermal necrolysis, co-trimoxazole was the most commonly implicated medication (26%); there was seasonal variation, with a significant increase in the number of cases during the spring [192A]. Immunologic A 23-year-old patient with lupus nephritis had recurrent fever, thrombocytopenia, anaphylaxis, and aseptic meningitis after taking co-trimoxazole for prophylaxis of Pneumocystis pneumonia [193A].

529

Drug–drug interactions Emtricitabine In rats trimethoprim reduced the renal clearance of emtricitabine by 60%, and increased emtricitabine plasma concentrations would be expected when these compounds are co-administered [194E]. Paliperidone There was no clinically significant pharmacokinetic interaction of co-trimoxazole, an inhibitor of organic cation transport, and paliperidone, which is an organic cation that is mainly eliminated by renal excretion; paliperidone did not affect steady-state plasma concentrations of trimethoprim [195c]. Prednisolone In 30 patients with P. jirovecii pneumonia, there was a higher incidence of hyperkalemia when co-trimoxazole was combined with prednisolone (in 7 of 18 patients) compared with co-trimoxazole alone (none of 12 patients). Although the authors concluded that hyperkalemia is more likely when co-trimoxazole is combined with prednisolone, the data have to be interpreted with caution, because of the small number of patients studied and the observational design of the study [196c]. Warfarin In 22 of 40 chronically anticoagulated patients taking either co-trimoxazole or levofloxacin the INR rose significantly after 5 days, leading to transient interruption of warfarin therapy in 12 patients [197c]. The effect was more pronounced in those who took co-trimoxazole. In 18 patients in whom the dosage of warfarin was pre-emptively reduced the INR did not change significantly.

OTHER ANTIMICROBIAL DRUGS Daptomycin

[SED-15, 1053; SEDA-30, 309; SEDA-31, 446; SEDA-32, 478]

Respiratory After a 14-day course of daptomycin for methicillin-resistant S. aureus a 54-year-old man developed a fever and

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dry cough. He had a raised white blood cell count and an eosinophilia [198A]. A CT scan showed patchy infiltrates and peripheral opacities. Over the next 24 hours he developed respiratory failure and needed intubation. A lung biopsy showed a diffuse eosinophilic pneumonia. Daptomycin was withdrawn and he was given a tapering dose of a glucocorticoid. He recovered fully within a few days, with complete resolution of the radiographic findings within 4 weeks. Musculoskeletal Rhabdomyolysis and acute renal failure have been associated with daptomycin 7.2 mg/kg/day in a patient taking simvastatin 80 mg/day [199A]. After 16 days creatine kinase activity rose to 8995 IU/l and there was weakness and diffuse aching in the forearms, with deterioration of renal function. Daptomycin was switched to linezolid and ciprofloxacin and the creatine kinase activity normalized. Drug dosage regimens The pharmacokinetics of daptomycin 4 or 6 mg/kg intravenously as a 2-minute injection were comparable to those after a 30-minute infusion [200c]. The adverse effects of high-dose daptomycin (mean 8, range 7–11, mg/kg) have been assessed in a retrospective chart review in patients receiving long-term treatment (mean 14, range 14–82 days) for complicated and

Natascia Corti, Anne Taegtmeyer, and Alexander Imhof

uncomplicated bloodstream infection, leftsided infective endocarditis, complicated skin and soft-tissue infections, bone and/or joint infections, intra-abdominal infections, or febrile neutropenia with Gram-positive organisms [201c]. Of 61 patients, six had symptomatic rises in creatine kinase activity, which resolved after daptomycin withdrawal. There were no serious adverse events. In a retrospective multicenter study of daptomycin in doses up to 6 mg/kg (n ¼ 188) or over 6 mg/kg (n ¼ 139). 10% in both groups had adverse reactions that were possibly related to daptomycin; 15 had increased creatine kinase activity and two had rhabdomyolysis, both of whom had normal renal function and were receiving 4 mg/kg/day [202c].

Fusidic acid

[SED-15, 1460;

SEDA-32, 479] Skin A 22-year-old woman without a history of drug allergy developed generalized pruritus with urticaria on the hands, trunk, and neck after using oral and topical fusidic acid for 10 days [203A]. Her symptoms resolved after glucocorticoid treatment. The urticaria later recurred after oral provocation with fusidic acid, although skin tests had been negative.

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inhibitor. J Antimicrob Chemother 2009; 63(6): 1299–300. Chakraborty A, Roy S, Loeffler J, Chaves RL. Comparison of the pharmacokinetics, safety and tolerability of daptomycin in healthy adult volunteers following intravenous administration by 30 min infusion or 2 min injection. J Antimicrob Chemother 2009; 64(1): 151–8. Figueroa DA, Mangini E, AmodioGroton M, Vardianos B, Melchert A, Fana C, Wehbeh W, Urban CM, SegalMaurer S. Safety of high-dose intravenous daptomycin treatment: three-year cumulative experience in a clinical program. Clin Infect Dis 2009; 49(2): 177–80. Crompton JA, North DS, McConnell SA, Lamp KC. Safety and efficacy of daptomycin in the treatment of osteomyelitis: results from the CORE Registry. J Chemother 2009; 21(4): 414–20. Bobadilla-González P, García-Menaya JM, Cordobés-Durán C, Pérez-Rangel I, Sánchez-Vega S. Generalized urticaria to fusidic acid. Allergy 2009; 64(5): 817–8.

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27 [SEDA-30, 316; SEDA-31, 457; SEDA-32, 491]

ALLYLAMINES

Terbinafine [SED-15, 3316; SEDA-30, 316; SEDA-31, 457; SEDA-32, 491] Nervous system Bilateral anterior optic neuropathy has been reported in an otherwise healthy 43-year-old man who took terbinafine 500 mg/day for onychomycosis [1A]. Terbinafine was withdrawn and his visual acuity improved considerably within 1 month, but there was slight pallor of the left optic disc and the visual fields of both eyes were still concentrically constricted. One plausible explanation for this effect of terbinafine may be that it is amphiphilic, which may allow binding to polar lipids and accumulation within lysosomes. Druginduced lysosomal impairment has been presumed to be the basis of the retinal changes observed with other amphiphilic drugs, such as amiodarone, perhexilene, and suramin. Skin In a retrospective cohort study of terbinafine 250 mg/day for cutaneous sporotrichosis in 50 patients in whom itraconazole was contraindicated or resulted in severe or moderate pharmacological interactions, 47 had co-morbidities—high blood pressure (30), diabetes mellitus (14), dyslipidemia (8), depression (5), and migraine, Parkinson's disease, peptic ulcer disease, heart Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00027-1 # 2011 Elsevier B.V. All rights reserved.

Antifungal drugs failure, and dysrhythmias (one each) [2c]. Terbinafine was withdrawn because of a rash in one patient. There were no recurrences of the mycosis during a mean follow-up period of 37 weeks. A further case of acute generalized exanthematous pustulosis associated with oral terbinafine has been reported; it was refractory to oral glucocorticoids but responsive to high-dose intravenous glucocorticoids [3A]. Terbinafine has been associated with a cutaneous lupus-like syndrome [4A]. Susceptibility factors Children A new pediatric formulation of terbinafine hydrochloride oral granules 5–8 mg/kg/day (n ¼ 1040) has been compared with griseofulvin oral suspension 10–20 mg/kg/day (n ¼ 509) for 6 weeks in the treatment of tinea capitis in children aged 4–12 years [5c]. Rates of complete cure and mycological cure were significantly higher with terbinafine (45% versus 39% and 62% versus 56% respectively). About half of the patients in each group reported an adverse event, almost all mild or moderate in intensity. Nasopharyngitis, headache, and pyrexia were the most common events in both groups. There were no drug-related serious adverse events, no deaths, and no significant effects on weight or laboratory measurements, including aminotransferases. Drug–drug interactions Acenocoumarol A possible interaction of topical terbinafine with acenocoumarol has been reported in a 71-year-old man who took acenocoumarol 13 mg/week for atrial fibrillation and used topical terbinafine 1% spray solution once daily for seborrheic dermatitis [6A]. 541

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Other medications included diltiazem 60 mg bd, lansoprazole 30 mg bd, atorvastatin 20 mg/day, and metformin 850 mg tds. The international normalized ratio (INR) had been 2.0–3.0, but after using terbinafine for 15 days his INR rose to greater than 8. Acenocoumarol and terbinafine were stopped and he was given a single dose of phytonadione 10 mg and then bemiparin 5000 IU/ day. After 6 days, acenocoumarol 13 mg/ week was reintroduced and therapy was stable thereafter. Topical terbinafine could have displaced acenocoumarol from plasma protein-binding sites. Alternatively, although acenocoumarol is mainly metabolized by CYP2C9, other isoenzymes could also be involved; terbinafine is a potent competitive inhibitor of CYP2D6. Finally, terbinafine could have inhibited the clearance of diltiazem, which is metabolized by CYP2D6 and itself inhibits CYP3A4, by which acenocoumarol is weakly metabolized.

[SED-15, 192; SEDA-30, 317; SEDA-31, 458; SEDA32, 493]

AMPHOTERICIN

Amphotericin B colloidal dispersion (ABCD) Observational studies In clinical trials, in the absence of premedication, the rates of infusion-related reactions have been higher with amphotericin B colloidal dispersion (ABCD) than with other forms of amphotericin B, including amphotericin B deoxycholate [7R]. Data on pre-medication practices and infusion-related reactions in 170 patients (median age 37 years; 52% men) who received 1230 infusions of ABCD (mean dose 2.8 mg/kg/day) have been captured in a multicenter, worldwide, observational registry [8c]. Treatment was according to the site's standard treatment practice. Common pre-medications included glucocorticoids, antihistamines, paracetamol (acetaminophen), and metamizole. The overall rate of infusion-related reactions

was 12% (147/1230) and was lower in infusions with premedication (11%) versus no premedication (22%); glucocorticoids were also associated with a lower incidence, but paracetamol and antihistamines were not. The most common infusion-related reactions were chills (7%), fever (7%), and rigors (5%).

Amphotericin B deoxycholate (DAMB) Comparative studies Amphotericin B deoxycholate (DAMB) is still a cornerstone in the treatment of cryptococcal meningoencephalitis, alone or in combination with flucytosine or fluconazole. In a randomized comparison, 64 HIV-positive, antiretroviral therapy-naive patients in Cape Town, with a first episode of cryptococcal meningitis, received either DAMB 0.7 mg/kg/day plus flucytosine 25 mg/kg qds (n ¼ 30), or DAMB 1 mg/kg/day plus flucytosine 25 mg/kg qds (n ¼ 34) [9C]. Regimens were given for 2 weeks, followed by oral fluconazole. The frequency of renal impairment did not differ between the groups. Anemia was associated with female sex and less strongly with the higher dose of DAMB. Renal impairment and anemia reversed after the regimen was switched to fluconazole. Two- and 10-week mortality rates were 6% and 24% respectively, with no difference between the groups. All the adverse reactions were manageable and reversible. In a randomized, open, phase II trial in Thailand and the USA, DAMB 0.7 mg/kg/ day (standard therapy) was compared with DAMB 0.7 mg/kg/day plus fluconazole 400 mg/day (low-dosage combination therapy), or DAMB 0.7 mg/kg/day plus fluconazole 800 mg/day (high-dosage combination therapy) in 143 HIV-positive patients [10c]. All regimens were given daily for 14 days, followed by fluconazole alone in the randomized dosage (400 or 800 mg/day) for 56 days. There were no differences in treatment-related adverse events among the three arms. Adverse effects were predictable and most often related to DAMB; they

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included electrolyte abnormalities, anemia, nephrotoxicity, and infusion-related events.

creatinine, blood urea nitrogen, sodium, or potassium [12c].

Susceptibility factors Neonates The nephrotoxicity of DAMB in neonates has not been well defined. In a retrospective, single-center, cohort study, the medical records of 92 infants aged up to 90 days, admitted to the neonatal intensive care unit, who received at least three doses of DAMB between January 1990 and December 2004 were reviewed [11c]. Nephrotoxicity was defined as a rise in serum creatinine of at least 35 mmol/l any time during DAMB therapy. Median gestational age of the infants was 26 (range 23–41) weeks and median birth weight was 863 (range 546–4000) g. Overall, 15 infants had nephrotoxicity, and 16 developed hypokalemia (below 3.0 mmol/l). Gestational age, birth weight, sex, underlying medical conditions, or the use of other potentially nephrotoxic medications all had no apparent effect on the risk of nephrotoxicity. DAMB exposure and duration of therapy were similar between the infants who developed nephrotoxicity and those who did not, with a mean cumulative dose of 14 mg/kg and a mean duration of 16 days. With the exception of one infant, the raised creatinine concentrations resolved in all infants by the end of DAMB therapy. The authors concluded that DAMB does not appear to be associated with lasting nephrotoxicity in neonates, although renal function and potassium concentrations should be monitored closely during therapy.

Drug administration route Aerosol In a retrospective analysis of 60 patients with lung transplants, who were given aerosolized ABLC 50 mg postoperatively for prophylaxis once every 2 days for 2 weeks and then once a week for at least 13 weeks, only one patient developed a possible invasive fungal infection due to Aspergillus fumigatus; four had nausea and vomiting, but aerosolized amphotericin was not discontinued [13c].

Amphotericin B Lipid Complex (ABLC) Susceptibility factors Neonates In a retrospective, single-center, case–control study in 35 infants of very low birth weights (mean 764 g) who received ABLC for at least 2 weeks, and 35 controls matched by gestational age (mean 26 weeks), ABLC had no significant adverse effects on serum

Management of adverse reactions Administration of amphotericin B lipid complex (ABLC) may be associated with infusion-related reactions, such as fever, rigors, and chills. Premedication with hydrocortisone may reduce the incidence of these reactions, but there are currently limited confirmatory data from clinical practice [7R]. In a prospective 18-month study, patients with cancers were given intravenous hydrocortisone 100 mg 15–30 minutes before each infusion of ABLC (275 cycles; mean dose per cycle 931 mg) [14c]. There were 44 infusionrelated reactions (16%), most of which followed the first infusion of a cycle (15%; subsequent infusions 2.9%). The most common reactions were rigors (15%) and fever (13). There was no significant difference in the rates or types of reactions between ABLC-naïve and previously treated patients. The dose of ABLC had no effect on the rate of reactions, but female sex, neutropenia, and being younger were predictive.

Liposomal Amphotericin (L-AmB) Observational studies In a retrospective, multicenter study of the use of LAMB in 179 patients admitted to 30 Spanish intensive Care Units, in which invasive fungal infections were proven, probable, and

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possible in 44%, 16%, and 25% of cases respectively, the mean duration of treatment was 15 days and the mean dose was 3.7 mg/kg/day [15c]. LAMB was used as rescue treatment in 47% of patients and as first line in 52%, with a satisfactory clinical response in 54% of all cases. There were adverse events in 51 patients, but they were severe in only four. In a retrospective study in 84 children and adolescents (median age 11 years) who received 141 consecutive courses of LAMB for prophylaxis (n ¼ 32), empirical therapy (83), and possible (19) or probable/proven (7) invasive infections, LAMB was given until intolerance or maximum efficacy at dosages individually determined by the responsible physician [16c]. The median duration of therapy was 13 (range 1–79) days and the median maximum dosage was 2.8 (range 0.9–5.1) mg/kg. There were mild to moderate adverse events during 109 courses (total 77%; hepatic 59%; electrolyte loss 53%; renal 32%; infusionrelated reactions 8.5%). There were adverse events that necessitated withdrawal of LAMB in six courses (three renal, two anaphylaxis, one hepatic). While median hepatic aminotransferase and alkaline phosphatase activities and blood urea nitrogen concentrations were slightly higher at the end of treatment, bilirubin and creatinine were not different from baseline. Comparative studies In a substudy of a double-blind, randomized, multinational comparison of LAMB 3 mg/kg and micafungin 2 mg/kg as first-line treatment of invasive candidiasis in 98 children, 57 were under 2 years old, including 19 who were premature at birth, and 41 were aged 2–16 years; 91 of them had candidemia and seven had other forms of invasive candidiasis [17c]. There was a higher incidence of adverse events leading to withdrawal in those who received LAMB (9/54, 17%) compared with those who received micafungin (2/52, 3.8%). Electrolyte balance Hyperkalemia occurred in a 36-year-old man with acute myeloid leukemia who was given LAMB 5 mg/ kg/day for an infection with Absidia

corymbifera during voriconazole and caspofungin therapy for invasive pulmonary aspergillosis [18A]. There were four episodes of hyperkalemia on days 9, 10, 11, and 24, and the last episode was characterized by severe, refractory hyperkalemia and fatal cardiac arrest. Renal function was normal and there were no signs of rhabdomyolysis, hemolysis, or acidosis; a medication error could not be identified. However, he was being given concomitant drugs that can cause hyperkalemia, including ciclosporin, mycophenolate mofetil, propofol, nadroparin, and co-trimoxazole, and the most likely mechanism was an interaction with one or more of these drugs. Urinary tract Urinary tract in a post-hoc analysis of a phase III trial of LAMB (3 mg/kg/day) versus micafungin (100 mg/ day for subjects over 40 kg; 2 mg/kg/day for subjects weighing 40 kg or less), renal function was significantly worse in those who were given LAMB [19c]. The difference in mean peak change in eGFR was 18 ml/ minute/1.73 m2. Multivariate regression after controlling for potential confounding factors suggested that the APACHE II score was a potential explanatory factor associated with treatment success, mortality at day 8, and mortality at day 30. Although nephrogenic diabetes insipidus and renal tubular acidosis are known adverse effects of conventional amphotericin, nephrogenic diabetes insipidus has been uncommonly associated with liposomal amphotericin. An 18-year-old woman with invasive aspergillosis and aplastic anemia developed nephrogenic diabetes insipidus while receiving high-dose liposomal amphotericin 10 mg/kg/day; the symptoms resolved after withdrawal, but recurred after rechallenge with 5 mg/kg/day, and she was successfully treated with diuretics [20A]. Drug administration route Aerosol The effects of aerosolized LAMB on pulmonary function have been recorded in a placebocontrolled trial in the prevention of invasive pulmonary aspergillosis in 77 patients with chemotherapy-induced neutropenia; 38 (41 episodes) received LAMB and 39

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(49 episodes) received placebo [21C]. There were no differences in the proportions of patients with a greater than 20% fall in FEV1 or forced vital capacity between the groups and most patients (26/38 and 31/ 39) had no significant changes during the entire treatment period. However, cough was significantly more common in those who received LAMB. There were no differences between baseline and post-nebulization renal function and hepatic enzymes. The steady-state concentrations of amphotericin in the respiratory tract and serum after inhalation of LAMB and its effects on respiratory function have been assessed after 32 consecutive bronchoscopies in 27 lung transplant patients [22c]. At 2 days, mean amphotericin concentrations were 11 mg/l (95% CI ¼ 17, 5.7) and 9.0 mg/l (95% CI ¼ 14, 3.8), and at 14 days 3.0 mg/l (95% CI ¼ 4.4, 1.5) and 4.1 mg/l (95% CI ¼ 6.1, 2.1) in the first and third aliquots of the bronchoalveolar lavage fluid respectively. There were traces of amphotericin (0.1 mg/l) in serum samples from only one patient. Mean FEV1 was similar before and after LAMB.

ANTIFUNGAL AZOLES [SED-15, 301; SEDA-30, 320; SEDA-31, 459; SEDA-32, 497] For metronidazole see Chapter 28

Drug–drug interactions with antifungal azoles Aliskiren In an open, multiple-dose study in healthy subjects of the pharmacokinetic interaction of aliskiren 300 mg and ketoconazole 200 mg bed (n ¼ 21), aliskiren AUCt was significantly increased by ketoconazole (by 76%) through mechanisms that most probably involved transporters such as P glycoprotein and organic aniontransporting peptide and possibly through

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metabolic pathways such as CYP3A4 in the gut wall [23c]. All-trans retinoic acid Hyperkalemia due to an interaction of all-trans retinoic acid (ATRA) and itraconazole has been reported [24A]. • A 38-year-old man with acute promyelocytic leukemia who was taking itraconazole 200 mg bd was given all-trans retinoic acid and during the third course of maintenance therapy developed acute renal insufficiency and symptomatic hypercalcemia, which was treated with highvolume crystalloid infusions and furosemide. Renal function was restored, and the serum calcium concentration returned to normal within 4 days after withdrawal of ATRA. The peak serum calcium concentration was 3.67 mmol/l. Serum parathyroid hormone was undetectable, and there were no increases in the concentrations of prostaglandins or vitamin D metabolites. Hypercalcemia recurred during a fourth course of ATRA.

The most important pathways of ATRA metabolism involve CYP2C9 and CYP3A4 and inhibition of ATRA-metabolizing enzymes induces hypercalcemia, as reported with inhibitors of CYP2C9, CYP2C19, and CYP3A4, such as itraconazole is a potent CYP3A4 inhibitor. Antiretroviral drugs (see also individual agents) In a retrospective cohort study of serum itraconazole concentrations in 10 HIV-positive patients with disseminated histoplasmosis taking antiretroviral drugs (non-nucleoside reverse transcriptase inhibitors, NNRTIs, or protease inhibitors) [25c]. Six itraconazole concentration measurements during concomitant treatment with a protease inhibitor were in the target range in contrast with none in those who were taking an NNRTI, all of whom had undetectable serum itraconazole concentrations. Two patients switched from NNRTI-based to protease inhibitor-based regimens and subsequently reached therapeutic itraconazole concentrations. Although the sample size was small, this study has shown that co-administration of an NNRTI and itraconazole results in a significant reduction in itraconazole concentrations, probably by induction of CYP3A4.

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Atazanavir In a phase 1, open, randomized, crossover study in healthy volunteers of co-administration of posaconazole 400 mg bd with atazanavir 300 mg/day, alone and with either ritonavir 100 mg/day or efavirenz 400 mg/day, posaconazole increased the Cmax of atazanavir by 2.6 times and the AUC by 3.7 times [26c]. Posaconazole increased the Cmax and AUC of atazanavir when it was given with ritonavir by 1.5 and 2.5 times respectively. Most of those who took atazanavir with or without ritonavir plus posaconazole had clinically relevant increases in total bilirubin. Coadministration of posaconazole and efavirenz resulted in clinically relevant reductions of posaconazole Cmax and AUC by about 45% and 50% respectively. As a result, frequent monitoring of adverse events is recommended when posaconazole and atazanavir are co-administered with or without ritonavir. Because of reduced posaconazole exposure, co-administration with efavirenz should be avoided if possible. Bortezomib The effect of concomitant administration of ketoconazole on the pharmacokinetics and pharmacodynamics of bortezomib has been investigated in a prospective, multicenter, open, randomized, multiple-dose, two-way, crossover study in 12 patients (median age 57 years; 14 men) with advanced solid tumors. All received intravenous bortezomib 1.0 mg/m2 on days 1, 4, 8, and 11 of two 21-day cycles and were randomized to concomitant ketoconazole 400 mg on days 6, 7, 8, and 9 of cycle 1 or 2 [27c]. Ketoconazole increased exposure to bortezomib by 35% and was associated with a corresponding increase of 24–46% in the blood proteasome inhibitory effect. Calcineurin inhibitors See also individual names. The interaction of oral itraconazole in solution and calcineurin inhibitors (ciclosporin or tacrolimus) has been retrospectively studied in 10 recipients of allogeneic hemopoietic stem cell transplants [28c]. Itraconazole significantly increased the dose-corrected blood concentrations of the

calcineurin inhibitors by 94% (range 37–328%) at 7–10 days. The plasma concentration ratio of itraconazole/hydroxyitraconazole correlated significantly with the increase in the dose-corrected blood concentrations of the calcineurin inhibitors. The wide interindividual variability in the degree of interaction may in part be explained by the variable systemic availability of itraconazole in oral solution. Chloramphenicol Inhibition of voriconazole metabolism by chloramphenicol has been reported in an adolescent with bacterial meningitis and subsequent central nervous system aspergillosis [29A]. Intravenous voriconazole dosage requirements fell substantially during co-administration of intravenous chloramphenicol and rose considerably after its withdrawal. In agreement with in vitro evidence, these data suggest that chloramphenicol inhibits hepatic CYP3A4 and/or CYP2C19. Citalopram Citalopram is a substrate of CYP2C19, and inhibition of its metabolism by fluconazole can result in serotonin syndrome, as occurred in two patients, who developed prolonged delirium without tremor, myoclonus, rigidity, or autonomic instability [30A]. Serotonin toxicity in patients with cancers may not present with the classic constellation of signs and symptoms and delirium may be the only presenting feature. Darunavir The interaction of ketoconazole with darunavir alone and in combination with low-dose ritonavir has been investigated in HIV-negative volunteers, who took ketoconazole 200 mg bd, darunavir 400 mg bd, darunavir 400 mg bd plus ketoconazole 200 mg bd, darunavir þ ritonavir 400/ 100 mg bd, or darunavir þ ritonavir 400/ 100 mg bd plus ketoconazole 200 mg bd; all the treatments were taken with food for 6 days [31c]. Ketoconazole increased the AUC0!12h, Cmax, and Cmin of darunavir by 155% (80, 261), 78% (28, 147), and 179% (58, 393) respectively. Darunavir AUC0!12h,

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Cmax, and Cmin increased by 42% (23, 65), 21% (4, 40), and 73% (39, 114) respectively during darunavir þ ritonavir and ketoconazole co-administration. Ketoconazole pharmacokinetics were unchanged by coadministration of darunavir alone. Ketoconazole AUC0!12h, Cmax, and Cmin increased by 212% (165, 268), 111% (81, 144), and 868% (544, 1355) respectively during co-administration of darunavir þ ritonavir. The increase in darunavir exposure by ketoconazole was lower than that observed previously with ritonavir. A maximum ketoconazole dose of 200 mg/day is recommended if it is used concomitantly with darunavir þ ritonavir, and no dose adjustments of darunavir þ ritonavir is required. Ebastine In a study of the effects of itraconazole on the pharmacokinetics and pharmacodynamics of ebastine in a crossover sequential design with 2-week washout periods in 10 healthy participants, itraconazole pretreatment reduced the oral clearance of ebastine to 10% and increased the AUC of its active metabolite, carebastine, threefold [32c]. Efavirenz Voriconazole is not recommended for use in combination with efavirenz; however, when they are coadministered, the dosage of voriconazole should be increased to 400 mg 12-hourly and the dosage of efavirenz reduced to 300 mg/day, in order to provide systemic exposures similar to standard-dose monotherapy [SEDA-32, 498]. The combination of voriconazole and efavirenz in doses adjusted according to steady-state plasma concentration monitoring has been studied in a 40-year-old man with AIDS, cryptococcosis, and mild liver cirrhosis [33A]. Adequate concentrations of voriconazole in both plasma and cerebrospinal fluid were obtained and target plasma concentrations of efavirenz were achieved at the final dosage adjustment (oral voriconazole 200 mg bd plus oral efavirenz 300 mg/day). There was stable suppression of cryptococcosis and plasma HIV viremia at long-term follow-up (66 weeks), with no significant adverse events.

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Etoricoxib The effect of oral voriconazole (400 mg bd on day 1 and 200 mg bd on day 2) on the pharmacokinetics of a single dose of etoricoxib 60 mg has been studied in 12 healthy volunteers [34c]. Etoricoxib AUC and Cmax were increased by 49% (90% CI ¼ 37%, 61%) and 19% (90% CI ¼ 8%, 31%) respectively, presumably by inhibition of CYP3A. Everolimus The management of a pharmacokinetic interaction of voriconazole with everolimus has been described in a 65-yearold man who underwent orthotopic liver transplantation complicated by intestinal perforation, sepsis, and acute renal insufficiency [35A]. He received intravenous fluconazole 400 mg, followed by 100 mg/day and oral everolimus 0.75 mg bd; the steady-state Cmin of everolimus was satisfactory. On day 72 after transplantation, because of invasive aspergillosis, antifungal therapy was switched to intravenous voriconazole 400 mg bd on the first day followed by 200 mg bd; to prevent drug toxicity the dosage of everolimus was promptly lowered to 0.25 mg/day. The dose-corrected Cmin of everolimus at steady-state was markedly lower during fluconazole versus voriconazole co-treatment (mean 3.5 versus 11 mg/l per mg/kg/day). During everolimus þ azole co-treatment, everolimus dosage reduction is needed to avoid overexposure. Because of different CYP3A4 inhibitory potencies, the reduction should be greater during cotreatment with voriconazole than with fluconazole. Halofantrine The effect of fluconazole 50 mg on the pharmacokinetics of a single 500-mg oral dose of halofantrine, which is mainly metabolized by CYP3A4 to the active metabolite N-desbutylhalofantrine, has been evaluated in 15 healthy volunteers in a Latin square crossover design [36C]. Co-administration of fluconazole did not alter the pharmacokinetics of halofantrine, but significantly altered the pharmacokinetics of its active metabolite, reducing Cmax, AUC, and the ratio of N-desbutylhalofantrine to halofantrine by 35–41% and increasing the tmax by 50%. Although the therapeutic consequences of this

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interaction are not clear caution should be taken during co-administration to avoid accumulation and subsequent cardiotoxic effects of halofantrine, particularly if higher doses of fluconazole are used. Lopinavir þ ritonavir Itraconazole had no effect on the lopinavir trough concentration during co-administration with lopinavir þ ritonavir in a 34-year-old HIV-positive man with histoplasmosis [37A]. Meloxicam The effects of voriconazole on the pharmacokinetics and pharmacodynamics of meloxicam 15 mg have been investigated in 12 healthy volunteers in a crossover study [38c]. The plasma concentrations of meloxicam and voriconazole and thromboxane B2 generation were monitored. Voriconazole increased the mean AUC0!72 h of meloxicam by 47% and prolonged its mean half-life by 51%, without affecting its Cmax. Plasma protein binding of meloxicam was unchanged by voriconazole. Reduced plasma meloxicam concentrations during co-administration of itraconazole phase were associated with reduced pharmacodynamic effects of meloxicam, as reflected in weaker inhibition of thromboxane B2 generation. The mechanism was thought to be impaired absorption of meloxicam. Methadone Itraconazole-induced torsade de pointes have been reported in a heroindependent woman taking methadone substitution therapy who was given itraconazole for vaginal thrush [39A]. She developed chest discomfort and had an episode of syncope after taking two doses of itraconazole 200 mg. Electrocardiography showed a prolonged QTc interval leading to torsade de pointes. The electrocardiogram returned to normal after withdrawal of methadone. This cardiac dysrhythmia was thought to have resulted from an interaction of methadone with itraconazole. Midazolam Midazolam is metabolized by CYP3A4. In a phase I, randomized, open, crossover study, 12 healthy volunteers

(mean age 43 years; mean weight 81 kg; mean body mass index 26 kg/m2; 11 men) were randomized to one of two regimens: posaconazole 200 mg bd for 7 days, posaconazole 400 mg bd for 7 days, no drugs during a 28-day washout, and ketoconazole 400 mg/day for 7 days; or posaconazole and ketoconazole in the reverse order [40c]. Oral midazolam 2 mg and intravenous midazolam 0.4 mg were given on consecutive days before the first phase and at the end of each phase thereafter. Posaconazole 200 and 400 mg bd were associated with significant increases in midazolam Cmax (up to 1.3 and 2.4 times respectively) and AUC (up to 4.6 and 6.2 times respectively). Ketoconazole 400 mg/day was associated with significantly increased midazolam Cmax and AUC (up to 2.8 and 8.2 times respectively). Posaconazole prolonged the half-life of midazolam. Seven subjects reported at least one adverse event during the study (five with posaconazole alone and four with posaconazole þ midazolam). The most common adverse events were diarrhea (n ¼ 3 with posaconazole alone, n ¼ 2 with ketoconazole alone, and n ¼ 1 with posaconazole þ midazolam) and flatulence (n ¼ 1 with posaconazole alone and n ¼ 1 with midazolam alone).

Morphine In a randomized, placebocontrolled, crossover study of the effect of itraconazole, a potent inhibitor of P-glycoprotein and CYP3A4, on the pharmacokinetics and pharmacodynamics of oral morphine, 12 healthy men took itraconazole 200 mg/day for 4 days and then morphine 0.3 mg/kg [41C]. Itraconazole increased the mean AUC0!9 h of morphine by 29%, the AUC0!48 h by 22%, and the Cmax by 28%. Itraconazole did not significantly affect the pharmacokinetics of morphine-3-glucuronide or morphine-6-glucuronide or the pharmacodynamics of morphine. Thus, itraconazole moderately increases plasma concentrations of oral morphine, probably by enhancing its absorption by inhibiting intestinal wall P-glycoprotein.

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Nevirapine In a substudy within a large double-blind, randomized, placebo-controlled study of the use of fluconazole 200 mg three times per week in primary prophylaxis of cryptococcal disease in HIVinfected adults in rural south-western Uganda, fluconazole increased the nevirapine AUC0!8h by 29% [42c]. In the larger cohort from which the participants were drawn, co-administration of fluconazole did not increase the risk of hepatotoxicity, despite increased exposure to nevirapine. Nifedipine Hypotension due to an interaction of voriconazole with eplerenone and nifedipine has been reported [43A]. • A 48-year-old man with myelodysplastic syndrome and a bone marrow transplant took ciclosporin and methylprednisolone for acute graft-versus-host disease while taking candesartan 8 mg/day, nifedipine 40 mg/day, and eplerenone 50 mg/day for hypertension, and his blood pressure was maintained at 130–146/ 70–88 mmHg. Intravenous voriconazole was added for prophylaxis of fungal infections in a maintenance dosage of 4 mg/kg 12-hourly. His blood pressure fell to 76/48 mmHg. There was no evidence of hypovolemia, acute blood loss, or septicemia. Candesartan, nifedipine, and eplerenone were withdrawn and his blood pressure rose to 116–124/64–80 mmHg after 1 day and to 164–180/80–84 mmHg 5 days later. Candesartan and nifedipine were started again, the dosage of nifedipine was reduced to 20 mg/ day, and eplerenone was no longer needed.

As both nifedipine and eplerenone are metabolized by CYP3A4, inhibition of the metabolism of both agents by voriconazole is plausible. Omeprazole Omeprazole 40 mg/day significantly reduced posaconazole serum trough concentrations in a 58-year-old man with invasive aspergillosis, and when it was withdrawn the serum trough concentration of posaconazole returned to baseline [44A]. Omeprazole probably suppressed gastric acid production, causing reduced systemic availability of posaconazole. Oxycodone The effect of voriconazole for 4 days on the pharmacokinetics and pharmacodynamics of a single dose of oxycodone

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10 mg have been investigated in a randomized, placebo-controlled, crossover study in 12 healthy subjects [45C]. Voriconazole increased the AUC of oxycodone 3.6 times (range 2.7–5.6) and the Cmax 1.7 times, and prolonged the half-life two fold. The AUC ratio of noroxycodone to oxycodone was reduced by 92% and that of oxymorphone increased by 108%. The pharmacodynamic effects of oxycodone were modestly increased by voriconazole. Thus, voriconazole markedly increased exposure to oral oxycodone by inhibiting CYP3A-mediated N-demethylation. Lower doses of oxycodone may be needed during voriconazole treatment to avoid opioid-related adverse effects. Sirolimus The effect of posaconazole 400 mg bd on the pharmacokinetics of a single 2-mg dose of sirolimus, a substrate of CYP3A4, has been investigated in an open, multiperiod study in 12 healthy subjects [46c]. Posaconazole increased sirolimus Cmax and AUC by 6.7 and 8.9 times respectively, consistent with inhibition of CYP3A4 by posaconazole. These two agents should probably not be coadministered. Tacrolimus The co-prescription of posaconazole with tacrolimus has been evaluated in 14 lung transplant recipients with cystic fibrosis. Posaconazole inhibited CYP3A4mediated tacrolimus metabolism, resulting in a threefold reduction in tacrolimus dosage requirements [47c]. The effects of single nucleotide polymorphisms (SNPs) in CYP3A4, CYP3A5, and MDR1 on interactions of tacrolimus with fluconazole have been examined in 29 renal allograft recipients, who were genotyped for CYP3A4*1/*1B, CYP3A5*1/*3, MDR1 C3435T, and G2677T/A [48c]. Dose-corrected trough blood tacrolimus concentrations did not change significantly from baseline in heterozygous CYP3A5*1 carriers during exposure to fluconazole, in contrast to homozygous CYP3A5*3 carriers, in whom there was a 3.3-fold increase. Homozygous CYP3A5*3 carriers had a significant reduction in weight-corrected tacrolimus dosage requirements during

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fluconazole administration, in contrast to heterozygous carriers of CYP3A5*1. These effects were not influenced by fluconazole dose or duration of administration. Significantly more CYP3A5*3/*3 carriers were exposed to tacrolimus dose-uncorrected trough blood tacrolimus concentrations of at least 15 mg/l during administration of fluconazole compared with CYP3A5*3/*1 carriers. Thus, in renal allograft recipients, the CYP3A5*3/*1 genotype is associated with reduced susceptibility for the inhibitory effects of fluconazole on tacrolimus metabolism, thereby identifying a genetic determinant of the clinical variability of CYP3A-mediated drug interactions. Tilidine The effect of voriconazole 400 mg on the pharmacokinetics and analgesic effects of tilidine 100 mg have been investigated in 16 healthy volunteers in a placebocontrolled study [49C]. Voriconazole caused a 20-fold increase in the serum AUC of tilidine and the AUC of nortilidine increased 2.5-fold; the serum concentrations of bisnortilidine were much reduced. The onset of analgesic activity occurred later with voriconazole, concordant with the prolonged tmax of nortilidine from 0.78 to 2.5 hours, due to additional inhibition of nortilidine metabolism to bisnortilidine. After voriconazole the AUC under the pain withdrawal versus time curve was reduced compared, mainly because of a shorter withdrawal time. Thus, voriconazole significantly inhibited the sequential metabolism of tilidine, with increased exposure to the active metabolite, nortilidine. Furthermore, the incidence of adverse events was almost doubled after voriconazole and tilidine. Tipranavir þ ritonavir In a controlled, two-period study in 20 healthy volunteers who took tipranavir þ ritonavir 500/ 200 mg, fluconazole 100 mg increased the AUC of tipranavir by 50% [50c]. However, the authors concluded that no dosage adjustments are necessary when tipranavir þ ritonavir is combined with fluconazole.

Vincristine Vincristine-associated neurotoxicity has been reported in association with posaconazole co-administration in a 9-yearold girl with acute lymphoblastic leukemia [51A]. Six days after the last dose of vincristine, she reported symptoms of severe peripheral neuropathy, abdominal cramps, and constipation; she then developed fluctuating impairment of consciousness and seizures. There was complete resolution within 7 days after withdrawal of posaconazole. Vincristine-related neuropathy was also exacerbated by voriconazole in a patient with previously undiagnosed, Xlinked Charcot–Marie–Tooth disease [52A]. In a retrospective cohort study of 50 adults with acute lymphoblastic leukemia who received vincristine-based chemotherapy with (n ¼ 21) or without (n ¼ 29) an azole, the mean dose of vincristine had to be reduced by 47% when an azole was added [53c]. Symptoms of reduced peristalsis were more common in those who took an azole (66% versus 29%) and on average occurred after the second dose of vincristine. These symptoms occurred in 50%, 75%, and 67% of those who took fluconazole, voriconazole, and posaconazole respectively. The course of vincristine was more likely to take be incomplete when patients took an azole (48% versus 9.5%). These studies confirm that caution should be taken when vincristine and azoles are coadministered. Moreover, the reduction in vincristine dosage has uncertain effects in cancer chemotherapy. Alternatives to azoles for prophylaxis of fungal infections in this population are urgently needed. Warfarin In a nested case–control and case–crossover study using US Medicaid data and logistic regression to determine the association between gastrointestinal bleeding in patients taking warfarin, antibacterial drugs (ciprofloxacin, levofloxacin, gatifloxacin, co-trimoxazole, fluconazole) were associated with increased odds ratios compared with cephalexin, which is not expected to interact with warfarin; the odds ratio for fluconazole when used in

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the prior 11–15 days was 2.09 (95% CI ¼ 1.34, 3.26) [54c].

Fluconazole

[SED-15, 1377; SEDA-30, 325; SEDA-31, 462; SEDA-32, 502]

Placebo-controlled studies In a doubleblind, placebo-controlled, randomized trial in 26 centers in the USA of the use of intravenous fluconazole 800 mg/day for 2 weeks in 249 adults in ICU with a high risk of invasive candidiasis, seven who were given fluconazole and 10 who were given placebo had adverse events resulting in withdrawal of the study drug: there were abnormal liver function tests in three and five subjects respectively [55C]. Cardiovascular Antifungal triazoles, as a class, can cause QT interval prolongation and potentially fatal cardiac dysrhythmias by blocking inward-rectifying potassium (hERG) channels in the heart. In a phase II trial, 141 patients with AIDS and cryptococcal meningitis were randomly assigned to amphotericin (0.7 mg/kg/day) alone or plus fluconazole (400 or 800 mg/day) for 14 days [56C]. At day 7 the mean QTc interval adjusted for baseline was similar in all the treatment arms. However, day 7 median and adjusted mean changes from baseline were higher with amphotericin þ fluconazole 800 mg than with amphotericin alone. Predictive factors were higher baseline cerebrospinal fluid (CSF) opening pressure, Karnofsky scales, serum potassium, age, and lower CD4þ count. There was a trend to a significant correlation between the change in QTc interval from baseline and the fluconazole Cmin on day 14. Nevertheless, the proportions of patients with clinically significant abnormalities were comparable in the two groups The role of electrolyte abnormalities in cardiac dysrhythmias has been emphasized in a report of a patient with diabetic ketoacidosis who developed torsade de pointes leading to nine episodes of cardiac arrest secondary to intravenous fluconazole on a

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background of hypokalemia and hypocalcemia [57A]. Skin Sclerosing lymphangitis of the penis has been reported after co-administration of tadalafil 20 mg and fluconazole 300 mg once weekly in a 50-year-old man [58A]. The penile lesion appeared about 24 hours after the third day of fluconazole treatment, when the patient also took tadalafil. Sexual and pharmacological abstinence were recommended and 4 weeks later all the symptoms had resolved. Immunologic In a case of allergy to fluconazole there was no cross-reactivity with voriconazole [59A]. • A 65-year-old immunocompetent, HIV-negative man was given fluconazole 400 mg/day for cerebral cryptococcosis. After 5 weeks he developed a rash on the abdomen, torso, legs, and arms, associated with edema periorbitally and in the right arm. There were no other features of anaphylaxis. Fluconazole was withdrawn and antihistamines were begun. Over the next week, he had asymptomatic increases in liver enzymes and an eosinophilia. Skin biopsy showed an inflammatory cell infiltrate with eosinophils, consistent with a drug reaction. After resolution of the eosinophilia and liver function abnormalities, he underwent a supervised graded challenge with oral voriconazole, starting with a dose of 25 mg on day 1, 75 mg bd on day 2, 150 mg bd on day 3, 300 mg on day 4, and then 200 mg bd thereafter. There was no recurrence of symptoms, liver enzyme rises, or eosinophilia.

This case shows that hypersensitivity reactions to fluconazole can occur and that voriconazole can be successfully introduced without cross-sensitization. In cases of azole hypersensitivity, one could consider using another azole cautiously before choosing another class of antifungal agent. Teratogenicity Fluconazole may be teratogenic when it is taken in a dosage of 400–800 mg/day. Common features include multiple synostosis (including craniosynostosis and digital synostosis), congenital heart defects, skeletal anomalies, and recognizable dysmorphic facial features. The association between maternal use of

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fluconazole during pregnancy and the risk of congenital malformations has been assessed in a population-based cohort study in Northern Denmark in 1079 women who had a live birth or a stillbirth after 20 weeks of gestation and who redeemed at least one prescription for fluconazole during the first trimester [60]. The controls comprised 170 453 pregnant women who redeemed no fluconazole prescriptions during pregnancy. The women were identified through the Danish Medical Birth Registry and data on drug use, birth outcomes, and co-variates were extracted from population-based health-care databases. The prevalence odds ratios (POR) for congenital malformations after fluconazole exposure were adjusting for maternal smoking, parity, maternal age, and concurrent prescriptions of antiepileptic or antidiabetic drugs. Among the 1079 women in the study group, 797 (74%) took a total of 150 mg of fluconazole, 235 (22%) took 300 mg, 24 (2%) took 350 mg, and 23 (2%) took 600 mg. These women gave birth to 44 (4.1%) children with congenital malformations. The 170 453 controls gave birth to 6152 (3.6%) children with congenital malformations. For congenital malformations overall, the adjusted POR associated with first trimester use of fluconazole was 1.0 (95% CI ¼ 0.8, 1.4).

Itraconazole [SED-15, 1932; SEDA-30, 326; SEDA-31, 463; SEDA-32, 504] Liver Fatal hepatitis occurred in a 61-yearold woman 1 week after the last dose of a course of pulse itraconazole therapy for 24 weeks [61A]. She had no apparent risk factors for liver damage. Monitoring of liver enzymes was not performed during the treatment period. The alanine and aspartate aminotransferases were 3330 and 3250 U/l respectively, and bilirubin was 360 mmol/l. Her liver function continued to deteriorate, and she underwent liver

transplantation 17 days after admission. Histology showed massive panlobular necrosis. Immunologic A 36-year-old woman with acute lymphoblastic leukemia developed anaphylactic shock after intravenous itraconazole 200 mg on day 17 of a course of treatment; she responded to glucocorticoid treatment [62A]. On two subsequent days she had recurrences during itraconazole administration. Intravenous itraconazole was replaced by oral voriconazole 200 mg bd and there was no recurrence. T cell reduction, caused by immunosuppression, and itraconazole accumulation in patients with acute lymphoblastic leukemia are considered to be important causal factors for delayed hypersensitivity reactions.

Teratogenesis Women who called two Italian Teratology Information Services after being exposed to itraconazole during the first trimester and a contemporary group of pregnant women who contacted the Services because they had been exposed to a non-teratogenic drug during the first trimester have been compared in a prospective cohort study [63c]. Information was obtained by a trained operator via a structured questionnaire no earlier than 1 month after delivery. A conducted the interview. Information about major congenital anomalies, type of delivery, birth weight, and any pregnancy or neonatal complications was collected on 206 women who had been exposed to itraconazole and 207 controls. There were no significant differences in major congenital anomalies (3/163 versus 4/190 respectively). There were no statistical differences in the rates of vaginal delivery, premature birth, low birth weight, or high birth weight. However, the rates of live births (163/206 versus 190/207), spontaneous abortions (23/206 versus 10/207), and termination of pregnancy (19/206 versus 7/ 207) were significantly different. Thus, itraconazole exposure in the first trimester did

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not increase the risk of major congenital anomalies, but did increase the rates of spontaneous and induced abortion. Given the relatively small sample size, larger studies are warranted. Monitoring therapy The relation of adverse effects to itraconazole concentration has been explored in patients taking itraconazole 100–400 mg/day for at least 3 weeks for prophylaxis or an Aspergillus-related syndrome [64c]. Of 216 patients, 99 (46%) had an adverse event: fluid retention (n ¼ 46; of whom 43 had peripheral edema and three had features suggestive of congestive cardiac failure); gastrointestinal intolerance (45), with nausea and/or vomiting in 32 and abdominal pain, flatulence, and diarrhea in 13; sleep disturbances, with frequent waking, daytime somnolence, and associated low mood (21); a diffuse non-pruritic maculopapular rash during therapy, which resolved 2–4 weeks after stopping itraconazole (16); a sensorimotor polyneuropathy of the hands and feet (11); headache (8); tremor (8); abnormal liver function (5); and dysgeusia (3). Six who were taking concomitant oral or inhaled glucocorticoids had features of Cushing's syndrome. Withdrawal of therapy was required in 72 of the 99 patients who had adverse events. The adverse events resolved with a 50% reduction in dose in 20 patients and with a 75% reduction in dose in seven. Although gastrointestinal intolerance resolved rapidly when itraconazole was withdrawn or when the dosage was reduced, the resolution of fluid retention, peripheral neuropathy, and tremor was protracted and took up to 6 months in some patients. In 45 patients whose itraconazole was withdrawn, an alternative antifungal triazole was given without recurrence. The mean plasma itraconazole concentration was 16 mg/l in patients who had at least one adverse event and 7.0 mg/l in those who did not have any adverse events. There was a progressive increase in the probability of toxicity with increasing itraconazole concentrations. Classification and regression tree analysis suggested that 17.1 mg/l was the itraconazole concentration at which the population of patients was

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separated into two groups, with high and low probabilities of adverse effects.

Posaconazole [SED-15, 2905; SEDA30, 327; SEDA-31, 463; SEDA-32, 504] Observational studies The efficacy and safety of posaconazole in patients with underlying renal impairment has been determined in a post-hoc subanalysis of a phase III, multicenter, open trial in 238 patients with invasive fungal infections taking posaconazole 800 mg/day in divided doses, including 65 patients with renal impairment (creatinine clearance under 50 ml/minute or serum creatinine over 177 mmol/l) [65c]. There were adverse events in 32 of 65 patients with renal impairment (49%) and in 72 of the 173 others (42%). The most common adverse events in both groups were nausea (14% versus 8%), increased serum creatinine (6% versus 0%), vomiting (6% versus 4%), abdominal pain (5% versus 5%), and dizziness (5% versus 1%). Systematic reviews Adverse effects data from 18 single-dose and multiple-dose trials of posaconazole in healthy volunteers plus two additional healthy subsets from other trials have been pooled and analysed [66M]. Of 449 healthy volunteers (354 men; 95 women), 327 were white and their mean ages and weights were similar across all dosing groups. There were no confounding factors of underlying disease or concomitant medications. Evaluations included spontaneously reported adverse events, clinical laboratory test results, electrocardiography, and vital sign measurements. A total of 448 subjects took posaconazole in single or multiple doses of 50–1200 mg/day for up to 14 days; 217 took at least 800 mg/day and 188 took multiple doses of 800 mg/day; 231 took less than 800 mg/day; 48 took placebo. The incidence of treatment–emergent adverse events with posaconazole was similar to that seen with placebo (57% versus 63% respectively)

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and was unrelated to dose. The most common (posaconazole versus placebo) were headache (17% versus 13%), dry mouth (9% versus 0%), and dizziness (6% versus 2%). There were no clinically significant changes in vital signs or laboratory tests, except for transient, mild to moderate rises in liver function tests. Posaconazole also had minimal effect on the QT interval. Monitoring therapy In a retrospective review of 54 adults who took posaconazole for at least 5 days, low plasma posaconazole concentrations (defined as below 500 mg/l) tended to be more frequent in cases of digestive disease (63% versus 30%) and were significantly more frequent among patients with diarrhea (71% versus 27%) or mucositis (100% versus 33%) [67c]. Hepatotoxicity, which occurred in two patients, was not related to high plasma drug concentrations. Therapeutic drug monitoring of posaconazole is recommended for immunosuppressed adults, at least for those with gastrointestinal disorders.

Voriconazole

[SED-15, 3688; SEDA-30, 328; SEDA-31, 463; SEDA-32, 505]

Observational studies Of 72 patients undergoing allogeneic transplantation who were given voriconazole as antifungal prophylaxis starting from 2 days before transplantation and continuing until withdrawal of immunosuppression, 10 required interruption of voriconazole therapy because of adverse effects: hepatotoxicity (n ¼ 6), QT interval prolongation (n ¼ 1), or other adverse effects (n ¼ 4) [68]. Cardiovascular A 57-year-old man with HIV infection taking abacavir, nevirapine, tenofovir, voriconazole, and methadone developed new-onset seizures [69A]. An electrocardiogram showed sinus bradycardia and a prolonged QTc interval of 690 msec. He had several episodes of torsade de pointes and ventricular tachycardia, which resolved spontaneously. They were accompanied by altered cognition and

generalized twitching. Magnesium and amiodarone terminated the dysrhythmia. The patient had multiple susceptibility factors for prolongation of the QT interval, including HIV infection, methadone therapy, and polypharmacy leading to potential drug interactions. Sensory systems Vision Voriconazole inhibits brain cholesterol 24S-hydroxylase (CYP46A1) in vitro and in vivo; as CYP46A1 is also expressed in the neural retina, it is possible that inhibition of CYP46A1 contributes to visual disturbances associated with voriconazole [70E]. Psychiatric In a prospective cohort study 12 of 72 patients taking voriconazole had hallucinations [71c]. Symptoms in eight patients occurred during administration of the initial two intravenous loading doses of voriconazole (6 mg/kg every 12 hours) and symptoms in two patients occurred on only the first day when they received 4 mg/kg of voriconazole every 12 hours. Only two patients reported symptoms beginning at the end of the first week, one of whom had symptoms while taking oral voriconazole. Four also had auditory hallucinations, three of whom had them on the first day of treatment. Although there was also altered color perception or blurred vision in some patients in this study, only three had both hallucinations and altered vision. A recurring feature was that symptoms worsened when the patients’ eyes were closed when they tried to sleep, but in all cases, the patient remained oriented, alert, and able to recognize hallucinations as being unreal. Six patients failed to report their hallucinations spontaneously and were hesitant to describe them. There was no temporal relation between voriconazole infusion and symptoms. No connection was found between the hallucinations and the many other drugs administered. None of the patients needed specific treatment. Doses of voriconazole were within the approved range. None of the patients had a history of psychiatric illness or similar symptoms, and all had hematological or other malignancies. In eight cases the

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symptoms disappeared soon after treatment was withdrawn. In two cases the hallucinations disappeared after treatment was changed from intravenous to oral voriconazole. Two patients had mild hallucinations only on the first day despite continued treatment. There were no residual symptoms or sequelae after voriconazole was withdrawn. Voriconazole trough blood concentrations on the day of withdrawal or just before a change from intravenous to oral treatment in six of the patients were 1.97–7.66 mg/l, and there may be an increased risk of hallucinations in patients with above average voriconazole concentrations (i.e. above 5 mg/l). Of 20 Japanese patients who took voriconazole after chemotherapy for hematological malignancies, six had visual disturbances, complicated by hallucinations in four cases [72c]. The authors suggested that these effects may be associated with a polymorphism in CYP2C19, but they presented no evidence to support this hypothesis. Liver In a retrospective study of antifungal prophylaxis in 67 lung transplant recipients, itraconazole (n ¼ 32) was compared with voriconazole plus inhaled amphotericin (n ¼ 35) to assess the incidence of hepatotoxicity [73c]. There were no significant differences between groups in demographic characteristics, co-morbidities, concomitant use of hepatotoxic medications, or APACHE scores at the time of transplantation. There was hepatotoxicity in 12 patients receiving voriconazole and inhaled amphotericin and in no patients receiving itraconazole. There was no significant difference between the groups with regard to the percentage of fungal infections. Skin Five patients who were initially thought to be having a flare of cutaneous chronic graft-versus-host disease were actually exhibiting phototoxicity due to voriconazole [74c]. A high index of suspicion of this adverse reaction after bone marrow transplantation is needed to prevent misdiagnosis and avoid immunosuppressive therapy.

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Musculoskeletal Drug-induced myopathy has not been reported with voriconazole, although it is recognized with other triazoles. A 34-year-old African-American woman with a renal transplant and a history of probable statin-induced myopathy developed severe generalized weakness with markedly raised muscle enzymes and inflammatory changes on T2-weighted fatsuppressed STIR-sequence MRI while taking voriconazole for invasive aspergillosis [75A]. Her symptoms resolved and the creatine kinase activity normalized when the drug was withdrawn. Possible drug-induced periostitis associated with long-term use of voriconazole after lung transplantation has been reported in five patients [76c]. The diagnosis was made because of bone pain, raised serum alkaline phosphatase, and characteristic findings on radionuclide bone imaging in the absence of any identifiable rheumatological disease. The periostitis was similar to hypertrophic osteoarthopathy, but did not meet all of the diagnostic criteria. In all patients, the symptoms resolved rapidly after voriconazole withdrawal. Tumorigenicity Squamous cell carcinoma has been associated with voriconazole in four patients who had taken it for 2–3 years [77c]. The lesions were preceded by lesions photosensitization, and were predominantly in photoexposed areas, particularly the face. Replacement by posaconazole or itraconazole did not trigger other photosensitive lesions. Once voriconazole was withdrawn, preneoplastic lesions regressed. In a retrospective review of patients who developed one or more squamous cell carcinomas during long-term treatment with voriconazole (median duration 47, range 13–60, months), 51 lesions were identified in eight patients (median age 35, range 9–54, years) [78c]. Underlying diagnoses included graftversus-host disease, HIV, and Wegener's granulomatosis. Signs of chronic phototoxicity and accelerated photoageing included erythema, actinic keratoses, and lentigines. A prospective cohort study is needed to determine the true population risk of squamous cell carcinomas associated with voriconazole,

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but a high index of suspicion for photosensitivity and squamous cell carcinoma is warranted when voriconazole is used chronically in patients with immunosuppression. Drug overdose The effects of voriconazole during massive intentional poisoning have been reported [79A]. • A middle-aged man with cystic fibrosis after lung transplantation intentionally took voriconazole 9.8 g, prednisolone 60 mg, sulfamethoxazole 4 g, azithromycin 2.5 g, and bromazepam 120 mg. He was found at home in a state of altered consciousness and was intubated for airway protection, sedated with midazolam and sufentanil, and mechanically ventilated. He had moderate rhabdomyolysis and acute renal failure, with a creatinine clearance of 22 ml/minute. The voriconazole blood concentration was 30 mg/l. He awoke within 48 hours, but was extremely agitated, and his renal function improved without respiratory or hemodynamic failure. Bilirubin, alkaline phosphatase, the aminotransferases, and gamma-glutamyl transferase increased slightly every day until 126 hours after the overdose, but without any clinical evidence of liver failure. At 144 hours he was no longer agitated and 1 week later the blood tests were normal. In this case report the patient survived the intoxication but presented with signs of immediate neurological toxicity and a delayed increase in liver enzymes, but without any clinical signs of liver failure.

It is difficult to ascertain the role of each drug in this case, as both voriconazole and bromazepam can cause neurological toxicity and raised liver enzymes. However, this report shows that a very large overdose of voriconazole with high blood concentrations does not necessarily result in severe clinical complications or death, but that delayed hepatotoxicity can occur. Monitoring therapy The treatment of fungal infections with voriconazole has been monitored in 49 analyses of 34 patients with hematological diseases [80c]. The voriconazole concentration was highly variable, regardless of renal function, liver function, or age, and the effect of changing dose was not constant, indicating the difficulty of predicting voriconazole concentration without blood concentration monitoring. There was a concentration–response relation only in

patients without refractory hematological disease, in whom a concentration over 2 mg/l was associated with a good response. Rises in hepatic enzymes were associated with a voriconazole concentration over 6 mg/l. The authors concluded that a voriconazole concentration of 2–6 mg/l should be targeted, in order to improve efficacy and to reduce the risk of adverse effects.

[SED-15, 1197; SEDA-30, 329; SEDA-31, 464; SEDA-32, 507]

ECHINOCANDINS

Caspofungin

[SEDA-30, 330; SEDA-32,

508] Observational studies In a prospective, non-comparative study of the use of caspofungin 50 mg/day as first-line monotherapy in invasive aspergillosis in patients with hematological malignancies, there were no serious drug-related adverse events or withdrawals because of drug-related adverse events [81c]. In a prospective study of caspofungin for 16 (range 4–46) days for prevention of intra-abdominal invasive candidiasis in 19 high-risk surgical patients with recurrent gastrointestinal perforation/anastomotic leakage or acute necrotizing pancreatitis, there were no drug-related adverse events requiring caspofungin withdrawal [82c]. In a prospective, multicenter, non-comparative, open trial of the prophylactic use of caspofungin for at least 21 days in 71 adult liver transplant recipients at high risk of invasive fungal infections, six stopped taking caspofungin because of drug-related altered liver function, but there were no symptomatic adverse effects [83c]. There were changes in laboratory data compatible with grade 4 adverse effects, irrespective of caspofungin attribution, in 20 patients at the end of caspofungin prophylaxis and in 11 patients 14 days after end of caspofungin administration; eight patients died, six during caspofungin administration and two

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during follow-up, but none was attributed to fungal infection or caspofungin. In a retrospective analysis of the medical records of 63 adults with cancer who had candidemia treated with caspofungin alone for at least three consecutive days, 20 of whom had hematological malignancies, caspofungin was well tolerated by all patients [84c]. Comparative studies The usefulness of caspofungin has been substantiated by the results of a double-blind, randomized, phase III trial, in which 204 patients with proven invasive candidiasis were randomized to caspofungin in a standard or high-dose (150 mg/day) regimen [85C]. There were significant drug-related adverse events in 1.9% of those who received the standard regimen and 3.0% of those who received the highdose regimen; the most common drugrelated adverse events were phlebitis (3.8% and 2.0% respectively), increased alkaline phosphatase (6.9% and 2.0%), and increased aspartate aminotransferase (4.0% and 2.0%). Immunologic A patient with a hemopoietic stem cell transplant and a history of an immediate hypersensitivity reaction to micafungin was considered for a trial of caspofungin, but a caspofungin intradermal skin test was positive, suggesting cross-reactivity [86A]. Thus, the cyclic peptide nucleus chemical structure shared by echinocandins may be the site of IgE recognition, and it would be prudent to avoid challenging patients with history of immediate hypersensitivity to one echinocandin with another. Susceptibility factors Children Adverse reactions to caspofungin in five clinical registration studies in 171 children have been analysed [87M]. The median age of the caspofungin recipients was 6.0 years (range 1 week to 17 years). Most (77%) were taking a maintenance dose of 50 mg/m2/day. The rest took 1 mg/kg/day (9 patients), 25 mg/ m2/day (18 neonates or infants under months of age), or 70 mg/m2/day (12 patients). The maximum absolute dose in all cases was 70 mg/day. The median duration of treatment was 9 (range 1–87) days

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overall and 10 (range 2–87) days in patients taking 50 mg/m2/day. The incidences of drug-related clinical and laboratory adverse events were 26% and 16% respectively. The most common drugrelated clinical adverse events were fever, rash, and headache. Most of these were mild in intensity and transient. Increased aminotransferase activities and reduced potassium were the most common drugrelated laboratory adverse events; these returned to within the reference range during subsequent caspofungin therapy or by 14 days of follow-up visit in 10 of the 13 patients with increased aspartate aminotransferase, six of the 11 with increased alanine aminotransferase, and four of the six with reduced potassium. None of these laboratory adverse events was serious or led to caspofungin withdrawal. Although 37 (22%) of the 171 patients who received caspofungin had a serious clinical adverse event, only one event (hypotension) was considered to be related to caspofungin. Eleven patients (6%) died during or within 14 days of completing the course of caspofungin, but none of the deaths was considered to be related to caspofungin. Two patients (1%) stopped taking caspofungin because of a drug-related adverse event: moderate hypotension in one patient (see above) and a moderate rash in the other; the hypotension resolved after a bolus of isotonic saline, and the rash resolved without treatment 10 days later. The incidences of drug-related adverse events in patients taking caspofungin were generally similar in different age ranges and in patients of different sex, race, ethnicity, and body weight. The incidences of drug-related adverse events were comparable with all dosing regimens. Caspofungin 50 mg/m2/day has been studied in a multicenter, prospective, open study in children aged 3 months to 17 years with invasive aspergillosis, invasive candidiasis, or esophageal candidiasis [88c]. There were adverse events in seven patients, but none was considered drug related. There were laboratory adverse events in five patients, which were considered to be drug related in three. There were no infusionrelated events or withdrawals because of

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adverse effects. The pharmacokinetics of caspofungin were generally comparable with those in adults [89C]. In a dose-finding study, patients aged 1–11 weeks, weighing 0.68–3.8 kg, gestational ages 24–41 weeks, receiving intravenous amphotericin for documented or suspected candidiasis, were enrolled in a single-dose (n ¼ 6) or subsequent multiple-dose (n ¼ 12) panel; all received caspofungin 25 mg/m2/day as a 1-hour infusion [90c]. Clinical and laboratory adverse events occurred in 17 and 8 patients respectively. Five patients had serious adverse events, none of which was considered drug related. However, the small number of patients precluded definitive recommendations. Drug–device interactions Sequestration of caspofungin and voriconazole during extracorporeal membrane oxygenation (ECMO) has been demonstrated in a 31-year-old woman with fulminant myocarditis [91A]. The system comprised a membrane oxygenator (Quadrox Bioline, Jostra-Maquet, Orléans, France) and a centrifugal pump (Rotaflow, Jostra-Maquet). Continuous venovenous hemodiafiltration (PRISMA machine; respective blood, dialysate, and ultrafiltration flows 120 ml/minute, 500 ml/ hour, and 1000 ml/hour) was started because of acute renal insufficiency. Because of probable invasive pulmonary aspergillosis, combined intravenous antifungal therapy was introduced, with voriconazole 4 mg/kg bd and caspofungin 50 mg/day. Because of persistent extensive tracheal pseudomembranous lesions, positive tracheal aspirate cultures, positive bronchoalveolar lavage, and a galactomannan index of 8, all indicating treatment failure, treatment was switched on day 15 to intravenous liposomal amphotericin 3 mg/ kg/day and flucytosine 1.5 g/day. The patient was weaned from extracorporeal membrane oxygenation (ECMO) 21 days after ICU admission, bronchoalveolar lavage fluid cultures became negative 16 days after starting the new regimen, and the patient was discharged on day 53. During ECMO, voriconazole and caspofungin

concentrations in blood were low to undetectable, suggesting sequestration by binding to extracorporeal circuit components.

Micafungin [SEDA-30, 331; SEDA-31, 464; SEDA-32, 510] Observational studies In a prospective study in 98 hemopoietic stem cell transplant recipients who received micafungin either alone (n ¼ 8) or in combination with other licensed antifungal therapies (n ¼ 90), 81 had pulmonary aspergillosis, 42 had graftversus-host disease, and 26 had neutropenia at the start of treatment; there were no significant adverse effects [92]. In a prospective multicenter trial of micafungin, mean dosage and duration 171 mg/ day for 22 days, in 277 patients with invasive fungal infections in hematological disorders, 197 were assessed for clinical efficacy; there were adverse events related to micafungin in 39 (14%), but most of them were mild and reversible [93c]. In a multicenter postmarketing study, micafungin, mean dosage and duration 104 mg/day for 14 days, was given to 180 patients with a temperature exceeding 37.5  C, either with a proven fungal infection, or who were regarded as having probable or possible fungal infections; 178 (58 with proven candidiasis, one with proven aspergillosis, and 53 with suspected fungal infections) were evaluated [94c]. There were 69 drug-related adverse reactions, mainly abnormal hepatic function tests, in 37 patients. One adverse reaction, a rash, was probably causally related to the drug. Comparative studies In a prospective randomized study, 106 adults undergoing hemopoietic stem cell transplantation were randomly assigned to prophylaxis with either micafungin 150 mg/day (n ¼ 52) or fluconazole 400 mg/day (n ¼ 52); micafungin did not cause more adverse effects than fluconazole [95C]. Liver Hepatitis associated with micafungin has been reported in a preterm infant [96A].

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Immunologic Micafungin-mediated immune hemolysis is an uncommon but potentially life-threatening adverse reaction that can lead to renal insufficiency. Two patients with hematological diseases had massive intravascular hemolysis followed by renal insufficiency after administration of micafungin [97A]. An indirect antiglobulin test showed significant agglutination when erythrocytes were exposed to a mixture of micafungin and either of the patients’ plasma samples, suggesting that antibodies directed against both micafungin and erythrocyte membranes had caused hemolysis. However, the drugdependent antibodies from each patient did not cross-react with caspofungin, suggesting the presence of an antibody against a specific part of the structure of micafungin, not common to all echinocandins. Another case of micafungin-induced hemolysis during conditioning therapy for hemopoietic stem cell transplantation has been reported, in which the direct antiglobulin test was negative [98A]. A test for drug–anti-drug immune complexes against micafungin, phosphate-buffered saline, and complement (fresh serum) was positive in a reactive system containing the patient's serum, micafungin, and complement, but was negative in a system containing the patient's serum and voriconazole or micafungin and a serum sample from healthy individual. Susceptibility factors Neonates The adverse effects and pharmacokinetics of an high dose of micafungin (15 mg/kg/day for 5 days) have been assessed in a repeated dose, open study in 12 preterm neonates (median gestational age 27 weeks), with suspected systemic infections [99c]. There

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were no adverse events related to micafungin. The clearance and apparent volume of distribution were greater than in older children and adults. These data suggest that a dose of 15 mg/kg in premature neonates corresponds to a dose of about 5 mg/kg in adults. Children In a retrospective study, children with neutropenia were given prophylactic intravenous micafungin 3 mg/kg/day in 131 cycles after chemotherapy (39 patients) and 15 cycles after hemopoietic stem cell transplantation (14 patients) [100c]. There were no adverse events that could be related to micafungin.

FLUCYTOSINE

[SED-15, 1388;

SEDA-32, 497] Comparative studies In a randomized comparison, 64 HIV-positive, antiretroviral therapy-naive patients in Cape Town, with a first episode of cryptococcal meningitis, received either amphotericin 0.7 mg/kg/day plus flucytosine 25 mg/kg qds (n ¼ 30), or amphotericin 1 mg/kg/day plus flucytosine 25 mg/ kg qds (n ¼ 34) [9C]. Regimens were given for 2 weeks, followed by oral fluconazole. The frequency of renal impairment did not differ between the groups. Anemia was associated with female sex and less strongly with the higher dose of amphotericin, which may have been exacerbated by reduced renal clearance of flucytosine.

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institution study. Int J Antimicrob Agents 2009; 34: 95–8. Betts RF, Nucci M, Talwar D, Gareca M, Queiroz-Telles F, Bedimo RJ, Herbrecht R, Ruiz-Palacios G, Young JA, Baddley JW, Strohmaier KM, Tucker KA, Taylor AF, Kartsonis NA. Caspofungin High-Dose Study Group. A Multicenter, double-blind trial of a highdose caspofungin treatment regimen versus a standard caspofungin treatment regimen for adult patients with invasive candidiasis. Clin Infect Dis 2009; 48: 1676–84. Patel S, Alangaden GJ, Lum LG, Cronin SM, Abidi MH, Dieterle N, Ibrahim RB. Immediate cross-hypersensitivity between micafungin and caspofungin: a case report. J Oncol Pharm Pract 2009; 15: 187–9. Zaoutis T, Lehrnbecher T, Groll AH, Steinbach WJ, Jafri HS, Maertens J, Ngai AL, Chow JW, Taylor AF, Strohmaier KM, Bourque M, Bradshaw SK, Petrecz M, Kartsonis NA. Safety experience with caspofungin in pediatric patients. Pediatr Infect Dis J 2009; 28: 1132–5. Zaoutis TE, Jafri HS, Huang LM, Locatelli F, Barzilai A, Ebell W, Steinbach WJ, Bradley J, Lieberman JM, Hsiao CC, Seibel N, Laws HJ, Gamba M, Petrecz M, Taylor AF, Strohmaier KM, Chow JW, Kartsonis NA, Ngai AL. A prospective, multicenter study of caspofungin for the treatment of documented Candida or Aspergillus infections in pediatric patients. Pediatrics 2009; 123: 877–84. Neely M, Jafri HS, Seibel N, Knapp K, Adamson PC, Bradshaw SK, Strohmaier KM, Sun P, Bi S, Dockendorf MF, Stone JA, Kartsonis NA. Pharmacokinetics and safety of caspofungin in older infants and toddlers. Antimicrob Agents Chemother 2009; 53: 1450–6. Sáez-Llorens X, Macias M, Maiya P, Pineros J, Jafri HS, Chatterjee A, Ruiz G, Raghavan J, Bradshaw SK, Kartsonis NA, Sun P, Strohmaier KM, Fallon M, Bi S, Stone JA, Chow JW. Pharmacokinetics and safety of caspofungin in

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[91]

[92]

[93]

[94]

[95]

[96]

[97]

[98]

neonates and infants less than 3 months of age. Antimicrob Agents Chemother 2009; 53: 869–75. Ruiz S, Papy E, Da Silva D, Nataf P, Massias L, Wolff M, Bouadma L. Potential voriconazole and caspofungin sequestration during extracorporeal membrane oxygenation. Intensive Care Med 2009; 35: 183–4. Kontoyiannis DP, Ratanatharathorn V, Young JA, Raymond J, Laverdière M, Denning DW, Patterson TF, Facklam D, Kovanda L, Arnold L, Lau W, Buell D, Marr KA. Micafungin alone or in combination with other systemic antifungal therapies in hematopoietic stem cell transplant recipients with invasive aspergillosis. Transpl Infect Dis 2009; 11: 89–93. Tamura K, Urabe A, Yoshida M, Kanamaru A, Kodera Y, Okamoto S, Maesaki S, Masaoka T. Efficacy and safety of micafungin, an echinocandin antifungal agent, on invasive fungal infections in patients with hematological disorders. Leuk Lymphoma 2009; 50: 92–100. Aikawa N, Kusachi S, Oda S, Takesue Y, Tanaka H. Clinical effects of micafungin, a novel echinocandin antifungal agent, on systemic fungal infections in surgery, emergency, and intensive-care medicine: evaluation using the AKOTT algorithm. J Infect Chemother 2009; 15: 219–27. Hiramatsu Y, Maeda Y, Fujii N, Saito T, Nawa Y, Hara M, Yano T, Asakura S, Sunami K, Tabayashi T, Miyata A, Matsuoka K, Shinagawa K, Ikeda K, Matsuo K, Tanimoto M. West-Japan Hematology and Oncology Group. Use of micafungin versus fluconazole for antifungal prophylaxis in neutropenic patients receiving hematopoietic stem cell transplantation. Int J Hematol 2008; 88: 588–95. King KY, Edwards MS, Word BM. Hepatitis associated with micafungin use in a preterm infant. J Perinatol 2009; 29: 320–2. Nanri T, Iwanaga E, Fujie S, Yamada Y, Horikawa K, Mitsuya H, Asou N. Micafungin-induced immune hemolysis attacks. Int J Hematol 2009; 89: 139–41. Yoshizawa S, Gotoh M, Kitahara T, Kiguchi T, Akahane D, Sakuta J,

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Sunaga K, Ohyashiki K. Micafungininduced hemolysis attack due to drugdependent antibody persisting for more than 6 weeks. Leuk Res 2010; 34: e60–1. [99] Smith PB, Walsh TJ, Hope W, Arrieta A, Takada A, Kovanda LL, Kearns GL, Kaufman D, Sawamoto T, Buell DN, Benjamin Jr. DK. Pharmacokinetics of an elevated dosage of micafungin in

premature neonates. Pediatr Infect Dis J 2009; 28: 412–5. [100] Kusuki S, Hashii Y, Yoshida H, Takizawa S, Sato E, Tokimasa S, Ohta H, Ozono K. Antifungal prophylaxis with micafungin in patients treated for childhood cancer. Pediatr Blood Cancer 2009; 53: 605–9.

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Antiprotozoal drugs

ANTIMALARIAL DRUGS Various public health programs that involve mass administration of medicines call for responsive pharmacovigilance systems to allow identification of signals of rare or even common adverse reactions. In developing countries in Africa, these systems are mostly absent, and where they exist their performance is difficult to predict, given shortages of human, financial, and technical resources. Nevertheless, there is no doubt of their importance, and research to identify problems, with the aim of offering pragmatic solutions, is urgently needed. In order to examine the effects of training and monitoring of health-care workers, making supervisory visits, and the availability of telecommunication and transport facilities on the implementation of a pharmacovigilance system, a descriptive study has been performed in Mozambique [1c]. The lessons learnt were enumerated, as were the challenges faced in implementing a spontaneous reporting system in two rural districts challenged by remote location, poor telecommunication services, and poor education of health professionals. A standardized yellow card system for spontaneous reporting of adverse drug reactions was instituted after 35 health workers in the selected districts had been trained to diagnose, treat, and report adverse drugs reactions to all medicines. They made routine site visits to identify and clarify any Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00028-3 # 2011 Elsevier B.V. All rights reserved.

problems in filling in and sending the forms. One focal person was identified in each district to facilitate communication between the health-care professionals and the National Pharmacovigilance Unit (NPU). The report form was assessed for quality and causality. The availability of telecommunications and transport was assessed. Within the 14 months after the first training period, the NPU received 67 reports of suspected adverse drug reactions involving 74 adverse events associated with 25 separate drugs, 16 of which were causally certainly, probably, or possibly linked to the reaction. Most of the reported events were dermatological reactions (83%). Antimalarial drugs (chloroquine, amodiaquine, quinine, artesunate, and sulfadoxine þ pyrimethamine) were mentioned in 33 reports; 14 reactions were classified as serious and there were no fatal reactions. There were no reports on adverse effects of antihelminthic drugs.

4-AMINOQUINOLINES (CHLOROQUINE AND CONGENERS) [SEDA-30, 336; SEDA-31, 469; SEDA-32, 521]

Amodiaquine [SED-15, 178; SEDA-31, 469; SEDA-32, 521] Liver The risk of hepatitis in patients taking long-term amodiaquine has been estimated at one in 15 500, and two further cases have been reported in patients with malaria who were also given artesunate [2A]. 567

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Susceptibility factors Children The adverse effects of amodiaquine have been described in two children [3A]. In one there was an acute dystonic reaction and in the other persistent asymptomatic bradycardia; in both cases, plasma concentrations of N-desethylamodiaquine and N-bis-desethylamodiaquine, the main metabolites of amodiaquine, were normal, despite a supposed inadvertent overdose in the first case. Drug–drug interactions Artesunate Artemisinin-based combinations, including with amodiaquine, are being increasingly used in uncomplicated falciparum malaria. The interaction of amodiaquine 10 mg/kg and artesunate 4 mg/kg has been investigated in a randomized, three-phase, crossover study in 12 healthy volunteers [4c]. When the combination was used, the mean AUCs for dihydroartemisinin and desethylamodiaquine were both reduced by one-third. There were adverse events in four volunteers: grade 3 rises in aminotransferase activities (n ¼ 1), neutropenia (n ¼ 2), and hypersensitivity reactions (n ¼ 1). The clinical significance of these interactions is not known and the mechanism is unclear [5r].

Chloroquine and hydroxychloroquine

[SED-15, 722; SEDA-30, 336; SEDA-31, 470; SEDA-32, 521] Cardiovascular Cardiac toxicity due to chronic chloroquine use includes conduction disorders, congestive heart failure, prolongation of the QT interval, myocardial hypertrophy, and restrictive cardiomyopathy. Third degree atrioventricular block and sudden cardiac arrest due to ventricular fibrillation caused by chloroquine, unusual reactions, have been reported [6A]. • A 21-year-old man who had taken chloroquine 250 mg/day for primary hemosiderosis since the age of 8, suddenly collapsed with ventricular fibrillation and had no spontaneous circulation. A single shock was delivered and he regained

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consciousness, but an electrocardiogram showed complete atrioventricular block and a prolonged QT interval. There were no previous cardiac symptoms and physical examination, blood gas analysis, biochemistry, hematology, and echocardiography were unremarkable. Ten days after stopping chloroquine, he was still in heart block and a permanent pacemaker was implanted.

It could be that increasingly prolonged atrioventricular conduction could have led to complete heart block with simultaneous QT interval prolongation, thus triggering ventricular fibrillation. Skin Pigmentation of the oral mucosa is not uncommon in dark-skinned people and is due to deposition of melanin. However in white people, oral pigmentation calls for robust investigation. Two Caucasians with oral pigmentation have been described [7A]. • A 65-year-old white woman developed diffuse blue-grey pigmentation on the hard palate mucosa and on the pretibial skin. She had taken chloroquine diphosphate for rheumatoid arthritis for 3 years. • A 71-year-old woman developed a burning sensation on the dorsal surface of the tongue. There were atrophic areas on the tongue and blue-grey pigmentation on the hard palate mucosa and on the skin of her arm. She had taken chloroquine diphosphate for 10 years for Sjögren's syndrome.

Biopsies in both patients showed darkbrown granular pigment in the lamina propria, mainly located in fibroblasts and in the subepithelial and perivascular regions. Together with the clinical appearances, these findings confirmed the diagnosis of drug-induced pigmentation. In Caucasians, isolated and well-circumscribed pigmented lesions are usually diagnosed as melanocytic nevi, melanotic macules, amalgam tattoos, or more uncommonly as initial signs of melanoma. Diffuse pigmentation may be due to underlying systemic disorders, such as Addison's disease, Peutz–Jegher syndrome, or HIV infection. It may also be due to drugs such as antimalarials, tetracyclines, and non-steroidal anti-inflammatory drugs.

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Hair Depigmentation of scalp and body hair following hydroxychloroquine treatment (generalized poliosis) has been reported [8A]. • A 25-year-old Caucasian woman taking hydroxychloroquine for discoid lupus erythematous developed generalized symmetrical depigmentation of the scalp and body hair, or acquired poliosis. Hydroxychloroquine was withdrawn and she grew new hair in her natural color within 3 months.

Generalized poliosis in patients with strawberry blonde hair and in African patients with vitiligo have been reported in patients taking antimalarial drugs. The mechanism is not known but it is said to be due to binding of antimalarial drugs to eumelanin and pheomelanin, disturbing melanogenesis.

Mefloquine [SED-15, 2232; SEDA-30, 337; SEDA-31, 471; SEDA-32, 523]

Au1

Nervous system The literature on mefloquine neurotoxicity has been reviewed [9R]. Nausea, dizziness, sleep disturbances, anxiety, and psychosis have been reported. Female patients and patients with a low body mass index are at greater risk. It has been hypothesized that the mechanisms whereby mefloquine increases the risk of seizures in patients with a history of seizures, which may be via altered neuronal calcium homeostasis, altered gap-junction functioning, and neuronal cell death, are particularly associated with a mutation in EPM1, a gene that is associated with progressive myoclonic epilepsy type 1, and hence altered GABA activity [10H]. The author proposed that mefloquine should be contraindicated in people with the EPM1 mutation and in those with a history of myoclonus or ataxia, or a family history of degenerative neurological disorders that are consistent with the presence of the EPM1 mutation. Psychiatric Psychiatric adverse effects of mefloquine are common in adults, but rare

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in children. Acute mania has been reported in an 11-year-old otherwise healthy girl from Eastern India after a therapeutic dose of mefloquine for Plasmodium falciparum malaria; she recovered with risperidone [11A].

PRIMAQUINE AND CONGENERS [SED-15,

2919]

Tafenoquine and primaquine Comparative studies Tafenoquine is an 8aminoquinoline analogue of primaquine, which is being developed for treatment and prevention of malaria. It has been particularly recommended for the radical cure of Plasmodium vivax, which causes up to 80 million cases of relapsing malaria annually. Tafenoquine and primaquine, currently the drug of choice for vivax malaria, have been compared in an open study in 1512 Australian military personnel serving in the South Pacific, who were assigned to one of three tafenoquine 3-day regimens: 400 mg/day, 200 mg bd, 200 mg/day, or primaquine 22.5 mg/day þ doxycycline 100 mg/day over 14 days in Bougainville and in Timor Leste for post-exposure prophylaxis. The most common adverse effects were nausea, abdominal discomfort, and diarrhea. There was a dose-related reduction in adverse events when the dose of tafenoquine was reduced: the lowest dosage of 600 mg/day over 3 days produced rates of adverse events similar to that of primaquine þ doxycycline. A short course of tafenoquine appears to offer better adherence outcomes than the longer course of primaquine.

Proguanil hydrochloride and atovaquone Skin Bullous erythema multiforme occurred in a patient who took atovaquone and proguanil hydrochloride (MalaroneÒ) [12A].

570 • A 55-year-old Kenyan woman with uncomplicated malaria and a history of allergies to sulfadoxine/pyrimethamine (FansidarÒ) and chloroquine was given artesunate 2.4 mg/kg/ day for 3 days, with successful clearance of symptoms and parasites and no adverse events. To ensure parasite clearance she was then given MalaroneÒ (atovaquone 250 mg þ proguanil hydrochloride 100 mg) once a day for three consecutive days. The first dose was associated with mild generalized pruritus and within 2 hours of the second she developed intense whole-body pruritus and erythema of the nipples and pubic areas. The final dose was withheld, but by this time she had developed a dusky, erythematous, macular rash on the medial aspects of both arms with early bullae. By the next day the eruption had markedly progressed, and an aspirate of the bulla fluid contained primarily eosinophils. She was given a single intravenous dose of hydrocortisone 250 mg and gradually recovered.

Bullous erythema multiforme following treatment with MalaroneÒ is rare. Artesunate was well tolerated by the patient, and given its short half-life is less likely to have provoked the bullous eruption.

PYRIMETHAMINE AND CONGENERS [SED-15, 2984; SEDA-32, 523] Observational studies During a surveillance period of 2 years, 1552 patients with uncomplicated P. falciparum malaria who had received sulfadoxine þ pyrimethamine with artesunate on the Northern coast of Peru were followed up; 8.8% reported at least one adverse effect, the most common being vomiting, nausea, headache, abdominal pain, dizziness, and fever; there were no severe adverse effects [13c]. Pregnancy The pharmacokinetics of sulfadoxine and pyrimethamine 1500 þ 75 mg have been studied in Papua New Guinea in 30 women in the second or third trimester of pregnancy and in 30 age-matched non-

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Oscar Ozmund Simooya

pregnant women [14C]. Pregnancy was associated with significantly lower AUCs of sulfadoxine and pyrimethamine (both by 33%) and of N-acetylsulfadoxine (by 50%). The authors recommended that higher doses than those recommended for non-pregnant patients should be considered in pregnancy.

QUININE AND CONGENERS [SED-15,

3002; SEDA-31, 472; SEDA-32, 524] Cardiovascular A 5-year-old AfricanNigerian girl was given intravenous quinine dihydrochloride for uncomplicated malaria, developed ventricular fibrillation, and died within 1.5 hours of the start of the infusion [15A].

Hematologic Drug-induced immune thrombocytopenia can occur when drug-dependent antibodies, themselves non-reactive, bind to specific platelet membrane glycoproteins in the presence of the drug [16E]. When two murine monoclonal antibodies that recognized the N-terminus of the glycoprotein IIb beta-propeller domain only when quinine was present were incubated with platelets in the presence of quinine, both mimicked the behavior of antibodies from patients with quinine-induced immune thrombocytopenia. These antibodies could be useful in further exploring the mechanistic nature of this adverse reaction. Thrombocytopenia with or without microangiopathy and schistocytes in patients taking quinine can be associated with deficiency of a protease, ADAMTS13, that cleaves von Willebrand factor. In a retrospective review, of six women (mean age 62, range 43–73 years), with quinine-associated thrombotic microangiopathy, in whom ADAMTS13 was measured before plasma exchange was performed, four had renal failure requiring dialysis; D-dimers were raised in five, markedly in four [17c].

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ADAMTS13 was normal in four patients and mildly reduced in two. The authors concluded that the pathophysiology of quinine-associated thrombocytopenia and schistocytosis is distinct from that seen in most cases of idiopathic thrombocytopenia. They recommended that the term quinineassociated thrombotic microangiopathy should be used. Skin Fixed drug eruptions have been attributed to quinine [18A,19A]. Management of adverse reactions In a genome-wide screen using the yeast deletion strain collection, quinine-sensitive mutants included several that were defective in tryptophan biosynthesis (trp strains) [20EH]. This sensitivity was confirmed in independent assays and was suppressible with exogenous tryptophan. Quinine also inhibited [3H]-tryptophan uptake by the cells, and the quinine sensitivity of a trp1Delta mutant could be rescued by overexpression of tryptophan permeases, encoded by TAT1 and TAT2. The site of quinine action was identified specifically as the high-affinity tryptophan/tyrosine permease, Tat2p, with which quinine associated in a tryptophan-suppressible manner. Quinine also reduced tyrosine concentrations through tyrosine-suppressible hypersensitivity of an aro7Delta deletion strain, which is auxotrophic for tyrosine (and phenylalanine). The authors therefore suggested that dietary tryptophan supplements might help to prevent the adverse effects of quinine.

[SED-15, 342; SEDA-30, 338; SEDA-31, 473; SEDA-32, 525]

ENDOPEROXIDES

There are five artemisinin derivatives that are active in malaria: arteether, artemether, artemisinin, artesunate, and dihydroartemisinin.

571

Uses The antiviral activities of artemisinin and artesunate have been reviewed, including actions on human cytomegalovirus and other members of the herpesvirus family (for example, herpes simplex virus type 1 and Epstein–Barr virus), hepatitis B virus, hepatitis C virus, and bovine viral diarrhea virus [21R]. Systematic reviews Adverse reactions to artemisinin derivatives have been reviewed in a preliminary survey of 188 studies, of which 108 (9241 patients) fulfilled criteria for an analysis that partly used the Cochrane methods [22M]. They included healthy volunteers and patients with both uncomplicated and severe malaria in either controlled or non-controlled studies. Adverse events, laboratory measurements (hematology in 4062 patients and blood chemistry in 3893 patients), and electrocardiography (2638 patients) were analysed. There were no differences among the various derivatives. There were no serious or severe adverse events. The most commonly reported adverse events were gastrointestinal. Occasional neutropenia (1.3%), reticulocytopenia (0.6%), and raised liver enzymes (0.9%) were reported. Transient bradycardia and prolongation of the QT interval were reported in about 1.1% of patients. Neurological assessment was performed primarily in patients with severe malaria; there was no difference from quinine and four neuropsychiatric adverse events were reported in patients taking concomitant mefloquine. Teratogenicity After 62 pregnant Sudanese women had been given an artemisinin compound during the first trimester of pregnancy they were followed until delivery and their babies were followed for 1 year [23C]. The treatments were artemether injections (n ¼ 48), artesunate þ sulfadoxine þ pyrimethamine (n ¼ 11), and artemether þ lumefantrine (n ¼ 3). Records were available for 51 of these patients, and in each case malaria was confirmed. Two of the women given artemether in the first trimester had spontaneous miscarriages; one at 20 weeks of gestation and the other at 22 weeks, both

572

while receiving quinine for a second attack of malaria. The other 60 all had normal deliveries of full-term babies. There were no congenital malformations in any one baby and none died during the first year of life. This small study suggests that artemisinin derivatives are safe during early pregnancy, but further research is needed.

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arteether administration was the most likely cause in this case. The family history of chloroquine-induced psychosis suggests a possible hereditary predisposition, which requires further investigation.

Artesunate Arteether Psychiatric There is still concern about the potential of artemisinin derivatives to cause neurotoxic effects, and severe and irreversible brain damage has been reported in some animal and human studies. Mania developed in an adolescent with a family history of chloroquine-induced psychosis after treatment with a/b-arteether [24A]. • A 16-year-old female student with normal motor and mental milestones and no previous history of psychiatric illness developed falciparum malaria and was given a/b-arteether 150 mg/day for 3 days. A few days later she started talking excessively, boasting about her abilities, appearing blissful, and always on the move. Her father and paternal uncle had developed psychoses after taking chloroquine for malaria, which in both cases had resolved spontaneously. She had no motor deficits, but she was talkative and over-familiar, with an elevated mood, thought acceleration, and grandiose delusions. Blood chemistry and hematology, liver function tests, and electroencephalography were normal. She was treated successfully with sodium valproate and quetiapine titrated to doses of 500 and 100 mg/day respectively.

Fever and malaria can induce a psychosis, but in this case, fever was an unlikely cause, as fever-induced psychosis is usually polymorphic and associated with some alteration of consciousness and orientation, which were absent; there was also no past history of an altered mental state after febrile illnesses. Falciparum malaria leading to psychiatric sequelae usually presents with cerebral malaria, which has well-defined neurological signs. Antimalarial drugs such as chloroquine, mefloquine, and quinine can cause psychoses, and given substantial evidence of neurotoxicity after exposure to artemisinin compounds,

Nervous system Artesunate and mefloquine are the recommended first-line drugs for uncomplicated malaria in much of South East Asia. However, there are no detailed studies of the potential central nervous system effects of this combination in very young children. In 91 children with uncomplicated malaria, who were randomized to artesunate monotherapy (n ¼ 45) for 7 days or artesunate for 7 days plus mefloquine on days 7 and 8 (n ¼ 46), coordination and behavior were assessed on days 0, 7, 9, 10, 14, and 28 [25C]. As controls, 36 non-febrile children from the same population were tested on days 0, 7, 14, and 28. The presence of malaria and fever had significant negative effects, but antimalarial treatment did not. Sensory systems Auditory and vestibular function In 93 patients with acute uncomplicated malaria auditory function was tested before and after a 3-day course of artesunate 4 mg/kg/day combined with mefloquine 25 mg/kg, using tympanometry, audiometry, and auditory brain stem response [26c]. Hearing loss on day 0 was common (57%) and was associated with age only. However, no patient had a threshold change exceeding 10 decibels between day 0 and day 7 at any tested frequency, and none had a shift in wave III peak latency of more than 0.3 msec between baseline and day 7. Thus, there was no evidence of auditory toxicity in these patients 7 days after a course of artesunate and mefloquine. Drug–drug interactions Amodiaquine See “Amodiaquine” above.

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DRUGS USED IN THE TREATMENT OF PNEUMOCYSTIS JIROVECII INFECTIONS For sulfonamides and co-trimoxazole (trimethoprim þ sulfamethoxazole) see Chapter 26; for dapsone see Chapter 30.

DRUGS USED IN THE TREATMENT OF OTHER PROTOZOAL INFECTIONS For the benzimidazoles see Chapter 31.

Metronidazole [SED-15, 2323; SEDA30, 339; SEDA-31, 475; SEDA-32, 525] For regimens used in the eradication of Helicobacter pylori, see Chapter 36. Systematic reviews It is estimated that 40–50 million people worldwide who are infected with Entameba histolytica develop amebic colitis, resulting in up to 100 000 deaths per year. Metronidazole is the drug of choice and is often given in combination with other drugs in order to eliminate the parasites. However, there is insufficient evidence to support combination therapy, while the occurrence of adverse reactions to metronidazole and the possibility of parasite resistance are other concerns. The different drugs used against amebic colitis alone or in combination have been compared in a systematic review, as have single-dose regimens compared with longer regimens [27M]. In all, 37 trials with 4487 participants were included. The key outcomes were clinical failure (absence of parasites in the stool but little or no relief of symptoms), parasitological failure (persistence of Entameba histolytica cysts or trophozoites), relapse (reappearance of

573

parasites in the stool after initial clearance), and serious adverse events. Metronidazole was associated with more clinical failures than tinidazole and with more adverse events. Combination therapy resulted in fewer parasitological failures than metronidazole alone. There were more adverse events in those who took metronidazole compared with tinidazole; they included mild to moderate gastrointestinal complaints, such as nausea, reduced appetite, vomiting, and a metallic or bitter taste. Placebo-controlled studies Intravaginal and oral metronidazole have been compared in the treatment of bacterial vaginosis in a double blind, randomized, placebo-controlled study in 129 women (mean age 36 years) who took oral metronidazole 2 g/day for 2 days and 134 women (mean age 36 years) who used intravaginal metronidazole 1 g/day for 2 days [28C]. There was no difference in cure rates. Nausea was the most common adverse event; it was reported in 10% of those who used intravaginal metronidazole and 30% of those who used oral metronidazole; other adverse events were abdominal pain (17% versus 32%) and a metallic taste (8.8% versus 18%). The authors concluded that intravaginal metronidazole is as effective as oral metronidazole in the treatment of bacterial vaginosis with significantly fewer adverse events. Skin Contact dermatitis, a rare manifestation of topical metronidazole, has been reported in two nurses [29A]. • A 67-year-old female community nurse with rosacea and no history of allergies, but a long history of a basal cell carcinoma caused by exposure to X-rays when she was young, used topical metronidazole, as RozexÒ cream (Galderma Nordic AB, Bromma, Sweden), for 2 days and developed a weeping vesicular erythematous dermatitis. The cream was discontinued and she was given systemic tetracycline. Patch tests with Rozex cream 5% and metronidazole were positive. She had previously handled metronidazole tablets and had used metronidazole pessaries without any adverse reactions. • A 40-year-old nurse with a history of contact allergy to metronidazole developed rosacea and used metronidazole cream (Alpharma,

Chapter 28

574 Gentofie, Denmark) for a few days. She developed facial edema, swelling, and itching. Tests with metronidazole cream 1% and Rozex gel (0.75% metronidazole) were positive after 3 days. She had handled parenteral metronidazole and oral tablets before without any adverse reactions.

The rapid onset of the facial dermatitis after topical metronidazole cream in both patients suggested previous sensitization, most probably from occupational exposure.

MISCELLANEOUS DRUGS For praziquantel see Chapter 31.

Eflornithine

[SED-15, 1207; SEDA- 30, 341; SEDA-32, 526] Comparative studies A standard regimen of intravenous eflornithine has been

Oscar Ozmund Simooya

compared with oral nifurtimox þ intravenous eflornithine in a multicenter, open, randomized, active control, phase III, noninferiority trial for 10 days in the Republic of the Congo and the Democratic Republic of the Congo in 287 patients aged 15 years or older with confirmed second-stage Trypanosoma brucei gambiense infection [30c]. Drug-related adverse events were frequent in both groups; 41 of those who took eflornithine and 20 of those who took the combination had major (grade 3 or 4) reactions, which resulted in temporary treatment interruption in nine and one patients respectively. The most common major adverse events with eflornithine were fever (n ¼ 18), seizures (n ¼ 6), and infections (n ¼ 5), and with the combination fever (n ¼ 7), seizures (n ¼ 6), and confusion (n ¼ 2); four deaths were regarded as being related to the study drug (three with eflornithine and one with the combination).

References [1] Sevene E, Mariano A, Mehta U, MacHai M, Dodoo A, Vilardell D, Patel S, Barnes K, Carne X. Spontaneous adverse drug reaction reporting in rural districts of Mozambique. Drug Saf 2008; 31 (10): 867–76. [2] Guévart E, Aguémon A. Deux hépatites fulminantes survenues au cours d'un traitement curatif par l'association artésunate–amodiaquine. [Two cases of fulminant hepatitis during a curative treatment with an artesunate-amodiaquine combination.] Med Mal Infect 2009; 39(1): 57–60. [3] Adjei GO, Goka BQ, Rodrigues OP, Hoegberg LC, Alifrangis M, Kurtzhals J. Amodiaquine-associated adverse effects after inadvertent overdose and after a standard therapeutic dose. Ghana Med J 2009; 43(3): 135–8. [4] Orrell C, Little F, Smith P, Folb P, Taylor W, Olliaro P, Barnes KI. Pharmacokinetics and

[5]

[6]

[7]

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tolerability of artesunate and amodiaquine alone and in combination in healthy volunteers. Eur J Clin Pharmacol 2008; 64(7): 683–90. Srinivas NR. Single-dose pharmacokinetic interaction between artesunate and amodiaquine: assembling the clues for the purported interaction. Eur J Clin Pharmacol 2008; 64(12): 1231–3. Aslanger E, Altun I. Sudden cardiac arrest in a patient taking chloroquine. Resuscitation 2009; 80(2): 285–6. Gallo CB, Luiz AC, Ferrazzo KL, Migliari DA, Sugaya NN. Drug induced pigmentation of hard palate and skin due to chronic chloroquine therapy: report of two cases. Clin Exp Dermatol 2009; 34(7): e266–7. Meller S, Gerber PA, Homey B. Clinical image: blonde by prescription. Arthritis Rheum 2008; 58(8): 2286.

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[9] Toovey S. Mefloquine neurotoxicity: a literature review. Travel Med Infect Dis 2009; 7 (1): 2–6. [10] Nevin RL. Epileptogenic potential of mefloquine chemoprophylaxis: a pathogenic hypothesis. Malar J 2009; 8: 188. [11] Thapa R, Biswas B. Childhood mefloquineinduced mania and psychosis: a case report. J Child Neurol 2009; 24(8): 1008–9. [12] Remich SA, Otieno W, Polhemus ME, Ogutu B, Walsh DS. Bullous erythema multiforme after treatment with MalaroneÒ, a combination antimalarial composed of atovaquone and proguanil hydrochloride. Trop Doct 2008; 38(3): 190–1. [13] Cairo J, Durand S, Marquiño W, Cabezas C, Lachira A, Quintana F, Vegas W, Ruebush 2nd TK, Utz G, Bacon DJ. Surveillance for adverse drug reactions to combination antimalarial therapy with sulfadoxine-pyrimethamine plus artesunate in Peru. Am J Trop Med Hyg 2008; 79(1): 42–4. [14] Karunajeewa HA, Salman S, Mueller I, Baiwog F, Gomorrai S, Law I, PageSharp M, Rogerson S, Siba P, Ilett KF, Davis TM. Pharmacokinetic properties of sulfadoxine-pyrimethamine in pregnant women. Antimicrob Agents Chemother 2009; 53(10): 4368–76. [15] Busari O, Busari O. Ventricular fibrillation in a 5-year-old child on therapeutic dose of quinine dihydrochloride infusion for acute malaria. J Natl Med Assoc 2008; 100 (8): 945–7. [16] Bougie DW, Birenbaum J, Rasmussen M, Poncz M, Aster RH. Quinine-dependent, platelet-reactive monoclonals mimic antibodies found in patients with quinineinduced immune thrombocytopenia. Blood 2009; 113(5): 1105–11. [17] Park YA, Hay SN, King KE, Matevosyan K, Poisson J, Powers A, Sarode R, Shaz B, Brecher ME. Is it quinine TTP/HUS or quinine TMA? ADAMTS13 levels and implications for therapy. J Clin Apher 2009; 24(3): 115–9. [18] Gázquez V, Gómez C, Daimau G, Gaig P, Landeyo J. A case of fixed drug eruption due to quinine. Clin Exp Dermatol 2009; 34(1): 95–7.

575 [19] Bel B, Jeudy G, Bouilly D, Dalac S, Vabres P, Collet E. Fixed eruption due to quinine contained in tonic water: positive patch-testing. Contact Dermatitis 2009; 61 (4): 242–4. [20] Khozoie C, Pleass RJ, Avery SV. The antimalarial drug quinine disrupts Tat2p-mediated tryptophan transport and causes tryptophan starvation. J Biol Chem 2009; 284(27): 17968–74. [21] Efferth T, Romero MR, Wolf DG, Stamminger T, Marin JJG, Marschall M. The antiviral activities of artemisinin and artesunate. Clin Infect Dis 2008; 47(6): 804–11. [22] Ribeiro IR, Olliaro P. Safety of artemisinin and its derivatives. A review of published and unpublished clinical trials. Med Trop (Mars) 1998; 58(3 Suppl): 50–3. [23] Adam I, Elhassan EM, Omer EM, Abdulla MA, Mahgoub HM, Adam GK. Safety of artemisinins during early pregnancy in 62 Sudanese women. Ann Trop Med Parasitol 2009; 103(3): 205–10. [24] Haq MZL, Mishra BR, Goyal N, Sinha VK. a/b-Arteether-induced mania in a predisposed adolescent. Gen Hosp Psychiatry 2009; 31(4): 391–3. [25] Ambler MT, Dubowitz LM, Arunjerdja R, Hla EP, Thwai KL, Viladpainguen J, Singhasivanon P, Luxemburger C, Nosten F, McGready R. The neurological assessment in young children treated with artesunate monotherapy or artesunate–mefloquine combination therapy for uncomplicated Plasmodium falciparum malaria. Malar J 2009; 8: 2007. [26] Carrara VI, Phyo AP, Nwee P, Soe M, Htoo H, Arunkamomkiri J, Singhasivanon P, Nosten F. Auditory assessment of patients with acute uncomplicated Plasmodium falciparum malaria treated with three-day mefloquine–artesunate on the North-Western border of Thailand. Malar J 2008; 7: 233. [27] Gonzales ML, Dans LF, Martinez EG. Antiamoebic drugs for treating amoebic colitis. Cochrane Database Syst Rev 2009; (2): CD006085. [28] Brandt M, Abels C, May T, Lohmann K, Schmidts-Winkler I, Hoyme UB. Intravaginally applied metronidazole is as

576 effective as orally applied in the treatment of bacterial vaginosis, but exhibits significantly less side effects. Eur J Obstet Gynecol Reprod Biol 2008; 141(2): 158–62. [29] Madsen JT, Lorentzen HF, Paulsen E. Contact sensitization to metronidazole from possible occupational exposure. Contact Dermatitis 2009; 60(2): 117–8. [30] Priotto G, Kasparian S, Mutombo W, Ngouama D, Ghorashian S, Arnold U,

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Ghabri S, Baudin E, Buard V, KazadiKyanza S, Ilunga M, Mutangala W, Pohlig G, Schmid C, Karunakara U, Torreele E, Kande V. Nifurtimoxeflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial. Lancet 2009; 374(9683): 56–64.

M. Lartey, K. Torpey, and J.K. Aronson

29 Editor's notes: Interferons are covered in Chapter 37. Key to abbreviations and alternative names of some antiviral drugs: • • • • • •

3TC: lamivudine (dideoxythiacytidine) AZT: zidovudine (azidothymidine) D4T: stavudine (didehydrodideoxythmidine) DDI: didanosine (dideoxyinosine) DDC: zalcitabine (dideoxycytidine) TMC125: etravirine

Antiviral drugs dysplasia of the larynx during treatment (2.7%), which is similar to the incidence of spontaneous malignant degeneration in the condition (2–3%). The authors concluded that intralesional cidofovir does not increase the risk of laryngeal dysplasia. Other adverse effects of intralesional and intravenous cidofovir were also reviewed in this article.

DRUGS ACTIVE AGAINST HERPESVIRUSES [SEDA-29,

DRUGS ACTIVE AGAINST CYTOMEGALOVIRUS

301; SEDA-30, 343; SEDA-31, 478; SEDA-32, 530]

Cidofovir [SED-15, 771; SEDA-30, 343; SEDA-31, 477; SEDA-32, 529]

Aciclovir

Tumorigenicity The potential carcinogenicity of cidofovir has been highlighted in animal and in vitro experiments [1E], and an invasive squamous cell cancer has anecdotally been reported to have arisen from squamous papillomatosis in a patient who was given multiple injections of cidofovir [2A]. The adverse effects of intralesional cidofovir in recurrent respiratory papillomatosis of the larynx have therefore been the subject of a systematic review of 31 studies involving 188 patients, with particular attention to concerns about its potential carcinogenicity [3MR]. Five patients developed Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00029-5 # 2011 Elsevier B.V. All rights reserved.

Psychiatric Cotard's syndrome is a rare psychiatric condition, in which the patient has a strong delusion of being dead. Two cases have been reported in patients taking aciclovir or valaciclovir [4A]. • A 35-year-old woman on long-term hemodialysis, taking prednisolone 5 mg/day and ciclosporin 50 mg/day developed herpes zoster and was given valaciclovir 1 g/day. After two doses she became restless and on the next day she was tired, her body felt unfamiliar, and she felt shut off from the surrounding world. That night, after the third dose she developed anxiety and visual and auditory hallucinations. The next morning she could barely walk, cried out, and appeared terrified. Her mother reported that this had been present for several hours. After 45 minutes of hemodialysis her condition improved—she no longer cried out and could speak. After an hour of dialysis she explained that she had been convinced she was dead, but that now she was not quite so sure. Valaciclovir was 577

578 withdrawn and 30 hours after the last dose her serum aciclovir concentration before dialysis was high, at 19.4 mmol/l; the serum concentration of the main metabolite, 9-carboxymethoxymethylguanine (CMMG) was also high, at 90 mmol/l, and fell during dialysis to 21 mmol/l, which is still high. • A 36-year-old man who had received a bone marrow transplant was taking ciclosporin 400 mg/day and prednisolone 25 mg/day. He developed herpes mucositis and was given oral valaciclovir 500 mg bd. After 6 days he developed diarrhea and dehydration but was afebrile, normotensive, and lucid. His plasma creatinine concentration was 419 mmol/l. The next day he was confused but a CT scan of the brain was normal. On day 8 valaciclovir was replaced with intravenous aciclovir 500 mg/day. On day 9 he awoke with fear, anxiety, and slurred speech; he was screaming and asking if he was dead. Intravenous diazepam resolved the symptoms only temporarily. The feeling of being dead reappeared the following night and he felt depressed and tired the day after. However, his confusion had subsided and his speech improved. During the next night he again believed that he was dead and considered that everybody around him was dangerous. His mental state and renal function finally returned to baseline on day 12. A blood sample 16 hours after the final dose on day 9 contained aciclovir 39 mmol/l and CMMG 29 mmol/l.

Skin In a 20-year-old woman with acute allergic contact dermatitis of the lips and perioral skin after the application of a cream containing aciclovir, scratch–patch tests (patch tests after scarification of the epidermis) with aciclovir 1%, 5% petrolatum, and the other components of the cream (CycloviranÒ) produced strong positive reactions to aciclovir and petrolatum only; conventional patch tests had been negative or doubtful [5A]. Topical 1% foscarnet cream did not produce a reaction.

Valaciclovir Placebo-controlled studies In a doubledummy, randomized, placebo-controlled study of 839 patients aged 18–75 years with Bell's palsy, prednisolone, alone and in combination with valaciclovir, shortened the time to recovery [6C]. Headache and

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gastrointestinal disturbances were the most common adverse events, and the frequencies of all adverse events were similar in all the groups.

DRUGS ACTIVE AGAINST HEPATITIS VIRUSES Adefovir

[SED-15, 35; SEDA-30, 344; SEDA-31, 480; SEDA-32, 530]

Urinary tract In 290 patients with chronic hepatitis B, of whom 145 had taken adefovir 10 mg/day, and 145 patients matched for age, sex, and baseline estimated glomerular filtration rate (eGFR), adefovir was a significant predictor of renal dysfunction (HR ¼ 3.94) [7C]. There was impaired renal tubular concentrating function within 2 years of therapy with adefovir in 11 recipients of kidney transplants with chronic hepatitis B virus infection [8c]. There was a significant rise in serum creatinine from 125 to 141 mmol/l and a significant increase in 24-hour proteinuria. Urinary pH fell from 6.60 to 5.65 and bicarbonaturia from 0.33 to 0.10 mmol/hour. Urinary hydrogen ion excretion rose from 1.79 to 2.44 mmol/l and there were significant falls in phosphatemia, phosphaturia threshold, and tubular phosphorus reabsorption; the phosphorus index of excretion rose. In 37 patients with hepatitis B virus infection, including 17 with hepatic cirrhosis, who were given adefovir plus lamivudine, serum creatinine concentrations rose in 14 cases and serum phosphate concentrations fell in six [9c]. Those who took combination therapy for 36 months or longer had a significantly increased incidence of raised serum creatinine concentrations. Fanconi syndrome occurred in a 57-year-old woman with cirrhosis after adefovir was added to lamivudine. • A 58-year-old man developed Fanconi syndrome and acute renal insufficiency after taking adefovir 10 mg/day for more than 1 year; there was also generalized osteoporosis

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579

(see “Musculoskeletal” below) [10A]. The syndrome resolved after drug withdrawal.

withdrawn. Scratch tests and patch tests were positive with entecavir.

Musculoskeletal Severe hypophosphatemic osteomalacia occurred in a 42-year-old man with hepatitis B virus-related chronic liver disease after he had taken adefovir dipivoxil 10 mg/day for 6 months; the bone lesions resolved when the hypophosphatemia was corrected [11A].

Liver A 49-year-old-man, a healthy carrier of hepatitis B virus, was given chemotherapy for non-Hodgkin's lymphoma, and entecavir was added when his hepatitis B virus DNA rose [15A]. However, the liver function tests rose over threefold and entecavir was withheld; the liver function tests quickly improved.

Drug resistance Among 65 patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B who took adefovir dipivoxil 10 mg/day for more than 1 year, adefovir resistance mutations A181V or N236T developed in 13, and were first observed after 195 weeks [12c]. Adefovir caused no serious adverse effects.

Entecavir Acid–base balance Of 16 patients with hepatic cirrhosis and chronic hepatitis B infection, five developed lactic acidosis after 4–240 days of treatment with entecavir; all five had highly impaired liver function [13c]. One patient died, but in the other four the lactic acidosis resolved after withdrawal of entecavir. The serum lactate concentrations were not increased in the other 11 patients, who all had less severe liver impairment. Child–Pugh scores did not correlate with the development of lactic acidosis, but MELD (Model for End-Stage Liver Disease) scores did, as did serum bilirubin, creatinine, and international normalized ratio (INR). The authors suggested that entecavir should be used cautiously in patients with severely impaired liver function. Hematologic A 30-year-old man with hepatitis B virus infections took oral entecavir 0.5 mg/day for 2 days and developed a hoarse voice, erythema with pruritus on his buttocks, and a leukocytosis, with a subsequent eosinophilia [14A]. Entecavir was

Ribavirin Since ribavirin is almost always used in combination with interferons, it can be difficult to know whether adverse events, if drug-induced, are due to one or the other. In many cases authors do not even discuss this problem, often attributing the supposed adverse effects to the interferon. In some cases withdrawal of one of the agents can provide evidence, and in other cases there may be other clues. For example, in cases of skin pigmentation at the site of injection of interferons, the adverse effect may be presumed to be due to interferon [16A], a type II between-the-eyes adverse effect [17H]. In one case hemolytic anemia was attributed to interferon rather than ribavirin because the patient had previously taken a course of interferon without adverse effects [18A]; presumably the inference was that the patient had been sensitized by the previous course. A systematic review of cases in which the drugs were used together and individually can also yield useful information, as in the case of pneumonitis in patients being treated with interferon and ribavirin, attributed to interferon [19AM]. Similarly, in cases of ocular myasthenia [20A], pleural effusion [21A], and cataract [22A] the interferon was blamed because no previous cases were found in association with ribavirin alone. In cases in which the adverse event persists for some time after the withdrawal of pegylated interferon and ribavirin, the long half

580

of peginterferon is cited as a possible explanation, but this is weak evidence in such cases. In some cases it may be impossible to tell whether the adverse event, if druginduced, was due to one or other of the drugs or to the combination. See also Interferons in Chapter 37. Respiratory A 50-year-old man developed progressive dyspnea over 4 months, progressing to a cough followed by frequent and abundant elimination of bronchial casts. The symptoms resolved 30 days after withdrawal and no other causes were found [23A]. Nervous system A 64-year-old man developed parkinsonism while taking peginterferon alfa-2a and ribavirin for chronic hepatitis C and did not improve when the drugs were withdrawn; he responded to co-beneldopa [24A]. This may have been coincidental. Sensory systems Auditory function Sensorineural hearing loss has been attributed to interferon plus ribavirin [25A]. • A 57-year-old man developed vertigo, tinnitus, bilateral hearing loss, and postural intolerance temporally related to the administration of pegylated interferon alfa-2b þ ribavirin for chronic hepatitis C viral infection. He had bilateral high-frequency sensorineural hearing loss, vertigo with saccadic intrusions during fixation and smooth visual pursuit, supine hypertension and orthostatic hypotension with inadequate reflex compensatory cardiovascular responses, and a hemolytic anemia. Audiometry showed changes that suggested damage to the cochlear outer hair cells. Withdrawal of therapy resulted in rapid clinical resolution with mild residual hearing loss and tinnitus.

Other similar cases have been reported, albeit in some cases with unilateral effects [26A, 27A], which suggests that the drugs may not have been responsible. Psychological Cognitive dysfunction has been studied in 47 patients with chronic hepatitis C during treatment with peginterferon alfa þ ribavirin for 48 weeks in standard doses; cognitive performance was

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significantly impaired after 12 weeks compared with controls [28C]. In 26 patients with chronic hepatitis C taking peginterferon alfa-2a or alfa-2b and ribavirin all aspects of attention were impaired after 12 weeks and the dysfunction did not resolve 8 weeks after withdrawal [29c]. The authors hypothesized that there may have been irreversible damage to the dorsolateral prefrontal cortex or anterior cingulate cortex. Endocrine Of 107 patients with non-cirrhotic chronic hepatitis C, who were given interferon plus ribavirin for 24 weeks, 20 developed thyroid dysfunction compared with 60 controls awaiting treatment [30C]. Women were at a higher risk (RR ¼ 11). Hypothyroidism was more common than hyperthyroidism. Hematologic Factors that could help predict hematological abnormalities in patients with chronic hepatitis C taking pegylated interferon and ribavirin have been studied in 136 patients over 4 years, of whom 52 developed neutropenia (n ¼ 28), anemia (30), or thrombocytopenia (11). Genotype 1, a history of hypertension, a low baseline platelet count, a low baseline hemoglobin, and a raised serum creatinine concentration were significant factors [31c]. Pure red cell aplasia has been attributed to pegylated interferon alfa-2b plus ribavirin [32A, 33A]. Mouth Hyperpigmentation of the oral mucosa and tongue has been reported in a 40-year-old Caucasian woman with hepatitis C infection who had taken peginterferon alfa-2a 90–180 micrograms/week plus ribavirin 1 g/day for 12 weeks; she had tongue discomfort and noticed irregular black patches on the lateral surface of the tongue and oral mucosa [34A]. Similarly, a 54-yearold woman developed numerous asymptomatic dark brown macules on her tongue and oral mucosa after taking peginterferon alfa-2a and ribavirin for 4 months [35A], and a 66-year-old woman developed dark brown, asymptomatic pigmentation on the dorsum of the tongue after taking

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peginterferon alfa plus ribavirin for 32 weeks; her lesions resolved within 6 months after withdrawal [36A]. Gastrointestinal 53-year-old woman with hepatitis C infection was given peginterferon 180 micrograms/week and ribavirin 1.2 g/day. After 12 weeks she developed a neutropenia of 550  106/l and a secondary enterocolitis, with bowel wall thickening involving the cecum and proximal ascending colon; she responded to broad-spectrum antibiotics, supportive treatment, and GCSF (filgastrim) [37A]. Skin The addition of ribavirin to interferon therapy may be associated with an increased risk of adverse skin reactions [38c]. The adverse cutaneous events that can occur in patients taking interferon plus ribavirin have been reviewed [39R]. In three cases oral lichen planus worsened during treatment of chronic hepatitis C with pegylated interferon and ribavirin [40A]. A 58-year-old woman developed a lichenoid eruption on the hands after taking interferon alfa-2b and ribavirin for 6 days; the lesions resolved within 1 week after withdrawal [41A]. Sexual function In a 37-year-old man taking ribavirin and pegylated interferon for hepatitis C, the percentage of progressive spermatozoa and the number of motile sperm per ejaculate fell during treatment [42A]. The round cell/spermatozoa ratio, a measure of abnormal spermatogenesis, rose from 2.6% to 24% and returned to baseline 4 months later. The sperm DNA fragmentation index increased markedly during treatment from 15% to 69% at 7 months and was still raised 8 months later. Infection risk The susceptibility factors for bacterial infections have been studied in patients co-infected with HIV and hepatitis C virus taking pegylated interferon with or without ribavirin [43c]. There were 18 bacterial infections in 17 of the 383 patients who received at least one dose of study medication. There were two cases of

581

pyelonephritis and one case of prostatitis (Escherichia coli), one case of diarrhea (Klebsiella oxytoca), two of septicemia (one due to Salmonella enterica and one to Staphylococcus aureus), one case of Streptococcus pneumoniae meningitis, eight lower respiratory tract infections (two in the same patient), one case of sinusitis, and two cases of cellulitis. Factors that were independently associated with the risk of bacterial infection were related to the duration of hepatitis C infection and to markers of liver fibrosis but not to neutropenia or characteristics of the HIV infection, including CD4 cell count. • A 35-year-old man, who had had a splenectomy at age 14 years but had not been immunized against Streptococcus pneumoniae, developed pneumococcal meningitis while taking interferon and ribavirin for chronic hepatitis C [44A].

A similar case has been reported in a 61year-old woman, with a fatal outcome [45A]. Pregnancy Ribavirin is a category X product in the US FDA's classification, which applies when “studies in animals or human beings have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience or both, and the risk of use of the drug in pregnant women clearly outweighs any possible benefit”; in such cases the drug is contraindicated in women who are or may become pregnant [46S]. It is also contraindicated in men whose partners may become pregnant. The US Ribavirin Pregnancy Registry is a surveillance system for exposure to ribavirin during pregnancy or within 6 months after treatment is stopped; it relies on patients and health-care providers to provide voluntary outcome data [47S]. Drug–drug interactions Azathioprine In a retrospective review of the medical records of eight patients who developed severe pancytopenia after-administration of azathioprine, interferon alfa, and ribavirin, bone marrow suppression reached nadir after a mean interval of 4.6 weeks, at which

582

time the mean platelet count was 70  109/l, the mean hemoglobin 7.8 g/dl, and the mean neutrophil count 450  106/l [48c]. All had a normal thiopurine methyltransferase genotype. In two patients in whom azathioprine metabolites were measured, myelotoxicity was accompanied by raised total methylated metabolite concentrations and reduced 6-tioguanine nucleotide concentrations. Pegylated interferon alfa and ribavirin were withdrawn and the full blood count returned to normal. There was no recurrence when peginterferon was reintroduced with ribavirin or azathioprine alone. The authors concluded that the combination of inosine monophosphate dehydrogenase inhibitors with purine analogues should be avoided. Another similar case has been reported [49A]. Monitoring drug therapy In a systematic review of the use of plasma ribavirin concentrations to monitor therapy in patients with chronic hepatitis C (30 studies), a previously published nine-step decision-making algorithm was used to help determine whether measurement is warranted [50M]. Some studies have supported and others have refuted the usefulness of ribavirin measurement; most had methodological limitations, such as small sample size, retrospective analyses, and lack of P value adjustment for multiple analyses. Interference with diagnostic tests The HbA1C concentration was falsely reduced by joint ribavirin and peginterferon alfa-2b therapy in a 59-year-old man with type 2 diabetes mellitus; after treatment was withdrawn the HbA1C returned to baseline [51A].

Telbivudine Cardiovascular The effects of telbivudine 600 and 1800 mg/day for 7 days on cardiac repolarization have been evaluated in 62 healthy volunteers in a randomized, placebo-controlled crossover study with moxifloxacin 400 mg as a positive control [52C].

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Moxifloxacin produced the expected significant prolongation of the QTc interval but telbivudine did not.

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS Adverse metabolic effects of antiretroviral drugs Lipodystrophy is a feature of treatment with antiretroviral drugs, particularly protease inhibitors and nucleoside reverse transcriptase inhibitors. It has been attributed to inhibition of mitochondrial DNA polymerase g [53H]. It is associated with other metabolic alterations, such as lactic acidosis, dyslipidemia, and insulin resistance, and may in turn be associated with an increase in the longterm risk of cardiovascular diseases [54R, 55C]. It causes loss of fat from the face and limbs and can be accompanied by accumulation of fat in the trunk and the back of the neck. It affects up to 50% of the patients taking highly active antiretroviral drug treatment (HAART). Efavirenz Although non-nucleoside reverse transcriptase inhibitors have not typically been associated with lipodystrophy, recent reports suggest that efavirenz may also be associated with this complication. Efavirenz prevents murine pre-adipocytes from accumulating lipids, and at high concentrations also alters the magnitude of adipocyte differentiation [56E]. However, efavirenz does not cause mitochondrial DNA depletion or cytokine expression in adipose tissue, in contrast to the antiretroviral thymidine analogues [57E]. The clinical trials data have also been reviewed [58M]. Randomized comparative trials involving efavirenz suggest that it causes a small increase (1.4–9.3%) in limb fat, more than nelfinavir, similar to atazanavir, and less than lopinavir. Although

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efavirenz increases serum cholesterol it also increases high-density lipoprotein (HDL) cholesterol, and the overall effect is neutral. Stavudine The patterns of change in body fat and metabolism caused by stavudine have been studied in 42 South African subjects [59c]. At baseline, those who went on to develop lipodystrophy were fatter and had greater skinfold thickness and higher insulin concentrations than those who never developed lipodystrophy. Triglyceride and cholesterol concentrations increased in both groups, but in those who developed lipodystrophy blood lactate and glucose concentrations increased more and insulin concentrations increased less. The lipoatrophy that has been associated with nucleoside reverse transcriptase inhibitors is accompanied by mitochondrial dysfunction, and in 10 patients who had taken stavudine, lamivudine, and lopinavir þ ritonavir for over 6 years, mitochondrial function and morphology improved after switching from stavudine to tenofovir [60c]. Weight gain has been used as a marker of recovery from stavudine-associated lipoatrophy in 114 Rwandan women [61c]. Replacement with tenofovir þ abacavir was associated with a progressive increase in weight, but zidovudine was associated with progressive weight loss. The authors suggested that alternatives such as tenofovir þ abacavir should be preferred to zidovudine in such cases. Similarly, when 62 patients taking stavudine were switched to tenofovir in a prospective study, without changing any other drug, median malar fat thickness increased by 0 8 mm within 24 months and total fat mass increased by 3.9 kg [62c]. Plasma lactate concentrations fell from 3.05 to 1.19 mmol/l, mainly in patients with baseline hyperlactatemia. There were significant improvements in total cholesterol (–12%), triglycerides (–31%), and total cholesterol/HDL cholesterol ratio (–11%). Lopinavir New-onset diabetes mellitus and exacerbation of pre-existing diabetes mellitus have been reported during post-marketing

583

surveillance of lopinavir. Treatment of HIV-negative volunteers with ritonavirboosted lopinavir for 4 weeks caused increases in triglycerides, very low density lipoprotein (VLDL) cholesterol, and free fatty acids; it also worsened glucose tolerance at 2 hours [63c]. In a 4-year follow-up of patients taking lopinavir þ ritonavir, increased non-fasting lipids was the most common laboratory abnormality [64C]. After 7 years in the same cohort of 100 patients, the commonest grade 3 and 4 laboratory abnormalities were total cholesterol over 7.8 mmol/l (cumulative incidence 27%) and triglycerides over 8.5 mmol/l (cumulative incidence 29%) [65C]. Increases in total cholesterol and triglycerides occur within the first month of starting therapy and are subsequently relatively stable [66c]. Zidovudine The differential effects of antiretroviral drugs on body fat disposition have been studied in 50 HIV-1 infected men in a randomized single-blind comparison of zidovudine þ lamivudine with lopinavir þ ritonavir and nevirapine with lopinavir þ ritonavir [67C]. In those who took the zidovudine-based therapy limb fat fell progressively from 3 months onward by a mean of 684 g up to 24 months, whereas abdominal fat increased, but exclusively in the visceral compartment. In contrast, in those who took nevirapine-based therapy there was a generalized increase in fat mass. After 24 months there were no significant differences in HDL cholesterol and the total/HDL cholesterol ratio, but total and low density lipoprotein (LDL) cholesterol were higher in those who had taken nevirapine. The mechanism whereby zidovudine is antiadipogenic has been studied in 3T3-F442A preadipocytes, which were exposed to zidovudine (1, 3, 6, and 180 mmol/l), stavudine (3 mmol/l), and dideoxycytosine (0.1 mmol/l) for up to 15 days [68E]. When they were induced to differentiate in the presence of zidovudine, the cells failed to accumulate cytoplasmic triacylglycerol and failed to express normal amounts of the later adipogenic transcription factors, CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated

584

receptor gamma. Zidovudine inhibited the completion of the mitotic clonal expansion, which resulted in incomplete cell differentiation and a reduction in the degree of adiponectin expression. It also impaired constitutive proliferation. In contrast, dideoxycytosine and stavudine had no effects. In a study of subcutaneous fat samples from 32 HIV-positive treatment-naïve patients before and 6 months after randomization to zidovudine þ lamivudine þ efavirenz (n ¼ 15) or tenofovir þ emtricitabine þ efavirenz (n ¼ 17) and 15 HIV-negative matched controls, the expression of genes involved in adipocyte differentiation, lipid metabolism, mitochondrial function, and glucocorticoid generation were profiled using real-time PCR [69c]. Lipoprotein lipase and hepatic lipase activity were assessed before treatment. Zidovudine was associated with significant increases in visceral adipose tissue and the ratio of visceral adipose tissue to subcutaneous adipose tissue, down-regulation of cytochrome B and cytochrome oxidase-3 gene expression, and up-regulation of NADH dehydrogenase and nuclear-encoded cytochrome oxidase-4 (complex IV) gene expression. Genes involved in adipocyte cortisol generation, fatty acid metabolism, and the tricarboxylic acid cycle were up-regulated. In those who took tenofovir, there were no significant changes in regional body fat or mitochondrial genes. Changes in the expression of genes involved with cortisol and fatty acid metabolism were less marked with tenofovir. In a 48-week, open, randomized comparison of continuation of twice-daily zidovudine þ lamivudine or replacement with once-daily tenofovir þ emtricitabine in 100 individuals taking successful efavirenz-based antiretroviral therapy, limb fat mass was assessed by dual X-ray absorptiometry [70C]. Fat was preserved or increased in the switch group but fell in the continuation group (mean difference 448 g, 95% CI ¼ 57, 839). The loss of limb fat was attributed to zidovudine. Genetic factors The adverse effects of nucleoside reverse transcriptase inhibitors,

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including myopathies, lactic acidosis, and peripheral neuropathy, have been associated with inhibition of human mitochondrial DNA polymerase g [71E, 72E, 73E], and an autosomal recessive mutation, arginine 964 to cysteine (R964C), has been suggested to confer a predisposition to stavudine-induced mitochondrial toxicity. In steady-state enzyme kinetic studies, the R964C polymerase g holoenzyme was only 67% efficient in incorporating deoxythymidine triphosphate (dTTP), its natural substrate, and three times less discriminatory for 2',3'-didehydro-3'-deoxythymidine-5'-triphosphate (d4TTP), the active phosphorylated metabolite of stavudine (d4T), relative to the wildtype enzyme [74E]. Lipoatrophy due to long-term use of zidovudine and stavudine may occur through different mechanisms. Surgical biopsies from 18 HIV-1 patients, 10 of whom were taking zidovudine and eight stavudine, showed that zidovudine was associated with lower adipogenesis gene expression, while stavudine was associated with significantly lower expression of genes associated with mitochondrial biogenesis [75c].

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: COMBINATIONS Cardiovascular A previously healthy young man had several episodes of syncope while taking tenofovir, emtricitabine, and nevirapine for primary HIV-1 infection. The symptoms resolved after withdrawal of antiretroviral therapy [76A]. An HIV-infected patient developed right leg edema while taking tenofovir and emtricitabine, which was attributed to a transient drug-induced fivefold increase in peripheral arterial flow caused by reduced peripheral arterial resistance attributable

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to the antiretroviral drugs [77A]. However, that this effect was unilateral suggests that it may not have been drug-induced. Musculoskeletal Changes in bone mineral density and bone turnover have been studied in 50 patients taking lopinavir þ ritonavir with either zidovudine þ lamivudine or nevirapine [78c]. Bone mineral density rapidly fell in both the femoral neck and lumbar spine after the start of therapy, and there was greater loss after 24 months in those who took zidovudine þ lamivudine. Osteocalcin and the urine deoxypyridinoline:creatinine ratio increased to the same extent in both groups. Changes in parathyroid hormone did not explain the greater bone loss with zidovudine þ lamivudine. In a comparison of changes in bone mineral density in 106 HIV-1 infected, antiretroviral drug-naive patients, who were randomized to zidovudine þ lamivudine with either efavirenz (n ¼ 32) or lopinavir þ ritonavir (n ¼ 74) for 96 weeks, the mean changes from baseline in total bone mineral density were –2.5% (lopinavir þ ritonavir) and –2.3% (efavirenz) [79c]. The authors concluded that loss of bone mineral density during antiretroviral drug therapy is independent of the drug regimen. Body temperature Within 5 hours of taking the first dose of an antiretroviral drug regimen of tenofovir 245 mg þ emtricitabine 200 mg þ abacavir 600 mg, a 45-yearold man developed a fever of 39.3 C, felt unwell, and had nausea and abdominal pain; there was no rash [80A]. The symptoms subsequently resolved, but the fever remained. During the next 13 days, he had temperatures exceeding 39 C every day, with no specific diurnal variation. The regimen was changed to lamivudine þ zidovudine þ tenofovir þ lopinavir þ ritonavir and within hours his temperature normalized and remained so thereafter. He was HLA-B*5701 negative.

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DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: NUCLEOSIDE ANALOGUE REVERSE TRANSCRIPTASE INHIBITORS (NRTI) [SED-15, 2586; SEDA-30, 349; SEDA-31, 482; SEDA-32, 534]

Abacavir [SED-15, 3; SEDA-30, 348; SEDA-31, 482; SEDA-32, 524] Cardiovascular Several studies have suggested that abacavir is associated with a high risk of cardiovascular disease [81R]. In a study of the past use of zidovudine, didanosine, stavudine, lamivudine, and abacavir in relation to myocardial infarction during 157 912 person-years of therapy in 33 347 patients, adjusted for cohort, calendar year, the use of other antiretroviral drugs, and cardiovascular risk factors that are unlikely to be affected by antiretroviral drug therapy, 517 patients had a myocardial infarction [82C]. There were no associations between the rates of myocardial infarction and cumulative or recent use of zidovudine, stavudine, or lamivudine, but recent use of abacavir or didanosine was associated with an increased rate (RR for abacavir ¼ 1.90; 95% CI ¼ 1.47, 2.45; RR for didanosine ¼ 1.49; CI ¼ 1.14, 1.95); the rates were not significantly increased in those who had stopped taking these drugs more than 6 months before. After adjustment for the predicted 10-year risk of coronary heart disease, recent use of both didanosine and abacavir was still associated with an increased rate of myocardial infarction. These results have been criticized on the grounds of possible confounding by chronic kidney disease [83r]; however, adjustment for a low eGFR did not alter the findings [84r]. This study confirms a signal that was earlier generated by a data-mining study of 4 million spontaneous reports in the WHO database, VigiBase [85c].

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Based on these data it has been calculated that the NNTH for myocardial infarction due to abacavir changes with the underlying individual risk; for example, in smokers with a systolic blood pressure of 160 mmHg and a 5-year risk of myocardial infarction of 1.3% the NNTH is 85, but it increases to 277 if the patient is a nonsmoker and to 370 if the systolic blood pressure is below 120 mmHg [86C]. The association between the use of abacavir and an increased risk of myocardial infarction has been confirmed in a prospective nationwide cohort study that included 2952 Danish HIV-infected patients taking highly active antiretroviral therapy (HAART) from 1995 to 2005 [87C]. Hospitalization rates for myocardial infarction were 2.4 per 1000 person-years (95% CI ¼ 1.7, 3.4) for abacavir non-users and 5.7 per 1000 person-years (95% CI ¼ 4.1, 7.9) for abacavir users. The risk of myocardial infarction increased after abacavir was started (unadjusted IRR ¼ 2.22; 95% CI ¼ 1.31, 3.76; IRR adjusted for confounders ¼ 2.00; 95% CI ¼ 1.10, 3.64; IRR adjusted for propensity score ¼ 2.00; 95% CI ¼ 1.07, 3.76). This effect was also observed among patients who started to take abacavir within 2 years after the start of HAART and among patients who started to take abacavir as part of a triple nucleoside reverse transcriptase inhibitor (NRTI) regimen. In contrast to these findings, a retrospective investigation of the clinical trials database held by the manufacturer showed no association of abacavir with myocardial infarction [88c, 89M]. Markers associated with cardiovascular disease may alter during therapy with abacavir. For example, there was a 20% increase in Creactive protein and interleukin-6 (IL-6) [90C]. However, in 11 patients there were no consistent changes in concentrations of Ddimers, IL-6, IL-8, TNFa, MCP-1, HGF, hsCRP, leptin, or adiponectin [91c]. Nervous system The Parsonage–Turner syndrome, an idiopathic brachial plexus neuritis, has been reported during a hypersensitivity reaction to abacavir in a 35-year-

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old man, positive for HLA B*5701, after 2 weeks of therapy [92A]. The cause of this syndrome is unknown; it could have been coincidental in this case, since it has occasionally been reported during seroconversion in HIV infection. Hematologic Neutropenia (neutrophil count 80  106/l) occurred in a 38-year-old woman who took abacavir þ lamivudine with lopinavir þ ritonavir for 3 weeks [93A]. She had a fever and mild erythema and edema on the face, trunk, and arms. She was positive for HLA-B*5701. Subsequent therapy with tenofovir þ emtricitabine and lopinavir þ ritonavir was uneventful. Liver Liver function tests became abnormal in two young HLA B*5701-negative women shortly after they switched to abacavir; they had no history of underlying liver abnormalities or concurrent susceptibility factors for liver disease [94A]. Susceptibility factors Genetic The association of HLA B*5701 with the risk of abacavir hypersensitivity skin reactions has been repeatedly reviewed [95R, 96R, 97R, 98R, 99R]. It provides an excellent example of the successful translation of a pharmacogenetic test into clinical practice and affords insights into why other tests have not been successful [100R]. However, testing may not be necessary in all communities; for example of 534 Koreans none had the HLA B*5701 polymorphism [101C]; this suggests that the incidence of hypersensitivity in this population is likely to be less than 0.6%, and testing would not be cost-effective. Nevertheless, hypersensitivity reactions to abacavir can occur in individuals who are negative for HLA B*5701, as in the case of a 41-year-old Caucasian woman who developed a fever and a severe rash after taking abacavir for 10 weeks [102A]. In one case even a patch test to abacavir was negative, in a 61-year-old man who took abacavir for 10 days before developing a fever over 40 C, muscle aches, watery diarrhea, a rash, and rhabdomyolysis; the authors suggested that another genetic association may be waiting to be found [103A].

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In populations with European ancestry, an HCP5 single-nucleotide polymorphism (SNP), rs2395029, is in linkage disequilibrium with HLA-B 5701 [104C]. In 1103 HIV-positive individuals the HCP5 SNP was present in all 98 HLA-B 5701-positive individuals and was absent in 999 of 1005 HLA-B 5701-negative individuals; rs2395029 was over-represented in 25 individuals with clinically probable abacavir hypersensitivity, compared with its frequency in 175 abacavir-tolerant individuals (80 versus 2%). The authors therefore suggested that HCP5 genotyping could serve as a simple screening tool for abacavir hypersensitivity, particularly when sequencebased HLA typing is not available. Polymorphisms at position 245 of HIV type 1 (HIV-1) reverse transcriptase are associated with HLA B*5701, and in a study of 1179 sequences from 752 patients infected with HIV-1 mutant amino acid residues were found in 31% of sequences [105C]. Among 239 patients with multiple longitudinal genotypes, residues at position 245 varied in 37 (16%) from wild type to mutant and/or vice versa. All these changes appeared during antiretroviral drug treatment. Of 229 patients who took abacavir, 15 (6.5%) developed a hypersensitivity reaction; all carried B subtypes. There was no significant difference in the prevalence of mutants at position 245 between those with hypersensitivity (27%) and those without (29%), even after limiting the analysis to carriers of subtype B. The authors concluded that the large variability in residues at position 245 and the lack of association with hypersensitivity reactions argue against using them as viral genetic markers to exclude patients at risk.

Didanosine [SED-15, 1113; SEDA-30, 348; SEDA-31, 483; SEDA-32, 535] Cardiovascular See “Abacavir”. Liver Long-term didanosine therapy was associated with non-cirrhotic portal hypertension in three HIV-positive individuals with chronic hepatitis C, mild liver fibrosis, and

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normal liver function tests, who presented with bleeding from esophageal varices [106A]. In a nested case–control study conducted by the Swiss HIV Cohort there was a strong association between prolonged exposure to didanosine and non-cirrhotic portal hypertension [107C]. In 15 patients with non-cirrhotic portal hypertension and 75 controls matched for duration of HIV infection, absence of viral hepatitis, and duration of follow-up, cumulative exposure to antiretroviral drug therapy (OR per year ¼ 1.3; 95% CI ¼ 1.0, 1.6), nucleoside reverse transcriptase inhibitors (OR ¼ 1.3; 95% CI ¼ 1.1, 1.7), didanosine (OR ¼ 3.4; 95% CI ¼ 1.5, 8.1), ritonavir (OR ¼ 1.4; 95% CI ¼ 1.0, 1.9), and nelfinavir (OR ¼ 1.4; 95% CI ¼ 1.0, 1.9) were longer in the patients with portal hypertension. Exposure to non-nucleoside reverse transcriptase inhibitors and other protease inhibitors were not different.

Lamivudine

[SED-15, 1989, SEDA-30, 344; SEDA-31, 480; SEDA-32, 531]

Hematologic Pure red cell aplasia has been attributed to lamivudine in a 29-year-old woman; it improved rapidly after drug withdrawal [108A]. In another case a patient with lamivudine-associated pure red cell aplasia required 15 units of blood over 3 weeks but recovered swiftly after withdrawal of lamivudine [109A]. The onset of pure red cell aplasia due to lamivudine is variable and occurs at any CD4 count; rapid improvement after withdrawal of lamivudine is a consistent feature. Pancreas Pancreatitis occurred in a 59-yearold man with a history of chronic hepatitis B infection after he had taken lamivudine 150 mg/day for 15 days [110A].

Stavudine

[SED-15, 3180; SEDA-32,

535] Nervous system A distal sensory polyneuropathy is a complication of HIV

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infection and is often difficult to distinguish from stavudine-associated polyneuropathy, the mechanism of which is most probably mitochondrial toxicity. Of 102 HIV-positive individuals who took stavudine-based HAART, 30 developed peripheral neurotoxicity, which was attributed to stavudine [111c]. In 96 patients in Jakarta who had taken stavudine, the prevalence of neuropathy (symptoms and signs) was 34% [112c]. The neuropathy was associated with increasing age, increasing height, and the TNFA-1031*2 gene allele. Isoniazid exposure was not associated with neuropathy and all those taking isoniazid had also taken pyridoxine. The authors suggested that based on these observations it should be possible to predict the individual risk of symptomatic neuropathy before prescribing stavudine. In patients in Melbourne, Kuala Lumpur, and Jakarta the prevalence of neuropathy was 42% in Melbourne (n ¼ 100), 19% in Kuala Lumpur (n ¼ 98), and 34% in Jakarta (n ¼ 96); increasing age and height were independently associated with the risk of neuropathy, explaining some of these differences [113c]. Acid–base balance A 42-year-old woman with advanced HIV disease who had taken stavudine, lamivudine, nevirapine, and prophylactic co-trimoxazole for 9 months developed a high anion gap metabolic acidosis with a pH of 7.15, due to lactic acidosis [114A]. She was also discovered to have persistent glycosuria, phosphaturia, and aminoaciduria, in keeping with proximal renal tubular dysfunction. The lactic acidosis was attributed to the stavudine and the Fanconi syndrome to the combination of stavudine and lamivudine.

Zidovudine [SED-15, 3713; SEDA-31, 485; SEDA-32, 536] Nervous system Palpebral ptosis in a patient taking zidovudine was attributed to mitochondrial toxicity from zidovudine; it resolved when the treatment was changed [115A].

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Hematologic Of 1089 adults taking stavudine-containing HAART (median observation time, 3 years), 290 (27%) had zidovudine substituted for didanosine, after which there were higher frequencies of anemia and leukopenia [116c]. Conversely, in 158 patients taking zidovudine, 77 of whom switched to another drug, the switch occasioned a net increase in hemoglobin of 1.1 g/dl and a net increase in neutrophil count of 541  106/l [117c]. Pure red cell aplasia occurred in a 27year-old woman who had taken zidovudine, lamivudine, and nevirapine for 1 year; it resolved when zidovudine was replaced by stavudine [118A].

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: NUCLEOTIDE ANALOGUE REVERSE TRANSCRIPTASE INHIBITORS Tenofovir

[SED-15, 3314; SEDA-30, 349; SEDA-31, 485; SEDA-32, 537]

Urinary tract Tenofovir can cause renal tubular damage, with or without small changes in glomerular filtration [119c, 120c]. Fanconi syndrome and nephrogenic diabetes insipidus have again been reported in three patients, who developed polydipsia, polyuria, weight loss, anorexia, and wasting while taking tenofovir disoproxil fumarate and didanosine [121c]. The tubular abnormalities that tenofovir can cause may be due to down-regulation of a variety of ion transporters. Because rosiglitazone, a PPAR-g agonist induces the expression of many of these transporters, it has been successfully used to ameliorate tenofovir-induced nephrotoxicity in rats [122E]. Tenofovir can also cause impaired glomerular function [123c]. In 99 patients

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taking antiretroviral drug therapy that included tenofovir, the fall in GFR during treatment was least in those who responded best [124c]. The authors suggested that improvement in GFR that occurs as a result of viral suppression may more than offset any adverse effects of tenofovir on renal function. However, tenofovir-induced renal damage may be potentiated by co-administration with a ritonavir-boosted protease inhibitor [125c]. A 31-year-old HIV-positive woman developed progressive renal insufficiency while taking tenofovir and emtricitabine in combination with efavirenz; she was also taking oral glucocorticoids, low-dose colecalciferol 25 micrograms/day, and calcium 500 mg/day, which resulted in hypercalcemia and contributed to the renal impairment [126A]. Two 16-year-old African-Americans with HIV infection developed tenofovir-associated nephropathy and renal rickets [127A]. Musculoskeletal Tenofovir can sometimes cause osteomalacia and bone fractures because of renal tubular impairment and phosphaturia [128A, 129A]. Of 22 patients, 12 had bone pain due to osteomalacia associated with abnormal tubular function, including tubular proteinuria, a reduced tubular transport maximum of phosphate, and glycosuria, all consistent with abnormal proximal tubular function [130c]. Susceptibility factors Genetic Polymorphisms in the transporter proteins that are involved in the renal elimination of tenofovir, such as organic anion transporter 1 or multidrug-resistant proteins 2 or 4, may confer an increased risk of renal tubulopathy [131R]. Twelve single-nucleotide polymorphisms (SNPs) in the ABCC2, ABCC4, SCL22A6, SLC22A11, and ABCB1 genes have been analysed in 115 HIV-infected patients, of whom 19 had renal tubular dysfunction [132c]. There were more patients with tubular dysfunction among those with genotype CC at position –24 of ABCC2 than among those with genotypes CT and TT (24 versus 6%). In a multivariate analysis, older age (OR ¼ 1.1; 95% CI ¼ 1.0, 1.2), lower body weight

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(OR ¼ 0.9; 95% CI ¼ 0.8, 0.9), and genotype CC at ABCC2 position –24 (OR ¼ 5; 95% CI ¼ 1.2, 21) were independently associated with renal tubular dysfunction. The authors suggested that homozygosity for the C allele at position –24 of the ABCC2 gene may help to identify patients who are at greater risk of tenofovir-associated tubulopathy. Pregnancy In a retrospective study of 15 pregnant HIV-infected women who took regimens containing tenofovir during 16 pregnancies (median in utero exposure 127, range 6–259, days) there were 15 successful deliveries at a median of 36 (30–40) weeks, with a median birth weight of 3255 (1135–3610) g [133c]. There was one spontaneous abortion, not attributed to tenofovir. Eleven women had abnormal laboratory results, including six with grade 1 hemoglobin abnormalities; four of them had pre-existing anemia. There were no major effects on renal function. Drug–drug interactions Amprenavir See below. Diclofenac An HIV-1-positive patient who had taken long-term tenofovir developed severe acute tubular necrosis with proximal tubular dysfunction when she also started to take diclofenac [134A]. Since she had tolerated tenofovir well for several years, the authors suggested that diclofenac had interfered with tenofovir clearance, thereby causing nephrotoxicity. However, the effect could have been due to the diclofenac alone. Oral contraceptives In a 30-day, fixedsequence, open study in 20 non-pregnant and non-lactating women aged 19–45 years who were taking norgestimate þ ethinylestradiol, tenofovir had no effect on the pharmacokinetics of deacetylnorgestimate or ethinylestradiol [135c]. Although tenofovir is unlikely to affect the pharmacokinetics of hormonal oral contraceptives, a study of this size cannot rule out an interaction in a small susceptible subset of women.

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Vancomycin Renal failure developed after a prolonged course of vancomycin in two patients who were also taking tenofovir [136A]. The authors implied that the effects of these two nephrotoxic drugs had been additive.

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTI) [SED15, 2553; SEDA-30, 349; SEDA-31, 486; SEDA-32, 537] Liver In 296 patients, of whom 151 took efavirenz and 145 nevirapine, there was severe hepatotoxicity (grade 3 to 4 rises in aspartate and/or alanine aminotransferases) in two of the former and three of the latter, and mild-to-moderate hepatotoxicity (grade 2 rises) in 6.0% and 3.4% [137c]. The only susceptibility factor for mild-tomoderate hepatotoxicity was hepatitis C co-infection. Skin Rashes are common in patients taking nevirapine, and efavirenz is often substituted. The factors that predict unsuccessful switching from have been studied retrospectively in 109 HIV-infected patients who developed a rash after taking nevirapine, of whom 20 subsequently developed an efavirenz-associated rash [138r]. A history of drug allergy apart from nevirapine (OR ¼ 11) and a CD4 cell count below 100  106/l (OR ¼ 6) were significant predictive factors.

Efavirenz [SED-15, 1204; SEDA-30, 349; SEDA-31, 486; SEDA-32, 537] Nervous system and psychiatric The most common neuropsychiatric adverse reactions

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M. Lartey, K. Torpey, and J.K. Aronson

to efavirenz have been reviewed [139R]. Status epilepticus and severe neuropsychiatric symptoms have been reported in an HIV-infected patient with cirrhosis and a high plasma efavirenz concentration; the presence of a mutation in the gene for CYP2B6 may have been relevant [140A]. The frequencies of adverse neuropsychiatric reactions have been evaluated in a comparison of two dosage regimens in a randomized, double-blind, controlled trial in 114 HIV-infected patients [141A]. They were given efavirenz either in a stepped dosage regimen (200 mg/day on days 1–6, 400 mg/day on days 7–13, and 600 mg/day on day 14 and after) or an immediate full dosage regimen (600 mg/day). In both cases two nucleoside or nucleotide reverse transcriptase inhibitors were added. The fulldose group had higher incidences and intensities of dizziness (66 versus 33%), hangover (46 versus 21%), impaired concentration (23 versus 8.9%), and hallucinations (6.1% versus 0%) during the first week. From week 2, the incidences were similar, although the intensities were greater in the full-dose group. This implies that these adverse reactions are of the early tolerant time-course in the DoTS classification (see p. xxxiii). Liver A 9-year-old boy developed liver impairment leading to hepatic encephalopathy after taking lamivudine, efavirenz, and zidovudine for 13 weeks, attributed to the antiretroviral drugs and requiring liver transplantation; he was subsequently given lamivudine, zidovudine, and raltegravir, in addition to immunosuppressants, without incident [142A]. Sweat glands Some patients taking efavirenz report excessive nocturnal sweating, which resolves after dosage reduction. A man taking efavirenz 600 mg at night developed hyperhidrosis and was found to have a high serum concentration of efavirenz; the hyperhidrosis abated with reduction of the dose to 400 mg at night and eventually stopped [143A].

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Musculoskeletal Osteomalacia in a 45-yearold woman has been attributed to induction of vitamin D metabolism by efavirenz [144A]. Susceptibility factors Genetic The ethnic and pharmacogenetic variants that affect the pharmacokinetics and actions of efavirenz have been reviewed; genetic variation is more important than ethnic variation [145R]. Efavirenz is mainly metabolized by CYP2B6, which has two important alleles, 516G and 516T. The 516T/T genotype is more frequent in Americans of African descent than in those descended from Europeans; it is associated with higher plasma concentrations of efavirenz and nevirapine and with nervous system adverse effects of efavirenz. The 16G>T polymorphism is also associated with higher plasma efavirenz concentrations, regardless of ethnic background. However, since there is a poor correlation of efavirenz concentrations with effects such as adverse neuropsychiatric reactions [146C], it is hard to know how to interpret these differences. In a UK study the 516GT polymorphism was more prevalent in Blacks than in Caucasians [147c]. There were no significant differences in the distributions of genotypes between 31 individuals who had discontinued efavirenz and 74 who had continued taking it. CYP2B6516G>T polymorphisms significantly affect the metabolism of efavirenz. In 63 HIV-infected children, median age 12 (range 3–19) years, who took efavirenz for at least 4 weeks, CYP2B6516 G/G, G/T, and T/T genotypes were found in 48%, 41%, and 11% respectively [148c]. The516G>T allele frequency was 32%. The mean concentrations of efavirenz for children with the G/G, G/T, and T/T genotypes were 1604, 2635, and 11 582 ng/ml respectively. There was a correlation between efavirenz concentrations over 4000 ng/ml and psychiatric adverse effects, but no association with rashes, hepatotoxicity, or central nervous system disturbances.

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In men from South China there was no association between efavirenz concentrations and adverse reactions; however, the authors postulated that accumulation of efavirenz can occur, causing toxicity in TT and GT genotypes [149c]. The effect of CYP2B6 genetic variation on the steady-state pharmacokinetics of efavirenz 600 mg/day in patients also taking the enzyme inducer rifampicin has been studied in 26 patients, in whom the CYP2B6 c. 516GG, GT, and TT genotype frequencies were 0.27, 0.50, and 0.23 respectively [150c]. Mean plasma efavirenz AUC was four times higher and the apparent oral clearance four times lower in patients with the c. 516TT variant than in those with the GT or GG genotypes. The authors concluded that the c. 516TT genotype can be used to identify efavirenz poor metabolizers in patients co-treated with rifampicin. The effects of rifampicin co-administration on the steady-state pharmacokinetics of efavirenz 600 mg/day have been studied in 72 patients with HIV-1 infection in South India [151c]. Peak and trough concentrations and exposure to efavirenz were significantly higher in patients with the CYP2B6 TT genotype than in those with the GT and GG genotypes. Although rifampicin co-administration reduced the peak and trough concentrations and exposure to efavirenz by 18%, 20%, and 19% respectively, the differences were not statistically significant. The trough concentration of efavirenz was subtherapeutic (less than 1.0 mg/l) in six patients. Thus, the CYP2B6 G516T polymorphism significantly altered the pharmacokinetics of efavirenz, but rifampicin did not. Liver disease In 134 HIV-infected patients, 35 co-infected with hepatitis C virus and 22 with hepatitis B virus, who took efavirenz 600 mg/day in combination with other antiretroviral drugs, the presence of hepatitis and the stage of fibrosis affected efavirenz

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plasma concentrations [152c]. The authors suggested that it would be helpful to monitor plasma efavirenz concentrations in such patients. Drug–drug interactions Antifungal azoles In a phase I, open, randomized, crossover study in healthy volunteers of co-administration of posaconazole 400 mg bd with atazanavir 300 mg/day, alone and with either ritonavir 100 mg/day or efavirenz 400 mg/day, co-administration of posaconazole and efavirenz resulted in clinically relevant reductions of posaconazole Cmax and AUC by about 45% and 50% respectively [153c]. Because of reduced posaconazole exposure, co-administration with efavirenz should be avoided if possible. Voriconazole is not recommended for use in combination with efavirenz; however, if they are co-administered, the dosage of voriconazole should be increased to 400 mg 12-hourly and the dosage of efavirenz reduced to 300 mg/day, in order to provide systemic exposure similar to standarddose monotherapy [SEDA-32, 498]. The combination of voriconazole and efavirenz in doses adjusted according to steady-state plasma concentrations has been studied in a 40-year-old man with AIDS, cryptococcosis, and mild liver cirrhosis [154A]. Adequate concentrations of voriconazole in both plasma and cerebrospinal fluid were obtained and target plasma concentrations of efavirenz were achieved at the final dosage adjustment (oral voriconazole 200 mg bd plus oral efavirenz 300 mg/day). There was stable suppression of cryptococcosis and plasma HIV viremia at long-term follow-up (66 weeks), with no significant adverse events. Antimalarial drugs There were lower concentrations of atovaquone þ proguanil in HIV-infected individuals taking efavirenz. The authors compared the pharmacokinetics of atovaquone þ proguanil between healthy volunteers and HIV-infected patients taking efavirenz and found that the geometric mean ratio AUC0!t for

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atovaquone in patients taking efavirenz. Relative to the healthy volunteers was 0.25 (95% CI ¼ 0.16, 0.38). Proguanil plasma concentrations were also significantly lower (38–43%) [155c]. Ginkgo biloba Virological failure in a 47year-old HIV-infected patient who had taken antiretroviral drug therapy for 10 years was associated with falling efavirenz plasma concentrations after he started to take Ginkgo biloba [156A].

Etravirine Etravirine is an antiretroviral drug of the non-nucleoside reverse transcriptase inhibitor (NNRTI) family that has been approved by the regulatory agencies for the treatment of patients with evidence of active viral replication who have prior experience with antiretroviral drugs and who harbor multidrug-resistant strains of HIV-1. Observational studies In clinical assessments of etravirine, the main adverse effects were rash, nausea, vomiting, and hypercholesterolemia [157r]. In the randomized double-blind DUET studies, rash was more common in those who took etravirine, and led to withdrawal in 2% of patients [158C]. Drug–drug interactions Etravirine is metabolized by cytochrome P450 enzymes and interacts in vitro with high-dose ritonavir, atazanavir, fosamprenavir, rifampicin, and some antiepileptic drugs [159E]. Darunavir þ ritonavir The interaction of etravirine 100 or 200 mg bd with darunavir þ low-dose ritonavir 600/100 mg bd has been evaluated in an open, randomized, two-way crossover phase I study in 23 HIV-negative volunteers [160c]. Darunavir þ ritonavir reduced the AUC0!12h of etravirine 100 mg bd by 37%, the Cmax by 32%,

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and the Cmin by 49%. The AUC0!12h of etravirine 200 mg bd was 80% greater than that of etravirine 100 mg bd when darunavir þ ritonavir were co-administered, and the Cmax was 81% greater, and the Cmin 67% greater (i.e. less than one would expect). The pharmacokinetics of darunavir þ ritonavir were not altered, except for a 15% increase in AUC0!12h when etravirine 200 mg bd was co-administered. The authors suggested that no dosage adjustment of etravirine is needed when it is combined with darunavir þ ritonavir.

Nevirapine Skin Nevirapine has again been associated with fatal toxic epidermal necrolysis [161A] and Stevens–Johnson syndrome extensive enough to have been called toxic epidermal necrolysis [162A, 163r]. Based on studies in rats, it has been suggested that the molecule that is responsible for such reactions is formed from nevirapine by hydroxylation to a reactive quinone methide, and cotreatment with a CYP enzyme inhibitor, 1-aminobenzotriazole, resulted in a lower incidence of reactions [164E]. The authors proposed that the hepatotoxicity of nevirapine is due to the quinone methide after its formation in the liver, and that rashes may be due to the quinone methide formed in the skin by sulfation of the 12-hydroxy metabolite followed by loss of the sulfate species. Pregnancy In 103 HIV-positive women who took nevirapine-based HAART (n ¼ 56) or non-nevirapine-based HAART (n ¼ 47) during pregnancy, there were adverse reactions necessitating withdrawal in six of the former and in only one of the latter [165c]. Susceptibility factors Genetic In HIVinfected Thai patients HLA-B*3505 had a 99% specificity in identifying nevirapineinduced rashes [166c].

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DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: PROTEASE INHIBITORS [SED-15, 2586; SEDA-30, 351; SEDA-31, 487; SEDA-32, 541] Drug–drug interactions Cat's claw In a 45year-old HIV-positive woman with cirrhosis due to hepatitis C infection the serum trough concentrations of atazanavir, ritonavir, and saquinavir increased when she took cat's claw (Uncaria tomentosa), perhaps because of inhibition of CYP3A4 [167A]. The respective concentrations with and without cat's claw were 0.30 and 1.22 mg/l (atazanavir), 0.92 and 6.13 mg/l (ritonavir), and 0.64 and 3.4 mg/l (saquinavir).

Amprenavir/fosamprenavir Liver The incidence of hepatotoxicity has been evaluated in 636 HIV-positive patients with a high frequency of viral hepatitis co-infection taking fosamprenavir þ ritonavir 700/100 mg bd; 341 (54%) had hepatitis C virus antibodies, 38 (5.6%) had serum HBsAg, and 93 (27%) of those with hepatitis C virus antibodies had an AST to platelet ratio index higher than 1.5, consistent with significant hepatic fibrosis [168c]. After a median (range) follow-up time of 7 (0.5–21) months, three patients developed grade 3 rises in alanine aminotransferase activity; all had hepatitis virus co-infections. The frequency of grade 3 rises in alanine aminotransferase activity in patients with hepatitis C antibodies was 0.58% and in those with HBsAg it was 2.6%. Four patients developed liver decompensation and one died. None of the patients with hepatic fibrosis had grade 3 rises in alanine aminotransferase activity. Drug–drug interactions Atazanavir The pharmacokinetic interaction of fosamprenavir

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1400 mg/day with atazanavir 400 mg/day for 14 days have been studied in a randomized, open, three-way crossover study in 11 men and 10 women who were HIV-seronegative [169C]. Atazanavir significantly increased exposure to amprenavir by about two times after fosamprenavir and the Cmax of amprenavir increased by about 60%. In contrast, the AUC and Cmax of atazanavir fell significantly by about 30% when fosamprenavir was co-administered. The authors recommended that this combination should not be used. Tenofovir In an open, three-period study of the interaction of tenofovir disoproxil fumarate 300 mg/day with either fosamprenavir 1400 mg bd or fosamprenavir þ ritonavir 700/100 mg for 14 days in 36 healthy subjects, steady-state plasma amprenavir and tenofovir pharmacokinetics were minimally or not significantly altered [170C].

Atazanavir Drug–drug interactions Antifungal azoles In a phase 1, open, randomized, crossover study in healthy volunteers of co-administration of posaconazole 400 mg bd with atazanavir 300 mg/day, alone and with either ritonavir 100 mg/day or efavirenz 400 mg/ day, posaconazole increased the Cmax of atazanavir by 2.6 times and the AUC by 3.7 times [153c]. Posaconazole increased the Cmax and AUC of atazanavir when it was given with ritonavir by 1.5 and 2.5 times respectively. Most of those who took atazanavir with or without ritonavir plus posaconazole had clinically relevant increases in total bilirubin. Coadministration of posaconazole and efavirenz resulted in clinically relevant reductions of posaconazole Cmax and AUC by about 45% and 50% respectively. As a result, frequent monitoring of adverse events is recommended when posaconazole and atazanavir are co-administered with or without ritonavir.

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Cat's claw See above. Fosamprenavir See above. Nevirapine Co-administration of atazanavir þ ritonavir (300 þ 100 mg/day) plus nevirapine 200 mg bd resulted in a reduction in the Cmin of atazanavir by nearly half [171c]. Monitoring of trough atazanavir concentrations is recommended in patients taking this drug combination, and it may be necessary to increase the dose of atazanavir.

Darunavir Darunavir is a protease inhibitor with activity against wild-type and protease inhibitorresistant viruses. It is indicated for treatment-experienced patients and is coadministered with ritonavir 600/100 mg bd to improve its systemic availability. Observational studies In a study of 44 treatment-experienced children who were given darunavir in doses that were based on a prior pharmacokinetic study, one withdrew because of grade 3 anxiety that was not thought to be drug-related [172C]. Comparative studies In an open randomized comparison of darunavir þ ritonavir and lopinavir þ ritonavir in 689 patients the former was associated with fewer possibly treatment-related grade 2–4 gastrointestinal adverse events (7 versus 14%) and specifically treatment-related moderate-tosevere diarrhea (4 versus 10%); adverse events that led to withdrawal occurred in 3% and 7% respectively [173c]. In the TITAN and POWER series of studies [174c, 175c, 176c], the following adverse reactions were reported: nasopharyngitis, increases in triglycerides, low density lipoprotein, total cholesterol, and blood glucose, neutropenia, nausea and diarrhea, often a cause of withdrawal, rashes, and raised aminotransferase, pancreatic lipase, and amylase activities. There was an increase in adverse events affecting the

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liver in patients co-infected with hepatitis B or C [177c]. Drug–drug interactions Atazanavir Hyperbilirubinemia and jaundice occurred during administration of atazanavir in all 23 healthy volunteers taking part in a 30-day follow-up study; there was a 52% increased minimum plasma concentration with coadministration of darunavir [178c]. Etravirine See above. Nevirapine Nevirapine has no clinically important interaction with darunavir [179C]. Oral contraceptives Norethindrone and ethinylestradiol concentrations were considerably reduced by the combination of darunavir þ ritonavir in healthy volunteers [180c]. Saquinavir The combination of saquinavir with darunavir þ ritonavir is not recommended, as plasma concentrations of darunavir are increased [181c].

595

UGT1A1*28, UGT1A3 –66T/C, UGT1A7 –57T/G, and UGT1A7(N129K/R131K), there was hyperbilirubinemia in 42%. UGT1A1*28 frequencies did not differ between HIV-positive patients and controls but were significantly more common in patients with hyperbilirubinemia [183c]. The frequency of homozygous carriers of the four UGT1A marker haplotype increased with hyperbilirubinemia, and affected all patients with bilirubin concentrations over 85 mmol/l. The authors concluded that in patients taking indinavir the risk of severe hyperbilirubinemia is associated with genetic variants of the UGT1A3 and UGT1A7 genes in addition to Gilbert's syndrome (UGT1A1*28) and that this haplotype is a useful predictor of protease inhibitor-induced adverse effects. Drug–drug interactions American ginseng In 13 healthy volunteers American ginseng had no effect on the pharmacokinetics of indinavir 800 mg tds [184c].

Lopinavir Indinavir Susceptibility factors Genetic Of 40 patients eight with the *1B/*1B genotype for the CYP3A4 gene had a 70% reduction in absorption compared with those with the *1A/*1B or *1A/*1A genotypes; those with the *1B/*1B genotype also had a significantly lower indinavir Cmax than those with the *1A/*1B or *1A/*1A genotypes and a lower increase in triglycerides during the first 4 weeks of treatment [182c]. Protease inhibitors can inhibit UDP glucuronosyl transferases (UGT) and UGT1A gene variants can influence gene transcription, inducibility, and glucuronidation activity. Indinavir can cause hyperbilirubinemia in Gilbert's syndrome, which is associated with the UGT1A1*28 polymorphism. Among 125 HIV-positive patients taking indinavir and 427 healthy blood donors who were genotyped for the presence of

Pregnancy Among 955 live births prenatally exposed to lopinavir þ ritonavir reported to the Antiretroviral Pregnancy Registry, 23 had birth defects (2.4%); among 267 live births with first-trimester exposure, five had birth defects (1.9%) [185c]. These rates are similar to the population rate of 2.7% and the rate in infants with second- or third-trimester exposure (2.6%). There was no common pattern of birth defects. Drug formulations The heat-stable formulation of lopinavir þ ritonavir has a better gastrointestinal adverse effects profile than the soft gel capsule [186c]. Drug–drug interactions Oxycodone Coadministration of oral oxycodone with lopinavir increases the oxycodone concentration [187c].

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Nelfinavir Nelfinavir has been largely displaced by second-generation protease inhibitors but is thought to inhibit experimentally induced tissue degeneration or cell damage by preventing loss of the mitochondrial membrane potential, and may even protect mitochondria in cancer cells. However, conversely, it selectively induces mitochondriaindependent cell death in cancer cells by the so-called endoplasmic reticulum/ unfolded protein stress response, allowing nelfinavir to act on otherwise chemoresistant cancer cells [188R]. Cardiovascular The effect of nelfinavir on the QT interval has been evaluated in a randomized, four-way crossover, thirdparty-blinded study in 68 healthy subjects with moxifloxacin as a positive control. Nelfinavir had no effect on the QT or QTc intervals or the RR interval, even in poor metabolizers of CYP2C19, in whom exposure was high [189C].

Ritonavir Endocrine In a systematic review of 25 cases (15 adults and 10 children) of significant adrenal suppression secondary to an interaction between ritonavir and inhaled fluticasone, and three cases involving ritonavir and intranasal fluticasone, cases with other steroids were not reported [190M]. The authors concluded that the combination of long-term fluticasone with ritonavir should be avoided and if ritonavir is required, another inhaled glucocorticoid, such as low-dose budesonide or beclomethasone, can be used cautiously. When inhaled glucocorticoids are withdrawn, the patient should be closely monitored for adrenal insufficiency. The risk of iatrogenic Cushing's syndrome followed by secondary adrenal failure, which is unusual after only a single-dose of a synthetic glucocorticoid, may

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be increased by previous exposure to ritonavir, as has been suggested by three cases of patients in whom this sequence of events occurred after they were given a single intra-articular injection of triamcinolone acetonide 40 mg [191A]. Other cases of Cushing's syndrome in patients taking ritonavir have been reported after intraarticular triamcinolone [192A], epidural triamcinolone [193A], and inhaled fluticasone [194A, 195A]. Drug–drug interactions Interactions of ritonavir with other drugs have been systematically reviewed [196M]. Ritonavir inhibits the metabolism of medications that are substrates of CYP3A and CYP2D6. It also induces CYP3A, CYP1A2, CYP2B6, CYP2C9, and CYP2C19, and glucuronyl transferase. It also has a biphasic, timedependent effect on P glycoprotein, first inhibiting then inducing its activity. These effects have been observed at both therapeutic and boosting doses, but most of the studies of low-dose ritonavir have involved a second protease inhibitor, such as darunavir, lopinavir, or tipranavir, making it difficult to distinguish the relative effects of additional medications. The inhibitory effect of ritonavir on CYP3A activity is increased in patients with HIV infection with chronic viral hepatitis [197c]. Albendazole and mebendazole In 16 healthy volunteers the pharmacokinetics of single oral doses of albendazole 400 mg or mebendazole 1000 mg were not changed by short-term ritonavir; however, long-term ritonavir resulted in significant changes in albendazole and mebendazole disposition, with significant reductions in AUC0!24h (27% and 43% of baseline respectively) and Cmax (26% and 41% of baseline) [198c]. Cat's claw See above. Quinine Downward dosage adjustment of quinine may be necessary when it is coadministered with ritonavir [199c].

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Saquinavir Drug–drug interactions Cat's claw See above.

Tipranavir Nervous system A 55-year-old HIV-infected patient ritonavir-boosted tipranavir as part of HAART developed intracranial hemorrhage during the acute phase of cryptococcal meningitis [200A]. After this, 10 cases of intracranial hemorrhage in patients taking tipranavir were identified in the Food and Drug Administration's Adverse Events Reporting System from July 2006 to March 2007 [201c]. This resulted in a black box warning stating that tipranavir “has been associated with reports of both fatal and non-fatal intracranial hemorrhage”, based on 2.6 events per 1000 person-years of surveillance, a 10-fold higher rate than that observed in an older, HIV-negative population. In a cohort study of 16 541 HIV-positive veterans, matched with 34 305 demographically similar HIV-negative veterans receiving care, and 28 023 HIV-positive MediCal recipients, 33 HIV-negative veterans, 33 HIV-positive veterans, and 373 HIV Medi-Cal recipients received incident care for intracranial hemorrhage [202C]. The crude event rates were: • HIV Medi-Cal cohort—4 cases per 1000 person-years (95% CI ¼ 3.6, 4.5); • HIV-positive veterans—0.4 cases per 1000 person-years (95% CI ¼ 0.3, 0.6); • HIV-negative veterans—0.1 cases per 1000 person-years (95% CI ¼ 0.1, 0.2).

Overall HIV status was associated with an IRR of 2.48 (95% CI ¼ 1.53, 4.02). Other independent associations were with age over 50 years (IRR ¼ 1.46; 95% CI ¼ 1.16, 1.85), minority status (IRR ¼ 1.38; 95% CI ¼ 1.14, 1.67), vascular disease (IRR ¼ 1.92; 95% CI ¼ 1.57, 2.35), alcohol abuse or dependence (IRR ¼ 1.53; 95% CI ¼ 1.18, 1.97), and liver disease (IRR ¼ 2.30; 95% CI ¼ 1.59, 3.33). The NNTH for one event per year of treatment with tipranavir was 455–5000, although the authors

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thought that they had probably overestimated the risk. Metabolism Tipranavir is associated with raised triglyceride concentrations [203C]. Liver The most common laboratory abnormalities observed in the RESIST trials were raised aminotransferase activities [203C, 204C, 205c]. Susceptibility factors included infection with hepatitis B or C and high baseline aminotransferases. In a review of the adverse hepatic effects of tipranavir in five phase IIb/III trials, there were grade 3/4 rises in aminotransferases in 144/1299 (11%) patients; 123/144 of these were asymptomatic and in most cases treatment was either temporarily interrupted or continued, and the aminotransferase activities returned to grade 2 or better [206M]. After 96 weeks the incidence of grade 3/4 rises was higher among those with liver disease (17%) than among those without (10%). The risk was greatest during the first 24 weeks (6.1%) and it fell thereafter (24–48 weeks: 3.4%; 48–72 weeks: 2.0%; 72–96 weeks: 2.2%). Four of the 144 patients developed serious hepatic adverse events and overall, 14/1299 patients (1.1%) had serious events, including six with hepatic failure. Independent susceptibility factors for grade 3/4 rises in aminotransferases included co-infection with hepatitis B and/or C and a CD4þ count over 200  106/l at baseline. Skin Toxic epidermal necrolysis has been attributed to tipranavir in a 45-year-old man; desensitization was successfully carried out using incrementally increasing oral doses over a very short period of time (Table 1) [207A]. Drug–drug interactions Tipranavir þ ritonavir In some studies co-administration of rifabutin and tipranavir þ ritonavir increased the concentrations of rifabutin and its main metabolite 25-O-desacetylrifabutin; this combination should be used with caution and adverse effects should be monitored [208r, 209c, 210c].

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598 Table 1 An oral desensitization protocol for tipranavir hypersensitivity Time (hours)

Dose

0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8 8.5

3.125 micrograms 6.25 micrograms 12.5 micrograms 50 micrograms 100 micrograms 200 micrograms 400 micrograms 900 micrograms 1.9 mg 3.9 mg 7.8 mg 15.6 mg 31.25 mg 65.25 mg 125 mg 250 mg 500 mg

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: INHIBITORS OF HIV FUSION [SEDA-28, 337; SEDA-29, 310]

Enfuvirtide Enfuvirtide is a 36 amino acid synthetic peptide used for managing HIV treatment-experienced patients. It is in powder form and must be reconstituted with sterile water for subcutaneous administration. The adult dose is 90 mg bd. Absorption does not vary by site of injection (for example, thigh, arm, or abdomen) [211C]. Enfuvirtide binds to HR 1, blocking a conformational change on gp41 required for the fusion of the lipid envelope of HIV to the cytoplasmic membrane of CD4 T lymphocytes, thus preventing viral entry [212R]. In trials adverse effects have included diarrhea and nausea, eosinophilia, and

M. Lartey, K. Torpey, and J.K. Aronson

depression (which was the most frequent adverse effect that led to withdrawal) [213C, 214C]. Enfuvirtide does not require dosage adjustment in chronic renal insufficiency [215c]. Skin Local injection site reactions are common with enfuvirtide. In the TORO 2 study, among the 338 patients given enfuvirtide 98% had at least one injection site reaction. The common signs and symptoms of injection site reactions were induration, erythema, nodules, and cysts; only 3.3% discontinued treatment as a result [213C]. There were similar and consistent findings in the TORO 1 study, which was conducted in North and South America [214C]. Biopsies of the lesion showed an inflammatory response consistent with a localized hypersensitivity reaction [216C]. In a 47-year-old man amyloidosis occurred at the injection site [217A]. Immunologic Of the 663 patients who took enfuvirtide group in the TORO 1 and 2 studies, two had systemic hypersensitivity reactions. Both recurred on rechallenge. In the first case, the reaction occurred after 8 days of treatment and was associated with a rash, fever, and vomiting [214C]. Delayed hypersensitivity reactions can occur [218A]. Drug–drug interactions Niacin Caution should be exercised when co-administering niacin and enfuvirtide in HIV-infected patients, in the light of a single report of a possible interaction [219A]. • A 47-year-old HIV-infected man with dilated cardiomyopathy, a prolonged QT interval, and an automatic implantable cardiovascular defibrillator device was given subcutaneous enfuvirtide 90 mg bd and oral extendedrelease niacin 500 mg/day. After 1 week he developed extreme redness, edema, and swelling at the injection site that corresponded with the flushing sensation due to niacin. The niacin was withdrawn and no further problems occurred with enfuvirtide alone.

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Tipranavir þ ritonavir Co-administration of enfuvirtide with tipranavir þ ritonavir was associated with markedly higher tipranavir and ritonavir trough concentrations [220c].

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: INTEGRASE INHIBITORS Raltegravir Raltegravir is the first HIV integrase inhibitor approved for treatment of HIV infection. Integration of proviral DNA into human DNA is a multi-step process, which involves binding of the enzyme to viral DNA, formation of a preintegration complex, movement of the preintegration complex from the cytoplasm to the nucleus, and then transfer of viral strands to human DNA [221R]. Raltegravir blocks the strand transfer step, by blocking the active site of the enzyme [222R]. Raltegravir is thought to have some activity against HIV-2 [223A]. Nervous system Two middle-aged men developed insomnia soon after starting to take raltegravir; it resolved rapidly after withdrawal in both cases [224Ar]. Psychiatric There have been four cases of exacerbation of depression in treatmentexperienced patients with HIV infection, who were taking antidepressants when raltegravir was introduced; the mechanism is not known [225A]. Gastrointestinal Gastrointestinal reactions, such as nausea, flatulence, and constipation, have been reported [226C]. Liver Increased aminotransferase activities have been associated with raltegravir [226C, 227C]. In a prospective study of 218

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HIV-positive patients who took raltegravir, of whom 126 were HIV mono-infected and 92 had co-infection with hepatitis C, any degree of rises in liver enzymes occurred in 10 (7.9%) and 23 (25%) respectively (RR ¼ 3.1; 95% CI ¼ 2.9, 3.4) [228C]. There was severe hepatotoxicity (grade 3–4) in three patients (1.4%), all co-infected, but in all three cases it was probably not due to raltegravir. Hepatitis C co-infection was the only independent variable associated with any degree of hepatotoxicity during raltegravir therapy. Musculoskeletal Rhabdomyolysis has been associated with raltegravir in a 46-year-old African-American man with multidrugresistant HIV [229A]. Tumorigenicity In the BENCHMRK trials, 16 of 462 patients (3.5%) who took raltegravir, compared with four of 237 (1.7%) who took placebo had a diagnosis of a new, recurrent, or progressive cancer [230C]. All the cancers were reported as serious adverse events not related to the study drug, except for a lymphoma in the placebo group that was thought to have been possibly drug-related. When adjusted for person-years of follow-up, the relative risk of cancer in those who took raltegravir was 1.54. The cancers included Kaposi's sarcoma, non-Hodgkin's lymphoma, anal and laryngeal squamous cell carcinomas, rectal adenocarcinoma, hepatocellular carcinoma, and skin carcinoma. Susceptibility factors Hepatic and renal disease Neither moderate hepatic disease nor severe renal disease alters the pharmacokinetics of raltegravir [231C]. Drug–drug interactions The pharmacokinetics and interactions of raltegravir have been reviewed [232R]. It is mainly eliminated by UGT1A1-mediated glucuronidation and it does not inhibit or induce CYP isoenzymes; there is therefore minimal risk of interactions with most commonly used drugs. This may even include drugs that are glucuronidated; for example raltegravir

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did not affect the glucuronidation of lamotrigine in 12 health volunteers [233C]. Indeed, in a systematic review of 14 drug–drug interaction studies none showed an adverse effect of raltegravir [234M]. Etravirine In an open study in 20 healthy adults etravirine had no significant effect on the steady-state pharmacokinetics of raltegravir 400 mg bd [235c]. Rifampicin Rifampicin induces drug metabolizing enzymes, leading to lower raltegravir concentrations [236c]. Tipranavir þ ritonavir In an open study in 18 healthy adults tipranavir þ ritonavir had no significant effect on the steady-state pharmacokinetics of raltegravir 400 mg bd [237c].

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: CHEMOKINE RECEPTOR CCR5 ANTAGONISTS Maraviroc Maraviroc is a cell surface chemokine receptor CCR5 antagonist, approved for the treatment of HIV-1 infection in treatment-experienced patients with CCR5 tropic HIV-1. It is used in combination with other antiretroviral drugs. It has no activity against CXCR4 tropic virus [238C]. Inhibition of CCR5 blocks the entry of HIV-1 into the cell. Cardiovascular Postural hypotension emerged as a dose-limiting event during the development of maraviroc. In a phase I single-dose study, there was orthostatic hypotension in four of nine patients who took a dose of 1200 mg [239c].

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In a single-dose, double-blind, placebocontrolled, crossover study in healthy subjects, with moxifloxacin 400 mg as an active control, maraviroc 100, 300, and 900 mg had no significant effect on the QT interval [240C]. Respiratory In the MOTIVATE trials, upper respiratory infections were more common in those who took maraviroc compared with placebo [241C]. Liver Maraviroc carries a black box warning regarding hepatotoxicity [242S]. This warning is included because the development of aplaviroc, an investigational CCR5 antagonist, was halted because of reports of hepatotoxicity [243C]. There is currently no evidence of an increased risk of hepatotoxicity associated with maraviroc [244C]. Tumorigenicity A concern related to the use of CCR5 antagonists is the potential risk of malignancies, as suggested by ACTG 5211, a trial of vicriviroc [239R]. In the MOTIVATE trials, 12 malignancies were reported—three cases of Kaposi's sarcoma and four of lymphoma in those who took maraviroc, compared with three cases of Kaposi's sarcoma and two of lymphoma in those who took placebo; this represented a lower incidence of malignancy with maraviroc [241C]. Drug–food interactions Food reduces maraviroc absorption by about 50% [245C]. When possible it should be taken on an empty stomach. Drug–drug interactions Maraviroc is a substrate of P glycoprotein and CYP3A4, by which it is about 65% metabolized. Maraviroc should therefore be used with caution when inhibitors of CYP3A4 are used concomitantly. Potent CYP 3A4 inhibitors, such as ketoconazole and protease inhibitors, except tipranavir þ ritonavir, increase maraviroc exposure; dosage reduction can compensate [246c]. Conversely, enzyme inducers, such as rifampicin and efavirenz, reduce exposure [247C]. In contrast, drugs

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that are inhibitors of renal transporters, such as co-trimoxazole and tenofovir, do not affect the pharmacokinetics of maraviroc [248C]. Co-administration of ritonavir-boosted elvitagravir and maraviroc leads to a 2–4 times increase in maraviroc concentrations, presumably because of ritonavir-mediated inhibition of CYP3A and P glycoprotein [249C]. Yellow fever vaccine The mechanism of action of maraviroc is based on the fact that a homozygous mutation of the gene encoding for CCR5 (CCR5d32) results in almost complete resistance to HIV-1 infection. However, this mutation is associated with increased severity of infection with flaviviruses, such as West Nile virus and to a lesser extent tick-borne encephalitis virus. A heterozygous mutation has been described in a patient with yellow fever vaccine-associated viscerotropic disease and it has therefore been suggested that maraviroc might potentiate the risk of this adverse effect of yellow fever vaccine [250Hr].

DRUGS ACTIVE AGAINST INFLUENZA VIRUSES: NEURAMINIDASE INHIBITORS [SED-15, 2436; SEDA-30, 352; SEDA-31, 489; SEDA32, 544]

Oseltamivir Systematic reviews In a review of 20 trials (four in prophylaxis, 12 in treatment, and four in postexposure prophylaxis), oseltamivir caused nausea (OR ¼ 1.79; 95% CI ¼ 1.10, 2.93); evidence of rarer adverse events from pharmacovigilance data was of poor quality and such events may in any case have been under-reported [251M]. In seven trials involving 7021 participants, nausea and vomiting were more common among those who took oseltamivir (RR ¼ 1.48; CI ¼ 1.86, 2.33). All the trials

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were company-sponsored and no study was powered to detect rare adverse events [252M]. Psychiatric There is some controversy about the potential of oseltamivir to cause adverse neuropsychiatric effects, since concerns were raised about the risk of hallucinations, delirium, and abnormal activity [253S, 254S]. Even deaths have been reported [255c]. The relation between oseltamivir and adverse behaviors was investigated in a large epidemiological study in Japan in the winter of 2006–2007 and the preliminary results were reported in Japanese; oseltamivir had no adverse effects [256c]. However, the statistical analysis of the results has been criticized, and it has been suggested that a more appropriate analysis shows that the rate ratio of psychiatric adverse reactions to oseltamivir was 1.57 (95% CI ¼ 1.34, 1.83) [257r]. Two other studies have since been published. In a retrospective study using electronic health-care service and pharmacy records in children aged 1–21 years with influenza there was no evidence that oseltamivir increased the risk of adverse neuropsychiatric outcomes [258c]. Similarly, in a retrospective study of patients with influenza with and without exposure to oseltamivir (n ¼ 60 267 and 175 933 respectively) and stratified according to age (17 years or under and 18 years or over), there were no increases in the incidences of claimsbased neuropsychiatric events in those for whom oseltamivir was dispensed [259c]. It should be noted that the second of these studies was carried out by the marketing authorization holder. In a cross-sectional online survey of oseltamivir prophylaxis in 95 school children with confirmed influenza A (H1N1) in London in April–May 2009, only 48% of the primary schoolchildren completed a full course, compared with 76% of the secondary school children [260c]. Mild neuropsychiatric adverse effects were reported by 18% of the children. It is still not clear what the balance of benefit to harm is in this case [261cr].

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Susceptibility factors Genetic Oseltamivir phosphate is an ethyl ester prodrug that is hydrolysed by carboxylesterase 1 (CES1) to an active metabolite, oseltamivir carboxylate. Two functional CES1 variants have been identified in a subject who had significantly reduced ability to metabolize the selective CES1 substrate, methylphenidate; they are called p.Gly143Glu and p.Asp260fs. In vitro functional studies have shown that the presence of either of the two mutations can result in greatly reduced catalytic efficiency of CES1 for methylphenidate, and a similar finding has been shown for the conversion of oseltamivir to oseltamivir carboxylate [262E]. The Vmax of the p.Gly143Glu variant was about 25% of that of the wildtype enzyme and the catalytic activity of the p.Asp260fs variant was negligible. The authors suggested that the therapeutic efficacy of oseltamivir could be compromised in patients who express either functional CES1 mutation and that there may be an increased risk of adverse effects in those who are thus exposed to high concentrations of the non-hydrolysed prodrug. Drug overdose The pattern of cases of oseltamivir self-poisoning reported to Texas poison centers during 2000–2008 has been reported, in the expectation of an increase during the influenza season [263c]. Of 298 total ingestions, 92% occurred in December–March, 77% involved patients aged 0–19 years, 73% resulted from therapeutic errors, 90% were managed on-site, and 80% had no effect. The most common adverse reactions were vomiting (7.5%), nausea (3.8%), and abdominal pain (3.8%). Drug–drug interactions Probenecid In a three-arm, open study 48 healthy volunteers were randomized to oral oseltamivir 75 mg/ day, oseltamivir 75 mg every 48 hours þ probenecid 500 mg qds, or oseltamivir 75 mg every 48 hours þ probenecid 500 mg bd for 15 days. Probenecid reduced the systemic availability of oseltamivir by about 30% and the steady-state apparent oral clearance by about 25% [264c]. The authors noted that alternate-day dosing of oseltamivir plus probenecid four times a day achieved trough

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oseltamivir concentrations adequate for neuraminidase inhibition in vitro. The effects of probenecid on the pharmacokinetics of four doses of oseltamivir have been studied in healthy Thai adults [265c]. The median half-lives were 1.0 hour for oseltamivir and 5.1 hours for oseltamivir carboxylate. In one subject there was markedly reduced hydrolysis of oseltamivir to its carboxylate, consistent with impaired carboxylesterase activity. Co-administration of probenecid resulted in a mean 40% reduction in the apparent volume of distribution of oseltamivir carboxylate and a 61% reduction in its renal elimination, with a consequent 154% increase in the AUC. The AUC increase in saliva was about three times less than the AUC increase in plasma. The authors concluded that probenecid coadministration may reduce oseltamivir dose requirements considerably. However, there is also evidence that adverse reactions may be more common when this combination is used. During a pharmacokinetic study in healthy volunteers a 68-year-old woman developed severe thrombocytopenia after taking the combination, and no other drug therapy, for 2 weeks [266A]. Her platelet count fell from 200 to 15  109/l. The two drugs were discontinued and her platelet count returned to normal within 1 week. In a review of the FDA's Adverse Event Reporting System database there were 93 cases of reduced platelet counts associated with oseltamivir and 24 associated with probenecid. Signal detection analyses were significant for oseltamivir but not probenecid.

DRUGS ACTIVE AGAINST INFLUENZA VIRUSES: ION CHANNEL INHIBITORS [SED-15, 105, 3051; SEDA-31, 489; SEDA-32, 544]

Amantadine and corneal edema Corneal edema has occasionally been attributed to amantadine, and since the first

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reports appeared in 1977 [267A, 268A] and the early 1990s [269A, 270A, 271A] sporadic cases have continued to be reported. It may be due to direct damage to endothelial cells, but its pathogenesis is not fully understood. Case reports Three patients who took amantadine developed diffuse corneal edema [272A]. In two cases the symptoms started within a few weeks and in the third case after 6 years. In the first two cases withdrawal of amantadine resulted in resolution of the corneal edema. However, the other patient received a full-thickness corneal transplant while still taking amantadine, and edema developed in the grafted cornea; withdrawal of amantadine then resulted in resolution of the corneal edema in both eyes, but the ungrafted corneal eventually also became edematous, requiring transplantation. Histopathology showed significant loss of endothelial cells. As in the last of these cases, another report documented corneal edema in a corneal transplant until amantadine withdrawn [273A]. • A 14-year-old boy with a tremor took amantadine and developed corneal edema. The corneal thickness was over 900 mm [274A]. The edema rapidly resolved after withdrawal and the corneal thickness returned to normal. • A 61-year-old man with Parkinson's disease took amantadine 300 mg/day for 8 months and developed corneal endothelial edema; withdrawal of amantadine resulted in rapid improvement of visual acuity [275A]. • A 74-year-old woman took amantadine for 8 years without problems; after a break she started taking it again and after a further 2 years developed bilateral corneal edema, which resolved within 1 month of withdrawal [276A]. • A 52-year-old woman with Parkinson's disease who had taken amantadine for 6 years developed bilateral corneal edema for 2 months; amantadine was withdrawn and the edema resolved; amantadine was reintroduced and the corneal edema recurred; amantadine was then permanently withdrawn and the corneal edema again resolved [277A]. • A 12-year-old girl took amantadine HCl 100 mg bd for 4 months and developed bilateral blurred vision which progressed. She had corneal edema and the central corneal thicknesses were 851 mm in the right eye and 886 mm in the left eye (reference range 509–613) [278A]. • A 55-year-old woman took amantadine HCl 100 mg bd for several years and developed severe corneal edema in both eyes; central corneal thicknesses were 930 and 934 mm [278A].

603 • A 39-year-old woman developed bilateral corneal edema after taking amantadine for 2 months [279A]. Corneal thicknesses were 940 mm in the right eye and 802 mm in the left. There was diffuse stromal edema, folds in Descemet's membrane, and microcystic subepithelial edema. Specular microscopy showed significant pleomorphism and polymegathism with an endothelial cell count of 1504 cells in the right eye and 1596 in the left eye. • A 68-year-old woman with Parkinsonism took amantadine HCl 100 mg bd for 2 years and developed corneal edema, with central corneal thicknesses of 871 mm in the right eye and 746 mm in the left eye [280A]. There was bilateral diffuse stromal and epithelial edema with marked folds in Descemet's membrane. The amantadine was withdrawn and topical prednisolone acetate 1% and sodium chloride eye-drops were given. There was complete resolution within 3 weeks, and the corneal thicknesses resolved (592 mm in the right eye and 567 mm in the left eye). • A 45-year-old woman developed amantadineassociated corneal edema, which did not resolve despite withdrawal of amantadine and treatment with glucocorticoids [281A]. She therefore underwent sequential phakic Descemet's stripping automated endothelial keratoplasty (DSAEK), with significant. Histology of Descemet's membrane by light microscopy showed a paucity of endothelial cells. • A 61-year-old woman with Parkinson's disease was given amantadine, followed over the next 6 years by pramipexole, ropinirole, co-careldopa, and entacapone [282A]. She subsequently developed severe corneal edema. Amantadine was withdrawn and within 1 month the corneal edema had completely resolved. The corneal thicknesses improved from 810 to 640 mm in the right eye and from 780 to 660 mm in the left eye.

Post-marketing surveillance In a post-marketing surveillance study of patients with a new diagnosis of corneal disease and new prescriptions for amantadine over 2 years, 36 (0.27%) of 13 137 patients developed corneal edema [283C]. The relative risk of corneal edema was 1.7 (95% CI ¼ 1.1, 2.8); in 12 patients (0.09%) the diagnosis was made in the first month. However, it has been suggested that the specific keratopathy that is associated with a pseudoexfoliation (PEX) syndrome, caused by direct involvement of the corneal endothelium is part of the differential diagnosis of corneal edema in such cases. The authors of this suggestion reported that they had found that about 10% of patients diagnosed as having corneal edema (also called

604

Fuchs’ dystrophy) in fact had PEX keratopathy [284r]. In response, the authors of the original study replied that they agreed that it was not possible to be sure whether amantadine causes corneal decompensation, or if it merely accelerates an underlying endothelial process, and that the pathogenesis of amantadine-associated corneal edema is obscure and may be multifactorial. However, they were confident that none of their patients had any clinical findings that would have suggested a diagnosis of PEX keratopathy. Furthermore, in support of a direct effect of amantadine, they cited clear cases in which dechallenge and rechallenge had resulted in corneal edema [285r]. Psychiatric A 19-year-old man took amantadine 100 mg bd for influenza and the next developed auditory and visual hallucinations, which resolved after withdrawal of amantadine [286A]. Altered mental status has also been attributed to amantadine in a 27-year-old woman with a kidney transplant [287A]. Endocrine A 66-year-old woman with Parkinson's disease developed muscle weakness, anorexia, weight loss, and had severe hyponatremia due to the syndrome of inappropriate ADH secretion (SIADH) after taking amantadine; after withdrawal the symptoms disappeared and the sodium concentration returned to normal [288A]. Urinary tract A 69-year-old woman developed seizures and acute renal insufficiency

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with hydronephrosis, which was attributed to urinary retention due to amantadine; a single hemodialysis, with reduction of amantadine concentrations, resolved the problem [289A]. Skin Livedo reticularis has again been reported, in a 58-year-old woman with chronic genotype 1b hepatitis C, who developed an asymptomatic, mild, mottled, reddish-brown eruption on the thighs and arms, associated with severe edema, after taking peginterferon alfa-2a 180 micrograms/week, ribavirin 400 mg bd, and amantadine 100 mg bd; it resolved when the amantadine was withdrawn and the other drugs were continued [290A]. Drug overdose Two cases of massive, acute ingestion of amantadine hydrochloride were associated with serious adverse cardiovascular effects [291A]. • A 47-year-old woman took 10 g of amantadine (150 mg/kg) and had a pulseless cardiac arrest with ventricular tachycardia; she was resuscitated with difficulty. A 33-year-old woman took 10 g of amantadine hydrochloride; her QTc interval was 526 msec and the serum potassium 3.0 mmol/l; she recovered after potassium repletion. • A 2-year-old boy who took 0.8–1.5 g of amantadine developed generalized seizures followed by status epilepticus, with alternating generalized tonic–clonic and partial seizures, over 7 hours; he also had a sinus tachycardia and reactive bilateral mydriasis [292A]. All the symptoms resolved within 20 hours.

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concomitante de fluticasone et de ritonavir. [Cushing's syndrome induced by combined treatment with inhaled fluticasone and oral ritonavir.] Rev Mal Respir 2009; 26(7): 779–82. Foisy MM, Yakiwchuk EM, Hughes CA. Induction effects of ritonavir: implications for drug interactions. Ann Pharmacother 2008; 42(7): 1048–59. Knox TA, Oleson L, von Moltke LL, Kaufman RC, Wanke CA, Greenblatt DJ. Ritonavir greatly impairs CYP3A activity in HIV infection with chronic viral hepatitis. J Acquir Immune Defic Syndr 2008; 49(4): 358–68. Corti N, Heck A, Rentsch K, Zingg W, Jetter A, Stieger B, Pauli-Magnus C. Effect of ritonavir on the pharmacokinetics of the benzimidazoles albendazole and mebendazole: an interaction study in healthy volunteers. Eur J Clin Pharmacol 2009; 65(10): 999–1006. Soyinka JO, Onyeji CO, Omoruyi SI, Owolabi AR, Sarma PV, Cook JM. Pharmacokinetic interactions between ritonavir and quinine in healthy volunteers following concurrent administration. Br J Clin Pharmacol 2010; 69(3): 262–70. Chrysos G, Gerakari S, Stasini F, Kokkoris S, Kourousis D, Velegraki A. Intracranial haemorrhage possibly related to tipranavir in an HIV-1 patient with cryptococcal meningitis. J Infect 2008; 57 (1): 85–7. Chan-Tack KM, Struble KA, Birnkrant DB. Intracranial hemorrhage and liver-associated deaths associated with tipranavir/ritonavir: review of cases from the FDA's Adverse Event Reporting System. AIDS Patient Care STDS 2008; 22 (11): 843–50. Justice AC, Zingmond DS, Gordon KS, Fultz SL, Goulet JL, King Jr. JT, Bravata DM, Valdez H, Kraft M, Mattocks KM. Veterans Aging Cohort Study Project Team. Drug toxicity, HIV progression, or comorbidity of aging: does tipranavir use increase the risk of intracranial hemorrhage? Clin Infect Dis 2008; 47(9): 1226–30. Walmsley SL, Katlama C, Lazzarin A, Arestéh K, Pierone G, Blick G,

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Johnson M, Meier U, MacGregor TR, Leith JG. Pharmacokinetics, safety, and efficacy of tipranavir boosted with ritonavir alone or in combination with other boosted protease inhibitors as part of optimized combination antiretroviral therapy in highly treatment-experienced patients (BI Study 1182.51). J Acquir Immune Defic Syndr 2008; 47(4): 429–40. Hicks CB, Cahn P, Cooper DA, Walmsley SL, Katlama C, Clotet B, Lazzarin A, Johnson MA, Neubacher D, Mayers D, Valdez H. RESIST investigator group. Durable efficacy of tipranavir–ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. Lancet 2006; 368(9534): 466–75. Gathe Jr. JC, Pierone G, Piliero P, Arasteh K, Rubio R, Lalonde RG, Cooper D, Lazzarin A, Kohlbrenner VM, Dohnanyi C, Sabo J, Mayers D. Efficacy and safety of three doses of tipranavir boosted with ritonavir in treatment-experienced HIV type-1 infected patients. AIDS Res Hum Retroviruses 2007; 23(2): 216–23. Mikl J, Sulkowski MS, Benhamou Y, Dieterich D, Pol S, Rockstroh J, Robinson PA, Ranga M, Stern JO. Hepatic profile analyses of tipranavir in phase II and III clinical trials. BMC Infect Dis 2009; 9: 203. Martínez Castro B, Ferrando Piqueres R, Martínez García M, Soler Company E. Desensitization to tipranavir caused by toxicodermia. Farm Hosp 2009; 33(6): 340–2. Apseloff G. Severe neutropenia among healthy volunteers given rifabutin in clinical trials. Clin Pharmacol Ther 2003; 74 (6): 591–2. Cato 3rd A, Cavanaugh J, Shi H, Hsu A, Leonard J, Granneman R. The effect of multiple doses of ritonavir on the

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Kolmer EW, van der Kolk M, Hoitsma A, da Silva HG, Burger DM. The effect of raltegravir on the glucuronidation of lamotrigine. J Clin Pharmacol 2009; 49(10): 1220–7. Burger DM. Drug-drug interactions with raltegravir. Eur J Med Res 2009; 14 (Suppl 3): 17–21. Anderson MS, Kakuda TN, Hanley W, Miller J, Kost JT, Stoltz R, Wenning LA, Stone JA, Hoetelmans RM, Wagner JA, Iwamoto M. Minimal pharmacokinetic interaction between the human immunodeficiency virus nonnucleoside reverse transcriptase inhibitor etravirine and the integrase inhibitor raltegravir in healthy subjects. Antimicrob Agents Chemother 2008; 52(12): 4228–32. Wenning LA, et al. Effect of rifampin, a potent inducer of drug-metabolizing enzymes, on the pharmacokinetics of raltegravir. Antimicrob Agents Chemother 2009; 53(7): 2852–6. Hanley WD, Wenning LA, Moreau A, Kost JT, Mangin E, Shamp T, Stone JA, Gottesdiener KM, Wagner JA, Iwamoto M. Effect of tipranavir–ritonavir on pharmacokinetics of raltegravir. Antimicrob Agents Chemother 2009; 53(7): 2752–5. Dorr P, Westby M, Dobbs S, Griffin P, Irvine B, Macartney M, Mori J, Rickett G, Smith-Burchnell C, Napier C, Webster R, Armour D, Price D, Stammen B, Wood A, Perros M. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother 2005; 49(11): 4721–32. McNiff T, Dezube BJ. CCR5 antagonists in the treatment of HIV-infected persons: is their cancer risk increased, decreased, or unchanged. AIDS Read 2009; 19(6): 218–22 224. Davis JD, Hackman F, Layton G, Higgins T, Sudworth D, Weissgerber G. Effect of single doses of maraviroc on the QT/QTc interval in healthy subjects. Br J Clin Pharmacol 2008; 65(Suppl 1): 68–75.

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Drugs used in tuberculosis and leprosy

Multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis Despite the availability of effective anti-mycobacterial agents and many technological advances in the diagnosis and treatment of tuberculosis over the past 65 years, the disease still continues to cause major morbidity and mortality, especially in developing countries. The HIV epidemic and the increasing resistance of strains of Mycobacterium tuberculosis to antituberculosis drugs are posing potent threats to global control. During 2008, there were an estimated 8.9–9.9 million new cases and 1.55–2.32 million deaths in patients with tuberculosis [1S]. The phenomenon of drug resistance in tuberculosis is not new. Soon after the efficacy of streptomycin against Mycobacterium tuberculosis was discovered, the UK's Medical Research Council reported that deaths in patients were the same irrespective of whether they were treated with streptomycin, and most of the deaths in the treated group occurred in those who were suffering a relapse due to streptomycin-resistant strains [2c]. Standard short-course chemotherapy using multiple drugs kills all bacilli located in different environments (pulmonary cavities, pus, solid caseous material, macrophages), including naturally occurring

Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00030-1 # 2011 Elsevier B.V. All rights reserved.

monodrug-resistant strains (killed by the other drugs) and controls the further emergence of resistance [3R]. Multidrug-resistant (MDR) tuberculosis, defined as disease caused by Mycobacterium tuberculosis resistant to isoniazid and rifampicin, the two most potent antituberculosis drugs first attracted global attention in the late 1980s and early 1990s with a rash of institutional outbreaks of MDR tuberculosis in predominantly HIV-infected patients in the USA [4C]. Since then there have been reports of outbreaks in other parts of the world, fuelling global apprehension of increasing levels of drug resistance in tuberculosis. Extensively drug-resistant (XDR) tuberculosis was first described in South Africa in 2006 [5C], and is defined as MDR tuberculosis with additional resistance to any of the fluoroquinolones and to any of the following injectable agents: kanamycin, capreomycin, amikacin. Commissioned by the WHO and the International Union against Tuberculosis and Lung Diseases, the Global Project on Antituberculous Drug Resistance Surveillance published a series of reports in 1997, 2001, 2006 and 2008. According to the last report, between 390 000 and 510 000 new cases of MDR tuberculosis emerged globally (best estimate 440 000 cases) in 2008 [6S]. Among all incident cases of tuberculosis, 3.6% (95% CI ¼ 3.0, 4.4) were estimated to have MDR tuberculosis. Almost 50% of these cases are estimated to have occurred in India and China. In the same year MDR tuberculosis caused an estimated 150 000 deaths. Data from 46 countries that have continuous surveillance or representative 623

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surveys of second-line drug resistance among patients with MDR tuberculosis suggests that 5.4% of this category of patients have XDR tuberculosis. Eight countries reported XDR tuberculosis in more than 10% of cases of MDR tuberculosis. A total of 58 countries have confirmed at least one case of XDR tuberculosis. Considering that these figures are most probably underestimates of the real prevalences, it would be fair to say that this issue is of alarming significance.

tuberculosis, are also available [10R]. These are the tetrazolium salt-based assay, used for direct detection of rifampicin resistance from sputum samples, the risazurin microtiter assay and the nitrate reduction assay, which provides rapid, accurate, and costeffective diagnosis of MDR tuberculosis. Phage-based assays use mycobacteriophages to infect live Mycobacterium tuberculosis in the absence or presence of antituberculosis drugs and detect the bacilli using either a phage amplification assay (FAST Plaque tuberculosis-response assay) or production of light, using luciferase reporter mycobacteriophages [11E]. These methods provide results in 2 days. Molecular genotypic susceptibility testing methods detect resistance-associated mutations in target genes of Mycobacterium tuberculosis and can be performed on clinical samples directly [12E]. Genotypic methods have been developed for all first-line and many secondline drugs. Since 90–95% of rifampicin-resistant strains contain mutations in a small region of a single gene (rpoB), and rifampicin resistance is a surrogate marker for MDR tuberculosis, the detection of resistance to rifampicin is a priority [13E]. For other drugs the sensitivity of resistance detection varies widely, owing to the number of gene loci involved and the diversity of mutations [14R]. The PCR-restriction fragment length polymorphism (PCR-RFLP) analysis is a simple and rapid method for detecting polymorphisms at a single or few codons that are mutated. The test is used to detect mutations in katG315 for isoniazid resistance [15E] and in embB306 for ethambutol resistance [16E]. DNA sequencing is the most reliable method of detecting mutations that may contribute to resistance, and is most practical if the majority of drug-resistant strains contain mutations in a limited region of a single gene, such as with the rpoB gene for rifampicin resistance. DNA sequencing is still considered impracticable in most developing countries for analysing large volume of samples. However, recent technological advances may result in rapid, accurate, and cost-effective analysis of DNA sequences for diagnosis of MDR tuberculosis [17R]. A commercial real-time PCR-based assay is now available for detection of

Diagnosis of multidrug-resistant tuberculosis The building of laboratory capacity to diagnose MDR tuberculosis and undertake surveillance of antituberculosis drug resistance is one of the most important challenges in scaling-up care for MDR and XDR tuberculosis. The rapid detection of drug resistance facilitates effective treatment and limits further development of resistance to additional drugs. Conventional phenotypic methods require culture and detection of growth of Mycobacterium tuberculosis in the presence of antituberculosis drugs on solid media. This may take up to 6 weeks, a delay that is expensive in terms of denial of appropriate treatment and continued transmission of drugresistant disease in the community. Recent research has significantly shortened this time lag by introducing improved diagnostic techniques, using both conventional (phenotypic) and molecular (genotypic) methods. The radiometric BACTEC TB system using broth-based media makes drug susceptibility test results available in 4–12 days from primary cultures [7E]. Recently, nonradiometric fully automated liquid culture systems have been developed, of which the most important is the BACTEC MGIT system [8M]. However, these automated liquid culture systems are expensive for resourcepoor countries. The microscopic observation drug susceptibility (MODS) test is a lowcost, rapid, and direct assay for detection and susceptibility testing of Mycobacterium tuberculosis in sputum specimens, results being available within 2 weeks [9E]. Calorimetric methods, based on redox indicators that are added to the culture medium during in vitro growth of Mycobacterium

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rifampicin resistance (Xpert MTB, Cepheid). Another important technology that has emerged is the reverse hybridization based Line Probe Assay (macro-arrays) and microarray-based assays for detection of MDR strains directly from clinical specimens. The INNO-LiPA Rif TB assay (Immunogenetics) detects mutations in the rpoB gene [18E]. The GenoType MTBDRplus assay (Hain Lifesciences) detects MDR tuberculosis by simultaneously detecting mutations in the rpoB gene for rifampicin resistance, and the katG315 and inhA genes for isoniazid resistance [19E]. Results are available within one working day. Line probe assays have also been developed for detecting resistance of Mycobacterium tuberculosis to pyrazinamide [20E] and fluoroquinolones [21E]. Multidrug-resistant tuberculosis and HIV The association between MDR tuberculosis and HIV infection is still not clear. A systematic review has suggested no clear association between MDR tuberculosis and HIV infection across time and geographic locations. In the 32 eligible studies the prevalence ratios for MDR tuberculosis were 0.21–41 [22M]. The summary prevalence ratios for acquired and primary MDR tuberculosis were 1.17 (95% CI ¼ 0.86, 1.6) and 2.72 (95% CI ¼ 2.03, 3.66), respectively. However, the studies qualifying for review were few, and most studies were not adjusted for confounders and heterogeneity. Of 270 South African patients with XDR tuberculosis, 55% were HIV negative [17R]. Management There is evidence that an efficiently organised and implemented TB control programme with rational use of first line antiTB drugs can prevent the emergence of drug resistance in the community. While the treatment of drug-susceptible tuberculosis is efficacious and cost-effective, the management of MDR tuberculosis is a therapeutic challenge. Second line antituberculosis drugs are mainly bacteriostatic, less effective, and costly and have more adverse effects. The treatment costs for MDR tuberculosis are prohibitive, and many developing countries can ill afford this. Current guidelines for management of MDR tuberculosis require the availability of

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rapid diagnostic facilities and susceptibility testing for first-line and second-line antituberculosis drugs. Because of the poor prognosis, rapid diagnosis of MDR tuberculosis is even more crucial in HIV co-infected individuals. The susceptibility profile is useful for tailoring individual treatment regimens and for monitoring responses to treatment. There is evidence that individual treatment regimens guided by susceptibility results have better clinical outcomes [23C]. Regimens should include a fluoroquinolone, an injectable agent from among kanamycin, amikacin, and capreomycin, and three or four other second-line drugs for a minimum of 24 months. The best results are achieved with in-patient treatment [24C]. However, recent studies have shown that successful outcomes can also be obtained in community settings [25C]. Community-based treatment, apart from the advantage of not disrupting routine activities, also reduces the chances of nosocomial transmission of infection. Many developing countries are now implementing a DOTS Plus component that provides diagnosis and treatment of MDR tuberculosis with a standardized regimen, under the aegis of national tuberculosis control programs. The WHO's Green Light Committee has subsidized drug prices, but still only about 10% of patients with MDR tuberculosis in developing countries are currently being treated under the GLC program [17R]. The treatment of XDR tuberculosis is even more difficult, as the choice of effective drugs is severely limited. Chemotherapy with appropriate drugs, close monitoring for adherence and adverse reactions, and other interventions, such as surgery, will be required. XDR tuberculosis is virtually untreatable, and every effort should be made to minimize its emergence by effectively treating MDR tuberculosis. The most recent specific tuberculosis drug, rifampicin, was introduced more than 40 years ago. The challenges posed by the HIV epidemic and drug resistance over the past two decades have finally prompted a search for new tuberculosis drugs. Initiatives such as the Global Alliance for New TB Drug Development have ensured that efforts are now in place to develop new agents with

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novel modes of action. The Global Alliance is an NGO that facilitates the development of new drugs for tuberculosis. A number of promising new drugs are in the pipeline, and some are in advanced stages of clinical testing. These are TMC 207, a diarylquinoline that inhibits ATP synthase [26R], and PA-824, a nitro-imidazo-oxazine [27E], both of which are undergoing phase II clinical trials; OPC 67683, a nitro-imidazo-oxazone [28E]; and SQ-109, an ethylenediamine related to ethambutol [29E]. However, it will be many years before these drugs become available for clinical use. Meanwhile, properly designed clinical trials to evolve optimum regimens for the treatment of MDR tuberculosis and XDR tuberculosis are sorely needed.

Liver function normalized in 10 of these within 2 weeks from the end of therapy. Drug-induced hepatotoxicity did not recur after reintroduction of therapy. Only one patient died from fulminant hepatic failure, despite withdrawal of all antituberculosis drugs. Univariate analysis showed that patients with drug-induced hepatotoxicity had more pre-existing liver disease (OR ¼ 3.60; 95% CI ¼ 1.16, 11), a lower body mass index (OR ¼ 3.73; 95% CI ¼ 1.04, 11), a lower serum albumin (OR ¼ 3.31; 95% CI ¼ 1.04, 11), and more extensive disease (OR ¼ 3.50; 95% CI ¼ 1.11, 11). Age, sex, raised baseline aminotransferase activities, the use of pyrazinamide, and inactive hepatitis B or C carrier state were not significant susceptibility risk factors. Multivariate regression analysis showed that only pre-existing liver disease and a lower body mass index (20 kg/m2 or under) were independent predictors of druginduced hepatotoxicity. The authors concluded that antituberculosis drug-induced hepatotoxicity is not uncommon, needs early recognition and treatment, and is more common in patients with pre-existing liver disease and a low body mass index. Tuberculosis chemoprophylaxis has been retrospectively evaluated in 63 Spanish patients with latent tuberculosis out of 497 with inflammatory bowel disease who were candidates for anti-TNFa therapy [31C]. Skin tests for tuberculosis were positive in 86% after a single exposure, but 14% needed a booster. There were no susceptibility factors for hepatotoxicity. All but one was treated with isoniazid alone for 6 or 9 months, and only one required chemoprophylaxis withdrawal because of hepatotoxicity. There were no cases of active tuberculosis in the patients who were treated with anti-TNFa therapy. The authors concluded that chemoprophylaxis is safe in patients with inflammatory bowel disease, even in those taking concomitant, potentially hepatotoxic drugs.

Conclusions Mycobacterium tuberculosis has been in existence for many centuries and has adapted to the many challenges it has faced over time, including the development of resistance to the agents used against it. The many recent advances in the management of tuberculosis are being threatened by the emergence of drug resistance and the HIV epidemic. The rational treatment of drug susceptible tuberculosis and the establishment of adequate laboratory support is essential in combating the threat of drug resistance. The lessons of the past have to be borne in mind to manage this challenge better. Initiatives for new rapid diagnostics and the handful of new antituberculosis drugs that are in the pipeline are belated but nevertheless welcome developments to combat this threat. Sustained activities in these and other fields are mandatory if the millennium goals for global tuberculosis control are to be achieved. Liver The incidence and susceptibility factors for antituberculosis drug-induced hepatotoxicity have been assessed in a prospective cohort study in 100 Egyptian patients with active pulmonary and extrapulmonary tuberculosis [30c]. Therapy included daily doses of isoniazid, rifampicin, ethambutol, and pyrazinamide, or streptomycin. There was drug-induced hepatotoxicity in 15 patients within 15–60 (median 30) days from the onset of therapy.

M.S. Jawahar and V.V. Banu Rekha

Susceptibility factors HIV infection The effect of HIV co-infection on the frequency of serious adverse events of antituberculosis drugs has been studied retrospectively in 400

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South African patients, of whom 141 were coinfected with HIV, 23 taking antiretroviral drugs [32c]. Details of serious adverse events were ascertainable in 331 patients and occurred in 27% of HIV-infected and 13% of HIV-uninfected individuals. The excess was attributable to increase incidences of peripheral neuropathy (8.3% versus 1.9%) and persistent vomiting (13% and 3.3%). The occurrence of serious adverse events was not related to antiretroviral drug use, although median CD4 cell counts were lower in those with adverse effects (130 versus 259  106/l).

Antituberculosis drug treatment in transplant recipients Renal transplant recipients The characteristics of tuberculosis in renal transplant recipients have been analysed in a retrospective study in China [33c]. There were 41 documented post-transplant tuberculosis cases out of the 2333 patients who received kidney transplants between 1991 and 2007. Tuberculosis in these patients had the following characteristics: (i) a high incidence within a short time after transplantation, the median interval between renal transplantation and diagnosis of tuberculosis being 8 (range 1–156) months and 56% were diagnosed within the first year after transplantation; (ii) a high prevalence (51%) of extra-pulmonary tuberculosis; (iii) a high co-infection rate with other pathogens (20%), including Candida albicans, Pseudomonas aeruginosa, Staphylococcus aureus, Acinetobacter hemolyticus, and cytomegalovirus; (iv) fever (83%), cough (56%), and sputum production (39%) were the most common clinical manifestations; (v) PPD skin testing had little diagnostic value, with negative results in all 41 cases; (vi) acute rejection (29%) and liver function damage (17%) were the main adverse effects of antituberculosis chemotherapy; (vii) mortality among patients with tuberculosis after transplantation was 22%. The authors concluded that renal transplant recipients face a high risk

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of tuberculosis because of their immunocompromised state and the prevalence of the disease. Balancing the benefits and disadvantages of antituberculosis treatment is of importance for this specific population. The incidence of tuberculosis among renal transplant recipients between 1984 and 2007 has been analysed in a retrospective study in Brazil [34c]. Of 1342 renal transplant recipients, 31 received treatment for clinical tuberculosis (n ¼ 23) or as prophylaxis (n ¼ 8). The overall incidence of tuberculosis was 1.71%, diagnosed at a mean of 53 months after transplantation. The indications for tuberculosis prophylaxis were a previous history of tuberculosis (n ¼ 6) or direct contact with a tuberculosis carrier (n ¼ 1). The most common clinical presentation was extrapulmonary tuberculosis (n ¼ 13). Classical treatment was effective in 16 cases. However, seven cases of drug-resistant tuberculosis required additional ethambutol. Adverse events included liver toxicity (n ¼ 1) and peripheral neuropathy (n ¼ 1). Three patients died with tuberculosis-related complications. There was graft loss in three patients after the end of antituberculosis drug treatment. None of those on prophylaxis developed clinical disease. Thus, the incidence of tuberculosis was significantly higher among renal transplant recipients compared with the local population, with a higher incidence of extrapulmonary disease. Tuberculosis prophylaxis in selected cases was effective in avoiding new infections. Heart transplant recipients The incidence of tuberculosis among 315 heart transplant recipients has been studied in Taiwan [35C]. Clinical records were reviewed for demographic data, clinical presentation, treatment, and outcomes. Ten patients who had received heart transplants (3.17%) developed pulmonary and/or extrapulmonary tuberculosis, a higher rate than that reported for the general Taiwan population (0.067%). Treatment consisted of isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, ciprofloxacin, and levofloxacin. Seven patients completed treatment, with a median treatment duration of 1 year. Three patients developed

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hepatitis. There was no tuberculosis-related mortality. The authors concluded that tuberculosis in heart transplant recipients may be completely treated by a combination of at least three drugs, except pyrazinamide because of adverse effects and tolerance.

pyrazinamide for 6–12 months, with good tolerance, but one had a recurrence. Another had raised hepatic enzyme activities after the start of therapy. In this series, the frequency of tuberculosis after liver transplantation was 1.57%, and there was no confirmed hepatotoxicity with conventional treatment. The survival rate was 100%.

Liver transplant recipients The efficacy of isoniazid in latent and active Mycobacterium tuberculosis infection in liver transplant recipients has been studied in a systematic review [36M]. Treatment was evaluated in seven studies, including 139 cases of active tuberculosis infection in liver transplant recipients. Isoniazid was associated with reduced tuberculosis reactivation in transplant patients with risk factors for latent tuberculosis (0.0% versus 8.2%), and there was isoniazid-related hepatotoxicity in 6% of treated patients, with no reported deaths. The prevalence of active tuberculosis infection in transplant recipients was 1.3%. Nearly half of all the recipients with active tuberculosis had an identifiable pre-transplant tuberculosis risk factor. Among recipients who developed active tuberculosis infection, extrapulmonary involvement was common (67%), including multiorgan disease (27%). The short-term mortality rate was 31%. Surviving patients were more likely to have received three or more drugs for tuberculosis induction therapy, more likely to have had the diagnosis within 1 month of symptom onset, less likely to have multiorgan disease, and less likely to have had episodes of acute transplant rejection. The authors concluded that compared with the general population, liver transplant recipients have an 18-fold increase in the prevalence of active tuberculosis infection and a fourfold increase in the case-fatality rate. For high-risk transplant candidates, isoniazid appears to be safe and is probably effective in reducing tuberculosis reactivation. In a retrospective study in Brazil in 319 patients who underwent liver transplant and survived more than 1 month tuberculosis was identified in five women, mean age 40 years [37C]. None received chemoprophylaxis before or after liver transplant. Two had disseminated tuberculosis, two had pulmonary disease, and one had extrapulmonary disease. Cultures were positive in four. Four patients received isoniazid, rifampicin, and

M.S. Jawahar and V.V. Banu Rekha

Problems in interpreting interaction studies with protease inhibitors in patients co-infected with tuberculosis and AIDS Pharmacokinetic studies in healthy volunteers have shown an unexpectedly high incidence of gastrointestinal intolerance and liver enzyme rises. For example, some studies of the interaction of rifampicin with lopinavir þ ritonavir in healthy volunteers have also shown increased hepatotoxicity, but some observational studies have reported a lower incidence. The methodological problems of pharmacokinetic studies, which could affect the incidence of hepatotoxicity, have been discussed [38r]. Time course Rifampicin induces CYP3A4 at about 15 days, and interaction studies have generally started treatment with protease inhibitors within 15 days of the start of rifampicin therapy. Furthermore, pharmacological tolerance to effects can occur. The problems of variations in pharmacokinetics with time have been illustrated by a study of the effects of rifampicin on the pharmacokinetics of nevirapine in 16 patients coinfected with HIV-1 and tuberculosis [39c]. They took standard antituberculosis therapy and a fixed-dose combination of stavudine, lamivudine, and nevirapine. The median AUC of nevirapine was reduced by rifampicin by 26% at 4 weeks, but by only 7.5% at 10 weeks. The median Cmin was reduced by 20% at 4 weeks and by 7.1% at 10 weeks. The authors concluded that the effect of rifampicin on the pharmacokinetics of nevirapine substantially decreases over time.

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Overlapping adverse effects Both rifampicin and protease inhibitors produce hepatotoxicity, more often within the first week of treatment. Body weight There are well-known pharmacokinetic differences between healthy volunteers and patients who are co-infected with tuberculosis and HIV—patients with co-infection may absorb drugs less well and be of lower body weight than healthy volunteers. In a prospective randomized comparison of standard doses of efavirenz-based and nevirapine-based antiretroviral drug therapy, 142 patients with concurrent HIV-1 infection and tuberculosis who were taking rifampicin were randomized to antiretroviral drug therapy that included either efavirenz 600 mg/day or nevirapine 400 mg/day [40C]. Efavirenz and nevirapine concentrations at 12 hours after dosing were monitored at weeks 6 and 12. CD4þ cell counts and HIV-1 RNA concentrations were assessed every 12 weeks. At weeks 6 and 12, the mean efavirenz concentrations were 4.3 and 3.5 mg/l respectively, and the mean nevirapine concentrations were 5.6 and 5.6 mg/l respectively. At week 12, 3.1% of patients taking efavirenz group and 21% of those taking nevirapine had concentrations that were less than the recommended minimum concentrations (OR ¼ 8.4; 95% CI ¼ 1.8, 39). Intention-to-treat analysis showed that 73% and 72% respectively of patients taking efavirenz or nevirapine achieved HIV-1 RNA concentrations below 50 copies/ml at week 48, with respective mean CD4þ cell counts of 274 and 252  106/l. Multivariate analysis showed that patients with low concentrations and those with a body weight below 55 kg were respectively 3.6 and 2.4 times more likely to develop all-cause treatment failure. Antiretroviral therapy regimens containing efavirenz were less compromised by concomitant use of rifampicin than those that contained nevirapine in patients with concurrent HIV-1 infection and tuberculosis. Low drug exposure and low body weight were important predictive factors for treatment failure.

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Pharmacokinetic variability Plasma concentrations of protease inhibitors have high interindividual and intraindividual variability; sequential design is a better option than parallel group design, because of reduced interindividual variability. Co-medication Co-medications in coinfected patients could result in interactions with CYP3A4 and P glycoprotein; excessive alcohol consumption is not unusual in coinfected patients. Co-morbidities About 30% of HIV-infected patients also have hepatitis C infection. Conclusions It is therefore difficult to generalize the conclusions of studies in healthy volunteers to patients co-infected with tuberculosis and HIV.

Diagnosis of adverse drug reactions The usefulness of the drug-lymphocyte stimulation test to identify the antituberculosis drugs that caused adverse effects in 436 patients with tuberculosis has been studied in Japan [41C]. Lymphocyte stimulation was performed in patients who had had adverse drug reactions during antituberculosis drug treatment and the causative drug was identified by a drug provocation test. The tested drugs were mainly isoniazid, rifampicin, ethambutol, and pyrazinamide. Of 436 patients, 69 (16%) had adverse reactions to antituberculosis drugs. Of the 261 agents that were tested, 28 (11%) in 20 patients (29%) were positive by the lymphocyte stimulation test, and 67 (26%) in 46 patients (67%) were identified as causative drugs by the drug provocation test. The sensitivity of the lymphocyte stimulation test was only 15% for all drugs (isoniazid 14%, rifampicin 14%, ethambutol 14%, pyrazinamide 0%). The authors concluded that lymphocyte stimulation offers little contribution to the detection of causative agents in patients with adverse reactions to antituberculosis drugs.

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Cycloserine

[SED-15, 1033]

Nervous system A 69-year-old woman developed hypersomnolence and asterixis while taking cycloserine; an MRI scan of the brain showed bilateral symmetrical thalamic hyperintensities, which resolved after withdrawal of cycloserine as did her symptoms [42A].

Dapsone

[SED-15, 1050; SEDA-29, 315; SEDA-30, 357; SEDA-31, 406] Observational studies In a retrospective study of the effects of dapsone 100 mg/day for at least 30 days in 52 adults with immune thrombocytopenic purpura, in whom firstline therapy with glucocorticoids had failed [43c]. Dapsone resulted in a sustained increase in platelet count in 23 patients after a median follow-up of 21 months and none of those who responded required splenectomy compared with 20 of the other 29. Dapsonerelated adverse events were mild and were promptly reversed by withdrawal. Cardiovascular Complete atrioventricular block has been reported in the context of dapsone hypersensitivity [44A].

• A 45-year-old woman took dapsone 150 mg/ day for 5 weeks for pustular palmoplantar psoriasis and developed dyspnea, numbness of all four limbs, and syncope. She had multiple enlarged mobile cervical and retroauricular lymph nodes measuring 1.5–3.0 cm and an itchy maculopapular rash. Her liver enzymes were raised but urea and electrolytes were normal. An electrocardiogram showed sinus rhythm and left anterior fascicular block. She had three further episodes of syncope, on each occasion associated with bradycardia. Dapsone was withdrawn and she was given atropine, dopamine, and isoprenaline, but her heart rate and blood pressure remained low and eventually a pacemaker was inserted.

It is not clear whether dapsone could be incriminated in the heart block that occurred in this case.

M.S. Jawahar and V.V. Banu Rekha

Dapsone-induced hematological abnormalities and their management EIDOS classification: Extrinsic species Dapsone N-hydroxylated metabolites Intrinsic species? Distribution Erythrocytes Outcome (pathophysiological adverse effect) Hemolysis and/or hemoglobin reduction Sequela (adverse reaction) Hemolytic anemia and/or methemoglobinemia DoTS classification: Dose-relation Collateral Time-course Intermediate Susceptibility factors Genetic (G6PD deficiency; cytochrome b5 reductase deficiency); diseases (?renal insufficiency) The most common hematological adverse effects of dapsone are hemolytic anemia and methemoglobinemia. Agranulocytosis [45A, 46A] can also occur, as can rarely sulfhemoglobinemia [47A, 48A], aplastic anemia [49A], and pure red cell aplasia [50A]. Pathogenesis Dapsone is metabolized either by acetylation to non-toxic acetyldapsone or by N-hydroxylation by multiple CYP isoenzymes to toxic hydroxylamines [51E]. The latter are thought to be responsible for methemoglobinemia and hemolysis. Agranulocytosis due to dapsone occurs particularly in the first 3 months of therapy, and the risk is increased in patients with dermatitis herpetiformis [52R]. The mechanism is not known, but it has been proposed that selective preservation of basophils, as found in a patient with severe dapsone-induced agranulocytosis, could be relevant [53A]. • A 40-year-old woman took dapsone 100 mg/ day for 3 weeks for discoid lupus and developed a fever, sweats, and severe pharyngitis associated with dysphagia for solids and fluids. She was also taking atorvastatin, codeine phosphate, indometacin, and lansoprazole. Her

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throat was congested, with ulceration of the uvula and white exudates covering the palate and tonsils. Her leukocyte count was 0.4  109/l, hemoglobin 9.7 g/dl, platelet count 534  109/l, C reactive protein 441 mg/l, and erythrocyte sedimentation rate 80 mm/hour. On blood smear there was a complete absence of neutrophils and eosinophils, but basophils were preserved. The bone marrow contained no myeloid precursors, but erythroid, megakaryocytic, and lymphoid lineages were present in normal numbers. All medications, including dapsone, were withdrawn and she was given antibiotics and subcutaneous G-CSF 300 mg/ day. The clinical features and neutrophil count gradually returned to normal.

These observations suggest that if dapsone was responsible for the agranulocytosis in this case, the pathogenetic process was operating at the myeloid progenitor stage. It could also be that preservation of basophils, which lack significant peroxidase activity, is an indication that dapsone-induced agranulocytosis may be due to a hypersensitivity reaction caused by active metabolites of dapsone, mediated by myeloperoxidases. Susceptibility factors The association of dapsone-induced hemolysis with G6PD deficiency is well known [SED-15, 1051]. Cytochrome b5 reductase deficiency can be associated with an increased risk of methemoglobinemia [54c]. Dapsone-induced hemolytic anemia in lung transplant recipients who received dapsone for prophylaxis of Pneumocystis jirovecii pneumonia has been reported in a retrospective study of 43 patients, of whom 10 had hemolytic anemia without G6PD deficiency [55c]. The mean fall in hemoglobin from baseline was 2.7 g/dl (95% CI ¼ 1.9, 3.5). The odds ratio for hemolysis was 4.75 for each 1.0 mg/dl increase in serum creatinine (95% CI ¼ 1.07, 21). The authors concluded that the prevalence of dapsone-induced hemolytic anemia in lung transplant recipients is five times higher than the reported rates for other groups who routinely use dapsone prophylaxis for Pneumocystis pneumonia and that individuals with renal insufficiency or low body weight and for whom the dose exceeds 1.5 mg/kg may be at increased risk of dapsone-induced hemolytic anemia.

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Topical TM dapsone The use of dapsone 5% gel (Aczone ) in acne vulgaris has been reviewed [56R]. In a 12-month, open study and two open, phase I pharmacokinetic studies the serum concentrations of dapsone and Nacetyldapsone remained low and did not accumulate over time after steady state was reached. Of 50 patients with G6PD deficiency in all the studies, only two had a fall in hemoglobin concentration, consistent with fluctuations observed in other study participants. The risk of hemolysis in 64 patients, aged 12 years or over, with G6PD deficiency and acne vulgaris has been reported from a double-blind, randomized, vehicle-controlled, crossover study of topical dapsone gel 5% bd [57c]. There was a 0.32 g/dl fall in hemoglobin concentration from baseline to 2 weeks during dapsone treatment. It was not accompanied by changes in other laboratory parameters, including reticulocytes, haptoglobin, bilirubin, or lactate dehydrogenase activity, and was not apparent at 12 weeks as treatment continued. The number of subjects with a 1-g/dl fall in hemoglobin concentration was similar between treatment groups at weeks 2 and 12. The largest falls in hemoglobin concentration were 1.7 g/dl with the vehicle and 1.5 g/dl with dapsone gel. There were no signs or symptoms of hemolytic anemia. Management Cimetidine The use of cimetidine to reduce dapsone-dependent hematological adverse effects in a patient with mucous membrane pemphigoid has been reported [58A]. • A 77-year-old man with COPD who was using long-term oxygen developed mucous membrane pemphigoid, which did not respond to high-dose oral glucocorticoids, azathioprine, and minocycline. He was given dapsone 50 mg in the morning and 25 mg at night in place of azathioprine, and there was clinical improvement. His G6PD activity was normal. However, within 4 weeks, he developed a hemolytic anemia (hemoglobin 10.2 g/dl, absolute reticulocyte count 206  109/l) and methemoglobinemia of 9.4% with mild cyanosis. He was given cimetidine 400 mg tds and over the next 4 months his blood counts gradually improved and the cyanosis resolved. There was no interference with the efficacy of dapsone, and the disease was controlled with dapsone 75 mg/day and prednisolone 5 mg/day.

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Cimetidine increases plasma dapsone concentrations without increased hemolysis, reduces methemoglobin concentrations by selective inhibition of dapsone N-hydroxylation, and does not interfere with the control of the skin disorder. These features seem to be detectable within weeks and are sustained. The effects of cimetidine appear to be greatest on methemoglobin concentrations.

51 g/dl and a peripheral blood smear showed Heinz bodies, indicating oxidative stress. He was treated with hemodialysis for 3 days. During the second day, the methemoglobin concentration fell from 51 to 11.5 g/dl and on the third day was 0.9 g/dl. However, there was a progressive fall in hemoglobin concentration from 12.6 g/dl on the first day to 6.5 g/dl on the fifth day. He was given three units of erythrocytes and the hemoglobin concentration rose to 10.6 g/dl.

Darbepoetin alfa Darbepoetin alfa has been used to treated dapsone-induced hemolysis [59A].

Dapsone is 50–80% bound to plasma proteins and the remainder is probably available in the free form for dialysis.

• An 84-year-old man with linear IgA disease was given dapsone 25 mg/day. In a few days his hemoglobin concentration fell from 12.1 to 10.7 g/dl. There was no therapeutic effect, so the dose was increased to 50 mg/day. His hemoglobin concentration fell further to 9.8 g/ dl and he became pale, with cyanotic lips, but not icteric. The dose of dapsone was reduced to 50 and 25 mg on alternate days and the lesions became worse. He was given subcutaneous darbepoetin alfa 50 micrograms/week and the dosage of dapsone was gradually increased to 150–200 mg/day. His hemoglobin concentration rose and was on average 13.0 g/ dl during 3 years of follow-up, during which time the total bilirubin was normal. Haptoglobin was undetectable during treatment with darbepoetin alfa.

Control of anemia with darbepoetin alfa has been reported in association with cancer chemotherapy, treatment of renal insufficiency, to control anemia due to inflammatory bowel disease, and in diabetes-induced anemia. However, this appears to be the first time it has been used successfully to control a drug-induced anemia. Hemodialysis Severe dapsone poisoning, which resulted in methemoglobinemia and hemolytic anemia, improved after hemodialysis [60A]. • A 19-year-old man with a depressive disorder, taking olanzapine, lorazepam, and aripiprazole, took an intentional overdose of 40–45 tablets of dapsone 100 mg (a total of 4–4.5 g). He became drowsy but was conscious and responded to oral commands. There were signs of cyanosis and sinus tachycardia. The serum methemoglobin concentration was increased at

Skin Dapsone-induced photosensitivity has been reported in an Indian patient with leprosy [61A]. • A 37-year-old man with borderline lepromatous leprosy was given multidrug therapy according to the WHO guidelines and after 5 weeks developed redness and a burning sensation with erythema and tiny papules over the face, the neck, the ears, and the extensor surfaces of the arms. The lesions progressed over 3–4 days. He was afebrile. There was no pallor or icterus, hepatosplenomegaly or lymphadenopathy. The natural skin folds were spared, as were the other photoprotected areas of the body. Routine hematology, biochemistry, including anti-nuclear antibody, and a chest X-ray, were normal. He was given oral prednisolone, an antihistamine, and a sunscreen lotion. The drug therapy was continued without dapsone and after 1 week, the lesions started to improve and the redness abated significantly. Prednisolone was gradually tapered over 3 weeks and withheld. He was later challenged with dapsone 50 mg, after which he developed a rash similar to the previous episode.

Dapsone-induced photosensitivity is a rare hypersusceptibility reaction to sulfones and can occur in patients with inflammatory skin disorders treated with dapsone. Only 12 cases have been reported. Photoallergic reactions are based on an immunological mechanism and can be provoked by UV radiation in a minority of people, with prior sensitization to the molecule. The characteristic sulfone group (C SO2 C) present in the parent molecule, as well as its metabolites, is responsible.

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Immunologic In the dapsone syndrome (or sulfone syndrome) there is fever, exfoliative dermatitis and photosensitivity, jaundice, hepatosplenomegaly, generalized lymphadenopathy, and pruritus. In one case there was a bullous skin eruption with circulating 190 and 230 kDa autoantibodies [62A]. • A 44-year-old Korean woman developed generalized, pruritic, erythematous, edematous patches associated with vesicles and bullae on the limbs, with fever and tenderness in the right hypochondrium. She had been taking dapsone 100 mg/day, prednisolone 10 mg/day, and ebastine 10 mg/day for urticarial vasculitis for 1 month. There was edema with diffuse erythema over the entire body, and tense vesiculobullous lesions on the forearms. The oral and genital mucosae were intact. Multiple enlarged cervical lymph nodes were palpable. She had a persistent fever (> 38  C), a leukocytosis (white blood cell count 16.2  109/l), abnormal liver function tests (aspartate aminotransferase 248 U/l, alanine aminotransferase 196 U/l, gamma-glutamyl transferase 214 U/l, total bilirubin 65 mmol/l), and lactate dehydrogenase. There was an atypical lymphocytosis 10–15% and an eosinophilia of 14%. Viral markers for acute hepatitis were negative. Abdominal ultrasonography showed parenchymal liver disease. Biopsy of a vesicle from the forearm showed subepidermal bullae with marked edema in the upper dermis and perivascular lymphocytic infiltrates with eosinophils. Indirect immunofluorescence on normal human foreskin showed deposition of immunoglobulin G linearly along the basement membrane zone. Immunoblotting using human epidermal extracts showed IgG antibodies bound to polypeptides of 190 and 230 kDa. ELISA using antidesmoglein-1, antidesmoglein-3, anti-bullous pemphigoid 180NC16a, and anti-BP230 was negative. HHV-6 gene-nested PCR (GenBank accession No. S57540) using the patient's serum was negative.

The pathophysiology of the dapsone syndrome is unclear, but dapsone metabolites may act as haptens, resulting in the formation of antidapsone antibodies. Dapsone is metabolized primarily via N-acetylation and N-hydroxylation. The N-hydroxylation pathway is thought to be the initial step in the formation of toxic intermediate

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metabolites, including hydroxylamine. These metabolites bind covalently to or modify various molecules, including major histocompatibility complex peptides, so that drug-specific T-cell recognition contributes to the dapsone syndrome. Reactive metabolites act as haptens and bind to endogenous proteins to form a compound that triggers an immune reaction. Haptenated compounds may also be directly toxic to cells. The incidence of the dapsone syndrome is estimated to be 2% in patients with leprosy, but it can occur in patients without leprosy. In a retrospective Taiwanese study of 361 patients without leprosy, of whom 126 (35%) had vascular diseases, who were given dapsone between June 2001 and December 2005, the average duration of therapy was 126 days and the average dosage was 110 (range 50–300) mg/day [63c]. Dapsone syndrome developed in six (1.66%) during the first 6 weeks of treatment (mean time to onset 20, range 8–36, days), necessitating hospitalization and withdrawal of dapsone. There was no correlation between the risk of the dapsone syndrome and the primary clinical diagnosis. None of the patients received rifampicin. All had fever and a rash, either maculopapular or vesiculopapular. All but one had evidence of hepatic damage. There was lymphadenopathy in three and hepatosplenomegaly and pedal edema in one. All six had a low hemoglobin, five had raised activities of serum liver enzymes and alkaline phosphatase, there was a lymphocytosis with atypical cells, raised bilirubin, or raised C-reactive protein concentration in four patients each, hypoalbuminemia and leukocytosis in three patients each, and eosinophilia in two. Biopsy of inflamed skin in one patient showed a predominantly mononuclear cell infiltrate around small blood vessels. Dapsone was withdrawn and five patients were managed with systemic glucocorticoids. The syndrome abated in 5–14 days and all had favorable outcomes. Rechallenge was not performed.

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Ethambutol

ganglion cells and may affect only the small papillomacular bundle of axons, resulting in normal initial fundoscopy, delayed optic atrophy, and normal MR imaging. In a retrospective study of 857 Korean patients who took ethambutol, 89 had impaired vision [65c]. Ethambutol-induced optic neuropathy was diagnosed in during a mean follow-up period of 13 months. The average dose of ethambutol was 18 mg/kg/ day and the duration of therapy was 9.4 months. Ophthalmic findings included reduced visual acuity (n ¼ 58), abnormal visual fields (n ¼ 58), abnormal color vision (55), optic disc pallor (34), and increased latency on VEP tests (58). Slightly less than one-third of the patients had improved visual function after discontinuing ethambutol. The mean time to recovery was 5.4 months. However, no patient with optic disc pallor at the time of diagnosis had improved visual function. Renal dysfunction and the daily dose of ethambutol, but not the duration of treatment, contributed. The authors estimated the incidence of ethambutol-induced optic neuropathy in Koreans to be under 2%. Thus, visual function after withdrawal of ethambutol is reversible in only a minority of patients and does not occur if optic disc pallor is present. Two patients who developed reduced visual acuity after taking ethambutol for several months for Mycobacterium aviumintracellulare infection had bitemporal visual field defects that suggested damage to the optic chiasm [66A].

[SED-15, 1282; SEDA-29, 316; SEDA-30, 358; SEDA-31, 407] Sensory systems Optic neuropathy EIDOS classification: Extrinsic species Ethambutol Intrinsic species Not Known Distribution Optic nerve fibers and retinal ganglion cells Outcome Altered physiology initially; later nerve cell degeneration Sequela Optic neuropathy and retinopathy due to ethambutol DoTS classification: Dose-relation Collateral Time-course Intermediate Susceptibility factors Diseases (renal impairment, zinc deficiency)

Reduced visual acuity and central or centrocecal scotomas on visual field testing have been reported as the usual presentation of ethambutol-induced optic neuropathy. Bilateral temporal hemianopia has been reported in a case of ethambutol toxicity [64A]. • A 75-year-old woman developed progressively worse peripheral vision in both eyes after taking ethambutol 1200 mg/day for almost 1 year, plus clarithromycin and rifampicin for infection with Mycobacterium avium complex and Mycobacterium kansasii. Best corrected visual acuity was 20/80 in the right eye and 20/60þ in the left eye. Eye movements were full. Slit lamp exam showed þ 1 nuclear sclerosis in both eyes. On fundoscopy the optic discs were not swollen or pale. A 30–2 Humphrey visual field showed bitemporal hemianopia. An MRI scan of the brain was normal, as was optical coherence tomography.

The mechanism of ethambutol-induced optic neuropathy is unclear. It has been postulated that it is caused by a disturbance in mitochondrial metabolism. Ethambutol is also a strong chelator of copper, a co-factor of cytochrome c oxidase, which is required for axonal transport in the optic nerves, failure of which, secondary to mitochondrial insufficiency, results in optic neuropathy. Ethambutol is specifically toxic to retinal

M.S. Jawahar and V.V. Banu Rekha

• A 48-year-old woman developed progressively blurred vision, difficulty in identifying colors, and peripheral visual field loss after taking clarithromycin and ethambutol 16 mg/kg/day for 7 months for pulmonary Mycobacterium avium intracellulare infection. Ethambutol was promptly withdrawn. The best-corrected visual acuities were 20/50 in the right eye and 20/60 in the left eye. She correctly identified 7/8 and 5/8 Ishihara color plates in the right and left eyes respectively. Automated (Humphrey) visual field testing showed bilateral superotemporal defects that respected the vertical meridian and extended to fixation. However, the probability map of the total deviation plot crossed the vertical meridian, which made it unlikely that the pattern of visual loss was caused solely by a chiasmal lesion. Multifocal

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electroretinography was performed on the VERIS system using 103 hexagons. Multiple hexagons showed responses with significantly reduced amplitudes in the central and nasal macular regions in both eyes that corresponded to the visual field defects. Her visual acuity recovered to 20/30 in both eyes 7 months after withdrawal ethambutol. • A 78-year-old woman developed blurred vision, impaired color vision, new floaters, and soreness in her left eye after taking ethambutol 19.6 mg/ kg/day, clarithromycin, rifampicin, anastrozole, zolpidem, and felodipine for 6 months. Ethambutol was withdrawn. Her best-corrected visual acuities were 20/80 in the right eye and 20/400 in the left eye. She was able to identify only the test plate on Ishihara color testing. Automated (Humphrey) visual field testing showed reduced sensitivity in the temporal paracentral aspect of the visual fields in both eyes. The threshold abnormalities of the total deviation plot crossed the vertical meridian, which made it unlikely that the pattern of visual loss was solely attributable to a chiasmal lesion. Dilated stereoscopic ophthalmoscopy showed temporal pallor of both optic discs. There were retinal pigment epithelial changes in the nasal mid-peripheral retina in the right eye and in the nasal peripheral area in the left eye. There were several flame hemorrhages along the inferior temporal arcade in the left eye. Full-field electroretinography showed reduced B wave amplitudes; on multifocal electroretinography multiple hexagons showed reduced amplitude responses in the central and nasal macular regions in both eyes, corresponding to the visual field defects. Her visual acuities improved to 20/30 in both eyes 7 months after ethambutol withdrawal.

These results suggested that visual dysfunction due to ethambutol may be entirely attributable to retinal rather than optic nerve toxicity. These are the first reports to show abnormalities in multifocal electroretinography that correspond to bitemporal visual field defects and add to the growing evidence that ethambutol damages the retina. In a prospective evaluation of various visual parameters for early detection of ethambutol toxicity in 52 patients with tuberculosis attending a Directly Observed Treatment Strategy Centre [67c] visual acuity, visual fields, visual-evoked responses, stereoacuity, and retinal nerve fiber layer thickness on optical coherence tomography were assessed after 1 and 2 months of treatment, and 1 month after withdrawal. There was no visual functional defect at baseline. On follow-up, visual acuity, color vision,

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contrast sensitivity, fundoscopy, and stereoacuity were not affected in any patient. Visual field defects developed in eight of the 104 eyes. Pattern visual-evoked responses showed an increased mean latency of the P100 wave after 1 and 2 months of therapy, and 15 eyes had more than a 10-msec increase in latency. Optical coherence tomography showed significant loss of mean temporal retinal nerve fiber layer thickness in three eyes. There was subclinical toxicity in 20 eyes, with reversal of this in 80% within 1 month of ethambutol withdrawal, although mean visual-evoked response latencies remained delayed. The authors concluded that pattern visual-evoked responses and visual field examinations are sensitive tests in the detection of early ethambutol toxicity. Together with optical coherence tomography, they may help to identify patients who are likely to develop clinical toxicity.

Isoniazid

[SED-15, 1923; SEDA-29, 317, SEDA-30, 359; SEDA-31, 498]

Systematic reviews In a meta-analysis of published studies of compliance, toxicity, and cost-effectiveness, comparing isoniazid monotherapy for 9 months and rifampicin for 4 months [68M] in a total of 3586 patients, the latter was associated with a significant reduction in the risk of non-completion (RR in a random-effects model ¼ 0.53; 95% CI ¼ 0.44, 0.63). Non-completion rates were lower among patients who took rifampicin for 4 months (range 8.6–28) than in those who took isoniazid for 9 months (range 24–47%). Rates of hepatotoxicity (defined as grade 3 or 4 liver failure leading to drug withdrawal) were lower in patients who took rifampicin (range 0–0.7% versus 1.4–5.2%), and rifampicin was associated with significant reduction in the risk of hepatotoxicity (RR ¼ 0.12; 95% CI ¼ 0.05, 0.3). Nervous system Central nervous system toxicity due to isoniazid has been reported in a child [69A].

636 • A 5-year-old girl with pulmonary tuberculosis was given isoniazid, rifampicin, pyrazinamide, and ethambutol and within 1 week developed somnolence, reduced appetite, and vomiting. A few days later she had two seizures lasting about 5 minutes each. She was afebrile, had normal vital signs, and was alert but had a fluctuating level of consciousness over the next 48 hours, with times when she was rousable only by painful stimuli. Blood culture was sterile and cerebrospinal fluid culture was negative for bacteria, mycobacteria, and viruses. An MRI scan of the brain showed symmetrical, strikingly increased signal intensity in the thalami. MR angiography, venography, and MR spectroscopy were normal, and there was no abnormal enhancement or mass to suggest meningeal disease or a tuberculoma on either CT or MR imaging. The serum isoniazid concentration taken 12 hours after the seizures was 20 mg/l (147 mmol/l) and fell to 1 mg/l (5.3 mmol/l) 19 hours later. The calculated half-life of isoniazid was 3.9 hours. Investigation of the abnormally raised concentration of isoniazid established that a dispensing error had been made. Rather than 100mg tablets she had received 300-mg tablets and had taken 750 mg/day (43 mg/kg/day). All medications were withheld and she had no further seizures. Within 7 weeks the imaging abnormalities had resolved.

The mechanism of isoniazid-induced neurotoxicity is believed to be reduced concentrations of GABA by inhibition of pyridoxine (vitamin B6) metabolism. Human studies describing white matter changes in isoniazid toxicity have also corroborated a potential toxic effect on myelin. Rapid resolution of diffusion-restricted lesions in this patient suggested a similar process of intramyelinic edema. In addition, the half-life of isoniazid was 3.9 hours, suggestive of the slow acetylator phenotype, with increased susceptibility to adverse effects of isoniazid. Liver Isoniazid-induced liver damage is histologically indistinguishable from viral hepatitis and is related to individual susceptibility in patients who hydrolyse the drug to isonicotinic acid at different rates. Histologically proven isoniazid hepatotoxicity in complicated tuberculous salpingitis has been reported [70A]. • A 49-year-old woman with tuberculous salpingitis was given isoniazid 300 mg/day, rifampicin 600 mg/day, pyrazinamide 2.0 g/day, and

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ethambutol 1.5 g/day. She developed fever and disseminated joint pain after 21 days. Liver aminotransferases rose and the drugs were withheld. When she resumed isoniazid, the fever returned, with chills and flushing. Liver histology showed prominent hepatocellular damage and bilirubin accumulation, compatible with a diagnosis of drug-induced liver toxicity, which was attributed to isoniazid. Acetylator status and CYP polymorphisms were not measured.

Drug–drug interactions Clozapine Increased plasma concentrations of clozapine have been reported after the addition of isoniazid [71A]. • A 65-year-old man with paranoid schizophrenia, generalized anxiety disorder, social anxiety disorder, hypertension, frequent constipation, and mild anemia, taking clozapine 200 mg bd, venlafaxine XR 150 mg bd, metoprolol 25 mg bd, docusate 100 mg bd, and milk of magnesia 30 ml when necessary, was given isoniazid 300 mg/day for 9 months. Clozapine and norclozapine concentrations were measured before he started to take isoniazid, because it was anticipated that isoniazid might increase clozapine concentrations. After 3 days the clozapine and norclozapine concentrations rose from 397 and 384 mg/l respectively to 569 and 520 mg/l and after 9 days 756 and 725 mg/l. The patient did not have any significant adverse effects, except for excess sedation. The dose of clozapine was reduced to 150 mg bd and 11 days later the clozapine and norclozapine concentrations had fallen to 527 and 614 mg/l respectively. The dose of clozapine was reduced again to 100 mg bd and 21 days later, the clozapine and norclozapine concentrations were 385 and 379 mg/l respectively. After 9 months isoniazid was withdrawn and after 54 the clozapine and norclozapine concentrations were 239 and 221 mg/l respectively at a clozapine dosage of 100 mg/day.

This case shows the affect that isoniazid can have on serum clozapine and norclozapine concentrations. Isoniazid inhibits CYP isoenzymes, including CYP1A2, of which clozapine is a substrate.

PA-824 PA-824 is a novel nitroimidazo-oxazine, a prodrug that requires activation by a bacterial F420-dependent glucose-6-

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phosphate dehydrogenase (Fgd) and nitroreductase to activate components that then inhibit bacterial mycolic acid and protein synthesis [72E]. It has a minimum inhibitory concentration (MIC) as low as 0.015–0.250 mg/l against drug sensitive and multidrug resistant Mycobacterium tuberculosis. Pharmacokinetic studies of PA-824 in rats have shown that it has excellent tissue penetration [73E]. In animals, it was active against non-growing bacilli, even in microaerophilic conditions, and its activity is comparable to that of isoniazid, rifampicin, and moxifloxacin. PA-824 had bactericidal activity in mice in the first 2 months of treatment and also in the continuation phase, which suggests that it has significant activity against non-growing persistent bacilli in vivo. Urinary tract The effects of PA-824 on renal function have been evaluated in 47 healthy volunteers, who took PA-824 800 or 1000 mg/day or matching placebo for 8 days [74c]. The serum creatinine concentration increased and there were trends towards reductions in creatinine clearance and extraglomerular creatinine excretion (defined as creatinine clearance minus glomerular filtration rate). All the changes resolved within 1 week of withdrawal. Thus, the reversible increase in serum creatinine observed in this and earlier studies of PA-824 did not appear to result from a pathological effect on renal function. That extraglomerular creatinine excretion fell maximally when drug concentrations were highest suggests that PA-824 causes creatinine concentrations to rise by inhibiting renal tubular creatinine secretion. Such an effect, considered clinically benign, has been described for several drugs.

Pyrazinamide

[SED-15, 2979;

SEDA-32, 563] Sensory systems Olfaction Alterations in taste and smell function, which are rare, have been reported for pyrazinamide when combined with other drugs. Reversible olfactory

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impairment related to pyrazinamide, with positive rechallenge, has been reported [75A]. • A 53-year-old woman with diabetes was given isoniazid 300 mg/day, rifampicin 600 mg/day, pyrazinamide 1500 mg/day, and streptomycin 1 g/day for skeletal tuberculosis. On the first day she had a sensation of smelling something burning 15 minutes after taking her medications and had the same sensation every day thereafter. The sensation lasted 4–5 hours and then spontaneously ceased completely. Three weeks later she had equilibrium disorders, with rotatory dizziness when shaking her head; investigations localized it to a vestibular origin. Streptomycin was withdrawn and replaced by ethambutol, but the dysosmia persisted. Pyrazinamide and ethambutol were withdrawn and the olfactory effects resolved completely. She then inadvertently took a single dose of pyrazinamide 1500 mg and 15 minutes later experienced the olfactory symptoms as before. She continued to take isoniazid and rifampicin without recurrence.

Olfactory disorders are often caused by affections of the nose and sinuses, such as rhinitis, sinusitis, nasal polyps, nasal septal deviation, and less frequently diabetes, hepatic diseases, or renal insufficiency. In this case, even though pyrazinamide was the probable cause, a role of diabetes cannot be totally excluded. Altered sense of smell has been associated with pyrazinamide plus levofloxacin [76c] and altered taste or smell has been reported with pyrazinamide plus isoniazid plus rifampicin and with gatifloxacin [77c].

[SED-15, 3040; SEDA-30, 359; SEDA-31, 498; SEDA-32, 563]

RIFAMYCINS

Rifabutin Skin Acute generalized exanthematous pustulosis (AGEP) is a clinical reaction pattern that is principally drug induced; more than 90% of cases are drug induced, mainly by antibiotics, especially b-lactams and macrolides. It has also been attributed to rifabutin

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[78A]. The incidence is probably underestimated, because many cases are either unrecognized or confused with pustular psoriasis.

treatment discontinuation in four and six patients.

Drug–drug interactions Lopinavir þ ritonavir The steady-state pharmacokinetics of rifabutin and its active metabolite 25desacetyl-rifabutin have been examined before and after the addition of lopinavir þ ritonavir in 10 patients with HIV infection and active tuberculosis [79c]. Samples were collected at 2–4 weeks after starting rifabutin 300 mg thrice weekly without lopinavir þ ritonavir, 2 weeks after the addition of lopinavir þ ritonavir 400/100 mg bd to rifabutin 150 mg thrice weekly, and (if rifabutin plasma concentrations were below the target range) 2 weeks after an increase in rifabutin dosage to 300 mg thrice weekly with lopinavir þ ritonavir. Lopinavir þ ritonavir reduced the Cmax of total rifabutin and most unbound rifabutin Cmax values were below the tuberculosis MIC. For most patients, the AUC was low or lower than associated with treatment failure or relapse and with acquired rifampicin resistance. The authors concluded that the recommended doses of rifabutin for use with lopinavir þ ritonavir may be inadequate in many patients and recommended monitoring of plasma concentrations.

Rifampicin Comparative studies In a prospective comparison of a combination of rifampicin and linezolid with a combination of rifampicin and co-trimoxazole in the treatment of bone and joint infections in 56 adults, 36 had infected orthopedic devices and 20 had chronic osteomyelitis [80c]. Patients who discontinued antibiotic therapy within 4 weeks of starting treatment were considered to be cases of treatment failure and were excluded. The rates of adverse effects were similar in the two groups; 43% versus 46% respectively, and led to

M.S. Jawahar and V.V. Banu Rekha

Liver In a retrospective cohort study of the effect of adding rifampicin to standard therapy in 42 cases of S. aureus endocarditis on native valves, confirmed by modified Duke criteria in a large urban hospital between 2004 and 2005 and 42 controls, the cases received a rifampicin for median of 20 (range 14–48) days [81c]. Rifampicin-resistant S. aureus isolates emerged in nine patients who had received rifampicin before clearance of bacteremia (56%), while there were significant rises in hepatic aminotransferases in nine cases, all of whom had hepatitis C infection. Unrecognized significant drug–drug interactions with rifampicin were common (52%). Cases were more likely to have a longer duration of bacteremia than controls (5.2 versus 2.1 days) and were less likely to survive (79% versus 95%). The authors concluded that the potential for hepatotoxicity, drug–drug interactions, and the emergence of resistant S. aureus isolates warrants a careful assessment of the benefit-to-harm balance before adding rifampicin to standard antibiotic treatment in such cases. Both linezolid and co-trimoxazole are antibiotics that are well suited for oral therapy of bone and joint infections caused by otherwise resistant Gram-positive cocci (resistant to fluoroquinolones, macrolides, beta-lactams). Hematologic Two patients developed severe intravascular hemolysis during daily low-dose rifampicin treatment of meticillin-resistant Staphylococcus aureus (MRSA) [82A]. • A 14-year-old girl with cystic fibrosis, who was taking ciprofloxacin, amikacin, co-trimoxazole, and rifampicin for a chronic pulmonary infection with culture-proven MRSA, was given oral rifampicin 16 mg/kg/day (300 mg bd) and after 5 weeks developed fatigue and weight gain and had marked dependent edema. There was no splenomegaly or jaundice. She had an anemia (hemoglobin 6.6 g/dl), reticulocytopenia (0.3%), thrombocytopenia (platelets 64  109/l), and

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acute renal insufficiency. Renal biopsy showed acute tubular necrosis. All antibiotics were stopped and then restarted 48 hours later at renal doses. However, even after dialysis, the anemia did not improve and she required erythrocyte transfusions. A peripheral blood smear showed occasional echinocytes and rare schistocytes. Her lactate dehydrogenase activity and bilirubin were raised and haptoglobin mildly reduced. Specific antibody testing showed a specific hemolytic anti-rifampicin antibody. Rifampicin and all antibiotics were withdrawn and the hemoglobin and platelet count recovered within 2 months. • A 6-month-old boy with trisomy 21, hypothyroidism on replacement therapy, and a repaired atrioventricular canal was given parental vancomycin and oral rifampicin 35 mg bd for MRSA bacteremia. He had had hematuria and a non-hemolytic normocytic anemia before starting rifampicin. He was transfused with packed erythrocytes to hemoglobin of 12.2 g/dl, but returned 2 weeks later with hemoglobin of 7.3 g/dl, MCV 88 fl, and reticulocyte count 6.9%. He had no jaundice, splenomegaly, or tachycardia. An antibody that reacted with erythrocytes in the presence of rifampicin and complement was found. Rifampicin was withdrawn and his hemoglobin rose to 11.0 and 15.5 g/dl at 1 and 9 months respectively.

Hemolytic anemia associated with rifampicin was hypothesized to be hapten mediated, as the patient's serum fixed complement in the presence of rifampicin. However, subsequent studies identified circulating erythrocyte-specific antibodies in the serum with specificity for both the Lutheran (Lu) and I antigens. The presence of the I antigen on the surface of leukocytes, platelets, and renal tubular epithelial cells may have accounted for the hemolysis, thrombocytopenia, and renal failure with acute tubular damage observed in the first patient. Drug–drug interactions Atazanavir þ ritonavir In a phase I, open, one-arm study, 14 HIV-seronegative volunteers first took rifampicin 600 mg/day for 8 days and then added atazanavir 300 mg bd and ritonavir 100 mg bd; however, when atazanavir and ritonavir were added, the first three subjects developed vomiting and rises in aminotransferases and the study was terminated [83c].

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Atorvastatin Both atorvastatin and rifampicin are substrates of OATP1B1 (organic anion transporting polypeptide 1B1), encoded by the SLCO1B1 gene. Rifampicin is a potent inhibitor of SLCO1B1 (IC50 1.5 mmol/l) and the SLCO1B1 521T>C functional genetic polymorphism alters the kinetics of atorvastatin in vivo. The hypothesis that rifampicin might influence atorvastatin kinetics in a SLCO1B1 polymorphismdependent manner has been evaluated in a two-phase crossover study in 16 subjects with known SLCO1B1 genotypes (six c.521TT, six c.521TC, and four c.521CC) [84c]. Rifampicin increased atorvastatin plasma concentrations in accordance with SLCO1B1 521T>C genotype, while the increases in AUC0!48 among c.521TT, c.521TC, and c.521CC individuals were 833%, 468%, and 330% respectively. In contrast, SLCO1B1 521T>C had no effect on rifampicin pharmacokinetics. Lopinavir þ ritonavir The interaction of rifampicin with lopinavir þ ritonavir has been assessed in 34 patients, of whom 23 took a non-adjusted dose of lopinavir þ ritonavir (400/100 mg bd or 800/200 mg/ day), six took a slightly adjusted dose (500/ 125 or 533/133 mg bd), and five took a recommended dose (400/400 or 800/200 mg bd) [85c]. Seven prematurely stopped taking the combination within 4 weeks because of acute adverse events (4/23, 1/6, and 2/5 in the three respective dosage groups). Combined use of lopinavir þ ritonavir and rifampicin is challenging, as it implies a balance between suboptimal efficacy and toxicity. Oxycodone Oxycodone is metabolized mainly in the liver by CYP3A and CYP2D6, which rifampicin induces. The interaction of rifampicin 600 mg/day for 7 days with a single dose of oxycodone, 0.1 mg/kg intravenously or 15 mg orally, has been studied in a four-session, paired, placebo-controlled crossover study in 12 volunteers [86C]. Concentrations of oxycodone and its metabolites noroxycodone, oxymorphone, and noroxymorphone were determined for 48 hours. Psychomotor

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effects were characterized for 12 hours by several visual analogue scales. Analgesic effects were characterized by measuring the heat pain threshold and cold pain sensitivity. Rifampicin reduced the oxycodone intravenous and oral AUCs by 53% and 86% respectively. The systemic availability of oxycodone was reduced from 69% to 21%. Rifampicin greatly increased the plasma metabolite-to-parent drug ratios for noroxycodone and noroxymorphone. The pharmacological effects of oral oxycodone were attenuated. To maintain adequate analgesia, dosage adjustment of oxycodone may be necessary when it is used concomitantly with rifampicin.

fixed-sequence study [88c]. They took a single oral dose of roflumilast 500 mg on days 1 and 12 and oral rifampicin 600 mg/day on days 5–15. Rifampicin the AUC of roflumilast by 80% and the Cmax by 68%; it reduced the AUC of roflumilast N-oxide by 56% and increased the Cmax by 30%; total phosphodiesterase PDE4 inhibitory activity due to roflumilast fell by 58%.

Protease inhibitors For problems in interpreting drug interactions studies in patients who are co-infected with tuberculosis and AIDS, see the special review above. See also individual drug names in this section. Ritonavir þ saquinavir The effects of rifampicin 600 mg/day on the steady-state pharmacokinetics of co-administered saquinavir þ ritonavir 1000/100 mg bd have been evaluated in 28 healthy HIV-negative subjects in an open, randomized, one sequence, two-period crossover study [87c]. Following substantial rises (grade 2) in hepatic aminotransferases in those who took the co-administered agents, the study was discontinued prematurely. Nausea, vomiting, abdominal pain, and headache were common. The symptoms abated and the aminotransferases normalized after drug withdrawal. There was a possible relation between the rises in aminotransferases and raised rifampicin and desacetyl-rifampicin concentrations. Although they have not been confirmed in HIVinfected patients, these data suggest that rifampicin should not be co-administered with saquinavir þ ritonavir. Roflumilast Roflumilast is metabolized by CYP3A4 and CYP1A2, with further involvement of CYP2C19 and extrahepatic CYP1A1. The effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide have been studied in 16 healthy men in an open, three-period,

M.S. Jawahar and V.V. Banu Rekha

Rifaximin Immunologic Rifaximin is widely used for the local treatment of intestinal infections because of its very poor absorption in the gastrointestinal tract (less than 0.4%). IgE-mediated reactions to rifaximin are rare, but one has been reported [89A]. • A 64-year-old man had a severe anaphylactic reaction (cough, dyspnea, convulsions, and transient loss of consciousness) a few minutes after topical medication of a surgical wound with rifamycin SV solution (RifocinÒ, SanofiAventis, Milan). He had a history of generalized urticaria after the removal of stitches after saphenectomy 4 years before, but no information was available about the drug used for disinfection. Three months before the lifethreatening episode, he had had severe abdominal pain, dyspnea, and urticaria, requiring emergency admission, about 10 minutes after taking one tablet of rifaximin (NorntixÒ, Alfa Wassermann, Bologna, Italy) for diverticular disease. His serum was studied twice, 1 month and 1 year after the anaphylactic reaction. On the first occasion serum IgE to rifamycin SV and rifampicin, but not to rifaximin, was detected; total IgE was 415 kU/l. However, there were specific IgE antibodies to rifaximin, because pre-incubation of serum with rifaximin almost completely inhibited the binding of IgG to the rifampicin–sepharose complex. One year later, serum-specific IgE to rifampicin, rifabutin, and rifapentin was still present; total IgE was 102 kU/l.

The time-course of the reactions suggested that the small amount of rifaximin absorbed not only provoked the first, relatively mild systemic reaction, but could have had a booster effect on IgE synthesis in response to rifampicin (probably present since the first reaction, 4 years earlier), which enhanced the subsequent severe reaction to rifamycin SV.

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Pure red cell aplasia associated with dapsone therapy. Ann Pharmacother 2005; 39 (6): 1137–8. Gill HJ, Tingle MD, Park BK. N-hydroxylation of dapsone by multiple enzymes of cytochrome P450: implications for inhibition of haemotoxicity. Br J Clin Pharmacol 1995; 40(6): 531–8. Coleman MD. Dapsone-mediated agranulocytosis: risks, possible mechanisms and prevention. Toxicology 2001; 162(1): 53–60. Besser M, Vera J, Clark J, Chitnavis D, Beatty C, Vassiliou G. Preservation of basophils in dapsone-induced agranulocytosis suggests a possible pathogenetic role for leukocyte peroxidases. Int J Lab Hematol 2009; 31(2): 245–7. Williams S, MacDonald P, Hoyer JD, Barr RD, Athale UH. Methemoglobinemia in children with acute lymphoblastic leukemia (ALL) receiving dapsone for Pneumocystis carinii pneumonia (PCP) prophylaxis: a correlation with cytochrome b5 reductase (Cb5R) enzyme levels. Pediatr Blood Cancer 2005; 44(1): 55–62. Naik PM, Lyon 3rd GM, Ramirez A, Lawrence EC, Neujahr DC, Force S, Pelaez A. Dapsone-induced hemolytic anemia in lung allograft recipients. J Heart Lung Transplant 2008; 27(11): 1198–202. Stotland M, Shalita AR, Kissling RF. Dapsone 5% gel: a review of its efficacy and safety in the treatment of acne vulgaris. Am J Clin Dermatol 2009; 10(4): 221–7. Piette WW, Taylor S, Pariser D, Jarratt M, Sheth P, Wilson D. Hematologic safety of dapsone gel, 5%, for topical treatment of acne vulgaris. Arch Dermatol 2008; 144 (12): 1564–70. Goolamali SI, Macfarlane CS. The use of cimetidine to reduce dapsone-dependent haematological side-effects in a patient with mucous membrane pemphigoid. Clin Exp Dermatol 2009; 34(8): e1025–6. Flosadóttir E, Bjarnason B. Full dapsone dose made possible by control of anaemia with darbepoetin-alpha. Acta Derm Venereol 2008; 88(5): 540–1. Thunga G, Sam KG, Patel D, Khera K, Sheshadhri S, Bahuleyan S, Vansalan R, Pandit VR, Manohar C. Effectiveness of hemodialysis in acute dapsone overdose—a

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clozapine after addition of isoniazid. J Clin Psychopharmacol 2009; 29(2): 190–1. Stover CK, Warrener P, VanDevanter DR, Sherman DR, Arain TM, Langhorne MH, Anderson SW, Towell JA, Yuan Y, McMurray DN, Kreiswirth BN, Barry CE, Baker WR. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature 2000; 405: 962–6. Tyagi S, Nuermberger E, Yoshimatsu T, Williams K, Rosenthal I, Lounis N, Bishai W, Grosset J. Bactericidal activity of the nitroimidazopyran PA-824 in the murine model of tuberculosis. Antimicrob Agents Chemother 2005; 49(6): 2289–93. Ginsberg AM, Laurenzi MW, Rouse DJ, Whitney KD, Spigelman MK. Assessment of the effects of the nitroimidazo-oxazine PA824 on renal function in healthy subjects. Antimicrob Agents Chemother 2009; 53(9): 3726–33. El Aïdli S, Kastalli S, Zaïem A, Lakhoua G, Rejeibi I, Loueslati MH, Daghfous R, Belkahia C. Recurrent dysosmia induced by pyrazinamide. Fundam Clin Pharmacol 2009; 23(5): 539–41. Papastavros T, Dolovich LR, Holbrook A, Whitehead L, Loeb M. Adverse events associated with Pyrazinamide and levofloxacin in the treatment of latent multi-drug resistant tuberculosis. CMAJ 2002; 167(2): 131–6. McIlleron H, Norman J, Kanyok TP, Fourie PB, Horton J, Smith PJ. Elevated gatifloxacin and reduced rifampicin concentrations in a single-dose interaction study amongst healthy volunteers. J Antimicrob Chemother 2007; 60(6): 1398–401. Chen CP, Hsu YH, Hong SJ. Acute generalized exanthematous pustulosis caused by rifabutin. Arch Dermatol 2009; 145(9): 1069–70. Boulanger C, Hollender E, Farrell K, Stambaugh JJ, Maasen D, Ashkin D, Symes S, Espinoza LA, Rivero RO, Graham JJ, Peloquin CA. Pharmacokinetic evaluation of rifabutin in combination with lopinavir–ritonavir in patients with HIV infection and active tuberculosis. Clin Infect Dis 2009; 49(9): 1305–11.

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[80] Nguyen S, Pasquet A, Legout L, Beltrand E, Dubreuil L, Migaud H, Yazdanpanah Y, Senneville E. Efficacy and tolerance of rifampicin-linezolid compared with rifampicin-cotrimoxazole combinations in prolonged oral therapy for bone and joint infections. Clin Microbiol Infect 2009; 15(12): 1163–9. [81] Riedel DJ, Weekes E, Forrest GN. Addition of rifampin to standard therapy for treatment of native valve infective endocarditis caused by Staphylococcus aureus. Antimicrob Agents Chemother 2008; 52(7): 2463–7. [82] Neunert CE, Paranjape GS, Cameron S, Rogers ZR. Intravascular hemolysis following low dose daily rifampin. Pediatr Blood Cancer 2008; 51(6): 821–3. [83] Haas DW, Koletar SL, Laughlin L, Kendall MA, Suckow C, Gerber JG, Zolopa AR, Bertz R, Child MJ, Hosey L, Alston-Smith B, Acosta EP. Hepatotoxicity and gastrointestinal intolerance when healthy volunteers taking rifampin add twice-daily atazanavir and ritonavir. J Acquir Immune Defic Syndr 2009; 50(3): 290–3. [84] He YJ, Zhang W, Chen Y, Guo D, Tu JH, Xu LY, Tan ZR, Chen BL, Li Z, Zhou G, Yu BN, Kirchheiner J, Zhou HH. Rifampicin alters atorvastatin plasma concentration on the basis of SLCO1B1 521T>C polymorphism. Clin Chim Acta 2009; 405(1–2): 49–52. [85] L'homme RF, Nijland HM, Gras L, Aarnoutse RE, van Crevel R, Boeree M, Brinkman K, Prins JM, Juttmann JR, Burger DM. Clinical experience with the combined use of lopinavir/ritonavir and rifampicin. AIDS 2009; 23(7): 863–5. [86] Nieminen TH, Hagelberg NM, Saari TI, Pertovaara A, Neuvonen M, Laine K, Neuvonen PJ, Olkkola KT. Rifampin greatly reduces the plasma concentrations of intravenous and oral oxycodone. Anesthesiology 2009; 110(6): 1371–8. [87] Schmitt C, Riek M, Winters K, Schutz M, Grange S. Unexpected hepatotoxicity of rifampin and saquinavir/ritonavir in healthy male volunteers. Arch Drug Info 2009; 2(1): 8–16.

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Antihelminthic drugs

Metabolism In a systematic review of the literature on drug-induced hypoglycemia electronic databases (MEDLINE, EMBASE, Web of Science, and SCOPUS) and the drug information system Micromedex were searched and additional references were sought from experts [1M]. Studies were eligible if they reported hypoglycemia as an adverse effect of a drug not used to treat hyperglycemia, regardless of their design, size, or follow-up duration, or the language of the report. Hypoglycemia caused by industrial exposures, non-pharmacological chemical exposures, alcohol, herbs, and nutritional supplements were excluded, as were in vitro and animal studies. There were 448 eligible studies, describing 2696 cases of hypoglycemia associated with 164 different drugs. The quality of evidence supporting the associations was mostly very poor, with methodological limitations and imprecision. The most commonly reported offending drugs were quinolones, pentamidine, quinine, betablockers, angiotensin-converting enzyme inhibitors, and insulin-like growth factor. These data suggest that antihelminthic drugs are not associated with significant drug-related hypoglycemia.

Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00031-3 # 2011 Elsevier B.V. All rights reserved.

[SED-15, 424; SEDA-30, 364; SEDA-31, 508; SEDA-32, 572]

BENZIMIDAZOLES

Albendazole [SED-15, 48; SEDA-30, 364; SEDA-31, 508; SEDA-32, 572] Observational studies In a study in Sri Lanka, 2319 patients, aged 10–90 years, were randomly selected from urban and rural areas and interviewed about the type and severity of adverse reactions to mass drug administration of albendazole and diethylcarbamazine, which is a component of the World Health Organization's efforts to eliminate filariasis worldwide [2C]. Seeking medical treatment and requiring hospitalization were used as indicators of the severity of infection. Almost 64% (n ¼ 1478) of the population said that they had taken the drug and 36% had not. Adverse drug reactions were reported by 187 patients (13%), the proportions being similar in urban and rural areas; the total number of reactions was 268 (range 1–4 per person). Commonly reported symptoms were drowsiness (35%), headache (23%), gastrointestinal symptoms (19%), and dizziness and faintness (12%). Most of the symptoms were mild and only one person was hospitalized (with abdominal pain). Persons those aged 31–50 years had more adverse reactions than those younger than 20 years. Women had more adverse reactions than men, but more men sought medication for their symptoms. Placebo-controlled studies In a doubleblind, randomized, placebo-controlled trial in Kenya [3C] of the effect of treating helminth and HIV co-infection, 208 antiretroviral drugnaive adults were given albendazole 400 mg/ day for 3 days or placebo. Albendazole 647

648

resulted in significantly higher CD4 cell counts among individuals with Ascaris lumbricoides infection after 12 weeks but there was no benefit in those with infections due to other species of soil-transmitted helminths. There were no adverse events reported. In a randomized placebo-controlled trial [4C] of the effects of albendazole on cyst disappearance, reduction of the number of cysts, and seizure recurrence in 178 patients with new-onset symptoms due to active or transitional neurocysticercosis, antiepileptic drugs were given with or without albendazole 15 mg/kg/day in two divided doses for 28 days; all patients also received prednisone. Active cysts were identified in 59 of 88 patients who were randomized to albendazole and 57 of the 90 patients in the placebo arm. By 1 month, 31% were free of active cysts in the treatment group compared with 7% in the placebo group. In addition, albendazole group produced a greater reduction in the number of active cysts than placebo. However, albendazole had little effect on cysts in the transitional stage or on calcified cysts. There was no difference in symptoms between albendazole and placebo during treatment or in seizure recurrence during the 12 months after treatment. The three most common symptoms reported during treatment and the first month after treatment were headache, seizures, and stomach problems, which were comparable in the two groups. During the 8 days of treatment, three patients developed intracranial hypertension, all in the placebo group. The efficacy of combining albendazole 15 mg/kg/day for 7 days with either praziquantel 75 mg/kg/day (n ¼ 53) or placebo (n ¼ 50) for 1 day has been studied in a double-blind, placebo-controlled, randomized study in North India in children with seizures and single-lesion neurocysticercosis [5C]. Repeat CT scans were performed after 1, 3, and 6 months. Seizure control and adverse reactions were similar in the two groups. Adverse effects were mild. There was no evidence of raised intracranial pressure and none of the patients reported epigastric discomfort or other gastrointestinal symptoms. None of the patients required drug withdrawal because of adverse reactions.

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P.J.J. van Genderen

Hematologic In unresectable cases of alveolar echinococcosis, liver transplantation has been undertaken. A technically difficult liver transplant was performed in a 68-yearold man with end-stage liver disease after treatment with albendazole was tried for a short period but had to be stopped because of pancytopenia [6A]. Liver In two cases of alveolar echinococcosis with multiple-organ involvement (the liver, lungs, and bone) resection of the bone lesion was complete in one case but incomplete in the other [7A]. Albendazole caused no adverse reactions other than mild disturbances of liver function tests. Albendazole 10 mg/kg/day has been used to treat cystic echinococcosis (hydatid disease) in 11 children aged 4–14 years, with at least 10 cysts in the same organ [8c]. The children had a total of 296 cysts located mostly in the liver (178 cysts) and the lungs (78 cysts). With exclusive albendazole therapy, 58% of pulmonary cysts, 96% of peritoneal cysts, but only 32% of hepatic cysts were cured. There were no adverse events related to treatment, apart from slight rises in serum aminotransferase activities in two cases, which normalized without withdrawal of albendazole. The high rate of viable cysts after medical therapy is problematic and in this case was attributed to poor diffusion of albendazole into the cysts, because of their multiplicity and contiguity, variable sensitivity of each cyst to albendazole, and/or insufficient duration of treatment; resistance to albendazole was unlikely.

Benznidazole

[SED-15, 426]

Benznidazole, a nitroheterocyclic compound, was developed early in the 1970s and acts by direct toxic inhibition of the DNA synthesis of Trypanosoma cruzi, acting on both amastigotes and trypomastigotes. Its main adverse effects, which have been reviewed [9R] are related to the enzymatic activity of nitroreduction and the generation of free radicals. This enzymatic activity is very low in children and young adults, which explains the fewer adverse

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reactions in these age groups. The main adverse reactions to benznidazole include: • nervous system—polyneuritis, which is dose related and occurs at dosages of over 18 g; • gastrointestinal—digestive intolerance consisting of vomiting and abdominal pain; • liver—hepatitis, which occurs in 0.8% of patients taking benznidazole; • skin—dermatitis from hypersensitivity, the principal undesirable adverse effect of benznidazole, which affects 20–25% of patients; it is a hypersusceptibility reaction that occurs 10 days after the start of treatment; • bone marrow—depression of the bone marrow is rare; it has been proposed that neutropenia, agranulocytosis, and thrombocytopenia could be dose related; • tumorigenicity—animal studies suggest that at high doses, benznidazole may induce the development of lymphomas.

Other adverse effects include anorexia, chronic headache, fatigues, myalgia, and insomnia. In order to prevent these adverse reactions, and hence improve adherence to benznidazole, the following measures are recommended: a low fat and hypoallergenic diet, daily administration, patient education, and treatment for no more than 30 days. In particular, patients should be reassured that the adverse effects that benznidazole causes are reversible and non-life-threatening.

Diethylcarbamazine [SED-15, 1115; SEDA-31, 365; SEDA-32, 574] See “Albendazole”.

649

of ivermectin, combined with permethrin 5% and salicylic acid 5%, was given at the end of the fourth week for non-responders to the second dose. Two patients were completely cured after a single dose of ivermectin, four required a second dose, and two patients were cured after combined therapy. There were no recurrences at the end of 8 weeks. There was an inverse relation between the response to ivermectin and the severity of immunosuppression, crust thickness, and mite burden. No major adverse effects or changes in laboratory data were reported after ivermectin.

Levamisole [SED-15, 2028; SEDA-30, 366; SEDA-31, 510; SEDA-32, 575] Skin Drug rash with eosinophilia and systemic symptoms (DRESS) has been studied in an observational study of 30 patients aged 13–78 years in Taiwan [11c]. The most common offending drug was allopurinol, followed by carbamazepine. In one case it was associated with levamisole, but details were not given. In the 30 cases the most common pathological changes were lichenoid dermatitis, erythema multiforme, pseudolymphoma, and vasculitis. Impairment of liver and renal functions and blood dyscrasias were frequent complications. There was active infection or reactivation of human herpesvirus-6 in seven of 11 patients who were studied serologically. Two patients developed type 1 diabetes mellitus. The mortality rate was 10%.

Ivermectin

[SED-15, 1946; SEDA-30, 365; SEDA-31, 509; SEDA-32, 575]

Observational studies The use of oral ivermectin has been evaluated in eight Egyptian patients with crusted scabies who took a single oral dose of ivermectin 200 micrograms/ kg and were re-examined at 2, 4, 6, and 8 weeks [10c]. A second dose of ivermectin was given if there was treatment failure at the end of the second week, and a third dose

Myrrh (Commiphora molmol) [SED-15, 2409; SEDA-31, 511] Uses The use of myrrh in treating human trematode infections in Egypt has been reviewed [12R]. Placebo-controlled studies Guggul 2160 mg/day has been studied in a double-blind,

650

randomized, placebo-controlled trial in 43 Norwegian women and men, aged 27–70 years, with moderately increased cholesterol [13C]. After 12 weeks, mean concentrations of total cholesterol and HDL cholesterol were significantly reduced by guggul, but mean concentrations of LDL cholesterol, triglycerides, and total cholesterol/HDL ratio did not change significantly. Ten guggul users (versus four with placebo) reported adverse effects: mild gastrointestinal discomfort (n ¼ 7), possible thyroid problems (n ¼ 2), and a generalized rash (n ¼ 1); the latter resulted in withdrawal from the trial.

Praziquantel

[SED-15, 2911; SEDA-30, 366; SEDA-31, 511] Comparative studies The combination of artemether with praziquantel in different regimens has been studied in 205 Chinese subjects with acute Schistosoma japonicum infection, who were randomly assigned to four regimens: praziquantel 60 mg/kg þ artemether 6 mg/kg; praziquantel 60 mg/kg þ placebo; praziquantel 120 mg/kg þ artemether 6 mg/kg; placebo þ praziquantel 120 mg/kg [14C]. All the participants were followed up for 45 days. Treatment was efficacious in over 96% in all the groups, although the first group had a faster fever clearance time, resulting in shorter hospitalization. Pain in the upper abdominal region, accompanied by diarrhea, occurred in 26% of those who took praziquantel; other adverse events included headache, nausea, and lower abdominal discomfort. Adverse events in patients who took artemether included allergy, nausea, vomiting, and abdominal pain. The authors concluded that combining artemether and praziquantel did not improve treatment efficacy compared with praziquantel alone. The use of praziquantel in the treatment of Schistosoma hematobium has been studied in 767 patients in Zimbabwe [15C]. Two single oral doses of praziquantel 40 mg/kg were given 6 weeks apart, and

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624 participants were available for followup 6 weeks later. The overall cure rate was 89% and the egg reduction rate was 98%; 72 individuals remained infected at 6 weeks after treatment, 46 of whom resolved after a second round of treatment, and the remainder after a third round of treatment 6 months later. The most common adverse events reported 24 hours after treatment were stomach discomfort and nausea; they were mild and transient.

Suramin [SED-15, 3249; SEDA-30, 367; SEDA-31, 512] Uses Human African trypanosomiasis, also known as sleeping sickness, has been reviewed [16R]. All four main drugs used are toxic, and melarsoprol, the only drug that is effective for both types of central nervous system disease, kills 5% of patients who take it. Eflornithine, alone or combined with nifurtimox, is being used increasingly as first-line therapy for gambiense disease. There is a pressing need for an effective, safe oral drug for both stages of the disease, but this will require a significant increase in investment for new drug discovery from Western governments and pharmaceutical companies. Suramin is the drug of choice for the early hemolymphatic stage of both Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense infections before nervous system invasion occurs [17R]. The dose is 15–20 mg/kg/week, given intravenously, up to a maximum single dose of 1 g. Suramin, which is excreted by the kidneys, binds to plasma proteins and can persist in the circulation in low concentrations for as long as 3 months. A single course for an adult is usually 5 g, never to exceed 7 g. The primary adverse reactions are fever, rash, conjunctivitis, renal insufficiency, abdominal pain, paresthesia, and muscle pain. Observational studies The potential of non-cytotoxic doses of suramin to reverse

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chemotherapy resistance in advanced chemonaive and chemoresistant non-smallcell lung cancer has been evaluated in a phase II study [18c]. Patients received paclitaxel 200 mg/m2 and carboplatin (AUC ¼ 6 minutes mg/ml) every 3 weeks. The total dose of suramin per cycle was calculated using a nomogram derived from a preceding phase I trial to obtain the desirable plasma concentration

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range of 10–50 mmol/l. In all, 39 responseassessable chemonaive patients received 213 cycles of suramin and 38 cycles were given to 15 patients with resistance to paclitaxel and carboplatin. The pattern and frequency of adverse effects were similar to those expected with paclitaxel and carboplatin alone. There was no evidence of clinically significant reversal of primary resistance.

References [1] Murad MH, Coto-Yglesias F, Wang AT, Sheidaee N, Mullan RJ, Elamin MB, Erwin PJ, Montori VM. Drug-induced hypoglycemia: a systematic review. J Clin Endocrinol Metab 2009; 94: 741–5. [2] Gunawardena S, Ranganathan SS, Fernandopulle R. Pharmacovigilance through consumer feedback (reporting) in the mass treatment of lymphatic filariasis using diethylcarbamazine and albendazole in two districts of Sri Lanka. Trop Med Int Health 2008; 13(9): 1153–8. [3] Walson JL, Otieno PA, Mbuchi M, Richardson BA, Lohman-Payne B, MacHaria SW, Overbaugh J, Berkley J, Sanders EJ, Chung MH, John-Stewart GC. Albendazole treatment of HIV-1 and helminth co-infection: a randomized, doubleblind, placebo-controlled trial. AIDS 2008; 22: 1601–9. [4] Carpio A, Kelvin EA, Bagiella E, Leslie D, Leon P, Andrews H, Hauser WA, Lisanti N, Aguirre R, Serrano M, Pesantes J, Moncayo J, Roman M. Effects of albendazole treatment on neurocysticercosis: a randomised controlled trial. J Neurol Neurosurg Psychiatry 2008; 79: 1050–5. [5] Kaur S, Singhi P, Singhi S, Khandelwal N. Combination therapy with albendazole and praziquantel versus albendazole alone in children with seizures and single lesion neurocysticercosis: a randomized, placebocontrolled double blind trial. Pediatr Infect Dis J 2009; 28: 403–6. [6] Haider HH, Nishida S, Selvaggi G, Levi D, Tekin A, Moon JI, Tzakis AG. Alveolar

[7]

[8]

[9]

[10]

[11]

[12]

Echinococcosis induced liver failure: salvage by liver transplantation in an otherwise uniformly fatal disease. Clin Transplant 2008; 22: 664–7. Ishikawa Y, Sako Y, Itoh S, Ohtake T, Kohgo Y, Matsuno T, Ohsaki Y, Miyokawa N, Nakao M, Nakaya K, Ito A. Serological monitoring of progression of alveolar echinococcosis with multiorgan involvement by use of recombinant Em18. J Clin Microbiol 2009; 47: 3191–6. Ben Brahim M, Nouri A, Ksia A, El Ezzi O, Krichene I, Mekki M, Belghith M. Management of multiple echinococcosis in childhood with albendazole and surgery. J Pediatr Surg 2008; 43: 2024–30. Viotti R, Vigliano C, Alvarez MG, Petti M, Bertocchi G, Armenti A. Side effects of benznidazole as treatment in chronic Chagas disease: fears and realities. Expert Rev Anti Infect Ther 2009; 7(2): 157–63. Nofal A. Variable response of crusted scabies to oral ivermectin: report on eight Egyptian patients. J Eur Acad Dermatol Venereol 2009; 23: 793–7. Chiou CC, Yang LC, Hung SI, Chang YC, Kuo TT, Ho HC, Hu S, Hong HS, Chung WH. Clinicopathological features and prognosis of drug rash with eosinophilia and systemic symptoms: a study of 30 cases in Taiwan. J Eur Acad Dermatol Venereol 2008; 22: 1044–9. Abdul-Ghani RA, Loutfy N, Hassan A. Myrrh and trematodoses in Egypt: an overview of safety, efficacy and effectiveness profiles. Parasitol Int 2009; 58(3): 210–4.

652 [13] Nohr LA, Rasmussen LB, Straand J. Resin from the mukul myrrh tree, guggul, can it be used for treating hypercholesterolemia? A randomized, controlled study. Complement Ther Med 2009; 17(1): 16–22. [14] Hou XY, McManus DP, Gray DJ, Balen J, Luo XS, He YK, Ellis M, Williams GM, Li YS. A randomized, double blind, placebo-controlled trial of safety and efficacy of combined praziquantel and artemether for acute schistosomiasis japonica in China. Bull World Health Organ 2008; 86(10): 788–95. [15] Midzi N, Sangweme D, Zinyowera S, Mapingure MP, Brouwer KC, Kumar N, Mutapi F, Woelk G, Mduluza T. Efficacy and side effects of praziquantel treatment against Schistosoma hematobium infection among primary school children in

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Zimbabwe. Trans R Soc Trop Med Hyg 2008; 102(8): 759–66. [16] Kennedy PGE. The continuing problem of human African trypanosomiasis (sleeping sickness). Ann Neurol 2008; 64: 116–26. [17] Lupi O, Bartlett BL, Haugen RN, Dy LC, Sethi A, Klaus SN, Machado Pinto J, Bravo F, Tyring SK. Tropical dermatology: tropical diseases caused by protozoa. J Am Acad Dermatol 2009; 60: 897–925. [18] Villalona-Calero MA, Otterson GA, Wientjes MG, Weber F, Bekaii-Saab T, Young D, Murgo AJ, Jensen R, Yeh T-K, Wei Y, Zhang Y, Eng C, Grever M, Au JLS. Non-cytotoxic suramin as a chemosensitizer in patients with advanced nonsmall-cell lung cancer: a phase II study. Ann Oncol 2008; 19: 1903–9.

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Vaccines

Editor’s note: Abbreviations used in this and previous issues of SEDA:

GENERAL

• aP: Acellular pertussis • • AVA: Anthrax vaccine adsorbed • • BCG: Bacillus Calmette–Guérin • • DTP: Diphtheria þ tetanus toxoids • þ pertussis vaccine • DTaP: Diphtheria þ tetanus • toxoids þ acellular pertussis • • DTaP-Hib-IPV-HB: • Diphtheria þ tetanus toxoids þ acellular pertussis þ IPV þ • Hib þ hepatitis B (hexavalent vaccine) • • DTwP: Diphtheria þ tetanus toxoids þ whole cell pertussis • HAV: Hepatitis A virus • HbOC (also called • PRP-CRM): • Conjugated Hib vaccine (Hib capsular antigen polyribosylphosphate • covalently linked to the non-toxic diphtheria toxin variant CRM197) • • HBV: Hepatitis B • virus • Hib: Haemophilus influenzae type b •

Surveillance The applicability, reliability, sensitivity, and specificity of six standardized case definitions for adverse events following immunization (AEFI) (for fever, generalized convulsive seizures, hypotonic –hyporesponsive episodes, intussusception, nodules, and persistent crying) developed by the Brighton Collaboration using the US Vaccine Adverse Event Reporting System (VAERS) have been evaluated [1H]. The evaluation included: (a) the development of codified search strings using standardized coding terminology, and (b) for sensitivity and specificity analyses, the development of a “gold standard” for case determination by clinical expert reviews, and its comparison with the application of the definitions to VAERS reports by nonclinicians. Application of the case definitions in an automated approach proved to be valid, feasible, and unlikely to miss confirmed cases of the reported clinical event. The definitions had variable but generally high sensitivity and specificity compared with clinician review, which in itself yielded inconsistent case determination. These results demonstrate the need for standardized definitions for AEFI and their usefulness in surveillance.

HZV vaccine: Herpes zoster virus vaccine IPV: Inactivated polio vaccine JE vaccine: Japanese encephalitis vaccine MCV4: Meningococcal conjugate vaccine, 4-valent MMR: Measles þ mumps þ rubella MR: Measles þ rubella MMRV: Measles þ mumps þ rubella þ varicella OPV: Oral polio vaccine PRP-D-Hib: Conjugated Hib vaccine (Hib capsular antigen polyribosylphosphate covalently linked to a mutant polypeptide of diphtheria toxin) SV40: Simian virus 40 Td: Diphtheria þ tetanus toxoids (adult formulation) Tdap: Tetanus toxoid þ reduced diphtheria toxoid þ acellular pertussis wP: Whole cell pertussis YF vaccine: Yellow fever vaccine YFV: Yellow fever virus

Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00032-5 # 2011 Elsevier B.V. All rights reserved.

Cardiovascular A systematic review of the literature on immunization myocarditis or pericarditis after immunization identified 37 publications, in which 269 cases were reported during the search period (1966–2007); the cardiac symptoms occurred at 1–30 days after immunization [2MA]. Eosinophilic myocarditis was also reported 653

654

in two cases of single administrations of conjugate meningococcal C vaccine or hepatitis B vaccine. The histological findings strongly supported hypersensitivity reactions and there was no evidence of a viral etiology, which is typically characterized by a lymphocytic infiltrate. Both episodes resolved with glucocorticoid therapy. Cardiac complications, including myopericarditis, can also occur with smallpox vaccine (see below). Nervous system Five patients developed symptoms of paresthesia within 1 day to 2 months after immunization against rabies, varicella, or Lyme disease [3c]. There was mild sensory loss in the legs, preserved strength, normal or minimally abnormal electrodiagnostic findings, and reduced epidermal nerve fiber densities per skin biopsy. Empirical immunomodulatory therapy was tried in two patients but was ineffective. The symptoms improved spontaneously in all the patients but did not fully resolve. Skin Discoloration of the leg after immunization is a relatively unknown entity, which has been studied during a 10-year period after immunization of infants in the Dutch National Vaccination Program [4R]. Discolored leg syndrome was defined as an even or patchy red, blue, or purple discoloration of the leg(s) and/or petechiae with or without swelling. In all, 1162 reports of adverse events after immunization were made to the passive surveillance system between 1994 and 2003. Red, blue, or purple discoloration and isolated petechiae were reported in 39%, 19%, 27%, and 14% of these cases respectively; 1105 cases were considered to be related to immunization, based on a predefined risk window with the onset of symptoms after immunization—48 hours for discoloration and 2 weeks for petechiae. Of the 1105 cases, about 50% occurred after DTP-IPV þ Hib1 immunization, and 30% occurred after DTP-IPV þ Hib2 immunization. Discolored leg syndrome was often accompanied by fierce crying (78%). The median interval between immunization and the occurrence of the syndrome was 3.8 hours

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and the median duration was short (2 hours). Changing the immunization schedule from 3 to 2 months of age caused a small increase in the frequency of discolored leg syndrome. The syndrome manifested mainly after the first and/or second dose. In addition to dose it may be slightly age-dependent. The pathophysiology is unknown but it may be the result of a vasomotor reaction. Nicolau’s syndrome, or embolia cutis medicamentosa, is a rare condition that is characterized by acute cutaneous and softtissue necrosis after intramuscular injection of drugs, including modified-release formulations of penicillin, NSAIDs, and glucocorticoids [5RH]. In a retrospective study of seven children (mean age 9.8 months) who developed Nicolau’s syndrome after intramuscular immunization, the reactions were observed after the use of different combinations of vaccine antigens, and were no more common after repeated than after primary injections of the vaccines [6c]. Three children developed scars without functional impairment, two made a full recovery, and the final outcome was unknown in four. Taken into account the large number of intramuscular injections during infancy, Nicolau’s syndrome seems to be rare, but there is a possibility of under-reporting of less severe reactions. Immunologic In a prospective trial in neonates, in which an acellular pertussis vaccine was administered at 2–5 days of age, the vaccine was well-tolerated and immunogenic; however, there were reduced antibody responses, predominantly to Haemophilus influenzae type b [7C]. Infection risk Some have hypothesized that the simultaneous administration of combinations of vaccines might overload the immune system and therefore facilitate the development of bacterial and viral infections. In a case-series analysis of bacterial and viral infections during risk periods of 0–30, 31–60, and 61–90 days after the administration of either MMR vaccine or MMR vaccine plus serogroup C meningococcal conjugate vaccine (given

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concomitantly), there was a reduced risk at 0–30 days after the administration of MMR vaccine for both bacterial infections (relative incidence ¼ 0. 68; 95% CI ¼ 0.54, 0.86) and viral infections (relative incidence ¼ 0.68; 95% CI ¼ 0.49, 0.93) [8c]. There was no increased risk in any period when looking at combined viral or bacterial infections or for individual infections, with the single exception of an increased risk at 31–60 days after immunization for herpesvirus infections (relative incidence ¼ 1.69; 95% CI ¼ 1.06, 2.70). In the children given meningococcal group C vaccines concomitantly there was no significantly increased risk in either bacterial infections (relative incidence ¼ 0.54; 95% CI ¼ 0.26, 1.13) or viral infections (relative incidence ¼ 0.46; 95% CI ¼ 0.11, 1.93). These results confirm that these vaccines do not increase the risk of invasive bacterial or viral infection in the 90 days after immunization and do not support the hypothesis that there is an induced immune deficiency due to overload from combinations of vaccines. Susceptibility factors Preterm infants Several investigators have reported an increased incidence of cardiorespiratory events in preterm infants after immunization. For example, of 64 preterm infants of very low birth weights, 33 had a cardiorespiratory event after the first immunization, and six of these had a recurrence after the second immunization, including two who had previously been discharged home; a cardiorespiratory event associated with the first vaccination was the sole susceptibility factor for recurrence identified [9C]. However, the American Academy of Pediatrics recommends immunization of preterm infants with diphtheria–tetanus–acellular pertussis vaccine at a chronological age of 2 months, regardless of birth weight and gestational age. The relation between the use of diphtheria–tetanus–acellular pertussis vaccine and objectively assessed cardiorespiratory events has been examined in 191 preterm infants aged 56–60 days, who had been born before 37 weeks, in a randomized controlled study in 10 hospitals

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[10C]. The infants were randomly assigned to diphtheria–tetanus–acellular pertussis vaccine (n ¼ 93) at 2 months or a control group (n ¼ 98). Recording monitors were used continuously during the next 48 hours to document prolonged apnea and prolonged bradycardia. In the immunized group, 16% had at least one episode of prolonged apnea compared with 20% of the controls. One or more episodes of prolonged bradycardia occurred in 58% of immunized infants and 56% of the controls. The frequency of episodes was not significantly different, with an average of 0.5 episodes of prolonged apnea in each group. The mean numbers of episodes of prolonged bradycardia were 2.6 and 2.7 respectively. These results support the recommendation of the American Academy of Pediatrics that diphtheria–tetanus–acellular pertussis immunization should be offered to preterm infants at 2 months of age.

BACTERIAL VACCINES Anthrax vaccine

[SED-15. 260; SEDA-28, 357; SEDA-29, 357]

Observational studies Anthrax vaccine adsorbed (AVA) is the only US licensed AVA vaccine approved by the Food and Drug Administration. In recent years, the safety of anthrax vaccine has been controversial, stimulating reviews of its safety and efficacy. During 1 March 1998 to 14 January 2007, about 6 million doses of AVA vaccine were administered. As of 16 January 2007, 4753 reports of adverse events after the use of AVA had been submitted to the Vaccine Adverse Event Reporting System (VAERS) [11C]. The most commonly reported were: myalgia, arthralgia, pain, headache, depression, “asthenia”, rash, anxiety and insomnia, and back pain. Reports to VAERS did not definitively link any serious unexpected risks to this vaccine, and a review of deaths

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and serious reports did not show a distinctive pattern suggestive of a causal relation with AVA.

Bacille Calmette–Guérin (BCG) vaccine [SED-15, 397; SEDA-30, 372] Although intravesical therapy is an integral part of the management of non-muscle invasive bladder cancer, both intravesical chemotherapy and BCG have potential adverse effects that may lead to treatment withdrawal and incomplete treatment courses. An International Bladder Cancer Group has reviewed the current literature on adverse events associated with intravesical therapy [12R]. They concluded that cystitis, hematuria, contracted bladder, and ureteral obstruction are adverse reactions that can follow both chemotherapy and BCG. BCG-specific adverse events include granulomatous prostatitis, epididymoorchitis, systemic BCG reactions, and allergic reactions. Adverse reactions that are specific to intravesical chemotherapy include contact dermatitis, bladder calcification, and myelosuppression. Preventive strategies include instructing health-care professionals about proper treatment techniques, prophylactic use of antibiotics, and the possibility of BCG dose reduction. Hematologic Lymphadenitis due to disseminated BCG-itis has been described in a patient with X-linked chronic granulomatous disease 25 years after immunization [13c]. Skin BCG-induced keloid has been investigated in 60 patients [14c]. The mean length of the maximum dimension was 42.4 mm and the length increased proportionally to age at first visit. Keloids grew rapidly between the ages of 20 and 40 years. The authors recommended early therapeutic intervention, which might prevent keloids from growing larger, and underlined the need to provide adequate information. The complications of BCG immunization were reviewed in SED-15 (p. 397). Recent

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case reports have included lupus vulgaris [15c], osteomyelitis [16c], and psoriasis [17c]. Extensive ulcerating vasculitis after BCG immunization has been reported in a 12-year-old girl, who developed extensive primary ulceration involving most of her left upper arm at the site of BCG immunization [18c]. Over a period of 18 months, secondary lesions developed on her forehead, prompting further investigation of a systemic disease process. Vaccine-induced granulomatous vasculitis was diagnosed and she responded to a combination of antituberculosis therapy and glucocorticoids. Skin grafting of the ulcerated area achieved wound closure. Susceptibility factors HIV infection At its meeting on 3–4 December 2009, the Global Advisory Committee on Vaccine Safety (GACVS) reviewed data from studies in Argentina and South Africa, which confirmed the significantly high risk of disseminated BCG disease in HIV-positive infants, with rates approaching 1% [19S]. Other studies have shown that infection with HIV severely impairs BCG-specific T-cell responses during the first year of life. Thus, BCG may provide little, if any, protection against tuberculosis in HIV-infected infants. Considering the significant risk of disseminated BCG disease, these data strongly support the WHO recommendation that BCG should not be given to children who are infected with HIV.

Meningococcal vaccine

[SED-15, 2250; SEDA-30, 372; SEDA-31, 519; SEDA-32, 580]

Observational studies At its meeting on 3–4 December 2009, the Global Advisory Committee on Vaccine Safety (GACVS) reviewed the safety profile on meningococcal A conjugate vaccine (MenAfri-VacTM vaccine) from clinical trials [20S]. MenAfri-VacTM vaccine is a lyophilized meningitis A conjugate vaccine developed

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by the Meningitis Vaccine Project and manufactured in the Serum Institute of India, Poona. Its reactogenicity and safety have been evaluated in four clinical studies and two other studies are in progress. A phase I study was conducted in volunteers in India aged 18–34 years and phase II and II/III studies were performed in Africa and India in people aged 1–29 years. To date, 1126 subjects have been followed for adverse events after immunization for at least 1 month and for serious adverse events up to at least 1 year. The vaccine did not cause any adverse reactions beyond 4 days after immunization; the adverse events observed were comparable between study and control vaccine groups, except for injection site tenderness, which was more common (13%) among those who received the vaccine. None of the 137 serious adverse events (including 14 deaths) reported in the vaccine studies were thought to be related to the study vaccines. The committee concluded that the available data for MenAfriVacTM vaccine do not indicate any special cause for concern. However, further studies, particularly postmarketing surveillance, are needed to assess the safety profile of the vaccine better.

Pertussis vaccine (including diphtheria–tetanus–whole cell pertussis vaccine [DTwP]) [SED15, 2780; SEDA-31, 520; SEDA-32, 580] In the early 1980s there were concerns about the safety of whole cell pertussis vaccines; in particular, it was claimed by some that the vaccine was associated with sudden infant death syndrome and encephalopathy [21H]. Immunization rates fell, and many vaccines were withdrawn from the market. However, epidemiological studies have consistently failed to identify an association. It has been recently argued that such reactions may have occurred in metabolically vulnerable children, specifically those with defects in fatty acid oxidation, in whom the combination of anorexia and fever due to the vaccine may have resulted

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in hypoglycemia and possibly death. Of course, this argument presupposes that the postulated association was a true one. Observational studies A combined tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine containing three pertussis antigens (Boostrix, Tdap3v) or five pertussis antigens (Adacel, Tdap5v) has been evaluated in 2284 healthy adults aged 19–64 years in a randomized study [22C]. Injection site reactions (pain, redness, and swelling) and fever of at least 37.5 C were significantly more common in those who received the pentavalent pertussis and fatigue was slightly more common in those who received the trivalent pertussis.

VIRAL VACCINES Hepatitis B vaccine

[SED-15, 1600; SEDA-30, 374; SEDA-31, 520] Immunologic The medical records of 10 patients, mean age 35 (26–44) years who developed systemic lupus erythematosus after hepatitis B immunization, have been analysed retrospectively, to determine the prevalence of different manifestations and the time course after immunization [23C]. Two patients had received one dose, two had received two doses, and six had received three doses. The mean interval between the first dose and the onset of autoimmune symptoms was 56 days. The authors concluded that data from this case-series, and previously documented cases, could only demonstrate a temporal relation between hepatitis B immunization and the appearance of systemic lupus erythematosus and not a causative one.

Human papilloma virus (HPV) vaccine [SED-15, 1698; SEDA-30, 374] Cervical cancer is the second most common cause of cancer deaths in women worldwide. It is almost invariably associated with

658

human papilloma virus (HPV) infection. Two HPV vaccines have been developed and licensed. Both vaccines, GardasilÒ and CervarixÒ, are highly effective in preventing persistent infections with HPV types 16 and 18, two high-risk viruses that cause 70% of all cervical cancers. Gardasil also prevents infection with HPV types 6 and 11, which cause 90% of all genital warts. Before licensing the vaccines were trialled in over 60 000 women and assessed as safe, within the statistical constraints of the trials to detect very rare events. Observational studies In June 2006, the Food and Drug Administration licensed the quadrivalent human papilloma virus (qHPV) (types 6, 11, 16, and 18) recombinant vaccine in the USA for use in girls and women aged 9–26 years; the Advisory Committee on Immunization Practices then recommended a qHPV vaccine for routine immunization of girls aged 11–12 years. Reports to the Vaccine Adverse Event Reporting System (VAERS) after the use of qHPV from 1 June 2006 to 31 December 2008 have been summarized [24R]. The authors performed additional analyses for some adverse effects following immunization (AEFIs) in prelicensing trials, those of unusual severity, or those that had received public attention. The VAERS received 12 424 reports of AEFIs after the use of qHPV, a rate of 54 reports per 100 000 doses distributed. A total of 772 reports (6.2% of all reports) described serious AEFIs, including 32 deaths. The reporting rates per 100 000 doses distributed were 8.2 for syncope; 7.5 for local site reactions; 6.8 for dizziness; 5.0 for nausea; 4.1 for headache; 3.1 for hypersensitivity reactions; 2.6 for urticaria; 0.2 for venous thromboembolic events, autoimmune disorders, and Guillain–Barré syndrome; 0.1 for anaphylaxis and death; 0.04 for transverse myelitis and pancreatitis; and 0.009 for motor neuron disease. Data mining revealed disproportionate reporting of syncope and venous thromboembolism. The authors concluded that most of the AEFI rates were not greater than the background rates associated with other vaccines, apart from

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syncope and venous thromboembolism. The significance of these findings must be tempered by considering the limitations of the reporting system, notably the high likelihood of under-reporting. Nervous system Several vaccines have been reported as potential triggers of acute disseminated encephalomyelitis, including HPV [25A]. • A 15-year-old girl developed acute disseminated encephalomyelitis 23 days after receiving a second dose of HPV vaccine. She had no history of other recent diseases, immunization, or infections. She was given high-dose glucocorticoids, which produced rapid neurological improvement and complete recovery after 3 weeks.

The authors cautioned that a single case report should not lead to unjustified misperceptions about the safety of a vaccine. A 19-year-old girl developed left brachial plexus neuritis after immunization with a qHPV vaccine [26A]. Pregnancy The pregnancy outcomes in 20 551 women aged 15–45 years, enrolled in five phase III placebo-controlled studies of two doses of qHPV 6/11/16/18 vaccine at 2 and 6 months, have been analysed [27M]. Urine pregnancy tests were performed immediately before each injection and participants with positive tests were not immunized. Women who became pregnant after enrolment were withdrawn from further immunization until resolution of the pregnancy. During the studies, 1796 vaccine recipients and 1824 placebo recipients became pregnant, resulting in 2008 and 2029 pregnancies with known outcomes. There were no significant differences in the proportions of pregnancies that resulted in live births, fetal losses, or spontaneous abortions. A total of 40 neonates born to women given the vaccine and 30 born to women given placebo had one or more congenital anomalies, which were diverse and consistent with those most commonly observed in the general population. The authors concluded that the administration of qHPV vaccine to women who

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became pregnant during phase III clinical trials did not appear to affect pregnancy outcomes negatively. The effects of HPV vaccine on pregnancy outcomes (live births, abortions, fetal deaths, and congenital anomalies) have been analysed using postmarketing data from the USA, France, and Canada [28R]. Among the 517 prospective reports with known outcomes, 451 (87%) were live births, including three sets of twins. Of 454 neonates, 439 (96.7%) were normal. The overall rate of spontaneous abortions was 6.9 per 100 outcomes. The prevalence of major birth defects was 2.2 per 100 liveborn neonates. There were seven fetal deaths (1.5 per 100 outcomes). Rates of spontaneous abortions and major birth defects were not greater than in the unexposed population. Although no adverse signals have been identified to date, HPV vaccines are not recommended for use in pregnant women.

Influenza vaccine

[SED-15, 1753; SEDA-30, 374; SEDA-32, 581]

Pandemic influenza H1N1 vaccines At its meeting on 3–4 December 2009, the Global Advisory Committee on Vaccine Safety (GACVS) preliminarily reviewed the safety of pandemic A (H1N1) influenza vaccines [29S]. From 21 September to 2 December 2009, tens of millions of doses of the 2009 H1N1 vaccine were administered, providing the basis for this first safety review by the GACVS. Pandemic influenza vaccines include live attenuated vaccines, inactivated unadjuvanted vaccines (split, subunit virion, or whole virion), and inactivated adjuvanted vaccines (split or subunit virion). At the time of the GACVS review, it was estimated that nearly 150 million doses of vaccine had been distributed in many countries around the world. About 30% of those 150 million doses were adjuvanted vaccines.

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No unexpected safety concerns were identified for any of the pandemic H1N1 vaccines. In these immunization campaigns, deaths in temporal association with immunization have been reported in many countries. Given the large number of people who have been immunized, it is expected that deaths that were unrelated to immunization would occur in temporal association with immunization. Investigation of deaths that have been reported after immunization have identified that the cause of death has been unrelated to immunization in all but a few instances. There have been a few individual reports of deaths associated with anaphylactic reactions to immunization. Immediate hypersensitivity reactions have been reported after the use of all types of 2009 pandemic H1N1 vaccines. These events include urticaria, angioedema, and anaphylaxis, with reactions ranging from mild to serious. The overall reporting rates for anaphylaxis range from 1 per 1 000 000 to 1 per 100 000 doses distributed. Anaphylaxis is a rare but potentially life-threatening adverse reaction to all vaccines, and immunization providers must be prepared to recognize such reactions and treat them appropriately. Although some cases of Guillain–Barré syndrome have been reported after the use of pandemic H1N1 vaccines, the evidence to date is reassuring, with no increase in reporting rates above what is expected, based on background rates. Surveillance for Guillain–Barré syndrome has been instituted in several countries and should provide additional information by the first quarter of 2010. Concerns have been raised about the use of adjuvanted pandemic vaccines in patients with immune disorders, such as immunodeficiency, autoimmune disorders, and solid organ transplants. To date, postmarketing surveillance has not found evidence for causality of any adverse reactions in such patients. Viral infections, such as influenza, can lead to severe complications in immunocompromised patients. Conclusion Ten weeks into the worldwide immunization campaign against pandemic H1N1 in 2009, the GACVS reviewed the safety of the vaccines that are currently in

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use. To date, the safety data are reassuring. Most of the adverse events that have been reported after immunization have not been serious. To date, no unexpected safety concerns have been identified. Observational studies In October 2003 the Advisory Committee on Immunization Practices (ACIP) recommended influenza immunization for all children aged 6–23 months [30R]. The safety of this recommendation has been evaluated using the Vaccine Adverse Event Reporting System (VAERS) to study serious adverse events reported between 1 July 2003 and 30 June 2006 in children aged 6–23 months who had been given trivalent inactivated influenza vaccine. There were 104 serious adverse events at a median time after immunization of 1 day. The two most common serious adverse events were fever (52 reports) and seizures (35 reports). Causality assessment suggested that none was definitely related to influenza vaccine. No new or unexpected concerns were identified. Nervous system A 44-year-old man who developed a stroke with a left hemiparesis after influenza immunization had a large, contrast-enhancing brainstem lesion, and multiple punctate lesions suggesting microhemorrhages in both cerebral hemispheres [31A]. Detailed diagnostic studies failed to yield any results to support inflammatory or demyelinating diseases, suggesting that influenza immunization may have been associated with the event. The patient had a remarkable response to high-dose glucocorticoid treatment. Immunologic There is controversy about whether autoimmune or rheumatic diseases can be precipitated by immunization. Vasculitis after influenza vaccines have been discussed as a possible new entity [32H]. Four cases of new or relapsing vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA) have been described after influenza immunization [33c]. Several trials in patients with pre-existing autoimmune diseases failed to show an

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increased risk of disease recurrence after influenza immunization, but these studies were probably underpowered to detect very rare adverse reactions. The authors concluded a causal relation between immunization and vasculitis has not been proved, but it seems possible that in rare cases vaccines might cause vasculitis. Pregnancy In the USA, routine influenza immunization is recommended for all women who are or will be pregnant during the influenza season. During pandemics and seasonal epidemics of influenza, pregnancy places otherwise healthy women at increased risk of serious complications from influenza, including death. The evidentiary basis for recommending immunization in women who will be pregnant during the influenza season and the adverse reactions to influenza immunization during pregnancy have been reviewed [34R]. No study to date has shown an increased risk of either maternal complications or adverse fetal outcomes associated with inactivated influenza vaccine. Moreover, there is no scientific evidence that vaccines that contain thimerosal cause adverse reactions among children born to women who received influenza vaccine during pregnancy. Drug–drug interactions Anticoagulants Although most reports of concomitant warfarin therapy and influenza immunization have shown no significant change in the average degree of anticoagulation, there have been reports of individuals who may have had increased anticoagulation after influenza immunization, as illustrated by another such report [35A]. • A 64-year-old man with a 2-day history of bleeding from the rectum became unresponsive. He had taken long-term warfarin because of atrial fibrillation and had received an inactivated influenza vaccine 1 month before admission. The INR was raised, after having been stable for at least 6 months. A CT scan showed a large parenchymal hemorrhagic infarct involving the left temporal, parietal, and occipital lobes. He died about 17 hours after admission.

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The authors considered the raised INR in this case to have been due to an interaction of warfarin with the influenza immunization. They suggested that the INR should be measured more often during the 4–6 weeks after influenza immunization.

Measles–mumps–rubella (MMR) vaccine [SED-15, 2207; SEDA-30, 375; SEDA-31, 521; SEDA-32, 581] Nervous system In 2003, a 4-week national measles–rubella immunization program was implemented in Iran, during which the incidence of Guillain–Barré syndrome was studied among children aged 5–14 years, using the national surveillance system for acute flaccid paralysis from 2002 to 2004 [36R]. There were 370 confirmed case reports. The annual incidence was relatively constant over the 3-year period, and ranged from 0.65 per 100 000 population in 2004 to 0.76 per 100 000 population in 2003. In comparison with other 10-week periods, there was no increase in the incidence of Guillain–Barré syndrome during 2002–2004.

Autism and vaccines The controversy about vaccines as a possible cause of autism is not over. In the USA, some doctors and scientists, some groups representing families with autistic children, and many parents fervently believe that there is a connection. More than 4800 such US families (Autism Omnibus) have petitioned the Federal Vaccine Injury Compensation Program (VICP) for compensation, based on the claim that their children’s autism/autistic spectrum disorder was caused through vaccines, either caused by MMR vaccine alone or in combination with thimerosal-containing vaccines (Theory 1) or through thimerosal-containing vaccines (Theory 2). Autism decisions and background information on the Omnibus Autism processing (OAP) can be accessed on the US Court of Federal Claims website [37S].

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Cases under Theory 1 In February 2009, special masters of the US Court of Federal Claims ruled in favor of the United States Department of Health and Human Services (HHS) on general causation and three test cases under this theory. All three test cases were appealed to judges of the CFC and all three were affirmed in July and August, 2009. Two of the three test cases, Hazlehurst and Cedillo, were then appealed to the Federal Circuit. On 13 May 2010, the US Court of Appeals for the Federal Circuit released its decision in Hazlehurst. The Federal Circuit affirmed the decision of the HHS. The Hazlehurst family may next seek review by the Supreme Court. On 27 August 2010 the US Court of Appeals to the Federal Circuit affirmed the denial of Cedillo’s petition for compensation. Cases under Theory 2 On 12 March 2010, special masters decided in favor of the HHS on general causation and three test cases for Theory 2. None of the three test cases was appealed by petitioners.

Hematologic The risk of immune thrombocytopenia purpura during 42 days after MMR immunization has been studied in children aged 12–15 months, 12–23 months, and 1–18 years, using the Vaccine Safety Datalink [38C]. Those affected had a platelet count of less than 50  109/l with bleeding and normal erythrocyte and leukocyte indices. The study comprised 1 036 689 children who received 1 107 814 doses of MMR vaccine; 259 had immune thrombocytopenia purpura. Because only five exposed cases occurred after the age of 2 years, analyses were limited to children aged 12–23 months; they had lower median platelet counts than those who were not exposed and had a similar median duration of illness (11 versus 10 days). The incidence rate ratio was highest for children aged 12–15 months, at 7.10, with a sex difference: 14.6 in boys and 3.22 in girls. In children aged 12–23 months 76% of cases were attributable to MMR. The authors concluded that MMR immunization in the second year of life is associated with an increased risk

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of immune thrombocytopenia purpura and causes one case per 40 000 doses.

Measles–mumps–rubella–varicella (MMRV) vaccine Nervous system Pre-licensing clinical trials data have shown a significant increase in the risk of fever during days 5–12 after MMRV immunization compared with the vaccines given separately (MMR þ varicella). The incidence of febrile convulsions after MMRV immunization has been studied in a retrospective cohort study in children aged 12–60 months, who received a first dose of MMRV from February 2006 to June 2007, matched by age, sex, and calendar date of immunization with children who received separate MMR þ varicella vaccines concomitantly from November 2003 to January 2006, before MMRV was licensed [39C]. During the 30 days after immunization, there were respectively 128 and 94 cases of potential convulsions among the 31 298 children in the MMRV and MMR þ varicella cohorts. Review of the available medical charts resulted in 84 cases of confirmed febrile convulsions, 44 (1.41 per 1000) and 40 (1.28 per 1000) in the two groups. During days 5–12 after immunization, the pre-specified period of interest, the respective numbers were 22 (0.70 per 1000) and 10 (0.32 per 1000). The authors concluded that the risk of febrile convulsions is increased during days 5–12 after immunization with MMRV compared with MMR þ varicella given separately at the same visit, when postimmunization fever and rash are also increased in clinical trials. However, there was no evidence of an increase in the month after immunization.

Mumps vaccine Infection risk Transmission of the Leningrad–Zagreb mumps vaccine strain from a vaccinee to a susceptible contact has been described [40c].

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• A 14-month-old boy developed unilateral parotitis after immunization with MMR vaccine containing the Leningrad–Zagreb mumps strain. Six weeks later his 32-year-old mother developed fever, unilateral parotitis, and meningism, having never had mumps nor having received mumps immunization. Mumps virus was isolated from cerebrospinal fluid and confirmed by indirect immunofluorescence assay. The isolate was subsequently characterized as Leningrad–Zagreb mumps vaccine strain by genomic sequencing and comparing the genome with the reference sequences (GenBank NIH, Bethesda). Both patients were treated symptomatically and recovered completely.

This was a definitive (“between-the-eyes”) adverse reaction of type 4 [41H]. In addition to a few other reports, the report of virologically confirmed parotitis and meningitis in a fully immunocompetent family member provides further strong evidence that horizontal transmission after mumps immunization with the Leningrad–Zagreb strain can occur.

Rabies vaccine

[SED-15, 301;

SEDA-32, 582] Observational studies An adsorbed human diploid cell rabies vaccine (Rabivax) has been tested in a post-licensing study in 150 cases of suspect rabid animal bites [42c]. Adverse events included pain at the injection site (3.4%), swelling with induration (2.8%), and fever and headache (1.4%); there were no serious adverse events.

Rotavirus vaccine [SED-15, 3082; SEDA-27, 338; SEDA-28, 365; SEDA-30, 376; SEDA-31, 376] Gastrointestinal Reports of intussusception after RotaTeq immunization have been assessed, using data from the VAERS and the Vaccine Safety Datalink, in children enrolled in managed care [43R]. Observed versus expected rate ratios were determined using vaccine dose distribution data and

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Vaccine Safety Datalink background rates of intussusception. Between 1 February 2006 and 25 September 2007, the VAERS received 160 reports of intussusception. Assuming that reporting completeness was 75% and that 75% of the distributed doses of RotaTeq were administered, the observed versus expected rate ratios were 0.53 and 0.91 during 1–21 and 1–7 days after immunization respectively. There were three cases of intussusception within 30 days after 111 521 RotaTeq immunizations, compared with six cases after 186 722 non-RotaTeq immunizations during the same period. The authors concluded that these data do not suggest that RotaTeq is associated with intussusception.

Smallpox vaccine

[SED-15, 3150;

childhood, but a case has also been reported after immunization against tickborne encephalitis [45c]. • A 34-year-old woman with immune thrombocytopenic purpura was treated with splenectomy and was immunized against pneumococci, meningococci, and Haemophilus influenzae type b. She had been well for 3 years, but 2 weeks after a first dose of tick-borne encephalitis vaccine (FSME-Immun, BaxterÒ), her platelet count fell to 37  109/l. She was given dexamethasone 40 mg/day for 4 days and her platelet count normalized and remained stable.

Varicella vaccine and Herpes zoster vaccine [SED-15, 3606; SEDA-31, 522; SEDA-32, 584]

SEDA-32, 582] Cardiovascular Following a federal campaign to vaccinate US military personnel and civilians in 2002, to counter a possible bioterrorism attack, more than 1 200 000 military personnel and about 40 000 civilians were vaccinated [44AR]. The incidence of myopericarditis exceeded calculated background rates, prompting discussion about cardiac inflammation and other potential vaccine-associated cardiac complications such as dilated cardiomyopathy and myocardial ischemia. A causal relation between smallpox-associated myopericarditis and dilated cardiomyopathy has not been demonstrated, since there have been only a few cases, while historical and current data have not substantiated a causal association with myocardial ischemia.

Tick-borne meningoencephalitis vaccine [SEDA-15; 3423] Hematologic There have been several reports of the development or reactivation of immune thrombocytopenic purpura after immunization. Most of them have been related to MMR immunization in

Varicella vaccine See also “Measles–mumps–rubella–varicella (MMRV) vaccine” above. Sensory systems Eyes Interstitial keratitis has been reported after varicella immunization [46A]. Infection risk Recurrent herpes zoster in an immunocompetent 2-year-old child was associated with the vaccine strain of varicella zoster virus by polymerase chain reaction; this is a rare complication [47A]. A previously healthy boy who had received varicella vaccine developed herpes zoster with meningitis [48A]. The vaccine strain recovered from scabs of three skin lesions had the wild-type allele at position 108111, a vaccine marker never previously associated with vaccine-associated adverse events. The vaccine strain from cerebrospinal fluid also contained mutations never previously observed at vaccine-associated single nucleotide polymorphisms that would alter amino acid sequences in ORF54 and ORF59. The presence of distinct strains in the skin lesions and

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cerebrospinal fluid suggested that more than one variant strain can reactivate and cause herpes zoster. A 19-month-old child developed varicella caused by co-infection with two genotypes of varicella zoster virus 3 days after immunization with live varicella vaccine [49A]. The presence of two different wildtype viruses in vesicular fluid was confirmed by amplification from single virus genomes and genotyping of single nucleotide polymorphisms that distinguish the five different genotypes of varicella zoster virus. This finding has important implications for recombination of the wild-type virus.

Yellow fever vaccine [SED-15, 3703; SEDA-30, 336; SEDA-31, 523; SEDA-32, 586] Observational studies Adverse events after yellow fever immunization reported to the US Vaccine Adverse Event Reporting System (VAERS) from 2000 to 2006 have been reviewed [50C]. There were 660 adverse events that met the inclusion criteria, 627 (95%) of which were reported to have occurred after primary immunization. Most of them occurred in female recipients (61%) and in recipients aged 19–49 years. Adverse events occurred within a median of 1 day after immunization (range 0–50 days), and 60% occurred within 2 days. The most commonly reported adverse event coding terms included fever, pain, pruritus, headache, injection site erythema, urticaria, rash, nausea, dizziness, dyspnea, and fatigue. Local inflammatory events accounted for a larger proportion of the adverse events reported by female than by male recipients. Most of the events (71%) occurred after administration of yellow fever vaccine given at the same time as one or more other vaccines; 29% of the events occurred after yellow fever vaccine given alone. The age and sex distributions of events reported after yellow fever immunization given alone were similar to those reported after immunization in combination with other vaccines. In 72 cases (11%) adverse events were classified

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as severe, including 12 cases of vaccineassociated neurological disease, six cases of vaccine-associated viscerotropic disease, and four deaths, two of which were attributed to viscerotropic disease. All but three of the severe adverse events occurred after primary vaccination and all the cases of neurological and viscerotropic disease occurred in primary vaccinees. Nervous system Longitudinal myelitis occurred in a 56-year-old man 45 days after yellow fever immunization [51c]. There was no history of other immunization or infection. An MRI scan of the spine showed longitudinal intramedullary hyperintense signals (D512) without gadolinium enhancement. There was a high concentration of yellow fever vaccine-specific IgM antibody in the cerebrospinal fluid. Serological tests for other flaviviruses were negative. His symptoms improved 5 days later. Infection risk On 10 April 2009, during a routine record review in connection with a subsequent blood drive, a blood bank supervisor learned of a breach in the deferral protocol for blood products collected from trainees [52c]. Further investigation showed that the blood that had been obtained during the previous drive had been from trainees who had been immunized with yellow fever vaccine 4 days before the drive. All of those blood products had already been processed and incorporated into the inventory at the hospital’s blood bank. The blood bank supervisor reviewed the blood bank’s records and identified 87 units of whole blood and three units of platelet that had been obtained from the recently immunized trainees. Blood products that had been released for transfusion were tracked forward to identify the patients who had received the implicated blood products. Unused blood products were identified and destroyed. Five patients had received six blood products (three units of platelets, two units of fresh frozen plasmas, and one unit of packed erythrocytes) from six of the trainees, who had no previous history of immunization or travel consistent with

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exposure to wild-type yellow fever virus. An 82-year-old man with terminal prostate cancer and a B-cell lymphoma died 20 days after receiving one of the implicated units of platelets. The other four recipients had no documented laboratory abnormalities or symptoms attributable to yellow fever vaccine. Three of the four had IgM antibodies to yellow fever virus 26–37 days after transfusion, but no flavivirus IgM and IgG antibodies; of these, two had been immunized with yellow fever vaccine at least 20 years before. A booster response was identified in these two previously immunized donor recipients by the presence of IgM antibodies to yellow fever virus and high neutralizing antibody titers. This report has documented for the first time serological evidence for transmission of yellow fever vaccine virus through infected blood products. Yellow fever vaccine virus can be transmitted via breast-feeding [53A]. • Meningoencephalitis occurred in an infant whose mother had recently received yellow fever vaccine during a postpartum visit. The mother had headache, malaise, and low fever

665 for 2 days 5 days after immunization. The infant, who was exclusively breast-fed, was hospitalized at age 23 days with seizures due to meningoencephalitis. Yellow fever virus was detected by reverse transcription-polymerase chain reaction in the infant’s cerebrospinal fluid and there were yellow fever-specific IgM antibodies in the serum and CSF. The infant was given antimicrobial and antiviral drugs, recovered completely, and had normal neurodevelopment up to 6 months of age.

Yellow fever vaccine should not be given to breast-feeding women, except when exposure to yellow fever viruses cannot be avoided or postponed.

OTHER COMPONENTS OF VACCINES Thimerosal [SED-15, 2259; SEDA-30, 268; SEDA-31, 391; SEDA-32, 587] See Mercury in Chapter 22.

References [1] Kohl KS, Magnus M, Ball R, Halsey N, Shadomy S, Farley TA. Applicability, reliability, sensitivity, and specificity of six Brighton Collaboration standardized case definitions for adverse events following immunization. Vaccine 2008; 26: 6349–60. [2] Barton M, Finkelstein Y, Opavsky MA, Ito S, Ho T, Ford-Jones LE, Taylor G, Benson L, Gold R. Eosinophilic myocarditis temporally associated with conjugate meningococcal C and hepatitis B vaccines in children. Pediatr Infect Dis J 2008; 27: 831–5. [3] Souayah N, Ajroud-Driss S, Sander W, Brannagan TH, Hays AP, Chin RL. Small fiber neuropathy following vaccination for rabies, varicella or Lyme disease. Vaccine 2009; 27: 7322–5. [4] Kemmeren JM, Vermeer-de Bondt PE, van der Maas NAT. Discolored leg syndrome

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after vaccination—descriptive epidemiology. Eur J Pediatr 2009; 168(1): 43–50. Hauben M, Aronson JK. Gold standards in pharmacovigilance: the use of definitive anecdotal reports of adverse drug reactions as pure gold and high-grade ore. Drug Saf 2007; 30(8): 645–55. Kienast AK, Mentze D, Hoeger PH. Nicolau’s syndrome induced by intramuscular vaccinations in children: report of seven patients and review of the literature. Clin Exp Dermatol 2008; 33: 555–8. Ulloa-Gutierrez R. Pertussis vaccination in newborns. Expert Rev Vaccines 2009; 8: 153–7. Stowe J, Andrews N, Taylor B, Miller E. No evidence of an increase of bacterial and viral infections following measles, mumps and rubella vaccine. Vaccine 2009; 27: 1422–5.

666 [9] Flatz-Jequier A, Posfay-Barbe KM, Pfister E, Siegrist C-A. Recurrence of cardiorespiratory events following repeat DTaP-based combined immunization in very low birth weight premature infants. J Pediatr 2008; 153: 429–31. [10] Carbone T, McEntire B, Kissin D, Kelly D, Steinschneider A, Violaris K, Karamchandani N. Absence of an increase in cardiorespiratory events after diphtheria-tetanus-acellular pertussis immunization in preterm infants: a randomized, multicenter study. Pediatrics 2008; 121: e1085–90. [11] Niu MT, Ball R, Woo EJ, Burwen DR, Knippen M, Braun MM. Adverse events after anthrax vaccination reported to the Vaccine Adverse Event Reporting System (VAERS), 1990–2007. Vaccine 2009; 27: 290–7. [12] Witjes JA, Palou J, Soloway M, Lamm D, Brausi M, Spermon JR, Persad R, Buckley R, Akaza H, Colombel M, Bohle A. Clinical practice recommendations for the prevention and management of intravesical therapy-associated adverse events. Eur Urol 2008; 7(Suppl): 667–74. [13] Kusuhara K, Ohga S, Hoshina T, Saito M, Sasaki Y, Ishimura M, Takada H, Fujita M, Hara T. Disseminated Bacillus CalmetteGuérin. Eur J Pediatr 2009; 168: 745–7. [14] Tosa M, Murakami M, Ghazizadeh M, Hyakusoku H. Chronologic change of the maximum dimension of Bacillus CalmetteGuérin-induced keloids. Dermatol Surg 2009; 35: 189–94. [15] Farsinejad K, Daneshpazhooh M, Sairafi H, Barzegar M, Mortazavizadeh M. Lupus vulgaris at the site of BCG vaccination: report of three cases. Clin Exp Dermatol 2009; 34: e167–9. [16] Kim SH, Kim SY, Eun BW, Yoo WJ, Park KU, Choi EH, Kim EC, Lee HJ. BCG osteomyelitis caused by the BCG Tokyo strain and confirmed by molecular method. Vaccine 2008; 26: 4379–81. [17] Takayama K, Satoh T, Hayashi M, Yokozeki H. Psoriatic skin lesions induced by BCG vaccination. Acta Derm Venereol 2008; 88: 621–2. [18] Ghattaura A, Eley KA, Molenaar E, Smith G. A case of extensive ulcerating vasculitis following BCG vaccination. J Plast Reconstr Aesthet Surg 2009; 62: e286–9.

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[19] Global Advisory Committee on Vaccine Safety (GACVS). 3–4 December 2009. Use of BCG vaccine in HIV-infected infants. Wkly Epidemiol Rec 2010; 85: 32–3. [20] Global Advisory Committee on Vaccine Safety (GACVS). Review of safety profile on meningococcal A conjugate vaccine from clinical trials. Wkly Epidemiol Rec 2010; 85: 31–2, 3–4 December 2009. [21] Wilson K, Potter B, Manuel D, Keelan J, Chakraborty P. Revisiting the possibility of serious adverse events from the whole cell pertussis vaccine: were metabolically vulnerable children at risk? Med Hypotheses 2010; 74(1): 150–4. [22] Blatter M, Friedland LR, Weston WM, Li P, Howe B. Immunogenicity and safety of a tetanus toxoid, reduced diphtheria toxoid and three-component acellular pertussis vaccine in adults 19–64 years of age. Vaccine 2009; 27(5): 765–72. [23] Agmon-Levin N, Zafrir Y, Paz Z, Shilton T, Zandman-Goddard G, Shoenfeld Y. Ten cases of systemic lupus erythematosus related to hepatitis B vaccine. Lupus 2009; 18: 1192–7. [24] Slade BA, Leidel L, Vellozzi C, Woo EJ, Hua W, Sutherland A, Izurieta HS, Ball R, Miller N, Braun MM, Markowitz LE, Iskander J. Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. JAMA 2009; 302: 750–7. [25] Schaffer V, Wimmer S, Rotaru I, Topakian R, Haring H-P, Aichner FT. HPV vaccine: a cornerstone of female health a possible cause of ADEM? J Neurol 2008; 255: 1818–20. [26] Debeer Ph, De Munter P, Bruyninckx F, Devlieger R. Brachial plexus neuritis following HPV vaccination. Vaccine 2008; 26: 4417–9. [27] Garland SM, Ault KA, Gall SA, Paavonen J, Sings HL, Ciprero KL, Saah A, Marino D, Ryan D, Radley D, Zhou H, Haupt R, Garner EIO. Pregnancy and infant outcomes in the clinical trials of a human papillomavirus type 6/11/16/18 vaccine: a combined analysis of five randomized controlled trials. Obstet Gynecol 2009; 114: 1179–88. [28] Dana A, Buchanan KM, Goss MA, Seminack MM, Shields KE, Korn S,

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Cunningham ML, Haupt RM. Pregnancy outcomes from the pregnancy registry of a human papillomavirus type6/11/16/18 vaccine. Obstet Gynecol 2009; 114: 1170–8. Global Advisory Committee on Vaccine Safety (GACVS). Safety of pandemic A (H1N1) influenza vaccines. Wkly Epidemiol Rec 2010; 85: 29–31, 3–4 December 2009. Rosenberg M, Sparks R, McMahon A, Iskander J, Campbell JD, Edwards KM. Serious adverse events rarely reported after trivalent inactivated. Vaccine 2009; 27: 4278–83. Turkoglu R, Tuzun E. Brainstem encephalitis following influenza vaccination: favorable response to steroid treatment. Vaccine 2009; 27: 7253–6. Zafrir Y, Agmon-Levin N, Shoenfeld Y. Post-influenza vaccination vasculitides: a possible new entity. J Clin Rheumatol 2009; 15: 269–70. Birck R, Kaelsch I, Schnuelle P, FloresSuarez LF, Nowack R. ANCA-associated vasculitis following influenza vaccination: causal association or mere coincidence? J Clin Rheumatol 2009; 15: 289–91. Tamma PD, Ault KA, del Rio C, Steinhoff MC, Halsey NA, Omer SB. Safety of influenza vaccination during pregnancy. Am J Obstet Gynecol 2009; 201: 547–52. Carroll DN, Carroll DG. Fatal intracranial bleed potentially due to a warfarin and influenza vaccine interaction. Ann Pharmacother 2009; 43: 754–60. Esteghamati A, Gouya MM, Keshtkar AA, Mahoney F. Relationship between occurrence of Guillain–Barré syndrome and mass campaign of measles and rubella immunization in Iranian 5–14 years old children. Vaccine 2008; 26: 5058–61. US Court of Federal Claims. Autism decisions and background information on the Omnibus Autism Processing (OAP). http:// www.uscfc.uscourts.gov/node/5026. France EK, Glanz J, Xu S, Hambidge S, Yamasaki K, Black SB, Marcy M, Mullooly JP, Jackson LA, Nordin J, Belongia EA, Hohman K, Chen RT, Davis R. Risk of immune thrombocytopenic purpura after measles–mumps–rubella immunization in children. Pediatrics 2008; 121: e687–92.

667 [39] Jacobsen SJ, Ackerson BK, Sy LS, Tran TN, Jones TL, Yao JF, Xie F, Craig Cheetham T, Saddier P. Observational safety study of febrile convulsion following first dose MMRV vaccination in a managed care setting. Vaccine 2009; 27: 4656–61. [40] Vukic BT, Pavic I, Milotic I, Slavuljica I. Aseptic meningitis after transmission of the Leningrad–Zagreb mumps vaccine from vaccinee to susceptible contact. Vaccine 2008; 26: 4879. [41] Aronson JK, Hauben M. Anecdotes that provide definitive evidence. BMJ 2006; 332: 1267–9. [42] Sudarshan MK, Bhardwaj S, Mahendra BJ, Sharma H, Sanjay TV, Ashwathnarayana DH, Bilagumba G. An immunogenicity, safety and post-marketing surveillance of a novel adsorbed human diploid cell rabies vaccine (Rabivax) in Indian subjects. Hum Vaccin 2008; 4(4): 275–9. [43] Haber P, Patel M, Izurieta HS, Baggs J, Gargiullo P, Weintraub E, Cortese M, Braun MM, Belongia EA, Miller E, Ball R, Iskander J, Parashar UD. Postlicensure monitoring of intussusception after RotaTeq vaccination in the United States, February 1, 2006, to September 25, 2007. Pediatrics 2008; 121: 1206–12. [44] Mora LF, Khan AH, Sperling LS. Cardiac complications after smallpox vaccination. South Med J 2009; 102(6): 615–9. [45] Benz R, Krause M, Taverna C. Immune thrombocytopenic purpura reactivation after tick-borne encephalitis vaccination. Vaccine 2009; 27: 5172–3. [46] Nagpal A, Vora R, Margolis TP, Acharya NR. Interstitial keratitis following varicella immunization. Arch Ophthalmol 2009; 127: 222–3. [47] Ota K, Kim V, Lavi S, Ford-Jones EL, Tipples G, Scolnik D, Tellier R. Vaccinestrain varicella zoster virus causing recurrent herpes zoster in an immunocompetent 2-year-old child. Pediatr Infect Dis J 2008; 27: 847–8. [48] Levin MJ, Debiasi RL, Bostik V, Schmid DS. Herpes zoster with skin lesions and meningitis caused by 2 different genotypes of the OKA varicella-zoster virus vaccine. J Infect Dis 2008; 198: 1444–7.

668 [49] Quinlivan M, Sengupta N, Breuer J. A case of varicella caused by co-infection with two different genotypes of varicella-zoster virus. J Clin Virol 2009; 44: 66–9. [50] Lindsey NP, Schroeder BA, Miller ER, Braun MM, Hinckley AF, Marano N, Slade BA, Barnett ED, Brunette GW, Horan K, Staples JE, Kozarsky PE, Hayes EB. Adverse event reports following yellow fever vaccination. Vaccine 2008; 26: 6077–82. [51] Chaves M, Riccio P, Patrucco L, Rojas J, Cristiano E. Longitudinal myelitis

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associated with yellow fever vaccination. J Neurovirol 2009; 15: 348–50. [52] Centers for Disease Control and Prevention (CDC). Transfusion-related transmission of yellow fever vaccine virus—California, 2009. MMWR Morb Mortal Wkly Rep 2010; 59(2): 34–7. [53] Centers for Disease Control and Prevention (CDC). Transmission of yellow fever vaccine virus through breast-feeding—Brazil, 2009. MMWR Morb Mortal Wkly Rep 2010; 59(5): 130–2.

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Blood, blood components, plasma, and plasma products

The risks of infections from transfusions The administration of blood, blood components, plasma, and plasma products always carries the potential risk of transmission of infectious agents [1R, 2R]. Owing to increased standards of donor screening, serological testing, and nucleotide amplification testing (NAT), resulting in reduced window periods, transmission of blood-borne infections by blood products has become very rare in Western countries [3R]. This is especially the case for plasma products, with the continuing development of dedicated viral inactivation/ reduction methods, including heat (pasteurization and dry heat), cold ethanol fractionation, solvent–detergent processes, low pH, addition of pepsin or caprylic acid, and nanofiltration [1R, 2R]. The risk of ABO-incompatible blood transfusion, although completely preventable, is 1000 to 10 000 times higher than the risk of viral infection from blood. However, geographical location is important in evaluation of the risk of transfusion-related infections [3R]. Bacteria Transfusion-related infections are mainly caused by contamination with skincommensal bacteria [3R]. One in every 3000 donated blood units is contaminated with bacteria. The estimated prevalence of Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00033-7 # 2011 Elsevier B.V. All rights reserved.

contaminated blood products varies from 1 in 20 000 to 1 in 30 000, with an aseptic transfusion reaction in between 1 in 20 000 and 1 in 250 000, depending on the specific product [3R, 4c]. As platelet concentrates are stored at room temperature, these products are most susceptible to bacteria growth. Because of the short shelf-life of platelet concentrates, these products are sometimes already transfused before the results of bacterial culture have been evaluated. In a study of 121 402 platelet concentrates, 544 cultures (0.45%) were flagged positive, of which 181 units had already been transfused, with 160 truly positive units (from two patients, clinical data were lacking). Two of 158 patients developed a transfusion reaction. In both cases Propionibacterium was cultured from the transfused platelet concentrates, but both events were classified as being unrelated to the platelet concentrate [4c]. One case of a near-fatal septic transfusion reaction was reported with a platelet concentrate unit that did not undergo bacterial detection [5A]. Viruses The risk of transfusion-related viral infection is significantly lower than the risk of bacterial infections [3R]. Of all human herpesviruses, cytomegalovirus (CMV) is the most significant cause of transfusionrelated morbidity and mortality. Because CMV may be associated with leukocytes in blood products, the incidence of transfusion-related CMV infection is significantly reduced after the use of leukocyte reduction techniques. The residual risks of transfusion-related infection with hepatitis B virus, hepatitis C virus, and HIV are respectively 669

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estimated to be 1 per 153 000 donations, 1 per 2.3 million donations, and 1 per 7.8 million donations [3R]. Despite cases of transmission of hepatitis C associated with intravenous immunoglobulin in the 1990s, no cases of transmission of hepatitis, HIV, or Creutzfeldt–Jakob disease have since been reported with immunoglobulins [6R]. Before 1996, PCCs (prothrombin complex concentrates) were associated with minimal risk of transmission of infective agents [7R]. There are no documented cases of viral transmission in patients with von Willebrand disease or hemophilia A treated with Haemate P/Humate P in over 25 years of clinical experience in Europe and more than 17 years in the USA [8R]. In the IMPACT-1 and IMPACT-2 trial in 124 patients there were no cases of HIV, hepatitis, or human B19 virus conversion. Furthermore, no cases of viral transmission have been reported during 30 years of post-marketing surveillance of C1-esterase inhibitor concentrate [9R, 10C]. No cases of transmission of HIV or hepatitis have been associated with the use of fibrin sealants, but there have been reports of transmission of parvovirus B19 [11M]. Transmission of parvovirus B19 in blood products and its resistance to common viral inactivation techniques raises concern about blood safety [3R].

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P.F.W. Strengers and K.J. Velthove

isoimmunization on seven occasions (in one case in 1970, before the start of the at-risk period for vCJD in 1980); and one dose of albumin [12c]. The authors considered it unlikely that plasma products had been the source of vCJD disease in these cases, but could not rule out the possibility that the use of plasma products may result in vCJD transmission in the future. Because of this uncertainty, steps have been taken to reduce the risk. Donors who have spent more than 6 months in the UK during the period 1986 to the present are excluded from donating blood or plasma in the USA and Europe [2R].

ALBUMIN AND DERIVATIVES [SED-15, 54; SEDA-30, 381; SEDA-31, 527; SEDA-32, 591]

Albumin

[SEDA-30, 381; SEDA-31, 527; SEDA-32, 591] The use of 20% albumin infusion in the treatment of neonatal hypoalbuminemia is controversial, because of lack of evidencebased guidelines. In a retrospective study of 30 neonates, no adverse effects of albumin infusion were registered [13c].

Protozoa In Western countries transfusionrelated malaria is rare. However, on a global scale malaria remains one of the most common transfusion-related infections [3R].

Albumin-derived hemostatics

Prions The use of bovine thrombin in fibrin sealants increases the risk of transmission of bovine spongiform encephalitis (BSE) [11M]. However, the risk of transmitting prion diseases by giving human blood or blood products is theoretical at present. Because of the long incubation time it is challenging to evaluate the risk [2R]. In 168 UK cases of variant Creutzfeldt–Jakob disease (vCJD), nine patients had received fractionated plasma products on 12 occasions, intramuscular immunoglobulins for travel on four occasions; Rh(D) immunoglobulin for rhesus

BioGlue, which is based on albumin and glutaraldehyde, was introduced into the European market in 1998. In patient studies, no related adverse events have been reported; however, there has been one report of severe active inflammatory response. In 75 pediatric neurosurgical patients there was a strong association between BioGlue and postoperative wound complications. Embolization and stenosis have also been associated with BioGlue. Other reports include valve malfunction because of BioGlue migration, an aseptic mediastinal cyst, massive lung fibrosis, and an anastomotic pseudoaneurysm [11M].

Blood, blood components, plasma, and plasma products

ANTICOAGULANT PROTEINS [SED-15, 266;

SEDA30, 381; SEDA-31, 527; SEDA-32, 591]

Drotrecogin alfa (activated) (recombinant human activated protein C) [SEDA-32, 591] Hematologic In 100 consecutive patients who received drotrecogin alfa for severe sepsis, 30 of whom underwent surgery and 70 of whom did not, seven fulfilled pre-set criteria for bleeding complications (transfusion of more than 3 units of blood, an intracranial hemorrhage, or other serious adverse bleeding events), four of the former and three of the latter [14c]. There were no deaths. All the bleeding complications were due to falls in hemoglobin or platelets. In a retrospective review of the medical records of 73 patients who had received drotrecogin alfa for sepsis, there were serious bleeding events in 7 of 20 with any baseline susceptibility factor for bleeding and only two of 53 patients without; more of the former died and they had higher APACHE II scores and more bloodstream infections [15c]. In a review of six large phase III and phase IV post-approval clinical studies (two placebo-controlled studies and four open studies), involving 8615 adults with severe sepsis, serious bleeding events were analysed according to the drug infusion period and during the overall study (28 days) [16MR]. The rates of serious bleeding during the infusion period were consistent at about 2.4% compared with a background bleeding rate in severe sepsis of about 1.1%; the 28day serious bleeding rates were 3.1–6.5% compared with 1.7–2.2% in the placebo group. Central nervous system bleeding occurred in 0.2–0.6% during infusion and in 0.2–1.5% during the entire 28-day study, compared with placebo rates of 0–0.2% and 0.1–0.4% respectively. Drug–drug interactions Heparin Heparin increases the risk of bleeding in patients

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who are receiving drotrecogin. In a double-blind, randomized, placebo-controlled trial of prophylactic heparin in patients with severe sepsis treated with drotrecogin 24 micrograms/kg/hour for 96 hours, patients were randomized to unfractionated heparin 5000 units bd (n ¼ 511), enoxaparin 40 mg/ day (n ¼ 493), or placebo (n ¼ 990) every 12 hours [17C]. There were more bleeding events overall during infusion of drotrecogin in those who also received heparin compared with placebo (11% versus 8.1%), but serious bleeding events were similar (2.3% versus 2.5%), and central nervous system bleeds were uncommon in both groups (0.3% versus 0.3%).

BLOOD TRANSFUSION [SED-15, 529; SEDA-30, 381; SEDA-31, 528; SEDA-32, 593] Adverse events related to transfusion of blood components have been reported, including febrile non-hemolytic transfusion reactions, mild febrile reactions, acute and delayed hemolytic transfusion reactions, transfusion-related acute lung injury (TRALI), anaphylactic and other allergic reactions, graft-versus-host disease (GvHD), transfusion-associated circulatory overload (TACO), viral infections, post-transfusion bacteremia, transfusion-associated sepsis (TAS), hemosiderosis, post-transfusion purpura, and new allo-antibody formation [18S, 19S]. Whole blood, erythrocytes, leukocytes, platelets, and plasma for transfusion (fresh frozen plasma, FFP) are involved. Quite a number of these adverse effects, such as TRALI, TACO, TAS, and allergic/anaphylactic reactions can be difficult to evaluate. Susceptibility factors Children In pediatric practice, such as intensive treatment of malignant disease, cardiac surgery including extracorporeal membrane oxygenation,

672

transplant surgery, and transfusion support for neonates and for children with hemoglobinopathies, the availability of blood has enabled enormous advances. Of all erythrocyte transfusions, 4.2% are in patients under 18 years and 1.7% in children under 12 months. Adverse outcomes are estimated to occur in 18 per 100 000 erythrocyte transfusions in children under 18 years and 37 per 100 000 in those under 12 months, compared with 13 per 100 000 in adults [20C].

Erythrocytes In several studies, transfusion of “older” compared with “fresh” erythrocytes has been associated with increased mortality, prolonged hospitalization, intensive care treatment, mechanical ventilation, an increased risk of postoperative pneumonia, infection at any site, and multiorgan failure [21C, 22C]. However, most studies suffered from not adjusting the data for the number of units transfused. Patients who received “old” erythrocytes often received more cells on average than recipients of “fresh” erythrocytes. The amount of cells transfused reflects the severity of the illness, co-morbidity, and a poorer baseline prognosis [23R]. A meta-analysis did not support the suspicion that “old” erythrocytes are associated with common adverse morbidity/mortality outcomes [24M]. Leukocyte contamination has been associated with increased transfusion associated mortality as a result of transfusion-related immune modulation, with cancer growth and impaired immunity against infections as suspected consequences. However, in two randomized studies, cancer growth was not found to be influenced by transfusion of leukodepleted and non-depleted erythrocytes [25R]. The association with postoperative infections and leukocytecontaining transfusions could not be confirmed in a meta-analysis [26M].

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P.F.W. Strengers and K.J. Velthove

BLOOD SUBSTITUTES [SEDA-30, 383; SEDA-31, 531; SEDA-32, 593]

Hemoglobin-based oxygen carriers Hemoglobin-based oxygen carriers are infusible oxygen-carrying fluids prepared from purified human or animal hemoglobin; they do not need to be refrigerated and cross-matching is unnecessary [27R, 28R]. However, small amounts of residual cell membranes are very toxic. The firstgeneration of compounds, prepared from modified tetrameric hemoglobin molecules, was mainly associated with vasoconstriction and renal dysfunction. Clinical trials were stopped because of increased mortality, myocardial infarction, and stroke [28R, 29C]. A meta-analysis of 16 trials involving a total of 3711 patients showed that hemoglobin-based oxygen carriers are associated with a 30% increased risk of death (RR 1.3; 95% CI 1.1–1.6) and a 2.7-fold increased risk of myocardial infarction (RR 2.7; 95% CI 1.7–4.4) [30M], although other authors have debated these results [29C]. Other adverse effects that are associated with hemoglobin-based oxygen carriers include abdominal pain, diarrhea, skin rash, jaundice, hemoglobinuria, oliguria, fever, and interference with laboratory assays [28R, 31R]. Increases in the activities of serum liver enzymes and lipase may be related to interference with clearance of these proteins by the reticuloendothelial system [32C]. In phase III clinical trials in 171 patients undergoing surgery, the use of human polyhemoglobin was not associated with adverse effects [27R]. In 714 patients hypertension, coagulopathy, and myocardial infarction occurred more in those who were given hemoglobin-based oxygen carriers than in the controls [29C]. Although polymerized hemoglobin products appear to have a better safety profile, their safety remains a topic of considerable debate.

Blood, blood components, plasma, and plasma products

Cardiovascular Tetrameric hemoglobin can cause vasopressor effects. It is hypothesized that it enters the interstitial space through the intercellular junctions of the endothelial lining of the vascular wall, where it binds nitric oxide, which is needed for maintaining normal muscle tone in smooth muscles, leading to vasoconstriction. Binding of nitric oxide also leads to increased platelet aggregation. To avoid vasopressor or cardiac effects, polyhemoglobin products must contain less than 2% of tetrameric hemoglobin [27R, 28R, 29C]. Liposome-encapsulated hemoglobin-based oxygen carriers can activate the reticuloendothelial system and the complement and coagulation pathways, and can cause platelet aggregation [31R]. Gastrointestinal Binding of nitric oxide by tetramer hemoglobin leads to smooth muscle dysfunction and gastrointestinal adverse effects such as abdominal pain, diarrhea, nausea, and vomiting [28R, 31R]. Pancreas Pancreatitis has been reported as an adverse event in three studies of hemoglobin-based oxygen carriers; the most plausible mechanism is production of reactive oxygen species [31R]. Urinary tract Hemoglobin tetramers rapidly degrade into dimers and monomers, which are filtered by the kidney and can damage renal tubular cells; this is prevented by polymerization of free hemoglobin molecules [28R]. Susceptibility factors In a phase III trial in 688 patients there were more adverse events, primarily affecting the cardiac and nervous systems, reported with hemoglobin-based oxygen carriers than with erythrocyte transfusions. Three main factors were considered to have contributed: age over 80 years, volume overload, and undertreatment. Patients with pre-existing cardiac disease are more vulnerable to adverse effects at lower total hemoglobin concentrations [32C]. A re-analysis of the same data showed that cardiac adverse events and mortality were much more common among patients aged over

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70 years [33c]. The authors hypothesized that younger patients tolerate vasoconstriction and persistent anemia related to hemoglobin-based oxygen carriers better because of larger physiological reserve, a lower incidence of co-morbid cardiovascular disease, and better microvascular compensatory properties.

Perfluorocarbons [SEDA-30, 383; SEDA-31, 531; SEDA-32, 594] Perfluorocarbons are completely synthetic molecules made of 8–10 carbon molecules with fluorine atoms replacing hydrogen atoms. They are immiscible with water and can dissolve oxygen and carbon dioxide. Unlike hemoglobin, which binds oxygen covalently, perfluorocarbons require a high PaO2 (300 mmHg) to be effective [31R]. Second-generation perfluorocarbons that have been developed include Oxygent, Oxyfluor, Oxycyte, and Perftoran. There is limited clinical experience. A phase III study of Oxygent was terminated because of a possible increase in strokes. Oxyfluor was associated with mild thrombocytopenia and flu-like symptoms in phase I and II trials, but its development has been ended. The flu-like symptoms may be due to immunological activation of macrophages by the particle size of the product. Perftoran was associated with hypotension and pulmonary complications in about 1% of cases in a randomized trial. Clinical experience with large volumes of Perflubron (Oxygent) yielded few adverse events, diarrhea being the most common. Perfluorocarbons interfere with laboratory assays such as CO oximetry [31R]. Cardiovascular Perfluorocarbons that unload oxygen in a linear manner can cause excessive tissue oxygenation, which could lead to reflex vasoconstriction, increased blood pressure, a reduced heart rate, and a reduced cardiac output [31R].

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PLASMA AND PLASMA PRODUCTS [SED-15, 2847; SEDA-30, 383; SEDA-31, 532; SEDA-32, 594]

Alpha1-antitrypsin

[SEDA-31, 532]

Augmentation therapy for alpha1-antitrypsin uses partially purified plasma, which is highly enriched with alpha1-antitrypsin. Adverse reactions to this are rare (under 0.03 events per patient-month) and generally mild. They include headache, dizziness, nausea, and dyspnea [34R]. • A non-smoking 61-year-old man with severe emphysema due to alpha1-antitrypsin deficiency was given intravenous human alpha1antitrypsin 60–120 mg/kg once a week or every second week for 10 years [35A]. His plasma alpha1-antitrypsin concentration was restored. There were no significant changes in FEV1, vital capacity, or the ratio of FEV1 to vital capacity, and the emphysema progressed, but there were fewer exacerbations. There were no adverse reactions.

Drug administration route Six healthy subjects, seven patients with alpha1-antitrypsin deficiency, and seven patients with cystic fibrosis were given alpha1-antitrypsin by nebulization. One healthy subject developed tongue vesicles and dysphagia and one patient with cystic fibrosis had mild headache, which was possibly related to alpha1-antitrypsin [36c].

Antithrombin III

P.F.W. Strengers and K.J. Velthove

C1 esterase inhibitor concentrate [SEDA-30, 383; SEDA-31, 532; SEDA-32, 594] In the IMPACT-1 trial of C1-esterase inhibitor, 39 patients received 10 U/kg, 46 received 20 U/kg, and 41 received placebo [10C]. In the 4 hours after the dose, eight of the 10 U/kg recipients, five of the 20 U/ kg recipients, and eight of the placebo recipients reported adverse events that were considered at least possibly related to treatment; none was considered serious. The difference in the rates of reported adverse events between 20 U/kg and placebo can be explained by the fact that most of the patients had attacks of abdominal pain, which were recorded as adverse events [10C]. The most commonly reported adverse events with 20 U/kg included nausea, diarrhea, abdominal pain, and muscle spasms, all of which occurred less often in the 20 U/kg group compared with placebo. In the IMPACT-2 trial, an extension of IMPACT-1 [9R], 16 of 39 patients who were given 20 U/kg reported adverse events, of which four were considered at least possibly related to the drug, including dry mouth, influenza-like symptoms, infusion-related reactions, dizziness, and headache. During almost 20 years of postmarketing surveillance, few adverse events have been reported, including injection-site redness, fever, chills, headache, and anaphylactic reactions. These events are rare and mostly related to over-rapid infusion or giving the product before it has reached room temperature.

[SEDA-32, 594]

Observational studies In a retrospective cohort analysis, using an intensive care unit database, of the effect of antithrombin III compared with standard therapy on outcomes and erythrocyte transfusion rates in 545 postoperative surgical patients with severe sepsis, antithrombin III therapy was associated with a significantly higher frequency of erythrocyte transfusion (22 versus 9 units); there was no beneficial effect on mortality [37c].

Fibrin glue

[SED-15, 1363]

The compositions of fibrin sealants differ: all consist of fibrinogen in combination with thrombin and in some cases they include factor XIII and/or an antifibrinolytic agent, which stabilizes the clot. Their adverse effects have been highlighted [11M]. Bovine thrombin is potentially immunogenic and can cause immunological sequelae, anaphylaxis, and

Blood, blood components, plasma, and plasma products

coagulopathy. Coagulopathy is hypothesized to be related to cross-reactive antibodies against bovine products, which react with human products, especially factor V. However, not all cases of coagulopathy result in hemorrhage, and spontaneous resolution is common. The antifibrinolytic drugs in the product can also be associated with adverse events. Bovine aprotinin has been associated with anaphylactic reactions in case reports [11M, 38A] and tranexamic acid has been reported to be neurotoxic. Completely patient-derived (autologous) fibrin products without antifibrinolytic drugs minimize these risks. Lastly, higher concentrations of thrombin in fibrin sealants are associated with a higher risk of thrombosis [11M].

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Fluid balance Because of the low concentration of coagulation proteins in fresh frozen plasma, large volumes may be needed when it is used to reverse excess oral anticoagulation treatment, with a risk of fluid overload [41R, 42R]. Susceptibility factors There is no correlation between the risk of TRALI and age, history of transfusions, previous transfusion reactions in the recipient, or ABO compatibility of donor and recipient; the volume of donor plasma correlates poorly with the risk [39A].

PLASMA SUBSTITUTES Plasma

[SEDA-30, 384; SEDA-31, 532]

Respiratory Transfusion-related acute lung injury (TRALI) can be a serious adverse event after transfusion of plasma that contains antibodies against the recipient's leukocytes, and is the most common cause of transfusion-related mortality. About 90% of cases of TRALI are associated with human leukocyte antigen (HLA) antibodies from the donor [39A, 40A]. Two mechanisms of TRALI have been suggested: (1) an antigen–antibody reaction leads to a series of events; (2) neutrophils are primed and become activated [7R]. • A 79-year-old woman with myasthenia gravis developed TRALI after being given plasma exchange therapy for 4 days; she recovered completely [39A]. • A 25-year-old man with factor V deficiency developed TRALI after receiving 5 units of plasma; he recovered completely [40A]. However, recurrent TRALI developed after he was given 2 units of plasma 5 months later.

The second case shows that the risk of recurrent TRALI may persist longer than previously thought. The authors suggested screening donors that are at risk of alloimmunization to HLA antigens and excluding donations from positive donors.

[SEDA-30, 384; SEDA-31, 533; SEDA-32, 594]

Dextrans

[SEDA-32, 595]

Immunologic Dextran 70 has been used as stabilizer in a measles–mumps–rubella (MMR) vaccine product named Morupar. This vaccine was associated with dextrandriven hypersensitivity reactions with high concentrations of dextran-specific IgG [43r]. The most probable mechanism is immune complex-mediated reactions caused by naturally occurring dextranspecific antibodies. Morupar was withdrawn from the market.

Etherified starches

[SED-15, 1237; SEDA-30, 384; SEDA-31, 533; SEDA-32, 595]

Hydroxyethyl starch has been widely used as plasma volume expander in bleeding patients. Each product is characterized by its molecular weight, concentration, molar substitution, origin, and solvent [44C]. Adverse reactions include excessive intravascular volume expansion, metabolic acidosis, anaphylaxis, renal dysfunction, hepatic dysfunction, and coagulopathy [45A]. It has been suggested that adapting the formulation to the

676

electrolytic composition of plasma will yield a safer product, but this is debated [46r, 47r, 48c]. [Authors’ note: Among those who have taken part in the debate about the usefulness of etherified starches is Joachim Boldt. However, many papers authored by Dr. Boldt have been retracted by the Editors of the journals in which they have appeared, namely Acta Anaethesiologica Scandinavica, Anaesthesia, Anästhesiologie Intensivmedizin Notfallmedizin Schmerztherapie, Anesthesia & Analgesia, Anesthesiology, Annals of Thoracic Surgery, British Journal of Anaesthesia, Canadian Journal of Anesthesia, Der Anästhesist, European Journal of Anaesthesiology, Intensive Care Medicine, Journal of Cardiothoracic and Vascular Anesthesia, Journal of Cranio-Maxillo-Facial Surgery, Medical Science Monitor, Minerva Anestesiologica, Thoracic and Cardiovascular Surgeon, and Vox Sanguinis [49S]. The Editors wrote that “The retraction of the 88 articles for lack of IRB (Institutional Review Board) approval means that the research was unethical, and that IRB approval for the research was misrepresented in the published article. It does not mean that the research results per se are fraudulent. Klinikum Ludwigshafen has commissioned an investigating committee to systematically assess the veracity of the findings presented in Dr. Boldt's articles against patient and laboratory records.”] Hematologic Colloid plasma expanders are associated with coagulopathy and increase the risk of bleeding and the need for transfusion. The coagulatory effects of hydroxyethyl starch are dose-related in the therapeutic range (i.e. they are collateral adverse effects), and they may be associated with higher molecular weights and higher degrees of saturation [44C, 45A]. The mechanism of the coagulopathy is unknown and is the subject of debate. Hydroxyethyl starch molecules of high molecular weights interfere with fibrinogen, factor VIII, and von Willebrand factor more than expected from hemodilution only [45A, 48c]. It has been hypothesized that hydroxyethyl starch

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impairs thrombin–fibrinogen–factor XIII interactions, with enhanced fibrinolysis and reduced platelet activity, which may play a role [45A]. From the results of a study in 20 bleeding patients with substitution of hydroxyethylstarch 130/0.4 up to a target level of 30%, it seems that this coagulopathy is predominantly caused by acquired fibrinogen deficiency [50c]. Earlier reports suggested that hydroxyethyl starch 130/0.4 would be safer than hydroxyethyl starch 200/0.5, but these were contradicted by later reports [46r, 47r, 48c]. In 45 patients undergoing cardiac surgery, 6% hydroxyethyl starch 200/0.5 and 6% hydroxyethyl starch 130/0.4 produced similar impairment of fibrin formation and clot strength [47r]. Two neonates underwent major operations and received hydroxyethyl starch along with albumin, fresh frozen plasma, erythrocytes, and thrombocytes; there were no changes in coagulation status and no other adverse events [51A].

Urinary tract Renal dysfunction has been associated with hydroxyethyl starch. • A 67-year-old man developed acute renal insufficiency after the administration of over 10 liters of 10% pentastarch over 2 months [52A]. Renal biopsy showed hydropic changes in the renal tubular cells, compatible with colloid-induced damage. These changes were long-lasting and irreversible.

In a cohort study of 563 adults undergoing cardiac surgery, pentastarch 10% with an intermediate molecular weight (hydroxyethyl starch 200/0.5) was identified as an independent risk factor for acute kidney injury at doses as low as 14 ml/kg, the manufacturer's maximally recommended dosage being 28 ml/kg [44C]. The authors proposed that the mechanism is hyperviscosity of the urine, resulting in stasis of tubular flow and obstruction of the tubular lumen with nephrosis-like lesions. Formulations with higher molecular weights and degrees of substitution are more likely to cause renal damage [52A].

Blood, blood components, plasma, and plasma products

GLOBULINS Immunoglobulins

[SED-15, 1719; SEDA-30, 385; SEDA-31, 534; SEDA-32, 595]

Intravenous immunoglobulin Intravenous immunoglobulin is being used for a wide range of other disorders beyond its licensed indications [53R]. This increased use has resulted in an increased number of reported adverse reactions. Systemic reactions include fever, malaise, flushing, chills, fatigue, myalgia, arthralgia, flu-like symptoms, and very rarely life-threatening events, such as anaphylaxis and death [1R, 6R, 53R, 54r, 55c, 56c]. Intravenous immunoglobulin products differ in excipients and physicochemical characteristics. Each may have slightly different profiles of efficacy and adverse reactions. The reported adverse reaction rate varies between 2% and 25% of all infusions, depending on the disease being treated and the patient population. There is a higher incidence rate after a first exposure. Most of the adverse reactions are classified as being of mild-to-moderate intensity [1R, 54r, 57c, 58c]. In one prospective study in almost 400 patients with immunodeficiency (over 13 000 infusions), the adverse reaction rate was 0.8%; none of these events was classified as severe [54r]. In 38 children there was an adverse reaction rate of 9% of all infusions; none was life-threatening [59c]. In 70 patients who received 1085 infusions there was an adverse events rate of 4.3% of all infusions (33% of all patients); none was serious [58c]. In one study of 341 infusions, severe adverse reactions led to discontinuation of therapy in 4% of all treatment courses [53R]. Cardiovascular Hypotension, hypertension, chest pain, and rarely dysrhythmias or myocardial infarction have been associated with the use of intravenous immunoglobulin [1R, 53R, 54r, 55c, 57c]. In a small crossover study in patients with multifocal motor neuropathy there was one case of phlebitis

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during intravenous immunoglobulin treatment [60c]. Respiratory Dyspnea, cough, and bronchospasm have been reported during intravenous immunoglobulin treatment. Rare adverse effects include pleural effusion, pulmonary edema, and TRALI [1R, 53R, 54r, 61A]. Nervous system The most common adverse reactions to intravenous immunoglobulin are neurological, headache being the most frequent, occurring in 30–67% of all patients [1R, 19c, 53R, 54r, 57c, 61A, 62A]. Headache may be associated with increased serum viscosity [62A], and is mostly mitigated by pretreatment with analgesics [54r]. Other reported adverse reactions are migraine, dizziness, meningism, and back pain. Rare adverse reactions include aseptic meningitis, dysesthesia, weakness, convulsions, and a posterior reversible encephalopathy syndrome [1R, 53R, 54r, 55c, 57c]. • A 14-year-old Japanese girl with Guillain–Barré syndrome was given intravenous immunoglobulin 0.4 g/kg/day and after 3 days developed severe headaches without disturbed consciousness [62A]. An MRI scan of the brain showed characteristics consistent with posterior reversible encephalopathy syndrome. After the end of the course of intravenous immunoglobulin she recovered.

Hematologic Hematological adverse events are rare; they include hemolysis, venous thrombosis and stroke, hyperviscosity, leukopenia, and anemia [1R, 54r, 57c]. • A 40-year-old Caucasian woman with systemic lupus erythematosus received intravenous immunoglobulin 2 g/kg on three consecutive days monthly [63A]. This treatment was effective for 12 months, but after switching to a new batch of the same product she developed a hemolytic anemia, with mild abdominal pain, fatigue, and a rash. She was given glucocorticoids and the hematocrit returned to normal within 4 weeks. However, 1 month later she was again given intravenous immunoglobulin (the same dose and batch as 1 month before) and had the same adverse reactions. Again she was given glucocorticoids and recovered in 4 weeks.

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The authors considered it probable that the patient's AB blood type had increased the risk of hemolysis and they concluded that patients with severe hemolysis can switch from one batch of intravenous immunoglobulin to another batch of the same product after recovery. Gastrointestinal Gastrointestinal adverse events include nausea, vomiting, anorexia, diarrhea, and cramping [1R, 53R, 54r, 55c, 57c]. Necrotizing enterocolitis after phototherapy and intravenous immunoglobulin for hemolytic disease of the newborn has been reported in three cases [64A]. Urinary tract Renal insufficiency and hematuria are rare after the administration of intravenous immunoglobulin, and most often occur in patients with pre-existing renal impairment. Products that contain sucrose carry a higher risk of renal adverse events [1R, 53R, 54r]. Skin Cutaneous reactions associated with intravenous immunoglobulin are uncommon, but include pruritus, non-specific eruptions, erythema, urticaria, eczema, pompholyx, petechiae, and skin hemorrhage [53R, 54r, 55c, 57c, 59c].

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rare after administration of intravenous immunoglobulin [54r]. Differences in product tolerance because of IgA content could be explained by the presence of an Fc-a on leukocytes that is activated by interaction with IgA. Activation of IgA receptors could result in infusion-related fevers after the use of products with a high IgA content [59c]. Susceptibility factors Most adverse reactions occur after the first dose of intravenous immunoglobulin [1R, 54r, 59c]. Furthermore, adverse events are associated with several factors including the presence of infection, a high concentration of IgG in the product (which carries a risk of immunoglobulin aggregate formation), a switch of product, a high dosage, and a rapid infusion rate [1R, 54r, 55c, 67c]. Severe adverse reactions are very rare and occur mainly in patients who repeatedly receive high-dose infusions for diseases other than primary immune deficiencies [1R]. In a case–control study of the susceptibility factors that are associated with thromboembolic adverse reactions in 19 patients and 38 agematched controls, no single cardiovascular susceptibility factor increased the risk of thrombosis, but the risk was significantly higher in patients with four or more susceptibility factors [68c].

• A 54-year-old woman with carbamazepineinduced Stevens–Johnson syndrome was given intravenous immunoglobulin 1 g/kg/day for 3 days and topical glucocorticoids to the nonerosive skin lesions [65A]. However, 3 days later she developed multiple non-pruritic vesicobullae with clear fluid contents on the palms after most of the previous lesions had resolved. The new lesions resolved spontaneously within 1 week without treatment.

Children In 38 children with juvenile dermatomyositis the rate of adverse events, particularly fever, fatigue, nausea, and vomiting, was higher with intravenous immunoglobulin containing more than 15 mg/ml of IgA [59c]. Children may be more sensitive to immunological triggers than adults [59c].

• A 26-year-old Korean man with Guillain–Barré syndrome was given intravenous immunoglobulin 0.4 g/kg/day for 3 and 6 days later developed multiple reddish severely pruritic vesicles on both palms, diagnosed as pompholyx [66A]. The vesicles resolved after treatment with topical diflucortolone valerate ointment.

Subcutaneous immunoglobulin

Immunologic The risk of anaphylaxis in patients with anti-IgA antibodies is not precisely known. Although 10–25% of patients with common variable immunodeficiency have anti-IgA antibodies, anaphylaxis is

One of the advantages of subcutaneous over intravenous administration is a more stable plasma IgG concentration, because some adverse effects of intravenous administration are possibly associated with high peak serum IgG concentrations. Subcutaneous administration of immunoglobulin leads to fewer systemic adverse effects compared with intravenous immunoglobulin. Local adverse reactions, such as redness, swelling,

Blood, blood components, plasma, and plasma products

and pain are common but mild [1R, 54r, 69R, 70c]. Other advantages of subcutaneous immunoglobulin are a better quality of life, less emotional stress, improved convenience, less absence from school or work, and lower costs [1R, 69R, 70c]. In a 6-month open pilot intervention study, nine patients switched from intravenous to subcutaneous immunoglobulins once or twice a week. All had local adverse effects after subcutaneous treatment during 330 treatments, with a reduced frequency of adverse effects during prolonged treatment. Swelling and redness of the skin occurred more often, followed by induration of the skin and soreness. Systemic adverse effects included fever, malaise, palpitation, and rash. There were no serious adverse events. The intensity of adverse effects was comparable between subcutaneous and intravenous treatment, but there were fewer systemic adverse effects with subcutaneous immunoglobulin [70c]. A limitation of subcutaneous administration is the large volume that needs to be injected, requiring multiple injection sites [69R]. Drug formulations Studies of premedication with hyaluronidase to allow the administration of larger volumes of subcutaneous immunoglobulin at one injection site or the use of a 20% concentration product in order to minimize the volume showed similar rates of adverse reaction as with established subcutaneous immunoglobulin [69R]. Drug administration route Rapid bolus dose administration of subcutaneous immunoglobulin 3–20 ml per dose was associated with a similar adverse event rate to pump administration; local infusion-site reactions were the most common adverse effects [69R].

Intravenous anti-D immunoglobulin Respiratory Transfusion-related acute lung injury (TRALI) occurred 5 hours after treatment with intravenous anti-D immunoglobulin in a 14-year-old girl with idiopathic

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thrombocytopenic purpura; there were no pulmonary sequelae [71A]. Hematologic Extravascular hemolysis is the major complication of treatment with anti-D immunoglobulin. Usually, the hemoglobin falls to a nadir at 6–7 days after infusion and normalizes after 15–42 days. However, hemolysis can be delayed when concurrent glucocorticoids are used [72A]. There have been 15 previous cases of acute hemoglobinemia or hemoglobinuria associated with intravenous anti-D immunoglobulins [73c] and six cases of disseminated intravascular coagulation, of whom five died [74c], both severe unpredictable adverse effects but very rare.

COAGULATION PROTEINS [SED-15, 845; SEDA-30, 387; SEDA31, 537; SEDA-32, 596]

Factor VIIa

[SED-15, 1318; SEDA-30, 387; SEDA-32, 596]

Hematologic Recombinant factor VIIa (rFVIIa) is being investigated as a possible reversal agent for new anticoagulants. In general, the risk of thrombosis is increased with products that contain activated factor VII. However, the incidence of thrombotic complications is reported as low as 4–8 per 100 000 infusions [7R]. Because of its short half-life, repeated dosing may be needed, increasing the risk of thrombosis, which complicates treatment in up to 7–9% of cases [41R, 42R]. However, a similar rate was found in neonates who received fresh frozen plasma only, and neonates with coagulopathy and/or bleeding may be at a significant risk of thrombosis [75M].

Factor VIII

[SED-15, 1319; SEDA-30,

387] In 171 patients with hemophilia A and inhibitors, treated with factor VIII concentrate,

680

adverse events were reported during 10 courses, six of these events were allergic reactions [76R].

Factor IX

[SED-15, 1324; SEDA-30, 388; SEDA-32, 596]

Adverse events, mainly allergic reactions, occurred in 11 of 16 courses of immune tolerance induction therapy in patients with hemophilia B and inhibitors. Three cases of nephritic syndrome were also reported, with edema, proteinuria, and hypoalbuminemia 7–9 months after they had received factor IX 100 U/kg/day [76R].

Prothrombin complex concentrate [SEDA-31, 537; SEDA-32, 596] Several prothrombin complex concentrate products are available, with different amounts of vitamin K-dependent factors. Products that contain therapeutic concentrations of factors II, IX, and X are referred to as three-factor concentrates; those with additional factor VII are called four-factor concentrates. The clinical differences between these types are unclear, but fourfactor concentrates should more effectively correct the international normalized ratio (INR) [41R]. Hematologic Historically, there was concern that prothrombin complex concentrates were associated with thrombotic events such as stroke, myocardial infarction, pulmonary embolism, deep venous thrombosis, and disseminated intravascular coagulation. These events resulted mainly from the use of prothrombin complex concentrates as source of factor IX in patients with hemophilia B, and in particular after surgery, but the reported incidence is low and there is considerable evidence that the risk of thrombosis has been minimized with current prothrombin complex concentrates by reduced use of activated factors and the

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inclusion of coagulation inhibitors [7R, 42R, 77c]. However, it is still possible that activated coagulation factors could increase the risk of thrombosis and myocardial infarction in patients with susceptibility factors. Most current products contain one or more coagulation inhibitors (antithrombin, protein C, protein S, protein Z, or heparin) to maintain hemostatic balance while the coagulation factors are increased. Unfortunately, many products do not mention the inhibitor concentrations in the label [7R]. In two studies in 24 and 8 patients undergoing surgery, there were no thrombotic complications or other adverse events, and several other studies have reported similar safety [7R, 77c]. Pharmacokinetic studies of factor IX 50 U/kg in healthy volunteers have shown rapid increases in coagulation factors, no increase in D-dimer concentrations, and no clinical evidence of thrombosis. On the other hand, a review revealed seven thrombotic complications in 460 patients. It has been suggested that the risk of thrombosis is due to a high concentration of factor II (thrombin) [7R]. • A 72-year-old man with diabetes mellitus, hypertension, a recent ischemic stroke, chronic renal disease, and a deep venous thrombosis developed severe hypoglycemia and was found to have an INR over 12.8 [78A]. An echocardiogram showed cardiac tamponade. It was decided to reverse anticoagulation rapidly with prothrombin complex concentrate 50 U/kg, vitamin K 10 mg, and desmopressin acetate 24 micrograms, and to drain the pericardial effusion. Immediately after the pericardiocentesis he developed a right-sided ventricular thrombus occupying the entire right side of the ventricle and died.

The authors suggested that thrombus had formed from a combination of the effects of prothrombin complex concentrate, desmopressin acetate, which releases von Willebrand factor and factor VIII from endothelial cells, and blood stasis of on re-expansion of the right ventricle following pericardiocentesis, creating a hypercoagulable state. The failure of the prothrombin complex concentrate to correct the INR was probably due to consumption of the active factors by the ventricular thrombus.

Blood, blood components, plasma, and plasma products

Von Willebrand factor/factor VIII concentrates [SEDA-30, 388; SEDA-32, 597] Von Willebrand factor/factor VIII concentrates play a key role in the treatment of patients with von Willebrand disease. The von Willebrand factor multimer fraction is very effective in achieving hemostasis. The available products differ in production techniques, von Willebrand factor multimer content, and activity. No serious adverse events have been related to Haemate P/Humate P in clinical trials. Non-serious adverse events include allergic symptoms in under 6% of patients, chills, phlebitis, edema, pain in the limbs, and pseudothrombocytopenia in a few patients. No cases of thrombosis have been reported in clinical trials, although caution should be taken in patients with von Willebrand disease who have other thrombotic risk factors [8R].

ERYTHROPOIETIN AND DERIVATIVES [SED-15, 1243; SEDA-30, 388; SEDA-31, 538; SEDA-32, 597] Erythropoietin derivatives, such as epoetin alfa, epoetin beta, epoetin delta, and darbepoetin alfa, have been used to correct the anemia of chronic renal insufficiency and in the management of a variety of refractory anemias, including the anemia of chronic diseases, anemias in patients with various neoplasms undergoing chemotherapy, in patients with multiple myeloma, and in some patients with myelodysplasia, in aplastic anemia, and in anemia associated with the use of antiretroviral drugs. The dosages required in these anemias are significantly higher than in the anemia of chronic renal insufficiency. Erythropoietin derivatives have also been successfully used to stimulate blood production in patients without anemias who have to undergo frequent phlebotomy to accumulate blood for

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autologous blood transfusion at the time of orthopedic surgery [79R]. Observational studies The European Medicines Agency's Committee for Medical Products for Human use (CHMP) has reviewed new data from studies that showed an increased risk of tumor progression, venous thromboembolism, and shorter overall survival in patients with cancer who received erythropoietin derivatives compared with patients who did not [80S]. The CHMP concluded that the benefits of erythropoietin derivatives continue to outweigh their harms in the approved indications. However in patients with cancer and a reasonably long life-expectancy, the benefit of using erythropoietin derivatives does not outweigh the risk of tumor progression and shorter overall survival. The CHMP therefore concluded that in these patients anemia should be corrected with blood transfusions. Death Several groups have published evidence that erythropoietin derivatives maintain normal hemoglobin concentrations but also shorten the overall survival of patients with cancers or multiple myeloma [81M, 82C, 83r, 84r]. Although the explanation is uncertain, thromboembolic events, interactions of erythropoietin derivatives with erythropoietin receptors on tumor cells, and stimulation of angiogenesis by actions on erythropoietin receptors on endothelial cells have been suggested. Guidelines based on these results limit the use of erythropoietin derivatives to patients with chronic kidney disease and cancers undergoing chemotherapy, with a target hemoglobin concentration of 12 g/dl [85S, 86M]. Susceptibility factors Children Studies on the use of erythropoietin derivatives in children have suggested that although children need almost the same doses of erythropoietin derivatives as are used in adults range and should be dosed according to the hemoglobin deficit and not according to body weight, there is no evidence of unexpected serious adverse events attributable to erythropoietin derivatives [87r, 88c, 89c].

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Darbepoetin alfa

Epoetin beta

Several studies on the use of erythropoietin stimulating agents in the treatment of anemia in patients with cancers with or without chemotherapy or radiotherapy, the most common adverse reactions to darbepoetin alfa were myalgia, rash, pruritic rash, and cardiovascular and thrombotic events, such as dysrhythmias, congestive heart failure, strokes, myocardial infarction/coronary artery disorders, embolism/thrombosis (arterial and venous), hypertension, and seizures [90C, 91C, 92C]. Switching from subcutaneous to intravenous administration can maintain hemoglobin in the defined range of 10–13 g/dl at comparable dose requirements without compromising safety and tolerability [93C].

Erythropoietin derivatives are associated with an increased frequency of thrombovascular events in a variety of tumor types [97C]. However, whether patients with susceptibility factors should receive prophylactic antithrombotic treatment has not been confirmed. The adverse effects of combination therapy with epoetin beta and all-trans retinoic acid (ATRA) in 59 patients with myelodysplastic syndromes were muscle pain, raised liver enzymes without hepatic failure, fatigue, headache, dry skin, and dry mucosa [98c].

Susceptibility factors Elderly In elderly patients with chronic renal disease oncemonthly darbepoetin alfa for anemia was not associated with different rates of adverse events in patients aged under 65, 65–74, or 75 years and over [94c].

Epoetin alfa The most frequently reported adverse events are headache, polycythemia, tiredness, common cold, diarrhea, nausea, stomach pains, chest pressure sensation, back pain, leg pain, and dizziness, as confirmed in a phase I open bioequivalence parallel group study of two recombinant human epoetin alfa products; the pattern of the adverse events revealed no relevant differences between the erythropoietin derivatives [95c]. Patients who were randomized to early intervention with immediate epoetin alfa (n ¼ 68) or to standard intervention with epoetin alfa (n ¼ 68), and a further 50 who were not randomized, pain, injectionsite pain, bone pain, and deep vein thrombosis were observed [96c].

Epoetin delta Epoetin delta differs from the other erythropoietin derivatives in that it is produced in a human cell line using gene-activation technology. It has been approved in Europe but not in the USA for the treatment of anemia associated with chronic kidney disease. In patients with cancer and anemia who were given epoetin delta, possible treatment-related serious adverse events were hypertension, increased serum creatinine, and peripheral vascular disease [99C]. There was a correlation with higher doses, suggesting that a dose of 150 IU/kg would be most appropriate to start with for this indication.

STEM CELLS [SEDA-30, 389; SEDA-31, 539; SEDA-32, 599] Cardiovascular There is a high rate of stent restenosis if intra-coronary infusion of stem cells is carried out within 4 weeks after coronary stenting [100C, 101C, 102C, 103C, 104C]. It should be possible to mitigate this effect by delaying stem cell injection [105c].

Blood, blood components, plasma, and plasma products

The release of biomarkers of myocardial damage has been studied in 71 patients with severe coronary artery disease, after direct intramyocardial injection of vascular endothelial growth factor genes or mesenchymal stromal stem cells [106c]. Plasma creatine kinase MB fraction rose from 2 to 6 mg/l after 8 hours and normalized to 4 mg/l after 24 hours. Eight patients who received a volume of 0.3 ml per injection had rises exceeding three times the upper limit, whereas none of those who received 0.2 ml had a more than two-fold rise. No patient developed new electrocardiographic changes, and there were no ventricular dysrhythmias or deaths. The authors suggested that injection volumes of 0.2 ml are probably safer than 0.3 ml. The possibility that stem cells are prodysrhythmic has been reviewed [107R] and disputed [108R]. Gastrointestinal Nausea and vomiting are common during infusion of cryopreserved peripheral blood stem cells, but the symptoms were significantly attenuated by the use of a strawberry-flavored lollipop during infusion in 158 patients with malignancies [109c]. Other infusion-related adverse events were hypoxia, cough, dyspnea, abdominal cramping, tachycardia, hiccup, fever, chills, chest pain, hypotension, hypertension, agitation, sore throat, and dysrhythmias.

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Immunologic Cord blood transplantation is used as a source of hemopoietic stem cells. Ideally, cells from a human leukocyte antigen (HLA)-identical sibling or relative should be used, but it is often unavailable. Maternal sources or partially HLAmatched cells of unrelated donors with T-cell depletion can be used as alternatives, but graft-versus-host disease (GvHD) has been reported in several cases [110A, 111A, 112A]. It results from transfusion of donor T lymphocytes that proliferate and attack the recipient's tissues and organs. It occurs in 25–50% of patients, with considerable morbidity and mortality, commonly involving the skin, mouth, liver, eyes, esophagus, and upper respiratory tract. It can be acute or chronic and can develop after transplantation as soon as 20 days or as late as 650 days. Death Although umbilical cord blood transplantation has become standard treatment in children with hematological malignancies, in adults it is limited by a minimum cell dose. A new option is administration of two partially matched units of cord blood, but this increases the risk of complications. Death has occurred after double cord blood transplantation and multiple transfusions in a woman in whom an earlier pregnancy might have predisposed to sensitization [113A].

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in a patient with Guillain–Barré syndrome. Pediatr Neurol 2008; 39(2): 123–5. Yin F, Nesbitt JA, Tobian AA, Holt PA, Mikdashi J. Hemolytic anemia following intravenous immunoglobulin administration. Am J Hematol 2008; 83(10): 825. Navarro M, Negre S, Matoses ML, Golombek SG, Vento M. Necrotizing enterocolitis following the use of intravenous immunoglobulin for haemolytic disease of the newborn. Acta Paediatr 2009; 98(7): 1214–7. Lin WL, Lin WC, Chang YC, Yang LC, Hung SI, Hong HS, Chung WH. Intravenous immunoglobulin-induced, noneczematous, vesiculobullous eruptions in Stevens–Johnson syndrome. Am J Clin Dermatol 2009; 10(5): 339–42. Rhee DY, Park GH, Chang SE, Lee MW, Choi JH, Moon KC, Koh JK. Pompholyx after intravenous immunoglobulin therapy for treatment of Guillain–Barré syndrome. J Eur Acad Dermatol Venereol 2009; 23 (5): 602–4. Baumann A, Hess CW, Sturzenegger M. IVIg dose increase in multifocal motor neuropathy: a prospective six month follow-up. J Neurol 2009; 256(4): 608–14. Caress JB, Hobson-Webb L, Passmore LV, Finkbiner AP, Cartwright MS. Case-control study of thromboembolic events associated with IV immunoglobulin. J Neurol 2009; 256(3): 339–42. Misbah S, Sturzenegger MH, Borte M, Shapiro RS, Wasserman RL, Berger M, Ochs HD. Subcutaneous immunoglobulin: opportunities and outlook. Clin Exp Immunol 2009; 158(Suppl 1): 51–9. Eftimov F, Vermeulen M, de Haan RJ, Van den Berg LH, van Schaik IN. Subcutaneous immunoglobulin therapy for multifocal motor neuropathy. J Peripher Nerv Syst 2009; 14(2): 93–100. Berger-Achituv S, Ellis MH, Curtis BR, Wolach B. Transfusion-related acute lung injury following intravenous anti-D administration in an adolescent. Am J Hematol 2008; 83(8): 676–8. Rubinstein PG, Chen YH. Delayed hemolysis after intravenous anti-D immune globulin infusion in a patient with

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idiopathic thrombocytopenic purpura. Am J Hematol 2008; 83(8): 684–5. Gaines AR. Acute onset hemoglobinemia and/or hemoglobinuria and sequelae following Rh(o)(D) immune globulin intravenous administration in immune thrombocytopenic purpura patients. Blood 2000; 95(8): 2523–9. Gaines AR. Disseminated intravascular coagulation associated with acute hemoglobinemia or hemoglobinuria following Rh(0) (D) immune globulin intravenous administration for immune thrombocytopenic purpura. Blood 2005; 106(5): 1532–7. Puetz J, Darling G, Brabec P, Blatny J, Mathew P. Thrombotic events in neonates receiving recombinant factor VIIa or fresh frozen plasma. Pediatr Blood Cancer 2009; 53(6): 1074–8. DiMichele D. The North American Immune Tolerance Registry: contributions to the thirty-year experience with immune tolerance therapy. Haemophilia 2009; 15 (1): 320–8. Bruce D, Nokes TJ. Prothrombin complex concentrate (Beriplex P/N) in severe bleeding: experience in a large tertiary hospital. Crit Care 2008; 12(4): R105. Warren O, Simon B. Massive, fatal, intracardiac thrombosis associated with prothrombin complex concentrate. Ann Emerg Med 2009; 53(6): 758–61. Fried W. Erythropoietin and erythropoiesis. Exp Hematol 2009; 37(9): 1007–15. European Medicines Agency Press Office. Epoetins Press Release New Warning for Use in Cancer Patients, London, UK: European Medicines Agency Press Office; 2007. http://www.cbg-meb.nl/NR/ rdonlyres/5AD07ADE-FEE8-4611-9FEAC0897A0E80C6/0/EpoetinsPressReleaseNewwarningforuseincancerpatients.pdf. Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, Zwahlen M, Clarke M, Weingart O, Kluge S, Piper M, Rades D, Steensma DP, Djulbegovic B, Fey MF, Ray-Coquard I, Machtay M, Moebus V, Thomas G, Untch M, Schumacher M, Egger M, Engert A. Recombinant human erythropoiesis-stimulating agents and

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mortality in patients with cancer: a metaanalysis of randomised trials. Lancet 2009; 373(9674): 1532–42. Katodritou E, Verrou E, Hadjiaggelidou C, Gastari V, Laschos K, Kontovinis L, Kapetanos D, Constantinou N, Terpos E, Zervas K. Erythropoiesis-stimulating agents are associated with reduced survival in patients with multiple myeloma. Am J Hematol 2008; 83(9): 697–701. Steensma DP. Prospects and perils of retrospective risk assessment of erythropoiesis-stimulating agents. Am J Hematol 2008; 83(9): 693–4. Ribatti D. Erythropoietin and cancer, a double-edged sword. Leuk Res 2009; 33 (1): 1–4. National Kidney Foundation. KDOQI Clinical practice guideline and clinical practice recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target. Am J Kidney Dis 2007; 50: 471–530. Gascon P. Safety update on erythropoiesis-stimulating agents: trials within and outside the accepted indications. Oncologist 2008; 13(Suppl 3): 4–10. Port RE, Mehls O. Erythropoietin dosing in children with chronic kidney disease: based on body size or on hemoglobin deficit? Pediatr Nephrol 2009; 24(3): 435–7. Juul SE, McPherson RJ, Bauer LA, Ledbetter KJ, Gleason CA, Mayock DE. A phase I/II trial of high-dose erythropoietin in extremely low birth weight infants: pharmacokinetics and safety. Pediatrics 2008; 122(2): 383–91. Zhu C, Kang W, Xu F, Cheng X, Zhang Z, Jia L, Ji L, Guo X, Xiong H, Simbruner G, Blomgren K, Wang X. Erythropoietin improved neurologic outcomes in newborns with hypoxic-ischemic encephalopathy. Pediatrics 2009; 124(2): e218–26. Smith Jr. RE, Aapro MS, Ludwig H, Pinter T, Smakal M, Ciuleanu TE, Chen L, Lillie T, Glaspy JA. Darbepoetin alpha for the treatment of anemia in patients with active cancer not receiving chemotherapy or radiotherapy: results of a phase III, multicenter, randomized, double-blind, placebo-controlled study. J Clin Oncol 2008; 26(7): 1040–50.

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[91] Pirker R, Ramlau RA, Schuette W, Zatloukal P, Ferreira I, Lillie T, Vansteenkiste JF. Safety and efficacy of darbepoetin alpha in previously untreated extensive-stage small-cell lung cancer treated with platinum plus etoposide. J Clin Oncol 2008; 26(14): 2342–9. [92] Gordon D, Nichols G, Ben Jacob A, Tomita D, Lillie T, Miller C. Treating anemia of cancer with every-4-week darbepoetin alfa: final efficacy and safety results from a phase II, randomized, double-blind, placebo-controlled study. 6. Oncologist 2008; 13: 715–24. [93] Bommer J, Asmus G, Wenning M, Bommer G. A comparison of haemoglobin levels and doses in haemodialysis patients treated with subcutaneous or intravenous darbepoetin alfa: a German prospective, randomized, multicentre study. Nephrol Dial Transplant 2008; 23(12): 4002–8. [94] Silver MR, Agarwal A, Krause M, Lei L, Stehman-Breen C. Effect of darbepoetin alfa administered once monthly on maintaining hemoglobin levels in older patients with chronic kidney disease. Am J Geriatr Pharmacother 2008; 6(2): 49–60. [95] Sorgel F, Thyroff-Friesinger U, Vetter A, Vens-Cappell B, Kinzig M. Bioequivalence of HX575 (recombinant human epoetin alfa) and a comparator epoetin alfa after multiple subcutaneous administrations. Pharmacology 2009; 83(2): 122–30. [96] Glaspy JA, Charu V, Luo D, Moyo V, Kamin M, Wilhelm FE. Initiation of epoetin-alpha therapy at a starting dose of 120,000 units once every 3 weeks in patients with cancer receiving chemotherapy: an open-label, multicenter study with randomized and nonrandomized treatment arms. Cancer 2009; 115(5): 1121–31. [97] Aapro M, Barnadas A, Leonard RC, Marangolo M, Untch M, Ukarma L, Burger HU, Scherhag A, Osterwalder B. What is the impact of antithrombotic therapy and risk factors on the frequency of thrombovascular events in patients with metastatic breast cancer receiving epoetin beta? Eur J Cancer 2009; 45(17): 2984–91. [98] Itzykson R, Ayari S, Vassilief D, Berger E, Slama B, Vey N, Suarez F, Beyne-Rauzy O, Guerci A, Cheze S,

Blood, blood components, plasma, and plasma products

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Thomas X, Stamatoullas A, Gardembas M, Bauduer F, Kolb A, Chaury MC, Legros L, Damaj G, Chermat F, Dreyfus F, Fenaux P, Ades L. Is there a role for all-trans retinoic acid in combination with recombinant erythropoetin in myelodysplastic syndromes? A report on 59 cases. Leukemia 2009; 23(4): 673–8. Krzakowski M. Epoetin delta: efficacy in the treatment of anaemia in cancer patients receiving chemotherapy. Clin Oncol (R Coll Radiol) 2008; 20(9): 705–13. Kang HJ, Lee HY, Na SH, Chang SA, Park KW, Kim HK, Kim SY, Chang HJ, Lee W, Kang WJ, Koo BK, Kim YJ, Lee DS, Sohn DW, Han KS, Oh BH, Park YB, Kim HS. Differential effect of intracoronary infusion of mobilized peripheral blood stem cells by granulocyte colony-stimulating factor on left ventricular function and remodeling in patients with acute myocardial infarction versus old myocardial infarction: the MAGIC Cell-3-DES randomized, controlled trial. Circulation 2006; 114(Suppl 1): I145–51. Mansour S, Vanderheyden M, De Bruyne B, Vandekerckhove B, Delrue L, Van Haute I, Heyndrickx G, Carlier S, Rodriguez-Granillo G, Wijns W, Bartunek J. Intracoronary delivery of hematopoietic bone marrow stem cells and luminal loss of the infarct-related artery in patients with recent myocardial infarction. J Am Coll Cardiol 2006; 47(8): 1727–30. Kang HJ, Kim HS, Zhang SY, Park KW, Cho HJ, Koo BK, Kim YJ, Soo Lee D, Sohn DW, Han KS, Oh BH, Lee MM, Park YB. Effects of intracoronary infusion of peripheral blood stem-cells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell randomised clinical trial. Lancet 2004; 363 (9411): 751–6. Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin M, Colombo A, Schuler G, Barragan P, Guagliumi G, Molnàr F, Falotico R. RAVEL Study Group. Randomized Study

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with the Sirolimus-Coated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients with de Novo Native Coronary Artery Lesions. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002; 346(23): 1773–80. Steinwender C, Hofmann R, Kammler J, Kypta A, Pichler R, Maschek W, Schuster G, Gabriel C, Leisch F. Effects of peripheral blood stem cell mobilization with granulocyte-colony stimulating factor and their transcoronary transplantation after primary stent implantation for acute myocardial infarction. Am Heart J 2006; 151(6): 1296. Kim KS, Jin J, Lee YY, Choi SI, Shin JH, Kim JH, Lim HG, Lee BH, Choi YY, Lee SM, Koh HC. The timing of intra-coronary infusion of G-CSF mobilized peripheral blood stem cells influences cardiac function and in-stent restenosis in patients with myocardial infarction. Int J Cardiol 2010; 143(2): 202–5. Baldazzi F, Jrgensen E, Ripa RS, Kastrup J. Release of biomarkers of myocardial damage after direct intramyocardial injection of genes and stem cells via the percutaneous transluminal route. Eur Heart J 2008; 29(15): 1819–26. Macia E, Boyden PA. Stem cell therapy is proarrhythmic. Circulation 2009; 119(13): 1814–23. Ly HQ, Nattel S. Stem cells are not proarrhythmic: letting the genie out of the bottle. Circulation 2009; 119(13): 1824–31. Ozdemir E, Akgedik K, Akdogan S, Kansu E. The lollipop with strawberry aroma may be promising in reduction of infusion-related nausea and vomiting during the infusion of cryopreserved peripheral blood stem cells. Biol Blood Marrow Transplant 2008; 14(12): 1425–8. Norris R, Paessler M, Bunin N. Donor Tcell-mediated pancytopenia after haploidentical hematopoietic stem cell transplant for severe combined immunodeficiency. J Pediatr Hematol Oncol 2009; 31(2): 148–50. Kawakami Y, Ohtsuka M, Kikuta A, Yamamoto T. Multiple morphea-like

690 lesions associated with chronic graft-versus-host disease after cord blood transplantation. Acta Derm Venereol 2009; 89 (1): 86–7. [112] Kordes U, Binder TM, Eiermann TH, Hassenpflug-Diedrich B, Hassan MA, Beutel K, Nagy M, Kabisch H, Schneppenheim R. Successful donor-lymphocyte infusion for extreme immunehemolysis following unrelated BMT in a patient with X-linked chronic

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granulomatous disease and McLeod phenotype. Bone Marrow Transplant 2008; 42(3): 219–20. [113] Rokicka M, Styczynski J, Michalewska B, Torosian T, Tomaszewska A, Gronkowska A, Pogorzala M, Wysocki M, Lakomy M, Wiktor-Jedrzejczak W. Fatal combined immune hemolytic anemia after double cord blood transplantation in imatinib-resistant CML. Bone Marrow Transplant 2009; 44(6): 383–5.

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Vitamins, intravenous solutions, and drugs and formulations used in nutrition

VITAMIN A (CAROTENOIDS)

[SED-15, 3642; SEDA-31, 548; SEDA-32, 607] The adverse effects of vitamin A in so-called “tolerable upper intake levels” have been reviewed [1R]. Chronic hypervitaminosis A is relatively rare. Its effects are varied and non-specific. In adults they include central nervous system effects, skin disorders, conjunctivitis, nausea, vomiting, teratogenicity, and hepatotoxicity. In infants and young children, skeletal and intracranial (e.g. transient bulging fontanelle) abnormalities can occur. There are conflicting data on the risks of bone fractures from high chronic dosing in industrialized countries. Prolonged high doses of beta-carotene can cause carotenodermia, a yellow-orange discoloration of the skin, which is harmless. There have been reports of increased frequencies of lung cancer in heavy tobacco smokers and asbestos workers associated with beta-carotene supplements of 30 and 20 mg/day respectively, but these are very high doses, exceeding those normally available in the diet. The authors reviewed models for minimizing the risks of these adverse effects.

Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00034-9 # 2011 Elsevier B.V. All rights reserved.

Vitamin A supplementation in infants at times of immunization The WHO has recommended the use of high-dose vitamin A supplements at times of immunization after 6 months of age, since it is associated with reduced morbidity and mortality [2S, 3C, 4C]. Consequently, the expanded programme on immunization has been established to provide the opportunity of giving vitamin A supplements to young infants [5S, 6S]. This has given rise to three concerns: first, whether vitamin A supplementation interferes with immune responses to vaccines; this has not been shown to be the case [7C, 8C, 9C, 10C, 11C, 12C, 13C]; secondly, whether high doses of vitamin A cause adverse effects during immunization; the main adverse reaction that has been reported is transient bulging of the anterior fontanelle, which is uncommon and not associated with neurological complications [14C, 15C, 16C, 17C]; thirdly, whether highdose vitamin A is associated with increased mortality at the time of immunization. The effects of vitamin A given with different vaccines have been studied in 982 children aged 6–17 months in Guinea–Bissau, who were given DTP or DTP þ measles vaccine and were followed until they were 18 months of age; 20 died during follow-up and the mortality rate ratio (MRR) for vitamin A with DTP þ measles vaccine or with DTP was 3.43 (1.36, 8.61) compared with vitamin A alone [18C]. There were no deaths among those who received vitamin A with measles vaccine alone. Children who received vitamin A with DTP had a higher 691

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mortality than non-participants who did not receive vitamin A (3.04; CI ¼ 1.31, 7.07). In 3349 infants randomized to vitamin A 50 000 IU or placebo with BCG immunization adverse events were monitored by daily clinical examinations by a doctor during the first 3 days and by weekly interviews by a trained assistant during the first month [19C]. Vitamin A supplementation was associated with a relative risk of bulging fontanelles of 1.16 (95% CI ¼ 0.82, 1.65). There were more local reactions to BCG in boys, but not in girls. However, concerns have been raised about the safety of administering high dose vitamin A supplements to infants less than 6 months of age in developing countries. The safety and immunogenicity of 15 mg of retinol equivalents of vitamin A with a pentavalent vaccine containing diphtheria, polio, tetanus, Haemophilus influenzae b, and hepatitis B at 6, 10, and 14 weeks of age have been studied in a randomized controlled trial in 1077 infants in the Kintampo Health Research Centre [20C]. There were significantly fewer reports of fever and illnesses in infants who had been given vitamin A compared with infants in the control group. However, there were six deaths, five in the intervention group and one in the control group (RR ¼ 4.65; CI ¼ 0.55, 40). Although this was not statistically significant, because of the large confidence interval, the authors urged caution in giving young infants high doses of vitamin A with the pentavalent vaccine. On the other hand, a systematic review of six randomized, quasi-randomized, or cluster-randomized placebo-controlled studies of the effect of prophylactic neonatal supplementation with synthetic vitamin A in developing countries has shown no effect on mortality (RR ¼ 0.92; 95% CI ¼ 0.75, 1.12) or morbidity, including bulging fontanelle (RR ¼ 1.16; CI ¼ 0.81, 1.65) [21M]. Skin The use of topical tretinoin 0.075% cream once at night to treat mild photoageing in middle-aged Japanese women was associated with skin irritation in only

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M.C. Allwood and J.K. Aronson

three cases; 0.04% cream for 13 weeks was less beneficial but there was minimal irritation [22c]. Musculoskeletal The risk of hip and total fractures has been determined in 75 747 women from the Women's Health Initiative Observational Study [23C]. After adjustment for covariates such as age, protein, vitamin D, vitamin K, calcium, caffeine, and alcohol intake, body mass index use of therapeutic hormones, smoking, and ethnicity, the association between vitamin A and retinol intake and the risk of fractures was not statistically significant. However, there was an association with the highest dose of retinol in conjunction with low vitamin D status. Women with lower vitamin D intake had a modest increased risk of total fracture if they were in the highest quintile of vitamin A intake (HR ¼ 1.19; 95% CI ¼ 1.04, 1.37) and retinol intake (HR ¼ 1.15; 95% CI ¼ 1.03, 1.29). Drug overdose The hepatotoxicity of the retinoids is well known. Fulminant hepatic failure followed an intentional overdose of acitretin 600 mg, with poor prognostic criteria at 66 hours after overdose, but there was rapid improvement thereafter and liver transplantation was not required [24A]. It has been national government policy in India, via the Integrated Child Development Programme, which covers 90% of rural India, to provide nutrition education to mothers, nutritional supplements in physiological doses to children under 6 years of age, and mega-doses of vitamin A. A total of nine massive doses of synthetic vitamin A are given to children between the ages of 9 and 60 months. While the programme undoubtedly reverses and prevents deficiency it has been criticized on account of the risks of adverse effects of the high doses of vitamin A (200 000 units) that are commonly used [25r].

Vitamins, intravenous solutions, and drugs and formulations used in nutrition

VITAMINS OF THE B GROUP [SED-15, 2700; SEDA-31, 548; SEDA-32, 608]

Cobalamins Cardiovascular In 41 healthy volunteers who received single intravenous doses of hydroxocobalamin 2.5, 5, 7.5, or 10 g over 7.5–30 minutes there were transient increases in blood pressure, which returned nearly to baseline after 4 hours [26c]. The changes in mean arterial pressure correlated with changes in plasma total and unbound cobalamins-(III). Nervous system Three infants developed movement disorders during vitamin B12 administration, with a combination of tremor and myoclonus affecting the face, tongue, and limbs; in two cases the involuntary movements resolved with clonazepam and in the other with piracetam [27A].

Folic acid Respiratory Data from experimental animals suggest that folic acid given to the mother during pregnancy may be associated with an increased risk of asthma in the offspring by an epigenetic effect involving altered DNA methylation [28E]. In an analysis of data from the Mother and Child Cohort study in Norway, where foods are not fortified, wheezing and lower respiratory tract infections during the first 18 months of life were examined in 32 077 children born between 2000 and 2005 in relation to maternal reported intake of folic acid 400 mg/day and cod liver oil 5 ml/day [29C, 30r]. The relative risks in the infants of mothers who took folate supplements during the first trimester were 1.06 (95% CI ¼ 1.03, 1.10) for wheezing, 1.09 (95% CI ¼ 1.02, 1.15) for lower respiratory tract infections, and 1.24 (95% CI ¼ 1.09, 1.41) for hospitalization associated with lower respiratory tract infections. Although small, these relative risks were statistically significant.

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In a study of the effect of the timing, dose, and source of folate during pregnancy on childhood asthma, using data from an Australian prospective birth cohort study from 1998 to 2005, 490 and 423 mothers and children took part at 3.5 and 5.5 years respectively [31c]. Asthma was reported in 12% of children at both 3.5 years (n ¼ 57) and 5.5 years (n ¼ 50). Supplementary folic acid taken during late pregnancy was associated at 3.5 years with an increased risk of childhood asthma (RR ¼ 1.26; 95% CI ¼ 1.08, 1.43) and persistent asthma (RR ¼ 1.32; 95% CI ¼ 1.03, 1.69). The effect sizes did not change with adjustment for potential confounders. The association was similar at 5.5 years but did not reach statistical significance (RR ¼ 1.17; 95% CI ¼ 0.96, 1.42). In contrast, in 8083 women of childbearing potential in the 2005–2006 US National Health and Nutrition Examination Survey, higher serum folate concentrations were associated with a lower risk of high total serum IgE concentrations, atopy, and wheezing [32C]. There was a dose–response relationship between higher serum folate concentrations and lower risks of these outcomes, and the associations were independent of age, sex, race/ethnicity, and poverty. Immunologic Hypersusceptibility reactions to folic acid are very rare, but new cases have been reported [33A]. • A 42-year-old woman developed generalized urticaria and dyspnea 2 hours after taking a folic acid-containing supplement; 2 years before she had taken folic acid for 2 months without any symptoms. Skin prick tests were positive for the supplement and one of its ingredients, folic acid, but not any other ingredients, including riboflavin, biotin, niacin, thiamine, pyridoxine hydrochloride, pantothenate calcium, or yeast. There was also a positive reaction to methotrexate, but not to folinic acid. Folic acid and methotrexate stimulated basophils to release significant amounts of histamine, but folinic acid did not. • A 72-year-old woman developed urticaria after taking folic acid, 400 micrograms/day for 2 years. Folic acid was withdrawn, and a few days later the urticaria disappeared. Intradermal tests with folic acid 1 and 5 mg/ml were

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694 negative, but single-blind oral challenge tests with increasing doses of folic acid at 30-minute intervals (0.25, 0.50, and 1 mg) were positive. Ten minutes after the 1-mg dose she developed red pruriginous wheals and 2 hours later generalized urticaria, facial and lingual edema, and bilateral conjunctival congestion. Folic acid-specific IgE was not detected. Three weeks after the folic acid challenge, a singleblind parenteral challenge test with intramuscular folinic acid 50 mg/5 ml was performed; after 1 hour she developed a red pruriginous macule over her torso. There were no reactions at the site of injection.

Tetrahydrobiopterin and sapropterin [SEDA-32, 609] Observational studies In 80 patients aged at least 8 years, who had taken part in a 6-week, randomized, placebo-controlled study of sapropterin, and who were enrolled in a 22-week, multicenter, open, extension study there were dose-related reductions in plasma phenylalanine concentrations from 844 to 645 mmol/l; 68 patients had at least one adverse event, all but one of which were mild or moderate in intensity [34c]. Neither the one severe event nor any of the three serious events was considered related to sapropterin. No adverse event led to treatment withdrawal.

VITAMIN C (ASCORBIC ACID) [SED-15, 351; SEDA-30,

394;

SEDA-31, 548; SEDA-32, 611] Cardiovascular In a systematic review of seven studies of the effect of combined vitamin C and vitamin E supplements in 5969 pregnant women at risk of pre-eclampsia, of whom 2982 received vitamin C þ vitamin E and 2987 received placebo, there were increased risks of gestational hypertension (RR ¼ 1.3; 95% CI ¼ 1.08, 1.57) and low birth weight

M.C. Allwood and J.K. Aronson

(RR ¼ 1.13; 95% CI ¼ 1.004, 1.27) [35M]. Pre-eclampsia (RR ¼ 0.7; 95% CI ¼ 0.58, 1.08) and preterm delivery (RR ¼ 1.12; 95% CI ¼ 0.96, 1.32) were not affected. Sensory systems Vision In a prospective study of the effect of high doses of vitamin C supplements (about 1 g/day) and multivitamins containing vitamin C (about 60 mg/day) on the risk of age-related cataracts in 24 593 women aged 49–83 years (184 698 person-years of follow up) the multivariable hazard ratio for vitamin C users compared with non-users was 1.25 (95% CI ¼ 1.05, 1.50) [36C]. The hazard ratio for those who had used vitamin C for over 10 years was 1.46 (95% CI ¼ 0.93, 2.31). The hazard ratio for the use of multivitamins containing vitamin C was 1.09 (95% CI ¼ 0.94, 1.25). Vitamin C supplements increased the risk of cataract by 38% among women aged at least 65 years, by 56% among those who used hormone replacement therapy, and by 97% among glucocorticoid users. Urinary tract Vitamin C can rarely cause nephrotoxicity due to oxalate crystal deposition. This can be fatal, as in the case of a patient who chose to forgo treatment and failed to disclose his use of high-dose vitamin C; intra-renal oxalate crystal deposition was demonstrated at autopsy [37A]. Infection risk The effects of vitamin E and beta-carotene supplements on the risk of tuberculosis have been studied using data from the Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) Study, a 6-year, randomized, controlled trial in which the effects of vitamin E (50 mg/day) and beta-carotene (20 mg/day) on lung cancer were studied in Finland in 1985–1993 in 29 023 male smokers aged 50–69 years, at baseline [38C]. Vitamin E supplementation had no overall effect on the incidence of tuberculosis (RR ¼ 1.18; 95% CI ¼ 0.87, 1.59) and neither had beta-carotene (RR ¼ 1.07; 95% CI ¼ 0.80, 1.45). However, dietary vitamin C significantly modified the vitamin E effect. Among participants

Vitamins, intravenous solutions, and drugs and formulations used in nutrition

who took vitamin C 90 mg/day or more in food (n ¼ 13 502), vitamin E supplementation increased the risk of tuberculosis by 72% (95% CI ¼ 4, 185). This effect was restricted to participants who smoked heavily. The authors concluded that vitamin E transiently increased the risk of tuberculosis in those who smoked heavily and had a high dietary intake of vitamin C. However, confounding factors were not ruled out [39r]. In 21 657 participants in the Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) Study vitamin E supplementation had no effect on the risk of pneumonia in those whose body weights were 70–89 kg (n ¼ 12 495; RR ¼ 0.99; 95% CI ¼ 0.81, 1.22), but increased the risk of pneumonia in those who weighed under 60 kg (n ¼ 1054; RR ¼ 1.61; CI ¼ 1.03, 2.53) and in those who weighed over 100 kg (n ¼ 1328; RR ¼ 2.34; CI ¼ 1.07, 5.08); these effects were restricted to those with dietary vitamin C intakes above the median [40C].

VITAMIN D ANALOGUES [SED-15, 3669; SEDA-30, 394; SEDA-31, 549; SEDA-32, 612] Systematic reviews In a systematic review of 23 randomized controlled trials of the effects of calcitriol and alfacalcidol on the risks of fractures and fall in 2139 participants, of which 16 trials had sufficient data for meta-analysis, vertebral fractures were not significantly reduced, although subgroup analyses showed a significant reduction with alfacalcidol (13 trials; OR ¼ 0.50; 95% CI ¼ 0.25, 0.98) [41M]. There was a significant reduction in non-vertebral fractures (six trials; OR ¼ 0.51; 95% CI ¼ 0.30, 0.88), and falls (two trials; OR ¼ 0.66; 95% CI ¼ 0.44, 0.98). There was an increased risk of hypercalcemia (OR ¼ 3.63; 95% CI ¼ 1.51, 8.73) and a trend toward an increased risk of hypercalciuria.

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In contrast, a systematic review of double-blind randomized controlled trials, eight dealing with falls (n ¼ 2426) and 12 with non-vertebral fractures (n ¼ 42 279), there was a significant dose–response relation between the dose of 25-hydroxycolecalciferol and prevention of falls and fractures and no association between serum 25-hydroxycolecalciferol concentrations of 75–110 nmol/l and serum calcium concentrations [42M]. The authors suggested that the ideal oral dose of 25-hydroxycolecalciferol is in the range of 1800–4000 IU/ day. Mineral metabolism Milk-alkali syndrome (hypercalcemia, metabolic alkalosis, and impaired kidney function) has been reported in an 85-year-old Japanese woman who had taken oral alfacalcidol plus large doses of magnesium oxide without calciumcontaining drugs or supplements [43A]. She had severely impaired renal function (serum creatinine 386 mol/l; eGFR 10 ml/minute/ 1.73 m2), hypercalcemia (serum calcium 3.62 mmol/l), hypermagnesemia (serum magnesium 4.20 mmol/l), and a metabolic alkalosis (pH 7.445; serum bicarbonate 36 mmol/l). She responded to fluid replacement and furosemide. The coexistence of hypercalcemia and hypermagnesemia in this case was unusual—the syndrome tends to present with hypomagnesemia. The authors suggested that the syndrome should be renamed calcium–alkali syndrome, although they confusingly ended by pointing out that the syndrome can be caused by factors other than ingestion of large amounts of calcium and alkali. Immunologic A leukocytoclastic vasculitis has been attributed to cinacalcet in an 80year-old woman on maintenance hemodialysis therapy [44A]. After taking cinacalcet for 3 days she developed palpable purpura on all four limbs, which resolved after withdrawal of cinacalcet and administration of glucocorticoids.

696

VITAMIN E (TOCOPHEROL)

[SED-15, 3677; SEDA-30, 395; SEDA-31, 549; SEDA-32, 612] Cardiovascular See also Vitamin C. There are discordant results between the effects of vitamin E supplements in observational studies, in which they seem to reduce the risk of cardiovascular disease, and the results of interventional studies, in which they seem to have the opposite effect. In an extensive review of the benefits and adverse effects of vitamin E, the authors, employees of IdeaSphere Inc., which markets vitamins and nutrients, concluded that “healthy consumers should not change their current use of vitamin E supplements” since “most of the studies included in the three recent neutral to unfavorable meta-analyses were not conducted on free-living healthy individuals . . . [and] only four of 28 studies included in these meta-analyses involved healthy individuals” [45R]. They urged that “the guidelines set forth by the Institute of Medicine [in 2000] should still be embraced” and that “healthy individuals should not use more than 1000 mg of vitamin E daily”. They concurred with the findings of the HOPE study, a randomized, placebo-controlled study of the use of vitamin E 400 IU/day over 7 years [46C], that vitamin E did not prevent cancer or major cardiovascular disease events in subjects with pre-existing vascular disease or diabetes mellitus, and may have increased the risk of heart failure, and that, as the authors of the HOPE study concluded, such individuals should be warned to beware of “natural products”. However, the possibility that the differences between observational studies and interventional studies may be due to differences between healthy subjects and those with pre-existing cardiovascular disease has not been supported by the results of a Framingham Study in 4270 subjects stratified by baseline cardiovascular disease status [47C]. In those with pre-existing cardiovascular disease, there were 28 (44%)

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and 20 (32%) incident cases of cardiovascular disease and all-cause mortality in the vitamin E supplement users versus 249 (47%) and 202 (38%) respectively in the non-users. In those without pre-existing cardiovascular disease there were 51 (13%) and 47 (12%) cases of cardiovascular disease and all-cause mortality in the vitamin E supplement group versus 428 (13%) and 342 (10%) respectively in the non-vitamin E supplement group. The authors concluded that cardiovascular disease status has no effect on the risks of supplementation with vitamin E. Infection risk See Vitamin C. Death In a Bayesian meta-analysis of studies that had previously been included in meta-analyses of the relation between dose of vitamin E and all-cause mortality there was no evidence of an increases risk in those taking vitamin E [48M]. The weaknesses of the Bayesian approach have been discussed [49r], as have problems with other types of meta-analysis [50M]. Teratogenicity In a case–control study in 276 mothers of children with congenital heart defects and 324 control mothers with healthy children, dietary vitamin E intake was higher in the former and the risk increased with increasing dietary vitamin E intake [51C]. Retinol intake was not significantly different between the groups and was not associated with a risk of congenital heart defects. Drug–drug interactions Vitamin K The mechanism by which vitamin E interferes with vitamin K activity is not known, but it has been hypothesized that it involves vitamin K metabolism [52R]. Phylloquinone (vitamin K1) is converted to menaquinone, the most potent extrahepatic form of vitamin K by truncation of the side chain and replacement with geranylgeranyl. Possible mechanisms for the interaction of vitamin E with vitamin K include: competition for the as yet undiscovered enzyme that truncates the K1 side chain; competition with vitamin K1 for the hypothetical CYP

Vitamins, intravenous solutions, and drugs and formulations used in nutrition

isoenzyme that omega-hydroxylates the K1 side chain, thereby preventing its beta-oxidation and its conversion to menaquinone; increased hepatic metabolism and excretion of all forms of vitamin K. Warfarin In a Canadian survey of the prevalence of the use of complementary and alternative medicines (CAM) among patients taking warfarin and of the effect on the risk of warfarin-related adverse effects, 314 patients completed the survey, of whom 139 (44%) reported using CAM at least weekly [53C]. Potentially interacting medicines were used by 107 (34%) of the respondents, or 57 (18%) respondents if vitamin E was excluded. Vitamin E was used by 76 (24%) of all respondents, or 71% of those who used potentially interacting medicines. It was recommended that health-care professionals should stay abreast with the literature on complementary and alternative medicines and routinely query the use of these and other non-prescription products when documenting medication histories of patients taking warfarin.

PARENTERAL NUTRITION [SED-15, 2700; SEDA-31, 549; SEDA-32, 613] Cardiovascular In a study of the risk of pulmonary embolism in 64 patients aged 3 months to 22 years. receiving parenteral nutrition, 25 (39%) had an abnormal ventilation–perfusion scan and 29 episodes of pulmonary embolism were diagnosed. The median age at time of diagnosis was 4.6 years [54C]. Pulmonary embolism was bilateral in 56% and unilateral in 44% and was the main cause of two of 15 recorded deaths. Respiratory A unilateral pleural effusion occurred during parenteral nutrition in an 8week-old preterm boy because of intra-

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abdominal extravasation of parenteral fluid with leakage into the pleural cavity [55A]. Bilateral pleural effusions and respiratory distress have also been reported [56A]. • A 79-year-old Japanese woman with advanced gastric carcinoma developed dyspnea and a massive right-sided pleural effusion during postoperative nutritional management. Her symptoms resolved after thoracentesis, but she again developed severe respiratory distress and required mechanical ventilation. The tip of the central venous catheter had become displaced out of the wall of the superior vena cava, causing mediastinitis and leakage of intravenous fluid. The patient recovered after removal of the catheter.

In a prospective survey of 2346 patients aged 16 years and over who underwent mechanical ventilation within the first 48 hours of admission after trauma, 404 (17%) were exposed to parenteral nutrition and 192 (8.2%) met criteria for late adult respiratory distress syndrome (ARDS) [57C]. The incidence of late ARDS among those exposed to parenteral nutrition was 29% (116/404) compared with 3.9% (76/1942) among those not so exposed. The authors concluded that parenteral nutrition is independently associated with late ARDS. Metabolism Exposure to light of total parenteral nutrition solutions increases oxidation products such as lipid peroxides and hydrogen peroxide and oxidative stress impairs glucose uptake and affects lipid metabolism [58c]. In a secondary analysis of a prospective study in which preterm infants were allocated to light-exposed (n ¼ 32) or light-protected (n ¼ 27) parenteral nutrition solutions, blood glucose was higher and accumulation of triglycerides with increasing lipid intake was twice as high in those who received the light-exposed solutions. The authors concluded that shielding parenteral nutrition solutions from light provides a potential benefit for preterm infants by avoiding hypertriglyceridemia and allowing increased substrate delivery. Hyperglycemia has been reported in two children who developed severe insulin resistance requiring intravenous insulin

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therapy at doses up to 13 units/kg/hour during parenteral nutrition [59A]. In 276 patients who received parenteral nutrition for a mean of 15 days, after adjustment for age, sex, and diabetes status, mortality was independently predicted by pretreatment blood glucose concentrations of 6.72–8.33 mmol/l (OR ¼ 2.2; 95% CI ¼ 1.1, 4.4), 8.34–9.99 mmol/l (OR ¼ 3.41; CI ¼ 1.3, 8.7), and 10 mmol/l or over (OR ¼ 2.2; CI ¼ 0.9, 5.2) and by blood glucose concentrations within 24 hours of 10 mmol/l or over (OR ¼ 2.8; CI ¼ 1.2, 6.8) [60c]. A blood glucose concentration 10 mmol/l or over within 24 hours was associated with increased risks of pneumonia (OR ¼ 3.1; 95% CI ¼ 1.4, 7.1) and acute renal insufficiency (OR ¼ 2.3; CI ¼ 1.1, 5.0). Metabolomics of the urine from an 8year-old patient with epilepsy and an 11year-old patient with malignant lymphoma who was being treated with methotrexate, both of whom were receiving parenteral nutrition, showed identical metabolic profiles to that of phenylketonuria [61A]. Neopterin concentrations were markedly raised and in one case the biopterin concentration was also above normal. The metabolic profiles were normal when they were not receiving parenteral nutrition. Mineral metabolism Refeeding hypophosphatemia is a risk during parenteral nutrition. In 70 patients with refeeding hypophosphatemia who were matched with controls the independent susceptibility factors were: significant malnutrition; a dose of less than 12 mmol of total phosphate during the first day; and an initial rate of infusion of more than 70% of calculated requirements [62C]. Increasing amounts of non-lipid phosphate in the first day's regimen were protective. Metal metabolism Aluminium toxicity during parenteral nutrition has been studied retrospectively in 36 adults with impaired renal function, of whom 12 received hemodialysis [63c]. Mean aluminium exposure was 3.8 micrograms/kg/day in the 36 patients. Of these, 29 had safe calculated aluminium exposure (less than 5 micrograms/kg/day)

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and seven had high exposure (over 5 micrograms/kg/day). The former had significantly higher serum creatinine concentrations. The authors concluded that most patients with acute kidney damage who require parenteral nutrition do not receive excessive exposure to aluminium. Bone area and bone mineral content were measured in the lumbar spine, hip, and whole body with dual radiograph absorptiometry in 59 children aged 13–15 years who were born preterm and randomly assigned standard or aluminium-depleted parenteral nutrition solutions during the neonatal period [64c]. Those who were randomly assigned to standard parenteral nutrition had lower lumbar spine bone mineral content, explained by a reduction in bone size. Those who were exposed to neonatal aluminium intakes above the median (55 micrograms/kg) had lower hip bone mineral content (by 7.6%; 95% CI ¼ 0.12, 14) independent of bone or body size. Liver In a 5-day, randomized, double-blind comparison of the effects of structured triglycerides, a mixture of medium- and long-chain triglycerides, and an emulsion of long-chain triglycerides on liver function in 45 patients undergoing abdominal surgery, the structured triglycerides were associated with preserved liver function, whereas both of the other formulations caused subclinical hepatic damage [65C]. The role of phytosterols in the hepatotoxicity of parenteral nutrition has been studied in 27 adults [66c]. Total plasma phytosterol concentrations correlated with total bilirubin and aspartate aminotransferase activity. A poor oral diet and the infused dose of phytosterols were susceptibility factors. Biopsies showed moderate to severe liver impairment in five patients. Progression of liver disease during parenteral nutrition in two infants with intestinal failure was rapidly exacerbated by ischemic liver damage [67A]. In a prospective study of 994 patients who required parenteral nutrition, hepatic dysfunction was identified by a greater than 1.5fold increase above of the top reference range

Vitamins, intravenous solutions, and drugs and formulations used in nutrition

of alkaline phosphatase (40–450 U/l) and gamma-glutamyltranspeptidase (11–49 U/l) associated with increased aminotransferases (5–32 U/l) and a total bilirubin over 20 mmol/l [68C]. The incidence of hepatic dysfunction was 4.9% (n ¼ 49). The susceptibility factors were the critical patient condition, the duration of parenteral nutrition, and a total calorie contribution over 25 kcal/kg, specifically carbohydrates in excess of 3 g/kg, lipids 0.8 g/kg, and nitrogen 0.16 g/kg. Currently approved parenteral lipid emulsions generally contain safflower or soybean oils, which are both rich in omega-6 polyunsaturated fatty acids, which may contribute to liver damage [69R]. Fish oil-based lipid emulsions, which are primarily composed of omega-3 polyunsaturated fatty acids, have been used to reduce hepatotoxicity (see also biliary tract below). Biliary tract In a study of 66 infants with cholestasis associated with parenteral nutrition, there were 10 deaths and one referral for liver transplant in the first year of life, all of whom had at least one positive blood culture after the onset of cholestasis [70c]. Maximum conjugated bilirubin in these 11 infants was 270 mmol/l, compared with 145 mmol/l in babies who recovered. A maximum conjugated bilirubin concentration over 170 mmol/l was a susceptibility factor for death or transplantation. In a 2-year retrospective study of liver damage and cholestasis in premature babies with cholestasis associated with parenteral nutrition, 17 received ursodeoxycholic acid and 7 did not [71c]. In the treated group there were significant reductions in gamma-glutamyltranspeptidase activity and conjugated bilirubin after 4–5 weeks of treatment. There was a significant correlation between conjugated bilirubin and duration of total parenteral nutrition. The susceptibility factors for cholestasis associated with parenteral nutrition have been studied in 62 premature infants in a neonatal intensive care unit, of whom 11 (18%) developed cholestasis [72c]. There were significant differences in terms of

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gestational age, weight at birth, duration of parenteral nutrition, septic episodes, and average energy intake during the second and third weeks of life between those with and without cholestasis; the duration of parenteral nutrition was most significant factor. A fish oil-based intravenous lipid emulsion in the treatment of liver disease associated with parenteral nutrition has been compared with soybean oil in an open study in 42 infants with short-bowel syndrome who developed cholestasis [73c]. There were three deaths and one liver transplantation in those who received the fish oil, compared with 12 deaths and 6 transplants in those who received soybean oil. The fish oil was not associated with hypertriglyceridemia, coagulopathy, or deficiency of essential fatty acids. In another study a lipid emulsion based on soybean oil, medium-chain triglycerides, and olive and fish oil was compared with one based on olive and soybean oil in a double-blind, randomized trial in 44 postoperative patients [74C]. On days 2 and 5, there were significantly lower aminotransferase and alpha-glutathione S-transferase activities with the former. Musculoskeletal When 45 patients using parenteral nutrition at home were asked about adverse reactions to their treatment they reported that muscle cramps were the most common minor adverse reaction (12/ 45; 27%); the frequency in patients with inflammatory bowel disease was 24% [75c]. The cramps were of sufficient severity to warrant pharmacological intervention in nine patients. Skin A rash with subsequent urticaria in an infant receiving parenteral nutrition, confirmed by positive rechallenge, resolved after the amino acid solution was replaced with a non-bisulfite-containing product [76A]. The authors speculated that the bisulfite additive in the amino acid solution may have interacted with the lipid emulsion to sensitize the patient. Infection risk In a study of biofilms and micro-organisms adhering to 39 central

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venous catheters used for parenteral nutrition in patients with and without clinical signs of infection, those with signs of infection had more positive cultures [77c]. However, scanning electron microscopy showed that there were biofilms in all catheters used, and 55% of them showed structures that suggested central venous catheters colonization by micro-organisms. About 53% of the catheter infections evolved to systemic infections, confirmed by blood cultures. The epidemiology of catheter-related bloodstream infections during parenteral nutrition has been reviewed [78R]. They occur in 1.3–26% of patients with central venous catheters used to administer. Contamination during preparation and handling is rare in hospitals and home-infusion pharmacies but may be difficult to control in the home. The risk of infection is increased in hospitalized patients because of immunosuppression associated with malnutrition, hyperglycemia exacerbated by dextrose infusion, microbial colonization/ contamination of catheter hubs and the skin surrounding insertion site, and poor nursing care. During long-term catheter use, an intraluminal biofilm, catheter-tip fibrin sheath or tail, or central venous thrombosis creates sites for microbial seeding and infection. In hospital the most common infective organisms are coagulase-negative staphylococci, Staphylococcus aureus, Enterococcus, Candida spp., Klebsiella pneumoniae, and Pseudomonas aeruginosa. In patients receiving long-term parenteral nutrition, about 60% of catheter-related bloodstream infections are caused by coagulase-negative staphylococci. Parenteral nutrition was a susceptibility factor for central venous catheter-related bloodstream infections in 109 patients who received chemotherapy after surgery for colorectal cancer for a total of 5558 catheter-days in a retrospective database evaluation (OR ¼ 13; 95% CI ¼ 2.5, 62). Similarly, early administration of parenteral nutrition after severe injury was associated with an increased risk of nosocomial infections in a retrospective cohort study of 567 patients, of whom 95

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(17%) received early parenteral nutrition (RR ¼ 2.1; 95% CI ¼ 1.6, 2.6); mortality tended to be higher in patients who received additional enteral nutrition and parenteral nutrition versus enteral nutrition alone (RR ¼ 2.3; 95% CI ¼ 1.0, 5.2) [79c]. Catheter-related sepsis is the most frequent complication in patients receiving home parenteral nutrition for short bowel syndrome. A low-grade systemic inflammatory state and an altered mucosal immune response, as well as diminished intestinal barrier function have been characterized in these patients. The possibility of systemic immunocompromise has only recently been suggested. Catheter-related sepsis in patients on parenteral nutrition is usually caused by Gram-positive or Gram-negative bacteria or by Candida species. However, other organisms can be involved in patients who are immunocompromised [80A]. • A 45-year-old woman with short-bowel syndrome, asplenia, and insulin-dependent diabetes mellitus developed catheter-related sepsis with a large skin ulcer on the left calf. A chest X-ray and a CT scan showed multiple subpleural pulmonary infiltrates consistent with bacterial or fungal dissemination. Blood cultures from the catheter port and the peripheral blood grew Staphylococcus haemolyticus and Fusarium oxysporum. The catheter was removed, and she was given flucloxacillin and voriconazole. The sepsis resolved slowly.

ENTERAL NUTRITION [SED-15, 1221; SEDA-30, 396] Metabolism Refeeding syndrome is normally associated with large calorie loads delivered by parenteral or enteral feeding. Acute respiratory failure has been attributed to refeeding syndrome induced by hypocaloric enteral tube feeding [81c]. • A 60-year-old man with esophageal carcinoma and local metastases was fed via a jejunal tube at a rate of 4.4 kcal/kg/day, increased over 2 days to 27 kcal/kg/day. By day 4 his serum

Vitamins, intravenous solutions, and drugs and formulations used in nutrition potassium, magnesium, and phosphate had fallen to below normal, the last being particularly low. He developed abdominal pain and acute respiratory failure. Intravenous therapy successfully normalized the serum electrolytes over the next 4 days, and enteral feeding was restarted 36 hours after ITU admission. He was gradually weaned from the ventilator.

Refeeding syndrome is a series of metabolic complications linked to artificial nutritional support in patients who are severely malnourished, with conditions such as kwashiorkor, chronic malnutrition, or anorexia nervosa. This study shows that even hypocaloric feeding should be considered a susceptibility factor for the refeeding syndrome. The prevalence of undiagnosed diabetes mellitus in elderly patients received enteral nutrition was 21%; in 79% of them hemoglobin A1c concentrations were over 7%, and in 24% over 8% [82c]. Skin An allergic skin reaction to casein and soy has been described [83A]. • A 13-year-old girl who had had skin lesions on her limbs for 12 years was found to be allergic to the enteral feeding formulation that she had received during that time (Ensure LiquidÒ; Abbott Japan Co, Ltd, Tokyo, Japan), which contains casein and soy. Patch, prick, and scratch patch tests with Ensure LiquidÒ, casein, and soy were all negative, as was a radioallergosorbent test for immunoglobulin E to both casein and soy. However, a druginduced lymphocyte stimulating test was strongly positive with Ensure Liquid (stimulating index of 316%), casein (471%), and soy (378%). In addition, challenge tests by oral provocation with all three items were positive. The skin lesions disappeared without any other treatment after changing from Ensure LiquidÒ to another enteral nutrition formulation containing neither casein nor soy.

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Infection risk Patients with severe acute pancreatitis are always at a high risk of infectious complications, which contributes to a high mortality rate. Loss of gut barrier function appears to lead to local and systemic infectious complications. Enteral nutrition, rather than parenteral nutrition, has been used in attempts to reduce loss of gut barrier function, although the evidence has so far failed to provide convincing support for this approach. In order to address this, a meta-analysis of five randomized controlled comparisons of enteral and parenteral nutrition has been undertaken [84M]. Enteral feeding (by nasogastric or nasojejunal delivery) reduced the risk of infectious complications (RR ¼ 0.47; 95% CI ¼ 0.28, 0.77), pancreatic infections (RR ¼ 0.48; CI ¼ 0.26, 0.91), and mortality (RR ¼ 0.32; CI ¼ 0.11, 0.98). The risk reduction for organ failure was not statistically significant (RR ¼ 0.67; CI ¼ 0.30, 1.52). The authors concluded that enteral nutrition results in a clinically important and statistically significant risk reduction in the risk of infectious complications, pancreatic infections, and mortality in patients with predicted severe acute pancreatitis, when compared with parenteral nutrition. Drug–food interactions In a survey of the use of medications in patients receiving enteral nutrition, 46 medications commonly given to hospitalized patients were evaluated [85M]. Of these, 24 had recommendations based on available data and the remaining 22 had recommendations based on a consensus of clinicians. The authors concluded that there was a dearth of published data on drug–nutrient interactions for most of the drugs that are commonly given to patients receiving enteral nutrition.

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food fortification efforts? Nutr Rev 2008; 66(9): 517–25. [2] Beaton GH, Martorell R, Aronson KJ, Edmonston B, Ross AC, Harvey B,

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[11] Bhaskaram P, Jyothi SA, Rao KV, Rao BSN. Effects of subclinical vitamin A deficiency and administration of vitamin A as a single large dose on immune function in children. Nutr Res 1989; 9(9): 1017–25. [12] Bhaskaram MDP, Arun Jyothia S, Visweswara Raoa DK, Newton S, OwusuAgyei S, Ampofo W, Zandoh C, Adjuik M, Adjei G, Tchum S, Filteau S, Kirkwood BR. Vitamin A supplementation enhances infants’ immune responses to hepatitis B vaccine but does not affect responses to Haemophilus influenzae type b vaccine. J Nutr 2007; 137(5): 1272–7. [13] Newton S, Cousens S, Owusu-Agyei S, Filteau S, Stanley C, Linsell L, Kirkwood B. Vitamin A supplementation does not affect infants’ immune responses to polio and tetanus vaccines. J Nutr 2005; 135(11): 2669–73. [14] WHO/CHD Immunization Linked Vitamin A Supplementation Study Group. Randomized trial to assess benefits and safety of vitamin A linked to immunization in early infancy. Lancet 1998; 352(9136): 1257–63. [15] De Francisco A, Chakraborty J, Chowdhury HR, Yunus M, Baqui AH, Siddique AK, Sack RB. Acute toxicity of vitamin A given with vaccines in infancy. Lancet 1993; 342(8870): 526–7. [16] Baqui AH, De Francisco A, Arifeen SE, Siddique AK, Sack RB. Bulging fontanelle after supplementation with 25,000 IU of vitamin A in infancy using immunisation contacts. Acta Paediatr 1995; 84(8): 863–6. [17] Semba RD. The role of vitamin A and related retinoids in immune function. Nutr Rev 1998; 56(1 Pt 2): S38–48. [18] Benn CS, Martins C, Rodrigues A, Ravn H, Fisker AB, Christoffersen D, Aaby P. The effect of vitamin A supplementation administered with missing vaccines during national immunization days in Guinea–Bissau. Int J Epidemiol 2009; 38(1): 304–11. [19] Nante JE, Diness BR, Ravn H, Roth A, Aaby P, Benn CS. No adverse events after simultaneous administration of 50 000 IU vitamin A and Bacille Calmette–Guerin vaccination to normal-birth-weight newborns in Guinea–Bissau. Eur J Clin Nutr 2008; 62(7): 842–8.

Vitamins, intravenous solutions, and drugs and formulations used in nutrition [20] Newton S, Owusu-Agyei S, Filteau S, Gyan T, Kirkwood BR. Vitamin A supplements are well tolerated with the pentavalent vaccine. Vaccine 2008; 26(51): 6608–13. [21] Gogia S, Sachdev HS. Neonatal vitamin A supplementation for prevention of mortality and morbidity in infancy: systematic review of randomised controlled trials. BMJ 2009; 338: b919. [22] Kikuchi K, Suetake T, Kumasaka N, Tagami H. Improvement of photoaged facial skin in middle-aged Japanese females by topical retinol (vitamin A alcohol): a vehicle-controlled, double-blind study. J Dermatolog Treat 2009; 20(5): 276–81. [23] Caire-Juvera G, Ritenbaugh C, WactawskiWende J, Snetselaar LG, Chen Z. Vitamin A and retinol intakes and the risk of fractures among participants of the Women's Health Initiative Observational Study. Am J Clin Nutr 2009; 89(1): 323–30. [24] Leithead JA, Simpson KJ, MacGilchrist AJ. Fulminant hepatic failure following overdose of the vitamin A metabolite acitretin. Eur J Gastroenterol Hepatol 2009; 21(2): 230–2. [25] Kapil U. Time to stop giving indiscriminate massive doses of synthetic vitamin A to Indian children. Public Health Nutr 2009; 12(2): 285–6. [26] Uhl W, Nolting A, Gallemann D, Hecht S, Kovar A. Changes in blood pressure after administration of hydroxocobalamin: relationship to changes in plasma cobalamins(III) concentrations in healthy volunteers. Clin Toxicol (Phila) 2008; 46(6): 551–9. [27] Ozdemir O, Baytan B, Gunes AM, Okan M. Involuntary movements during vitamin B12 treatment. J Child Neurol 2010; 25(2): 227–30. [28] Hollingsworth JW, Maruoka S, Boon K, Garantziotis S, Li Z, Tomfohr J, Bailey N, Potts EN, Whitehead G, Brass DM, Schwartz DA. In utero supplementation with methyl donors enhances allergic airway disease in mice. J Clin Invest 2008; 118(10): 3462–9. [29] Håberg SE, London SJ, Stigum H, Nafstad P, Nystad W. Folic acid supplements in pregnancy and early childhood respiratory health. Arch Dis Child 2009; 94(3): 180–4.

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[30] Ownby DR. Has mandatory folic acid supplementation of foods increased the risk of asthma and allergic disease? J Allergy Clin Immunol 2009; 123(6): 1260–1. [31] Whitrow MJ, Moore VM, Rumbold AR, Davies MJ. Effect of supplemental folic acid in pregnancy on childhood asthma: a prospective birth cohort study. Am J Epidemiol 2009; 170(12): 1486–93. [32] Matsui EC, Matusi W. Higher serum folate levels are associated with a lower risk of atopy and wheeze. J Allergy Clin Immunol 2009; 123(6): 1253–9. [33] Nishitani N, Adachi A, Fukumoto T, Ueno M, Fujiwara N, Ogura K, Horikawa T. Folic acid-induced anaphylaxis showing cross-reactivity with methotrexate: a case report and review of the literature. Int J Dermatol 2009; 48(5): 522–4. [34] Lee P, Treacy EP, Crombez E, Wasserstein M, Waber L, Wolff J, Wendel U, Dorenbaum A, Bebchuk J, Christ-Schmidt H, Seashore M, Giovannini M, Burton BK, Morris AA. Sapropterin Research Group. Safety and efficacy of 22 weeks of treatment with sapropterin dihydrochloride in patients with phenylketonuria. Am J Med Genet A 2008; 146A(22): 2851–9. [35] Rahimi R, Nikfar S, Rezaie A, Abdollahi M. A meta-analysis on the efficacy and safety of combined vitamin C and E supplementation in preeclamptic women. Hypertens Pregnancy 2009; 28(4): 417–34. [36] Rautiainen S, Lindblad BE, Morgenstern R, Wolk A. Vitamin C supplements and the risk of age-related cataract: a population-based prospective cohort study in women. Am J Clin Nutr 2010; 91(2): 487–93. [37] McHugh GJ, Graber ML, Freebairn RC. Fatal vitamin C-associated acute renal failure. Anaesth Intensive Care 2008; 36(4): 585–8. [38] Hemilä H, Kaprio J. Vitamin E supplementation may transiently increase tuberculosis risk in males who smoke heavily and have high dietary vitamin C intake. Br J Nutr 2008; 100(4): 896–902. [39] Hernández-Garduño E. Vitamin E supplementation may transiently increase

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tuberculosis risk in males who smoke heavily and have high dietary vitamin C intake—comments by Hernández-Garduño. Br J Nutr 2009; 101(1): 145. Hemilä H, Kaprio J. Vitamin E supplementation and pneumonia risk in males who initiated smoking at an early age: effect modification by body weight and dietary vitamin C. Nutr J 2008; 7: 33. O'Donnell S, Moher D, Thomas K, Hanley DA, Cranney A. Systematic review of the benefits and harms of calcitriol and alfacalcidol for fractures and falls. J Bone Miner Metab 2008; 26(6): 531–42. Bischoff-Ferrari HA, Shao A, DawsonHughes B, Hathcock J, Giovannucci E, Willett WC. Benefit-risk assessment of vitamin D supplementation. Osteoporos Int 2010; 21(7): 1121–32. Hanada S, Iwamoto M, Kobayashi N, Ando R, Sasaki S. Calcium-alkali syndrome due to vitamin D administration and magnesium oxide administration. Am J Kidney Dis 2009; 53(4): 711–4. Giannikopoulos G, Zorzou MP, Stamoulis I, Panagi G, Sitaras P, Georgopoulos I, Hadjileontis C, Malakos I, Kyriazis J. Cinacalcet-induced leukocytoclastic vasculitis. Am J Kidney Dis 2009; 54(2): e5–8. Bell SJ, Grochoski GT. How safe is vitamin E supplementation? Crit Rev Food Sci Nutr 2008; 48(8): 760–74. Lonn E, Bosch J, Yusuf S, Sheridan P, Pogue J, Arnold JM, Ross C, Arnold A, Sleight P, Probstfield J, Dagenais GR. HOPE and HOPE-TOO Trial Investigators. Effects of long-term vitamin E supplementation on cardiovascular events and cancer. JAMA 2005; 293(11): 1338–47. Dietrich M, Jacques PF, Pencina MJ, Lanier K, Keyes MJ, Kaur G, Wolf PA, D'Agostino RB, Vasan RS. Vitamin E supplement use and the incidence of cardiovascular disease and all-cause mortality in the Framingham Heart Study: does the underlying health status play a role? Atherosclerosis 2009; 205(2): 549–53. Berry D, Wathen JK, Newell M. Bayesian model averaging in meta-analysis: vitamin E supplementation and mortality. Clin Trials 2009; 6(1): 28–41.

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[49] Greenland S. Weaknesses of Bayesian model averaging for meta-analysis in the study of vitamin E and mortality. Clin Trials 2009; 6(1): 42–6. [50] Gerss J, Köpcke W. The questionable association of vitamin E supplementation and mortality—inconsistent results of different metaanalytic approaches. Cell Mol Biol (Noisy-leGrand) 2009; 55(Suppl): OL1111–20. [51] Smedts HP, de Vries JH, Rakhshandehroo M, Wildhagen MF, Verkleij-Hagoort AC, Steegers EA, SteegersTheunissen RP. High maternal vitamin E intake by diet or supplements is associated with congenital heart defects in the offspring. BJOG 2009; 116(3): 416–23. [52] Traber MG. Vitamin E and K interactions—a 50-year-old problem. Nutr Rev 2008; 66(11): 624–9. [53] Leung VW, Shalansky SJ, Lo MK, Jadusingh EA. Prevalence of use and the risk of adverse effects associated with complementary and alternative medicine in a cohort of patients receiving warfarin. Ann Pharmacother 2009; 43(5): 875–81. [54] Pifarré P, Roca I, Irastorza I, Simó M, Hill S, Biassoni L, Gordon I. Lung ventilation–perfusion scintigraphy in children on long-term parenteral nutrition. Eur J Nucl Med Mol Imaging 2009; 36(6): 1005–8. [55] Been JV, Degraeuwe PL. Pleural effusion due to intra-abdominal extravasation of parenteral nutrition. Pediatr Pulmonol 2008; 43(10): 1033–5. [56] Inaba K, Sakurai Y, Furuta S, Sunagawa R, Isogaki J, Komori Y, Uyama I. Delayed vascular injury and severe respiratory distress as a rare complication of a central venous catheter and total parenteral nutrition. Nutrition 2009; 25(4): 479–81. [57] Plurad D, Green D, Inaba K, Belzberg H, Demetriades D, Rhee P. A 6-year review of total parenteral nutrition use and association with late-onset acute respiratory distress syndrome among ventilated trauma victims. Injury 2009; 40(5): 511–5. [58] Khashu M, Harrison A, Lalari V, Lavoie JC, Chessex P. Impact of shielding parenteral nutrition from light on routine monitoring of blood glucose and triglyceride levels in preterm neonates. Arch Dis Child Fetal Neonatal Ed 2009; 94(2): F111–5.

Vitamins, intravenous solutions, and drugs and formulations used in nutrition [59] Suresh D, Athanassaki I, Jeha GS, Heptulla RA. Total parenteral nutrition associated with severe insulin resistance following hematopoietic stem cell transplantation in patients with hemophagocytic syndrome: report on two cases. Pediatr Diabetes 2010; 11(1): 70–3. [60] Pasquel FJ, Spiegelman R, McCauley M, Smiley D, Umpierrez D, Johnson R, Rhee M, Gatcliffe C, Lin E, Umpierrez E, Peng L, Umpierrez GE. Hyperglycemia during total parenteral nutrition: an important marker of poor outcome and mortality in hospitalized patients. Diabetes Care 2010; 33(4): 739–41. [61] Kuhara T, Ohse M, Inoue Y, Shinka T, Okano Y, Shintaku H, Hongou K, Miyawaki T, Morinobu W, Tamai H, Omura K. Urinary metabolic profile of phenylketonuria in patients receiving total parenteral nutrition and medication. Rapid Commun Mass Spectrom 2009; 23(19): 3167–72. [62] Marvin VA, Brown D, Portlock J, Livingstone C. Factors contributing to the development of hypophosphataemia when refeeding using parenteral nutrition. Pharm World Sci 2008; 30(4): 329–35. [63] Brown RO, Morgan LM, Bhattacharya SK, Johnson PL, Minard G, Dickerson RN. Potential aluminum exposure from parenteral nutrition in patients with acute kidney injury. Ann Pharmacother 2008; 42(10): 1410–5. [64] Fewtrell MS, Bishop NJ, Edmonds CJ, Isaacs EB, Lucas A. Aluminum exposure from parenteral nutrition in preterm infants: bone health at 15-year follow-up. Pediatrics 2009; 124(5): 1372–9. [65] Piper SN, Röhm KD, Boldt J, Odermatt B, Maleck WH, Suttner SW. Hepatocellular integrity in patients requiring parenteral nutrition: comparison of structured MCT/ LCT vs. a standard MCT/LCT emulsion and a LCT emulsion. Eur J Anaesthesiol 2008; 25(7): 557–65. [66] Llop JM, Virgili N, Moreno-Villares JM, García-Peris P, Serrano T, Forga M, Solanich J, Pita AM. Phytosterolemia in parenteral nutrition patients: implications for liver disease development. Nutrition 2008; 24(11–12): 1145–52.

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[67] Santra S, McKiernan P, Lander A, Dalzell AM, Baillie C, Beath S, Gupte GL. Ischemic hepatitis is a risk factor for progression of liver disease associated with parenteral nutrition in intestinal failure. J Pediatr Gastroenterol Nutr 2008; 47(3): 367–9. [68] Servia L, Schoenenberger JA, Trujillano J, Badia M, Rodríguez-Pozo A. Factores de riesgo de la disfunción hepática asociada a la nutrición parenteral. [Risk factors of the hepatic dysfunction associated with parenteral nutrition.] Med Clin (Barc) 2009; 132 (4): 123–7. [69] de Meijer VE, Gura KM, Le HD, Meisel JA, Puder M. Fish oil-based lipid emulsions prevent and reverse parenteral nutrition-associated liver disease: the Boston experience. JPEN J Parenter Enteral Nutr 2009; 33(5): 541–7. [70] Willis TC, Carter BA, Rogers SP, Hawthorne KM, Hicks PD, Abrams SA. High rates of mortality and morbidity occur in infants with parenteral nutrition-associated cholestasis. JPEN J Parenter Enteral Nutr 2010; 34(1): 32–7. [71] Garzón L, Ledo A, Cubells E, Sáenz P, Vento M. Cholestasis associated with prolonged parenteral nutrition in neonates: the role of urso-deoxycholic acid. An Pediatr (Barc) 2009; 70(6): 547–52. [72] Hsieh MH, Pai W, Tseng HI, Yang SN, Lu CC, Chen HL. Parenteral nutritionassociated cholestasis in premature babies: risk factors and predictors. Pediatr Neonatol 2009; 50(5): 202–7. [73] Puder M, Valim C, Meisel JA, Le HD, de Meijer VE, Robinson EM, Zhou J, Duggan C, Gura KM. Parenteral fish oil improves outcomes in patients with parenteral nutrition-associated liver injury. Ann Surg 2009; 250(3): 395–402. [74] Piper SN, Schade I, Beschmann RB, Maleck WH, Boldt J, Röhm KD. Hepatocellular integrity after parenteral nutrition: comparison of a fish-oil-containing lipid emulsion with an olive-soybean oil-based lipid emulsion. Eur J Anaesthesiol 2009; 26(12): 1076–82. [75] Elphick DA, Baker M, Baxter JP, Nightingale JM, Bowling T, Page KB, McAlindon ME. Muscle cramps are the

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commonest side effect of home parenteral nutrition. Clin Nutr 2009; 28(3): 351–4. Huston RK, Baxter LM, Larrabee PB. Neonatal parenteral nutrition hypersensitivity: a case report implicating bisulfite sensitivity in a newborn infant. JPEN J Parenter Enteral Nutr 2009; 33(6): 691–3. Machado JD, Suen VM, Figueiredo JF, Marchini JS. Biofilms, infection, and parenteral nutrition therapy. JPEN J Parenter Enteral Nutr 2009; 33(4): 397–403. Opilla M. Epidemiology of bloodstream infection associated with parenteral nutrition. Am J Infect Control 2008; 36(10): S173. e5–8. Sena MJ, Utter GH, Cuschieri J, Maier RV, Tompkins RG, Harbrecht BG, Moore EE, O'Keefe GE. Early supplemental parenteral nutrition is associated with increased infectious complications in critically ill trauma patients. J Am Coll Surg 2008; 207 (4): 459–67. Müller C, Schumacher U, Gregor M, Lamprecht G. How immunocompromised are short bowel patients receiving home parenteral nutrition? Apropos a case of disseminated Fusarium oxysporum sepsis.

[81]

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JPEN J Parenter Enteral Nutr 2009; 33(6): 717–20. Patel U, Sriram K. Acute respiratory failure due to refeeding syndrome and hypophosphatemia induced by hypocaloric enteral nutrition. Nutrition 2009; 25: 364–7. Arinzon Z, Shabat S, Shuval I, Peisakh A, Berner Y. Prevalence of diabetes mellitus in elderly patients received enteral nutrition long-term care service. Arch Gerontol Geriatr 2008; 47(3): 383–93. Watanabe T, Yoshida Y, Yamamoto O. Enteral nutrition induced systemic allergic dermatitis. Contact Dermatitis 2008; 59(6): 374–5. Petrov MS, Van Santvoort HC, Besselink MGH, Van Der Heijden GJMG, Windsor JA, Gooszen HG. Enteral nutrition and the risk of mortality and infectious complications in patients with severe acute pancreatitis: a meta-analysis of randomized trials. Arch Surg 2008; 143: 1111–7. Wohlt PD, Zheng L, Gunderson S, Balzar SA, Johnson BD, Fish JT. Recommendations for the use of medications with continuous enteral nutrition. Am J Health Syst Pharm 2009; 66(16): 1458–67.

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35

Drugs that affect blood coagulation, fibrinolysis, and hemostasis

Editor’s note: The clotting factors and anticoagulant proteins are included in Chapter 33.

COUMARIN ANTICOAGULANTS

[SED-15, 983; SEDA-30, 399; SEDA-31, 553; SEDA-32, 617] Cardiovascular The incidence of mitral and aortic valve calcification has been studied in 1155 patients with atrial fibrillation, of whom 725 were taking warfarin [1c]. There was a significant association between the use of warfarin and the risk of calcification (unadjusted OR ¼ 1.71; 95% CI ¼ 1.34, 2.18), and the association remained after adjustment for confounding factors. In contrast, in a cross-sectional analysis of the extent of coronary artery calcification in 70 patients without coronary heart disease, currently taking or referred for warfarin therapy, univariate analysis showed a non-significant trend to increased coronary artery calcification with increasing warfarin Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00035-0 # 2011 Elsevier B.V. All rights reserved.

exposure, but bivariate analysis showed no correlation between warfarin duration and coronary artery calcification [2c]. Calciphylaxis, a rare, usually fatal disorder characterized by cutaneous ischemia and necrosis due to calcification of arterioles, has been described in a 63-year-old Polynesian woman who was taking warfarin [3A]. Enoxaparin was used instead and after 40 sessions of hyperbaric oxygen therapy her leg ulcers resolved. The authors attributed the calciphylaxis in this case to warfarin. Respiratory Respiratory complications can occur due to bleeding in patients taking warfarin. An 84-year-old woman developed hemoptysis due to diffuse alveolar hemorrhage when her INR rose to 6 during treatment with phenprocoumon [4A] and an 83-year-old woman with an INR of 10 developed upper airway obstruction due to hemorrhage in the epiglottis and arytenoid cartilages [5A]. Nervous system The association between cerebral microbleeds and the risk of recurrent hemorrhagic stroke in patients who have taken warfarin after cerebral embolic strokes associated with atrial fibrillation has been studied in 87 patients [6c]. Microbleeds were more common in patients with intracerebral hemorrhage than in those with cerebral infarction (87% versus 39%) and there were more of them per patient (8.4 versus 2.1). The mean INR was higher in patients with intracerebral hemorrhage (2.2 versus 1.4), as was the frequency of 707

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hypertension (87% versus 46%). Multivariate analysis showed that the presence of cerebral microbleeds (OR ¼ 7.38; 95% CI ¼ 1.05, 52) was associated with intracerebral hemorrhage independent of an increased INR and hypertension. Similarly, among 24 patients more of those with intracerebral hemorrhage had microbleeds than the controls (79% versus 23%) and there were more microbleeds in each patient (9.0 versus 0.5) [7c]. The number of microbleeds correlated significantly with the presence of warfarin-related intracerebral hemorrhage. Conditional logistic regression analysis showed that increased prothrombin time and the presence of microbleeds were independently related to the incidence of warfarin-related intracerebral hemorrhage. In contrast, in 141 patients with ischemic strokes taking warfarin therapy and 105 controls, there were cerebral microbleeds in 31 patients (22%) and 17 controls (16%), a non-significant difference [8c]. Sensory systems Eyes A spontaneous hyphema has been attributed to over-anticoagulation with warfarin [9A]. The risk of subconjunctival hemorrhages in patients taking warfarin has been assessed in a retrospective chart review of 4334 patient visits over 2 years; there were 15 events, giving an event rate of 0.35% [10c]. Nutrition The effect of warfarin therapy for 6 months on folate status has been studied in 114 patients, using measurements of erythrocyte folate and 5-methyltetrahydrofolate and plasma folate, total homocysteine, phylloquinone, vitamin B12, and methylmalonic acid [11c]. There were significant falls in total erythrocyte folate and 5-methyltetrahydrofolate and a concurrent increase in plasma phylloquinone, attributed to altered vitamin K metabolism. Hematologic Rebound coagulation after warfarin withdrawal is supposed not to be a major risk, since the action of warfarin is only slowly reversible. However, rapid occurrence of an intraluminal thrombus

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and secondary myocardial ischemia has been described after a brief period of withdrawal of warfarin in a 15-year-old with a Kawasaki-related chronic giant coronary aneurysm [12A]. In another case splenic infarction occurred after withdrawal of warfarin for atrial fibrillation [13A]. Liver In 30 patients with suspected phenprocoumon-induced liver disease peripheral blood mononuclear cells were subjected to an in vitro lymphocyte transformation test for reactivity with phenprocoumon; 15 had sensitized lymphocytes [14c]. One of 20 controls, who either had not taken phenprocoumon or had taken it without adverse reactions, had sensitized lymphocytes. The authors suggested that immune mechanisms may play a part in phenprocoumon-induced liver disease. Urinary tract The pathological findings in kidney biopsy specimens from nine patients with warfarin overdose (mean INR 4.4), hematuria, and acute kidney damage have been reported [15c]. In each case there was evidence of acute tubular damage, glomerular hemorrhage, and chronic kidney damage. Skin Skin necrosis due to warfarin has been reviewed, emphasizing the occasional difficulty that can arise in diagnosis; skin biopsy typically shows diffuse dermal microthrombi with endothelial cell damage and red cell extravasation, with progression to full-thickness coagulative necrosis [16AR]. Two patients, a 60-year-old man and a 51-year-old woman, developed dark purple lesions on the arms and legs distal to the elbows and knees after taking warfarin for a few days; the authors hypothesized that these lesions were precursors of skin necrosis [17A]. However, it has also been suggested that purple toes in patients taking warfarin are due to microembolism of cholesterol crystals in small blood vessels [18A]. Musculoskeletal In a case–control survey of bone density in 70 patients taking warfarin, there was a marked reduction in bone

Drugs that affect blood coagulation, fibrinolysis, and hemostasis

mineral density in the lumbar spine compared with 103 randomly selected matched controls; duration of warfarin use was the only susceptibility factor of significant importance [19c]. Death In a retrospective review of 27 812 patients admitted to trauma centers, 2791 were aged 65 or over and had fallen from a standing position; the use of warfarin (mean INR 2.8) increased the risk of death after such falls (OR ¼ 1.54; 95% CI ¼ 1.09, 2.19), the deaths being attributed to head injuries [20c]. Teratogenicity A 35-year-old woman took warfarin 9 mg/day for 17 weeks before realizing that she was pregnant, when she stopped taking it; she gave birth at full term to a girl with bilateral corneal opacities and microphthalmia, which the authors thought was most probably due to warfarin, even though the child had no other features of warfarin embryopathy, such as optic atrophy, cataracts, large prominent eyes, small eyelids, hypertelorism, small orbital arches, palpebral ptosis, mesodermal dysgenesis, antimongoloid slants, Peter’s anomaly, optic nerve dysfunction, and goniodysgenesis [21A]. Fetotoxicity Although warfarin can be used for anticoagulation during the second and early third trimesters of pregnancy, it can occasionally cause fetal hemorrhage, as has again been reported [22A, 23A]. Susceptibility factors Genetic In a systematic review of randomized trials of genotype-guided dosing of warfarin in reducing the occurrence of serious bleeding events and over-anticoagulation, three studies (423 patients) met the inclusion and exclusion criteria [24M]. Summary estimates showed no statistically significant difference in bleeding rates or time within the INR target range. The highest quality study showed no significant difference in primary or secondary outcomes, although there was a trend towards more rapid achievement of a stable dose (14 versus 20 days) in the pharmacogenetic arm.

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Decision-tree modeling to simulate the effects of genotype-guided dosing according to CYP2C9 and VKORC1 genotyping has shown that it is not a cost-effective strategy, with mean ICERs of US$347 059 per QALY gained, $170 192 per adverse event averted, and $1 106 250 per life saved [25M]. Monte Carlo simulations showed that 62% of the time the ICER per QALY gained was over $50 000. The authors concluded that the cost-effectiveness of genotype-guided dosing could be improved by reducing the cost of genotyping, improving effectiveness of the genotype-guided dosing algorithm in controlling the INR, and using the algorithm in places where high out-of-range INRs are common. A Markov model has been used to evaluate whether and under what circumstances genotype-guided warfarin dosing could be cost-effective for patients with atrial fibrillation [26H]. The cost-effectiveness depended greatly on the assumed effectiveness of genotyping in increasing the amount of time patients spend in the INR target range. The ICER would be over $100 000 per QALY if genotyping increased the time spent by less than 5% and below $50 000 per QALY if the time increased by 9%. The authors concluded that, given current uncertainty surrounding genotyping efficacy, caution should be taken in advocating the widespread adoption of this strategy. In a non-randomized study the addition of CYP2C9 pharmacogenetic testing improved the time spent in the target range by 7% overall (4% supratherapeutic and 3% subtherapeutic); the hazard ratio for adverse reactions was reduced (HR ¼ 0.54; 95% CI ¼ 0.29, 0.97); VKORC1 contributed to only 1% of the variability [27c]. Not surprisingly, the algorithm that best predicted the therapeutic dosage requirements included the first three doses and the INR on day 4. Use of statins, smoking, and a history of liver disease were not significant predictors. In a systematic review of 39 studies in 7907 patients, compared with the CYP2C9*1/*1 genotype, the CYP2C9*1/*2,

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CYP2C9*1/*3, CYP2C9*2/*2, CYP2C9*2/ *3, and CYP2C9*3/*3 genotypes required warfarin doses that were respectively 20%, 34%, 36%, 57%, and 78% lower; the effect of CYP2C9 genotype tended to be larger in patients without interacting drugs [28M]. A new CYP2C9 polymorphism, G1078A coding for a D360N in the cDNA coding region of exon 7, one codon downstream from the I359L coding change seen in CYP2C9*3, has been associated with gastrointestinal bleeding in a 63-year-old African–American man [29A]. Deficiencies of anticoagulant proteins can increase the risk of skin necrosis due to warfarin. In a 19-year-old man with protein C deficiency, recurrent (stuttering) priapism attributed to warfarin was complicated by skin necrosis, presumably because of paradoxical hypercoagulability [30A]. Activated protein C concentrate can be used to treat such cases [31A]. In another case, skin necrosis occurred on the pinna of an 82-year-old man with protein S deficiency after warfarin therapy for 2 weeks [32A]. Renal disease The effect of renal function on warfarin dosage, anticoagulation control, and the risk of hemorrhagic complications has been evaluated in a secondary analysis of a prospective cohort of 578 patients [33c]. Patients with severe chronic kidney disease (eGFR < 30 ml/minute/ 1.73 m2) required significantly lower warfarin dosages, spent less time with their INR in the target range, and were at a higher risk of over-anticoagulation, compared with patients with no, mild, or moderate disease. In those with severe disease the risk of major hemorrhage was more than double that in those with lesser degrees of renal dysfunction (HR ¼ 2.4; 95% CI ¼ 1.1, 5.3). Drug overdose Two cases of overdose of phenprocoumon have been reported, in a 57-year-old woman and a 76-year-old man, fatal in the former; there were multiple hemorrhages in both cases [34A]. In patients who take a long time to recover from warfarin overdose the use of a long-acting superwarfarin [SED-15, 984]

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may be suspected; however, in the case of an 86-year-old woman who took an overdose of warfarin, slow recovery, despite large repeated doses of vitamin K, was attributed to the fact that her CYP2C9 genotype was CYP2C9*3/*3 [35A]. Drug–drug interactions Ambrisentan In an open crossover study in 22 healthy subjects, ambrisentan 10 mg/day for 8 days had no effects on the pharmacokinetics and pharmacodynamics of the enantiomers of warfarin after a single dose of racemic warfarin 25 mg [36c]. Cannabinoids An interaction of warfarin with marijuana smoking has been reported in a 56-year-old man, in whom the INR rose from 1.8 to 12 and who had a constant nose-bleed and increased bruising [37A]. During the next 9 months, while he did not smoke marijuana, his INR was 1.08–4.40 and there were no bleeding complications. The authors suggested that marijuana may have inhibited the metabolism of warfarin and to a lesser extent displaced it from protein-binding sites. Duloxetine In a steady-state study of oncedaily warfarin and once-daily duloxetine in 60 healthy subjects with a stable INR of 1.5–2.0, duloxetine had no clinically or statistically significant effects on the pharmacodynamics or pharmacokinetics of warfarin [38c]. Fibrates An interaction of gemfibrozil with warfarin has been described in a 62-yearold man, whose INR rose to 5.8 within 3 weeks of the addition of gemfibrozil 600 mg bd. The authors recommended a dosage reduction of 20% and close monitoring during administration of this combination [39Ar]. Fluoroquinolone antibiotics Moxifloxacin 400 mg/day markedly increased the action of warfarin in a 74-year-old patient with a prosthetic mitral valve, whose INR rose to 12 [40A].

Drugs that affect blood coagulation, fibrinolysis, and hemostasis

In a retrospective study of 21 patients taking warfarin there was a significant increase in INR after the addition of levofloxacin [41c]. Gefitinib In a retrospective study of 296 patients taking gefitinib for non-small-cell lung cancer, 12 also took warfarin; there was a raised prothrombin time in six, associated with liver dysfunction [42c]. It is not clear to what extent a direct interaction of gefitinib with warfarin was responsible in these cases, as opposed to liver impairment. Gemcitabine Gemcitabine caused a rise in INR during warfarin therapy in a 70-yearold woman with pancreatic cancer [43A]. Hormonal contraceptives An interaction of warfarin with hormonal contraceptives has been described in a 33-year-old woman [44A]. While taking warfarin 38.5 mg/week she switched from a monophasic combined oral contraceptive (ethinylestradiol þ norethindrone) to an implantable progestogen-only contraceptive (etonogestrel); 19 days later her INR fell to 1.8 and she required an increase in warfarin dose to 60 mg/week. After 10 months she decided to have the implant removed, and 9 days later her INR rose to 6.5. The warfarin dose was reduced to 55.5 mg/week. She then started to use an oral progestogenonly contraceptive (norethindrone) and the effective warfarin dose was 53.5 mg/ week. The authors hypothesized that the predominant mechanism of this interaction was inhibition of CYP1A2 and CYP2C19 by ethinylestradiol. Influenza vaccine Most reports of influenza immunization in patients taking warfarin have shown no significant changes in anticoagulation. A 64-year-old man had gastrointestinal bleeding and a large cerebral hemorrhage while taking warfarin (INR > 15) 4 weeks after influenza immunization, when his INR had previously been 2.0 [45A]. It is likely that something other than the immunization was responsible in this case.

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Laropiprant Multiple-dose laropiprant had no effects on the pharmacokinetics and pharmacodynamics of the enantiomers of warfarin after a single dose of 30 mg in 13 subjects [46c]. Methylsalicylate Topical methylsalicylate 50% has been reported to have enhanced the action of warfarin in a 53-year-old man, resulting in a large right retroperitoneal hematoma and right iliac intramuscular hematoma after trauma [47A]. Nitazoxanide In a phase I, open, randomized, two-way crossover study in 14 healthy men, nitazoxanide administration for 6 days had no effect on the pharmacokinetics or pharmacodynamic actions of a single dose of warfarin 25 mg [48c]. Oxcarbazepine Resistance to warfarin has been described in a 16-year-old boy with the VKORC1 1173CC genotype and CYP2C9 *2 allele [49A]. It is not clear what the mechanism was in this case, nor the relevance of the pharmacogenetic polymorphisms. Paracetamol (acetaminophen) In a study of the interaction of warfarin with paracetamol, using a large post-mortem toxicology database, the contribution of anticoagulant use to death was evaluated from death certificates based on medicolegal autopsies [50c]. In 33% of the 328 warfarin-positive cases, at least one interacting drug was present, and paracetamol was the most frequent, accounting for 49% (n ¼ 53). When paracetamol and warfarin were detected simultaneously, the numbers of fatal bleeds were 4.6 higher than with paracetamol alone and 2.7 times higher than with warfarin alone. An NSAID was used in combination with warfarin in only six cases. The authors concluded that the results supported the clinical evidence that suggests that warfarin–paracetamol interactions may create significant life-threatening conditions. Proton pump inhibitors Proton pump inhibitors increase the INR when they are

712

taken concomitantly with warfarin. Of 240 patients who took warfarin after surgery, 114 also took rabeprazole 10 mg/day and 126 took lansoprazole 15 mg/day; there were delayed cardiac adverse effects in those who took lansoprazole (tamponade in six and hemothorax in one) [51C]. Selective serotonin reuptake inhibitors (SSRIs) In a cohort study, 117 patients taking warfarin for atrial fibrillation and an SSRI were compared with 117 controls matched for age and sex [52C]. Bleeding occurred in 17 exposed patients (23 episodes) and in two unexposed patients (two episodes). The incidences of bleeding episodes per 1000 treatment years were 51 and 24 respectively, and the unadjusted incidence rate ratio was 2.15 (95% CI ¼ 0.88, 5.11). Cox regression analysis including first episodes showed an adjusted hazard ratio of 3.49 (1.37, 8.91) for bleeding during combined treatment with warfarin and an SSRI. Sorafenib A 70-year-old man had a rise in INR during warfarin therapy when sorafenib 200 mg/day was added [53A]. Tamoxifen The literature on the potential interaction of tamoxifen with warfarin, based on the possibility that tamoxifen inhibits CYP2C9, has been reviewed [54M]. Of 31 patients taking warfarin and tamoxifen concomitantly, described in two letters, two case reports, and two retrospective reviews, eight had bleeding complications. The authors concluded that evidence about this supposed interaction is limited. Torsemide The anticoagulant effect of warfarin was potentiated by torsemide in a 43-year-old Hispanic woman; the authors postulated that this was due to inhibition of CYP2C9 and protein binding displacement of warfarin [55A]. Drug–food interactions Cranberry juice Another case of increased anticoagulation in a patient taking warfarin and cranberry juice has been reported, with fatal internal hemorrhage in an elderly man [56A].

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However, despite anecdotal reports, small formal studies have failed to show any interaction of warfarin with cranberry juice. In 30 patients taking warfarin with stable INRs of 1.7–3.3, who were randomized to 240 ml of cranberry juice or a placebo beverage, matched for color and taste, once daily for 2 weeks, cranberry juice had no effect on plasma S- or R-warfarin plasma concentrations, and there were only minimal changes in INR on one day during the study [57C]. However, a study of this size does not rule out an effect in a susceptible subpopulation, and a larger case–control study may be the only way to settle the apparent discrepancy between formal studies and anecdotal reports. Pomegranate juice In mice consumption of pomegranate juice reduced total hepatic content of cytochrome P450 enzymes and reduced the expression of CYP1A2 and CYP3A [58E]. Pomegranate juice also inhibited carbamazepine 10,11-epoxidation by CYP3A in human liver microsomes and inhibited enteric CYP3A in rats [59E]; it also inhibited diclofenac 40 -hydroxylation by CYP2C9 in human liver microsomes [60E]. Now an interaction of pomegranate juice with warfarin has been described in a 64-year-old woman, in whom the INR was in the target range while she was drinking pomegranate juice 2–3 times/week and then became subtherapeutic when she stopped drinking the juice, requiring an increase in the dosage of warfarin [61A]. The presumption was that the pomegranate juice had inhibited the metabolism of warfarin. Enteral feeding Resistance to warfarin in patients receiving enteral feeding has been attributed to vitamin K. However, it has been suggested that other mechanisms may be responsible, since reducing the vitamin K content of enteral feeding solutions has not eradicated the problem [62R]. For example, there is evidence of binding of warfarin in the gut by enteral nutrition solutions. The author recommended that enteral feeding should be withheld for 1 hour before and after warfarin administration and that the feeding rate should be

Drugs that affect blood coagulation, fibrinolysis, and hemostasis

increased slightly, to compensate for the reduced duration of infusion. In contrast, there is also evidence that o-3 polyunsaturated fatty acids in fish oil supplements can impair platelet aggregation and reduce factor VII, increasing anticoagulation [63c]. Drug–device interactions Photodynamic therapy Massive suprachoroidal hemorrhage in a 78-year-old woman after photodynamic therapy may have been made more likely by concurrent warfarin therapy [64A]. Management of adverse drug reactions In 417 patients from 22 centers with a mean initial INR of 7.7, 85% of whom had an INR under 9.0 or were not bleeding and 15% had serious bleeding, treatment did not adhere to guidelines in 170 cases (41%); 15% were undertreated and 48% over-treated [65c]. Lack of adherence was attributed primarily to excessive doses of vitamin K1 (mean initial dose ¼ 6.9 mg) and inappropriate routes of administration (subcutaneous or intramuscular). Factor VII Rapid reversal of warfarin over-anticoagulation can be achieved with factor VII [66A]. Factor IX complex In a retrospective chart review of 28 patients treated with intravenous factor IX complex for warfarininduced coagulopathy, the INR was reduced from 5.1 to 1.9 within a mean of 14 minutes; there were no early thrombotic events or allergic reactions [67c]. Prothrombin complex concentrates In a retrospective chart review of 72 patients who received activated prothrombin complex concentrate factor VIII inhibitor bypassing activity and 69 patients who received fresh-frozen plasma to reverse the effects of warfarin during life-threatening bleeding, the former resulted in lower INR and a shorter time from drug administration to an INR of 1.4 or less [68c]. There were no significant differences in survival or in the length of hospital stay. There were five adverse events that could have been related to the prothrombin

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complex concentrate: a perioperative myocardial infarction, a deep vein thrombosis, chest pain with a raised serum troponin, a raised troponin, and ventricular fibrillation; however, the authors considered that none of the five events was directly related to prothrombin complex concentrate. In contrast, in 40 patients with INRs over 5.0, of whom 29 were bleeding and 11 were at high risk of bleeding, who were treated with a three-factor prothrombin complex concentrate and were compared with 42 historical controls treated with plasma alone, the prothrombin complex concentrate did not satisfactorily reduce the INR, because of a low factor VII content [69c]. Treatment with plasma alone lowered the INR to below 3.0 in 63% of the controls, while low-dose (25 U/kg) and high-dose (50 U/kg) prothrombin complex concentrate alone lowered the INR to below 3.0 in 50% and 43% of patients respectively. Additional transfusion of a small amount of plasma improved these rates to 89% and 88%. Vitamin K In a multicenter, randomized, placebo-controlled trial of low-dose vitamin K 1.25 mg/day in 724 non-bleeding patients with INRs of 4.5–10.0, 56 patients (16%) in the vitamin K group and 60 patients (16%) in the placebo group had at least one bleeding complication; there were major bleeding events in nine patients (2.5%) and four patients (1.1%) respectively and thromboembolism in four (1.1%) and three (0.8%) patients [70C].

[SED-15, 1590; SEDA30, 404; SEDA-31, 556; SEDA-32, 626]

HEPARINS

Electrolyte balance Heparin-induced hyperkalemia is usually associated with intravenous heparin, but it can occasionally occur during subcutaneous administration, as in the case of a 75-year-old woman, whose serum potassium rose from 5.0 to 6.9 mmol/l when she was given unfractionated heparin 5000 units bd subcutaneously for 6 days [71A].

714

Hematologic EIDOS classification: Extrinsic species Heparin Intrinsic species Platelet factor 4 Distribution Plasma Outcome Formation of platelet factor 4/heparin antibodies Sequela Heparin-induced thrombocytopenia (HIT), type II DoTS classification: Dose-relation Hypersusceptibility Time-course Early persistent Susceptibility factors Renal disease for some forms of heparin

Incidence Platelet factor 4/heparin antibodies are not always associated with thrombocytopenia. In 135 children who underwent cardiac surgery and were given unfractionated heparin (60 neonates undergoing first-time surgery and 75 older children undergoing re-operations), platelet factor 4/heparin antibodies were not detected preoperatively in either group [72c]. However, there were antibodies in one neonate on postoperative days 5 and 10, and in 12 of the older children on day 5 and 39 on day 10. Seroconversion in the older children on day 10 was significantly associated with previous exposure to heparin, and one patient seroconverted and developed HIT without thrombosis or skin lesions. The authors concluded that in older children the incidence of antibodies is similar to that reported in adults, that HIT is rare, and that both age and previous exposure to unfractionated heparin correlated with seroconversion; in contrast, the rate of seroconversion in neonates undergoing first-time surgery was substantially lower. In a prospective analysis of antibodies in 31 pregnant women who received dalteparin 2500–10 000 IU/day for 6–45 (median 33) weeks, IgG, IgM, and IgA antibodies were not detected and there were no thromboembolic events [73c]. One woman developed a prolonged fall in platelet count to less than

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J.K. Aronson

50% of baseline after 35 weeks, with spontaneous resolution after delivery. In a retrospective study, 37 women with high-risk pregnancies were given tinzaparin 175 IU/kg/day; there were no episodes of recurrent venous thromboembolism but there were two unusual thrombotic complications, a parietal infarct in one patient and a postpartum cerebral venous thrombosis in another [74c]. However, false positive tests for platelet factor 4/heparin antibodies can occur in patients with the phospholipid antibody syndrome or systemic lupus erythematosus, as illustrated by the results of a study in 42 such patients, of whom 32 were positive for platelet factor 4/heparin IgG antibodies and 24 were positive for platelet factor 4 antibodies [75c]. However, there were no abnormalities in heparin-induced platelet activation or aggregation. Time-course The time-course of production of heparin-induced antibodies has been studied in 435 patients receiving heparin thromboprophylaxis [76c]. Antibodies formed in 56%, and in over 90% of cases they appeared at 4–14 days. After reaching maximum reactivity by days 10–12, the antibody titers fell, despite heparin continuation, even in two patients with HIT. Individual IgG, IgA, and IgM classes had identical times of onset (median day 6). Most of the antibody-positive patients (59%) developed all three immunoglobulin classes; only 11% lacked an IgG response, and all three immunoglobulins usually increased simultaneously. In a study of IgG, IgA, and IgM antibodies in 12 patients with HIT and 36 patients who formed antibodies but did not develop HIT, the antibodies became detectable in the former at a median of 4 days after the start of treatment and preceded the fall in platelet count by a median of 2 days [77c]. Patients with HIT produced higher titers of IgG antibodies than the seropositive controls, but similar IgA and IgM titers. Of 500 patients treated with unfractionated heparin 131 (26%) developed platelet factor 4/heparin antibodies, which

Drugs that affect blood coagulation, fibrinolysis, and hemostasis

persisted for a median of 90 (IQ range 31–186) days [78c]. At 30 days, patients with antibodies had a higher incidence of thrombotic events (28% versus 15%) and death/myocardial infarction (15% versus 7.8%). Of the 131 patients with antibodies, 78 had already developed antibodies before cardiac surgery, and they became serologically negative more slowly than those who developed antibodies after surgery. Over 3 years of follow-up, the patients with antibodies had 65 thrombotic events; 25 developed deep vein thrombosis and/or pulmonary embolism and 20 had a myocardial infarction. Management It has been suggested that platelet transfusions are contraindicated in HIT, because of the risk of thrombosis. However, no complications occurred in four patients with clinically suspected HIT who received platelet transfusions [79cM]. The authors also reviewed the literature and found no cases of complications clearly attributable to platelet transfusion and concluded that platelet transfusions should not be withheld when indicated in patients with HIT. Treatment with plasmapheresis to remove the antibodies was effective in a 60-year-old man with HIT after cardiac surgery [80A] and has also been described in a series of 11 patients, in whom a single plasmapheresis reduced titers by 50–84% [81c]. Reports and reviews continue to appear on the successful use of other anticoagulants in patients with a history of HIT, including argatroban [82A, 83A, 84A, 85A, 86A, 87A, 88A, 89c, 90R, 91R, 92R], bivalirudin [93A, 94A, 95c, 96M], danaparoid [97A], fondaparinux [98A, 99A, 100c, 101c, 102M], hirudin [103A], lepirudin [104A, 105c, 106R, 107M], and rivaroxaban [108A]. In 82 adults there was no significant difference in outcomes between argatroban and lepirudin [109c]. Skin Of 320 patients, 24 (7.5%; 95% CI ¼ 4.7, 11) had heparin-induced skin lesions, which were delayed-type hypersensitivity reactions in all cases [110c]. The

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susceptibility factors were a body mass index greater than 25 (OR ¼ 4.6; 95% CI ¼ 1.7, 15), duration of heparin therapy longer than 9 days (OR ¼ 5.9; 95% CI ¼ 1.9, 26), and female sex (OR ¼ 3.0; 95% CI ¼ 1.1, 8.8). Skin necrosis can occur occasionally in patients receiving heparin, in association with heparin-induced thrombocytopenia [111A]. Recall urticaria occurred in a 42-year-old woman at previous dalteparin injection sites in the abdomen when she was given intracutaneous dalteparin and certoparin in the forearms [112A]. Subcutaneous calcinosis occurred in two patients with renal failure who developed erythematous nodules with calcium deposition in the dermis and hypodermis [113A], a between-the-eyes reaction of type 1a [114H]. Bullous hemorrhagic dermatosis is a rare adverse reaction to subcutaneous heparin [115A, 116A]. Musculoskeletal Long-term heparin can cause osteoporosis, as illustrated by the case of a 19-year-old woman with protein C deficiency, who had a fracture of the right wing of the sacrum after receiving low-molecular-weight heparin daily during her pregnancy [117A]. The effect of low-molecular-weight heparin on bone mineral density has been assessed in a multicenter multinational randomized study in pregnant women with thrombophilia [118c]. There was no significant difference in mean bone mineral density between those who were given low-molecular-weight heparin prophylaxis and those who were given no prophylaxis, but the study was not adequately powered to detect differences in the absolute risk of fractures. Pregnancy In a prospective study of 130 pregnancies in 114 women treated with prophylactic or therapeutic low-molecularweight heparins, there was one allergic skin reaction in a patient with hereditary thrombophilia treated with enoxaparin and then with nadroparin in the third trimester of pregnancy, hemorrhagic complications in a patient with dysfibrinogenemia and placental abruption, and one case of minor epistaxis in

716

a patient treated with heparin and aspirin [119c]. There were no pathological fractures, significant reductions in platelet counts, or episodes of arterial thrombosis. Drug formulations A multimatrix oral formulation of parnaparin sodium, MMX, releases heparin in the colon, avoiding systemic absorption and has been used for 8 weeks to treat left-sided ulcerative colitis in 10 patients with mild-to-moderate relapses [120c]. There were no adverse reactions and at the end of treatment, seven patients were in clinical remission, although only one achieved endoscopic healing. A heparin-coated stent was associated with a giant aneurysm in the left anterior descending coronary artery immediately distal to the stent, which had been in place for 3 years, in a 79-year-old woman [121A]. Drug contamination Adverse reactions to heparin contaminated with oversulfated chondroitin sulfate have been evaluated in a US case–control study of patients in dialysis facilities who had signs and symptoms of allergic reactions after 1 November 2007 [122C]. There were 152 adverse reactions associated with heparin in 113 patients from 13 states from 19 November 2007 to 31 January 2008. The use of heparin manufactured by Baxter Healthcare was the factor most strongly associated with reactions, which occurred in 100% of 21 facilities in which cases were reported versus 4.3% of 23 control facilities. Vials of heparin manufactured by Baxter from facilities that reported reactions contained a contaminant identified as oversulfated chondroitin sulfate. Adverse reactions to the contaminated heparin were often characterized by hypotension, nausea, and shortness of breath within 30 minutes of administration. Of 130 reactions for which information on the heparin lot was available, 128 occurred in a facility that had contaminated heparin on the premises. Of 54 reactions for which the lot number of the heparin was known, 52 occurred after the administration of contaminated heparin. Plasma samples obtained from dialysis patients in 2006 and 2007 had a low (5%)

Chapter 35

J.K. Aronson

prevalence of platelet factor 4/heparin antibodies, whereas in samples from 78 patients on maintenance hemodialysis who had been potentially exposed to contaminated heparin there were antibodies in 15 (19%); there was also a higher prevalence of IgG antibodies [123c]. The authors suggested that the contaminant in the recalled heparin may have triggered an immunogenic response not seen with non-contaminated heparin. Management of adverse drug reactions Heparin allergy, which caused a pruritic urticaria-like rash on the back in a 55-yearold man, without associated angioedema, wheezing, flushing, or anaphylaxis, has been successfully managed with an intravenous desensitization protocol (Table 1) [124Ar]. Two earlier protocols, which were used in a 34-year-old man [125A] and a 55 year-old woman [126A], are also shown in Table 1 for comparison. An even faster protocol has also been described [127A]. A combined subcutaneous and intravenous protocol that was used in a 55-year-old woman is shown in Table 2 [128A]. In four patients with delayed hypersensitivity reactions to different forms of heparin, prick tests, intradermal tests, and patch tests were performed using unfractionated sodium heparin, low-molecular-weight heparins (nadroparin, enoxaparin, bemiparin, and dalteparin), and fondaparinux [129A]. There were different patterns of cross-reactivity; all were sensitive to at least two forms of heparin and one patient was sensitive to all five drugs.

Danaparoid sodium

[SEDA-32, 631]

Immunologic A patient with delayed-type hypersensitivity to heparins was given danaparoid subcutaneously for thrombosis prophylaxis after orthopedic surgery and after the first few injections developed eczematous plaques followed by generalized eczema despite treatment with topical and oral glucocorticoids; danaparoid was replaced by intravenous heparin, and there was rapid resolution of the skin lesions [130A].

Drugs that affect blood coagulation, fibrinolysis, and hemostasis

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Table 1 Intravenous heparin desensitization protocols described in three different reports Desensitizing dose (U/h) Ar

Time of administration (hours)

[124 ]

0–12 12–24 24–36 36–48 48–60 60–72 72–84 84–96 96–120

0.5 1.5 4.5 13.6 40.8 122.5 367.4 1008 –

[125A]

[126A]

4.2 4.2 42 42 208 8 208 < 5000 U bd subcutaneously :

0.42 0.42 4.2 4.2 42 42 210 210 500

Table 2 A combined subcutaneous and intravenous heparin desensitization protocol [128A] Time of administration

Desensitizing dose (units)

Route

Day 1 Day 1 after 40 minutes Day 1 after 80 minutes

50 250 500

Subcutaneous Subcutaneous Subcutaneous

Day 2 Day 2 after 40 minutes Day 2 after 80 minutes

500 1500 3000

Subcutaneous Subcutaneous Subcutaneous

Day 3 Day 3 after 40 minutes Day 3 after 80 minutes

500 1500 3000

Intravenous Intravenous Intravenous

Day 4

5000

Intravenous

Pregnancy In 91 pregnancies in 83 patients with a history of thrombophilia and/or intra-uterine growth retardation, all of whom had intolerance to heparins, subcutaneous and/or intravenous danaparoid 1000–7500 U/day was started in the first, second, and third trimesters in 60%, 19%, and 21% respectively and was continued for a median of 105 (range 1–252) days during pregnancy and for 7 (range 2–56) days post-partum [131c]. The live birth rate was 90% (75/81) and danaparoid was restarted after 37 deliveries. Maternal adverse events in 46% of the pregnancies included two post-cesarean deaths, three non-fatal major bleeds, three thromboembolic events unresponsive to an increased dose of danaparoid, and 10 recurrent rashes. There were seven early miscarriages, one therapeutic

termination, and one neonatal death. In 13 cases a maternal, but no fetal, adverse event was attributed to danaparoid.

DIRECT THROMBIN INHIBITORS [SED-15, 1142; SEDA-30, 409; SEDA-31, 559; SEDA-32, 632]

Argatroban

[SEDA-32, 632]

Pregnancy Argatroban has been used in a 26-year-old pregnant woman with portal vein thrombosis and thrombocytopenia from the 33rd to the 39th week, when labor was

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induced; argatroban was discontinued 7 hours before epidural anesthesia, and there were no adverse events attributable to it [132A].

Dabigatran

man with a history of heparin-induced thrombocytopenia (HIT) due to enoxaparin [135A].

[SEDA-32, 633]

Susceptibility factors Liver disease The effects of moderate hepatic impairment on the pharmacokinetics and pharmacodynamics of a single oral dose of dabigatran etexilate 150 mg have been evaluated in an open, parallel-group study in 12 healthy subjects and in 12 patients with hepatic impairment (Child–Pugh classification B) [133c]. Conversion of the dabigatran intermediate BIBR1087 to active dabigatran was slower in patients with hepatic impairment, but total drug exposure was comparable between the groups. Dabigatran glucuronidation was unchanged by liver disease. The activated partial thromboplastin time, ecarin clotting time, and thrombin time were essentially identical in the two groups. Drug–drug interactions HMG Co-A reductase inhibitors (statins) The interaction of dabigatran etexilate with atorvastatin has been studied in 22 healthy men and women in an open, randomized, multiple-dose, three-way crossover study [134c]. They took dabigatran 150 mg bd on days 1–3 and 150 mg/day on day 4, or atorvastatin 80 mg/day on days 1–4, or both treatments together on days 1–4. During co-administration, the steady-state AUC of dabigatran fell by 18% and the plasma atorvastatin concentration increased by 18%. Exposure to 20 -hydroxyatorvastatin was unchanged and exposure to 40 -hydroxyatorvastatin increased by 15%. The small changes observed were thought to be of little clinical relevance, given the overall interindividual variability in the metabolism of atorvastatin.

Lepirudin

J.K. Aronson

[SEDA-32, 633]

Hematologic Thrombocytopenia has been attributed to lepirudin in a 61-year-old

INDIRECT FACTOR XA INHIBITORS [SEDA-30, 412; SEDA-31, 563; SEDA-32, 636]

Fondaparinux

[SEDA-32, 636]

Hematologic The association between major bleeding and death at 30 days has been derived from individual patient data from eight large randomized controlled comparisons of fondaparinux with either low-molecular-weight heparin or placebo in prophylaxis of venous thromboembolism in 13 085 hospitalized patients [136M]. Those who had major bleeding were older, were more likely to be men, had lower body weights and lower creatinine clearances, and were more likely to be receiving fondaparinux. At 30 days, the risk of death was 7 times higher among patients with a major bleeding event (8.6% versus 1.7%; adjusted HR ¼ 6.96; 95% CI ¼ 4.60, 11). There was a consistent pattern of reduced mortality in patients treated with fondaparinux, irrespective of whether the patients had major bleeding (6.8% versus 11%; HR ¼ 0.58; 95% CI ¼ 0.27, 1.23) or not (1.5% versus 1.9%; HR ¼ 0.77; 95% CI ¼ 0.59, 1.02).

Idraparinux

[SEDA-32, 636]

Skin The Amadeus comparison of a vitamin K antagonist and a weekly subcutaneous injection of idraparinux was stopped early because of excessive bleeding in patients assigned idraparinux. There were also unusual skin lesions in 15 of 56 participants who were assigned to idraparinux compared with none of 59 patients assigned to warfarin at one center [137c]. There were raised, blood-filled vesicles 0.5–2.0 cm in

Drugs that affect blood coagulation, fibrinolysis, and hemostasis

diameter, remote from the subcutaneous injection sites. Most of the patients had 2–8 lesions, usually on the arms and legs, which appeared on average 3 (range 2–8) months after starting idraparinux. After that, new lesions continued to appear, but the severity of the lesions did not increase, despite continuing medication. On first appearance the lesions were bright red, suggesting fresh blood. They would then darken before gradually resolving over 2 weeks. They were not painful or itchy.

DRUGS THAT ALTER PLATELET FUNCTION [SEDA-30, 413; SEDA-31. 564; SEDA-32, 637]

Anagrelide

[SEDA-32, 637]

Cardiovascular In a database study cardiomyopathy was temporally associated with the use of anagrelide in six patients, all of whom had symptomatic and/or objective improvement after drug withdrawal [138c]. Mid-ventricular takotsubo syndrome (see also p. 313) has also been described in a 75-year-old woman taking anagrelide [139A]. The authors hypothesized that accumulation of anagrelide, a phosphodiesterase type II inhibitor, had caused major inotropic stimulation and sympathetic hyperactivation in a vulnerable myocardium.

Dipyridamole [SED-15, 1140; SEDA30, 413; SEDA-31, 564; SEDA-32, 638] Cardiovascular Asystole has been reported during the administration of dipyridamole [140A]. • A 67-year-old woman with hypertension, who was taking metoprolol 50 mg bd, underwent dipyridamole stress testing, and during the infusion of dipyridamole developed nausea, dizziness, and sudden loss of consciousness.

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Electrocardiography showed asystole, which resolved after 20 seconds, with return of consciousness. She was given theophylline, which was associated with a brief period of atrial fibrillation followed by chest discomfort. Her electrolytes were normal, and there was no rise in cardiac enzymes nor electrocardiographic evidence of myocardial infarction. Angiography showed normal coronary arteries and echocardiography showed normal cardiac function.

It has been suggested that dipyridamole inhibits cardiac conduction by autonomic dysregulation [141A]. An interaction with beta-blockers has also been described [142c] and that may have been the case here. Nervous system The susceptibility factors for dipyridamole-induced headache have been studied in an analysis of data from the European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) and the Second European Stroke Prevention Study (ESPS 2). In ESPRIT, dipyridamole-induced headache was significantly associated with female sex, absence of hypertension, and nonsmoking, and in ESPS 2 with female sex and absence of ischemic lesions on imaging [143C]. The risk of dipyridamole-induced headache can be reduced by slow upward titration of the dose. The susceptibility factors for headache during such a regimen have been studied in 20 stroke units in Sweden, where 174 patients with newly diagnosed strokes and transient ischemic attacks were offered a titration regimen of the combination of aspirin 25 mg/day þ dipyridamole 200 mg/day for 5 days followed by 200 mg/ day bd [144c]. Headache of any kind was reported in 70 patients (40%), and 37 (21%) assessed it as moderate/severe; six stopped taking the medication because of headache. The headache subsided over a mean of 3.1 days. Patients who had transient ischemic attacks had a significantly higher risk of headache than those with strokes, regardless of localization. There was a trend towards a higher risk in younger patients and women.

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Glycoprotein IIb–IIIa inhibitors [SED-15, 4; SEDA-30, 414; SEDA-31, 565; SEDA-32, 638] Cardiovascular Cardiac tamponade resulting from hemorrhagic pericarditis has been attributed to abciximab [145A]. • A 66-year-old man had a myocardial infarction and was given intravenous heparin, and oral aspirin 200 mg/day, clopidogrel 75 mg/ day, and cilostazol 200 mg/day. After 5 days he was given abciximab 10 mg during percutaneous coronary intervention followed by 10 micrograms/minute for 12 hours, but 11 hours after coronary intervention he developed chest discomfort and dyspnea, his blood pressure fell to 60/30 mmHg, and the ST segment elevation increased. Echocardiography showed a scanty pericardial effusion with no evidence of tamponade. Three days later he complained of chest discomfort and dyspnea, and again developed shock. Echocardiography showed a large pericardial effusion, with tamponade. A bloody pericardial effusion of about 950 ml was aspirated.

A 56-year-old man developed acute transient phlebitis during an intravenous injection of eptifibatide; the eptifibatide was withdrawn and the signs of phlebitis disappeared within minutes [146A]. Hematologic Thrombocytopenia has again been attributed to eptifibatide [147A, 148A, 149A, 150AM] and tirofiban [151A, 152A, 153A].

THIENOPYRIDINES [SED-15, 821; SEDA-30, 415; SEDA-31, 566; SEDA-32, 639] Observational studies Cross-reactivity between clopidogrel and ticlopidine, which are structurally very similar, has been studied by reviewing the medical records of 76 patients who had an allergic or hematological adverse reaction to either drug and who were subsequently given the other [154c]. In 14 patients who had allergic or

J.K. Aronson

hematologic adverse reactions to clopidogrel there was a similar reaction to ticlopidine; none was life-threatening and the most common reaction was a rash (93%). Hematologic In a systematic review of the English-language literature on thrombotic thrombocytopenic purpura associated with thienopyridines, epidemiological studies identified recent initiation of antiplatelet drugs as the most common susceptibility factor, and ticlopidine and clopidogrel were the two most common drugs implicated in FDA safety databases [155M]. Most cases associated with thienopyridines involve an antibody to ADAMTS13 metalloprotease, which is present in severe thrombocytopenia and responds to therapeutic plasma exchange; in a minority of cases there is severe renal insufficiency, due to direct endothelial cell damage.

Clopidogrel

[SEDA-32, 639]

Nervous system In a retrospective casecontrol study of 3817 patients with closed head trauma, of 131 who were taking clopidogrel, aspirin or warfarin, those taking clopidogrel (n ¼ 21) were more likely to die (OR ¼ 15; 95% CI ¼ 2.3, 94) and be discharged to an in-patient long-term facility (OR ¼ 3.25; 95% CI ¼ 1.06, 9.96). Mortality in those taking aspirin (n ¼ 90) or warfarin (n ¼ 20) did not differ from controls, although those taking warfarin had longer hospital and ICU stays [156c]. Psychological In a double-blind, placebocontrolled, balanced, between-subject study in 54 young healthy volunteers, single oral doses of clopidogrel 37.5 mg had no significant effects on psychomotor performance [157C]. Hematologic In a retrospective review of 453 patients who underwent off-pump bypass graft surgery and who received clopidogrel preoperatively (n ¼ 101) or not (n ¼ 352), clopidogrel was associated with higher intraoperative and postoperative

Drugs that affect blood coagulation, fibrinolysis, and hemostasis

bleeding and with more platelet transfusions; however, in those in whom clopidogrel was withdrawn 3 days before surgery there was similar blood loss compared with controls [158c]. In a retrospective chart study of 50 patients who underwent a general surgical procedure, patients who took clopidogrel within 6 days before surgery (n ¼ 28) were compared with those who stopped taking it for 7 days or more (n ¼ 22); more patients who took their last dose of clopidogrel within 1 week of surgery (21% versus 9.5%) had significant bleeding after surgery requiring blood transfusion [159c]. In 4794 patients who underwent bypass grafting, treatment with clopidogrel within 5 days before the operation was modestly associated with erythrocyte transfusion (OR ¼ 1.40; 95% CI ¼ 1.04, 1.89), but more weakly than other factors, including which surgeon performed the procedure; it was not associated with re-operation for bleeding [160c]. However, in a secondary post-hoc analysis of inhibition of platelet aggregation and bleeding complications, as assessed by the TIMI, GUSTO, and BleedScore scales, in patients with coronary artery disease (n ¼ 246) and previous ischemic strokes (n ¼ 117), inhibition of platelet aggregation of over 50% correlated strongly with minor but not severe bleeding [161c]. The authors concluded that chronic oral combination antiplatelet regimens are associated with a very high prevalence of episodes of superficial bleeding (57–61%), which they thought to be greatly underestimated in trials and registries. Acute severe pancytopenia has been associated with clopidogrel [162A]. Gastrointestinal There was an increased risk of major gastrointestinal bleeding, but not other major or minor bleeding events, in the year after percutaneous coronary intervention in 1816 patients in whom clopidogrel or placebo was added to aspirin after 4 weeks [163C]. Liver Clopidogrel can occasionally cause liver damage, as has again been reported [164Ar].

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• A 78-year-old woman developed mixed hepatocellular and cholestatic liver damage after taking clopidogrel and aspirin for 3 weeks. Clopidogrel was withdrawn, and her liver function tests improved. Clopidogrel was reintroduced and her liver enzyme activities again rose. Clopidogrel was again withdrawn and her liver function tests gradually started to improve after 3 days.

Skin A fixed drug eruption has been reported in a 68-year-old man, who developed a few well-circumscribed, darkly pigmented, oval-shaped lesions in his shoulder, forehead, and trunk after taking clopidogrel 75 mg/day for 4 days. A patch test with clopidogrel was negative, but oral rechallenge with a dose of 18.75 mg caused the appearance of similar lesions over the exact sites of the previous lesions within a few hours [165A]. Infection risk In a retrospective cohort study of 1677 patients undergoing coronary artery bypass surgery, in which preoperative aspirin þ clopidogrel was compared with aspirin alone, clopidogrel was associated with an increased risk of postoperative surgical site infection and bacteremia, both unadjusted (HR ¼ 1.51; 95% CI ¼ 1.09, 2.08) and after adjustment for demographic, socioeconomic, preoperative, and intraoperative risk factors (HR ¼ 1.42; 95% CI ¼ 1.01, 2.00) and propensity score (HR ¼ 1.43; 95% CI ¼ 1.01, 2.01) [166c]. Susceptibility factors Genetic The pharmacogenetic determinants of the response to clopidogrel have been studied in 2208 patients with acute myocardial infarction, of whom 225 died [167c]. None of the selected single-nucleotide polymorphisms (SNPs) in CYP3A5, P2RY12, or ITGB3 was associated with a risk of an adverse outcome during follow-up. Patients with two variant alleles of ABCB1 (TT at nucleotide 3435) had a higher rate of cardiovascular events at 1 year than those with the ABCB1 wild-type genotype (CC at nucleotide 3435) (16% versus 11%; adjusted HR ¼ 1.72; 95% CI ¼ 1.20, 2.47). Patients carrying any two CYP2C19 loss-of-function alleles (*2, *3, *4, or *5)

722

had a higher event rate than patients with none (22% versus 13%; adjusted HR ¼ 1.98; 95% CI ¼ 1.10, 3.58). Among the 1535 patients who underwent percutaneous coronary intervention during hospitalization, the rate of cardiovascular events among patients with two CYP2C19 loss-offunction alleles was 3.58 times the rate among those with none (95% CI ¼ 1.71, 7.51). The association between functional genetic variants in CYP genes, plasma concentrations of active metabolite, and platelet inhibition in response to clopidogrel has been studied in 162 healthy subjects, and the association between these genetic variants and cardiovascular outcomes in a separate group of 1477 subjects with acute coronary syndromes who were taking clopidogrel [168C]. Carriers of at least one CYP2C19 reduced-function allele (about 30% of the population) had a relative reduction of 32% in plasma exposure to the active metabolite of clopidogrel compared with non-carriers. Carriers also had an absolute reduction in maximal platelet aggregation in response to clopidogrel. Carriers had a relative increase of 53% in the composite primary efficacy outcome of the risk of death from cardiovascular causes, myocardial infarction, or stroke, compared with non-carriers (12% versus 8.0%; HR ¼ 1.53; 95% CI ¼ 1.07, 2.19) and an increased risk of stent thrombosis (2.6% versus 0.8%; HR ¼ 3.09; 95% CI ¼ 1.19, 8.00). In 60 patients undergoing elective percutaneous coronary intervention who were genotyped for polymorphisms in the CYP2C19, CYP2C9, CYP3A4, CYP3A5, ABCB1, P2Y12, and CES genes, CYP2C19*1*1 carriers had greater platelet inhibition 2 hours after a dose of 600 mg compared with carriers of CYP2C19*2, *4, or *17 [169c]. In a prospective observational study of 15 603 patients in Singapore, of whom 12 502 (80%) were white, 486 (3.1%) black, 775 (5.0%) Asian, and 1613 (10%) Hispanic, ethnicity was not a significant predictor of the primary composite cardiovascular event, but it was a significant

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J.K. Aronson

independent predictor of the secondary outcomes, cardiovascular and all-cause mortality (blacks and Hispanics) and moderate bleeding complications (blacks and Asians) [170C]. Drug overdose A 49-year-old woman had a pulmonary hemorrhage and hemothorax after taking an overdose of clopidogrel 1875 mg [171A]. Drug–drug interactions Aprotinin In 15 patients with acute coronary syndrome taking clopidogrel and undergoing coronary surgery, aprotinin increased platelet aggregation in 11 cases from 84% to 94% and reduced it in two [172c]. Calcium channel blockers In 200 patients undergoing percutaneous coronary intervention, platelet reactivity was increased in patients taking clopidogrel and calcium channel blockers compared with clopidogrel alone; the effect was not related to cardiovascular risk factors and was attributed to inhibition of CYP3A4, since in vitro incubation with amlodipine, nimodipine, diltiazem, and verapamil had no effect on aggregation of platelets from patients taking clopidogrel [173c]. Similarly, the addition of calcium channel blockers in patients taking clopidogrel increased platelet reactivity in 162 patients after percutaneous intervention with stent implantation [174c]. HMG Co-A reductase inhibitors (statins) In a cohort study of 10 491 patients who took clopidogrel after percutaneous coronary intervention, the co-prescription of CYP3A4-metabolized statins was not associated with an increased risk of adverse outcomes (HR ¼ 1.16; 95% CI ¼ 0.91, 1.47) [175C]. In patients with coronary artery disease who took part in a double-blind comparison of atorvastatin 20–80 mg/day (n ¼ 22) and rosuvastatin 10–40 mg/day (n ¼ 24), the platelet inhibitory effects of clopidogrel were not altered [176C]. In an open, randomized, crossover, twoarm, parallel-group study in 69 healthy

Drugs that affect blood coagulation, fibrinolysis, and hemostasis

men aged 18–60 years, atorvastatin 80 mg/ day had no clinically significant effects on the pharmacokinetics or pharmacodynamics of clopidogrel or prasugrel [177c]. Proton pump inhibitors A systematic review of the evidence has suggested that omeprazole reduces the antiplatelet effects of clopidogrel, probably by competitive inhibition of CYP2C19, that the interaction is clinically significant, and that it may not be shared by other proton pump inhibitors [178M]. Other reviewers have concluded similarly [179R, 180R]. New studies have mostly supported these conclusions. In a nested case–control study of 734 patients aged 66 years or older who were given clopidogrel following an acute myocardial infarction and had a second admission within 90 days, and 2057 controls, current use of proton pump inhibitors was associated with an increased risk of reinfarction (adjusted OR ¼ 1.27; 95% CI ¼ 1.03, 1.57) [181C]. In a stratified analysis, pantoprazole, which does not inhibit CYP2C19, was not associated with readmission for myocardial infarction (adjusted OR ¼ 1.02; 95% CI ¼ 0.70, 1.47). Similarly, in a retrospective cohort study of 8205 patients with acute coronary syndrome who took clopidogrel after discharge, of whom 5244 also took a proton pump inhibitor, combined use was associated with an increased risk of death or rehospitalization for acute coronary syndrome (adjusted OR ¼ 1.25; 95% CI ¼ 1.11, 1.41) [182c]. In a study of the effect of pantoprazole, omeprazole, and esomeprazole on platelet responses to clopidogrel in 1000 patients, of whom 268 were taking a proton pump inhibitor at the time of platelet function testing with adenosine diphosphate (pantoprazole, n ¼ 162; omeprazole, n ¼ 64; esomeprazole, n ¼ 42), platelet aggregation was significantly greater in those taking omeprazole, but not pantoprazole or esomeprazole, compared with patients who were not taking proton pump inhibitors [183C]. However, other studies have shown small effects or none. In 18 565 clopidogrel users,

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2.6% of those who were also taking a proton pump inhibitor versus 2.1% of nonusers were hospitalized with a myocardial infarction; 1.5% versus 0.9% died and 3.4% versus 3.1% underwent revascularization [184C]. The propensity score-adjusted rate ratios were: 1.22 (95% CI ¼ 0.99, 1.51) for the primary end-point of myocardial infarction or death; 1.20 (95% CI ¼ 0.84, 1.70) for death; and 0.97 (95% CI ¼ 0.79, 1.21) for revascularization. The authors concluded that if there is an interaction, it is unlikely to exceed a 20% increase in risk. In the PRINCIPLE-TIMI 44 trial, 201 patients undergoing elective percutaneous coronary intervention were randomly assigned to prasugrel (n ¼ 102) or highdose clopidogrel (n ¼ 99); mean inhibition of platelet aggregation was significantly lower in patients taking a proton pump inhibitor at 6 hours after a loading dose of clopidogrel 600 mg and there was a smaller difference after a loading dose of prasugrel 60 mg [185C]. However, in the TRITONTIMI 38 trial, in which 13 608 patients with an acute coronary syndrome were randomly assigned to prasugrel (n ¼ 6813) or clopidogrel (n ¼ 6795), there was no association between the use of proton pump inhibitors and the risk of the primary endpoint in those taking clopidogrel or prasugrel. Ranitidine In an open, two-period, twotreatment, crossover study in 47 healthy men, ranitidine had no clinically significant effects on the pharmacokinetics of the active metabolites of either prasugrel or clopidogrel [186c]. Drug–smoking interactions In 259 patients who underwent coronary stenting and were taking clopidogrel, 104 were current smokers and 155 were non-smokers. Smoking was independently associated with reduced platelet aggregability and lower active glycoprotein IIb/IIIa expression, and smokers had greater platelet inhibition with clopidogrel [187c]. This was probably due to a pharmacodynamic interaction, although smoking also induces the activity

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of CYP1A2, which is involved in the conversion of clopidogrel to its active metabolite. When platelet aggregation was studied in 102 patients taking dual antiplatelet therapy 24 hours after peripheral, coronary, or carotid artery stenting, current smokers had significantly lower P2Y12 Reaction Units compared with non-smokers, and in a multivariate regression analysis smoking was an independent influencing variable for ADP-inducible platelet reactivity; smoking was associated with enhanced clopidogrel-mediated but not aspirin-mediated inhibition of platelet aggregation [188c]. In a study of the relation between smoking status (current smoker, former smoker, or never smoker) and treatment with clopidogrel on the risk of mortality in 12 152 patients, current smoking was associated with an increase in all-cause mortality (adjusted HR ¼ 2.58; 95% CI ¼ 1.85, 3.60), cardiovascular mortality (HR 2.26; 95% CI ¼ 1.48, 3.45), and cancer-related mortality (HR ¼ 3.56; 95% CI ¼ 1.96, 6.46) compared with never smoking [189C]. Among current smokers, clopidogrel was associated with a reduction in allcause mortality (HR ¼ 0.68; 95% CI ¼ 0.49, 0.94), but it did not reduce all-cause mortality among former smokers (HR ¼ 0.95; 95% CI ¼ 0.75, 1.19) or never smokers (HR ¼ 1.14; 95% CI ¼ 0.83, 1.58); there was a similar pattern for cardiovascular mortality but not for cancerrelated mortality. Clopidogrel was also associated with a significantly increased risk of severe or moderate bleeding among current smokers. The authors concluded that in current smokers clopidogrel may be more effective but may also be associated with a greater risk of bleeding. Management of adverse drug reactions Desensitization in a case of clopidogrel and ticlopidine allergy has been described in a 55-year-old man; he was given increasing oral doses of clopidogrel from 0.005 to 75 mg at half-hour intervals over 7 hours [190A]. In a retrospective study of the efficacy of an out-patient oral clopidogrel

J.K. Aronson

desensitization protocol, eight patients were successfully desensitized using 10 doses given during 2–3 half-day clinical visits and were able to go home between desensitization sessions without complications [191c]. There were no recurrences of allergic reactions 3 months after the procedure. The authors suggested that outpatient desensitization is cheaper than inpatient desensitization. Of 2701 patients who underwent percutaneous coronary intervention, 20 had adverse skin reactions to clopidogrel and were treated with a combination of oral prednisolone 30 mg/day for 5 days and chlorphenamine 4 mg tds for 7 days, while clopidogrel was continued [192c]. There was complete resolution in most of the patients within an average of 3.2 days; one had partial resolution and one had no response to treatment, but both were able to continue clopidogrel.

Ticlopidine

[SEDA-32, 642]

Hematologic Neutropenia due to ticlopidine usually occurs within the first 3 months (i.e. has an intermediate time course), but has also been reported after about 18 months [193A]. Liver Acute cholestatic hepatitis has been attributed to ticlopidine in a 68-year-old woman [194A].

HEMOSTATIC AGENTS Aprotinin

[SED-15, 331; SEDA-31, 566; SEDA-32, 642]

Aprotinin and renal function The use of aprotinin in patients undergoing surgery has been reported to increase the

Drugs that affect blood coagulation, fibrinolysis, and hemostasis

risk of renal impairment (SEDA-32, 642), and the authors of a review of data from basic science studies in tissues, animals, and man, as well as data from observational studies and randomized controlled trials, concluded that aprotinin causes a transient small rise in plasma creatinine concentration in some patients, but that there is no evidence of an increased risk of new renal insufficiency requiring renal replacement therapy [195R]. Further reports have appeared, many being comparisons between aprotinin and either tranexamic acid or aminocaproic acid. The results have been conflicting. Studies showing renal impairment In a systematic review of 11 studies, including 10 that studied renal function and seven that studied deaths, aprotinin was associated with renal dysfunction (risk ratio, RR ¼ 1.42; 95% CI ¼ 1.13, 1.79) and long-term mortality (HR ¼ 1.22; 95% CI ¼ 1.08, 1.39) [196M]. Pooled estimates were lower for short-term mortality (RR ¼ 1.16; 95% CI ¼ 0.84, 1.58) and renal failure requiring dialysis (RR ¼ 1.17; 95% CI ¼ 0.99, 1.38). Time on bypass was a significant source of heterogeneity, with a 29% increased risk of renal dysfunction for every 10-minute increase in bypass time. In a prospective comparison of aprotinin (n ¼ 1507) and aminocaproic acid (n ¼ 1830) in patients undergoing surgery, postoperative renal failure was significantly more common in the former (6.2% versus 2.7%) and at median 5.4-year follow-up (up to 12 years) mortality was higher (Kaplan–Meier failure rates 44% versus 24% at 8 years), with a stepwise relation between weight-based aprotinin dose and mortality [197C]. In a non-randomized prospective study of 1188 patients who underwent cardiac surgery, the first 596 received aprotinin and the next 592 received tranexamic acid [198c]. Postoperatively, in those who underwent primary valve surgery, tranexamic acid was associated with significantly higher incidences of seizures (4.6% versus 1.2%), persistent atrial fibrillation (7.9% versus 2.3%), and renal insufficiency (9.7% versus 1.7%). In those who underwent primary

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coronary artery bypass surgery and received aprotinin, there were more cases of acute myocardial infarction (5.8% versus 2.0%) and renal dysfunction (23% versus 15%). In a follow-up database study of 3535 patients who underwent cardiac surgery, 635 were treated with aprotinin and 2900 with tranexamic acid. Those who received aprotinin had an increased risk of postoperative dialysis (adjusted RR ¼ 1.76; 95% CI ¼ 1.15, 2.70) [199c]. Studies showing no renal impairment In a non-randomized study in 2101 patients who underwent coronary artery bypass grafting and valve surgery, alone or combined, and who received either aprotinin (n ¼ 1898) or aminocaproic acid (n ¼ 203), operative mortality was higher with aprotinin in univariate analysis (4.3% versus 1%) but not propensity score-adjusted multivariate analysis (4% versus 0.9%) [200c]. In propensity score-adjusted analysis, aprotinin was also associated with a lower rate of blood transfusion (39% versus 50%), a lower rate of hemorrhage-related re-exploration (3.7% versus 7.9%), a higher risk of in-hospital cardiac arrest (3.7% versus 0%), and a marginally but not statistically significantly higher risk of acute renal failure (6.8% versus 2.6%). In Cox proportional hazards regression analysis, the risk of late death was higher with aprotinin (HR ¼ 4.33, 95% CI ¼ 1.60, 12). In a non-randomized study, 391 patients who were given aprotinin after median sternotomy for non-bypass surgery were compared with 370 controls; postoperative cardiac, renal, neurological, and respiratory complications and hospital mortality were similar in the two groups [201c]. In a matched cohort study, in which 200 patients who received high-dose aprotinin were compared with 200 age- and sexmatched patients who received tranexamic acid during primary isolated coronary surgery, there were no significant differences in fractional change in creatinine clearance or any other assessments of postoperative renal function between the two groups [202c]. Adverse events rates were also similar for early mortality (3.5% versus 4.5%), stroke

726

(1.5% versus 2%), re-operation for bleeding (3.5% versus 2.5%), and 5-year survival (87% versus 84%). Patients in the aprotinin group needed fewer transfusions (48% versus 61%) and fewer units of packed erythrocytes (2.0 versus 1.4) and plasma (1.3 versus 0.5), but more units of platelets (0.2 versus 0.1). In a single-center non-randomized study in patients undergoing primary cardiac operations, 3334 were given aprotinin and 3417 were not [203c]. The former were older, and had more unstable symptoms, lower ejection fractions, more preoperative hemodynamic support, more urgent operations, and more combined coronary or valvular operations. Postoperative bleeding and blood product transfusion were considerably reduced by aprotinin, as was median duration of mechanical ventilation. Aprotinin was not related to postoperative myocardial infarction, renal insufficiency, neurological dysfunction, or operative death. In a placebo-controlled study of 26 neonates who underwent cardiac surgery, aprotinin was not efficacious and had no deleterious effect on renal function; the authors suggested that it is unclear whether adverse reactions data on aprotinin from studies in adults are relevant to neonates [204c]. Similarly, in a controlled study in 31 patients who underwent neuromuscular scoliosis surgery, aprotinin reduced total blood loss and did not cause renal impairment. However, these studies were too small to draw any conclusions. In a retrospective survey of 200 neonates scheduled for palliative or corrective congenital cardiac surgery requiring cardiopulmonary bypass, 156 were given aprotinin and 44 were not [205c]. There was more renal dysfunction in those who received aprotinin, although the difference was not statistically significant. Time on bypass and age were significant predictors of postoperative renal dysfunction irrespective of the use of aprotinin. In a retrospective cohort study of 395 children who underwent cardiac surgery, 55% received aprotinin and 45% did not; 17% were neonates [206c]. Although there was a

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significant difference in the unadjusted risk of renal dysfunction, adjustment with the preoperative propensity score showed that there was no association between aprotinin and renal dysfunction (OR ¼ 1.32; 95% CI ¼ 0.55, 3.19). The duration of bypass was the only independent variable associated with renal dysfunction (OR ¼ 1.0; 95% CI ¼ 1.00, 1.01). Conclusions On the whole, although not exclusively, the positive associations of aprotinin with impaired renal function have come from systematic reviews and large randomized studies, while the negative studies have tended to be small or retrospective. Immunologic Allergic reactions to intravenous aprotinin continue to be reported, as in the case of a 67-year-old man who had been treated with an aprotinin-containing fibrin sealant and 3 years later had an anaphylactic reaction after intravenous administration of aprotinin, associated with aprotinin-specific IgG and IgE antibodies [207A], and a 66-year-old man who had anaphylactic shock within 2 minutes of a rapid infusion of aprotinin 4 million units following two previous infusions of 2 million units each [208A]. Death In a double-blind, randomized, placebo-controlled trial, 298 patients scheduled for low- or intermediate-risk firsttime cardiac surgery with cardiopulmonary bypass were randomized to tranexamic acid, high-dose aprotinin, or placebo. Neither antifibrinolytic agent increased the incidence of death [209C]. However, a meta-analysis, updated in the light of these data, still showed increased mortality attributable to aprotinin (OR ¼ 1.50; 95% CI ¼ 1.04, 2.27) [210M]. The problems with meta-analyses that include small trials whose primary aims were not relevant to the analyses have been highlighted, throwing doubts on meta-analyses that have not shown an increased mortality in patients who have received aprotinin [211H].

Drugs that affect blood coagulation, fibrinolysis, and hemostasis

Protamine [SED-15, 2964; SEDA-30, 417; SEDA-32, 646] Cardiovascular In 242 consecutive patients (mean age 58 years, 193 men) with drug refractory atrial fibrillation who underwent catheter ablation and received protamine immediately after catheter ablation to reverse the effects of heparin, 58 had prior exposure to protamine; three developed an adverse reaction to protamine (1.2%), each with profound hypotension [212c]. Life-threatening pulmonary vasoconstriction occurred in a 62-year-old male chronic smoker with long-standing systemic hypertension and hypercholesterolemia within 10 minutes of an intravenous infusion of protamine 4 mg/kg after coronary artery bypass graft surgery; the authors attributed this to the formation of large heparin–protamine complexes after rapid infusion of protamine [213A]. In another case acute pulmonary hypertension induced by protamine during elective coronary artery

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bypass surgery was refractory to inotropes and vasopressors, but responded to inhaled prostacyclin within 10 minutes [214A]. Immunologic Anaphylactic reactions to protamine sulfate during cardiac surgery have been systematically reviewed in a survey of nine retrospective studies and 16 prospective studies, of which only three of the latter were optimally designed as far as inclusion criteria, randomization, and description of symptoms were concerned; the incidence of anaphylactic reactions in the prospective studies was 0.69% and 0.19% in the retrospective studies [215M]. • A 72-year-old man developed hypotension and generalized urticaria during protamine infusion after coronary artery bypass grafting [216A]. There was no response to adrenaline, noradrenaline, vasopressin, diphenhydramine, hydrocortisone, calcium chloride, and crystalloid boluses, but 15 minutes after the administration of methylthioninium chloride 100 mg the blood pressure stabilized.

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injured patients. J Trauma 2008; 65(6): 1303–8. Adam JK, Rmaih WN. A double-blind placebo-controlled investigation of the psychomotor profile of clopidogrel in healthy volunteers. J Cardiovasc Pharmacol 2008; 52(6): 507–9. Maltais S, Perrault LP, Do QB. Effect of clopidogrel on bleeding and transfusions after off-pump coronary artery bypass graft surgery: impact of discontinuation prior to surgery. Eur J Cardiothorac Surg 2008; 34(1): 127–31. Ozao-Choy J, Tammaro Y, Fradis M, Weber K, Divino CM. Clopidogrel and bleeding after general surgery procedures. Am Surg 2008; 74(8): 721–5. Kim JH, Newby LK, Clare RM, Shaw LK, Lodge AJ, Smith PK, Jolicoeur EM, Rao SV, Becker RC, Mark DB, Granger CB. Clopidogrel use and bleeding after coronary artery bypass graft surgery. Am Heart J 2008; 156(5): 886–92. Serebruany V, Rao SV, Silva MA, Donovan JL, Kannan AO, Makarov L, Goto S, Atar D. Correlation of inhibition of platelet aggregation after clopidogrel with post discharge bleeding events: assessment by different bleeding classifications. Eur Heart J 2010; 31(2): 227–35. Matthews KE, Hameed B, Jawed S. Acute severe pancytopenia associated with clopidogrel. Br J Hosp Med (Lond) 2009; 70 (1): 52. Aronow HD, Steinhubl SR, Brennan DM, Berger PB, Topol EJ. CREDO Investigators. Bleeding risk associated with 1 year of dual antiplatelet therapy after percutaneous coronary intervention: insights from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. Am Heart J 2009; 157(2): 369–74. Goyal RK, Srivastava D, Lessnau KD. Clopidogrel-induced hepatocellular injury and cholestatic jaundice in an elderly patient: case report and review of the literature. Pharmacotherapy 2009; 29(5): 608–12. Ghosh SK, Bandyopadhyay D. Clopidogrel-induced fixed drug eruption. J Eur Acad Dermatol Venereol 2009; 23(10): 1202–3.

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[166] Blasco-Colmenares E, Perl TM, Guallar E, Baumgartner WA, Conte JV, Alejo D, Pastor-Barriuso R, Sharrett AR, Faraday N. Aspirin plus clopidogrel and risk of infection after coronary artery bypass surgery. Arch Intern Med 2009; 169(8): 788–96. [167] Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Méneveau N, Steg PG, Ferrières J, Danchin N, Becquemont L. French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360(4): 363–75. [168] Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360(4): 354–62. [169] Gladding P, Webster M, Zeng I, Farrell H, Stewart J, Ruygrok P, Ormiston J, ElJack S, Armstrong G, Kay P, Scott D, Gunes A, Dahl ML. The pharmacogenetics and pharmacodynamics of clopidogrel response: an analysis from the PRINC (Plavix Response in Coronary Intervention) trial. JACC Cardiovasc Interv 2008; 1(6): 620–7. [170] Mak KH, Bhatt DL, Shao M, Hankey GJ, Easton JD, Fox KA, Topol EJ. Ethnic variation in adverse cardiovascular outcomes and bleeding complications in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study. Am Heart J 2009; 157(4): 658–65. [171] Borderías Clau L, Garrapiz López J, Caballero G. Hemorragia pulmonary hemotórax tras ingesta masiva de clopidogrel con fines autolíticos. [Pulmonary haemorrhage and haemothorax after massive ingestion of clopidogrel as a suicide attempt.] Arch Bronconeumol 2009; 45 (11): 570–1. [172] Lindvall G, Sartipy U, Bjessmo S, Svenarud P, Lindvall B, van der Linden J. Aprotinin reduces the antiplatelet effect of clopidogrel. Interact Cardiovasc Thorac Surg 2009; 9(2): 178–81.

Drugs that affect blood coagulation, fibrinolysis, and hemostasis [173] Siller-Matula JM, Lang I, Christ G, Jilma B. Calcium-channel blockers reduce the antiplatelet effect of clopidogrel. J Am Coll Cardiol 2008; 52(19): 1557–63. [174] Gremmel T, Steiner S, Seidinger D, Koppensteiner R, Panzer S, Kopp CW. Calcium-channel blockers decrease clopidogrel-mediated platelet inhibition. Heart 2010; 96(3): 186–9. [175] Blagojevic A, Delaney JA, Lévesque LE, Dendukuri N, Boivin JF, Brophy JM. Investigation of an interaction between statins and clopidogrel after percutaneous coronary intervention: a cohort study. Pharmacoepidemiol Drug Saf 2009; 18(5): 362–9. [176] Malmström RE, Ostergren J, Jrgensen L, Hjemdahl P. CASTOR investigators. Influence of statin treatment on platelet inhibition by clopidogrel—a randomized comparison of rosuvastatin, atorvastatin and simvastatin co-treatment. J Intern Med 2009; 266(5): 457–66. [177] Farid NA, Small DS, Payne CD, Jakubowski JA, Brandt JT, Li YG, Ernest CS, Salazar DE, Konkoy CS, Winters KJ. Effect of atorvastatin on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in healthy subjects. Pharmacotherapy 2008; 28(12): 1483–94. [178] Norgard NB, Mathews KD, Wall GC. Drug-drug interaction between clopidogrel and the proton pump inhibitors. Ann Pharmacother 2009; 43(7): 1266–74. [179] Howard PA, Vacek JL. Potential interaction between clopidogrel and proton pump inhibitors. Am J Cardiovasc Drugs 2009; 9(6): 353–9. [180] Last EJ, Sheehan AH. Review of recent evidence: potential interaction between clopidogrel and proton pump inhibitors. Am J Health Syst Pharm 2009; 66(23): 2117–22. [181] Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV, Henry DA, Kopp A, Mamdani MM. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009; 180(7): 713–8. [182] Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, Rumsfeld JS. Risk

[183]

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of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009; 301(9): 937–44. Sibbing D, Morath T, Stegherr J, Braun S, Vogt W, Hadamitzky M, Schömig A, Kastrati A, von Beckerath N. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost 2009; 101(4): 714–9. Rassen JA, Choudhry NK, Avorn J, Schneeweiss S. Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome. Circulation 2009; 120(23): 2322–9. O’Donoghue ML, Braunwald E, Antman EM, Murphy SA, Bates ER, Rozenman Y, Michelson AD, Hautvast RW, Ver Lee PN, Close SL, Shen L, Mega JL, Sabatine MS, Wiviott SD. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials. Lancet 2009; 374(9694): 989–97. Small DS, Farid NA, Li YG, Ernest 2nd CS, Payne CD, Salazar DE, Winters KJ. Effect of ranitidine on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. Curr Med Res Opin 2008; 24(8): 2251–7. Bliden KP, Dichiara J, Lawal L, Singla A, Antonino MJ, Baker BA, Bailey WL, Tantry US, Gurbel PA. The association of cigarette smoking with enhanced platelet inhibition by clopidogrel. J Am Coll Cardiol 2008; 52(7): 531–3. Gremmel T, Steiner S, Seidinger D, Koppensteiner R, Panzer S, Kopp CW. Smoking promotes clopidogrel-mediated platelet inhibition in patients receiving dual antiplatelet therapy. Thromb Res 2009; 124(5): 588–91. Berger JS, Bhatt DL, Steinhubl SR, Shao M, Steg PG, Montalescot G, Hacke W, Fox KA, Lincoff AM, Topol EJ, Berger PB. CHARISMA Investigators. Smoking, clopidogrel, and mortality in patients with established cardiovascular disease. Circulation 2009; 120(23): 2337–44.

738 [190] Kammer RT. Successful clopidogrel desensitization after drug-eluting stent implantation. J Invasive Cardiol 2009; 21(3): 134–5. [191] Fajt M, Petrov A. Clopidogrel hypersensitivity: a novel multi-day outpatient oral desensitization regimen. Ann Pharmacother 2010; 44(1): 11–8. [192] McKenzie DB, Rao U, Hobson A, Levy T, Talwar S, Swallow R. A novel strategy for managing clopidogrel-induced adverse skin reactions. EuroIntervention 2009; 5 (4): 470–4. [193] Bellarosa I, Nargi L, Scarano V, Terracciano AM, Orlando V. Neutropenia indotta da ticlopidina. Un caso ad insorgenza ritardata. [Neutropenia induced by ticlopidine: a delayed onset case.] Recenti Prog Med 2009; 100(1): 27–30. [194] Kowalski R, Dropi nski J, Brzostek T, Szot P, Rzeszutko M, Kasper M, Sawicka A, Szczeklik A. Cholestatyczne zapalenie wątroby jako powikłanie leczenia tiklopidyną—opis przypadku. [Cholestatic hepatitis as a ticlopidine-induced complication of treatment—a case report.] Kardiol Pol 2008; 66(7): 758–60. [195] Bosman M, Royston D. Aprotinin and renal dysfunction. Expert Opin Drug Saf 2008; 7(6): 663–77. [196] Gagne JJ, Griesdale DE, Schneeweiss S. Aprotinin and the risk of death and renal dysfunction in patients undergoing cardiac surgery: a meta-analysis of epidemiologic studies. Pharmacoepidemiol Drug Saf 2009; 18(4): 259–68. [197] Olenchock Jr. SA, Lee PH, Yehoshua T, Murphy SA, Symes J, Tolis Jr. G. Impact of aprotinin on adverse clinical outcomes and mortality up to 12 years in a registry of 3,337 patients. Ann Thorac Surg 2008; 86(2): 560–6. [198] Martin K, Wiesner G, Breuer T, Lange R, Tassani P. The risks of aprotinin and tranexamic acid in cardiac surgery: a oneyear follow-up of 1188 consecutive patients. Anesth Analg 2008; 107(6): 1783–90. [199] Jakobsen CJ, Sndergaard F, Hjortdal VE, Johnsen SP. Use of aprotinin in cardiac surgery: effectiveness and safety in a population-based study. Eur J Cardiothorac Surg 2009; 36(5): 863–8.

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[200] Stamou SC, Reames MK, Skipper E, Stiegel RM, Nussbaum M, Geller R, Robicsek F, Lobdell KW. Aprotinin in cardiac surgery patients: is the risk worth the benefit? Eur J Cardiothorac Surg 2009; 36(5): 869–75. [201] Bittner HB, Lange M, Lemke J, Rastan A, Mohr FW. Aprotinin-associated risks in off-pump coronary artery bypass grafting. Thorac Cardiovasc Surg 2009; 57(8): 455–9. [202] Lindvall G, Sartipy U, Ivert T, van der Linden J. Aprotinin is not associated with postoperative renal impairment after primary coronary surgery. Ann Thorac Surg 2008; 86(1): 13–9. [203] Ngaage DL, Cale AR, Cowen ME, Griffin S, Guvendik L. Aprotinin in primary cardiac surgery: operative outcome of propensity score-matched study. Ann Thorac Surg 2008; 86(4): 1195–202. [204] Kasimian S, Skaggs DL, Sankar WN, Farlo J, Goodarzi M, Tolo VT. Aprotinin in pediatric neuromuscular scoliosis surgery. Eur Spine J 2008; 17(12): 1671–5. [205] Guzzetta NA, Evans FM, Rosenberg ES, Fazlollah TM, Baker MJ, Wilson EC, Kaiser AM, Tosone SR, Miller BE. The impact of aprotinin on postoperative renal dysfunction in neonates undergoing cardiopulmonary bypass: a retrospective analysis. Anesth Analg 2009; 108(2): 448–55. [206] Manrique A, Jooste EH, Kuch BA, Lichtenstein SE, Morell V, Munoz R, Ellis D, Davis PJ. The association of renal dysfunction and the use of aprotinin in patients undergoing congenital cardiac surgery requiring cardiopulmonary bypass. Anesth Analg 2009; 109(1): 45–52. [207] Kober BJ, Scheule AM, Voth V, Deschner N, Schmid E, Ziemer G. Anaphylactic reaction after systemic application of aprotinin triggered by aprotinincontaining fibrin sealant. Anesth Analg 2008; 107(2): 406–9. [208] Lango R, Kowalik MM, Klajbor K, Pawlaczyk R, Musiał-Swiatkiewicz V, Rogowski J. High-volume hemofiltration as rescue therapy for refractory shock after inadvertent rapid aprotinin administration. J Cardiothorac Vasc Anesth 2009; 23(4): 526–8.

Drugs that affect blood coagulation, fibrinolysis, and hemostasis [209] Later AF, Maas JJ, Engbers FH, Versteegh MI, Bruggemans EF, Dion RA, Klautz RJ. Tranexamic acid and aprotinin in low- and intermediaterisk cardiac surgery: a non-sponsored, double-blind, randomised, placebo-controlled trial. Eur J Cardiothorac Surg 2009; 36(2): 322–9. [210] Brown JR. Mortality manifesto: a metaanalysis of aprotinin and tranexamic acid mortality. Eur J Cardiothorac Surg 2009; 36(4): 781–2. [211] Rosén M. The aprotinin saga and the risks of conducting meta-analyses on small randomised controlled trials—a critique of a Cochrane review. BMC Health Serv Res 2009; 9: 34. [212] Chilukuri K, Henrikson CA, Dalal D, Scherr D, MacPherson EC, Cheng A, Spragg D, Nazarian S, Sinha S, Berger R, Marine JE, Calkins H. Incidence and outcomes of protamine reactions in patients undergoing catheter ablation of atrial

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fibrillation. J Interv Card Electrophysiol 2009; 25(3): 175–81. Hiong YT, Tang YK, Chui WH, Das SR. A case of catastrophic pulmonary vasoconstriction after protamine administration in cardiac surgery: role of intraoperative transesophageal echocardiography. J Cardiothorac Vasc Anesth 2008; 22(5): 727–31. Jerath A, Srinivas C, Vegas A, Brister S. The successful management of severe protamine-induced pulmonary hypertension using inhaled prostacyclin. Anesth Analg 2010; 110(2): 365–9. Nybo M, Madsen JS. Serious anaphylactic reactions due to protamine sulfate: a systematic literature review. Basic Clin Pharmacol Toxicol 2008; 103(2): 192–6. Del Duca D, Sheth SS, Clarke AE, Lachapelle KJ, Ergina PL. Use of methylene blue for catecholamine-refractory vasoplegia from protamine and aprotinin. Ann Thorac Surg 2009; 87(2): 640–2.

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36

Gastrointestinal drugs

[SED-15, 243; SEDA30, 423; SEDA-31, 573; SEDA-32, 665]

ANTACIDS

Drug–drug interactions Eltrombopag The effects of food and an antacid containing aluminum hydroxide and magnesium carbonate on the pharmacokinetics of eltrombopag have been studied in two single-dose, open, randomized-sequence, crossover studies in 18 and 26 healthy adults. Mean plasma AUC and Cmax fell by about 70% when eltrombopag was given with the antacid [1c]. Pirfenidone In an open, single-dose, crossover study of the effects of food and an antacid (MylantaÒ Maximum Strength Liquid) on the pharmacokinetics of pirfenidone in 16 healthy adults, co-administration with food reduced the rate and, to a lesser degree, the extent of pirfenidone absorption; the antacid had no significant effect [2c].

management of chemotherapy-induced nausea and vomiting in patients with cancer, nabilone, dronabinol, and levonantradol were superior to placebo and neuroleptic drugs [3M]. However, the cannabinoids caused adverse effects in some patients, even when they were given orally and even when their use was limited to 24 hours. Some untoward reactions occurred almost exclusively in patients who were exposed to them: paranoid delusions (5%), hallucinations (6%), and dysphoria and/or depression (13%). Although the patients had more adverse effects and greater intensity of symptoms during treatment with cannabinoids, most of the dropouts, associated with these events which were responsible for almost 30% of the nearly 400 dropouts in all the studies included in the systematic review, were probably not due to cannabinoid toxicity.

Cisapride ANTIEMETICS AND DRUGS THAT AFFECT GASTROINTESTINAL MOTILITY [SEDA-30, 423; SEDA-31, 573; SEDA-32, 665]

Cannabinoids (see also Chapter 4) Systematic reviews In a systematic review of the evidence for using cannabinoids in the Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00036-2 # 2011 Elsevier B.V. All rights reserved.

[SED-15, 789; SEDA-31, 573]

Cardiovascular The possible association between cisapride and ventricular dysrhythmias has been evaluated in a nested case– control study of 145 cases and 7520 controls exposed to cisapride, metoclopramide, or proton pump inhibitors [4C]. Cases included hospitalized patients with sudden cardiac death or ventricular dysrhythmias. Cisapride, but not metoclopramide, was associated with a two- to threefold increased risk of hospitalization for ventricular dysrhythmias, with a nearly eightfold risk during the initial prescription period. In this analysis, the risk associated with cisapride seemed not to be dose related, which implies one of four different interpretations: 741

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• The effect was not real. • The effect had its dose–response curve at much lower doses than the authors studied, and the reported observations were made at the top of the dose-response curve; this is unlikely in this case. • The interindividual variability was so large that it obscured the dose responsiveness; however, in that case the mean estimates of effect at each dose should have been dose-related, even if the overall relation was not apparently significant. • The dose–response curve for the effect was very shallow compared with the range of doses being studied.

In addition, the use of potentially dysrhythmogenic CYP3A4 inhibitors was associated with an increased risk, but this appeared to depend on a direct dysrhythmogenic effect of the drugs themselves, rather than on an interaction with cisapride.

Clebopride Nervous system An 83-year-old woman developed acute hemifacial dystonia, involving the masticatory and tongue muscles, after self-medication with clebopride 1.5 mg/day for constipation [5A]. She had a dystonic facial posture, with torsion and mouth deviation, while cranial/neck MRI and electroencephalography showed no abnormalities. The event persisted after reduction of the dosage of clebopride to 0.5 mg/day for 2 weeks, but resolved within 2 days after drug withdrawal. This event was interpreted as having resulted from extrapyramidal effects of clebopride, but a possible diagnosis of a transient ischemic attack was not considered.

Domperidone [SED-15, 1178; SEDA-30, 423; SEDA-32, 665] Comparative studies Regurgitation and gastroesophageal reflux are common pediatric problems, and cisapride is no longer available for this indication in several countries. Domperidone (0.8 mg/kg/day; n ¼ 10)

Corrado Blandizzi and Carmelo Scarpignato

and cisapride (0.8 mg/kg/day; n ¼ 10) have been compared in a single-blind, randomized trial in infants. Cisapride caused QT interval prolongation in one infant [6c]. Systematic reviews The efficacy of domperidone in diabetic gastroparesis has been evaluated in a systematic review of 28 clinical trials in a total of 1016 patients [7M]. Domperidone improved symptoms, enhanced gastric emptying, and reduced hospital admissions in 60–70% of trials. None of the studies assessed the risk of adverse reactions to domperidone versus comparators. The most common adverse reaction was hyperprolactinemia, but in no case was it serious.

Metoclopramide

[SED-15, 2317; SEDA-30, 423; SEDA-31, 574]

Comparative studies In a double-blind, randomized comparison of a single intravenous bolus dose of metoclopramide 10 mg or midazolam 2 mg in reducing emesis in 80 women undergoing elective cesarean delivery under spinal anesthesia (0.5% bupivacaine 10 mg), the frequency of intraoperative nausea and vomiting was lower with midazolam than with metoclopramide [8C]. However, sedation scores and the frequency of respiratory depression were higher with midazolam—17 of those who were given midazolam had a respiratory rate below 10/minute. Neonatal outcomes were similar in the two treatment groups, and all the neonates had Apgar scores over 8, evaluated at 1 and 5 minutes after delivery. Cardiovascular A 17-year-old man with a 3-year history of ulcer symptoms, diarrhea, and bouts of abdominal colic developed severe hypotension (50/20 mmHg) after receiving intravenous metoclopramide for acute vomiting with diarrhea [9A]. He then developed pneumonia, rhabdomyolysis, renal tubular necrosis, and disseminated intravascular coagulation. A diagnosis of gastrinoma was made. During hormonal assessment, he received a second dose of

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Chapter 36

metoclopramide for abdominal pain and vomiting. His condition then deteriorated again; his blood pressure fell to 90/50 mmHg, and he was resuscitated with plasma expanders and inotropic drugs. Although positive rechallenge in this case suggested a drug-related effect, the underlying neuroendocrine disorder with its autonomic consequences made it very difficult to interpret this particular adverse event. An 86-year-old man with a history of hypertension, hypothyroidism, and gastroesophageal reflux developed symptoms of cardiac failure while taking lisinopril, levothyroxine, and metoclopramide 10 mg qds [10A]. Furosemide administration was associated with renal impairment, and followed by QT interval prolongation, which evolved into torsade de pointes. After successful defibrillation, the QT interval prolongation persisted and resolved only after metoclopramide withdrawal. Nervous system A 40-year-old man was treated with metoclopramide by intravenous infusion of 10 mg over 5 minutes and famotidine 20 mg as premedication for elective endoscopic sinus surgery. About 10–15 minutes after metoclopramide administration, he developed agitation, tachycardia, and hypertension, which resolved after treatment with oxygen 2 liters/minute and intravenous diphenhydramine 25 mg [11M]. Endocrine Metoclopramide can cause gynecomastia, and has been reported to do so in a neonate. • A full-term male neonate with trisomy 21, patent ductus arteriosus, stridor, and feeding intolerance was thought to have irritation of the airways due to gastroesophageal reflux [12A]. He was given metoclopramide 0.15 mg/kg every 8 hours for 45 days. Owing to symptom persistence, lansoprazole 1.5 mg/ kg/day was added and the dose of metoclopramide was increased to 0.2 mg/kg every 6 hours. Two weeks later, he was noted to have prominent breasts (asymmetrical gynecomastia, greater on the right than on the left) with milk outflow. Serum prolactin concentrations were two times higher than the upper limit of the reference range, but scrotal ultrasound was normal. Metoclopramide was withdrawn and both the gynecomastia and galactorrhea

743 resolved within 1 week. The prolactin concentrations returned within the reference range 2 weeks after withdrawal

Drug dosage regimens The effect of the rate of infusion of metoclopramide on the incidence of acute akathisia has been investigated in a double-blind, randomized trial in 68 adults with acute nausea, vomiting, or migraine [13C]. They were randomized to one of two dosage regimens, in which metoclopramide 10 mg was given either as a 2-minute bolus or as an intravenous infusion over 15 minutes. They all received isotonic saline as a placebo in a doubledummy design, to maintain blinding. Of those who received bolus doses 11% developed akathisia, compared with none in the infusion group, supporting the conclusion that giving metoclopramide by infusion, rather than by bolus injection, will reduce the incidence of akathisia.

Prucalopride Prucalopride is the first of a new class (dihydrobenzofurancarboxamide derivatives) of highly selective 5HT4 receptor agonists, with strong enterokinetic activity and efficacy in patients with chronic constipation in whom laxatives do not provide adequate relief [14R]. It has affinity for other receptors, ion channels, and transporters at concentrations that exceed its 5HT4 receptor-affinity by at least 150 times, suggesting a wide safety margin at therapeutic doses. Placebo-controlled studies The efficacy and safety of prucalopride 2 or 4 mg/day for 12 weeks has been assessed in a double-blind, placebo-controlled trial in patients with severe chronic constipation [15C]. The most common drug-related adverse events included headache, abdominal pain, nausea, and diarrhea (which occurred mainly on day 1 of treatment). However, there were no differences in the incidences of serious adverse effects or cardiovascular events compared with placebo.

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In a double-blind, randomized, placebocontrolled trial of prucalopride 2 or 4 mg/day for 12 weeks in 716 patients with chronic constipation, the most common drug-related adverse events were headache, nausea, abdominal pain, and diarrhea [16C]. The overall incidence of prolongation of the QT interval was low and similar among all treatment groups. Withdrawals as a result of these adverse events accounted for a higher dropout rate in those who took prucalopride 4 mg/day (15%), than in the other treatment groups (6.3% and 6.7% with 2 mg/day and placebo respectively). In a phase II, double-blind, randomized, dose-escalation study of prucalopride 0.5, 1, and 2 mg/day for 28 days in 89 elderly chronically constipated patients in nursing homes, the most common adverse events, which were probably related to prucalopride, were diarrhea and abdominal pain [17C]. Relative to placebo, there were no differences in vital signs, electrocardiography, and the incidence of dysrhythmias.

Corrado Blandizzi and Carmelo Scarpignato

1 year in 780 women with functional dyspepsia, the most commonly reported adverse events occurred in the first 6 months and consisted mainly of diarrhea, headache, nausea, abdominal pain, vomiting, and constipation, all of which were mostly transient and mild or moderate in intensity [21C]. One patient developed bradycardia, dizziness, and hypoglycemia. There was no association of tegaserod with adverse cardiovascular events. Placebo-controlled studies The efficacy of tegaserod 6 mg bd for 6 weeks in 2667 women with dysmotility-like functional dyspepsia has been evaluated in two randomized, double-blind, placebo-controlled trials [22C]. There were some improvements in symptom severity and quality of life in those who took tegaserod, although the clinical implication of these improvements is uncertain. Diarrhea, requiring drug withdrawal, was more common with tegaserod than with placebo.

Tegaserod Tegaserod is a selective partial agonist at 5HT4 receptors, which normalizes gastrointestinal function by stimulating neurotransmitter release from enteric nerves. The resulting effects include increased intestinal secretions and contractility, enhancement of peristaltic and secretory reflexes, and inhibition of visceral afferent responses involved in abdominal pain signal transmission. Tegaserod has been used in women with irritable bowel syndrome associated with constipation and in patients with idiopathic constipation [18R]. However, marketing was suspended at the request of regulatory authorities after they had reviewed reports of ischemic cardiovascular events in patients who had been enrolled in double-blind trials [19R], although these findings were not confirmed in a matched case-control study [20C]. Observational studies In two prospective cohort studies of tegaserod 6 mg bd for

5HT 3 RECEPTOR ANTAGONISTS [SED-15, 1365; SEDA-30, 423; SEDA-31, 575; SEDA-32, 666] Comparative studies Azasetron versus ondansetron Intravenous azasetron 10 mg and ondansetron 8 mg have been compared in a double-blind, randomized trial in 98 patients with postoperative nausea and vomiting after gynecological laparoscopic surgery under general anesthesia [23C]. Azasetron was more efficacious in the intermediate postoperative period (12–24 hours). Both drugs caused headache, dizziness, and constipation and the frequencies were similar. Granisetron versus palonosetron In a randomized, double-blind comparison of a single intravenous dose of palonosetron 0.25 mg and granisetron 3 mg in 208 patients with cancer who were about to

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Chapter 36

receive highly emetogenic chemotherapy, palonosetron was non-inferior to granisetron and there were no clinically relevant differences in the overall incidences of adverse events [24C]. The main adverse events were: headache (1% in both groups), constipation (1% in both groups), and hypokalemia (1.9% versus 1%). Single-dose intravenous palonosetron 0.75 mg and granisetron 40 micrograms/kg (both combined with intravenous dexamethasone and given 30 minutes before highly emetogenic chemotherapy) have been compared in a double-blind, randomized study in 1114 patients with cancer [25C]. Palonosetron was non-inferior to granisetron in the acute phase of vomiting, but significantly better in the delayed phase. The main adverse events were constipation (17% versus 16%), raised serum aminotransferases activities (aspartate aminotransferase 4.3% versus 6%; alanine aminotransferase 2.9% versus 5.9%), headache (3.2% versus 3.7%), and QT interval prolongation (2.7% versus 3.2%). One patient developed hepatitis possibly related to palonosetron. Granisetron versus ramosetron In a doubleblind, randomized comparison of ramosetron or granisetron 3 mg, each given with dexamethasone 20 mg, for the prevention of acute chemotherapy-induced nausea and vomiting in 285 patients with cancer who were scheduled to receive cisplatin, doxorubicin, epirubicin, or oxaliplatin, the ramosetron combination was non-inferior to the granisetron combination in preventing nausea and vomiting [26C]. Seven patients (2.46%; 3 in the ramosetron group and 4 in the granisetron group) had drug-related adverse effects of mild to moderate intensity, which included raised liver enzymes and uric acid, hiccups, rash, and constipation. Ondansetron versus ramosetron In a double-blind, randomized study of intravenous ramosetron 0.3 mg and ondansetron 4 mg followed by 12 mg in preventing nausea and vomiting related to opioid-based patient-controlled analgesia in 94 women

745

subjected to lumbar spine surgery, ramosetron was superior to ondansetron, and the proportion of patients who had headache, drowsiness, and dizziness was higher in those who received ondansetron [27C].

Alosetron

[SEDA-29, 372; SEDA-30, 423; SEDA-31, 575; SEDA-32, 666]

A quantitative benefit-harm balance analysis of alosetron for the treatment of irritable bowel syndrome from the patient's perspective has been reported [28C]. There was greater than 99% chance that both the incremental benefit and the incremental risk associated with alosetron are greater than with placebo. The incremental net benefit of alosetron was greatest in patients with the worst quality of life at baseline.

Azasetron Azasetron, a potent selective 5HT3 receptor antagonist, is a benzamide derivative that has a different chemical structure and a longer duration of action than other 5HT3 receptor antagonists, such as granisetron, ondansetron, and tropisetron [29E]. For a comparison of azasetron with ondansetron, see above.

Dolasetron Drug–drug interactions See “Neurokinin NK1 receptor antagonists” below.

Granisetron Drug–drug interactions See “Neurokinin NK1 receptor antagonists” below.

Ondansetron Cardiovascular There have been reports of bradycardia attributed to ondansetron [30A]. • An 8-year-old child with a perianal abscess was given intravenous ondansetron 2 mg and

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within 2–3 minutes developed severe sinus bradycardia (16/minute), which resolved after intravenous atropine 0.2 mg and ventilation with 100% oxygen. • A 60-year-old man with gastric carcinoma was given intravenous glycopyrrolate 10 mg/kg followed by ondansetron 4 mg as pre-medication for surgical operation. Within 2 minutes from ondansetron administration, the patient developed severe bradycardia (20 beats/min) associated with respiratory arrest and loss consciousness, which was resolved by intravenous administration of atropine 0.6 mg and ventilation with 100% oxygen.

Other cardiac dysrhythmias have also been reported [31A]. • Postoperatively, a 51-year-old man was given intravenous ondansetron 4 mg and glycopyrrolate 0.3 mg, followed by intravenous ondansetron 4 mg about 3 hours later. Immediately after the second dose he vomited and complained of chest pain. Electrocardiography showed ST segment elevation and new-onset atrial fibrillation. The systolic blood pressure fell from 160 to 90 mmHg, and the QTc interval increased from 416 to 457 ms. Cardiac investigations, including troponin concentrations, catheterization, and transesophageal echocardiography, were normal. Electrical cardioversion restored sinus rhythm. His symptoms and cardiac dysrhythmia did not recur during the next 3 years.

Nervous system A 26-year-old woman undergoing emergency cesarean delivery under spinal anesthesia with bupivacaine 10 mg was pre-medicated with intravenous ranitidine 50 mg and metoclopramide 10 mg, and received intramuscular diclofenac for postoperative analgesia [32A]. Starting at 12 hours postoperatively she was given intravenous ondansetron 6 mg every 12 hours for nausea and vomiting. About 2 hours after the first dose she developed a severe headache, which persisted for over 90 hours and was characterized by aggravation of symptoms in coincidence with doses of ondansetron. The headache resolved completely a few hours after ondansetron withdrawal. Ondansetron has both proconvulsant and anticonvulsant effects in animals. Seizures have been reported in two women and one man (ages 38–56 years) after

Corrado Blandizzi and Carmelo Scarpignato

intravenous administration of ondansetron 4 mg in order to manage severe nausea and vomiting associated with migraine, gastritis, and diabetic ketoacidosis [33A]. They had generalized tonic–clonic seizures 12, 15, and 22 minutes after the injection. In all cases, brain MRI and electroencephalography were normal, the seizures resolved spontaneously, and there were no relapses. Liver Rises in serum aminotransferases have been attributed to ondansetron [34A]. • A 44-year-old woman with extensive coronary artery disease developed nausea, shortness of breath, and angina unrelieved by sublingual glyceryl trinitrate. Her other drug therapy consisted of gemfibrozil 600 mg bd, aspirin 81 mg/day, clopidogrel 75 mg/day, omeprazole 20 mg/day, and duloxetine 60 mg/day. She was given intravenous ondansetron 4 mg and morphine 4 mg, sublingual glyceryl trinitrate 0.4 mg, oral aspirin 325 mg and clopidogrel 75 mg, and heparin 60 U/kg. The chest pain resolved. On the next day her aminotransferase activities increased to nearly 18 times the upper limit of the reference range, in the absence of other abnormalities of liver function or liver ultrasonography. Ondansetron was withdrawn and the aminotransferases promptly fell and normalized within a few days.

Immunologic Hypersensitivity reactions to ondansetron are rare but have been reported, including both IgE- and nonIgE-mediated anaphylactic reactions. • A 44-year-old woman was given ondansetron, vecuronium, and propofol at induction for elective surgery and immediately became hypotensive (60/30 mmHg) [35A]. There were no accompanying skin or systemic symptoms, and the episode resolved completely after treatment with intravenous adrenaline, promethazine, hydrocortisone, and fluids. Subsequent skin prick tests with ondansetron, vecuronium, and propofol were negative, but intradermal testing with ondansetron 0.02 mg/ml produced a positive wheal reaction.

Drug overdose Severe toxicity occurred in a 12-month-old boy who unintentionally took 7 or 8 tablets of ondansetron 8 mg (5.6–6.4 mg/kg against a therapeutic dosage of 0.15 mg/kg), and developed obtundation and myoclonic movements of the limbs

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within 20 minutes [36A]. He then developed seizures, hepatotoxicity, QT interval prolongation, and serotonin syndrome, which required endotracheal intubation and treatment with intravenous midazolam, morphine, and suxamethonium. A brief generalized tonic–clonic seizure, associated with significant oxygen desaturation, was treated with lorazepam. His conditions improved over the course of 24 hours with supportive care and there were no sequelae.

• A 43-year-old woman with breast cancer and no history of seizures was scheduled to undergo chemotherapy with cyclophosphamide, 5-fluorouracil, and epirubicin and to receive antiemetic treatment with intravenous dexamethasone 8 mg and palonosetron 0.25 mg. During the fourth cycle of chemotherapy, she developed a generalized tonic– clonic seizure, which lasted 8 minutes and was followed by a period of drowsiness. She was given intravenous diazepam 10 mg and a saline infusion. Detailed investigations, including brain CT scan, did not reveal abnormalities, and she recovered completely.

Drug–drug interactions Droperidol In a double-blind, randomized, crossover study 16 healthy volunteers were treated with single intravenous doses of ondansetron 4 mg, droperidol 1 mg, or ondansetron 4 mg þ droperidol 1 mg, in order to assess the effects of these drugs on QT interval duration [37C]. Droperidol and ondansetron, alone and in combination, induced significant QT interval prolongation. However, the combination did not significantly increase QT prolongation compared with droperidol alone.

Although other 5HT3 receptor antagonists (particularly ondansetron) have been previously reported to cause seizures, in this case the role of palonosetron was uncertain.

Palonosetron Palonosetron is a second-generation, potent, highly selective 5HT3 receptor antagonist, with high binding affinity to the receptor and a long terminal half-life (about 40 hours), which is effective as a single-dose treatment in preventing both acute and delayed nausea and vomiting associated with both moderately and highly emetogenic chemotherapy [38R]. The most common adverse reactions in clinical trials include headache (9%) and constipation (5%). Less frequent adverse effects (<1%) involved the cardiovascular system (tachycardia, sinus dysrhythmia, supraventricular extra beats, and QT interval prolongation), the gastrointestinal system (diarrhea, dyspepsia, abdominal pain, dry mouth, and flatulence), the nervous system (dizziness, somnolence, insomnia, hypersomnia, and paresthesia), and altered hearing and vision. Nervous system A seizure has been attributed to palonosetron [39A].

Drug dosage regimens Different single intravenous doses of palonosetron (0.025, 0.050, and 0.075 mg) have been compared with placebo in a double-blind, randomized study of its use in preventing postoperative nausea and vomiting in 489 patients undergoing either outpatient abdominal or gynecological laparoscopic surgery [40C]. There was a dose–response trend in the proportion of patients with a complete antiemetic response, and the effect over placebo was significant at the highest dose. Most of the adverse events were of mild to moderate intensity, and they were not apparently dose related. The most common treatmentrelated adverse events with placebo and the three doses of palonosetron were headache (4%, 4%, 7%, and 3% respectively) and constipation (3%, 2%, 4%, and 3%). No patients withdrew because of serious adverse events. QT intervals were similar in all the groups.

Ramosetron Ramosetron is a selective 5HT3 receptor antagonist, which has a high receptor binding affinity due to a slow dissociation rate, resulting in more potent and more prolonged receptor blockade and antiemetic effects compared with older 5HT3 receptor antagonists [41R].

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Drug–drug interactions Fluvoxamine In an open crossover study in healthy men and women who took a single dose of ramosetron 10 micrograms, steady-state fluvoxamine 50 mg/day increased the Cmax and AUC of ramosetron by 42% (90% CI ¼ 35, 49) and 178% (90% CI ¼ 153, 205) respectively [42c].

NEUROKININ NK 1 RECEPTOR ANTAGONISTS [SEDA-32, 667]

Corrado Blandizzi and Carmelo Scarpignato

HISTAMINE H 2 RECEPTOR ANTAGONISTS [SED-15, 1629; SEDA-30, 423; SEDA-31, 576; SEDA-32, 667]

Cimetidine Hematologic There have been a few reports of immune hemolytic anemia in association with cimetidine, but without convincing evidence of an association. Now there has been a report of a hemolytic anemia in which the direct antiglobulin test was positive (C3 only) and a serum antibody to cimetidine was detected; an eluate from the patient's erythrocytes was non-reactive [45A].

Aprepitant and fosaprepitant A single intravenous dose of fosaprepitant 115 mg, a prodrug of aprepitant, is bioequivalent to oral aprepitant 125 mg. Cardiovascular In a double-blind, activecontrolled, randomized, three-treatment, three-period, crossover study in young healthy subjects fosaprepitant 200 mg had no effect on the QT interval; moxifloxacin 400 mg had the expected effect [43C].

Casopitant Drug–drug interactions 5HT3 receptor antagonists The effects of casopitant, a neurokinin NK1 receptor antagonist, on the pharmacokinetics of dolasetron 100 mg/day for 3 days and granisetron 2 mg/day for 3 days have been studied in a phase I, open, single-sequence study in 18 and 19 healthy subjects respectively [44c]. The largest changes in exposure to hydrodolasetron after co-administration with casopitant were seen in CYP2D6 extensive metabolizers, with a 24% increase in AUC on day 1 and a 30% increase in Cmax on days 1 and 3; these changes were not considered to be clinically important. Granisetron exposure was not significantly altered.

Famotidine Liver Famotidine has been associated with acute hepatitis in a 47-year-old man with a history of hepatitis C [46A].

Ranitidine Immunologic The incidence of anaphylactic reactions to ranitidine has been reported to be 0.3–0.7%. Two cases of anaphylactic shock have been attributed to intravenous ranitidine, in one case fatal. • A 51-year-old man had a prostate resection under epidural anesthesia and 24 hours later was given a single intravenous dose of ranitidine 50 mg in isotonic saline as prophylaxis for stress ulceration [47A]. Within a few minutes he developed a combination of wheezing, dyspnea, and hypotension, followed by loss of consciousness. Despite intensive resuscitation attempts, he died 30 minutes later. Autopsy showed pulmonary congestion with widespread upper airway edema and petechial hemorrhages and brain swelling with diffuse petechial hemorrhages. Histology confirmed the presence of widespread hypolaryngeal and pharyngeal edema with an inflammatory cell infiltrate and abundant mast cells. • A 47-year-old woman developed an anaphylactic reaction to ranitidine used as intravenous premedication before induction of anesthesia [48A]. She had previously used oral

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ranitidine for peptic ulceration without any adverse reactions. An intradermal test with ranitidine at a dilution of 1:100 was intensely positive.

Drug–drug interactions Clopidogrel and prasugrel In an open crossover study in 47 healthy men, ranitidine had no significant effect on the AUC, Cmax, or tmax of the active metabolites of clopidogrel 75 mg/ day or prasugrel 10 mg/day for 7 days [49c].

HELICOBACTER PYLORI ERADICATION REGIMENS [SED-15, 1586; SEDA-30, 425; SEDA-31, 579]

Lansoprazole þ amoxicillin þ metronidazole or clarithromycin There is limited information on Helicobacter pylori eradication in children in developing countries. In a study of 2-week triple therapy in Vietnam, 238 H. pylori infected children aged 3–15 years (mean 8.6) were divided into two weight categories 13–22 and 23–45 kg [50C]. The former received lansoprazole 15 mg/day þ amoxicillin 500 mg bd þ either metronidazole 250 mg bd or clarithromycin 250 mg/day. The latter received twice daily lansoprazole 15 mg þ amoxicillin 750 mg þ either metronidazole 500 mg or clarithromycin 250 mg. Adverse events included a burning sensation in the mouth, a metallic taste in the mouth, abdominal pain, nausea, vomiting, dizziness, headache, and rash.

PROTON PUMP INHIBITORS [SED-15, 2973; SEDA-30, 424; SEDA-31, 577; SEDA-32, 667] Comparative studies Esomeprazole versus lansoprazole In an open, randomized, comparative study of esomeprazole 40 mg/day

749

and lansoprazole 30 mg/day in patients with Barrett's esophagus, the most common adverse events in those taking esomeprazole were pharyngolaryngeal pain, sinusitis, and headache [51c]. In contrast, the most common adverse events in those taking lansoprazole were diarrhea, nausea, anxiety, and headache. Only two patients had treatment-related adverse events, both while taking lansoprazole; these included three cases of diarrhea and one of abdominal pain. Esomeprazole versus rabeprazole In a multicenter, double-blind, double dummy, randomized, non-inferiority comparison of rabeprazole 20 mg/day and esomeprazole 20 or 40 mg/day for 4 weeks in primary care in 1392 patients with gastroesophageal reflux disease complaining of heartburn, with or without regurgitation, 800 adverse events were recorded in 464 patients and 13 required hospitalization (rabeprazole 20 mg: 1.7%; esomeprazole 20 mg: 2.7%; esomeprazole 40 mg: 0.4%) [52C]. The most common adverse events for rabeprazole 20 mg/day, esomeprazole 20 mg/day, and esomeprazole 40 mg/day respectively were: gastrointestinal signs and symptoms (n ¼ 86, 77, 80), gastrointestinal motility and defecation disorders (n ¼ 26, 40, 32), headache (n ¼ 22, 32, 30), and infections (n ¼ 22, 29, 10). There was a statistically significant difference between treatments for the number of adverse events considered by the investigator to be treatment related; the highest proportion of therapyrelated adverse events occurred with esomeprazole 20 mg/day. However, no plausible biological mechanism could be proposed for these findings. In an open study of lansoprazole in the prevention of relapse of erosive esophagitis, 206 of 241 patients (85%) healed after treatment with lansoprazole 30 mg/day for 8 weeks [53c]. They then received doubleblind maintenance treatment with lansoprazole 15 mg/day or ranitidine 150 mg bd for up to 1 year. During the 8-week treatment period, 37 (15%) of 241 patients taking lansoprazole reported at least one adverse event that was considered to be possibly

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or probably related to treatment. The only event reported by more than 5% of patients was diarrhea (6% of patients). Seven patients discontinued treatment because of the following adverse events: abdominal pain (two patients); myalgia; abdominal and chest pain; abdominal pain and flatulence; anorexia and nausea; headache. During the comparative phase of the study, the most frequently reported adverse events were abdominal pain (5%) and headache (5%) with lansoprazole, and headache (6%) with ranitidine. Systematic reviews Laboratory and clinical evidence suggest that the increase in gastric pH caused by proton pump inhibitors may be linked to increased bacterial colonization of the stomach and may predispose patients to an increased risk of respiratory infections. The association of proton pump inhibitors (esomeprazole, rabeprazole, pantoprazole, and omeprazole) with respiratory infections has been studied in a systematic review of seven studies, four of which showed a trend towards an association, although most of the studies failed to show a significant correlation [54M].

Dexlansoprazole Dosage formulations Dexlansoprazole MR is a modified-release formulation of dexlansoprazole, an enantiomer of lansoprazole, which uses an innovative dual delayed release (DDR) technology designed to prolong the plasma dexlansoprazole concentration versus time profile and provide extended duration of acid suppression with once-daily dosing [55R]. The DDR formulation uses different types of granules with pH-dependent dissolution profiles that release dexlansoprazole at different times and over a longer period of time. Dexlansoprazole MR must therefore be administered at a higher daily dose than conventional delayed-release lansoprazole. In a randomized, placebo-controlled study, 451 patients who had had their erosive esophagitis healed in two previous

Corrado Blandizzi and Carmelo Scarpignato

dexlansoprazole MR healing trials took placebo or lansoprazole MR 60 or 90 mg/day for 6 months [56C]. The most common treatment-emergent adverse events respectively were: diarrhea (<1%, 6%, and 7%); gastritis (<1%, 6%, and 4%); gastrointestinal and abdominal pain (1%, 6%, and 4%); flatulence, bloating, and distension (0%, 5%, and 2%); and respiratory tract infections (4%, 3%, and 7%). The increases in fasting serum gastrin concentrations with dexlansoprazole MR 60 and 90 mg were within the range expected with proton pump inhibitors; however, no patients developed neuroendocrine cell proliferation, enterochromaffin-like cell hyperplasia, or adenocarcinomas.

Esomeprazole Gastrointestinal Lansoprazole has been associated with diarrhea and microscopic colitis, but this association has not been clearly established with other proton pump inhibitors. Microscopic colitis has been reported after treatment with esomeprazole (two cases) and omeprazole (two cases) [57A].

Lansoprazole

[SEDA-31, 578;

SEDA-32, 668] Observational studies The long-term clinical safety of dose-titrated lansoprazole 15–120 mg/day as maintenance therapy has been assessed in an open study for up to 82 months in 195 subjects who had achieved healed erosive reflux esophagitis in a phase III multicenter trial [58C]. There were 2825 treatment-emergent adverse events in 189 subjects (97%); most of them occurred during the first year of treatment, were mild or moderate in intensity, and resolved during treatment. Of 155 serious adverse events in 74 patients, only two (colitis and rectal hemorrhage in one subject) were considered to have been treatment related. There were 187 treatment-related adverse events in 69 subjects (35%),

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diarrhea (10%), headache (8%), and abdominal pain (6%) being the most common. Serum gastrin concentrations over 400 pg/ ml were recorded in 9%. However, in these patients hypergastrinemia was not associated with any gastrointestinal adverse event or presence of gastric nodules/polyps. Placebo-controlled studies In a 4-week multicenter, double-blind, parallel-group, randomized study of lansoprazole in 162 infants aged 1–12 months with persistent symptoms attributed to gastroesophageal reflux disease there was no difference between lansoprazole and placebo in terms of efficacy [59C]. However, serious adverse events, particularly lower respiratory tract infections, occurred in 12 infants, and were significantly more common with lansoprazole. Urinary tract Acute tubulointerstitial nephritis has been reported with proton pump inhibitors, and although it is rare it tends to occur more commonly in elderly patients. • A 70-year-old Caucasian developed nausea, and loose stools after taking lansoprazole for 4 days, and stopped taking it. He had also taken omeprazole intermittently, and had taken the last dose of 4 weeks earlier. He was taking lisinopril for hypertension. The blood urea nitrogen and creatinine concentrations were raised but urine analysis and renal ultrasound were normal. Lisinopril was withdrawn. A renal biopsy showed diffuse infiltration with lymphocytes, monocytes, and occasional eosinophils, normal glomeruli, and mild changes suggestive of acute tubulointerstitial nephritis.

Based on literature data and the temporal relationship, this adverse event was attributed to lansoprazole, although the association was by no means clear [60A]. Immunologic Kounis syndrome (acute myocardial infarction following an allergic reaction) has been associated with lansoprazole [61A]. • A 52-year-old-man developed generalized itching, malaise, shortness of breath, difficult in swallowing, abdominal pain, and numbness

751 all over the body. He had an erythematous rash covering the whole body and facial edema. He was pale, sweating, and agitated. His symptoms started 10 minutes after a dose of lansoprazole 30 mg for abdominal pain. After treatment with intravenous hydrocortisone sodium succinate 500 mg and dimetiridene 4 mg plus an inhaled glucocorticoid, he suddenly developed severe retrosternal pain radiating to both arms and started vomiting. There was ST segment elevation, compatible with an acute inferior myocardial infarction. The serum troponin T and creatinine kinase were increased. The blood eosinophil count was 9%. Coronary angiography showed a 90% right coronary artery lesion, which was successfully stented. A skin prick test with lansoprazole elicited a wheal of 3 mm at 20 minutes; there was no reaction with omeprazole, pantoprazole, ranitidine, or buffered saline, confirming only lansoprazole hypersensitivity.

Omeprazole and esomeprazole [SED-15, 1252, 2615; SEDA-30, 424; SEDA-31, 578; SEDA-32, 668] Mineral and metal metabolism Severe hypomagnesemia impairs parathyroid hormone (PTH) secretion and is a recognized cause of hypocalcemia. Proton pump inhibitors have been associated with cases of symptomatic hypocalcaemia and hypomagnesemia [62A] and with refractory chronic hypokalemia and hypocalcemia secondary to hypomagnesemia, which resolved after withdrawal of omeprazole [63A]. Gastrointestinal Two cases of microscopic colitis associated with omeprazole have been reported [57A]. Urinary tract Severe acute tubulointerstitial nephritis with tubular atrophy and minimal fibrosis has been reported in a 69-year-old Caucasian man who was taking irbesartan, hydrochlorothiazide, ezetimibe, and omeprazole [64M]. Withdrawal of irbesartan and hydrochlorothiazide had no effect. Omeprazole was withdrawn, and there was dramatic improvement.

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Immunologic Allergic reactions have been attributed to omeprazole [65A]. • Itching of the palms, facial angioedema, generalized urticaria, bronchospasm, dizziness, and collapse occurred in a 37-year-old woman 15 minutes after taking a capsule of omeprazole. She had previously taken omeprazole several times without problems, and had no history of atopy. Skin prick tests with commercial common inhalant, food allergens, other imidazole derivatives (ketoconazole, metronidazole), lansoprazole, pantoprazole, rabeprazole, and esomeprazole were negative, but skin prick and intradermal tests with omeprazole were positive. A serum analysis was negative for specific IgE to omeprazole. Oral challenges with lansoprazole, pantoprazole, and the capsule shell caused no reactions. • A 58-year-old man developed generalized urticaria, vomiting, and diarrhea 1 hour after taking an omeprazole capsule; 15 days later he received an intravenous injection of pantoprazole before a surgical operation and 5 minutes later developed generalized itching, shock, and loss of consciousness. Skin prick and intradermal tests were positive with omeprazole and pantoprazole, while skin prick tests with esomeprazole, lansoprazole, and rabeprazole were negative, as was an oral challenge with esomeprazole. Of note, this patient, who was sensitive to omeprazole, tolerated esomeprazole, the S-enantiomer of omeprazole.

The second case highlights cross-reactivity among the drugs of this class, which is at variance with previous reports of anaphylactic reactions to proton pump inhibitors.

Pantoprazole Observational studies Stress ulcer prophylaxis with ranitidine has been associated with an increased risk of ventilator-associated pneumonia. The use of proton pump inhibitors has also been linked to an increased risk of community-acquired pneumonia, and pantoprazole is commonly used in stress ulcer prophylaxis. In a retrospective observational study the database of a cardiothoracic surgery unit was used to identify all patients who had received stress ulcer prophylaxis with pantoprazole or ranitidine; 887 patients met the inclusion criteria [66c]. Nosocomial pneumonia was

Corrado Blandizzi and Carmelo Scarpignato

found to have developed in 35 of 377 patients (9.3%) who had received pantoprazole, compared with 7 of the 457 patients (1.5%) who had received ranitidine (OR ¼ 6.6; 95% CI ¼ 2.9, 15). After propensity-adjusted multivariate logistic regression, pantoprazole was found to be an independent risk factor for nosocomial pneumonia (OR ¼ 2.7; 95% CI ¼ 1.1, 6.7). Hematologic Some reports have highlighted cases of thrombocytopenia associated with proton pump inhibitors in adults and possible pantoprazole-induced thrombocytopenia has also been reported in an infant [67A]. In an 8-week, open, prospective, multicenter, community-based, post-marketing study of oral rabeprazole 20 mg/day in 2579 patients with erosive esophagitis the most commonly reported adverse events included abdominal pain (1.2%), chest pain (0.5%), diarrhea (1.5%), dizziness (0.7%), dyspepsia (0.6%), belching (0.5%), headache (1.6%), nausea (1.0%), rash (0.5%), and upper respiratory tract infection (0.5%) [68c]. At least one adverse event was reported by 15% of patients, 2.4% withdrew because of adverse events, and 1.4% reported a serious adverse event. All serious adverse events were considered to be unrelated to rabeprazole, except for one case of esophageal spasm. Three patients died during the study, but the deaths were judged to be unrelated to the study drug. A total of 2.2% of patients were hospitalized after the initiation of rabeprazole treatment. Some of these hospitalizations occurred as a result of serious adverse events, most commonly involving the cardiovascular system; however, none of these were considered by investigators to be related to rabeprazole.

OTHER ULCER-HEALING AGENTS Bismuth compounds

[SED-15, 518]

Mouth Black tongue has been associated with bismuth compounds, and has again been reported, this time in a 55-year-old

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man with metastatic melanoma who chewed two Pepto-Bismol (bismuth subsalicylate) tablets before going to sleep [69A]. His black tongue was then noticed on the following morning. The patient agreed to a re-challenge and chewed two tablets at 23.00 h; there was no change in the color of his tongue 2 hours later, but at 10.00 hours the next morning his tongue was black again; later that night, it had spontaneously regained its normal pink color.

dried senna leaves and drink about 200 ml/day, developed epigastric pain, anorexia, episodic vomiting, and intermittent fever [71A]. A color Doppler scan showed a thrombus occluding the portal vein bifurcation and the right branch, with complete interruption of blood flow. Treatment with tissue plasminogen activator (intravenous infusion of 50 mg total over 48 hours), followed by enoxaparin sodium 4000 IU/day for 14 days and then warfarin 7.5 mg/day for 2 months failed to resolve the portal obstruction.

LAXATIVES AND ORAL BOWEL PREPARATIONS

Gastrointestinal A 74-year-old woman developed severe melanosis coli of the whole colon after using anthraquinone laxatives over many decades [72A]. Endoscopy showed marked black pigmentation of the colonic mucosa, which was confirmed by histology as widespread lipofuscin granulation. Several adenomatous lesions were found, although no colorectal cancer was detected.

[SED-15, 2008; SEDA-30, 426; SEDA-31, 581; SEDA-32, 668] Comparative studies In a randomized study, patients took Pico-SalaxÒ (a smallvolume, osmotically active laxative containing sodium picosulfate 10mg þ magnesium oxide 3.5 g) at 17.00 and 22.00 hours the night before colonoscopy, having taken bisacodyl 10 mg at 17.00 hours on the two previous evenings (n ¼ 105), or Pico-Salax alone at 17.00 and 22.00 hours the night before colonoscopy (n ¼ 109), or oral sodium phosphate at 17.00 and 22.00 hours the night before colonoscopy (n ¼ 101). All were encouraged to drink 3–4 liters of Gatorade or other clear fluids the night before the colonoscopy. More of the patients who took oral sodium phosphate reported nausea compared with Pico-Salax alone (40% versus 22%) and Pico-Salax þ bisacodyl (19%). There was a rise in serum phosphate and a reciprocal fall in serum calcium in a significant number of those who took oral sodium phosphate. Significantly more of those who took oral sodium phosphate than Pico-Salax had hypokalemia (oral sodium phosphate 73% versus Pico-Salax þ bisacodyl 10%) [70M].

Anthraquinones Cardiovascular A 42-year-old woman, who for 2 years had been accustomed to boil

Bisacodyl Comparative studies A high oral dose of bisacodyl (30 mg) plus water lavage (2 liters) and oral sodium phosphate (90 ml in divided doses) has been evaluated in a randomized study in 276 adults undergoing elective colonoscopy [73c]. There was more nausea in those who took sodium phosphate compared with bisacodyl (28% versus 7%). There were no significant differences between the two groups in overall tolerance (95% versus 96%), vomiting (4% versus 2%), or abdominal cramps (31% versus 34%). Drug dosage regimens Three low-volume regimens, consisting of an oral sodium phosphate solution 45/45 ml, a reduceddose oral sodium phosphate solution 45/30 ml, and polyethylene glycol þ bisacodyl have been evaluated in a single-blind, randomized study in 121 adults who were scheduled to undergo screening colonoscopy [74c]. Thirst was reported more often

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by those who took in the sodium phosphate 45/45 than in those who took sodium phosphate 45/30 or polyethylene glycol þ bisacodyl. There was a significant interaction of sex by regimen for the incidence of vomiting, which was reported by more of the women who took polyethylene glycol þ bisacodyl. There was also a significant sex difference in the incidences of nausea, weakness, anal irritation, indigestion, and overall discomfort among regimens— women reported these adverse events more often than men, regardless of regimen assignment.

Bran Gastrointestinal Bran is a natural fiber which undergoes considerable expansion and thickening when hydrated, and is currently being used for weight loss as tablets, which undergo expansion in the stomach and are expected to cause early satiety. These products can rarely cause severe adverse reactions, such as sudden esophageal obstruction [75A]. • A 45-year-old woman developed acute dysphagia, with retrosternal pain, difficult in swallowing and drinking, and a sensation of air hunger, after taking two capsules of a dietetic bran product before lunch. She was given intravenous hyoscine butylbromide, but the symptoms persisted. After a plain X-ray of the upper gastrointestinal tract, which was negative, a contrast esophagogram with water-soluble medium showed an esophageal obstruction by a pair of radiotransparent soft masses in the region of upper esophagus. Complete resolution of symptoms was obtained by pushing the obstructing masses downward during endoscopy.

Lactulose Placebo-controlled studies The efficacy of lactulose in preventing the recurrence of hepatic encephalopathy has been the subject of an open, randomized, placebo-controlled trial in 140 patients with cirrhosis [76c].

Corrado Blandizzi and Carmelo Scarpignato

Lactulose was administered at a dose of 30–60 ml in 2–3 divided doses, in order to allow patients to pass 2–3 semisoft stools per day. Lactulose was effective in this setting. Of 61 patients, 14 (23%) had diarrhea, 6 (10%) had abdominal bloating, and 8 (13%) had distaste for lactulose; in these patients, the dose of lactulose was reduced but not stopped. In the placebo group, constipation was reported in 10 (16%) and was managed by dietary modifications.

Magnesium salts

[see also Chapter 22]

Metal metabolism Magnesium hydroxide is widely used as laxative, and it can therefore cause diarrhea, which can be followed by excessive magnesium loss [77A]. • A 39-year-old woman developed severe watery diarrhea and carpopedal spasm after taking at least 20 tablets of magnesium hydroxide in a suicidal attempt; each contained magnesium hydroxide 500 mg. Laboratory tests detected hypomagnesemia, hypocalcemia, and normokalemia. She was given calcium gluconate, but her symptoms did not improve. The adverse event disappeared spontaneously 2 days after the watery diarrhea had subsided.

Senna Gastrointestinal High-dose senna is superior to polyethylene glycol-electrolyte solution (PEG-ES) for the quality of bowel cleansing, but its acceptance may be influenced by the incidence of abdominal pain. In a randomized investigator-blinded study of a combination of PEG-ES and senna in ensuring adequate bowel preparation in 296 patients scheduled for elective colonoscopy, the patients were assigned to either 12 tablets of senna 12 mg þ 2 liters of PEG-ES (half-dose group) or 24 tablets of senna divided in two doses (senna group) the day before colonoscopy [78C]. The cleansing activity was excellent in both groups. There was moderate-to-severe abdominal pain in 6% of patients in the half-dose group and 15% in the senna

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group. However, there were no statistically significant differences in the frequency and intensity of nausea, vomiting, dizziness, or headache.

Phosphates [SED-15, 2820; SEDA-30, 427, SEDA-31, 581; SEDA-32, 668] Observational studies The use of oral sodium phosphate and polyethylene glycol solutions as bowel cleansing preparation for radiological examination of the colon has been evaluated in an observational survey in 592 adults [79c]. Sodium phosphate was rated superior to polyethylene glycol by both patients and physicians. There were similar patterns of adverse reactions, in particular nausea (26% and 24% respectively) and cramps (20% and 27%). Abdominal bloating was more frequent with polyethylene glycol (35% versus 17%), while dry mouth occurred more frequently with sodium phosphate (16% versus 8%). Mineral balance Hypocalcemia and hyperphosphatemia have been attributed to a phosphate enema [80A]. • A 37-year-old woman with suspected celiac disease was prepared for colonoscopy using sodium phosphate solution (Fleet PhosphoSodaÒ) 90 ml. About 12 hours later, she developed perioral paresthesia, Chvostek's sign, numbness in the limbs, and carpopedal spasm. Blood tests showed hypocalcemia and hyperphosphatemia. She was treated immediately with repeated doses of intravenous calcium gluconate and her electrolyte balance normalized over the next 2 days.

Urinary tract Acute phosphate nephropathy has been described as a possible complication after the use of oral sodium phosphate or phosphorus-containing medications. • A 13-year-old boy with Costello syndrome (neonatal macrosomia with subsequent slow growth, developmental delay, coarse facial dysmorphisms, gingival hyperplasia, skeletal anomalies, and hypertrophic cardiomyopathy) and chronic constipation developed signs and symptoms of acute renal insufficiency, after having received four phosphate-containing enemas (125 ml containing sodium

755 biphosphate 28 g and sodium monophosphate 12.5 g) [81A]. He had reduced consciousness, with a low blood pressure, tachycardia, increased respiratory rate, and room air saturation of 88%. There was severe hypertonic dehydration, hyperphosphatemia, and hypocalcemia. He was given fluids and electrolytes. His urine flow started immediately and his creatinine and blood urea nitrogen normalized within the next few days. • A 64-year-old man took oral sodium phosphate tablets in preparation for endoscopic colon polyp resection [82A]. He had a history of hypertension, which was being managed with a calcium channel blocker, and had a normal serum creatinine concentration. One day after the bowel preparation and colonoscopic intervention, his serum creatinine concentration rose. With supportive treatment the creatinine gradually normalized over the course of 8 weeks after reaching a peak concentration of 270 mmol/l on day 4. • A 76-year-old woman with rectal bleeding underwent sigmoidoscopy after taking two sachets of sodium phosphate solution (Fleet Phospho-SodaÒ) and sodium phosphate enema (Fleet Ready-To-UseÒ) [83A]. She was then given mesalazine for chronic active ulcerative colitis and 2 days later developed acute renal insufficiency, with normocalcemia and mild hyperphosphatemia. Mesalazine was replaced with prednisolone enemas. Renal biopsy showed normal glomeruli but widespread tubular calcification with high phosphate content; the tubules were dilated and the tubular epithelium was flattened, with minimal lymphocytic infiltration.

As the last case shows, this adverse reaction is accompanied by the presence of phosphate in the renal tubules. This is therefore a type 1a between-the-eyes adverse reaction [84H]. From July 2006 to September 2008, 10 cases of acute phosphate nephropathy, associated with sodium phosphate tablets for bowel cleansing, were reported to the FDA's Adverse Event Reporting System database [85c]. Renal biopsy in these patients showed nephrocalcinosis (calcium phosphate crystal deposition in the distal tubules and collecting ducts). All these patients had at least one underlying susceptibility factor for acute renal insufficiency, such as pre-existing renal impairment, hypertension, diabetes mellitus, advanced age, underlying electrolyte imbalance, and

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concomitant medications that affect renal perfusion or function (for example, angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, non-steroidal anti-inflammatory drugs, or diuretics). Moreover, the reduction in intravascular volume, caused by bowel cleansing, is likely to have promoted increased phosphate concentrations in the renal tubular fluid. Some patients, especially those with underlying susceptibility factors, developed acute phosphate nephropathy with doses as low as 30 g of sodium phosphate. In addition, some patients who developed renal damage did not present with symptoms of acute phosphate nephropathy for up to several months after using sodium phosphate tablets. There is currently insufficient information to make global recommendations regarding standard pre- and post-procedural renal function testing for patients who may be at risk. However, the importance of taking sodium phosphate correctly (i.e. with adequate hydration and separating the two doses by 12 hours) should be stressed in order to reduce the risk of developing acute phosphate nephropathy and acute renal insufficiency.

Corrado Blandizzi and Carmelo Scarpignato

AMINOSALICYLATES [SED-15, 138; SEDA-30, 428; SEDA-31, 583; SEDA-32, 669] Observational studies Mesalazine (mesalamine, 5-aminosalicylic acid) has been linked with tubulointerstitial nephritis in patients with inflammatory bowel disease. In a retrospective analysis of renal impairment during long-term use of aminosalicylates in 171 patients with inflammatory bowel disease, the mean daily dose was 3.65 g/day and the mean treatment duration 8.4 years; treatments included mesalazine (74%), sulfasalazine (15%), and the combination (11%) [87c]. Serum creatinine concentrations increased significantly during treatment, from 77 to 89 mmol/l, and creatinine clearance fell significantly from 105 to 93 ml/minute. The fall in creatinine clearance correlated positively with the mean daily dose. There was one case of interstitial nephritis.

Balsalazide

[SEDA-31, 583; SEDA-32,

669]

Sodium picosulfate Electrolyte balance Electrolyte disturbances are well-recognized complications of all bowel preparations. Rarely, they can be of clinical significance, as in one case of seizures secondary to hyponatremia [86A]. • An 80-year-old woman underwent bowel cleansing before colonoscopy. She was taking no regular medications and did not have any susceptibility factors for hyponatremia. Within 3 hours of the first dose of sodium picosulfate þ magnesium citrate she became confused and dysphasic, and within 6 hours developed generalized seizures due to hyponatremia. She was treated with slow intravenous hydration with isotonic saline. Within 72 hours, she was fully alert and oriented with no neurological deficit, and her blood sodium concentration had normalized. A brain MRI scan was normal.

Cardiovascular Myocarditis has attributed to balsalazide [88A].

been

• A 38-year-old man with ulcerative colitis who had taken mesalazine for many years was switched to balsalazide 2.25 g tds and prednisolone 15 mg/day. However, 14 days later, while his bowel symptoms were improving, he developed intermittent chest pain (not typical of ischemia or pericarditis). Cardiac troponin I and C reactive protein were raised and there was widespread T wave inversion. Echocardiography showed apical and posterior segment wall motion abnormality with no effusion. A diagnosis of myocarditis was made, and balsalazide was withdrawn. His cardiac symptoms resolved within 48 hours.

Drug dosage regimens In a randomized, double-blind study of two oral dosage regimens of balsalazide, 6.75 or 2.25 g/day for 8 weeks, in 68 children (age range 5–17 years) with mild-to-moderate ulcerative

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colitis, there was clinical improvement in 45% and 37% and clinical remission in 12% and 9% of those who took 6.75 and 2.25 g/day respectively [89C]. The most common treatment-related adverse events were headache (15% versus 14%), abdominal pain (12% versus 11%), vomiting (3% versus 17%), and diarrhea (6% versus 11%).

Mesalazine (5-aminosalicylic acid, mesalamine) [SEDA-30, 428; SEDA-31, 583; SEDA-32, 669] Placebo-controlled studies In a doubleblind, randomized study, 122 children with Crohn's disease took either mesalazine 50 mg/kg/day or placebo for 1 year after successful treatment of flare-ups [90C]. Mesalazine did not appear to be effective. Most of the reported adverse events were not considered to be serious, and there was no difference between mesalazine and placebo. However, there was one case of interstitial nephritis among those who took mesalazine. Cardiovascular Myocarditis has attributed to mesalazine [91A].

been

• A 36-year-old man with Crohn's disease taking long-term mesalazine and low doses of prednisone developed repeated bouts of syncope. He had trifascicular block (a prolonged PR interval, anterior hemiblock, and complete right bundle branch block), and predominately anterior and septal hypertrophy. An MRI scan with gadolinium also showed interatrial septal hypertrophy with nodular formation in the lowest section, myocardial edema, a perfusion defect in the hypertrophic areas, epicardial late enhancement in the anterior wall, and transmural extension in the interventricular and interatrial septa. Mesalazine was withdrawn and a pacemaker implanted. One year later the electrocardiogram was normal and echocardiography showed thinning with dyskinesia of the previously hypertrophic areas.

The type I variant of Kounis syndrome has been attributed to mesalazine [92A]. • A 12-year-old boy with an exacerbation of ulcerative pancolitis was given mesalazine

800 mg tds and prednisone 20 mg/day followed by intravenous 6-methylprednisolone 8 mg 6 hourly). While his symptoms of colitis were improving, he complained of chest pain. There were non-specific ST-T wave changes with T wave inversion, and echocardiography showed low-normal to mildly depressed left ventricular systolic function. The left main coronary artery and left anterior descending artery were mildly prominent, and measured 5 and 4.7 mm respectively. The chest pain resolved completely within 24–36 hours after mesalazine withdrawal. Echocardiography 2 days later showed normal left ventricular function with normal coronary arteries (<3.5 mm).

This variant of the Kounis syndrome includes patients of any age, with normal coronary arteries, without predisposing factors for coronary artery disease, in whom the acute release of inflammatory mediators from mast cells can cause either sudden coronary artery narrowing, without increases in cardiac enzymes or troponins, or coronary artery spasm that progresses to acute myocardial infarction, with raised cardiac enzymes and troponins [93A]. Respiratory Lung toxicity is rare in patients taking mesalazine; a hypersensitivity pneumonitis can occur. • A 23-year-old man with ulcerative proctitis was treated successfully with topical mesalazine and beclometasone dipropionate [94A]. After 1 month the treatment was stopped, but 5 years later, a relapse was treated with topical mesalazine and then oral mesalazine 2.4 g/day. After 3 days the patient developed pleuritic chest pain, exertional dyspnea, fever (38 C), and arthralgias, in particular in the shoulders and spine. Chest X-ray showed a right-sided basal pleural effusion. He was given intramuscular ceftriaxone 1 g/day and oral methylprednisolone 16 mg/day and after 11 days the chest symptoms resolved; 1 month later mesalazine and glucocorticoid treatment were withdrawn, but 1 month later a relapse was treated again with oral mesalazine 2.4 g/ day. After 3 days the same pleuritic symptoms occurred and disappeared promptly on withdrawal of mesalazine. • A 25-year-old woman, with an 8-year history of ulcerative colitis limited to the distal colon, during which time she had taken mesalazine 900 mg/day, developed a non-productive cough accompanied by a high-grade fever [95A]. The white blood cell count, ESR, and

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C reactive protein were increased. Chest X-ray and a CT scan showed bilateral infiltrates and large peripheral pulmonary nodules with cavitation. There were mild increases in antinuclear antibodies and antiproteinase-3, and cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) were positive. There was complete resolution of both clinical and radiological findings after mesalazine withdrawal and treatment with ciprofloxacin and clindamycin.

Hematologic Eosinophilia has been attributed to mesalazine [96M]. • A 9-year-old boy with inflammatory bowel disease, without pathognomonic signs of ulcerative colitis or Crohn's disease, was given oral mesalazine 30 mg/kg/day, rectal mesalazine 250 mg/day, and oral metronidazole 30 mg/ kg/day for 15 days, and the disease activity was partly controlled. However, after 2 years of mesalazine therapy, he developed a severe eosinophilia and an increased leukocyte count, together with a flare-up of his bowel symptoms. A peripheral smear and a bone marrow aspirate showed 74% and 16% eosinophils respectively. Parasite infestation, hypereosinophilic syndrome, and eosinophilic leukemia were excluded by appropriate tests. Mesalazine was withdrawn and he was given a glucocorticoid. The eosinophilia resolved and did not relapse during the next 2 years.

Aplastic anemia has been attributed to mesalazine [97A]. • A 52-year-old woman with ileocolonic Crohn's disease took mesalazine 1 g tds for several years before developing progressive lethargy, fatigue, and bright red blood in her stools. She had small macular petechiae on the palate and bilaterally on the legs. The white blood cell count was 3.4  109/l, the platelet count 10  109/l, and hemoglobin 9 g/dl. The absolute neutrophil count was 550  109/l, and the absolute reticulocyte count was 20  1015/l. Bone marrow biopsy showed a hypocellular marrow composed of erythroid precursors, lymphocytes, and plasma cells; myeloid precursors were significantly reduced.

Corrado Blandizzi and Carmelo Scarpignato

given sulfasalazine 4 g/day, but this was poorly tolerated, because of fever and a rash. It was replaced by oral prednisolone 60 mg/day for 8 weeks. The abdominal symptoms did not subside, and she was given azathioprine which was hepatotoxic and was withdrawn. Infliximab stabilized the disease, but there was residual activity in the distal 20 cm of large bowel. She was given a mesalazine enema and 3 days later developed nausea, abdominal pain, and blood-stained diarrhea. Colonoscopy showed confluent disease activity up to the descending colon with granular mucosa and contact hemorrhage. The patient was then subjected to proctocolectomy, which was followed by a complete uneventful recovery.

Liver Hepatitis has been attributed to mesalazine [99A]. • A 45-year-old man, who had taken mesalazine 1.6 g/day for 8 years for ulcerative colitis, developed right upper abdominal pain, jaundice, and pale stools. He had a raised white cell count with eosinophilia, and raised bilirubin, alkaline phosphatase, and alanine aminotransferase. Abdominal ultrasonography showed a normal liver without ductal dilatation. A liver biopsy showed eosinophil infiltration in the sinusoids, parenchyma, and, in particular, the central veins and portal tracts, consistent with drug-induced hepatitis. Mesalazine was withdrawn and the blood tests improved or normalized over the next week. After 3 years, liver function tests and blood cell counts were normal.

Urinary tract Nephritis has been attributed to mesalazine [100A].

Gastrointestinal Mesalazine has reportedly, and paradoxically, exacerbated ulcerative colitis [98A].

• A 15-year-old boy with idiopathic proctocolitis took sulfasalazine for 1 year and then mesalazine 3 g/day, azathioprine up to 3 mg/kg, and prednisolone in a tapering daily dose of 8 mg/kg. He developed weight loss of 4.5 kg, a high ESR, anemia, and a raised blood urea nitrogen and borderline serum creatinine. Mesalazine was withdrawn, but the laboratory findings did not improve and he then developed a fever with erythema nodosum. There was proteinuria and creatinine clearance was reduced. Renal scintigraphy showed a bilateral diffuse non-homogeneous pattern with multifocal defects in isotope uptake. Renal biopsy showed chronic tubulointerstitial involvement with sclerosed glomeruli. There was remarkable improvement after 21 days of therapy with glucocorticoids.

• A 30-year-old woman with distal ulcerative colitis and joint involvement was initially

It is not clear whether mesalazine was the culprit in this case.

It is not clear whether mesalazine was the culprit in this case.

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Musculoskeletal A toxic non-inflammatory myopathy has been attributed to mesalazine [101A]. • An 11-year-old girl with ulcerative colitis developed muscle pain in the limbs while taking oral mesalazine 2 g/day and prednisolone. She had also received a sulfasalazine suppository as initial therapy. Serum creatine kinase activity was markedly raised, and 98% of the enzyme originated from skeletal muscle. The peripheral eosinophil cell count was normal and there were no signs or autoantibodies to suggest dermatomyositis or systemic lupus. There was no cardiomegaly or cardiac hypokinesis, but there were ST-T wave changes on the electrocardiogram. An adverse reaction to mesalazine was hypothesized, and it was withdrawn, resulting in prompt and spontaneous resolution of the muscle pain, raised creatine kinase activity, and electrocardiographic abnormalities. Biopsy of the left rectus femoris muscle showed atrophy of both type 1 and 2 fibers, focal myofibrillar degeneration, necrosis, regenerative changes, and phagocytosis of degenerative and necrotic fibers, with a few intermyseal lymphocytes. She was given azathioprine and prednisolone. After withdrawal of prednisolone, a drug-induced lymphocyte stimulation test for mesalazine was strongly positive, suggesting that the myopathy had resulted from a hypersensitivity reaction to mesalazine.

Drug formulations Mesalazine formulated with the MMX Multi Matrix SystemÒ technology contains 1.2 g per tablet for oncedaily administration [102R]. The MMX technology comprises hydrophilic and lipophilic excipients enclosed within a gastroresistant, pH-dependent coating. This system is designed to prolong exposure of the colonic mucosa to the drug. In an open study, 304 patients with active, mild-tomoderate ulcerative colitis, who had not achieved clinical and endoscopic remission after 8 weeks of treatment with MMX mesalazine (2.4 or 4.8 g/day), or delayedrelease mesalazine (AsacolÒ, tablets 2.4 g/day), or placebo, were treated with MMX mesalazine 4.8 g/day for 8 weeks [103c]. There was disease remission in 60%, but 27 patients (8.7%) had a total of 60 treatment-related adverse reactions, of which 15 were gastrointestinal in nature, including aggravated ulcerative colitis, diarrhea, nausea, and vomiting. Nine patients

759

(2.9%) had adverse effects that led to withdrawal; four of these had a total of four treatment-related adverse effects, including two cases of aggravated ulcerative colitis, one case of pancreatitis, and one case of aggravated headache.

Sulfasalazine Immunologic There have been further reports of drug rash with eosinophilia and systemic symptoms (DRESS) in patients taking sulfasalazine, a 47-year-old white Brazilian woman who developed DRESS after 8 weeks [104A], a 60-year-old man with polyarthritis who also developed fulminant liver failure after additional vancomycin treatment [105A], and a 68-year-old woman in whom the reaction may have been precipitated by the addition of sulbactam þ ampicillin [106A]. In another case, drug-induced hypersensitivity syndrome was associated with reactivation of an infection with human herpesvirus-6 in a 15-yearold boy with juvenile rheumatoid arthritis who was taking sulfasalazine [107A].

ANTISPASMODIC AGENTS Hyoscine (scopolamine) butylbromide Nervous system Patients with migraine can develop migraine-like headaches after the administration of hyoscine butylbromide. The clinical features have been evaluated in 54 adults with history of migraine, who developed a headache within 20 minutes after a single intramuscular dose of hyoscinebutylbromide 20 mg during gastric X-ray examination [108C]. There was pulsating/throbbing pain in diffuse or bilateral areas of the head. The headache worsened at 20–30 minutes after onset, persisted for 6–18 hours, and gradually ameliorated after 8 hours. All the subjects had repeated nausea and vomiting. Assessment of intensity

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showed that 50 subjects had a severe headache, requiring complete bed rest. The hyoscine-induced headache had characteristics similar to migraine without aura. Of 1865 non-migraineurs, only one had a mild degree of migraine-like headache triggered by hyoscine butylbromide. The pathophysiological basis of hyoscine-induced headache is not clear. Studies in preclinical models support the notion that migraine is associated with the cholinergic neuronal network, in addition to serotonergic pathways in the central nervous system. Accordingly, an abnormal interaction between cholinergic and serotonergic neurons could play a role in the pathogenesis of migraine-like headache triggered by hyoscine butylbromide.

ANTIDIARRHEAL AGENTS Loperamide Gastrointestinal In a retrospective review of the clinical records of patients admitted to hospital during 1 year, Clostridium difficile-associated diarrhea was diagnosed using the following criteria: (i) loose stools or diarrhea more than twice per day and (ii) stool positive for Clostridium difficile toxin A or identification of the organism by stool culture [109c]. Six patients with Clostridium difficile-associated diarrhea had taken loperamide and 80 others were chosen as controls matched for age, duration of hospitalization, and ward of admission. There were no differences in the duration of fever over 37.5 C, the intensity of the diarrhea, white blood cell count or C-reactive protein concentration; however, in those who had taken loperamide the duration of twice-daily diarrhea was longer (9.0 versus 3.7 days), the maximum number of episodes of diarrhea per day was greater (9.2 versus 5.6 episodes), and the duration of the disease was longer (13 versus 5.6 days). The authors reiterated the

Corrado Blandizzi and Carmelo Scarpignato

observation that drugs that are often used to treat diarrhea, such as loperamide, diphenoxylate, and bismuth compounds, worsen the clinical course of Clostridium difficile-associated diarrhea, and recommended that antimotility agents should not be used in such cases.

CHOLELITHOLYTIC AGENTS, BILE ACIDS Ursodeoxycholic acid Respiratory Pegylated interferon alfa combined with ribavirin is currently the standard treatment for hepatitis C virus infection, and ursodeoxycholic acid is used as a supportive treatment in patients who are non-responders or develop severe adverse reactions. Interstitial pneumonia has been attributed to this [110A]. • A 65-year-old man with chronic hepatitis C developed a cough, exertional dyspnea, and an increase in serum Krebs Von den Lungen6 (KL-6), a marker of interstitial pneumonia, while receiving peginterferon alfa-2b 40– 80 micrograms once a week and ribavirin 400 mg/day. A chest X-ray and a CT scan showed bilateral linear and reticular pulmonary infiltration, suggestive of interstitial pneumonia. The signs of pneumonia abated and KL-6 normalized after peginterferon and ribavirin were withdrawn. Ammonium glycyrrhizate 300–600 mg/day and ursodeoxycholic acid 300 mg/day were then introduced and although the aminotransferase activities improved, the productive cough and exertional dyspnea returned along with an increase in KL-6. Ursodeoxycholic acid was withdrawn, but the symptoms persisted and ursodeoxycholic acid was restarted. However, the KL-6 increased and there was a further reduction in blood oxygen saturation. There was complete relief of the respiratory symptoms and normalization of KL-6 after ursodeoxycholic acid had been withdrawn and prednisolone 15 mg/day was given.

The association in this case was not convincing.

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OTHER GASTROINTESTINAL AGENTS Mercaptamine (cysteamine) [SED-15, 2258] Immunologic Drug-induced lupus has been attributed to cysteamine [111A]. • A girl with nephropathic cystinosis was given cysteamine bitartrate 30–45 mg/kg/day. However, despite adequate intracellular cystine depletion, her renal function declined and she was given enalapril for proteinuria. When she was 14 years old she was found to have a persistently positive lupus anticoagulant with anticardiolipin, antinuclear, and antihistone antibodies, weakly positive double-stranded DNA antibodies, negative extractable nuclear antibodies, an increased ESR, and low serum complement concentrations. Cysteamine was withdrawn and 1 month later the ESR and complement had fallen and the antibody titers had become weakly positive.

Cysteamine is structurally similar to penicillamine, a known cause of drug-induced lupus.

Ion-exchange resins

[SED-15, 1902]

See also Chapter 23 for polystyrene sulfonates Acid–base balance Sevelamer hydrochloride is an ion-exchange resin, used to reduce serum phosphorus concentrations in patients with chronic kidney disease, that can cause a

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metabolic acidosis. Sevelamer carbonate is a buffered formulation that has been developed to prevent the occurrence of metabolic acidosis. Several clinical studies in patients with chronic kidney disease and hyperphosphatemia, who received hemodialysis or peritoneal dialysis, have shown reductions of serum bicarbonate concentrations after the use of sevelamer hydrochloride, while sevelamer carbonate did not have this negative effect on bicarbonate concentrations [112M]. The two salts were equivalent in their ability to lower serum phosphorus concentrations.

Pancreatic enzymes Drug formulations Impaired digestion in cystic fibrosis affects about 90% of patients. As soon as pancreatic insufficiency is identified, enzyme supplementation is prescribed, even for breast fed infants. In a prospective, randomized study 40 infants and toddlers were treated with CreonÒ for children, a formulation that contains smaller granules and is administered with a dosing spoon (5000 lipase units per scoop) and CreonÒ 10 000 for 2 weeks each in a crossover design [113C]. The former was superior in terms of parents’ preference, but equally effective with regard to fat absorption. Three patients who took CreonÒ for children had treatment-related adverse events (abdominal pain, constipation, vomiting, with one withdrawal) compared with one who took CreonÒ 10 000 (severe diaper dermatitis/nappy rash).

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nausea and vomiting. Drugs Today (Barc) 2002; 38: 75–89. Kadokura T, den Adel M, Krauwinkel WJ, Takeshige T, Nishida A. The effect of fluvoxamine on the pharmacokinetics, safety, and tolerability of ramosetron in healthy subjects. Eur J Clin Pharmacol 2008; 64(7): 691–5. Marbury TC, Jin B, Panebianco D, Murphy MG, Sun H, Evans JK, Han TH, Constanzer ML, Dru J, Shadle CR. Lack of effect of aprepitant or its prodrug fosaprepitant on QTc intervals in healthy subjects. Anesth Analg 2009; 109(2): 418–25. Adams LM, Johnson B, Zhang K, Yue L, Kirby LC, Lebowitz P, Stoltz R. Effect of casopitant, a novel NK-1 antagonist, on the pharmacokinetics of dolasetron and granisetron. Support Care Cancer 2009; 17(9): 1187–93. Arndt PA, Garratty G, Brasfield FM, Vemuri SL, Asuncion DJ. Immune hemolytic anemia due to cimetidine: the first example of a cimetidine antibody. Transfusion 2010; 50(2): 302–7. Gupta N, Patel C, Panda M. Hepatitis following famotidine: a case report. Cases J 2009; 2(1): 89. Oliva A, Partemi S, Arena V, De Giorgio F, Colecchi C, Fucci N, Pascali VL. Fatal injection of ranitidine: a case report. J Med Case Rep 2008; 2: 232. Foti C, Cassano N, Panebianco R, Calogiuri GF, Vena GA. Hypersensitivity reaction to ranitidine: description of a case and review of the literature. Immunopharmacol Immunotoxicol 2009; 31(3): 414–6. Small DS, Farid NA, Li YG, Ernest 2nd CS, Payne CD, Salazar DE, Winters KJ. Effect of ranitidine on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. Curr Med Res Opin 2008; 24(8): 2251–7. Nguyen TVH, Bengston C, Nguyen GK, Hoang TTH, Phung DC, Sörberg M, Granström M. Evaluation of two tripletherapy regimens with metronidazole or clarithromycin for the eradication of H. pylori infection in Vietnamese children: a randomized, double-blind clinical trial. Helicobacter 2008; 13(6): 550–6.

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[51] Spechler SJ, Barker PN, Silberg DG. Clinical trial: intragastric acid control in patients who have Barrett's oesophagus— comparison of once- and twice-daily regimens of esomeprazole and lansoprazole. Aliment Pharmacol Ther 2009; 30: 138–45. [52] Eggleston A, Katelaris PH, Nandurkar S, Thorpe P, Holtmann G. Clinical trial: the treatment of gastro-oesophageal reflux disease in primary care—prospective randomized comparison of rabeprazole 20 mg with esomeprazole 20 and 40 mg. Aliment Pharmacol Ther 2009; 29: 967–78. [53] Peura DA, Freston JW, Haber MM, Kovacs TO, Hunt B, Atkinson S. Lansoprazole for long-term maintenance therapy of erosive esophagitis: double-blind comparison with ranitidine. Dig Dis Sci 2009; 54: 955–63. [54] Sultan N, Nazareno J, Gregor J. Association between proton pump inhibitors and respiratory infections: a systematic review and meta-analysis of clinical trials. Can J Gastroenterol 2008; 22: 761–6. [55] Croxtall JD, Scott LJ. Dexlansoprazole modified release: in erosive oesophagitis and non-erosive reflux disease. Drugs 2010; 70: 1593–601. [56] Howden CW, Larsen LM, Perez MC, Palmer R, Atkinson SN. Clinical trial: efficacy and safety of dexlansoprazole MR 60 and 90 mg in healed erosive oesophagitis—maintenance of healing and symptom relief. Aliment Pharmacol Ther 2009; 30: 895–907. [57] Wilcox GM, Mattia AR. Microscopic colitis associated with omeprazole and esomeprazole exposure. J Clin Gastroenterol 2009; 43: 551–3. [58] Freston JW, Hisada M, Peura DA, Haber MM, Kovacs TO, Atkinson S, Hunt B. The clinical safety of long-term lansoprazole for the maintenance of healed erosive oesophagitis. Aliment Pharmacol Ther 2009; 29: 1249–60. [59] Orenstein SR, Hassall E, FurmagaJablonska W, Atkinson S, Raanan M. Multicenter, double-blind, randomized, placebo-controlled trial assessing the efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of

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gastroesophageal reflux disease. J Pediatr 2009; 154: 514–20. Eken J, Phadke G, Ahmed S, Mahale A. Lansoprazole-induced acute interstitial nephritis. Southern Med J 2009; 102: 335–6. Vlahos NP, Vavilis GK, Giannelou AG, Georgopoulou CN, Kommata VJ, Kougias CT, Tsartsalis DN, Kounis GN, Mazarakis A, Batsolaki M, GouvelouDeligianni GV, Hahalis G, Kounis NG. Hypersensitivity to proton pump inhibitors: lansoprazole-induced Kounis syndrome. Int J Cardiol 2009; 134: e94–6. Cundy T, Dissanayake A. Severe hypomagnesaemia in long-term users of proton-pump inhibitors. Clin Endocrinol 2008; 69: 338–41. Shabajee N, Lamb EJ, Sturgess I, Sumathipala RW. Omeprazole and refractory hypomagnesaemia. BMJ 2008; 337: a425. Krishnamurthy M, Snyder R, Bachurina M. Long-term use of proton pump inhibitors: are they really safe? A case of delayed acute interstitial nephritis. J Am Geriatr Soc 2009; 57: 1513–4. Vovolis V, Koutsostathis N, Stefanaki E. IgE-mediated anaphylaxis to proton pump inhibitors—cross-reacting study. Allergy 2008; 63: 1251–2. Miano TA, Reichert MG, Houle TT, MacGregor DA, Kincaid EH, Bowton DL. Nosocomial pneumonia risk and stress ulcer prophylaxis. A comparison of pantoprazole vs ranitidine in cardiothoracic surgery patients. Chest 2009; 136: 440–7. Miller JL, Gormley AK, Johnson PN. Pantoprazole-induced thrombocytopenia. Indian J Pediatr 2009; 76: 1278–9. Cutler A, Robinson M, Murthy A, De Lemos B. Rabeprazole 20 mg for erosive esophagitis-associated symptoms in a large, community-based study: additional results. Dig Dis Sci 2010; 55: 338–45. Cohen PR. Black tongue secondary to bismuth subsalicylate: case report and review of exogenous causes of macular lingual pigmentation. J Drugs Dermatol 2009; 8: 1132–5. Hookey LC, Vanner SJ. Pico-Salax plus two-day bisacodyl is superior to Pico-Salax

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alone or oral sodium phosphate for colon cleansing before colonoscopy. Am J Gastroenterol 2009; 104: 703–9. Soyuncu S, Cete Y, Nokay AE. Portal vein thrombosis related to Cassia angustifolia. Clin Toxicol (Phila) 2008; 46: 774–7. Abendroth A, Klein R, Schlaak J, Metz KA, Dobos GJ, Langhorst J. Impressive picture of a melanosis coli after chronic anthraquinone laxative use—is there an increased risk for colorectal cancer? Z Gastroenterol 2009; 47: 579–82. Chen TA, Wong HY, Lin CK, Yu HC, Hsu PI, Lo GH, Lai KH. High-dose bisacodyl plus water lavage compared with oral sodium phosphate as bowel preparation for outpatient colonoscopy. J Chin Med Assoc 2009; 72: 402–7. Malik P, Balaban DH, Thompson WO, Galt DJ. Randomized study comparing two regimens of oral sodium phosphates solution versus low-dose polyethylene glycol and bisacodyl. Dig Dis Sci 2009; 54: 833–41. Losacco T, Cagiano R, Luperto P, Bera I, Santacroce L. An unusual foreign body in the upper aerodigestive tract: esophageal obstruction due to bran impaction. Eur Rev Med Pharmacol Sci 2009; 13: 475–8. Sharma BC, Sharma P, Agrawal A, Sarin SK. Secondary prophylaxis of hepatic encephalopathy: an open-label randomized controlled trial of lactulose versus placebo. Gastroenterology 2009; 137: 885–91. Joo Suk O. Paradoxical hypomagnesemia caused by excessive ingestion of magnesium hydroxide. Am J Emerg Med 2008; 26: 837. Amato A, Radaelli F, Paggi S, Terruzzi V. Half doses of PEG-ES and senna vs. highdose senna for bowel cleansing before colonoscopy: a randomized, investigatorblinded trial. Am J Gastroenterol 2010; 105: 675–81. Martí-Bonmatí L, Bouzas R, Galbe R, Gimeno F, González I, Pérez M, Leal R, Gómez A, López J, Garrido J, Navarro F, Iraola I, Martínez A, Pruna X. Oral sodium phosphates solution versus polyethylene glycol for colon cleansing prior to radiological assessment.

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Expert Rev Gastroenterol Hepatol 2009; 3: 113–9. Oztas E, Bektas M, Kurt M, Onal IK, Ozden A. Oral Fleet Phospho-Soda laxative induced symptomatic hypocalcemia in an adult patient with celiac disease. Am J Gastroenterol 2009; 104: 1607–8. Biebl A, Grillenberger A, Schmitt K. Enema-induced severe hyperphosphatemia in children. Eur J Pediatr 2009; 168: 111–2. Uchiyama T, Inamori M, Iida H, Endo H, Hosono K, Akiyama T, Takahashi H, Koide T, Tokoro C, Yoneda M, Fujita K, Goto A, Abe Y, Kobayashi N, Kirikoshi H, Shimamura T, Kubota K, Saito S, Nakajima A. Renal dysfunction caused by oral sodium phosphate tablets for colonoscopy. Digestion 2009; 80: 159. Connor A, Sykes L, Roberts IS, Weston CE. Acute phosphate nephropathy after sodium phosphate preparations. Br Med J 2009; 338: 47–9. Aronson JK, Hauben M. Anecdotes that provide definitive evidence. BMJ 2006; 332: 1267–9. Corken Mackey A, Green L, St. Amand K, Avigan M. Sodium phosphate tablets and acute phosphate nephropathy. Am J Gastroenterol 2009; 104: 1903–6. Dillon CE, Laher MS. The rapid development of hyponatraemia and seizures in an elderly patient following sodium picosulfate/magnesium citrate (Picolax). Age Ageing 2009; 38: 487. Patel H, Barr A, Jeejeebhoy KN. Renal effects of long-term treatment with 5-aminosalicylic acid. Can J Gastroenterol 2009; 23: 170–6. Robertson E, Austin D, Jamieson N, Hogg KJ. Balsalazide-induced myocarditis. Int J Cardiol 2008; 130: e121–2. Quiros JA, Heyman MB, Pohl JF, Attard TM, Pieniaszek HJ, Bortey E, Walker K, Forbes WP. Safety, efficacy, and pharmacokinetics of balsalazide in pediatric patients with mild-to-moderate active ulcerative colitis: results of a randomized, double-blind study. J Pediatr Gastroenterol Nutr 2009; 49: 571–9. Cezard JP, Munck A, Mouterde O, Morali A, Lenaerts C, Lachaux A,

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Turck D, Schmitz J, Maurage C, Girardet JP, Belli D, Lamireau T, Sarles J, Chouraqui JP, Descos B, Dabadi A, Meyer M, Olives JP, Mary JY. Prevention of relapse by mesalazine (Pentasa) in pediatric Crohn's disease: a multicenter, double-blind, randomized, placebo-controlled trial. Gastroenterol Clin Biol 2009; 33: 31–40. García-Ferrer L, Estornell J, Palanca V. Myocarditis by mesalazine with cardiac magnetic resonance imaging. Eur Heart J 2009; 30: 1015. Atay O, Radhakrishnan K, Arruda J, Wyllie R. Severe chest pain in a pediatric ulcerative colitis patient after 5-aminosalicylic acid therapy. World J Gastroenterol 2008; 14: 4400–2. Kounis GN, Kouni SA, Hahalis G, Kounis NG. Mesalamine hypersensitivity and Kounis syndrome in a pediatric ulcerative colitis patient. World J Gastroenterol 2008; 14: 7141–2. Tozzi A, Biagini MR, Rastelli C, Galli A, Baldi D, Milani S. Mesalamine-induced pleuritis in a patient with ulcerative colitis. Inflamm Bowel Dis 2009; 15: 158–9. Tayer-Shifman OE, Shuvy M, Hershko AY. Mesalamine-induced multiple pulmonary cavitary nodules associated with cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA). J Clin Rheumatol 2009; 15: 256–7. Usta Y, Ozen H, Gurakan F, Uslu N, Saltik-Temizel IN, Demir H, Yuce A. Hypereosinophilia due to mesalazine treatment. J Clin Gastroenterol 2009; 43: 382. Wiesen A, Wiesen J, Limaye S, Kaushik N. Mesalazine-induced aplastic anemia. Am J Gastroenterol 2009; 104: 1063. Bousseaden A, Ajana FZ, Essamri W, Benelbarhdadi I, Afifi R, Benazzouz M, Essaid A. Mesalamine enema-induced exacerbation of ulcerative colitis. Int J Colorectal Dis 2009; 24: 1359–60. Nayar M, Cunliffe W, Cross P, Oppong K. Mesalazine-induced jaundice, eosinophilia, and thrombocytopenia. Inflamm Bowel Dis 2008; 14: 1320–1. Skalova S, Dedek P, Pozler O, Podhola M. Mesalazine-induced interstitial nephritis. Ren Fail 2009; 31: 159–61.

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[101] Tabata N, Sugimoto K, Ueda S, Sakata N, Okada M, Miyake T, Shinohara T, Yagi M, Satou T, Takemura T. Severe skeletal muscle damage following the administration of mesalazine to a patient with ulcerative colitis. Pediatr Int 2009; 51: 759–60. [102] Yang LP, McCormack PL. MMXÒ Mesalazine: a review of its use in the management of mild to moderate ulcerative colitis. Drugs 2011; 71: 221–35. [103] Kamm MA, Lichtenstein GR, Sandborn WJ, Schreiber S, Lees K, Barrett K, Joseph R. Effect of extended MMX mesalamine therapy for acute, mild-to-moderate ulcerative colitis. Inflamm Bowel Dis 2009; 15: 1–8. [104] Aquino RT, Vergueiro CS, Magliari ME, de Freitas TH. Sulfasalazine-induced DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms). Sao Paulo Med J 2008; 126(4): 225–6. [105] Mennicke M, Zawodniak A, Keller M, Wilkens L, Yawalkar N, Stickel F, Keogh A, Inderbitzin D, Candinas D, Pichler WJ. Fulminant liver failure after vancomycin in a sulfasalazine-induced DRESS syndrome: fatal recurrence after liver transplantation. Am J Transplant 2009; 9(9): 2197–202. [106] Bahat G, Celik HG, Tufan F, Saka B. Drug rash with eosinophilia and systemic symptoms syndrome induced by sulfasalazine. Joint Bone Spine 2010; 77(1): 87–8. [107] Balci DD, Peker E, Duran N, Dogramaci CA. Sulfasalazine-induced hypersensitivity syndrome in a 15-year-old boy associated with human herpesvirus-6

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reactivation. Cutan Ocul Toxicol 2009; 28 (1): 45–7. Ikeda K, Kawase Y, Takazawa T, Iwamoto K, Ito H, Murata K, Sato R, Nagaoka T, Sekine T, Nagata R, Nakamura Y, Hirayama T, Ishikawa Y, Miura K, Yoshii Y, Iwasaki Y. Scopolamine-induced migraine like headache. Intern Med 2009; 48: 681–5. Kato H, Kato H, Iwashima Y, Nakamura M, Nakamura A, Ueda R. Inappropriate use of loperamide worsens Clostridium difficile-associated diarrhoea. J Hosp Infect 2008; 70(2): 194–5. Kaneko R, Ogawa M, Iwata T, An Y, Nagakawa M, Kusayanagi S, Kamisago S, Umeda T, Sato Y. Ursodeoxycholic acid exacerbates peginterferon-induced interstitial pneumonia in a patient with hepatitis C. Clin J Gastroenterol 2009; 2: 296–9. Krischock L, Horsfield C, D'Cruz D, Rigden SP. Drug-induced lupus and antiphospholipid syndrome associated with cysteamine therapy. Nephrol Dial Transplant 2009; 24: 1997–9. Pai AB, Shepler BM. Comparison of sevelamer hydrochloride and sevelamer carbonate: risk of metabolic acidosis and clinical implications. Pharmacotherapy 2009; 29: 554–61. Munck A, Duhamel JF, Lamireau T, Le Luyer B, Le Tallec C, Bellon G, Roussey M, Foucaud P, Giniès JL, Houzel A, Marguet C, Guillot M, David V, Kapel N, Dyard F, Henniges F. Pancreatic enzyme replacement therapy for young cystic fibrosis patients. J Cyst Fibros 2009; 8: 14–8.

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Drugs that act on the immune system: cytokines and monoclonal antibodies

COLONY-STIMULATING FACTORS [SEDA-30, 435; SEDA-31, 589; SEDA-32, 675]

Granulocyte colony-stimulating factor (G-CSF) and granulocytemacrophage colony-stimulating factor (GM-CSF) [SED-15, 1542; SEDA-30, 435; SEDA-31, 589; SEDA-32, 675] Comparative studies It is of concern that biosimilars may have different efficacy and safety profiles. In a comparison of a biosimilar (XM02) with filgrastim, the former had equivalent efficacy and a similar safety profile as filgrastim. It ameliorated severe neutropenia and febrile neutropenia in patients with non-Hodgkin's lymphoma receiving chemotherapy and was comparable to filgrastim [1C]. Systematic reviews A meta-analysis of eight randomized controlled trials on the use of granulocyte colony-stimulating factor (G-CSF) for cardiac repair after acute myocardial infarction has yielded divergent results [2M]. The effect of G-CSF therapy on left ventricular function and structure in these patients is unclear. There were no Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00037-4 # 2011 Elsevier B.V. All rights reserved.

significant differences in the incidence of death or recurrent myocardial infarction between patients who received G-CSF and controls. The pooled analysis of 328 patients showed no difference in the risk of in-stent restenosis.

Filgrastim Observational studies In 2408 unrelated donors of peripheral blood stem cells, adverse events associated with filgrastim were evaluated using the Cancer and Leukemia Group B (CALGB) criteria [3c]. The events assessed included allergy, anorexia, chills, fever, sweats, fatigue, headache, myalgia, nausea, vomiting, other flu-like symptoms, local reactions, rashes, pain, and infections. Women had higher rates of adverse events, obese donors had more bone pain, and heavy donors had higher rates of adverse reactions. There were grade 3–4 adverse reactions in 6% of donors, and 0.6% had adverse reactions that were considered serious and unexpected. Nearly all donors have bone pain, 1 in 4 have significant headache, nausea, or citrate toxicity, and a small percentage have serious short-term adverse reactions. Although the short-term safety profile of recombinant human (rh)G-CSF seems to be acceptable, there are minimal data on its long-term safety. In a questionnaire study 95 donors (64%) responded, but only 69 of them (46%) reported on their actual 769

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health status and quality of life, which was good to very good in the majority [4c]. Two donors developed malignancies in the post-donation course. In general, collection of peripheral blood progenitor cells after rhG-CSF mobilization was well tolerated by the responding donors. Although the reported events after donation do not seem to be associated with rhG-CSF administration or the collection procedure, lifelong follow-up of donors should be obligatory. Cardiovascular Concerns about adverse cardiac reactions to filgrastim could not be substantiated in a prospective study in a selected population of neutropenic patients, other than a significant reduction in mean heart rate [5c]. A 54-year-old man with squamous cell carcinoma of the lung developed abdominal aortitis after the use of G-CSF [6A]. Hematologic G-CSF stimulates myeloid progenitors and is routinely used to accelerate neutrophil recovery in the treatment of hematological malignancies and blood or marrow transplantation. However, filgrastim has never been conclusively proven to produce a survival benefit in allogeneic human stem cell transplantation. Filgrastim may cause enhanced leukemic transformation through actions mediated by the GCSF receptor. G-CSF receptor mutations predispose to expansions of clonal populations by exogenous G-CSF, and it is therefore best avoided in all patients with abnormalities of chromosome 7. In the final analysis of the benefit to harm balance, the immediate benefits of G-CSF related to recovery of the leukocyte count, which were substantial in the case of cord blood grafts, may be insignificant for a peripheral blood progenitor graft [7R]. Susceptibility factors Sickle cell disease Of 11 patients with sickle cell disease who were given G-CSF, seven had severe adverse reactions, including vaso-occlusive episodes, acute chest syndrome, multiorgan system failure, and death [8c]. This suggests that G-CSF should not be used in individuals with sickle cell disease except in the

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absence of alternatives and after full disclosure of the risks involved.

Lenograstim Observational studies In 184 healthy donors who were mobilized using lenograstim and were assessed with a median follow-up of 62 (range 2–155) months, bone pain was the most frequent short-term adverse reaction (71%) [9c]. Other common short-term symptoms included headache (28%), insomnia (22%), fatigue (19%), nausea (12%), and fever (5.4%). Spleen size increased in 4.3% of the donors. There were no vascular disorders or cardiac diseases. Long-term follow-up included a transient ischemic attack in one donor at 39 months. There were no cases of hematological disease. There was one case of ankylosing spondylitis at 28 months. One donor with chronic obstructive pulmonary disease developed secondary polyglobulia at 50 months. One donor developed lung cancer at 19 months after donation.

Pegfilgrastim Observational studies There have been several studies of pegfilgrastim in preventing infections in patients with different cancers [10c, 11M]. In 14 patients with congenital neutropenia, pegfilgrastim replaced G-CSF (filgrastim or lenograstim) after a median of 6.9 years of G-CSF therapy [12c]. The absolute neutrophil count tended to increase more with pegfilgrastim than GCSF, but the difference was not statistically significant. During pegfilgrastim therapy, four patients had severe infections and bone pain was reported by nine. WHO grade 3 reactions (anemia, thrombocytopenia, or chronic urticaria) occurred in two patients. A patient with glycogen storage disease type Ib received developed respiratory distress after one injection and died 15 days later. Pegfilgrastim is more difficult to use in congenital neutropenia, with more frequent adverse reactions and sometimes poor efficacy.

Drugs that act on the immune system: cytokines and monoclonal antibodies

Sargramostim Observational studies Six patients with moderately to severely active Crohn's disease were enrolled in an open, phase I study of subcutaneous sargramostim followed in five cases by an open study of tolerability of subcutaneous sargramostim over 8 weeks [13c]. Drug-related adverse events included injection site reactions, pyrexia, back pain, and bone pain. Long-term adverse reactions to sargramostim over 3 years have been evaluated in 98 patients with melanoma [14c]. There were grade 1 or 2 reactions in 82% and no grade 3 or 4 treatment-related reactions. Two patients developed acute myelogenous leukemia after completing 3 years of GMCSF treatment.

Human keratinocyte growth factor Palifermin (Kepivance; Amgen Inc., Thousand Oaks, CA, USA) is a truncated, recombinant form of human sickle cell disease (KGF) that specifically stimulates the growth of epithelial cells that express KGF receptors, thereby reducing mucosal injury due to chemotherapy and radiation. Palifermin is approved for use in reducing the incidence and duration of severe mucositis in patients with hematological malignancies who receive myelotoxic chemotherapy with autologous stem-cell support. Observational studies In 30 patients who underwent allogeneic stem-cell transplantation for leukemia and a retrospectively matched group of controls, the palifermin recipients who received a transplant from an unrelated donor had reduced severity, incidence, and duration of oral mucositis WHO grades 2–4, reduced need for opioid analgesics, and a shorter duration of total parenteral nutrition [15c]. However, there was no beneficial effect of palifermin on the incidence and severity of acute graftversus-host disease. Febrile neutropenia,

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infections, hemopoietic recovery, and overall survival were unchanged. The most common adverse reactions included rashes or erythema, white coating of the oral mucosa, and altered taste, which was generally mild and transient. In 15 patients who underwent autologous stem-cell transplantation and who received sickle cell disease, oral and intestinal mucositis were significantly less severe [16c]. Adverse reactions that were attributable to the drug included erythema, mild rashes, pruritus, nasal congestion, and low-grade fever. All the complications were easily manageable and resolved after completion of treatment. Placebo-controlled studies Ten onceweekly doses of palifermin 60 micrograms/kg were well tolerated compared with placebo in patients who received concurrent chemoradiotherapy for advanced head and neck squamous cell carcinomas [17c]. Palifermin appeared to reduce the incidences of mucositis, dysphagia, and xerostomia during hyperfractionated radiotherapy (n ¼ 40) but not during standard radiation therapy (n ¼ 59). Adverse events were similar in the two treatment groups. Skin Five patients (aged 53–63 years, 3 men) with malignant hematological diseases developed flexural hyperpigmentation after treatment with palifermin [18c]. All had ill-defined symmetrical hyperpigmented papillomatous plaques with slight erythema in the skin folds, especially affecting the axillae and inguinal areas. The most striking histological finding was a thickened granular layer and an increase in cytoplasmic filaggrin staining in the stratum granulosum in all patients. A patient who had an autologous hemopoietic stem cell transplantation and was given palifermin developed erythema and lichenoid papules that were distributed primarily in intertriginous areas [19A]. Histology of the papules showed a striking resemblance to verrucae, but in situ hybridization studies were negative for human papillomavirus. Immunohistochemical staining with antibodies to Ki-67 and cytokeratin 5/6 showed increased

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keratinocyte proliferation in lesional skin. The eruption did not required treatment and resolved spontaneously.

Human epidermal growth factor (rhEGF) Human epidermal growth factor (EGF) is a polypeptide growth hormone that plays an important role in the regulation of growth, proliferation, and differentiation of a wide range of cells by binding to EGF receptors. By binding to cell-surface receptors, EGF activates an extensive network of signal transduction pathways that include the PI3K/ AKT, RAS/ERK, and JAK/STAT pathways. Recombinant human EGF (rhEGF) may enhance growth of new epidermal and stem cells and promote cell metabolism. Uses Topical rhEGF has been used to treat exfoliated lesions on the penis and scrotum in a 79-year-old man with Stevens–Johnson syndrome; within 1 day the pain in the area of the external genitalia had markedly reduced and the rash had improved [20A]. Adverse reactions were not reported. The rhEGF was also applied to the left axillary area and the eruption resolved after 10 days. The rhEGF cream was prepared by the local pharmacy department by mixing lyophilized rhEGF powder 0.02% with a plain cream base. Comparative studies In a double-blind study of two doses of rhEGF in 41 patients with type 1 or 2 diabetes and Wagner's grade 3 or 4 foot ulcers, with a high risk of amputation, intralesional injections of 25 or 75 micrograms were given three times a week for 5–8 weeks with standard good wound care [21C]. The rates of adverse events were similar with the two doses. The most frequent were sepsis (33%), burning sensations (29%), and tremors, chills, and local pain (25% each). Placebo-controlled studies Topical rhEGF has been evaluated in patients with head and neck cancers with oral mucositis

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induced by radiotherapy, with or without chemotherapy [22C]. Patients were assigned to a placebo group or to one of three concentrations of EGF (10, 50, or 100 micrograms/ml). The grade of mucositis was evaluated using the Radiation Therapy Oncology Group (RTOG) scoring criteria. Of 113 patients, 28 used placebo, 29 used EGF 10 micrograms/ml, 29 used 50 micrograms/ml, and 27 used 100 micrograms/ml. EGF significantly reduced the incidence of severe oral mucositis at the primary endpoint (a 64% response with EGF 50 micrograms/ml versus a 37% response in the control group). The frequency of minor and serious adverse events was similar in all the groups and there were no systemic adverse reactions, based on the numbers of peripheral blood leukocytes and granulocytes. In a multicenter, double-blind, placebocontrolled study of intralesional infiltration of rhEGF in Wagner's grade 3 or 4 diabetic foot ulcers in 149 patients who were randomized to EGF 25 or 75 micrograms or placebo three times per week for 8 weeks and standard good wound care, the main endpoint was granulation tissue covering at least 50% of the ulcer at 2 weeks [23C]. This occurred in 19/48 controls versus 44/ 53 with 75 micrograms (OR ¼ 7.5; 95% CI ¼ 2.9, 19) and 34/48 with 25 micrograms (OR ¼ 3.7; 1.6, 8.7). Most of the adverse events were mild and there were no drugrelated severe adverse reactions.

Insulin-like growth factor (mecasermin) [SED-15, 1792; SEDA-32, 676] Injectable recombinant human insulin-like growth factor (rhIGF-I; rINN mecasermin) has been available for nearly 20 years for treatment of the rare instances of growth hormone (GH) insensitivity caused by GH receptor defects or GH-inhibiting antibodies. It has also been used as an insulin-sensitizing agent in severe insulin-resistant conditions. Adverse reactions to mecasermin have been reviewed [24R]. The most common adverse reaction is hypoglycemia, which is readily controlled by administration with meals.

Drugs that act on the immune system: cytokines and monoclonal antibodies

Other common adverse reactions involve hyperplasia of lymphoid tissue, which may require tonsillectomy/adenoidectomy, accumulation of body fat, and coarsening of the facies. Drug abuse Since IGF-I mediates many of the anabolic actions of growth hormone, it is on the World Anti-Doping Agency list of prohibited substances [25R].

[SED-15, 1841; SEDA-30, 436; SEDA-31, 591; SEDA-32, 676]

INTERFERONS

Since interferons are almost always used in combination with ribavirin in patients with hepatitis C infection, it can be difficult to know whether adverse events, if druginduced, are due to one or the other. In many cases authors do not even discuss this problem, often attributing the supposed adverse effects to the interferon. In some cases withdrawal of one of the agents can provide evidence, and in other cases there may be other clues. For example, in cases of skin pigmentation at the site of injection of interferons, the adverse effect may be presumed to be due to interferon [26A], a type II between-the-eyes adverse effect [27H]. In one case hemolytic anemia was attributed to interferon rather than ribavirin because the patient had previously taken a course of interferon without adverse effects [28A]; presumably the inference was that the patient had been sensitized by the previous course. A systematic review of cases in which the drugs were used together and individually can also yield useful information, as in the case of pneumonitis in patients being treated with interferon and ribavirin, attributed to interferon [29AM]. Similarly, in cases of ocular myasthenia [30A], pleural effusion [31A], and cataract [32A] the interferon was blamed because no previous cases were found in association with ribavirin alone. In cases in which the adverse event persists

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for some time after the withdrawal of pegylated interferon and ribavirin, the long halflife of peginterferon is cited as a possible explanation, but this is weak evidence in such cases. In some cases it may be impossible to tell whether the adverse event, if drug-induced, was due to one or other of the drugs or to the combination. See also Ribavirin in Chapter 29. Susceptibility factors Genetic Genetic polymorphisms associated with or hematological adverse reactions to interferon-based combination therapy in Japanese patients with chronic hepatitis C have been identified [33c]. Single nucleotide polymorphisms were detected in all exonic regions of the 12 genes involved in the interferon signalling pathway in 32 healthy Japanese. Of 167 identified polymorphisms, 35 were genotyped and tested for an association with the efficacy of interferon plus ribavirin or adverse reactions in 240 patients with chronic hepatitis C. Multiple linear regression analyses showed that two polymorphisms (IFNAR1 10848-A/G and STAT2 4757-G/T) were significantly associated with interferon-induced neutropenia. Thrombocytopenia was associated with IRF7 789-G/A.

Interferon alfa [SED-15, 1793; SEDA30, 436; SEDA-31, 591; SEDA-32, 676] Systematic reviews In a systematic review of antiviral drug therapy in 16 studies, in which pegylated interferon alfa was used in combination with ribavirin for recurrent hepatitis C after liver transplantation, the mean sustained viral response rate was 30% (range 8–50%) [34M]. Dosage reduction and withdrawal of treatment were common (73% and 28% respectively). Respiratory In a patient with chronic hepatitis C, peginterferon alfa-2b was associated with interstitial pneumonia, which was exacerbated by ursodeoxycholic acid [35A]. After a first course failed, a second course of antiviral therapy achieved normalization of serum aminotransferases and hepatitis

774

C viral RNA, but also caused interstitial pneumonia, which improved after withdrawal of peginterferon. When ursodeoxycholic acid was started 4 months later for relapsing hepatitis the interstitial pneumonia recurred. A 62-year-old Japanese man with a renal cell carcinoma and multiple metastases, who had had inactive idiopathic interstitial pneumonia for 5 years without treatment, was given three intramuscular injections of standard-dose interferon-alfa and had an acute exacerbation of the interstitial pneumonia [36A]. A rare case of desquamative interstitial pneumonitis occurred during treatment with peginterferon alfa and ribavirin in a man with hepatitis C infection; it responded to glucocorticoids [37A]. Nervous system Interferon alfa has been used to investigate pathways by which innate immune cytokines affect the brain and behavior [38c]. There were reduced motor speed and reaction times and slower response times in the rapid visual information processing task in patients who were treated with interferon alfa and ribavirin. Reduced motor speed correlated with increased symptoms of depression and fatigue. Sensory systems Eyes When conjunctival and corneal intraepithelial neoplasia were treated with topical interferon alfa-2b there was complete clinical resolution in 27 of the 28 eyes treated after a median of 2 months; adverse reactions included mild conjunctival hyperemia and follicular conjunctivitis in three patients [39c]. In 15 patients with ocular surface squamous neoplasia treated with topical interferon alfa-2b, one developed follicular conjunctivitis, but treatment was continued [40c]. The frequency of ophthalmological complications was determined in a retrospective analysis of 183 patients with hepatitis C virus infection, of whom 29 had diabetes and 85 had hypertension; 71 received interferon alfa-2a, 100 received interferon alfa2b, and 12 received consensus interferon

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[41c]. Seven had retinal changes on followup and treatment was discontinued in three. Of seven with ocular changes, two had hypertension and one had both hypertension and diabetes. Ocular sarcoidosis has been reported in three patients, in two of whom conventional interferon alfa was used and in one peginterferon alfa-2b; all had granulomatous panuveitis with choroidal granulomata of various sizes [42c]. All had also taken ribavirin. The intraocular inflammation was managed by reducing the dose of interferon and all patients received topical glucocorticoids. A 56-year-old black woman developed with bilateral orbital swelling in the region of the lacrimal glands after taking interferon-alfa þ ribavirin for 4 months for occupationally acquired hepatitis C infection [43A]. Bilateral lacrimal gland biopsies showed granulomatous inflammation. All other tests were negative for sarcoidosis. Auditory function Cochlear damage has been attributed to interferon alfa [44A]. • A 57-year-old man developed vertigo, tinnitus, bilateral hearing loss, and postural intolerance temporally related to administration of peginterferon alfa-2b þ ribavirin for chronic hepatitis C viral infection. He had bilateral sensorineural hearing loss, subjective vertigo with saccadic intrusions during fixation and smooth visual pursuit, and supine hypertension followed by orthostatic hypotension with inadequate reflexive compensatory cardiovascular responses. There was also a marked hemolytic anemia. Formal audiometry showed high-frequency sensorineural hearing loss with abnormal high-frequency distortion product otoacoustic emissions, suggestive of damage to the cochlear outer hair cells. Withdrawal of therapy resulted in rapid resolution with mild residual hearing loss and tinnitus.

A 51-year-old man with chronic obstructive pulmonary disease and hepatitis C genotype 2b suddenly developed left-sided acute sensorineural hearing loss after taking peginterferon þ ribavirin for 6 weeks [45A]. Endocrine Treatment of chronic hepatitis C with interferon is associated with thyroid dysfunction in 5–14% of patients. Among

Drugs that act on the immune system: cytokines and monoclonal antibodies

511 patients, 45 with thyroid dysfunction were identified (8.8%) [46c]. Pegylated interferon alfa was associated with higher rates of thyroid dysfunction than interferon (14% versus 6.0%). Female sex and Asian ethnicity were independent predictors. There was persistent thyroid dysfunction in 16 patients by the end of the follow-up period, predicted by female sex, non-Asian ethnicity, a prior history of thyroid dysfunction, and peroxidase antibodies. The occurrence and distribution of thyroid antibodies and non-organ-specific autoantibodies before, during, and after treatment with daily high-dose consensus interferon alfa-1 (interferon alfacon-1) have been reported in 217 patients with chronic hepatitis C [47c]. TSH concentrations were abnormal (over 3.0 or under 0.4 mU/l) before treatment in 16% and significantly more often in women (25%). Thyroid antibodies were detected in only 2.6% and non-organ-specific autoantibodies in up to 30% (47% women versus 24% men). During induction therapy, there were low TSH concentrations in 14%, whereas there were raised TSH concentrations later (week 48) in up to 16%, again preferentially in women (42%). In 1.4% of all the patients, treatment had to be withdrawn because of symptomatic hyperthyroidism. Thyroid antibodies were detected in 11% (31% women) and non-organ-specific autoantibodies in up to 58% during treatment. Interferon alfa-2b can cause both hyperthyroidism and hypothyroidism, the commonest cause being thyroiditis. Seven women and four men developed thyroiditis over 30 months while using peginterferon alfa-2b and ribavirin for hepatitis [48c]. The average time to the development of thyroid disease was 10 weeks and the duration of the disease was 9 weeks. All eventually recovered normal biochemical thyroid function, although two required short-term supplementation. Thyroid function and changes in ultrasound morphology have been studied in 59 patients with chronic hepatitis C during antiviral therapy with pegylated interferon and ribavirin [49c]. All had ultrasonography of the thyroid gland before treatment, and

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after 1, 3, and 6 months of antiviral drug therapy. Before and during the course of therapy, 11 patients developed thyroid dysfunction (one hypothyroidism, nine hyperthyroidism, and one hyperthyroidism followed by hypothyroidism). Hyperthyroidism was due to Graves’ disease in one patient and destructive thyroiditis in nine. There was reduced echogenicity suggestive of a destructive process in the thyroid gland even before changes in thyroid function or antibodies were detected. Susceptibility factors for thyroid dysfunction were age, female sex, pre-treatment thyroid volume, pre-existing thyroglobulin/thyroid peroxidase antibodies, and viral load. Liver In a 38-year-old man who took peginterferon alfa-2b plus ribavirin for hepatitis C, the aminotransferase activities normalized [50A]. However, repeated treatment resulted in both a low hepatitis C RNA titer and an increase in aminotransferases. Immunostaining of the liver showed accumulation of peginterferon alfa-2b and when it was withdrawn and recombinant interferon alfa-2a was used instead, the aminotransferases normalized within about 2 months. The authors suggested that the rise in aminotransferase activities was related to polyethylene glycol. A 55-year-old man with hepatitis C virus (genotype 1a) infection, which did not respond to peginterferon alfa (type not mentioned) and ribavirin, was subsequently treated with interferon alfacon-1 þ ribavirin [51A]. He developed raised aminotransferase activities, despite a reduced viral load. The aminotransferases returned to baseline when interferon alfacon-1 was withdrawn and rose again after rechallenge. Interferon alfacon-1 differs from interferon alfa-2b in 19/166 amino acids (88% homology), and from interferon alfa-2a in 18/166 amino acids (88% homology). Skin A patient developed two histologically confirmed subcutaneous sarcoid nodules 15 months after starting adjuvant therapy with interferon for lymph node metastatic melanoma in which the primary tumor was not known [52A]. As imaging techniques do

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not necessarily differentiate between sarcoidosis and the radiological signs of metastases, histological evaluation is essential. Oral lichen planus can appear or be exacerbated during treatment of chronic hepatitis C. Improvement after withdrawal of therapy suggests that interferon can cause or worsen these lesions in some patients. In three patients oral lichen planus worsened during treatment of chronic hepatitis C with pegylated interferon and ribavirin [53c]. Linear IgA bullous dermatosis has been associated with interferon alfa-2a in a patient with Kaposi's sarcoma [54A]. Immunologic A large variety of autoimmune adverse reactions have been reported during interferon alfa therapy. • A 46-year-old man with chronic hepatitis C developed antiphospholipid syndrome after taking peginterferon alfa þ ribavirin for 12 weeks; the presentation was primary adrenal insufficiency secondary to bilateral adrenal hematoma and subclavian vein thrombosis [55A]. • Dermatomyositis occurred in a 57-year-old patient who took interferon beta for multiple sclerosis [56A]. Immunohistochemical staining of skin biopsies for myxovirus-resistance protein A (a surrogate marker of cutaneous type I interferon signalling) showed increased staining that correlated temporally with interferon beta treatment and subsequent disease activity. In vitro treatment with interferon beta of peripheral blood mononuclear cells isolated from this patient showed enhanced type I interferon signaling, assessed by interferon-induced gene expression profiles. • A 64-year-old woman developed polymyositis associated with chronic hepatitis C after taking peginterferon-alfa þ ribavirin [57A]. She had raised serum CK, aminotransferases, and LDH activities after 28 weeks of treatment. Further investigations suggested polymyositis, possibly triggered by the peginterferon. She was given prednisolone and the polymyositis remained in remission.

A lupus-like syndrome occurred during therapy with peginterferon alfa-2b for chronic hepatitis B virus infection after 8 months [58A] and other cases have been reported. • A 43-year-old man developed a lupus-like syndrome, including life threatening myopericarditis and vasculitis, after receiving

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peginterferon alfa and ribavirin for chronic hepatitis C, with eight features of the American Rheumatological Association's diagnostic criteria, including high titers of antinuclear antibodies, and anti-double-stranded DNA antibodies [59A]. • A 20-year-old woman with chronic hepatitis C virus infection and end-stage renal disease due to systemic lupus erythematosus was admitted to hospital with fever, pain in the abdomen, seizures, and altered consciousness [60A]. She was on maintenance dialysis and was receiving peginterferon monotherapy. Investigations showed activation of systemic lupus erythematosus with cerebritis after peginterferon. Management included temporary withdrawal of peginterferon and pulse methylprednisolone 500 mg/day for 3 days followed by oral prednisolone 40 mg/day.

Interferon beta

[SED-15, 1793;

SEDA-30, 437] Immunologic Vasculitis has been attributed to interferon beta. • A 52-year-old woman with an oligoastrocytoma received postoperative radiotherapy and intravenous interferon beta [61A]. She continued to have a high fever and impaired consciousness, and an MRI scan showed multiple enhanced lesions in the residual tumor. A biopsy showed vasculitis in the residual tumor. She improved quickly with glucocorticoid treatment. Radiotherapy produced complete remission of the tumor. • A 38-year-old woman with relapsing-remitting multiple sclerosis received subcutaneous interferon beta-1b and developed disseminated cutaneous lesions after three injections, reappearing after drug readministration [62A]. Histopathology confirmed non-specific cutaneous lymphocytic vasculitis. She improved with glucocorticoids and withdrawal of interferon beta.

Systemic sclerosis developed in a 38-yearold woman with multiple sclerosis after treatment with interferon beta [63A]. Infection risk A 43-year-old woman with multiple sclerosis treated with subcutaneous interferon beta developed right lower abdominal quadrant pain, fever, and an indurated McBurney point [64A]. An

Drugs that act on the immune system: cytokines and monoclonal antibodies

abdominal CT scan showed inflammatory subcutaneous fat infiltration reaching the surface of the right lateral rectus muscle. Laparoscopic appendectomy produced no improvement, and the infiltration near a site of subcutaneous injection progressed with areas of liquefaction. A deep cutaneous biopsy specimen showed septal panniculitis without vasculitis. Teratogenicity There are controversial and discrepant results on the risk of spontaneous abortions and teratogenesis induced by interferon in 38 patients with multiple sclerosis who became pregnant in 10 year period [65c]. Neonates who had been exposed in utero had slightly lower birth weights, but the difference was not statistically significant, Developmental milestones were within the reference ranges in all groups. The authors concluded that interferon beta should be withdrawn until delivery and should not be considered to be a reason for interrupting an intact pregnancy.

[SED-15, 1831; SEDA-30, 438; SEDA-31, 592; SEDA-32, 676]

INTERLEUKINS

Aldesleukin (interleukin-2, IL-2) [SED-15, 58; SEDA-30, 438; SEDA-32, 676] Observational studies In 19 patients with acute lymphoblastic malignancies who received interleukin-2 for recurrence after hemopoietic stem cell allotransplantation, adverse reactions were mainly fever, pain, redness, and swelling at the injection site; four patients withdrew because of fever [66c]. In 17 patients with pancreatic adenocarcinoma adverse reactions to preoperative interleukin-2 were mild, and included injection site reactions in all 17, fever in 15, and hypotension in one patient; the symptoms resolved completely within 24 hours [67c]. Of 259 patients with metastatic renal cell carcinoma, who were treated with high-

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dose interleukin-2, 23 had a complete response and 30 a partial response [68c]. There were two treatment-related deaths. Adverse reactions, including hematological and hepatic reactions, were generally limited to grade 1 and grade 2. Other grade 1 and grade 2 reactions included edema, chills, fatigue, dyspnea, rashes, diarrhea, and nausea. Because of the capillary leak syndrome, vasodilatation, and diarrhea, patients often had hypotension and oliguria. Confusion and impaired consciousness were among the other major grade 3 and grade 4 reactions. All these reactions were readily reversible after withdrawal of interleukin-2. Patients aged 60 years and older with acute myeloblastic leukemia in complete remission were randomly assigned to no further therapy or a 90-day regimen of 14day cycles of low-dose rIL-2 (n ¼ 66); of the latter, 24 stopped early because of adverse reactions or relapse [69C]. Grade 4 reactions during rIL-2 therapy included thrombocytopenia (65%) and neutropenia (64%), and grade 3 reactions included anemia (33%), infections (24%), and malaise/ fatigue (14%). Cardiovascular In 23 patients with advanced renal cell carcinoma 15 of whom had previously received tyrosine kinase inhibitors and eight bevacizumab none achieved a partial or complete response to therapy, and the incidence of severe cardiac adverse reactions in those who had previously received tyrosine kinase inhibitors was 40%. This suggests that interleukin-2 cannot be safely given to patients who have previously received a tyrosine kinase inhibitor [70c]. Reversible left posterior fascicular block occurred in a 50-year-old man with metastatic clear-cell renal carcinoma when he was given two doses of high-dose interleukin-2; it resolved 18 hours after the second dose [71A]. He had similar electrocardiographic changes during two subsequent cycles of high-dose interleukin-2, both of which resolved spontaneously Hematologic In chronically HIV-infected adults taking antiretroviral drugs and interleukin-2 there were significant increases in

778

high-sensitivity C-reactive protein (hsCRP) and D dimers by the end of the first cycle of treatment, returning to baseline by the end of study [72c]. Although this suggests the possibility of an increased risk of thrombotic events, there were no serious thrombotic or cardiovascular adverse events during interleukin administration. In a phase I study in 10 patients with metastatic renal cell carcinoma who were given intravenous Innacell gdÒ, an autologous celltherapy product based on g9d2 T lymphocytes, combined with a low dose of subcutaneous interleukin-2, one patient developed disseminated intravascular coagulation [73c]. Other treatment-related adverse events included gastrointestinal disorders and flu-like symptoms (fatigue, pyrexia, rigors). Hypotension and tachycardia also occurred. During interleukin-2 administration there was fever in 60%, grade 1–2 weakness and fatigue (25%), grade 1–2 anemia (13%), neutropenia (11%), and thrombocytopenia (11%), and reversible episodes of grade 3–4 anemia (4.3%) and thrombocytopenia (11%). There were episodes of nausea/vomiting in 6.5% and grade 1–2 diarrhea and mucositis in 17%. Clinical signs of autoimmunity appeared at 4–9 months in six cases, discoid lupus erythematosus in one, and mono/oligoarticular arthritis accompanied by fever and increased inflammatory markers in five. Anti-double-stranded DNA antibodies, antinuclear antibodies, and anticyclic citrulline peptide antibodies were always in the reference ranges. There were increases in circulating immune complexes in two cases. Tumorigenicity Concerns about a possible excess risk of lymphomas in HIV-infected patients exposed to interleukin-2 were not confirmed in a large observational study [74C].

Interleukin-11 (IL-11; oprelvekin) [SED-15, 1845; SEDA-30, 438] Observational studies Recombinant human interleukin-11 (rhIL-11) is a gp-130 signalling cytokine with hemopoietic and

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anti-inflammatory activity. In an open trial of three dosage regimens of subcutaneous rhIL-11 in nine patients with mild von Willebrand's disease, concentrations of von Willebrand factor and factor VIII increased gradually and progressively over 7 days and returned to baseline by day 14 [75c]. Adverse reactions were limited to less than grade-1 hypertension, hypokalemia, and fluid retention. In 14 patients with chronic myeloid leukemia and thrombocytopenia associated with tyrosine kinase inhibitors, interleukin11 increased the platelet count in eight cases and allowed an increased in the dose of imatinib in one [76c]. One patient stopped taking interleukin-11 because of grade 4 fatigue. Grade 1 or 2 peripheral edema was the most common adverse event (n ¼ 6) and was manageable with diuretics in all but one patient with grade 2 edema, who required dosage reduction. One patient developed grade 1 blurred vision, and one developed a grade 1 rash.

Interleukin-12 (IL-12)

[SED-15,

1848; SEDA-32, 677] Observational studies Mucosal immunization offers potential protection against pneumococcal disease, but the lack of a suitable adjuvant for use in humans is an obstacle. In animals interleukin-12 has been successfully used as an adjuvant. The use of interleukin-12 in humans has been reviewed, with suggested approaches by which it could be developed as a mucosal adjuvant [77R]. However, in 48 patients with multiple myeloma who were initially given intravenous interleukin-12 there was an unexpectedly high rate of adverse reactions and although the subcutaneous route was used instead, with some improvement, the adverse reactions were also unacceptable [78c]. Changing the route of administration from intravenous to subcutaneous improved the rate of grade 3 and 4 nonhematological reactions from 63% to 31%; there were no deaths.

Drugs that act on the immune system: cytokines and monoclonal antibodies

Interleukin-18 (IL-18) Interleukin-18, a member of the IL-1 superfamily of cytokines, is an immunostimulatory cytokine that regulates both innate and adaptive immune responses. It is produced by several cells, including macrophages, dendritic cells, microglial cells, and keratinocytes. It enhances the production of interferon gamma by T cells and natural killer cells, augments the cytolytic activity of natural killer cells and cytolytic T lymphocytes, and promotes the differentiation of activated CD4 T cells into helper effector cells. It acts synergistically with IL-12 to induce interferon gamma production and stimulate Th1 immune responses. Its role in cardiac disease has been reviewed [79R]. The effects of prolonged therapy with rhIL-18 in escalating doses have been described in patients with advanced cancer [80c]. Common adverse reactions included chills, fever, headache, fatigue, and nausea. Common laboratory abnormalities included transient asymptomatic grade 1–3 lymphopenia, grade 1–4 hyperglycemia, grade 1–2 anemia, neutropenia, hypoalbuminemia, rises in liver enzymes, and rises in serum creatinine. In a phase 2 study of rhIL-18 in stage IV melanoma, 64 patients were randomized to three doses [81c]. Five patients had 10 grade 3 drug-related adverse events: polyarthritis; deep vein thrombosis, pulmonary embolism; cognitive disorder; fatigue, dyspnea, pleural effusion, and lymphopenia. One patient had a grade 4 increase in lipase activity, which led to permanent withdrawal from the study.

Anakinra (interleukin-1 receptor antagonist) [SED-15, 215; SEDA-31, 592; SEDA-32, 677] Skin An interstitial granulomatous reaction to anakinra resulted in pink dermal plaques and nodules in the periaxillary region which resolved after withdrawal of anakinra and recurred on rechallenge [82A]. Biopsy showed diffuse dermal infiltration of lymphocytes and histiocytes with interspersed neutrophils and eosinophils, and

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fragmentation and degeneration of collagen and elastic fibers. Immunologic An IgE-mediated anaphylactic reaction has been attributed to anakinra in a 46-year-old Indian woman with rheumatoid arthritis who had had an urticarial rash and infusion reactions after three doses of infliximab, and autoantibodies, worsening Raynaud's phenomenon, and digital microinfarcts after treatment with etanercept for 1 year [83A]. Skin prick tests were positive to both anakinra and histamine. She then had an urticarial reaction to adalimumab. Infection risk Two injection site reactions to subcutaneous anakinra have been reported: Wells’ cellulitis of the thigh and a bacterial cellulitis with deep necrosis [84A].

TUMOR NECROSIS FACTOR ALFA (TNF-a) AND ITS ANTAGONISTS [SEDA-30, 439; SEDA-31, 592; SEDA-32, 677]

Tumor necrosis factor The effect on tumor progression of tumor necrosis factor (TNF), a peptide produced by macrophages with cytostatic and cytolytic effects, has recently raised concern, since tumor inhibiting and stimulating properties have been identified [85R]. The best option may be to combine it with other treatments [86R]. Observational studies Recombinant TNF (rTNF) and dactinomycin have been studied in 19 patients with recurrent or refractory Wilms’ tumor. Three had a complete response, five had stable disease, and 11 had progressive disease. After 59 patient treatment cycles, the most common grade 3/4 adverse reactions were thrombocytopenia (41%), raised aminotransferases

780

(24%), neutropenia (20%), leukopenia (14%), anemia (12%), and myalgias (10%). Nervous system Peripheral nerve damage has been reported in 1–48% of patients, including a 49-year-old man in whom hyperthermic isolated limb perfusion was performed with TNF-alpha and melphalan for an irresectable desmoid tumor and caused extensive local edema and a common peroneal nerve palsy, which was still severe 10 months later [87A]. In such cases emergency compartmental pressure measurement may guide the need for fasciotomy

Tumor necrosis factor antagonists Nervous system Demyelinating neuropathy is a rare adverse reaction to anti-TNF therapy, including adalimumab, etanercept, and infliximab; improvement usually occurs after drug interruption and/or in association with usual treatments for demyelinating neuropathies [88Ar]. Hematologic During treatment with TNF antagonists in 67 patients, four had thrombocytopenia. The platelet count recovered after withdrawal in three patients and recurred after re-exposure in two. The overall estimated frequency of thrombocytopenia in this study was 4.3% (95% CI ¼ 0,6.2%). Liver Reactivation of hepatitis B virus has been reported in patients who are chronic carriers and who are receiving TNF antagonists [89c]. Use of these agents in patients with hepatitis virus infections can be associated with transient increases in aminotransferases but appears to be safe overall. Skin Cutaneous adverse reactions to TNF antagonists have been studied in 252 patients with rheumatoid arthritis (146 treated with infliximab, 72 with adalimumab, and 34 with etanercept) and in 183 with spondyloarthropathies (138 treated with infliximab, 37 with etanercept, and 8 with

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adalimumab) [90C]. Of the former, 11 developed psoriatic skin lesions and 10 granuloma annulare; there were five cases of vasculitis, two of alopecia areata, two of discoid lupus erythematosus, one of lichen planus, and one vitiligo. Of the 183 patients with spondyloarthropathies, six developed psoriatic skin lesions, one developed granuloma annulare one lichen planus, and one alopecia areata; there was one case of vasculitis. • A 49-year-old woman with seronegative rheumatoid arthritis developed pustular psoriasis while taking etanercept and subsequently developed disseminated herpes simplex during infliximab therapy, with fever, a widespread itchy vesicular rash, and worsening inflammatory arthritis [91A].

Infection risk Fatal disseminated systemic nocardiosis with Nocardia farcinica, involving the brain, lymph nodes, and adrenal glands, occurred in a 66-year-old woman with psoriasis after sequential therapy with alefacept and then infliximab [92A].

Adalimumab

[SED-15, 2380; SEDA-30, 439; SEDA-31, 597; SEDA-32, 679] Observational studies In an open pilot study in 41 patients with rheumatoid arthritis who had previously failed infliximab therapy, neither former adverse reactions to infliximab nor baseline human antichimeric infliximab antibodies had an effect on adverse event frequency or severity [93c].

Cardiovascular A severe cardiomyopathy occurred 1 week after a single dose of adalimumab in a 25-year-old woman with Crohn's disease [94A]. Ear, nose, throat A possible link between sinusitis and adalimumab has been reported [95A]. Nervous system Miller–Fisher syndrome has been reported in a patient with rheumatoid arthritis taking adalimumab [96A]. Bilateral

Drugs that act on the immune system: cytokines and monoclonal antibodies

phrenic nerve palsy has been reported after adalimumab therapy for psoriasis in 65-yearold woman [97A].

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Etanercept

[SED-15, 1279; SEDA-30, 440; SEDA-31, 600; SEDA-32, 681]

Skin Lichen planus-like eruptions have been attributed to adalimumab and infliximab [98A]. In a comparative study, patients with rheumatoid arthritis treated with adalimumab had a significantly higher rate of incident psoriasis than patients who used etanercept and infliximab [99c].

Hematologic In a postmarketing Swedish cohort study (n ¼ 820) the incidence of hematological disorders in patients treated with etanercept was 3.4 per 1000 patientyears [106C]. However, half of these patients were using at least one other disease-modifying anti-rheumatic drug (DMARD), in most cases methotrexate, and attribution was not clear.

Musculoskeletal Severe myalgia associated with adalimumab has been reported in a patient with Crohn's disease [100A].

Gastrointestinal New Crohn's disease or non-specific inflammatory bowel disease has been attributed to etanercept [107c].

Reproductive system Menorrhagia and severe dysmenorrhea have been reported after adalimumab [101A].

Skin Angiokeratomata have been attributed to etanercept [108A].

Immunologic Two patients with worsening injection site reactions to adalimumab have been described [102A]. Skin tests suggested immediate type I hypersensitivity reactions. Exposure of peripheral blood leukocytes to adalimumab caused significant histamine release and passive transfer of serum from one of the allergic patients to basophils from a non-atopic, healthy donor sensitized those cells to release significant amounts of histamine after exposure to adalimumab. Lupus erythematosus has also been reported [103A]. In a retrospective study in 30 patients with Crohn's disease, the presence of antibodies to adalimumab in 17 patients was related to non-response to adalimumab [104c]. Infection risk There have been reports of tuberculosis in patients receiving adalimumab, in most cases extrapulmonary [105c]. The risk of tuberculosis was higher in patients receiving anti-TNF monoclonal antibodies than those who were receiving soluble TNF receptors. Some patients who have previously received treatment for latent or active tuberculosis have developed active tuberculosis while being treated with adalimumab.

• A 43-year-old man used acitretin, phototherapy, methotrexate, ciclosporin, and infliximab and had an initially good response, but then relapsed. Etanercept 50 mg twice a week for 3 months, then 25 mg twice a week, was introduced, and after 14 months he noticed black lesions over injection sites, initially on the abdomen. He then carried out injections into the thigh, where the same reactions occurred. A biopsy of a black papule was consistent with angiokeratoma.

Hypopigmented mycosis fungoides Hypopigmented mycosis fungoides is a rare variant of mycosis fungoides, which occurs mostly in patients of Asian or African descent, as in the case of a 61-year-old African–American woman in whom a hypopigmented T-cell dyscrasia evolved to hypopigmented mycosis fungoides during treatment with etanercept [109A]. Because of the risk of lymphoma, TNF inhibitors are typically avoided in patients with history of systemic lymphoma. Injection site reactions Etanercept recall reactions bear some similarity to fixed-drug eruptions [110A]. • A 50-year-old woman with psoriasis developed an erythematous edematous plaque at the site of a second injection and simultaneously at a previous injection site, both on the abdomen. The lesions regressed after 1

782 week with topical glucocorticoids, oral antihistamines, and withdrawal of etanercept. After resolution, etanercept was restarted and there were no further local reactions.

Pemphigus vulgaris Pemphigus has been attributed to etanercept [111A] • A 51-year-old man presented with plaque-type psoriasis took etanercept and 2 years later developed painful ulcers in the mouth and on the penis, shoulders, chest, and back. Etanercept was withdrawn and most of the lesions cleared within a few weeks. Several months later, etanercept was started again, but within 3 months he developed more lesions on the chest and back, in the mouth, and in new areas in the inguinal region and on the limbs. A biopsy showed suprabasal acantholysis and intercellular deposition of IgG and C3.

Squamous cell carcinomas A penile cutaneous squamous cell carcinoma developed rapidly in a 71-year-old man who took etanercept for psoriasis [112A]. Infection risk Virus infections can develop during treatment with TNF antagonists, as in a case of varicella zoster infection [113A]. • A 58-year-old man with severe chronic plaque psoriasis used etanercept 50 mg subcutaneously twice a week, and after 1 month about 15 scattered, symptomless, erythematous, slightly edematous macules with central papulovesicles appeared on the trunk, arms, and face, without dermatomal clustering. PCR of the vesicle fluid was strongly positive for varicella zoster virus DNA, and there were specific IgG and IgM. He had had chickenpox at the age of 4 years.

Infliximab

[SED-15, 1747; SEDA-30, 440; SEDA-31, 601; SEDA-32, 683]

Respiratory Exacerbations of fibrosing alveolitis, interstitial pneumonitis, and bronchospasm in patients using infliximab have been described [114A, 115A]. Nervous system Infliximab has been associated in rare cases with optic neuritis [116A] and other nervous system disorders, including Guillain–Barré syndrome [117A] and Lewis–Sumner syndrome [118A].

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Liver Reactivation of hepatitis B virus in patients who are chronic carriers who are receiving TNF antagonists, including infliximab, has been reported [119A] Toxic hepatitis has been attributed to infliximab in a 38-year-old woman with rheumatoid arthritis [120A]. Skin Eczema-like eruptions In a prospective cohort study in 92 patients treated with infliximab for a variety of disorders, with the exception of cutaneous psoriasis, 15 developed eczema [121C]. In univariate analyses, a personal history of atopic symptoms was the only predictive factor (OR ¼ 3.6); sex, age, principal diagnosis, dose and duration of infliximab, and concomitant use of other immunosuppressant had no effect. Pityriasis lichenoides chronica Pityriasis lichenoides chronica has been attributed to infliximab in a patient with psoriasis [122A]. • A 58-year-old man with severe recalcitrant psoriasis was treated with intravenous infliximab and after 10 weeks developed new lesions affecting both lower legs and feet. Histology was consistent with pityriasis lichenoides chronica. His psoriatic plaques cleared progressively, and 5 months after the first infusion of infliximab his skin was clear of psoriasis; however, the crop of lesions of pityriasis lichenoides chronica had still not resolved.

Primary cutaneous melanoma A 70-yearold man with rheumatoid arthritis developed a malignant melanoma after taking infliximab for 12 months [123A]. Psoriasis New-onset psoriasis is a paradoxical adverse effect of TNF antagonists and has been described with infliximab [124c], for example in a young woman who developed pustular psoriasis for the first time while receiving infliximab for Crohn's disease [125A], and a 14-year-old girl with Crohn's disease who developed guttate psoriasis [126A]. Immunologic Infliximab-induced lupus-like syndrome has been reported in a patient with ankylosing spondylitis [127A].

Drugs that act on the immune system: cytokines and monoclonal antibodies

Infection risk Patients receiving infliximab are more susceptible to serious infections, including mycobacterial infections [128A] and pneumonia [129A]. Concomitant treatment with glucocorticoids was the only independent susceptibility factor for infections in patients with inflammatory bowel disease treated with infliximab [130C]. Atypical acute infectious mononucleosis has been reported in a patient with juvenile ankylosing spondylitis who was treated with infliximab [131A]. Mucormycosis has been reported in a patient with Crohn's disease receiving infliximab [132A]. Leprosy A 58-year-old man with ankylosing spondylitis, receiving infliximab, developed multiple plaques on the face, chest, and limbs, a thickened, tender ulnar nerve, and severe neuritis of the feet; biopsy showed lepromatous Hansen's disease [133A]. In this case the use of infliximab may have resulted in either a new infection or reactivation of a latent infection with Mycobacterium leprae. Tuberculosis In a case-control analysis, exposure to infliximab versus etanercept was an independent susceptibility factor for tuberculosis. The authors concluded that the risk of tuberculosis is higher in patients receiving anti-TNF monoclonal antibodies than in those receiving soluble TNF receptors [105c]. Before starting therapy with infliximab, all patients must be evaluated for both active and inactive (latent) tuberculosis infection. The interferon gamma release assay is preferred over tuberculin skin testing [134c]. Varicella infection A 36-year-old man with plaque psoriasis developed a generalized pruritic vesicular eruption, weakness, a high fever, myalgias, anorexia, and progressive respiratory insufficiency after being treated with infliximab for 15 months [135A]. He had never had chicken pox. A Tzanck smear and a skin biopsy from a vesicle showed typical signs of herpetic infection involving

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the epidermis and the follicular epithelia with ballooning degeneration and multinucleated giant cells containing intranuclear inclusions; PCR showed varicella zoster virus DNA in the vesicle. Tumorigenicity In a 9-year, single-center, cohort study of 147 patients with inflammatory bowel disease, 60 episodes of hospitalizations were at least possibly related to the use of infliximab [136C]. Nine patients developed malignancies: four cases of colorectal carcinoma, one carcinoid tumor with another primary signet-ring cell carcinoma of the small bowel, one breast cancer, two skin cancers, and one superficial melanoma; eight died, six as a result of malignancies, one as a result of a complication of short bowel syndrome, and one patient for unknown reasons. In studies with infliximab in which 5780 patients were treated, representing 5494 patient years, there were five cases of lymphomas and 26 non-lymphomatous malignancies, compared with no lymphomas and one non-lymphomatous malignancy in 1600 placebo-treated patients representing 941 patient years. Interference with diagnostic tests In a study of infliximab in patients with cancer, there was neutralization of serum TNF-a after 1 hour, while plasma concentrations of the leukocyte activating chemokine CCL2 and interleukin-6 and serum CRP were reduced at 24 and 48 hours after infliximab administration [137c].

MONOCLONAL ANTIBODIES [SED-15,

2380; SEDA-30, 442; SEDA-31, 602; SEDA-32, 686]

Abciximab See Chapter 35.

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Adalimumab See “TNF-a antagonists” above.

Alemtuzumab (Campath-1HÒ) [SED-15, 71; SEDA-30, 442; SEDA-31, 602; SEDA-32, 686] Uses Alemtuzumab is indicated for the treatment of patients with B-cell chronic lymphocytic leukemia for whom fludarabine combination chemotherapy is not appropriate. Alemtuzumab may also be effective in early multiple sclerosis [138C], as induction therapy before transplantation [139c, 140C], and in vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA) [141c]. Nervous system Infusion-related headache affected more than 50% of treated individuals in a cohort of patients with multiple sclerosis [138C]. Anxiety, syncope, vertigo, dizziness, tremor, paresthesia, and hypesthesia are common undesirable reactions during treatment or within 30 days after the completion of treatment with alemtuzumab. Guillain–Barré syndrome and its chronic form, chronic inflammatory demyelinating polyradiculoneuropathy, have also been reported. Sensory systems There was an increased incidence of cytomegalovirus retinitis in four unrelated patients undergoing hemopoietic stem cell transplantation using a non-myeloablative alemtuzumab-based conditioning regimen [142c]. Liver There were abnormal liver function tests in 2.3% of patients with multiple sclerosis treated with alemtuzumab [138C]. Skin Infusion-related rashes affected more than 90% of treated patients with multiple sclerosis [138C]. Urticaria is one of the commonest types of rash during alemtuzumab therapy. Immunologic Serious infusion reactions occurred in 1.4% of patients with multiple sclerosis treated with alemtuzumab [138C].

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Patients should be premedicated with an oral or intravenous glucocorticoid, an antihistamine, and an analgesic 30–60 minutes before each infusion of alemtuzumab during dose escalation. Infection risk Recurrent oral herpes simplex virus type 1 was seen in 1.4% of patients with multiple sclerosis immediately after each cycle of alemtuzumab [138C]. Inactive tuberculosis was incidentally identified in one patient who received alemtuzumab 24 mg. There were no cases of progressive multifocal leukoencephalopathy, cytomegalovirus infection, or pneumocystis pneumonia. In a study of graft-versus-host disease prevention strategies in patients after bone marrow transplantation for aplastic anemia, a significantly higher proportion of alemtuzumab-treated patients developed cytomegalovirus reactivation compared with control patients [139c]. Prophylaxis with aciclovir has been recommended [143R]. Asymptomatic laboratory positive cytomegalovirus viremia should not necessarily be considered a serious infection requiring interruption of therapy. In a study in Korean patients receiving alemtuzumab as part of a conditioning regimen for allogeneic hemopoietic stem cell transplantation, alemtuzumab recipients had a high incidence of cytomegalovirus disease as well as BK virus-associated hemorrhagic cystitis compared with recipients of antithymocyte globulin [144c]. In renal and pancreas transplant recipients, infections and malignancies were similar after alemtuzumab versus antithymocyte globulin induction [140C]. In a phase II study of alemtuzumab, symptomatic cytomegalovirus reactivation occurred in six of 20 patients; there were two deaths, one from bacterial pneumonia and one from an adenovirus infection [145c]. Tumorigenicity Lymphoproliferative disorders have been reported after pancreas transplantation following alemtuzumab induction in 100 patients [146c]. Epstein– Barr virus-positive immunodeficiency lymphoma after therapy with alemtuzumab

Drugs that act on the immune system: cytokines and monoclonal antibodies

þ CHOP for peripheral T-cell lymphoma has also been reported in three of 20 patients [147c]. In a study of alemtuzumab for the treatment of acute rejection in 15 kidney transplant recipients, the rates of malignancies in alemtuzumab-treated patients were not increased during 12 years follow-up; in particular, no patients treated with alemtuzumab for acute rejection developed post-transplantation lymphoproliferative disorders [148c].

Basiliximab [SED-15, 418; SEDA-30, 443; SEDA-31, 603; SEDA-32, 687] Uses Basiliximab is indicated for the prophylaxis of acute organ rejection in de novo allogeneic renal transplantation in adults and children, and is used concomitantly with ciclosporin for microemulsion-based and glucocorticoid-based immunosuppression, in patients with panel reactive antibodies less than 80%, or in triple maintenance immunosuppressive regimens containing ciclosporin, glucocorticoids, and either azathioprine or mycophenolate mofetil. Basiliximab has also been studied in 221 liver transplant recipients [149c] and in nine patients with metastatic cancer [150c]. Observational studies Adverse events have been studied in a 2-year, non-placebo-controlled trial in 164 children and adolescents undergoing renal transplantation [151C], who were randomized to tacrolimus, azathioprine, and glucocorticoids or tacrolimus, azathioprine, glucocorticoids, and two doses of basiliximab. Basiliximab conferred no additional benefit. There were no differences between the groups in mean eGFR, blood pressure, or serum cholesterol concentrations, and no differences in the incidences of infections or malignancies. Respiratory Basiliximab-induced noncardiogenic pulmonary edema has been described in two pediatric renal transplant recipients [152A].

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Infection risk In a comparison of antithymocyte globulin and basiliximab after renal transplantation in 12 children, there were no cases of opportunistic infections [153c].

Bevacizumab See also Chapter 47. Possible adverse reactions to bevacizumab and their management have been reviewed [154R]. Uses Bevacizumab, in combination with fluoropyrimidine-based chemotherapy, is indicated: for patients with metastatic carcinoma of the colon or rectum [155c, 156C, 157C, 158C]; in combination with paclitaxel or docetaxel for first-line treatment of patients with metastatic breast cancer [159c, 160R]; in addition to platinum-based chemotherapy, for first-line treatment of patients with unresectable, advanced, metastatic or recurrent non-small cell lung cancer, other than with predominantly squamous cell histology [161C, 162R]; and in combination with interferon alfa-2a, for first-line treatment of patients with advanced and/or metastatic renal cell cancer [163R, 164C]. Bevacizumab has been approved in some countries for the treatment of recurrent glioblastoma after first-line treatment with temozolomide [165c, 166M]. Bevacizumab has been studied in advanced carcinoid tumors [167c], prostate cancer [168c], high-risk corneal transplantation [169c], diabetic retinopathy [170c, 171C, 172R], ischemic retinal diseases [173c], refractory choroidal neovascularization secondary to uveitis [174c], macular edema secondary to branch retinal vein occlusion [175c], retinal angiomatous proliferation [176c], choroidal neovascularization attributable to pathological myopia [177c, 178], exudative age-related macular degeneration [179M], multifocal lymphangioendotheliomatosis with thrombocytopenia [180A], in combination with chemotherapy for the treatment of recurrent ovarian cancer [181c], advanced melanoma [182c], malignant pleural mesothelioma [183c],

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metastatic pancreatic cancer [184c, 185c], unresectable hepatocellular carcinoma [186c, 187c], poor-prognosis head and neck cancer [188c, 189c], persistent or recurrent squamous cell carcinoma of the cervix [190c], and ovarian cancer [191c, 192c]. This list is not meant to be exhaustive. Cardiovascular There was an increased incidence of hypertension in bevacizumabtreated patients [159c]. Clinical safety data suggest that the incidence of hypertension is likely to be dose-related. Arterial hypertension has been suggested to correlate with clinical outcomes in patients with colorectal cancer treated with first-line bevacizumab [193c]. In randomized clinical trials, the incidence of arterial thromboembolic events, including strokes, transient ischemic attacks, and myocardial infarctions, was higher in patients receiving bevacizumab in combination with chemotherapy compared with those who received chemotherapy alone [194R]. Events consistent with congestive heart failure have been reported in clinical trials [154R]. The symptoms ranged from asymptomatic reductions in left ventricular ejection fraction to symptomatic congestive heart failure, requiring treatment or hospitalization. Most of the patients who had congestive heart failure had metastatic breast cancer and had received previous treatment with anthracyclines or prior radiotherapy to the left chest wall, or had other risk factors for congestive heart failure, such as pre-existing coronary heart disease or concomitant cardiotoxic therapy. Sinusoidal obstruction syndrome (venoocclusive disease) has been reported in a patient receiving bevacizumab for metastatic colorectal cancer [195A]. Venous thromboembolism in general has been reported to occur with a higher incidence during bevacizumab treatment [196M]. Nervous system There have been rare reports in bevacizumab-treated patients of signs and symptoms that are consistent with reversible posterior leukoencephalopathy syndrome (RPLS), a rare neurological

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disorder, which can present with the following signs and symptoms among others: seizures, headache, altered mental status, visual disturbances, or cortical blindness, with or without associated hypertension [154R]. Sensory systems Adverse reactions have been reported from unapproved intravitreal use. These reactions included infectious endophthalmitis, intraocular inflammation (such as sterile endophthalmitis, uveitis, and vitritis), retinal detachment, retinal pigment epithelial tears, increased intraocular pressure, and intraocular hemorrhage (such as vitreous hemorrhage or retinal hemorrhage and conjunctival hemorrhage) [197c, 198c]. Vitreous hemorrhage has also been reported during treatment with bevacizumab for metastatic rectal cancer [199A]. Hematologic Patients treated with bevacizumab have an increased risk of hemorrhage, especially tumor-associated hemorrhage [154R]. Major or massive pulmonary hemorrhage/hemoptysis has been observed primarily in trials in patients with non-small cell lung cancers, who were excluded from subsequent phase III trials. Gastrointestinal Patients may be at increased risk of fistulae when treated with bevacizumab [188c, 200A]. In clinical trials, gastrointestinal fistulae have been reported with an incidence of up to 2% in patients with metastatic colorectal cancer, but were also reported less commonly in patients with other types of cancers. Diarrhea, nausea, and vomiting are very common adverse reactions [187c]. Urinary tract Patients with a history of hypertension may be at increased risk of proteinuria when treated with bevacizumab [159c]. Progressive bevacizumab-associated renal thrombotic microangiopathy has been reported [201A]. Skin Bevacizumab can adversely affect wound healing [202c]. There was an increased incidence of postoperative bleeding or wound healing complications within

Drugs that act on the immune system: cytokines and monoclonal antibodies

60 days of major surgery if patients were being treated with bevacizumab at the time of surgery. The incidence was 10–20%. In locally recurrent and metastatic breast cancer, wound healing complications were observed in up to 1.1% of patients receiving bevacizumab compared with up to 0.9% of patients in the control arms. Hand-foot skin reactions have been reported as an adverse reaction to bevacizumab [203c]. Musculoskeletal Reversible skeletal changes after treatment with bevacizumab in a child with cutaneovisceral angiomatosis and thrombocytopenia have been reported [204A]. Immunologic Patients may be at risk of infusion/hypersensitivity reactions [154R], which have occurred in up to 5% of patients.

BG9588 BG9588 is a humanized anti-human CD40L antibody that blocks antigen-specific IgG responses in non-human primates (baboons and rhesus monkeys) immunized with a variety of T-dependent antigens. Observational studies BG9588 has been studied in humans with lupus glomerulonephritis, but the study was terminated prematurely because of thromboembolic events [205c]. CD40L stabilizes arterial thrombi by a b3 integrin-dependent mechanism; inhibition of these interactions by anti-CD40L may make platelet plugs unstable and thus ready to embolize. This problem has not been further evaluated and the project was abandoned by the company. There were no statistically significant changes in neutrophil or total lymphocyte counts (including T cell subsets, such as CD4þ and CD8þ cells), hematocrit, platelet counts, or serum anticardiolipin antibodies after therapy. Serum concentrations of immunoglobulins (IgA, IgG, and IgM) were transiently reduced from baseline to

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28 days after the last dose. Of 18 patients in whom efficacy could be evaluated, two had a 50% reduction in proteinuria without worsening of renal function. There was a significant reduction in anti-dsDNA titers and a significant increase in mean serum C3 concentrations after treatment.

Daclizumab

[SED-15, 1047; SEDA-30, 444; SEDA-31, 605; SEDA-32, 687] Daclizumab is a recombinant humanized, IgG1 antibody to the alpha subunit of the IL-2 receptor of T cells. It is produced in a murine NSO myeloma cell line using a glutamine synthetase expression system by recombinant DNA technology. It was first approved for the prophylaxis of acute organ rejection in de novo allogenic renal transplantation. However, on 27 November 2006, the marketing authorization holder responsible for daclizumab, Roche, notified the European Commission of its decision to withdraw the marketing authorization for daclizumab voluntarily, for commercial reasons. Roche stated that this decision was not related to any safety concerns. Daclizumab was withdrawn from the market in the European Union on 1 January 2009.

Uses Daclizumab has been studied in cases of active posterior uveitis [206c]; in children with refractory and steroid-resistant/dependent graft-versus-host disease [207c, 208c]; for recalcitrant ocular inflammatory disease [209c]; in multiple sclerosis [210c, 211c]; and in patients with moderate to severe persistent asthma [212C]. Daclizumab has been used as induction therapy before liver transplantation [213c, 214C] and renal transplantation [215c], as well as in active anterior uveitis associated with juvenile idiopathic arthritis [216c]. Hematologic Two patients developed adverse events that required transient withdrawal of daclizumab because of lymphopenia and generalized lymphadenopathy in an open baseline versus treatment phase II clinical trial of daclizumab in patients

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with multiple sclerosis with an inadequate response to interferon beta [211c]. Skin One participant among six studied in a trial of high-dose daclizumab for the treatment of juvenile idiopathic arthritisassociated active anterior uveitis developed a rash possibly induced by daclizumab [216c]. Musculoskeletal In a study of intravenous daclizumab for recalcitrant ocular inflammatory disease adverse reactions to daclizumab included fatigue and muscle aches [209c]. Immunologic Two patients developed systemic immune responses 1–2 months after withdrawal of interferon beta, characterized by mouth ulcers, a photosensitivity rash, and transient formation of autoantibodies that required glucocorticoid therapy for resolution in an open baseline versus treatment phase II clinical trial of daclizumab in patients with multiple sclerosis and an inadequate response to interferon beta [211c]. In rare cases severe hypersensitivity reactions after daclizumab have been reported.

Edrecolomab Edrecolomab is a murine monoclonal antibody to the cell-surface glycoprotein 171A, which is expressed on epithelial tissues and on various carcinomas. This 17-1A antigen is also known as EGP-2, EpCAM, CO17-1A, or GA733-2. Preliminary data suggested that it might be of use in the adjuvant treatment of patients with resected stage III colon cancer. In the initial clinical study, which focused on patients with minimal residual disease because of the presumption that overt metastatic disease might overwhelm the capacity of the immune system, 189 patients with stage III colon or rectal cancer were randomized to edrecolomab or no treatment [217c]. On the strength of the results the drug was approved by the regulatory

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authorities in Germany and was available there by prescription for the treatment of patients with stage III colorectal cancer. To our knowledge no other countries approved the agent for routine use on the basis of these data [218R]. All studies reported to date, with the exception of the Riethmüller trial, have been negative [219C, 220C, 221C]. In the last of these trials, the most common hematological adverse reaction was neutropenia, the most common non-hematological adverse reactions were diarrhea (80%) and nausea (72%), and there were hypersensitivity reactions, defined as any adverse events possibly involving an immune response and occurring within 1 day of edrecolomab infusion, in 31% of patients, including fever (8% overall), flushing (6%), hypotension (<1%), rashes (3%), and breathing disorders (<1%). Edrecolomab has been withdrawn from the German market and production has been suspended.

Efalizumab [SEDA-30, 445; SEDA-31, 605; SEDA-32, 688] On 9 April 2009, Genentech announced that the company was voluntarily withdrawing efalizumab from the marketplace because of continuing concerns about its association with progressive multifocal leukoencephalopathy. Hematologic In post-marketing surveillance, isolated cases of severe hemolytic anemia have been reported during treatment with efalizumab. Thrombocytopenia can occur [222A, 223A] and thrombocytosis has also been attributed to efalizumab [224A]. Skin A localized papular rash or aggravation of psoriasis in an edematous or even pustular form are the two most commonly observed complications of treatment with efalizumab [223A]. Efalizumab can cause exacerbation of psoriasis, including pustular, erythrodermic, and guttate subtypes [225A], and rebound can also occur after

Drugs that act on the immune system: cytokines and monoclonal antibodies

withdrawal of the drug [226c]. The occurrence of autoimmunity during an immunomodulating therapy blocking T-cell activation is paradoxical and might be related to disruption of immune balance rather than a specific drug-induced pathway requiring simultaneous binding of the drug to the target molecule, as in a case of bullous pemphigoid attributed to efalizumab in an 82-year-old patient with diabetes and psoriasis who received efalizumab for 6 weeks [227A]. A patient with psoriasis developed typical lesions of familial benign chronic pemphigus after four doses of efalizumab [228A]. In another case there was exacerbation of psoriasis during efalizumab treatment, associated with a reversible lymphocytosis with a normal total leukocyte count [229A]. In another study, an inflammatory flare occurred in six cases after 23– 72 weeks, with pronounced worsening of the cutaneous psoriatic lesions accompanied by severe musculoskeletal involvement in all cases [230c]. Lymphomatoid papulosis occurred in a 60-year-old woman after treatment with efalizumab for psoriasis taking for 8 months, with red crusted papules and plaques on the forearms and back. Biopsies of the lesions were consistent with CD30þ lymphomatoid papulosis. Efalizumab was withdrawn and the lesions resolved during a 6week course of narrowband ultraviolet B phototherapy. However, 4 months later a red ulcerated plaque formed in her left axilla and a biopsy was again consistent with CD30þ lymphomatoid papulosis, which resolved over 2 months with intralesional triamcinolone. Seborrheic keratoses have been reported in a 56-year-old man with recalcitrant psoriasis that had responded to efalizumab [231A]. Urticaria associated with a raised serum IgE concentration has been associated with efalizumab in a 50-year-old man with psoriasis, perhaps due to the formation of antibodies against efalizumab or other epitopes [232A].

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Autacoids Recurrent angioedema has been reported in a 63-year-old man with severe plaque psoriasis after efalizumab treatment for 15 weeks [233A]. There was swelling of the periorbital area, cheek, tongue, and lips, and after the next dose he developed the same symptoms as well as acute abdominal pain. Efalizumab was withdrawn and the swelling and abdominal pain resolved within 3 weeks. Infection risk Efalizumab can increase the risk of infections or at least their severity, for example tuberculous pneumonia, and reactivate latent chronic infections, such as JC virus infection. However, in an open extension of a phase IIIb trial, the incidence of infections was 10–15% during the 12-week segments of efalizumab therapy, compared with 19% in placebo-treated patients [234c]. Tumorigenicity It is not known whether efalizumab increases the risk of lymphoproliferative disorders or other malignancies in patients with psoriasis. Of the 15 malignancies that were reported in 418 efalizumab-treated patients in a phase IIIb clinical trial, four were basal cell carcinomas and nine were squamous cell carcinomas [234c].

Gemtuzumab ozogamicin [SED-15, 1488; SEDA-30, 446; SEDA-32, 689] Combination studies The effects of gemtuzumab in combination with other treatments have been studied in patients with relapsed CD33-positive acute myeloid leukemia [235c, 236c, 237c, 238c] and in patients with acute promyelocytic leukemia [239c]. The Committee for Medicinal Products for Human Use (CHMP) noted that there were adverse reactions associated with gemtuzumab. These included severe and long-lasting bone marrow suppression causing reduced leukocyte and platelet counts, liver problems, and adverse reactions related to the infusion, such as chills,

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fever, and low blood pressure. In a study of gemtuzumab in advanced childhood myeloid leukemia five patients had infections [240c]. On 20 September 2007, the CHMP recommended refusal of the marketing authorization for the medicinal product because of an unfavorable benefit to harm balance.

HA-1A (Centoxin) HA-1A (Centoxin; Centocor, Malvern, PA) is a human IgM monoclonal antibody that binds to the lipid A domain of endotoxin and is produced by the stable heteromyeloma cell line A6(H4C5). This hybridoma was created by fusion of a murine–human heteromyeloma line with splenic B lymphocytes sensitized in vivo by immunization with killed Escherichia coli J5 cells and subsequently transformed in vitro by Epstein–Barr virus. HA-1A was developed for use in the treatment of sepsis. However, it was voluntarily withdrawn by the manufacturer in 1992 because of excess mortality in patients without Gram-negative bacteremia [241S]. Placebo-controlled studies In a multicenter, double-blind, randomized, placebo-controlled, phase III trial in 543 patients with sepsis, no overall benefit of HA-1A could be demonstrated [242C]; however, among 102 patients with Gram-negative bacteremia and shock, the 28-day all-cause mortality rate was significantly reduced from 56% among patients receiving placebo to 33% among those receiving HA-1A. These results were not confirmed in a second study, a large, group-sequential, placebo-controlled trial that enrolled 2199 patients, of whom 621 (28%) had Gram-negative bacteremia [243C]. In a later double-blind, randomized, placebo-controlled trial (n ¼ 269), the authors compared the effectiveness of HA1A and placebo in reducing the 28-day allcause mortality rate among children with a presumptive diagnosis of meningococcal septic shock; there was no significant benefit [244C].

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Ibalizumab Ibalizumab (formerly TNX-355) is a humanized monoclonal antibody that binds CD4, the primary receptor for HIV-1, and inhibits the viral entry process [245R]. It has been studied for the potential treatment of HIV infection [246R]. The most common adverse event in a phase I study in HIV-infected individuals was headache [247c]; there were mean increases from baseline in CD4– T-cell counts during the 9-week infusion period, with the largest mean increases at week 1. However, there was no evidence of CD4þ T-cell and ibalizumab was not immunogenic. There were no serious drug-related adverse events.

Infliximab See “TNF-a antagonists” above.

Natalizumab [SEDA-30, 447; SEDA-32, 690] Assessment of the benefit to harm balance of natalizumab continues [248R]. Nervous system Subclinical reactivation of JC virus is common in patients with multiple sclerosis who are treated with natalizumab [249c] and there is an increased risk of JC virus-associated progressive multifocal leukoencephalopathy, which can be fatal or result in severe disability. The risk appears to increase with treatment duration, especially beyond 2 years. There is limited experience in patients who have received natalizumab for more than 3 years and the risk in these patients cannot therefore currently be estimated. Hematologic Natalizumab increases the percentage of activated leukocytes producing proinflammatory cytokines in the blood, presumably due to sequestration of activated cells in the peripheral circulation [250c]. It can increase circulating lymphocytes, monocytes, eosinophils, basophils, and nucleated erythrocytes, without

Drugs that act on the immune system: cytokines and monoclonal antibodies

affecting neutrophils. Increases from baseline for lymphocytes, monocytes, eosinophils, and basophils were 35–140% for individual cell types, but mean cell counts remained within the reference ranges. Immunologic Hypersensitivity reactions occurred in up to 4% of patients with multiple sclerosis in 2-year controlled trials; anaphylactic or anaphylactoid reactions occurred in under 1%. Among 234 consecutive natalizumab-treated patients, followed for at least 3 months, there were nine anaphylactoid reactions, mainly urticarial [251c]. Hypersensitivity reactions usually occurred during infusion or within the 1 hour after the completion of the infusion. In post-marketing experience there have been reports of hypersensitivity reactions in association with one or more of the following symptoms: hypotension, hypertension, chest pain, chest discomfort, dyspnea, and angioedema, in addition to more usual symptoms, such as urticaria. The risk of hypersensitivity reactions was greatest in patients who were re-exposed to natalizumab after an initial short exposure (one or two infusions) or after an extended period (3 months or more) without treatment. In 10% of patients antibodies against natalizumab were detected. Persistent anti-natalizumab antibodies (one positive test reproducible on retesting at least 6 weeks later) developed in 3–6%. Immune reconstitution inflammatory syndrome is a reported rebound phenomenon after withdrawal of natalizumab [252A, 253A]. Tumorigenicity A primary central nervous system lymphoma has been reported in a patient treated with natalizumab [254A].

Omalizumab [SED-15, 2614; SEDA-30, 447; SEDA-32, 690] Skin During clinical trials in adults and adolescents the most commonly reported adverse reactions were injection site

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reactions [255C, 256C], including injection site pain, swelling, erythema, and pruritus. Immunologic Type I local or systemic allergic reactions, including anaphylaxis and anaphylactic shock, can occur during omalizumab therapy, but also after a long duration of treatment [257R]. Most of these reactions occurred within 2 hours after the first and subsequent injections of omalizumab, but some started beyond 2 hours and even beyond 24 hours. Serum sickness and serum sickness-like reactions have been seen, typically 1–5 days after administration of the first or subsequent injections, but also after longer durations of treatment. The suggested mechanism includes immune-complex formation and deposition due to development of antibodies against omalizumab.

Ranibizumab See Chapter 47.

Rituximab [SED-15, 3069; SEDA-30, 448; SEDA-31, 607] Uses Rituximab has been studied in a wide range of diseases, including different vasculitic disorders [258R, 259C, 260c, 261c], chronic immune thrombocytopenic purpura [262c], collapsing glomerulopathy with dominant C1q-containing mesangial immune deposits [263A], severe glucocorticoid- or ciclosporin-dependent nephrotic syndrome [264c, 265c], immune-mediated neuropathies [266C], treatment-refractory myasthenia gravis and inflammatory myopathies [267c, 268R], systemic lupus erythematosus [269c, 270c, 271R, 272M], Sjögren's syndrome [273c, 274M], autoimmune bullous diseases [275c, 276A], relapsing Graves’ disease [277c], chronic graft-versus-host disease [278M], primary gastric lymphoma [279c], autoimmune hemolytic anemia [280c], and thrombotic thrombocytopenic purpura [281cM].

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Respiratory Cases of interstitial lung disease, dyspnea, and pneumonitis associated with rituximab, some fatal, have been reported [282M, 283A, 284A, 285A, 286A, 287c]. Infection risk Serious infections, including deaths, can occur during therapy with rituximab. Infectious events (predominantly bacterial and viral) occurred in 30–55% of patients with non-Hodgkin's lymphoma and in 30–50% of patients with chronic lymphocytic leukemia. In other therapeutic indications, the risk of infections seems to be less, but still increased compared with placebo [272M, 288c, 289c, 290M, 291M]. Hepatitis B reactivation has been reported in subjects receiving rituximab including fulminant hepatitis with a fatal outcome [292c, 293c]. Localized candidiasis and herpes zoster infection have been reported [279c]. Nervous system Rituximab can be associated with an increased risk of progressive multifocal leukoencephalopathy [294A, 295R]. Hyperammonemic encephalopathy has been reported after chemotherapy including rituximab for solid and hematological malignancies [296A]. Hematologic Catastrophic multiple organ ischemia due to an anti-Pr cold agglutinin has been reported in a patient with mixed cryoglobulinemia after treatment with rituximab [297A]. Gastrointestinal Gastrointestinal perforation, in some cases fatal, has been observed in patients receiving rituximab for malignant disease; in most of these cases, rituximab was administered with chemotherapy [295R, 298A]. Immunologic The most common adverse drug reactions in patients receiving rituximab are infusion-related reactions, which occur during the first infusion in most cases

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[274M, 299c]. The symptoms are mainly fever, chills, and rigors. Other symptoms include flushing, angioedema, bronchospasm, vomiting, nausea, urticaria, fatigue, headache, throat irritation, rhinitis, pruritus, pain, tachycardia, hypertension, hypotension, dyspnea, dyspepsia, weakness, and features of tumor lysis syndrome. Severe infusion-related reactions (such as bronchospasm and hypotension) occur in up to 12% of cases. The incidence of infusion-related symptoms falls substantially with subsequent infusions and is less than 1% after eight doses of rituximab. Human antichimeric antibodies develop in some patients after a first course of rituximab and can be associated with worsening of infusion or allergic reactions after subsequent infusions. In one case, there was failure to deplete B-cells after further courses [270c]. The safety of immunization with live viral vaccines after rituximab therapy has not been studied in patients with nonHodgkin's lymphoma or chronic lymphocytic leukemia, and immunization with live virus vaccines is not recommended. Immunization with other non-live vaccines seems to be impaired following rituximab therapy [270c], but immunization is not contraindicated. Common variable immunodeficiency has been reported in an 8-year-old boy treated with rituximab for idiopathic thrombocytopenia [300A]. Autacoids Rituximab vials contain polysorbate 80 (polyoxyethylene-sorbitan-20monooleate, Tween 80), a solubilizing agent that can cause severe non-IgE-mediated anaphylactic reactions [301Ar]. Fetotoxicity There are no adequate and well-controlled data from studies of rituximab in pregnant women; however, transient B-cell depletion and lymphopenia have been reported in an infant born to a mother exposed to rituximab during pregnancy [302A].

Drugs that act on the immune system: cytokines and monoclonal antibodies

Trastuzumab

[SED-15, 3480]

Cardiovascular Heart failure (New York Heart Association classes II–IV) has been observed in patients receiving trastuzumab, alone or in combination with paclitaxel or docetaxel, particularly after chemotherapy containing an anthracycline (doxorubicin or epirubicin) [303M, 304M, 305R, 306c]. It can be moderate or severe and can be fatal. The results of many randomized trials have shown that the degree of cardiotoxicity is generally acceptable; the incidence of cardiac damage caused by trastuzumab was 0.4–4.1% [307R]. Older age, lower left ventricular ejection fraction, and antihypertensive medications are associated with an increased risk of cardiac dysfunction in patients receiving trastuzumab [308C]. The cardiac dysfunction associated with trastuzumab is usually reversible on withdrawal and standard medical therapy [309R]. In one case, trastuzumab-associated cardiomyopathy presented with complete left bundle-branch block mimicking acute coronary syndrome [310A]. Respiratory Severe pulmonary events, such as interstitial lung disease [311A], have been reported with trastuzumab in postmarketing surveillance and can occasionally be fatal. Hematologic Febrile neutropenia has been observed very commonly in trastuzumabtreated patients; anemia, neutropenia, and thrombocytopenia were common laboratory findings in these patients [312c]. Gastrointestinal In 10 patients treated with trastuzumab, diarrhea, vomiting, nausea, or abdominal pain were each reported in more than one case. In a retrospective study there were gastrointestinal adverse reactions after 12% of administrations, including nausea and vomiting, diarrhea, abdominal pain, and bloating [313c]; mucositis was more rare [314c, 315c]. Liver Trastuzumab-induced hepatotoxicity has been reported [316A].

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Visilizumab Visilizumab is a humanized anti-CD3 monoclonal antibody characterized by a mutated IgG2 isotype, lack of binding to Fcg receptors, and the ability to induce apoptosis selectively in activated T cells. Observational studies In 17 patients with steroid-refractory acute graft-versus-host disease, there were no consistent variations in chest X-ray findings or electrocardiograms after visilizumab therapy; there was no difference in liver function tests, or serum creatinine, and human antibodies against visilizumab were not detected; there were no allergic reactions [317c]. Three of 53 visilizumab infusions were followed by single transient grade 1 adverse events (facial flushing, upper limb weakness, and a low-grade fever). None of the 17 patients had serum cytokine concentrations above 1 ng/ml and those without postinfusional adverse events did not have detectable peaks in cytokines. In an open phase I study of intravenous visilizumab 15 micrograms/kg in 32 patients with ulcerative colitis, the dose was reduced to 10 micrograms/kg in 24 because of adverse reactions [318c]. Mild to moderate symptoms of cytokine release occurred in 100% and 83% of patients in the 15 and 10 micrograms/kg dose groups respectively. One patient had chest pain and had a modest rise in serum troponin I concentration 30 minutes after a second infusion; the symptoms resolved within 20 minutes. One patient had mild bilateral blurring of vision on the first day; ophthalmologic examination 1 month later showed several small peripheral retinal hemorrhages in one eye. After visilizumab administration, the fall in the numbers of peripheral T-cells was associated with increased Epstein–Barr virus DNA titers in the blood in most of the patients and 34% of patients reported eight types of infections, including urinary tract infections, cellulitis, candidiasis, nasopharyngitis, rhinitis, tonsillitis, and upper respiratory tract infections; all were mild or moderate and resolved with out-patient management.

794

In two prospective studies in 34 patients with Crohn's disease who received intravenous visilizumab 10 micrograms/kg on two consecutive days, there were symptoms of cytokine release at a median of 45 minutes after the infusion [319c]. The cytokine profile was characterized by increases interferon-inducible protein-10, monocyte chemotactic protein 1, tumor necrosis factor-alpha, interferon gamma, interleukins 2, 6, 8, and 10, and interleukin 1 receptor antagonist. TNF-alpha and IL-2 peaked at 1 hour and all the others at 6 hours. In 86% of the patients there were transient rises above the upper limit of the reference

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ranges in hepatic enzymes, but not bilirubin, within 6 hours.

Zanolimumab (HuMax-CD4) Zanolimumab is a fully human monoclonal anti-CD4 antibody. It is isolated from transgenic mice as a hybridoma clone but subsequently expressed in Chinese hamster ovary cells. It has been tested in the treatment of psoriasis [320C] and non-cutaneous peripheral T cell lymphomas [321c].

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Sherry RM, Royal RE, Steinberg SM, Rosenberg S. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma. Cancer 2008; 113(2): 293–301. Baer MR, George SL, Caligiuri MA, Sanford BL, Bothun SM, Mrózek K, Kolitz JE, Powell BL, Moore JO, Stone RM, Anastasi J, Bloomfield CD, Larson RA. Low-dose interleukin-2 immunotherapy does not improve outcome of patients age 60 years and older with acute myeloid leukemia in first complete remission: Cancer and Leukemia Group B Study 9720. J Clin Oncol 2008; 26(30): 4934–9. Cho DC, Puzanov I, Regan MM, Schwarzberg T, Seery V, Lee M-Y, Liu V, Bhatt R, Koon H, Mier JW, Sosman JA, Atkins MB, McDermott DF. Retrospective analysis of the safety and efficacy of interleukin-2 after prior VEGF-targeted therapy in patients with advanced renal cell carcinoma. J Immunother 2009; 32(2): 181–5. Singla A, Denmeade SR. Left posterior fascicular block due to high-dose interleukin-2. Ann Pharmacother 2008; 42(9): 1340–3. Porter BO, Shen J, Kovacs JA, Davey RT, Rehm C, Lozier J, Csako G, Nghiem K, Costello R, Lane HC, Sereti I. Interleukin-2 cycling causes transient increases in high-sensitivity C-reactive protein and Ddimer that are not associated with plasma HIV-RNA levels. AIDS 2009; 23(15): 2015–9. Correale P, Tagliaferri P, Fioravanti A, Del Vecchio MT, Remondo C, Montagnani F, Rotundo MS, Ginanneschi C, Martellucci I, Francini E, Cusi MG, Tassone P, Francini G. Immunity feedback and clinical outcome in colon cancer patients undergoing chemoimmunotherapy with gemcitabine þ FOLFOX followed by subcutaneous granulocyte macrophage colony-stimulating factor and aldesleukin (GOLFIG-1 Trial). Clin Cancer Res 2008; 14(13): 4192–9. Fontas E, Kousignian I, Pradier C, Duvivier C, Poizot-Martin I, Durier C, Jarrousse B, Weiss L, Levy Y, Costagliola D. Interleukine-2 therapy does not increase the risk of Hodgkin or non-

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Constantinescu CS, Miller A, De Angelis T, Matiello M, Cree BAC. Treatment of neuromyelitis optica with rituximab: retrospective analysis of 25 patients. Arch Neurol 2008; 65(11): 1443–8. Kanbayashi Y, Nomura K, Fujimoto Y, Yamashita M, Ohshiro M, Okamoto K, Matsumoto Y, Horiike S, Takagi T, Ishida Y, Taniwaki M. Japan Haematology/Oncology Study (J-HOST) Group (Morioka, Japan). Risk factors for infection in haematology patients treated with rituximab. Eur J Haematol 2009; 82: 26–30. Salliot C, Dougados M, Gossec L. Risk of serious infections during rituximab, abatacept and anakinra treatments for rheumatoid arthritis: meta-analyses of randomised placebo-controlled trials. Ann Rheum Dis 2009; 68(1): 25–32. Aksoy S, Dizdar Ö, Hayran M, Harputluoğlu H. Infectious complications of rituximab in patients with lymphoma during maintenance therapy: a systematic review and meta-analysis. Leuk Lymph 2009; 50(3): 357–65. Yeo W, Chan TC, Leung NWY, Lam WJ, Mo FKF, Chu MT, Chan HLY, Hui EP, Lei KIK, Mok TSK, Chan PKS. Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis b undergoing anticancer therapy with or without rituximab. J Clin Oncol 2009; 27(4): 605–11. Garcia-Rodriguez MJ, Canales MA, Hernandez-Maraver D, HernandezNavarro F. Late reactivation of resolved hepatitis B virus infection: an increasing complication post rituximab-based regimens treatment? Am J Hematol 2008; 83: 673–5. Fleischmann RM. Progressive multifocal leukoencephalopathy following rituximab treatment in a patient with rheumatoid arthritis. Arthritis Rheum 2009; 60: 3225–8. Ram R, Ben-Bassat I, Shpilberg O, Polliack A, Raanani P. The late adverse events of rituximab therapy—rare but there! Leuk Lymph 2009; 50(7): 1083–95. Nott L, Price TJ, Pittman K, Patterson K, Young R, Fletcher J. Hyperammonaemic encephalopathy associated with

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rituximab-containing chemotherapy. Intern Med J 2008; 38: 800–3. Ruch J, McMahon B, Ramsey G, Kwaan HC. Catastrophic multiple organ ischemia due to an anti-Pr cold agglutinin developing in a patient with mixed cryoglobulinemia after treatment with rituximab. Am J Hematol 2009; 84: 120–2. Cornejo A, Bohnenblust M, Harris C, Abrahamian G. Intestinal perforation associated with rituximab therapy for post-transplant lymphoproliferative disorder after liver transplantation. Cancer Chemother Pharmacol 2009; 64(4): 857–60. Schwartzberg LS, Stepanski EJ, Walker MS, Mathias S, Houts AC, Fortner BV. Implications of IV monoclonal antibody infusion reaction for the patient, caregiver, and practice: results of a multicenter study. Support Care Cancer 2009; 17(1): 91–8. Gentner J, Morra M, Knutsen AP. Development of common variable immunodeficiency in an 8-year-old boy treated with rituximab for idiopathic thrombocytopenia. Pediatr Asthma Allergy Immunol 2008; 21(2): 99–104. Coors EA, Seybold H, Merk HF, Mahler V. Polysorbate 80 in medical products and nonimmunologic anaphylactoid reactions. Ann Allergy Asthma Immunol 2005; 95(6): 593–9. Klink DT, van Elburg RM, Schreurs MWJ, van Well GTJ. Rituximab administration in third trimester of pregnancy suppresses neonatal B-cell development. Clin Dev Immunol 2008; 2008: 271363. Dahabreh IJ, Linardou H, Siannis F, Fountzilas G, Murray S. Trastuzumab in the adjuvant treatment of early-stage breast cancer: a systematic review and meta-analysis of randomized controlled trials. Oncologist 2008; 13(6): 620–30. McKeage K, Lyseng-Williamson KA. Trastuzumab: a pharmacoeconomic review of its use in early breast cancer. Pharmacoeconomics 2008; 26(8): 699–719. Rayson D, Richel D, Chia S, Jackisch C, van der Vegt S, Suter T. Anthracycline– trastuzumab regimens for HER2/neu-

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overexpressing breast cancer: current experience and future strategies. Ann Oncol 2008; 19(9): 1530–9. Portera CC, Walshe JM, Rosing DR, Denduluri N, Berman AW, Vatas U, Velarde M, Chow CK, Steinberg SM, Nguyen D, Yang SX, Swain SM. Cardiac toxicity and efficacy of trastuzumab combined with pertuzumab in patients with trastuzumab-insensitive human epidermal growth factor receptor 2-positive metastatic breast cancer. Clin Cancer Res 2008; 14(9): 2710–6. Mariani G, Fasolo A, De Benedictis E, Gianni L. Trastuzumab as adjuvant systemic therapy for HER2-positive breast cancer. Nat Clin Pract Oncol 2009; 6(2): 93–104. Perez EA, Suman VJ, Davidson NE, Sledge GW, Kaufman PA, Hudis CA, Martino S, Gralow JR, Dakhil SR, Ingle JN, Winer EP, Gelmon KA, Gersh BJ, Jaffe AS, Rodeheffer RJ. Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 Adjuvant Breast Cancer Trial. J Clin Oncol 2008; 26(8): 1231–8. Martin M, Esteva FJ, Alba E, Khandheria B, Perez-Isla L, GarciaSaenz JA, Marquez A, Sengupta P, Zamorano J. Minimizing cardiotoxicity while optimizing treatment efficacy with trastuzumab: review and expert recommendations. Oncologist 2009; 14(1): 1–11. Tu C-M, Chu K-M, Yang S-P, Cheng S-M, Wang W-B. Trastuzumab (Herceptin)associated cardiomyopathy presented as new onset of complete left bundle-branch block mimicking acute coronary syndrome: a case report and literature review. Am J Emerg Med 2009; 27(7): 903.e1–3. Pepels MJ, Boomars KA, van Kimmenade R, Hupperets PS. Life-threatening interstitial lung disease associated with trastuzumab: case report. Breast Cancer Res Treat 2009; 113(3): 609–12. Bartsch R, Wenzel C, Gampenrieder S, Pluschnig U, Altorjai G, Rudas M, Mader R, Dubsky P, Rottenfusser A, Gnant M, Zielinski C, Steger G.

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Trastuzumab and gemcitabine as salvage therapy in heavily pre-treated patients with metastatic breast cancer. Cancer Chemother Pharmacol 2008; 62(5): 903–10. Al-Dasooqi N, Bowen J, Gibson R, Sullivan T, Lees J, Keefe D. Trastuzumab induces gastrointestinal side effects in HER2-overexpressing breast cancer patients. Investig New Drugs 2009; 27(2): 173–8. Ruiz M, Salvador J, Bayo J, Lomas M, Moreno A, Valero M, Bernabé R, Vicente D, Jiménez J, Lopez-Ladrón A. Phase-II study of weekly schedule of trastuzumab, paclitaxel, and carboplatin followed by a week off every 28 days for HER2þ metastatic breast cancer. Cancer Chemother Pharmacol 2008; 62(6): 1085–90. Storniolo AM, Pegram DM, Overmoyer B, Silverman P, Peacock NW, Jones SF, Loftiss J, Arya N, Koch KM, Paul E, Pandite L, Fleming RA, Lebowitz PF, Ho PTC, Burris HA. Phase I dose escalation and pharmacokinetic study of lapatinib in combination with trastuzumab in patients with advanced ErbB2-positive breast cancer. J Clin Oncol 2008; 26(20): 3317–23. Srinivasan S, Parsa V, Liu CY, Fontana CA. Trastuzumab-induced hepatotoxicity. Ann Pharmacother 2008; 42 (10): 1497–501. Carpenter PA, Appelbaum FR, Corey L, Deeg HJ, Doney K, Gooley T, Krueger J, Martin P, Pavlovic S, Sanders J, Slattery J, Levitt D, Storb R, Woolfrey A, Anasetti C. A humanized non-FcR-binding anti-CD3 antibody, visilizumab, for treatment of steroid-refractory acute graft-versus-host disease. Blood 2002; 99(8): 2712–9. Plevy S, Salzberg B, Van Assche G, Regueiro M, Hommes D, Sandborn W, Hanauer S, Targan S, Mayer L, Mahadevan U, Frankel M, Lowder J. A phase I study of visilizumab, a humanized anti-CD3 monoclonal antibody, in severe steroid-refractory ulcerative colitis. Gastroenterology 2007; 133(5): 1414–22. Baumgart DC, Lowder JN, Targan SR, Sandborn WJ, Frankel MB. Transient cytokine-induced liver injury following

814 administration of the humanized anti-CD3 antibody visilizumab (HuM291) in Crohn's disease. Am J Gastroenterol 2009; 104(4): 868–76. [320] Skov L, Kragballe K, Zachariae C, Obitz ER, Holm EA, Jemec GB, Slvsten H, Ibsen HH, Knudsen L, Jensen P, Petersen JH, Menné T, Baadsgaard O. HuMax-CD4: a fully human monoclonal anti-CD4 antibody for

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the treatment of psoriasis vulgaris. Arch Dermatol 2003; 139(11): 1433–9. [321] d'Amore F, Radford J, Relander T, Jerkeman M, Tilly H, Osterborg A, Morschhauser F, Gramatzki M, Dreyling M, Bang B, Hagberg H. Phase II trial of zanolimumab (HuMax-CD4) in relapsed or refractory non-cutaneous peripheral T cell lymphoma. Br J Haematol 2010; 150(5): 565–73.

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38

Drugs that act on the immune system: immunosuppressive and immunostimulatory drugs

Ciclosporin [SED-15, 743; SEDA-30, 452; SEDA-31, 619; SEDA-32, 705] Nervous system A posterior reversible encephalopathy syndrome in a child with Langerhans cell histocytosis resolved completely when ciclosporin was withdrawn [1A]. Similar cases have been reported in a 27-year-old man with collapsing focal glomerulosclerosis [2A] and in a 68-year-old woman and a 19-year-old man after heart transplantation [3A]. Several cases of parkinsonism have been attributed to ciclosporin. • A 42-year-old man developed parkinsonism after taking ciclosporin for 10 days; after conversion of ciclosporin to tacrolimus the condition resolved [4A]. • A 51-year-old man developed parkinsonism after taking ciclosporin 3 mg/kg/day for 2 months; an MRI scan showed only bilateral chronic frontal subdural hematomas and withdrawal of ciclosoporin led to complete resolution within 2 months [5A]. • Disabling parkinsonism occurred in a 59year-old Thai woman who had taken ciclosporin for several years and began to resolve within a few days of withdrawal [6A].

Mouth Of 50 patients taking ciclosporin 32 developed minimal gingival overgrowth and 18 had clinically significant overgrowth; the mutated C3435T genotype of the MDR1 gene was significantly more frequent in the latter and a significant association between gingival overgrowth and the 3435TT genotype was confirmed by logistic regression analysis [7c]. The involvement of cystatin C in gingival overgrowth has been studied in human gingival samples, comparing 15 samples from patients with gingival overgrowth and five normal samples [8cE]. Cystatin C staining in gingival tissue was stronger in those with ciclosporin-induced overgrowth, and intensive staining for cystatin C expression was seen mainly in the cytoplasm of fibroblasts, epithelial cells, and inflammatory cells. Cystatin C expression was also significantly increased in samples with greater degrees of inflammatory infiltration. The addition of ciclosporin 200 mg/l increased cystatin C expression in human gingival fibroblasts, and this effect was increased by addition of periodontal pathogens and proinflammatory cytokines. Biliary tract See Tacrolimus below.

Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00038-6 # 2011 Elsevier B.V. All rights reserved.

Pancreas There was biochemical evidence of acute pancreatitis in a 49-year-old woman after she had taken ciclosporin for 20 days, although an abdominal CT scan 815

816

and ultrasonography showed a normal pancreas; it responded to dosage reduction and supportive care [9A].This may simply have been hyperamylasemia. Urinary tract In 53 patients with steroiddependent nephrotic syndrome taking ciclosporin, there was nephropathy in 22 biopsies; nephropathy was positively associated with the use of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and hyperuricemia [10c]. In 18 patients with minimal change nephrotic syndrome or IgA nephropathy taking ciclosporin, tubular expression of Toll-like receptors was increased, as were TLR4 mRNA and protein expression in a dose-related fashion [11cE]. In a retrospective review of 235 childhood liver transplant recipients with no known risk factors for formation of renal cysts and no evidence of cysts at the time of transplantation, 26 (11%) developed at least one cyst and had a reduced mean GFR [12c]. Two (1.4%) of the 146 patients who took tacrolimus and 24 (27%) of the 89 patients who took ciclosporin acquired renal cysts, and ciclosporin was the only independent variable associated with renal cysts. Hemolytic–uremic syndrome occurred in a 41-year-old Chinese man with diffusetype systemic sclerosis when he took ciclosporin for 1–2 months; it responded to plasma exchange [13A]. Skin Acne with cysts and nodules on the face in a 9-month-old boy was attributed to ciclosporin; it resolved after withdrawal of ciclosporin and administration of isotretinoin [14A]. Hair Hypertrichosis and darkening of the hair occurred in a 59-year-old man who took ciclosporin 2.5 mg/kg/day for 2 months [15A]. Musculoskeletal Bone pain occurred in a 6year-old boy during infusion of ciclosporin [16A]. An MRI scan showed periosteal soft tissue changes and mild bone marrow edema of the femora and tibiae. Ciclosporin was replaced by tacrolimus, and after 9 days the pain had abated; it resolved

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J.K. Aronson

completely when tacrolimus was withdrawn. The authors suggested that the bone changes had been mediated by calcineurininduced vascular changes, leading to intraosseous vasoconstriction and bone marrow edema. Genotoxicity Sister chromatid exchange was significantly increased in 20 renal transplant recipients who were taking ciclosporin; there were no changes in 17 patients taking tacrolimus [17c]. Tumorigenicity A digital fibrokeratoma occurred in association with gingival overgrowth in a 39-year-old Chinese woman who had taken ciclosporin for 6 years [18A]. Susceptibility factors Genetic The associations between ABCB1 genotypes (in exons 12, 21, and 26) and ciclosporin-related outcomes have been studied in 147 renal transplant recipients [19C]. Carriers of T allelic variants in exons 21 or 26 had a threefold increased risk of delayed graft function, a trend to slower recovery of renal function and a lower GFR at study end, and significantly higher incidences of new-onset diabetes and cytomegalovirus reactivation compared with carriers of the wild-type genotype. T variants in both exons 21 and 26 were independently associated with 3.8fold and 3.5-fold respectively higher risks of delayed graft function. Age Patients taking ciclosporin aged over 65 years (n ¼ 11, mean 73 years) were compared with patients aged 18–64 years (n ¼ 14, mean 43 years), with measurements of ciclosporin concentrations in whole blood and T lymphocytes [20c]. The older patients achieved target concentrations with lower doses because of a lower clearance and had 44% higher ratios of intracellular to whole blood ciclosporin concentrations. The CYP3A5*1 and ABCB1 genotypes had no effect on ciclosporin pharmacokinetics. The authors suggested that in elderly recipients it might be safe to aim for lower whole blood target concentrations than current guidelines recommend.

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Drug–drug interactions Escitalopram A case of serotonin syndrome in an 84-yearold woman has been attributed to co-administration of escitalopram and ciclosporin; the authors suggested that ciclosporin inhibited the metabolism of escitalopram by CYP3A4 [21A].

817

Nifedipine The incidence of gingival hyperplasia has been studied in 31 patients taking ciclosporin, 31 taking ciclosporin þ amlodipine, and 31 taking ciclosporin þ nifedipine [23c]. There was gingival hyperplasia in 16, 18, and 28 respectively; furthermore, more of those who took ciclosporin þ nifedipine had severe hyperplasia (n ¼ 7), compared with ciclosporin alone (n ¼ 0) and ciclosporin þ amlodipine (n ¼ 5).

Of 1471 adult renal transplant recipients, 205 were switched from calcineurin inhibitors to sirolimus (n ¼ 88) or everolimus (n ¼ 117) [29c]. Six (2.9%) developed pneumonitis, one associated with sirolimus and five with everolimus. Median times from conversion to the onset of pneumonitis were 34 days in four patients (range 24–46 days) and 491 days in 2 subjects (range 454–528 days). The most common symptoms were dry cough (n ¼ 6), fever (n ¼ 5), and dyspnea (n ¼ 4). Imaging tests showed lower lobe involvement in all cases. Bronchoalveolar lavage in four patients showed lymphocytic alveolitis. All recovered completely after drug withdrawal. In a retrospective study of 64 patients taking everolimus 10 mg/day, 24 had radiographic evidence of pneumonitis; in 16 cases it was thought to be either possibly (n ¼ 12) or probably (n ¼ 4) related to everolimus [30c]. The most common radiographic findings were focal areas of consolidation at the lung bases or ground-glass opacities.

Rimonabant The pharmacokinetic interaction of ciclosporin with rimonabant has been studied in 10 stable renal transplant recipients [24c]. Rimonabant caused a moderate but significant increase in ciclosporin AUC0!12h, with non-significant rises in Cmax and C2 concentrations. Tacrolimus pharmacokinetics were not significantly affected by rimonabant in eight patients.

Metabolism Before heart transplantation in 15 patients the mean concentration of serum triglycerides was 1.55 mmol/l; after transplantation it rose to 2.12 mmol/l; and after treatment with sirolimus or everolimus there was a further rise to 4.00 mmol/l [31c]. After treatment with omega-3 fatty acids for 4 months the triglyceride concentration fell to 2.55 mmol/l.

HMG CoA reductase inhibitors Rhabdomyolysis and renal failure in a 55-year-old man has been attributed to inhibition by concomitant ciclosporin and risperidone of the metabolism of simvastatin by CYP3A4 [22A].

Everolimus (SDZ-RAD)

[SED-15, 1306; SEDA-30, 453; SEDA-31, 622; SEDA-32, 708]

Respiratory Pneumonitis occurred in a 57year-old renal transplant recipient taking everolimus, whose trough blood concentrations were in the usual target range; it resolved completely after drug withdrawal [25A]. Interstitial pneumonitis has also been attributed to everolimus in five heart transplant recipients [26A, 27A] and a liver transplant recipient [28A].

Drug–drug interactions Antifungal azoles The management of a pharmacokinetic interaction of voriconazole with everolimus has been described in a 65-year-old man who underwent orthotopic liver transplantation complicated by intestinal perforation, sepsis, and acute renal insufficiency [32A]. He received intravenous fluconazole 400 mg followed by 100 mg/day and oral everolimus 0.75 mg bd; the steady-state Cmin of everolimus was satisfactory. On day 72 after transplantation, because of invasive aspergillosis, antifungal therapy was switched to intravenous voriconazole 400 mg bd on the first day followed by 200 mg bd; to prevent drug toxicity the dosage of

818

everolimus was promptly lowered to 0.25 mg/day. The dose-corrected Cmin of everolimus at steady-state was markedly higher during co-treatment with voriconazole than with fluconazole (mean 11 vs. 3.5 mg/l per mg/kg/day). During everolimus þ azole co-treatment, everolimus dosage reduction is needed to avoid overexposure. Because of different CYP3A4 inhibitory potencies, the reduction should be greater during cotreatment with voriconazole than with fluconazole.

Leflunomide [SED-15, 2015; SEDA-30, 454; SEDA-31, 625; SEDA-32, 709] Respiratory More cases of respiratory adverse reactions to leflunomide have been reported, manifesting as interstitial pneumonitis [33A], diffuse alveolar damage with secondary organizing pneumonia [34A], and diffuse alveolar hemorrhage [35A]. A review counted 32 cases of leflunomide-induced pneumonitis (not including the one mentioned above) reported in the English language literature [36R]. Of 5043 patients in the postmarketing surveillance of leflunomide in Japan, 61 had lung damage, and 24 died as a result. Multivariate regression analysis showed that pre-existing interstitial lung disease, the use of a loading dose, a history of smoking, and a body weight of 40 kg or less were susceptibility factors. Based on these findings, it has been proposed that leflunomide should only be used as a second-line drug, that it should not be used in those with pre-existing interstitial lung disease, and that a loading dose should not be used in those with other susceptibility factors [37R]. The prevalence and susceptibility factors for new and/or exacerbated interstitial lung disease have been studied in a post-marketing surveillance review of 5054 Japanese patients with rheumatoid arthritis taking leflunomide [38C]. Interstitial lung disease developed and/or was exacerbated in 61 patients (1.2%). Pre-existing interstitial lung disease (OR ¼ 8.17; 95% CI ¼ 4.63,

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J.K. Aronson

14), cigarette smoking (OR ¼ 3.12; 95% CI ¼ 1.73, 5.60), a low body weight (OR ¼ 2.91; 95% CI ¼ 1.15, 7.37), and the use of a loading dose (OR ¼ 3.97; 95% CI ¼ 1.22, 13) were independent susceptibility factors. The authors suggested that leflunomide should not be prescribed for patients with rheumatoid arthritis complicated by interstitial lung disease. The factors associated with a poor prognosis in leflunomide-induced lung injury have been studied in 22 patients with rheumatoid arthritis, of whom 9 died and 13 recovered [39c]. The patients who died tended to have pre-existing interstitial pneumonia (8/9 vs. 6/13). The loading and maintenance doses, the serum concentration of the leflunomide metabolite A771726, and the duration of treatment did not differ between the groups. The patients who died had more frequent hypoxemia and mechanical ventilation, had a high serum CRP concentration (190 vs. 100 mg/l), and had a low albumin concentration (27 versus 33 g/l). The lymphocyte count was persistently low in those who died, but recovered in those who survived. Colestyramine wash-out therapy has been used to treat a 32-year-old Chinese woman with leflunomide-induced pneumonitis [40A]. Nervous system Leflunomide-associated progressive multifocal leukoencephalopathy has been reported in a 68-year-old man [41A]. Gastrointestinal Persistent diarrhea and weight loss occurred during therapy with leflunomide, with histological evidence of lymphocytic colitis; leflunomide was withdrawn, the diarrhea settled, and histologically there was no colitis 3 months later [42A]. Skin Toxic epidermal necrolysis has been attributed to leflunomide in a patient with rheumatoid arthritis [43A]. • A 36-year-old woman with seropositive rheumatoid arthritis was given leflunomide 20 mg/ day, and 2 weeks later developed a painful, febrile, maculopapular rash involving the face and upper torso. The skin lesions had a bull's-eye appearance with a dark center and

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Chapter 38

spread rapidly to the rest of her body. After 4 days the lesions coalesced into large areas of epidermal detachment involving 55% of the body surface area. There was catarrhal conjunctivitis and symblepharon. Liver enzymes were raised. All medications were stopped and colestyramine and prednisolone were started. The patient was eventually left completely blind as a result of punctuate keratitis with keratinization of the cornea.

Another case has been reported in a 36year-old woman 1 week after a 3-week course of leflunomide [44A]. Cutaneous ulceration occurred after treatment with leflunomide 20 mg/day for 1 month in two patients with psoriasis [45A, 46A], including a 31-year-old woman with psoriatic arthropathy who took leflunomide 20 mg/day for 1 month. Musculoskeletal Polymyositis occurred in a 53-year-old woman after leflunomide treatment for rheumatoid arthritis [47A]. Teratogenicity Healthy twins born were born after maternal exposure to leflunomide [48A]. Susceptibility factors Genetic Isoforms of cytochromes P450, mainly CYP1A2 and CYP2C19, may be involved in leflunomide activation. Genotyping in 105 patients with rheumatoid arthritis suggested that the CYP1A2*1F allele may be associated with leflunomide toxicity [49c]. In addition, the dihydro-orotate dehydrogenase A40C polymorphism was associated with leflunomide toxicity in 105 patients with rheumatoid arthritis [50c].

Mycophenolate mofetil [SED-15, 2402; SEDA-30, 455; SEDA-31, 627; SEDA-32, 710] Drug–drug interactions Ciclosporin In 18 kidney transplant recipients taking mycophenolate mofetil, ciclosporin in concentration-related fashion increased trough concentrations of the acyl glucuronide and phenol glucuronide metabolites of

819

mycophenolate; tacrolimus had no effect on mycophenolate or its metabolites in 17 patients [51c].

Pimecrolimus [SED-15, 2833; SEDA30, 456; SEDA-31, 628; SEDA-32, 712] Observational studies In 52 patients with seborrheic dermatitis who used pimecrolimus 1% cream bd, the most frequent adverse reaction was a burning-tingling sensation, which abated after 7 days (i.e. it was of the early tolerant variety, see p. xxxiii) [52c]. Placebo-controlled studies In a doubleblind, randomized, placebo-controlled study in 68 patients with vitiligo, the only adverse reaction to pimecrolimus in combination with narrow-band ultraviolet B irradiation was self-limited erythema and pruritus [53C]. Tumorigenicity The rates of tumors among patients with atopic dermatitis or eczema who used topical pimecrolimus have been evaluated in a retrospective cohort study of 953 064 subjects and controls [54c]. The age- and sex-adjusted hazard ratio for all cancers was 1.15 (95% CI ¼ 0.99, 1.31). T-cell lymphoma was the only tumor associated with a significantly increased risk (HR ¼ 3.76; 95% CI ¼ 1.71, 8.28). However, after exclusion of patients who had had suspicious lesions before exposure the hazard ratio fell to 2.32 (95% CI ¼ 0.89, 6.07). In a cohort study of 92 585 patients with dermatitis, who used pimecrolimus for 121 289 person-years of follow-up, there was no increased risk of lymphoma compared with tacrolimus (rate ratio, RR ¼ 1.16; 95% CI ¼ 0.74, 1.82) and glucocorticoids (RR ¼ 1.15; 95% CI ¼ 0.49, 2.72) [55c]. All three topical treatments were associated with an increased risk of lymphoma compared with the general population, suggesting increased detection of pre-existing tumors.

820

Drug–alcohol interactions See Tacrolimus below.

Sirolimus (rapamycin) [SED-15, 3148; SEDA-30, 457; SEDA-31, 628; SEDA-32, 712] Respiratory More cases of sirolimus-associated interstitial pneumonitis have been reported (see also Everolimus) [56Ar, 57A]. A 50-year-old man developed bronchiolitis obliterans with organizing pneumonia after taking sirolimus monotherapy 2 mg/day for 8 days [58A]. Hematologic Severe, sustained, unilateral and bilateral lymphedema has been reported in eight patients taking sirolimus [59A]. In six cases it was unilateral and in seven cases there was no improvement after withdrawal; both of these factors throw some doubt on a causative relation. Metabolism The rate of new-onset diabetes mellitus has been studied in 20 124 patients taking sirolimus after kidney transplantation, using data from the US Renal Data System, compared with patients taking ciclosporin, mycophenolate mofetil, or azathioprine [60c]. Those who took sirolimus were at increased risk of diabetes, whether it was used in combination with ciclosporin (adjusted HR ¼ 1.61; 95% CI ¼ 1.36, 1.90), tacrolimus (adjusted HR ¼ 1.66; 95% CI ¼ 1.42, 1.93), or mycophenolate mofetil or azathioprine (adjusted HR ¼ 1.36; 95% CI ¼ 1.09, 1.69). Mouth Mouth ulcers are common in patients who take sirolimus. In a study of the case notes of 37 renal transplant recipients who took sirolimus, eight had mouth ulcers [61c]. Painful confluent aphthous ulcers on the tongue and lower lip in a 45year-old man taking sirolimus 2 mg/day resolved when everolimus 0.75 mg bd was used instead [62A]. Urinary tract Factors that affect proteinuria in patients taking sirolimus have been

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elucidated in 48 patients, of whom 25 had new-onset proteinuria or a greater than 25% increase in proteinuria after starting sirolimus; men were more likely to have proteinuria and those taking statins were less likely; those with proteinuria had a higher rate of acute rejection [63c]. Skin In 148 patients taking sirolimus after transplantation, wound complications were more common (46% versus 19%) in those who continued to take glucocorticoids, as follows: lymphocele 32% versus 5%; dehiscence 10% versus 0%, leakage 8.8% versus 6.2%, seromas 7.5% versus 1.4% [64c]. A multivariate analysis suggested that the addition of glucocorticoids to sirolimus increases the risk of wound complications about fourfold. Avoiding overweight subjects (BMI over 30 kg/m2), using closed suction drains, and avoiding a loading dose of sirolimus may reduce the risk of wound complications [65c]. Musculoskeletal Growth retardation in an 11-year-old girl occurred when she started to take sirolimus; before treatment her growth rate had been 5.5 cm/year and it slowed down to 2.2 cm/year [66A]. The authors attributed this to the anti-proliferative and anti-angiogenic properties of sirolimus. Reproductive function In a questionnaire study of men aged 20–40 years who received a kidney transplant and used sirolimus throughout the post-transplant period, there was a significantly reduced total sperm count compared with patients who did not use sirolimus (29  106 versus 292  106) and a reduced proportion of motile spermatozoa (22% versus 41%) [67c]. The fathered pregnancy rates (pregnancies/1000 patient years) were 5.9 (95% CI ¼ 0.8, 42.1) and 93 (95% CI ¼ 66, 130) respectively. Of six patients in whom sirolimus was withdrawn, only three had significant improvement in sperm parameters. Of 170 kidney transplant patients, nine (six men and three women) were taking sirolimus; four of the men developed gonadal dysfunction and infertility on average 5–12 months after transplantation [68c].

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Sirolimus was withdrawn in all four, with full recovery and restoration of fertility. Two of the women developed amenorrhea after transplantation, and withdrawal of sirolimus in one resulted in resumption of menstrual cycles. In a retrospective chart review of 57 islet transplant recipients, ovarian cysts were found in 31 of 44 premenopausal women and only two of 13 postmenopausal women [69c]. No woman who used combined oral contraception developed ovarian cysts. Sirolimus withdrawal was associated with a reduction in cyst size and resolution of cysts in 80% of subjects. Body temperature Fever occurred in a renal transplant recipient after he took sirolimus for 1 month [70A]. During treatment with broad-spectrum antibiotics the inflammatory markers and fever worsened. Other causes were ruled out and the fever and other symptoms disappeared within 24 hours of withdrawal of sirolimus. Drug–drug interactions Antifungal azoles The effect of posaconazole 400 mg bd on the pharmacokinetics of a single 2-mg dose of sirolimus, a substrate of CYP3A4, has been investigated in an open, multiperiod study in 12 healthy subjects [71c]. Posaconazole increased sirolimus Cmax and AUC by 6.7 and 8.9 times respectively, consistent with inhibition of CYP3A4 by posaconazole. These two agents should probably not be co-administered.

Tacrolimus

[SED-15, 3279; SEDA-30, 458; SEDA-31, 630; SEDA-32, 714]

Observational studies In a retrospective study in 42 patients who took tacrolimus for a mean of 288 days, tacrolimus was withdrawn in 28 patients, because of adverse reactions in 21 cases [72c]. Gastrointestinal symptoms were the most common adverse reactions (19/42 patients), followed by infections and hyperglycemia; nausea and vomiting led to withdrawal in seven

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patients, within 60 days of starting treatment in six cases. The incidence of gastrointestinal symptoms was higher in patients taking a daily dose of 2 mg or more. Systematic reviews In a systematic review of adverse reactions to tacrolimus ointment in patients with atopic dermatitis who used it for at least 6 months, there were no increased risks of cancer or immunosuppression during follow-up for up to 4 years [73M]. Short-term adverse events included increased burning and stinging of the skin and a temporary increase in skin infections. Nervous system Brachial neuritis in an 8year-old boy resolved after tacrolimus was withdrawn and everolimus used instead [74A]. Akinetic mutism has been reported in a 66-year-old man who was given intravenous methylprednisolone and tacrolimus after liver transplantation [75A]. On day 3 he developed acute onset mutism, akinesia, and waxy rigidity of passive limb movements. The serum tacrolimus concentration was 21 mg/l. Tacrolimus was replaced with ciclosporin and mycophenolate mofetil, and his symptoms resolved completely over the next few days. A reversible leukoencephalopathy have been attributed to tacrolimus in several cases. • A 62-year-old, liver transplant recipient developed posterior reversible encephalopathy syndrome after taking tacrolimus 2 mg/day and metoprolol 150 mg/day; when her serum tacrolimus concentration fell to 1.5 mg/l she recovered [76A]. • Posterior reversible encephalopathy syndrome occurred in an 18-year-old woman who had taken tacrolimus for 14 days; an MRI scan 4 weeks after withdrawal of tacrolimus showed almost complete resolution of all the changes that were noted in a scan that was taken at the time of presentation [77A]. • A 68-year-old woman who had taken tacrolimus 4 mg/day for 7 months developed a posterior reversible leukoencephalopathy, which resolved within 6 months of tacrolimus withdrawal [78A]. • A 22-year-old woman who developed posterior leukoencephalopathy while taking tacrolimus recovered completely after drug withdrawal [79A].

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There has also been a report of a progressive necrotic encephalopathy following tacrolimus therapy in a 57-year-old man; although there was some improvement after drug withdrawal, he was left with a residual hemiplegia [80A]. Metabolism In a retrospective analysis of 122 non-diabetic patients taking tacrolimus-based triple drug immunosuppression 55% developed abnormal glycemic control and 33% required drug therapy, of whom only 5.5% required insulin [81c]. In 25 renal transplant recipients who took tacrolimus, of whom nine also took a statin, tacrolimus significantly increased plasma triglyceride concentrations, which the authors attributed to reduced lipoprotein lipase activity [82c]. Hematologic Thrombotic microangiopathy occurred in a 56-year-old woman after therapy with tacrolimus for 6 days, associated with a high trough concentration [83A]. Thrombotic thrombocytopenic purpura has been attributed to tacrolimus in a 61year-old woman [84A]. Gastrointestinal Severe new-onset colitis occurred in two kidney transplant recipients shortly after the introduction of a modified-release formulation of tacrolimus instead of standard twice-daily tacrolimus in one case and ciclosporin in the other [85A]. Both developed severe, intermittent bloody diarrhea, with abdominal pain, weight loss, dehydration, and worsening graft function. The symptoms did not abate after dosage reduction or withdrawal of mycophenolate. Biliary tract The frequencies of gallbladder sludge and cholelithiasis in 25 patients taking tacrolimus and 51 taking ciclosporin have been compared [86c]. With tacrolimus the incidence of biliary sludge was 4% (1 of 25) and of gallstones 28% (7 of 25); the rates with ciclosporin were 4% (2 of 51) and 25% (13 of 51). Urinary tract In 15 transplant recipients a diagnosis of chronic tacrolimus-associated

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J.K. Aronson

nephrotoxicity was established at an average of 55 months postoperatively [87c]. The mean dosage at the time of diagnosis was 0.054 mg/kg, with a mean whole blood trough concentration of 5.09 mg/l, which is within the usual target range. There was moderate to severe arteriosclerosis of medium-sized arteries in 12 cases, and the authors concluded that arteriosclerosis in medium-sized arteries was more likely to be associated with chronic nephrotoxicity than the dosage or whole blood trough concentration of tacrolimus. Skin Granuloma annulare has been attributed to topical tacrolimus 0.1% in three women aged 37, 55, and 43 [88A]. Tumorigenicity The rates of tumors among patients with atopic dermatitis or eczema who used topical tacrolimus have been evaluated in a retrospective cohort study of 953 064 subjects and controls [89c]. The age- and sex-adjusted hazard ratio for all cancers was 0.93 (95% CI ¼ 0.81, 1.07). T-cell lymphoma was the only tumor associated with a significantly increased risk among those who used tacrolimus (HR ¼ 5.04; 95% CI ¼ 2.39, 11). Even after exclusion of patients who had had suspicious lesions before exposure the hazard ratio remained significant at 5.44 (95% CI ¼ 2.51, 12). Susceptibility factors Genetic In 51 children with liver transplants taking tacrolimus, there was a higher incidence of ABCB1 variant-alleles among patients with at least a 30% reduction in eGFR at 6 months after transplantation (1236T allele: 63% versus 38% in controls; 2677T allele: 63% versus 36%; 3435T allele: 60% versus 39%). Carriers of the G2677>T variant allele also had a significant 23% reduction in eGFR at 12 months after transplantation [90c]. Haplotype analysis showed a significant association between T–T–T haplotypes and an increased incidence of nephrotoxicity at 6 months after transplantation (haplotype frequency ¼ 53% in nephrotoxic patients versus 29% in controls). Furthermore, G2677>T and C3435>T polymorphisms and T–T–T

Drugs that act on the immune system

Chapter 38

haplotypes correlated significantly with higher tacrolimus dose-adjusted trough concentrations. A genetic factor that may predispose to post-transplantation diabetes mellitus in patients taking tacrolimus is polymorphism in the calpain-10 gene (CAPN10), which is associated with an increased risk of type 2 diabetes in the general population. Of 214 non-diabetic kidney transplant recipients taking tacrolimus, 56 developed diabetes and 158 did not, and they were genotyped for CAPN10 gene variants (SNP-43: rs3792267:G>A, SNP-19: rs3842570 ins/ del, and SNP-63: rs5030952:C>T) [91c]. The frequency of the SNP-63 minor allele was slightly increased in those who developed post-transplantation diabetes mellitus, and there was an association of SNP-63 heterozygosity with the risk of diabetes (OR ¼ 2.45). There was an increased risk of diabetes in patients carrying the 1–1–2 haplotype (rs3792267:G-rs3842570:ins-rs5030952:T) compared with non-carriers (OR ¼ 2.35). A higher body mass index and SNP-63 minor T allele carrier status were independent susceptibility factors. Drug overdose A 3-year-old girl with an acute overdose of tacrolimus developed abdominal pain, a poor appetite, vomiting, diarrhea, headache, tachypnea, leg pains, gingival bleeding, easy bruisability, epistaxis, and ecchymoses all over the body [92A]. The hemoglobin was 10 g/dl, platelets 307  109/l, prothrombin time 13.6 seconds, partial thromboplastin time 98 seconds, and bleeding time 12.5 seconds. The tacrolimus trough concentration was 28 (target 7–12) ng/ml. An accidental overdose of tacrolimus, prescribed instead of thiamine, in a 42 year-old woman resulted in non-oliguric renal failure and a metabolic acidosis; the tacrolimus concentration 27 hours after the last dose was 97 (usual target range 5–20) mg/l and she recovered without sequelae [93A]. Drug–drug interactions Amlodipine A 19-year-old woman, who took tacrolimus after renal transplantation and amlodipine

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5 mg/day, developed galactorrhea and mastalgia; the dose of tacrolimus was reduced, but her symptoms persisted until amlodipine was withdrawn [94A]. Her serum prolactin concentration was slightly raised. When amlodipine was reintroduced her symptoms returned within 5 days. Antifungal azoles The co-prescription of posaconazole with tacrolimus has been evaluated in 14 lung transplant recipients with cystic fibrosis. Posaconazole inhibited CYP3A4-mediated tacrolimus metabolism, resulting in a threefold reduction in tacrolimus dosage requirements [95c]. The effects of single nucleotide polymorphisms (SNPs) in CYP3A4, CYP3A5, and MDR1 on interactions of tacrolimus with fluconazole have been examined in 29 renal allograft recipients, who were genotyped for CYP3A4*1/*1B, CYP3A5*1/*3, MDR1 C3435T, and G2677T/A [96c]. Dose-corrected trough blood tacrolimus concentrations did not change significantly from baseline in heterozygous CYP3A5*1 carriers during exposure to fluconazole, in contrast to homozygous CYP3A5*3 carriers, in whom there was a 3.3-fold increase. Homozygous CYP3A5*3 carriers had a significant reduction in weight-corrected tacrolimus dosage requirements during fluconazole administration, in contrast to heterozygous carriers of CYP3A5*1. These effects were not influenced by fluconazole dose or duration of administration. Significantly more CYP3A5*3/*3 carriers were exposed to tacrolimus dose-uncorrected trough blood tacrolimus concentrations of at least 15 mg/l during administration of fluconazole compared with CYP3A5*3/*1 carriers. Thus, in renal allograft recipients, the CYP3A5*3/*1 genotype is associated with reduced susceptibility for the inhibitory effects of fluconazole on tacrolimus metabolism. Carbamazepine In a pharmacokinetic investigation in a woman in her 40s, tacrolimus trough concentrations fell within 7 days of treatment with carbamazepine 200 mg/day, and a 30–40% increase in tacrolimus dosage was required to maintain

Chapter 38

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adequate blood concentrations [97A]. The dose-corrected AUC0!12h after 11 days was about 50% of the value before carbamazepine and apparent oral clearance was about twice as high. Mirtazapine In a 68-year-old woman with renal failure on chronic hemodialysis, the combination of tacrolimus with mirtazapine resulted in asymptomatic hypotension after 2 hours; the tacrolimus blood concentration was over 15 mg/l [98A]. The authors hypothesized that tacrolimus, in a high concentration, had inhibited the metabolism of mirtazapine via CYP3A4. Drug–alcohol interactions In 25 patients who applied either pimecrolimus 1% cream (n ¼ 13) or tacrolimus 0.1% ointment (n ¼ 12) to lesions of vitiligo on the face twice daily for 24 weeks and then took small quantities of beer or wine, facial flushing occurred in two of the former and five of the latter [99c]. There was an itching-burning sensation, quickly followed by flushing within 5–10 minutes after alcohol and at 2–4 weeks after the start of treatment; it disappeared after 20–30 minutes. This reaction has previously been described in 6–7% of patients using topical tacrolimus [100C, 101c]. The authors proposed three hypotheses for this interaction: release of neuropeptides, causing extreme vasodilatation; local accumulation of acetaldehyde due to inhibition of aldehyde dehydrogenase by the calcineurin inhibitors; and an interaction at the calcineurin–calmodulin– calcium complex.

Temsirolimus

[SEDA-32, 716]

Observational studies In 208 patients with advanced renal cell carcinoma who were randomized to subcutaneous interferon up to 18 MU thrice weekly, intravenous temsirolimus 25 mg/week, or intravenous temsirolimus 15 mg/week þ subcutaneous interferon 6 MU thrice weekly, the most common temsirolimus-related grades 3–4

J.K. Aronson

adverse events were anemia (13%), hyperglycemia (9%), and weakness (8%) [102c]. Grades 3–4 hypercholesterolemia (1%), hypertriglyceridemia (3%), and hypophosphatemia (4%) also occurred. Pneumonitis was infrequent. In 32 patients with advanced renal cell carcinoma who were treated with temsirolimus 25 mg/week, common adverse events included weakness/fatigue (44%), increased creatinine (41%), mucositis (31%), secondary diabetes (28%), hypothyroidism (13%), rashes (13%), and hypercholesterolemia and hypertriglyceridemia (9.3%) [103c]. Urinary tract A 58-year-old man with advanced renal cell carcinoma developed grade 3 proteinuria (8.5 g/24 hours) without microscopic hematuria or renal insufficiency 5 days after an infusion of temsirolimus [104A]. Kidney biopsy showed ischemic glomeruli and focal segmental glomerulosclerosis. His proteinuria fell to 2.8 g/day 2 weeks after temsirolimus withdrawal. Skin A 73-year-old woman with metastatic renal cell carcinoma developed a pruritic rash after receiving two infusions of temsirolimus 25 mg/week; the rash was located on both antecubital areas and the backs of the knees [105A]. Biopsy showed spongiotic dermatitis with eosinophils. The authors hypothesized that temsirolimus, an mTOR kinase inhibitor, has a direct inhibitory effect on signalling pathways that regulate cell growth and tissue repair.

THIOPURINES Cross-reactivity between thiopurines Azathioprine, 6-(1-methyl-4-nitroimidazole5-yl)-thiopurine, is a prodrug that is converted non-enzymatically to mercaptopurine (Figure 1) and subsequently to thioguanine nucleotides. It is therefore not unexpected

Drugs that act on the immune system Imidazole derivatives

8-hydroxy azathioprine

AO

Chapter 38

8-hydroxy mercaptopurine

Inhibited by ribavirin

Thioxanthosine triphosphate

Thioxanthosine diphosphate

ITPA

AO HPRT Mercaptopurine

Azathioprine

825

XO/XDH

Thioinosine monophosphate

TMPT

TMPT

IMPDH

Thioxanthosine monophosphate

GMPS

Thioguanine nucleotides

Kinase Thioguanine

Inhibited by allopurinol

Thiouric acid

Methylmercaptopurine

Methyl thioinosine monophosphate

AO Methylmercapto8-hydroxypurine

AO 8-hydroxy thioguanine

Figure 1 The metabolism of azathioprine and mercaptopurine. Key: AO, aldehyde oxidase; GMPS, guanine monophosphate synthetase; HPRT, hypoxanthine phosphoribosyl transferase; IMPDH, inosine monophosphate dehydrogenase; ITPA, inosine triphosphate pyrophosphohydrolase; TPMT, thiopurine methyltransferase; XO/XDH, xanthine oxidase/dehydrogenase; dark shading: thiopurines; light shading: active metabolites.

for patients who have experienced adverse reactions to azathioprine to have similar reactions to the other thiopurines. However, in some cases mercaptopurine [106c] and thioguanine [107A] do not elicit the same adverse reactions. Observational studies Patients with Crohn's disease (n ¼ 14) or ulcerative colitis (n ¼ 15) with previous hypersensitivity reactions to azathioprine were given gradually increasing doses of mercaptopurine from 0.5 to 1.0–1.5 mg/kg/day [108c]. In nine patients mercaptopurine was withdrawn in the first 2 weeks because of early hypersensitivity reactions; the other 20 patients tolerated it. Of 135 patients with Crohn's disease (n ¼ 88) or ulcerative colitis (n ¼ 47), 65 stopped taking it because of adverse events after 25 (8–92) days; the other 70 patients tolerated mercaptopurine and were followed up for 736 (362–1080) days [109c]. Mercaptopurine was tolerated in 12 of 17 patients with hepatotoxicity and in 13 of 19 with arthralgia/myalgia during azathioprine treatment. Previous abdominal surgery was more common in those who had adverse reactions to mercaptopurine (39/65 vs. 27/70), and thiopurine methyltransferase activity was higher in those who were tolerant of mercaptopurine. Of 32 patients with inflammatory bowel disease who had adverse reactions to

azathioprine or mercaptopurine, thioguanine 20 or mg/day was well tolerated in 26; in three patients there were adverse reactions that were probably or obviously related to thioguanine and that necessitated withdrawal [110c]. Of 95 patients in whom thioguanine 0.3–0.4 mg/kg/day was used after adverse reactions to azathioprine or mercaptopurine, only 20 had adverse reactions that required withdrawal [111c]. The main reasons were gastrointestinal complaints (31%), malaise (15%), and hepatotoxicity (15%). There were hematological events in three patients and seven cases of hepatotoxicity. In 22 patients with inflammatory bowel disease who had adverse reactions to azathioprine, mercaptopurine was tolerated for longer (median 219, range 3–503 days) than azathioprine (median 14, range 2–180 days) [112c]. The adverse reactions to azathioprine were nausea and vomiting (n ¼ 14), flu-like symptoms (n ¼ 5), myalgia/arthralgia (n ¼ 6), headaches (n ¼ 6), and diarrhea (n ¼ 2). Gastrointestinal adverse effects In 15 patients (11 with Crohn's disease and four with ulcerative colitis) azathioprine caused epigastric pain, nausea, and vomiting, which developed within the first weeks of treatment [113c]. Azathioprine was withdrawn and mercaptopurine substituted; 11 patients

826

tolerated mercaptopurine and only two patients had to stop taking it because of adverse effects. In two patients with severe intestinal toxicity, which was life-threatening in one after rechallenge, there was no recurrence after the use of mercaptopurine [114A]. Hepatotoxicity In two boys, aged 11 and 15, liver damage that resolved after withdrawal of azathioprine did not occur when mercaptopurine was introduced [115A]. Either there was no cross-reactivity in these cases or azathioprine was not responsible for the liver damage. A 50-year-old man had a severe hypersensitivity reaction to azathioprine resulting in hepatitis; however, he tolerated mercaptopurine for 6 years without hepatotoxicity, despite high concentrations of methylmercaptopurine [116A]. In a retrospective study of 31 patients (14 with Crohn's disease and 17 with ulcerative colitis), in whom azathioprine (mean dose 2.2 mg/kg/day) was withdrawn because of liver damage (cytolytic in 32%, cholestatic in 39%, and mixed in 29%), mercaptopurine (mean dose 1.3 mg/kg/day) was used instead [117c]. In 27 patients there was no further liver damage; of these, 24% tolerated full doses of mercaptopurine. In four patients liver damage recurred 1–3 months after the onset of exposure to mercaptopurine. Hypersensitivity reactions In 21 patients with inflammatory bowel disease who had hypersensitivity reactions to azathioprine or mercaptopurine within 6 weeks, thioguanine 10–40 mg/day elicited hypersensitivity reactions in only four, after a median of 9 days; pancreatitis did not recur [118c]. • A 56-year-old woman with chronic intermittent urticarial vasculitis was given oral azathioprine 100 mg/day for 10 days, but developed severe nausea and vomiting [119c]. Oral re-challenge 1 year later caused similar symptoms. A second re-challenge with a single intravenous dose of 50 mg caused an immediate hypersensitivity reaction, with severe vomiting, fever, urticaria, and hypotension, followed by myalgia. A prick

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J.K. Aronson

test was strongly positive with azathioprine but not mercaptopurine. Subsequent therapy with mercaptopurine was uneventful.

Conclusions In some cases reactions to azathioprine may be due to azathioprine itself, or to metabolites that are not formed after conversion to mercaptopurine, such as 8hydroxyazathioprine (Figure 1) or a imidazole glutathione conjugate [120A]. In such cases the adverse reactions may not occur when mercaptopurine or thioguanine are used instead. In some cases in which crossreactivity did not apparently occur, the original adverse event may not have been due to the thiopurine to which it was attributed. Pancreas During 82 episodes of acute pancreatitis, most cases were attributed to drug exposure: azathioprine/mercaptopurine (n ¼ 46) and mesalazine (n ¼ 6) [121c]. In those with acute pancreatitis due to thiopurines, female sex (OR ¼ 3.4; 95% CI ¼ 1.3, 9.3) and Crohn's disease (OR ¼ 5.8; 95% CI ¼ 1.6, 21) were susceptibility factors. Skin Sweet's syndrome (neutrophilic dermatosis) has been attributed to thiopurines [122A]. • A 55-year-old man developed a fever with a non-pruritic rash 1 week after starting to take azathioprine 2.5 mg/kg/day. There were erythematous, edematous plaques, with painful pseudovesicles scattered over the face, neck, back, palms, soles, and limbs, three painless ulcers in the mouth, and bilateral conjunctivitis. He then developed right knee and bilateral elbow pain associated with erythema, warmth, and swelling. A biopsy confirmed Sweet's syndrome, which was treated with an anti-TNFa antibody. Azathioprine was withdrawn and then re-introduced; 6 hours later he developed a high-grade fever, arthralgia, a papular eruption, and unilateral conjunctivitis. Azathioprine was immediately withdrawn and he recovered completely within 48 hours. He was then given mercaptopurine 1.6 mg/kg/ day and the symptoms of Sweet's syndrome recurred after 7 hours and on two subsequent occasions after oral challenge.

Sweet's syndrome has been reported in other cases [123A, 124A].

Drugs that act on the immune system

Chapter 38

Azathioprine

[SED-15, 377; SEDA-30, 459; SEDA-31, 635; SEDA-32, 717]

Observational studies in 106 patients with Crohn's disease taking azathioprine, there was at least one adverse reaction in 56, and 18 had to stop taking it, often because of hypersensitivity reactions; there was nausea and vomiting in 29 and leukopenia in 36 [125c]. Hematologic Eryptosis is a process of suicidal cell death undergone by erythrocytes, in which the process known as scrambling of the cell membrane occurs; there is erythrocyte shrinkage, exposure of membranebound phosphatidylserine, and annexin binding, mimicking features of apoptosis in nucleated cells [126R]. Erythrocytes from patients taking azathioprine showed significantly increased exposure of phosphatidylserine within 1 week of treatment, and in vitro exposure to azathioprine in concentrations of 2 mg/l and over for 48 hours increased cytosolic Ca2þ activity and annexin V binding and reduced forward scatter [127cE]. The effect of azathioprine on both annexin V binding and forward scatter was significantly blunted in the absence of extracellular Ca2þ. The authors proposed that eryptosis might contribute to azathioprine-induced anemia. Liver A 48-year-old patient with Crohn's disease developed hepatic nodular regenerative hyperplasia, with fatigue, icterus, hepatosplenomegaly, and ascites, accompanied by pancytopenia; liver histology suggested a drug-induced cause and after withdrawal of azathioprine he improved substantially [128A]. A 50-year-old man with ulcerative colitis developed severe acute cholestatic hepatitis after taking azathioprine for 20 days. Despite withdrawal of azathioprine and methylprednisolone therapy it persisted for 2 months and may have been coincidental [129A]. Skin In five patients the minimal erythema dose for UVB, UVA, and solar-simulated radiation was determined before and after

827

azathioprine therapy for at least 12 weeks [130c]. Azathioprine was associated with increased sensitivity of the skin and reduced minimal erythema doses to UVA and solar-simulated radiation; there were no changes in UVB-induced erythema or minimal erythema dose. DNA from the skin during azathioprine therapy contained the metabolite 6-thioguanine. The authors concluded that the interaction of 6-thioguanine with UVA results in abnormal cutaneous photosensitivity. An unusual case of contact hypersensitivity to azathioprine has been reported [131A]. • A man in his early 30s developed an intermittent eczematous eruption over the shaft of his penis and scrotum coinciding with his wife's intermittent courses of azathioprine for Crohn's disease. During four courses of such treatment over 4 years her vaginal secretions were yellow, and the authors thought that vaginal secretion of azathioprine or its metabolites could have led to allergic contact dermatitis in the husband. Patch testing with azathioprine and mercaptopurine was positive in the husband but not the wife.

Nails Beau's lines, transverse depressions on the nails, developed in two patients taking azathioprine, a 68-year-old African–American woman and a 62-year-old man; in each case there was evidence of an associated hypersensitivity reaction, in one case with neutropenia and raised aminotransferase activities and in the other raised aminotransferase activities [132A]. Infection risk In 230 taking azathioprine who were studied prospectively and compared with patients who were not taking azathioprine, there was no difference in the incidence of upper respiratory tract infections, but the incidence of herpes flares was significantly increased in those taking azathioprine and there were significantly more patients with new or worsening viral warts [133c]. Tumorigenicity The increased risk of squamous cell carcinoma in patients who are immunosuppressed by azathioprine has been reviewed [134R].

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PTCH gene mutations have been analysed in 60 basal cell carcinomas, 39 from patients taking azathioprine and 21 from individuals who had never used it [135cM]. PTCH was mutated in 55% of all tumors, independent of azathioprine treatment. In both the azathioprine and non-azathioprine groups, transitions at dipyrimidine sequences, considered to indicate mutation by ultraviolet-B radiation, were frequent in tumors from chronically sun-exposed skin. In basal cell carcinomas from nonsun-exposed skin there was an over-representation of unusual G:C to A:T transitions at non-dipyrimidine sites only in those who had taken azathioprine, and all in the same TGTC sequence context at different positions within PTCH. Meta-analysis of 247 basal cell carcinomas from published studies showed that these mutations are rare in sporadic cases and have never previously been reported in this specific sequence context. The authors suggested that exposure to azathioprine may be associated with PTCH mutations, particularly in tumors from non-sun-exposed skin. Reversible Hodgkin's lymphoma associated with Epstein–Barr virus infection during azathioprine therapy for systemic lupus erythematosus in a 47-year-old woman was attributed to azathioprine, which she had taken for several years [136A]. A locally invasive mass associated with lymphadenopathy in the neck regressed significantly after withdrawal of azathioprine, and after about 5 months had almost completely resolved without the need for chemotherapy. Unbalanced whole-arm chromosomal translocations, including der(1;7)(q10;p10), der(1;15)(q10;q10), der(1;16)(q10;p10), and der(1;19)(q10;p10), have been reported in hematological malignancies, but der(1;7) (q10;p10) has rarely been associated with acute erythroleukemia. A 64-year-old Korean woman with severe neutropenia and erythroid hyperplasia during azathioprine therapy had an unbalanced translocation between the whole arms of chromosomes 1 (long arm) and 7 (short arm); the detailed karyotype was 46,XX,þ1, der(1;7)(q10;p10),inv(9)(p11q13)c [137A].

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J.K. Aronson

The authors suggested that der(1;7)(q10; p10) may be a susceptibility factor in azathioprine-associated acute erythroleukemia. A 67-year-old renal transplant recipient developed a nodular malignant melanoma after 30 years of immunosuppression with azathioprine and prednisolone [138A]. Teratogenicity In the infants of 476 Swedish women who reported using azathioprine in early pregnancy, mostly for inflammatory bowel disease, the rate of congenital malformations was 6.2%, compared with 4.7% among all infants born (adjusted OR ¼ 1.41; 95% CI ¼ 0.98, 2.04) [139C]. Exposed infants were also more likely to be preterm, to weigh under 2500 g, and to be small for gestational age. Aplasia cutis congenita involving over 90% of body surface area occurred in a baby born to a mother with pemphigus vulgaris who had taken oral prednisolone and azathioprine during pregnancy [140A]. Susceptibility factors Genetic In 50 patients with systemic lupus erythematosus taking azathioprine, the erythrocytic concentrations of thioguanine nucleotides that were associated with clinical responses were lower than the target range established for inflammatory bowel disease [141c]. The frequencies of four common TPMT mutant alleles, TPMT*2, *3A, *3B, and *3C have been determined in 150 Chinese patients who had taken azathioprine, 30 of whom had stopped taking it or were taking a reduced dosage because of adverse reactions [142c]. The mean TPMT activity in those who had never had adverse reactions was 38 (range 17–68) units and the mean value in 12 patients with hemotoxicity was significantly lower (23 units). However, there was no significant difference in 18 patients with hepatotoxicity. There were no cases of TPMT deficiency, and TPMT*2, *3A, and *3B were not detected. TPMT*3C heterozygous alleles were found in seven patients, all of whom had intermediate TPMT activity, and the mean activity was 17 units, much lower than other TPMT wild-type patients; of these seven,

Drugs that act on the immune system

Chapter 38

four had adverse reactions. The authors concluded that TPMT activity is reduced in Chinese patients with the TPMT*3C mutation. In a study of the association between gene polymorphisms in TPMT and ITPA (see Figure 1) and drug intolerance in 157 renal transplant recipients taking azathioprine, each was genotyped for variant TPMT alleles (*2, *3A, *3B, and *3C) and ITPA alleles (94C>A and IVS2þ21A>C) [143c]. Mean azathioprine dose, mean white blood-cell count, and platelet count during treatment were lower in carriers of variant TPMT alleles compared with those with the TPMT wild-type genotype. Leukocyte numbers fell below 4.0  109/l in 41% of TPMT heterozygotes compared with 18% of the wild-type patients. In contrast, the ITPA genotype did not influence azathioprine, hematology, or the risk of leukopenia. TPMT genotype polymorphisms (TPMT*2, *3A, *3B, and *3C) have been studied in 108 patients with vasculitis associated with positive antineutrophil cytoplasmic antibodies (ANCA), who were given azathioprine and followed for 47 months [144c]. Adverse reactions (leukopenia, anemia, thrombocytopenia, gastrointestinal adverse reactions including hepatitis, and hypersensitivity reactions) did not differ between patients who were heterozygous and those who were homozygous or between the tertiles of patients who were homozygous. The frequencies of TPMT mutant alleles have been studied retrospectively in 147 Japanese patients with inflammatory bowel disease taking azathioprine, of whom 144 were wild-type for TPMT (TPMT*1/*1) and three carried a mutant TPMT allele (TPMT*1/*3C) [145c]. The incidence of adverse reactions to azathioprine was 38/ 114 in the wild-type group. Leukopenia occurred in 16% of the patients with wildtype TPMT. The authors concluded that determination of TPMT genotype may not be useful in Japanese patients in predicting adverse reactions to azathioprine. In contrast, in 139 kidney transplant recipients in Thailand, nine of whom were heterozygous for the TPMT*1/*3C

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genotype, TPMT activity in those patients was significantly lower than in those with the homozygous wild-type genotype [146c]. The risk of azathioprine-induced myelosuppression in the patients with the heterozygous TPMT*1/*3C genotype was significantly higher than in those with the wild-type genotype. The sensitivity and specificity of TPMT*3C genotyping for predicting azathioprine-induced myelosuppression were 27% and 97% respectively. Genetic polymorphisms in aldehyde oxidase (AOX1), xanthine dehydrogenase (XDH) (see Figure 1), and MOCOS (the product of which activates the essential cofactor for aldehyde oxidase and xanthine dehydrogenase) have been studied in patients with inflammatory bowel disease taking azathioprine [147c]. The single nucleotide polymorphism AOX1 c.3404A>G (Asn1135Ser, rs55754655) predicted a lack of response to azathioprine, and combined with TPMT activity allowed stratification of a patient's chance of response, ranging from 86% in patients in whom both markers were favorable to 33% in those in whom they were unfavorable. There was also a weak protective effect against adverse drug reactions from the single nucleotide polymorphisms XDH c.837C>T and MOCOS c.2107A>C, which was stronger when they coincided. Drug–drug interactions Ribavirin The interaction of ribavirin, an inosine monophosphate dehydrogenase inhibitor (see Figure 1), with azathioprine has been retrospectively studied in eight patients who developed severe pancytopenia after concomitant use [148c]. All had normal thiopurine methyltransferase (TPMT) activity. Bone marrow suppression reached a nadir after a mean of 4.6 weeks. Myelotoxicity was accompanied by raised total concentrations of the methylated metabolites and reduced concentrations of 6-thioguanine nucleotides. The authors suggested that inosine monophosphate dehydrogenase inhibitors, such as ribavirin, should not be used in combination with purine analogues.

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Mercaptopurine Skin Hand-foot syndrome (acral erythema, palmoplantar erythrodysesthesia) has been attributed to mercaptopurine in a 4-yearold child with acute lymphoblastic leukemia who developed dry painful palmar and plantar erythema with fissures after receiving mercaptopurine for 3 weeks [149A]. Hair Myelosuppression that occurred after treatment with mercaptopurine for 6 weeks in a 15-year-old woman with Crohn's disease was preceded by alopecia, which occurred after only 3 days [150A]. Drug overdose Accidental overdose occurred when a woman with hypothyroidism was erroneously given mercaptopurine 100 mg tds instead of propylthiouracil [151A]. Her symptoms began on day 3, when she developed fatigue, night sweats, headaches, chest pain, hair loss, aching in the thighs, neck, and back, nausea, and one episode of non-bloody, non-bilious vomiting. She also developed drooping of the right eyelid without change in vision or diplopia. The symptoms progressively worsened, and she stopped taking mercaptopurine on day 6 (total dose 1800 mg). She had raised aminotransferase activities and a prolonged prothrombin time with an INR of 1.7. This is not the first time that this error has been made [152A, 153A]. Drug–drug interactions Methotrexate The pharmacokinetic interaction between methotrexate and mercaptopurine has been studied in 20 children with acute lymphoblastic leukemia [154c]. High-dose methotrexate (5 g/m2 over 24 hours) produced a rapid reduction in erythrocyte concentrations of thioguanine within 24 hours, and

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the effect was sustained for at least 3 days, with a median reduction of 21%. The thioguanine concentrations normalized by the time that the next course of methotrexate was due 14 days later.

Thioguanine

[SEDA-32, 718]

Observational studies In 23 patients with Crohn's disease with prior intolerance (n ¼ 18) or resistance (n ¼ 5) to azathioprine and/or mercaptopurine and eight patients who had tried mycophenolate mofetil, thioguanine was used in a dosage of 20–60 mg/ day for 259 (15–2272) days [155c]. Seven of 13 patients (54%) with active disease went into remission after 8 (4–26) weeks; 16 had adverse events that led to either discontinuation (n ¼ 10) after 85 (15–451) days or dosage reduction (n ¼ 6) after 78 (10–853) days. Ten of 18 patients with prior thiopurine intolerance stopped taking thioguanine because of adverse events. There was no significant difference in maximum thioguanine nucleotide concentrations between patients with adverse events that led to withdrawal or dosage reduction and patients without adverse events. Liver In a retrospective study in 30 patients with Crohn's disease who had failed treatment with thiopurines with or without methotrexate, thioguanine 40 mg/ day was used instead [156c]. Seven stopped taking it because of adverse reactions; seven developed abnormal liver function tests during treatment, mostly transient and mild, and one developed portal hypertension, which resolved after withdrawal. Of 11 liver biopsies, none showed nodular regenerative hyperplasia.

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[37] Inokuma S, Sato T, Sagawa A, Matsuda T, Takemura T, Ohtsuka T, Saeki Y, Takeuchi T, Sawada T. Proposals for leflunomide use to avoid lung injury in patients with rheumatoid arthritis. Mod Rheumatol 2008; 18(5): 442–6. [38] Sawada T, Inokuma S, Sato T, Otsuka T, Saeki Y, Takeuchi T, Matsuda T, Takemura T, Sagawa A. Study Committee for Leflunomide-induced Lung Injury, Japan College of Rheumatology. Leflunomide-induced interstitial lung disease: prevalence and risk factors in Japanese patients with rheumatoid arthritis. Rheumatology (Oxford) 2009; 48(9): 1069–72. [39] Sato T, Inokuma S, Sagawa A, Matsuda T, Takemura T, Otsuka T, Saeki Y, Takeuchi T, Sawada T. Study Committee for Leflunomide-induced Lung Injury, Japan College of Rheumatology. Factors associated with fatal outcome of leflunomide-induced lung injury in Japanese patients with rheumatoid arthritis. Rheumatology (Oxford) 2009; 48(10): 1265–8. [40] Wong SP, Chu CM, Kan CH, Tsui HS, Ng WL. Successful treatment of leflunomide-induced acute pneumonitis with cholestyramine wash-out therapy. J Clin Rheumatol 2009; 15(8): 389–92. [41] Rahmlow M, Shuster EA, Dominik J, Deen Jr. HG, Dickson DW, Aksamit Jr. AJ, Robles HA, Freeman WD. Leflunomide-associated progressive multifocal leukoencephalopathy. Arch Neurol 2008; 65(11): 1538–9. [42] Gugenberger C, Donner P, Naami A, Berges W. Persistierende Diarrhoe und Gewichtsverlust unter Leflunomid-Therapie. [Persistent diarrhea and loss of weight during therapy with leflunomide.] Dtsch Med Wochenschr 2008; 133(34–35): 1730–2. [43] Hassikou H, El Haouri M, Tabache F, Baaj M, Safi S, Hadri L. Leflunomideinduced toxic epidermal necrolysis in a patient with rheumatoid arthritis. Joint Bone Spine 2008; 75(5): 597–9. [44] Schmutz JL, Barbaud A, Tréchot P. Léflunomide et syndrome de Lyell. [Leflunomide and Lyell syndrome.] Ann Dermatol Venereol 2009; 136(4): 395. [45] Vesić S, Bogdanovic A, Medenica L, Bremec T, Pavlović MD. Pyoderma

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Vidaurre C, Seeger JD. Topical treatments with pimecrolimus, tacrolimus and medium- to high-potency corticosteroids, and risk of lymphoma. Dermatology 2009; 219(1): 7–21. Feagans J, Victor D, Moehlen M, Florman SS, Regenstein F, Balart LA, Joshi S, Killackey MT, Slakey DP, Paramesh AS. Interstitial pneumonitis in the transplant patient: consider sirolimusassociated pulmonary toxicity. J La State Med Soc 2009; 161(3): 166, 168–172. Calle L, Tejada C, Lancho C, Mazuecos A. Neumonitis por sirolimus: resolucion tras conversion a everolimus. [Pneumonitis caused by sirolimus: improvement after switching to everolimus.] Nefrologia 2009; 29(5): 490–1. Rivero M, Crespo L, Arranz G, Ledo A, Teruel C, Graus J, Bárcena R. Bronchiolitis obliterans with organizing pneumonia associated with sirolimus in a patient after liver transplantation. Rev Esp Enferm Dig 2009; 101(8): 583–4. Desai N, Heenan S, Mortimer PS. Sirolimus-associated lymphoedema: eight new cases and a proposed mechanism. Br J Dermatol 2009; 160(6): 1322–6. Johnston O, Rose CL, Webster AC, Gill JS. Sirolimus is associated with new-onset diabetes in kidney transplant recipients. J Am Soc Nephrol 2008; 19(7): 1411–8. Fricain JC, Cellerié K, Sibaud V, Catros S, Taïeb A, Merville P. Ulcérations buccales chez les patients transplantés rénaux traités par sirolimus. [Oral ulcers in kidney allograft recipients treated with sirolimus.] Ann Dermatol Venereol 2008; 135(11): 737–41. Ram R, Swarnalatha G, Neela P, Dakshinamurty KV. Sirolimus-induced aphthous ulcers which disappeared with conversion to everolimus. Saudi J Kidney Dis Transpl 2008; 19(5): 819–20. Liew A, Chiang GS, Vathsala A. Factors associated with proteinuria in renal transplant recipients treated with sirolimus. Transpl Int 2009; 22(3): 313–22. Sandrini S, Setti G, Bossini N, Maffei C, Iovinella L, Tognazzi N, Maffeis R, Nodari F, Portolani N, Cancarini G. Steroid withdrawal five days after renal

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835 [82] Tory R, Sachs-Barrable K, Goshko CB, Hill JS, Wasan KM. Tacrolimus-induced elevation in plasma triglyceride concentrations after administration to renal transplant patients is partially due to a decrease in lipoprotein lipase activity and plasma concentrations. Transplantation 2009; 88(1): 62–8. [83] Saito M, Satoh S, Kagaya H, Tsuruta H, Obara T, Kumazawa T, Inoue T, Inoue K, Miura M, Yuasa T, Komatsuda A, Tsuchiya N, Habuchi T. Thrombotic microangiopathy developing in early stage after renal transplantation with a high trough level of tacrolimus. Clin Exp Nephrol 2008; 12(4): 312–5. [84] Go O, Naqvi A, Tan A, Amzuta I, Lenox R. The spectrum of thrombotic thrombocytopenic purpura: a clinicopathologic demonstration of tacrolimus-induced thrombotic thrombocytopenic purpura in a lung transplant patient. South Med J 2008; 101(7): 744–7. [85] Kurnatowska I, Banasiak M, Daniel P, Wagrowska-Danilewicz M, Nowicki M. Two cases of severe de novo colitis in kidney transplant recipients after conversion to prolonged-release tacrolimus. Transpl Int 2010; 23(5): 553–8. [86] Stief J, Stempfle HU, Götzberger M, Uberfuhr P, Köpple M, Lehnert P, Kaiser C, Schiemann U. Biliary diseases in heart transplanted patients: a comparison between cyclosporine A versus tacrolimus-based immunosuppression. Eur J Med Res 2009; 14(5): 206–9. [87] Shimizu T, Ishida H, Shirakawa H, Omoto K, Tanabe K, Yamaguchi Y. Clinical and histological analysis of chronic tacrolimus nephrotoxicity in renal allografts. Transplant Proc 2008; 40(7): 2370–2. [88] Grieco T, Cantisani C, Faina P, Cantoresi F, Lacobellis F, Silvestri E, Faina V, Calvieri S. Tacrolimus 0.1% and granuloma annulare: description of three cases. J Eur Acad Dermatol Venereol 2009; 23(12): 1445–6. [89] Hui RL, Lide W, Chan J, Schottinger J, Yoshinaga M, Millares M. Association between exposure to topical tacrolimus

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or pimecrolimus and cancers. Ann Pharmacother 2009; 43(12): 1956–63. Hawwa AF, McKiernan PJ, Shields M, Millership JS, Collier PS, McElnay JC. Influence of ABCB1 polymorphisms and haplotypes on tacrolimus nephrotoxicity and dosage requirements in children with liver transplant. Br J Clin Pharmacol 2009; 68(3): 413–21. Kurzawski M, Dziewanowski K, Kedzierska K, Gornik W, Banas A, Drozdzik M. Association of calpain-10 gene polymorphism and posttransplant diabetes mellitus in kidney transplant patients medicated with tacrolimus. Pharmacogenomics J 2010; 10(2): 120–5. Akl KF, Bulatova N, Yousef AM. Recurrent ecchymoses after acute tacrolimus intoxication. Pediatr Nephrol 2008; 23 (11): 2101. O'Connor AD, Rusyniak DE, Mowry J. Acute tacrolimus toxicity in a non-transplant patient. Clin Toxicol (Phila) 2008; 46(9): 838–40. Khaira A, Rathi OP, Gupta A, Mahajan S, Bhowmik D, Agarwal SK, Tiwari SC. Galactorrhoea and mastalgia in a renal transplant recipient on tacrolimus and amlodipine. Nephrology (Carlton) 2009; 14(7): 700–1. Berge M, Chevalier P, Benammar M, Guillemain R, Amrein C, Lefeuvre S, Boussaud V, Billaud EM. Safe management of tacrolimus together with posaconazole in lung transplant patients with cystic fibrosis. Ther Drug Monit 2009; 31 (3): 396–9. Kuypers DR, de Jonge H, Naesens M, Vanrenterghem Y. Effects of CYP3A5 and MDR1 single nucleotide polymorphisms on drug interactions between tacrolimus and fluconazole in renal allograft recipients. Pharmacogenet Genomics 2008; 18(10): 861–8. Wada K, Takada M, Sakai M, Ochi H, Kotake T, Okada H, Morishita H, Oda N, Mano A, Kato TS, Komamura K, Nakatani T. Drug interaction between tacrolimus and carbamazepine in a Japanese heart transplant recipient: a case report. J Heart Lung Transplant 2009; 28 (4): 409–11.

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[98] Fraile P, Garcia-Cosmes P, Garcia T, Corbacho L, Alvarez M, Tabernero JM. Hypotension, as consequence of the interaction between tacrolimus and mirtazapine, in a patient with renal transplant. Nephrol Dial Transplant 2009; 24(6): 1999–2001. [99] Stinco G, Piccirillo F, Sallustio M, Patrone P. Facial flush reaction after alcohol ingestion during topical pimecrolimus and tacrolimus treatment. Dermatology 2009; 218(1): 71–2. [100] Reitamo S, Wollenberg A, Schöpf E, Perrot JL, Marks R, Ruzicka T, Christophers E, Kapp A, Lahfa M, Rubins A, Jablonska S, Rustin M. The European Tacrolimus Ointment Study Group. Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis. Arch Dermatol 2000; 136(8): 999–1006. [101] Milingou M, Antille C, Sorg O, Saurat JH, Lübbe J. Alcohol intolerance and facial flushing in patients treated with topical tacrolimus. Arch Dermatol 2004; 140(12): 1542–4. [102] Bellmunt J, Szczylik C, Feingold J, Strahs A, Berkenblit A. Temsirolimus safety profile and management of toxic effects in patients with advanced renal cell carcinoma and poor prognostic features. Ann Oncol 2008; 19(8): 1387–92. [103] Gerullis H, Bergmann L, Maute L, Eimer C, Otto T. Experiences and practical conclusions concerning temsirolimus use and adverse event management in advanced renal cell carcinoma within a compassionate use program in Germany. Cancer Chemother Pharmacol 2009; 63 (6): 1097–102. [104] Izzedine H, Boostandoot E, Spano JP, Bardier A, Khayat D. Temsirolimusinduced glomerulopathy. Oncology 2009; 76(3): 170–2. [105] Gandhi M, Kuzel T, Lacouture M. Eosinophilic rash secondary to temsirolimus. Clin Genitourin Cancer 2009; 7(2): E34–6. [106] Bowen DG, Selby WS. Use of 6-mercaptopurine in patients with inflammatory bowel disease previously intolerant of azathioprine. Dig Dis Sci 2000; 45(9): 1810–3. [107] de Boer NK, van Nieuwkerk CM, Aparicio Pages MN, de Boer SY, Derijks LJ,

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Mulder CJ. Promising treatment of autoimmune hepatitis with 6-thioguanine after adverse events on azathioprine. Eur J Gastroenterol Hepatol 2005; 17(4): 457–61. Nagy F, Molnar T, Szepes Z, Farkas K, Nyari T, Lonovics J. Efficacy of 6-mercaptopurine treatment after azathioprine hypersensitivity in inflammatory bowel disease. World J Gastroenterol 2008; 14(27): 4342–6. Hindorf U, Johansson M, Eriksson A, Kvifors E, Almer SH. Mercaptopurine treatment should be considered in azathioprine intolerant patients with inflammatory bowel disease. Aliment Pharmacol Ther 2009; 29(6): 654–61. Derijks LJ, de Jong DJ, Gilissen LP, Engels LG, Hooymans PM, Jansen JB, Mulder CJ. 6-Thioguanine seems promising in azathioprine- or 6-mercaptopurine-intolerant inflammatory bowel disease patients: a short-term safety assessment. Eur J Gastroenterol Hepatol 2003; 15(1): 63–7. de Boer NK, Derijks LJ, Gilissen LP, Hommes DW, Engels LG, de-Boer SY, den Hartog G, Hooymans PM, Mäkelburg AB, Westerveld BD, Naber AH, Mulder CJ, de Jong DJ. On tolerability and safety of a maintenance treatment with 6-thioguanine in azathioprine or 6-mercaptopurine intolerant IBD patients. World J Gastroenterol 2005; 11 (35): 5540–4. McGovern DPB, Travis SPL, Duley J, Shobowale-Bakre ElM, Dalton HR. Azathioprine intolerance in patients with IBD may be imidazole-related and is independent of TPMT activity. Gastroenterology 2002; 122(3): 838–9. Domènech E, Nos P, Papo M, LópezSan Román A, Garcia-Planella E, Gassull MA. 6-mercaptopurine in patients with inflammatory bowel disease and previous digestive intolerance of azathioprine. Scand J Gastroenterol 2005; 40(1): 52–5. Marbet U, Schmid I. Severe life-threatening diarrhea caused by azathioprine but not by 6-mercaptopurine. Digestion 2001; 63(2): 139–42. Kiefer K, El-Matary W. 6-mercaptopurine as an alternative to azathioprine in azathioprine-induced hepatoxicity. Inflamm Bowel Dis 2009; 15(2): 318–9.

837 [116] Andrejic J, Rojas-Balcazar J, Dennis M, Berkelhammer C. Azathioprine-induced hypersensitivity hepatitis: tolerance to 6-mercaptopurine. Inflamm Bowel Dis 2010; 16(11): 1828–9. [117] Bermejo F, López-Sanromán A, Algaba A, Van-Domselaar M, Gisbert JP, GarcíaGarzón S, Garrido E, Piqueras B, De La Poza G, Guerra I. Mercaptopurine rescue after azathioprine-induced liver injury in inflammatory bowel disease. Aliment Pharmacol Ther 2010; 31(1): 120–4. [118] Dubinsky MC, Feldman EJ, Abreu MT, Targan SR, Vasiliauskas EA. Thioguanine: a potential alternate thiopurine for IBD patients allergic to 6-mercaptopurine or azathioprine. Am J Gastroenterol 2003; 98(5): 1058–63. [119] Schmitt K, Pfeiffer U, Stiehrle HE, Thuermann PA. Absence of azathioprine hypersensitivity after administration of its active metabolite 6-mercaptopurine. Acta Derm Venereol 2000; 80(2): 147–8. [120] Godeau B, Paul M, Autegarden JE, Leynadier F, Astier A, Schaeffer A. Hypersensitivity to azathioprine mimicking gastroenteritis. Absence of recurrence with 6-mercaptopurine. Gastroenterol Clin Biol 1995; 19(1): 117–9. [121] Bermejo F, Lopez-Sanroman A, Taxonera C, Gisbert JP, Pérez-Calle JL, Vera I, Menchén L, Martín-Arranz MD, Opio V, Carneros JA, VanDomselaar M, Mendoza JL, Luna M, López P, Calvo M, Algaba A. Acute pancreatitis in inflammatory bowel disease, with special reference to azathioprineinduced pancreatitis. Aliment Pharmacol Ther 2008; 28(5): 623–8. [122] Treton X, Joly F, Alves A, Panis Y, Bouhnik Y. Azathioprine-induced Sweet's syndrome in Crohn's disease. Inflamm Bowel Dis 2008; 14(12): 1757–8. [123] El-Azhary RA, Brunner KL, Gibson LE. Sweet syndrome as a manifestation of azathioprine hypersensitivity. Mayo Clin Proc 2008; 83(9): 1026–30. [124] Yiasemides E, Thom G. Azathioprine hypersensitivity presenting as a neutrophilic dermatosis in a man with ulcerative colitis. Australas J Dermatol 2009; 50(1): 48–51.

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838 [125] Colli MV, Amaro TA, Pinto AL, Gaburri PD, Chebli JM. Azathioprine toxicity in Crohn's disease: incidence, approach and course. Rev Assoc Med Bras 2008; 54(5): 415–21. [126] Lang KS, Lang PA, Bauer C, Duranton C, Wieder T, Huber SM, Lang F. Mechanisms of suicidal erythrocyte death. Cell Physiol Biochem 2005; 15(5): 195–202. [127] Geiger C, Föller M, Herrlinger KR, Lang F. Azathioprine-induced suicidal erythrocyte death. Inflamm Bowel Dis 2008; 14(8): 1027–32. [128] Schumann M, Preiss JC, Loddenkemper C, Günther U, Somasundaram R, Siegmund B, Zeitz M. Noduläre regenerative Hyperplasie als Nebenwirkung von Azathioprin bei Morbus Crohn. [Nodular regenerative hyperplasia as a side effect of azathioprine in a patient with Crohn's disease.] Dtsch Med Wochenschr 2008; 133(38): 1897–900. [129] Roda G, Caponi A, Belluzzi A, Roda E. Severe cholestatic acute hepatitis following azathioprine therapy in a patient with ulcerative pancolitis. Dig Liver Dis 2009; 41(12): 914–5. [130] Perrett CM, Walker SL, O'Donovan P, Warwick J, Harwood CA, Karran P, McGregor JM. Azathioprine treatment photosensitizes human skin to ultraviolet A radiation. Br J Dermatol 2008; 159(1): 198–204. [131] Cooper HL, Louafi F, Friedmann PS. A case of conjugal azathioprine-induced contact hypersensitivity. N Engl J Med 2008; 359(14): 1524–6. [132] Makhzoumi Z, DeCapite T, Gaspari A. Development of Beau's lines in two patients receiving azathioprine. J Dermatolog Treat 2009; 20(4): 246–7. [133] Seksik P, Cosnes J, Sokol H, NionLarmurier I, Gendre JP, Beaugerie L. Incidence of benign upper respiratory tract infections, HSV and HPV cutaneous infections in inflammatory bowel disease patients treated with azathioprine. Aliment Pharmacol Ther 2009; 29(10): 1106–13. [134] Maddox JS, Soltani K. Risk of nonmelanoma skin cancer with azathioprine use. Inflamm Bowel Dis 2008; 14(10): 1425–31. [135] Harwood CA, Attard NR, O'Donovan P, Chambers P, Perrett CM, Proby CM,

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McGregor JM, Karran P. PTCH mutations in basal cell carcinomas from azathioprinetreated organ transplant recipients. Br J Cancer 2008; 99(8): 1276–84. Evans SJ, Watson DK, O'Sullivan M. Reversible Hodgkin's lymphoma associated with Epstein–Barr virus occurring during azathioprine therapy for SLE. Rheumatology (Oxford) 2008; 47(7): 1103–4. Park TS, Cheong JW, Song J, Lee KA, Lee SG, Kim J, Yoon S, Choi JR, Park R. Acute erythroleukemia with der (1;7)(q10;p10) as a sole acquired abnormality after treatment with azathioprine. Cancer Genet Cytogenet 2008; 186(1): 58–60. Guenova E, Lichte V, Hoetzenecker W, Woelbing F, Moehrle M, Roecken M, Schaller M. Nodular malignant melanoma and multiple cutaneous neoplasms under immunosuppression with azathioprine. Melanoma Res 2009; 19(4): 271–3. Cleary BJ, Källén B. Early pregnancy azathioprine use and pregnancy outcomes. Birth Defects Res A Clin Mol Teratol 2009; 85(7): 647–54. Iftikhar N, Ejaz A, Butt UA, Ali S. Aplasia cutis congenita associated with azathioprine. J Pak Med Assoc 2009; 59(11): 782–4. Askanase AD, Wallace DJ, Weisman MH, Tseng CE, Bernstein L, Belmont HM, Seidman E, Ishimori M, Izmirly PM, Buyon JP. Use of pharmacogenetics, enzymatic phenotyping, and metabolite monitoring to guide treatment with azathioprine in patients with systemic lupus erythematosus. J Rheumatol 2009; 36(1): 89–95. Xin HW, Xiong H, Wu XC, Li Q, Xiong L, Yu AR. Relationships between thiopurine S-methyltransferase polymorphism and azathioprine-related adverse drug reactions in Chinese renal transplant recipients. Eur J Clin Pharmacol 2009; 65 (3): 249–55. Kurzawski M, Dziewanowski K, Lener A, Drozdzik M. TPMT but not ITPA gene polymorphism influences the risk of azathioprine intolerance in renal transplant recipients. Eur J Clin Pharmacol 2009; 65 (5): 533–40.

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[144] Stassen PM, Derks RP, Kallenberg CG, Stegeman CA. Thiopurinemethyltransferase (TPMT) genotype and TPMT activity in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis: relation to azathioprine maintenance treatment and adverse effects. Ann Rheum Dis 2009; 68(5): 758–9. [145] Takatsu N, Matsui T, Murakami Y, Ishihara H, Hisabe T, Nagahama T, Maki S, Beppu T, Takaki Y, Hirai F, Yao K. Adverse reactions to azathioprine cannot be predicted by thiopurine S-methyltransferase genotype in Japanese patients with inflammatory bowel disease. J Gastroenterol Hepatol 2009; 24(7): 1258–64. [146] Vannaprasaht S, Angsuthum S, Avihingsanon Y, Sirivongs D, Pongskul C, Makarawate P, Praditpornsilpa K, Tassaneeyakul W, Tassaneeyakul W. Impact of the heterozygous TPMT*1/*3C genotype on azathioprine-induced myelosuppression in kidney transplant recipients in Thailand. Clin Ther 2009; 31(7): 1524–33. [147] Smith MA, Marinaki AM, Arenas M, Shobowale-Bakre M, Lewis CM, Ansari A, Duley J, Sanderson JD. Novel pharmacogenetic markers for treatment outcome in azathioprine-treated inflammatory bowel disease. Aliment Pharmacol Ther 2009; 30(4): 375–84. [148] Peyrin-Biroulet L, Cadranel JF, Nousbaum JB, Oussalah A, Seddik M, Canva V, Cortot A, Sogni P, Gueant JL, Bigard MA, Roblin X, Bronowicki JP. Interaction of ribavirin with azathioprine metabolism potentially induces myelosuppression. Aliment Pharmacol Ther 2008; 28(8): 984–93. [149] Giacchero D, Monpoux F, Chiavérini C, Lacour JP. Syndrome mains-pieds secondaire à la prise de 6-mercaptopurine chez

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un enfant de quatre ans. [6-mercaptopurine-related hand-foot syndrome in a four-year-old child.]. Ann Dermatol Venereol 2008; 135(8–9): 580–3. Ugajin T, Miyatani H, Demitsu T, Iwaki T, Ushimaru S, Nakashima Y, Yoshida Y. Severe myelosuppression following alopecia shortly after the initiation of 6-mercaptopurine in a patient with Crohn's disease. Intern Med 2009; 48(9): 693–5. Gupta N, Lee CC, Lim TH, Singer AJ. The presentation of 6-mercaptopurine overdose in ED. Am J Emerg Med 2009; 27(4): 513e1–2. Lin RL, Stein RJ, Schaffer MI. A Purinethol (6-mercaptopurine) fatality in a case of prescription negligence: a gas chromatographic determination of 6-mercaptopurine. J Forensic Sci 1982; 27(2): 454–60. Blum M. Alert: 6-mercaptopurine may be erroneously dispensed instead of propylthiouracil. Thyroid 2005; 15(11): 1315. Adam de Beaumais T, Dervieux T, Fakhoury M, Medard Y, Azougagh S, Zhang D, Yakouben K, Jacqz-Aigrain E. The impact of high-dose methotrexate on intracellular 6-mercaptopurine disposition during interval therapy of childhood acute lymphoblastic leukemia. Cancer Chemother Pharmacol 2010; 66(4): 653–8. Almer SH, Hjortswang H, Hindorf U. 6-Thioguanine therapy in Crohn's disease—observational data in Swedish patients. Dig Liver Dis 2009; 41(3): 194–200. Ansari A, Elliott T, Fong F, ArenasHernandez M, Rottenberg G, Portmann B, Lucas S, Marinaki A, Sanderson J. Further experience with the use of 6-thioguanine in patients with Crohn's disease. Inflamm Bowel Dis 2008; 14(10): 1399–405.

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39

Corticotrophins, corticosteroids, and prostaglandins

Editor's notes: In this chapter adverse effects arising from the oral or parenteral administration of corticosteroids (glucocorticoids and mineralocorticoids) are covered in the section on systemic administration. Other routes of administration are dealt with in the sections after that; inhalation and nasal administration are dealt with in Chapter 16, topical administration to the skin in Chapter 14, and ocular administration in Chapter 47. All the uses of prostaglandins are covered in this chapter, apart from topical administration to the eyes, which is covered in Chapter 47.

SYSTEMIC GLUCOCORTICOIDS

[SED-15, 906; SEDA 30, 463; SEDA-31, 651; SEDA-32, 723] Systematic reviews In a pooled analysis of data from five double-blind, randomized, placebo-controlled, multicenter trials of budesonide capsules 6 mg in Crohn's disease, the most common adverse reactions were gastrointestinal and endocrine (budesonide 6 mg/day, n ¼ 208; placebo, n ¼ 209) [1M]. The frequencies were similar, except for a Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00039-8 # 2011 Elsevier B.V. All rights reserved.

higher incidence of endocrine disorders when comparing budesonide with placebo, caused by a higher overall occurrence of cutaneous reactions with budesonide. Patients who used budesonide had an increased incidence of acne, moon face, and viral infections compared with placebo, but at significantly lower frequencies than with systemic glucocorticoids, such as prednisolone. The number of patients with normal adrenal function was significantly lower at 13 weeks (in three of five studies), but not at 52 weeks (two studies) when comparing budesonide with placebo. Sepsis, cataracts, and adrenal insufficiency were rare and similar in the two groups. Cardiovascular Early initiation of glucocorticoids in cardiac sarcoidosis, as soon as the diagnosis is made and before the onset of heart failure, is considered to be crucial to prevent permanent damage and improve prognosis. A patient with cardiac sarcoidosis had a non-sustained ventricular tachycardia, mimicking right ventricular cardiomyopathy [2A]. Glucocorticoid therapy was not effective and the dysrhythmia deteriorated into multifocal and sustained prolonged ventricular tachycardia. The authors suggested that the glucocorticoid may have converted granulomatous inflammation into fibrosis and aggravated the dysrhythmias, which were finally controlled by catheter ablation. Nervous system A 67-year-old woman with a dural arteriovenous fistula developed acute paraparesis 2 hours after receiving an intravenous bolus of methylprednisolone 1 g [3A]. 841

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She complained of pain in the legs and weakness and developed a paraparesis and L2 level hypoalgesia. The treatment was temporarily withdrawn and 48 hours later she had recovered. However, when glucocorticoid therapy was restarted the same effect occurred. It is uncommon for a dural arteriovenous fistula to manifest with acute clinical effects. Since vasogenic edema is the main pathogenic factor in dural arteriovenous fistula, one would have expected a glucocorticoid to produce clinical benefit. However, in this patient it aggravated the symptoms. The authors hypothesized that rapid infusion of saline, in which the methylprednisolone was diluted, and fluid retention produced by the drug, could have resulted in hypervolemia and a secondary increase in venous pressure. Hypokalemic periodic paralysis is a rare heterogeneous disorder characterized by paroxysmal attacks of flaccid muscle weakness associated with low serum potassium concentrations. It is due to mutations in transmembrane voltage gated ion channels in skeletal muscle, with familial autosomal dominant inheritance or sporadic occurrence. In one report of 12 cases, a single dose or short-term use of glucocorticoids caused periodic paralysis associated with hypokalemia in patients with a variety of genotypes [4c]. The authors hypothesized that glucocorticoids cause hypokalemia in patients with periodic paralysis by stimulating the Naþ–Kþ ATPase.

Sensory systems Vision Steroid cataract is one of the most serious adverse reactions to glucocorticoids, because it affects quality of life. The risk factors for steroid cataracts in children with rheumatic diseases were initiation of glucocorticoid therapy in children under 12 years of age and intravenous methylprednisone pulse therapy [5c]. Unilateral severe visual loss occurred in a 51-year-old woman after injection of triamcinolone acetonide into the nasal mucosa, resulting in permanent and severe visual disturbance with marked retinal atrophy [6A].

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Psychiatric The French Association of Regional Pharmacovigilance Centers has summarized the results of spontaneous reports submitted from 1 January 1985 to 30 March 2007 to the French Pharmacovigilance Database, in which glucocorticoids were suspected of causing psychiatric and/ or behavioral adverse reactions in patients aged under 18 years [7S]. Among the 455 spontaneous reports there were psychiatric and/or behavioral reactions to glucocorticoids in 95 (21%) patients under 18 years of age, including 136 adverse reactions; 15 were classified as “serious” (one death and 14 hospitalizations). The mean age of the patients was 5.9 years and 57 were under 6 years of age. The glucocorticoid dosage was unknown in 16 cases. Adverse reactions occurred in 29 cases (31%) after prescription or administration errors (16 cases of overdose and 13 of high doses). They were observed in 13 other children (14%) after the use of high doses (n ¼ 8) or supratherapeutic doses (n ¼ 5) for different therapeutic indications (serious asthma, nephrotic syndrome, or leukemia). In four cases the indications were as recommended in the Summary of Product Characteristics, and there was off-label prescription or administration in 25 cases (26%) (21 cases of overdose and four off-label indications). The most frequent adverse reactions were agitation or excitation and sleep disturbances. Adverse reactions occurred most often with oral administration (n ¼ 72), but were also reported after administration of intravenous or inhaled forms. In 75% of cases, the time to onset was less than 7 days. Most of the adverse reactions (82 cases, 86%) resolved completely after glucocorticoid withdrawal. The glucocorticoids that were most often involved were betamethasone (n ¼ 38), prednisolone (n ¼ 21), and prednisone (n ¼ 17). The authors suggested that these results should be interpreted with caution, because of the low reporting rate of adverse drug reactions in France. Glucocorticoids can cause severe emotional and even psychiatric disturbances. There is a great deal of controversy about

Corticotrophins, corticosteroids, and prostaglandins

whether emotional and psychiatric adverse reactions to glucocorticoids are linked to patients’ pre-existing mental health. The findings from a pilot study that explored prior mental health and the effects of glucocorticoids in 10 hematology patients in Australia have provided evidence that emotional disturbances associated with the use of glucocorticoids result directly from the drugs used and are not expressions of the individual's prior emotional health [8c]. Endocrine The prevalence of adrenal insufficiency after systemic glucocorticoid therapy has been evaluated in 16 infants with hemangiomas, using a combined lowdose/high-dose corticotropin stimulation test [9c]. They were given prednisolone at a starting dose of 2–3 mg/kg/day for 4 weeks, followed by a tapering period. The mean duration of glucocorticoid treatment was 7.2 months. Corticotropin testing at a mean of 13 days after the completion of therapy showed that only one of the 16 infants had adrenal insufficiency. Skin Lichen planus has been attributed to intramuscular triamcinolone [10A]. • A 21-year-old Japanese man with alopecia multiplex developed pruritic linear eruptions on the left thigh. He was given intramuscular triamcinolone acetonide 40 mg once a month, and after 10 such injections developed numerous eruptions on his left thigh consisting of multiple pigmented brownish macules and papules with a tendency to disseminate. Skin biopsy was consistent with lichen planus. He used topical 0.05% difluprednate ointment for more than 1 year, without improvement.

The onset in this case was during the administration of triamcinolone for alopecia areata. Although glucocorticoids have not been previously reported to have caused lichen planus, the possibility that triamcinolone might have affected the immune system cannot be excluded. Patients with psoriasis who become exposed to high doses of systemic glucocorticoids (7.5 mg prednisolone equivalents or more per day) for more than 7–10 days may develop generalized pustular psoriasis during tapering of the dosage or complete

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withdrawal. Four cases of generalized pustular psoriasis attributed to systemic glucocorticoids have been reported, with recommendations for treatment [11cr]. Musculoskeletal Osteonecrosis As the use of glucocorticoids increased in acute lymphoblastic leukemia, osteonecrosis became an increasingly frequent complication. To further explore genetic predictors of osteonecrosis, 12 candidate polymorphisms potentially involved in osteonecrosis have been studied by the Children's Cancer Group (CCG1882); there was a relatively high incidence of osteonecrosis in children 10 years and older [12c]. Candidate genes (TYMS, MTHFR, ABCB1, BGLAP, ACP5, LRP5, ESR1, PAI-1, VDR, PTH, and PTHR) were chosen based on putative mechanisms underlying the risk of osteonecrosis. A polymorphism in PAI-1 (rs6092) was associated with a risk of osteonecrosis in a univariate analysis (OR ¼ 2.79) and a multivariate analysis (OR ¼ 2.89) (adjusted for age, sex, and treatment arm). Overall, 21 (27%) of 78 children with PAI-1 GA/AA genotypes, versus 25 (12%) of 214 children with GG genotype, developed osteonecrosis. There has been a report of Kienböck disease (osteonecrosis of the lunate bone) resulting from local glucocorticoid injections in a 51-year-old man [13A]. Osteoporosis EIDOS classification: Extrinsic species Glucocorticoids Intrinsic species Osteoblasts and osteoclasts Distribution Bone Outcome Atrophy Sequela Osteoporosis from glucocorticoids DoTS classification: Dose-relation Collateral reaction Time-course Late Susceptibility factors Age (elderly patients); sex (female sex, postmenopausal)

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Quality of studies Many studies of glucocorticoid-induced osteoporosis are of moderate (37%) or poor (31%) quality, and the quality of a study is an independent predictor for the degree of prevention for glucocorticoidinduced osteoporosis reported in the study [14M]. It is apparent that patients who take glucocorticoids often do not receive appropriate prophylaxis. However, there has been a noticeable improvement from earlier studies, which were conducted in the mid-1990s, particularly if specific interventions have been undertaken. Future intervention studies that assess prophylaxis should aim to recruit only patients who require prophylaxis according to the prevalent guidelines. Furthermore, these studies should state clearly which part (s) of the decision-making steps, as stated in the prevalent guideline at the time of the study, have been assessed for adherence. Future interventions should comply with five major quality criteria. A multifaceted approach involving health providers who care for glucocorticoid users, public education, and increased access to absorptiometry is required in order to make an impact on the underprescribing of prophylaxis of glucocorticoid-induced osteoporosis.

Susceptibility factors Inflammatory bowel disease is a susceptibility factor for abnormal bone metabolism, with a large amount of evidence of increased incidences of osteopenia and osteoporosis in adults. However, only a few studies of bone mineral density have been performed in children and adolescents with inflammatory bowel disease. Bone mineral density in the lumbar spine has been evaluated in 40 children and adolescents with inflammatory bowel disease, mean age 12 years, 26 with ulcerative colitis and 14 with Crohn's disease, in order to identify the associated susceptibility factors [15c]. There was a low bone mineral density (Z-score worse than 2) in 25% of patients, with equal prevalences in Crohn's disease and ulcerative colitis. Height for age, basal metabolic index, and cumulative glucocorticoid dose had independent effects, and these effects remained significant after adjustment for disease duration.

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Children The effects of systemic glucocorticoids on acute changes in bone formation and resorption markers (amino-terminal type I collagen propeptide (PINP) and carboxyterminal telopeptide of type I collagen (ICTP)), and markers of inflammation have been studied in 22 children, mean age 12 years, with inflammatory bowel disease, before and during treatment [16c]. In addition, GH-related IGF-I and sex hormonebinding protein (SHBG) were measured. The control group comprised 22 patients with inflammatory bowel disease in remission. Serum PINP and IGF-I concentrations were already lower before glucocorticoid treatment in the children with active inflammatory bowel disease, and PINP fell further after 2 weeks of glucocorticoid treatment; serum ICTP and SHBG also fell. In contrast, serum IGF-I increased. One month after the withdrawal of the glucocorticoid, all the bone markers had returned to control values. The authors concluded that bone formation in children with active inflammatory bowel disease is compromised and systemic glucocorticoid treatment further suppresses bone turnover. Prevention Recommendations for the registration of agents for the prevention and treatment of glucocorticoid-induced osteoporosis were produced by the Group for the Respect of Ethics and Excellence in Science (GREES) in 1996 and updated in 2005. The 2005 update mainly addressed the design of clinical studies in glucocorticoid-treated postmenopausal women and its authors concluded that for agents with proven efficacy in postmenopausal osteoporosis, a placebo-controlled trial with measurement of lumbar spine bone mineral density at 1 year as the primary endpoint was required. This work has since been updated [17H], with the aim of considering separately the appropriate recommendations for registering agents for use in glucocorticoid-induced osteoporosis in men and in premenopausal and postmenopausal women. At present etidronate, alendronate, risedronate, and teriparatide are approved for the prevention and treatment of glucocorticoid-induced osteoporosis in Europe.

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Chapter 39

Risedronate (the only compound that has been centrally registered) is limited to postmenopausal women. Zoledronic acid (5 mg intravenous infusion) and risedronate (5 mg/day orally) for the prevention and treatment of glucocorticoid-induced osteoporosis have been evaluated in a 1-year double-blind, doubledummy, randomized, non-inferiority study in 833 patients in 54 centers in 12 European countries, Australia, Hong Kong, Israel, and the USA [18C]. The treatment subgroup consisted of those treated for more than 3 months (272 patients with zoledronic acid and 273 with risedronate), and the prevention subgroup consisted of those treated for less than 3 months (144 patients on each drug); 62 patients did not complete the study because of adverse events, withdrawal of consent, loss to follow-up, death, misrandomization, or protocol deviation. Adverse events were more frequent in patients taking zoledronic acid. The authors of an accompanying editorial commentary commented that although a once-yearly intravenous infusion of zoledronic acid would seem to have obvious advantages over an oral regimen, the best dosing strategy for zoledronic acid is not currently known in terms of cost-effectiveness and the adverse effects of long-term regimens in glucocorticoid-induced osteoporosis. This information is especially important in view of the long duration of action of zoledronic acid and concerns about possible deleterious effects from long-term oversuppression of bone turnover [19r].

minutes developed generalized urticaria, facial angioedema, nausea, and severe dyspnea, and required nasal oxygen. The prednisolone was withdrawn and his symptoms resolved within 30 minutes. A subsequent skin prick test was positive with prednisolone-21-hydrogen succinate in a dilution of 1:10; there were no reactions with prednisone (RectodeltTM), betamethasone (Celestamine N liquidumTM), or dexamethasone (FortecortinTM).

845

Immunologic Immediate hypersensitivity to glucocorticoids is rare. To date, about 100 cases have been reported, mostly in adults who had anaphylaxis within several minutes of oral or intravenous administration. There has also been a report in a child [20A].

Infection risk Aspergillosis is a well-known complication in patients using long-term glucocorticoids, but until now, there have been only two reports of pulmonary and cerebral aspergillosis in patients using short-term course of glucocorticoids for idiopathic thrombocytopenic purpura. In both cases, the patient survived without any sequelae. A fatal case of pulmonary and cerebral aspergillosis has now been reported in a 24-year-old man who took a short course of glucocorticoids for idiopathic thrombocytopenic purpura [21A]. When a 26-year-old man was infected with Cladophialophora bantiana, a dematiaceous fungus found in soil in a worldwide distribution, the fungus was unable to proliferate and was controlled by a local immune response [22A]. However, the residual multiple scars were initially managed 4 months later with serial injections of intralesional glucocorticoids, after which he developed erythema, edema, and tenderness around the largest scar. A biopsy from the area of erythema showed the presence of septate fungal hyphae. Severe Cytomegalovirus esophagitis occurred after short-term glucocorticoid therapy in a patient with no other apparent cause of immune deficiency, such as human immunodeficiency virus infection, neoplasia, or previous organ transplantation [23A]. Two cases of Strongyloides stercoralis hyperinfection after glucocorticoid therapy have been reported [24A].

• A 2-year-old boy had used inhaled fluticasonedipropionate 100 micrograms/day for frequent episodes of asthma and had also intermittently received prednisone suppositories (RectodeltTM) for acute bronchopulmonary obstruction with no adverse outcomes. During a bout of severe bronchospasm he was given intravenous prednisolone-21-hydrogen succinate 50 mg (Solu-DecortinTM) and within a few

Pregnancy The first large UK populationbased study to assess the risk of maternal asthma and exposure to current asthma treatments during pregnancy on overall and system-specific major congenital malformations in their offspring has been reported [25C]. It was a matched case-control

846

study using The Health Improvement Network primary care database. Children with malformations were matched with control children by year of birth, general practice, and singleton or twin delivery. There were 5124 live-born children with major congenital malformations and 30 053 controls. The risk of any malformation in children born to women with asthma was marginally higher than that in children born to women without asthma (adjusted OR ¼ 1.10, 95% CI ¼ 1.01, 1.20). However, there was no association in children born to mothers who had received asthma treatment in the year before or during pregnancy (OR ¼ 1.06; 95% CI ¼ 0.94, 1.20). In assessing the teratogenicity of the medications that had been used, there were no increases in the risks of malformation with gestational exposure to short- or long-acting b-adrenoceptor agonists, inhaled or oral glucocorticoids, other bronchodilators, or cromones. These findings were similar for each of 11 system-specific malformations, except for an increase in musculoskeletal system malformations associated with exposure to cromones. The findings suggest that gestational exposure to commonly used asthma medications is safe overall, although a moderate teratogenic risk of cromones cannot be excluded. There was some evidence of a small increased risk of congenital malformation in children born to women with asthma, but this was not explained by gestational exposure to asthma drugs. Methylprednisolone is used for the treatment of acute exacerbations of Crohn's disease in pregnancy, since its use is considered to be less harmful than the effect of the active disease on the fetus. However, adrenal suppression in a fetus has been associated with administration of methylprednisolone [26A]. • A 29-year-old pregnant woman with active Crohn's disease received high doses of methylprednisolone (32 mg/day) and a daily enema containing hydrocortisone acetate 100 mg for at least 1 month before labor. She delivered a boy at 37 weeks of gestation by elective cesarean section. At delivery the infant's weight was 3380 g, length 53 cm, head circumference 36 cm, and the Apgar score was 10 at

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J. Costa and M. Farré

1 and 5 minutes. He cried normally and his breathing was effortless. However, 3 hours after birth he developed respiratory distress syndrome and a mild metabolic acidosis, and became hemodynamically unstable, with falls in blood pressure and anuria. An ACTH stimulation test confirmed profound adrenal suppression.

An adverse effect of the hydrocortisone acetate enemas in this case cannot be either confirmed or excluded. Since the concentration of methylprednisolone or its metabolites in the blood was not measured, the relation between adrenal insufficiency in the child and maternal exposure to methylprednisolone was not unequivocal. Twin pregnancies have a much higher rate of glucose intolerance and/or gestational diabetes than singleton pregnancies. In a study of maternal glucose concentrations after the administration of dexamethasone in singleton versus twin pregnancies, 10 patients with singleton pregnancies and nine patients with twin pregnancies who needed glucocorticoids were enrolled at 24–34 weeks of gestation and received four doses of intramuscular dexamethasone 6 mg 12 hours apart [27c]. Mean glucose concentrations were significantly higher in the twin group at 4 hours (6.33 versus 5.31 mmol/l), 8 hours (6.34 versus 5.00 mmol/l), and 24 hours (6.44 versus 4.50 mmol/l).

PROSTAGLANDINS AND ANALOGUES [SED-15, 2955; SEDA-30, 465; SEDA-31, 651; SEDA32, 729]

Alprostadil (prostaglandin E1) [SED-15, 94; SEDA-32, 729]

Cardiovascular Unstable angina has been reported after intracavernous injection of alprostadil in a 72-year-old man; there was inferolateral ST segment depression and a tight stenosis of the first marginal coronary artery [28A].

Corticotrophins, corticosteroids, and prostaglandins

Bimatoprost [SED-15, 517; SEDA-31, 655; SEDA-32, 729] See Chapter 47.

Epoprostenol [SED-15, 1228; SEDA30, 465; SEDA-30, 465] Hematologic The risk of thrombocytopenia has been studied in 47 patients with advanced pulmonary arterial hypertension during intravenous epoprostenol therapy, and compared with 44 patients with an inadequate response to initial therapy with oral agents in a crosssectional study [29c]. There was thrombocytopenia in 34% of patients treated with epoprostenol, compared with 15% of patients receiving oral therapy (OR ¼ 2.9), and the association between epoprostenol and thrombocytopenia remained significant after adjustment for differences in hemodynamics (OR ¼ 5.0). Right atrial pressure (OR ¼ 1.12 per mmHg) and mixed venous oxygen saturation (OR ¼ 0.92 per percentage) were also associated with thrombocytopenia in univariate analyses; after logistic regression analysis, both epoprostenol and oxygen saturation were independently associated with thrombocytopenia. In a separate analysis including only patients with current or prior epoprostenol use, epoprostenol dose and right atrial pressure were inversely associated with platelet count. Nervous system The headache eliciting effect of prostacyclin (PGI2) has been studied in 12 healthy subjects in a double-blind, crossover, study [30c], in which epoprostenol 10 nanograms/kg/minute was infused for 25 minutes. During the immediate phase (0–30 minutes) and the post-infusion phase (30–90 minutes) 11 subjects reported headache after epoprostenol and none reported headache on the placebo day. The headache was associated with dilatation of the superficial temporal artery but there was no dilatation of the middle cerebral artery. These data suggest that PGI2-induced headache may be due to activation and sensitization of sensory afferents around extracranial arteries.

Chapter 39

Iloprost

847

[SED-15, 1716; SEDA-32, 729]

Comparative studies Studies of prostanoids in intermittent claudication have yielded inconsistent results. In a multicenter comparison of three doses of oral iloprost, pentoxifylline, and placebo, conducted in 1998–1999 but published only in 2008, oral iloprost did not improve exercise performance or quality of life [31C]. Serious adverse events did not differ among the groups and neither did any specific cardiovascular events. However, oral iloprost was poorly tolerated and therapy was often interrupted because of headache, flushing, nausea, or diarrhea. Skin A curious but non-serious local adverse reaction to iloprost, a linear erythematous facial rash, has been described in an 11-year-old boy with severe pulmonary hypertension associated with right ventricular failure, who was given iloprost by inhalation [32A]. On one occasion, the child removed the mouthpiece and chamber lid and applied iloprost directly to his cheek. A few minutes later, he developed two erythematous linear skin lesions spreading over his face and neck, which resolved spontaneously within 3 days.

Latanoprost

[SED-15, 2002; SEDA-30, 465; SEDA-31, 655; SEDA-32, 729] See Chapter 47.

Misoprostol

[SED-15, 2357; SEDA-30, 466; SEDA-31, 655; SEDA-32, 730] Systematic reviews Sublingual and vaginal misoprostol administration in the third trimester of pregnancy for induction of labor has been studied in women with a live, full-term fetus and an unripe cervix [33M]. There were no significant differences between the two groups with respect to the rate of vaginal delivery not achieved within 24 hours (OR ¼ 1.27; 95%

Chapter 39

848

CI ¼ 0.87, 1.84), uterine hyperstimulation syndrome (OR ¼ 1.20; 95% CI ¼ 0.61, 2.33), or cesarean section (OR ¼ 1.33; 95% CI ¼ 0.96, 1.85). There was an increased risk of uterine tachysystole with sublingual misoprostol (OR ¼ 1.70; 95% CI ¼ 1.02, 2.83). When the studies were grouped according to the initial dose of misoprostol, there was no significant difference between sublingual or vaginal administration. The authors concluded that the sublingual route of administration is as effective as the vaginal route in inducing labor in full-term pregnancies with live fetuses. However, the adverse effects, optimal dose, and perinatal outcomes related to this route of administration

J. Costa and M. Farré

remain to be established, and it cannot be recommended for routine use.

Sulprostone

[SED-15, 3246]

Respiratory Pulmonary edema has been reported after a high rate of infusion of sulprostone [34A].

Travoprost

[SED-15, 3481; SEDA-30, 466; SEDA-31, 655; SEDA-32, 731] See Chapter 47.

References [1] Lichtenstein GR, Bengtsson B, HaptenWhite L, Rutgeerts P. Oral budesonide for maintenance of remission of Crohn's disease: a pooled safety analysis. Aliment Pharmacol Ther 2009; 29(6): 643–53. [2] Hiramastu S, Tada H, Naito S, Oshima S, Taniguchi K. Steroid treatment deteriorated ventricular tachycardia in a patient with right ventricle-dominant cardiac sarcoidosis. Int J Cardiol 2009; 132(2): e85–7. [3] Cabrera M, Paradas C, Marquez C, Gonzalez A. Acute paraparesis following intravenous steroid therapy in a case of dural spinal arteriovenous fistula. J Neurol 2008; 255(9): 1432–3. [4] Arzel-Hézode M, McGoey S, Sternberg D, Vicart S, Eymard B, Fontaine B. Glucocorticoids may trigger attacks in several types of periodic paralysis. Neuromuscul Disord 2009; 19(3): 217–9. [5] Nerome Y, Imanaka H, Nonaka Y, Takei S, Kawano Y. Frequent methylprednisone pulse therapy is a risk factor for steroid cataracts in children. Pediatr Int 2008; 50(4): 541–5. [6] Hirata A, Kubo M, Okinami S. Severe retinal atrophy due to retinal and choroidal vascular occlusion following triamcinolone

[7]

[8]

[9]

[10]

[11]

injection into the nasal mucosa. Jpn J Ophthalmol 2008; 52(6): 504–22. Tavassoli N, Montastruc-Fournier J, Montastruc JL. French Association of Regional Pharmacovigilance Centres. Psychiatric adverse drug reactions to glucocorticoids in children and adolescents: a much higher risk with elevated doses. Br J Clin Pharmacol 2008; 66(4): 566–7. McGrath P, Patton MA, James S. “I was never like that”: Australian findings on the psychological and psychiatric sequelae of corticosteroids in haematology treatments. Support Care Cancer 2009; 17(4): 339–47. Lomenick JP, Reifschneider KL, Lucky AW, Adams D, Azizkhan RG, Woo JG, Backeljauw PF. Prevalence of adrenal insufficiency following systemic glucocorticoid therapy in infants with hemangiomas. Arch Dermatol 2009; 145(3): 262–6. Numata Y, Okuyama R, Tagami H, Aiba S. Linear lichen planus distributed in the lines of Blaschko developing during intramuscular triamcinolone acetonide therapy for alopecia areata multiplex. J Eur Acad Dermatol Venereol 2008; 22(11): 1370–2. Brenner M, Molin S, Ruebsam K, Weisenseel P, Ruzicka T, Prinz JC.

Corticotrophins, corticosteroids, and prostaglandins

[12]

[13]

[14]

[15]

[16]

[17]

[18]

Generalized pustular psoriasis induced by systemic glucocorticosteroids: four cases and recommendations for treatment. Br J Dermatol 2009; 161(4): 964–6. French D, Hamilton LH, Mattano Jr. LA, Sather HN, Devidas M, Nachman JB, Relling MV. Children's Oncology Group. A PAI-1 (SERPINE1) polymorphism predicts osteonecrosis in children with acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood 2008; 111(9): 4496–9. Ko H-J, Kim Y-R, Park K-S, Cho C-S, Kim H-Y. Clinical Images: Kienbock disease resulting from local corticosteroid injections. Arthritis Rheum 2009; 60(6): 1596. Duyvendak M, Naunton M, van Roon EN, Bruyn GA, Brouwers JR. Systematic review of trends in prophylaxis of corticosteroid-induced osteoporosis: the need for standard audit guidelines. Osteoporos Int 2008; 19(10): 1379–94. Lopes LH, Sdepanian VL, Szejnfeld VL, de Morais MB, Fagundes-Neto U. Risk factors for low bone mineral density in children and adolescents with inflammatory bowel disease. Dig Dis Sci 2008; 53(10): 2746–53. Vihinen MK, Kolho KL, Ashorn M, Verkasalo M, Raivio T. Bone turnover and metabolism in paediatric patients with inflammatory bowel disease treated with systemic glucocorticoids. Eur J Endocrinol 2008; 159(6): 693–8. Compston J, Reid DM, Boisdron J, Brandi ML, Burlet N, Cahall D, Delmas PD, Dere W, Devogelaer JP, Fitzpatrick LA, Flamion B, Goel N, Korte S, Laslop A, Mitlak B, Ormarsdottir S, Ringe J, Rizzoli R, Tsouderos Y, Van Staa T, Reginster JY; Group for the Respect of Ethics and Excellence in Science. Recommendations for the registration of agents for prevention and treatment of glucocorticoid-induced osteoporosis: an update from the Group for the Respect of Ethics and Excellence in Science. Osteoporos Int 2008; 19(9): 1247–50. Reid DM, Devogelaer JP, Saag K, Roux C, Lau CS, Reginster JY, Papanastasiou P, Ferreira A, Hartl F, Fashola T, Mesenbrink P, Sambrook PN. HORIZON

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[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

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Investigators. Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON): a multicentre, double-blind, double-dummy, randomised controlled trial. Lancet 2009; 373(9671): 1253–63. Gennari L, Bilezikian JP. Glucocorticoidinduced osteoporosis: hope on the HORIZON. Lancet 2009; 373(9671): 1225–6. Lehmann S, Ott H. Glucocorticoid hypersensitivity as a rare but potentially fatal side effect of paediatric asthma treatment: a case report. J Med Case Rep 2008; 2: 186. Papadopoulos A, Ntaios G, Kaiafa G, Girtovitis F, Charisopoulos G, Chryssogonidis I. Fatal pulmonary and cerebral aspergillosis after a short course of corticosteroids for idiopathic thrombocytopenic purpura. Ann Hematol 2008; 87(8): 685–6. Pincus LB, Schwartz BS, Cunningham G, Saeed S, Berger TG. Cutaneous phaeohyphomycosis caused by Cladophialophora bantiana in a scar after treatment with intralesional corticosteroid injections. J Am Acad Dermatol 2009; 61(3): 537–8. Weile J, Streeck B, Muck J, Krebs G, Jakobus KH, Knabbe C, Weber F. Severe cytomegalovirus-associated esophagitis in an immunocompetent patient after shortterm steroid therapy. J Clin Microbiol 2009; 47(9): 3031–3. Al Maslamani MA, Al Soub HA, Al Khal AL, Al Bozom IA, Abu Khattab MJ, Chacko KC. Strongyloides stercoralis hyperinfection after corticosteroid therapy: a report of two cases. Ann Saudi Med 2009; 29(5): 397–401. Tata LJ, Lewis SA, McKeever TM, Smith CJP, Doyle P, Smeeth L, Gibson JE, Hubbard RB. Effect of maternal asthma, exacerbations and asthma medication use on congenital malformations in offspring: a UK population-based study. Thorax 2008; 63(11): 981–7. Homar V, Grosek S, Battelino T. Highdose methylprednisolone in a pregnant woman with Crohn's disease and adrenal suppression in her newborn. Neonatology 2008; 94(4): 306–9. Foglia LM, Deering SH, Lim E, Landy H. Maternal glucose levels after

850 dexamethasone for fetal lung development in twin vs singleton pregnancies. Am J Obstet Gynecol 2008; 199(4): 380.e1–4. [28] Delongchamps NB, Legrand G, Zerbib M, Peyromaure M. Unstable angina following intracavernous injection of alprostadil: a case study. BMJ Case Rep 2009; pii: bcr03.2009.1658. Epub 2009 Jun 3. PMID 21686977. [29] Chin KM, Channick RN, De Lemos JA, Kim NH, Torres F, Rubin LJ. Hemodynamics and epoprostenol use are associated with thrombocytopenia in pulmonary arterial hypertension. Chest 2009; 135(1): 130–6. [30] Wienecke T, Olesen J, Oturai PS, Ashina M. Prostacyclin (epoprostenol) induces headache in healthy subjects. Pain 2008; 139(1): 106–16.

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[31] Creager MA, Pande RL, Hiatt WR. A randomized trial of iloprost in patients with intermittent claudication. Vasc Med 2008; 13: 5–13. [32] Feito Rodriguez M, Floristan U, De Lucas Laguna R. A curious but non-serious local side effect of inhaled iloprost: sudden linear erythematous facial rash. Clin Exp Dermatol 2009; 34(8): e1014. [33] Souza ASR, Amorim MMR, Feitosa FEL. Comparison of sublingual versus vaginal misoprostol for the induction of labour: a systematic review. BJOG 2008; 115(11): 1340–9. [34] Hagenaars M, Knape JTA, Backus EMJM. Pulmonary oedema after high infusion rate of sulprostone. Br J Anaesth 2009; 102(2): 281–2.

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40

Sex hormones and related compounds, including hormonal contraceptives

Author's note: Sex hormones, particularly estrogens and progestogens, can be used separately or in combination, and for various purposes. It is often not possible to determine to which compound or combination a particular adverse reaction can be attributed; information on particular types of adverse reactions may therefore need to be sought under a series of differing headings.

[SED-15, 1536; SEDA-30, 468; SEDA-31, 656; SEDA-32, 735]

GONADOTROPINS

Cardiovascular Human chorionic gonadotrophin has been used for two generations in patients with cryptorchidism, in the hope of inducing testicular descent. Failures are common (in which case one resorts to corrective surgery) but complications are not. In one case injection of human chorionic gonadotrophin was followed by a stroke and hemiparesis, the mechanism being unclear [1A]. There have been occasional earlier reports of ischemic reactions. Cerebral infarction is seen in both boys and girls given gonadotrophin;

since cerebrovascular disorders are increasingly being recognized as important causes of mortality and morbidity in children, this possible complication deserves to be taken seriously. Reproductive system Attempts to avoid severe ovarian hyperstimulation and its accompanying risks during gonadotrophin therapy continue, without notable success. There is some preliminary evidence that the joint use of dopamine receptor agonists and gonadotrophin-releasing hormone antagonists, administered as soon as hyperstimulation is diagnosed, rapidly suppress the symptoms of the complication, but further study of the method is called for [2c]. Drug formulations Whatever the relative merits of recombinant (rh) as against urinary (uh) chorionic gonadotrophin, safety does not seem to be a determinant factor. When the two were compared using generally recognized doses, the resulting pregnancy rates were similar; of 64 women who received rhCG, 30% became pregnant; of the 61 patients who received uhCG, 25% became pregnant [3c]. No adverse effects were noted in either group.

Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00040-4 # 2011 Elsevier B.V. All rights reserved.

851

852

[SED-15, 1253; SEDA-30, 469; SEDA-31, 657; SEDA-32, 736]

ESTROGENS

Autacoids Angioedema is a disease of women that is often but not always aggravated by exogenous estrogens. In four women who had attacks of angioedema of the pharynx and limbs, some episodes were apparently precipitated by local trauma, upper respiratory tract infections, and pregnancy [4A]. A maternal aunt of one patient had suffocated during an attack at age 20. These patients had normal concentrations of C1 esterase inhibitor at baseline. During attacks, their C1 esterase inhibitor activity fell, but the inhibitor concentrations themselves remained normal. Concentrations of the complement proteins C1q, C3, and C4 also remained normal during attacks, which is considered strong evidence against classic hereditary angioedema. The women had reduced kallikrein concentrations during episodes, suggesting activation of the contact system, which generates bradykinin and allows vascular leakage of plasma and the development of angioedema. One patient had a mutation related to a gainof-function of Hageman factor, which has been suggested as the genetic basis of this disease. Tumorigenicity Over the years there has been a lack of consistent evidence as to the possible association between combined oral contraceptives (or other estrogen-containing hormonal formulations) and the occurrence of melanoma. In the Netherlands, material from a large pharmacy database and a pathology database have now been brought together to examine possible links [5C]. Women aged 18 years or over who were the subject of database entries for primary cutaneous melanoma recorded during the years 1991–2004 and followed up for not less than 3 years were the primary study population, and controls were matched for age and geographic region. In

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all, 778 cases and 4072 controls were included. The risk of cutaneous melanoma was significantly associated with use for 6 months or more (adjusted OR ¼ 1.42; 95% CI ¼ 1.19, 1.69). This effect was dose related with respect to the cumulative dose taken. The risk of melanoma was also significantly associated with the use of hormone replacement therapy (HRT) for more than 6 months (OR ¼ 2.08; 95% CI ¼ 1.37, 3.14) and oral contraceptives (OR ¼ 1.28; 95% CI ¼ 1.06, 1.54).

Diethylstilbestrol [SED-15, 1119; SEDA-31, 657; SEDA-32, 739] Urinary tract In data from a collaborative follow-up of three US cohorts of diethylstilbestrol-exposed sons, prenatal exposure was not associated with varicocele, structural abnormalities of the penis, urethral stenosis, benign prostatic hyperplasia, or inflammation/infection of the prostate, urethra, or epididymis [6C]. However, there were increased risks of cryptorchidism (RR ¼ 1.9; 95% CI ¼ 1.1, 3.4), epididymal cysts (RR ¼ 2.5; CI ¼ 1.5, 4.3), and testicular inflammation/infection (RR ¼ 2.4; CI ¼ 1.5, 4.4). There were stronger associations with exposure that began before the 11th week of pregnancy: cryptorchidism (RR ¼ 2.9; 95% CI ¼ 1.6, 5.2), epididymal cysts (RR ¼ 3.5; CI ¼ 2.0, 6.0), and testicular inflammation/infection (RR ¼ 3.0; CI ¼ 1.7, 5.4). The authors suggested that these findings support the hypothesis that endocrine disrupting chemicals may contribute to the increased prevalence of cryptorchidism that has been seen in recent years. Tumorigenicity A clear cell adenocarcinoma of the ovary has been linked to early diethylstilbestrol exposure in utero in a 45year-old woman; her mother had taken diethylstilbestrol throughout the pregnancy [7A]. Acute monocytic leukemia occurred in a neonate whose mother had been exposed

Sex hormones and related compounds, including hormonal contraceptives

to diethylstilbestrol in utero; the child presented with leukemia cutis, hemorrhagic skin lesions, a leukocytosis, and disseminated intravascular coagulation [8A]. In a database study of 3140 diethylstilbestrol-exposed and 826 unexposed women, those who had been exposed in utero to diethylstilbestrol were more likely than unexposed women to receive recommended or additional screening examinations for breast cancer (adjusted OR ¼ 2.20; 95% CI ¼ 1.04, 4.67) among women without a history of benign breast disease compared with unexposed women [9c]. There were no other statistically significant differences between exposed and unexposed women. Most of the exposed women received breast cancer screenings at least at recommended intervals, but over two-thirds did not perform monthly self-examination. The authors concluded that future efforts should be focused on education about the benefits of screening examinations of at-risk populations through mailed reminders and during patient consultations. Epigenetic effects In 4029 sons and 3808 daughters of women whose mothers had used diethylstilbestrol during pregnancy (i.e. the third generation) and a subcohort of 793 third generation daughters, overall birth defects were more common in both the sons (OR ¼ 1.53; 95% CI ¼ 1.04, 2.23) and in the daughters (OR ¼ 2.35; 95% CI ¼ 1.44, 3.82) [10C]. Most estimates of association were imprecise, but the daughters appeared to have an excess of heart conditions (OR ¼ 4.56; 95% CI ¼ 1.27, 16). These data suggest a possible association between the mother's prenatal exposure and birth defects in their offspring, particularly in their daughters. However, the authors could not rule-out reporting bias.

Equine estrogens See next section

[SEDA-32, 739]

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853

Hormone replacement therapy (HRT) [SED-15, 1684, 1686, 1692; SEDA-30, 469; SEDA-31, 659; SEDA-32, 740]

Attitudes to the use of hormone replacement therapy With half a century of experience of various forms of HRT, well-documented reviews continue to appear regarding the safety or otherwise of this treatment [11R]. When one recalls the initial enthusiasm with which oral HRT was originally greeted the caution now widely expressed about its use is striking, although there is still some doubt as to its long-term effects, especially when very low doses are used [12R]. The authors of one recent review concluded that the risk of venous thrombosis is increased 2.5 times in current users of oral formulations, although the risk is not increased in those using transdermal hormone patches. Several large trials have now shown that oral estrogens do not protect against, and might even increase, the risk of coronary heart disease, and slightly increase the risk of breast cancer after prolonged use. On the basis of such results, HRT is no longer considered to be indicated for long-term use: short-term use to alleviate menopausal symptoms seems defensible, and skin patches are likely to be safer than orally administered hormones [13R]. There has naturally been some criticism of the move away from HRT. For example, some have argued that the findings in the Women's Health Initiative were wrongly interpreted [14R]; however, this is a minority view, and it seems fair to conclude that for many women the risks of this treatment outweigh the possible benefits. Helpful reviews continue to provide guidance on the use of HRT in individual cases, bearing in mind both objective risks and the fears expressed by individual women [15R]. Here too, HRT still has its champions, who consider that this form of treatment as a whole has been unfairly condemned. Some

854

among them point to the extent to which heart disease presents differently between the sexes, non-obstructive coronary disease and angina unrelated to exercise being considerably more prevalent in women than in men. When the outcomes of large controlled trials failed to demonstrate cardiac risk protection, many women and their physicians abandoned HRT as primary or secondary prevention for cardiovascular disease. However, some believe that insufficient distinction has been made between the cardiovascular actions of estrogen, progesterone, and medroxyprogesterone acetate. In their opinion one can already distil from the literature mounting evidence that progesterone improves cardiovascular function, and proposals have been advanced for further research on this issue [16R]. Placebo-controlled studies Preliminary placebo-controlled studies of the use of a combination of the selective estrogen receptor modulator (SERM) bazedoxifene (10–40 mg/day) and conjugated estrogens (0.45–0.625 mg/day) given daily for up to 2 years for menopausal symptoms have suggested that the method provides relief without inducing any detectable degree of endometrial hyperplasia [17c]. Cardiovascular The extent to which certain genetic subgroups of women may be at greater risk of thromboembolic complications than others when using HRT is not well-defined. However, one may note that such an effect might be modulated by the expression of CYP3A5 and CYP1A2, which are involved in the hepatic metabolism of estrogens. In a French study of women with such adverse effects it appeared that women with the CYP3A5*1 allele using oral estrogens comprised a subgroup at high risk of venous thromboembolism [18C]. CYP1A2 polymorphism was not associated with any increased risk. These findings provide only a preliminary pointer; as the investigators themselves stressed, further data are needed to assess the relevance of this genetic biomarker in the

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medical management of the menopause and policy regarding the use of HRT. In a population register study in Denmark 698 098 healthy women aged 51–69 were followed over 6 years with respect to the use of HRT and the incidence of myocardial infarction [19C]. There were 4947 cases of myocardial infarction. There was no increased risk in current HRT users compared with women who had never used HRT. However, there was an increased risk with longer duration of HRT among younger women only. The highest risk of infarction was found with a continuous HRT regimen. There was no increase in risk with unopposed, cyclic combined therapy or with tibolone. There was a significantly lower risk with the transdermal route than with oral unopposed therapy. There were no associations with a particular progestogen type or estrogen dose. Psychiatric Postmenopausal conjugated equine estrogens increase the risk of cognitive impairment in women aged 65 years or older and are associated with smaller regional brain volumes. Of 1403 women aged 65–80 years, studied 1–4 years after they had participated in randomized placebo-controlled clinical trials of conjugated equine estrogens, during which they had been free of dementia and mild cognitive impairment when originally enrolled, 53 developed mild cognitive impairment or probable dementia during follow-up [20c]. Among women who had taken conjugated equine estrogens, cognitive impairment was associated with relatively smaller hippocampal and total brain volumes. Among those who had taken placebo cognitive impairment was associated with greater ischemic lesion volume in the frontal lobe and overall. The authors proposed that conjugated equine estrogens may cause cognitive impairment through increased brain atrophy. Brain MRI scans have also been recorded in a subset of 1403 women aged 71–89 years who participated in the Women's Health Initiative Memory Study, an ancillary study to the Women's Health Initiative, which consisted of two

Sex hormones and related compounds, including hormonal contraceptives

randomized, placebo-controlled trials involving conjugated equines 0.625 mg with or without 2.5 mg medroxyprogesterone acetate in one daily tablet [21C]. The scans were performed, on average, 3.0 years after the trial for the combined therapy (average follow-up interval 4.0 years) and 1.4 years after the trial for the conjugated estrogens alone (average follow-up interval 5.6 years). Compared with placebo, mean frontal lobe volume was 2.37 ml lower among women assigned to HRT, mean hippocampal volume was slightly but still significantly lower (0.10 ml), and the difference in total brain volume approached significance. The results were similar for both regimens. HRT-associated reductions in hippocampal volumes were greatest in women with the lowest baseline Modified Mini-Mental State Examination scores (scores <90). The authors concluded that conjugated equine estrogens with or without a progestogen are associated with greater brain atrophy among women aged 65 years and older; however, the adverse effects are most evident in women who have cognitive deficits before they start hormone therapy. This work has drawn international attention [22r]. It is disappointing, to say the least, that this form of treatment, which was at the outset intended to attenuate the ageing process, now appears at least in this respect to accentuate it. Gastrointestinal Ischemic colitis has been reported as a complication of both estrogens and progestogens and must be expected to occur in some women taking HRT. In a Greek study of women who had used various forms of HRT for several months before the complication developed, none had a history of bowel disorders [23c]. Fasting, parenteral nutrition, intravenous antibiotic treatment with metronidazole, and withdrawal of HRT brought about recovery; the antibiotics were continued after the patients were discharged from the hospital. Follow-up colonoscopy at 3–4 months after the initial episode was normal in all cases. Raised concentrations of estrogen and progesterone can increase the chance of

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gastroesophageal reflux, although one must bear in mind that this is not an unusual phenomenon in the general population. In an analysis of data on 51 637 postmenopausal women, enrolled in the Nurses’ Health Study, who provided data on the use of postmenopausal hormone treatment, no fewer than 12 018 women (23%) had symptoms of reflux [24C]. Compared with women who were not taking hormone therapy, the multivariate odds ratio was 1.46 (95% CI ¼ 1.36, 1.56) for past hormone users, 1.66 (95% CI ¼ 1.54, 1.79) for current users of estrogen only, and 1.41 (95% CI ¼ 1.29, 1.54) for current users of combined estrogen and progesterone. The risk of symptoms of gastroesophageal reflux increased significantly with increasing estrogen dosage and increasing duration of estrogen use. Moreover, current users of selective estrogen receptor modulators (SERMs) had an odds ratio of 1.39 (95% CI ¼ 1.22, 1.59) for symptoms and women currently using over-the-counter hormone formulations had an odds ratio of 1.37 (95% CI ¼ 1.16, 1.62). Breasts Susceptibility factors for benign proliferative epithelial disorders of the breast have been the subject of a cohort study of 68 132 postmenopausal women who were prospectively followed; those who had an open surgical biopsy or a core needle biopsy had histological sections obtained for centralized pathology review. Over an average of 7.8 years of follow-up, 1792 women with benign proliferative disorders were identified. Women who had used postmenopausal hormones for 15 years or more had a twofold increase in the risk of such disorders of the breast compared with women who had never used postmenopausal hormones (HR ¼ 2.03; 95% CI ¼ 1.73, 2.38) and the increase in risk was observed both for proliferation without atypia and for atypical hyperplasia. Furthermore, the risk of such complications decreased with time since cessation of use so that there was essentially no increase in risk five or more years after withdrawal of HRT [25C].

856

Tumorigenicity Breast cancer The risk of invasive breast cancer as a consequence of hormonal replacement therapy varies markedly with the drugs and combinations used. A group in France has sought to characterize the risk more precisely, using data from the French E3N cohort study, in the course of which 80 391 postmenopausal women were followed for an average of 8.1 years, and 2265 histologically confirmed invasive breast cancers were traced [26C]. Compared with non-users of HRT in the same age group, ever-use of additional progesterone was not significantly associated with the risk of any breast cancer subtype, but increasing duration of a combined estrogen þ progesterone regimen was associated with increasing risks of lobular and estrogen receptor-positive/progesterone receptor-negative (ERþ/PR) tumors. Estrogen þ dydrogesterone was associated with a significant increase in the risk of lobular carcinoma (RR ¼ 1.7; 95% CI ¼ 1.1, 2.6). Estrogen þ other progestogens was associated with significant increases in the risks of ductal carcinomas (RR ¼ 1.6; 95% CI ¼ 1.3, 1.8), lobular carcinomas (RR ¼ 2.0; 95% CI ¼ 1.5, 2.7), ERþ/PRþ carcinomas (RR ¼ 1.8; 95% CI ¼ 1.5, 2.1), and ERþ/PR carcinomas (RR ¼ 2.6; 95% CI ¼ 1.9, 3.5), but not of ER/PRþ or ER/PR carcinomas. The authors concluded that the increased risk of breast cancer with combined HRT other than estrogen þ progesterone and estrogen þ dydrogesterone seems to apply preferentially to ERþ carcinomas, especially those that are ERþ/PR, and to affect both ductal and lobular carcinomas. Endometrial cancer In an unusually large investigation into the incidence of endometrial cancer as a complication of various forms of HRT in Finland, using data from the country's Cancer Registry and Medical Reimbursement system, all postmenopausal women who during the years 1994–2006 had been treated with HRT for at least 6 months were identified and compared with the general population [27C]. Continuous estradiol þ progestogen therapy for 3 years or more was associated with

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a 76% reduction in the risk of type 1 cancers (95% CI ¼ 6, 60%). In contrast, use of a sequential estradiol þ progestogen regimen for at least 5 years was accompanied by a 69% increase (95% CI ¼ 43, 96%) if the progestogen was added monthly, and with a significantly higher increase in risk of 276% (95% CI ¼ 190, 379%) if a progestogen was added at 3month intervals. The use of a continuous rather than a sequential estradiol þ progestogen regimen reduces the risk of endometrial cancer, whereas the route of administration or type of progestogen used do not affect the risk. Ovarian cancer The evidence that HRT in postmenopausal women significantly increases the risk of ovarian cancer is now incontrovertible (SEDA-32, 740). In particular, there is evidence of a substantial increase in risk if unopposed estrogens are used. However, a Danish study has also shown an increase in risk irrespective of the nature of the product used. In view of this, one must be cautious in accepting the view that the risk of ovarian cancer can be substantially reduced by giving a progestogen alongside the estrogen. That is, however, still the approach favored, albeit hesitantly, by some writers, as reflected in a recent review [28R], pointing to findings suggesting that whereas treatment with unopposed estrogen for more than 5 years increases the risk of ovarian cancer by some 20% compared with controls, periodic addition of a progestogen to the regimen reduces the risk to some 10% above control values, although the effect remains significant; the reviewers suggest that the risk might be further reduced by giving a progestogen daily, though this is still unproven.

Can HRT activate latent breast cancer? One of the various reasons that has caused physicians and their patients to turn away

Sex hormones and related compounds, including hormonal contraceptives

in recent years from HRT is the likelihood that, in one way or another, it is associated with an increased incidence of cancer of the breast. There is evidence of an increased risk among American women of Asian origin, in whom the use of HRT increased the risk by 26% for every 5 years of estrogen and progestogen treatment. Many other studies have come to similar conclusions, and workers in the field have been somewhat reluctant to accept the findings of a French paper that concluded in 2006, in the light of earlier results from the MISSION study, that among HRT users the risk of breast cancer is unchanged, or perhaps even very slightly reduced [29C]. In seeking an explanation as to why the risk might—as is widely believed—be increased among HRT users, Horwitz and Sartorius have advanced an unusual hypothesis [30H]. Their starting point is the observation that experimental estrogen receptor-positive (ERþ) and progesterone receptor-positive (PRþ) human breast cancers contain a rare subpopulation of ER,PR cancer stem cells. Especially in small, nascent ERþ,PRþ tumor colonies, progestogens (but not estrogens) reactivate cells with ER,PR stem cell-like properties. In addition there may be a reservoir of occult, undetected, preinvasive breast cancer in some women who are candidates for HRT. The hypothesis is that women who develop breast cancer while taking estrogens þ progestogens harbour nascent but undiagnosed disease before the start of therapy. The progestogen component, in a non-proliferative step, reactivates receptornegative cancer stem cells within such germinal, perhaps even dormant, tumors. After reacquiring receptors, these tumor cells are expanded by the mitogenic properties of estrogens. In their view, screening methods need to be improved so that they can detect small, pre-existing malignancies before the start of HRT. Women who harbor such malignancies could and should then be excluded from regimens that include systemic progestogens. It is a theory that at the very least merits consideration and further study. In the meantime one may note the findings of a German study whose authors

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sought to examine the effect of the decline in HRT on the incidence of breast cancer, using population-based surveys [31M]. Prescription of HRT started to decline in Germany in 1999; about 2 years later, there was a parallel decline in the incidence of breast cancer. The number of HRT prescriptions fell by 69% up to 2006, and the incidence of breast cancer fell by 6.8% in all age groups (in 2002–2005) and by 13% in those aged 50–69 years. The reductions in HRT prescriptions and the incidence of breast cancer were markedly correlated across the federal states in Germany. While there is still much to be learnt about the epidemiology of breast cancer—the incidence of which, for example, varies between the various states of Germany and for unknown reasons—the success achieved in reducing its incidence across the board by adopting a more critical approach to the “feminine forever” fable of the 1960s is a monument to good sense. Susceptibility factors HIV infection Metabolic dysregulation is a common long-term complication associated with HIV infection, but it is also observed as a complication of HRT and is difficult to manage. There are still no clear guidelines for dealing with this problem when HIV-positive women take HRT, but the need to be alert for the occurrence of metabolic dysregulation is clear [32R].

Drug–drug interactions Tacrolimus A serious interaction has been described between HRT and tacrolimus [33A]. • A 65-year-old woman with a renal transplant was taking tacrolimus 9 mg/day, mycophenolic acid 540 mg/day, prednisolone 4 mg/day, lisinopril 20 mg/day, atorvastatin 10 mg/day, levothyroxine 100 micrograms/day, and alprazolam 0.5 mg/day. After transplantation renal function was good, but after 10 days her renal function suddenly deteriorated and the tacrolimus plasma concentration was very high (trough concentrations of 14–18 ng/ml). The serum creatinine increased and eGFR fell to 28 ml/minute/m2. She had been taking

858 HRT (Estreva 0.1%) comprising estradiol 0.5 mg/day (one-third of the recommended dose). The serum creatinine fell and eGFR rose to 44 ml/minute/m2 2 weeks after a progressive 60% reduction in tacrolimus dosage (trough concentration 6.4 ng/ml).

Both tacrolimus and estradiol are metabolized by CYP3A4 and tacrolimus is a potent inhibitor of 2-estradiol metabolism. Conversely, estradiol inhibits hepatic and intestinal CYP3A4 and reduces tacrolimus metabolism. Transdermal administration avoids hepatic first-pass metabolism, which explains why even small doses have a systemic effect. Co-administration of tacrolimus is possible, but close monitoring of tacrolimus trough concentrations and renal function is necessary.

Ecotoxicity The possible environmental health implications of conjugated equine estrogens, including discharge into the environment, their uptake, potency, and ability to induce biological effects in wildlife, have been evaluated. Influents and effluents from four UK sewage treatment works and the bile of effluent-exposed fish were screened for six equine estrogens [34E]. Low concentrations of the equine estrogen equilenin and its metabolite 17-betadihydroequilenin were detected by tandem GC–MSMS in all sewage influent samples and 83% of effluent samples and were taken up by effluent-exposed fish. These estrogens bound to and activated the fish estrogen receptors. Exposure of fish for 21 days to equilenin and 17-beta-dihydroequilenin induced estrogenic responses, including hepatic growth and vitellogenin production at concentrations as low as 0.6–4.2 ng/l. Hepatic ERa and ERb1 gene expression was induced. The authors suggested that these compounds may contribute to feminization of exposed wildlife.

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HORMONAL CONTRACEPTIVES

[SED-15, 1642; SEDA-30, 473; SEDA-31, 663; SEDA-32, 741] Cardiovascular The risk of thromboembolic complications, especially as regards the third generation of hormonal contraceptives, is considered in some detail in the Side Effects of Drugs Essay that opens this Annual. The overall conclusion must be essentially the same as that presented in SED-15 at pages 1645–1652, namely that the two-component oral contraceptives that are currently in use most widely, with desogestrel or gestodene as their progestogenic component, present an appreciably greater risk of thromboembolic complications than the products that were in use a generation earlier. This added risk must be a matter of public health concern, particularly in view of the scale on which these formulations are used by healthy women worldwide.* Drug formulations and administration route Although most forms of hormonal contraception, including combination tablets, progestogens alone, and injections, have now been in use for several decades, physicians still have difficulty in advising individual women on the method that they are likely to tolerate best, and comparisons continue to be carried out. In a US study, menstrual, physiological, and psychological symptoms were examined over 2 years in 608 women who used depot medroxyprogesterone acetate or an oral contraceptive formulation containing 20 micrograms of estrogen and in untreated controls [35C]. The oral contraceptives protected against mastalgia, cramping, hair loss, acne, nervousness, and mood swings. Depot medroxyprogesterone acetate protected against bloating and mood swings (OR ¼ 0.7)

*Editorial note: In SED-15 there is a transcription error in the first column on page 1646. The sentence 16 lines from the bottom of the page, which cites an incidence of thromboembolism of 15 per 100 000 women per year should refer to the second generation of products and not to the third generation; the correct statement appears at the bottom of the page.

Sex hormones and related compounds, including hormonal contraceptives

but it tended to cause weight gain (OR ¼ 2.3), bleeding episodes lasting more than 20 days (OR ¼ 13.4), and missed periods (OR ¼ 96.9). Both methods caused intermenstrual bleeding.

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ANTIESTROGENS AND SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMS) [SEDA-30, 474; SEDA-31, 664; SEDA-32, 743]

Drug–drug interactions Warfarin In a single case an interaction of hormonal contraceptives with warfarin made dosage changes necessary [36A]. • A 33-year-old women who required long-term anticoagulation following an aortic valve replacement, and who was taking warfarin 38.5 mg/week, changed from a monophasic combined oral contraceptive (ethinylestradiol þ norethindrone) to an implantable progestogen-only contraceptive (etonogestrel); 19 days later her INR fell to 1.8 and she required an increase in warfarin dosage to 60 mg/week. Within 10 months, she elected to have the implant removed because of vaginal bleeding, and 9 days later had a transient increase in INR to 6.5. Her INR returned to within the target range after the dosage of warfarin was reduced to 55.5 mg/week.

In the light of literature data the authors suggested that the predominant mechanism of interaction was inhibition of CYP1A2 and CYP2C19 by ethinylestradiol.

Emergency contraception

[SEDA-

32, 742] Skin A 28-year-old woman developed a fever, rash, and sore throat, followed by ulceration of the mucosae, dysuria, and conjunctivitis [37A]. Over the next 4 days, she developed a purulent conjunctival discharge and bullae over 80% of her body surface area, consistent with toxic epidermal necrolysis. She had used four contraceptive pills (each containing levonorgestrel 0.125 mg þ ethinylestradiol 0.03 mg) as a single dose 5 days before her visit as a “morning after” agent to avoid becoming pregnant. Treatment included intravenous immunoglobulin and she made a full recovery within 14 days.

While tamoxifen remains an important component of endocrine therapy for breast cancer, major clinical trials of the aromatase inhibitors anastrozole, letrozole, and exemestane suggest that these agents are more effective and better tolerated than tamoxifen. On the other hand, some comparative studies have suggested that the aromatase inhibitors have less favorable effects than tamoxifen on cardiovascular risk. An occasional review puts the controversy into perspective [38R], but the debate is obscured by the publication of many papers that appear biased in favor either of tamoxifen or the inhibitors as regards efficacy, safety, or both. Psychiatric Estrogens have long been considered to have some type of positive effect on cognitive function, and it is not surprising that occasional reports have described a contrary effect of antiestrogens. The possibility of such a negative effect appears to have been examined systematically for the first time in a study undertaken at the Netherlands Cancer Institute in Amsterdam and published in 2009 [39c]. Postmenopausal patients with breast cancer who had received doxorubicin þ cyclophosphamide were randomized to follow-up with tamoxifen (n ¼ 30) or exemestane (n ¼ 50); an average of 2 years after completion of the original chemotherapy they were interviewed, answered questionnaires, and were subjected to cognitive tests; 48 healthy controls were similarly tested. Memory complaints were reported by 28% of those who had used tamoxifen, 24% of those who had used exemestane, and 6% of the healthy controls. Both patient groups performed significantly less well than the healthy controls on verbal fluency and information processing speed. Cognitive testing showed no statistically significant

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differences between tamoxifen and exemestane, but suggested that tamoxifen is possibly related to poorer verbal functioning, while exemestane is possibly related to slower manual motor speed. Tamoxifen users had lower scores in executive functioning (which includes such things as being able to shift attention between two different parts of a task) than did women without breast cancer. Women taking exemestane had smaller falls and the changes were not statistically significant, compared with the healthy women. There were no substantial differences between any of the three groups in terms of visual memory, working memory, reaction speed, or motor speed. Not surprisingly, this work has elicited much comment and some criticism [40r]. Noting the less satisfactory test results with tamoxifen, one commentator pointed out that the research was sponsored by the manufacturer of exemestane, apparently implying some form of bias in the study design. However, most reviewers remarked that, as the investigators themselves suggested, further work is needed, and that the mechanism of the effects observed needs to be understood. Victor G. Vogel, of the American Cancer Society, said the results were not surprising, and although the reason why women on tamoxifen had more cognitive decline is not known, he said a logical though unproven explanation is that “it may just not be good for your brain not to have estrogen” [41r]. Management of adverse drug reactions Zoledronic acid has been used to counter the adverse effects of aromatase inhibitors on bone density [SEDA-32, 753]. It seems very likely that the risk of accelerated bone loss and consequent fractures during adjuvant aromatase inhibitor therapy would similarly be reduced by the use of denosumab, a fully human monoclonal antibody against receptor activator of NFk-B. A US group has reported on a group of 252 patients with breast cancer and low bone mass (but no osteoporosis) taking aromatase inhibitors for long periods [42C]. All received supplementary calcium

M.N.G. Dukes

and vitamin D, but beyond that they were randomly assigned to either placebo (n ¼ 125) or subcutaneous denosumab 60 mg (n ¼ 127) every 6 months. At 12 and 24 months, bone mineral density in the lumbar spine increased by 5.5% and 7.6% respectively in those who took denosumab compared with those who took placebo. Increases were observed as early as 1 month and were not influenced by the duration of aromatase inhibitor therapy. There were also increases in bone mineral density at the total hip, total body, femoral neck, and the predominantly cortical onethird radius. Bone turnover markers fell with denosumab treatment. The overall incidence of treatment-emergent adverse events was similar in the two treatment groups.

Anastrozole Musculoskeletal Susceptibility factors for arthralgia and arthritis have been studied in 9366 postmenopausal women who were assigned to anastrozole 1 mg/day, tamoxifen 20 mg/day, or a combination of the two; 5433 of them were examined for joint symptoms [43C]. Of 1914 women in this subgroup who had earlier taken HRT, 777 (41%) developed joint symptoms, compared with 1001 of 3519 women (28%) who had not used HRT, a highly significant difference. Women with hormone-receptornegative breast cancer developed significantly fewer joint symptoms than those with hormone-receptor-positive tumors. As one might have expected, obese women reported more joint symptoms than others. Women who took anastrozole reported more joint symptoms than those taking tamoxifen (35% versus 30%). The tenosynovial changes and the associated functional impairment seen when tamoxifen or an aromatase inhibitor adversely affects the small joints of the hand and wrist have been studied in 17 patients [44c]. At 6 months, patients taking an aromatase inhibitor had reduced grip strength and significant tenosynovial

Sex hormones and related compounds, including hormonal contraceptives

changes, as assessed by MSI scanning, and worsening of morning stiffness and an increase in intra-articular fluid. There were only minor changes in patients taking tamoxifen. The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, with its median follow-up of 68 months, has provided the best evidence to date that an adjuvant anastrozole regimen is better tolerated (and more effective) than tamoxifen alone, but the problem remains that anastrozole reduces circulating estrogen, and that low estradiol concentrations cause reduced bone mineral density and hence an increased risk of fractures. In a substudy of the ATAC trial, the effects of prolonged long-term aromatase inhibitor therapy on bone mineral density have been examined in 197 patients, who took anastrozole 1 mg/day or tamoxifen 20 mg/day as adjuvant therapy for 5 years [45CR]. Anastrozole-treated women had reduced median bone mineral density compared with those who took tamoxifen, but it is striking that no patients with normal bone mineral density at the outset developed osteoporosis at 5 years. The real risks with anastrozole thus seem to be limited to women who have osteopenia at the start of treatment. Reproductive system Further analysis of the findings in the ATAC trial has quantified the extent to which tamoxifen was clearly associated in that study with a significantly higher incidence of gynecological adverse events compared with anastrozole (34% versus 21%) [46C]. This led to more diagnostic and/or therapeutic interventions, including an almost fourfold increase in the number of hysterectomies (5.1% versus 1.3%). Most of the gynecological adverse events in those taking tamoxifen occurred during the first 2.5 years of treatment.

Clomifene [SED-15, 812; SEDA-30, 474; SEDA-31, 665; SEDA-32, 743] Tumorigenicity A study involving the major Swedish clinics providing treatment

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for female infertility was designed to determine the possible effect of such treatment on the incidence of breast cancer [47c]. Among 1135 women who had taken treatment at some time over a 15-year review period, 54 had breast cancer, which was essentially as expected. However, users of high-dose clomiphene citrate had an almost twofold increase in risk (standardized incidence ratio ¼ 1.90; 95% CI ¼ 1.08, 3.35). This association was more pronounced among women who were referred for nonovulatory factors, with a threefold increased risk (standardized incidence ratio ¼ 3.00; 95% CI ¼ 1.35, 6.67).

Exemestane

[SEDA-31, 665; SEDA-32,

744] Comparative studies Exemestane 25 mg/ day and raloxifene 60 mg/day and the combination have been compared in 11 postmenopausal women with hormonereceptor-negative breast cancers [48C]. Initial therapy with one drug was for 2 weeks, and the patients then took combination therapy for a minimum of 1 year. Plasma concentration-time profiles for each drug were the same during monotherapy and combination therapy. Raloxifene monotherapy did not affect plasma estrogen concentrations, but plasma estrogen concentrations were suppressed below the lower limit of detection by exemestane both as monotherapy and when combined with raloxifene. The most common adverse events of any grade included arthralgias, hot flushes, vaginal dryness, and myalgias. Liver Severe prolonged cholestatic hepatitis has been attributed to exemestane [49A]. • A 47-year-old woman was given exemestane 25 mg daily and after 3 weeks reported fatigue, jaundice, and pruritus, associated with rises in total bilirubin, aminotransferases, and alkaline phosphatase. Hepatitis serology, including hepatitis A IgM, hepatitis B surface antigen, hepatitis B core IgM, and hepatitis C antibody, was negative, as were autoantibodies associated with autoimmune hepatitis,

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862 including antimitochondrial antibodies and antinuclear antibodies. Exemestane was withdrawn, but although the aminotransferases fell quickly, the serum bilirubin concentration continued to rise for another 4 weeks, before resolving.

This case was complicated by the use of other medications, and it is not clear that exemestane was to blame. Musculoskeletal Changes in bone mineral density from baseline to 24 months have been studied in 167 women taking either exemestane 25 mg/day or tamoxifen 20 mg/day [50C]. There was more bone loss at both the spine and the hip with exemestane during the first 12 months, but by 2 years the differences were less apparent and the bone loss with exemestane had slowed, the difference being significant only at the hip.

Letrozole Observational studies The most common adverse effects letrozole are, as might be expected, those of estrogen deprivation. The frequencies of unwanted effects based on clinical trials do not necessarily parallel those subsequently seen in long-term practical use. The adverse effects seen over 2 years of treatment have been studied in 185 women who took letrozole after breast cancer surgery [51C]. The most prominent problem was musculoskeletal pain (see also below). In addition hot flushes, increased fatigue, nausea, vomiting, anorexia, mood disturbances, vaginal dryness, hair loss, and rashes were recorded. In contrast to the findings in prospective randomized clinical trials, there was a high drop-out rate (20%), mainly due to the fact that arthralgia interfered significantly with daily life. Musculoskeletal Musculoskeletal symptoms have been studied in 100 women who took letrozole or exemestane and were followed up for at least 6 months [52C]. Of 97 eligible patients 44 met predetermined criteria for referral to a rheumatologist. No baseline

M.N.G. Dukes

characteristics were significantly associated with referral. The median time to onset of symptoms was 1.6 months (range 0.4–10 months). Clinical and laboratory evaluation of patients suggested that most developed either non-inflammatory musculoskeletal symptoms or inflammation localized to tenosynovial structures. Letrozole was withdrawn in 13 cases because of musculoskeletal effects after a median 6.1 (range 2.2–13) months. The etiology of this complication remains elusive.

Raloxifene

[SEDA-31, 666; SEDA-32,

745] Susceptibility factors Renal disease In a randomized study of raloxifene in 7707 postmenopausal women with chronic kidney disease, the incidence of adverse reactions was similar to that in a control group without kidney disease [53C].

Tamoxifen

[SED-15, 3296; SEDA-30, 475; SEDA-31, 667; SEDA-32, 745]

Uses Although tamoxifen increased bone mineral density in clinical trials, it is less clear whether this significantly affects fracture rates in ordinary practice. In a population-based case–control study in women aged 50 years or over in one Canadian Province, 11 096 women with osteoporotic fractures (involving the vertebrae, wrist, or hip) were compared with 33 209 women who had not had fractures [54C]. There were fewer osteoporotic fractures in those taking current tamoxifen (univariate OR ¼ 0.68; 95% CI ¼ 0.55, 0.84). After controlling for demographic and medical diagnoses known to affect the risk of fractures, current use of the drug was associated with a significantly reduced overall risk of osteoporotic fractures (adjusted OR ¼ 0.68). However, neither recent nor remote past tamoxifen use was associated with a reduced risk.

Sex hormones and related compounds, including hormonal contraceptives

Metabolism The effects of adjuvant tamoxifen on the lipid profile have been compared with those of exemestane in 142 postmenopausal patients with breast cancer in the Greek substudy of the Tamoxifen and Exemestane Adjuvant Multicenter International trial [55c]. Total cholesterol and LDL cholesterol were consistently and significantly reduced by tamoxifen only. The mean HDL cholesterol concentration was higher in those taking tamoxifen compared with exemestane. Neither drug had a significant effect on triglycerides. Hematologic Pseudolymphoma as a complication of tamoxifen treatment has been reported briefly [56A]. Reproductive system Endometrial polyps during tamoxifen treatment can be prevented by the simultaneous use of intrauterine levonorgestrel (the MirenaÒ system), but the method is of limited usefulness, since its effects lasts only as long as the MirenaÒ is in place; once it is removed, and while tamoxifen is continued, the polyps recur [57c]. There are differing opinions on this form of administration (see the special review below). Autacoids Exacerbation of hereditary angioedema has been attributed to tamoxifen [58A]. • A 69-year-old woman with hereditary angioedema type I used danazol 200 mg three times a week and had only occasional crises requiring tranexamic acid. She developed breast cancer and took tamoxifen, after which the severity and frequency of episodes of angioedema rapidly increased, despite maintenance of her usual treatment. After replacement of tamoxifen by letrozole, her symptoms improved.

Tumorigenicity Uterine cancer Although it is widely considered that tamoxifen increases the risk of uterine corpus cancer, the evidence has been derived from a series of small studies that have thrown little light on the degree of risk or the prognosis. In a retrospective cohort study in 332 patients who developed

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such cancers after treatment with tamoxifen for breast malignancy, follow-up data on 309 cases studied earlier were also examined [59C]. Long-term tamoxifen users had a higher proportion of non-endometrioid tumors than non-users (33% versus 17%), especially serous adenocarcinomas and carcinosarcomas. There was also an increased proportion of International Federation of Gynecology and Obstetrics (FIGO) stage III and IV tumors (20% versus 11%). Within FIGO stage I, both short-term and long-term tamoxifen users had a higher proportion of tumors limited to the endometrium than non-users (36% versus 23%). Uterine corpus cancers in long-term tamoxifen users were more often steroid receptor-negative (ERa, PRA, and PRB) and P53-positive. The 3-year uterine corpus cancer-specific survival was worse for long-term tamoxifen users than for non-users (82% versus 93%). The survival difference remained after adjustment for histological and immunohistochemical characteristics. The unwanted effects of tamoxifen on the endometrium have long been a source of concern, and cases continue to be reported, sometimes with a range of associated complications affecting the ovary and the adnexa as well. Effects that have been observed include malignancy, endometriosis, leiomyomata, endometrial polyps, and apparently benign endometrial hyperplasia, and cases continue to be reported in detail [60c]. Repeated attempts have been made to reduce or reverse these complications. An Italian study has continued this work, notably in a series of 70 postmenopausal patients with estrogen receptor-positive breast tumors who were switched to anastrozole after a course of tamoxifen [61c]. The introduction of anastrozole was associated with reversal of both the thickening of the endometrium and the histological changes caused by tamoxifen. The mechanism by which tamoxifen induces endometrial neoplasms is not known. Possible associations with the MSI, PTEN, beta-catenin, and KRAS genes have been sought in 18 cases of endometrial carcinoma after the use of tamoxifen

864

compared with various other cases of endometrial cancer in which the drug had not been used [62C]. A control group included 15 patients with endometrial carcinoma unassociated with the use of the drug. There was a direct relation between tamoxifen exposure and overexpression of beta-catenin oncoprotein, which plays a major role in the pathogenesis of estrogen-driven type I endometrial adenocarcinoma. Patients with tamoxifen exposure also had more K-ras mutations and fewer PTEN mutations and MSI compared with controls, but these results were not statistically significant. Among the less common complications attributed, anecdotally but credibly, to the use of tamoxifen is the development of an extrauterine leiomyoma [63A]. Teratogenicity Animal studies have shown evidence of teratogenicity of tamoxifen, and hence the FDA classifies it in category D. In 1994 a report appeared of apparent induction of Goldenhar's syndrome (the oculo-auriculo-vertebral syndrome), a rare defect that is characterized by incomplete development of the ear, nose, mandible, soft palate, and lip, and the authors stated that the manufacturer of tamoxifen knew of two earlier cases associated with congenital craniofacial defects. The Pierre Robin sequence, which comprises severe micrognathia and cleft palate, has now also been described [64Ar]. Both this and Goldenhar's syndrome have earlier been observed in infants exposed in utero to isotretinoin. However, it must be emphasized that with tamoxifen these complications are very rare; most infants exposed to the drug before birth appear to be entirely normal. Susceptibility factors Genetic The occurrence of hot flushes during tamoxifen treatment has long been recognized, but only recently has there been evidence that a woman's susceptibility to this effect can be influenced by her phenotype, as well as by her menopausal status and her earlier treatment. In a US study in premenopausal women, women with the alleles ESR1 PvuII and XbaI CG had higher baseline hot flush scores after 4 months of tamoxifen

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M.N.G. Dukes

treatment than in those who had other haplotypes [65c]. Women with the ESR1 PvuII CC and ESR2-02 GG genotypes had increased hot flush scores 4.6 times more often than other postmenopausal women (56 versus 12). Women who had the ESR202 AA genotype were significantly less likely to have tamoxifen-induced hot flushes than women with at least one ESR-02 G allele (HR ¼ 0.26; 95% CI ¼ 0.10, 0.63). Bearing in mind the evidence that there is a genetic predisposition to thromboembolic complications of hormonal contraceptives (see above), it is not unexpected that there is a similar predisposition to thrombotic complications of antiestrogenic treatment with tamoxifen. Banked DNA obtained from tamoxifen-treated individuals with breast cancer was tested for an association between the incidence of tamoxifen-associated thromboembolic events and single nucleotide polymorphisms encoding the estrogen receptors 1,2 (ESR1, ESR2) or the drug metabolizing enzymes CYP2D6 and aromatase (CYP19) [66C]. There were thromboembolic events in 16/220 subjects, and there was an association with the XbaI (rs9340799) genotype and the ESR1 Xbal/PvuII diplotype (rs9340799 and rs2234693) (HR ¼ 3.47; 95% CI ¼ 0.97, 12). The association persisted after adjusting for classical susceptibility factors, including age at diagnosis and body mass index at enrolment. The same group of investigators also found an association between CYP2D6 genotype and tamoxifen-induced hot flushes in 297 women who took tamoxifen for 12 months [67C]. At 4 months, there was a trend to fewer severe hot flushes in poor metabolizers compared with intermediate and extensive metabolizers combined. Renal disease Tamoxifen has been found to be safe and effective in patients with normal renal function, but until recently there was no evidence regarding its safety or otherwise in women with impaired renal function. A study in 29 patients in whom impaired renal function ranged from mild to severe has suggested that a tamoxifen

Sex hormones and related compounds, including hormonal contraceptives

dose of 20 mg/day every 4 weeks is well tolerated, adverse effects being no more severe or frequent than in women with normal kidney function [68c]. Drug–radiation interactions There have been few experimental or clinical studies of the combined effects of hormone and radiation therapy. Although data from in vitro studies have supported the notion that there is an antagonistic effects of concurrent tamoxifen and radiotherapy on tumor cells, in vivo research has suggested that there is a synergistic effect that could be attributable to micro-environmental changes in tumor responsiveness to ionizing radiation and hormone therapy [69R]. Retrospective studies have suggested that concurrent use of tamoxifen and radiotherapy does not compromise local control but might increase toxicity. Further studies are needed to clarify possibly undesirable interactions.

PROGESTOGENS [SED-15, 2930; SEDA-30, 477; SEDA-31, 669; SEDA-32, 747] Hematologic Sideroblastic anemia with iron overload has been previously reported shortly after the administration of progesterone [70A]. Removal of the progestogen led to prompt disappearance of the anemia as well as the ringed sideroblasts. There was enhanced sensitivity of erythroid progenitors to progesterone. This complication must be excessively rare, but a further case has been described, this time in a pregnant woman, in whom sideroblastic anemia followed the use of progesterone [71A]. Drug administration route During in vivo fertilization, progesterone in an oily solution is commonly given to provide luteal-phase support [72C]. An unusual case has been reported in which a 35-year-old primigravida treated in this way developed acute eosinophilic pneumonia. She was given glucocorticoids, and the remaining course of

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progesterone treatment was given intravaginally, resulting in marked improvement and complete recovery. The incident appears to have represented an allergic reaction, but it is not clear whether this was due to the progesterone itself or the solvent.

Intrauterine administration of levonorgestrel The Mirena system for intrauterine administration of levonorgestrel is estimated to release some 20 micrograms of the drug daily. This has been the subject of some sharply differing assessments. In a mailed questionnaire study of 1056 British women who had been treated with this product for menstrual disorders, 73% had continued using the system, having found that it provided relief; the most common adverse effect was menstrual spotting (19%) [73c]. The possible long-term effects of a levonorgestrel-releasing intrauterine system on the endometrium and lipid profile have been examined in 142 postmenopausal women with breast cancer who took tamoxifen and were studied for 36 months. At the end of this period there were only very minor changes in serum lipids, fewer endometrial polyps, and no endometrial hyperplasia in the study group compared with a control group taking tamoxifen alone. The authors concluded that use of the levonorgestrel-releasing intrauterine system may reduce the need for investigation of adverse effects in women taking tamoxifen and may also reduce patient discomfort while improving adherence to treatment [74C]. However, some women express a dislike for the levonorgestrel intrauterine releasing system, declaring that they have an excessive incidence of adverse reactions. When another hospital sent questionnaires to 203 British women in whom the device had been inserted over a 5-year period it was found that the continuation rate fell progressively from 85% after the first 6 months to 50% after 4 or 5 years [75c]. The median duration of use was only 270 days. The principal reasons for requesting removal were unscheduled bleeding, progestogenic adverse effects, or abdominal pain.

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This may well prove to be one of the situations in which patient satisfaction with a method of treatment appears to differ markedly from one place to another, and especially between countries. Differences in the tradition of treatment or in the manner in which a physician presents a proposed therapy to the patient may be important factors determining patients’ expectations. The British report (published under the heading “Why do some people dislike it?”) needs to be set alongside an Austrian study of 180 000 users of the intrauterine system, many of them apparently very satisfied with the method. To cite a group of 13 Austrian authors: “Reliability, comfort, excellent compatibility and less severe, shorter and less painful monthly periods were the most frequently named advantages of the levonorgestrel-releasing [intrauterine system]. Medication-induced cervical priming before insertion can be carried out on a routine or selective basis (for example in nullipara, in women who have undergone cervical conisation or in women who have previously experienced painful insertion). There is, at present, no evidence of an increased rate of breast cancer . . . A directly comparative study with oral contraceptives in young nullipara showed excellent results for the levonorgestrel-releasing [intrauterine system]” [76c]. A Spanish group similarly considered that the system “meets the effectiveness and tolerability criteria for being considered as a first choice treatment option for women with idiopathic menorrhagia” [77c].

Drospirenone

[SEDA-31, 670;

SEDA-32, 748] See Hormonal contraceptives above.

Medroxyprogesterone

[SED-15,

2225; SEDA-32, 749] Skin The pigmented purpuric dermatoses are a group of chronic diseases of mostly unknown cause that have a very distinctive clinical appearance. They are characterized by extravasation of erythrocytes in the skin,

M.N.G. Dukes

with marked hemosiderin deposition. Although the condition is more common in men, a number of cases have in the course of the years occurred in women, either early or late after administration of medroxyprogesterone acetate [78A, 79A].

Megestrol acetate [SED-15, 1679, 2932; SEDA-31, 670; SEDA-32, 749] Endocrine In some centers, megestrol acetate is being used to promote weight gain in malnourished elderly patients. The suspicion that this might lead to impaired adrenal function has been incidentally voiced in the past, and a US group has described such a case in detail [80Ar]. • An 80-year-old woman with worsening dyspnea was transferred to a university clinic from a psychiatric hospital where she was being treated for major depressive disorder with psychotic features. She had weight loss and anorexia, and 1 month before she had been given megestrol acetate 400 mg/day to stimulate her appetite and improve her nutritional state. Her dyspnea worsened and she rapidly became hypotensive. A cosyntropin stimulation test elicited a suboptimal response, and the ACTH concentration was 8 pg/ml (reference range 10–60 pg/ml). Megestrol was withdrawn and she was given corticosteroids. Her blood pressure normalized and she improved slowly. Two months later a repeat cosyntropin stimulation test was normal.

PROGESTERONE ANTAGONISTS [SEDA-30,

477;

SEDA-31, 671; SEDA-32, 749]

Mifepristone [SED-15, 2344; SEDA-30, 477; SEDA-31, 671; SEDA-32, 749] Uses There is currently increasing interest in the use of mifepristone as a once-a-month oral contraceptive. In a study in which 86 women took mifepristone 200 mg in tablet form on the 16th day of the menstrual cycle, while a control group of 92 women took a combined oral contraceptive, the latter had worse

Sex hormones and related compounds, including hormonal contraceptives

biochemical parameters [81c]. Much larger studies will be needed to assess the benefit to harm balance of this contraceptive method. Observational studies In a phase 2 trial of mifepristone 200 mg/day in women with advanced or recurrent endometrioid adenocarcinoma or low-grade endometrial stromal sarcoma, there were no partial or complete responses [82c]. The most frequent grade 1 and 2 adverse reactions were anorexia, fatigue, and mood alterations which occurred in 50%, 50%, and 58% of patients respectively. The most common grade 3 adverse reactions were fatigue and dyspnea, which occurred in 25% and 17% of patients respectively. One patient had grade 4 dyspnea. There were asymptomatic rises in corticotrophin in 33%.

SEX HORMONE AGONISTS Tibolone [SEDA-30, 485; SEDA-31, 671; SEDA-32, 750] Cardiovascular In some cases tibolone prevents bone loss in elderly subjects, although after 40 years of use some questions regarding its clinical role remain unanswered. In a randomized study in the US, in which 4538 older women took either tibolone 1.25 mg/day or placebo, tibolone reduced the risk of vertebral fractures and of breast cancer. However, there was an increased risk of stroke (relative hazard ¼ 2.19; 95% CI ¼ 1.14, 4.23); the study was stopped after a mean treatment period of 34 months at the recommendation of the data and safety monitoring board [83Cr]. There were no significant differences between the two groups in the risks of either coronary heart disease or venous thromboembolism. However, as others have pointed out, the long-term safety and efficacy of tibolone on major health outcomes in younger postmenopausal women are unknown [84r]. In older, mostly white, women with osteoporosis, tibolone 1.25 mg/day for 3 years seemed in earlier studies to have a beneficial effect on the breast

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and skeleton without any deleterious effect on cardiovascular outcomes or thrombosis. However, that study was not adequately powered to evaluate the effect of tibolone on these outcomes. The use of tibolone should be avoided in older women, those at a high risk of stroke, and those who have breast cancer or are at high risk of the disease. Reproductive system The endometrial effects of tibolone 1.3 mg/day have been examined in a 3-year placebo-controlled study in 635 elderly women with osteoporosis [85C]. During the first year, mean endometrial thickness increased significantly by 1 mm in women taking tibolone, but there were no further increases during the next 2 years. Diagnostic biopsies in 499 women taking tibolone and 136 who taking placebo showed cumulative incidences of endometrial hyperplasia of less than 1%. Among the 15% of women whose biopsies showed an endometrial polyp (with similar rates in the tibolone and placebo groups), those taking tibolone were more than twice as likely to have hyperplasia within the polyp. There was a marginal increase in grade 1 endometrioid adenocarcinoma in women taking tibolone. Prevalences of vaginal bleeding during the study were 11% with tibolone and 2.8% with placebo. All these effects were regarded as minimal. Tumorigenicity The possible risks of tibolone when it is used to attenuate the unwanted effects of adjuvant treatment for breast cancer have been studied in a multicenter investigation, with particular attention to the possibility that it might increase the risk of cancer recurrence [86C]. Women who had been surgically treated for histologically confirmed breast cancer with vasomotor symptoms were randomly assigned to either tibolone 2.5 mg/day or placebo at 245 centers in 31 countries (1556 in the tibolone group and 1542 in the placebo group). The mean age at randomization was 53 years and the mean time since surgery was 2.1 years. Of 3098 women, 1792 (58%) were node-positive and 2185 (71%) were receptor-positive. At study entry, 2068 women (67%) used tamoxifen and 202 (6.5%) used aromatase inhibitors. After a median

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follow-up of 3.1 years, 237 of 1556 women taking tibolone (15%) had a cancer recurrence, compared with 165 of 1542 (11%) taking placebo (HR ¼ 1.40; 95% CI ¼ 1.14, 1.70). Tibolone was not different from placebo with regard to other safety outcomes, such as mortality, cardiovascular events, or gynecological cancers. The authors concluded that tibolone increased the risk of recurrence in breast cancer patients, although it relieved vasomotor symptoms and prevented bone loss. The significance of these findings has been stressed by Patricia Goodwin [87R], particularly in view of the fact that the increased recurrence rate of breast cancer led the investigators to stop the trial. “It is worrying,” she noted, “that over 70% of the recurrence events were distant metastases, since these metastases will ultimately lead to death. The effect of tibolone seemed to be highest in individuals with hormone-receptor-positive breast cancer, although there were not enough study participants with hormonereceptor-negative breast cancer to conclude that tibolone use was safe in that group. No other subgroups were identified where the power of the study was sufficient to conclude tibolone use was safe. . . An adverse effect of tibolone on the recurrence of breast cancer was also reported in the HABITS trial.” With its unusual mixture of hormonal effects, tibolone has always been a puzzling compound, seeking as it were a role for itself. At least in the treatment of women who have undergone surgery for breast cancer, that quest seems, on present evidence, to have been unsuccessful.

SEX HORMONE ANTAGONISTS Danazol

[SEDA-31, 672; SEDA-32, 750]

Cardiovascular The short-term and longterm effects of danazol on proatherogenic intermediate end-points have been evaluated in 15 healthy volunteers and 17 patients with hereditary angioedema in a

M.N.G. Dukes

4-week, crossover, placebo-controlled trial [88C]. Short-term danazol treatment in the former was associated with a 21% reduction from baseline in apolipoprotein A-I and a 23% reduction in HDL cholesterol. Long-term danazol treatment in the patients with hereditary angioedema did not adversely affect HDL cholesterol, HDL-related transfer proteins such as paraoxonase-1, cholesteryl-ester transfer protein mass, lecithin cholesterol acyltransferase activity, plasma phospholipid transfer protein activity or apolipoproteins. However, the patients who used danazol had increased coagulation compared with controls. Liver In a study of the potential hepatotoxic or liver tumor-inducing effects of long-term danazol prophylaxis in 92 patients with hereditary angioedema, half of whom took danazol [89c]. There were no clinically important differences between the liver function parameters in years 0 and 5 in the two groups. Abdominal ultrasound did not detect neoplastic or other potentially treatment-related alterations in the liver parenchyma. Drug–drug interactions Lovastatin As monotherapies, both danazol and lovastatin have been reported to cause myopathy and pancreatitis, and a case report suggests that the combination may do likewise [90A].

ANABOLIC STEROIDS, ANDROGENS, AND RELATED COMPOUNDS [SED-15, 216; SEDA-30, 477; SEDA-31, 672; SEDA-32, 751]

Anabolic steroids Uses Among the very few medical uses of anabolic steroids that continue to be defended by certain centers is in promoting recovery in cases of severe burns, even in

Sex hormones and related compounds, including hormonal contraceptives

children. The published evidence, examined in a recent critical review of eight prospective controlled studies in which oxandrolone was used for this purpose, suggests that oxandrolone stimulates protein synthesis by binding to androgen receptors [91R]. During the rehabilitation period, oxandrolone 0.1 mg/kg/day improved muscle strength, especially when combined with exercise. Based on clinical studies, oxandrolone 0.1 mg/kg bd is safe when it is used for up to 12 months in such cases. However, there were mild increases in serum aminotransferase activities and reversible sexual changes during therapy. As the reviewers pointed out, limitations of the available data are that they originated from a single study center and that measurement of wound healing is lacking in children with severe burns. If oxandrolone and other compounds of this type are to be used in children, close monitoring of liver function, sexual development, and growth is recommended during treatment. Cardiovascular Over the years there have been repeated reports of cardiac enlargement and associated complications in athletes who have attempted to improve their performance with anabolic steroids. In bodybuilders using anabolic steroids there were smaller diastolic velocities in both ventricles compared with sedentary counterparts [92c]. Cases of dilated cardiomyopathy have been reported [93AR, 94A], but most of them were at least partially reversible after withdrawal. However, fatal cases of hypertrophic cardiomyopathy have been reported in the past [95A].

Abuse of anabolic steroids and the justification of control measures Although “anabolic” androgenic steroids are widely misused, their relative abuse and dependence liability have not been fully characterized. As Wood has pointed out in

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an extensive review, it is difficult in humans to separate the direct psychoactive effects of these compounds from physical reinforcement due to their systemic anabolic effects [96R]. However, studies in animals using conditioned place preference and selfadministration techniques show that anabolic steroids have a “reinforcing” effect, even in a context in which athletic performance is irrelevant. They also have brain receptor sites and neurotransmitter systems in common with other drugs of abuse. Some recent evidence has shown that in this respect they are analogous to the opioids; indeed, anabolic steroid abuse is sometimes associated with use of prescribed opioids. In animals, overdose of anabolic steroids produces symptoms resembling opioid overdose, and these compounds have been found to modify the activity of the endogenous opioid system. Continuing concerns regarding the social consequences of the widespread and still increasing misuse of anabolic steroids, particularly by young people, have led in many countries to imposition of controls. In January 2008, the UK's Advisory Council on the Misuse of Drugs wrote to the Home Office (the UK Government's ministry for internal affairs) proposing the compilation and submission of an expert report titled “Consideration of the Anabolic Steroids”. The report appeared 2 years later [97R] and was submitted to the Secretary of State for Health in September 2010 [98R]. Reliable data on the extent of misuse in England and Wales proved to be elusive, but in the “British Crime Survey” published in 2010 it was estimated that in the 16–59 age group some 226 000 people had admitted to ever having used anabolic steroids, with 50 000 users in the year preceding the survey and 19 000 in the most recent month [99R]. The UK Report (2010) The expert report provided evidence that by the mid-1960s the use of anabolic steroids was an accepted practice among weightlifters and bodybuilders (including amateurs). During the 1980s a number of reports began to appear

870

about the use of these drugs in “health and fitness clubs”, while newspaper reports at the time described a thriving black market in the buying and selling of anabolic steroids in and around such centers. The number of people who report using anabolic steroids is relatively low by comparison with some other illicit drugs, but similar to rates reported for heroin and crack cocaine. The numbers of women reporting anabolic steroid use are relatively small; the ratio of men to women has been reported as ranging from 3:1 to as high as 10:1. Among schoolchildren aged 11–15 years, 2% had been offered anabolic steroids at some stage. Anabolic steroids are generally used in patterns called “cycling”, in which they are taken for a period of time (for example 6–12 weeks), known as an “on” cycle, followed by a similar period of steroid-free training, known as an “off” cycle. Such a cyclical method is practiced in the belief that it prevents tolerance to the steroids, reduces the risk of adverse effects from prolonged use, and allows the hypothalamic–pituitary–gonadal axis time to resume normal function. Users also often combine several different types of anabolic steroids in a process known as “stacking”. Here, two or more anabolic steroids are taken at the same time (using, for example, oral and injectable products). Users believe that stacking will have specific additional, or synergistic, effects, although this theory has not been scientifically evaluated. The report goes on to provide an extraordinarily detailed account of the adverse physical, mental, and social ill effects of anabolic steroid misuse. Some of the harmful physical effects are commonly self-reported, for example acne, endocrine effects, and gynecomastia in men; however, others are rarer and therefore the causal link to use of anabolic steroids is equivocal. Most of the harmful effects of anabolic steroids are not life-threatening, although a few deaths have been attributed to liver damage associated with long term steroid use. Many, but not all, of the adverse effects are reversible on withdrawal of anabolic steroids. However, there are special concerns about the use of anabolic steroids by young people, as the use of these substances can lead to virilization and, more broadly,

Chapter 40

M.N.G. Dukes

potentially disrupt the normal pattern of growth and behavioral maturation. Adult women are exposed to virilization, which can involve marked physical effects, such as hirsutism, deepening of the voice, amenorrhea/anovulation, clitoral enlargement, atrophy of breast tissue, and changes in libido. These changes can be pronounced and in some cases permanent. Most users administer anabolic steroids by injection. As a consequence, they are potentially at risk of a number of serious forms of harm that can include damage to the injection site as a result of poor injection technique, bacterial and fungal infections (as a result of using contaminated drug products, sharing vials, and/or reusing injecting equipment) and blood-borne virus infections, such as HIV, hepatitis B, and hepatitis C (again largely as a result of sharing equipment). Use of anabolic steroids has been associated with a range of psychological and behavioral effects in case reports, such as hypomania, mania, aggression, violence, depression, and, after withdrawal, suicide. Although there is not enough evidence to connect chronic anabolic steroid use with substance dependence, the positive psychological effects experienced by many users and other positive effects (including increased training capacity or strength, enhanced appearance, and feelings of well-being) appear to reinforce the continuing use of steroids in some individuals. Finally, the expert report notes the existence of a market in substandard and counterfeit anabolic steroids; the composition and purity of which are unknown. Recommendations In the light of this report, the Advisory Council on the Misuse of Drugs recommended in September 2010 that anabolic steroids should continue to be controlled as Class C drugs under the Misuse of Drugs Act 1971. In essence this would retain the possibility of prescribing these compounds for certain medicinal purposes, but severe measures would be maintained to prevent, so far as possible, their importation outside the medical sector. Supplementary measures would be required to

Sex hormones and related compounds, including hormonal contraceptives

discourage the use of these substances other than on prescription, including “personal custody” provisions and educational measures. Severe penalties would be retained for illegal possession of anabolic steroids (up to 2 years’ imprisonment and/or an unlimited fine) and for illegal supply (up to 14 years’ imprisonment and/or a fine). General conclusions The data provided by the UK report greatly exceed the scope of this review. It can be highly recommended as a current source of information and informed opinion on the problems posed by anabolic steroids. It is clear that in various circumstances the misuse of these products has given rise to social problems as well as purely medical complications, and that on both counts society is now obliged to look for effective solutions.

Androgens Uses Use in men with hypogonadism While the debate on the acceptability of androgen replacement therapy in elderly men as a group shows no sign of dying down, there is some agreement that in men who have severe hypogonadism as a consequence of successful treatment for prostate cancer there can be a sufficient argument for cautious androgen supplementation as a means of improving the quality of life [100R]. So long as there is any possibility of residual cancer, the use of androgens remains firmly excluded; however, a somewhat different view of this issue, advanced by Morgenthaler, is noted below. Use in women This topic was considered in detail in SEDA-29 (p. 510) and the controversy shows no sign of abating. The authors of an extensive review have again concluded that testosterone replacement in women can be used safely without an increased risk of endometrial or breast cancer [101R]. However, the available evidence on long-term use remains limited, and the

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widely held view that such treatment should not last more than 2 years still appears to hold good. Respiratory Peliosis is a rare lesion of unknown incidence and cause, characterized by the presence of blood-filled cysts. It has been most often reported to affect the liver (peliosis hepatis), sometimes in association with the use of anabolic steroids, but it has also been localized elsewhere in the mononuclear phagocytic system, such as the spleen, bone marrow, and lymph nodes, and occasionally at other sites. Pulmonary peliosis has been reported in a 29-year-old man who was abusing testosterone [102A]. This appears to be only the third published case involving the lungs, and it is highly unusual in that no other organ system was affected. Tumorigenicity There is still uncertainty regarding the belief (which originated with a single case report) that androgen replacement therapy in men might increase the risk of prostatic neoplasms, but there have been two reports arguing that the risk was in fact negligible or absent (SEDA-32, 751). A critical and very extensive systematic review of the literature now seems to have underpinned this optimistic conclusion. Of 44 studies that met the authors’ strict inclusion criteria, none showed that testosterone therapy for hypogonadism increased the risk of prostate cancer or increased the Gleason grade of cancer detected in treated versus untreated men [103M]. Testosterone therapy did not have a consistent effect on prostate-specific antigen concentrations. Susceptibility factors Prostate cancer Androgen treatment of men has a striking number of champions, ready to spring to its defence whenever critics express reservations. That is the case regarding the widely expressed view [SEDA-30, 477] that administration of androgens is undesirable in men with a history of prostatic cancer. In a recent review, Morgenthaler has argued

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for a less absolute attitude [104R]. Hesitation regarding the use of testosterone in these cases is, in his opinion, based on a model that assumes that androgen sensitivity of prostate cancer extends throughout the range of testosterone concentrations. Although it is clear that prostate cancer is exquisitely sensitive to changes in serum testosterone at low concentrations, he finds considerable evidence that prostate cancer growth becomes androgen indifferent at higher concentrations. The most likely mechanism for this loss of androgen sensitivity at higher testosterone concentrations is the finite capacity of the androgen receptor to bind androgen. This saturation model explains why serum testosterone appears to be unrelated to the risk of prostate cancer in the general population and why testosterone administration in men with metastatic prostate cancer causes rapid progression in castrated but not hormonally intact men. Worrisome features of prostate cancer, such as a high Gleason score, extracapsular disease, and biochemical recurrence after surgery, have been reported in association with low but not high testosterone. Anecdotal evidence suggests that testosterone therapy does not necessarily cause increased prostate-specific antigen concentrations, even in men with untreated prostate cancer. Morgenthaler has concluded that although no controlled studies have been performed to date to document the safety of testosterone therapy in men with prostate cancer, the limited available evidence suggests that such treatment may not pose an undue risk of prostate cancer recurrence or progression. Drug administration route Published experience with testosterone pellets of an older type has noted relatively high rates of pellet extrusion (8.5–12%) and infection (1.4–6.8%). A study in 80 men with longacting testosterone implants (TestopelÒ), which are smaller and have a smooth surface, has shown that with this formulation extrusion occurred in only 0.3% of cases and infection also in only 0.3% [105c].

M.N.G. Dukes

[SEDA-29, 510; SEDA-30, 479; SEDA-31, 673; SEDA-32, 755]

ANTIANDROGENS

Bicalutamide Quality of life The positive effects that can be achieved with intensive androgen blockade (using a drug such as bicalutamide) need to be weighed against the possibility of such adverse effects as gynecomastia and breast pain, but also against possible deterioration in the quality of life as a whole. A Japanese group sought to evaluate the latter, using a standard questionnaire in 203 previously untreated cases of prostate cancer, who were questioned at intervals during 24 weeks of maximum androgen blockade, involving use of bicalutamide together with an LH agonist; a control group was receiving an LH agonist only [106C]. The patients on maximum androgen blockade had a better therapeutic response and there was no evidence that their quality of life was in any way impaired compared with the controls.

Cyproterone acetate Drug–alcohol interactions An apparently unprecedented case has been reported in which cyproterone induced disulfiram-like interference with the metabolism of alcohol [107A]. • A 31-year-old woman who had had bacterial vaginosis while using of an intrauterine contraceptive device was instead given the oral contraceptive DianeÒ, which contains cyproterone acetate 2 mg and ethinylestradiol 35 micrograms. She developed a reaction to alcohol, marked by facial flushing, sweating, palpitation, abdominal pain, nausea, vomiting, and diarrhea within about 10 minutes of taking a drink. Each reaction lasted for 3–4 hours. When DianeÒ was replaced by a combination of drospirenone þ ethinylestradiol the adverse reaction to alcohol disappeared.

There is evidence that certain drugs that interfere with the metabolism of alcohol appear to do so by inducing a “toxic

Sex hormones and related compounds, including hormonal contraceptives

serotonin syndrome” [108c], and it has been suggested that this may be the case with cyproterone [109r].

Finasteride

[SED-15, 3132; SEDA-30, 480; SEDA-31, 675; SEDA-32, 755]

Musculoskeletal Reversible myalgia associated with raised creatine kinase activity has been attributed to finasteride [110A] • A 30-year-old man who had been taking finasteride 5 mg/day for 10 years for frontal baldness developed diffuse muscle aches associated with a raised creatine kinase activity to 10 117 IU/l; there were no signs of weakness or pigmenturia. His symptoms resolved and his creatine kinase activity fell to 256 IU/l 3 weeks after finasteride withdrawal.

Skin A fixed drug eruption has been attributed to finasteride [111A]. • A 39-year-old Japanese male with a 2-month history of a pruritic sore erythematous spot on the dorsal surface of the shaft of the penis used a topical steroid, but the eruption remained almost unchanged. It consisted of a solitary violaceous erythematous macule without erosions or blisters. Finasteride was withdrawn; topical steroid therapy was restarted. The erythema rapidly resolved leaving mild pigmentation.

Sexual function Adverse effects of finasteride on male sexual function are not uncommon (SEDA-30, 480). These effects are dose related, and in the low doses used to treat hair loss (1 mg/day) they are unusual. However, they can occur in certain instances, as in two patients with azoospermia and severe oligospermia resulting in infertility when they took finasteride 1 mg/ day for hair loss; the drug was withdrawn and the sperm count recovered within 3–6 months [112A]. The use of finasteride and other 5-alpha reductase inhibitors in benign prostatic hyperplasia has been associated with adverse sexual outcomes, including dysfunction of erection or ejaculation and

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reduced libido. In an extensive literature review of these complications it was concluded that in clinical trials they have occurred at rates of 2.1–38%, the most common problem being erectile dysfunction [113R]. These effects occur early in therapy and attenuate over time. A proposed mechanism for sexual dysfunction involves impaired nitric oxide synthase activity, due to reduced dihydrotestosterone concentrations. Drug–drug interactions St John's wort The effects of St John's wort on finasteride and its metabolites, hydroxyfinasteride and carboxyfinasteride, have been studied in 12 men, in whom finasteride 5 mg was administered directly into the intestine via a catheter before and after 14 days of treatment with St John's wort 300 mg bd [114c]. St John's wort significantly reduced the Cmax, the AUC0!24h, and the half-life of finasteride; the kinetics of carboxyfinasteride were also significantly altered.

Flutamide

[SED-15, 1427; SEDA-30, 484; SEDA-31, 675; SEDA-32, 755]

Observational studies Although flutamide is effective in treating hirsutism, adverse reactions are very frequent and longterm adherence is poor. In one study over 7 years, of 83 women who took flutamide 250 mg/day alone or in combination with an oral contraceptive containing ethinylestradiol 20 micrograms and desogestrel 150 micrograms, 34 had one or more adverse reaction during follow-up, 28 had at least one adverse reaction that was possibly related to the study drug, and 20 withdrew because of adverse reactions, hepatotoxicity being the most troublesome; during follow-up, as many as 59% abandoned the study [115c]. Liver The use of flutamide for hirsutism in premenopausal women over 15 years has been reported [116c]. The dosage of flutamide, alone or in combination with oral

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contraceptives, was reduced yearly (250, 125, and 62.5 mg/day), and individual women were treated for up to 8 years. During the first year, 6% abandoned the study because of hepatic disorders, but as the dosage was reduced, tolerance improved. The authors considered that this is a satisfactory therapeutic regimen for any form of hirsutism in the long term, but if one seeks to achieve minimal adverse reactions and a high degree of adherence, the lowest dose should be used. A 26-year-old woman developed hepatotoxicity while taking a low dose of flutamide, 250 mg/day [117A].

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Nilutamide Liver Fulminant hepatic failure occurred in a 76-year-old man taking nilutamide; other causes of the hepatic failure were excluded [118A]. Sensory systems Vision An 87-year-old man with prostate cancer experienced delayed dark adaptation while taking nilutamide 150 mg/day; this took the form of episodes of isolated, bilateral blindness lasting for 10–15 minutes whenever he moved from a bright to a darker environment [119A].

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[109] Karamanakos PN, Pappas P, Marselos M. Comment on “Disulfiram-like effect of cyproterone acetate” Eur J Obstet Gynecol Reprod Biol 2009; 146: 237. [110] Al-Harbi TM, Kagan J, Tarnopolsky MA. Finasteride-induced myalgia and hyperCKemia. J Clin Neuromuscul Dis 2008; 10(2): 76–8. [111] Oyama N, Kaneko F. Solitary fixed drug eruption caused by finasteride. J Am Acad Dermatol 2009; 60(1): 168–9. [112] Liu KE, Binsaleh S, Lo KC, Jarvi K. Propecia-induced spermatogenic failure: a report of two cases. Fertil Steril 2008; 90: 849.e17–9. [113] Erdemir F, Harbin A, Hellstrom WJG. 5-alpha reductase inhibitors and erectile dysfunction: the connection. J Sex Med 2008; 5(12): 2917–24. [114] Lundahl A, Hedeland M, Bondesson U, Knutson L, Lennernas H. The effect of St John's wort on the pharmacokinetics, metabolism and biliary excretion of finasteride and its metabolites in healthy men. Eur J Pharm Sci 2009; 36: 433–43. [115] Castelo-Branco C, Moyano D, Gomez O, Balasch J. Long-term safety and tolerability of flutamide for the treatment of hirsutism. Fertil Steril 2009; 91: 1183–8. [116] Paradisi R, Venturoli S. Retrospective observational study on the effects and tolerability of flutamide in a large population of patients with various kinds of hirsutism over a 15-year period. Eur J Endocrinol 2010; 163: 139–47. [117] Castelo-Branco C, Del Pino M. Hepatotoxicity during low-dose flutamide treatment for hirsutism. Gynecol Endocrinol 2009; 25: 419–22. [118] Merwat SN, Kabbani W, Adler DG. Fulminant hepatic failure due to nilutamide hepatotoxicity. Dig Dis Sci 2009; 54: 910–3. [119] Chan P, Odel JG. Delayed dark adaptation caused by nilutamide. J Neuroophthalmol 2008; 28: 158–9.

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41

Thyroid hormones, iodine, and antithyroid drugs

Thyrotropin (thyroid-stimulating hormone, TSH) [SEDA-31, 683; SEDA-32, 763] Uses Recombinant human TSH (rhTSH) is used to increase the efficacy of radioiodine (131I) administration in the treatment of symptomatic non-toxic goiter. This approach can achieve a doubling in thyroid 131 I uptake, reducing the volume of the goiter by 35–56%, at the expense of a fivefold higher rate of permanent hypothyroidism [1R, 2c]. In addition rhTSH is used in the preparation of patients with differentiated thyroid cancer undergoing thyroid remnant ablation, and this is effective even in patients undergoing low dose ablative 131I therapy [3c]. Furthermore, this approach results in lower extra-thyroidal irradiation. Reduced rates of transient headaches, thrombocytopenia, neutropenia, hyperamylasemia, and acute sialoadenitis were reported when 30 patients treated with rhTSH were compared with 64 subjects who underwent levothyroxine withdrawal before receiving 3.7 GBq of ablative 131I [4c].

Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00041-6 # 2011 Elsevier B.V. All rights reserved.

THYROID HORMONES [SED-15, 3409; SEDA-30, 490; SEDA-31, 687; SEDA-32, 763] Uses Thyroid hormones (levothyroxine, T4, and liothyronine, T3) are used to treat overt hypothyroidism. In addition, supraphysiological doses of levothyroxine are widely used to reduce the risk of thyroid cancer recurrence by suppressing serum TSH concentrations. The use of levothyroxine suppressive therapy to induce shrinkage of benign thyroid nodules remains controversial and its routine use is not recommended in view of its low efficacy and potential long-term effects on the cardiovascular system and the skeleton caused by the induction of subclinical hyperthyroidism [5C]. Non-immune fetal goitrous hypothyroidism can cause obstetric and/or neonatal complications as well as neurodevelopmental impairment. Intra-amniotic levothyroxine administration in doses of 200–800 micrograms per injection every 1–4 weeks from 24 weeks gestation onward resulted in significant goiter size reduction in eight out of nine fetuses. Nevertheless, all the babies were hypothyroid at birth despite reductions in intra-amniotic TSH concentrations in more than 50% of cases [6c]. Liothyronine is used to accelerate and enhance the response to antidepressants, especially in patients with major depression who have not responded to conventional therapy. Randomized controlled trials and meta-analyses have demonstrated the benefit of using liothyronine in conjunction with 881

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tricyclic antidepressants, although the evidence base for combined use of selective serotonin reuptake inhibitors (SSRIs) and liothyronine is more limited. A review of five randomized controlled trials suggested that liothyronine was well tolerated and adverse reactions did not impede its clinical use. However, the overall efficacy of combination treatment with SSRIs and liothyronine remains unclear and requires further investigation [7R]. Two separate reports have suggested that supraphysiological doses of liothyronine may be beneficial in refractory major depression when combined with both tricyclic antidepressants and SSRIs [8c, 9c]. Preliminary evidence suggests that the presence of a functional polymorphism in the type 1 deiodinase enzyme, resulting in reduced peripheral conversion of T4 to T3, may be associated with increased benefit from combination therapy of antidepressants with liothyronine [10c]. The systematic treatment of subclinical hypothyroidism remains controversial. In a double-blind, randomized, controlled study of patients with co-existing iron deficiency anemia and subclinical hypothyroidism, a combination of levothyroxine 75 micrograms/day and oral iron 240 mg/day resulted in increased serum iron, hemoglobin, and serum ferritin concentrations compared with subjects who took oral iron monotherapy. These findings suggest that normalization of serum TSH concentrations may be beneficial if patients with subclinical hypothyroidism are found to have iron deficiency anemia [11c]. Nervous system Iatrogenic subclinical hyperthyroidism is induced in patients with differentiated thyroid cancer in order to reduce the risk of recurrence. Long-term exogenous subclinical hyperthyroidism causes autonomic nervous system abnormalities, and lower heart rate variability and increased urinary catecholamine excretion are common. After restoration of euthyroidism for a minimum of 6 months in 12 patients who underwent TSH suppressive therapy for more than 10 years, autonomic nervous system abnormalities

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Kristien Boelaert

remained unchanged, suggesting irreversible changes or adaptation during long-term exposure [12c]. Electrolyte balance In patients with metastatic thyroid carcinoma undergoing treatment with 131I, levothyroxine is withdrawn and a low iodine diet prescribed to improve treatment efficacy. Significant hyponatremia, associated with symptoms including weakness, dizziness, fainting spells, lethargy, and nausea, has been reported in five patients during levothyroxine withdrawal and a low iodine diet. Combined low sodium intake and the syndrome of inappropriate antidiuretic hormone secretion secondary to hypothyroidism or metastatic disease were proposed as potential underlying mechanisms [13c]. Drug dosage regimens The timing of administration in relation to food affects the effects of levothyroxine on thyroid function—nonfasting regimens are associated with higher and more variable serum TSH concentrations [14c]. If a specific serum TSH goal is desired, in order to avoid iatrogenic subclinical thyroid disease, fasting administration of levothyroxine ensures that serum TSH concentrations remain within the narrowest therapeutic target range. There has been a report of thyrotoxic periodic paralysis due to excessive replacement with levothyroxine in a patient with panhypopituitarism secondary to a craniopharyngioma [15A]. Choreoathetosis due to excessive doses of levothyroxine has been reported [16A]. The patient had an underlying diagnosis of autoimmune hypothyroidism and tripled her daily dose of levothyroxine during a 6month period. Drug–drug interactions Sunitinib and paracetamol Acute fatal liver failure following the addition of levothyroxine in a patient taking sunitinib and paracetamol for a metastatic gastric stromal tumor has been reported. Sunitinib can cause hypothyroidism, and it is plausible that correction of the hepatic hypothyroidism with levothyroxine resulted in potentiation of

Thyroid hormones, iodine, and antithyroid drugs

Chapter 41

the hepatotoxicity of paracetamol, thereby triggering hepatic necrosis [17A].

goiters that are not amenable to surgery. In 34 women who received four separate doses of 131I 800 MBq at 3-monthly intervals, the highest response of thyroid volume was observed after the first course of treatment; 24 months after the completion of treatment, 60% of the patients remained euthyroid and 40% were hypothyroid [20c].

Susceptibility factors There is impaired absorption of levothyroxine, due to reduced acid secretion, in patients with Helicobacter pylori gastritis, suggesting that screening for H. pylori in patients taking thyroxine replacement should be considered at the start of therapy [18M].

IODINE AND IODIDES [SED-15, 1896; SEDA-30, 490; SEDA-31, 688; SEDA-32, 764] Fetotoxicity Excess iodine ingestion can cause goiter and hypothyroidism. Congenital goiter and increased iodide uptake in a neonate is considered diagnostic of dyshormonogenesis, a permanent form of congenital hypothyroidism. Eight cases of congenital goiter, caused by ingestion of large amounts of iodine by mothers who took prenatal vitamin supplements, have been reported [19c]. The vitamin supplements were found to have errors in their formulation, resulting in 400 times the recommended dose of iodine. The presence of goiter was associated with biochemical hypothyroidism in three infants who required temporary thyroid hormone supplements. There was complete resolution of goiter in all babies within the first 30 days of life. The differentiation between excess maternal iodine intake and dyshormonogenesis is important and may prevent lifelong use of thyroxine supplements in babies with transient abnormalities.

Radioactive iodine Uses Radioiodine (131I) is widely used in the treatment of hyperthyroidism and thyroid cancer. It is also used to reduce thyroid volume in patients with large multinodular

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Endocrine Patients with moderate- or high-risk differentiated thyroid cancer undergo postsurgical 131I therapy for remnant ablation. In a comparison of 68 patients who received 131I in a dose of 1110 MBq and 115 patients who were given a dose of 3700 MBq there were similar ablation success rates, with a reduction in the frequency and severity of radiation thyroiditis in those treated with lower doses [21c]. Radiation-induced thyroiditis can also occur in patients who receive radioiodine for hyperthyroidism. In a retrospective review of 1333 patients with Graves’ disease who received an empirical fixed dose of 131I (185–370 MBq), insufficient doses of radioiodine resulted in early and paradoxical exacerbation of Graves’ disease in five patients. The clinical course of these patients was distinct from those with radiation-induced thyroiditis and all five required treatment with antithyroid drugs [22C]. Salivary glands A wide spectrum of salivary gland complaints, ranging from mild transient discomfort to permanent xerostomia and tooth decay, have been described after the administration of radioiodine. In a retrospective study of 262 patients who underwent remnant ablation with 131I there were significant salivary gland adverse reactions in 40%. In most cases the reactions were transient, and after a median follow-up of 7 years the incidence of persistent adverse reactions was only 5% [23C].

Drug–drug interactions Diuretics Diuretics are often used in patients who receive high doses of 131I, in an attempt to accelerate the

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elimination of unbound radioiodine, in order to reduce the risk of adverse reactions and to shorten the time spent in hospital. However, in a study of the use of lowdose furosemide (20 mg) in 23 patients 3 hours after 131I compared with 20 control patients, who received the same dose of 131 I, there was significantly reduced urinary excretion of radioiodine and higher blood concentrations in those who received furosemide, in contrast to expectations [24c]. The authors therefore did not recommend the use of furosemide as adjuvant to radioiodine.

ANTITHYROID DRUGS [SEDA-15, 3387; SEDA-30, 490; SEDA-31, 689; SEDA-32, 765] Uses The optimal treatment of Graves’ disease in children is controversial, although antithyroid drugs are usually favored initially. In 51 children induction of euthyroidism within 3 months of starting propylthiouracil treatment was an independent predictor of remission. Other factors that predicted cure included lower serum free T3 concentrations at presentation and older age [25c]. Cardiovascular The serum free thyroxine (fT4) concentration is associated with QT interval prolongation, which is a susceptibility factor for sudden cardiac death. Investigation of a prospective population-based cohort and a case–control study have shown a threefold increased risk of sudden cardiac death in patients taking antithyroid drugs. Although a direct link between the use of thionamides and sudden cardiac death cannot be ruled out, these findings could more readily be explained by underlying poorly controlled hyperthyroidism, since patients who died had low serum TSH concentrations before death [26C].

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Hematologic Drug-induced agranulocytosis is the most serious disorder associated with thionamide therapy; it can be life threatening, with a reported mortality of 5–15%. EIDOS classification: Extrinsic species: Thionamides Intrinsic species: White blood cells Distribution: Bone marrow Outcome: Not known Sequela: Agranulocytosis due to thionamides DoTS classification: Dose-relation: Collateral Time-course: Intermediate Susceptibility factors: Exogenous (other drugs that can cause agranulocytosis)

In a large multinational case–control study in Latin America there was a relatively low overall incidence of agranulocytosis (0.38 cases per million inhabitant-years). Patients who developed agranulocytosis more often took medications already associated with agranulocytosis than controls, mainly methimazole (OR ¼ 44; 95% CI ¼ 6.8, 1) [27C]. The development of aplastic anemia following treatment with thionamide drugs has been reviewed [28R]. At least 34 cases have been described previously in addition to two further reports of this condition in subjects undergoing treatment with methimazole or carbimazole. Patients usually developed symptoms suddenly after a relatively short time (50% of cases occurred within the first 15 weeks of therapy) and concomitant agranulocytosis was present in all patients. Most of the subjects recovered rapidly after withdrawal of the thionamide and supportive treatment with broad spectrum antibiotics, glucocorticoids, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), androgens, and intravenous immunoglobulin. Only two deaths related to thionamide-induced aplastic anemia have been reported.

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Chapter 41

Liver The association between propylthiouracil and hepatocellular inflammation is well described. During the past 20 years, there have been 33 published reports of severe propylthiouracil-related liver failure in adults and 14 in children, resulting in 16 liver transplants in adults and seven in children between 1990 and 2007. In addition propylthiouracilinduced liver injury has resulted in death both among adults and children [29r]. This has led to the recommendation that propylthiouracil should not be prescribed as a first-line agent in children or adults. The settings in which propylthiouracil is preferred before methimazole include the first trimester of pregnancy, life-threatening thyrotoxicosis or thyroid storm (because of inhibition of peripheral conversion of T4 to T3 by propylthiouracil), and if patients have had adverse reactions (other than agranulocytosis) to methimazole. Patients taking propylthiouracil should be counseled regarding the risk of liver failure, and liver function tests should be monitored in symptomatic patients [30r]. Methimazole can also cause liver damage, although this is typically characterized by cholestatic dysfunction [31A] and no cases of liver damage resulting in transplantation or death have been described.

thionamides is well described. In 92 patients with thionamide-induced vasculitis there was a variable time of onset (1–372, median 42, months) after the start of treatment [34c]. The median dose at onset was 15 (range 2.5–45) mg/day for methimazole and 200 (range 50–450) mg/day for propylthiouracil. The intensity and the number of organs involved did not correlate with the MPO-ANCA titer, indicating a need for vigilance even when the MPOANA titer is only weakly positive. There have been separate case reports of alveolar hemorrhage secondary to propylthiouracil-induced vasculitis [35A] and central nervous system vasculitis attributed to methimazole [36A]. Withdrawal of thionamides results in resolution of vasculitis in many cases, although immunosuppressive therapy may be indicated. In a study of the long-term outcomes in 15 patients with propylthiouracil-induced vasculitis who received immunosuppressive therapy for up to 12 months there was complete remission in 12 patients, partial remission in one, and progression to end-stage renal failure in two [37c].

Skin A 38-year-old man developed purpura fulminans on both breast areas and the abdomen after having taken propylthiouracil for 7 years; after withdrawal of propylthiouracil and administration of methylprednisolone he made a full recovery [32A]. Topical methimazole is used as a skin depigmenting agent for conditions that include epidermal melasma. In 20 patients who used this treatment once daily for 6 weeks there were no significant changes in circulating thyroid hormone or thyroidstimulating hormone (TSH) and no significant cutaneous adverse reactions [33c]. Immunologic Vasculitis associated with myeloperoxidase antineutrophil cytoplasmic antibodies (MPO-ANCA) caused by

885

Teratogenicity During pregnancy, propylthiouracil is considered the treatment of choice, especially during the first trimester. Methimazole has been associated with fetal abnormalities, including aplasia cutis and choanal atresia. In a controlled cohort study of 115 propylthiouracilexposed pregnancies and 1141 controls there were similar rates of major abnormalities in both groups (13% versus 3.2%). Hypothyroidism was found in 9.5% of fetuses/neonates and was associated with goiter in 57%. Goiters diagnosed prenatally by ultrasound were successfully treated in utero by maternal dosage adjustments. Median neonatal birth weight was lower in the propylthiouracil group compared with controls (3145 g versus 3300 g) [38c].

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References [1] Fast S, Nielsen VE, Bonnema SJ, Hegedus L. Time to reconsider nonsurgical therapy of benign non-toxic multinodular goitre: focus on recombinant human TSH augmented radioiodine therapy. Eur J Endocrinol 2009; 160(4): 517–28. [2] Fast S, Nielsen VE, Grupe P, Bonnema SJ, Hegedus L. Optimizing 131I uptake after rhTSH stimulation in patients with nontoxic multinodular goiter: evidence from a prospective, randomized, double-blind study. J Nucl Med 2009; 50(5): 732–7. [3] Chianelli M, Todino V, Graziano FM, Panunzi C, Pace D, Guglielmi R, Signore A, Papini E. Low-activity (2.0 GBq; 54 mCi) radioiodine post-surgical remnant ablation in thyroid cancer: comparison between hormone withdrawal and use of rhTSH in low-risk patients. Eur J Endocrinol 2009; 160(3): 431–6. [4] Rosario PW, Borges MA, Purisch S. Preparation with recombinant human thyroid-stimulating hormone for thyroid remnant ablation with 131I is associated with lowered radiotoxicity. J Nucl Med 2008; 49(11): 1776–82. [5] Fast S, Bonnema SJ, Hegedus L. The majority of Danish nontoxic goitre patients are ineligible for levothyroxine suppressive therapy. Clin Endocrinol (Oxf) 2008; 69 (4): 653–8. [6] Ribault V, Castanet M, Bertrand AM, Guibourdenche J, Vuillard E, Luton D, Polak M. French Fetal Goiter Study Group. Experience with intraamniotic thyroxine treatment in nonimmune fetal goitrous hypothyroidism in 12 cases. J Clin Endocrinol Metab 2009; 94(10): 3731–9. [7] Cooper-Kazaz R, Lerer B. Efficacy and safety of triiodothyronine supplementation in patients with major depressive disorder treated with specific serotonin reuptake inhibitors. Int J Neuropsychopharmacol 2008; 11(5): 685–99. [8] Kelly T, Lieberman DZ. The use of triiodothyronine as an augmentation agent in treatment-resistant bipolar II and bipolar disorder NOS. J Affect Disord 2009; 116 (3): 222–6.

[9] Kelly TF, Lieberman DZ. Long term augmentation with T3 in refractory major depression. J Affect Disord 2009; 115 (1–2): 230–3. [10] Cooper-Kazaz R, van der Deure WM, Medici M, Visser TJ, Alkelai A, Glaser B, Peeters RP, Lerer B. Preliminary evidence that a functional polymorphism in type 1 deiodinase is associated with enhanced potentiation of the antidepressant effect of sertraline by triiodothyronine. J Affect Disord 2009; 116(1–2): 113–6. [11] Cinemre H, Bilir C, Gokosmanoglu F, Bahcebasi T. Hematologic effects of levothyroxine in iron-deficient subclinical hypothyroid patients: a randomized, double-blind, controlled study. J Clin Endocrinol Metab 2009; 94(1): 151–6. [12] Eustatia-Rutten CF, Corssmit EP, Heemstra KA, Smit JW, Schoemaker RC, Romijn JA, Burggraaf J. Autonomic nervous system function in chronic exogenous subclinical thyrotoxicosis and the effect of restoring euthyroidism. J Clin Endocrinol Metab 2008; 93(7): 2835–41. [13] Shakir MK, Krook LS, Schraml FV, Hays JH, Clyde PW. Symptomatic hyponatremia in association with a low-iodine diet and levothyroxine withdrawal prior to I131 in patients with metastatic thyroid carcinoma. Thyroid 2008; 18(7): 787–92. [14] Bach-Huynh TG, Nayak B, Loh J, Soldin S, Jonklaas J. Timing of levothyroxine administration affects serum thyrotropin concentration. J Clin Endocrinol Metab 2009; 94 (10): 3905–12. [15] Hannon MJ, Behan LA, Agha A. Thyrotoxic periodic paralysis due to excessive L-thyroxine replacement in a Caucasian man. Ann Clin Biochem 2009; 46(Pt 5): 423–5. [16] Kondziella D, Brederlau A, Asztely F. Choreathetosis due to abuse of levothyroxine. J Neurol 2009; 256(12): 2106–8. [17] Weise AM, Liu CY, Shields AF. Fatal liver failure in a patient on acetaminophen treated with sunitinib malate and levothyroxine. Ann Pharmacother 2009; 43(4): 761–6.

Thyroid hormones, iodine, and antithyroid drugs [18] Lahner E, Annibale B, Delle FG. Systematic review: Helicobacter pylori infection and impaired drug absorption. Aliment Pharmacol Ther 2009; 29(4): 379–86. [19] Thomas JdeV, Collett-Solberg PF. Perinatal goiter with increased iodine uptake and hypothyroidism due to excess maternal iodine ingestion. Horm Res 2009; 72(6): 344–7. [20] Baczyk M, Pisarek M, Czepczy nski R, Ziemnicka K, Gryczy nska M, Pietz L, Sowi nski J. Therapy of large multinodular goitre using repeated doses of radioiodine. Nucl Med Commun 2009; 30(3): 226–31. [21] Cherk MH, Kalff V, Yap KS, Bailey M, Topliss D, Kelly MJ. Incidence of radiation thyroiditis and thyroid remnant ablation success rates following 1110 MBq (30 mCi) and 3700 MBq (100 mCi) postsurgical 131I ablation therapy for differentiated thyroid carcinoma. Clin Endocrinol (Oxf) 2008; 69(6): 957–62. [22] Lee SW, Lee J, Bae JH, Seo JH, Kang SM, Ahn BC, Lee I. Paradoxical exacerbation of preexisting Graves’ disease induced by insufficient radioiodine treatment: a report of five patients. Nucl Med Commun 2009; 30(4): 275–80. [23] Grewal RK, Larson SM, Pentlow CE, Pentlow KS, Gonen M, Qualey R, Natbony L, Tuttle RM. Salivary gland side effects commonly develop several weeks after initial radioactive iodine ablation. J Nucl Med 2009; 50(10): 1605–10. [24] Matovic MD, Jankovic SM, Jeremic M, Tasic Z, Vlajkovic M. Unexpected effect of furosemide on radioiodine urinary excretion in patients with differentiated thyroid carcinomas treated with iodine 131. Thyroid 2009; 19(8): 843–8. [25] Glaser NS, Styne DM. Predicting the likelihood of remission in children with Graves’ disease: a prospective, multicenter study. Pediatrics 2008; 121(3): e481–8. [26] van Noord C, Sturkenboom MC, Straus SM, Hofman A, Witteman JC, Stricker BH. Population-based studies of antithyroid drugs and sudden cardiac death. Br J Clin Pharmacol 2009; 68(3): 447–54. [27] Hamerschlak N, Maluf E, Biasi Cavalcanti A, Avezum Júnior A, ElufNeto J, Passeto Falcão R, Lorand-Metze IG,

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[30]

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[34]

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Goldenberg D, Leite Santana C, de Oliveira Werneck Rodrigues D, Nascimento da Motta Passos L, Oliveira de Miranda Coelho E, Tostes Pintão MC, Moraes de Souza H, Borbolla JR, Pasquini R. Incidence and risk factors for agranulocytosis in Latin American countries—the Latin Study: a multicenter study. Eur J Clin Pharmacol 2008; 64(9): 921–9. Thomas D, Moisidis A, Tsiakalos A, Alexandraki K, Syriou V, Kaltsas G. Antithyroid drug-induced aplastic anemia. Thyroid 2008; 18(10): 1043–8. Cooper DS, Rivkees SA. Putting propylthiouracil in perspective. J Clin Endocrinol Metab 2009; 94(6): 1881–2. Bahn RS, Burch HS, Cooper DS, Garber JR, Greenlee CM, Klein IL, Laurberg P, McDougall IR, Rivkees SA, Ross D, Sosa JA, Stan MN. The role of propylthiouracil in the management of Graves’ disease in adults: report of a meeting jointly sponsored by the American Thyroid Association and the Food and Drug Administration. Thyroid 2009; 19(7): 673–4. Gallelli L, Staltari O, Palleria C, De Sarro G, Ferraro M. Hepatotoxicity induced by methimazole in a previously healthy patient. Curr Drug Saf 2009; 4(3): 204–6. Akman A, Dicle O, Ciftcioglu MA, Alpsoy E. Unusual location of purpura fulminans associated with acquired protein C deficiency and administration of propylthiouracil. Clin Exp Dermatol 2009; 34(7): e463–4. Kasraee B, Safaee Ardekani GH, Parhizgar A, Handjani F, Omrani GR, Samani M, Nikbakhsh M, Tanideh N, Eshraghian A, Sorg O, Saurat JH. Safety of topical methimazole for the treatment of melasma. Transdermal absorption, the effect on thyroid function and cutaneous adverse effects. Skin Pharmacol Physiol 2008; 21(6): 300–5. Noh JY, Yasuda S, Sato S, Matsumoto M, Kunii Y, Noguchi Y, Mukasa K, Ito K, Ito K, Sugiyama O, Kobayashi H, Nihojima S, Okazaki M, Yokoyama S. Clinical characteristics of myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis caused by antithyroid drugs. J Clin Endocrinol Metab 2009; 94(8): 2806–11.

888 [35] El-Fakih R, Chehab BM, Shaver T. Thionamide-induced vasculitis: a case of alveolar haemorrhage secondary to propylthiouracil. J Intern Med 2008; 264(6): 610–2. [36] Tripodi PF, Ruggeri RM, Campenni A, Cucinotta M, Mirto A, Lo Gullo R, Baldari S, Trimarchi F, Cucinotta D, Russo GT. Central nervous system vasculitis after starting methimazole in a woman with Graves’ disease. Thyroid 2008; 18(9): 1011–3.

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[37] Gao Y, Chen M, Ye H, Yu F, Guo XH, Zhao MH. Long-term outcomes of patients with propylthiouracil-induced anti-neutrophil cytoplasmic auto-antibody-associated vasculitis. Rheumatology (Oxford) 2008; 47(10): 1515–20. [38] Rosenfeld H, Ornoy A, Shechtman S, DiavCitrin O. Pregnancy outcome, thyroid dysfunction and fetal goitre after in utero exposure to propylthiouracil: a controlled cohort study. Br J Clin Pharmacol 2009; 68(4): 609–17.

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Insulin, other hypoglycemic drugs, and glucagon

[SED-15, 1510; SEDA-31, 689; SEDA-32, 769]

GLUCAGON

Cardiovascular Transient branch hepatic artery vasospasm followed the intravenous administration of glucagon 1 mg on two separate occasions during visceral angiography in a 69-year-old man with a vasculitis [1A]. Gastrointestinal Glucagon affects the smooth muscle of the gastrointestinal tract. In 10 healthy volunteers, mean age 32 years, intravenous glucagon 1 mg resulted in paralysis of small bowel motility after about 13.4 seconds; motility returned after 18 minutes [2c].

[SED-15, 1761; SEDA-30, 494; SEDA-31, 689; SEDA-32, 769]

INSULIN

Metabolism Hypoglycemia When 97 patients mean age 53 years with severe brain injury were randomized to an insulin infusion when their blood glucose concentrations exceeded 12 mmol/l or to maintain blood glucose concentrations between 4.4 and 6.7 mmol/l, those who received more intensive insulin therapy not surprisingly Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00042-8 # 2011 Elsevier B.V. All rights reserved.

had more episodes of hypoglycemia (median 15 versus 7 per patient), however duration of stay in intensive care was shorter (7.7 versus 10 days). Mortality was similar in the two groups [3c]. In a study of critically ill patients in intensive care, mean age 60 years, 3054 were randomized to intensive blood glucose control (4.5–6 mmol/l) and 3050 to blood glucose concentrations of less than 10 mmol/l. Mortality at 90 days was higher in those who had been randomized to tight blood glucose control (28% versus 25%); severe hypoglycemia, defined as a blood glucose concentration less than 2.2 mmol/l, was also more common (6.8% versus 0.5%) [4C]. Patients admitted to hospital with acute myocardial infarction between 2000 and 2005 were identified from a database; those who had a blood glucose concentration on admission of less than 7.8 mmol/l were excluded [5C]. Of 7820 patients with a mean age of 72 years, 482 had hypoglycemia during admission, of whom 346 were treated with insulin. Mortality was higher in those who developed hypoglycemia but had not been treated with insulin. Thus, spontaneous hypoglycemia appeared to be a marker of increased mortality, but insulin did not appear to increase the risk of mortality. Intensive treatment of blood glucose concentrations in critically ill patients with insulin increases the risk of hypoglycemia and may increase mortality. In 175 children, mean age 13 years, who were randomized to insulin glargine (n ¼ 85) or an intermediate-acting insulin (n ¼ 90), with insulin lispro at meal times, 889

890

the adjusted event rate per patient year of blood glucose concentrations less than 3.9 mmol/l was 116 for those who used insulin glargine and 94 for those who used an intermediate-acting insulin [6c]. However, the patients who used insulin glargine and had a higher initial HbA1c concentration appeared to have greater reductions in HbA1c. Data from three studies of patients with type 2 diabetes, aged 30–80 years, in whom hypoglycemia was defined as a blood glucose less than 3.5 mmol/l, and all of whom were treated with metformin and insulin, showed that there was an inverse relation between the frequency of hypoglycemia and HbA1c concentration, whether insulin lispro mixtures or glargine was used [7M]. This reinforces the difficulty of trying to achieve tight blood glucose control with insulin.

Skin Lipodystrophy at the site of insulin injection is well documented, although the mechanism remains unknown, and cases continue to be reported [8A]. However, other effects can occur at the site of injection. • A 40-year-old man with insulin-dependent diabetes, who was using Humulin insulin, developed a lump on his upper arm at the site of his injections [9A]. It was thought to be a lipoma but histology suggested amyloid deposition.

The skin manifestations of continuous subcutaneous insulin infusion have been studied in 40 children aged under 6 years (mean age 2.3 years) compared with 38 children over 6 years (mean age 8.4 years) [10c]. Small scars of less than 3 mm were the most commonly reported events, and there were slightly fewer in the younger children: 20 (50%) compared with 27 (71%). Lipohypertrophy was also common at the insertion sites: 18 (45%) and 18 (47%) respectively. Erythema and blisters were less common, but occurred more often in those who had reported an allergic predisposition before starting subcutaneous

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infusion. Overall, young children did not have an increased risk of skin problems. Immunologic Insulin allergy is rare but as insulin is often an essential therapy it can cause major clinical problems. Sometimes a change to a less immunogenic insulin is helpful, and if not continuous subcutaneous insulin infusion has been tried [11R]. In one case desensitization was successful [12A]. • A 68-year-old man with type 2 diabetes treated with insulin and oral hypoglycemic agents developed pruritic plaques of more than 15 cm diameter at the site of his insulin injections. Skin biopsy showed an Arthus type reaction. Various insulin therapies, including insulin glargine, insulin detemir, and human insulin, produced the same response. Intradermal tests were positive to a variety of insulins and protamine. He was desensitized using subcutaneous human insulin and orally fexofenadine 180 mg bd and was then successfully treated with insulin glargine. The fexofenadine was stopped 6 months later.

Drug overdose The duration of action of insulin glargine is dose related, and this should be remembered when treating patients who have taken a massive overdose [13A]. • A 31-year-old woman deliberately injected insulin glargine 1000 units subcutaneously. Her blood glucose concentration was 2.4 mmol/l and she was treated with oral feeding and continuous intravenous dextrose. The last documented hypoglycemic episode on trying to withdraw dextrose occurred 106 hours after the overdose. Intravenous dextrose was stopped at 130 hours.

Is there an increased risk of cancer in patients using insulin? In 127 031 patients without known malignancies, mean age 68 years, who had received human insulin exclusively or only one type of analogue insulin (lispro, aspart, or glargine), who were identified from the German health insurance fund and followed for a mean of 1.6 years, the insulin dose was

Insulin, other hypoglycemic drugs, and glucagon

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positively associated with the risk of malignancy [14C]. This risk was higher with insulin glargine than human insulin, but not higher among those who used insulin lispro or insulin aspart. The hazard ratios for insulin glargine compared with human insulin were 1.19 with 10 units/day of glargine and 1.31 with 50 units/day. Although the methods of analysis in this study were thought to have been inappropriate, the results raised a question that resulted in further investigation [15r]. In Sweden malignancies that occurred between 1 January 2006 and 31 December 2007 were recorded in 114 841 people who had had a prescription for insulin between 1 July and 31 December 2005 [16C]. Women who had used only insulin glargine had an increased risk of breast cancer, with an incidence ratio of 1.9 compared with those who used other insulins. Those who used insulin glargine in combination with other insulins did not have an increased risk. In an analysis of the pharmacovigilance database of the manufacturer, Sanofi Aventis, 5657 patients using insulin glargine were compared with 5223 patients who had used other therapies [17R]. The data included patients with type 1 and type 2 diabetes. There were no differences in the rates of malignancy, with 52 events in those using glargine compared with 48 controls. The most common cancers were skin, colorectal, and breast. Most of the trials that formed the basis of this analysis were for 6 months, although one was for 5 years. In a similar study, 3983 patients who used insulin detemir were compared with 2661 who used NPH insulin, and 1219 who used insulin detemir were compared with 830 who used insulin glargine [18M]. The patients had type 1 and type 2 diabetes and the mean age was 50 years. The exposure in weeks was 0.1–114. There was no difference in cancer rates between those who used insulin detemir (n ¼ 8; 0.87 per 100 exposure years) and those who used insulin glargine (n ¼ 8; 1.27 per 100 exposure years). In a 5-year study of 1017 patients randomized to insulin glargine or NPH insulin, there were 57 neoplasms in those who used insulin glargine (11%) compared with 62

(12%) in those who used NPH insulin [19c]. The numbers of patients with breast cancer was small (three of those who used insulin glargine compared with five of those who used NPH) and did not suggest an excess risk. These studies have mostly been too short to be conclusive. The current data are difficult to interpret, because the risks of cancer are complex and include increasing age and obesity, which are common features of type 2 diabetes, along with many other confounding factors. The possibility that insulin is associated with a risk of cancer requires longer exposure data to be collected to provide useful information.

891

Pregnancy In a retrospective cohort study of 112 women with both pregestational diabetes (n ¼ 53) and gestational diabetes (n ¼ 59) pregnancy outcomes were reported in relation to the use of NPH insulin and insulin glargine [20c]. Women with pregestational diabetes were significantly more likely to have used insulin glargine (37 compared with 16). Insulin glargine did not increase the risk of, pre-eclampsia, maternal hypoglycemia, maternal weight gain, or cesarean delivery. Neonatal outcomes were also similar. Of the women with pregestational diabetes, those who had used insulin glargine had fewer large-for-dates babies (19% versus 50%). This is reassuring, as insulin glargine has a high affinity for insulin-like growth factor receptors [21E]. In a similar study, 114 women, 67 of whom used insulin glargine, of whom 47 had pregestational diabetes, were compared with 49 patients who used NPH insulin, of whom 37 had pregestational diabetes. The outcomes were similar in the two groups, with the exception of shoulder dystocia, which was more frequent in those who used NPH (8.2% compared with 0%) [22c]. Prospective safety data with long-term follow-up are required to confirm the safety of insulin glargine in pregnancy. Drug administration route Continuous subcutaneous insulin infusion (CSII) There are limited data about the use of

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CSII in patients with type 2 diabetes. In a meta-analysis of the use of CSII in patients with type 2 diabetes hypoglycemia, including severe hypoglycemia, was as common as with multiple injection insulin therapy [23M]. Another similar analysis showed similar outcomes in patients using CSII compared with multiple daily injections [24R]. In a retrospective study in which data were collected from 16 European countries and Israel, of 1098 patients with type 1 diabetes, mean age 12 years, who were treated with CSII for a mean of 2 years, 18 had a single episode of severe hypoglycemia (6.6 events per 100 patient-years) [25C]. The event rate for diabetic ketoacidosis was 6.2 events per 100 years. There was no comparison group. It has been suggested that in adults CSII can help improve HbA1c slightly, but the impact on hypoglycemia compared with multiple injections of analogue insulin is not clear [24R]. Skin infections at the infusion site vary from 0.06 to 12 events per patient per year and are a major reason for discontinuing pump therapy [11R]. Pump failure continues to be a problem. Of 640 consecutive new pumps used from 2001 to 2007 by 252 adults with type 1 diabetes, 232 broke down after 0.1–64 months; 103 had complete failure and were immediately unusable [26c]. There was hyperglycemia in 40 patients, with ketones in 10; none required admission to hospital. Pump failure is frequent and it is important that patients know what to do when it occurs. Inhaled insulin AIRÒ insulin given preprandially as an inhalation has been studied in 208 patients with type 2 diabetes and compared with 203 patients receiving preprandial injections of insulin [27c]. The study was stopped early owing to the withdrawal of AIR insulin. The mean age was 56 years, and just over 50% of patients were men. FEV1 fell compared with baseline in those who received AIR insulin. This change was observed at 1 month and persisted, but did not decline further. Forced vital capacity (FVC) was also lower. There was no change in lung diffusion capacity. Cough was the most frequently reported

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adverse effect (20% of those using AIR compared with 10% injecting insulin). In all, 175 patients completed 6 months of AIR, 141 patients completed 12 months, and only one patient completed the planned 2 years. In a similar study, which was also stopped, in patients with type 1 diabetes, 82 of 193 patients who used prandial AIR insulin and 84 of 192 who used injections completed the 2-year study [28c]. The mean age was 39 years. AIR insulin was associated with significantly greater reductions in diffusion capacity, but not FVC. Hypoglycemia was the most frequent significant adverse event in those using AIR and injected insulin, and it occurred at a similar frequency (5.3 events per patient per 30 days). Intranasal insulin Intranasal insulin has been studied in 25 patients with Alzheimer's disease; 12 received placebo and 13 received Novolin R 20 units using a Vianase Electronic Atomizer [29c]. Fasting glucose and insulin concentrations did not change, but there was a reduction in postprandial insulin concentrations in those who used insulin. At 21 days those who used insulin appeared to have improved attention compared with controls. In six children with 22q13 deletion syndrome, Actrapid insulin given intranasally via an Aero pump was gradually titrated to 0.5–1.5 units/kg/day in three divided doses [30c]. Blood glucose concentrations did not change. One patient had intermittent nose bleeds. The children were assessed after 6 weeks and 12 months of treatment and were thought to have had improved cognitive function. There was no control group. Drug–drug interactions The manufacturer of insulin glargine does not recommend mixing it with rapid-acting insulin analogues. In 19 children with type 1 diabetes, mean age 11 years, who used insulin glargine mixed with a rapid-acting analogue and who were compared with 17 children who used NPH insulin mixed with a rapidacting analogue for 3 months, those who

Insulin, other hypoglycemic drugs, and glucagon

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used insulin glargine had better blood glucose control [31c].

pramlintide in adolescents are similar to those found in adults.

ALPHA-GLUCOSIDASE INHIBITORS [SED-15, 85; SEDA30, 496; SEDA-31, 691; SEDA-32, 772]

Acarbose Metabolism German guidelines have reminded us that if acarbose is combined with insulin in the treatment of diabetes, hypoglycemia must be treated with glucose and not with oligosaccharides [32S]. Skin Acute generalized exanthematous pustulosis has been attributed to acarbose in a 38-year-old woman, using the EuroSCAR Study Group criteria [33A].

AMYLIN ANALOGUES [SEDA-30, 496; SEDA-31, 692; SEDA-32, 773]

Pramlintide Metabolism In 10 people, aged 13–17 years, who were randomized unblinded to pramlintide in addition to insulin or to continue taking their usual insulin, the initial dose of pramlintide was 15 micrograms/day subcutaneously, titrated to 30 micrograms/day after 4 days [34c]. At 4 weeks those who used pramlintide had reduced weight by 0.8 kg compared with a gain of 0.9 kg in those who used insulin alone, although this was not statistically significant. The dose of insulin fell in those who used pramlintide, without an increase in blood glucose concentrations. Susceptibility factors Age The use of pramlintide in adolescents with type 1 diabetes has been evaluated in small studies. The results suggest that the effects of

893

[SED-15, 506; SEDA-30, 497; SEDA-31, 692; SEDA-32, 773]

BIGUANIDES

Metformin Acid–base balance In 42 patients with metformin-associated lactic acidosis between 1998 and 2007, who were identified from a database, all of whom had type 2 diabetes, 13 had taken an intentional overdose and all survived; 29 developed lactic acidosis in association with circulatory or respiratory failure, of whom 14 died [35c]. A predictive factor for death was prothrombin time at the time of admission. The difference in mortality rates was highly significant. Metformin increases lactate by stimulating anerobic glucose metabolism, even in the presence of adequate oxygen. In overdose large amounts of lactate are produced. Blood concentrations of metformin correlated with pH but the concentrations of lactate in these circumstances do not appear to correlate with mortality. Patients treated with metformin with other significant illnesses need early recognition of the possibility of lactic acidosis and intensive treatment. The outcome is often poor. In a similar retrospective study over 5 years, 30 patients with metformin-associated lactic acidosis were admitted to intensive care; three had taken an overdose; 21 survived [36c]. Prothrombin time was also related to survival, which may imply that liver function is particularly important. Not all patients received hemodialysis, but there was no difference in survival between those who did and did not. Of 21 patients with lactic acidosis between 2001 and 2005, 13 were taking metformin; 18 had acute gastrointestinal problems and three had congestive heart failure [37c]. None of the patients stopped taking metformin, despite having had several days of illness before

894

admission; four patients died within hours, despite intensive medical therapy. Two case reports have demonstrated the importance of withdrawing metformin at the time of anesthesia and ensuring that the patient is well before restarting. • A 64-year-old woman with mild chronic renal impairment who was taking metformin 3 g/day, allopurinol 300 mg/day, verapamil 120 mg/day, irbesartan 300 mg/day, and furosemide 25 mg/ day, developed nausea, vomiting, and abdominal pain 6 days after a surgical procedure [38A]. The serum creatinine concentration had risen to 500 mmol/l, and the pH was 7.16 with a serum bicarbonate of 11 mmol/l. She was treated with sustained low-efficiency daily dialysis (SLEDD) with GENIUSÒ. Acid–base balance returned to normal after three treatments. • A 49-year-old woman who was taking metformin, losartan, bendroflumethiazide, and atenolol, developed diarrhea and vomiting after general anesthesia for a minor procedure [39A]. Her symptoms continued for 5 days and worsened with the development of dyspnea. Her pH was less than 6.8 and the serum creatinine concentration was 769 mmol/l. She was treated with continuous hemofiltration for 4 days and made a good recovery.

Patients taking metformin should be reminded to discontinue therapy when they have another illness and to seek medical help [40R]. Hematologic Metformin-induced hemolytic anemia is rare and generally not fatal; the time to onset of symptoms after starting metformin is about 10 days. A fatal case has been reported [41A]. • A 56-year-old man with type 2 diabetes and a hemoglobin of 14.7 g/dl took metformin 500 mg bd for 4 days, in addition to pantoprazole, levothyroxine, and glibenclamide. The day after starting metformin he developed palpitation and labored breathing and discontinued the therapy. On the next day he was given ciprofloxacin for hematuria. Two days later his hemoglobin had fallen to 6.6 g/dl. There was severe hemolysis and a direct antiglobulin test was positive for anti-IgG. Despite intensive treatment the hemoglobin fell to 3.3 g/dl and the patient died 12 hours later.

It was thought that metformin may have been the cause of the hemolytic

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anemia, although ciprofloxacin was also a possibility. Susceptibility factors Genetic An epidemiological study has suggested that genetic susceptibility may alter the effectiveness of metformin. Polymorphisms in MATE1 may be important in the pharmacokinetics of metformin. Impairment of the MATE1 transporter leads to increased metformin plasma concentrations, owing to reduced efflux of metformin at the renal brush border. In 116 people with type 2 diabetes using metformin, the SNP rs2289669 in the SLC47A1 gene that encodes the MATE1 transporter was associated with a 0.3% reduction in HbA1c for each copy of the A allele [42c]. Drug overdose There have been two further reports of self-poisoning with metformin, both associated with acidosis. • A 30-year-old woman took 85 g of metformin about 6 hours before admission to hospital. Her pH was 6.88 and bicarbonate 7.3 mmol/l; she was hemodialysed with bicarbonate and plasma exchange and made a complete recovery [43A]. • A 28-year-old pregnant woman took 40 g of metformin at 24 weeks of pregnancy [44A]. Her pH was 7.07. She was treated with intravenous 0.9% saline and sodium bicarbonate and activated charcoal via nasogastric tube. After 10 hours of treatment her pH was 7.3. A healthy baby was delivered 8 weeks later and had no significant health problems after 2 years.

DIPEPTIDYL PEPTIDASE 4 (DDP-4) INHIBITORS [SEDA30, 498; SEDA-31, 693; SEDA-32, 774] The DDP-4 inhibitors are chemically variable and their metabolic pathways are different. Sitagliptin, (2R)-4-oxo-4[3-(trifluoromethyl)-5,6-dihydrol[1,2,4]triazolol[4, 3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine, is primarily eliminated unchanged, 80% being excreted in the

Insulin, other hypoglycemic drugs, and glucagon

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urine. Vildagliptin, 1-[[(3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrolidine, is largely metabolized by the kidney, and only 23% is found unchanged in the urine. Saxagliptin is metabolized by CYP isoenzymes, and its metabolite is half as potent [45S]. In reviews of trials of sitagliptin and vildagliptin there were no cases of significant hypoglycemia. Nasopharyngitis, upper respiratory tract infections, urinary tract infections [46R], and headache [47R] were the most commonly reported adverse reactions. Studies of saxagliptin and vildagliptin have taken place in patients without significant heart failure and so there are no safety data in this patient group.

saxagliptin with pioglitazone or rosiglitazone, 565 patients with a mean age of 54 years were randomized [50C]. Peripheral edema was more common in those taking saxagliptin 5 mg/day than with 2.5 mg/day or placebo (8%, 3%, and 4% respectively).

Alogliptin Skin In a 26-week randomized placebocontrolled study in 527 patients, mean age 55 years, with type 2 diabetes taking metformin, alogliptin 12.5 or 25 mg/day was associated with skin-related adverse events in 7.7% of those taking placebo compared with 12% in both alogliptin groups. Dry skin, pruritus, rashes, and eczema were reported; one patient stopped taking alogliptin because of an eruption [48C].

Saxagliptin Fluid balance In a study of 768 patients, mean age 55 years, with type 2 diabetes taking glibenclamide, who were randomized to additional saxagliptin or 5 mg/day or placebo for 24 weeks, patients were excluded if they had had a cardiovascular event in the preceding 6 months or a diagnosis of congestive heart failure, significant renal or liver disease, or had taken potent CYP3A4 inhibitors or inducers. There were two cases of localized edema, one in a patient taking saxagliptin 2.5 mg/day and one taking 5 mg/day; both continued therapy [49C]. In a similar study combining

895

Sitagliptin Immunologic Serious hypersensitivity reactions, including anaphylaxis and angioedema, have occurred in patients taking sitagliptin [51A]. These are individual case reports and the frequency is unknown.

Vildagliptin Ear, nose, and throat A 52-week study was extended for a further 52 weeks with a double-blind extension for those who agreed to continue; 569 people completed the initial study and 402 completed the extension [52c]. The patients had type 2 diabetes and had not taken drug therapy before the study. In 304 predominantly Caucasian patients, mean age 54 years and BMI 33, who took vildagliptin 100 mg/day, the most common adverse reaction was nasopharyngitis (16%). Upper respiratory tract infections occurred in 10%. Headache was reported in 13%. Metabolism A confirmed case of hypoglycemia was reported in one of 304 patients who took vildagliptin for 2 years; it was of moderate intensity and was precipitated by strenuous exercise [52c]. Liver Rare case reports of liver abnormalities have been reported in patients taking vildagliptin; liver function returns to normal on withdrawal; it is recommended that liver function be checked before starting therapy and 3-monthly during the first year [53S].

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896

[SEDA30, 49; SEDA-31, 695; SEDA-32, 775]

INCRETIN MIMETICS

Gastrointestinal The most frequent adverse reactions reported with incretin mimetics are gastrointestinal symptoms. These include nausea, vomiting, and diarrhea, which occur in 10–15% of patients, are dose-related, and tend to abate during the first few weeks of treatment [54R]. EIDOS classification: Extrinsic species Incretin mimetics Intrinsic species Not known Distribution ?Stomach, ?brain Outcome Altered function Sequela Nausea and vomiting due to incretin mimetics DoTS classification: Dose-relation Collateral Time-course Intermediate Susceptibility factors None known In a systematic review of 17 controlled trials of subjects with poorly controlled diabetes nausea was the most common adverse event in placebo-controlled trials. The rates of hypoglycemia were similar in comparisons of exenatide and insulin, but were more common with exenatide 10 micrograms bd than with placebo; hypoglycemia occurred predominantly when a sulfonylurea was co-administered with exenatide [55M].

Exenatide Pancreas Acute pancreatitis has been attributed to exenatide in a woman with type 2 diabetes [56A]. Urinary tract It has been suggested, on the basis of a single case, that exenatide may cause further impaired renal function in patients with type 2 diabetes and pre-existing mild to moderate renal impairment [57A].

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• A 66-year-old man with type 2 diabetes, who was already using insulin, was given exenatide 5 micrograms bd, and in the next 4 weeks his serum creatinine rose 192 to 244 mmol/l, with a reduction in Cockcroft–Gault calculated creatinine clearance from 53 to 42 ml/minute. There was no evidence of urinary tract infection, obstruction, or dehydration. Exenatide was withdrawn, and within the next 2 weeks his renal function returned to pretreatment values (creatinine 196 mmol/l, creatinine clearance 52 ml/minute).

In four patients with type 2 diabetes (three men and one woman; ages 52–73 years), who were taking stable doses of ACE inhibitors and diuretics, exenatide was associated with renal impairment [58c]. The time between starting exenatide and the diagnosis of renal failure was 2–9 months, and the drug was withdrawn within 3 months after diagnosis except in one patient, whose symptoms improved after dosage reduction. In three cases recovery of renal function was incomplete after drug withdrawal or dosage reduction. The authors proposed that exenatide could contribute to extracellular volume contraction by causing nausea, vomiting, or reduced fluid intake, which, in combination with diuretics and ACE inhibitors, could lead to impaired renal function. They also pointed out that glucagon-like peptide causes a natriuresis, which could reduce renal perfusion, an effect that could be shared by incretin mimetics.

Liraglutide Liraglutide is a GLP-1 analogue, administered subcutaneously once a day as an isotonic solution. It has a substitution of lysine to arginine at position 34 and attachment of a C16 fatty acid at position 26. The tmax and half-life are both about 12 hours. Steady state occurs at about 4 days [59R, 60R]. Pancreas In the LEAD (Liraglutide Effect and Action in Diabetes) studies, nine cases of pancreatitis were reported, eight of which were in those taking liraglutide. The rates were: 2.2, 0.0, 0.9, and 0.6 events per 1000

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subject-years of exposure for total liraglutide, placebo, active comparator, and total comparator respectively. Patients who take exenatide are warned of the risk of pancreatitis similar warnings are required for liraglutide [61R] [59R].

no consistent trend. The half-life varied from 11 hours in those with end-stage renal failure to 14 hours in healthy subjects.

Immunologic It has been reported that antibodies to liraglutide do not develop [46R]. However, in the LEAD-5 study, which was a 26-week study of 581 patients with type 2 diabetes, mean age 57 years, in which patients were randomized to liraglutide 1.8 mg/day, placebo, or insulin glargine, antibodies were present in 9.8% [62C]. However, the antibodies did not appear to impair the blood glucose-lowering effect of liraglutide. Tumorigenicity Rodents who are given liraglutide have an increased risk of thyroid C-cell tumors and increased concentrations of calcitonin [63E]. In the LEAD-6 study, which was an open comparison of liraglutide (n ¼ 233) and exenatide (n ¼ 231), in patients with type 2 diabetes, mean age 56 years for 26 weeks, calcitonin concentrations fell slightly in both groups [64C]. Calcitonin screening is not thought to be necessary. Papillary thyroid cancer has been reported to occur at a rate of 1.6% per 1000 patient-years of exposure in patients who use liraglutide, compared with 0.6% in those who use exenatide. Longerterm data are required to determine the importance of these findings [65r]. Susceptibility factors Renal disease Of 30 subjects, aged 31–82 years, three with type 2 diabetes, who received a single subcutaneous dose of liraglutide 0.75 mg, six had normal renal function, six mild renal impairment (creatinine clearance 50–80 ml/ minute), seven moderate renal impairment (creatinine clearance 30–50 ml/minute), five severe renal impairment (creatinine clearance less than 30 ml/minute), and six endstage renal failure treated with CAPD [66c]. Concentration profiles were similar in all groups. Cmax varied from 7.9 nmol/l in those with mild renal impairment to 10.5 in those with end-stage renal failure, but there was

897

MEGLITINIDES [SED-15, 2238; SEDA-31, 695; SEDA-32, 776] Metabolism The use of meglitinides has been evaluated in China in patients with type 2 diabetes, 433 of whom used nateglinide and 436 repaglinide, mean age 55 years and BMI 25 kg/m2. There was no statistically difference in the rates of adverse events, but the risk of an event was 0.59 times higher in those who took nateglinide; the most common adverse event was hypoglycemia [67R]. The incidence of episodes of hypoglycemia and the patterns of their occurrence during the first 9 months of treatment with four oral hypoglycemic drugs, rosiglitazone, pioglitazone, nateglinide, and repaglinide, have been studied in a prescription-event monitoring (PEM) study in 14 373, 12 768, 4549, and 5727 patients respectively, of whom 276 had at least one episode of hypoglycemia [68C]. The incidence rate was 50–100% higher in patients taking meglitinides compared with those taking thiazolidinediones (9.94, 9.64, 15.7, and 20.3 per 1000 patient-years for rosiglitazone, pioglitazone, nateglinide, and repaglinide respectively). The person-time in days was 999 060 for nateglinide and 1 275 333 for repaglinide. Hypoglycemia occurred more often soon after starting treatment, and the risk fell with time.

Repaglinide Metabolism Hypoglycemia has again been reported [69A]. • An 82-year-old man developed dizziness and confusion due to hypoglycemia and was given one ampoule (quantity not specified) of 50% intravenous dextrose. His symptoms resolved. Laboratory tests showed high concentrations

Chapter 42

898 of C-peptide and insulin and he was therefore given 75 micrograms of octreotide subcutaneously and remained well over the next 6 hours.

Octreotide is useful in the management of prolonged hypoglycemia due to sulfonylureas. Repaglinide has a short half-life and there was no suggestion of overdose in this case. Whether the octreotide added to the management is uncertain. Drug–drug interactions Gemfibrozil Gemfibrozil increases the blood glucose-lowering effect of repaglinide. The timing of the last dose of gemfibrozil has been studied in 10 healthy volunteers who took repaglinide 0.25 mg without gemfibrozil and then again 0, 3, 6, or 12 hours after gemfibrozil 600 mg [70c]. The AUC was increased for all doses taken with or after gemfibrozil, gradually falling from a sevenfold increase when taken simultaneously to a fivefold increase when taken 12 hours after. Thus, taking tablets at different times of day does not alter the effect of gemfibrozil on the pharmacokinetics of repaglinide.

SODIUM GLUCOSE TRANSPORTER TYPE 2 (SGLT2) INHIBITORS SGLT2 inhibitors block the transport of glucose into the renal tubule. Sergliflozin etabonate [71E, 72R, 73M] and dapagliflozin [74R, 75R] are two such drugs under development.

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cancer, of which gastrointestinal cancer was most common (n ¼ 48). When cases were compared with controls identified from the same cohort, there appeared to be an increased risk of cancer in those receiving glibenclamide. The odds ratio for those who had used glibenclamide for at least 36 months was 2.62. This was not found for gliclazide, which had an odds ratio of 0.4. This study was small and the data were partly selfreported, so further studies are warranted.

Glibenclamide Pregnancy When 99 women with gestational diabetes were randomized to either insulin or glibenclamide (n ¼ 49) for blood glucose control, 82 of their neonates, 41 in each group, were examined for adiposity using measures such as skin-fold thickness and BMI [77c]. There were no differences between the groups. However, 22% of babies whose mothers took glibenclamide had macrosomia, defined as a birth weight above 4 kg, compared with 2% of those who used insulin.

Gliclazide Drug overdose In a case of overdose with gliclazide there was severe hypoglycemia without adrenergic or autonomic responses [78A].

Glimepiride [SED-15, 3230; SEDA-30, 500; SEDA-31, 695; SEDA-32, 777]

SULFONYLUREAS

Tumorigenesis In a case–control study of the tumorigenic effect of sulfonylureas, 1919 people with type 2 diabetes, mean age 64 years, 1092 men, were followed for 6.5 years [76C]. There were 195 cases of

Respiratory Asthma has been attributed to glimepiride in a 40-year-old woman with type 2 diabetes but no allergies or history of asthma [79A]. It occurred 2 hours after the first dose. A subsequent drug-induced lymphocyte stimulating test against glimepiride was positive, and tests against pioglitazone, gliclazide, and glibenclamide were negative.

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THIAZOLIDINEDIONES (GLITAZONES) [SED-15, 3380;

records at the Cleveland Clinic between 1998 and 2006; 1079 had used rosiglitazone monotherapy and 1508 pioglitazone [84C]. There was no difference in the risk of coronary artery disease or mortality. Studies of adipocytes have suggested that there is only 40% concordance between pioglitazone and rosiglitazone in gene expression; 23 genes are commonly regulated, with 12 additional genes only regulated by pioglitazone and five only regulated by rosiglitazone. These differences may explain some of the variation in clinical outcomes in studies [85R, 86R]. Heart failure in those taking thiazolidinediones has been explained by fluid retention in susceptible individuals; PPAR-g receptors are present in the distal renal tubule collecting ducts [87R].

SEDA-30, 501; SEDA-31, 697; SEDA32, 779] Cardiovascular Previous reports have suggested that pioglitazone may have better cardiovascular safety than rosiglitazone [SEDA-31, 697; SEDA-32, 779]. Further studies have supported this finding [80R]. Out-patients (n ¼ 39 736) aged 66 years or older who had used either pioglitazone or rosiglitazone were identified from the Ontario Public Drug Benefit Program prescription records [81C]. Those who had taken pioglitazone had a lower risk of death or hospital admission for either acute myocardial infarction or heart failure compared with rosiglitazone, with an adjusted hazard ratio of 0.8. Further analysis showed that this was due to a reduction in death (adjusted hazard ratio ¼ 0.86) and heart failure (0.77). There was no difference in the risk of acute myocardial infarction (0.95). In a population-based retrospective cohort study, which used data from the National Health Insurance database in Taiwan in 473 483 patients who had newly diagnosed type 2 diabetes and who had taken oral antihyperglycemic agents at least three times from 2001 to 2005, those who had received rosiglitazone alone (n ¼ 2093) had a higher risk of any cardiovascular event than those who had received pioglitazone alone (n ¼ 495): 13% (n ¼ 266) compared with 8.9% (n ¼ 44) [82C]. However, the differences between the drugs when they were used as additional therapy were not significant. In a case–control study of 9870 cases and 29 610 controls, mean age 63 years, there was difference in the risk of myocardial infarction in those taking pioglitazone compared with rosiglitazone [83C]. Data were obtained from the Integrated Healthcare Information Services claims database. Cases were defined as people with a diagnosis of myocardial infarction at least 3 months after developing diabetes. In a further similar study, patients with type 2 diabetes were identified from electronic

899

Sensory systems Vision An increased risk of macular edema is a recognized adverse reaction to thiazolidinediones. Using data obtained from a US Kaiser Permanente diabetes database 996 new cases of macular edema were recorded in 2006 in 59 013 patients with diabetes [88c]. Those who took a thiazolidinedione (98% pioglitazone) and or insulin were at an increased risk of macular edema compared with patients who took other oral agents. Odds ratios were 1.6 for thiazolidinediones and 2.8 for insulin, compared with odds ratios of 0.8 for sulfonylureas and 0.9 for metformin. Musculoskeletal Reduced bone density and risk of fracture EIDOS classification: Extrinsic species Thiazolidinediones Intrinsic species Osteoclasts Distribution Bone Outcome Atrophy Sequela Reduced bone density and increased risk of fractures due to thiazolidinediones DoTS classification: Dose-relation Collateral Time-course Late

900

Susceptibility factors Age (elderly patients); sex (female sex, postmenopausal) Data from a prospective cohort study of 84 339 patients in Canada, mean age 59 years, 43% women, have confirmed the increased risk among women of peripheral fractures when taking thiazolidinediones; the NNTH for one additional peripheral fracture in patients taking a thiazolidinedione for 3 years was 86 [89c]. The data also suggested an increased risk in men using pioglitazone compared with sulfonylureas.

Pioglitazone Observational studies In a general practice study in England using prescription-event monitoring, 34 151 patients were given pioglitazone between November 2000 and June 2001. Useful data were available for 12 772 patients (53% male, median age 62 years); 3690 discontinued treatment, most commonly because of hyperglycemia (n ¼ 1143) and lack of hypoglycemic effect (n ¼ 831). Other reasons included edema (n ¼ 121) and weight gain (n ¼ 118) [90C]. The most common adverse events were malaise and lassitude (0.23%; n ¼ 30), nausea and vomiting (0.22%; n ¼ 28), and dizziness (0.17%; n ¼ 22). Systematic reviews In a meta-analysis of five randomized, controlled trials in 9965 patients taking pioglitazone, in which data on myocardial infarction were available, the relative risk of myocardial infarction was 0.86 (95% CI ¼ 0.69, 1.07) [91M]. The relative risks for stroke and revascularization were 0.79 (0.61, 1.02) and 0.40 (0.13, 1.23) respectively. The authors concluded that pioglitazone does not increase the risk of myocardial infarction. Cardiovascular In 518 patients with type 2 diabetes and New York Heart Association functional heart failure class II/III, mean

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age 64 years, who were randomized to pioglitazone 30 mg/day (n ¼ 262) or glibenclamide 10 mg/day (n ¼ 256) for 6 months, those who took pioglitazone had a higher incidence of heart failure; 30 required hospitalization or acute attendance at hospital compared with 15 taking glibenclamide, but there was no difference in death rates [92C]. Metabolism Weight gain is a well-recognized adverse effect of pioglitazone therapy. In 31 Japanese patients with type 2 diabetes who took pioglitazone 15 mg/day for 3 months, increasing to 30 mg/day for a further 9 months, 14 of whom also took the alpha-glucosidase inhibitor voglibose 0.9 mg/day, those who took voglibose gained 0.1 kg compared with 2.5 kg in the control group [93c]. Voglibose is an alphaglucosidase inhibitor. It is unclear why there should be less weight gain in those taking pioglitazone and voglibose. Liver Patients aged 18–80 years (mean 54 years) with type 2 diabetes were randomized to either pioglitazone 15–45 mg/ day (n ¼ 1063) or glibenclamide 5–15 mg/ day (n ¼ 1057). Liver enzymes were measured every 2 months in the first year of the study and then every 3 months for the remaining 2 years [94C]. Only 411 and 413 patients completed the study in the two groups. Those who took pioglitazone had fewer hepatobiliary events (n ¼ 15; 1.4%) compared with those taking glibenclamide (n ¼ 26; 2.5%). Two patients stopped taking pioglitazone because of abnormal liver function compared with eight taking glibenclamide. Statin therapy was used by about 33% of the patients. These results suggest that pioglitazone does not cause more problems with liver function than glibenclamide and can be safely used in conjunction with statins. However, the withdrawal rate was high. In the PROactive study of patients with type 2 diabetes and pre-existing cardiovascular disease, the frequency of serious liver disorders was similar in those taking pioglitazone (n ¼ 4 of 2605) compared with those taking placebo (n ¼ 5 of 2633) [95C].

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Urinary tract In 10 patients with type 2 diabetes treated with hemodialysis, mean age 67 years, who were taking pioglitazone 15 mg/day, which was increased after 4 weeks to 30 mg/day for a further 8 weeks, there were no significant adverse reactions [96c].

death (136 compared with 157). However, the risk of heart failure doubled (HR ¼ 2.1; 61 compared with 29), and although cardiovascular death rates were similar (60 compared with 71), deaths due to heart failure were significantly increased. In a multicenter, open trial in 4447 patients with type 2 diabetes taking metformin or sulfonylurea monotherapy, who were randomized to additional rosiglitazone (n ¼ 2220) or to a combination of metformin and a sulfonylurea (n ¼ 2227), there was a non-significant excess of myocardial infarction (HR 1.14) [97C]. The safety of rosiglitazone has continued to be examined. The 2010 FDA metaanalysis did not include large trials, but included data from 52 studies of 2 months to 2 years duration in a total of 12 069 patients, mean age 58 years, 59% men, with a mean BMI of 30 kg/m2 [98M]. The odds ratio for myocardial infarction in those taking rosiglitazone was 1.8 and for congestive heart failure 1.93. These data support the continued concern about the use of rosiglitazone in type 2 diabetes.

Tumorigenicity In the PROactive study, which randomized 5238 people with type 2 diabetes, mean age 62 years, to pioglitazone (n ¼ 2605) or placebo (n ¼ 2633), the incidence of any malignant neoplasm was similar in the two groups, 3.7% and 3.8%. The types of neoplasia differed between the groups. There were 14 cases of bladder neoplasm compared with six in the placebo group, but only three cases of breast cancer compared with 11 in the placebo group [95C]. Whether long-term use of pioglitazone carries a risk of bladder neoplasia continues to be explored. Pregnancy Two pregnancies have been reported in women taking pioglitazone [90C]. One woman gave birth to a live baby at term; exposure had been only in the first month of pregnancy. The other woman, whose exposure had been during the first 6 weeks, gave birth to a baby with sirenomelia, who died within 3 hours of birth.

Rosiglitazone Cardiovascular In September 2010, the European Medicines Agency completed a review focused on cardiovascular safety and decided that medicines containing rosiglitazone should stop being available in Europe. In patients with type 2 diabetes aged 40–75 years (mean 58 years) with a BMI of more than 25 kg/m2 (mean 31 kg/m2) taking metformin and a sulfonylurea, who were randomly allocated to additional rosiglitazone or metformin or sulfonylurea, there was no difference at 5 years between those taking rosiglitazone (n ¼ 2220) and those taking the metformin and sulfonylurea combination (n ¼ 2227) for all causes of

901

Liver In 63 patients with non-alcoholic steatohepatitis who were randomized to rosiglitazone 4 mg/day for 1 month, increasing to 8 mg/day for 11 months (n ¼ 32, mean age 53 years, 19 men) or placebo (n ¼ 31, mean age 54 years, 18 men), rosiglitazone did not cause adverse liver reactions [99C]. Susceptibility factors Renal disease A study of the Dialysis Outcomes and Practice Patterns Study (DOPPS) identified 2393 patients taking oral hypoglycemic agents, of whom 177 were taking rosiglitazone and 118 pioglitazone. Mean age was 63 years and about 47% were men. Those taking rosiglitazone had an increased risk of all-cause mortality (HR ¼ 1.38) and cardiovascular mortality (HR ¼ 1.59) compared with those taking non-thiazolidinedione oral hypoglycemic agents [100C]. Drug–drug interactions Fibrates Case reports have reinforced the need to

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monitor HDL concentrations when rosiglitazone is combined with a fibrate [SEDA32, 781; 101A]. • A 66-year-old woman with raised triglycerides and type 2 diabetes taking metformin, rosiglitazone, aspirin, metoprolol, fluvastatin, and hydrochlorothiazide had the dose of metformin increased and fenofibrate added. The HDL cholesterol fell from 1.19 to 0.26 mmol/l. Rosiglitazone was changed to pioglitazone and the HDL cholesterol increased to 1.22 mmol/l. • A 71-year-old man with type 2 diabetes taking amlodipine, warfarin, valsartan, hydrochlorothiazide, atenolol, and rosiglitazone was given fenofibrate. The HDL cholesterol fell from 0.96 to 0.60 mmol/l but rose to 0.80 mmol/l on changing the rosiglitazone to pioglitazone. • A 64-year-old woman with type 2 diabetes taking metoprolol, aspirin, niacin, warfarin, simvastatin, rosiglitazone, and metformin was given fenofibrate. The HDL cholesterol fell from 1.09 to 0.44 mmol/l. The fenofibrate was withdrawn and the HDL rose to 1.09 mmol/l.

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PEROXISOME PROLIFERATORACTIVATED DUAL RECEPTOR AGONISTS [SEDA-32, 782] Cardiovascular In the SYNCHRONY double-blind study, patients with type 2 diabetes (either drug-naive or pre-treated with only one or two oral agents) were enrolled from 47 sites in seven countries, in order to establish the glucose-lowering and lipid-modifying effects and adverse effects of the dual PPAR-alpha and PPAR-gamma agonist aleglitazar [102C]. Edema, hemodilution, and weight gain were dose related; at doses below 300 micrograms/day no patients had congestive heart failure and the frequency of edema was similar to that with placebo and less than with pioglitazone. Weight gain was also less than with pioglitazone.

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[74] Woo VC. Dapagliflozin: where does it fit in the treatment of type 2 diabetes? Expert Opin Pharmacother 2009; 10(15): 2527–35. [75] Brooks AM, Thacker SM. Dapagliflozin for the treatment of type 2 diabetes. Ann Pharmacother 2009; 43(7): 1286–93. [76] Manami M, Lamanna C, Balzi D, Marchionni N, Mannucci E. Sulphonylureas and cancer: a case-control study. Acta Diabetol 2009; 46: 279–84. [77] Lain KYL, Garabedian MJ, Daftary A, Jeyabalan A. Neonatal adiposity following maternal treatment of gestational diabetes with glyburide compared with insulin. Am J Obstet Gynecol 2009; 200: 501.e1–6. [78] Ling GR, Singh K, Wong SY, Toh VK. Severe neuroglycopaenia secondary to severe hypoglycaemia from serendipitous overdose of gliclazide without adrenergic or autonomic response. Diabet Med 2009; 26(11): 1182–3. [79] Tsukamoto K, Ohta K, Suzuki R, Hara M, Osuga J, Tobe K, Kadowaki T. Glimepiride-induced bronchial asthma: case report. Diabetes Care 2008; 31(12): e91. [80] Krentz A. Thiazolidinediones: effect on the development and progression of type 2 diabetes and associated vascular complications. Diabetes Metab Res Rev 2009; 25: 112–26. [81] Juurlink DN, Gomes T, Lipscombe LL, Austin PC, Hux JE, Mamdani MM. Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study. BMJ 2009; 339: b2942. [82] Hsiao F-Y, Huang W-F, Wen Y-W, Chen P-F, Kuo KN, Tsai Y-W. Thiazolidinediones and cardiovascular events in patients with type 2 diabetes mellitus. A retrospective cohort study of over 473 000 patients using the national health insurance database in Taiwan. Drug Saf 2009; 32: 675–90. [83] Koro CE, Fu Q, Stender M. An assessment of the effect of thiazolidinedione exposure on the risk of myocardial infarction in type 2 diabetic patients. Pharmacoepidemiol. Drug Saf 2008; 17(10): 989–96.

Insulin, other hypoglycemic drugs, and glucagon [84] Pantalone KM, Kattan MW, Yu C, Wells BJ, Arrigain S, Jain A, Atreja A, Zimmerman RS. The risk of developing coronary artery disease or congestive heart failure and overall mortality, in type 2 diabetic patients receiving rosiglitazone, pioglitazone, metformin or sulfonylureas: a retrospective analysis. Acta Diabetol 2009; 46: 145–54. [85] Rohatgi A, McGuire DK. Effects of the thiazolidinedione medications on micro and macrovascular complications in patients with diabetes—update 2008. Cardiovasc Drugs Ther 2008; 22: 233–40. [86] Khanderia U, Pop-Busui R, Eagle KA. Thiazolidinediones in type 2 diabetes: a cardiology perspective. Ann Pharmacother 2008; 42: 1466–74. [87] Bettridge DJ. CHICAGO, PERISCOPE and PROactive CV risk modification in diabetes with pioglitazone. Fundam Clin Pharmacol 2009; 23: 675–9. [88] Fong DS, Contreras R. Glitazone use associated with diabetic macular edema. Am J Ophthalmol 2009; 147: 583–6. [89] Dormuth CR, Carney G, Carleton B, Bassett K, Wright JM. Thiazolidinediones and fractures in men and women. Arch Intern Med 2009; 169: 1395–402. [90] Kasliwal R, Wilton LV, Shakir SAW. Monitoring the safety of pioglitazone: results of a prescription-event monitoring study of 12 772 patients in England. Drug Saf 2008; 31: 839–50. [91] Nagajothi N, Adigopula S, Balamuthusamy S, Velazquez-Cecena JLE, Raghunathan K, Khraisat A, Singh S, Molnar J, Khosla S, Benatar D. Pioglitazone and the risk of myocardial infarction and other major adverse cardiac events: a meta-analysis of randomized controlled trials. Am J Ther 2008; 15: 506–11. [92] Giles TD, Miller AB, Elkayam U, Bhattacharya M, Perez A. Pioglitazone and heart failure: results from a controlled study in patients with type 2 diabetes mellitus and systolic dysfunction. J Cardiac Fail 2008; 14: 445–52. [93] Negishi M, Shimomura K, Proks P, Shimomura Y, Mori M. Alpha glucosidase inhibitor voglibose can prevent

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[94]

[95]

[96]

[97]

[98]

[99]

[100]

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pioglitazone-induced body weight gain in type 2 diabetic patients. Br J Clin Pharmacol 2008; 66: 318–9. Tolman KG, Freston JW, Kupfer S, Perez A. Liver safety in patients with type 2 diabetes treated with pioglitazone. Results from a 3-year randomized comparator-controlled study in the US. Drug Saf 2009; 32: 787–800. Dormandy J, Bhattacharya M, van Troostenburg de Bruyn AR. PROactive Investigators. Safety and tolerability of pioglitazone in high-risk patients with type 2 diabetes. An overview of data from PROactive. Drug Saf 2009; 32: 187–202. Abe M, Kikuchi F, Okada K, Matsumoto K. Plasma concentration of pioglitazone in patients with type 2 diabetes on hemodialysis. Ther Apher Dial 2009; 13: 238–9. Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, Jones NP, Komajda M, McMurray JJV. For the RECORD study team. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 2009; 373: 2125–35. Callaghan F. Rosiglitazone cardiovascular safety meta-analysis. 13-14 July 2010. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM224738. pdf. Ratziu V, Giral P, Jacqueminet S, Charlotte F, Hartemann-Heurtier A, Serfaty L, Podevin P, Lacorte JM, Bernhardt C, Bruckert E, Grimaldi A, Poynard T. LIDO Study Group. Rosiglitazone for nonalcoholic steatohepatitis: oneyear results of the randomized placebocontrolled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology 2008; 135(1): 100–10. Ramirez SPB, Albert JM, Blayney MJ, Tentori F, Goodkin DA, Wolfe RA, Young EW, Baille GR, Pisoni RL, Port FK. Rosiglitazone is associated with mortality in chronic hemodialysis patients. J Am Soc Nephrol 2009; 20: 1094–101.

908 [101] Venero CV, Thompson PD, Fernandez AB. Reduced high-density lipoprotein cholesterol in patients receiving rosiglitazone and fenofibrate. Am J Med 2008; 121: e3–4. [102] Henry RR, Lincoff AM, Mudaliar S, Rabbia M, Chognot C, Herz M. Effect of

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the dual peroxisome proliferator-activated receptor-alpha/gamma agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase II, randomised, dose-ranging study. Lancet 2009; 374 (9684): 126–35.

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Miscellaneous hormones

Calcitonin [SED-15, 595; SEDA-30, 507; SEDA-31, 703; SEDA-32, 789] The adverse effects of salmon calcitonin have again been reviewed [1R]. Salmon calcitonin nasal spray is thought to be safe. Hypersensitivity is the only contraindication. The systemic adverse reactions of flushing and nausea that occur with injections are rare. Local reactions due to nasal irritation are the most common adverse reactions.

Gonadotropins (gonadorelin, GnRH, and analogues) [SED-15, 1536; SEDA-30, 507; SEDA-31, 703; SEDA-32, 789] A review of the use of gonadorelin analogues for precocious puberty showed that in general they were well tolerated [2R]. Headache and hot flushes were usually short-term problems. Local adverse events at the injection site occasionally required a change of therapy. Anaphylaxis has been described. Bone mineral density was not thought to be adversely affected in this group. In contrast gonadorelin therapy alone was not recommended for the management of idiopathic short stature, when the delay in puberty can compromise bone mineral density. Cardiovascular In 945 men with prostate cancer who were randomly allocated to Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00043-X # 2011 Elsevier B.V. All rights reserved.

external beam radiotherapy combined with goserelin acetate or to radiotherapy followed by goserelin only if there was relapse, the mean period of follow-up was 8.1 years, during which there were 574 deaths, 117 of which were due to cardiovascular disease [3C]. There was no increased risk of cardiovascular mortality in men who used adjuvant goserelin compared with those not using goserelin (8.4% versus 11%). The risk of cardiovascular disease has previously been reported to increase in men using GnRH agonists for prostate cancer. Nervous system Drug-induced chorea has previously been described with the use of the combined oral contraceptive, but the mechanism is uncertain. A case involving goserelin has been reported [4A]. • A 77-year-old man complained of involuntary movements after taking goserelin for prostate cancer for 6 weeks. He continued therapy for about 10 months and his symptoms persisted, but 3 months after stopping goserelin the abnormal movements stopped.

Reproductive system Ovarian hyperstimulation syndrome has been attributed to triptorelin [5A]. • A 35-year-old woman with infertility received triptorelin 3.75 mg on day 21 of her menstrual cycle and 10 days later a scan showed 12 follicles measuring 16–19 mm in both ovaries. She had symptoms of nausea and abdominal bloating. • A 26-year-old woman with infertility received triptorelin 3.75 mg and 2 weeks later developed abdominal heaviness; a scan showed bilateral follicles of 15–21 mm in both ovaries.

Ovarian hyperstimulation has been previously been reported but is uncommon after the sole administration of triptorelin. 909

910

In an uncontrolled study in 13 patients aged 30–42 years with endometriosis or menorrhagia, who took the aromatase inhibitor letrozole 2.5 mg/day for the first 5 days after receiving leuprolide acetate 3.75 mg intramuscularly, the initial increase in estrogen concentrations was not apparent [6c]. In a randomized study in healthy subjects, mean age 30 years, who received triptorelin 3.75 mg (two injections 4 weeks apart), with or without oral exemestane 25 mg/day for 56 days, there was no effect on the initial flare of FSH, LH, and estrogen, although there was subsequent increased suppression of estrogen [7c]. Of the 14 women who received placebo with triptorelin, 11 had hot flushes compared with nine of the 15 who took exemestane. Musculoskeletal Gonadorelin has been used for the management of endometriosis in adolescents [8R]. In this group the effect on bone mineral density can be minimized by using norethindrone acetate with or without estrogen at the same time. Tumorigenicity In an analysis of data from 54 362 women referred to Danish hospitals between 1963 and 1968 with infertility problems (median age at first evaluation 30 years), there were 156 patients with epithelial ovarian tumors, who were compared with a randomly selected subcohort [9C]. Various infertility therapies had been used. The risk of ovarian cancer was not increased after any use of gonadotropins (rate ratio ¼ 0.83). Drug formulations In patients, mean age 73 years, with prostate cancer, a study of the use of leuprorelin acetate 11.25 mg injections every 3 months for 12 months (n ¼ 58), compared with six monthly injections of depot leuprorelin acetate containing either 22.5 or 30 mg (n ¼ 120), the results suggested no differences in adverse reactions [10C]. Flushing was the most common adverse reaction; it occurred in 43% of those who received 11.25 mg and in 34% of those who received 30 mg. Increased sweating was also slightly more common in those who received 11.25 mg. Injection site

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reactions were more common in those who received 30 mg, 12% versus 2%. Overall the frequency of adverse reactions was similar.

Somatropin (human growth hormone, hGH) [SED-15, 3163; SEDA-30, 508; SEDA-31, 705; SEDA-32, 791] Cardiovascular In 14 patients with growth hormone deficiency (aged 33–62 years, four men), who were given growth hormone at an initial dose of 0.015 mg/kg/week, the dose was then titrated depending on IGF1 concentrations [11c]. Echocardiography was performed at baseline and at 24, 48, and 60 months. There was progressive increase in left ventricular mass from 116 to 174 g. The long-term effects of growth hormone replacement in adults are unknown. In 122 men, mean age 70 years, who were randomized to testosterone gel 5 g/ day (n ¼ 61) or 10 g/day with different doses of growth hormone (0, 3, or 5 micrograms/kg/day) for 12 weeks, there was an increase in blood pressure, which persisted 4 weeks after the study ended [12c]. The blood pressure at 16 weeks was 130/ 76 mmHg compared with 117/68 mmHg at baseline. In 10 patients (mean age 58 years, one man) with acromegaly, which was thought to have been cured, who were treated with growth hormone with the dose adjusted to normalize IGF-1 concentrations, and 10 patients with previous non-functioning pituitary adenomas, who also received growth hormone (mean age 54 years, one man), three of the former had cardiovascular events during 2 years; one patient died with a myocardial infarction after 5 months; two had cerebral infarctions at 2 and 6 weeks and continued growth hormone therapy [13c]. None of the patients with non-functioning pituitary disease had cardiovascular events. The numbers were small in this study, and the safety of using growth

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hormone in patients with previous acromegaly needs further evaluation. Metabolism A review of growth hormone therapy for adults with growth hormone deficiency has shown a correlation of growth hormone dose and duration with the development of impaired glucose tolerance [14R]. A meta-analysis of studies of growth hormone therapy for obesity in adults showed a small but significant increase in fasting plasma glucose concentrations [15M]. Pancreas Pancreatitis has been attributed to growth hormone. • A 40-year-old man used growth hormone 0.6 mg/day for 2 weeks to enhance muscle development. He developed pancreatitis 10 days later. There was no other apparent risk factor [16A]. • A 13-year-old girl with a craniopharyngioma was using growth hormone 0.033 mg/kg/day subcutaneously six times per week, levothyroxine, hydrocortisone, and an antidiuretic hormone analogue [17A]. She developed severe abdominal pain and was admitted 1 month later with persistent symptoms. The diagnosis was pancreatitis. Growth hormone was withdrawn and she recovered. Six months later growth hormone was restarted without recurrence of pancreatitis.

In the second case the authors speculated that the pancreatitis might have been related to a high cholesterol concentration (6.5 mmol/l) caused by the use of growth hormone. Musculoskeletal Of 19 patients with de Quervain's tenosynovitis, mean age 33 years, nine were using growth hormone for body building purposes [18c]. Four stopped using growth hormone when requested. The patients who were not using growth hormone responded to non-surgical treatment. Four of the five patients who continued growth hormone therapy required surgical therapy, compared with two of the four who stopped. Growth hormone may make de Quervain's tenosynovitis more difficult to treat. Eight children with Hurler's syndrome, mean age 9 years, were treated with growth hormone, mean dose 0.32 mg/kg/week

911

[19c]. There was radiographic data for six children. There was progression of scoliosis in one, kyphosis progression in one, and worsening of genu valgum in one. One child discontinued therapy owing to a slipped capital femoral epiphysis, which is not a typical feature of Hurler's syndrome. In 39 children with isolated growth hormone deficiency and five with multiple pituitary hormone deficiencies (aged 8–16 years, 30 boys), who were treated with growth hormone 33 micrograms/kg/day, Southwick's angle was measured using pelvic X-rays at baseline, 1 year, and 2 years [20c]. Data were available for 28 patients at 1 year, of whom 17 had an increased angle. Data at 2 years were available for 10 patients, of whom nine had further progression. It is thought that an increased Southwick's angle is a marker for a risk of slipped capital femoral epiphysis, and growth hormone can increase the risk of epiphysiolysis. Drug administration route Inhaled growth hormone In a randomized crossover trial, somatotropin inhalation powder was given to 22 children with growth hormone deficiency, mean age 11 years [21c]. Eight received inhaled growth hormone 8.4 mg/ day or subcutaneous growth hormone 0.5 mg per day; six received inhaled growth hormone 16.8 mg/day or subcutaneous growth hormone 1.0 mg/day; and eight received inhaled growth hormone 33.6 mg/ day or subcutaneous growth hormone 2.0 mg/day. Each treatment was given for 7 days. There were no effects on lung function in this short study.

Growth hormone receptor antagonists [SEDA-30, 510; SEDA-31, 707; SEDA-32, 794] Liver In a 40 week, open, randomized, controlled study in patients with acromegaly, who were inadequately treated with long-acting octreotide, adding pegvisomant therapy to octreotide was compared with changing to pegvisomant alone [22c].

912

The mean age of the 25 patients randomized to pegvisomant alone was 49 years, 10 of whom had diabetes. The 26 patients randomized to combined therapy had a mean age of 40 years and four had diabetes. Pegvisomant was begun at 10 mg/day and titrated, according to IGF-1 concentrations, to a maximum of 30 mg/day and a minimum of 5 mg/day. There were significant increases in liver enzymes to more than three times the upper limit of the reference range in one patient who received pegvisomant alone and in four who received combination therapy. Three patients using combination therapy had activities more than 10 times the upper limit, and they returned to normal or near normal on withdrawal. Liver function should be monitored, especially when combination therapy is used. Current recommendations suggest monthly liver function tests for the first 6 months of treatment, followed by 6monthly tests [23R]. Tumorigenicity Two boys and one girl with pituitary gigantism, who were not cured by surgery, a somatostatin analogue, and a dopamine receptor agonist, were given pegvisomant [24A]. One child, aged 5 years received 10 mg/day subcutaneously; the others, aged 10 and 11 years, received 20 mg/day. One child had a documented increase in tumor size and stopped taking pegvisomant after about 3 years; 3 months after the end of therapy there was no further increase in tumor size. One patient in each group of a randomized control comparison of pegvisomant alone with pegvisomant plus long-acting octreotide had an increased pituitary volume at 40 weeks [22c]. Long-term surveillance of pituitary volume is required for patients receiving pegvisomant.

Melatonin and analogues

[SED-15, 2245; SEDA-31, 708; SEDA-32, 794] Melatonin analogues are under development with varying binding affinities for

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melatonin receptors [25R]. Large-scale evidence for their use in circadian rhythm sleep disorders is not yet available. Ramelteon, (S)-N-[2-(1,6,7,8-tetrahydro2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide (TAK-375), has four times the potency as melatonin at MT1 receptors and 17 times the potency at MT2 receptors. Adverse effects in trials so far suggest effects similar to placebo. Agomelatine, N-[2-(7-methoxy-1naphthyl)ethyl]acetamide, is a melatonin MT1 and MT2 receptor agonist. It is also an antagonist at 5-HT2C receptors. Tasimelteon, (1R-trans)-N-[[2-(2,3-dihydro-4-benzofuranyl)cycloproplyl]methyl] propanamide, has high affinity for melatonin MT1 and MT2 receptors. Melatonin has been used in neonates at pharmacological doses without apparent adverse reactions, although studies are usually small [26R]. Circadin is a prolonged-release tablet containing melatonin 2 mg. It has received European Medicine Agency approval for treatment of primary insomnia. Adverse reactions are uncommon, but include headache, pharyngitis, back pain, and weakness. There do not appear to be withdrawal effects. Drug–drug interactions Melatonin is metabolized mainly by CYP1A, but CYP2C19 is also involved to a lesser extent [27r]. Melatonin concentrations can be increased by cimetidine, quinolones, and estrogens. They are reduced by carbamazepine and cigarette smoking.

Oxytocin and analogues

[SED-15, 2657; SEDA-30, 511; SEDA-31, 708; SEDA-32, 795]

Observational studies The use of oxytocin in low income countries has been reviewed [28R]. The use of oxytocin compared with no use of oxytocin in normal labor had a relative risk of 1.9 for stillbirth. The adjusted relative risk for neonatal resuscitation was 2–5.6. Oxytocin is useful for the

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913

management of postpartum hemorrhage, but it is important that in low resource settings its use does not result in increased harm to the neonate. In 80 women, mean age 31 years, undergoing cesarean section, who were randomized to oxytocin 2 or 5 units as an intravenous bolus over 5–10 seconds after the delivery of a baby and cord clamping, followed by a continuous infusion of oxytocin 10 units/hour over 4 hours, 13 reported nausea after receiving 5 units compared with two who received 2 units [29C]. Mean arterial pressure fell more in those who were given 5 units (13 compared with 6 mmHg), and six patients had a reduction of more than 30 mmHg. Electrolyte balance Hyponatremia been attributed to oxytocin [30A].

has

• A 26-year-old woman in the second stage of labor received an infusion of oxytocin 10 U/l in 5% dextrose at a variable rate of 10–150 ml/ hour. In the 5 hours after delivery, which was complicated by a retained placenta requiring general anesthesia for removal, she received isotonic fluid 5500 ml, 5% dextrose 3500 ml with oxytocin 50 U/l, hydroxyethyl starch 1000 ml, and 4 units of blood. She then received 5% dextrose 7500 ml with oxytocin 100 U/l over 15 hours; 24 hours later her serum sodium concentration was 113 mmol/l. She became unconscious and had a generalized convulsion. She subsequently made a full recovery.

Consideration of how oxytocin is infused to minimize the risk of hyponatremia is essential.

Thyrotropin-releasing hormone and thyrotropin See Chapter 41.

Parathyroid hormone

[SED-15, 2689;

SEDA-32, 796] Potential novel uses of parathyroid hormone therapy are being explored through its effects on the cardiovascular system, which include arterial vasodilatation [32R]. Observational studies Women aged more than 45 years with low bone mineral density were randomized to hormone replacement therapy with (n ¼ 90) or without (n ¼ 90) 100 micrograms of subcutaneous PTH 1–84 [33c]. Those who received PTH 1–84 had more hypercalciuria (43%), hypercalcemia (14%), nausea (25%), vomiting (11%), and dizziness (10%). It was thought that they might not have had as great an increase in calcium concentrations as would have been expected, because of a tendency of hormone replacement therapy to lower calcium concentrations.

Somatostatin (growth hormone release-inhibiting hormone) and analogues [SED-15, 3160; SEDA-30, 510; SEDA-31, 709; SEDA-32, 796]

Skin Extravasation of concentrations of oxytocin in the hand has reportedly caused vasoconstriction [31A]. • A 24-year-old woman had vaginal bleeding at 15 weeks gestation. She received 2 units of packed erythrocytes and then 3 units of oxytocin through a cannula on the back of the hand. Within 30 minutes the hand had become edematous and cyanotic. Extravasation was apparent. The radial and ulnar pulses were not palpable and were faint on a Doppler scan. The hand was elevated and the symptoms gradually abated, with improvement of the pulses.

Adverse reactions to somatostatin analogues have been extensively reported. The asymptomatic effects have been reviewed [23R, 34R]. There are asymptomatic gallstones in 20–40, bradycardia in up to 25%, and conduction abnormalities in 10%. Somatostatin analogues may alter the absorption of other drugs, especially oral hypoglycemic agents, b blockers, calcium channel blockers, and ciclosporin, while effects on CYP isoenzymes may alter concentrations of quinidine, terfenadine, and warfarin. Somatostatin analogues

914

should not be used with drugs that prolong the QT interval, such as cisapride. Nervous system In one case a high dose of octreotide may have altered the balance between brain dopamine and GABA, and thus caused Parkinson-like symptoms [35A]. • A 31-year-old woman with carcinoid syndrome was given octreotide in doses that gradually increased over the years, so that after 4 years she was receiving 30 mg intramuscularly every 2 weeks and an additional 6–8 mg of subcutaneous octreotide each month. She developed slowness of movement and a tendency to bump into things. The dose of octreotide was reduced to 10 mg every 2 weeks and her neurological symptoms improved. The dose of octreotide was temporarily increased to 30 mg 2 weekly with a recurrence of symptoms.

Metabolism In 112 patients with acromegaly (mean age 47 years, 51 men), who were treated with somatostatin analogues, there was an increase in fasting plasma glucose concentrations after 1 month, which correlated with a reduction in insulin concentrations [36C]. The fasting glucose concentration had returned to baseline by 3 months. At the end of 12 months the most important predictor of blood glucose concentration was control of growth hormone concentrations; 11 patients had improved their glucose tolerance status and 17 had worsened.

Octreotide [SEDA-30, 510; SEDA-31, 709; SEDA-32, 797] Hematologic Thrombocytopenia has been attributed to octreotide [37A]. • A 53-year-old man with hematemesis and melena due to variceal bleeding was given octreotide 50 micrograms as an initial intravenous bolus, followed by 50 micrograms/hour as a continuous intravenous infusion. His platelet count fell from 144 to 4  109/l over the next 50 hours. The platelet count gradually increased after the octreotide was withdrawn at 72 hours. He was again given octreotide 3 months later, and the platelet count fell from 214 to 89  109/l. The

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octreotide was withdrawn and the platelet count returned to 221  109/l.

The mechanism of this effect is unknown. Gastrointestinal In 125 patients being treated with pelvic radiation for various cancers of the pelvis, randomly allocated to subcutaneous octreotide 100 micrograms on day 1 followed by depot octreotide 20 mg on days 2 and 29, or placebo, octreotide did not improve symptoms and may have worsened abdominal cramps, nocturnal bowel movement, and melena [38C]. Biliary tract Nine subjects with Prader– Willi syndrome (mean age 15 years) received either octreotide 30 mg or saline intramuscularly every 4 weeks for 16 weeks. After a 24-week wash-out period, they then received the alternative therapy. Three developed gallbladder abnormalities on ultrasound by the end of the octreotide phase; two went on to have cholecystectomy 12–24 months later [39c]. Nails Beau's lines, or onychomadesis, are seen in patients receiving certain drugs, and has been associated with octreotide [40A]. • Beau's lines were noted in a 72-year-old lady with carcinoid syndrome who was receiving subcutaneous octreotide every 28 days. The distance of the lines from the proximal nail fold suggested that they had developed at around the time of octreotide injection, although there were only two lines when she had received four injections.

VASOPRESSIN RECEPTOR ANTAGONISTS There are three subtypes of arginine vasopressin receptor, V1A, V1B, and V2. The V2 receptor is mainly situated in the kidney and is important in free water reabsorption [41R]. The V1B receptor mediates adrenocoticotropin release in the anterior pituitary. The V1A receptor has multiple

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functions, including vasoconstriction and glycogenolysis. Drugs that block activation of the V2 receptor have been developed for the management of hyponatremia. This induces excretion of free water without changed electrolyte excretion. Lixivaptan, satavaptan, and tolvaptan are all V2 receptor antagonists that are taken orally. Conivaptan is a V1A and V2 receptor antagonist that has been licensed by the FDA for intravenous use.

Conivaptan Although oral conivaptan, [1,10 -biphenyl]-2carboxamide, N-[4-[(4,5-dihydro-2-methylimidazo[4,5-d][1]benzazepin-6(1H)-yl)carbonyl] phenyl] monohydrochloride, was efficacious, drug development has been discontinued because of significant inhibition of CYP3A4. In 84 adults with hyponatremia (euvolemic or hypervolemic) who were randomized to a bolus of conivaptan 20 mg followed by a 4-day continuous infusion of 40 mg/day (n ¼ 29) or 80 mg/day (n ¼ 26) compared with placebo (n ¼ 29), the main adverse reactions were infusion site reactions [41R].

Tolvaptan Tolvaptan, 40 -[(7-chloro-2,3,4,5-tetrahydro5-hydroxy-1H-1-benzazepin-1-yl) carbonyl]o-tolu-m-toluidide, has been approved by the FDA and EMA for management of hyponatremia. It is taken orally in a dose of 15 mg/day and is titrated to a maximum of 60 mg, depending on sodium concentrations and volume status. Tolvaptan is metabolized by the liver. Blood concentrations of tolvaptan are increased when it is co-administered with CYP3A4 inhibitors such as diltiazem, ketoconazole, and grapefruit juice, and reduced when it is co-administered with CYP3A4 inducers such as rifampicin. Placebo-controlled studies Patients, mean age 66 years, with hyponatremia were

915

randomized to tolvaptan (n ¼ 15) or placebo with fluid restriction (n ¼ 8). The underlying diagnoses were heart failure, hepatic cirrhosis, and the syndrome of inappropriate antidiuretic hormone secretion. The numbers in this study were small and the adverse events were not fully documented, but thirst scores between the groups were not different [42c]. In two randomized placebo-controlled trials of tolvaptan 15–60 mg in patients with either euvolemic or hypervolemic hyponatremia, adverse events were similar to those with placebo [43C]. The most common adverse reactions were thirst (14% versus 5%) and dry mouth (13% versus 4%). Death rates were similar: 14 of 223 patients who took tolvaptan compared with 13 of 220 patients who took placebo. Four patients who took tolvaptan had an increased serum sodium concentration to over 146 mmol/l, and in four patients the rate of increase of sodium was more rapid than clinically appropriate. Close monitoring of serum sodium concentrations and plasma volume status is essential. Fluid restriction is not required. Polyuria is common.

VASOPRESSIN AND ANALOGUES [SED-15, 3609; SEDA-30, 511; SEDA-31, 710; SEDA-32, 798] Cardiovascular Bradycardia has been attributed to intrauterine vasopressin [44A]. • A woman who underwent laparoscopic myomectomy had 56 ml of diluted vasopressin (0.2 units/ml) injected into the uterine wall. Within 2 minutes her pulse rate had fallen from 58 to 35/minute. She had a cardiac arrest a short time later, from which she recovered.

Electrolyte balance In 24 children (11 boys, median age 3 years) with non-septic critical illnesses, who were randomized to either vasopressin 0.5 milliunits/kg/minute

Chapter 43

916

or 0.9% sodium chloride 1 ml/hour for 48 hours, there was hyponatremia in eight of the former compared with one of the latter [45c]. Blood pressure increased in normotensive children who received vasopressin, with rebound hypotension on withdrawal. Urine output fell in those who were given vasopressin. Death In a randomized study, 35 children (mean age 9 years, 19 boys) with vasodilatory shock were given arginine vasopressin at a starting dose of 0.5 milliunits/kg/minute and were compared with 34 children (mean age 11 years, 17 boys) who were treated with saline as a placebo. Although not statistically significant, there were 10 deaths in the vasopressin group and only five in the placebo group (relative risk 1.94). Vasopressin did not appear to confer benefit. In a subgroup analysis of a comparison of vasopressin 40 IU þ adrenaline 1 mg (n ¼ 1442) with adrenaline alone (n ¼ 1452) in cardiopulmonary resuscitation, when the initial electrocardiogram showed pulseless activity the rate of survival was higher in those treated with adrenaline alone (5.8% compared with 0%) [46C]. Overall, 1-year survival was 1.3% versus 2.1% respectively; although this was a non-significant difference, it was clear that vasopressin in addition to adrenaline was not beneficial and could be harmful.

Desmopressin (N-deamino-8-Darginine vasopressin, DDAVP) [SED-15, 1076; SEDA-30, 512; SEDA-31, 710; SEDA-32, 798] Electrolyte balance The risk of hyponatremia as a consequence of inappropriate fluid administration after a single dose of desmopressin has been highlighted [47A]. • A 48-year-old woman received intravenous desmopressin 0.4 micrograms/kg over 30 minutes as part of assessment for a bleeding tendency and 4 hours later drank large

R.C.L. Page

amounts of water. The serum sodium concentration fell to 116 mmol/l and she had seizures and became unconscious. She was treated with hypertonic saline. On recovery she had mild impairment of short-term memory for 3 months.

Hematologic Another report of the increased risk of thrombosis when desmopressin is used in von Willebrand's disease has highlighted the need for caution [48A]. • A 52-year-old woman with von Willebrand's disease was admitted for a surgical procedure. Preoperatively she received intravenous desmopressin 0.3 micrograms/kg and on the day after surgery she developed bilateral pulmonary emboli and an acute ischemic stroke. Echocardiography showed a small patent foramen ovale. She was anticoagulated and recovered without clinical sequelae.

Terlipressin

[SEDA-30, 512; SEDA-31, 710; SEDA-32, 798] Cardiovascular QT interval prolongation and torsade de pointes have been attributed to terlipressin [49A].

• A 50-year-old man with alcohol problems had endoscopy, which showed multiple ulcers at D1 and D3. He had a small amount of coffee-ground vomit and was given intravenous terlipressin 1 mg 6 hourly. Electrocardiography showed gradual prolongation of the QTc interval from 0.34 to 0.44 seconds. He developed melena and signs of incipient shock 9 days later. Bleeding at D2 was identified at endoscopy and treated with embolization. Intravenous terlipressin 1 mg 6 hourly was restarted. The next day he collapsed and an electrocardiogram showed torsade de pointes. One hour before that the QTc interval was 0.49 seconds.

Minor electrolyte abnormalities at the time of bleeding may have increased the risk of ventricular dysrhythmia in this case. Skin Two further case reports of thrombosis of superficial dermal capillaries have been reported. One patient presented with widespread lesions and the other had more localized involvement [50A].

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• A 68-year-old man with alcoholic cirrhosis, hepatocellular carcinoma, esophageal varices, and hepatorenal syndrome was given intravenous boluses of terlipressin 1 mg qds and 3 days later developed diffuse purpuric necrotic plaques all over his body, including the tongue and scrotum. A week later the reticulated erythema of the trunk and the purpuric plaque on the scrotum became necrotic. He died 3 weeks later from staphylococcal septicemia.

917 • A 74-year-old man with multiple metastases and an unknown primary developed acute renal failure. He was given terlipressin 0.5 mg/hour via an infusion pump together with albumin and antibiotics and 4 days later developed an isolated large erythematous plaque on the scalp. Biopsy showed thrombosis of dermal capillaries. He died a few days later from tumor progression.

References [1] Chesnut III CH, Azria M, Silverman S, Engelhardt M, Olson M, Mindeholm L. Salmon calcitonin: a review of current and future therapeutic indications. Osteoporosis Int 2008; 19: 479–91. [2] Carel JC, Eugster EA, Rogol A, Ghizzoni L, Palmert MR. ESPE-LWPES GnRH Analogs Consensus Conference Group, Antoniazzi F, Berenbaum S, Bourguignon JP, Chrousos GP, Coste J, Deal S, de Vries L, Foster C, Heger S, Holland J, Jahnukainen K, Juul A, Kaplowitz P, Lahlou N, Lee MM, Lee P, Merke DP, Neely EK, Oostdijk W, Phillip M, Rosenfield RL, Shulman D, Styne D, Tauber M, Wit JM. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics 2009; 123(4): e752–62. [3] Efstathiou JA, Bae K, Shipley WU, Hanks GE, Pilepich MV, Sandler HM, Smith MR. Cardiovascular mortality after androgen deprivation therapy for locally advanced prostate cancer: RTOG 85-31. J Clin Oncol 2009; 27: 92–9. [4] Gironell A, Malo de Molina R, Sancho G, Kulisevsky J. Chorea induced by a luteinizing hormone-releasing hormone analog. J Neurol 2008; 255: 1264–5. [5] Qublan HS, Beni-Merei Z, Megdadi M, AlQuraan G. Ovarian hyperstimulation syndrome following the sole administration of injectable gonadotropin-releasing hormone agonist (triptorelin) for the pituitary downregulation and in vitro fertilization treatment: report of two cases. Arch Gynecol Obstet 2009; 279: 221–3. [6] Bedaiwy MA, Mousa NA, Casper RF. Aromatase inhibitors prevent the estrogen rise

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associated with the flare effect of gonadotropins in patients treated with GnRH agonists. Fertil Steril 2009; 91: 1574–7. Jannuzzo MG, di Salle E, Spinelli R, Pirotta N, Buchan P, Bello A. Estrogen suppression in premenopausal women following 8 weeks of treatment with exemestane and triptorelin versus triptorelin alone. Breast Cancer Res Treat 2009; 113(3): 491–9. Laufer MR. Current approaches to optimizing the treatment of endometriosis in adolescents. Gynecol Obstet Invest 2008; 66 (Suppl 1): 19–27. Jensen A, Sharif H, Frederiksen K, Kjaer SK. Use of fertility drugs and risk of ovarian cancer: Danish population based cohort study. BMJ 2009; 338: b249. Tunn UW, Wiedey K. Safety and clinical efficacy of a new 6-month depot formulation of leuprorelin acetate in patients with prostate cancer in Europe. Prostate Cancer Prostatic Dis 2009; 12: 83–7. Cenci MC, Soares DV, Spina LD, de Lima Oliveira Brasil RR, Lobo PM, Mansur VA, Gold J, Michmacher E, Vaisman M, Conceição FL. Effects of 5 years of growth hormone (GH) replacement therapy on cardiac parameters and physical performance in adults with GH deficiency. Pituitary 2009; 12: 322–9. Sattler FR, Castaneda-Sceppa C, Binder EF, Schroeder ET, Wang Y, Bhasin S, Kawakubo M, Stewart Y, Yarasheshi KE, Ulloor J, Colletti P, Roubenoff R, Azen SP. Testosterone and growth hormone improve body composition and muscle performance in older men. J Clin Endocrinol Metab 2009; 94: 1991–2001.

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918 [13] Norman L-L, Johannsson G, Sunnerhargen KS, Svensson J. Baseline characteristics and the effects of two years of growth hormone (GH) replacement therapy in adults with GH deficiency previously treated for acromegaly. J Clin Endocrinol Metab 2008; 93: 2531–8. [14] Moller N, Jorgensen JOL. Effects of growth hormone on glucose, lipid and protein metabolism in human subjects. Endocr Rev 2009; 30: 152–77. [15] Mekala KC. Tritos NA Effects of recombinant human growth hormone therapy in obesity in adults: a meta-analysis. J Clin Endocrinol Metab 2009; 94: 130–7. [16] Rutten J-P, Poeze M, DeJong CHC. Acute pancreatitis caused by excessive use of growth hormone in a 40-year-old man. Pancreas 2008; 36: 2. [17] Faienza MF, Delvecchio M, Indrio F, Francavilla R, Acquafredda A, Cavallo L. Acute pancreatitis in a girl with panhypopituitarism due to craniopharyngioma on growth hormone treatment. A combination of risk factors. Horm Res 2009; 71: 372–5. [18] Pagonis T, Ditsios K, Givissis P, Pagonis A, Christodoulou A. Abuse of growth hormone increases the risk of persistent de Quervain tenosynovitis. Am J Sports Med 2009; 37: 2228–33. [19] Polgreen LE, Plog M, Schwender JD, Tolar J, Thomas W, Orchard PJ, Miller BS, Petryk A. Short term growth hormone treatment in children with Hurler syndrome after hematopoietic cell transplantation. Bone Marrow Transplant 2009; 44: 279–85. [20] De Andrade AC, Longui CA, Damasceno FLV, Santili C. Southwick's angle determination during growth hormone treatment and its usefulness to evaluate risk of epiphysiolysis. J Pediatr Orthop 2009; 18: 11–5. [21] Walvoord EC, de la Pena A, Park S, Silverman B, Cuttler L, Rose SR, Cutler G, Drop S, Chipman JJ. Inhaled growth hormone compared with subcutaneous GH in children with GH deficiency: pharmacokinetics, pharmacodynamics and safety. J Clin Endocrinol Metab 2009; 94: 2052–9. [22] Trainer PJ, Ezzat S, D'Souza GA, Layton G, Strasburger CJ. A randomized controlled multicentre trial comparing

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pegvisomant alone with combination therapy of pegvisomant and long-acting octreotide in patients with acromegaly. Clin Endocrinol 2009; 71: 549–57. Ben-Shlomo A, Melmed S. Acromegaly. Endocrinol Metab Clin N Am 17 June 2009; author manuscript PMC. North America 2008; 32: 101–102. Goldenberg N, Racine MS, Thomas P, Degnan B, Chandler W, Barkan A. Treatment of pituitary gigantism with the growth hormone receptor antagonist pegvisomant. J Clin Endocrinol Metab 2008; 93: 2953–6. Rajaratnam SMW, Cohen DA, Rogers NL. Melatonin and melatonin analogues. Sleep Med Clin 2009; 4: 179–93. Gitto E, Pellegrino S, Gitto P, Barberi I, Reiter RJ. Oxidative stress of the newborn in the pre and postnatal period and the clinical utility of melatonin. J Pineal Res 2009; 46: 128–39. Greener M. Circadin: a new option in sleep disorders. Prog Neurol Psychiatry 2008; 12 (8): 12–4. Lovold A, Stanton C, Armbruster D. How to avoid iatrogenic morbidity and mortality while increasing availability of oxytocin and misoprostol for PPH prevention? Int J Gynecol Obstet 2008; 103: 276–82. Sartain JB, Barry JJ, Howat PW, McCormack DI, Bryant M. Intravenous oxytocin bolus of 2 units is superior to 5 units during elective Caesarean section. Br J Anaesth 2008; 101(6): 822–6. Bergum D, Lonnee H. Hakli TF Oxytocin infusion: acute hyponatraemia, seizures and coma. Acta Anaesthesiol Scand 2009; 53: 826–7. Pollock RA, Olges JR, Stewart DH. Oxytocin hand: extravasation and vascular compromise after obstetrical pitocin. Plast Reconstr Surg 2009; 124: 177E–9. Pagliarulo C, Salvatore P, Napoli C. Targeting vascular niche by parathyroid hormone. Curr Med Chem 2008; 15(28): 2984–90. Fogelman I, Fordham JN, Fraser WD, Spector TD, Christiansen C, Morris SA, Fox J. Parathyroid hormone (1–84) treatment of postmenopausal women with low bone mass receiving hormone replacement therapy. Calcif Tissue Int 2008; 83: 85–92.

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[34] Prommer EE. Established and potential therapeutic applications of octreotide in palliative care. Support Care Cancer 2008; 16: 1117–23. [35] Espay AJ. Reversible parkinsonism and ataxia associated with high-dose octreotide. Neurology 2008; 70: 2345–6. [36] Calao A, Auriemma RS, Savastano S, Galdiero M, Grasso LFS, Lombardi G, Pivonello R. Glucose tolerance and somatostatin analog treatment in acromegaly: a 12-month study. J Clin Endocrinol Metab 2009; 94: 2907–14. [37] Chisholm S, Gummadi B, Vega KJ, House J. Sandostatin causing reversible thrombocytopenia. Eur J Gastroenterol Hepatol 2009; 21: 384–5. [38] Martenson JA, Halyard MY, Sloan JA, Proulx GM, Miller RC, Deming RL, Dick SJ, Johnson HA, Tai THP, Zhu AW, Keit J, Stioen KJ, Atherton PJ. Phase III double blind study of depot octreotide versus placebo in the prevention of acute diarrhea in patients receiving pelvic radiation therapy: results of north central cancer treatment group N00CA. J Clin Oncol 2008; 32: 5248–53. [39] De Waele K, Ishkanian SL, Bogarin R, Miranda CA, Ghatei MA, Bloom SR, Pacaud D, Chanoine J-P. Long acting octreotide treatment causes a sustained decrease in ghrelin concentrations but does not affect weight, behaviour and appetite in subjects with Prader–Willi syndrome. Eur J Endocrinol 2008; 159: 381–8. [40] Gregoriou S, Chiolou Z, Rigopoulos D. Beau's lines after octreotide therapy. Clin Exp Dermatol 2009; 34: e1020–1. [41] Verbalis JG. AVP receptor antagonists as aquaretics. Review and assessment of clinical data. Cleve Clin J Med 2006; 73: S24–33. [42] Gheorghiade M, Gottlieb SS, Udelson JE, Konstam MA, Czerwiec F, Ouyang J, Orlandi C. Tolvaptan investigators. Vasopressin V2 receptor blockade with tolvaptan versus fluid restriction in the treatment of hyponatremia. Am J Cardiol 2006; 97: 1064–7. [43] Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, Orlandi C. SALT investigators. Tolvaptan

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a selective oral vasopressin V2-receptor antagonist for hyponatremia. N Engl J Med 2006; 355: 2099–112. Hobo R, Netsu S, Koyasu Y, Tsutsumi O. Bradycardia and cardiac arrest caused by intramyometrial injection of vasopressin during a laparoscopically assisted myomectomy. Obstet Gynecol 2009; 113: 484–6. Baldasso E, Garcia PCR, Piva JP, Branco RG, Tasker RC. Pilot safety study of low dose vasopressin in non septic critically ill children. Intensive Care Med 2009; 35: 355–9. Gueugniaud P-Y, David J-S, Chanzy E, Hubert H, Dubien P-Y, Mauriaucourt P, Braganca C, Billeres X, ClotteauLambert M-P, Fuster P, Thiercelin D, Debaty G, Ricard-Hibon A, Roux P, Espesson C, Querellou E, Ducros L, Ecollan P, Halbout L, Savary D, Guillaumee F, Maupoint R, Capelle P, Bracq C, Dreyfus P, Nouguier P, Gache A, Meurisse C, Boulanger B, Lae C, Metzger J, Raphael V, Beruben A, Wenzel V, Guinhouya C, Vilhelm C, Marret E. Vasopressin and epinephrine vs. epinephrine alone in cardiopulmonary resuscitation. N Engl J Med 2008; 359: 21–30. Posthouwer D, Rommes JH, van Bemmel J, Schaar CG. Severe hyponatraemia after DDAVP stimulation test in an adult patient. Haemophilia 2008; 14: 844–5. De Wee EM, Ikram MK, Dippel DWJ, Leebeek WG. Transient focal cerebral ischaemia and bilateral pulmonary embolism after desmopressin treatment for von Willebrand's disease. Haemophilia 2008; 14: 1133–4. Urge J, Sincl F, Procházka V, Urbánek K. Terlipressin induced ventricular arrhythmia. Scand J Gastroenterol 2008; 43(9): 1145–8. Mégarbané H, Barete S, Khosrotehrani K, Izzedine H, Moguelet P, Chosidow O, Frances C, Aractingi S. Two observations raising questions about risk factors of cutaneous necrosis induced by terlipressin (Glypressin). Dermatology 2009; 218(4): 334–7.

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Drugs that affect lipid metabolism

Ezetimibe

[SED-15, 1308; SEDA-30, 515; SEDA-31, 715; SEDA-32, 803] Ezetimibe has been the subject of recent criticism, arising from clinical trials that have cast doubt on its efficacy to improve outcomes and unsubstantiated suggestions of a possible carcinogenic effect.

Comparative studies A disappointing study of the efficacy of ezetimibe, the ENHANCE trial, raised the possibility of unidentified adverse effects that nullified its LDL lowering effect. This trial tested the efficacy of either reducing or slowing the progression of carotid intima-media thickness (CIMT), a surrogate for cardiovascular events, in 720 subjects with heterozygous hypercholesterolemia, who were randomized to simvastatin 80 mg/day alone or simvastatin þ ezetimibe 10 mg/day [1C]. The combination achieved significantly lower LDL concentrations than simvastatin alone. However, there was no difference in the progression of CIMT over 2 years. In the absence of an adverse proatherogenic effect of ezetimibe, the favored explanation lies in the virtually normal CIMT parameters at baseline in the trial participants, which appears to have resulted from long-term statin therapy before the trial began [2C]. The most recent large ezetimibe trial, which also appears to have been initially misinterpreted, was the ARBITER 6-HALTS Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00044-1 # 2011 Elsevier B.V. All rights reserved.

trial, in which ezetimibe was compared with extended-release niacin in 208 patients with coronary heart disease or a coronary heart disease risk equivalent, who had previously taken statin monotherapy and were given extended-release niacin (target dose 2000 mg/day) or ezetimibe (10 mg/day) [3C]. The primary end-point was the between-group difference in the change from baseline in the mean common carotid intimamedia thickness after 14 months. It was expected that both interventions would lower LDL cholesterol beyond the reduction produced by previous statin monotherapy, but that niacin would increase HDL cholesterol more than ezetimibe. This proved correct, and the trial was terminated early, after 14 months, when it was discovered that extended-release niacin caused significant regression of carotid intima-media thickness when combined with a statin and that niacin was superior to ezetimibe. The greater benefit with niacin in this study has cast further doubt on the usefulness of ezetimibe, an interpretation that appears to be unjustified. Several studies in which ezetimibe was co-administered with a statin in comparison with the statin alone, for example atorvastatin, have shown no significant differences between the two treatments in serious adverse events involving the liver or muscle [4C]. Musculoskeletal Serious myopathy has been studied in a systematic review of PubMed listed studies of ezetimibe alone or combined with a statin. The frequency of musculoskeletal disorders was identical with placebo or, in the case of combination therapy, with the 921

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frequency associated with the statin [5M]. It should be noted that these reports relate to serious events defined as myopathies and not to the occurrence of myalgia, in which no objective measure of muscle damage is demonstrable. Tumorigenicity In the SEAS trial simvastatin 40 mg þ ezetimibe 10 mg was compared with placebo in 1873 elderly subjects with mild to moderately severe aortic stenosis [6C]. The hypothesis was that intensive lipid lowering would reduce the rate of progression of stenosis. The result over 4.1 years did not support the hypothesis, despite a 50% reduction in LDL cholesterol. However, there was a statistically significant increase in the incidence of cancers (93 versus 65 cases in the placebo group). There were several types of cancer but no temporal relation between therapy and diagnosis. Nevertheless, this led to further interim investigations in two larger studies of the combination of simvastatin þ ezetimibe, the SHARP trial [7C] and the IMPROVE-IT trial [8C]. Analysis of the incidences of cancers in all three trials established an overall absence of increased cancer risk compared with placebo in SHARP and compared with simvastatin alone in IMPROVE-IT [9M]. The rates of some cancers rose slightly but the rates of others fell. A very large post-marketing survey based on cancer adverse event reports filed with the FDA did not show excess cancer rates linked to 52 million prescriptions for ezetimibe and 55 million prescriptions for ezetimibe þ simvastatin [10S].

Fibrates [SED-15, 1358; SEDA-30, 515; SEDA-32, 804] Observational studies In a large interventional study of the use of fenofibrate in patients with mostly uncomplicated type 2 diabetes, in which cardiovascular mortality was not reduced, several potentially lifethreatening complications occurred, namely

Paul Nestel

significantly increased incidences of pulmonary thromboembolism and acute pancreatitis [11C]. However, unpublished presentations at major meetings have revealed that these two complications were no longer observed at significant rates in subjects who had continued taking fenofibrate for several more years. However, three clinical laboratory abnormalities that were initially documented in the FIELD study, namely raised concentrations of homocysteine and creatinine (which were correlated) and increased albuminuria have been confirmed in smaller studies. The importance of these potentially serious adverse findings is uncertain. In further analyses of the FIELD study, clear benefits on microvascular complications have become apparent. The need for laser therapy of the retina for diabetic retinopathy and the risk of amputation of the legs (because of both macrovascular and microvascular damage) were significantly less in those who took fenofibrate [12C, 13C]. Systematic reviews In a meta-analysis of 18 prospective randomized controlled trials of fibrates, involving 45 058 patients, the frequency of serious adverse events was not significantly increased; furthermore, the risk of progression of albuminuria was significantly reduced, despite a rise in serum creatinine [14M].

Bezafibrate Cardiovascular In a 2-year, double-blind, placebo-controlled study of 108 patients with coronary artery disease and class III heart failure, enrolled in the Bezafibrate Infarction Prevention Study, bezafibrate caused a small increase in the concentration of N-terminal pro-B type natriuretic peptide (ProBNP) [15C]. However, the patients who took bezafibrate were older and had lower baseline ProBNP concentrations, and there were no significant differences in ProBNP concentrations between the groups after 2 years.

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Fenofibrate Musculoskeletal The major concern about myopathy when fibrates are combined with statins, as in the cerivastatin þ gemfibrozil disaster, has largely abated. Several large analyses have not shown an increased risk of serious adverse events when fenofibrate was co-administered with a statin. Specifically, the frequency of myopathy was not increased when fenofibrate was added to a statin [16c]. The frequencies of raised creatine kinase activities to more than 5–10 times the upper limit of the reference range, signifying probable muscle damage, were the same with fenofibrate þ a statin as with a statin alone; however, raised liver transaminases (more than three times the upper limit of the reference range) appeared to occur slightly more often with additional fibrate [17C].

923 the INR rose from a stable value of 2.0–3.0 to 5.8 after he had taken gemfibrozil 600 mg bd for 3 weeks. He denied any changes in dietary vitamin K or alcohol use or the use of non-prescription or herbal agents. No other causes could be found. The dose of warfarin was reduced to 35–37.5 mg/week (a 22% reduction) and a therapeutic INR was maintained until gemfibrozil was later withdrawn because of myalgia. After consecutive subtherapeutic INRs, the dose of warfarin was increased to 45 mg/week and a therapeutic INR was maintained.

The exact mechanism of the proposed interactions between fibric acid derivatives and warfarin is not known but may be inhibition of CYP isoenzymes, displacement from protein binding sites, or changes in coagulation factor synthesis. The authors recommended that, regardless of the fibric acid derivative chosen, a dosage reduction of 20% and close INR monitoring are warranted in patients taking warfarin.

Gemfibrozil Musculoskeletal Myositis has been described in a patient with normal renal function taking gemfibrozil monotherapy [18A]. Drug–drug interactions Tiagabine An interaction of gemfibrozil with tiagabine has been reported [19A]. • A 39-year-old man took oral tiagabine 16 mg tds and carbamazepine 500 mg bd for complex partial seizures secondary to mesial temporal sclerosis. He was given gemfibrozil for type IV hypertriglyceridemia and reported severe confusion and altered consciousness soon after a single dose of 600 mg. Later, after a controlled challenge with a single dose of gemfibrozil 300 mg, he developed lightheadedness, and the total tiagabine serum concentrations rose by 59% and 75% at 2 and 5 hours respectively, without a significant change in baseline carbamazepine concentrations.

Warfarin An interaction of gemfibrozil with warfarin [SED-15, 1361] has again been described and the interaction reviewed [20AR]. • In a 62-year-old man who was taking warfarin 45 mg/week for paroxysmal atrial fibrillation

Fish oils [SED-15, 1364; SEDA-30, 515; SEDA-32, 806] Cardiovascular In a systematic review of deaths in 12 randomized controlled trials of fish oil as dietary supplements in 32 779 patients there was no beneficial effect in three studies (n ¼ 1148) of implantable cardiac defibrillators (OR ¼ 0.90; 95% CI ¼ 0.55, 1.46) or in six studies (n ¼ 31 111) of sudden cardiac death (OR ¼ 0.81; 0.52, 1.25). In 11 studies (n ¼ 32 439 and n ¼ 32 519) there was a reduction in deaths from cardiac causes (OR ¼ 0.80; 0.69, 0.92) but no effect on dysrhythmias or all-cause mortality [21M]. However, it was later pointed out that there is some evidence that fish oils may be dysrhythmogenic in some subgroups of patients with heart disease [22r]. These include an increased risk of ventricular tachycardia in patients with implantable cardiovertor defibrillators whose primary dysrhythmia was ventricular tachycardia [23C], and an increased risk of cardiac death in patients with angina [24C].

924

HMG-CoA reductase inhibitors [SED-15, 1632; SEDA-30, 516; SEDA-31, 715; SEDA-32, 807] The safety of HMG-CoA reductase inhibitors (statins) has been assessed repeatedly in studies involving hundreds of thousands of patients. Those who have participated in trials have included healthy people in primary prevention trials, but they have mostly been patients at increased risk, varying from very high to relatively low risk, but still exceeding that among healthy subjects. Included in the high-risk category are those with a previous cardiovascular event; more recently patients with diabetes mellitus have been included in this category, although not with absolute unanimity. Many studies have compared different statins at different dosages, often in conjunction with other lipid-modifying agents that alter the risk. Recent concern has centred on the likelihood of a small but significant increase in the incidence of diabetes. Concern about an increased risk of cancer arises regularly, but has again been recently refuted in a large analysis (see below). Comparative studies Adverse events have been studied in 10 384 patients taking rosuvastatin and 14 854 taking other statins [25C]. There were two cases of myopathy, one with rosuvastatin and one with another statin. The relative risk of myopathy in patients taking rosuvastatin compared with other statins was 1.31 (95% CI ¼ 0.13, 13). There were two cases of rhabdomyolysis among current rosuvastatin users, i.e. 2.9 per 10 000 person-years (95% CI ¼ 0.8, 11) and no cases of acute liver injury. There were 17 cases of acute renal insufficiency (five with rosuvastatin, 12 with other statins) and the relative risk in rosuvastatin users compared with other statins was 0.49 (95% CI ¼ 0.16, 1.50). There were 285 deaths (87 among rosuvastatin users, 198 among those taking other statins), and the relative risk was 0.42 (95% CI ¼ 0.32, 0.57). The same group found similar results in a study of 10 289 patients taking

Chapter 44

Paul Nestel

rosuvastatin and 117 102 taking other statins, using the UK General Practice Research Database (GPRD) [26C]. Combination studies Statins þ fibrates Fibrates, such as gemfibrozil or fenofibrate are valuable in the management of disorders that are characterized by hypertriglyceridemia as the major abnormality or more frequently together with a statin or other lipid-modifying drug when LDL cholesterol concentrations are also increased. The adverse effects of combinations of statins and fibrateshave been reviewed [27R, 28R]. Furthermore, in a recent large study of fenofibrate, the FIELD study, there were unexpected adverse events, albeit in very few individuals, that have led to debate about the cost-benefit of fibrate therapy [11C]. Nevertheless subsequent analysis showed significant protection against progressive retinopathy in this trial [13C]. Comparative studies Reports of the recognized adverse effects of statins on muscle and liver have been published as comparisons of the most recent statins (rosuvastatin, atorvastatin, pitavastatin) or from meta-analyses. A comparison of rosuvastatin and atorvastatin included some 20 000 patients studied in 25 trials [29M]. There were no differences between the two statins at any doses or at any dose ratio of the two. The incidences of myalgia and of rises in liver and muscle enzymes were similar and resembled the incidences reported in earlier studies. There were no cases of rhabdomyolysis, which was not surprising, since the expected incidence is in the region of one case per 100 000. Since adverse effects on renal function were suggested during the initial process of registering rosuvastatin, several of the reports focused on glomerular filtration rate (GFR); however, both statins improved GFR to about the same extent. Pitavastatin, which is marketed in Japan, has been compared with atorvastatinin in a randomized trial in 250 subjects; the authors claimed that there were significantly fewer adverse effects with pitavastatin in terms of raised liver enzymes

Drugs that affect lipid metabolism

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[30C]. This may reflect differences in metabolism—CYP3A4 for atorvastatin and CYP2C9 for pitavastatin.

Musculoskeletal Myalgia, myopathy, and rhabdomyolysis due to statins.

Metabolism Of considerable importance is the consistency with which small but important increments in the incidence of new diabetes mellitus have been reported in patients taking statins. This adverse effect was noted in the early Heart Protection Study with simvastatin (although it was not statistically significant) and in the ASCOT Trial with atorvastatin; in both trials the hazard ratio for type 2 diabetes was 1.15 [31R]. Atorvastatin at different dosages (10–80 mg/day) compared with placebo reduced insulin sensitivity significantly within 2 months as glycemia increased. Confirmation that statins can be associated with new-onset diabetes came with the publication of the JUPITER trial, a primary prevention trial of rosuvastatin in 17 802 apparently healthy subjects [32C]. The trial was stopped after a median period of only 1.9 years, because of a clear reduction in cardiovascular outcomes in the treated group. However, physician-reported type 2 diabetes was reported significantly more often with rosuvastatin than placebo (270 versus 216 cases). This finding stimulated a meta-analysis of 13 randomized statin trials involving 91 140 patients, of whom 4278 developed newly diagnosed diabetes; 2226 had been assigned to a statin and 2052 to placebo. The odds ratio of 1.09 was not statistically significant. The authors concluded that the risk of diabetes was small in relation to the large benefit in reducing cardiovascular events. Urinary tract The initial concern with rosuvastatin, which has now abated, was the occurrence of minimal proteinuria (which was subsequently shown to occur with other statins) and a rise in serum creatinine concentration. In a placebo-controlled study of the role of rosuvastatin 10 mg/day in about 2500 patients in heart failure, a minor rise in creatinine after treatment for 1 year was similar to the rise in the placebo group [33C].

EIDOS classification: Extrinsic species HMG Coenzyme A reductase inhibitors Intrinsic species Skeletal muscle mitochondria Distribution Skeletal muscle Outcome Necrosis Sequela Myalgia, myopathy, and rhabdomyolysis due to statins DoTS classification: Dose-relation Collateral Time-course Intermediate Susceptibility factors Genetic (the C-allele of the rs4149056 SNP in SLCO1B1 on chromosome 12; COQ2 mutations); age (over 65 years); drugs (fibrates; compounds that inhibit statin metabolism, e.g. grapefruit); diseases (hypothyroidism; trauma and physical exertion; nephrotic syndrome) The classification and management of muscle disorders due to statins are beginning to become clearer. It is now recognized that as many as 10% of patients who take a statin will develop muscle symptoms of varying severity. Myalgia remains the main therapeutic problem, and although it is not a major health concern, it occurs with sufficient frequency to affect adherence to therapy. However, most reviews of adverse effects focus on the much rarer myopathy or the very rare but potentially fatal rhabdomyolysis. Statins are mostly well tolerated, and minor myalgia is rarely a reason for withdrawal [34M]. Muscle-related problems include myalgia without raised muscle creatine kinase activity, raised creatine kinase activity alone, and severe muscle pain with or without a raised creatine kinase activity to more than 10 times the upper level of the reference range. Exercise can cause myalgia and increased serum creatine kinase activity in patients taking even low

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doses of a statin [35C]. Substantial muscle damage or rhabdomyolysis can cause acute renal failure and death. Serious adverse effects are more likely in elderly patients and in those with diabetes and pre-existing hepatic or renal impairment. Serious myopathy has been estimated to occur once in about 30 000 treatments and rhabdomyolysis about three times less often. Statin-induced muscle disorders are associated with one candidate gene, which has been reported in several publications. A variant of the SLCO1B1 gene can lead to suboptimal hepatic uptake of statins, resulting in high circulating concentrations at conventional dosages. The gene encodes a polypeptide that regulates the uptake of statins by the liver. The variant affects 15% of the population, giving an odds ratio for myopathy of 4.5 [36C]. Patients with this variant can be successfully treated by titrating the dosage to very small amounts and/ or administering the drug only every second day. In one patient with myopathy associated with pravastatin, the function of a novel mutation (c.1628T>G, p.Leu543Trp) in the SLCO1B1 gene was studied [37AE]. OATP1B1 variants with the mutation (OATP1B1*1aþc.1628T>G or *1bþc.1628T>G) had reduced transporting activity for typical substrates and pravastatin compared with other variants (OATP1B1*1a or *1b), with a reduction in the Vmax of transport and a normal KM. The variant was normally expressed on the plasma membrane of HEK293 cells, suggesting that the mutation reduced the function of OATP1B1, probably by reducing its turnover rate. Tumorigenicity The remote possibility that cancers may be attributable to statins has been constantly under watch, and several studies have shown that there is no increased risk. In a 26-year prospective study in the UK in patients who took statins for 46 580 person-years, 90 subjects died from cancers, one-third fewer than the fatality rate from cancers in the general population [38C]. In a meta-analysis of 15

Paul Nestel

controlled trials involving 437 017 personyears, a metaregression analysis showed that statins did not affect the risk of cancers across all concentrations of LDL cholesterol [39M]. Susceptibility factors Ethnicity The special risk of adverse effects among Asians has been confirmed, as Asians participate more widely in trials of statins. It had been claimed for some time that Asians appear to require lower doses than Caucasians in order to achieve optimal LDL targets, and it now seems likely that clearance of statins from plasma among Asians is less efficient than among Caucasians [40c].

Atorvastatin Placebo-controlled studies Atorvastatin 10 mg/day has been compared with placebo in 2838 patients with type 2 diabetes mellitus and no history of coronary heart disease over 3.9 years [41C]. The percentages of patients with treatment-associated adverse events, serious adverse events, and who withdrew because of adverse events respectively were 23% versus 25%, 1.1% versus 1.1%, and 2.9% versus 3.4%. The most common treatment-associated adverse events were gastrointestinal (8.9% versus 10%) and there was myalgia in (5.0% and 6.0%). Endocrine In 77 men with coronary heart disease atorvastatin 40–80 mg/day and for 12 weeks had no significant effects on serum total testosterone, free testosterone, sex hormone-binding globulin, luteinizing hormone, or follicle stimulating hormone compared with 83 men who took 10–20 mg/day [42C]. Liver Severe acute hepatitis with symptomatic cholestasis has again been attributed to atorvastatin. This is a rare adverse effect, which cause mixed hepatotoxicity and canalicular cholestasis [43Ar]. In another case, that of a 68-year-old man who was taking

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atorvastatin 20 mg/day, there was repeated cholestatic liver damage without evidence of bile obstruction but with positive serology for antinuclear antibodies, antimitochondrial antibodies, M2 autoantibodies; a liver biopsy showed non-specific changes and the association with the drug was not clear [44A].

18%, but had no significant effect on its Cmax or half-life; it had minimal effect on parahydroxyatorvastatin AUC [50C]. The authors suggested that these results could be explained by inhibition of P-glycoprotein by istradefylline.

Urinary tract A 77-year-old woman took atorvastatin 5 mg/day for 1 week and developed hemorrhagic cystitis, which resolved on withdrawal [45A]. Immunologic A vasculitis with a positive titer of P-ANCA (1:160) in a 45-year-old man has been attributed to atorvastatin 10 mg/day, which he had taken for 6 months [46A]. A drug reaction with eosinophilia and systemic symptoms (DRESS) has been attributed to atorvastatin in a 58-year-old woman after 6 weeks of therapy [47A]. Genotoxicity Lymphocytes exposed in vitro to the peak concentration of atorvastatin that would be achieved in a patient weighing 70 kg and taking 80 mg/day showed genotoxic changes, using comet assays to evaluate basal DNA damage and possible oxidative DNA damage produced by reactive oxygen species [48E]. Tail length, tail intensity, and tail moment were significantly increased, which suggests that oxidative stress is likely to be responsible for the DNA damage that was detected. Drug–drug interactions Dabigatran In an open, randomized, three-way crossover study in 22 healthy volunteers, atorvastatin 80 mg/day had no effect on the pharmacokinetics or pharmacodynamics of dabigatran 150 mg bd, and vice versa [49C]. Istradefylline In 20 subjects who took a single dose of atorvastatin 40 mg before and after steady-state therapy with istradefylline 40 mg/day (n ¼ 16) or placebo (n ¼ 4) for 14 days, istradefylline increased atorvastatin Cmax by 53%, the AUC by 54%, and the half-life by 27%; it increased the AUC of orthohydroxyatorvastatin by

Omega-3-acid ethyl esters In a randomized, open, repeated-dose, two-way crossover, interaction study omega-3-acid ethyl esters 4 g/day had no effect on the steady-state pharmacokinetics of atorvastatin 80 mg/ day in 50 healthy adults [51c]. Thienopyridines In an open, randomized, crossover, two-arm, parallel-group study in 69 health men, aged 18–60 years, atorvastatin 80 mg/day had no effects on the antiplatelet actions of the thienopyridines prasugrel and clopidogrel [52C].

Pravastatin Gastrointestinal Colitis has been attributed to pravastatin in an 80-year-old woman within 48 hours of starting treatment [53A]. Colonoscopy showed diffuse ulceration throughout the colon with relative sparing of the rectum, and biopsies showing ulceration and inflammation. The authors thought that the combination of pravastatin with amitriptyline could have caused this uncommon complication. Skin An erythematous pigmented rash has been attributed to olanzapine in a severely depressed 55-year-old woman, who was also taking lithium and pravastatin [54A]. The authors proposed that pravastatin and lithium had aggravated the rash. Drug–drug interactions Rifampicin In a single-blind, placebo-controlled, crossover study in 12 healthy Chinese men a single oral dose of rifampicin 600 mg increased the Cmax and AUC and reduced the apparent oral clearance of pravastatin 20 mg/day [55c]. Since rifampicin is an enzyme inducer, it would normally have been expected to do the opposite; the authors

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proposed that it inhibited the hepatic uptake and biliary secretion of pravastatin.

Paul Nestel

NICOTINIC ACID DERIVATIVES [SED-15, 2512; SEDA-32, 815]

Rosuvastatin

Niacin

Drug–drug interactions Omega-3-acid ethyl esters In an open, randomized, twoway crossover study omega-3-acid ethyl esters 4 g/day had no effect on the steadystate pharmacokinetics of rosuvastatin 40 mg/day in 48 adults [56c].

Observational studies In 71 subjects with low HDL cholesterol, 12 months of treatment with niacin significantly reduced carotid plaque wall area [63c].

St John's wort Reduced efficacy of rosuvastatin 10 mg/day has been attributed to enzyme induction by St John's wort in a 59-year-old black man [57A].

Simvastatin Immunologic Dermatomyositis with positive Mi-2 antibodies has been attributed to simvastatin in a 71-year-old woman [58A]. Drug overdose Rhabdomyolysis occurred in a 57-year-old woman who accidentally took four times the prescribed dose of simvastatin for 18 days [59A]. In another case, a 39-year-old woman mistakenly took simvastatin for weight reduction and developed a bilateral leg compartment syndrome and acute renal insufficiency due to myonecrosis [60A]. Drug–drug interactions Erlotinib Rhabdomyolysis due to an interaction of simvastatin with erlotinib in a 75-year-old woman has been attributed to inhibition of CYP3A4 by erlotinib [61A]. Podophyllotoxin In four patients concurrent administration of a podophyllotoxincontaining cytotoxic drug and simvastatin caused muscle pain, soreness, fatigue, or weakness, and in some cases rhabdomyolysis. These effects were attributed to competitive inhibition of CYP3A4-mediated metabolism of simvastatin [62A].

Comparative studies In the ARBITER 6HALTS ER niacin þ simvastatin was compared with ezetimibe þ simvastatin [3C]. It was expected that both interventions would lower LDL cholesterol beyond that due to the statin but that niacin would additionally raise HDL cholesterol more than ezetimibe. This proved correct, and in fact the trial was halted prematurely at 14 months when the progression of carotid intimamedia thickness among the 208 patients was significantly slowed only in the niacin group. It should be noted that this study does not diminish the benefits attributable to lowering LDL cholesterol but focuses on the additional value of raising HDL cholesterol, which will be the major target in future with nicotinic acid formulations, especially those that are associated with tolerable degrees of flushing. Niacin has also been trialled in combination with a statin and its safety compared with a statin alone [64C]. Flushing occurred in 67% of patients and was the most common treatment-related adverse effect; 21% of patients stopped taking niacin for a variety of symptoms and the incidence of adverse effects apart from flushing was 85%. There were three cases of chest pain, which were regarded as serious adverse events. Gastrointestinal discomfort was not uncommon. Fasting blood glucose concentrations rose by 7.7% over the 12 weeks of the study. In contrast in another study there was improved whole-body insulin sensitivity in an open study over 6 months [65c]. Drug formulations The development of an extended-release formulation of nicotinic acid, named ER niacin has been an

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advance. The circulating concentrations of the drug, when it is given once or twice a day in this formulation, are much less variable, and severe flushing does not occur in the majority of patients. The demonstration of a specific prostanoid receptor in the skin, with which prostaglandin PGD2 interacts to cause flushing, has led to the use of a combination of ER niacin with laropiprant (a specific antagonist at prostaglandin D1 receptors), which has further reduced the adverse effects of niacin [66c]. This combination has been accepted in some major countries in Europe and Asia but not in the USA. To date there have been no reports of serious adverse effects attributable to laropiprant, but its usage is recent. Efficacy and safety studies with ER niacin have shown benefit, albeit with some safety concerns that were reported many years ago with nicotinic acid, such as small increased risks of hyperglycemia and hyperuricemia. The addition of laropiprant to ER niacin significantly reduced the frequency of flushing in a worldwide, multicenter, doubleblind, randomized 24-week study in 800 subjects with dyslipidemia randomized to active treatment (n ¼ 543) compared with placebo (n ¼ 270), using an electronic diary to record and transmit the incidence and severity of flushing episodes [67C]. Nevertheless, 29% withdrew, compared with 11% of those taking placebo. The addition of laropiprant to ER niacin did not affect the reduction in LDL cholesterol (20%) and triglycerides (25%) or the increase in HDL (20%); lipoprotein(a) was also reduced, nicotinic acid being one of the few drugs capable of a significant effect. The laboratory safety data showed that about 1% of those taking either ER niacin or ER niacin þ laropiprant had increases in hepatic aminotransferase activities to more than three times the upper limit of the reference range. Creatine kinase activity increased to more than 10 times the upper limit of the reference range in three of 762 patients taking the combined therapy. Five of 661 taking the combined therapy developed diabetes mellitus compared with none of those taking placebo. There was

worsening of pre-existing diabetes in 19 of 78 taking ER niacin alone and in 23 of 137 taking ER niacin þ laropiprant; however none of these was significantly different from placebo (two of 38). There were no cases of myopathy. Six patients, three in each treatment group, developed gout, and uric acid rose by 40 mmol/l in both groups. In a 12-week study of 1398 patients taking ER niacin 2 g/day and laropiprant 20 mg/day, plus increasing doses of simvastatin, the maximum reduction in LDL cholesterol was 48% and the maximum increase in HDL cholesterol was 27% [68C]. Flushing and gastrointestinal symptoms were the main reasons for withdrawal, but the rate was regarded as low. The low incidence rates of increased hepatic transaminase and creatine kinase activities were similar across the treatment groups. Fasting blood glucose rose by 0.22 mmol/l and uric acid by 20 mmol/l.

Torcetrapib

[SEDA-32, 817]

Cardiovascular As was reported in SEDA32 (p. 817), ILLUMINATE, an outcome study that recruited around 15 000 statineligible patients with coronary heart disease or type 2 diabetes mellitus was terminated after a median follow-up of only 550 days, because of a small but significant increase in major cardiovascular events in those taking torcetrapib þ atorvastatin compared with those taking atorvastatin alone (49 versus 35 cardiovascular deaths) [69C]. This occurred despite a 72% increase in HDL cholesterol and a 25% reduction in LDL cholesterol compared with the statin alone. This was almost certainly correctly attributed to activation of the renin–angiotensin–aldosterone system, resulting in increments in blood pressure and aldosterone and reduced potassium. In a placebo-controlled study (RADIANCE 2) in 752 subjects, torcetrapib failed to improve carotid-intima thickness and confirmed the blood pressure raising effect [70C].

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This experience is worth revisiting. Does it suggest that such large effects on HDL cholesterol cannot overcome the adverse effects of a modest increase in blood pressure? Does that itself cast some doubt on the HDL hypothesis, or will other inhibitors of cholesterol ester transfer protein (CETP) reveal problems not associated with blood pressure? Several major companies are advanced in their trials of CETP inhibitors. One, anacetrapib, has been found to be free of the mineralocorticoidrelated blood pressure effects and is equipotent with torcetrapib and another compound already in a large outcome trial. These inhibitors bind CETP to HDL and there are differences between the compounds to the extent of the reversibility of the binding [SEDA-32, 816]. The failure of torcetrapib has led to a reexamination of the safety of raising HDL concentrations excessively and the possibility that high concentrations of the very large

Paul Nestel

cholesterol-rich HDL may be dysfunctional. A genetic variation that confers low CETP concentrations and therefore increases HDL cholesterol concentrations is associated with an increased 10-year mortality mainly of cardiovascular origin; carriers of the TaqIB-B2 allele had reduced CETP and higher HDL cholesterol concentrations, but higher risks of death from all causes and specifically from atherosclerotic disease and ischemic heart disease; one risk-haplotype was identified that was highly significantly associated with these end-points [71C]. Small numbers of patients with very high HDL concentrations in trials involving statins have been reported as having experienced an increased risk of cardiovascular events. The HDL hypothesis has been returned to the laboratory for further testing of dysfunctionality, but at this stage the paradigm that higher HDL concentrations are protective has not been seriously damaged.

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lipoprotein cholesterol, and risk of cancer. J Am Coll Cardiol 2008; 52(14): 1141–7. Liao JK. Safety and efficacy of statins in Asians. Am J Cardiol 2007; 99(3): 410–4. Newman CB, Szarek M, Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Demicco DA, Auster S, Fuller JH. Cards Investigators. The safety and tolerability of atorvastatin 10 mg in the Collaborative Atorvastatin Diabetes Study (CARDS). Diab Vasc Dis Res 2008; 5(3): 177–83. Kocum TH, Ozcan TI, Gen R, Tekin A, Erol T, Akcay B, Doven O. Does atorvastatin affect androgen levels in men in the era of very-low LDL targeting therapy? Exp Clin Endocrinol Diabetes 2009; 117 (2): 60–3. Rahier JF, Rahier J, Leclercq I, Geubel AP. Severe acute cholestatic hepatitis with prolonged cholestasis and bileduct injury following atorvastatin therapy: a case report. Acta Gastroenterol Belg 2008; 71(3): 318–20. Minha S, Golzman G, Adar I, Rapoport M. Cholestatic jaundice induced by atorvastatin: a possible association with antimitochondrial antibodies. Isr Med Assoc J 2009; 11(7): 440–1. Martinez-Suarez HJ, Wang R, Faerber GJ. Atorvastatin-induced hemorrhagic cystitis: a case report. Urology 2009; 73(3): 681. e5–6. Haroon M, Devlin J. A case of ANCAassociated systemic vasculitis induced by atorvastatin. Clin Rheumatol 2008; 27 (Suppl 2): S75–7. Gressier L, Pruvost-Balland C, Dubertret L, Viguier M. Syndrome d'hypersensibilité médicamenteuse induit par l'atorvastatine. [Atorvastatin-induced drug reaction with eosinophilia and systemic symptoms (DRESS).] Ann Dermatol Venereol 2009; 136(1): 50–3. Gajski G, Garaj-Vrhovac V, Orescanin V. Cytogenetic status and oxidative DNAdamage induced by atorvastatin in human peripheral blood lymphocytes: standard and Fpg-modified comet assay. Toxicol Appl Pharmacol 2008; 231(1): 85–93. Stangier J, Rathgen K, Stähle H, Reseski K, Körnicke T, Roth W. Coadministration of

dabigatran etexilate and atorvastatin: assessment of potential impact on pharmacokinetics and pharmacodynamics. Am J Cardiovasc Drugs 2009; 9(1): 59–68. Rao N, Dvorchik B, Sussman N, Wang H, Yamamoto K, Mori A, Uchimura T, Chaikin P. A study of the pharmacokinetic interaction of istradefylline, a novel therapeutic for Parkinson's disease, and atorvastatin. J Clin Pharmacol 2008; 48(9): 1092–8. Di Spirito M, Morelli G, Doyle RT, Johnson J, McKenney J. Effect of omega3-acid ethyl esters on steady-state plasma pharmacokinetics of atorvastatin in healthy adults. Expert Opin Pharmacother 2008; 9 (17): 2939–45. Farid NA, Small DS, Payne CD, Jakubowski JA, Brandt JT, Li YG, Ernest CS, Salazar DE, Konkoy CS, Winters KJ. Effect of atorvastatin on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in healthy subjects. Pharmacotherapy 2008; 28(12): 1483–94. Mukhopadhya A, Gilmour H, Plevris J. Pravastatin-induced colitis. Eur J Gastroenterol Hepatol 2008; 20(8): 810–2. Walder A, Baumann P. Mood stabilizer therapy and pravastatin: higher risk for adverse skin reactions? Acta Medica (Hradec Kralove) 2009; 52(1): 15–8. Deng S, Chen XP, Cao D, Yin T, Dai ZY, Luo J, Tang L, Li YJ. Effects of a concomitant single oral dose of rifampicin on the pharmacokinetics of pravastatin in a twophase, randomized, single-blind, placebocontrolled, crossover study in healthy Chinese male subjects. Clin Ther 2009; 31(6): 1256–63. Gosai P, Liu J, Doyle RT, Johnson J, Carter R, Sica D, McKenney JM. Effect of omega-3-acid ethyl esters on the steadystate plasma pharmacokinetics of rosuvastatin in healthy adults. Expert Opin Pharmacother 2008; 9(17): 2947–53. Gordon RY, Becker DJ, Rader DJ. Reduced efficacy of rosuvastatin by St John's wort. Am J Med 2009; 122(2): e1–2. Rasch A, Schimmer M, Sander CA. Simvastatin-induzierte Dermatomyositis. [Simvastatin-induced dermatomyositis.] Hautarzt 2009; 60(6): 489–93.

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934 [59] Greve T. Et tilfælde af svær rabdomyolyse efter længerevarende overdosering med simvastatin. [Case of severe rhabdomyolysis after protracted overdose of simvastatin.] Ugeskr Laeger 2008; 170(38): 2981. [60] Chochola M, Lubanda JC, Skalicka L, Varejka P, Horejs J, Prskavec T, Balík M, Semrád M, Linhart A. Syndrome de compression des loges bilatéral des membres inférieurs et myonécrose sévère due à l'usage inapproprié de la simvastatine. [Bilateral leg compartment syndrome due to severe myonecrosis caused by inappropriate use of simvastatin.] J Mal Vasc 2008; 33(4–5): 229–33. [61] Veeraputhiran M, Sundermeyer M. Rhabdomyolysis resulting from pharmacologic interaction between erlotinib and simvastatin. Clin Lung Cancer 2008; 9(4): 232–4. [62] Kaipiainen-Seppänen O, Savolainen E, Elfving P, Kononoff A. Adverse muscle effects of a podofyllotoxin-containing cytotoxic drug product with simvastatin. Duodecim 2009; 125(7): 788–91. [63] Lee JMS, Robson MD, Yu LM, Shirodaria CC, Cunnington C, Kylintireas I, Digby JE, Bannister T, Handa A, Wiesmann F, Durrington PN, Channon KM, Neubauer S, Choudhury RP. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function: a randomized, placebo-controlled, magnetic resonance imaging study. J Am Coll Cardiol 2009; 54(19): 1787–94. [64] Insull Jr. W, Basile JN, Vo AN, Jiang P, Thakkar R, Padley RJ. Efficacy and safety of combination therapy with niacin extended-release and simvastatin versus atorvastatin in patients with dyslipidemia: The SUPREME Study. J Clin Lipidol 2009; 3(2): 109–18. [65] Linke A, Sonnabend M, Fasshauer M, Höllriegel R, Schuler G, Niebauer J, Stumvoll M, Blüher M. Effects of extended-release niacin on lipid profile and adipocyte biology in patients with impaired glucose tolerance. Atherosclerosis 2009; 205(1): 207–13.

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[66] Gleim G, Ballantyne CM, Liu N, Thompson-Bell S, Sisk CM, Pasternak RC, Mitchel Y, Paolini JF. Efficacy and safety profile of co-administered ER niacin/laropiprant and simvastatin in dyslipidaemia. Br J Cardiol 2009; 16(2): 90–7. [67] Maccubbin D, Bays HE, Olsson AG, Elinoff V, Elis A, Mitchel Y, Sirah W, Betteridge A, Reyes R, Yu Q, Kuznetsova O, Sisk CM, Pasternak RC, Paolini JF. Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolaemia or mixed dyslipidaemia. Int J Clin Pract 2008; 62(12): 1959–70. [68] Airan-Javia SL, Wolf RL, Wolfe ML, Tadesse M, Mohler E, Reilly MP. Atheroprotective lipoprotein effects of a niacinsimvastatin combination compared to lowand high-dose simvastatin monotherapy. Am Heart J 2009; 157(4): 687.e1–8. [69] Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, Lopez-Sendon J, Mosca L, Tardif JC, Waters DD, Shear CL, Revkin JH, Buhr KA, Fisher MR, Tall AR, Brewer B. ILLUMINATE Investigators. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007; 357(21): 2109–22. [70] Bots ML, Visseren FL, Evans GW, Riley WA, Revkin JH, Tegeler CH, Shear CL, Duggan WT, Vicari RM, Grobbee DE, Kastelein JJ. RADIANCE 2 Investigators. Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial. Lancet 2007; 370(9582): 153–60. [71] Regieli JJ, Jukema JW, Grobbee DE, Kastelein JJ, Kuivenhoven JA, Zwinderman AH, van der Graaf Y, Bots ML, Doevendans PA. CETP genotype predicts increased mortality in statin-treated men with proven cardiovascular disease: an adverse pharmacogenetic interaction. Eur Heart J 2008; 29(22): 2792–9.

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45

Cytostatic and cytotoxic drugs

Editor’s note: The wide range of cytostatic and cytotoxic drugs, the multitude of their adverse effects, and the fact that they are generally used in combinations of several agents all make it impossible to provide as detailed a review of adverse reactions to all the drugs in this field as the Annual gives in others. This year this chapter is devoted to a special review of the taxanes and other microtubule stabilizing agents and a short additional review on the use of carboxypeptidase in the treatment of methotrexate toxicity. Previous special reviews of anticancer drugs in the SEDA series have been as follows: • Anthracyclines (SEDA-25, 533) • Antimetabolites (SEDA-29, 551): Purine antagonists, pyrimidine antagonists, antifolate drugs, phosphatidylcholine antagonists, adenosine deaminase inhibitors • DNA alkylating N-Lost derivatives (SEDA-31, 721) • Fluorouracil (SEDA-23, 476) • Inhibitors of topoisomerase I and topoisomerase II (SEDA-27, 477) • Monofunctional alkylating agents (dacarbazine and temozolomide) (SEDA-32, 827) • Paclitaxel (SEDA-21, 463) • Platinum compounds (SEDA-26, 490) • Tyrosine kinase inhibitors (SEDA-30, 520) • Vinca alkaloids (SEDA-28, 538)

Taxanes and other microtubule stabilizing agents Microtubules play an important role in various cellular functions, including intracellular transport, maintenance of cell shape and polarity, cell signaling, and cell division by mitosis. Their role in cell division in particular makes them suitable as targets for anticancer drugs. The taxane chemotherapy drugs paclitaxel and docetaxel exert their cytotoxic effect by stabilizing microtubules, promoting polymerization, and suppressing microtubule dynamics. This leads to cell cycle arrest and apoptosis. Both paclitaxel and docetaxel have significant antitumor activity against a variety of solid tumors, both as monotherapy and in combination with other chemotherapeutic drugs. More recently, a new class of microtubule stabilizing agents has emerged, called epothilones. These also have antitumor activity against various solid tumors, including taxane-resistant cancers. Although taxanes and epothilones have a similar mechanism of action, there are important differences in both efficacy and toxicity profiles [1R].

Paclitaxel

Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00045-3 # 2011 Elsevier B.V. All rights reserved.

Paclitaxel (TaxolÒ) is a complex plant product derived from the bark of the yew tree, Taxus brevifolia. It is currently indicated for first-line treatment of advanced and metastatic ovarian cancer, metastatic breast cancer (in which it can be given in combination with trastuzumab in patients who 935

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overexpress HER2), non-small cell lung cancer (in combination with platinum agents), and as a single agent for the treatment of AIDS-related Kaposi’s sarcoma in patients who have failed prior liposomal anthracycline therapy [2S]. Paclitaxel, given 3-weekly, was previously indicated in the adjuvant treatment of nodepositive breast cancer, following anthracycline and cyclophosphamide chemotherapy, but a large randomized study showed that weekly paclitaxel or 3-weekly docetaxel regimens are superior [3C]. Thus, in the UK NICE recommends the use of docetaxel rather than paclitaxel as adjuvant treatment for lymph node-positive breast cancer [4S]. Paclitaxel has also been investigated in the treatment of other carcinomas, including melanomas, head and neck cancers, and leukemia. The recommended dosage for the treatment of ovarian and breast cancer is generally 175 mg/m2 given intravenously over 3 hours every 21 days, although various other dosage and administration schedules have been investigated and are appropriate in different settings. In the treatment of AIDS-related Kaposi’s sarcoma the recommended dose is 100 mg/m2 given intravenously over 3 hours every 14 days [2S]. Paclitaxel is poorly water-soluble and so is conventionally administered via a polyoxyethylated castor oil derivative, Cremophor EL, which is a micelle-forming vehicle. This has now been found to affect the pharmacokinetics of paclitaxel, as well as its adverse reactions, as detailed below. More recently, two new formulations have been developed: albumin-bound paclitaxel (marketed as AbraxaneÒ) and docosahexaenoic acid paclitaxel (DHA paclitaxel, marketed as TaxoprexinÒ). Both have different pharmacokinetics and adverse reactions from conventional paclitaxel, as discussed separately below.

formation of the mitotic spindle during cell division, but they are also active in many interphase functions, such as cellular motility, intracellular transport, and signal transmission. Paclitaxel inhibits the depolymerization of tubulin, and the microtubules formed in the presence of paclitaxel are extremely stable and dysfunctional. This stabilization impairs the essential assembly and disassembly required for dynamic cellular processes, and death of the cell results through disruption of the normal microtubular dynamics required for interphase processes and cell division. In tumor cells cytotoxicity is represented by the appearance of abnormal microtubular bundles, which accumulate during G2 and mitosis, blocking the cell cycle [7R]. There is also increasing evidence that paclitaxel has antiangiogenic effects, via selective inhibition of endothelial cell proliferation, migration, and tube formation [8E, 9R].

Mechanism of action Paclitaxel acts by enhancing microtubule assembly and stabilizing microtubules [5R, 6R]. Microtubules consist of polymers of tubulin in dynamic equilibrium with tubulin heterodimers. The principal function of microtubules is

Avinash Gupta and Mark Middleton

Pharmacokinetics The pharmacokinetics of paclitaxel depend on both its schedule of administration and its formulation. Conventional paclitaxel administered in Cremophor EL has non-linear pharmacokinetics [10r]. Both biphasic [11c] and triphasic [12C] models have been reported. Peak plasma concentrations and drug exposure increase disproportionately with increasing doses. For a 30% increase in dose from 135 to 175 mg/m2, the Cmax and AUC increase by 75% and 81% respectively [2S]. The duration of paclitaxel infusion also influences the peak plasma concentration, as well as the half-life. In 25 patients treated with paclitaxel 100 mg/m2 weekly, administered over 1 hour or 3 hours there was a significantly longer half-life and higher Cmax in patients who received the shorter infusion [13c]. The half-life of paclitaxel in plasma has been estimated to be 3–53 hours [2S]. The frequency of dosing of paclitaxel also affects its pharmacokinetics, through induction of CYP2C8 and CYP3A4 [14E]. This may have significance as weekly paclitaxel regimens become more popular, because of

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better tolerability and demonstrable responses in patients refractory to 3-weekly regimens [15c, 16R]. Traditionally both saturable distribution and elimination were thought to be the main mechanisms underlying the non-linear pharmacokinetics of paclitaxel [17R]. However, the formulation vehicle Cremophor EL also has a major effect. The clearance of Cremophor EL increases significantly and disproportionately with prolongation of the infusion [18r, 19r]. Indeed, unbound paclitaxel has linear pharmacokinetics, with a half-life of about 22 hours [20r, 21r]. The rate of infusion also has an effect on the adverse reactions profile of paclitaxel. Shorter infusions are associated with less myelotoxicity but more acute hypersensitivity and peripheral neuropathy [22r]. After intravenous administration paclitaxel is widely distributed, despite extensive binding to plasma proteins (89%) [6R]. There is no evidence for accumulation of paclitaxel with multiple treatment courses [2S]. The routes of elimination of paclitaxel have not been fully established in humans. Only a small proportion of the drug (1.3–13%) is excreted unchanged in the urine [23c]. The main route of elimination appears to be via hepatic metabolism (specifically CYP3A4 and CYP2C8 activity) and biliary clearance. The three major metabolites of paclitaxel are 6a-hydroxypaclitaxel, 30 -para-hydroxypaclitaxel, and 6a-30 -para-dihydroxypaclitaxel [24E]. After intravenous administration of paclitaxel, the amounts of each metabolite excreted via the feces were 26%, 2%, and 6% respectively [2S]. The metabolites of paclitaxel do not have significant cytotoxic properties themselves [25E]. The effect of reduced renal function on paclitaxel elimination has not been fully established. However, as renal clearance accounts for only a small proportion of total clearance, dosage modifications are not considered necessary in patients with renal impairment [2S]. Hepatic impairment reduces the elimination of paclitaxel, which in turn results in greater toxicity, particularly hematological

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toxicity and mucositis [26c]. Caution is required in patients with hepatic impairment, and dosage reductions or avoidance are recommended, depending on the severity of liver dysfunction. Total bilirubin in particular is a good predictor of paclitaxel elimination and potential toxicity in patients with liver dysfunction. Based on a study in 35 patients with moderate to severe liver dysfunction treated with paclitaxel monotherapy given over 3 hours, recommendations on dosage adjustments, based on total bilirubin, have been proposed, as outlined in Table 1. Paclitaxel does not penetrate the central nervous system [27c]. It can be detected in ascitic fluid after intravenous administration. There is no evidence that it is secreted in human breast milk, but in lactating rats given radiolabelled drug, concentrations of radioactivity in breast milk were higher than those in plasma and fell in parallel with plasma concentrations. Cardiovascular Paclitaxel has been associated with disturbances in cardiac rhythm, but the relevance of these effects has not been fully established. Originally, all patients in trials of paclitaxel were under continuous cardiac monitoring, owing to the risk of hypersensitivity reactions. Cardiac disturbances were therefore more likely to be detected. Many trials limited eligibility to patients without a history of cardiac abnormalities and to those who were not taking medications likely to alter cardiac conduction. The incidence of cardiac dysrhythmias without paclitaxel treatment is unknown, and it is therefore not always Table 1 Proposed dosage adjustments for paclitaxel in liver impairment Total serum bilirubin

Recommended initial dose of paclitaxel (mg/m2)

1.25  ULN 1.26–2.0  ULN 2.1–3.5  ULN 3.6–10  ULN

175 115 100 70

ULN, upper limit of normal (i.e. the reference range).

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possible to attribute dysrhythmias in these patients to paclitaxel. One mechanism by which paclitaxel affects the heart appears to be through impairment of the autonomic modulation of heart rate [28c]. The most common cardiovascular adverse reactions observed in patients receiving paclitaxel are hypotension and bradycardia [29R]. Hypotension has been observed in up to 23% of patients and is thought to be mostly secondary to hypersensitivity reactions [30r]. Asymptomatic bradycardia occurs in 9–29% of patients, usually starting several hours after the start of infusion and resolving spontaneously on withdrawal [31r]. It is recommended that vital signs should be monitored regularly during the first hour of an infusion [2S]. However, bradycardia is not an indication for withdrawal of treatment altogether, unless it is associated with atrioventricular conduction disturbances or clinically significant effects (such as symptomatic hypotension). The authors of a review of the cardiac toxicity associated with paclitaxel treatment concluded that the overall incidence of serious cardiac events is low (0.1%). The causal relation of paclitaxel to atrial and ventricular dysrhythmias and cardiac ischemia is not entirely clear [32r]. Reported events include ventricular tachycardia, Mobitz I (Wenckebach syndrome), Mobitz II atrioventricular block, complete atrioventricular block (requiring pacemaker insertion), acute myocardial infarction, supraventricular tachycardia, and atrial fibrillation. One patient died in heart failure 7 days after receiving paclitaxel by infusion; this patient had no prior history of cardiac problems, apart from mild hypertension [33A]. Cremophor EL may be implicated in the incidence of dysrhythmias, particularly as a result of hypotension associated with hypersensitivity reactions [34R]. Another mechanism may be through histamine release, which in animals results in conduction disturbances and dysrhythmias [35R]. Routine cardiac monitoring is considered unnecessary in patients without a history of cardiac conduction abnormalities. If a patient has a history of serious cardiac dysrhythmias or develops cardiac dysrhythmias

that are clearly associated with paclitaxel treatment, suitable treatment should be started and paclitaxel should be administered with continuous cardiac monitoring [2S]. Further studies are needed to determine the risks in patients with predisposing cardiac risk factors who are being treated with paclitaxel. A retrospective review of patients with major cardiac risk factors who were treated with paclitaxel (either monotherapy or in combination with cisplatin or carboplatin) did not find any evidence of reduced cardiac function after treatment with paclitaxel. However the series only consisted of 15 patients [36c]. Respiratory The effects of paclitaxel on the respiratory system are mostly related to hypersensitivity reactions, causing dyspnea, with or without bronchospasm. There have been reports of patients who have developed pulmonary infiltrates or interstitial pneumonia after paclitaxel treatment, with an incidence of 3% in one phase II study [37c]. These infiltrates usually resolve spontaneously or after glucocorticoid therapy; once resolved, patients can be successfully rechallenged with paclitaxel without developing recurrent pneumonitis [38A]. There has been one reported death, possibly secondary to paclitaxel-related interstitial pneumonia, in a 71-year-old Japanese man with stage IV non-small cell lung carcinoma [39A]. However, whether death was secondary to progressive disease or interstitial pneumonia was unclear. There have been reports of radiation pneumonitis after chemotherapy with paclitaxel. However, a large phase III study in breast cancer patients showed no significant difference in clinically relevant radiation pneumonitis between patients treated with radiotherapy with or without prior exposure to paclitaxel [40C]. Nervous system Neurotoxicity associated with paclitaxel is dose-related, cumulative, and characterized principally by a sensory peripheral neuropathy, although motor weakness has occasionally been reported [41c]. In patients treated with paclitaxel 135

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or 175 mg/m2 (depending on whether they had had three previous chemotherapy regimens or only one or two respectively), administered over 3 hours every 21 days, grade 1–2 sensory neuropathy occurred in 52%, and grade 3–4 neuropathy occurred in 9% [42C]. Toxicity appears to be related to axonal degeneration and demyelination and is usually reversible after withdrawal [43c]. While withdrawal of therapy is rarely required, peripheral neuropathy has been the dose-limiting adverse reaction in some phase I trials of paclitaxel monotherapy [11c, 21c, 44c]. The intensity of neurotoxicity increases with higher doses [31r, 34c]. While doses up to 725 mg/m2 have been found to be tolerable (when administered as a one-off infusion in combination with other chemotherapy drugs as part of a high-dose chemotherapy treatment regimen) [45c], most cases of neurotoxicity occur at doses over 200 mg/ m2 and particularly after multiple courses monotherapy [11c, 34c, 43c]. Peripheral neuropathy presents as numbness, burning, and tingling in a glove-andstocking distribution. Symptoms usually begin 24–72 hours after treatment with paclitaxel, with a symmetrical distal loss of sensation. Once treatment is stopped, the symptoms generally subside within several weeks to months [34c]. Previous exposure to potentially neurotoxic chemotherapeutic agents, such as platinum compounds and vinca alkaloids, does not appear to increase the risk of neurotoxicity with paclitaxel [5R]. However, patients with co-existing medical illnesses associated with peripheral neuropathy, such as diabetes mellitus and alcohol abuse, may be more likely to develop a peripheral neuropathy. A pre-existing neuropathy as a result of prior therapy is not a contraindication to paclitaxel, but in severe cases of peripheral neuropathy a dosage reduction of 20% is recommended for subsequent courses. Tricyclic antidepressants, in particular amitriptyline and venlafaxine, are helpful in relieving symptoms of paclitaxel-induced peripheral neuropathy [5R, 46A]. Other rare neurological adverse reactions include development of autonomic

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neuropathy, resulting in paralytic ileus, optic nerve and/or visual disturbances, ototoxicity (hearing loss and tinnitus), dizziness, headaches, and convulsions [2S, 44c]. Sensory systems Vision Transient scintillating scotomata have been observed in the visual fields of both eyes in nine patients receiving paclitaxel infusions in doses of 175 and 225 mg/m2 [47r]. Involvement of the optic nerve was confirmed, and this is likely to have been related to optic nerve conduction abnormalities associated with the neurological effects of paclitaxel. The abnormalities were not progressive and there was some degree of recovery, although one patient had permanently impaired vision. Hematologic Bone-marrow suppression is the most common dose-limiting adverse reaction to paclitaxel. Neutropenia occurs most commonly 8–10 days after treatment, and recovery usually occurs by days 15–21. Paclitaxel is relatively platelet sparing, and thrombocytopenia and anemia are rare [21c]. There is no evidence that neutropenia is cumulative, suggesting that paclitaxel may not irreversibly damage hemopoietic stem cells [5R]. Neutropenia is dose- and schedulerelated, and is less common with shorter infusion schedules. At doses of 110–250 mg/m2 over 24 hours, neutropenia is generally severe, and grade 4 neutropenia (absolute neutrophil count below 0.5  109/ l) develops in a large proportion of patients [21c, 48R]. Paclitaxel given as a 3-hour infusion causes less severe neutropenia [41c, 49R]. In a large randomized trial, in which patients received either a 3-hour or a 24hour infusion of 135 or 175 mg/m2, grade 4 neutropenia was more common with the 24-hour infusion regimen; 75% of patients developed severe neutropenia and episodes of fever [50C]. The duration of neutropenia is usually brief, and treatment delays for unresolved adverse hematological reactions on day 21 are rare. Paclitaxel-induced neutropenia does not always lead to infectious complications, and therefore a dosage reduction for

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neutropenia alone is not considered necessary [51C, 52c]. Prior myelotoxic chemotherapy appears to be a major susceptibility factor in determining the severity of neutropenia [5R, 34R]. Doses of 200 and 250 mg/m2 over short infusion times cause minimal myelosuppression in patients who have had minimal prior therapy [21C, 52C]; however, seven patients (1.6%) died because of toxicity in another study in patients with ovarian cancer who had received extensive previous chemotherapy; deaths were due to sepsis or severe neutropenia [34R]. Prior radiotherapy has also been reported to be associated with increased severity of myelosuppression, but this does not appear to be the case. Paclitaxel administered in a weekly regimen rather than the more common 3-weekly schedule has been found to be better tolerated, with less myelosuppression (as well as fewer non-hematological adverse reactions) and comparable, if not improved, efficacy [16R, 53C]. The incidence of neutropenia has also been investigated in combination schedules. Patients who receive paclitaxel in combination with cyclophosphamide have severe neutropenia more often than with monotherapy (72% of patients). Paclitaxel given as a 24-hour infusion before cyclophosphamide is more likely to cause severe neutropenia compared with patients who receive cyclophosphamide first [54R]. Conversely, in studies of paclitaxel and cisplatin combination chemotherapy, myelosuppression is worse when paclitaxel is given after cisplatin rather than before. This appears to be due to reduced plasma clearance of paclitaxel when cisplatin is administered first. Attempts to overcome neutropenia include the use of human granulocyte colony-stimulating factor (G-CSF). The absolute neutrophil counts are generally higher and the duration of severe neutropenia is shorter when G-CSF is given 24 hours after paclitaxel and continued until there is recovery of the neutrophil count. When paclitaxel is given in combination with G-CSF, doses of 250 mg/m2 given over 24 hours every 3 weeks are possible without causing doselimiting neutropenia [49C]. Three-hour

infusion schedules have also been successful using doses of 250 mg/m2 in combination with G-CSF and doxorubicin [55c]. Other dose-limiting adverse reactions, such as neurotoxicity and gastrointestinal adverse reactions, tend to predominate when paclitaxel is given in higher doses in combination with G-CSF. Recommendations currently specify that patients should not be re-treated with paclitaxel until the neutrophil count recovers to 2.5  109/l and the platelet count recovers to over 100  109/l. Gastrointestinal Severe nausea, vomiting, and diarrhea are uncommon with paclitaxel [5R]. Although about half of the patients in one study had vomiting or diarrhea, under 5% were severe [31R]. In another phase II trial there were 11 episodes of nausea and vomiting in 281 courses [48R]. Four patients developed diarrhea, but this was not considered clinically significant. Mucositis and stomatitis have been commonly reported with paclitaxel. Mucositis is characterized by ulceration of the lips, pharynx, and oral cavity, occurring 3–7 days after paclitaxel treatment [21c, 34R, 48R, 49R, 50C, 56C]. Mucositis appears to be more common during treatment of acute leukemias than with solid tumors, when doses above 390 mg/m2 are used [41c]. Severe mucositis occurred during second and third courses, suggesting a cumulative effect, and was more severe if treatment was given at 15 days or earlier after previous courses. Patients with hematological malignancies are more susceptible to breakdown of the mucosal barrier, and this may account for the increased incidence of mucositis. Narcotic analgesics are effective in controlling the pain associated with mucositis [5R]. In a phase I study of intraperitoneal paclitaxel in patients with advanced ovarian cancer, severe abdominal pain was the doselimiting toxicity at doses over 175 mg/m2 [57c]. Significant gastrointestinal adverse reactions have been noted in other trials of intraperitoneal paclitaxel chemotherapy, and this has limited its usefulness as a means of administering chemotherapy via this route [58C, 59r].

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Transient paralytic ileus occurred in two patients in one study [50C]. Both patients had diabetes mellitus, and these symptoms may have been an additional manifestation of autonomic neuropathy. Post-mortem examination of patients treated with paclitaxel has shown mucosal ulcers in the esophagus, stomach, small intestine, and colon [60c]. Changes associated with epithelial necrosis and mitotic arrest were most prominent in patients who had recently been treated with paclitaxel. These findings suggest that paclitaxel causes transient mitotic arrest associated with cell necrosis. Similar findings have been found in studies of the gastrointestinal tract of patients who have received taxane chemotherapy treatment at some time [61c]. Urinary tract Reversible renal insufficiency has been reported in one patient who was treated with paclitaxel by the intraperitoneal route [57c]. Skin Local venous effects, including erythema, tenderness, and discomfort, can occur at the injection site during paclitaxel infusion [34R]. Inflammation is usually evident within hours and normally resolves within 21 days. Inflammation occurs in areas of drug extravasation along with prolonged soft tissue injuries. Necrotic changes have been reported in one patient at the site of extravasation [62r]. A soft tissue injury occurred in one patient at the site of previous extravasation after treatment with paclitaxel in a different limb [63c]. This resolved within 7 days. Inflammation is most likely to be due to the drug, but the Cremophor EL vehicle may also be implicated, as it produces mild inflammation in animals. There is little information on the treatment of extravasation of paclitaxel, as it has not been common during clinical trials. Radiation dermatitis has been reported in a patient who received a single infusion of paclitaxel [64A]. This was attributed to potentiation of radiation effects by paclitaxel, because of the close time relation between the radiotherapy and paclitaxel therapy.

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Hair Alopecia occurs in nearly all patients who receive paclitaxel, but it has unique characteristics. Hair loss is sudden and complete, and many patients often lose all body hair, including axillary and pubic hair, eyelashes, and eyebrows [42R, 65c]. The loss of body hair often occurs with cumulative therapy and is more severe after longer infusion times. Nails Onycholysis occurred in five of 21 patients who received more than six doses of paclitaxel 100 mg/m2/week [66cr]. The authors provided a useful review of onycholysis caused by other chemotherapy drugs. Subungual hemorrhages after paclitaxel treatment have also been reported [67A]. A felon (a closed space infection of the fingertip pulp) was reported in one case [68A]. The infection resolved after removal of the nail to allow drainage of pus, followed by intravenous antibiotics. Musculoskeletal Arthralgia and/or myalgia have been reported in 20–30% of patients receiving paclitaxel; they typically occur 2–5 days after chemotherapy [5R]. Symptoms commonly occur at doses above 170 mg/m2 [50C]. Symptoms of myalgia usually involve the shoulder and paraspinal muscles, while arthralgia is commoner in the large joints of the arms and legs [5R, 34R]. Symptoms can be controlled by nonsteroidal anti-inflammatory drugs [34R] and prophylactic gabapentin [69r]. The incidences of arthralgia and myalgia are also increased in patients who receive G-CSF, in whom symptoms occurred in 86% of patients compared with 28% of patients who received similar doses without growth factor support [51C]. The intensity of myalgia and arthralgia correlated significantly with the total cumulative dose of paclitaxel 210 mg/m2/cycle by 3-hour infusion in 247 patients with a median cumulative dose of 630 mg/m2 [70r]. Immunologic Acute hypersensitivity reactions were common during phase I trials of paclitaxel, and this caused delays in the completion of many trials. Early in the development of paclitaxel, premedication with

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glucocorticoids and antihistamines was introduced to counter these reactions [71r]. Since then, the incidence of mild hypersensitivity reactions has been reported as occurring in under 44% of cases and severe reactions in under 10% [72r]. Symptoms consist of cutaneous flushing, urticaria, bronchospasm, bradycardia, and hypotension; the reactions mostly occur within the first 10 minutes of infusion, usually after either the first or second dose [73r]. Fatal reactions are rare [72r]. Longer infusion schedules are associated with a reduced incidence of hypersensitivity reactions; the frequency of severe reactions is reduced from 12% or more to 5% with longer infusion times [11c, 31R, 73c]. Infusions of less than 1 hour have been found to be intolerable, even with appropriate premedication [74r]. The mechanism of paclitaxel-induced hypersensitivity reactions is uncertain. The symptoms suggest histamine release from mast cells to be a likely cause. Cremophor EL is thought to play a significant role in inducing hypersensitivity reactions. Cremophor EL causes similar reactions in dogs by direct release of histamine [17R]. Hypersensitivity reactions have also been directly linked to complement activation secondary to binding of naturally occurring anticholesterol antibodies to the hydroxyl-rich surface of Cremophor EL micelles [75E]. However, there is evidence that paclitaxel alone, without the Cremophor EL vehicle, can also cause hypersensitivity reactions [76E]. Premedication regimens of glucocorticoids and histamine H1 and H2 receptor antagonists have been used to try to prevent or reduce hypersensitivity reactions. Various phase I trials have been successfully completed using infusion schedules of 1–120 hours and doses of 135–390 mg/m2, with a lower incidence of hypersensitivity reactions [31R, 49R, 42R, 50C, 56c, 65C, 71r]. However, the use of premedication does not completely prevent such reactions. There were incidences of 16%, 13%, and 7% with 3, 6, and 24-hour infusion schedules respectively, despite premedication [71r], while only 1.5% of patients developed

reactions in a trial with doses of 125–250 mg/m2 over 24 hours, with glucocorticoid and histamine receptor antagonist pre-treatment [50C]. Only one patient out of 26 developed a hypersensitivity reaction with doses of 150–250 mg/m2 over 24 hours [21c]. In one study of paclitaxel 175–275 mg/ m2 infused over 6 hours without premedication there was only one hypersensitivity reaction in 32 patients [73c], while patients who received paclitaxel administered over 1 hour with premedication had no serious hypersensitivity reactions [56C]. There were no hypersensitivity reactions in 40 patients who received fractionated doses of paclitaxel administered over 3–5 days, with cumulative doses of 120–250 mg/m2 [77R]. In a randomized comparison of two doses of paclitaxel given by 3-hour or 24-hour infusions, premedication alone was sufficient to prevent hypersensitivity reactions with either infusion duration [50C]. Premedication consisting of dexamethasone 20 mg intravenously 12 and 6 hours before the infusion, and diphenhydramine 50 mg and cimetidine 300 mg intravenously 30 minutes before the infusion are now routinely given before patients are treated with paclitaxel, and this, as well as a recommended infusion time of 3 hours, has reduced the incidence and severity of hypersensitivity reactions. Single-dose dexamethasone 16 mg given 30 minutes before paclitaxel was effective in preventing hypersensitivity reactions in 43 patients [78r] and is now commonly used, although there remain concerns about the effectiveness of this shorter course of premedication [72r]. In a large single-institution study, there was a 9% incidence of clinically important hypersensitivity reactions to paclitaxel in 450 women with gynecological malignancies treated with paclitaxel alone or in combination regimens [79C]. All patients were eventually able to be re-treated with paclitaxel, although in five cases a desensitization regimen was required first. There was also a significant association between bee sting or animal allergy and paclitaxel hypersensitivity in 57 patients with a variety of tumors [80c].

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Drug–drug interactions Interactions with paclitaxel have been reviewed [81R, 82R]. The most important of these are pharmacodynamic interactions with other cytostatic drugs, but pharmacokinetic interactions have also been described. Paclitaxel is metabolized by CYP2C8 and CYP3A4 [23r, 83E], and drugs that inhibit or induce these isoenzymes would be expected to alter the metabolism of paclitaxel. In vitro ranitidine, diphenhydramine, vincristine, vinblastine, and doxorubicin had little or no effect on the metabolism of paclitaxel, but barbiturates stimulated hydroxylation of the side-chain by induction of CYP3A isoforms [83E]. Although cimetidine and famotidine have quite different CYP-modulating abilities, a clinical study showed no difference in paclitaxel clearance or associated neutropenia when cimetidine or famotidine were used as part of the premedication regimen [84c].

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cancer, carboplatin had no effect on the pharmacokinetics of paclitaxel 135–200 mg/ m2 as a 24-hour intravenous infusion [90c]. Peripheral neuropathy occurred in 13 of 37 patients treated with paclitaxel 175 mg/m2 þ carboplatin [91c]. The authors concluded that clinically important neurotoxicity increases with every cycle of chemotherapy. The peripheral neuropathy mainly affected sensory fibers, without involving motor nerves. The same paclitaxel þ carboplatin chemotherapy in 28 women caused no signs of acute central neurotoxicity or neuropsychological deterioration; however, 11 patients had a peripheral neuropathy [92c].

Albumin-bound paclitaxel In recent years, a Cremophor-free formulation of paclitaxel has been developed, with the trade name AbraxaneÒ. It uses nanoparticle albumin-bound (nab) technology as a vehicle for the delivery of paclitaxel. AbraxaneÒ is a Cremophor-free, 130-nanometer particle form of paclitaxel, which delivers paclitaxel as a suspension of albumin particles in saline. It therefore avoids the adverse reactions that are associated with Cremophor EL. It does not need premedication with glucocorticoids and antihistamines. In animals albumin-bound paclitaxel has increased and prolonged antitumor activity and more effective intratumor accumulation of paclitaxel, compared with Cremophorbased paclitaxel [93E]. It is currently licensed for second-line treatment of metastatic breast cancer.

Anthracyclines Paclitaxel given in combination with anthracyclines increases cardiac toxicity. In one study, 35 women with chemotherapy-naive metastatic breast cancer were treated with increasing doses of paclitaxel and doxorubicin in combination. After a median cumulative anthracycline dose of 480 mg/m2, 50% of the patients had a reduced left ventricular ejection fraction and 18% developed reversible congestive cardiac failure [85c]. Paclitaxel also dose-dependently increased the plasma concentrations of doxorubicin and its metabolite doxorubicinol; this was attributed to competition for biliary excretion of taxanes and anthracyclines mediated by P-glycoprotein [86E]. With epirubicin, excretion of the active metabolite epirubicinol is reduced. Two studies of the combination of epirubicin plus paclitaxel have shown less reduction in left ventricular ejection fraction and no clinical evidence of cardiac failure [87c, 88c]. The cumulative dose of anthracyclines remains important and should be lower in combination regimens with paclitaxel, compared with monotherapy [89r].

Pharmacokinetics The apparent volume of distribution and clearance of albuminbound paclitaxel are significantly higher than Cremophor-based paclitaxel, in both animals and humans [94E]. Albumin-bound paclitaxel has linear pharmacokinetics over a dosage range of 135–300 mg/m2 [95c]. The half-life is 22 hours, which is similar to that of Cremophor-based paclitaxel [96R].

Platinum-containing cytotoxic drugs In 21 patients with advanced non-small cell lung

Cardiovascular In most studies to date there has been no significant evidence of

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cardiotoxicity associated with albuminbound paclitaxel. However, in one phase II study in which the drug was administered in a dose of 300 mg/m2 one patient death was considered to have been possibly due to treatment-related cardiac ischemia or infarction [97c].

Gastrointestinal Nausea and diarrhea have been reported in 8–10% of cases, with grade 3 diarrhea in 13% of patients in one phase II trial [97c, 98c, 99c].

Nervous system Most studies of albuminbound paclitaxel have used a higher dose of paclitaxel than with Cremophor-based paclitaxel, and this has correlated with a higher incidence of peripheral neuropathy. In phase II studies, 11–38% of patients had grade 2 or worse sensory neuropathy [97c, 98c, 99c]. In a phase II comparison of 3weekly cycles of albumin-bound paclitaxel 260 mg/m2 and conventional Cremophorbased paclitaxel 175 mg/m2, grade 3 peripheral neuropathy was reported in 10% versus 2% of cases [100C]. Neuropathy typically occurs in a glove-and-stocking distribution, with symptoms of numbness or pain. Perioral numbness has also been reported [95c]. No cases of motor neuropathy have been reported so far.

Musculoskeletal Myalgia and/or arthralgia have been reported in about 7–10% of cases in clinical trials to date [97c, 98c, 99c].

Sensory systems Vision Ocular adverse reactions have been reported in phase I studies, with symptoms of blurred or “smoky” vision, “flashing lights”, and photosensitivity at a dose of 300 mg/m2 and superficial keratopathy during the first cycle of treatment at 375 mg/m2, which constituted the dose-limiting adverse reaction in this study [95c]. Hematologic Although regimens with albumin-bound paclitaxel involve higher doses of paclitaxel, the incidence of myelosuppression is less than with Cremophor-based paclitaxel. This is in keeping with evidence that some of the myelotoxicity of conventional paclitaxel is related to the Cremophor vehicle. Adverse reactions are dose-related. In phase II studies to date, the incidence of grade 2 or worse neutropenia was 28–51% [97c, 98c, 99c]. The risk of grade 2 or worse anemia is reported at 7–31%. Thrombocytopenia is rare. In a direct comparison of albumin-bound paclitaxel and Cremophor-based paclitaxel, the incidences of grade 4 neutropenia were 9% and 22% respectively [100C].

Avinash Gupta and Mark Middleton

Hair In phase II trials alopecia was reported in 60–67% of patients [97c, 98c, 99c].

Immunologic In clinical studies albuminbound paclitaxel has been administered without glucocorticoid or antihistamine premedication. In phase I and phase II studies there were no reported hypersensitivity reactions. In a phase III study in patients with breast cancer there was a <1% incidence of hypersensitivity reactions and no grade 3 or 4 reactions [100C].

Docosahexaenoic acid (DHA) paclitaxel DHA paclitaxel is a novel formulation of paclitaxel, made by covalently conjugating the essential fatty acid DHA to the 20 -OH position on the paclitaxel molecule [101E]. Preclinical studies have suggested that there is increased uptake of fatty acids by cancer cells, for use as biochemical precursors and energy sources [102c]. DHA paclitaxel has been developed as a prodrug that harnesses this process to target tumor cells selectively. It has no cytotoxic activity until it is metabolized intracellularly to the active molecule paclitaxel by hydrolysis [101E]. Animal studies have confirmed higher concentrations of DHA paclitaxel compared with conventional paclitaxel within tumor cells after equimolar dosing [103E]. Pharmacokinetic studies suggest that DHA paclitaxel has a long half-life of 85 hours [102c]. Thus, higher doses of paclitaxel can be delivered to tumor cells for prolonged periods compared with conventional paclitaxel. DHA paclitaxel has been tested in a number of solid tumors so far in phase I and phase II trials and has shown some efficacy

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in esophagogastric cancer [104c] and nonsmall cell lung cancer [105c]. In a phase III trial in patients with metastatic melanoma there was no significant difference in efficacy between 3-weekly DHA paclitaxel and standard dacarbazine [106C]. Both weekly and 3-weekly regimens have been investigated in phase I and phase II trials [107c]. Doses of 900–1100 mg/m2 administered 3-weekly have been reasonably well tolerated. The dose-limiting adverse reactions in phase I and phase II trials have been neutropenia and hyperbilirubinemia [108c]. Significant anemia and thrombocytopenia are relatively uncommon. In a phase II study, two out of four deaths were thought to have been related to DHA paclitaxel, with one death due to neutropenic sepsis and the other secondary to cardiac failure. Postmortem examination in the second case showed diffuse alveolar damage consistent with drug-related pneumonitis [104c]. In a phase III trial three patients died from adverse events thought to be related to DHA paclitaxel. One had congestive cardiac failure, the second had a cardiopulmonary arrest, and the third developed congestive heart failure, pneumonia, and renal failure [106C]. However, the authors did not go into further details regarding these patients and why the deaths were considered to be related to DHA paclitaxel. Other adverse reactions in the phase III study included rashes (24% of patients), fatigue (54%), nausea (39%), diarrhea (18%), constipation (25%), and peripheral edema (13%). In phase I and phase II studies DHA paclitaxel has been administered with glucocorticoid and antihistamine premedication [104c, 108c]. However, there have been reports of hypersensitivity reactions despite this [104c]. A significant difference compared with conventional paclitaxel is the relatively small incidence of peripheral neuropathy and no reports of alopecia so far [102c, 106C].

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Docetaxel

needles of the European yew tree (Taxus baccata). Docetaxel is indicated, in combination with doxorubicin and cyclophosphamide, for adjuvant treatment of node-positive breast cancer and, in combination with doxorubicin, for treating locally advanced or metastatic breast cancer. It is also indicated as monotherapy or in combination with capecitabine for the treatment of locally advanced or metastatic breast cancer in patients who have relapsed or progressed after previous anthracycline or alkylating agents. It can be administered concurrently with trastuzumab, with which it is synergistic in vitro [109r], unlike paclitaxel, which appears to have simply an additive effect with trastuzumab [110E]. Docetaxel in combination with cisplatin is indicated as first-line treatment for advanced non-small cell lung cancer. Docetaxel monotherapy is indicated as second-line treatment for advanced non-small cell lung cancer, following previous platinum-based chemotherapy. Docetaxel in combination with prednisolone is indicated for the treatment of hormone-refractory metastatic prostate cancer. Docetaxel in combination with cisplatin and fluorouracil is indicated in the treatment of gastric adenocarcinoma and locally advanced squamous cell carcinoma of the head and neck [111S]. The recommended dose of docetaxel is generally 75–100 mg/m2, administered intravenously over 1 hour once every 3 weeks. Premedication with dexamethasone is generally given; for example, dexamethasone 8 mg bd for 3 days, starting the day before treatment with docetaxel. This helps to reduce fluid retention, as well as hypersensitivity reactions. Weekly docetaxel regimens have also been investigated, but there are mixed reports regarding tolerability; some studies have reported a fairly similar adverse reactions profile to 3-weekly docetaxel [112C], while others have reported significantly less myelosuppression with the weekly regimens [113R].

Docetaxel is a water-soluble, semisynthetic analogue of paclitaxel, synthesized from the

Mechanism of action Like paclitaxel, docetaxel promotes tubulin assembly in

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microtubules and inhibits their depolymerization [114R]. Compared with paclitaxel, docetaxel has greater affinity for the tubulin-binding site, accumulates in tumor cells to a greater extent, and remains in cells for longer [115R, 116R]. Thus, a lower dose of docetaxel is required to produce the same cytotoxic effect, compared with paclitaxel.

receiving trastuzumab should undergo regular cardiac monitoring, but there is no indication that increased monitoring is required when it is given in combination with docetaxel.

Pharmacokinetics Docetaxel administered intravenously over 1–2 hours has linear pharmacokinetics and the AUC increases proportionately with dose [117R]. Plasma protein binding is 76–89% [118R]. The half-life is 11 hours. Elimination is mainly by biliary excretion into the feces [119R]. In patients with raised bilirubin and/or liver aminotransferases, there is a 12–27% reduction in docetaxel elimination, and dosage reductions should be considered [117R]. In patients with raised bilirubin concentrations or aminotransferases more than 3.5 times the upper limit of the reference range, and alkaline phosphatase more than six times, no recommendations for dosage reduction can be made and docetaxel should be avoided [111S]. Docetaxel is mainly metabolized by CYP3A4. Its metabolism is inhibited by inhibitors of CYP3A4, such as ketoconazole and ritonavir [120c, 121E]. Renal excretion is minimal (<5%) [117R]. Pregnancy There are no data on the use of docetaxel in pregnant women. However, in animals, docetaxel is both embryotoxic and fetotoxic and, like other cytotoxic compounds, it should not be used in pregnancy unless clearly indicated [111S]. Lactation Docetaxel is lipophilic, but it is not known whether it is secreted into breast milk. However, because of the potential for adverse reactions in nursing infants, breastfeeding must be stopped while the mother is receiving docetaxel [111S]. Cardiovascular There are no significant reports of cardiotoxicity associated with docetaxel. The combination of docetaxel þ trastuzumab is not associated with significant cardiotoxicity [122R]. Patients who are

Avinash Gupta and Mark Middleton

Respiratory There are reports of interstitial pneumonitis after treatment with docetaxel [123r, 124A]. In one case series four patients developed symptoms within 1–2 weeks of receiving docetaxel. All ended up requiring mechanical ventilation and two died from progressive pulmonary disease [123r]. The risk of interstitial pneumonitis appears to be greater when docetaxel is given in combination with gemcitabine or radiotherapy [125R]. Nervous system About 30% of patients treated with docetaxel develop symptoms of peripheral neuropathy [112C]. Generally, the symptoms settle within months. Peripheral neuropathy is less frequent with docetaxel than with paclitaxel; grade 3/4 sensory neuropathy occurs in about 5% of patients treated with docetaxel 100 mg/m2 [126C]. Proximal and distal muscle weakness has also been reported (about 5% in a review of 186 patients in phase I and phase II studies) [127C]. The pathogenesis, incidence, susceptibility factors, diagnosis, characteristics, and management of taxane-induced peripheral neuropathy have been critically reviewed [128R]. Sensory systems Eyes Blockage of the lacrimal ducts, resulting in epiphora (overflow of tears on to the face due to disturbed outflow) is a little known but common adverse reaction to weekly docetaxel, and required corrective surgery in 30 out of 71 patients in one study [129C]. The incidence of epiphora was much less in patients treated with 3weekly docetaxel; only three of 72 patients required surgery in the same study. Fluid balance Fluid retention has been reported in up to 50% of patients treated with docetaxel, usually after cumulative doses. This commonly manifests as peripheral edema, but pleural effusions and ascites have also been reported [130c]. As a result,

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docetaxel is usually administered with glucocorticoid cover, which is very effective at reducing the incidence and severity of fluid retention. Some believe that the development of fluid retention depends on the dose and the duration of infusion, and that high concentrations of M4, the cyclized oxazolidinedione metabolite of docetaxel, cause more pronounced fluid retention [130R, 131c]. Hematologic Neutropenia was the doselimiting adverse reaction in most phase I and phase II studies of docetaxel, with a median duration to nadir counts of 7 days [132R]. This appears to be dose-related, but not schedule-related (unlike paclitaxel). In a large phase III trial, 9.6% of patients receiving 3-weekly docetaxel 75 mg/m2 developed grade 3/4 neutropenia [112C]. Anemia is also commonly reported and dose-related, affecting up to 97% of patients [133C]. Thrombocytopenia is less common, occurring in 7.4–12% of patients [131C]. Docetaxel can cause a significant but reversible non-specific lymphopenia. Patients treated with docetaxel-containing regimens have been found to be at increased risk of non-neutropenic infections, compared with patients treated with paclitaxel or non-taxane-based chemotherapy [134C]. Gastrointestinal Nausea/vomiting, diarrhea, and mucositis are commonly reported adverse reactions to docetaxel, affecting about 40%, 30%, and 20% of patients respectively [112C, 130R]. Neutropenic enterocolitis is a rare but severe consequence of docetaxel treatment and, while it is more commonly reported during treatment of hematological malignancies, there have been cases reported after docetaxel chemotherapy for solid tumors as well [135r]. It is characterized by segmental cecal and ascending colon ulceration and is often fatal, because of rapid progression to sepsis and shock. Non-neutropenic colitis and ischemic colitis associated with docetaxel and vinorelbine combination chemotherapy have also been reported [136A]. Skin In one study, of 99 patients who received low-dose docetaxel (60 mg/m2

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every 3 or 4 weeks), 25 had skin toxicity, mainly erythema and nail changes [137c]. Of a subset of 25 patients who received irradiation before docetaxel, four had recall dermatitis during their first infusion of docetaxel. All had previously been treated with doxorubicin, which may in part have explained some of the toxicity. In a phase II trial in patients with nonsmall cell lung cancer, docetaxel 100 mg/m2 resulted in at least a grade 2 rash in 41% of cases. In a further study with docetaxel 75 mg/m2 plus prednisolone cover there was a 25% reduction in rashes. However, whether this was due to the prednisolone or the lower dose of docetaxel was unclear [138c]. Palmar–plantar erythrodysesthesia syndrome (commonly called hand–foot syndrome) has been reported to be associated with docetaxel, although various patterns of spread, from solitary erythematous plaques to widespread involvement of the trunk, have been observed [139c, 140A]. There has been one report of increased photosensitivity with docetaxel. A 58-yearold man with prostate cancer developed lichenoid eruptions on the forearms and face 2–3 days after each docetaxel infusion [141A]. The lesions would fade within 2 weeks, but then recur after the next infusion, and were associated with pruritus which increased on exposure to the sun. Nails Nail changes have been reported in up to 44% of patients treated with docetaxel, with manifestations including onycholysis, subungual hemorrhages, and subungual abscesses [142R, 143R]. Hair Docetaxel is commonly associated with significant and sometimes complete hair loss [130R, 144R]. This usually develops by the second cycle of treatment of a 3-weekly regimen. Musculoskeletal Docetaxel is associated with arthralgias and myalgias, usually starting 1–2 days after infusion and lasting up to 5 days [142R]. As with paclitaxel, gabapentin given prophylactically controls symptoms in some patients [69r].

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Immunologic Hypersensitivity reactions to docetaxel occur in about 20–30% of cases, usually within a few minutes of starting an infusion [142R]. They most commonly occur during the first or second cycle of treatment. The symptoms may be minor, such as flushing or localized cutaneous reactions, or more severe, such as severe hypotension, bronchospasm, or generalized rash/ erythema. Patients who develop severe hypersensitivity reactions should not be rechallenged with docetaxel [111S]. In one phase II study, infusion-related reactions were reported in 34% of patients treated with docetaxel 100 mg/m2. This was reduced by 25% after the use of oral prednisone (100 mg orally before treatment and 50 mg once on the morning of treatment and the following 2 days) [136c].

[148E]. Furthermore, compared with paclitaxel, the potency of the epothilones appears to be significantly less affected by cells that overexpress the P-glycoprotein efflux pump, which is considered a key mechanism by which cells become resistant to chemotherapy drugs [149E]. Ixabepilone, patulipone, and sagopilone are the main epothilones to be investigated so far, although others are in development.

Drug–drug interactions Anthracyclines Unlike paclitaxel, docetaxel does not appear to affect the metabolism of doxorubicin. Thus, the combination of docetaxel and doxorubicin does not increase the risk of cardiotoxicity, compared with doxorubicin alone [145r] or doxorubicin þ cyclophosphamide combination chemotherapy [146C].

Epothilones The naturally occurring products epothilone A and B were originally isolated from the myxobacterium Sorangium cellulosum. The epothilones are 16-membered macrolides with a similar mechanism of action to taxanes, stabilizing microtubules and promoting tubulin polymerization, thus inducing mitotic arrest in the G2–M phase of the cell cycle, resulting in apoptosis [147R]. Their name is derived from their molecular structure, which includes an epoxide, methyl thiazole, and a ketone [1R]. Epothilones compete with paclitaxel for the same binding sites to tubulin, although they interact with the binding sites in a different way to paclitaxel [1R]. In in vitro studies epothilone A and paclitaxel have similar activity in inducing tubulin polymerization, while epothilone B is a more potent microtubule stabilizer

Avinash Gupta and Mark Middleton

Ixabepilone Ixabepilone is a semisynthetic derivative of epothilone B. It has been approved by the US FDA, for use as monotherapy or in combination with capecitabine for the treatment of locally advanced or metastatic breast cancer that is resistant or refractory to standard chemotherapy options (anthracyclines, taxanes, capecitabine) [1R]. It also has activity in prostate, renal, and pancreatic cancers and in non-small cell lung cancer. Pharmacokinetics Ixabepilone is more stable than natural epothilone B and has a half-life of 16–72 hours [150c, 151R]. Like taxanes, ixabepilone is mostly metabolized in the liver, by CYP3A4/5. The clearance of ixabepilone is reduced in patients with hepatic impairment and dosage reductions are required [156R]. General adverse reactions The adverse reactions to ixabepilone are similar to those seen with standard taxanes. Most data so far come from phase II studies, although there has been one large phase III study with ixabepilone given in combination with capecitabine [152C]. Nervous system Peripheral neuropathy has been common in studies to date and in some cases has been the dose-limiting adverse reaction. Sensory neuropathy is most common, of grade 2 or greater intensity in about 45% of cases. However, motor neuropathy and autonomic neuropathy have also been reported [153c, 154c, 155c, 156c]. In some phase II studies, some patients already had

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grade 1 neuropathy on entering the study, due to residual toxicity from previous chemotherapy. Hematologic Neutropenia is the most commonly reported hematological adverse reaction, and is of grade 2 or worse in 71–79% of cases [153c, 154c, 155c, 156c]. Grade 2 or worse anemia has been reported in about 35% of cases. Thrombocytopenia is less common (grade 2 or worse in 8–12% of cases), but severe thrombocytopenia with subsequent hemorrhage has been reported [153c]. Gastrointestinal Nausea and vomiting has been reported in 41–57% of patients. Bowel disturbances are common; diarrhea has been reported in 22–47% of patients (grade 2 or worse in 6–10%) and constipation in 20–56% [153c, 154c, 155c, 156c]. Mucositis or stomatitis has been reported in 10–29% of patients (grade 2 in 2–14%). Musculoskeletal Arthralgia/myalgia has been reported in 30–65% of patients [153c, 154c, 155c, 156c]. Skin, nails, hair Rash and/or palmar–plantar erythema has been reported in 8–22% of cases. Nail changes are reported in 9–56% of cases. Alopecia of varying severity has been reported in 43–92% of cases [153c, 154c, 155c, 156c]. Immunologic Ixabepilone is formulated in Cremophor EL and so is usually administered with premedication using histamine H1 and H2 receptor antagonists. There have been reports of hypersensitivity in about 5–8% of cases, but these are usually mild and not treatment-limiting [153c, 154c, 155c, 156c]. Drug–drug interactions Like taxanes, ixabepilone is metabolized by CYP3A4/5 and inhibitors of this enzyme, such as ketoconazole, inhibit its clearance and increase drugrelated adverse reactions [151R].

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Patupilone Patupilone is naturally occurring epothilone B. It is twice as potent in promoting tubulin polymerization in vitro, compared with paclitaxel and epothilone A [147R]. Phase I/II studies have been conducted in patients with non-small cell lung cancer, renal cell cancer, and ovarian cancer. Patupilone crosses the blood–brain barrier and has activity in patients with non-small cell lung cancer and cerebral metastases [1R]. The major dose-limiting adverse reaction to patupilone is diarrhea, rather than neuropathy. Other significant adverse reactions include fatigue and nausea. In phase I/II studies severe diarrhea has been reported in 14–19% of patients [157R, 158c]. Hematological toxicity appears to be minimal [158c]. Grade 3 peripheral neuropathy was the dose-limiting adverse reaction in one phase I study, along with grade 3 diarrhea [159c]. Premedication has not been required and there have been no reports of hypersensitivity reactions so far.

Sagopilone Sagopilone is a fully synthetic epothilone B analogue that has efficacy in ovarian cancer, melanoma, and prostate cancer [160R]. In in vitro studies sagopilone induces tubulin polymerization more rapidly than paclitaxel or patupilone [161E]. In animals sagopilone crosses the blood–brain barrier and has activity against glioblastomas and nervous system metastases [162E]. In phase I studies, sagopilone has a similar adverse reactions profile to those of taxanes and ixabepilone; neuropathy and neutropenia are the most commonly reported adverse events [163c]. Motor neuropathy has not been reported so far, although in one phase I study, two patients reported symptoms of central ataxia [164c]. Diarrhea is less common with sagopilone than with ixabepilone and patupilone. Premedication is not routinely given with sagopilone and hypersensitivity reactions have not been reported so far.

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OTHER CYTOTOXIC DRUGS

continuous intravenous infusion, and standard pharmacokinetically guided leucovorin rescue, carboxypeptidase G2 and thymidine resulted in a rapid 95.6–99.6% reduction in the plasma methotrexate concentration; renal function recovered after a median of 22 days [179c].

Methotrexate Use of carboxypeptidase in the treatment of methotrexate toxicity Carboxypeptidases are regulatory peptideprocessing enzymes that are secreted by human cells [165E]. Carboxypeptidase G2, which is produced by Pseudomonas strain RS-16, hydrolyses the glutamate residue from methotrexate and other folate analogues [166Ec] and rapidly hydrolyses methotrexate to the inactive metabolite DAMPA (4-[[2,4diamino-6-(pteridinyl)methyl]-methylamino]benzoic acid) and glutamate. It has been used when unexpected toxicity or renal insufficiency occurs during high-dose methotrexate therapy [167A, 168A, 169A, 170A, 171A, 172c, 173c], including intrathecal administration [174c], and for example when folinic acid and other interventions have failed [175c, 176c]. High-dose methotrexate has successfully been used again after rescue with carboxypeptidase G2 [177c]. Observational studies In four patients with recurrent primary nervous system lymphomas who were given methotrexate 3.0 g/m2 infused over 2 hours and carboxypeptidase G2, 50 U/kg 12 hours later, followed by a second dose 6 hours after the first, plasma methotrexate concentrations fell to the subtherapeutic range within 5 minutes of the first dose of carboxypeptidase G2, but the second dose had no further effect [178c]. In contrast, cerebrospinal fluid methotrexate concentrations were not altered. Anti-carboxypeptidase antibodies were not detected. Comparative studies In 20 patients with high-dose methotrexate-induced renal dysfunction, who received one to three doses of carboxypeptidase G2, 50 U/kg intravenously, thymidine 8 g/m2/day by

Avinash Gupta and Mark Middleton

Urinary tract Methotrexate-induced renal damage appears to be physicochemical in nature. Both the parent compound and its major metabolite, 7-hydroxymethotrexate, are less soluble at acidic pH values, increasing the risk of precipitation in the kidneys, particularly at high dosages. An amorphous yellow material—very probably methotrexate—has been isolated in the kidneys of patients who died as a result of methotrexate-induced renal dysfunction. For physicochemical reasons, it is recommended that the urine be alkalinized (target urinary pH above 7.5) before intensive methotrexate regimens are started. Supportive agents include sodium bicarbonate orally or intravenously, acetazolamide 500 mg qds, or both in combination [180c, 181c, 182A]. If there is acute renal insufficiency despite appropriate urinary alkalinization, one may need to use carboxypeptidase G2 as an antidote, which is also appropriate in cases of accidental intrathecal overdose of methotrexate [183A, 184A]. • A 14-year-old Hispanic boy (59 kg, 1.78 m) with non-metastatic osteosarcoma of the right tibia was given methotrexate 12 000 mg/m2 weekly together with doxorubicin. High-dose methotrexate was administered over 4 hours and leucovorin rescue (12 mg/m2 intravenously 6-hourly) was started 20 hours after methotrexate and was intended to be continued until methotrexate concentrations were below 0.2 mmol/l. During the sixth cycle, the methotrexate plasma concentration was 657 mmol/l (compared with 3.3 mmol/l during the first cycle) 24 hours after methotrexate had been started. Acute renal insufficiency and cytolytic hepatitis developed. The dose of leucovorin was increased to 35 mg/m2 6-hourly, and furosemide and aminophylline were given. However, 4 days later, the serum creatinine, blood urea, uric acid, and methotrexate concentrations were still abnormal, with a creatinine clearance of 10 ml/minute. The next day, he

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was given carboxypeptidase G2 50 units/kg, which resulted in a reduction in methotrexate plasma concentrations from 614 mmol/l to 24 mmol/l within 16 hours. However, 5 days after methotrexate infusion, renal insufficiency was still severe. Although the dosage of leucovorin was increased again to 90 mg/m2 6-hourly and a second dose of carboxypeptidase G2 was given, he worsened on the following day, with grade 2 mucositis and jaundice. However, 15 days after the start of the sixth methotrexate cycle, renal and hepatic function had normalized.

Drug–drug interactions Leucovorin Leucovorin is used to antagonize the effects of methotrexate on purine metabolism, but its protective effect is antagonized by carboxypeptidase G2, which should therefore be administered to patients with caution [185Er].

951

Vincristine

[SED-15, 3632]

Nervous system Hereditary motor and sensory neuropathy type 1 (HMSN-1) is an autosomal dominant disorder, which is usually not associated with neoplastic diseases. HMSN is diagnosed in most cases retrospectively, usually suggested by the observation of foot abnormalities or family history, and it predisposes to severe vincristine neurotoxicity. For example, a 31-year-old woman with recurrent Hodgkin’ lymphoma and unrecognized HMSN-1 developed a severe motor neuropathy 3 weeks after the first cycle of chemotherapy, which included vincristine 2 mg [186A]. The authors suggested that recognition of the early signs of HMSN, such as areflexia and pes cavus, can prevent severe neurotoxicity by avoiding vincristine.

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Julie Olliff and Peter Riley

46 Radiological contrast agents and radiopharmaceuticals Iodinated contrast agents and CT scanning have been compared with gadoliniumenhanced MRI scanning in a review of contrast medium-induced nephropathy [SEDA 32, 846], nephrogenic systemic fibrosis [SEDA 32, 852], extravasation of contrast media, allergy and allergic-type reactions to contrast media, and the role of contrast agents in pregnancy [1R]. Comparative studies In a retrospective review of 456 930 doses of iodinated and gadolinium-containing contrast media, there were 522 adverse reactions (0.11% of the total), of which 458 were to lowosmolar iodinated media and 64 to gadolinium [2c]. Urticaria, which occurred in 274 patients, was the commonest reaction. Management of adverse reactions The use of intravenous adrenaline in patients with reactions to contrast media has been retrospectively reviewed in nine of 456 930 patients who received either an intravenous iodinated contrast medium or intravenous gadolinium over a 5-year period [3R]. Seven had reactions to intravenous lowosmolar contrast media and two to gadolinium. Laryngeal edema was the most frequently documented reason for adrenaline administration (six of nine patients). Transient cardiovascular adverse reactions to adrenaline, including vague chest Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00046-5 # 2011 Elsevier B.V. All rights reserved.

tightness and labile hypertension, were recorded in four patients. One had a cardiac arrest and died; autopsy showed retroperitoneal hemorrhage.

Water-soluble intravascular iodinated contrast agents [SED-15, 1848; SEDA-29, 573; SEDA-30, 533; SEDA-31, 731] There are four types of iodinated water-soluble contrast media, classified according to their physicochemical properties (Table 1). They are mainly used intravascularly, but can also be injected into body cavities, particularly the low-osmolar contrast agents. Some are also used for oral or rectal administration, and the high-osmolar water-soluble contrast agent diatrizoate is suitable only for these purposes. Low-osmolar and iso-osmolar iodinated contrast media have almost completely replaced high-osmolar agents for intravascular use and administration into body cavities. Observational studies There were 57 adverse events after the use of non-ionic contrast media in 12 494 consecutive children or young adults aged under 21 years, an incidence of 0.46% [4c]. There were no serious adverse events, and the authors noted a significant relation between age and the incidence per 1000 studies, independent of sex, season, or year of study, with an increase in the frequency of reactions to contrast media with increasing age. 963

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Table 1 Some iodinated water-soluble contrast media Properties

Examples (INNs)

Brand names

High-osmolar ionic monomers

Diatrizoate

Angiografin, Hypaque, Gastrografin, Renografin, Urografin Conray Telebrix Isopaque, Triosil Hexabrix Xenetrix Omnipaque Iomeron Isovue, Niopam, Solutrast Imagopaque Ultravist Optiray Amipaque Visipaque Iosmin Isovist

Low-osmolar ionic dimers Low-osmolar non-ionic monomers

Iso-osmolar non-ionic dimers

Iotalamic acid Ioxitalamic acid Metrizoate Ioxaglic acid Iobitridol Iohexol Iomeprol Iopamidol Iopentol Iopromide Ioversol Metrizamide Iodixanol Iosimenol Iotrolan

Nervous system Intracranial hemorrhage has been reported after injection of contrast medium through microcatheters during intra-arterial thrombolysis for acute ischemic stroke in a study in 98 patients [5C]. After the procedure CT scans were reviewed for evidence of contrast extravasation or intracranial hemorrhage (defined as a hyperdensity suggestive of contrast medium, Hounsfield units >90 at 24 hours or present before 24 hours and persisting or replaced by intracranial hemorrhage at 24 hours). There were intracranial hemorrhages in 57 of the 98 patients. There were more microcatheter injections in those with intracranial hemorrhage (median 2 versus 1). The authors concluded that the effect may be due to an adverse reaction to contrast medium in this small subset of patients, although the effect could also have been secondary to a pressure effect following injection. Salivary glands Iodide-induced sialadenitis (“iodide mumps”) is the name given to swelling of the salivary glands due to compounds that contain iodine [SEDA-32, 845]. Further cases have been reported

[6A, 7A]. The EIDOS and DoTS descriptions of this reaction are shown in Figure 1.

Urinary tract Contrast-induced nephrotoxicity has been reviewed in successive volumes of SEDA [SEDA-29, 575; SEDA-30, 535; SEDA-31, 731; SEDA-32, 846]. The EIDOS and DoTS descriptions of this reaction are shown in Figure 2. Susceptibility factors include: age (over 70 years), drugs (nephrotoxic drugs, such as non-steroidal anti-inflammatory drugs; metformin; mannitol, and diuretics, particularly loop diuretics; multiple repeat exposures to contrast media within 72 hours), and diseases (pre-existing renal insufficiency, particularly if it is associated with diabetes mellitus, congestive heart failure, dehydration). There is also an increased risk in organ transplant recipients. Contrast-induced nephrotoxicity is defined as an acute rise in serum creatinine by at least 44 mmol/l (0.5 mg/dl), or 25% above baseline within 48–72 hours after the administration of an intravascular contrast agent, in the absence of any other cause.

Radiological contrast agents and radiopharmaceuticals EIDOS

Chapter 46

Extrinsic species (E) lodine-containing compounds

965

Intrinsic species (I) Not known

Distribution Salivary glands Manifestations (test results) Ultrasonography/histology

Outcome (the adverse effect) Oedema, increased vascularity

Manifestations (clinical) Salivary gland swelling

Sequela (the adverse reaction) Sialadenitis (“iodide mumps”)

DoTS 0–24 h

Dose-responsiveness Hypersusceptibility

Time-course First-dose

Susceptibility factors lodine hypersensitivity

>24 h

Dose-responsiveness Toxic/hypersusceptibility

Time-course Intermediate

Susceptibility factors Renal impairment

Figure 1 The EIDOS and DoTS descriptions of iodide-induced sialadenitis.

EIDOS

Extrinsic species (E) lodinated water-soluble contrast media

Intrinsic species (I) Renal tubular cells

Distribution Kidney Outcome (the adverse effect) Inhibition of apoptosis Manifestations (test results) Impaired renal function Manifestations (clinical) Clinical effects of renal failure

Sequela (the adverse reaction) Contrast medium-induced nephrotoxicity

DoTS Dose-responsiveness Collateral

Time-course Susceptibility factors Intermediate Age, drugs, and diseases (see text)

Figure 2 The EIDOS and DoTS descriptions of contrast-induced nephrotoxicity.

The number of comparisons of different contrast agents and potential methods of prevention is increasing with increasing awareness of clinicians. Several authors have described potential mechanisms of injury, compared different contrast agents, and discussed prevention, including the

use of prophylactic drugs and various hydration regimens [8R, 9R, 10r]. In a retrospective case–cohort study in 809 patients who developed contrastinduced nephrotoxicity after either intraarterial or intravenous contrast administration and 2427 patients who did not,

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nephrotoxicity was significantly associated with both mortality at 30 days (OR ¼ 3.37; 95% CI ¼ 2.58, 4.41) and overall mortality (HR ¼ 1.57; 95% CI ¼ 1.32, 1.86), after adjustment for other susceptibility factors [11C]. Choice of contrast agent Several studies have compared the use of non-ionic lowosmolar agents with the iso-osmolar agent iodixanol, given either intra-arterially or intravenously, in patients at risk of contrast-induced nephrotoxicity. Previous studies have supported the use of an isoosmolar agent in susceptible patients undergoing intra-arterial injection of contrast material when compared with a lowosmolar agent. However, more recent studies have suggested that there is little difference between the two, particularly when they are given intravenously. In a meta-analysis of 25 randomized controlled trials involving 3270 patients, iodixanol was not associated with a significantly reduced risk of contrast-induced nephrotoxicity compared with all low-osmolar media pooled together (RR ¼ 0.80; 95% CI ¼ 0.61, 1.04) [12M]. There were no significant risk reductions in subgroups after intravenous administration (RR ¼ 1.08; 95% CI ¼ 0.62, 1.89) or intra-arterial administration (RR ¼ 0.68; 95% CI ¼ 0.46, 1.01), or in the subgroup with preexisting renal insufficiency (RR ¼ 0.59; 95% CI ¼ 0.33, 1.07). However, there was an increased risk after intra-arterial administration in patients with pre-existing renal insufficiency for iohexol compared with iodixanol (RR ¼ 0.38; 95% CI ¼ 0.21, 0.68). There was no significant difference between iodixanol and other low-osmolar media. In a comparison of the effects of iso-osmolar media and low-osmolar media on renal function in high-risk patients undergoing intravenous contrast medium-enhanced CT scanning, intravenous contrast media were unlikely to be associated with permanent adverse outcomes [13C]. There were no significant effects of either iodixanol or iopromide on serum creatinine concentrations over the subsequent 3 days. Iodixanol

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increased eGFR and iopromide reduced it on all 3 days, but the changes were not significant. Fewer patients who were given iodixanol (8.5%) compared with iopromide (28%) had an increase in serum creatinine of 44 mmol/l (0.5 mg/dl) or more. The authors concluded that serum creatinine concentrations after contrast administration are lower after iodixanol than after iopromide. Prevention Several agents have been tried in the past in order to prevent contrastinduced nephrotoxicity. These have all been directed at various proposed methods of causation [SEDA-32, 848]. The most effective to date has been intravenous hydration before and after administration of the iodinated contrast medium, either with 0.9% saline or sodium bicarbonate; bicarbonate is superior to saline. Some practitioners advocate the use of oral N-acetylcysteine, although the evidence is conflicting. In a randomized placebo-controlled study of 200 patients who were given iodixanol, oral N-acetylcysteine 600 mg bd the day before and on the day of the procedure or placebo were combined with intravenous saline 1 ml/kg/hour 12–24 hours before the procedure and 12–24 hours after [14C]. The rates of contrast-induced nephrotoxicity were 8.1% in those who were given acetylcysteine and 5.9% in those who were given saline, a non-significant difference. The authors concluded that acetylcysteine did not prevent contrast-induced nephrotoxicity in patients who received iso-osmolar contrast media with adequate hydration. Skin Acute generalized exanthematous pustulosis has been described in an 84-yearold man on two separate occasions after infusions of an ioversol-containing contrast medium [15A]. Immunologic Acute and delayed allergic reactions after the intravenous administration of iodinated low-osmolar contrast media are well documented but rare. They range in intensity from mild, involving urticaria, rash, and pruritus, to severe, including cardiopulmonary arrest and death.

Radiological contrast agents and radiopharmaceuticals

The medical records of 545 patients who received intravenous non-ionic contrast media out of a total of 84 928 injections over 6 years have been reviewed; 418 (77%) of the reactions were classified as mild, 116 (21%) as moderate, and 11 (2%) as severe; 221 (41%) received treatment [16C]. The most frequent mild reaction was urticaria (n ¼ 286) followed by pruritus (n ¼ 131) and erythema or rash (n ¼ 114). Moderate reactions included shortness of breath (n ¼ 55), cardiac-like symptoms (n ¼ 48), and laryngeal edema (n ¼ 38). Severe reactions included the aforementioned and either hypotension, tachycardia, bronchospasm, and/or a neurological event. Follow-up data on 402 of the patients with a mild reaction showed that 51% resolved within 1 hour and 48% resolved at 1–24 hours. In those with a moderate reaction, the symptoms resolved within 1 hour in 53%; in the other 47% the symptoms had resolved within 24 hours. Only two patients with severe reactions had documented sequelae lasting more than 24 hours and there were no deaths. It has been proposed that the mechanism of these hypersensitivity reactions is related to a connection between antibodies to contrast media, in the light of a single case [17A]. • A 75-year-old man developed an acute reaction after injection of amidotrizoate for retrograde ureteropyelography. He developed a sinus bradycardia and hypotension, which responded quickly to resuscitation. Subsequent intradermal testing was positive to amidotrizoate, with cross reactivity with iomeprol. Basophil activation tests confirmed the presence of anti-amidotrizoate basophils and upregulation of CD203c antibodies.

In 32 patients with a history of rashes after injection of iodinated contrast media, skin tests in six cases strongly suggested a delayed-type allergic hypersensitivity to three different contrast agents; in four patients alternative non-ionic monomers were identified by controlled challenge tests [18c].

Chapter 46

Barium sulfate

967

[SED-15, 414]

Gastrointestinal “Barium appendicitis” is rare but several cases have recently been reported. • A 48-year-old woman developed a fever and pain in the right lower quadrant of the abdomen 8 hours after a barium study that was performed through an ileostomy stoma [19A]. Her temperature was 38.5 C and there was tenderness and rebound tenderness over McBurney's point. The white cell count was raised. A supine plain abdominal X-ray showed retained barium in the cecum and appendix, which was confirmed by a CT scan, which also showed mild swelling of the appendiceal wall. The appendix was resected. It was red and edematous and there was barium in the lumen. • An 18-year-old man developed right lower quadrant pain 2 weeks after upper gastrointestinal imaging [20A]. A CT scan of the abdomen and pelvis appeared to show a foreign body in the region of the terminal ileum, but a plain X-ray of the abdomen showed radiopaque appendicoliths. Pathology confirmed the diagnosis of barium appendicitis. • A 75-year-old woman had a double-contrast barium examination of her colon and developed severe right lower quadrant pain [21A]. There was tenderness in the right lower abdominal quadrant with a positive McBurney's sign. The white blood cell count was 16.3  109/l, with 88% neutrophils. A plain abdominal Xray showed a densely radio-opaque tubular lesion in the right lower quadrant and CT scans showed dense barium retention in the appendix with surrounding prominent fatty infiltration. The appendix was enlarged and erythematous with a perforation near the base.

In another case, chronic right lower quadrant pain, which persisted for 1 year after an upper gastrointestinal contrast study, was attributed to retained barium in a 47-year-old woman; her appendix was mildly inflamed and the lumen was filled with barium [22A]. Breasts Opacification seen on mammography in a 60-year-old woman with a right breast lump, thought to be microcalcification in a ductal carcinoma, turned out to be barium particles [23A]. She had previous

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drainage of an abscess in the same region of the right breast 10 years before, and the authors thought that the source of the barium had been dressings used at the time, since dressings sometimes have barium incorporated as a radio-opaque marker.

MRI CONTRAST MEDIA Gadolinium salts [SED-15, 1469; SEDA-29, 578; SEDA-30, 538; SEDA-31, 734] The gadolinium salts that are used as contrast media in magnetic resonance imaging (MRI) and have been assigned International Non-proprietary Names (INNs) by the WHO are listed in Table 2. The gadolinium chelates, the most commonly used MR contrast agents, are available in three forms: extracellular fluid agents, which are excreted unchanged by the kidneys, liver agents, which are taken up by hepatocytes and excreted via the hepatobiliary system, and blood pool agents, which remain longer in the vascular space than the extracellular fluid agents. Gadolinium has been used successfully as the contrast agent for hysterosalpingography performed on women allergic to Table 2 Gadolinium salts that are used as contrast media in magnetic resonance imaging Name (INN)

Brand name

Gadobenic acid Gadobutrol Gadocoletic acid Gadodenterate Gadodiamide Gadofosveset Gadomelitol Gadopenamide Gadopentetic acid Gadoteric acid Gadoteridol Gadoversetamide Gadoxetic acid

Multihance Gadovist

Omniscan Ablavar Vistarem Magnevist Dotarem Prohance OptiMARK Eovist, Primovist

Julie Olliff and Peter Riley

iodinated contrast in a small case–control study [24A]. In a prospective study of MR arthrography in 1085 patients using 2 mmol/l gadopentetate dimeglumine (Magnevist; Bayer-Schering-Pharma) in the shoulder, elbow, hip, knee, and ankle and 5 mmol/l gadoterate (Dotarem; Guerbet, Aulnaysous-Bois, France) in the wrist, there were no signs of joint infection [25c]. None of the patients had any other major adverse reactions, including anaphylactic reactions, cellulitis, or vascular complications. Increased pain was most pronounced 4 hours after the procedure, and patients under 30 years were more severely affected. The authors concluded that MR arthrography temporarily increases jointrelated pain, depending on age, but not on sex, joint type, or contrast medium volume. In a retrospective review of adverse reactions over 4 years in 158 439 patients who received gadolinium, there were only 64 cases and only 15 required treatment; four had a severe reaction and there were no deaths [2c]. Cardiovascular Data from two multicenter phase II studies of the use of gadoversetamide (OptiMARK Tyco Healthcare/Mallinkrodt. St Louis MO) in 577 patients with acute and chronic myocardial infarction trials have been reviewed [26C]. They were randomly assigned to four dosage groups (0.05, 0.1, 0.2, or 0.3 mmol/kg) for delayed hyperenhancement MRI. There were 164 adverse events in 124 patients; 139 were mild or moderate. Electrocardiographic changes were the most frequent adverse events. The investigators judged that eight adverse events were likely to have been due to the contrast agent. No serious adverse event was thought to have been due to gadoversetamide. Immunologic Two cases of anaphylactic shock after first exposure to gadoterate meglumine (Gd-DOTA; Dotarem; Guerbet, Roissy, France) have been reported [27A], with the implication that the tetraazacyclododecane derivative ligand of macrocyclic MRI contrast agents are involved in the genesis of anaphylactic reactions, as

Radiological contrast agents and radiopharmaceuticals

demonstrated by (1) positive skin tests with contrast media sharing the same macrocyclic ligand, (2) negative skin tests with linear MRI contrast media, and (3) the tolerance of intravenous linear Gd-DTPA. The authors suggested that patients who are allergic to macrocyclic MRI contrast media can still tolerate linear contrast media, and they emphasized the theory that the structures of these contrast media predict allergenicity [28r]. Multiorgan damage Systemic fibrosis due to gadolinium-based contrast agents was reviewed in SEDA-31 (p. 735) and many other reviews have appeared [SEDA-32, 852]. The EIDOS and DoTS descriptions of this reaction are shown in Figure 3; the susceptibility factors include drugs (epoetin therapy, sevelamer) and diseases (renal insufficiency, acidosis, inflammatory events, hyperphosphatemia). The risks from different contrast agents are shown in Table 3. Susceptibility factors Renal disease In a retrospective study of 61 subjects who had received at least 40 ml of gadodiamide during a single imaging (median dose 80 ml, range 40–200 ml), who were followed for at least 1 year and had moderate to severe EIDOS

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end-stage renal disease (median eGFR 30, range 3–57 ml/minute/1.73 m2), nephrogenic systemic fibrosis eventually developed in one patient, yielding a prevalence of 1.6% [29c]. Among 33 patients who were not undergoing dialysis eGFR within 5 days of contrast medium injection changed by 8.8 to þ43 ml/minute/1.73 m2, with a statistically significant median improvement of 2.4 ml/minute/1.73 m2. The authors concluded that although the use of a gadolinium-based contrast agent was a prerequisite for the development of nephrogenic systemic fibrosis, it was not the only factor, even in patients receiving very high doses. The renal adverse effects of gadoliniumbased contrast agents have been reviewed in patients with chronic renal insufficiency [30R]. The authors suggested that gadolinium chelates are safe and not nephrotoxic when used intravenously for MRI or MRA in patients with normal renal function, or in patients with pre-existing renal insufficiency when they are used in doses similar to those recommended for MRI. They also suggested that renal function is likely to deteriorate in most cases after intra-arterial administration of gadoliniumbased media at doses over 0.2 mmol/kg

Extrinsic species (E) Intrinsic species (I) Gadolinium-containing contrast media Fibroblasts Distribution Skin, lungs, liver, serous membranes, skeletal, cardiac muscle

Manifestations (test results) Histology [SEDA-32, 852] Manifestations (clinical) Changes in skin and hair [SEDA-32, 852]

DoTS

Outcome (the adverse effect) Fibrosis Sequela (the adverse reaction) Skin symptoms (e.g. pain, pruritus, stiffness); hair loss; sleeplessness

Dose-responsiveness Collateral

Time-course Susceptibility factors Late Drugs and diseases (see text)

Figure 3 The EIDOS and DoTS descriptions of systemic fibrosis due to gadolinium-based contrast agents.

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Table 3 Risks of systemic fibrosis from gadolinium-containing salts Name (INN)

Chelate

Charge

Structure

Risk

Gadodiamide Gadopentetic acid Gadoversetamide Gadobenic acid Gadofosveset Gadoxetic acid Gadobutrol Gadoteric acid Gadoteridol

DTPA-BMA DTPA DTPA-BMEA BOPTA DTPA-DPCP EOB-DTPA BT-DO3A DOTA HP-DO3A

Non-ionic Ionic Non-ionic Ionic Ionic Ionic Non-ionic Ionic Non-ionic

Linear Linear Linear Linear Linear Linear Cyclic Cyclic Cyclic

High (3–7%) High (0.1–1%) High Intermediate Intermediate Intermediate Low Low Low

DPTA, diethylene triamine penta-acetic acid; BMA, 5,8-bis(carboxymethyl)-11-[2-(methylamino)-2-oxoethyl]-3-oxo-2,5,8,11-tetra-azatridecan-13-oic acid; BMEA, N,N'-bis[methoxyethylamide); BOPTA, benzyloxypropionic tetra-acetic-acid; DPCP, N,N'-bis[pyridoxal-5-phosphate)-trans-1,2-cyclohexyldiamine-N,N'-diacetic acid; EOB-DTPA, ethoxybenzyldiethylene triamine penta-acetic acid; BT-DO3A, 10-[2,3-dihydroxy-1-hydroxymethylpropyl)-1,4,7,10-tetra-azacyclododecane-1,4,7-triacetic acid; HP-DO3A, 10-[2-hydroxypropyl)-1,4,7-tetra-azacyclododecane-1,4,7-triacetic acid; DOTA, 1,4,7,10-tetra-azacyclododecane-N,N',N",N"'-tetra-acetic acid.

for diagnostic or interventional angiography in patients with renal insufficiency (creatinine clearance less than 60 ml/minute/ 1.73 m2), which is often associated with diabetes mellitus and/or hypertension. Therefore, although high doses of gadolinium-based contrast media (over 0.2–0.3 mmol/kg) can be used safely in patients with renal insufficiency, doses over 0.2 mmol/kg for angiography should be avoided in these patients, especially when the intra-arterial route is chosen. Dialysis In a 26-month observational study, fever, chills, and nausea were recorded in 13 of 136 patients undergoing hemodialysis or CAPD within hours of a dose of gadolinium DTPA used for cardiovascular evaluation before transplantation [31c]. No other susceptibility factor was identified. The authors suggested that such reactions may be relevant to the poorly understood pathogenesis of skin reactions to some gadolinium-containing products in patients with end-stage renal disease. Several late sequelae of the use of gadolinium-containing MRI contrast agents have been described in patients with advanced renal failure, for example nephrogenic systemic fibrosis [SEDA 32, 852].

Superparamagnetic iron oxide (SPIO) MRI contrast agents [SEDA-28, 564] Iron oxide-containing contrast agents consist of suspended colloids of iron oxide nanoparticles, which reduce T2 MRI signals. They are taken up by the reticuloendothelial system. Superparamagnetic iron oxide (SPIO) contrast agents are taken up into the liver and spleen. The ultrasmall superparamagnetic iron oxide (USPIO) contrast agents have a longer plasma circulation time and have greater uptake into marrow and lymph nodes. They also have a greater T1 shortening effect than SPIO contrast agents. Some examples are listed in Table 4; of these, feruglose and ferumoxtran have been discontinued.

Table 4 Some superparamagnetic and ultrasmall superparamagnetic iron oxide agents for use as contrast media in magnetic resonance imaging Name (INN)

Brand name

Ferucarbotran Feruglose Ferumoxide Ferumoxtran Ferumoxytol

Cliavist, Resovist Clariscan Endorem, Feridex Combidex, Sinerem Feraheme

Radiological contrast agents and radiopharmaceuticals

Observational studies In a questionnaire study about unwanted symptoms over 7 days after injection of ferucarbotran, an SPIO contrast agent, in 315 patients who underwent MRI scans of the liver, here were 169 adverse events in 78 patients, of which 70 adverse events in 45 patients were judged to be adverse reactions to the contrast agent, defined as possibly or definitely related to ferucarbotran [32c]. All the reactions were of mild intensity. However, the incidence of all adverse events was less than that of baseline symptoms. In a multicenter study of 375 patients who received a lymph node-specific contrast agent (USPIO) ferumoxtran-10 (Sinerem, Guerbet, France) by intravenous infusion, there were no serious adverse events [33C]. In six patients low back pain during the infusion resolved after the infusion was stopped and did not recur when the infusion was restarted about 10 minutes later. Other minor adverse events were diarrhea and abdominal cramps (n ¼ 9), pruritus and urticaria (n ¼ 4), and headache (n ¼ 2).

Carbon dioxide

[SED-15, 642]

Observational studies In 18 patients who underwent endovascular repair of abdominal aortic aneurysms using angiography with CO2 delivered through the endograft sheath, there were no ischemic or systemic complications related to CO2 administration and there was no significant deterioration in renal function [34c].

ULTRASOUND CONTRAST AGENTS [SED-15, 3543; SEDA-30, 540; SEDA-32, 855] Ultrasound contrast agents contain microbubbles of air, nitrogen, or fluorocarbon gas, coated with a thin shell of material such as

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albumin, galactose, or lipid. Their acoustic impedance is markedly different from that of blood or tissues. The contrast is usually injected intravenously and the bubbles must measure less than 7 microns if they are to cross the lungs and reach the arterial circulation. They remain intact for only a short time. Modification of the composition of the microbubble shell and the use of a lower solubility substance can improve resistance to pressure and make the microbubbles more resilient and able to resist destruction by the ultrasound beam. Adverse reactions to ultrasound contrast agents (SonoVue 46% and Luminity 54%) have been assessed in 3704 patients, of whom 1150 underwent stress echocardiography with exercise or dobutamine [35C]. There was no excess of adverse events in those with stable chest pain or suspected acute coronary syndrome.

Perfluorocarbons Observational studies In a retrospective analysis of 26 774 patients who underwent stress echocardiography the 10 792 patients who comprised the contrast cohort received second-generation perfluorocarbon-based agents for left ventricular opacification [36C]. The controls comprised 15 982 patients who had their first stress echocardiography during the same period but without contrast agents. Short-term end-points (< 72 h and <30 days) and long-term endpoints (up to 4.5 years) were death and myocardial infarction. The patients in the contrast cohort were older (mean ages 66 versus 63 years), with higher percentages of men (57% versus 53%), and higher-risk patients. In addition, patients who underwent dobutamine stress echocardiography had greater cardiac risk than those who underwent exercise stress echocardiography. Abnormal findings in patients who received contrast agents were more frequent (32% versus 28%). There was no significant difference in the incidences of

972

short-term events (death and myocardial infarction). Within 72 hours, one patient in the contrast cohort and two controls died; three and seven respectively had myocardial infarctions. Within 30 days, 37 patients (0.34%) in the contrast cohort and 57 patients (0.36%) controls; 17 patients (0.16%) in the contrast cohort and 16 controls (0.10%) had a myocardial infarction. Adjusted hazard ratios were not different between cohorts for death (HR ¼ 0.99; 95% CI ¼ 0.88, 1.11) or myocardial infarction (HR ¼ 0.99; 95% CI ¼ 0.80, 1.22). Comparative studies Perflubutane microbubbles have been used in 190 patients to assess their efficacy and safety in the use of contrast-enhanced ultrasound and to compare it with unenhanced ultrasound and dynamic CT in the detection and characterization of focal liver lesions [37C]. The microbubbles consisted of perfluorobutane (C4F10) stabilized by a monomolecular membrane of hydrogenated egg phosphatidyl serine. When the liver is imaged in the phasemodulation harmonic mode, contrastenhanced ultrasound with perflubutane microbubbles has two phases: the vascular and Kupffer phases. The vascular phase of enhancement occurs soon after intravenous injection and can be used to characterize lesions using patterns of contrast enhancement. The perflubutane microbubbles are then taken up by the Kupffer cells in normal liver, allowing recognition of abnormal tissues that are not part of the reticuloendothelial system. The patients received Sonazoid (GE Healthcare), a lyophilized formulation reconstituted for injection containing 16 ml of perflubutane microbubbles in one vial. The contents of each vial were resuspended in 2 ml of water for injection. Each patient received a single injection of 0.12 ml/kg of microbubbles (0.015 ml/kg of the reconstituted suspension) into a forearm vein, followed by a 10-ml saline flush. There were no deaths or serious or severe adverse events. Adverse events occurred in 49% of patients and adverse drug reactions in 10%; they were self-limiting. The authors graded the adverse reactions as mild in intensity and thought that the high incidence of adverse events could

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mostly be attributed to factors other than the contrast agent. Perflubutane polymer microspheres (ImagifyTM, Acusphere Inc, Watertown, MA, USA) have been used to assess myocardial perfusion and wall motion in patients with chest pain, in two phase III studies [38C]. Perfusion stress echocardiography was performed with Imagify and compared with stress perfusion imaging using 99mTc singlephoton emission computed tomography (SPECT). There were serious adverse events in four of 662 patients (0.6%); none was life threatening, and all occurred at least 1 hour after contrast administration and resolved without residual effect. Adverse events were reported in 454 patients (69%). Most (98%) were mild or moderate in intensity, were not serious, and resolved. There were adverse events in 10% of patients after the first dose of Imagify, before dipyridamole administration. The most common adverse events (in at least five patients each) before dipyridamole were headache (2.6%), flushing (1.8%), and hypotension (0.8%). Overall, the most frequently reported adverse events were headache (34%), chest pain (10%), nausea (10%), flushing (9%), and chest discomfort (8%); they mainly occurred after dipyridamole infusion. The investigators were more likely to attribute these events to dipyridamole rather than the imaging agent.

Sulfur hexafluoride Cardiovascular Sinus bradycardia with hypotension has been attributed to sulfur hexafluoride [39A]. • A 55-year-old man was given sulfur hexafluoride (Sonovue, Bracco Imaging, Plan-lesOuates, Geneva, Switzerland) via a VuJect pump (Bracco) at a rate of 0.8 ml/minute [40A]. Within 3 minutes he became unresponsive, with sinus bradycardia and hypotension. The hypotension did not improve with atropine, although the heart rate normalized. This was followed by a tonic-clonic seizure and a rash with edema. He was successfully treated with intravenous hydrocortisone and chlorphenamine, followed by intravenous boluses of phenylephrine 100 micrograms.

Radiological contrast agents and radiopharmaceuticals

The authors discussed the safety record of ultrasound contrast agents and stressed that they are generally safe, with no increase in the risk of death seen in a registry of over 4 million patients exposed [41C].

THOROTRAST

[SED-15, 3401;

SEDA-28, 565] Tumorigenicity Induction by Thorotrast of a primary cerebral angiosarcoma has been reported 62 years after previous cranial surgery for a childhood cerebral abscess [42A]. It was thought that Thorotrast had been instilled into the cavity of the abscess for future monitoring. The histology of the tumor showed a well differentiated angiosarcoma with a background consistent with a so-called “Thorotrast granuloma”. The authors suggested that the histology, the confirmation of radioactivity in the material obtained from within the tumor, and the latency period provided compelling support for tumor induction by Thorotrast.

RADIOPHARMACEUTICALS [SED-15, 3017] 99m

Technetium sestamibi

Autacoids Angioedema, with significant tongue swelling, drooling, and difficulty in speaking, occurred 6 hours after administration of 99mTc sestamibi tracer during adenosine nuclear stress testing in a 63year-old woman [43A]. The authors thought that the short half-life of adenosine (10 seconds) made it unlikely to have been the causative drug.

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References [1] Halvorsen RA. Which study when? Iodinated contrast-enhanced CT versus gadolinium-enhanced MR imaging. Radiology 2008; 249: 9–15. [2] Hunt CH, Hartman RP, Hesley GK. Frequency and severity of adverse effects of iodinated and gadolinium contrast materials: retrospective review of 456,930 doses. AJR Am J Roentgenol 2009; 193: 1124–7. [3] Collins MS, Hunt CH, Hartman RP. Use of IV epinephrine for treatment of patients with contrast reactions: lessons learned from a 5 year experience. AJR Am J Roentgenol 2009; 192: 455–61. [4] Callahan MJ, Poznaukskis BS, Zurakowski D, Taylor GH. Nonionic iodinated intravenous contrast media-related reactions: incidence in large urban children's hospital- retrospective analysis of data in 12,494 patients. Radiology 2009; 250: 674–81. [5] Khatri P, Broderick J, Khoury J, Carrozzella J, Tomsick T. IMS I and II Investigators. Microcatheter contrast injections during intra-arterial thrombolysis may increase intracranial hemorrhage risk. Stroke 2008; 39: 3283–7. [6] Capoccia L, Sbarigia E, Speziale F. Monolateral sialadenitis following iodinated contrast media administration for carotid artery stenting. Vascular 2010; 18(1): 34–6. [7] Greco S, Centenaro R, Lavecchia G, Rossi F. Iodide mumps: sonographic appearance. J Clin Ultrasound 2010; 38(8): 438–9. [8] Solomon R. Contrast-induced acute kidney injury. Radiol Clin North Am 2009; 47: 783–8. [9] Morcos SK. Contrast-induced nephropathy: are there differences between low osmolar and iso-osmolar iodinated contrast media? Clin Radiol 2009; 64: 468–72. [10] Katzberg RW, Lamba R. Contrast-induced nephropathy after intravenous administration: fact or fiction. Radiol Clin North Am 2009; 47: 789–800.

974 [11] From AM, Bartholmai BJ, Williams AW, Cha SS, McDonald FS. Mortality associated with nephropathy after radiographic contrast exposure. Mayo Clin Proc 2008; 83 (10): 1095–100. [12] Heinrich MC, Haberle L, Muller V, Bautz W, Uder M. Nephrotoxicity of isoosmolar iodixanol compared with nonionic low-osmolar contrast media: meta-analysis of randomized controlled trials. Radiology 2009; 250: 68–86. [13] Nguyen S, Suranyi P, Ravenel J, Randall P, Romano P, Strom K, Costello P, Schoepf U. Iso-osmolality versus low-osmolality iodinated contrast medium at intravenous contrast-enhanced CT: effect on kidney function. Radiology 2008; 248: 97–105. [14] Ferrario F, Barone M, Landoni G, Genderini A, Heidenperger M, Trezzi M, Piccaluga E, Danna P, Scorza D. Acetylcysteine and non-ionic isosmolar contrastinduced nephropathy—a randomized controlled study. Nephrol Dial Transplant 2009; 24(10): 3103–7. [15] Hammerbeck AA, Daniels NH, Callan JP. Ioversol induced acute generalised exanthematous pustulosis. Arch Dermatol 2009; 145: 683–7. [16] Wang C, Cohan R, Ellis J, Caoili J, Wang G, Francis IF. Frequency, outcome and appropriateness of treatment of nonionic iodinated contrast media reactions. AJR Am J Roentgenol 2008; 191: 409–15. [17] Dewachter P, Nicaise-Roland P, Kalaboka S, Lefevre J, Chollet-Martin S. Anaphylaxis to amidatrizoate proved by skin testing and flow cytometry-based basophil activation test. Allergy 2009; 64: 496–502. [18] Seitz C, Pfeuffer P, Raith P, Brocker EB, Trautmann A. Radiocontrast media-associated exanthema: identification of crossreactivity and tolerability by allergologic testing. EJR 2009; 72: 167–71. [19] Wu JM, Liang JT. Barium-induced acute appendicitis. J Gastroenterol Hepatol 2008; 23(7 Pt 1): 1159. [20] Novotny NM, Lillemoe KD, Falimirski ME. Barium appendicitis after upper gastrointestinal imaging. J Emerg Med 2010; 38(2): 148–9. [21] Fang YJ, Wang HP, Ho CM, Liu KL. Barium appendicitis. Surgery 2009; 146(5): 957–8.

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[22] García Marín A, Martín Gil J, Pérez Díaz MD, Bernardos García L, Turégano Fuentes F. Chronic right lower quadrant pain due to retained barium. Rev Esp Enferm Dig 2009; 101(2): 151–2. [23] Bamford L, Lioe TF, O'Rourke DM, Buckley MR. Barium sulphate particles in breast mimicking malignant type microcalcification. Breast J 2009; 15(3): 305–6. [24] Belt MM, Rodenko G, Taylor K, Maguire DO, Bello S. Use of gadolinium for hystero-salpingography in iodine allergic women: a case control study. Fertil Steril 2008; 90: 835–8. [25] Saupe N, Zaneti N, Pfirrmann CWA, Wels T, Schwenke C, Hodlet J. Pain and other side effects after MR arthrography: prospective evaluation 1085 patients. Radiology 2009; 250: 830–8. [26] Huber S, Muthupillai R, Cheong B, Wible Jr. JH, Shah D, Woodard P, Grothues F, Mahrholdt H, Rochitte CE, Masoli O, Kim RJ, Schwaiger CM, Fuisz A, Kramer C, van Rossum AC, Biederman R, Lombardi M, Martin E, Kevorkian R, Flamm SD. Safety of gadoversetamide in patients with acute and chronic myocardial infarction. J Magn Reson Imaging 2008; 28: 1368–78. [27] Hasdenteufel F, Luyasu S, Renaudin JM, Paquay JL, Carbutti G, Beaudouin E, Moneret-Vautrin DA, Kanny G. Anaphylactic shock after first exposure to gadoterate meglumine: two case reports documented by positive allergy assessment. J Allergy Clin Immunol 2008; 121: 527–8. [28] Hasdenteufel F, Luyasu S, Renaudin JM, Paquay JL, Carbutti G, Beaudouin EJ, Moneret-Vautrin DA, Kanny G. Reply. Allergy Clin Immunol 2008; 122: 216–7. [29] Bridges MD, St Amant BS, McNeil RB, Cernigliaro JG, Dwyer JP, Fitzpatrick PM. High dose gadodiamide for catheter angiography and CT in patients with varying degrees of renal insufficiency: prevalence of subsequent nephrogenic systemic fibrosis and decline in renal function. AJR Am J Roentgenol 2009; 192(6): 1538–43. [30] Ledneva E, Karie S, Launay-Vacher V, Janus N, Deray G. Renal safety of gadolinium based contrast media in patients with

Radiological contrast agents and radiopharmaceuticals

[31]

[32]

[33]

[34]

[35]

[36]

[37]

chronic renal insufficiency. Radiology 2009; 250: 618–28. Steen H, Giannitsis E, Sommerer C, Bahner U, Brandl M, Merbach C, Merten C, Ritz E, Katus HA, Zeier M, Schwenger V. Acute phase reaction to gadolinium-DTPA in dialysis patients. Nephrol Dial Transplant 2009; 24: 1274–7. Onishi H, Murakami T, Kim T, Hori M, Hirohashi S, Matsuki M, Narumi Y, Imai Y, Sakurai K, Nakamura H. Safety of ferucarbotran in MR imaging of the liver: a pre- and postexamination questionnairebased multicenter investigation. J Magn Reson Imaging 2009; 29: 106–11. Heesakkers RA, Hövels AM, Jager GJ, van den Bosch HC, Witjes JA, Raat HP, Severens JL, Adang EM, van der Kaa CH, Fütterer JJ, Barentsz J. MRI with lymph node specific contrast agent as an alternative to CT scan and lymph node dissection in patients with prostate cancer: a prospective multicohort study. Lancet Oncol 2008; 9: 850–6. Criado E, Kabbani L, Cho K. Catheter-less angiography for endovascular aortic aneurysm repair: a new application of carbon dioxide as a contrast agent. J Vasc Surg 2008; 48(3): 527–34. Anantharam B, Chahal N, Chelliah R, Ramzy I, Gani F, Senior R. Safety of contrast in stress echocardiography in stable patients and in patients with suspected acute coronary syndrome but negative 12 hour troponin. Am J Cardiol 2009; 104(1): 14–8. Abdelmoneim SS, Bernier M, Scott CG, Dhoble A, Ness SA, Hagen ME, Moir S, McCully RB, Pellikka PA, Mulvagh SL. Safety of contrast agent use during stress echocardiography. J Am Coll Cardiol Img 2009; 2: 1048–56. Moriyasu F, Itoh K. Efficacy of perflubutane microbubble enhanced ultrasound in the characterisation and detection of focal liver lesions: phase 3 multi-center clinical trial. AJR Am J Roentgenol 2009; 193: 86–95.

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[38] Senior R, Monaghan M, Main ML, Zamorano JL, Tiemann K, Agati L, Weissman NJ, Klein AL, Marwick TH, Ahmad M, DeMaria AN, Zabalgoitia M, Becher H, Kaul S, Udelson JE, Wackers FJ, Walovitch RC, Picard MH. RAMP-1 and RAMP-2 Investigators. Detection of coronary artery disease with perfusion stress echocardiography using a novel ultrasound imaging agent: two phase three international trials in comparison with radionuclide perfusion imaging. Eur J Echocardiogr 2009; 10: 26–35. [39] Ionescu A. Bubble trouble: anaphylactic shock, threatened myocardial infarction and transient renal failure after intravenous echo contrast for left ventricular cavity opacification preceding dobutamine stress echo. Eur J Echocardiogr 2009; 10(5): 707–10. [40] Ionescu A. Bubble trouble: anaphylactic shock, threatened myocardial infarction and transient renal failure after intravenous echo contrast for left ventricular cavity opacification preceding dobutamine stress echo. Eur J Echocardiogr 2009; 10(5): 707–10. [41] Main ML, Ryan AC, Davis TE, Albano MP, Kusnetzky LL, Hibberd M. Acute mortality in hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent (multicenter registry results in 4,300,966 consecutive patients). Am J Cardiol 2008; 102: 1742–6. [42] Balamurali G, du Plessis DG, Wengoy M, Bryan N, Herwadkar A, Richardson PL. Thorotrast-induced primary cerebral angiosarcoma: case report. Neurosurgery 2009; 65(1): E210–1. [43] Makaryus JN, Makaryus AN, Azer V, Diamond JA. Angioedema after injection of Tc-99 m sestamibi tracer during adenosine nuclear stress testing. J Nucl Cardiol 2008; 15(4): e26–7.

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47

Drugs used in ocular treatment

DRUGS USED IN THE MANAGEMENT OF AGE-RELATED MACULAR DEGENERATION [SEDA-30, 545; SEDA-31, 739; SEDA-32, 865]

Bevacizumab

[SEDA-30, 545;

SEDA-32, 865] Observational studies The short-term and long-term safety of topical bevacizumab 5 mg/ml for progressive corneal neovascularization secondary to a variety of corneal diseases and not responding to conventional anti-inflammatory treatment have been evaluated in 30 eyes of 27 patients [1c]. Five patients (five eyes) developed new corneal epithelial defects. The authors warned against using bevacizumab in patients with epithelial defects and neurotrophic keratopathy. There were no allergic reactions, ocular drug-related complaints, or systemic adverse reactions.

Pegaptanib [SEDA-31, 739; SEDA-32, 865] Comparative studies The safety of pegaptanib has been studied in two randomized trials in 161 patients with exudative ageSide Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00047-7 # 2011 Elsevier B.V. All rights reserved.

related macular degeneration during their third year, who had been using pegaptanib throughout years 1 and 2 and had received at least one dose in year 3; they received 0.3, 1, or 3 mg intravitreally every 6 weeks [2C]. There were ocular adverse events in 114 subjects (71%) in the primary safety population in year 3, and most of the events were associated with the injection procedure. There were serious ocular or nonocular adverse events in 27 (17%) subjects and 3% withdrew because of an adverse event. There were two cases of endophthalmitis, one of rhegmatogenous retinal detachment, and one of vitreous hemorrhage. One case of loss of vision of at least four lines was related to the injection procedure, and one case of retinal and vitreous hemorrhages was related to the injection procedure. Intraocular pressure rose after the injection procedure in some cases, but remained stable throughout the 3 years in those who received pegaptanib 0.3 or 1 mg for 3 years. There were no thromboembolic cerebrovascular accidents; two subjects had myocardial infarctions and one had angina. The incidence of these thromboembolic events was the same among the entire cohort of 422 subjects treated with pegaptanib sodium in year 3 and was similar to those observed in the pegaptanib and sham groups in years 1 and 2. There were no serious non-ocular hemorrhagic events. Among the entire cohort of 422 subjects treated with pegaptanib sodium in year 3, the most common serious adverse events were neoplasms and cardiac disorders, each experienced by 12 subjects, gastrointestinal disorders (10 subjects), 977

978

and vascular disorders (nine subjects). With the exception of one case of hypertension none was related to the injection procedure or the study drug. There were six deaths among the 422 subjects who received pegaptanib sodium in year 3 (including also those who had not received pegaptanib in year 1 or 2); none of the deaths was considered to be related to the study drug or injection procedure. The adverse events associated with these deaths were glioblastoma, cardiac arrest, Clostridium colitis, cardiorespiratory arrest, hypotension, and metastatic lung cancer (one case each). There were no findings in relation to electrocardiography or vital signs performed at each clinical assessment that suggested a relation to treatment with pegaptanib sodium; in particular, there was no evidence of an increase in mean blood pressure over the 3 years of treatment. There were no laboratory test findings suggestive of adverse reactions to pegaptanib sodium. Pegaptanib (0.3 mg intravitreally every 6 weeks for 30 weeks) has been studied in an open, randomized, controlled study in 10 patients with proliferative diabetic retinopathy and compared with 10 patients who received panretinal photocoagulation [3c]. The eyes that were exposed to pegaptanib had mild to moderate transient ocular adverse events, including most commonly subconjunctival hemorrhages after injection. One eye developed an epiretinal membrane. There were no other ocular adverse events. Fellow eyes in this group developed an epiretinal membrane (one eye), a vitreous hemorrhage (two eyes), cataract (one eye), and diabetic macular edema (one eye). Study eyes that had been treated with panretinal photocoagulation developed epiretinal membranes (four eyes), vitreous hemorrhages (two eyes), iritis (one eye), and a macular hole (one eye). The fellow eyes in this group developed an epiretinal membrane (one eye), vitreous hemorrhages (two eyes), and diabetic macular edema (one eye). Sensory systems Eyes A case of cultureproven endophthalmitis after intravitreal pegaptanib for exudative age-related

Chapter 47

J.S.A.G. Schouten

macular degeneration presented as frosted branch angiitis [4A].

Ranibizumab

[SEDA-30, 545; SEDA-31, 739; SEDA-32, 867]

Comparative studies Adverse reactions have been studied in 32 patients with exudative age-related macular degeneration who received standard fluence photodynamic therapy with verteporfin at baseline and months 3, 6, and 9 and ranibizumab 0.5 mg at baseline and months 1, 2, and 3 [5c]. The main adverse reactions outcome measure was severe loss of vision (a loss of best-corrected visual acuity of at least 30 letters). There was no severe loss of vision due to ocular inflammation or uveitis. One patient had moderate loss of vision (of at least 15 letters). Three patients had mild/moderate uveitis. There were two serious ocular adverse events (a retinal pigment epithelial tear and a moderate reduction in best-corrected visual acuity). There were no systemic adverse events. In an open, prospective, uncontrolled study, 10 patients with macular edema due to central retinal vein occlusion were randomly assigned to ranibizumab 0.3 or 0.5 mg and adverse reactions were studied [6c]. There were no severe adverse events. Ranibizumab has been studied in 4300 patients with choroidal neovascularization secondary to age-related macular degeneration [7c]. One group was randomized to ranibizumab 0.3 or 0.5 mg and the second group received open ranibizumab 0.5 mg. Some 82% of the first group and 50% of the second group completed the 12-month study. The average total numbers of ranibizumab injections were 4.9 and 3.6 respectively. The incidences of vascular and non-vascular deaths during the 12 months were 0.9% and 0.7% in those who took 0.3 mg, 0.8% and 1.5% in those who took 0.5 mg in the first group, and 0.7% and 0.9% in those who took 0.5 mg in the second group. The incidence of death due to unknown cause was 0.1% in all the groups. The numbers of vascular deaths and deaths

Drugs used in ocular treatment

Chapter 47

due to unknown causes did not differ across the groups. Stroke rates were 0.7%, 1.2%, and 0.6% in the three groups. The rates of individual key ocular serious adverse events in the first group were less than 1%; two of those who took 0.3 mg and five of those who took 0.5 mg developed endophthalmitis or presumed endophthalmitis (i.e. ocular infection treated with antibiotics), and one subject in each dosage group had a serious cataract event. The rates of individual key ocular serious adverse events in the second group were less than 1%; one subject developed endophthalmitis, and one had a serious cataract event. The incidences of ocular inflammation, including iritis, uveitis, vitritis, and iridocyclitis, were 1.0% in those who took 0.3 mg, 1.5% in those who took 0.5 mg in the first group, and 0.5% in the second group. The overall incidences of cataract were 5.4%, 6.0%, and 2.8%. The rates of key non-ocular serious adverse events were similar across the two dosages in the first group, but non-vascular deaths, strokes, and hemorrhages were numerically higher in the 0.5 mg group. Eight subjects who took 0.3 mg and 15 who took 0.5 mg had a stroke during the 12 months. The incidences of myocardial infarctions and Antiplatelet Trialists’ Collaboration (APTC) three arterial thromboembolic events, which included vascular deaths and deaths of unknown cause, non-fatal myocardial infarctions, and non-fatal cardiovascular accidents, were similar across the two dosages. The rates of key non-ocular serious adverse events in the second group were generally lower than those in the first group, which may have been a result of under-reporting, because of the large number of subjects in the second group who withdrew. The incidence of non-ocular adverse events that were potentially related to VEGF inhibitors was low and comparable across all the groups. A prior stroke, a history of dysrhythmias, and a history of congestive heart failure were significant susceptibility factors for stroke. Although the numbers were small, there was a nonstatistically significant trend toward a higher incidence of stroke in those in the

979

first group who took 0.5 mg with a history of stroke. Seven of the 73 subjects with a history of stroke who took 0.5 mg had a stroke during the study compared with two of the 73 subjects with a history of stroke who took 0.3 mg. None of the subjects in the second group with a history of stroke had a stroke during the study. There were 82 deaths during the study (20, 29, and 33 subjects in the respective groups);.the numbers of vascular deaths and deaths due to unknown causes did not differ across the groups. In the ANCHOR study of ranibizumab 0.3 and 0.5 mg versus photodynamic therapy for neovascular age-related macular degeneration in 423 patients the adverse events were reported after 2 years [8C]. Overall, there was no imbalance among the three treatment groups in the rates of serious and non-serious ocular adverse events in the study eye. The percentages of patients with any serious ocular adverse event in the study eye were similar among those who received photodynamic therapy (7.7%), ranibizumab 0.3 mg (7.3%), and ranibizumab 0.5 mg (9.3%). “Presumed” endophthalmitis occurred in three of 277 patients (1.1%) in the pooled ranibizumab groups and in none in the photodynamic therapy group. Vitreous hemorrhage was reported in two of 277 patients (0.7%) in the former and none of 143 patients in the latter. Rhegmatogenous retinal detachment occurred in two (0.7%) and one patient (0.7%) respectively and the rates per ocular injection were two out of 5921 (0.03%) and two out of 2571 (0.07%). The percentage of patients who had any serious or non-serious intraocular inflammation in the study eye was higher in the ranibizumab groups (12% with 0.3 mg and 17% with 0.5 mg) than in the photodynamic therapy group (3.5%). As in all previous trials of ranibizumab, transient increases in intraocular pressure in the study eye were common in the hour after intravitreal injection. No cases of traumatic lens damage were reported. There was a trend to a higher rate of cataract in the study eye with ranibizumab (17% with 0.3 mg and 20% with 0.5 mg) compared with photodynamic therapy (11%); post hoc analysis showed that the

980

difference between ranibizumab 0.5 mg and photodynamic therapy was statistically significant. Cataract surgery was performed during the 24 months in five of 137 patients (0.3 mg), five of 140 patients (0.5 mg), and one of 143 patients (photodynamic therapy). Overall, there was no imbalance among the three treatment groups in the rates of serious non-ocular adverse events, including those known to be potentially associated with systemic administration of VEGF inhibitors in patients with cancers. The rates of arterial thromboembolic events (defined using the Antiplatelet Trialists’ Collaboration criteria) were similar across the groups 4.4% (0.3 mg), 5.0% (0.5 mg), and 4.2% (photodynamic therapy). Although the rate of arterial thromboembolic events with ranibizumab 0.5 mg (3.6%) was slightly higher than with ranibizumab 0.3 mg and photodynamic therapy (2.2% and 2.1% respectively) during the first treatment year, it was slightly lower than in the other two groups during the second year: 1.6% (2/128) compared with 2.4% (3/127) and 2.3% (3/128) respectively; none of these differences was statistically significant. There were no deaths from myocardial infarction or stroke during the study. Rates of non-fatal strokes were 2.2%, 0%, and 1.4% respectively. Hypertension was not more common with ranibizumab than photodynamic therapy. Non-ocular hemorrhages were more common with ranibizumab (8.8% with 0.3 mg, 9.3% with 0.5 mg, 4.9% with photodynamic therapy), although these differences were not statistically significant. The incidence of serious non-ocular hemorrhage was also slightly higher with ranibizumab (2.9% with 0.3 mg, 2.1% with 0.5 mg, and 0.7% with photodynamic therapy). Serious hemorrhages with ranibizumab included gastrointestinal hemorrhage (n ¼ 4), traumatic subdural hematoma (n ¼ 2), and duodenal ulcer hemorrhage (n ¼ 1). The temporal pattern of these events in relation to ranibizumab dosing did not suggest a causal association. No ranibizumab-treated patient had proteinuria. The risks of strokes and myocardial infarctions have been calculated in patients who received ranibizumab (0.3 or 0.5 mg

Chapter 47

J.S.A.G. Schouten

intravitreally) for age-related macular degeneration in three large randomized trials (MARINA, ANCHOR, and FOCUS) in a total of 859 subjects who were treated with monthly ranibizumab, and 434 subjects who were sham-treated [9M]. During the 2year observation period, 19 of those who received ranibizumab (2.2%) had strokes and 16 (1.9%) had myocardial infarctions. Of the sham-treated subjects, three (0.7%) had strokes and 13 (3.0%) had myocardial infarctions. Intravitreal ranibizumab was associated with an increased risk of stroke (OR ¼ 3.24; 95%CI ¼ 0.96, 11), whereas there was no apparent association between intravitreal ranibizumab and myocardial infarction. In a randomized controlled trial in patients with diabetic macular edema who were randomised to intravitreal ranibizumab 0.5 mg, focal or grid laser, and a combination of these interventions, there was one serious adverse event (a stroke in a high-risk patient), which was presumed to be unrelated to the use of ranibizumab because it occurred 6 weeks after the injection [10C]. There was no difference in blood pressure. Eight patients across the groups had vitreous hemorrhages, and in one patient it was combined with worsening of the macular edema, while in the others it was mild and had cleared at 6 months. Sensory systems Eyes In 138 patients with subfoveal choroidal neovascular agerelated macular degeneration who received ranibizumab 0.5 mg the observed adverse events were vitreous hemorrhage (n ¼ 1), extrafoveal tears in the retinal pigment epithelium (n ¼ 13; 9%), conjunctival hemorrhages (n ¼ 33; 24%), small floaters (n ¼ 42; 30%), and mild pain without inflammation (n ¼ 37; 27%); there were no systemic adverse events [11c]. Retinal pigment epithelium tears can complicate exudative age-related macular degeneration or its treatment. An 81-yearold woman with retinal angiomatous proliferation and pigment epithelial detachment had a retinal pigment epithelial tear 10 days after an intravitreal injection of ranibizumab [12A].

Drugs used in ocular treatment

Chapter 47

Verteporfin and photodynamic therapy [SEDA-30, 545; SEDA-31, 739; SEDA-32, 868] Observational studies No adverse reactions were observed in 31 patients with choroidal hemangioma who received photodynamic therapy with verteporfin (6 mg/m2) and a light dose of 50 J/cm2 at 692 nm [13c]. In a case series of 21 patients (22 eyes) with exudative age-related macular degeneration with a suspected chorioretinal anastomosis or age-related macular degeneration that was resistant to prior photodynamic therapy alone, photodynamic therapy was given combined with intravitreal triamcinolone 2 mg [14c]. The patients were followed for 12 months. The incidence of adverse reactions accompanying treatment was not as high as that reported previously for combined therapy that used higher doses of intravitreal triamcinolone. Comparative studies Reduced-fluence photodynamic therapy has been compared with standard photodynamic therapy, in both cases with intravitreal triamcinolone, in a randomized controlled trial in 40 patients with exudative age-related macular degeneration [15C]. The reduced-fluence intervention gave better visual outcomes and fewer patients had choroidal hypoperfusion (three versus 14). Photodynamic therapy with intravitreal triamcinolone has been compared with photodynamic therapy alone in a randomized study in patients with exudative agerelated macular degeneration [16C]. There was a better short-term effect on visual acuity in the combined treatment group, but not at 24 months. Areas with reduced/ absent fundus autofluorescence within the photodynamic therapy spot area were significantly greater with the combined therapy. The number of operations for cataract was higher in the combined therapy group (49% versus 20%). In the combined therapy group four patients (9.3%) had an intraocular pressure higher than 24 mmHg; they were treated successfully with additional therapy.

981

Full-fluence verteporfin þ photodynamic therapy has been compared with photodynamic therapy in combination with intravitreal triamcinolone in a double-blind, randomized, sham-controlled trial in 100 patients with exudative age-related macular degeneration and subfoveal neovascularization [17C]. There was no difference in visual acuity after 1 year and visual acuity was reduced in both groups. Fewer retreatments with verteporfin þ photodynamic therapy were needed in those who received triamcinolone. Intraocular pressure rose more in those who received triamcinolone, but it could be treated with topical ocular antihypertensive drugs. In a study of verteporfin þ photodynamic therapy combined with intravitreal bevacizumab 1.25 mg for neovascular age-related macular degeneration in 1196 patients, most of the serious adverse events (26/30, 22 non-ocular, eight ocular) were judged by the investigators not to have been related to the treatments [18C]. Three ocular events were judged to have been possibly related to bevacizumab alone, and one ocular event was to both bevacizumab and photodynamic therapy. The latter was a reduction loss of vision of 20 letters within 7 days after photodynamic therapy with standard light fluence; vision slowly improved to baseline after 6 months. The other four ocular events (a suspected infection in the right eye, attributed to dry eyes, a cataract extraction, an advanced cataract, and reduced vision) were judged not to have been related to either bevacizumab or verteporfin. All eight patients recovered from the ocular adverse events. There were 22 reports of non-ocular serious adverse events; they occurred over 11–435 days with bevacizumab and 42–423 days with verteporfin. No non-ocular serious adverse events were judged to have been related to either bevacizumab or photodynamic therapy. The serious adverse events reported were myocardial infarctions (n ¼ 4), respiratory failure (n ¼ 3), unknown cause of death (n ¼ 3), transient ischemic attacks (n ¼ 3), stroke (n ¼ 1 event), and one event each of renal failure, renal cell carcinoma, colon cancer,

Chapter 47

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gastrointestinal hemorrhage, hepatic cirrhosis, accidental fall, hip osteoarthritis, and hip dislocation; 11 of these patients died. Eight of the 22 non-ocular serious adverse events were cardiovascular, four of which had a temporal relation to treatment. However, the Registry Oversight Board reviewed the context of these events, and based on the available information judged that none was associated with either treatment. Placebo-controlled studies In a randomized placebo-controlled trial (n ¼ 64; 21 placebo) of verteporfin photodynamic therapy in acute symptomatic central serous choroidopathy with half-dose verteporfin (3 mg/m2) and 83 seconds laser treatment 10 minutes after the start of the infusion, there were no ocular or systemic adverse reactions [19C]. Sensory systems Eyes Half-fluence verteporfin photodynamic therapy (300 mW/cm2 light intensity) for central serous chorioretinopathy is generally regarded as safer than fullfluence photodynamic therapy (600 mW/cm2 light intensity). However, in one case a pigment epithelial tear occurred after half-fluence verteporfin photodynamic therapy in central serous chorioretinopathy [20A]. In 11 patients with exudative age-related macular degeneration who received verteprofin þ pdt and ranibizumab, optical coherence tomography showed that subretinal and intraretinal leakage increased with verteporfin but resolved after 2 weeks [21c]. Non-perfusion of small/medium choroidal vessels occurred, and although reperfusion began after 1 month it was not restored completely.

ADRENOCEPTOR AGONISTS [SEDA-31,

740;

SEDA-32, 869]

Apraclonidine

[SEDA-32, 869]

Observational studies Adverse reactions to apraclonidine 0.5% have been studied

J.S.A.G. Schouten

retrospectively in 75 children with glaucoma who underwent 179 treatment sessions, 91% during or after angle surgery [22c]. The glaucoma was congenital or infantile in 53% of cases. The median age was 5.3 months (range 0–17 year). The median number of apraclonidine exposures was 15 (range 4–5745). There were nonthreatening adverse reactions in 8% (6/75): topical allergy (n ¼ 2), lethargy (n ¼ 3), and reduced appetite (n ¼ 1). The authors concluded that in contrast to brimonidine, topical apraclonidine 0.5% can safely be used in short-term treatment of most infants and children undergoing angle surgery for glaucoma, and that it rarely causes systemic adverse reactions. However, care should be taken, since the study group was too small to detect (severe) adverse events with a low incidence.

ANTI-GLAUCOMA DRUGS Observational studies In a German registry of 20 506 patients with glaucoma who used anti-glaucoma drugs, 57% had dry eyes [23C]. The occurrence of dry eyes was related to the duration of glaucoma and the number of anti-glaucoma drugs used. Systematic reviews In a meta-analysis of studies of adverse reactions to anti-glaucoma drugs, conjunctival hyperemia was more common in patients who used travoprost [24M]. The authors noted that this was in contrast to the results of trials in which there was a higher incidence of this adverse reaction in patients who used bimatoprost. Travoprost also caused more stinging/burning and dry eye sensations and timolol had a higher incidence of superficial punctuate keratopathy. Sensory systems Eyes The frequency of nasolacrimal duct obstruction has been studied in 384 patients [25c]. There was lacrimal drainage obstruction, especially upper

Drugs used in ocular treatment

Chapter 47

lacrimal duct obstruction, in 20% of those who used anti-glaucoma drugs compared with 8.6% of the controls. The combinations of timolol þ dorzolamide and timolol þ dorzolamide þ pilocarpine were related to this adverse reaction.

983

heart rate, or nocturnal dip in blood pressure with either medication.

CARBONIC ANHYDRASE INHIBITORS See Chapter 21.

BETA-ADRENOCEPTOR ANTAGONISTS [SEDA-31, 740; SEDA-32, 870]

GLUCOCORTICOSTEROIDS Comparative studies In 105 children who were treated with either betaxolol hydrochloride ophthalmic suspension 0.25% or timolol maleate ophthalmic gel-forming solution 0.25% and 0.5% after randomization, adverse events were mostly non-serious and mild to moderate in intensity [26C]. No patient stopped treatment because of adverse events, which were hyperemia of the eye, discomfort, irritation of the eye, discharge from the eye, lid margin crusting, pruritus of the eye, a sticky sensation, bradycardia, and hypotension. In 148 of 286 long-term users of betablockers, prostaglandins, or the combination there was no statistically significant difference between the beta-blockers and prostaglandins in the risks of falls, orthostatic hypotension, or dizziness [27c].

[SED-15, 906; SEDA-30, 548; SEDA-31, 741; SEDA-32, 871] Comparative studies In a randomized, single-masked, controlled trial in 315 patients with persistent macular edema, the patients were randomized to intravitreal surgical placement of a dexamethasone drug delivery system 350 or 700 micrograms or observation [29C]. The patients with uveitis or Irvine–Gass syndrome (n ¼ 41) were evaluated. There was an increase in intraocular pressure of 10 mmHg or more in five of 13 patients who took 700 micrograms, in one of 12 patients who took 350 micrograms, and in no patients in the control group. There were no reports of endophthalmitis.

Timolol

Endocrine Adrenal insufficiency and obesity occurred as a result of continuous use of topical corticosteroids for uveitis in a child [30A].

Comparative studies In 29 patients with normal blood pressures, the intraocular pressure and blood pressure were measured during several times in a 24-hour period during the use of either a fixed combination of latanoprost þ timolol or timolol [28c]. The patients received the drugs in a crossover design for two periods of 8 weeks. There were no statistical differences between untreated and treated 24-hour systolic, diastolic, or mean blood pressures,

Drug administration route Intravitreal The two main adverse reactions to intravitreal inserts of sustained-release glucocorticoids are cataracts and increased intraocular pressure [31R]. Glucocorticoids can also be associated with central serous chorioretinopathy or exacerbation of existing chorioretinopathy, a disorder that is characterized by serous detachment of the neurosensory retina at the posterior pole of the fundus. Central serous chorioretinopathy has been reported in a 42-year-old

[SED-15, 3428; SEDA-31, 741; SEDA-32, 870]

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man after intravitreal injection of triamcinolone acetonide 4 mg in 0.1 ml for the treatment of macular edema secondary to branch retinal vein occlusion [32A].

J.S.A.G. Schouten

(OR ¼ 0.51; 95% CI ¼ 0.39, 0.67) and bimatoprost (OR ¼ 0.32; 95% CI ¼ 0.24, 0.42).

Bimatoprost [SED-15, 517; SEDA-31, 655; SEDA-32, 729] PROSTAGLANDIN ANALOGUES (SEE ALSO CHAPTER 39) [SEDA-32, 871] Systematic reviews Adverse reactions to prostaglandin analogues have been reviewed [33M]. Common adverse reactions include conjunctival hyperemia, elongation and darkening of the eyelashes, iris darkening, and periocular skin pigmentation. Uncommon adverse reactions with no definitive causal relation are iris cysts, cystoid macular edema, anterior uveitis, and reactivation of herpes simplex keratitis. In a meta-analysis of all clinical trials with a direct comparison of prostaglandins (latanoprost, bimatoprost, and travoprost) in which adverse events were reported, there was a higher incidence of conjunctival hyperemia in patients who used bimatoprost 0.03%. [34M]. Sensory systems Eyes In a retrospective case series in 84 consecutive patients with uveitis, prostaglandins did not increase the frequency of anterior uveitis or cystoid macular edema compared with other antiglaucoma drugs [35c]. A lower rate of conjunctival hyperemia has been reported with latanoprost in comparison with bimatoprost and travoprost, and there has been a meta-analysis of 13 randomized clinical trials in 2222 patients with ocular hypertension and/or glaucoma, comparing latanoprost with bimatoprost and travoprost, either together or in separated studies [36M]. Five of the studies compared latanoprost and travoprost, seven compared latanoprost and bimatoprost, and one compared latanoprost, travoprost, and bimatoprost. The combined results showed that latanoprost was associated with a lower incidence of conjunctival hyperemia than both travoprost

Sensory systems Eyes Conjunctival hyperemia has been studied in patients using bimatoprost 0.03% as initial therapy and compared with that in patients in whom latanoprost was replaced by bimatoprost; changes in hyperemia scores from baseline were highly significant only in first-line therapy [37c]. Skin Periorbital fat atrophy has been observed after treatment with bimatoprost 0.03%, with deepening of the upper eyelid sulcus [38A]. In five patients using bimatoprost 0.03% unilaterally for glaucoma, the following adverse events were reported: periorbital fat atrophy, deepening of the upper eyelid sulcus, relative enophthalmos, loss of lower eyelid fullness, and involution of dermatochalasis compared with the fellow untreated eye [39c]. These events were assumed to be related to the use of bimatoprost, because the effects were unilateral and were confirmed by inspecting old photographs not to have been present before the use of bimatoprost. The changes were partly reversible after drug withdrawal.

Latanoprost

[SED-15, 2002; SEDA-30, 465; SEDA-31, 655; SEDA-32, 729]

Respiratory A 51-year-old woman developed a chronic cough after using latanoprost for glaucoma [40A]. A citric acid cough challenge was performed while she was using latanoprost and repeated after the drug had been withdrawn. The initial cough challenge showed marked hypersensitivity of the cough reflex, and this was significantly reduced after latanoprost had been withdrawn for 10 days. After 3 days of restarting latanoprost, cough sensitivity again increased.

Drugs used in ocular treatment

Chapter 47

Sensory systems Eyes Progression of keratoconus has been attributed to latanoprost, which is known to affect metalloproteinases [41A]. • A 47-year-old man with keratometric values of 42.75 D at 30 degrees and 45.00 D at 120 degrees had mild keratoconus in the right eye; the left eye was normal. The right eye was treated with latanoprost for normal-tension glaucoma for 2 years. The keratometric values were 40.75 D at 42 degrees and 48.25 degrees at 132 degrees. There was more advanced keratoconus. Latanoprost was changed to timolol and no further progression was observed.

Adverse reactions to latanoprost have been studied in 115 children who had used latanoprost for a mean of 20 months [42c]. The reported adverse reactions were eyelash growth (in all eyes exposed for at least 6 months; latanoprost was withdrawn in one case), conjunctival hyperemia/irritation (n ¼ 6; two withdrawn), headache (n ¼ 3), and difficulty in focusing, iris pigmentation, and sleep disturbances (n ¼ 1 each).

Travoprost

[SED-15, 3481; SEDA-30, 466; SEDA-31, 655; SEDA-32, 731] Observational studies Adverse events during the administration of travoprost have been studied in 75 eyes of 57 children in a retrospective medical record review [43c]. Eyelash thickening and elongation occurred in all 75 eyes, conjunctival injection in 13 (17%); ocular irritation in 4 (5%), and eyelid swelling and blurring of vision in one each. There was no iris heterochromia or periorbital skin pigmentation.

Skin A patient with unilateral normal-tension glaucoma and another with unilateral primary open-angle glaucoma, both of whom used travoprost monotherapy unilaterally for 2 years, gradually developed deepening of the eyelid superior sulcus, with hyperpigmentation in the eyelid skin of the treated eye [44A]. The disparity between the treated eye and the fellow eye was clearly visible and resolved after

985

withdrawal of travoprost for 15 months. The authors suggested that the mechanism could be fatty degeneration and reduced collagen fibers in the levator complex; however, the exact mechanism remains to be determined.

PROCEDURES Intravitreal injection

[SEDA-29, 581;

SEDA-32, 874] The rise in intraocular pressure after intravitreal injections of pegaptanib (0.09 ml, 27gauge needle), bevacizumab (0.05 ml, 30or 32-gauge needle), ranibizumab (0.05 ml, 30- or 32-gauge needle), or triamcinolone (0.1 ml, 27-gauge needle) has been investigated in 213 consecutive injections [45C]. Mean preinjection intraocular pressure was 14 (range 7–22) mmHg. Mean baseline intraocular pressure was 14 (range 7–22) mm Hg. Mean intraocular pressure directly after injection was 44 (range 4–87) mmHg, when all but one eye had at least handmovement vision and a perfused optic nerve. Intraocular pressure fell to less than 30 mmHg in 70% by 5 minutes, in 96% of injections by 15 minutes, and in 100% by 30 minutes. Eyes with a history of glaucoma took significantly longer to normalize intraocular pressure. There were statistically significant spikes in intraocular pressure with smaller needle bore sizes, even though this was related to smaller injected volumes, and in eyes with a history of glaucoma. Adverse reactions to intravitreal injections of VEGF inhibitors have been reviewed [46R] There is circumstantial evidence that systemic adverse events could occur in patients who receive intravitreal injections, especially thromboembolic events. Moreover, VEGF inhibitors are detectable in the circulation after intravitreal injection. Since adverse events are infrequent, the authors proposed using several highly sensitive methods to identify them.

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J.S.A.G. Schouten

References [1] Koenig Y, Bock F, Horn F, Kruse F, Straub K, Cursiefen C. Short-and long-term safety profile and efficacy of topical bevacizumab eye drops against corneal neovascularization. Graefes Arch Clin Exp Ophthalmol 2009; 247: 1375–82. [2] Singerman LJ, Masonson H, Patel M, Adamis AP, Buggage R, Cunningham E, Goldbaum M, Katz B, Guyer D. Pegaptanib sodium for neovascular age-related macular degeneration: third-year safety results of the VEGF Inhibition Study in Ocular Neovascularisation (VISION) trial. Br J Ophthalmol 2008; 92: 1606–11. [3] Gonzalez VH, Giuliari GP, Banda RM, Guel DA. Intravitreal injection of pegaptanib sodium for proliferative diabetic retinopathy. Br J Ophthalmol 2009; 93: 1474–8. [4] Chen E, Ho AC, Garg SJ, Brown GC, Kaiser RS. Streptococcus mitis endophthalmitis presenting as frosted branch angiitis after intravitreal pegaptanib sodium injection. Ophthalmic Surg Lasers Imaging 2009; 40: 192–4. [5] Schmidt-Erfurth U, Wolf S. Same-day administration of verteporfin and ranibizumab 0.5 mg in patients with choroidal neovascularisation due to age-related macular degeneration. Br J Ophthalmol 2008; 92: 1628–35. [6] Pieramici DJ, Rabena M, Castellarin AA, Nasir M, See R, Norton T, Sanchez A, Risard S, Avery RL. Ranibizumab for the treatment of macular edema associated with perfused central retinal vein occlusions. Ophthalmology 2008; 115: e47–54. [7] Boyer DS, Heier JS, Brown DM, Francom SF, Ianchulev T, Rubio RG. A phase IIIb study to evaluate the safety of ranibizumab in subjects with neovascular age-related macular degeneration. Ophthalmology 2009; 116: 1731–9. [8] Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T. ANCHOR Study Group. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: twoyear results of the ANCHOR Study. Ophthalmology 2009; 116: 57–65.

[9] Ueta T, Yanagi Y, Tamaki Y, Yamaguchi T. Cerebrovascular accidents in ranibizumab. Ophthalmology 2009; 116: 362. [10] Nguyen QD, Shah SM, Heier JS, Do DV, Lim J, Boyer D, Abraham P, Campochiaro PA. Primary end point (six months) results of the Ranibizumab for Edema of the mAcula in Diabetes (READ-2) Study. Ophthalmology 2009; 116: 2175–81. [11] Rothenbuehler SP, Waeber D, Brinkmann CK, Wolf S, WolfSchnurrbusch UEK. Effects of ranibizumab in patients with subfoveal choroidal neovascularization attributable to age-related macular degeneration. Am J Ophthalmol 2009; 147: 831–7. [12] Pece A, Isola V, Milani P. Retinal pigment epithelial tear after intravitreal ranibizumab (LucentisÒ) for retinal angiomatous proliferation (RAP) associated with pigment epithelial detachment. Semin Ophthalmol 2009; 24: 210–3. [13] Boixadera A, Arumi JG, MartinezCastillo V, Encinas JL, Elizalde J, BlancoMateos G, Caminal J, Capeans C, Armada F, Navea A, Olea JL. Prospective clinical trial evaluating the efficacy of photodynamic therapy for symptomatic circumscribed choroidal hemangioma. Ophthalmology 2009; 116: 100–5. [14] Iwama D, Otani A, Sasahara M, Yodoi Y, Gotoh N, Tamura H, Tsujikawa A, Yoshimura N. Photodynamic therapy combined with low-dose intravitreal triamcinolone acetonide for age-related macular degeneration refractory to photodynamic therapy alone. Br J Ophthalmol 2008; 92: 1352–6. [15] Sacu S, Varga A, Michels S, Weigert G, Polak K, Vecsei-Marlovits PV, SchmidtErfurth U. Reduced fluence versus standard photodynamic therapy in combination with intravitreal triamcinolone: short-term results of a randomised study. Br J Ophthalmol 2008; 92: 1347–51. [16] Piermarocchi S, Sartore M, Lo Giudice G, Maritan V, Midena E, Segato T.

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[17]

[18]

[19]

[20]

[21]

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[23]

[24]

[25]

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Combination of photodynamic therapy and intraocular triamcinolone for exudative age-related macular degeneration and long-term chorioretinal macular atrophy. Arch Ophthalmol 2008; 126: 1367–74. Maberley D. Photodynamic therapy and intravitreal triamcinolone for neovascular age-related macular degeneration: a randomized clinical trial. Ophthalmology 2009; 116: 2149–57. Kaiser PK. Registry of Visudyne AMD Therapy Writing Committee. Verteporfin photodynamic therapy combined with 1.25 mg intravitreal bevacizumab for neovascular age-related macular degeneration. Ophthalmology 2009; 116: 747–55. Chan W-M, Lai TYY, Lai RYK, Liu DTL, Lam DSC. Half-dose verteporfin photodynamic therapy for acute central serous chorioretinopathy: one-year results of a randomized controlled trial. Ophthalmology 2008; 115: 1756–65. Kim SW, Oh J, Oh IK, Huh K. Retinal pigment epithelial tear after half fluence PDT for serous pigment epithelial detachment in central serous chorioretinopathy. Ophthalmic Surg Lasers Imaging 2009; 40: 300–3. Kiss CG, Simader C, Michels S, SchmidtErfurth U. Combination of verteporfin photodynamic therapy and ranibizumab: effects on retinal anatomy, choroidal perfusion and visual function in the protect study. Br J Ophthalmol 2008; 92: 1620–7. Wright TM, Freedman SF. Exposure to topical apraclonidine in children with glaucoma. J Glaucoma 2009; 18: 395–8. Erb C, Gast U, Schremmer D. German register for glaucoma patients with dry eye. I. Basic outcome with respect to dry eye. Graefes Arch Clin Exp Ophthalmol 2008; 246: 1593–601. Stewart WC, Konstas AGP, Nelson LA, Kruft B. Meta-analysis of 24-hour intraocular pressure studies evaluating the efficacy of glaucoma medicines. Ophthalmology 2008; 115: 1117–22. Kashkouli MB, Rezaee R, Nilforoushan N, Salimi S, Foroutan A, Naseripour M. Topical antiglaucoma medications and lacrimal drainage system obstruction. Ophthal Plast Reconstr Surg 2008; 24: 172–5.

987 [26] Plager DA, Whitson JT, Netland PA, Vijaya L, Sathyan P, Sood D, Krishnadas SR, Robin AL, Gross RD, Scheib SA, Scott H, Dickerson JE. BETOPTIC S Pediatric Study Group. Betaxolol hydrochloride ophthalmic suspension 0.25% and timolol gel-forming solution 0.25% and 0.5% in pediatric glaucoma: a randomized clinical trial. J AAPOS 2009; 13: 384–90. [27] Ramdas WD, van der Velde N, van der Cammen TJM, Wolfs RCW. Evaluation of risk of falls and orthostatic hypotension in older, long-term topical beta-blocker users. Graefes Arch Clin Exp Ophthalmol 2009; 247: 1235–41. [28] Konstas AGP, Pikilidou MI, Tsironi S, Mikropoulos D, Kozobolis VP, Sarafidis PA, Lasaridis AN, Nelson LA, Stewart WC. 24-hour intraocular pressure and blood pressure levels with latanoprost/ timolol fixed combination versus timolol. Curr Eye Res 2009; 34: 369–77. [29] Williams GA, Haller JA, Kuppermann BD, Blumenkranz MS, Weinberg DV, Chou C, Whitcup SM. Dexamethasone posteriorsegment drug delivery system in the treatment of macular edema resulting from uveitis or irvine-gass syndrome. Am J Ophthalmol 2009; 147: 1048–54. [30] Kroger L, Kotaniemi K, Jaaskelainen J. Topical treatment of uveitis resulting in adrenal insufficiency. Acta Paediatr Int J Paediatr 2009; 98: 584–5. [31] Montero JA, Ruiz-Moreno JM. Intravitreal inserts of steroids to treat diabetic macular edema. Curr Diabetes Rev 2009; 5: 26–32. [32] Kocabora MS, Durmaz S, Kandemir N. Exacerbation of central serous chorioretinopathy following intravitreal triamcinolone injection. Graefes Arch Clin Exp Ophthalmol 2008; 246: 1783–6. [33] Alm A, Grierson I, Shields MB. Side effects associated with prostaglandin analog therapy. Surv Ophthalmol 2008; 53: S93–S105. [34] Aptel F, Cucherat M, Denis P. Efficacy and tolerability of prostaglandin analogs: a meta-analysis of randomized controlled clinical trials. J Glaucoma 2008; 17: 667–73. [35] Chang JH, McCluskey P, Missotten T, Ferrante P, Jalaiudin B, Lightman S. Use of ocular hypotensive prostaglandin analogues

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[36]

[37]

[38]

[39]

[40]

[41]

in patients with uveitis: does their use increase anterior uveitis and cystoid macular oedema? Br J Ophthalmol 2008; 92: 916–21. Honrubia F, García-Sánchez J, Polo V, de la Casa JM, Soto J. Conjunctival hyperaemia with the use of latanoprost versus other prostaglandin analogues in patients with ocular hypertension or glaucoma: a metaanalysis of randomised clinical trials. Br J Ophthalmol 2009; 93: 316–21. Kurtz S, Mann O. Incidence of hyperemia associated with bimatoprost treatment in naïve subjects and in subjects previously treated with latanoprost. Eur J Ophthalmol 2009; 19: 400–3. Yam JC, Yuen NS, Chan CW. Bilateral deepening of upper lid sulcus from topical bimatoprost therapy. J Ocul Pharmacol Ther 2009; 25: 471–2. Filippopoulos T, Paula JS, Torun N, Hatton MP, Pasquale LR, Grosskreutz CL. Periorbital changes associated with topical bimatoprost. Ophthal Plast Reconstr Surg 2008; 24: 302–7. Fahim A, Morice AH. Heightened cough sensitivity secondary to latanoprost. Chest 2009; 136: 1406–7. Amano S, Nakai Y, Ko A, Inoue K, Wakakura M. A case of keratoconus

[42]

[43]

[44]

[45]

[46]

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progression associated with the use of topical latanoprost. Jpn J Ophthalmol 2008; 52: 334–6. Black AC, Jones S, Yanovitch TL, Enyedi LB, Stinnett SS, Freedman SF. Latanoprost in pediatric glaucoma—pediatric exposure over a decade. J AAPOS 2009; 113: 558–62. Yanovitch TL, Enyedi LB, Schotthoeffer EO, Freedman SF. Travoprost in children: adverse effects and intraocular pressure response. J AAPOS 2009; 13: 91–3. Yang HK, Park KH, Kim T-W, Kim DM. Deepening of eyelid superior sulcus during topical travoprost treatment. Jpn J Ophthalmol 2009; 53: 176–9. Kim JE, Mantravadi AV, Hur EY, Covert DJ. Short-term intraocular pressure changes immediately after intravitreal injections of anti-vascular endothelial growth factor agents. Am J Ophthalmol 2008; 146: 930–4. Csaky K, Do DV. Safety implications of vascular endothelial growth factor blockade for subjects receiving intravitreal anti-vascular endothelial growth factor therapies. Am J Ophthalmol 2009; 148: 647–56.

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48

Treatments used in complementary and alternative medicine

Pharmacovigilance in complementary and alternative medicine Pharmacovigilance in complementary and alternative medicine has attracted much attention worldwide. The awareness of the need for surveillance of adverse reactions to natural health products has stimulated the implementation of a reporting system for suspected adverse reaction in Italy [1C]. From April 2002 to March 2007, 233 spontaneous reports of suspected adverse reactions to natural health products were collected. A large proportion of the suspected adverse reactions were serious: hospitalization was reported in 35% of cases; 6% reported life-threatening clinical events, and there were two fatal events. Most of the reported cases involved herbal products (66%); 21 reports were associated with 27 homeopathic preparations, most of which contained a mixture of substances; 14 reports attributed the suspected reactions to products containing propolis. A review in China has shown that traditional Chinese medicine (TCM) led to several adverse drug reactions during the past few years and that pharmacovigilance in TCM remains problematic, although great efforts have been made to improve it [2R]. In order to report adverse effects of interventions in randomized controlled trials Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00048-9 # 2011 Elsevier B.V. All rights reserved.

transparently, it has been suggested that Consolidated Standards of Reporting Trials (CONSORT) for TCM should include background information on adverse reactions to each intervention, specific outcome assessments of adverse effects, and interpretation of the occurrence of adverse reactions in a structural report [3R]. In South India, a pharmacist-coordinated program has been initiated to improve the reporting of adverse reactions to complementary and alternative medicines [4C].

ASIAN HERBAL MEDICINES [SED-15, 1609; SEDA-32, 879]

Ling yang gan mao capsule Immunologic Ling yang gan mao capsule is a commonly used over-the-counter Chinese herbal mixture for the treatment of colds and flu. It contains Cornu Saigae Tataricae (antelope horn, ling yang jiao), Fructus Arctii (achene of great burdock, niu bang zi), glycine max (fermented soybean, dan dou chi), Flos Lonicerae Japonicae (honeysuckle flower, jin yin hua), Herba Schizonepetae (fineleaf schizonepeta herb, jing jie), Fructus Forsythiae (lian qiao), Herba Lophatheri (dan zhu ye), Radix Platycodonis (platycodon root, jie geng), Oleum Menthae (peppermint oil, bo he you), and 989

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Radix Glycyrrhizae (liquorice root, gan cao). An allergic reaction has been reported to Ling yang gan mao capsule [5A].

Cortex Dictamnus dasycarpus (bai xian pi) and Radix Sophora flavescens (ku shen), is commonly used to treat hematochezia, anal bulge, and constipation caused by hemorrhoids. The State Food and Drug Administration of China (SFDA) has received several reports of adverse reactions to Zhi xue capsule in recent years [7A, 8S]. Up to September 2008, 35 cases of adverse reactions associated with Zhi xue capsule had been reported, of which 21 were associated with abnormal liver function, cholestatic hepatitis, and drug-induced liver damage. After withdrawal and symptomatic treatment, there was full recovery in eight cases, and the rest improved markedly.

• A 62-year-old woman took Ling yang gan mao capsule three times in 2 days to treat a cold. She gradually developed increasing numbness, distension and itching of the lips, pain in the palms, swollen fingers, and erythema and itching in the hands. After she took cyproheptadine, triprolidine, and dexamethasone her symptoms gradually disappeared.

Shen ling bai zhu san Skin Shen ling bai shu san, an over-thecounter Chinese herbal formula that is commonly used to help digestion, consists of 10 herbs: Radix Ginseng (ren shen), Poria (fu ling), Rhizoma Atractylodis macrocephalae (bai zhu), Tuber Dioscores opposita (shan yao), Semen Lablab album (bai bian dou), Semen Nelumbo nucifere (lian zi), Semen Coicis (yi yi ren), Fructus Amomi xanthioidis (sha ren), Radix Platycodonis (jie geng), and Radix Glycyrrhizae (gan cao). It has been reported to cause erythema multiforme [6A]. • A 5-month-old girl developed swollen red skin around her eyes and mouth 1 day after taking three doses of Shen ling bai zhu san. After stopping the medication, her skin lesion worsened and spread to the whole body, with erythema multiforme and exfoliation. She became agitated, and cried and moved restlessly. She was given hydrocortisone, penicillin, promethazine, vitamin C, and calamine lotion, and her skin condition gradually resolved after 1 week. • An 8-month-old boy developed similar symptoms after two doses of the same brand of Shen ling bai zhu san. The skin lesion also included bullae, which was easily ruptured. He made a gradual recovery treatment with hydrocortisone, ceftriaxone, calamine lotion, a sedative, and medications for anaphylaxis.

Zhi xue capsule Liver Zhi xue capsule, a preparation that contains two Chinese medicinal herbs,

K. Chan, H.W. Zhang, and Z.X. Lin

Zhuang gu guan jie wan Liver Zhuang gu guan jie wan is a compound herbal preparation consisting of Rhizoma Cibotii (gou ji), Flos Epimedium brevicornum (yin yang huo), Radix Angelicae biseratae (du huo), Rhizoma Drynariae fortuei (gu sui bu), Radix Dipsaci asperoidis (xu duan), Fructus Psoralea corylifolia (bu gu zhi), Herba Taxilli Chinensis (sang ji sheng), Caulis Spatholobus suberectus Dunn (ji xue teng), Radix Rehmanniae preparata (shu di huang), Radix Aucklandiae (mu xiang), Boswellia carterii (ru xiang), and Commiphora myrrha (mo yao). It is commonly used in the treatment of osteoarthritis and lumbar muscle strains. Since 2001, there have been increasing numbers of reports of adverse reactions to zhuang gu guan jie wan [9S, 10A]. The most common adverse reaction is liver damage, of which 47 cases have been recorded among 158 patients monitored. The other adverse reactions include rashes, pruritus, nausea and vomiting, stomach ache, abdominal pain, diarrhea, and high blood pressure. After drug withdrawal there is good recovery. No drug-related deaths have been reported. It has been speculated that olibanum and myrrh are the main hepatotoxic ingredients in zhuang gu guan jie wan, and Fructus Psoraleae may also have detrimental effects on liver function [11E].

Treatments used in complementary and alternative medicine

INJECTABLE FORMULATIONS OF CHINESE MEDICINES

Chapter 48

991

pneumonia, and acute tonsillitis. It has been associated with acute renal failure, and the SFDA has issued warnings on its clinical use [14A, 15A, 16S].

Ci wu jia injection Skin Allergic skin reactions have been reported to be associated with the use of ci wu jia injection [12A]. • A 40-year-old woman with vertebrobasilar insufficiency was given an intravenous infusion of ci wu jia 250 ml for vertigo after an injection of xue sai tong (Panax notoginsenosides as the main ingredients) in isotonic saline 250 ml. Nearly 40 minutes into the infusion she developed a pruritic maculopapular rash from the neck to the chest, and then spreading all over the body. The rash resolved with oral cetirizine hydrochloride 10 mg, intravenous dexamethasone sodium phosphate 5 mg, and intravenous calcium gluconate 20 ml.

Ku die zi injection Immunologic Ku die zi injection is made from Herba Ixertis Sonchifoliae, which is believed to improve blood circulation and is generally used to treat coronary heart disease and angina pectoris in China. However, it has been reported to cause serious allergic reactions [13A]. • A 65-year-old woman with coronary heart disease and unstable angina pectoris was treated with an intravenous infusion of Ku die zi injection 40 ml in 5% dextrose. On the third day of the treatment, she suddenly developed shivering, cold limbs, and palpitation. The infusion was stopped immediately, and she gradually recovered after a combination treatment of dexamethasone, promethazine, and bromisoval and procaine injection.

Lian bi zhi injection Urinary tract Lian bi zhi injection is a sterilized fluid that contains andrographolide sodium bisulfate, which has antibacterial and anti-inflammatory effects and is commonly used to treat bacillary dysentery,

Shu xue ning injection Immunologic Shu xue ning injection is a sterilized fluid made from Ginkgo biloba leaves, with total flavonol glycosides and ginkgolides as the main active principles. It is generally used in China for the treatment of ischemic cardiovascular and cerebrovascular diseases. Eight cases of adverse effects have been reported. Allergic reactions, such as urticaria, bronchospasm, macular rashes, palpitation, nausea, and chest distension, were observed in six cases after an intravenous infusion of Shu xue ning injection [17A, 18A]. Two cases of anaphylactic shock were observed 2–3 minutes into the infusion, and the patients gradually recovered after treatment [19A, 20A].

Xing nao jing injection Immunologic Xing nao jing injection, a sterilized aqueous extract of Calculus bovis (niu huang), Moschus (she xiang), Dry Obalanopsaromatica Gwaertn. (bing pian), and Fructus Gardeniae (zhi zi), is commonly used in China to treat coma in stroke or traumatic injuries. It has been reported to cause serious allergic reactions [21A]. • A 73-year-old man developed shivering and spasm 25 minutes into an intravenous infusion of Xing nao jing injection 20 ml in isotonic saline 250 ml for cerebral infarction. The infusion was stopped immediately. He gradually recovered 40 minutes later after receiving oxygen, adrenaline, and promethazine. • A 62-year-old man was given Xing nao jing injection 30 ml in 5% dextrose 250 ml. About 10 minutes into the infusion, he developed chest distension, shortness of breath, a flushed complexion, a tachycardia, and a raised blood pressure. The infusion was stopped immediately. After receiving oxygen, dexamethasone, and promethazine he made an uneventful recovery.

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Zedoray tumeric oil and glucose injection

gastrointestinal complaints in 0.1% of patients. A crossover study reported no difference in the occurrence of adverse events between black cohosh and placebo, without providing further details. In two uncontrolled trials there were bleeding episodes in 59 women (36 spotting, eight mild bleeding, nine moderate bleeding, and six major bleeding) and in four women respectively. In three postmarketing surveillance studies involving 5405 patients, adverse events included stiff limbs, gastric pain, allergic reactions, breast tenderness, bleeding, and gastrointestinal complaints. Case reports included liver damage, seizures, muscle damage, and pseudolymphoma. Of all these effects, hepatotoxicity was most often reported.

Zedoray tumeric oil and glucose injection is an oil/water lipid emulsion made from the naphtha of Rhizoma Curcumae aeruginosae, Rhizoma Curcumae Kwangsiensis (or Rhizoma Curcumae Wenyujin) and is commonly used to treat virus infections. It has been reported to cause adverse effects such as allergic reactions, rashes, dyspnea, and even anaphylactic shock, and the SFDA has issued warnings on its clinical use [22S, 23A].

INDIAN MEDICINES Kadda Drug contamination In India, a 39-year-old man with jaundice developed vomiting and severe abdominal pain after consuming 10–15 ml of kadda (in local language) every morning on an empty stomach for 10 days [24A]. Lead poisoning was confirmed when the blood lead concentration was measured. A combination of chelation therapy and nutritional supplements reduced the body lead burden. The original syrup had been consumed and could not be tested for lead content.

SPECIFIC PLANTS Actaea racemosa (Ranunculaceae, black cohosh; formerly Cimicifuga racemosa) Systematic reviews There has been a systematic review of adverse reactions to black cohosh as reported in 13 clinical trials, three postmarketing surveillance studies, four case series, and eight single case reports [25M]. Three studies reported no serious adverse events. In one trial one of 21 patients had joint pain in the hands. Another trial reported

K. Chan, H.W. Zhang, and Z.X. Lin

Liver Cases of liver damage associated with black cohosh continue to appear [26c, 27c]. The hepatotoxic effects of black cohosh have been analysed by the Dietary Supplement Information Expert Committee of the US Pharmacopeia's Council of Experts. Reports were obtained from diverse sources, including the European Medicines Agency [28S]. There were 30 reports, all of which were considered to be possibly associated with the plant, using Naranjo's algorithm. The Expert Committee proposed that black cohosh products should be labeled with a cautionary statement. This is a change from a previous in 2002, which required no such statement. Meanwhile, other national regulatory authorities have issued similar warnings [29S, 30S, 31S, 32S]. In contrast, in a prospective study of 87 postmenopausal women who took a dry extract of black cohosh 40 mg/day for 12 months total hepatic blood flow, assessed by color Doppler ultrasound, was unaffected as were prothrombin time and concentration, serum albumin and bilirubin concentrations, and gamma-glutamyltransferase, alkaline phosphatase, and aminotransferase activities [33c]. However, these results do not rule out an incidence of hepatotoxicity of up to 3.4%. The use of a causality algorithm in four subjects with liver disease suggested that it was not related to the black cohosh that they had taken [34c]. Another group with the same first authors used the same methods in nine patients, in whom they judged that

Treatments used in complementary and alternative medicine

causality was excluded (n ¼ 4) or unlikely (n ¼ 4) and possible in only one case [35c]. Pursuing the same theme, the same group analysed data from 69 reported cases of liver disease in patients taking black cohosh, using the same method [36c]. They considered that causality had been excluded or was unlikely, unrelated, or unassessable in 68 cases; in the other case causality was possible. A major problem with these analyses was that in general the cases were poorly documented. Furthermore, the drawbacks of causality algorithms are well known [37M].

Agauria salicifolia (Ericaceae) See Rhododendron spp. below

Allium sativum (Liliaceae, garlic bulb) Hematologic A renal hematoma after extracorporeal shock-wave lithotripsy was attributed to the antiplatelet action of a garlic extract that the patient was taking [38A]. The authors suggested that herbal medications, such as garlic, ginkgo, and ginseng, should be withdrawn for up to 15 days before urological surgery or shock-wave lithotripsy, in order to minimize the risk of bleeding. Gastrointestinal A 60-year-old woman had severe sustained chest pain due to bullous necrosis of the esophagus when a piece of raw garlic measuring 2.7  1.5 cm impacted and had to be removed at endoscopy [39A]. Skin The application of fresh garlic to the skin can cause erythema and blistering (“garlic burns”), as has been reported in three young people in whom topical garlic was used as an analgesic by naturopaths; they all felt a burning sensation in the area, but did not remove the bandage, even when the burning sensation became severe [40cr]. The risks of garlic burns depend on various factors, such as the concentration,

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freshness of the garlic, duration of exposure, the area of application, the preexisting skin condition, and individual reactivity [41r].

Artemisia vulgaris (Asteraceae, mugwort, moxa) Tumorigenicity The formation of a basal cell carcinoma on a burn scar has been reported after repeated exposure to moxa cautery for 10 years, with occasional accidental burns [42A]. Malignant degeneration can occur in long-standing burn scars, and the authors proposed that moxa had encouraged the formation of the tumor in this case.

Camellia sinensis (Theaceae; green tea) Liver See Garcinia gambogia below.

Crataegus orientalis (Rosaceae, Anatolian hawthorn) Urinary tract Crataegus orientalis contains flavonoids and oligomeric procyanthins as its main active constituents. A multisystem hypersensitivity reaction and progressive acute renal failure has been associated with consumption of this plant [43A]. • A 68-year-old man developed weakness, fatigue, difficulty in breathing, reduced urine output, and epistaxis after eating 1 or 2 kg of raw Crataegus orientalis and drinking five cups of tea made from its leaves. He developed acute renal failure with moderate metabolic acidosis and fluid overload and hemodialysis was performed. A renal biopsy showed acute tubulointerstitial nephritis.

Cynomorium songaricum Rupr. (Cynomoriaceae) Urinary tract Cynomorium songaricum (also called Herba cynomorii) is commonly

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used to treat kidney disorders in traditional Chinese medicine. A high oral dose has been associated with acute renal insufficiency [44A].

perforation of 2–3 cm in the anterocaudal part of the septal cartilage. The right inferior and middle conchae were hypertrophic, and the remaining parts of the septum were deviated to the left. In another case, a 22-year-old man developed a headache, shortness of breath, and a sore throat 1.5 hours after aspirating an unknown amount of the undiluted juice of Ecballium elaterium intranasally [47A]. He responded to oxygen, methylprednisolone 1 g intravenously, and adrenaline 2 mg subcutaneously.

• A 49-year-old woman developed nausea and vomiting after self-administering a decoction made by boiling 100–150 g of Cynomorium songaricum for about 30 minutes. She developed acute renal failure after 7 days and required hemodialysis.

Datura stramonium (Solanaceae, Jimson weed, thorn apple, angel's trumpet) Nervous system Datura stramonium has been traditionally used in North America, East Asia, and Africa to treat asthma, chronic bronchitis, arthritis, and pain. All parts of the plant contain poisonous alkaloids, including atropine, hyoscyamine, and hyoscine (scopolamine). The highest concentration of anticholinergic alkaloids is present in the seeds (equivalent to 0.1 mg of atropine per seed). Adverse anticholinergic effects can occur [45A]. • Two elderly women developed agitation, confusion, urinary retention, dry mouth, and dilated pupils within 3 hours of taking the dried seeds of Datura stramonium. They recovered completely after symptomatic treatment for 5 days.

Ecballium elaterium (Cucurbitaceae, squirting cucumber) Ear, nose, and throat A 42-year-old man had a perforation of the nasal septum after using nasal drops prepared from Ecballium elaterium [46A]. Within minutes of using the drops, he started to have a burning sensation in the nose and the pharynx, followed by a watery and then a purulent discharge from the nose. After 2 months of regular use he reported not being able to breathe through the nose with excessive crusting. There was a

K. Chan, H.W. Zhang, and Z.X. Lin

Ephedra See Chapter 13.

Garcinia gambogia (Clusiacaeae; brindleberry, gamboge) Liver In recent years, there have been many reports of hepatotoxicity associated with herbal products used for weight reduction. These products, which are sold as dietary supplements, do not usually undergo safety tests before they are marketed [48R]. Proprietary formulations such as Hydroxycut (MuscleTech Research and Development, Inc; Iovate Health Sciences Research, Oakville, Ontario, Canada) and Exilis (Fusion Health Products, Houston, Texas) contain mixtures of ingredients, including Garcinia gambogia. Hydroxycut is said to contain Garcinia gambogia, L-carnitine, chromium picolinate, and guaraná extract; some preparations have also contained MaHuang extract. Exilis is said to contain Garcinia gambogia, Gymnema Sylvestre, calcium, L-carnitine fumarate, chitosan, green tea extract, conjugated linoleic acid, magnesium chelate, and white kidney bean extract. The US Food and Drug Administration (FDA) has issued warnings that Hydroxycut products should not be used [49S], because of the possibility of liver damage, of which there have been several reports [50A, 51A, 52A, 53A, 54A, 55Ar, 56cr, 57r]. In one case an interaction with montelukast was postulated [58A].

Treatments used in complementary and alternative medicine

There has been a review of eight patients who developed liver injury after taking Hydroxycut; all were hospitalized, and three required liver transplantation [59cr]. Nine other cases with adequate clinical information were obtained from the FDA MedWatch database, including one fatal case of acute liver failure. The usual symptoms were jaundice, fatigue, nausea, vomiting, and abdominal pain. Most patients had hepatocellular liver damage. Exilis has also been associated with fulminant hepatic failure [60A]. • A 25-year-old man presented to a walk-in clinic with tea-colored urine and fatigue. He had taken Exilis for less than 3 weeks, and after taking it for 1 week he had developed nausea, vomiting, aches, and fever. His serum aspartate aminotransferase, alanine aminotransferase, and total bilirubin were 1394 U/l, 2362 U/l, and 180 mmol/l (10.5 mg/dl) respectively. He underwent cadaveric liver transplantation.

The principal hepatotoxic ingredient of Garcinia gambogia is thought to be hydroxycitric acid. However, it has been pointed out that 14 different formulations of Hydroxycut have been marketed, that only eight contained hydroxycitric acid, and that products of this sort contain numerous ingredients [61r]. For example, green tea (Camellia sinensis), present in some of these formulations, has also been associated with hepatotoxicity [SEDA-28, 575; 62A, 63A, 64A, 65c, 66C].

Ginkgo biloba (Ginkgoaceae, maidenhair) Placebo-controlled studies An adequately powered placebo-controlled trial of the effect of Ginkgo biloba in the primary prevention of dementia included over 3000 volunteers aged 75 years and over [67C]. They were randomized to twice daily doses of either Ginkgo biloba extract 120 mg or placebo and were followed for a median of 6.1 years. The extract had no effect on the incidence of dementia. The adverse

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events profiles for Ginkgo and placebo were similar and there was no statistically significant difference in the rate of serious adverse events. The rates of major bleeding did not differ between the groups, nor in individuals who combined the study drug with regular aspirin. There were twice as many hemorrhagic strokes in the Ginkgo group, but the number of cases was too low (16 versus eight) to reach significance. Drug–drug interactions Antiplatelet and anticoagulant drugs A systematic review of the potential interaction of Ginkgo biloba with antiplatelet or anticoagulant drugs has shown that concerns about the safety of Ginkgo when used in combination with anticoagulants or antiplatelet drugs are not supported by the currently available evidence [68M]. The author also pointed to the discrepancy between controlled trials of the EGb 761 extract, which has consistently been found to have no significant effect on hemostasis and case reports of episodes of bleeding with Ginkgo, which have rarely implicated this well-defined extract. Efavirenz Virological failure in a 47-yearold HIV-infected patient who had taken antiretroviral drug therapy for 10 years was associated with falling efavirenz plasma concentrations after he started to take Ginkgo biloba [69A].

Hypericum perforatum (Clusiaceae, St John's wort) Drug–drug interactions Finasteride The effects of St John's wort on finasteride and its metabolites, hydroxyfinasteride and carboxyfinasteride, have been studied in 12 men, in whom finasteride 5 mg was administered directly into the intestine via a catheter before and after 14 days of treatment with St John's wort 300 mg bd [70c]. St John's wort significantly reduced the Cmax, the AUC0!24h, and the half-life of finasteride; the kinetics of carboxyfinasteride were also significantly altered.

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Morinda citrifolia (Rubiaceae)

25 patients with ischemic strokes in a randomized, open, controlled study [75c]. The results suggested that co-administration of Panax ginseng did not affect the pharmacological action of warfarin.

Liver Hepatotoxicity related to the consumption of noni juice, prepared from the fruits of Morinda citrifolia, has again been reported [71R]. • A 43-year-old white man with a glioblastoma underwent surgery and was scheduled for radiation and chemotherapy. After drinking noni juice 20 ml bd for 2 weeks, he developed raised aminotransferases in routine prechemotherapy blood tests. The aminotransferases returned to normal as soon as he stopped drinking noni juice.

The hepatotoxic potential of noni fruit juice has been assessed in in vitro tests in the HepG2 cell line of human liver cells and in subchronic oral toxicity tests in rats [72E]. Freeze-dried filtered noni fruit puree did not alter the viability of HepG2 cells or cause neutral lipid accumulation and phospholipidosis and there were no changes in liver function tests in the rats. The authors therefore suggested that consumption of noni fruit juice is unlikely to cause adverse liver reactions.

Panax ginseng (Araliaceae, Asian ginseng) Drug–drug interactions Gefitinib It has been reported in Korea that the use of complementary herbal medicines caused gefitinib treatment failure [73r]. • A 36-year-old woman with a stage IV adenocarcinoma of the lung was given oral gefitinib 250 mg/day as the first-line chemotherapy. Within 9 weeks she became progressively short of breath. She had simultaneously taken multiple complementary herbal medicines including ginseng, Fomes fomentarius, Inonotus obliquus, Phellinus linteus, and selenium along with gefitinib without notifying her physician. After all the complementary herbal medicines were withdrawn, her symptoms improved significantly.

Previous studies have suggested that ginseng may increase the clearance of gefitinib by inducing the activity of CYP3A4 [74E]. Warfarin The interaction between warfarin and Panax ginseng has been investigated in

K. Chan, H.W. Zhang, and Z.X. Lin

Panax notoginseng (Araliaceae) Sanqi pian, a tablet made from Panax notoginseng, is a widely used traditional Chinese medicinal herb. It is commonly used to treat bleeding disorders and traumatic injuries and has been associated with anaphylactic shock [76A]. • A 20-year-old man developed limb weakness, chills, cold sweats, and shortness of breath about 30 minutes after taking two tablets of Sanqi pian. He was given oxygen, dexamethasone, and promethazine, and made a complete recovery.

Panax quinquefolius (Araliaceae, American ginseng) Drug–drug interactions Indinavir In 13 healthy volunteers American ginseng had no effect on the pharmacokinetics of indinavir 800 mg tds [77c]. Warfarin In a randomized, controlled trial in healthy volunteers, American ginseng reduced the effect of warfarin [78c].

Rhododendron spp. (Ericaceae, rhododendron) Cardiotoxicity of “mad honey” Certain species of rhododendron contain grayanotoxins (andromedotoxins), which open sodium channels. In the heart this effect can trigger the Bezold–Jarisch reflex and cause bradycardia, heart block, asystole, and hypotension [79R].

Treatments used in complementary and alternative medicine

Case reports There have been several reports of these complications in people who have eaten honey prepared by bees from Rhododendron luteum, Rhododendron mucronulatum, Rhododendron ponticum, or Castanea sativa [80A–95A]; myocardial infarction has also been reported [96A]. In the eastern Black Sea region of Turkey, where most cases have been reported, such honey is called “bitter honey” or “mad honey”, which is often used as a household remedy for various conditions, including stomach pains, bowel disorders, hypertension, and erectile dysfunction [97R]. Because of variations in the plant content of grayanotoxins, poisoning with honey made in the spring is more severe [97r]. However, honey poisoning is rarely fatal and the effects generally last for no more than 24 hours. This type of poisoning is thought to have been described by Xenophon 2400 years ago [98R]. In one case poisoning from Rhododendron simsii occurred when a baby's grandmother prepared a decoction of this plant in milk [99A]. Poisoning from eating rhododendrons has also been reported in animals such as sheep and goats [100R]. Other Ericaceae can do likewise, as has been reported in a series of cases of poisoning with Agauria salicifolia from Reunion Island [101c]and a case from the Mascarene Islands, where a 28-year-old woman mistakenly drank a herbal tea made with leaves of Agauria salicifolia and developed symptoms characteristic of grayanotoxin intoxication, with vomiting, hypotension, and bradycardia. [102Ar]. Case series In a retrospective series of 19 patients poisoned by “mad honey”, all had nausea, vomiting, sweating, dizziness, and weakness several hours after ingestion [103c]. There was hypotension in 15, sinus bradycardia in 15, and complete atrioventricular block in four. The hypotension and conduction disorders resolved with atropine treatment, resulting in complete recovery within 24 hours. In 66 patients symptoms that occurred several hours after the ingestion of small amounts of “mad honey” included nausea,

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vomiting, salivation, dizziness, weakness, hypotension, bradycardia, and syncope [104c]. All had hypotension and most had bradycardia. These features resolved completely in 24 hours with intravenous fluids and atropine; none died. In a review of 47 patients who had ingested “mad honey” 0.5–9 (mean 2.8) hours before presentation, the heart rate was 30–77 (mean 47) per minute and the systolic blood pressure was 50–140 (mean 47) mmHg [105c]. Cardiac rhythms on arrival were sinus bradycardia (n ¼ 37), nodal rhythm (6), sinus rhythm (3), and complete atrioventricular block (1). All were given atropine 0.5–2 mg. In a prospective study of 42 patients (33 men; median age 49 years) who had been hospitalized with “mad honey” intoxication, all had nausea, vomiting, dizziness, fainting, and sweating; five had syncope [106c]. The mean blood pressure was 73/52 mmHg and the mean heart rate 38/minute; 18 had sinus bradycardia, 15 had complete atrioventricular block, and nine had nodal rhythm. None needed temporary pacing and all were discharged without complications. In 33 patients (30 men, median age 52 years) the most common effects of poisoning with “mad honey” were sinus bradycardia (91%), nausea and vomiting (82%), and dizziness (79%); average heart rate was 55/minute and mean blood pressure was 78/46 mmHg [107c]. In seven cases of grayanotoxin poisoning due to consumption of wild honey that was brought from the Himalayan belt of Nepal, most had blurring of vision, diplopia, and nausea and vomiting; two had cardiac effects [108c]. Chronic mad honey intoxication syndrome has also been described in a prospective evaluation of 173 patients with bradycardia or atrioventricular conduction abnormalities; in five cases there was a history of ingestion of non-commercial honey made by different amateur beekeepers in the eastern Back Sea region of Turkey [109c]. When they stopped taking the honey there was prompt normalization of conduction and significant symptomatic improvement.

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Although most cases of poisoning are accidental, in a few cases deliberate selfpoisoning has occurred. In 21 patients (18 men) with acute grayanotoxin poisoning, enhancement of sexual performance was the reason for the would-be therapeutic use of “mad honey” [110c].

Uncaria tomentosa (Rubiacaeae, cat's claw)

Incidence This type of poisoning is said to be rare, but the incidence is not known. In one report 69 published reports were reviewed [111M]. Management Muscarinic M2 receptors in the vagus are involved in the cardiotoxicity of grayanotoxin [112AE, 113AE], and bradycardia and heart block in these cases respond to atropine, as in toxicity with veratrum alkaloids. However, temporary pacing may sometimes be required [114Ar].

Tripterygium wilfordii Hook. f. (Celastraceae, bittersweet) Skin Tripterygium wilfordii, also called Lei-gong-teng in Chinese (literally meaning “thunder vine god”), is a common herb used in traditional Chinese medicine for the treatment of many autoimmune disorders. The multiglycosides derived from this plant have been made into tablet form as over-the-counter herbal products in China. Lei-Gong-Teng Multiglycosides tablets have immunodepressant and anti-inflammatory effects, and are widely used to treat rheumatoid arthritis, nephrotic syndrome, and some systemic autoimmune diseases. However, it has been reported to cause skin pigmentation [115A]. • A 35-year-old woman with nephrotic syndrome developed brown to dark pigmented spots on the face after taking Lei-Gong-Teng Multiglycosides tablets 20 mg tds for 20 days. She stopped taking the medication for about 1 month, and the pigmentation gradually disappeared.

K. Chan, H.W. Zhang, and Z.X. Lin

Drug–drug interactions HIV protease inhibitors In a 45-year-old HIV-positive woman with cirrhosis due to hepatitis C infection, the serum trough concentrations of atazanavir, ritonavir, and saquinavir increased when she took cat's claw (Uncaria tomentosa), perhaps because of inhibition of CYP3A4 [116A]. The respective concentrations with and without cat's claw were 0.30 and 1.22 mg/l (atazanavir), 0.92 and 6.13 mg/l (ritonavir), and 0.64 and 3.4 mg/l (saquinavir).

Vaccinium macrocarpon (Ericaceae, cranberry) Drug–drug interactions Warfarin The possible effects of two commonly used herbal medicines, garlic and cranberry, on the pharmacokinetics and pharmacodynamics of warfarin have been investigated in an open, three-treatment, randomized, crossover trial in 12 healthy men [117c]. They took a single oral dose of warfarin 25 mg alone or after 2 weeks of pretreatment with either garlic or cranberry. Pretreatment with cranberry significantly increased the area under the INR versus time curve by 30% compared with warfarin alone. Co-administration of garlic did not significantly alter warfarin pharmacokinetics or pharmacodynamics. Both herbal medicines showed some evidence of VKORC1 (but not CYP2C9) genotype-dependent interactions with warfarin. Co-administration of warfarin and cranberry requires careful monitoring.

ANIMAL DRUGS Carp gallbladder Urinary tract Fish gallbladder has long been used as a folk remedy in China, and its consumption has been linked to acute renal failure [118A].

Treatments used in complementary and alternative medicine • A 67-year-old woman developed nausea and epigastric pain 2 hours after taking grass carp gallbladder stewed with honey. She also had raised alanine aminotransferase activity after 8 hours. On day 3 she developed oliguria, and hemodialysis was performed on day 5, following which she gradually recovered and was discharged on day 26.

Toad extract (Chan Su) Toad extract, obtained from the secretions of the salivary and skin glands of Chinese toads, is commonly used in Chinese medicine. It contains bufotenine and a series of bufadienolides that are structurally similar to cardiac glycosides [119E]. • A 24-year-old man collapsed and died soon after an intravenous injection of 35–40 ml of what was thought to be ecstasy [120A]. MDMA was not detected in toxicological analyses, but a low concentration of bufotenine was identified instead. In addition, resibufogenin, cinobufagin, and bufalin, which are bufadienolides present in toad venom, were found in the injected material.

ACUPUNCTURE Observational studies In a Korean retrospective cross-sectional survey of 1095 subjects who used acupuncture, 75 (6.8%) described negative short-term acupuncture reactions, including feelings of pain in 37 (3.4%), tiredness in 24 (2.2%), and dizziness in nine (0.8%). The only adverse event reported was bleeding in 92 (8.4%) of the participants [121c]. In a German observational study of 503 397 treatments documented between July 2001 and June 2003, physicians recorded at least one adverse effect in 7.8% of all patients, the most frequent being needling pain in 3.9% [122C]. Serious adverse events were reported in 17 cases, the most frequent event being pneumothorax (five cases). Of 6140 patients who received acupuncture, 9.3% reported adverse reactions, and

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a quarter of these were considered to be troublesome. The most frequent adverse reactions were pain, fatigue, and circulatory disturbances. In 20 patients who received acupuncture for acute non-penetrating limb injuries, only minor complications were reported, including local pain at the acupuncture site, light-headedness, sweating and pruritus, erythema, and minor bleeding at the acupuncture site [123c]. In a review of case reports and prospective surveys of adverse events focusing on “Japanese acupuncture”, almost all of the adverse reactions commonly seen in acupuncture practice, such as fatigue, drowsiness, aggravation of existing symptoms, minor bleeding, pain on insertion, and subcutaneous hemorrhage, were mild and transient [124R]. Anecdotal reports Some serious adverse events have also been reported in individual patients who have received acupuncture. • A 52-year-old woman presented with a 3-day history of anorexia and jaundice after receiving acupuncture twice a day for 7 weeks, performed bilaterally at the Zusanli (ST36) acupoint to a depth of 22 mm [125A]. Electrical stimulation was performed, with the stimulation frequency fixed at 5 Hz for 20 minutes. Her aspartate aminotransferase and alanine aminotransferase activities and total bilirubin concentrations were 84 U/l, 109 U/l, and 216 mmol/l respectively She developed pale stools, dark urine, pruritus, pedal edema, and diarrhea during the next 12 days. Her laboratory results continued to worsen. No specific therapy was provided for the severe cholestatic jaundice. Over the next 12 weeks, her symptoms and the laboratory results gradually improved. • A 42-year-old man received acupuncture at the Jiaji (EX-B2, L4 & 5) and Weizhong (BL40) acupoints, with electrical stimulation for about 30 minutes 2 days after a back sprain [126A]. While he was walking from the clinic to a hospital pharmacy, he suddenly felt dizzy, blacked out, and became flustered; he sweated heavily and his face was pale. After receiving oxygen and intravenous dextrose, he made a full recovery. • A 35-year-old woman received conventional acupuncture and stauntoniae injection 2 ml at Jiaji points (EX-B2, C6 & 7) for the treatment of pain and numbness in the right neck

1000 and arm [126A]. After about 3 minutes, she developed dizziness, chest distension, shortness of breath, and a hot flush. Her face was flushed, and her eyelids and mouth were swollen. The needles were removed immediately and she was given intramuscular dexamethasone 10 mg. She then began to lose consciousness and had a blood pressure of 75/55 mmHg. Several minutes after being given oxygen and a series of anti-allergy treatments, she regained consciousness. The swellings on the eyelids and mouth disappeared after 2 days. • A 43-year-old woman suddenly developed a headache, dizziness, and heavy sweating with vomiting during the second acupuncture treatment for low back and leg pain [126A]. The needles were removed immediately and she was helped to lie down. Most of her symptoms resolved but the headache persisted for 2 days. A subarachnoid hemorrhage was later confirmed by CT scan.

Immunologic Allergic reactions to the metal used in acupuncture needles have been reported [127A]. • A 72-year-old man who received acupuncture for neck and shoulder pain developed erythema, pruritus, and swelling on the needling region after the needles had been removed from Jiaji points (EX-B2, C5, 6, & 7), which had been stimulated with electrical pulsation for 30 minutes. The next day he developed mung bean-sized blisters on the needling region. He was found to be allergic to the metal in the needle. Acupuncture was stopped and the blisters disappeared after symptomatic treatment for 1 week. • A 49-year-old woman with cervical spondylopathy developed pruritus at the needling region 1 day after acupuncture at Jiaji points (EX-B2, C5, 4, 5, & 6) with electronic stimulation. She then developed rice grain-sized blisters at the needling region on the third day. She was allergic to the metal in the needle. Acupuncture was discontinued and the blisters disappeared after symptomatic treatment for 5 days.

CHIROPRACTIC Observational studies In a case–control and case-crossover study there was no difference in the risk of vertebrobasilar artery stroke associated with chiropractic care and primary care [128C].

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In a cross-sectional survey of pediatric chiropractic, chiropractors reported three adverse events per 5438 office visits involving the treatment of 577 children. The parents reported two adverse events from 1735 office visits involving the care of 239 children [129C]. Systematic reviews A systematic review of the reported adverse events of chiropractic procedures has shown that most of the adverse events reported were benign and transient; however, there were reports of complications that were serious or life threatening, such as arterial dissection, myelopathy, vertebral disc extrusion, and epidural hematoma [130M]. The frequency of adverse events was 33–61%, while the frequencies of serious adverse events were 5 strokes/ 100 000 manipulations, 1.46 serious adverse events per 10 000 000 manipulations, and 2.68 deaths per 10 000 000 manipulations. Nervous system Chiropractic has been reported to be associated with a case of quadriparesis [131A]. • A 41-year-old man with chronic neck pain developed weakness of the legs a few hours after undergoing chiropractic manipulation. He recalled hearing a snapping sound during the manipulation and felt tingling and numbness in his arms and legs immediately after. He had no power in the legs, 2/5 in the arms, reduced sensation for light touch over all four limbs, bilateral extensor plantar responses, reduced anal sphincter tone, and urinary retention. He rapidly developed complete quadriparesis. An MRI scan showed a large paracentral C6–C7 disc herniation with marked cord edema. After intravenous injection of methylprednisone and an emergency C6–C7 anterior cervical discectomy and fusion, he had partial improvement, but remained paraplegic 3 months after the incident.

SKIN BRANDING Branding refers to a process whereby thirddegree burns are inflicted on the skin with a hot iron rod or metallic object. Branding uses the phenomenon of counter-irritation, by briefly using moderately intense pain to

Treatments used in complementary and alternative medicine

relieve chronic pain. Branding is used by faith healers in some developing countries for therapeutic purposes. Some methods, which are very crude and inhumane, carry a high risk of complications. Four Pakistani patients aged 25–60 years developed severe medical complications after being branded with a red-hot iron rod for various medical reasons [132cr]. The mean duration between the procedure and presentation to the hospital was 6 days. At the time of admission, two had septic shock, one had a cavernous sinus thrombosis, and one had multiple splenic abscesses. All received standard care for wound management and systemic infections. Two eventually died.

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SPA THERAPY Observational studies A postal questionnaire concerning drug prescriptions during spa therapy conducted in France showed that spa therapy was often associated with a reduction in the use of prescribed drugs [133C]. Adverse reactions to spa therapy were rare or usually graded as “unserious” events. However, causality is difficult to establish, justifying the need for specific vigilance.

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[7] Li CR, Xu L, Qiu JM. One case of liver damage caused by zhi xue capsule. Chin J Pharmacovigil 2009; 6(11): 687. [8] State Food and Drug Administration. Chinese Adverse Drug Reaction Information Bulletin 2008; 17. [Notice on the liver damage caused by zhi xue capsule.] http://www. sfda.gov.cn/WS01/CL0304/33571.html. [9] State Food and Drug Administration. Chinese Adverse Drug Reaction Information Bulletin 2008; 16. [Warnings on the liver damage caused by Zhuang gu guan jie wan.] http://www.sda.gov.cn/ WS01/CL0078/32614.html. [10] Song XJ. One case of liver damage caused by zhuang gu guan jie wan. Chin Foreign Med 2009; 28(18): 181. [11] Zhou K, Dai Z, Liu ZB, Tan Y, Hu LM, et al. Experimental study of screening the hepatotoxic medicinal materials in zhuang gu guan jie pill. Chin J Pharmacovigil 2009; 6(11): 641–8. [12] Gong SY, Shi CS. One case of allergic reaction to the Ci Wu Jia injection. Pract Pharma Clin Rem 2008; 11(5): 284. [13] Yuan LY. One case of hypersensitive reactions caused by Chinese medicine preparation of Ku Die Zi injection. Baotou Med 2009; 33(4): 252. [14] Jiang Z, Tan HH, Luo LN. Two cases of acute kidney failure caused by Lian Bi

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[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

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[116] López Galera RM, Ribera Pascuet E, Esteban Mur JI, Montoro Ronsano JB, Juárez Giménez JC. Interaction between cat's claw and protease inhibitors atazanavir, ritonavir and saquinavir. Eur J Clin Pharmacol 2008; 64(12): 1235–6. [117] Mohammed Abdul MI, Jiang X, Williams KM, Day RO, Roufogalis BD, Liauw WS, Xu H, McLachlan AJ. Pharmacodynamic interaction of warfarin with cranberry but not with garlic in healthy subjects. Br J Pharmacol 2008; 154(8): 1691–700. [118] Kung SW, Chan YC, Tse ML, Lau FL, Chau TL, Tam MK. Acute renal failure and hepatitis following ingestion of carp gallbladder. Clin Toxicol 2008; 46(8): 753–7. [119] Barry TL, Petzinger G, Zito SW. GC/MS comparison of the West Indian aphrodisiac “Love Stone” to the Chinese medication “chan su”: bufotenine and related bufadienolides. J Forensic Sci 1996; 41(6): 1068–73. [120] Kostakis C, Byard RW. Sudden death associated with intravenous injection of toad extract. Forensic Sci Int 2009; 188 (1–3): e1–5. [121] Park SU, Ko CN, Bae HS, Jung WS, Moon SK, Cho KH, Kim YS, Park JM. Short-term reactions to acupuncture treatment and adverse events following acupuncture: a cross-sectional survey of patient reports in Korea. J Altern Complement Med 2009; 15(12): 1275–83. [122] Weidenhammer W, Streng A, Melchart D, Linde K. Adverse effects and complications of acupuncture treatment: results from a large-scale, nation-wide observational study. Dtsch Z Akupunkt 2008; 51 (3): 6–14. [123] Arnold AA, Ross BE, Silka PA. Efficacy and feasibility of acupuncture for patients in the ED with acute, nonpenetrating musculoskeletal injury of the extremities. Am J Emerg Med 2009; 27(3): 280–4. [124] Yamashita H, Tsukayama H. Safety of acupuncture practice in Japan: patient reactions, therapist negligence and error reduction strategies. Evid Based Complement Alternat Med 2008; 5(4): 391–8. [125] Hong L, Chen Z, Zhou X, Han Z, Zhang X, Wu K, Fan D. Acupuncture

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[130] Gouveia LO, Castanho P, Ferreira JJ. Safety of chiropractic interventions: a systematic review. Spine 2009; 34(11): E405–13. [131] Talluri SK, Talluri J, Besur S, Kakarala R, Klair N. Catastrophic complication of chiropractic manipulation: a report of quadriparesis. Am J Med 2009; 122(11): e3–4. [132] Mazokopakis EE, Karefilakis CM, Starakis IK. The safety and efficacy of the fruit juice of Ecballium elaterium in the treatment of acute rhinosinusitis. J Altern Complement Med 2009; 15(12): 1273–4. [133] Fontanel F, Durrieu G, Damase-Michel C, Montastruc JL. Drug prescription and pharmacovigilance in spa therapy: a comparative study at a 20-year interval (1987 versus 2007). Therapie 2008; 63(2): 135–40.

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Alcohol

Miscellaneous drugs, materials, medical devices, and techniques [SEDA-31, 757; SEDA-32, 891]

Cardiovascular Heavy drinking may be the commonest cause of reversible hypertension, and reducing heavy alcohol intake plays an important public health role in management. In addition to the mechanism, which is not known, unresolved questions include whether there is a threshold dosage of alcohol for the association with hypertension, the sequelae of alcohol-associated hypertension, and the role of interactions with sex, ethnicity, other lifestyle traits, drinking pattern, and choice of beverage. These areas have been reviewed, including new data about the effects of different types of beverage [1R]. Nervous system It has been hypothesized that the right hemisphere of the brain is more sensitive to alcohol-related damage than the left hemisphere. This hypothesis has been tested by using functional MRI to determine whether the pattern of right hemispheric activity is different in alcoholdependent patients, compared with healthy individuals [2HC]. Two different types of memory-encoding tasks were performed separately: word and face encoding. The data from the healthy volunteers suggested that the left prefrontal region is more active Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00049-0 # 2011 Elsevier B.V. All rights reserved.

during word encoding, whereas the right parahippocampal region is more active during face encoding. However, in the patients there was left lateralization in the prefrontal area during word encoding, and no right lateralization in the parahippocampal region during face encoding. Thus, alcoholism appears to have no effect on left hemispheric activity, since the activation pattern was similar to that observed in healthy individuals. However, the absence of right hemispheric lateralization in alcoholdependent patients was consistent with the hypothesis that the right hemisphere is more vulnerable to alcohol-related damage than the left. In another study, the neuromotor effects of acute alcohol ingestion, postural sway, hand tremor, and reaction time were measured before and after ingestion of alcohol or fruit juice in 13 healthy volunteers aged 20–22 years [3A]. The mean dose of ethanol was 590 mg/kg and the blood ethanol concentrations were 860 mg/l at 30 minutes; 880 mg/l at 70 minutes, and 740 mg/l at 130 minutes. The 1-hour and 2-hour changes in sway area and total transversal sway with eyes closed were significantly larger after alcohol. Similarly, the 2-hour changes in sway area with eyes open were significantly larger after alcohol. There were no differences between alcohol and fruit juice regarding changes in hand tremor or reaction time. These data suggest that static balance due to acute alcohol ingestion is characterized mainly by transversal sway of low frequency with the eyes 1009

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closed, which seems to differ from the characteristics of postural sway in alcoholics. Sensory systems Balance Otolith function is significantly affected by alcohol, and the higher the dosage, the greater the effect. The effect of alcohol on ocular counterrolling has been studied in 20 subjects, who were tested before and after drinking 80 proof vodka, and three measures of ocular counter-rolling were considered [4A]. Blood alcohol concentrations after a dose of 150 ml were 0.09–0.18%. The amplitude of ocular counter-rolling was significantly reduced after alcohol; disconjugacy was significantly increased; smoothness was not significantly affected. In contrast, a study of a lower dose, 90 ml, produced blood alcohol concentrations of 0.04–0.09% and resulted in significantly reduced amplitude, no significant change in disconjugacy, and a significant improvement in smoothness. An increase in blood alcohol concentrations produced further impairment of amplitude and conjugacy but eliminated the benefit of smoothness. Psychological Alcohol consumption has been associated with increased aggressive behavior. However, experimental evidence of a direct association is equivocal, and possible mechanisms are poorly understood. One mechanism by which alcohol consumption may increase aggressive behavior is by altering the processing of emotional facial cues. The effects of acute alcohol consumption on sensitivity to facial expressions of emotion have been investigated in three experimental sessions during which participants took a drink of alcohol (0, 200, or 400 mg/kg) and completed a psychophysical task to distinguish expressive from neutral faces [5c]. The level of emotion in the expressive face varied across trials and the threshold at which the expressive face was reliably identified was measured. There was a significant three-way interaction involving emotion, the sex of the participant, and alcohol use. Men had significantly higher perceptual thresholds for sad facial expressions compared with women after

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consumption of the highest dose of alcohol. There was no evidence that alcohol altered the processing of angry facial expressions. Liver Alcoholic hepatitis has been reviewed [6r]. This association has been well documented, although cirrhosis of the liver develops in only a small proportion of heavy drinkers. Since up to 40% of patients with severe alcoholic hepatitis die within 6 months after the onset of the clinical syndrome, appropriate diagnosis and treatment are essential. Death The changes in Russian mortality rates during the past two decades are unprecedented in a modern industrialized country. These fluctuations have attracted much interest, and trends for major groups of causes of death might shed light on the underlying determinants. Cause-specific mortality in Russia for the period 1991–2006 has been studied, using the records of 24 836 forensic autopsies carried out during 1990–2004 in a specific city, and then analysed with respect to blood alcohol concentration [7M]. Cardiovascular diseases (in those aged 35–69 years) and external causes (in those aged 15–34 years) were the main contributors to the fluctuations in mortality rates. The largest relative changes were for conditions directly related to alcohol. Among cardiovascular diseases, fluctuations were due to “other forms” of acute and chronic ischemia and atherosclerotic heart disease, while rates of myocardial infarction were low and relatively constant. In the autopsy series a very high proportion of deaths were attributed to “other” or “not classified” cardiovascular diseases and lethal or potentially lethal blood ethanol concentrations. The increases in mortality in 1991–1994 and in 1998–2003 coincided with the economic and societal crisis, while decreases in 1994–1998 and 2003–2006 correlated with economic improvements. Excessive alcohol intake is a major cause of premature male mortality in Russia, although many alcohol-related deaths are wrongly attributed to cardiovascular diseases.

Miscellaneous drugs, materials, medical devices, and techniques

Artificial sweeteners

[SED-15, 348;

SEDA-32, 892] Tumorigenicity The possible association of artificial sweeteners and urinary tract tumors is controversial. In a case-control study in Argentina in 197 patients with histologically confirmed transitional urinary tract tumors and 397 controls with acute, non-neoplastic, and non-urinary tract diseases between 1999 and 2006, 51 of the former (26%) and 87 of the latter (22%) had used artificial sweeteners [8C]. The risk of urinary tract tumors was significantly increased in long-term users (10 years or more). The odds ratio for long-term consumers was 2.18 (95% CI ¼ 1.22, 3.89) and for short-term users 1.10 (0.61, 2.00) after adjustment for age, sex, BMI, social status, and years of tobacco use. The role of artificial sweeteners on the risks of cancers of the stomach, pancreas, and endometrium has been studied in 230 patients with histologically confirmed cancers of the stomach and 547 controls, 326 cancers of the pancreas and 652 controls, and 454 cancers of the endometrium and 908 controls [9C]. After allowing for various confounding factors, the odds ratios for ever users of sweeteners versus non-users were 0.80 (95% CI ¼ 0.45, 1.43) for gastric

EIDOS

Chapter 49

cancer, 0.62 (0.37, 1.04) for pancreatic cancer, and 0.96 (67, 1.40) for endometrial cancer. Corresponding odds ratios for saccharin were 0.65, 0.19, and 0.71, and for other sweeteners 0.86, 1.16, and 1.07 respectively for the three cancer sites. The authors concluded that low-calorie sweeteners (including aspartame) do not increase the risk of common neoplasms.

Bisphosphonates [SED-15, 523; SEDA-30, 561; SEDA-32, 893] Uses Bisphosphonates encourage osteoclasts to undergo apoptosis [10r] and in addition to their other uses have been used to reduce fracture rates in children with osteogenesis imperfecta [11r] and in the treatment of otosclerosis [12r]. Musculoskeletal Osteonecrosis of the jaw Osteonecrosis of the jaw is becoming more common (SEDA-32, 893). It is most often identified in patients with multiple myeloma or other malignancies, but cases have also been reported in patients taking bisphosphonates for non-oncological diseases. The EIDOS and DoTS descriptions of this reaction are shown in Figure 1.

Extrinsic species (E) Bisphosphonates (especially zoledronate)

Intrinsic species (I) Osteoclasts

Distribution Bone

Manifestations (test results) Osteolytic lesions; softtissue edema (x-ray, MRI)

Outcome (the adverse effect) Increased apoptosis

Manifestations (clinical) Bone pain, paresthesia, dehiscence of bone

Sequela (the adverse reaction) Osteonecrosis of the jaw

DoTS

Dose-responsiveness Collateral

1011

Time-course Delayed

Susceptibility factors Tooth extraction; diseases (dental disease; myeloma and breast cancer)

Figure 1 The EIDOS and DoTS descriptions of bisphosphonate-induced osteonecrosis of the jaw.

1012

In a 4-year study of 102 patients with osteonecrosis of the jaw associated with bisphosphonates, 24 had non-neoplastic diseases, and had used bisphosphonates mainly for postmenopausal osteoporosis (n ¼ 20) [13c]. The duration of therapy before the diagnosis of osteonecrosis was 11–40 months and the most common triggering event was dentoalveolar surgery. All were nonsmokers; six had multiple lesions and only three had possible co-morbidities. Surgical debridement was performed in 19 patients for a total of 22 lesions; there was complete remission in 21 of the lesions. The prevalence of osteonecrosis of the jaw has been studied in 75 patients with breast cancer taking bisphosphonates for osseous metastases [14M]. Four patients (5.3%) developed osteonecrosis; three had used zoledronate only and one had first used pamidronate followed by zoledronate and ibandronate. Tooth extraction was identified as a trigger factor for osteonecrosis in two patients. The susceptibility factors and the potential outcomes have been further categorized in a retrospective study in 310 patients with metastatic bone disease who were treated with intravenous bisphosphonates between 1996 and 2006; 28 had osteonecrosis of the jaw at presentation and osteonecrosis was subsequently diagnosed in another seven [15R]. Statistically significant factors that were associated with an increased likelihood of osteonecrosis of the jaw included the type of cancer, the duration of bisphosphonate therapy, sequential intravenous treatment with pamidronate followed by zoledronic acid, co-morbid osteoarthritis or rheumatoid arthritis, and benign hematological conditions. The data did not support glucocorticoid use or oral health as predictors. The clinical outcomes were variable; only 11 patients had improvement or healing with conservative management. The incidence and susceptibility factors in cases of bisphosphonate-induced osteonecrosis of the jaw have been studied in patients with breast cancer and gynecological malignancies [16c]. Of 345 patients, 10 (2.9%) developed osteonecrosis while taking bisphosphonates. Six had a history of

Chapter 49

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recent dental procedures. All had taken zoledronic acid. The time of exposure to bisphosphonates and the number of treatment cycles were significant susceptibility factors (27 versus 12 in those without osteonecrosis). Susceptibility factors for osteonecrosis of the jaw have been sought in 34 cases [17C]. The most frequently used bisphosphonate was zoledronic acid (n ¼ 29). Microbiological data obtained in 25 patients showed that 72% of these were infected or colonized by an actinomycete. Eight of the 14 patients who received only medical treatment were cured. Of the 20 patients who underwent surgical treatment, only four were completely cured. Osteonecrotic lesions smaller than 1 cm were associated with a better prognosis in terms of treatment outcomes. Local treatments combined with long-term antibiotics also correlated with a better prognosis. In a study of the records of 638 patients who were treated with intravenous bisphosphonates [18r] there was osteonecrosis in six (0.94%). There was no significant relation between the incidence of osteonecrosis and demographic parameters, the primary tumor, the cumulative drug dose, or dosing intervals. However, those who developed osteonecrosis had received a significantly greater mean number of infusions and significantly more mean hours of infusion time. These findings suggest a positive correlation between the risk of osteonecrosis and overall drug exposure. However, the relatively low incidence of osteonecrosis precluded definition of the dose–response relation. The effects of a prevention program in 186 patients with cancer and bone involvement using pamidronate or zoledronate have been studied in two different groups of patients treated from 2003 to 2005 and from 2005 to 2007, based on examination of the oral cavity and education of dentists and patients. The prevention program started for all patients in June of 2005; 16 developed osteonecrosis of the jaw, eight before and eight after June 2005 [19M]. There was a consistent difference in the evolution of the disease in the two groups:

Miscellaneous drugs, materials, medical devices, and techniques

in the first group, four patients underwent major surgery (one partial maxillectomy; two partial mandibulectomy; one segmental mandibular resection), with important impairment in quality of life; on the other hand, the eight patients with osteonecrosis of the jaw diagnosed after June 2005 were successfully treated without aggressive dental interventions and achieved good control of symptoms. The authors therefore concluded that bisphosphonate-related osteonecrosis of the jaw is common (8.6%) and that the monitoring program was very efficient in improving the clinical outcomes, avoiding aggressive treatment and using a conservative approach and medical therapy. It has been suggested that parathyroid hormone may be of benefit in the management of osteonecrosis of the jaw [20A]. • A 74-year-old woman, who was referred for evaluation of pain and persistently abnormal exposure of jaw bone after extraction of teeth, had been using weekly oral alendronate for osteoporosis for about 5 years. She had the clinical features of bisphosphonate-associated osteonecrosis of the mandible, which was precipitated by extraction of teeth 14 months before she was referred for assessment. She had multiple susceptibility factors for osteonecrosis of the jaw, including older age, type 2 diabetes mellitus, and a long duration of bisphosphonate therapy. The mandibular lesions did not improve despite repeated operations over 14 months. Bisphosphonate therapy was withdrawn and parathyroid hormone therapy was started; after 2 months the oral mucosa had healed, after 4 months the pain had completely subsided, and after 6 months the patient's eating and drinking habits had returned. The serum concentration of osteocalcin, a marker of bone formation, which was initially suppressed, increased by 174% from baseline after 6 months of treatment with parathyroid hormone.

Fractures Rarely, long-term combined antiremodelling therapy in patients with osteoporosis can be associated with skeletal damage. Atypical skeletal fragility occurred in three subjects after long-term combined antiremodelling therapy [21c]. Despite minimal or no trauma they had chalk-stick type metadiaphysial femoral fractures while taking long-term bisphosphonates. The

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fracture location, type, bilaterality, prodromal pain, and delayed healing were atypical for uncomplicated postmenopausal osteonecrosis. All three had concomitant factors (endogenous estrogens) or were taking medications (glucocorticoids, hormone replacement therapy, and raloxifene) that probably suppressed bone remodelling beyond the effect of the bisphosphonate alone. Biochemical markers of bone turnover were very low or in the low premenopausal rate. Double tetracycline-labelled bone biopsies showed a very low activation frequency in one subject and limited single tetracycline labelling in a second patient was consistent with severely suppressed bone turnover. While nitrogen-containing bisphosphonates reduce the risk of fractures in men and postmenopausal women, their safety in the period after a fracture is unclear. In fully adjusted multivariable regression models, the use of bisphosphonates in the period after a fracture was associated with an increased probability of non-union. The risk of non-union associated with bisphosphonates after a fracture has been studied in older adults after fracture of the humerus in a nested case-control study [22M]. Cases of non-union were defined as those who had an orthopedic procedure related to non-union 91–365 days after the initial fracture. Exposure to bisphosphonates was assessed during the 365 days before non-union among cases or the matched date for controls. Among 19 731 patients with fractures, 81 (0.4%) had non-union, of whom 13 had used bisphosphonates (16%); 69 of the 810 controls (8.5%) had used bisphosphonates. In fully adjusted multivariable regression models, the use of a bisphosphonate after the fracture was associated with an increased risk of non-union; the increased risk persisted in the subgroup of patients without a history of osteonecrosis or prior fractures. Drug formulations Patients with Paget's disease of bone who use daily oral bisphosphonates can have serious upper gastrointestinal adverse events, and a

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once-weekly oral dose of a bisphosphonate in buffered solution may be as effective, better tolerated, and more convenient. In 63 patients who were randomized to either oral alendronate solution 280 mg once a week or tablets of alendronate 40 mg/day in a double-blind, randomized, controlled trial, the primary end-point was the mean percentage reduction in total serum alkaline phosphatase activity from baseline after 6 months [23C]. There was no significant difference between the groups, but there was a higher incidence of adverse events, including drug-related adverse events, in those who took the weekly oral solution, and the study was terminated.

Cyanoacrylates

[SED-15, 1022;

SEDA-32, 894] Cyanoacrylates are a common class of household substances used as adhesives and are commonly sold under brand names such as Super Glue, Krazy Glue, and others. N-butyl-2-cyanoacrylate (rINN enbucrilate) is used to arrest bleeding in gastrointestinal ulcers and elsewhere and occasionally to help wound closure. Cardiovascular Enbucrilate is often combined with lipiodol (lipid-soluble ethiodized oil) for injection of bleeding gastrointestinal ulcers; the advantage of this combination is slower polymerization of enbucrilate, with more accurate administration of the glue, but a potential disadvantage is a higher frequency of embolism, several cases of which have been reported. • Injection of 0.5 ml of enbucrilate and lipiodol in a 79-year-old woman resulted in extravasation of sclerosant along the left subphrenic area, causing epigastric pain [24A]. • Embolism of cyanoacrylate occurred in an 87year-old man occurred 5 days after injection of a bleeding duodenal ulcer with a 5:3 mixture of enbucrilate and lipiodol [25A]. A CT scan showed linear opacification of the common hepatic artery, its right branch, some splenic branches, and lesions in the head of the pancreas suggestive of infarction.

N.H. Choulis

• A 36-year-old man had a pulmonary embolus after percutaneous embolization of a varicocele with enbucrilate (HistoacrylÒ) þ lipiodol [26A]. • In a 47-year-old woman in whom a gastric varix was injected with enbucrilate þ lipiodol, cyanoacrylate migrated into the inferior vena cava and left renal vein; thrombus formation on the plug surface in the stomach caused a pulmonary embolus, which became infected with vancomycin-resistant enterococci, and she died with multiple lung abscesses [27A]. • A 77-year-old man died after an acute episode in which multiple pulmonary emboli arose from an injection of enbucrilate (GlubranÒ) diluted 50/50 with lipiodol into gastric varices [28A]. • A 70-year-old Chinese woman had a gastric varix injected with enbucrilate plus lipiodol followed by transarterial chemoembolization for hepatocellular carcinoma, at which time radio-opaque lipiodol was noted in the gastric varix and in several branches of the right pulmonary artery [29A]. • A 48-year-old woman who had endoscopic injection of enbucrilate for variceal bleeding rapidly had portal and splenic vein emboli, causing intestinal ischemia secondary to abdominal compartment syndrome, with raised intra-abdominal pressure [30A]. There were no enbucrilate emboli in the mesenteric arteries. • A 36-year-old woman with esophageal varices injected with a 1:2 mixture of enbucrilate plus lipiodol and 4 days later had a right-sided stroke [31A]. A CT scan of the brain showed an acute infarction in the left middle cerebral artery territory with evidence of embolic lipiodol and glue. • A 58-year-old man had bleeding gastric varices injected with a 50/50 mixture of enbucrilate and lipiodol, but a follow-up X-ray showed radiopaque material in the left lobe of the liver and a CT scan showed cyanoacrylate embolization via the right gastric vein into the main and left portal veins [32A]. A CT scan 2 years later showed atrophy of the leftlateral segment of the liver, with portal-vein thrombosis and little residual lipiodol retention. • A 46-year-old woman had an internal iliac arteriovenous malformation obliterated using enbucrilate mixed with lipiodol and 3 days later had a pulmonary embolism [33A]. • An 11-year-old boy had fundal varices injected with enbucrilate plus lipiodol and soon afterwards developed hypotension and bradycardia associated with a pulmonary embolism [34A]. • A 50-year-old man had a bleeding esophageal varix injected three times with enbucrilate plus lipiodol, but 2 weeks later developed an esophageal ulcer, which was thought to be

Miscellaneous drugs, materials, medical devices, and techniques

•

•

•

•

•

secondary to the glue. A CT scan 5 weeks later showed a sealed perforation in association with the injection site and a right-sided empyema. He subsequently developed a fistula between the esophagus and the pulmonary vein and died of hemorrhage [35A]. A 77-year-old woman had an injection of a 50/ 50 mixture of enbucrilate (HistoacrylÒ) and lipiodol for esophageal varices, and immediately developed epigastric pain and fever associated with portal-vein thrombosis [36A]. A 58-year-old man had a gastric varix injected twice with a mixture of enbucrilate plus lipiodol and subsequently needed anticoagulant therapy for four episodes of venous thromboembolism. A CT scan showed a linear hyperdense lesion in the left renal vein due to the presence of enbucrilate and renal vein thrombosis. The thrombus extended into the inferior vena cava and there was splenic infarction [37A]. A 60-year-old man had a gastric varix injected with a 50/50 mixture of enbucrilate (HistoacrylÒ) and lipiodol and within 1 week developed acute hepatic failure associated with multiple emboli in the portal vein and its branch [38A]. A 62-year-old man had bleeding gastric varices injected with enbucrilate (HistoacrylÒ) and 4 weeks later developed hepatic impairment associated with cyanoacrylate in the aorta and iliac arteries [39A]. He then developed a diffuse ascending spondylodiscitis, with osteolysis of the fifth lumbar vertebra, probably as a result of septic emboli and died 10 months later. A 56-year-old man had a bleeding ulcerative gastric tumor injected with a 50/50 mixture of enbucrilate plus lipiodol and 3 days later a CT scan showed high-density material extending from the gastric wall to the splenic hilum, near-total occlusion of the splenic artery and its branches, and a cystic mass with an air– fluid cavity in the spleen, due to splenic infarction with abscess formation [40A].

Respiratory A 25-year-old woman developed symptoms of rhinoconjunctivitis and asthma, attributed to an allergy to cyanoacrylate in a fingernail adhesive gel, which as a manicurist she had used for 6 months [41A]. Skin prick tests were positive with dog and cat dander and grass pollens. Patch tests were positive with nickel, cadmium, and silver salts. An inhalation challenge with cyanoacrylate for 30 minutes elicited a late asthmatic response, with a 24% fall in FEV1, with rhinorrhea and asthma that worsened progressively until she received short-acting b2-adrenoceptor agonists.

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Nervous system Embolization of a spinal dural arteriovenous fistula with enbucrilate resulted in progressive venous congestion, which was treated with antithrombin therapy, and dual antiplatelet therapy and resolved after more than 2 months [42A]. Gastrointestinal A 30-year-old man had selective embolization of a bleeding sigmoid artery with N-butyl cyanoacrylate and 6 months later developed colonic occlusion due to an ischemic stricture that required surgical treatment [43A]. Skin The use of enbucrilate (IndermilÒ) for closing the incision after parotidectomy in 100 patients resulted in hypertrophic scars in eight and keloid scars in nine; the authors quoted a frequency of 5–16% in such cases after the use of sutures [44c]. Infection risk A glue plug provides an ideal surface for bacterial colonization. Injection of an arteriovenous malformation with enbucrilate (Hystoacryl glue) in a 24-yearold non-immunocompromised man resulted in multiple granulomatous brain abscesses, with which he presented 4 years later [45A]. In one case portosplenic vein thrombosis after injection of gastric varices led to a persistent fatal septicemia with Klebsiella pneumoniae [46A]. Drug overdose Accidental aspiration of a cyanoacrylate adhesive by a toddler was complicated by tracheal and bronchial obstruction [47A]. At bronchoscopy several pieces of glue were removed from both main-stem bronchi and the child made a full recovery.

Dimethylsulfoxide (DMSO) [SED-15, 1131; SEDA-32, 894] Systematic reviews In a systematic review of the evidence from randomized controlled trials in patients with osteoarthritis of the knee, six studies were included, involving 681 patients treated with DMSO

Chapter 49

1016

(297 on active treatment) and 168 patients treated with methylsulfonylmethane (52 on active treatment) [48M]. Two of the four studies of DMSO and both of the studies of methylsulfonylmethane reported significant improvement in pain outcomes in the treatment group. However, no definitive conclusions can currently be drawn; the findings from all the studies of DMSO need to be viewed with caution, because of poor methods, including possible unblinding and questionable treatment duration and dosage. Mutagenicity DMSO increases mutation rates in the polymerase chain reaction (PCR) [49r].

Disulfiram [SED-15, 1148; SEDA-31, 760; SEDA-32, 895] Psychiatric Punding, a type of complex repetitive stereotyped behavior with compulsive features, has been attributed to disulfiram in a 39-year-old woman who took it for 4 months; it persisted for 2 months until disulfiram was withdrawn [50A]. Drug overdose An acute peripheral neuropathy with quadriparesis, lancinating pain, sensory loss, paresthesia of the distal limbs, and a vocal fold palsy occurred 1 month after a disulfiram overdose of 130 tablets in a 49-year-old woman [51A]. A severe toxic encephalopathy with coma, convulsions, and quadriparesis occurred in a 35-year-old man who took an overdose of disulfiram [52A]. In another case, a 49-year-old woman developed cardiogenic shock after taking 60 disulfiram tablets (15 g), 16 clonazepam tablets (8 mg), and six maprotiline tablets (450 mg) in association with alcohol [53A]. Drug–drug interactions Alcohol An acute myocardial inferior infarction has been attributed to the formation of acetaldehyde in a 22-year-old chronic alcoholic man who

N.H. Choulis

took oral disulfiram and alcohol together [54A]. Coronary angiography showed normal coronary arteries. Cocaine As well as inhibiting acetaldehyde dehydrogenase, disulfiram inhibits dopamine beta-hydroxylase, increasing dopamine and reducing noradrenaline concentrations. • A 31-year-old man with cocaine dependence was given disulfiram 250 mg/day to prevent relapse, but 8 months later started to use cocaine again. A few minutes after taking 1 g of cocaine nasally his pulse rate increased. He became sensually more sensitized, complained about the radio being too loud and the headlights of cars being too bright. He took another dose of cocaine 1 g nasally and 30 minutes later started to feel very sick and anxious, with paranoid delusions and illusions. He had irregular breathing and began sweating profusely. The next day his speech was disturbed and his body was shaking. He thought that his face was very small and he felt exhausted. The next morning he had recovered.

The authors hypothesized that this interaction had resulted in increased dopamine activity [55A]. Colchicine Acute colchicine intoxication occurred after co-administration of disulfiram in a 44-year-old man; it was attributed to inhibition of CYP3A4 and P glycoprotein by disulfiram [56A].

DYESTUFFS Fluorescein

[SEDA-29, 607; SEDA-32,

895] Nervous system Leakage of cerebrospinal fluid (CSF) may be iatrogenic (for example, after otolaryngological or neurological surgery), traumatic (from blunt or penetrating trauma), non-traumatic (from bony erosion by tumor, infection, empty sella syndrome, meningoencephaloceles, and congenital defects), and spontaneous. An important component in the management of any CSF

Miscellaneous drugs, materials, medical devices, and techniques

leak is proper identification and localization of the dural defect, which can originate from the anterior, middle, or posterior cranial fossae [57r]. Fluorescein is a fluorochrom dye that is occasionally administered by intrathecal injection to identify and localize CSF leaks. Although it is generally considered to be benign, intrathecal administration of fluorescein has resulted in adverse events, such as status epilepticus [58A]. • A 59-year-old woman with progressive left periorbital pain and edema 2 days after extensive endoscopic sinus surgery and reconstruction for recurrent paranasal sinusitis was thought to have leakage of CSF and was given intrathecal fluorescein 50 mg as 0.5 ml of a 10% solution diluted in 9.5 ml of CSF, and 70 minutes later had seizure-like shaking of the legs while under anesthesia. She was given intravenous dextrose, midazolam 1 mg, and thiopental 125 mg and the shaking resolved. After another episode 20 minutes later thiopental 250 mg and dextrose were effective within seconds. A third episode of generalized stiffness and shaking occurred about 40 minutes later and resolved spontaneously after 10 seconds. After a third dose of thiopental 250 mg she was taken to the intensive care unit, intubated, and sedated, but continued to have intermittent episodes of decerebrate posturing and generalized tremors lasting up to 20 seconds. She had intermittent seizure activity throughout the first postoperative day and frequent episodes of decerebrate posturing. She recovered after 5 days and was given phenytoin.

Indocyanine green

[SED-15, 2595; SEDA-31, 760; SEDA-32, 896] Sensory systems Eyes Subretinal migration of indocyanine green dye and subsequent retinal pigment epithelial atrophy has been reported during macular surgery for serous macular detachment in a 65-year-old woman [59A].

Fluoride

[SED-15, 1395; SEDA-32, 892]

Skeletal fluorosis is endemic in some parts of the world owing to life-long ingestion of high amounts of fluoride in the drinking

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water. It is characterized by dental changes and diffuse densification of bones, with ossification of many ligaments and interosseous membranes. Nervous system Neurological complications of fluoride occur in 10% of patients, mostly in the late stages of fluorosis [60r]. High cervical myelopathy caused by ossification of the posterior longitudinal ligament and ligamentum flavum has been reported in a patient from an area endemic for skeletal fluorosis [61c]. • A 48-year-old man developed stiffness and weakness of upper and lower limbs, which started insidiously with slowly progressive stiffness of the neck and back. After 1 year he started to have difficulty in walking, and a few months later developed symmetrical weakness of both hands with urinary incontinence. There was a severe spastic quadriparesis with spasticity as the dominant finding, accompanied by signs of posterior column involvement and generally brisk deep tendon reflexes with clonus. There were diffuse opaque white areas with brownish mottling and discrete pitting on his teeth. A urodynamic study showed an overactive urinary bladder. Plain X-rays of the cervical and thoracic spine showed markedly increased bond density and ossification of the ligamentum flavum, and ossification of the patellar tendons and interosseous membranes of the ribs. The urine fluoride concentration was 11.2 mg/l (reference range 0.2–1.1 mg/l) with normal renal function. The fluoride concentration in drinking water was 4.5 mg/l (permitted concentration less than 1.5 mg/l). Somatosensoryevoked potentials showed slowing of posterior column conduction in all limbs. Decompressive laminectomy at T11–12 followed by median corpectomy at C2–3 with a bone graft fusion 1 month later resulted in slight recovery. At the last neurological examination, 2 years later, he was unable to stand without support, was severely spastic and incapacitated by frequent flexor spasms, and required intermittent catheterization.

Glycols

[SED-15, 1516; SEDA-30, 567]

Observational studies Exposures to the potentially harmful pharmaceutical excipients benzyl alcohol and propylene glycol

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present in parenteral medications routinely administered in neonatal and pediatric intensive care units have been examined in 170 episodes of exposure to parenteral medications [62C]. Patients who received medications by continuous infusion received significantly higher doses of the excipient than those who received medications intermittently. In this subset of patients, the median cumulative doses of the excipients were about 21 and 180 times the acceptable daily intakes of benzyl alcohol and propylene glycol respectively, and exceeded the doses above which adverse reactions have been reported in infants. There was no significant correlation between the duration of medication administration and cumulative excipient exposure. The authors concluded that critically ill neonates, especially those receiving medication by continuous infusion, are at risk of being exposed to benzyl alcohol and propylene glycol at potentially toxic doses during routine medication administration. Metabolism Probable propylene glycol toxicity has been reported in a patient receiving a continuous infusion of pentobarbital for refractory status epilepticus [63c]. • A 59-year-old woman with worsening mental status developed status epilepticus. She was given a continuous infusion of propofol, but this failed to achieve the therapeutic end-point of electroencephalogram burst suppression and she was given a continuous infusion of pentobarbital instead, starting with a loading dose of 450 mg and followed by a maintenance infusion of 10 mg/kg/hour to achieve burst suppression. After 12 hours she developed an anion gap metabolic acidosis, a raised serum lactate concentration, hyperosmolality, and an increased osmolal gap. The pentobarbital was withdrawn, and the acidosis and hyperosmolality resolved.

Pentobarbital contains 40% v/v propylene glycol, which was thought to have caused this patient's metabolic derangements. Reports of toxicity with drugs containing propylene glycol, particularly intravenous lorazepam, have been well described, but this is one of few reports involving intravenous pentobarbital.

Latex

N.H. Choulis

[SED-15, 2005; SEDA-31, 761]

Immunologic Exposure to latex is associated with three clinical syndromes: irritant dermatitis, delayed hypersensitivity reactions, and the most serious, but least common, immediate or type 1 hypersensitivity. Exposure to latex can occur through the skin, mucous membranes, or airways. Gloves used for examination, surgical or household, are often the cause of allergic reactions. Natural rubber latex has also become a major cause of occupational asthma (OA) in workers using natural rubber latex gloves. The time course of occupational asthma due to natural rubber latex in Belgium and the relation to the different types of gloves used in hospitals have been studied over 5 years [64r]. Based on the results of diagnostic procedures, occupational asthma due to natural rubber latex was categorized as definite, probable, unlikely, or indeterminate. The patterns of glove usage were characterized through a questionnaire survey in hospitals. A total of 298 claims for occupational asthma due to natural rubber latex were identified, including 127 subjects with definite and 68 with probable occupational asthma. As a result, the use of powdered natural rubber latex gloves fell from 81% to 18% over the 5 years and they were predominantly substituted by latex-free gloves, especially for non-sterile procedures.

Methylthioninium chloride (methylene blue) [SED-15, 2314; SEDA-30, 569; SEDA-32, 896] Skin Methylthioninium chloride has been used for lymphatic mapping/sentinel lymphadenectomy in staging melanoma and breast cancer. It can cause skin necrosis, but more mild adverse reactions from intraparenchymal breast injection are not well characterized. Of patients undergoing staging for breast cancer and melanoma, 95 received intraparenchymal breast injected of methylthioninium chloride [65R].

Miscellaneous drugs, materials, medical devices, and techniques

There was no frank skin necrosis in any case, but six patients who underwent breast conservation had local inflammatory changes; four had changes indistinguishable from infectious cellulitis, two had skin telangiectases before radiotherapy, and two had fat necrosis. Most of these effects resolved with conservative management. The authors concluded that methylthioninium chloride can cause cutaneous changes that are more subtle than have been previously described. Drug–drug interactions Methylthioninium chloride is a monoamine oxidase inhibitor, and can cause serotonin toxicity when it is combined with drugs that increase central serotonin neurotransmission. It has been associated with a toxic metabolic encephalopathy in 26 cases [66r]. Autonomic, neurological, and neuromuscular instability has been reported after infusion of methylthioninium chloride for parathyroidectomy, and the authors suggested that this was due to serotonin syndrome [67A]. • A 58-year-old woman, with a background of obsessive compulsive disorder treated with paroxetine, underwent parathyroidectomy under general anesthesia and was given methylthioninium chloride. Postoperatively she had symptoms and signs of serotonin syndrome and specifically tachycardia, agitation, dystonia, and abnormal eye movements. These spontaneously resolved over the next 48 hours.

Nicotine

[SED-15, 2508; SEDA-30, 571; SEDA-31, 571; SEDA-32, 987]

Observational studies In a study of the use of nicotine replacement therapy, smokers were followed by phone at 2 weeks (n ¼ 33 690), and a randomly selected subsample was followed for 3 months (n ¼ 1187) [68C]. Among those who reported having used nicotine replacement therapy after 2 weeks, about one in four reported an adverse reaction; this rate increased to about 42% among those surveyed at 3 months. The prevalence and specific types

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of adverse effects reported were consisted with findings from clinical trials of nicotine replacement therapy and varied in relation to the type of formulation used (patches, gum, lozenges). Most of the adverse reactions were rated mild, and only about 5% of subjects (across the 2-week and 3-month follow-ups) reported having stopped using nicotine replacement therapy as a result of adverse reactions. Psychiatric The association of smoking, smoking cessation, and cessation medications with suicide has been reviewed [69r]. Current smoking has been associated with an increase in the risk of suicide in both case-control and cohort studies. The three most plausible (but relatively untested) explanations for this association are that smokers have pre-existing conditions that increase their risk of suicide, that smoking causes painful and debilitating conditions that might lead to suicide, and that smoking reduces serotonin concentrations and monoamine oxidase activity. Stopping smoking appears to lead to major depression in some smokers, which could result in suicide; however, smoking cessation has not been associated with suicide in the few studies available. Regulatory agencies have stated that bupropion, rimonabant, and varenicline appear to be associated with suicide; however, the data for these statements have not been presented in sufficient detail to assess their validity. Genotoxicity Genotoxic effects of nicotine have been reported in tumor-free salivary gland cells in 10 patients with parotid gland tumors [70E]. Single cells were prepared by enzymatic digestion immediately after surgery and exposed for 1 hour to nicotine 0.125–4.0 mmol/l. Nicotine caused a significant concentration-related increase in DNA migration in parotid gland single cells. The lowest concentration that caused significant DNA damage, 0.25 mmol/l, was only 10-fold higher than the maximal concentrations of nicotine reported in the saliva after unrestricted smoking. Although conclusive evidence of a carcinogenic potential of nicotine is still lacking, the

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effects of long-term nicotine replacement therapy should be carefully monitored. Tumorigenicity The effects of smoking and drinking on the development of squamous cell carcinoma of head and neck have been investigated in 152 patients and 157 healthy controls matched for age and sex, and analyses were performed to evaluate possible differences in cancer susceptibility among the anatomical subregions of the head and neck [71r]. The association between five single nucleotide polymorphisms (SNPs) in the homologous recombination DNA repair pathway and the risk of carcinomas was also investigated. Stratification according to smoking habits and alcohol consumption highlighted the importance of tobacco and alcohol as two susceptibility factors for squamous cell carcinoma of head and neck. Stratification according to the anatomical region of the tumor showed sitespecific differences in sensitivity to tobacco smoke, with an increase in cancer susceptibility from the oral cavity down to the pharynx and larynx. Pregnancy In a retrospective review of the medical records of participants in the Baby Steps Trial, a study of nicotine replacement therapy, data that were abstracted from 157 records were combined with baseline characteristics for logistic regression modeling of serious adverse events and adjusted to co-variates [72c]. There were serious adverse events in 31% of those who took nicotine replacement therapy and 17% of the controls. Black race, an adverse pregnancy history, and use of analgesic medications during pregnancy were significant predictors of adverse events. Teratogenicity The association between maternal smoking and alcohol use during the periconceptional period and the risk of congenital defects in the offspring has been studied in a case-control study of fetuses and live-born infants with orofacial clefts, neural tube defects, and conotruncal heart defects [73r]. Information on smoking and alcohol consumption was obtained via telephone interviews with mothers of 1355

N.H. Choulis

cases and 700 non-malformed, live-born controls. Smoking more than five cigarettes was associated with higher risks of neural tube defects and the risk associated with higher consumption of cigarettes was lower for conotruncal heart defects.

Oleic acid Uses Oleic acid is a mono-unsaturated omega-9 fatty acid found in various animal and vegetable sources. Triglyceride esters of oleic acid comprise the majority of olive oil. Oleic acid is used as an excipient in pharmaceuticals and as an emulsifying or solubilizing agent in aerosol products. It may hinder the progression of adrenoleukodystrophy, a fatal disease that affects the brain and adrenal glands, and it may help boost memory [74r]. Oleic acid may also be responsible for the hypotensive (or blood pressure reducing) effects of olive oil [75r]. Placebo-controlled studies Oleic acid premeal supplements have been used to trigger the ileal brake and thus lengthen transit time and the opportunity for nutrient absorption in patients with short bowel syndrome and it affects diarrhea and weight. In a double-blind, controlled, random-order, crossover trial in eight participants with long-standing severe short bowel syndrome, blue food color appearance, breath hydrogen testing, and radio-opaque markers were used as measures of transit time [76r]. Only seven completed the study. Transit time was not significantly different affected by oleic acid, although peptide YY concentrations tended to be increased. Energy absorption was reduced 14% by oleic acid, significantly more than the 3% reduction by placebo. Fat, protein, and fluid absorption were not significantly changed. Neither diarrhea nor weight was affected. The authors concluded that energy absorption is reduced by oleic acid supplements in severe short bowel syndrome, although the study may have lacked

Miscellaneous drugs, materials, medical devices, and techniques

the power to determine whether oleic acid affects diarrhea or body weight. Tumorigenicity Oleic and mono-unsaturated fatty acid concentrations in erythrocyte membranes have been associated with an increased risk of breast cancer [77r].

Polyvinyl alcohol Observational studies Polyvinyl alcohol fibers and films are used in medicine and pharmacology because of their ability to swell, absorb toxic products, decompose necrotic masses, and reduce blood loss [78r]. A mixture of polyvinyl alcohol with ketoprofen has been used to reduce pelvic pain after uterine artery embolization [79C] in a randomized prospective study in 80 patients, 40 of whom received ketoprofen mixed with polyvinyl alcohol particles and 40 polyvinyl alcohol alone. During embolization, only five patients recorded a pain score of 1–2. One had an allergic reaction to the contrast medium; 13 of the patients who received polyvinyl alcohol alone reported severe or very severe pain, compared with none of those who received ketoprofen plus polyvinyl alcohol.

Sclerosants

[SED-15, 3107]

Foam sclerotherapy is a technique that involves injecting sclerosant drugs into a blood vessel. The sclerosant drug (sodium tetradecyl sulfate or polidocanol) is mixed with air or a physiological gas (carbon dioxide) in a syringe or mechanical pump. This increases the surface area of the drug. Foam sclerosants are more efficacious than liquid sclerosants in causing sclerosis (thickening of the vessel wall and sealing off blood flow) [80r], as they do not mix with the blood in the vessel and in fact displace it, thus avoiding dilution of the drug and causing maximal sclerosant action. They are therefore useful for longer and larger

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veins. Thick foam, like tooth-paste, has revolutionized the non-surgical treatment of varicose veins [81r]. Observational studies Transcatheter foam sclerotherapy has been studied retrospectively in 38 patients (mean age 37 years) with pelvic congestion syndrome [82C]. Pelvic pain was associated with dyspareunia in 23 patients, urinary urgency in nine, and worsening of pain during menstruation and at the end of the day of work in seven and 38 respectively. Pelvic and transvaginal color Doppler ultrasonography showed ovarian or pelvic varices with a diameter over 5 mm preventing venous reflux. Foam sclerotherapy was performed in all patients, using 3% sodium tetradecyl sulfate foam. Pelvic colicky pain occurred immediately after injection in three patients and disappeared spontaneously after a few minutes. Hemodynamic changes after sclerotherapy have been evaluated in a prospective observational trial in 53 patients, in whom 67 sites were treated with polidocanol foam [83C]. With the exception of two sites, all the treatments resulted in at least an improvement, and about 80% of the treated veins were completely occluded as demonstrated by duplex ultrasonography. Patients with post-thrombotic syndrome had poorer results. In a study of the use of transthoracic echocardiography and middle cerebral artery transcranial Doppler performed during ultrasound-guided foam sclerotherapy circulating emboli were detected in superficial, perforating, communicating, and deep veins and the central circulation [84C]. Transthoracic echocardiography detected bright echoes in the right heart after every injection and in the left heart in up to 655 of selected patients. Transcranial Doppler high-intensity transient signals were detected in 14–42% of patients, with an incidence higher than patient reports of adverse events: the incidence of high-intensity transient signals was independent of the volume of foam injected. Placebo-controlled studies In a multicenter controlled study in which patients were

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treated with foam sclerotherapy for trunk incompetence of the great and small saphenous veins in 1025 patients the saphenous trunk was occluded in 90.3% [85C]. There were 27 (2.6%) adverse reactions reported: migraine (n ¼ 8), visual disturbances alone (n ¼ 7), chest pressure alone (n ¼ 7), and chest pressure associated with visual disturbances (n ¼ 5). There were 10 cases of deep vein thrombosis and one case of pulmonary embolism 19 days after foam sclerotherapy without deep vein thrombosis. There was one transient ischemic stroke, with complete clinical recovery in 30 minutes, and one case of septicemia with a satisfactory outcome. Systematic reviews Foam and liquid sclerotherapy for primary varicose veins in the legs have been compared in a review of the literature [86M]. For treatment of saphenous veins, six trials were considered. Despite containing much less sclerosing agent, foam sclerotherapy was markedly more effective, the difference being 20–50%. In a metaanalysis of four comparisons, foam sclerotherapy had an efficacy of 77% and liquid sclerotherapy 40%. The adverse reactions that were reported did not differ between the two forms of sclerotherapy, although visual disturbances seemed to be more common with foam sclerotherapy. In a literature survey of randomized controlled trials, meta-analyses, and observational studies using survival analysis for long-term outcomes, foam was more effective than liquid for ultrasound-guided sclerotherapy [87R]. The two types of sclerosants are equally effective for sclerotherapy of small veins, but little else is known, according to this study, about the optimal preparation of foam sclerosants and the best technique for administering foam. Drug dosage regimens The proportion of sclerosant that enters deep veins after injection of polidocanol foam has been studied in 107 patients with superficial venous incompetence; they were randomized to multiple small-dose injections of 1% polidocanol foam (less than 0.5 ml per

N.H. Choulis

injection) or a few injections of 1% polidocanol foam (more than 0.5 ml per injection), for the treatment of varicose tributaries [88C]. All then received ultrasound-guided foam sclerotherapy for refluxing great saphenous veins using 3% polidocanol foam. Ultrasonography immediately after sclerotherapy showed that there was less foam in the deep veins after the multiple small-volume injections, but there were no significant differences in the success rates between the groups at 6 months. Two patients developed migraine during the procedure. These findings suggest that multiple smallvolume injections can reduce the amount of foam sclerosant and the risk of foam sclerosant entering the deep veins in patients with superficial venous insufficiency.

Silicone

[SED-15, 3137; SEDA-31, 766]

Sexual function Penile augmentation with liquid injectable silicone has been reported and the literature reviewed [89cr]. The injection of medical grade silicone for soft tissue augmentation has a role in carefully controlled settings. Traditionally, the use of liquid injectable silicone for penile augmentation has had poor outcomes and surgical interventions are often required to correct complications. The authors discourage its use for penile augmentation until carefully designed and evaluated trials have been completed.

Sodium metabisulfite [SEDA-30, 572] Respiratory Three cases of occupational airways disease with episodes of increased breathlessness and symptoms typical of asthma have been attributed to sodium metabisulfite exposure [90r]. • A 44-year-old trawlerman and a 43-year-old man and a 39-year-old woman working as prawn processors developed work-related

Miscellaneous drugs, materials, medical devices, and techniques airways disease due to exposure to sodium metabisulfite, the first with irritant-induced asthma with a positive-specific bronchial challenge associated with very high sulfur dioxide exposures, the second with occupational asthma, and the third with vocal cord dysfunction and underlying asthma.

Of nine reported cases, most were nonatopic and responses to specific bronchial challenge when undertaken showed an immediate response. Exposure to sulfur dioxide in these settings is very high, in excess of 30 ppm and the authors concluded that sodium metabisulfite should be regarded as a cause of occupational airways disease and that its use in the fish- and prawn-processing industry should be investigated further to identify the risks of exposure and handling of the agent in the workplace.

Sulfites

[SED-15, 3215]

Nervous system It has been hypothesized that amyotrophic lateral sclerosis of the non-mutant superoxide dismutase type may be caused by adverse effects of glutamate and cysteine, which are reduced glutathione precursors, and by sulfite (a metabolite of cysteine), which accumulate when one or more of the enzymes needed for glutathione synthesis are defective. In one case there was a raised sulfur concentration in the hair, a raised blood cysteine, a positive urine sulfite, a raised urine glutamate, and a low whole blood glutathione concentration [91c]. When strict dietary and supplement measures normalized the patient's whole blood glutathione, blood cysteine, and urine sulfite, there was no additional physical decline. Patients with the non-mutant superoxide dismutase type of amyotrophic lateral sclerosis should be tested for sulfite toxicity and for cysteine, glutamate, and glutathione concentrations, and for enzymes involved in glutathione metabolism.

Talc

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[SED-15, 3592; SEDA-32, 898]

Respiratory In a retrospective review of the use of the combination of talc and doxycycline for pleurodesis in 33 sequential patients (20 women and 13 men; average age 64 years) over 2 years, the doses of talc (2.5 g) and doxycycline (250 mg) were half the usual doses [92c]. There were no immediate perioperative complications. Chest tube duration average 4.2 and the total amount drained averaged 880 ml. Mean length of stay after the procedure in outpatients was 4.8 days. There was persistent or worsening dyspnea in 11 patients in the immediate postoperative period. Only two developed respiratory distress and neither had any parenchymal changes on chest radiology or required ventilatory support. Other immediate postoperative events included chest pain in 18 patients and fever in three. Follow-up imaging was available in 29 patients, an average of 3.9 months postoperatively; 20 had complete pleurodesis, four had partial pleurodesis, and five failed. In no case did follow-up imaging show new adult respiratory distress-like infiltrates. Tumorigenicity Several studies have established preliminary links between talc and pulmonary issues [93r], lung cancer [94r], and skin cancer and ovarian cancer [95r]. This is a major concern, considering the widespread commercial and household uses of talc. Epidemiological evidence also suggests a possible association between genital use of talcum powder and the risk of epithelial ovarian cancer; however, the biological basis for this association is not clear. The interactions between talc and genes in detoxification pathways, glutathione Stransferase M1 (GSTM1), glutathione Stransferase T1 (GSTT1), and N-acetyltransferase 2 (NAT 2) have been analysed, in order to assess whether the association of talc with ovarian cancer is modified by variants of genes that are potentially involved in the response to talc [96M]. The analysis included 1175 cases and 1202 controls from

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a New England case-control study and 210 cases and 600 controls from a prospective Nurses’ Health Study. Regular talc use was associated with an increased risk of ovarian cancer in the combined study population. Independent of talc, the genes examined were not clearly associated with an increased risk. However, the association of talc with ovarian cancer varied by GSTT1 genotype and combined GSTM1/GSTT1 genotype. Ιn the pooled analysis, the association with talc was stronger among women with the GSTT1-null genotype, particularly in combination with the GSTM1-present genotype. There was no clear evidence of an interaction with GSTM1 alone or NAT2. These results suggest that women with certain genetic variance may have a higher risk of ovarian cancer associated with genital use of talc.

Toluene

[SEDA-32, 899]

Nervous system The results of 30 studies of long-term exposure to toluene in humans, using neuroimaging and neuropsychological methods, have been reviewed [97M]. There were nine case studies, 11 group studies with controls, and 10 without controls. Toluene preferentially affects white matter relative to gray matter and periventricular/subcortical regions relative to cortical regions. The lipid-dependent distribution and pharmacokinetic properties of toluene appear to explain the pattern of MRI abnormalities as well as the common

N.H. Choulis

symptoms and signs of toluene encephalopathy. The commonly observed neuropsychological deficits, such as impairment of processing speed, sustained attention, memory retrieval, executive function, and language, are also consistent with white matter pathology. In six cases involving drivers arrested for driving under the influence who subsequently tested positive for toluene, blood toluene concentrations were 12–45 mg/l [98c]. All were intoxicated, and had symptoms that included balance problems, confusion and disorientation, loss of coordination, and inability to follow instructions. They also had horizontal nystagmus but not vertical nystagmus, tachycardia and raised blood pressure, and reduced body temperature. These findings are consistent with prior reports that subjects with blood toluene concentrations above 10 mg/l have impaired driving skills. A reversible leukoencephalopathy has been attributed to chronic unintentional exposure to toluene in a 40-year-old chemical salesman [99A]. An MRI scan showed extensive, diffuse white matter changes with increased T2-weighted signal intensity throughout the subcortical and periventricular white matter. Metabolism A 47-year-old woman developed a severe metabolic acidosis with a raised anion gap [100A]. She had a chronic distal renal tubular acidosis, which was attributed to chronic toluene toxicity secondary to paint thinner and spray paint inhalation.

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Tunick SJ, Huryn JM. Osteonecrosis of the maxilla and mandible in patients with advanced cancer treated with bisphosphonate therapy. Oncologist 2008; 13(8): 911–20. Fehm T, Beck V, Banys M, Lipp HP, Hairass M, Reinert S, Sollmayer EF, Wallwiener D, Krimmel M. Bisphosphonate-induced osteonecrosis of the jaw (ONJ): incidence and risk factors in patients with breast cancer and gynecological malignancies. Gynecol Oncol 2009; 112 (3): 605–9. Saussez S, Javadian R, Hupin C, Magremanne M, Chantrain G, Loeb I, Decaestecker C. Bisphosphonate-related osteonecrosis of the jaw and its associated risk factors: a Belgian case series. Laryngoscope 2009; 119(2): 323–9. Stumpe MR, Chandra RK, Yunus F, Samant S. Incidence and risk factors of bisphosphonate-associated osteonecrosis of the jaws. Head Neck 2009; 31(2): 202–6. La Verde N, Bareggi C, Garassino M, Borgonovo K, Sburlati P, Padretti D, Bianchi C, Perrone S, Mihali D, Cobelli S, Mantica C, Rizzo A, Farina G. Osteonecrosis of the jaw (ONJ), in cancer patients treated with bisphosphonates: how the knowledge of a phenomenon can change its evolution. Support Care Cancer 2008; 16(11): 1311–5. Song KE, Myn YK, Lee JK, Lee KB, Joo HJ, Kwack KS, Chung YS. A probable case of oral bisphosphonate-associated osteonecrosis of the jaw and recovery with parathyroid hormone treatment. Curr Ther Res Clin Exp 2008; 69(4): 356–62. Visekruna M, Wilson D, McKiernan FE. Severely suppressed bone turnover atypical skeletal fragility. J Clin Endocrinol Metab 2008; 93(8): 2948–52. Solomon DH, Hochberg MC, Mogun H, Schneeweiss S. The relation between bisphosphonate use and non-union of fractures of the humerus in older adults. Osteoporos Int 2009; 20(6): 895–901. Hooper M, Faustino A, Reid IR, Hosking D, Gilchrist NL, Selby P, Wu M, Salzmann G, West J, Leung A. Randomized, active-controlled study of onceweekly alendronate 280 mg high dose oral

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buffered solution for treatment of Paget's disease. Osteoporos Int 2009; 20(1): 141–50. Soon MS, Chen YY, Yen HH. Extravasation of sclerosant after injection of Nbutyl-2-cyanoacrylate for a bleeding gastric Dieulafoy lesion. Endoscopy 2008; 40 (Suppl 2): E51–2. Peixoto P, Ministro P, Sadio A, Castanheira A, Cancela E, Araújo R, Silva A, Caldas A. Embolic complications associated with endoscopic injection of cyanoacrylate for bleeding duodenal ulcer. Endoscopy 2008; 40(Suppl 2): E126. Kolilekas L, Kalomenidis I, Manali E, Triantafillidou C, Brountzos E, Papiris S. Cyanoacrylate-related pulmonary embolism following percutaneous varicocele embolization. South Med J 2008; 101(10): 1073–4. Hamad N, Stephens J, Maskell GF, Hussaini SH, Dalton HR. Case report. Thromboembolic and septic complications of migrated cyanoacrylate injected for bleeding gastric varices. Br J Radiol 2008; 81(971): e263–5. Marion-Audibert AM, Schoeffler M, Wallet F, Duperret S, Mabrut JY, Bancel B, Pere-Verge D, Wander L, Souquet JC. Embolie pulmonaire fatale au décours d'une injection de varices gastriques par cyanoacrylate. [Acute fatal pulmonary embolism during cyanoacrylate injection in gastric varices.] Gastroenterol Clin Biol 2008; 32(11): 926–30. Wai CT, Lin M, Tan KC. Hepatobiliary and pancreatic: pulmonary embolism after injection therapy for gastric varices. J Gastroenterol Hepatol 2008; 23(8 Pt 1): 1306. Thijs WJ, de Groot EH, Hofstra LS. Portal and splenic vein occlusion complicating Histoacryl injection therapy in bleeding gastric varices. Endoscopy 2008; 40(Suppl 2): E187. Joshi D, Wendon J, Auzinger G. Stroke after injection of gastric varices. Liver Int 2009; 29(3): 374. Shih KL, Yen HH, Soon MS. Portal-vein embolization after sclerotherapy treatment of bleeding gastric varices: report of a case with long-term follow-up. Gastrointest Endosc 2009; 69(6): 1176–8.

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[33] Favrolt N, Bonniaud P, Cercueil JP, Logerot S, Foucher P, Camus C, Camus P. Embolie pulmonaire de cyanoacrylate après embolisation d'une malformation artérioveineuse. [Pulmonary embolism by cyanoacrylate following embolisation of an arteriovenous malformation.] Rev Mal Respir 2009; 26(1): 74–7. [34] Prytuła A, Veereman-Wauters G, Duval EL. Pulmonary embolism due to injection of Histoacryl and Lipiodol during endoscopic sclerotherapy of fundic varices. Acta Gastroenterol Belg 2008; 71(4): 387–9. [35] Barclay S, Cameron I, Stewart I, Forrest E. Massive hemorrhage from a pulmonary vein-esophageal fistula: a late complication of Histoacryl glue injection. Gastrointest Endosc 2009; 70(5): 1037–8. [36] Amouroux C, Cervoni JP, Delabrousse E, Koch S, Thevenot T, Di Martino V. Thrombose portale par diffusion de cyanoacrylate au décours de l'obturation de varices gastriques hémorragiques. [Portal vein thrombosis after cyanoacrylate injection therapy in bleeding gastric varices.] Gastroenterol Clin Biol 2009; 33(3): 205–7. [37] Vincent M, Lerat F, Trogrlic S, Laurent V, Feray C, Dupas B. Thrombose de la veine rénale gauche après sclérothérapie de varice cardio-tubérositaire. [Left renal vein thrombosis following sclerotherapy for gastric varices.] J Radiol 2009; 90(6): 745–6. [38] Lee KM, Kim YB, Sin SJ, Hwang JC, Yoo BM, Jung JY, Kim JH, Cho SW. Hepatic failure requiring transplantation caused by portal vein embolism as a complication of N-buty-2-cyanoacrylate injection for a bleeding gastric varix. Gastrointest Endosc 2009; 69(4): 967–9. [39] Neumann H, Scheidbach H, Mönkemüller K, Pech M, Malfertheiner P. Multiple cyanoacrylate (Histoacryl) emboli after injection therapy of cardia varices. Gastrointest Endosc 2009; 70(5): 1025–6. [40] Chang CJ, Su CW, Hou MC. Abdominal pain after endoscopic hemostasis of gastric tumor bleeding. Splenic infarction with abscess formation. Gastroenterology 2009; 137(5): e7–8.

Miscellaneous drugs, materials, medical devices, and techniques [41] Jurado-Palomo J, Caballero T, FernándezNieto M, Quirce S. Occupational asthma caused by artificial cyanoacrylate fingernails. Ann Allergy Asthma Immunol 2009; 102(5): 440–1. [42] Ohta T, Gomi M, Oowaki H, Ishikawa M. Chronic venous congestion following embolization of spinal dural arteriovenous fistula. J Neurosurg Spine 2008; 9(2): 186–90. [43] Toyoda H, Kumada T, Sone Y, Isogai M, Kaneoka Y. Late-onset colonic occlusion after emergent selective embolization of sigmoid artery with N-butyl cyanoacrylate for life-threatening traumatic bleeding. J Vasc Interv Radiol 2009; 20(10): 1376–9. [44] Greenhill GA, O'Regan B. Incidence of hypertrophic and keloid scars after Nbutyl 2-cyanoacrylate tissue adhesive had been used to close parotidectomy wounds: a prospective study of 100 consecutive patients. Br J Oral Maxillofac Surg 2009; 47(4): 290–3. [45] Chagla AS, Balasubramaniam S. Cerebral N-butyl cyanoacrylate glue-induced abscess complicating embolization. J Neurosurg 2008; 109(2): 347. [46] Chang CJ, Shiau YT, Chen TL, Hou MC, Sun CH, Liao WC, Lin HC, Lee SD. Pyogenic portal vein thrombosis as a reservoir of persistent septicemia after cyanoacrylate injection for bleeding gastric varices. Digestion 2008; 78(2–3): 139–43. [47] Vitale C, George M, Sheroff A, Hernon C, Boyer E. Tracheal and bronchial obstruction following cyanoacrylate aspiration in a toddler. Clin Toxicol (Phila) 2008; 46 (6): 560–2. [48] Brien S, Prescott P, Bashir N, Lewith H, Lewith G. Systematic review of the nutritional supplements dimethyl sulfoxide (DMSO) and methyl-sulfonylmethane (MSM) in the treatment of osteoarthritis. Osteoarthritis Cartilage 2008; 16(11): 1277–88. [49] Chakrabarti R, Schutt CE. The enhancement of PCR amplification by low molecular-weight sulfones. Genes 2001; 274(1–2): 293–8. [50] Fan CC, Lin SK, Huang MC. Disulfiraminduced punding. J Clin Psychopharmacol 2008; 28(4): 473–4.

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[51] Bae JS. Acute vocal fold palsy after acute disulfiram intoxication. J Voice 2009; 23 (1): 125–7. [52] Lemoyne S, Raemaekers J, Daems J, Heytens L. Delayed and prolonged coma after acute disulfiram overdose. Acta Neurol Belg 2009; 109(3): 231–4. [53] Jerónimo A, Meira C, Amaro A, Campello GC, Granja C. Cardiogenic shock caused by disulfiram. Arq Bras Cardiol 2009; 92(3): e16–8. [54] Tayyareci Y, Acarel E. Acute myocardial infarction associated with disulfiram–alcohol interaction in a young man with normal coronary arteries. Turk Kardiyol Dern Ars 2009; 37(1): 48–50. [55] Mutschler J, Diehl A, Kiefer F. Pronounced paranoia as a result of cocainedisulfiram interaction: case report and mode of action. J Clin Psychopharmacol 2009; 29(1): 99–101. [56] Chen SC, Huang MC, Fan CC. Potentially fatal interaction between colchicine and disulfiram. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33(7): 1281. [57] Kerr JT, Chu FW, Bayles SW. Cerebrospinal fluid rhinorrhea: diagnosis and management. Otolaryngol Clin North Am 2005; 38: 597–611. [58] Jacob AK, Dilger JA, Hebl JR. Status epilepticus and intrathecal fluorescein: anesthesia providers beware. Anesth Analg 2008; 107(1): 229–31. [59] Hussain N, Jalali S, Rani A, Rawal H. Retinal pigment epithelial atrophy following indocyanine green dye-assisted surgery for serous macular detachment. Indian J Ophthalmol 2008; 56(5): 423–5. [60] Reddy DR. Fluorosis. In: Ramamurthi B, Tanton PN, editors. Textbook of Neurosurgery. New Delhi: Churchill Livingstone; 1966. p. 798–803. [61] Kumar H, Boban M, Tiwari M. Skeletal fluorosis causing high cervical myelopathy. J Clin Neurosci 2009; 16: 828–30. [62] Shehab N, Lewis CL, Streetman DD, Donn SM. Exposure to the pharmaceutical excipients benzyl alcohol and propylene glycol among critically ill neonates. Pediatr Crit Care Med 2009; 10(2): 256–9. [63] Miller MA, Forni A, Yogaratnam D. Propylene glycol-induced lactic acidosis in a

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Chapter 49

1029

[91] Woolsey PBE. Cysteine, sulfite, and glutamate toxicity: a cause of ALS? J Altern Complement Med 2008; 14(9): 1159–64. [92] Abouzgheib WB, Bartter T, Kanaan R, Rodman D. Low-dose talc plus low-dose doxycycline for pleuroscopic pleurodesis: initial experience. J Bronchol Interv Pulmonol 2009; 16(2): 91–4. [93] Hollinger MA. Pulmonary toxicity of inhaled and intravenous talc. Toxicol Lett 1990; 52(2): 121–7. [94] National Toxicology Program . NTP toxicology and carcinogenesis studies of talc (non asbestiform) in rats and mice (inhalation studies). Natl Toxicol Program Tech Rep Ser 1993; 421: 1–287. [95] Henderson WJ, Joslin CA, Turnbull AC, Griffiths K. Talc and carcinoma of the ovary and cervix. J Obstet Gynecol Br Commonw 1971; 78(3): 266–72. [96] Gates MA, Tworoger SS, Terry KL, TitusErnstoff L, Rosner B, De Vivo I, Cramer DW, Hankinson SE. Talc use variants of the GSTM 1, GSTT 1 and NAT 2 genes, and risk of epithelial ovarian cancer. Cancer Epidemiol Biomarkers Prev 2008; 17(9): 2436–44. [97] Yücel M, Takagi M, Walterfang M, Lubman DI. Toluene misuse and longterm harms: a systematic review of the neuropsychological and neuroimaging literature. Neurosci Biobehav Rev 2008; 32 (5): 910–26. [98] Capron B, Logan BK. Toluene-impaired drivers: behavioral observations, impairment assessment, and toxicological findings. J Forensic Sci 2009; 54(2): 486–9. [99] Qureshi SU, Blanchette AR, Jawaid A, Schulz PE. Reversible leukoencephalopathy due to chronic unintentional exposure to toluene. Can J Neurol Sci 2009; 36(3): 388–9. [100] Dickson RP, Luks AM. Toluene toxicity as a cause of elevated anion gap metabolic acidosis. Respir Care 2009; 54(8): 1115–7.

Index of drugs A abacavir liver function tests, 586 myocardial infarction, 585 neutropenia, 586 Parsonage–Turner syndrome, 586 ABCD see amphotericin B colloidal dispersion abciximab see also glycoprotein IIb–IIIa inhibitors hemorrhagic pericarditis, 720 ABLC see amphotericin B lipid complex acarbose acute generalized exanthematous pustulosis (AGEP), 893 hypoglycemia, 893 acetazolamide adynamic ileus, 438 cerebral blood flow, 437 ciliary muscle spasm, 437 corneal swelling, 437 edema, 437 hypokalemia, 437–8 hypoxic sensitivity, 437–8 metabolic acidosis, 437–8 migraine-like headache, 437 myopia, 437 pemphigus, 438 acetylsalicylic acid asthma, 248 DRESS, 248 drug overdose, 249 hematospermia, 248 mortality, 248 peptic ulceration, 248 spinal epidural hematoma, 248 utricaria, 248 aciclovir allergic contact dermatitis, 578 Cotard's syndrome, 577–8 acitretin darkening hair previously white hair, 339 fulminant hepatic failure, 340

Actaea racemosa allergic reactions, 992 bleeding episodes, 992 breast tenderness, 992 gastrointestinal complaints, 992 joint pain, hand, 992 liver damage, 992 muscle damage, 992 pseudolymphoma, 992 seizures, 992 stiff limb, 992 acupuncture allergic reactions, 1000 anorexia, 999 bleeding, 999 dizziness, 999 erythema and minor bleeding, 999 fatigue and circulatory disturbances, 999 jaundice, 999 light-headedness, sweating, and pruritus, 999 neck and shoulder pain, 1000 neck numbness, 999 pain, 999 pale stools, dark urine, pruritus, pedal edema, and diarrhea, 999 pneumothorax, 999 subcutaneous hemorrhage, 999 tiredness, 999 adalimumab, 784 Crohn's disease, 781 lichen planus-like eruptions, 781 lupes erythematosus, 781 menorrhagia and dysmenorrhea, 781 Miller–Fisher syndrome, 780–1 myalgia, 781 sinusitis, 780 Adderall cardiomyopathy, 2 adefovir Fanconi syndrome, 578–9 hypophosphatemic osteomalacia, 579 impaired renal tubular concentrating function, 578

renal dysfunction, 578 adenosine and analogues atrial fibrillation, 379 chest discomfort, 379 dyspnea, 379 esophageal distensibility reduced, 379 ventricular tachycardia, 379 visceral hyperalgesia, 379 adenosine receptor agonists body mass index, 380 chest pain, 380 dizziness and dyspnea, 380 flushing, 379–80 gastrointestinal discomfort, 380 headache, 380 tachycardia, 379–80 adrenaline (epinephrine) acute macular neuroretinopathy, 316 atrial fibrillation, 315 corneal endothelial decompensation, 316 denervation hypersensitivity, 316 dysrhythmias, 315 Kounis syndrome, 316 paradoxical hypotension, 316 sinus tachycardia, 317 splenic infarction, 316 thrombosis, coronary stent, 315 Agauria salicifolia, 993 agomelatine back pain, 33 constipation, 33 headache, 33 albendazole drowsiness, 647 faintness, 647 gastrointestinal symptoms, 647 headache, 647 liver function tests, 648 pancytopenia, 648 albumin-bound paclitaxel alopecia, 944 cardiotoxicity, 943–4 metastatic breast cancer, 943 myalgia and arthralgia, 944 nausea and diarrhea, 944 numbness or pain, 944 1031

Index of drugs

1032 albumin-derived hemostatics anastomotic pseudoaneurysm, 670 aseptic mediastinal cyst, 670 embolization, 670 massive lung fibrosis, 670 postoperative wound complications, 670 severe active inflammatory response, 670 stenosis, 670 alcohol aggressive behavior, 1010 blood alcohol, 1010 chronic ischemia and atherosclerotic heart disease, 1010 hepatitis, 1010 hypertension, 1009 myocardial infarction, 1010 aldesleukin (interleukin-2, IL-2) anemia, infection, and malaise, 777 capillary leak syndrome, 777 confusion and impaired consciousness, 777 disseminated intravascular coagulation, 778 dyspnea, rashes, diarrhea, and nausea, 777 edema, chills, fatigue, 777 fever, pain, redness, 777 flu-like symptoms, 778 gastrointestinal disorders, 778 hypotension, 777 left posterior fascicular block, 777 mono/oligoarticular arthritis, 778 neutropenia, 777 oliguria, 777 swelling at the injection site, 777 thrombocytopenia, 777 alemtuzumab abnormal liver function, 784 anxiety, syncope, vertigo, 784 aplastic anemia, 784 chronic inflammatory demyelinating polyradiculoneuropathy, 784 cyomegalovirus retinitis, 784 dizziness, tremor, paresthesia, and hypesthesia, 784 Guillain–Barré syndrome, 784 infusion reaction, 784 lymphoproliferative disorders, 784–5

multiple sclerosis, 784 urticaria, 784 alfentanil apnea, 209 emergence agitation, 209 nausea, 209 vomiting, 209 aliskiren acute renal insufficiency, 420 back pain, 420 diarrhea, 420 furosemide, interaction, 420–1 headache, 420 nasopharyngitis, 420 prolongation of the QT interval, 420 Allium sativum bullous necrosis, esophagus, 993 erythema and blistering, 993 garlic burns, 993 renal hematoma, 993 allopurinol DRESS, 250 oral ulceration, 250 toxic epidermal necrolysis, 250 all-trans retinoic acid see tretinoin alogliptin dry skin, pruritus, rashes, and eczema, 895 alosetron irritable bowel syndrome, benefit to harm balance, 745 alpha1-antitrypsin dizziness, 674 dysphagia, 674 dyspnea, 674 headache, 674 nausea, 674 tongue vesicles, 674 alprostadil (prostaglandin E1) unstable angina, 846 aluminium Alzheimer's disease, 447 bone area and bone mineral content, 447 chronic fatigue syndrome, 447 kidney disease, 448 lumbar spine and hip bone mass, 447 macrophagic myofasciitis, 447 neurotoxicity and osteotoxicity, 447 reduced neurodevelopmental scores, 447

amantadine auditory and visual hallucinations, 604 cardiovascular effects, 604 Fuchs dystrophy (corneal edema), 602–4 livedo reticularis, 604 syndrome of inappropriate ADH secretion (SIADH), 604 urinary retention, 604 ambrisentan aminotransferase abnormalities, 421 flushing, 421 nasal congestion, 421 nasopharyngitis, 421 palpitation, 421 peripheral edema, 421 sinusitis, 421 tadalafil, interaction, 421 warfarin, interaction, 422 amfebutamone see bupropion amfetamine blood pressure and heart rate, increased, 1–2 mortality rate, 1 American ginseng see Panax quinquefolius amikacin lipoatrophy, 510 nephrotoxicity, 510 type 5 Bartter-like syndrome, 510 vestibular function, 510 aminoglycoside antibiotics hypokalemia and acidosis/ alkalosis, 509 proximal renal tubular acidosis, 509 vestibular toxicity, 509 aminolevulinic acid erosive pustular dermatosis, 338–9 pain, 338 phototoxic reactions, 339 aminosalicylates inflamatory bowel disease, 756 renal impairment, 756 tubulointerstitial nephritis, 756 amiodarone acute cardiogenic shock, 381 chest trauma, 381 congenital heart defects, 380 cornea verticillata, 382 fever and leukocytosis, 382 glucocorticoids, 383 hepatotoxicity, 383–4 ischemic heart disease, 381

Index of drugs liver cirrhosis, 381 liver injury, 383–4 lymphoplasmacytic infiltrates, 381 nodular goiter, 382 peripheral neuropathy and cognitive impairment, 382 plasma concentrations, 383 QT interval prolongation, 381 steatohepatitis, 384 thyroid hormone resistance syndrome, 382 torsade de pointes, 381 tremor and gait ataxia, 382 thyroid-stimulating hormone (TSH), 382 ventricular tachydysrhythmias, 381 amisulpride extrapyramidal adverse effects, 99 amlodipine angioedema, 401 blood pressure, 401 mimicking mycosis fungoides, 401–2 skin infiltration of atypical lymphoid cells, 401–2 amodiaquine artesunate, interaction, 568 hepatitis, 567 amoxicillin allergic reaction, 496 Kounis syndrome, 496 maculopapular rash, 496 molar incisor hypomineralization, 496 vasospastic angina, 496 amphotericin B colloidal dispersion (ABCD) chills, fever, rigors, 542 amphotericin B deoxycholate (DAMB) anemia, 542–3 electrolyte abnormality, 542–3 infusion-related events, 542–3 neonates, 543 nephrotoxicity, 542–3 renal impairment, 542 amphotericin B lipid complex (ABLC) infusion-related reactions, 543 nausea, 543 neonates, 543 vomiting, 543 ampicillin impaired platelet function, 496 platelet aggregation, 496

1033 amprenavir/fosamprenavir atazanavir, interaction, 593–4 tenofovir, interaction, 594 anabolic steroids acne, 870 amenorrhea/anovulation, 870 cardiac enlargement, 869 clitoral enlargement, 870 dilated cardiomyopathy, 870 gynecomastia, 870 hepatitis B, 870 hepatitis C, 870 HIV, 870 anagrelide cardiomyopathy, 719 sympathetic hyperactivation, 719 takotsubo syndrome, 719 Anatolian hawthorn see Crataegus orientalis anakinra (interleukin-1 receptor antagonist) anaphylactic reaction, 779 bacterial cellulitis, 779 interstitial granulomatous reaction, 779 Wells' cellulitis, 779 anastrozole arthralgia and arthritis, 860 fractures, 861 reduced bone mineral density, 861 tenosynovial changes, 860–1 androgens endometrial or breast cancer, risk of, 871 hypogonadism, 871 peliosis, 871 prostate cancer, 871 prostatic neoplasms, risk of, 871 angel's trumpet see Datura stramonium angiotensin converting enzyme (ACE) inhibitors angioedema, 417 cholestasis, 418 contact dermatitis, 418 cough, 416 electrolyte imbalance, 416 erythroderma, 418 hyperkalemia, 416–18 hypoglycemia, 417 pseudopolymyalgia, 418 renal impairment, 416 aniline derivatives paracetamol (acetaminophen), 244–5 antacids, 741 anthranilic acid derivatives etofenamate, 245 mefenamic acid, 245

anthraquinones anorexia and episodic vomiting, 753 epigastric pain, 753 intermittent fever, 753 melanosis coli, 753 anthrax vaccine anxiety, 655–6 arthralgia, 655–6 asthenia, 655–6 back pain, 655–6 depression, 655–6 headache, 655–6 insomnia, 655–6 myalgia, 655–6 pain, 655–6 rash, 655–6 anticholinergic drugs agitation, 324 anxiety, 324 confusion, 324 desaturation, 269–70 hallucinations, 324 heart failure, 364 insomnia, 324 lung function, 364 migrainous headaches, 324 myocardial infarction, 364–5 nausea and vomiting, 324 sedation, 324 stroke, 364–5 urinary tract, 268 antidepressant drugs see also individual names cardiac disease, 25 anti-D immunoglobulin see intravenous anti-D immunoglobulin antiepileptic drugs see also individual names anticonvulsant hypersensitivity syndrome, 129 antipsychotic drugs, 128 bipolar disorder, 128 cognitive adverse effects, 127 constipation, 126 drug-resistant epilepsy, 125 gestational hypertension, 130 glaucoma, 126 hip bone mineral density, 129 hypersensitivity, 129 hyponatremia, 126 hypothyroidism, 126 idiopathic epilepsy, 126–7 immunoallergic mechanism, 129 initima media thickness, 126 lamotrigine, 126, 132 (see also lamotrigine) lamotrigine and phenytoin, 131

Index of drugs

1034 levetiracetam, 126 (see also levetiracetam) liver injury, 129 metabolic acidosis, 132 nausea, 126 osteopenia, 130 osteoporosis, 126 oxcarbazepine, 131 (see also oxcarbazepine) oxcarbazepine monotherapy, 130 pre-eclampsia, 130 psychiatric diagnosis, 128 psychiatric disorder, 127 Stevens–Johnson syndrome, 132 teratogenic effect, 131 thyroid hormone deficiency, 126 valproate-induced liver injury, 129 weight gain, 129 antiestrogens and selective estrogen receptor modulators (SERMs) breast cancer, 859–60 cognitive function, 859–60 antifungal azoles aliskiren, interaction, 545 all-trans retinoic acid, interaction, 545 antiretroviral drugs, interaction, 545 atazanavir, interaction, 546 bortezomib, interaction, 546 calcineurin inhibitors, interaction, 546 chloramphenicol, interaction, 546 citalopram, interaction, 546 darunavir, interaction, 546–7 ebastine, interaction, 547 efavirenz, interaction, 547 etoricoxib, interaction, 547 everolimus, interaction, 547 halofantrine, interaction, 547–8 lopinavir and ritonavir, interaction, 548 meloxicam, interaction, 548 methadone, interaction, 548 midazolam, interaction, 548 morphine, interaction, 548 nevirapine, interaction, 549 nifedipine, interaction, 549 omeprazole, interaction, 549 oxycodone, interaction, 549 sirolimus, interaction, 549 tacrolimus, interaction, 549 tilidine, interaction, 550 tipranavir and ritonavir, interaction, 550 vincristine, interaction, 550

warfarin, interaction, 550–1 anti-glaucoma drugs conjunctival hyperemia, 982 dry eyes, 982 lacrimal drainage obstruction, 982–3 stinging/ burning, 982 superficial punctuate keratopathy, 982 antihelminthic drugs hypoglycemia, 647 antimony abdominal colic, 448 diarrhea and rashes, 448 hepatotoxicity and cardiotoxicity, 448 nausea, 448 vomiting, 448 weakness and myalgia, 448 antipsychotic drugs bipolar disorder, 95 carbohydrate intolerance, 94–5 catract formation, 94 coronary heart disease, 93 diabetes mellitus, 95–6 dyslipidemia, 90 extrapyramidal acute symptoms, 89–90 extrapyramidal effects, 93 genetic factors and metabolic reactions, 98 hyperlipidemia, 96 hyperprolactinemia, 89–90 involuntary movements, 93–4 ischemic priapism, 99 metabolic abnormalities, 95 metformin, 97–9 obesity/weight gain, 90 orthostatic hypotension, 90 parkinsonism risk, 91 psychosis, 95 schizophrenia, 90–1 sedation, 89–90, 93–4 seizures, 93–4 sudden cardiac death, 93 tardive dyskinesia, 89–90 type 2 diabetes, 90 urinary retention, 99 weight gain, 90, 96–9 antiretroviral drugs see also individual names fever, 585 edema, 584–5 musculoskeletal changes, 585 syncope, 584 antithrombin III sepsis, 674 antithyroid drugs agranulocytosis, 884 alveolar hemorrhage, 885 anemia, 884

aplasia cutis and choanal atresia, 885 goiter, 885 Graves' disease, 884 hepatocellular inflammation, 885 purpura fulminans, 885 QT interval prolongation, 884 vasculitis, 885 antituberculosis drugs HIV co-infection, 626–7 Mycobacterium tuberculosis, 623, 624 appetite, drugs that suppress see also individual names apraclonidine lethargy, 982 reduced appetite, 982 topical allergy, 982 aprotinin acute myocardial infarction, 725 allergic reactions, 726 aminocaproic acid, 725 anaphylactic reactions, 726 atrial fibrillation, 725 blood transfusion, 725 cardiopulmonary bypass, 726 coronary artery bypass surgery, 725 death, 725 ejection fraction reduced, 726 heterogeneity, 725 neurological dysfunction, 725, 726 non-bypass surgery, 725 plasma concentrations, 724–5 postoperative cardiac, 725 postoperative renal failure, 725 renal function, 725 renal replacement therapy, 724–5 tranexamic acid, 725 argatroban epidural anesthesia, 717–18 portal vein thrombosis, 717–18 thrombocytopenia, 717–18 aripiprazole akathisia, 99–101 anxiety, 99–101 body weight changes, 99 cellulitis, 100–1 chest pain, 100–1 cocaine interaction, 102 depression, 99–100 extrapyramidal disorders, 99 fatigue, 100–1 flu-like symptoms, 101

Index of drugs headache, 101 hepatic impairment, 100–2 insomnia, 100–1 metamfetamine, interaction, 102 migraine, 100–1 nausea, 101 neuroleptic malignant syndrome, 101 prolactin concentration, 99 restlessness, 100–1 sedation, 101 sinusitis, 99–100 somnolence, 99–101 thrombosis, 100–1 tremor, 99 upper respiratory infection, 99–100 arsenic acute promyelocytic leukemia, 448 blindness, 449 intraocular pressure, 449 retinal damage, 449 systemic arsenic toxicity, 449 toothache, 449 arteether mania, 572 Artemisia vulgaris basal cell carcinoma, 993 artesunate amodiaquine, interaction, 572 artificial sweeteners endometrial cancer, 1011 gastric cancer, 1011 non-neoplastic diseases, 1011 pancreas and endometrium, 1011 pancreatic cancer, 1011 stomach cancer, 1011 urinary tract tumors, 1011 arylalkanoic acid derivatives bufexamac, 245 diclofenac, 245–6 flurbiprofen, 246 ibuprofen, 246 ketoprofen, 246 ketorolac, 246 loxoprofen, 246 ascorbic acid see vitamin C Asian ginseng see Panax ginseng aspart see insulins aspirin see acetylsalicylic acid atazanavir antifungal azoles, interaction, 594

1035 fosamprenavir, interaction, 594 nevirapine, interaction, 594 atenolol bradycardia, 397 sinus heart rate, 397 atomoxetine aggression, 7 agitation and suicidal ideation, 7 alcohol abuse and dependence, 7 bruxism, nocturnal, 7 methylphenidate, interactions, 7 mydriasis, 7 QT interval prolongation, 7 transient ischemic attack, 7 atorvastatin coronary heart disease, 926 DNA damage, 927 gastrointestinal, 926 hemorrhagic cystitis, 927 hepatitis, 926–7 istradefylline, inhibition, 927 myalgia, 926 vasculitis, 927 ATRA see tretinoin azasetron, 745 azaspirones, 71 azathioprine acute erythroleukemia, 828 anemia, 829 aplasia cutis congenita, 828 ascites, 827 Beau's lines, 827 cholestatic hepatitis, 827 Crohn's disease, 827 eryptosis, 827 fatigue, icterus, 827 hepatitis, 829 herpes flares, 827 Hodgkin's lymphoma, 828 hypersensitivity reaction, 829 inflammatory bowel disease, 829 leukopenia, 827 nausea and vomiting, 827 nodular malignant melanoma, 828 pancytopenia, 827 ribavirin, interactions, 829 squamous cell carcinoma, 827 thrombocytopenia, 829 azithromycin agranulocytosis, 523 alveolar hemorrhage, 522 exacerbation of myasthenia gravis, 522–3 myocarditis, 522 statins, interaction, 523

vanishing bile duct syndrome, 523 aztreonam cystic fibrosis, 495 hypersensitivity reaction, 495 B Bacille Calmette-Guérin (BCG) vaccine allergic reactions, 656 bladder calcification, 656 contact dermatitis, 656 contracted bladder, 656 cystitis, 656 epididymo-orchitis, 656 granulomatous prostatitis, 656 hematuria, 656 keloid, 656 lupus vulgaris, 656 lymphadenitis, 656 myelosuppression, 656 osteomyelitis, 656 psoriasis, 656 systemic reactions, 656 ulcerating vasculitis, 656 ureteral obstruction, 656 baclofen abdominal discomfort, 302–3 back pain due to worsening scoliosis, 302–3 constipation, 302–3 drooling and swallowing difficulties, 302–3 head balance, reduced, 302–3 increased tolerance of baclofen, 302–3 Mycobacterium fortuitum, 303 paralytic ileus, 303 transient drowsiness, 303 balsalazide bowel symptoms, 756 cardiac symptoms, 756 chest pain, 756 diarrhea and vomiting, 756–7 headache and abdominal pain, 756–7 ischemia or pericarditis, 756 myocarditis, 756 ulcerative colitis, 756 barium sulfate appendicitis, 967 breast lump, 967–8 ductal carcinoma, 967–8 lower quadrant pain, 967 upper gastrointestinal, 967 basiliximab non-cardiogenic pulmonary edema, 785 BCG vaccine see Bacille Calmette-Guérin (BCG) vaccine

Index of drugs

1036 benazepril see also angiotensin converting enzyme (ACE) inhibitors cholestasis, 418 benzalkonium compounds breathing and pain, 481 burning, 481 episodes of flushing, 481 itching, 481 red eyes, 481 benznidazole agranulocytosis, 649 anorexia, 649 chronic headache, 649 dermatitis, 649 digestive intolerance, 649 fatigue, 649 hepatitis, 649 insomnia, 649 lymphoma, 649 myalgia, 649 neutropenia, 649 polyneuritis, 649 thrombocytopenia, 649 benzocaine contact dermatitis, 290 methemoglobinemia, 289 benzodiazepine antagonists flumazenil, 79–82 benzodiazepine-like drugs see also individual names benzodiazepines delirium, 72 teratogenicity, 72 benzydamine (benzindamine) agitation, 249 convulsions, 249 dizziness, 249 hallucinations, 249 nausea, 249 vomiting, 249 benzylpiperazine seizures, increased frequency, 54–5 3-trifluoromethylphenyl piperazine, interaction, 55 bepridil interstitial pneumonia, 384 beta-adrenoceptor antagonists bradycardia, 983 discomfort, 983 erectile dysfunction, 397 eye discharge, 983 eye hyperemia, 983 eye irritation, 983 eye pruritus, 983 hypotension, 983 lid margin crusting, 983 sticky sensation, 983 betaxolol bradycardia and hypotension, 397–8

discomfort, 397–8 hyperemia, 397–8 irritation in the eyes, 397–8 bevacizumab breast cancer, 785 carcinoid tumors, 785–6 congestive heart failure, 786 corneal epithelial defects, 977 diarrhea, nausea, and vomiting, 786 fistulae, 786 glioblastoma, 785 high risk corneal transplantation, 785–6 hypertension, 786 infectious endophthalmitis, intraocular inflammation, 786 infusion/hypersensitivity reaction, 787 ischemic retinal diseases, 785–6 leukoencephalopathy syndrome, 786 pancreatic cancer, 785–6 postoperative bleeding or wound healing complications, 786–7 prostate cancer, 785–6 proteinuria, 786 sinusoidal obstruction syndrome, 786 systemic adverse reactions, 977 thromboembolic events, 786 bezafibrate coronary artery disease, 922 heart failure, 922 BG9588 lupus glomerulonephritis, 787 bicalutamide breast pain, 872 gynecomastia, 872 prostate cancer, 872 bimatoprost, 847 conjunctival hyperemia, 984 dermatochalasis involution, 984 lower eyelid fullness, loss, 984 periorbital fat atrophy, 984 relative enophthalmos, 984 upper eyelid sulcus, deepening, 984 bisacodyl abdominal cramps, 753 indigestion, 753–4 nausea and vomiting, 753 weakness and anal irritation, 753–4 bismuth acute confusion, 449

delusions and verbal aggression, 449 disorientation, 449 myoclonic jerks, 449 bismuth compounds black tongue, 752–3 bisoprolol FEV1, reduction, 398 bisphosphonates breast cancer, 1012 metadiaphysial femoral fractures, 1013 metastatic bone, 1012 multiple myeloma, 1012 non-neoplastic, 1012 non-oncological, 1011 osteonecrosis of jaw, 1011 Paget's disease, 1013–14 parathyroid hormone, 1013 tetracycline-labelled bone, 1013 tooth extraction, 1012 upper gastrointestinal, 1013–14 bittersweet see Tripterygium wilfordii Hook black cohosh see Actaea racemosa blood substitutes abdominal pain, 672, 673 blood pressure, increased, 673 diarrhea, 672, 673 fever, 672 flu-like symptoms, 673 hemoglobinuria, 672 hypotension, 673 increased mortality, 672 interference with laboratory assay, 672 jaundice, 672 myocardial infarction, 672 nausea, 673 oliguria, 672 pancreatitis, 673 pulmonary complications, 673 renal dysfunction, 672 stroke, 672, 673 thrombocytopenia, 673 vasoconstriction, 672, 673 vasopressor effects, 673 vomiting, 673 blood transfusion acute and delayed hemolytic transfusion reactions, 671 anaphylactic and other allergic reactions, 671 bacteremia, 671 febrile non-hemolytic transfusion reaction, 671 graft-versus-host disease (GvHD), 671

Index of drugs hemosiderosis, 671 hospitalization prolonged, 672 infection at any site, 672 intensive care treatment, 672 mechanical ventilation, 672 mortality increased, 672 multiorgan failure, 672 new allo-antibody formation, 671 pneumonia, postoperative, increased risk, 672 purpura, 671 transfusion-associated circulatory overload (TACO), 671 transfusion-associated sepsis (TAS), 671 transfusion-related acute lung injury (TRALI), 671 viral infections, 671 bosentan dyspnea, 422 edema, peripheral 422 headache, 422 hemoglobin, reduced, 422 hypersensitivity, delayed 422–3 liver enzymes, abnormal 422 nasopharyngitis, 422 nausea, 422 rash, 422 botulinum toxins anal fissure, 304 chronic pain, 304 muscle hypertrophy, 305 muscle weakness, 304–5 Parkinson's disease, 304 brachial plexus anesthesia Horner's syndrome, 283 motor block, 283 bran acute dysphagia, 754 esophageal obstruction, 754 retrosternal pain, 754 weight loss, 754 brindleberry see Garcinia gambogia bufexamac pigmented purpuric dermatosis, 245 bupivacaine cardiac arrest, 290 dysrhythmia, 290 buprenorphine constipation, 225 dizziness, 225 drug formulations, 226 drug overdose, 226–7 hepatitis, 225 mortality, 226 nausea, 225 during pregnancy, 226 sedation, 225

1037 sweating, 225 transdermal administration, 226 withdrawal symptoms, 226 bupropion (amfebutamone) see also antidepressant drugs angioedema and serum sickness-like reactions, 33 CYP2D6 metabolism, 33 seizures, 33 buspirone dizziness, 71 dry mouth, 71 flushing/sweating, 71 butorphanol dizziness, 227 drug withdrawal, 227 nausea, 227 sedation, 227 vomiting, 227 C caffeine hyperkinetic disorder risk, 11–2 lactic acidosis, 12 orofacial clefts, 12 calcitonin flushing and nausea, 909 local reactions, 909 calcium channel blockers see also individual names gingival enlargement, 401 calcium salts absorption of phosphate, 449 bloating and gas, 449 constipation, 449 myocardial infarction, 449 camphor bag-valve-mask ventilation, 334 cold, 334 seizures, 333–4 candesartan calvarial dysplasia, 419 hypoplasia, 419 renal dysplasia, 419 cannabinoids Aspergillus infection, 58 cerebellar-dependent learning, 56–7 cognitive function worsening, 57 depression, 741 dizziness, 55 dysphoria, 741 gray matter loss, 55 hallucinations, 741 hallucinations and dysphoria, 55 multiple sclerosis, 55

myocardial infarction, 56 nausea and vomiting, 741 paranoid delusions, 55, 741 periodontal disease, 57 steatosis, 57–8 captopril see also angiotensin converting enzyme (ACE) inhibitors contact dermatitis, 418 hyperkalemia, 418 carbamazepine see also antiepileptic drugs acute interstitial pneumonitis, 133 acute mania, 132–3 acute pulmonary failure, 135 adjunctive therapy, 132 anaplastic large cell lymphoma, 134 aripiprazole, interaction, 135 atrioventricular conduction defects, 133 bipolar disorder, 133–4 comparative efficacy, 132–3 corpus callosum lesion, 133 diplopia, 132 DRESS, 134 drug hypersensitivity syndrome, 134 erythema multiforme, 134–5 hyperammonemia, 133–4 hypertension, 132 hyponatremia, 132 leukoencephalopathy, 133 paracetamol, interaction, 135 rashes, 132 schizophrenia, 135 serum thyroxine, 133 Stevens–Johnson syndrome, 134 tachycardia, 134 tacrolimus, interaction, 135–6 toxic epidermal necrolysis, 134 valproate, 134–5 carbapenem audiogenic seizure, 491 compromised renal function and renal insufficiency, 492 doripenem, 492 epilepsy, 492 inhibitory neurotransmitter gama-aminobutyric acid (GABA), 491 meningitis, chronic or acute nervous system damage, 492 methotrexate, prior intrathecal therapy, 492

Index of drugs

1038 nervous system excitation and convulsions, 491 nervous system infection, 492 seizures, 491, 492 stroke, 492 theophylline, 492 valproate, 492 carbon dioxide abdominal aortic aneurysms, 971 renal function, 971 carbonic anhydrase inhibitors see also individual names cardiac glycosides see also individual names atrioventricular block, 377 bradydysrhythmias, 377 chronic heart failure, 377 hyperkalemia, 378 carp gallbladder acute renal failure, 998 nausea and epigastric pain, 999 carvedilol blood pressure, 398 Peyronie's disease, 398 caspofungin alkaline phosphatase increased, 557 aspartate aminotransferase increased, 557 hypersensitivity, immediate, 557 hypotension, 557 phlebitis, 557 voriconazole, interaction, 558 cat's claw see Uncaria tomentosa cefotaxime acute generalized exanthematous pustulosis (AGEP), 493 inspissated bile syndrome, 493 positive patch test, 493 ceftriaxone acute pancreatitis, 494 biliary pseudolithiasis, 494 calcium deposition, 494 cerebrovascular disease, 493 encephalopathy, 493 hemolytic anemia, 493–4 hyperbilirubinemia, 494 hypersensitivity, 494 Lyme disease, 494 neurological sequelae, 493–4 palmar pruritus, rashes, nausea, and abdominal cramp, 493 sickle cell disease, 493–4 urinary tract infection, 493

celecoxib anaphylaxis, 246 docetaxel, interaction, 247 drug overdose, 246–7 celiprolol wheeze, 398 Centoxin see HA-1A cephalosporins see also individual names hemolytic anemia, 493 cetirizine acute dystonia, 345 anaphylactic shock, 345 anaphylaxis, 345 chelators see also individual names contact eczema, 474 distal limb muscles, 474 electrophysiological test, 474 herpes simplex, 473 hypocalcemia, 474 hypocupremia, 474 pruritic rash on chest and back, 473 Stevens–Johnson syndrome, 473–4 Yersinia, 473 chiropractic therapy arterial dissection, myelopathy, vertebral disc extrusion, and epidural hematoma, 1000 chronic neck pain, 1000 quadriparesis, 1000 vertebrobasilar artery stroke, 1000 chloramphenicol hepatitis, 514 chlorhexidine bloodstream infection, 481 central venous catheters, 480–1 contact dermatitis, 481 dental plaque biofilms, 481 pneumonia, 480–1 skin allergy, 481 skin dryness, 481-2 Staphylococcus aureus, 481 chloroform carbon monoxide poisoning, 257 dysrhythmias, 257 hepatitis, 257 chloroquine and hydroxychloroquine depigmentation, 569 pigmentation of oral mucosa, 568 third-degree atrioventricular block, 568 ventricular fibrillation, 568 chlorphenamine

contact dermatitis, 346 generalized convulsion, 345–6 sedation, 345 cibenzoline chewing difficulty and dyspnea, 385 headache, dull 385 kidney disease, chronic 385 myasthenia, 385 ciclosporin bone pain, 816 digital fibrokeratoma, 816 gingival overgrowth, 815 hair, dark, 816 hemolytic–uremic syndrome, 816 hyperplasia, 817 hypertrichosis, 816 pancreatitis, 815–16 parkinsonism, 815 posterior reversible encephalopathy syndrome, 815 renal cysts, 816 renal failure, 817 rhabdomyolysis, 817 serotonin syndrome, 817 cidofovir dysplasia, 577 cilomilast exacerbation of COPD, 367–8 cilostazol glycyrrhetic acid, 407–8 spinal epidural hematoma, 407 thrombosis, 407 cimetidine hemolytic anemia, 748 Cimicifuga racemosa see Actaea racemosa ciprofloxacin Achilles' tendinitis, 515 Achilles' tendon rupture, 515 acute generalized exanthematous pustulosis (AGEP), 515 clozapine, interaction, 516 hemibalismus, 515 hemolytic anemia, 515 hemorrhagic vasculitis, 515 hepatitis, cholestatic, 515 myalgia, 515 serotonin syndrome, 516 simvastatin toxicity, 516 Stevens–Johnson syndrome, 515 thrombocytopenia, 515 torsade de pointes, 514–15 tuberculosis, 627–8 urinary tract infection, 515

Index of drugs cisapride ventricular dysrhythmias, 741–2 citalopram and escitalopram herpes zoster infection, 29 propafenone interactions, 29–30 seizures, 29 torsade de pointes, 29 ci wu jia injection allergic skin reactions, 991 vertigo, 991 clarithromycin anaphylactic reaction, 524 cholestatic hepatitis, 524 chronic coronary artery disease, 523–4 colchicine, interaction, 524 Hoigné syndrome, 524 mania, 523 rhabdomyolysis, 524 visual hallucinations, 523 clebopride hemifacial dystonia, 742 ischemic attack, 742 clavulanic acid see co-amoxiclav clenbuterol adulteration, 53 blood and urine symptoms, 323 chest pain, 323 dyspnea, 323 hyperglycemia, 323 hypokalemia, 323 nausea, 323 palpitation, 323 tachycardia and hypotension, 323 tremor, 323 clindamycin allergic rash, 522 cytolytic hepatitis, 522 diarrhea, 522 clobazam Stevens–Johnson syndrome, 72 clomifene breast cancer, 861 clonazepam drug abuse, 73 hair loss, 73 malignant catatonia, 73 psychomotor performance impairment, 72 clonidine escitalopram, interaction, 424 fever, 424 hypotension, 424 clopidogrel acute coronary syndromes, 722 allergic reactions, 724

1039 antiplatelet, 723 bleeding, 720–1 carotid artery stenting, 724 cholestatic liver damage, 721 coronary artery disease, 721, 722 death, 723 fixed drug eruption, 721 gastrointestinal bleeding, 721 head trauma, 720 hemothorax, 722 liver damage, 721 myocardial infarction, 721–2 pancytopenia, 721 peripheral, 724 pharmacodynamic interaction, 723–4 plasma concentrations, 722 platelet inhibition, 722 platelet transfusions, 720–1 prasugrel, 723 proton pump inhibitors, 723 psychomotor performance, 720 pulmonary hemorrhage, 722 ranitidine, 723 revascularization, 723 smoking, 723–4 ticlopidine allergy, 724 clozapine agranulocytosis, 103 benzodiazepines, interactions, 103 and haloperidol, 102–3 leukopenia, 103 neutropenia, 103 and olanzapine, 102 venous thromboembolism, 103 coal tar skin-to-skin and skin-tomouth contact, 334 co-amoxiclav and clavulanic acid acute generalized exanthematous pustulosis and contact dermatitis, 496 fixed drug eruption, 496 linear IgA bullous eruption, 496 psychosis, 496 urticaria and angioedema, 496 cobalamins (vitamin B12) blood pressure, 693 movement disorders, 693 tremor and myoclonus, 693 cobalt aseptic lymphocytedominated vasculitisassociated lesion (ALVAL), 450 groin pain, 450

cocaine aortic dissection, 58 cerebral blood flow, 61 exogenous lipoid pneumonia, 59 fetotoxicity, 60–1 fibromuscular dysplasia, 61 lung cavitation, 59 myocardial infarction, 58 osteonecrosis, 60 panhypopituitarism, 60 peripheral vasospasm, 59 pleural empyema, 59 pneumothorax, 59 vasculitides and purpura, 60 codeine, 209-10 colchicine, 250 colistin Acinetobacter infection, 528 nephrotoxicity, 527–8 neurotoxicity, 528 Commiphora molmol see myrrh complementary and alternative medicine adverse reactions, 989 C1 esterase inhibitor concentrate abdominal pain, 674 anaphylactic reactions, 674 chills, 674 diarrhea, 674 dizziness, 674 dry mouth, 674 fever, 674 headache, 674 influenza-like symptoms, 674 infusion-related reactions, 674 injection-site redness, 674 muscle spasms, 674 nausea, 674 conivaptan see vasopressin receptor antagonists copper ovarian penetration, 450 Wilson's disease, 450 co-trimoxazole see trimethoprim coumarin anticoagulants see also individual names acute kidney damage, 708 acute tubular damage, 708 allergic reactions, 713 atrial fibrillation, 707–8, 709 bleeding, 707 bone mineral density, reduction, 708–9 calciphylaxis, 707 carbamazepine, 712 cardiac, 711–2 cerebral hemorrhage, 711

Index of drugs

1040 cerebral microbleeds, 707–8 chest pain, 713 chronic giant coronary aneurysm, 708 chronic kidney damage, 708 coagulopathy, 713 coronary artery calcification, 707 cutaneous ischemia, 707 cytochrome P450 (CYP), 712 deep vein thrombosis, 713 endothelial cell damage, 708 folate status, 708 gastrointestinal bleeding, 710 hemoptysis, 707 hepatic, 712 hypertension, 707–8 hyphema, 708 influenza, 711 intracerebral hemorrhage, 707–8 life-threatening bleeding, 713 liver disease, 708 lung cancer, 711 mitral and aortic valve calcification, 707 myocardial, infarction, 713 myocardial ischemia, 708 optic nerve dysfunction, 709 pancreatic cancer, 711 paracetamol interaction, 711 photodynamic therapy, 713 prothrombin, 713 prothrombin time, increased, 708 proton pump inhibitors, 711–2 rebound coagulation, 708 renal dysfunction, 710 retroperitoneal hematoma, 711 serum troponin, 713 skin necrosis, 708 SSRIs, 712 subconjunctival hemorrhage, 708 suprachoroidal hemorrhage, 713 tamoxifen, 712 thromboembolism, 713 trauma, 711 upper airway obstruction, 707 ventricular fibrillation, 713 COX-2 selective inhibitors see also individual names cranberry see Vaccinium macrocarpon Crataegus orientalis acute renal failure, 993 acute tubulointerstitial nephritis, 993 epistaxis, 993

cyanoacrylates abdominal compartment syndrome, 1014 acute hepatic failure, 1015 acute infarction, 1014 anticoagulant therapy, 1015 antithrombin therapy, 1015 aorta and iliac arteries, 1015 bradycardia, 1014 brain abscesses, 1015 dual antiplatelet therapy, 1015 embolism, 1014 epigastric pain, 1014 esophageal ulceration, 1014 fever, 1015 gastrointestinal bleeding, 1014 hemorrhage, 1014 hepatic artery, 1014 hepatocellular carcinoma, 1014 hypertrophic scars, 1015 intestinal ischemia, 1014 ischemic stricture, 1015 pulmonary embolus, 1014 rhinoconjunctivitis and asthma, 1015 septicemia, 1015 tracheal and bronchial obstruction, 1015 variceal bleeding, 1014 cyclobenzaprine serotonin syndrome, 305 torticollis, 305 cycloserine asterixis, 630 hypersomnolence, 630 Cynomorium songaricum acute renal insufficiency, 993–4 nausea and vomiting, 994 cyproterone acetate abdominal pain, nausea, vomiting, 872 facial flushing, sweating, 872 serotonin syndrome, 872–3 cysteamine drug-induced lupus, 761 D dabigatran atorvastatin, 718 enoxaparin, 718 liver disease, 718 thrombin time, 718 thrombocytopenia, 718 thromboplastin time, 718 daclizumab fatigue and muscle aches, 788 lymphopenia and generalized lymphadenopathy, 787–8 rash, 788

DAMB see amphotericin B deoxycholate danaparoid sodium eczema, 716 glucocorticoids, 716 hypersensitivity, delayed-type, 716 neonatal death, 717 orthopedic surgery, 716 skin lesions, 716 thromboembolism, 717 thrombophilia, 717 thrombosis, 716 danazol angioedema, 868 lovastatin, interaction, 868 myopathy and pancreatitis, 868 dantrolene sodium acneiform eruption, 305 dapsone agranulocytosis, 630, 631 aplastic anemia, 630 cimetidine, interaction, 631 complete atrioventricular block, 630 darbepoetin alfa, interaction, 632 dermatitis herpetiformis, 630 hemolytic anemia, 630–2 methemoglobinemia, 630, 632 photosensitivity, 632 platelet count, increased, 630 pure red cell aplasia, 630 sulfhemoglobinemia, 630 sulfone syndrome (dapsone syndrome), 633 daptomycin eosinophilic pneumonia, 529 rhabdomyolysis, 530 darbepoetin alfa congestive heart failure, 682 dysrhythmias, 682 embolism/thrombosis, 682 hypertension, 682 myalgia, 682 myocardial infarction/ coronary artery disorders, 682 rash, 682 seizures, 682 strokes, 682 darunavir amylase activity, 594–5 atazanavir, interaction, 595 blood glucose, 594 diarrhea, 594 etravirine, interaction, 595 low density lipoprotein, 594 nasopharyngitis, 594 nausea, 594

Index of drugs neutropenia, 594 nevirapine, interaction, 595 oral contraceptives, interaction, 595 pancreatic lipase, 594 raised aminotransferase, 594 rashes, 594 saquinavir, interaction, 595 total cholesterol, 594 triglycerides, raised, 594 Datura stramonium anticholinergic effects, 994 confusion, 994 dilated pupils, 994 dry mouth, 994 urinary retention, 994 deferasirox agranulocytosis, 497 blood dyscrasias, 467 Fanconi syndrome, 468 gastrointestinal hemorrhage, 467 hepatic failure, 467 hungry bone syndrome, 468 hypocalcemia, 468 impaired renal function, 468 interstitial nephritis and renal failure, 468 lenticular opacities, 467 mucormycosis, 468 neutropenia, 467 obstructive jaundice, 467 renal impairment and failure, 468 symptomatic hypocalcemia, 467 thrombocytopenia, 467 deferiprone agranulocytosis, 469 arthritis, 469, 470 arthropathy, 470 axial hypotonia, 470 cardiotoxicity, 469 cerebellar syndrome, 470 dilated hypokinetic cardiomyopathy, 469 dizziness, 470 heart failure, 469 hydroxyl radicals, 468–9 neurological reactions, 470 nystagmus and diplopia, 470 reactive oxygen species, 468–9 sideroblastic anemia, 469 deferoxamine bone dysplasia, 471 central blurring, 471 reduced central response on electroretinography, 471 retinal damage, 471 retinal pigmentary changes, 471

1041 sensorineural hearing loss, 471 dental anesthesia multiple sclerosis, precipitation, 287 desferrioxamine see deferoxamine desloratadine fixed drug eruption, 346 oral ulceration, 346 pruritic lesions, 346 desmopressin hyponatremia, 916 seizures, 916 thrombosis, 916 desvenlafaxine see venlafaxine and serotonin and noradrenaline re-uptake inhibitors (SNRIs) detemir see insulins dexlansoprazole adenocarcinomas, 750 diarrhea, 750 flatulence, bloating, and distension, 750 gastrointestinal and abdominal pain, 750 hyperplasia, 750 respiratory tract infection, 750 dextrans hypersensitivity reactions, 675 dextromethorphan agitation, 210 nausea, 210 paranoia, 210 psychosis, 210 vomiting, 210 dextropropoxyphene, 210 diacerein (diacetylrhein) soft stools, 249 yellow discoloration of the urine, 249 diamorphine (heroin) drug overdose, 211 hallucinations, 211 myocarditis, 210–1 respiratory depression, 211 rhabdomyolysis, 211 seizures, 211 spongiform leukoencephalopathy, 211 diarylquinoline tuberculosis, 625–6 diazepam drug resistance, 73 transient pain, 73 watery eyes, 73 diazoxide heart failure, 427–8

neutropenia, 427–8 pulmonary hypertension, 427–8 diclofenac allergic contact dermatitis, 245 aminotransferases, rises, 245 anastomotic leakage, 245 gastrointestinal bleeding, 246 Kounis syndrome, 245 photoallergic contact dermatitis, 245 didanosine non-cirrhotic portal hypertension, 587 diethylstilbestrol acute monocytic leukemia, 852–3 adenocarcinoma of the ovary, 852 breast cancer, 853 cryptorchidism, 852 inflammation/infection of the prostate, 852 inflammation/infection of the testicles, 852 dihydrocodeine convulsions, 211 dimethylfumarate contact dermatitis, 336 dimethylhydralazine see hydralazine dimethylsulfoxide (DMSO) 1015–16 dipeptidyl peptidase 4 (DDP4) inhibitors see also individual names headache, 894 nasopharyngitis, 420 upper respiratory tract infection, 895 urinary tract infection, 895 diphenhydramine allergic contact dermatitis, 346–7 blood pressure fall, 347 cardiogenic shock, 347 death, 347 dry skin, 347 manifestation of coma, 347 metabolic acidosis, 347 muscle tone, 347 pulmonary edema, 347 status epilepticus, 347 dipyridamole asystole, 719 atrial fibrillation, 719 cardiac enzymes, 719 chest discomfort, 719 dizziness, 719 headache, 719 loss of consciousness, 719 myocardial infarction, 719

Index of drugs

1042 nausea, 719 non-smoking, 719 theophylline, 719 transient ischemic attacks, 719 disopyramide myasthenia gravis, 385 disulfiram alcohol, 1016 colchicine intoxication, 1014 lancinating pain, 1016 myocardial infarction, 1014 paresthesia of distal limbs, 1016 peripheral neuropathy, 1014 punding, 1016 dobutamine chest pain, 319 compelete heart block, 319 coronary artery spasm, 319 empty ventricle syndrome, 319–20 heart block, 319 myocardial infarction, 319 serpentine tongue, 320 splenic artery aneurysm, reputure, 320 transient global amnesia, 320 docetaxel adverse reactions, 946 anemia, 947 arthralgia and myalgia, 947 bronchospasm, 948 cardiotoxicity, 948 colon ulceration, 947 cytotoxic effect, 945–6 epiphora, 946 erythema, 947 fluid retention, 946–7 flushing, 948 gastric adenocarcinoma, 945 generalized rash/erythema, 948 hair loss, 947 localized cutaneous reactions, 948 lymphopenia, 947 metastatic breast cancer, 945 muscle weakness, 946 nausea/vomiting, diarrhea, and mucositis, 947 neutropenia, 947 neutropenic enterocolitis, 947 non-neutropenic colitis and ischemic colitis, 947 non-small-cell lung cancer, 945, 947 onycholysis, 947 palmar–plantar erythrodysesthesia syndrome, 947 peripheral neuropathy, 946

pneumonitis, 946 prostate cancer, 947 pruritus, 947 recall dermatitis, 947 reduce fluid retention, 945 renal excretion, 946 severe hypotension, 948 squamous cell carcinoma, 945 subungual hemorrhages and subungual abscesses, 947 docosahexaenoic acid (DHA) paclitaxel constipation, 945 diarrhea, 945 esophagogastric cancer, 944–5 fatigue, 945 metastatic melanoma, 944–5 nausea, 945 neutropenia and hyperbilirubinemia, 945 non-small-cell lung cancer, 944–5 peripheral edema, 945 peripheral neuropathy, 945 rashes, 945 dofetilide heart failure, 386 torsade de pointes, 385 dolasetron see neurokinin NK1 receptor antagonists domperidone diabetic gastroparesis, 742 gastroesophageal reflux, 742 hyperprolactinemia, 742 QT interval prolongation, 742 donepezil anemia, 15 delusions, 15 dizziness, 15 gait disorder, 15 headache, 15–16 insomnia, 15 dopamine fibrotic heart valve disease, 321 panic attacks and pramipexole, 322 Parkinson's disease, 321 restless legs syndrome, 322 sleep attacks, 322 syncope, 321 tachypnea, 322 dorzolamide bevacizumab interaction, 438 choroidal detachment, 438 doxazosin retrograde ejaculation, 426 doxycycline DRESS, 499

hepatitis, 499 Jarisch–Herxheimer reaction, 499 malaria prophylaxis, 499 pancreatitis, 499 Sweet's syndrome, 499 tachycardia, tachypnea, hypoxia, hypotension, 499 drospirenone see hormonal contraceptives drotrecogin alfa bleeding complication, 671 heparin, interaction, 671 duloxetine binge eating, 31 dry mouth, 31 encephalastrapy, 31 hyponatremia, 31 nausea, 31 sexual desire, increased, 31 suicide, 31 tachycardia, 31 warfarin interaction, 32 E Ecbalium elaterium headache, 994 nasal septum perforation, 994 shortness of breath, 994 sore throat, 994 ecstasy anaphylactic reaction, 64 angle closure, 62 cardiac valvular disease, 62 cognitive function and impulsivity, 63–4 prospective memory, 63 sex differences, 64 working memory, 63 edrecolomab breathing disorders, 788 colon cancer, 788 diarrhea and nausea, 788 fever, 788 flushing, 788 hypotension, 788 efalizumab angioedema, 789 familial benign chronic pemphigus, 788–9 lymphomatoid papulosis, 789 lymphoproliferative disorders, 789 progressive multifocal leukoencephalopathy, 788 seborrheic keratoses, 789 thrombocytopenia, 788 thrombocytosis, 788 urticaria, 789 efavirenz antifungal azoles, interaction, 592

Index of drugs antimalarial drugs, interaction, 592 dizziness, 590 Ginkgo biloba, interaction, 592 hallucinations, 590 hangover, 590 hepatic encephalopathy, 590 impaired concentration, 590 limb fat, increased, 582–3 nocturnal sweating, 590 osteomalacia, 591 status epilepticus, 590 eflornithine confusion, 574 fever, 574 infections, 574 seizures, 574 Trypanosoma brucei gambiense, 574 emergency contraception dysuria, 859 toxic epidermal necrolysis, 859 EMLA see prilocaine enalapril see also angiotensin converting enzyme (ACE) inhibitors pseudopolymyalgia, 418 endoperoxides see also individual names bradycardia, 571 liver enzymes, raised, 571 neutropenia, 571 QT interval, 571 reticulocytopenia, 571 enfuvirtide depression, 598 diarrhea, 598 eosinophilia, 598 hypersensitivity reactions, 598 injection site reactions, 598 nausea, 598 niacin, interaction, 598–9 tipranavir and ritonavir, interaction, 599 entecavir eosinophilia, 579 lactic acidosis, 579 leukocytosis, 579 enteral nutrition abdominal pain, 700 allergic skin reaction, 701 diabetes mellitus, 701 esophageal carcinoma, 700 organ failure, 701 pancreatic infections, 701 refeeding syndrome, 700 respiratory failure, 700 serum potassium, 700

1043 Ephedra and ephedrine anencephaly, 317–18 aortic stenosis, 317–18 weight loss, 317–18 epinephrine see adrenaline epidural anesthesia hiccups, 284 Horner's syndrome, 283–4 leg pain, 284 epoetin alfa see also erythropoietin and derivatives back pain, 682 bone pain, 682 chest pressure sensation, 682 common cold, 682 deep vein thrombosis, 682 diarrhea, 682 dizziness, 682 headache, 682 injection-site pain, 682 leg pain, 682 nausea, 682 pain, 682 polycythemia, 682 stomach pains, 682 tiredness, 682 epoetin beta see also erythropoietin and derivatives dry mucosa, 682 dry skin, 682 fatigue, 682 headache, 682 liver enzymes, raised, 682 muscle pain, 682 thrombovascular events, 682 epoetin delta see also erythropoietin and derivatives hypertension, 682 peripheral vascular disease, 682 serum creatinine, increased, 682 epoprostenol headache, 847 hypertension, 847 thrombocytopenia, 847 epothilones apoptosis, 948 mitotic arrest, 948 eptifibatide see glycoprotein IIb–IIIa inhibitors equine estrogens, 853 ertapenem antiepileptic drugs, 492 nervous system disorder, 492 renal insufficiency, 492 erythromycin biliary colic, 523

gastrointestinal symptoms, 523 erythropoietin and derivatives see also epoetin alfa, epoetin beta, and epoetin delta back pain, 682 bone pain, 682 chest pressure sensation, 682 common cold, 682 congestive heart failure, 682 deep vein thrombosis, 682 diarrhea, 682 dizziness, 682 dry mucosa, 682 dry skin, 682 dysrhythmias, 682 embolism/thrombosis, 682 fatigue, 682 headache, 682 hypertension, 682 injection-site pain, 682 leg pain, 682 liver enzymes, raised, 682 muscle pain, 682 myalgia, 682 myocardial infarction/ coronary artery disorders, 682 nausea, 682 pain, 682 peripheral vascular disease, 682 polycythemia, 682 pruritic rash, 682 rash, 682 seizures, 682 serum creatinine, increased, 682 stomach pains, 682 strokes, 682 thrombovascular events, 682 tiredness, 682 escitalopram see citalopram esmolol bradycardia, 398 hypokalemia, 398 hypotension, 398 injection site reactions, 398 metabolic acidosis, 398 postoperative agitation, 398 postoperative anemia, 398 postoperative pain, 398 systolic blood pressure, 398 wheezing, 398 esomeprazole see omeprazole estrogens angioedema, 852 melanoma, 852 etanercept angiokeratomata, 781 Crohn's disease, 781

Index of drugs

1044 non-specific inflammatory bowel disease, 781 varicella zoster, 782 ethambutol bilateral temporal hemianopia, 634 central/centrocecal scotomas, 634 drug-resistant tuberculosis, 627 liver toxicity, 627 Mycobacterium aviumintracellulare infection, 634 reduced visual acuity, 634 tuberculosis, 627–8 etherified starches anaphylaxis, 675–6 coagulopathy, 675–6 excessive intravascular volume expansion, 675–6 hepatic dysfunction, 675–6 metabolic acidosis, 675–6 renal dysfunction, 675–6 ethosuximide see also antiepileptic drugs behavioral changes, 136 loss of appetite, 136 sleep disturbance, 136 somnolence, 136 systemic lupus erythematosus, 136 vomiting, 136 etofenamate, 245 etomidate adrenal insufficiency, 262–3 adrenal suppression, 263 etravirine darunavir and ritonavir, interaction, 592–3 hypercholesterolemia, 592 nausea, 592 rash, 592 vomiting, 592 everolimus aspergillosis, invasive, 817–18 pneumonitis, 817 serum triglycerides, 817 exemestane arthralgias, hot flushes, 861 bone mineral density, 862 cholestatic hepatitis, 861 fatigue, jaundice, and pruritus, 861 myalgia, 861 vaginal dryness, 861 exenatide acute pancreatitis, 896 impaired renal function, 864 Exilis see Garcinia gambogia

extrapleural anesthesia Horner's syndrome, 287 ezetimibe cancers, 922 carotid intima-media thickness (CIMT), 921 coronary heart disease, 921 myopathy, 921–2 F factor VIIa (coagulation proteins) thrombosis, 679 factor VIII (coagulation proteins) allergic reactions, 679–80 factor IX (coagulation proteins) allergic reactions, 680 edema, 680 hypoalbuminemia, 680 nephritic syndrome, 680 proteinuria, 680 famotidine acute hepatitis, 748 febuxostat diarrhea, 250 dizziness, 250 fenfluramine thrombocytopenia, 6 valvular disease, 6 fenofibrate liver transaminases, raised, 923 myopathy, 923 fentanyl adrenal insufficiency, 212 bradycardia, 212 bradykinesia and rigidity, 212 bronchospasm, 212–13 cough, 212 erythema, 212–13 hypotension, 212–13 and ketamine, 213 muscle rigidity, 212 nebulizer administration, 213 paroxetine interaction, 213 and propofol, 213–14 ropivacaine interaction, 213 transdermal administration, 213 fibrates albuminuria, increased, 922 diabetes, 922 homocysteine and creatinine concentrations, raised, 922 pancreatitis, 922 pulmonary thromboembolism, 922 fibrin glue anaphylactic reactions, 674–5 coagulopathy, 674–5

immunological sequelae, 674–5 thrombosis, 674–5 filgrastim abdominal aortitis, 770 allergy, anorexia, chills, fever, 769 citrate toxicity, 769 enhanced leukemic transformation, 770 local reactions, rashes, pain, and infections, 769 nausea, vomiting, flu-like symptoms, 769 sickle cell disease, 770 sweats, fatigue, headache, myalgia, 769 finasteride azoospermia, 873 erythema, 873 fixed drug eruption, 873 hair loss, 873 myalgia, 873 oligospermia, 873 fish oils cardiac death, 923 ventricular tachycardia, 923 flecainide Brugada syndrome, 387 chest discomfort, 387 fixed drug eruption, 387 hyponatremia, 387 flucloxacillin acute interstitial nephritis, 497 cholestatic hepatitis, 497 fluconazole allergy, 551 congenital malformation, 551–2 liver function tests, abnormal, 551 QT interval prolongation, 551 sclerosing lymphangitis, 551 flucytosine anemia, 559 flumazenil adrenocorticotrophic responses, reduced, 81 ballismus, 81 depressive mood, 80 drug overdose, 82 drug withdrawal, 81 dysrhythmias, 81 heart block, 81 myoclonic-like movements, 81 nausea, 80 opisthotonos, 81 psychosis, 81 seizures, 81 shivering, 80 ventricular fibrillation, 80–1

Index of drugs ventricular tachycardia, 80–1 vomiting, 80 flunitrazepam acute ischemia, 73–4 road traffic accidents, 74 fluorescein empty sella syndrome, 1016–17 status epilepticus, 1016–7 fluoride brisk deep tendon reflexes, 1017 high cervical myelopathy, 1017 ligamentum flavum, 1017 overactive urinary bladder, 1017 skeletal fluorosis, 1017 symmetrical weakness, 1017 fluoroquinolones arthropathy, 514 diplopia, 514 tendinitis, 514 tuberculosis, 624–5 flupirtine, 249 flurazepam, 74 flurbiprofen fixed drug eruption, 246 flutamide hepatotoxicity, 873 hirsutism, 873–4 folic acid asthma, increased risk, 693 dyspnea, 693 generalized urticaria, 693 hypersusceptibility reactions, 693 lower respiratory tract infections, 693 methotrexate reaction, 693 red pruriginous macules, 693 wheezing, 693 fondaparinux bleeding, 718 death, 718 venous thromboembolism, 718 formaldehyde brain tumors, 480 leukemia, 479–80 lymphohemopoietic malignancies, 480 nasopharyngeal cancer, 479–80 sinonasal cancer, 479–80 formoterol asthma exacerbations, 360–1 cardiac mortality, 360 fosphenytoin see phenytoin fumaric acid esters psoriasis, 337

1045 squamous cell carcinoma, 337 furosemide bronchopulmonary dysplasia, 440 bullous pemphigoid, 440 hypersensitivity, 441 hyperthermia, 440 nephrocalcinosis, 440 reduced radioiodine excretion, 440 respiratory distress syndrome, 440 urticaria, 440 fusidic acid urticaria, 530 G gabapentin see also antiepileptic drugs alopecia, 138 androgen deprivation therapy program, 136–7 chemotherapy-induced neuropathic pain, 136 chorea, 137 clonazepam, 137 delirium, 138 delirium tremens, 136 diabetic neuropathy, 138 diabetic polyneuropathy, 136 dry mouth, 136 encephalopathy, 137 fatigue/somnolence, 137 fever, 137 fixed drug eruption, 137–8 hearing loss, 137 imbalance and dizziness, 137 lorazepam, 136 loss of appetite and constipation, 136–7 monotherapy, 136 myoclonus, 137 myoglobinuria, 138 myopathy, 138 nausea, 138–9 nortriptyline, 136 Parkinson's disease, 137 post-herpetic neuralgia, 136 pruritus, 136 psychomotor retardation, vertigo and sedation, 138–9 renal disease, 137, 138 rhabdomyolysis, 138 sedation, 136 seizure, 136 syncope, 136 tremulousness and dizziness, 137 urticaria, 136, 138 gadolinium salts

anaphylactic reactions, cellulitis, or vascular complications, 968 anaphylactic shock, 968–9 contrast media, 968 diabetes mellitus, 969–70 electrocardiographic changes, 968 fever, chills, and nausea, 970 hepatocytes, 968 hypertension, 969–70 myocardial infarction, 968 nephrogenic systemic fibrosis, 969 non-proprietary names, 968, 968 renal insufficiency, 969–70 skin reactions, 970 systemic fibrosis, 969, 969, 970 gamboge see Garcinia gambogia gamma-hydroxybutyric acid (GHB) confusion, 64–5 drug abuse, 65 drug overdose, 65 euphoria, 64–5 fixed, dilated, asymmetric pupils, 65 sedation and dizziness, 64–5 somnolence, 64–5 garlic see Allium sativum gemfibrozil hypertriglyceridemia, 923 myositis, 923 paroxysmal atrial fibrillation, 923 seizures, 923 gemifloxacin probenecid, interaction, 516 prodromal convulsive episode, 516 gemtuzumab ozogamicin bone marrow suppression, 789–90 chills fever, and low blood pressure, 789–90 liver problems, 789–90 gentamicin Bartter-like syndrome, 511 endotoxin-like reaction, 512 macular infarction, 510 nephrotoxicity, 511–2 pruritic eczematous rash, 512 Staphylococcus aureus, 511 vestibular function, 511 geraniol allergic contact dermatitis, 336–7 leg ulcers, 336–7

Index of drugs

1046 Ginkgo biloba dementia, 995 hemostasis, 995 virological failure, 995 glargine see insulins glibenclamide gastrointestinal cancer, 898 macrosomia, 898 gliclazide hypogycemia, 898 glimepiride asthma, 898 glucagon hepatic artery vasospasm, 889 paralysis, 889 short bowel syndrome, 889 glucocorticosteroids see also individual names Achilles' tendinitis, 355 acne, 841 adrenal suppression/ insufficiency, 355, 843, 983 anaphylaxis, 845 Aspergillus infection, 845 asthma, 355, 842, 845 bone mineral accretion, 356 bone mineral density, 356 bowel disease, 844 cataract, 355, 842 chorioretinopathy, 983–4 Cladophialophora bantiana, 845 Crohn's disease, 841 cytomegalovirus esophagitis, 845 death, 353, 354 emotional disturbances, 842–3 fracture risk, 356 hypokalemia, 842 hypokalemic periodic paralysis, 842 intraocular pressure, increased, 983 Kienböck disease, 843 leukemia, 842 lichen planus, 843 moon face, 841 muscle weakness, 842 nephrotic syndrome, 842 oropharyngeal candidiasis, 354 osteonecrosis, 843 osteoporosis, 356, 844 paraparesis, 841–2 pharyngitis, 354 psoriasis, 843 psychiatric effects, 842 retinal vein occlusion, 983–4 rheumatic disease, 842 skin bruising, 354 Strongyloides stercoralis, 845

throat irritation/soreness, 354 ventricular tachycardia, 841 viral infections, 841 visual loss, 842 voice, weakness/hoarseness, 354 glutaral (glutaraldehyde) abdominal pain, 480 bloody diarrhea, 480 deep ulceration, 480 iliac fossa, 480 ischemic colitis, 480 necrosis, 480 patchy erythema, 480 rectal bleeding, rectocolitis, 480 glycols acidosis and hyperosmolality, 1018 anion gap metabolic acidosis, 1018 benzyl alcohol and propylene glycol, 1017–8 intravenous lorazepam, 1018 status epilepticus, 1018 glycopeptides see also individual names all-cause mortality, 519 DRESS, 519 fever and rash, 519 neutropenia, 519 glycoprotein IIb–IIIa inhibitors see also individual names blood pressure, 720 bloody pericardial effusion, 720 chest discomfort and dyspnea, 720 coronary intervention, 720 hemorrhagic pericarditis, 720 myocardial infarction, 720 phlebitis, 720 thrombocytopenia, 720 gold and gold salts auranocyanide anion, 451 rheumatoid arthritis, 451 gonadotropin cryptorchidism, 851 hemiparesis, 851 morbidity, 851 mortality, 851 ovarian hyperstimulation, severe, 851 stroke, 851 gonadotropins (gonadorelin, GnRH, and analogues) anaphylaxis, 909 bone mineral density, 910 chorea, 909

flushing, 910 headache and hot flushes, 909 infertility, 910 injection site reactions, 910 ovarian hyperstimulation syndrome, 909 prostate cancer, 909 sweating, 910 granisetron see neurokinin NK1 receptor antagonists granulocyte colony-stimulating factor (G-CSF) acute myocardial infarction, 769 non-Hodgkin's lymphoma, 769 green tea see Camellia sinensis growth hormone receptor antagonists liver enzymes, increased, 911–2 pituitary gigantism, 912 pituitary volume, increased, 912 H HA-1A (Centoxin) sepsis, 790 hair dyes basal cell carcinoma, 336 halothane hepatitis, 257 henna contact allergy, 336 contact leukoderma, 336 hypertrichosis, 336 immediate hypersensitivity reactions, 336 heparins see also individual names allergy, 716 anaphylaxis, 716 angioedema, 716 arterial thrombosis, 715–6 bone mineral density, 715 bullous hemorrhagic dermatosis, 715 cardiac, 714 cerebral venous thrombosis, 714 certoparin, 715 death/myocardial infarction, 714–5 dermis and hypodermis, 715 enoxaparin, 715–6 epistaxis, 715–6 flushing, 716 fracture, 715 hemodialysis, 716

Index of drugs hemorrhagic complications, 715–6 hyperkalemia, 713 hypersensitivity reactions, 715, 716 hypotension, 716 immunoglobulins, 714 myocardial infarction, 714 osteoporosis, 715 pathological fractures, 715–6 phospholipid antibody syndrome, 714 plasma, 716 plasmapheresis, 715 platelet, 714 pulmonary embolism, 714–5 recall urticaria, 715 renal failure, 715 serum potassium, 713 skin lesions, 714 skin necrosis, 715 spontaneous, 714 subcutaneous calcinosis, 715 systemic lupus erythematosus, 714 thrombocytopenia, 714 thromboembolic events, 714 thrombophilia, 715 thrombotic complications, 714 wheezing, 716 hepatitis B vaccine systemic lupus erythematosus, 657 Herba cynomorii see Cynomorium songaricum heroin see diamorphine HIV, drugs active against see antiretroviral drugs HMG-CoA reductase inhibitors see also individual names cancers, risk, 926 diabetes mellitus, 924 liver and muscle enzymes, rises, 924 myalgia, 924 myopathy, 924 proteinuria, 925 renal insufficiency/failure, 924, 925–6 retinopathy, 924 rhabdomyolysis, 925 serum creatinine concentration rise, 925 honey see Rhododendron hormonal contraceptives acne, 858 hair loss, 858 mood swings, 858–9 nervousness, 858–9 thromboembolism, 858

1047 warfarin, interactions, 859 weight gain, 858–9 hormone replacement therapy (HRT) beneign proliferative epithelial disorders, 855 breast cancer, 853 cognitive impairment, 854 coronary heart disease, 853 endometrial cancer, 856 gastroesophageal reflux, 855 HIV infection, 857 hyperplasia, 854 ischemic colitis, 855 myocardial infarction, 856 ovarian cancer, 854 skin patches, 853 tacrolimus interaction, 857 thromboembolism, 854 5HT3 receptor antagonists see also individual names anesthesia, 744 drowsiness, 745 headache, dizziness, and constipation, 744 hepatitis, 745 hiccups, 745 hypokalemia, 744–5 liver enzyme and uric acid, rises, 745 nausea, 745 QT interval prolongation, 745 rash, 745 serum aminotransferase activities, rises, 745 vomiting, 745 human epidermal growth factor (rhEGF) chills and local pain, 772 sepsis, burning sensations, and tremors, 772 Stevens–Johnson syndrome, 772 human immunodeficiency virus, drugs active against see antiretroviral drugs human keratinocyte growth factor erythema and lichenoid papules, 771–2 febrile neutropenia, 771–2 flexural hyperpigmentation, 771 nasal congestion, 771 rashes or erythemia, 771 white coating of the oral mucosa, 771 human papilloma virus (HPV) vaccine acute disseminated encephalomyelitis, 658 anaphylaxis, 658

autoimmune disorders, 658 brachial plexus neuritis, 658 death, 658 dizziness, 658 Guillain–Barré syndrome, 658 headache, 658 hypersensitivity reactions, 658 local site reactions, 658 motor neuron disease, 658 nausea, 658 pancreatitis, 658 syncope, 658 transverse myelitis, 658 urticaria, 658 venous thromboembolism, 658 hydralazine and dimethylhydralazine cholestatic jaundice, 428 drug-induced lupus, 428 vasculitis, 428 hydrochlorothiazide allergic reaction, 439 contact dermatitis, 439 insulin sensitivity, 439 lichenoid eruption, 438 retinal phototoxicity, 439 hydromorphone bradycardia, 214 nausea, 214 oxygen desaturation, 214 pruritus, 214 vomiting, 214 hydroxychloroquine see chloroquine Hydroxycut see Garcinia gambogia hydroxyethylmethacrylate and ethylmethacrylate inflammation and swelling, 335 nodules, 335 hydroxyisohexyl-3cyclohexene carboxaldehyde see Lyral hydroxyzine QT interval prolongation, 347–8 syncope, 348 hyoscine (scopolamine) butylbromide migraine-like headaches, 759–60 nausea and vomiting, 759–60 Hypericum perforatum finasteride, interactions, 995 hyperzine arthralgia, 16 bradycardia and headache, 16 tachycardia, dry mouth, and hypertension, 16 hypochlorous acid, 484

Index of drugs

1048 I ibalizumab HIV infection, 790 ibuprofen acute localized exanthematous pustulosis, 246 esophageal perforation, 246 hyperbilirubinemia, 246 idraparinux bleeding, 718–9 subcutaneous injection, 718–9 iloperidone dizziness, 104 and haloperidol, 103–4 nasal congestion, 104 orthostatic hypotension, 104 tachycardia, 104 weight gain, 104 iloprost headache, flushing, 847 linear erythematous facial rash, 847 nausea, diarrhea, 847 imipenem bacterial meningitis, 492 cilastatin, 492 malignancies, 492 neutropenic fever, 492 renal function, 492 immunoglobulin see intravenous immunoglobulin and subcutaneous immunoglobulin incretin mimetics see also individual names hypoglycemia, 896 nausea, 896 vomiting and diarrhea, 896 indacaterol cough, 361–2 indinavir American ginseng, interaction, 595 indocyanine green retinal pigment epithelial atrophy, 1017 indometacin, 247 indoramin cardiotoxicity, 426 torsade de pointes, 426 infiltration anesthesia pain, 286 infliximab bowel syndrome, 783 bronchospasm, 782 fibrosing alveolitis, 782 Guillian–Barré syndrome, 782 Hansen's disease, 783

infectious mononucleosis, 783 inflammatory bowel disease, 783 interstitial pneumonitis, 782 leprosy, 783 Lewis–Sumner syndrome, 782 lupes-like syndrome, 782 mucormycosis, 783 optic neuritis, 782 pityriasis lichenoides chronica, 782 psoriasis, 782 toxic hepatitis, 782 varicella infection, 783 influenza vaccines see pandemic influenza H1N1 vaccines insulins allergy, 480 Alzheimer's disease, 483 brain injury, severe, 479 breast cancer, risk of, 481 erythema and blisters, 890 hypoglycemia, 479 ketoacidosis, 483 lipodystrophy, 480 myocardial infarction, 479 pre-eclampsia, 482 insulin-like growth factor (mecasermin) accumulation of body fat and coarsening of the facies, 772–3 hyperplasia of lymphoid tissue, 772–3 hypoglycemia, 772–3 interferon alfa cochlear damage, 774 conjunctival hyperemia and follicular conjunctivitis, 774 depression and fatigue, 774 granulomatous inflammation, 774 Graves' disease, 775 hemolytic anemia, 773 hyperthyroidism and hypothyroidism, 775 interstitial pneumonia, 773–4 Kaposi's sarcoma, 776 linear IgA bullous dermatosis, 776 lupus-like syndrome, 776 ocular sarcoidosis, 774 oral lichen planus, 776 sensorineural hearing loss, 774 subcutaneous sarcoid nodules, 775–6 thyroid antibodies, 775

thyroid dysfunction, 774–5 interferon beta systemic sclerosis, 776 vasculitis, 776 interleukin-11 (IL-11, oprelvekin) fatigue, 778 hypertension, 778 hypokalemia and fluid retention, 778 pheripheral edema, 778 interleukin-12 (IL-12) pneumococcal disease, 778 interleukin-18 (IL-18) anemia, 779 chills fever, headache, fatigue, and nausea, 779 cognitive disorder, 779 deep vein thrombosis, 779 fatigue and dyspnea, 779 hypoalbuminemia, 779 liver enzymes, increased, 779 neutropenia, 779 plueral effusion and lymphopenia, 779 polyarthritis, 779 pulmonary embolism, 779 serum creatinine, increased, 779 intravenous anti-D immunoglobulin disseminated intravascular coagulation, 679 extravascular hemolysis, 679 hemoglobinemia/ hemoglobinuria, 679 transfusion-related acute lung injury (TRALI), 679 intravenous immunoglobulin anaphylaxis, 677, 678 anemia, 677 anorexia, 678 arthralgia, 677 aseptic meningitis, 677 back pain, 677 bronchospasm, 677 chest pain, 677 chills, 677 convulsions, 677 cough, 677 cramping, 678 death, 677 diarrhea, 678 dizziness, 677 dysesthesia, 677 dyspnea, 677 dysrhythmias, 677 eczema, 678 erythema, 678 fatigue, 677, 678 fever, 677, 678 flu-like symptoms, 677

Index of drugs flushing, 677 headache, 677 hematuria, 678 hemolysis, 677 hypertension, 677 hyperviscosity, 677 hypotension, 677 leukopenia, 677 malaise, 677 meningism, 677 migraine, 677 myalgia, 677 myocardial infarction, 677 nausea, 678 necrotizing enterocolitis, 678 non-specific eruptions, 678 petechiae, 678 phlebitis, 677 pleural effusion, 677 pompholyx, 678 posterior reversible encephalopathy syndrome, 677 pruritus, 678 pulmonary edema, 677 renal insufficiency, 678 skin hemorrhage, 678 stroke, 677 urticaria, 678 venous thrombosis, 677 vomiting, 678 weakness, 677 intravenous regional anesthesia cardiac event, 287 seizures, 287 intravitreal injection glaucoma, 985 intraocular pressure, 985 systemic adverse events, 985 iodinated contrast agents see water-soluble intravascular iodinated contrast agents iodine fever, 485 serum creatinine, increased, 779 headache, 485 hepatitis, 485 malaise, 485 phlebitis, 485 sweating, 485 ion-exchange resins chronic kidney disease, 761 metabolic acidosis, 761 iron chelators see also individual names autoantibodies, 471 basal cell carcinomas, 465 intracellular compartment, 466

1049 osteoporosis and cholelithiasis, 465 reactivation of hepatitis B infection, 471–2 thalassemia, 465 toxicity and detoxification, 466 iron salts anaphylaxis, 451 kidney desease, 451 isoflurane generalized chorea and hallucinations, 258 tremor and facial tremor, 258 isoniazid clozapine, interaction, 636 hepatotoxicity, 628, 635 liver damage, 636 Mycobacterium tuberculosis, 623 neurotoxicity, 636 tuberculosis, 627–8 isotretinoin central retinal vein occlusion, 340 corneal steepening, 340 homocysteine concentrations, 340 inflammatory bowel disease, 340 liver enzymes increased, 340 melena, 340 panenteritis, 340 serum lipids increased, 340 tear secretion and tear quality, 340 itraconazole anaphylactic shock, 552 Aspergillus, 553 congenital anomalies, 552–3 dysgeusia, 553 fluid retention, 553 gastrointestinal intolerance, 553 headache, 553 hepatitis, 552 liver function, abnormal, 553 maculopapular rash, 553 sensorimotor polyneuropathy, 553 sleep disturbances, 553 tremor, 553 ivermectin, 649 ixabepilone adverse reactions, 949 arthralgia/myalgia, 949 bowel disturbances, 949 breast cancer, 948 constipation, 949 diarrhea, 949 mucositis or stomatitis, 949

nausea and vomiting, 949 neutropenia, 949 non-small-cell lung cancer, 948 peripheral neuropathy, 948–9 prostate, renal, and pancreatic cancers, 948 rash and/or palmar–plantar erythema, 949 sensory neuropathy, 948–9 thrombocytopenia, 949 J Jimson weed see Datura stramonium K ketamine agitation, 264–6 avoidance, 263 blood presure increased, 264 bradycardia, 266 bradypnea, 266 breath holding, 264–5 clonic movement, 264 desaturation, 264 dizziness, 266 emergence delirium, 267 hallucinations, 264 heart rate increased, 264 hyperarousal, 263 hypotension, 266 hypoxia, 265 nervous system, 267 opioid, 263 oversedation, 266 postoperative nausea and vomiting, 265 post-traumatic stress disorder, 263 psychotomimetic effects, 266 salivation excessive, 264–5 sedation, 263 shivering, 266 tachycardia, 265–6 vomiting, 264 ketoprofen erythema multiforme, 246 ketorolac acute asthma, 246 khat chest pain, 66 headache, 66 hypertension, 66 intracerebral hemorrhage, 66 myalgia, 66 myocardial ischemia, 66 nausea, 66 pulmonary edema, 66 smoking during pregnancy, 66

Index of drugs

1050 substance use and misuse, 65 sympathomimetic effect, 65 tachycardia, 66 violent expression, 65–6 vomiting, 66 ku die zi injection allergic reactions, 991 cold limbs, 991 palpitation, 991 L labetalol alveolar edema, 399 fever, 399 hepatic steatosis, 399 interstitial nephritis, 399 peripheral blood and urine samples, 399 lacosamide see also antiepileptic drugs adjunctive therapy, 139 antidysrhythmic drugs, 139 behavioral or cognitive effect, 140–1 cardiac arrest, 140 central nervous system adverse effects, 140–1 depression, 139–40 diarrhea, 140 distal diabetic neuropathy, 139 dizziness, 139–40 double vision, 139–40 drug-resistant focal epilepsy, 139–40 fatigue, 139–40 headache, 140 irritability, 139–40 memory impairment, 140–1 nausea, 139–40 neuropathic pain, 139 painful diabetic neuropathy, 140 partial-onset seizures, 139 peripheral edema, 140 sedative effect, 139 tremor, 139–40 word-finding difficulties, 139–40 lactulose abdominal bloating and distaste, 754 carpopedal spasm, 754 cirrhosis, 754 diarrhea, 754 hypocalcemia, 754 hypomagnesemia, 754 normokalemia, 754 LAM see levacetylmethadol lamivudine pancreatitis, 587

pure red cell aplasia, 587 lamotrigine see also antiepileptic drugs affective switches, 143 alopecia and weight gain, 143–4 anticonvulsant hypersensitivity syndrome, 144 antipsychotic drugs, 142 aseptic meningitis, 143 binge-eating disorder, 142 bipolar disorder, 142 central nervous system adverse effects, 141–2 cutaneous drug reactions, 144 depression, 142 divalproex sodium, 142 DRESS, 144 drug-resistant epilepsy, 142 epilepsy, 141 facial dysmorphism, 145 facial pain, 142–3 gastrointestinal adverse effects, 141–2 gingival infection, 142–3 hallucinations, 143 hyperammonemic encephalopathy, 146 hyperandrogenism or ovulatory dysfunction, 143–4 insomnia, 142 irritability, 141 levetiracetam, 142 mania, 143 monotherapy, 145 polycystic ovary syndrome, 143–4 pruritus, 141 psychiatric symptoms, 142–3 rashes, 141 schizophrenia or schizoaffective disorder, 142 seizure activity, 141 Sjögren's syndrome, 144 Stevens–Johnson syndrome, 132 suicidal thought or tremor, 142 toxic epidermal necrolysis, 146 tremor, 141, 143–4 unilateral radius aplasia, 145 urticaria, 141 valproate monotherapy, 142 vanished twin syndrome, 145 lansoprazole acute myocardial infarction, 751

acute tubulointerstitial nephritis, 751 allergic reaction, 751 colitis, 750–1 diarrhea, headache, and abdominal pain, 750–1 itching, malaise, shortness of breath, 751 Kounis syndrome, 751 lower respiratory tract infections, 751 nausea, 751 pallor, sweating, and agitation, 751 rectal hemorrhage, 750–1 swallowing difficulty, 751 vomiting, 751 lansoprazole þ amoxicillin þ metronidazole or clarithromycin abdominal pain, 749 burning sensation and metllic taste in mouth, 749 dizziness, headache, and rash, 749 nausea and vomiting, 749 lanthanum carbonate abdominal pain, 451 abdominal radiography, 451 constipation, 451 diarrhea, 451 mucous membrane inflammation, 451 nausea, 451 vomiting, 451 latanoprost chronic cough, 984 conjunctival hyperemia/ irritation, 985 difficulty focusing, 985 headache, 985 iris pigmentation, 985 keratoconus progression, 985 linear erythematous facial rash, 847 sleep disturbances, 985 latex allergic reactions, 1018 asthma, 1018 delayed hypersensitivity reactions, 1018 irritant dermatitis, 1018 laxatives and oral bowel preparations see also individual names hypokalemia, 753 nausea, 753 serum calcium, fall in, 753 serum phosphate, rise in, 753 leflunomide cutaneous ulceration, 819 diffuse alveolar damage, 818

Index of drugs diffuse alveolar hemorrhage, 818 interstitial lung disease, 818 interstitial pneumonitis, 818 polymyositis, 819 progressive multifocal leukoencephalopathy, 818 rheumatoid arthritis, 818 toxic epidermal necrolysis, 818–9 lenograstim ankylosing spondylitis, 770 bone pain, 770 fatigue, 770 fever, 770 headache, 770 insomnia, 770 lung cancer, 770 nausea, 770 polyglobulia, 770 transient ischemic attack, 770 lepirudin thrombocytopenia, 718 lercanidipine chylous ascites, 402 letrozole anorexia, mood disturbances, 862 arthralgia, 862 fatigue, nausea, vomiting, 862 hot flushes, 862 musculoskeletal pain, 862 vaginal dryness, hair loss, rashes, 862 levacetylmethadol, 214 levetiracetam adjunctive therapy, 147 aggression, 148 aggressive behavior, 146 altered platelet function, 149 aspiration pneumonia, 150 cardiac dysrhythmias, 146–7, 150–1 congenital malformation, 150 depression, 148 drowsiness, 146 energy, altered, 147, 148 fatigue, 148 headache, 148 hyperactivity, 147 interstitial nephritis, 149 irritability, 147 liver failure, fulminant, 149 metabolic encephalopathy, 148 monotherapy, 146 mood instability, 147 nasopharyngitis, 148 negative behavioral effect, 148

1051 pancytopenia, 149 pharmacokinetics, 149–50 psychiatric disorder, 150 psychomotor agitation, 146 psychotropic effect, 148 reduced platelet counts, 147 renal insufficiency/failure, 148, 149 restlessness, 148 seizure frequency, increased, 148 self-control, loss, 148 sleeping problem, 148 somnolence, 147, 148 thrombocytopenia, 149 tiredness, 148 vegetative symptoms, 148 vigilance, 148 visual hallucinations, 147 vomiting, 148 levodopa hiccups, 320 Parkinson's disease, 320 levofloxacin Achilles' tendinitis, 517 Achilles' tendon rupture, 517 aminotransferase activity, 516, 517 anemia and eosinophilia, 517 benign intracranial hypertension, 517 cutaneous vasculitis, 517–8 delirium, 517 diarrhea, nausea, and vomiting, 516, 517 gastrointestinal disorders, 516 headache, 516, 517 hypoglycemia, 517 hypokalemia, 516 leukocytosis, 516 local irritation, 516 myalgia, 517 phototoxic reaction, 517 smell sensation, altered, 637 thrombocythemia, 516 tonic-clonic seizures, 517 warfarin, interaction, 518 levonorgestrel abdominal pain, 865 breast cancer, 865 menorrhagia, 866 menstrual disorder, 865 lian bi zhi injection acute renal failure, 991 pneumonia, 991 lidocaine allergic reaction, 291 bronchospasm, 388 Brugada syndrome, 290–1, 388 cardiac arrest, 388

chest discomfort and profound bradycardia, 388 hallucinations, 388–9 hypotension and eventual cardiac arrest, 388 intubation and adrenaline infusion, 388 nausea and vomiting, 388–9 pain and dysalgesia, 389 reduced airway diameter, 291 somnolence and bradypnea, 388 ling yang gan mao capsule allergic reaction, 989–90 erythema, 990 fingers swollen, 990 hands itching, 990 lips itching, 990 numbness, 990 palms, pain, 990 liposomal amphotericin (L-AmB) Absidia corymbifera, 544 hyperkalemia, 544 nephrogenic diabetes insipidus, 544 liraglutide antibodies, 898 pancreatitis, 896–7 renal disease, 897 thyroid tumor, 897 lisinopril see also angiotensin converting enzyme (ACE) inhibitors erythroderma, 418 lispro see insulins lithium ACE inhibitors, interaction, 46 acute mania, 39 amyotrophic lateral sclerosis, 41–2 bipolar depression, 40 bone density, increased, 45 bone marrow neutrophil production, 45 cardiac conduction changes, 42 cerebral ischemia, 42 cognitive deficits, 43–4 concentrations, 47 creatinine clearance, 47 dementia, 41 diabetes insipidus, 43, 44 Hashimoto's encephalopathy, 43 headaches, 45 HIV infection, 42 inflammatory bowel disease, 45

Index of drugs

1052 kidney microcysts, 45 mood changes, 40, 42 mood disorders, 45 multiple sclerosis, 42 non-steroidal antiinflammatory drugs, 46 parathyroid adenomas, 44 pseudotumor cerebri, 43 psoriasis, 45 renal dysfunction, 45 seizures, 45 syndrome of irreversible lithium-effectuated neurotoxicity, 43 teratogenicity, 46 thyroid carcinoma, 44 unipolar depression, 40 long-acting beta2adrenoceptor agonists (LABAs) see also individual names asthma, 357 atrial tachycardia, 359 autism spectrum disorders, 359 bronchitis and upper respiratory tract infections, 359 headache, 359 hoarseness and dysphonia, 358–9 lung functionand short-term growth, 357 morbidity and mortality, 358 muscle cramps and muscle twisting, 359 myocardial infarction, 358 oral candidiasis, 357 pneumonia, 359 psychiatric disorders, 359 salmeterol, 359 tremor frequency, 357 loop diuretics see furosemide loperamide Clostridium difficile, 760 diarrhea, 760 fever, 760 lopinavir non-fasting lipids, increased, 583 oxycodone, interaction, 595 lorazepam Passiflora incarnata, interaction, 75 propylene glycol toxicity, 74–5 sexual desire, enhanced, 74 Valeriana officinalis, interaction, 75 lormetazepam, 75 losartan

angioedema, 419 complete sinus arrest, 419 dysgeusia, 419 hyperkalemia, 419 hypotension, 419 renal impairment, 419 sinoatrial block, thirddegree, 419 sinus arrest, 419 loxoprofen intrahepatic cholestasis, 246 Lyral contact dermatitis, 337 M macrolide antibiotics see also individual names breast-feeding infants, 522 digoxin, interaction, 522 magnesium salts abdominal hysterectomy, 452 hypermagnesemia, 452 kidney dysfunction, 452 muscle spasm, 452 maidenhair see Ginkgo biloba manganese birth weight, 452–3 fetal intra uterine growth retardation, 452 lower birth weights, 452 manganese concentrations, 452–3 mannitol asthma, 442 cystic fibrosis, 442 hypocalcemia, 442 hyponatremia, 442 pulmonary edema, 442 maraviroc food, interaction, 600 postural hypotension, 600 upper respiratory infections, 600 yellow fever vaccine, interaction, 601 mascara allergic conjunctivitis, 334–5 blepharitis, 334–5 contact dermatitis, 334–5 corneal ulcers and conjunctival mass, 334–5 madarosis, 334–5 pigmented conjunctival lesions, 334–5 measles–mumps–rubella (MMR) vaccine autism/autistic spectrum disorder, 661 Guillain–Barré syndrome, 661 thrombocytopenia purpura, 661–2

measles–mumps–rubella– varicella (MMRV) vaccine febrile convulsions, 662 medroxyprogesterone pigmented purpuric dermatosis, 866 mefenamic acid bilateral transient myopia, 245 choroidal detachment, 245 glaucoma, 245 mefloquine anxiety, 569 dizziness, 569 mania, 569 nausea, 569 Plasmodium falciparum malaria, 569 psychosis, 569 seizures, 569 sleep disturbances, 569 megestrol acetate impaired adrenal function, 866 meglitinides hypoglycemia, 897 type 2 diabetes, 897 melatonin back pain, 912 cigarette smoking, 912 circadian rhythm sleep disorders, 912 headache, 912 pharyngitis, 912 weakness, 912 meloxicam antifungal azoles, interaction, 247 memantine anxiety, nausea, anorexia, and arthralgia, 16 constipation, vomiting, back pain, 16 hallucinations, 16 headache, 16 influenza-like symptoms, 16 urinary incontinence, 16 meningococcal vaccine injection site tenderness, 656–7 meperidine see pethidine mercaptopurine acute lymphoblastic leukemia, 830 alopecia, 830 chest pain, 830 Crohn's disease, 830 fatigue, night sweats, headache, 830 hand-foot syndrome, 830 methotrexate, interaction, 830

Index of drugs nausea and vomiting, 830 mercury and mercurial salts attention deficit disorder, 453 autism spectrum disorders, 453 blood mercury concentration, 453 emotional disturbances, 453 tics, 453 urine mercury, 453 meropenem bacterial meningitis, 492 clearance of autoantibody, 493 intravascular hemolysis, 493 neurotoxicity, 492 mesalazine (5-aminosalicylic acid, mesalamine) abdominal pain, upper 758 aplastic anemia, 758 chest pain, 757 coronary artery disease, 757 Crohn's disease, 757 diarrhea, 759 dyspnea, exertional, 757 eosinophilia, 758 exertional dyspnea, 757 fatigue, 758 fever, 757 headache, 759 hepatitis, 758 hypersensitivity pneumonitis, 757 interstitial nephritis, 757 jaundice, 758 Kounis syndrome, 757 leukocyte count, increase, 758 myocardial infarction, 757 myocarditis, 757 nausea and vomiting, 759 nephritis, 758 pancreatitis, 759 progressive lethargy, 758 stools, blood in, 758 toxic inflammatory myopathy, 759 ulcerative colitis, 759 metamfetamine chest pain, 3 congenital cataract, 6 intracerebroventricular hemorrhage, 4 ischemic colitis, 4–5 ischemic stroke, 4 neurodevelopment differences, 6 periventricular leukomalacia, 4 smoking, 5 subarachnoid hemorrhage, 4

1053 white matter maturation, altered, 5 metamizole (dipyrone), 244 metformin anesthesia, 484 congestive heart failure, 484 hemodialysis, 484 hemolytic anemia, 484 lactic acidosis, 483 respiratory failure, 483 methadone antiretroviral drugs, interaction, 216 cannabis, interaction, 216 confusion, 214 constipation, 214 drowsiness, 214 fetotoxicity, 215 HIV infection, 215–16 mortality, 215 nausea, 214 necrolytic migratory erythema, 215 nicotine, interaction, 216 pregnancy, 215 sensorineural hearing loss, 215 sweating, 214 torsade de pointes, 214 vomiting, 214 methotrexate cytolytic hepatitis, 950 leucovorin, interactions, 951 mucositis and jaundice, 950 osteosarcoma, 950 renal damage/dysfunction, 950 renal dysfunction, 950 urinary alkalinization, 950 methoxyflurane analgesia, 258 renal toxicity, 258 methyldopa acute hepatitis, 424 hemolytic anemia, 424 methylene blue see methylthioninium chloride methylnaltrexone abdominal pain, 227 dizziness, 227 flatulence, 227 nausea, 227 methylphenidate blood pressure and heart rate increase, 7–8 cytogenetic damage, 9–10 enuresis, 9 fluoxetine interactions, 10 Huntington's disease, 10 placebo-controlled trial, 8 psychosis, 9

seizure aggravation, 9 suicide risk, 8 vasculopathy, 9 methylthioninium chloride agitation, 1017 breast cancer, 1016–7 dystonia and abnormal eye movements, 1017 intraparenchymal breast injection, 1016–7 melanoma, 1016–7 monoamine oxidase inhibitors, 1017 serotonin syndrome, 1017 serotonin toxicity, 1017 skin reactions, 1016–7 tachycardia, 1017 toxic metabolic encephalopathy, 1017 metoclopramide abdominal pain, 742–3 agitation, 743 akathisia, 743 cardiac failure, 743 diarrhea, 742–3 gastroesophageal reflux, 743 gynecomastia, 743 hypertension, 743 hypotension, 742–3 hypothyroidism, 743 migraine, 743 nausea, 743 QT interval prolongation, 743 respiratory depression, 742 sedation, 742 tachycardia, 743 torsade de pointes, 743 ulcer symptoms, 742–3 vomiting, 742–3 metoprolol hyperadrenergic syndrome, 399 left ventricular ballooning syndrome, 399 sleepwalking, 399 metronidazole abdominal pain, 573 bitter taste, 573 contact dermatitis, 573 Entameba histolytica, 573 metallic taste, 573 nausea, 573 reduced appetite, 573 vomiting, 573 mexiletine dizziness and incoordination, 389 nausea and fatigue, 389 palpitation, 389 micafungin hepatic function tests, abnormal, 558

Index of drugs

1054 hepatitis, 558 immune hemolysis, 559 neonates, 559 midazolam agitation, 75 antifungal azoles, interaction, 76 blood pressure reduction, 75 desaturation, 75 dizziness, 75 drug overdose, 77 extrapyramidal adverse effect, 76 herbal medicines, interaction, 77 hiccups, 75 hyperchloremic metabolic acidosis, 76 intranasal administration, 76 opioids, interaction, 76 protease inhibitors, 76–7 tidal and minute volume reduction, 75–6 mifepristone anorexia, fatigue, and mood alterations, 867 dyspnea, 867 milrinone atrial fibrillation, 378–9 hypertension, 378–9 mitral valve surgery, 378–9 pre-operative ejection fraction, 378–9 pulmonary artery pressure, 378–9 right ventricular dysfunction, 378–9 minocycline anaphylactic reaction, 500 antinuclear antibody, positive, 499 benign intracranial hypertension, 499 black discoloration of the thyroid gland, 499 blue discoloration of a palate, 500 dark discoloration, 499 diarrhea, 499 drug hypersensitivity syndrome, 500 eosinophilic pneumonia, 499 fragile X syndrome, 499 Graves' disease, 500 hypersensitivity, 500 hyperthyroidism, 499, 500 lupus-like syndrome, 500 lymphomatoid papulosis, 500 matrix metalloproteinases (MMPs), 499 papillary microcarcinoma, 499 skin pigmentation, 500

toxoplasmic encephalitis, 500 minoxidil toxic epidermal necrolysis, 428 mirtazapine see also antidepressant drugs hyponatremia, 34 restless legs syndrome, 33–4 Stevens–Johnson syndrome, 34 misoprostol uterine tachysystole, increased, 847–8 moclobemide see also antidepressant drugs carbamazepine and valproate, interaction, 25 modafinil appetite, reduced, 11 headache, palpitation, nausea, and dizziness, 11 psychosis exacerbation, 11 psychotic symptoms, 11 monoamine oxidase inhibitors see moclobemide monobactams and monocarbams see aztreonam montelukast agitation and aggression, 366–7 angioedema, 367 anxiousness and dream abnormalities, 366–7 behavior and tremor, 366–7 Churg–Strauss syndrome, 366 hallucinations and depression, 366–7 insomnia and irritability, 366–7 pharyngitis and fever, 366 restlessness and suicidal thinking, 366–7 upper respiratory tract infections, 366 worsening asthma, 366 Morinda citrifolia gliobastoma, 996 phospholipidosis, 996 morphine allergy, 216 and dexmedetomidine, 218 dizziness, 216 downbeat nystagmus, 217 and gabapentin, 218 intranasal administration, 218 itraconazole, interaction, 218 and ketamine, 218 laryngospasm, 217 and mirtazapine, 219 muscle rigidity, 217

and nalbuphine, 219 and naloxone, 219 nausea, 216 and ondansetron, 219 oprelvekin, interaction, 218 postoperative nausea, 217 pruritus, 216 respiratory compromise, 217 respiratory depression, 217 reversible encephalopathy syndrome, 217 urinary retention, 216 vomiting, 216 moxa see Artemisia vulgaris moxifloxacin acute generalized exanthematous pustulosis (AGEP), 519 aminotransferase activity, 518 Clostridium difficileassociated disease, 518 cutaneous reactions and allergies, 518 drug hypersensitivity syndrome, 519 linear immunoglobulin A bullous dermatosis, 518 tendon rupture, 518 torsade de pointes, 518 moxonidine blood pressure, increased, 427 convulsions, 427 headache, 427 sleepiness, 427 mucolytics epigastric pain, 369 heartburn and diarrhea, 369 nausea, 369 mugwort see Artemisia vulgaris mumps vaccine Leningrad–Zagreb strain, 662 mycophenoate mofetil ciclosporin, interaction, 819 myrrh gastrointestinal discomfort, 649–50 N naftidrofuryl intermittent claudication, 408 nalmefene, 227 naloxone cardiac arrest, 227–8 cholestasis, 228 naltrexone dry mouth, 228 gastrointestinal discomfort, 228 headache, 228 hepatotoxicity, 228 insomnia, 228

Index of drugs nausea, 228 opioid withdrawal, 228 sertraline interaction, 228 vomiting, 228 natalizumab anaphylactoid reactions, 791 chest pain and discomfort, 791 dyspnea and angioedema, 791 hypotension and hypertension, 791 immune reconstitution inflammatory syndrome, 791 nervous system lymphoma, 791 progressive multifocal leukoencephalopathy, 790 urticaria, 791 nelfinavir QT interval, 596 neomycin allergic reaction, 513 recall dermatitis, 513 neurokinin NK1 receptor antagonists, 748 nevirapine toxic epidermal necrolysis, 593 niacin carotid plaque wall area, reduced, 928 chest pain, 928 creatine kinase activity, increased, 929 diabetes mellitus, 929 fasting blood glucose concentrations, 928 flushing, 928 gastrointestinal discomfort, 928 gastrointestinal symptoms, 929 hepatic transaminase activities, increased, 929 hyperglycemia, 929 hyperuricemia, 929 nicardipine heparin, 402 liver enzymes, raised, 402 nickel chest pain, 453 nickel allergy, 453 pericardial effusion, 453–4 skin patch testing, 453 nicorandil ulcers of the vulva, 400 nicotine adverse effects, 1017 bupropion, 1017 conotruncal heart defects, 1018

1055 effects of smoking and drinking, 1018 monoamine oxidase activity, 1017 neural tube defects, 1018 replacement therapy, 1017 result of adverse reaction, 1017 single nucleotide polymorphisms (SNPs), 1018 smoking, 1017 smoking and alcohol consumption, 1018 squamous cell carcinoma, 1018 suicide, 1017 nifedipine acute graft-versus-host disease, 402 antihypertensive therapy, 402 blood loss and septicemia, 402 blood pressure, 402 nilutamide bilateral blindness, 874 fulminant hepatic failure, 874 prostate cancer, 874 nimesulide fixed drug eruptions, 249 liver failure, 249 premature closure, ductus arteriosus, 249 nimodipine hemiplegic migraine, 403 nitrates, organic dizziness and skin irritation, 401 headache, 400, 401 neurological symptoms, 400–1 vasodilatation, 400 nitric oxide hypertension, arterial, 260 nitrofurantoin acute toxic hepatitis, 525 bronchiolitis obliterans, 524–5 granulomatous interstitial nephritis, 525 hypersensitivity reactions, 525 nitrous oxide agitation, 260–1 gastrointestinal, 262 genotoxicity, 262 headache, 261 hypoxia, 261 megaloblastic anemia, 261–2 myelopathy, 261–2 nausea, 260–1 nervous system, 261

orthopedic, 260 postoperative nausea, 262 vomiting, 260–1 non-animal stabilized hyaluronic acid (NASHA) granulomas and sarcoidosis, 335 hypersensitivity reactions, 335 vasculitis, 335 non-nucleoside reverse transcriptase inhibitors (NNRTI) hepatotoxicity, 590 rashes, 590 O octreotide abdominal cramps, 914 Beau's lines/onychomadesis, 914 gallbladder abnormalities, 914 melena, 914 nocturnal bowel movement, 914 thrombocytopenia, 914 variceal bleeding, 914 ocular anesthesia brain damage, 287–8 central retinal artery occlusion, 287 olanzapine bradycardia, 104 breast cancer, risk, 1019 and clozapine, 104–5 direct bilirubin increase, 106 and droperidol, 105 drowsiness and sedation, 104 drug withdrawal, 107–8 dry mouth, 104 fasting LDL cholesterol increase, 106 fasting total cholesterol increase, 106 hepatic enzyme increase, 106 hypertension, 104 hypotension, 104 increased appetite and weight gain, 106 increased prolactin, 104 and lithium, 105 orthostatic hypertension, 104 prolactin increase, 106 pulmonary thromboembolism, 107 and quetiapine, 105 and risperidone, 106 schizophrenia, 107 sedation, 104 weight gain, 104

Index of drugs

1056 oleic acid blood pressure reduced, 1020 brain and adrenal glands, 1020 short bowel syndrome, 1020–1 olmesartan dizziness, 419 omalizumab allergic reaction, 791 anaphylaxis and anaphylactic shock, 791 injection-site reactions, 791 omeprazole and esomeprazole acute tubulointerstitial nephritis, 751 allergic reaction, 752 anaphylactic reactions, 752 chronic hypokalemia, 751 generalized urticaria, bronchospasm and dizziness, 752 hypocalcemia, 751 hypomagnesemia, 751 itching of the palms and facial angioedema, 752 microscopic colitis, 751 vomiting and diarrhea, 752 ondansetron anaphylactic reactions,746 anesthesia, 746 bradycardia, 745 cardiac dysrhythmias, 746 consciousness, loss of, 746 coronary artery disease, 746 diabetic ketoacidosis, 746 headache, 746 hepatotoxicity, 746–7 nausea and vomiting, 746 QT interval prolongation, 746–7 seizures, 746 serotonin syndrome, 746–7 serum aminotransferases, rises in, 746 opioid analgesics age factor, 208 cognitive impairment, 206 critically ill patients, 208 drug abuse, 207 narcotic bowel syndrome, 206 neonatal abstinence syndrome, 207 obstructive, central, and combined sleep apnea, 205 reduced cortisol concentrations, 206 respiratory depression, 205 sexual dysfunction, 206 sexual excitation, 206

opioid receptor agonists see also individual names opioid receptor antagonists see also individual names oseltamivir abnormal activity, 601 delirium, 601 hallucinations, 601 nausea, 601 probenecid, interaction, 602 oxazolidinones see also individual names acute interstitial nephritis, 526 anemia, 525, 526 auditory nerve neuropathy, 526 creatine kinase activity, 527 DRESS, 526 encephalopathy, 525 hyperbilirubinemia, 526 lactic acidosis, 526 linezolid, interaction, 527 nephrotoxicity, 525 optic disc hyperemia, 526 optic neuropathy, 525 peripheral neuropathy, 525–6 petechiae and purpura, 526 reversible hypertension, 527 seizures, 526 serotonin syndrome, 527 thrombocytopenia, 526 oxcarbazepine adjunctive therapy, 132 bipolar disorder, 152 dizziness, nausea, and vomiting, 151 fatigue and drowsiness, 151 gammaglutamyl transferase activity, raised, 151 headache, 151 hyponatremia, 132 leukopenia, 152–3 nausea, 151 neuroleptic malignant syndrome, 152 parkinsonism, 152 radius aplasia, 153 rashes, 151 sedation, 151 serum concentrations, 153 Stevens–Johnson syndrome, 153 oxicams see meloxicam and piroxicam, 247 oxycodone constipation, 220 delusions, 220 dizziness, 220 headache, 220 and naloxone, 220 nausea, 220

and pregabalin, 221 pruritus, 220 QT interval prolongation, 220 rifampicin, interactions, 220 somnolence, 220 vomiting, 220 voriconazole, interactions, 220 oxymorphone, 221 oxytocin and analogues anesthesia, 913 hyponatremia, 913 mean arterial pressure fall, 913 nausea, 913 stillbirth, 912–3 vaginal bleeding, 913 P PA-824 Mycobacterium tuberculosis, 636–7 serum creatinine, increased, 637 paclitaxel see also albumin-bound paclitaxel and docosahexaenoic acid paclitaxel abnormal microtubular bundles, 936 anemia, 939 arthralgia and/or myalgia, 941 atrial fibrillation, 938 bone-marrow suppression, 939 bradycardia, 941–2 bronchospasm, 941–2 cardiac ischemia, 938 cardiac rhythm, 937–8 cardiac toxicity, increased, 943 convulsions, 939 cutaneous flushing, 941–2 diabetes mellitus and alcohol abuse, 939 dizziness, 939 dysrhythmias, 938 gynecological malignancies, 942 hair loss, 941 headaches, 939 head and neck cancers, 936 hemopoietic stem cell damage, 939 hepatic metabolism, 937 hypersensitivity, 937 hypertension, 938 hypotension, 938, 941–2 interstitial pneumonia, 938 leukemia, 936, 940

Index of drugs liver dysfunction, 937 mucositis and stomatitis, 940 myocardial infarction, 938 neutropenia, 939–40 numbness, burning, 939 onycholysis, 941 ototoxicity, 939 ovarian cancer, 935–6, 940 peak plasma concentrations, 936 peripheral neuropathy, 937–9 pharmacokinetic interactions, 943 pneumonitis, 938 progressive disease, 938 radiation dermatitis, 941 renal function, 937 renal insufficiency, 941 severe nausea, vomiting, and diarrhea, 940 supraventricular tachycardia, 938 thrombocytopenia, 939 transient mitotic arrest, 941 urticaria, 941–2 ventricular dysrhythmias, 938 visual disturbances, 939 paliperidone atrial fibrillation, 109 carbamazepine, interaction, 109 palonosetron breast cancer, 747 diarrhea, dyspepsia, abdominal pain, 747 dizziness, somnolence, 747 drowsiness, 747 dry mouth and flatulence, 747 headache and constipation, 747 insomnia, hypersomnia, and paresthesia, 747 nausea and vomiting, 747 QT interval prolongation, 747 seizure, 747 supraventricular extra beats, 747 tachycardia, sinus dysrhythmia, 747 Panax ginseng anaphylactic shock, 996 limb weakness, chills, cold sweats, and shortness of breath, 996 Panax quinquefolius indinavir, interactions, 996 pancreatic enzymes abdominal pain, 761 constipation and vomiting, 761 diaper dermatitis/nappy rash, 761

1057 pandemic influenza H1N1 vaccines anaphylaxis, 659 angioedema, 659 anticoagulants, interactions, 660 autoimmune disorders, 659 fever, 660 Guillain–Barré syndrome, 659 immunodeficiency, 659 influenza, 659 seizures, 660 solid organ transplants, 659 stroke, 660 urticaria, 659 vasculitis, 660 pantoprazole abdominal pain and chest pain, 752 belching, headache, nausea, and rash, 752 diarrhea, dizziness, and dyspepsia, 752 pneumonia, 752 thrombocytopenia, 752 upper respiratory tract infection, 752 papaverine 221 paracetamol (acetaminophen) anaphylaxis and angioedema, 245 asthma, 244–5 vulval fixed drug eruption, 245 parathyroid hormone arterial vasodilatation, 913 hypercalcemia, 913 hypercalciuria, 913 nausea, vomiting, and dizziness, 913 parenteral nutrition adult respiratory distress syndrome (ARDS), 697 aluminium toxicity, 698 blood glucose concentrations, 697–8 bloodstream infections, 700 bone mineral content, 698 Candida spp, 700 cholestasis, 699 colorectal cancer, 700 death, 699 enterococcus, 700 epilepsy, 698 Fusarium oxysporum, 700 gastric carcinoma, 697 hepatic damage, 698 hepatic dysfunction, 698–9 hyperglycemia, 697–8 hypertriglyceridemia, 697 hypophosphatemia, 698 inflammatory bowel disease, 699

intestinal failure, 698 intravenous insulin therapy, 697–8 ischemic liver damage, 698 Klebsiella pneumoniae, 700 liver disease, 698 malignant lymphoma, 698 muscle cramps, 699 neonatal aluminium, 698 nosocomial infections, 700 phenylketonuria, 698 pleural effusion, 697 Pseudomonas aeruginosa, 700 pulmonary embolism, 695 serum creatinine, 698 short-bowel syndrome, 699 skin ulcer, 700 Staphylococcus aureus, 700 Staphylococcus haemolyticus, 700 triglycerides, increased, 697 ursodeoxycholic acid, 699 paromomycin alanine aminotransferase activity, 513 injection site pain, 513 paroxetine see also antidepressant drugs flecainide, interactions, 30 personality measures, 30 partial opioid receptor agonists see buprenorphine and butorphanol patupilone diarrhea, 949 fatigue and nausea, 949 non-small-cell lung cancer, 949 ovarian cancer, 949 peripheral neuropathy, 949 renal cell cancer, 949 pegaptanib cardiorespiratory arrest, 977–8 Clostridium colitis, 977–8 diabetic macular edema, 978 endophthalmitis, 977–8 epiretinal membrane, 978 hypotension, 977–8 iritis, 978 macular hole, 978 metastatic lung cancer, 977–8 retinal and vitreous hemorrhage, 977–8 rhegmatogenous retinal detachment, 977–8 subconjunctival hemorrhages, 978 pegfilgrastim anemia, thrombocytopenia, or chronic urticaria, 770

Index of drugs

1058 bone pain, 770 respiratory distress, 770 penicillamine arthralgia, 472 bullous pemphigoid, 473 elastosis perforans serpiginosa, 472 generalized amino-aciduria, 472 goitrous hypothyroidism, 472–3 hypersensitivity pneumonitis, 472 intralobular and interlobular septa, 472 lip elastosis, 473 neurological symptoms, 472 thyroglobulin and thyroperoxidase, 473 Wilson's disease, 472 penicillins see also individual names acute inflammatory response, 495 cerebral inflammation, 495 Jarisch–Herxheimer reaction, 495 neurosyphilis, 496 tachycardia, fever, chills, arthralgia, and headache, 495 tertiary syphilis, 495 pentachlorophenol hemopoietic tumors, 486 neuropsychological health effects, 485–6 non-Hodgkin's lymphoma, 486 soft tissue sarcoma, 486 pentazocine, 221 perfluorocarbons chest discomfort, 972 chest pain, 972 flushing, 972 headache, 972 hypotension, 972 left ventricular opacification, 971–2 myocardial infarction, 971–2 nausea, 972 peroxisome proliferatoractivated dual receptor agonists congestive heart failure, 902 edema, 902 hemodilution, 902 weight gain, 902 pertussis vaccine encephalopathy, 657 fever, 657 injection site reactions, 657 sudden infant death syndrome, 657

pethidine (meperidine), 221 phenazopyridine sulfhemoglobinemia and methemoglobinemia, 249–50 phenobarbital and primidone see also antiepileptic drugs acute intermittent prophyria, 154 acute severe axonal motor neuropathy, 154 alopecia areata universalis, 154 anticonvulsant hypersensitivity syndrome, 154 dizziness, 154 drowsiness, 154 epilepsy, 154 erythema multiforme, 154 gastrointestinal complaints, 154 Ledderhose syndrome, 154 plantar fibromatosis, 154 seizures, 154–5 severe cerebrovascular disease, 154 Stevens–Johnson syndrome, 154 Sturge–Weber syndrome, 154 toxic epidermal necrolysis, 154 phentermine ventricular tachycardia/ fibrillation, 13 phenylbutazone DRESS, 247–8 serum testosterone rise, 248 Sweet's syndrome with sialadenitis, 248 phenylephrine blood pressure increased, 318–19 phenytoin and fosphenytoin see also antiepileptic drugs acute nervous system toxicity, 156–7 agranulocytosis, 156 antiepileptic drug hypersensitivity syndrome, 156 cardiac dysrhythmias, 155 clozapine, 157 DRESS, 156 fibrillary glomerulonephritis, 156 granulomatous interstitial nephritis, 156 high-flux hemodialysis, 157 hyponatremia, 155 hypothyroidism, 155 intestinal obstruction, 157

junctional bradycardia, 155 motor neuron disease, 155 myopericarditis, 155 osteopenia, 156 osteoporosis, 156 pneumonitis, 155 skin necrosis, 156 urolithiasis, 156 vertigo, 155 pholcodine, 222 phosphates abdominal bloating, 755 acute phosphate nephropathy, 755 celiac disease, 755 chronic constipation, 755 Chvostek's sign, 755 Costello syndrome, 755 dry mouth, 755 gingival hyperplasia, 755 hyperphosphatemia, 755 hypertrophic cardiomyopathy, 755 hypocalcemia, 755 low blood pressure, 755 nausea and cramps, 755 renal insuffciency, 755–6 tachycardia, 755 phosphodiesterase type V inhibitors ambrisentan, interaction, 421 flushing and nasal congestion, 409 headache, 409 intracerebral hemorrhage, 409–10 respiratory distress, 410 retinal artery occlusion, 410 thrombocytopenia, 410 pimecrolimus atopic dermatitis, 819 burning-tingling sensation, 819 eczema, 819 erythema and pruritus, 819 lymphoma, 819 pimecrolimus and tacrolimus burning, 337–8 feeling of warmth, 337–8 flushing, 338 itching-burning sensation, 338 pain, 337–8 smarting, 337–8 soreness and rosaceiform dermatitis, 337–8 pioglitazone bladder neoplasm, 901 edema, 900 heart failure, 900 hyperglycemia, 900 liver disorder, 900

Index of drugs malaise and lassitude, 900 myocardial infarction, 900 nausea and vomiting, 900 weight gain, 900 piperacillin þ tazobactam acute generalized exanthematous pustulosis (AGEP), 497 cystic fibrosis, 497 hemolytic anemia, 497 hypokalemia, 497 non-thrombocytopenic petechial rash, 497 psychiatric effect, 497 thrombocytopenia, 497 piritramide respiratory depression, 222 piroxicam fixed drug eruption, 247 plasma transfusion-related acute lung injury (TRALI), 675 polystyrene sulfonates colonic necrosis, 474 ileal perforation, 474 intestinal injury, 474–5 ischemic colitis, 474 polyvinyl alcohol allergic reaction, 1021 ketoprofen, 1021 pelvic pain, 1021 uterine artery, 1021 polyvinylpyrrolidone (povidone) and povidone iodine altered metabolism of thyroid hormones, 485 hypothyroidism, 485 systemic reactions, 485 posaconazole abdominal pain, 553 dizziness, 553–4 dry mouth, 553–4 headache, 553–4 hepatotoxicity, 554 nausea, 553 serum creatinine increased, 553 vomiting, 553 postsynaptic a-adrenoceptor antagonists chest pain, 426 dizziness, 425 ejaculatory disorders, 427 ejaculatory dysfunction, 425 endophthalmitis, 426 fractures, 425 intraoperative floppy iris syndrome (IFIS), 425 pre-syncope, 425 priapism, 426–7 retinal detachment, 426 retrograde ejaculation, 426

1059 syncope, 425 pramlintide age, effect of, 483 pranlukast diarrhea, 367 somnolence, 367 thirst, 367 pravastatin colitis, 927 erythematous pigmented rash, 927 praziquantel abdominal discomfort, 650 allergy, 650 headache, 650 nausea, 650 Schistosoma hematobium, 650 Schistosoma japonicum, 650 stomach discomfort, 650 vomiting, 650 prazosin chest pain, 426 pregabalin see also antiepileptic drugs ataxia, 158 balance worsened, 157–8 blurred vision, 158 controlled-release oxycodone monotherapy, 158 delirium and delusions, 159 diabetic polyneuropathy, 158 dizziness, 158 double vision, 158 dysautonomic crisis, 157–8 fatigue, 159 flu-like symptoms, 158–9 headaches, 158 hemodialysis, 160 hyponatremia, 159–60 inadequately controlled epilepsy, 160 Lennox–Gastaut syndrome, 160 lethargy, 158 myoclonus, 159 nausea, 157–8 neuropathic pain, 159 parkinsonium, 159 peripheral edema, 157–8 postherpetic neuralgia, 158 postural instability, 158–9 rufinamide, 160 seizures, 160 somnolence, 158 tiredness, 158 unsteadiness, 158 weight gain, 157–8 prilocaine and EMLA allergic reaction, 292 erythema and swelling, 292 methemoglobinemia, 291

primaquine see tafenoquine primidone see phenobarbital pristinamycin leukocytoclastic vasculitis, 528 procainamide ventricular tachycardia and fibrillation, 389 progestogens allergic reaction, 865 eosinophilic pneumonia, 865 sideroblastic anemia, 865 proguanil hydrochloride and atovaquone bullous erythema multiforme, 569 promethazine anticholinergic symptoms and signs, 349 digital necrosis, 348 erythematous, 348 ischemia and tissue necrosis, 348 left antecubital fossa, 348 neuroleptic malignant syndrome, 349 QT interval prolongation, 348 small vessel muscular arteries, 348 swelling and discoloration, 348 thumb and little finger, 348 propafenone atrial tachycardia, 389–90 lupus-like syndrome, 390 propitocaine fixed drug eruption, 293 propofol allergic complication, 271 anaphylaxis, 275 cardiac arrest, 270–1 desaturation, 270 diabetes insipidus, 274 green urine, 275 hypotension, 271 hypoxia, 270 metabolic acidosis, 274 nervous system, 273 pancreatitis, 274–5 propofol infusion syndrome, 272 rhabdomyolysis, 272 secretion, 270–1 prostaglandin analogues anterior uveitis, 984 conjunctival hyperemia, 984 cystoid macular edema, 984 elongation, 984 eyelashes darkening, 984 herpes simplex keratitis, reactivation, 984

Index of drugs

1060 iris cysts, 984 iris darkening, 984 periocular skin pigmentation, 984 protamine acute pulmonary hypertension, 727 adrenaline, 727 anaphylactic reactions, 727 atrial fibrillation, 727 blood pressure, 727 cardiac surgery, 727 chronic smoker, 727 coronary artery bypass graft, 727 hypercholesterolemia, 727 hypotension, 727 methylthioninium chloride, 727 pulmonary vasoconstriction, 727 vasopressin, 727 protease inhibitors see also individual names CYP3A4, interactions, 629 efavirenz, interaction, 629 gastrointestinal intolerance, 628 liver enzymes, raised, 628 nevirapine, interaction, 629 P glycoprotein, interactions, 629 rifampicin, interaction, 628–9 prothrombin complex concentrate deep venous thrombosis, 680 disseminated intravascular coagulation, 680 myocardial infarction, 680 pulmonary embolism, 680 stroke, 680 proton pump inhibitors see also individual names abdominal pain, 749 defecation disorders, 749 flatulence and anorexia, 749–50 gastrointestinal motility, 749 myalgia, chest pain, 749–50 nausea, anxiety, diarrhea, 749 pharyngolaryngeal pain, 749 respiratory infection, 750 sinusitis and headache, 749 prucalopride dysrhythmias, 744 headache, abdominal pain, 743 nausea and diarrhea, 743 QT interval prolongation, 744 pseudoephedrine facial edema, 318

fever, 318 malaise, 318 myocardial infarction, 318 nausea and headache, 318 psilocybin abdominal pain, 66 altered mental status, 66 diarrhea, 66 nausea, 66 vomiting, 66 PUVA basal cell carcinoma, 339 pyrazinamide olfactory disorders, 637 pyrazolone derivatives see phenylbutazone pyrimethamine and congeners abdominal pain, 570 dizziness, 570 fever, 570 headache, 570 nausea, 570 vomiting, 570 Q quetiapine dizziness, 110 drug abuse, 111 dry mouth, 110 dyskinesias, 110 increased appetite, 110 and lithium, 110–11 nausea, 110 orthostatic hypotension, 110 and risperidone, 111 sedation, 110 somnolence, 110 and valproate, 111 weight gain, 110 quinidine and derivatives atrioventricular block, 390–1 hypotension, 390–1 nausea, 390–1 supraventricular and ventricular extra beats, 390–1 quinine and congeners fixed drug eruptions, 571 immune thrombocytopenia, 570 thrombotic microangiopathy, 570–1 ventricular fibrillation, 570 R rabies vaccine fever, 662 headache, 662 injection site pain, 662 swelling with induration, 662 radioactive iodine Graves' disease, 883

hyperthyroidism and thyroid cancer, 883 radiaion-induced thyroiditis, 883 raloxifene renal disease, 862 raltegravir aminotransferase activities, increased, 599 constipation, 599 depression, 599 etravirine, interaction, 600 flatulence, 599 insomnia, 599 nausea, 599 rhabdomyolysis, 599 rifampicin, interaction, 600 tipranavir and ritonavir, interaction, 600 ramelteon, 82 ramosetron fluvoxamine, interaction, 748 ranibizumab age-related macular degeneration, 978–9 cataract, 978–9 conjunctival hemorrhages, 980 endophthalmitis, 978–80 floaters, 980 intraocular pressure, transient increases, 979–80 macular edema, 978 mild pain, 980 non-ocular hemorrhages, 978 ocular inflammation, 978–9 retinal pigment epithelial tear, 978 rhegmatogenous retinal detachment, 979–80 stroke, 980 vitreous hemorrhage, 979–80 ranitidine anaphylactic reaction, 748 anaphylactic shock, 748 anesthesia, 748 clopidogrel and prasugrel, interaction, 748 consciousness, loss of, 748 edema, 748 wheezing, dyspnea, and hypotension, 748 rapamycin see sirolimus rasburicase hemolysis and methemoglobinemia, 250 remifentanil bradycardia, 222 cough, 222–3 drug tolerance, 223 drug withdrawal, 223

Index of drugs hypotension, 222 intensive care, 223 mean arterial pressure, reduced, 222 morphine interaction, 223 muscle rigidity, 223 respiratory depression, 222 repaglinide gemfibrozil, interaction, 898 hypoglycemia, 897 octreotide, 898 Rhododendron spp. Bezold–Jarisch reflex, 996 bowel disorders, 997 bradycardia, 996 dizziness, 997 erectile dysfunction, 997 hypertension, 997 hypotension, 997 myocardial infarction, 997 nausea, 997 nodal rhythm, 997 sinus rhythm, 997 stomach pains, 997 sweating, 997 syncope, 997 systolic blood pressure, 997 vomiting, 997 weakness, 997 ribavirin anemia, 580 azathioprine, interaction, 581–2 cognitive dysfunction, 580 enterocolitis, 581 hyperpigmentation of oral mucosa and tongue, 580–1 lichenoid eruption, 581 neutropenia, 580 oral lichen planus, 581 parkinsonism, 580 pure red cell aplasia, 580 sensorineural hearing loss, 580 spermatogenesis, abnormal, 581 thrombocytopenia, 580 thyroid dysfunction, 580 rifabutin acute generalized exanthematous pustulosis (AGEP), 637–8 lopinavir þ ritonavir interaction, 638 rifampicin atazanavir þ ritonavir, interaction, 639 atorvastatin, interaction, 639 hemolytic anemia, 639 hepatotoxicity, 638 intravascular hemolysis, 638

1061 lopinavir þ ritonavir, interaction, 639 oxycodone, interaction, 639–40 protease inhibitors, interaction, 640 ritonavir þ saquinavir, interaction, 640 roflumilast, interaction, 640 tuberculosis, 623–8 rifaximin IgE-mediated reactions, 640 rimonabant atrial fibrillation, 14 ciclosporin, interaction, 14 depressive episode, 13 partial seizures, 14 risperidone akathisia, 112 amenorrhea, 113 anxiety, 113 depression, 113 and divalproex, 112 dysmenorrhea, 111–2 fatigue, 111 galactorrhea, 113 gynecomastia, 111–3 and haloperidol, 112 headache, 113 impaired sensorimotor function, 113 increased appetite, 111 increased prolactin concentrations, 111 insomnia, 112, 113 menorrhagia, 113 prolactin-related adverse events, 113 psychiatric aggravation, 111–2 somnolence, 111 tardive dyskinesia, 113 tremor, 112 weight gain, 111–2 weight increase, 113 ritodrine muscle pain, 323–4 rhabdomyolysis, 323–4 ritonavir adrenal suppression, 596 albendazole, interaction, 596 cat's claw, interaction, 596 mebendazole, interaction, 596 quinine, interaction, 596 rituximab chronic graft-versus-host disease, 791 ciclosporin-dependent nephrotic syndrome, 791 common variable immunodeficiency, 792

flushing, angioedema, bronchospasm, 792 gastrointestinal perforation, 792 Graves' disease, 791 hyperammonemic encephalopathy, 792 interstitial lung disease, dyspnea, and pneumonitis, 792 progressive multifocal leukoencephalopathy, 792 refractory myasthenia gravis, 791 Sjögren's syndrome, 791 tumor lysis syndrome, 792 vasculitic disorders, 791 vomiting, nausea, urticaria, fatigue, 792 rivastigmine erythema, 16–17 fasciculation, 17 hepatotoxicity, 17 nausea and vomiting, 16–17 pruritus, 16–17 rocuronium benefit to harm balance, 301 rofecoxib death, 247 edema, 247 embolism, 247 hemorrhage, 247 thrombosis, 247 roflumilast blood glucose and glycosylated hemoglobin, 368–9 headaches, 368 nausea and diarrhea, 368 weight loss, 368 ropivacaine seizures, 293 tonic-clonic seizures, 293 rosiglitazone fibrates, interaction, 901–2 heart failure, 901 mortality, 901 myocardial infarction, 901 renal disease, 901 rosuvastatin drug interactions, 928 enzyme induction, 928 rotavirus vaccine intussusception, 662–3 roxithromycin abdominal pain, 524 dry mouth, 524 headache, 524 nausea, 524 rupatadine cardiac rhythm disturbances, 349 cold symptoms, 349

Index of drugs

1062 diabetes and dyslipidemia, 349 intermittent claudication, 349 kidney and liver impairment, 349 QT interval prolongation, 349 S sagopilone central ataxia, 949 diarrhea, 949 neuropathy, 949 neutropenia, 949 Saint John's wort see Hypericum perforatum salicylates see acetylsalicylic acid salmeterol asthma mortality, 362 asthma treatment, 363 brain-derived neurotrophic factor (BDNF), 362 sapropterin see tetrahydrobiopterin saquinavir cat's claw, interaction, 597 sargramostim acute myelogenous leukemia, 771 back and bone pain, 771 Crohn's disease, 771 injection site reactions, 771 pyrexia, 771 saxagliptin congestive heart failure, 895 edema, 895 renal or liver disease, 895 sclerosants deep vein thrombosis, 1021–2 duplex ultrasonography, 1021 migraine, 1021–2 pelvic colicky pain, 1021 pelvic congestion syndrome, 1021 pelvic pain, 1021 post-thrombotic syndrome, 1021 pulmonary embolism, 1021–2 saphenous veins, 1022 septicemia, 1021–2 transient ischemic stroke, 1021–2 transthoracic echocardiography, 1021 varicose tributaries, 1022 visual disturbances, 1021–2 scopolamine see hyoscine selective serotonin re-uptake inhibitors (SSRIs)

see also individual names and antidepressant drugs carotidynia, 26 emergent suicidal ideation, 26–7 erectile difficulties, 27 genetic predictor, 29 impaired orgasm, 27 paroxetine, 30 photosensitivity, 27 in pregnancy, 27–9 reduced libido, 27 sertraline, 30 selenium dental caries, 454 dizziness, 454 fatigue and amenorrhea, 454 fatigue and malaise, 454 glutathione peroxidase (GPX), 454 hair loss, 454 nails, 454 superoxide dismutase (SOD), 454 total body formula, 454 senna abdominal pain, 754–5 dizziness and headache, 754–5 nausea and vomiting, 754–5 serotonin and noradrenaline re-uptake inhibitors (SNRIs) see also antidepressant drugs, duloxetine, venlafaxine, and desvenlafaxine mania and hypomania, 30–1 sertindole, 114 sertraline, 30 sevoflurane cardiac rhythm, 260 delirium, 259–60 emergence delirium, 258–9 malignant hyperthermia, 260 shen ling bai zhu san erythema multiforme, 990 eyes swollen, 990 skin lesion, 990 shu xue ning injection anaphylactic shock, 991 bronchospasm, 991 chest distension, 991 macular rashes, 991 nausea, 991 palpitation, 991 urticaria, 991 sibutramine myocardial infarction, 13 obesity, 13 silicone penile augmentation, 1022 silver salts and derivatives sensation in limbs, 454

simvastatin acute renal insufficiency, 928 bilateral leg compartment syndrome, 928 CYP3A4 inhibition, 928 dermatomyositis, 928 muscle pain, soreness, fatigue, or weakness, 928 myonecrosis, 928 rhabdomyolysis, 928 sirolimus (rapamycin) bronchiolitis obliterans, 820 diabetes mellitus, 820 fever, 821 gonadal dysfunction, 820–1 growth retardation, 820 infertility, 820–1 interstitial pneumonitis, 820 lymphedema, 820 mouth ulser, 820 ovarian cysts, 821 proteinuria, 820 sperm count, reduced, 820 sitagliptin anaphylaxis, 895 angioedema, 895 sitaxsentan acenocoumarol, interaction, 423 aminotransferases, raised, 423 cough, 423 dyspnea, 423 hepatitis, 423 nasopharyngitis, 423 peripheral edema, 423 skin branding cavernous sinus thrombosis, 1000–1 multiple splenic abscesses, 1000–1 septic shock, 1000–1 smallpox vaccine myopericarditis, 663 sodium hypochlorite allergic disease, 484–5 lower respiratory tract symptoms, 484–5 pulmonary function, 484 sodium metabisulfite asthma, 1022 occupational airways disease, 1022 vocal cord dysfunction and underlying asthma, 1022 sodium picosulfate hyponatremia, 756 somatostatin (growth hormone release-inhibiting hormone) and analogues bradycardia, 913–4 carcinoid syndrome, 914 conduction abnormalities, 913–4

Index of drugs fasting plasma glucose, increased, 914 gallstones, 913–4 parkinson-like symptoms, 914 somatropin (human growth hormone, hGH) abdominal pain, 911 blood pressure, increased, 910 de Quervain's tenosynovitis, 911 epiphysiolysis, 911 Hurler's syndrome, 911 impaired glucose tolerance, 911 inhaled growth hormone, 911 left ventricular mass, increased, 910 myocardial infarction, 910–1 pancreatitis, 911 sotalol torsade de pointes, 399 spa therapy, 1001 spinal (intrathecal) anesthesia apnea, 284–5 cardiac arrest, 286 chemical meningitis, 286 heart rate, 284 hypotension, 284 microradiculopathy, 285 propriospinal myoclonus, 285–6 spinal myoclonus, 285 subdural hematoma, 286 transient neurological symptoms, 285 spironolactone gynecomastia, 440–2 hyperkalemia, 440–2 polycystic ovary syndrome, 442 renal function, 440–2 squirting cucumber see Ecbalium elaterium stavudine distal sensory polyneuropathy, 587–8 hyperlactatemia, 583 mitochondrial dysfunction, 583 proximal renal tubular dysfunction, 588 weight gain, 583 stem cells abdominal cramping, 683 agitation, 683 chest pain, 683 chills, 683 cough, 683 dyspnea, 683 fever, 683 graft-versus-host disease (GvHD), 683

1063 hiccups, 683 hypertension, 683 hypotension, 683 hypoxia, 683 myocardial damage, 683 nausea, 683 sore throat, 683 stent restenosis, 682 tachycardia, 683 vomiting, 683 stiripentol see also antiepileptic drugs adjunctive therapy, 160 appetite, 160–1 ataxia, 160–1 Dravet's syndrome, 160 hyperactivity or irritability, 160–1 severe myoclonic epilepsy, 160 sleep disturbance, 160–1 street drugs adulteration, 53 clenbuterol, 53 contamination, 53 dilution, 53 substitution, 53 streptomycin tuberculosis, 623, 627–8 strontium salts alopecia, 455 DRESS, 455 gastrointestinal disturbances, 455 green monkey kidney cells, 455 hypocalcemia, 455 kidneys and bones receptors, 455 memory loss, 455 minor skin complaints, 455 Stevens–Johnson syndrome, 455 toxic epidermal necrolysis, 455 venous thromboembolism, 455 subcutaneous immunoglobulin fever, 678–9 induration of skin, 678–9 malaise, 678–9 pain, 678–9 palpitation, 678–9 rash, 678–9 redness, 678–9 skin induration, 678–9 soreness, 678–9 swelling, 678–9 succinylcholine see suxamethonium sufentanil, 223 sugammadex QT interval prolongation, 302

sulfadiazine hemolytic anemia, 528 methemoglobinemia, 528 urolithiasis, 528 sulfasalazine DRESS, 759 hypersensitivity syndrome, 759 juvenile rheumatoid arthritis, 759 sulfites amyotrophic lateral sclerosis, 1023 cysteine, 1023 glutathione metabolism, 1023 urine sulfite, 1023 sulfonylureas gastrointestinal cancer, 898 sulfur hexafluoride hypotension, 972 sinus bradycardia, 972 tonic-clonic seizures, 972 sulprostone pulmonary edema, 848 superparamagnetic iron oxide (SPIO) abdominal cramps, 971 diarrhea, 971 headache, 971 low back pain, 971 pruritus, 971 reticuloendothelial system, 970, 970 urticaria, 971 suramin abdominal pain, 650 conjunctivitis, 650 fever, 650 muscle pain, 650 paresthesia, 650 rash, 650 renal insufficiency, 650 Trypanosoma brucei gambiense, 650 suxamethonium anaphylaxis, 299–300 malignant hyperthermia, 300 muscle fasciculation, 299 spontaneous subluxation, temporomandibular joint, 299 takotsubo syndrome, 299 T tacrolimus abdominal pain, 822 abnormal glycemic control, 822 akinetic mutism, 821 amlodipine, interactions, 823 antifungal azoles, interactions, 823

Index of drugs

1064 appetite, 823 asymptomatic hypotension, 823–4 atopic dermatitis, 822 brachial neuritis, 821 carbamazepine, interactions, 823–4 cholelithiasis, 822 colitis, 822 eczema, 822 epistaxis and ecchymoses, 823 gallbladder sludge, 822 gastrointestinal symptoms, 821 infections and hyperglycemia, 821 intermittent bloody diarrhea, 821 nausea and vomiting, 821 plasma triglyceride, increased, 822 progressive necrotic encephalopathy, 822 renal failure, 824 reversible leukoencephalopathy, 821–2 tachypnea, leg pains, gingival bleeding, 823 thrombotic microangiopathy, 822 thrombotic thrombocytopenic purpura, 822 type 2 diabetes, 823 vomiting, diarrhea, headache, 823 weight loss and dehydration, 822 tafenoquine and primaquine abdominal discomfort, 569 diarrhea, 569 nausea, 569 talc chest pain, 1023 lung cancer, 1023–4 ovarian cancer, 1023–4 respiratory distress, 1023 skin cancer, 1023–4 tamoxifen breast cancer, 863 endometrial cancer, 863–4 endometrial polyps, 863 fractures, 862 Goldenhar's syndrome, 864 heriditary angioedema, 863 leiomyoma, 864 oculo-auriculo-vertebral syndrome, 864 pseudolymphoma, 863 renal disease, 864–5

thromboembolism, 864 tamsulosin ejaculatory disorders, 427 endophthalmitis, 426 priapism, 426–7 retinal detachment, 426 taxanes see also docetaxel, paclitaxel apoptosis, 935 cell cycle arrest, 935 technetium sestamibi angioedema, 973 difficulty in speaking, 973 drooling, 973 tongue swelling, 973 tegaserod bradycardia, dizziness, and hypoglycemia, 744 diarrhea, 744 headache, nausea, and abdominal pain, 744 irritable bowel syndrome, 744 ischemic events, 744 vomiting and constipation, 744 teicoplanin osteomyelitis and prosthetic infection, 519 pigmented eruption, 519 telavancin nausea and vomiting, 520 telbivudine cardiac repolarization, 582 telithromycin hepatotoxicity, 521–2 oxycodone, interaction, 522 telmisartan mycophenolate mofetil, interaction, 419–20 temazepam, 77 temsirolimus anemia, hyperglycemia, and weakness, 824 creatinine, increased, 824 hypercholesterolemia, 824 hypophosphatemia, 824 hypothyroidism, 824 mucositis, 824 pneumonitis, 824 proteinuria, 824 rashes, 824 weakness/fatigue, 824 tenofovir bone fractures, 589 Fanconi syndrome, 588 impaired glomerular function, 588–9 nephrogenic diabetes insipidus, 588 terbinafine acenocoumarol, interaction, 541–2

acute generalized exanthematous pustulosis (AGEP), 541 anterior optic neuropathy, 541 cutaneous lupus-like syndrome, 541 headache, 541 nasopharyngitis, 541 pyrexia, 541 terlipressin alcoholic cirrhosis, 917 esophageal varices, 917 hepatocellular carcinoma, 917 hepatorenal syndrome, 917 interval prolongation, 916 multiple ulcers, 916 renal failure, 917 superficial dermal capillaries thrombosis, 916 ventricular dysrhythmia, 916 tesofensine blood pressure, increased, 14–15 constipation, diarrhea, and insomnia, 14–15 dry mouth and nausea, 14–15 tetrabenazine akathisia, 306 constipation, 306 depression, 306 Huntington's disease, 306 insomnia, 306 Tourette syndrome, 305 tetracyclines see also individual names environment, 497–8 and glycylcycline, 498 tetrahydrobiopterin and sapropterin plasma phenylalanine concentrations, 694 theophylline acute pancreatitis, 13 status epilepticus, 12–13 thiazide and thiazide-like diuretics see also hydrochlorothiazide hypokalemia, 438–9 hyponatremia, 438–9 rhabdomyolysis, 439 thiazolidinediones (glitazones) coronary artery disease, 899 heart failure, 899, 900 macular edema, 899 mortality, 901 myocardial infection, 899, 900 thienopyridines see also individual names allergic, 720

Index of drugs rash, 720 thrombocytopenic purpura, 720 thioguanine abnormal liver function, 830 Crohn's disease, 830 nodular regenerative hyperplasia, 830 portal hypertension, 830 thiopental sodium electrolyte balance, 276 gastrointestinal, 275 hypotension, 275 thiopurines arthralgia/myalgia, 825 Crohn's disease, 825 diarrhea, 825 flu-like symptoms, 825 headaches, 825 hepatitis, 826 hypersensitivity reaction, 826 inflammatory bowel disease, 825 malaise, 825 nausea and vomiting, 825 pancreatitis, 826 Sweet's syndrome, 826 ulcerative colitis, 825 thorn apple see Datura stramonium thorotrast granuloma, 973 primary cerebral angiosarcoma, 973 thyroid hormones anemia, 882 antidepressants, 881–2 autonomous nervous system abnormalities, 882 depression, 882 heart rate, low, 882 hemoglobin, rise in, 882 hyponatremia, 882 increased serum ferritin, 882 increased urinary catecholamine excretion, 882 lethargy, nausea, 882 liver failure, 882–3 neonatal complications, 881 obstetric, 881 serum iron, rise in, 882 subclinical hyperthyroidism, 881 subclinical thyroid disease, 882 thyroid cancer, 881 weakness, dizziness, fainting spells, 882 thyrotropin (thyroidstimulating hormone, TSH) hyperamylasemia, 881 neutropenia, 881

1065 non-toxic goiter, 881 sialoadenitis, 881 thrombocytopenia, 881 thyrotropin-releasing hormone and thyrotropin, 913 tiagabine see also antiepileptic drugs anxiety/mood disorder, 161 gemfibrozil interaction, 161 headache/nausea, 161 hepatic insufficiency, 161 somnolence/fatigue, 161 tibolone breast cancer, 867 coronary heart disease, 867 endometrial hyperplasia, 867 gynecological cancers, 867–8 mortality, 867–8 osteoporosis, 867 stroke, 867 venous thromboembolism, 867 vertebral fractures, 867 tick-borne meningoencephalitis vaccine thrombocytopenic purpura, 663 ticlopidine acute cholestatic hepatitis, 724 neutropenia, 724 tigecycline hypofibrinogenemia, 501 pancreatitis, 501 severe coagulation disorder, 501 tilidine, 223–4 timolol, 983 dorzolamide, 400 tiotropium bromide constipation, 363 dry mouth, 363 dysuria, 363 gastrointestinal obstruction, 363 urinary retention, 363 urinary symptoms, 363 tipranavir intracranial hemorrhage, 597 ritonavir, interaction, 597 toxic epidermal necrolysis, 597 triglyceride concentrations, raised, 597 titanium allergic symptoms, 597 ceramic debris, 596 cytokine release, 456 dental implantation, 457 diplopia, 456 DRESS, 457

endothelial cells, hypertrophied, 457 giant cell granuloma, 457 hearing aids, 456 immunogenicity, 456 inflammatory reactions, 457 lung disease, granulomatous, 457–8 lymphocyte reactivity, 456 macrophage, spindle-shaped, 457 tizanidine brain injury, 307 limb muscle, 307 spinal cord injury, 307 toad extract intravenous injection, 999 salivary and skin glands, secretions, 999 tobramycin aquagenic wrinkling of the palms, 513 loss of vestibular function, 513 toluene balance problems, 1024 blood pressure, raised, 1024 body temperature, reduced, 1024 confusion and disorientation, 1024 coordination, loss of, 1024 horizontal nystagmus, 1024 leukoencephalopathy, 1024 metabolic acidosis, 1024 neuropsychological deficits, 1024 tolvaptan see vasopressin receptor antagonists topical anesthesia allergic reactions, 289 cardiac arrest, 288 fixed dilated pupils, 288–9 topiramate see also antiepileptic drugs acute myopia, 164 angle-closure glaucoma, 164, 167 anorexia, 162 ataxia, 163 behavioral disturbances, 166–7 blue pseudochromhidrosis, 165 cognitive effects, 162, 164 dizziness, 162, 162 epistaxis, 163, 165 fatigue, 162 glucocorticoids, interaction, 167 headache, 161

Index of drugs

1066 hyperammonemic encephalopathy, 164–5 hyperesthesia, 163 hyperkinesia, 166–7 hyperthermia, 165 hypesthesia, 162 hypohidrosis, 165 hypotensive therapy, 167 hypothermia, 166 maculopathy, 164 memory impairment, 161 metabolic acidosis, 165 migraine, 163 monotherapy, 162, 163 nephrolithiasis, 165 osteoporosis, 165 paresthesia, 161, 162 posaconazole, 167 pseudochromhidrosis, 165 psychiatric disorders, 164–7 renal calculus, 163 renal stones, 165 restless legs syndrome, 164 sexual dysfunction, 165–6 somnolence, 162 speech disorder, 161–2 symptomatic epilepsy, 161 tremor and myoclonus, 164 valproate, 164 vitanin B12 deficiency, 165 weight loss, 161 torcetrapib atherosclerotic disease, 930 blood pressure, increased, 929 cardiovascular events, 930 coronary heart disease, 929 diabetes mellitus, 929 ischemic heart disease, 930 tramadol constipation, 224 dizziness, 224 drug overdose, 225 multiorgan failure, 224 nausea, 224 paracetamol, interaction, 225 respiratory depression, 224 tremor, 224 vomiting, 224 withdrawal syndrome, 224–5 transfusion see blood transfusion trastuzumab abdominal pain and bloating, 793 coronary syndrome, 793 diarrhea, vomiting, nausea, 793 febrile neutropenia, 793 heart failure, 793 interstitial lung disease, 793 travoprost, 848

blurring vision, 985 conjunctival injection, 985 eyelash thickening and elongation, 985 eyelid skin hyperpigmentation, 985 eyelid superior sulcus, deepening, 985 eyelid swelling, 985 ocular irritation, 985 tretinoin (all-trans retinoic acid, ATRA) photoallergenicity, 341 triazolam drug overdose, 78 sleep-dependent motor skill memory consolidation, 77–8 trimethoprim and co-trimoxazole emtricitabine, interaction, 529 erythrodermic psoriasis, 529 fixed drug eruption, 529 gait disorder, 528 liver abscesses, 528–9 Pneumocystis jirovecii, 528–9 Pneumocystis pneumonia, 529 Stevens–Johnson syndrome, 529 Sweet's syndrome, 529 toxic epidermal necrolysis, 529 triphenylmethane dyes airways obstruction, 482 allergy, 483 anesthesia, 482 bladder injury, 483 blood cultures, 482 burning pain, 483 ceftriaxone, 482 Chagas, disease, 481–2 conjunctival abrasions, 483 corneal stain, 483 cough and feeding difficulty, 482 cystitis, 483 DNA damage, 484 edema, 484 edema and hematuria, 483 fever, 482 fungal tracheitis, 482 hepatocellular carcinoma, 484 hypotension, 484 HIV/AIDS, 481–2 intravenous fluconazole, 482 laryngotracheitis, 482 lateral neck radiographs, 482 light-fastness, 481 methemoglobinemia, 483 mononuclear cell leukemia, 484

mucosal ulceration, 482 nasal congestion, 482 nasopharyngeal, 482 neutrophil infiltration, 483 oral candidiasis, 482 pararosaniline pamoate, 482 Philippines, 482 respiratory syncytial virus, 482 rhinorrhea, 482 schistosomiasis, 482 sepsis, 482 skin necrosis, 483 thyroid, follicular cell adenocarcinoma, 484 ulceration, 483 urgency and dysuria, 483 urticaria, 484 vaginal candidiasis, 481-2 viral cultures, 482 triptans acute dystonia and pathological laughter, 408 akathisia, 408 coronary artery disease, 408 difficulty in thinking, 408 dizziness, 408 epileptic syndromes, 409 headache, 409 hemiparesis, 409 ischemic colitis, 409 migraine, 409 myocardial infarction, 408 sleepiness and tiredness, 408 symptoms of migraine, 409 Tripterygium wilfordii Hook nephrotic syndrome, 998 rheumatoid arthritis, 998 skin pigmentation, 998 systemic autoimmune diseases, 998 trovafloxacin liver toxicity and acute liver failure, 519 TSH see thyrotropin tumor necrosis factor alfa (TNF-a) aminotransferases, raised, 779–80 anemia, 779–80 leukopenia, 779–80 myalgias, 779–80 neutropenia, 779–80 peripheral nerve damage, 780 thrombocytopenia, 779–80 tumor necrosis factor antagonists alopecia areata, 780 aminotransferases, raised, 780

Index of drugs demyelinating neuropathy, 780 discoid lupus erythematosus, 780 liches planus, 780 Nocardia farcinica, 780 psoriatic skin lesions, 780 thrombocytopenia, 780 vasculitis, 780 U ultrasound contrast agents acoustic impedance, 971 arterial circulation, 971 Uncaria tomentosa cirrhosis, 998 hepatitis C infection, 998 urapidil respiratory depression, 427 ursodeoxycholic acid dyspnea, 760 hepatitis C virus infection, 760 interstitial pneumonia, 760 V Vaccinium macrocarpon, 998 valaciclovir gastrointestinal disturbances, 578 headache, 578 valproate sodium and semisodium (divalproex) see also antiepileptic drugs abdominal obesity, 171 alopecia, 173 appetite, increased, 168 Baller–Gerold syndrome, 174 bipolar disorder, 168 carbapenem, 175 cardiac dysrhythmias, 175 carotid artery intima-media thickness, 169 chitosan, 175 cholestatic hepatitis, 172 cognitive impairment, 168 delirium, 170 dementia, 170 diarrhea, 167–8 encephalopathy, 169 eosinophilic pleural effusion, 169 epilepsy refractory, 175 erythema multiforme, 172 fetal valproate syndrome, 174 fibrinogen concentration, 171 fibular aplasia, 174 gastrointestinal disorder, 167–8 glucose concentration, 171

1067 headache, 169 hepatic failure, 172 hepatotoxicity, 176 Huntington's disease, 169–70 hyperammonemia, 170–1 hyperammonemic encephalopathy, 176 hyperandrogenism, 173 hyperglycemia, 171 hyperhomocysteinemia, 169 hyperinsulinemia, 171 hyperkeratosis, 172 hypertriglyceridemia, 171 hyponatremia, 175 lamotrigine, 175–6 leukopenia, 172 lithium effect, 170 lupus-like syndrome, 173 mania, 168 menstrual irregularities, 173 mental retardation, 175 metabolic syndrome, 171 monotherapy, 167–8 myopathy, 172–3 neuroendocrine dysfunction, 173 neutropenia, 172 non-alcoholic fatty liver disease, 172 olanzapine, 168–9 onychomadesis, 172 ovulatory dysfunction, 173 oxcarbazepine, 176 pancreatitis, 172 parakeratosis, 172 parkinsonism, 169 plasma ammonia concentration, 173 polycystic ovary syndrome, 173 psoriasiform eruption, 172 pulmonary anomalies, 174 quetiapine, 172, 176 Rowell's syndrome, 173 schizoaffective disorder, 172–3 schizophrenia, 175 sinusitis, 168 Sjögren's syndrome, 169 somnolence, 167–8 Stevens–Johnson syndrome, 172 stuttering, 170 supportive therapy, 176 thrombelastography, 171 thrombocytopenia, 171 thrombophilia, 171–2 toxic epidermal necrolysis, 172, 173 tremor, 167–8 upper respiratory tract infection, 168

valproate formulations, 174 valproate poisoning, 176 vertigo, 175 vomiting, 167–8 weight gain, 168 von Willebrand's disease, 171 worsening, 170 valsartan headache, 420 hypotension, 420 vancomycin asthma, 520 DRESS, 520–1 furosemide, interaction, 521 leukocytoclastic necrotizing vasculitis, 520 lupus-like syndrome, 521 neuralgic amyotrophy, 520 red man syndrome, 521 renal insufficiency, 520 thrombocytopenia, 520 varicella vaccine interstitial keratitis, 663 vasopressin and analogues bradycardia, 915 cardiopulmonary resuscitation, 916 hyponatremia, 915–6 placebo, 916 vasopressin receptor antagonists blood concentrations, 915 dry mouth, 915 heart failure, 915 hepatic cirrhosis, 915 infusion site reactions, 915 serum sodium concentration, increased, 915 venlafaxine and desvenlafaxine see also antidepressant drugs and serotonin and noradrenaline re-uptake inhibitors (SNRIs) constipation, 32 coronary artery disease, 31 hepatic failure, 340 nausea and insomnia, 32 verapamil bradycardia and loss of consciousness, 403 extreme hypotension, 403 invasive hemodynamic monitoring, 403 levosimendan, effect of, 404 massive bowel irrigation, 403 prolonged cardiac pacing, 403 verteporfin and photodynamic therapy accidental fall, 981–2 age-related macular degeneration, 981 cataract, 981

Index of drugs

1068 choroidal hypoperfusion, 981 colon cancer, 981–2 gastrointestinal hemorrhage, 981–2 hepatic cirrhosis, 981–2 hip osteoarthritis, 981–2 myocardial infarction, 981–2 pigment epithelial tear, 981–2 renal cell carcinoma, 981–2 renal failure, 981–2 respiratory failure, 981–2 stroke, 981–2 subretinal and intraretinal leakage, increased, 981–2 transient ischemic attacks, 981–2 vigabatrin see also antiepileptic drugs fatigue or drowsiness, 177 hypertension, 177 hypoxic brain injury, 177 induced ocular adverse effect, 178 infantile spasms, 176–7 intramyelinic edema, 176–7 metamfetamine, 177 neurological or cognitive deficit, 178 ophthalmological examination, 179 retinal function, 178 seizure, 177 somnolence, 177 tuberous sclerosis, 176–7 visual abnormalities, 177 white matter vacuolation, 177 vildagliptin headache, 895 hypoglycemia, 895 nasopharyngitis, 895 upper respiratory tract infections, 895 vincristine Hodgkin's lymphoma, 951 motor neuropathy, 951 neurotoxicity, 951 visilizumab cellulitis, candidiasis, 793 chest pain, 793 Crohn's disease, 794 cytokine release, 794 facial flushing, upper limb weakness, and low-grade fever, 793 nasopharyngitis, rhinitis, tonsillitis, 793 peripheral retinal hemorrhages, 793 upper respiratory tract infection, 793 urinary tract infection, 793

vitamin A (carotenoids) beta-carotene, 691 body mass index, 691 bone fractures, 692 chronic hypervitaminosis A, 691 fever, 692 fractures, 692 Guinea–Bissau, 691–2 Haemophilus influenzae b, 692 hepatitis B, 692 hepatotoxicity, 691 hepatic failure, 692 liver transplantation, 692 lung cancer, 691 mortality rate ratio (MRR), 691–2 nausea, 691 skin disoders, 691 skin irritation, 692 teratogenicity, 691 vomiting, 691 yellow-orange discoloration of skin, 691 vitamin A (retinoids) see also individual names vitamin B12 see cobalamins vitamin C (ascorbic acid) beta-carotene, 694–5 cataracts, 694 gestational hypertension, 694 oxalate crystal deposition, 694 pneumonia, risk of, 694–5 tuberculosis, 694–5 vitamin D analogues calcium–alkali syndrome, 695 fracture, risk of, 695 hemodialysis therapy, 695 hypercalcemia, 695 leukocytoclastic vasculitis, 695 metabolic alkalosis, 695 milk-alkali syndrome, 695 non-vertebral fractures, 695 palpable purpura, 695 vitamin E (tocopherol) congenital heart defect, 696 diabetes mellitus, 696 heart failure, 696 hepatic metabolism, 696–7 pre-existing vascular disease, 696 vitamin K metabolism, 696–7 von Willebrand factor/factor VIII concentrates allergic symptoms, 681 chills, 681 edema, 681 pain in the limbs, 681 phlebitis, 681

pseudothrombocytopenia, 681 voriconazole auditory hallucinations, 554–5 color perception altered/ blurred vision, 554–5 hepatotoxicity, 554, 555 myopathy, 555 neurological toxicity, 556 periostitis, 555 phototoxicity, 555 QT interval prolongation, 554 squamous cell carcinoma, 555 W water soluble intravascular iodinated contrast agents acute generalized exanthematous pustulosis (AGEP), 966 allergic reactions, 963, 966 bronchospasm, 967 cardiac-like symptoms, 697 chest tightness, 963 congestive heart failure, 964 contrast-induced nephrotoxicity, 964, 965 contrast media, 963, 964 dehydration, 964 diabetes mellitus, 964 erythema or rash, 967 hypersensitivity, delayed, 967 hypertension, labile, 963 hypotension, 967 injury, 965 intra-arterial injection, 966 intracranial hemorrhage, 964 intravenous hydration, 966 iodide-induced sialadenitis, 964, 965 iodide mumps, 964, 965 laryngeal edema, 963, 967 nephrogenic systemic fibrosis, 963 neurological event, 967 pruritus, 967 renal function, 966 shortness of breath, 967 sialdenitis, 964, 965 tachycardia, 967 urticaria, 963, 967 X xing nao jing injection allergic reactions, 991 blood pressure, raised, 991 cerebral infarction, 991 chest distension, 991 shortness of breath, 991

Index of drugs Y yellow fever vaccine dizziness, 664 dyspnea, 664 fatigue, 664 fever, 664 headache, 664 injection site erythema, 664 longitudinal myelitis, 664 nausea, 664 pain, 664 pruritus, 664 rash, 664 urticaria, 664 Z zaleplon drug overdose, 78 perceptual disturbances, 78 zanolimumab non-cutaneous peripheral T-cell lymphomas, 794 psoriasis, 794 zedoray tumeric oil and glucose injection allergic reactions, 992 anaphylactic shock, 992 dyspnea, 992 lead poisoning, 992 rashes, 992 vomiting and severe abdominal pain, 992 zhi xue capsule anal bulge, 990 constipation, 990 hematochezia, 990 liver damage, 990 zhuang gu guan jie wan abdominal pain and diarrhea, 990

1069 high blood pressure, 990 liver damage, 990 rashes, pruritus, nausea, and vomiting, 990 zidovudine adiponectin expression, reduction, 583–4 anemia, 588 incomplete cell differentiation, 583–4 leukopenia, 588 lipoatrophy, 584 palpebral ptosis, 588 pure red cell aplasia, 588 zileuton headache and nausea, 369 zinc anemia, 458 ataxia and falls, 458 back pain, 458 cold symptoms, 458 hyperzincemia, 458 hypocupremia, 458 knee pain, 458 paresthesia, 458 sense of smell loss, 458 ziprasidone insomia, 114 nausea, 114 QT interval prolongation, 114 sedation, 114 somnolence, 114 zolpidem sleep driving, 79 sleep walking, 78–9 zonisamide see also antiepileptic drugs

abdominal discomfort, 180 anorexia, 181 anticonvulsant hypersensitivity syndrome, 181 blurred vision, 181 diarrhea, 180 dry lips, 181 emotional lability, 180 fatigue, 180 headache, 180 hostility, 180 hyperammonemia, 181 hypersensitivity syndrome, 181 insomnia, 180 irritability, 179–80 loss of appetite, 179–80 lymphocyte toxicity, 181 nervousness, 180 nervous system irritability, 180 pancreatitis, 180 paresthesia, 180 pruritus, 180 rashes, 180 reduced sweating, 180 restless legs syndrome, 180 sedative effect, 180 seizure, 180 serum creatinine, increased, 181 sexual dysfunction, 180 somnolence, 179–80 topiramate, 180 zopiclone, 79 zotepine, 114 zuclopenthixol, 115

Index of adverse effects and reactions A abdominal aortic aneurysms carbon dioxide, 971 abdominal bloating lactulose, 754 phosphates, 755 abdominal colic antimony, 448 abdominal compartment syndrome cyanoacrylates, 1014 abdominal cramps bisacodyl, 753 octreotide, 914 stem cells, 683 superparamagnetic iron oxide, 971 abdominal discomfort baclofen, 302–3 praziquantel, 650 tafenoquine and primaquine, 569 zonisamide, 180 abdominal pain balsalazide, 756–7 blood substitutes, 672, 673 C1 esterase inhibitor concentrate, 674 dexlansoprazole, 750 enteral nutrition, 700 glutaral (glutaraldehyde), 480 kadda, 992 lansoprazole, 750–1 lansoprazole þ amoxicillin þ metronidazole or clarithromycin, 749 lanthanum carbonate, 451 levonorgestrel, 865 methylnaltrexone, 227 metoclopramide, 742–3 metronidazole, 573 palonosetron, 747 pancreatic enzymes, 761 pantoprazole, 752 posaconazole, 553 proton pump inhibitors, 749 prucalopride, 743 psilocybin, 66

pyrimethamine and congeners, 570 roxithromycin, 524 senna, 754–5 somatropin, 911 suramin, 650 tacrolimus, 822 tegaserod, 744 zedoray tumeric oil and glucose injection, 992 accidental fall verteporfin and photodynamic therapy, 981–2 Achilles' tendinitis inhaled glucocorticoids, 355 acidosis see metabolic acidosis acne hormonal contraceptives, 858–9 systemic glucocorticoids, 841 acneiform eruption dantrolene sodium, 305 acute coronary syndromes clopidogrel, 722 acute disseminated encephalomyelitis human papilloma virus (HPV) vaccine, 658 acute generalized exanthematous pustulosis (AGEP) cefotaxime, 493 co-amoxiclav and clavulanic acid, 496 moxifloxacin, 519 piperacillin þ tazobactam, 497 rifabutin, 637–8 terbinafine, 541 acute intermittent porphyria phenobarbital and primidone, 154 acute localized exanthematous pustulosis ibuprofen, 246 acute macular neuroretinopathy

adrenaline (epinephrine), 316 adenocarcinomas dexlansoprazole, 750 adrenal function, impaired megestrol acetate, 866 adrenal insufficiency etomidate, 262–3 glucocorticoids, 983 systemic glucocorticoids, 843 adrenal suppression etomidate, 263 inhaled glucocorticoids, 355 ritonavir, 596 adrenaline protamine, 727 adult respiratory distress syndrome (ARDS) parenteral nutrition, 697 adults death diphenhydramine, 347 adverse reactions apraclonidine, 982 docetaxel, 946 ixabepilone, 949 paclitaxel, 936 superparamagnetic iron oxide, 971 ultrasound contrast agents, 971 adverse risk increase tiotropium bromide, 363–364 age-related macular degeneration ranibizumab, 978–979 verteporfin and photodynamic therapy, 981 AGEP see acute generalized exanthematous pustulosis aggression atomoxetine, 7 levetiracetam, 148 montelukast, 366–367 agitation anticholinergic drugs, 324 atomoxetine, 7 benzydamine (benzindamine), 249

1071

Index of adverse effects and reactions

1072 dextromethorphan, 210 ketamine, 264, 265–266 lansoprazole, 751 methylthioninium chloride, 1019 metoclopramide, 743 midazolam, 75 montelukast, 366–367 nitrous oxide, 260–261 stem cells, 683 agranulocytosis See also leukopenia; neutropenia antithyroid drugs, 884 azithromycin, 523 benznidazole, 649 clozapine, 103 dapsone, 630, 631 deferasirox, 467 deferiprone, 469 phenytoin and fosphenytoin, 156 airwars obstruction triphenylmethane dyes, 482 akathisia aripiprazole, 99–100, 101 metoclopramide, 743 risperidone, 112 tetrabenazine, 306 triptans, 408 alcohol abuse paclitaxel, 939 alkalosis aminoglycoside antibiotics, 509 allergic conjunctivitis mascara, 334–5 allergic contact dermatitis aciclovir, 578 diclofenac, 245 diphenhydramine, 346–7 allergic disease sodium hypochlorite, 484–5 allergic rash see rashes allergic reaction See also anaphylactic reaction Actaea racemosa, 992 acupuncture, 1000 amoxicillin, 496 aprotinin, 726 bacille Calmette-Guérin (BCG) vaccine, 656 ci wu jia injection, 991 clopidogrel, 724 coumarin anticoagulants, 713 enteral nutrition, 701 factor IX (coagulation proteins), 680 factor VIII (coagulation proteins), 679–680 filgrastim, 769

fluconazole, 551 heparins, 716 hydrochlorothiazide, 439 insulin, 480 ku die zi injection, 991 lansoprazole, 751 latex, 1018 lidocaine, 291 ling yang gan mao capsule, 989–90 morphine, 216 neomycin, 513 nickel, 453 omeprazole and esomeprazole, 752 polyvinyl alcohol, 1021 praziquantel, 650 prilocaine and EMLA, 292 progestogens, 865 propofol, 271 thienopyridines, 720 titanium, 456 topical anesthesia, 289 von Willebrand factor/factor VIII concentrates, 681 water soluble intravascular iodinated contrast agents, 966 xing nao jing injection, 991 zedoray tumeric oil and glucose injection, 992 alopecia albumin-bound paclitaxel, 944 clonazepam, 73 docetaxel, 947 finasteride, 873 gabapentin, 138 hormonal contraceptives, 858–9 lamotrigine, 143–4 letrozole, 862 mercaptopurine, 830 paclitaxel, 941 phenobarbital and primidone, 154 selenium, 454 strontium salts, 455 valproate sodium and semisodium (divalproex), 173 aluminium toxicity parenteral nutrition, 698 alveolar edema labetalol, 399 alveolar hemorrhage antithyroid drugs, 885 azithromycin, 522 Alzheimer's disease aluminium, 447 insulin, 483 amenorrhea risperidone, 113

aminotransferases see liver function tests amyotrophic lateral sclerosis lithium, 41–2 anal fissure botulinum toxins, 304 anal irritation bisacodyl, 753–4 analgesia methoxyflurane, 258 anaphylactic reaction aprotinin, 726 blood transfusion, 671 C1 esterase inhibitor concentrate, 674 celecoxib, 246 cetirizine, 345 clarithromycin, 524 etherified starches, 675–6 fibrin glue, 674–5 gadolinium salts, 968 glucocorticoids, systemic, 845 gonadotropins, 909 heparins, 716 human papilloma virus (HPV) vaccine, 658 immunoglobulin, intravenous, 677, 678 iron salts, 451 influenza H1N1 vaccines, 659 minocycline, 500 omeprazole and esomeprazole, 752 ondansetron, 746 paracetamol (acetaminophen), 245 protamine, 727 ranitidine, 748 sitagliptin, 895 suxamethonium, 299–300 anaphylactic shock aprotinin, 726 cetirizine, 345 gadolinium salts, 968–9 itraconazole, 552 Panax ginseng, 996 ranitidine, 748 shu xue ning injection, 991 zedoray tumeric oil and glucose injection, 992 anemia See also aplastic anemia, hemolytic anemia, megaloblastic anemia, sideroblastic anemia aldesleukin (interleukin-2, IL-2), 777 alemtuzumab, 784 antithyroid drugs, 884 azathioprine, 829 DAMB, 542–3

Index of adverse effects and reactions docetaxel, 947 donepezil, 15 flucytosine, 559 immunoglobulin, intravenous, 677 interferon alfa, 773 interleukin-18 (IL-18), 779 levofloxacin, 517 metformin, 484 oxazolidinones, 525, 526 paclitaxel, 939 pegfilgrastim, 770 ribavirin, 580 temsirolimus, 824 thyroid hormones, 882 tumor necrosis factor alfa, 779–80 zidovudine, 588 zinc, 458 anesthesia 5HT3 receptor antagonists, 744 metformin, 484 ondansetron, 746 oxytocin, 913 ranitidine, 748 triphenylmethane dyes, 482 angina See also myocardial infarction alprostadil (prostaglandin E 1), 846 angioedema amlodipine, 401 angiotensin converting enzyme (ACE)inhibitors, 417 bupropion (amfebutamone), 33 estrogens, 852 heparins, 716 influenza H1N1 vaccines, 659 losartan, 419 montelukast, 367 sitagliptin, 895 technetium sestamibi, 973 anion gap metabolic acidosis glycols, 1018 anorexia see appetite loss anterior optic neuropathy terbinafine, 541 anterior uveitis prostaglandin analogues, 984 anticholinergic symptoms and signs promethazine, 349 antiepileptic drugs hypersensitivity syndrome antiepileptic drugs, 129 lamotrigine, 144

phenobarbital and primidone, 154 phenytoin and fosphenytoin, 156 zonisamide, 181 anxiety anthrax vaccine, 655–6 anticholinergic drugs, 324 aripiprazole, 99–101 mefloquine, 569 memantine, 16 proton pump inhibitors, 749 risperidone, 113 tiagabine, 161 anxiousness and dream abnormalities montelukast, 366–7 aortic dissection cocaine, 58 aplasia cutis antithyroid drugs, 885 aplasia cutis congenita azathioprine, 828 aplastic anemia See also anemia dapsone, 630 mesalazine (5-aminosalicylic acid, mesalamine), 758 apnea alfentanil, 209 spinal (intrathecal) anesthesia, 284–285 apoptosis epothilones, 948 taxanes, 935 appendicitis barium sulfate, 967 appetite loss acupuncture, 999 anthraquinones, 753 benznidazole, 649 ethosuximide, 136 gabapentin, 136–7 immunoglobulin, intravenous, 678 letrozole, 862 memantine, 16 mifepristone, 867 proton pump inhibitors, 749–50 stiripentol, 160–1 tacrolimus, 823 topiramate, 162 valproate sodium and semisodium (divalproex), 168 zonisamide, 179–81 appetite, reduced apraclonidine, 982 metronidazole, 573 modafinil, 11

1073 argyria silver salts and derivatives, 454–5 arrhythmias see dysrhythmias arterial occlusion flunitrazepam, 73–4 arterial pressure cobalamins (vitamin B12), 693 arterial thrombosis heparins, 715–6 arterial vasodilatation parathyroid hormone, 913 arthralgia albumin-bound paclitaxel, 944 anthrax vaccine, 655–6 docetaxel, 947 exemestane, 861 huperzine, 16 immunoglobulin, intravenous, 677 ixabepilone, 949 letrozole, 862 memantine, 16 paclitaxel, 941 penicillamine, 472 penicillins, 495 thiopurines, 825 arthritis deferiprone, 469–70 gold and gold salts, 451 leflunomide, 818 Tripterygium wilfordii Hook, 998 arthropathy deferiprone, 470 fluoroquinolones, 514 aseptic lymphocyte-dominated vasculitis-associated lesion (ALVAL) cobalt, 450 aseptic mediastinal cyst albumin-derived hemostatics, 670 aseptic meningitis immunoglobulin, intravenous, 677 lamotrigine, 143 aspergillosis everolimus, 817–8 glucocorticoids, systemic, 845 itraconazole, 553 asterixis cycloserine, 630 asthma acetylsalicylic acid, 248 anticholinergic drugs, inhaled, 364 cyanoacrylates, 1015 formoterol, 360–1

Index of adverse effects and reactions

1074 glimepiride, 898 glucocorticoids, inhaled, 355 glucocorticoids, systemic, 842 latex, 1018 long-acting beta2adrenoceptor agonists (LABAs), 357, 358 mannitol, 442 montelukast, 366, 367 paracetamol (acetaminophen), 244–5 salmeterol, 362, 363 sodium metabisulfite, 1022 vancomycin, 520 zileuton, 369 asthma, worsening montelukast, 366 asystole dipyridamole, 719 ataxia pregabalin, 158 stiripentol, 160–1 topiramate, 163 zinc, 458 atherosclerotic disease alcohol, 1010 torcetrapib, 930 atopic dermatitis pimecrolimus, 819 tacrolimus, 822 atrial fibrillation adenosine and analogues, 379 adrenaline (epinephrine), 315 aprotinin, 725 gemfibrozil, 923 milrinone, 378–9 paclitaxel, 938 paliperidone, 109 protamine, 727 rimonabant, 14 atrial tachycardia long-acting beta2adrenoceptor agonists (LABAs), 359 propafenone, 389–90 atrioventricular block cardiac glycosides, 377 dapsone, 630 attention deficit disorder mercury and mercurial salts, 453 auditory hallucinations amantadine, 604 voriconazole, 554–5 auranocyanide anion gold and gold salts, 451 autism spectrum disorders long-acting beta2adrenoceptor agonists (LABAs), 359

measles-mumps-rubella (MMR) vaccine, 661 mercury and mercurial salts, 453 autoantibodies iron chelators, combinations, 471 autoimmune disorders human papilloma virus (HPV) vaccine, 658 influenza H1N1 vaccines, 659 Tripterygium wilfordii Hook, 998 avascular osteonecrosis titanium, 457 axial hypotonia deferiprone, 470 axonal motor neuropathy phenobarbital and primidone, 154 azoospermia finasteride, 873 B back pain agomelatine, 33 aliskiren, 420 anthrax vaccine, 655–6 erythropoietin and derivatives, 682 immunoglobulin, intravenous, 677 melatonin, 912 memantine, 16 zinc, 458 bacterial cellulitis anakinra (interleukin-1 receptor antagonist), 779 bacterial meningitis imipenem, 492 meropenem, 492 balance problems toluene, 1024 Baller–Gerold syndrome valproate sodium and semisodium (divalproex), 174 ballismus flumazenil, 81 Bartter-like syndrome amikacin, 510 gentamicin, 511 basal cell carcinoma Artemisia vulgaris, 993 hair dyes, 336 iron chelators, 465 PUVA, 339 basal tear secretion isotretinoin, 340 Beau's lines azathioprine, 827 behavior and tremor montelukast, 366–7

behavioral changes ethosuximide, 136 lacosamide, 140–1 topiramate, 166–7 belching pantoprazole, 752 benign proliferative epithelial disorders hormone replacement therapy (HRT), 855 benign intracranial hypertension see intracranial hypertension, benign bilateral leg compartment syndrome simvastatin, 928 bilateral temporal hemianopia ethambutol, 634 biliary pseudolithiasis ceftriaxone, 494 binge-eating disorder lamotrigine, 142 bipolar disorder antiepileptic drugs, 128 antipsychotic drugs, 95 carbamazepine, 133–4 lamotrigine, 142 oxcarbazepine, 152 valproate sodium and semisodium (divalproex), 168 birth weight, low manganese, 452–3 bitter taste metronidazole, 573 black tongue bismuth compounds, 752–3 bladder calcification bacille Calmette-Guérin (BCG) vaccine, 656 bladder ulceration gentian violet, 483 bleeding Actaea racemosa, 992 acupuncture, 999 clopidogrel, 720–1 coumarin anticoagulants, 707 drotrecogin alfa, 671 fondaparinux, 718 idraparinux, 718–9 blepharitis mascara, 334–5 blindness arsenic, 449 nilutamide, 874 blisters insulin, 890 bloating calcium salts, 449 dexlansoprazole, 750 blood cysteine sulfites, 1023

Index of adverse effects and reactions blood dyscrasias deferasirox, 467 blood loss nifedipine, 402 blood pressure, increased. See also hypertension amfetamine, 1–2 blood substitutes, 673 ketamine, 264 methylphenidate, 7–8 moxonidine, 427 phenylephrine, 318–9 somatropin, 910 tesofensine, 14–15 toluene, 1024 torcetrapib, 929 xing nao jing injection, 991 zhuang gu guan jie wan, 990 blood pressure, reduced see hypotension bloodstream infection see septicemia bloody diarrhea glutaral (glutaraldehyde), 480 tacrolimus, 822 blue pseudochromhidrosis topiramate, 165 blurred vision pregabalin, 158 voriconazole, 554–5 zonisamide, 181 body temperature, reduced toluene, 1024 bone density, increased lithium, 45 bone dysplasia deferoxamine, 471 bone mineral accretion inhaled glucocorticoids, 356 bone pain ciclosporin, 816 epoetin alfa, 682 erythropoietin and derivatives, 682 lenograstim, 770 pegfilgrastim, 770 sargramostim, 771 bowel disease etanercept, 781 infliximab, 783 glucocorticoids systemic, 844 bowel disorder ixabepilone, 949 Rhododendron spp., 996–8 bowel syndrome balsalazide, 756 glucagon, 889 brachial neuritis human papilloma virus (HPV) vaccine, 658 tacrolimus, 821 bradycardia

atenolol, 397 beta-adrenoceptor antagonists, 983 betaxolol, 397–8 cyanoacrylates, 1014 endoperoxides, 571 esmolol, 398 fentanyl, 212 huperzine, 16 hydromorphone, 214 ketamine, 266 olanzapine, 104 ondansetron, 745 paclitaxel, 941–942 phenytoin and fosphenytoin, 155 remifentanil, 222 Rhododendron spp., 996–8 somatostatin, 913–4 tegaserod, 744 vasopressin, 915 verapamil, 403 bradydysrhythmias cardiac glycosides, 377 bradykinesia fentanyl, 212 bradypnea ketamine, 266 lidocaine, 388 brain abscesses cyanoacrylates, 1015 brain damage insulin, 479 ocular anesthesia, 287–8 tizanidine, 307 brain tumors formaldehyde, 480 breast cancer bevacizumab, 785 bisphosphonates, 1012 diethylstilbestrol, 853 hormone replacement therapy (HRT), 853 insulin, 481 ixabepilone, 948 levonorgestrel, 865 methylthioninium chloride, 1018–9 oleic acid, 1021 palonosetron, 747 tamoxifen, 863 tibolone, 867 breast lump barium sulfate, 967–8 breast tenderness Actaea racemosa, 992 breath holding ketamine, 264–5 breathing and pain benzalkonium compounds, 481 bronchiolitis obliterans nitrofurantoin, 524–5

1075 bronchitis memantine, 16 bronchopulmonary dysplasia furosemide, 440 bronchospasm See also asthma docetaxel, 948 fentanyl, 212–3 immunoglobulin, intravenous, 677 lidocaine, 388 omeprazole and esomeprazole, 752 paclitaxel, 941–2 shu xue ning injection, 991 water soluble intravascular iodinated contrast agents, 967 Brugada syndrome flecainide, 387 lidocaine, 290–1, 388 bullous hemorrhagic dermatosis heparins, 715 bullous pemphigoid furosemide, 440 penicillamine, 473 burning sensation benzalkonium compounds, 481 lansoprazole þ amoxicillin þ metronidazole or clarithromycin, 749 paclitaxel, 939 pimecrolimus and tacrolimus, 337–8 burning-tingling sensation pimecrolimus, 819 C calcium-alkali syndrome vitamin D analogues, 695 calvarial dysplasia candesartan, 419 cancers See also individual names and organs ezetimibe, 922 imipenem, 492 capillary leak syndrome aldesleukin (interleukin-2, IL-2), 777 carbon monoxide poisoning chloroform, 257 carcinoid tumors infliximab, 783 cardiac arrest bupivacaine, 290 lacosamide, 140 lidocaine, 388 naloxone, 227–8 propofol, 270–1

Index of adverse effects and reactions

1076 spinal (intrathecal) anesthesia, 286 topical anesthesia, 288 cardiac dysrhythmias see also bradydysrhythmias adrenaline (epinephrine), 315 bupivacaine, 290 chloroform, 257 erythropoietin and derivatives, 682 flumazenil, 81 immunoglobulin, intravenous, 677 levetiracetam, 146–7 ondansetron, 746 paclitaxel, 937–8 phenytoin and fosphenytoin, 155 prucalopride, 744 rupatadine, 349 sevoflurane, 260 valproate sodium and semisodium (divalproex), 175 cardiac failure metoclopramide, 743 cardiac ischemia paclitaxel, 938 cardiac mortality formoterol, 360 cardiac repolarization telbivudine, 582 cardiac symptoms balsalazide, 756 cardiac toxicity, increased paclitaxel, 943 cardiac valvular disease ECSTASY, 62 cardiac-like symptoms water soluble intravascular iodinated contrast agents, 967 cardiogenic shock diphenhydramine, 347 cardiomyopathy adderall, 2 anagrelide, 719 cardiorespiratory arrest pegaptanib, 977–8 cardiotoxicity Agauria salicifolia, 997 albumin-bound paclitaxel, 943–944 antimony, 448 deferiprone, 469 docetaxel, 948 indoramin, 426 cardiovascular effects amantadine, 604 carpopedal spasm lactulose, 754 cataract

antipsychotic drugs, 94 glucocorticoids inhaled, 355 ranibizumab, 978–9 verteporfin and photodynamic therapy, 981 vitamin C (ascorbic acid), 694 cellulitis aripiprazole, 100–1 gadolinium salts, 968 visilizumab, 793 central blurring deferoxamine, 471 central nervous system effect lacosamide, 140–1 lamotrigine, 141–2 central retinal artery occlusion ocular anesthesia, 287 central retinal vein occlusion isotretinoin, 340 central venous catheters chlorhexidine, 480–1 central/centrocecal scotomas ethambutol, 634 ceramic debris titanium, 456 cerebellar syndrome deferiprone, 470 cerebral infarction xing nao jing injection, 991 cerebral inflammation penicillins, 495 cerebral ischemia lithium, 42 cerebral microbleeds coumarin anticoagulants, 707–8 cerebral venous thrombosis heparins, 714 cerebrovascular disease ceftriaxone, 493 phenobarbital and primidone, 154 certoparin heparins, 715 chemical meningitis spinal (intrathecal) anesthesia, 286 chemotherapy-induced neuropathic pain gabapentin, 136 chest discomfort adenosine and analogues, 379 dipyridamole, 719 flecainide, 387 glycoprotein IIb-IIIa inhibitors, 720 perfluorocarbons, 972 chest distension xing nao jing injection, 991 chest pain adenosine receptor agonists, 380

aripiprazole, 100–1 balsalazide, 756 clenbuterol, 323 coumarin anticoagulants, 713 dobutamine, 319 immunoglobulin, intravenous, 677 khat, 66 mercaptopurine, 830 mesalazine (5-aminosalicylic acid, mesalamine), 757 metamfetamine, 3 natalizumab, 791 niacin, 928 nickel, 453 pantoprazole, 752 perfluorocarbons, 972 postsynaptic a-adrenoceptor antagonists, 426 prazosin, 426 proton pump inhibitors, 749–50 stem cells, 683 talc, 1023 visilizumab, 793 chest pressure sensation erythropoietin and derivatives, 682 chest tightness idinated contrast agents, 963 chest trauma amiodarone, 381 chills amphotericin (ABCD), 542 C1 esterase inhibitor concentrate, 674 gadolinium salts, 970 intravenous immunoglobulin, 677 Panax ginseng, 996 penicillins, 495 stem cells, 683 von Willebrand factor/factor VIII concentrates, 681 choanal atresia antithyroid drugs, 885 cholelithiasis iron chelators, 465 cholestasis angiotensin converting enzyme (ACE)inhibitors, 418 benazepril, 418 loxoprofen, 246 naloxone, 228 parenteral nutrition, 699 cholestatic hepatitis azathioprine, 827 ciprofloxacin, 515 clarithromycin, 524 exemestane, 861 flucloxacillin, 497 ticlopidine, 724

Index of adverse effects and reactions valproate sodium and semisodium (divalproex), 172 cholestatic jaundice hydralazine and dimethylhydralazine, 428 cholestatic liver damage clopidogrel, 721 flucloxacillin, 497 chorea and hallucinations isoflurane, 258 chorioretinopathy glucocorticosteroids, 983–4 choroidal detachment dorzolamide, 438 choroidal hypoperfusion verteporfin and photodynamic therapy, 981 chronic obstructive pulmonary disease (COPD) cilomilast, 367–8 glucocorticoids inhaled, 353 Churg–Strauss syndrome montelukast, 366 chylous ascites lercanidipine, 402 circadian rhythm sleep disorders melatonin, 912 circulatory disturbances acupuncture, 999 cirrhosis see hepatic cirrhosis clenbuterol dyspnea, 323 hyperglycemia, 323 hypokalemia, 323 clonic movement ketamine, 264 clopidogrel thienopyridines, 720 coagulopathy coumarin anticoagulants, 713 etherified starches, 675–6 fibrin glue, 674–5 tigecycline, 501 cognitive deficit lithium, 43–4 vigabatrin, 178 cognitive impairment hormone replacement therapy (HRT), 854 ribavirin, 580 valproate sodium and semisodium (divalproex), 168 colchicine intoxication disulfiram, 1014 cold limbs ku die zi injection, 991 cold sweats Panax ginseng, 996

colitis lansoprazole, 750–1 pravastatin, 927 tacrolimus, 822 colon cancer edrecolomab, 788 verteporfin and photodynamic therapy, 981–2 colon ulceration docetaxel, 947 colonic necrosis polystyrene sulfonates, 474 colorectal cancer parenteral nutrition, 700 coma manifestation diphenhydramine, 347 common cold camphor, 334 erythropoietin and derivatives, 682 rupatadine, 349 zinc, 458 conduction abnormalities somatostatin, 913–4 confusion anticholinergic drugs, 324 bismuth, 449 Datura stramonium, 994 eflornithine, 574 gamma-hydroxybutyric acid (GHB), 64–5 methadone, 214 confusion and disorientation toluene, 1024 congenital anomalies itraconazole, 552–3 congenital heart defects amiodarone, 380 vitamin E (tocopherol), 696 congenital malformation fluconazole, 551–2 levetiracetam, 150 congestive heart failure bevacizumab, 786 darbepoetin alfa, 682 erythropoietin and derivatives, 682 metformin, 484 peroxisome proliferatoractivated dual receptor agonists, 901–2 rosiglitazone, 901 saxagliptin, 895 water soluble intravascular iodinated contrast agents, 964 conjunctival abrasions triphenylmethane dyes, 483 conjunctival hyperemia anti-glaucoma drugs, 982 bimatoprost, 984 latanoprost, 985

1077 conjunctivitis suramin, 650 conotruncal heart defects nicotine, 1020 consciousness, loss of ondansetron, 746 ranitidine, 748 constipation 5HT3 receptor antagonists, 744 agomelatine, 33 baclofen, 302–3 buprenorphine, 225 calcium salts, 449 docosahexaenoic acid (DHA) paclitaxel, 945 gabapentin, 136–7 ixabepilone, 949 lanthanum carbonate, 451 memantine, 16 methadone, 214 oxycodone, 220 palonosetron, 747 pancreatic enzymes, 761 phosphates, 755 raltegravir, 599 tegaserod, 744 tesofensine, 14–15 tetrabenazine, 306 tiotropium bromide, 363 tramadol, 224 venlafaxine and desvenlafaxine, 32 zhi xue capsule, 990 contact allergy henna, 336 contact dermatitis angiotensin converting enzyme (ACE) inhibitors, 418 bacille Calmette-Guérin (BCG) vaccine, 656 benzocaine, 290 captopril, 418 chlorhexidine, 481 chlorphenamine, 346 dimethylfumarate, 336 hydrochlorothiazide, 439 Lyral, 337 mascara, 334–5 metronidazole, 573 contact eczema chelators, 474 contact leukoderma henna, 336 convulsions benzydamine (benzindamine), 249 dihydrocodeine, 211 intravenous immunoglobulin, 677 moxonidine, 427 paclitaxel, 939

Index of adverse effects and reactions

1078 COPD see chronic obstructive pulmonary disease cornea verticillata amiodarone, 382 corneal endothelial decompensation adrenaline (epinephrine), 316 corneal steepening isotretinoin, 340 corneal swelling acetazolamide, 437 corneal ulcers mascara, 334–5 coronary artery calcification coumarin anticoagulants, 707 coronary artery disease bezafibrate, 922 clopidogrel, 721 mesalazine (5-aminosalicylic acid, mesalamine), 757 ondansetron, 746 thiazolidinediones (glitazones), 899 triptans, 408 venlafaxine and desvenlafaxine, 31 coronary artery spasm dobutamine, 319 coronary heart disease antipsychotic drugs, 93 atorvastatin, 926 ezetimibe, 921 hormone replacement therapy (HRT), 853 tibolone, 867 torcetrapib, 929 coronary stent adrenaline (epinephrine), 315 Costello syndrome phosphates, 755 Cotard's syndrome aciclovir, 577–78 cough angiotensin converting enzyme (ACE) inhibitors, 416 fentanyl, 212 immunoglobulin, intravenous, 677 indacaterol, 361–2 latanoprost, 984 remifentanil, 222–3 sitaxsentan, 423 stem cells, 683 triphenylmethane dyes, 482 cramping intravenous immunoglobulin, 678 cutaneous flushing paclitaxel, 941–2

cutaneous ischemia coumarin anticoagulants, 707 cutaneous lupus-like syndrome terbinafine, 541 cutaneous vasculitis levofloxacin, 517–8 cystic fibrosis mannitol, 442 piperacillin þ tazobactam, 497 cystitis bacille Calmette-Guérin (BCG) vaccine, 656 hematologic, 483 cystoid macular edema prostaglandin analogues, 984 cytotoxicity docetaxel, 945–6 D dark urine acupuncture, 999 darkening hair acitretin, 339 de Quervain's tenosynovitis somatropin, 911 death aprotinin, 725 clopidogrel, 723 fondaparinux, 718 heparins, 714–5 human papilloma virus (HPV) vaccine, 658 intravenous immunoglobulin, 677 parenteral nutrition, 699 deep ulceration glutaral (glutaraldehyde), 480 deep vein thrombosis coumarin anticoagulants, 713 erythropoietin and derivatives, 682 prothrombin complex concentrate, 680 sclerosants, 1021–2 defecation disorders proton pump inhibitors, 749 dehydration tacrolimus, 822 water soluble intravascular iodinated contrast agents, 964, 967 delirium gabapentin, 138 levofloxacin, 517 oseltamivir, 601 pregabalin, 159 sevoflurane, 259–60 valproate sodium and semisodium (divalproex), 170

delusions bismuth, 449 oxycodone, 220 pregabalin, 159 dementia Ginkgo biloba, 995 lithium, 41 valproate sodium and semisodium (divalproex), 170 denervation hypersensitivity adrenaline (epinephrine), 316 dental implantation titanium, 457 dental plaque biofilms chlorhexidine, 481 depression anthrax vaccine, 655–6 aripiprazole, 99–100 cannabinoids, 741 enfuvirtide, 598 flumazenil, 80 lacosamide, 139–40 lamotrigine, 142 levetiracetam, 148 memantine, 16 raltegravir, 599 risperidone, 113 tetrabenazine, 306 thyroid hormones, 882 dermatitis See also allergic contact dermatitis; contact dermatitis; radiation dermatitis benznidazole, 649 dermatomyositis simvastatin, 928 desaturation anticholinergic drugs, 269–70 ketamine, 264 propofol, 270 diabetes insipidus liposomal amphotericin (L-AmB), 544 lithium, 43–44 propofol, 274 diabetes mellitus antipsychotic drugs, 95–6 enteral nutrition, 701 gadolinium salts, 969–70 HMG-CoA reductase inhibitors, 924 niacin, 929 paclitaxel, 939 sirolimus (rapamycin), 820 tacrolimus, 823 torcetrapib, 929 vitamin E (tocopherol), 696 water soluble intravascular iodinated contrast agents, 964

Index of adverse effects and reactions diabetic gastroparesis domperidone, 742 diabetic ketoacidosis ondansetron, 746 diabetic macular edema pegaptanib, 978 diabetic neuropathy lacosamide, 139 diabetic polyneuropathy gabapentin, 136 diarrhea see also bloody diarrhea acupuncture, 999 albumin-bound paclitaxel, 944 aldesleukin (interleukin-2, IL-2), 777 aliskiren, 420 antimony, 448 balsalazide, 756–7 blood substitutes, 672, 673 C1 esterase inhibitor concentrate, 674 clindamycin, 522 darunavir, 594–5 dexlansoprazole, 750 docetaxel, 947 docosahexaenoic acid (DHA) paclitaxel, 945 enfuvirtide, 598 erythropoietin and derivatives, 682 febuxostat, 250 immunoglobulin, intravenous, 678 incretin mimetics, 896 ixabepilone, 949 lacosamide, 140 lactulose, 754 lansoprazole, 750–1 lanthanum carbonate, 451 levofloxacin, 516, 517 loperamide, 760 memantine, 16 mesalazine (5-aminosalicylic acid, mesalamine), 759 metoclopramide, 742–3 minocycline, 499 omeprazole and esomeprazole, 752 paclitaxel, 940 palonosetron, 747 pantoprazole, 752 patupilone, 949 pranlukast, 367 proton pump inhibitors, 749 prucalopride, 743 psilocybin, 66 sagopilone, 949 superparamagnetic iron oxide, 971 tacrolimus, 822–823 tafenoquine and primaquine, 569

tegaserod, 744 tesofensine, 14–15 thiopurines, 825 valproate sodium and semisodium (divalproex), 167–8 zonisamide, 180 difficulty in thinking triptans, 408 diffuse alveolar damage leflunomide, 818 diffuse alveolar hemorrhage leflunomide, 818 digestive intolerance benznidazole, 649 digital necrosis promethazine, 348 dilated hypokinetic cardiomyopathy deferiprone, 469 diplopia carbamazepine, 132 deferiprone, 470 fluoroquinolones, 514 titanium, 456 discomfort beta-adrenoceptor antagonists, 983 betaxolol, 397–8 disorientation bismuth, 449 disseminated intravascular coagulation intravenous anti-D immunoglobulin, 679 prothrombin complex concentrate, 680 distaste lactulose, 754 distension dexlansoprazole, 750 dizziness 5HT3 receptor antagonists, 744 acupuncture, 999 adenosine receptor agonists, 380 albendazole, 647 alpha1-antitrypsin, 674 benzydamine (benzindamine), 249 buprenorphine, 225 buspirone, 71 butorphanol, 227 C1 esterase inhibitor concentrate, 674 cannabinoids, 55 deferiprone, 470 dipyridamole, 719 donepezil, 15 efavirenz, 590 erythropoietin and derivatives, 682

1079 febuxostat, 250 gabapentin, 137 gamma-hydroxybutyric acid (GHB), 64–5 human papilloma virus (HPV) vaccine, 658 iloperidone, 104 immunoglobulin, intravenous, 677 ketamine, 266 lacosamide, 139–40 lansoprazole þ amoxicillin þ metronidazole or clarithromycin, 749 mefloquine, 569 memantine, 16 methylnaltrexone, 227 mexiletine, 389 midazolam, 75 modafinil, 11 morphine, 216 nitrates organic, 401 olmesartan, 419 omeprazole and esomeprazole, 752 oxcarbazepine, 151 oxycodone, 220 paclitaxel, 939 palonosetron, 747 pantoprazole, 752 parathyroid hormone, 913 phenobarbital and primidone, 154 posaconazole, 553–4 postsynaptic a-adrenoceptor antagonists, 425 pregabalin, 158 pyrimethamine and congeners, 570 quetiapine, 110 Rhododendron spp., 996–8 selenium, 454 senna, 754–5 tegaserod, 744 thyroid hormones, 882 topiramate, 161 tramadol, 224 triptans, 408 yellow fever vaccine, 664 double vision lacosamide, 139–40 pregabalin, 158 downbeat nystagmus morphine, 217 Dravet's syndrome stiripentol, 160 DRESS see drug rash with eosinophilia and systemic symptoms drowsiness 5HT3 receptor antagonists, 745

Index of adverse effects and reactions

1080 albendazole, 647 baclofen, 303 levetiracetam, 146 methadone, 214 olanzapine, 104 oxcarbazepine, 151 palonosetron, 747 phenobarbital and primidone, 154 vigabatrin, 177 drug rash with eosinophilia and systemic symptoms (DRESS) acetylsalicylic acid, 248 allopurinol, 250 carbamazepine, 134 doxycycline, 499 glycopeptides, 519 lamotrigine, 144 oxazolidinones, 526 phenylbutazone, 247–8 phenytoin and fosphenytoin, 156 strontium salts, 455 sulfasalazine, 759 titanium, 457 vancomycin, 520–521 drug-resistant tuberculosis ethambutol, 627 dry eyes anti-glaucoma drugs, 982 dry lips zonisamide, 181 dry mouth buspirone, 71 C1 esterase inhibitor concentrate, 674 Datura stramonium, 994 duloxetine, 31 gabapentin, 136 huperzine, 16 naltrexone, 228 olanzapine, 104 posaconazole, 553–4 quetiapine, 110 roxithromycin, 524 tesofensine, 14–15 tiotropium bromide, 363 vasopressin, 915 dry mucosa erythropoietin and derivatives, 682 dry skin chlorhexidine, 480–1 diphenhydramine, 347 erythropoietin and derivatives, 682 ductal carcinoma barium sulfate, 967–8 dysgeusia itraconazole, 553 losartan, 419 dyskinesias

quetiapine, 110 dyslipidemia antipsychotic drugs, 90 rupatadine, 349 dysmenorrhea risperidone, 111–2 dyspepsia palonosetron, 747 pantoprazole, 752 dysphagia alpha1-antitrypsin, 674 baclofen, 302–3 bran, 754 lansoprazole, 751 dysphoria cannabinoids, 55, 741 dysplasia cidofovir, 577 dyspnea adenosine and analogues, 379 adenosine receptor agonists, 380 aldesleukin (interleukin-2, IL-2), 777 alpha1-antitrypsin, 674 bosentan, 422 clenbuterol, 323 folic acid, 693 glycoprotein IIb-IIIa inhibitors, 720 immunoglobulin, intravenous, 677 mifepristone, 867 ranitidine, 748 rituximab, 792 sitaxsentan, 423 stem cells, 683 ursodeoxycholic acid, 760 yellow fever vaccine, 664 zedoray tumeric oil and glucose injection, 992 dysrhythmias see cardiac dysrhythmias dystonia cetirizine, 345 methylthioninium chloride, 1019 triptans, 408 dysuria emergency contraption, 859 tiotropium bromide, 363 E eczema alogliptin, 895 danaparoid sodium, 716 immunoglobulin, intravenous, 678 pimecrolimus, 819 tacrolimus, 822 edema See also specific forms, such as peripheral edema

acetazolamide, 437 aldesleukin (interleukin-2, IL-2), 777 basiliximab, 785 factor IX (coagulation proteins), 680 interleukin-11 (IL-11, oprelvekin), 778 natalizumab, 791 Patent Blue Violet dye, 484 peroxisome proliferatoractivated dual receptor agonists, 902 pioglitazone, 900 ranitidine, 748 rituximab, 792 rofecoxib, 247 saxagliptin, 895 sulprostone, 848 von Willebrand factor/factor VIII concentrates, 681 ejaculatory disorder postsynaptic a-adrenoceptor antagonists, 425, 427 tamsulosin, 427 electrolyte abnormality amphotericin (DAMB), 542–3 electrolyte imbalance angiotensin converting enzyme (ACE) inhibitors, 416 embolism cyanoacrylates, 1014 rofecoxib, 247 embolism/thrombosis darbepoetin alfa, 682 erythropoietin and derivatives, 682 emergence delirium ketamine, 267 sevoflurane, 258–9 emesis see vomiting emotional disturbances mercury and mercurial salts, 453 glucocorticoids, 842–843 emotionalability zonisamide, 180 empty sella syndrome fluorescein, 1016–7 empty ventricle syndrome dobutamine, 319–20 encephalastrapy duloxetine, 31 encephalitis minocycline, 500 encephalomyelitis human papilloma virus (HPV) vaccine, 658 encephalopathy ciclosporin, 815

Index of adverse effects and reactions gabapentin, 137 immunoglobulin, intravenous, 677 morphine, 217 oxazolidinones, 525 pertussis vaccine, 657 valproate sodium and semisodium (divalproex), 169 endometrial cancer artificial sweeteners, 1011 hormone replacement therapy (HRT), 856 tamoxifen, 863–4 endometrial hyperplasia tibolone, 867 endometrial polyps tamoxifen, 863 endophthalmitis pegaptanib, 977–8 postsynaptic a-adrenoceptor antagonists, 426 ranibizumab, 978–80 tamsulosin, 426 endothelial cell damage coumarin anticoagulants, 708 energy, increased levetiracetam, 148 enterocolitis ribavirin, 581 eosinophilia See also drug reaction with eosinophilia and systemic symptoms enfuvirtide, 598 entecavir, 579 levofloxacin, 517 mesalazine (5-aminosalicylic acid, mesalamine), 758 eosinophilic pneumonia daptomycin, 529–30 minocycline, 499 epigastric pain anthraquinones, 753 carp gallbladder, 999 cyanoacrylates, 1014 mucolytics, 369 epilepsy See also myoclonus, status epilepticus carbapenem, 492 chlorphenamine, 345–6 diphenhydramine, 347 parenteral nutrition, 698 triptans, 409 epiphora docetaxel, 946 epiphysiolysis somatropin, 911 epistaxis Crataegus orientalis, 993 heparins, 715–6 tacrolimus, 823

topiramate, 163 erectile dysfunction beta-adrenoceptor antagonists, 397 Rhododendron spp., 996–8 erosive pustular dermatosis aminolevulinic acid, 338–9 eryptosis azathioprine, 827 erythema acupuncture, 999 docetaxel, 947, 948 fentanyl, 212–3 finasteride, 873 glutaral (glutaraldehyde), 480 immunoglobulin, intravenous, 678 insulin, 890 ling yang gan mao capsule, 990 pimecrolimus, 819 prilocaine and EMLA, 292 rivastigmine, 16–17 water soluble intravascular iodinated contrast agents, 967 erythema multiforme carbamazepine, 134–5 phenobarbital and primidone, 154 valproate sodium and semisodium (divalproex), 172 erythroderma angiotensin converting enzyme (ACE) inhibitors, 418 lisinopril, 418 erythrodermic psoriasis trimethoprim and cotrimoxazole, 529 esophageal carcinoma enteral nutrition, 700 esophageal obstruction bran, 754 esophageal perforation ibuprofen, 246 esophageal ulceration cyanoacrylates, 1014 esophagogastric cancer docosahexaenoic acid (DHA) paclitaxel, 944–5 euphoria gamma-hydroxybutyric acid (GHB), 64–65 exanthematous pustulosis ciprofloxacin, 515 exertional dyspnea mesalazine (5-aminosalicylic acid, mesalamine), 757 extrapyramidal effects amisulpride, 89–90, 99

1081 antipsychotic drugs, 93 aripiprazole, 99 extravascular hemolysis intravenous anti-D immunoglobulin, 679 eye discharge beta-adrenoceptor antagonists, 983 eye hyperemia beta-adrenoceptor antagonists, 983 eye movements, abnormal methylthioninium chloride, 1019 eye pruritus beta-adrenoceptor antagonists, 983 eyelid swelling travoprost, 985 eyes swollen shen ling bai zhu san, 990 F facial angioedema omeprazole and esomeprazole, 752 facial dysmorphism lamotrigine, 145 facial edema pseudoephedrine, 318 facial pain lamotrigine, 142–3 facial tremor isoflurane, 258 faintness albendazole, 647 Fanconi syndrome adefovir, 578–9 deferasirox, 468 tenofovir, 588 fasting plasma glucose, increased somatostatin, 914 fatal disease oleic acid, 1020 fatigue See also malaise, weakness acupuncture, 999 aldesleukin (interleukin-2, IL-2), 777 aripiprazole, 100–1 azathioprine, 827 benznidazole, 649 daclizumab, 788 docosahexaenoic acid (DHA) paclitaxel, 945 erythropoietin and derivatives, 682 exemestane, 861 filgrastim, 769 gabapentin, 137 immunoglobulin, intravenous, 677–678

Index of adverse effects and reactions

1082 interferon alfa, 774 interleukin-11 (IL-11, oprelvekin), 778 interleukin-18 (IL-18), 779 lacosamide, 139–40 lenograstim, 770 letrozole, 862 levetiracetam, 148 memantine, 16 mercaptopurine, 830 mesalazine (5-aminosalicylic acid, mesalamine), 758 mifepristone, 867 oxcarbazepine, 151 patupilone, 949 pregabalin, 159 risperidone, 111 rituximab, 792 selenium, 454 simvastatin, 928 temsirolimus, 824 tiagabine, 161 topiramate, 161–2 vigabatrin, 177 yellow fever vaccine, 664 zonisamide, 180 febrile convulsions measles-mumps-rubellavaricella (MMRV) vaccine, 662 fetal intrauterine growth retardation manganese, 452 fetal valproate syndrome valproate sodium and semisodium (divalproex), 174 fetotoxicity cocaine, 60–1 methadone, 215 fever aldesleukin (Interleukin-2, IL-2), 777 amiodarone, 382 amphotericin (ABCD), 542 anthraquinones, 753 blood substitutes, 672 C1 esterase inhibitor concentrate, 674 clonidine, 424 cyanoacrylates, 1015 edrecolomab, 788 eflornithine, 574 Exilis, 994–5 filgrastim, 769 formoterol, 360 furosemide, 440 gabapentin, 137 gadolinium salts, 970 gemtuzumab ozogamicin, 789–90 glycopeptides, 519

immunoglobulin, intravenous, 677–678 immunoglobulin, subcutaneous, 678–9 influenza H1N1 vaccines, 660 interleukin-18 (IL-18), 779 iodine, 485 labetalol, 399 lenograstim, 770 loperamide, 760 mesalazine (5-aminosalicylic acid, mesalamine), 757 penicillins, 495 pertussis vaccine, 657 pseudoephedrine, 318 pyrimethamine and congeners, 570 rabies vaccine, 662 sargramostim, 771 sirolimus (rapamycin), 821 stem cells, 683 suramin, 650 terbinafine, 541 topiramate, 165 triphenylmethane dyes, 482 vitamin A (carotenoids), 692 yellow fever vaccine, 664 fibrotic heart valve disease dopamine, 321 fistulae bevacizumab, 786 fixed dilated pupils topical anesthesia, 288–9 fixed drug eruption clopidogrel, 721 desloratadine, 346 finasteride, 873 flecainide, 387 gabapentin, 137–138 nimesulide, 249 paracetamol (acetaminophen), 245 piroxicam, 247 propitocaine, 293 quinine and congeners, 571 trimethoprim and cotrimoxazole, 529 flatulence dexlansoprazole, 750 methylnaltrexone, 227 palonosetron, 747 proton pump inhibitors, 749–50 raltegravir, 599 floaters ranibizumab, 980 flu-like symptoms see influenza fluid retention docetaxel, 945

flushing adenosine receptor agonists, 379–80 ambrisentan, 421 buspirone, 71 docetaxel, 948 gonadotropins, 910 heparins, 716 immunoglobulin, intravenous, 677 niacin, 928 perfluorocarbons, 972 phosphodiesterase type V inhibitors, 409 pimecrolimus and tacrolimus, 338 fractures heparins, 715–6 inhaled glucocorticoids, 356 postsynaptic a-adrenoceptor antagonists, 425 tamoxifen, 862 tenofovir, 589 tibolone, 867 vitamin A (carotenoids), 692 fragile X syndrome minocycline, 499 Fuchs dystrophy (corneal edema) amantadine, 602–4 fungal infections, invasive See also individual organisms liposomal amphotericin (L-AmB), 543–4 fungal tracheitis triphenylmethane dyes, 482 G gait disorder donepezil, 15 trimethoprim and co-trimoxazole, 528 galactorrhea risperidone, 113 gallbladder abnormalities octreotide, 914 gallbladder sludge tacrolimus, 822 gallstones somatostatin, 913–4 gastric adenocarcinoma docetaxel, 945 gastric cancer artificial sweeteners, 1011 parenteral nutrition, 697 gastric pain Actaea racemosa, 992 gastroesophageal reflux domperidone, 742 hormone replacement therapy (HRT), 855 metoclopramide, 743

Index of adverse effects and reactions gastrointestinal bleeding clopidogrel, 721 coumarin anticoagulants, 710 cyanoacrylates, 1014 glutaral (glutaraldehyde), 480 gastrointestinal cancer sulfonylureas, 898 gastrointestinal disorder Actaea racemosa, 992 adenosine receptor agonists, 380 albendazole, 647 atorvastatin, 926 deferasirox, 467 dexlansoprazole, 750 erythromycin, 523 itraconazole, 553 lamotrigine, 141–2 levofloxacin, 516 myrrh, 649–50 naltrexone, 228 niacin, 928–929 nitrous oxide, 262 phenobarbital and primidone, 154 protease inhibitors, 628 semisodium (divalproex), 167–8 strontium salts, 455 tacrolimus, 821 thiopental sodium, 275 valaciclovir, 578 valproate sodium and semisodium (divalproex), 167–8 gastrointestinal hemorrhage deferasirox, 467 diclofenac, 246 verteporfin and photodynamic therapy, 981–982 gastrointestinal motility proton pump inhibitors, 749 gastrointestinal obstruction tiotropium bromide, 363 gastrointestinal ulceration glutaral (glutaraldehyde), 480 genotoxicity nitrous oxide, 262 gestational hypertension antiepileptic drugs, 130 vitamin C (ascorbic acid), 694 gingival bleeding tacrolimus, 823 gingival hyperplasia calcium channel blockers, 401 phosphates, 755 gingival infection lamotrigine, 142–3

glaucoma intravitreal injection, 985 topiramate, 164, 167 gliobastoma Morinda citrifolia, 996 glomerular function, impaired tenofovir, 588–589 glucocorticoids amiodarone, 383 danaparoid sodium, 716 glucose tolerance, impaired somatropin, 911 goiter amiodarone, 382 antithyroid drugs, 885 iodine and iodides, 883 thyrotropin (thyroidstimulating hormone, TSH), 881 goitrous hypothyroidism penicillamine, 472–3 Goldenhar's syndrome tamoxifen, 864 gonadal dysfunction sirolimus (rapamycin), 820–1 graft-versus-host disease (GvHD) blood transfusion, 671 nifedipine, 402 stem cells, 683 granulomas non-animal stabilized hyaluronic acid (NASHA), 335 thorotrast, 973 granulomatous interstitial nephritis phenytoin and fosphenytoin, 156 granulomatous lung disease titanium, 457–8 granulomatous prostatitis bacille Calmette-Guérin (BCG) vaccine, 656 Graves' disease antithyroid drugs, 884 interferon alfa, 775 minocycline, 500 radioactive iodine, 883 rituximab, 791 green monkey kidney cells strontium salts, 455 green urine propofol, 275 groin pain cobalt, 450 growth retardation sirolimus (rapamycin), 820 Guillain–Barré syndrome alemtuzumab, 784 Human papilloma virus (HPV) vaccine, 658

1083 infliximab, 782 influenza H1N1 vaccines, 659 measles-mumps-rubella (MMR) vaccine, 661 gynecological malignancies paclitaxel, 942 tibolone, 867–8 gynecomastia metoclopramide, 743 risperidone, 111–3 H hair loss see alopecia hallucinations anticholinergic drugs, 324 benzydamine (benzindamine), 249 cannabinoids, 55 diamorphine (heroin), 211 efavirenz, 590 isoflurane, 258 lamotrigine, 143 lidocaine, 388–9 memantine, 16 montelukast, 366–7 oseltamivir, 601 hand-foot syndrome mercaptopurine, 830 hands itching ling yang gan mao capsule, 990 hangover efavirenz, 590 Hansen's disease infliximab, 783 Hashimoto's encephalopathy lithium, 43 head cancers paclitaxel, 936 headache see also migraine 5HT3 receptor antagonists, 744 adenosine receptor agonists, 380 agomelatine, 33 albendazole, 647 aliskiren, 420 alpha1-antitrypsin, 674 anthrax vaccine, 655–6 aripiprazole, 101 balsalazide, 756–7 benznidazole, 649 bosentan, 422 cibenzoline, 385 C1 esterase inhibitor concentrate, 674 dipyridamole, 719 donepezil, 15–16 Ecballium elaterium, 994 epoprostenol, 847

Index of adverse effects and reactions

1084 erythropoietin and derivatives, 682 gonadotropins, 909 human papilloma virus (HPV) vaccine, 658 huperzine, 16 iloprost, 847 intravenous immunoglobulin, 677 iodine, 485 itraconazole, 553 khat, 66 lacosamide, 140 lansoprazole, 750–1 lansoprazole þ amoxicillin þ metronidazole or clarithromycin, 749 latanoprost, 985 levetiracetam, 148 levofloxacin, 516, 517 lithium, 45 long-acting beta2adrenoceptor agonists (LABAs), 359 melatonin, 912 memantine, 16 mercaptopurine, 830 mesalazine (5-aminosalicylic acid, mesalamine), 759 modafinil, 11 moxonidine, 427 naltrexone, 228 nitrates organic, 400, 401 nitrous oxide, 261 ondansetron, 746 oxycodone, 220 paclitaxel, 939 palonosetron, 747 pantoprazole, 752 penicillins, 495 perfluorocarbons, 972 phosphodiesterase type V inhibitors, 409 posaconazole, 553–4 praziquantel, 650 pregabalin, 158 proton pump inhibitors, 749 prucalopride, 743 pseudoephedrine, 318 pyrimethamine and congeners, 570 rabies vaccine, 662 risperidone, 113 roflumilast, 368 roxithromycin, 524 senna, 754–5 superparamagnetic iron oxide, 971 tacrolimus, 823 tegaserod, 744 terbinafine, 541 thiopurines, 825 tiagabine, 161

topiramate, 161 triptans, 409 valaciclovir, 578 valproate sodium and semisodium (divalproex), 169 valsartan, 420 vildagliptin, 895 yellow fever vaccine, 664 zileuton, 369 zonisamide, 179–80 hearing loss gabapentin, 137 heart See also cardiheart block dobutamine, 319 flumazenil, 81 heart failure anticholinergic drug, inhaled, 364 bezafibrate, 922 deferiprone, 469 diazoxide, 427–8 dofetilide, 386 rosiglitazone, 899 thiazolidinediones (glitazones), 899 trastuzumab, 793 vasopressin, 915 vitamin E (tocopherol), 696 heart rate increase ketamine, 264 heart rate reduction blood substitutes, 673 thyroid hormones, 882 heartburn and diarrhea mucolytics, 369 hematochezia zhi xue capsule, 990 hematuria bacille Calmette-Guérin (BCG) vaccine, 656 immunoglobulin, intravenous, 678 hemifacial dystonia clebopride, 742 hemiparesis gonadotropin, 851 triptans, 409 hemiplegic migraine nimodipine, 403 hemoglobinemia/ hemoglobinuria intravenous anti-D immunoglobulin, 679 hemodialysis heparins, 716 metformin, 484 pregabalin, 160 vitamin D analogues, 695 hemoglobin, reduced bosentan, 422

hemoglobin, rise in thyroid hormones, 882 hemoglobinuria blood substitutes, 672 hemolysis immunoglobulin, intravenous, 677 micafungin, 559 rasburicase, 250 hemolytic anemia See also anemia ceftriaxone, 493–4 cephalosporins, 493 cimetidine, 748 ciprofloxacin, 515 dapsone, 630, 631, 632 methyldopa, 424 piperacillin þ tazobactam, 497 rifampicin, 639 sulfadiazine, 528 hemolytic-uremic syndrome ciclosporin, 816 hemopoietic cancers pentachlorophenol, 486 hemorrhage cyanoacrylates, 1014 deferasirox, 467 Ginkgo biloba, 995 rofecoxib, 247 hemorrhagic cystitis atorvastatin, 927 hemorrhagic pericarditis glycoprotein IIb-IIIa inhibitors, 720 hepatic cirrhosis amiodarone, 381 lactulose, 754 terlipressin, 917 Uncaria tomentosa, 998 vasopressin, 915 verteporfin and photodynamic therapy, 981–2 hepatic damage Actaea racemosa, 992 amiodarone, 383–4 antiepileptic drugs, 129 clopidogrel, 721 coumarin anticoagulants, 708 dabigatran, 718 ethambutol, 627 Exilis, 994–5 Garcinia gambogia, 994–5 gemtuzumab ozogamicin, 789–90 Hydroxycut, 994–5 isoniazid, 636 parenteral nutrition, 698 pioglitazone, 900 trovafloxacin, 519 zhi xue capsule, 990 zhuang gu guan jie wan, 990

Index of adverse effects and reactions hepatic dysfunction paclitaxel, 937 parenteral nutrition, 698–9 hepatic encephalopathy efavirenz, 590 hepatic failure acitretin, 340 cyanoacrylates, 1015 levetiracetam, 149 nilutamide, 874 nimesulide, 249 thyroid hormones, 882–3 trovafloxacin, 519 valproate sodium and semisodium (divalproex), 172 venlafaxine and desvenlafaxine, 32 vitamin A (carotenoids), 692 hepatic impairment aripiprazole, 101–2 rupatadine, 349 hepatic insufficiency tiagabine, 161 hepatic nodular regenerative hyperplasia azathioprine, 827 hepatic steatosis labetalol, 399 hepatitis See also cholestatic hepatitis, steatohepatitis 5HT3 receptor antagonists, 745 alcohol, 1008 amodiaquine, 567 atorvastatin, 926–7 azathioprine, 829 benznidazole, 649 buprenorphine, 225 chloramphenicol, 514 chloroform, 257 doxycycline, 499 famotidine, 748 halothane, 257 iodine, 485 itraconazole, 552 mesalazine (5-aminosalicylic acid, mesalamine), 758 methyldopa, 424 micafungin, 558 sitaxsentan, 423 thiopurines, 826 hepatitis, autoimmune minocycline, 500 hepatitis, cytolytic methotrexate, 950 hepatitis B virus infection iron chelators, combinations, 471–2 vitamin A (carotenoids), 692 hepatitis C virus infection ursodeoxycholic acid, 760

hepatocellular carcinoma cyanoacrylates, 1014 hematologic, 484 terlipressin, 917 hepatocellular inflammation antithyroid drugs, 885 hepatorenal syndrome terlipressin, 917 hepatotoxicity amiodarone, 383–4 antimony, 448 Camellia sinensis, 995 flutamide, 873 isoniazid, 628, 635 NNRTIs, 590 ondansetron, 746–7 posaconazole, 554 rifampicin, 638 rivastigmine, 17 telithromycin, 521–2 valproate sodium and semisodium (divalproex), 176 vitamin A (carotenoids), 691 voriconazole, 554, 555 heriditary angioedema, exacerbation tamoxifen, 863 herpes simplex keratitis, reactivation prostaglandin analogues, 984 herpes zoster infection citalopram, 29 hiccups epidural anesthesia, 284 levodopa, 320 midazolam, 75 stem cells, 683 hip osteoarthritis verteporfin and photodynamic therapy, 981–2 hirsutism flutamide, 873–4 HIV infection hormone replacement therapy (HRT), 857 ibalizumab, 790 iodine, 485 lithium, 42 triphenylmethane dyes, 481–2 hoarseness glucocorticoids inhaled, 354 long-acting beta2adrenoceptor agonists (LABAs), 358–9 Hodgkin's lymphoma azathioprine, 828 vincristine, 951 Hoigné syndrome clarithromycin, 524

1085 horizontal nystagmus toluene, 1024 Horner's syndrome brachial plexus anesthesia, 283 epidural anesthesia, 283–4 extrapleural anesthesia, 287 hostility zonisamide, 180 hot flushes letrozole, 862 hungry bone syndrome deferasirox, 468 Huntington's disease tetrabenazine, 306 valproate sodium and semisodium (divalproex), 169–70 Hurler's syndrome somatropin, 911 hyperactivity levetiracetam, 147 stiripentol, 160–1 hyperadrenergic syndrome metoprolol, 399 hyperammonemic encephalopathy lamotrigine, 146 topiramate, 164–5 valproate sodium and semisodium (divalproex), 176 hyperamylasemia thyrotropin (thyroidstimulating hormone, TSH), 881 hyperandrogenism lamotrigine, 143–4 valproate sodium and semisodium (divalproex), 173 hyperarousal ketamine, 263 hyperbilirubinemia docosahexaenoic acid (DHA) paclitaxel, 945 ibuprofen, 246 oxazolidinones, 526 hypercalcemia parathyroid hormone, 913 vitamin D analogues, 695 hypercalciuria parathyroid hormone, 913 hyperchloremic metabolic acidosis midazolam, 76 hypercholesterolemia etravirine, 592 protamine, 727 temsirolimus, 824 hyperemia betaxolol, 397–8 oxazolidinones, 526

Index of adverse effects and reactions

1086 hyperesthesia topiramate, 163 hyperglycemia niacin, 929 parenteral nutrition, 697–8 pioglitazone, 900 tacrolimus, 821 temsirolimus, 824 valproate sodium and semisodium (divalproex), 171 hyperhomocysteinemia valproate sodium and semisodium (divalproex), 169 hyperinsulinemia valproate sodium and semisodium (divalproex), 171 hyperkalemia angiotensin converting enzyme (ACE) inhibitors, 416, 417–8 captopril, 418 cardiac glycosides, 378 heparins, 713 liposomal amphotericin (L-AmB), 544 losartan, 419 spironolactone, 440–2 hyperkeratosis valproate sodium and semisodium (divalproex), 172 hyperkinesias topiramate, 166–7 hyperlactatemia stavudine, 583 hyperlipidemia antipsychotic drugs, 96 hypermagnesemia magnesium salts, 452 hyperphosphatemia phosphates, 755 hyperpigmentation ribavirin, 580–1 hyperplasia ciclosporin, 817 dexlansoprazol, 750 hormone replacement therapy (HRT), 854 hyperprolactinemia antipsychotic drugs, 89–90 domperidone, 742 hypersensitivity pneumonitis mesalazine (5-aminosalicylic acid, mesalamine), 757 penicillamine, 472 hypersensitivity/ hypersusceptibility reactions See also antiepileptic drug hypersensitivity, denervation hypersensitivity

azathioprine, 829 aztreonam, 495 bosentan, 422–3 caspofungin, 557 ceftriaxone, 494t dextrans, 675 enfuvirtide, 598 folic acid, 693 furosemide, 441t henna, 336 heparins, 715, 716 human papilloma virus (HPV) vaccine, 658 minocycline, 500 nitrofurantoin, 525 non-animal stabilized hyaluronic acid (NASHA), 335 paclitaxel, 937 thiopurines, 826 hypersensitivity syndrome carbamazepine, 134 minocycline, 500 moxifloxacin, 519 sulfasalazine, 759 zonisamide, 181 hypersomnia palonosetron, 747 hypersomnolence cycloserine, 630 hypertension See also blood pressure, increased alcohol, 1009 bevacizumab, 786 carbamazepine, 132 coumarin anticoagulants, 707–8 dipyridamole, 719 epoprostenol, 847 erythropoietin and derivatives, 682 gadolinium salts, 969–70 huperzine, 16 immunoglobulin, intravenous, 677 interleukin-11 (IL-11, oprelvekin), 778 iodinated contrast agents, 963 khat, 66 metoclopramide, 743 milrinone, 378–9 olanzapine, 104 paclitaxel, 938 Rhododendron spp., 996–8 stem cells, 683 vigabatrin, 177 hypertension, arterial nitric oxide, 260 hyperthermia See fever hyperthyroidism

minocycline, 499, 500 radioactive iodine, 883 thyroid hormones, 881–2 hypertrichosis ciclosporin, 816 henna, 336 hypertriglyceridemia gemfibrozil, 923 parenteral nutrition, 697 valproate sodium and semisodium (divalproex), 171 hypertrophic cardiomyopathy phosphates, 755 hypertrophied endothelial cells titanium allergy, 457 hyperuricemia niacin, 929 hyperviscosity immunoglobulin, intravenous, 677 hypervitaminosis vitamin A (carotenoids), 691 hyperzincemia zinc, 458 hypethesia topiramate, 162 hyphema coumarin anticoagulants, 708 hypoalbuminemia factor IX (coagulation proteins), 680 hypocalcemia chelators, 474 deferasirox, 467, 468 lactulose, 754 mannitol, 442 omeprazole and esomeprazole, 751 phosphates, 755 strontium salts, 455 hypocupremia chelators, 474 zinc, 458 hypofibrinogenemia tigecycline, 501 hypoglycemia angiotensin converting enzyme (ACE) inhibitors, 417 antihelminthic drugs, 647 gliclazide, 898 incretin mimetics, 896 insulin, 479 levofloxacin, 517 meglitinides, 897 repaglinide, 897 tegaserod, 744 vildagliptin, 895 hypohidrosis topiramate, 165

Index of adverse effects and reactions hypokalemia 5HT3 receptor antagonists, 744–5 acetazolamide, 437–8 aminoglycoside antibiotics, 509 esmolol, 398 glucocorticoids, 842 laxatives and oral bowel preparations, 753 levofloxacin, 516 omeprazole and esomeprazole, 751 piperacillin þ tazobactam, 497 thiazide and thiazide-like diuretics, 438–9 hypomagnesemia lactulose, 754 omeprazole and esomeprazole, 751 hyponatremia antiepileptic drugs, 126 carbamazepine, 132 desmopressin, 916 duloxetine, 31 flecainide, 387 mannitol, 442 mirtazapine, 34 oxcarbazepine, 132 oxytocin and analogues, 913 phenytoin and fosphenytoin, 155 pregabalin, 159–60 sodium picosulfate, 756 thiazide and thiazide-like diuretics, 438–9 thyroid hormones, 882 valproate sodium and semisodium (divalproex), 175 vasopressin, 915–6 hypophosphatemia parenteral nutrition, 698 temsirolimus, 824 hypophosphatemic osteomalacia adefovir, 579 hypoplasia candesartan, 419 hypotension See also orthostatic hypotension, paradoxical hypotension aldesleukin (interleukin-2, IL-2), 777 beta-adrenoceptor antagonists, 983 blood substitutes, 673 caspofungin, 557 clenbuterol, 323 clonidine, 424 diphenhydramine, 347 docetaxel, 948 doxycycline, 499

esmolol, 398 fentanyl, 212–3 hematologic, 484 heparins, 716 immunoglobulin, intravenous, 677 ketamine, 266 losartan, 419 metoclopramide, 742–3 midazolam, 75 natalizumab, 791 olanzapine, 104 paclitaxel, 938, 941–2 pegaptanib, 977–8 perfluorocarbons, 972 phosphates, 755 propofol, 271 protamine, 727 quinidine and derivatives, 390–1 ranitidine, 748 remifentanil, 222 Rhododendron spp., 996–8 spinal (intrathecal) anesthesia, 284 stem cells, 683 sulfur hexafluoride, 972 tacrolimus, 824 thiopental sodium, 275 valsartan, 420 verapamil, 403 water soluble intravascular iodinated contrast agents, 967 hypotension, paradoxical adrenaline (epinephrine), 316 hypothermia topiramate, 166 hypothyroidism antiepileptic drugs, 126 iodine and iodides, 883 metoclopramide, 743 phenytoin and fosphenytoin, 155 polyvinylpyrrolidone, 485 temsirolimus, 824 hypoxia doxycycline, 499 ketamine, 265 nitrous oxide, 261 propofol, 270 stem cells, 683 hypoxic brain injury vigabatrin, 177 hypoxic sensitivity acetazolamide, 437–8 I icterus see jaundice IFIS see intraoperative floppy iris syndrome (IFIS)

1087 ileal perforation polystyrene sulfonates, 474 imbalance gabapentin, 137 immunodeficiency influenza H1N1 vaccines, 659 immunological sequelae fibrin glue, 674–5 incontinence see urinary incontinence indigestion bisacodyl, 753–4 infantile spasms vigabatrin, 176–7 infections eflornithine, 574 tacrolimus, 821 infertility sirolimus (rapamycin), 820–1 inflammation hydroxyethylmethacrylate and ethylmethacrylate, 335 inflammation/infection of the prostate diethylstilbestrol, 852 inflammation/infection of the testicular diethylstilbestrol, 852 inflammatory bowel disease aminosalicylates, 756 azathioprine, 829 isotretinoin, 340 lithium, 45 parenteral nutrition, 699 thiopurines, 825 inflammatory reactions albumin-derived hemostatics, 670 penicillins, 495 titanium, 457 influenza aldesleukin (interleukin-2, IL-2), 778 aripiprazole, 101 blood substitutes, 673 coumarin anticoagulants, 711 immunoglobulin, intravenous, 677 pandemic influenza H1N1 vaccines, 659 pregabalin, 158–9 thiopurines, 825 influenza-like symptoms C1 esterase inhibitor concentrate, 674 memantine, 16 infusion-related events amphotericin (DAMB), 542–3 infusion-related reactions amphotericin (ABLC), 543 C1 esterase inhibitor concentrate, 674

Index of adverse effects and reactions

1088 injection site reactions C1 esterase inhibitor concentrate, 674 erythropoietin and derivatives, 682 esmolol, 398 meningococcal vaccine, 656–7 paromomycin, 513 pertussis vaccine, 657 rabies vaccine, 662 yellow fever vaccine, 664 insomnia anthrax vaccine, 655–6 anticholinergic drugs, 324 aripiprazole, 100–1 benznidazole, 649 donepezil, 15 lamotrigine, 142 memantine, 16 montelukast, 366–7 naltrexone, 228 palonosetron, 747 raltegravir, 599 risperidone, 112, 113 tesofensine, 14–15 tetrabenazine, 306 ziprasidone, 114 zonisamide, 180 inspissated bile syndrome cefotaxime, 493 insulin sensitivity, reduced hydrochlorothiazide, 439 intermittent claudication naftidrofuryl, 408 rupatadine, 349 intermittent fever anthraquinones, 753 interstitial keratitis varicella vaccine, 663 interstitial lung disease leflunomide, 818 interstitial nephritis deferasirox, 468 flucloxacillin, 497 labetalol, 399 levetiracetam, 149 mesalazine (5-aminosalicylic acid, mesalamine), 757 nitrofurantoin, 525 oxazolidinones, 526 interstitial pneumonia bepridil, 384 ursodeoxycholic acid, 760 interstitial pneumonitis carbamazepine, 133 leflunomide, 818 sirolimus (rapamycin), 820 intestinal failure parenteral nutrition, 698 intestinal damage polystyrene sulfonates, 474–5 intestinal ischemia

cyanoacrylates, 1014 intestinal obstruction phenytoin and fosphenytoin, 157 intracerebral/intracranial hemorrhage coumarin anticoagulants, 707–8 khat, 66 phosphodiesterase type V inhibitors, 409–10 tipranavir, 597 water soluble intravascular iodinated contrast agents, 964 intracranial hypertension, benign levofloxacin, 517 minocycline, 499 intrahepatic cholestasis see cholestasis intramyelinic edema vigabatrin, 177 intraocular pressure, increased arsenic, 449 intravitreal injection, 985 intraoperative floppy iris syndrome (IFIS) postsynaptic a-adrenoceptor antagonists, 425 intravascular hemolysis rifampicin, 638 intravascular volume expansion, excessive etherified starches, 675–6 intussusception rotavirus vaccine, 662–3 iris cysts prostaglandin analogues, 984 iritis pegaptanib, 978 irritability lacosamide, 139–40 lamotrigine, 141 levetiracetam, 147 stiripentol, 160–1 zonisamide, 179–80 irritant dermatitis latex, 1018 irritation, local levofloxacin, 516 ischemia balsalazide, 756 promethazine, 348 ischemic attack clebopride, 742 ischemic colitis docetaxel, 947 glutaral (glutaraldehyde), 480 hormone replacement therapy (HRT), 855 metamfetamine, 4–5 polystyrene sulfonates, 474

triptans, 409 ischemic events tegaserod, 744 ischemic heart disease amiodarone, 381 torcetrapib, 930 ischemic liver damage parenteral nutrition, 698 ischemic priapism antipsychotic drugs, 99 ischemic retinal diseases bevacizumab, 785–6 ischemic stricture cyanoacrylates, 1015 ischemic stroke metamfetamine, 4 itching see pruritus J jaundice See also cholestatic jaundice acupuncture, 999 azathioprine, 827 blood substitutes, 672 exemestane, 861 mesalazine (5-aminosalicylic acid, mesalamine), 758 methotrexate, 950 joint pains Actaea racemosa, 992 juvenile Huntington disease, 10 juvenile rheumatoid arthritis sulfasalazine, 759 K Kaposi's sarcoma interferon alfa, 776 keratoconus latanoprost, 985 ketoacidosis insulin, 483 kidney see renal and nephrKienböck disease systemic glucocorticoids, 843 Klebsiella pneumoniae parenteral nutrition, 700 Kounis syndrome, 245 adrenaline (epinephrine), 316 amoxicillin, 496 lansoprazole, 751 mesalazine (5-aminosalicylic acid, mesalamine), 757 L labile hypertension iodinated contrast agents, 963 lactic acidosis See also metabolic acidosis caffeine, 12

Index of adverse effects and reactions entecavir, 579 metformin, 483 oxazolidinones, 526 lancinating pain disulfiram, 1016 laryngeal edema iodinated contrast agents, 963, 967 laryngospasm morphine, 217 laryngotracheitis triphenylmethane dyes, 482 lastosis perforans serpiginosa penicillamine, 472 laughter, pathological triptans, 408 lead poisoning kadda, 992 ledderhose syndrome phenobarbital and primidone, 154 left antecubital fossa promethazine, 348 left ventricular ballooning syndrome metoprolol, 399 leg pain epidural anesthesia, 284 epoetin alfa, 682 erythropoietin and derivatives, 682 Lennox–Gastaut syndrome pregabalin, 160 lenticular opacities deferasirox, 467 leprosy infliximab, 783 lethargy apraclonidine, 982 mesalazine (5-aminosalicylic acid, mesalamine), 758 pregabalin, 158 leukemias azathioprine, 828 diethylstilbestrol, 852–3 formaldehyde, 479–80 gentian violet, 484 mercaptopurine, 830 paclitaxel, 936, 940 leukocytoclastic vasculitis pristinamycin, 528 vancomycin, 520 vitamin D analogues, 695 leukocytosis entecavir, 579 levofloxacin, 516 mesalazine (5-aminosalicylic acid, mesalamine), 758 leukoencephalopathy see also specific types bevacizumab, 786 diamorphine (heroin), 211

toluene, 1024 tacrolimus, 821–2 leukopenia azathioprine, 827 clozapine, 103 immunoglobulin, intravenous, 677 oxcarbazepine, 152–3 valproate sodium and semisodium (divalproex), 172 zidovudine, 588 Lewis–Sumner syndrome infliximab, 782 lichen planus glucocorticoids, 843 ribavirin, 581 lichenoid eruption hydrochlorothiazide, 439 ribavirin, 581 limb weakness Panax ginseng, 996 lip elastosis penicillamine, 473 lipoatrophy amikacin, 510 lipodystrophy insulin, 480 lipoid pneumonia cocaine, 59 lips itching ling yang gan mao capsule, 990 liquid sclerotherapy sclerosants, 1022 livedo reticularis amantadine, 604 liver see hepat- and non-alcoholic fatty liver disease liver function tests, abnormal 5HT3 receptor antagonists, 745 albendazole, 648 alemtuzumab, 784 bosentan, 422 endoperoxides, 571 erythropoietin and derivatives, 682 fenofibrate, 923 fluconazole, 551 growth hormone receptor antagonists, 911–912 isotretinoin, 340 nicardipine, 402 thioguanine, 830 long-QT syndrome rupatadine, 349 longitudinal myelitis yellow fever vaccine, 664 loss of consciousness dipyridamole, 719

1089 low back pain superparamagnetic iron oxide, 971 lower ejection fractions aprotinin, 726 lower eyelid fullness, loss bimatoprost, 984 lower quadrant pain barium sulfate, 967 lower respiratory tract infections folic acid, 693 lansoprazole, 751 sodium hypochlorite, 484–485 lung see pulmonary and respiratory lung cancer coumarin anticoagulants, 711 lenograstim, 770 paclitaxel, 935–6 talc, 1023–4 vitamin A (carotenoids), 691 lung cavitation cocaine, 59 lupus vulgaris bacille Calmette-Guérin (BCG) vaccine, 656 lupus-like syndrome see also systemic lupus erythematosus adalimumab, 781 cysteamine, 761 hydralazine and dimethylhydralazine, 428 infliximab, 782 interferon alfa, 776 minocycline, 500 oxcarbazepine, 153 propafenone, 390 valproate sodium and semisodium (divalproex), 173 vancomycin, 521 Lyme disease ceftriaxone, 494 lymphadenitis bacille Calmette-Guérin (BCG) vaccine, 656 lymphedema sirolimus (rapamycin), 820 lymphocyte toxicity zonisamide, 181 lymphoma benznidazole, 649 carbamazepine, 134 parenteral nutrition, 698 lymphopenia docetaxel, 947 lymphoproliferative disorders alemtuzumab, 784–5

Index of adverse effects and reactions

1090 M macular edema ranibizumab, 978 macular neuroretinopathy adrenaline (epinephrine), 316 maculopathy topiramate, 164 madarosis mascara, 334–5 malaise aldesleukin (interleukin-2, IL-2), 777 immunoglobulin, intravenous, 677 immunoglobulin, subcutaneous, 678–9 iodine, 485 lansoprazole, 751 pioglitazone, 900 pseudoephedrine, 318 thiopurines, 825 malignant catatonia clonazepam, 73 malignant hyperthermia sevoflurane, 260 suxamethonium, 300 mania arteether, 572 carbamazepine, 132–3 clarithromycin, 523 lamotrigine, 143 mefloquine, 569 valproate sodium and semisodium (divalproex), 168 megaloblastic anemia see also anemia nitrous oxide, 261–2 melanoma estrogens, 852 methylthioninium chloride, 1018–19 paclitaxel, 936 sagopilone, 949 melena isotretinoin, 340 octreotide, 914 memory impairment lacosamide, 140–1 topiramate, 161 memory loss strontium salts, 455 meningism immunoglobulin, intravenous, 677 meningitis See also aseptic meningitis carbapenem, 492 menorrhagia levonorgestrel, 866 risperidone, 113 menstrual disorder levonorgestrel, 865

menstrual irregularities valproate sodium and semisodium (divalproex), 173 mental retardation valproate sodium and semisodium (divalproex), 175 metabolic acidosis See also lactic acidosis acetazolamide, 437–8 aminoglycoside antibiotics, 509 antiepileptic drugs, 132 diphenhydramine, 347 endocrine, 274 esmolol, 398 glycols, 1018 ion-exchange resins, 761 toluene, 1024 topiramate, 165 metabolic alkalosis vitamin D analogues, 695 metabolic encephalopathy levetiracetam, 148 methylthioninium chloride, 1019 metabolic syndrome valproate sodium and semisodium (divalproex), 171 metallic taste metronidazole, 573 methemoglobinemia benzocaine, 289 dapsone, 630, 632 malachite green, 483 phenazopyridine, 249–50 prilocaine and EMLA, 291–2 sulfadiazine, 528 microradiculopathy spinal (intrathecal) anesthesia, 285 microscopic colitis esomeprazole, 750 omeprazole and esomeprazole, 751 migraine and migraine-like headache acetazolamide, 437 anticholinergic drugs, 324 see also hemiplegic migraine aripiprazole, 100–101 hyoscine (scopolamine) butylbromide, 759–60 immunoglobulin, intravenous, 677 metoclopramide, 743 sclerosants, 1021–2 topiramate, 163 triptans, 409 milk-alkali syndrome vitamin D analogues, 695

Miller–Fisher syndrome adalimumab, 780–1 mitochondrial dysfunction stavudine, 583 mitral valve surgery milrinone, 378–9 molar incisor hypomineralization amoxicillin, 496 mood disturbances hormonal contraceptives, 858–9 letrozole, 862 levetiracetam, 147 lithium, 40, 45 mifepristone, 867 tiagabine, 161 mortality glucocorticoids, inhaled, 354 gonadotropin, 851 rosiglitazone, 901 tibolone, 867–8 mortality, increased blood substitutes, 672 blood transfusion, 672 motor block brachial plexus anesthesia, 283 motor neuron disease human papilloma virus (HPV) vaccine, 658 phenytoin and fosphenytoin, 155 motor neuropathy vincristine, 951 movement disorders cobalamins (vitamin B12), 693 mucormycosis deferasirox, 468 mucosal ulceration triphenylmethane dyes, 482 mucositis docetaxel, 947 ixabepilone, 949 methotrexate, 950 paclitaxel, 940 temsirolimus, 824 mucous membrane inflammation lanthanum carbonate, 451 multifocal leukoencephalopathy leflunomide, 818 multiorgan failure blood transfusion, 672 multiple sclerosis alemtuzumab, 784 cannabinoids, 55 lithium, 42 multiple sclerosis, precipitation dental anesthesia, 287

Index of adverse effects and reactions muscle cramps long-acting beta2adrenoceptor agonists (LABAs), 359 parenteral nutrition, 699 muscle damage Actaea racemosa, 992 muscle fasciculation suxamethonium, 299 muscle hypertrophy botulinum toxins, 305 muscle pain erythropoietin and derivatives, 682 ritodrine, 323–4 simvastatin, 928 suramin, 650 muscle rigidity fentanyl, 212 morphine, 217 remifentanil, 223 muscle spasm acetazolamide, 437 C1 esterase inhibitor concentrate, 674 magnesium salts, 452 muscle tone altered diphenhydramine, 347 muscle weakness botulinum toxins, 304–5 docetaxel, 946 glucocorticoids, 842 musculoskeletal pain letrozole, 862 mutagenicity dimethylsulfoxide, 1016 myalgia adalimumab, 781 albumin-bound paclitaxel, 944 anthrax vaccine, 655–6 antimony, 448 benznidazole, 649 ciprofloxacin, 515 erythropoietin and derivatives, 682 filgrastim, 769 finasteride, 873 HMG-CoA reductase inhibitors, 924 immunoglobulin, intravenous, 677 ixabepilone, 949 khat, 66 levofloxacin, 517 paclitaxel, 941 proton pump inhibitors, 749–50 thiopurines, 825 tumor necrosis factor alfa (TNF-1), 779–80 myalgias docetaxel, 947 myasthenia gravis azithromycin, 522–3

cibenzoline, 385 disopyramide, 385 mycosis fungoides, mimicking amlodipine, 401–2 mydriasis atomoxetine, 7 myelopathy chiropractic therapy, 1000 nitrous oxide, 261–2 myelosuppression bacille Calmette-Guérin (BCG) vaccine, 656 myocardial damage stem cells, 683 myocardial infarction alcohol, 1010 anticholinergic drugs, inhaled, 364–5 aprotinin, 725 blood substitutes, 672 calcium salts, 449 cannabinoids, 56 cocaine, 58 erythropoietin and derivatives, 682 hormone replacement therapy (HRT), 854 immunoglobulin, intravenous, 677 insulin, 479 lansoprazole, 751 long-acting beta2adrenoceptor agonists (LABAs), 358 mesalazine (5-aminosalicylic acid, mesalamine), 757 paclitaxel, 938 perfluorocarbons, 971–2 pioglitazone, 901 prothrombin complex concentrate, 680 pseudoephedrine, 318 Rhododendron spp., 996–8 rosiglitazone, 901 somatropin, 910–1 thiazolidinediones (glitazones), 899 triptans, 408 verteporfin and photodynamic therapy, 981–2 myocardial ischemia alcohol, 1010 khat, 66 myocarditis azithromycin, 522 balsalazide, 756 diamorphine (heroin), 210–1 mesalazine (5-aminosalicylic acid, mesalamine), 757 myoclonus bismuth, 449 cobalamins (Vitamin B12), 693 gabapentin, 137

1091 pregabalin, 159 stiripentol, 160 topiramate, 164 myonecrosis simvastatin, 928 myopathy ezetimibe, 921–2 fenofibrate, 923 gabapentin, 138 HMG-CoA reductase inhibitors, 924 valproate sodium and semisodium (divalproex), 172–3 voriconazole, 555 myopericarditis phenytoin and fosphenytoin, 155 smallpox vaccine, 663 myopia acetazolamide, 437 mefenamic acid, 245 topiramate, 164 myositis gemfibrozil, 923 N nail discoloration selenium, 454 narcotic bowel syndrome opioid analgesics, 206 nasal congestion ambrisentan, 421 iloperidone, 104 phosphodiesterase type V inhibitors, 409 triphenylmethane dyes, 482 nasal septum perforation Ecballium elaterium, 994 nasopharyngeal cancer formaldehyde, 479–80 triphenylmethane dyes, 482 nasopharyngitis aliskiren, 420 ambrisentan, 421 bosentan, 422 darunavir, 594–5 levetiracetam, 148 sitagliptin, 895 sitaxsentan, 423 terbinafine, 541 vildagliptin, 895 nausea 5HT3 receptor antagonists, 745 albumin-bound paclitaxel, 944 aldesleukin (interleukin-2, IL-2), 777 alfentanil, 209 alpha1-antitrypsin, 674 amphotericin (ABLC), 543 anticholinergic drugs, 324 antiepileptic drugs, 126

Index of adverse effects and reactions

1092 antimony, 448 aripiprazole, 101 azathioprine, 827 benzydamine (benzindamine), 249 bevacizumab, 786 bisacodyl, 753 blood substitutes, 673 bosentan, 422 buprenorphine, 225 butorphanol, 227 C1 esterase inhibitor concentrate, 674 calcitonin, 909 cannabinoids, 741 carp gallbladder, 999 clenbuterol, 323 Cynomorium songaricum, 994 darunavir, 594–5 dextromethorphan, 210 dipyridamole, 719 docetaxel, 947 docosahexaenoic acid (DHA) paclitaxel, 945 duloxetine, 31 edrecolomab, 788 enfuvirtide, 598 erythropoietin and derivatives, 682 etravirine, 592 Exilis, 994–5 filgrastim, 769 flumazenil, 80 gabapentin, 138–9 gadolinium salts, 970 human papilloma virus (HPV) vaccine, 658 hydromorphone, 214 hyoscine (scopolamine) butylbromide, 759–60 iloprost, 847 immunoglobulin, intravenous, 678 incretin mimetics, 896 interleukin-18 (IL-18), 779 ixabepilone, 949 khat, 66 lacosamide, 139–40 lansoprazole, 751 lansoprazole þ amoxicillin þ metronidazole or clarithromycin, 749 lanthanum carbonate, 451 laxatives and oral bowel preparations, 753 lenograstim, 770 letrozole, 862 levofloxacin, 516, 517 lidocaine, 388–9 mefloquine, 569 memantine, 16 mercaptopurine, 830

mesalazine (5-aminosalicylic acid, mesalamine), 759 methadone, 214 methylnaltrexone, 227 metoclopramide, 743 metronidazole, 573 mexiletine, 389 modafinil, 11 morphine, 216 mucolytics, 369 naltrexone, 228 nitrous oxide, 260–1 ondansetron, 746 oseltamivir, 601 oxcarbazepine, 151 oxycodone, 220 oxytocin, 913 paclitaxel, 940 palonosetron, 747 pantoprazole, 752 parathyroid hormone, 913 patupilone, 949 perfluorocarbons, 972 phosphates, 755 pioglitazone, 900 posaconazole, 553 praziquantel, 650 pregabalin, 157–158 proton pump inhibitors, 749 prucalopride, 743 pseudoephedrine, 318 psilocybin, 66 pyrimethamine and congeners, 570 quetiapine, 110 quinidine and derivatives, 390–1 raltegravir, 599 Rhododendron spp., 996–8 rituximab, 792 rivastigmine, 16–17 roflumilast, 368 roxithromycin, 524 senna, 754–5 shu xue ning injection, 991 stem cells, 683 tacrolimus, 821 tafenoquine and primaquine, 569 tegaserod, 744 telavancin, 520 tesofensine, 14–15 thiopurines, 825 thyroid hormones, 882 tiagabine, 161 tramadol, 224 trastuzumab, 793 venlafaxine and desvenlafaxine, 32 yellow fever vaccine, 664 zhuang gu guan jie wan, 990 zileuton, 369 ziprasidone, 114

neck cancers paclitaxel, 936 neck numbness acupuncture, 999 neck pain acupuncture, 1000 chiropractic therapy, 1000 necrolytic migratory erythema methadone, 215 necrosis See also individual organs glutaral (glutaraldehyde), 480 necrotic encephalopathy tacrolimus, 822 necrotic skin lesions gentian violet, 483 necrotizing enterocolitis immunoglobulin, intravenous, 678 neonatal abstinence syndrome opioid analgesics, 207 neonatal complications thyroid hormones, 881 neonatal death danaparoid sodium, 717 nephritic syndrome factor IX (coagulation proteins), 680 nephritis See also tubulointerstitial nephritis; granulomatous interstitial nephritis; interstitial nephritis mesalazine (5-aminosalicylic acid, mesalamine), 758 nephrocalcinosis furosemide, 440 nephrogenic diabetes insipidus tenofovir, 588 nephrogenic systemic fibrosis gadolinium salts, 969 iodinated contrast agents, 963 nephrolithiasis topiramate, 163, 165 nephropathy phosphates, 755 nephrotic syndrome Tripterygium wilfordii Hook, 998 nephrotoxicity amikacin, 510 amphotericin (DAMB), 542, 543 colistin, 527–8 gentamicin, 511–2 oxazolidinones, 525 nervous system see neuronervousness hormonal contraceptives, 858–9 zonisamide, 180

Index of adverse effects and reactions neural tube defects nicotine, 1020 neuroendocrine dysfunction valproate sodium and semisodium (divalproex), 173 neuroleptic malignant syndrome aripiprazole, 101 oxcarbazepine, 152 promethazine, 349 neurological adverse reactions aluminium, 447 aprotinin, 726 carbapenems, 492 colistin, 528 ertapenem, 492 isoniazid, 636 meropenem, 492 nitrates organic, 400–1 penicillamine, 472 phenobarbital and primidone, 154 phenytoin and fosphenytoin, 156–7 spinal (intrathecal) anesthesia, 285 vigabatrin, 178 vincristine, 951 voriconazole, 556 zonisamide, 180 neuromuscular blockade rocuronium, 301 neuropathic pain lacosamide, 139 pregabalin, 159 neuropsychological deficits toluene, 1024 neuroretinopathy adrenaline (epinephrine), 316 neutropenia aldesleukin (interleukin-2, IL-2), 777 benznidazole, 649 clozapine, 103 deferasirox, 467 diazoxide, 427–8 docetaxel, 947 docosahexaenoic acid (DHA) paclitaxel, 945 endoperoxides, 571 glycopeptides, 519 interleukin-18 (IL-18), 779 ixabepilone, 949 paclitaxel, 939–40 ribavirin, 580 thyrotropin (thyroidstimulating hormone, TSH), 881 ticlopidine, 724 trastuzumab, 793 tumor necrosis factor alfa (TNF-1), 779–80

valproate sodium and semisodium (divalproex), 172 neutropenic enterocolitis docetaxel, 947 neutropenic fever imipenem, 492 neutrophil infiltration triphenylmethane dyes, 483 nocturnal bowel movement octreotide, 914 nocturnal sweating efavirenz, 590 nodal rhythm Rhododendron spp., 996–8 nodular goiter amiodarone, 382 nodular regenerative hyperplasia thioguanine, 830 nodules ethylmethacrylate, 335 hydroxyethylmethacrylate, 335 non-small-cell lung cancer docetaxel, 947 docosahexaenoic acid (DHA) paclitaxel, 944–5 non-alcoholic fatty liver disease valproate sodium and semisodium (divalproex), 172 non-cirrhotic portal hypertension didanosine, 587 non-small cell lung cancer docetaxel, 945 ixabepilone, 948 patupilone, 949 nosocomial infections parenteral nutrition, 700 numbness albumin-bound paclitaxel, 944 ling yang gan mao capsule, 990 paclitaxel, 939 nystagmus deferiprone, 470 O obesity valproate sodium and semisodium (divalproex), 171 obstructive jaundice deferasirox, 467 occupational airways disease sodium metabisulfite, 1022 ocular irritation travoprost, 985 oculo-auriculo-vertebral syndrome tamoxifen, 864

1093 oedema see edema oligospermia finasteride, 873 oliguria blood substitutes, 672 onycholysis docetaxel, 947 paclitaxel, 941 onychomadesis octreotide, 914 valproate sodium and semisodium (divalproex), 172 optic neuropathy oxazolidinones, 525 oral candidiasis long-acting beta2adrenoceptor agonists (LABAs), 357 oral lichen planus ribavirin, 581 oral ulceration allopurinol, 250 desloratadine, 346 orbital adherence syndrome titanium, 456 orofacial clefts caffeine, 12 oropharyngeal candidiasis glucocorticoids inhaled, 354 osteolysis titanium, 456 osteomalacia efavirenz, 591 osteomyelitis bacille Calmette-Guérin (BCG) vaccine, 656 osteonecrosis cocaine, 60 glucocorticoids, 843 osteopenia antiepileptic drugs, 130 phenytoin and fosphenytoin, 156 osteoporosis antiepileptic drugs, 126 glucocorticoids, inhaled, 356 glucocorticoids, systemic, 844 heparins, 715 iron chelators, 465 phenytoin and fosphenytoin, 156 tibolone, 867 topiramate, 165 osteosarcoma methotrexate, 950 othostatic hypertension olanzapine, 104 othostatic hypotension antipsychotic drugs, 90 iloperidone, 104 quetiapine, 110

Index of adverse effects and reactions

1094 ototoxicity paclitaxel, 939 ovarian cancer hormone replacement therapy (HRT), 856 paclitaxel, 940 patupilone, 949 sagopilone, 949 talc, 1023–4 ovarian cysts sirolimus (rapamycin), 821 ovarian hyperstimulation syndrome gonadotropins, 851, 909 overactive urinary bladder fluoride, 1017 oversedation ketamine, 266 ovulatory dysfunction lamotrigine, 143–4 valproate sodium and semisodium (divalproex), 173 oxalate crystal deposition vitamin C (ascorbic acid), 694 P pain See also parts affected acupuncture, 999 albumin-bound paclitaxel, 944 aminolevulinic acid, 338 anthrax vaccine, 655–6 botulinum toxins, 304 diazepam, 73 erythropoietin and derivatives, 682 immunoglobulin, subcutaneous, 678–9 infiltration anesthesia, 286 lidocaine, 389 pimecrolimus and tacrolimus, 337–338 ranibizumab, 980 yellow fever vaccine, 664 painful diabetic neuropathy lacosamide, 140 pale stools acupuncture, 999 palmar-plantar erythema ixabepilone, 949 palmar-plantar erythrodysesthesia syndrome docetaxel, 947 palms, pain ling yang gan mao capsule, 990 palpitation ambrisentan, 421 clenbuterol, 323 immunoglobulin, subcutaneous, 678–9

ku die zi injection, 991 mexiletine, 389 modafinil, 11 shu xue ning injection, 991 pancreatic cancer artificial sweeteners, 1011 coumarin anticoagulants, 711 ixabepilone, 948 pancreatic infarction cyanoacrylates, 1014 pancreatic infections enteral nutrition, 701 pancreatic lipase darunavir, 594–5 pancreatitis blood substitutes, 673 ceftriaxone, 494 ciclosporin, 815–6 doxycycline, 499 endocrine, 274–5 exenatide, 896 fibrates, 922 human papilloma virus (HPV) vaccine, 658 lamivudine, 587 liraglutide, 896 mesalazine (5-aminosalicylic acid, mesalamine), 759 somatropin, 911 thiopurines, 826 tigecycline, 501 valproate sodium and semisodium (divalproex), 172 zonisamide, 180 pancytopenia albendazole, 648 azathioprine, 827 clopidogrel, 721 levetiracetam, 149 panenteritis isotretinoin, 340 panhypopituitarism cocaine, 60 panic attacks dopamine, 322 papillary microcarcinoma minocycline, 499 paradoxical hypotension adrenaline (epinephrine), 316 parakeratosis valproate sodium and semisodium (divalproex), 172 paralysis glucagon, 889 paralytic ileus baclofen, 303 paranoia dextromethorphan, 210 paranoid delusions cannabinoids, 55 paraparesis

glucocorticoids, 841–2 paresthesia palonosetron, 747 suramin, 650 topiramate, 161 zinc, 458 zonisamide, 180 Parkinson's disease botulinum toxins, 304 dopamine, 321 abnormalities, 322 gabapentin, 137 levodopa, 320 Parkinson-like symptoms somatostatin, 914 Parkinsonism antipsychotic drugs, 91 ciclosporin, 815 oxcarbazepine, 152 pregabalin, 159 ribavirin, 580 valproate sodium and semisodium (divalproex), 169 paroxysmal atrial fibrillation gemfibrozil, 923 pathological laughter triptans, 408 pedal edema acupuncture, 999 pelvic congestion syndrome sclerosants, 1021 pelvic pain polyvinyl alcohol, 1021 sclerosants, 1021 pemphigus acetazolamide, 438 peptic ulceration acetylsalicylic acid, 248 pericardial effusion nickel, 453–4 pericarditis balsalazide, 756 periodontal disease cannabinoids, 57 periorbital fat atrophy bimatoprost, 984 peripheral edema ambrisentan, 421 bosentan, 422 docosahexaenoic acid (DHA) paclitaxel, 945 lacosamide, 140 pregabalin, 157–158 sitaxsentan, 423 peripheral giant cell granuloma titanium allergy, 457 peripheral neuropathy disulfiram, 1014 docetaxel, 946 docosahexaenoic acid (DHA) paclitaxel, 945 ixabepilone, 948–949

Index of adverse effects and reactions oxazolidinones, 525–526 paclitaxel, 937, 938–939 patupilone, 949 peripheral vascular disease epoetin delta, 682 erythropoietin and derivatives, 682 peripheral vasospasm cocaine, 59 periventricular leukomalacia metamfetamine, 4 petechiae intravenous immunoglobulin, 678 oxazolidinones, 526 Peyronie's disease carvedilol, 398 pharyngitis inhaled glucocorticoids, 354 melatonin, 912 montelukast, 366 pharyngolaryngeal pain proton pump inhibitors, 749 phlebitis caspofungin, 557 glycoprotein IIb-IIIa inhibitors, 720 intravenous immunoglobulin, 677 iodine, 485 von Willebrand factor/factor VIII concentrates, 681 phospholipid antibody syndrome heparins, 714 phospholipidosis Morinda citrifolia, 996 photoallergenicity tretinoin (all-trans retinoic acid, ATRA), 341 photosensitivity dapsone, 632 phototoxic nor photoallergenic tretinoin (all-trans retinoic acid, ATRA), 341 phototoxic reactions aminolevulinic acid, 339 phototoxicity voriconazole, 555 pigment epithelial tear verteporfin and photodynamic therapy, 982 pigmentation, skin minocycline, 500 pigmented conjunctival lesions mascara, 334–335 pigmented purpuric dermatosis bufexamac, 245 medroxyprogesterone, 866 pituitary gigantism growth hormone receptor antagonists, 912 pituitary volume, increase

growth hormone receptor antagonists, 912 plantar fibromatosis phenobarbital and primidone, 154 plasma triglyceride, increased tacrolimus, 822 platelet aggregation ampicillin, 496 platelet count, increased dapsone, 630 platelet inhibition clopidogrel, 722 pleural effusion intravenous immunoglobulin, 677 parenteral nutrition, 697 pleural empyema cocaine, 59 pneumonia See also specific types chlorhexidine, 480–481 levetiracetam, 150 lian bi zhi injection, 991 long-acting beta2adrenoceptor agonists (LABAs), 359 pantoprazole, 752 pneumonitis docetaxel, 946 everolimus, 817 paclitaxel, 938 phenytoin and fosphenytoin, 155 temsirolimus, 824 pneumothorax acupuncture, 999 cocaine, 59 polycystic ovarian syndrome lamotrigine, 143–144 spironolactone, 442 valproate sodium and semisodium (divalproex), 173 polycythemia epoetin alfa, 682 erythropoietin and derivatives, 682 polymyositis leflunomide, 819 polyneuritis benznidazole, 649 pompholyx intravenous immunoglobulin, 678 porphyria phenobarbital and primidone, 154 portal hypertension didanosine, 587 thioguanine, 830 portal vein thrombosis argatroban, 717–718

1095 post-thrombotic syndrome sclerosants, 1021 post-transfusion bacteremia blood transfusion, 671 post-transfusion purpura blood transfusion, 671 post-traumatic stress disorder ketamine, 263 posterior reversible encephalopathy syndrome ciclosporin, 815 immunoglobulin, intravenous, 677 postherpetic neuralgia pregabalin, 158 postoperative anemia esmolol, 398 postoperative cardiac aprotinin, 725 postoperative nausea nitrous oxide, 262 postoperative pain esmolol, 398 postoperative pneumonia blood transfusion, 672 postoperative wound complications albumin-derived hemostatics, 670 postural hypotension see orthostatic hypotension pre-eclampsia insulin, 482 priapism postsynaptic a-adrenoceptor antagonists, 426–7 tamsulosin, 426–7 prolactin-related adverse events risperidone, 113 prolonged QT interval see QT interval prolongation propofol infusion syndrome propofol, 272 proteinuria factor IX (coagulation proteins), 680 HMG-CoA reductase inhibitors, 925 sirolimus (rapamycin), 820 temsirolimus, 824 pruritic lesions desloratadine, 346 pruritus acupuncture, 999 benzalkonium compounds, 481 chelators, 473 docetaxel, 947 exemestane, 861 hydromorphone, 214 immunoglobulin, intravenous, 678

Index of adverse effects and reactions

1096 lansoprazole, 751 morphine, 216 oxycodone, 220 pimecrolimus, 338, 819 superparamagnetic iron oxide, 971 tacrolimus, 338 water soluble intravascular iodinated contrast agents, 967 yellow fever vaccine, 664 zhuang gu guan jie wan, 990 zonisamide, 181 pseudolymphoma Actaea racemosa, 992 tamoxifen, 863 pseudopolymyalgia angiotensin converting enzyme (ACE) inhibitors, 418 enalapril, 418 pseudothrombocytopenia von Willebrand factor/factor VIII concentrates, 681 pseudotumor cerebri lithium, 43 psoriasis and psoriasiform eruptions bacille Calmette-Guérin (BCG) vaccine, 656 fumaric acid esters, 337 glucocorticoids, 843 infliximab, 782 lithium, 45 valproate sodium and semisodium (divalproex), 172 zanolimumab, 794 psychiatric disorder antiepileptic drug, 127 lamotrigine, 142–3 levetiracetam, 150 long-acting beta2adrenoceptor agonists (LABAs), 359 risperidone, 111–2 topiramate, 164–165 psychomotor performance clopidogrel, 720 psychomotor retardation gabapentin, 138–9 psychosis antipsychotic drugs, 95 dextromethorphan, 210 flumazenil, 81 mefloquine, 569 methylphenidate, 9 modafinil, 11 psychotomimetic effects ketamine, 266 pulmonary complications blood substitutes, 673 pulmonary edema diphenhydramine, 347

intravenous immunoglobulin, 677 khat, 66 pulmonary failure carbamazepine, 135 chlorhexidine, 481 pulmonary fibrosis albumin-derived hemostatics, 670 pulmonary function, impaired long-acting beta2adrenoceptor agonists (LABAs), 357 pulmonary hemorrhage clopidogrel, 722 pulmonary hypertension diazoxide, 427–8 protamine, 727 pulmonary thromboembolism See venous thromboembolism pulmonary vasoconstriction protamine, 727 punding disulfiram, 1016 pure red cell aplasia dapsone, 630 lamivudine, 587 ribavirin, 580 zidovudine, 588 purpura vitamin D analogues, 695 pyrexia see fever Q QT interval prolongation 5HT3 receptor antagonists, 745 aliskiren, 420 amiodarone, 381 antithyroid drugs, 884 atomoxetine, 7 domperidone, 742 endoperoxides, 571 fluconazole, 551 hydroxyzine, 347–8 metoclopramide, 743 nelfinavir, 596 ondansetron, 746–7 palonosetron, 747 promethazine, 348 prucalopride, 744 rupatadine, 349 sugammadex, 302 voriconazole, 554 quadriparesis chiropractic therapy, 1000 R radiation dermatitis paclitaxel, 941 radius aplasia lamotrigine, 145 oxcarbazepine, 153

rashes See also drug rash with eosinophilia and systemic symptoms, urticaria aldesleukin (interleukin-2, IL-2), 777 alogliptin, 895 amoxicillin, 496 anthrax vaccine, 655–6 blood substitutes, 672 bosentan, 422 carbamazepine, 132 clindamycin, 522 daclizumab, 788 erythropoietin and derivatives, 682 darunavir, 594 docosahexaenoic acid (DHA) paclitaxel, 945 erythropoietin and derivatives, 682 etravirine, 592 filgrastim, 769 iloprost, 847 immunoglobulin, intravenous, 678 immunoglobulin, subcutaneous, 678–9 itraconazole, 553 lamotrigine, 141 lansoprazole þ amoxicillin þ metronidazole or clarithromycin, 749 latanoprost, 847 letrozole, 862 methylthioninium chloride, 1016–7 NNRTI, 590 oxcarbazepine, 151 pantoprazole, 752 pravastatin, 927 strontium salts, 455 suramin, 650 temsirolimus, 824 yellow fever vaccine, 664 zedoray tumeric oil and glucose injection, 992 zhuang gu guan jie wan, 990 zonisamide, 180 recall dermatitis docetaxel, 947 neomycin, 513 recall urticaria heparins, 715 rectal bleeding glutaral (glutaraldehyde), 480 rectal hemorrhage lansoprazole, 750–1 rectocolitis glutaral (glutaraldehyde), 480 red eyes benzalkonium compounds, 481

Index of adverse effects and reactions red man syndrome vancomycin, 521 refeeding syndrome enteral nutrition, 700 renal calculi see nephrolithiasis renal cancer ixabepilone, 948 patupilone, 949 verteporfin and photodynamic therapy, 981–2 renal cysts ciclosporin, 816 lithium, 45 renal damage cibenzoline, 385 coumarin anticoagulants, 708 ion-exchange resins, 761 methotrexate, 950 raloxifene, 862 renal disease aluminium, 448 gabapentin, 137 gadolinium salts, 969 iron salts, 451 liraglutide, 897 raloxiene, 862 rosiglitazone, 901 tamoxifen, 864–5 renal dysfunction adefovir, 578 blood substitutes, 672 coumarin anticoagulants, 710 lithium, 45 magnesium salts, 452 methotrexate, 950 renal dysplasia candesartan, 419 renal excretion docetaxel, 946 renal failure aprotinin, 725 carp gallbladder, 998 ciclosporin, 817 Crataegus orientalis, 993 deferasirox, 468 gadolinium salts, 969–70 heparins, 715 HMG-CoA reductase inhibitors, 925–6 levetiracetam, 149 lian bi zhi injection, 991 tacrolimus, 824 terlipressin, 917 verteporfin and photodynamic therapy, 981–982 renal hematoma Allium sativum, 993 renal impairment aminosalicylates, 756 amphotericin (DAMB), 542

angiotensin converting enzyme (ACE) inhibitors, 416 carbapenems, 492 deferasirox, 468 losartan, 419 renal insufficiency aliskiren, 420 carbapenem, 492 Cynomorium songaricum, 993–4 gabapentin, 138 HMG-CoA reductase inhibitors, 924 immunoglobulin, intravenous, 678 methotrexate, 950 paclitaxel, 941 phosphates, 755–6 simvastatin, 928 suramin, 650 vancomycin, 520 renal stones see nephrolithiasis renal toxicity colistin, 528 methoxyflurane, 258 renal tubular acidosis aminoglycoside antibiotics, 509 renal tubular dysfunction coumarin anticoagulants, 708 stavudine, 588 respiratory depression diamorphine (heroin), 211 metoclopramide, 742 morphine, 217 opioid analgesics, 205 piritramide, 222 remifentanil, 222 tramadol, 224 urapidil, 427 respiratory distress furosemide, 440 phosphodiesterase type V inhibitors, 410 talc, 1023 respiratory failure enteral nutrition, 700 metformin, 483 verteporfin and photodynamic therapy, 981–2 respiratory infection aripiprazole, 99–100 maraviroc, 600 montelukast, 366 pantoprazole, 752 proton pump inhibitors, 750 valproate sodium and semisodium (divalproex), 168 vildagliptin, 895

1097 respiratory syncytial virus triphenylmethane dyes, 482 restless legs syndrome See also akathisia dopamine, 322 mirtazapine, 33–4 topiramate, 164 zonisamide, 180 restlessness See also akathisia aripiprazole, 100–1 levetiracetam, 148 montelukast, 366–7 reticulocytopenia endoperoxides, 571 retinal artery occlusion phosphodiesterase type V inhibitors, 410 retinal damage arsenic, 449 deferoxamine, 471 retinal detachment postsynaptic a-adrenoceptor antagonists, 426 tamsulosin, 426 retinal phototoxicity hydrochlorothiazide, 439 retinal pigment epithelial tear ranibizumab, 978 retinal pigmentary changes deferoxamine, 471 retinal vein occlusion glucocorticoids, 983–4 retinopathy HMG-CoA reductase inhibitors, 924 retroperitoneal hematoma coumarin anticoagulants, 711 retrosternal pain bran, 754 rhabdomyolysis ciclosporin, 817 clarithromycin, 524 daptomycin, 530 diamorphine (heroin), 211 gabapentin, 138 HMG-CoA reductase inhibitors, 925 propofol, 272 raltegravir, 599 ritodrine, 323–324 simvastatin, 928 thiazide and thiazide-like diuretics, 439 rheumatic disease glucocorticoids, 842 rheumatoid arthritis see arthritis rhinorrhea triphenylmethane dyes, 482 right ventricular dysfunction milrinone, 378–9

Index of adverse effects and reactions

1098 rigors amphotericin (ABCD), 542 Rowell's syndrome valproate sodium and semisodium (divalproex), 173 S salivation excessive ketamine, 264–5 schizoaffective disorder valproate sodium and semisodium (divalproex), 172–3 schizophrenia carbamazepine, 135 lamotrigine, 142 olanzapine, 107 paliperidone, 108 valproate sodium and semisodium (divalproex), 175 sedation anticholinergic drugs, 324 antipsychotic drugs, 89–90, 93–4 aripiprazole, 101 buprenorphine, 225 butorphanol, 227 chlorphenamine, 345 gabapentin, 136, 138–9 ketamine, 263 olanzapine, 104 oxcarbazepine, 151 quetiapine, 110 ziprasidone, 114 seizures Actaea racemosa, 992 antipsychotic drugs, 93–4 bupropion (amfebutamone), 33 camphor, 333–4 carbapenem, 491 citalopram, 29 darbepoetin alfa, 682 desmopressin, 916 diamorphine (heroin), 211 eflornithine, 574 erythropoietin and derivatives, 682 flumazenil, 81 gabapentin, 136 gemfibrozil, 923 influenza H1N1 vaccines, 660 intravenous regional anesthesia, 287 lacosamide, 139 lamotrigine, 141 levetiracetam, 148 lithium, 43 mefloquine, 569 methylphenidate, 9

ondansetron, 746 oxazolidinones, 526 palonosetron, 747 phenobarbital and primidone, 154–5 pregabalin, 160 ropivacaine, 293 vigabatrin, 177 zonisamide, 180 sensorimotor polyneuropathy itraconazole, 553 sensorineural hearing loss deferoxamine, 471 methadone, 215 ribavirin, 580 sensory loss zinc, 458 sensory neuropathy ixabepilone, 948–9 sepsis antithrombin III, 674 triphenylmethane dyes, 482 septic shock skin branding, 1000–1 septicemia chlorhexidine, 481 cyanoacrylates, 1015 nifedipine, 402 parenteral nutrition, 700 sclerosants, 1021–2 serotonin syndrome ciclosporin, 817 ciprofloxacin, 516 cyclobenzaprine, 305 methylthioninium chloride, 1019 ondansetron, 746–7 oxazolidinones, 527 serotonin toxicity methylthioninium chloride, 1019 serpentine tongue dobutamine, 320 serum aminotransferases see liver function tests serum calcium, fall in laxatives and oral bowel preparations, 753 serum creatinine erythropoietin and derivatives, 682 methotrexate, 950 PA-824, 637 parenteral nutrition, 698 serum iron, rise in thyroid hormones, 882 serum lipids isotretinoin, 340 serum phosphate, rise in laxatives and oral bowel preparations, 753 serum potassium enteral nutrition, 700

heparins, 713 serum transaminases see liver function tests serum troponin coumarin anticoagulants, 713 sexual dysfunction opioid analgesics, 206 topiramate, 165–6 zonisamide, 180 sexual excitation opioid analgesics, 206 shivering flumazenil, 80 ketamine, 266 short bowel syndrome oleic acid, 1020–1 parenteral nutrition, 699 shortness of breath Ecballium elaterium, 994 lansoprazole, 751 Panax ginseng, 996 water soluble intravascular iodinated contrast agents, 967 xing nao jing injection, 991 shoulder pain acupuncture, 1000 SIADH See syndrome of inappropriate ADH secretion sialoadenitis thyrotropin (thyroidstimulating hormone, TSH), 881 sickle cell disease ceftriaxone, 493–4 filgrastim, 770 sideroblastic anemia See also anemia deferiprone, 469 progestogens, 865 sinonasal cancer formaldehyde, 479–80 sinus bradycardia sulfur hexafluoride, 972 sinus dysrhythmia palonosetron, 747 sinus tachycardia adrenaline (epinephrine), 317 sinusitis adalimumab, 780 ambrisentan, 421 aripiprazole, 99–100 proton pump inhibitors, 749 valproate sodium and semisodium (divalproex), 168 sinusoidal obstruction syndrome bevacizumab, 786

Index of adverse effects and reactions Sjögren's syndrome lamotrigine, 144 rituximab, 791 valproate sodium and semisodium (divalproex), 169 SJS see Stevens-Johnson syndrome (SJS) skeletal fluorosis fluoride, 1017 skin allergy chlorhexidine, 481 skin bruising glucocorticoids, inhaled, 354 skin cancer hair dyes, 336 talc, 1023–4 skin hemorrhage intravenous immunoglobulin, 678 skin induration immunoglobulin, subcutaneous, 678–9 skin irritation nitrates organic, 401 vitamin A (carotenoids), 692 skin lesions chlorhexidine, 481 danaparoid sodium, 716 gadolinium salts, 970 heparins, 714 shen ling bai zhu san, 990 skin necrosis coumarin anticoagulants, 708 hematologic, 483 heparins, 715 methylthioninium chloride, 1018–19 phenytoin and fosphenytoin, 156 sleep apnea, obstructive, central, and combined opioid analgesics, 205 sleep attacks dopamine, 322 sleep disturbance ethosuximide, 136 itraconazole, 553 latanoprost, 985 mefloquine, 569 stiripentol, 160–1 sleep driving zolpidem, 79 sleep walking metoprolol, 399 zolpidem, 78–9 sleepiness moxonidine, 427 triptans, 408 sleeplessness levetiracetam, 148 smarting

pimecrolimus and tacrolimus, 337–8 smell loss zinc, 458 soft tissue sarcoma pentachlorophenol, 486 somnolence aripiprazole, 99, 100–1 ethosuximide, 136 gabapentin, 137 gamma-hydroxybutyric acid (GHB), 64–5 levetiracetam, 147 lidocaine, 388 memantine, 16 oxycodone, 220 pregabalin, 158 quetiapine, 110 risperidone, 111 tiagabine, 161 topiramate, 162 valproate sodium and semisodium (divalproex), 167–8 vigabatrin, 177 ziprasidone, 114 zonisamide, 179–80 sore throat Ecballium elaterium, 994 glucocorticoids, inhaled, 354 stem cells, 683 soreness simvastatin, 928 subcutaneous immunoglobulin, 678–9 speech disorder topiramate, 161–2 spermatogenesis, abnormal ribavirin, 581 spinal cord injury tizanidine, 307 spinal epidural hematoma acetylsalicylic acid, 248 cilostazol, 407 spinal myoclonus spinal (intrathecal) anesthesia, 285 spindle-shaped macrophages titanium allergy, 457 splenic artery aneurysm dobutamine, 320 splenic infarction adrenaline (epinephrine), 316 spongiform leukoencephalopathy diamorphine (heroin), 211 squamous cell carcinoma azathioprine, 827 docetaxel, 945 fumaric acid esters, 337 nicotine, 1020 voriconazole, 555

1099 Staphylococcus aureus chlorhexidine, 481 gentamicin, 511 parenteral nutrition, 700 titanium allergy, 456 Staphylococcus haemolyticus parenteral nutrition, 700 status epilepticus See also epilepsy efavirenz, 590 fluorescein, 1016–7 glycols, 1016 theophylline, 12–13 steatohepatitis amiodarone, 384 steatosis cannabinoids, 57–8 stenosis albumin-derived hemostatics, 670 stent restenosis stem cells, 682 Stevens–Johnson syndrome (SJS), 34, 72 antiepileptic drugs, 132 carbamazepine, 134 chelators, 473–4 ciprofloxacin, 515 lamotrigine, 132 oxcarbazepine, 153 phenobarbital and primidone, 154 strontium salts, 455 trimethoprim and co-trimoxazole, 529 valproate sodium and semisodium (divalproex), 172 stiff limbs Actaea racemosa, 992 stinging/burning anti-glaucoma drugs, 982 stomach cancer artificial sweeteners, 1011 stomach discomfort praziquantel, 650 stomach pains epoetin alfa, 682 erythropoietin and derivatives, 682 Rhododendron spp., 996–8 stomatitis ixabepilone, 949 paclitaxel, 940 stools, pale acupuncture, 999 stroke blood substitutes, 672, 673 carbapenem, 492 darbepoetin alfa, 682 erythropoietin and derivatives, 682 gonadotropin, 851

Index of adverse effects and reactions

1100 immunoglobulin, intravenous, 677 influenza H1N1 vaccines, 660 prothrombin complex concentrate, 680 ranibizumab, 980 tibolone, 867 verteporfin and photodynamic therapy, 981–2 Sturge–Weber syndrome phenobarbital and primidone, 154 stuttering valproate sodium and semisodium (divalproex), 170 subarachnoid hemorrhage metamfetamine, 4 subconjunctival hemorrhage coumarin anticoagulants, 708 subcutaneous calcinosis heparins, 715 subdural hematoma spinal (intrathecal) anesthesia, 286 subluxation suxamethonium, 299 sudden infant death syndrome pertussis vaccine, 657 suicidal thoughts lamotrigine, 142 suicide atomoxetine, 7 duloxetine, 31 methylphenidate, 8 sulfhemoglobinemia and methemoglobinemia phenazopyridine, 249–50 sulfone syndrome (dapsone syndrome) dapsone, 633 superoxide dismutase (SOD) selenium, 454 suprachoroidal hemorrhage coumarin anticoagulants, 713 swallowing difficulties see dysphagia sweating buprenorphine, 225 efavirenz, 590 gonadotropins, 910 iodine, 485 lansoprazole, 751 methadone, 214 Rhododendron spp., 996–8 zonisamide, 180 Sweet's syndrome doxycycline, 499 thiopurines, 826 trimethoprim and co-trimoxazole, 529

Sweet's syndrome with sialadenitis phenylbutazone, 248 swelling hydroxyethylmethacrylate and ethylmethacrylate, 335 immunoglobulin, subcutaneous, 678–9 promethazine, 348 rabies vaccine, 662 swollen fingers ling yang gan mao capsule, 990 sympathetic hyperactivation anagrelide, 719 symptomatic asthma long-acting beta2adrenoceptor agonists (LABAs), 358 syncope dopamine, 321 gabapentin, 136 human papilloma virus (HPV) vaccine, 658 hydroxyzine, 348 postsynaptic a-adrenoceptor antagonists, 425 Rhododendron spp., 996–8 syndrome of inappropriate ADH secretion (SIADH) amantadine, 604 systemic fibrosis gadolinium salts, 969, 969f, 970t systemic lupus erythematosus ethosuximide, 136 heparins, 714 hepatitis B vaccine, 657 systolic blood pressure esmolol, 398 Rhododendron spp., 996–8 T tachycardia adenosine receptor agonists, 379–80 carbamazepine, 132 clenbuterol, 323 doxycycline, 499 duloxetine, 31 huperzine, 16 iloperidone, 104 ketamine, 265–6 khat, 66 methylthioninium chloride, 1019 metoclopramide, 743 palonosetron, 747 penicillins, 495 phosphates, 755 stem cells, 683 water soluble intravascular iodinated contrast agents, 967

tachypnea dopamine, 322 doxycycline, 499 tacrolimus, 823 takotsubo syndrome anagrelide, 719 suxamethonium, 299 tamoxifen coumarin anticoagulants, 712 tardive dyskinesia antipsychotic drugs, 89–90 risperidone, 113 taste disturbance see dysgeusia tear quality isotretinoin, 340 temporal hemianopia ethambutol, 634 temporomandibular joint subluxation suxamethonium, 299 TEN see toxic epidermal necrolysis tendinitis fluoroquinolones, 514 tendon rupture moxifloxacin, 518 teratogenicity vitamin A (carotenoids), 691 third degree atrioventricular block chloroquine and hydroxychloroquine, 568 third-degree sinoatrial block losartan, 419 thirst and somnolence pranlukast, 367 throat irritation glucocorticoids inhaled, 354 thrombin time dabigatran, 718 thrombocytopenia argatroban, 717–8 azathioprine, 829 benznidazole, 649 blood substitutes, 673 ciprofloxacin, 515 dabigatran, 718 deferasirox, 467 epoprostenol, 847 fenfluramine, 6 glycoprotein IIb-IIIa inhibitors, 720 heparins, 714 ixabepilone, 949 lepirudin, 718 levetiracetam, 149 octreotide, 914 oxazolidinones, 526 paclitaxel, 939 pantoprazole, 752

Index of adverse effects and reactions phosphodiesterase type V inhibitors, 410 piperacillin þ tazobactam, 497 quinine and congeners, 570 ribavirin, 580 tumor necrosis factor alfa, 779–80 valproate sodium and semisodium (divalproex), 171 vancomycin, 520 thrombocytopenic purpura measles-mumps-rubella (MMR) vaccine, 661–662 thienopyridines, 720 tick-borne meningoencephalitis vaccine, 663 thrombophilia valproate sodium and semisodium (divalproex), 171–2 thrombosis adrenaline (epinephrine), 315 aripiprazole, 100–1 cilostazol, 407 danaparoid sodium, 716 desmopressin, 916 factor VIIa (coagulation proteins), 679 fibrin glue, 674–5 rofecoxib, 247 thrombotic complications heparins, 714 thienopyridines, 720 thrombotic microangiopathy quinine and congeners, 570–1 thrombovascular events erythropoietin and derivatives, 682 thyroid cancer radioactive iodine, 883 thyroid hormones, 881 thyroid carcinoma lithium, 44 thyroid dysfunction ribavirin, 580 thyroid hormone deficiency antiepileptic drug, 126 thyroid tumors liraglutide, 897 thyrotropin (thyroidstimulating hormone, TSH) thrombocytopenia, 881 tics mercury and mercurial salts, 453 tiredness acupuncture, 999 erythropoietin and derivatives, 682

levetiracetam, 148 pregabalin, 158 triptans, 408 tissue necrosis promethazine, 348 tongue swelling technetium sestamibi, 973 tongue vesicles alpha1-antitrypsin, 674 tonic-clonic seizures ropivacaine, 293 sulfur hexafluoride, 972 toothache arsenic, 449 torsade de pointes amiodarone, 381 ciprofloxacin, 514–5 dofetilide, 385 indoramin, 426 methadone, 214 metoclopramide, 743 moxifloxacin, 518 sotalol, 399 torticollis cyclobenzaprine, 305 Tourette syndrome tetrabenazine, 305 toxic epidermal necrolysis (TEN) allopurinol, 250 carbamazepine, 134 emergency contraception, 859 lamotrigine, 146 minoxidil, 428 nevirapine, 593 phenobarbital and primidone, 154 strontium salts, 455 tipranavir, 597 trimethoprim and co-trimoxazole, 529 valproate sodium and semisodium (divalproex), 172 toxic inflammatory myopathy mesalazine (5-aminosalicylic acid, mesalamine), 759 tracheitis, fungal triphenylmethane dyes, 482 transaminases see liver function tests transfusion associated mortality blood transfusion, 672 transfusion-associated circulatory overload (TACO) blood transfusion, 671 transfusion-associated sepsis (TAS) blood transfusion, 671 transfusion-related acute lung injury (TRALI)

1101 anti-D immunoglobulin, intravenous, 679 blood transfusion, 671 plasma, 675 transient global amnesia dobutamine, 320 transient ischemic attack atomoxetine, 7 dipyridamole, 719 sclerosants, 1019–20 verteporfin and photodynamic therapy, 981–2 transverse myelitis human papilloma virus (HPV) vaccine, 658 tremor aripiprazole, 99 clenbuterol, 323 cobalamins (vitamin B12), 693 isoflurane, 258 itraconazole, 553 lacosamide, 139–40 lamotrigine, 141, 142 long-acting beta2adrenoceptor agonists (LABAs), 357 risperidone, 112 topiramate, 164 tramadol, 224 valproate sodium and semisodium (divalproex), 167–8 triglyceride concentrations, raised darunavir, 594–5 tipranavir, 597 Trypanosoma brucei gambiense eflornithine, 574 suramin, 650 Trypanosoma brucei rhodesiense suramin, 650 tuberous sclerosis vigabatrin, 176–7 tubulointerstitial nephritis aminosalicylates, 756 lansoprazole, 751 omeprazole and esomeprazole, 751 tumor lysis syndrome rituximab, 792 U ulcer symptoms metoclopramide, 742–3 ulcerating vasculitis bacille Calmette-Guérin (BCG) vaccine, 656 unipolar depression lithium, 40

Index of adverse effects and reactions

1102 upper abdominal pain mesalazine (5-aminosalicylic acid, mesalamine), 758 upper airway obstruction coumarin anticoagulants, 707 ureteral obstruction bacille Calmette-Guérin (BCG) vaccine, 656 urgency and dysuria hematologic, 483 uric acid, rise in 5HT3 receptor antagonists 745 urinary incontinence memantine, 16 urinary retention amantadine, 604 antipsychotic drugs, 99 Datura stramonium, 994 morphine, 216 tiotropium bromide, 363 urinary symptoms tiotropium bromide, 363 urinary tract infection ceftriaxone, 493 ciprofloxacin, 515 memantine, 16 urinary tract tumors artificial sweeteners, 1011 urine mercury mercury and mercurial salts, 453 urolithiasis phenytoin and fosphenytoin, 156 urticaria acetylsalicylic acid, 248 alemtuzumab, 784 efalizumab, 789 furosemide, 440 fusidic acid, 530 gabapentin, 136 heparins, 715 human papilloma virus (HPV) vaccine, 658 intravenous immunoglobulin, 678 iodinated contrast agents, 963 lamotrigine, 141 natalizumab, 791 omeprazole and esomeprazole, 752 paclitaxel, 941–2 pandemic influenza H1N1 vaccines, 659 Patent Blue Violet dye, 484 pegfillgrastim, 770 rituximab, 792 shu xue ning injection, 991 superparamagnetic iron oxide, 971 water soluble intravascular iodinated contrast agents, 967

yellow fever vaccine, 664 uterine artery polyvinyl alcohol, 1021 uterine tachysystole misoprostol, 847–8 V vaginal bleeding oxytocin, 913 vaginal candidiasis triphenylmethane dyes, 481–2 vaginal dryness letrozole, 862 valvular disease fenfluramine, 6 vanished twin syndrome lamotrigine, 145 varicella zoster infection etanercept, 782 infliximab, 783 vascular complications gadolinium salts, 968 vasculitis antithyroid drugs, 885 atorvastatin, 927 cocaine, 60 hydralazine and dimethylhydralazine, 428 influenza H1N1 vaccines, 660 non-animal stabilized hyaluronic acid (NASHA), 335 vasoconstriction blood substitutes, 672, 673 vasodilatation aldesleukin (interleukin-2, IL-2), 777 nitrates organic, 400 vasopressor effects blood substitutes, 673 vasospastic angina amoxicillin, 496 venous thromboembolism clozapine, 103 cyanoacrylates, 1012 fibrates, 922 fondaparinux, 718 heparins, 714–5 human papilloma virus (HPV) vaccine, 658 olanzapine, 107 parenteral nutrition, 697 prothrombin complex concentrate, 680 sclerosants, 1019–20 strontium salts, 455 tibolone, 867 venous thrombosis intravenous immunoglobulin, 677 ventricular dysrhythmias

cisapride, 741–2 paclitaxel, 938 terlipressin, 916 ventricular fibrillation chloroquine and hydroxychloroquine, 568 coumarin anticoagulants, 713 flumazenil, 80–1 quinine and congeners, 570 ventricular tachycardia adenosine and analogues, 379 fish oils, 923 flumazenil, 80–1 phentermine, 13 systemic glucocorticoids, 841 ventricular tachycardia and fibrillation procainamide, 389 ventricular techydysrhythmias amiodarone, 381 verbal aggression bismuth, 449 vertebrobasilar artery strok chiropractic therapy, 1000 vertigo alemtuzumab, 784 ci wu jia injection, 991 gabapentin, 138–9 phenytoin and fosphenytoin, 155 valproate sodium and semisodium (divalproex), 175 vestibular toxicity aminoglycoside antibiotics, 509 viral infections blood transfusion, 671 virological failure Ginkgo biloba, 995 visceral hyperalgesia adenosine and analogues, 379 visual abnormalities vigabatrin, 177 visual acuity, reduced ethambutol, 634 visual disturbances paclitaxel, 939 sclerosants, 1021–2 visual hallucinations amantadine, 604 clarithromycin, 523 levetiracetam, 147 vitamin K metabolism vitamin E (Tocopherol), 696–7 vitreous hemorrhage ranibizumab, 979–80 vocal cord dysfunction sodium metabisulfite, 1022 volume expansion, excessive etherified starches, 675–6

Index of adverse effects and reactions vomiting 5HT3 receptor antagonists, 745 alfentanil, 209 amphotericin (ABLC), 543 anthraquinones, 753 anticholinergic drugs, 324 antimony, 448 azathioprine, 827 balsalazide, 756–7 benzydamine (benzindamine), 249 bisacodyl, 753 blood substitutes, 673 butorphanol, 227 cannabinoids, 741 Cynomorium songaricum, 994 dextromethorphan, 210 docetaxel, 947 ethosuximide, 136 etravirine, 592 Exilis, 994–5 flumazenil, 80 hydromorphone, 214 hyoscine (scopolamine) butylbromide, 759–60 immunoglobulin, intravenous, 678 ixabepilone, 949 kadda, 992 ketamine, 264 khat, 66 lansoprazole, 751 lansoprazole þ amoxicillin þ metronidazole or clarithromycin, 749 lanthanum carbonate, 451 letrozole, 862 levetiracetam, 148 levofloxacin, 516, 517 memantine, 16 mercaptopurine, 830 mesalazine (5-aminosalicylic acid, mesalamine), 759 methadone, 214 metoclopramide, 742–3 metronidazole, 573

morphine, 216 naltrexone, 228 nitrous oxide, 260–1 omeprazole and esomeprazole, 752 ondansetron, 746 oxcarbazepine, 151 oxycodone, 220 paclitaxel, 940 palonosetron, 747 pancreatic enzymes, 761 parathyroid hormone, 913 pioglitazone, 900 posaconazole, 553 praziquantel, 650 psilocybin, 66 pyrimethamine and congeners, 570 Rhododendron spp., 996–8 senna, 754–755 stem cells, 683 tacrolimus, 821, 823 tegaserod, 744 telavancin, 520 thiopurines, 825 tramadol, 224 valproate sodium and semisodium (divalproex), 167–8 vitamin A (carotenoids), 691 zedoray tumeric oil and glucose injection, 992 zhuang gu guan jie wan, 990 von Willebrand's disease valproate sodium and semisodium (divalproex), 171 vulnerable myocardium anagrelide, 719 W weakness See also fatigue bisacodyl, 753–4 fluoride, 1015 immunoglobulin, intravenous, 677 melatonin, 912

1103 simvastatin, 928 temsirolimus, 824 thyroid hormones, 882 weakness of voice glucocorticoids inhaled, 354 weight gain antiepileptic drugs, 129 antipsychotic drugs, 90, 96–9 hormonal contraceptives, 858–9 iloperidone, 104 lamotrigine, 143–4 olanzapine, 104 peroxisome proliferatoractivated dual receptor agonists, 902 pioglitazone, 900 pregabalin, 157–8 quetiapine, 110 risperidone, 111–2 stavudine, 583 weight loss bran, 754 roflumilast, 368 tacrolimus, 822 topiramate, 161 weight gain valproate sodium and semisodium (divalproex), 167–8 Wells' cellulitis anakinra (interleukin-1 receptor antagonist), 779 wheezing celiprolol, 398 esmolol, 398 folic acid, 693 heparins, 716 ranitidine, 748 Wilson's disease copper, 450 penicillamine, 472 Y yellow-orange discoloration of skin vitamin A (carotenoids), 691