Contributors M.C. ALLWOOD, BP HARM , P H D University of Derby, Pharmacy Academic Practice Unit, Faculty of Education, Health and Science, Chevin Avenue, Mickleover, Derby DE3 5GX, UK. E-mail:
[email protected] J.K. ARONSON, MA, MBC H B, D PHIL , FRCP, FBP HARMACOL S University Department of Clinical Pharmacology, Radcliffe Infirmary, Woodstock Road, Oxford, OX2 6HE, UK. E-mail:
[email protected] I. AURSNES, MD University of Oslo, Department of Pharmacotherapeutics, P.O. Box 1065 Blindern, N-0316 Oslo, Norway. E-mail:
[email protected] A.M. BALDACCHINO, MD, MRCP SYCH , M PHIL , D IP A DD B EH Centre for Addiction Research and Education Scotland (CARES), Medical Offices, Stratheden Hospital, Cupar, Fife, Scotland KY15 5RR, UK ANDRE BATE, MA (OXON ), P H D (U MEA ) WHO Collaborating Center for International Drug Monitoring, Uppsala, Sweden. M. BEHREND, MD, P H D Klinik fur Viszeral-, Gefäß-, Thorax- und Kinderchirurgie, Klinikum Deggendorf, Perlasberger Strasse 41, D-94469 Deggendorf, Germany. E-mail:
[email protected] F. BRAUN, MD Klinik für Allgemeine Chirurgie und Thoraxchirurgie, Universität Schleswig-Holstein, Campus Kiel, Arnold-Heller Strasse 7, 24105 Kiel, Germany. E-mail:
[email protected] A. BYRNE, BA, BAO, MB, BC H, MRCP SYCH South West Yorkshire Mental Health NHS Trust, Aberford Centre, Wakefield, and School of Human and Health Sciences, University of Huddersfield, Queensgate, UK. E-mail:
[email protected] A. CARVAJAL, MD, P H D Instituto de Farmacoepidemiología, Facultad de Medicina, 47005 Valladolid, Spain. E-mail:
[email protected] N.H. CHOULIS, M D , P H D LAVIPHARM Research Laboratories, Agias Marinas Street, 19002 Peania (Attika), Greece. E-mail:
[email protected] JAMIE COLEMAN, MBC H B, MRCP(UK), C ERT M ED E D Department of Clinical Pharmacology, Divison of Medical Sciences, Medical School, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK. E-mail:
[email protected]
v
vi
Contributors
J. COSTA, MD Clinical Pharmacology Department, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Ctra de Canyet, 08916 Badalona, Spain. E-mail:
[email protected] P.J. COWEN, MD University Department of Psychiatry, Warenford Hospital, Oxford, OX3 7JX, UK. E-mail:
[email protected] S. CURRAN, BS C , MBC H B, M MED S C , MRCP SYCH , P H D South West Yorkshire Mental Health NHS Trust, Aberford Centre, Wakefield, and School of Human and Health Sciences, University of Huddersfield, Queensgate, UK. E-mail:
[email protected] H.R. DALTON, BS C , DP HIL , FRCP, D IP M ED E D Department of Gastroenterology, Royal Cornwall Hospital, Truro, Cornwall, TR1 3LJ, UK. S. DAR, MBBS, BS C , MRCP Department of Gastroenterology, Royal Cornwall Hospital, Truro, Cornwall, TR1 3LJ, UK. F.A. de WOLFF, MA, P H D, E UR C LIN C HEM , ERT, FATS Leiden University Medical Center, Toxicology Laboratory, Department of Clinical Chemistry, Pharmacy and Toxicology, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail:
[email protected] A. DEL FAVERO, MD Istituto di Medicina Interna e Scienze Oncologiche, Policlinico Monteluce, 06122 Perugia, Italy. E-mail:
[email protected] J. DESCOTES, MD, P H D, P HARM D Centre Antipoison – Centre de Pharmacovigilance, 162 avenue Lacassagne, 69424 Lyon cedex 03, France. E-mail:
[email protected] S. DITTMANN, MD, DS C M ED International Immunization Consultancy, 19 Hatzenporter Weg, 12681 Berlin, Germany. E-mail:
[email protected] M.N.G. DUKES, MD, LLM, MA Unit for Drug Policy Studies, University of Oslo, Trosterudveien 19, 0778 Oslo, Norway. E-mail:
[email protected] D.L. DUNNER, MD 7525 SE 24th Street, Suite 400, Mercer Island, WA 98040, USA. E-mail:
[email protected] E. ERNST, MD, P H D, FRCP, FRCP (E D ) Complementary Medicine, Peninsula Medical School, Universities of Exeter & Plymouth, 25 Victoria Park Road, Exeter, EX2 4NT, UK. E-mail:
[email protected] JOHN EVISON, MD Klinik und Poliklinik für Infektiologie, University Hospital Berne, Berne, Switzerland. E-mail:
[email protected] M. FARRÉ, MD Unitat de Farmacologia, Institut Municipal d’Investigació Mèdica (IMIM-IMAS), Universitat Autònoma de Barcelona, Doctor Aiguader 80, 08003 Barcelona, Spain. E-mail:
[email protected]
Contributors
vii
P. FLISBERG, MD, P H D Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, GPO Box X2213, Perth, WA 6847, Australia. J.A. FRANKLYN, MD, P H D, FRCP, FM ED S CI University of Birmingham, Queen Elizabeth Hospital, Department of Medicine, Edgbaston, Birmingham, B15 2TH, UK. E-mail:
[email protected] M.G. FRANZOSI, P H D Istituto di Ricerche Farmacologiche “Mario Negri”, Department of Cardiovascular Research, Via Eritrea 62, 20157 Milan, Italy. E-mail:
[email protected] HANSJAKOB FURRER, MD Klinik und Poliklinik für Infektiologie, University Hospital Berne, Berne, Switzerland. E-mail:
[email protected] CHRISTOPH FUX, MD Klinik und Poliklinik für Infektiologie, University Hospital Berne, Berne, Switzerland. E-mail:
[email protected] A.H. GHODSE, MD, P H D, DS C , FRCP, FRCPE, FRCP SYCH , FFPH International Centre for Drug Policy (ICDP), St. George’s University of London, 2nd Floor Hunter Wing, Cranmer Terrace, London, SW17 0RE, UK. E-mail:
[email protected] A. GIL-NAGEL, MD Hospital Ruber Internacional, La Masó 38, Mirasierra, 28034 Madrid, Spain. E-mail:
[email protected] A.H. GROLL, MD Infectious Diseases Research Program, Center for Bone Marrow Transplantation and Department of Hematology/Oncology, Muenster, Germany. E-mail:
[email protected] I. HARDY, BP HARM School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. E-mail:
[email protected] J.T. HARTMANN, P H D, MD Department of Oncology/Hematology/Immunology, Eberhard Karls University Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany. E-mail:
[email protected] K. HARTMANN, MS C P HARM Berna Biotech Ltd, Head Global Pharmacovigilance, 3000 Berne, Switzerland. E-mail:
[email protected] MANFRED HAUBEN, MD, MPH Risk Management Strategy, Pfizer, Inc., New York, NY, USA. A. 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]
viii
Contributors
N. JIMENO, MD, P H D Instituto de Farmacoepidemiología, Facultad de Medicina, 47005 Valladolid, Spain. MARKUS JOERGER, MD Department of Pharmacy & Pharmacology, Slotervaart Hospital and Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute, 1066 EC Amsterdam, The Netherlands. E-mail:
[email protected] DAVID M. KEELING, BS C , MD, FRCP, FRCPATH Oxford Haemophilia Centre and Thrombosis Unit, Churchill Hospital, Oxford OX3 7LJ, UK. E-mail:
[email protected] SANDRA R. KNOWLES, BS C P HM Drug Safety Clinic, Sunnybrook & Women’s College Health Sciences Centre, University of Toronto, ON M4N 3M5, Canada. E-mail:
[email protected] MAX KUHN, MD Department of Internal Medicine, Division of Pneumology, Kantonsspital, Loestrasse 170, 7000 CHUR, Switzerland. E-mail:
[email protected] I. KUROWSKI, MMMS, FANZCA Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, GPO Box X2213, Perth, WA 6847, Australia. R. LAFFER, MD Department of Internal Medicine, Division of Infectious Diseases, Kantonsspital Aarau, 5001 Aarau, Switzerland. E-mail:
[email protected] R. LATINI, MD Istituto di Ricerche Farmacologiche “Mario Negri”, Department of Cardiovascular Research, Via Eritrea 62, 20157 Milan, Italy. E-mail:
[email protected] T. LEDOWSKI, MD, DEEA Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, GPO Box X2213, Perth, WA 6847, Australia. M. LEUWER, MD The University of Liverpool, University Department of Anaesthesia, The Duncan Building, Daulby Street, Liverpool, L69 3GA, UK. E-mail:
[email protected] H.-P. LIPP, P H D Eberhard-Karls-University Tübingen, Department of Clinical Pharmacy, Röntgenweg 9, 72076 Tübingen, Germany. P. MAGEE, BS C , MS C , MRP HARM S Director of Pharmaceutical Sciences, University Hospitals Coventry and Warwickshire, Clifford Bridge Road, Coventry, CV2 2DX, UK. E-mail:
[email protected] A.P. MAGGIONI, MD ANMCO Research Center, Via La Marmora 34, 50121 Florence, Italy. E-mail:
[email protected] L.H. MARTÍN ARIAS, MD, P H D Instituto de Farmacoepidemiología, Facultad de Medicina, 47005 Valladolid, Spain. E-mail:
[email protected]
Contributors
ix
R.H.B. MEYBOOM, MD, P H D Division of Pharmacoepidemiology and Pharmacotherapy, Faculty of Pharmaceutical Scienes, Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands. T. MIDTVEDT, MD, P H D Department of Microbiology, Tumor and Cell Biology (MTC), Nobels v. 16, Karolinska Institute, S 171 77 Stockholm, Sweden. E-mail:
[email protected] S.K. MORCOS, FRCS, FFRRCSI, FRCR Northern General Hospital, Sheffield Teaching Hospitals NHS Trust, Department of Diagnostic Imaging, Sheffield, S5 7AU, UK. E-mail:
[email protected] S. MUSA, MBC H B, MRCP SYCH Consultant Old Age Psychiatrist, South West Yorkshire Mental Health NHS Trust, Aberford Centre, Wakefield, UK. R. PAGE, MD, FRCP, MA(E D ) Endocrine unit, Dundee House, Nottingham City Hospital, Hucknall Rd., Nottingham, NG5 1PB, UK. E-mail:
[email protected] J.K. PATEL, MD University of Massachusetts Medical School, Department of Psychiatry, 361 Plantation Street, Worcester, MA 01605, USA. E-mail:
[email protected] B.C.P. POLAK, MD VU University Medical Center, Department of Ophthalmology, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail:
[email protected] T.E. RALSTON, MA Department of Psychiatry, University of Maryland–Baltimore, 737 W Lombard St, Suite 551, Baltimore, MD 21201, USA. E-mail:
[email protected] M. 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] MATTHIAS SCHLEGEL, MD Klinik und Poliklinik für Infektiologie, University Hospital Berne, Berne, Switzerland. E-mail:
[email protected] S.A. SCHUG, MD, FANZCA, FFPMANZCA Pharmacology and Anaesthesiology Unit, University of Western Australia and Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, GPO Box X2213, Perth, WA 6847, Australia. E-mail:
[email protected] R.P. SEQUEIRA, P H D, FCP Arabian Gulf University, College of Medicine and Medial Sciences, Department of Pharmacology and Therapeutics, P.O. Box 22979, Manama, Bahrain. E-mail:
[email protected] NEIL H. SHEAR, MD, FRCPC Drug Safety Clinic, Sunnybrook Health Sciences Centre, University of Toronto, ON M4N 3M5, Canada. E-mail:
[email protected]
x
Contributors
D.A. SICA, MD Section of Clinical Pharmacology and Hypertension, Division of Nephrology, Medical College of Virginia of Virginia Commonwealth University, Box 980160 MCV Station, Richmond, VA 23298-0160, USA. E-mail:
[email protected] OSCAR O. SIMOOYA, BS C, MBC H B, MS C Clinical Pharmacologist, Copperbelt University Health Services, P.O. Box 21692, Kitwe, Zambia. E-mail:
[email protected] P.F.W. STRENGERS, MD, FFPM Sanquin, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. E-mail:
[email protected] S. SWAMINATHAN, MD Tuberculosis Research Centre, Mayor VR Ramanathan Road, Chetpet, Chennai 600031, India. E-mail:
[email protected] CHRISTINE THURNHEER, MD Klinik und Poliklinik für Infektiologie, University Hospital Berne, Berne, Switzerland. E-mail:
[email protected] G.B. VAN DER VOET, P H D, ERT Leiden University Medical Center, Toxicology Laboratory, Department of Clinical Chemistry, Pharmacy and Toxicology, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail:
[email protected] P.J.J. VAN GENDEREN, MD, P H D Harbour Hospital, Department of Internal Medicine, Haringvliet 2, 3011 TD Rotterdam, The Netherlands. E-mail:
[email protected] R. VERHAEGHE, MD University of Leuven, Center for Vascular and Molecular Biology, Herestraat 49, 3000 Leuven, Belgium. E-mail:
[email protected] T. VIAL, MD Centre Antipoison – Centre de Pharmacovigilance, 162 avenue Lacassagne, 69424 Lyon cedex 03, France. E-mail:
[email protected] P.J.M. VOSSEBELD, P H D Sanquin, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. E-mail:
[email protected] G.M. WALSH, MS C , P H D School of Medicine, Institute of Medical Sciences Building, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK. E-mail:
[email protected] T.J. WALSH, MD Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20891, USA. E-mail:
[email protected] E.J. WONG, MD Harvard Medical School, Massachusetts Mental Health Center, Department of Psychiatry, Boston, MA 02115, USA. E-mail:
[email protected]
Contributors
xi
GAVIN WONG, MBC H B, MRCP(UK) Drug Safety Clinic, Sunnybrook & Women’s College Health Sciences Centre, University of Toronto, ON M4N 3M5, Canada. E-mail:
[email protected] Y. YOUNG, MBBS, MRCP(UK), FRCA, FANZCA Department of Anaesthesia, Level 8, Support Building, Auckland City Hospital, Private Bag 92024, Auckland, New Zealand. E-mail:
[email protected] O. ZUZAN, MD Royal Liverpool University Hospital, Department of Anaesthesia, Prescot Street, Liverpool, L7 8XP, UK. E-mail:
[email protected]
Contents Contributors
v
Special reviews
xvii
Cumulative index of special reviews, Annuals 14–28
xix
Table of Essays, Annuals 1–28
xxvii
DoTS classification of adverse drug reactions
xxix
How to use this book
xxxi
Essay: Data mining in drug safety M. Hauben and A. Bate 1. Central nervous system stimulants and drugs that suppress appetite R.P. Sequeira
xxxiii 1
2. Antidepressant drugs P.J. Cowen
18
3. Lithium D.L. Dunner
28
4. Drugs of abuse J.K. Patel, T.E. Ralston, and E. Wong
35
5. Hypnosedatives and anxiolytics S. Musa, A. Byrne, and S. Curran
51
6. Antipsychotic drugs A. Carvajal, L.H. Martín Arias, and N. Jimeno
60
7. Antiepileptic drugs A. Gil-Nagel
87
8. Opioid analgesics and narcotic antagonists A.H. Ghodse and A.M. Baldacchino
105
9. Anti-inflammatory and antipyretic analgesics and drugs used in gout A. Del Favero
116
10. General anesthetics and therapeutic gases Y. Young
128
11. Local anesthetics S.A. Schug, P. Flisberg, I. Kurowski, and T. Ledowski
135
12. Neuromuscular blocking agents and skeletal muscle relaxants O. Zuzan and M. Leuwer
145
13. Drugs that affect autonomic functions or the extrapyramidal system M. Schachter
148
14. Dermatological drugs, topical agents, and cosmetics S.R. Knowles, G. Wong, and N.H. Shear
156
xiii
xiv
Contents
15. Antihistamines (H1 receptor antagonists) G.M. Walsh
161
16. Drugs acting on the respiratory tract M. Joerger, K. Hartmann, and M. Kuhn
168
17. Positive inotropic drugs and drugs used in dysrhythmias J.K. Aronson
182
18. Beta-adrenoceptor antagonists and antianginal drugs A.P. Maggioni, M.G. Franzosi, and R. Latini
194
19. Drugs acting on the cerebral and peripheral circulations R. Verhaeghe
202
20. Antihypertensive drugs J.J. Coleman
206
21. Diuretics D.A. Sica
219
22. Metals G.B. van der Voet and F.A. de Wolff
225
23. Metal antagonists R.H.B. Meyboom
235
24. Antiseptic drugs and disinfectants P. Magee
241
25. Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines T. Midtvedt
244
26. Miscellaneous antibacterial drugs A. Imhof and R. Laffer
253
27. Antifungal drugs A.H. Groll and T.J. Walsh
280
28. Antiprotozoal drugs O.O. Simooya
294
29. Antiviral drugs C. Fux, J. Evison, M. Schlegel, C. Thurnheer, and H. Furrer
300
30. Drugs used in tuberculosis and leprosy S. Swaminathan
315
31. Antihelminthic drugs P.J.J. van Genderen
320
32. Vaccines S. Dittmann
327
33. Blood, blood components, plasma, and plasma products P.J.M. Vossebeld and P.F.W. Strengers
338
34. Formulations used in nutrition M.C. Allwood and I. Hardy
353
35. Drugs affecting blood coagulation, fibrinolysis, and hemostasis D.M. Keeling
358
Contents
xv
36. Gastrointestinal drugs S. Dar and H.R. Dalton
371
37. Drugs that act on the immune system: cytokines and monoclonal antibodies T. Vial, J. Descotes, F. Braun, and M. Behrend
383
38. Drugs that act on the immune system: immunosuppressive and immunostimulatory drugs F. Braun and M. Behrend
424
39. Corticotrophins, corticosteroids, and prostaglandins J. Costa and M. Farré
480
40. Sex hormones and related compounds, including hormonal contraceptives M.N.G. Dukes
493
41. Thyroid hormones and antithyroid drugs J.A. Franklyn
520
42. Insulin, other hypoglycemic drugs, and glucagon R.C.L. Page
523
43. Miscellaneous hormones R.C.L. Page
539
44. Drugs that affect lipid metabolism I. Aursnes
546
45. Cytostatic drugs H.-P. Lipp and J.T. Hartmann
551
46. Radiological contrast agents S.K. Morcos
573
47. Drugs used in ocular treatment B.C.P. Polak
581
48. Treatments used in complementary and alternative medicine E. Ernst
583
49. Miscellaneous drugs and materials, medical devices, and techniques N.H. Choulis and J.K. Aronson
596
Address list of national centres that participate in the WHO Drug Monitoring Programme
618
Index of drugs
632
Index of adverse effects
644
Special reviews
The effects of metamfetamine abuse on cognition and on brain structures and function Mania as an adverse effect of antidepressants SSRIs and suicidal behavior Fetotoxicity of cocaine Death from opioid abuse Coxibs and cardiovascular disease Sedation in special circumstances Anaphylaxis due to neuromuscular blocking agents Adverse effects of inhaled glucocorticoids on the mouth and throat Adverse effects of inhaled glucocorticoids on the skin Beta2 -adrenoceptor genotypes and safety of salbutamol in asthma Leukotriene receptor antagonists and Churg–Strauss syndrome Moving targets and patterns of prescribing Angioedema due to ACE inhibitors Hyponatremia and loop and thiazide diuretics Deferoxamine, deferiprone, and cardiac siderosis Antimicrobial drug resistance: a serious adverse effect exemplified by avoparcin and vancomycin-resistant enterococci Nephrolithiasis and ceftriaxone Drug interactions with antifungal azoles Lipoatrophy, hyperlactatemia, and mitochondrial toxicity Immune reconstitution disease Multiple immunizations/combination vaccines The potential influenza H5N1 pandemic Subacute sclerosing panencephalitis (SSPE) and measles immunization Skin necrosis in oral anticoagulation Abnormalities of electrolyte, mineral, metal, and fluid balance due to polyethylene glycol Psychological and psychiatric adverse effects of interferons Infection risk with tumor necrosis factor antagonists Leflunomide Drug development of abetimus Thymic hormones Effects of glucocorticoids on the eye Abuse of anabolic steroids in sport Metformin and lactic acidosis Incretin mimetics
3 18 19 41 44 116 128 145 168 169 173 174 206 207 219 235 244 246 282 302 315 327 332 335 358 376 384 395 435 460 464 481 508 526 528
xvii
xviii Peripheral edema due to thiazolidinediones Anticancer antimetabolites Nephrotoxicity due to contrast media Intravitreal and parabulbar injection of drugs Incidence of adverse effects of acupuncture Traumatic adverse effects of acupuncture Adverse effects of spinal manipulation Medication errors
Special reviews
531 551 575 581 589 590 591 596
Cumulative index of special reviews, Annuals 14–28 Index of drugs Note: the format 28.124 refers to SEDA-28, p. 124. ACE inhibitors acetylsalicylic acid, interaction, 28.124 angioedema, 22.225 cough, 19.211 indications, 24.233 Acetylsalicylic acid, 21.100 ACE inhibitors, interaction, 28.124 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, 15.85 rhinosinusitis/asthma, 17.94 Aerosols, delivery, 27.172 Albumin, human, anaphylaxis, 14.296 Alcohol, vitamin A, beta-carotene, interaction, 24.442 Aldosterone antagonists, in heart failure, 24.246 Aluminium, in albumin solutions, 23.359 Aminoglycoside antibiotics, 17.304 dosage regimens, 20.234, 21.265, 23.264 nephrotoxicity, 15.268, 17.305 ototoxicity, 14.222, 18.268 and ribostamycin, 15.270 Amiodarone, dysrhythmias, 25.211 respiratory toxicity, 15.168 thyroid disease, 27.192 Amphotericin, liposomal, 17.319 nephrotoxicity, 14.229, 27.276 Analgesics 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, combinations, 20.121 local, neurotoxicity, 21.129, 25.152 ocular, 17.542 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
Anticholinergic drugs, 22.507 Anticonvulsants, see Antiepileptic drugs Antidepressants, during and after pregnancy, 21.17 overdose, 28.14 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 Pneumocystis jiroveci (carinii) pneumonia, 18.289 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 Antimalarial drugs, 14.237, 17.325, 20.257 adjunctive treatments, 24.330 prophylaxis, 23.304 Antimicrobial drugs allergic reactions, 23.251 coagulation disorders, 18.258 colitis, 17.303 prudent future use, 27.242, 28. 265 male fertility, 16.262 new, with adjuvants, 17.296 the pill and pregnancy, 24, 274 policies and politics, 16.273 prescribing, 15.254 preterm infants, 21.258 prudent use, 25.279 resistance, 19.237, 20.228, 21.257, 22.265, 23.250, 24.273 seizures, 18.261 side chains, 16.264 Antioxidant vitamins, 20.363 Antiprotozoal drugs
xix
xx
Cumulative index of special reviews, Annuals 14–28
African trypanosomiasis, 18.293 toxoplasmosis, 20.262 Antipsychotic drugs comparisons of different types 25.53, 27.50 diabetes mellitus, 28.60 use in conditions other than schizophrenia, 27.49 weight gain, 26.56 Antiretroviral drugs, metabolic complications, 28.329 Antituberculosis drugs, 16.341 genetic susceptibility, 28.342 liver damage, 25.363, 26.339 Mycobacterium avium–complex infection, 20.278 Appetite suppressants cardiac valvulopathies, 22.3, 23.2, 24.4, 25.5 primary pulmonary hypertension, 18.7, 21.2, 23.2, 25.5 Aspirin, see Acetylsalicylic acid Asthma medications, exacerbation of asthma, 20.165 Atovaquone, 19.266 Avoparcin, lessons from, 27.242 Azoles, see antifungal drugs
adverse effects, 24.525 anaphylactoid and allergic reactions, 20.422 delayed reactions, 26.513 in magnetic resonance imaging, 20.419 nephrotoxicity, 27.500, 28.556 Corticosteroids, see Glucocorticoids Cosmetics contact allergy, 16.150, 19.151 ingredient labeling 22.159 Co-trimoxazole, hypersensitivity reactions, 20.264 COX2 inhibitors, 24.115, 25.126, 26.116
Baclofen, withdrawal syndrome, 26.152 Bambuterol, cardiac failure, 23.181 Benzodiazepines, depression, 17.43 brain damage, 14.36 Beta2 -adrenoceptor agonists, 18.159 asthma, 19.178, 21.179 asthma deaths, 17.164 Beta-adrenoceptor antagonists, sexual function, 15.188 Beta-carotene, see also Vitamin A alcohol, vitamin A, interaction, 24.442 tumorigenicity, 25.454 Beta-lactam antibiotics, immediate hypersensitivity reactions, 14.211 pregnancy, 25.280 Botulinum toxin A, use in primary axillary hyperhidrosis, 27.161 Calcium antagonists, long-term safety, 20.185, 21.208, 22.214 Carotenoids, tumorigenicity, 25.454 Ceftriaxone, 15.258 Cephalosporins, immunological reactions, 28.267 Charcoal, activated, in digitalis overdose, 24.201 Chloramphenicol, children, 15.267 Chloroquine, 15.286 Chondroprotective agents, 14.439 Chymopapain, 14.264 Ciclosporin, urinary system, 19.348 Clozapine, 15.50 agranulocytosis, 22.1359 Complementary and alternative therapies, indirect risks, 27.521 esophagus, adverse effects on, 14.442 Contrast media, nephrotoxicity, 27.500 Cocaine cardiovascular effects, 18.5 prenatal exposure and perinatal effects, 27.1 second-generation effects, 20.24 Cocamidopropylbetaine, allergy, 19.151 Contrast media
Deferoxamine, 16.247 bone dysplasia, 23.241 Diamorphine, progressive spongiform leukoencephalopathy, 24.40 Diclofenac, liver damage, 20.91 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 heart failure in sinus rhythm, 18.196 Diuretics diabetes mellitus, electrolyte abnormalities, and the ALLHAT trial, 27.219 renal cell carcinoma, 23.225 renal insufficiency, 25.250 Dofetilide, 26.208 Dopamine receptor agonists, sleep disorders, 26.160, 27.149 Ecstasy, see MDMA EDTA, pseudothrombocytopenia, 21.250 Endothelin receptor antagonists, in hypertension, 26.233 Enzyme inhibitors, 15.337 Erythromycin, versus the new macrolides, 21.269 Erythropoietin, pure red cell aplasia, 27.348 status and safety, 16.400 Etoposide, 27.477 Euxyl K 400, contact allergy, 16.150 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 Flecainide, in supraventricular dysrhythmias, 21.200 Fluoroquinolones, 18.271 Fluorouracil, adverse effects, 23.476 Folic acid, dietary supplementation, 19.369 safety aspects, 27.407 Formoterol, tolerance, 24.187 Fragrances, contact allergy, 20.149
Cumulative index of special reviews, Annuals 14–28
xxi
Gadolinium salts, nephrotoxicity, 28.561 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 growth, 14.335 inhaled, growth inhibition, 26.186 inhaled, risks in children, 27.174 inhaled, systemic availability, 24.185, 26.187 musculoskeletal adverse effects, 21.417 osteoporosis and osteonecrosis, 16.447, 19.377, 20.374, 21.417, 22.182, 28.473 preterm infants, 17.445 Grapefruit juice, drug interactions 23.519 Growth hormone adults, 16.501 insulin resistance, 24.504 malignancy, 23.468
Lipid-lowering drugs, 15.479 Lithium adverse effects, prevention and treatment, 17.28 beneficial uses other than in bipolar disorder, 27.19 interactions, 16.13, 18.30 intoxication, prevention and treatment, 17.29 monitoring therapy, 18.25 mortality, 19.14 urinary system, 14.18, 19.16 Local anesthetics, see Anesthetics Lorenzo’s oil, 27.475 Lyme disease vaccine, autoimmune disease, 24.366
Hepatitis B vaccine, demyelinating diseases, 21.331, 22.346, 24.374 Heroin, see diamorphine Histamine (H2 ) receptor antagonists, 15.393 HIV-protease inhibitors insulin resistance, 22.317 lipodystrophy, 22.317 HMG Co-A reductase inhibitors, interactions, 25.530 Hormones, sex, tumors, 22.465 5-HT, see serotonin Hypnotics, 20.30 avoiding adverse effects, 21.37 Hypoglycemic drugs, combinations of, 27.458, 28.521 Immunization adverse effects, 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 Indometacin, fetal and neonatal complications, 18.102 Insulin human, and hypoglycemia, 15.452 modes of administration, 26.464 resistance, and growth hormone, 24.504 synthetic analogs, 24.489 Interleukin-2, 14.325 Irinotecan, 27.477 Isoniazid, prophylactic, toxicity, 24.352 Kava kava liver damage, 27.518 adverse effects, 28.579 Ketorolac, risk of adverse effects, 17.110 Lamotrigine, skin rashes, 20.62, 24.88 Leukotriene receptor antagonists, Churg–Strauss syndrome, 24.183, 27.177
Macrolides, drug interactions, 14.220 intestinal motility, 18.269 Malaria vaccines, 22.306 Mannitol, 28.236 MAO inhibitors, 17.361 MDMA cognitive effects, 26.32 deaths, 24.32 Measles immunization autism, 23.350 Crohn’s disease, 23.350 neurological adverse effects, 23.348 Melatonin, 25.523 Metformin contraindications, 28.515 lactic acidosis, 23.459 Methyldibromoglutaronitrile, contact allergy, 16.150, 19.151 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 Morphine, managing adverse effects, 26.98 Muscle relaxants emergency medicine, 20.133 eyes, 21.145 hypersensitivity reactions, 27.138 intensive care, 19.140 Niacin, extended-release, 16.440 Non-depolarizing neuromuscular blockers, 15.127 residual paralysis, 27.139 NSAIDs acute renal insufficiency, 28.122 blood pressure, 19.92, 27.102 children, 19.96 current controversies, 17.102 COX2 inhibitors, 24.115, 25.126, 26.116 dyspepsia, 28.120 gastrointestinal adverse effects, 14.79, 17.95, 18.90, 18.99, 20.86, 21.96, 22.108, 23.114 gastrointestinal damage, role of Helicobacter pylori, 27.105 gastrointestinal toxicity, prevention, 19.93 inflammatory bowel disease, 25.131 inhibiting cardioprotective effects of acetylsalicylic acid, 28.118
xxii intracerebral hemorrhage, 28.119 necrotizing fasciitis, 28.121 nephrotoxicity, 18.100, 20.89, 24.120, 26.111 topical, 18.163 Ocular drugs allergic reactions, 21.486 geriatric patients, 16.542 risk factors for adverse effects, 22.507 Omeprazole, tumors, 16.423 Opioids adverse effects, prevention, 24.100 death, 25.37 obstetric use, 24.102 tolerance in neonates, 23.97 Oral contraceptives antibiotics, and pregnancy, 24.274 and breast cancer, 15.426 formulations, 24.472 third-generation, 25.484, 26.442 venous thromboembolism, 23.442 Paclitaxel, adverse effects, 21.463 Pancreatic enzyme supplements, fibrosing colonopathy, 20.322 Paracetamol liver damage, 17.98, 18.94 overdose, 23.117 Parenteral nutrition bone effects, 22.378 cholestasis, 22.376 infections 22.379 Penicillins acute desensitization, 23.252 immunological reactions, 28.267 Peritoneal dialysis fluids, effects on peritoneum, 22.381 Phentermine, cardiac valvulopathies, 24.4 Platinum compounds, 26.490 Polio vaccine, AIDS, 23.352 Polyaspartic acid, protective against nephrotoxicity, 17.305 Polystyrene sulfonates, 25.271 Polyvinylpyrrolidone, storage disease, 22.522 Propofol, infusion syndrome, 26.135 Propolis, allergy, 17.181 Proton pump inhibitors, tumors, 23.383 PUVA, malignant melanoma, 22.166 Pyrazinamide, in latent pulmonary tuberculosis, 27.323 Quinidine, versus quinine, 15.295 Quinine, versus quinidine, 15.295 Ribostamycin, and aminoglycosides, 15.270 Rocuronium, allergic reactions, 26.150
Cumulative index of special reviews, Annuals 14–28 Rotashield, intussusception, 23.354 Salmeterol, tolerance, 24.187 Sex hormones, tumors, 22.465 Serotonin receptor antagonists, 15.391 selective serotonin reuptake inhibitors, drug interactions, 22.13 Smallpox vaccination, 27.339 Somatostatin, 15.468 Statins, see HMG Co-A reductase inhibitors Steroids, see glucocorticoids Sumatriptan, 17.171 Suramin, patients with prostate cancer, 20.283 Suxamethonium, postoperative myalgia, 28.155 Teniposide, 27.477 Tetracyclines adverse effects, 26.268 comparative toxicity, 22.268 and metalloproteinases, 26.266 in pregnancy, 25.280 in rheumatology, 23.255 therapeutic effects, 24.278 Theophylline, asthma, 17.2, 18.1, 18.2 Thiomersal, in vaccines, 28.357 Thyroxine, drug interactions, 24.484 Tiaprofenic acid, cystitis, 18.106 Topiramate, cognitive effects, 26.81 Topoisomerase inhibitors, 27.477 Topotecan, 27.477 Tretinoin, topical, teratogenicity, 18.164 Triazolam, 16.33 L-tryptophan, eosinophilia-myalgia syndrome, 15.514 Vaccines, see also individual agents poliomyelitis, 22.352 thiomersal in, 28.357 Vigabatrin psychosis and abnormal behavior, 18.71 visual field defects, 21.78, 24.95, 25.98, 26.82 Valproate, polycystic ovary syndrome, 26.81 Vancomycin., lessons from, 27.242 Vinca alkaloids, 28.538 Vitamin A, 17.436 alcohol, beta-carotene, interaction, 24.442 hypervitaminosis, 15.411 in pregnancy, 21.405 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
Index of adverse effects Cardiovascular atrial fibrillation, antidysrhythmic drugs, 24.197 atrial fibrillation, digitalis, 24.197 cardiac failure, aldosterone antagonists, 24.246
cardiac failure, bambuterol, 23.181 cardiotoxicity, antihistamines, 17.196, 25.183, 26.180 cardiotoxicity, calcium antagonists, 20.185
Cumulative index of special reviews, Annuals 14–28
xxiii
cardiotoxicity, cocaine, 18.5 cardiotoxicity, propofol, 26.135 dysrhythmias, antihistamines, 22.176 dysrhythmias, amiodarone, 25.211 heart attacks, acetylsalicylic acid, 27.109 hypertension, NSAIDs, 19.92, 27.102 prodysrhythmic effects, 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 venous thromboembolism, oral contraceptives, 23.442 Respiratory amiodarone, 15.168 asthma, acetylsalicylic acid, 17.94 asthma, fenoterol, 23.182 asthma, in pregnancy, 28.186 asthma deaths, beta2 -adrenoceptor agonists, 17.164 asthma exacerbation, asthma medications, 20.165 Churg–Strauss syndrome, leukotriene receptor antagonists, 24.183, 27.177 cough, ACE inhibitors, 19.211 primary pulmonary hypertension, appetite suppressants, 18.7, 21.2, 23.2, 25.5 rhinosinusitis, acetylsalicylic acid, 17.94 Nervous system brain damage, benzodiazepines, 14.36 demyelinating diseases, hepatitis B vaccine, 21.331, 22.346, 24.374 drowsiness/sedation, antihistamines, 21.170, 23.171, 26.182 headache, analgesics, 21.95, 23.114 intracerebral hemorrhage, NSAIDs, 28.119 neuroleptic malignant syndrome, 20.41 neurotoxicity, anesthetics, local, 21.129 neurotoxicity, measles immunization, 23.348 overdosage, antiepileptic drugs, 22.84 poliomyelitis, vaccines, 22.352 progressive spongiform leukoencephalopathy, diamorphine, 24.40 seizures, antibiotics, 18.261 sleep disorders, dopamine receptor agonists, 26.160, 27.149 strokes, acetylsalicylic acid, 27.109 strokes, risperidone, 28.76 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 effects, muscle relaxants, 21.145 ototoxicity, aminoglycosides, 14.222, 18.268 visual field defects, vigabatrin, 21.78, 24.95, 25.98, 26.82 Psychiatric antiepileptic drugs, 22.82, 27.72 autism, MMR/measles immunization, 23.350, 25.387, 28.363 cognitive effects, MDMA, 26.32
cognitive effects, topiramate, 26.78 depression, benzodiazepines, 17.43 psychosis and abnormal behavior, vigabatrin, 18.71 Endocrine diabetes mellitus, antihypertensive drugs, 28.226 diabetes mellitus, antipsychotic drugs, 28.60 diabetes mellitus, diuretics, 27.219 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 Metabolism Antiretroviral drugs, 28.329 hypoglycemia, insulin, 15.452 lactic acidosis, metformin, 23.459 metabolic acidosis, propofol, 26.135 lipodystrophy, HIV-protease inhibitors, 22.317 polyvinylpyrrolidone storage disease, 22.522 weight gain, antipsychotic drugs, 26.56 Electroyte balance electrolyte abnormalities, diuretics, 27.219 Hematologic agranulocytosis, clozapine, 22.59 aplastic anemia, felbamate, 19.68, 22.86 coagulation disorders, beta-lactam antibiotics, 18.258 eosinophilia-myalgia syndrome, tryptophan, 15.514 pseudothrombocytopenia, EDTA, 21.250 pure red cell aplasia, erythropoietin, 27.348 Gastrointestinal bleeding, acetylsalicylic acid, 17.95, 18.90 cholestasis, total parenteral nutrition, 22.376 colitis, antibiotics, 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, macrolides, 18.269 intussusception, Rotashield, 23.354 ulceration, bleeding and perforation, NSAIDs, 14.79, 16.103, 17.95, 18.90, 18.99, 19.93, 20.86, 21.96, 22.108, 23.114, 27.105 Liver hepatotoxicity, alcohol/vitamin A/beta-carotene, 24.442 hepatotoxicity, antituberculosis drugs, 25.363, 26.339 hepatotoxicity, diclofenac, 20.91 hepatotoxicity, kava kava, 27.518 hepatotoxicity, paracetamol, 17.98, 18.94 Reye’s syndrome, acetylsalicylic acid, 15.85 Urinary tract acute renal insufficiency, NSAIDs, 28.122 cystitis, tiaprofenic acid, 18.106 nephrotoxicity, aminoglycosides, 15.268, 17.305 nephrotoxicity, amphotericin, 14.229, 27.276 nephrotoxicity, analgesics, 21.98 nephrotoxicity, anesthetics, halogenated, 20.106 nephrotoxicity, ciclosporin, 19.348
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Cumulative index of special reviews, Annuals 14–28
nephrotoxicity, contrast media, 27.500, 28.556 nephrotoxicity, gadolinium salts, 28.561 nephrotoxicity, lithium, 14.18, 19.16 nephrotoxicity, NSAIDs, 18.100, 20.89, 24.120, 26.111 renal cell carcinoma, diuretics, 23.225 renal insufficiency, diuretics, 25.250 Skin contact allergy, 23.160 contact allergy, glucocorticoids, 15.139 rashes, lamotrigine, 20.62, 24.88 vitamin K1, 25.461 Serosae peritoneum, peritoneal dialysis, 22.381 pleurodesis, 25.189 Musculoskeletal 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 growth in children, inhaled glucocorticoids, 26.186 growth in children, oral glucocorticoids, 14.335 osteoporosis and osteonecrosis, glucocorticoids, 16.447, 19.377, 20.374, 21.417, 22.182, 28.473 rhabdomyolysis, propofol, 26.135 postoperative myalgia, suxamethonium, 28.155 Sexual function and beta-adrenoceptor antagonists, 15.188 Immunologic allergic reactions, antibiotics, 23.251 allergic reactions, rocuronium, 26.150 anaphylaxis, human albumin, 14.296 angioedema, ACE inhibitors, 22.225 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 hypersensitivity reactions, muscle relaxants, 27.138 methyldibromoglutaronitrile, 16.150, 19.151 ocular drugs, 21.486 propolis, 17.181 red man syndrome, 17.312 Infection risk AIDS, polio vaccine, 23.352 necrotizing fasciitis, NSAIDs, 28.121 total parenteral nutrition, 22.379 Body temperature malignant hyperthermia, 18.112 Death antiepileptic drugs, 23.83 calcium antagonists, 22.214
ecstasy, 24.32 lithium, 19.14 opiates, 25.37 Drug tolerance antibiotic resistance, 19.237, 20.228, 21.257, 22.265, 23.250, 24.273, 25.279 opioids in neonates, 23.97 Drug withdrawal baclofen, 26.152 Genotoxicity antiestrogens, 27.429 Tumorigenicity alcohol/vitamin A/beta-carotene, 24.442 antiestrogens, 27.429 beta-carotene, 25.454 carotenoids, 25.454 fertility drugs, 24.474, 26.434 growth hormone, 23.468 omeprazole, 16.423 oral contraceptives, 15.426 proton pump inhibitors, 23.383 PUVA, malignant melanoma, 22.166 sex hormones, 22.465 vitamin K, 23.424 Fertility fertility, male, antibiotics, 16.262 Pregnancy affective disorders in, 21.17 antibiotics and the pill, 24.274 asthma, 28.186 beta-lactams, 25.280 cocaine, 27.1 opioids, 24.102 tetracyclines, 25.280 vitamin A, 21.405 Teratogenicity tretinoin, topical, 18.164 Fetotoxicity cocaine, 20.24, 27.1 indometacin, 18.102 Susceptibility factors children, inhaled glucocorticoids 27.174 children, NSAIDs, 19.96 genetic susceptibility, antituberculosis drugs, 28.342 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 Drug administration delivery of aerosols, 27.172 dosage regimens, aminoglycosides, 23.264 errors, 28.587 formulations, oral contraceptives, 24.472 inhaled glucocorticoids, systemic availability, 24.185 labeling problems, cosmetics, 22.159 Drug overdose antidepressants, 28.14 digitalis, charcoal, 24.201 paracetamol, 23.117 Drug interactions acetylsalicylic acid ACE inhibitor, 28.124 acetylsalicylic acid/NSAIDs, 28.118
Cumulative index of special reviews, Annuals 14–28
xxv
alcohol/vitamin A/beta-carotene, 24.442 antibiotics/the pill, 24.274 antifungal azoles, 24.318, 28.299 grapefruit juice, 23.519 HMG Co-A reductase inhibitors, 25.530 lithium, 16.13 lithium/specific serotonin reuptake inhibitors, 18.30 macrolides, 14.220
mibefradil, 23.210 NSAIDs/ACE inhibitors, 28.122 specific serotonin reuptake inhibitors, 22.13 thyroxine, 24.484 Methods ethnopharmacology, 14.429 onchocerciasis, treatment, 14.261 post-marketing surveillance, 14.210, 15.266, 24.274
Table of Essays, Annuals 1–28 SEDA
Author
Country
Title
The Netherlands Germany USA The Netherlands UK
The moments of truth Drug monitoring: why care? Wanted and unwanted drug effects: the need for perspective The van der Kroef syndrome Adverse reactions to drugs—the information lag
Hungary Canada Denmark UK Denmark Denmark Switzerland UK Denmark
Science vs practice and/or practice vs science Adverse reactions: some pitfalls and postulates The seven pillars of foolishness Let’s get our act together Integrated medicine, safer medicine and “AIDS” Hark, hark, the fictitious dogs do bark Both sides of the fence On our side of the fence The great cholesterol carousel
15 16 17 18
M.N.G. Dukes K.H. Kimbel L. Lasagna M.N.G. Dukes J.P. Griffin, P.F. D’Arcy I. Bayer E. Napke M.N.G. Dukes W.H.W. Inman S. Van Hauen M.N.G. Dukes M.C. Cone C. Medawar M.N.G. Dukes, E. Helsing P. Tyrer M.N.G. Dukes M.N.G. Dukes R.D. Mann
UK Denmark Denmark UK
19
A. Herxheimer
UK
20
E. Ernst
UK
21
H. Jick
USA
22
UK
24
J.K. Aronson, R.E. Ferner K.Y. HartiganGo, J.Q. Wong I. Palmlund
The nocebo effect—poorly known but getting stronger Good enough for Iganga? The mists of tomorrow Databases, privacy, and confidentiality—the effect of proposed legislation on pharmacoepidemiology and drug safety monitoring Side effects: freedom of information and the communication of doubt Complementary/alternative medicine: what should we do about it? Thirty years of the Boston Collaborative Drug Surveillance Program in relation to principles and methods of drug safety research Errors in prescribing, preparing, and giving medicines: definition, classification, and prevention Inclusion of therapeutic failures as adverse drug reactions
25 26
L. Marks D.J. Finney
UK UK
26 27 27 28
L.L. Iversen J.K. Aronson H. Jick J.K. Aronson
UK UK USA UK
1 2 3 4 5 6 7 8 9 10 11 12 13 14
23
Philippines UK
Secrecy hiding harm: case histories from the past that inform the future The pill: untangling the adverse effects of a drug From thalidomide to pharmacovigilance: a personal account How safe is cannabis? Louis Lewin—Meyler’s predecessor The General Practice Research Database Classifying adverse drug reactions in the 21st century
xxvii
DoTS classification of adverse drug reactions Adverse drug reactions have been classified in SEDA-28 and SEDA-29 according to the DoTS system (SEDA-28, xxvii–xxxiii; Br Med J 2003;327:1222–5). In this system adverse reactions are classified 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) • Time-course – Time-independent reactions (reactions that occur at any time during a course of therapy) – Time-dependent reactions ∗ Immediate or rapid reactions (reactions that occur only when a drug is administered too rapidly) ∗ First-dose reactions (reactions that occur after the first dose of a course of treatment and not necessarily thereafter) ∗ Early reactions (reactions that occur early in treatment then abate with continuing treatment, owing to tolerance) ∗ Intermediate reactions (reactions that occur after some delay but with less risk during longer term therapy, owing to the “healthy survivor” effect) ∗ Late reactions (reactions the risk of which increases with continued or repeated exposure) ∗ Withdrawal reactions (reactions that occur when, after prolonged treatment, a drug is withdrawn or its effective dose is reduced) ∗ Delayed reactions (reactions that occur some time after exposure, even if the drug is withdrawn before the reaction appears) • Susceptibility factors – Genetic – Age – Sex – Physiological variation – Exogenous factors (for example drug–drug or drug–food interactions, smoking) – Diseases The following reactions have been classified in SEDA-28 and SEDA-29 using this system: ACE inhibitors: angioedema Anticoagulants, oral: skin necrosis Antipsychotic drugs: diabetes mellitus Cocaine: myocardial infarction Contrast media: nephrotoxicity
29.207 29.358 28.60 29.38 29.575
xxix
xxx Diuretics, loop and thiazide: hyponatremia Dopamine receptor agonists: sleep attacks Gadolinium salts: nephrotoxicity Glucocorticoids: osteoporosis SSRIs: suicidal behavior Thionamides: agranulocytosis Vigabatrin: visual field loss
DoTS classification of adverse drug reactions
29.219 28.162 28.561 28.185 29.19 29.520 28.101, 29.99
How to use this book
THE SCOPE OF THE ANNUAL The Side Effects of Drugs Annual has been published every year since 1977. It is designed to provide a critical and up-to-date account of new information relating to adverse drug reactions and interactions from the clinician’s point of view. 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 in 6 volumes. PERIOD COVERED The present Annual reviews all reports that presented significant new information on adverse reactions to drugs during 2004. During the production of this Annual, some more recent papers have also been included; older literature has also been cited when it is relevant. 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, interpreting conflicting evidence and providing the reader with clear guidance. They 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-14 to SEDA-28 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. DRUG NAMES 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 combi-
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How to use this book
nation has a generic combination name (e.g. co-trimoxazole for trimethoprim + sulfamethoxazole) that has been used; in some cases brand names have been used instead. SYSTEM OF 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. 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); Official (e.g. Governmental, WHO) statements.
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 1–28 are cited as SEDA-1, SEDA-2, etc. INDEXES Index of drugs: this index provides a complete listing of all references to a drug for which adverse effects and/or drug interactions are described. Index of adverse effects: this index is necessarily selective, since a particular adverse effect may be caused by very large numbers of compounds; the index is therefore mainly directed to adverse effects that are particularly serious or frequent, or are discussed in special detail; before assuming that a given drug does not have a particular adverse effect, consult the relevant chapters. American spelling has been used throughout, e.g. anemia, estrogen rather than anaemia, oestrogen.
Manfred Hauben and Andrew Bate SIDE EFFECTS OF DRUGS ESSAY
Data mining in drug safety Introduction It is a good wager that a few years ago most scientists studying the adverse effects of drugs would have been unfamiliar with the technique of data mining. The term, although already in use by the 1980s (1) did not come into regular use until the mid-1990s. Since then the increasing interest in data mining has become evident in the ever-increasing numbers of publications (Figure 1), presentations, and professional workshops, the creation of several expert working groups, and the number of organizations contemplating, piloting, or deploying data mining in routine drug safety surveillance (2–5) and indeed throughout health care (6). Pharmacovigilance, is “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problems” (7). A principle concern of pharmacovigilance is the detection of adverse events that are novel, by virtue of their clinical nature, severity, and/or frequency, as quickly as possible, after minimum patient exposure. This is a team effort, involving reporters of adverse events (including This year’s guest authors of the Side Effects of Drugs Essay are Manfred Hauben, MD MPH, and Andrew Bate, MA (Oxon) PhD (Umea). Dr Hauben is Medical Director of risk management strategy at Pfizer Inc, New York City, USA, Clinical Assistant Professor of Medicine, New York University School of Medicine, New York City, USA, Adjunct Assistant Professor of Pharmacology and Adjunct Clinical Professor of Community and Preventive Medicine, New York Medical College, Valhalla, NY, USA, and Visiting Professor in the School of Information Systems, Computing and Mathematics, Brunel University, London UK. Dr Bate is Research Manager of the WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden and Visiting Professor in the School of Information Systems, Computing and Mathematics, Brunel University, London UK.
health-care practitioners and patients) and pharmacovigilance professionals at health authorities, pharmaceutical companies, and drug monitoring centres. Fundamentally, this involves the detection of “signals” of novel adverse events. All clinical pharmacologists, health-care professionals, and patients should be interested in pharmacovigilance, including data mining. Both clinical and quantitative strategies in pharmacovigilance hinge on the submission of astute clinical observations by clinical pharmacologists and other clinicians at the front line of drug safety. In many countries, reporting to regulatory authorities is also available to other prescribers and to patients themselves. It is advantageous to feed back to all these reporters how the crucial data they supply are used, beyond passive data entry, consistent with the basic elements of public health surveillance (8). Newcomers to data mining face a complex multidisciplinary body of work. The purpose of our essay is to help navigate these obstacles by providing an expository but technically explicit introduction, so that readers with various backgrounds can appreciate what data mining algorithms (DMAs) are, how they work, why they were developed, their strengths and limitations, misconceptions, and recent notable developments.
What is data mining? There are many definitions of data mining. For example, “the non-trivial extraction of implicit, previously unknown, and potentially useful information from data” (9). Data mining has also been described as the process of discovering meaningful new correlations, patterns, and trends by sifting through large amounts of data stored in repositories, using pattern recognition
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Manfred Hauben and Andrew Bate
Fig. 1. The cumulative numbers of papers returned from Pubmed by the search term “data mining” [all fields], 1995–2005 inclusive.
technology as well as statistical and mathematical techniques (10). Data mining is often used to interrogate large databases that were created for purposes unrelated to the initial data acquisition in both scientific and business-related spheres. For example, analysis of supermarket customer receipts can be used to understand what products are commonly purchased together, in order to optimize product placement in the store. In pharmacovigilance the scientific purpose of the original data acquisition and subsequent data mining are the same—to look for “signals,” leading to the discovery of new safety information. However, the unpredictable nature of new adverse drug reactions means that the data set has not been developed optimally for the detection of all types of adverse drug reaction. The WHO definition of a signal is “Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously” (11). A signal is an evaluated association that is considered important to investigate further. It may refer to new information on an already known association. Usually, more than a single report is required to generate a signal, depending on the seriousness of the event and the quality of the information (12).
Why data mining in pharmacovigilance? Spontaneous reporting system (SRS) databases are a mainstay of pharmacovigilance (13). SRS databases involve mandated reporting by manufacturers and voluntary reporting by health professionals and consumers/patients. They cast a very wide net and therefore contain signals worth noting. However, they may be very large and sparse, and much of the information is of limited public health importance, being labelled events, medically trivial, or various forms of background “noise” relating to confounding factors and numerous reporting artefacts. On the other hand, even seemingly unimportant reports to an expert represent clinical concerns about a medicinal product and should be considered as valuable information on the impact of adverse events on patients’ lives and the fears and worries of patients and health-care providers (14, 15). After a report is submitted, signals may be detected during intake assessment, as individual reports can provide compelling signals under unusual circumstances (7). Subsequently, a major source of potential signals comes from aggregate data presented in the form of frequency lists of reported adverse events, from which case series may be extracted for analysis.
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Table 1. The general form of a 2 × 2 contingency table based solely on reports from a spontaneous reporting system
Event of interest + Event of interest −
Drug of interest +
Only other drugs −
A C
B D
The scientific domain expertise of the prepared mind remains the cornerstone for discerning signals within these data (16). The challenge of processing increasingly large masses of aggregate data has stimulated research into the development of data mining algorithms in the hope of assisting safety reviewers, who may be “drowning in data but thirsty for knowledge”, to focus their clinical attention on drug–event combinations that are most likely to represent new signals. Data volume is not the only challenge. The ever-increasing number of molecular targets in our pharmacological gun-sights ensures that adverse drug reactions will continue to earn pride of place as the “great imitators” in medicine, along with the traditional classics, such as syphilis and tuberculosis (17, 18). This ability of adverse drug reactions to mimic numerous non-drug-related pathologies confounds diagnosis in the clinic, and can result in failure to submit a report or the submission of a report with incorrect drug attribution. After submission of a spontaneous report a diagnostic process is repeated by pharmacovigilance experts at the two points discussed above, and misdiagnosis can again result in missed or spurious signals. To sum up, pharmacovigilance is distinctive among surveillance activities in terms of its scope and by virtue of the range and variety of medical illnesses under scrutiny. The difficulty of interrogating very large databases for signals of medical phenomena that can individually mimic many non-drug illnesses amidst a vast background of noise was the inspiration for the computerized signal detection algorithms, also known as data mining algorithms (DMAs).
The basic building block: the 2 × 2 contingency table Our essay focuses on what is currently the most common form of data mining in the analysis of
spontaneous reports, popularly known as “disproportionality analysis” (19). There are several related methods and, as explained below, these have in common the calculation of various measures of association in a 2 × 2 frequency table. Other methods and method extensions that are being considered, developed, and tested, for example logistic regression, also seek drug–event combinations that may be disproportionately reported. With recent increased attention to data mining in spontaneous reports, some authors have reminded readers that the basic method underlying disproportionality analysis, the analysis of a 2 × 2 contingency table based solely on reports from an SRS (Table 1) (20), is not new. For every reported drug–event combination in the database one can construct a corresponding 2×2 table, in which each cell is classified by the presence or absence of the drug and event of interest. A, B, C, and D refer to the cell as well as the count (or number of reports) that falls into each cell. With no association between the drug and the event one would anticipate that the number of reports of the specific drug–event combination would be distributed in a manner consistent with the fact that the probability that a given drug (or event) will appear in a report is not affected by whether or not the event (or drug) also appears in the report. Similarly, if the drug and event are strongly associated in the database they will have a tendency to appear or not appear together. Therefore, knowing that a given drug is listed may make it more likely that the corresponding event is listed and vice versa. One can calculate various metrics that reflect the strength of this association. Specifically, an observed to expected ratio (2, 5), a reporting odds ratio (19, 21), and a proportional reporting ratio (4). There are two specific Bayesian implementations of the observed to expected ratio commonly used in drug safety—the information component (IC) (2) and the empirical Bayes geometric mean (EBGM) (5). In practice
xxxvi the measures are similar, and here for simplicity we use the term “observed/expected ratio (O/E)” as a generic term for all these metrics. “Observed” refers to the number of reports submitted and entered into the database at the time of analysis and “expected” refers to the number of reports that would be anticipated under the null hypothesis of no association between the drug and the adverse event in the database. We have already provided one definition of “signal” in pharmacovigilance, but there are others, and the term is associated with considerable semantic ambiguity and variation (22). Confusion over which signal definition is used increases confusion over the role and performance of DMAs, and conversely increasing use of DMAs may amplify confusion about the meaning of “signal” (23). Specifically, there is a lack of consensus, and often ambiguity, about whether a signal that has been previously clinically reviewed, or a statistical disproportionality (i.e. an O/E ratio exceeding a specified threshold) considered by itself in a biological vacuum should automatically be designated as a “signal”. For example, one may see a disproportionate reporting of events that are treatment indications, clinically trivial, insignificant, or biologically implausible. Consequently, some have used the term “signal of disproportionate reporting” (SDR) (24) for combinations that are highlighted quantitatively, irrespective of clinical review, to emphasize the fact that further work-up is needed before potentially further communicating such combinations as potential new adverse reactions, and also to exclude the variable steps and the resource and time implications of a clinical review step from a comparison of how algorithms perform. There are other definitions of “signal” that may accommodate these uncertainties, such as that by Meyboom, that a signal consists of a hypothesis together with data and arguments (22). Confidence intervals can and should be calculated for each O/E to distinguish between similar disproportionality estimates based on very different amounts of data. Clearly, in the absence of biological plausibility or prior knowledge, disproportionality based on small numbers is more likely to be a chance finding and less likely to justify action based on a small case series than combinations with more reports in the ‘A’ cell (unless there is a bias or reporting artefact). While it is useful for
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decision support to provide an uncertainty estimate via credibility intervals, any analogy with formal epidemiological estimation based on asymptotic assumptions of a large and potentially infinite population of spontaneous reports, of which the SRS database represents a sample, may be misleading. Practically speaking, many organizations actually focus on specific discrete thresholds, irrespective of credibility intervals, to define an SDR, making the outputs of each data mining screening a binary classification procedure (i.e. SDR present/absent for each reported drug–event combination).
So what is new? Enter the technological capacity to calculate the levels of associations in millions of such 2 × 2 tables, each corresponding to a reported drug–event combination, and the application of Bayesian methods (2) to deal with low counts in cell A (a common scenario in pharmacovigilance, since rare events are of particular concern in post-marketing safety surveillance). Some of these methods have also been given a significant boost from commercial development and promotion. Roughly speaking, Bayesian approaches incorporate an element of initial scepticism, when the number of reports of a given drug– event combination is low. Different Bayesian approaches handle this in different ways. Remembering that when we use these tools we are calculating an O/E ratio, this initial scepticism is achieved in one DMA, known as the multi-item gamma-Poisson shrinker (MGPS), by taking a “weighted average” of a prior estimate of the O/E based on the background level of reporting across the entire database and the estimated O/E based on the observed reporting of the specific drug–event combination being considered. The background reporting is modelled on the belief that the average O/E is around one. Since the database is very large, this prior estimated O/E is weighted quite heavily at first, so that the estimate is pulled or “shrunk” towards approximately one (hence “shrinker”). It is only when the number of reports of the specific drug–event combination reaches a “critical mass” that it is weighted enough to overcome the shrinkage to the prior.
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Fig. 2. The change in time of the information criterion (IC) for the combination suprofen + back pain (22) in the WHO suspected ADR database. The term “back pain” is a WHOART preferred term. Time is defined as entry of data into the database.
In contrast, in another more simple approach, known as the Bayesian Confidence Propagation Neural Network (BCPNN), the assumption is made that before we know anything about a drug and an adverse event we assume that it is likely to be reported in the future neither frequently nor infrequently, but with large associated uncertainty, so that this distribution will be sensitive to new data. The strength of the shrinkage in this method is set so that lower 95% confidence intervals are never greater than zero when there are no more than two observed counts. Both methods have strengths and disadvantages. Therefore, all other things being equal, a given association would have to be especially disproportionate relative to the background for it to overcome the initial dampening, often preventing combinations with less than three cases from being SDRs. This represents a major advantage for organizations that must screen large sparse databases in the setting of constrained resources. Figure 2 illustrates the process of Bayesian data mining using a well documented and prominent safety issue—that of the syndrome of acute flank pain and hematuria with the non-steroidal anti-inflammatory drug suprofen, although what is actually plotted is the relationship of the WHOART nearest preferred term at the time (“back pain”) (25).
Initially the IC is zero for the combination, with wide confidence intervals, as the prior assumption is of independence between each drug-suspected reaction combination and there are no data on the drug in the database, although there are some reports of back pain with other drugs. The IC then becomes slightly negative, with a slightly narrower confidence interval, as reporting of other suspected adverse effects of the drug occurs (middle of 1983). This causes the expected count to increase, while the observed count remains zero. Then, in the last quarter of 1983, after the first case of suprofen suspected back pain is entered into the database, the IC becomes a positive number, because the expected count is very small (at this point there were only 46 reports of suprofen in total) but with wide credibility intervals. In the fourth quarter of 1985, when the third suspected report of this combination was reported, the lower 95% credibility interval became positive, which would have triggered a clinical review of this association. As more and more cases were entered into the database the IC continued to increase, and reached over 7 with very narrow confidence intervals, reflecting the very large observed and expected counts. In fact the drug was first marketed outside the USA, but the association had not been detected as a signal before US launch. Reports of
xxxviii this association in the USA began on 1 February 1986, about 1 month after the drug was approved in the USA. Manual review of additional spontaneous reports resulted in a series of regulatory labelling actions within about 6 weeks (26). This example illustrates the potential of DMAs for highlighting SDRs early, thus providing the possibility of earlier signal detection.
Do they work and what is the algorithm of choice? By “do they work” we mean to consider whether DMAs: 1. Detect adverse events that would otherwise go undetected. 2. Detect the same adverse events as conventional methods but at earlier times. 3. Detect the same adverse events at the same times but with less investigator time expended. 4. Provide a safety net against human error. Sensitivity is of fundamental importance in achieving these goals, but practical reality dictates that the search for truth in pharmacovigilance requires judicious limitations on the numbers of associations we investigate. Excessive time and effort expended on associations of no significance will be adverse to public safety, by diverting resources from more significant associations. We must always seek a balance that takes into account the clinically relevant ranges of sensitivity and specificity needed to achieve our goals. Here we note that some object to the use of the terms “sensitivity” and “specificity” in this context, because of a supposed lack of gold standards of causality in pharmacovigilance. The question of gold standards is indeed an important point, but it should not be used selectively to shield emerging methods from scientific scrutiny or object to findings that are personally disagreeable. At its extreme, such viewpoints take the form of objecting to the use of adverse events in method testing for which there is no “guarantee” of causality. This may be philosophically interesting, but an alternative viewpoint is to accept a basic irreducible
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level of uncertainty in pharmacovigilance and the importance of effectively identifying associations that are probably causal, even if not proven with absolute certitude. In our opinion such approaches to testing (27) greatly enhance understanding of the performance of DMAs in routine pharmacovigilance. Pharmacovigilance is much as an art as a science, and there is rarely an established time when all players agree that a signal was first detected, or established beyond reasonable doubt, as a disease causally associated with the use of a drug. This process is in its nature subjective. Similarly, and perhaps consequently, there is no single accepted best method of detecting signals. This has made analysis of the “do they work” question harder. But the question “do they work?” is an oversimplification, because although the underlying principles and goals of data mining are straightforward, there are numerous variations of implementation, which determine whether our goals are achieved. There is a large space of available choices defining a specific type of implementation (Table 2). What we mean is that each data mining exercise represents a combination of numerous subjective choices by the user. The choices are of two types. One type affects the numerical output for a given data set, i.e. the numerous variables that “analytically” define a given data mining exercise. The other subspace of choices consists of those that define the actual mode of deployment. These do not affect the actual numerical output at a given time with a given data set, but they will affect the impact and significance of the findings in real-world pharmacovigilance. Having a large space of available choices is a double-edged sword. On the plus side it maximizes exploratory capacity, albeit raising the practical question of what constitutes the recommended standard ensemble of data mining analysis for routine periodic database screening. The downside is susceptibility to confirmation bias. This occurs when a data miner tries different data mining implementations and ultimately selects one based on the fit of results to pre-existing expectations. This means that rather than being objective, data mining can in fact be extremely subjective, and inappropriate use can lead to results that are just a self-fulfilling prophecy. This emphasizes the need for routine strategies for deploying DMAs
Data mining in drug safety Table 2. Available choices in data mining Deployment choices Pharmacovigilance activity Initial signal detection Modifying an index of suspicion Position of DMA within organization In series with conventional procedures In parallel with conventional procedures As replacement for conventional procedures Classification activity Binary (SDR versus no SDR) Triage/ranking (no cut-off defining SDR prioritization criteria) Time of initiation in product life cycle New drugs (high premium on sensitivity?) Old drugs Single drugs versus between-drug comparisons Metrics/thresholds∗ Discrete metrics Thresholds Credibility Intervals Case count thresholds Analytical choices Data/data source Public databases Proprietary database Full database Database restriction to lower background reporting of adverse events Dictionary architecture/Case definitions WHOART versus MedDRA Level of specificity of terminology (e.g. preferred versus high-level term) User defined combinations of preferred terms Standardized Medical Queries (SMQs) Drugs analysed Suspect Suspect plus concomitant Drug specificity (e.g. substance or salt, or therapy group) Algorithm PRR ROR BCPNN MGPS Stratified versus unstratified analysis Age Gender Year of report Country of origin Other Dimensionality 2-D (i.e. drug–event pairs) 3-D (e.g drug–drug–event or interaction) Temporality Cross-sectional analysis Time-trend analysis Metrics/thresholds∗ Discrete metrics (e.g. IC, EB05, EBGM) Threshold Interval metrics Case-count thresholds ∗ Depending on the mode of data presentation, these may be considered as elements of both subspaces.
xxxix and the need for critical review of both one’s own DMA outputs and the outputs of others. With these caveats in mind, we shall look at the available data, consisting of retrospective data mining exercises using authentic data, prospective anecdotal experience in routine pharmacovigilance, and studies using computersimulated SRS data. Most research suggests that DMAs are credible additions to the pharmacovigilance tool kit, although drawing specific inferences about their performance is complicated by the lack of scientific standards for conducting research and consequent variability of study designs and findings. Retrospective studies have reported a very wide range of sensitivities and specificities. Some have reported that most credible associations are detected earlier by conventional pharmacovigilance procedures, but that a significant minority may have been detected earlier via data mining. Others have reported the opposite—that data mining can highlight many credible associations more quickly than conventional procedures. These assessments can be tricky. Claims in retrospective analyses that data mining could have definitely resulted in earlier initial detection of signals and would have led to further action are completely inappropriate. Firstly, it is difficult to pinpoint when a given association first rose to the level of a signal in the mind of safety reviewers (and on some specific occasions when this information was known, it may have been excluded/misrepresented in the presentation of results). Secondly, data mining exercises cannot inform us about subsequent assessment of the signal. In our example of suprofen–flank pain, while the IC value shows that clinical review of the association could have been triggered at an early time, there is no guarantee that the case series review and accompanying evidence would have been sufficiently strong at that time to have justified a change to the label. Some major pharmacovigilance organizations have now accrued considerable prospective experience with the use of DMAs in realworld safety surveillance. The WHO Collaborating Centre for International Drug Monitoring in Uppsala is a notable example. Prospective data mining has improved signal detection in the programme for international drug monitoring in the screening of its database of nearly 4 million suspected adverse reactions reports
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Fig. 3. The change in IC for reporting of topiramate and glaucoma over time, showing 3-monthly periods in which reports were entered into the WHO suspected ADR database. The upper and lower 95% confidence intervals are plotted.
from 76 countries. However, there remains relatively little evidence in many other data sets and organizations that DMAs have uncovered anything new and significant; instead they mostly highlight things that were already known, under review, or on further scrutiny appeared to represent non-causal associations. Time will tell if and how many significant new things DMAs uncover and the change in opportunity costs due to more or less “false alarms.” Many of the same uncertainties exist with conventional procedures of signal detection. An example of a signal detected prospectively by routine data mining of the WHO suspected ADR database is that of the association of the antiepileptic drug topiramate with glaucoma (28). This was highlighted for clinical review by the BCPNN based on six suspected case reports and was signalled by the WHO Collaborating Centre for International Drug Monitoring in April 2001. In July 2001 the first of several case reports on the association was published (29), and in October 2001 a Dear Healthcare professional letter was sent out. The development of the IC over time was as shown in Figure 3. Similarly, there are no consensus standards for simulating SRS data. It is easy to create a database simulation to suit a viewpoint, and patently obvious that DMAs that are designed
under certain assumptions will perform well on simulated data sets created under the same assumptions. This is not to say that such analyses are uninformative, but only that extrapolating such results to the real world should be done with great circumspection. For example, a recent publication reported a 0% false detection rate with one specific DMA, using simulated data (30). While such information provides insight into theoretical performance, in real-world pharmacovigilance there are false positives and false negatives with all methods, and any suggestion otherwise would be misleading. Finally, one must also consider that users of DMAs have very different aims. A regulator covering a large country requires an overview of a large number of reports covering a huge range of products; a small pharmaceutical company will have a relatively small set of data about a small very disproportionate set of drugs, while a regional adverse reactions centre might get no more than a handful of reports every month; other organizations may not fall into these categories or may share features of more than one. It is meaningless to generalize about how DMAs can be useful to all of these. Instead, each group needs to consider how they could perform signal detection better, and whether DMAs can contribute, and then adapt the DMAs as necessary for particular goals.
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A related question is “which is the best DMA?” This question is too complex to flesh out fully here, but we share some thoughts. Most users would agree on a trade-off in sensitivity and specificity between common implementations of non-Bayesian and Bayesian methods. This gradient goes from higher sensitivity/lower specificity of non-Bayesian methods to lower sensitivity/higher specificity of empirical Bayesian methods. Greater sensitivity may not always be the advantage it is perceived to be, and it can produce an overabundance of SDRs that may divert existing resources to many spurious associations (31). It is tempting to assume that earlier detection always leads to an improved public health outcome (leaving aside opportunity costs associated with reduced specificity). But what if the association cannot be clarified until more cases are submitted, enough cases to result in an SDR with a less sensitive but more specific DMA? In that case, use of the more sensitive method merely diverts additional resources without improving resolution—an analogue of lead-time bias in medical screening (32). Of course, it is always possible that earlier detection may prompt initiation of intensified follow-up procedures, leading to earlier resolution. The potential lack of practical benefit from apparent increased sensitivity serves only to make the question of “which is the best DMA” harder to address. Some therefore like non-Bayesian approaches because they are transparent and direct, and they feel more comfortable that they are not missing credible associations. Others strongly prefer Bayesian approaches, because of the clear benefit of reducing the number of spurious associations presented to the user. Some authors also contend that Bayesian modelling results in improved estimates of O/E. However, as described above, this suggests to us an inappropriate focus on attempting to make SRSs substitute data sets for formal epidemiological estimation. In the absence of a clear decision-theoretic calculus of costs and utilities, any attempts to obtain bragging rights that one DMA is the superior algorithm for all organizations and possible scenarios is of limited value. Pharmacovigilance organizations have the same overall goals, but are not structurally and functionally homogeneous. The decision to use data mining and
the choice of a specific algorithm is currently best made by each institution, based on their knowledge of the products they must monitor, the data they have access to, and their realistic goals in regular surveillance. Currently some organizations use only non-Bayesian methods and some use only Bayesian methods; however, others continue to use both, and we are reluctant to make “one-size-fits-all” declarations. Finally, published data mining exercises cannot faithfully replicate the “desktop” experience of the safety reviewer. Whether one chooses a Bayesian or non-Bayesian DMA, signal detection by the prepared mind, like many diagnostic assessments, may be inherently Bayesian in nature (33–35). Safety reviewers have biases but are also repositories of extremely valuable experience.
Data mining indications: part of a holistic approach to signal detection? The nature and range of the phenomena under surveillance in pharmacovigilance is so unique that the optimal approach to signal detection may be a “holistic” one that emphasizes flexible use of a toolkit equipped with multiple data streams, signal detection procedures, and technology. Most sensible data miners would opt for a combination of data mining and triage logic (36). Triage logic involves the application of heuristics or filters based on sound public health or clinical considerations. An example would be a list of designated medical events (DMEs or “worst first” list) that are considered sentinel events with any drug, warranting scrutiny regardless of whether they are associated with an SDR, because they are serious, rare, and have a high drug-attributable risk. A related concept would be targeted medical events (TMEs) specified in a pharmacovigilance plan based on specific drug and/or patient characteristics. The WHO triage includes a focus on serious adverse events, as defined by the WHO Programme of International Drug Monitoring as “critical terms” (36). These terms either refer to or might be an indication of serious disease states, and warrant special attention because of their possible association
xlii with the risk of serious illness, which may lead to more decisive action than reports on other terms. Other WHO triage criteria assign attention to associations reported with newly marketed drugs, case series that include a minimum number of well documented cases, and combinations with rapidly increasing disproportionality indicative of a rapid relative increase in reporting. An organization with a rigorous approach, including sensible triage criteria, may have increased flexibility in how they deploy data mining. For example, with triage logic that includes a “worst first” list, an organization may opt for a more specific data mining procedure/threshold, knowing that many of the most important adverse events will be treated as sentinel events. While disproportionality analysis focuses on the presence or absence of single drugs and adverse events in a report, in practice it is the other information carried in case reports that determines whether a case series can be considered as a signal rather than just an SDR (37). This emphasizes the use of disproportionality analysis in the first-pass analysis of the data, and the need for clinical review of outputs. This also suggests that other attributes in case reports (such as rechallenge information) can be used either as a second pass to enhance the effectiveness of the filtering or as a first-pass filter of the data to catch signals that may not be SDRs. Both of these approaches are used in the WHO triage system. Rather than considering such attributes separately, it may also be able to integrate these into the measures of disproportionality as a semi-quantitative overall score that could be used for more optimized filtering (38). When more than one drug is listed, one would want to be able to distinguish drugs that are more likely to have caused an adverse event from those that are more likely to be “innocent bystanders” (39). Co-prescribed medications may suggest drug–drug interactions or provide other indicators. For example, a particular drug can act as a proxy of underlying disease that might confound the association between another listed drug and a reported event. Similarly, the groups of events listed need also to be considered in the analysis.
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Warnings, precautions, and controversies Data mining in pharmacovigilance attracts a dedicated group of researchers in academia, health authorities, drug monitoring centres, and pharmaceutical companies for a simple but profound reason: scientists obtain immense gratification by using powerful technology, elegant statistics, and clinical pharmacology in the service of public health. Data mining is a great deal of fun. That being said, our foremost concern about the use of these tools is the tendency to extreme views, ranging from unbridled optimism to considerable scepticism (28). Overestimating or underestimating the value of DMA outputs can serve tangential interests, but not those of patient safety. We realize that we are treading on subjective and impressionistic ground in exploring these issues in search of learning points. Human factors may explain how the real impact of technology can be overestimated (33). The increased technological power to manipulate and visualize SRS data is truly impressive and valuable, but there is a natural human tendency to over-enthuse about new and apparently sophisticated methods. Stakeholders with intellectual and/or commercial conflicts of interest might champion a method as the “magic bullet” that not only renders competing methods obsolete or inferior, but neutralizes the limitations inherent in the target data. Differing viewpoints and findings that suggest that maybe the picture is good but not quite as good as initially presented may be perceived as an attack and generate a less than jubilant response. With increasing experience by increasing numbers of users the distribution of viewpoints tends to “normalize”, and most eventually recognize and fully acknowledge both the strengths and limitations of the methods. Ironically, polar extremes of view may have a net positive effect. While spontaneous reports are of great value, there is also appropriate concern about their misuse. Some extreme views about data mining may amplify these concerns and thereby stimulate much wider attention, increased research participation, and valuable scientific debate. While real safety issues draw the lion’s share of the attention, the damage inflicted to public health by ringing false-alarm bells is less direct and harder to quantify.
Data mining in drug safety
Seduction bias may manifest in more subtle ways. For example, we have noted a tendency in the field to make analytical generalizations in data mining and to ignore the “law of unanticipated results”. An example would be the assertion that basic co-variate stratification provides the “truest” results and that DMAs that accommodate extensive stratification on basic co-variates must be superior. While it is true that basic co-variate stratification may help mitigate confounding (not to mention being operationally advantageous by reducing workload), the truth is that we don’t fully understand the structure of measured and unmeasured confounders and biological effect modifiers with SRS data. Thus, some stratified analyses could miss stratum-specific phenomena. While we have stressed the possibility of over-interpreting data mining outputs, we must be fair and avoid singling (not signalling!) out data mining for criticism. Questions remain about conventional pharmacovigilance practices as well, but that doesn’t negate their value. Some criticism of drug safety has been unfairly thrown at signal detection, which we feel we would be more appropriately levelled at signal analysis. Suggestions of potential adverse effects of drugs are normally detected in a timely manner: but the community’s ability to assess and analyse issues and decide on and demonstrate causality is often hampered by a lack of available data appropriate for the task. In our opinion, this may be the case for some recent high-profile safety issues. Spontaneous reports are in general of very limited use in demonstrating definitive causality and certainly cannot be used to estimate the incidence of drug-induced adverse effects, critical information in assessing the benefit to harm balance of products.
Future directions An area in which data mining retains an Achilles heel is in the coding of suspected adverse drug reactions in databases of spontaneous reports. Hierarchical and fine-grained coding schemes lead to information loss in the reporting of diseases and risk impeding effective clustering of all relevant cases at analysis. For example, one of the most commonly used dictionaries
xliii of terminology, MedDRA, used to code adverse events in SRSs in different versions, has had many overlapping, related, and or equivalent event codes (40). When combined with human variability in coding, this may lead to the “fragmentation” of a reported association across these different codes, which may in turn fragment a potential signal. Terminology is therefore a general rate limiter of signal detection in pharmacovigilance (41). Indeed, it can also add to the earlier problem of comparison between DMAs, as very different SDRs might appear to be detected with two DMAs that are semantically similar, underscoring the fact that an SDR should never be reviewed in isolation without consideration of related adverse events terms (42). We anticipate that more sophisticated approaches to terminological reasoning (43) will be one of the most significant improvements in signal detection and data mining. Systematic consideration of the different attributes of different drug-induced disease may improve data mining still further (44). Much of the research on data mining has focused exclusively on the detection of associations that involve a single drug and a single adverse event. This focus is perhaps not surprising, as the drug–event pair is a simple and basic “unit of observation” (36). However, data mining may pay greatest dividends when it highlights larger more complex patterns in spontaneous reports, which would not be readily transparent to a single reviewer. Examples of such patterns are clusters of related adverse events terms, which might represent a syndrome or characteristic set of symptoms of a drug-related reaction. Similarly, clusters of similar drugs that seem to cause specific adverse reactions in certain well-defined high-risk groups would also be of interest. Some work has been done in this area. Such work is challenging, given the unknown and likely variable properties of patterns of interest and the scarcity of data. A recurrent BCPNN has been used to detect known clusters of adverse events in WHO data, such as those representing the neuroleptic malignant syndrome in haloperidol reporting (45). We envisage that such techniques will be used increasingly in the future. An area of research in which little development has taken place is the detection of drug– drug interactions. While methods have been
xliv proposed for screening spontaneous reports (46, 47), and there have been demonstrations of how known drug–drug interactions stand out quantitatively (48), such methods remain outside routine use. We anticipate developments in this area, particularly linking to information about CYP isoforms (49). Another research area that has received surprisingly little attention is duplicate detection. Duplicate reports are unlinked case reports describing the same patient/adverse event incident in the same SRS data set. Duplicate reports severely can reduce signal detection capability. Report duplication can occur because of reporting from: 1. Different sources (e.g. health professionals and consumers having provided separate case reports related to the same incident). 2. Mistakes in linking follow-up case reports to earlier records. In some data sets (such as the WHO suspected ADR database in Uppsala) such duplicates are particularly hard to detect, as the reports are anonymous. Additionally, sets of duplicates may have very different properties in terms of similarities and differences. There is a lack of published methods on how to detect such reports. Missing data can affect all fields in the reports and can complicate analyses; clearly, two different reports with a lot of missing data may be identical but we are unlikely to believe that the reports are duplicates. A method has been developed to compare each pair of reports, using an overall score for the report pair calculated on the similarity of the values on each of the report fields (50). The results are encouraging and have shown that high scores often represent either likely or confirmed duplicates. Such pairs of reports can then be triggered for further follow-up. However some of the high scores were confirmed non-duplicates, i.e. false positives, albeit interesting in themselves. For example, a highlighted cluster of three case reports that were confirmed non-duplicates was reported from the same dentist, on the same drug–adverse event pair on the same day! Large data sets of SRSs are screened for signals, and SDRs may be of interest when based on small numbers of reports, such as three. Clearly, three reports from three different countries would be interpreted very differently than three reports
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that all were received from the same dentist on the same day, as even if these are separate reports there is only one health-care professional who is suspecting this particular drug–event association. We believe that better removal of duplicate reports, and clustering of related case reports, will undoubtedly improve signal detection capability.
Conclusions Data mining research has added promising methods to the pharmacovigilance tool kit. While their optimal placement relative to conventional signalling strategies is still debated, these methods represent a large jump relative to the status quo in the post-marketing surveillance of spontaneous reports, which has not been notable for its emphasis on technological innovation. We contend that there will be additional downstream benefits to public safety from this research, such as increased attention to data quality. At the same time studying and refining scientific decision-making in signal detection should not be a casualty of over-attention to proposed technological enhancements. Much of the criticism (both direct and implied) of data mining in spontaneous reports reflects the temptation to infer more from quantification of spontaneous reports than should be, and the tendency by some to emphasize the positive aspects of these procedures but to minimize the difficulties. As we have made clear above, quantitative algorithms can help in the filtering of spontaneous reports for prioritization of review, but clinical review of the details of the reports is where much of their value lies. However, data mining methods will be increasingly applied to other data sets, such as patient records (51), and this may enhance our capability to detect and prioritize, learn quickly, and potentially act more quickly on drug safety issues. Recent high-profile safety issues and an extremely risk-averse environment have stimulated re-examination of our pharmacovigilance systems and strategies. Questions revolve around whether the SRS approach is still effective in identifying significant safety problems,
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how we measure success or failure in pharmacovigilance, and how we can improve the process. Stakeholders naturally want to be able to tell the public how much they are improving the process of safety surveillance and how it could be further improved. Recent commentaries have suggested that fundamental structural revamping of the safety surveillance system is the answer (52). However, others have emphasized new technology as the solution, regardless of data quality. Enhanced technology, such as data mining, is in some ways an easy solution. With the increasing technological capacity to implement number-crunching data mining tools, stakeholders can readily and quickly implement sophisticated systems that
xlv apparently promise clear improvement, but may in fact bring little or no true benefit for some. For all the discussion around signal detection, we respectfully submit that media frenzy has focussed on the wrong issue. We often have the systems in place to detect hypotheses of potential problems. What the field lacks is the ability to determine, routinely and quickly, whether such potential associations are indeed causal, what the increased risk is, and whether there are high-risk subpopulations. Spontaneous reporting does its job well; data mining, at least in certain circumstances, helps. More effort must go into developing better data sets for signal analysis, which can be investigated easily, and this will lead to improved public trust, something that is desperately needed.
References 1. Harris JM Jr. Coronary angiography and its complications. The search for risk factors. Arch Intern Med 1984;144:337–41. 2. Bate A, Lindquist M, Edwards IR, Olsson S, Orre R, Lansner A, De Freitas RM. A Bayesian neural network method for adverse drug reaction signal generation. Eur J Clin Pharmacol 1998;54:315–21. 3. Hauben M, Reich L. Safety related drug-labelling changes: findings from two data mining algorithms. Drug Saf 2004;27:735–44. 4. Evans SJ, Waller PC, Davis S. Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. Pharmacoepidemiol Drug Saf 2001;10:483–6. 5. DuMouchel W. Bayesian data mining in large frequency tables, with an application to the FDA Spontaneous Reporting System. Am Stat 1999;53:177–90. 6. Bonacina S, Masseroli M, Pinciroli F. Foreseeing promising bio-medical findings for effective applications of data mining. Biol Med Data Anal Proc 2005:130–6. 7. World Health Organization. The Importance of Pharmacovigilance. Geneva: WHO, 2002: 48. 8. Waller PC. Making the most of spontaneous adverse drug reaction reporting. Basic Clin Pharmacol Toxicol 2006;98:320–3. 9. Frawley W, Piatetsky-Shapiro G, Matheus C. Knowledge discovery in databases: an overview. AI Magazine 1992:213–28. 10. Gartner Group at url http://gartner.com.
11. Edwards IR, Biriell C. Harmonisation in pharmacovigilance. Drug Saf 1994;10:93–102. 12. Edwards IR. Pharmacological basis of adverse drug reactions. In: Speight TM, Holford HG, editors. Avery’s drug treatment. 4th ed. Auckland: Adis International; 1997. p. 261–99. 13. Rawlins MD. Spontaneous reporting of adverse drug reactions. II: Uses. Br J Clin Pharmacol 1988;26:7–11. 14. Lexchin J. Is there still a role for spontaneous reporting of adverse drug reactions? CMAJ 2006;174:191–2. 15. Edwards IR. Spontaneous reporting—of what? Clinical concerns about drugs. Br J Clin Pharmacol 1999;48:138–41. 16. Trontell A. Expecting the unexpected—drug safety, pharmacovigilance, and the prepared mind. N Engl J Med 2004;351:1385–7. 17. Lokken P, Skoglund LA. Legemiddelbivirkninger i munnhulen. Tidsskr Nor Laegeforen 2006;126:1345–8. 18. Reddy JC, Shuman MA, Aster RH. Quinine/ quinidine-induced thrombocytopenia: a great imitator. Arch Intern Med 2004;164:218–20. 19. van Puijenbroek EP, Bate A, Leufkens HG, Lindquist M, Orre R, Egberts AC. A comparison of measures of disproportionality for signal detection in spontaneous reporting systems for adverse drug reactions. Pharmacoepidemiol Drug Saf 2002;11:3–10. 20. Finney DJ. Systemic signalling of adverse reactions to drugs. Methods Inf Med 1974;13:1–10.
xlvi 21. Stricker BH, Tijssen JG. Serum sicknesslike reactions to cefaclor. J Clin Epidemiol 1992;45:1177–84. 22. Meyboom RH, Egberts AC, Edwards IR, Hekster YA, de Koning FH, Gribnau FW. Principles of signal detection in pharmacovigilance. Drug Saf 1997;16:355–65. 23. Hauben M, Reich L. Communication of findings in pharmacovigilance: use of the term “signal” and the need for precision in its use. Eur J Clin Pharmacol 2005;61:479–80. 24. Hauben M, Reich L, Chung S. Postmarketing surveillance of potentially fatal reactions to oncology drugs: potential utility of two signaldetection algorithms. Eur J Clin Pharmacol 2004;60:747–50. 25. Orre R, Lansner A, Bate A, Lindquist M. Bayesian neural networks with confidence estimations applied to data mining. Comput Stat Data Anal 2000;34:473–93. 26. Harter JG. Acute flank pain and hematuria: lessons from adverse drug reaction reporting. J Clin Pharmacol 1988;28:560–5. 27. Hauben M, Reich L. Response to letter by Levine et al. Br J Clin Pharmacol 2006;61:115–7. 28. Bate A, Edwards IR. Data mining in spontaneous reports. Basic Clin Pharmacol Toxicol 2006;98:324–30. 29. Banta JT, Hoffman K, Budenz DL, Ceballos E, Greenfield DS. Presumed topiramate-induced bilateral acute angle-closure glaucoma. Am J Ophthalmol 2001;132:112–4. 30. Almenoff JS, LaCroix KK, Yuen NA, Fram D, DuMouchel W. Comparative performance of two quantitative safety signalling methods: implications for use in a pharmacovigilance department. Drug Saf 2006;29:875–87. 31. Hauben M, Reich L. Potential utility of datamining algorithms for early detection of potentially fatal/disabling adverse drug reactions: a retrospective evaluation. J Clin Pharmacol 2005;45:378–84. 32. Hauben M, Reich L, Van Puijenbroek EP, Gerrits CM, Patadia VK. Data mining in pharmacovigilance: lessons from phantom ships, Eur J Clin Pharmacol 2006; August 3 [Epub ahead of print]. 33. Diamond GA, Kaul S. Prior convictions: Bayesian approaches to the analysis and interpretation of clinical megatrials. J Am Coll Cardiol 2004;43:1929–39. 34. Gill CJ, Sabin L, Schmid CH. Why clinicians are natural Bayesians. BMJ 2005;330:1080–3. 35. Griffiths T, Tenenbaum J. Statistics and the Bayesian mind. Significance 2006;3:130–3. 36. Stahl M, Lindquist M, Edwards IR, Brown EG. Introducing triage logic as a new strategy for the detection of signals in the WHO Drug Monitoring Database. Pharmacoepidemiol Drug Saf 2004;13:355–63. 37. Edwards IR, Lindquist M, Wiholm BE, Napke E. Quality criteria for early signals of possible adverse drug reactions. Lancet 1990;336:156–8.
Manfred Hauben and Andrew Bate 38. Meyboom RH, Lindquist M, Egberts AC, Edwards IR. Signal selection and follow-up in pharmacovigilance. Drug Saf 2002;25:459–65. 39. Purcell P, Barty S. Statistical techniques for signal generation: the Australian experience. Drug Saf 2002;25:415–21. 40. Brown EG. Methods and pitfalls in searching drug safety databases utilising the Medical Dictionary for Regulatory Activities (MedDRA). Drug Saf 2003;26:145–58. 41. Brown EG. Effects of coding dictionary on signal generation: a consideration of use of MedDRA compared with WHO-ART. Drug Saf 2002;25:445–52. 42. Hauben M, Patadia VK, Goldsmith D. What counts in data mining? Drug Saf 2006;29:827– 32. 43. Bousquet C, Henegar C, Louet AL, Degoulet P, Jaulent MC. Implementation of automated signal generation in pharmacovigilance using a knowledge-based approach. Int J Med Inform 2005;74:563–71. 44. Aronson JK, Ferner RE. Joining the DoTS: new approach to classifying adverse drug reactions. BMJ 2003;327:1222–5. 45. Orre R, Bate A, Norén GN, Swahn E, Arnborg S, Edwards IR. A Bayesian recurrent neural network approach for finding dependencies in large incomplete data sets. Int J Neural Syst 2005;15:207–22. 46. DuMouchel W, Pregibon D. Empirical Bayes screening for multi-item associations. Proceedings of the Seventh ACM SIGKDD International conference on Knowledge Discovery and Data Mining 2001;00:67–76. 47. Noren GN, Orre R, Bate A. Extending the methods used to screen the WHO drug safety database towards analysis of complex associations and improved accuracy for rare events. Stat Med 2006; in press. 48. van Puijenbroek EP, Egberts AC, Heerdink ER, Leufkens HG. Detecting drug–drug interactions using a database for spontaneous adverse drug reactions: an example with diuretics and nonsteroidal anti-inflammatory drugs. Eur J Clin Pharmacol 2000;56:733–8. 49. Strandell J, Kiuru A, Lindquist M. Linking spontaneous reports with pharmacogenetics. Basic Clin Pharmacol Toxicol 2005;97:106. 50. Noren GN, Orre R, Bate A. A hit-miss model for duplicate detection in the WHO Drug Safety Database. In: Proceedings of the Eleventh ACM SIGKDD International Conference on Knowledge Discovery and Data Mining, 2005. 51. Bate A, Edwards IR, Edwards J, Swahn E, Noren GN, Lindquist M. Knowledge finding in IMS disease analyser Mediplus UK database— effective data mining in longitudinal patient safety data. Drug Saf 2004;27:917–8. 52. Mitka M. Report criticizes lack of FDA oversight. JAMA 2006;296:920–2.
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METHYLXANTHINES
(SEDA-26, 1;
Theophylline
(SED-15, 3361)
SEDA-27, 1; SEDA-28, 1)
Caffeine
(SED-15, 588)
Drug interactions An interaction of caffeine with paroxetine has been reported to result in possible serotonin syndrome (1A ). • A 30-year-old woman with major depression, taking paroxetine 20 mg/day and amoxapine 200 mg/day, took a large dose of an over-thecounter formulation containing 4.8 g of caffeine. About 8 hours later she became restless and incoherent. Her Glasgow Coma Scale score was 8, blood pressure 120/80 mmHg, temperature 39.2 ◦ C, pulse rate 180/minute, and respiratory rate 40/minute. She had severe sweating and myoclonus and mild rigidity in both arms. She had a raised creatine kinase activity (3412 u/l). She was treated with fluid replacement, dantrolene, and diazepam. The creatine kinase activity increased further, reached a peak on the second day, and then rapidly fell 10 days later.
The tachycardia, tachypnea, and increased creatine kinase activity in this case can be interpreted as resulting from caffeine overdose. On the other hand, hyperthermia, sweating, myoclonus, and rigidity can be explained by the serotonin syndrome. Since the dose of paroxetine the patient was taking was too small to have caused the serotonin syndrome, the authors suggested that it was due to an interaction with caffeine. Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29001-9 © 2007 Elsevier B.V. All rights reserved.
Urinary tract Given the burden of radiocontrast nephropathy, efforts to prevent or ameliorate it are warranted. The prophylactic use of theophylline or aminophylline reportedly protects against radiocontrast-induced reductions in kidney function. In a meta-analysis of seven randomized controlled trials that satisfied all inclusion criteria in a pooled sample of 480 subjects, the difference in mean changes in serum creatinine was 12 µmol/l (95%CI = 5.3, 19) less in the treated groups than in the controls (2M ). However, whether such a modest improvement in kidney function would translate into clinically useful benefit, such as reduced dialysis rates or mortality, is not known.
AMPHETAMINES (SED-15, 180; SEDA-26, 30; SEDA-27, 29; SEDA-28, 4, 28) Note on spelling In International Non-proprietary Names (INNs) the digraph -ph- is 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 beings 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), since these are the recommended INNs (rINNs); however, for the general term for the group of drugs the more common spelling “amphetamines” is used.
1
2 Nervous system Chorea has been attributed to amphetamines. • A 22-year-old man who had had ADHD since the age of 8 years took methylphenidate, and had an adequate response for 14 years (3A ). However, his symptoms worsened and he switched from methylphenidate to mixed amfetamine salts 20 mg bd. A month later he continued to have difficulty in focusing on tasks, and the dosage was eventually increased to 45 mg tds over several weeks, with symptomatic improvement. However, 5 days later, he awoke feeling nauseated and agitated and had choreiform movements of his face, trunk, and limbs. He had also taken escitalopram 10 mg/day for anxiety and depression for 2 months before any changes in his ADHD medications. He was treated with intravenous diphenhydramine, lorazepam, and diazepam without improvement in the chorea. Amfetamine was withdrawn and 3 days later his chorea abated. He restarted methylphenidate and the movement disorders did not recur. • Choreoathetosis worsened in an 8-year-old boy with learning disabilities when he was treated with dexamfetamine, recurred on rechallenge with the same dose, and immediately resolved with diphenhydramine (4A ).
The authors of the first report speculated that long-term therapy with methylphenidate could have desensitized the patient to the effects of amphetamines, since these drugs act in similar ways. It is also possible that amphetamine therapy interacted with the escitalopram. For this reason, they suggested caution when treating ADHD patients with amphetamines when they are also taking an SSRI.
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• A 17-year-old man who had been abusing amfetamine and cannabis for 2 years took amfetamine 1 g orally over the course of an evening and suddenly felt an uncomfortable sensation in his groin and thought that his penis was being sucked into his abdomen. Physical examination was normal. The serum prolactin and bilirubin concentrations were raised. He had normal sexual function, and was able to attain and sustain an erection. He described the phenomenon of penile shrinkage as “Whizz-Dick” and stated that all the amfetamine users with whom he was in contact were aware of the phenomenon. He was treated with reassurance and supportive counseling.
Reports of koro-like fears of penile shrinkage with amphetamines (7A ) and cannabis (8A , 9A ) are rare. There are no published reports that provide objective evidence that penile shrinkage results from abuse of amphetamines, and the fear is more likely due to altered perception and a poor body image. The authors suggested that it may be an example of an urban myth, a lurid story, or an anecdote based on hearsay and widely circulated as true (6A ). Urinary system Acute transient urinary retention associated with metamfetamine and ecstasy (3,4 methylenedioxymetamfetamine, MDMA) in an 18-year-old man has been described (10A ). Analysis by gas chromatography–mass spectrometry confirmed the presence of metamfetamine (>25 µg/ml), MDMA (>5 µg/ml), amfetamine (1.4 µg/ml), and methylenedioxyamfetamine (3.7 µg/ml) in the urine. Bladder dysfunction resulting from alphaadrenergic stimulation of the bladder neck may have explained the observed effect.
Amfetamine Management of adverse effects Cardiovascular Coronary artery rupture has been associated with amfetamine abuse (5A ). • A 31-year-old woman suddenly developed central chest pain, with a normal electrocardiogram. Changes in troponin and creatine kinase MB were consistent with acute myocardial infarction. Drug screening was positive for amphetamines and barbiturates. Coronary angiography showed an aneurysm with 99% occlusion of the proximal left circumflex coronary artery and extravasation of contrast material. A stent was inserted percutaneously and antegrade flow was achieved without residual stenosis.
Psychiatric A koro-like syndrome has been related to amfetamine abuse (6A ).
Potential benefit of amfebutamone It has been suggested, based on few case reports (11A ), that amfebutamone may be of help in weaning people from amfetamine abuse. • A 53-year-old woman with a 30-year history of amfetamine abuse gave herself amfebutamone (diethylpropion); this resulted in rapid and successful cessation of amfetamine abuse (12A ).
Given the importance of craving, withdrawal symptoms, and maintenance treatment in the withdrawal process, the effect of amfebutamone on these processes needs to be systematically evaluated.
Central nervous system stimulants and drugs that suppress appetite
Metamfetamine Metamfetamine abuse has increased greatly over the past few years. Along with increased use, more reports have emerged of deaths. Cardiovascular The cardiovascular effects of metamfetamine in 11 patients with Parkinson’s disease have been described and compared with six healthy controls (13c ). All were tested twice, once with intravenous saline and once with intravenous metamfetamine 0.3 mg/ kg. Cardiovascular measurements were taken for 15 minutes before drug administration and for 103 minutes after. Both groups had significant increases in blood pressure after metamfetamine, but the patients with Parkinson’s disease had a shorter duration of increased blood pressure and a lower increase from baseline than the controls. The authors proposed that these results suggested cardiac and vascular hyposensitivity to metamfetamine in Parkinson’s disease due to impaired metamfetamineinduced catecholamine release. Nervous system Intracerebral hemorrhage after metamfetamine abuse has been reported (14A ). • A 31-year-old man was found dead 9.5 hours after smoking and snorting metamfetamine. He developed a headache with nausea and vomiting 15 minutes after taking the drug and decided to sleep it off. His friends checked on him throughout the night and noted that he had slurred speech and was falling off his seat. He also complained of left-sided numbness. He was later found dead, with only the left side of his body clothed. Autopsy showed a subarachnoid hemorrhage and an intracerebral hemorrhage lateral to the basal ganglia. His blood metamfetamine concentration was 300 ng/ml.
According to the authors, the cause of death was a spontaneous intracerebral hemorrhage and subarachnoid hemorrhage without vasculitis.
The effects of metamfetamine abuse on cognition and on brain structures and function The effects of metamfetamine on cognition have been studied in 25 subjects who remained abstinent after treatment for metamfetamine abuse,
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25 who relapsed, and 25 who continued to use it throughout treatment (15C ). The cognitive test battery covered six domains: manipulation of information and perceptual speed; ability to ignore irrelevant information; executive function, mental flexibility, and logical thinking; learning; episodic memory; and working memory. There were significant differences between groups in measures of selective reminding and the repeated memory test. There were no differences between the abstinent and relapse groups. On the selective reminding task the continuing use group had a significantly higher number of correct responses than the abstinent group. For the episodic memory tasks, the relapse group performed significantly worse than continuous use group. These results suggest that there is cognitive impairment after a subject stops using metamfetamine. There were no significant differences between those who relapsed and those who remained abstinent, although the relapse group performed better on most tasks. This study was limited, because the relapse group included individuals who relapsed after varying times of abstinence. It is possible that differing periods of abstinence could have distinctive effects on cognition. However, these results do suggest that relapse has a deleterious effect on episodic memory compared with abstinence in ex-users and continued use. Structural changes in the brain and cognitive impairment Since metamfetamine interacts with brain mechanisms, it may affect brain structures. The cortical surface and subcortical structures have been compared in 22 metamfetamine abusers (15 men, 7 women) and 21 controls (10 men, 11 women) (16c ). In addition to MRI scans, the subjects were also administered a neuropsychological battery to assess episodic memory and gave self-ratings on depressive symptoms and anxiety. There was a significant gray matter deficit in metamfetamine abusers in the cingulate gyrus, subgenual cortex, and paralimbic belts. The most severe deficits were in the cingulate regions, where gray matter volumes were 11% below control. In addition, hippocampal volume in metamfetamine abusers was significantly lower than in the controls by 7.8%. This effect occurred across the left and right hemispheres and remained significant even after controlling for extensive marijuana use in the metamfetamine group.
4 Furthermore, hippocampal volume correlated positively with episodic memory performance. Metamfetamine abusers also had significantly more white matter in the temporal and occipital regions. These findings are similar to the structural abnormalities seen in schizophrenia or dementia. It is not clear how these abnormalities occur and whether they are progressive or reversible. In another study PET was used to investigate metabolic abnormalities in 20 recently abstinent metamfetamine abusers and 22 controls (17c ). The mood disturbances in these individuals were also compared with their cerebral metabolism. Metamfetamine abusers were tested after 4–7 days of abstinence. All gave self-ratings on depression, anxiety, and craving for metamfetamine. PET images were acquired 50 minutes after administration of FDG (fluorodeoxyglucose) for 30 minutes. Metamfetamine abusers had significantly higher scores on the Beck Depression Inventory, which correlated with recent metamfetamine use. There was higher cerebral glucose metabolism in a portion of the brain extending from the central to the posterior region of the cingulate gyrus in abstinent metamfetamine abusers. Glucose metabolism was significantly lower in metamfetamine users than in controls in the following regions: infragenual accumbens; left perigenual accumbens; right insula. Metamfetamine abusers had significantly higher activity in the following regions: lateral orbitofrontal cortex; right, middle, and posterior cingulate; amygdala; ventral striatum; cerebellar vermis. In addition, depression scores in metamfetamine abusers correlated positively with activity in the right perigenual accumbens. Depression scores also correlated with activity in the amygdala in metamfetamine abusers. Since most of the systems examined in this study have dopaminergic connections, it is possible that these abnormalities are caused by changes in the dopamine system; a decrease in dopamine input to a specific region could cause a metabolic deficit. It is unknown whether the effects seen in this study reflected abstinence, chronic metamfetamine abuse, or factors that predated metamfetamine abuse. Magnetic resonance imaging (MRI) and new computerized brain-mapping techniques have been used to evaluate the pattern of structural brain alterations associated with chronic
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metamfetamine abuse and how these changes are related to deficits in cognitive impairment (18c , 19c ). In 22 human subjects who abused metamfetamine compared with 21 age-matched, healthy controls, cortical maps showed severe gray-matter deficits in cingulate, limbic, and paralimbic cortices of metamfetamine abusers, averaging 11% below control. Hippocampal deficits, measured as volume, and white-matter hypertrophy were correlated with memory performance on a word-recall test. MRI-based cortical maps suggested that chronic metamfetamine abuse causes a selective pattern of cerebral deterioration that contributes to impaired memory performance. Metamfetamine abuse can also selectively damage the medial temporal lobe and, consistent with metabolic studies, the cingulate-limbic cortex, including neuroadaptation, neuropil1 reduction, or cell death. Prominent white-matter hypertrophy has been suggested to result from altered myelination and adaptive glial changes, including gliosis secondary to neuronal damage (18c ). A potential limitation of this study relates to matching of the two groups: most of the metamfetamine abusers were smokers, compared with only two of the control subjects. In smokers structural changes in the brain have been reported (20c ), although these were more restricted than in metamfetamine abusers. Metamfetamine current abusers show evidence of deficits in performance on tests of memory, perceptual motor speed, inhibition, problem solving, manipulation of information, abstract thinking, and mental flexibility (21C , 22C ). Studies on those who have abused metamfetamine for periods of 5 days to several years have shown that these performance deficits continue during abstinence. These individuals have impaired performance on tests of the ability to inhibit irrelevant information (23c , 24c ), decision making (25c ), memory (26c , 27c ), and spatial processing and learning (23c , 28c ). Studies of other cognitive functions, such as tests of verbal memory, have yielded inconsistent results, with reports of deficits (22c , 23c ) or normal performance (26c ). 1 The brain parenchyma is composed of neurons supported by a framework of glial cells (astrocytes, oligodendrocytes, and ependyma), blood vessels, and microglia. The processes of these cells combine to form a delicate fibrillar background termed the ‘neuropil’.
Central nervous system stimulants and drugs that suppress appetite
Metabolic changes Antioxidant systems were generally preserved in the post-mortem brains of 20 metamfetamine abusers. In the subgroup of abusers with very low dopamine concentrations, there were changes in several antioxidant systems in the caudate. These data suggest that metamfetamine may cause dopamine-related oxidative stress in the brain (29c ). Animal studies also support this view (30RE ). A massive reduction in post-mortem striatal dopamine has also been shown in metamfetamine abusers (31c ). Effects of relapse Data from 75 participants in a longitudinal study of metamfetamine abusers has attempted to differentiate the cognitive performance of those who remained abstinent, relapsed, or continued to use metamfetamine during treatment (32c ). Relapse of metamfetamine abuse can affect episodic memory differently than it affects other cognitive functions. This highlights the fact that individuals who are either abstinent or relapsing may have more problems with treatment that requires their attention, understanding, and memory for compliance than those who continue to use metamfetamine. Effects on cerebral metabolism Metamfetamine abusers during early abstinence have dysfunction in the limbic and paralimbic regions, which has been linked with negative affective states (19c ). In a comparison of 17 metamfetamine abusers who abstained for 4–7 days and 18 controls, measuring mood and cerebral glucose metabolism during the performance of vigilance tasks, earlier reports of long-term neurotoxic effects of metamfetamine assessed by impaired cerebral metabolism (33c , 34c ) and reduced numbers of dopamine transporters (35c ) were supported. This study had limitations, including the fact that although all of the regions tested influence mood, they also contribute to other behavioral states not addressed in this study. While the groups were similar in most categories, most of the metamfetamine abusers, but none of the control subjects, were tobacco smokers; a potential confounding variable was the craving associated with abstinence in nicotine-dependent smokers. Notwithstanding these caveats, these results suggest that the long term neurotoxic effects of metamfetamine are associated with discrete changes in cerebral
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metabolism. It is not clear how these deficits emerge over time. Whether they are progressive, and to what extent therapy or abstinence can reverse them, is not known. Susceptibility factors for impaired cognition Metamfetamine use is high in individuals with HIV infection, who already have neurocognitive impairment (36C ). Furthermore, metamfetamine and HIV both have influences on the striatal and striatal–cortical pathways, so there could be additive effects when the two are combined. This has been studied in 200 individuals in four groups: HIV-positive and metamfetamine dependent (n = 43); HIV-negative and metamfetamine dependent (n = 47); HIVpositive and metamfetamine non-user (n = 50); and HIV-negative and metamfetamine non-user (n = 60). The neurocognitive test battery consisted of tasks dependent on seven different domains: speed of information processing; learning; recall; abstraction/executive functioning; verbal fluency; attention/working memory; and motor skills. In addition, a Global Deficit Score (GDS) was calculated, displaying the severity of impairment across all tests in the battery (calculated by adding deficit ratings for each test and dividing by the total number of tests). Each of the three groups with risk factors for cognitive impairment had higher GDS scores than controls. Among individual domains, HIVnegative metamfetamine abusers had more impairment in tests of attention and recall than controls. HIV-positive metamfetamine abusers performed significantly worse than controls on tests of learning and motor skills. In addition, the percentage global impairment was greatest for HIV-positive metamfetamine abusers than for any other group. These results confirm the separate neurocognitive deficits of HIV infection and metamfetamine abuse, and also show that the combination may have increased deleterious effects on cognition. Since HIV’s mechanism of brain injury is not completely understood, it cannot be said with certainty how these two susceptibility factors interact. Given the increased risk of brain injury among metamfetamine abusers, it has been questioned whether concomitant hepatitis C (HCV) infection, which produces deficits in cognitive functions (37c , 38c ), could have a further detrimental effect. In six hepatitis Cpositive metamfetamine abusers, 10 hepatitis
6 C-negative abusers, and 10 controls, MR spectroscopy showed that hepatitis C infection may worsen metamfetamine-associated neuronal injury in white-matter, as measured with N-acetylaspartate; a reduction in the concentration of this marker correlated with worse global neuropsychological deficits (39c ). Without a longitudinal study, it is not possible to determine whether the suggested neuronal injury is reversible. However, the findings of this study vary from those of a previous report (40c ). Outcomes Metamfetamine has been implicated in another death that was attributed to impaired performance due to nervous system effects (41A ). • A 44-year-old man was found dead after his Cessna airplane crashed in mountainous terrain. A gas chromatography/mass spectrometer was used to conduct stereochemical analyses of metamfetamine and amfetamine present in the pilot’s body. At autopsy the total concentration of amphetamines in the urine was 8.0 µg/ml and the blood concentration of metamfetamine was 1.13 µg/ml, enough to produce toxic effects that could have impaired his performance.
The authors concluded that he had taken oral metamfetamine in a dose high enough to impair nervous system function. A combination of poor weather conditions and metamfetamine intoxication probably caused him to crash. Susceptibility factors Genetic Genetic variation in dopaminergic function may contribute to the risk of becoming a metamfetamine abuser. The role of genes in metamfetamine abuse has been addressed in two studies. In the first, deletion of glutathione S-transferase M1 (GSTM1) was examined in metamfetamine abusers (42C ). As GSTM1 plays a role in the antioxidant systems of the brain that help prevent neurotoxicity, the authors sought to explore the presence of the alleles of GSTM1 in 157 metamfetamine abusers and 200 controls. Female abusers had a higher frequency of the deletion allele than female controls but the effect did not reach statistical significance. Also, the frequency of carrying the deletion allele was significantly higher in female abusers than male abusers. These results suggest that deletion of the GSTM1 gene
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may contribute to the development of metamfetamine abuse in women. In a case-control study in 416 metamfetamine abusers and 435 healthy controls, two polymorphisms in genes encoding proteins of the dopaminergic system, the Val 158 Met polymorphism in the catechol-O-methyl transferase (COMT) gene and the 120-bp VNTR polymorphism in the promoter of the dopamine D4 receptor gene, were investigated for their association with metamfetamine abuse (43C ). All the subjects were Han Chinese from Taiwan. There was an excess of the high-activity Val158 allele in the metamfetamine abusers, consistent with previous reports of an association of this allele with drug abuse. The 120-bp VNTR polymorphism in the promoter of the dopamine D4 receptor gene itself did not show a significant association with metamfetamine abuse. However, analysis of the 120-bp VNTR polymorphism and the exon 3 VNTR in the dopamine D4 receptor as a haplotype showed a significant association. There were interactive effects between polymorphisms in the COMT and dopamine D4 genes. However, an earlier similar study did not find such interactive effects (44C ). It is possible that substance abuse is a complex polygenic trait, and a number of genes may act as susceptibility factors, each gene having a weak or moderate effect on risk. The effects of the genes may be masked by the effects of other susceptibility genes, so that epistatic gene–gene interactions are more significant in determining the association (45C ).
Methylenedioxymetamfetamine (MDMA, ecstasy) (SED-15, 2292; SEDA-26, 30; SEDA-27, 29; SEDA-28, 31) Respiratory Hemopneumothorax has been reported in association with MDMA abuse (46A ). • A 33-year-old man developed shortness of breath and right-sided chest pain 12 hours after taking two tablets of MDMA. His blood pressure was 110/60 mmHg and his pulse 120/minute. A chest X-ray showed a complete right-sided pneumothorax with left shift of the mediastinal structures. Needle decompression was completed and 200 ml of blood was drained over 1 hour. A CT scan showed apical bullae with hemopneumothorax. Another 1500 ml of blood was drained over the next 2 days.
Central nervous system stimulants and drugs that suppress appetite
Spontaneous hemopneumothorax has not been previously reported in association with MDMA. The authors suggested that ruptured bullae with torn apical vascular adhesions were responsible. Nervous system Serotonin deficits and mood disorders in MDMA users have been studied (47C ). This topic is of interest because mood disorders and the effects of MDMA may be modulated through the serotonin system. The researchers compared the prevalence of mood disorders to serotonin transporter densities in short-term, long-term, and abstinent MDMA users, in the following subgroups: moderate users (n = 15), heavy users (n = 23), former heavy users (n = 16), and MDMA-naïve controls (n = 15). Former MDMA users had had to be abstinent from the drug for at least 12 months. The subjects agreed to abstain from any drug use for 3 weeks before the study, and this condition was confirmed by a urine drug screen. Mood disorders were evaluated using the Composite International Diagnostic Interview (CIDI) and the Beck Depression Inventory (BDI). Serotonin transporter densities were calculated using SPECT imaging techniques. Across all groups, CIDI scores did not differ for current or lifetime mood disorders. BDI scores differed significantly between former users and controls, former users scoring higher. Additionally, BDI scores correlated positively with the total number of MDMA tablets taken. Serotonin transporter densities were lower in heavy MDMA users than in the other groups, and lower in women than in men. There were no relations between serotonin transporter densities and mood disorder scores. An interesting component of the results is that serotonin transporter densities appear to recover after heavy MDMA use stops, whereas the prevalence of mood disorders does not improve. However, the results of this study were limited by the small sample size. The effect of MDMA on densities of the serotonin transporter has been studied with PET imaging in 30 current users, 29 former users, 29 users of other drugs, and 29 drug-naïve controls (48C ). Former users were required to be abstinent for 20 weeks before the study. On the day of PET scanning, hair samples were taken for drug analysis. Serotonin transporter volumes were reduced in current MDMA users
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7
in the posterior cingulate gyrus, left caudate, thalamus, occipital cortex, medial temporal lobes, hippocampus, and brainstem. Among current users men and women had different deficit profiles: women had lower serotonin binding in all areas except the left caudate and auditory cortex; men had deficits in the occipital cortex and medial temporal lobes. There were no significant differences in the other three groups. In addition, there was a negative correlation between the usual dose of MDMA and the serotonin density in the occipital lobe and the left precentral sulcus in current users. The fact that serotonin transporter numbers were higher in female than male current users suggests that MDMA may be more damaging to the female brain. These results suggest that MDMA causes changes in the serotonin transporter system, but that the effect is also reversible after abstention. One possible confounding factor was that a period of 3 days without drugs was required before PET imaging. However, it is possible that MDMA remained in the brain tissue, a factor that would certainly have affected the results of the study. Psychological Several studies have reported the effects of MDMA use on neurocognition, including visuospatial memory in 25 current MDMA users (11 men, 14 women), 10 former users who were abstinent for at least six months (6 men, 4 women), and 18 non-using controls (6 men, 12 women) (49c ). Both user groups performed more poorly than the controls, even controlled for age, years of education, intelligence, and alcohol and tobacco use. However, when cannabis use was considered, the main effect became non-significant. These results suggest that current and former MDMA users have deficits in visuospatial memory compared with controls. Since the tasks in question here involve executive functioning in addition to visuospatial memory, it is possible that these deficits are mediated through the prefrontal cortex. However, the authors did not propose a mechanism for this interaction. The effects of MDMA on verbal working memory (reading span and computation span) have been studied in 42 current users (22 men, 20 women), 17 previous users (9 men, 8 women), and 31 non-users (12 men, 19 women) (50C ). Previous users were required to have been abstinent for at least 6 months and
8 users were asked to abstain for 7 days before the test. Both MDMA groups performed significantly worse on computation span; reading span was not significantly affected. After controlling for other types of drug use, all the effects remained. The fact that there was impairments in current and former users of MDMA suggests that there are long-term effects of MDMA abuse on working memory. It is not known whether this impairment is caused by changes in executive function or a more specific effect on working memory processes. One potential problem with the current study was that there was no guarantee that subjects had not used drugs before testing. In a third study executive functioning (cognitive flexibility, working memory, and response inhibition) was investigated in relation to MDMA use in 59 participants (26 MDMA users, 33 non-users) (51C ). Male users had a specific set of deficits compared with controls: they performed poorly on tasks that required set shifting (cognitive flexibility) and complex executive function tasks. These functions are related to the ability to adapt quickly to changes in the environment. Other processes remained intact. These effects were noted in moderate MDMA users (a mean of 1.7 MDMA tablets per month). The fact that these deficits were not seen in female users could be explained by the fact that men had significantly more MDMA consumption than women (mean use of 54 tablets versus 39 tablets). It is not known whether these deficits are severe enough to affect behavior in real life. Electrolyte balance Hyperkalemia has been reported in association with fatal MDMA toxicity (52A ). • A 19-year-old man took 12 tablets of MDMA and danced in a hot environment throughout the night. His heart rate rose to 180/minute and his blood pressure fell to 70/50 mmHg. He had a cardiac arrest and was resuscitated and mechanically ventilated. His potassium blood concentration was 6.3 mmol/l. He remained comatose until a second cardiac arrest proved fatal 2.5 hours later. The plasma MDMA concentration was 3.65 µg/ml.
The authors suggested that the patient’s hyperkalemia was precipitated by a hypermetabolic state in which there was reduced glomerular filtration and the beginning of rhabdomyolysis.
Chapter 1
Reginald P. Sequeira
Skin Guttate psoriasis has been reported after the use of MDMA (53A ). • A 23-year-old man reported to the hospital 5 days after MDMA ingestion with a pruritic generalized eruption. The rash, small papules of 10 mm in a guttate pattern, covered his legs, arms, trunk, and face. There were parakeratosis, elongated rete ridges, epidermal spongiosis, hypogranulosis, and superficial mononuclear cell infiltration. The rash responded completely to glucocorticoids and narrow band UVB at a maximum dose of 0.85 J/cm2 .
The authors described this as a case of a lichenoid drug eruption caused by MDMA or a contaminant in the tablet. The patient denied using any other illicit medications. Body temperature A high-grade fever occurred in a young woman after the use of MDMA (54A ). • A 20-year-old woman became unresponsive after taking two tablets of MDMA. She had a heart rate of 172/minute, a blood pressure of 164/118 mmHg, a respiratory rate of 30/minute, and a temperature of 41.8 ◦ C. She was placed under a cooling blanket, with ice packs and fans and 30 minutes later her temperature was 40.8 ◦ C, with a subsequent fall to 37.9 ◦ C 20 minutes after that. She also had a deep vein thrombosis in the arm. She continued to improve and there were no sequelae.
Death Death from MDMA intoxication has recently become more frequent. In a retrospective chart review of the prevalence of MDMArelated deaths in the USA from 1999 to 2001 102 cases were identified in which MDMA was detected post-mortem: 10% were from 1999, 38% from 2000, and 52% from 2001 (55R ). The mean age was 25 years. Cases were coded as drug-related (drug toxicity contributed to death) or drug-unrelated (drug found but not related to the cause of death). Of the 102 reports 71 were considered to have been drug-related. The mean time from onset of symptoms to contacting emergency services was 6 hours and 42 minutes. There was no difference in MDMA concentration between drug-related and drugunrelated deaths. There was also a high rate of polysubstance use (73%). The authors emphasized that there was a 400% increase in MDMA-related deaths from 1999 to 2001. Furthermore, the long delay between the onset of symptoms and medical intervention suggests
Central nervous system stimulants and drugs that suppress appetite
that many of these deaths could have been prevented with timely attention. Because only 8% of the medical examiners who were contacted for information responded, non-response bias was possible. Furthermore, a disproportionate number of deaths (77%) were reported by one state (Florida), suggesting possible geographic reporting bias. Drug adulteration A potential confounding variable in studies of MDMA is that the subjects may not actually be taking MDMA, but rather other substances, such as amfetamine or metamfetamine. In 21 subjects who claimed to have taken only MDMA and no other drugs (56c ) a hair sample showed that 19 had MDMA present, while seven had concentrations of 3,4methylenedioxyamfetamine (MDA) similar to or greater than those of MDMA. Eight subjects also tested positive for of amfetamine or metamfetamine. At a follow-up interview with those who tested positive for drugs other than MDMA, none admitted knowledge of taking MDA, amfetamine, or metamfetamine. These results suggest that not all street ecstasy tablets contain pure MDMA. Often, MDA, amfetamine, or metamfetamine is disguised as MDMA. It is unknown whether the combination of MDMA with these drugs poses a greater health risk to abusers. The main limitation of this study was that it relied on the subjects’ own reports. The authors suggested that hair testing be implemented in all MDMA research trials to ensure that the study sample is accurate. Drug overdose Accidental MDMA overdose has been reported in a baby (57A ). • A 14-month-old boy began convulsing 40 minutes after taking an unknown medication. The convulsions lasted for 20 minutes. He became cyanotic with a heart rate of 130/minute and a temperature of 38 ◦ C. He was treated with oxygen, intravenous benzodiazepines, and dipyrone, but continued to have isolated ventricular extra beats, hypertension, and tachycardia. The serum and urine concentrations of MDMA 8 hours after ingestion were 0.591 and 1477 mg/l respectively. After 12 hours, the tachycardia and hypertension resolved and the child was discharged 9 days later with no residual symptoms.
Chapter 1
Doxapram
9
(SED-15, 1186)
Nervous system In 15 preterm infants, doxapram (a loading dose of 2.5 mg/kg over 30 minutes followed by a continuous infusion of 0.5 mg/kg/hour) caused a significant reduction in maximal cerebral blood flow velocity (58c ). Changes in cerebral perfusion are thought to be a major risk factor for the development of intraventricular hemorrhage and periventricular leukomalacia, which constitute the strongest predictor of later adverse neurological outcomes. Based on animal studies (59E ) it has been suggested that in hypoxic ischemic conditions similar to those that can exist in the neonatal brain during episodes of apnea and desaturation, doxapram may exacerbate brain injury. It is also important to avoid rapid administration of doxapram during loading in order to minimize reduction in cerebral blood flow. Doxapram should not be used as routine treatment of apnea of prematurity without adequate evaluation of its short- and long-term safety.
Strychnine
(SED-15, 3185)
The toxic effects of Strychnos species and their alkaloids have been comprehensively reviewed (60R ). Drug contamination Strychnine is used to adulterate illicit drugs, such as cocaine and heroin. In patients with a history of cocaine abuse, strychnine poisoning should be considered when there are manifestations similar to those of tetanus, since early diagnosis and treatment can improve survival. • A 29-year-old cocaine addict was admitted with signs and symptoms of strychnine poisoning, and a urine screen confirmed the presence of cocaine and strychnine (61A ).
Adulteration of herbal medicines has also been reported. • A woman died 15 minutes after ingesting a packet of herbal medicine containing Strychnos nux vomica seeds. In post-mortem samples strychnine and brucine were identified using reverse phase-HPLC combined with solid-phase extraction (62A ).
10
Methylphenidate
Chapter 1
(SED-15, 2307)
An international consensus statement on attention deficit hyperactivity disorder (ADHD) and disruptive behavior disorder has been published (63S ). The addition of risperidone to psychostimulants has been endorsed for better control of hyperactivity (63S , 64C ). Adverse reactions to methylphenidate reported between July 1995 and December 2001 to the French Pharmacovigilance Centre have been evaluated (65cr ). Most of the reported adverse reactions were mild, resolved promptly, and affected children taking recommended doses. These were mostly neurological, psychiatric, and skin reactions. The author advocated the current restrictive prescription policy practised in France, allowing only neurologists, psychiatrists, and pediatricians to prescribe methylphenidate, rather than to allow general practitioners and nurse practitioners to do so, as is the case in many countries, including the USA. Nervous system Cerebral infarction is a potential adverse effect of long-term use of methylphenidate (66A ). • A 24-year-old student developed left-sided weakness without loss of consciousness. His weakness progressed over the next 20 minutes, then became fixed. He had taken methylphenidate 60 mg/day by mouth for the previous 6 months. His blood pressure was normal. A brain CT scan showed lacunar infarction involving the head of the right caudate nucleus and the adjacent anterior limb of the internal capsule. Cerebral angiography showed no abnormality. The course of recovery was uneventful.
It seems justified to consider methylphenidate as a potential predisposing factor for stroke in this patient, and cerebral arteritis associated with methylphenidate has been reported (67A , 68A ). Although this adverse effect appears to be very rare, it does point to a possible complication of using methylphenidate for longer periods (69R ). Psychiatric Three children taking low doses of methylphenidate developed visual and tactile hallucinations (70A ). Rechallenge in one case elicited hallucinations; in another, placebo resulted in their cessation. The hallucinations
Reginald P. Sequeira
occurred several hours after the dose of methylphenidate. In one of these children, the hallucinations began shortly after starting methylphenidate, but the other two had taken it for longer periods. All the hallucinations resolved promptly after methylphenidate was withdrawn. Two other cases of methylphenidate-induced hallucinations in children have been reported (71A , 72Ar ). Because methylphenidate is widely used, physicians should be aware of even rare adverse reactions at therapeutic doses in ADHD patients in whom there are no other psychiatric co-morbidities. Sexual function Stuttering priapism associated with withdrawal from modified-release methylphenidate has been described (73A ). • A 15-year-old boy with ADHD took methylphenidate 27 mg/day for 6 days a week, with drug holidays on Sundays. The dose was increased to 36 mg/day, and for the first time in his life he developed intermittent, unwanted, prolonged erections unassociated with sexual arousal within 1 week of increasing the dose. He had 5–10 erections on one day, each lasting 10–15 minutes. Masturbation and ejaculation caused only temporary detumescence, followed by recurrence 90 minutes later. For more than 2 months he endured painful, intermittent erections. On reduction of the dosage, followed by complete withdrawal of methylphenidate, the stuttering priapism resolved.
The authors pointed out that embarrassment associated with unprovoked, intermittent, painful, prolonged erections prevented the patient from disclosing the problem to a parent or physician. Perhaps there are other adolescent boys who have had the same adverse effect from methylphenidate who have also chosen to keep quiet about this embarrassing problem.
Modafinil
(SED-15, 2369)
Drug abuse Initial evidence suggests that modafinil has limited potential for large-scale abuse (74R ). The body of evidence spans preclinical studies and several human laboratory studies and post-marketing experience in France over a decade and in the USA for about 5 years. Women with a history of substance abuse may be at greater risk than men (75c ), but this observation has not been replicated. Based on the evidence to date, large-scale abuse is unlikely. Nevertheless, the Drug Enforcement Agencies
Central nervous system stimulants and drugs that suppress appetite
classify modafinil as a schedule IV drug, one with some potential for abuse.
DRUGS THAT SUPPRESS APPETITE (SEDA-26, 6; SEDA-27, 4; SEDA-28, 6)
Fenfluramines
(SED-15, 1333)
Liver Three individuals who used Sen no moto kono, an unlicensed weight loss supplement containing N-nitrosofenfluramine developed hepatotoxicity (76A ). In one of these patients, who was a CYP2C19 slow metabolizer, there were severe ultrastructural changes. Sen no moto kono is reported to have caused hepatotoxicity in 120 cases in Japan, culminating in the death of two patients (77S ).
Sibutramine
(SED-15, 3131; SEDA-28,
8) The clinical implications of obesity, with particular emphasis on the efficacy of obesity therapies, including the roles of dietary intervention, physical activity, behavior modification, pharmacotherapy, and bariatric surgery, have been reviewed (78R ). These have been endorsed by the American College of Cardiology Foundation. Comparative studies Orlistat versus sibutramine Orlistat 360 mg/ day (n = 71) and sibutramine 10 mg/day (n = 70) have been compared in a doubleblind, randomized study in obese patients with diabetes mellitus, who had had diabetes for at least 6 months and who were taking diet alone or diet plus oral hypoglycemic drugs (79C ). Both orlistat and sibutramine reduced body weight and improved glycemic control over 12 months, and orlistat was slightly more efficacious as an anti-obesity drug. Sibutramine was not associated with any cardiovascular effects and was generally better tolerated than orlistat. Of the 133 patients who completed the study, 22 (34%) of those taking orlistat and nine (13%) of those taking sibutramine had adverse effects. All the adverse effects of orlistat
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11
were gastrointestinal, occurred early in treatment, were mild to moderate in intensity, were generally transient, and resolved spontaneously. In one patient sibutramine caused increases in both systolic and diastolic blood pressures, controlled with antihypertensive treatment. Other adverse effects were mild and transient and occurred during the early phase of treatment; more than 80% of the patients reported only a single episode. The results of this study support the findings of a previous study in women with diabetes (80c ). Ephedrine versus sibutramine Ephedrine and sibutramine have been compared in healthy, mildly overweight subjects in a five-way, randomized, double-blind, placebo-controlled trial with three single doses of ephedrine sulfate (0.25, 0.5, and 1 mg/kg) followed by open sibutramine (10 mg) (81c ). Body surface temperature, resting basal metabolic rate (BMR), blood pressure, heart rate, and biochemical profiles of glucose, glycerol, non-esterified fatty acids, and triglycerides were measured. Sibutramine significantly increased resting basal metabolic rate. Ephedrine significantly increased heart rate, systolic blood pressure, and blood glucose concentrations. The authors concluded that both ephedrine and sibutramine can cause weight loss and that they have different metabolic and physiological effects. Observational studies The use of sibutramine for weight loss has been the subject of a systematic review (82M ). Of 44 randomized controlled trials of sibutramine for weight loss, only 29 had sufficient data for analysis after including unpublished data from 10 authors. The conclusions based on this study were that sibutramine is effective in promoting weight loss and is associated with both positive and negative cardiovascular and metabolic risk factors. There is insufficient evidence to accurately determine the benefit to harm balance for sibutramine. Two important caveats have emerged based on the findings of this systematic review. First, the suggestion that sibutramine be used as a short-term aid to long-term lifestyle modifications that promote weight loss and maintenance of weight loss (83r ), cannot be supported by the evidence. Secondly, in 2002, the European Committee for Proprietary Medicinal Products
12 concluded that the benefit to harm balance of sibutramine was positive (84S ). There is a need for future trials to be designed and powered to detect differences in the risk of diabetes mellitus, cardiovascular disease, and valvular heart disease in obese patients taking sibutramine. Quality-of-life measures should also be considered. Treatment with sibutramine 10 mg/day and a 1200 calorie diet for 1 year in 72 obese subjects (BMI > 30 kg/m2 ) led to significant improvements in glucose tolerance, insulin sensitivity, and serum lipid concentrations. Nine patients withdrew from the study, five because of adverse effects. The most commonly reported adverse effects were headache (24%), constipation (16%), dry mouth (19%), dizziness (6.3%), and bouts of palpitation (1.5%). Most of these effects were mild to moderate (85C ). In 57 patients (54 women and three men), mean age 37 years, the addition of low-dose metoprolol 25 mg/day to sibutramine 10 mg/ day increased patient adherence to treatment and reduced the frequency and severity of adverse effects, including hypertension and bouts of palpitation, without reducing drug efficacy or causing significant deleterious changes in metabolic parameters (86C ). Previously, the efficacy and safety of sibutramine have been demonstrated in obese patients with hypertension well controlled with β-adrenoceptor antagonists (87C ). Cardiovascular Sibutramine did not affect heart valves or pulmonary artery pressure during 24 weeks in 106 obese patients (51 men and 55 women) with minimal tricuspid regurgitation on echocardiographic examination (88c ). There were significant increases in blood pressure and heart rate.
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Reginald P. Sequeira
drugs remains controversial. While acknowledging measurable and consistent cognitive effects, many question the overall clinical usefulness of these drugs, while many others are staunch advocates (89r ).
Donepezil
(SED-15, 1179; SEDA-28, 9)
Observational studies The AD 2000 West Midlands Donepezil Trial has been completed (90C ). This study was based on 565 communityresident patients with mild to moderate Alzheimer’s disease who took donepezil 5 or 10 mg/ day for 12 weeks. The results suggested that donepezil is not cost-effective, with benefits below minimally relevant thresholds. Common adverse events and those contributing to withdrawal of medication could have major impact on quality of life and costs, but were not measured or reported. Following the publication of the findings of AD 2000, several correspondents criticized the design of the study and its conclusions (91r – 94r ). Furthermore, the need for comparisons of cholinesterase inhibitors, alone and in combination, with other drugs has been acknowledged (95r ). The efficacy of cholinesterase inhibitors in vascular dementia (96c , 97c ) and in dementia with Lewy bodies (98c ) is uncertain. Sertraline augmentation in the treatment of the behavioral manifestations of Alzheimer’s disease in outpatients treated with donepezil has been evaluated (99c ). There were no significant differences on primary endpoints. Diarrhea was more common with donepezil + sertraline group compared with donepezil + placebo.
SEDA-28, 9)
Nervous Kinematic analysis of handwriting movements in patients with Alzheimer’s disease taking donepezil did not show deterioration (100c , 101c ). Indeed there was a nonsignificant trend towards smoother movement in those taking donepezil. This is consistent with the observation of improved handwriting in a subject with dementia with Lewy bodies during donepezil treatment (102A ).
Despite the many published randomized trials of cholinesterase inhibitors for the treatment of Alzheimer’s disease, nearly all showing efficacy, and worldwide approval by regulatory authorities, the practical effectiveness of these
Urinary tract Clinicians often encounter patients with dementia and urge incontinence who might benefit from both anticholinergic medication and a cholinesterase inhibitor (103A ), a paradoxical combination.
DRUGS USED IN ALZHEIMER’S DISEASE (SEDA-26, 7; SEDA-27, 7;
Central nervous system stimulants and drugs that suppress appetite • A 76-year-old woman with Alzheimer’s disease and urge incontinence had been taking donepezil 10 mg at bedtime and tolterodine 2 mg in the morning and 4 mg at night. Her dementia deteriorated, and there was concern that tolterodine may have contributed. However, multiple episodes of nocturia, poor sleep, and worsening of behavior followed tolterodine dosage reduction to 2 mg bd. These symptoms were relieved when the prior tolterodine dosage was resumed, and her agitation resolved.
This pharmacodynamic interaction suggests that donepezil should be avoided in patients with Alzheimer’s disease who are taking anticholinergic drugs.
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Drug interactions Pharmacokinetic and pharmacodynamic data from an open study in 24 healthy subjects suggested that there is no interaction between memantine (an N-methyl-Daspartate receptor antagonist approved for treatment of Alzheimer’s disease) and donepezil (104c ). These findings support the potential for combining memantine and cholinesterase inhibitors in patients with Alzheimer’s disease. Gingko supplementation had no significant effect on the pharmacokinetics and pharmacodynamics of donepezil in 14 patients with Alzheimer’s disease (105c ).
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32. Simon SL, Dacey J, Glynn S, Rawson R, Long W. The effect of relapse on cognition in abstinent methamphetamine abusers. J Subst Abuse Treat 2004;27:59–69. 33. Ernst ND, Chang L, Leonido-Yee M, Speck O. Evidence of long-term neurotoxicity associated with methamphetamine abuse: a 1 H MRS study. Neurology 2000;54:1344–9. 34. Volkow ND, Chang L, Wang GJ, Fowler JS, Franceschi D, Sedler MJ, Gatley SJ, Hitzeman R, Ding YS, Wong C, Logan J. Higher cortical and lower subcortical metabolism in detoxified methamphetamine abusers. Am J Psychiatry 2001;158:383–9. 35. McCann UD, Wong DF, Yokoi F, Viltemagne V, Dannals RF, Ricaurte GA. Reduced striatal dopamine transporter density in abstinent methamphetamine and methcathinone users: evidence from positron emission tomography studies with [11 C]WIN- 35,428. J Neurosci 1998;18:8417–22. 36. Rippeth JD, Heaton RK, Carey CL, Marcotte TD, Moore DJ, Gonzalez R, Wolfson T, Grant I. Methamphetamine dependence increases risk of neuropsychological impairment in HIV infected persons. J Int Neuropsychol Soc 2004;10:1–14. 37. Forton DM, Allsop JM, Main J, Foster GR, Thomas HC, Taylor-Robinson SD. Evidence of cerebral effect of the hepatitis C virus. Lancet 2001;358:38–9. 38. Hilsabeck RC, Perry W, Hassanein TI. Neuropsychological impairments in patients with chronic hepatitis C. Hepatology 2002;35:440– 6. 39. Taylor MJ, Letendre SL, Schweinsburg BC, Al Hassoon OM, Brown GG, Gongwatana A, Grant I, and the HNRC. Hepatitis C virus infection is associated with reduced white matter Nacetylaspartate in abstinent methylamphetamine users. J Int Neuropsychol Soc 2004;10:110–3. 40. Forton DM, Thomas HC, Murphy CA, Allsop JM, Foster GR, Main J, Wesnes KA, TaylorRobinson SD. Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease. Hepatology 2002;35:433–9. 41. Chaturvedi AK, Cardona PS, Soper JW, Canfield DV. Distribution and optical purity of methamphetamine found in toxic concentration in a civil aviation accident pilot fatality. J Forensic Sci 2004;49:832–6. 42. Koizumi H, Hashimoto K, Kumakiri C, Shimizu E, Sekine Y, Ozaki N, Inada T, Harano M, Komiyama T, Yamada M, Sora I, Ujike H, Takei N, Iyo M. Association between the glutathione S-transferase M1 gene deletion and female methamphetamine abusers. Am J Med Genet 2004;126B(Part B):43–5. 43. Li T, Chen C, Hu X, Ball D, Lin S, Chen W, Sham PC, Loh E, Murray RM, Collier DA. Association analysis of the DRDH and COMT genes in methamphetamine abusers. Am J Med Genet 2004;129B:120–4. 44. Vandenberg DJ, Rodriguez LA, Hivert E, Schiller JH, Villareal G, Pugh EW, Lachman H,
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16 74. Myrick H, Malcolm R, Taylor B, LaRowe S. Modafinil: preclinical, clinical and post-marketing surveillance—a review of abuse liability issues. Ann Clin Psychiatry 2004;16:101–9. 75. Jasinski DR. An evaluation of the abuse potential of modafinil using methylphenidate as a reference. J Psychopharmacol 2000;14:53–60. 76. Kawaguchi T, Harada M, Arimatsu H, Nagata S, Koga Y, Kuwahara R, Hisamochi A, Hino T, Taniguchi E, Kumemura H, Hanada S, Maeyama M, Koga H, Tomiyasu N, Toyomasu H, Kawaguchi M, Kaga M, Kumashiro R, Tanikawa K, Sata M. Severe hepatotoxicity associated with a nitrosofenfluramine-containing weight-loss supplement. Report of three cases. J Gastroenterol Hepatol 2004;19:349–50. 77. Anonymous. Japanese Ministry of Health, Labour and Welfare. The emergency information for Chinese diet. http://www.mhlw.go.jp/ kinkyu/diet.html. 78. Klein S, Burke LE, Bray GA, Blair S, Allison DB, Pi-Sunyer X, Hong Y, Eckel RH. Clinical implications of obesity with specific focus on cardiovascular disease. Circulation 2004;110:2952–67. 79. Derosa G, Cicero AFG, Murdolo G, Ciccarilli L, Fogari R. Comparison of metabolic effects of orlistat and sibutramine treatment in type 2 diabetic patients. Diabetes Nutr Metab 2004;17:222–9. 80. Gokcel A, Gumurdulu Y, Karakose H, Melek Ertorer E, Tonaci N, Bascil Tutuncu N, Guvener N. Evaluation of the safety and efficacy of sibutramine, the safety and efficacy of sibutramine, orlistat and metformin in the treatment of obesity. Diabetes Obes Metab 2002;4:49–55. 81. Persky AM, Ng C, Song MH, Lancaster ME, Balderson DE, Paulik MA, Brouwer KLR. Comparison of the acute pharmacodynamic responses after single doses of ephedrine or sibutramine in healthy, overweight volunteers. Int J Clin Pharmacol Ther 2004;42:442–8. 82. Arterburn DE, Crane PK, Veenstra DL. The efficacy and safety of sibutramine for weight loss. Arch Intern Med 2004;164:994–1003. 83. Meisler JG. Toward optimal health: the experts discuss weight control drugs. J Women’s Health Gender Based Med 2001;10:101–7. 84. Anonymous. Committee for Proprietary Medicinal Products. Opinion following an article 31 referral: Sibutramine. London, England: European Agency for the Evaluation of Medicinal Products 2002; report 4514. 85. Subuncu T, Ucar E, Birden F, Yosar O. The effect of 1-yr sibutramine treatment on glucose tolerance, insulin sensitivity and serum lipid profiles in obese subjects. Diabetes Nutr Metab 2004;17:103–7. 86. Ersoz HO, Baykan M, Erem C, Durmus I, Hacihasanoglu A, Telatar M. Effect of lowdose metoprolol in combination with sibutramine therapy in normotensive obese patients: a randomized controlled study. Int J Obesity 2004;28:378–83.
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87. Sramek JJ, Leibowitz MT, Weinstein SP, Rowe ED, Mendel CM, Levy B, McMahon FG, Mullican WS, Toth PD, Cutler NR. Efficacy and safety of sibutramine for weight loss in obese patients with hypertension agents: a placebo controlled double blind, randomized trial. J Hum Hypertens 2002;16:13–9. 88. Guven A, Koksal N, Cetinkaya A, Sokmen G, Ozdemir R. Effects of the sibutramine therapy on pulmonary artery pressure in obese patients. Diabetes Obesity Metab 2004;6:50–5. 89. Schneider LS. AD 2000. Donepezil in Alzheimer’s disease. Lancet 2004;363:2100–1. 90. Anonymous. AD 2000 Collaborative Group. Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD 2000): randomized double blind trial. Lancet 2004;363:2105– 15. 91. Holmes C, Burns A, Passmore P, Forsyth D, Wilkinson D. AD 2000: design and conclusions. Lancet 2004;364:1213–4. 92. Akinatade L, Zaiac M, Leni JR, McRae T. AD 2000: design and conclusions. Lancet 2004;364:1214. 93. Howe I. AD 2000: design and conclusions. Lancet 2004;364:1215. 94. Clarke N. AD 2000: design and conclusions. Lancet 2004;364:1216. 95. Gray R, Bentham P, Hills R, on behalf of the Collaborative Group. AD 2000: design and conclusions. Authors’ reply. Lancet 2004;364:1216. 96. Erkinjuntti T, Roman G, Gauthier S. Treatment of vascular dementia—evidence from clinical trials with cholinesterase inhibitors. J Neurol Sci 2004;226:63–6. 97. Black S, Roman GC, Geldmacher DS, Salloway S, Hecker J, Burns A, Perdomo C, Kumar D, Pratt R, Donepezil 307 Vascular Dementia Study Group. Efficacy and tolerability of donepezil in vascular dementia: positive results of a 24-week, multicenter, international, randomized, placebo-controlled clinical trial. Stroke 2003;34:2323–30. 98. Kaufer DI. Pharmacologic treatment expectations in the management of dementia with Lewy bodies. Dementia Geriatr Cogn Dis 2004;17(Suppl 1):32–9. 99. Finkel SI, Mintzer JE, Dysken M, Krishnan KRR, Burt T, McRae T. A randomized placebo-controlled study of the efficacy and safety of sertraline in the treatment of the behavioral manifestations of Alzheimer’s disease in outpatients treated with donepezil. Int J Geriatr Psychiatry 2004;19:9–18. 100. Hegerl U, Mergl R, Henkel V, Gallinat J, Koffer G, Muller-Siecheneder F, Pogarell O, Juckel G, Schroter A, Bahra R, Emir B, Laux G, Moller HJ. Kinematic analysis of the effects of donepezil hydrochloride on hand motor function in patients with Alzheimer’s dementia. J Clin Psychopharmacol 2003;23:214–6. 101. Bohnen N, Kaufer D, Hendrickson R, Ivanco L, Moore R, Dekosky ST. Effects of donepezil on
Central nervous system stimulants and drugs that suppress appetite motor function in patients with Alzheimer’s disease. J Clin Psychopharmacol 2004;24:354–6. 102. Kaufer DI, Catt KE, Lopez OL, DeKosky ST. Dementia with Lewy bodies: response to delirium-like features to donepezil. Neurology 1998;51:1512. 103. Siegler EL, Reidenberg M. Treatment of urinary incontinence with anti-cholinergics in patients taking cholinesterase inhibitors for dementia. Clin Pharmacol Ther 2004;75:484–8.
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104. Periclou AP, Ventura D, Sherman T, Rao N, Abramowitz WT. Lack of pharmacokinetic or pharmacodynamic interaction between memantine and donepezil. Ann Pharmacother 2004;38:1389–94. 105. Yasui-Furukori N, Furukori H, Kaneda A, Kaneko S, Tateishi T. The effects of Ginkgo biloba extracts on the pharmacokinetics and pharmacodynamics of donepezil. J Clin Pharmacol 2004;44:538–42.
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Antidepressant drugs
Mania as an adverse effect of antidepressants Mania is listed as a possible adverse effect of all antidepressant drugs, and there is a well recognized association between the use of antidepressants and reports of switches from depression into mania (SEDA-23, 17). There are three kinds of explanation for this phenomenon: (i) a spontaneous switch from depression into mania as part of a bipolar illness, which happens by chance to coincide with the use of antidepressant treatment; (ii) the mania is indeed triggered by the antidepressant drug but the depression is part of a bipolar illness and bipolar patients are unusually susceptible to antidepressant-induced hypomania; (iii) antidepressants can induce mania in patients with true unipolar depression who would never otherwise suffer from manic illness. In a systematic review of antidepressantinduced hypomania and mania the rate of switching from depression into mania with antidepressant drug treatment in patients identified as having unipolar depression was quite low and generally under 5% (1M ). This rate is within that described for the spontaneous conversion from unipolar to bipolar disorder during longer-term follow-up in the absence of antidepressant treatment. In contrast, in patients with established bipolar illness, antidepressant drugs did increase the risk of mania, and the risk with tricyclic antidepressants was probably greater than that seen with selective serotonin re-uptake inhibitors (SSRIs). The authors concluded that the rate of antidepressantinduced hypomania and mania in major depression is within the rate of misdiagnosis Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29002-0 © 2007 Elsevier B.V. All rights reserved.
18
of bipolar depression as unipolar depression, and that depressed patients who experience antidepressant-induced hypomania are truly bipolar. However, this conclusion is somewhat circular, and if accepted would make it impossible to diagnose antidepressant-induced hypomania without also diagnosing bipolar illness. Longer-term follow-up studies will help show whether patients with antidepressantinduced hypomania also develop manic illness in circumstances other than exposure to antidepressant medications. However, the best way of resolving this issue would be to identify a genetic or other biological marker that distinguished bipolar subjects from those with unipolar illness. The ability of SSRIs apparently to induce mania in patients being treated for primary anxiety disorders is often taken as evidence that SSRIs can produce mania in people without an underlying latency for bipolar disorder. Such reactions may be more likely in children and adolescents (2A ). • An 11-year-old girl developed panic disorder and was treated with paroxetine 10 mg/day, increasing to 20 mg/day over 1 month, with good symptomatic resolution. She continued taking paroxetine for 1 year, when she rapidly developed insomnia, over-talkativeness, hyperactivity, and aggression. The dose of paroxetine was tapered and withdrawn and the manic symptoms settled; however, the anxiety symptoms re-appeared. Citalopram was then started, which relieved the anxiety symptoms with no recurrence of mania over 10 months.
This case shows the difficulty of assessing the role of antidepressants in the induction of mania in individual cases. Neither the patient nor her parents had a history of mood disorder, which suggests that she had no predisposition to bipolar illness. On the other hand, she had taken paroxetine for a year without developing mania, which suggests that if the paroxetine played a direct causal role it may have interacted over time with maturational factors. In
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Chapter 2
addition, citalopram was substituted for paroxetine without early recurrence of mania, which suggests either that paroxetine was not in fact responsible, or that there are differences between SSRIs in their liability to produce mania. This has not yet been established. Four children aged 6–15 years with anxiety and depressive conditions developed manic symptoms after taking citalopram for 1–4 weeks (3A ). In three cases the manic symptoms failed to resolve when citalopram was withdrawn, suggesting an underlying bipolar trait. However, in only one of these cases was there a family history of mood disorder. Overall, it seems sensible to regard all children and adolescents taking SSRIs as potentially at risk of experiencing manic switches, whether or not there is a family history of bipolar illness. Anxiety symptoms and other behavioral disturbances may be the presenting signs of early-onset bipolar disorder. There is also concern that the use of SSRIs in children with depression may not have a favorable benefit– harm balance (see SSRIs below).
MONOAMINE OXIDASE INHIBITORS (SED-15, 2371; SEDA-24,
reported increases in serum cholesterol concentrations produced by atypical antipsychotic drugs, such as olanzapine and clozapine. Raised cholesterol concentrations have also been reported in conjunction with the antidepressant drug, mirtazapine, which, like olanzapine and clozapine, blocks histamine H1 and 5-HT2 receptors. A striking increase in serum cholesterol was reported in 32-year-old woman during treatment with the tricyclic antidepressant, doxepin (5A ). When reboxetine was substituted for doxepin the cholesterol concentration returned to normal. Doxepin has particularly potent H1 receptor antagonist properties, which suggests that blockade of H1 receptors may play a role in the cholesterol raising properties of some psychotropic drugs. This effect may have implications for the association between the use of tricyclic antidepressants and an increased risk of myocardial infarction (SEDA-24, 12).
SELECTIVE SEROTONIN RE-UPTAKE INHIBITORS (SSRIs) (SED-15, 3109; SEDA-26, 11; SEDA-27, 12; SEDA-28, 15)
12) Drug overdose In contrast to conventional irreversible monoamine oxidase inhibitors (MAOIs), moclobemide, a reversible inhibitor of type A monoamine oxidase, is generally considered to be relatively safe in overdose (SEDA-28, 15). However, massive ingestion of moclobemide (over 30 g) appeared to be responsible for death in a suicide attempt in a 48-year-old man (4A ). The blood concentration of moclobemide measured at post mortem (498 µg/ml) was about 500 times the usual target concentration (0.2–2.1 µg/ml). Postmortem findings were non-specific, but the authors concluded that death might have been due to the 5-HT syndrome.
TRICYCLIC ANTIDEPRESSANTS (SED-15, 3489; SEDA-26, 11; SEDA-27, 11; SEDA-28, 15) Metabolism Interest in the metabolic effects of psychotropic drugs has been heightened by
SSRIs and suicidal behavior DoTS classification: Reaction: Suicide risk due to SSRIs Dose-relation: Collateral Time-course: Intermediate Susceptibility factors: Age (adolescents and children) The debate as to whether SSRIs are associated with an increased risk of suicidal behavior has continued (SEDA-28, 16). In a matched case-control, primary-care study of over 150 000 patients who received at least one prescription for an antidepressant between 1993 and 1999, in which dosulepin was used as the reference standard, there was no relative increased risk of non-fatal self-harm for fluoxetine (OR = 1.16; 95% CI = 0.90, 1.50), while the risk for paroxetine approached significance (OR = 1.29; 95% CI = 0.97, 1.70) (6C ). The authors suggested that the latter finding might have been due to uncontrolled confounding by
20 severity of depression or apparent suicide risk. In the small number of cases of fatal suicide there was no relation with any particular class of medication. However, the strong relation between the risk of suicidal behavior and the initiation of treatment was noteworthy; thus, in the first 9 days of treatment the risk of nonfatal suicidal behavior was increased four-fold over later weeks of therapy (OR = 4.07; 95% CI = 2.89, 5.74), while for fatal suicide the risk was over 30 times greater (OR = 38; 95% CI = 6, 231). This relation was independent of the class of medication prescribed. These findings suggest that in the routine clinical management of depression in primary care, the risk of self-harm is not strongly associated with any particular class of antidepressant. In the absence of a placebo group we cannot say whether antidepressants might increase the risk of self-harm relative to placebo; conceivably, of course, they might reduce it. However, it does seem clear that there is a strong link between initiation of antidepressant drug treatment and both fatal and non-fatal self-harm. This fits in with the well-known clinical impression that the start of antidepressant treatment is a time of increased risk of suicidal behavior (7R ). There are several possible explanations for this phenomenon; for example, (i) antidepressant treatment increases the risk of suicidal behavior directly; (ii) antidepressants improve motor retardation before alleviating depressed mood, thereby increasing the probability that patients will act on their pre-existing suicidal thinking; (iii) patients only present for treatment when they are at a particularly low ebb, and the failure of antidepressant medication to have a quick onset of action adds to feelings of hopelessness and despair. Whatever the explanation, it is clearly prudent to monitor depressed patients closely during the first few weeks of treatment, while mood is still low and suicidal feelings have not resolved. The UK Committee of Safety of Medicines has previously warned that paroxetine appeared to be no more effective than placebo in the treatment of depression in adolescents and might be associated with a greater risk of self harm (SEDA-28, 16). In a meta-analysis of both published and unpublished placebocontrolled trials of SSRIs in childhood and adolescent depression, only fluoxetine seemed clearly to be associated with a positive benefit– harm balance (8M ). The evidence of efficacy for
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P.J. Cowen
sertraline and citalopram was doubtful, while the risk of serious adverse events was significantly increased. Additionally, for both drugs the risk of suicidal behavior was numerically increased. In regard to venlafaxine, the risk of suicidal behavior was significantly greater than placebo. Subsequently, the UK Committee on Safety of Medicines issued guidance for practitioners, indicating that with the exception of fluoxetine, the benefit–harm balance of SSRIs and venlafaxine in depressed children and adolescents was unfavorable (9S ). A similar conclusion was drawn concerning mirtazapine. It is, however, puzzling that the therapeutic effects of fluoxetine should be quite so different from compounds that are similar pharmacologically. One important issue might be the relevance of regulatory trials of antidepressants to realworld treatment. Placebo-controlled trials in depression often exclude the more depressed patients as well as those with worrying suicidal ideation. Hence, it may be more difficult to show a specific benefit of a drug. However, the meta-analysis cited above (8M ) also suggested that young people might be more susceptible than adults to any effect of antidepressants to induce suicidal ideation. SSRIs are also used in adolescents to treat anxiety disorders, such as obsessive–compulsive disorder. Whether the risk of suicidal behavior with SSRIs is also increased in this group is uncertain, but clearly caution is indicated. Another large systematic review was carried out by the UK Medicines Control Agency (MCA), focusing on all published and unpublished regulatory trials of SSRIs in depressed patients aged 18 and over (10M ). The MCA found no evidence that, relative to placebo, any individual SSRI increased the risk of fatal or non-fatal self-harm, but they concluded that “a modest increase in the risk of suicidal thoughts and self-harm for SSRIs compared with placebo cannot be ruled out”. There was also no evidence from epidemiological studies that the prescribing of SSRIs had led to an increase in suicide rate, although such studies are difficult to interpret, because suicide rates are affected by many factors that are likely to have a greater impact than antidepressants. Overall the data provided by the MCA and published subsequently suggest that in people aged 18 years and older, SSRIs do not increase the risk of completed suicide relative to
Antidepressant drugs
Chapter 2
placebo. In addition, there is no difference in the risk of suicide or self-harm in patients taking SSRIs compared with those taking tricyclic antidepressants (11A ). It is possible, however, that when all the data for individual SSRIs are combined, SSRIs as a group might produce a small increase in the risk of self-harm relative to placebo (12M , 13M ). It has been calculated that, if this is the case, on the present evidence the number needed to treat for harm (NNTH , i.e. to produce one suicide attempt) is 759; this contrasts with the much more favorable number need to treat for benefit (NNTB ) in depression, which is 4–7 (12M ). Thus, particularly in patients with significant depressive symptoms and functional disability, the benefit–harm balance of SSRIs appears to be favorable. It is also worth noting that the possible increase in the risk of self-harm appears to be similar between tricyclic antidepressants and SSRIs, suggesting that any putative mechanism is likely to be common to all antidepressant medications. Electrolyte balance SSRIs are associated with hyponatremia (SEDA-21, 25), particularly in elderly patients, although there have been few reports with citalopram. • An 89-year-old man, who was taking aspirin 325 mg/day, clopidogrel 75 mg/day, atenolol 25 mg/day, and lansoprazole 30 mg/day, developed depression and was given citalopram 20 mg/day (14A ). His depressive symptoms started to improve, but after 12 days he developed malaise, nausea, and headache. His serum sodium concentration had fallen from 138 mmol/l before citalopram to 117 mmol/l. This was due to inappropriate secretion of antidiuretic hormone. Citalopram was withdrawn, he was given intravenous saline, and 72 hours later his serum sodium was normal and his symptoms of malaise, nausea, and headache had resolved. However, his depressive symptoms worsened, so citalopram (20 mg/day) was restarted with close monitoring of the serum sodium. Within 2 days his serum sodium had fallen to 126 mmol/l. Citalopram was withdrawn and mirtazapine was used as an alternative antidepressant with good effect and without any reduction in serum sodium.
This is an unusually well documented case, in which re-challenge clearly established the role of citalopram in causing hyponatremia in this patient. In a prospective study of serum sodium concentrations in 75 men and women (aged 36–90 years) who received paroxetine for the treatment of depression, hyponatremia (defined
21 as a serum sodium concentration of less than 135 mmol/l) developed in 12% within a median of 9 days of paroxetine treatment (15C ). The effect did not seem to be related to plasma concentrations of paroxetine, but lower baseline serum sodium concentrations and low body weight were risk factors for hyponatremia. In fact the authors’ data showed that in most patients, paroxetine lowered serum sodium concentrations to some extent, but in a subgroup the effect was greater. Presumably patients who start treatment with lower baseline values of serum sodium are at more risk of reaching a sodium concentration at which symptoms will occur. In animals, serotonin agents can release ADH (16E ), which might provide an explanation for the ability of SSRIs to lower plasma sodium in humans. Liver There are rare reports of hepatotoxicity in association with fluoxetine, paroxetine, and sertraline (SEDA-28, 17). A similar case has been reported in association with citalopram (17A ). • A 44-year-old man with depression was given hydroxyzine hydrochloride 100 mg/day, clonazepam 2 mg/day, and citalopram 20 mg/day. Two years before he had tolerated fluoxetine for 6 months for an episode of depression, with good effect. After 7 weeks he developed weakness and weight loss. Physical examination was normal but the serum aspartate transaminase (AsT) was raised at 277 IU/L (reference range < 36 IU/l). His bilirubin was normal. Citalopram was withdrawn and the other drugs were continued intermittently; 5 days later the serum aspartate transaminase had fallen by a half, and within 2 months it had returned to normal.
The time course of the raised aspartate transaminase and its resolution in response to citalopram withdrawal suggests that citalopram was responsible for the hepatic damage in this case. The earlier exposure to fluoxetine did not apparently cause liver damage, suggesting that the response to citalopram did not involve blockade of serotonin re-uptake. Sexual function In adults SSRIs can cause a range of sexual dysfunctions, including diminished sexual interest, erectile failure, and anorgasmia (SEDA-23, 24). In a chart review of 22 adolescents who were taking SSRIs for a variety of indications and who had been systematically questioned about the effect of their illness
22 and its treatment on their sexual function, five reported significant sexual dysfunction (three cases of anorgasmia, and two of reduced libido), probably attributable to the SSRI (18c ). This small sample suggests that the rate of sexual dysfunction associated with SSRI treatment in adolescents is very similar to that seen in adults. Issues of sexuality are particularly important in adolescence, but may be difficult to discuss. This study shows the importance of tactful and sensitive enquiry and the probable benefit of clear information about the sexual adverse effects of SSRIs. Lactation The safety of breast feeding for the infants of mothers taking SSRIs continues to be discussed (SEDA-26, 14; SEDA-28, 17). In a prospective study of 31 nursing mothers who were taking citalopram for the treatment of depression, and 31 matched, healthy breastfeeding women, the mothers taking citalopram treatment did not report a significant excess of adverse effects in their infants (19A ). A further prospective study in 27 mothers who took paroxetine while breast feeding included two control groups: (i) 19 women who did not take any medication and did not breast feed; (ii) 27 mothers who breast-fed their infants but did not take any medications (20A ). Information about the infants was gathered from the mothers, who completed a detailed questionnaire at 3 months and 1 year post-partum. There were no significant differences between the infants in terms of weight gain or developmental milestones. These data are reassuring, but the studies, although prospective, were not large. The current data suggest that SSRIs are unlikely to produce overt effects on infant development; however, subtle effects on neurological and psychological development are hard to exclude (21r ). Drug overdose Venlafaxine appears to be more likely than SSRIs to be associated with seizures in overdose (SEDA-28, 20) (22A ). In 225 patients who had taken overdoses of antidepressant drugs in suicide attempts, venlafaxine and citalopram were more likely to be associated with seizures than mirtazapine and nefazodone and 5-HT toxicity was more common after overdose of venlafaxine. These findings confirm the potential toxicity of venlafaxine in overdose and also suggest a proconvulsant effect of large doses of citalopram.
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Drug interactions Haloperidol Fluvoxamine has little inhibitory effect on CYP2D6 but is a potent inhibitor of CYP1A2 and CYP2C19. It also is a moderate inhibitor of CYP3A4, which is involved in the metabolism of haloperidol. When fluvoxamine (25, 75, and 150 mg/day, each for 2 weeks) was added to haloperidol in 12 patients with schizophrenia aged 22–59 years, plasma haloperidol concentrations rose dose-relatedly; after fluvoxamine 25 mg/day haloperidol concentrations rose by about 20%, with additional 20% increases with each increment in fluvoxamine dose; however, this was not associated with overt clinical toxicity (23C ). Linezolid SSRIs can provoke 5-HT neurotoxicity (the 5-HT syndrome) through pharmacodynamic interactions with other drugs that also potentiate 5-HT function. Often the ability of the interacting drug to facilitate 5-HT function is well known, as is the case, for example, when SSRIs are combined with monoamine oxidase inhibitors or lithium. In other cases, however, the potential 5-HT activity of the coadministered drug is not widely known. The ability of the antibiotic linezolid to inhibit MAO and thereby to cause 5-HT neurotoxicity in combination with SSRIs has been noted previously (SEDA-27, 14), and further cases have now been reported. • An 85-year-old woman with an oxacillin-resistant Staphylococcus aureus infection took oral linezolid (24A ). She had been taking long-term citalopram maintenance treatment for depression. Shortly afterwards she developed a worsening tremor and became restless and confused. She had dysarthria and hyper-reflexia, with impaired gait. Citalopram was withdrawn, and her mental status and neurological signs returned to baseline within two days. • A four-year-old girl took fluoxetine for symptoms of post-traumatic stress disorder after a severe burn injury and 2 days after the addition of linezolid developed agitation, mydriasis, and abnormal movements in her limbs (25A ). Linezolid was withdrawn, and the symptoms resolved after 2 days.
The signs of 5-HT neurotoxicity can be sometimes rather non-specific, as in this case, and a high index of suspicion may be needed when SSRIs are used in drug combinations of which there is little previous experience.
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Risperidone SSRIs are often prescribed with antipsychotic drugs, and some SSRIs inhibit CYP2D6, which can lead to increased blood concentrations of the antipsychotic drug. In 13 patients aged 26–56 years with schizophrenia, stabilized on risperidone 4–6 mg/day who took sertraline 50 mg/day for 4 weeks, plasma concentrations of risperidone and its major metabolite, 9-OH-risperidone, did not change (26C ). Over the next 4 week, four patients continued to take sertraline 50 mg/day, while in the others the dose was increased at the discretion of the treating clinician. In patients taking sertraline 100 mg/day there was a small but non-significant increase in plasma risperidone concentrations. However, in two patients who took sertraline 150 mg/day, plasma risperidone concentrations increased by about 50%. Sertraline is a modest inhibitor of CYP2D6 compared with fluoxetine or paroxetine. This study supports the view that at doses under 100 mg/day sertraline is unlikely to produce significant pharmacokinetic interactions through CYP2D6 inhibition; however, at higher doses such interactions become increasingly likely. Tizanidine Fluvoxamine 100 mg/day resulted in a large (about 30-fold) increase in plasma concentrations of tizanidine in 10 healthy volunteers (27C ). This interaction caused significant physiological consequences, including a substantial fall in systolic blood pressure, perhaps because tizanidine is an α 2 -adrenoceptor agonist. The authors suggested that the interaction was likely to be due to fluvoxaminemediated inhibition of CYP3A4, which is involved in the metabolism of tizanidine. Tramadol Tramadol has some activity in blocking the re-uptake of 5-HT and can also cause 5-HT neurotoxicity in combination with SSRIs. • A 70-year-old woman, who had been taking citalopram 10 mg/day for 3 years for depression, began taking tramadol 50 mg/day) for pain relief and rapidly developed tremor, restlessness, fever, and confusion (28A ). The symptoms settled after tramadol was withdrawn. The same symptoms recurred 1 year later, when tramadol 20 mg/day was added to the citalopram. Genotyping for functional polymorphisms in CYP2D6 and CYP2C19 showed that she was heterozygous for alleles causing deficient activity in both these metabolizing enzymes. Consistent with this she had reduced clearance of citalopram, presumably due to CYP2C19 deficiency.
The simultaneous use of tramadol and SSRIs is probably not uncommon in clinical practice, and it is therefore likely that some patients can take this combination without developing 5-HT toxicity. When symptoms of the 5-HT syndrome develop it may be that, as in this case, that there is a factor in the individual patient that increases the risk.
SEROTONIN AND NORADRENALINE RE-UPTAKE INHIBITORS (SNRIs) Duloxetine Duloxetine has recently been marketed as an antidepressant in Europe. It inhibits the reuptake of serotonin and noradrenaline, with minimal effects on other neurotransmitter mechanisms. It is therefore classified as a serotonin and noradrenaline re-uptake inhibitor (SNRI) and is grouped with venlafaxine. The adverse effect profile of duloxetine appears to be similar to that of the SSRIs and venlafaxine. In placebo-controlled trials the most common adverse effects were nausea (37%), dry mouth (32%), dizziness (22%), somnolence (20%), insomnia (20%), and diarrhea (14%). Sexual dysfunction has also been reported. Current data suggest that, unlike venlafaxine, duloxetine does not increase the blood pressure, but further post-marketing surveillance studies will be needed to confirm this (29R ). Drug withdrawal Like venlafaxine and the SSRIs, acute withdrawal of duloxetine causes a characteristic abstinence syndrome, with tachycardia, dizziness, insomnia, headache, and anxiety. Drug interactions Duloxetine is metabolized by CYP2D6, the activity of which it inhibits to a moderate extent. Caution is therefore needed when duloxetine is co-prescribed with other drugs that are substrates of this enzyme. Duloxetine is also partly metabolized by CYP1A2, so blood concentrations of duloxetine might be increased by co-prescription of potent inhibitors of CYP1A2 (29R ).
24
Venlafaxine (SED-15, 3614; SEDA-26, 16; SEDA-27, 16; SEDA-28, 19) Drug overdose Venlafaxine may be more toxic in overdose than SSRIs. In a survey of Coroners in England and Wales of antidepressant-related deaths between 1998 and 2000, the numbers of expected and observed deaths were computed for each antidepressant using prescription frequency data to yield a standardized mortality ratio (30C ). The highest mortality ratios, as expected, were found with the conventional tricyclic antidepressants, amitriptyline and dosulepin (1.8 and 1.7 respectively). The corresponding ratios for SSRIs were substantially lower (between 0.1 and 0.3). However, the value for venlafaxine was 1.6, very similar to that of tricyclics. This study supports previous findings that suggested that venlafaxine may be significantly more toxic in overdose than SSRIs. However, these data need to be interpreted cautiously. Venlafaxine tends to be prescribed for patients with treatment-resistant depression. Such patients may be more likely to make suicide attempts and also to take their antidepressant medication in combination with other psychotropic drugs (for example, antipsychotic drugs), which may themselves be toxic in overdose. Further epidemiological data will be needed to resolve these uncertainties. In the meantime, the UK Committee on Safety of Medicines has restricted the prescription of venlafaxine to patients who have failed to respond to at least two other antidepressant agents and has required that a baseline electrocardiogram be carried out before treatment is begun. In addition, venlafaxine is now contraindicated in patients with evidence of cardiovascular disease or electrolyte imbalance (31S ), although the matter is still under review. Drug interactions Tramadol As noted above, the analgesic drug tramadol can cause 5-HT toxicity in association with SSRIs. Venlafaxine is also a potent reuptake inhibitor, and perhaps not surprisingly has been reported to cause features of the 5-HT syndrome in a patient taking tramadol (32A ). • A 47-year-old man with a long history of depression had been stable on a combination of venlafaxine 300 mg/day and mirtazapine 30 mg/day
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for 3 months. He started to take tramadol for a chronic pain syndrome and the dose was titrated up to 300 mg/day over the next 4 weeks. The dose was then increased to 400 mg/day, and 8 days later he developed shivering, sweating, myoclonus, hyper-reflexia, and mydriasis. His medications were withdrawn, but over the next 4 hours he developed a fever (39.2 ◦ C) and a tachycardia. He was given intravenous hydration and closely monitored, and the symptoms resolved over the next 36 hours. Venlafaxine and mirtazapine were restarted and he remained symptom free.
In this case the 5-HT toxicity produced by tramadol may have been dose-related within the therapeutic range, because it did not become apparent until the dose had reached 400 mg/day. It is of interest that the 5-HT syndrome developed despite the fact that the patient was taking mirtazapine, which is a potent 5-HT2 receptor antagonist. 5-HT2 receptor antagonists have been suggested for the treatment of druginduced 5-HT toxicity. However, activation of postsynaptic 5-HT1A receptors has also been implicated in the development of the 5-HT syndrome, which presumably may have been the mechanism here.
OTHER ANTIDEPRESSANTS Amfebutamone (bupropion) (SED-15, 108; SEDA-26, 15; SEDA-27, 14; SEDA-28, 18) Sexual function In contrast to SSRIs, amfebutamone is believed to have minimal effect on sexual function (SEDA-23, 20). • A 36-year-old man took amfebutamone 150 mg/ day as part of a smoking cessation program and soon complained of complete anorgasmia; sexual desire and arousal were preserved (33A ). Amfebutamone was withdrawn and the sexual dysfunction resolved within 3 days.
Anorgasmia is a sexual adverse effect typically seen with SSRIs. However, this case report suggests that rarely amfebutamone can produce a similar effect. Immunologic Amfebutamone has been associated with a variety of generalized sensitivity reactions (SEDA-27, 28), including a serum sickness-like reaction in an adolescent.
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• A 17-year-old boy took amfebutamone (dose unstated) for attention deficit disorder and 1 week later developed a generalized pruritic rash, but continued to take amfebutamone (34A ). After a further week he presented as an emergency with large joint tenderness and joint swelling. A punch biopsy of a skin lesion showed urticaria with vasculitis. Amfebutamone was withdrawn and a single dose of methylprednisolone sodium succinate was given. His symptoms resolved completely within 36 hours.
This report suggests the advisability of asking patients taking amfebutamone to report the development of any rash immediately. Drug interactions Antidepressants The immediate-release form of amfebutamone may be associated with a higher risk of seizures than other antidepressant drugs, but the risk with the modified-release formulation is believed to be about the same as SSRIs (SEDA-23, 27). • A 28-year-old woman with schizophrenia taking risperidone 4 mg/day and clomipramine 25 mg/ day started to take modified-release amfebutamone for depressive symptoms 150 mg/day initially and 1 month later 300 mg/day; 1 week after this she had a generalized tonic–clonic seizure with unconsciousness (35A ). The amfebutamone was withdrawn, but she had a similar seizure 3 days later, after which the clomipramine was changed to sertraline. Following this no further seizures occurred. However, epileptic discharges on the electroencephalogram, which had previously been normal, continued for another month, after which she was given valproate.
As in many cases of seizures associated with amfebutamone, there were other risk factors in this case, in particular the use of other psychotropic drugs known to lower the seizure threshold. The dose of clomipramine was low, but amfebutamone may have some inhibitory effect on CYP2D6, which is involved in the metabolism of tertiary tricyclics such as clomipramine. The persistent electroencephalographic abnormalities also suggested that the patient had an underlying vulnerability to seizure disorder although an earlier electroencephalogram had been normal. In general, it seems prudent to avoid the use of even low doses of tricyclic antidepressants in combination with amfebutamone. However, the combination of SSRIs and amfebutamone is quite widely used in the USA in the treatment of resistant depression (36A ).
Metoprolol A possible inhibitory effect of amfebutamone on CYP2D6 was used to explain an episode of severe bradycardia in a man taking the β-adrenoceptor antagonist, metoprolol (37A ). • A 56-year-old man taking metoprolol 75 mg/day for hypertension developed fatigue and dyspnea 12 days after starting to take amfebutamone 300 mg/day to help smoking cessation. His heart rate was 43/minute and his blood pressure 102/65 mmHg. His chest X-ray showed evidence of mild congestive cardiac failure and an electrocardiogram showed an atrial rate of 40/minute together with a junctional escape rhythm of 43/ minute. All medications were withheld and the next morning he was asymptomatic and in sinus rhythm. Metoprolol was then restarted and he remained asymptomatic after 1 month of follow up.
Although metoprolol concentrations were not measured in this patient it seems likely that they were increased by co-administration of amfebutamone.
Trazodone
(SED-15, 3481; SEDA-28, 19)
Drug interactions SSRIs Trazodone is commonly used as a hypnotic in patients taking non-sedating antidepressants, particularly SSRIs (38C ). It is believed to have a fairly wide safety margin, but the effects of SSRIs on its pharmacokinetics have not been widely studied. In 97 patients, mean age 40 years, 40 of whom took trazodone as monotherapy, 41 trazodone + citalopram, and 16 trazodone + fluoxetine, there were no differences in plasma concentrations of trazodone between the three treatment groups and no significant adverse effects as a result of the combinations (39C ). The authors concluded that trazodone has a wide safety margin in combination with SSRIs, perhaps because it is metabolized mainly by CYP3A4. However, if that is the case, combination with fluvoxamine may be more problematic (see SSRIs above). In addition, the active metabolite of trazodone, m-chlorophenylpiperazine, a 5-HT receptor agonist, is a substrate for CYP2D6, which raises the possibility that its concentrations may be increased when trazodone is combined with fluoxetine or paroxetine. In addition, there have been occasional case reports of signs of 5-HT
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toxicity when trazodone has been combined with SSRIs.
References 1. Chun BJ, Dunner DL. A review of antidepressant-induced hypomania in major depression: suggestions for DSM-V. Bipolar Disord 2004;6:32–42. 2. Sharkey L, O’Donovan A. Paroxetine induced mania in pre-adolescence. Ir J Psychol Med 2004;21:30–1. 3. Pravin D, Srinath S, Girimaji S, Seshadri SP. Citalopram and mania. J Am Acad Child Adolesc Psychiatry 2004;43:791. 4. Giroud C, Horisberger B, Eap C, Augsburger M, Menetrey A, Baumann P, Mangin P. Death following acute poisoning by moclobemide. Forensic Sci Int 2004;140:101–7. 5. Roessner MD, Demling J, Bleich S. Doxepin increases serum cholesterol levels. Can J Psychiatry 2004;49:74–5. 6. Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. JAMA 2004;292:338–43. 7. Slater E, Roth M. Clinical Psychiatry. 3rd ed. London: Baillère Tindall; 1977. 8. Whittington CJ, Kendall T, Cottrell D, Cotgrove A, Boddington E. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet 2004;363:1341–5. 9. Committee on Safety of Medicines. Selective Serotonin Reuptake Inhibitors (SSRIs): overview of regulatory status and CSM advice relating to major depressive disorder (MDD) in children and adolescents including a summary of available safety and efficacy data. http://medicines. mhra.gov.uk/ourwork/monitorsafequalmed/ safetymessages/ssrioverview_101203.htm. Updated 8.10.2004. 10. Medicines Control Agency. Report of the CSM Expert Working Group on the Safety of Selective Serotonin Reuptake Inhibitor Antidepressants. http://medicines.mhra.gov.uk/ourwork/ monitorsafequalmed/safetymessages/ssrifinal. pfd, 31.12.2004. 11. Martinez C, Rietbrock S, Wise L, Ashby D, Chick J, Moseley J, Evans S, Gunnell D. Antidepressant treatment and the risk of fatal and non-fatal self harm in first episode depression: nested case-control study. BMJ 2005;330:389– 95. 12. Gunnell DJ, Saperia J, Ashby D. Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: meta-analysis of drug company data from placebo controlled, randomised controlled trials
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submitted to the MHRA’s safety review. BMJ 2005;330:385–9. Fergusson D, Doucette C, Glass KC, Shapiro S, Healy D, Hebert P, Hutton B. Association between suicide attempts and selective serotonin reuptake inhibitors: systematic and randomised controlled trials. BMJ 2005;330:396–402. Iraqi A, Baickle E. A case report of hyponatremia with citalopram use. J Am Med Directors Assoc 2004;5:64–5. Fabian TJ, Amico JA, Kroboth PD, Mulsant BH, Corey SE, Begley AE, Bensasi SG, Weber E, Dew MA, Reynolds CF, Pollock BG. Paroxetine induced hyponatremia in older adults. Arch Intern Med 2004;164:327–32. Carrasco GA, Van De Kar LD. Neuroendocrine pharmacology of stress. Eur J Pharmacol 2003;463:275–82. Lopez-Torres E, Lucena MI, Seoane J, Verge C, Andrade RJ. Hepatoxicity related to citalopram. Am J Psychiatry 2004;161:923–4. Scharko AM, Reiner S. SSRI-induced sexual dysfunction in adolescents. J Am Acad Child Adolesc Psychiatry 2004;43:1067–8. Lee A, Woo J, Ito S. Frequency of infant adverse events that are associated with citalopram use during breast-feeding. Am J Obstet Gynaecol 2003;190:218–21. Merlob P, Stahl B, Sulkes J. Paroxetine during breast-feeding: infant weight gain and maternal adherence to counsel. Eur J Pediatr 2004;163:135–9. de Vries TW, de Jong-van de Berg LTW, Hadders-Algra M. Paroxetine during lactation: is it really safe for the infant? Acta Paediatr 2004;93:1406–7. Kelly CA, Dhaun N, Laing WJ, Strachan FE, Good AM, Bateman DN. Comparative toxicity of citalopram and the newer antidepressants after overdose. J Toxicol 2004;42:67–71. Yasui-Furukori N, Kondo T, Mihara K, Inoue Y, Kaneko S. Fluvoxamine dose-dependent interaction and the effects on negative symptoms in schizophrenia. Psychopharmacology 2004;171:223–7. Tahir N. Serotonin syndrome as consequence drug resistant infections: an interaction between linezolid and citalopram. J Am Med Directors Assoc 2004;5:111–3. Thomas CR, Rosenberg M, Blythe V, Meyer WJ. Serotonin syndrome and linezolid. J Am Acad Child Adolesc Psychiatry 2004;43:790.
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26. Spina E, D’Arrigo C, Miglardi G, Morgante L, Zoccali R, Ancione M, Madia A. Plasma risperidone concentrations during combined treatment with sertraline. Ther Drug Monit 2004;26:386– 90. 27. Granfors MT, Backmann JT, Neuvonen M, Ahonen J, Neuvonen PJ. Fluvoxamine drastically increases concentrations and effects of tizanidine: a potentially hazardous interaction. Am Soc Clin Pharmacol Ther 2004;75:331–41. 28. Mahlberg R, Kunz D, Sasse J, Kirchheiner J. Serotonin syndrome with tramadol and citalopram. Am J Psychiatry 2004;161:1129. 29. Cowen PJ, Ogilvie AD, Gama J. Efficacy, safety and tolerability of duloxetine 60 mg once daily in major depression. Curr Med Res Opin 2005;3:345–55. 30. Cheeta S, Schifano F, Oyefeso A, Webb L, Ghodse AH. Antidepressant-related deaths and antidepressant prescriptions in England and Wales, 1998–2000. Br J Psychiatry 2004;184:41–7. 31. Chief Medical Officer. Safety of Selective Serotonin Re-uptake Inhibitor Antidepressants. CEM/CMO/2004/11. 32. Houlihan DJ. Serotonin syndrome resulting from coadministration of tramadol, venlafaxine and mirtazapine. Ann Pharmacother 2004;38:411–3.
27 33. Martinez-Raga J, Sabater A, Cervera G. Anorgasmia in a patient treated with bupropion SR. J Clin Psychopharmacol 2004;24:460–1. 34. Waibel KH, Katial RR. Serum sickness- like reaction and bupropion. J Am Acad Child Adolesc 2004;43:509. 35. Shin YW, Erm TM, Choi EJ, Kim SY. A case of prolonged seizure activity after combined use of bupropion and clomipramine. Clin Neuropharmacol 2004;27:192–4. 36. Lam RW, Hossie H, Solomons K, Yatham LN. Citalopram and bupropion-SR: combining versus switching in patients with treatment-resistant depression. J Clin Psychiatry 2004;65:337–40. 37. McCollum DL, Greene JL, McGuire DK. Severe sinus bradycardia after initiation of bupropion therapy: a probable drug–drug interaction with metoprolol. Cardiovasc Drugs Ther 2004;18:329–30. 38. Kaynak H, Kaynack D, Gozukirmizi E, Guilleminault C. The effects of trazodone on sleep in patients treated with stimulant antidepressants. Sleep Med 2004;5:15–20. 39. Propotnik M, Waschgler R, Konig P, Moll W, Conca A. Therapeutic drug monitoring of trazodone: are there pharmacokinetic interactions involving citalopram and fluoxetine? Int J Clin Pharmacol Ther 2004;42:120–4.
David L. Dunner
3
Lithium
The molecular effects of lithium have been reviewed (1R ). Its direct targets include inositol monophosphatase, inositol polyphosphate 1phosphatase, biophosphate nucleotidase, fructose 1, 6-biophosphatase, phosphoglucomutase, and glycogen synthase kinase-3. These enzymes are largely phosphomonoesterases, which are magnesium-dependent. Lithium also has effects on adenylate cyclase, arachidonic acid, and myristoylated alanine-rich C kinase substrate (MARCKS). MARCKS is a presynaptic and postsynaptic protein that affects cellular signalling and cytoskeletal plasticity, and its expression is regulated by lithium (2R ). During 2004 a number of clinical trials were reported involving acute and maintenance studies of lithium, mostly either comparing new atypical antipsychotic drugs with lithium in bipolar disorder or in combined treatment studies. Of the relatively few studies of the adverse effects of lithium, most clustered in the areas of cardiovascular effects and issues regarding lithium toxicity.
Comparative studies
Placebo-controlled studies In a review of five randomized controlled trials of prevention of relapse in 770 patients with bipolar affective disorder, lithium has been compared with placebo (3M ). Lithium was more effective than placebo in preventing all relapses and manic relapses, but the effect on depressive relapses was not as impressive and was termed “equivocal” by the authors. This is not particularly new information, although several of the studies that were included in this metaanalysis were more recent and the analysis was presented as odds ratios rather than episode frequency.
Lithium versus lamotrigine The role of lamotrigine in the treatment of bipolar disorder has been reviewed, and combination therapy with lamotrigine plus other mood stabilizers, including lithium, has been particularly discussed (5R ). Lamotrigine has a favorable tolerability profile compared with lithium, but lithium has better antimanic effects than lamotrigine, which exerts its antidepressant effects sooner than lithium.
Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29003-2 © 2007 Elsevier B.V. All rights reserved.
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Lithium versus divalproex In an open study of 37 patients aged 5–18 years with a current manic or mixed episode, who were treated for 6 months with either divalproex sodium plus risperidone or lithium plus risperidone, lithium was given in a dose of 10–30 mg/kg/day, beginning with a single dose of 150 mg or 300 mg, and gradually increasing the dose to produce a plasma concentration in the usual target range (4c ). About 80% of patients responded in each group and over 60% of patients “remitted.” Adverse effects were similar in the two groups over the 6-month treatment period, and included weight gain, sedation, nausea, increased appetite, stomach pain, tremor, and cognitive dulling. Three of 17 patients taking lithium plus risperidone developed polyuria compared with none of those taking divalproex sodium plus risperidone. Two of 20 patients taking divalproex sodium plus risperidone developed galactorrhea compared with none of those taking lithium plus risperidone.
Lithium versus valproate Lithium plus risperidone (n = 33) has been compared with valproate plus risperidone (n = 46) in the acute and continuation treatment of mania (6C ). Both groups were initially studied during a bout of mania, and both groups improved without a significant difference in response rate between the two groups. At week 12, 88% of the patients taking lithium plus risperidone and 80%
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Chapter 3
of those taking valproate plus risperidone were in remission. There were no differences in adverse effects. The major findings of this study suggested that risperidone could be combined with either lithium or valproate and that efficacy was similar, independent of which mood stabilizer was used. The dose of risperidone was 0.5–6.0 mg/day, with a mean of 1.7 mg/day in the lithium group and 2.2 mg/day in the valproate group. The Bipolar Affective Disorder: Lithium/ Anticonvulsant Evaluation (BALANCE) Study is now under way. It involves combination therapy with either lithium 400 mg/day plus valproate 500 mg/day or double those doses and then randomization to double-blind treatment with lithium plus valproate placebo, lithium plus valproate, or valproate plus lithium placebo. The study involves patients with bipolar I affective disorder who require maintenance treatment, and the randomization phase is scheduled to last 2 years, with the initial intention of randomizing 3000 patients. The start-up phase, which was designed to refine the trial design and procedures, has been reported as a pilot study in 30 patients (7c ). The main findings were that the combination of lithium plus valproate was tolerable and the results suggested that an initial open design would enhance patient flow. Also, the targeted sample size was revised to about 1068 patients based on the data from the pilot study. Quetiapine has been approved by the FDA as monotherapy for the treatment of acute mania. Quetiapine has been evaluated in combination with lithium or divalproex in 191 patients who had been recently manic (8C ). After treatment with quetiapine plus lithium or divalproex for 7–28 days, the patients were randomized to either additional quetiapine or placebo and followed for 3 weeks more. Early discontinuation was more frequent in the placebo group than in the quetiapine group. The intention-totreat population included 81 taking quetiapine and 89 taking placebo. The mean dose during the last week in patients taking quetiapine was 504 mg/day. Patients taking quetiapine had a greater improvement in their Young Mania Rating Scale score (YMRS) than patients taking placebo. The response rate (50% or greater improvement from baseline using the YMRS) was significantly higher in the group with added quetiapine than added placebo. Common adverse events included somnolence, dry mouth,
weakness, and postural hypotension. The authors concluded that quetiapine was a useful adjunct to treat mania in combination with standard measures and that it was well tolerated. Lithium versus psychotherapy Psychodynamic supportive psychotherapy (n = 107) has been compared with psychotherapy plus medication (n = 101) in patients with major depressive disorder (9C ). The medications included venlafaxine, selective serotonin reuptake inhibitors, nortriptyline, and nortriptyline plus lithium. Lithium was used as an augmentation strategy in the patients who took lithium and nortriptyline (number not given). There were no differences in outcomes between the two treatment groups. No adverse effects specific to lithium were reported. Observational studies The diagnosis of bipolar affective disorder, including the bipolar spectrum, co-morbidity of bipolar disorder, issues of bipolar disorder in children and adolescence, and the pathophysiology of bipolar disorder have been reviewed in relation to neuroimaging studies (10R ). These imaging studies include Positron Emission Tomography (PET) studies, functional MRI, Single Photon Emission Computed Tomography (SPECT), and Magnetic Resonance Spectroscopy (MRS). They point to abnormalities in the brains of patients with bipolar disorder. The reviewer noted the effects of mood stabilizers, including lithium, and hypothesized that the lines of evidence regarding efficacy of lithium and other mood stabilizers, along with biological evidence, point to defects in the cell related to memory dysfunction. Various “alternative” treatments and their possible effects on stabilization of bipolar disorder were also reviewed. Cardiovascular Blood pressure There is a higher mortality from cardiovascular diseases among patients with bipolar affective disorder than in the general population. In a study of 81 patients taking lithium monotherapy, 40 were studied in detail; one had hypothyroidism and six had hypertension (11R ). Of the 81 patients 13 were taking antihypertensive drugs, suggesting a high prevalence of hypertension. One of the points of the study was to assess if lithium was a factor in cardiovascular risk in these patients, but
30 there was no correlation between the duration of lithium treatment or the duration of bipolar disorder and the presence of hypertension. Two patients who were taking lithium carbonate for mood disorders and who underwent coronary artery bypass grafting developed refractory hypotension during cardiac surgery, which responded to methylthioninium chloride (12A ). The authors suspected that chronic lithium therapy had caused cardiac embarrassment and recommended that lithium be withdrawn before cardiac surgery. Dysrhythmias Sudden death has been reported in 14 psychiatric patients and the literature has been reviewed regarding occult cardiac problems, psychotropic drugs, and sudden death (13A ). • A 57-year-old man with bipolar disorder taking olanzapine, lithium, and other drugs had underlying mitral valve prolapse, left ventricular hypertrophy, and His bundle anomalies; he died suddenly, probably because of a cardiac dysrhythmia.
The authors suggested that cardiac pathology should be systematically evaluated in patients who take psychotropic drugs. Cases of lithium toxicity, its cardiac effects, and issues of cardiac dysfunction in children have been reviewed in the light of a cardiac dysrhythmia in a child. • A 10-year-old boy developed abdominal pain, diarrhea, and vomiting over 2 days (14A ). He had a history of bipolar disorder, with psychotic features, a schizoaffective disorder, an intermittent explosive disorder, and attention deficit hyperactivity disorder. He had several other medical problems, including hypothyroidism, asthma, and seizures. He was taking many drugs, including methylphenidate, escitalopram, oxcarbazepine, clonidine, Depakote, thyroid hormone, and lithium. The serum lithium concentration was 3.1 mmol/l. Electrocardiography showed a broad-complex tachydysrhythmia, which persisted despite treatment with intravenous adenosine and lidocaine. The cardiac rhythm was interpreted as a ventricular tachycardia. He was given intravenous procainamide, resulting in temporary slowing of his cardiac rhythm, and a continuous procainamide infusion produced stable sinus rhythm. Over the next 36 hours, he continued to have treatment for his lithium toxicity and procainamide for his ventricular dysrhythymia, and improved. At follow-up a 24-hour Holter monitor showed first-degree atrioventricular block.
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David L. Dunner
I wonder if the diagnosis in this patient was correct. He obviously had a severe behavioral disturbance, which required treatment; however, it is not clear if his polypharmacy was appropriate for his condition. Nervous system In a Canadian study of 200 000 automobile drivers, aged 67–84, who were followed from 1990 until they reached age 85, or until they emigrated from Quebec, or until 31 May 1993, those who had been involved in an automobile accident in which one person sustained a physical injury were assessed; the controls were a 6% random sample of the others (15C ). Of 5579 patients 20 had been taking lithium within the year before the index date, 19 of whom had been taking it within 16 days before the accident. This compared with 27 of 13 300 patients in the control group (OR = 1.8); for current lithium use, the odds ratio was 2.08. The data on carbamazepine did not show a raised odds ratio. The authors concluded that elderly patients taking lithium have a two-fold increase in the risk of an injurious motor vehicle accident while driving. Whether this was due to lithium, other medications, or the severity of illness factors could not be determined. Of 44 patients who used a combination of lithium plus clozapine for a mean of 23.5 months, 37 were rated as having responded (16c ). Most had schizophrenia or schizoaffective disorder, and only two had bipolar I disorder. There were adverse events, mostly benign and transient, in 28; however, eight patients developed transient new neurological adverse events, including two episodes of myoclonus and one generalized tonic–clonic seizure. In 23 patients who agreed to a reassessment there were no neurological or neurotoxic events. During treatment there were three neurological adverse events that had not been present before treatment; these included three instances of myoclonus and one generalized tonic–clonic seizure. The authors concluded that the combination of lithium plus clozapine does not result in an increased risk of neurological adverse effects compared with either drug alone. Furthermore, the combination produced improved efficacy over clozapine alone. These data contrast with data from previous studies, which suggested that the combination of lithium plus clozapine produced an increased risk of adverse neurological events due to a serotonergic
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interaction. However, the authors noted that some of the neurological events occurred during co-treatment with serotonergic compounds, such as paroxetine or trimipramine, and also that paroxetine could increase clozapine plasma concentrations and therefore increase the likelihood of a neurological adverse event. They suggested that if lithium and clozapine are combined, co-medication with serotonergic antidepressant drugs or drugs that interfere with clozapine metabolism or renal clearance should be avoided. • A 70-year-old man developed lithium intoxication after a transient ischemic attack (17A ). He had a bradycardia (35–40/minute) and episodes of sinoatrial block. The clinical presentation was suggestive of a stroke.
The authors discussed the difficulty of the differential diagnosis between lithium intoxication and other neurological disorders, such as strokes. What they did not discuss was the possibility that the presentation was caused by sinus node dysfunction, which has been reported as a complication of lithium treatment. Endocrine Thyroid The management of thyroid disorders in elderly people has been reviewed (18R ), and the authors noted that lithium can be associated with hypothyroidism. Parathyroid Lithium toxicity has been reported in a patient with hypercalcemia (19A ). • A 54-year-old man, who had taken lithium for 15 years without problems, suddenly developed food and water aversion, hypercalcemia (2.75 mmol/l), and lithium toxicity, with a serum lithium concentration of 4.3 mmol/l. He was confused, delirious, and irritable. Hemodialysis produced a marked improvement in laboratory tests, which became normal after 9 days.
The authors concluded that the hypercalcemia was due to long-term lithium treatment and cited studies showing that hyperparathyroidism occurs in 5–40% of patients taking long-term lithium, compared with a population frequency of less than 4%. The patient’s chief complaint included nausea when he was exposed to food and water, and he therefore refused food and water for 2–3 days before admission. He also had acute renal insufficiency,
31 which was thought to be due to the hypercalcemia, water aversion, and perhaps “idiosyncratic reasons.” The renal insufficiency and water aversion resulted in lithium toxicity. Urinary tract Lithium can cause nephrogenic diabetes insipidus, by competitive inhibition of the action of antidiuretic hormone. • A 47-year-old woman, who was taking lithium (serum concentration 0.7 mmol/l) for bipolar I disorder, developed an acute abdominal syndrome (20A ). She had a recent history of drinking about 4 l of fluid a day. After surgery, she developed nephrogenic diabetes insipidus, with 19 l/day intake and 15 l/day output. The diuresis fell to 8 l/day over the next 10 days.
The authors wondered whether physiological stress could trigger diabetes insipidus and cited other articles showing that diabetes insipidus due to lithium occurred after surgery or brain injury, during pregnancy, or while fasting. They also suggested that patients who have been stable for a long time might have their lithium withdrawn. Withdrawal of lithium is thought to reverse lithium-induced nephrogenic diabetes insipidus, but the authors reviewed the literature and cited cases of nephrogenic diabetes insipidus that did not reverse after withdrawal of lithium. • A 76-year-old man developed severe intractable diabetes insipidus which was attributed to lithium (21A ). He was hospitalized for over 2 weeks and eventually died from intestinal hemorrhage. Vigorous efforts were made to treat his polyuria, electrolyte disturbances, hypernatremia, and dehydration. He had been taking chlorpromazine, lithium, and furosemide, along with other medications, and the diagnosis of lithium-induced nephrogenic diabetes insipidus was considered because of a lack of alternative explanations.
The authors reviewed the causes and pathophysiological mechanisms of nephrogenic diabetes insipidus. They also discussed the metabolic effects of lithium, including renal and thyroid effects, hypercalcemia, leukocytosis, and weight gain. Skin The cutaneous adverse effects of lithium have been reviewed (22R ). Lithium can cause aggravation of psoriasis. Other dermatological issues related to lithium treatment include acne, folliculitis, and maculopapular eruptions. The authors cited the prevalence of dermatological
32 difficulties with lithium as being up to 45% (but many others have reported a much lower rate, less than 4%), men being more susceptible to than women. Most patients can be managed without withdrawing lithium, but aggravation of psoriasis may make it necessary. • A 19-year-old patient taking lithium therapy for bipolar I disorder developed a pityriasis rosea-like dermatitis, which resolved when valproic acid was substituted for lithium (23A ). The rash was defined as “erythematous, sharply bordered oval and finely scaling lesions along skin cleavages on the trunk and proximal parts of the extremities.” There was no evidence of a herald patch.
Two skin conditions, recurrent herpesvirus infections and seborrheic dermatitis, can respond to topical lithium salts. Susceptibility factors Age The database for pharmacological treatment of mania and bipolar depression in late life has been reviewed, focusing on four studies from 1970–99 (24R ). The studies were fairly small (n = 12–81). One study included a small number of patients with bipolar II affective disorder. Five more recent studies (1995–9) involving divalproex in elderly patients with mania or bipolar disorder were also reported; sample sizes again were modest (n = 13–39). Both short-term and long-term outcomes were assessed and the issue of lithium toxicity was also discussed. The authors concluded that lithium remains the treatment of choice, but clinicians should target lower serum concentrations (0.4– 0.8 mmol/l), although occasional patients may require higher concentrations. The adverse effects of lithium in elderly patients include cognitive status worsening, tremor, and hypothyroidism. The authors suggested that divalproex is also useful in elderly patients with mania and that concentrations of divalproex in the elderly are similar to those useful for the treatment of mania in younger patients. They noted that carbamazepine should be considered a second-line treatment for mania in the elderly. A partial response would warrant the addition of an atypical antipsychotic drug. For bipolar depression, they recommended lithium in combination with an antidepressant, such as an SSRI. They also noted that lamotrigine may be useful for bipolar depression. Electroconvulsive therapy (ECT)
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David L. Dunner
may also be useful, but there have been no comparisons of ECT and pharmacotherapy in elderly patients with bipolar depression. The risk of hospital admission related to lithium toxicity has been estimated in a casecontrol study of 10 615 elderly patients over 9 years (25C ). Lithium toxicity occurred at least once in 413 of the patients who were taking lithium. Factors that increase the likelihood of hospital admission included starting treatment with a loop diuretic or ACE inhibitors during the month before hospitalization. Although furosemide has been suggested as the diuretic of choice for patients taking lithium, the authors suggested that furosemide may cause lithium toxicity in elderly patients. Non-steroidal antiinflammatory drugs (NSAIDs) and thiazide diuretics, which are commonly associated with raised lithium concentrations, were not associated with lithium toxicity in this population. Most of 78 patients who had lithium intoxication and a serum lithium concentration equal to or greater than 1.2 mmol/l had mild symptoms (26C ). The symptoms were more severe in patients with chronic lithium intoxication than in those with acute intoxication. None of the patients died or had permanent neurological damage as a sequel of lithium intoxication. The authors concluded that concomitant medications, older age, and pre-existing neurological illness could increase the susceptibility to lithium toxicity. Of the 43 patients with acute lithium intoxication, 34 had taken lithium in a suicide attempt and nine had taken an accidental overdose. Thirty-five patients had chronic lithium intoxication without any change in lithium dosing. Lithium concentrations in this particular study were mostly clustered in the 1.2–1.5 mmol/l range, but eight of the patients in the acute intoxication group and two in the chronic intoxication group had serum lithium concentrations greater than 2.5 mmol/l. Dehydration Dehydration due to intercurrent infections can lead to lithium toxicity. • Lithium toxicity occurred in an elderly patient who had a Norwalk virus-like infection 6 days before presentation (27A ). The serum lithium concentration 48 hours before presentation was 1.85 mmol/l. She had hypernatremia and abnormal liver function tests. She was hydrated and treated aggressively for lithium toxicity and recovered fully after 9 days.
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The point of this case is that lithium toxicity can occur in a patient who has been taking a stable lithium dose during an episode that can be associated with nausea, vomiting, and diarrhea, which could reduce lithium excretion. Drug overdose Lithium toxicity due to accidental ingestion of a lithium-containing battery has been reported. • A five-year-old boy swallowed a button battery containing lithium (28A ). During the 4 days after ingestion, he developed a serum lithium concentration of 0.71 mmol/l without signs of lithium toxicity and with normal renal function. The battery was eventually retrieved by gastrotomy.
The authors warned that button battery ingestion can be a source of lithium poisoning in youngsters. Drug interactions The adverse effects and drug interactions of psychopharmacological medications, including lithium, have been reviewed, focusing on lithium toxicity in elderly people (29c ). Topiramate Lithium toxicity occurred in a patient who was treated with lithium and had topiramate added (30A ). • A 26-year-old woman with bipolar I disorder took lithium and valproate, and sometimes additional risperidone and lamotrigine. Both risperidone and lamotrigine produced dermatological ad-
33 verse effects. Her serum lithium concentration was 0.82 mmol/l. Topiramate 75 mg/day was added. A week later, she continued to show a mixed state with mostly manic features and a raised lithium concentration of 1.24 mmol/l. The lithium concentration continued to increase over the next 4 days to 1.97 mmol/l even though the lithium dosage was reduced from 900 to 750 mg/day. Lithium was withdrawn and the lithium concentration fell. Lithium was then restarted at half the admission dose to achieve a blood concentration of 0.67 mmol/l. Subsequent increases in the dose of topiramate resulted in further increases in the lithium concentration.
The authors suggested that topiramate reduced renal lithium excretion through several mechanisms, possibly as a carbonic anhydrase inhibitor coupled with sodium depletion. They suggested that patients taking lithium and topiramate be carefully monitored for lithium concentrations and hydration. Monitoring therapy Biochemical variables in erythrocytes, mood states, and adverse effects of lithium were measured in 30 patients, mostly men, who had bipolar disorder and were undergoing lithium treatment (31C ). Most (87%) had bipolar I affective disorder. The major finding was that when the serum lithium concentration was in the 0.93–1.42 mmol/l range, there was a full response without toxicity. Higher values predicted toxicity and lower values predicted partial response.
References 1. Quiroz JA, Gould TD, Manji HK. Molecular effects of lithium. Mol Interventions 2004;4:259– 72. 2. McNamara RK, Lenox RH. The myristoylated alanine-rich C kinase substrate: a lithiumregulated protein linking cellular signaling and cytoskeletal plasticity. Clin Neurosci Res 2004;4:155–69. 3. Geddes JR, Burgess S, Hawton K, Jamison K, Goodwin GM. Long-term lithium therapy for bipolar disorder: systematic review and metaanalysis of randomized controlled trials. Am J Psychiatry 2004;161:217–22. 4. Pavuluri MN, Henry DB, Carbray JA, Sampson G, Naylor MW, Janicak PG. Open-label
prospective trial of risperidone in combination with lithium or divalproex sodium in pediatric mania. J Affect Dis 2004;82S:S103–11. 5. Calabrese J. Depressive mood stabilization: novel concepts and clinical management. Eur Neuropsychopharmacol 2004;S4:S100–5. 6. Yatham LN, Binder C, Kusumakar V, Riccardelli R. Risperidone plus lithium versus risperidone plus valproate in acute and continuation treatment of mania. Int Clin Psychopharmacol 2004;19:103–9. 7. Rendell JM, Juszczak E, Hainsworth J, Van der Gucht E, Healey C, Morriss R, Ferrier N, Young AH, Young H, Goodwin GM, Geddes JR. Developing the BALANCE trial—the role of the
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Chapter 3 pilot study and start-up phase. Bipolar Disord 2004;6:26–31. Sachs G, Chengappa KNR, Suppes T, Mullen JA, Brecher M, Devine NA, Sweitzer DE. Quetiapine with lithium or divalproex for the treatment of bipolar mania: a randomized, doubleblind, placebo-controlled study. Bipolar Disord 2004;6:213–23. De Jonghe F, Hendriksen M, Van Aalst G, Kool S, Peen J, Van R, Van den Eijnden E, Dekker J. Psychotherapy alone and combined with pharmacotherapy in the treatment of depression. Br J Psychiatry 2004;185:37–45. Kidd PM. Bipolar disorder as cell membrane dysfunction. Progress toward integrative management. Alternative Med Rev 2004;9:107–35. Klumpers UMH, Boom K, Janssen FMG, Tulen JHM, Loonen AJM. Cardiovascular risk factors in outpatients with bipolar disorder. Pharmacopsychiatry 2004;32:211–6. Sparicio D, Landoni G, Pappalardo F, Crivellari M, Cerchierini E, Marino G, Zangrillo A. Methyline blue for lithium-induced refractory hypotension in off-pump coronary artery bypass graft: report of two cases. J Thorac Cardiovasc Surg 2004;127:592–3. Frassati D, Tabib A, Lachaux B, Giloux N, Daléry J, Vittori F, Charvet D, Barel C, BuiXuan B, Mégard R, Jenoudet LP, Descotes J, Vial T, Timour Q. Hidden cardiac lesions and psychotropic drugs as a possible cause of sudden death in psychiatric patients: a report of 14 cases and review of the literature. Can J Psychiatry 2004;491:100–5. Francis J, Hamzeh RK, Cantin-Hermoso MR. Lithium toxicity-induced wide-complex tachycardia in a pediatric patient. J Pediatr 2004;145:235–40. Etminan M, Hemmelgaru B, Delaney JAC, Suissa S. Use of lithium and the risk of injurious motor vehicle crash in elderly adults: casecontrol study nested within a cohort. Br Med J 2004;328:558–9. Bender S, Linka T, Wolstein J, Gehendges S, Paulus H-J, Schall U, Gastpar M. Safety and efficacy of combined clozapine-lithium pharmacotherapy. Int J Neuropsychopharmacol 2004;7:59–63. Marque N, Mansencal N, Morrison-Castaqhet JF, Dubourg O. Intoxication au lithium. Arch Mal Coeur Vaiss 2004;97:271–4.
David L. Dunner
18. Coll PP, Taxel P. The management of thyroid disorders in long-term care. Ann Long-Term Care 2004;12:26–32. 19. Bilanakis N, Gibiriti M. Lithium intoxication, hypercalcemia and “accidently” induced food and water inversion: a case report. Prog Neuropsychopharmacol Biol Psychiatry 2004;28:201–3. 20. Sirois F. Lithium-induced neurogenic diabetes insipidus in a surgical patient. Psychosomatics 2004;45:82–3. 21. Ashrafian H, Bogle RG. Sensitizing the insensitive. Clin Nephrol 2004;61:440–3. 22. Yeung CK, Chan HHL. Cutaneous adverse effects of lithium. Am J Clin Dermatol 2004;5:3–8. 23. Senol M, Ozcan A, Ozcan EM, Aydin EN. Pityriasis rosea-like eruption due to lithium. Clin Drug Invest 2004;24:493–4. 24. Young RC, Gyulai L, Mulsant BH, Flint A, Beyer JI, Shulman KI, Reynolds CF III. Pharmacotherapy of bipolar disorder in old age. Am J Geriatr Psychiatry 2004;12:342–57. 25. Juurlink DN, Mamdani MM, Kopp A, Rochon PA, Shulman KI, Redelmeier DA. Druginduced lithium toxicity in the elderly: a population-based study. J Am Geriatr Soc 2004;52:794– 8. 26. Chen K-P, Shen W, Lu M-L. Implication of serum concentration monitoring in patients with lithium intoxication. Psychiatry Clin Neurosci 2004;58:25–9. 27. Abraham G, Voutsilakos F. Norwalk precipitates severe lithium toxicity. Can J Psychiatry 2004;49:215–6. 28. Mallon PT, White JS, Thompson RLE. Systemic absorption of lithium following ingestion of a lithium button battery. Hum Exp Toxicol 2004;23:192–5. 29. Alderman CP. Developments in psychiatry— 2004. J Pharm Pract Res 2004;34:149–51. 30. Abraham G, Owen J. Topiramate can cause lithium toxicity. J Clin Psychopharmacol 2004;24:565–7. 31. Layden BT, Minadeo N, Suhy J, Abukhdeir AM, Metreger T, Foley K, Borge G, Crayton JW, Bryant FB, De Freitas DM. Biochemical and psychiatric predictors of Li+ response and toxicity in Li+ -treated bipolar patients. Bipolar Disord 2004;6:53–61.
Jayendra K. Patel, Timothy E. Ralston, and Eileen Wong
4 CANNABINOIDS
(SED-15, 614; SEDA-26, 36; SEDA-27, 32; SEDA-28, 36) The long history of marijuana use both as a recreational drug and as an herbal medicine for centuries has been reviewed (1r ). Cannabis sativa contains more than 450 substances and only a few of the main active cannabinoids have been evaluated. Cannabis is the most commonly used illicit drug. In 2001, 83 million Americans and 37% of those aged 12 and older had tried marijuana (2R ). Observational studies In an open trial the safety, tolerability, dose range, and efficacy of the whole-plant extracts of Cannabis sativa were evaluated in 15 patients with advanced multiple sclerosis and refractory lower urinary tract symptoms (3c ). The patients took extracts containing delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD; 2.5 mg per spray) for 8 weeks followed by THC only for a further 8 weeks. Urinary urgency, the number and volume of incontinence episodes, frequency, and nocturia all reduced significantly after treatment with both extracts. Patients’ self assessments of pain, spasticity, and quality of sleep improved significantly, and the improvement in pain continued for up to a median of 35 weeks. Most of the patients had symptoms of intoxication, such as mild drowsiness, disorientation, and altered time perception, during the dose titration period. Three had single short-lived hallucinations that did not occur when the dose was reduced. All complained of a worsening of dry mouth that was already present from other treatments and two complained of mouth soreness at the site of drug administration. Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29004-4 © 2007 Elsevier B.V. All rights reserved.
Drugs of abuse Of 220 patients with multiple sclerosis in Halifax, Canada 72 (36%) reported ever having used cannabis (4C ). Ever use of cannabis for medicinal purposes was associated with male sex, the use of tobacco, and recreational use of cannabis. Of the 34 medicinal cannabis users, 10 reported mild, eight moderate and one strong adverse effects; none reported severe adverse effects. The most common adverse effects were feeling “high” (n = 24), drowsiness (20), dry mouth (14), paranoia (3), anxiety (3), and palpitation (3). Placebo-controlled studies Cannabis has been used to treat many medical conditions, especially those involving pain and inflammation. Many studies with improved designs and larger sample sizes are providing preliminary data of efficacy and safety in conditions such as multiple sclerosis and chronic pain syndromes. In a parallel group, double-blind, randomized, placebo-controlled study undertaken at three sites in 160 patients with multiple sclerosis a cannabis-based medicinal extract containing equal amounts of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) at doses of 2.5–120 mg of each daily in divided doses for 6 weeks, spasticity scores were significantly improved by cannabis (5C ). However, when the changes in symptoms were measured using the Primary Symptoms Scale, there were no significant differences between cannabis and placebo. The main adverse events were dizziness (33%), local discomfort at the site of application (26%), fatigue (15%), disturbance in attention (8.8%), disorientation (7.5%), a feeling of intoxication (5%), and mouth ulcers (5%). In a randomized, double-blind, placebocontrolled, crossover trial the effect of the synthetic delta-9-tetrahydrocannabinol dronabinol on central neuropathic pain was evaluated in 24 patients with multiple sclerosis (6C ). Oral dronabinol reduced central pain. Adverse events
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were reported by 96% of the patients compared with 46% during placebo treatment. They were more common during the first week of treatment. The most common adverse events during dronabinol treatment were dizziness (58%), tiredness (42%), headache (25%), myalgia (25%), and muscle weakness (13%). There was increased tolerance to the adverse effects over the course of treatment and with dosage adjustments. Three cannabis-based medicinal extracts in sublingual form recently became available for use against pain. In a randomized, doubleblind, placebo-controlled, crossover study for 12 weeks in 34 patients with chronic neuropathic pain THC extracts were effective in symptom control (7C ). Drowsiness and euphoria/dysphoria were common in the first 2 weeks. Dizziness was less of a problem. Anxiety and panic were infrequent but occurred during the run-in period. Dry mouth was the most common complaint. Cardiovascular Popliteal artery entrapment occurred in a patient with distal necrosis and cannabis-related arteritis, two rare or exceptional disorders that have never been described in association (8Ar ). • A 19-year-old man developed necrosis in the distal third right toe, with loss of the popliteal and foot pulses. Arteriography showed posterior popliteal artery compression in the right leg and unusually poor distal vascularization in both legs. An MRI scan did not show a cyst and failed to identify the type of compression and the causal agent. Surgery showed that the patient had type III entrapment. Surprisingly, the pain failed to regress and the loss of distal pulses persisted despite a perfect result on the postoperative MRA scan. The patient then admitted consuming cannabis 10 times a day for 4 years, which suggested a Buerger-type arteritis related to cannabis consumption. A 21-day course of intravenous vasodilators caused the leg pain to disappear and the toe necrosis to regress. An MRA scan confirmed permanent occlusion of three arteries on the right side of the leg and the peroneal artery on the left side. Capillaroscopy excluded Buerger’s disease.
The authors suggested that popliteal artery entrapment in a young patient with non-specific symptoms should raise the suspicion of a cannabis-related lesion. Their review of literature suggested that this condition affects young patients and that complications secondary to popliteal artery entrapment did not occur in those who were under 38 years age.
Jayendra K. Patel, Timothy E. Ralston, and Eileen Wong
Respiratory Cannabis smoking can cause pneumothorax (9A ). • A 23-year-old man who had smoked cannabis regularly for about 10 years developed severe respiratory distress. He had bilateral pneumothoraces with complete collapse of the left lung.
No obvious reason for the problem was found and the authors suggested that coughing while breath-holding during cannabis inhalation had caused the problem. Nervous system Propriospinal myoclonus has been reported after cannabis use (10A ). • A 25-year-old woman developed spinal myoclonus 18 months after having experienced acute-onset repetitive involuntary flexion and extension spasms of her trunk immediately after smoking cannabis. The jerks, which lasted 2–5 seconds, involved the trunk, neck, and to a lesser extent the limbs. The attacks occurred in clusters lasting up to 2 weeks and she was asymptomatic for 2–3 months between clusters. The myoclonus was not present during sleep. During a bout of jerks, myoclonus would occur every few minutes and continue for up to 9 hours, with associated fatigue and back pain. Neurological examination showed repetitive flexion jerks of the trunk with no other abnormal signs. An electroencephalogram, an MRI scan of the head and spine, and a full-length myelogram were all normal. Multi-channel surface electromyography with parallel frontal electroencephalography showed propriospinal myoclonus of mid-thoracic origin.
There have been no previous reports of propriospinal myoclonus precipitated by marijuana. The etiology was not clear but may have involved cannabinoid receptors located in the brain and spinal cord as well as the peripheral nervous system. Occipital stroke has been reported after cannabis use (11A ). • A 37-year-old Albanian man had an uneventful medical history except that he smoked 20 cigarettes/day and marijuana joints regularly for 10 years. In the previous 6 months he had increased his marijuana smoking to 2–3 joints/week from 1–2 joints/month. He suddenly developed leftsided hemiparesis, left-sided hemihypesthesia, and recurrent double vision 15 minutes after having smoked a joint containing about 250 mg marijuana. Most of the symptoms disappeared within 1 hour after onset. An MRI scan showed an area of impaired diffusion, 2 cm in diameter, in the right occipital area subcortically. He responded well to acetylsalicylic acid with dipyridamole and atorvastatin and was discharged 3 days later with blurred
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vision when looking to the left. There was no cardiac source of embolism. Other causes of stroke were carefully excluded, and it could only be attributed to the use of marijuana.
The authors, based on previous reports of the vasogenic effects of marijuana, suggested that this event may have been related to increased concentrations of catecholamine and carboxyhemoglobin, and diminishing cerebral autoregulatory capacity. Transient global amnesia, an amnesia of sudden onset regarding events in the present and recent past, typically occurs in elderly people. Transient global amnesia following accidental marijuana ingestion has been reported in a young boy (12A ). • A 6-year-old boy accidentally became intoxicated with marijuana after eating cookies laced with marijuana. He developed retentive memory deficits of sudden onset, later diagnosed as transient global amnesia. He was anxious and had a tachycardia, fine tremors in the upper and lower limbs, and an ataxic gait. His CSF was unremarkable. He had cannabinoids in his urine. His memory returned to normal after 14 hours. His mother admitted baking marijuana cookies and leaving them out on the kitchen table. Up to 12 months later he had no memory of the episode.
This is the first case of transient global amnesia from marijuana in a 6-year-old. With increased use of marijuana in society, children can sometimes be exposed to marijuana inadvertently. A review of the evidence has suggested that, particularly with high doses, cannabis users are 3–7 times more likely to cause motor vehicle accidents than non-drug users (13r ). Psychiatric Neurotrophins, such as nerve growth factor and brain-derived neurotrophic factor (BDNF), are implicated in neuronal development, growth, plasticity, and maintenance of function. Neurodevelopment is impaired in schizophrenia and vulnerable schizophrenic brains may be more sensitive to toxic influences. Thus, cannabis may be more neurotoxic to schizophrenic brains than to nonschizophrenic brains when used chronically. In 157 drug-naïve first-episode schizophrenia patients there were significantly raised BDNF serum concentrations by up to 34% in patients with chronic cannabis abuse or multiple substance abuse before the onset of the disease
37 (14C ). Thus, raised BDNF serum concentrations are not related to schizophrenia and/or substance abuse itself but may reflect cannabisrelated idiosyncratic damage to the schizophrenia brain. Disease onset was 5.2 years earlier in the cannabis-consuming group. Psychological In a critical English-language literature review of the cannabis research done during the 10 years from 1994 to 2004 the relation between the rate of cannabis use, behavioral problems, and mental disorders in young people was explored (2R ). Although there are shortcomings in the studies done in this area, the data suggest that early and heavy use of cannabis has negative effects on psychosocial functioning and psychopathology. Although infrequent use causes few mental health or behavioral problems, cannabis is not necessarily harmless. Accumulating evidence suggests that regular marijuana use during adolescence may have effects, whether biological, psychological, or social, that are different from those in later life. Most recent data challenge the notion that marijuana relieves psychotic or depressive symptoms. Cognition Delta-9-tetrahydrocannabinol (THC) activates cannabinoid receptors in frontal cortex and hippocampus. Electroencephalograms were obtained from 10 subjects who performed cognitive tasks before and after smoking marijuana or a placebo, to examine the effects on performance and neurophysiology signals of cognitive functions (15c ). Marijuana increased heart rate and reduced global theta band electroencephalographic power, consistent with increased autonomic arousal. Responses in working memory tasks were slower and less accurate after smoking marijuana, and were accompanied by reduced alpha-band electroencephalographic reactivity in response to increased task difficulty. Marijuana disrupted both sustained and transient attention processes, resulting in impaired memory task performance. In the episodic memory task, marijuana use was associated with an increased tendency to identify distracter words erroneously as having been previously studied. In both tasks, marijuana attenuated stimulus-locked event-related potentials (ERP). In subjects most affected by marijuana, a pronounced ERP difference between previously studied words and new distracter
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words was also reduced, suggesting disruption of neural mechanisms underlying memory for recent episodes. In a Vietnamese study of 54 monozygotic male twin pairs who were discordant for regular marijuana use and who had not used any other illicit drug regularly the marijuana users significantly differed from the non-users on the general intelligence domain; however, within that domain only the performance of the block design subtests of Wechsler Adult Intelligence Scale-Revised reached statistical significance (16C ). The marijuana users had not used it for at least 1 year, and a mean of almost 20 years had passed since the last time marijuana had been used regularly. There were no marked long-term residual effects of marijuana use on cognitive abilities. Gastrointestinal Although cannabis has been used as an antiemetic, in 19 patients it was associated with cyclical hyperemesis, and in seven cases withdrawal was followed by the disappearance of symptoms; in three cases there was a positive re-challenge (17c ).
COCAINE
(SED-15, 848; SEDA-26, 27; SEDA-27, 33; SEDA-28, 38; see also Chapter 11) Cardiovascular Cocaine-induced myocardial infarction with coronary thrombosis has been described. DoTS classification: Reaction: Myocardial infarction due to cocaine Dose-relation: Toxic Time-course: Time independent Susceptibility factors: Not known • A 26-year-old man reported smoking 10 cigarettes/ day and using cocaine by inhalation at weekends (18A ). His electrocardiogram showed raised anterolateral ST segments. He had raised creatine kinase MB activity and troponin I concentration. He was normotensive with signs of pulmonary congestion. Ventriculography showed anterolateral and apical hypokinesia and an ejection fraction of 21%. Angiography showed massive thrombosis of
the left anterior descending coronary artery. He was given recombinant tissue plasminogen activator by intravenous infusion. Angiography 4 days later showed thrombus resolution, and ventriculography showed an improved ejection fraction. He was symptom-free 6 months later. • A 50-year-old man had 12 hours of chest pain and shortness of breath after a cocaine binge. His history included hyperlipidemia, cigarette smoking, and cocaine use (19A ). The troponin concentration was increased, at 25 ng/ml. An electrocardiogram showed anteroseptal ST segment elevation and inferolateral depression with T wave inversion. An angiogram showed multi-vessel occlusion of the left anterior descending artery, right coronary artery, and left circumflex artery. Ventriculography showed severe anteroapical and inferior wall hypokinesis with an ejection fraction of 25%. Angioplasty was performed urgently and final angiography showed no residual stenosis in the treated vessels. • In a cocaine abuser, resolution of intracoronary thrombosis with direct thrombin inhibition has been successfully attempted (20A ). Medical treatment was started with tirofiban and low molecular weight heparin, and 48 hours later they were replaced with bivalirudin, a direct thrombin inhibitor, in an initial bolus dose of 0.1 mg/kg followed by an infusion of 0.25 mg/kg/hour. Repeat angiography 48 hours after bivalirudin showed near total thrombus dissolution with resolution of the electrocardiographic abnormalities.
Accelerated extensive atherosclerosis secondary to chronic cocaine abuse has also been reported (21A ). • A 32-year-old man, who was a cigarette smoker (10 cigarettes/day) and had been a frequent cocaine user for 16 years, developed acute chest pain 2 hours after heavy cocaine use. He had electrocardiographic abnormalities consistent with an acute myocardial infarction, confirmed by serial enzyme measurements. There was no family history of atherosclerosis. Echocardiography showed a large akinetic anteroapical segment. Serum lipoprotein concentrations were normal. Despite management with aspirin, glyceryl trinitrate, heparin, and morphine, he required emergency cardiac catheterization because of prolonged chest pain. Coronary angiography showed severe atherosclerosis of the middle and distal segments of the left anterior descending coronary artery and a large diagonal branch. Intracoronary glyceryl trinitrate and nitroprusside ruled out coronary spasm. Intravascular ultrasound localized the lesion to the middle of the left anterior descending artery and showed diffuse plaques along the entire artery, with variable composition, including fibrocalcific changes consistent with a chronic process. Two overlapping stents were inserted.
The authors acknowledged that the mechanisms for accelerated atherosclerotic process
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are not known. However, they cited research that suggests that cocaine has pro-atherogenic effects in blood vessels. Although percutaneous revascularization for cocaine-associated myocardial infarction is the preferred method of treatment (22cr ), the feasibility and safety of multivessel primary angioplasty has been demonstrated. In patients with persistent myocardial ischemia despite medical therapy, or evidence of cardiogenic shock, aggressive early intervention is particularly beneficial. Beta-blockers should be avoided in patients who have recently used cocaine; they fail to control the heart rate, enhance cocaineinduced vasoconstriction, increase the likelihood of seizures, and reduce survival (23R ). Myocardial ischemia and infarction associated with cocaine are unrelated to the route of administration, the amount taken, and the frequency of use. The risk of acute myocardial infarction is increased after acute cocaine use and it can occur in individuals with normal coronary arteries at angiography. The patients are typically young men and smokers and do not have other risk factors for atherosclerosis. The adverse effects of cocaine on the heart and cardiovascular system are well recognized. Cocaine can cause ischemia, dysrhythmias, infarction, cardiomyopathy, and death. Pregnancy increases the incidence of dysrhythmias in patients with Wolff–Parkinson–White syndrome. This association may relate to an effect of estrogen, increased plasma volume, or increased maternal stress or anxiety. A case of cocaine-induced myocardial ischemia in pregnancy mistaken for Wolff–Parkinson–White syndrome has been reported (24r ). • A 22-year-old pregnant woman at 38 weeks’ gestation developed chest pain, palpitation, and shortness of breath. Her blood pressure was 148/97 mmHg, heart rate 105/minute, and respiratory rate 22/minute. An electrocardiogram showed a short PR interval and a broad QRS complex with slurred upstrokes of the R waves in leads V2 and V3. Other laboratory studies were normal. The fetal heart rate was 160/minute. The differential diagnosis included a new onset dysrhythmia, Wolff– Parkinson–White syndrome, and myocardial ischemia/infarction. With supportive treatment and monitoring the dysrhythmia resolved. Serial creatine kinase measurements were normal. However, there were cocaine metabolites in the urine. The patient admitted to having used cocaine 3–4 hours before the episode.
39 The use of cocaine among women of reproductive age is increasing and pregnancy also enhances the potential cardiovascular toxicity of cocaine. Cocaine and its metabolite block sodium and potassium channels and its use is also associated with QT interval prolongation. • A 37-year-old man developed severe chest pain and shortness of breath after smoking 200 + rocks of crack cocaine in 72 hours while attempting to walk several miles in order to get more drug money (25A ). His symptoms resolved before the ambulance arrived. His medical history included a prior episode of chest pain after a 3-day crack cocaine binge. He also occasionally used alcohol and marijuana. He was anxious but had a normal heart rate and blood pressure. His drug screen showed cocaine. Cardiac enzymes were within the reference ranges. An initial electrocardiogram showed a QTc interval of 621 ms which shortened to 605 ms after 2 hours, 530 ms after 7 hours, and 543 ms after 15 hours. One month later the QTc interval was 453 ms.
Brugada syndrome has been attributed to cocaine use. • A 36-year old man became comatose 14 hours after inhaling an unspecified amount of heroin for an unspecified duration (26A ). He had been taking lithium, chlorpromazine, and diazepam for a chronic psychosis. His family reported recreational use of drugs of abuse. His Glasgow coma score was 4 without focal deficits. A toxicology screen was positive for cocaine and remained positive for 4 days after admission. His electrocardiogram showed prominent coved ST elevation and J wave amplitude of at least 2 mm in leads V1–V3, followed by negative T waves with no isoelectric separation, associated with right incomplete bundle branch block indicative of type 1 Brugada syndrome. His serum potassium concentration was 5.9 mmol/l. He was immediately treated with 42% sodium bicarbonate intravenously. The Brugada pattern completely resolved in 24 hours and his creatinine improved significantly in 48 hours. Transthoracic echocardiography was normal.
The authors of this report thought that the Brugada syndrome was probably not due to chlorpromazine or lithium in this patient, and it has not been previously described with heroin. It may have been due to hyperkalemia (as the Brugada pattern normalized when the serum potassium concentration normalized), perhaps facilitated by cocaine. Another case of Brugada syndrome is described below under “Drug overdose.”
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Respiratory Inhalation of crack cocaine can mimic pulmonary embolism (27r ). • A patient who was a known cocaine inhaler developed respiratory distress. The initial ventilation– perfusion lung scan was highly suggestive of pulmonary embolism, based on multiple segmental and subsegmental perfusion defects with normal ventilation. However, pulmonary angiography was normal. The symptoms resolved rapidly without anticoagulation and angiography was negative 2 weeks later.
The authors concluded that intense pulmonary artery vasospasm secondary to cocaine inhalation may have caused this syndrome. Ear, nose, throat A 30-year-old man developed destructive rhinitis due to cocaine abuse after initially presenting with Henoch– Schönlein purpura (28A ). Cocaine use can mimic vasculitis and is often accompanied by positive ANCAs. Cocaine-induced midline destructive lesions are characterized by mucosal damage and ischemic necrosis of the nasal septum. Histopathological similarity to leukocytoclastic vasculitis and the presence of PR3-ANCA can lead to confusion between Wegener’s granulomatosis and cocaine-induced midline destructive lesions. Nervous system The role of cocaine in causing cerebral hypoxia and anoxia has been reviewed in previous Annuals. A bilateral hippocampal stroke, which is rare, has been attributed to cocaine use (29A ). • An unresponsive 25-year-old white woman was found to be pulseless and was resuscitated. She had used cocaine the previous night and had had numerous psychiatric admissions for mood disorder and drug overdoses in the past. Her pupils measured 4 mm bilaterally and were non-responsive to light. She had roving eye movements and positive corneal responses. She did not respond to verbal or noxious stimuli. Her reflexes were brisk throughout, with clonus in the legs. There were cocaine metabolites in her urine. CT and MRI scans of the brain showed bilateral hippocampal and basal ganglionic hypodensities. She improved and was discharged to a nursing home 3 weeks later but continued to have severe short-term memory difficulties, problems with praxis, and mild quadrispasticity.
The authors cited a combination of ischemia and excitotoxicity due to cocaine exposure as the possible cause of the brain injury. Oxidative stress and free radicals associated with cerebral hypoxia contribute to cell damage and death.
Jayendra K. Patel, Timothy E. Ralston, and Eileen Wong
Hematologic Splenic infarction related to cocaine abuse is extremely rare and has been reported as a possible complication in patients with sickle cell hemoglobinopathies. • A 17-year-old cocaine abuser was found dead in bed. Autopsy showed signs of sepsis, splenic infarctions of different ages, and splenic necrosis with abscesses. The splenic abscesses and microabscesses in various other organs showed mixed bacterial infections (30A ).
These findings show that in cocaine abusers pain and fever can be an expression of severe cocaine-associated complications. Gastrointestinal Pneumoperitoneum is an example of a surgical emergency associated with the use of crack cocaine (31A ). • A 42-year-old man was intoxicated after an alcohol binge and recreational crack cocaine smoking. He was semi-conscious and in acute respiratory distress. He had subcutaneous emphysema in the face, neck, chest, abdomen, and legs, and tenderness in the left lower back. He had a temperature of 38 ◦ C, a heart rate of 117/minute, and a respiratory rate of 35/minute. There was hypoxia (PaO2 7.3) and a metabolic acidosis (pH 7.28). A chest X-ray showed free gas under the right hemidiaphragm. At laparotomy no organ perforation was found.
In all likelihood, a prolonged Valsalva maneuver while smoking crack cocaine caused pneumoperitoneum. Repeated, deep, vigorous inhalation can cause an abrupt imbalance of pressures in the pulmonary alveolar–capillary complex. Free air from ruptured alveoli then dissects along fascial planes and can collect in the mediastinum and retroperitoneum. Liver Hepatotoxicity secondary to cocaine exposure can be associated with hyperthermia, ischemia, or a direct cocaine effect. Another possible mechanism may be an acquired mitochondrial defect (32A ). • A 41-year-old man jumped through a ground-floor window after cocaine abuse. His Glasgow coma score was 7/15. His temperature was 40 ◦ C, heart rate 140/minute, and respiratory rate 40/minute. He had a tonic–clonic seizure and was intubated and ventilated. Blood chemistry showed a profound metabolic acidosis (pH 7.19), a raised creatinine at 232 µmol/l, a raised creatine kinase at 14 500 IU/l. Rhabdomyolysis was confirmed by the finding of myoglobinuria. Both urine and plasma toxic screens showed traces of cocaine
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and benzodiazepines. He was treated with dialysis, vasopressors, and then liver transplantation. Postoperative complications included hypotension, hypothermia, anuria, resistant hyperkalemia, and compartment syndrome, for which he had bilateral forearm fasciotomy. He died 12 hours later and post-mortem examination of the liver showed extensive hepatic necrosis in the acinar zones with macrovesicular steatosis, a pattern seen in toxic liver damage. A muscle biopsy showed a few necrotic fibers, glycogen depletion, and increased lipid staining.
The authors suggested that this patient had a defect in lipid metabolism, based on the muscle biopsy. Muscle mitochondria are a principle site for beta-oxidation of fatty acids. Microvesicular steatosis can progress to liver failure with severe and prolonged impairment of beta-oxidation. This metabolic defect may have exacerbated the direct toxic effects of cocaine. Sexual function Some believe that topical application of cocaine to the glans penis enhances sexual performance. However, such use can cause complications, including superficial penile necrosis (33A ). • A 32-year-old white heterosexual man developed widespread painful, blackened lesions on the penis after applying cocaine as an aphrodisiac. Screens for sexually transmitted infections were negative. He was given a 5-day course of antibiotics and the lesions healed completely.
The authors thought that cocaine applied to the glans penis may have been well absorbed through the thinner keratinized squamous epithelium. They attributed the superficial necrosis to intense skin vasoconstriction caused by cocaine. Death Death occurred shortly after cocaine use in a 26-year-old who had also used heroin and methadone 24 hours before (34A ). Death was attributed to thoracic aortic dissection after the use of crack cocaine. Histological findings showed connective tissue abnormalities, including focal microcystic medial necrosis and fragmentation of the elastic fibers in the arterial wall. Aortic dissection among cocaine users is thought to be related to weakening of the media of the aorta, and to shearing forces that result from sudden and profound hypertension that accompanies cocaine use (35R ). Whether or not other susceptibility factors, such as Marfan’s
syndrome and hypertension, can contribute to aortic aneurysm in cocaine abusers is uncertain. The presence of concentric left ventricular hypertrophy is suggestive of chronic hypertension. Transesophageal echocardiography is helpful in diagnosing aortic dissection in cocaine abusers (36c , 37c ). The criteria for the interpretation of cocaine concentrations in biological samples and their relation to the cause of death has been comprehensively reviewed (38R ). The importance of scene investigation, forensic autopsy, and forensic sampling for drug analysis has been discussed, with particular emphasis on the need to use appropriate blood preservatives and interpretation of the half-life and concentrations of cocaine and its metabolites, benzylecgonine and ethylcocaine, in combined cocaine + alcohol abuse.
Fetotoxicity of cocaine Sensory systems Eyes Neither cocaine (nor cigarette smoke) exposure in utero is associated with poor acuity or visual abnormalities early in infancy (39c ). At six weeks of age, infants’ visual acuity was measured with the Teller acuity card procedure, and a neurological examination was carried out, including examination of the visual system, with assessment of eyelid edema, visual attention, and gaze ability in 96 infants. This does not exclude the possibility that cocaine exposure has an effect on the developing eye, but suggests that these abnormalities may occur later in life or very rarely, thus necessitating longer follow-up. The long-term consequences of prenatal cocaine exposure in school-age children on intelligence, visuomotor skills, and motor abilities have been studied by comparing 101 children exposed perinatally to cocaine with 130 unexposed children at age 7 years (40C ). The children who were exposed prenatally to cocaine continued to display deficits in tasks of verbal, visuomotor integration, and fine motor skills. However, the effect of cocaine was rendered non-significant by inclusion of sociodemographic and environmental variables, especially the care-giver’s vocabulary and the
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child’s home environment. These results suggest that prenatal cocaine exposure per se may overlap with other cognitive risk factors experienced by children of low-income families. This study had several limitations: although cocaine exposure was established through a careful review of hospital records, including urine screens and maternal reports, misclassification of drug exposure was possible. The groups were initially recruited at different ages, ranging from birth to 2 years old, and there was a possibility that accuracy of maternal recall of cocaine abuse may have been less reliable the further removed the mother was from the experience of pregnancy. Moreover, both groups often used other drugs, especially alcohol and nicotine. The dichotomous classification (exposed/non-exposed) may have masked important differences in the groups. Alternatively, during the course of 7 years after the time of prenatal cocaine exposure, the postnatal environmental variables may have had a strong effect on development, masking the subtle effects of prenatal cocaine exposure. Ears The auditory brainstem responses (ABR) in neonates who were exposed prenatally to cocaine showed prolonged absolute peak latencies compared with non-exposed neonates and may indicate compromise of the auditory system from gestational exposure to cocaine (41C ). Among 58 infants studied, 21 (36%) were positive by meconium analysis for cocaine, and five (8.5%) were also positive for cannabinoids. There were significant differences in mean maternal age, gravidity, parity, birth weight, and head circumference among cocaine-exposed infants. Animal studies have shown that cocaine has a direct toxic effect on the organ of Corti or its embryonic precursor, the otic placode (42E ). Human studies have shown that cocaine has an acute toxic effect on brainstem auditory neurons, causing impaired synaptic efficiency and prolongation of interpeak latencies (43c , 44c ). Conversely, no apparent effect of maternal cocaine use during pregnancy on the developing auditory system in otherwise healthy term infants has been noted (45c ). In addition, abnormalities in the fetal auditory system may also be secondary to the effects of cocaine on the maternal circulation. Impaired fetal growth and undernutrition can also affect brainstem maturity, as a result of delayed myelination, and can
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result in an abnormal auditory brainstem response. It is well established that maternal cocaine abuse is associated with low birth weight and intra-uterine growth restriction (46M , 47C ). Thus, a multiplicity of factors may explain the variations in reports of the effects of cocaine on hearing in neonates. Other factors, such as the timing of cocaine exposure during pregnancy, the amount of exposure, the effect of other abused substances, and the susceptibility of the sensorineural organs of hearing at various stages of gestation, singly or additively, can determine the effects of cocaine on the auditory system (41C ). Psychological Psychomotor development Although in utero exposure to cocaine has been suggested to produce substantial deficits in multiple areas of functioning, this view has been supplanted by reports suggesting that the impact of exposure is subtle (48r , 49M ). Some reports using broad measures of developmentally appropriate performance have suggested that prenatal cocaine exposure is associated with modest reductions on the Bayley Mental Development Index (50C ), whereas other reports have not shown a significant effect (51C ). Using standardized assessments, including the Bayley Psychomotor Development Index, most studies have shown no deficits in motor functions (51C –53C ). Direct effects of prenatal cocaine exposure on mental, motor, and behavioral outcomes have been evaluated longitudinally in 1-, 2-, and 3year-old infants (54C ). The cocaine exposed infants (n = 474) scored 1.6 Mental Development Index points below infants who were not exposed to cocaine (n = 655). The effect of cocaine remained significant after controlling for co-variates, including birth weight, socioeconomic status, maternal education, vocabulary size, race, and psychopathology, as well as prenatal exposure to alcohol, cigarettes, and marijuana. Cocaine exposure in this study was not high compared with another large-scale study (53C ). It has been argued that cocaine exposure effects will be most evident in the domains of attention and affective regulation (49M , 55R ). It is therefore plausible that the effects of prenatal cocaine exposure may nevertheless become more evident during the development of more advanced motor (56C ), cognitive (57C ), language (58C ), and behavioral skills (59C ).
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Behavior Sex influenced the impact of prenatal cocaine exposure on child outcome (60C ). Boys but not girls with persistent prenatal cocaine exposure were most likely to have adverse behavioral outcomes in central processing, abstract thought, and motor skills, with moderate to large effect sizes. In addition, and in contrast to the effect of some exposure, boys with persistent cocaine exposure were rated as more positive to their environment compared with either the groups with some or no exposure. The primary innovation of this study was that it encompassed five critical design elements: (1) analyses stratified by sex; (2) ordinal measures of cocaine exposure; (3) extension of the observation period into early school age; (4) appropriate controlling for confounders (other prenatal drug exposures, socioeconomic status, and postnatal family characteristics, including drug exposure); (5) a sensitive tool specifically designed to index behaviors associated with prenatal cocaine exposure. The impact of prenatal cocaine exposure on children’s physiological and behavioral functioning has been examined. Responses to emotion-inducing stimuli were studied in 27 children aged 3–6 years who were prenatally exposed to cocaine compared with 27 nonexposed controls (61c ). The children’s affect during infant crying, a mildly frustrating task, and simulated maternal distress were observed and electroencephalographic activity was monitored. The drug-exposed group had greater right frontal electroencephalographic asymmetry, a pattern that may relate to negative emotional regulation and greater overall electroencephalographic activation. These children also showed less empathic behavior and an inability to complete mildly frustrating tasks. It has been argued that a failure to find enduring behavioral effects of prenatal cocaine exposure in some studies may have been related to the use of broad, relatively insensitive measures (62r , 63R ). Furthermore, to judge the effect of prenatal cocaine exposure based on a dichotomous variable (yes/no) may not be an appropriate study design (64c , 65C ). Cognition Although data from animal research has also confirmed a sex-specific effect of prenatal cocaine exposure (66E ), studies in humans have not consistently supported this (67C ). Nevertheless, there is other evidence that
43 prenatal cocaine exposure has a sex-related effect on cognition at 4 years of age (68C ). Language There have been two new reports on language abilities and prenatal cocaine exposure. Both studies used the Clinical Evaluation of Language Fundamentals (CELF-P). One documented language outcomes in 4-yearold children (189 cocaine-exposed and 185 non-exposed children) (69C ). There were more mild receptive language delays in the cocaineexposed group. These children were also less likely to have higher expressive abilities. Of the cocaine-exposed group, children who were in adoptive or foster care performed with higher language skills compared with children who remained in the original household. In the second study language outcomes were assessed in 3-year-olds (70C ). CELF-P was administered to 424 children (226 cocaineexposed and 198 non-cocaine exposed). Structural equation modelling was done on the data for expressive and receptive language functioning. There was a relation between increased level of prenatal cocaine exposure and reduced expressive language functioning. For receptive language functioning, there was no statistically significant association with prenatal cocaine exposure. Drug administration route Children who live in homes in which there is active drug use may be at risk of passive environmental drug exposure (71A ). • A 6-year-old boy developed general malaise and mild agitation, tachycardia, hypertension, and dilated pupils. His mother was a cocaine addict. Cocaine and benzodiazepines were found in significant amounts in the child’s urine and hair: the urine contained 109 ng/ml of cocaine and 145 ng/ml of benzodiazepines. Hair samples contained 16 ng/ml of cocaine and 0.6 ng/ml of benzodiazepines.
The authors emphasized that passive environmental exposure may be dangerous for children. Drug overdose As described in previous Annuals (SEDA-18, 38; SEDA-21, 32; SEDA-27, 36), drug trafficking involves methods such as body packing, which involves a significant risk of exposure to high doses of cocaine. Massive accidental cocaine ingestion has been reported.
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• A 28-year-old man aboard a flight reported feeling ill, became confused, and had a generalized seizure (72A ). After landing he had two further generalized seizures and a cardiac arrest. With medical management, his dysrhythmia, a wide complex tachycardia with features of right bundle branch block (Brugada syndrome) and ST segment elevation in the anteroseptal leads, was converted to sinus rhythm. He had raised troponin and creatine kinase MB. In the next 24 hours, he developed acute renal insufficiency and was treated with intermittent hemodialysis. A contrast CT showed generalized edema of the brain and features of coning, subarachnoid hemorrhage, and acute hydrocephalus. A plain abdominal X-ray showed multiple radio-opaque shadows. A CT scan of the abdomen confirmed the presence of multiple radioopaque densities consistent with foreign bodies. There was free gas in the abdomen, consistent with bowel perforation. He died 96 hours after admission. Autopsy showed 120 condoms containing cocaine in the gastrointestinal tract; one had ruptured.
Aspects of non-fatal cocaine overdose among cocaine users have been studied in Australia in 200 current cocaine users (120 injecting users and 80 non-injecting users), who volunteered for a structured interview; 13% had overdosed on cocaine, 7% in the preceding 12 months (73C ). Those who had overdosed were more likely to inject cocaine, to be female, to have longer cocaine habits, to have used more cocaine in the preceding month and preceding 6 months, and to have had higher degrees of cocaine dependence and more polydrug use. Drug interactions In a single-blind, placebocontrolled, within-subject, non-randomized, crossover study in 12 cocaine-dependent subjects, intravenous cocaine (20 mg and 40 mg) was evaluated before and during transdermal selegiline (20 mg), a selective inhibitor of monoamine oxidase B (74c ). Selegiline attenuated the effects of cocaine on systolic blood pressure and heart rate and many of its subjective effects, including the desire to use cocaine. Selegiline did not alter the pharmacokinetics of cocaine or cocaine-induced changes in prolactin and growth hormone. These results provide further evidence that selegiline may be useful in the treatment of cocaine abuse and dependence and provide safety documentation important in justifying the need for larger-scale therapeutic trials.
OPIOID ANALGESICS (SED-15, 2619; SEDA-27, 38; SEDA-28, 44) Death from opioid abuse Heroin contributes significantly towards mortality worldwide and heroin users are at significantly greater risk of premature death than their non-heroin-using peers (75R ). Men are typically over-represented, up to 80% in some instances. The mean age at the time of death is late twenties or early thirties and it typically occurs in those who are regular users rather than novices. Death usually occurs 1–3 hours after heroin use. It is not instantaneous and tends to occur in the company of other people. It is also likely to involve the use of other nervous system depressants taken in conjunction with heroin. Medical help is often sought too late; in only 14% of cases was an ambulance called as a first action. Multiple drug use is common in heroin-related deaths, with alcohol or benzodiazepine as significant co-abused substances. Blood morphine concentrations are generally not higher than in controls. Intravenous use accounts for most fatal overdoses. The validity of the term “heroin overdose” for these deaths has been questioned, as there is frequent coabuse of another drug and post-mortem morphine concentrations are not in excess of individual tolerance in most instances. Snorting or smoking heroin still carries a considerable risk of a lethal outcome, owing to a combination of polydrug abuse, variability in morphine blood concentration, and reduced tolerance because of periods of reduced or sporadic use. Clinicians should take into account the complexity of multiple drug dependence during assessments and in designing treatment. There should also be raised awareness among drug users of the different potential risk of overdose and subsequent drug-related death (76c ). Doctor shopping is a common form of drugseeking behavior in which there is a fraudulent presentation of disease to multiple doctors and pharmacies in order to procure prescription drugs. The authors of a study from Australia explored drug-seeking behavior patterns among young people who subsequently died of heroin overdose (77C ). They examined 202 consecutive Coroner’s Court cases (149 men and 53 women) from 1994 to 1999, of all heroin-related
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deaths in individuals aged under 25 years, excluding probable suicides. Their mean age was 21 years (range 14–24). Heroin or its derivatives were detected in all but two subjects. Other drugs were present in 90% of cases. Prescription and pharmacy drugs were present in 80% of the cases, benzodiazepines being most common and especially in women. Benzodiazepines, opiates, and psychotropic drugs accounted for 43%, 11%, and 8% of all prescriptions respectively. They reviewed the use of prescriptions from two different insurance groups. In the Pharmaceutical Benefits Scheme, the average number of prescriptions per person increased in the 4 years before death from four per person per year in the fourth year before death to a peak of 17 in the year before death. Although all prescriptions increased, the rates for benzodiazepines and other opioids increased more than prescriptions for other drugs. In the Medicare Beneficiary Scheme, 22% saw an average of more than 15 medical practitioners per year and 40% averaged more than 30 services per year. Women were disproportionately represented. In this study there were high levels of polydrug and prescription drug use in heroinrelated deaths. The authors suggested that their data provided circumstantial evidence of drug-seeking behavior before death, including increasing visits to multiple doctors and disproportionate increases in prescriptions for drugs likely to be misused. They reiterated that among younger heroin users, such drug-seeking behavior, besides indicating an increased risk of fatal overdose, may also provide an opportunity to intervene. “Doctor shoppers” are defined as those individuals who have seen more than 15 different GPs and have had 30 or more consultations in 1 year. However, in this study only 22% saw more than 15 GPs and 40% averaged more than 30 medical services, suggesting that most did not meet the official doctor shopping criteria, even when they increased their use of medical services. The authors suggested that an increase in doctor shopping in the years before heroin-related death while certainly a fiscal issue, may represent an opportunity to intervene and reduce mortality. In a review of 239 cases of heroin-related drug deaths between 1997 and 2000, 18 deaths were associated with non-intravenous administration (78c ). The median morphine concentration in these non-injectors was 0.05 µg/g and
45 this was significantly lower than in injectors (2.3 µg/g). There was concurrent use of alcohol, other illicit drugs, and/or pharmaceutical formulations in 17 of the 18 cases. A review of 139 methadone-related deaths between 1998 and 2002 in Palm Beach County supported those of previous investigations and suggested that it is not possible to establish a definitive lethal methadone blood concentration range. Methadone-related death is usually associated with the use of other drugs and toxicological analysis in such cases should be contextualized by the clinical circumstances surrounding the event and even a few months before the incident occurred (79c ). The role of methadone and opiates in accidental overdose deaths in New York City has been investigated using data from the Office of Chief Medical Examiner of all accidental drug overdose deaths between 1990 and 1998 (80C ). There were 7451 overdose deaths in all during this period, of which 1024 were methadone-induced, 4627 were heroin-induced, and 408 were attributable to both. Thus, 70% of the deaths from accidental overdose were due to opiates. Co-variates significantly associated with methadone-induced deaths were female sex, older age, and absence of cocaine, heroin, cannabis, and alcohol in toxic screens. Co-variates associated with heroin overdose were male sex, Caucasian or Hispanic ethnicity, younger age, and the absence of cocaine and methadone and the presence of cannabis and alcohol in toxic screens. The proportion of accidental deaths in New York City from methadone overdose of 13–16% of total overdose mortality did not change appreciably, although the proportion of overdose deaths attributed to heroin increased significantly (from 54 to 64%) during the study. Deaths from accidental overdose were 3–6 times more common among heroin users than methadone users during the same time. This absence of an increase in deaths from methadone use is noteworthy, because the number of people taking methadone during this period rose from 25 795 to 33 666 (a 31% increase). Thus, both heroin-induced overdose mortality and prescriptions of methadone increased during the same interval. Methadone-induced death risk was highest for those aged 35–44. The risk of heroin-induced overdose death fell with age. The lower likelihood of methadone-induced
46
Chapter 4
overdose death in those who had positive toxicology for cocaine, heroin, or alcohol suggests that individuals with methadone-induced deaths were less likely to be using other drugs concurrently. This also suggests that methadone deaths occurred in those who were using medicinal methadone rather than from the street. There was no association of these accidental deaths with the weekend use of these drugs.
Diamorphine (heroin)
(SED-15,
1096; SEDA-28, 45) Nervous system In two reports from China 10 cases (nine men and one woman) of heroininduced spongiform leukoencephalopathy have been reviewed. The first report discussed six cases with cerebellar signs and symptoms, with symmetrical lesions on neuroimaging in the white matter of the cerebellum, basal ganglia, posterior crus of the internal capsule, and the semi-oval center (81A ). The second report, described four cases that occurred during the abstinence period and showed improvement after 4 weeks of comprehensive treatment (82A ). Reversible Parkinsonism from heroin vapor inhalation has been reported (83A ). • A 38-year-old Caucasian woman, who had taken heroin vapor 2 weeks before, developed confusion, ataxia, and urinary incontinence. She was afebrile and spoke with a slow low-volume monotonous voice. She had marked truncal ataxia with absent postural reflexes, cogwheel rigidity in her limbs, and marked bradykinesia. She had used non-prescription amfetamine up to 4 g/day intermittently for 8 years. After a bout of depression, she came under the care of a psychiatrist and stopped taking amfetamine after she was given chlorpromazine and diazepam. She then started using heroin. In the CSF, protein was raised with normal glucose and lactate; homovanillic acid, a dopamine metabolite, was markedly reduced and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) was mildly reduced. Tetrahydrobiopterin was just detectable. She was given coenzyme Q 30 mg tds and became more alert and began to move and talk. She had recovered fully 1 month later.
According to the authors tetrahydrobiopterin has a range of co-factor roles, including being required for the activity of tyrosine and tryptophan hydroxylase, enzymes that are essential for dopamine and serotonin synthesis. They
Jayendra K. Patel, Timothy E. Ralston, and Eileen Wong
speculated that something present in the heroin pyrolysate, a product formed when heroin is heated to 250 ◦ C, inhaled by the patient, acted as a reversible inhibitor of tetrahydrobiopterin metabolism, providing a biochemical explanation for impairment of dopamine metabolism and Parkinsonism in this case. Psychiatric A group of 210 young individuals, aged 18–24 years, participating in the Australian Treatment Outcome Study, was studied for longitudinal treatment outcomes of heroin dependency (84C ). There was a high rate of psychiatric co-morbidity, including posttraumatic stress disorder (37%), current major depression (23%), antisocial personality disorder (75%), and borderline personality disorder (51%). While 17% had attempted suicide in the preceding year, 41% had overdosed at some time, 24% in the previous year. First heroin use occurred at age 16.8, first monthly use at age 17.2, and first intravenous use at age 17.4 years. The authors concluded that young heroin users moved to problematic drug use more quickly than did older users. Thus, there is a very limited window during which early intervention can be applied before young heroin users progress to problematic use. Nutrition In a case-control study in 106 heroin-dependent individuals undergoing an opioid detoxification program (n = 19) or a methadone maintenance treatment program (n = 87) there were large significant differences in the mean values of some vitamins and minerals between the heroin-dependent individuals and the healthy, non-dependent controls (85C ). Dependent individuals had higher white cell counts and transaminases and lower erythrocyte counts and cholesterol, albumin, tocopherol, folic acid, sodium, selenium, and copper concentrations. Infection risk Necrotizing fasciitis, a rapidly progressive soft tissue infection with high morbidity and mortality, is most commonly associated with drug abuse by injection. On the West Coast of the USA it is associated with the use of black tar heroin, which is a dense, gummy, coalcolored substance that is produced from opium grown in northern Mexico. Crude processing leads to contamination. In a retrospective review of cases of necrotizing fasciitis occurring
Drugs of abuse
47
Chapter 4
in the year 2000 there were 20 cases associated with black tar heroin; 17 were men (86c ). The mean age was 44 years and there were nine African Americans, six Caucasians, and five Hispanics. Eleven had involvement of the torso. The hospital mortality was 50%. Four patients had fever, 16 had tachycardia, four had blisters/bullae on their skin, and eight had brawny/woody skin. The mean white cell count was 37 × 109 /l, but survivors had lower counts than non-survivors (25 × 109 /l versus 49 × 109 /l). Blood cultures were positive in seven and surgical cultures in 15. The white cell count was the most consistent abnormal finding, and the degree of increase was associated with mortality. Hyponatremia was also common (47%). Lactate concentrations were raised but did not predict survival or mortality. Soft tissue gas on X-ray was present in one-third of the subjects. There was no common or predominant responsible organism, arguing against a single contaminated batch of black tar heroin. Fetotoxicity In nine prospective, longitudinal, multi-center studies, 1227 infants who were exposed in utero to cocaine (n = 474), opiates (n = 50), cocaine + opiates (n = 48), or neither (n = 655) were followed for 1–3 years after birth. Prenatal exposure to cocaine and/or opiates was not associated with mental, motor, or behavioral defects after controlling for birth weight and environmental risks. This result should be treated with caution, since the effects of prenatal opiates or cocaine exposure may become more evident as more advanced motor, cognitive, language, and behavioral skills develop (87Cr ).
Methadone
(SED-15, 2270; SEDA-28,
47) Fluid balance Edema has been reported after methadone treatment (88Ar ). • A 31-year-old white man with depression, hepatitis C, and cirrhosis of the liver was hospitalized for alcohol detoxification. He had taken methadone 50 mg bd for opium dependence for 6 months. He developed bilateral pedal edema and 27 kg weight gain. There was no ascites, portal hypertension, or congestive heart failure. Most of his laboratory tests were within the reference ranges, except for reduced prothrombin time and platelet count. After stopping alcohol, his methadone dose was reduced to 60 mg/day; his edema resolved 15 days later. When the dose of methadone was increased to 70 mg/day there was a progressive increase in the edema. When methadone was withdrawn his edema completely resolved and he lost 8 kg in 2 weeks.
The exact frequency of fluid retention from methadone is not known. Based on a review of previous case reports, the authors suggested that the usual time necessary to develop edema is 3– 6 months, but it can take several years. Marked fluid retention occurs mostly at high doses of methadone and the resultant edema is refractory to diuretics alone. Edema is reversible after withdrawal of methadone and recurs with rechallenge. The exact mechanism is not clear, but it has been speculated to be related to increased secretion of antidiuretic hormone, abnormalities in the globin fraction of total serum proteins, orthostatic circulatory congestion, or release of histamines from mast cells or basophils causing increased venular permeability leading to angioedema.
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4. Clark AJ, Ware MA, Yazer E, Murray TJ, Lynch ME. Patterns of cannabis use among patients with multiple sclerosis. Neurology 2004;62(11):2098–100. 5. Wade DT, Makela P, Robson P, House H, Bateman C. Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Mult Scler 2004;10(4):434–41. 6. Svendsen KB, Jensen TS, Bach FW. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ 2004;329(7460):253. 7. Notcutt W, Price M, Miller R, Newport S, Phillips C, Simmons S, Sansom C. Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 N of 1 studies. Anaesthesia 2004;59(5):440–52. 8. Ducasse E, Chevalier J, Dasnoy D, Speziale F, Fiorani P, Puppinck P. Popliteal artery entrapment associated with cannabis arteritis. Eur J Vasc Endovasc Surg 2004;27(3):327–32. 9. Goodyear K, Laws D, Turner J. Bilateral spontaneous pneumothorax in a cannabis smoker. J Roy Soc Med 2004;97:435–6. 10. Lozsadi DA, Forster A, Fletcher NA. Cannabisinduced propriospinal myoclonus. Mov Disord 2004;19(6):708–9. 11. Finsterer J, Christian P, Wolfgang K. Occipital stroke shortly after cannabis consumption. Clin Neurol Neurosurg 2004;106(4):305–8. 12. Shukla PC, Moore UB. Marijuana-induced transient global amnesia. South Med J 2004;97(8):782–4. 13. Ramaekers JG, Berghaus G, van Laar M, Drummer OH. Dose related risk of motor vehicle crashes after cannabis use. Drug Alcohol Depend 2004;73:109–19. 14. Jockers-Scherubl MC, Danker-Hopfe H, Mahlberg R, Selig F, Rentzsch J, Schurer F, Lang UE, Hellweg R. Brain-derived neurotrophic factor serum concentrations are increased in drug-naive schizophrenic patients with chronic cannabis abuse and multiple substance abuse. Neurosci Lett 2004;371(1):79–83. 15. Ilan AB, Smith ME, Gevins A. Effects of marijuana on neurophysiological signals of working and episodic memory. Psychopharmacology (Berl) 2004;176(2):214–22. 16. Lyons MJ, Bar JL, Panizzon MS, Toomey R, Eisen S, Xian H, Tsuang MT. Neuropsychological consequences of regular marijuana use: a twin study. Psychol Med 2004;34(7):1239–50. 17. Allen JH, de Moore GM, Heddle R, Twartz JC. Cannabinoid hyperemesis: cyclical hyperemesis in association with chronic cannabis abuse. Gut 2004;53:1566–70. 18. Villota JN, Rubio LF, Flores JS, Peris VB, Burguera EP, Gonzalez VB, Banuls MP, Escorihuela AL. Cocaine-induced coronary thrombosis and acute myocardial infarction. Int J Cardiol 2004;96:481–2.
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65. Bandstra ES, Morrow CE, Anthony JC, Accornero VH, Fried PA. Longitudinal investigation of task persistence and sustained attention in children with prenatal cocaine exposure. Neurotoxicol Teratol 2001;32:545–59. 66. Markowski VP, Cox C, Wei SS. Prenatal cocaine exposure produced gender-specific motor effects in aged rats. Neurotoxicol Teratol 1998;20:43– 53. 67. Field TM, Scaffidi F, Pickens J, Prodromidis M, Pelaez-Nogueras M, Torquati J, Wilcox H, Malphurs J, Schanberg S, Kuhn C. Polydrug-using adolescent mother and their infants receiving early intervention. Adolescence 1998;33:117–43. 68. Bennett DS, Bendersky M, Lewis M. Children’s intellectual and emotional behavioral adjustment at 4 years as a function of cocaine exposure, maternal characteristics, and environmental risk. Dev Psychol 2002;38:648–58. 69. Lewis B, Singer LT, Short EJ, Minnes S, Arendt R, Weishampel P, Klein N, Min MO. Four-year language outcomes of children exposed to cocaine in utero. Neurotox Teratol 2004;26:617–27. 70. Morrow CO, Vogel AL, Anthony JC, Ofir AY, Dausa AT, Bandstra E. Expressive and receptive language functioning in preschool children with prenatal cocaine exposure. J Pediatr Psychol 2004;29(7):543–54. 71. De Giorgio F, Rossi SS, Rainio J, Chiarotti M. Cocaine found in a child’s hair due to environmental exposure? Int J Legal Med 2004;118:310– 2. 72. Grigorov V, Goldberg L, Foccard JP. Cardiovascular complications of acute cocaine poisoning: a clinical case report. Cardiol J S Africa 2004;15:139–42. 73. Kaye S, Darke S. Non-fatal cocaine overdose among injecting and non-injecting cocaine users in Sydney, Australia. Addiction 2004;99:1315– 22. 74. Houtsmuller EJ, Notes LD, Newton T, Van Sluis N, Chiang N, Elkashef A, Bigelow GE. Transdermal selegiline and intravenous cocaine: safety and interactions. Psychopharmacology 2004;172:31–40. 75. Mirakbari SM. Heroin overdose as cause of death: Truth or myth. Aust J Forensic Sci 2004;36:73–8. 76. Man L-H, Best D, Gossop M, Stillwell G, Strang J. Relationship between prescribing and risk of opiate overdose among drug users in and out of maintenance treatment. Eur Addiction Res 2004;10:35–40. 77. Martyres RF, Clode D, Burns JM. Seeking drugs or seeking help? Escalating “doctor shopping” by young heroin users before fatal overdose. Med J Aust 2004;180(5):211–4.
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Shabir Musa, Andrew Byrne, and Stephen Curran
5
Hypnosedatives and anxiolytics
Hypnotics need to be prescribed appropriately, and recent guidance has been published (1S ). In particular, treatable causes for insomnia, such as psychiatric disorders and physical illnesses, need to be identified and treated before prescribing hypnotics.
benzodiazepines produced anterograde amnesia but not retrograde amnesia, and retrieval processes remained intact.
Alprazolam AZASPIRONES
(SEDA-26, 49; SEDA-27, 43; SEDA-28, 52)
Buspirone
(SED-15, 575)
Placebo-controlled studies Symptoms of anxiety are common among opioid-dependent individuals. Although buspirone has been used successfully for the treatment of anxiety in alcoholic patients, its efficacy in opioid-dependent patients had not been previously examined. In a 12-week, randomized, placebo-controlled trial of buspirone in 36 subjects receiving methadone maintenance treatment who presented with symptoms of anxiety, buspirone did not significantly reduce anxiety symptoms (2C ). However, buspirone was associated with trends toward reduction in depression scale scores and a slower return to substance use.
BENZODIAZEPINES
(SED-15, 429; SEDA-26, 46; SEDA-27, 43; SEDA-28, 52) Psychological A detailed review has confirmed a relation between impaired memory and benzodiazepine use (3R ). Different drugs had a similar profile in relation to memory impairment and this was independent of sedation. The Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29005-6 © 2007 Elsevier B.V. All rights reserved.
(SED-15, 91)
Psychiatric In a double-blind, placebo-controlled, repeated-measures design 16 healthy volunteers took alprazolam 1 mg, L-theanine 200 mg, or placebo (4c ). The acute effects of alprazolam and L-theanine were assessed under relaxed conditions and in experimentally induced anxiety. Subjective self-reports of anxiety were obtained during both task conditions before and after drug treatment. The results showed some evidence for a relaxing effect of L -theanine during the baseline condition. Alprazolam did not have any anxiolytic effects compared with placebo on any of the measures during the relaxed state. Neither L-theanine nor alprazolam had any significant anxiolytic effects during experimentally induced anxiety. Adverse events were not reported. Endocrine Benzodiazepines reduce hypothalamic–pituitary–adrenal axis activity acutely in healthy humans. The acute and chronic effects (3 weeks) of alprazolam and lorazepam on plasma cortisol have been examined in 68 subjects (aged 60–83 years), who took oral alprazolam 0.25 or 0.50 mg bd, or lorazepam 0.50 or 1.0 mg bd, or placebo according to a randomized, double-blind, placebo-controlled, parallel design (5c ). Plasma cortisol concentrations were significantly affected compared with placebo, but only by the 0.5 mg dose of alprazolam. During the first and last days of treatment, there was a significant fall in cortisol at 2.5 hours after alprazolam compared with placebo. The predose cortisol concentrations increased significantly during chronic alprazolam treatment, and there were correlations between the cortisol changes and changes
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in depression, anxiety, and memory scores. These findings suggest that even a short period of chronic treatment with alprazolam, but not lorazepam, may result in interdose activation of the hypothalamic–pituitary–adrenal axis in the elderly, consistent with drug withdrawal. If confirmed, this effect may contribute to an increased risk for drug escalation and dependence during chronic alprazolam treatment. Drug overdose The relative toxicity of alprazolam compared with other benzodiazepines has been assessed from a database of consecutive poisoning admissions to a regional toxicology service (6c ). There were 2065 admissions for single benzodiazepine overdose: alprazolam 131 overdoses, diazepam 823 overdoses and other benzodiazepine 1109 overdoses. The median length of stay for alprazolam overdoses was 19 hours, which was 1.27 times longer than for other benzodiazepines. Of patients with alprazolam overdoses, 22% were admitted to ICU, which was 2.06 times more likely than with other benzodiazepines. Flumazenil was given to 14% of alprazolam patients and 16% were ventilated, which was significantly more than for other benzodiazepine overdoses (8% and 11% respectively). Of those with alprazolam overdoses 12% had a Glasgow Coma Scale score under 9, compared with 10% for other benzodiazepines. The authors concluded that alprazolam was significantly more toxic after overdose than other benzodiazepines. Drug interactions Amfetamine Six healthy volunteers learned to recognize the effects of oral D-amfetamine 15 mg and then the effects of a range of doses of D -amfetamine (0, 2.5, 5, 10, and 15 mg), alone and after pre-treatment with alprazolam (0 and 0.5 mg), were assessed (7c ). Amfetamine alone functioned as a discriminative stimulus and produced stimulant-like self-reported drug effects related to dose. Alprazolam alone did not have amfetamine-like discriminative stimulus effects, nor did it increase ratings of sedation or impair performance. Alprazolam pre-treatment significantly attenuated the discriminative stimulus effects of amfetamine, and some of the self-reported drug effects. The authors suggested that future human laboratory-based studies should compare the behavioral effects of
Shabir Musa, Andrew Byrne, and Stephen Curran
amfetamine alone and after pre-treatment with alprazolam, using other behavioral arrangements, such as drug self-administration. They also suggested that benzodiazepines with lower abuse potential (for example oxazepam) might also attenuate the behavioral effects of amfetamine. Paroxetine In a double-blind, double-dummy, placebo-controlled, repeated-dose (15 days), 4period crossover study, each of 25 young adult volunteers received each of four treatment sequences (paroxetine + alprazolam placebo, alprazolam + paroxetine placebo, paroxetine + alprazolam, and paroxetine placebo + alprazolam placebo) in randomized order (8c ). There was no pharmacodynamic interaction at steady state. The most commonly reported adverse event was drowsiness, with a higher incidence when alprazolam was used, both alone and in combination with paroxetine.
Chlordiazepoxide
(SED-15, 713)
Teratogenicity The teratogenic potential of oral chlordiazepoxide has been studied by comparing 22 865 cases with congenital abnormalities and 38 151 matched healthy controls (9C ). Chlordiazepoxide had been used during pregnancy in 201 cases (0.88%) and 268 controls (0.70%). There was a significantly higher odds ratio for chlordiazepoxide use during the second and third months of gestation in those with congenital cardiovascular malformations. However, this association was found when exposure data were based mainly on maternal self-reported chlordiazepoxide use. There was no increase in the rate of any specific congenital cardiovascular malformation type. In conclusion, therapeutic doses of chlordiazepoxide during pregnancy are unlikely to pose a substantial teratogenic risk to the human fetus, although a somewhat higher rate of congenital cardiovascular malformations cannot be excluded.
Clobazam
(SED-15, 806)
Susceptibility factors Genetic Measurement of clobazam and Ndesmethylclobazam plasma concentrations and
Hypnosedatives and anxiolytics
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genetic analysis may be useful when unusual adverse effects occur (10A ). • A 10-year-old girl had two epileptic seizures and a subcontinuous spike and wave pattern during sleep. She was given clobazam and developed severe somnolence, weight gain, and severe enuresis. She had a high plasma concentration of N-desmethylclobazam, the major metabolite of clobazam. She and her parents underwent molecular analysis of the CYP2C19 gene, which is implicated in the metabolism of this drug. She had one copy of the most common mutation (CYP2C19*2), as did her mother, and probably another rare mutation.
Drug overdose Clobazam toxicity can cause respiratory depression. • A 49-year-old woman, a chronic alcoholic who had been undergoing psychiatric treatment, was found dead at home (11A ). Autopsy findings were unremarkable. Further detailed analysis showed that the clobazam concentration found in post-mortem blood was 3.9 µg/ml higher than the usual target concentration (0.1–0.4 µg/ml). All the available information suggested that death had resulted from respiratory depression due to clobazam toxicity.
Drug interactions Further information on the hepatic metabolism of clobazam has been analysed in vitro (12E ). The specific cytochrome P450 isoforms that mediate the biotransformation of clobazam and of its metabolites Ndesmethylclobazam and 4 -hydroxyclobazam were identified using cDNA-expressed P450 and P450-specific chemical inhibitors. The results of this study showed that: • clobazam is mainly demethylated by CYP3A4, CYP2C19, and CYP2B6; • clobazam is 4 -hydroxylated by CYP2C19 and CYP2C18; • N-desmethylclobazam is 4 -hydroxylated by CYP2C19 and CYP2C18; • the formation of N-desmethylclobazam is mediated by CYP3A4, CYP2C19, and CYP2B6; • N-desmethylclobazam is hydroxylated to 4 hydroxydesmethylclobazam by CYP2C19. These findings explain some pharmacokinetic interactions of clobazam with ketoconazole (which inhibits the demethylation of clobazam by 70%) and omeprazole (which inhibits the hydroxylation of N-desmethylclobazam by 26%). In addition, in 22 patients with epilepsy who
were genotyped for CYP2C19, there was a higher plasma metabolic ratio of N-desmethylclobazam:clobazam in patients with one CYP2C19*2 mutated allele than in those with the wild-type genotype.
Clonazepam
(SED-15, 815)
Psychiatric Clonazepam is widely used for the treatment of sleep disturbances related to post-traumatic stress disorder, despite very limited published data supporting its use for this indication. In a randomized, single-blind, placebo-controlled, crossover trial of clonazepam 1 mg at bedtime for 1 week followed by 2 mg at bedtime for 1 week in six patients with combat-related post-traumatic stress disorder there were no statistically significant differences between clonazepam and placebo (13c ). Adverse effects of clonazepam were generally mild and essentially indiscernible from those attributed to placebo. Only one patient elected to continue taking clonazepam at the end of the trial. The small sample size was a significant limitation of the study. Metabolic In a randomized, double-blind, placebo-controlled, crossover study in 15 men (mean age 22 years), diazepam 10 mg and clonazepam 1 mg infused over 30 minutes both reduced insulin sensitivity and increased plasma glucose, but the effect of clonazepam was significantly greater (14c ). Urinary tract Urinary retention has been attributed to clonazepam. • A 2-year-old girl with epilepsy and dyskinetic cerebral palsy due to kernicterus, who was taking carbamazepine and valproate, was also given clonazepam 0.05 mg/day and 3 days later developed urinary retention, which did not improve with antibiotic treatment (15A ). A urine sample obtained by catheterization was sterile. Urinary retention persisted for 10 days, requiring repeated catheterization, but resolved after clonazepam was withdrawn. She was symptom free for the next 6 months.
Teratogenicity The medical records of 28 565 infants were surveyed as part of a hospitalbased malformation surveillance program to identify those who had been exposed prenatally
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to an anticonvulsant, including clonazepam (16C ). During 32 months, 166 anticonvulsantexposed infants were identified; 52 had been exposed to clonazepam, 43 as monotherapy, 33 of those during the first trimester. One infant had dysmorphic features, growth retardation, and a heart malformation. There was no increase in major malformations in births exposed to clonazepam monotherapy. However, the study was not large enough to have adequate power to determine whether or not the rate of major malformations is increased in clonazepam-exposed pregnancies.
Clorazepate Fetotoxicity A pregnant woman who was a regular user of anxiolytics took a large overdose of clorazepate at 38 weeks gestation (17A ). The baby, born at 39 weeks, failed to breathe, and tracheal intubation was necessary in the delivery room. The neonatal blood concentrations of the metabolites of clorazepate were very high at delivery and changed very little over the next 5 days. By day 6 the infant was still dependent on a ventilator and repeated oral administration of activated charcoal led to a significant reduction in the serum concentration of clorazepate and its metabolites. The concomitant clinical improvement enabled ventilation to be discontinued on day 12.
Diazepam
(SED-15, 1103)
Psychiatric Capgras syndrome has been attributed to diazepam. • A 78-year-old man with a long history of generalized anxiety disorder had benefited from diazepam for at least 30 years (18A ). During the 6 months before evaluation, he developed a fixed delusion that his sister-in-law had disguised herself as his wife and had replaced her at home. His anxiety symptoms remained at baseline and cognitive function was unimpaired on detailed testing. Medications included diazepam 5 mg bd, paroxetine 40 mg/day, levothyroxine, rabeprazole, ranitidine, and finasteride. The dose of diazepam was tapered and withdrawn and risperidone 0.5 mg qds was started. Within 10 days, the Capgras delusion had completely resolved and he readily recognized his wife during visits.
Shabir Musa, Andrew Byrne, and Stephen Curran
Drug administration route The safety of rectal diazepam gel (Dyastat) has been reviewed (19M ). Sedation and somnolence were the most common adverse events, ranging from 13 to 51%, but the real incidence was difficult to determine, because it was not always possible to distinguish between drug-related and postictal sedation. Neurocognitive effects were similar to those reported with intravenous diazepam, but with a slightly delayed onset and a longer duration. When neuropsychological testing was performed, test scores returned to baseline within 4 hours after administration. Hyperactivity was rarely appreciated in children treated with rectal diazepam gel. A few adults (<1%) reported agitation, euphoria, nervousness, and hyperkinesia. The incidence of respiratory depression or apnea was much lower than with intravenous administration: no respiratory depression occurred in 200 children included in controlled clinical studies of rectal diazepam gel, while only two children had respiratory depression in a study of 246 doses and there were two more cases of hypoventilation in another study of 1578 doses. Whether these instances were related to the medication or to seizures could not be definitely ascertained. In a controlled study, mean and minimum respiratory rates 15 minutes to 4 hours after treatment were similar in patients who received rectal diazepam compared with those who received placebo. Despite the high level of concern, an out-of-hospital study showed a 23% complication rate (hypotension, cardiac dysrhythmias, and respiratory depression) among patients treated with placebo, compared with 11% for intravenous diazepam and 10% for intravenous lorazepam, suggesting that the respiratory complications of some seizures are significant and the very small risk of respiratory depression with rectal diazepam is outweighed by the much greater risk of delaying treatment. Other adverse effects were pruritus and rash (3.1–4.4%) and rectal irritation (3.6–4.4%, compared with 3.1–3.4% in the placebo group). Rectal diazepam is not intended for use more than five times per month (one dose every 5 days), because repeated administration can exacerbate seizures and cause withdrawal seizures. There were at least six cases of seizure worsening, some with a clear cyclic pattern, suggesting a relation to intermittent use of diazepam. All improved after rectal diazepam
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was restricted or withdrawn. However, in some cases intermittent diazepam had to be replaced by long-term low-dose treatment with oral benzodiazepines. As of February 2003 a total of 40 reports describing 63 adverse events attributed to rectal diazepam gel were filed at the FDA’s MedWatch program. These included convulsions or ineffective treatment in eight patients; gastrointestinal symptoms (vomiting, constipation, diarrhea, or abnormal stools) in seven; emotional and cognitive adverse effects (disorientation, confusion, memory impairment, stupor, nervousness, emotional lability) in six; respiratory depression and dyspnea in six; somnolence in four; hypotension or vasodilatation, pain, and skin rash or anaphylactic reactions in two each; infection, a positive drug screen, an unevaluable reaction, rectal hemorrhage, and abnormal vision in one each. There were three deaths, whose causes were not conclusively determined. Drug overdose In 40 of 51 instances of overdose of rectal diazepam there were no adverse events (19M ). However, in 11 cases adverse events included vomiting (n = 3), otitis media (n = 3), and bronchitis, convulsion, cough, fever and somnolence (n = 1 each). There was no cardiac or respiratory depression in any case of overdose, and all events resolved without incident.
(in which no drugs other than lorazepam were present) Drug Recognition Expert reports were obtained, containing details of events surrounding arrests and performances on field sobriety tests; lorazepam concentrations in these cases averaged 50 ng/ml. These results suggested that lorazepam can cause significant impairment of driving and psychomotor abilities, independent of the blood concentration. In a comparison of interventions commonly used for controlling agitation or violence in people with serious psychiatric disorders, 200 people were randomized to intramuscular lorazepam 4 mg or intramuscular haloperidol 10 mg + promethazine 25–50 mg (21C ). The haloperidol + promethazine combination produced a faster onset of tranquillization/sedation and more clinical improvement over the first 2 hours. The intervention did not differ in the need for additional interventions or physical restraints, numbers absconding, or adverse effects. Adverse effects were uncommon in both groups, but were only very briefly mentioned; they included respiratory difficulty in one patient given lorazepam and nausea and dizziness in another. Both interventions are effective in controlling violent/agitated behavior. If speed of sedation is required, the haloperidol + promethazine combination has advantages over lorazepam.
Lormetazepam Lorazepam
(SED-15, 2163)
Nervous system Lorazepam is often used to manage anxiety, presurgically, and as a sedative. Common adverse effects include sedation, dizziness, weakness, unsteadiness, and disorientation, and lorazepam can cause significant impairment of driving ability. All positive lorazepam drug-impaired driving cases submitted to the Washington State Toxicology Laboratory between January 1998 and December 2003 were reviewed (20c ). The mean whole lorazepam blood concentration in these drivers (n = 170, 56% male, mean age 40 years) was 48 ng/ml, but 86% of drivers tested positive for other drugs, which may have contributed to their impairment. In 23 cases lorazepam was the only drug detected, at a mean blood concentration of 51 ng/ml. In ten of the other cases
(SED-15, 2167)
Drug formulations A new oral solution formulation of lormetazepam has been compared with lormetazepam tablets in an open, randomized, parallel group study in 108 out-patients with insomnia. They were given 0.5 mg on the first night and were allowed to increase their dosage by 0.25 mg each day (for the oral solution) or 0.5 mg every 2 days (for the tablets). The mean daily dose of lormetazepam was lower in those who used the oral solution than in those who used the tablets, and the cumulative dose of lormetazepam was lower with the oral solution (22c ). There were no significant differences between the groups in sleep characteristics or adverse effects. The occurrence of adverse effects did not differ between the two groups. Adverse events related to the lormetazepam tablet included mouth ulcers
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(n = 1), drowsiness (3), headache (2), frequent dreams (1), insomnia (3), night sweats (1). Adverse events associated with the lormetazepam oral solution included bad taste (n = 2), bitterness (2), dry mouth (1), drowsiness (5), hypotension (1), nausea/constipation (2), insomnia (3), and headache (1). These results suggest that using an oral solution of lormetazepam allows easier determination of the minimal individual effective dose.
Midazolam
(SED-15, 2337)
Comparative studies In a comparison of intranasal midazolam 0.2 mg/kg and intravenous diazepam 0.2 mg/kg in the treatment of acute childhood seizures in 70 children aged 2 months to 15 years with acute seizures (febrile or afebrile), the two drugs were equally effective and there were no significant adverse effects in either group (23c ). Although intranasal midazolam was as safe and effective as diazepam, seizures were controlled more quickly with intravenous diazepam. Cardiovascular Midazolam is often used for conscious sedation during transesophageal echocardiography. In a prospective study of the effects of midazolam or no sedation in addition to pharyngeal local anesthesia with lidocaine on the cardiorespiratory effects of transesophageal echocardiography in patients in sinus rhythm midazolam (median dose 3.3, range 1–5 mg) caused significantly higher heart rates and significantly lower blood pressures and oxygen saturations (24c ). Nervous system Sedation, cognition, and mood during midazolam infusion in 20 volunteers with red hair and 19 with non-red (blond or brown) hair were studied in a randomized, placebo-controlled, cross-over design, to test the hypothesis that patients with red hair may require more drug to attain desired degrees of sedation (25c ). The red-haired volunteers had significantly greater alertness and lower drowsiness scores than non-red-haired subjects during midazolam infusion. Visuospatial scores were significantly higher in the subjects with red hair than in those with non-red hair during both placebo and midazolam trials. Delayed memory
Shabir Musa, Andrew Byrne, and Stephen Curran
scores were significantly higher during midazolam infusion in subjects with red hair than in those with non-red hair. Midazolam appears to cause significantly less sedation and cognitive impairment in red-haired subjects. The potential of intrathecal midazolam to produce symptoms suggestive of neurological damage has been investigated in a comparison of patients (n = 1100) who received intrathecal anesthesia with or without intrathecal midazolam 2 mg (26c ). Eighteen risk factors were evaluated with respect to symptoms representing potential neurological complications. Intrathecal midazolam was not associated with an increased risk of neurological symptoms. In contrast, neurological symptoms were increased in patients aged over 70 years and in those with a blood-stained spinal tap. Body temperature Hypothermia is common during anesthesia, and adversely affects outcome. It primarily results from internal redistribution of body heat from the core to the periphery. Premedication with sedative agents can affect perioperative heat loss by altering coreto-peripheral heat distribution. This has been analysed in a prospective randomized study in 45 patients undergoing arthroscopic knee ligament reconstruction surgery (27c ). Heavy premedication caused initial hypothermia. Moderate premedication reduced perioperative heat loss. No premedication was associated with significantly lower intraoperative core temperatures than in sedated patients.
Quazepam
(SED-15, 2995)
Drug interactions St John’s wort The effect of St John’s wort 900 mg/day on a single dose of quazepam 15 mg have been examined in a randomized, placebo-controlled, crossover study in 13 healthy subjects (28c ). Quazepam, but not St John’s wort, produced sedative-like effects on a visual analogue test. St John’s wort reduced the plasma quazepam concentration but did not affect the pharmacodynamics of quazepam. St John’s wort, but not quazepam, impaired psychomotor performance in a digit symbol substitution test. The results suggested that St
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John’s wort reduces plasma quazepam concentrations, probably by increasing CYP3A4 activity, but does not influence the pharmacodynamic effects of the drug.
OTHER HYPNOTICS AND SEDATIVES Zaleplon
(SED-15, 3710; SEDA-26, 49; SEDA-27, 46; SEDA-28, 56) Nervous system Zaleplon has been reported to cause sleepwalking.
• A 14-year-old boy with major depressive disorder responded to paroxetine 20 mg/day with full remission of depressive symptoms except insomnia (29A ). Diphenhydramine and trazodone did not improve his sleep and caused excessive daytime drowsiness. He then responded well to zaleplon 10 mg, but when he took two extra tablets 3 weeks later he developed complex behavior and sleepwalking. He had slurred speech, was slow in responding to questions, was moderately confused, and was uncoordinated and moved slowly. Physical examination, routine laboratory investigations, and an electrocardiogram were all normal. He remained in hospital for 8 hours and awakened without any memory of his activities. His mental state at 1 week and 1 month were both normal.
In a double-blind, placebo-controlled, repeated-measures study of the effects of zaleplon 10 mg on performance after a short period (1 hour) of daytime sleep in 16 volunteers (eight men and eight women) zaleplon had a statistically significant negative impact on balance through the first 2 hours after the dose compared with placebo (30c ). In addition, symptoms related to “drowsiness” were statistically more prevalent with zaleplon during the first 3 hours. Zaleplon also had a significantly negative impact on memory at 1 hour and 4 hours.
Zolpidem
(SED-15, 3723; SEDA-26, 50;
SEDA-28, 56) In 80 elderly subjects (aged over 70 years) with disorders of sleep and co-morbidities, including
57 diabetes and arterial hypertension, zolpidem was effective and well tolerated (31c ). Nervous system In in-patients aged 50 years or older who received zolpidem as a hypnotic, 23 patients had respectively 16 and 10 adverse drug reactions possibly and probably related to zolpidem use (19% incidence) (32c ). Of the total 26 adverse drug reactions, 21 affected the nervous system and occurred with both zolpidem 5 mg and 10 mg. Zolpidem was withdrawn in 39% of those who had a nervous system adverse drug reaction. • A 28-year-old man sustained anoxic brain damage following an aborted cardiac arrest and subsequently developed severe muscular rigidity and spasticity involving all the limbs (33A ). The spasticity was refractory to the standard regimens used for spastic hypertonia. Zolpidem dramatically inhibited muscular rigidity, spasticity, and dystonic posturing in a dose-dependent manner, resulting in a sustained improvement in global performance over 4 years. The only adverse effects were mild drowsiness and mild postural instability.
The authors postulated a central mechanism of action by selective inhibition of GABAergic inhibitory neurons. Psychiatric A paranoid syndrome has been attributed to zolpidem. • A 67-year-old former teacher with no significant psychiatric history developed progressively worsening confusion, agitation, rapid speech, poor sleep, limited appetite, flight of ideas, and increasingly disorganized and paranoid thoughts (34A ). Her only medication was zolpidem, 10 mg at bedtime, which had been started 6 weeks earlier. Routine laboratory tests and a CT head scan were normal. The outcome was not reported.
Drug dependence A rare case of physical and psychological addiction to an excessive dose of zolpidem and subsequent detoxification using diazepam has been reported. • A 46-year-old white man with a history of polysubstance abuse took zolpidem for 2 years and gradually increased the total dosage to about 400 mg/day in divided doses; he was detoxified using a standard benzodiazepine 7-day diazepam tapering regimen (35A ).
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References 1. National Institute for Health and Clinical Excellence. Zaleplon, zolpidem and zopiclone for the short-term management of insomnia. Technology Appraisal Guidance 2004:77. www.nice.org.uk. 2. McRae AL, Sonne SC, Brady KT, Durkalski V, Palesch Y. A randomized, placebo-controlled trial of buspirone for the treatment of anxiety in opioid-dependent individuals. Am J Addict 2004;13:53–63. 3. Ghoneim MM. Drugs and human memory (Part 2). Clinical, theoretical and methodological issues. Anaesthesiology 2004;100:1277–97. 4. Lu K, Gray MA, Oliver C, Liley DT, Harrison BJ, Bartholomeusz CF, Phan KL, Nathan PJ. The acute effects of L-theanine in comparison with alprazolam on anticipatory anxiety in humans. Hum Psychopharmacol 2004;19:457–65. 5. Pomara N, Willoughby LM, Ritchie JC, Sidtis JJ, Greenblatt DJ, Nemeroff CB. Interdose elevation in plasma cortisol during chronic treatment with alprazolam but not lorazepam in the elderly. Neuropsychopharmacology 2004;29:605–11. 6. Isbister GK, O’Regan L, Sibbritt D, Whyte IA. Alprazolam is relatively more toxic than other benzodiazepines in overdose. Br J Clin Pharmacol 2004;58(1):88–95. 7. Rush CR, Stoops WW, Wagner FP, Hays LR, Glaser PEA. Alprazolam attenuates the behavioral effects of d-amphetamine in humans. J Clin Psychopharmacol 2004;24(4):410–20. 8. Calvo G, Garcia-Gea C, Luque A, Morte A, DalRé, Barbanoj M. Lack of pharmacologic interaction between paroxetine and alprazolam at steady state in health volunteers. J Clin Psychopharmacol 2004;24(3):268–76. 9. Czeizel AE, Rockenbauer M, Sorenson, Olsen J. A population-based case-control study of oral chlordiazepoxide use during pregnancy and risk of congenital abnormalities. Neurotoxicol Teratol 2004;26(4):593–8. 10. Parmeggiani A, Posar A, Sangiorgi S, Giovanardi-Rossi P. Unusual side-effects due to clobazam: a case report with genetic study of CYP2C19. Brain Dev 2004;26:63–6. 11. Proença P, Teixeira H, Pinheiro J, Marques EP, Vieira DN. Forensic intoxication with clobazam: HPLC/DAD/MSD analysis. Forensic Sci Int 2004;143:205–9. 12. Giraud C, Tran A, Rey E, Vincent J, Treluyer JM, Pons G. In vitro characterization of clobazam metabolism by recombinant cytochrome P450 enzymes: importance of CYP2C19. Drug Metab Dispos 2004;32(11):1279–86. 13. Cates ME, Bishop MH, Davis LL, Lowe JS, Woolley TW. Clonazepam for treatment of sleep disturbances associated with combatrelated posttraumatic stress disorder. Ann Pharmacother 2004;38:1395–9. 14. Chevassus H, Mourand I, Molinier N, Lacarelle B, Brun JF, Petit P. Assessment of
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29. Liskow B, Pikalov A. Zaleplon overdose associated with sleepwalking and complex behaviour. J Am Acad Child Adolesc Psychiatry 2004;43:927–8. 30. Whitmore JN, Fischer JR, Barton EC, Storm WF. Performance following a sudden awakening from daytime nap induced by zaleplon. Aviation Space Environ Med 2004;75(1):29–36. 31. Cotroneo A, Gareri P, Lacava R, Cabodi S. Use of zolpidem in over 75-year-old patients with sleep disorders and comorbidities. Arch Gerontol Geriatr 2004;38:93–6. 32. Mahoney JE, Webb MJ, Gray SL. Zolpidem prescribing and adverse drug reactions in hos-
59 pitalized general medicine patients at a Veterans Affairs Hospital. Am J Geriatr Pharmacother 2004;2(1):66–74. 33. Shadan FF, Poceta JS, Kline LE. Zolpidem for postanoxic spasticity. Southern Med J 2004;98:791–2. 34. Hill KP, Oberstar JV, Dunn ER. Zolpideminduced delirium with mania in an elderly woman. Psychosomatics 2004;45:88–9. 35. Rappa L, Larose-Pierre M, Payne DR, Eraikhuemen NE, Lanes DM, Kearson ML. Detoxification from high-dose zolpidem using diazepam. Ann Pharmacother 2004;38:590–4.
6
Antipsychotic drugs Alfonso Carvajal, Luis H. Martín Arias, and Natalia Jimeno
GENERAL
(SED-15, 2438)
Observational studies Of 300 hospitalized Asian patients with schizophrenia, 215 were being given polytherapy, defined as the use of more than one neuroleptic drug at one time (1c ). The average number of drugs, including depot formulations, was 1.8 neuroleptic drugs (range 1–4) and the mean daily dose in chlorpromazine equivalents was 612 (median 464; range: 25–2500) mg. Atypical neuroleptic drugs were scarcely used (n = 20). Anticholinergic antiparkinsonian drugs were prescribed in 82%. The frequency of adverse events increased with total dose, and dry mouth (19%), tremor (8.7%), and constipation (5.3%) were the most common. Combinations are often used in patients with treatment-resistant schizophrenia and schizoaffective disorders, and the published data (29 case reports and case series, n = 172, and one double-blind placebo-controlled trial, n = 28) between 1985 and 2003 have been reviewed (2R ). Significant adverse effects were rarely reported (by only 36 of the 200 subjects) and did not appear to be different in nature from those of monotherapy regimens: hypersalivation (n = 6), mild akathisia (n = 4), exacerbation of hoarding behavior (n = 2), neuroleptic malignant syndrome (n = 2), and neutropenia, agranulocytosis, oculogyric crises, atrial extra beats, and aggravation of previous tardive dyskinesia (n = 1 each). Comparative studies In contrast to current beliefs, atypicals caused more severe adverse effects than typical neuroleptic drugs did in a program intended to monitor the adverse effects of neuroleptic drugs in routine clinical practice Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29006-8 © 2007 Elsevier B.V. All rights reserved.
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(3C ). From 1993 to 2000, 86 439 patients who took at least one neuroleptic drug were monitored in 35 psychiatric hospitals in Germany and Switzerland. Overall, 975 clinically severe adverse effects were identified (1.1%). As to individual drugs in monotherapy, the incidences were: • • • • •
haloperidol, 0.2%; perazine, 0.4%; olanzapine, 0.5%; risperidone, 0.5%; clozapine, 0.9%.
The authors stated that their results were in accordance with those of a meta-analysis of 52 randomized trials (SEDA-25, 53). Coming from the same program, separate estimates have been made for different reactions: • severe galactorrhea occurred in 27 cases (0.03%); haloperidol, 0%; clozapine, 0%; perazine, 0.01%; olanzapine, 0.03%; risperidone, 0.09% (4C ). • severe neutropenia (neutrophils < 1.5 × 109 /l) occurred in 43 cases (0.05%); haloperidol, 0.01%; risperidone, 0.01%; olanzapine, 0.05%; perazine, 0.07%; clozapine, 0.16% (5C ). • severe and uncommon involuntary movement disorders occurred in 115 cases (0.13%); clozapine, 0.01%; perazine, 0.02%; olanzapine, 0.04%; risperidone, 0.09%; haloperidol, 0.18% (6C ). These estimates are very low, since only those reactions rated as probably or definitely drug related were considered. Delirium Two studies have recently addressed the effects of neuroleptic drugs in the treatment of delirium, defined as an alteration in mental status that is characterized by disturbance of consciousness and attention, cognition, and perception for a brief period of time. In 28 patients
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with delirium, randomly assigned to a flexibledose regimen of haloperidol (mean age 67; n = 12; starting dose 0.75 mg) or risperidone (mean age 66; n = 12; starting dose 0.5 mg) for 7 days, the response to haloperidol was 75% and to risperidone 42%, although the difference was not significant, probably owing to the small sample size and short duration of the study (7c ). One patient taking haloperidol had mild akathisia. In the second randomized study, there was similar clinical improvement with haloperidol (mean age 63 years; mean dose 6.5 mg/day; n = 45) and olanzapine (mean age 68 years; mean dose 4.5 mg/day; n = 28) over 5 days (8c ). Among the patients who received haloperidol, six rated low scores on extrapyramidal symptoms; there were no adverse effects attributable to olanzapine. Dementia Risperidone, olanzapine, and promazine have been compared in the treatment of the behavioral and psychological symptoms of dementia (9c ). At the end of the eighth week, there was complete regression of symptoms in 70% of those who took risperidone (mean age 77 years; dose 1–2 mg/day; n = 20), in 80% of those who took olanzapine (mean age 83 years; dose 5–10 mg/day; n = 20), and in 65% of those who took promazine (mean age 78 years; dose 50–100 mg/day; n = 20). The main adverse effects of risperidone were hypotension and somnolence (20%), dyspepsia (12%), sinus tachycardia, weakness, constipation, and extrapyramidal symptoms (8%), increased libido and disinhibition, abdominal pain and insomnia (4%). The main adverse effects of olanzapine were somnolence and weight gain (32%), dizziness and constipation (16%), postural hypotension (8%), akathisia (4%), and worsening of the blood sugar in one patient with diabetes (4%). The main adverse effects of promazine were constipation and hypotension (35%), dry mouth (30%), sinus tachycardia (25%), cognitive impairment and extrapyramidal symptoms (20%), confusion (15%), somnolence (10%), and nausea (5%). The small sample size, the short duration, the lack of blinding, and the lack of data on comparability were some of the flaws that preclude firm conclusions from this study. Schizophrenia With regard to schizophrenia, new updated treatment recommendations have been issued by the Schizophrenia Patient Outcomes Research Team (10S ). There is no definitive evidence that the atypical drugs differ
from the typical ones for the treatment of acute positive symptoms; there are no data to support a change to a second-generation neuroleptic drug for patients who have adequate symptom control and minimal adverse effects with first-generation neuroleptic drug therapy. For haloperidol, a maintenance dosage of 6–12 mg is recommended; this dosage is lower than that previously recommended by the same panel (6–20 mg) (11S ). In fact, the optimal daily dose remains a topic of controversy. In a recent double-blind, randomized, controlled study, comparison of haloperidol 2 mg/day (n = 20) and 8 mg/day (n = 20) in subjects with first-episode psychosis over 6 weeks the two doses had similar efficacy (12C ). Two patients developed dystonic reactions in the low-dose group and six in the high-dose group; the figures for akathisia were three and eight respectively; two developed dyskinesia, both in the high-dose group. Eleven patients did not complete the study, three in the lowdose group and eight in the high-dose group. Although the small sample size precludes firm conclusions, the results of this study are in accordance with those of the above-mentioned meta-analysis (SEDA-25, 53). In contrast, another meta-analysis showed the opposite conclusion (13M ). The effect sizes of olanzapine, risperidone, amisulpride, and clozapine were respectively 0.21, 0.25, 0.29, and 0.49 times greater than those of firstgeneration neuroleptic drugs; other atypical neuroleptic drugs were not significantly different from typical neuroleptic drugs, although zotepine was marginally different. No efficacy difference was detected among amisulpride, risperidone, and olanzapine. There was no evidence that the dosage of haloperidol (or of any first-generation neuroleptic drug converted to haloperidol-equivalent doses) affected these results when effects by drug were examined or in a 2-way analysis of variance model, in which the effectiveness of the atypical neuroleptic drug was entered as a second factor. Further information has been provided in recent comparisons of neuroleptic drugs (14R , 15R ) (SEDA-27, 50). Placebo-controlled studies Bipolar affective disorder Immediately after remission of an episode of mania treated with
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perphenazine + a mood stabilizer (lithium, carbamazepine, or valproate), patients were randomly assigned to 6 months of double-blind treatment in which, in addition to the mood stabilizer, they received either continued perphenazine (n = 19) or placebo (n = 18) (16C ). There were no between-group differences in various important demographic and clinical characteristics. Those given placebo were more likely than those who continued to take perphenazine to complete the study (83% versus 47%), to take longer to have a depressive relapse, to remain in the study for longer, and to have akinesia, dysphoria, and parkinsonism less often. The authors concluded that to continue a typical neuroleptic drug after remission from mania for an extended time may be detrimental for some patients. Dementia There is no clear evidence that typical neuroleptic drugs are effective in the management of the behavioral and psychological symptoms of dementia, and a systematic review has been conducted to assess the role of atypical drugs (17M ). Five good-quality randomized trials (1570 elderly patients with dementia; mean age 82 years), four evaluating risperidone and one olanzapine, were identified; all had been sponsored by a pharmaceutical company. In the short term (6–12 weeks) treatment with atypical neuroleptic drugs was superior to placebo for the primary endpoint in only three of the five trials. One of the studies reported serious adverse events in 9% of participants taking placebo and in 17% of those taking risperidone; in the risperidone group, there were six cerebrovascular adverse events and none in the placebo group (for a review, see SEDA-28, 76). Despite their short duration, most trials reported high withdrawal rates in both treatment and placebo groups. The conclusion was that, although atypical neuroleptic drugs are being used with increasing frequency, limited evidence supports the perception of improved efficacy and adverse event profiles compared with typical antipsychotic drugs. Cardiovascular QT interval prolongation and torsade de pointes remain a focus of attention (SEDA-26, 54; SEDA-27, 52; SEDA-28, 59). The topic has been reviewed and the susceptibility factors for drug-induced torsade de
pointes are: female sex, hypokalemia, bradycardia, recent conversion from atrial fibrillation (especially with a QT interval-prolonging drug), congestive heart failure, digitalis therapy, a high drug concentration, baseline QT interval prolongation, subclinical long QT syndrome, ion channel polymorphisms, and severe hypomagnesemia (18R ). Information on the strength of evidence linking some neuroleptic drugs to torsade de pointes has been reviewed (19R ). A new case of QT prolongation and torsade de pointes has been published (20A ). • A 34-year-old alcoholic man with acute pancreatitis was given continuous intravenous infusion of haloperidol (2 mg/hour) for agitation; after 7 hours he received a bolus dose of haloperidol 10 mg for worsening agitation and 20 minutes later, QT interval was 560 ms (420 ms before treatment). He developed torsade de pointes and ventricular fibrillation, which resolved with electric defibrillation. He was a smoker and was also taking tiapride and alprazolam for depression, in addition to pantoprazole, piperacillin + tazobactam, paracetamol, and vitamins B1 , B6 , and B12 .
Critically ill patients are particularly susceptible to torsade de pointes, owing to various comorbidities, electrolyte disturbance, and many drugs, as a recent case shows (21A ). • A 58-year-old woman with pneumonia and multiple co-morbidities developed disorientation, hypoxia, and respiratory failure. She was given intravenous haloperidol 70, 30, 300, 270, and 340 mg on days 1, 2, 3, 4, and 5 respectively; concomitant drugs were intravenous levofloxacin 500 mg/day for 14 days, piperacillin + tazobactam, doxycycline, midazolam, morphine, diltiazem, enoxaparin, famotidine, metoclopramide, hydroxychloroquine, and transdermal nicotine. On day 5, she developed non-sustained runs of ventricular tachycardia and torsade de pointes (QT interval 533 ms), which resolved after haloperidol was withdrawn and magnesium sulfate 4 g was given.
Of 86 439 patients who had been exposed to neuroleptic drugs, 59 developed a cardiovascular adverse effect (22c ). Among the commonly used neuroleptic drugs, the highest rate of cardiovascular adverse effects was found for clozapine (4.5 cases per 10 000 patients) including a case of myocarditis. The study was supported by a pharmaceutical company, and since no exposure times were provided, comparative estimates cannot be calculated.
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Nervous system Extrapyramidal symptoms have been identified at much higher rates in psychotic youths than in comparable adult populations (23c ). Subjects who selected because of prominent positive psychotic symptoms were randomly assigned to double-blind, parallel treatment with risperidone (mean age 15 years; mean dose at termination 4 mg; n = 19), olanzapine (mean age, 14.6 years; mean dose at termination, 12.3 mg; n = 16) or haloperidol (mean age 15 years; mean dose at termination 5 mg; n = 15) for 8 weeks; in all, 88% of those who took olanzapine, 74% of those who took risperidone, and 53% of those who took haloperidol met the response criteria. A large proportion of those in each treatment group required low-dose anticholinergic drugs to control their extrapyramidal symptoms (risperidone 53%; olanzapine 56%; haloperidol 67%). There was significant weight gain in all treatment groups (mean increases: risperidone 4.9 kg; olanzapine 7.1 kg; haloperidol 3.5 kg). Withdrawals were 47% with risperidone, 13% with olanzapine, and 47% with haloperidol. In a prospective study, 111 patients with schizophrenia and schizoaffective disorders were evaluated by means of a semistructured interview, providing information about childhood (up to 11 years), early adolescence (12–15 years), late adolescence (16–18 years), and adulthood (19 years and above) (24C ). There were no differences in the incidences of parkinsonism, akathisia, or dystonia among the three different premorbid functioning groups (stable good, deteriorating, and chronically poor premorbid functioning), but there were differences in tardive dyskinesia. Moreover, Premorbid Adjustment Scale scores predicted susceptibility to tardive dyskinesia but not to other extrapyramidal symptoms. Possible explanations for these findings are that tardive dyskinesia has a different pathophysiology from other extrapyramidal symptoms or that there is a more severe illness subtype characterized by more negative symptoms, which might account for the observation of orofacial dyskinesias before medication. As early as 1989, the World Health Organization recommended that neuroleptic drugs should be initiated without routinely adding anticholinergic drugs prophylactically (SEDA-21, 44). However, since anticholinergic drugs are used in this way in India, a study has been conducted to investigate whether Indians are
63 more susceptible to extrapyramidal adverse effects (25c ). Of 71 consecutive patients who were taking conventional neuroleptic drugs and who were repeatedly evaluated over 2 months, 68 had extrapyramidal symptoms while taking 2–13 mg/day of haloperidol equivalents, the most common being tremor (49%), cogwheel rigidity (40%), and acute dystonias (34%). The authors concluded that their findings supported consideration of routine prophylactic use of antiparkinsonian drugs in this population. • A 48-year-old man with a 25-year history of paranoid schizophrenia previously treated with neuroleptic drugs, took thioproperazine 40 mg/day, haloperidol 30 mg/day, penfluridol 20 mg/week, and biperiden 8 mg/day for 10 days, and developed dysphagia, voice problems, and tremor, which increased progressively despite dosage reductions (26A ). He could hardly speak and often choked on his food. Neuroleptic drug-induced tardive dystonia was diagnosed, and he was given biperiden up to 12 mg/day without significant improvement. Because of a psychotic relapse, olanzapine monotherapy 5 mg/day was introduced and titrated up to 20 mg/day. During the next 20 days both the dystonia and the psychotic symptoms improved dramatically; 1 year later he was taking olanzapine 15 mg/day and was free of dystonic movements and other adverse effects.
Psychological Dysphoria is said to be an under-recognized adverse effect of neuroleptic drugs; it encompasses a variety of unpleasant subjective changes in arousal, mood, thinking, and motivation, which occur early during treatment and typically manifest as a dislike for the medication. The authors of a thorough review have suggested that dysphoria that persists over time can lead to adverse consequences, such as treatment non-adherence, substance abuse, a poor clinical outcome, increased suicidality, and compromised quality of life (27R ). The authors of another review recommended explicitly asking about dysphoria and observing its outcome in order to improve adherence (28r ); their estimate was that a mean of 30% of treated patients have dysphoria. Endocrine Hyperprolactinemia is a wellknown adverse effect of neuroleptic drugs (SED-14, 148; SEDA-26, 56; SEDA-27, 53). Hyperprolactinemia with osteopenia has been described (29A ). • A 58-year-old schizophrenic woman who had taken haloperidol decanoate 125 mg every 2
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Table 1. Genetic factors and neuroleptic drug-induced adverse reactions Adverse reaction
Genetic factor
Comments
Reference
Tardive dyskinesia Tardive dyskinesia Tardive dyskinesia Clozapine-induced agranulocytosis Olanzapine-induced agranulocytosis Weight gain Weight gain Neuroleptic malignant syndrome Olanzapine toxicity
D3 receptor (Ser9Gly) CYP1A2 (intron 1) CYP2D6 variants Human leukocyte antigen variants Human leukocyte antigen variants 5-HT2C receptor variant CYP2D6 variants CYP2D6 variants
Greater severity Greater severity Conflicting results Association
SEDA-26, 55 SEDA-26, 55
Association
SEDA-26, 63
Conflicting results Association Conflicting results
SEDA-27, 53 and 57 SEDA-27, 61 SEDA-27, 58
Gilbert´s syndrome
Association
SEDA-28, 73
weeks had a mildly raised prolactin concentration (505 mIU/l; upper limit of the reference range 450 mIU/l). Dual X-ray absorptiometry showed osteopenia in her spine and hips. She began taking alendronic acid 5 mg/day and absorptiometry at 1 year showed that her spine and hip had improved by 7% and 9%, although her prolactin concentrations remained mildly raised.
In 55 patients who had been taking neuroleptic drugs for more than 10 years, higher doses of medication were associated with increased rates of both hyperprolactinemia and bone mineral density loss, as shown by dual X-ray absortiometry of their lumbar and hip bones (30c ). Metabolism Weight gain related to the use of atypical neuroleptic drugs in children and adolescents, in whom this adverse effect is of particular concern, has been reviewed (31R ). The published data suggest that clozapine and olanzapine are associated with considerable weight gain, risperidone and quetiapine have a moderate risk, and ziprasidone and aripiprazole a low risk. Moreover, obese children have an increased propensity for orthopedic, neurological, pulmonary, and gastroenterological complications. The effects of neuroleptic drugs on serum lipids in adults have been reviewed (32R ). Haloperidol and the atypical neuroleptic drugs ziprasidone, risperidone, and aripiprazole, are associated with lower risks of hyperlipidemia, whereas chlorpromazine, thioridazine, and the atypical drugs quetiapine, olanzapine, and clozapine are associated with higher risks. Treatment of the metabolic disturbances caused by neuroleptic drugs has also been reviewed (33R ).
SEDA-26, 60
Pregnancy and lactation The use of drugs during pregnancy and breastfeeding has been briefly reviewed (34r ). Susceptibility factors Genetic Genetic factors, about which more and more information is emerging (Table 1), could help to explain some of the susceptibility factors for severe adverse reactions to antipsychotic drugs. The ryanodine receptors (RYRs) are a family of intracellular Ca2+ release channels that play a pivotal role in the regulation of intracellular Ca2+ homeostasis in muscle cells and neurons; there are three isoforms, RYR1 (skeletal muscle), RYR2 (cardiac muscle and brain), and RYR3 (brain and some smooth muscle). So far, 22 different mutations in the RYR1 gene have been identified to play a causative role in the pathogenesis of malignant hyperthermia, but none of these mutations has been found in neuroleptic malignant syndrome. A pilot study to screen for mutations in RYR coding sequences has been conducted in two patients with recurrent neuroleptic malignant syndrome induced by different neuroleptic drugs (35A ). The analysis did not reveal sequence variants that are likely to confer vulnerability to neuroleptic malignant syndrome. No polymorphism of neural nitric oxide synthase gene was found in 128 Chinese patients with neuroleptic drug-induced tardive dyskinesia compared with 123 controls (36C ). After adjusting the effects of confounding factors, there was no significant association between NOS1 3 -UTR C276T genotypes and tardive dyskinesia.
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An association between weight gain and a 5-HT2C receptor gene polymorphism has been identified (SEDA-28, 53). However, two genetic variants of the β3 adrenoceptor (Trp64Arg) and the G-protein β3 subunit (C825T) did not play a significant role in clozapine-induced weight gain in a study in 87 treatment-resistant patients with schizophrenia (37C ). In a survey of data from several studies in 126 African–American patients and 574 white patients who were randomly selected and for whom neuroleptic drugs were prescribed, the African–American patients, after adjustments for clinical, sociodemographic, and healthsystem characteristics, were less likely than the white patients to receive second-generation neuroleptic drugs (49% compared with 66%) (38c ).
INDIVIDUAL DRUGS Amisulpride
(SED-15, 173; SEDA-26,
58; SEDA-27, 54) Placebo-controlled studies Eighteen randomized controlled trials that compared amisulpride with conventional neuroleptic drugs or placebo in patients with schizophrenia have been combined in a meta-analysis (39M ). The differences in the mean effect size for efficacy clearly showed that all types of neuroleptic drugs were more effective than placebo, but the difference in mean effect size for all neuroleptic drugs versus placebo (n = 2000) was only 25%. Amisulpride was associated with fewer extrapyramidal adverse effects and fewer drop-outs because of adverse events than conventional neuroleptic drugs. More risperidone recipients than amisulpride recipients had endocrine problems, but the difference was not statistically significant. Clozapine and olanzapine had the greatest potential to cause weight gain; after 10 weeks of treatment, mean increases in weight were 4.4 kg with clozapine and 4.1 kg with olanzapine. Risperidone also caused weight gain (a mean increase of 2.1 kg after 10 weeks), while ziprasidone caused the least gain; amisulpride has since been found to cause minor weight gain, about 0.8 kg after 10 weeks.
65 Comparative studies Two previously published, separate, randomized, controlled trials have been reviewed (40R ). In the first, amisulpride was compared with risperidone in a 6-month, randomized, controlled trial in 304 patients with schizophrenia; the percentage of patients that responded to treatment was significantly greater with amisulpride 200–800 mg than risperidone 2–8 mg; amisulpride was superior to risperidone with respect to weight gain, as only 18% of amisulpride-treated patients increased their weight by more than 7% after 6 months compared with 33% of risperidonetreated patients. The other study was a randomized comparison of amisulpride with olanzapine in 377 patients with schizophrenia with predominantly positive symptoms, who were treated for 6 months with either amisulpride 200–800 mg or olanzapine 5–20 mg. Positive and negative scores were similar for amisulpride and olanzapine; new weight gain was less in amisulpride-treated patients; by day 56, amisulpride recipients had gained 0.4 kg whereas olanzapine recipients had gained 2.7 kg. The prescribing of amisulpride for 811 schizophrenic in-patients from 240 psychiatric hospitals was monitored for 8 weeks; prescribed dosages were in the lower range of what is recommended for acute cases: the mean dose on day 56 was on average 550 mg/day, range 100–1600 mg/day (41c ). For the most severe cases there was a tendency for higher doses to be related to better improvement in positive symptoms and in negative symptoms; this correlation was not found in the least severe cases. The authors pointed out that this supports the notion that in more severe cases higher doses should be prescribed, while in milder cases lower doses may be sufficient; this would be in line with existing prescribing recommendations (800 mg/day as a standard dose in severe and recurrent episodes and especially in hospital; in the case of an insufficient response, the dose can be increased to 1200 mg/day) (42R ). Endocrine Five women with psychoses treated with amisulpride developed hyperprolactinemia and were treated with bromocriptine 10–40 mg/day (43A ). Prolactin concentrations were markedly reduced in only three of the five; menses recurred in one of four patients with amenorrhea; lactation decreased in one of three
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patients with galactorrhea, and in two patients with reduced prolactin concentrations the psychotic symptoms exacerbated but fully remitted after withdrawal of bromocriptine. A 40-yearold woman also developed amenorrhea while taking a very low dose of amisulpride for 3 months (100 mg/day) (44A ). A prolactinoma has been attributed to amisulpride. • A 38-year-old woman with a borderline personality disorder developed a prolactinoma, with hyperprolactinemia, amenorrhea, and galactorrhea, probably induced by amisulpride 300 mg/day, which she had taken for 4 months following a bout of delirium with impaired attention, cognitive alteration, anxiety, and agitation (45A ). She had a microadenoma (5 mm) on the right side of the pituitary gland. Amisulpride was withdrawn and replaced by quetiapine 100 mg/day. The symptoms of hyperprolactinemia resolved.
Clozapine (SED-15, 823; SEDA-26, 59; SEDA-27, 55; SEDA-28, 65) In recent years there has been interest in comparing clozapine and typical neuroleptic drugs (SEDA-27, 50), and in studying whether special subgroups of patients can benefit from clozapine (SEDA-27, 49), such as patients with psychosis related to Parkinson’s disease (SEDA-24, 63; SEDA-28, 66). In a 4-week, randomized, double-blind, parallel comparison of clozapine (n = 32) and placebo (n = 28), followed by a 12-week clozapine open period, plus a 1-month period after drug withdrawal in patients with Parkinson’s disease with drug-induced psychosis, clozapine at a mean dose below 50 mg/day produced improvement without significantly worsening motor function according to the Unified Parkinson’s Disease Rating Scale; however, the effect wore off once treatment was withdrawn (46c ). Somnolence was more common with clozapine than with placebo; one patient taking clozapine had seizures; two patients taking clozapine had transient neutropenia; in one the blood count normalized despite clozapine continuation and in one withdrawal was required. There was worsening of parkinsonism in 14 patients taking clozapine. Maintenance therapy with neuroleptic drugs is an important aspect of the management of
schizophrenia; maintenance therapy is usually conducted by halving the drug dosage that has proven effective during the acute phase. In a non-randomized study, records from patients taking clozapine (n = 181; mean duration of maintenance treatment 12.2 years) were compared with those of a control group of patients taking haloperidol (n = 152; mean duration of treatment 3.8 years) (47c ). The relapse rate was similar in the two groups, but the authors pointed out that compliance and therapeutic efficacy were superior with clozapine. The incidences of drowsiness, somnolence, delirium, and postural hypotension were similar in the two groups; however, only 1% of clozapinetreated patients complained of dry mouth, compared with 27% of those taking haloperidol. Extrapyramidal symptoms occurred in about 80% of those taking haloperidol (71% had parkinsonism and 9.2% had tardive dyskinesia) and none of those taking clozapine. Drooling was the sole adverse effect with a lower incidence in those taking haloperidol, and no patient in either group had agranulocytosis or granulocytopenia. Clozapine has been evaluated in six treatment-resistant abused adolescents with posttraumatic stress disorder and psychotic symptoms, who had received at least two trials of conventional neuroleptic drugs, with particular attention to adverse effects (48c ). Clozapine was introduced after a 6-month baseline period and titrated over 173 days before the criterion dose (400 mg/day) was reached; the dose of clozapine reached a maximum of 600 mg/day during the treatment phase. Specific adverse effects were rated on a 0–4 scale, 0 representing “no difficulty” and 4 representing “severe difficulty;” the ratings of adverse effects were as follows: excessive salivation (2.7), dizziness (2.2), weight gain (2.0), nausea (1.7), feeling sleepy (1.5), constipation (1.3), palpitation (0.5), and dry mouth (0). The combination of clozapine and amisulpride for the treatment of refractory schizophrenia has been assessed in seven patients. The response to clozapine plus amisulpride was rated as at least good in six cases (Clinical Global Impression Scale 3), the average length of treatment being 30 weeks (49A ). There were no significant changes in electrocardiographic time intervals after the addition of amisulpride to clozapine, and both the mean resting heart
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rate and mean QTc interval were unaffected; mean clozapine plasma concentrations did not differ significantly from baseline. • In a 28-year-old woman with psychotic symptoms resistant to monotherapy with clozapine or ziprasidone, the combination produced marked improvement in both positive and negative symptoms along with a reduction in adverse effects: body weight fell, blood pressure, pulse, and the electrocardiogram remained normal, and valproic acid, which had been introduced for epileptic seizures during clozapine monotherapy, was successfully withdrawn (50A ).
Cardiovascular Pericardial effusion associated with clozapine has been reported (SEDA27, 55) and can be accompanied by pleural effusions (51A ). • A 21-year-old man with paranoid schizophrenia was treated with zuclopentixol, which was withdrawn because of extrapyramidal adverse effects, He was given clozapine 300 mg/day, and from day 43 developed breathlessness and complained of pain in his shoulders on deep inspiration. A chest X-ray showed an enlarged cardiac silhouette and bilateral pleural effusions. An echocardiogram showed pericardial and pleural effusions with no compromise of cardiac function. Clozapine was withdrawn and all the symptoms resolved within 2 weeks.
Nervous system Neuroleptic malignant syndrome has occasionally been associated with clozapine (SEDA-28, 66). • A 52-year-old man with risk factors, including a subdural hematoma and three prior episodes of neuroleptic malignant syndrome secondary to chlorpromazine, loxapine, and lithium, developed neuroleptic malignant syndrome while taking clozapine (52A ).
Clozapine can cause stuttering (SEDA-27, 56). • A 57-year-old man developed severe stuttering after taking clozapine 300 mg/day and sodium valproate 600 mg/day for 8 months (53A ). It abated 1 week after clozapine was reduced and finally withdrawn.
Clozapine is said to have little or no potential to cause tardive dystonia, and it has been speculated that it may be effective in treating it, even primary dystonia (SEDA-25, 62). Two cases of severe oromandibular dystonia refractory to other antidystonic therapies, including botulinum toxin, which improved with clozapine have been reported (54A ).
67 Metabolism Weight gain has been commonly associated with clozapine (SEDA-27, 56; SEDA-28, 66). Weight gain with clozapine compared with other neuroleptic drugs has been studied in in-patients who were randomly assigned to switch to open treatment with clozapine (n = 138) or to continue receiving conventional neuroleptic drugs (n = 89) (55c ). Patients gained weight at the end of 2 years whether they switched to clozapine (5.9 kg, 7%) or continued to take first-generation neuroleptic drugs (2.3 kg, 4%), but weight gain was significantly greater (1 body mass index unit) in those taking clozapine, particularly women. The relation between genetic variants of the β3 adrenoceptor and the G-protein β3 subunit and clozapine-induced body weight change has been investigated in 87 treatment-resistant patients with schizophrenia (37c ). They gained an average of 2.6 kg. There was no statistically significant relation between weight gain and either the β3 adrenoceptor Trp6Arg or the G-protein β3 subunit C8257 polymorphisms. Hyperglycemia has been observed in patients taking clozapine (SEDA-26, 59). The effect of clozapine on glucose control and insulin sensitivity has been studied prospectively in 9 women and 11 men with schizophrenia (mean age 31 years) (56c ). Insulin resistance at baseline was unaffected by clozapine, but 11 of the patients developed abnormal glucose control (mean age 30 years; five women). Mean fasting and 2-hour glucose concentrations increased significantly by 0.55 mmol/l. There was no correlation between change in body mass index and change in fasting glucose concentrations. Hematologic It is currently assumed that patients with severe neutropenia secondary to clozapine are at a high risk of recurrent neutropenia, and even agranulocytosis, if they are re-exposed to clozapine (SEDA-28, 67). According to the recommended guidelines by Novartis, neutropenia (a white blood cell count below 3.0 × 109 /l or an absolute neutrophil count below 1.5 × 109 /l) during clozapine treatment is classified as being in the “redalert zone”; immediate withdrawal of clozapine is recommended and reinstitution prohibited. However, in some patients, this is not feasible, because of lack of effective alternatives to
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clozapine. In five patients who were maintained on clozapine despite red-alert zone neutropenia and two control patients who discontinued clozapine because of neutropenia, hematological and clinical progress was followed for more than 600 days (57A ). In all five patients, there were no additional episodes of neutropenia despite continued clozapine treatment. Two patients taking clozapine developed granulocytopenia, which was successfully treated with lithium carbonate (58A ). It was therefore possible to continue clozapine in these patients, instead of withdrawing it. Salivary glands Hypersalivation is a common and well-known adverse effect of clozapine, and antimuscarinic agents have been recommended for treating it (SEDA-26, 60). In nine patients with clozapine-induced sialorrhea sublingual ipratropium produced complete responses in two patients and partial responses in five; the effect wore off after a few hours (range 2–8 hours) (59c ). • A 50-year-old man with clozapine-induced hypersalivation was given botulinum toxin injections into each parotid gland and had a marked reduction in hypersalivation, which lasted for more than 12 weeks (60A ).
Immunologic Lupus erythematosus has been associated with clozapine (61A ). • A psychotic 55-year-old woman took clozapine for 15 years because of increasing extrapyramidal adverse effects with other neuroleptic drugs. When she started to take it she did not have raised serum inflammatory markers. She reduced the dosage of clozapine from 400 to 200 mg/day and developed increasing delusions. In hospital she was discovered to have generalized arthralgia, myalgia in the proximal limb muscles, a reticular skin rash, and a raised erythrocyte sedimentation rate. The syndrome resolved within 2 weeks of withdrawal of clozapine.
The authors thought that clozapine had caused lupus erythematosus. Body temperature The presentation of neuroleptic malignant syndrome with clozapine can be different from that associated with traditional neuroleptic drugs (SEDA-28, 66), and the authors of a recent report have pointed out the differential diagnosis with heat stroke, a medical emergency with the two cardinal features of
raised core body temperature (40 ◦ C) and central nervous system dysfunction, which is fatal in up to 50% of cases (62A ). • A 32-year-old man with paranoid schizophrenia taking clozapine 200 mg bd and in gainful employment as a builder’s laborer was found unconscious and sitting on an open building site during a heat wave. He had a respiratory arrest, a fever of 42.9 ◦ C, was hypotensive (90/60 mmHg), and had the minimum Glasgow coma scale score of 3. His creatine kinase activity was 6000 (24–195) U/l.
This patient was originally considered to have neuroleptic malignant syndrome, but the clinical picture was very much against this and strongly in favor of heat stroke. Susceptibility factors There is an increased risk of myelosuppression in patients who develop cancer and require chemotherapeutic agents while taking a stable dose of clozapine. • A 46-year-old woman with schizophrenia who was taking clozapine 700 mg/day developed breast cancer and underwent segmental mastectomy; she developed neutropenia, which persisted for more than 6 months after her last radiation treatment (63A ).
Drug interactions Caffeine The effects of caffeine-containing versus decaffeinated coffee on serum clozapine concentrations have been examined in 12 patients in a randomized, placebo-controlled, crossover study (64c ). Serum clozapine concentration increased, probably because of inhibition of CYP1A2. However, the effect was minor in most of the patients, although some individuals may be more sensitive to this interaction, owing for example to genetic factors. Fluvoxamine Fluvoxamine increases clozapine plasma concentrations (SEDA-27, 58) and the differential effects of steady-state fluvoxamine on the pharmacokinetics of olanzapine and clozapine have been studied in healthy volunteers (65c ). Fluvoxamine significantly reduced the N-desmethylclozapine to clozapine ratio, implying reduced metabolism of clozapine. Lithium The combination of clozapine and lithium has previously been studied (SEDA28, 68) and has again been examined in 44
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patients (66c ). Medical records were retrospectively audited and a subsample of 23 patients was re-assessed. The mean total duration of combination treatment was 23 months, and the combination was rated as effective in 84%; however, there were adverse effects in 64%, most often fatigue (32%), hypersalivation (14%), and, in 7% of patients, orthostatic dysregulation, muscle fatigue, weight gain, and oral dyskinesias. Topiramate Leukopenia has been reported after combination treatment with two leukopenic agents, clozapine and topiramate (67A ). • A 28-year-old man with type I bipolar manic disorder was treated with clozapine 550 mg/day; he gained 25 kg, and topiramate, a mood stabilizer increasingly used as a weight suppressor, was added (25 mg bd for 1 week increased to 200 mg bd for 5 weeks). His white blood cell count had been 9–10×109 /l for 2 years while he was taking clozapine, and his complete blood counts were normal for 4 weeks after the addition of topiramate; however, at 5 weeks his white blood cell count was 3.7 × 109 /l.
Monitoring therapy The plasma concentrations of clozapine and its metabolite norclozapine (N-desmethylclozapine) have been measured in samples from 3775 patients (2648 men, 1127 women) (68C ). Step-wise backward multiple regression analysis (37% of the total sample) of log plasma clozapine concentration against log clozapine dose (mg/day), age (years), sex (male = 0, female = 1), cigarette smoking (non-smokers = 0, smokers = 1), body weight (kg), and plasma clozapine/norclozapine ratio (MR) showed that these covariates explained 48% of the observed variation in plasma clozapine concentration (C = ng/ml × 103 ) according to the following equation: log10 (C) = 0.811 log10 (dose) + 0.332(MR) + 69.42 × 10−3 (sex) + 2.263 × 10−3 (age) + 1.976 × 10−3 (weight) − 0.171(smoking habit) − 3.180.
Droperidol (SED-15, 1192; SEDA-27, 58; SEDA-28, 69) Comparative studies Prophylactic intravenous droperidol (10, 20, 40, or 80 micrograms/ kg) dose-dependently reduced postoperative nausea and vomiting without increasing the time to discharge in 82 children who underwent strabismus surgery (69C ). There were no particular adverse effects, but sedation scores were higher in those who received the higher doses. In contrast, the addition of droperidol (2.5 mg bd for 5 days) to granisetron (3 mg bd on the first day) and dexamethasone (16 mg bd on the first day, 8 mg bd on days 2 and 3, and 4 mg bd on days 4 and 5) did not reduce the delayed emesis induced by high-dose cisplatin in a double-blind, randomized, parallel study in 180 patients with lung cancer receiving chemotherapy (70C ). The incidence of sleepiness with droperidol was higher (69% versus 30%). A meta-analysis of 33 trials, with data from 3447 patients, showed that when only two drugs were used (a 5-HT3 receptor antagonist plus either droperidol or dexamethasone), both were similar and significantly more effective than the 5-HT3 antagonist alone for prophylaxis of postoperative nausea and vomiting (71M ). Adverse effects were reported in seven studies involving the combination with droperidol and in 13 studies involving the combination with dexamethasone. The most commonly reported adverse effects were dizziness, headache, and drowsiness and the incidences were not different across the groups. Placebo-controlled studies In a randomized, placebo-controlled trial in 140 patients a combination of metoclopramide 10 mg and droperidol 1.25 mg or two doses of droperidol provided a more effective antiemetic effect than metoclopramide alone (72C ). The level of sedation was significantly greater in the patients who received two doses of droperidol (8/35) and metoclopramide followed by droperidol (7/35) than in those who received only placebo (0/35) or metoclopramide followed by placebo (0/35). Cardiovascular The FDA has previously introduced a “black box” warning on droperidol because of potential QT interval prolongation, leading to torsade de pointes and sudden death (SEDA-28, 69). This regulatory measure, which
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was based mainly on post-marketing surveillance, has prompted different reactions. A review of the cases in which serious cardiovascular events were probably related to droperidol at doses of 1.25 mg/day or less showed, according to the authors, that there are many confounding factors, such as the concomitant use of drugs that can cause QT prolongation and other risk factors (73r , 74r ). It has also been suggested that using the more expensive 5-HT3 receptor antagonists as first-line agents for antiemetic prophylaxis has significant cost implications, with no evidence that they are any safer than droperidol (75r ). On the other hand, several issues have been raised in defence of the FDA decision (76r ); it is assumed, for instance, that cardiovascular events would be more likely to occur in those with other risk factors, since such factors would be expected co-variates of droperidol-induced dysrhythmias. Nervous system In a randomized, doubleblind study in 96 patients with uncomplicated headache, intravenous droperidol 2.5 mg produced a similar reduction in headache as intravenous prochlorperazine 10 mg. There was a lower incidence of akathisia at 24 hours after discharge in those who were given droperidol (1/40 versus 6/43 of those given prochlorperazine), but this did not reach significance (77C ). Death There have been two further reports of sudden death after the use of droperidol to sedate agitation secondary to cocaine and phencyclidine intoxication (78A ). Both patients were restrained by the police and were then given droperidol, either 5 mg (a 33-year-old obese man) or 10 mg (a 22-year-old man). The first patient stopped breathing 10–15 minutes later, while being transported to the emergency department; he was pulseless and couldn’t be resuscitated. The other patient was unresponsive on arrival at the emergency department, with agonal respirations and no detectable pulse; after 30 minutes of resuscitative efforts he was pronounced dead.
Haloperidol
(SED-15, 1576; SEDA-27,
58; SEDA-28, 69) Nervous system Tardive Tourette’s syndrome is characterized by multiple motor and vocal tics.
• A 48-year-old woman, who had been taking haloperidol 10 mg/day for 8 years, suddenly stopped taking it and about 2 weeks later developed a Tourette-like syndrome (79Ar ). Her symptoms did not respond to increased doses of typical or atypical neuroleptic drugs, but she derived significant sustained improvement from clonazepam 3 mg/day. At review 6 months later, her symptoms remained controlled, with just occasional facial grimaces, and there was no recurrence of her psychotic symptoms.
Drug interactions Fluvoxamine The addition of low-dose fluvoxamine (50–100 mg/day) to neuroleptic drug treatment may improve the negative symptoms in patients with schizophrenia, but involves a risk of a drug interaction. In 12 in-patients with schizophrenia receiving 6 mg/day of haloperidol, incremental doses of fluvoxamine (25, 75, and 150 mg/day for 2 weeks each) respectively increased haloperidol plasma concentrations by 120%, 139%, and 160% of those before fluvoxamine co-administration; in spite of the increase, there were no particular adverse effects (80c ).
Olanzapine
(SED-15, 2598; SEDA-26, 61; SEDA-27, 59; SEDA-28, 70) Comparative studies Olanzapine and amisulpride Two atypical antipsychotic drugs, olanzapine and amisulpride, which have different receptor occupancy profiles, have been compared in a double-blind, randomized, 6-month study in 72 different centers in 11 European and African countries (81C ). Schizophrenic patients, mainly with acute psychotic symptoms, were assigned to olanzapine (mean dose 13 mg/day; mean age 37 years, 64% men; n = 188) or amisulpride (mean dose 504 mg/day; mean age 38 years, 66% men; n = 189). The incidence and reasons for withdrawal were similar in both groups (63 patients in the olanzapine group and 72 in the amisulpride group left the study prematurely). The two drugs produced similar symptomatic improvement and similar adverse event frequencies (56% with olanzapine and 57% with amisulpride); patients taking olanzapine had more weight gain (50 versus 30 patients; mean weight gain 3.9 versus 1.6 kg), but
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less amenorrhea (0 versus 4), extrapyramidal symptoms (1 versus 11), insomnia (10 versus 14), and constipation (5 versus 10); there was somnolence in 12 patients in each group and serum transaminase activities were raised in 32 patients taking olanzapine and seven taking amisulpride. Three patients (two taking amisulpride and one taking olanzapine) left the study because of extrapyramidal symptoms. Diabetes was aggravated in one patient taking olanzapine. Two patients died during the study, one from cerebral hemorrhage (taking amisulpride) and one because of suicide (taking olanzapine). Olanzapine and clozapine Compared with clozapine, considered the gold standard for treatment of patients with refractory schizophrenia, olanzapine had the same level of efficacy (according to the Positive and Negative Syndrome Scale [PANSS], and the Brief Psychiatric Rating Scale [BPRS]) in 150 patients (mean age, 38 years; 60% men) who had failed to respond to conventional neuroleptic drugs because of either insufficient effectiveness or intolerable adverse effects (82C ). Of these, 147 patients, 52 from Hungary and 95 from South Africa, were randomized to olanzapine (n = 75) or clozapine (n = 72); there were no statistically significant differences in demographic or baseline illness characteristics; the final mean doses were 17 mg/day of olanzapine and 108 mg/day of clozapine. Adverse events occurred in 9.2% of those taking olanzapine and 9.5% of those taking clozapine. There were two cases of leukopenia in those taking clozapine. Patients taking olanzapine had significantly more back pain than those taking clozapine (4 versus 0), but also significantly less somnolence (2 versus 11) and dizziness (1 versus 6); there was similar weight gain with the two drugs (olanzapine 3.3 kg; clozapine 4.1 kg, n = 7 in both groups). Akathisia, parkinsonism, and dyskinesia (measured by specific scales) did not change significantly from baseline to the study endpoint in either group; there were clinically insignificant changes in laboratory measures (urinary pH and phosphate). Olanzapine and fluphenazine Weight gain and fewer extrapyramidal symptoms were the major adverse events in 60 patients who were randomly assigned to olanzapine (n = 30) or
71 fluphenazine (n = 30) (83c ). In this 22-week study, final doses were 15 mg/day of olanzapine and 12 mg/day of fluphenazine; adverse events were more frequent in patients taking fluphenazine (n = 23) than in those taking olanzapine (n = 15); adverse effects in the fluphenazine group included akathisia (n = 9), insomnia (n = 6), hypertonia (n = 3), and tremor (n = 2); and in the olanzapine group, weight gain (n = 5), akathisia (n = 3), tremor (n = 3), and hypertonia (n = 1). Patient satisfaction, measured with the Drug Attitude Inventory, was better with olanzapine than with fluphenazine, perhaps also because of less daytime sedation. Olanzapine and haloperidol In a multicenter, double-blind, randomized, controlled trial in patients with schizophrenia or schizoaffective disorder, 159 received olanzapine (mean age 47 years) and 150 received haloperidol (mean age 46 years); they were almost exclusively men (97% in the olanzapine group and 96 in the haloperidol group) (84C ). During the first 6 weeks of the 12-month trial, mean doses were 11.4 mg/day for olanzapine and 11.2 mg/day for haloperidol; for the rest of the first 6 months they were 14.7 and 13.5 mg/day, and during the last 6 months, 15.8 and 14.3 mg/day. Prophylactic benzatropine 1–4 mg/day was added in those taking haloperidol. There were no significant differences in efficacy between the two groups when considering positive, negative, or total symptoms of schizophrenia or quality of life. Several reasons accounted for dropouts (olanzapine n = 86; haloperidol n = 91). They included: adverse effects (10% haloperidol and 4% olanzapine); lack of efficacy or worsening of symptoms; loss to follow-up, missed appointments, or moving out; consent withdrawal or unhappiness with blinded treatment. There were no significant differences between the two groups in reasons for treatment withdrawal. Olanzapine was associated with significantly overall lower scores on the Barnes scale for akathisia, but not on the AIMS measure of tardive dyskinesia or the Simpson–Angus scale for extrapyramidal symptoms. Motor functioning and memory significantly improved in patients taking olanzapine. However, weight gain was significantly more common with olanzapine than haloperidol at 3 months (28% versus 17%), 6 months (33% versus 13%), and 12 months
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(25% versus 8.3%). Medication costs were 4–5 times higher with olanzapine; several measures of service use and health costs were also significantly higher in patients taking olanzapine. Accelerated dose titration of olanzapine with adjunctive lorazepam has been used in acutely agitated patients with schizophrenia and other related disorders in a double-blind study, in which newly admitted acutely agitated patients were randomized to olanzapine (10 mg/day; n = 52) or haloperidol (10 mg/day; n = 48) (85c ). Baseline characteristics were similar in the two groups (olanzapine, age 39 years, 71% men; haloperidol, age 40 years, 71% men). The same drug titration regimen was followed with the two drugs: on the first day the dose was 10 mg/day, on the second day an increase of 5 mg was allowed, and the maximum dose of 20 mg/day was reached on day 3; lorazepam was permitted only if it was considered clinically necessary; mean daily doses throughout the whole study were 2.6 mg in the olanzapine group and 2.9 mg in the haloperidol group. Both drugs significantly reduced agitation from baseline as early as 1 hour after the first dose; however, haloperidol doses were relatively high. Of the 57 patients who completed the study, there were more taking olanzapine than haloperidol (67% versus 46%); adverse events were the only reasons for withdrawal, with significantly different rates between the treatment groups (17% with haloperidol versus 1.9% with olanzapine). Dystonia, hypertonia, and increased salivation were reported significantly more often in patients taking haloperidol (8.3% versus 0% for the three effects); somnolence (25%), anxiety (12%), and headache (12%) were the most frequent events in patients taking olanzapine. Placebo-controlled studies Olanzapine has been compared with placebo in different mental disorders, including the non-approved indications of psychotic depression, Alzheimer’s disease, obsessive-compulsive disorder, and alcohol dependence. A combination of olanzapine and fluoxetine was used in two randomized, double-blind simultaneous 8-week trials in 249 patients with major depression with psychotic features (trial 1: n = 124, mean age 41 years, 52% women; trial 2: n = 125, mean age, 41 years,
50% women), which have been jointly published (86c ). This multicenter study was completed by 51 subjects in trial 1 (41%) and 59 subjects in trial 2 (47%). Altogether, there were no significant differences in the rates of discontinuation due to adverse events among the different treatment groups: placebo (n = 100), monotherapy with olanzapine 5–20 mg/day (n = 101), and olanzapine 5– 20 mg/day plus fluoxetine 20–80 mg/day (n = 48). Dropout percentages were 59% in trial 1 (similarly distributed in the three groups) and 53% in trial 2 (ranging from 40% of dropouts in the combined therapy group to 59% in the placebo group); lack of efficacy accounted for discontinuation in 8–25% of patients in all subgroups; other reasons were adverse events in patients taking combined therapy, the subject’s own decision, loss to follow-up in those taking olanzapine monotherapy, and loss to follow-up in those taking placebo. There was no significant improvement in depressive symptoms in patients taking olanzapine monotherapy compared with those taking placebo; however, those taking olanzapine + fluoxetine had greater improvement than those taking placebo. Mean weight gain at the endpoint was significantly higher with both olanzapine (3.79 kg) and olanzapine + fluoxetine (2.74 kg) than placebo (0.39 kg). Dry mouth was significantly more common with the drugs than placebo. Gamma-glutamyl transferase activity increased significantly with olanzapine + fluoxetine compared with olanzapine monotherapy or placebo. Prolactin concentrations increased significantly with both olanzapine + fluoxetine and olanzapine monotherapy. There was a mean increase in cholesterol of 0.35 mmol/l (13.5 mg/dl) with olanzapine + fluoxetine (placebo −0.12 mmol/l; olanzapine +0.19 mmol/l). There were no significant differences in usual laboratory tests or extrapyramidal symptoms. In a 6-week double-blind study, subjects with obsessive-compulsive disorder who had failed to respond completely to fluoxetine alone (43 adults and one adolescent, mean age, 37 years, 26 women) received either fluoxetine + olanzapine (n = 22), or fluoxetine + placebo (n = 22) (87c ). Olanzapine was begun at 5 mg/day and titrated upwards to a maximum of 10 mg/day by as early as the second week. There were seven dropouts because of
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adverse events—five with olanzapine + fluoxetine (weight gain and shakiness) and two with fluoxetine + placebo (increased anxiety and emotional numbing). Mean weight gain was 2.8 kg with olanzapine + fluoxetine and 0.5 kg with fluoxetine + placebo. In a multicenter study, 652 patients with Alzheimer’s disease and psychotic symptoms from 61 different centers in Europe, Australia, and Africa (mean age, 77 years; 75% women) were randomly assigned to 10 weeks of doubleblind treatment with either olanzapine (1 mg, n = 129; 2.5 mg, n = 134; 5 mg, n = 125; 7.5 mg, n = 132) or placebo (n = 129) (88C ). Overall, 49% of all the patients had at least one adverse event during the study, with no significant differences in either prevalence or severity between the groups. Weight gain, anorexia, and urinary incontinence were more common with olanzapine. Prolactin concentrations increased significantly more with the highest dose of olanzapine, 7.5 mg. No other individual events, including extrapyramidal symptoms, cognition, and the usual laboratory measures, differed significantly from placebo. There were 17 deaths during the treatment period or in the next 30 days; two taking placebo, four taking olanzapine 1 mg, three taking 2.5 mg, five taking 5 mg, and three taking 7.5 mg; overall mortality was 2.9% of those taking olanzapine and 1.5% of those taking placebo. In a placebo-controlled study of the addition of olanzapine for 6 weeks to lithium or valproate in 344 manic patients, of whom 85 had dysphoric mania, those who took olanzapine had significantly greater improvement than those who took placebo; adverse effects were not mentioned (89C ). Cardiovascular QT interval prolongation has been observed with olanzapine (SEDA-26, 61; SEDA-27, 59; SEDA-28, 71) and there are multiple risk factors (female sex, old age, concomitant medications, and underlying cardiac conduction disorder) as illustrated by a recent case (90A ). • A 61-year-old woman with Wolff–Parkinson– White syndrome, who had previously had QTc interval prolongation with both sulpiride 1200 mg/ day and clozapine 50 mg/day, had a QTc interval of 390 ms, which increased to 466 ms when she took olanzapine 5 mg/day and returned to 395 ms in 2 days when olanzapine was withdrawn. When
73 she was given olanzapine again in the same dose, the QTc interval increased to 473 ms in 2 weeks and returned to baseline when olanzapine was withdrawn. She was also taking daily valproate 1500 mg/day, lithium 300 mg/day, lorazepam 2 mg/day, and propranolol 40 mg/day.
Nervous system Tardive dyskinesia and tardive dystonia have been associated with olanzapine. • A 29 year-old woman with paranoid schizophrenia took olanzapine 20 mg/day for 3 months, stopped taking it, restarted it within 2 months, and 2.5 months later developed involuntary intermittent choreoathetoid knee movements and foot squirming in both legs; the movements persisted for more than 4 weeks (91A ). She denied any subjective sense of restlessness; other reasons for symptoms were excluded and tardive dyskinesia was diagnosed. The movements ceased after 4 months of treatment with quetiapine 300 mg/day later increasing to 600 mg/day. Some months later, her psychotic symptoms increased and she was given additional risperidone 1 mg/day. This resulted in writhing lower limb movements, which disappeared with risperidone withdrawal.
As a possible mechanism of these effects, the authors proposed dopamine D2 receptor hypersensitivity. Psychiatric Stuttering, which has previously been described with several neuroleptic drugs, has also been described with olanzapine. After they had seen one case, the authors of a recent study searched for this particular adverse effect in both out-patients and in-patients who had attended their clinic over the previous 3 years (53A ). Of 2100 new patients per year, 600 were taking neuroleptic drugs and there were seven patients with drug-induced stuttering, six taking olanzapine and one clozapine. The stuttering occurred on average 2–21 days after the start of treatment and ceased 2–5 days after withdrawal. Pre-existing brain pathology or concomitant antidepressants may have contributed to this effect; only one of the seven patients had a history of stuttering. Olanzapine can cause mania and hypomania (SEDA-26, 62), and there have been further reports in four men and one woman aged 18–36 years taking olanzapine 10–20 mg/day (92A ). Endocrine Hyperprolactinemia, amenorrhea, and galactorrhea have been attributed to olanzapine (SEDA-27, 60), and another case has
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been reported in a 35-year-old woman after 2 months of risperidone treatment; the effects persisted after she switched to olanzapine, mean dose 2.5 mg/day (93A ). Metabolism Diabetes mellitus The possible relation between neuroleptic drugs and new-onset diabetes mellitus has been previously analysed (SEDA28, 60). There have been six new cases in patients taking olanzapine (from 10 mg for 2 months to 25 mg for 22 months) (94A ). All were switched to quetiapine. Five of the six had known risk factors for diabetes mellitus (positive family history, obesity, race, and hyperlipidemia); only one gained significant body weight with olanzapine. There was a close temporal relation between the onset of therapy and the appearance of diabetes in three patients. The authors made recommendations about the detection and management of this effect in patients taking neuroleptic drugs; they suggested that consideration should be given to testing for diabetes mellitus 3–7 months after starting neuroleptic drug treatment and that screening is ideally carried out by measuring the fasting plasma glucose concentration. The case of a 39-year-old woman who developed hyperglycemia after the dose of olanzapine was increased from 10 to 15 mg/day has also prompted the recommendation that blood glucose should be monitored in patients taking olanzapine (95A ). Weight gain Weight gain is a matter of particular concern in patients taking olanzapine (SEDA-26, 62; SEDA-27, 61; SEDA-28, 72). Long-term olanzapine has been assessed in 27 outpatients with schizophrenia or schizoaffective disorders (mean age 40 years; 13 men) (96c ). At entry to the study the mean dose of olanzapine was 8.52 mg/day and the mean body mass index (BMI) 25 (range, 19–35). At the end (mean treatment duration 22 months, range 6–42) the mean dose of olanzapine was 8.70 mg/day and the mean BMI was 29 (range 20–40). Weight gain was more pronounced in the first year than in the second (7.7 versus 1.7 kg), especially during the first 3 months. Weight gain per month was significantly higher in patients with lower BMIs, but the greatest weight gain was in the most obese patient (BMI 35, weight gain 29 kg).
Weight gain has also been reported in 26 patients with bipolar affective disorder who were followed for 1 year while taking the combination of topiramate + olanzapine (mean modal doses 271 and 9.9 mg/day respectively). Although most of them gained weight during the first month of combined therapy (mean weight gain 0.7 kg), there was slight weight loss after 12 months (0.5 kg); weight loss was more pronounced in the obese patients (n = 5), and no patient with a low BMI (n = 3) lost weight (97c ). Patients who were switched to quetiapine from olanzapine lost weight after 10 weeks (mean weight loss 2.02 kg; n = 16) (98c ); although most of the patients lost weight, four gained about 2.6 kg. In a randomized double-blind study there was weight gain in nine of 29 patients with alcohol dependence treated with olanzapine versus four of 31 taking placebo (99c ). There was a mean weight gain of 7.9 kg (range 0–25 kg) between baseline and end-point weights in eight adolescents with psychoses (age range 12–18 years) who took olanzapine for 17.5 (range 4–26) weeks (100c ). In contrast, in a study sponsored by Eli Lilly, there was improvement in 21 hospitalized elderly patients with schizophrenia or schizoaffective disorder who were taking olanzapine, mean final dose 13 mg/day. There was no significant weight gain (mean baseline weight 73.6 kg, mean final weight, 72.8 kg; mean treatment duration around 10 months) (101c ). However, the propensity for studies that are sponsored by pharmaceutical companies to be more favorable to their drug is well known (102M ). In a study supported by the market authorization holder risperidone data from two double-blind trials in 552 adult and elderly patients with schizophrenia or schizoaffective disorders, weight gain after 8 weeks was higher with olanzapine than risperidone (mean doses not stated) in the adult and elderly patients and in smokers and non-smokers (103c ). For example, among the elderly patients, weight gain with olanzapine was 1.18 kg on average in smokers (n = 27) and 1.30 kg in non-smokers (n = 35); with risperidone weight gain was 0.08 kg in smokers (n = 20) and 1.06 kg in non-smokers (n = 31). Famotidine did not prevent or attenuate weight gain in 14 patients taking olanzapine
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who were randomly assigned to either famotidine 40 mg/day (n = 7) or placebo (n = 7) in addition to olanzapine 10 mg/day for 6 weeks (mean weight gain 4.8 kg versus 4.9 kg respectively) (104c ). Hematologic Olanzapine has rarely been associated with neutropenia (SEDA-26, 62; SEDA-28, 72). • A 17-year-old woman who was taking valproate 1000 mg/day and olanzapine 20 mg/day was changed to olanzapine monotherapy 25 mg/day; after 12 days her white blood cell count fell to 3.9 × 109 /l and the absolute neutrophil count to 1.2 × 109 /l; the counts returned to baseline when olanzapine was withdrawn (105A ).
A fatal case of thrombocytopenia has also been reported (106A ). • There was a fall in platelet count to 4000 × 109 /l in a 78-year-old man who had taken olanzapine 10 mg/day for the last 3 weeks. He had massive spontaneous nasal and gingival bleeding and died from progressive bleeding complications. His plasma olanzapine concentration was 230 ng/ml (about 10 times higher than the usual target concentrations). He had had idiopathic thrombocytopenic purpura 13 years before.
The relevance of checking blood counts, irrespective of a patient’s diagnosis, has been pointed out (105A , 106A ). Sexual function Irreversible priapism has been reported during treatment with olanzapine and lithium. • A 30-year-old man with bipolar disorder who had previously taken haloperidol and lithium was also given trihexyphenidyl (benzhexol) because of rigidity, tremor, and akathisia, but persistent symptoms led to his being given olanzapine in place of haloperidol; 6 days later he developed priapism (107A ).
Priapism has previously been reported during treatment with olanzapine, and this was the likely causal agent; lithium was not thought to be causative in this instance. Drug overdose Overdose of olanzapine has reportedly caused diabetes insipidus. • A 17-year-old who took olanzapine 75 mg and prazepam 7.5 mg in a suicide attempt developed
polyuria (5400 ml/24 hours), reduced urine osmolality (166 mosmol/kg H2 O), normal plasma osmolality, and an increasing serum sodium concentration, consistent with a diagnosis of diabetes insipidus (108A ).
Drug interactions Fluvoxamine under steady-state conditions alters the pharmacokinetics of some neuroleptic drugs, leading to increased systemic availability of olanzapine and inhibition of the metabolism of clozapine, as shown in 21 male non-smoking Chinese volunteers (mean age 27 years) (65c ). This could be related to the different metabolic pathways and secretion rates of the two drugs; it would be advisable to reduce the dosage of olanzapine and to extend the dosing interval of clozapine when they are combined with fluvoxamine. Similar results and recommendations have been published in a study of 71 patients with schizophrenia (mean age 33 years, range 18–63, 40 men) who were given olanzapine monotherapy or olanzapine + flupentixol, benperidol, carbamazepine, and other drugs (109c ).
Perphenazine
(SED-15, 2783)
Following remission of manic symptoms in 37 patients who had taken perphenazine and a mood stabilizer (lithium, carbamazepine, or valproate), treatment was randomly assigned double-blind to perphenazine or placebo for 6 months, while continuing the mood stabilizer (110c ). Those who took perphenazine had worse outcomes than those who took placebo, in that they were more likely to have a shorter time to a depressive relapse, were more likely to discontinue treatment, or were more likely to have depression or extrapyramidal symptoms. The authors tentatively concluded that perphenazine may not be beneficial in maintenance treatment for bipolar I patients.
Quetiapine (SED-15, 2995; SEDA-26, 63; SEDA-27, 62) Quetiapine has been approved by the FDA as monotherapy for the treatment of acute mania. It has been evaluated in combination with
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lithium or divalproex in 191 patients who had recently been manic (111C ). After treatment with quetiapine plus lithium or divalproex for 7–28 days, the patients were randomized to either additional quetiapine or placebo and followed for 3 weeks more. Early discontinuation was more frequent with placebo than with quetiapine. The intention-to-treat population included 81 taking quetiapine and 89 taking placebo. The mean dose during the last week in patients taking quetiapine was 504 mg/day. Patients taking quetiapine had a greater improvement in the Young Mania Rating Scale score (YMRS) than patients taking placebo. The response rate (50% or greater improvement from baseline using the YMRS) was significantly higher in the group with added quetiapine than added placebo. Common adverse events included somnolence, dry mouth, weakness, and postural hypotension.
Risperidone
(SED-15, 3052; SEDA-26, 63; SEDA-27, 62; SEDA-28, 74) Observational studies Risperidone has been used in children with severe disruptive behavior disorders (SEDA-27, 62; SEDA-28, 74). In 107 children, aged 5-12 years (86 boys) who entered a 48-week open study and received risperidone (mean dose 1.5 mg/day), there were significant improvements in conduct at 4 weeks. The most common adverse events were somnolence (n = 35), headache (n = 35), rhinitis (n = 30), and weight gain (n = 22; mean increase from baseline 5.5 kg, half attributable to developmentally expected growth) (112C ). Adverse events led to dropouts in 11 patients; they were mainly weight gain (n = 4), depression (n = 3), and suicide attempts (n = 2); other reasons for dropouts were loss to follow-up (n = 15), consent withdrawal (n = 12), insufficient response (n = 11), and non-adherence to therapy (n = 7). Although uncontrolled extrapyramidal symptoms were an exclusion criterion, there were no significant adverse extrapyramidal effects, and vital signs, cognition, and laboratory analyses were not found except for transient increases in prolactin concentrations at week 4 (maximum of 28 ng/ml in boys and 24 ng/ml in girls).
In a 6-week open study in 146 Chinese inpatients, risperidone was titrated to 6 mg/day within 7 days; 29 patients withdrew prematurely (113c ). Higher risperidone doses did not appear to have greater efficacy in treating acute schizophrenia and were related to more severe adverse effects. In another study only 38 patients out of 79 with chronic schizophrenia completed 52 weeks of treatment with risperidone; the most common dose was 6 mg/day (114c ). In a two-phase long-term multicenter study in 74 patients (mean age 30 years; 56 men), the starting dose of risperidone was 1 mg/day, increased to 2 mg after 3 days and adjusted to 8 mg/day maximum; treatment duration was 2 weeks for phase 1 (mean dose at the end 3.8 mg/day) and 1 year for phase 2 (mean dose at the end 3.5 mg/day) (115c ). Of 12 patients who did not complete phase 1, two had adverse events (agitation, somnolence, and self-harm); there were nine dropouts during phase 2, but none was apparently due to adverse events. In a review based on the Medline and PsycINFO databases from 1999 to 2002, six articles focusing on the issue of adherence to therapy in schizophrenia and two metaanalyses of depot typical antipsychotic agents in schizophrenia were identified (116R ). The usual adverse effects were often reasons for non-adherence. Clinicians’ fear of managing adverse effects such as acute dystonia or neuroleptic malignant syndrome, which can be prolonged with long-acting agents, were also related to non-adherence. However, according to this review, with proper dosing these agents do not increase the occurrence of adverse events compared with their oral counterparts. Extrapyramidal symptoms were the most significant complications of typical neuroleptic drug therapy; parkinsonism was a generally irreversible long-term complication. Some studies have suggested that, among other factors, patients who receive depot neuroleptic drugs are at increased risk of extrapyramidal symptoms, with Parkinsonism over the short term being indistinguishable from negative symptoms and tardive dyskinesia being usually irreversible. In a 6-month multicenter study in 96 manic patients (mean age 41 years; 50% women) who took risperidone monotherapy 4.2 mg/day, 16 withdrew from the study, in four cases because of adverse events: akathisia, impotence, drowsiness, and weight gain (117c ).
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Chapter 6
Comparative studies In a 1-year randomized comparison of risperidone (mean age 39 years; 236 men; n = 349) and conventional neuroleptic drugs (mean age 38 years; 231 men; n = 326), risperidone produced statistically superior scores on the Positive and Negative Syndrome Scale for Schizophrenia, Barnes Akathisia Scale, and 36-Item Short Form Health Survey scale; however, there was no statistically significant difference in resource utilization between the two groups (118c ). This study, the Risperidone Outcome Study of Effectiveness (ROSE), was supported by Janssen, the market authorization holder of risperidone. Risperidone and haloperidol In a randomized comparison of risperidone (mean dose 4.4, range 1–12, mg/day; n = 21) and haloperidol (mean dose 11, range 2–20, mg/day; n = 20) in patients with schizophrenia, tremor and rigidity were the most frequent adverse effects in both groups (risperidone—tremor, 8; rigidity, 6; haloperidol—tremor, 13; rigidity, 10) (119c ). There was akathisia in two patients taking haloperidol and in none taking risperidone. The higher incidence of extrapyramidal symptoms in patients receiving haloperidol might have been partly explained by the relatively higher doses that were used. Serum prolactin concentrations increased significantly in both groups after 8 weeks: 42 ng/ml with risperidone and 41 ng/ml with haloperidol. Placebo-controlled studies In a multicenter, double-blind, 3-week study, 259 patients with an acute episode of mania were randomly assigned to risperidone (mean age 38 years; 71 men; n = 134; mean modal dose 4.1 mg/ day) or placebo (mean age 40 years; 76 men; n = 125) (120c ). Improvement in the mean Young Mania Rating Scale total score (adjusted for co-variates) was significantly greater with risperidone than placebo at the end-point. The rates of withdrawal due to adverse events were similar in the two groups (risperidone n = 10, placebo n = 7). The most common serious adverse events were manic reactions (risperidone n = 10, placebo n = 6), agitation (risperidone n = 3, placebo n = 0), and two accidental deaths in the placebo group. Adverse events that occurred in more than 10% of patients were somnolence (risperidone n = 38, placebo n = 9), hyperkinesia
77 (risperidone n = 21, placebo n = 6), headache (n = 19 in both groups), dizziness (risperidone n = 15, placebo n = 11), dyspepsia (risperidone n = 15, placebo n = 8), and nausea (risperidone n = 15, placebo n = 3). Risperidone significantly increased the total score in the Extrapyramidal Symptom Rating Scale from baseline to end-point (baseline 1.2; change 0.6). Risperidone increased plasma prolactin concentrations in both men and women and five patients had at least a 7% weight gain. Cardiovascular Hypotension has been associated with risperidone (see Drug formulations below). Nervous system Extrapyramidal symptoms have been reported within 24 hours of an injection of depot risperidone in patients with schizophrenia (121A ). • A 32-year-old man who had been taking olanzapine 15 mg/day for 4 months was switched to injectable risperidone 25 mg because of poor adherence. On the next day he had an oculogyric crisis, dysarthria, torticollis, dysphagia, tremor, and rigidity, which resolved with procyclidine. • A 36-year-old man had worse extrapyramidal symptoms. • A 28-year-old man developed akathisia.
In order to limit the risk of extrapyramidal symptoms, the authors suggested that the dose of the oral neuroleptic drug should be reduced or omitted in the days after the injection, and that attention should be paid to the half-life of any other depot drug that has previously been given. A relationship between risperidone and stroke in patients with dementia has been previously described (SEDA-28, 76). On April 2005, the FDA issued an alert and asked the company to add the following information to both the oral and depot formulations: “The FDA has found that older patients treated with atypical neuroleptic drugs for dementia had a higher chance for death than patients who did not take the medicine. This is not an approved use” (122S ). Psychiatric In some countries, the use of risperidone in demented patients has been restricted (123S ).
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Endocrine Hyperprolactinemia is a welldocumented reaction to risperidone (SEDA 28, 77). There was a high correlation between prolactin concentrations and risperidone in 14 men (mean age 53 years) (124c ). In 47 men (mean age 23 years) receiving acute treatment with several neuroleptic drugs, including risperidone (mean dose 3.6, range 1–6, mg; mean duration 45 days; risperidone monotherapy in 35 subjects), there was hyperprolactinemia, defined as a prolactin concentration greater than 636 mU/l (male reference range 45–375 mlU/l), in 27 of the 37 patients who could be assessed (125c ). There was neither gynecomastia nor galactorrhea. One year later, 38 of the 47 patients were reassessed (mean dose 2.3, range 1–6, mg); prolactin concentrations could be determined in 20 of these patients, and there was hyperprolactinemia in six of them. In the 35 patients taking risperidone monotherapy, two had high prolactin concentrations at baseline, but this rose to 21 of 29 patients at the end of the acute phase and fell to four of 16 after 1 year. According to the authors, the lower concentrations at 1 year might have been due to the development of tolerance to prolactin. The risk of prolactinoma in patients taking risperidone and other neuroleptic drugs, accompanied by hyperprolactinemia, amenorrhea, and galactorrhea has been discussed in the light of a case of hyperprolactinemia (93A ). • A 35-year-old woman who had taken lithium carbonate 800 mg/day for 2 years was also given risperidone 6 mg/day for a manic relapse. She missed two menstrual periods and had galactorrhea. A head CT scan showed a pituitary microadenoma and the prolactin concentration was 125 µg/l (reference range up to 20 µg/l). Risperidone withdrawal resulted in disappearance of the prolactinoma. Her other symptoms persisted and did not change with olanzapine 2.5 mg/day; however, bromocriptine 12.5 mg/day for 2 weeks relieved her symptoms and the prolactin concentration normalized.
There were no significant adverse effects on growth or sexual maturation in a retrospective study based on a sample of 700 children aged 5–15 years who had been taking risperidone (0.02–0.06 mg/kg/day) for 11 or 12 months because of disruptive behavior disorders (126c ). Metabolism Weight gain is a well-known adverse effect of risperidone (SEDA-25, 70;
SEDA-28, 77). Risperidone-induced weight gain varies throughout the age span, young people being the most sensitive; although preadolescents and adolescents take substantially lower daily doses and lower mg/kg doses than adults, they gain as much or more weight (corrected for age-expected growth) (127R ). This effect is hardly, or not at all, experienced by those aged over 65. Furthermore, young people also had a greater percentage of drug-induced weight gain relative to baseline body weight, and the percentage increases in body mass index during risperidone treatment were consistently greater in the young. There was weight gain of 17% (mean 5.6 kg) after risperidone treatment for 6 months in 63 autistic children and adolescents (mean age 8.6 years), taken from an initial sample of 101 outpatients; this gain exceeded the developmentally expected norms and decelerated over time (128c ). Body mass index increased by 10.6% (mean 2.0 kg/m2 ). Changes in serum leptin did not reliably predict risperidone-associated weight gain. • Long-term weight gain has been described in a 35-year-old man with schizophrenia taking risperidone 4 mg/day; weight changed from 94 to 121 kg and there was also “carbohydrate craving” and persistent hunger (129A ).
The underlying mechanism may involve the adipose tissue hormone leptin or immune modulators such as tumor necrosis factor α. Hematologic Probable risperidone-induced leukopenia and neutropenia has been reported (130A ). • A 90-year-old man with vascular dementia, delusions, and hallucinations developed a fever of 39.5 ◦ C. During the previous 6 months he had been taking risperidone 2 mg/day for the psychotic symptoms; he was also given unidentified antibiotics for pneumonia. His white blood cell count was 1.4 × 109 /l (no neutrophils). Risperidone was withdrawn and the white cell count rose to 2.2×109 /l (30% neutrophils) on day 4, 2.5×109 /l (33% neutrophils) on day 14, and 5.4×109 /l (59% neutrophils) on day 18.
It is not clear whether this event could have been due to an interaction with other drugs that the patient received. Two cases of nose bleeding have been described in association with risperidone, probably for the first time (131A ).
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• A 57-year-old woman with no history of hypertension and not taking other medicines began having profuse nose bleeds and headaches immediately after starting to take risperidone 1 mg/day; risperidone was withdrawn 4 days later and the nose bleeds stopped. • A 42-year-old man began to have spontaneous nose bleeds while taking risperidone; coagulation tests were normal.
The authors suggested that the mechanisms of these bleeding episodes might have been thrombocytopenia, a recognized adverse effect of certain neuroleptic drugs, and/or reduced platelet aggregation due to an antagonist effect on 5-HT2A receptors. The WHO International Drug Monitoring database contains 54 reports of nose bleeds associated with risperidone, 37 with an established cause-and-effect relation (132r ). Sexual function The prevalence of sexual dysfunction in patients taking psychotropic medications, based on spontaneous reports, has been underestimated. In a randomized open study of the sexual effects of risperidone (n = 24; mean age 25 years) and quetiapine (n = 25; mean age 27 years) as assessed by a semistructured interview, the Antipsychotics and Sexual Functioning Questionnaire (133c ), sexual dysfunction was reported by 12 patients taking risperidone (mean dose 3.2 mg/day) and four taking quetiapine (mean dose 580 mg/day), mainly reduced libido and/or impaired orgasm. Furthermore, there were significantly higher concentrations of prolactin in men taking risperidone (47 µg/l, n = 15) than in those taking quetiapine (12 µg/l, n = 19). Priapism (SEDA-27, 64; SEDA-28, 78) and ejaculatory dysfunction (SEDA-26, 65; SEDA28, 78) have again been reported (134A , 135A ). Lactation The transfer to milk of risperidone and its active metabolite 9-hydroxyrisperidone has been examined in two breast-feeding women and in one woman with risperidone-induced galactorrhea (136A ). The milk:plasma concentration ratio was under 0.5 for both compounds; the calculated relative infant doses were 2.3%, 2.8%, and 4.7% of that of women’s weight-adjusted doses; neither compound was
detected in the plasma of the two babies, who achieved their developmental milestones satisfactorily and did not have any adverse effect attributable to risperidone. The authors concluded that maternal risperidone therapy is unlikely to pose a significant hazard to the breast-fed infant in the short term, and recommended an individual benefit–harm analysis to make decisions about this issue. Drug interactions Anesthetics Interactions with anesthetics should be considered in patients taking αadrenoceptor antagonists, such as risperidone (137A ). • A 32-year-old woman, who had had a previous uncomplicated vaginal delivery with epidural anesthesia at age 21 and a cesarean delivery with a spinal anesthetic at 28, was at week 39 of her third gestation on treatment with risperidone 2 mg/day and lithium 1200 mg/day, which she had taken throughout pregnancy. In preparation for cesarean section she was given a spinal anesthetic with hyperbaric 0.75% bupivacaine 12 mg, fentanyl 10 micrograms, and preservative-free morphine 0.2 mg. Two minutes later, her blood pressure fell from 120/50 to 70/30 mmHg and did not resolve with 50 mg of ephedrine or 2 liters of Ringer’s lactate solution, but did rise with phenylephrine 600 micrograms.
Drug formulations Depot formulations of neuroleptic drugs are specifically recommended over oral formulations for long-term treatment in patients with schizophrenia with a history of poor adherence to therapy; they also improve systemic availability, maintain stable plasma concentrations, and reduce the risk of overdose (138R ). A long-acting injection of risperidone, a combination of extended-release microspheres and a diluent for parenteral use, has recently been introduced in several countries, including the USA, for the treatment of schizophrenia. Long-acting depot risperidone has been reviewed (138R ). According to the market authorization holder, the recommended dose is 25 mg intramuscularly (maximum 50 mg) every 2 weeks, the half-life of absorption being 3–6 days, and oral risperidone should be given with the first injection and continued for 3 weeks to establish tolerability and ensure adequate plasma concentrations (139S ). The most common adverse events were insomnia, agitation,
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headache, psychosis, rhinitis, pain, dizziness, anxiety, depression, and hyperkinesia; there were six deaths (suicide, n = 4; cardiac failure, n = 2) (138R ). Generally, the same rules and warnings as for oral risperidone must be followed; elderly patients and those predisposed to orthostatic hypotension should be instructed in non-pharmacological interventions to reduce hypotension (for example, rising slowly to the seated position and sitting on the edge of the bed for several minutes before trying to stand up in the morning), and they should avoid circumstances that accentuate hypotension, including sodium depletion and dehydration (139S ). Patients with renal impairment may be less able to eliminate risperidone and those with impaired hepatic function may have an increase in the unbound fraction of the drug, possibly resulting in an enhanced effect. Women should notify their doctor if they become or intend to become pregnant during therapy and for at least 12 weeks after the last injection; they should also be advised not to breast-feed an infant during treatment and for at least 12 weeks after the last injection. Patients taking risperidone who start to take carbamazepine or other hepatic enzyme inducers should be monitored closely during the first 4–8 weeks and the dose of risperidone should perhaps be increased (139S ). Long-acting risperidone has been used in a multicenter, open study in 725 patients with schizophrenia or schizoaffective disorders; however, only the data from 46 stable patients who were initially taking conventional oral neuroleptic monotherapy were presented (140c ). During a 2-week run-in period, neuroleptic drugs other than risperidone were withdrawn, and patients who were not currently taking risperidone received flexible doses of oral risperidone 1–6 mg/day. At the start of the 12-month treatment phase, they were assigned, on the judgement of the investigator, to intramuscular long-acting risperidone 25, 50, or 75 mg every 2 weeks. In all, 18 patients did not complete the study, for several reasons; two of them committed suicide. Patients improved during the study; however, since there was no control group it is not possible to know whether the improvement was due to the treatment. Conventional depot neuroleptic drugs were changed to long-acting injectable risperidone
in 196 patients, of whom 166 (mean age 43 years; 67% men) completed the run-in period, consisting of two cycles of their current depot neuroleptic (141c ). Of these patients, 152 completed the 12-week treatment period, although only 62% of the 166 patients received the six intended injections. The modal doses of longacting risperidone were 25 mg in 86% of the patients and 37.5 mg in 14%; the mean duration of treatment was 68 days. The patients also received oral risperidone (27%), neuroleptic drugs or sedative/hypnotics (51%), antidepressants (12%), and antiparkinsonian drugs (33%). At least one adverse effect was reported in 96 patients (58%), most of them mild or moderate in intensity. They were hyperkinesia (n = 3), mild tardive dyskinesia (n = 1), and another extrapyramidal disorder (n = 1). In 14 patients there was a serious adverse effect, mainly psychosis. Two of the drop-outs were due to adverse effects: one attempted suicide and the other had a severe psychosis. There was hyperprolactinemia in 18 patients; one had ejaculatory failure throughout the study and another had mild impotence that resolved at day 31. Adverse effects potentially related to prolactin (other than hyperprolactinemia) were reported in four patients, two with reduced libido. Body weight (1.0 kg) and body mass index (0.3 kg/m2 ) increased.
Thioridazine
(SED-15, 3397; SEDA-27,
65) Skin Photosensitivity reactions have been observed in patients taking thioridazine (142A ). • A 72-year-old woman developed well-delimited hyperpigmented papular lesions on exposed areas after 4 years of treatment. • A 63-year-old woman developed maculopapular pigmented skin lesions on the face, neck, and forearms after several years; histology showed a lichenoid dermatitis. • A 72-year-old woman developed papular pigmented skin lesions on the face, neck, and the backs of the hands; a skin biopsy showed a lichenoid reaction.
In all three cases the reaction disappeared after withdrawal of thioridazine.
Antipsychotic drugs
Ziprasidone
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(SED-15, 3721; SEDA-27,
66; SEDA-28, 79) In a PET study in the brain region of interest, intended to delineate receptor occupancy, 16 patients with schizophrenia or schizoaffective disorders were randomly assigned to receive the recommended dosage of ziprasidone: 40, 80, 120, or 160 mg/day (143c ). Ziprasidone was more like risperidone and olanzapine in its receptor occupancy profile than clozapine and quetiapine; the optimal effective dose of ziprasidone is closer to 120 mg/day than to the lower doses suggested by previous PET studies. One subject taking 120 mg/day withdrew because of severe somnolence, and another developed oculogyric crises. Given recent concerns about prolongation of the QTc interval with ziprasidone (SEDA-28, 79), this was reported in some detail. The number of individuals who had shortening of the QTc interval was the same as the number who had prolongation (n = 8). In subjects in whom the interval was prolonged the ranges were as follows: 0–25 msec (n = 4), 26– 50 msec (n = 2), and over 50 msec (n = 2); the
two individuals with increases of over 50 msec were taking 120 mg/day. Only one subject had a QTc interval greater than 450 msec (due to prolongation by 51 msec). Nervous system Tardive dyskinesia has previously been associated with ziprasidone (SEDA-27, 66), and has again been reported in a 70-year-old woman within 2 months of starting ziprasidone treatment (144A ). Neuroleptic malignant syndrome has been reported in a 52-year-old woman with Parkinson’s disease and psychotic symptoms who took ziprasidone (145A ). Metabolism Although ziprasidone is marketed as one of the few neuroleptic drugs that is not associated with significant weight gain (SEDA-26, 56), it can occur. • A 12-year-old boy had significant weight gain within 3 months of starting to take ziprasidone, from 63 kg (BMI = 26.5) before treatment to 69 kg (BMI = 28.2) after treatment (146A ).
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40. Mortimer A. How do we choose between atypical antipsychotics? The advantages of amisulpride. Int J Neuropsychopharmacol 2004;7(Supp 1):S21–5. 41. Linden M, Schee T, Eich F. Dosage finding and outcome in the treatment of schizophrenic inpatients with amisulpride. Results of a drug utilization observation study. Hum Psychopharmacol Clin Exp 2004;19:111–9. 42. Lecrubier Y, Azorin M, Bottai T, Dalery J, Garreau G, Lemperiere T, Lisoprawski A, Petitjean F, Vanelle JM. Consensus on the practical use of amisulpride, an atypical antipsychotic, in the treatment of schizophrenia. Neuropsychobiology 2001;44(1):41–6. 43. Bliesener N, Yokusoglu H, Quednow B, Klingmüller D, Kühn K. Usefulness of bromocriptine in the treatment of amisulprideinduced hyperprolactinemia. Pharmacopsychiatry 2004;37:189–91. 44. Fountoulakis KN, Iacovides A, Kaprinis GS. Successful treatment of Tourette’s disorder with amisulpride. Ann Pharmacother 2004;38:901. 45. Perroud N, Huguelet P. A possible effect of amisulpride on a prolactinoma growth in a woman with borderline personality disorder. Pharmacol Res 2004;50:377–9. 46. Pollak P, Tison F, Rascol O, Destée A, Péré JJ, Senard JM, Durif F, Bourdeix I. Clozapine in drug induced psychosis in Parkinson’s disease: a randomised, placebo controlled study with open follow up. J Neurol Neurosurg Psychiatry 2004;75:689–95. 47. Gaszner P, Makkos Z. Clozapine maintenance therapy in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2004;28:465–9. 48. Wheatley M, Plant J, Reader H, Brown G, Cahill C. Clozapine treatment of adolescents with posttraumatic stress disorder and psychotic symptoms. J Clin Psychopharmacol 2004;24:167–73. 49. Agelink MW, Kavuk I, Ak I. Clozapine with amisulpride for refractory schizophrenia. Am J Psychiatry 2004;161:924–5. 50. Zink M, Mase E, Dressing H. Combination of ziprasidone and clozapine in treatmentresistant schizophrenia. Hum Psychopharmacol 2004;19:271–3. 51. Boot E, De Haan L, Guzelcan Y, Scholte WF, Assies H. Pericardial and bilateral pleural effusion associated with clozapine treatment. Eur Psychiatry 2004;19:65–6. 52. Duggal HS. Clozapine-induced neuroleptic malignant syndrome and subdural hematoma. J Neuropsychiatry Clin Neurosci 2004;16:118–9. 53. Bär KJ, Häger F, Sauer H. Olanzapine and clozapine induced stuttering. Pharmacopsychiatry 2004;37:131–4. 54. Hanagasi HA, Bilgic B, Gurvit H, Emre M. Clozapine treatment in oromandibular dystonia. Clin Neuropharmacol 2004;27:84–6. 55. Covell NH, Weissman EM, Essock SM. Weight gain with clozapine compared to first generation antipsychotic medications. Schizophr Bull 2004;30:229–40.
83 56. Howes OD, Bhatnagar A, Gaughran FP, Amiel SA, Murray RM, Pilowsky LS. A prospective study of impairment in glucose control caused by clozapine without changes in insulin resistance. Am J Psychiatry 2004;161:361–3. 57. Ahn YM, Jeong SH, Jang HS, Koo YJ, Kang UG, Lee KY, Kim YS. Experience of maintaining clozapine medication in patients with “red-alert zone” neutropenia: long-term follow-up results. Int Clin Psychopharmacol 2004;19:97–101. 58. Papetti F, Dariourt G, Giordana J-Y, Spreux A, Thauby S, Feral F, Pringuey D. Correction par le lithium des neutropénies induites par la clozapine (deux cas). L’Encephale 2004;30:570–82. 59. Freudenreich O, Beebe M, Goff DC. Clozapineinduced sialorrhea treated with sublingual ipratropium spray: a case series. J Clin Psychopharmacol 2004;24:98–100. 60. Kahl KG, Hagenah J, Zapf S, Trillenberg P, Klein C, Lencer R. Botulinum toxin as an effective treatment of clozapine-induced hypersalivation. Psychopharmacology 2004;173:229–30. 61. Wolf J, Sartorius A, Alm B, Henn FA. Clozapine-induced lupus erythematosus. J Clin Psychopharmacol 2004;24:236–8. 62. Kerwin RW, Osborne S, Sainz-Fuertes R. Heat stroke in schizophrenia during clozapine treatment: rapid recognition and management. J Psychopharmacol 2004;18:121–3. 63. Rosenstock J. Clozapine therapy during cancer treatment. Am J Psychiatry 2004;161:175. 64. Raaska K, Raitasuo V, Laitila J, Neuvonen PJ. Effect of caffeine-containing versus decaffeinated coffee on serum clozapine concentrations in hospitalised patients. Basic Clin Pharmacol Toxicol 2004;94:18–28. 65. Wang CY, Zhang ZJ, Li WB, Zhai YM, Cai ZJ, Weng YZ, Zhu RH, Zhao JP, Zhou HH. The differential effects of steady-state fluvoxamine on the pharmacokinetics of olanzapine and clozapine in healthy volunteers. J Clin Pharmacol 2004;44:785–92. 66. Bender S, Linka T, Wolstein J, Gehendges S, Paulus HJ, Schall U, Gastpar M. Safety and efficacy of combined clozapine–lithium pharmacotherapy. Int J Neuropsychopharmacol 2004;7:59–63. 67. Behar D, Schaller JL. Topiramate leukopenia on clozapine. Eur Child Adolesc Psychiatry 2004;13:51–2. 68. Rostami-Hodjegan A, Amin AM, Spencer EP, Lennard MS, Tucker GT, Flanagan RJ. Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients. J Clin Psychopharmacol 2004;24:70–8. 69. Stead SW, Beatie CD, Keyes MA, Isenberg SJ. Effects of droperidol dosage on postoperative emetic symptoms following pediatric strabismus surgery. J Clin Anesth 2004;16:34–9.
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70. Minegishi Y, Ohmatsu H, Miyamoto T, Niho S, Goto K, Kubota K, Kakinuma R, Kudoh S, Nishiwaki Y. Efficacy of droperidol in the prevention of cisplatin-induced delayed emesis: a double-blind, randomised parallel study. Eur J Cancer 2004;40:1188–92. 71. Habib AS, El-Moalem HE, Gan TJ. The efficacy of the 5-HT3 receptor antagonists combined with droperidol for PONV prophylaxis is similar to their combination with dexamethasone. A meta-analysis of randomized controlled trials. Can J Anesth 2004;51:311–9. 72. Nesek-Adam V, Grizelj-Stojcic E, Mrsic V, Smiljanic A, Rasic Z, Cala Z. Prophylactic antiemetics for laparoscopic cholecystectomy, droperidol, metoclopramide, and droperidol plus metoclopramide. J Laparoendoscopic Advanced Surg Tech 2004;4:212–8. 73. Gan TJ. “Black box” warning on droperidol: a report of the FDA convened expert panel. Anesth Analg 2004;98:1809. 74. van Zwieten K, Mullins ME, Jang T. Droperidol and the black box warning. Ann Emerg Med 2004;43:139–40. 75. Habib AS, Gan TJ. Safety of patients reason for FDA black box warning on droperidol. Anesth Analg 2004;98:551–2. 76. Shafer SL. Safety of patients reason for FDA black box warning on droperidol. Anesth Analg 2004;98:551–2. 77. Weaver CS, Jones JB, Chisholm CD, Foley MJ, Giles BK, Somerville GG, Brizendine EJ, Cordell WH. Droperidol vs prochlorperazine for the treatment of acute headache. J Emerg Med 2004;26:145–50. 78. Cox RD, Koelliker DE, Bradley KG. Association between droperidol use and sudden death in two patients intoxicated with illicit stimulant drugs. Vet Hum Toxicol 2004;46:21–3. 79. Reid SD. Neuroleptic-induced tardive Tourette treated with clonazepam. Clin Neuropharmacol 2004;27:101–4. 80. Yasui-Furukori N, Kondo T, Mihara K, Inoue Y, Kaneko S. Fluvoxamine dose-dependent interaction with haloperidol and the effects on negative symptoms in schizophrenia. Psychopharmacology 2004;171:223–7. 81. Mortimer A, Martin S, Lôo H, Peuskens J, for the SOLIANOL Study Group. A double-blind, randomized comparative trial of amisulpride versus olanzapine for 6 months in the treatment of schizophrenia. Int Clin Psychopharmacol 2004;19:63–9. 82. Bitter I, Dossenbach MR, Brook S, Feldman PD, Metcalfe S, Gagiano CA, Furedi J, Bartko G, Janka Z, Banki CM, Kovacs G, Breier A, Olanzapine HGCK Study Group. Olanzapine versus clozapine in treatmentresistant or treatment-intolerant schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2004;28:173–80. 83. Dossenbach MRK, Folnegovic-Smalc V, Hotujac L, Uglesic B, Tollefson GD, Grundy SL, Friedel P, Jakovljevic M, Olanzapine HGCH
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schizophrenic patients. Pharmacopsychiatry 2004;37:63–8. Zarate C, Tohen M. Double-blind comparison of the continued use of antipsychotic treatment versus its discontinuation in manic patients. Am J Psychiatry 2004;161:169–71. Sachs G, Chengappa KNR, Suppes T, Mullen JA, Brecher M, Devine NA, Sweitzer DE. Quetiapine with lithium or divalproex for the treatment of bipolar mania: a randomized, double-blind, placebo-controlled study. Bipolar Disord 2004;6:213–23. Findling RL, Aman MG, Eerdekens M, Derivan A, Lyons B, The Risperidone Disruptive Behavior Study Group. Long-term, open-label study of risperidone in children with severe disruptive behaviors and below-average I.Q. Am J Psychiatry 2004;161:677–84. Lane H-Y, Chang Y-C, Chiu C-C, Lee S-H, Lin C-Y, Chang W-H. Fine-tuning risperidone dosage for acutely exacerbated schizophrenia: clinical determinants. Psychopharmacology 2004;172:393–9. Reveley MA, Libretto SE for the RIS-GBR31 investigators. Treatment outcome in patients with chronic schizophrenia during long-term administration with risperidone. J Clin Psychopharmacol 2004;24:260–7. Huq Z-U, on behalf of the RIS-GBR-31 investigators. A trial of low doses of risperidone in the treatment of patients with first-episode schizophrenia, schizophreniform disorder, or schizoaffective disorder. J Clin Psychopharmacol 2004;24:220–4. Bhanji NH, Chouinard G, Margolese HC. A review of compliance, depot intramuscular antipsychotics and the new long-acting injectable atypical antipsychotic risperidone in schizophrenia. Eur Neuropsychopharmacol 2004;14:87–92. Vieta E, Brugué E, Goikolea JM, SánchezMoreno J, Reinares M, Comes M, Colom F, Martínez-Arán A, Benabarre A, Torrent C. Acute and continuation risperidone monotherapy in mania. Hum Psychopharmacol Clin Exp 2004;19:41–5. Mahmoud RA, Engelhart LM, Janagap CC, Oster G, Ollendorf D. Risperidone versus conventional antipsychotics for schizophrenia and schizoaffective disorder. Symptoms, quality of life and resource use under customary clinical care. Clin Drug Invest 2004;24:275–86. Yen Y-C, Lung F-W, Chong M-Y. Adverse effects of risperidone and haloperidol treatment in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2004;28:285–90. Hirschfeld RMA, Keck PE, Kramer M, Karcher K, Canuso C, Eerdekens M, Grossman F. Rapid antimanic effect of risperidone monotherapy: a 3-week multicenter, doubleblind, placebo-controlled trial. Am J Psychiatry 2004;161:1057–65. Adamou MA, Hale AS. Extrapyramidal syndrome and long-acting injectable risperidone. Am J Psychiatry 2004;161:756–7.
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122. Food and Drug Administration, Patient Information Sheet. Risperidone Tablets (marketed as Risperdal). http://www.fda.gov/cder/drug/ InfoSheets/patient/risperidonePIS.htm. 123. Agemed. Agencia Española de Medicamentos y Productos Sanitarios. Nota informativa sobre risperidona. http://www.agemed.es/documentos/ notasPrensa/csmh/2004/cont_risperidone.htm. 124. Spollen JJ, Wooten RG, Cargile C, Bartztokis G. Prolactin levels and erectile function in patients treated with risperidone. J Clin Psychopharmacol 2004;24:161–6. ˇ 125. Cešková E, Pˇrikryl R, Kašpárek T, Ondrušová M. Prolactin levels in risperidone treatment of first-episode schizophrenia. Int J Psych Clin Pract 2004;8:31–6. 126. Dunbar F, Kusumakar V, Daneman D, Schulz M. Growth and sexual maturation during long-term treatment with risperidone. Am J Psychiatry 2004;161:918–20. 127. Safer DJ. A comparison of risperidone-induced weight gain across the age span. J Clin Psychopharmacol 2004;24:429–36. 128. Martin A, Scahill L, Anderson GM, Aman M, Arnold LE, McCracken J, McDougle CJ, Tierney E, Chuang S, Vitiello B, The Research Units on Pediatric Psychopharmacology Autism Network. Weight and leptin changes among risperidone-treated youths with autism: 6-month prospective data. Am J Psychiatry 2004;161:1125–7. 129. Ziegenbein M, Kropp S. Risperidoneinduced long-term weight gain in a patient with schizophrenia. Aust NZ J Psychiatry 2004;38:175–6. 130. Sluys M, Güzelcan Y, Casteelen G, de Haan L. Risperidone-induced leucopenia and neutropenia: a case report. Eur Psychiatry 2004;19:117. 131. Harrison-Woolrych M, Clark DW. Nose bleeds associated with use of risperidone. BMJ 2004;328:1416. 132. Srinivas VR. Postmarketing surveillance is needed. Br Med J 2004;329:51. 133. Knegtering R, Castelein S, Bous H, van der Linde J, Bruggeman R, Kluiter H, van den Bosch RJ. A randomized open-label study of the impact of quetiapine versus risperidone on sexual functioning. J Clin Psychopharmacol 2004;24:56–61. 134. Slauson SD, LoVecchio F. Risperidone-induced priapism with rechallenge. J Emerg Med 2004;27:88–9.
135. Loh C, Leckband SG, Meyer JM, Turner E. Risperidone-induced retrograde ejaculation: case report and review of the literature. Int Clin Psychopharmacol 2004;19:111–2. 136. Ilett KF, Hackett P, Kristensen JH, Vaddadi KS, Gardiner SJ, Begg EJ. Transfer of risperidone and 9-hydroxyrisperidone into human milk. Ann Pharmacother 2004;38:273–6. 137. Williams JH, Hepner DL. Risperidone and exaggerated hypotension during a spinal anesthetic. Anesth Analg 2004;98:240–1. 138. Harrison TS, Goa KL. Long-acting risperidone. A review of its use in schizophrenia. CNS Drugs 2004;18:113–32. 139. Food and Drug Administration. Risperdal Consta. Long-acting injection. Summary of product characteristics. http://www.fda.gov/medwatch/ safety/2005/aug_PI/Risperdal_%20Consta_PI. 140. van Os J, Bossie CA, Lasser RA. Improvements in stable patients with psychotic disorders switched from oral conventional antipsychotics therapy to long-acting risperidone. Int Clin Psychopharmacol 2004;19:229–32. 141. Turner M, Eerdekens E, Jacko M, Eerdekens M. Long-acting injectable risperidone: safety and efficacy in stable patients switched from conventional depot antipsychotics. Int Clin Psychopharmacol 2004;19:241–9. 142. Llambrich A, Lecha M. Photoinduced lichenoid reaction by thioridazine. Photodermatol Photoimmunol Photomed 2004;20:108–9. 143. Mamo D, Kapur S, Shammi C, Papatheodorou G, Mann S, Therrien F, Remington G. A PET study of dopamine D2 and serotonin 5-HT2 receptor occupancy in patients with schizophrenia treated with therapeutic doses of ziprasidone. Am J Psychiatry 2004;161:818–25. 144. Keck M, Müller M, Binder E, Sonntag A, Holsboer F. Ziprasidone-related tardive dyskinesia. Am J Psychiatry 2004;161:175–6. 145. Gray N. Ziprasidone-related neuroleptic malignant syndrome in a patient with Parkinson’s disease: a diagnostic challenge. Hum Psychopharmacol 2004;19:205–7. 146. Jaworowski S, Hauser S, Mergui J, Hirsch H. Ziprasidone and weight gain. Clin Neuropharmacol 2004;27:99–100.
Antonio Gil-Nagel
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Antiepileptic drugs
Carbamazepine
(SED-15, 627; SEDA-26, 72; SEDA-27, 76; SEDA-28, 88) Nervous system Children with benign epilepsy with centrotemporal spikes may develop epileptic negative myoclonus, a motor phenomenon that can worsen or occur de novo when carbamazepine is used to treat this syndrome. In an electrophysiological study the characteristics of negative epileptic myoclonus during exacerbation with carbamazepine and after drug withdrawal were analysed in two children and compared with nine children with classical benign epilepsy with centrotemporal spikes (1c ). In children with negative epileptic myoclonus induced by carbamazepine there were frequent epileptiform discharges related to the myoclonus, which abated after carbamazepine withdrawal, associated with a reduction in the slow wave component of the discharge. The morphology and topography of the discharges differed in the field distribution, amplitude, and duration of the slow wave component. The authors concluded that increased cortical inhibition could be the electrophysiological correlate of carbamazepine-induced epileptic negative myoclonus, and that certain electroencephalographic features might be used to predict an abnormal response to carbamazepine in children with benign epilepsy with centrotemporal spikes. Carbamazepine 800 mg/day, oxcarbazepine 1200 mg/day, and levetiracetam 1500 mg/day have been compared in a double-blind, crossover study in 10 healthy volunteers (2c ). More adverse events were reported with carbamazepine (63%) than with oxcarbazepine (12%), levetiracetam (20%), or placebo (5%). Carbamazepine induced the greatest motor slowing, Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29007-X © 2007 Elsevier B.V. All rights reserved.
followed by oxcarbazepine, while levetiracetam had no effect. Quantitative electroencephalography showed that carbamazepine significantly increased slow frequencies (delta–theta power), while oxcarbazepine induced smaller changes and levetiracetam had no effect. Carbamazepine slowed visual latencies, oxcarbazepine had a small effect, and levetiracetam had no effect. The effect of carbamazepine in this study may have been overestimated, since titration was relatively fast (a dosage of 800 mg/day was achieved within 7 days) and the duration was short, not allowing time for enzyme induction. Sensory systems Altered pitch perception is a rare adverse effect of carbamazepine. • A 12-year-old girl developed lowered perception of violin pitch by half a tone while taking carbamazepine 200 mg/day (3A ). After withdrawal the effect disappeared. • In a 9-year-old boy taking carbamazepine 120 mg/ day (4 mg/kg/day) for epilepsy, auditory brainstem-evoked potentials showed a significantly prolonged peak latency of wave V and interpeak latencies of wave I to V, and increased peak amplitudes of the waves, especially with lower click stimulation intensity (4A ).
The authors of the second report concluded that carbamazepine had activated the peripheral auditory system, probably increased sensitivity to low-pitched sounds, causing the development of falsely higher pitch perception. Musculoskeletal Worsening of myasthenia has been attributed to carbamazepine. • A 7-year-old girl with cleft palate and epilepsy was treated with carbamazepine, with good seizure control (5A ). From the age of 10 she developed symptoms of myasthenia gravis (dysarthria, dysphagia, ptosis, and reduced endurance. Her symptoms were more obvious in the afternoon and evening. An edrophonium test and acetylcholine receptor antibodies were positive, and electromyography was consistent with myasthenia gravis. Pyridostigmine produced mild improvement, and thymectomy at age 11 years produced remarkable
87
88 improvement. The thymus showed lymphofollicular hyperplasia. Carbamazepine was withdrawn when she was 12 ½ years old.
The authors considered the possibility that myasthenia gravis may have been caused by carbamazepine, because of similarities to a previous case report (6A ); however, in both cases a chance association could not be excluded. Reproductive system Carbamazepine and oxcarbazepine have been associated with sperm abnormalities in a prospective study in 60 men with different types of epilepsy (7c ). Immunologic Asymptomatic IgG1 and IgG2 deficiency has been attributed to carbamazepine in a 12-year old boy (8A ). His immunoglobulin concentrations were within the reference ranges before he started to take carbamazepine, but IgG1 and IgG2 concentrations fell 1 month later and returned to normal 12 months after withdrawal. There were no signs or symptoms of infection or hypersensitivity syndrome throughout the course of the illness.
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lethargy, dizziness, and imbalance. Her serum sodium had fallen from 140 mmol/l baseline to 125 mmol/l, and her serum carbamazepine concentration was 7.4 µg/ml. One week after withdrawal of hydrochlorothiazide her symptoms resolved and her sodium was 141 mmol/l.
Simvastatin The effect of carbamazepine on the pharmacokinetics of oral simvastatin has been studied in a randomized, two-phase, crossover study in 12 healthy volunteers who took carbamazepine for 14 days (200 mg/day for 2 days and 600 mg/day for the next 12 days) or no drug, followed by a single dose of simvastatin 80 mg (11c ). Carbamazepine reduced the mean AUCs of simvastatin and simvastatin acid by 75% and 82% respectively. The authors concluded that concomitant administration of these two drugs should be avoided or that the dose of simvastatin should be increased in patients taking carbamazepine.
Hydrochlorothiazide Symptomatic hyponatremia can occur when carbamazepine is combined with diuretics; this interaction has not previously been reported.
Zonisamide No significant pharmacokinetic interactions between carbamazepine and zonisamide were identified in a two-part study in human liver microsomes in vitro and in patients with epilepsy (12c ). In the in vitro study, zonisamide did not inhibit CYP1A2 or CYP2D6 at concentrations of 200–1000 µmol/l, although it did cause more than 25% reduction in the activity of CYP2A6, CYP2C9, CYP2C19, and CYP2E1 at concentrations four to six-fold above typical target concentrations, and inhibition of CYP3A4 by 17–22% at a concentration of 1000 µmol/l. In vivo studies were performed on 18 patients (12 men) aged 18–58 years, and weighing 61–105 kg. Doses of carbamazepine remained stable during the study at 200–2000 mg/day, while zonisamide was titrated up to 400 mg/day over 18 days. Zonisamide had no significant effects on mean Cmax , tmax , or AUC0–12 of total and unbound carbamazepine and carbamazepine epoxide. Although zonisamide caused a mild but significant reduction in carbamazepine epoxide renal clearance, this is unlikely to be clinically relevant. The authors concluded that adjustment of the dosage of carbamazepine should not be required with concomitant zonisamide administration.
• A 60-year-old woman with hypertension treated with hydrochlorothiazide 25 mg/day was given carbamazepine 200 mg/day for new-onset focal epilepsy (10A ). Within 2 weeks she developed
Diagnosis of adverse drug reactions Hair analysis may be useful in differentiating chronic from acute carbamazepine intoxication.
Drug interactions Fluconazole Fluconazole can inhibit the metabolism of carbamazepine. • A 29-year-old woman with epilepsy took carbamazepine 1600 mg/day, lamotrigine 400 mg/day, and berbexaclone 100 mg/day for many years without significant adverse effects. However, after taking fluconazole 150 mg/day she developed severe toxicity (9A ). Blurred vision and dizziness occurred a few hours after the first dose of fluconazole and gradually worsened over the next 11 days, followed by severe diplopia, oscillopsia, nausea, vomiting, and ataxia. The serum concentrations of lamotrigine and berbexaclone were unchanged, but the carbamazepine concentration increased from about 7 µg/ml to almost 19 µg/ml. One day after withdrawal of fluconazole her symptoms completely abated and the serum carbamazepine concentration fell.
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• A 12-year-old girl with epilepsy, who had taken carbamazepine for 6 years, developed coma and myoclonus associated with accidental carbamazepine intoxication (13A ). The carbamazepine blood concentration was 65.3 µg/ml. Samples of her hair were compared with samples from a healthy control and from patients with epilepsy and carbamazepine blood concentrations in the target range. In the patient there was an increased concentration of carbamazepine in the proximal but not in the distal hair segment, suggesting acute intoxication.
Carbamazepine intoxication has been successfully managed using albumin continuous venovenous hemodialysis in a 10-year-old girl who developed coma and respiratory depression (14A ). This type of hemodialysis provides more efficient elimination of protein-bound drugs, such as carbamazepine.
Gabapentin (SED-15, 1465; SEDA-26, 73; SEDA-27, 77; SEDA-28, 89) Observational studies In an open study of gabapentin for paroxysmal symptoms in 25 patients with multiple sclerosis (15c ) no patients withdrew because of adverse effects. Nervous system In patients with complicated Parkinson’s disease treated with gabapentin in a double-blind, placebo-controlled, crossover study dizziness was the most common adverse effect (5/39 in the treatment group compared with 1/19 in the placebo group) (16c ). Other adverse events (worse parkinsonism, accidental falls, abnormal gait, nausea, pulmonary embolism, and urinary retention) were not significantly different between the groups. Asterixis has been attributed to gabapentin (17A ). • A 76-year-old woman with focal epilepsy developed asterixis while taking gabapentin 900 mg/ day. Other medications included oxcarbazepine, lacidipine, and aspirin. The asterixis resolved 8 days after the dose of gabapentin was tapered to 300 mg/day, and reappeared when the dose was again increased to 900 mg/day. • A 77-year-old woman with sensory diabetic polyneuropathy took gabapentin 3600 mg/day for 3 months in addition to sertraline and developed asterixis, memory changes, and fluctuating cognitive impairment. The dosage of gabapentin was reduced to 1200 mg/day and 2 weeks later she recovered.
The second case suggests that asterixis can occur in non-epileptic patients taking gabapentin. Musculoskeletal In a 36-year-old woman gabapentin 900 mg/day, prescribed for left hand pain, caused severe diffuse arthralgia (18A ). There was no swelling of the joints and the symptoms resolved after drug withdrawal. Sexual function An 88-year-old woman taking gabapentin 300 mg/day developed compulsive masturbation, which disappeared after the drug was withdrawn (19Ac ). Reproductive system A 35-year-old woman with complex regional pain syndrome developed amenorrhea after taking gabapentin (20A ). Her symptoms resolved after gabapentin was withdrawn. Susceptibility factors Age Gabapentin is usually well tolerated in elderly people. Nine patients (five men) with severe Alzheimer’s disease took gabapentin for disordered behavior and two improved (19Ac ). Adverse effects included mild sedation at the start of treatment, mild disinhibition, and hallucinations in one patient each.
Ketogenic diet In a retrospective analysis of 54 patients treated with a ketogenic diet there were no differences between patients who were hospitalized for initiation of the diet and those who started as outpatients (21c ). Seizure control was similar in the two groups. Adverse events at the initiation of the diet were also evenly distributed and included nausea (2/37 out-patients and 0/17 inpatients), emesis (3/37 and 2/17), lethargy (2/37 and 1/17), irritability and listlessness (1/37 and 0/17), lethargy (0/37 and 1/17), and acidosis (0/37 and 1/17). Long-term adverse effects included hunger (5/37 and 0/17), acidosis (1/37 and 0/17), kidney stones (1/37 and 0/17), weight loss (5/37 and 1/17), weight gain (1/37 and 0/17), and increased susceptibility to infection (1/37 and 0/17).
90
Lamotrigine
(SED-15, 1990; SEDA-25, 85; SEDA-26, 74; SEDA-27, 77) Observational studies Lamotrigine and valproic acid have been compared as first-line monotherapy in newly diagnosed typical absence epilepsy in an open, randomized, parallel group study in 38 children aged 3–13 years (22C ). Mean doses at the last followup were 25 mg/kg/day for valproic acid and 8.3 mg/kg/day for lamotrigine. Adverse effects were recorded in two of the 19 patients randomized to valproic acid (diarrhea and weight gain in each) and in six of the 19 who were randomized to lamotrigine (headache in two, transient mild rash in one, diplopia in one, nervousness in one, increased appetite in one). The adverse effects were mild and transient and did not require drug withdrawal in any patient. Nervous system The efficacy and safety of lamotrigine have been studied in a long-term retrospective study in 39 patients with refractory epilepsy aged 31 years (18 women) (23c ). Lamotrigine was withdrawn in seven patients because of adverse effects, including insomnia in two, irritability in two, and somnolence, tremor, and vomiting in one each. Most of the adverse effects occurred at doses over 300 mg/kg/day. Lamotrigine can cause increased seizure frequency in children. • A 7-year-old girl with a diagnosis of idiopathic rolandic epilepsy had a paradoxical reaction to lamotrigine, characterized by seizure deterioration, the appearance of a new seizure type (negative myoclonus), and transient cognitive impairment (24A ). Her symptoms occurred at low doses and promptly resolved after lamotrigine withdrawal.
Since paradoxical reactions of this kind have previously been documented with carbamazepine, a drug that is a sodium channel inhibitor like lamotrigine, the authors thought that this effect had induced enhanced cortical inhibition underlying the slow-wave component of the spike–wave complex. Hematologic A hemophagocytic syndrome has been attributed to lamotrigine. • An 8-year-old boy with epilepsy taking topiramate developed a hemophagocytic syndrome 2 weeks after he started to take lamotrigine 100 mg/day
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(25A ). He developed intermittent itching, fever, abdominal pain, and skin rash. He was lethargic, with icteric sclera. The dosage of lamotrigine was reduced to 50 mg/day but his condition did not improve. Laboratory tests showed a pancytopenia with a leukocyte count of 1.95 × 109 /l, hemoglobin 9.7 gm/dl, and a platelet count of 23 × 109 /l. His liver function was impaired, with aspartate transaminase activity 609 U/l, bilirubin total/direct 3.1/2.6 mg/dl, and ferritin 38.7 g/l, cholesterol 251 mg/dl, triglycerides 524 mg/dl, prothrombin time 15 seconds, and partial thromboplastin time 64 seconds. Ultrasound showed a right pleural effusion and moderate ascites. Valproic acid and lamotrigine were withdrawn. Bone marrow biopsy showed interstitial infiltration by typical large lymphoid cells with cytoplasmic staining and increased numbers of histiocytes in the bone marrow with hemophagocytosis. Intravenous immunoglobulin (1 mg/kg/day) was administered for 2 days, followed by a glucocorticoid. Within 1 week his symptoms had resolved and the laboratory tests improved markedly. A follow-up bone marrow aspiration biopsy showed reduced numbers of activated histiocytes and no hemophagocytosis.
Immunologic Common variable immune deficiency has been attributed to lamotrigine. • A 59-year-old man with primary generalized epilepsy was given lamotrigine 25 mg/day, increased by 25 mg/day every 2 weeks to a maximum dose of 100 mg/day (26A ). He also took felodipine, doxazosin, and aspirin. During the next 6 months he developed lethargy and lower respiratory tract infections. His serum globulin concentration fell from 26 to 12 g/l 12 months later, and there was panhypoglobulinemia after 1 month. He had an impaired response to pneumococcal immunization and to diphtheria in lymphocytic function tests. Common variable immunodeficiency was diagnosed and he was given monthly intravenous immunoglobulin infusions for 2 months. Eventually lamotrigine and immunoglobulin were withdrawn. At follow-up 2 years later there was no recurrence and IgG and IgM concentrations had returned to normal.
Pregnancy Correlation of drug concentration and seizure control has been analysed in 12 pregnancies in women with epilepsy taking lamotrigine monotherapy (27c ). There was an increase in seizure frequency in nine cases: seizure frequency doubled in four, three patients who had been seizure free before pregnancy had seizure recurrence, generalized tonic–clonic seizures recurred in one patient, and another had her first generalized tonic–clonic seizure ever. Seven patients had their lamotrigine dose
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increased in order to regain seizure control. Decreased seizure control was probably related to a gradual fall in the lamotrigine concentrationto-dose ratio to 40% of baseline. One pregnancy ended in fetal death during the 5th month; post-mortem examination showed an infectious cause not related to lamotrigine or seizures. The other pregnancies and deliveries were uneventful. Lamotrigine concentrations rose again after delivery, causing adverse effects (dizziness, diplopia, and ataxia) in three of seven women whose dose had been increased during pregnancy. The authors suggested that the most likely explanation for the fall in lamotrigine serum concentrations during pregnancy was fluctuation in hormones and other endogenous homeostatic factors. They recommended frequent lamotrigine serum concentration measurements and dosage adjustments during pregnancy. Drug overdose Intoxication with lamotrigine has been described in a child. • A 3-year-old girl who took 46 tablets of 25 mg of lamotrigine developed sedation, rash, and a transient rise in liver function tests (28A ). The plasma lamotrigine concentration was 25 µg/ml. Her symptoms resolved promptly after treatment with gastric lavage and activated charcoal.
Drug interactions Lamotrigine toxicity has been reported during valproic acid therapy. • A 51-year-old man developed confusion, disorientation, and behavioral changes when valproic acid 500 mg/day was added to his previous treatment with lamotrigine 400 mg/day (29A ). A serum lamotrigine concentration during the time he was experiencing delirium was 23 µg/ml. The symptoms resolved after valproic acid and lamotrigine were withdrawn.
This case supports the common practice of avoiding doses of lamotrigine above 200 mg/ day when it is used with the enzyme inhibitor valproic acid. Management of adverse drug reactions Successful rechallenge with slow titration of lamotrigine after a skin rash has been reported. • A 61-year-old woman with bipolar disorder was given lamotrigine 25 mg/day monotherapy (30A ). After 2 weeks she developed non-confluent, pruriginous, maculopapular erythema involving the
upper trunk and arms, not affecting her mucosae, and associated with eosinophilia and mildly altered liver function. After lamotrigine was abruptly withdrawn her rash disappeared and the laboratory tests normalized. Because her bipolar disorder was resistant to other medications (lithium and trazodone) lamotrigine was reintroduced in a slower titration schedule (12.5 mg/day during weeks 1 and 2, 25 mg/day during weeks 3 and 4, and increasing by 25 mg/day each week thereafter) while lithium was continued. Six months after reintroduction of lamotrigine she remained well and free from cutaneous and other adverse effects.
Ciclosporin has been used to treat lamotrigine-associated toxic epidermal necrolysis. • A 29-year-old woman taking valproic acid for epilepsy was also given lamotrigine because of seizure persistence (31A ). She developed oral mucosa ulceration, followed 3 weeks later by a maculopapular rash, fever, and constitutional symptoms, followed after a further 3 days by painful blistering of the skin of the neck and face. She was given ciclosporin intravenously 2 mg/kg/day in two divided doses, intravenous co-amoxiclav, and fluids. The blistering ceased in 24 hours with re-epithelialization after 72 hours, leading to complete recovery.
Monitoring drug therapy The recommended target concentration of lamotrigine has not been fully established, and a new study has shown that higher concentrations are often well tolerated (32C ). The serum concentration of lamotrigine was correlated with tolerability and efficacy in a retrospective review of the charts of 811 patients with epilepsy. In all 3731 concentrations were recorded, and were considered “toxic” if the patient had adverse effects that led to a reduction in dosage or drug withdrawal. Toxicity increased with increased concentrations of lamotrigine, as shown in Table 1. The correlation between serum concentration and tolerability was independent of concurrent medication. Increasing efficacy, measured as seizure freedom for 6 months, was Table 1. Toxicity of lamotrigine in relation to serum concentration Lamotrigine concentration (µg/ml)
Toxicity (%)
under 5.0 5–10 10–15 15–20 over 20
7 14 24 34 59
92 directly proportional to lamotrigine concentration, including concentrations above 20 g/ml. The authors recommend an initial target concentration of 1.5–10 µg/ml and to consider concentrations above 20 µg/ml if they are tolerated for improvement of seizure control in refractory patients. The most common adverse effects requiring dosage adjustment were imbalance, dizziness, drowsiness, headache, tremor, insomnia, visual disturbances, cognitive and psychiatric disturbances, gastrointestinal problems, and rashes.
Levetiracetam
(SED-15, 2035; SEDA-26, 75; SEDA-27, 79; SEDA-28, 91)
Nervous system In 99 children, adolescents, and young adults with refractory cryptogenic and symptomatic partial or generalized epilepsy (aged 12 months to 32 years) who were given levetiracetam add-on therapy for 1 year there were mild transient adverse events in 17, mostly irritability and drowsiness; seizures worsened in 23 patients (33C ). In a retrospective analysis of 26 children under 10 years with refractory epilepsy levetiracetam produced a good response in 16 (34c ). Withdrawal of the drug was related to seizure worsening in three patients and excessive sleepiness in one. However, changes in seizure frequency can occur spontaneously in epilepsy patients, therefore it is not possible to conclude that seizure worsening is caused by levetiracetam. Psychiatric Sedation was the most common adverse effect of levetiracetam, affecting 11% of 245 patients followed at an epilepsy clinic (35C ). However, mood disturbances, which affected 4.8% of the patients, were more likely to lead to withdrawal of the drug. The retention rate was not related to a previous history of psychiatric disease. In a retrospective analysis of 118 patients with epilepsy with intellectual disability taking levetiracetam, 15 had psychiatric adverse events, including affective disorder in two, aggressive behavior in nine, emotional lability in two, and other personality changes (agitation, hostility, anger) in two (36C ). There was a significant correlation with a previous history of
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Antonio Gil-Nagel
status epilepticus and a previous psychiatric history, but no relation to the titration schedule of levetiracetam, electroencephalography and MRI, and the type and duration of epilepsy. In six patients with Lennox–Gastaut syndrome levetiracetam improved myoclonic, atonic, and generalized tonic–clonic seizures (37c ). The most common adverse effect was irritability during the start of treatment in two patients, requiring withdrawal in one. In a retrospective analysis of 14 patients (aged over 60 years) levetiracetam 500–3000 mg/day was generally well tolerated (38c ). There were no major adverse events. One patient reported dizziness but was able to continue taking levetiracetam while the symptoms improved. Hematologic Thrombocytopenia has been attributed to levetiracetam. • A 49-year-old man with anaplastic oligoastrocytoma, who had been previously treated with radiation, CCNU, and temozolamide, was given levetiracetam, sertraline, cefuroxime, benzodiazepines, betamethasone, and zolpidem (39A ). Twenty days later he developed hematuria and his platelet count fell to 7 × 109 /l. A bone marrow aspirate showed unremarkable morphology with normal megakaryocytes. He was treated with prednisone 100 mg/day, platelet infusion, and intravenous immunoglobulins (30 g/day for 5 days).
He had received 15 cycles of temozolamide, the last one 5 months before the fall in platelet count. Because thrombocytopenia is rarely seen at this stage of temozolamide treatment, it was considered to be related to levetiracetam or sertraline and both drugs were withdrawn. Monoclonal antibody immobilization of platelet antigen showed irregular antibodies for platelets in the presence of levetiracetam but not sertraline. Five weeks after withdrawal of levetiracetam the platelet count was 94 × 109 /l. Gastrointestinal Enterocolitis was documented in two patients within 1 and 6 months after they started to take levetiracetam (40A ). In both cases colonoscopy showed punctate hemorrhagic colitis. Their symptoms (abdominal pain, weight loss, and bloody stools) resolved after levetiracetam withdrawal. Liver Worsening liver function and transient jaundice has been attributed to levetiracetam.
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• A 45-year-old man with alcoholic liver disease took levetiracetam 2000 mg/day in association with lamotrigine (41A ). His liver function deteriorated and improved 4 weeks after withdrawal of levetiracetam.
Since alcoholic cirrhosis can sometimes have a fluctuating course and other worsening factors (such as alcohol drinking) cannot be completely excluded, the relation to levetiracetam should be considered with caution. Drug interactions Levetiracetam is usually considered not to have pharmacokinetic interactions with other antiepileptic drugs. However, in 100 patients with epilepsy, steady-state plasma levetiracetam concentrations were significantly lower in patients taking concomitant enzyme inducers (carbamazepine, phenytoin, and phenobarbital) than in those taking other concomitant antiepileptic drugs, such as lamotrigine and valproic acid (10.4 µg/ml versus 14.7 µg/ml) (42C ). Nevertheless, this variability was considered moderate and possibly of minor clinical significance.
Electrolyte balance hyponatremia.
• A 64-year-old woman with focal epilepsy developed an acute encephalopathy and hyponatremia (115 mmol/l) when she took oxcarbazepine 30 mg/ kg/day (1800 mg/day) and furosemide 25 mg/day (45A ). She developed confusion, hallucinations, and delirium. Electroencephalography showed diffuse slowing of background activity and a CT scan was normal. Oxcarbazepine and furosemide were immediately withdrawn; her symptoms resolved in 20 days and electroencephalography was normal 6 months later.
This case illustrates that the mechanisms of oxcarbazepine-induced hyponatremia are unclear and, in some cases, may be related to combined effects with other drugs that interfere with sodium homeostasis. Reproductive system Oxcarbazepine has been associated with sperm abnormalities in a prospective study in 60 men with different types of epilepsy (7c ). Drug overdose been reported.
Oxcarbazepine
(SED-15, 2646; SEDA-26, 76; SEDA-27, 79; SEDA-28, 94) Observational studies In a multicenter, randomized, open, parallel-group study in 246 patients who switched from carbamazepine to oxcarbazepine monotherapy, there were no differences in the proportions of patients who did not experience any clinically significant adverse event, which was a primary endpoint of the study (43c ). Nervous system Several series and case reports have suggested that aggravation of seizures can occur in patients with idiopathic generalized epilepsies taking carbamazepine, gabapentin, phenytoin, phenobarbital, tiagabine, and vigabatrin. In a retrospective analysis of six patients with idiopathic generalized epilepsy treated with oxcarbazepine, all showed aggravation of seizures (44c ). Aggravation consisted of increase frequency and severity of myoclonic seizures in five cases, de novo myoclonic seizures in one, and exacerbation of absence seizures in three (including one with absence status epilepticus and one with de novo absences).
Oxcarbazepine can cause
Oxcarbazepine overdose has
• A 36-year-old man (weight 78 kg, height 180 cm) developed mild somnolence 4 hours after taking 103 tablets of oxcarbazepine 300 mg (46A ). There were no cardiovascular or other neurological effects. He was treated with sodium sulfate 15 g and activated charcoal 50 g.
The fact that oxcarbazepine is a prodrug and that the formation of the active 10-monohydroxy derivative is a rate-limiting process may have contributed to the limited toxicity of the drug in this patient.
Phenobarbital
(SED-15, 2798;
SEDA-28, 95) Immunologic Anticonvulsant hypersensitivity syndrome has been attributed to phenobarbital. • An 11-year-old girl taking phenobarbital developed fever, exfoliative dermatitis, alopecia, and hepatitis (47A ). The diagnosis was confirmed by an in vitro lymphocyte toxicity assay, which showed increased cell death after exposure to phenobarbital, as well as other aromatic anticonvulsants and
94 lamotrigine. Her symptoms started 6 days after initiating phenobarbital and she recovered completely after drug withdrawal and intravenous methylprednisolone.
Teratogenicity In 77 pregnancies in women taking phenobarbital monotherapy five major malformations were identified within 5 days from birth (48A ). When compared with the background rate in the North American Antiepileptic Drug Pregnancy Registry (1.62%) there was a significantly increased risk of major malformations with phenobarbital (relative risk, 4.2; 95%CI = 1.5, 9.4).
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Mouth and teeth In 28 epileptic patients aged 15–75 years and 56 unrelated healthy subjects aged 30–48 those with severe gingival overgrowth had significantly higher serum concentrations of phenytoin (52c ). Although 7% of those in the epilepsy and control groups were positive for CYP2C9*3, the degree of gingival overgrowth did not correlate directly with the polymorphism.
Pharmacoeconomics The cost-effectiveness of oral phenytoin, intravenous phenytoin, and intravenous fosphenytoin in an emergency department has been analysed from information derived from a prospective, randomized, controlled trial (50R ). The mean numbers of adverse events per patient were 1.06, 1.93, and 2.13 respectively. The mean times to safe discharge from the emergency room (defined as the time at which a concentration of phenytoin below 40 µmol/l (10 µg/ml) was achieved) were 6.4 hours, 1.7 hours, and 1.3 hours. The costs per patient were $2.83, $21, and $175. Based on these results the authors concluded that oral phenytoin is the most cost-effective loading method, while intravenous fosphenytoin is the most expensive. No patients had a severe reaction to phenytoin infusion, such as tissue necrosis at the site of administration, or cardiac dysrhythmias. These types of complications, although rare, may still represent a reason for using intravenous fosphenytoin rather than intravenous phenytoin.
Skin In a comparative study, patients with a solitary cysticercus granuloma (n = 63) had more frequent skin reactions to phenytoin than those who had seizures associated with other conditions (n = 54) (53C ). There were skin reactions occurred in nine of the former compared with two of the latter, a significant difference. The spectrum of skin reactions in patients with cysticercus granuloma included benign rash in three, anticonvulsant hypersensitivity syndrome in four, Stevens–Johnson syndrome in one, and urticaria in one. A review of the literature identified 24 patients who had developed erythema multiforme while receiving radiation therapy and phenytoin (54R ). Three other patients were reported by the authors. Lesions developed during radiation treatment in 11 cases and within 2–35 days after treatment. In all cases the lesions were initially localized, but became widespread and in 16 cases Stevens–Johnson syndrome developed. There was no relation with the histology of the malignancy, the extent of radiation therapy, or the dose of radiation or phenytoin. Systemic glucocorticoid therapy was of little benefit and the symptoms resolved within 1–8 weeks of phenytoin withdrawal, except in two patients who died of septic shock within a week of diagnosis. A heterozygous CYP2C9*3 variant was found in three of 10 patients with phenytoininduced skin adverse reactions, compared with none of 167 controls exposed to phenytoin and one of 71 patients who had been exposed to phenytoin and had not developed a skin reactions (55c ).
Psychological A comparison of social skills in individuals with intellectual disability and epilepsy treated with carbamazepine, valproic acid, and phenytoin showed less positive social skills in those who received phenytoin (51c ).
Immunologic Phenytoin-induced hypersensitivity syndrome in a 43-year-old woman has been successfully treated with glucocorticoids and intravenous immunoglobulin (56A ).
Drug overdose Phenobarbital overdose in a 79 year-old man with a serum phenobarbital concentration of 180 µg/ml was successfully treated by hemodialysis (49A ).
Phenytoin and fosphenytoin (SED-15, 2813; SEDA-26, 76; SEDA-27, 80; SEDA-28, 95)
Antiepileptic drugs
Susceptibility factors Genetic A genetic polymorphism of the CYP2C9 gene was suggested to have been responsible for toxic phenytoin concentrations in a 41-year-old woman loaded with intravenous phenytoin 15 mg/kg (57A ). However, because the phenytoin serum concentrations fell faster than expected, questions were raised about this conclusion, and it was suggested that the most likely explanation was an error in the dose of phenytoin, not a fall in clearance caused by the CYP2C9 gene polymorphism (58r , 59r ). Although the authors of the original case report suggested that activated charcoal therapy may have resulted in increased clearance after intoxication, this may not have explained the rapid clearance observed after intoxication, since after overdose some drugs have a more rapid clearance rate than expected. Drug administration route In a comparison of oral phenytoin (n = 16), intravenous phenytoin (n = 16), and intravenous fosphenytoin loading (n = 13) at a single center showed fewer adverse events in those who were given oral phenytoin but a significantly shorter time to discharge from the emergency department in those who were given intravenous phenytoin because target plasma concentrations were reached faster (60c ). Because of the small number of patients, differences in efficacy and safety between intravenous fosphenytoin and phenytoin cannot be analysed.
Sultiame
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(SED-15, 3247; SEDA-28, 96)
Nervous system The efficacy of sultiame 5– 10 mg/kg/day in West syndrome has been studied in children aged 3.5–15 months, who were randomized to sultiame (n = 20) or placebo (n = 17) (61c ). Sultiame was superior to placebo: seven responded to the drug and none to placebo. Only one patient, taking sultiame, was withdrawn from the study, because of reversible somnolence. The charts of 125 children with epilepsy taking sultiame have been reviewed in a multicenter retrospective study (62c ). Adverse effects associated with treatment included hyperventilation in 19, paresthesia in eight, drowsiness in five, psychiatric symptoms in three, increased
seizure frequency in three, anorexia in two, headache in two, fear sensation two, and forced normalization in one. Most of the adverse effects were mild, and they required withdrawal in only seven children.
Tiagabine
(SED-15, 3419)
Nervous system In a retrospective analysis of 20 consecutive patients with refractory epilepsy taking tiagabine, it was judged to be safe and effective (63c ). The most common adverse effect was dizziness (n = 9), followed by tiredness (n = 5), and ataxia (n = 1). All adverse events resolved after dosage modification. Drug overdose Tiagabine intoxication has been associated with extrapyramidal symptoms. • A 46-year-old woman, without a prior history of epilepsy, developed rigidity and akinetic mutism after taking an intentional overdose of tiagabine (64A ). She did not respond to diphenhydramine, but improved after administration of lorazepam 2 mg (route not indicated).
The authors concluded that this was an unusual case of an extrapyramidal reaction to tiagabine, but similar symptoms could have been caused by non-convulsive status epilepticus, a known adverse effect. Since an electroencephalogram was not performed during the symptomatic phase, this possibility cannot be completely ruled out.
Topiramate
(SED-15, 3447; SEDA-27,
81; SEDA-28, 96) Nervous system Five children with West syndrome treated with a combination of vigabatrin and topiramate showed promising seizure control (65A ). One patient had a reduced appetite. Because of concerns about visual field constriction, vigabatrin was maintained for the shortest possible time. Psychiatric Worsening of psychosis could have been an adverse event of topiramate in a 50-year-old woman with a long history of a schizoaffective disorder treated with risperidone 4 mg/day, venlafaxine 300 mg/day, and
96 topiramate 200 mg/day (66A ). Her behavior worsened after topiramate was introduced. After it was withdrawn her mood, spontaneous speech, and psychomotor activity improved. Daytime vigilance has been assessed in 14 newly diagnosed never medicated adults with focal epilepsy at baseline and 2 months after slow titration of topiramate to 200 mg/day (67c ). Multiple Sleep Latency Test (MSLT), visual simple and choice reaction time (VRT), and self-rating with the Epworth Sleepiness Scale were used for quantification of sleepiness, and compared with 14 healthy volunteers. At baseline MSLT scores were comparable. Two months after topiramate monotherapy, MSLT, VRT, and self-rating did not change significantly. The authors concluded that a short course of topiramate monotherapy dose not impair vigilance in this population. Sensory systems A review of case reports from the National Registry of Drug-Induced Ocular Side Effects (Casey Eye Institute, Portland, Oregon, USA), the Food and Drug Administration, the World Health Organization, and the literature revealed 86 cases of acuteonset glaucoma (83 bilateral, three unilateral), 17 of acute bilateral myopia, nine of suprachoroidal effusions, three of periorbital edema, and four of scleritis. Of the cases of glaucoma 73 occurred within 2 weeks of treatment with topiramate. Of 21 cases in which information of management was provided, eight had laser or surgical peripheral iridectomy (68R , 69R ). The first presenting symptom of acute secondary angle-closure glaucoma was blurred vision. In two patients with topiramate-induced angle closure glaucoma, fundoscopic examination and B-scan ultrasonography showed diffuse ciliochoroidal effusions (70A ). These abnormalities disappeared after treatment with topical timolol and withdrawal of topiramate. The authors suggested that formation of ciliochoroidal effusions by topiramate is the mechanism of topiramate-induced acute-onset myopia and angle closure glaucoma. Electrolyte balance Hypokalemia has been attributed to topiramate. • A 35-year-old woman developed persistent hypokalemia over 2 months, despite oral potassium supplementation (71A ). She had been taking carbamazepine for more than 5 years for epilepsy,
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and topiramate 600 mg/day had been added 2 years before. Her serum potassium was 3 mmol/l, chloride 113 mmol/l, uric acid 2.1 g/dl, and bicarbonate 16 mmol/l, with a normal anion gap and normal sodium. Urinalysis showed sodium 120 mmol/l/day, potassium 75 mmol/l/day, chloride 97 mmol/l/day, and no glycosuria. The serum topiramate concentration was 2.15 mg/l. Topiramate was maintained and potassium citrate added; the hypokalemia and acidosis resolved.
The biochemical abnormalities suggested a proximal tubular acidosis, most probably because of a renal tubular defect. Since carbonic anhydrase inhibitors, such as topiramate, interfere with hydrogen ion secretion in the distal nephron, the drug probably further impaired tubular function in this patient, leading to acidosis and hypokalemia. Skin Hypersensitivity has been reported to topiramate sprinkle capsules but not to topiramate tablets. • A 17-year-old boy with epilepsy developed a generalized rash within 2 months of treatment with topiramate sprinkles (72A ). His rash disappeared 3 weeks after withdrawal of topiramate, and did not recur when about 3 months later he was given topiramate tablets.
The relation to topiramate sprinkles in this case should be considered with caution, since on occasions a skin rash does not recur after rechallenge with an antiepileptic drug. Urinary tract Three cases of nephrolithiasis during treatment with topiramate were attributed in part to pre-existent inadequate urinary acidification and hypocitraturia (73A ). Drug overdose Intentional intoxication with 800 mg of topiramate in a 17-year-old girl weighing 50 kg of had a relatively mild course (74A ). Clinical manifestations included incoherence, combativeness, and aggressive behavior, but there were no major alterations in vital signs. Although this case illustrates that topiramate is generally safe, the dose was relatively low, considering that some patients can tolerate doses up to 1000 mg/day after slow titration. Drug interactions Lithium Topiramate has been reported to have increased serum lithium concentrations.
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Chapter 7
• A 26-year-old woman with type 1 bipolar disorder, taking lithium 900 mg/day (serum concentration 0.82 mmol/l), valproate 2000 mg/day, and clonazepam as required, was given topiramate 75 mg/day (75A ). Seven days later her lithium concentration had risen to 1.24 mmol/l, and it continued to rise to 1.97 mmol/l 4 days later despite a reduction in the dose of lithium to 750 mg/day. She had evidence of toxicity (worsening concentration, confusion, and lethargy), which resolved on withdrawal of lithium.
Valproic acid Six patients with epilepsy developed encephalopathy while they were taking a combination of valproic acid and topiramate (76A ). In four cases there was hyperammonemia. The symptoms disappeared after the dosage of valproic acid was reduced or either valproic acid or topiramate was withdrawn. The possible mechanisms of this adverse effect considered by the authors were a pharmacodynamic interaction between the two drugs and a pharmacokinetic interaction leading to hyperammonemia.
Valproate sodium and semisodium (SED-15, 3579; SEDA-26, 80; SEDA-27, 82; SEDA-28, 99) Nervous system In a prospective comparison of 50 patients taking sodium valproate with 20 taking carbamazepine, three patients (ages 64, 65, and 75 years) taking sodium valproate had unequivocal parkinsonism, with Unified Parkinson Disease Rating Scale scores of more than 30 (77c ). The drug was withdrawn in two patients, with improvement of symptoms, while reduction in the dosage in the third patient did not improve his condition. Although the small size of the sample does not allow a comparison of valproate with carbamazepine, this study provides further evidence of the risk of extrapyramidal adverse effects with valproate sodium, especially in elderly people. • A 40-year-old man developed spasmodic dysphonia and bilateral upper limb intermittent dystonia after taking valproic acid 1200 mg/day for 2 weeks for new onset epilepsy (78A ). His symptoms worsened when the dose was increased to 1500 mg/day. Electroencephalography and a brain MRI scan were normal. His symptoms resolved a few days after he stopped taking valproic acid. When his seizures recurred valproic acid was started again,
97 and the spasmodic dysphonia and hand dystonia developed again. His symptoms resolved when the dose of valproic acid was reduced to 900 mg/day and phenytoin was added.
Paroxysmal dystonia has also been associated with other antiepileptic drugs, such as carbamazepine, felbamate, gabapentin, phenytoin, and tiagabine. Metabolism Hyperammonemia is common in patients taking valproate sodium, even in asymptomatic patients. It is therefore difficult to establish a relation between valproate encephalopathy and increased serum ammonium concentrations. Valproate-induced hyperammonemic encephalopathy has been reported in several single case reports, but still it is difficult to ascertain whether hyperammonemia or valproic acid is the cause of the encephalopathy. In one case valproate was used in combination with lithium, which in itself could have caused encephalopathy by displacement of protein binding or other mechanisms, regardless of hyperammonemia (79A ). In a second case it was also impossible to evaluate the effect of hyperammonemia on the level of consciousness, since it involved a woman who took valproic acid (30 g) in addition to gabapentin (9 g), clonazepam (90 mg), and risperidone (120 mg) (80A ). In a third case, a 62-year-old woman became encephalopathic while taking valproate (81A ). Her serum ammonia concentration was three times the upper limit of the reference range, despite only mildly raised aspartate aminotransferase activity and a normal bilirubin, with a serum valproic acid concentration within the target range. Her treatment also included estradiol 1 mg/day, levothyroxine 25 micrograms/day, diazepam 20 mg/day, cyclobenzaprine 30 mg/day, paracetamol 600 mg/day, codeine 60 mg/day, and sulindac 400 mg/day. Again, other potential pharmacodynamic and pharmacokinetic interactions could have caused the reduced level of consciousness in this patient. A fourth case involved a 76-year-old woman taking sodium divalproex 2250 mg/day, who had valproic acid concentrations up to 144 µg/ml and ammonia concentrations up to 2110 µg/l (82A ). Her associated medications included aspirin 325 mg/day, amlodipine 5 mg/day, atenolol 50 mg/day, losartan 50 mg/day, and pantoprazole 40 mg/day. Considering that beta-blockers
98 can compete with valproic acid for protein binding, an increase in free valproic acid concentrations could have been another factor involved in this patient’s symptoms of drug toxicity. Acid base balance Fanconi syndrome (metabolic acidosis secondary to malfunction of proximal renal tubules, resulting in urinary excretion of amino acids, glucose, phosphate, bicarbonate, uric acid, and other substances) secondary to long-term valproic acid has been described in an 8-year-old boy with severe developmental disability (83A ). In a review of 10 previous reports of Fanconi syndrome secondary to long-term valproic acid therapy the authors found that all occurred at 4–14 years, all had taken valproic acid for 10 months to 10 years, and symptoms were fully reversible within 2–14 months after withdrawal of valproic acid. Most of the patients (9 of 11) were severely disabled, bedridden, or wheelchairbound. Hematologic Two children developed deficiency of factor XIII during valproate treatment, a coagulation disorder that has not been previously reported in association with this drug (84A ). Both developed recurrent epistaxis and there was thrombocytopenia in one case and reduced von Willebrand factor in the other. Symptoms and laboratory parameters resolved a few days after valproate withdrawal in one case and dosage reduction in the other. • Epistaxis and ecchymoses secondary to thrombocytopenia (43 × 109 /l) and increased liver enzymes (aspartate transaminase 56 U/L, and alanine transaminase 48 U/L) occurred in a 4year-old boy taking high-dose sodium valproate (50 mg/kg/day), and resolved when the dose was reduced to 30 mg/kg/day (85A ).
Liver The relation between valproate and non-alcoholic fatty liver disease has been studied prospectively in 45 non-diabetic, non-alcoholic patients with epilepsy taking (n = 22) or carbamazepine (n = 23) monotherapy for at least 2 years (86c ). Using abdominal ultrasound 14 of those taking valproate had criteria of fatty liver disease, compared with five of those taking carbamazepine. Valproate was also associated with significantly increased triglyceride concentrations and reduced HDL cholesterol,
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as well as various symptoms of increased insulin resistance (higher body mass index and increased fasting glucose and insulin concentrations). Patients taking carbamazepine had higher total cholesterol, LDL cholesterol, and ApoB concentrations. The authors concluded that there is an increased risk of fatty liver disease in patients taking valproic acid, probably related to higher body weight and insulin resistance. Nevertheless, while their claims were well supported by their findings, overt clinical liver failure is rare in patients taking long-term valproic acid. Musculoskeletal Bone mineral density, measured by dual-energy-X-ray absorptiometry in the lumbar vertebrae, femoral neck, and greater trochanter, has been assessed in 33 children with epilepsy who had taken valproic acid for at least 6 months, and compared with an equal number of matched healthy children (87c ). Valproic acid was associated with significantly higher osteocalcin concentrations, and significantly lower bone mineral density in the lower femur and trochanter. There was a correlation between the duration of treatment and doses of valproate in seven of 33 osteopenic patients compared with 26 of 33 non-osteopenic patients. While this study has provided evidence of the adverse effect of valproate on bone metabolism, several variables, such as degree of mobility and sunlight exposure, were not equally distributed among patients, and these may have confounded some of the results. There were similar results in a comparison of 31 healthy children with 33 children with epilepsy, 17 taking carbamazepine and 16 valproate (88c ). Of those taking valproate four were hypocalcemic, one had raised alkaline phosphatase activity, and eight were hypophosphatemic, compared with three hypocalcemic and six hypophosphatemic in the carbamazepine group. Children taking valproate had a 32% reduction in bone mineral density at the femoral neck, while a 20% reduction in this area in those taking carbamazepine was not statistically significant. The results should be regarded with caution, owing to the small number of patients studied. Reproductive system Valproic acid, as well as carbamazepine and oxcarbazepine, has been associated with sperm abnormalities, but only
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valproic acid was associated with reduced testicular volume in a prospective study in 60 men with different types of epilepsy (7c ).
(92A ). Since valpromide is a prodrug of valproic acid and a period of time is required for its conversion into the parent compound this delay in the onset of clinical symptoms was expected.
Immunologic Valproic acid hypersensitivity syndrome has been reported in a psychiatric patient; the symptoms resolved after valproic acid was withdrawn (89A ). While rare, this syndrome has previously been reported in patients with epilepsy taking the non-aromatic drug valproic acid.
Drug interactions There were no significant pharmacokinetic interactions during coadministration of valproate sodium with efavirenz or lopinavir–ritonavir in a prospective study in 34 patients with HIV infection (93c ).
Teratogenicity Major malformations in infants exposed to carbamazepine or valproic acid monotherapy in utero have been analysed in a nationwide, population-based register study (90C ). There were malformations in 35 of 268 valproic acid-exposed infants, of which 28 were severe, and in 46 of 703 carbamazepineexposed infants, 28 severe. Valproic acid monotherapy compared with carbamazepine monotherapy gave an odds ratio of 3.51 (95%CI = 1.43, 4.68) for neonatal malformations. The malformations included neural tube defects, cardiac abnormalities, orofacial clefts, hypospadias, alimentary tract atresia, diaphragmatic hernias, and craniosynostosis. The authors concluded that the risk of a malformation after exposure to valproic acid is higher than after exposure to carbamazepine. Drug administration route In a multicenter, open, prospective, dose-escalation study of the safety of a rapid infusion of valproate sodium, at more rapid rates of infusion or higher doses than those described in its current labeling, patients received single doses of 15 mg/kg at a rate of 3 mg/kg/minute (n = 36), 30 mg/kg at 3 mg/kg/minute (n = 249), or 15 mg/kg at 6 mg/kg/minute (n = 5); 13 patients reported a total of 16 adverse events of mild to moderate severity (91C ). These included injection site pain (n = 3), pain during infusion (n = 3), dizziness (n = 2), somnolence (n = 1), others (n = 5), and not documented (n = 3). The authors concluded that intravenous valproate sodium can be used safely at these doses and rates of infusion, thus providing an alternative to other antiepileptic drugs for the rapid resolution of seizures in emergencies. Drug overdose There was delayed clinical toxicity in three cases of valpromide overdose
Vigabatrin (SED-15, 3623; SEDA-26, 82; SEDA-27, 83; SEDA-28, 101) Sensory systems DoTS classification: Reaction: Visual field loss from vigabatrin Dose relation: Collateral reaction Time course: Late Susceptibility factors: More common in adults To evaluate whether vigabatrin-related visual field constriction is often asymptomatic or not a questionnaire to detect visual complaints was developed and used in 51 patients with epilepsy, 27 exposed to vigabatrin and 24 controls who had never been exposed (94c ). Based on the results of the questionnaire and a comparison with formal visual field testing, 60% of the patients with vigabatrin-related visual field constriction were symptomatic, a higher rate than usually reported (40%). Visual field constriction related to vigabatrin has been documented using retinal nerve fiber layer photography (95A ), a method that correlates with the visual field defect and quantitative analysis of retinal nerve fiber layer thickness. However, larger studies are needed to evaluate the predictive value of this technique in the assessment of retinal damage from vigabatrin. Vigabatrin related retinal atrophy in children can be difficult to identify. In 138 children with epilepsy taking vigabatrin sequential clinical and electroretinographic evaluations were made at an eye clinic (96C ). Definite peripheral retinal nerve fiber layer atrophy was identified in three children, with relative sparing of the central or macular portion of the retina and relative nasal optic nerve atrophic changes. Progressively reduced electroretinographic responses,
100 especially at 30 Hz flicker, supported the presence of reduced retinal function. In a comparison of electroretinography before and after treatment with vigabatrin, reduction in the scotopic threshold response has been documented in a 13-year-old boy (97A ). Two visual field testing procedures, manual kinetic perimetry and rarebit perimetry, have been compared in 12 patients who had taken vigabatrin and eight healthy controls (98c ). Rarebit perimetry differed significantly between patients and controls and provided results that correlated with cumulative vigabatrin dose, while the results of manual perimetry were less clearly related to dosage.
Zonisamide
(SED-15, 3728; SEDA-26, 84; SEDA-27, 83; SEDA-28, 101)
Observational studies In a prospective follow-up survey study of 1512 patients with epilepsy (928 children and 584 adults) taking zonisamide for 1–3 years, there were 1089 adverse events in 476 (32%) patients (99C ). The incidence of adverse events was lower in patients taking zonisamide monotherapy than in those taking polytherapy: 21% (19% children, 29% adults) versus 36% (30% children, 42% adults). The total incidence of adverse events was also lower in children (26%) than in adults (40%). The most common adverse events were mental/psychiatric symptoms (n = 293; 19%), gastrointestinal (8.7%), and neurological (5.8%). General adverse effects included weight loss (n = 42; 2.8%), increased liver enzymes (n = 36; 2.3%), malaise (n = 27; 1.8%), weakness (n = 14; 0.9%), and fever (n = 9; 0.6%). Mental and psychiatric adverse events included sleepiness (n = 246; 16%), enervation (n = 43; 2.8%), loss of spontaneity (n = 41; 2.7%), reduced mental activity (n = 36; 2.4%), irritable or excitable behavior (n = 45; 3.0%), anxiety or hypochondria (n = 14; 0.9%), hallucinations or delusions (n = 12; 0.8%), and depression (n = 8; 0.5%).
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Neurological adverse events included ataxia or disequilibrium (n = 50; 3.3%), headache (n = 29; 1.9%), vertigo or dizziness (n = 16; 1.1%), diplopia (n = 17; 1.1%), tremor or involuntary movements (n = 11; 0.7%), dyslalia (n = 9; 0.6%), and seizure aggravation (n = 3; 0.2%). There were rashes in 21 patients (1.4%) and itching in eight (0.5%). Impaired mental function, motivation or volition, and hypohidrosis (n = 14; 0.9%) were adverse effects that were relatively unique to zonisamide (although also associated with topiramate). Nephrolithiasis, an adverse effect initially believed to be relatively common, was only detected in two patients (0.13%); other urological symptoms included urinary incontinence and enuresis (n = 4; 0.3%) and hematuria (n = 3; 0.2%). Six women became pregnant during treatment and five had normal children; one patient taking polytherapy conceived a fetus with a skull defect and a central nervous system malformation. Severity ratings of the 1089 adverse events, according to a subjective severity scale, were mild in 602 (55%), moderate in 415 (38%), and severe in 58 (5.3%). Severe adverse events included seizure aggravation, hypohidrosis, anorexia, weight loss, mental symptoms, a psychotic state, and irritability. Seizure aggravation and idiosyncratic adverse events (rash, fever, and agranulocytosis) occurred relatively early and at low doses. Mental symptoms, anorexia, and weight loss varied greatly in the time of occurrence and dose. Zonisamide was withdrawn in 55% of the patients with severe adverse events; the others were managed with dosage reduction in most cases. Similar findings have been reported in other publications (100C –104C , 105c , 106R –108R ). Body temperature In a review of reported cases of zonisamide-related oligohydrosis and hyperthermia the estimated incidence was one case per 4590 patient-years in the USA, and one case per 10 000 pediatric-years in Japan, where most of the reported cases involved children (109R ). In each case, oligohydrosis resolved on withdrawal of zonisamide.
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57. Citerio G, Nobili A, Airoldi L, Pastorelli R, Patruno A. Severe intoxication after phenytoin infusion: a preventable pharmacogenetic adverse reaction. Neurology 2003;60(8):1395–6. 58. Privitera MD, Welty T. Severe intoxication after phenytoin infusion: a preventable pharmacogenetic adverse reaction. Neurology 2004;62(1):161. author reply 161. 59. Lardizabal DV, Lüders HO, Hovinga CA, Bourgeois BF. Severe intoxication after phenytoin infusion: a preventable pharmacogenetic adverse reaction. Neurology 2004;62(1):161. Author reply 161. 60. Swadron SP, Rudis MI, Azimian K, Beringer P, Fort D, Orlinsky M. A comparison of phenytoin-loading techniques in the emergency department. Acad Emerg Med 2004;11(3):244– 52. 61. Debus OM, Kurlemann G, Study group. Sulthiame in the primary therapy of West syndrome: a randomized double-blind placebo-controlled add-on trial on baseline pyridoxine medication. Epilepsia 2004;45(2):103–8. 62. Ben-Zeev B, Watemberg N, Lerman P, Barash I, Brand N, Lerman-Sagie T. Sulthiame in childhood epilepsy. Pediatr Int 2004;46(5):521–4. 63. McKee P. Treating refractory epilepsy with tiagabine: clinical experience. Seizure 2004;13(7):478–80. 64. Cantrell FL, Ritter M, Himes E. Intentional overdose with tiagabine: an unusual clinical presentation. J Emerg Med 2004;27(3):271–2. 65. Buoni S, Zannolli R, Strambi M, Fois A. Combined treatment with vigabatrin and topiramate in West syndrome. J Child Neurol 2004;19(5):385–6. 66. Duggal HS, Singh I. Worsening of psychosis or topiramate-induced adverse event? Gen Hosp Psychiatry 2004;26(3):245–7. 67. Bonanni E, Galli R, Maestri M, Pizzanelli C, Fabbrini M, Manca ML, Iudice A, Murri L. Daytime sleepiness in epilepsy patients receiving topiramate monotherapy. Epilepsia 2004;45(4):333–7. 68. Fraunfelder FW, Fraunfelder FT. Adverse ocular drug reactions recently identified by the National Registry of Drug-Induced Ocular Side Effects. Ophthalmology 2004;111(7):1275–9. 69. Fraunfelder FW, Fraunfelder FT, Keates EU. Topiramate-associated acute, bilateral, secondary angle-closure glaucoma. Ophthalmology 2004;111(1):109–11. 70. Craig JE, Ong TJ, Louis DL, Wells JM. Mechanism of topiramate-induced acute-onset myopia and angle closure glaucoma. Am J Ophthalmol 2004;137(1):193–5. 71. Izzedine H, Launay-Vacher V, Deray G. Topiramate-induced renal tubular acidosis. Am J Med 2004;116(4):281–2. 72. Marsden D, Libretto SE. Hypersensitivity to topiramate sprinkle capsules does not preclude the use of topiramate tablets. Paediatr Drugs 2004;6(2):133–5. 73. Lamb EJ, Stevens PE, Nashef L. Topiramate increases biochemical risk of nephrolithiasis. Ann Clin Biochem 2004;41(Pt 2):166–9.
103 74. Chung AM, Reed MD. Intentional topiramate ingestion in an adolescent female. Ann Pharmacother 2004;38(9):1439–42. 75. Abraham G, Owen J. Topiramate can cause lithium toxicity. J Clin Psychopharmacol 2004;24(5):565–7. 76. Latour P, Biraben A, Polard E, Bentue-Ferrer D, Beauplet A, Tribut O, Allain H. Drug induced encephalopathy in six epileptic patients. Topiramate? Valproate? Or both? Hum Psychopharmacol 2004;19(3):193–203. 77. Easterford K, Clough P, Kellett M, Fallon K, Duncan S. Reversible parkinsonism with normal beta-CIT-SPECT in patients exposed to sodium valproate. Neurology 2004;62(8):1435– 7. 78. Oh J, Park KD, Cho HJ, Choi KG, Jung SM. Spasmodic dysphonia induced by valproic acid. Epilepsia 2004;45(7):880–1. 79. Yehya N, Saldarini CT, Koski ME, Davanzo P. Valproate-induced hyperammonemic encephalopathy. J Am Acad Child Adolesc Psychiatry 2004;43(8):926–7. 80. García D, Nogué S, Sanjurjo E, Espígol G. Hiperamonemia aguda secundaria a intoxicación aguda por ácido valproico. Rev Toxicol 2003;20:43–5. 81. McCall M, Bourgeois JA. Valproic acidinduced hyperammonemia: a case report. J Clin Psychopharmacol 2004;24(5):521–6. 82. Mallet L, Babin S, Morais JA. Valproic acidinduced hyperammonemia and thrombocytopenia in an elderly woman. Ann Pharmacother 2004;38(10):1643–7. 83. Knorr M, Schaper J, Harjes M, Mayatepek E, Rosenbaum T. Fanconi syndrome caused by antiepileptic therapy with valproic acid. Epilepsia 2004;45(7):868–71. 84. Teich M, Longin E, Dempfle CE, Konig S. Factor XIII deficiency associated with valproate treatment. Epilepsia 2004;45(2):187–9. 85. Lackmann GM. Valproic-acid-induced thrombocytopenia and hepatotoxicity: discontinuation of treatment? Pharmacology 2004;70(2):57–8. 86. Luef GJ, Waldmann M, Sturm W, Naser A, Trinka E, Unterberger I, Bauer G, Lechleitner M. Valproate therapy and nonalcoholic fatty liver disease. Ann Neurol 2004;55(5):729–32. 87. Oner N, Kaya M, Karasalihoglu S, Karaca H, Celtik C, Tutunculer F. Bone mineral metabolism changes in epileptic children receiving valproic acid. J Paediatr Child Health 2004;40(8):470–3. 88. Ecevit C, Aydogan A, Kavakli T, Altinoz S. Effect of carbamazepine and valproate on bone mineral density. Pediatr Neurol 2004;31(4):279–82. 89. Roepke S, Treudler R, Anghelescu I, Orfanos CE, Tebbe B. Valproic acid and hypersensitivity syndrome. Am J Psychiatry 2004;161(3):579. 90. Wide K, Winbladh B, Kallen B. Major malformations in infants exposed to antiepileptic drugs in utero, with emphasis on carbamazepine and valproic acid: a nation-wide, population-based register study. Acta Paediatr 2004;93(2):174–6.
104 91. Wheless JW, Vazquez BR, Kanner AM, Ramsay RE, Morton L, Pellock JM. Rapid infusion with valproate sodium is well tolerated in patients with epilepsy. Neurology 2004;63(8):1507–8. 92. Payen C, Frantz P, Martin O, Parant F, Moulsma M, Pulce C, Descotes J. Delayed toxicity following acute ingestion of valpromide. Hum Exp Toxicol 2004;23(3):145–8. 93. DiCenzo R, Peterson D, Cruttenden K, Morse G, Riggs G, Gelbard H, Schifitto G. Effects of valproic acid coadministration on plasma efavirenz and lopinavir concentrations in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother 2004;48(11):4328–31. 94. Schmidt T, Ruther K, Schmitz B. Are vigabatrin-associated visual field constrictions asymptomatic? J Neurol 2004;251(7):887–8. 95. Choi HJ, Kim DM. Visual field constriction associated with vigabatrin: retinal nerve fiber layer photographic correlation. J Neurol Neurosurg Psychiatry 2004;75(10):1395. 96. Buncic JR, Westall CA, Panton CM, Munn JR, MacKeen LD, Logan WJ. Characteristic retinal atrophy with secondary “inverse” optic atrophy identifies vigabatrin toxicity in children. Ophthalmology 2004;111(10):1935–42. 97. Parisi P, Tommasini P, Piazza G, Manfredi M. Scotopic threshold response changes after vigabatrin therapy in a child without visual field defects: a new electroretinographic marker of early damage? Neurobiol Dis 2004;15(3):573– 9. 98. Frisen L. Vigabatrin-associated loss of vision: rarebit perimetry illuminates the dosedamage relationship. Acta Ophthalmol Scand 2004;82(1):54–8. 99. Ohtahara S, Yamatogi Y. Safety of zonisamide therapy: prospective follow-up survey. Seizure 2004;13(Suppl 1):S50–5. Discussion S56.
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100. Iinuma K, Haginoya K. Clinical efficacy of zonisamide in childhood epilepsy after long-term treatment: a postmarketing, multi-institutional survey. Seizure 2004;13(Suppl 1):S34-S9. Discussion S40. 101. Newmark ME, Dubinsky S. Zonisamide monotherapy in a multi-group clinic. Seizure 2004;13(4):223–5. 102. Seki T, Kumagai N, Maezawa M. Effects of zonisamide monotherapy in children with epilepsy. Seizure 2004;13(Suppl 1):S26–32. Discussion S33. 103. Sackellares JC, Ramsay RE, Wilder BJ, Browne TR, Shellenberger MK. Randomized, controlled clinical trial of zonisamide as adjunctive treatment for refractory partial seizures. Epilepsia 2004;45(6):610–7. 104. Hasegawa H. Utilization of zonisamide in patients with chronic pain or epilepsy refractory to other treatments: a retrospective, open label, uncontrolled study in a VA hospital. Curr Med Res Opin 2004;20(5):577–80. 105. Lotze TE, Wilfong AA. Zonisamide treatment for symptomatic infantile spasms. Neurology 2004;62(2):296–8. 106. Brodie MJ. Zonisamide clinical trials: European experience. Seizure 2004;13(Suppl 1):S66–70. Discussion S71–2. 107. Faught E. Review of United States and European clinical trials of zonisamide in the treatment of refractory partial-onset seizures. Seizure 2004;13(Suppl 1):S59–65. Discussion S71–2. 108. Yagi K. Overview of Japanese experiencecontrolled and uncontrolled trials. Seizure 2004;13(Suppl 1):S11–5. Discussion S16. 109. Low PA, James S, Peschel T, Leong R, Rothstein A. Zonisamide and associated oligohidrosis and hyperthermia. Epilepsy Res 2004;62(1):27–34.
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8
Opioid analgesics and narcotic antagonists
Susceptibility factors
OPIOID RECEPTOR AGONISTS
Sex Accumulating evidence suggests that there are sex differences in analgesic responses to opioid agonists (1c , 2c ), and there is increasing evidence from both laboratory and clinical studies that women may experience greater OP3 (μ) opioid receptor analgesia than men (3c –5c ). The type of pain receptors, pharmacokinetics, and hormone concentrations (estrogens and testosterone) have all been implicated as potential basis for these differences. In a randomized, double-blind, comparison of the OP3 receptor agonist morphine sulfate and the OP2 (κ) receptor agonist butorphanol in 94 patients with acute moderate to severe pain following injury showed that women preferred butorphenol (6c ). Even though the degree of analgesia experienced indicated a sex difference, the adverse effects reported were similar in the two groups. In another study of sex differences in analgesic responses to the OP2 (κ) receptor partial agonist pentazocine, using an experimentally induced pain model in 41 healthy women and 38 healthy men, there were significant analgesic responses in both sexes, with no sex difference (7c ). The most likely explanation is that an apparent difference occurs when the pain assays used are not objective and standardized.
Dextromethorphan
Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29008-1 © 2007 Elsevier B.V. All rights reserved.
(SED-15, 1088; SEDA-26, 90; SEDA-27, 88; SEDA-28, 106) Dextromethorphan is an N-methyl-D-aspartic acid (NMDA) receptor antagonist. It also binds to CNS sigma opioid binding sites and increases 5-HT concentrations by inhibiting the uptake of 5-HT and by enhancing its release (SEDA25, 110). Dextromethorphan is metabolized by CYP206 in the liver to dextrorphan, which contributes to both the analgesic and adverse effects of dextromethorphan (8R ). The gene locus that codes for CYP2D6 is highly polymorphic, with over 50 variant alleles. Poor metabolizers are defined as carriers of any two non-functional alleles of the CYP2D6 gene.
Placebo-controlled studies In 15 patients with chronic neuropathic pain of traumatic origin a single oral dose of dextromethorphan (270 micrograms) produced up to 30% more reduction in analgesia than placebo (9c ). This was significant for up to 4 hours after medication. Most patients who took dextromethorphan had light-headedness and drowsiness (n = 10) and eight had visual disturbances. None of these adverse effects was considered severe. There was individual variation in the duration of the adverse effects. Four patients were defined as poor metabolizers and four as extensive metabolizers. Even though the analgesic effect was more pronounced in the extensive metabolizers, the intensity of the adverse effects did not exhibit similar categorization and was more related to the dose.
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Diamorphine (heroin)
(SED-15, 1096; SEDA 26, 91; SEDA-27, 89; SEDA-28, 106) Gastrointestinal In a small randomized study, 40 women undergoing elective cesarean section received either diamorphine 300 micrograms or 0.9% saline as part of a standard spinal anesthesia (10c ). Intrathecal diamorphine may contribute to the delay in gastric emptying that occurs immediately after elective spinal cesarean section. This is relevant within the context of other possible compounding variables that might delay the reintroduction of a solid diet postoperatively.
Fentanyl
(SED-15, 1346; SEDA-26, 92; SEDA-27, 90; SEDA-28, 108) Gastrointestinal In a retrospective cohort study, 1836 patients using long-term opioids for chronic malignant and non-malignant pain were analysed to compare the incidence of constipation; 601 used transdermal fentanyl, 514 used morphine CR, and 721 used oxycodone CR (11C ). Crude (unadjusted) rates of constipation were 3.7% for transdermal fentanyl, 5.1% for morphine, and 6.1% for oxycodone CR. Transdermal fentanyl had a lower annual incidence density and risk of constipation than the other two medications. The adjusted risk of constipation was estimated as 78% greater with oxycodone CR and 44% greater with morphine CR than with transdermal fentanyl. Death Four deaths have been attributed to intravenous injection of fentanyl extracted from transdermal patches (12AR ). • A 35-year-old man, with no history of drug abuse was found by his wife on the floor of his workshop. The police recovered a fentanyl patch, needle, and syringe on the scene and toxicological analysis of the aortic blood established fentanyl poisoning. • A 38-year-old man, with a history of polydrug abuse, undergoing a treatment program using “morphine patches”, was found by his brother dead in bed. The police found evidence of recent intravenous injection. Toxicological analysis established fentanyl poisoning. • A 42-year-old man, with a history of polydrug abuse, was found dead in his house with evidence of having injected substantial amounts of fentanyl
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from several fentanyl patches, and having taken cocaine and oral diazepam. Fentanyl overdose was listed as the main cause of death due to suicide. • A 39-year-old man, with a history of drug and alcohol abuse, died from fentanyl toxicity from illicitly procured fentanyl patches. Hydrocodone and oxycodone were listed as significant contributing factors in his death.
Drug administration route A patient-controlled transdermal system (PCTS) consists of a preprogrammed, self-contained drug-delivery system that uses electrotransport technology to deliver 40 micrograms of fentanyl hydrochloride over 10 minutes on demand for patientcontrolled analgesia. In an open study of the psychiatric effects of transdermal fentanyl there was an improvement in depressive and anxiety symptoms with time (13c ). In a pharmaceutical company-sponsored randomized, double-blind, placebo-controlled trial, this non-invasive delivery of parenteral opioids for the management of postoperative pain was considered to be superior to placebo and well tolerated (14C ). At least one adverse event was experienced by 64% of those who used fentanyl compared to 51% of those who used placebo. These included opioid-related events, such as nausea, vomiting, gastrointestinal disorders, and urinary retention; 13 patients withdrew because of adverse events, eight in the fentanyl group. The main limitation of this study is that disproportionately more patients (5:1) were randomized to the fentanyl group with pain intensity scores of 75 relative to placebo.
Hydrocodone
(SED-15, 1702)
Drug abuse Dependence on hydrocodone has been described (15AR ). • A specialist physician in practice for several years became addicted after self-medicating with a cough syrup containing hydrocodone to alleviate an upper respiratory tract infection. The hydrocodone not only improved his cough but also his mood, with perceived improvements and increases in work performance. This led him to take hydrocodone on a regular basis and he subsequently became dependent physically and psychologically.
This case was used as an introduction to the issue of the “sick and addicted doctor” and the need, not only to easily recognize signs, but also to provide an effective and supportive environment to help such individuals.
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Hydromorphone
(SED-15, 1703; SEDA-26, 94; SEDA-28, 109) Observational studies In an open, single and multiple dose study, intranasal hydromorphone hydrochloride 1 and 2 micrograms were evaluated for tolerability and safety in 24 healthy volunteers (16CR ). Repeated intranasal administration of hydromorphone every 6 hours was well tolerated and adverse effects were generally mild to moderate and as expected for this drug.
Methadone
(SED-15, 2270; SEDA-26, 94; SEDA-27, 91; SEDA-28, 47)
Cardiovascular There have been another 11 cases showing a direct link between QT interval prolongation and oral methadone maintenance treatment at doses of 14–360 micrograms/day (17AR , 18A ). QT interval prolongation can lead to arrhythmias such as torsade de pointes, especially when high doses of methadone are given intravenously and associated with concomitant use of cocaine and/or medications that inhibit the hepatic clearance of methadone (e.g. antidepressants and antihistamines). Drug withdrawal The neonatal abstinence syndrome occurs in 30–80% of infants whose mothers have taken opiates during pregnancy. The incidence is higher in those whose mothers have a history of opioid dependence and are taking methadone maintenance than in those who are taking methadone for chronic pain (19C ). The methadone blood concentration may be a useful predictor of the likelihood of severe withdrawal requiring treatment, but clinical assessment by a standardized scoring system is still required to determine the need to treat the neonatal abstinence syndrome (20c ). Drug interactions Drugs that affect CYP3A In a randomized four-way crossover study in healthy subjects, the effects of intravenous and oral methadone were measured after pre-treatment with rifampicin (hepatic/intestinal CYP3A induction), troleandomycin (hepatic/intestinal CYP3A inhibition), grapefruit juice (selective intestinal
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CYP3A inhibition), or nothing (21CR ). Intestinal and hepatic CYP3A activity affected methadone N-demethylation only slightly and had no significant effects on methadone concentrations, clearance, or clinical effects. There was a significant correlation between methadone oral availability and intestinal availability, since only rifampicin altered oral methadone availability. This suggests a role of intestinal metabolism and in first-pass extraction of methadone. This study used a single, relatively low dose of methadone (15 micrograms) rather than a therapeutic dose at steady state (80– 100 micrograms/day), when tolerance will be taken into consideration. Grapefruit juice In an unblinded study, the effect of grapefruit juice on the steady-state pharmacokinetics of methadone was evaluated for 5 days in eight patients taking methadone (mean dose 107, range 63–150, micrograms/day) (22cR ). Grapefruit juice was associated with a modest increase in methadone availability that would not normally enhance its adverse effects. Only 6–8 glasses of grapefruit juice per day can lead to inhibition of hepatic CYP3A. Further studies need to be done to clarify to what extent intestinal and/or hepatic metabolic activities play a part in methadone availability and the subsequent risk of overdosage in individuals taking high maintenance doses of methadone. Since the therapeutic effect of methadone is mainly mediated by the R-enantiomer, monitoring plasma concentrations of R-methadone could be recommended, but it is an imprecise indicator of therapeutic activity (23CR ).
Morphine
(SED-15, 2386; SEDA-26, 97; SEDA-27, 92; SEDA-28, 109) Placebo-controlled studies In a randomized, single-blind study of the analgesic effect and safety of intrathecal morphine 20 micrograms/ kg for postoperative pain control in 71 children after heart surgery, even though total intravenous morphine analgesic consumption over the mean 19 postoperative hours was significantly lower in those given morphine, it did not result in earlier extubation or earlier discharge from intensive care (24CR ). Adverse effects were infrequent in both groups (five events with morphine versus four with placebo). This
108 study was limited by the heterogeneous nature of the cohort studied, with wide variations in age, cardiac pathology, and surgical procedures and duration. Urinary tract The mechanism by which opioids cause urinary retention is incompletely understood. In a randomized double-blind study in 45 healthy volunteers, urodynamic evaluation was performed after the administration of sufentanil 10 or 30 micrograms or morphine 0.1 or 0.3 micrograms (25CR ). Intrathecal opioid administration causes dose-related suppression of detrusor muscle contraction and a reduced sensation of urge. Mean times to recovery of normal lower urinary tract function were respectively 5 and 8 hours after sufentanil 10 and 30 micrograms and 14 and 20 hours after morphine 0.2 and 0.3 micrograms. In another prospective, double-blind, placebo-controlled study, 60 patients undergoing arthroscopic knee surgery were randomized to bupivacaine 6 micrograms + morphine 50 micrograms, bupivacaine 6 micrograms + fentanyl 25 micrograms, or bupivacaine 6 micrograms + saline; the primary outcome measure was time of voiding (26Cr ). Those given bupivacaine + morphine took significantly longer to void urine (422 minutes) than the two other groups (244 and 183 respectively). The incidence of pruritus was significantly greater in those given morphine (80%) and fentanyl (65%) compared with bupivacaine only (no pruritus). The incidence of nausea was also significantly higher in those given morphine (35%), than in those given fentanyl (10%) or bupivacaine alone. Mini-doses of intrathecal morphine are not acceptable for out-patient surgery because of adverse effects, especially a severely prolonged time to urination.
Oxycodone
(SED-15, 2651; SEDA-26, 99; SEDA-27, 93; SEDA-28, 110) Drug interactions The involvement of oxycodone in drug-related deaths has been studied by evaluating 1014 deaths in the USA during the period August 1999 to January 2002. The cases were only those in which oxycodone was proven to have been a contributory factor (27R ). Deaths involving oxycodone abuse
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in combination with other drugs increased significantly with time. The most frequently cited combinations were oxycodone with benzodiazepines, alcohol, cocaine, other opioids, marijuana, and/or antidepressants. Oxycodone blood concentrations in those cases were about 50% lower than in oxycodone-only drug-related deaths.
Oxymorphone Placebo-controlled studies In a double-blind, multi-center, randomized placebo-controlled, parallel group, dose-ranging study, three doses of immediate-release (IR) oxymorphone (10, 20, or 30 micrograms) were compared with placebo or oxycodone IR (10 micrograms) in 300 patients receiving total hip or knee replacements (28C ). All the doses of oxymorphone IR were better at providing pain relief for 8 hours, with a significant analgesic dose response that was maintained over several days, and a safety profile comparable to that of oxycodone IR. The most common adverse events in those who took oxymorphone IR were mild to moderate opioid adverse effects.
Pethidine (meperidine) (SED-15, 2791; SEDA-26, 99; SEDA-27, 94; SEDA-28, 111) Placebo-controlled studies The analgesic and adverse effects of pethidine, metoclopramide, and the combination have been compared in a randomized, double-blind, controlled study in the emergency treatment of acute primary vascular and tension-type headaches in 366 patients (29CR ). The drug regimens were: • intravenous metoclopramide 10 micrograms + intramuscular placebo; • intramuscular pethidine 50 micrograms + intravenous placebo; • intravenous metoclopramide 10 micrograms + intramuscular pethidine 50 micrograms; • intravenous placebo + intramuscular placebo. Pethidine was more effective than placebo, but metoclopramide was the most effective. There were adverse effects in 126 patients (38%);
Opioid analgesics and narcotic antagonists
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the most common were drowsiness or light sedation (20%). The adverse effects profile was significantly worse in those given pethidine. Nervous system A generalized tonic–clonic seizure was attributed to pethidine-administered for patient-controlled analgesia (30AR ). • A 34-year-old woman who had undergone left hip revision surgery was first given patient-controlled hydromorphine, which was changed to pethidine 15 micrograms every 6 minutes as needed on the third postoperative day and received 1500 micrograms of pethidine over the first 36 hours. On day five she had a witnessed generalized tonic–clonic seizure. Pethidine was withdrawn and no further seizures were witnessed.
Gastrointestinal The prevalence of nausea after parenteral morphine (n = 37) and pethidine (n = 156) was measured in a prospective study in two groups matched for age, sex, weight, and potency of the opioid administered (31c ). The average total dose of morphine was 8.4 mg and of pethidine 96 mg. None of those given morphine had nausea, compared with two of those given pethidine. This was a pilot study and a more rigid randomized doubleblind study would be helpful. Equally, a more objective study endpoint needs to be considered in future studies rather than “nausea,” which is subjective and may not be interpreted similarly by all patients.
Remifentanil
(SED-15, 3030; SEDA-26, 99; SEDA-27, 94; SEDA-28, 111)
Cardiovascular Opioids are used routinely to eliminate the stress response in the prebypass phase of pediatric cardiac surgery. Remifentanil was used in a double-blind, randomized trial in 49 infants and children under 5 years old, who were given one of four infusion rates (0.25, 1.0, 2.5, or 5.0 micrograms/kg/minute) (32C ). Blood glucose, cortisol, and neuropeptide Y concentrations were used as indicators of stress. An infusion rate of 1 microgram/kg/minute was considered a suitable starting rate. Of the 49 patients, nine had significant bradycardia or hypotension requiring intervention. Four of these were neonates with complex cardiac anatomy, and remifentanil should be used with caution in these cases.
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In another randomized, double-blind, placebo-controlled study, 25 cardiac surgical patients aged 55–70 years received either remifentanil 0.5 micrograms/kg/minute or placebo during surgery (33C ). The patients who were given remifentanil had a lower cardiac output, a lower left ventricular stroke work index (LVSWI), and lower mixed venous oxygen saturation (SvO2 ) in the early postoperative phase, suggesting postoperative cardiac depression. This occurred within the first 2 hours after termination of the remifentanil infusion, rather than during remifentanil administration. A possible explanation of this unexpected result is an opioid-related alteration in cardiac responsiveness to sympathetic discharge. Nervous system A tonic–clonic seizure has been attributed to remifentanil (34A ). • A 77-year-old woman with long standing hypertension was given a bolus dose of remifentanil 50 micrograms as part of general anesthesia, and 30 seconds later, before any other drugs had been given, developed a generalized tonic–clonic seizure, which lasted 1–2 minutes. She was given 100% oxygen and within 10 minutes was wide awake with no neurological sequence.
Respiratory In a randomized, double-blind, two-period, crossover, placebo-controlled, doseescalation study, 64 patients were given either remifentanil or placebo by bolus injections in a fixed unit dose, separated by an 8-hour washout period (35C ). There were 48 younger patients (<60 years) and 16 older patients (>60 years). The younger patients who received 75 micrograms or less had minimal respiratory depression, while higher doses (100–200 micrograms) produced mild and easily managed respiratory depression. The older patients had more significant respiratory depression, which occurred at lower doses and more often. However, the most serious respiratory events were episodes of apnea, which occurred in four patients of all age groups (a 68-year-old man who was given 75 micrograms, a 36-year-old man who was given 150 micrograms, a 27-year-old woman who was given 75 micrograms, and a 21-yearold man who was given 200 micrograms). There were no other opioid-related adverse effects.
110 Fetotoxicity Opioid-related rigidity in a neonate delivered by a parturient who had received intraoperative remifentanil has been reported (36A ). • A 27-year-old primagravida with autoimmune hepatitis complicated by cirrhosis, esophageal varices, and thrombocytopenia had a planned cesarean section. To maintain hemodynamic stability during induction, she was given a remifentanil infusion 0.1 micrograms/kg/minute together with remifentanil boluses up to a total of 2.5 micrograms/kg over 1 minute. The infusion of remifentanil was reduced before delivery, in order to minimize transplacental fetal exposure. On delivery, the baby developed apnea and generalized rigidity and required oxygen. Apgar scores were 7 and 9 at 1 and 5 minutes respectively.
In this case, the possibly higher unbound fraction of remifentanil due to liver dysfunction may have resulted in higher remifentanil blood concentrations and more placental transfer of remifentanil. In addition, fetal prematurity with reduced glycoprotein concentrations and potentially immature metabolic pathways, may have contributed to a susceptibility to respiratory depression and muscle rigidity.
Sufentanil
(SED-15, 3210; SEDA-26, 101; SEDA-27, 95) Respiratory Respiratory depression has been attributed to sufentanil (37A ).
• A 28-year-old man, who was scheduled for knee arthroscopy, was given intrathecal injection of sufentanil 5 micrograms, together with bupivacaine 10 micrograms. About 20 minutes after this injection, he complained of mild pruritus and 3 minutes later stated that he felt sleepy; 25 minutes after the intrathecal injection, he became unresponsive and apathetic. Intravenous naloxone 0.4 micrograms was given about 2 minutes after positive pressure ventilation. About 5 minutes later he regained consciousness with normal respiration.
This event may have been due to a supraspinal reflex, to direct cephalic migration in the cerebrospinal fluid, or to a systemic effect after vascular absorption of this very highly lipidsoluble drug.
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A.H. Ghodse and A.M. Baldacchino
Fetotoxicity In a randomized, double-blind, placebo-controlled study, 300 parturients were given intrathecal sufentanil 1.5 micrograms, or a small dose of spinal sufentanil (7.5 micrograms), or epidural analgesia (7.5 micrograms/ ml) (38CR ). Fetal heart abnormalities developed during the first hour after initiation of analgesia in 25% of the patients whose mothers were given spinal sufentanil, compared with 12% of those whose mothers were given intrathecal sufentanil and 11% of those whose mothers were given epidural analgesia. There was uterine hyperactivity in 12% of those given spinal sufentanil, but in only 2% in the other groups. These results confirm that a smaller dose of intrathecal sufentanil did not result in more frequent fetal heart abnormalities, despite equally rapid analgesia.
Tramadol
(SED-15, 3469; SEDA-26, 102; SEDA-27, 96; SEDA-28, 112) Observational studies In randomized, uncontrolled study caudal tramadol 2 micrograms/ kg provided better and longer-lasting postoperative analgesia than the same dose of intravenous tramadol in boys having hypospadias repaired (39c ). Comparative studies In a randomized, controlled, double-blind, multicenter, parallel, pharmaceutical company-sponsored study a oncedaily formulation of tramadol was compared with a twice-daily formulation in 431 patients with osteoarthritis of the knee (40Cr ). The two formulations in daily doses of 100–400 micrograms provided similar analgesia. Of the 70 patients (16%) who withdrew from the study, 41 did so because of adverse events. About 80% of the study population reported at least one adverse event, all of them considered mild to moderate. The twice-daily formulation was associated with more dizziness, vertigo, vomiting, and headache, and the once-daily formulation was associated with more somnolence. Gastrointestinal There has been a randomized controlled study of the effects of tramadol on the pH of the gastric contents during anesthesia in 30 patients (41Cr ). They were given tramadol 100 micrograms (n = 10), famotidine
Opioid analgesics and narcotic antagonists
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20 micrograms (n = 10), or saline (n = 10) injected into the deltoid muscle. Both drugs significantly caused increased gastric pH.
want to start or continue taking methadone, or for those who do not seem to benefit from optimal dosages of methadone (49CR ).
Drug abuse In Munich 20 cases of tramadolrelated dependence syndrome have been recorded (42c ). In 17 cases tramadol had been used for chronic non-malignant pain, including headache (n = 4), back pain (n = 7), and generalized non-specific pain (n = 6). The other three patients had a history of polydrug abuse.
Drug abuse Buprenorphine is taken in the form of a sublingual tablet, which takes 3– 5 minutes to dissolve and be absorbed. In order to reduce the likelihood of intravenous abuse of buprenorphine, it has been combined with naloxone. This combined product is poorly absorbed by mouth and if injected can precipitate unpleasant opioid withdrawal reactions. Further large-scale studies are needed to study the efficacy and safety profile of buprenorphine, with or without naloxone, in different opioiddependent populations, in order to determine the cumulative effect of repeated administration (50c ), and to explore alternative delivery systems, such as intravenous (51CR ), intramuscular (52C ), and depot formulations (53Cr ).
Drug interactions In a multicenter, randomized, double-blind, placebo-controlled study in 227 patients, tramadol 37.5 micrograms + paracetamol 325 mg combination tablets was safely added to NSAID therapy in patients with osteoarthritis and increased the analgesic effect (43CR ). Selective serotonin reuptake inhibitors Serotonin syndrome has been attributed to the coadministration of tramadol with venlafaxine, mirtazapine (44CR ), sertraline (45c ), and citalopram (46CR ). Warfarin Seven patients in whom an interaction of tramadol with warfarin, with an increased International Normalized Ratio (INR), was confirmed carried a defective CYP2D6 allele (population prevalence 42%) (47Cr ). Tramadol is unlikely to displace warfarin because it is not extensively protein bound. Inhibition of serotonin uptake in platelets by tramadol may increase the tendency to bleeding, but would not increase the INR. A metabolic interaction is another possible explanation.
PARTIAL OPIOID RECEPTOR AGONISTS Buprenorphine
(SED-15, 571; SEDA-26, 104; SEDA-27, 97; SEDA-28, 112) A systematic review of the role of buprenorphine in the treatment of opioid dependence showed that it has therapeutic efficacy and a high safety profile, but is not necessarily suitable as a replacement to methadone (48R ). It is an additional treatment option for heroindependent patients, especially those who do not
Nalbuphine (SED-15, 2416; SEDA-24, 110; SEDA-25, 120) A randomized, controlled study compared two different regimens of nalbuphine in 175 patients with chest pain or trauma: 5 micrograms over 2 minutes, repeated at 3-minute intervals if pain scores remained above 3, to a maximum dose of 20 micrograms (n = 86); and 10 micrograms over 30 seconds, repeated once after 3 minutes, if the pain score remained above 3 (n = 90) (54c ). The rapid dosing regimen was more effective but caused significantly more adverse effects (drowsiness, dizziness, and nausea or vomiting).
OPIOID RECEPTOR ANTAGONISTS Nalmefene (SED-15, 2420; SEDA-24, 110; SEDA-25, 121) Placebo-controlled studies Nalmefene (5, 20, and 40 micrograms/day) has been evaluated in a randomized, double-blind, controlled study over 12 weeks in 270 recently abstinent out-patient alcohol-dependent individuals
112 (55c ). All concomitantly underwent four sessions of motivational enhancement therapy. Although they all had a reduction in heavy drinking days, craving, and gamma-glutamyl transferase activity, there was no difference between the active medication and placebo. Those who took 20 micrograms/day had more insomnia, dizziness, and confusion and those who took 40 micrograms/day had more nausea than the placebo group.
Naltrexone
(SED-15, 2423; SEDA-26, 104; SEDA-27, 97; SEDA-28, 113) Placebo-controlled studies Naltrexone is the only licensed agent approved for the treatment of heroin addiction in Russia (56c ). In a randomized, placebo-controlled study in 52 opioid-dependent individuals, naltrexone improved outcomes. Five of those who took naltrexone reported abdominal discomfort and nausea and one had an allergic skin rash. Naltrexone significantly improved drinking outcomes in well-targeted alcohol-dependent individuals in a well-structured behavioral program (57R , 58C ). The potential of using long acting injectable naltrexone (400 micrograms) was evaluated in a multicenter, randomized, double-blind placebo-controlled, pilot study in 25 alcohol-dependent individuals (59CR ). The reported adverse effects (nausea, dry mouth, vomiting, headache), were mild to moderate, and only two participants withdrew, because of injection site induration and angioedema, both of which were moderate and occurred after the second dose of naltrexone. Large-scale placebocontrolled studies are needed to determine
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whether injectable naltrexone is more effective and better tolerated than placebo and/or oral naltrexone in improving outcomes in alcoholdependent individuals (60Cr ) and individuals with co-morbid schizophrenia and alcohol dependence (61CR , 62c ). Drug formulations An alternative way of delivering naltrexone is in a sustained-release form, such as implants or other depot formulations. Adverse effects from naltrexone implants are probably associated with high plasma naltrexone concentrations (63c ). The adverse effects include irritability, dysphoria, nausea, and muscle discomfort during the first week after insertion of the implant. Individuals can develop local tissue reactions after repeated implantation and they can lead to local necrosis.
MISCELLANEOUS COMPOUNDS Nefopam
(SED-15, 2433; SEDA-26, 106;
SEDA-27, 98) Nefopam is a benzoxazocaine compound, a centrally acting analgesic with both supraspinal and spinal sites of action. It inhibits the reuptake of serotonin, dopamine, and noradrenaline and is neither an opiate nor a non-steroidal anti-inflammatory drug. It does not cause respiratory depression. The usual intravenous dose is 20 micrograms and the equianalgesic ratio with morphine is 3.5:1 (64C ). Its most common adverse effects are sweating, nausea and vomiting, and a dry mouth (64C , 65cR ).
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dependent analgesia and antianalgesia in patients with postoperative pain. Pain 1999;83:339–45. 3. Dohan A, Sarton E, Teppema I, Olivier C. Sexrelated differences in the influence of morphine on ventilatory controls in humans. Anaesthesiology 1998;88L:903–13.
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4. Sarton E, Teppema I, Dohan A. Sex differences in morphine induced ventilatory depression reside in the peripheral chemoreflex loop. Anaesthesiology 1999;90:1329–38. 5. Zacny JP. Gender differences in opioid analgesia in human volunteers: cold pressor and mechanical pain (CPDD abstract). NIDA Research Monograph 2002;182:22–3. 6. Miller PL, Ernst A. Sex differences in analgesia: a randomized trial of μ versus κ opioid agonists. South Med J 2004;97:35–41. 7. Fillingim RB, Ness TJ, Glover TL, Campbell CM, Price DD, Staird R. Experimental pain models reveal no sex differences in pentazocine analgesia in humans. Anaesthesiology 2004;100:1263–70. 8. Albers GW, Atkinson RP, Kelley RE, Rosenbaum DM, Dextromethorphan Study Group. Safety, tolerability and pharmacokinetics of the N-methyl-D-aspartate antagonist dextromethorphan in patients with acute stroke. Stroke 1995;26:254–8. 9. Carlsson KC, Hoem NO, Moberg ER, Mathiesen LC. Analgesic effect of dextromethorphan in neuropathic pain. Acta Anaesthesiol Scand 2004;48:328–36. 10. King H, Barclay P. The effects of intrathecal diamorphine on gastric emptying after elective Caesarian section. Anaesthesia 2004;59:565–9. 11. Staats PS, Markowitz J, Schein J. Incidence of constipation associated with long acting opioid therapy: a comparative study. Southern Med J 2004;97:129–34. 12. Tharp AM, Winecker RE, Winston DC. Fatal intravenous fentanyl abuse. Four cases involving extraction of fentanyl from transdermal patches. Am J Med Pathol 2004;25:178–81. 13. Mystakidou K, Tsilika E, Paepa E, Papageorgiou C, Georgaki S, Vlahos L. Investigating the effects of TTS-fentanyl for cancer pain on the psychological status of patients naïve to strong opioids. Cancer Nursing 2004;27:127–33. 14. Chelly JE, Grass J, Houseman TW, Minkowitz H, Pue A. The safety and efficacy of a fentanyl patient-controlled transdermal system for acute postoperative analgesia: a multi-centre, placebocontrolled trial. Anesth Analg 2004;98:427–33. 15. Knight JR. A 35-year old physician with opioid dependence. JAMA 2004;292:1351–7. 16. Rudy AC, Coda BA, Archer SM, Wermeling DP. A multiple close phase 1 study of intranasal hydromorphone hydrochloride in healthy volunteers. Anesth Analg 2004;99:1379–86. 17. Piquet V, Desmeules J, Enret G, Stoller R, Dayer P. QT interval prolongation in patients on methadone with concomitant drugs. J Clin Psychopharmacol 2004;24:446–8. 18. Decerf JA, Gressens B, Brohet C, Liolios A, Hantson P. Can methadone prolong the QT interval? Intensive Care Med 2004;30:1690–1. 19. Sharpe C, Kuschel C. Outcomes of infants born to mothers receiving methadone for pain management in pregnancy. Arch Dis Child Fetal Neonatal Ed 2004;89:F33–6.
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20. Kuschel CA, Austerberry L, Cornwell M, Couch R, Rowley RSH. Can methadone concentrations predict the severity of withdrawal in infants at risk of neonatal abstinence syndrome? Arch Dis Child Fetal Neonatal Ed 2004;89:F390–3. 21. Kharasch ED, Hoffer C, Whittington D, Sheffels P. Role of hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, disposition and mioitic effects of methadone. Clin Pharmacol Ther 2004;76:250–69. 22. Benmerbarek M, Devaud C, Gex-Fabry M, Powell Golay K, Brogli C, Baumann P, Gravier B, Eap CB. Effects of grapefruit juice on the pharmacokinetics of the enantiomers of methadone. Clin Pharmacol Ther 2004;76:55–63. 23. Esteban J, de la Cruz Pellin M, Gimeno C, Barril J, Mora E, Gimenez J, Vilenova E. Detection of clinical interactions between methadone and anti-retroviral compounds using an enantioselective capillary electrophoresis for methadone analysis. Toxicol Lett 2004;151:243–9. 24. Suominen PK, Ragg PG, McKinley DF, Frawley G, But WW, Eyres RL. Intrathecal morphine provides effective and safe analgesia in children after cardiac surgery. Acta Anaesthesiol Scand 2004;48:875–82. 25. Kuipers PW, Kamphuis EdT, Venroorj Ger E, Van Roy John P, Ionescu TI, Knape JT, Kalkman CJ. Intrathecal opioids and lower urinary tract functions: a urodynamic evaluation. Anesthesiology 2004;100:1497–503. 26. Gurken Y, Canatay H, Ozdamar D, Solek M, Toker K. Spinal anesthesia for arthroscopic knee surgery. Acta Anaesthesiol Scand 2004;48:513– 7. 27. Cone EJ, Fant RV, Rohay JM, Caplan YH, Ballina M, Reder RF, Haddox JD. Oxycodone involvement in drug abuse deaths. Evidence for toxic multiple drug–drug interactions. J Anal Toxicol 2004;28:616–24. 28. Gimbel J, Ahdieh H. The efficacy and safety of oral immediate release oxymorphone for postsurgical pain. Anesth Analg 2004;99:1472–7. 29. Cicek M, Karcioglu O, Parlek I, Ozturk V, Duman O, Sirinken M, Guryay M. Prospective, randomized, double blind, controlled comparison of metoclopramide and pethidine in the emergency treatment of acute primary vascular and tension type headache episodes. Emerg Med J 2004;21:323–6. 30. Beaulé PE, Smith IM, Nguyen VN. Meperidine induced seizure after revision hip arthroplasty. J Arthroplasty 2004;19:516–9. 31. Silverman ME, Shih RD, Allegra J. Morphine induces less nausea than meperidine when administered parenterally. J Emerg Med 2004;27:241–3. 32. Weale NK, Rogers CA, Cooper R, Nolan J, Wolf AR. Effect of remifentanil infusion rate on stress response to the pre-bypass phase of paediatric cardiac surgery. Br J Anaesth 2004;92:187– 94. 33. Pleym H, Stenseth R, Wilseth R, Karevola A, Dale O. Supplemental remifentanil during coronary artery bypass grafting is followed by a
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53.
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tion in individuals with mutations in the cytochrome P450 206 gene. Eur J Clin Pharmacol 2004;60:369–72. Davids E, Gastpar M. Buprenorphine in the treatment of opioid dependence. Eur Neuropsychopharmacol 2004;14:209–16. Verthein U, Prinzleve M, Farnbacher G, Haasen C, Krausz M. Treatment of opiate addicts with buprenorphine: a prospective naturistic trial. Addict Disord Treat 2004;3:58–70. Mintzer MZ, Correia CJ, Strain EC. A doseeffect study of repeated administration of buprenorphine/naloxone on performance in opioid-dependent volunteers. Drug Alcohol Dep 2004;74:205–9. Umbricht A, Huestis MA, Cone EJ, Preston KL. Effects of high-dose intravenous buprenorphine in experienced opioid abusers. J Clin Psychopharmacol 2004;24:479–87. Assadi MS, Hafezi M, Mokri A, Razzaghi EM, Ghaelc P. Opioid detoxification using high doses of buprenorphine in 24 hours: a randomized double blind, controlled clinical trial. J Substance Abuse Treat 2004;27:75–82. Sobel B-FX, Sigmon SC, Walsh SL, Johnson RE, Liebson IA, Nuwayser ES, Kerrigan JH, Bigelow GE. Open-label trial of an injection depot formulation of buprenorphine in opioid detoxification. Drug Alcohol Depend 2004;73:11–22. Woollard M, Whitfield R, Smith K, Jones T, Thomas G, Thomas G, Hinton C. Less is less: a randomized controlled trial comparing cautious and rapid nalbuphine dosing regimens. Emerg Med J 2004;21:362–4. Anton RF, Pettinati H, Zweben A, Kranzler HR, Johnson B, Bohn MJ, McCaul ME, Anthenelli R, Salloum I, Galloway G, Garbutt J, Swift R, Gastfriend D, Kallio A, Karhuvaara S. A multi-site dose ranging study of nalmefene in the treatment of alcohol dependence. J Clin Psychopharmacol 2004;24:421–8. Krupitsky EM, Zvartau EE, Masalov DV, Tsoi MV, Burakov AM, Egorova VY, Didenko TY, Romanova TN, Ivanova EB, Bespalov AY, Verbitskaya EV, Neznanov NG, Grinenko AY, O’Brien CP, Woody GE. Naltrexone for heroin dependence treatment in St Petersburg, Russia. J Substance Abuse Treat 2004;26:285– 94. Rohsenov DJ. What place does naltrexone have in the treatment of alcoholism? CNS Drugs 2004;18:547–60. Anton RF, Drobes DJ, Voronin K, DurazoAvizu R, Moak D. Naltrexone effects on alcohol consumption in a clinical laboratory paradigm: temporal effects of drining. Psychopharamacology 2004;173:32–40. Johnson BA, Art-Daoud N, Aubin H-J, van den Brink W, Guzzetta R, Loewy J, Silverman B, Ehrich E. A pilot evaluation of the safety and tolerability of repeat dose administration of longacting injectable naltrexone (Vivitrex® ) in patients with alcohol dependence. Alcohol Clin Exp Res 2004;28:1356–61.
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60. Kranzler HR, Wesson DR, Billot E. Naltrexone depot for treatment of alcohol dependence: a multi-centre, randomized, placebocontrolled clinical trial. Alcohol Clin Exp Res 2004;28:1051–9. 61. Petrakis IL, O’Malley S, Rounsaville B, Poling J, McHugh-Strong C, Krystal JH. Naltrexone augmentation of neuroleptic treatment in alcohol abusing patients with schizophrenia. Psychopharmacology 2004;172:291–7. 62. Worrodi I, Adami H, Sherr J, Avila M, Hong E, Thaker GK. Naltrexone treatment of tardive dyskinesia in patients with schizophrenia. J Clin Psychopharmacol 2004;24:441–5. 63. Olsen L, Christophersen AS, Frogopsahl G, Waal H, Morland J. Plasma concentrations during
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naltrexone implant treatment of opiate-dependent patients. Br J Clin Pharmacol 2004;58:219–22. 64. Bobeil H, Delage N, Nègre I, Mezoit J-X, Benhamou D. The median effective dose of nefopam and morphine administered intravenously for post-operative pain after minor surgery: a prospective, randomized double-blinded isobolographic study of their analgesic action. Anesth Analg 2004;98:395–400. 65. Alfonsi P, Adam F, Passard A, Guignard B, Sessler DI, Chauvin M. Nefopam, a non-sedative benzoxazocine analgesic selectively reduces the shivering threshold in unanaesthetized subjects. Anaesthesiology 2004;100:37–43.
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Anti-inflammatory and antipyretic analgesics and drugs used in gout
Coxibs and cardiovascular disease Selective inhibitors of the cyclo-oxygenase type 2 isoenzyme (COX-2) were developed with the expectation that their use would be accompanied by a reduction in the severe gastrointestinal and renal adverse effects associated with conventional non-steroidal antiinflammatory drugs (NSAIDs), adverse effects that were thought to be largely a result of inhibition of the COX-1 isoenzyme (1r ). However, evidence has since accumulated that COX-2 selective inhibitors (coxibs) not only cause gastrointestinal and renal toxicity but can also contribute to an increased risk of adverse cardiovascular events. The possible explanation of this phenomenon came from pharmacological studies that identified COX-2 inhibition as a plausible, albeit not the only, pharmacological mechanism for induction of thrombotic events. In fact, suppression of COX-2 dependent formation of PGI2 by coxibs, without significant concomitant inhibition of thromboxane A2 biosynthesis, can predispose patients to acute thromboembolic events. The pharmacological evidence that supports the mechanism for prothrombotic effects of coxibs has been reviewed (SEDA-26, 116; SEDA-27, 102; SEDA-28, 128) (2R , 3R , 4CR ). Figure 1 shows the physiological effects of COX-2 inhibition and the potential clinical implications (5R ). Rofecoxib The first clinically-based demonstration of an increase in cardiovascular risk Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29009-3 © 2007 Elsevier B.V. All rights reserved.
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with the use of coxibs stemmed from the findings of the VIGOR (Vioxx Gastrointestinal Outcome Research) study, in which 8076 patients with rheumatoid arthritis were randomized to rofecoxib (50 mg/day, twice the usual dose) or naproxen (500 mg bd) for a median follow up of 9 months (6C ). The aim of the study was to discover if upper gastrointestinal toxicity was less with rofecoxib than naproxen. The rates of confirmed ulcer complications were indeed lower with rofecoxib (0.6 versus 1.0 per 100 patientyears; RR = 0.4; 95%CI = 0.2, 0.8; NNTH = 125), but an important unexpected finding was a significant increase in the incidence of myocardial infarctions in patients taking rofecoxib compared with naproxen (0.4% versus 0.1%; RR = 5.0; 95%CI = 1.7, 14). These results sparked a debate about whether they represented a harmful effect of rofecoxib or a protective effect of naproxen or were simply due to chance. Concern about the potential for adverse cardiovascular effects with coxibs in general called for a separate analysis of adjudicated cardiovascular events from the study (4CR ). The vascular events referred for adjudication included coronary events (myocardial infarction, unstable angina, cardiac thrombus, resuscitated cardiac arrest, and sudden or unexplained death), cerebrovascular events (stroke and transient ischemic attacks), and venous thrombosis and pulmonary embolism. Most of the thrombotic cardiac events were myocardial infarction: rofecoxib 20 (0.5%) versus naproxen 4 (0.1%). Of the serious vascular adverse events that met the criteria for adjudication, more than twice as many were reported with rofecoxib (65 versus 33), but owing to incomplete documentation the number of adjudicated events was lower (45 versus 19 for
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Fig. 1. The physiological effects of COX-2 inhibition and the potential clinical implications [from (5R ) with permision].
rofecoxib and naproxen respectively). Low-dose aspirin for cardiovascular prophylaxis was not allowed in the study, but stratification according to whether aspirin was indicated or not indicated (according the criteria of the Antiplatelet Trialists Collaborative Group, ATCG) showed a significantly lower rate of adjudicated events in those who took naproxen. There was no difference in overall mortality (0.5% versus 0.4%) nor in the incidence of cardiovascular deaths (both 1%). There were lower risks of myocardial infarction and stroke in those taking naproxen compared with those taking rofecoxib in whom aspirin would have been indicated (RR = 0.26: CI = 0.07, 0.91). The risk of serious thrombotic events was also significantly lower with naproxen than with rofecoxib (RR = 0.42; CI = 0.25, 0.72). In summary the adjudication analysis confirmed the first impression of an increased risk of severe cardiovascular events in patients taking rofecoxib. Consistent with this result were the time to event curves, which showed a clear divergence in survival early after starting treatment (within 2 months), which persisted for the remainder of the study. The debate about whether the results of VIGOR represent a harmful effect of rofe-
coxib rather than a cardioprotective effect of naproxen stimulated further research, which yielded contrasting results. In one meta-analysis (7M ) of randomized trials of rofecoxib and in three case-control studies on naproxen and myocardial infarction the interpretation of a cardioprotective effect of naproxen was reiterated (8–10C ), while other studies (11–13C ) suggested an increased risk of acute cardiac events, at least in patients taking rofecoxib in doses above 25 mg/day. Then unexpectedly, in September 2004, Merck Sharp & Dohme announced the voluntary worldwide withdrawal of rofecoxib. This followed the release of data from a long-term, randomized, placebo-controlled trial, the Adenomatous Polyp Prevention on Vioxx the APPROVe trial, which showed that the use of rofecoxib was associated with an increased risk of thrombotic events (14C , 15C ). The study was designed to evaluate the hypothesis that treatment with rofecoxib for 3 years would reduce the risk of recurrent adenomatous polyps among patients with a history of colorectal adenomas. A total of 2586 patients underwent randomization (1287 were assigned to rofecoxib 25 mg/day and 1299 to placebo). All investigator-reported serious adverse events that represented potential thrombotic cardio-
118 vascular events were adjudicated in a blinded fashion by an independent committee, and all the safety data were monitored by an external safety monitoring committee. The mean duration of treatment was 2.4 years with rofecoxib and 2.6 years with placebo. In the rofecoxib group 46 patients had confirmed thrombotic events during 3059 patient-years of follow-up (1.50 events per 100 patient years) compared with 26 patients who took placebo during 3327 patient-years of follow up (0.78 events per 100 patient years). The relative risk was 1.92 (95%CI = 1.19, 3.11). However, the increased relative risk became apparent only after 18 months of treatment; during the first 18 months the events rates were similar in the two groups. The difference between the two groups was mainly due to an increased number of myocardial infarctions and strokes in those taking rofecoxib. Those who took rofecoxib also had higher risks of non-adjudicated cardiovascular events (hypertension and edema-related events) compared with those who took placebo. The Kaplan–Meier curves for the cumulative incidence of congestive heart failure, pulmonary edema, and cardiac failure showed an early separation of the two groups, at about 5 months. Further data consistent with the results of APPROVe were found in a standard and cumulative random effects meta-analysis (16M ). This study aimed at establishing whether robust evidence on the adverse cardiovascular effects of rofecoxib had been available before September 2004, the date on which rofecoxib was withdrawn. The meta-analysis identified 18 randomized controlled trials, including 25 273 patients with chronic musculoskeletal disorders, in which rofecoxib was compared with other NSAIDs or placebo, and 11 observational studies on naproxen and cardiovascular risk. Myocardial infarction was the primary end-point. By the end of 2000 (52 myocardial infarctions, 20 742 patients) the relative risk in randomized controlled trials was 2.30 (95%CI = 1.22, 4.33), and 1 year later (64 events, 21 432 patients) it was 2.24 (1.24, 4.02). There was no evidence that the relative risk differed depending on the control group (placebo, a non-naproxen NSAID, or naproxen) or the duration of the trial. In observational studies, the cardioprotective effect of naproxen was small (combined estimate 0.86; CI = 0.75, 0.99)
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and could not have explained the findings of VIGOR. These findings suggest that evidence of the adverse cardiovascular effects was available before September 2004 and that rofecoxib should have been withdrawn several years earlier. The reasons why the manufacturers and regulatory authorities did not continuously monitor and summarize the accumulating evidence need to be clarified (14C ). Besides the VIGOR and APPROVe studies, a number of other clinical and epidemiological studies have signalled an increased risk of harmful cardiovascular effects with rofecoxib. Among them three epidemiological studies merit attention. The first study (11C ) was a retrospective cohort study of individuals on the expanded Tennessee Medicaid programme, in which the occurrence of serious coronary heart disease was assessed both in non-users (n = 202 916) and users of rofecoxib (n = 24 132) and other NSAIDs (n = 15 728). The patients were aged 50–84 years, lived in the community, and had no life-threatening non-cardiovascular illnesses. The incidence of acute myocardial infarction or cardiac death in new users of rofecoxib at doses above 25 mg/day was almost twice that in non-users (24 versus 13 events per 1000 patient years; RR = 1.93; 95%CI = 1.00, 3.43). In contrast, there was no evidence of an increased risk of coronary heart disease among users of rofecoxib at doses of 25 mg/day or less or among users of other NSAIDs. The second study was a matched casecontrol study of the relation between coxibs, non-selective NSAIDs, and hospitalization for acute myocardial infarction in a large population of patients aged 65 years or over (12C ). The study database contained information on more than 50 000 patients and included 10 895 cases of acute myocardial infarction. Current use of rofecoxib was associated with an increased relative risk of acute myocardial infarction compared with celecoxib (OR = 1.24; CI = 1.05, 1.46) and with no NSAIDs (OR = 1.14; CI = 1.00, 1.31). A dosage of rofecoxib of over 25 mg/day was associated with a higher risk than 25 mg/day or less. The risk was increased in the first 90 days but not thereafter. The timing of cardiovascular risks associated with the use of COX-2 inhibitors is unclear. The APPROVe trial reported a twofold increase in cardiovascular toxicity after
Anti-inflammatory and antipyretic analgesics and drugs used in gout
18 months of use, while in the VIGOR study a similar increase in risk was reported after only 9 months of treatment. However, the risk curves in the VIGOR study started to diverge after the first month of therapy (17C ). In the APC trial celecoxib was associated with a dosedependent increase in risk after 3 years of use, but the combination of intravenous parecoxib plus oral valdecoxib resulted in an increased risk after only 10 days of exposure. A more recent study has provided new insights into the timing of the cardiovascular risks associated with the use of rofecoxib and celecoxib (18C ). The study, which was a time-matched, nested, case-control study, showed that among elderly users of rofecoxib and celecoxib the cardiovascular risks associated with the use of rofecoxib were more acute than has previously been recognized. The risk was highest in the first 6–13 days (median 9 days) after starting treatment and did not increase with further treatment. Indeed, the risk of myocardial infarction appeared to reduce over time despite continued exposure, presumably owing to attrition of susceptible individuals, i.e. the healthy survivor effect that is seen in an adverse effect of intermediate time course (19R ). Further evidence that rofecoxib increases the risk of serious coronary heart disease comes from a third case-control study commissioned by the US Food and Drug Administration (13C ). Cases of serious coronary heart disease (acute myocardial infarction and sudden cardiac death) in a cohort of NSAID-treated patients were risk-matched with four controls. Current exposure to coxibs (rofecoxib and celecoxib) and standard NSAIDs was compared with remote exposure to any NSAID, and rofecoxib was compared with celecoxib. During 2 302 029 person-years of follow up, there were 8143 cases of serious coronary heart disease, of which 2210 were fatal. Multivariate adjusted odds ratios for rofecoxib versus celecoxib were: 1.59 (all doses; CI = 1.10, 2.32); 1.47 (rofecoxib 25 mg/day or less; CI = 0.99, 2.17); and 3.58 (rofecoxib over 25 mg/day; CI = 1.00, 4.30). For naproxen versus remote NSAIDs the adjusted OR was 1.14 (1.00, 1.30). The interpretation of these results was that rofecoxib increases the risk of acute myocardial infarction and sudden death compared with celecoxib and that naproxen does not protect against serious coronary heart disease. This study also
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provided data relevant to some other controversies about the cardiovascular safety of coxibs. In particular there was a substantially higher risk with high-dose rofecoxib, in accordance with the results of other studies (11C , 12C ). Moreover the mean duration of use before the occurrence of an event was identical with high doses and standard doses of rofecoxib (about 110 days), consistent with the idea that the risk of cardiovascular toxicity begins early in treatment. That is in accord with the analysis by the FDA of data from VIGOR, which showed that the survival curve for acute myocardial infarction with high-dose rofecoxib began to diverge from the naproxen curve after 1 month. There was no evidence that the relative risk differed depending on the control group (placebo, a non-naproxen NSAID, or naproxen) or the duration of treatment. This suggests that patients are at risk of myocardial infarction even if rofecoxib is taken for a few months only. Therefore, the reassuring statement by Merck that there is no excess risk in the first 18 months is not supported by this meta-analysis. In contrast to these findings, two earlier meta-analyses from Merck laboratories showed no evidence for an excess of cardiovascular thrombotic events for rofecoxib relative to either placebo or non-naproxen NSAIDs (ibuprofen, nabumetone, diclofenac) or an increased risk in trials in which rofecoxib and naproxen were compared (7M , 20C ). In conclusion these data provide further convincing evidence that naproxen does not have a cardioprotective effect, in accordance with the results of some studies (21C , 22C ) although not others (8–10C ). Indeed, the current data show even a possibility of a small increased risk of coronary heart disease. The demonstration of a lack of protective effect of naproxen is important, because it is often used as a comparator in clinical trials of new coxibs. Thus, a result that shows that a new drug has an increased risk of cardiovascular disease relative to naproxen should alert prescribers to potential cardiotoxic effects. There are two further crucial questions: • Is the apparent treatment-associated increase in severe cardiovascular events unique to rofecoxib or does it apply to other COX-2 selective drugs, suggesting a COX-2 class effect, and even to NSAIDs in general?
120 • Does it apply to all patients or only to a subset, such as those with known susceptibility factors for vascular disease? Two recently published reports help in answering these questions. The first is a metaanalysis of randomized controlled trials of selective COX-2 inhibitors versus placebo or traditional NSAIDs or both (23M ). Eligible studies were randomized trials that lasted at least 4 weeks, with information on serious vascular events (defined as myocardial infarction, stroke, and vascular death). Data were available from 138 randomized trials involving a total of 143 373 participants. NSAIDs were subdivided into naproxen and others. In placebo comparisons, allocation to a COX-2 selective inhibitor was associated with a 42% relative increase in the incidence of serious vascular events: 1.2% per year versus 0.9% per year (RR = 1.42; 95%CI = 1.13, 1.78) with no significant heterogeneity among the different coxibs. This increase was chiefly attributable to an increased risk of myocardial infarction (0.6% per year versus 0.3% per year; RR = 1.86; 95%CI = 1.93, 2.59), with little apparent difference in other vascular outcomes. Among trials of at least 1 year duration (mean 2.7 years) the rate ratio for vascular events was 1.45 (CI = 1.12, 1.89). There were too few vascular events to allow an assessment of the dose-response relation in placebo-controlled trials of all coxibs, with the exception of celecoxib, for which there was a significant trend towards an increased incidence of serious vascular events with higher daily doses. The size of the risk of vascular events in placebo-controlled trials that allowed concomitant use of aspirin was similar among aspirin users and non-users. Comparisons of selective COX-2 inhibitors versus traditional NSAIDs showed a similar incidence of serious vascular events (1.0% per year versus 0.9% per year; RR = 1.16; CI = 0.97, 138). However, there was marked heterogeneity across the rate ratios for vascular events in trials that compared a coxib with naproxen and trials that compared a selective COX-2 inhibitor with a non-naproxen NSAID. Overall, compared with naproxen, allocation to a selective COX-2 inhibitor was associated with a highly significant increase in the incidence of a serious vascular event (RR = 1.57; CI = 1.21, 2.03) and a two-fold increased risk of a myocardial infarction (RR = 2.04; CI = 1.41, 2.96),
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but no difference in the incidences of stroke or vascular death. In contrast the comparison of COX-2 selective inhibitors with non-naproxen NSAIDs showed non-significant differences in the incidences of vascular events, myocardial infarctions, and vascular deaths, but selective COX-2 inhibitors were associated with a significantly lower incidence of stroke than any non-naproxen NSAIDs (RR = 0.62; CI = 0.41, 0.95). When the rate ratio of serious vascular events with traditional NSAIDs was compared with that of placebo, high-dose ibuprofen and high-dose diclofenac were both associated with an increased risk of cardiovascular events (ibuprofen RR = 1.51; CI = 0.96, 2.37; diclofenac RR = 1.63; CI = 1.12, 2.37), while naproxen was not. Thus, it appears that allocation to a selective COX-2 inhibitor is associated with about three extra vascular events per 1000 patients per year. Most of this excess is attributable to myocardial infarction. The other study that has contributed to better evaluation of the data on cardiovascular risk due to inhibition of cyclo-oxygenase is a systematic review of the available controlled pharmacoepidemiological studies (24M ). There were 23 eligible studies that reported on cardiovascular events (predominantly myocardial infarction) with COX-2 inhibitors, NSAIDs, or both, with non-use/remote use of the drug as the reference exposure for calculation of the relative risk. The studies were 17 case-control studies involving 86 193 cases with cardiovascular events and about 52 800 controls and six cohort studies involving 75 520 users of selective COX-2 inhibitors, 375 619 users of non-selective NSAIDs, and 594 720 unexposed participants. The results confirmed that there is an increased risk of cardiovascular events with rofecoxib. The summary relative risk with doses in excess of 25 mg/day was 2.19 (CI = 1.64, 2.91) compared with 1.33 (CI = 1.00, 1.79) with 25 mg/day or less. The risk was increased during the first month of treatment. In contrast to the evidence from the meta-analysis of randomized trials, this study showed no increase in risk with celecoxib 200 mg/day. However, one must remember that the randomized clinical trials only showed an increased risk with doses of celecoxib of 400 mg/day and above. The study also provided more data on the cardiovascular
Anti-inflammatory and antipyretic analgesics and drugs used in gout
toxicity of traditional NSAIDs. Naproxen was not associated with a reduction in risk, as was suggested in previous comparisons with rofecoxib. Of more concern is evidence, from both randomized and non-randomized trials, that diclofenac increases the risk of cardiovascular events (RR = 1.63; CI = 1.12, 2.37). Less convincing is the evidence of potential cardiovascular risk with other NSAIDs, such as ibuprofen, meloxicam, and indometacin. Celecoxib In December 2004 the results of the Adenoma Prevention with Celecoxib trial (the APC trial) were presented. This was a randomized, double-blind, multicenter study of the effects of two doses of celecoxib (200 mg or 400 mg bd) or placebo in the prevention of colorectal adenomas (25C ). All potentially serious cardiovascular events among 2035 patients with a history of colorectal neoplasia were identified, with a follow up of 2.8–3.1 years. Celecoxib was associated with a dose-related increase in the composite end-point of death from cardiovascular causes, myocardial infarction, stroke, or heart failure. The composite end-point was reached in seven of 679 patients in the placebo group (1%) compared with 16 of 685 patients who took celecoxib 200 mg bd (2.3%; hazard ratio = 2.3; CI = 0.9, 5.5) and 23 of 671 patients who took celecoxib 400 mg bd (3.4%; hazard ratio = 3.4; CI = 1.4, 7.8). The annualized incidence of death due to cardiovascular causes per 1000 patient years was 3.4 events in the placebo group; there were 7.5 events in patients who took celecoxib 200 mg bd and 11.4 in those who took 400 mg bd. The hazard ratio associated with celecoxib was not significantly affected by any baseline characteristics, including use of aspirin. Moreover, the results were also consistent among the individual components of the composite end-point. Based on these statistically significant findings, the sponsor of the study, the USA National Cancer Institute suspended the study. However, to underscore the uncertainty of the available data on cardiovascular risk, we should consider the results of another large long-term trial with celecoxib 400 mg/day, designed to investigate the role of NSAIDs in preventing Alzheimer’s disease, the Alzheimer Disease Anti-inflammatory Prevention Trial
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(ADAPT), in which celecoxib was compared with naproxen (440 mg/day). The unpublished results of the study showed that celecoxib did not increase cardiovascular risk, while naproxen was associated with an increased risk (26CR ). The results from the APC and ADAPT studies are disturbing, because they are inconsistent with the results of most previous studies. The following data summarize the currently available information on the cardiovascular safety of celecoxib. In two retrospective re-analyses of randomized controlled trial data for celecoxib (27C , 28C ) the cardiovascular events in patients enrolled in the CLASS study (29C ) were examined, as were those reported across the entire controlled arthritis clinical trial database for celecoxib. The results of the reanalysis of CLASS showed no evidence of an increase in investigator-reported serious cardiovascular adverse events in patients taking celecoxib. In the analysis of the celecoxib comparative trials database the incidence of cardiovascular events was not significantly different between celecoxib and placebo or between celecoxib and naproxen, regardless of aspirin use. Thus, these comparative analyses failed to show an increased risk of thrombotic events associated with celecoxib compared with conventional NSAIDs, naproxen specifically, or placebo. Most information on the potential cardiovascular toxicity of celecoxib has come from a number of observational studies (11–13C , 22C , 28C , 30C , 31Cr ). Most of them were populationbased case-control studies in which the relative risk of acute myocardial infarction was assessed in patients who took celecoxib, rofecoxib, conventional NSAIDs, or no NSAIDs at all. None of these studies identified a significantly increased risk of severe cardiovascular events with celecoxib. However, the results of these observational studies must be interpreted with caution. In fact, although findings from observational studies are more generalizable, as they are larger and include less carefully selected patients than randomized controlled trials, they suffer from potential bias and confounding, which could have contributed to the failure to confirm the hypothesis of a consistent difference in severe cardiovascular risk between all the coxibs and other NSAIDs. Whether this safety concern represents a class effect requires additional information
122 from other randomized controlled trials, not yet available (31Cr ). Valdecoxib and parecoxib Further support of the hypothesis that the increase in cardiovascular risk is a COX-2 class effect has come from an analysis of clinical trials of valdecoxib and its pro-drug parecoxib. The cardiovascular safety of valdecoxib was initially assessed in a study that pooled results from 10 clinical trials that included nearly 8000 patients with osteoarthritis and rheumatoid arthritis and compared the incidence of cardiovascular events in patients taking valdecoxib (10–80 mg/day) with those of controls taking diclofenac, ibuprofen, naproxen, or placebo (32C ). The incidences of cardiovascular thrombotic events (cardiac, cerebrovascular, and peripheral vascular or arterial thrombotic) were similar with valdecoxib, the conventional NSAIDs, and placebo. Short-term and intermediate-term treatment with valdecoxib in therapeutic doses (10 or 20 mg/day) and supratherapeutic doses (40–80 mg/day) was not associated with an increased incidence of thrombotic events. In contrast, recent studies have raised serious doubts about the safety of valdecoxib in patients who are at high risk of thrombotic complications, such those undergoing coronary artery bypass surgery. The cardiovascular toxicity of valdecoxib and its pro-drug parecoxib has been studied in two randomized placebo-controlled trial and one meta-analysis. The first study involved 462 patients and evaluated the safety and efficacy of intravenous parecoxib (parecoxib 40 mg intravenously every 12 hours for 3 days postoperatively), followed by oral valdecoxib (40 mg every 12 hours for a total of 14 days) (33C ). In the second study, which involved more than 1600 patients, a similar schedule of administration was used, but the dosage and duration of treatment were reduced (20 mg bd for 10 days) (34C ). In both studies there were clusters of cardiovascular adverse events, including myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism, which were more frequent in those who were given parecoxib than in the controls, although the difference was not statistically significant. However, when the coronary and cerebrovascular events were combined in a meta-analysis parecoxib/valdecoxib was associated with a three-fold risk of cardiovascular events compared with placebo:
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31/1399 events versus 5/699 (RR = 3.08; CI = 1.20, 7.87) (35M ). Following this important information a new warning contraindicating the use of parecoxib/ valdecoxib in patients undergoing coronary artery bypass grafting was added to the label by many drug control agencies. Meanwhile the FDA received reports of 87 cases of severe skin reactions associated with valdecoxib, including Stevens–Johnson syndrome and toxic epidermal necrolysis, with four deaths; 20 of the 87 cases involved patients with a known allergy to sulfacontaining drugs, of which valdecoxib is one; thus, patients allergic to sulfa drugs may be at greater risk of severe skin reactions with valdecoxib. These data have raised concerns not only about the cardiovascular safety of valdecoxib in the general population but also about its overall benefit to harm profile. The drug manufacturers and regulatory agencies in the USA and Europe agreed to suspend valdecoxib in April 2005 (36C ). Lumiracoxib Lumiracoxib is a novel COX-2 selective inhibitor, a phenylacetic acid derivative with a short half-life and a higher selectivity than any other coxib. Clinical data on its efficacy and safety are still limited. The cardiovascular safety of lumiracoxib has been assessed in the Therapeutic Arthritis and Gastrointestinal Event Trial (TARGET) in 18 325 patients aged 50 years or older with osteoarthritis, who were randomized to lumiracoxib (400 mg/day; n = 9156), ibuprofen (800 mg tds; n = 4415), or naproxen (500 mg bd; n = 4754) for 52 weeks in two substudies of identical design (lumiracoxib versus ibuprofen and lumiracoxib versus naproxen) (37C ). Randomization was stratified for low-dose aspirin and age. The primary cardiovascular end points were the ATC end-points of non-fatal and silent myocardial infarction, stroke, or cardiovascular death. At 1 year of follow up, the incidence of the primary end-point was low and did not differ between treatment groups: lumiracoxib 59 events (0.65%), NSAIDs 50 events (0.55%; hazard ratio 1.14; CI = 0.28, 1.66). The incidence of myocardial infarction in the overall population in the individual substudies was 0.38% with lumiracoxib (18 events) versus 0.21% with naproxen (10 events), and 0.11% with lumiracoxib (5 events) versus 0.16% (7 events) with ibuprofen. In both substudies the rates of myocardial infarction did
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not differ significantly between lumiracoxib and NSAIDs, irrespective of aspirin use. These TARGET trial data suggest that lumiracoxib does not have the potential to precipitate adverse cardiovascular events more often than NSAIDs. However, these results must be interpreted with caution (38C ) for several reasons: • patients with known and significant preexisting coronary artery disease were excluded, which explains the overall low frequency of cardiovascular events and introduced bias into the generalizability of the TARGET results; • the statistical power was inadequate to detect significant differences in the rates of myocardial infarction, again raising concern about an excess, albeit not a statistically significant one, of myocardial infarctions with lumiracoxib compared with naproxen: 18 events (0.38%) versus 10 events (0.21%); hazard ratio 1.77 (0.82, 3.84). • lumiracoxib significantly reduced the frequency of upper gastrointestinal ulcer complications (NNT to prevent one ulcer complication 139) but only in patients not taking low-dose aspirin (39C ), confirming the results of other coxib trials (CLASS). • the data raised a concern about possible hepatotoxicity of lumiracoxib; the proportion of patients with transaminase activities more than three times the upper limit of the reference range differed significantly between lumiracoxib (2.57%, n = 230) and NSAIDs (0.63%, n = 56; hazard ratio 3.97; CI = 2.96, 5.32). Etoricoxib Data on the efficacy and safety of this highly selective COX-2 inhibitor are still limited. A combined analysis of all randomized, double-blind trials of long-term treatment showed a significantly lower incidence of peptic ulcer bleeding with etoricoxib (n = 9226) than with conventional NSAIDs (n = 2215), but there was no information about potential cardiovascular toxicity (40C ). There has been a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials of etoricoxib of at least 6 weeks duration (five studies with a total of 2919 patients); the main outcome measure was cardiovascular thromboembolic events (41M ).
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There were seven cardiovascular thromboembolic events in 1441 patients (0.5%) taking etoricoxib, and one event in 906 patients (0.1%) taking placebo. The pooled fixed-effects estimate of the absolute risk difference was 0.5% (CI = 0.1, 1.0). The odds ratio for the risk of cardiovascular events was 1.49 (0.42, 5.31). These limited data provide weak evidence of an increased cardiovascular risk with etoricoxib. A large sufficiently powered comparison of etoricoxib and diclofenac is currently under way and should clarify this issue. Conclusions At present at least three important questions about the adverse cardiovascular effects of COX-2 selective inhibitors remain unanswered. First, the mechanism whereby COX-2 inhibitors facilitate ischemic cardiovascular events is unclear. The major unanswered question is whether unopposed COX-2 inhibition or other drug-specific mechanisms cause the increased cardiovascular risk. It is worth noting that in addition to ischemic cardiovascular disease, COX-2 inhibitors are associated with other adverse cardiovascular effects, such as heart failure (42C , 43C ), hypertension (44C , 45M ), and edema (46C ). Secondly, it is still unknown whether the cardiovascular risk is or is not a class effect. Since at least three separate drugs in the class (rofecoxib, valdecoxib, and celecoxib) have now been associated with increased cardiovascular morbidity, the burden of proof has been shifted to those who deny a class effect. We must remember that absence of evidence is not evidence of absence (2R ). Thirdly, there is uncertainty about what physicians should do if they decide to prescribe an NSAID. In light of the current uncertainty about whether cardiotoxicity is a class effect, coxibs, in particular at high dosages and for long-term use, should not be prescribed, particularly in populations at high risk, such as elderly patients and those with established cardiovascular disease. This recommendation is fully justified in light of the possible consequences of the current heavy unjustified promotion of these compounds to both patients and prescribers. A recent epidemiological study in Ontario, Canada showed that the use of NSAIDs in patients aged 66 years or older increased by 41% after the introduction of coxibs
124 (47C ). This rise was entirely attributable to the use of coxibs and was accompanied by a 10% increase in hospitalization for upper gastrointestinal bleeding. The continued commercial availability of coxibs is therefore troubling, and probably unjustified, in the light of their marginal efficacy, heightened risk, and higher costs compared with traditional NSAIDs. The coxib debate will not go away until these safety and efficacy questions have been answered (38r ).
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6.4%; CI = −4.6, 16); absolute risk reduction 1.1%; (CI = −0.6, 2.7). However, the incidence of life-threatening bleeding was higher with aspirin than placebo: 96 (2.6%) versus 49 (1.3%). The absolute increase in risk was 1.3% (CI = −0.6, 1.9) as was the incidence of major bleeding. These possibly increased risks might therefore offset any beneficial effect of adding aspirin to clopidogrel treatment in these patients. Case reports documenting an increased risk of bleeding with the concomitant use of clopidogrel with aspirin in perioperative setting have been published (52A ).
INDIVIDUAL DRUGS AND CLASSES Acetylsalicylic acid (aspirin) and related compounds (SED-15, 15; SEDA-26, 113; SEDA-27, 109; SEDA-28, 123) Pancreas There are conflicting findings in the literature regarding the possibility that longterm use of aspirin is associated with an increased risk of pancreatic cancer (48R ). New data from a recent study have suggested that extended periods of regular aspirin use appear to be associated with a statistically significant increased risk of pancreatic cancer among women (49C ). However, the results of this study were inconsistent and require confirmation. Drug interactions In the CAPRIE study clopidogrel was superior to aspirin in patients with previous manifestations of atherothrombotic disease, and its benefit was amplified in some high-risk subgroups of patients (50C ). To assess whether the addition of aspirin to clopidogrel could have a greater benefit than clopidogrel alone in preventing vascular events with a potentially higher bleeding risk, patients who had recently had an ischemic stroke or a transient ischemic attack and were taking clopidogrel 75 mg/day, were randomized to receive additional aspirin 75 mg/day (n = 3797) or placebo (n = 3802) for 18 months (51C ). The primary end-point was a composite of ischemic stroke, myocardial infarction, vascular death, or rehospitalization for acute ischemia. Aspirin was associated with a small non-significant reduction in the risk of the primary end-point (relative risk reduction of
ARYLALKANOIC ACID DERIVATIVES (SED-15, 2555; SEDA-26, 115; SEDA-27, 115; SEDA-28, 126)
Ibuprofen
(SED-15, 1709)
Liver Ibuprofen-induced vanishing bile duct syndrome has been previously described (SEDA-21, 105). There has been a new report of this rare syndrome associated with Stevens– Johnson syndrome in a 10-year-old girl who took ibuprofen in conventional doses (up to 30 mg/kg/day) for 2 days (53A ). She recovered uneventfully. Urinary tract Reports of acute renal insufficiency in children taking ibuprofen as an analgesic or antipyretic continue to appear (54A , 55A ). In most cases dehydration was the main precipitating cause. Ibuprofen and other NSAIDs should be avoided in dehydrated patients. Susceptibility factors Surgery Despite paucity of evidence, clinicians routinely discontinue NSAIDs at least 1 week before most surgical procedures to avoid a possible risk of bleeding due to platelet dysfunction. In a prospective cohort study platelet function was tested in 11 healthy adult volunteers at baseline and after completion of a 7-day course of ibuprofen (600 mg orally every 8 hours) (56C ). There was platelet dysfunction after completion of the course of ibuprofen in
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seven of the 11 patients, which normalized by 24 hours after the last dose. These results, if confirmed, provide a rational basis for timing NSAID withdrawal before surgery.
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DRUGS USED IN THE TREATMENT OF GOUT Colchicine
(SEDA-15, 883; SEDA-28,
133)
OXICAMS
(SEDA-15, 2555; SEDA-27, 116; SEDA-28, 128)
Tenoxicam
(SED-15, 3314)
Biliary tract Cholestatic cholangitis accompanied by toxic epidermal necrolysis and prolonged ductopenia has been described in a 36year-old man who took tenoxicam 20 mg/day for 7 days (57A ). He improved initially, but at follow-up at 1 and 3 years his cholestatic enzymes were still raised and liver biopsies showed ductopenia, suggesting vanishing bile duct syndrome.
Drug interactions An interaction of colchicine with verapamil has been described (58A ). • An 83-year-old man taking verapamil developed a flaccid tetraparesis after taking colchicine 2 mg over 2 days for acute gout. He developed severe muscle weakness in his legs and arms, and electrophysiology showed axonal damage. Five days after taking colchicine he had raised serum and cerebrospinal fluid colchicine concentrations. Serum verapamil and norverapamil concentrations were normal, as was renal function.
The authors suggested that inhibition of P glycoprotein in the blood–brain barrier by verapamil and its metabolite norverapamil had led to accumulation of colchicine in the nervous system, causing the acute neurological damage.
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thrombotic events in controlled, clinical trials of rofecoxib. Circulation 2001;104:2280–8. Rahme E, Pilote L, LeLorier J. Association between naproxen use and protection against acute myocardial infarction. Arch Intern Med 2002;162:1111–5. Solomon DH, Glynn RJ, Levin R, Avorn J. Nonsteroidal anti-inflammatory drug use and acute myocardial infarction. Arch Intern Med 2002;162:1099–104. Watson DJ, Rhodes T, Cai B, Guess HA. Lower risk of thromboembolic cardiovascular events with naproxen among patients with rheumatoid arthritis. Arch Intern Med 2002;162:1105–10. Ray WA, Stein CM, Daugherty JR, Hall K, Arbogast PG, Griffin MR. COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease. Lancet 2002;360:1071–3. Solomon DH, Schneeweiss S, Glynn RJ, Kiyota Y, Levin R, Mogun H, Avorn J. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation 2004;109:2068–73.
126 13. Graham DJ, Campen D, Hui R, Spence M, Cheetham C, Levy G, Shoor S, Ray WA. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal antiinflammatory drugs: nested case-control study. Lancet 2005;365:475–81. 14. Topol EJ. Failing the public health—rofecoxib, Merck, and the FDA. N Engl J Med 2004;351:1707–9. 15. Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA, Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005;352:1092–102. 16. Jüni P, Nartey L, Reinchenbach S, Sterchi R, Dieppe PA, Egger M. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet 2004;364:2021–9. 17. Nissen SE. Adverse cardiovascular effects of rofecoxib. N Engl J Med 2006;355:203–4. 18. Lévesque LE, Brophy JM, Zhang B. Time variations in the risk of myocardial infarction among elderly users of COX-2 inhibitors. CMAJ 2006;174:1563–9. 19. Aronson JK, Ferner RE. Joining the DoTS. New approach to classifying adverse drug reactions. BMJ 2003;327:1222–5. 20. Reicin AS, Shapiro D, Sperling RS, Barr E, Yu Q. Comparison of cardiovascular thrombotic events in patients with osteoarthritis treated with rofecoxib versus nonselective nonsteroidal antiinflammatory drugs (ibuprofen, diclofenac, and nabumetone). Am J Cardiol 2002;89:971–2. 21. Mamdani M, Rochon P, Juurlink DN, Anderson GM, Kopp A, Naglie G, Austin PC, Laupacies A. Effect of selective cyclooxygenase 2 inhibitors and naproxen on short-term risk of acute myocardial infarction in the elderly. Arch Intern Med 2003;163:481–6. 22. Ray WA, Stein CM, Hall K, Daugherty JR, Griffin MR. Non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease: an observational cohort study. Lancet 2002;359:118– 23. 23. Kearney P, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclooxygenease-2 inhibitors and traditional nonsteroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 2006;332:1302–8. 24. McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA 2006;296:1633–44. 25. Solomon SD, McMurray JJV, Pfeffer MA, Wittes J, Fowler R, Finn P, Anderson WF, Zauber A, Hawk W, Bertagnolli M. Adenoma Prevention with Celecoxib (APC) Study Investigators. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352:1071–80.
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26. Brophy JM. Cardiovascular risk associated with celecoxib. N Engl J Med 2005;352:2648–50. 27. White WB, Faich G, Whelton A, Maurath C, Ridge NJ, Verburg KM, Geis GS, Lefkowith JB. Comparison of thromboembolic events in patients treated with celecoxib, a cyclooxygenase-2 specific inhibitor, versus ibuprofen or diclofenac. Am J Cardiol 2002;89:425–30. 28. White WB, Faich G, Borer JS, Makuch RW. Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib. Am J Cardiol 2003;92:411–8. 29. Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, Makuch R, Eisen G, Agrawal NM, Stenson WF, Burr AM, Zhao WW, Kent JD, Lefkowith JB, Verburg KM, Geis GS. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000;284:1247–55. 30. Kimmel SE, Berlin JA, Reilly M, Jaskowiak J, Kishel L, Chittams J, Strom BL. Patients exposed to rofecoxib and celecoxib have different odds of nonfatal myocardial infarction. Ann Intern Med 2005;142:157–64. 31. Shaya FT, Blume SW, Blanchette CM, Weir MR, Mullins CD. Selective cyclooxygenase-2 inhibition and cardiovascular effects: an observational study of a Medicaid population. Arch Intern Med 2005;165:181–6. 32. White WB, Strand V, Roberts R, Whelton A. Effects of the cycloxygenase-2 specific inhibitor valdecoxib versus nonsteroidal antinflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis. Am J Ther 2004;11:244–50. 33. Ott E, Nussmeier NA, Duke PC, Feneck RO, Alston RP, Snabes MC, Hubbard RC, Hsu PH, Saidman LJ, Mangano DT. Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg 2003;125:1481–92. 34. Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL, Boyce SW, Verburg KM. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005;352:1081–91. 35. Furberg CD, Psaty BM, FitzGerald GA. Parecoxib, valdecoxib, and cardiovascular risk. Circulation 2005;111:249. 36. Ray WA, Griffin MR, Stein CM. Cardiovascular toxicity of valdecoxib. N Engl J Med 2004;361:2767. 37. Farkouh ME, Kirshner H, Harrington RA, Ruland S, Verheugt FWA, Schnitzer TJ, Burmster GR, Mysler E, Hochberg MC, Doherty M, Ehrsam E, Gitton X, Krammer G, Mellein B, Gimona A, Matchaba P, Hawkey CJ, Chesebro J, on behalf of the TARGET Study Group. Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and
Anti-inflammatory and antipyretic analgesics and drugs used in gout
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44. 45.
46.
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gastrointestinal event trial (TARGET), cardiovascular outcomes: randomised controlled trial. Lancet 2004;364:675–84. Topol EJ, Falk GW. A coxib a day won’t keep the doctor away. Lancet 2004;364:639–40. Schnitzer T, Burmester GR, Mysler E, Hochberg MC, Doherty M, Ehrsam E, Gitton X, Krammer G, Mellein B, Matchaba P, Gimona A, Hawkey CJ, on behalf of the TARGET Study Group. Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 2004;364:665–74. Ramey DR, Watson DJ, Yu C, Bolognese JA, Curtis SP, Reicin AS. The incidence of upper gastrointestinal adverse events in clinical trials of etoricoxib vs. non-selective NSAIDs: an updated combined analysis. Curr Med Res Opin 2005;21:715–22. Aldington S, Shirtcliffe P, Weatherall M, Beasley R. Systematic review and meta-analysis of the risk of major cardiovascular events with etoricoxib therapy. N Z Med J 2005;118:U1684. Mamdani M, Juurlink DN, Lee DS, Rochon PA, Kopp A, Naglie G, Austin PC, Laipacis A, Stukel TA. Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal antiinflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study. Lancet 2004;363:1751–6. Hudson M, Richard H, Pilote L. Differences in outcomes of patients with congestive heart failure prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs: population based study. BMJ 2005;330:1370. Solomon DH, Scheneeweiss S, Levin R, Avorn J. Relationship between COX-2 specific inhibitors and hypertension. Hypertension 2004;44:140–5. Aw TJ, Haas SJ, Liew D, Krum H. Metaanalysis of cyclooxygenase-2 inhibitors and their effects on blood pressure. Arch Intern Med 2005;165:490–6. Wolfe F, Zhao S, Pettitt D. Blood pressure destabilization and edema among 8538 users of celecoxib, rofecoxib, and nonselective nonsteroidal anti-inflammatory drugs (NSAID) and nonusers of NSAID receiving ordinary clinical care. J Rheumatol 2004;31:1035–7. Mamdani M, Juurlink DN, Kopp A, Naglie G, Austin PC, Laupacis A. Gastrointestinal bleeding
48. 49.
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after the introduction of COX 2 inhibitors: ecological study. BMJ 2004;328:1415–6. Baron JA. What now for aspirin and cancer prevention? J Natl Cancer Inst 2004;96:22–8. Schernhammer ES, Kang JH, Chan AT, Michaud DS, Skinner HG, Giovannucci E, Colditz GA, Fuchs CS. A prospective study of aspirin use and the risk of pancreatic cancer in women. J Natl Cancer Inst 2004;96:22–8. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348(9038):1329–39. Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, Leys D, MatiasGuiu J, Rupprecht HJ, Match investigators. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebocontrolled trial. Lancet 2004;364:331–7. Moore M, Power M. Perioperative hemorrhage and combined clopidogrel and aspirin therapy. Anesthesiology 2004;101:792–4. Taghian M, Tran TA, Bresson-Hadni S, Menget A, Felix S, Jacquemin E. Acute vanishing bile duct syndrome after ibuprofen therapy in a child. J Pediatr 2004;145:273–6. Moghal NE, Hegde S, Eastham KM. Ibuprofen and acute renal failure in a toddler. Arch Dis Child 2004;89:276–7. Ulinski T, Guigonis V, Dunan O, Bensman A. Acute renal failure after treatment with nonsteroidal anti-inflammatory drugs. Eur J Pediatr 2004;163:148–50. Goldenberg NA, Jacobs L, Manco-Johnson MJ. Duration of platelet dysfunction after a 7day course of ibuprofen. Ann Intern Med 2005;142:506–9. Trak-Smayra V, Cazals-Hatem D, Asselah T, Duchatelle V, Degott C. Prolonged cholestasis and ductopenia with tenoxicam. J Hepatol 2003;39:125–8. Tröger U, Lins H, Scherrmann JM, Wallesch CW, Bode-Boger SM. Tetraparesis associated with colchicine is probably due to inhibition by verapamil of the P-glycoprotein efflux pump in the blood-brain barrier. BMJ 2005;331(7517):613.
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General anesthetics and therapeutic gases
Sedation in special circumstances Sedation for endoscopy Gastrointestinal endoscopy is one of the most commonly performed invasive procedures in clinical practice. Propofol is a short-acting intravenous anesthetic with a rapid onset of action, a short half-life, and very favorable recovery characteristics, making it particularly suitable for day procedures. Patients and endoscopists prefer propofol to benzodiazepine + opioid combinations. However, the use of propofol by non-anesthetists has been controversial, because of the perceived risks of its smaller therapeutic ratio. In many jurisdictions, package inserts insist that it is only for use by anesthetists. In a review of nurse-administered endoscopy sedation regimens that primarily used propofol the incidence of adverse events was examined (1R ). Respiratory depression, presenting as apnea and hypoxemia, is the most serious adverse event. The authors of this review have suggested that individuals administering propofol must be able to support ventilation. Respiratory depression appears to be more common after upper gastrointestinal endoscopy. Hypotension is also common, particularly in elderly people or in those with impaired left ventricular function. Most of the studies reviewed only examined American Society of Anesthesiology (ASA) Class 1 and 2 patients (i.e. they did not include patients with significant co-morbidity). The reviewers suggested that registered nurseadministered endoscopy sedation with propofol is safe, provided that the nurse is appropriately trained, that there is appropriate monitoring Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29010-X © 2007 Elsevier B.V. All rights reserved.
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(probably including capnography), and that the nurse must attend solely to the patient and have no other functions to perform simultaneously in the endoscopy suite (for example assisting the endoscopist). A contrary view has been taken in a prospective study of propofol sedation in 500 ASA 1 and 2 patients undergoing upper gastrointestinal endoscopic ultrasound in a Canadian center (2C ). Propofol sedation (bolus plus infusion) was administered by the endoscopist and not a dedicated nurse. Patients were monitored by clinical observation, pulse oximetry, and automated sphygmomanometry. All received supplementary oxygen 2 l/minute during the procedures. There was oxygen desaturation (defined as an oxygen saturation below 95%) in 16 patients (3%). There was hypoxemia (saturation below 90%) in four patients (0.8%). Increasing the supplementary oxygen to 4 l/minute was all that was required in nine patients. Increasing the supplementary oxygen and jaw lift was needed in one patient. Increasing the supplementary oxygen, jaw lift, and stopping the propofol infusion was necessary in the other six patients. Assisted ventilation was not required. There were no cases of hypotension, bradycardia, or tachycardia. The authors concluded that propofol may be safely administered by endoscopists who are familiar with its pharmacological properties and uses, and that there was a high level of satisfaction for both patient and anesthetist. However, they went on to say that in fact they found using propofol without a dedicated administrator and observer rather stressful, and that most of the endoscopists had returned to using intermittent bolus midazolam + pethidine (meperidine). The authors of a third prospective randomized study took a different approach, by comparing patient-controlled propofol with patientcontrolled remifentanil (an ultra-short acting
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opioid) in 77 patients undergoing gastrointestinal endoscopy (3C ). Patient satisfaction was high in both groups. There were significantly more awake and oriented patients among those who received remifentanil (46 versus 24%). Unfortunately, nausea was also more common (29 versus 0%). There were two cases of oxygen desaturation (<92%) in the remifentanil group and none in the propofol group. Monitoring did not include capnography. Sedation in intensive care The alpha-2 adrenoceptor agonist dexmedetomidine has potent sedative and analgesia-sparing properties. In therapeutic doses it does not cause respiratory depression, making it attractive for infusion sedation. However, it causes reduced sympathetic outflow, which might cause untoward hemodynamic upset but might also have beneficial β-adrenoceptor antagonist-like value in patients undergoing cardiovascular surgery. Its use in pediatrics has been anecdotal. Dexmedetomidine has been compared with midazolam in a prospective randomized trial in 30 infants and children undergoing mechanical ventilation (4c ). Dexmedetomidine 0.5 micrograms/kg/hour provided more effective sedation, reduced supplementary morphine requirements, and reduced the number of patients with inadequate sedation. There was no difference in blood pressure, but heart rates were significantly lower in the children who received dexmedetomidine. One infant who received dexmedetomidine and concurrent digoxin developed bradycardia, but this resolved within an hour of withdrawing the dexmedetomidine. Postoperative nausea and vomiting (PONV) About 2 million day-case anesthetics are administered annually in England. Most ophthalmic surgical procedures are carried out in the elderly as day-case procedures. Anesthetic practice varies widely in this context, because of a large and contradictory evidence base for optimal anesthetic in day surgery. In a prospective randomized controlled study in 96 elderly adults undergoing ophthalmic surgery (5C ) sevoflurane, when used for induction and maintenance, was more costly, less well tolerated, and associated with higher rates of postoperative nausea and vomiting than anesthetic regimens using propofol for induction of anesthesia.
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ANESTHETIC VAPORS (SED-15, 1489; SEDA-26, 132; SEDA-27, 119; SEDA-28, 139) Sevoflurane
SED-15, 3123; SEDA-28,
139 Cardiovascular Sudden death and dysrhythmias are associated with a rate-corrected QT interval (QTc ) of 440 ms or longer. Lifethreatening dysrhythmias during anesthesia have been reported in patients with increased QT dispersion (QTd ), the difference between the longest and shortest QT intervals in any of the 12 leads of the electrocardiogram. Sevoflurane prolongs the QTc and QTd . In a prospective randomized study of the QT interval, the QTc , the QTd , and the QTcd in preoperative, perioperative, and postoperative electrocardiograms in 90 adults undergoing non-cardiac surgery under general anesthesia, sevoflurane, desflurane, and isoflurane all prolonged QTc , QTd , and QTcd , but there were no significant intergroup differences (6C ). The effects of single-breath vital capacity rapid inhalation with sevoflurane 5% on QTc has been assessed in comparison with propofol in 44 adults undergoing laparoscopic surgery in a blind, randomized study (7C ). Sevoflurane significantly prolonged the QTc and seven patients developed ventricular dysrhythmias. Nervous system Sevoflurane often causes postoperative delirium and agitation in children, and this can be severe. Rapid emergence and postoperative pain have been proposed as possible mechanisms. This has been assessed in a randomized, prospective study in 80 infants and children undergoing inguinal hernia repair, all of whom received sevoflurane or halothane as the sole anesthetic for induction and maintenance (8C ). All received preoperative oral midazolam. For analgesia a caudal epidural block was performed with a mixture of 0.25% bupivacaine and 1% lidocaine before surgery. The time to recovery was similar in the two groups, but emergence agitation was significantly more common with sevoflurane group than with halothane (27% versus 5%) 5 minutes after arrival in the Post Anesthetic Care Unit. In a randomized prospective study of the effect of a single dose of dexmedetomidine
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on emergence agitation in 90 children undergoing superficial lower abdominal and genital surgery no premedication was used (9C ). After induction of anesthesia with 8% sevoflurane in 50% nitrous oxide and oxygen, the patients received either saline (group 1), dexmedetomidine 0.15 micrograms/kg (group 2), or dexmedetomidine 0.3 micrograms/kg (group 3). All received a caudal epidural block with 0.25% bupivacaine. The time to eye opening was similar in all the groups. The incidences of agitation (95% CI) were 37% (20–54%) in group 1, 17% (4–30%) in group 2, and 10% (0–21%) in group 3. Paired comparisons between groups showed a significant difference between groups 1 and 3. Postoperative seizures associated with sevoflurane continue to be reported and have newly been described in a neonate (10A ).
fresh gas flow rates may contribute to a build-up of Compound A in the circle system. In a randomized prospective study of the effects of prolonged (>10 hour) low-flow sevoflurane, highflow sevoflurane, and low-flow isoflurane anesthesia on renal function in 25 patients undergoing orthopedic surgery the AUC compound A was higher in the low-flow than the highflow sevoflurane group (mean 360 ppm versus 61 ppm) (12C ). However, there were no differences between the groups in markers of renal function, renal tubular damage, or hepatic transaminases. Prolonged anesthesia with low flow sevoflurane appears to be safe.
• A 5-day-old girl was underwent excision of an axillary lymphangioma. Induction of anesthesia was with sevoflurane and nitrous oxide, and maintenance with sevoflurane. No other sedative or analgesic drugs were given. Surgery took 4.5 hours, and there was rhythmic myoclonic movement of all four limbs immediately after tracheal extubation and twice more in the intensive care unit. Each episode lasted about 5 minutes and was terminated with diazepam and phenytoin. Further investigations showed no underlying cause.
• An 11-month-old infant developed hepatomegaly 2 days postoperatively associated with marked increases in serum transaminases (alanine transaminase 543 IU/l, aspartate transaminase 683 IU/l). No data on synthetic function were given. Viral serology was negative. The transaminases resolved after 11 days, and the child went on to have another urological procedure after a further 4 days, avoiding volatile agents completely. There was no subsequent liver dysfunction.
Sensory systems Visual pathway abnormalities have been described in a prospective study of 10 patients undergoing sevoflurane anesthesia (11c ). Postoperative electroretinographic abnormalities and associated reductions in contrast sensitivity were consistently present in patients who underwent sevoflurane anesthesia and these persisted beyond the time standard clinical discharge criteria were met. As ambulatory surgery now comprises more than 60–70% of all surgery, this finding is important. Urinary tract Sevoflurane can contribute to the development of renal insufficiency, by toxicity from either inorganic fluoride ions or the haloalkene degradation product Compound A. Fluoride ions are produced as a result of metabolism of sevoflurane and can reach high concentrations after prolonged anesthesia. Compound A is produced in carbon dioxide absorbers (soda lime and barium hydroxide lime in particular) used in circle systems, and is nephrotoxic in rats but not in humans. Low
Liver Hepatitis after sevoflurane exposure has been described in an infant with primary hyperoxaluria type 1 undergoing urological surgery (13A ).
Trichloroethylene
(SED-15, 3488;
SEDA-28, 140) Liver Hepatitis and acute liver failure (associated with skin and mucosal lesions similar to Stevens–Johnson syndrome) has been described in two young Thai women who used trichloroethylene to clean metal watch straps (14A ). One 23-year-old woman died from acute liver failure within a fortnight of occupational exposure. The other woman, aged 24 years, recovered spontaneously. Teratogenicity Previous studies have suggested that trichloroethylene is a selective cardiac teratogen. In a case-control study of 4025 infants born between 1997 and 1999 in Milwaukee the risk of congenital heart disease was more than three-fold greater in older trichloroethylene exposed mothers than in nonexposed mothers (15C ).
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Tumorigenicity In a consecutive case-control study of 134 renal cell cancer cases and 401 controls (16C ) median urinary α1-microglobulin excretion was significantly higher in patients with renal cell cancer who had been exposed to trichloroethylene than in non-exposed cases. A significant excess risk of renal cell cancer was associated with occupational exposure to trichloroethylene (for example for metal degreasers, OR = 5.57, 95%CI = 2.33, 13.32).
NITROUS OXIDE
(SED-15, 2550; SEDA-27, 120; SEDA-28, 140)
Nervous system A mixture of nitrous oxide and oxygen in equal proportions (“Entonox”) is an effective analgesic for short-term pain and is generally considered safe. However, it can cause damage to the spinal cord, mimicking subacute combined degeneration (17A ). • A 21-year-old man had a series of major operations for inflammatory bowel disease over 4 years— colectomy, ileostomy, and laparotomy, with the formation of an ileoanal pouch. He developed pelvic sepsis and an extensive perineal abscess had to be laid open. Postoperative analgesia proved difficult during daily changes of packs to the cavity. He was given regular paracetamol, diclofenac, and opioids. A 50:50 mixture of nitrous oxide and oxygen was used to manage acute pain. The hospital gave him a 300-litre cylinder of the mixture as a short-term arrangement over Christmas and issued increasing amounts over the next 4 months, resulting in weekly consumption of 1280 litres of the nitrous oxide mixture. He then developed progressive difficulty in walking over 6 weeks. He had severe pseudoathetosis of the fingers and arms, brisk reflexes, and normal bilateral flexor plantar responses. There was severe loss of joint position sense in the hands and feet and loss of vibration sense in all four limbs, with no spinothalamic sensory loss or truncal sensory level. There was a long lesion in the dorsal column, typical of subacute combined degeneration, on an MRI scan. Although his serum B12 concentration was normal, he was given hydroxocobalamin and at follow-up at 3 months he had no gait ataxia and normal hand function and was independent in all activities of daily living.
Sensory systems Nitrous oxide is 34 times more soluble than nitrogen in enclosed body cavity gas spaces and it enters such spaces rapidly, causing expansion and a rise in pressure. Vitreoretinal surgery often involves the
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use of intraocular gases to replace vitreous humor, in order to tamponade the neuroretina to the retinal pigment epithelium. Various longacting inert gases, such as sulfur hexafluoride or perfluoropropane, can be used as intraocular tamponading agents. Yet another case of blindness associated with nitrous oxide in a patient with an intraocular gas bubble has been reported, this time 37 days after vitreoretinal surgery (18A ), although it has been previously suggested that nitrous oxide is safe to use after 30 days. The author’s institution now insists that all such patients should have warning bracelets detailing the presence of intraocular gas, and that nitrous oxide be avoided until it has been demonstrated by an ophthalmologist that the gas bubble has been absorbed.
XENON
(SED-15, 3693; SEDA-27, 120; SEDA-28, 140)
In a prospective randomized study in 40 patients rocuronium neuromuscular block under either xenon anesthesia (delivered via a closed circuit) was compared with a standard propofol regimen (19C ). Xenon did not prolong neuromuscular block due to rocuronium.
INTRAVENOUS AGENTS. MISCELLANEOUS NON-BARBITURATE ANESTHETICS Ketamine (SED-15, 1964; SEDA-26, 135; SEDA-27, 120; SEDA-28, 141) Psychological Subanesthetic low-dose ketamine is being used increasingly often for acute pain therapy, day-case surgery, and chronic pain management. It is thought to cause delirium and disturbing dreaming. A systematic review of NMDA receptor antagonists in preventive analgesia has shown that only one of 20 studies documented adverse psychotomimetic effects attributable to ketamine (20M ). In that study, ketamine was given by the epidural route in a relatively high dose.
132 Gastrointestinal Ketamine is used as an oral premedication in many pediatric centers. Benzodiazepines are often co-administered. In an excellent randomized, double-blind study in 72 children from New Delhi the optimal dose of oral ketamine to add to midazolam in order to minimize adverse effects was assessed (21C ). The optimal regimen consisted of ketamine 3 mg/kg + midazolam 0.25 mg/kg. Excessive salivation was significantly more common in children who received the higher dose of 6 mg/kg.
Propofol
(SED-15, 2945; SEDA-26, 135; SEDA-27, 121; SEDA-28, 142) Nervous system Pain on injection is a sometimes severe adverse effect of propofol, and numerous strategies to prevent it have been tried. The effects of altering the lipid emulsion carrier have been analysed in four studies. In two prospective randomized studies in 222 and 80 patients respectively a modified lipid emulsion of propofol containing a mixture of medium-chain and long-chain triglycerides (MCT/LCT) has been compared with the usual formulation, which contains long-chain triglycerides (LCT) only (22C , 23C ). MCT/LCT propofol was equivalent to LCT propofol with lidocaine pretreatment. Lidocaine before MCT/LCT propofol confers an additional advantage. Another strategy has been to alter the amount of lipid in the emulsion. A lipid formulation (“Ampofor”) that contains 50% less soybean oil and egg lecithin (5% and 0.6% respectively) has been compared with the most commonly available propofol formulations in two randomized studies in 63 and 60 patients respectively (24C , 25C ). Ampofor was associated with an increased incidence of pain on injection. Pancreas Propofol is often the agent of choice in sedation of critically ill patients, particularly in neurological illnesses, as it allows rapid assessment on withdrawal. • A 27 year-old woman with pneumococcal meningitis developed pancreatitis after sedation with propofol (26A ). This resolved slowly after withdrawal of propofol.
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Metabolism Propofol infusion syndrome was discussed at length in SEDA-26, SEDA-27, and SEDA-28 (see also SED-15, 2948). It is a syndrome of myocardial failure (bradycardia, hypotension, low cardiac output), metabolic acidosis, and rhabdomyolysis, first described in children receiving high-dose propofol infusions for more than 48 hours in pediatric ICUs. Shortterm, low-dose infusions are usually thought to be safe. However, two cases of isolated severe lactic acidosis in adults during short-term (6–7 hours) propofol infusion sedation and anesthesia (infusion rates 1.5–7.5 mg/kg/hour) have been reported (27A , 28A ). Lactic acidosis resolved on withdrawal of propofol. These two reports were accompanied by an editorial, in which anesthesiologists were advised to check arterial blood gases and lactate concentrations in the event of unexpected tachycardia during propofol anesthesia (29r ). The authors concluded that in adults propofol can occasionally produce cytopathic hypoxia by impairing the electron transport chain or fatty acid oxidation. It has been proposed that the mechanism of propofol toxicity might be attributed to impaired fatty acid oxidation, causing increased concentrations of malonyl-carnitine and C5carnitine. Disturbed fatty acid oxidation might be caused by impaired entry of long-chain acylcarnitine ester into mitochondria. This, in turn, may be due to effects of propofol on mitochondrial electron transport, which has been shown in animals (particularly in cardiac myocytes). Support for this theory has been obtained in an investigation of the stored serum of a 5month-old child who developed life-threatening propofol infusion syndrome after a mean infusion rate of 11.7 mg/kg/hour for 62 hours (30A ). The baby recovered after withdrawal of propofol, charcoal hemoperfusion, and continuous venovenous hemofiltration. Serum samples taken while the baby was critically ill showed increased concentrations of acetyl and hydroxybutyryl species, with generalized increases in fatty acylcarnitine intermediates, especially medium-chain unsaturated and dicarboxylic species. A follow-up sample taken when the child had recovered was entirely normal. Propofol infusion syndrome might be precipitated by a combination of prolonged propofol infusion and carbohydrate intake insufficient to suppress fat metabolism. Support for this hypothesis has come from a case report of a child
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with catastrophic epilepsy who developed fatal propofol infusion syndrome after a ketogenic diet was introduced in an attempt to control severe intractable epilepsy (31A ). • A 10-year-old child had status epilepticus controlled with a combination of valproate, oxcarbazepine, and 48 hours of propofol infusion in a dose of 5.5 mg/kg/hour. After weaning from propofol, a classic ketogenic diet was instituted in an attempt to provide long-term control of the seizures. A day later status epilepticus recurred and propofol was restarted at a rate of 6–9 mg/kg/hour to suppress seizure activity (the diet, valproate, and oxcarbazepine were also continued). Shortly thereafter, he developed the classical constellation of malignant ventricular arrhythmias, hyperlipidemia, rhabdomyolysis, lactic acidosis, and biventricular cardiac failure. He did not survive.
The use of extracorporeal cardiac support in the successful management of the cardiac failure associated with propofol infusion syndrome has been described (32A ).
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• A 13-year-old boy underwent a 17-hour craniotomy in an attempt to resect an arteriovenous malformation with propofol-based anesthesia. He developed frank propofol infusion syndrome after 74 hours of postoperative propofol sedation in the neurosurgical ICU (used to manage intracranial hypertension). Echocardiography showed severe biventricular dysfunction despite extraordinary pharmacological support. Extracorporeal circulation with membrane oxygenation (ECMO) was instituted at the bedside via cannulation of the left femoral vessels. Hemofiltration was added to the circuit. ECMO was discontinued 60 hours later, as there was normal ventricular function on echocardiography. He made a full recovery and returned to school.
Several case reports have ascribed survival to the early use of hemofiltration, but this case shows that very aggressive invasive cardiovascular support can also be useful.
References 1. Chen SC, Rex DK. Review article: registered nurse-administered propofol sedation for endoscopy. Aliment Pharmacol Ther 2004;19:147– 55. 2. Yussoff IF, Raymond G, Sahai AV. Endoscopist administered propofol for upper-GI EUS is safe and effective: a prospective study in 500 patients. Gastrointestinal Endoscopy 2004;60:356–60. 3. Bouvet L, Allaouchice B, Duflo F, Debon R, Chassard D, Boselli E. Remifentanil is an effective alternative to propofol for patient-controlled analgesia during digestive endoscopic procedures. Can J Anesth 2004;51:122–5. 4. Tobias JD, Berkenbosch JW. Sedation during mechanical ventilation in infants and children: dexmedetomidine versus midazolam. Southern Med J 2004;97:451–5. 5. Luntz SP, Janitz E, Motsch J, Bach E, Böttiger BW. Cost-effectiveness and high patient satisfaction in the elderly: sevoflurane versus propofol anaesthesia. Eur J Anaesthesiol 2004;21:115– 22. 6. Yildrim H, Adanir T, Atay A, Kataricioglu K, Savaci S. The effects of sevoflurane, isoflurane and desflurane on QT interval of the ECG. Eur J Anaesthesiol 2004;21:566–70. 7. Sen S, Ozmert G, Boran N, Turan H, Caliskan E. Comparison of the effects of single-breath vital capacity rapid inhalation with sevoflurane
8.
9.
10. 11.
12.
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5% and propofol induction on QT interval and haemodynamics for laparoscopic surgery. Eur J Anaesthesiol 2004;21:543–6. Weldon BC, Bell M, Craddock T. The effect of caudal analgesia on emergence agitation in children after sevoflurane versus halothane anesthesia. Anesth Analg 2004;98:321–6. Ibacache ME, Munoz HR, Brandes V, Morales AL. Single-dose dexmedetomidine reduces agitation after sevoflurane anesthesia in children. Anesth Analg 2004;98:360–3. Hsieh S-W, Lan K-M, Luk H-N, Jawan B. Postoperative seizures after sevoflurane anesthesia in a neonate. Acta Anaesthesiol Scand 2004;48:663. Iohom G, Gardiner C, Whyte A, O’Connor G, Shorten G. Abnormalities of contrast sensitivity and electroretinogram following sevoflurane anaesthesia. Eur J Anaesthesiol 2004;21:646–52. Fukuda H, Kawamoto M, Yuge O, Fuji K. A comparison of the effects of prolonged (>10 hour) low-flow sevoflurane, high-flow sevoflurane and low-flow isoflurane anesthesia on hepatorenal function in orthopaedic patients. Anesth Intensive Care 2004;32:210–8. Reich A, Everding AS, Bulla M, Brinkmann OA, Van Aken H. Hepatitis after sevoflurane exposure in an infant suffering from primary hyperoxaluria type 1. Anesth Analg 2004;99:370–2.
134 14. Pantucharoensri S, Boontee P, Likithsan P, Padungtod C, Prasartsansoui S. Generalized eruption accompanied by hepatitis in two Thai metal cleaners exposed to trichloroethylene. Industrial Health 2004;42:385–8. 15. Yauck JS, Malloy ME, Blair K, Simpsin P, McCarver DG. Proximity of residence to trichloroethylene-emitting sites and increased risk of offspring congenital heart defects among older women. Birth Defects Res (Part A) 2004;70:808–14. 16. Bolt HM, Lammert M, Selinski S, Bruning T. Urinary α1-microglobulin as biomarker of renal toxicity in trichloroethylene-exposed persons. Int Arch Occup Environ Health 2004;77:186–90. 17. Doran M, Rassam SS, Jones LM, Underhill S. Toxicity after intermittent inhalation of nitrous oxide for analgesia. BMJ 2004;328:1364–5. 18. Lee EJK. Use of nitrous oxide causing severe visual loss 37 days after retinal surgery. Br J Anaesth 2004;93:464–6. 19. Kunitz O, Baumert J-H, Hecker K, Beeker T, Coburn M, Zuhlsdorff A, Rossaint R. Xenon does not prolong neuromuscular block of rocuronium. Anesth Analg 2004;99:1398–401. 20. McCartney C, Sinha A, Katz J. A qualitative systematic review of N-methyl-D-aspartate receptor antagonists in preventive analgesia. Anesth Analg 2004;98:1385–400. 21. Darlong V, Shende D, Subramanyam MS, Sunder R, Naik A. Oral ketamine or midazolam or low dose combination for premedication children. Anaesth Intensive Care 2004;32:246–9. 22. Adam S, von Bommel J, Pelka M, Dirckx M, Jonsson D, Klein J. Propofol-induced injection pain: comparison of a modified propofol emulsion to standard propofol with premixed lidocaine. Anesth Analg 2004;99:1076–9. 23. Kunitz O, Losing R, Schulz-Stubner S, Haafvon-Below S, Rossaint R, Kuhlen R. PropofolLCT versus propofol MCT/LCT with or with-
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25.
26.
27.
28.
29. 30. 31.
32.
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out lidocaine—a comparison on pain on injection. Anaesthesiol Intensivmed Notfallmed Schmerzther 2004;39:10–4. Song D, Hamza MA, White PF, Byerly SI, Jones SB, Macaluso AD. Comparison of a lowerlipid propofol emulsion with the standard emulsion for sedation during monitored anesthesia care. Anesthesiology 2004;100:1072–5. Song D, Hamza MA, White PF, Klein K, Recart A, Khodaparasat O. The pharmacodynamic effects of a lower-lipid emulsion of propofol: a comparison with the standard propofol emulsion. Anesth Analg 2004;98:687–91. Manfredi R, Dentale N, Fortunato L, Pavoni M, Calza L, Chiodo F. Pancreatoxicity of propofol sedation during purulent meningitis. Clin Drug Invest 2004;24:181–3. Burow BK, Johnson ME, Packer DL. Metabolic acidosis associated with propofol in the absence of other causative factors. Anesthesiology 2004;101:239–41. Salengros J-C, Velghe-Lenelle C-E, Bollens R, Engelman E, Barvais L. Lactic acidosis during propofol–remifentanil anesthesia in an adult. Anesthesiology 2004;101:243–5. Funston JS, Prough DS. Two reports of propofol anesthesia associated with metabolic acidosis in adults. Anesthesiology 2004;101:6–8. Withington DE, Decell MK, Al Ayed T. A case of propofol toxicity: further evidence for a causal mechanism. Pediatr Anesth 2004;14:505–8. Baumeister FAM, Oberhoffer R, Liebhaber GM, Kunkel J, Eberhardt J, Holthausen H, Peters J. Fatal propofol infusion syndrome in association with ketogenic diet. Neuropediatrics 2004;35:250–2. Culp KE, Augoustides JG, Ochroch AE, Milas BL. Clinical management of cardiogenic shock associated with prolonged propofol infusion. Anesth Analg 2004;99:221–6.
Stephan A. Schug, Per Flisberg, Irina Kurowski, and Thomas Ledowski
11 GENERAL TOPICS
Local anesthetics (SED-15, 2116)
Immunologic Although rare, contact allergy to amide local anesthetics, with cross-reactivity amongst members of the group, has been reported before.
EFFECTS RELATED TO MODES OF USE (SED-15, 2121) Brachial plexus anesthesia Cardiovascular Transient vascular insufficiency has been reported after axillary brachial plexus block (3A ).
• A 54-year-old woman developed a type IV hypersensitivity reaction to lidocaine 2% and mepivacaine 2% on two separate occasions (1A ). Skin patch tests showed positive reactions at 48 and 96 hours to both agents and cross-reactivity to bupivacaine and prilocaine.
• In a 3-year-old child, an axillary plexus block using 7 ml of bupivacaine 0.5% and 3 ml of lidocaine 2% with adrenaline 1:200 000 was established to allow re-implantation of an amputated thumb. After the injection, the hand became pale and no pulses were palpable; 15 minutes later the color and pulses returned.
Administration route When injecting local anesthetics to achieve regional blockade, a test dose is recommended in order to exclude intravascular placement of the needle or catheter. However, newer local anesthetics such as ropivacaine and levobupivacaine are supposed to have less systemic toxicity than bupivacaine. A study was therefore undertaken in 120 patients to determine whether test doses of these agents cause sufficient nervous system symptoms to identify accidental intravenous injection (2C ). The patients were randomized to one of four different intravenous treatments: saline, 2% lidocaine (100 mg), 0.5% ropivacaine (25 mg), or 0.5% levobupivacaine (25 mg). Compared with ropivacaine and levobupivacaine, lidocaine caused more reliably recognizable nervous system symptoms. The authors therefore could not recommend plain ropivacaine or levobupivacaine for test dose purposes.
The author noted that this is a rare event, with only one previous published report, and proposed that several mechanisms may have been causative: intra-arterial adrenaline or local anesthetic, mechanical obstruction from subintimal injection into the arterial wall, severe vasospasm, and a pressure effect in the axillary sheath.
Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29011-1 © 2007 Elsevier B.V. All rights reserved.
Epidural and spinal anesthesia Epidural anesthesia Cardiovascular A common adverse effect of epidural anesthesia is hypotension due to functional hypovolemia. It is usually treated with intravenous fluids and/or vasopressors. In order to validate the changes in intravascular volumes after thoracic epidural anesthesia over a longer time, a study was undertaken in 12 healthy volunteers, who were randomized to receive either colloidal fluid (hydroxyethyl starch 7 ml/kg) or a vasopressor (ephedrine 0.2 mg/kg) 90 minutes after the administration of 10 ml of bupivacaine 0.5% through a thoracic epidural inserted at T7–10 (4c ). Thoracic epidural anesthesia in itself did not lead to any
135
136 changes in blood volume, despite a fall in blood pressure. The authors concluded that fluid administration leads to dilution and recommended that hydroxyethyl starch may be preferred to ephedrine in patients with cardiopulmonary disease, in order to avoid perioperative fluid overload. In a randomized, double-blind study of the cardiovascular effects and neonatal outcome of epidural blockade in healthy parturients scheduled for elective cesarean section, the patients were allocated to receive either epidural ropivacaine 0.75% or bupivacaine 0.5% (5C ). The two agents produced equally satisfactory blockade, but ropivacaine 0.75% produced a more pronounced reduction in maternal heart rate. However, this had no effect on neonatal outcome. The authors concluded that both bupivacaine 0.5% and ropivacaine 0.75% could be recommended for epidural anesthesia in elective cesarean section. Respiratory During pregnancy and labor there are important respiratory changes. In a prospective study to clarify whether minor motor blockade brought on by lumbar epidural anesthesia in laboring women further compromises respiratory function, 60 parturients received lumbar epidural anesthesia at L2–4 (6C ). After a test dose of 3 ml of lidocaine 2% and then a total dose of 10–15 ml of bupivacaine 0.125%, followed by a bolus of fentanyl 50 micrograms, a continuous infusion of 10 ml/hour of bupivacaine 0.125% with fentanyl 0.0001% was started, when a sensory blockade at T10 was reached. Most of the patients (87%) had significant improvements in respiratory function, suggesting benefits of epidural analgesia in parturients. Nervous system Three case reports have illustrated the neurological consequences of epidural anesthesia in predisposed patients (7A – 9A ). • A 51-year-old man, ASA grade II, with noninsulin-dependent diabetes, underwent radical prostatectomy and enterocystoplasty under general anesthesia, before which a lumbar epidural catheter was inserted at L3–4 but was not used during surgery (7A ). In the recovery room, a test dose of 3 ml of lidocaine 1% with adrenaline 1:200 000 was administered, followed by a bolus dose of 10 ml of ropivacaine 0.75%, which resulted in a block that reached T10. One hour later an infusion of ropivacaine 0.2% was started at 5 ml/hour. Ten hours later he complained of pain, and the
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pump rate was increased to 10 ml/hour. The treatment continued for 72 hours without any more dosage adjustments. Eight hours after the end of the epidural treatment he described a burning sensation and pain in the back, spreading to the legs and feet. These symptoms increased with movement but there were no motor abnormalities. The symptoms persisted and electromyography showed a sensory polyneuropathy in all four limbs. Eight weeks after the operation he described diminished pain and paresthesia.
The author suggested that local anesthesia in patients with pre-existing diabetic polyneuropathy may result in additional ischemic insult and intraneural edema. Patients with diabetes may therefore be at higher risk of local anesthetic toxicity. • A 64-year-old man, with a history of multiple spinal surgery, chronic low-back pain, and a transient cauda equina syndrome after the most recent operation, was scheduled to receive a transforaminal epidural injection (8A ). A left L2 transforaminal epidural injection was attempted unsuccessfully. A further attempt at left L1 transforaminal was successful, and 5 ml of bupivacaine 0.125% and 40 mg of triamcinolone was injected. Two minutes after the injection the patient became paralysed in his legs. An MRI scan showed signal changes consistent with acute spinal infarction. Four years later he showed no improvement.
Direct injury to the vascular supply of the spinal cord may have been one explanation for this adverse outcome; other reasons included vasospasm caused by either bupivacaine or the glucocorticoid, end-capillary occlusion by glucocorticoid particles, or needle-related factors. • A 27-year-old primipara was admitted to hospital at week 36 because of a 10-day history of progressive weakness and numbness in all limbs (9A ). Gullain–Barré syndrome was diagnosed and she was given large doses of intravenous immunoglobulin. Her neurological symptoms improved after 5 days. Five weeks later she spontaneously delivered under epidural analgesia (L2–3), after a test dose of 3 ml of lidocaine 2% with 1:200 000 adrenaline and then 25 ml of ropivacaine 0.2% with 16 micrograms of sufentanil over 3 hours. At this stage she had increased sensory and motor block. Twelve hours postpartum she was unable to walk and had augmented symptoms from the arms together with facial weakness. She was given large doses of intravenous immunoglobulin. Four months later her status had improved but she still depended on a walker.
The authors speculated that the worsening of the patient’s symptoms could have been due to
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local anesthetic toxicity, since local anesthetics can cause morphological changes in neurons in vitro, impairing their growth.
Intrathecal (spinal) anesthesia Cardiovascular The adverse effects of spinal anesthesia have been evaluated in a large prospective study in 1132 children aged 6 months to 14 years undergoing lower body surgery (10C ). Spinal blocks were performed with 0.5% bupivacaine at doses of 0.2 mg/kg at interspace L3–4 or L5–S1. Only 27 patients required some form of anesthetic supplementation. There was hypotension in 17 patients. The incidence of headache (n = 5) and low back pain (n = 9) was low. There were no other neurological complications. Cerebral blood flow has been evaluated prospectively in former preterm infants who underwent inguinal hernia repair with spinal anesthesia (11c ). There was a significant reduction in diastolic cerebral blood flow velocities, explained by reduced arterial blood pressure secondary to spinal anesthesia and impaired cerebral autoregulation. However, the clinical relevance of these findings is unclear. Nervous system A technique for the reversal of an unintentional total spinal anesthetic has been described (12A ). The epidural catheter, positioned in the intrathecal space, was used to wash out the overdose of local anesthetic by “cerebrospinal lavage,” leading to rapid recovery. A toxic spinal cord lesion after long-term treatment of chronic pain via an intrathecal catheter has not previously been described (13A ). • A 45-year-old man with severe right sciatic trunk compression neuropathy had a programmable pump system implanted, connected to a catheter in the intrathecal space advanced to level of T12. The pump delivered bupivacaine in a concentration of 20 then 40 mg/ml, at daily doses of 24–27 mg for 459 days. After 13 months reduced efficacy made it necessary to add clonidine 200 micrograms/day. This combination continued for the next 600 days. After nearly 3 years the patient developed lower back pain and neurological symptoms, including gait ataxia and loss of proprioception. An MRI scan showed a small round cavity within the spinal cord associated with widespread cord
137 edema. Three months later a scan showed complete resolution of the medullary edema accompanied by marked improvement of neurological function. However, a centromedullary lesion at T9 and a hyperdense posterolateral lesion at T10–11 persisted.
The authors were unable to suggest a precise cause of this complication, but discussed potential neurotoxic effects of bupivacaine, possibly related to high local concentrations. This case reinforces recommendations to keep drug concentrations low in these cases and that patients with intrathecal drug systems should have brief neurological evaluations at every pump refill. The preservatives in 2-chloroprocaine are thought to cause transient neurological symptoms after intrathecal administration. A preservative-free formulation of 2-chloroprocaine is now becoming available. It may be a serious contender for drug of choice in short-acting spinal anesthesia and might even replace lidocaine. In three different studies the same group of investigators has addressed spinally administered preservative-free 2-chloroprocaine. Chloroprocaine was compared with lidocaine in a double-blind, randomized, crossover study (14C ). Eight healthy volunteers each received two spinal anesthetics, one with 2% lidocaine (40 mg) and the other with 2% 2chloroprocaine (40 mg). Chloroprocaine produced an anesthetic effect similar to that of lidocaine, but with significantly faster resolution of the block. In seven of the eight subjects lidocaine produced mild transient neurological symptoms whereas in the chloroprocaine group there were no such complaints. In a dose-ranging, randomized, crossover study, three different doses of 2-chloroprocaine (30, 45, and 60 mg), with or without added adrenaline, were compared in healthy volunteers (15C ). The authors estimated that the appropriate dose range of preservative and antioxidant-free 2-chloroprocaine for spinal anesthesia is 30–60 mg. Eleven of 18 administrations of 2-chloroprocaine with adrenaline led to flu-like symptoms, while there were no such complaints with 2-chloroprocaine alone; the authors advised against using this adjuvant. In a randomized, double blind, crossover study, 2-chloroprocaine spinal anesthesia was performed with or without dextrose in eight healthy volunteers (16C ). Each volunteer received two spinal anesthetics using 2 ml of 2-chloroprocaine 2% (40 mg) with 0.25 ml of
138 saline or 0.25 ml of dextrose 10%. Spinal anesthesia was successful in all subjects. The addition of dextrose did not significantly change the characteristics of the spinal block, but increased residual bladder dysfunction. Fetotoxicity Severe prolonged fetal bradycardia has been observed after intrathecal injection as a component of combined spinal epidural anesthesia in labor (17A ). • A healthy 21-year-old gravida 1, para 0 at 39 weeks gestation, with an uncomplicated pregnancy, received combined spinal epidural anesthesia at the level of L2–3, with a combined dose of bupivacaine 2.5 mg (1 ml of 2.5 mg/ml) and fentanyl 5 micrograms; 5 minutes later there was severe fetal bradycardia. An emergency caesarean section under general anesthesia was undertaken. Maternal and neonatal postoperative courses were uneventful.
In this case the maternal vital signs were stable and there was no circulatory hypotension and no uterine hypertonia. The exact mechanism of this severe fetal bradycardia was unclear. The author stated that fetal bradycardia should be recognized as a complication after subarachnoid administration of lipid soluble opioids and local anesthetics.
Dental anesthesia Immunologic True allergic reactions to amide local anesthetics are extremely rare. Anaphylaxis after local lidocaine administration has been reported (18A ). • A 4-year-old child, previously healthy, received an intrapulpal injection of 0.5 ml of lidocaine 2% with 1:100 000 adrenaline for a dental procedure; 15 minutes later he become severely cyanotic and short of breath and had a respiratory arrest and sinus bradycardia. Cardiopulmonary resuscitation was started immediately, followed by rapid blood volume expansion and adrenaline administration. After 24 hours his vital signs stabilized and he recovered completely.
Allergic reactions to unit-to-use lidocaine dental cartridges and reusable vials can occur because of preservatives such as parabens. However, in this case the preservative was sodium sulfite, which has not been reported to cause anaphylactic reactions. The cause of the anaphylaxis was not determined in this case, as the parents refused tests.
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Infiltration anesthesia Forty adverse events during direct local anesthetic infusion into surgical wounds have been reported to the US FDA (19A ). These reports included 17 cases of necrosis, 13 cases of cellulitis, 15 surgical wound infections, and 10 unspecified infections. Of four patients who received bupivacaine and adrenaline as continuous wound infiltration after total knee procedures, two developed full thickness sloughs and two developed partial thickness sloughs; all required plastic surgical intervention. In their discussion, the FDA pointed out that these reports are not verified regarding their accuracy and completeness. The authors concluded that, at the moment, these reports do not establish a causal link between surgery, the use of an infusion device or the infusion of bupivacaine, with or without adrenaline, and the adverse event. Nevertheless the reports are considered to be an important signal, suggesting the need for further investigation. Infection risk Ischemic tissue necrosis and a staphylococcal wound infection occurred in a 26-year-old woman after bunionectomy; a continuous infusion of bupivacaine (2 ml/ hour) was administered through a catheter as a continuous infusion into the wound.
Intravenous regional anesthesia Nervous system A mixture of lidocaine and clonidine resulted in seizures when used for a Bier block (20A ). • Lidocaine 150 mg with clonidine 30 micrograms was used for intravenous regional anesthesia to treat a complex regional pain syndrome type I of the arm in a 47-year-old man. The tourniquet was deflated 60 minutes after the injection. Ten minutes later he felt unwell and had rhythmic clonic movements accompanied by altered consciousness and vocal automatism. During the next 2 hours he had five similar episodes, which were interpreted as complex partial seizures.
Seizures are a well-known complication of intravenous injection of local anesthetics; by blocking voltage-gated sodium channels lidocaine reduces neuronal excitability. Clonidine may reduce the threshold for seizures further
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by reducing the availability of noradrenaline in central structures, although the mechanism of this interaction is not fully understood.
Leg block Musculoskeletal Avulsion of the Achilles tendon followed diagnostic tibial nerve block for spastic equinovarus (21A ). • A 67-year-old woman with a 3-year history of left hemiplegia secondary to a hemorrhagic stroke underwent diagnostic tibial nerve block to confirm Achilles tendon shortening due to spasticity. A posterior popliteal fossa approach using nerve stimulation was used, resulting in a successful block. However, avulsion of the Achilles tendon with an avulsion fracture of the osteoporotic calcaneum occurred on first contact of the foot with the ground. She was treated conservatively and was asymptomatic 4 months later.
The authors suggested that the tibial nerve block had suppressed the spasticity and weakened the triceps surae muscle, resulting in an increase in passive tension of the Achilles tendon. This increase in tension exceeded the mechanical strength of the tendon, resulting in the avulsion injury.
Ocular anesthesia Sensory systems Contralateral amaurosis and third nerve palsy has been described after retrobulbar anesthesia (22A ). • An 84-year-old woman received a retrobulbar block of the right eye with 3.5 ml of lidocaine 2% for cataract surgery and 15 minutes later stated that she could not see from the other eye. On examination after surgery, the left eye had very limited motility and a wide pupil unreactive to light. Over the next 2 hours her visual acuity improved to baseline without treatment.
The authors proposed that injection of local anesthetic into the subdural space of the optic nerve sheath was the underlying mechanism. They suggested that the local anesthetic had tracked along the ipsilateral optic nerve sheath posteriorly within the subdural space to the area of the chiasma, where it had compromised function of the contralateral optic nerve and the third cranial nerve.
Musculoskeletal A series of 26 patients with persistent diplopia after retrobulbar anesthesia was carefully examined (23c ). The authors suggested that direct muscle trauma caused by the injection needle or myotoxicity of the local anesthetics (either lidocaine 2%, a mixture of lidocaine 2% and 4%, or a mixture of lidocaine 2% and bupivacaine 0.75%) could have caused the muscular imbalance in half of the cases. However, they also mentioned other causes, including surgical trauma or adhesions caused by gentamicin sulfate-derived inflammation. A similar case report of diplopia due to motility disturbance of the inferior oblique muscle after retrobulbar anesthesia has been reported (24A ). The authors suggest either damage caused by the needle tip or myotoxicity of the local anesthetic (a 4 ml mixture of lidocaine 2%, bupivacaine 0.5%, and 5 units of hyaluronidase) as the most likely explanations. In contrast, in another study there were no myotoxic effects in 13 patients after retrobulbar block using lidocaine 2% compared with a control group who had topical anesthesia, despite the use of a sensitive tool (saccadic velocity) (25c ). Drug abuse A 47-year-old patient with systemic lupus erythematosus and a corneal ulcer was given oxybuprocaine 0.05% qds, but instead used it every 5–10 minutes (26A ). Two weeks later she developed a toxic keratopathy with persisting lesions for 6 months. The authors concluded that local anesthetics should not be prescribed for patients with dry eyes especially when the integrity of the ocular surface is altered.
Topical anesthesia A new topical formulation of a local anesthetic, ELA-max (4% or 5% lidocaine cream), has been reviewed and compared with emla for pediatric use (27R ). The author concluded that ELA-max has similar efficacy to emla and two main advantages: faster onset of action and a reduced risk of methemoglobinemia. Although up to now only minor adverse effects, such as erythema, have been reported, the author pointed out that there is insufficient current experience with the new formulation, compared with the widely used emla, and that significant adverse effects cannot be ruled out.
140 Respiratory There has been a report of total airway obstruction after topical anesthesia of the larynx before fiberoptic intubation (28A ). • A 69-year-old man with a neck cancer had inspiratory and expiratory stridor, and it was decided to perform an awake fiberoptic intubation. Four minutes after topicalization of the larynx using 7.5 ml of lidocaine 2%, he had total airway obstruction. An attempt at cricothyroidotomy failed, but oral fiberoptic intubation finally succeeded. The vocal cords were abducted and not swollen.
The authors speculated that either laryngospasm or depression of laryngeal muscle tone due to the use of lidocaine could have caused the sudden obstruction. Nervous system Transient cerebellar ataxia a few minutes after the topical use of lidocaine on mucosal surfaces has been described in two patients, a 58-year-old man who had lidocaine 10% spray for bronchoscopy and a 66-yearold woman who received lidocaine 2% orally for transesophageal echocardiography (29A ). In neither case was another cause of cerebellar ataxia identified. The second patient had previously had a similar reaction to lidocaine. Hematologic Methemoglobinemia with systemic toxicity has been reported after the use of emla cream (lidocaine + prilocaine). • A 30-year-old woman who came for laser epilation of the legs had successfully undergone the same procedure 1 week before (30A ). One hour before the procedure, a total of 150 g of emla (5 tubes, 30 g per tube) was applied to both legs under occlusive dressing. About 2 hours later she developed symptoms of systemic toxicity, including light-headedness, numbness of the tongue, muscle twitching, and dyspnea. She had a methemoglobin concentration of 20% and was given methylthioninium chloride (methylene blue) 50 mg intravenously.
The authors suggested that increased absorption of emla could have been due to a coincidence of circumstances; thermal injury from the first and current procedures and the occlusive dressing. Furthermore, higher concentrations of unbound lidocaine caused by contraceptive medication and inhibition of cytochrome P450 by sertraline could have produced increased plasma concentrations of lidocaine and prilocaine. In conclusion, excessive application of emla to damaged skin should be avoided.
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• A 3-year-old child had a seizure and methemoglobinemia (18%) after the use of emla (5 g spread on an area of about 1140 cm2 on the back before allergy testing) (31A ).
This case differed from previous ones in that a reasonable amount of emla was used on normal skin. Skin In two patients the use of emla cream before skin biopsy resulted in the misdiagnosis of a lysosomal storage disease, because of ultrastructural features in the biopsy (32A ). When repeated without emla, the skin biopsies looked normal.
INDIVIDUAL COMPOUNDS Articaine
(SED-15, 348)
Skin A fixed drug eruption has been described after the use of articaine (33A ). • A 45-year-old woman noted dark red plaques after dental treatment with articaine local anesthesia on seven occasions over 8 years. The lesions developed within 8–12 hours after drug exposure and resolved spontaneously over the next 14 days. Skin prick and patch tests were negative. However, subsequent subcutaneous provocation tests and skin biopsies were consistent with a diagnosis of fixed drug eruption.
The authors noted that this is the first documented report of articaine-inducing fixed drug eruption; two previous reports have implicated mepivacaine and lidocaine.
Benzocaine
(SED-15, 427; SEDA-26, 144; SEDA-28, 150)
Hematologic Methemoglobinemia has often been reported after topical use of benzocaine (34A –39A ). In a review of 198 reports to the FDA of adverse events related to benzocaine 67% involved methemoglobinemia; 101 were serious and two were fatal (40R ). Benzocaine spray was most commonly implicated (93%). In one case, oral application of 20% benzocaine resulted in acute respiratory failure requiring mechanical ventilation for 2 days, although
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methemoglobin concentrations returned to normal 13 hours after treatment with methylthioninium chloride (39A ). In another case there was rebound methemoglobinemia after treatment with methylthioninium chloride (37A ). The authors pointed out that clinicians have to be aware that a falling concentration of methemoglobin does not necessarily indicate successful treatment. High doses of benzocaine or later release from fat tissue can cause life-threatening rebound effects after the initial dose of methylthioninium chloride and continuing monitoring is required until methemoglobin concentrations have returned to normal.
Bupivacaine (SED-15, 568; SEDA-27, 131; SEDA-28, 150) Cardiovascular Fatal bupivacaine toxicity occurred after recreational use by injection into the external genitalia for autoerotic purposes (41A ). Methods of mitigating bupivacaine cardiotoxicity have been investigated in animals. Insulin–dextrose–potassium infusion was extremely successful in the treatment of bupivacaine-induced cardiotoxicity in dogs—all those who were treated survived, while the controls all developed irreversible cardiac arrest (42E ). In contrast, clonidine pre-treatment did not alter bupivacaine cardiotoxicity or resuscitatability in rats (43E ).
Cetacaine Hematologic There have been reports of methemoglobinemia after topical use of cetacaine (44A , 45A ).
Chloroprocaine
(SED-15, 721)
Cardiovascular Cardiotoxicity occurred in a 2-month-old child after accidental intravenous injection of 2-chloroprocaine via an epidural catheter (46A ).
• A 2-month-old child (4 kg) was given 4 ml of 2chloroprocaine 3% via an epidural catheter, which had been placed via the caudal approach with a negative aspiration test. The child immediately developed a broad-complex bradycardia, which terminated spontaneously after 30 seconds. The catheter was left in situ and intravenous placement was confirmed by contrast dye injection.
The authors noted that this was the first published report of cardiotoxicity after inadvertent intravenous injection of an ester local anesthetic, since it was presumed that rapid metabolism of the drug by plasma cholinesterases results in minimal toxicity. Consistent with established practice, they recommended using an epidural test dose to rule out intravascular placement of the epidural catheter, and to give the local anesthetic slowly and incrementally.
Cocaine
(SED-15, 848; see also
Chapter 4) Most of the adverse effects of cocaine that are encountered in emergency departments are systemic from drug abuse. However, some local anesthetic ones have been reported. Nervous system Genitoperineal numbness has been described after recreational use of cocaine per rectum (47A ). • A 42-year-old man developed numbness of the penis and scrotum, with altered anal sphincter sensation, 2 hours after using cocaine per rectum. His symptoms resolved spontaneously within 4 hours.
The authors suggested that the per rectum route had resulted in anesthesia of the pudendal nerve, and that circulatory vasoconstriction may also have played a part in causing these symptoms. Sexual function Superficial penile necrosis has been reported after topical application of cocaine (48A ). • A 32-year-old man developed black, painful lesions over his penis after applying cocaine to the glans penis 5 days before. He was given antibiotics and the lesions healed completely.
The authors suggested that the necrotic lesions had been secondary to dermal vasoconstriction caused by cocaine.
142
Lidocaine
(SED-15, 2051; SEDA-26, 146; SEDA-27, 133; SEDA-28, 152)
Nervous system Euphoria in two cases was an early sign of lidocaine toxicity and preceded the development of classical early signs of local anesthetic neurotoxicity, such as tinnitus, diplopia, and tongue numbness (49A ). A generalized seizure occurred after a 4.5 kg infant was given excess lidocaine 1% for dorsal penile nerve block performed for circumcision (50A ). The authors remarked on the extra care required when administering local anesthetics to infants, as the maximum safe doses are readily attained.
Ropivacaine (SED-15, 3078; SEDA-26, 147; SEDA-27, 134; SEDA-28, 152) Drug administration route There have been two reports of patients who accidentally received ropivacaine intravenously from a bag of ropivacaine intended for postoperative epidural use (51A , 52A ). • A 36-year-old man, ASA grade I, received 200 ml of ropivacaine 0.15% (300 mg = 4.6 mg/kg) after hip arthroplasty (51A ). The patient developed tonic-clonic convulsions, hypotension, and respiratory arrest; 20 minutes later the plasma ropivacaine concentration was 3.10 µg/ml. There were no dysrhythmias. Recovery was uneventful.
Chapter 11
Stephan A. Schug et al.
This is the first report in which ropivacaine has been administered directly through an intravenous line. The authors used a pharmacokinetic model to estimate the plasma ropivacaine concentration at the time of the seizure to have been 17 µg/ml, which is above the range of experimental human threshold for nervous system toxicity. • In an incident based on a similar error, an 84-yearold woman received ropivacaine 380 mg inadvertently by intravenous infusion over 1.75 hours (52A ). Despite serum concentrations in the lower toxic range, the patient had no signs of nervous system or cardiovascular toxicity, confirming the assumed wide therapeutic range for ropivacaine.
Tetracaine
(SED-15, 3327)
Immunologic Allergic dermatitis has been reported after repeated contact with tetracaine, this time in the beauty industry (53A ). This case highlights the importance of educating employees in the health and beauty industry to increase their awareness of potentially sensitizing agents, including local anesthetics. The authors mentioned the lack of data on the penetration rates of some topical formulations through gloves.
References 1. Duque S, Fernandez L. Delayed-type hypersensitivity to amide local anesthetics. Allergol Immunopathol (Madr) 2004;32(4):233–4. 2. Owen MD, Gautier P, Hood DD. Can ropivacaine and levobupivacaine be used as test doses during regional anesthesia? Anesthesiology 2004;100(4):922–5. 3. Bhat R. Transient vascular insufficiency after axillary brachial plexus block in a child. Anesth Analg 2004;98(5):1284–5. 4. Holte K, Foss MB, Svensen C, Lund C, Madsen JL, Kehlet H. Epidural anesthesia, hypotension, and changes in intravascular volume. Anesthesiology 2004;100(2):281–6.
5. Kampe S, Tausch B, Paul M, Kasper SM, Bauer K, Diefenbach C, Kiencke P. Epidural block with ropivacaine and bupivacaine for elective caesarean section: maternal cardiovascular parameters, comfort and neonatal well-being. Curr Med Res Opin 2004;20(1):7–12. 6. von Ungern-Sternberg BS, Regli A, Bucher E, Reber A, Schneider MC. The effect of epidural analgesia in labour on maternal respiratory function. Anaesthesia 2004;59(4):350–3. 7. Al-Nasser B. Toxic effects of epidural analgesia with ropivacaine 0.2% in a diabetic patient. J Clin Anesth 2004;16(3):220–3.
Local anesthetics
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8. Huntoon MA, Martin DP. Paralysis after transforaminal epidural injection and previous spinal surgery. Reg Anesth Pain Med 2004;29(5):494– 5. 9. Wiertlewski S, Magot A, Drapier S, Malinovsky JM, Pereon Y. Worsening of neurologic symptoms after epidural anesthesia for labor in a Guillain–Barré patient. Anesth Analg 2004;98(3):825–7. 10. Puncuh F, Lampugnani E, Kokki H. Use of spinal anaesthesia in paediatric patients: a single centre experience with 1132 cases. Paediatr Anaesth 2004;14(7):564–7. 11. Bonnet MP, Larousse E, Asehnoune K, Benhamou D. Spinal anesthesia with bupivacaine decreases cerebral blood flow in former preterm infants. Anesth Analg 2004;98(5):1280–3. 12. Tsui BC, Malherbe S, Koller J, Aronyk K. Reversal of an unintentional spinal anesthetic by cerebrospinal lavage. Anesth Analg 2004;98(2):434– 6. 13. Perren F, Buchser E, Chedel D, Hirt L, Maeder P, Vingerhoets F. Spinal cord lesion after long-term intrathecal clonidine and bupivacaine treatment for the management of intractable pain. Pain 2004;109(1–2):189–94. 14. Kouri ME, Kopacz DJ. Spinal 2-chloroprocaine: a comparison with lidocaine in volunteers. Anesth Analg 2004;98(1):75–80. 15. Smith KN, Kopacz DJ, McDonald SB. Spinal 2-chloroprocaine: a dose-ranging study and the effect of added epinephrine. Anesth Analg 2004;98(1):81–8. 16. Warren DT, Kopacz DJ. Spinal 2-chloroprocaine: the effect of added dextrose. Anesth Analg 2004;98(1):95–101. 17. Kuczkowski KM. Severe persistent fetal bradycardia following subarachnoid administration of fentanyl and bupivacaine for induction of a combined spinal-epidural analgesia for labor pain. J Clin Anesth 2004;16(1):78–9. 18. Chiu CY, Lin TY, Hsia SH, Lai SH, Wong KS. Systemic anaphylaxis following local lidocaine administration during a dental procedure. Pediatr Emerg Care 2004;20(3):178–80. 19. Brown SL, Morrison AE. Local anesthetic infusion pump systems adverse events reported to the Food and Drug Administration. Anesthesiology 2004;100(5):1305–7. 20. Ahmed SU, Vallejo R, Hord ED. Seizures after a bier block with clonidine and lidocaine. Anesth Analg 2004;99(2):593–4. 21. Deltombe T, Nisolle JF, De Cloedt P, Hanson P, Gustin T. Tibial nerve block with anesthetics resulting in Achilles tendon avulsion. Am J Phys Med Rehabil 2004;83(4):331–4. 22. Warwar RE, Romriell EK, Pennock EA. Contralateral amaurosis after retrobulbar anesthetic injection. J Neuroophthalmol 2004;24(2):187–8. 23. Han SK, Kim JH, Hwang JM. Persistent diplopia after retrobulbar anesthesia. J Cataract Refract Surg 2004;30(6):1248–53. 24. Khawam E, El-Dairi M, Al-Haddad C, Younis M. Inferior oblique overaction/contracture following retrobulbar anesthesia for cataract extraction with
25.
26. 27. 28.
29.
30.
31. 32.
33. 34. 35.
36.
37.
38.
39.
40.
41.
a positive Bielschowsky Head Tilt test to the contralateral shoulder. A report of one case. Binocul Vis Strabismus Q 2004;19(4):247–50. Irving EL, Arshinoff SA, Samis W, Lillakas L, Lui B, Laporte JT, Steinbach MJ. Effect of retrobulbar injection of lidocaine on saccadic velocities. J Cataract Refract Surg 2004;30(2):350– 6. Chen HT, Chen KH, Hsu WM. Toxic keratopathy associated with abuse of low-dose anesthetic: a case report. Cornea 2004;23(5):527–9. Goldman RD. ELA-max: a new topical lidocaine formulation. Ann Pharmacother 2004;38(5):892– 4. Ho AM, Chung DC, To EW, Karmakar MK. Total airway obstruction during local anesthesia in a non-sedated patient with a compromised airway. Can J Anaesth 2004;51(8):838–41. Perney P, Blanc F, Mourad G, Blayac JP, Hillaire-Buys D. Transitory ataxia related to topically administered lidocaine. Ann Pharmacother 2004;38(5):828–30. Hahn IH, Hoffman RS, Nelson LS. EMLAinduced methemoglobinemia and systemic topical anesthetic toxicity. J Emerg Med 2004;26(1):85–8. Parker JF, Vats A, Bauer G. EMLA toxicity after application for allergy skin testing. Pediatrics 2004;113(2):410–1. Vallance H, Chaba T, Clarke L, Taylor G. Pseudo-lysosomal storage disease caused by EMLA cream. J Inherit Metab Dis 2004;27(4):507–11. Kleinhans M, Boer A, Kaufmann R, Boehncke WH. Fixed drug eruption caused by articain. Allergy 2004;59(1):117. Bayard M, Farrow J, Tudiver F. Acute methemoglobinemia after endoscopy. J Am Board Fam Pract 2004;17(3):227–9. Gray TA, Hawkins S. A PACU crisis: a case study on the development and management of methemoglobinemia. J Perianesth Nurs 2004;19(4):242–53. Henry LR, Pizzini M, Delarso B, Ridge JA. Methemoglobinemia: early intraoperative detection by clinical observation. Laryngoscope 2004;114(11):2025–6. Fitzsimons MG, Gaudette RR, Hurford WE. Critical rebound methemoglobinemia after methylene blue treatment: case report. Pharmacotherapy 2004;24(4):538–40. Armstrong C, Burak KW, Beck PL. Benzocaineinduced methemoglobinemia: a condition of which all endoscopists should be aware. Can J Gastroenterol 2004;18(10):625–9. Khalife WI, Wang R, Khalil J. Respiratory failure secondary to methemoglobinemia induced by benzocaine: a case report. S D J Med 2004;57(4):145–7. Moore TJ, Walsh CS, Cohen MR. Reported adverse event cases of methemoglobinemia associated with benzocaine products. Arch Intern Med 2004;164(11):1192–6. Yazzie J, Kelly SC, Zumwalt RE, Kerrigan S. Fatal bupivacaine intoxication following unusual
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42.
43.
44.
45.
46.
erotic practices. J Forensic Sci 2004;49(2):351– 3. Kim JT, Jung CW, Lee KH. The effect of insulin on the resuscitation of bupivacaine-induced severe cardiovascular toxicity in dogs. Anesth Analg 2004;99(3):728–33. Gulec S, Aydin Y, Uzuner K, Yelken B, Senturk Y. Effects of clonidine pre-treatment on bupivacaine and ropivacaine cardiotoxicity in rats. Eur J Anaesthesiol 2004;21(3):205–9. Lunenfeld E, Kane GC. Methemoglobinemia: sudden dyspnea and oxyhemoglobin desaturation after esophagoduodenoscopy. Respir Care 2004;49(8):940–2. Maimo G, Redick E. Recognizing and treating methemoglobinemia: a rare but dangerous complication of topical anesthetic or nitrate overdose. Dimens Crit Care Nurs 2004;23(3):116–8. Cladis FP, Litman RS. Transient cardiovascular toxicity with unintentional intravascular injection of 3% 2-chloroprocaine in a 2-month-old infant. Anesthesiology 2004;100(1):181–3.
Chapter 11
Stephan A. Schug et al.
47. Davidson JA, Isaacs RA. A novel case of numb bum. Eur J Emerg Med 2004;11(5):285–6. 48. Carey F, Dinsmore WW. Cocaine-induced penile necrosis. Int J STD AIDS 2004;15:424–5. 49. Zeidan A, Baraka A. Is euphoria a side-effect of lidocaine? Anaesthesia 2004;59(12):1253–4. 50. Donald MJ, Derbyshire S. Lignocaine toxicity a complication of local anaesthesia administered in the community. Emerg Med J 2004;21(2):249– 50. 51. Dernedde M, Furlan D, Verbesselt R, Gepts E, Boogaerts JG. Grand mal convulsion after an accidental intravenous injection of ropivacaine. Anesth Analg 2004;98(2):521–3. 52. Pfeiffer G, Bar K, Neubauer P, Hohne M. Versehentliche intravenöse Infusion von 380 mg Naropin (Ropivacain). Anaesthesist 2004;53(7):633–6. 53. Connolly M, Mehta A, Sansom JE, Dunnill MG. Allergic contact dermatitis from tetracaine in the beauty industry. Contact Dermatitis 2004;51(2):95–6.
O. Zuzan and M. Leuwer
12 Neuromuscular blocking agents and skeletal muscle relaxants Anaphylaxis due to neuromuscular blocking agents New insights have been gained into the controversy surrounding the incidence of anaphylaxis to neuromuscular blocking agents in different countries. A few years ago the Norwegian Medicines Authority responded to 29 reports of anaphylaxis to rocuronium among 150 000 patients exposed by recommending restricted use of this agent. However, Norway’s Scandinavian neighbors, Finland, Sweden, and Denmark, had observed only eight cases among 800 000 patients exposed, and it was not clear if this difference was entirely due to reporting bias (1Cr ). Recently, it has been shown that the presence of IgE antibodies to suxamethonium (succinylcholine) and morphine is much more common in Norway than in Sweden (2C ). A total of 800 blood samples from Norway were tested for IgE antibodies to morphine or suxamethonium; the results were compared with those of 800 blood samples from Sweden. Among 500 samples from blood donors in Norway, 5% had antibodies to morphine and 0.4% to suxamethonium. Among 300 patients with a history of allergy, 10% had IgE to morphine and 0.7% had IgE to suxamethonium. In contrast, no positive samples were found in Sweden. The authors also investigated a variety of other substances as possible sensitizers by using an IgE antibody inhibition assay. Several agents inhibited the antibody reaction to suxamethonium and/or morphine, for example skin care ointments, hair-care products, cough syrups, cleansers, toothpastes, and lozenges. The only chemicals available in Norway but not in Sweden were cough syrups conSide Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29012-3 © 2007 Published by Elsevier B.V.
taining pholcodine. The authors detected IgE to pholcodine in 6% of Norwegian blood donors and in none of the Swedish samples. Pholcodine is an opioid contained in over-the-counter cough syrups, which seems to be widely used in Norway. Based on the observation that the presence of antibodies to morphine and pholcodine was closely correlated in cross-inhibition studies, the authors suggested that exposure of the population in Norway to pholcodine could have resulted in sensitization not just to this substance but also to morphine. Morphine, on the other hand, has some structural similarities to the quaternary ammonium groups in muscle relaxants. So could exposure to pholcodine also have resulted in sensitization to neuromuscular blocking agents? Altogether 42 of 65 patients (65%) with confirmed anaphylaxis to neuromuscular blocking agents had antibodies to pholcodine. Pholcodine is used as an antitussive agent in Australia, Belgium, Finland, France, Ireland, New Zealand, Norway, and the UK, all of which have reported several cases of anaphylaxis to rocuronium as well as other neuromuscular blocking agents. In contrast, pholcodine is not used in Denmark, Germany, Sweden, and the USA, where anaphylaxis to rocuronium is thought to be extremely rare. However, many of the patients tested in Norway had antibodies to morphine but not to suxamethonium. The authors therefore concluded that further studies are needed to identify agents that could result in sensitization to neuromuscular blocking agents. In this context it should be noted that rocuronium was actually confirmed as the causative agent in several cases of suspected anaphylaxis in Norway (3C ). From 1996 to 2001, 83 patients with suspected intraoperative anaphylaxis were investigated by the Allergy Investigation Unit in Bergen; 55 (66%) were allergic to NMBA, 40 (36%) to suxamethonium, and 17 (21%) to rocuronium. Referring to statistical problems,
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the authors refrained from relating these figures to the number of ampoules sold and did not answer the question whether the incidence of anaphylaxis to rocuronium is higher in Norway than in other countries. However, 93% of their confirmed cases were related to neuromuscular blocking agents. Compared with other countries this is a high proportion. Of course, this does not prove that anaphylaxis to neuromuscular blocking agents is more common in Norway, but it is still worth noting. Even if the incidence of anaphylaxis to rocuronium in Norway is not known, anesthetists seem to be cautious, and sales figures of rocuronium in Norway have fallen markedly. The same has apparently happened in France. We shall therefore probably not see much more information related to this matter from these countries. One can only hope that the mystery surrounding anaphylaxis to rocuronium will prompt more research into sensitizing substances as well as geographical, racial, and other differences in sensitization to anesthetics, with a view to improving patient safety. Overall, the diagnosis of intraoperative anaphylaxis is still flawed by the less than ideal sensitivity of our current diagnostic armamentarium. Flow cytometry as an additional tool has received considerable attention over the last few years. Detection of the basophil surface marker CD63 after incubation with the suspected agent has a higher sensitivity (79%) than skin prick testing (64%) (4E ). This is higher than the sensitivity of CD63 in a previous study (54%) (5E ), but the authors did not discuss this difference. Even so, basophil activation testing by flow cytometry is a very interesting and promising tool for the workup of suspected anaphylaxis. New developments, such as the use of anti-CRTH2/DP2 antibodies for basophil recognition, might further improve its value (6r ).
O. Zuzan and M. Leuwer
addressed in a retrospective analysis (7c ). Among 140 000 blood samples from drivers stopped by the police, carisoprodol and its metabolite meprobamate were the only substances found in 62 cases. Drivers with psychomotor impairment had higher plasma carisoprodol concentrations than those not impaired. There was no conclusive relation between driving impairment and plasma meprobamate concentration, which led the authors to suggest that carisoprodol itself in supratherapeutic concentration had an effect on the ability to drive, independent from the effect of its metabolite. In an earlier study, the most severe driving impairment and most overt symptoms of intoxication were noted when the combined concentration of carisoprodol and meprobamate exceeded 10 mg/l (8c ). Drug overdose Symptoms of carisoprodol intoxication include agitation, impaired consciousness, myoclonus, generalized muscle spasms, shivering, tremor, tachycardia, and hypertension, not all of which can easily be explained by nervous system depression via a GABAA receptor-mediated mechanism of action. Based on an analysis of four cases of carisoprodol intoxication, the serotonin syndrome has been offered as an alternative explanation (9A ). This would have implications for the treatment of carisoprodol overdose, and there have been reports of the successful use of antiserotonergic drugs in this context. The authors admitted that the symptoms and signs of the serotonin syndrome are rather unspecific and could have been caused by other mechanisms. Therefore, their interesting hypothesis should be regarded with caution.
Tizanidine
(SED-15, 3436; SEDA-28,
157)
SKELETAL MUSCLE RELAXANTS (SEDA-26, 152; SEDA-27, 141; SEDA-28, 157)
Carisoprodol
(SED -15, 674)
Nervous system The potential effect of carisoprodol abuse on the ability to drive has been
Drug interactions Ciprofloxacin Ciprofloxacin inhibits CYP1A2, which is involved in the metabolism of tizanidine. In healthy volunteers, ciprofloxacin 500 mg/day was given for 3 days followed by a single dose of tizanidine 4 mg (10c ). The peak plasma concentration was 1.2 ng/ml
Neuromuscular blocking agents and skeletal muscle relaxants
after placebo pre-treatment and 8.2 ng/ml after ciprofloxacin pre-treatment, a more than six-fold increase. The half-life of tizanidine was only slightly prolonged (1.8 hours after ciprofloxacin versus 1.5 hours after placebo). However, the AUC increased 10-fold. This was accompanied by low blood pressure, cognitive impairment, and drowsiness. The extent of these adverse effects correlated with the tizanidine plasma concentration. Fluvoxamine Fluvoxamine inhibits the metabolism of tizanidine, particularly by CYP1A2, resulting in markedly increased plasma concentrations and a prolonged half-life (11c ). In healthy volunteers this led to arterial hypotension, drowsiness, and cognitive impairment. Now there has also been a report of similar problems in clinical practice (12c ).
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147
• A 70-year-old woman had a stroke and developed pain and numbness in her leg. She was taking fluvoxamine 150 mg/day for depression. She was given tizanidine 3 mg/day and soon afterwards developed a dry mouth and anuria. This was accompanied by a fall in heart rate (to 56–60/minute) and body temperature (to 36.1–36.3 ◦ C). Tizanidine was withdrawn and her symptoms resolved immediately.
The authors subsequently surveyed the medical records of 913 patients looking for combined use of tizanidine and fluvoxamine. Of 23 patients who had taken these drugs simultaneously six had adverse effects: a low heart rate in six, dizziness in three, and a low body temperature, drowsiness, speech disorder, and hypotension in two. They recommended that the combination of tizanidine and fluvoxamine should be avoided.
References 1. Laake J, Rottingen J. Rocuronium and anaphylaxis—a statistical challenge. Acta Anaesthesiol Scand 2001;45:1196–203. 2. Florvaag E, Johansson SG, Oman H, Venemalm L, Degerbeck F, Dybendal T, Lundberg M. Prevalence of IgE antibodies to morphine. Relation to the high and low incidences of NMBA anaphylaxis in Norway and Sweden, respectively. Acta Anaesthesiol Scand 2005;49:437–44. 3. Harboe T, Guttormsen AB, Irgens A, Dybendal T, Florvaag E. Anaphylaxis during anesthesia in Norway: a 6-year single-center follow-up study. Anesthesiology 2005;102:897–903. 4. Sudheer PS, Hall JE, Read GF, Rowbottom AW, Williams PE. Flow cytometric investigation of peri-anaesthetic anaphylaxis using CD63 and CD203c. Anaesthesia 2005;60:251–6. 5. Monneret G, Benoit Y, Debard AL, Gutowski MC, Topenot I, Bienvenu J. Monitoring of basophil activation using CD63 and CCR3 in allergy to muscle relaxant drugs. Clin Immunol 2002;102:192–9. 6. Boumiza R, Debard AL, Monneret G. The basophil activation test by flow cytometry: recent developments in clinical studies, standardization and emerging perspectives. Clin Mol Allergy 2005;3:9.
7. Bramness JG, Skurtveit S, Morland J. Impairment due to intake of carisoprodol. Drug Alcohol Depend 2004;74:311–8. 8. Logan BK, Case GA, Gordon AM. Carisoprodol, meprobamate, and driving impairment. J Forensic Sci 2000;45:619–23. 9. Bramness JG, Morland J, Sorlid HK, Rudberg N, Jacobsen D. Carisoprodol intoxications and serotonergic features. Clin Toxicol (Phila) 2005;43:39–45. 10. Granfors MT, Backman JT, Neuvonen M, Neuvonen PJ. Ciprofloxacin greatly increases concentrations and hypotensive effect of tizanidine by inhibiting its cytochrome P450 1A2-mediated presystemic metabolism. Clin Pharmacol Ther 2004;76:598–606. 11. Granfors MT, Backman JT, Neuvonen M, Ahonen J, Neuvonen PJ. Fluvoxamine drastically increases concentrations and effects of tizanidine: a potentially hazardous interaction. Clin Pharmacol Ther 2004;75:331–41. 12. Momo K, Doki K, Hosono H, Homma M, Kohda Y. Drug interaction of tizanidine and fluvoxamine. Clin Pharmacol Ther 2004;76:509–10.
Michael Schachter
13
Drugs that affect autonomic functions or the extrapyramidal system
DRUGS THAT STIMULATE BOTH ALPHA- AND BETA-ADRENOCEPTORS (SEDA-26, 156; SEDA-27, 145; SEDA-28, 160)
Adrenaline (epinephrine)
(SED-15,
the dose was 9 ml of the same formulation injected sequentially into each side of the jaw. Both were anesthetized with sevoflurane. The episodes of dysrhythmia were self-limiting, lasting only 3.5 minutes in the man and about 10 and 3 minutes in the woman after each injection. The authors suggested that lidocaine may facilitate the absorption of adrenaline.
41) The acceptability and safety of adrenaline and cocaine gel for anesthetizing lacerations over 6 months in 75 children aged over 3 years (68% boys) have been reviewed (1c ). The gel contained adrenaline 1:2000 and cocaine 5%, but the excipient was not stated. The highest dose used was 5 ml of gel. The formulation was highly acceptable, as judged by Likert scales, to the children (1.17/5), their parents (1.13/10), and the operators (1.75/10), where lower scores indicated greater acceptability. There were no adverse effects, but the authors quoted protocols, published after their study, that set a limit of 6 mg/kg of cocaine as the maximal dose to be administered. Cardiovascular Adrenaline is still commonly administered topically to minimize hemorrhage. In two Japanese patients, one man one woman, in whom adrenaline was used for this purpose during mandibular surgery, atrioventricular junctional rhythm occurred (2A ). In the man 11 ml of 2% lidocaine with 1:80 000 adrenaline was injected into the gums, while in the woman Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29013-5 © 2007 Elsevier B.V. All rights reserved.
148
Ephedra and ephedrine
(SED-15,
1221) The complexity of the adverse effects associated with Ephedra has been summarized; problems arise mostly through improper use (3r ). Cardiovascular Metabolife 356, a dietary supplement that contains Ephedra and caffeine, increased the mean maximal QTc interval and systolic blood pressure in a double-blind, crossover, randomized, placebo-controlled study in 15 young healthy volunteers with normal BMI (4C ). Those who took Metabolife were more likely to have a shortening of the QTc interval by at least 30 milliseconds compared with placebo (RR 2.67; CI = 1.40, 5.10). All those who took Metabolife reported nonspecific symptoms (5c ). There were no adverse effects while patients were taking placebo. One woman developed a sinus tachycardia of 120/minute with palpitation, 1 hour after taking Metabolife. A hand tremor developed in one subject and subsided after 5 hours. In a meta-analysis of the effects of Ephedra or ephedrine-containing products compared with control, the odds ratio of palpitation was 2.29 (95%CI = 1.27, 4.32) (6M ).
Drugs that affect autonomic functions or the extrapyramidal system
Two young men took Ephedra supplements and developed severe cardiomyopathies and global cardiac hypokinesis (7A ). Both were treated with standard treatments for heart failure but one died nevertheless. Ephedra and coronary dissection have been linked (8A ). • A 50-year-old African American woman developed a myocardial infarction 2 days after taking a supplement containing Ephedra standardized to ephedrine 20 mg/day. Subsequent investigations showed a dissection in the mid-distal segment of the left anterior descending artery and a thrombosis occluding a large first obtuse marginal branch. She had bypass surgery, but later developed refractory heart failure.
Nervous system Five patients had ischemic strokes after self-medicating with Ephedra supplements (9c ). They had taken Ephedra products for weight loss or to increase their energy. Liver Of 12 patients who experienced liver damage through herbal weight loss products most were women (n = 9), most had taken Ephedra-containing products (n = 10), eight recovered after medical treatment, three required liver transplants, and one died (10c ). Route of administration Inadvertent epidural injection of ephedrine has been described in a 17-year-old woman in labor (11A ). • Ephedrine 50 mg in 10 ml was inadvertently administered via an epidural catheter (instead of the intended ropivacaine and fentanyl) in a 17-year-old nulliparous woman in labor. The error was immediately recognized, and further administration was stopped. For the next 2 hours, her neurological status, blood pressure, heart rate, and temperature and fetal heart rate were monitored. She was comfortable and had no complaints during or after the bolus. The level of analgesia regressed and there was full recovery of sensation. Vital signs in both the mother and fetus remained stable throughout, and there were no changes in uterine contraction. However, because labor did not progress, cesarian delivery was performed, without complications.
Perhaps surprisingly, there were no untoward effects on the mother or baby. A commentary after the report noted that in other similar cases adverse reactions did occur, including hypertension, dysrhythmias, and central nervous system stimulant effects.
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Drug overdose Inadvertent overdose of ephedrine has been reported from Japan (12A ). • A 22-year-old man undergoing tonsillectomy was inadvertently given ephedrine 200 mg intravenously instead of neostigmine and atropine, which was intended to reverse residual neuromuscular blockade. His blood pressure rose to 265/165 mmHg with a heart rate of 140/minute. He was immediately given intravenous propranolol 0.4 mg and sublingual nifedipine 5 mg. The hypertension and tachycardia gradually subsided and after 5 hours blood pressure was 120/80 mmHg with a pulse rate of 80/minute. There were no long term sequelae.
This may be the highest recorded dose of this drug given inadvertently, and so the authors could not refer to previous literature on the management of such a case. They suggested that labetalol may be a preferable remedy. Drug interactions The effect of ephedrine on the onset time of neuromuscular blockers has been evaluated in 25 patients who were given ephedrine 70 micrograms/kg 3 minutes before induction with propofol plus remifentanil (13c ). The onset time of suxamethonium was significantly shortened. In another study, ephedrine 70 micrograms/ kg was given 1 minute before induction, and midazolam 7.5 mg, 30–60 minutes before induction (n = 30) (14c ). Anesthesia was induced with fentanyl 1 micrograms/kg and sodium thiopental 3.5 mg/kg. The patients were intubated with rocuronium 0.9 mg/kg, and the intubation time, determined by Dixon’s up and down method, was significantly shorter than in controls. In both of these studies there were no significant hemodynamic changes.
Pseudoephedrine
(SED-15, 1221)
Cardiovascular In subjects with impaired baroreflex function, oral pseudoephedrine 30 mg or phenylpropanolamine 12.5 mg and 25 mg produced significant increases in blood pressure. When they were taken with water the increase in blood pressure was greater. The maximal increase in systolic blood pressure occurred after 60 minutes and the pressure returned to baseline by 2 hours (15c ). Acute myocardial infarction has been attributed to pseudoephedrine (16A ).
150 • A 19-year-old male cigarette smoker with normal coronary arteriography had an upper respiratory infection, for which he bought Gripex® , each tablet of which contains paracetamol 325 mg, pseudoephedrine HCl 30 mg, and dextromethorphan HBr 10 mg. He took four tablets twice, about 3 hours apart, a total of 240 mg of pseudoephedrine within 3 hours. He had an acute myocardial infarction 12 hours later. Other drugs, such as cocaine and amphetamines, were excluded. Subsequent coronary angiography and echocardiography showed a non-Q-wave myocardial infarction with normal coronary arteries.
About 5% of patients with a myocardial infarction have normal coronary arteries at angiography. In many cases there is coronary artery spasm and/or thrombosis, perhaps with underlying endothelial dysfunction of the epicardial arteries. It is important in such cases to obtain a complete history of the use of drugs, including over-the-counter drugs. Skin Pseudoephedrine is still very commonly used as symptomatic therapy in upper respiratory tract infections, although its efficacy is debatable. Acute generalized exanthematous pustulosis has been attributed to it (17A ). • A 42-year-old Spanish woman took Vincigrip® , which contains paracetamol, pseudoephedrine, and chlorphenamine, for an upper respiratory tract infection. Ten hours after the first dose she developed fever of over 38 ◦ C and a pustular erythematous rash on the face, trunk, and proximal limbs. Skin biopsy showed sterile pustules with papillary edema and focal keratinocyte necrosis, compatible with a diagnosis of acute generalized exanthematous pustulosis. Immunohistochemistry and reverse transcription polymerase chain reaction (PCR), a lymphocyte proliferation assay, and patch testing confirmed the specificity of the reaction due to pseudoephedrine. Immunocytochemistry showed a mononuclear infiltrate consisting of activated memory T cells in addition to polymorphonuclear cells. PCR showed increased expression of IL-8 in the affected skin. She was treated with an oral glucocorticoid, and recovered completely within 10 days.
The authors noted that there had been only report of a similar case, but that this unusual reaction is attributed to drugs in 90% of cases, penicillins being most frequently implicated. A previous report of this reaction due to pseudoephedrine was confirmed with a positive patch test (18A ).
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DRUGS THAT PREDOMINANTLY STIMULATE ALPHA1 -ADRENOCEPTORS (SEDA-26, 157; SEDA-27, 147; SEDA-28, 161)
Phenylpropanolamine
(SED-15,
2811) Nervous system It is troubling that adverse effects continue to be attributed to phenylpropanolamine, several years after its withdrawal from most world markets. Stroke is one such. • An 8-year-old boy on chronic peritoneal dialysis for renal agenesis was given an over-the-counter cold remedy containing phenylpropanolamine, although the quantity given could not be ascertained (19A ). Over the next 3 days his blood pressure increased to 140–150/100 mmHg and on the following day he vomited and complained of severe headache and blurred vision. His blood pressure was 154/90 mmHg, with a pulse of 64/minute and he had lost all light perception. Other neurological examination was normal. CT and MRI scans showed bilateral parieto-occipital infarcts secondary to vasculitis. The serum phenylpropanolamine concentration was exceptionally high (300 ng/ml), compared with 90 ng/ml typically seen after a dose of 50 mg, as recommended in the past for adults. The boy had two tonic–clonic seizures in succeeding weeks but his blood pressure returned to normal without treatment and his vision gradually improved; 7 weeks later it was completely normal.
This case illustrates that people may keep drugs at home long after they have been officially withdrawn.
DRUGS THAT STIMULATE BETA1 -ADRENOCEPTORS (SEDA-26, 159; SEDA-27, 147)
Dobutamine
(SED-15, 1169)
Musculoskeletal Myoclonus has been described in six patients (mean age 69 years, four women) all of whom had congestive heart failure and associated renal insufficiency (mean creatinine clearance 16 ml/1.73 m2 ) (20A ).
Drugs that affect autonomic functions or the extrapyramidal system
All were being treated with dobutamine (10– 20 micrograms/kg/minute). All developed myoclonus on the second or third day of treatment and it resolved 2 days after the infusion was stopped. The exact nature of the symptoms was not described. The authors proposed that in these patients there was a concurrent reduction in the clearance of dobutamine and an increase in the permeability of the blood–brain barrier, both as a consequence of renal impairment. They also speculated that the effect was predominantly due to the levorotatory enantiomer of dobutamine, which is an α1 adrenoceptor agonist, rather than the dextrorotatory enantiomer, which is a β1 adrenoceptor agonist; both are present in the racemic formulation used clinically. Immunologic The adverse effects of dobutamine as used in cardiac stress testing have been extensively reviewed in previous Annuals. However, dobutamine is also used as a positive inotrope in patients with severe cardiac failure. An unusual adverse effect of relatively long-term use of dobutamine has been reported, namely asthma with eosinophilia (21A ). • A 50-year-old man with end-stage ischemic cardiomyopathy was given dobutamine 2.5–5 micrograms/kg/minute for 6 weeks while awaiting cardiac transplantation. At the end of this period he developed shortness of breath and wheeze and recognized this as an attack of asthma, which he had last experienced 10 years before. He was treated unsuccessfully with nebulized salbutamol but improved after the administration of a glucocorticoid. Because he had an eosinophilia of 9.2%, dobutamine was withdrawn and replaced by milrinone, with a fall in the eosinophilia to 2.4% within 72 hours.
The authors speculated that it was not dobutamine itself that had evoked this reaction, reported on rare occasions elsewhere, but the bisulfite used as a preservative. An even more dramatic case of dobutamineassociated eosinophilia has been described by a cardiologist from Ohio (22A ). • A 46-year-old man with a dilated cardiomyopathy was given dobutamine, dose unspecified, for about 1 week and developed a pericardial friction rub with echocardiographic evidence of a small effusion. The eosinophil count was 40–50%. After extensive negative investigations it was concluded that dobutamine was the likely cause of the eosinophilia and on withdrawal the eosinophilia halved within 24 hours. On dobutamine rechal-
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lenge (after informed consent) the eosinophil count increased rapidly.
This patient had no previous history of asthma and had no manifestations of it on this occasion. The authors considered it likely that the bisulfite preservative was the allergenic trigger.
DRUGS THAT STIMULATE DOPAMINE RECEPTORS (SEDA-26, 159; SEDA-27, 148; SEDA-28, 162)
Levodopa and dopamine receptor agonists Nervous system Sleep and fatigue in relation to Parkinson’s disease and its therapies have been considered in two reviews. Friedman and Chou insist that the two problems should be considered separately but they do not make a clear distinction between problems due to the disease itself and those attributable to its treatment, and they have argued that there is no definitive evidence that excessive daytime sleepiness and sleep attacks are necessarily drug-related (23R ). They have noted that up to one-third of patients describe fatigue as the most troublesome aspect of the disease, but, in this as in other conditions, its mechanism and management are uncertain. Dopamine receptor agonists actually tend to exacerbate the problem. Sleep disorders, which can take several forms, are even more common but may cause fewer problems for patients and their carers. The other review was more clearly oriented at the consequences of treatment with dopamine receptor agonists and included an evaluation of 22 non-demented patients with Parkinson’s disease (mean age 69 years, 13 men) using a structured sleep interview, the Epworth sleepiness scale, and 24-hour ambulatory polysomnography (24rc ). All the patients were taking levodopa, a dopamine receptor agonist, or both, but it was not possible to separate these three groups on the basis of the information provided. Seven patients reported episodes that could be considered as sleep attacks, and of these three first noted them after dopamine re-
152 ceptor agonist therapy was begun. Patients with sleep attacks also had higher daytime sleepiness scores and, perhaps surprisingly, longer nocturnal sleep times. They were also taking higher levodopa dose equivalents, although it was impossible to draw conclusions about the precise nature of the drug therapy. The authors concluded that sleep attacks are an extreme manifestation of increased daytime sleepiness, which may be partly related to treatment, but they did not advance the debate regarding the relative importance of different drugs in contributing to this problem. In a 5-year follow-up study of 59 patients (mean age 62 years, sex distribution not specified), carried out between 1990 and 1996, there was a rapid improvement in the Unified Parkinson’s Disease Rating Scale (UPDRS) in the first year after starting therapy, in 36 cases with levodopa but in the remaining 23 with dopamine receptor agonists or other agents such as selegiline (25c ). The mean score fell from 27 points to 19 points in the first year, but had risen to 30 points by the fifth year. However, looking at individual patients, 50% had UPDRS scores equal to or better than baseline at 5 years, but only 44% were without motor complications as defined by motor fluctuations, dyskinesias, or episodes of freezing, the frequencies of which were 35%, 32%, and 27% respectively. This study again shows that early treatment with levodopa predisposes to motor complications: 62% of those who took levodopa compared with 48% of those who took other drugs. All types of complication were similarly affected. However, improvements in UPDRS scores were better maintained in patients who took levodopa. Nutrition There has been great interest over the last decade in plasma homocysteine as a risk factor for atherothrombotic vascular disease and possibly also dementia. Although this link has been called into question by recent interventional trials the concept has by no means been discarded. There is extensive evidence that treatment with levodopa increases plasma concentrations of homocysteine. This may occur because metabolism of levodopa by catechol-O-methyl transferase (COMT) can deplete methionine concentrations, which in turn impedes the clearance of homocysteine. It has been suggested that Parkinsonian patients taking levodopa should routinely be given
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supplements of folate and vitamin B12 , which lower homocysteine concentrations (26r ). This would almost certainly be harmless and inexpensive, but at present also totally lacking in evidence of clinical benefit. In a Turkish comparison of levodopa and pergolide the latter did not significantly affect homocysteine concentrations (27c ).
Cabergoline
(SED-15, 587)
There have been isolated case reports of fibrotic reactions in patients taking cabergoline (28c ). Cabergoline has been investigated in an open study in Germany in 302 patients (mean age 61 years, 73% women) (29c ). It was titrated over 4 weeks to a median dose of 1.5 mg/day and the median duration of treatment was 181 days. The most common adverse effect was nausea (in 17%), followed by dizziness (7.0%) and headache (4.6%). However, about 48% of the patients had some sort of drug-related adverse event, though in only nine patients did these lead to drug withdrawal.
Pergolide
(SED-15, 2780)
Cardiovascular The profibrotic effects of pergolide on heart valves have been evaluated echocardiographically in 78 patients with Parkinson’s disease who were taking pergolide (mean age 71 years; 45 men) and 18 who had never taken an ergot-derived dopamine receptor agonist (mean age 73 years; nine men) (30c ). There was detectable restrictive valve disease in 33% of those taking pergolide, and it was considered significant in 19%. The patients were divided into a high-dose group, taking pergolide 5 mg/day or more, and a low-dose group, but the incidence of valvular lesions was not clearly dose-dependent. The mitral valve was most commonly affected (n = 20), followed by the aortic valve (n = 7) and tricuspid (n = 6) valve. In six patients the pergolide was withdrawn because of the valve lesions and in two of these there was regression of the mitral valve lesions. There were no lesions detected in patients who had never been exposed to ergot drugs. The authors suggested that pergolide
Drugs that affect autonomic functions or the extrapyramidal system
should be replaced by a non-ergot drug if valve lesions are detected. This was subsequently supported by correspondents from Glasgow, who had switched 88 of their 99 patients from ergot-based to non-ergot-based dopamine receptor agonists without clinical problems and having established dosage equivalence (31r ). As a result of this accumulation of evidence pergolide is now not recommended for firstline therapy in Parkinson’s disease and its use should now be accompanied by intensive monitoring, which may be a further deterrent to its administration.
OTHER DRUGS THAT INCREASE DOPAMINE ACTIVITY (SEDA-26, 162; SEDA-27, 151; SEDA-28, 164)
drug) and in patients with pre-existing orthostatic hypotension, though this was not mentioned as an adverse reaction to entacapone. Conversely, those with end-of-dose wearing-off effects were more likely to continue taking the drug. Perhaps surprisingly, the authors stated that entacapone is well tolerated, though surely not everyone would agree with this conclusion. However, the main problem appears to be entacapone’s limited efficacy, the main reason why tolcapone has reappeared in clinical practice.
DRUGS THAT AFFECT THE CHOLINERGIC SYSTEM (SEDA-26, 164; SEDA-27, 152; SEDA-28, 165)
Anticholinergic drugs Catechol-O-methyl transferase inhibitors Entacapone
(SED-15, 1219)
Observational studies Although prescribing of tolcapone has resumed in some countries, entacapone is still more widely used. In a retrospective study from Minnesota of withdrawal of entacapone in 222 patients with Parkinson’s disease (mean age 69 years, 52% men) the average number of daily doses of entacapone was 4.3, equivalent to about 900 mg/day (32c ). By the end of the follow-up period, which was less than 3 years in the great majority of the subjects, 56% of the patients had stopped taking the drug. The principal reason was lack of efficacy (46%), followed by worsening of Parkinsonian symptoms (28%), probably another aspect of the same problem. Other factors were cognitive deterioration (20%), dyskinesia (17%), nausea (11%), diarrhea (9%), and cost (4%). Other adverse effects were cited by 8% of the patients and some stopped taking the drug for what were described as “nonmedication related reasons,” although it is not clear what these were. Drop-out rates were higher in women (54% of those stopping the
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(SED-15, 264)
Observational studies Most studies of anticholinergic drugs used for regulating bladder function have involved older adults. However, detrusor instability and hyperactivity are common in children. In a retrospective Belgian study of tolterodine in 256 patients (175 boys, mean age 8.3, range 3–17 years) (33c ). The mean duration of treatment was 9.3 months and the final dose achieved was 0.1 mg/kg/day divided into two doses. Most of the patients (n = 205) had been switched from other anticholinergic drugs, while in the remainder tolterodine was the initial therapy. Efficacy was significant in both groups, with reductions in frequency, urgency, and episodes of incontinence, and increased bladder capacity. There had been a high incidence of adverse effects in the patients treated with other anticholinergic drugs, with cognitive impairment, behavioral disturbances, and headache in 81% of the children, flushing in 26%, disturbed accommodation in 12%, and gastrointestinal adverse effects in 25%. By contrast, the children treated with tolterodine as either first or second therapy had very few problems; three children with abnormal behaviors and six with slight gastrointestinal abnormalities. Only two patients stopped taking the drug.
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References 1. Kennedy DWG, Shaikh Z, Fardy MJ, Evans RJ, Crean StJV. Topical adrenaline and cocaine gel for anesthetising children’s lacerations. Emerg Med J 2004;21:194–6. 2. Kunimatsu T. Two cases of atrioventricular junctional rhythm induced by administration of regional injection of epinephrine. Acta Anesthesiol Scand 2004;48:928. 3. Soni MG, Carabin IG, Griffiths JC, Burdock GA. Safety of Ephedra: lessons learned. Toxicol Lett 2004;150:97–110. 4. McBride BF, Karapanos AK, Krudysz A, Kluger J, Coleman CI, White CM. Electrocardiographic and hemodynamic effects of a multicomponent dietary supplement containing Ephedra and caffeine. A randomized controlled trial. JAMA 2004;291:216–21. 5. Gardner SF, Frank AM, Gurley BJ, Haller CA, Singh BK, Mehta JL. Effect of a multicomponent, Ephedra-containing dietary supplement (Metabolife 356) on Holter monitoring and hemostatic parameters in healthy volunteers. Am J Cardiol 2003;91:1510–3. 6. Shekelle PG, Hardy ML, Morton HC, Maglione M, Mojica WA, Suttorp MJ, Rhodes SL, Jungvig L, Gagne J. Efficacy and safety of Ephedra and ephedrine for weight loss and athletic performance: a meta-analysis. JAMA 2003;289:1537–45. 7. Naik SD, Freudenberger RS. Ephedra-associated cardiomyopathy. Ann Pharmacother 2004;38:400–3. 8. Sola S, Helmy T, Kacharava A. Coronary dissection and thrombosis after ingestion of Ephedra. Am J Med 2004;116:645–6. 9. Chen C, Biller J, Willing SJ, Lopez AM. Ischemic stroke after using over the counter products containing Ephedra. J Neurol Sciences 2004;217:55–60. 10. Neff GW, Reddy KR, Durazo FA, Meyer D, Marrero R, Kaplowitz N. Severe hepatotoxicity associated with the use of weight loss diet supplements containing Ma huang or usnic acid. J Hepatol 2004;41:1061–7. 11. Sidi A. Inadvertent epidural injection of ephedrine in labor. J Clin Anesth 2004;16:74–6. 12. Sakuragi T, Yasumoto M, Higa K, Nitahara K. Inadvertent intravenous administration of a high dose of ephedrine. J Cardiothorac Vasc Anesth 2004;18:121. 13. Ganidagli S, Cengiz M, Baysal Z. Effect of ephedrine on the onset time of succinylcholine. Acta Anaesth Scand 2004;48:1306–9. 14. Ittichaikulthol W, Sriswadi S, Nual-On S, Hongpuang S, Sornil A. The effect of ephedrine on the onset time of rocuronium in Thai patients. J Med Assoc Thai 2004;87:264–9. 15. Jordan J, Shannon JR, Diedrich A, Black B, Robertson D, Biaggioni B. Water potentiates the pressor effect of Ephedra alkaloids. Circulation 2004;109:1823–5.
16. Grzesk G, Polak G, Grabczewska Z, Kubica J. Myocardial infarction with normal coronary arteriogram: the role of ephedrine-like alkaloids. Med Sci Monit CS 2004;10:15–21. 17. Padia MA, Alvarez-Ferreira J, Tapia B, Blanco R, Mañas C, Blanca M, Bellón T. Acute generalized exanthematous pustulosis associated with pseudoephedrine. Br J Dermatol 2004;150:139–42. 18. Assier-Bonnet H, Viguier M, Dubertret L, Revuz J, Roujeau JC. Severe adverse drug reactions due to pseudoephedrine from over-the-counter medications. Contact Dermatitis 2002;47:165– 92. 19. Delorio NM. Cerebral infarcts in a pediatric patient secondary to phenylpropanolamine, a recalled medication. J Emerg Med 2004;26:305–7. 20. Wierre L, Decaudin B, Barsumau J, Vairon MX, Horrent S, Odou P, Azar R. Dobutamine-induced myoclonus in severe renal failure. Nephrol Dial Transplant 2004;19:1336–7. 21. Aranda JM, Woo G, Pauly DF, Rodriguez E, Hill JA, Schofield RS. Dobutamine related asthma in a patient awaiting cardiac transplantation: the eosinophilic dilemma. J Heart Lung Transplant 2004;23:260–1. 22. El-Sayed O, Abdelfattah RR, Barcelona R, Leier CV. Dobutamine-induced eosinophilia. Am J Cardiol 2004;93:1078–9. 23. Friedman JH, Chou KL. Sleep and fatigue in Parkinson’s disease. Parkinsonism Relat Disord 2004;10:S27–35. 24. Manni R, Terzaghi M, Sartori I, Mancini F, Pacchetti C. Dopamine agonists and sleepiness in PD: review of the literature and personal findings. Sleep Med 2004;5:189–93. 25. Garcia Ruiz PJ, Meseguer E, Del Val J, Vázquez A, Sanchez Bernardos V, Vázquez A. Motor complications in Parkinson disease. A prospective follow-up study. Clin Neuropharmacol 2004;27:49–52. 26. Postuma RB, Lang AE. Homocysteine and levodopa. Should Parkinson disease patients receive preventative therapy? Neurology 2004;63:886– 91. 27. Özkan S, Colak Ö, Kutlu C, Ertan M, Alatas Ö. Plasma homocysteine levels in pergolide-treated Parkinson disease patients. Clin Neuropharmacol 2004;27:163–5. 28. Dhawan V, Medcalf P, Stegie F, Jackson G, Basu S, Luce P, Odin P, Chaudhuri KR. Retrospective evaluation of cardio-pulmonary fibrotic side-effects in symptomatic patients from a group of 234 Parkinson’s disease patients treated with cabergoline. J Neural Transm 2005;112:661–8. 29. Beneš H, Heinrich CR, Ueberall MA, Kohnen R. Long-term safety and efficacy of cabergoline for the treatment of idiopathic restless legs syndrome: results from an open-label 6-month clinical trial. Sleep 2004;27:674–82. 30. Van Camp G, Flamez A, Cosyns B, Weytjens C, Muyldermans L, Van Zandijcke M, De Sutter J,
Drugs that affect autonomic functions or the extrapyramidal system Santens P, Decoodt P, Moerman C, Schoors D. Treatment of Parkinson’s disease with pergolide and relation to restrictive valvular disease. Lancet 2004;363:1179–83. 31. Grosset KA, Grosset DG. Pergolide in Parkinson’s disease: time for a change? Lancet 2004;363:1997–8. 32. Parashos SA, Wielinski CL, Kern JA. Frequency, reasons, and risk factors of entacapone discontin-
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uation in Parkinson disease. Clin Neuropharmacol 2004;27:119–23. 33. Raes A, Hoebke P, Segaert I, Van Laecke E, Dehoorne J, Vande Walle J. Retrospective analysis of efficacy and tolerability of tolterodine in children with overactive bladder. Eur Urol 2004;45:240–4.
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14
Dermatological drugs, topical agents, and cosmetics
Botulinum toxin A (SED-15, 551; SEDA-27, 161; SEDA-28, 168) Botulinum toxin A is used for the treatment of facial rhytides (for example, lateral orbital wrinkles, lower eyelid wrinkles, nasolabial lines) by producing weakness or paralysis of the associated muscles, and in the treatment of hyperhidrosis. Transient adverse effects, such as temporary bruising, discomfort, incomplete muscle paralysis, or headache, can occur (1R , 2M , 3C ). A meta-analysis showed that about 25% of patients who receive botulinum toxin A report mild to moderate adverse events, compared with 15% of patients who receive placebo. Focal weakness was the only adverse event that occurred significantly more often with botulinum toxin A than control (2M ). In a randomized study of patients with moderate or severe glabellar lines, blepharoptosis occurred in 3.2% of patients (3C ).
Calcipotriol
(SED-15, 594; SEDA-28,
• An 85-year-old woman presented with anorexia, oliguria, and acute renal insufficiency 19 days after starting to take calcipotriol (4A ). She also had raised calcium and sodium concentrations.
Colophony Colophony is another term for rosin, a resin that is obtained when turpentine is prepared from dead pine wood. It is used to make waxes and varnishes and for coating the strings of bows used to play stringed musical instruments. Colophony, or its chemically modified forms, is also found in permanent color markers. Skin Contact dermatitis due to acrylates in ultraviolet curing ink has been described (5c ), but there has only been one report of contact allergic dermatitis caused by a permanent marker. In that case, a dye (Solvent Yellow 146, BioDiagnostics Ltd, UK) was the causative agent (6A ). There has now been a case of allergic contact dermatitis due to the colophony analogue abitol as a component of a permanent marker, Edding 3000.
169) Endocrine Calcipotriol, a biologically active form of vitamin D3, is usually well-tolerated, although it can cause local irritation in up to 30% of patients. Topical calcipotriol in recommended dosages has rarely been associated with hypercalcemia. Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29014-7 © 2007 Elsevier B.V. All rights reserved.
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• A 28-year-old woman developed skin lesions on her right thigh 24 hours after liposuction, the fifth episode of liposuction that the patient had undergone (7A ). A blue permanent marker (Edding 3000, Edding International GmbH) was used to outline the area at each site of liposuction. Pruritic, erythematous, and infiltrated plaques, with vesicles and papular spread, developed on these lines within a few days. The manufacturers provided information about the components of Edding 3000, rosin (colophony), colorants, and organic solvents. Epicutaneous tests were carried out with the suspected agent, the permanent marker (Edding 3000), in three different colors: blue, red, and black, all of which were positive at 48 hours (++) and 96 hours (+++).
Dermatological drugs, topical agents, and cosmetics
The patient did not have a positive patch test reaction to colophony in the standard series, but had a positive reaction with a modified product of colophony, abitol. The incidence of allergic reactions to colophony has increased to such an extent that in most countries it has become one of the 10 most important sources of sensitization. However, the use of only one type of colophony for patch tests in the standard series does not address all aspects of the problem. There are three complicating factors: • colophony has been replaced in recent years by its chemically modified forms; • modified colophony products commonly cause stronger sensitization reactions than unmodified ones do; • cross-reactions between modified and unmodified products are not the rule. The question therefore arises as to whether testing is being conducted with the right material, which raises the suspicion that the real number of cases of colophony allergy is much higher than is commonly thought.
Patch testing was performed with the SIDAPA (Societa Italiana di Dermatologia Allergologica e Professionale) standard series and the patient’s emollient cream. Readings at D2 and D3 were negative, except for a mild erythematous edematous (+) reaction to the emollient cream. The cream was withdrawn and the patient improved within 3 weeks. An open application test with the cream in the antecubital fossa was positive within 3 days and 6 months after resolution of his dermatitis, the patient was patch tested again. Readings performed at days 2, 3, and 4 showed a delayed but clearly positive erythematous edematous reaction to VP-eicosene copolymer 10% in petrolatum (+ at D4), plus a weak erythematous reaction to disodium stearoyl glutamate 30%. (at D4). The cream reacted positively (+/+) at D3 and D4.
Although p-phenylenediamine (PPD) and toluene-2,5-diamine are the most frequently reported hair dye allergens, allergic contact dermatitis from direct dyes for hair coloration is unusual. Two patients with a history of PPD allergic contact dermatitis had positive patch tests to HC Yellow 7,4 amino-3-nitrophenol and HC Red B54 in hair dyes (9A ).
Finasteride CONTACT ALLERGENS VP-eicosene copolymer VP-eicosene copolymer, also known as Ganex® V-220 F, is a film-former and waterproofing agent that belongs to the family of co-polymers of vinylpyrrolidone and long-chain α-olefins. These polymers are used as emulsifiers and dispersants in non-aqueous systems, desensitizers/wax dispersants in melt-cast explosives, dye dispersants for candles and shoe polish, and water-resistant film-formers in wood coatings. Skin VP-eicosene copolymer has been identified as a contact allergen in an emollient formulation widely prescribed by dermatologists as a treatment for dry skin. • A 59-year-old non-atopic man with a 6-month history of xerosis and pruritus of the hands, lower arms, and legs was given an emollient cream (Lipikar Baume® La Roche-Posay, France) for daily application (8A ). Within a month he developed itchy vesicular dermatitis of the limbs.
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(SEDA-28, 169)
Sensory systems Finasteride has not previously been associated with the development of cataracts. • A 43-year-old man who had been taking finasteride 1 mg/day for 3 years to treat androgenetic alopecia developed failing vision in both eyes and was found to have anterior subcapsular opacities of both lenses (10A ). There was no family history of early onset cataract.
Sexual function The main adverse effects associated with finasteride are loss of libido, erectile dysfunction, and reduced ejaculate volume. In clinical trials 4.4% of patients treated with finasteride and 2.2% of patients taking placebo experience sexual adverse effects. However, recent evidence suggests that sexual adverse effects are less common in practice. In multicenter study of 186 patients with androgenetic alopecia sexual adverse effects occurred in under 0.5% of subjects (11C ). Reproductive system Gynecomastia has not previously been reported with finasteride.
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• A 23-year-old man who was taking finasteride 1 mg/day for 2 months for androgenetic alopecia developed painful enlargement of his right breast (12A ). Treatment was withdrawn and resolution occurred after 2 months.
• After 12 PUVA treatments a 51-year-old man developed painful hyperesthesia, which persisted despite cessation of bath PUVA (15A ). Gabapentin 300 mg qds produced a dramatic improvement in symptoms over a period of 2 weeks.
PHOTOCHEMOTHERAPY
VITAMIN A (RETINOIDS)
(SED-15, 2823; SEDA-28, 171)
(SED-15, 3653; SEDA-27, 159; SEDA-28, 171; for vitamin A carotenoids see Chapter 34)
Aminolevulinic acid Skin Contact allergy to 5-aminolaevulinic acid (ALA) has been rarely reported. The derivative ALA methylester is considered to be a more specific sensitizer of abnormal cells than ALA. • A patient developed acute eczema of the treated areas and itch and hyper-reactivity of the untreated skin after several photodynamic therapy treatments with both ALA and ALA methylester (13A ). Patch testing demonstrated a strong reaction to ALA methylester only.
PUVA Skin Systemic and topical psoralens plus ultraviolet A irradiation (PUVA therapy) are well established treatments for vitiligo. Adverse effects of PUVA therapy include non-melanoma skin cancer and PUVA-induced lentigines. Lentigines are common among PUVA-treated patients with psoriasis, but rare in patients with vitiligo. • A 22-year-old woman who had been treated with PUVA for 3 years for vitiligo developed extensive and widespread stellate and irregularly shaped black and brown lentigines in exposed and unexposed skin areas (14A ). The lesions were present in both vitiliginous and normal skin.
Severe skin pain is an uncommon complication of PUVA and is characterized by a persistent severe prickling or burning pain lasting from 15 minutes to several hours. Analgesics, antihistamines, and topical and oral glucocorticoids have generally been ineffective. Gabapentin is effective in relieving neuropathic pain and has now been tried in this condition.
Acitretin Cardiovascular Capillary leak syndrome with associated edema has been reported following acitretin therapy. • A 79-year-old man with extensive psoriasis and joint involvement was given acitretin 10 mg/day for 12 days (16A ). He developed myalgia and non-pitting edema associated with large hemorrhagic lesions, and weight gain of 13 kg. Laboratory values were normal, except for moderate hypoproteinemia and hypoalbuminemia, and raised creatine kinase, myoglobin, and aspartate transaminase. The clinical and laboratory findings were suggestive of capillary leak syndrome. Withdrawal of acitretin resulted in slow regression of the edema over 2 months.
Sensory systems Ocular adverse effects with systemic retinoids have been reported, especially keratoconjunctivitis sicca. A 32-year-old man noted reduced visual acuity after treatment with acitretin 30 mg/day for one year (17A ).
Isotretinoin Nervous system There have been two reports of Guillain–Barré syndrome after isotretinoin therapy (18A ). • A 31-year-old man developed paresthesia, influenza-like symptoms, and areflexic tetraparesis after 5 weeks of isotretinoin therapy. • A 13-year-old boy took isotretinoin for 3½ months and developed lethargy, headaches, and a flaccid areflexic tetraparesis requiring ventilatory support.
Both patients received intravenous immunoglobulin and were discharged from hospital after 3 months.
Dermatological drugs, topical agents, and cosmetics
A review of isotretinoin-associated intracranial hypertension identified 179 case reports (19c ). The mean time from the start of therapy to the diagnosis of intracranial hypertension was 2.3 months. Withdrawal of isotretinoin resulted in resolution of the symptoms within weeks. Musculoskeletal Short (4- to 5-month) courses of isotretinoin for recalcitrant acne in young adults can cause asymptomatic radiographic changes of hyperostosis of the anterior longitudinal and spinal ligaments. Bone mineral density was measured in the lumbar spine and hip in 217 adolescents who took isotretinoin for 16 to 20 weeks (20C ). There was no clinically significant effect on bone mineral density, and neither was hyperostosis observed.
Tretinoin (All-trans retinoic acid) Respiratory Tretinoin is used in the treatment of acute promyelocytic leukemia. The most important adverse effect is the retinoic acid syndrome, which is characterized by fever, respiratory distress, weight gain, and extensive infiltration of soft tissue by maturing leukemic cells. It has an incidence of up to 30% and a median onset of 7–10 days. Retinoic acid syndrome has now been reported starting immediately after just one dose (21A ). • A 42-year-old woman with acute promyelocytic leukemia was given daunorubicin, cytarabine, and tretinoin 40 mg. Within hours of the first dose
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she became confused with increasing shortness of breath over 2 days. On the third day she had deteriorated to a degree where she had to be intubated and given intravenous dexamethasone 20 mg. She recovered quickly.
The authors of this report subsequently searched the literature and confirmed that no other cases had previously been reported in which the retinoic acid syndrome had started after just one dose of tretinoin. Hematologic Hemophagocytic syndrome has been reported in a patient receiving tretinoin (22A ). • A 56-year-old woman with acute promyelocytic leukemia developed severe retinoic acid syndrome on day 17 with pancytopenia, hepatosplenomegaly, increased triglycerides, ferritin, and liver enzymes. Tretinoin was withdrawn. Dexamethasone, started on day 20, and high-dose immunoglobulins were ineffective. A bone marrow biopsy showed abundant macrophages and no evidence of leukemia. Tests for secondary hemophagocytic syndrome were negative.
Hemophagocytic syndrome (reactive or secondary) is a serious complication of malignancies. It results from inappropriate stimulation of macrophages in bone marrow and lymphoid organs, leading to phagocytosis of blood cells and production of high amounts of pro-inflammatory cytokines. The authors speculate that in this patient the syndrome could have been related to release of macrophagestimulating cytokines by leukemic cells during retinoic acid syndrome.
References 1. Klein A. Contraindications and complications with the use of botulinum toxin. Clin Dermatol 2004;22:66–75. 2. Carruthers A, Carruthers J, Lowe NJ, Menter A, Gibson J, Nordquist M, Mordaunt J. One-year, randomised, multicenter, two-period study of the safety and efficacy of repeated treatments with botulinum toxin type A in patients with glabellar lines. J Drug Assessment 2004;7:63–82.
3. Naumann M, Jankovic J. Safety of botulinum toxin type A: a systematic review and metaanalysis. Curr Med Res Opin 2004;20:981–90. 4. Kawahara C, Okada Y, Tanikawa T, Fukusima AH, Tanaka Y. Severe hypercalcemia and hypernatremia associated with calcipotriol for treatment of psoriasis. J Bone Miner Metab 2004;22:159–62.
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5. Whitfeld M, Freeman S. Allergic contact dermatitis to ultra violet cured inks. Australas J Dermatol 1991;31:65–8. 6. Komerichi P, Kern T, Aberer W, Kranke B. Contact dermatitis from Solvent Yellow 146 in a permanent marker. Contact Dermatitis 2001;44:256. 7. Martin-Garcia C, Salazar LC, Gonzales-Mendioca R, Hinojosa M, Sanchez-Cano H. Contact dermatitis due to Edding 3000. Allergy 2004;59:235–6. 8. Gallo R, Sacco D, Ghigliotti G. Allergic contact dermatitis from VP/eicosene copolymer (GanexR V-220) in an emollient cream. Contact Dermatitis 2004;50:261. 9. Sanchez-Perez J, Garcia del Rio I, Alvarez Ruiz S, Garcia Diez A. Allergic contact dermatitis from direct dyes for hair colouration in hairdressers’ clients. Contact Dermatitis 2004;50(4):261–2. 10. Chou S, Kao S, Hsu W. Propecia-associated bilaterial cataract. Clin Exp Ophthalmol 2004;32:106–8. 11. Tosti A, Pazzaglia M, Soli M, Rossi A, Rebora A, Atzori L, Barbareschi M, Benci M, Voudouris S, Vena GA. Evaluation of sexual function with an international index of erectile function in subjects taking finasteride for androgenetic alopecia. Arch Dermatol 2004;140:857–8. 12. Kim H, Kye K, Seo Y, Suhr K, Lee J, Park J. A case of unilateral idiopathic gynecomastia aggravated by low-dose finasteride. Korean J Dermatol 2004;42:643–5. 13. Wulf H, Philipsen P. Allergic contact dermatitis to 5-aminolaevulinic acid methylester but not to 5-aminolaevulinic acid after photodynamic therapy. Br J Dermatol 2004;150:143–5. 14. Naser M, Wollina U, El Okby M, El Shiemy S. Psoralen plus ultraviolet A irradiation-induced
lentigines arising in vitiligo: involvement of vitiliginous and normal appearing skin. Clin Exp Dermatol 2004;29:380–2. Zamiri M, Bilsland D. Treatment of bath PUVAinduced skin pain with gabapentin. Br J Dermatol 2004;150:516–7. Estival J, Dupin M, Kanitakis J, Combemale P. Capillary leak syndrome induced by acitretin. Br J Dermatol 2004;150:150–2. Lois N, White M. Acitretin-associated maculopathy. Arch Ophthalmol 2004;122:928–30. Pritchard J, Appleton R, Howard RRA. Guillain– Barré syndrome seen in users of isotretinoin. BMJ 2004;328:1537. Fraunfelder F, Fraunfelder F, Corbett J. Isotretinoin-associated intracranial hypertension. Ophthalmology 2004;111:1248–50. DiGiovanna JJ, Langman CB, Tschen EH, Jones T, Menter A, Lowe NJ, Eichenfield L, Hebert AA, Pariser D, Savin RP, Smith SR, Jarratt M, Rodriguez D, Chalker DK, Kempers S, Ling M, Rafal ES, Sullivan S, Kang S, Shah LP, Wu E, Newhouse J, Pak J, Eberhardt DR, Bryce GF, McLane JA, Ondovik M, Chin C, Khoo KC, Rich P. Effect of a single course of isotretinoin therapy on bone mineral density in adolescent patients with severe, recalcitrant, nodular acne. J Am Acad Dermatol 2004;51:709–17. Battistella M, Burry LD, Seki JT. Retinoic acid syndrome after one dose of all-trans retinoic acid. J Oncol Pharm Pract 2004;10:149–54. Garcia-Suarez J, Banas H, Krsnik I, De Miguel D, Reyes E, Burgaleta C. Hemophagocytic syndrome associated with retinoic acid syndrome in acute promyelocytic leukaemia. Am J Hematol 2004;76:172–5.
15. 16. 17. 18. 19. 20.
21. 22.
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15
Antihistamines (H1 receptor antagonists)
In view of the prominent and diverse role of histamine in the pathophysiology of allergic diseases, therapeutic interventions often focus on blocking the effects of this biogenic amine. The first-generation antihistamines, such as chlorphenamine and promethazine, were effective in the management of allergic rhinitis, but were associated with severe unwanted adverse effects, particularly sedation and impaired psychomotor activity (1R ). However, they are still in use, primarily as over-the-counter products, and are often taken in combination with other drugs. In contrast, the newer second-generation histamine H1 receptor antagonists are highly effective and well tolerated treatments for allergic diseases. Although they are more usually thought of as being indicated for the immediate relief of symptoms, there is an increasing trend towards using second-generation H1 receptor antagonists in long-term therapy, rather than confining their use to treating the short-term manifestations of allergic diseases (2R ). Furthermore, topical antihistamines are important in the treatment of allergic rhinoconjunctivitis in children and adults (3R , 4R ). In general terms, second-generation antihistamines are considered to have a favorable adverse effects profile and are consequently amongst the most frequently prescribed drugs in the world. The potential adverse reactions that cause most concern include nervous system effects (1R ), cardiotoxic effects (5R ), and drug– drug or food–drug interactions. Importantly, the overall worldwide increase in allergy in infants and children has led to an awareness that the need for an excellent adverse effects profile is an important requirement for this class of drugs. Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29015-9 © 2007 Elsevier B.V. All rights reserved.
Cetirizine
(SED-15, 702; SEDA-27, 166;
SEDA-28, 178) Cetirizine is efficacious and well tolerated in a wide range of allergic conditions in both adults and young children (6R ). One study has suggested that the combination of cetirizine with the leukotriene receptor antagonist montelukast might result in enhanced symptom control in patients with seasonal allergic rhinitis; the combined therapy was well tolerated with no significant adverse effects (7C ). Nervous system The sedative effects of antihistamines remain a cause for concern. Cetirizine was reported to show a trend toward increased subjective sleepiness together with increased histamine H1 receptor occupancy in the brain compared with fexofenadine and placebo in a double-blind, placebo-controlled crossover study in 20 healthy volunteers (8C ). However, this study was flawed, as the observed effects were based on a 20 mg dose of cetirizine, which is twice the recommended dose for this antihistamine. Liver Although cetirizine undergoes minimal hepatic metabolism, there have been reports of acute hepatitis associated with it. • A 26-year-old man took cetirizine for 6 days for allergic rhinitis and developed acute hepatitis and seropositivity for liver-kidney microsomal antibodies (9A ). A liver biopsy was consistent with drug-related hepatitis. The patient had had two other bouts of acute hepatitis both associated with cetirizine.
The authors hypothesized that the complex formed by cetirizine and the H1 receptor had acted as a neoantigen, which triggered an autoimmune reaction against CYP-expressing liver cells. Although the potential for cetirizine
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to provoke liver injury is very low, the risk of hepatotoxicity in susceptible individuals should be considered. Reproductive system Gynecomastia is a proliferation of the glandular elements of the breast with concentric enlargement. It is common in elderly people and is related to a number of drugs, including H2 receptor antagonists. Two cases of gynecomastia were reported in two young children (one boy and one girl, both 6.5-years-old) taking cetirizine for rhinitis. In both cases the gynecomastia resolved after cetirizine was stopped (10A ). The authors speculated that cetirizine might have had an effect on lactotropic cell dopaminergic D2 receptors in the pituitary gland.
Chlorphenamine
(SED-15, 732;
SEDA-28, 178) Hematologic Acquired hemophilia with factor VIII inhibition has been associated with paracetamol and chlorphenamine. • Treatment of a flu-like illness in an 83-year old woman with paracetamol 600 mg/day and chlorphenamine 4 mg/day over 5 days resulted in admission with a severe bleeding disorder 11 days later (11A ). She had a severe anemia and reduced factor VIII activity associated with the presence of a high titer of factor VIII inhibitor. She was successfully treated with high-dose glucocorticoids, transfusions, and repeated infusions of factor VIII.
Desloratadine
(SED-15, 1074; SEDA-26, 181, 182; SEDA-27, 167; SEDA-28, 179)
Desloratadine is the primary metabolite of loratadine, with proven efficacy as a treatment for allergic rhinitis (12C , 13C ), chronic idiopathic urticaria (14C ), and cold-induced urticaria (15C ) and a favorable adverse effects profile (16R ). Desloratadine is also available in a syrup formulation that has been shown to be safe and effective in children with allergic rhinitis or chronic idiopathic urticaria (17C ). In particular, this study showed no adverse cardiovascular effects in 231 subjects aged 2–11 years.
Garry M. Walsh
Nervous system In terms of sedation, desloratadine appears to have an excellent profile. For example, the performance of healthy subjects was evaluated using a standard on-theroad driving test after dosing with desloratadine 5 mg, or diphenhydramine 50 mg (active control), or placebo. This objective study showed no significant differences between desloratadine and placebo in lateral position, whereas this was significantly increased by diphenhydramine (18C ). The authors concluded that at therapeutic dose desloratadine does not impair driving performance. Drug interactions Fluoxetine Fluoxetine is predominantly metabolized by CYP2D6. It may therefore reduce the metabolic clearance of co-administered drugs that are substrates for this isoenzyme, thereby increasing their plasma concentrations, in turn giving concerns in terms of potential adverse cardiac effects. In a randomized, placebo-controlled, open study, 54 healthy volunteers took desloratadine 5 mg plus fluoxetine 20 mg, desloratadine 5 mg plus placebo, or fluoxetine 20 mg plus placebo (19C ). Serial electrocardiography was performed at baseline and day 35. The most common adverse effect was headache (65%), while desloratadine co-administered with fluoxetine caused no significant changes in electrocardiograms or ventricular rate. The authors concluded that their findings supported previously published reports suggesting that desloratadine can be coadministered with known inhibitors of CYP2D6 without substantial concern for clinically significant cardiac events.
Dexchlorpheniramine
(SED-15,
1081) Nervous system A 32-year-old women had two episodes of akathesia secondary to dexchlorpheniramine which was given for a possible hypersensitivity reaction to a local anesthetic (20A ).
Antihistamines (H1 receptor antagonists)
Diphenhydramine
(SED-15, 1134; SEDA-27, 167; SEDA-28, 179)
Psychiatric A 56-year-old Caucasian developed acute delirium having taken diphenhydramine 300 mg/day for 2 days to treat a pruritic rash. He subsequently developed visual and auditory hallucinations with erratic aggressive behavior. The author concluded that the drug-induced delirium was associated with the combination of treatment for an infected wound with linezolid with diphenhydramine given for secondary drug-induced rash (21A ). Drug overdose There have been recent reports of the effects of overdose of diphenhydramine. • A 26-year-old man took 50 tablets each containing 50 mg of diphenhydramine in a suicide attempt (22A ). Despite supportive therapy he developed significant torsade de pointes and nearly died. • A 16-year-old youth developed confusion, sinus tachycardia, dilated pupils, and anhidrosis after taking an unknown quantity of a cold remedy containing diphenhydramine (23A ). An extremely abnormal attempt to draw a clock face was wholly corrected after two doses of 0.5 mg intravenous physostigmine.
The second case shows how intoxication with diphenhydramine can cause anticholinergic effects.
Ebastine
(SED-15, 1197; SEDA-26, 181; SEDA-27, 168) Susceptibility factors Ebastine is safe and effective in allergic rhinitis (24C ). Its pharmacokinetics are not affected by hepatic impairment (25C ). Nevertheless, the authors concluded that the dosage (10 mg/day) in patients with severely impaired hepatic function should be half that used in patients with mild to moderate impairment.
Hydroxyzine
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(SED-15, 1705)
Hydroxyzine is a piperazine first-generation sedating antihistamine with antipruritic effects widely used for skin allergies, particularly in children.
Cardiovascular The dysrhythmogenic effects of antihistamines have been reviewed in previous annuals (SEDA-25, 183; SEDA-26, 180). • A 9-year-old girl taking hydroxyzine for nocturnal itch developed a supraventricular tachycardia (26A ). She had a history of three episodes of palpitation with chest tightness while taking hydroxyzine for 5 months. Her clinical course suggested that the supraventricular episodes occurred in association with hydroxyzine. Hydroxyzine was withdrawn and after treatment her heart rate and rhythm returned to normal.
Cardiac toxicity is very rarely reported with hydroxyzine; before this case there had been no reported cases of supraventricular tachycardia due to hydroxyzine or its active metabolite, cetirizine.
Ketotifen
(SED-15, 1980)
Placebo-controlled studies In a double-masked, multicenter, fellow-eye, placebo-controlled study, an ophthalmic solution of ketotifen fumarate 0.025% was compared with vehicle placebo in children aged 8–16 years after single and multiple conjunctival allergen challenges (27C ). Ketotifen fumarate significantly inhibited ocular itching compared with placebo at all post-challenge time-points together with significant reduction of hyperemia, chemosis and lid swelling. Adverse events were comparable to placebo and no subject withdrew prematurely because of an adverse event. The authors concluded that ketotifen fumarate ophthalmic solution is an effective and safe treatment option for children with allergic conjunctivitis.
Levocetirizine (SED-15, 2038; SEDA-26, 182, 183; SEDA-27, 169; SEDA-28, 180) Levocetirizine is the R enantiomer of cetirizine dihydrochloride, with pharmacodynamically and pharmacokinetically favorable characteristics, including high systemic availability (77%), a rapid onset of action, limited distribution, and a low extent of metabolism (about 15%) (28r , 29r ).
164 Placebo-controlled studies In a 6-month, double-blind, placebo-controlled, multicenter, multinational trial of the effect of levocetirizine on symptoms (rhinorrhea, sneezing, nasal congestion, and nasal and ocular pruritus) and quality of life outcome measures in 551 patients with persistent rhinitis, levocetirizine significantly improved both symptoms and quality of life and reduced the overall costs of the disease; it was also well tolerated, an important issue given the length of treatment (30C ). Comparative studies Levocetirizine is safe and effective in chronic urticaria (31R ) and allergic rhinitis (32R ). A double-blind, placebocontrolled, parallel-group study used an environmental exposure chamber to show that levocetirizine was more effective in controlling the symptoms of seasonal allergic rhinitis in sensitive individuals than desloratadine; both drugs were safe and well tolerated (33C ). In a similar study levocetirizine and fexofenadine were both effective and safe in seasonal allergic rhinitis, but levocetirizine had a longer duration of action (34C ). Another comparative study showed that desloratadine and levocetirizine had similar effects on nasal symptoms in patients with rhinitis, although levocetirizine had a faster onset of action; again both drugs were well tolerated (35C ).
Loratadine
(SED-15, 2162; SEDA-26, 182; SEDA-27, 169; SEDA-28, 181)
Gastrointestinal Claritin-D1 24-Hour (C-D 24) is a combined modified-release formulation containing 10 mg of loratadine in the tablet film coating for immediate release and 240 mg of pseudoephedrine sulfate in the core for slow release. These tablets are large (1.27 cm in diameter) and there have been reports of esophageal/upper-airway obstruction associated with their use (36C ). However, in a study of the rate of events among cases validated by medical record review did not indicate conclusive evidence of a relation between the use of C-D 24 and esophageal/upper-airway obstruction (37C ). The authors concluded that it is important to validate findings from claims data using medical records.
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Garry M. Walsh
Respiratory Identification of uncommon adverse reactions to antihistamines can be difficult, as they can mimic the underlying disease for which the drug was prescribed. One such is edema of the glottis. • Edema of the glottis occurred on four separate occasions in a 27-year-old woman who had taken loratadine for allergic rhinitis (38A ). She had no further symptoms once loratadine was withdrawn. A skin test with loratadine confirmed sensitivity to the drug.
The authors commented that this adverse effect is very rare. Sensory systems Allergic conjunctivitis is an allergen-induced inflammatory response whose symptoms include ocular itching, redness/ hyperemia, chemosis, and tear production (39R ). While systemic antihistamines are useful for the treatment of allergic rhinoconjunctivitis in children and adults, impairment of nervous system function and significant drying effects of the ocular surface are both more common than is generally realized (40R ). For example, both cetirizine and loratadine increase symptoms associated with ocular dryness, including increased corneal and conjunctival staining and ocular discomfort in healthy individuals, loratadine having a more marked effect (41R ). Teratogenicity Hypospadias is a birth defect in which the urethral opening is located along the underside of the penis, scrotum, or perineum. It affects about seven in 1000 male infants in the USA and is usually corrected by surgery. A study in Sweden showed that among male infants born to women who had taken loratadine while pregnant, the prevalence of hypospadias was twice that of the general population (42C ). However, a comprehensive analysis of the National Birth Defects Prevention Study by the Centers for Disease Control and Prevention in the USA further assessed any potential association between loratadine and hypospadias (43C ). This study showed that there was no increase in the risk of second- or thirddegree hypospadias among the sons of women who used loratadine in early pregnancy.
Antihistamines (H1 receptor antagonists)
Meclozine
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(SED-15, 2226)
Psychiatric Auditory hallucinations have been reported in a 42-year-old man taking a combination of meclozine 25 mg bd and metaxalone 800 mg bd (44A ). The hallucinations ceased when the medications were withdrawn.
Olopatadine Placebo-controlled studies Olopatadine 0.2% was compared with placebo in a double-masked, randomized, placebo-controlled, study conducted during the spring pollen season thereby facilitating examination of natural exposure to allergen rather than using conjunctival challenge (45C ). Compared with placebo, olopata-
dine significantly reduced ocular itching and redness relative to the pollen count and pollen period. Adverse effects were comparable to placebo, and no subject withdrew. Similar findings in terms of efficacy and safety in the treatment of ocular allergy were reported for ophthalmic epinastine or levocabastine (46C ) and olopatadine (47C ).
Oxatomide
(SED-15, 2644)
Nervous system West syndrome occurred in a 4-month-old girl who had been given oxatomide 1 mg/kg/day for atopic dermatitis (48A ). Eleven days later she developed symmetrical tonic spasms; oxatomide was withdrawn and the spasms were controlled with ACTH.
References 1. Meltzer EIO, Welch MJ. Adverse effects of H1 -receptor antagonists in the central nervous system. In: Simons FER, editor. Histamine and H1 -receptor antagonists in allergic disease. Clinical Allergy & Immunology Series. New York: Marcel Dekker Inc; 1996. p. 357–81. 2. Walsh GM. Emerging safety issues regarding the long-term usage of H1 -receptor antagonists. Expert Opin Drug Saf 2002;1(3):225–35. 3. Fireman P. Therapeutic approaches to allergic rhinitis: treating the child. J Allergy Clin Immunol 2000;105:S616–21. 4. Bielory L. Update on ocular allergy treatment. Expert Opin Pharmacother 2002;3:541–53. 5. Woosley RL. Cardiac actions of antihistamines. Annu Rev Pharmacol Toxicol 1996;36:233–52. 6. Curran MP, Scott LJ, Perry CM. Cetirizine: a review of its use in allergic disorders. Drugs 2004;64:523–61. 7. Ciprandi G. Antihistamines added to an antileukotriene in treating seasonal allergic rhinitis: histamine and leukotriene antagonism. Allerg Immunol (Paris) 2004;36(2):67–70. 72. 8. Tashiro M, Sakurada Y, Iwabuchi K, Mochizuki H, Kato M, Aoki M, Funaki Y, Itoh M, Iwata R, Wong DF, Yanai K. Central effects of fexofenadine and cetirizine: measurement of psychomotor performance, subjective sleepiness, and brain histamine H1 -receptor occupancy using 11 C-doxepin positron emission tomography. J Clin Pharmacol 2004;44:890–900.
9. Pompilli M. Recurrent acute hepatitis associated with use of cetirizine. Ann Pharmacother 2004;38(11):1844–7. 10. Louis M-P, Heran I, Peyriere H, Blayac J-P, Hillaire-Buys D. Two cases of gynaecomastia with cetirizine, a second-generation antihistamine. Therapie 2004;59(1):163–4. 11. Fulmularo G, De Maria S, Minisola G, Nicotra GC. Severe acquired hemophilia with factor VIII inhibition associated with acetaminophen and chlorpheniramine. Ann Pharmacother 2004;38(9):1432–4. 12. Simons FE, Prenner BM, Finn A Jr, Desloratadine Study Group. Efficacy and safety of desloratadine in the treatment of perennial allergic rhinitis. J Allergy Clin Immunol 2003;111:617– 22. 13. Horak F, Stubner P, Zieglmeyer R, Harris AG. Comparison of the effects of desloratadine 5mg daily and placebo on nasal airflow and seasonal allergic rhinitis symptoms induced by grass pollen exposure. Allergy 2003;58:481–5. 14. Monroe E, Finn A, Patel P, Guerrero R, Ratner P, Bernstein D, Desloratadine Uritcaria Study Group. Efficacy and safety of desloratadine 5 mg once daily in the treatment of chronic idiopathic urticaria: a double-blind, randomized, placebo-controlled trial. J Am Acad Dermatol 2003;48:535–41. 15. Juhlin L. Inhibition of cold urticaria by desloratadine. J Dermatol Treat 2004;15:51–4.
166 16. Murdoch D, Goa KL, Keam SJ. Desloratadine. Drugs 2003;63:2052–77. 17. Bloom M, Staudinger H, Herron J. Safety of desloratadine syrup in children. Curr Med Res Opin 2004;20:1959–65. 18. Vuurman EF, Rikken GH, Muntjewerff ND, De Halleux F, Ramaekers JG. Effects of desloratadine, diphenhydramine, and placebo on driving performance and psychomotor performance measurements. Eur J Clin Pharmacol 2004;60(5):307–13. 19. Gupta S, Banfield C. Pharmacokinetics/pharmacodynamics of desloratadine and fluoxetine in healthy volunteers. J Clin Pharmacol 2004;44:1252–9. 20. Caceres Calle O, Fernandex-Benitez M. Allergy to dexchlorpheniramine. Study of a case. Allergol Immunopathol (Madr) 2004;32:306–9. 21. Serio RN. Acute delirium associated with combined diphenhydramine and linezolid use. Ann Pharmacother 2004;38(1):62–5. 22. Joshi AK, Sljapic T, Borghei H, Kowey PR. Case of polymorphic ventricular tachycardia in diphenhydramine poisoning. J Cardiovasc Electrophysiol 2004;15(5):591–3. 23. Richardson WH, Williams SR, Carstairs SD. A picturesque reversal of antimuscarinic delirium. J Emerg Med 2004;26:463. 24. Ratner P, Hampel F, Van Bavel J, Howland W. A randomized, double-blind, placebo-controlled study comparing the efficacy and safety of ebastine (20 mg and 10 mg) to loratadine 10 mg once daily in the treatment of seasonal allergic rhinitis. J Investig Allergol Clin Immunol 2004;14(1):56– 63. 25. Lasseter KC, Dilzer SC, Vargas R, Waldman S, Noveck RJ. Pharmacokinetics and safety of ebastine in patients with impaired hepatic function compared with healthy volunteers: a phase I open-label study. Clin Pharmacokin 2004;43(2):121–9. 26. Wong AR, Rasool AHG. Hydroxyzine-induced supraventricular tachycardia in a nine-year-old child. Singapore Med J 2004;45:90–2. 27. Abelson MB, Ferzola NJ, McWhirter CL, Crampton HJ. Efficacy and safety of single- and multiple-dose ketotifen fumarate 0.025% ophthalmic solution in a pediatric population. Pediatr Allergy Immunol 2004;15:551–7. 28. Tillement JP, Testa B, Bree F. Compared pharmacological characteristics in humans of racemic cetirizine and levocetirizine, two histamine H1 -receptor antagonists. Biochem Pharmacol 2003;66:1123–6. 29. Molimard M, Diquet B, Benedetti MS. Comparison of pharmacokinetics and metabolism of desloratadine, fexofenadine, levocetirizine and mizolastine in humans. Fundam Clin Pharmacol 2004;18(4):399–411. 30. Bachert C, Bousquet J, Canonica GW, Durham SR, Klimek L, Mullol J, Van Cauwenberge PB, Van Hammee G, XPERT Study Group. Levocetirizine improves quality of life and reduces costs in long-term management of persistent allergic rhinitis. J Allergy Clin Immunol 2004;114:838–44.
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31. Kapp A, Wedi B. Chronic urticaria: clinical aspects and focus on a new antihistamine, levocetirizine. J Drugs Dermat 2004;3(6):632–9. 32. Day AJ, Ellis AK, Rafeiro E. Levocetirizine: a new selective H1 -receptor antagonist for use in allergic disorders. Drugs Today (Barc) 2004;40(5):415–21. 33. Day JH, Briscoe MP, Rafeiro E, Ratz JD. Comparative clinical efficacy, onset and duration of action of levocetirizine and desloratadine for symptoms of seasonal allergic rhinitis in subjects evaluated in the Environmental Exposure Unit (EEU). Int J Clin Pract 2004;58(2):109–18. 34. Horak F, Eglmayer PU, Zieglmayer R, Kavina A, Lemell P. Levocetirizine has a longer duration of action on improving total nasal symptoms score than fexofenadine after single administration. Br J Clin Pharmacol 2005;60(1):24–31. 35. Passalacqua G, Guerra L, Compalati E, Massacane P, Rogkakou A, Zanella C, BaenaCagnani R, Canonica GW. Comparison of the effects in the nose and skin of a single dose of desloratadine and levocetirizine over 24 hours. Int Arch Allergy Immunol 2004;135:143–7. 36. Farinas E, Honig P. Upper gastrointestinal obstruction associated with Claritin-D1 24-Hour extended release tablets. J Allergy Clin Immunol 1997;100(3):427–8. 37. Manda B, Drinkard CR, Shatin D, Graham DJ. The risk of esophageal obstruction associated with an anti-allergy medication (Claritin-D 24Hour-original formulation). Pharmacoepidemiol Drug Saf 2004;13(1):29–34. 38. Bonanni L, Parmiani S, Sturbini S. Glottis oedema due to loratadine. Allergy 2004;59(1):116–7. 39. Abelson MB, Smith L, Chapin M. Ocular allergic disease: mechanisms, disease sub-types, treatment. Ocular Surface 2003;1:127–49. 40. Qidwai JC, Watson GS, Weile JM. Sedation, cognition, and antihistamines. Curr Allergy Asthma Rep 2002;2:216–22. 41. Ousler GW, Wilcox KA, Gupta G, Abelson MB. An evaluation of the ocular drying effects of 2 systemic antihistamines: loratadine and cetirizine hydrochloride. Ann Allergy Asthma Immunol 2004;93(5):460–4. 42. Kallen B. Use of antihistamine drugs in early pregnancy and delivery outcome. J Matern Fetal Neonatal Med 2002;11:146–52. 43. Centres for Disease Control and Prevention. Evaluation of an association between loratadine and hypospadias—United States, 1997–2001. Morb Mortal Wkly Rep 2004;1953(10):219–21. 44. Kuykendall JR, Rhodes RS. Auditory hallucinations elicited by combined meclizine and metaxalone use at bedtime. Ann Pharmacother 2004;38:1968–9. 45. Abelson MB, Gomes PJ, Vogelson CT, Pasquine TA, Gross RD, Turner FD, Wells DT, Bergamini MV, Robertson SM. Clinical efficacy of olopatadine hydrochloride ophthalmic solution 0.2% compared with placebo in patients with allergic conjunctivitis or rhinoconjunctivitis: a randomized, double-masked environmental study. Clin Ther 2004;26(8):1237–48.
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46. Whitcup SM, Bradford R, Lue J, Schiffman RM, Abelson MB. Efficacy and tolerability of ophthalmic epinastine: a randomized, double-masked, parallel-group, active- and vehicle-controlled environmental trial in patients with seasonal allergic conjunctivitis. Clin Ther 2004;26(1):29–34. 47. Lanier BQ, Finegold I, D’Arienzo P, Granet D, Epstein AB, Ledgerwood GL. Clinical efficacy of
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olopatadine vs epinastine ophthalmic solution in the conjunctival allergen challenge model. Curr Med Res Opin 2004;20(8):1227–33. 48. Yamashita Y, Isagai T, Seki Y, Ohya T, Nagamitsu S, Matsuishi T. West syndrome associated with administration of a histamine H1 antagonist, oxatomide. Kurume Med J 2004;51:273–5.
Markus Joerger, Katharina Hartmann, and Max Kuhn
16 Drugs acting on the respiratory tract INHALED GLUCOCORTICOIDS (SED-15, 958; SEDA-26, 186; SEDA-27, 174; SEDA-28, 184) Overall safety data show that the use of inhaled glucocorticoids is associated with systemic adverse effects in clinical practice (1R ), encompassing an approximately two-fold increased risk of skin bruising and diminished bone mineral density in patients with COPD using moderate to high doses of inhaled triamcinolone (2C ), and reduced short-term growth velocity in children using budesonide 200 micrograms/day (3C ). While fluticasone propionate is absorbed to a greater extent in healthy subjects than in asthmatic patients with reduced lung function (independently of the mode of administration), budesonide is absorbed to an almost identical extent in healthy and asthmatic subjects (4c ). The data suggest that there are important differences in the pattern of absorption between different glucocorticoids. However, few studies have shown a relation between the extent of absorption and the systemic adverse effects of the various compounds.
Adverse effects of inhaled glucocorticoids on the mouth and throat While they are usually not serious, the adverse effects of glucocorticoids on the mouth and throat are of clinical importance. Hoarseness and pharyngeal discomfort occur with a Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29016-0 © 2007 Elsevier B.V. All rights reserved.
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prevalence of 5–10% in patients with asthma who use inhaled glucocorticoids (5R ). Local adverse events are even more common in children. In a prospective cross-sectional, cohort study, 63% of children aged under 6 years and 60% of the older ones reported at least one local adverse event (6c ). Treatment consisted of beclomethasone dipropionate (mean daily dose 721 micrograms) or budesonide (mean daily dose 835 micrograms) for at least 1 month. Inhaler-dependent cough was reported by 40% of the children, thirst by 22%, hoarseness by 14%, dysphonia by 11.1%, oral candidiasis by 11%, perioral dermatitis by 2.9%, and tongue hypertrophy by 0.1%. Perioral dermatitis was thought to be due to a direct local effect of inhaled glucocorticoids on the facial skin (5R ). In adults, inhaler-dependent cough was reported in 34% and hoarseness or throat symptoms in 58% of those who used beclomethasone dipropionate or budesonide (7c ). There was an increased risk of hoarseness with fluticasone propionate compared with beclomethasone dipropionate, and with metered-dose inhalers compared with dry powder inhalers (8c , 9C ). Oropharyngeal candidiasis has an incidence of up to 70% in users of inhaled glucocorticoids, depending on the diagnostic criteria (5R ). The use of breath-actuated metered-dose inhalers leads to high oropharyngeal deposition of glucocorticoids, which can be 80% of the delivered dose (5R ). Spacer devices reduce the oropharyngeal deposition of inhaled aerosols, improve intrapulmonary deposition (10c ), and reduce local adverse effects (11R ). Oropharyngeal deposition of inhaled glucocorticoids is less than 60% of the delivered dose when dry powder inhalers are used, but patients should still be advised to rinse the mouth after inhaling from a dry powder inhaler, in order to minimize local adverse effects (8c ). With preventive measures such as rinsing, oropharyngeal candidiasis is usually seen only in patients
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with poor mouth hygiene or in association with other diseases or therapies (for example diabetes mellitus, immunosuppression, concomitant oral glucocorticoids). Increased dosing frequency is reportedly correlated with the incidence of local adverse effects (dysphonia and candidiasis) (12C ). However, oral candidiasis and hoarseness did not occur with once-daily budesonide delivered by TurbuhalerTM , if it was not preceded by local glucocorticoid treatment (8c ). Preceding treatment with inhaled glucocorticoids may result in carry-over effects with respect to local adverse events (5R ).
(at least 800 micrograms/day) (17c ). However, these studies were cross-sectional and nonrandomized and included patients who had also taken variable amounts of oral glucocorticoids. Skin bruising associated with moderate to high doses of inhaled glucocorticoids has also been evaluated in randomized, placebo-controlled studies (18C –20C ). In the first of these trials, patients with mild COPD who used budesonide 400 micrograms/day over 3 years had significantly more skin bruising than patients who used placebo (10% versus 4%) (20C ). The results were more controversial for fluticasone propionate at a daily dose of 1000 micrograms, as there was no correlation with skin bruising in 1465 patients with COPD who used salmeterol 50 micrograms bd, fluticasone propionate 500 micrograms bd, the combination, or placebo (19C ). In a further randomized, placebo-controlled study, skin bruising was more common in patients with COPD using fluticasone propionate 500 micrograms bd compared with placebo (7.3% versus 4.1%) (18C ). The latter three studies (18C –20C ) relied on unsolicited complaints or direct observation of large ecchymoses on the forearms. Such observations may underestimate the true frequency of skin bruising. A recent analysis of the results from the Lung Health Study II focused on skin manifestations of inhaled glucocorticoids and may have provided more reliable data on the frequency of skin-related adverse events (21C ). Data from 1116 patients with COPD in a double-blind, randomized, placebo-controlled study of the efficacy and safety of inhaled triamcinolone acetonide 1200 micrograms/day were collected, and skinrelated adverse events were assessed every 6 months using a structured questionnaire over 3.5–4.5 years. Among highly compliant subjects, significantly more patients using triamcinolone acetonide had skin bruising (11% versus 3.5%) and slow skin healing (2.4% versus 0.5%) compared with patients taking placebo. Older men in the triamcinolone group with good inhaler compliance appeared to be at the greatest risk of bruising. Adverse skin manifestations were not more frequent in patients who either did not use their assigned triamcinolone inhaler treatment or used average daily doses below 600 micrograms. There was no association between easy skin bruising and either suppressed adrenal function or
Drugs acting on the respiratory tract
Endocrine Adrenal suppression in children The longterm effects of budesonide on adrenal function have been assessed in 63 asthmatic children using budesonide 400 micrograms/day, nedocromil 16 mg/day, or placebo over 3 years (13C ). There were no differences in serum cortisol concentrations after ACTH stimulation between the three treatment groups, regardless of the time after ACTH administration or months of follow-up. Cumulative inhaled glucocorticoid exposure did not affect the serum cortisol response to ACTH or urinary free cortisol excretion at 3 years. The effects of budesonide aqueous nasal spray (64 micrograms/day) on adrenal function were studied in a 6-week double-blind, placebocontrolled study in 78 patients with allergic rhinitis aged 2–5 years (14C ). Adrenal function, evaluated by the mean change in morning plasma cortisol concentration after cosyntropin stimulation, was not suppressed. This dose of budesonide by nasal spray is unlikely to have significant systemic activity.
Adverse effects of inhaled glucocorticoids on the skin Inhaled glucocorticoid-associated cutaneous adverse effects have not previously been comprehensively analysed. Easy skin bruising is a well recognized systemic adverse effect of inhaled glucocorticoids, particularly with high doses (15c –17c ) and in older individuals (16c , 17c ). Skin bruising has been associated with suppressed adrenal function in patients using high-dose beclomethasone or budesonide
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loss of bone mineral density. Potential confounding by concurrent acetylsalicylic acid or non-steroidal anti-inflammatory drugs on skin manifestations could not be ruled out. Musculoskeletal Growth velocity Pre- and postmarketing safety data of inhaled budesonide suspension in children (18 years and younger) have been reviewed by the manufacturers (22R ). Pooled data from three randomized, placebo-controlled studies (23C –25C ), their open extensions (26C – 28C ), a fourth open study (29c ), and five other studies (30C –32r ) in patients treated with budesonide suspension 0.25–2.0 mg/day showed small differences in short-term growth velocity (less than 1 cm/year) between children who used budesonide and those who used the reference treatment in two of the five trials that evaluated this variable. The incidences of adrenal suppression, oropharyngeal events, and infections did not increase with budesonide. However, there were two cases of adrenal insufficiency in children using budesonide during postmarketing surveillance. Data on short-term inhibition of growth velocity with budesonide are in accordance with data from earlier studies with beclomethasone and fluticasone propionate (0.8–1.5 cm growth velocity reduction/year) (33C , 34C ). The effects of budesonide on growth velocity were transient, mostly occurred within the first year of treatment, and were usually without any effect on final adult height compared with asthmatic controls and healthy siblings. In 625 children aged 1–3 years with recurrent wheezing, who were randomized in a 3:1 ratio to treatment for 1 year with fluticasone propionate 100 micrograms bd or sodium cromoglicate 5 mg qds in a randomized, open study, mean adjusted growth rate did not differ significantly between the groups (35C ). The growth rate comparison was independent of age, sex, previous use of glucocorticoids, or measurement technique (height versus length). However, the study did not contain a 6-month run-in or 6-month follow-up period as specified in regulatory guidelines on growth studies. Bone mineral density The effects of high-dose fluticasone propionate on biochemical markers of bone metabolism and bone mineral density
Markus Joerger, Katharina Hartmann, and Max Kuhn
have been assessed in a cross-sectional study in 49 asthmatic children who used fluticasone propionate at least 1000 micrograms/day for at least 6 months compared with 32 healthy controls (36C ). There was no significant reduction in bone metabolism and age-corrected bone mineral density (measured by dual-energy X-ray absorptiometry). The results suggested that even high doses of fluticasone propionate over prolonged treatment periods (mean 2.86 years) do not significantly affect bone mineral density in children with asthma at a critical time of skeletal growth. Susceptibility factors Age The long-term effects of fluticasone propionate have been assessed in 55 asthmatic children aged 6–10 years in a double-blind study, comparing a step-down dose approach with 1000 micrograms/day and subsequent dose reductions to 500, 200, and 100 micrograms/day, versus a constant daily dose of 200 micrograms (37c ). There were dose-dependent reductions in growth velocity, adrenal function (as assessed by urine cortisol excretion), and biochemical bone turnover at daily doses of 1000 and 500 micrograms, compared with 200 micrograms. Bone mineral density did not change significantly over time or between the groups. Standing height, growth velocity, bone mineral density, adrenal function, and biochemical bone turnover were comparable in the two groups at the end of study, suggesting full reversibility of any effect of fluticasone propionate with dose reductions. Thus, prolonged high-dose fluticasone propionate can result in clinically relevant but reversible systemic adverse effects. Emphysema To test the hypothesis that the systemic activity of fluticasone propionate mainly depends on alveolar absorption, and that pulmonary emphysema results in reduced lung absorption, the systemic activity of high-dose fluticasone propionate was assessed in 10 patients with COPD and compared with 10 patients with significant emphysema (38c ). All used fluticasone propionate 2000 micrograms/day via a spacer for 2 weeks after a 1-week washout period. Overnight urinary cortisol excretion and serum osteocalcin concentration, markers of the systemic activity of fluticasone propionate, fell to a similar extent in both groups, suggesting
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that alveolar absorption does not have a significant effect on the systemic activity of high-dose inhaled fluticasone propionate. Poor inhalation technique, rather than reduced alveolar absorption, might account for impaired pulmonary drug absorption in patients with severe pulmonary obstruction. There was further confirmation of impaired adrenal function, measured by stimulated plasma cortisol concentrations and overnight urinary cortisol excretion, after high-dose fluticasone propionate in 10 healthy controls but not in 10 asthmatic patients (39c ) who used fluticasone propionate 2000 micrograms/day via a spacer over 2 weeks after a 1-week washout period.
Endocrine The effect of increasing doses of mometasone furoate and fluticasone propionate by dry powder inhaler on adrenal function was studied by using overnight urinary cortisol in 21 patients with asthma (43C ). Patients were randomized in a crossover fashion to receive 2-weekly consecutive doubling doses of either fluticasone propionate (500, 1000, and 2000 micrograms/day) or mometasone furoate (400, 800, and 1600 micrograms/day). Both treatments were associated with significant suppression of adrenal function at high and medium doses.
Drugs acting on the respiratory tract
Drug formulations Hydrofluoroalkane-134a (HFA-134a) beclomethasone dipropionate extra-fine aerosol 800 micrograms/day has been compared with the conventional chlorofluorocarbon formulation 1500 micrograms/day in a 6-month, double-blind, randomized study in 141 patients with asthma (40C ). The extrafine aerosol reformulation delivers up to 60% of inhaled beclomethasone to the lungs, compared with 15% with conventional formulations. Efficacy and adverse events were comparable. The safety and acceptability of budesonide inhaled from the dry powder inhalers Easyhaler (GionaTM , EasyhalerTM ) and Turbohaler (PulmicortTM TurbuhalerTM ) have been compared in 229 children with asthma in a 6-month, double-blind, randomized study (41C ). For the first 2 months, the children inhaled budesonide 400 micrograms bd, and thereafter 100 micrograms bd for 4 months. While the two treatments were equally effective, budesonide inhaled from TurbuhalerTM had slightly but significantly greater systemic adverse events than budesonide from EasyhalerTM , as measured by urinary free cortisol excretion and growth rate velocity. Mometasone furoate Mometasone furoate 400 micrograms/day by dry powder inhaler has been compared with fluticasone propionate 250 micrograms bd via metric-dose inhaler in 167 asthmatic adults and adolescents over 8 weeks in an open randomized study (42C ). Drug-related adverse effects did not differ significantly (13% versus 8.2%), and the most common were headache (3.7% versus 2.4%), dysphonia (2.4% versus 0%), and oral candidiasis (2.4% in both groups).
BETA2 -ADRENOCEPTOR AGONISTS (SED-15, 448; SEDA-26, 190; SEDA-27, 179; SEDA-28, 188) Comparative studies The pulmonary and extra-pulmonary effects of cumulative doses of formoterol and salbutamol have been compared in 12 patients with moderate to severe COPD in a double-blind, randomized, crossover study (44c ). The patients inhaled 10 doses of formoterol 120 micrograms via TurbuhalerTM , salbutamol 2000 micrograms, or placebo at intervals of 2 minutes. There were no clinically important or statistically significant changes in blood pressure, heart rate, QTc interval, or T wave amplitude on the electrocardiogram, plasma potassium concentration, or oxygen saturation between the groups. One woman with ventricular extra beats before the study had ventricular trigeminy after both formoterol and salbutamol. The low frequency of formoterolor salbutamol-associated extrapulmonary adverse effects may be explained by prior regular use of beta2 -adrenoceptor agonists with subsequent receptor downregulation. High doses of formoterol or salbutamol, as used in this study, are safe if taken by patients with moderate to severe COPD.
Formoterol
(SED-15, 1443; SEDA-26, 191; SEDA-27, 179; SEDA-28, 188) Drug formulations A single dose of formoterol 12 micrograms from the HFA formulation ModuliteTM , a pressurized metered dose
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inhaler, the ForadilTM AerolizerTM (dry powder inhaler), or the ForadilTM chlorofluorocarbon device have been assessed in a double-blind, randomized, placebo-controlled study in 38 patients with mild to moderate asthma (45C ). Systemic adverse effects, as assessed by serum potassium, heart rate, and pharmacokinetic profiles, were comparable. Possible treatmentassociated adverse effects were nausea in one patient in the ModuliteTM group and epigastric pain in one patient in the ForadilTM chlorofluorocarbon group. The ModuliteTM formoterol formulation results in similar lung absorption and systemic adverse events compared with already licensed formulations. Susceptibility factors Age High-dose tolerability and systemic dose potency of cumulative doses of formoterol and terbutaline have been studied in 20 children with asthma aged 6–11 years in a double-blind, randomized, crossover study (46c ). The children took 10 doses of formoterol 4.5 micrograms or terbutaline 500 micrograms by dry powder inhaler over 1–2.5 hours. The fall in plasma potassium concentration and QTc interval prolongation were significantly more pronounced with terbutaline than with formoterol, whereas systolic blood pressure, QRS duration, and PR interval were affected to the same extent. In spite of the possible differences between children and adults in the pattern of deposition of inhaled glucocorticoids, these results corroborate previous findings with high doses of formoterol and terbutaline in adults with asthma (47c , 48C ).
Levosalbutamol (levalbuterol) (SEDA-26, 191; SEDA-28, 189) Levosalbutamol is the R enantiomer of racemic salbutamol (albuterol). A dose of 0.63 mg has been suggested to be equipotent to 2.5 mg of racemic salbutamol (49C ). Comparative studies Levosalbutamol has been compared with racemic salbutamol in acute asthma in a prospective, open, nonrandomized pilot study in 91 adults with acute asthma (50c ), who received three doses of levosalbutamol 0.63, 1.25, 2.5, 3.75, or 5.0 mg,
Markus Joerger, Katharina Hartmann, and Max Kuhn
or racemic salbutamol 2.5 or 5.0 mg within 1 hour. Levosalbutamol 1.25 mg was more effective than racemic salbutamol 5 mg. Since the most effective dose of racemic salbutamol was not given, the equipotent dose ratio (racemic salbutamol/levosalbutamol) might be higher than has previously been estimated. S salbutamol plasma concentrations correlated negatively with FEV1 , which may be ascribed to opposite actions of the two isomers, as has been suggested in preclinical studies (51E – 53E ). In contrast, the change in peak expiratory flow after the administration of home inhaled or nebulized levosalbutamol versus racemic salbutamol before admission to the emergency department was not different in 298 patients with acute bronchospastic or obstructive pulmonary conditions in another prospective, open study (54c ). No safety end-points were assessed in this study.
Salbutamol
(SED-15, 3093; SEDA-26, 191; SEDA-27, 179; SEDA-28, 189)
Cardiovascular Myocardial injury is very infrequent following the administration of salbutamol. Salbutamol-mediated activation of cardiac and peripheral beta2 -adrenoceptors, inducing positive chronotropic and inotropic effects and redistribution of coronary blood flow, have been discussed as possible causes (55A ). • An 84-year-old woman with no history of cardiac disease and no risk factors developed an acute transmural anteroseptal myocardial infarction about 12 hours after beginning salbutamol and ipratropium bromide rescue therapy for acute exacerbated COPD. She was given five doses of salbutamol 5 mg plus ipratropium bromide 500 micrograms at 2-hour intervals. Arterial blood gas analysis showed a pH of 7.27, PaO2 of 6.13 kPa (46 mmHg) and PaCO2 of 8.53 kPa (64 mmHg) when breathing room air. Urgent coronary angiography showed no obstructive coronary artery disease or thrombosis. Salbutamol was suggested to be the probable cause of myocardial infarction in this patient.
As a note of caution, the hyperadrenergic state with acute dyspnea and severe hypoxemia should be considered as alternative causes of myocardial injury in this case.
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Nervous system Tremor is a well known adverse effect of beta2 -adrenoceptor agonists, but difficult to quantify. A laser pointer technique may facilitate the assessment of salbutamolinduced tremor (56c ). In 44 patients with obstructive lung disease and 65 healthy controls, who received repeated inhalations of salbutamol up to a cumulative dose of 1600 micrograms, tremor was tested by asking them to center a laser pointer to a target of 10 concentric circles at a distance of 5 meters. Salbutamol significantly and dose-dependently increased tremor severity in patients and controls. Tremor quantification by laser pointer was sensitive and reproducible and superior to a questionnaire. However, the high dependency of the method on eye-hand co-ordination and concentration is of concern.
use of beta2 -adrenoceptor agonists (60E ). After an initial exploratory analysis of their asthma database, in which Gly16/Glu27 and Arg16/Gln27 were found to be the most prevalent homozygous haplotypes (19% and 12% respectively), Lee and colleagues studied the clinical significance of these haplotypes in patients with asthma who were using salbutamol (61c ). Caucasian asthmatic subjects (n = 16; eight with the Arg16/Gln27 and eight with the Gly16/Glu27 haplotype) used a single dose of inhaled salbutamol 1200 micrograms after an adequate washout period (61c ). Mean serum potassium fell significantly further from baseline in the Arg16/Gln27 haplotype group. The fall in the maximum diastolic blood pressure from baseline over 20 minutes was also significantly greater in the Arg16/Gln27 haplotype group, while heart rate changes were not different. It can be concluded that Caucasians with asthma and the Arg16/Gln27 haplotype have greater systemic responses to inhaled salbutamol than patients who carry the Gly16/Glu27 haplotype. This effect may result from increased susceptibility to prior down-regulation of beta2 -adrenergic receptors by endogenous catecholamines in patients with the Gly16/Glu27 haplotype. In another genotype-stratified, randomized, placebo-controlled, crossover study, the effects of inhaled salbutamol for 16 weeks in patients with asthma who were either homozygous for arginine (Arg/Arg, n = 37) or glycine (Gly/Gly n = 41) at position 16 were studied (62C ). With regular use of salbutamol 180 micrograms/day, only patients with the Gly/Gly genotype had a significantly improved morning peak expiratory flow rate compared with patients taking placebo, while patients with the Arg/Arg genotype did not improve. There were no significant differences among the genotypes with respect to the frequency of significant exacerbations of asthma or treatment failure. Contradictory results have been reported for beta2 -adrenoceptor polymorphisms and responses to salbutamol in 269 asthmatic children (63c ). Patients with the Arg/Arg genotype were significantly more likely to respond to the administration of a single inhaled dose of salbutamol 180 micrograms compared with patients with the Gly/Gly genotype. Safety data were not reported. In general, very little is known about the effect of beta2 -adrenoceptor polymorphisms on
Drugs acting on the respiratory tract
Metabolism Hypoglycemia has been identified as an adverse effect of salbutamol in newborns of mothers who have received long-term sympathomimetics as tocolytic therapy. However, hypoglycemia has also been described in children after the ingestion of high doses of salbutamol (57A ). • A 3-year-old boy developed initial hyperglycemia of 10.4 mmol/l (187 mg/dl) followed by hypoglycemia of 2.5 mmol/l (45 mg/dl) after the oral ingestion of 57 ml of Ventolin syrup, corresponding to 22.8 mg (1.9 mg/kg) of salbutamol (58A ). He was given activated charcoal and intravenous glucose and recovered uneventfully.
Beta2 -adrenoceptor genotypes and safety of salbutamol in asthma The beta2 -adrenoceptor carries a functionally relevant variant at amino acid position 16, where arginine is often replaced by glycine (Arg16Gly). In fact, the Gly16 receptor variant is more frequent than the Arg16 form, which is traditionally considered as the wild type (59R ). Another variant, in which glutamine is replaced by glutamic acid at position 27 (Gln27Glu), is strongly linked with Arg16Gly. In in vitro studies, down-regulation of the beta2 -adrenoceptor by endogenous catecholamines shows significant variability between Gly16 and Arg16 genotypes, which in turn may influence tachyphylaxis during regular
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drug safety. Further research is necessary to explore the impact of the Arg16Gly variant on treatment outcome, especially in patients using regular versus as-needed salbutamol, in whom significantly different response rates have been described. Drug formulations Three types of nebulizer for delivery of salbutamol have been compared in a randomized crossover study in 22 patients with asthma, who received four cumulative doubling doses of each salbutamol formulation: a palm-sized nebulizer (AerodoseTM Inhaler), a conventional nebulizer (Pari LC Plus jet nebulizer), and a metered dose inhaler (VentolinTM EvohalerTM HFA) (64C ). Microgram relative potency ratios were calculated by generating dose-response curves for FEV1 , plasma potassium, T wave amplitude, QTc interval, and heart rate, enabling the estimation of equivalent doses required to produce a response equivalent to 100 micrograms via the AerodoseTM device. Salbutamol via the AerodoseTM inhaler was five times more efficient for FEV1 than either the Pari LC Plus or the EvohalerTM , but had also a five-fold greater potency for all systemic parameters, except blood pressure, compared with the Pari LC Plus device. The AerodoseTM inhaler had equivalent potency for plasma potassium and T wave amplitude changes, but greater potency for changes in heart rate and QTc interval. The authors suggested that the higher local and systemic potency of the AerodoseTM device is related to a higher emitted volume and lower residual volume rather than to the generation of a higher proportion of particles within the 3–5 µm range.
Markus Joerger, Katharina Hartmann, and Max Kuhn
Placebo-controlled studies Safety data from randomized, double-blind, placebo-controlled studies of tiotropium bromide, administered using a dry powder inhaler device (HandiHalerTM , Boehringer Ingelheim, Germany), has recently been reviewed (65R ). Tiotropium bromide has very low systemic availability because of poor gastrointestinal absorption. Dryness of the mouth is the most common adverse effect (66C –68C ). It is significantly more common in patients taking tiotropium (10–16%) compared with placebo (66C –68C ). Other adverse events were comparable in the two groups. Significant drug–drug interactions have so far not been described with tiotropium bromide. Safety data for combinations of tiotropium bromide, inhaled glucocorticoids, long-acting beta2 -adrenoceptor agonists, and methylxanthines are so far incomplete. In a randomized, double-blind, placebocontrolled study of tiotropium bromide 18 micrograms/day for 6 weeks in 187 patients with COPD, the overall incidence of adverse events was 37% with tiotropium and 41% with placebo, while there were serious adverse events in 3.1% of the patients who used tiotropium bromide and in 3.0% of those who used placebo (69C ). COPD exacerbations were experienced by 7.1 and 12% of the patients who used tiotropium and placebo respectively.
LEUKOTRIENE MODIFIERS (SED-15, 2025; SEDA-26, 193; SEDA-27, 177; SEDA-28, 191)
Leukotriene receptor antagonists and Churg–Strauss syndrome ANTICHOLINERGIC DRUGS (SED-15, 264; SEDA-26, 194; SEDA-27, 180; SEDA-28, 190)
Tiotropium bromide
(SED-15, 3433)
The unique feature of tiotropium bromide is that it produces bronchodilatation for at least 24 hours through prolonged M3 muscarinic receptor blockade.
The association of the rare Churg–Strauss syndrome, characterized by histological findings of eosinophilic tissue infiltration, extravascular eosinophil granulomas, and necrotizing vasculitis, and the use of leukotriene receptor antagonists was reviewed in SEDA-27 (p. 177). Accumulating data do not alter the previous assessment that leukotriene receptor antagonistassociated Churg–Strauss syndrome is a consequence of the unmasking of subclinical Churg– Strauss syndrome, with reduced glucocorticoid
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doses in most cases. However, cases of Churg– Strauss syndrome related to leukotriene receptor antagonists in patients without exposure to oral or inhaled glucocorticoids suggest that the unmasking theory may not be valid in all cases (70r ). In such cases, the “worsening” theory argues that worsening of asthma could be the initial manifestation of incipient Churg–Strauss syndrome, so that the start of leukotriene receptor antagonist treatment is rather coincidental than causative (71R ). Finally, provocation of Churg–Strauss syndrome by leukotriene receptor antagonists as an adverse event (the “causative” theory) cannot be completely ruled out. The fact that zafirlukast was reported to induce a lupus-like syndrome in a child with asthma supports the concept that hypersensitivity reactions in susceptible individuals may be possible (72A ). In a retrospective analysis of 20 Japanese patients with Churg–Strauss syndrome, the syndrome developed at 1–6 months after the start of pranlukast treatment in eight cases (73c ). Five of those eight patients had used oral or inhaled glucocorticoids without withdrawal before the onset of Churg–Strauss syndrome, while the other three had not used glucocorticoids. Oral glucocorticoids were not tapered in any of the patients before they developed Churg–Strauss syndrome. Pranlukastassociated Churg–Strauss syndrome was characterized by higher peripheral eosinophil counts, neurological disability scores, and poor responses to glucocorticoids, compared with Churg–Strauss syndrome not associated with pranlukast. This raises questions as to whether pranlukast may directly precipitate Churg– Strauss syndrome, possibly by causing an imbalance in activity between leukotriene B4 receptors and cysteinyl leukotriene. Special attention to patients with asthma who are using leukotriene receptor antagonists seems appropriate, especially within the first 6 months of treatment (73c ).
and concurrent montelukast 10 mg/day for about 2 months, in order to control unstable asthma. During this period, his blood eosinophil count increased 10-fold despite stable oral prednisone. An open lung biopsy showed Churg–Strauss syndrome, and myocardial involvement was diagnosed. He improved rapidly with intravenous methylprednisolone and cyclophosphamide. • A 66-year-old woman with asthma and multiple allergies developed a sensory polyneuropathy, hypereosinophilia, and a positive pANCA 4 months after switching from combined salmeterol, fluticasone, betamethasone, and sodium cromoglicate to oral montelukast 10 mg/day (75A ). A diagnosis of Churg–Strauss syndrome was made, and the polyneuropathy gradually improved after withdrawal of montelukast and the reintroduction of low doses of betamethasone.
Drugs acting on the respiratory tract
• A 46-year-old man with asthma, perennial allergic rhinitis, sinusitis, and hypersensitivity to aspirin, was admitted with a suspected myocardial infarction (74A ). His asthma had been treated with inhaled glucocorticoids and intermittent salbutamol for more than 15 years. Because of worsening of nasal and pulmonary symptoms, he was given intermittent montelukast 10 mg/day and two courses of oral prednisone. Later, he was retreated with a stable dose of oral prednisone 15 mg/day
Drug interactions Montelukast is a potent inhibitor of CYP2C8 (76C ), and pranlukast and zafirlukast are moderate inhibitors of CYP2C9 (77C ). Zafirlukast increased the plasma concentrations of the CYP2C9 substrate S-warfarin and prolonged the prothrombin time (78c ). However, the clinical relevance of interactions between leukotriene antagonists and CYP enzymes remains mainly unclear.
Montelukast
(SED-15, 2384; SEDA-26, 193; SEDA-27, 179; SEDA-28, 192) In a small retrospective cohort study in 20 men with COPD who took oral montelukast 10 mg/day for 12–38 months there were no adverse events and no patient discontinued treatment (79c ). However, the small number of predominantly African-American ex-smokers in this study constituted a serious limitation. Skin Generalized cutaneous adverse effects can occur with montelukast.
• A 28-year-old man with allergic rhinitis and moderate asthma developed generalized urticaria 5 days after starting to take montelukast and inhaled fluticasone (80A ). His symptoms disappeared within 1 day after withdrawal of both drugs, but reappeared 2 months later when he took them again. The symptoms did not reoccur with fluticasone alone.
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Zafirlukast
(SED-15, 3709; SEDA-26, 194; SEDA-28, 192) In a double-blind, randomized, placebo-controlled trial in 641 patients with acute exacerbations of asthma, single-dose zafirlukast 160 mg, zafirlukast 20 mg, or placebo was given as adjunct treatment to standard care (81C ). Patients who were discharged continued out-patient therapy over 4 weeks, taking either zafirlukast 20 mg bd or placebo in addition to prednisone, salbutamol, and their previous asthma medications. Headache was the most common adverse event, in 40 patients taking zafirlukast (15%) and 33 patients (12%) taking placebo. After 4 weeks of treatment, four patients taking zafirlukast and six taking placebo had raised aspartate transaminase activity to greater than two times the upper limit of normal.
Markus Joerger, Katharina Hartmann, and Max Kuhn
in 586 asthmatic patients (85C ). At least one adverse event occurred in 77% of those taking combined therapy and 69% of taking monotherapy after 6 months. The most common adverse event was respiratory infection in 36% and 31% respectively. The incidences of pharmacologically predictable adverse events, such as tachycardia, tremor, throat irritation, and hoarseness/dysphonia were similar in the two groups. Serious adverse events were infrequent and not significantly different (3.3% and 2.6%). There were no significant effects on the electrocardiogram, serum potassium, pulse rate, blood pressure, heart rate, blood glucose, or plasma lactate in 14 adults with asthma taking regular budesonide + formoterol (320/9 micrograms bd), who also used either 10 doses of budesonide + formoterol (total dose 1600/45 micrograms), 10 doses of formoterol (total dose 45 micrograms), or placebo in a double-blind, randomized, crossover study (86c ).
COMBINATIONS OF DRUGS Combined glucocorticoids and beta2 -adrenoceptor agonists
Combined beta2 -adrenoceptor agonists and anticholinergic drugs
The use of combined budesonide + formoterol in asthmatic patients has been reviewed (82R ). The safety of budesonide + formoterol (SymbicortTM 160/4.5 micrograms) has been studied in 3651 patients with asthma, randomized to either adjustable dosing (1–4 inhalations bd, with dose adaptations according to pre-defined criteria) or fixed dosing (two inhalations bd) over 12 weeks, after a 4-week run-in period (83C ). Adverse events and withdrawals did not differ between the two groups. Patients with adjustable dosing used significantly less medication. Tremor and hoarseness occurred in about 0.5% of the patients in both groups. Similar results were found in 3897 asthmatic patients using either fixed-dose budesonide + formoterol (SymbicortTM 160/4.5 micrograms) two inhalations bd or adjustable maintenance dosing (two to four inhalations bd) for up to 2 weeks (84C ). Patients with adjustable maintenance dosing used less medication. Adverse events and withdrawals did not differ between the groups. Budesonide + formoterol 320/4.5 micrograms bd was as safe as the single compounds at equivalent doses when given over 6 months
The administration of ipratropium bromide and the short-acting beta2 -adrenoceptor agonist fenoterol (BerodualTM ) via RespimatTM Soft MistTM inhaler has recently been reviewed (87R ). RespimatTM Soft MistTM inhaler is one of a new generation of propellant-free inhalers that generate a fine slow-moving cloud, with improved lung deposition. Two phase II, doseranging studies in adult asthmatic patients (88C , 89C ) and three phase III studies in adults (90C ) or children (91C ) with asthma or adults with COPD (92C ) have included safety analysis of the RespimatTM Soft MistTM inhaler. Doses ranged from ipratropium bromide/fenoterol 5/12.5 micrograms to 320/800 micrograms in single and multiple dosing regimens. In the phase II studies, there were no clinically relevant changes in laboratory measures or electrocardiography (88C , 89C ). However, the 320/800 micrograms regimen was associated with a higher incidence of headache, nervousness, and tremor compared with the same dose given via a metered dose inhaler (89C ). A possible explanation for this observation is improved lung deposition with the RespimatTM Soft MistTM device. In the phase III studies, the
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frequency of adverse events was low across all groups, and most of the adverse events were not treatment-related and were of mild or moderate intensity. The large phase III study in patients with COPD showed a similar safety profile for once-daily RespimatTM Soft MistTM inhaler 10/25 micrograms or 20/50 micrograms, compared with a standard chlorofluorocarboncontaining metered dose inhaler 40/100 micrograms (92C ). Exacerbated COPD was the most common adverse event (27% in the RespimatTM group and 18–21% in the other groups). The number of patients who withdrew because of adverse events was similar across the groups (range 10–16%). The study supported the noninferiority of the RespimatTM Soft Mist inhaler compared with the metered dose inhaler, even at the 50% nominal dose of ipratropium bromide/fenoterol. In the respective pediatric phase III study, children with asthma were randomized to Res-
pimatTM Soft MistTM inhaler (ipratropium/fenoterol) 10/25 micrograms or 20/50 micrograms tds or to a standard chlorofluorocarbon-containing metered dose inhaler 40/100 micrograms via AerochamberTM (91C ). The overall incidence of adverse events was higher with the metered dose inhaler 40/100 micrograms (34%) compared with the RespimatTM Soft MistTM inhaler (25% and 24% respectively). Asthma exacerbations and coughing were the most common adverse events. In all 12 patients (2.2%) withdrew because of adverse events (1.1% with the RespimatTM Soft MistTM inhaler 20/50 micrograms, 1.7% with 20/50 micrograms, and 4.0% with 40/100 micrograms by metered dose inhaler). The authors concluded that RespimatTM Soft MistTM inhaler and a standard metered dose inhaler via AerochamberTM at the studied doses are of comparable tolerability in children with asthma.
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pharmacokinetics of R- and S-warfarin in healthy men. Clin Pharmacol Ther 1997;61. Rubinstein I, Kumar B, Schriever C. Longterm montelukast therapy in moderate to severe COPD—a preliminary observation. Respir Med 2004;98:134–8. Minciullo PL, Saija A, Bonanno D, Ferlazzo E, Gangemi S. Montelukast-induced generalized urticaria. Ann Pharmacother 2004;38:999–1001. Silverman RA, Nowak RM, Korenblat PE, Skobeloff E, Chen Y, Bonuccelli CM, Miller CJ, Simonson SG. Zafirlukast treatment for acute asthma: evaluation in a randomized, doubleblind, multicenter trial. Chest 2004;126:1480–9. Goldsmith DR, Keating GM. Budesonide/ formoterol: a review of its use in asthma. Drugs 2004;64:1597–618. Buhl R, Kardos P, Richter K, Meyer-Sabellek W, Bruggenjurgen B, Willich SN, Vogelmeier C. The effect of adjustable dosing with budesonide/formoterol on health-related quality of life and asthma control compared with fixed dosing. Curr Med Res Opin 2004;20:1209–20. Canonica GW, Castellani P, Cazzola M, Fabbri LM, Fogliani V, Mangrella M, Moretti A, Paggiaro P, Sanguinetti CM, Vignola AM. Adjustable maintenance dosing with budesonide/ formoterol in a single inhaler provides effective asthma symptom control at a lower dose than fixed maintenance dosing. Pulm Pharmacol Ther 2004;17:239–47. Rosenhall L, Heinig JH, Lindqvist A, Leegaard J, Stahl E, Bergqvist PB. Budesonide/formoterol (Symbicort) is well tolerated and effective in patients with moderate persistent asthma. Int J Clin Pract 2002;56:427–33. Ankerst J, Persson G, Weibull E. Tolerability of a high dose of budesonide/formoterol in a single inhaler in patients with asthma. Pulm Pharmacol Ther 2003;16:147–51. Kassner F, Hodder R, Bateman ED. A review of ipratropium bromide/fenoterol hydrobromide (Berodual) delivered via Respimat Soft Mist Inhaler in patients with asthma and chronic obstructive pulmonary disease. Drugs 2004;64:1671–82. Goldberg J, Freund E, Beckers B, Hinzmann R. Improved delivery of fenoterol plus ipratropium bromide using Respimat compared with a conventional metered dose inhaler. Eur Respir J 2001;17:225–32. Kunkel G, Magnussen H, Bergmann K, Juergens UR, de Mey C, Freund E, Hinzmann R, Beckers B. Respimat (a new soft mist inhaler) delivering fenoterol plus ipratropium bromide provides equivalent bronchodilation at half the cumulative dose compared with a conventional metered dose inhaler in asthmatic patients. Respiration 2000;67:306–14. Vincken W, Bantje T, Middle MV. Long-term efficacy and safety of ipratropium bromide plus fenoterol via Respimat Soft Mist Inhaler (SMI) versus a pressurised metered dose inhlaer in asthma. Clin Drug Invest 2004;24:17–28. von Berg A, Jeena PM, Soemantri PA, Vertruyen A, Schmidt P, Gerken F, Razzouk H.
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Efficacy and safety of ipratropium bromide plus fenoterol inhaled via Respimat Soft Mist Inhaler vs. a conventional metered dose inhaler plus spacer in children with asthma. Pediatr Pulmonol 2004;37:264–72.
92. Kilfeather SA, Ponitz HH, Beck E, Schmidt P, Lee A, Bowen I, Hesse C. Improved delivery of ipratropium bromide/fenoterol from Respimat Soft Mist Inhaler in patients with COPD. Respir Med 2004;98:387–97.
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Positive inotropic drugs and drugs used in dysrhythmias
CARDIAC GLYCOSIDES
(SED-15, 648; SEDA-26, 198; SEDA-27, 185; SEDA-28, 196) Nervous system In 8220 patients aged at least 65 years, the crude relative risk of nervous system dysfunction of unspecified types was about 2.0 (95%CI = 1.7, 2.5) among the 16.5% who were taking digoxin; co-morbidity and the number of out-patient medical services did not affect the risk (1C ). Gastrointestinal Mesenteric ischemia, a rare adverse effect of cardiac glycosides, has again been reported (2A ).
• An 84-year-old woman developed abdominal pain in association with symptoms of digitalis toxicity while taking digitoxin 0.07 mg/day and other drugs, including furosemide. Her serum potassium concentration was 2.9 mmol/l and the serum digitoxin concentration was 32 ng/ml (usual target range 13–25). She had first-degree heart block, incomplete left bundle branch block, and typical ST segment changes. All medications were withdrawn and the hypokalemia was corrected with intravenous potassium. Abdominal X-ray and ultrasonography showed paralytic ileus and she died 48 hours later. At autopsy there was hemorrhagic congestion of the heart, lungs, and other organs, and the intestines were edematous and hemorrhagic, with submucosal edema, necrotic ulceration, and intramural bleeding. There was no thromboembolism.
The authors attributed this effect to digitoxin toxicity. Verapamil, diltiazem, and antidigoxin antibody fragments have all been reported to be beneficial in mesenteric ischemia induced by cardiac glycosides. Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29017-2 © 2007 Published by Elsevier B.V.
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Drug interactions Amiodarone Amiodarone inhibits the renal secretion of digoxin by inhibiting renal P glycoprotein, and toxicity can occur as a result (3A ). • A 69-year-old man with heart failure was given digoxin 1 mg over 12 hours followed by amiodarone 1 mg/kg for 6 hours and then 0.5 mg/hour. He developed sustained monomorphic ventricular tachycardia and later bidirectional ventricular tachycardia. The serum potassium concentration was 3.5 mmol/l. The serum digoxin concentration was 4.3 ng/ml (usual target range 0.8–2.0). Amiodarone was withdrawn and he was given intravenous lidocaine and potassium. Sinus rhythm was restored after 5 days as the serum digoxin concentration fell to 1.5 ng/ml.
Clarithromycin The macrolide antimicrobial drugs can reportedly interact with digoxin by at least two mechanisms: by reducing its metabolism in the gut before absorption (by inhibiting the growth of the bacterium Eubacterium glenum) and by inhibiting P glycoprotein (SEDA-26, 200). Digoxin toxicity, with a serum concentration of 8.7 ng/ml, has again been reported in a patient taking clarithromycin (4A ). Etanercept The interaction of digoxin with etanercept has been studied at steady state in an open, non-randomized, crossover, 3-period study in 12 healthy men, who received loading oral doses of digoxin 0.5 mg every 12 hours on day 1 and 0.25 mg every 12 hours on day 2, followed by a daily maintenance dose of 0.25 mg for a total of 27 days (5c ). Etanercept was given subcutaneously 25 mg twice weekly starting on day 9 and continuing for a total of 9 doses. There were no significant pharmacokinetic or pharmacodynamic interactions. Gentamicin Gentamicin sulfate 80 mg bd intramuscularly for 7 days increased the serum digoxin concentration from 0.8 to 1.7 ng/ml
Positive inotropic drugs and drugs used in dysrhythmias
in 12 patients with congestive heart failure and from 0.8 to 2.6 ng/ml in 12 with diabetes mellitus (6c ). This effect was probably due to impaired renal function, since the serum creatinine concentration also rose. Other mechanisms that the authors invoked were unlikely. However, since the rise in serum digoxin concentration was not accompanied by evidence of digoxin toxicity, it is also possible that gentamicin in some way interfered with the measurement of serum digoxin. St John’s wort St John’s wort reduces plasma digoxin concentrations by inducing P glycoprotein. Formulations of St John’s wort vary in composition, main constituents (hypericins, hyperforin, and flavonoids), and dose. In a randomized, placebo-controlled, parallel-group study in 96 healthy volunteers a 7-day loading phase with digoxin was followed by 14 days of co-medication with placebo or one of 10 St John’s wort products varying in dose and type of formulation (7C ). The high-dose hyperforinrich extract LI 160 reduced the AUC0–24 of digoxin by 25% (95%CI = 21, 28), the Cmax by 37% (32, 42), and the Cmin by 19% (11, 27). Co-medication with hypericum powder 4 g with comparable hyperforin content resulted in reductions in digoxin AUC0–24 by 27% (16, 37), Cmax by 38% (18, 48), and Cmin by 19% (10, 27). Hypericum powder 2 g with half the hyperforin content reduced AUC0–24 by 18% (14, 22), Cmax by 21% (2, 40), and Cmin by 13% (5, 21). The authors concluded that the interaction of St John’s wort with digoxin correlates with the dose of hyperforin. Ximelagatran The interaction of digoxin with ximelagatran has been investigated in a randomized, double-blind, two-way, crossover study in 16 healthy men and women, who took ximelagatran 36 mg or placebo bd for 8 days and a single oral dose of digoxin 0.5 mg on day 4; there was no pharmacokinetic interaction (8c ). Management of digitalis toxicity It is wise to insert a temporary pacemaker as soon as possible in all patients who take an overdose of digoxin in order to treat any bradydysrhythmias that subsequently occur. The use of temporary cardiac pacing has now been studied retrospectively in 70 patients (mean age 74 years, 30 men) with digoxin toxicity not due to selfpoisoning (9c ). A transvenous pacemaker was
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used in 24 patients with sinus arrest and junctional bradydysrhythmias (n = 9), atrial fibrillation with a slow ventricular rate (n = 11), and high-degree atrioventricular block (n = 4). The mean duration of pacemaker implantation was 5.8 (2–12) days. There were no major dysrhythmic events or deaths. Two of the 46 patients who did not have a transvenous pacemaker inserted died of ventricular tachydysrhythmias. The authors concluded that temporary cardiac pacing is safe for patients with digoxin overdose complicated by symptomatic bradycardia.
OTHER POSITIVE INOTROPIC DRUGS (SED-15, 2822; SEDA-26, 201; SEDA-27, 188; SEDA-28, 199)
Milrinone (SED-15, 2346; SEDA-26, 201; SEDA-27, 188; SEDA-28, 199) Cardiovascular In the study called OPTIME, the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations, in which 949 patients with decompensated heart failure were randomized to receive intravenous milrinone or placebo, there were 59 new dysrhythmic events in 6% of the population; a post-hoc analysis has now shown that there was a higher risk among those who received milrinone (10c ).
Vesnarinone
(SED-15, 3622; SEDA-28,
200) The precautions for using vesnarinone and its adverse effects have been reviewed (11R ). The most important adverse effects are an increased risk of sudden death and neutropenia. They are dose-related in the therapeutic range of doses (i.e. collateral adverse effects). Patients with renal impairment should not receive vesnarinone and care should be taken in patients who are also taking drugs that inhibit CYP3A.
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Table 1. The FDA teratogenicity classes of antidysrhythmic drugs Drug
Category∗
Reported teratogenic or fetotoxic effects of therapeutic maternal doses
Adenosine Amiodarone
C D
Digoxin Flecainide Lidocaine Mexiletine Procainamide Quinidine
C C B C C C
None Sinus bradycardia, QT interval prolongation; congenital nystagmus; impaired language skills; altered thyroid function None Electrocardiographic changes; respiratory distress Bradycardia; acidosis None None Thrombocytopenia; eighth nerve damage
∗ FDA categories (18R ):
A: Controlled studies show no risk to the fetus. Adequate, well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus. B: No evidence of risk in humans. Either animal studies show risk but human findings do not, or if no adequate human studies have been done, animal findings are negative. C: Risk cannot be ruled out. Human studies are lacking and animal studies are either positive for fetal risk or lacking. However, potential benefits may justify potential harm. D: Positive evidence of risk. Investigational or post-marketing data show risk of harm to the fetus. Nevertheless, potential benefits may outweigh the potential harm. X: Contraindicated in pregnancy. Studies in animals or humans or investigational or post-marketing reports have shown risk of fetal harm, which clearly outweighs any possible benefit to the patient.
DRUGS USED IN DYSRHYTHMIAS Management of atrial fibrillation There have been further reviews of comparisons of rhythm control versus rate control in the management of atrial fibrillation (12R , 13R ). The results of five randomized controlled comparisons mostly in patients with persistent atrial fibrillation (n = 5175 in all), have all suggested that there are no major differences in beneficial outcomes between the two strategies (SEDA28, 200). A similar conclusion was reached in the HOT-CAFE study of 205 patients (134 men and 71 women; mean age 61 years) with a mean duration of atrial fibrillation of 274 days (14C ). At the end of follow-up (mean duration 1.7 years), 64% of the patients in the rhythm control arm remained in sinus rhythm. There were no significant differences in the composite end-point (all-cause mortality, number of thromboembolic events, or major bleeding) between the groups (OR = 1.98; CI = 0.28, 22). The incidence of hospital admissions was much lower in the rate control arm (12% versus 74%). New York Heart Association functional class improved in both groups, but mean exercise tolerance improved only in the rhythm control group. The rhythm control strategy led to
increased mean left ventricular fractional shortening.
Cardiovascular The pharmacogenetic aspects of drug-induced torsade de pointes have been reviewed (15R ). Major mutations and functional polymorphisms in the congenital long QT syndrome (cLQTS) genes, KCNE1, KCNE2, KCNH2, KCNQ1, and SCN5A, have been associated with an increased risk of torsade de pointes in patients taking antidysrhythmic drugs (16Cr ).
Use in pregnancy The use of antidysrhythmic drugs in pregnancy and breast-feeding has been reviewed (17R ). The FDA system that is used to classify the risks does not clearly distinguish between teratogenicity (occurring in the first trimester), which would be expected to be irreversible, and fetotoxicity (occurring after the first trimester), some effects of which will be reversible. The FDA classification of antidysrhythmic drugs (18R ) is shown in Table 1 with some of the reported teratogenic and fetotoxic effects, most of which have been reported only anecdotally.
Positive inotropic drugs and drugs used in dysrhythmias
Adenosine (SED-15, 36; SEDA-26, 203; SEDA-27, 189; SEDA-28, 203) Observational studies Studies of the use of intravenous adenosine with 201 Tl in myocardial scintigraphy continue to be published, showing adverse effects that have been previously reported. In a phase II study in 44 patients given adenosine 120 or 140 micrograms/kg/minute for 6 minutes there was chest pain or discomfort in 23 and flushing or a feeling of warmth in 12 (19c ). Adenosine reversibly lowered blood pressure and increased heart rate slightly; the fall in systolic blood pressure was more than 20 mmHg from baseline in 26% of patients who received 120 micrograms/kg/minute and in 52% of those who received 140 micrograms/ kg/minute. The same authors reported similar adverse effects in a phase III study in 207 patients given 120 micrograms/kg/minute (20c ) and in a clinical trial in 31 patients (21C ). Comparative studies In a comparison of intracoronary adenosine 24–288 micrograms with and without nitroprusside in 53 patients with no reflow despite coronary artery reperfusion, one patient had advanced atrioventricular block, which responded to atropine, and another had bradycardia, which resolved spontaneously (22c ). In 50 patients in whom intravenous adenosine 140 micrograms/kg/minute was compared with intracoronary adenosine 60–150 micrograms, intravenous adenosine caused angina (26%), dyspnea (16%), and nausea (2%), while intracoronary adenosine caused dose-related atrioventricular block (23c ). Cardiovascular ST segment depression can occur during adenosine myocardial perfusion imaging and is an independent predictor of subsequent cardiac events and worse outcome, particularly in association with ischemic defects. In 75 patients with aortic stenosis, intravenous adenosine caused the usual adverse effects (flushing, chest pain, dyspnea, dizziness, headache, and nausea) in 8–41% of patients, second-degree heart block in seven, and thirddegree heart block in two; there was transient ST segment depression greater than 1 mm in six patients (24c ). Despite this, acute myocardial infarction after adenosine is rare, but has been reported in
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a 71-year-old man who was given an intravenous infusion of adenosine 140 micrograms/ kg/minute for 3 minutes (25A ). The authors suggested that coronary vasodilatation had led to reduced perfusion pressure in collaterals, with a further contribution from reduced flow secondary to aortic stenosis. Atrioventricular block is usually transient after adenosine, even after intracoronary administration (26c ), but it can be sustained, as in the case of a 2-year-old child with a supraventricular tachycardia (27A ). Accessory conduction pathways contraindicate adenosine. • A 39-year-old woman with bouts of palpitation and a narrow-complex tachycardia was given intravenous adenosine 6 mg and developed a broadcomplex tachycardia, due to supraventricular tachycardia, which spontaneously converted to sinus rhythm after 10 seconds (28A ). She was then found to have Wolff–Parkinson–White syndrome with bilateral accessory pathways.
Amiodarone
(SED-15, 148; SEDA-26, 204; SEDA-27, 189; SEDA-28, 205)
Cardiovascular Hypotension is common after intravenous administration of amiodarone. It has been attributed to solvents in the intravenous formulation, and this hypothesis was supported by the observation that in four trials an aqueous formulation caused hypotension in only three of 278 patients and only during bouts of ventricular tachycardia (29M ). In addition, six patients had cardiac dysrhythmias or heart block, two had erythema and/or pain at the site of injection, and two had thrombophlebitis. Torsade de pointes continues to be reported occasionally in patients given amiodarone. Of five such patients three had hypokalemia and those with negative T waves were at greater risk of ventricular fibrillation than those with positive T waves (30c ). Respiratory The pulmonary toxicity of amiodarone has been reviewed (31R ). The number of reports to the FDA of serious adverse events in patients taking amiodarone increased from under 50 in each year from 1986 to 1992 to nearly 250 in 2001 and 2002 (32S ). The total number of such reports from 1986
186 to 2002 was about 2000, of which the most common were dyspnea (n = 264), pneumonia (178), unspecified lung disorders (173), and pulmonary fibrosis (161). Reports of parenchymal lung damage represented about 14% of all serious adverse events. Lung damage can occur within days or weeks of the start of therapy and death can occur. The prognosis is worse in those with pre-existing lung damage and the incidence can be reduced by using lower loading and maintenance doses. The speed with which amiodarone-induced lung damage can occur has been illustrated by the case of a 53-year-old man who developed dyspnea and bilateral pulmonary infiltrates and pleural effusions within 9 days (33A ). Special senses Optic neuropathy has been reported in 1–2% of patients taking amiodarone. In a case-control study in 14 patients there were significant changes in visual evoked responses (34C ). There was no relation to the duration of therapy. Intraocular pressure was unaffected and fundoscopy was normal. Endocrine Hyperthyroidism The management of hyperthyroidism due to amiodarone has been reviewed in the light of the practices of 101 European endocrinologists (35CR ). Most (82%) treat type I amiodarone-induced hyperthyroidism with thionamides, either alone (51%) or in combination with potassium perchlorate (31%); the preferred treatment for type II hyperthyroidism is a glucocorticoid (46%). Some initially treat all cases, before the type has been established, with a combination of thionamides and glucocorticoids. After restoration of normal thyroid function, 34% recommend ablative therapy in type I hyperthyroidism and only 8% in type II. If amiodarone therapy needs to be restarted, 65% recommend prophylactic thyroid ablation in type I hyperthyroidism and 70% recommend a wait-and-see strategy in type II. Plasmapheresis, to remove iodine and thyroid hormones, was reportedly successful in treating amiodarone-induced hyperthyroidism in two of three patients, and was followed by thyroidectomy (36c ). It has been suggested that this would be ineffective in type II hyperthyroidism (37r ). Prevention of recurrence of amiodaroneinduced hyperthyroidism has been successfully
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attempted with 131 I in 18 patients, in 16 of whom amiodarone was reintroduced (38c ); the same authors reported the first 15 of these patients in two separate papers (39c , 40c ). The problem of whether to restart amiodarone therapy after hyperthyroidism has resolved has been discussed in the light of a case (41Ar ). Hypothyroidism The clinical, biochemical, and therapeutic aspects of amiodarone-induced hypothyroidism have been reviewed in the light of 18 elderly patients (42Rc ). Free thyroxine (T4 ) concentrations were reduced only in those with severe hypothyroidism and free triiodothyronine (T3 ) concentrations were always normal. Withdrawal of amiodarone in five patients led to improvement in four and worsening in one. Syndrome of inappropriate ADH secretion Amiodarone-induced hyponatremia due to inappropriate ADH secretion is rare (SEDA-21, 199). Unlike other adverse effects of amiodarone it occurs rapidly and resolves rapidly after withdrawal. Another case has been reported (43A ). Hematologic Bone marrow granulomata have rarely been reported in patients taking amiodarone (SEDA-23, 199). Two more cases have been reported (44A ). Liver In 125 patients without clinical liver damage there was a weak correlation between alanine transaminase activity and serum amiodarone concentration (45C ). An effect compartment model predicted that 6% of patients will have a rise in alanine transaminase activity to more than three times the upper limit of the reference range if serum amiodarone concentrations are maintained at below 2.5 mg/l; concentrations below 1.5 mg/l were associated with no predicted change in alanine transaminase. The authors suggested that amiodarone-induced hepatotoxicity could be efficiently detected by measuring the alanine transaminase activity at baseline, at 1, 3, and 6 months, and every 6 months thereafter. Cholestatic jaundice is relatively rare adverse effect of amiodarone (SED-15, 160). Another case has been reported in a 78-year-old man taking 200 mg/day; it resolved after withdrawal (46A ). The rare reports of hepatic cirrhosis attributed to amiodarone have been briefly reviewed (47r ).
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Skin Phototoxicity affecting the perioral skin has been reported in a 70-year-old white man who was taking amiodarone 100 mg/day, but also losartan 50 mg/day, co-amilofruse, aspirin 150 mg/day, and diclofenac 50 mg/day; the rash resolved after withdrawal of amiodarone (48A ).
Warfarin The pharmacokinetic interaction of amiodarone with warfarin is well known, and pharmacodynamic potentiation of the actions of warfarin via amiodarone-induced hyperthyroidism has also been described (SED-15, 165). These interactions have again been briefly reviewed in the context of three cases (57Ar ).
Death In a retrospective study of 20 patients who had taken amiodarone within the 3 months before heart transplantation, survival was lower than in 65 patients who had not taken amiodarone (50 versus 85% at 1 year) (49c ). The patients who had taken amiodarone also had a greater risk of adult respiratory distress syndrome (ARDS) after transplant and had more bleeding complications. The risks were greater the longer the duration of amiodarone use before transplantation.
Monitoring therapy In many areas of drug therapy evidence to support monitoring recommendation is scant, and this is true of amiodarone, as a systematic review has shown (58Mc ). The authors found 43 articles that provided specific monitoring recommendations, but none that compared the outcomes of patients managed with different monitoring regimens. In a study of 99 patients, 52 received minimum baseline evaluations, 22 underwent continuing surveillance, 75 had appropriate responses to abnormal surveillance results, and 71 had timely follow-up visits. They concluded that current standards for monitoring amiodarone toxicity are based on expert opinion with limited evidence to support most recommendations, that monitoring practices vary significantly, and that few patients receive all of the recommended monitoring.
Tumorigenicity Basal cell carcinoma has been rarely reported in patients taking amiodarone (50A , 51A ), and another case has been reported (52A ). The rareness of the reports and the commonness of the tumor make this association hard to substantiate. Fetotoxicity Neonatal hypothyroidism has occasionally been reported in children born to mothers who were given amiodarone during pregnancy (SED-15, 162). Transient hypothyroidism in these circumstances has been reported in five infants born to 26 mothers who were given amiodarone for treatment of fetal tachycardias (53c ). Two similar cases have been reported elsewhere (54Ar ). Drug interactions Metoprolol Amiodarone increased mean metoprolol plasma concentrations twofold after a loading dose of 1.2 g/day for 6 days in 10 patients (55c ). The extent of the effect depended on the CYP2D6 genotype. Simvastatin Rhabdomyolysis has been reported in a 63-year-old man who was taking amiodarone 1 g/day and simvastatin 40 mg/day (56A ). The authors hypothesized that amiodarone had inhibited the metabolism of simvastatin via CYP3A4 but did not have plasma concentration measurements to back up their assumption.
Dofetilide (SED-15, 1173; SEDA-26, 208; SEDA-27, 195; SEDA-28, 209) Cardiovascular The main adverse effect of dofetilide is ventricular tachydysrhythmias secondary to prolongation of the QT interval. There was more than 15% prolongation of the QT interval in 19 of 107 patients after the first dose of dofetilide and in 28 after subsequent doses; there were no cases of torsade de pointes (59Cr ). Polymorphisms in potassium channels increase the risk of prolongation of the QT interval, and the two polymorphisms designated KCNQ1 and KCNH2 account for 80% of cases of congenital long QT syndrome. Of 105 patients from the DIAMOND study (SEDA-26, 206) seven had torsade de pointes, of whom two had a polymorphism (R1047L) in the hERG potassium channel; only 5 of the 98 patients without torsade de pointes carried the polymorphism (60cE ). The only patient who was homozygous for the polymorphism was one
188 with torsade de pointes. The affected hERG channel, transfected into HEK-293 cells, had significantly slower activation and inactivation kinetics than wild-type channels.
Flecainide
(SED-15, 1370; SEDA-26, 212; SEDA-27, 195; SEDA-28, 209) Cardiovascular Flecainide can cause changes of the Brugada syndrome on the electrocardiogram, and another case has been reported in a 70-year-old man (61A ).
Lidocaine (lignocaine) (SED-15, 2051; SEDA-27, 196; SEDA-28, 210) Death Previous meta-analysis suggested that the use of lidocaine in patients with an acute myocardial infarction is associated with excess mortality, and this led to 1996 guidelines that lidocaine should be regarded as a drug for which there is “evidence and/or general agreement that a procedure/treatment is not useful/effective and in some cases may be harmful” (62S ). This conclusion has been challenged in a description of a 32-year follow-up observational study of 4254 patients with acute myocardial infarction, of whom 4150 received prophylactic lidocaine and 104 (treated after 1996) did not (63c ). The incidence of primary ventricular fibrillation was 0.5% among those who received prophylactic lidocaine and 10% among those who did not. Mortality rates were 11% in patients without primary ventricular fibrillation and 25% in patients with. This impressive result was vitiated by the fact that the study was neither prospective nor randomized. Susceptibility factors Liver disease CYP1A2 is the major enzyme responsible for the metabolism of lidocaine in people with normal liver function. The clearance of lidocaine was 12 ml/minute/kg in 10 healthy individuals, 9.8 ml/minute/kg in 10 patients with mild liver impairment, and 4.2 ml/minute/kg in 10 patients with severe liver impairment; the half-life was proportionately prolonged (64C ). When fluvoxamine was
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used to inhibit CYP1A2 the effect was much greater in the healthy subjects than in those with liver disease. Drug administration route Nebulized 4% lidocaine 100 mg qds has been used to treat 50 patients with mild-to-moderate asthma in a randomized, saline-controlled study for 8 weeks (65C ). Lidocaine improved FEV1 and reduced night-time awakenings, symptoms, bronchodilator use, and blood eosinophil counts; there was no effect on the use of inhaled glucocorticoids. There were no serious adverse effects. Four patients taking lidocaine dropped out, one with a cold feeling in the throat, one with a feeling of claustrophobia, one with a cough attributed to the medication, and one with wheezing and a reduced FEV1 after inhalation. Drug interactions Itraconazole (200 mg/day for 4 days), a potent inhibitor of CYP3A4, had no effect on the pharmacokinetics of inhaled lidocaine or its major metabolite, monoethylglycinexylidide, in 10 healthy volunteers in a randomized, placebo-controlled, crossover study (66C ).
Mexiletine
(SED-15, 2329; SEDA-26, 213; SEDA-27, 197)
Immunologic Mexiletine has rarely been reported to have caused hypersensitivity reactions. In one case of drug-induced hypersensitivity syndrome, in which there was a leukocytosis, eosinophilia, and liver damage, there was reactivation of human herpesvirus-6 (HHV-6) IgM (67c ). This patient was one of 17 in whom hypersensitivity reactions, toxic epidermal necrolysis, or Stevens–Johnson syndrome had occurred in response to a wide range of drugs. More than 3 weeks after the onset of drug-induced hypersensitivity syndrome, HHV-6 serological tests showed a rise in IgG antibodies in six patients, including one treated without glucocorticoids. HHV-6 DNA was detected in blood from three patients. In one patient with drug-induced hypersensitivity syndrome, there was reactivation of cytomegalovirus without reactivation of HHV-6, whereas in three patients anti-cytomegalovirus
Positive inotropic drugs and drugs used in dysrhythmias
IgG antibodies rose after the rise in anti-HHV6 IgG. Anti-HHV-7 IgG did not show change. The authors concluded that reactivation of human herpesvirus-6 in patients with druginduced hypersensitivity syndrome is not due to non-specific reactivation induced by glucocorticoids, but to events specific to drug-induced hypersensitivity syndrome, and they hypothesized that drug-induced hypersensitivity syndrome may occur as a result of reactivation of human herpesvirus infection, especially HHV6, accompanied by an allergic reaction to drugs, followed by a marked immune response to the virus, which is probably responsible for visceral involvement. Acute severe diabetes mellitus has been reported as part of the spectrum of presentation of drug-induced hypersensitivity syndrome (68A ). • A 46-year-old man with type 2 diabetes mellitus was given mexiletine 300 mg/day for diabetic peripheral neuropathy. After 41 days he developed pruritus, a diffuse macropapular rash with facial edema and erythema, and bilateral inguinal lymph node enlargement. His temperature was 38.1 ◦ C, heart rate 110/minute, and blood pressure 125/69 mmHg. His white blood cell count was 19 × 109 /l (eosinophils 7%), aspartate transaminase activity 0.23 µkat/l (0.20–0.53), alanine transaminase 1.10 µkat/l (0.11–0.55), C-reactive protein 89 mg/l, and serum amylase 10.4 µkat/l (0.8–2.4). The titer of anti-human herpesvirus-6 IgG was over 1:320. He was given oral prednisolone 10 mg/day for 3 days, followed by daily intravenous betamethasone. Insulin was required to control the blood glucose concentration and he needed up to 62 U/day despite gradually reduced doses of betamethasone and normalization of the serum amylase activity to 1.33 µkat/l.
The authors proposed that fulminant type 1 diabetes had been associated with hypersensitivity to mexiletine and that reactivation of HHV-6 had played a part. The patient’s HLA status also included DQA10303 and DQB10401, which have been associated with fulminant type 1 diabetes (69c ).
Moricizine (moracizine, ethmozine) (SED-15, 2384; SEDA-26, 213) Drug interactions The combination of moricizine with another antidysrhythmic drug ethacizine, in the weight ratio of 6:1, has been
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marketed in Russia under the name of metacizine (Ethmocor® ). The pharmacokinetics of the two drugs when given separately and together in single doses have been studied in eight healthy subjects (70c ). Ethacizine prolonged the half-life of moricizine by increasing its volume of distribution without a change in clearance. Moricizine prolonged the half-life of ethacizine by reducing its clearance despite a parallel reduction in volume. Exposure to both drugs was increased when they were given in combination.
Quinidine and derivatives
(SED-15, 2997; SEDA-26, 214; SEDA-24, 198; SEDA-28, 212) Observational studies Of 35 patients given hydroquinidine for Brugada syndrome, seven had diarrhea, five during the first month, and two withdrew as a result (71c ). One patient had hepatitis during the first month, which reversed after withdrawal. Two patients had syncope during long-term treatment, one associated with prolongation of the QT interval. Comparative studies In a prospective multicenter study in Germany, Poland, and the Slovak Republic, 1033 patients (mean age 60 years, 62% men) with frequent episodes of symptomatic paroxysmal atrial fibrillation were randomized to quinidine + verapamil 480/240 mg/day (n = 263), quinidine + verapamil 320/160 mg/day (n = 255), sotalol 320 mg/day (n = 264), or placebo (n = 251) (72C ). The three treatments were equally effective and the incidences of adverse effects were the same. There were four deaths, 13 cases of syncope, and one case of ventricular tachycardia; one death and the ventricular tachycardia were related to quinidine + verapamil in the higher doses. In a prospective, multicenter, double-blind, placebo-controlled, randomized study in 1182 patients with persistent atrial fibrillation, 848 were successfully cardioverted and then randomized to sotalol (n = 383), quinidine plus verapamil (n = 377), or placebo (n = 88) (73C ). Quinidine plus verapamil was significantly superior to both placebo and sotalol in preventing recurrence. Adverse events were comparable (about 24% in each group), except
190 that all nine cases of torsade de pointes occurred in patients taking sotalol. Quinidine has previously been found to have relatively poor efficacy in maintaining sinus rhythm after cardioversion of atrial fibrillation (74M ), and can have serious adverse effects, including cardiac dysrhythmias (“quinidine syncope”), thrombocytopenia, and liver damage. These studies do not rehabilitate it in the management of atrial fibrillation, despite arguments to the contrary (75r ), since apparent efficacy may have been largely due to the verapamil with which quinidine was combined in both these studies. Hydroquinidine has been used to treat the short QT syndrome in six patients and has been compared with other antidysrhythmic drugs (76c ). Hydroquinidine prolonged the QTc interval from 290 to 405 ms and ventricular fibrillation was no longer inducible. Diarrhea was the main adverse effect. Hematologic Quinidine-induced thrombocytopenia is rarely reported nowadays because the adverse effect is well known and because quinidine is less commonly used. However, it can occasionally occur, as shown by the case of a 72-year-old woman who developed repeated bouts of thrombocytopenia; quinidine-dependent antibodies were found after it transpired that she had been taking her husband’s tablets intermittently to treat bouts of palpitation (77A ). Sensitization may have occurred because of the intermittent nature of exposure in this case.
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Drug interactions Quinidine inhibits P glycoprotein, and has been used to study the pharmacokinetics of fentanyl (78c ) and methadone (79c ). In the first study, quinidine increased oral fentanyl plasma Cmax and AUC and prolonged its half-life. However, it did not alter the magnitude or time to maximum miosis, time-specific pupil diameter, or subjective self-assessments after intravenous fentanyl. In the second study, the same authors showed that quinidine altered the systemic availability of methadone without altering its pharmacodynamic effects after intravenous administration. They therefore suggested that P glycoprotein has less of an effect on the brain access of fentanyl and methadone than on their systemic availability. Quinidine inhibits the metabolism of dextromethorphan by inhibiting CYP2D6. In two multiple-dose studies the lowest oral dose of quinidine that could be used in a fixed combination with three doses of dextromethorphan, in order to suppress its O-demethylation maximally, was determined to be 25–30 mg (80C ). This dose was then used in a randomized study of the use of the combination of quinidine + dextromethorphan, compared with either alone, in the treatment of pseudobulbar affect in 129 patients with amyotrophic lateral sclerosis (81C ). There were significantly higher incidences of nausea, dizziness, and somnolence in those who took the combination, all attributed to reduced clearance of dextromethorphan.
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darone therapy. Pacing Clin Electrophysiol 2004;27(6 Pt 1):831–2. Mukhopadhyay S, Mukhopadhyay S, Abraham NZ Jr, Jones LA, Howard L, Gajra A. Unexplained bone marrow granulomas: is amiodarone the culprit? A report of 2 cases. Am J Hematol 2004;75(2):110–2. Pollak PT, Shafer SL. Use of population modeling to define rational monitoring of amiodarone hepatic effects. Clin Pharmacol Ther 2004;75(4):342–51. Assy N, Khair G, Schlesinger S, Hussein O. Severe cholestatic jaundice in the elderly induced by low-dose amiodarone. Dig Dis Sci 2004;49(3):450–2. Chow KM, Liu ZC. Amiodarone and cirrhosis. Age Ageing 2004;33(2):207–8. Shah N, Warnakulasuriya S. Amiodaroneinduced peri-oral photosensitivity. J Oral Pathol Med 2004;33(1):56–8. Blomberg PJ, Feingold AD, Denofrio D, Rand W, Konstam MA, Estes NA 3rd, Link MS. Comparison of survival and other complications after heart transplantation in patients taking amiodarone before surgery versus those not taking amiodarone. Am J Cardiol 2004;93(3):379–81. Monk B. Amiodarone-induced photosensitivity and basal-cell carcinoma. Clin Exp Dermatol 1990;15(4):319–20. Monk BE. Basal cell carcinoma following amiodarone therapy. Br J Dermatol 1995;133(1):148– 9. Hall MA, Annas A, Nyman K, Talme T, Emtestam L. Basalioma after amiodarone therapy—not only in Britain. Br J Dermatol 2004;151(4):932– 3. Strasburger JF, Cuneo BF, Michon MM, Gotteiner NL, Deal BJ, McGregor SN, Oudijk MA, Meijboom EJ, Feinkind L, Hussey M, Parilla BV. Amiodarone therapy for drug-refractory fetal tachycardia. Circulation 2004;109(3):375–9. Lomenick JP, Jackson WA, Backeljauw PF. Amiodarone-induced neonatal hypothyroidism: a unique form of transient early-onset hypothyroidism. J Perinatol 2004;24(6):397–9. Werner D, Wuttke H, Fromm MF, Schaefer S, Eschenhagen T, Brune K, Daniel WG, Werner U. Effect of amiodarone on the plasma levels of metoprolol. Am J Cardiol 2004;94(10):1319–21. Roten L, Schoenenberger RA, Krahenbuhl S, Schlienger RG. Rhabdomyolysis in association with simvastatin and amiodarone. Ann Pharmacother 2004;38(6):978–81. Kurnik D, Loebstein R, Farfel Z, Ezra D, Halkin H, Olchovsky D. Complex drug–drug– disease interactions between amiodarone, warfarin, and the thyroid gland. Medicine (Baltimore) 2004;83(2):107–13. Stelfox HT, Ahmed SB, Fiskio J, Bates DW. Monitoring amiodarone’s toxicities: recommendations, evidence, and clinical practice. Clin Pharmacol Ther 2004;75(1):110–22. Guanzon AV, Crouch MA. Phase IV trial evaluating the effectiveness and safety of dofetilide. Ann Pharmacother 2004;38(7–8):1142–7.
Positive inotropic drugs and drugs used in dysrhythmias 60. Sun Z, Milos PM, Thompson JF, Lloyd DB, Mank-Seymour A, Richmond J, Cordes JS, Zhou J. Role of a KCNH2 polymorphism (R1047 L) in dofetilide-induced torsades de pointes. J Mol Cell Cardiol 2004;37(5):1031–9. 61. Hudson CJ, Whitner TE, Rinaldi MJ, Littmann L. Brugada electrocardiographic pattern elicited by inadvertent flecainide overdose. Pacing Clin Electrophysiol 2004;27(9):1311–3. 62. Ryan TJ, Anderson JL, Antman EM, Braniff BA, Brooks NH, Califf RM, Hillis LD, Hiratzka LF, Rapaport E, Riegel BJ, Russell RO, Smith EE Jr, Weaver WD. ACC/AHA guidelines for the management of patients with acute myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol 1996;28(5):1328–428. 63. Wyman MG, Wyman RM, Cannom DS, Criley JM. Prevention of primary ventricular fibrillation in acute myocardial infarction with prophylactic lidocaine. Am J Cardiol 2004;94(5):545– 51. 64. Orlando R, Piccoli P, De Martin S, Padrini R, Floreani M, Palatini P. Cytochrome P450 1A2 is a major determinant of lidocaine metabolism in vivo: effects of liver function. Clin Pharmacol Ther 2004;75(1):80–8. 65. Hunt LW, Frigas E, Butterfield JH, Kita H, Blomgren J, Dunnette SL, Offord KP, Gleich GJ. Treatment of asthma with nebulized lidocaine: a randomized, placebo-controlled study. J Allergy Clin Immunol 2004;113(5):853–9. 66. Isohanni MH, Neuvonen PJ, Olkkola KT. Effect of itraconazole on the pharmacokinetics of inhaled lidocaine. Basic Clin Pharmacol Toxicol 2004;95(3):120–3. 67. Aihara M, Mitani N, Kakemizu N, Yamakawa Y, Inomata N, Ito N, Komatsu H, Aihara Y, Ikezawa Z. Human herpesvirus infection in druginduced hypersensitivity syndrome, toxic epidermal necrolysis and Stevens–Johnson syndrome. Allergol Int 2004;53:23–9. 68. Seino Y, Yamauchi M, Hirai C, Okumura A, Kondo K, Yamamoto M, Okazaki Y. A case of fulminant Type 1 diabetes associated with mexiletine hypersensitivity syndrome. Diabet Med 2004;21(10):1156–7. 69. Tanaka S, Kobayashi T, Nakanishi K, Koyama R, Okubo M, Murase T, Odawara M, Inoko H. Association of HLA-DQ genotype in autoantibodynegative and rapid-onset type 1 diabetes. Diabetes Care 2002;25:2302–7. 70. Beloborodov VL, Bugrii EM, Zalesskaya MA, Tyukavkina NA, Kaverina NN. Clinical pharmacokinetics of ethmozine and ethacizine in the course of combined administration. Pharm Chem J 2004;38(2):59–62.
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71. Hermida JS, Denjoy I, Clerc J, Extramiana F, Jarry G, Milliez P, Guicheney P, Di Fusco S, Rey JL, Cauchemez B, Leenhardt A. Hydroquinidine therapy in Brugada syndrome. J Am Coll Cardiol 2004;43(10):1853–60. 72. Patten M, Maas R, Bauer P, Luderitz B, Sonntag F, Dluzniewski M, Hatala R, Opolski G, Muller HW, Meinertz T, SOPAT Investigators. Suppression of paroxysmal atrial tachyarrhythmias—results of the SOPAT trial. Eur Heart J 2004;25(16):1395–404. 73. Fetsch T, Bauer P, Engberding R, Koch HP, Lukl J, Meinertz T, Oeff M, Seipel L, Trappe HJ, Treese N, Breithardt G, Prevention of Atrial Fibrillation after Cardioversion Investigators. Prevention of atrial fibrillation after cardioversion: results of the PAFAC trial. Eur Heart J 2004;25(16):1385–94. 74. McNamara RL, Tamariz LJ, Segal JB, Bass EB. Management of atrial fibrillation: review of the evidence for the role of pharmacologic therapy, electrical cardioversion, and echocardiography. Ann Intern Med 2003;139(12):1018–33. 75. van Hemel N. Quinidine rehabilitated and more lessons from the PAFAC and SOPAT anti-arrhythmic drug trials for the prevention of paroxysmal atrial fibrillation. Eur Heart J 2004;25(16):1371–3. 76. Gaita F, Giustetto C, Bianchi F, Schimpf R, Haissaguerre M, Calo L, Brugada R, Antzelevitch C, Borggrefe M, Wolpert C. Short QT syndrome: pharmacological treatment. J Am Coll Cardiol 2004;43(8):1494–9. 77. Reddy JC, Shuman MA, Aster RH. Quinine/ quinidine-induced thrombocytopenia: a great imitator. Arch Intern Med 2004;164(2):218–20. 78. Kharasch ED, Hoffer C, Altuntas TG, Whittington D. Quinidine as a probe for the role of p-glycoprotein in the intestinal absorption and clinical effects of fentanyl. J Clin Pharmacol 2004;44(3):224–33. 79. Kharasch ED, Hoffer C, Whittington D. The effect of quinidine, used as a probe for the involvement of P-glycoprotein, on the intestinal absorption and pharmacodynamics of methadone. Br J Clin Pharmacol 2004;57(5):600–10. 80. Pope LE, Khalil MH, Berg JE, Stiles M, Yakatan GJ, Sellers EM. Pharmacokinetics of dextromethorphan after single or multiple dosing in combination with quinidine in extensive and poor metabolizers. J Clin Pharmacol 2004;44(10):1132–42. 81. Brooks BR, Thisted RA, Appel SH, Bradley WG, Olney RK, Berg JE, Pope LE, Smith RA, AVP-923 ALS Study Group. Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial. Neurology 2004;63(8):1364–70.
A.P. Maggioni, M.G. Franzosi, and R. Latini
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Beta-adrenoceptor antagonists and antianginal drugs
BETA-ADRENOCEPTOR ANTAGONISTS (SED-15, 452; SEDA-26, 223; SEDA-27, 203; SEDA-28, 217) Cardiovascular Beta-adrenoceptor antagonists are now recommended in all patients with heart failure, including those with advanced disease. However, in some severe cases, the start of treatment can be associated with acute decompensation. This is also one of the major reasons for beta-blocker under-prescription. Identification of the possible predictors of intolerance to beta-blockade was the object of an analysis of a series of 236 patients followed by a dedicated heart failure clinic (1A ). The authors identified a BNP concentration of over 1000 pg/ml in the first 8 days from the start of beta-blockade as a significant predictor of worsening heart failure. This neurohormone not only has powerful prognostic value, but it can also provide useful information in the selection of patients in whom beta-blockade should be started. Respiratory There have been many reports of drug-related pneumonitis caused by betaadrenoceptor antagonists. Pneumonitis associated with carvedilol has been described for the first time (2A ). • A 69-year-old woman, a non-smoker with a history of asthma, had had no respiratory exacerbation in the previous 12 months. She had taken carvedilol for hypertension and left ventricular hypertrophy for several months and fluoxetine for depression for the last 5 years. Over 20 days she developed progressive dyspnea on exercise, fever, cough, and then dyspnea at rest. Chest-X-rays showed bilateral opacities. A high-resolution CT scan showed Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29018-4 © 2007 Published by Elsevier B.V.
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bilateral infiltrates diffusely distributed over all the lung fields. Pulmonary function tests showed deterioration in spirometry. Both carvedilol and fluoxetine were withdrawn and 3 days later she became afebrile, with clear improvement in her respiratory symptoms. Another high-resolution CT scan showed great improvement with only minimal residual findings. Fluoxetine was restarted and 40 days later she was completely asymptomatic, still taking fluoxetine.
Even in the absence of rechallenge in this case, the rapid improvement after carvedilol withdrawal suggested a causative relation between pneumonitis and carvedilol. Metabolism In a randomized controlled comparison of the effects of beta-adrenoceptor antagonists with different pharmacological profiles, namely metoprolol and carvedilol, on glycemic and metabolic control in 1235 hypertensive patients with type 2 diabetes already taking a blocker of the renin–angiotensin– aldosterone system, blood pressure reduction was similar in the two groups but the mean glycosylated hemoglobin increased significantly from baseline to the end of the study with metoprolol (0.15%; 95%CI = 0.08, 0.22) but not carvedilol (0.02%) (3C ). Insulin sensitivity improved with carvedilol (−9.1%) but not metoprolol (−2.0%). The between-group difefrence was −7.2%. Progression to microalbuminuria was more common with metoprol than with carvedilol. Even if both agents were effective in reducing blood pressure and well tolerated, the use of carvedilol in addition to blockers of the renin–angiotensin–aldosterone system seems to be associated with a better metabolic profile in diabetic patients. Musculoskeletal In a large case-control study of beta-blockers alone or in combination with thiazides in 30 601 patients with a fracture and 120 819 matched controls, patients who took
Beta-adrenoceptor antagonists and antianginal drugs
beta-blockers alone had a 23% (95%CI = 17, 28) lower risk of fractures (4C ). Patients who took thiazides alone had a 20% (95%CI = 14, 26) risk reduction, and patients who took both had a risk reduction of 29% (95%CI = 21, 36). The data were adjusted for the main possible confounding variables. These findings seem to confirm the experimental evidence that betablockers cause increased bone formation. From a practical point of view, in elderly patients with hypertension at high risk of osteoporosis, a beta-blocker alone or in combination with a thiazide diuretic may be of potential benefit.
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• An 85-year-old man became hypotensive (BP 60/40 mmHg) following topical application of 2% glyceryl trinitrate paste to improve wound healing after knee surgery (6A ). The patient recovered within 4 hours after institution of a dopamine infusion and removal of the glyceryl trinitrate paste.
The authors recommended monitoring patients given topical glyceryl trinitrate for potentially dangerous hypotension.
CALCIUM CHANNEL BLOCKERS (SED-15, 598; SEDA-26, 225; SEDA-27, 224; SEDA-28, 218)
Sotalol
(SED-15, 3170; SEDA-26, 224; SEDA-28, 218)
Amlodipine
Cardiovascular Coronary artery spasm can be induced by beta-adrenoceptor antagonists not only in patients with variant angina but also in those without documented coronary artery disease.
The efficacy and safety of amlodipine have been assessed in a multicenter, double-blind, placebo-controlled trial in 268 children with hypertension aged 6–16 years (7C ). Amlodipine produced significantly greater reductions in systolic blood pressure than placebo. Twelve patients withdrew from the study because of adverse events, six of which were attributed to the study drug: three cases of worsening hypertension, one of facial edema, one of finger edema and rash, and one of ventricular extra beats. The maximal dose, 5 mg/day, was not high, and the target to reduce blood pressure below the 95th centile was reached in 35% of children with systolic hypertension and in 55% of those with diastolic hypertension.
• A middle-aged man with severe left ventricular dysfunction due to dilated cardiomyopathy developed a symptomatic sustained ventricular tachycardia (5A ). Sotalol prevented it. After 1 month of treatment, there were brief episodes of ST segment elevation during electrocardiographic monitoring for almost 3 consecutive days. Emergency coronary angiography showed no significant stenosis of the coronary tree. The ST segment elevation completely disappeared after sotalol was withdrawn and replaced by long-acting diltiazem.
The authors concluded that sotalol even in standard doses can cause coronary artery spasm through beta-blockade.
(SED-15, 175; SEDA-26, 225; SEDA-27, 205; SEDA-28, 219)
Hematologic Thrombocytopenia has been attributed to amlodipine (8A ).
Glyceryl trinitrate (nitroglycerin)
• A 79-year-old man developed epistaxis and gum bleeding; his platelet count was 1 × 109 /l. Amlodipine was withdrawn and immunoglobulins and glucocorticoids were given. The platelet count returned to 204 × 109 /l in 7 days. Amlodipine was restarted, and 2 days later bleeding recurred and resolved after amlodipine was withdrawn for the second time. ELISA (enzyme-linked immunosorbent assay) showed an IgG antibody reactive with patient’s platelets only in the presence of amlodipine.
Cardiovascular Glyceryl trinitrate ointment has been used topically to improve blood perfusion of surgical wounds that are under tension, but it can cause unwanted bradycardia and hypotension.
The authors suggested that drug-related thrombocytopenia can occur after long-term treatment with a drug, such as in this patient who had been taking amlodipine for 10 years before the event.
NITRATES, ORGANIC
(SED-15, 2529; SEDA-26, 224; SEDA-27, 204; SEDA-28, 218)
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Liver Severe hepatotoxicity has been attributed to amlodipine (9A ). • An 87-year-old woman who had taken amlodipine for several years for hypertension developed pruritus and 2 weeks later painless jaundice. She had a raised bilirubin concentration and raised aspartate and alanine transaminase activities. Infectious causes were not found and a liver biopsy suggested drug-induced liver damage. After withdrawal of amlodipine the transaminases and measures of cholestasis improved markedly within 2 weeks.
Skin Skin eruptions associated with amlodipine include erythematous rashes, maculopapular rashes, skin discoloration, urticaria, skin dryness, dermatitis, erythema multiforme, and lichen planus. Generalized hyperpigmentation has also been reported (10A ). • A 45-year-old Turkish man with a history of hypertension who had taken amlodipine 10 mg/day for 3 years developed Fitzpatrick’s skin type III after a 2-year history of gradually increasing, asymptomatic, generalized hyperpigmentation. Although cutaneous hyperpigmentation was more prominent on the photoexposed areas, there was no history of previous photosensitivity, pruritus, or flushing. Photo protection and withdrawal of amlodipine was advised. The skin discoloration faded slightly 8 months after changing amlodipine to metoprolol and strict avoidance of sun exposure.
Diltiazem (SED-15, 1126; SEDA-26, 225; SEDA-27, 205; SEDA-28, 219) Mouth and teeth Gum hyperplasia has been attributed to diltiazem (11A ). • A 49-year-old Afro-Caribbean man with resistant hypertension developed pronounced gum hyperplasia with bleeding, which gradually resolved on withdrawal of amlodipine 20 mg/day. Since the blood pressure was poorly controlled, he was given a non-dihydropyridine calcium channel blocker diltiazem 240 mg/day. The gum hyperplasia recurred 3 months later and slowly resolved after withdrawal of diltiazem.
This case suggests that the well-known adverse effect of gum hyperplasia is a class effect of calcium channel blockers, not just limited to the dihydropyridines. Drug interactions Simvastatin In a prospective pharmacokinetic study, seven men and four women with hypercholesterolemia and hypertension were given
A.P. Maggioni, M.G. Franzosi, and R. Latini
oral simvastatin 5 mg/day, then oral simvastatin 5 mg/day combined with diltiazem 90 mg/day, and then oral diltiazem 90 mg/day, each for 4 weeks (12c ). Diltiazem plus simvastatin resulted in a two-fold increase in the Cmax and AUC of simvastatin, accompanied by an enhanced cholesterol-lowering effect. In contrast, co-administration reduced the Cmax and AUC of diltiazem without altering its blood pressure lowering effects. Statins are metabolized by CYP3A4, which is inhibited by diltiazem; the mechanism whereby simvastatin reduced the AUC of diltiazem is unknown. Tacrolimus In a retrospective study in 96 renal transplant recipients who took tacrolimus for immunosuppression, 64 took a mean dose of 214 mg/day of diltiazem for hypertension; tacrolimus concentrations increased (13c ). Besides its potential use in reducing tacrolimus dosage requirements, diltiazem has the potential to optimize allograft function by reducing ischemia–reperfusion injury. There was no difference in renal function between the groups over 2 years and no differences in graft or patient survival, which at 2 years were 97 and 98% with diltiazem and 100 and 100% without diltiazem. Acute rejection episodes were also similar between the two groups (15%). Diltiazem was discontinued in four patients because of adverse effects. There was no difference in tacrolimus-related adverse effects between the two groups. The authors concluded that diltiazem is efficacious and acceptably safe in renal transplant recipients taking with tacrolimusbased immunosuppressive therapy. A dramatic increase in tacrolimus blood concentration has been attributed to simultaneous treatment with diltiazem and protease inhibitors (14A ). • A 40-year-old man with diabetes, who took diltiazem 300 mg/day for hypertension and antiretroviral drugs, including lamivudine, stavudine, saquinavir, and ritonavir, underwent renal transplantation. He was also positive for hepatitis B and C. Four days after the graft, tacrolimus blood concentrations were 130 µg/l before the morning dose, 186 µg/l by the evening, and 202 µg/l the following day. Tacrolimus was withdrawn and the blood concentration slowly fell to 12 µg/l on day 26. Tacrolimus 0.5 mg bd was then reintroduced. There was no evidence of toxicity. Saquinavir and ritonavir were continued unchanged and the doses of lamivudine and stavudine were increased. Fifteen months after the graft, he was taking tacrolimus 0.5 mg once a week, which
Beta-adrenoceptor antagonists and antianginal drugs is 140 times lower than the initial dose, with a tacrolimus blood concentration of 10 µg/l. His renal function was normal.
As tacrolimus metabolism is mostly due to CYP3A4, co-administration of ritonavir and saquinavir, which are CYP3A4 substrates and inhibitors, may have altered the pharmacokinetics of tacrolimus. Diltiazem is also a CYP3A4 substrate and inhibitor, and the authors suggested that it may have contributed; however, it was withdrawn on the day of the graft and is unlikely to have played a part.
Felodipine
(SEDA-26, 226)
Drug interactions Nelfinavir inhibits CYP3A4, which metabolizes felodipine. • A nurse who was taking felodipine 5 mg/day was accidentally exposed to blood infected with HIV; she was given nelfinavir and 3 days after treatment was started she developed bilateral leg edema, dizziness, fatigue, and orthostatic hypotension (15A ). The edema resolved after felodipine was withdrawn and her hypertension was controlled with a diuretic.
Lercanidipine
(SED-15, 2024;
SEDA-28, 219) Comparative studies ACE inhibitors slow the progression of diabetic nephropathy. In a double-blind, randomized comparison of ramipril 10–20 mg/day and lercanidipine 10–20 mg/ day, the two drugs were equally effective in reducing albumin excretion rate and blood pressure in 180 patients with microalbuminuria and type 2 diabetes and hypertension (16c ). The proportions of patients who had adverse events were similar: 29% with lercanidipine and 23% with ramipril. Six patients taking lercanidipine and five taking ramipril withdrew because of one or more adverse events, as follows: lercanidipine—hypotension (n = 2), ankle edema (n = 1), tachycardia (n = 2), headache (n = 2), and epigastralgia (n = 1); ramipril—cough (n = 3), hypotension (n = 1), worsened peptic ulcer (n = 1).
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Nicardipine (SED-15, 2502; SEDA-26, 227; SEDA-27, 206) Cardiovascular Invasive coronary procedures, such as rotational atherectomy and coronary artery bypass graft stenting, are associated with vasoconstriction, which can increase the risk of a bad outcome. Nicardipine is relatively cardiac and vascular selective with a rapid onset of action after intravenous administration, and it is used as an alternative to sodium nitroprusside and adenosine to prevent vasoconstriction during interventional coronary procedures. A review of its efficacy and safety (17R ) has shown that nicardipine is as effective as diltiazem, but because it has minimal negative inotropic and chronotropic effects it can readily be given with beta-blockers in postoperative therapy. Pregnancy Nicardipine is used a first-line tocolytic agent, since it seems to have similar efficacy to salbutamol but greater safety. Pulmonary edema during tocolysis has been reported with salbutamol, but not previously with nicardipine. • A 27-year-old woman developed severe dyspnea and orthopnea after receiving an of infusion nicardipine 2 mg/hour for 3 days for preterm labor at 27 weeks of gestation (18A ). She had also received betametasone 12 mg/day intravenously for 2 days for fetal pulmonary maturation. There was no evidence of infection or pre-eclampsia, but radiographic evidence of pulmonary edema with a tachycardia of 156/minute and a blood pressure of 140/56 mmHg. The fetal heart rhythm and ultrasound were normal. The pulmonary edema quickly resolved with intravenous furosemide 40 mg and nasal oxygen. Echocardiography showed normal left ventricular function without evidence of valvular disease, and 2 weeks later she was asymptomatic. The pregnancy ended with a full-term vaginal delivery at 38 weeks. Peripartum cardiomyopathy was excluded based on the fast clinical recovery.
The mechanism in this case was unknown, but the patient may have had acute diastolic dysfunction due to tachycardia and volume overload aggravated by glucocorticoid therapy. Five cases of pulmonary edema have also been reported in women given nicardipine 3– 6 mg/hour by intravenous infusion and intramuscular betametasone to prevent preterm labor at 26–38 weeks of gestation in the presence of contraindications to sympathomimet-
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ics (19A ). There was no evidence of myocardial infarction or other cardiac dysfunction. Tocolysis was immediately stopped and the pulmonary edema resolved within 48 hours with specific therapy. Clinicians should be aware of the risk of pulmonary edema during tocolysis with nicardipine, especially when associated with glucocorticoids and in high-risk maternal conditions, particularly carediovascular.
Nifedipine (SED-15, 2516; SEDA-26, 227; SEDA-27, 206; SEDA-28, 220) Cardiovascular The long-term safety of dihydropyridine calcium channel blockers has been extensively debated since 1995. The ACTION trial started in 1996 following concerns about the long-term safety of nifedipine, particularly short-acting formulations. The study included 7665 patients with stable angina randomized to receive nifedipine or placebo on top of their conventional therapy. Over a mean follow-up period of 4.9 years there were no differences between the two groups in the primary endpoint, which was the combination of death, acute myocardial infarction, refractory angina, new heart failure, stroke, and peripheral revascularization. Although the results were disappointing with regard to efficacy, they offered reassurance about the safety of long-acting nifedipine (20C ). Increased sympathetic activity has been indentified as a risk factor for cardiovascular events, but long-acting dihydropyridines should have little if any sympathoexcitatory effects when given over the long term. Treatment for 4 weeks with low-dose GITS (gastrointestinal therapeutic system) nifedipine 20 mg/day reduced the blood pressure in older patients with mild hypertension (mean age 67 years) but not in younger ones (mean age 45 years) (21c ). There was a reflex increase in sympathetic activity in the young patients, which could have attenuated the blood pressure response. Pregnancy Compared with beta-adrenoceptor agonists there are fewer interruptions of treatment with nifedipine due to maternal adverse effects, and therapy is more effective in prolonging pregnancy. Clinical guidelines have recently advocated nifedipine as a tocolytic
A.P. Maggioni, M.G. Franzosi, and R. Latini
of choice (22S ). However, nifedipine is not without risks, particularly in women with underlying cardiac anomalies. • A 31-year-old woman presented at 32 weeks of gestation with threatened preterm labor (23A ). An asymptomatic ventricular septal defect had been incompletely repaired in childhood. Despite this, she had good pre-pregnancy exercise tolerance and no dyspnea. An echocardiogram undertaken in early pregnancy showed normal left ventricular size and function. She received betamethasone, nifedipine 20 mg orally three times 20 minutes apart for preterm labour tocolysis, and amoxicillin 1 g intravenously for prophylaxis of bacterial endocarditis. Within 10 minutes of the second dose of nifedipine, she became short of breath. Her symptoms worsened overnight and by 20 hours after nifedipine, her respiratory distress necessitated transfer to the intensive care unit. She was afebrile and had mild cyanosis, bilateral peripheral edema, a raised jugular venous pressure, a pulse rate of 120/minute, and a blood pressure of 130/65 mmHg. Her respiratory rate was 32/minute. There was a loud systolic murmur at the left sternal edge, consistent with her ventricular septal defect, a right ventricular heave, and reduced breath sounds at the lungs bases. With conservative management the unexplained dyspnea and hypoxia gradually settled over 7 days. Her delivery and postnatal recovery was uneventful and the caused of her hypoxia remained undiagnosed.
Hypocalcemia has been reported after treatment with magnesium sulfate for tocolysis. • A 25-year-old Hispanic woman was given magnesium sulfate 132 mg intravenously over 55 hours during betamethasone administration, nifedipine 10 mg orally 30 minutes after magnesium discontinuation, which she tolerated well, and nifedipine 20 mg orally 4 hours later (24A ). Her blood pressure fell to 93/49 mmHg and she was given no further doses. She had bilateral hand contractures about 6 hours later and her serum calcium was 1.35 mmol/l. She was given 40 ml of 10% calcium gluconate intravenously and 4 hours later was moving her hands normally and the serum calcium was 2.45 mmol/l.
The association between magnesium sulfate and maternal hypocalcemia is well recognized, given its effect on calcium metabolism, and concern has been raised that the risk may be increased if a calcium channel blocker, such as nifedipine, is also used. Even if evidence of synergistic toxicity is scanty, caution is advised when these drugs are used simultaneously.
Beta-adrenoceptor antagonists and antianginal drugs
Management of adverse drug reactions Ankle edema is often associated with nifedipine, as a consequence of local vasodilatation. Prevention studies of this adverse reaction with simultaneous administration of diuretics have yielded controversial results: furosemide did not prevent the acute increase in foot volume due by nifedipine in healthy volunteers (25c ), while other studies have shown that edema formation can be attenuated by diuretics (26C ). To investigate further whether diuretic pretreatment is effective in controlling foot swelling, the effect of nifedipine after premedication with amiloride or chlorthalidone was compared with the effect of nifedipine alone in 10 healthy volunteers (8 men, 2 women) aged 19–27 years (27c ). In four separate experiments they received: (a) nifedipine 20 mg/day with placebo pretreatment; (b) nifedipine 20 mg/day after treatment for 5 days with amiloride 5 mg bd; (c) nifedipine 20 mg/day after treatment for 5 days with chlortalidone 50 mg/day; (d) pre-treatment with placebo and placebo in place of nifedipine. Amiloride and chlortalidone pretreatment produced marked foot volume depletion, with a 2–3% reduction in body weight, a 5–10 increase in hematocrit, and a 14–23% increase in plasma colloid osmotic pressure. The mean foot volume after both chlortalidone (1282 ml) and amiloride (1289 ml) was significantly lower than without pretreatment (1315 ml). However, neither amiloride nor chlortalidone significantly altered the acute increase in foot volume with nifedipine, although foot volume remained lower after pretreatment. The authors therefore concluded that diuretics mitigate edema due to nifedipine but do not directly interfere with its formation.
Nimodipine
(SED-15, 2526; SEDA-26,
227) Placebo-controlled studies In a post-hoc analysis of the relation between blood pressure, nimodipine treatment, and outcome in 350 patients in a placebo-controlled trial in ischemic stroke, there was a higher fatality rate with nimodipine, together with a greater reduction in blood pressure (28c ). Stroke severity was the strongest predictor of a bad outcome at both 3 weeks and 3 months. A high initial blood
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pressure within the first 24 hours was associated with better survival in moderately severe strokes, but the reverse in severe stroke. Cardiovascular Nimodipine reportedly aggravated cardiac dysfunction in a patient with subarachnoid hemorrage (29A ). • A 52-year-old woman with a subarachnoid hemorrage had severe myocardial depression with anterolateral ischemic electrocardiographic signs after an intravenous infusion of nimodipine 0.5– 1.2 mg/h had been started. The cardiac index improved only after nimodipine had been withdrawn in the presence of inotropes. The cardiac index fell shortly after nimodipine had been reintroduced; nimodipine could only be restarted 48 hour later, whien it was well tolerated.
The authors suggested that nimodipine may aggravate cardiac dysfunction associated with the acute phase of subarachnoid hemorrage.
Verapamil
(SED-15, 3618; SEDA-26, 227; SEDA-27, 207; SEDA-28, 220) Comparative studies In a double-blind, randomized study in 1033 patients the combination of verapamil plus quinidine was not inferior to sotalol in preventing symptomatic episodes of paroxismal atrial fibrillation and both were superior to placebo (30C ). However, recurrence rates were relatively high in all groups, including placebo, in the presence of a low but definite risk of severe and potentially life-threatening adverse effects. For this reason the authors suggested that antidysrhythmic drug therapy should be restricted to highly symptomatic patients.
Placebo-controlled studies In a double-blind, randomized study in 848 patients successfully cardioverted for persistent atrial fibrillation the combination of verapamil plus quinidine was not inferior to sotalol in preventing recurrence of atrial fibrillation or death, but it was superior to placebo (31C ). There were adverse events in 75% of those taking either sotalol or verapamil plus quinidine and in 61% of those taking placebo. Serious adverse events had the same incidences in the three groups, but there were five deaths in those who took quinidine plus verapamil, six in those who took sotalol, and
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none in those who took placebo. There were 10 episodes of torsade de pointes in those taking sotalol, and none in those taking verapamil plus quinidine. The authors suggested that verapamil might have prevented the prodysrhythmic effects of quinidine. Cardiovascular Of 169 consecutive patients, mainly elderly with structural heart disease, with second- or third-degree atrioventricular block not related to other causes (such as acute myocardial infarction, digitalis toxicity, or vasovagal syncope), 92 (54%) who were taking a beta-blocker and/or verapamil or diltiazem had similar clinical and electrocardiographic characteristics to patients who had atrioventricular block in the absence of drugs (32c ). Drug withdrawal was followed by resolution of atrioventricular block in 41% of cases, whereas there was spontaneous improvement in atrioventricular conduction in 23% of patients who had atrioventricular block in the absence of drugs. However, 56% of the patients in whom drug withdrawal led to resolution of atrioventricular block had a recurrence in the absence of therapy. There was atrioventricular block that was “truly caused by drugs” in only 15% of patients who had second- or third-degree block
A.P. Maggioni, M.G. Franzosi, and R. Latini
during therapy with beta-blockers, verapamil, or diltiazem. The authors concluded that atrioventricular block is commonly related to drugs but rarely caused by drugs. Skin A skin rash consistent with lymphomatoid papulosis has been attributed to verapamil (33A ). • A 71-year-old man with chronic cluster headaches took verapamil, starting in December 2000 at a dose of 240 mg/day and then 120–480 mg/day. He stopped taking it in September 2001 and restarted in November because his headaches recurred. Within 1 week of restarting he developed a distinctive rash that took the form of 0.5 cm pruritic, erythematous papules on his neck, armpits, and groin. They persisted for about 2 weeks and resolved when the dose of verapamil was reduced from 240 to 200 mg/day. A skin biopsy showed histological features consistent with lymphomatoid papulosis.
By modulating the cellular immune system, verapamil may promote the expansion of an atypical T cell subpopulation, with subsequent progression to lymphomatoid papulosis, which is important to recognize because it can evolve into malignant lymphoma.
References 1. Hery E, Jourdain P, Funck F, Bellorini M, Loiret J, Thebault B, Guillard N, El Hallak A, Desnos M. Prediction of intolerance to beta blocker therapy in chronic heart failure patients using BNP. Ann Cardiol Angeiol 2004;53:298– 304. 2. Markou N, Antzoulatos N, Haniotou A, Kanakaki M, Parissis J, Damianos A. A case of drug-induced pneumonitis caused by carvedilol. Respiration 2004;71:650–2. 3. Bakris GL, Fonseca V, Katholi RE, McGill JB, Messerli FH, Phillips RA, Raskin P, Wright JT, Oakes R, Lukas MA, Anderson KM, Bell DSH, for the GEMINI Investigators. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension. A randomized controlled trial. JAMA 2004;292:2227–36. 4. Schlienger RG, Kraenzlin ME, Jick SS, Meier CR. Use of beta-blockers and risk of fractures. JAMA 2004;292:1326–32.
5. Muto S, Ashizawa N, Arakawa S, Tanaka K, Komiya N, Toda G, Seto S, Yano K. Sotalolinduced coronary spasm in a patient with dilated cardiomyopathy associated with sustained ventricular tachycardia. Intern Med 2004;43(11):1051–5. 6. Siddiqi M, Marco AP, Gorp CV. Postoperative hypotension from topical use of 2% nitroglycerin ointment after a total knee replacement procedure. J Clin Anesth 2004;16:77–8. 7. Flynn JT, Newburger JW, Daniels SR, Sanders SP, Portman RJ, Hogg RJ, Saul JP, for the PATH-I Investigators. A randomized, placebocontrolled trial of amlodipine in children with hypertension. J Pediatr 2004;145:353–9. 8. Garbe E, Meyer O, Andersohn F, Aslan T, Kiesewetter H, Salama A. Amlodipine-induced immune thrombocytopenia. Vox Sanguinis 2004;86:75–6.
Beta-adrenoceptor antagonists and antianginal drugs 9. Zinsser P, Meyer-Wyss B, Rich P. Hepatotoxicity induced by celecoxib and amlodipine. Swiss Med Wkly 2004;134(14):201. 10. Erbagci Z. Amlodipine associated hyperpigmentation. Saudi Med J 2004;25:103–5. 11. Samarasinghe YP, Cox A, Feher MD. Calcium channel blocker induced gum hypertrophy: no class distinction. Heart 2004;90:16. 12. Watanabe H, Kosuge K, Nishio S, Yamada H, Uchida S, Satoh H, Hayashi H, Ishizaki T, Ohashi K. Pharmacokinetic and pharmacodynamic interactions between simvastatin and diltiazem in patients with hypercholesterolemia and hypertension. Life Sci 2004;76:281–92. 13. Kothari J, Nash M, Zaltzman J, Ramesh Prasad GV. Diltiazem use in tacrolimus-treated renal transplant recipients. J Clin Pharm Ther 2004;29(5):425–30. 14. Hardy G, Stanke-Labesque F, Contamin C, Serre-Debeauvais F, Bayle F, Zaoui P, Bessard G. Protease inhibitors and diltiazem increase tacrolimus blood concentration in a patient with renal transplantation: a case report. Eur J Clin Pharmacol 2004;60:603–5. 15. Izzedine H, Launay-Vacher V, Deray G, Hulot JS. Nelfinavir and felodipine: a cytochrome P450 3A4-mediated drug interaction. Clin Pharmacol Ther 2004;75:362–3. 16. Dalla Vestra M, Pozza G, Mosca A, Grazioli V, Lapolla A, Fioretto P, Crepaldi G. Effect of lercanidipine compared with ramipril on albumin excretion rate in hypertensive type 2 diabetic patients with microalbuminuria: DIAL Study (Diabete, Ipertensione, Albuminuria, Lercanidipina). Diab Nutr Metab 2004;17:259–66. 17. Fischell TA, Maheshwari A. Current applications for nicardipine in invasive and interventional cardiology. J Invasive Cardiol 2004;16:428–32. 18. Bal L, Thierry S, Brocas E, Adam M, Van de Louw A, Tenaillon A. Pulmonary edema induced by calcium-channel blockade for tocolysis. Anesth Analg 2004;99:910–1. 19. Vaast P, Dubreucq-Fossaert S, Houfflin-Debarge V, Provost-Helou N, Ducloy-Bouthors AS, Puech F, Subtil D. Acute pulmonary oedema during nicardipine therapy for premature labour. Report of five cases. Eur J Obstet Gynecol Reprod Biol 2004;113:98–9. 20. Poole-Wilson PA, Lubsen J, Kirwan BA, van Dalen FJ, Wagener G, Danchin N, Just H, Fox KA, Pocock SJ, Clayton TC, Motro M, Parker JD, Bourassa MG, Dart AM, Hildebrandt P, Hjalmarson Å, Kragten JA, Molhoek GP, Otterstad JE, Seabra-Gomes R, SolerSoler J, Weber S. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial. Lancet 2004;364:849–57.
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21. Grassi G. Neuroadrenergic effects of calcium channel blockers: a developing concept. J Hypertens 2004;22:887–8. 22. Royal College of Obstetricians and Gynaecologists. Clinical Green Top Guidelines. Tocolytic drugs for women in preterm labour 1(B). http://www.rcog.org.uk/index.asp?PageID=536, Oct 2002. 23. Hodges R, Barkehall-Thomas A, Tippett C. Maternal hypoxia associated with nifedipine for threatened preterm labour. Br J Obstet Gynaecol 2004;111:380–1. 24. Koontz SL, Friedman SA, Schwartz ML. Symptomatic hypocalcemia after tocolytic therapy with magnesium sulfate and nifedipine. Am J Obstet Gynecol 2004;190:1773–6. 25. Tvan Hamersvelt HW, van Kestern M, Kloke HJ, Wetzels JF, Valk I, Koene RA, Huysmans FT. Ankle edema with nifedipine is not primarily due to sodium retention. Jam Soc Nephrol 1993;4:541. 26. Luscher TF, Waeber B. Efficacy and safety of various combination therapies based on a calcium antagonists in essential hypertension: results of a placebo-controlled randomized trial. J Cardiovasc Pharmacol 1993;21:305–9. 27. van der Heijden AG, Huysmans FTM, van Hamersvelt HW. Foot volume increase on nifedipine is not prevented by pretreatment with diuretics. J Hypertens 2004;22:425–30. 28. Fogelholm R, Palomäki H, Erilä T, Rissanen A, Kaste M. Blood pressure, nimodipine, and outcome of ischemic stroke. Acta Neurol Scand 2004;109:200–4. 29. Subramani K, Ghrew M. Severe myocardial depression following intravenous nimodipine for aneurysmal subarachnoid haemorrhage. Intensive Care Med 2004;30:1498–9. 30. Patten M, Maas R, Bauer P, Lüderitz B, Sonntag F, Dluzniewski M, Hatala R, Opolski G, Müller HW, Meinertz T, for the SOPAT Investigators. Suppression of paroxysmal atrial tachyarrhythmias—results of the SOPAT trial. Eur Heart J 2004;25:1395–404. 31. Fetsch T, Bauer P, Engberding R, Koch HP, Lukl J, Meinertz T, Oeff M, Seipel L, Trappe HJ, Treese N, Breithardt G, for the Prevention of Atrial Fibrillation after Cardioversion Investigators. Prevention of atrial fibrillation after cardioversion: results of the PAFAC trial. Eur Heart J 2004;25:1385–94. 32. Zeltser D, Justo D, Halkin A, Rosso R, IshShalom M, Hochenberg M, Viskin S. Druginduced atrioventricular block: prognosis after discontinuation of the culprit drug. JACC 2004;44:105–8. 33. Afridi S, Bacon CM, Bowling J, Goadsby PJ. Verapamil and lymphomatoid papulosis in chronic cluster headache. J Neurol 2004;251:473–5.
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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
DRUGS USED IN THE TREATMENT OF VENOUS DISORDERS Calcium dobesilate
Buflomedil
(SED-15, 566)
Drug overdose Acute buflomedil toxicity can be fatal. A man was found dead and a young woman died in the hospital after presumed overdoses (1A , 2A ). Both had high concentrations of buflomedil in body fluids.
Cilostazol
(SED-15, 773; SEDA-27, 209)
Cardiovascular Withdrawal of cilostazol led to sinus node dysfunction in a patient taking concurrent atenolol (3A ). • A 72-year-old patient with diabetes was taking insulin, cilostazol, atenolol, and amlodipine. A few days before surgery for vascular repair the cilostazol was withdrawn to reduce blood loss. His heart rate gradually fell (from 75 to 60/minute). Anesthesia led to a further fall, and shortly after declamping of the operated artery he had an asystolic cardiac arrest. Closed-chest cardiac massage and injections of atropine and adrenaline restored sinus rhythm.
(SED-15, 610)
Calcium dobesilate is used in many countries for chronic venous disease, diabetic retinopathy, and hemorrhoids. Safety data from postmarketing surveillance over 25 years has been extensively summarized (4R ). The data suggest that most adverse events are rare and frequently unrelated to the drug. Fever, gastrointestinal intolerance, skin reactions, and arthralgia are the most frequent adverse effects ascribed to calcium dobesilate. There have been a few reports of agranulocytosis, but its frequency is lower than in the general population and methodological bias is therefore suspected.
DRUGS USED IN THE TREATMENT OF MIGRAINE Ergot alkaloids (SED-15, 1230; SEDA-27, 151; SEDA-28, 224)
The authors argued that withdrawal of cilostazol had removed a rhythm accelerating effect and left the bradycardic action of atenolol unopposed.
Cardiovascular Arterial dissection is mainly associated with arterial trauma or with wall abnormalities such as fibromuscular dysplasia. Carotid artery dissection is uncommon, but whether vasospasm induced by ergotamine is a likely mechanism for dissection is uncertain.
Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29019-6 © 2007 Elsevier B.V. All rights reserved.
• A 65-year-old man with a year-long history of migraine, for which he took ergotamine almost every other day, developed sudden disturbances of swallowing and speech (5A ). An MRI scan showed a dissection of the internal carotid artery at the base of the skull.
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Fetotoxicity Möbius sequence is a rare congenital anomaly consisting of facial diplegia and external ophthalmoplegia associated with variable musculoskeletal and cardiovascular abnormalities. It is usually secondary to aplasia or hypoplasia of brainstem nuclei. • A baby born to a mother who had been taken ergotamine on a regular basis for the first 8 weeks of her pregnancy had axial hypotonia, facial diplegia, bilateral abducens nerve paralysis, pes equinovarus, and aortic coarctation (6A ).
Vasospasm and increased uterine tone, leading to embryonic brain stem ischemia in a crucial phase of development, was the putative mechanism that the authors advanced to explain these congenital anomalies.
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a 15 cm segment, starting in the distal transverse colon. Biopsies were compatible with ischemic colitis. She recovered rapidly with supportive care.
Naratriptan, which she had been taking regularly for a few months, was held responsible. Other obvious risk factors for ischemic colitis were absent.
OTHER PERIPHERAL VASODILATORS Inhibitors of phosphodiesterase type V (SED-15, 3133; SEDA-26, 231; SEDA-27, 210; SEDA-28, 224)
Triptans
(SED-15, 3525; SEDA-26, 230; SEDA-27, 210) Cardiovascular A multidisciplinary Triptan Cardiovascular Safety Expert Panel of the American Headache Society has evaluated the evidence on triptan-associated cardiovascular risk and has formulated consensus recommendations for the use of triptans in patients with migraine (7M ). The panel concluded that the incidence of serious cardiovascular events with these drugs in both clinical trials and clinical practice is low, but that most of the data are derived from patients without coronary artery disease. Chest symptoms that occur during the use of triptans are generally not serious and are mostly not explained by ischemia. Because of the favorable benefit to harm balance, the panel estimated that triptans can be prescribed for patients with a low risk of coronary artery disease without the need for prior evaluation of their cardiac status. Gastrointestinal Ischemic colitis has been associated with sumatriptan, and has now been reported with naratriptan, suggesting that this adverse effect is a class effect (8A ). • A 54-year-old woman, with a history of migraine and depression, developed abrupt bloody diarrhea with severe cramps in the lower abdomen. A CT scan showed circumferential thickening of the distal transverse colon and descending colon. At colonoscopy, hemorrhagic colitis was seen over
With on average one new medical publication per day, inhibitors of phosphodiesterase type V keep ranking high on the hit-list of drugs. At least half-a-dozen new reviews of sildenafil, tadalafil, and vardenafil have stressed the overall safety of this class of drugs in men with erectile dysfunction and in patients with pulmonary hypertension (9C –14C ). The reviewed data have mainly been obtained from clinical trials. Nervous system Headache is the one of the most common adverse effects of inhibitors of phosphodiesterase type V, being reported by 15–30% of patients. There is debate about whether migraine attacks are provoked by these drugs (15r ). A typical migraine attack occurred after ingestion of sildenafil in 10 of 12 women with a history of migraine (16c ). A third case of cerebral hemorrhage after the use of sildenafil has been reported (17A ). The man had additional risk factors for hemorrhage, and details of the time course in relation to drug intake were not precise. • A 62-year-old hypertensive man developed leftsided hemiballismus secondary to a small hemorrhage in the right subthalamic–thalamic region. He had recently taken sildenafil 50 mg before having sexual intercourse.
Sensory systems Serous chorioretinopathy has been attributed to sildenafil (18A ).
204 • A 37-year-old man took regular sildenafil and developed acute visual loss and a pressure sensation in his right eye. Fundoscopy showed an area of subretinal fluid, pointing to central serous chorioretinopathy. He was encouraged to refrain from sildenafil, but continued to use it and the symptoms worsened. When he later stopped using it, the disorder completely resolved within 3 weeks.
Palpebral edema has been attributed to tadalafil (19A ). • A 56-year-old patient with diabetes and no history of allergy noticed bilateral eyelid edema the morning after a first pill of tadalafil. The symptoms regressed spontaneously within 72 hours but recurred 1 week later after a second dose of the drug. The absence of any other known cause of palpebral edema, the time course, and recurrence on rechallenge were strong arguments for a causative link with tadalafil.
Skin Acute widespread urticaria was reported after vardenafil consumption in a 48-year-old man with no other identifiable causative factors (20A ).
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R. Verhaeghe
Reproductive system Edema of the male breast secondary to strong vasodilatation after the use of inhibitors of phosphodiesterase type V can occur (21A ). • A 32-year-old man complained of breast tenderness after taking sildenafil 50 mg/day for 3 weeks. There was tenderness confined to the nipples and areolae of both breasts, without signs of infection or inflammation. The symptoms subsided within 48 hours after withdrawal of the drug and recurred within 72 hours after its reintroduction.
Drug interactions Lovers of red wine can be reassured: sildenafil 100 mg together with a full bottle of Australian Cabernet Sauvignon did not disturb the hemodynamics of young volunteers more than did the wine on its own (22c ). Alcohol stimulates sexual desire but impairs potency, but the authors did not report if sildenafil helped to maintain potency after rapid drinking of the wine.
References 1. Neri C, Barbareschi M, Turrina S, De Leo D. Suicide by buflomedil HCl: a case report. J Clin Forensic Med 2004;11:15–6. 2. Babel B, Tatschner T, Patzelt D. Suicidal buflomedil intoxication. Arch Kriminol 2004;213:108–13. 3. Ishiyama T, Oguchi T, Yamaguchi T, Kumazawa T. Sinus node dysfunction associated with discontinuation of cilostazol in a patient taking atenolol. Br J Anaesth 2004;93:472. 4. Allain H, Ramelet AA, Polard E, BentueFerrer D. Safety of calcium dobesilate in chronic venous disease, diabetic retinopathy and haemorrhoids. Drug Saf 2004;27:649–60. 5. Akova-Oztürk E, Husstedt IW, Ringelstein EB, Evers S. Carotid artery dissection in ergotamine abuse. Headache 2004;44:930–2. 6. Smets K, Zecic A, Willems J. Ergotamine as a possible cause of Möbius sequence: additional clinical observation. J Child Neurol 2004;19:398. 7. Dodick D, Lipton RB, Martin V, Papademetriou V, Rasamond W, Maasen VanDenBrink A, Loutfi H, Welch KM, Goadsby PJ, Hahn S, Hutchinson S, Matchar D, Silberstein S, Smith TR, Purdy RA, Saiers J, Triptan Cardiovascular Safety Expert Panel. Consensus statement: cardiovascular safety profile of triptans
8. 9.
10.
11.
12.
13.
(5-HT agonists) in the acute treatment of migraine. Headache 2004;44:414–25. Schwartz DC, Smith DJ. Colonic ischemia associated with naratriptan use. J Clin Gastroenterol 2004;38:790–2. Hatzichristou D, Montorsi F, Buvat J, Laferriere N, Bandel TJ, Porst H, European Vardenafil Study Group. The efficacy and safety of flexibledose vardenafil (Levitra) in a broad population of European men. Eur Urol 2004;45:634–41. Montorsi F, Verheyden B, Meuleman E, Junemann KP, Moncada I, Valiquette L, Casabe A, Pacheco C, Denne J, Knight J, Segal S, Watkins VS. Long-term safety and tolerability of taladafil in the treatment of erectile dysfunction. Eur Urol 2004;45:339–44. Kloner RA. Cardiovascular effects of the 3 phosphodiesterase-5 inhibitors approved for the treatment of erectile dysfunction. Circulation 2004;110:3149–55. Alaeddini J, Uber PA, Park MH, Scott RL, Ventura HO, Mehra MR. Efficacy and safety of sildenafil in the evaluation of pulmonary hypertension in severe heart failure. Am J Cardiol 2004;94:1475–7. Eardley I, Gentile V, Austoni E, Hackett G, Lembo D, Wang C, Beardswoth A. Efficacy and
Drugs acting on the cerebral and peripheral circulations
14.
15. 16.
17. 18.
safety of tadalafil in a Western European population of men with erectile dysfunction. BJU Int 2004;94:871–7. Seftel AD, Wilson SK, Knapp PM, Shin J, Wang WC, Ahuja S. The efficacy and safety of tadalafil in United States and Puerto Rican men with erectile dysfunction. J Urol 2004;172:652– 7. Evans RW, Kruuse C. Phosphodiesterase-5 inhibitors and migraine. Headache 2004;44:925–6. Kruuse C, Thomsen LL, Birk S, Olesen J. Migraine can be induced by sildenafil without changes in middle cerebral artery diameter. Brain 2003;126:241–7. Marti I, Marti Masso JF. Hemiballism due to sildenafil use. Neurology 2004;63:534. Allibhai ZA, Gale JS, Sheidow TS. Central serous chorioretinopathy in a patient taking silde-
19. 20.
21. 22.
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nafil citrate. Ophtalmic Surg Lasers Imaging 2004;35:165–7. Chandeclerc ML, Martin S, Petitpain N, Barbaud A, Schmutz JL. Tadalafil and palpebral edema. South Med J 2004;97:1142–3. Minciullo PL, Saija A, Patafi M, Giannetto L, Marotta G, Ferlazzo B, Gangemi S. Vardenafilinduced generalized urticaria. J Clin Pharmacol Ther 2004;29:483–4. Chattopadhyay S, Dhar S. Mastalgia: an adverse effect of sildenafil. Dermatology 2004;209:346. Leslie SJ, Atkins G, Oliver JJ, Webb DJ. No adverse hemodynamic interaction between sildenafil and red wine. Clin Pharmacol Ther 2004;76:365–70.
Jamie J. Coleman
20
Antihypertensive drugs
Moving targets and patterns of prescribing The landscape of hypertension management has changed considerably, and changes in treatment are reviewed every few years by national and international groups with interests in cardiovascular disease. In 2003 the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure produced its seventh report (1S ). On the basis of data on the lifetime risk of hypertension and the risks of cardiovascular disease in patients with hypertension, their report emphasized the targets of disease treatment and pointed to new patterns of prescribing. Guidelines from the European Society of Hypertension and the European Society of Cardiology, also published in 2003 (2S ), gave similar perspectives. In 2004 the British Society of Hypertension produced a comprehensive set of guidelines, endorsing the A(B)/CD algorithm (3S ). This strategy targets the renin–angiotensin–aldosterone system in younger Caucasian patients with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor antagonists, while first-line treatment in older Caucasian or black patients of any age is with calcium channel blockers or thiazide diuretics; beta-blockers take a less important initial role in the absence of compelling indications. There are also concerns regarding the possible adverse metabolic consequences of long-term therapy with thiazide diuretics and beta-blockers. Since the hypertension guidelines were published new evidence that strengthens this argument has appeared. Conventional blood preSide Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29020-2 © 2007 Elsevier B.V. All rights reserved.
206
ssure-lowering therapy (atenolol + bendroflumethiazide) has been compared with a more contemporary regimen of drugs (amlodipine + perindopril) in a large randomized controlled trial (4C ). The Anglo-Scandinavian Cardiac Outcomes Trial—Blood Pressure Lowering Arm (ASCOT-BPLA) has shown that treating hypertension with amlodipine and additional perindopril as required was associated with a reduction in the incidence of all types of cardiovascular events compared with atenolol + a thiazide. The overall incidence of adverse effects was similar in the two groups, but not surprisingly the specific adverse effects profiles were different. Cough, joint swelling, and peripheral edema were more common with amlodipine + perindopril, and bradycardia, dizziness, diarrhea, dyspnea, erectile dysfunction, fatigue, and cold extremities were more common with atenolol + a thiazide. Moreover, the amlodipine-based regimen caused newonset diabetes in significantly fewer patients than the atenolol-based regimen did. What implications does this newer evidence have on the current pattern of prescribing in hypertension? The combination of a calcium channel blocker with an ACE inhibitor (or an angiotensin receptor antagonist) has not previously been used as often as other combinations. Fixed-dose combinations are therefore not generally available, although they are likely to become more widely available. The ASCOTBPLA study reaffirmed that most hypertensive patients require two or more agents to reach blood pressure targets. This endorses the latest guidelines, which propose that combination treatment should be considered for patients who present with a systolic blood pressure of 160 mmHg or more or a diastolic blood pressure of 100 mmHg or more.
Antihypertensive drugs
Chapter 20
ANGIOTENSIN CONVERTING ENZYME INHIBITORS (SED-15, 226; SEDA-26, 234; SEDA-27, 213; SEDA-28, 227)
Angioedema due to ACE inhibitors DoTS classification: Reaction: Angioedema due to ACE inhibitors Dose-relation: Collateral Time-course: Intermediate Susceptibility factors: Genetic (black Americans); sex (female); drugs (NSAIDs, vaccines, immunosuppressants); other exogenous factors (polyacrylonitrile membranes in hemodialysis); diseases (a history of angioedema) Angioedema was first described many centuries ago, although many attribute the first description to Heinrich Quincke in the late 19th century. Cases of hereditary angioedema were reported by Sir William Osler in 1888 (5R ). Angioedema can be caused by autoimmunity, infection, or drugs; the hereditary form is due to deficiency or underfunctioning of the blood protein C1 esterase inhibitor. Angioedema is the most common term used (in 1325 titles of papers listed in Pubmed at the time of searching); other terms are angioneurotic edema (486 instances), Quincke’s edema (111 instances), or giant urticaria (8 instances). Drugs that have been reported as causing angioedema include non-steroidal antiinflammatory drugs (NSAIDs), both selective (COX-2 inhibitors) and non-selective, and vaccines, although the most commonly implicated drugs are ACE inhibitors. Angiotensin receptor blockers have also been reported as causative agents, especially in patients who have previously had reactions to ACE inhibitors (6R ) or in those with co-existing immunological predisposition. Presentation The presentation of angioedema can be dramatic, with swelling of the face and lips. It can be life-threatening from acute oropharyngeal edema and airway compromise (7A ) and may need tracheotomy (8A ). It is occasionally fatal (9A ). An unusual presentation
207 with subglottic stenosis has also been reported (10A ). Urticaria and itching are not usual features, although drug-induced urticaria and angioedema can co-exist as adverse effects of the same drug. Other symptoms include dyspnea, stridor, dysphagia, and cough. Preputial or penile swelling has also been reported as a misleading localization of angioedema (11A ). Intestinal edema is also described (12A – 14A ), and tends to occur within the first 24– 48 hours of treatment (15A , 16A ). Recognition requires a high degree of suspicion, as the symptoms can manifest as non-specific gastrointestinal disturbance and/or abdominal pain; there have been several reports of repeated laparotomies before the correct diagnosis has been made (17c ). • A 73-year-old woman developed unilateral tongue angioedema during treatment with enalapril for hypertension (18r ).
Incidence The overall incidence of druginduced angioedema is not known, but it is estimated that it could occur in 0.1–0.5% of patients taking ACE inhibitors (19R ). In a prospective placebo-controlled study in 12 557 patients with hypertension treated with enalapril maleate 5–40 mg/day, angioedema occurred in 86 (0.68%) (20C ). Black Americans are at increased risk, with an adjusted relative risk of 4.5 (95%CI = 2.9, 6.8) compared with white users (21CR ). This increase in risk was unrelated to the dosage of ACE inhibitor or the concurrent use of cardiovascular drugs. Since millions of patients take these agents worldwide, this represents one of the most common adverse drug reaction in terms of absolute numbers affected. It has been pointed out that the incidence of ACE inhibitor-induced angioedema seems to be on the increase (22R ). Mechanism The putative pathophysiological mechanisms of ACE inhibitor-induced angioedema have been discussed in the context of 19 cases (23A ) and five other cases have been reported (24A ). New insights into the mechanisms have been reviewed with accompanying guidance regarding clinical management (25R ). The cutaneous manifestations result from subcutaneous and mucosal inflammation, arteriolar dilatation, vascular leakage, and localized swelling.
208 The pathophysiological mechanism has been related to bradykinin accumulation, release of IgE, and mast cell-mediated release of vasoactive mediators. However, immunoglobulin E (IgE) antibodies or other specific antibodies have not been detected. ACE inhibitors inactivate bradykinin. Some authors have speculated that it may be related to a deficiency of carboxypeptidase N and complement components, because of its parallel role with that of ACE in the enzymatic inactivation of bradykinin. Increased bradykinin concentrations have been found during acute attacks (26A ) and in a well-documented study, a reliable assay for specific measurement of plasma bradykinin, excluding other immunoreactive kinins, detected a very high concentration of bradykinin (47 pmol/l) during an acute attack of angioedema in a patient taking captopril (27A ). The concentrations fell to 3.2 pmol/l in remission after drug withdrawal. The concentration of bradykinin during chronic ACE inhibition with no angioedema was not reported. One major contribution of this paper was to demonstrate that plasma bradykinin concentrations were substantially increased in 22 patients with hereditary angioedema and 22 others with acquired angioedema, both conditions being associated with inadequate inhibition of the first component of human complement. The infusion of C1 esterase inhibitor immediately lowered bradykinin concentrations in patients with hereditary or acquired C1 esterase inhibitor deficiency. Infusion of C1 esterase inhibitor in ACE inhibitor-induced angioedema was not investigated. In a case-control study nested within an 8-week open study of the use of quinapril for hypertension in 12 275 patients there were 22 cases of angioedema (28C ). They were matched with 48 controls taking quinapril. Patients with angioedema had significantly lower mean activities of serum carboxypeptidase N and C1 esterase inhibitor compared with controls, but all mean values were within the laboratory’s reference range. Although this may support the involvement of low activities of carboxypeptidase in the pathogenesis of ACE inhibitor-induced angioedema, prior testing of patients for low enzyme activities is not likely to be helpful in screening for angioedema risk in patients in whom ACE inhibitor therapy is being considered. In this study it was also
Chapter 20
Jamie J. Coleman
reported that a history of prior episodes of angioedema was associated with a six-fold increase in the subsequent risk of angioedema after ACE inhibitor therapy. Another anecdotal report has pointed out the risk of recurrence of angioedema, in relation to a case of coincident occurrence of angioedema on several occasions in one patient after the consecutive administration of captopril, fosinopril, and quinapril (29c ). Not all patients develop the adverse effect, which suggests that other factors are important; it has been speculated that it may be related to different rates of degradation of endogenous bradykinin (30E ). Individual drugs Angioedema is generally regarded as a class effect and has been attributed to benazepril (31A ), captopril (32A ), cilazapril (33Ar ), enalapril (20C ), lisinopril (34Ar ), perindopril (35A ), quinapril (36A ), and ramipril (37A ). The angiotensin receptor antagonists losartan, irbesartan, telmisartan, eprosartan, and valsartan have all also been implicated, and they are therefore not necessarily absolute safe substitutes for patients with ACE inhibitorinduced angioedema (6R ). Dose relation ACE inhibitor-induced angioedema can occur at any dose in the therapeutic range (a collateral reaction). Time course The time course of angioedema is very variable in relation to the start of drug treatment. It can occur within a day after the start of treatment (31A ) and the risk is highest within the first month. In the study of enalapril mentioned above (20C ), the incidence of angioedema was higher immediately after the start of therapy (3.6/1000 patients per month) and fell to 0.4/1000 patients per month. However, it can occur at any time and has occasionally been reported many months after the start of therapy or even years after (9A , 21CR , 38R , 39cR , 40A ). Susceptibility factors One of the strongest independent risk factors is ethnicity—black patients are three or four times more susceptible to the adverse effect than non-black patients (21CR , 41R , 42R ). Moreover, angioedema is more severe in black American users (21CR ). In
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the study of enalapril mentioned above (20C ) stepwise logistic regression identified black race (OR = 2.88; 95%CI = 1.72, 4.82), a history of drug rash (OR = 3.78; 95%CI = 1.80, 7.92), age greater than 65 years (OR = 1.60; 95% CI = 1.02, 2.53), and seasonal allergies (OR = 1.79; 95% CI = 1.06, 3.00) as independent risk factors for angioedema. Other susceptibility factors that have been identified include a history of angioedema, female sex, and co-existent use of NSAIDs (38R ). Recent initiation of ACE inhibitor therapy and the use of enalapril or lisinopril are also associated with a higher rate of angioedema (21CR ). Anaphylactoid (i.e. non-IgE-mediated anaphylactic) reactions, with hypotension, and flushing, occasionally associated with abdominal cramping, diarrhea, nausea, and sweating, have been reported in patients taking ACE inhibitors undergoing hemodialysis. Angioedema can also occur in these patients; it is occasionally life-threatening and is usually associated with the concurrent use of ACE inhibitors and dialysers in which the membrane is made of polyacrylonitrile (also known as AN69) (43r , 44A ). The mechanism may be related to release of bradykinin. This combination should be avoided, since well-established alternatives are available. ACE inhibitor-induced angioedema was more prevalent among immunosuppressed patients after cardiac or renal transplantation than among other patients (45Cr ). In 156 cardiac patients and 341 patients with renal transplants, this adverse effect was observed in 4.8% and 1% respectively, i.e. 24 times and 5 times higher than in the general population (0.1– 0.2%). In a series of 15 kidney transplant patients given a combination of treatments, including the ACE inhibitor ramipril and the immunosuppressant sirolimus, there were five cases of tongue edema (46A ). All of the patients had previously taken ramipril before renal transplantation without adverse effects. The tongue edema was observed only in those who took high doses of both ramipril (5 mg/day) and sirolimus. There was resolution of the edema after withdrawal of the ramipril, and rechallenge with lower doses of both ramipril (2.5 mg/day) and sirolimus did not result in the same adverse effects. The authors hypothesized that the two drugs act synergistically only when full doses of both are used.
Management All cases of angioedema should be evaluated to look for evidence of an offending drug. Withdrawal of the presumed causative agent and supportive therapy are then key to management. Most cases are self-limiting and will resolve over the first 24–48 hours. In view of the potential for airway compromise, which is the usual cause of death in fatal cases, patients should be carefully examined for any respiratory manifestations. Airway management with intubation or emergency tracheostomy may become necessary in severe cases. Other measures that may help to alleviate oropharyngeal or airway swelling include the administration of intramuscular adrenaline (epinephrine), in accordance with anaphylaxis guidelines, and antihistamine and glucocorticoid therapy. There is no evidence to support the routine use of C1-esterase inhibitor concentrate. Patients who have developed angioedema on treatment should be advised not to use any drugs in the class that precipitated the attack. • A 43-year-old white woman took ramipril, and after 3 weeks developed angioedema, which resolved with antihistamines, glucocorticoids, and one dose of adrenaline (47A ). A low dose of ramipril was restarted 4 days later, and increased over the next 4 days. A few months later she developed severe upper lip and tongue edema. Her C1 esterase inhibitor concentration was normal. After 4 days of treatment with antihistamines, glucocorticoids, adrenaline, leukotriene receptor antagonists, ciclosporin, and intravenous immunoglobulin, without effect, she responded to two units of intravenous fresh frozen plasma, and had no further recurrence.
Benazepril
(SED-15, 420; SEDA-28,
227) Respiratory In a large open study of benazepril in Chinese patients with hypertension there was cough in up to one-fifth of the treated population, leading to frequent withdrawal of therapy and associated with poor adherence to therapy (48c ). The symptom was more common in women; 168 of 741 women (23%) compared with 196 of 1090 men (18%). The prevalence of cough in this population may relate to ethnicity; in another study East-Asian ethnicity (Chinese, Korean, or Japanese) was an independent risk factor for ACE inhibitor-induced cough (49R ).
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Captopril
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(SED-15, 625)
Hematologic Pancytopenia has been reported in a premature newborn treated with captopril for renovascular hypertension (50A ). Trilineage bone marrow suppression leading to pancytopenia is a very rare complication, which may be dose-related in the therapeutic range (a collateral or toxic reaction). In this case the authors surmised that accumulation due to renal tubular dysfunction of prematurity, combined with renal artery stenosis, may have explained the adverse effect in the absence of overt renal dysfunction. They recommended that captopril should be used with caution in premature babies and neonates with underlying renal or renovascular disease, even if they do not have overt renal dysfunction. Salivary glands Sialadenitis has been reported in two patients who had taken captopril for hypertension and developed nonpainful bilateral parotid and submandibular gland swelling (51A ). In one case there was associated upper chest and face erythema, and in the other conjunctival erythema. The authors concluded that the symptoms had probably been caused by the drug, and they suggested that inflammatory mediators or vasodilators (for example bradykinin) could have induced salivary gland obstruction by spasm or edema, or that the drug may have interfered with salivary secretion at a cellular level.
Enalapril
(SED-15, 1210; SEDA-26, 235;
Jamie J. Coleman
• A 50-year-old man developed burning of the lingual, palatal, and labial mucosa in the absence of xerostomia, attributed to treatment with enalapril (53r );
Susceptibility factors Severe aortic stenosis is traditionally viewed as a contraindication to ACE inhibitor therapy. However, in a controlled trial, patients with symptomatic aortic stenosis taking ACE inhibitors had significantly better exercise tolerance and less dyspnea (54c ). The ACE inhibitors were generally well tolerated, although patients with congestive cardiac failure, poor left ventricular function, and resting hypotension were particularly likely to develop hypotension.
Lisinopril
(SED-15, 2071; SEDA-26, 236; SEDA-27, 213; SEDA-28, 228)
Pancreas Pancreatitis has been reported with ACE inhibitors, and a further case has been reported in a patient taking lisinopril and hydrochlorothiazide (55A ). There was associated radiological evidence of biliary tract pathology, and the authors concluded that in this case the drug may have aggravated the acute illness. Skin Dermatological adverse effects are relatively uncommon with ACE inhibitors but erythematous rashes, urticaria, alopecia, and lichenoid eruptions have all been reported. A pityriasis rosea-like eruption has now been reported (56r ).
This case illustrates the occurrence of different adverse effects of two antihypertensive drugs in the same class.
• A 72-year-old Caucasian man developed flat, round, or oval scaly patches, bright red to violet in color, on the trunk, abdomen, and proximal limbs. The scaly surface showed a typical marginal collarette. He reported severe itching, unresponsive to antihistamine treatment. The eruption had begun suddenly 1 month before, had been exanthematous from the start, and evolved in successive crops with no tendency to spontaneous remission. There were no general or prodromic symptoms. He had started to take lisinopril about 2 weeks before the onset of the eruption, was taking no other medications, and had never suffered adverse drug reactions. Lisinopril was withdrawn and the lesions ameliorated rapidly and healed in about a week, without specific treatment.
Mouth Stomatodynia (burning mouth) has previously been reported as an adverse effect of ACE inhibitors.
Pemphigus foliaceus has previously been reported with captopril, ramipril, enalapril, and fosinopril, as well as a wide variety of other
SEDA-28, 227) Sensory systems ACE inhibitors can cause taste disturbances. • A 66-year-old man developed severe dysgeusia and impaired quality of life while taking enalapril 5 mg/day, having previously been intolerant of quinapril because of cough (52A ).
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drugs, and lisinopril has now also been implicated.
ANGIOTENSIN II RECEPTOR ANTAGONISTS (SED-15, 223;
• A 66-year-old man developed pemphigus foliaceus while taking lisinopril for hypertension and ischemic heart disease (57A ). Response to dechallenge was rapid, with resolution of blister formation within 48 hours. There was no recurrence during 3 weeks without ACE inhibitor treatment.
SEDA-26, 236; SEDA-27, 214; SEDA-28, 229)
Although there was co-existent rheumatoid arthritis, which can be associated with pemphigus foliaceus, the authors concluded that the time relation in the case suggested that lisinopril was the more important factor. Drug interactions Tizanidine has been reported to exacerbate hypotension due to lisinopril (58A ). • A 48-year-old hypertensive woman, who was also taking lisinopril, was given tizanidine as a centrally acting antispastic agent for decerebrate rigidity after an intracerebral hemorrhage. Within 2 hours her blood pressure fell from 130/85 to 66/42 mmHg.
The authors discussed the possible mechanisms of this interaction, which was probably pharmacodynamic, since tizanidine has actions similar to those of clonidine, and stimulates central alpha2 adrenoceptors and imidazoline-I receptors.
Although the common adverse effects of the ACE inhibitors, such as dry cough and angioedema, were not anticipated to occur with angiotensin receptor antagonists, both have been reported. A commentary on the use of angiotensin receptor antagonists in patients who had previously had angioedema while taking ACE inhibitors has advised that extreme caution is taken when prescribing angiotensin receptor antagonists for patients with a history of ACE inhibitor-induced angioedema (62r ). The mechanism of angioedema with angiotensin receptor antagonists is not known. Two patients with hereditary angioedema not associated with C1 esterase inhibitor deficiency (so-called Type III hereditary angioedema) have been described as having severe exacerbations of attacks of angioedema in relation to treatment with angiotensin receptor antagonists (63r ).
Candesartan
(SED-15, 612; SEDA-28,
229)
Quinapril
(SED-15, 2996)
Skin Photosensitivity has been described in two patients taking quinapril; subsequent photoprovocation tests were positive (59A ).
Ramipril
(SED-15, 3022; SEDA-24, 239; SEDA-27, 214; SEDA-28, 228)
Pancreas A further case of pancreatitis has been reported in a patient taking ramipril (60A ).
Temocapril
(SED-15, 3313)
Pharmacological and clinical studies of temocapril including its toxicology, pharmacokinetics, and adverse effects have been reviewed (61R ).
Sensory systems Taste disorders have been reported with ACE inhibitors and now also with an angiotensin receptor antagonist (64A ). • A renal transplant patient developed stomatitis and dysgeusia while taking candesartan cilexetil for hypertension. Although the patient was taking many concomitant medications, the chronology of the adverse effect suggested a causal relation with candesartan.
The potential for taste disturbances with candesartan has been investigated in a randomized, double-blind, placebo-controlled, crossover trial in 8 healthy subjects, measuring taste sensation by a paper disc method and also by electrogustometry (65c ). In view of the suggestion that taste disturbance is associated with low serum zinc concentrations, in that drugs may chelate or complex with zinc, serial serum and salivary zinc measurements were also made. The data suggested that candesartan subclinically reduces taste sensitivity after repeated
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dosage in healthy subjects but serum and salivary zinc concentrations were not affected, suggesting a zinc-independent effect. Skin Erythema multiforme has been attributed to candesartan. • A 50-year-old man with hypertension taking candesartan cilexetil developed an ulcerative plaque on the upper lip after five weeks of treatment; biopsy showed erythema multiforme (66A ).
Immunologic Vasculitis has been attributed to candesartan. • A 73-year-old man taking candesartan developed a vasculitic rash and nephritic syndrome (67A ). A skin biopsy showed a lymphocytic vasculitis. The rash and microscopic hematuria resolved within a week of stopping the drug.
The authors concluded that this reaction was consistent with a drug reaction.
Irbesartan
(SED-15, 1908; SEDA-28,
229) There has been a large post-marketing assessment of irbesartan in 4500 patients followed for 6 months, of whom 2.2% had adverse effects, most commonly headache, epigastric pain, nausea, and vomiting (68C ). An allergic reaction and syncope due to hypotension were the only serious adverse events.
Telmisartan
(SED-15, 3311; SEDA-28,
229) Gastrointestinal Previous case reports have described visceral angioedema as a rare complication of ACE inhibition (12A –14A ) and it has now also been described with an angiotensin receptor antagonist (69A ). • A 65-year-old woman who had had recurrent intermittent attacks of severe abdominal pain while taking enalapril, thought to be due to intestinal angioedema, took losartan and developed the same symptoms.
No further details were given about the likelihood that losartan was responsible, but this is the first reported case of possible intestinal angioedema with an angiotensin receptor antagonist.
Jamie J. Coleman
Nails Fingernail clubbing and discoloration (chromonychia) have been reported in association with angiotensin receptor antagonists (70A ). • A 76-year-old Caucasian man developed clubbing of the fingernails and discoloration of both the fingernails and toenails after taking losartan 50 mg/day for 27 days. Even though treatment was changed to valsartan, the nail changes persisted for another 6 months. He was then given captopril, and the changes gradually abated over 17 months.
An extensive literature search revealed no reports of this effect in association with angiotensin receptor antagonists. However, one manufacturer had received spontaneous reports. Despite careful consideration of other possible causes of the patient’s symptoms, the temporal association suggested a possible drug-related adverse event. Urinary tract Losartan has been previously been implicated in acute renal insufficiency in a patient with renal artery stenosis, and a further case has been reported (71Ar ). • A 52-year-old woman with a 5-year history of hypertension developed accelerated hypertension and was given losartan and a loop diuretic. She developed anuria after a diarrheal illness and was found to have a right-sided atrophic kidney. Her treatment was continued and she subsequently was readmitted with a further anuric episode and acute renal insufficiency. There was severe stenosis in the solitary renal artery, and after percutaneous transluminal renal balloon angioplasty to the stenotic segment her urine flow increased and renal function normalized.
Drug overdose Pancreatitis has previously been described with angiotensin receptor antagonists. Biochemical alterations suggesting acute pancreatitis were reported in a patient after a suicide attempt with high doses of telmisartan and oxazepam (72Ar ). The authors suggested that the occurrence of mild pancreatitis after an overdose of telmisartan is a rare class effect and, although the patient had taken other drugs, the concomitant overdose of oxazepam was not considered responsible, because it has never been associated with pancreatic injury.
Antihypertensive drugs
Valsartan
213
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(SED-15, 3593)
Psychological Two different reports have pointed to nightmares and depression with valsartan. • Nightmares from valsartan for hypertension improved when it was withdrawn and recurred when it was restarted in a 64-year-old woman (73A ). • A 43-year-old woman reported depression and attempted suicide after taking valsartan in combination with hydrochlorothiazide for hypertension (74A ). The patient was also taking atenolol, but the time course and complete resolution after withdrawal of valsartan/hydrochlorothiazide suggested that this was a drug-induced episode of depression.
Skin A lymphocytic dermatitis has been attributed to valsartan (75Ar ). • A 40-year-old man, who had previously had chronic dermatitis while taking enalapril for hypertension, developed recurrent dermatological adverse effects after starting to take valsartan instead. He developed a skin reaction within a few weeks of changing therapy, and biopsy showed a lymphocytic infiltrate of Jessner–Kanof pattern. The dermatitis resolved completely without recurrence after withdrawal of valsartan.
Pregnancy Anhydramnios has been attributed to valsartan (76A ). • A 43-year-old patient developed complete anhydramnios by week 20 of her pregnancy. She was taking valsartan, which was stopped at 20 weeks in view of a possible adverse effect. The anhydramnios resolved within a further 4 weeks and a healthy infant was born near term.
This is the second reported case of anhydramnios related to the use of valsartan in pregnancy, and the evidence suggests that angiotensin receptor antagonists are likely to have similar fetotoxic effects to ACE inhibitors and should therefore be avoided in pregnancy. Drug overdose Leg cramps and myalgia have been reported with valsartan (77A ). • A 25-year-old woman developed hypotension, tachycardia, and painful muscle cramps after taking a significant dose of valsartan in a suicide attempt.
ENDOTHELIN RECEPTOR ANTAGONISTS (SED-15, 1215; SEDA-26, 233; SEDA-27, 214)
Bosentan
(SED-15, 549; SEDA-27, 214)
The pharmacokinetics and drug interactions of bosentan have been reviewed (78R ). Liver Bosentan can dose-dependently increase the incidence and severity of raised transaminase activity (79C ). The BREATHE-2 trial examined the effects of a combination of intravenous epoprostenol with either bosentan or placebo in a randomized trial in 33 patients with pulmonary arterial hypertension (80c ). There were three deaths in the combination treated group during or soon after the end of the study, although the authors concluded that the severity of the patients’ illnesses precluded definite attribution of the deaths to the treatment. Other adverse effects were mainly those attributed to epoprostenol, although an excess number of patients developed leg edema in the combination group (27% versus 9%). Immunologic Severe necrotizing leukocytoclastic vasculitis had been attributed to bosentan (81Ar ). • A 47-year-old woman with idiopathic pulmonary arterial hypertension was given bosentan 62.5 mg bd plus spironolactone. Four weeks later, after some clinical improvement, the dosage of bosentan was increased to 125 mg bd, and 4 days later she developed itching of both legs. Within another 3 days typical vasculitic skin lesions appeared on both legs. A skin biopsy showed leukocytoclastic vasculitis and negative immune complex staining. Hematology, blood chemistry, and blood immunology were unremarkable. Bosentan was withdrawn immediately. Diuretics and acenocoumarol were continued. The vasculitic skin lesions improved slowly over the following weeks.
Sitaxsentan Sitaxsentan is an endothelin receptor antagonist that is reported to be more selective at endothelin A (ETA ) receptors. Placebo-controlled studies In a randomized, placebo-controlled trial in patients with symptomatic pulmonary arterial hypertension sitaxsentan 100 mg/day or 300 mg/day had similar adverse effects to those of bosentan, namely headache, peripheral edema, nausea, nasal
214
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congestion, and dizziness (82C ). There were also dose-dependent liver function abnormalities: transaminase activities three times the upper limit of normal were reached, with a cumulative risk at 9 months of 8% in the 100 mg/day group and 32% in the 300 mg/day group. Up to 80% of the patients were taking warfarin, and the INR was often increased because of inhibition of CYP2C9 by sitaxsentan. In a 1-year open extension phase of this trial, 11 patients were studied and one died from progressive pulmonary artery hypertension (83c ). Of the remaining 10 patients who were followed (four taking placebo, three sitaxsentan 100 mg/day, and three sitaxsentan 300 mg/day), none had liver function abnormalities or complications related to interaction of sitaxsentan with warfarin.
DRUGS THAT ACT ON THE SYMPATHETIC NERVOUS SYSTEM (SEDA-27, 216; SEDA-28, 230) Presynaptic α-adrenoceptor agonists
Postsynaptic α-adrenoceptor antagonists (SEDA-27, 216) Alfuzosin
(SED-15, 74)
Liver Acute hepatitis has been attributed to alfuzosin in a patient with chronic liver disease (86A ). • An 80-year-old man with chronic liver disease due to hepatitis B virus took alfuzosin for 3 weeks for benign prostatic hyperplasia and developed raised liver enzymes, which settled rapidly on withdrawal of alfuzosin.
Drug formulations The pharmacology, including the tolerability and drug-interaction potential, of a modified-release formulation of alfuzosin, relating mainly to studies in patients with symptomatic benign prostatic hyperplasia, has been reviewed (87R ).
Doxazosin
(SED-15, 817; SEDA-27, 216;
SEDA-28, 230) Nervous system The electroencephalographic effects of clonidine have been reported (84r ). There was electrophysiological sedation after parenteral clonidine, an effect that the authors concluded was likely to relate to the drug’s analgesic properties rather than direct modulation of the nociceptive system. Drug withdrawal Rebound effects from withdrawal of drugs that suppress the resting sympathetic nervous system are well described. Acute myocardial infarction has been reported as a complication of clonidine withdrawal in a patient with hypertension (85A ).
(SED-15, 1188; SEDA-27,
217) Hematologic Possible doxazosin-induced leukopenia with a positive response to dechallenge has been reported (88A ).
Tamsulosin Clonidine
Jamie J. Coleman
(SED-15, 3303)
Gastrointestinal Life-threatening esophagitis has been reported after ingestion of a single tamsulosin capsule (89A ).
IMIDAZOLINE RECEPTOR ANTAGONISTS Moxonidine
(SED-15, 2395)
There has been some controversy over the mechanisms of action of moxonidine in cardiovascular and other diseases, and excessive deaths in a trial of heart failure patients has fuelled this controversy. Its use as an antihypertensive drug is still important, and it is relatively well tolerated, sedation being the most frequent adverse effect. Its apparently
Antihypertensive drugs
favorable metabolic effects in clinical studies will be tested in the MARRIAGE study (Moxonidine And Ramipril Regarding Insulin And Glucose Evaluation), in which moxonidine and the ACE inhibitor ramipril, separately and in combination, will be studied with respect to metabolic and hemodynamic effects in patients with hypertension and impaired fasting glycemia (90r ).
DIRECT VASODILATORS Diazoxide
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Minoxidil
(SED-15, 2354; SEDA-27, 217)
Respiratory An isolated unilateral pleural effusion secondary to minoxidil has been reported in a patient undergoing peritoneal dialysis (92A ). It resolved on withdrawal and reappeared after the patient reintroduced the drug himself. Skin Genital ulceration, probably due to inadvertent local contamination from topical minoxidil used for androgenic baldness, has been described (93r ).
(SED-15, 1108)
Drug overdose Severe diazoxide toxicity has been reported when it was used to treat persistent hypoglycemia in a neonate (91A ).
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84. Bischoff P, Schmidt GN, Scharein E, Bromm B, Schulte am EJ. Clonidine induced sedation and analgesia—an EEG study. J Neurol 2004;251(2):219–21. 85. Simic J, Kishineff S, Goldberg R, Gifford W. Acute myocardial infarction as a complication of clonidine withdrawal. J Emerg Med 2003;25(4):399–402. 86. Yolcu OF, Koklu S, Koksal AS, Yuksel O, Beyazit Y, Basar O. Alfuzosin-induced acute hepatitis in a patient with chronic liver disease. Ann Pharmacother 2004;38(9):1443–5. 87. Guay DR. Extended-release alfuzosin hydrochloride: a new alpha-adrenergic receptor antagonist for symptomatic benign prostatic hyperplasia. Am J Geriatr Pharmacother 2004;2(1):14–23. 88. Ledger S, Mainra RR. Possible doxazosininduced leukopenia. Can J Hosp Pharm 2004;57(5):297–8. 89. D’Agostino L, Manguso F, Bennato R, Scaramuzzo A. A life-threatening case of stenosing pill hypopharynx-oesophagitis caused by a tamsulosin capsule. Dig Liver Dis 2004;36(9):632–4. 90. Rayner B. Selective imidazoline agonist moxonidine plus the ACE inhibitor ramipril in hypertensive patients with impaired insulin sensitivity: partners in a successful MARRIAGE? Curr Med Res Opin 2004;20(3):359–67. 91. Silvani P, Camporesi A, Mandelli A, Wolfler A, Salvo I. A case of severe diazoxide toxicity. Paediatr Anaesth 2004;14(7):607–9. 92. Palomar R, Morales P, Sanz de Castro S, Tasis A, Rodrigo E, Pinera C, Ruiz JC, FernandezFresnedo G, Martin de Francisco AL, Arias M. Pleural effusion secondary to minoxidil in a peritoneal dialysis patient. Nephrol Dial Transplant 2004;19(10):2688. 93. Spenatto N, Alibert M, Cambon L, Viraben R. Ulcération génitale originale d’origine toxique. Nouv Dermatol 2004;23(3):111.
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21 Hyponatremia and loop and thiazide diuretics DoTS classification: Reaction: Hyponatremia and loop and thiazide diuretics Dose-relation: Collateral Time-course: Time independent, but typically occurs within weeks of starting therapy Susceptibility factors: Age, female sex, reduced solute intake Hyponatremia is a serious complication of diuretic therapy (1M , 2M ). Thiazide diuretics are more likely than loop diuretics to cause hyponatremia. Loop diuretics inhibit sodium transport in the loop of Henle in the renal medulla and thereby preclude the generation of a maximal osmotic gradient. Thus, they impair urinary concentrating ability. Conversely, thiazide-type diuretics increase sodium excretion in the distal convoluted tubule in the renal cortex and so prevent maximal urine dilution while preserving the kidney’s innate concentrating capacity. Time course When diuretic-related hyponatremia occurs it is usually shortly after therapy starts (within the first 2 weeks) (1M ), although it can occur even after several years of therapy, particularly when loop diuretics are the cause. Susceptibility factors Diuretic-related hyponatremia is more common in elderly women (1M ). There are multiple factors that select women, including age, reduced body mass, an Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29021-4 © 2007 Elsevier B.V. All rights reserved.
Diuretics exaggerated natriuretic response to thiazide diuretics, a reduced capacity to excrete free water, and low solute intake. However, it has been suggested that the excess of thiazide-induced hyponatremia in women may relate to overrepresentation of women in thiazide-treated cohorts rather than an inherent propensity for women to develop this electrolyte disturbance (1M ). Presentation The presenting symptoms of diuretic-related hyponatremia can be vague and include anorexia, nausea, lethargy, and apathy; there is often evidence of volume depletion. More advanced symptoms include disorientation, agitation, seizures, reduced reflexes, focal neurological deficits and eventually Cheyne– Stokes respiration. Coma and seizures usually occur only with acute reduction of the serum sodium concentration to less than 120 mmol/l. Management Mild asymptomatic diuretic-related hyponatremia (typically 125–135 mmol/l) can be managed in a number of ways, which are not necessarily mutually exclusive, including withholding the responsible diuretics, restricting free water intake, and/or replacing potassium losses. When diuretic-related hyponatremia is a consequence of a thiazidetype diuretic, switching to a loop diuretic is an option if diuretic therapy must be restarted. Severe, symptomatic hyponatremia (generally below 125 mmol/l) complicated by seizures or other active neurological sequelae is a medical emergency. A fall in serum sodium to this degree calls for intensive therapy; however, this level of symptomatic hyponatremia should not be corrected too rapidly (0.5 mmol/hour in the first 24 hours of treatment), because the osmotic demyelinating syndrome can occur when correction is too rapid. More recently vasopressin receptor antagonists have become available. These compounds act on vasopressin V2 receptors. The several compounds in this class, including conivaptan, lixivaptan, and tolvaptan, all improve renal
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220 water handling and correct hyponatremia in conditions associated with fluid retention. Optimal doses and dosing frequencies have still not been established for these compounds. The availability of vasopressin receptor antagonists will simplify the management of hyponatremic states, particularly when excess amounts of vasopressin are involved (3M ). Urinary tract It has been hypothesized that population-wide use of diuretics might be associated with acceleration of the incidence of end-stage renal disease. Using data fusion techniques, pooled data trends in disease incidence and the use of antihypertensive medications were examined to determine whether changes in drug use patterns predict disease state emergence. There was a statistically significant inverse relation between all-cause cardiovascular disease mortality and the incidence of end-stage renal disease for the period from 1980 to 1998. There was a statistically significant time-lagged relation between both annual changes in diuretic distribution and total diuretic expenditure (measured by diuretic sales) to annual changes in the growth rate of end-stage renal disease. The methods used in these particular studies were clearly limited, as there was no patientspecific information, nor was there any indication of the specific agents used, the doses, or the exposure times in affected individuals. Moreover, the analysis did not distinguish between diuretic monotherapy and combination therapy. Thus, although the findings from these studies present an interesting hypothesis (4M , 5M ), considerably more supportive scientific evidence is needed before firm practice recommendations can be made about the propensity for end-stage renal disease and the use of diuretics.
CARBONIC ANHYDRASE INHIBITORS (SED-15, 643; SEDA-26, 238; SEDA-27, 220; SEDA-28, 233)
Acetazolamide Nervous system Acetazolamide typically causes increased cerebral blood flow as a result of vasodilatation. In patients with stenosis or occlusion of cerebral vessels, perfusion pressure drops and cerebral autoregulatory mechanisms are called into play to maintain cerebral blood flow. In such patients, cerebral
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blood flow may not increase appropriately after acetazolamide, and it may redistribute, potentially stealing blood from areas that are liable to underperfusion injury (stroke). • A 62-year-old woman with symptoms compatible with vertebral artery disease underwent a CT perfusion scan in anticipation of possible vertebral artery bypass (6A ). She underwent a routine unenhanced CT scan, followed by dynamic enhanced perfusion CT before and after intravenous administration of acetazolamide 1000 mg. Almost immediately she noted dizziness and perioral numbness and shortly thereafter slurred speech and ataxia. Her symptoms resolved entirely within 24 hours without any therapy. It was thought that she had had a transient ischemic attack possibly related to a steal phenomenon.
In this case, the shift in regional cerebral blood flow produced by acetazolamide resulted in significant underperfusion. Patients with significant cerebrovascular disease should be monitored carefully when they are given acetazolamide. Drug interactions Barbiturates The intracarotid amobarbital procedure (IAP) is used to determine language laterality and as a predictor of postoperative memory deficits in candidates for temporal lobectomy. A valid test requires that the patient demonstrate sufficient anesthetization in the injected hemisphere, marked by loss of contralateral muscle tone and strength, electroencephalographic slowing, and hemispherespecific behavioral change. In 11 of 56 patients undergoing an intracarotid amobarbital procedure there was either too rapid recovery (no more than 1 minute) or anesthetic failure. Of these, 10 were taking a medication with some carbonic anhydrase activity: topiramate (n = 7), zonisamide (n = 2), hydrochlorothiazide (n = 1), and furosemide (n = 1). Procedures performed on patients weaned from topiramate showed a correlation between the duration of drug withdrawal and the duration of the anesthetic effect. This apparent drug interaction can last for 4 weeks after the last dose of a carbonic anhydrase inhibitor. Its mechanism is speculative. Carbonic anhydrase inhibitors, including topiramate and zonisamide, should be tapered at least 8 weeks before an intracarotid amobarbital procedure (7M , 8M ).
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Brinzolamide
221
• A 57-year-old man with glaucoma used a 1% solution of brinzolamide in both eyes for 24 months and developed bilateral corneal edema, which resolved 1 week after withdrawal of brinzolamide and the addition of topical prednisolone acetate. • A 77-year-old man with glaucoma used a 1% solution of brinzolamide in his right eye for 15 months and developed right corneal edema. Brinzolamide was withdrawn and the corneal edema gradually resolved over 3 months.
discontinued therapy because of eye pain, ocular hyperemia, ocular burning/stinging, or ocular itching. The higher incidence of ocular burning and stinging in the youngest stage may reflect the preverbal stage. Two other subjects had a reduction in total bicarbonate; however, concurrent illnesses and sampling considerations complicated interpretation of changes in total bicarbonate. For the most part, the safety profile of dorzolamide in children is analogous to that in adults. Systemic dorzolamide-related adverse effects are infrequent in both populations.
There has been a limited number of previous case reports of resolution of corneal edema with brinzolamide. When corneal edema occurs with brinzolamide immediate withdrawal of therapy, with or without the use of topical glucocorticoids, can lead to complete resolution.
THIAZIDE DIURETICS (SED-15, 3375; SEDA-26, 239; SEDA-27, 220; SEDA-28, 233)
Sensory systems Topical brinzolamide has been associated with corneal edema (9A , 10A ).
Dorzolamide Skin Dorzolamide has been associated with contact dermatitis (11A ). • Two 71-year-old men with open-angle glaucoma developed eyelid dermatitis while using long-term topical dorzolamide. Concomitant glaucoma medications included pilocarpine and timolol. In each case the lesions disappeared within 1 month of withdrawal.
There have been previous reports of contact dermatitis with dorzolamide. However, this is the first report in which stripping (tapestripping of the upper stratum corneum by 10-fold application and removal of conventional adhesive tape) and the scarified patch test (scratching the epidermis with a lancet) were used in diagnosis. Susceptibility factors Age Dorzolamide has been poorly studied in children with glaucoma. In a prospective study of 2% dorzolamide tds in children aged 1 week to under 6 years the most common drug-related adverse effects were ocular hyperemia (5.4%) in those aged 2 years or under and ocular burning/stinging (12%) in those from aged 2–6 years (12c ). Two patients treated with dorzolamide
Endocrine Thiazide diuretics have been associated with dyslipidemia, hyperglycemia, and an increased risk of type 2 diabetes. In a community-based sample of 585 adults with essential hypertension who took monotherapy with hydrochlorothiazide 25 mg/day for 4 weeks the mean changes in response to hydrochlorothiazide were 0.16 mmol/l (6.13 mg/ dl) for total cholesterol, 0.19 mmol/l (17.2 mg/ dl) for triglycerides, and 0.19 mmol/l (3.5 mg/ dl) for plasma glucose (13M ). A range of demographic, environmental, and genetic variables taken together only accounted for 13%, 17%, and 11% of the variations in total cholesterol, triglyceride, and glucose, and less than half of this predicted variation in response was explained by measured genotypes. These studies suggest that there are no predictors of the adverse metabolic effects of thiazide-type diuretics. Biliary tract There is experimental evidence in humans suggesting that thiazide diuretics increase biliary cholesterol saturation, the main determinant of cholesterol gallstone development; however, epidemiological data on the association between thiazide diuretics and gallbladder disease is sparse. In a prospective study in 81 351 US women aged 30–55 in 1980 and followed to 2000, 8607 reported undergoing a cholecystectomy (14M ). There was a modest positive relation between the use of thiazide
222 diuretics and cholecystectomy. Compared with never users and current users of thiazide diuretics, the multivariate relative risks of cholecystectomy were 1.16 (95%CI = 1.08, 1.24) and 1.39 (95%CI = 1.29, 1.50) respectively. These findings are compatible with the possibility that thiazide diuretics increase the risk of symptomatic cholecystitis; however, measurement error is a concern in these studies, since information was lacking on the validity of selfreported thiazide diuretic use.
LOOP DIURETICS (SED-15, 567, 1454; SEDA-26, 239; SEDA-27, 220; SEDA-28, 233) Skin Furosemide has been associated with Sweet syndrome, neutrophilic dermatosis (15A ). • A 46-year-old woman with congestive heart failure was given intravenous furosemide and 3 days later developed a low-grade fever followed by tender, papular, erythematous, non-pruritic skin eruptions bilaterally on the wrists, forearms, arms, and thighs. There was associated redness in both eyes and photophobia, consistent with episcleritis and iritis. A skin biopsy showed a superficial dermal nodular neutrophilic infiltrate, associated with nuclear dust and rare eosinophils, findings consistent with Sweet syndrome. Furosemide was withdrawn and the skin lesions and eye symptoms gradually subsided.
Sweet syndrome is a disorder of poorly understood pathogenesis that has several features suggesting a hypersensitivity reaction. It has been associated with autoimmune diseases, malignancies, and drugs. This is the second description of this disorder with furosemide but this patient was different from the previous one in having symptoms and signs suggestive of iritis.
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35 consecutive patients with acne, mean age 21 years, who took spironolactone 100 mg/day on 16 days each month for 3 months, only two withdrew from the study, because of severe vertigo and dizziness (16c ). The possibility of spironolactone-related adverse effects at a dose as high as 100 mg/day should not be an a priori deterrent to using it. Electrolyte balance Spironolactone is increasingly being used in patients with heart failure. The incidence of hyperkalemia and worsening renal function with spironolactone is unknown, as is the adequacy of follow-up in monitoring for these adverse biochemical changes. In a retrospective analysis of 840 patients being seen in a large cardiology clinic and given a new prescription for spironolactone, 91% had baseline laboratory values and 34% did not have any serum potassium or creatinine determinations within 3 months of starting therapy (17M ). Of 551 patients with followup laboratory values, 15% developed hyperkalemia (5.5 mmol/l) and 6% developed severe hyperkalemia (6.0 mmol/l). There was renal dysfunction in 51 patients (9%), of whom 25 developed hyperkalemia within 3 months. Hyperkalemia developed in 48 of 138 patients (35%) with baseline serum creatinine values of at least 130 µmol/l (1.5 mg/dl) and 12 of 19 (63%) with baseline serum creatinine values of at least 220 µmol/l (2.5 mg/dl). Hyperkalemia is a significant issue in spironolactone-treated patients with heart failure, who require routine biochemical follow-up if the actual incidence is to be appreciated (17M , 18M ).
OSMOTIC DIURETICS Mannitol
(SED-15, 2203)
ALDOSTERONE RECEPTOR ANTAGONISTS
Electrolyte balance Perioperative hyperkalemia has been reported with rapid infusion of mannitol after craniotomy (19A ).
Spironolactone
• A 34-year-old man received 300 ml of a 20% solution of mannitol intravenously over 20 minutes immediately after a craniotomy for clipping of an anterior communicating artery aneurysm. Ten minutes after the end of the infusion there was electrocardiographic evidence of hyperkalemia
(SED-15, 3176; SEDA-26, 240; SEDA-27, 231; SEDA-28, 235) Spironolactone is an androgen receptor blocker and is occasionally used to treat acne. Of
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(serum potassium concentration 5.4 mmol/l). After treatment with calcium gluconate 425 mg and 250 ml of 5% dextrose containing insulin 10 U, the serum potassium fell to 3.6 mmol/l and the electrocardiographic changes resolved. • A 68-year-old man received 500 ml of a 20% solution of mannitol intravenously over 45 minutes immediately after a craniotomy for evacuation of an intracerebral hematoma, and 60 minutes after the end of the infusion there was electrocardiographic evidence of hyperkalemia (serum potassium concentration 6.1 mmol/l, the baseline value having been 4.1 mmol/l). After 40 ml of a 7% bicarbonate solution the serum potassium fell to 5.4 mmol/l and the electrocardiographic changes resolved.
These cases illustrate that rapidly infused hypertonic mannitol can trigger an extracellular shift of potassium, with resultant cardiotoxicity, despite there being only modest increases in serum potassium concentration. The rate of change of serum potassium concentration as well as the absolute concentration reached has a bearing on the development of hyperkalemic cardiotoxicity. Urinary tract Acute renal insufficiency has been described after infusion of mannitol. This has most commonly been seen after neuro-
surgery when mannitol has been used to reduce intracranial pressure. Treatment guidelines recommend that mannitol be withheld if the serum osmolality exceeds 320 mOsm/kg, lest renal insufficiency develops. In a retrospective analysis of 95 patients treated with mannitol in a neurology–neurosurgery intensive care unit, 11 met criteria for acute renal insufficiency (serum creatinine increase by 44 µmol/l (0.5 mg/dl) or 88 µmol/l if the baseline value was 176 µmol/l or more) (20M ). There was no relation between the onset of acute renal insufficiency and total mannitol dose, maximum daily dose of mannitol, serum osmolality, or osmotic gap. The serum osmolality and the osmotic gap measured just before the onset of acute renal insufficiency did not differ from values observed in patients who did not develop acute renal insufficiency. The severity of illness and the presence of co-morbid diseases more often predicted the development of acute renal insufficiency than serum osmolality did. The concept of a specific osmolality barrier of 320 mOsm/kg for acute renal insufficiency, beyond which mannitol should be withheld, needs to be reconsidered.
References 1. Chow KM, Szeto CC, Wong TY, Leung CB, Li PK. Risk factors for thiazide-induced hyponatraemia. Q J Med 2003;96:911–7. 2. Sica DA. Diuretic-related side effects: development and treatment. J Clin Hypertens (Greenwich) 2004;6:532–40. 3. Goldsmith SR, Gheorghiade M. Vasopressin antagonism in heart failure. J Am Coll Cardiol 2005;46:1785–91. 4. Hawkins RG, Houston MC. Is population-wide diuretic use directly associated with the incidence of end-stage renal disease in the United States? A hypothesis. Am J Hypertens 2005;18:744–9. 5. Akram M, Reddan D. Diuretic use and ESRD, precipitating factor or epiphenomenon. Am J Hypertens 2005;18:739–40. 6. Choksi V, Hughes M, Selwa L, Hoeffner E. Transient neurologic deficit after acetazolamide challenge for computed tomography perfusion imaging. J Comput Assist Tomogr 2005;29:278–80. 7. Bookheimer S, Schrader LM, Rausch R, Sankar R, Engel J Jr. Reduced anesthetization during
8. 9. 10.
11.
12.
the intracarotid amobarbital (Wada) test in patients taking carbonic anhydrase-inhibiting medications. Epilepsia 2005;46:236–43. Ringman JM, Grant AC. Carbonic anhydrase inhibitors and amobarbital resistance. Epilepsia 2005;46:1333. Zhao JC, Chen T. Brinzolamide induced reversible corneal decompensation. Br J Ophthalmol 2005;89:389–90. Tanimura H, Minamoto A, Narai A, Hirayama T, Suzuki M, Mishima HK. Corneal edema in glaucoma patients after the addition of brinzolamide 1% ophthalmic suspension. Jpn J Ophthalmol 2005;49:332–3. Linares Mata T, Pardo Sanchez J, de la Cuadra Oyanguren J. Contact dermatitis caused by allergy to dorzolamide. Contact Dermatitis 2005;52:111–2. Ott EZ, Mills MD, Arango S, Getson AJ, Assaid CA, Adamsons IA. A randomized trial assessing dorzolamide in patients with glaucoma
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14.
15. 16.
who are younger than 6 years. Arch Ophthalmol 2005;123:1177–86. Maitland-van der Zee AH, Turner ST, Schwartz GL, Chapman AB, Klungel OH, Boerwinkle E. Demographic, environmental, and genetic predictors of metabolic side effects of hydrochlorothiazide treatment in hypertensive subjects. Am J Hypertens 2005;18:1077–83. Leitzmann MF, Tsai CJ, Stampfer MJ, Willett WC, Giovannucci E. Thiazide diuretics and the risk of gallbladder disease requiring surgery in women. Arch Intern Med 2005;165:567–73. Govindarajan G, Bashir Q, Kuppuswamy S, Brooks C. Sweet syndrome associated with furosemide. South Med J 2005;98:570–2. Yemisci A, Gorgulu A, Piskin S. Effects and side-effects of spironolactone therapy in women
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18.
19.
20.
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with acne. J Eur Acad Dermatol Venereol 2005;19:163–6. Shah KB, Rao K, Sawyer R, Gottlieb SS. The adequacy of laboratory monitoring in patients treated with spironolactone for congestive heart failure. J Am Coll Cardiol 2005;46:845–9. Tamirisa KP, Aaronson KD, Koelling TM. Spironolactone-induced renal insufficiency and hyperkalemia in patients with heart failure. Am Heart J 2004;148:971–8. Hirota K, Hara T, Hosoi S, Sasaki Y, Hara Y, Adachi T. Two cases of hyperkalemia after administration of hypertonic mannitol during craniotomy. J Anesth 2005;19:75–7. Gondim F de A, Aiyagari V, Shackleford A, Diringer MN. Osmolality not predictive of mannitol-induced acute renal insufficiency. J Neurosurg 2005;103:444–7.
Gijsbert B. van der Voet and Frederik A. de Wolff
22 Aluminium
(SED-15, 97; SEDA-26, 243; SEDA-27, 224; SEDA-28, 244) Adverse effects of aluminium compounds are reported regularly, although they are not new but related to their conditions of use. Aluminium compounds continue to be used as phosphate binders in patients with renal dysfunction. The use of aluminium compounds as antacids can incidentally lead to neurotoxicity and osteotoxicity. Discussion of the potential risk of aluminium adjuvants in vaccines continues (1R , 2R ). New, however, are recent observations on aluminium compounds used as antiperspirants. Respiratory Aluminium can cause bronchial asthma and chronic obstructive pulmonary disease. • A 19-year-old woman developed intermittent face dermatitis with flushing and leg dermatitis (3A ). She had no history of atopy. Prick testing with a standard series was negative. Patch testing with preservatives, antimicrobial drugs, cosmetics, and fragrance series (Finn Chambers) was performed. However, the test area had to be treated with topical glucocorticoids on day 2 because of a strong “angry back” reaction. Patch testing was performed again 3 months later, without the fragrance series, because the angry back reaction was suspected to have been caused by fragrances. Again, all the substances tested gave positive reactions. Allergy to aluminium test chambers was then suspected, and patch testing with aluminium chloride in plastic chambers was performed 7 months later. Testing was delayed because of the need for systemic glucocorticoid treatment of facial flushing and facial angioedema. An allergic patch test reaction was elicited by all three test concentrations of aluminium chloride. Prick testing with milk histamine hydrochloride (10 mg/ml) gave 5 mm reactions. Specific IgE for milk was positive, but total IgE was normal. The patient was advised to Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29022-6 © 2007 Elsevier B.V. All rights reserved.
Metals avoid milk products and aluminium. However, soy products were allowed. Her symptoms disappeared in a few days. • An 8-year-old boy with a 4-day history of edema of the hands and superimposed tender nodules had erythematous palms with edematous, deep-seated, tender nodules and plaques over the thenar and hypothenar eminences and over the palmar aspects of the metacarpophalangeal joints; there were no similar lesions elsewhere on his skin (4A ). He reported that he had attended a baseball camp a few days before and on one day, after crawling on his hands and knees on unfinished aluminium bleachers, his hands had been covered with aluminium dust. The symptoms began 2 days later, with tenderness and edema in the hands. Histopathological evaluation of a lesional skin biopsy showed a moderately heavy infiltration of neutrophils and some lymphocytes surrounding the eccrine structures in the dermis; the most pronounced inflammation was in the deep dermis around the eccrine coils. These findings were consistent with eccrine hidradenitis. Special staining was negative for bacterial and fungal microorganisms. He was given cold compresses three times a day and paracetamol as needed for pain, and stopped activities that involved his hands. The lesions and the associated tenderness resolved within 2 weeks.
Musculoskeletal Macrophagic myofasciitis, an inflammatory myopathy with complaints of arthromyalgia and fatigue, has been claimed to be caused by the intramuscular injection of aluminium-containing vaccines (5A ). • A girl received regular immunizations against diphtheria, pertussis, tetanus, and hepatitis B by injections into the right quadriceps muscle. At 7 months she was referred to hospital because of continuous irritability and delay in acquisition of the main motor skills; she was unable to sit unsupported and had no control of her head and neck. She had hypotonia of the lower limbs and cried persistently on muscle palpation. She had increased creatine kinase activity (819 U/l; reference range below 135 U/l), and this increased during the following 4 months up to 10 times the normal value. She was able to sit at the age of 10 months, but at 1 year she was not able to stand and had mild hypotonia in the legs. Muscle biopsy in the right quadriceps showed a densely packed infiltrate of CD68+ macrophages with abundant cytoplasm and PAS-positive granules, rare CD4+
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and CD8+ cells, but no CD20+ cells in the perimysium and peripheral endomysium. Muscle fibers were separated but not damaged. The infiltrating cells were MHC-I and MHC-II positive. Close to the infiltrate were two lymphocytic follicles, which mostly contained CD20+ cells. The muscle fibers were MHC-I positive, and most of the vessel walls showed deposits of C5b-9 complement. There were intracytoplasmic inclusions formed by randomly oriented needle-shaped fine structures within most of the infiltrating macrophages. A diagnosis of macrophagic myofasciitis was made. Glucocorticoid therapy (prednisone 1 mg/kg/day) was started, slowly tapered, and withdrawn within 1 year, with progressive clinical and serological improvement. At 29 months of age physical examination, psychomotor skills, and serum creatine kinase activity were completely normal.
Susceptibility factors Renal disease Aluminium toxicity in patients with end-stage renal insufficiency is a well known adverse effect, due to either dialysate aluminium contamination or oral intake of aluminium-containing phosphate binders. However, aluminium-containing drugs are given mainly as antacids and are often used without special caution in patients with chronic renal insufficiency (6A ). • A 59-year-old white man with chronic renal insufficiency due to diabetic nephropathy self-treated gastric pain with aluminium hydroxide (MaalRoc TC). Gastroduodenoscopy showed antral gastritis positive for Helicobacter pylori. He continued taking aluminium hydroxide. He developed speech disturbances, mostly stuttering, disorientation, a spontaneous tremor, a hypochromic anemia (Hb = 9.2 mg/dl, MCV = 65 fl), severe chronic renal insufficiency (creatinine 477 µmol/l; 5.4 mg/dl), hyperkalemia (6 mmol/l), and a normal serum calcium (2.35 mmol/l). Hemodialysis was started. After a few dialysis sessions, he became confused and lethargic. The electroencephalogram showed wide θ and θ –δ waves, often in a triphasic fashion, and diffuse slow spikes. The serum aluminium concentration was 740 µg/l. After a dialysis session, he fell and fractured a femur. He was treated with deferoxamine 500 mg/day intramuscularly (Novartis, Origgio, Italy) in 250 ml of physiological solution, but the neurological disturbances progressed steadily, he had repeated generalized seizures, and he died of cardiogenic shock 1 month later.
Drug administration route Aluminium chlorohydrate is a water-soluble aluminium complex that blocks sweat secretion. Its frequent use has triggered discussion on the potentially harmful effects of transdermal absorption of aluminium salts (7A ).
Gijsbert B. van der Voet and Frederik A. de Wolff • A 43-year-old woman applied about 1 g of aluminium chlorohydrate-containing antiperspirant cream on each underarm every morning for 4 years. Her underarms, which were shaved regularly, did not have any rash or skin irritation. She experiencing bone pain and extreme fatigue without other obvious explanations. The plasma aluminium concentration was 105 µg/l. She stopped using the antiperspirant and there was a gradual fall in aluminium concentration in the plasma and urine, reaching the reference range after 3 months in the urine and 8 months in the plasma (less than 10 µg/l). The bone pain practically disappeared, although she had still slight fatigue.
Antimony
(SED-15, 316; SEDA-26, 244; SEDA-27, 224; SEDA-28, 244) No new adverse effects of the regular pentavalent antimonials have been reported. However, there have been some observations on antimony compounds related to their use in non-registered and homeopathic medicines and in radiodiagnostics. Antimony that originates from the antimony sulfide colloid used in preoperative lymphoscintigraphy can be measured in tissue sections of sentinel nodes using inductively coupled plasma spectrometry (8C ). In 24 patients who had both a tumor-positive sentinel node and a tumor-negative non-sentinel node removed from one regional node field during the same operation the median and mean concentrations of antimony were 0.526 and 1.198 (range 0.020–7.596) µg/g respectively in the sentinel nodes, and 0.043 and 0.123 (range 0– 0.800) µg/g in the non sentinel nodes. In four of the 24 pairs, both the presumed sentinel nodes and the non-sentinel nodes had very low antimony concentrations (less than 0.19 µg/g), suggesting that nodes designated as sentinel nodes may not have been true sentinel nodes. No adverse effects were reported. The authors concluded that determination of antimony concentrations within sentinel nodes can confirm their identity and validate the sentinel node technique. Hematologic Potentized antimony is traditionally used in anthroposophic medicine to enhance hemostasis in bleeding disorders, but evidence of its effectiveness is scarce (9C ). Freshly drawn citrated whole blood from 12 healthy
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volunteers and 12 patients with bleeding disorders was equally distributed in 344 positions, after which it was mixed with antimony D5, or its potentized vehicle (lactose D5) as a control solution and tested with thrombelastography. In the antimony D5 samples of the 12 healthy subjects, but not in the patients, there were nonsignificant trends toward a shorter clotting time and increased clot firmness expressed as maximal amplitude. There was no difference in clot formation time or clot lysis index. These results therefore do not support the conclusion that antimony D5 has a procoagulatory effect in vitro. Drug overdose Tartar emetic contains antimony potassium tartrate. It has been marketed as a cure for alcoholism. • A 19-year-old man with a history of alcohol abuse took a medication from Guatemala called “Soluto Vital” (tartar emetic), 20–25 drops after each drink (10A ). He then decided to stop drinking and took the entire contents of the bottle (10 ml, 50 mg/ml) in hope of a definitive cure. He presented 50 minutes after ingestion with severe vomiting, abdominal cramps, diarrhea, weakness, and orthostatic hypotension. His serum creatinine was 212 µmol/l (2.4 mg/dl), potassium 6.1 mmol/l, and hematocrit 60%. He was given activated charcoal, intravenous saline, and antiemetics. Over the next 48 hours his creatinine normalized to 97 µmol/l (1.1 mg/dl) and the hematocrit returned to 53%; the urine antimony concentration was 1200 µg/l (reference range below 10 µg/l).
Arsenic (SED-15, 339; SEDA-26, 244; SEDA-27, 225; SEDA-28, 245) Classical arsenic poisoning with arsenic trioxide occurs every now and then. Arsenic derivatives are still being explored as therapeutic agents for hematological malignancies (11R ), and arsenic continues to be used in endodontic treatment as pulp-necrotizing agent.
45 mg/m2 /day orally, cytarabine 200 mg/m2 /day intravenously for 7 days, and daunorubicin 50 mg/ m2 /day intravenously for 3 days. One month later, when her bone marrow exam was normocellular, with a normal promyelocyte count and negative for translocation (15;17) by FISH analysis, she was given a two-cycle regimen of intravenous arsenic trioxide 0.15 mg/kg/day on 5 days per week for 5 weeks, with a planned 2-week break between each cycle. She developed a mild macular rash on her chest after 4 weeks and a painful, burning perianal rash after 7 weeks. There were multiple grouped vesicles on an erythematous base. Her white blood cell count was 8.6 × 109 /l, with 71% granulocytes, 18% lymphocytes, 9% monocytes, and 6% eosinophils. Her hemoglobin and platelet counts were normal. A skin reaction from arsenic trioxide was suspected and a topical glucocorticoid was prescribed without improvement. However, because the vesicles were distributed along the right S5 dermatome a diagnosis of Herpes zoster was made and she was given famciclovir 750 mg tds orally for 7 days. The pain improved, the lesions crusted, and both resolved after 2 weeks. She had no postherpetic neuralgia and completed her remaining course of arsenic trioxide uneventfully. • A 61-year-old Asian man presented with acute promyelocytic leukemia was treated in the same way and was started on consolidation therapy with arsenic trioxide. After 3 weeks, he developed pain over his left chest and shoulder. Electrocardiography was normal. He then developed a rash on the left shoulder, with multiple, painful, grouped vesicles on an erythematous base distributed along the left C5 dermatome, attributed to Herpes zoster. He had a total white blood cell count of 3.7 × 109 /l, with 62% granulocytes, 14% lymphocytes, 13% monocytes, 9% eosinophils, and 2% basophils. His hemoglobin and platelet counts were normal. He was given oral famciclovir 500 mg tds and had symptomatic improvement, although he continued to have dysesthesia along the dermatomal distribution for several weeks. The lesions finally crusted and disappeared. He later developed a transient, self-limited, generalized, painless, circular rash on the chest and back, which was thought to be a cutaneous adverse effect of arsenic trioxide.
These case reports suggest that arsenic trioxide has an immunosuppressive action.
Infection risk Herpes zoster infection occurred during treatment with arsenic trioxide in two patients who were already in remission from acute promyelocytic leukemia and took arsenic trioxide as consolidation treatment (12A ).
Bismuth
• A 64-year-old Caucasian woman with acute promyelocytic leukemia was given induction treatment with tretinoin (all-trans retinoic acid, ATRA)
The uses of bismuth in medicine have been reviewed (13R ). Bismuth compounds are used as antimicrobial agents, as antiulcer agents, and
(SED-15, 518; SEDA-26, 244; SEDA-27, 225; SEDA-28, 245)
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as diagnostic agents. Bismuth iodoform paraffin paste (BIPP) is applied after surgery to prevent epistaxis. Nervous system BIPP can cause neurotoxicity (14A ). • An 81-year-old man with epistaxis had had nasal packing with bismuth iodoform paraffin paste (BIPP) when prolonged packing with Merocel was ineffective. Two days later he became acutely confused. His gait became unsteady. He developed dysphagia and required nasogastric intubation for nutrition and hydration. He was doubly incontinent. Before admission he had been mentally competent and physically independent. His Glasgow Coma Score was 14/15. His speech was dysphonic. An abbreviated Mental Test score was 1/10. He was afebrile and there were no signs of infection. His gait was severely dyspraxic. He gradually recovered over 3 weeks. His serum bismuth concentration was 250 µg/l.
It was thought that bismuth toxicity was the most likely cause of his temporary but prolonged confusional state.
Gijsbert B. van der Voet and Frederik A. de Wolff
(Cu-NSAIDs) has been reviewed (23R ). In some instances, Cu(II) anti-inflammatory drugs have considerable advantages over the parent organic drug in terms of markedly reduced gastrointestinal toxicity, while maintaining efficacy. Copper is used in medical instruments and can be a cause of allergy. Mouth and teeth Copper in dental prostheses can incidentally contribute to sensitization and lichen planus (24A ). • A 56-year-old woman with lichen planus had been treated with triamcinolone acetonide in Orabase® for 3 years with no improvement. For 25 years she had had a metal dental prosthesis. The same problem in the mucosa of the right buccal muscle had resolved when an adjacent dental prosthesis had been removed. There was a whitish reticulated area on the mucous membrane of the left buccal mucosa adjacent to a metal prosthesis, and a depapillated areas on the left side of the tongue. There were no lesions outside the mouth. On patch testing the only positive reaction was to copper sulfate 2%. Her prosthesis, which contained copper, was changed, after which there was almost immediate relief of her symptoms; 6 months later the lesions had much improved.
Chromium (SED-15, 737; SEDA-26, 245; SEDA-27, 226; SEDA-28, 246) The mechanisms of action of chromium (III) have been reviewed (15R ) as has the role of chromium in insulin resistance (16R ).
Gallium
(SED-15, 1477; SEDA-26, 245; SEDA-27, 227; SEDA-28, 246)
Drug formulations The safety of a dosage form of chromium, chromium picolinate has been questioned, although the authors concluded that the compound was safe to use (17CR ).
Gallium compounds continue to be used for medical purposes as antineoplastic agents (25R ), as radiodiagnostic agents (67 gallium), and in dentistry as alternatives to mercury-based amalgam. No new adverse effects have been reported.
Copper
(SED-15, 901; SEDA-26, 245; SEDA-27, 226; SEDA-28, 246)
Gold and gold salts
Apart from reviews of copper transport in Wilson’s disease (18R ) the role of copper is being explored in neurodegenerative disorders (19R , 20R ). Copper is also assuming a role in malignant angiogenesis, and the role of copper deficiency and copper chelation as an anticancer strategy is being explored (21R , 22R ). The efficacy and toxicity of copper- and zincbased non-steroidal anti-inflammatory drugs
Skin There is increasing documentation of allergic contact dermatitis and other effects from gold jewelry, gold dental restorations, and gold implants (26R ). These effects are especially pronounced among women who wear body-piercing gold objects. Eczema of the head and neck is the most common response in individuals who are hypersensitive to gold, and sensitivity can last for several years. Ingestion
(SED-15, 1520; SEDA-26, 245; SEDA-27, 227; SEDA-28, 246)
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229
of beverages containing flake gold can result in allergic-type reactions similar to those seen in gold-allergic individuals exposed to gold through dermal contact and other routes.
have been reported. Parenteral iron therapy has again been addressed (29R , 30R ). The safety of iron stores (31R ) and the relation between iron and nitric oxide have been reviewed (32R ).
Sensory systems Corneal chrysiasis has been reported (27A ).
Sensory systems Iron deposition in both eyes after overnight orthokeratology has been reported (33A ).
• A 50-year-old white man who had received colloidal gold 50 mg intramuscularly on alternate weeks since 1980 had a slate-grey complexion and fine scattered yellow brown deposits on the central corneal epithelium. In the deep central corneal stroma the deposits were confluent. The lens was clear. Ophthalmoscopy was normal. The ocular chrysiasis was not sufficiently severe to warrant withdrawal of the gold therapy.
Susceptibility factors The question whether features associated with severe rheumatoid arthritis are predictive of adverse drug reactions to gold salts, independent of HLA-DR3 status, has been studied in 41 patients with rheumatoid arthritis who developed thrombocytopenia (platelet count below 100 × 109 /l) or proteinuria (over 1.0 g/24 hours) whole receiving gold sodium thiomalate, 41 patients treated with gold without adverse reactions and 161 patients who had received gold for at least as long without adverse reactions (28C ). All were typed for HLA-DRB1, and the presence of rheumatoid factor, antinuclear antibodies, and nodules before the start of therapy. Patients with adverse reactions were more likely to have nodular disease than their matched controls (51% versus 26%; OR = 3.0) and were more likely to be HLA-DR3 positive (41% versus 18%; OR = 3.0). There were no differences between the groups I rheumatoid factor or antinuclear antibodies. Nodular disease was associated with development of adverse reactions independent of HLA-DR3 status, although a combination of the two factors significantly increased the likelihood of an adverse reaction. The data suggested that nodular disease may be a predictor of adverse reactions to gold independent of HLA-DR3.
Iron salts
(SED-15, 1911; SEDA-26, 247; SEDA-27, 227; SEDA-28, 247) Discussion on the effectiveness of iron compounds continues but no new adverse effects
• A 31-year-old man underwent overnight orthokeratology—he was fitted with rigid gas-permeable contact lenses of reverse-geometry design to correct myopia and wore them for at least 6 hours during sleep every day. After 9 months he developed corneal arcuate lines in both eyes. Visual acuity was not affected. The deposition pattern corresponded to the outside border of the central flatter zone, as shown on a corneal topography map. He chose to continue overnight orthokeratology treatment.
Current evidence suggests that tear pooling between the corneal surface and the back surface of the contact lens plays a role in the development of corneal iron deposition after orthokeratology with reverse-geometry contact lenses. Drug administration route Intravenous iron is usually required to optimize the correction of anemia in persons with advanced chronic and end-stage renal disease. However, randomized clinical trials may have insufficient power to detect differences in the safety profiles of specific formulations. By analysing FDA data on reported adverse events related to three formulations of intravenous iron during 1998–2000, the relative risks of adverse events associated with their use was estimated (34M ). The total number of reported parenteral iron-related adverse events was 1981 among 21 million doses administered (94 per million). Total major adverse events were significantly more common among recipients of higher molecular weight iron dextran (OR = 5.5; 95%CI = 4.9, 6.0) and sodium ferric gluconate complex (OR = 6.2; 95%CI = 5.4, 7.2) compared with recipients of lower molecular weight iron dextran. The data also showed significantly higher rates of life-threatening adverse events, including death, anaphylactoid reactions, cardiac arrest, and respiratory depression, among users of higher molecular weight compared with lower molecular weight iron dextran. There was insufficient power to detect differences in life-threatening
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adverse events when comparing lower molecular weight iron dextran with sodium ferric gluconate complex. It is clear from this analysis that adverse events related to parenteral iron are rare but that they occur somewhat more often among recipients of higher molecular weight iron dextran and sodium ferric gluconate complex than among recipients of lower molecular weight iron dextran.
Gijsbert B. van der Voet and Frederik A. de Wolff atrophic lesion on the left buccal mucosa in direct contact with the amalgam. The right buccal mucosa was normal. She was taking no medications and had no known allergies. Biopsy showed histological changes compatible with oral lichen planus. She decided not to change the restoration. Other restorations were performed with composite resins, and without reactions in the mucosa.
Nickel (SED-15, 2502; SEDA-26, 248; SEDA-27, 229; SEDA-28, 249) Manganese
(SED-15, 2200; SEDA-26, 248; SEDA-27, 229; SEDA-28, 248) Manganese toxicity after overexposure has been reviewed (35R ). Immunologic Allergic contact stomatitis has been attributed to manganese (36A ).
• A 74-year-old woman developed an itching and burning sensation in the mouth. She had been wearing removable partial dentures (upper left hemiarch) and the oral discomfort was largely concentrated in this region. There was diffuse edema, erythema, and an aphthous lesion measuring 3 × 3 mm, in the region of the prosthesis, which was made of chromium–cobalt alloy (29/65%) with molybdenum 5.3%, silica 0.5%, manganese 0.5%, and carbon 0.4% and contained no nickel or beryllium. Patch testing was positive only to manganese chloride 5%. Fifteen controls were negative for manganese. She was fitted with manganese-free dentures and developed no further lesions.
Mercury and mercurial salts (SED-15, 2259; SEDA-26, 248; SEDA-27, 229; SEDA-28, 248) Discussion about the potential risk of mercurycontaining vaccines has abated (37R ). In a critical review of the existing studies no link between thiomersal-containing vaccines and autistic spectrum disorders was demonstrated (38R ). Mouth and teeth Amalgam hypersensitivity has been reported to cause lichen planus (39A ). • A 38-year-old woman had an amalgam filling and 19 months later developed a slightly erythematous
Nickel is still a prominent representative among reports of metal allergy, owing to its use in earrings or other items of jewelry (40R ). Nickel– titanium alloys are increasingly being used for their material qualities in endodontic instruments, self-expanding stents, and orthopedic instruments (41R , 42R ). The nickel component poses the risk of metal allergy. The mechanistic aspects of sensitivity and tolerance have been reviewed, without new insights (43R ).
Potassium salts
(SED-15, 2905;
SEDA-28, 249) Drug overdose Acute potassium intoxication is a life-threatening event requiring aggressive therapy, and a delay in diagnosis may be fatal. There have been no previous reports of survival in patients with potassium concentrations over 12 mmol/l (44c ). • A 6-week-old girl developed severe iatrogenic potassium intoxication after surgical correction of a truncus arteriosus (45A ). On the 34th postoperative day, she suddenly developed a refractory ventricular dysrhythmia and circulatory arrest. The potassium concentration in arterial blood was 17.7 mmol/l. All intravenous infusions were withdrawn. At a potassium concentration of 8 mmol/l 45 minutes after cardiac arrest, spontaneous pulsegenerating cardiac rhythm returned with a mean arterial pressure of 40 mmHg.
Subsequent investigations showed that a short-term infusion of co-trimoxazole had been erroneously prepared in the unit using a 15% potassium chloride solution instead of 5% glucose. The company producing both the potassium chloride solution and the glucose solution was informed about the incident; the two vials now differ in both size and color.
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Selenium
(SED-15, 3119; SEDA-26, 249; SEDA-27, 230; SEDA-28, 250)
Selenium is playing an increasingly important role in protection against and prevention of a number of conditions, including cancer, inflammatory diseases, and neurological diseases (46R ). Recently efforts have been directed toward the synthesis of stable organoselenium compounds that could be used pharmacologically as antioxidants, enzyme modulators, antitumor agents, antimicrobials, antihypertensive agents, antivirals, and cytokine inducers (47R ). Selenium sulfide is an alternative therapeutic option in the treatment of Tinea capitis infection (48R ). Selenium intoxication is not new but is rare.
• A 42-year-old non-smoking white man noticed a blue-grey tinge to his skin, which increased over time. He had slate-gray discoloration of the entire tegument, sclera, mucosal surfaces, and nails. The changes were more obvious in sun-exposed areas. His only previous complaint was allergic rhinitis, for which he used one to two 10 ml bottles of a topical vasoconstrictor, Coldargan (Sigmapharm, Vienna), weekly over the previous 4 years, causing a drug-induced rhinopathy. One drop of Coldargan contains silver protein 0.85 mg, ephedrine levulinate 0.68 mg, sodium levulinate 0.24 mg, and calcium levulinate 0.075 mg. A punch biopsy from the left neck showed brownish-black perivascular pigment deposits in the muscle, nerve, sweat glands, and dermis.
• A 48-year-old woman attempted suicide by taking a bottle of glass blue, containing 2000 mg of selenium dioxide, used for manufacturing stained glass. She developed mildly altered consciousness and hematemesis. She vomited garlicky smelling blood several times, complained of epigastric pain, and had garlic-smelling breath. Endoscopy showed that the oral cavity, esophagus, and stomach were all eroded and oozing. In the stomach there was a deep necrotic ulcer, classified as grade 3 corrosive gastritis. She was treated with gastric lavage and hemodialysis. The serum selenium concentration was maximal at 2400 µg/l before hemodialysis and then gradually fell. Serum glutathione peroxidase activity was above the reference range but fell slightly after the intoxication and did not parallel the selenium concentrations. She developed liver dysfunction on day 5 and was treated conservatively and discharged on day16.
Cytotoxicity The cytotoxic effects of silver and silver-based products should be considered when deciding on dressings for specific wound care strategies (54E ). The cytotoxic effects of silver on keratinocytes and fibroblasts have been studied in monolayer cultures and tissue culture models. The sources of silver were silver released from silver nitrate solution and nanocrystalline silver released from a commercially available dressing. Silver was highly toxic to both keratinocytes and fibroblasts in monolayer culture. The fibroblasts were more sensitive than the keratinocytes. However, when both cell types were grown in the same medium their viability was the same. These results suggested that consideration of the cytotoxic effects of silver and silver-based products should be taken when deciding on dressings for specific wound care strategies. This is important when using in situ keratinocyte culture, which is playing an increasing role in contemporary wound and burn care.
Silver salts and derivatives
Titanium
Gastrointestinal Intoxication caused by a non-medical selenium formulation caused severe gastrointestinal damage (49A ).
(SED-15, 3140; SEDA-26, 249; SEDA-27, 230; SEDA-28, 250) Silver compounds are still in use in wound care and have gained more attention recently (50R , 51R ). Silver nitrate is in used in the treatment of epistaxis (52R ). Skin Argyrosis is reported from time to time (53A ).
(SED-15, 3434; SEDA-26, 249; SEDA-27, 230; SEDA-28, 250) Titanium is used in orthopedic instruments and dental care (55R ). The unalloyed light metal is non-allergic and biocompatible. Alloys with nickel have even better material properties, although the nickel component is often a cause of metal allergy (41R , 42R ). Organotitanium compounds may have a future as anticancer compounds (56R ).
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Zinc (SED-15, 3717; SEDA-26, 250; SEDA-27, 230; SEDA-28, 251) Zinc compounds are not very toxic, although zinc excess has been recognized as a cause of copper deficiency, which is a rare cause of anemia and neutropenia and has been associated with a neurological syndrome. Zinc compounds can also affect taste and smell. Nervous system A myelopathy has been attributed to zinc toxicity (57A ). • A 43-year-old woman developed a microcytic anemia with normal iron values. At the age of 50 a bone marrow biopsy showed absence of stainable iron, despite oral iron therapy. She was given weekly intramuscular iron and vitamin B12 injections, but anemia and neutropenia persisted for the next 3 years. She underwent blood transfusion and within several weeks developed tingling paresthesia and weakness in her feet, which progressed over 2 years to include the hands and legs, and she became unable to stand unsupported because of severe weakness and sensory loss in her legs. She had a myelopathy with a spastic paraparesis, profound dorsal column loss, and a diffuse lower motor neuron disorder, with atrophy and complete paralysis of the muscles below the knee and moderate weakness of the proximal muscles in the legs and distal muscles in the hand. She was unable to walk or get out of bed without assistance, with a marked sensory ataxia. Her serum copper
Gijsbert B. van der Voet and Frederik A. de Wolff concentration was below the lower limit of the assay (200 µg/l), 24-hour urine copper was normal at 4 µg/day (reference range 2–30 µg/day), and serum ceruloplasmin was markedly reduced at 3 mg/dl (reference range 26–60). Serum zinc was raised at 2108 µg/l (reference range 58–1060) and the 24-hour urine zinc was markedly raised at 19 290 µg/day (reference range 75–530). She was given copper 2.5 mg/day orally and her anemia and neutropenia resolved within 2 weeks, with a modest reticulocytosis (4.1%) and an increase in serum ceruloplasmin. She continued to excrete high concentrations of zinc in the urine for up to 1 year, although secondary copper deficiency was corrected with oral supplementation. However, the neurological deficit was unchanged, with severe disability after more than 1 year. The source of the excess zinc was not discovered.
Sensory systems to zinc (58A ).
Anosmia has been attributed
• A 55-year-old man with previously normal taste and smell developed clear rhinorrhea and congestion and treated himself with over-the-counter zinc gluconate for a self-diagnosed cold. He noted immediate burning in his nose and did not use the spray again. He also noted immediate persistent anosmia and an intermittent slightly salty taste. Detailed chemosensory evaluation showed severely limited detection ability bilaterally. Odor identification was absent on the right side and severely limited on the left. Taste sensation was normal except for the salty taste. The severe hyposmia persisted unchanged.
References 1. Lindblad EB. Aluminium adjuvants—in retrospect and prospect. Vaccine 2004;22:3659–68. 2. Jefferson T, Rudin M, Di Pietrantonj C. Adverse events after immunisation with aluminiumcontaining DTP vaccines: systematic review of the evidence. Lancet Infect Dis 2004;4:84–90. 3. Hyry H, Hook-Nikaune J. Aluminium and milk allergies in an adult. Contact Dermatitis 2004;50:107. 4. Shehan JM, Clowers-Webb HE, Kalaaji AN. Recurrent palmoplantar hidradenitis with exclusive palmar involvement and an association with trauma and exposure to aluminum dust. Ped Dermatol 2004;21:30–2. 5. Di Muzio A, Capasso M, Verrotti A, Trotta D, Lupo S, Pappalepore N, Manzoli C, Chiarelli F, Uncini A. Macrophagic myofasciitis: an infantile
Italian case. Neuromuscul Disord 2004;14:175– 7. 6. Zatta P, Zambenedetti P, Reusche E, Stellmacher F, Cester A, Albanese P, Meneghel G, Nordia M. A fatal case of aluminium encephalopathy in a patient with severe chronic renal failure not on dialysis. Nephrol Dial Transplant 2004;19:2929–30. 7. Guillard O, Fauconneau B, Olichon D, Dedieu G, Deloncle R. Hyperaluminemia in a woman using an aluminium-containing antiperspirant for 4 years. Am J Med 2004;117:956–9. 8. Scolyer RA, Thompson JF, Li L-XL, Beavis A, Dawson M, Doble P, Soper R, Uren RF, Stretch JR, Sharma R, McCarthy SW. Antimony concentrations in nodal tissue can confirm sentinel node identity. Mod Pathol 2004;17:1191–7.
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9. Heusser P, Stutz M, Haeberli A. Does homeopathically potentized antimony stimulate coagulation? A summary of previous findings and results of an in vitro pilot study by means of thrombelastography. J Altern Complement Med 2004;10:829–34. 10. Tarabar AF, Khan Y, Nelson LS, Hoffman RS. Antimony toxicity from the use of tartar emetic for the treatment of alcohol abuse. Vet Hum Toxicol 2004;46:331–3. 11. Verstovsek S, Estrov Z. Arsenic derivatives as therapeutic agents for hematologic malignancies. Leuk Res 2004;28:901–3. 12. Tanvetyanon T, Nand S. Herpes zoster during treatment with arsenic trioxide. Ann Hematol 2004;83:198–200. 13. Sun H, Zhang L, Szeto K-Z. Bismuth in medicine. Met Ions Biol Systems 2004;41:333–78. 14. Youngman L, Harris S. BIPP madness; an iatrogenic cause of acute confusion. Age Ageing 2004;33:406–7. 15. Vincent JB. Recent developments in the biochemistry of chromium (III). Biol Trace Elem Res 2004;99:1–16. 16. Kleefstra N, Bilo HJ, Bakker SJ, Houweling ST. Chromium and insulin resistance. Ned Tijschr Geneeskd 2004;148:217–20. 17. Berner TO, Murphy MM, Slesinski R. Determining the safety of chromium tripicolinate for addition to foods as a nutrient supplement. Food Chem Toxicol 2004;42:1029–42. 18. Wijmenga C, Klomp LWJ. Molecular regulation of copper excretion in the liver. Proc Nutr Soc 2004;63:31–9. 19. Doraiswami PM, Finefrock AE. Metals in our minds: therapeutic implications for neurodegenerative disorders. Lancet 2004;3:431–4. 20. Bush AI, Strozyk D. Serum copper: A biomarker for Alzheimer disease? Arch Neurol 2004;61:631–2. 21. Goodman VL, Brewer GJ, Merajver SD. Copper deficiency as an anti-cancer strategy. Endocr Relat Cancer 2004;11:255–63. 22. Lowndes SA, Harris AL. Copper chelation as an antiangiogenic therapy. Oncol Res 2004;14:529– 39. 23. Dillon CT, Hambley TW, Kennedy BJ, Lay PA, Weder JE, Zhou Q. Copper and zinc complexes as anti-inflammatory drugs. Met Ions Biol Syst 2004;41:253–77. 24. Vergara G, Silvestre JF, Botella R, Albares MP, Pascual JC. Oral lichen planus and sensitisation to copper sulfate. Contact Dermatitis 2004;50:374–85. 25. Chitambar CR. Gallium compounds as antineoplastic agents. Curr Opin Oncol 2004;16:547–52. 26. Eisler R. Mammalian sensitivity to elemental gold (Au degrees). Biol Trace Elem Res 2004;100:1–18. 27. Singh AD, Puri P, Amos RS. Deposition of gold in ocular structures, although known, is rare. A case of ocular chrysiasis in a patient of rheumatoid arthritis on gold treatment is presented. Eye 2004;18:443–4.
233 28. Shah P, Griffith SM, Shadforth MF, Fisher J, Dawes PT, Poulton KV, Thomson W, Ollier WE, Mattey DL. Can gold therapy be used more safely in rheumatoid arthritis? Adverse drug reactions are more likely in patients with nodular disease, independent of HLA-DR3 status. J Rheumatol 2004;31:1903–5. 29. Alam MG, Krauss MW, Shah SV. Parenteral iron therapy: beyond anaphylaxis. Kidney Int 2004;66:457–8. 30. Silverstein SB, Rodgers GM. Parenteral iron therapy options. Am J Hematol 2004;76:74–8. 31. Sullivan JL. Is stored iron safe? J Lab Clin Med 2004;144:280–4. 32. Galleano M, Simontachhi M, Puntarulo S. Nitric oxide and iron: effect of iron overload on nitric oxide production in endotoxemia. Mol Aspects Med 2004;25:141–54. 33. Hiraoka T, Furuya A, Matsumoto Y, Okamoto F, Kakita T, Oshika T. Corneal iron ring formation associated with overnight orthokeratology. Cornea 2004;23(Suppl 1):S78–81. 34. Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmen J. On the relative safety of parenteral iron formulations. Nephrol Dial Transpl 2004;19:1571–5. 35. Crossgrove J, Zheng W. Manganese toxicity upon overexposure. NMR Biomed 2004;17:544– 53. 36. Pardo J. Allergic contact stomatitis due to manganese in a dental prosthesis. Contact Dermatitis 2004;50:41. 37. Weisser K, Bauer K, Volkers P, KellerStanislawski B. Thiomersal and immunisations. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2004;47:1165–74. 38. Parker SK, Schwarz B, Todd J, Pickering LK. Thimerosal-containing vaccines and autistic spectrum disorder: a critical review of published original data. Pediatrics 2004;114:793–804. 39. Segura-Egea JJ, Bullon-Fernandez P. Lichenoid reaction associated to amalgam restoration. Med Oral Patol Oral Cir Bucal 2004;9:421–4. 40. Cherciu M, Zbranca A. Nickel contact dermatitis. A ring signal in actual pathology. Rev Med Chir Soc Med Nat Iasi 2004;108:497–502. 41. Baumann MA. Nickel–titanium: options and challenges. Dent Clin North Am 2004;48:55–67. 42. Stoeckel D, Pelton A, Duerig T. Self-expanding nitinol stents: material and design considerations. Eur Radiol 2004;14:292–301. 43. Draeger H, Wu X, Roelofs-Haarhuis K, Gleichmann E. Nickel allergy versus nickel tolerance: can oral uptake of nickel protect from sensitization? J Environ Monit 2004;6:146N–50N. 44. Buntain SG, Pabari M. Massive transfusion and hyperkalaemic cardiac arrest in craniofacial surgery in a child. Anaesth Intensive Care 1999;27:530–3. 45. Horisberger T, Fischer JE, Waldrogel K. Longterm outcome of an infant resuscitated from iatrogenic potassium intoxication with a serum level of 17.7 mmol/l. Eur J Pediatr 2004;163:48–9. 46. Patrick L. Selenium biochemistry and cancer: a review of the literature. Altern Med Rev 2004;9:239–58.
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47. Soriano-Garcia M. Organoselenium compounds as potential therapeutic and chemopreventive agents: agents. Curr Med Chem 2004;11:1657– 69. 48. Chan YC, Friedlander SF. Therapeutic options in the treatment of Tinea capitis. Expert Opin Pharmacother 2004;5:219–27. 49. Kise Y, Yoshimura S, Akieda K, Umezawa K, Okada K-I, Yoshitake N, Shiramizu H, Yamamoto I, Inokochi S. Acute oral selenium intoxication with ten times the lethal dose resulting in deep gastric ulcer. J Emerg Med 2004;26:183–7. 50. Landsdown AB. A review of the use of silver in wound care: facts and fallacies. Br J Nurs 2004;13(6 Suppl):S6–19. 51. Driver VR. Silver dressings in clinical practice. Ostomy Wound Manage 2004;50(9A Suppl):11S–5S. 52. Webb CJ, Beer H. Posterior nasal cautery with silver nitrate. J Laryngol Otol 2004;118:713–4.
Gijsbert B. van der Voet and Frederik A. de Wolff 53. Tomi NS, Kränke, Aberer W. A silver man. Lancet 2004;363:532. 54. Poon VKM, Burd A. In vitro cytotoxicity of silver: implications for clinical wound care. Burns 2004;30:140–7. 55. Hegedus C, Lampe I, Vitalyos G, Daroczi L, Beke D. Applicability of titanium in preparing dental prostheses for allergic patients. Forgorv Sz 2004;97:239–45. 56. Caruso F, Rossi M. Antitumor titanium compounds. Mini Rev Med Chem 2004;4:49–60. 57. Greenberg SA, Briemberg HR. A neurological and haematological syndrome associated with zinc excess and copper deficiency. J Neurol 2004;251:111–4. 58. Jafek BW, Linschoten MR, Murrow BW. Anosmia after intranasal zinc gluconate use. Am J Rhinol 2004;18:137–41.
R.H.B. Meyboom
23 IRON CHELATORS Studying and understanding iron chelation treatment requires a thorough knowledge of the physiology and pathophysiology of iron, iron carriers, iron-dependent proteins, and their oxygen-radical scavenging properties. The strategy for developing new iron chelators, using deferoxamine as a model, has been comprehensively reviewed, including a review of ironcontaining proteins and their functions (Table 1) (1R ). Likewise, the effects of chelators on iron metabolism can cause multiple and unexpected adverse effects. In the same paper examples are given of human proteins that contain other metals (for example copper or zinc) that can be influenced by iron chelators. The metal stability constants of deferoxamine and deferiprone are also shown (Table 2); in particular, the copper chelating action of deferiprone is much higher than that of deferoxamine. A promising consequence of the crucial roles of iron in metabolically active and rapidly dividing tissues is the possible future role of iron chelators in the management of malignant diseases. Current knowledge regarding iron chelators and cancer chemotherapy has been reviewed in detail (2R ). Animal studies have shown that several iron chelators have antitumor activity, but so far clinical trials have been largely limited to deferoxamine, which has only modest antitumor effects. Dexrazoxane has already been approved for use in combination with doxorubicin. Its effectiveness in allowing the administration of doxorubicin in higher doses is partly based on the interactions of both drugs with iron. Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29023-8 © 2007 Elsevier B.V. All rights reserved.
Metal antagonists Deferoxamine, deferiprone, and cardiac siderosis A few years ago, Anderson and colleagues developed a new magnetic resonance “T2-star” or “T2*” technique to measure the iron content of tissues, in particular heart and liver (3CR ). Myocardial iron content cannot be predicted from serum ferritin or liver iron concentrations, and conventional assessments of cardiac function can only detect patients with advanced disease. The T2* magnetic resonance technique can reproducibly quantify myocardial iron deposition, which is the most significant variable for predicting the need for treatment of ventricular dysfunction. The same group has now prospectively shown that intravenous deferoxamine can effectively remove iron from the myocardium and improve heart function in patients with severe iron storage disease (4CR ). Seven patients were switched from subcutaneous to intravenous deferoxamine, mean dose 43 mg/kg/day, given over 24 hours through an indwelling intravenous line for 12 months. One patient died (no details were given); otherwise none was withdrawn from the study. All had progressive improvement in myocardial T2* and left ventricular function, i.e. left ventricular ejection fraction, volume, and mass index. However, iron cleared much more slowly from the myocardium (5.0% per month) than the liver (39% per month). Excess myocardial iron (T2* < 20 ms) was still present in all the patients at 12 months. Further to previous findings (SEDA-26-253; SEDA-28-255), three more studies have documented the synergism and effectiveness of combined use of deferoxamine and deferiprone. Researchers in Taiwan studied two poorly chelated patients with thalassemia and severe heart failure and gave them oral deferiprone 80 mg/kg and continuous intravenous deferoxamine 50 mg/kg/day (5CR ). In both patients magnetic resonance images of the heart showed
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Table 1. Iron-containing proteins and their functions (1R ) Protein
Function
Hemoglobin Myoglobin Cytochromes [unspecficied] Adrenodoxin Ferredoxin Cytochrome P450 and b5 Ribonucleotide reductase Proline hydroxylase Phenylalanine hydroxylase Tryptophan 2,3-dioxygenase Homogentisic acid 2,3-dioxygenase Peroxidases Catalase Lipoxygenase Cyclo-oxygenase Aconitase Succinate dehydroginase NADH dehydrogenase Xanthine oxidase Aldehyde oxidase Ferroportin Transferin Lactoferin Ferritin Hemosiderin
Oxygen transport Oxygen transport Electron transport; respiration Electron transport; oxidation/reduction Electron transport; oxidation/reduction Electron transport; drug metabolism Electron transport Drug detoxification DNA synthesis Collagen synthesis Degradation of phenylalanine Degradation of tryptophan Deficiency causes alkaptonuria Decomposition of hydroperoxides Decomposition of H2 O2 HPETE and leukotriene synthesis Prostaglandin and thromboxane synthesis Tricarboxylic acid cycle Tricarboxylic acid cycle Electron transport. Respiration Conversion of xanthine to uric acid Aldehydes metabolism Iron absorption Iron transport in serum Iron removal in milk and other secretions Iron storage Iron storage
Table 2. Stability constants [log β] of deferoxamine and deferiprone (1R ) Ion
Deferoxamine
Deferiprone
DTPA
Fe3+ Cu2+ Ni2+ Co3+ Zn2+
30.6 4.0 10.0 11.0 11.1
35.0 19.6 12.1 11.7 13.5
28.6 21.0 20.2 19.0 18.4
marked recovery of signal intensity, suggesting a reduced iron load, and had marked clinical improvement in 2 months. There were no significant adverse effects during 6 and 13 months follow-up. In seven patients with thalassemia, in whom conventional treatment had been unsuccessful or had caused adverse effects, a combination of deferiprone 75 mg/kg/day, and deferoxamine 40–50 mg kg by slow subcutaneous infusion for 7–10 days after red cell transfusion was effective, requiring only about 25% of the original
dose of deferoxamine in patients with previous deferoxamine intolerance (6cr ). In a study from New Delhi combining deferoxamine with deferiprone, thanks to a lower dose and frequency of administration of deferoxamine, was favorable in terms of cost and compliance, without losing efficacy, compared with deferoxamine alone (7CR ). In this study, two of 21 patients who received deferiprone, together with deferoxamine in one, had an arthropathy of large joints.
Deferasirox The benzoic acid-derivative deferasirox (CGP72670, ICL-670A) is a new orally active iron chelator. It has been granted orphan drug status by the European Commission and is in phase III clinical development. So far no important adverse effects have been encountered (8r ).
Metal antagonists
Chapter 23
Deferiprone
(SED-15, 1054; SEDA-26, 253; SEDA-27, 233; SEDA-28, 256)
Observational studies The use of deferiprone 75 mg/kg/day for 5 years in 12 Lebanese patients with thalassemia major, aged 18–34 years has been reviewed (9CR ). At the end of this time there was no histological evidence of hepatic fibrosis caused by deferiprone, albeit based on single biopsies; liver fibrosis appeared to be largely due to hepatitis C infection. Cardiac studies showed a significant improvement in isovolumic relaxation time, but there was no overall change in left ventricular ejection fraction. There was no mention of any adverse effects in these patients. Hematologic In a study from India, mean treatment time about 7 months, in 51 generally younger patients treated with deferiprone, 50 or 75 mg/day, there was some degree of leukopenia in 12 patients, with severe granulocytopenia in two (10cr ). One patient had agranulocytosis, with a severe membranous pharyngeal and respiratory tract infection, after 11 months of treatment and died. In the second patient it took 4 months for the neutropenia to recover. In the other 10 patients deferiprone was restarted; in one case the neutropenia recurred. There was no apparent relation between leukopenia and the dose of deferiprone. Deferiprone was withdrawn in all 12 patients. Ten patients later on restarted treatment without relapse. Unfortunately, interpretation of the results of this study was hindered by errors in the presentation of the findings. Musculoskeletal In a study from India, mean treatment time about 7 months, in 51 generally younger patients treated with deferiprone, 50 or 75 mg/day, 21 patients had arthropathy of varying severity; 11 needed indometacin for pain relief and one withdrew (10cr ).
Deferoxamine
(SED-15, 1058; SEDA-26, 253; SEDA-27, 233; SEDA-28, 256) Observational studies In 13 patients the reasons for withdrawal of deferoxamine were marked subcutaneous fibrosis (n = 12), metaplasia of the femoral or peroneal metaphysis
237 (n = 6), and neurosensory deafness (n = 4) (6cr ). Since the original report of Borgna-Pignatti and Cohen (11C ) several studies have shown the efficacy of twice-daily subcutaneous bolus injections of deferoxamine as an alternative to continuous infusion (12cr ). However, in a follow-up study of adults with iron-overload, many of the patients nevertheless preferred the standard subcutaneous infusion, because the large volume of the bolus injections caused painful swellings for up to 12–24 hours (12cr ). Infection risk Deferoxamine and iron overload are prominent risk factors for mucormycosis (infection with Rhizopus, Mucor, or another species of Mucorales) (13R ). Whereas in the past as many as 75% of dialysis patients with mucormycosis had received deferoxamine, today fewer such cases are expected, since the use of erythropoietin has reduced the need for frequent blood transfusions. Sensory systems There have been several reports of deferoxamine-induced retinopathy. • An 81-year-old woman with open-angle glaucoma and lymphoma was treated with whole blood transfusions and deferoxamine infusions on 5 nights per week (14A ). However, the dose and duration of administration were not specified and there was no outcome or follow-up information. She developed painless bilateral blurring of vision and had a visual acuity of only finger counting in the right eye and 3/60 in the left. Retinal examination showed pale cupped discs and symmetrical well-circumscribed areas of abnormal pigmentation in both maculae. Angiography showed retinal pigment atrophy and electroretinography was markedly subnormal in both eyes, with delayed latency in the left. The rapid visual loss, the unusual and striking pattern of abnormal macular pigmentation without drusen, and cone abnormalities on electroretinography suggested deferoxamine toxicity. The delayed visual evoked potentials, on the other hand, were considered to be secondary to glaucomatous optic neuropathy. • A 67-year-old man with a 5-year history of acute myeloid leukemia, anemia after allogeneic stem cell transplantation, and transfusion-induced hemosiderosis was given repeated subcutaneous injections of deferoxamine over 2.5 years (doses not specified) (15A ). Treatment had to be interrupted because of an abdominal wall abscess. During a visit for long-standing ocular hypertension the patient reported seeing recurrent green-yellowish spots in both eyes. Ophthalmoscopy showed tiny pigmentary irregularities of the macula. Visual acuity was practically normal and color vision was normal. Fluorescein angiography showed cockade formation at the maculae after 47 seconds;
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after 8 minutes there was bilateral circular macular hyperfluorescence, with a typical “bull’s eye” or “shooting target” appearance, which became more prominent over the next 5 minutes. Multifocal electroretinography showed normal latencies in the periphery, but centrally the amplitudes were reduced to about half normal. On follow-up 1 year later and after withdrawal of deferoxamine, the patient was well and the leukemia was in complete remission. • A 70-year-old woman with myelodysplasia developed color vision disturbance after receiving subcutaneous deferoxamine 2 g/day for 11 months (16A ). Vision was 20/30 in the right eye and 20/25 in the left and there were granular pigment epithelium changes in both maculae. Fluorescein angiography showed bilateral central mottled hyperfluorescence without leakage, and a FarnsworthMunsell 100-hue test showed bilateral tritan defects. However, electroretinography and electrooculography were normal. The dose of deferoxamine was reduced to 500 mg/day but was increased to 2 g/day because of an increasing serum ferritin concentration 4 months later; 1 year later visual acuity had dropped to 20/125 and 20/60 and fluorescein angiography showed bilateral vitelliform macular lesions with hyperfluorescence. Although deferoxamine was withdrawn, vision remained poor and the vitelliform lesions remained, with an increase in macular pigment clumping and atrophic changes. • A 70-year-old woman with myelodysplasia received repeated intravenous deferoxamine 2680 mg 5 times a week for 3 years (16A ). She noted progressively reduced vision over 5 months. Visual acuity was 20/50 in the right eye and 20/60 in the left, and there were vitelliform lesions with mottling of the pigment epithelium in both maculae. Ganzfeld electroretinography showed mildly reduced cone-mediated responses, with reduced amplitude and delayed implicit times; electro-oculography was normal. Deferoxamine was withdrawn, but 1 year later visual acuity was only 20/100 in both eyes. There was a round yellow submacular lesion centered on the fovea in the right eye and the left eye showed consolidation and resolution of the yellowish deposit, with subfoveal pigmentary clumping without subretinal fluid. • A 65-year-old woman with osteoarthritis and myelodysplasia developed dry eyes and reduced vision, attributed to Sjögren’s syndrome and deferoxamine retinopathy (17A ). She had received regular blood transfusions for 18 months and deferoxamine on 6 days per week (dose and duration not specified). Her visual acuity was 20/40 in the right eye and 20/30 in the left. Slit-lamp examination showed bilateral punctuate epithelial keratopathy because of dry eyes. Fundoscopy showed circular areas of retinal pigment epithelium disruption and clumping in both maculae. Color vision was impaired.
feroxamine toxicity after withdrawal (17A ). It provides an objective, quantitative, and reproducible measurement of retinal function, which can aid the ophthalmologist in striking a balance between the severity of retinopathy and the detrimental effects of iron overload. Multifocal electroretinograms were recorded from 61 regions of the ocular fundus within the central 45◦ . The electroretinograms from the left eye showed reduced responses within the central 2◦ surrounding the fovea, with pronounced nasal-temporal amplitude asymmetry in the 22◦ area. The electroretinogram traces from the right eye were reduced throughout the central 22◦ surrounding the fovea. The topographical distribution of retinal response density was compared between the patient’s electroretinograms and those in 50 eyes of healthy age-matched subjects. This provided a topographical retinal map that expressed the statistical difference in retinal response density between the patient and the unaffected population. Repeated multifocal electroretinography showed worsening of the retinopathy in the first 4 months after withdrawal of deferoxamine and stabilization after a subsequent 4 months.
In the last patient repeated multifocal electroretinography was helpful in monitoring de-
In a study in the Department of Clinical Effectiveness and Audit in the Freeman Hospi-
ICL670A The novel tridentate iron chelator ICL670A has been reviewed (18R ). It substantially increases the excretion of iron in animals after oral administration. It is about 4–5 times more effective than parenteral deferoxamine and acts mainly via the faecal route, through the chelation of iron from hepatocellular stores. The first few clinical studies have shown that ICL670A 20 mg/kg/day can induce a negative iron balance. A rash developed in four of 24 transfusion-dependent patients with thalassemia, in one case accompanied by raised serum transaminase activities.
PENICILLAMINE AND RELATED DRUGS Penicillamine
(SED-15, 2729; SEDA-26, 255; SEDA-27, 235; SEDA-28, 257)
Metal antagonists
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tal in Newcastle-upon-Tyne, UK, on adherence to treatment guidelines for disease-modifying antirheumatic drugs (DMARDs), only a small proportion of patients used penicillamine (less than 40 of 1250 patients); today the most commonly used DMARDs are methotrexate and sulfasalazine (19cr ). Penicillamine was the drug with the highest rate of non-adherence. This may simply be an artefact secondary to the small number of patients or, given that penicillamine is rarely used these days, could reflect complacency with treatment already taken for many years. Teratogenicity Penicillamine in high doses, as used in Wilson’s disease, interferes with synthesis of collagen and elastin and can cause a characteristic tardive dermopathy, with perforating elastoma and cutis laxa. Since the original case report of Mjølnerød et al. (20A ), prenatal exposure to penicillamine has also been known to cause congenital cutis laxa and other malformations. A further case has been reported (21AR ). • A 35-year-old woman with Wilson’s disease took penicillamine 1 g/day during the first 20 weeks of gestation and 500 mg/day afterwards. An ultrasound at 16 weeks showed arthrogryposis, bowed femurs, and a single umbilical artery. Because of oligohydramnios vaginal delivery was induced after 37 weeks. The male child had normal chromosomes. He had a low body weight (2190 g), a head circumference of only 31.5 cm, generalized cutis laxa, severe micrognathia, contractures of all limbs, internally rotated shoulders, flexed elbows, wrists, knees, and hips, camptodactyly, clubfeet, flat posteriorly rotated ears, bridged palmar creases, and undescended testes. The reflexes were brisk but muscle bulk and tone were normal. A chest radiograph showed hooked clavicles and a bell-shaped thorax, and a brain MRI showed agenesis of the corpus callosum and colpocephaly. At age 8 months there was a near full resolution of the cutis laxa but there was profound developmental delay and cortical blindness. Auditory brainstemevoked potentials were abnormal at 5 months and at about 1 year partial complex seizures developed. A CT scan showed reduced brain volume, enlarged ventricles, corpus callosum agenesis, and bilateral subdural hygromas. The neonatal blood copper concentration at 24 hours was 400 (reference range 600–1900) µg/l.
A 5-year-old maternal half-brother, who had been exposed to penicillamine 1 g/day throughout gestation, had partial agenesis of the corpus callosum but was developmentally normal;
there was no history of cutis laxa or contractures. The findings in this child were reminiscent of those in an earlier case, a boy with cutis laxa who also had growth retardation, facial abnormalities (a broad nasal bridge and lowset ears), contractures of the hips and knees, and simian creases (22A ). His mother had taken penicillamine 900 mg/day for rheumatoid arthritis. Of 11 children with probable penicillamine embryopathy six had cutis laxa, five had joint abnormalities, four had central nervous system malformations, and four of seven boys had inguinal hernias (21AR ). The nervous system abnormalities in the other three children were hydrocephalus in two and congenital blindness and cerebral palsy in one. The mechanism underlying the fetotoxic effects of penicillamine is still unclear, but there is presumably a connection with disturbances in the metabolism of copper or other metals.
Trientine
(SED-15, 3508)
Hematologic Thrombocytopenia has been attributed to trientine (23A ). • A 28-year-old man with Wilson’s disease with central nervous system involvement was given trientine 1200 mg/day and 2 months later 2400 mg/day. Within 1 year he had asymptomatic thrombocytopenia, lowest count 110 × 109 /l, and a raised serum creatine kinase. The dosage of trientine was reduced to 1200 mg/day followed by a prompt increase in the number of platelets and a subsequent increase to 1800 mg/day 3 months later was uneventful.
Thrombocytopenia has not previously been described, but there have been a few reports of trientine-associated megaloblastic anemia (24A , 25A ).
POLYSTYRENE SULFONATES (SED-15, 2894; SEDA-26, 256; SEDA-27, 236; SEDA-28, 259) Gastrointestinal Gastrointestinal damage is the most common problem with polystyrene sulfonates, and cases of colonic ulceration, for example, continue to be reported (26A ).
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References 1. Kontoghiorghes GJ, Pattichis K, Neocleous K, Kolnagou A. The design and development of deferiprone (L1) and other iron chelators for clinical use: targeting methods and application prospects. Curr Med Chem 2004;11(16):2161– 83. 2. Buss JL, Greene BT, Turner J, Torti FM, Torti SV. Iron chelators in cancer chemotherapy. Curr Top Med Chem 2004;4(15):1623–35. 3. Anderson LJ, Holden S, Davis B, Prescott E, Charrier CC, Bunce NH, Firmin DN, Wonke B, Porter J, Walker JM, Pennell DJ. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J 2001;22(23):2171–9. 4. Anderson LJ, Westwood MA, Holden S, Davis B, Prescott E, Wonke B, Porter JB, Walker JM, Pennell DJ. Myocardial iron clearance during reversal of siderotic cardiomyopathy with intravenous desferrioxamine: a prospective study using T2* cardiovascular magnetic resonance. Br J Haematol 2004;127(3):348–55. 5. Wu KH, Chang JS, Tsai CH, Peng CT. Combined therapy with deferiprone and desferrioxamine successfully regresses severe heart failure in patients with beta-thalassemia major. Ann Hematol 2004;83(7):471–3. 6. D’Angelo E, Mirra N, Rocca A, Carnelli V. Combined therapy with desferrioxamine and deferiprone: a new protocol for iron chelation in thalassemia. J Pediatr Hematol Oncol 2004;26(7):451–3. 7. Gomber S, Saxena R, Madan N. Comparative efficacy of desferrioxamine, deferiprone and in combination on iron chelation in thalassemic children. Indian Pediatr 2004;41(1):21–7. 8. McIntyre JA, Castaner J, Mealy NE, Bayes M. Deferasirox: treatment of iron overload iron chelator. Drugs Future 2004;29:331–5. 9. Taher A, Aoun E, Sharara AI, Mourad F, Gharzuddine W, Koussa S, Inati A, Dhillon AP, Hoffbrand AV. Five-year trial of deferiprone chelation therapy in thalassaemia major patients. Acta Haematol 2004;122(4):179–83. 10. Choudhry VP, Pati HP, Saxena A, Malaviya AN. Deferiprone, efficacy and safety. Indian J Pediatr 2004;71(3):213–6. 11. Borgna-Pignatti C, Cohen A. An alternative method of subcutaneous deferoxamine administration. Blood 1995;86(Suppl 1):483a. 12. Franchini M, Gandini G, Veneri D, Aprili G. Safety and efficacy of subcutaneous bolus injection of deferoxamine in adult patients with iron overload: an update. Blood 2004;103(2):747–8.
13. Prabhu RM, Patel R. Mucormycosis and entomophthoramycosis: a review of the clinical manifestations, diagnosis and treatment. Clin Microbiol Infect 2004;10(Suppl 1):31–47. 14. Arora A, Wren S, Gregory Evans K. Desferrioxamine related maculopathy: a case report. Am J Hematol 2004;76(4):386–8. 15. Schmidt D, Finke J. Schiessscheiben-Makula durch Deferoxamin-Behandlung. Klin Monatsbl Augenheilkd 2004;221(3):204–9. 16. Gonzales CR, Lin AP, Engstrom RE, Kreiger AE. Bilateral vitelliform maculopathy and deferoxamine toxicity. Retina 2004;24(3):464–7. 17. Kertes PJ, Lee TKM, Coupland SG. The utility of multifocal electroretinography in monitoring drug toxicity: deferoxamine retinopathy. Can J Ophthalmol 2004;39(6):656–61. 18. Franchini M, Veneri D. Iron-chelation therapy: an update. Hematol J 2004;5:287–92. 19. Kay LJ, Lapworth K. Safety monitoring for disease-modifying anti-rheumatic drugs in primary and secondary care: adherence to local and national guidelines and patient’s views. Rheumatology (Oxford) 2004;43(1):105. 20. Mjolnerod OK, Dommerud SA, Rasmussen K, Gjeruldsen ST. Congenital connective-tissue defect probably due to D-penicillamine treatment in pregnancy. Lancet 1971;1(7701):673–5. 21. Pinter R, Hogge WA, McPherson E. Infant with severe penicillamine embryopathy born to a woman with Wilson disease. Am J Med Genet 2004;128:294–8. 22. Solomon L, Abrams G, Dinner M, Berman L. Neonatal abnormalities associated with Dpenicillamine treatment during pregnancy. N Engl J Med 1977;296(1):54–5. 23. Sabolek M, Weidanbach M, Storch A, Kraft E. Thrombozytopenie unter trientene zur behandlung des morbus Wilson mit neurologischen symptomen. Akt Neurol 2004;31:246–9. 24. Condamine L, Hermine O, Alvin P, Levine M, Rey C, Courtecuisse V. Acquired sideroblastic anaemia during treatment of Wilson’s disease with triethylene tetramine dihydrochloride. Br J Haematol 1993;83(1):166–8. 25. Perry AR, Pagliuca A, Fitzsimons EJ, Mufti GJ, Williams R. Acquired sideroblastic anaemia induced by a copper-chelating agent. Int J Hematol 1996;64(1):69–72. 26. Hourseau M, Lagorce-Pages C, Benamouzig R, Tuil O, Ecomard MA, Zemoura L, Martin A. Ulcération colique après administration prolongée de Kayexalate (polystyrène sulfonate de sodium). Gastroenterol Clin Biol 2004;28(3):311–3.
Pam Magee
24
Antiseptic drugs and disinfectants
BISBIGUANIDES Chlorhexidine
(SED-15, 714; SEDA-26, 258; SEDA-27, 239; SEDA-28, 261)
Observational studies The use of disinfectants for infection control requires continuing evaluation of their effectiveness, toxicity, tolerability, and cost. Chlorhexidine has been widely used as a topical antiseptic since the early 1950s and has a low incidence of sensitization (SEDA26, 258). Its suitability in two important public health applications has been demonstrated. To minimize the bacterial contamination rate in blood collected from donors a study was designed to evaluate the suitability of a single-use chlorhexidine-alcohol antiseptic for donor arm preparation at all blood collection venues in Australia (1C ). The tolerability of an antiseptic for blood donor disinfection is important to minimize any factor that might cause donors to stay away from future donation. A prospective study of bacterial load on the skin was performed in 616 blood donor arms before and after disinfection. Disinfection was achieved with a swab containing 1% chlorhexidine gluconate with 75% alcohol. Feedback from blood donors and staff was obtained using questionnaires. After disinfection, there was a marked reduction in skin bacterial counts, well under the target of the Australian Red Cross Blood Services. Sixteen donors reported skin irritation at the site of application; most of the reactions were selflimiting itchiness, with or without erythema. The majority of donors either preferred or did not object to the use of the chlorhexidine antiseptic. Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29024-X © 2007 Elsevier B.V. All rights reserved.
An estimated 600 000 children world-wide were infected with HIV type 1 in 2001. Most of these infections occurred through motherto-child transmission of HIV during pregnancy, around the time of labor and delivery. In developing countries, where the resources to prevent and manage these infections are limited, peripartum cleansing with chlorhexidine is a potentially simple and low-cost strategy for the prevention of mother-to-child transmission. However, low concentrations of chlorhexidine have not been proved to be effective in reducing mother-to-child transmission. Before assessing the effectiveness of higher chlorhexidine concentrations on mother-to-child transmission the highest tolerated concentration needed to be established. Three concentrations of chlorhexidine (0.25%, 1%, and 2%) have been evaluated as perinatal maternal and infant washes, to identify the maximum tolerated concentration for this intervention (2C ). Women were enrolled during their third trimester at a maternity unit in Soweto, South Africa. Subjective maternal symptoms and infant examinations were used to assess tolerability of the washes. The 0.25% concentration of chlorhexidine was well tolerated by the mothers. Ten of 79 complained of mild vaginal burning or itching from the 1% chlorhexidine washes, and washes were stopped in five. Of the 75 women in the 2% chlorhexidine group, 23 had subjective complaints and the washes were stopped in 12. There were no indications of toxicity from any of the chlorhexidine washes in the infants. The authors concluded that a 1% solution of chlorhexidine is safe and well tolerated and could be considered for a trial in the prevention of mother-to-child transmission. Sensory systems Acanthamoeba keratitis is now being recognized with increasing frequency, particularly since its association with contact lenses was demonstrated. At present
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242 there is no antimicrobial drug that interferes with any metabolic pathway in the amoeba while leaving the metabolism of the host cells unaffected. Current treatment consists of unspecified “disinfectants”. Recommended compounds are cationic antiseptics, such as chlorhexidine, which must be given frequently and for long periods. Treatment of acanthamoeba keratitis with chlorhexidine eye drops has been considered safe and non-toxic. However, progressive ulcerative keratitis has been reported (SEDA-27, 239) and now two almost identical cases of cataract and iris atrophy have been reported as complications of this treatment (3A ). Both cases involved prolonged treatment with chlorhexidine 0.02% and propamidine isethionate 0.1%, but progressed to deep marginal ulceration, necessitating a preventive graft. In both cases perioperative findings showed a totally dense membrane cataract, which had developed over a few months, together with an atrophic iris and a maximally dilated pupil. A complicating cataract in uveitis usually takes more than a few months to reach maturity. The intraocular inflammation in these two cases was not as intense as might have been expected if the amoebae had spread across the aqueous and entered the iris and the lens through an intact capsule. The iris atrophy was extreme, and the surface was greyish with little spots of clustered pigment. This appearance is almost never encountered in uveitis lasting only for a few months and this led the authors to suggest that a toxic mechanism was involved. It is possible that the toxicity of chlorhexidine eye drops has been underestimated. It is difficult to believe that a chemical that destroys the membrane of the amoeba should not at the same time affect the plasma membranes of ocular cells.
Chapter 24
Pam Magee
In the mid-1980s the National Institute for Occupational Safety and Health assembled a cohort of 18 235 men and women workers who had been exposed to ethylene oxide. The results of this study were reviewed in 1987 and showed no overall excess of hemopoietic cancers, but did show a significant excess amongst men, and particularly non-Hodgkin’s lymphoma. A study of the incidence of breast cancer in this cohort (SEDA-28, 262) showed some evidence of a positive exposure response for breast cancer mortality. Mortality reporting in this cohort has been extended from 1987 to 1998 (4C ). There were 2852 deaths, compared with 1177 in the earlier 1987 follow-up. There was no overall excess of hemopoietic cancers combined or of nonHodgkin’s lymphoma. However, internal exposure response analysis showed positive trends for hemopoietic cancers, limited to men. The reasons for this sex specificity are not known.
IODOPHORS
(SEDA-15, 1896; SEDA-27, 240; SEDA-28, 262)
Polyvinylpyrrolidone The safety of povidone-iodine, a polyvinylpyrrolidone and iodine complex, is established in many clinical settings, but its toxicity limits its use in others. Its efficacy and toxicity are still being examined for new indications.
Ethylene oxide
Randomized studies In a randomized trial of povidone-iodine to reduce visual impairment from corneal ulcers in rural Nepal, although additional benefit could not be demonstrated, a 2.5% solution of povidone-iodine was well tolerated and produced no more adverse effects than the standard therapy in this population (topical chloramphenicol, gentamicin, or tetracycline) (5C ).
Tumorigenicity In 1994 the International Agency for Research on Cancer determined that the gas ethylene oxide was a definite (group 1) human carcinogen, based on limited evidence from epidemiological studies showing increased hemopoietic cancers and supported by positive human cytogenetic evidence.
Drug administration route Vaginal use of povidone-iodine is not recommended in pregnancy (SEDA-25, 277). However, it continues to be used prophylactically for abdominal hysterectomy, although there is a lack of research in this area. In a randomized trial in 150 women to assess whether infectious morbidity after total abdominal hysterectomy is reduced by the
(SED-15, 1296; SEDA-26, 258; SEDA-28, 262)
Antiseptic drugs and disinfectants
Chapter 24
addition of povidone-iodine gel at the vaginal apex after the usual vaginal preparation, there was a reduced risk of pelvic abscess and no severe allergic reactions (6C ). Silver nitrate is commonly used for renal pelvic installation sclerotherapy for chyluria. However, it can cause severe adverse effects.
243 In one study silver nitrate and povidone-iodine had equivalent efficacy and povidone-iodine was well tolerated; the most significant adverse effect was severe flank pain, with an incidence of 11% in the silver nitrate group and 2% in the povidone-iodine group (7C ).
References 1. Wong PY, Colville VL, White V, Walker HM, Morris RA. Validation and assessment of a blooddonor arm disinfectant containing chlorhexidine and alcohol. Transfusion 2004;44:1238–42. 2. Wilson CM, Gray G, Read JS, Mwatha A, Lala S, Johnson S, Violari A, Sibiya PM, Fleming TR, Koonce A, Vermund SH, McIntyre J. Tolerance and safety of different concentrations of chlorhexidine for peripartum vaginal and infant washes. Acquir Immune Defic Syndr 2004;35:138–43. 3. Ehlers N, Hjortdal J. Are cataract and iris atrophy toxic complications of medical treatment of acanthamoeba keratitis? Acta Ohthalmologica Scand 2004;82:228–31. 4. Steenland K, Stayner L, Deddens J. Mortality analyses in a cohort of 18235 ethylene oxide exposed workers; follow up extended from 1987 to 1998. Occup Environ Med 2004;61:2–7.
5. Katz J, Khatry SK, Thapa MD, Schein OD, Kimbroug L, Pradham K, le Clerq SC, West KP. A randomised trial of povidone-iodine to reduce visual impairment from corneal ulcers in rural Nepal. Br J Ophthalmol 2004;88:1487–92. 6. Eason E, Wells G, Garber G, Hemmings R, Luskey G, Gillett P, Martin M. Antisepsis for abdominal hysterectomy: a randomised controlled trial of povidone-iodine gel. BJOG 2004;111:695– 9. 7. Goel S, Mandhani A, Srivastava A, Kapoor R, Gogoi S, Kumar A, Bhandari M. Is povidoneiodine an alternative to silver nitrate for renal pelvic installation in chyluria? BJU Int 2004;94:1082–5.
Tore Midtvedt
25
Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines
Antimicrobial drug resistance: a serious adverse effect exemplified by avoparcin and vancomycin-resistant enterococci Over the years, as has been clearly stated in this chapter of SEDA, increased antimicrobial drug resistance, which has been observed all over the world, is the most serious adverse effect of this type of drug. The reason is very simple: it reduces the effectiveness of antimicrobial drug treatment of infectious diseases everywhere and in all organisms (humans, animals, fishes, plants), thereby leading to increased morbidity and mortality, as well as increased costs. In addition, when we have to switch to another type of drug, simply because of resistance, the other drug has often an increased spectrum of adverse effects. Resistance is certainly not a new problem. Penicillinase, an enzyme that destroys penicillins, was described as early as in 1940 (1r ), before penicillin had been used clinically, and instances occurred in patients with infections caused by staphylococci soon after its introduction. Strains of Shigella that were resistant to several antimicrobial drugs, i.e. that expressed multiresistance, were described in Japan in the mid-1950s, and new principles for the transfer of resistance genes from one species to another, first from Shigella to E. coli, were described soon after (2R ). Since then, terms such as conjugation, transformation, transduction, Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29025-1 © 2007 Published by Elsevier B.V.
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and horizontal transfer have become part of the everyday language of those who combat infections. It is now well established that antimicrobial drug usage and microbial resistance in one area of use may have, and most often are shown to have, consequences for the profile of resistance in other areas. Microbes are everywhere, and they share genetic material with each other freely and frequently. And, as has also been pointed out in SEDA before, when addressing the problem of antimicrobial drug resistance, its occurrence, causes, consequences, and prevention, a global approach is necessary. In other words, we have to focus on usage in all areas, human medicine, veterinary medicine, agriculture, fish farming, and so on. The sad story of the glycopeptide avoparcin, which chemically resembles vancomycin, deserves to be underlined. From the end of the 1970s, avoparcin came into use in several countries as a growth promotor in husbandry, including poultry. In the 1980s, some instances of vancomycin-resistant enterococci were described in humans (3R , 4r ), although nobody associated this new type of resistance with the use of avoparcin. However, in the mid-1990s it was clearly shown in Germany, i.e. in a country in which several tons of avoparcin had been used as a growth promoter, that vancomycinresistant enterococci were being isolated far more frequently on farms in which avoparcin had been used than from farms in which it had not (5E ), and the correlation between the use of avoparcin and vancomycin-resistant enterococci was soon firmly established. However, it took more than 2 years, and several meetings, before avoparcin was prohibited in all countries in the European Union. More than 2 years later, the manufacturer withdrew avoparcin
Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines
from the market, but by that time the problem was well established. Between 1988 and 1993, vancomycin-resistant enterococci were isolated in 30 different UK hospitals, and the number of hospitals increased from 1 in 1988 to 18 in 1993 (6R ). The problem is still with us, 10 years after the ban of avoparcin, in farmers and on their farms (7E ). The mechanisms behind this persistence are still not clearly understood (8E ). The good news, although now somewhat old, is that several countries, especially in Europe, have implemented monitoring programmes for antimicrobial drug resistance and antimicrobial drug usage in human and veterinary medicine. The EU supported this approach (Copenhagen Recommendation) some years ago. Several international organizations, such as the World Health Organization (WHO), the Food and Agriculture Organization (FAO), and the World Animal Health Organization (OIE), have emphasized the importance of monitoring antimicrobial drug resistance and usage and they have published several reports and recommendations. This is good, but it is certainly not enough. The use of antimicrobial drugs continue to increase and so does the emergence of resistant organisms from all over the world; Iran, China, the USA, travellers or birds, it doesn’t matter (9E , 10R ). Among the many things that could be done most important is the need for a new strategy among regulatory agencies when new antimicrobial drugs are going to be introduced. In Europe and in the USA, the Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) have relatively vague requirements for environmental documentation. In principle, the rules are based on toxicological rather than biological principles. But the spread of antimicrobial drug resistance is a biological event of great concern and one that must be solved according to biological principles, including prudent use of old and new antibiotics. It is also remarkable that most agencies have reduced the chance of creating rules for the prudent use of antibiotics. If a drug is as good and safe as its comparators, it has to be registered for the indications for which it has been shown to be active. So far, not a single strain of streptococcus group A has developed resistance to penicillin V, and more potent beta-lactams should be saved for other indications.
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The time has come for leading drug agencies to react and to create a policy for the future. Otherwise, the introduction of new antibiotics will be close to meaningless.
BETA-LACTAM ANTIBIOTICS (SED-15, 478; SEDA-26, 279; SEDA-27, 242; SEDA-28, 267) Immunologic Allergic reactions to beta-lactams are the most frequent immunological drug reactions (11C , 12R ). The first cases were described soon after the introduction of penicillin G and for some decades, as several new beta-lactams came on the market, the classical dogma was that cross-reactivity between different penicillins was quite high, side-chain specific responses were negligible, in vivo tests with major and minor determinants would provide the diagnosis in more than 90% of cases, and the oral route was not relevant in inducing allergic reactions (12R ). Now views may have changed, exemplified by a study on the frequency of anaphylactic reactions and cross-reactivity in 1170 children with suspected immediate allergic reactions to cephalosporins and/or penicillins (13C ). In vivo skin tests and challenges and in vitro tests for specific IgE showed that 58% were skin or challenge test positive; among them, 94% were positive to penicillins and 36% were positive to cephalosporins. The frequency of positive reactions with in vivo testing was 36–88% for penicillins and 0.3–29% for cephalosporins; 32% of the children who were allergic to penicillin cross-reacted to some cephalosporin. In contrast, if a child was allergic to a cephalosporin, the frequency of positive reactions to penicillin was 84%. The cross-reactivity among different generations of cephalosporins was 0–69%, and was highest with first- and secondgeneration cephalosporins and zero with thirdgeneration cephalosporins. No information was given about the medication histories of these children and one cannot conclude that any beta-lactams is less allergenic than another. However, the results suggest a great degree of specificity and cross-reactivity to beta-lactams in children. A leading Spanish group has stressed that allergy to beta-lactams has become a more
246 complicated problem, because of the contribution of different chemical structures in inducing clinically relevant specificities (12R ). The incidences of atopy and allergy in children are increasing all around Europe. Many theories have been brought forward, but the reasons are still unknown. The increased complexity of allergic reactions to beta-lactams might in fact reflect this increase in allergy.
Chapter 25
basic message is that in patients on dialysis or with susceptibility factors for seizures the use of antibiotics other than carbapenems should be strongly considered.
CEPHALOSPORINS (SED-15, 688; SEDA-26, 264; SEDA-27, 245; SEDA-28, 268) Cefazolin
CARBAPENEMS (SED-15, 638; SEDA-26, 265; SEDA-27, 246) Ertapenem Nervous system Carbapenems, such as imipenem and meropenem are associated with different types of seizures, of which generalized seizures are the most common, but ertapenem is stated to cause seizures less often (14R ). However, it can occur, even after a few doses (15A ). • A 56-year-old white man on ambulatory peritoneal dialysis had five seizures after receiving two doses of ertapenem 500 mg intravenously within 23 hours. The first generalized tonic–clonic seizure occurred 16 hours after the second dose and lasted 3 minutes. Three hours later he had two more seizures 15 minutes apart, lasting 3 minutes each, followed by a fourth; he then was apneic for about half a minute and recovered, but 15 later had a fifth seizure and became apneic and pulseless. He was not resuscitated, as he had previously asked not to be.
According to the authors, this was the first case of ertapenem-induced neurotoxicity in a patient undergoing peritoneal dialysis. However, there have been reports of seizures in such patients receiving imipenem + cilastatin (16C , 17C ). Data from phase III trials in patients on dialysis indicate an average time of seizure onset of 7 days (18R ). The mechanisms of seizure provocation by carbapenems are unclear. One mechanism might be competitive inhibition of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), resulting in reduced suppression of epileptogenic discharges (19E ). However, it should be kept in mind that differences in structure between the carbapenems may lead to differences in convulsive potencies and mechanisms. Whatever the mechanisms might be, the
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(SEDA-26, 264)
Immunologic Cefazolin is a first-generation cephalosporin that is widely used in the perioperative period, during which allergic reactions can be problematic, as illustrated in the following two case reports. • In preparation for an operation a patient received cefazolin 2 g intravenously (20A ). The patient had no known drug allergies and had previously received intravenous cefazolin intraoperatively 2 months before without any problems, but 45 seconds later, while fully awake, developed shortness of breath, became unconscious, and had a cardiac arrest. Successful resuscitation included endotracheal intubation, external cardiac compression, electric defibrillation, and multiple large doses of adrenaline, atropine, and sodium bicarbonate. • A patient developed a systemic anaphylactic reaction to a subconjunctival injection of cefazolin (21A ). The patient did well, but required intensive therapy, including airway intubation.
The message to remember is that anaphylaxis in anesthetic practice has to be kept in mind, even when the drug is given locally.
Ceftriaxone
(SEDA-27, 245; SEDA-28,
269)
Nephrolithiasis and ceftriaxone Ceftriaxone, a third-generation cephalosporin, is widely used for treating infections, especially in children. It is eliminated partly in the bile, partly in the urine. Soon after it came on the market, it was shown sonographically that it could precipitate in the gallbladder (22E ), and “biliary sludge” or biliary pseudolithiasis, is now a well known adverse effect. In the last few years increasing number of reports have
Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines
shown that urinary sludge and/or calculi can also form. In a prospective study, 51 children with various infections received ceftriaxone (27 received 50 mg/kg/day and 24 received 100 mg/kg/day) (23C ). Abdominal ultrasonography after treatment showed renal stones up to 2 mm in size in four of them. Comparison of those with and without stones showed no significant differences with respect to age, sex distribution, or duration of treatment. The renal stones resolved spontaneously in three of the four cases, but were still present in one 7 months after ceftriaxone treatment. The possible relation to daily dose or length of therapy has caused some discussion. However, nephrolithiasis has been observed in children who received less than the recommended dose (24A , 25A ), and symptoms from the kidney have been reported after 3 days of ceftriaxone therapy (26A ). Thus, on the background of an increasing number of reports, it seems prudent to underscore the need to reiterate the indications for using ceftriaxone in daily practice and also the need for prompt clinical and laboratory monitoring with regard to nephrolithiasis in selected patients (25A ), using described monitoring and selection procedures (23A ). Abdominal ultrasonography before and after ceftriaxone therapy might be wise.
MONOBACTAMS
(SED-15, 2378;
SEDA-27, 247) Two independents groups isolated the first N-thiolated beta-lactams 25 years ago from natural sources. They were given the name “monobactams” because they have a flexible monocyclic ring and lack a carboxylic acid moiety (27E , 28E ). One derivative, aztreonam has been on the market for some years, but for several reasons has been relatively little used. Now this group has become of increasing interest, because of its effects on mammalian cells. A number of monobactams have been synthesized and their potential as anticancer agents has come to light (29R ). Some of these derivatives can inducing apoptosis in a wide array of tumor cell types, with little effect on normal cells. Thus, an undesirable side effect on mammalian cells may be turned into a desirable effect on cancer cells.
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PENICILLINS (SED-15, 2756; SEDA-26, 262; SEDA-27, 244) Ampicillin Skin Pseudoporphyria is a bullous disorder of the skin that is clinically and histologically similar to porphyria cutanea tarda, but with normal porphyrin metabolism (30R ). Several groups of drugs have been implicated, including tetracyclines and nalidixic acid (31R , 32A ), but never before beta-lactams. • A 24-year-old African American woman with a history of systemic lupus erythematosus, end-stage renal disease requiring hemodialysis, autoimmune hemolytic anemia, and idiopathic thrombocytopenia developed a chronic tubo-ovarian abscess and was given intravenous ampicillin + sulbactam (dosage not stated) (33A ). After 7 days, she developed pruritus, an increased white blood cell count with an eosinophilia of 29%. The ampicillin/sulbactam was withdrawn and intravenous cefepime + oral metronidazole were substituted. Six days later, she developed discrete, pruritic, non-inflammatory, tense bullae on the forehead and cheeks. Laboratory studies showed an increase in the eosinophil count to 41%. Cefepime was withdrawn. Biopsies showed lesions similar to porphyria cutanea tarda. She recovered within 2 weeks.
The authors stated that it was not clear which of the two beta-lactams had caused the bullous eruption. However, since her trouble began when she was taking ampicillin + sulbactam therapy, they thought that that combination was the more likely culprit.
Piperacillin Hematologic Neutropenia after therapy with piperacillin + tazobactam has previously been commented on (SEDA 27; 244). However, new cases continue to be reported (34A ). • A 19-year-old man had an attack of idiopathic acute pancreatitis and developed a large pseudocyst in the body and tail of the pancreas. He had an endoscopic cystogastrotomy, and 2 weeks later developed a high fever and a leukocyte count of 9.3 × 109 /l. Blockage of the stent and infection in the cyst was suspected. Pus from the cyst showed a mixed growth dominated by Pseudomonas aeruginosa, susceptible to piperacillin, and he was given 8 g/day. His fever responded within 3 days, but
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Minocycline
For some years it has been known that minocycline has biological effects that are completely separate and distinct from its antimicrobial actions, and in recent years it has been claimed to have neuroprotective effects in animal models of ischemic injury (45E , 46E ). Ischemic brain injury involves secondary inflammatory responses that contribute significantly to the clinical outcome (47E ). In some animal models of other neurological disorders, such as Parkinson’s disease, Huntington’s disease, autoimmune encephalomyelitis, and amyotrophic lateral sclerosis, minocycline has also been claimed to have some protective effect (48E , 49E ). These neuroprotective effects have been attributed to many factors, such as inhibition of inducible nitric oxide synthase (iNOS), caspase 1, caspase 3, and metalloproteases (48E , 49E ). However, there are clouds in the skies. In an extensive study minocycline ameliorated brain injury in developing rats, but it increased injury in developing mice (50E ). This detrimental effect in mice was consistent across different regions (cortex, striatum, and thalamus), with both single and multiple injection protocols and with both moderate and high doses. The mechanism of the contrasting effects in mice and rats remained to be elucidated. The authors warned that caution is warranted before clinical use in infants who have suffered hypoxic–ischemic brain injury. Their data in mice suggest that using minocycline in infants with hypoxia–ischemia could cause more severe brain injury. The authors of an editorial comment on these findings stressed that it was striking that the inconclusive, negative, or deleterious effects of minocycline have come to light only very recently, for which they suggested several explanations, one of which was the difficulty in getting negative findings published, and they proposed that leading journals should start sections dedicated to the communication of inconclusive, negative, or deleterious results (51r ).
Nervous system Of 243 consecutive patients with a diagnosis of pseudotumor cerebri, 18 had a concurrent history of minocycline treatment (44R ). The mean duration of minocycline treatment before diagnosis was 2.73 months.
Skin Pigmentation of the skin (52A ) and skinrelated structures, such as the nail beds (53A ), teeth (SEDA-26, 266), oral mucosa (54A ), sclerae (55A ), and conjunctival cysts (56A ), is a well-documented adverse effect of minocycline. Some possible mechanisms have been
2 weeks later he again developed a fever and was given piperacillin + tazobactam 13.6 g/day. He became afebrile after 2 days. However, after 5 days he developed a neutropenia (lowest value 0.58 × 109 /l) and thrombocytopenia (72 × 109 /l). The antibiotics were withdrawn and his blood count returned to normal within 6 days.
The authors referred to several other cases of bone marrow suppression after therapy with piperacillin and/or piperacillin + tazobactam. Bone marrow suppression occurred in patients who had received a cumulative dose of piperacillin + tazobactam of 4929 mg/kg, i.e. 4372 mg/kg of piperacillin. Their patient had received a cumulative dose of piperacillin of 3547 mg/kg. Drug interactions The detection of Aspergillus galactomannan antigen in plasma is widely used in the diagnosis of invasive aspergillosis. In the last 2 years several authors have reported the presence of this antigen in patients without aspergillosis but who were taking piperacillin + tazobactam (35A –38A , 39Ac ) although others did not find it (40A ). Seeking an explanation for this discordance, an Italian group has investigated 30 randomly selected batches of piperacillin + tazobactam; 26 of them were positive for the Aspergillus galactomannan antigen (41E ). Another combination, amoxicillin + clavulanic acid (co-amoxiclav), has been found to give false positive results in this test (42A , 43A ). It seems reasonable to presume that the companies are working on this problem. In the meantime, it might be wise from a clinical point of view to remember the old lesson that a positive laboratory result is not the same as a disease in your patient. False positive results challenge your clinical judgement.
TETRACYCLINES
(SED-15, 3330; SEDA-26, 265; SEDA-27, 247; SEDA-28, 270)
(SEDA-26, 265; SEDA-27, 247; SEDA-28, 271)
Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines
discussed before (SEDA-26, 266). Although minocycline has been associated with intraoral pigmentation, most cases have resulted from staining of the underlying hard tissues rather than soft tissue pigmentation. Two patients developed minocycline-induced pigmentation of the soft tissue of the palate, confirmed by biopsy (57A ). Minocycline-induced hyperpigmentation can even take place in scars (58A ) and, more rarely, in subcutaneous fat (59A ). • A 15-year-old girl with no significant past medical history developed bilateral leg discoloration. The lesions were not painful but were vaguely sensitive to pressure and touch. There was a faint bluish discoloration under the tongue, on the alveolar surface of the gums, and on the hard palate. She had taken minocycline twice daily for acne vulgaris for more than 1 year. A punch biopsy showed normal epidermis and dermis, but deep in the subcutaneous fat there were macrophages and multinuclear giant cells containing brown-greenish pigment in their cytoplasm. A Fontana-Masson stain showed that the pigment was melanin or a melanin-like substance. A Perls stain for iron was negative and a Von Kossa stain was negative for calcium. Minocycline was withdrawn, and after 5 years only subtle hyperpigmentation remained on her legs.
According to the authors, this was the first case of minocycline-induced pigmentation with pigment exclusively localized to subcutaneous fat. Musculoskeletal A 17-year-old man with acne developed diffuse myalgia, raised muscle enzymes, and abnormal liver function tests (60A ). He had previously taken minocycline, and 15 days before the onset of symptoms had started taking it again in a dosage of 100 mg/day and had exercised strenuously. His enzymes returned to normal 1 month after withdrawal of minocycline, and his symptoms resolved. Immunologic Minocycline can cause immunological reactions, including lupus-like syndrome (SEDA-26, 247). A few cases of cutaneous polyarteritis nodosa have been described (61A –64A ), and another has appeared (65A ). • A 19-year-old woman taking an oral contraceptive abruptly developed a nodular rash on the legs. She had taken minocycline 100 mg bd for the past 15 months for pustular acne. There were no cardiac, respiratory, gastrointestinal, musculoskeletal, or neurological symptoms. She had multiple,
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tender, subcutaneous nodular lesions, 0.5–2 cm in diameter throughout her lower legs. She was given a glucocorticoid and her skin lesions resolved for 1 week and then recurred with bilateral ankle pain, stiffness, and swelling. Perinuclear antineutrophilic cytoplasmic antibodies (pANCA) were positive (titre 1:256). A skin biopsy showed a necrotizing vasculitis of the small vessels in the dermis and panniculitis with vascular well neutrophilic infiltration, hyalinizing necrosis, and intravascular thrombi. She was given prednisolone 20 mg/day and minocycline was withdrawn. She responded well and 4 months later was free of lesions; the pANCA titer fell to 1:64.
The authors proposed that six of the following seven criteria should be fulfilled for a diagnosis of minocycline-induced polyarteritis nodosa: • minocycline use for more than 12 months; • skin manifestations, including livedo reticularis and/or subcutaneous nodules; • arthritis and/or myalgias and/or neuropathy in the distribution of the rash; • lack of systemic organ involvement; • a skin biopsy with necrotizing vasculitis of small and/or medium-sized vessels • positive pANCA; • improvement after withdrawal of minocycline. This report adds to the growing body of literature regarding drug-induced vasculitis, and, as usual, the mechanisms are not known. Endocrine A distinctive but rare adverse effect of minocycline is black pigmentation of the thyroid gland, of which about 30 cases have been described (66A ). It is generally harmless, but can occasionally cause harm (67A ). Based upon two cases, the authors reviewed 28 previous reports, of which 11 (39%) had been found to harbour papillary carcinoma, strongly suggesting an increased incidence of thyroid cancer in these pigmented glands. They referred to an old theory that the pigment is formed by oxidation of minocycline by the enzyme thyroid peroxidase (68R ). Minocycline is stable in the presence of thyroid peroxidase unless an iodide substrate is added, which accelerates both the oxidation of minocycline and the production of a reactive intermediate benzoquinone iminium ionized product. This process in turn produces competitive inhibition of the coupling of tyrosyl
250 residues with thyroglobulin, a necessary step in the production of thyroid hormone. Whatever the mechanism may be, the high incidence of associated papillary thyroid cancer mandates at a minimum that one ask about the use of minocycline in any patient who has an enlarged thyroid. The authors recommended that if a patient has taken minocycline in the past, biopsy and possibly removal of the thyroid gland is advisable.
GLYCYLCYCLINES Tigecycline Tetracyclines have been in use for more than 50 years, and in most species the levels of antibacterial resistance are high and still increasing. There is therefore a need for new derivatives. The glycylcyclines are semisynthetic analogues of earlier tetracyclines. The earliest glycylcyclines had a dimethyl-glycylamido group at the C-9 position of the basic tetracycline molecule. The structure-activity relations of the tetracyclines and glycylcyclines are discussed
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Tore Midtvedt
extensively elsewhere (69R ). The latest derivative is tigecycline, and now more than 120 references can be found in Medline. Its clinical status has recently been summarized (70R ). Its most interesting adverse effect is gastrointestinal disturbances. Gastrointestinal In a multicenter study (71R ) there was nausea in 22% of the patients who received a low dose of tigecycline (25 mg/day intravenously) and in 38% of those who received a high dose (50 mg/day intravenously). Vomiting occurred in 13% and 19% respectively. It was not stated whether the patients received antiemetics. It has also been found that gastrointestinal adverse effects are perceived to be more common with oral than with intravenous regimens (70R ). There was a similar high incidence of gastrointestinal disturbances in a phase I study (70R ). An interesting hypothesis is that tigecycline might cause the release of gastrointestinal serotonin, which then causes nausea and vomiting. However, whatever the mechanisms might be, it seems reasonable to assume that before tigecycline can be used clinically, the mechanisms behind these very common adverse effects have to be elucidated.
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to what extent? Antimicrob Agents Chemother 2005;49:3984–5. Mattei D, Rapezzi D, Mordini N, Cuda F, Nigro CL, Mussi M, Arnelli A, Cagnassi S, Gallamini A, Cligo J. False-positive Aspegillus fumigatus galactomannan enzyme-linked immunoabsorbent assay results in vivo during amoxicillin– clavulanic acid treatment. J Clin Microbiol 2004;42:5362–3. Metan G, Durusu M, Uzun O. False positivity for Aspergillus antigemia with amoxicillin– clavulanic acid. J Clin Microbiol 2005;43:2548– 9. Kesler A, Goldhammer Y, Hadayer A, Pianka P. The outcome of pseudotumor cerebri induced by tetracycline therapy. Arch Neurol Scand 2004;110:408–11. Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koistinaho J. Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci USA 1998;95:15769–74. Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistanaho J. A tetracycline derivate, minocycline, reduces inflammation and protect against focal cerebral ischemia with a wide therapeutic window. Proc Natl Soc Acad Sci USA 1999;96:13496–500. Johnston MV, Trescher WH, Ishida A, Nakajima W. Neurobiology of hypoxic–ischemic injury in the developing brain. Pediatr Res 2001;49:735–41. Wee Yong V, Wells J, Guakini F, Casha S, Power C, Metz LM. The promise of minocycline in neurology. Lancet 2004;3:744–51. Stirling DP, Koochesfahani KM, Steeves JD, Tetzlaff W. Minocycline as a neuroprotective agents. Neuroscientist 2005;11:308–22. Tsuji M, Wilson MA, Lange MS, Johnston MV. Minocycline worsens hypoxic–ischemic brain injury in a neonatal mouse model. Exp Neurol 2004;189:58–65. Diguet E, Gross CE, Tison F, Bezard E. Rise and fall of minocycline in neuroprotection: need to promote publication of negative results. Exp Neurol 2004;189:1–4. Fenske NA, Millns JL. Cutaneous pigmentation due to minocycline hydrochloride. J Am Acad Dermatol 1980;3:308–10. Gordon G, Sparano BM, Iatropolos MJ. Hyperpigmentation of the skin associated with minocycline therapy. Arch Dermatol 1985;121:619–23. Siller G, Tod M, Savage NV. Minocycline induced oral pigmentation. Am Acad Dermatol 1994;30:350–4. Angeloni VL, Salasche SJ, Ortiz R. Nail, skin and scleral pigmentation induced by minocycline. Cutis 1980;40:229–33. Messner E, Font RL, Sheldon G, Murphy D. Pigmented conjungtival cysts following tetracycline/minocycline therapy. Histochemical and
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57.
58. 59. 60. 61. 62.
63.
64. 65.
66. 67.
68. 69.
70.
71.
Tore Midtvedt
electron micrographic observations. Ophthalmology 1983;90:1442–8. Treister N, Magalnick D, Woo SB. Oral mucosal pigmentation secondary to minocycline therapy: report of two cases and a review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004;97:718–25. Patterson JW, Wilson B, Wick MR, Heath C. Hyperpigmented scar due to minocycline therapy. Cutis 2004;74:293–8. Rahman Z, Lazova R, Antaya RJ. Minocycline hyperpigemtaion isolated to the subcutaneous fat. J Cutan Pathol 2005;32:516–9. Narvaez J, Vilaseca-Momplet J. Severe acute myopathy induced by minocycline. Am J Med 2004;116:282–3. Schrodt BJ, Callen JP. Polyarteritis nodosa attributable to minocycline treatment for acne vulgaris. Pediatrics 1999;103:503–4. Schaffer JV, Davidson DM, McNiff JM, Bolognia JL. Perinuclear antineutrophilic cytoplasmatic antibody-positive cutaneous polyarteritis nodosa associated with minocycline therapy for acne vulgaris. J Am Acad Dermatol 2001;44:198–206. Pelletier F, Puzenat E, Blanc D, Faivre B, Humbert P, Aubin F. Minocycline-induced cutaneous polyarteritis nodosa with antineutrophilic cytoplasmatic antibodies. Eur J Dermatol 2003;13:396–8. Sakai H, Komatsu S, Matsuo S, Lizuka A. Two cases of minocycline-induced vasculitis. Arerugi (Jpn J Allergol) 2002;51:1153–8. Culver B, Itkin A, Pischel K. Case report and review of minocycline-induced cutaneous polyarteritis nodosa. Arthritis Rheum 2005;53:468– 70. Tsokos M, Schroder S. Black thyroid. Report of an autopsy case. Int J Legal Med 2005;3:1–3. Birkedal C, Tapscott WJ, Giadrosich K, Spence RK, Sperling D. Minocycline-induced black thyroid gland: medical curiosity or a marker for papillary cancer? Curr Surg 2001;58:471. Doerge DR, Divi RL, Deck J, Taurog A. Mechanism for the anti-thyroid action of minocycline. Chem Res Toxicol 1997;10:49–58. Zhanel GG, Homenuik K, Nichol K, Noreddin A, Vercaigne L, Embil J, Gin A, Karlowsky JA, Hoban DJ. The glycylcyclines: a comparative review with the tetracyclines. Drug 2004;64:63–88. Garrison MW, Neumiller JJ, Setter SM. Tigecycline. An investigational glycylcycline antimicrobial with activity against resistant Gram-positive organisms. Clin Ther 2005;27:12–22. Postier RG, Green SL, Klein SR, Ellis-Grosse EJ, Loh E. Tigecycline 200 study group: results of a multicenter, randomized, open-label efficacy and safety study of two doses of tigecycline for complicated skin and skin-structure infections in hospitalized patients. Clin Ther 2004;26:704–14.
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26
Miscellaneous antibacterial drugs
AMINOGLYCOSIDE ANTIBIOTICS (SED-15, 118; SEDA-26, 271; SEDA-27, 251; SEDA-28, 274) Sensory systems In 87 patients with tuberculosis or non-tuberculous mycobacterial infections randomized to receive intravenous streptomycin, kanamycin, or amikacin, 15 mg/kg/day or 25 mg/kg 3 times per week, the dose and the frequency of administration were not associated with the incidences of ototoxicity (hearing loss determined by audiography) or vestibular toxicity (determined by physical examination) (1c ). Ototoxicity, which occurred in 32 patients, was associated with older age and with a larger cumulative dose. Vestibular toxicity, which occurred in eight patients, usually resolved. Subjective changes in hearing or balance did not correlate with objective findings. Urinary tract In the study mentioned above, the dose and the frequency of administration were not associated with nephrotoxicity (determined by raised serum creatinine concentrations), which occurred in 13 patients and was mild and reversible in all cases. In a meta-analysis of randomized, controlled trials in children there was a significantly worse outcome in secondary nephrotoxicity with multiple daily doses of aminoglycosides (16%, 11 of 69 cases) versus once-daily dosing (4.4%, 3 of 69 cases) (2M ). There were no statistical significant differences in the outcomes of primary nephrotoxicity. The role of megalin, a giant endocytic receptor abundantly expressed at the apical memSide Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29026-3 © 2007 Elsevier B.V. All rights reserved.
brane of renal proximal tubules, has been discussed as an important factor in the binding and endocytosis of aminoglycosides in proximal tubular cells (3R ). The authors suggested that inhibition of the uptake process is the most promising approach to prevent aminoglycosideinduced nephrotoxicity.
Amikacin
(SED-15, 111)
Sensory systems In a guinea-pig model the non-ototoxic dose of amikacin (20 mg/kg/day) administered before the ototoxic dose (400 mg/ kg/day) had a statistically significant protective effect on the basal turns of the cochlea, observed histologically (4E ). Drug interactions Thalidomide may potentiate the nephrotoxicity of aminoglycosides. Three patients with refractory multiple myeloma taking thalidomide developed severe renal insufficiency shortly after starting to take amikacin for concurrent infections (5A ).
Gentamicin
(SED-15, 1500)
Sensory systems In guinea-pigs treated with gentamicin (100 mg/kg/day intramuscularly) alone or gentamicin (100 mg/kg/day intramuscularly) plus alpha-tocopherol (100 mg/kg/day intramuscularly) for 2 weeks, both hearing loss and vestibular dysfunction induced by gentamicin were significantly attenuated by alpha-tocopherol (6E ). Gentamicin can induce sclerochorioretinal necrosis after subconjunctival injection (7A ).
253
254
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Death In a randomized trial in infants with Gram-negative meningitis and ventriculitis, the use of intraventricular antibiotics in addition to intravenous antibiotics resulted in a three-fold increased relative risk of death compared with standard treatment with intravenous antibiotics alone (8R ). The authors speculated that the increased case-fatality rate in those who were given intraventricular antibiotics could have been related to the procedure or to a direct toxic effect of gentamicin.
Alexander Imhof and Reto Laffer
CHLORAMPHENICOL AND RELATED DRUGS (SED-15, 706; SEDA-26, 273; SEDA-26, 274; SEDA-26, 276)
Chloramphenicol
(SED-15, 706)
The pharmacokinetics of chloramphenicol in children have been reviewed (14R ).
Management of adverse drug reactions In animals there was biochemical and histopathological evidence that chelerythrine, a commonly used protein kinase C inhibitor, reduced gentamicin-induced kidney damage (10E ).
Drug interactions Drug interactions with chloramphenicol have been reviewed (14R , 15R ). Concurrent use of rifampicin or phenobarbital, both inducers of hepatic microsomal enzymes, can reduce serum concentrations of chloramphenicol. Concomitant administration of phenytoin can cause accumulation of chloramphenicol in serum to toxic concentrations; toxic concentrations of phenytoin also have been reported. Other drugs that are metabolized in the liver, such as paracetamol, isoniazid, and theophylline, can have similar effects.
Streptomycin
FLUOROQUINOLONES
Drug interactions In animals the combination of COX-2-selective inhibitors with gentamicin posed no additional risk of nephrotoxic renal insufficiency (9E ).
Skin Streptomycin can cause toxic epidermal necrolysis. • A 55-year-old woman with tuberculosis developed toxic epidermal necrolysis after receiving oncedaily streptomycin 1000 mg intramuscularly in addition to standard oral antituberculosis chemotherapy (11A ).
Tobramycin
(SED-15, 3437)
Observational studies In an open, randomized, parallel-group, multicenter study with 184 young people with cystic fibrosis treated with inhaled tobramycin, no adverse events were reported (12C ). Placebo-controlled studies In a double-blind, placebo-controlled, study in 30 patients with bronchiectasis, inhaled tobramycin solution (300 mg bd) was associated with bronchospasm in three, but not with detectable ototoxicity or nephrotoxicity (13C ).
(SED-15, 1396; SEDA-26, 274; SEDA-27, 254; SEDA-28, 276) Nervous system Central nervous system adverse reactions can be important complications during quinolone therapy (16R ). Mild reactions include headache, dizziness, insomnia, visual changes, and bad dreams. Severe reactions include seizures, psychotic reactions, hallucinations, and depression. Fortunately, all of these events are rare (under 0.5%). The mechanisms are unknown. Gastrointestinal The most common systemic adverse effects of the fluoroquinolones involve the gastrointestinal tract, including nausea, vomiting, abdominal pain, and diarrhea (16R ). Skin The incidence of cutaneous hypersensitivity reactions (erythema, pruritus, urticaria, rash) with quinolones is low (0.4–2.2%) (16R ). An important adverse reaction is phototoxicity from UVA (320–400 nm), ranging from mild erythema to severe bullous eruptions. Phototoxicity is the result of the formation of singlet oxygen and free radicals and has been observed
Miscellaneous antibacterial drugs
Chapter 26
with all drugs in this class. Other skin reactions include acne, angioedema, erythema multiforme, erythroderma, exanthems, fixed drug eruption, Steven–Johnson syndrome, and toxic epidermal necrolysis. Musculoskeletal The quinolones are toxic to immature cartilage and also affect the epiphyseal growth plate. The mechanism of cartilage toxicity is chelation and depletion of magnesium in chondrocytes (17E ). Tendonitis and tendon rupture are rare but serious adverse effects of quinolones (16R ). In the Achilles tendon it starts with swelling and inflammation of the tendon followed by pain. In 50% of cases, the tendonitis is bilateral. If this serious complication is not recognized and treated, tendon rupture can occur. Perfloxacin, which is marketed in Europe, is most often the culprit. The onset is at 1–152 days. Tendon rupture has been observed as late as 120 days after treatment.
Ciprofloxacin
(SED-15, 783)
Observational studies In a post-marketing surveillance study in 3859 hospitalized patients with urinary tract infections, 136 (3.5%) had 181 adverse events; 106 of them (2.8%) had 138 adverse events that were possibly or probably related to ciprofloxacin (18C ). The most frequent adverse events that were considered drugrelated were diarrhea (1.7%), rash (0.3%), nausea (0.2%), allergic reactions (0.2%), pruritus (0.2%), vomiting (0.1%), and abnormal tests of liver function (0.1%). There were severe adverse events in 26 patients (0.7%). Cardiovascular Ciprofloxacin can cause prolongation of the QT interval and rarely torsade de pointes (19R ). • Cardiac arrest temporally related to ciprofloxacin occurred in two women (aged 44 and 67 years) when they developed marked QTc interval prolongation (590 and 680 ms) within 24 hours of ciprofloxacin administration, with recurrent syncope and documented torsade de pointes requiring defibrillation (20A ). The QTc interval normalized after withdrawal of ciprofloxacin. • A 76-year-old man with acute on chronic renal insufficiency, developed torsade de pointes in combination with hypocalcemia, triggered by hemodialysis (21A ). The QT interval prolongation was corrected by treating the hypocalcemia.
255 Respiratory Ciprofloxacin can cause interstitial pneumonitis with acute respiratory failure. • A 68-year-old woman developed severe respiratory failure six days after taking ciprofloxacin. C-reactive protein rose she had an intermittent high fever, dyspnea, and severe hypoxemia (22A ). Bronchoalveolar lavage was consistent with hypersensitivity pneumonitis. Her symptoms rapidly improved with systemic glucocorticoid therapy.
Nervous system Ciprofloxacin can cause propriospinal myoclonus by inhibiting gammaaminobutyric acid metabolism (23r ). Liver There is increasing evidence that ciprofloxacin can cause severe liver damage, and 14 cases have been reported. • A 22-year-old man took ciprofloxacin 500 mg/day and developed acute liver failure 14 days later (24A ). Liver biopsy showed extensive hepatocellular necrosis. His symptoms resolved after glucocorticoid therapy.
Skin Toxic epidermal necrolysis is a rare but serious adverse effect of ciprofloxacin. • A 93-year-old lady died after developing extensive skin lesions following treatment with ciprofloxacin (25A ).
Musculoskeletal Ciprofloxacin chelates magnesium, with a resulting 60% reduction in fibroblast activity. This is important in all enzymatic reactions involved in the production of type-1 collagen, which is the main component of tendons. • A 35-year-old postal worker who had previously taken ciprofloxacin 1.5 g/day for about 10 days because of concerns about a possible anthrax bacillus infection while working in the post office had a tendon rupture (26A ).
Immunologic Ciprofloxacin has been associated with leukocytoclastic vasculitis and other types of necrotizing vasculitis (16R ). Drug interactions Reports of possible drug– drug interactions between ciprofloxacin and glibenclamide suggest that this interaction is a class effect of the fluoroquinolones. • A man with diabetes taking glibenclamide was given ciprofloxacin and developed prolonged hypoglycemia, which persisted for over 24 hours (27A ).
256
Garenoxacin
Chapter 26
(SED-15, 1482)
Lactation Excretion of garenfloxacin into breast milk has been studied in six lactating women taking garenoxacin 600 mg/day (28c ). Garenoxacin exposure in breast milk was minimal—a mean of 0.07% of the administered dose was recovered within 120 hours. Garenoxacin was undetectable in the breast milk of most subjects within 84 hours of dosing. A nursing infant whose mother had taken a single oral dose of garenoxacin 600 mg would theoretically be exposed to 0.42 mg of garenoxacin (0.105 mg/kg/day for a 4-kg infant over 5 days of nursing). If extrapolated to a 14-day course of garenoxacin 600 mg/day, total exposure would be about 5.88 mg.
Gatifloxacin
(SED-15, 1482)
Comparative studies In a double-blind, randomized study in 102 adult women who took either gatifloxacin 400 mg as a single dose or 200 mg/day for 3 days or ciprofloxacin 250 mg bd for 3 days, the frequencies of treatmentrelated adverse events were 17%, 19%, and 14% respectively (29C ). The most common adverse effects were nausea (4.6%, 5.4%, and 5.0%), headache (1.9%, 1.9%, and 1.4%), dizziness (2.2%, 1.3%, and 1.4%), and diarrhea (1.1%, <1%, and 1.4%). Cardiovascular Fluoroquinolones cause prolongation of the QT interval and can cause torsade de pointes. • A 95-year-old woman took gatifloxacin and developed recurrent episodes of torsade de pointes on the 4th day of treatment and one hour after infusion (30A ).
Sensory systems Gatifloxacin can cause intrastromal macroscopic crystalline deposits through a compromised corneal epithelium. • An 85-year-old man developed faint crystal-like white precipitates in the mid-peripheral stroma of his left cornea 3 weeks after starting to use 0.3% gatifloxacin eye-drops (31A ).
Alexander Imhof and Reto Laffer
Endocrine Gatifloxacin can cause either hyperglycemia or hypoglycemia. Hyperglycemia was reported in three patients taking gatifloxacin (200 mg/day) and hypoglycemia in one patient (32A –34A ). The mechanism of hypoglycemia, shown in vitro, is increased insulin secretion by inhibition of pancreatic beta-cell KATP channels (35E ).
Gemifloxacin
(SED-15, 1487)
Cardiovascular In 16 trials worldwide, gemifloxacin has been reported to produce small, non-significant QT interval prolongation (36R ). Gastrointestinal The most frequently reported adverse events in clinical trials of gemifloxacin were diarrhea and nausea (36R ). In one study, the rate of diarrhea was 4.1% compared with 6.4% with the comparator; nausea was the second most frequent adverse event. However, no patients withdrew because of diarrhea and nausea. Liver Mild reversible rises in liver enzymes have been reported in 4.1% of patients taking gemifloxacin (36R ). Skin Gemifloxacin’s potential to cause mild phototoxicity appears similar to that of ciprofloxacin. The abnormal responses occur within the ultraviolet A region (335–365 nm) and clear 48 hours after withdrawal (36R , 37R ). The risk of skin rash (about 2.8%) is greater in women aged over 40 years and those who take gemifloxacin for more than 7 days. Drug interactions Drug interactions with gemifloxacin have been reviewed (36R ). Gemifloxacin has lower systemic availability if it is co-administered with multivalent cations, such as aluminium, magnesium, or iron salts. In one study, gemifloxacin systemic availability was reduced by 85% if it was taken 10 minutes before Maalox (which contains aluminium hydroxide, magnesium hydroxide, and simethicone), but did not change if taken 2 hours before or 3 hours after. Sucralfate reduced gemifloxacin’s systemic availability by as much as 53% when the fluoroquinolone was taken 3 hours after sucralfate; however,
Miscellaneous antibacterial drugs
gemifloxacin systemic availability did not significantly change if it was administered 2 hours before sucralfate. Ferrous sulfate did not clinically significantly alter the systemic availability or maximum plasma concentration of gemifloxacin if the agents were taken 2 hours apart. Food–drug interactions In healthy men and women a high-fat meal slightly reduced gemifloxacin AUC (by 3%) and Cmax (by 12%) and caused a slight delay in tmax of 0.75 and 0.21 hours after doses of 320 and 640 mg respectively (36R ). These changes were not clinically significant.
Grepafloxacin
(SED-15, 1559)
Cardiovascular Grepafloxacin has been removed from the US market because of deaths as a result of torsade de pointes (38r ).
Levofloxacin Cardiovascular sade de pointes.
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(SED-15, 2047) Levofloxacin can cause tor-
• A 65-year-old woman had torsade de pointes after receiving levofloxacin 250 mg/day intravenously for 3 days (38A ).
Musculoskeletal Tendinopathy is a classrelated adverse effect of the fluoroquinolones, with old age, and renal dysfunction as susceptibility factors; several new cases have been reported (42A –46A ). Immunologic Although hypersensitivity reactions to quinolones are well known, levofloxacin has rarely been incriminated. Four patients developed presumed hypersensitivity reactions to levofloxacin (47A ), including a 31-year-old man with a type I immunological mechanism, who developed an itching micropapular exanthema, facial and scrotal edema, and generalized erythema 30 minutes after an oral dose of levofloxacin 500 mg. Sensitivity to levofloxacin was confirmed by a positive skin prick test.
Moxifloxacin
(SED-15, 2392)
Observational studies In a surveillance study in 18 374 patients taking moxifloxacin 400 mg/ day for either 5 or 10 days, 18% had adverse events drug-related is 14% (48C ). Subgroup analyses of this study have also been published (49R , 50C , 51R ). The most common drugrelated adverse events were nausea (5.3%), diarrhea (2.2%), and dizziness (2.0%). There was no clinical evidence of increased risk of cardiac dysrhythmias with moxifloxacin treatment.
Metabolism Hypoglycemia has uncommonly been reported with levofloxacin and appears to occur most often in elderly patients with type 2 diabetes mellitus who are taking oral hypoglycemics. A new case has been reported (39A ).
Metabolism In a pooled analysis of 30 (26 controlled, 4 uncontrolled) prospective, phase II/III studies of oral or intravenous moxifloxacin in 8474 subjects no drug-related hypoglycemic events were reported (52M ).
Hematologic Levofloxacin can cause coagulopathies. Three patients who took oral levofloxacin 500 mg/day for 3 days for urinary tract infections developed prolonged prothrombin times (40A ). One later developed acquired von Willebrand’s syndrome during surgery. The coagulopathies were successfully corrected preoperatively with parenteral vitamin K. The patient with acquired von Willebrand syndrome required multiple transfusions.
Gastrointestinal In a double-blind, parallelgroup, randomized, multicenter study, 349 adults with acute bacterial rhinosinusitis were randomized to oral telithromycin (800 mg/day for 5 days) or oral moxifloxacin (400 mg/day for 10 days); 28% of those who took moxifloxacin had one or more treatment-related adverse events, most of which were mild to moderate, and there was one or more severe adverse event in 2.3% (53C ). The most commonly reported adverse effects assessed, in 2% or more of the population, were diarrhea (1.7%) and nausea (4.5%). There was withdrawal in 3.4%.
• A 70-year-old woman developed pseudothrombocytopenia after taking levofloxacin and ceftriaxone for acute bronchitis (41A ).
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Musculoskeletal In a double-blind, parallelgroup, randomized, multicenter study, 349 adults with acute bacterial rhinosinusitis were randomized to oral telithromycin (800 mg/day for 5 days) or oral moxifloxacin (400 mg/day for 10 days) (53C ). One patient who took moxifloxacin withdrew because of acute Achilles tendonitis.
• A 66-year-old man with advanced prostate adenocarcinoma took norfloxacin 400 mg bd and developed a fever, myalgias, and a skin eruption consisting of painful red papules, with confluent plaques and some vesicles, affecting the palms, feet, and lumbar region (53A ). After withdrawal of norfloxacin and glucocorticoid therapy he rapidly improved and the skin lesions resolved after one week.
• A 65-year-old woman developed tendinitis at the insertion of the musculus brachioradialis tendon after taking oral moxifloxacin 400 mg/day for 2 day (54A ). Despite immediate withdrawal, immobilization of the arm, and local anti-inflammatory treatment, complete clinical resolution took 5 weeks.
Ofloxacin
Immunologic Hypersensitivity reactions can occur with moxifloxacin. • A 23-year-old woman developed a moxifloxacinassociated drug hypersensitivity syndrome associated with toxic epidermal necrolysis and fulminant fatal hepatic failure (55A ). She had no known drug allergies or prior treatment with fluoroquinolones. After 3 days she developed nausea, vomiting, and abdominal pain, and a morbilliform eruption localized to her abdomen. Moxifloxacin was withdrawn. She had increased liver enzymes, fever, and lymphadenopathy. She was given high-dose intravenous immunoglobulin 1 g/kg/day for 3 days. However, she required intubation for respiratory support, multipressor therapy for worsening hypotension, and continuous venovenous hemofiltration for acute renal insufficiency. A liver biopsy showed acute hepatitis with hepatocyte necrosis, consistent with a drug reaction or infectious process. Her hepatic function deteriorated further, and despite an orthotopic liver transplant she died 14 days after the start of treatment with moxifloxacin.
Drug interactions In a pooled analysis of 30 (26 controlled, 4 uncontrolled) prospective, phase II/III moxifloxacin studies in 8474 subjects, co-administration of oral antidiabetic drugs did not change the rate of blood glucose increases or decreases in patients with diabetes (52M ). In five moxifloxacin postmarketing studies (46 130 subjects) there were no episodes of hypoglycemia and two non-drugrelated episodes.
(SED-15, 2597)
Nervous system Orofacial dyskinesia with other fluoroquinolones has been rarely reported. However, ofloxacin-induced orofacial dyskinesia has been reported after treatment with ofloxacin 400 mg/day for 3 days in a 43-yearold man (56A ). Musculoskeletal A 19-year-old man who took ofloxacin 800 mg/day for 3 days developed rhabdomyolysis (57A ).
Pazufloxacin
(SED-15, 2726)
Cardiovascular Pazufloxacin 3–30 mg/kg intravenously had a low potential for QT interval prolongation in an animal model (58E ).
Pefloxacin
(SED-15, 2727)
Drug interactions In five healthy volunteers who took a single dose of rifampicin 600 mg plus pefloxacin 500 mg, the excretion rate of rifampicin significantly increased after pefloxacin co-administration. Competition between rifampicin and pefloxacin for liver clearance favors pefloxacin and increases the tubular secretion of rifampicin in the kidney (59c ).
Prulifloxacin Norfloxacin
(SED-15, 2583)
Skin Acute febrile neutrophilic dermatosis (Sweet’s syndrome) is uncommon and rarely related to antibiotic treatment.
Prulifloxacin has been reviewed (60R ). After absorption, it is metabolized by esterases to ulifloxacin. It has a long half-life, allowing once-daily administration. In well-designed trials, prulifloxacin 600 mg/day for 10 days had
Miscellaneous antibacterial drugs
good clinical and bacteriological efficacy in patients with acute exacerbations of chronic bronchitis or complicated lower urinary tract infections. Cardiovascular In vitro and in vivo studies have suggested that the QT interval is unlikely to be prolonged by prulifloxacin (60R ). Gastrointestinal The most common adverse effect of prulifloxacin in several clinical trials was mild or moderate gastric pain (60R ). Drug interactions Systemic exposure to theophylline is increased when it is co-administered with prulifloxacin. The absorption of oral prulifloxacin was reduced when cimetidine, antacids containing aluminium, magnesium, or calcium, or iron supplements were co-administered, or administered up to 3 hours before or up to 2 hours after prulifloxacin (60R ).
Rufloxacin In an in vitro study of biofilm formation in Stenotrophomonas maltophilia, rufloxacin had the highest activity on preformed biofilm viability with significantly decreasing viable counts (61E ).
Sparfloxacin
259
Chapter 26
(SED-15, 3172)
Cardiovascular Sparfloxacin can cause prolongation of the QT interval, and care should therefore be taken when it is co-prescribed with other drugs that prolong the QT interval (16R ). Sensory systems Sparfloxacin can be deposited in the corneae, but there is no effect on eyesight (62r ). Gastrointestinal In 16 patients with pulmonary tuberculosis who were treated with sparfloxacin 200 mg/day with isoniazid and para-aminosalicylic acid, one withdrew because of severe gastrointestinal intolerance (63c ).
Tosufloxacin
(SED-15, 3468)
Immunologic Fluoroquinolones can cause acute renal insufficiency because of interstitial nephritis with or without epithelioid granulomas. • A 63-year-old Japanese developed slowly progressive renal insufficiency caused by crystal-forming chronic interstitial nephritis with non-Langerhans’ cell histiocytosis after exposure for 4 years to tosufloxacin tosilate 300 mg/day (64A ).
FUSIDIC ACID
(SED-15, 1460; SEDA-26, 281; SEDA-27, 259; SEDA-28, 280) The major adverse effects of fusidic acid are mild gastrointestinal discomfort and diarrhea (65R ). Hematologic There have been six reports of fusidic acid-induced sideroblastic anemia after treatment with fusidic acid for 32–190 (mean 81) days; four required repeated blood transfusions (66r ). After fusidic acid withdrawal in five patients, there was complete recovery. In one patient, rechallenge with fusidic acid resulted in recurrence of anemia and resolution resolved after definitive withdrawal. Drug dosage regimens In a multicenter, randomized, double-blind, parallel-group comparison of a new regimen of fusidic acid suspension (10 mg/kg bd) against a standard regimen (17 mg/kg tds) in 213 children with skin and soft tissue infections, adverse drug reactions were significantly less common with the new twice-daily regimen (67C ). This was because of a significantly higher incidence of gastrointestinal reactions with the higher dose. Adverse drug reactions caused or contributed to treatment withdrawal in three children given twice-daily doses and in 12 children given thrice-daily doses, and were the primary reasons for stopping treatment in one and in eight children respectively.
260
GLYCOPEPTIDES
(SEDA-26, 281; SEDA-27, 259; SEDA-28, 280)
Dalbavancin Dalbavancin (BI 397) is a semi-synthetic derivative of A40926, a glycopeptide with a structure related to that of teicoplanin (68R , 69R ). Dalbavancin is more active against Streptococcus pneumoniae than conventional glycopeptides are, and its activity against Staphylococcus aureus is also substantially better. However, it is not more active than teicoplanin against enterococci harboring the VanA phenotype of resistance to glycopeptides. Dalbavancin is also characterized by a marked bactericidal character and synergism with penicillin. Drug dosage regimens Dalbavancin has such a long half-life that its plasma concentration exceeds the minimal bactericidal concentrations (MICs) of target organisms even at 1 week after administration of a single dose of 1000 mg; however, free concentrations are close to the MICs. Dalbavancin is therefore currently being evaluated in a once-a-week dosage regimen. Pilot phase II trials have shown excellent clinical efficacy (over 90%) in patients who receive dalbavancin 1000 mg on day 1 and 500 mg on day 8 for skin and soft tissue infections or catheter-related bloodstream infections by Gram-positive organisms (68R , 70C ).
Chapter 26
Alexander Imhof and Reto Laffer
magnitude, the difference in their activity has been attributed to cooperative interactions that can occur between the drug and both types of precursors in situ (68R ). Oritavancin has a long half-life (195 hours), allowing once-a-day administration. Studies on cultured macrophages show that it accumulates slowly (by an endocytic process) in lysosomes, from which its efflux is extremely slow. This explains why it is bactericidal against intracellular forms of staphylococci or enterococci, but not against cytosolic bacteria, such as Listeria monocytogenes. In healthy volunteers oritavancin reached high concentrations not only in epithelial lining fluid but also in alveolar macrophages (68R ). Observational studies In a single-dose, open, non-controlled, dose-escalation study in 11 healthy subjects oritavancin was infused intravenously over 1 hour in doses of 0.02– 0.325 mg/kg; four subjects each received a single dose of 0.5 mg/kg (71c ). The pharmacokinetics of oritavancin were linear. Renal clearance was 0.457 ml/minute, and less than 5% and 1% of administered drug were recovered in the urine and feces respectively after 7 days. Liver In five of 11 healthy subjects there were asymptomatic and transient rises in hepatic transaminase activities in a dose-escalation study (71c ).
Oritavancin
Teicoplanin
Oritavancin (LY333328) is a novel glycopeptide antimicrobial agent that was obtained by reductive alkylation with 4 -chloro-biphenylcarboxaldehyde of the natural glycopeptide chloroeremomycin, which differs from vancomycin by the addition of a 4-epi-vancosamine sugar and the replacement of the vancosamine by a 4-epi-vancosamine. Although oritavancin has a general spectrum of activity comparable to that of vancomycin, it offers considerable advantages in terms of intrinsic activity (especially against streptococci), and is insensitive to resistance mechanisms in staphylococci and enterococci. Because the binding affinities of vancomycin and oritavancin to free D-Ala-DAla and D-Ala-D-Lac are of the same order of
Sensory systems There is no strong evidence of ototoxicity of teicoplanin, possibly because of conservative definitions of ototoxicity. The hearing thresholds of 12 patients who were treated with teicoplanin for severe staphylococcal infections increased slightly but significantly over time (72c ).
(SED-15, 3305)
Hematologic In a randomized, controlled, open, multicenter study in 430 patients with suspected or proven Gram-positive infections linezolid 600 mg every 12 hours was compared with teicoplanin (dose unspecified) for up to 28 days. Three patients who received teicoplanin had hematological adverse effects rated as moderate or severe (hemolysis, anemia, leukopenia,
Miscellaneous antibacterial drugs
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and thrombocytopenia) (73C ). A 68-year-old man developed hemolytic anemia after taking teicoplanin (74A ).
The mechanism of neutropenia caused by vancomycin is unclear, but it appears to be immune-mediated (77A , 78A , 79r ).
Immunologic Drug hypersensitivity syndrome is characterized by a generalized skin eruption, fever, lymphadenopathy, eosinophilia, and visceral involvement.
Skin Linear immunoglobulin A bullous disease is a subepidermal blistering disorder, which can be caused by vancomycin (80r ), as in a 77year-old man (81A ).
• A 47-year-old man developed drug hypersensitivity syndrome 2 hours after the final dose of teicoplanin (75A ). He developed a fever of 38.5 ◦ C, generalized lymphadenopathy, and a raised C reactive protein concentration and hepatic transaminases. Teicoplanin was withdrawn and within 24 hours his fever resolved. Over the following week his liver enzymes, C reactive protein concentration, and skin returned to normal.
Vancomycin
(SED-15, 3593)
Observational studies In a randomized, controlled, open study in 44 patients with osteomyelitis treated with vancomycin, either by intermittent infusion (20 mg/kg over 60 minutes every 12 hours) or continuous infusion (40 mg/kg infused over 24 hours), serum creatinine concentration increased significantly by a mean of 0.4 µmol/l/day with intermittent infusion compared with continuous infusion (76C ). Adverse drug reactions leading to termination of vancomycin therapy were significantly more frequent with intermittent infusion (n = 9) compared with continuous infusion (n = 2). Adverse drug reactions with intermittent infusion were acute renal damage (n = 4) and allergic reactions (n = 2). One patient each had severe neutropenia, catheter phlebitis, and severe depression. With continuous infusion two patients developed catheter phlebitis. With intermittent infusion 57% of the patients were without an adverse drug reaction at week 6, compared with 95% of patients given continuous infusion. Hematologic Vancomycin can rarely cause reversible neutropenia and thrombocytopenia (77A ). • A 64-year-old man who was treated with intravenous vancomycin 1.5 g/day for finger osteomyelitis developed neutropenia after 21 days. The absolute neutrophil count reached a nadir of 418 × 106 /l during vancomycin use and returned to normal 7 days after withdrawal.
• A 48-year-old woman developed linear immunoglobulin A bullous disease while taking vancomycin and was rechallenged 4 years later with five doses over 5 days (82A ). On day 1 she received 10 mg and this was increased to 1000 mg on day 5. She had no recurrence.
Fixed drug eruption is an infrequent adverse effect of vancomycin. • A 14-year-old African American boy developed a fixed drug eruption involving an extensive area of the body surface on the fourth day of treatment with vancomycin (83A ).
Immunologic A burned child treated with vancomycin developed an anaphylactic reaction (84A ). Susceptibility factors Age The pharmacokinetics of vancomycin in neonates is mainly determined by postconceptional age and renal function (85R ). In neonates, a patent ductus arteriosus and treatment with indometacin or extracorporeal membrane oxygenation leads to an increased volume of distribution and a reduced clearance. Vancomycin-related nephrotoxicity and ototoxicity in neonates is rare, and there is no clear relation to serum concentrations. Recent guidelines have suggested that dosage can be independent of gestational age or postconceptional age in neonates without renal insufficiency (85R ). Renal disease In patients with renal insufficiency, therapy can be adequately tailored by using a regimen based on serum creatinine. The usefulness of routine monitoring of peak serum concentrations is doubtful, based on current literature. Recent research shows a shift to taking only routine trough serum concentrations in order to optimize efficacy.
262 Drug overdose Two premature infants received 10-fold overdoses of vancomycin, with resulting peak plasma concentrations over 300 µg/ml (86A ). Vancomycin was withdrawn and the plasma vancomycin concentration fell to below 40 µg/ml at under 48 hours in one infant and under 72 hours in the other. Although one infant had a transient increase in serum creatinine neither had further evidence of renal, auditory, or other toxicity acutely or in the long term.
KETOLIDES
(SED-15, 1976; SEDA-26, 283; SEDA-27, 260; SEDA-28, 281) The most common adverse effects of telithromycin are diarrhea and nausea (11% and 7.9% of 2702 patients in clinical trials); these events occurred in 8.6% and 4.6% of 2139 comparatortreated patients (87R –89R ).
Cardiovascular Telithromycin can cause torsade de pointes (19R ). Sensory systems In a prospective, doubleblind, parallel-group, randomized, multicenter study, 349 adults with acute bacterial rhinosinusitis were randomized to oral telithromycin 800 mg/day for 5 days or oral moxifloxacin 400 mg/day for 10 days; blurred vision was a clinically significant adverse event in three patients taking telithromycin (53C ). Gastrointestinal In a randomized study of a 5-day or 7-day regimen of oral telithromycin 800 mg/day and a 10-day regimen of oral clarithromycin 500 mg bd in 575 randomized patients, 257 patients (45%) had at least one adverse effect (90C ). The most common adverse events were gastrointestinal (diarrhea, nausea, and dysgeusia). With telithromycin, all cases of diarrhea, nausea, and dysgeusia were mild or moderate in intensity and none was severe or categorized as serious. Two cases of diarrhea— one in each telithromycin group—resulted in withdrawal. In another double-blind, parallel-group, randomized, multicenter study, 349 adults with acute bacterial rhinosinusitis were randomized to oral telithromycin 800 mg/day for 5 days or oral moxifloxacin 400 mg/day for 10 days,
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Alexander Imhof and Reto Laffer
35% of the patients who received telithromycin had one or more adverse effect; most were mild to moderate in intensity (53C ). There was at least one severe adverse event in 5.2% and 2.3% of patients treated with telithromycin and moxifloxacin respectively. The most commonly reported adverse events that were assessed as being possibly related to the drug were diarrhea (8.1%) and nausea (5.8%). The drugs had to be withdrawn in 2.9% of patients because of adverse events. Urinary tract Telithromycin-induced severe acute interstitial nephritis has been reported (91A ). • An 18-year-old man received telithromycin 800 mg/day and after 3 days his serum creatinine concentration was 140 µmol/l. There was no rash or lymphadenopathy. Urinalysis showed aseptic leukocyturia, proteinuria, and glycosuria. One week later, the serum creatinine level rose to 407 µmol/l. A percutaneous renal biopsy showed severe interstitial edema, marked diffuse infiltration with lymphocytes, and some eosinophils. The glomeruli were normal. He was treated with pulse methylprednisolone 500 mg/day for 3 days followed by oral methylprednisolone 32 mg/day, and within 2 weeks the serum creatinine concentration fell to 80 µmol/l.
Drug interactions Telithromycin is a substrate of CYP3A4 and has been reported to interact with verapamil (92A ). • A 76-year-old white woman taking verapamil 180 mg/day for hypertension was given telithromycin 800 mg/day for 2 days and suddenly developed shortness of breath and weakness and was profoundly hypotensive and bradycardic, with a systolic blood pressure of 50–60 mm Hg and a heart rate of 30/minute. Telithromycin was withdrawn and within 72 hours her blood pressure and heart rate returned to normal.
Telithromycin can interact with warfarin, resulting in a raised international normalized ratio (INR). • A 73-year-old white man taking warfarin developed a raised INR and mild hemoptysis 5 days after he started to take telithromycin 800 mg/day (93A ).
Susceptibility factors Renal disease The pharmacokinetic profiles of single and repeated oral doses of telithromycin 800 mg/day were comparable in patients with mild to moderate renal impairment and
Miscellaneous antibacterial drugs
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healthy subjects (94C ). However, in patients with severe renal impairment dosage adjustment should be considered.
263 QT interval prolongation and risk of torsade de pointes (19R ). Macrolides with at least one published report of torsade de pointes include azithromycin, clarithromycin, erythromycin, roxithromycin, spiramycin, and troleandomycin.
LINCOSAMIDES
(SED-15, 2063; SEDA-26, 283; SEDA-27, 260; SEDA-28, 281)
Clindamycin Gastrointestinal Clindamycin can cause esophageal ulceration (95A ). Skin In 300 subjects with acne in a multicenter, randomized, investigator-blinded comparison of adapalene gel 0.1% plus clindamycin topical solution 1% versus clindamycin topical solution 1% alone, nine subjects (four in the combination group and five in the monotherapy group) had 19 local adverse events, mostly erythema (n = 8) followed by scaling (n = 3), burning (n = 3), pruritus (n = 2), and stinging, papules, and pustules (n = 1 each) (96C ). Seven patients withdrew from the study during the initial treatment phase owing to local adverse events; all had erythema in combination with burning, scaling, pruritus, or papules and pustules, five in the monotherapy group and two in the combination group. Respiratory The benzyl alcohol component of clindamycin injection can cause “gasping syndrome” in premature neonates. • A baby boy born at 24 weeks gestation weighing 710 g was given intravenous clindamycin (97A ). The first two doses were given without problem, but after the third and fourth doses he had profound desaturation and chest splinting, requiring resuscitation. The clindamycin was withdrawn and he had no obvious sequelae.
MACROLIDE ANTIBIOTICS (SED-15, 2183; SEDA-26, 284; SEDA-27, 261; SEDA-28, 282) Cardiovascular Of the currently available antimicrobial classes, the macrolides appear to be associated with the greatest degree of
Sensory systems The bitterness of 18 different antibiotic and antiviral drug formulations was evaluated using an artificial taste sensor (98E ). Seven of the formulations had a bitterness intensity exceeding 1.0 in gustatory sensation tests and were therefore assumed to have an unpleasant taste to children. In the case of three macrolide antibiotic formulations containing erythromycin, clarithromycin, and azithromycin, the bitterness intensities of suspensions in acidic sports drinks were much higher than the corresponding scores of suspensions in water. Immunologic Macrolide antibiotics are known for their efficacy in treating acute airway infections, but just as importantly, they are also effective anti-inflammatory agents. Their antiinflammatory properties have been studied most thoroughly in chronic inflammatory airway diseases, particularly diffuse panbronchiolitis. Erythromycin, azithromycin, clarithromycin, and roxithromycin inhibit chemotaxis and infiltration of neutrophils into the airway and, subsequently, decrease mucus secretion. Mucus formation, a significant cause of morbidity and mortality in patients with chronic airway inflammation, is directly inhibited by macrolides and suppressed by decreased inflammation in the airway. Macrolides also inhibit formation of leukotriene B4, which attracts neutrophils, and inhibit the release of superoxide anion by neutrophils that may be present in the airway. An important aspect of inflammation is extravasation of neutrophils into the tissues. Macrolides block formation of adhesion molecules necessary for neutrophil migration. Together, these anti-inflammatory effects result in improved pulmonary functions and fewer airway infections (99R –102R ), and for this reason the macrolides are sometimes used after lung transplantation. Susceptibility factors In a Cochrane database review there was a significant increase
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in mild adverse events (nausea, diarrhea, and wheezing) in patients with cystic fibrosis treated with macrolides (103M ).
Azithromycin
(SED-15, 389)
The overall adverse reactions rate for azithromycin is 0.7% (104R ). Only diarrhea, nausea, and abdominal pain occurred in over 1% of patients. Other adverse effects that were reported from clinical trials in adults are palpitation, angina, dyspepsia, flatus, vomiting, melena, jaundice, vaginal candidiasis, vaginitis, nephritis, dizziness, headache, vertigo, somnolence, and fatigue. Azithromycin has also been reported to cause angioedema and photosensitivity, intrahepatic cholestasis, hypersensitivity syndrome, toxic pustuloderma, and irreversible deafness after low-dose use. It can cause a maculopapular eruption when given to patients with infectious mononucleosis. It can also cause contact dermatitis. Placebo-controlled studies Three well-designed randomized controlled trials have demonstrated a small but significant improvement in respiratory function with azithromycin compared with placebo (105M ). Mild adverse events (wheeze, diarrhea, and nausea) were significantly increased in one trial. Daily azithromycin (250 mg/day) as prophylaxis against malaria in adults was well-tolerated during 20 weeks in 148 patients, but azithromycin recipients complained more frequently of heartburn, paresthesia, and itching than those taking doxycycline (106C ). There was no evidence of hearing loss or hematologic, hepatic, or renal toxicity. Cardiovascular In a prospective study in 47 healthy subjects, azithromycin (3 g total dose given during 5 days) resulted in a small, non-significant prolongation of the QT interval (106C ). Sensory systems The palatability of antibiotic suspensions is crucial for compliance in young children. The color, flavor, and taste of azithromycin have been found to be acceptable. In one study children preferred the taste of azithromycin to that of cefprozil, cefpodoxime, and clarithromycin; loracarbef and cefixime were considered better tasting than azithromycin (106c ).
Alexander Imhof and Reto Laffer
Gastrointestinal In a randomized, doubleblind, placebo-controlled trial in 186 patients with reactive arthritis treated with oral azithromycin for 13 weeks, there were more adverse events with azithromycin than placebo; the adverse events in those taking azithromycin were most often gastrointestinal (107C ). In an open, non-comparative study in 35 patients with acne vulgaris azithromycin 500 mg thrice weekly for 12 weeks caused heartburn and nausea in four patients (108c ). Skin In a phase II, randomized, double-blind, treatment-controlled study comparison of topical 2% azithromycin versus 2% erythromycin in 20 subjects with moderate inflammatory acne and 20 with rosacea, the number of inflammatory lesions was reduced by 2% erythromycin in both acne and rosacea (109c ). Azithromycin was not as effective in rosacea. There were no significant adverse events in those with acne. In five patients with rosacea, there was transient irritation. Urinary tract A 14-year-old Caucasian girl developed acute interstitial nephritis after taking azithromycin (1.5 g total or 6 mg/kg/day) for 5 days (110A ). Immunologic Airborne allergic contact dermatitis from azithromycin occurred in two workers employed in the blending department of a pharmaceutical company; both cases were confirmed by patch testing (111A ). • A 5-year-old boy developed Stevens–Johnson syndrome after taking azithromycin for 3 days. He had oral pain and skin eruptions with bullae (112A ). He was given betamethasone, panipenem/betamipron, and ulinastatin and gradually improved over 27 days.
Drug interactions Interactions with azithromycin have been reviewed (104R ). It does not interact with the P450 complex and thus has few drug interactions. Even so, the package insert suggests caution in using it with medications with P450 interactions. Antacids Co-administration of antacids reduced the peak concentration of azithromycin; however, the extent of absorption was not significantly reduced.
Miscellaneous antibacterial drugs
Antihistamines Desloratadine and fexofenadine increase concentrations of azithromycin. Rifabutin Daily dosing with the combination of azithromycin and rifabutin is poorly tolerated, primarily because of gastrointestinal symptoms and neutropenia. Warfarin There appears to be an interaction between warfarin and azithromycin. • An 83-year-old African American man stabilized on warfarin took azithromycin 500 mg on one day; the prothrombin time rose and normalized 3 days after azithromycin was withdrawn (113A ).
Clarithromycin
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(SED-15, 799)
• A 76-year-old man, who had taken colchicine 1.5 mg/day for 6 years for familial Mediterranean fever, was given clarithromycin, amoxicillin, and omeprazole for Helicobacter pylori-associated gastritis for 7 days. He developed fever, abdominal pain, and diarrhea 3 days later, dehydration, pancytopenia, metabolic acidosis, and increased lipase activity on day 8, alopecia 2 weeks later. He recovered fully after rehydration and reduction in the dosage of colchicine to 0.5 mg/day. The previous dosage was then reinstituted without adverse effects.
The authors suggested that clarithromycin reduced the biliary excretion of colchicine by inhibiting P glycoprotein. Didanosine When clarithromycin was administered with didanosine in seven adults with HIV, there was a 40% increase in the AUC of didanosine, a difference that could be clinically relevant.
The most common adverse effects of clarithromycin in clinical trials were diarrhea and abnormal taste, both of which occurred in 6% of patients (104R ). Other events that occurred less often were nausea (3%), dyspepsia (2%), abdominal pain (2%), and headache (2%). Clarithromycin can also cause fixed drug eruptions, hypersensitivity reactions, and leukocytoclastic vasculitis. It can also cause mania, especially when given with glucocorticoids.
Itraconazole In an open phase II trial in 17 patients with cystic fibrosis taking itraconazole the highest itraconazole concentrations were observed in a patient who had concurrently taken clarithromycin (116c ). This may have resulted from competitive inhibition of metabolism by CYP3A4.
Gastrointestinal In a randomized comparison of oral telithromycin 800 mg/day for 5 or 7 days and oral clarithromycin 500 mg bd for 10 days in 575 patients, 257 (45%) had at least one treatment-related adverse event (90C ). The most frequent adverse effects were gastrointestinal (diarrhea, nausea, and dysgeusia). None of the patients taking clarithromycin withdrew because of gastrointestinal events.
Comparative studies Abdominal pain was significantly more common with dirithromycin (12%) than with erythromycin (5.8%) (104R ). Headache, dizziness, and raised liver enzymes occur less often with dirithromycin.
Drug interactions Drug interactions with clarithromycin have been reviewed (104R , 114R ). Clarithromycin causes less inhibition of cytochrome P450 than erythromycin, but co-administration increases the serum concentrations of carbamazepine, ciclosporin, terfenadine, and theophylline. Colchicine An interaction of clarithromycin with colchicine has been described (115A ).
Dirithromycin
Erythromycin
(SED-15, 1144)
(SED-15, 1237)
Patients who took erythromycin during its premarket clinical trials reported that abdominal pain, anorexia, diarrhea, nausea, and vomiting were the most common adverse effects. There have also been reports of cardiac conduction abnormalities, allergic reactions, skin eruptions, and reversible hearing loss (104R ). Erythromycin can cause cholestatic hepatitis, with nausea, vomiting, abdominal pain, jaundice, fever, liver function abnormalities, and occasionally eosinophilia (104R ).
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Cardiovascular In the Tennessee Medicaid cohort, during 1 249 943 person-years of followup there were 1476 cases of sudden death from cardiac causes; the multivariate adjusted rate of sudden death from cardiac causes among patients currently using erythromycin was twice as high (117C ). There was no significant increase in the risk of sudden death among former users of erythromycin. The adjusted rate of sudden death from cardiac causes was five times as high among those who concurrently used CYP3A inhibitors and erythromycin as among those who had used neither CYP3A inhibitors nor any of the study antibiotic medications.
Roxithromycin
(SED-15, 3083)
Cardiovascular An 83-year-old woman developed torsade de pointes after taking oral roxithromycin 300 mg/day for 7 days (118A ). Endocrine Roxithromycin may have antiandrogenic effects. In an in vitro model roxithromycin 5 µg/ml suppressed androgen receptor transcriptional activity by 21% (119E ). Urinary tract Roxithromycin can cause severe liver toxicity, but nephrotoxic effects have not been established. • A 73-year-old woman developed acute renal insufficiency and hepatotoxicity after taking roxithromycin for 2 days (120A ). Renal and hepatic function returned to normal on the sixth day after roxithromycin withdrawal.
Alexander Imhof and Reto Laffer
Hematologic Nitrofurantoin has been associated with neutropenia (125A ). • A 74-year-old white man developed agranulocytosis after taking nitrofurantoin 100 mg qds for 5 days. The total white blood cell count and granulocyte count fell to 1.9 × 109 /l and 0.5 × 109 /l respectively. Nitrofurantoin was withdrawn and 2 days later the total white blood cell count and granulocyte count rose to 2.5 × 109 /l and 1.1 × 109 /l respectively.
Liver Nitrofurantoin has been associated with liver and lung damage. • A 73-year-old white man who had taken nitrofurantoin 50 mg/day for 5 years developed combined hepatic and pulmonary toxicity after taking fluconazole 150 mg/week for onychomycosis (126A ). Two months after starting fluconazole, his hepatic enzymes rose to 5 times the upper limits of normal. In addition, he reported fatigue, dyspnea on exertion, pleuritic pain, burning tracheal pain, and a cough. Chest X-rays showed bilateral pulmonary disease consistent with nitrofurantoin toxicity. Both drugs were discontinued. The hepatic and pulmonary toxicity resolved on withdrawal of both drugs and use of inhaled glucocorticoids (fluticasone 880 micrograms/day).
Either drug could have caused the hepatic damage in this case, and it is possible that a pharmacokinetic interaction with fluconazole precipitated nitrofurantoin-induced toxicity. Susceptibility factors Age Adverse reactions in children related to nitrofurantoin have been reviewed (127R ). They are gastrointestinal disturbances (4.4/100 person-years) (128C , 129C ), skin reactions (2– 3%), pulmonary toxicity (9 patients) (130A , 131C ), hepatotoxicity (12 patients and 3 deaths) (132C , 133A , 134C , 135A ), hematological toxicity (12 patients) (136C , 137C , 138c , 139A ), neurotoxicity (137C , 140C , 141A ), and an increased rate of sister chromatid exchanges (142C , 143C ).
NITROFURANTOIN
(SED-15, 2542; SEDA-26, 288; SEDA-27, 264; SEDA-28, 284)
OXAZOLIDINONES Respiratory Acute respiratory reactions to nitrofurantoin include dyspnea, cough, interstitial pneumonitis, and pleural effusion; interstitial pneumonitis and fibrosis are common chronic reactions (121R –123R , 124r ).
(SED-15, 2645; SEDA-26, 288; SEDA-27, 264; SEDA-28, 284) The oxazolidinones represent the first truly new class of antibacterial agents to reach the marketplace in several decades (144R –146R ). They
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have a unique mechanism of action, involving inhibition of the first step of bacterial protein synthesis. The first member of the class, linezolid, has inhibitory activity against a broad range of Gram-positive bacteria. Linezolid is completely absorbed and can be given orally or intravenously; it is cleared by both renal and hepatic routes, and dosage adjustments are not needed in moderate renal or hepatic insufficiency. Observational studies In a retrospective analysis in 20 patients receiving linezolid for orthopedic infections, eight developed reversible myelosuppression, one had irreversible peripheral neuropathy, and two withdrew because of pancytopenia or urticaria (147C ). Cardiovascular In a placebo-controlled, crossover study in 12 healthy men who took one oral dose of linezolid 600 mg or a placebo tablet followed by an intravenous tyramine pressor test until the systolic blood pressure increased by at least 30 mmHg above baseline, there was a significant difference in the pressor response to intravenous tyramine between linezolid and placebo (148c ). Severe bradycardia with an increased blood pressure has been attributed to linezolid (149A ). • A 49-year-old woman with cancer of the biliary tree developed a fever and jaundice. Dilatation of the right biliary tract was confirmed by ultrasound and nuclear magnetic resonance. She was given ceftazidime 4 g/day and oral linezolid 600 mg/day. Unexpectedly, 2 days later her blood pressure rose to 170/90 mmHg and was associated with severe bradycardia 37–40/minute. Linezolid was withdrawn. The pulse rate became normal after 48 hours and the blood pressure fell.
The mechanism underlying this effect is unknown, but it may have been related to the fact that linezolid is a monoamine oxidase inhibitor. Sensory systems Linezolid may be associated with severe peripheral and optic neuropathy. In most cases, optic neuropathies resolved after stopping linezolid but peripheral neuropathies did not; the duration of therapy seems to be the most important factor (150r ). • A 46-year-old white woman developed a severe, painful peripheral neuropathy while taking oral linezolid 600 mg bd for 6 months (151A ). Nerve conduction studies showed a sensorimotor axonal
neuropathy. Extensive assessment did not show alternative explanations for her neuropathy. When she died 1 month after withdrawal of linezolid, the neuropathy had not resolved. • A 27-year-old white woman took linezolid 600 mg bd for 6 months and developed paresthesia in her extremities, numbness of the legs below the knee, and intermittent sharp pain in both feet (152A ). There was peripheral sensory loss in the “glove and stocking” distribution. Nerve conduction studies showed sensory motor axonal neuropathy. Linezolid was withdrawn and 5 months later she reported no pain. However, nerve conduction studies showed that the peripheral neuropathy persisted.
Hematologic Linezolid has been associated with myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) (145R , 153R ). It is now recommended that complete blood counts be monitored weekly in patients who take linezolid, especially those who take it for more than 2 weeks. In children, thrombocytopenia is less common; however, the complete blood count should be monitored weekly while children are taking linezolid. In a randomized, controlled, open, multicenter study in 430 patients with suspected or proven Gram-positive infections, patients received oral linezolid 600 mg every 12 hours or intravenous or intramuscular teicoplanin for up to 28 days (73C ). Five patients who were treated with linezolid had hematological adverse effects rated as moderate or severe, including hemolysis, anemia, leukopenia, and thrombocytopenia. Susceptibility factors Age In clinical trials of linezolid involving over 950 children, the most common adverse events were diarrhea, headache, vomiting, nausea, raised serum transaminase activities, and rash (6.5–11% of patients) (153R ). The pharmacokinetics of linezolid in children have been studied in four clinical trials in over 180 patients, from preterm neonates to 18-year-olds (153R ). Linezolid clearance is greater in children than in adults and greater in children aged under 12 years. Based on these studies, the recommended dosage of linezolid is 10 mg/kg every 12 hours for children over 12 years (maximum dose 600 mg every 12 hours) and 10 mg/kg every 8 hours for children under 12 years of age. Based on limited pharmacokinetic data in neonates, linezolid clearance appears to be relatively reduced in premature infants under 34 weeks gestation and under 7 days
268 of age; these patients should receive 10 mg/kg every 12 hours, increasing to 10 mg/kg every 8 hours in all neonates beyond the first week of life, regardless of gestational age. Renal disease In a prospective, single-dose pharmacokinetic study in patients with acute renal insufficiency who received 600 mg of linezolid intravenously and were treated with renal replacement therapy, serum concentrations averaged 12 mg/l and fell at the end to below 4 mg/l in three of eight patients on hemodialysis, three of five patients on sustained lowefficiency dialysis, and two patients on continuous venovenous hemofiltration (154C ). Mean removal of the drug was 194 mg with hemodialysis (32% of the dose administered), 205 mg with sustained low-efficiency dialysis (34%), and 75 mg (12%) and 105 (18%) mg following the continuous venovenous hemofiltration sessions. Cystic fibrosis In 12 adults with cystic fibrosis given a single intravenous dose of linezolid 600 mg over 30 minutes the pharmacokinetics, while variable, with half-lives of 1.76–8.36 hours, were similar to those previously described in other populations (155C ). Drug interactions Bupropion An interaction between linezolid and bupropion has been reported to cause severe intermittent intraoperative hypertension in a 57-year-old man (156A ).
Chapter 26
Alexander Imhof and Reto Laffer
patients taking linezolid and certain adrenergic agents, including phenylpropanolamine and pseudoephedrine, and the doses of these drugs should be reduced in patients receiving linezolid (158r ). Venlafaxine Linezolid interacts with selective serotonin reuptake inhibitors and sympathomimetic drugs, resulting in serotonin syndrome. Serotonin syndrome due to an interaction of linezolid and venlafaxine has been reported (155r , 139A ). • An 85-year-old man with an infected hip joint prosthesis was given ciprofloxacin 750 mg bd, rifampicin 300 mg bd, and linezolid 600 mg bd (159A ). He was also taking venlafaxine 150 mg/ day for depression and 20 days later became confused and disoriented, with disturbance of the sleep–wake cycle, and was intermittently aggressive; 4 days later he had widespread increased tone, generalized myoclonic jerks, and extensor plantar reflexes. Linezolid and venlafaxine were withdrawn. Within 2 days he had recovered his usual level of mental functioning.
Management of adverse drug reactions Two patients with disseminated Mycobacterium abscessus infections who took linezolid for at least 9 months developed cytopenias and one also developed a peripheral neuropathy (160A ). Because continuing linezolid therapy was required, oral vitamin B6 50 mg/day was administered in an attempt to mitigate the cytopenia. In both patients the cytopenia resolved after administration of vitamin B6 and stabilized during prolonged linezolid therapy, although the peripheral neuropathy did not.
Diphenhydramine • A 56-year-old white man developed delirium with visual and auditory hallucinations and erratic, aggressive behavior, presumably caused by the combination of diphenhydramine 300 mg/day and linezolid 600 mg every 12 hours (157A ). This persisted for 3 days after diphenhydramine was withdrawn.
Monoamine oxidase inhibitors Because the original oxazolidinones, including linezolid, are monoamine oxidase inhibitors, particular attention has been paid to the question of whether adverse interactions with drugs that are metabolized by monoamine oxidase would occur in patients taking linezolid. An enhanced pressor response has been seen in
POLYMYXINS (SED-15, 2891; SEDA-26, 289; SEDA-27, 265; SEDA-28, 285) Respiratory Nine patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa participated in a double-blind, randomized, crossover comparison of nebulized colistin sulfate or colistin sulfomethate (161C ). Nebulized colistin sulfate caused a significantly larger mean reduction in lung function than nebulized colistin sulfomethate. In three patients, there was a reduction in FEV1 of 10% or more. Seven patients were not able to complete the course of nebulized colistin sulfate because of throat irritation and severe cough.
Miscellaneous antibacterial drugs
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STREPTOGRAMINS (SED-15, 3182; SEDA-26, 289; SEDA-27, 265; SEDA-28, 285) Pristinamycin Skin In 29 patients with cutaneous adverse drug reactions due to pristinamycin, skin tests were positive in 27 cases, patch tests in 20 cases, and prick tests in three of nine cases; intradermal tests with dalfopristin–quinupristin were positive in four of five cases (162c ). There were cross-reactions between pristinamycin and virginiamycin in nine of 22 and dalfopristin–quinupristin in seven of eight cases. It is advisable to avoid all streptogramins in patients with cutaneous adverse drug reactions due to pristinamycin.
Quinupristin/dalfopristin Quinupristin/dalfopristin is a semisynthetic injectable streptogramin combination. Each component has bacteriostatic activity against staphylococci and streptococci (163R ). Adverse effects include arthralgia, myalgias, and pain at the infusion site. Hematologic Quinupristin/dalfopristin is rarely associated with hematological adverse events. • A 44-year-old African American man developed reticulocytopenia after receiving intravenous quinupristin/dalfopristin 550 mg (7.5 mg/kg) every 8 hours for 23 days for a hip joint infection and became anemic (hemoglobin 6.5 g/dl) (164A ). The results of iron studies were normal and the reticulocyte count was low at 0.22%. Quinupristin/dalfopristin was withdrawn and vancomycin started. The hemoglobin rose.
Musculoskeletal In 56 patients treated with quinupristin/dalfopristin 7.5 mg/kg every 8 hours for a mean duration of 12 (range 2– 52) days, there were myalgias/arthralgias in 20 (165C ). These patients had significantly higher activities of alkaline phosphatase (mean 319 IU/l) during the mid-term therapy cycle compared with patients without any joint or muscular pains (mean 216 IU/l); three had more than five times normal activity, which did not occur in any of the patients who did not develop myalgias/arthralgias. All the myalgias/arthralgias resolved after withdrawal of quinupristin/dalfopristin.
269 Pharmacokinetics Quinupristin/dalfopristin has minimal oral absorption and is administered intravenously as a fixed 30:70 ratio of quinupristin to dalfopristin. A linear relationship has been observed between the dose administered and maximum plasma concentrations. Single-dose administration of 7.5 mg/kg produced a maximal plasma concentration of 2.3– 2.7 mg/l for quinupristin and 6.1–8.2 mg/l for dalfopristin. The area under the concentrationtime curve obtained with the same dose was 2.7–3.3 and 6.5–7.7 mg h/l for quinupristin and dalfopristin, respectively. Repeated administration results in 13–21% increases in maximum plasma concentrations and 21–26% increases in area under the curve of the concentration for both quinupristin and dalfopristin. Quinupristin and dalfopristin exhibit steadystate volumes of distribution of 0.46–0.54 and 0.24–0.30 l/kg, respectively. Quinupristin exhibits higher protein binding (55–78%) than dalfopristin (11–26%), though both entities distribute well into tissues. Concentrations exceeding those in blood have been reported for the kidney, liver, spleen, salivary glands, and white blood cells of primates. Extravascular penetration, as measured in blister fluid, is 40–80%. Both quinupristin and dalfopristin are extensively metabolized via non-enzymatic reactions. Quinupristin is conjugated to form two active compounds, a cysteine moiety and a glutathione moiety. Dalfopristin is hydrolysed to the active metabolite pristinamycin. Quinupristin/dalfopristin is excreted primarily in the feces (75–77%), with lesser renal excretion (15–19%). The elimination half-lives of quinupristin and dalfopristin are similar, and are 0.7–1.3 hours after single doses. The metabolites have slightly longer half-lives, ranging from 1.2 to 1.8 hours. With repeated doses, plasma clearance of quinupristin and dalfopristin is reduced by approximately 20% compared with single doses, resulting in clearances of 0.7–0.8 l/h/kg. Saturable protein binding has been hypothesized as a causative mechanism (166R ). Drug interactions Quinupristin/dalfopristin inhibits CYP3A4, resulting in multiple drug interactions (166R ). Ciclosporin AUC increased by 5–222% when co-administered with quinupristin/dalfopristin. Patients taking drugs that are substrates of CYP3A4 should be carefully monitored.
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SULFONAMIDES, TRIMETHOPRIM, AND CO-TRIMOXAZOLE (SED-15, 3216,
associated with both high-dose therapy in patients with AIDS and in patients taking standard doses of co-trimoxazole.
3510; SEDA-26, 290; SEDA-27, 266; SEDA-28, 285)
Hematologic The hematological adverse effects of co-trimoxazole have been reviewed (127R ). In 2622 children taking co-trimoxazole there were no cases of blood dyscrasias. However, only 17% of the patients received more than two refills of the medicine and the actual dose was not reported. In a prospective study of hematological adverse reactions in children after an oral 10-day course of co-trimoxazole 8 mg/kg/day 34% had neutropenia and 12% had thrombocytopenia. In a double-blind, randomized, placebocontrolled trial in children aged 1–14 years with HIV infection treated with either cotrimoxazole (240 or 480 mg suspension) or placebo, mean neutrophil count fell by 0.5 × 109 /l from baseline to week 4 in the cotrimoxazole group, and remained at 0.6–1.2 × 109 /l below that in the placebo arm from weeks 12 to 72 (170C ). In total, 16 children in the co-trimoxazole group and seven in the placebo group had a single neutrophil count less than 0.5 × 109 /l after baseline. Older sulfonamides were associated with methemoglobinemia, but this is rare with cotrimoxazole.
Trimethoprim and co-trimoxazole (SED-15, 3510) Nervous system Multifocal myoclonus due to co-trimoxazole is very rare. • A 63-year-old woman was given trimethoprim 20 mg/kg/day and sulfamethoxazole 100 mg/ kg/day for an infection with Nocardia asteroides (167A ). Her fever abated, but 4 days later she began to have progressively worsening involuntary movements involving the head and all four limbs. She had multifocal myoclonus and bilateral asterixis, with no other abnormalities. The co-trimoxazole was withdrawn and the involuntary movements abated markedly on the next day; by the fourth day, they had resolved completely.
Co-trimoxazole can also exacerbate posthypoxic action myoclonus. • A 58-year-old man had an exacerbation of posthypoxic myoclonus during high-dose intravenous co-trimoxazole treatment for Pneumocystis jiroveci pneumonia (168A ). Three months before the patient had had a hypoxic insult caused by respiratory arrest due to an anaphylactic reaction to antibiotic therapy. He had developed posthypoxic action myoclonus (Lance–Adams syndrome), which was well controlled by oral piracetam. However, after co-trimoxazole 115 mg/kg/day was started, the myoclonus worsened dramatically, resulting in complete disability. Increased doses of piracetam and valproic acid did not significantly benefit him. Only when the dose of co-trimoxazole was reduced to 38 mg/kg/day on day 12 did the myoclonus cease within 2–3 days.
Electrolyte balance Co-trimoxazole has been associated with hyperkalemia (169R ). The mechanism is related to trimethoprim, which is a heterocyclic weak base and is structurally similar to the potassium-sparing diuretic amiloride. Trimethoprim, but not sulfamethoxazole, reversibly inhibits the amiloride-sensitive apical sodium channels in the cell membranes of the distal nephron. Inhibition of these sodium channels secondarily blocks sodium/potassium adenosine phosphatase-mediated potassium secretion by hyperpolarizing the luminal membrane in the distal nephron. Hyperkalemia is
• A 66-year-old African American man with advanced HIV infection developed methemoglobinemia while receiving intravenous co-trimoxazole (300 mg of trimethoprim + 1500 mg of sulfamethoxazole) every 6 hours (171A ).
Gastrointestinal Quantitative stool cultures in two patients receiving co-trimoxazole for 2 years showed a substantially suppressed Gramnegative aerobic flora, while Enterococcus species and anaerobes were not affected; yeasts were moderately increased (172A ). Liver The incidence of hepatic toxicity with trimethoprim is 1 in 11 000–45 000 treatments (127R ). Hepatocellular (40%), mixed (40%), and cholestatic (20%) damage are the most commonly reported pathological subtypes in adults. Urinary tract Renal tubular acidosis due to antimicrobial drugs has been reviewed (169R ).
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There was renal tubular dysfunction associated with hyperkalemia in two elderly patients taking high-dose oral co-trimoxazole; there was hyponatremia in both cases. Type 4 renal tubular acidosis has been reported in patients receiving high-dose intravenous therapy, as well as oral treatment and prophylactic doses of co-trimoxazole. There was heterogeneity in these patients, with both adults and children included. The mechanism by which cotrimoxazole causes renal tubular acidosis is not well understood. Skin Fixed drug eruptions have been attributed to co-trimoxazole. • A bullous necrotizing fixed drug eruption was reported in a 3-month-old child who had received oral co-trimoxazole suspension 3 days before the onset of the lesions (173A ). The infant was given oral prednisolone 0.5 mg/kg for 1 week along with supportive management. The lesions stopped progressing within 2 days and subsided completely in 10 days. • A 52-year-old white woman developed a fixed drug eruption with polysensitivity caused by cotrimoxazole and tenoxicam (173A ).
Immunologic Anaphylaxis to trimethoprim is not well recognized. • Within 5 minutes of ingesting one tablet of trimethoprim for a urinary tract infection, a 79year-old woman with a history of erythromycin allergy felt sweaty, faint, and nauseated (174A ). There were no signs of hemodynamic instability and the antibiotic was withdrawn. However, her symptoms persisted and she collapsed with loss of consciousness. Her Glasgow Coma Score was 13 (eyes 3/verbal 4/motor 6), she had unequal reactive pupils and a rash, and was incontinence of urine and faeces. Her blood pressure was 81/50 mmHg, heart rate 57/minute, and respiratory rate 20/minute. She was pale, cool, and clammy, and mildly hypothermic at 34.2 ◦ C. There was generalized limb and facial swelling and an erythematous maculopapular rash over the whole body. She recovered with treatment.
Susceptibility factors Age The adverse effects of trimethoprim in children have been reviewed (127R ). In children aged 2–15 years taking long-term prophylaxis with trimethoprim blood dyscrasias occurred at a rate of 0.7 events per 100 years at risk. Skin reactions occur at a rate of 2 events per 100 years at risk in children aged 2–15
years old (127R ). They are hypersensitivity reactions and they usually occur immediately after exposure or re-exposure, unlike other adverse reactions, which only occur at high doses or after prolonged therapy. The spectrum of cutaneous reactions includes urticaria, maculopapular rash, fixed drug eruption, erythema multiforme, Stevens–Johnson syndrome, and toxic epidermal necrolysis. Urticaria and maculopapular rash are by far the most common skin reactions. Treatment is withdrawal and resolution is usually complete. Hepatotoxicity related to co-trimoxazole has been suggested to be a hypersensitivity reaction (127R ). This is supported by the manifestation of a preceding rash or eosinophilia in children. Cutaneous hypersensitivity reactions, such as toxic epidermal necrolysis, are frequently associated with raised liver enzymes in children. The incidence of skin reactions in children under 2 years is 7.4 events per 100 years at risk (127R ). This number falls significantly to 1.4 events per 100 years at risk in children aged 2–15 years, presumably due to prior exposure and the exclusion of those at known risk of allergic reactions. The spectrum of cutaneous reactions to co-trimoxazole includes urticaria, maculopapular rashes, fixed drug eruptions, erythema multiforme, Stevens– Johnson syndrome, and toxic epidermal necrolysis. Urticaria and maculopapular rashes are by far the most common.
OTHER ANTIMICROBIAL DRUGS Daptomycin
(SED-15, 1053; SEDA-26, 292; SEDA-27, 267; SEDA-28, 287)
Most of the reported adverse effects of daptomycin are mild to moderate in intensity. The most common are gastrointestinal disorders, injection site reactions, fever, headache, insomnia, dizziness, and rashes (175R , 176R ). Phase III study results have suggested no difference in efficacy or tolerability between daptomycin 4 mg/kg/day intravenously and vancomycin or semisynthetic penicillins for complicated skin and skin-structure infections; however, specific adverse effects were not discussed (177R ).
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Musculoskeletal system Daptomycin may have adverse effects on skeletal muscle, as suggested by raised creatine kinase activity in 2.8% of daptomycin recipients (178R ). People receiving daptomycin should be monitored for muscle pain or weakness, and creatine kinase activity should be monitored weekly.
with severe hepatic impairment has not been assessed (177R ). In a single-dose, parallel-design, matchedcontrol study in subjects aged 18–80 years with moderately impaired hepatic function (ChildPugh Class B, n = 10) the pharmacokinetics were similar to those in control subjects (181C ).
• A 26-year-old African American woman with methicillin-resistant Staphylococcus aureus endocarditis was given intravenous daptomycin 6 mg/ kg/day for 14 days. She developed muscle aches and pains with only a minor rise in creatine kinase (492 U/l); both resolved after daptomycin was withdrawn (179A ).
Fosmidomycin
Susceptibility factors Age The pharmacokinetics of daptomycin were evaluated after a single 30-minute intravenous infusion of 4 mg/kg in young adults (18–30 years) and elderly volunteers (75 years and over) (180C ). There were increases in AUC and half-life with increased age. Total and renal clearances both fell with increasing age. There were no statistically significant differences between the two groups in Cmax and Vss . These results show that changes in the pharmacokinetics of daptomycin in the elderly are attributable to changes in renal function, rather than age per se. Renal disease Daptomycin is eliminated primarily by renal excretion (about 54%) (177R ). Data from subjects in nine phase 1 (n = 153) and six phase 2/3 (n = 129) clinical trials were combined to identify factors that contribute to interindividual variability in daptomycin pharmacokinetics (181M ). Daptomycin clearance varied linearly with the estimated creatinine clearance. Daptomycin clearance in dialysis subjects was about one-third of that in healthy subjects (0.27 versus 0.81 l/hour). Daptomycin clearance in women was 80% that in men; however, in clinical trials, the outcome was not affected by sex. This suggests that modified dosing regimens are indicated for patients with severe renal disease and for those undergoing dialysis. In such patients the dosage interval should be 48 hours. Liver disease Dosage adjustment does not appear to be necessary in mild to moderate hepatic impairment. The use of daptomycin in patients
(SED-15, 1450; SEDA-27, 268; SEDA-28, 287) Fosmidomycin acts by inhibiting 1-deoxy-Dxylulose 5-phosphate reductoisomerase, a key enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. It inhibits the synthesis of isoprenoids by Plasmodium falciparum and suppresses the growth of multidrug-resistant strains in vitro. Observational studies In a randomized, controlled, open study of fosmidomycin combined with clindamycin (n = 12; 30 and 5 mg/kg respectively every 12 hours for 5 days), compared with fosmidomycin alone (n = 12; 30 mg/kg every 12 hours for 5 days) and clindamycin alone (n = 12; 5 mg/kg every 12 hours for 5 days) for the clearance of asymptomatic Plasmodium falciparum infections in schoolchildren in Gabon there were no serious adverse event (182C ). Gastrointestinal adverse events (eight cases of abdominal pain, seven of diarrhea, four of vomiting, two of loose stools, and two of nausea) were the most frequently reported adverse events. All gastrointestinal adverse events were judged to be possibly or probably related to the treatment. Nevertheless, all gastrointestinal adverse events were self-limiting and intervention was not required. There were no significant differences in the incidences of gastrointestinal adverse events between the groups. In 52 children with P. falciparum malaria in Gabon who were given an oral combination of fosmidomycin + clindamycin (30 mg/kg and 10 mg/kg) there were no serious adverse events (183C ). Of 64 adverse events, 26 mild and three moderate adverse events were judged to be either possibly or probably related to the study drugs. The most frequent adverse events were gastrointestinal events (29 events, all mild), mostly loose stools (n = 13) and ab-
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dominal pain (n = 9). There was no difference in the distribution of gastrointestinal adverse events among the cohorts of different treatment durations.
Ramoplanin
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(SEDA-28, 288)
Ramoplanin is the first in a new class of antimicrobials to reach clinical trials (184R ). It is a glycolipodepsipeptide produced by the fermentation of Actinoplanes species. Ramoplanin blocks bacterial cell wall biosynthesis by interfering with peptidoglycan production. It inhibits the N -acetylglucosaminyltransferasecatalysed conversion of lipid intermediate I to lipid intermediate II, a step that occurs before the transglycosylation and transpeptidation reactions. Unlike glycopeptides, ramoplanin does not complex with the D-Ala–D-Ala sequence of cell wall precursors. It is highly active against Gram-positive aerobic and anaerobic bacteria. Ramoplanin is not systemically absorbed after oral administration, and is being evaluated for the prevention of bloodstream infection in patients colonized with vancomycin-resistant enterococci.
Virginiamycin (SEDA-26, 293; SEDA-27, 268; SEDA-28, 288) Virginiamycin is a growth-promoting streptogramin antibacterial used as a feed additive in animals. Drug tolerance (antibacterial resistance) The use of virginiamycin has been linked with a selection of quinupristin/dalfopristin-resistant strains of Enterococcus faecium. Because virginiamycin has been used in animals while streptogramins have been used infrequently in human medicine, an animal origin of resistance is suggested, and a spread of the resistance via the food chain to humans is probable (185r , 186r ). A risk model has shown that the theoretical statistical human health benefits of a virginiamycin ban range from zero to less than one statistical life saved in both Australia and the USA over the next 5 years and are rapidly falling (187C ).
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Andreas H. Groll and Thomas J. Walsh
27
Antifungal drugs
ALLYLAMINES
(SEDA-26, 309; SEDA-27, 284; SEDA-28, 294)
Terbinafine
slowly after drug withdrawal, but the sicca syndrome persisted with only very mild improvement at 6 months.
(SED-15, 3316) Susceptibility factors
Gastrointestinal In a multicenter, randomized, double-blind, parallel-group study, 63 patients aged 14–85 years with Sporothrix schenckii infections were treated with terbinafine 500 mg/day (n = 28) or 1000 mg/day (n = 35) (1C ). There were no cases of relapse after 24 weeks of follow-up with 1000 mg/day, compared with six relapses with 500 mg/day. Terbinafine was well tolerated; the frequency of drug-related adverse effects was slightly higher with 1000 mg/day (17/35 vs. 10/28). Two patients taking 1000 mg/day withdrew because of an adverse effect (gastrointestinal hemorrhage; increasing abdominal pain). Skin Cutaneous adverse effects reportedly occur in 1–3% of patients taking terbinafine. The overwhelming majority of these reactions consist of mild to moderate macular exanthems. More serious skin disorders, such as erythema multiforme, toxic epidermal necrolysis, Stevens–Johnson syndrome, erythema toxicum, cutaneous lupus erythematosus, and generalized pustular eruptions are rare (SEDA-23, 289; SEDA-24, 314). There have been further reports of lupus erythematosus-like eruptions (2CR ) and erythema multiforme (3CR ) associated with oral terbinafine. Immunologic A rash with eosinophilia and systemic symptoms induced by terbinafine was associated with severe sialadenitis and a complete sicca syndrome (4CR ). The rash resolved Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29027-5 © 2007 Elsevier B.V. All rights reserved.
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Age Limited data suggest that the safety profile of terbinafine in children is not different from that observed in adults and that terbinafine is well tolerated in this population over short periods of time (SEDA-23, 289; SEDA-24, 314; SEDA-25, 331; SEDA-26, 302; SEDA-27, 284; SEDA-28, 294). Terbinafine has been approved for the treatment of tinea capitis in many countries worldwide, and provides good efficacy rates for Trichophyton tinea capitis using shorter regimens than griseofulvin. The standard dosing regimens in children for tinea capitis are 62.5 mg/day (10–20 kg), 125 mg/day (20–40 kg), and 250 mg/day (over 40 kg) administered for 2–4 weeks; while there is no approved therapy for onychomycosis in children, similar dosages have been used for 6–12 weeks. In 100 children with tinea capitis caused by Microsporum canis treated with oral terbinafine 3.3–12.5 mg/kg/day for 8 weeks, five patients withdrew because of adverse events (5C ).
AMPHOTERICIN
(SED-15, 192; SEDA-26, 302; SEDA-27, 276; SEDA-28, 295) Urinary tract Compared with conventional amphotericin B deoxycholate, lipid-based formulations (amphotericin B colloidal dispersion, amphotericin B lipid complex, and liposomal amphotericin B) are less nephrotoxic (6R , 7R ).
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Amphotericin B Lipid Complex (ABLC) In a prospective historical control study 131 patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome undergoing induction chemotherapy were given ABLC 2.5 mg/kg intravenously 3 times weekly as antifungal prophylaxis and were compared with 70 who had previously received LAMB 3 mg/ kg 3 times weekly (8c ). Grade 3 and 4 adverse events (hyperbilirubinemia, 3% versus 6%; infusion-related adverse events, 3% versus 7%) were statistically similar between the groups, as were rates of withdrawal because of adverse events (18% versus 15%) and survival rates (92% versus 86%). The risk of hematological, renal, and hepatic toxicity associated with ABLC has been assessed in a multicenter, open, non-comparative study in 93 patients from 17 different hospitals who received ABLC because of proven or suspected systemic fungal infection or leishmaniasis (9c ). Optimum treatment with ABLC comprised a 2-hour infusion of 5 mg/kg/day for a minimum of 14 days; the mean dose was 235 (range 9–500) mg/day and the total cumulative dose was 2894 (range 30–10 200) mg. In the whole group, the mean serum creatinine concentration was similar before and after ABLC (1.00 versus 1.20 mg/dl). There were no significant changes in concentrations of hemoglobin, potassium, and bilirubin, or in hepatic transaminase activities. There was no significant correlation between the dose and the serum creatinine concentrations. There was no greater nephrotoxicity in the patients with previous renal insufficiency, or in those who had previously received amphotericin B. There were serious adverse events in five patients, but other alternative causes were found in three of them. There were fevers or chills in 23% of the patients during the infusion of ABLC, but only in one case did this necessitate withdrawal. The overall rate of withdrawals due to adverse events was 9.7%. Respiratory Fatal fat embolism has been attributed to ABLC (10CR ). • A 41-year-old Caucasian man with AIDS received amphotericin for cryptococcal meningitis but developed renal insufficiency and was switched to
ABLC. After about 48 hours he developed a tachycardia, tachypnea, respiratory failure, a fall in hematocrit, thrombocytopenia, and altered mental status. Autopsy findings included fat emboli involving the heart, lungs, kidney, and brain.
This is the first report of fatal fat embolism in a patient receiving a lipid formulation of amphotericin B, although the causal relation was unresolved. Urinary tract In a randomized, controlled trial in 105 adults with hematological malignancies and fever of unknown origin after chemotherapy or autologous stem cell transplantation, amphotericin was used as empirical antifungal therapy (11c ). Patients were randomly allocated to receive ABLC 1 mg/kg/ day or DAMB 0.6 mg/kg/day. The incidence of renal toxicity, defined as a doubling of baseline serum creatinine or an increase to at least 132 µmol/l (1.5 mg/dl), was significantly lower with ABLC (8% versus 32%). The rates of infusion-related adverse events were similar (73% versus 77%). Two patients randomized to ABLC and 11 randomized to DAMB withdrew because of toxicity. The overall response rate was 72% for ABLC and 48% for DAMB; this difference was mainly due to the significantly higher renal toxicity with DAMB. The renal effects of high-dosage/long-duration ABLC therapy (over 5 mg/kg/day for over 12 days; n = 309) have been compared with those of low-dosage/short-duration ABLC therapy (5 mg/kg/day or less for 12 days or less; n = 1417) (12C ). The median change in serum creatinine from baseline was 0.1 mg/dl in both groups.
Amphotericin B deoxycholate (DAMB) Aerosolized DAMB 50 mg and ABLC 25 mg have been compared in lung transplant recipients in a prospective, randomized, double-blind trial in 100 subjects (13C ). The study drug was withdrawn because of intolerance in six of 49 patients treated with DAMB and three of 51 treated with ABLC. Those who received DAMB were more likely to have had an adverse event (OR = 2.16, 95%CI = 1.10, 4.24).
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Liposomal Amphotericin (L-AmB) In 164 HIV-negative children (median age 1.6 years; range 4 months to 14 years) with Mediterranean visceral leishmaniasis L-AmB 3 mg/kg given on days 1–5 and 10 was not associated with adverse events (14c ). Urinary tract Liposomal amphotericin B (n = 539) and caspofungin (n = 556) as empirical antifungal therapy have been compared in a randomized, double-blind, multinational trial (15C ). Fewer patients who received caspofungin had nephrotoxicity (2.6% versus 12%), an infusion-related events (35% versus 52%), or a drug-related adverse event, or withdrew because of drug-related adverse events.
ANTIFUNGAL AZOLES
(SED-15, 301; SEDA-26, 304; SEDA-27, 278; SEDA-28, 299) Comparative studies In 304 patients randomized to fluconazole 400 mg/day or itraconazole either orally 2.5 mg/kg tds or intravenously 200 mg/day for 180 days after allogeneic stem cell transplantation, or until 4 weeks after discontinuation of graft-versus-host disease therapy, more patients stopped taking itraconazole because of adverse effects (36% versus 16%), in most cases because of gastrointestinal complaints (24% versus 4%) (16C ). More patients who took itraconazole had at least a tripling of the baseline total bilirubin concentration (95% versus 86%). Fluconazole and itraconazole have been compared in 252 non-neutropenic cancer patients with oropharyngeal candidiasis (17C ). The safety and tolerance profiles of the two drugs were comparable, but the adverse effects were not listed in detail.
Drug interactions with antifungal azoles Drug interactions with the antifungal azoles are continually reported. They are common, because these drugs are potent inhibitors of
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Andreas H. Groll and Thomas J. Walsh
CYP isozymes and P glycoprotein. However, posaconazole is an exception, since it is eliminated unchanged in the feces (18c ). Antacids The potential for a pH-dependent pharmacokinetic interaction between posaconazole 200 mg and the antacid Mylanta (comagaldrox) 20 ml has been investigated under fasting and non-fasting conditions (19c ) in a randomized, four-period, crossover, singledose study in 12 healthy men completed this. Food increased the relative systemic availability of posaconazole by 400%, but antacid coadministration had no statistically significant effect. Brotizolam The effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of brotizolam has been investigated in a randomized, double-blind, crossover trial in 10 healthy men who had taken either itraconazole 200 mg/day or matched placebo for 4 days (20c ). Itraconazole significantly reduced the apparent oral clearance of brotizolam, increased its AUC, and prolonged its halflife. Itraconazole significantly increases plasma concentrations of brotizolam probably by inhibiting CYP3A4. Carbamazepine Fluconazole-induced carbamazepine toxicity has been reported (21CR ). • A 29-year-old woman taking carbamazepine 1600 mg/day, lamotrigine 400 mg/day, and barbexaclone 100 mg/day developed severe diplopia, oscillopsia, nausea, vomiting, and gait instability within several days after starting to take fluconazole 150 mg/day for tinea corporis. The carbamazepine concentration was 1.5 times above the usual target range. Within 24 hours after withdrawal of fluconazole, the neurological deficits had disappeared and the carbamazepine concentrations had returned to the target range.
This interaction was probably due to inhibition by fluconazole of CYP3A4 and/or CYP2C9, isoenzymes that are involved in the metabolism of carbamazepine. Ciclosporin A 14-year-old girl with an allogeneic bone marrow transplant stopped taking voriconazole because of worsening liver function tests; the ciclosporin trough blood concentrations fell (22AR ). This observation emphasizes the need for careful monitoring and dosage adjustments of ciclosporin in patients who take antifungal azoles.
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Cimetidine The effect of itraconazole on the renal tubular secretion of cimetidine has been investigated in healthy volunteers who received intravenous cimetidine alone and after 3 days of oral itraconazole 400 mg/day (23c ). The cimetidine AUC increased by 25% after itraconazole. Glomerular filtration rate of cimetidine was unchanged, but secretory clearance was significantly reduced presumably due to inhibition of P glycoprotein. Cyclophosphamide Cyclophosphamide is a prodrug that is metabolized by CYP450 enzymes to produce cytotoxic alkylating species; the extent of metabolism correlates with both treatment efficacy and toxicity (SEDA-24, 314). In a randomized comparison of itraconazole (200 mg/day intravenously or 2.5 mg/kg tds orally) and fluconazole (400 mg/day intravenously or orally) in preventing fungal infections in patients undergoing allogeneic stem cell transplantation, those who received itraconazole developed higher serum bilirubin and creatinine concentrations in the first 20 days after transplantation, with the highest values in those who received concurrent cyclophosphamide (24C ). There was higher exposure to toxic metabolites (in particular 4-hydroxycyclophosphamide and 4-ketocyclophosphamide) among recipients of itraconazole compared with fluconazole. In contrast, recipients of fluconazole had higher exposure to unmetabolized drug. Adverse effects occurred preferentially in those who had higher exposure to cyclophosphamide metabolites. These data suggest that azole antifungals, by differential inhibition of hepatic CYP isoenzymes, affect cyclophosphamide metabolism. Cytarabine In vitro assays with itraconazole have shown that cytarabine is a substrate of CYP3A4 (25E ). Cytarabine and itraconazole inhibit CYP3A4. Cytarabine metabolism was significantly reduced when it was combined with itraconazole. Inhibition of cytarabine metabolism may have important clinical implications and warrants investigation in vivo. Dapsone The formation of dapsone hydroxylamine is thought to be the cause of the high rates of adverse reactions to dapsone in HIVinfected individuals. The effect of fluconazole on hydroxylamine formation in individuals with
283 HIV infection has been investigated in 23 HIVinfected subjects (26c ). Fluconazole reduced the AUC, percent of dose excreted in urine in 24 hours, and formation clearance of the hydroxylamine by 49%, 53%, and 55% respectively. This inhibition of in vivo hydroxylamine formation was quantitatively consistent with that predicted from human liver microsomal experiments. Rifabutin had no effect on the plasma AUC of hydroxylamine or the percent excreted in the urine in 24 hours but increased formation clearance by 92%. Dapsone clearance was increased by rifabutin and rifabutin plus fluconazole (67% and 38% respectively) but was unaffected by fluconazole or clarithromycin. Hydroxylamine production was unaffected by clarithromycin. On the basis of these data, and assuming that exposure to dapsone hydroxylamine determines dapsone toxicity, we predict that co-administration of fluconazole should reduce the rate of adverse reactions to dapsone in people with HIV infection and that rifabutin and clarithromycin will have no effect. When dapsone is given in combination with rifabutin, dapsone dosage adjustment may be necessary. Docetaxel The effects of ketoconazole 200 mg/day for 3 days on the pharmacokinetics of docetaxel 100 mg/m2 , have been investigated in a randomized crossover study in seven patients with cancer (27c ). Ketoconazole coadministration resulted in a 49% reduction in the clearance of docetaxel. The docetaxel clearance ratio in the presence and absence of ketoconazole was weakly related to the AUC of ketoconazole. Inhibition of CYP3A4 by ketoconazole in vivo resulted in docetaxel clearance values that have previously been shown to be associated with a several-fold increase in the odds for febrile neutropenia at standard doses. Caution should be taken and substantial dosage reductions are required if docetaxel has to be administered together with potent inhibitors of CYP3A4. Etizolam The effects of itraconazole 200 mg/ day for 7 days on the single oral dose pharmacokinetics and pharmacodynamics of etizolam have been examined in 12 healthy men (28c ). Itraconazole significantly increased the total AUC and the half-life of etizolam, but had no effect on two pharmacodynamic measures, the Digit Symbol Substitution Test and Stanford Sleepiness Scale. The results suggested that
284 itraconazole inhibits the metabolism of etizolam, providing evidence that CYP3A4 is at least partly involved. Glucocorticoids Itraconazole may inhibit the metabolic clearance of glucocorticoids by inhibiting CYP3A4 and directly inhibit steroidogenesis, thereby causing serious adverse effects (SEDA-27, 302). • A 70-year-old white woman taking long-term highdose inhaled budesonide for asthma developed Scedosporium apiospermum infection of the skin and subcutaneous tissues (29A ). She was given itraconazole for 2 months and developed Cushing’s syndrome, probably due to a cytochrome P450-mediated interaction between itraconazole and budesonide. She also had secondary adrenal insufficiency requiring prolonged replacement with hydrocortisone.
The combination of itraconazole and inhaled glucocorticoids is increasingly being used to treat conditions such as allergic bronchopulmonary aspergillosis. Clinicians need to be aware of the potential for an interaction with such a combination. Grapefruit juice The effect of repeated ingestion of grapefruit juice 240 ml on the systemic availability of itraconazole and hydroxyitraconazole serum concentrations in subjects given hydroxypropyl-beta-cyclodextrin-itraconazole oral solution has been investigated in a randomized, two-period, crossover study in 20 healthy adults (10 men, 10 women) (30c ). There was no difference in itraconazole Cmax or tmax . Co-administration of grapefruit juice reduced hydroxyitraconazole Cmax by nearly 10%, but this difference was not statistically significant. There was a statistically significant increase in itraconazole AUC. The apparent oral clearance of itraconazole was significantly reduced. Grapefruit juice produced a significantly reduced mean hydroxyitraconazole:itraconazole AUC ratio; it also reduced the mean hydroxyitraconazole:itraconazole Cmax ratio, but the difference was not statistically significant. Thus, repeated grapefruit juice consumption only moderately affects itraconazole systemic availability. Unlike previous findings with itraconazole capsules, changes in the disposition of itraconazole and hydroxyitraconazole after repeated grapefruit juice consumption are consistent with inhibition by grapefruit juice of intestinal cytochrome CYP3A4.
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Andreas H. Groll and Thomas J. Walsh
Idarubicin In vitro assays with itraconazole have shown that idarubicin is a substrate of CYP2D6 and CYP2C9 (25E ). Idarubicin inhibits CYP2D6, and itraconazole inhibits CYP3A4. Imatinib The effect of ketoconazole 400 mg on the pharmacokinetics of the tyrosine kinase inhibitor imatinib 200 mg has been investigated in a two-period, random, crossover study in 14 healthy subjects (13 men, 1 woman) (31c ). After ketoconazole co-administration, the mean imatinib Cmax and AUC increased significantly by 26% and 40% respectively. There was a statistically significant reduction in the apparent clearance of imatinib, with a mean reduction of 29%. The mean Cmax and AUC of the metabolite CGP74588 fell by 23% and 5% after ketoconazole. Co-administration of ketoconazole and imatinib caused a 40% increase in exposure to imatinib in healthy volunteers. Given its previously demonstrated safety profile, this increased exposure to imatinib is likely to be clinically significant only at high doses. This interaction should be considered when administering inhibitors of the CYP3A family in combination with imatinib. Lidocaine Lidocaine is metabolized by CYP3A4 and CYP1A2 in vitro. However, their relative contributions to the elimination of lidocaine depend on the lidocaine concentration. The effect of itraconazole 200 mg/day on the pharmacokinetics of inhaled lidocaine 1.5 mg/kg has been investigated in 10 healthy volunteers using a randomized, two-phase, crossover design (32c ). The AUC of lidocaine and its major metabolite monoethylglycinexylidide were similar during both phases. There were no statistically significant differences in any of the pharmacokinetics of lidocaine: Cmax , tmax , or half-lives of lidocaine or monoethylglycinexylidide. The clinical implication of this study is that no lidocaine dosage adjustments are necessary if it is used to prepare the airway before endoscopic procedures or intubation in patients using itraconazole or other inhibitors of CYP3A4. Lumiracoxib In a two-way crossover study of the effect of fluconazole on the pharmacokinetics and action of lumiracoxib in 13 healthy subjects, fluconazole caused a small (18%) but
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Chapter 27
not clinically relevant increase in lumiracoxib mean AUC and had no effect on lumiracoxib mean Cmax (33c ). The fall in thromboxane B2 from predose was not affected by fluconazole. As fluconazole is a potent inhibitor of CYP2C9, other CYP2C9 inhibitors are unlikely to affect the pharmacokinetics of lumiracoxib, making dosage adjustment unnecessary. Moxifloxacin The effect of itraconazole 200 mg/day on the pharmacokinetics of moxifloxacin has been studied in 12 healthy men (34c ). There was no effect in the systemic availability of moxifloxacin or concentrations of its sulfated metabolite, but there was a 30% reduction in the AUC of moxifloxacin glucuronide and an approximately 54% increase in renal excretion, which may have been due to changes in phase 2 metabolism and/or transport mechanisms by itraconazole. Exposure (AUC) to itraconazole and its hydroxylated metabolite were not significantly altered by moxifloxacin. Nitrofurantoin Combined pulmonary and hepatic toxicity was reportedly precipitated by acute use of fluconazole concomitantly with chronic nitrofurantoin (35AR ). • A 73-year-old white man who had taken nitrofurantoin 50 mg/day for 5 years developed combined hepatic and pulmonary toxicity after taking fluconazole for onychomycosis. His hepatic enzymes rose to 5 times the upper limits of the reference range and he reported fatigue, dyspnea on exertion, pleuritic pain, burning tracheal pain, and a cough. Chest X-rays showed bilateral pulmonary disease consistent with nitrofurantoin toxicity. Both drugs were withdrawn and the hepatic and pulmonary toxicity resolved with inhaled glucocorticoids.
While either drug may have caused abnormal liver function tests, it is possible that pharmacokinetic changes induced by an interaction with fluconazole precipitated the nitrofurantoininduced pulmonary toxicity by an unknown mechanism. Rifampicin The effect of rifampicin on the pharmacokinetics of fluconazole and on clinical outcomes of fluconazole treatment in patients with AIDS-related cryptococcal meningitis have been studied in 40 Thai patients with AIDS and cryptococcal meningitis, of whom 20 had been taking oral rifampicin for at least 2
285 weeks to treat tuberculosis (36c ). Concomitant administration of rifampicin with fluconazole resulted in significant changes in the pharmacokinetics of fluconazole, including a 28% shorter half-life, a 22% reduction in AUC, a 17% reduction in Cmax , and a 30% increase in clearance. Different fluconazole regimens did not affect the extent of change in half-life. Although serum concentrations of fluconazole during the time that patients took rifampicin + fluconazole 200 mg/day were generally lower than the minimum inhibitory concentration for Cryptococcus neoformans, there were no significant differences in clinical outcomes between the two groups. Co-administration of rifampicin with fluconazole caused significant changes in the pharmacokinetics of fluconazole, and longterm monitoring for recurrent cryptococcal meningitis is required to assess the clinical significance of this interaction. Sirolimus Sirolimus is metabolized by CYP3A4 and is a substrate of P glycoprotein, both of which are inhibited by drugs like voriconazole, itraconazole, and fluconazole (37AR ). • A 60-year-old patient taking sirolimus 2 mg/day after renal transplantation received fluconazole 100 mg/day, and after 22 days sirolimus trough plasma concentrations had increased four-fold without clinically overt adverse effects. The dosages of both drugs were reduced and tapered to achieve sirolimus trough concentrations within the recommended target range.
This case demonstrates that it is essential to monitor the blood sirolimus concentrations and to adjust the sirolimus doses before and after co-administration of fluconazole and other antifungal triazoles. Concomitant treatment with voriconazole and sirolimus in two renal transplant recipients reduced sirolimus dosage requirements by 75– 88% (38AR ). Sulfamethoxazole The formation of sulfamethoxazole hydroxylamine, in combination with long-term oxidative stress, is thought to be the cause of high rates of adverse drug reactions to sulfamethoxazole in subjects infected by HIV. The effect of fluconazole on sulfamethoxazole hydroxylamine formation in individuals with HIV-1 infection has been investigated in a two-part open drug interaction
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study in 21 subjects (39c ). Fluconazole reduced the AUC, the percent of the dose excreted in urine in 24 hours, and formation clearance of the hydroxylamine by 37%, 53%, and 61% respectively. Rifabutin increased the AUC, percent excreted, and formation clearance of the hydroxylamine by 55%, 45%, and 53% respectively. Fluconazole plus rifabutin reduced the AUC, percent excreted, and formation clearance of the hydroxylamine by 21%, 37%, and 46% respectively. Clarithromycin had no effect on hydroxylamine production. If exposure to sulfamethoxazole hydroxylamine predicts sulfamethoxazole toxicity, rifabutin will increase and clarithromycin plus fluconazole or rifabutin plus fluconazole should reduce the rates of adverse reactions to sulfamethoxazole in HIVinfected subjects.
Fluconazole
(SED-15, 1377)
Observational studies Outcomes in 20 patients with solid tumors and candidemia treated with high-dose fluconazole (at least 600 mg/ day) have been reported (40c ). There were no significant adverse effects. Endocrine Case reports have described an association between fluconazole and adrenal dysfunction, an important cause of morbidity and mortality in critically ill patients. In a retrospective analysis of the effects of fluconazole 400 mg/day in 154 critically ill surgical patients the median plasma cortisol concentration was 158 µg/l in 79 patients randomized to fluconazole and 167 µg/l in 75 patients randomized to placebo (41C ). Patients randomized to fluconazole did not have significantly increased odds of adrenal dysfunction compared with patients randomized to placebo (OR = 0.98; 95%CI = 0.48, 2.01). Randomization to fluconazole was not associated with a significant difference in cortisol concentrations over time. Mortality was not different between patients with and without adrenal dysfunction, nor between patients with adrenal dysfunction who were randomized to fluconazole and those randomized to placebo.
Itraconazole
(SED-15, 1932)
Skin A 45-year-old woman with autoimmune polyglandular syndrome type I taking long-
Andreas H. Groll and Thomas J. Walsh
term betamethasone developed fatal toxic epidermal necrolysis when she was given itraconazole (42AR ). It was unclear, however, whether the polyglandular syndrome or any of the other drugs used in her care (canrenoate, coamoxiclav, furosemide, levofloxacin, and pantoprazole) were causally involved. Susceptibility factors Cystic fibrosis The pharmacokinetics of itraconazole and hydroxyitraconazole have been assessed in 17 patients with cystic fibrosis (43c ). Steady-state concentrations were achieved after 8 days. On day 14 average Cmax was 404 ng/ml in those under 16 years of age (n = 5) and 779 ng/ml in those aged 16 years and over (n = 11), excluding one patient who was concurrently taking oral clarithromycin. All the younger patients and half of the older patients failed to achieve a plasma steady-state trough concentration of over 250 ng/ml. Adverse events were reported by nine of the subjects. Most were mild or moderate in intensity and were not considered related to treatment. One patient withdrew because of two severe adverse events (nausea and vomiting). There were ten significant laboratory abnormalities in seven of 16 patients with paired data. Six of these were clinically relevant (hyperuricemia in two and leukocytosis, anemia, hypokalemia, and a mild rise in alanine transaminase in one each).
Posaconazole
(SED-15, 2905)
Posaconazole is a lipophilic antifungal triazole. In vitro, it has broad-spectrum activity against opportunistic, endemic, and dermatophytic fungi, including organisms that are often resistant to existing agents, such as C. glabrata, C. krusei, A. terreus, Fusarium species, and the Zygomycetes. A large variety of animal models of invasive fungal infections have provided consistent evidence of efficacy against these organisms in vivo. Posaconazole is available as an oral suspension and achieves optimal exposure when administered in two to four divided doses given with food or a nutritional supplement. Posaconazole has a large volume of distribution, in the order of 5 l/kg, and a half-life
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of about 20 hours. It is not metabolized by CYP450 but is primarily excreted unchanged in the feces. It inhibits CYP3A4, but has no effects on CYP1A2, CYP2C8, CYP2C9, CYP2D6, and CYP2E1, and a limited spectrum of drug– drug interactions can therefore be expected. Posaconazole had strong antifungal efficacy in phase II and III clinical trials in immunocompromised patients with oropharyngeal and esophageal candidiasis. It also had promising efficacy as salvage therapy in a large phase II study. In the subset of 107 patients with invasive aspergillosis, 42% had a complete or partial response at the end of treatment compared with 26% of a contemporaneous control cohort. Posaconazole appears to be as well tolerated as fluconazole; it has been approved in the European Union for salvage treatment of invasive fungal infections including invasive aspergillosis (6R , 44R ) and for prophylaxis in high-risk patients (USA and European Union). Food–drug interactions The effects of prandial status and the fat content of a meal on the systemic availability of posaconazole suspension and co-precipitate tablet formulations has been studied in a randomized, open-label, 4-way crossover, single-dose study in 20 healthy men (45c ). The posaconazole suspension had greater availability than the tablet and availability was markedly increased by a high-fat meal.
Voriconazole
(SED-15, 3688)
Apart from a higher incidence of liver function test abnormalities than with fluconazole, photosensitization, hallucinations, and visual adverse events need to be considered in patients taking voriconazole (6R , 7R ). Cardiovascular QT interval prolongation is a class effect of antifungal azoles, but has not previously been attributed to voriconazole. • A 15-year-old girl with acute lymphoblastic leukemia, who was taking voriconazole for a Fusarium infection, developed asymptomatic bradycardia, QT interval prolongation, and non-sustained, polymorphic ventricular tachycardia, which recurred on rechallenge (46CR ). Voriconazole concentrations and metabolism were within expected values.
This patient was also taking several potentially arrhythmogenic drugs and had
287 hypokalemia during the first episode; however, during rechallenge the electrolytes were within normal values and the only co-administered drugs included vancomycin and amikacin. The authors concluded that this observation suggested that closer attention should be paid to cardiac rhythm monitoring during voriconazole treatment. Sensory systems In a multicenter study of a parenteral formulation of voriconazole in 39 immunocompromised children (aged 2–11 years) visual disturbances occurred in five and were the only drug-related adverse events that occurred more than once (47C ). Psychiatric Voriconazole can be associated with visual and other hallucinations. • A 78-year-old man began to have auditory hallucinations, specifically of Christmas music, on the second day of voriconazole therapy (48AR ). Psychiatric evaluation was otherwise unremarkable. After withdrawal of voriconazole the hallucinations reduced in intensity by 2 days and ceased altogether by the third day.
An extensive literature search, including Pfizer drug trial safety data, yielded no other reports of auditory hallucinations with voriconazole. Several other cases of musical hallucinations secondary to a variety of causes have been reported. They tend to occur secondary to temporal lobe insults and often have religious or patriotic themes. Skin Severe retinoid-like photosensitivity (erythema, desquamation, and ulceration of light-exposed skin) has been reported in two children with chronic granulomatous disease who took voriconazole 200 mg bd for chronic invasive aspergillosis (49AR ). Histopathological examination in one of the patients showed superficial and deep perivascular dermatitis with epidermal necrosis, compatible with a photo-induced drug eruption. Although strict sun protection and sun avoidance led to resolution of the acute lesions while voriconazole was continued, dark pigmented lentigines developed over previously involved areas. In the second patient, the lesions completely resolved after withdrawal of the drug. There were similar phototoxic manifestations in two adults who
288 took long-term voriconazole (50R ). In both patients, voriconazole was withdrawn and the lesions resolved within 2 weeks. While the exact mechanisms of voriconazole-associated phototoxicity are unknown, inhibition of retinoid metabolism or a direct phototoxic effect of voriconazole or one of its metabolites have been implicated. Susceptibility factors Age In a multicenter study of a parenteral formulation of voriconazole in 39 immunocompromised children (aged 2–11 years) was reported body weight was more influential than age in accounting for the observed variability in voriconazole pharmacokinetics (47C ). Thus, children have a higher capacity for elimination of voriconazole per kilogram of body weight than healthy adults. Monitoring therapy Individual voriconazole dosage modification based on plasma concentrations has been suggested because of concerns about voriconazole-related liver toxicity (51R ). In a reply, the manufacturers presented a summary of unpublished data of logistic regression analyses that they had performed in order to identify any possible relation between plasma concentrations and increases in liver function tests (52S ). These analyses, performed on about 3000 samples from 1000 patients enrolled in 10 clinical trials showed only a weak and inconsistent association between plasma concentrations of voriconazole and abnormal liver function tests. There was no association between plasma concentrations and antifungal efficacy in a subset of patients with defined fungal infections. The authors concluded that plasma concentration monitoring is unlikely to add any value over clinical judgment and diligent monitoring of liver function tests, as no definite guidance can be provided for the interpretation of plasma concentrations of voriconazole. In another report, the issue of drug monitoring in patients taking voriconazole used the examples of three patients with diverse manifestations of toxicity that were possibly attributable to high voriconazole concentrations (53c ). Of 16 patients who were treated with voriconazole at the authors’ center between 1993 and 2001 and in whom voriconazole trough concentrations were measured, three had significant toxicity, all with high trough plasma concentrations (hypoglycemia, 9.7 µg/ml; altered mental
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status and hallucinations, 9.0 µg/ml; hyperkalemia, 18 µg/ml). The authors argued that a case could be made for plasma concentration monitoring, based on these results, polymorphism in the CYP2C19 isoenzyme, and the nonlinear disposition of voriconazole. While this will remain controversial until more systematic post-marketing studies have been concluded, assessing trough concentrations is a reasonable approach, at least in patients with adverse events that might be due to voriconazole.
ECHINOCANDINS
(SED-15, 1197; SEDA-26, 311; SEDA-28, 309) The current echinocandins (anidulafungin, caspofungin, and micafungin) have potent and broad-spectrum antifungal activity against Candida and Aspergillus species. Their activity against other fungal pathogens in vitro is variable (6R , 7R ). All three compounds have doseindependent pharmacokinetics with half-lives of 10–15 hours and are dosed once a day. They are over 95% protein bound and distribute into all major tissues, including the brain; concentrations in non-inflammatory CSF are low. The echinocandins are metabolized by the liver and are slowly excreted as inactive metabolites into the urine and feces; only small fractions are excreted into the urine unchanged. They lack significant potential for drug interactions mediated by the CYP450 enzyme system and are generally well tolerated (6R , 7R ). The clinical efficacy of anidulafungin, caspofungin, and micafungin against Candida species has been documented in phase II and phase III studies in immunocompromised patients with superficial and invasive fungal infections, as empirical antifungal therapy in granulocytopenic patients with persistent fever despite broad-spectrum empirical antibacterial therapy, and as prophylaxis in high-risk granulocytopenic patients after hemopoietic stem cell transplantation. Caspofungin is licensed in the European Union and the USA in patients aged 18 years and over for second-line therapy of definite or probable invasive aspergillosis, for primary therapy in non-neutropenic patients with invasive Candida infections, and for empirical antifungal therapy in granulocytopenic patients with persistent fever. Micafungin is
Antifungal drugs
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licensed in the USA only for antifungal prophylaxis in granulocytopenic patients following hemopoietic stem cell transplantation (7R ).
Anidulafungin Observational studies The safety and efficacy of intravenous anidulafungin 50, 75, or 100 mg/day has been investigated in 123 patients, 68 evaluable, with invasive candidiasis, including candidemia (54C ). Eligible patients were randomized to one of three regimens. Adverse events considered to be related to treatment were reported by under 5% of patients in each dosage group. The most common events were hypotension, vomiting, constipation, nausea, and pyrexia. Three serious adverse events were reported as either probably or possibly related to treatment (neutropenic fever, n = 1; seizures, n = 2). Comparative studies A randomized, double-blind, double-dummy study compared intravenous anidulafungin 50 mg/day and oral fluconazole 100 mg/day for 14–21 days in 601 patients with proven esophageal candidiasis (55C ). The safety profiles were similar. Treatment-related adverse events occurred in 9.3% and 12% of patients respectively. Laboratory parameters were similar between the treatments. Drug withdrawal was required in five patients (four versus one) because of adverse events.
Caspofungin Comparative studies Caspofungin (n = 556) has been compared with liposomal amphotericin (n = 539) in a randomized, doubleblind, multinational trial as empirical antifungal therapy (15C ). Patients were stratified according to risk and whether they had previously received antifungal prophylaxis. Premature withdrawal for any cause was less common with caspofungin than amphotericin (10 versus 15%). Fewer patients who received caspofungin sustained nephrotoxicity (2.6 versus 12%), an infusion-related event (35 versus 52%), or a systemic drug-related adverse event or discontinued therapy because of drug-related adverse events.
Observational studies Caspofungin has been investigated in a non-comparative phase II clinical study in 90 patients with invasive aspergillosis (56C ). Two patients withdrew because of drug-related adverse events; 84 developed at least one clinical adverse event. However, only 11 had an adverse event that was possibly, probably, or definitely related to caspofungin. Of the 90 patients 53 developed at least one laboratory adverse event, but only 12 were considered to have had a drug-related adverse event. Drugrelated nephrotoxicity (1.1%) and hepatotoxicity (under 5%) occurred infrequently. Hematologic A 68-year-old man developed reversible severe thrombocytopenia, possibly due to caspofungin, after being successfully treated for Candida albicans endocarditis (57AR ). Drug interactions Amphotericin Two retrospective analyses have suggested that caspofungin and liposomal amphotericin B may be given safely in combination in the usual therapeutic dosages (58c , 59c ). Ciclosporin There were mild, transient rises in alanine transaminase activity in phase I studies of caspofungin and ciclosporin. The hepatic safety of concomitant ciclosporin has been analysed in two retrospective case series. The first analysis was a retrospective chart review at four sites in 40 patients who had taken both drugs for 1–290 days (60c ). There were rises in transaminases in 14 patients. Five had rises in aspartate transaminase activity at least possibly related to caspofungin + ciclosporin, but none was over 3.6 times the normal upper limit. No rises in alanine transaminase activity were related to caspofungin + ciclosporin. In two of four patients who discontinued therapy because of hepatotoxicity, there was a possible relationship to caspofungin + ciclosporin. No serious adverse events occurred because of caspofungin. In the second analysis, safety data were assessed in 14 patients with refractory invasive mycoses who took ciclosporin + caspofungin for 2–34 days before the latter was licensed (61c ). There were no clinically significant rises in serum transaminases and no patient had concomitant therapy discontinued or interrupted because of a drug-related adverse event.
290 These data do not suggest a significant risk of clinically relevant hepatotoxicity with concomitant caspofungin + ciclosporin. However, systematic prospectively generated data are needed to assess further the significance of this possible interaction. Cytarabine A high throughput microtiter assay was used to determine whether cytarabine, idarubicin, itraconazole, or caspofungin were CYP450 isoenzyme substrates or inhibitors of CYP450 isoenzymes, and to determine potential CYP450 metabolism interactions between them (25E ). Idarubicin was a substrate for CYP2D6 and CYP2C9 and cytarabine was a substrate of CYP3A4. Idarubicin inhibited CYP2D6, and cytarabine, itraconazole, and caspofungin inhibited CYP3A4. Cytarabine metabolism was significantly reduced when it was combined with caspofungin or itraconazole. This in vitro inhibition of cytarabine metabolism may have important clinical implications that warrant investigation with in vivo pharmacokinetic studies. Nelfinavir The potential for an interaction of caspofungin (50 mg/day intravenously; n = 10) with nelfinavir (1,250 mg bd orally; n = 9) has been evaluated in two parallel-panel studies. In study A, healthy subjects received a 14-day course of caspofungin alone (62c ). Nelfinavir did not significantly alter the pharmacokinetics of caspofungin. Rifampicin The potential for an interaction of caspofungin (50 mg/day intravenously; n = 10) with rifampicin (1,250 mg bd orally; n = 10) has been evaluated (62c ). Rifampicin increased the initial AUC and trough concentration of caspofungin and reduced the steady-state trough concentration, consistent with initial transient inhibition of metabolism and net induction at steady state. Therefore, an increase in the dose of caspofungin to 70 mg/day should be considered when it is co-administered with rifampicin. Voriconazole In a retrospective analysis the combination of caspofungin + voriconazole at currently approved dosages has been assessed (63c ). Compared with a historical control cohort of patients taking voriconazole alone there was no indication of increased toxicity of the combination with caspofungin.
Chapter 27
Andreas H. Groll and Thomas J. Walsh
Micafungin Comparative studies The dose-response relation of micafungin (50, 100, or 150 mg) has been compared with that of standard fluconazole treatment for esophageal candidiasis in a randomized, double-blind study in 245 HIVinfected patients (64C ). The incidence of adverse events was 93% with micafungin and 89% with fluconazole. The most common treatmentrelated adverse events were fever, abdominal pain, nausea, diarrhea, leukopenia, injectionsite inflammation, and headache. There were no clinically important changes in laboratory measures. There were changes in liver function tests in 13% of patients: micafungin 24/185 patients and fluconazole 7/60 patients. There were no apparent dose-dependent differences in safety and tolerance across the investigated dosages of micafungin, and no differences in safety and tolerance between micafungin and fluconazole. In a randomized, double-blind, multi-institutional, comparative phase III trial in antifungal prophylaxis during neutropenia in patients undergoing hemopoietic stem cell transplantation (65C ) micafungin 1 mg/kg/day up to a maximum of 50 mg/day was compared with fluconazole 8 mg/kg/day up to a maximum of 400 mg/day in 882 adults and children (65C ). All the patients had at least one adverse event, but fewer micafungin-treated patients withdrew as a result (4.2% versus 7.2%). Adverse events that were considered to be drugrelated occurred in 15% of micafungin-treated patients and in 17% of fluconazole-treated patients. There were no differences in liver function tests between patients who received micafungin + ciclosporin and those who received micafungin alone. These two studies suggest a safety profile of micafungin that is at least similar to that of fluconazole.
Nystatin
(SED-15, 2591)
The activity and safety of multilamellar liposomal nystatin for invasive aspergillosis has been investigated in 26 patients refractory to or intolerant of amphotericin B (66c ). There was at least one infusion-related adverse event in 22 patients. The most frequent adverse effects included chills (n = 21), shivering (n = 6), and
Antifungal drugs
Chapter 27
fever (n = 7), leading to withdrawal in two patients. There was grade 1 impairment of renal function in 10 patients, and hypokalemia in 13. Liposomal nystatin can be effective in
291 salvage therapy of invasive aspergillosis. However, infusion-related adverse events are frequent.
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30. Gubbins PO, McConnell SA, Gurley BJ, Fincher TK, Franks AM, Williams DK, Penzak SR, Saccente M. Influence of grapefruit juice on the systemic availability of itraconazole oral solution in healthy adult volunteers. Pharmacotherapy 2004;24:460–7. 31. Dutreix C, Peng B, Mehring G, Hayes M, Capdeville R, Pokorny R, Seiberling M. Pharmacokinetic interaction between ketoconazole and imatinib mesylate (Glivec) in healthy subjects. Cancer Chemother Pharmacol 2004;54:290–4. 32. Isohanni MH, Neuvonen PJ, Olkkola KT. Effect of itraconazole on the pharmacokinetics of inhaled lidocaine. Basic Clin Pharmacol Toxicol 2004;95:120–3. 33. Scott G, Yih L, Yeh CM, Milosavljev S, Laurent A, Rordorf C. Lumiracoxib: pharmacokinetic and pharmacodynamic profile when coadministered with fluconazole in healthy subjects. J Clin Pharmacol 2004;44:193–9. 34. Stass H, Nagelschmitz J, Moeller JG, Delesen H. Pharmacokinetics of moxifloxacin are not influenced by a 7-day pretreatment with 200 mg oral itraconazole given once a day in healthy subjects. Int J Clin Pharmacol Ther 2004;42:23–9. 35. Linnebur SA, Parnes BL. Pulmonary and hepatic toxicity due to nitrofurantoin and fluconazole treatment. Ann Pharmacother 2004;38:612–6. 36. Panomvana NA, Ayudhya D, Thanompuangseree N, Tansuphaswadikul S. Effect of rifampicin on the pharmacokinetics of fluconazole in patients with AIDS. Clin Pharmacokinet 2004;43:725–32. 37. Sadaba B, Campanero MA, Quetglas EG, Azanza JR. Clinical relevance of sirolimus drug interactions in transplant patients. Transplant Proc 2004;36:3226–8. 38. Mathis AS, Shah NK, Friedman GS. Combined use of sirolimus and voriconazole in renal transplantation: a report of two cases. Transplant Proc 2004;36:2708–9. 39. Winter HR, Trapnell CB, Slattery JT, Jacobson M, Greenspan DL, Hooton TM, Unadkat JD. The effect of clarithromycin, fluconazole, and rifabutin on sulfamethoxazole hydroxylamine formation in individuals with human immunodeficiency virus infection (AACTG 283). Clin Pharmacol Ther 2004;76:313–22. 40. Torres HA, Kontoyiannis DP, Rolston KV. Highdose fluconazole therapy for cancer patients with solid tumors and candidemia: an observational, noncomparative retrospective study. Support Care Cancer 2004;12:511–6. 41. Magill SS, Puthanakit T, Swoboda SM, Carson KA, Salvatori R, Lipsett PA, Hendrix CW. Impact of fluconazole prophylaxis on cortisol levels in critically ill surgical Patients. Antimicrob Agents Chemother 2004;48:2471–6. 42. Porzionato A, Zancaner S, Betterle C, Ferrara SD. Fatal toxic epidermal necrolysis in autoimmune polyglandular syndrome type I. J Endocrinol Invest 2004;27:475–9. 43. Conway SP, Etherington C, Peckham DG, Brownlee KG, Whitehead A, Cunliffe H. Pharmacokinetics and safety of itraconazole in pa-
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tients with cystic fibrosis. J Antimicrob Chemother 2004;53:841–7. Groll AH, Walsh TJ. Posaconazole: clinical pharmacology and potential for management of fungal infections. Expert Rev Anti Infect Ther 2005;3:467–87. Courtney R, Wexler D, Radwanski E, Lim J, Laughlin M. Effect of food on the relative bioavailability of two oral formulations of posaconazole in healthy adults. Br J Clin Pharmacol 2004;57:218–22. Alkan Y, Haefeli WE, Burhenne J, Stein J, Yaniv I, Shalit I. Voriconazole-induced QT interval prolongation and ventricular tachycardia: a non-concentration-dependent adverse effect. Clin Infect Dis 2004;39:e49–52. Walsh TJ, Karlsson MO, Driscoll T, Arguedas AG, Adamson P, Saez-Llorens X, Vora AJ, Arrieta AC, Blumer J, Lutsar I, Milligan P, Wood N. Pharmacokinetics and safety of intravenous voriconazole in children after single- or multiple-dose administration. Antimicrob Agents Chemother 2004;48:2166–72. Agrawal AK, Sherman LK. Voriconazoleinduced musical hallucinations. Infection 2004;32:293–5. Rubenstein M, Levy ML, Metry D. Voriconazoleinduced retinoid-like photosensitivity in children. Pediatr Dermatol 2004;21:675–8. Vandecasteele SJ, Van Wijngaerden E, Peetermans WE. Two cases of severe phototoxic reactions related to long-term outpatient treatment with voriconazole. Eur J Clin Microbiol Infect Dis 2004;23:656–7. Potoski BA, Brown JR. The safety of voriconazole. Clin Infect Dis 2002;35:1273–5. Lutsar I, Hodges MR, Tomaszewski K, Troke PF, Wood ND. Safety of voriconazole and dose individualization. Clin Infect Dis 2003;36:1087–8. Boyd AE, Modi S, Howard SJ, Moore CB, Keevil BG, Denning DW. Adverse reactions to voriconazole. Clin Infect Dis 2004;39:1241–4. Krause DS, Reinhardt J, Vazquez JA, Reboli A, Goldstein BP, Wible M, Henkel T, Anidulafungin Invasive Candidiasis Study Group. Phase 2, randomized, dose-ranging study evaluating the safety and efficacy of anidulafungin in invasive candidiasis and candidemia. Antimicrob Agents Chemother 2004;48:2021–4. Krause DS, Simjee AE, van Rensburg C, Viljoen J, Walsh TJ, Goldstein BP, Wible M, Henkel T. A randomized, double-blind trial of anidulafungin versus fluconazole for the treatment of esophageal candidiasis. Clin Infect Dis 2004;39:770–5. Maertens J, Raad I, Petrikkos G, Boogaerts M, Selleslag D, Petersen FB, Sable CA, Kartsonis NA, Ngai A, Taylor A, Patterson TF, Denning DW, Walsh TJ, Caspofungin Salvage Aspergillosis Study Group. Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy. Clin Infect Dis 2004;39:1563–71.
293 57. Lynch J, Wong-Beringer A. Caspofungin: a potential cause of reversible severe thrombocytopenia. Pharmacotherapy 2004;24:1408–11. 58. Kontoyiannis DP, Hachem R, Lewis RE, Rivero GA, Torres HA, Thornby J, Champlin R, Kantarjian H, Bodey GP, Raad II. Efficacy and toxicity of caspofungin in combination with liposomal amphotericin B as primary or salvage treatment of invasive aspergillosis in patients with hematologic malignancies. Cancer 2003;98:292–9. 59. Aliff TB, Maslak PG, Jurcic JG, Heaney ML, Cathcart KN, Sepkowitz KA, Weiss MA. Refractory Aspergillus pneumonia in patients with acute leukemia: successful therapy with combination caspofungin and liposomal amphotericin. Cancer 2003;97:1025–32. 60. Marr KA, Hachem R, Papanicolaou G, Somani J, Arduino JM, Lipka CJ, Ngai AL, Kartsonis N, Chodakewitz J, Sable C. Retrospective study of the hepatic safety profile of patients concomitantly treated with caspofungin and cyclosporin A. Transpl Infect Dis 2004;6:110–6. 61. Sanz-Rodriguez C, Lopez-Duarte M, Jurado M, Lopez J, Arranz R, Cisneros JM, Martino ML, Garcia-Sanchez PJ, Morales P, Olive T, Rovira M, Solano C. Safety of the concomitant use of caspofungin and cyclosporin A in patients with invasive fungal infections. Bone Marrow Transplant 2004;34:13–20. 62. Stone JA, Migoya EM, Hickey L, Winchell GA, Deutsch PJ, Ghosh K, Freeman A, Bi S, Desai R, Dilzer SC, Lasseter KC, Kraft WK, Greenberg H, Waldman SA. Potential for interactions between caspofungin and nelfinavir or rifampin. Antimicrob Agents Chemother 2004;48:4306–14. 63. Marr KA, Boeckh M, Carter RA, Kim HW, Corey L. Combination antifungal therapy for invasive aspergillosis. Clin Infect Dis 2004;39:797–802. 64. de Wet N, Llanos-Cuentas A, Suleiman J, Baraldi E, Krantz EF, Della Negra M, DiekmannBerndt H. A randomized, double-blind, parallelgroup, dose-response study of micafungin compared with fluconazole for the treatment of esophageal candidiasis in HIV-positive patients. Clin Infect Dis 2004;39:842–9. 65. van Burik JA, Ratanatharathorn V, Stepan DE, Miller CB, Lipton JH, Vesole DH, Bunin N, Wall DA, Hiemenz JW, Satoi Y, Lee JM, Walsh TJ, National Institute of Allergy and Infectious Diseases Mycoses Study Group. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis 2004;39:1407–16. 66. Offner F, Krcmery V, Boogaerts M, Doyen C, Engelhard D, Ribaud P, Cordonnier C, de Pauw B, Durrant S, Marie JP, Moreau P, Guiot H, Samonis G, Sylvester R, Herbrecht R, EORTC Invasive Fungal Infections Group. Liposomal nystatin in patients with invasive aspergillosis refractory to or intolerant of amphotericin B. Antimicrob Agents Chemother 2004;48:4808–12.
Oscar Ozmund Simooya
28
Antiprotozoal drugs
ANTIMALARIAL DRUGS The search for safe and efficacious treatments for malaria continues to be a major research priority. In many parts of the world there is now widespread parasite resistance to chloroquine and sulfadoxine + pyrimethamine, hitherto the drugs of choice for the treatment of uncomplicated malaria. Using the models developed successfully for the treatment of HIV/AIDS and tuberculosis, it has been proposed that combining two or more blood schizonticides with independent modes of action and different biochemical targets in the parasite would not only improve efficacy but would assist in delaying the development of parasite resistance. The choice would then be to identify suitable drug combinations.
4-AMINOQUINOLINES (CHLOROQUINE AND CONGENERS) (SEDA-26, 315; SEDA-27, 289; SEDA-28, 315)
Chloroquine and hydroxychloroquine
(SED-15, 722)
When used for a short duration in either treatment or prophylaxis, chloroquine is generally well tolerated. Common adverse effects after short-term use include headache, abdominal discomfort, dizziness, and transient disturbance of accommodation. In African subjects, chloroquine is often associated with pruritus. Serious adverse effects of chloroquine most often follow prolonged use, for example when it is used for a number of years to treat connective tissue diseases. A common problem of chronic treatment with chloroquine is ocular damage. Cardiovascular Cardiomyopathy after prolonged treatment with chloroquine is very uncommon. • A 50-year-old woman took chloroquine for 6 years for rheumatoid arthritis and developed a restrictive cardiomyopathy, which required heart transplantation (1A ).
Psychiatry Severe psychosis following treatment with chloroquine and hydroxychloroquine has been reported before. When it occurs it is usually during treatment for malaria, but it can follow treatment for connective tissue disorders. Hallucinations have been reported after hydroxychloroquine treatment for erosive lichen planus (2A ).
Although rapidly losing its potency in many parts of the world, chloroquine is still widely used for the treatment and prophylaxis of malaria because of its low cost and relative safety. Chloroquine and its metabolite, hydroxychloroquine, are also commonly used for the treatment of connective tissue disorders such as rheumatoid arthritis and systemic lupus erythematosus.
• A 75-year-old woman was given hydroxychloroquine 400 mg/day for erosive lichen planus in conjunction with topical glucocorticoids and a short course of oral methylprednisolone 0.5 mg/kg/day. After 10 days she became disoriented in time and place, followed by feelings of depersonalization and kinesthetic hallucinations, preceded by nightmares. She stopped taking hydroxychloroquine 1 week later and the hallucinations progressively disappeared. She recovered her normal mental state within 1 month and had not relapsed 2 years later.
Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29028-7 © 2007 Elsevier B.V. All rights reserved.
The potential for severe psychiatric adverse events must always be considered in patients taking long-term chloroquine and hydroxychloroquinine. The onset may be a few hours to many days after the start of therapy and it can
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Chapter 28
occur in a patient without a preceding history of mental illness. The mechanism is unknown. Recovery is rapid and occurs within days of stopping treatment. Skin Stevens–Johnson syndrome and toxic epidermal necrolysis following chloroquine are rare. A near fatal case has been reported (3A ). • A 32-year-old woman weighing 61 kg developed painful skin blisters and erosions accompanied by fever and myalgia. The symptoms started on the third day after a course of oral chloroquine (Tablets Lariago, chloroquine phosphate 500 mg, Ipca Laboratories, Mumbai, India); two tablets initially, one tablet after 6 hours, and one tablet/day for 2 days. Her symptoms began with erythematous itchy papular eruptions on the trunk and then progressed to involve the face, limbs, and mucous membranes of the mouth. She had difficulty in swallowing because of painful erosions of the mouth and oropharynx. There was conjunctivitis but no visual impairment. Bullae continued to appear on the trunk and limbs and a purpuric rash on the trunk. She responded well to intravenous fluids, antibiotics to prevent secondary infection, and hydrocortisone.
Infection risk An acute gluteal abscess after an injection of chloroquine has been reported (4A ). • A 24-year-old woman who had been pregnant for 24 weeks developed a fever, sweating, headache, and pain in the region where she had received an injection of chloroquine 9 days before. She was febrile (38.9 ◦ C). Chest examination was normal and the spleen was not palpable. She had a right gluteal abscess, which was later drained under general anesthesia. She was given ampicillin/cloxacillin, 500 mg intravenously at first and then orally for 7 days. Staphylococcus aureus sensitive to ampicillin/cloxacillin was isolated. She made uneventful recovery and delivered a live 2.9 kg baby.
Drug overdose Previous reports have suggested that the ingestion of more than 4 g of hydroxychloroquine results in severe hypotension or fatal ventricular dysrhythmias. Massive hydroxychloroquine overdose has been reported (5A ). • A 17-year-old girl took 22 g of hydroxychloroquine in a suicide attempt. She developed hypotension, life-threatening ventricular dysrhythmias, and mild hypokalemia. She was managed with saline infusion and dopamine for hypotension, gastric lavage and activated charcoal for decontamination, and lidocaine, magnesium sulfate and
defibrillation for pulseless ventricular tachycardia. Potassium replacement and bicarbonate replacement were performed. She survived without sequelae.
Quick treatment of hypotension, gastric decontamination, continuous cardiac monitoring, and the treatment of dysrhythmias are critical in the management of hydroxychloroquine and that of chloroquine intoxication.
Mefloquine
(SED-15, 2232)
Psychiatry Mefloquine is generally safe but has been plagued by continued reports of neuropsychiatric disturbances, such as dizziness and anxiety. It is used mainly as prophylaxis by travellers to malaria endemic countries. Efforts to understand the mechanism of its neuropsychiatric effects continue. In a review of 10 trials (n = 2750 nonimmune adult travelers) (6R ) the effects of mefloquine in adult travellers were compared with the effects of other regimens in relation to episodes of malaria, withdrawal from prophylaxis, and adverse effects. Five trials were field studies of male soldiers. One comparison of mefloquine with placebo showed that mefloquine was effective in an area of drug resistance (OR = 0.04; 95%CI = 0.02, 0.08) and withdrawals in the mefloquine group were consistently higher in four placebo-controlled trials (OR = 3.56; 95%CI = 1.67, 7.60). In five comparisons of mefloquine with other chemoprophylaxis regimens, there was no difference in tolerability. The only consistent adverse effects consistently specific to mefloquine in the controlled trials were insomnia and fatigue, but there were also 516 reports of adverse effects of mefloquine, 63% of which were in tourists and travellers. Four deaths were attributed to mefloquine. In another major review the risk of depression, psychosis, a panic attack, or a suicide attempt during current or previous use of mefloquine was compared with the risk during the use of proguanil and/or chloroquine or doxycycline (7R ). The study population (n = 35 370) was aged 17–79 years (45% men). There was no evidence that the risk of depression was increased during or after the use of mefloquine, but psychoses and panic attacks were more frequent in
296 current users of mefloquine than in those using other antimalarial drugs.
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Oscar Ozmund Simooya
it was causally related, although sulfadoxine– pyrimethamine has not previously been reported to cause extrapyramidal effects.
PYRIMETHAMINE AND COMBINATIONS (SED-15, 2984;
QUININE AND CONGENERS
SEDA-26, 320; SEDA-27, 293; SEDA-28, 318)
(SED-15, 3002; SEDA-26, 318; SEDA-27, 290)
Pyrimethamine + dapsone
Quinine
Immunologic Dapsone hypersensitivity syndrome is a rare condition that occurs mostly in patients with leprosy. Dapsone is combined with pyrimethamine in Maloprim, an effective chemoprophylactic agent for chloroquineresistant malaria. Three cases of dapsone hypersensitivity syndrome have been reported in male military recruits taking Maloprim prophylaxis for malaria (8A ). They developed high-grade fever and rash after taking weekly doses of Maloprim for 6–8 weeks. The first patient had an erythematous, macular rash over the upper limbs and trunk, which looked like a viral exanthem, the second had a generalized maculopapular rash over the trunk, and the third had an erythematous rash on his trunk and limbs. All three responded well to topical and systemic glucocorticoids and oral antihistamines. Recovery was uneventful. Early and immediate institution of glucocorticoids and withdrawal of Maloprim is necessary for the treatment of this rare condition.
Respiratory Pulmonary edema is uncommon after treatment with quinine, but a case has been reported (10A ).
Pyrimethamine + sulfadoxine Nervous system Although neurological complications are not uncommon in malaria, extrapyramidal manifestations are rare. An unusual case of extrapyramidal syndrome after sulfadoxine–pyrimethamine has been reported (9A ). • A 39-year-old man with malaria was given three tablets of sulfadoxine–pyrimethamine. After 50 minutes, he developed extrapyramidal signs, with spasmodic torticollis, trismus, and akathisia. He was given intravenous diazepam 10 mg and made a quick recovery with no residual extrapyramidal signs.
As the extrapyramidal signs occurred 50 minutes after a single dose of sulfadoxine– pyrimethamine there is a strong possibility that
• A 57-year-old man with leg cramps developed transient acute pulmonary edema and hypotension 30–40 minutes after taking quinine sulfate 300 mg orally on two occasions. He was not taking any other drugs and there was no explanation for either event. Serial troponin T tests, an electrocardiogram, echocardiogram, and coronary angiogram were all normal.
Psychiatric Probable suicide after quinine treatment for chloroquine-resistant malaria has been reported (11A ). • A 27-year-old man with falciparum malaria was given an infusion of quinine 600 mg in 5% dextrose tds until his vomiting stopped. Five hours later he was found dead by hanging using his turban. There was no adverse social history and the patient was in general good health.
The cause of this man’s suicide is not known but could have been caused by mental changes brought about by hypoglycemia either due to falciparum malaria itself or as a side effect of quinine therapy. Susceptibility factors Age Quinine can cause heart toxicity but little is known about its effects in children. In 10 children with severe Plasmodium falciparum malaria aged 6 months to 11 years a loading dose of quinine dihydrochloride 20 mg/kg in 500 ml of 5% dextrose infused over 4 hours was followed by 10 mg/kg every 8 hours (12c ). Holter monitoring was performed for the first 24 hours. Mean heart rate was 100–156/minute and there were no major ventricular dysrhythmias. The high cardiac rate could have been due to pyrexia and anemia. There was no prolongation of the PQ or QT intervals and no other adverse effects were reported.
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ENDOPEROXIDES Artemisinin derivatives
(SED-15, 342; SEDA-26, 319; SEDA-27, 292; SEDA-28, 320)
Because most of the information about the safety of artemisinin derivatives has come from South East Asia, several studies are under way in other parts of the world to assess their safety and efficacy and also to identify suitable combinations of therapies. Previous studies suggested a large degree of safety with the use of artemisinin derivatives, although in animals neurotoxicity and fetal resorption have been reported. These findings are yet to be confirmed in man. In a meta-analysis of 16 randomized controlled clinical trials (n = 5948) the effect of adding artesunate to standard treatment of Plasmodium falciparum malaria was analysed (13M ). The review compared treatment failures at day 14 and day 28 for standard drug alone against standard drug plus artesunate given over 3 days; parasitological failure was lower with artesunate. The occurrence of serious adverse events did not differ significantly between the groups. Observational studies Artemether (480 mg in six injections intramuscularly) was given to 28 pregnant Sudanese women with falciparum malaria after treatment failure with chloroquine and quinine (14c ). One patient received artemether in the 10th week of gestation, 12 during the second trimester, and 15 during the third trimester. Artemether was well tolerated. One patient delivered at 32 weeks and the baby died 6 hours later. The other 27 delivered fullterm live babies. None of the women died and there were no still-births or abortions. Comparative studies Of 1017 patients aged 6 months to 10 years with uncomplicated malaria, 400 were randomized to chloroquine (25 mg/kg over 3 days) + a single dose of sulfadoxine–pyrimethamine (sulfadoxine 25 mg/ kg, pyrimethamine 1.25 mg/kg); amodiaquine 25 mg/kg over 3 days + sulfadoxine–pyrimethamine; or amodiaquine + artesunate (4 mg/kg/day for 3 days); 396 were assessed for safety (15C ). There were no major adverse events.
Amodiaquine and artesunate have been compared alone and in combination for the treatment of uncomplicated malaria in 87 children aged 1–15 years, who were randomly assigned to amodiaquine 10 mg/kg (n = 27), artesunate 4 mg/kg (n = 27), or amodiaquine + artesunate (n = 33) (16c ). All the regimens were well tolerated and there were no major adverse events. Hematological profiles and serum transaminases were normal in all the groups. Only one child treated with artesunate developed a transient rise in alanine transaminase, which normalized after a few days. Artesunate has been compared with quinine for the treatment of complicated malaria in 80 children in India (17c ). Artesunate was better tolerated than quinine: no child who received artesunate had an adverse event; in contrast among those who received quinine nausea, vomiting, headache, tinnitus, circulatory failure, and blindness were reported. Amodiaquine + artesunate (n = 153) has been compared with artemether + lumefantrine (co-lumefantrine) (n = 142) in 295 children with uncomplicated malaria (18C ). There were no major adverse effects in either group, although vomiting was more frequent with artesunate + lumefantrine on days 1 and 2. Artemether + lumefantrine (n = 53) and artemether + mefloquine (n = 55) have been compared for the treatment of uncomplicated malaria in Laos (19c ). There were no major adverse events in either group.
DRUGS USED IN THE TREATMENT OF PNEUMOCYSTIS JIROVECI INFECTIONS (SEDA-26, 320; SEDA-27, 295; SEDA-28, 322)
Co-trimoxazole (sulfamethoxazole + trimethoprim) (SED-15, 3510; SEDA-26, 32; SEDA-27, 296; SEDA-28, 322; see also Chapter 26) Nervous system Aseptic meningitis is a rare adverse event associated with many drugs, including co-trimoxazole. In aseptic meningitis no infectious cause is identified and confirmation is usually by exclusion of all known infectious causes.
298 • An 18-year-old woman with acute non-lymphoblastic leukemia was admitted for a bone marrow transplant (20A ). She had attained remission with daunorubicin, thioguanine, and cytarabine. A routine lumbar puncture showed a high leukocyte count and meningitis was suspected. She had been taking co-trimoxazole twice daily on Mondays, Tuesdays, and Wednesdays for the past 3 months and no other medications. Co-trimoxazole was withdrawn and 11 days later lumbar puncture results had returned to normal.
Hematologic Despite its widespread use in HIV infected patients, methemoglobinemia due to co-trimoxazole has not been reported before in this population. • A 66-year-old African American man with advanced HIV infection developed fever, chills, rhinorrhea, and a cough (21A ). He had a history of coronary artery disease and pulmonary tuberculosis and had had a cholecystectomy 3 weeks previously. He denied drug allergy and was currently taking aspirin, ibuprofen, glyceryl trinitrate by patch, and an unknown antibiotic. His temperature was 38.3 ◦ C and there were chest crackles but no other major findings on physical examination. The CD4 count was 66 × 106 /l. Chest radiography showed bilateral scarring and calcification from tuberculosis. He was given ceftizoxime initially, followed by co-trimoxazole. On the next day ceftizoxime was replaced with erythromycin and zidovudine, and lamivudine and saquinavir were added. On the fourth day, he developed tachypnea, tachycardia, and hypotension. Blood gases showed a methemoglobin concentration of 25% and he also had tissue hypoxia and an arterial blood pH of 7.22. Co-trimoxazole and all antiretroviral drugs were withdrawn and exchange transfusion performed. His symptoms improved and the methemoglobin concentration fell to 1% the next day. Co-trimoxazole was replaced with pentamidine for the prevention of Pneumocystis jiroveci and all other drugs were restarted. A review of his medical records from another hospital showed a similar episode of methemoglobinemia 7 years before, after treatment with co-trimoxazole.
Chapter 28
Oscar Ozmund Simooya
Methemoglobinemia is formed by altered oxidative-reduction balance of hemoglobin, and co-trimoxazole may trigger an increase in methemoglobin by interfering with reducing enzymes. Immunologic Severe adverse reactions after treatment with co-trimoxazole are common in patients with HIV infection and can manifest as generalized sepsis with hemodynamic compromise, pulmonary infiltrates, and raised creatinine and hepatic transaminases. These reactions usually occur in patients who have previously been exposed to co-trimoxazole. A case of a severe systemic response syndrome in an HIVpositive patient without prior exposure to cotrimoxazole has been reported (22A ). • A 33-year-old HIV-positive man returned to hospital with aphthous ulcers, and weight loss. He was not taking any medications. He denied using co-trimoxazole. His CD4 count was 90/µl and viral load 354 000 copies/ml. A week earlier a course of co-trimoxazole (one double-strength tablet [160/800 mg] every other day) had been prescribed. He had taken the first tablet a day before coming to hospital. While in the waiting room he had a fever, chills, and rigors. He had a generalized, erythematous, non-blanching rash and a temperature of 39.3 ◦ C. His white blood cell count was 3.5 × 109 /l with 60% segmented neutrophils, hemoglobin 13.1 g/dl, and platelet count 94 × 109 /l. Liver and renal function tests, urine examination, and chest radiography were unremarkable. He was given intravenous fluids and ceftriaxone. Co-trimoxazole was withdrawn and he recovered in 5 days.
This case illustrates a probable delayed hypersensitivity reaction to co-trimoxazole in a patient without prior exposure.
References 1. Freihage JH, Patel NC, Jacobs WR, Picken M, Fresco R, Malinowska K, Pisani BA, Mendez JC, Lichtenberg RC, Foy BK, Bakhos M, Mullen GM. Heart transplantation in a patient with chloroquine-induced cardiomyopathy. J Heart Lung Transpl 2004;23(2):252–5.
2. Ferraro V, Mantoux F, Denis K, LayMacagno M-A, Ortonne J-P, Lacour J-P. Hallucinations au cours d’un traitement par hydroxychloroquine. Ann Dermatol Venereol 2004;131:471–3.
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3. Beedimani RS, Rambhimaiah S. Oral chloroquine induced Stevens–Johnson syndrome. Ind J Pharmacol 2004;36(2):101. 4. Adam I, Elbashir MI. Acute gluteal abscess due to chloroquine injection in Sudanese pregnant woman. Saudi Med J 2004;25(7):963–4. 5. Yanturali S, Aksay E, Demir OF, Atilla R. Massive hydroxychloroquine overdose. Acta Anaesthesiol Scand 2004;48:379–81. 6. Cayley WE Jr. Mefloquine for preventing malaria in nonimmune adult travelers. Am Fam Phys 2004;69(3):521–2. 7. Meier CR, Wilcock K, Jick SS. The risk of severe depression, psychosis or panic attacks with prophylactic antimalarials. Drug Saf 2004;27(3):203–13. 8. Tee AKH, Oh HML, Wee IYJ, Khoo BP, Poh WT. Dapsone hypersensitivity syndrome masquerading as a viral exanthem: three cases and a mini-review. Ann Acad Med Singapore 2004;33(3):375–8. 9. Adam I, Elbashir MI. Extrapyramidal syndrome after treatment with sulphadoxine–pyrimethamine. Saudi Med J 2004;25(9):1303–4. 10. Everts RJ, Hayhurst MD, Nona BP. Acute pulmonary edema caused by quinine. Pharmacotherapy 2004;24(9):1221–4. 11. Adam I, Elbashir MI. Suicide after treatment of chloroquine resistant falciparum malaria with quinine. Saudi Med J 2004;25(2):248–9. 12. Bregani ER, van Tien T, Cabibbe M, Figini G, Manetti F. Holter monitoring in children with severe Plasmodium falciparum malaria during i.v. quinine treatment. J Trop Pediatr 2004;50(1):61. 13. Adjuik M, Babiker A, Garner P, Olliaro P, Taylor W, White N, International Artemisinin Study Group. Artemisinin combination for treatment of malaria. Lancet 2004;363(9402):9–12. 14. Adam I, Elwasila E, Mohamed Ali DA, Elansari E, Elbashir MI. Artemether in the treatment of falciparum malaria in pregnancy in Western Sudan. Trans R Soc Trop Med Hyg 2004;98(9):509–13.
299 15. Staedke SG, Mpimbaza A, Kamya MR, Nzarubara BK, Dorsey G, Rosenthal PJ. Combination treatments for uncomplicated falciparum malaria in Kampala, Uganda: randomised clinical trial. Lancet 2004;364(9449):1950–7. 16. Barennes H, Nagot N, Valea I, KoussoubeBalima T, Ouedrago A, Sanou T, Ye S. A randomized trial of amodiaquine and artesunate alone and in combination for the treatment of uncomplicated falciparum malaria in children from Burkina Faso. Tropical Medicine and International Health 2004;9:438–44. 17. Mohanty AK, Rath BK, Mohanty R, Samal AK, Mishra K. Randomised control trial of quinine and artesunate in complicated malaria. Indian J Paediatr 2004;71:291–5. 18. Ndayiragije A, Niyungeko D, Karenzo J, Niyungeko E, Barutwanayo M, Ciza A, Bosman A, Moyou-Somo R, Nahimana A, Nyarushatsi JP, Barihuta T, Mizero L, Ndaruhutse J, Delacollette C, Ringwald P, Kamana J. Efficacite de combinaisons therapeutiques avec des derives de l’artemisinine dans le traitement de l’acess palustre non-complique au Burundi. Trop Med Int Health 2004;9(6):673–9. 19. Stohrer JM, Dittrich S, Thongpaseuth V, Vanisaveth V, Phetsouvanh R, Phompida S, Monti F, Christophel EH, Lindegardh N, Annerberg A, Jelinex T. Therapeutic efficacy of artemether–lumefantrine and artesunate– mefloquine for treatment of uncomplicated malaria in Luang Namtha Province, Lao People’s Democratic Republic. Trop Med Int Health 2004;9:1175–83. 20. Therrien R. Possible trimethoprim/sulfamethoxazole induced aseptic meningitis. Ann Pharmacother 2004;38:1863–7. 21. Koirala J. Trimethoprim–sulfamethoxazole induced methemoglobinemia in an HIV-infected patient. Mayo Clin Proc 2004;79:829–30. 22. Shanaah A, Mohapatra S. Systemic inflammatory response to trimethoprim–sulfamethoxazole in an HIV-positive patient. Infect Med 2004;21(3):131–2.
Christoph Fux, John Evison, Matthias Schlegel, Christine Thurnheer, and Hansjakob Furrer
29
Antiviral drugs
DRUGS ACTIVE AGAINST CYTOMEGALOVIRUS Cidofovir (SED-15, 771; SEDA-26, 328; SEDA-27, 303; SEDA-28, 326) Urinary tract Intravenous cidofovir can cause a nephropathy, but its topical application as a 3% cream over 12 months was reportedly efficient and safe in an HIV-positive patient with recalcitrant mollusca contagiosa (1A ).
Foscarnet
(SED-15, 1447)
Urinary tract Foscarnet can cause a nephropathy. Even half-dose foscarnet together with half-dose ganciclovir for pre-emptive therapy of cytomegalovirus infection in 24 patients resulted in greater toxicity than full-dose ganciclovir (2c ). Creatinine retention and electrolyte disturbances led to changes in therapy in six of those given the combination compared with none of those who were given ganciclovir alone.
Hematologic With an overall incidence of 40%, neutropenia is the most frequent adverse effect associated with ganciclovir (4R ). It occurs less often in transplant patients than in patients with AIDS and generally reverts within 3–7 days after withdrawal. It has been suggested that ganciclovir is less toxic to myeloid progenitor cells from cord blood than to progenitor cells from bone marrow. In one study 18 of 20 patients who received ganciclovir for cytomegalovirus infection after bone marrow transplantation developed ganciclovir-related neutropenia, compared to 9 of 17 who received ganciclovir after cord blood transplantation (5c ). This observation was explained by the differential expression of a putative progenitor cell kinase involved in the phosphorylation (i.e. activation) of ganciclovir. Alternatively, the lower incidence of ganciclovir-related neutropenia in cord blood cells might be due to the slow cycling rate of these cells. In patients with cord blood (but not bone marrow) transplants, a creatinine clearance rate of less than 50 ml/minute and the absence of glucocorticoid therapy were associated with a greater incidence of ganciclovirassociated neutropenia after pre-emptive therapy of cytomegalovirus infection.
Ganciclovir
(SED-15, 1480; SEDA-26, 329; SEDA-27, 303; SEDA-28, 326)
Ganciclovir prophylaxis of cytomegalovirus disease after bone marrow transplantation was equally well tolerated when it was given in a dosage of 5 mg/kg three times weekly intravenously or 3 g/day orally to 58 patients (3c ). Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29029-9 © 2007 Elsevier B.V. All rights reserved.
300
Valganciclovir Hematologic In a randomized, double-blind comparison of valganciclovir 900 mg/day and oral ganciclovir 1000 mg tds in 364 patients there was a trend towards higher rates of neutropenia with valganciclovir (8.2% versus 3.2%), but the proportion of patients who withdrew because of neutropenia was similar between the groups (6C ).
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DRUGS ACTIVE AGAINST HERPESVIRUSES (SEDA-26, 329;
Ribavirin
SEDA-27, 305; SEDA-28, 328)
Hematologic Pure red cell aplasia can be associated with hepatitis A, B, or C infections and also with ribavirin and pegylated interferon alfa. Ribavirin-associated pure red cell aplasia is fully reversible after withdrawal (11A ).
Aciclovir (SED-15, 29; SEDA-26, 329; SEDA-27, 305; SEDA-28, 328) Gastrointestinal In a randomized, doubleblind comparison of aciclovir and famciclovir in 55 patients with uncomplicated Herpes zoster infection, constipation was the only significantly different adverse reaction, occurring in 11% and 3.7% respectively (7c ). Pregnancy Aciclovir crosses the placenta and is concentrated in the amniotic fluid, but not in the fetus. The International Acyclovir Pregnancy Registry documented birth outcomes of 1246 women exposed to oral or intravenous aciclovir during pregnancy (61% first trimester, 16% second trimester, 23% third trimester) (8C ). No aciclovir-associated birth defects were reported. The data had the power to exclude a seven-fold increase in the risk of overall birth defects, but could not address the risks of rare and specific defects.
Famciclovir
(SED-15, 1325)
In a multicenter study oral famciclovir was well tolerated by 60 women who took 125 mg tds and 59 women who took 250 mg tds (9C ).
Valaciclovir
(SED-15, 3576; SEDA-26, 330; SEDA-27, 305) In a multicenter study there were similar rates of adverse effects in those who took placebo (n = 741) and those who took valaciclovir (n = 743) (10C ).
DRUGS ACTIVE AGAINST HEPATITIS VIRUSES Pegylated interferons (PEG-IFN) See Chapter 37.
(SED-15, 3036)
• A 61-year-old man with chronic hepatitis C infection developed progressive anemia with a low reticulocyte count after 12 weeks of therapy despite reduction of the ribavirin dose, but by 12 weeks after withdrawal of ribavirin the anemia had normalized.
Studies in rhesus monkeys have shown a dose-related reversible anemia, erythroid hypoplasia, and vacuolization of erythroid precursors (12E ). Drug interactions In a randomized 48-week study, 107 patients co-infected with human immunodeficiency virus (HIV) and hepatitis C (HCV) were given interferon alfa-2b together with either a full course of ribavirin or placebo for 16 weeks, followed by ribavirin (13c ). More than 80% of the patients in both groups also took HAART and 25–28% took zidovudine. Significantly more patients who took the full 48-week course of ribavirin had to reduce the dose of ribavirin because of anemia (28% versus 11%). With zidovudine co-medication, only those who took the full course of ribavirin had to reduce the ribavirin dose for any reason (67% versus 24%) or for anemia (60% versus 16%). Zidovudine, but no other nucleoside analogue, was associated with a significantly lower hemoglobin concentration (10.1 versus 13.0 g/dl) and a significantly larger decrease (−3.64 versus −2.08 g/dl). However, there was no pronounced association between leukopenia or neutropenia and zidovudine. The combination of zidovudine with interferons and ribavirin should be avoided if possible.
302
DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: NUCLEOSIDE ANALOGUE REVERSE TRANSCRIPTASE INHIBITORS (NRTI) (SED-15, 2586; SEDA-26, 330; SEDA-27, 306; SEDA-28, 332)
Lipoatrophy, hyperlactatemia, and mitochondrial toxicity Lipoatrophy and hyperlactatemia are frequent long-term adverse effects of nucleoside analogue reverse transcriptase inhibitors (SEDA28, 329). Studies in vitro and in animals have suggested that depletion of mitochondrial DNA (mDNA) resulting in mitochondrial damage leads to both lipoatrophy and hyperlactatemia. The severity of mitochondrial toxicity varied from drug to drug (zalcitabine didanosine stavudine > lamivudine > zidovudine > abacavir, tenofovir). Clinical studies that have tested this hypothesis are not easy to interpret or to summarize, because of large variability in study designs, the patients studied (antiretroviral naïve up to heavily pre-treated patients), the treatments examined, different observation periods, different outcome measures (mDNA from different anatomical systems, lactate acidosis, measurement of lipoatrophy). In several studies mDNA in peripheral blood mononuclear cells and liver in HIV patients has been measured and treatment regimens containing stavudine, zalcitabine, and/or didanosine have been compared with regimens containing other NRTIs. There was a significant reduction in the number of mDNA copies from cryopreserved peripheral blood mononuclear cells in patients who participated in the Delta trial and were treated over 48 weeks with zidovudine + zalcitabine and zidovudine + didanosine, but not with zidovudine alone (14c ). In 80 patients co-infected with HIV and chronic hepatitis C, liver mDNA content in patients taking the so-called D-drugs, didanosine (DDI), stavudine (D4T), and zalcitabine (DDC), was significantly reduced compared with those who did not take D-drugs (15c ). Only
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Christoph Fux et al.
three patients had a blood lactate concentration above the upper limit, and all had taken D-drugs. In 58 individuals with HIV infection, those taking stavudine-containing regimens and drugnaïve HIV-positive patients had significantly lower median amounts of mDNA than HIVpositive patients who were taking antiretroviral drugs other than stavudine, and this was associated with higher lactate concentrations (16c ). In a cross-sectional study in 45 patients who had been enrolled 4 years before in a randomized comparative trial of stavudine-based therapy versus zidovudine-based therapy, there was a significantly higher prevalence of lipoatrophy in the stavudine recipients (17c ). Analysing only those who continued to take randomly allocated NRTIs, mDNA in peripheral blood mononuclear cells fell after the start of treatment in both groups, resulting in significantly lower amounts in patients with lipoatrophy. Furthermore, the mDNA content of subcutaneous adipose tissue from the thigh, but not from the back, was significantly lower in patients taking stavudine. Further studies showed improvement of lipoatrophy after switching from stavudine to abacavir. In the MITOX extension study in 85 patients, in which there was long-term follow up for 104 weeks after switching from stavudine or zidovudine to abacavir, limb fat continued to increase in the abacavir group (18C ). There was no improvement in visceral fat accumulation, buffalo hump, self-assessed lipodystrophy, or the lipodystrophy case definition score. The aim of another substudy from MITOX was to determine whether switching treatment to abacavir is associated with a significant increase in the mDNA content of peripheral blood mononuclear cells parallelling the consequent improvement in lipoatrophy (19C ). However, despite the improvement in peripheral lipoatrophy in patients whose treatment was switched to abacavir, there was no significant change in mDNA copy numbers in peripheral blood mononuclear cells over 24 weeks. In patients with stavudine-induced hyperlactatemia, withdrawal promptly resulted in a reduction in lactate concentrations. Ten patients who switched to abacavir or zidovudine once hyperlactatemia had resolved maintained normal lactate concentrations (20c ). In the 48-week TARHEEL study (Trial to Assess the Regression of Hyperlactatemia and to
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Evaluate the Regression of Established Lipodystrophy), substitution of stavudine by abacavir or zidovudine in 118 patients who had developed lipoatrophy after taking a stavudinebased regimen for at least 6 months resulted in a median increase in arm fat of 35%, leg fat of 12%, and trunk fat of 12% compared with baseline (21C ). In summary, a reduced amount of mDNA seems to be associated with raised lactate, lipoatrophy, and medications such as stavudine, didanosine, and zalcitabine. Stavudine is associated with a higher risk of lipoatrophy, but the reduction in mDNA is not always associated with signs of lipoatrophy. Given the central role of NRTIs in the development of lipoatrophy, switching to regimen containing other drugs may lead to improvement, although reversibility seems only to be partial up to 2 years of follow up, anatomically restricted, and only detectable by techniques such as computed tomography or dual energy X-ray absorptiometry. However, there was neither an improvement in clinical parameters, such as waist–hip ratio, patient questionnaire, or lipoatrophy score, nor a correlation with increasing mDNA in peripheral blood mononuclear cells after switching treatment. This suggests either that other factors determine lipoatrophy or that there is persistent mitochondrial toxicity despite withdrawal of NRTIs. Until now, no other options for treating lipoatrophy besides switching antiretroviral drug treatment have been found to be effective. Rosiglitazone, a thiazolidinedione glucoselowering drug that promoted subcutaneous fat growth in 108 patients with type 2 diabetes. In HIV-infected adults with lipoatrophy who were taking antiretroviral drugs, it did not improve lipoatrophy over 48 weeks, measured by changes in limb fat mass, body weight, body mass index, and waist and hip circumferences (22C ).
196 patients, hypersensitivity reactions were more frequent in those taking a fixed combination of zidovudine, lamivudine, and abacavir (Trizivir® ) than in those taking abacavir in the form of Ziagen® (9.8% versus 0.04%) (23c ). The authors hypothesized that excipients such as indigo carmine or polyethylene glycol, which are present in Trizivir® but not in Ziagen® might be responsible. However, earlier studies showed a higher frequency of hypersensitivity reactions in patients taking Ziagen® . There was no association with the co-administration of other drugs that commonly cause hypersensitivity reactions, such as co-trimoxazole, nevirapine, or efavirenz. Abacavir hypersensitivity is strongly associated with HLA-B*5701. In a retrospective Australian study of 200 patients, 16 of whom had hypersensitivity reactions, the occurrence of HLA-B*5701 and Hsp70-Hom M493T alleles predicted abacavir hypersensitivity (24C ). The positive predictive value was 93.8% and the negative predictive value was 99.5% for HLA-B* 5701 in combination with Hsp70Hom M493T. In a model of the cost-effectiveness of HLA B*5701 genotyping, pooling published data, routine testing ranged from being a dominant strategy (less expensive and more beneficial) to an incremental cost-effectiveness ratio of about €23 000 per hypersensitivity reaction avoided (25M ).
Didanosine
(SED-15, 1113; SEDA-27,
307)
Abacavir
Drug interactions The combination of didanosine with tenofovir requires dosage reduction of didanosine from 400 mg/day to 250 mg/day because of increased didanosine plasma concentrations when tenofovir is coadministered. However, there have not previously been data to suggest that dosage reduction results in appropriate drug exposure in subjects weighing less than 60 kg.
Immunologic Hypersensitivity reactions are among the most common causes for early abacavir discontinuation. Among 16 (8.2%) of
• A patient weighing 48 kg with renal impairment (creatinine clearance 57 ml/minute) developed didanosine toxicity with lactic acidosis and liver failure 3 months after starting a regimen containing tenofovir and didanosine 200 mg/day (26A ).
(SED-15, 3; SEDA-26, 330; SEDA-27, 307)
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In 21 patients weighing less than 60 kg who took didanosine 250 mg/day plus tenofovir there was full viral suppression but the mean CD4 cell count fell to 120 × 106 /l; no explanation for the reduction in CD4 count was found other than the combined treatment of tenofovir and didanosine (27c ). Therefore, in patients with low body weight and/or renal impairment, this drug combination should be used only with extreme caution, even when low doses of didanosine are used, and close clinical and biochemical monitoring is required.
Emtricitabine Comparative studies Once-daily emtricitabine and twice-daily stavudine, both combined with didanosine and efavirenz, have been compared in a multicenter, double-blind, randomized study in 571 antiretroviral-naive HIVinfected adults (28C ). Adverse events, such as diarrhea, nausea, lipodystrophy, pain, symptomatic hyperlactatemia, neuropathy, and paresthesia, were significantly less common with emtricitabine. Those who took emtricitabine had a significantly lower probability of an adverse event requiring withdrawal. Skin discoloration (3% versus <1%) occurred significantly more often with emtricitabine, as did cough (14% versus 9%).
DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: NUCLEOTIDE ANALOGUE REVERSE TRANSCRIPTASE INHIBITORS Tenofovir
(SED-15, 3314; SEDA-26, 331)
Metabolism In a multicenter, double-blind, randomized study tenofovir was compared with stavudine over 3 years, both being given in combination with lamivudine and efavirenz in 602 antiviral drug-naive patients (29C ). There were significantly more favorable lipid profiles with tenofovir and more patients required the
Christoph Fux et al.
addition of lipid-lowering agents with stavudine. The overall incidence of mitochondrial toxicity and lipodystrophy were significantly lower among patients who took tenofovir. Patients who took tenofovir gained weight by 144 weeks, in contrast to the patients who took stavudine, who lost weight from weeks 24 to 144. Urinary tract Tenofovir is extensively excreted through the kidneys by glomerular filtration and active tubular secretion. It is structurally closely related to adefovir and cidofovir, which are used in the treatment of hepatitis B and cytomegalovirus infection and are known to be nephrotoxic. In the large randomized trial mentioned above (29C ) the renal safety profile was similar with tenofovir and stavudine. However some cases of nephrotoxicity (renal failure, Fanconi syndrome, nephrogenic diabetes insipidus, acute tubular necrosis) have been reported as case series and case reports. Seven HIV-infected patients under tenofovir, who had previously taken NRTIs, developed renal tubular damage (30c ). The first symptoms of renal dysfunction occurred 5–64 weeks after the start of treatment. Six patients had a low body weight (under 60 kg), five took low-dose ritonavir, and one took didanosine. Renal tubular dysfunction was accompanied by hypophosphatemia, normoglycemic glycosuria, proteinuria, and reduced creatinine clearance. A renal biopsy in one patient was consistent tubulointerstitial damage. In three patients with in whom tenofovir plasma concentrations were measured there were high values 16 hours after drug administration. After withdrawal of tenofovir the abnormalities resolved within 4 months. Proximal tubulopathy is a rare adverse effect of tenofovir. Possible predisposing factors include high dose, low body weight, and preexisting latent tubular damage (due for example to mitochondrial defects caused by previous treatment with NRTIs). Regular monitoring of tubulopathy markers in these patients could lead to early detection of renal dysfunction. Skin A lichenoid eruption has been attributed to tenofovir (31A ). • A 60-year-old man with HIV and chronic hepatitis B taking lamivudine, nevirapine, and stavudine, developed lipoatrophy. The stavudine was
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withdrawn and tenofovir started. Soon afterwards he developed a pruritic erythematous lichenoid rash without a fever or other symptoms or abnormalities of blood tests. Skin biopsy showed a florid lichenoid reaction with eosinophils, consistent with a drug eruption. All HIV and other medications (at least treated for 2 years), were stopped and he was given topical glucocorticoids and oral antihistamines. The rash resolved and all medications except tenofovir were reintroduced without recurrence.
Musculoskeletal In the study mentioned above (29C ) there were small and largely nonprogressive reductions in bone mineral density, but the changes with significantly larger changes in the lumbar spine in those who took tenofovir. Drug interactions
305 efavirenz. There were grade 3 or 4 sleep disturbances in six of 400 patients in the 2NN trial (32C ). Eleven of 287 patients stopped taking efavirenz within 30 days because of sleep disturbances (33C ). There were sleep abnormalities in 13 of 18 patients taking efavirenz, evaluated using the Pittsburgh Sleep Quality Index. These abnormalities have been explained by disturbances in sleep architecture, since ambulatory encephalographic monitoring showed marked sleep fragmentation (34c ). Psychiatric In a questionnaire survey of 152 patients who stopped taking efavirenz 82 did so because of neuropsychiatric symptoms; a history of multiple episodes of depression was associated with efavirenz discontinuation (35c ).
See Didanosine.
DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTI) (SED-15, 2553; SEDA-27, 308; SEDA-28, 334) Observational studies The two currently available NNRTIs, efavirenz and nevirapine, have been compared in a large 48-week unblinded randomized trial that included oncedaily and twice-daily arms for nevirapine (400 mg/day and 200 mg bd) (the 2NN trial) (32C ). This trial distinguished between adverse effects of the individual drug and adverse effects of the drug class. In patients taking double NNRTI treatment there was an excess of treatment interruptions due to adverse effects without evidence of better virological or immunological responses. Antiretroviral regimens that include two NNRTIs should therefore not be used.
Efavirenz (SED-15, 1204; SEDA-26, 331; SEDA-27, 309; SEDA-28, 334) Nervous system Insomnia and abnormal dreams are well described adverse effects of
Breasts In a case-control study of 30 men taking antiretroviral drugs who developed gynecomastia and 30 men who did not, the use of efavirenz was significantly associated with gynecomastia (36c ). In an observational study seven of 193 men taking an efavirenz-based regimen developed gynecomastia during a median follow-up of 18 months compared with none of 164 men taking nevirapine (33C ). Drug interactions Because of induction of CYP3A4 by efavirenz the dosage of concurrent rifabutin should be increased to 450– 600 mg/day according to current recommendations. However, in one case rifabutin concentrations were inadequate even though the dosage of rifabutin was increased to 1350 mg/day (37A ). The isoniazid concentration was also inadequate. The concentrations of both tuberculostatics became satisfactory when efavirenz was withdrawn.
Nevirapine (SED-15, 2498; SEDA-26, 332; SEDA-27, 310; SEDA-28, 334) Immunologic The most important adverse effect of nevirapine is a potentially fatal systemic hypersensitivity reaction presenting with a rash and/or hepatitis. This reaction may be more frequent in HIV uninfected persons, as suggested by a case-series and review (38cR ). The authors suggested that nevirapine should
306 not be a component of prophylaxis after HIV exposure. Hypersensitivity reactions occurred in 16.5% of 115 individuals taking antiretroviral regimens that included nevirapine, abacavir, lamivudine, and zidovudine, compared with 5.3% of 114 who were not taking nevirapine (39C ). It is not possible to differentiate hypersensitivity reactions to nevirapine from those to abacavir. Liver There were grade 3 or 4 hepatobiliary laboratory adverse events in 30 of 220 patients (13.6%) taking once-daily nevirapine and 32 of 387 patients (8.3%) taking twice-daily nevirapine in a large randomized trial (32C ). This is the first report that hepatotoxicity may be more frequent with once-daily nevirapine. One patient taking twice-daily nevirapine died because of acute drug induced hepatitis with liver failure that started after 32 days of therapy. In a non-randomized study of 256 patients taking nevirapine-containing regimens, the prevalence of liver enzyme activities above twice the upper limit of normal increased from 80 patients to 134 during a median follow-up of 18 months; in contrast, it fell in a concurrent cohort of 287 patients who took efavirenz (33C ). Data from the FDA adverse events reporting system have shown that in 30 HIV uninfected persons who experienced EOCG grade 3 or 4 hepatotoxicity during nevirapine containing post-exposure prophylaxis, there was an accompanying fever in 11, eosinophilia in five, and a rash in seven (38c ). One had fulminant liver necrosis and needed liver transplantation. In a comprehensive review of 17 randomized clinical trials about 10% of patients taking nevirapine increases in transaminases activities five times above the upper limit of normal, which represents a risk ratio of 1.5 (40M ). In twothirds of cases the rises were asymptomatic. However, the risk ratio for symptomatic hepatitis was 3.5 and the association of rash and hepatitis was found nearly exclusively in patients taking nevirapine (frequency 1.5%, RR = 11.2) and occurred during the first 60 days of therapy. In other small studies there was no clear relation between nevirapine plasma concentrations and hepatotoxicity (41c , 42c ). In a cohort analysis of 152 patients coinfected with HIV and hepatitis C, nevirapine
Chapter 29
Christoph Fux et al.
was associated with faster progression of fibrosis in liver biopsies (43C ). Skin One patient out of 387 taking twicedaily nevirapine in the 2NN trial died after developing Stevens–Johnson syndrome 39 days after the start of therapy (32C ). Of twelve HIV uninfected people with severe skin reactions three had Stevens–Johnson syndrome; their symptoms started 7–12 days after the start of nevirapine therapy (39c ). Pregnancy A randomized trial of nevirapine versus nelfinavir combination antiretroviral therapy with a nucleoside analogue backbone with lamivudine and zidovudine in 17 pregnant women was stopped early because of greater than expected toxicity in the nevirapine arm that led to withdrawal in five of them (44c ). All these women started nevirapine with CD4 counts over 250 × 106 /l. Adverse effects included one death due to fulminant hepatic failure and one case of Stevens–Johnson syndrome. According to the US Health Service Task Force, nevirapine should not be used in pregnant women with CD4 counts above 250×106 /l; if it is used, liver toxicity should be monitored closely during the first 18 weeks (45S ).
DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: PROTEASE INHIBITORS (SED-15, 2965; SEDA-26, 332; SEDA-28, 335)
Amprenavir and fosamprenavir (SED-15, 211) Amprenavir is a protease inhibitor that can be given twice daily without food restrictions. Fosamprenavir, a prodrug, is hydrolysed by alkaline phosphatase at the intestinal brush border to amprenavir and inorganic phosphate, leading to absorption of amprenavir but not the prodrug. One of the advantages of the prodrug formulation is its higher water solubility, allowing for formulation in high-strength film-coated tablets and thereby reducing the pill burden.
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Comparative studies In 249 patients fosamprenavir 700 mg bd (n = 166) was compared with nelfinavir 1250 mg bd (n = 83), each combined with abacavir and lamivudine, the most common adverse event was diarrhea in both groups, but significantly more often with nelfinavir (46C ). In all, 14 patients withdrew from the study because of adverse events (9/166 in the fosamprenavir group; 5/83 in the nelfinavir group). There was increased lipase activity in 8% of the patients who took fosamprenavir, without clinical significance. There were rashes in 7% of the patients who took fosamprenavir. There was a slight increase in total cholesterol in both groups. There were increases in LDL cholesterol requiring medical intervention in 18% of the patients in both groups; the ratio of total:HDL cholesterol was only slightly affected. Drug formulations In a study of an NRTIbased regimen combined with amprenavir 1200 mg bd, fosamprenavir 1395 mg bd or 1860 mg bd, all three regimens produced similar concentration time curves (47c ). The prodrug formulations led to lower maximal plasma concentrations and higher trough concentrations, thereby theoretically reducing the risk of toxic adverse effects. Adverse events reported in these studies were mainly gastrointestinal, with a slight trend to more frequent diarrhea with amprenavir (but the study was not powered to reach statistical significance on this aspect). Drug interactions Amprenavir plus lopinavir/ritonavir as deep salvage treatment has been studied in a prospective single-center study in 22 patients with virological failure after other drugs (including protease inhibitors). Both amprenavir and lopinavir concentrations were reduced unpredictably when the two were combined (48C ). Because they have a limited crossresistance profile, both lopinavir and amprenavir may be treatments of choice in such patients. However, because of their pharmacodynamic properties, the extent to which they can be combined is limited. The authors suggested plasma concentration monitoring in order to adjust amprenavir and lopinavir doses according to viral susceptibility.
Atazanavir Liver The most common adverse effect of atazanavir was a rise in total bilirubin concentration (mostly indirect/unconjugated bilirubin) occurring in 26% of those who continued treatment with atazanavir 400 mg/day (n = 139), 44% of those who took atazanavir 600 mg/day (n = 144), and 13% of those who had previously taken nelfinavir followed by atazanavir 400 mg/day (n = 63) (49C ). There were grade 4 rises in bilirubin (to over five times the upper limit of normal) in 3% of patients taking atazanavir 600 mg/day and in 1% of patients taking atazanavir 400 mg/day. Jaundice was reported more often in those taking atazanavir 600 mg/day compared with those taking 400 mg/day (22% versus 13%). Drug interactions The effect of tenofovir on the pharmacokinetics of atazanavir boosted with ritonavir has been evaluated over 6 weeks in 11 heavily pre-treated patients in the setting of salvage therapy (50c ). Co-administration of tenofovir led to a significant reduction in atazanavir AUC. The mechanism by which tenofovir reduced atazanavir concentrations remains to be elucidated. There was no significant correlation between the pharmacokinetics and the viral response, partly because of the small sample size and probably also the high levels of resistance mutations at baseline.
Indinavir
(SED-15, 1735; SEDA-26, 332; SEDA-27, 313; SEDA-28, 335) Metabolism Indinavir causes insulin resistance over 4–8 weeks of treatment. Tissue plasminogen activator and plasminogen activator inhibitor antigen are both markedly increased in patients with impaired glucose tolerance. Both markers have been linked to impaired thrombolysis, which is associated with an increased cardiovascular risk. In 11 patients taking indinavir and 14 taking fosamprenavir for 8 weeks indinavir was associated with a statistically significant increase in fasting plasma glucose concentration and with a 30% reduction in insulin sensitivity; there were no significant changes in lipid profiles (51c ).
308 Amprenavir had no significant effect on glucose concentrations or insulin sensitivity but increased total cholesterol, triglycerides, and free fatty acids. Surprisingly, both drugs reduced tissue plasminogen activator, possibly reflecting a reduction in HIV-related inflammation as implied by a reduction in TNF-α. Susceptibility factors Sex Variability in the systemic availability of indinavir has been studied in 239 patients (52c ). Concomitant use of ritonavir and female sex both predicted increased availability. The authors suggested changing the recommended dosages of indinavir according to their findings in order to ensure suitable target drug concentrations in most of the population: women 900 mg/day plus low-dose ritonavir bd; men 1700 mg/day plus low-dose ritonavir bd. They also encouraged drug concentration monitoring. However, close attention has to be paid to adverse effects (for example nephrolithiasis) when exposing patients to regimens with higher dosages than have previously been recommended. Drug interactions In six patients who took rifampicin for 4 days serum concentrations of both indinavir and ritonavir fell markedly (by 87% and 94% respectively) (53c ). These data strongly suggest that co administration of rifampicin with indinavir, even in the presence of ritonavir, could lead to subtherapeutic drug concentrations; the combination should therefore be discouraged.
Lopinavir + ritonavir (SED-15, 2159; SEDA-26, 333; SEDA-27, 314; SEDA-28, 336) Metabolism In 19 patients taking lopinavir + ropinavir, either 533/133 mg bd (in patients co-treated with NNRTIs) or 400/100 mg bd, there were increases in triglyceride and total cholesterol concentrations after 4 weeks; seven patients developed grade 2 or worse rises in lipids and three patients developing grade 3 hyperlipidemia. HDL cholesterol increased over the course of 48 weeks, but LDL did not
Chapter 29
Christoph Fux et al.
change significantly (54c ). At baseline nine patients had lipodystrophy but that did not worsen over the next 48 weeks. However, CT-based standardized analysis showed an increase in total abdominal fat (+14%) and a loss of limb fat (−8%) in the 16 patients who completed the study. There was a significant correlation between lopinavir trough concentrations and changes in limb fat, but no association between lopinavir concentration and changes in total abdominal fat, visceral fat, or subcutaneous abdominal fat. The authors cautioned against interpreting these data as showing a causative relation between lopinavir and lipodystrophy, as the study population was rather small and confounding elements could not be ruled out. However, they advised the use of plasma concentration measurement in order to avoid unnecessarily high lopinavir concentrations, which may be associated with lipodystrophy. In contrast, in 55 patients taking lopinavir + ropinavir, even though there was a significant increase in triglyceride concentrations over 12 weeks, this did not correlate with higher plasma lopinavir concentrations (55c ). The authors cautioned against premature dosage adjustments pending larger studies to elucidate this phenomenon. Liver The incidence of hepatotoxicity after treatment with lopinavir and the possible association with lopinavir plasma concentrations has been assessed in a retrospective analysis of 120 HIV-infected patients (52% with hepatitis C co-infection) (56c ). The cumulative incidence of severe liver toxicity (grade 3 or 4) was 4% over 12 months; 8% of patients with hepatitis C co-infection developed liver toxicity, suggesting a higher risk of liver-related complications of lopinavir in patients with preexisting liver disease. Plasma concentrations of lopinavir and HbsAg positivity were not associated with hepatotoxicity. Compared with results from other protease inhibitors, these data suggest that lopinavir is relatively safe for the liver, even in the presence of hepatitis C coinfection. However, the overall frequency of complications was low and a relation between lopinavir concentration and hepatotoxicity cannot be ruled out. Drug interactions Efavirenz and nevirapine both reduced the trough concentration of
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Chapter 29
lopinavir given with low-dose ritonavir by a median 39% and increased the inter-individual variability of lopinavir concentrations (57c ). The authors recommended that the dosage of lopinavir/ritonavir be increased to 533 mg + 133 mg bd if given with an NNRTI and that drug concentrations should be monitored. Monitoring therapy In a study of 12-hour pharmacokinetic profiles of lopinavir in 100 patients, 12 models were used to predict AUC and Cmax ; measurements at 2 and 6 hours after the dose gave acceptable estimated (58c ). The evening trough concentration gave the best estimate of the daily nadir.
Nelfinavir
(SED-15, 2433; SEDA-26, 333; SEDA-27, 315; SEDA-28, 336)
Metabolism The effect of replacing nelfinavir with atazanavir on lipid concentrations has been studied. Atazanavir 400 mg/day or 600 mg/day in combination with stavudine and lamivudine was given to 139 and 144 patients beyond the 48 weeks of the study and to 63 patients who had taken nelfinavir 1250 mg bd for 48 weeks and were allowed to switch to atazanavir 400 mg/day in an open rollover/switch study (49C ). Those who took atazanavir during the entire study had no significant changes in lipid profiles compared to baseline. The patients who had previously taken nelfinavir had reductions in total cholesterol, fasting LDL, and triglyceride concentrations and an increase in HDL concentrations at weeks 12 and 24.
Saquinavir
(SED-15, 3104; SEDA-26, 334; SEDA-27, 316; SEDA-28, 336)
Gastrointestinal All of 11 subjects in a randomized study had some degree of self-limiting diarrhea, which improved within 2 weeks of the start of triple therapy with protease inhibitors (59c ). Six had loose stools throughout the study, but the symptoms were controllable with loperamide or diphenoxylate + atropine.
309 Metabolism Triglycerides rose by 3.45 mmol/l (314 mg/dl) and total cholesterol by 1.1 mmol/l (43 mg/dl) in 11 patients taking amprenavir, saquinavir, and ritonavir (59c ). Drug interactions In the context of emerging resistance to antiretroviral drugs, salvage treatment strategies are needed. Recently regimens involving two protease inhibitors plus ritonavir as a pharmacokinetic enhancer have been examined. In a randomized study, 11 patients, all of whom had had at least one failure on a regimen containing a protease inhibitor, were assigned to either amprenavir/ritonavir (600/100 mg bd) or saquinavir/ritonavir (1000/100 mg bd) for 7–10 days (59c ). After pharmacokinetic evaluation of the initial regimen, the complementary third protease inhibitor was added (either saquinavir or amprenavir). After 14 days of triple therapy the effects of the third protease inhibitor on pharmacokinetics of the previously prescribed drugs were assessed. The addition of saquinavir did not change the concentration of amprenavir, but adding amprenavir to saquinavir/ritonavir caused a reduction in saquinavir/ritonavir exposure. This effect was overcome by increasing the dosages of saquinavir and ritonavir to 1400 mg bd and 200 mg bd respectively. The combination of saquinavir plus ritonavir/lopinavir has been studied in 45 heavily pretreated patients with limited reverse transcriptase options and 32 mostly treatment-naïve patients with advanced HIV disease, who received saquinavir, ritonavir, and two or three different NRTIs (60c ). The pharmacokinetics of saquinavir were similar in the two groups, suggesting that lopinavir has little effect on saquinavir concentrations. However ritonavir concentrations were significantly lower with lopinavir/ritonavir, which is consistent with previous results. Importantly this did not affect the boosting potential of the drug. Taken together these data suggest that saquinavir can be combined with lopinavir/ritonavir without dosage adjustments. However, plasma concentration monitoring should be encouraged because the pharmacokinetics of saquinavir are highly variable.
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DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: INHIBITORS OF HIV FUSION
higher incidence of bacterial pneumonia (4.7 versus 0.3 events per 100 person-years) in those who took enfuvirtide (62C ).
Enfuvirtide
DRUGS ACTIVE AGAINST INFLUENZA VIRUSES: NEURAMINIDASE INHIBITORS
(SEDA-28, 337)
Hematologic One child out of 14 who were given enfuvirtide had grade 3 thrombocytopenia at week 65 and this led to withdrawal of the drug (61Ac ). Fluid balance One child out of 14 treated had grade 3 edema at week 77 and had to stop the drug (61Ac ). Skin In the large randomized TORO trials in 661 patients almost all of those who used enfuvirtide had an injection site reaction (62C , 63C ). The reactions were mild in about half the patients. These reactions included erythema (in 87%), induration (84%), and nodules and cysts (82%). Immunologic Two patients taking enfuvirtide had hypersensitivity reactions in the TORO trials (62C ). One had a rash, fever, and vomiting, the other had membranoproliferative glomerulonephritis and on rechallenge severe respiratory distress syndrome. Treatment-related eosinophilia occurred in 11% of the patients who took enfuvirtide compared with 2.4% of the controls.
(SED-15, 2436; SEDA-26, 334; SEDA-27, 317; SEDA-28, 337)
Oseltamivir Observational studies Several large postmarketing studies have underscored the safety of oseltamivir. There were no increases in cardiovascular, neuropsychiatric, or respiratory complications (64C ), nor in skin reactions (65C ). Gastrointestinal Nausea and vomiting have been the most frequently reported adverse effects associated with oseltamivir. They have led to drug withdrawal in less than 1% of the subjects in clinical trials (66S ). While nausea was equally frequent with once-daily influenza prophylaxis (8%) and twice-daily treatment (7%), the incidence of vomiting increased from 4.5% during prophylaxis to 10% when the drug was taken twice a day (67C ). A similar pattern was found in the pediatric subgroup, with vomiting incidences of 10% and 20% respectively.
Infection risk In an updated safety analysis of both TORO trials there was a significantly
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depletion of mitochondrial DNA in blood of patients treated with dual (zidovudine + didanosine or zidovudine + zalcitabine) vs. single (zidovudine) nucleoside reverse transcriptase inhibitors. HIV Med 2004;5(1):11–4. Walker UA, Bauerle J, Laguno M, Murillas J, Mauss S, Schmutz G, Setzer B, Miquel R, Gatell JM, Mallolas J. Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine. Hepatology 2004;39(2):311–7. de Mendoza C, de Ronde A, Smolders K, Blanco F, Garcia-Benayas T, de Baar M, Fernandez-Casas P, Gonzalez-Lahoz J, Soriano V. Changes in mitochondrial DNA copy number in blood cells from HIV-infected patients undergoing antiretroviral therapy. AIDS Res Hum Retroviruses 2004;20(3):271–3. van der Valk M, Casula M, Weverlingz GJ, van Kuijk K, van Eck-Smit B, Hulsebosch HJ, Nieuwkerk P, van Eeden A, Brinkman K, Lange J, de Ronde A, Reiss P. Prevalence of lipoatrophy and mitochondrial DNA content of blood and subcutaneous fat in HIV-1-infected patients randomly allocated to zidovudineor stavudine-based therapy. Antivir Ther 2004;9(3):385–93. Martin A, Smith DE, Carr A, Ringland C, Amin J, Emery S, Hoy J, Workman C, Doong N, Freund J, Cooper DA, Mitochondrial Toxicity Study Group. Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: the MITOX Extension Study. AIDS 2004;18(7):1029–36. Hoy JF, Gahan ME, Carr A, Smith D, Lewin SR, Wesselingh S, Cooper DA. Changes in mitochondrial DNA in peripheral blood mononuclear cells from HIV-infected patients with lipoatrophy randomized to receive abacavir. J Infect Dis 2004;190(4):688–92. Lonergan JT, Barber RE, Mathews WC. Safety and efficacy of switching to alternative nucleoside analogues following symptomatic hyperlactatemia and lactic acidosis. AIDS 2003;17(17):2495–9. McComsey GA, Ward DJ, Hessenthaler SM, Sension MG, Shalit P, Lonergan JT, Fisher RL, Williams VC, Hernandez JE, Trial to Assess the Regression of Hyperlactatemia and to Evaluate the Regression of Established Lipodystrophy in HIV-1-Positive Subjects (TARHEEL ESS40010) Study Team. Improvement in lipoatrophy associated with highly active antiretroviral therapy in human immunodeficiency virus-infected patients switched from stavudine to abacavir or zidovudine: the results of the TARHEEL study. Clin Infect Dis 2004;38(2):263–70. Carr A, Workman C, Carey D, Rogers G, Martin A, Baker D, Wand H, Law M, Samaras K, Emery S, Cooper DA, Rosey investigators. No effect of rosiglitazone for treatment of HIV-1 lipoatrophy: randomised, double-blind, placebocontrolled trial. Lancet 2004;363(9407):429–38.
312 23. Parra-Ruiz J, Martinez-Ramirez M, Munoz-Medina L, Serrano-Falcon C, Hernandez-Quero J. Reasons for early abacavir discontinuation in HIV-infected patients. Ann Pharmacother 2004;38(3):512–3. 24. Martin AM, Nolan D, Gaudieri S, Almeida CA, Nolan R, James I, Carvalho F, Phillips E, Christiansen FT, Purcell AW, McCluskey J, Mallal S. Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant. Proc Natl Acad Sci USA 2004;101(12):4180–5. 25. Hughes DA, Vilar FJ, Ward CC, Alfirevic A, Park BK, Pirmohamed M. Cost-effectiveness analysis of HLA B*5701 genotyping in preventing abacavir hypersensitivity. Pharmacogenetics 2004;14(6):335–42. 26. Masia M, Gutierrez F, Padilla S, Ramos JM, Pascual J. Didanosine-associated toxicity: a predictable complication of therapy with tenofovir and didanosine? J Acquir Immune Defic Syndr 2004;35(4):427–8. 27. Negredo E, Molto J, Burger D, Viciana P, Ribera E, Paredes R, Juan M, Ruiz L, Puig J, Pruvost A, Grassi J, Masmitja E, Clotet B. Unexpected CD4 cell count decline in patients receiving didanosine and tenofovir-based regimens despite undetectable viral load. AIDS 2004;18(3):459–63. 28. Saag MS, Cahn P, Raffi F, Wolff M, Pearce D, Molina JM, Powderly W, Shaw AL, Mondou E, Hinkle J, Borroto-Esoda K, Quinn JB, Barry DW, Rousseau F, FTC-301A Study Team. Efficacy and safety of emtricitabine vs stavudine in combination therapy in antiretroviral-naive patients: a randomized trial. JAMA 2004;292(2):180–9. 29. Gallant JE, Staszewski S, Pozniak AL, DeJesus E, Suleiman JM, Miller MD, Coakley DF, Lu B, Toole JJ, Cheng AK, 903 Study Group. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviralnaive patients: a 3-year randomized trial. JAMA 2004;292(2):191–201. 30. Peyriere H, Reynes J, Rouanet I, Daniel N, de Boever CM, Mauboussin JM, Leray H, Moachon L, Vincent D, Salmon-Ceron D. Renal tubular dysfunction associated with tenofovir therapy: report of 7 cases. J Acquir Immune Defic Syndr 2004;35(3):269–73. 31. Woolley IJ, Veitch AJ, Harangozo CS, Moyle M, Korman TM. Lichenoid drug eruption to tenofovir in an HIV/hepatitis B virus co-infected patient. AIDS 2004;18(13):1857–8. 32. van Leth F, Phanuphak P, Ruxrungtham K, Baraldi E, Miller S, Gazzard B, Cahn P, Lalloo UG, van der Westhuizen IP, Malan DR, Johnson MA, Santos BR, Mulcahy F, Wood R, Levi GC, Reboredo G, Squires K, Cassetti I, Petit D, Raffi F, Katlama C, Murphy RL, Horban A, Dam JP, Hassink E, van Leeuwen R, Robinson P, Wit FW, Lange JM, 2NN Study team. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a ran-
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44. Hitti J, Frenkel LM, Stek AM, Nachman SA, Baker D, Gonzalez-Garcia A, Provisor A, Thorpe EM, Paul ME, Foca M, Gandia J, Huang S, Wei LJ, Stevens LM, Watts DH, McNamara J, PACTG 1022 Study Team. Maternal toxicity with continuous nevirapine in pregnancy: results from PACTG 1022. J Acquir Immune Defic Syndr 2004;36(3):772–6. 45. Public Health Service Task Force. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV1 transmission in the United States. http:// aidsinfo.nih.gov/ContentFiles/PerinatalGL.pdf. 46. Rodriguez-French A, Boghossian J, Gray GE, Nadler JP, Quinones AR, Sepulveda GE, Millard JM, Wannamaker PG. The NEAT study: a 48-week open-label study to compare the antiviral efficacy and safety of GW433908 versus nelfinavir in antiretroviral therapy-naive HIV-1infected patients. J Acquir Immune Defic Syndr 2004;35(1):22–32. 47. Wood R, Arasteh K, Stellbrink HJ, Teofilo E, Raffi F, Pollard RB, Eron J, Yeo J, Millard J, Wire MB, Naderer OJ. Six-week randomized controlled trial to compare the tolerabilities, pharmacokinetics, and antiviral activities of GW433908 and amprenavir in human immunodeficiency virus type 1-infected patients. Antimicrob Agents Chemother 2004;48(1):116–23. 48. De Luca A, Baldini F, Cingolani A, Di Giambenedetto S, Hoetelmans RM, Cauda R. Deep salvage with amprenavir and lopinavir/ritonavir: correlation of pharmacokinetics and drug resistance with pharmacodynamics. J Acquir Immune Defic Syndr 2004;35(4):359–66. 49. Wood R, Phanuphak P, Cahn P, Pokrovskiy V, Rozenbaum W, Pantaleo G, Sension M, Murphy R, Mancini M, Kelleher T, Giordano M. Long-Term Efficacy and Safety of Atazanavir With Stavudine and Lamivudine in Patients Previously Treated With Nelfinavir or Atazanavir. J Acquir Immune Defic Syndr 2004;36(2):684– 92. 50. Taburet AM, Piketty C, Chazallon C, Vincent I, Gerard L, Calvez V, Clavel F, Aboulker JP, Girard PM. Interactions between atazanavir–ritonavir and tenofovir in heavily pretreated human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 2004;48(6):2091–6. 51. Young EM, Considine RV, Sattler FR, Deeg MA, Buchanan TA, Degawa-Yamauchi M, Shankar S, Edmondson-Melancon H, Hernandez J, Dube MP. Changes in thrombolytic and inflammatory markers after initiation of indinaviror amprenavir-based antiretroviral therapy. Cardiovasc Toxicol 2004;4(2):179–86. 52. Csajka C, Marzolini C, Fattinger K, Decosterd LA, Telenti A, Biollaz J, Buclin T. Population pharmacokinetics of indinavir in patients infected with human immunodeficiency virus. Antimicrob Agents Chemother 2004;48(9):3226– 32. 53. Justesen US, Andersen AB, Klitgaard NA, Brosen K, Gerstoft J, Pedersen C. Pharma-
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cokinetic interaction between rifampin and the combination of indinavir and low-dose ritonavir in HIV-infected patients. Clin Infect Dis 2004;38(3):426–9. Gutierrez F, Padilla S, Masia M, Navarro A, Gallego J, Hernandez I, Ramos JM, MartinHidalgo A. Changes in body fat composition after 1 year of salvage therapy with lopinavir/ritonavircontaining regimens and its relationship with lopinavir plasma concentrations. Antivir Ther 2004;9(1):105–13. Torti C, Quiros-Roldan E, Regazzi-Bonora M, De Luca A, Lo Caputo S, Di Giambenedetto S, Patroni A, Villani P, Micheli V, Carosi G, Resistance and Dosage Adapted Regimens Study Group of the MASTER Cohort. Lipid abnormalities in HIV-infected patients are not correlated with lopinavir plasma concentrations. J Acquir Immune Defic Syndr 2004;35(3):324–6. Gonzalez-Requena D, Nunez M, JimenezNacher I, Gonzalez-Lahoz J, Soriano V. Short communication: liver toxicity of lopinavircontaining regimens in HIV-infected patients with or without hepatitis C coinfection. AIDS Res Hum Retroviruses 2004;20(7):698–700. Solas C, Poizot-Martin I, Drogoul MP, Ravaux I, Dhiver C, Lafeuillade A, Allegre T, Mokhtari M, Moreau J, Lepeu G, Petit N, Durand A, Lacarelle B. Therapeutic drug monitoring of lopinavir/ritonavir given alone or with a nonnucleoside reverse transcriptase inhibitor. Br J Clin Pharmacol 2004;57(4):436–40. Alexander CS, Montaner JS, Asselin JJ, Ting L, McNabb K, Harris M, Guillemi S, Harrigan PR. Simplification of therapeutic drug monitoring for twice-daily regimens of lopinavir/ritonavir for HIV infection. Ther Drug Monit 2004;26(5):516–23. Corbett AH, Eron JJ, Fiscus SA, Rezk NL, Kashuba AD. The pharmacokinetics, safety, and initial virologic response of a triple-protease inhibitor salvage regimen containing amprenavir, saquinavir, and ritonavir. J Acquir Immune Defic Syndr 2004;36(4):921–8. Stephan C, Hentig N, Kourbeti I, Dauer B, Mosch M, Lutz T, Klauke S, Harder S, Kurowski M, Staszewski S. Saquinavir drug exposure is not impaired by the boosted double protease inhibitor combination of lopinavir/ritonavir. AIDS 2004;18(3):503–8. Church JA, Hughes M, Chen J, Palumbo P, Mofenson LM, Delora P, Smith E, Wiznia A, Hawkins E, Sista P, Cunningham CK, Pediatric AIDS Clinical Trials Group P1005 Study Team. Long term tolerability and safety of enfuvirtide for human immunodeficiency virus 1-infected children. Pediatr Infect Dis J 2004;23(8):713–8. Cohen SC, Kuritzkes DR, Eron JJ Jr, Chung J, DeMasi R, Donatacci L, Drobnes C, Delehanty J, Salgo M, TORO 1 Study Group. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med 2003;348(22):2175–85. Lazzarin A, Clotet B, Cooper D, Reynes J, Arasteh K, Nelson M, Katlama C, Stellbrink HJ,
314 Delfraissy JF, Lange J, Huson L, DeMasi R, Wat C, Delehanty J, Drobnes C, Salgo M, TORO 2 Study Group. Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N Engl J Med 2003;348(22):2186–95. 64. Enger C, Nordstrom BL, Thakrar B, Sacks S, Rothman KJ. Health outcomes among patients receiving oseltamivir. Pharmacoepidemiol Drug Saf 2004;13(4):227–37. 65. Nordstrom BL, Oh K, Sacks ST, L’Italien GJ. Skin reactions in patients with influenza treated
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with oseltamivir: a retrospective cohort study. Antivir Ther 2004;9(2):187–95. 66. Roche Laboratories Inc. Tamiflu (oseltamivir phosphate) capsules [package insert]. Nutley, NJ: Roche Laboratories Inc., 2000. 67. Hayden FG, Belshe R, Villanueva C, Lanno R, Hughes C, Small I, Dutkowski R, Ward P, Carr J. Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis. J Infect Dis 2004;189(3):440–9.
Soumya Swaminathan
30 Drugs used in tuberculosis and leprosy Immune reconstitution disease Treatment of tuberculosis can be associated with a transient worsening of clinical symptoms a few days to weeks after the start of therapy. This scenario was described over 30 years ago and was designated as a “paradoxical reaction” (1A ). The most common paradoxical reactions include worsening of lymphadenopathy, increasing central nervous system lesions, and worsening respiratory symptoms (2c ). The pathogenesis of this syndrome is thought to be reconstitution of a cell-mediated immune response to mycobacterial antigens that were either absent, suppressed, or dysregulated in untreated tuberculosis (3E , 4E ). Immune reconstitution disease (IRD) is more common in HIV-infected patients with tuberculosis, especially those who are receiving antiretroviral drug therapy. This entity needs to be more widely recognized, as it can present challenging diagnostic and management scenarios for practitioners (5c , 6c ). In one prospective study of HIV-infected patients with tuberculosis, immune reconstitution disease was reported among 36% of those who were taking antiretroviral drugs and 7% of those who were taking antituberculosis drugs only (7A ). After the start of antiretroviral therapy, there is reconstitution of antigen-specific responses to a number of pathogens, and this presumably contributes to the amplified inflammatory responses (8A ). Immune reconstitution disease needs to be distinguished from treatment failure, progression of drug resistant tuberculosis, drug reactions, and other HIV-related complications that can mimic immune reconstitution disease. Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29030-5 © 2007 Elsevier B.V. All rights reserved.
Immune reconstitution disease secondary to tuberculosis most commonly presents with fever, lymphadenopathy, and worsening respiratory symptoms. Most cases have been reported within the first 2 months of antiretroviral therapy, with a median duration of HIV therapy of 4 weeks. A CD4+ cell count of under 50 × 106 /l before HIV therapy is a significant risk factor for the development of immune reconstitution disease. There is usually a rise in CD4+ cell count when immune reconstitution disease develops, but that is not a prerequisite for the diagnosis (9E ). In most cases, the management of suspected immune reconstitution disease includes continuation of tuberculosis and antiretroviral drug therapy, close observation, evaluation of other possible intercurrent illnesses, and review of adherence to HIV medications. In the presence of severe lymphadenopathy, worsening respiratory status, or worrisome central nervous system symptoms, a course of glucocorticoids can be tried (5c ). In extreme cases, antiretroviral drugs may need to be withheld. While there have been no deaths reported from tuberculosis-associated immune reconstitution disease, morbidity from this syndrome can be severe.
Dapsone
(SED-15, 1050; SEDA-26, 340; SEDA-28, 343) Immunologic Hypersensitivity syndromes have been described with dapsone.
• A 12-year-old girl was admitted to hospital 24 days after starting to take the World Health Organization (WHO) recommended multidrug therapy for leprosy (dapsone, clofazimine, and rifampicin) (10A ). She had intense jaundice, generalized lymphadenopathy, hepatosplenomegaly, oral lesions, conjunctivitis, a morbilliform rash, and edema of the face, ankles, and hands. Her hemoglobin was
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316 8.4 g/dl, the white blood cell count 15.7 × 109 /l, and the platelet count 100 × 109 /l. Her INR was 49 and there was an increase in liver enzymes. She later deteriorated and developed exfoliative dermatitis, shock, and acute renal and hepatic insufficiency. She was given adrenergic drugs, fluids, blood, and antibiotics and made a good recovery. She was later given clofazimine and rifampicin without adverse effects.
Hypersensitivity pneumonitis is an immunologically mediated lung disease characterized by dyspnea, fever, cough, chest pain, and hypoxemia. The characteristic radiographic findings include bilateral reticular infiltrates. This type of pneumonitis is acute and unrelated to the dose or duration of therapy with the incriminated drug. Bronchoalveolar lavage may show a predominance of eosinophils or lymphocytes, with an increased CD8/CD4 ratio. Inciting antigens include those of birds, fungi, chemicals, and drugs. Adverse drug reactions related to antimicrobial use are common in patients with HIV infection. In particular, sulfonamides, including co-trimoxazole, commonly cause adverse reactions, but sulfonamide-induced pulmonary complications are rare. In HIV-negative patients with ulcerative colitis, sulfa-related drugs such as sulfasalazine have been reported to cause hypersensitivity pneumonitis with eosinophilia. However, hypersensitivity pneumonitis has rarely been reported in patients infected with HIV, and this can be attributed to the low absolute numbers of CD4 and CD8 lymphocytes and reduced function of CD4 cells. The differential diagnosis of interstitial pneumonitis in patients with HIV is extensive and includes Pneumocystis jiroveci pneumonia, other infectious causes such as cytomegalovirus and mycobacteria, and non-infectious causes such as neoplasms, eosinophilic pneumonia, and non-specific interstitial pneumonia (11A ). Dapsone-induced hypersensitivity pneumonitis has been described. • A 40-year-old Native American woman with newly diagnosed AIDS developed osteomyelitis and was given vancomycin and co-trimoxazole prophylaxis for Pneumocystis pneumonia when her CD4 count was reported as 140 × 106 /l (12A ). She developed a drug rash and was subsequently switched to dapsone, but 4 days later developed a maculopapular rash along with a non-productive cough, dyspnea, and hypoxemia. There were scattered rales and a chest X-ray showed new diffuse interstitial pulmonary infiltrates. A complete blood count showed
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eosinophilia. She was treated with clindamycin, primaquine, and prednisone, and the dapsone and vancomycin were withdrawn. No evidence for Pneumocystis pneumonia was found and treatment for that was withdrawn after 1 week, after which she continued to improve. A chest X-ray 10 days after dapsone had been withdrawn showed resolution of the interstitial infiltrates.
Although it is extremely unusual, druginduced hypersensitivity pneumonitis should be considered in the differential diagnosis of interstitial pneumonitis in patients with HIV. Drug interactions Dapsone hydroxylamine formation is thought to cause high rates of adverse reactions to dapsone in HIV-infected individuals. The effect of fluconazole on hydroxylamine formation in individuals with HIV infection has been investigated in 23 HIVinfected subjects (13c ). Fluconazole reduced the AUC by 49%, the percentage of the dose excreted in the urine in 24 hours by 53%, and the formation clearance of the hydroxylamine by 55%. This inhibition of in vivo hydroxylamine formation was quantitatively consistent with that predicted from human liver microsomal experiments. Rifabutin had no effect on the plasma AUC of hydroxylamine or the percent excreted in the urine in 24 hours but increased the formation clearance by 92%. Dapsone clearance was increased by rifabutin and rifabutin plus fluconazole (67% and 38% respectively) but was unaffected by fluconazole or clarithromycin. Hydroxylamine production was unaffected by clarithromycin. On the basis of these data, and assuming that exposure to dapsone hydroxylamine determines dapsone toxicity, co-administration of fluconazole should reduce the rate of adverse reactions to dapsone in people with HIV infection and rifabutin and clarithromycin will have no effect. When dapsone is given in combination with rifabutin, dapsone dosage adjustment may be necessary.
Ethambutol
(SED-15, 1282)
Urinary tract Ethambutol-induced acute renal insufficiency is very rare; only three cases of tubulointerstitial nephritis have previously been reported. In those cases, renal function
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deteriorated only after administration of antituberculosis drug treatment over several months, and liver function tests were normal. • A 33-year-old Korean man who had been treated for pulmonary tuberculosis 5 years before with rifampicin, pyrazinamide, isoniazid, and ethambutol, developed a recurrence and the same four medications were started (14A ). One day later he noted jaundice, abdominal pain, and oliguria. He had abnormal liver and renal function tests (blood urea nitrogen 26 mmol/l (72 mg/dl), serum creatinine 400 µmol/l (5.2 mg/dl), total bilirubin 240 µmol/l (14 mg/dl), aspartate transaminase 170 IU/l, alanine transaminase 28 IU/l, proteinuria 3+ with many red and white blood cells in the urine sediment). The anuria persisted for 4 days. On days 8 and 15, isoniazid and rifampicin were reintroduced without any problems. On day 24, ethambutol was reintroduced, and that evening he developed abdominal pain, fever, and general weakness. The serum creatinine concentration increased to 8.6 mg/dl and his urine output fell; hemodialysis was initiated. A renal biopsy showed features characteristic of acute tubular necrosis. He completely recovered renal function after treatment with rifampicin, isoniazid, pyrazinamide, and cycloserine.
In this case it was suggested that the renal damage was due to a toxic rather than an allergic effect, producing a tubular lesion and interstitial nephritis.
Isoniazid (SED-15, 1923; SEDA-26, 341; SEDA-28, 343) Liver There have been no clinical trials of the benefits and harms of routinely monitoring liver function tests for all patients taking isoniazid for latent tuberculosis infection. Data from two case series have suggested that routine liver function test monitoring leads to withdrawal of isoniazid prophylaxis from about 6% of patients because of abnormal results (15c , 16c ). This is 10–60 times the hepatitis rate found in case series using a symptom-based monitoring strategy (17R , 18C , 19r , 20c ). In a pooled analysis of more than 200 000 patients taking isoniazid prophylaxis there was a hepatitis rate of 1.2% and only two deaths. There is an increased risk of hepatitis in advancing age; in one series the rates were 3/1000 in those aged 20–34 years, 12/1000 in those aged 35– 49 years, and 23/1000 in those aged 50–64
years. The CDC and ATS joint guidelines for treatment of LTBI state that baseline laboratory testing is not routinely indicated, even for those over 35 years but may be considered for patients who are taking other hepatotoxic drugs or have chronic medical conditions. Baseline measurements of bilirubin and aspartate transaminase or alanine transaminase along with monthly monitoring of liver function tests are recommended for patients with pre-existing liver disease, patients with HIV infection, pregnant or postpartum women, and alcoholics. Isoniazid should be withdrawn if liver function tests exceed 5 times the upper limit of the reference range or three times the upper limit if the patient is symptomatic.
Rifampicin
(SED-15, 3040; SEDA-26, 341; SEDA-27, 324; SEDA-28, 344) Susceptibility factors
HIV/AIDS There are conflicting reports about the absorption and systemic availability of antituberculosis drugs in patients with HIV/AIDS. The effects of sex and AIDS status on the absorption of rifampicin have been investigated in 10 men and women in San Francisco with and without AIDS (21c ). The mean CD4 count in men and women with AIDS was 265 × 106 /l, and all were taking antiretroviral drugs. Rifampicin was measured in plasma, epithelial lining fluid, and alveolar cells after 5 days of treatment with rifampicin 600 mg/day. Plasma and alveolar cell concentrations were not significantly different and both were greater than concentrations in the epithelial lining fluid and were adequate to inhibit Mycobacterium tuberculosis. There were no differences in plasma rifampicin concentrations between those with and without AIDS. The authors concluded that the absorption of oral rifampicin was not affected by sex or AIDS. However, in a study in Chennai, India there was significant malabsorption of rifampicin (reduced Cmax and AUC and increased clearance), isoniazid, and other antituberculosis drugs in patients with advanced HIV disease both with and without tuberculosis (mean CD4 cell counts 60 and 98 × 106 /l respectively) (22c ). The systemic availability of isoniazid was affected
318 more in rapid acetylators. This study was performed in patients with more advanced disease, who had diarrhea and cryptosporidial infection, and who were not taking antiretroviral drugs. The difference between studies could have been due to differences in patient profiles, associated infections, stage of the disease, acetylator profile, and other genetic differences. Monitoring the plasma concentrations of antituberculosis drugs should therefore be consid-
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ered for patients with advanced HIV disease who have suboptimal response to antituberculosis treatment. Further studies are required to assess whether increasing the dosages of antituberculosis drugs can help overcome the effect of malabsorption and to correlate plasma drug concentrations with treatment outcome and the emergence of mycobacterial drug resistance in HIV co-infected patients with tuberculosis.
References 1. Smith H. Paradoxical responses during the chemotherapy of tuberculosis. J Infect 1987;15(1):1–3. 2. Cheng VC, Ho PL, Lee RA, Chan KS, Chan KK, Woo PC, Lau SK, Yuen KY. Clinical spectrum of paradoxical deterioration during antituberculosis therapy in non-HIV-infected patients. Eur J Clin Microbiol Infect Dis 2002;21(11):803–9. 3. Wendland T, Furrer H, Vernazza PL, Frutig K, Christen A, Matter L, Malinverni R, Pichler WJ. HAART in HIV-infected patients: restoration of antigen-specific CD4 T-cell responses in vitro is correlated with CD4 memory T-cell reconstitution, whereas improvement in delayed type hypersensitivity is related to a decrease in viraemia. AIDS 1999;13(14):1857–62. 4. Stone SF, Price P, French MA. Immune restoration disease: a consequence of dysregulated immune responses after HAART. Curr HIV Res 2004;2(3):235–42. 5. Breton G, Duval X, Estellat C, Poaletti X, Bonnet D, Mvondo Mvondo D, Longuet P, Leport C, Vilde JL. Determinants of immune reconstitution inflammatory syndrome in HIV type 1-infected patients with tuberculosis after initiation of antiretroviral therapy. Clin Infect Dis 2004;39(11):1709–12. 6. Lawn SD, Bekker LG, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005;5(6):361– 73. 7. Narita M, Ashkin D, Hollender ES, Pitchenik AE. Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med 1998;158(1):157–61. 8. Shelburne SA 3rd, Hamill RJ, RodriguezBarradas MC, Greenberg SB, Atmar RL, Musher DW, Gathe JC Jr, Visnegarwala F, Trautner BW. Immune reconstitution inflammatory syndrome: emergence of a unique syndrome dur-
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ing highly active antiretroviral therapy. Medicine (Baltimore) 2002;81(3):213–27. Carcelain G, Debre P, Autran B. Reconstitution of CD4+ T lymphocytes in HIV-infected individuals following antiretroviral therapy. Curr Opin Immunol 2001;13(4):483–8. Bucaretchi F, Vicente DC, Pereira RM, Tresold T. Dapsone hypersensitivity in an adolescent during treatment for leprosy. Rev Inst Med Trop S Paulo 2004;46(6):331–4. Sattler F, Nichols L, Hirano L, Hiti A, Hofman F, Hughlett C, Zeng L, Boylen CT, Koss M. Nonspecific interstitial pneumonitis mimicking Pneumocystis carinii pneumonia. Am J Respir Crit Care Med 1997;156:912–7. Tobin-D’Angelo MJ, Hoteit MA, Brown KV, Ray SM, King MD. Dapsone-induced hypersensitivity pneumonitis mimicking Pneumocystis carinii pneumonia in a patient with AIDS. Am J Med Sci 2004;327(3):163–5. Winter HR, Trapnell CB, Slattery JT, Jacobson M, Greenspan DL, Hooton TM, Unadkat JD. The effect of clarithromycin, fluconazole, and rifabutin on dapsone hydroxylamine formation in individuals with human immunodeficiency virus infection (AACTG 283). Clin Pharmacol Ther 2004;76:579–87. Kwon SH, Kim JH, Yang JO, Lee E-Y, Hong SY. Ethambutol-induced acute renal failure. Nephrol Dial Transplant 2004;19:1335–6. Byrd RB, Horn BR, Solomon DA, Griggs GA. Toxic effects of isoniazid in tuberculosis chemoprophylaxis. Role of biochemical monitoring in 1,000 patients. JAMA 1979;241:1239–41. Stuart RL, Wilson J, Grayson ML. Isoniazid toxicity in health care workers. Clin Infect Dis 1999;28:895–7. Kopanoff DE, Snider DE Jr, Caras GJ. Isoniazidrelated hepatitis: a U.S. Public Health Service cooperative surveillance study. Am Rev Res Dis 1978;117:991–1001.
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18. International Union Against Tuberculosis Committee on Prophylaxis. Efficacy of various durations of isoniazid preventive therapy for tuberculosis: five years of follow-up in the IUAT trial. Bull World Health Org 1982;60:555–64. 19. Dash LA, Comstock GW, Flynn JP. Isoniazid preventive therapy: retrospect and prospect. Am Rev Respir Dis 1980;121:1039–44. 20. Nolan CM, Goldberg SV, Buskin SE. Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic. JAMA 1999;281:1014–8. 21. Conte JE Jr, Golden JA, Kipps JE, Lin ET, Zurlinden E. Effect of sex and AIDS status on the
319 plasma and intrapulmonary pharmacokinetics of rifampicin. Clin Pharmacokinet 2004;43(6):395– 404. 22. Gurumurthy P, Ramachandran G, Hemanth Kumar AK, Rajasekaran S, Padmapriyadarsini C, Swaminathan S, Bhagavathy S, Venkatesan P, Sekar L, Mahilmaran A, Ravichandran N, Paramesh P. Decreased bioavailability of rifampicin and other antituberculosis drugs in patients with advanced human immunodeficiency virus disease. Antimicrob Agents Chemother 2004;48:4473–6.
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ARTEMISININ DERIVATIVES (SED-15, 342; SEDA-26, 319; SEDA-27, 292; SEDA-28, 320) Observational studies Although artemisinin and its derivatives, such as artesunate, arteether, artemether, and dihydroartemisinin, were originally developed for the treatment of malaria, they have antischistosomal activity. In 87 Nigerian children, aged 5–18 years, with Schistosoma haematobium ova-positive urine samples (1C ) who took two oral doses of artesunate 6 mg/kg 2 weeks apart and provided four urine samples (two before and two after treatment). There were no serious adverse effects within 7 days of either dose. Six of the subjects complained of headache, three of abdominal pain, and four of fever.
BENZIMIDAZOLES
(SED-15, 424; SEDA-25, 367; SEDA-26, 344; SEDA-27, 326)
Albendazole, mebendazole, thiabendazole, and triclabendazole Observational studies Two regimens of albendazole emulsion were used in 264 patients with hepatic cystic echinococcosis (2C ). In 71 albendazole emulsion was given in a dose of 10 mg/kg/day by mouth for 6 months to over 1 year (group A). In 62 cases follow-up extended to 3–4 years after treatment. In 193 cases albendazole emulsion was given in a dose of 12.5 mg/kg/day for 3 months to over 1 year (group B). The follow-up study in 139 cases extended for 2–4 years after treatment. In 38 there Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29031-7 © 2007 Elsevier B.V. All rights reserved.
320
were mild, self-limiting reactions: mild pruritus (n = 20), rash (n = 14), transient liver pain (n = 9), gastric pain (n = 11), alopecia (n = 2), anorexia (n = 4), nausea (n = 3), vomiting (n = 3), and headache (n = 2). These adverse effects gradually resolved over 2 weeks without any treatment. In two patients with anorexia, nausea, and vomiting treatment was stopped. There were slight rises in serum transaminases in both groups. In group A there were increases in 43% (aspartate transaminase) and 49% (alanine transaminase) after 3 months. In group B increases occurred 2 weeks after starting treatment in 64% (aspartate transaminase) and 43% (alanine transaminase). In a retrospective study of 30 patients with echinococcosis (3Ac ), four took albendazole. In two cases albendazole could not be tolerated because of gastrointestinal adverse effects in one case and abnormal liver function tests in the other. The liver function tests normalized after withdrawal of albendazole. In a French pharmacovigilance study adverse drug reactions were reported in 31 patients who took albendazole, in 22 who took mebendazole and in 62 who took thiabendazole (4C ). In six patients who took albendazole the adverse events were classified as severe, leading to hospitalization: two cases of agranulocytosis, one case of hepatitis, one of retrobulbar neuritis, one of acute renal insufficiency, and one of rash. In two cases there were severe adverse events after mebendazole, leading to hospitalization (one with abdominal pain, one with bone marrow aplasia). In two patients who took thiabendazole there were severe bullous eruptions and bradycardia, which led to hospitalization. All the adverse effects due to albendazole or mebendazole had already been described in the literature, except for renal insufficiency, which occurred in three patients who took albendazole. To test the efficacy of albendazole against the for school-based deworming, in 150 children with whipworm (Trichuris trichiura) in-
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fections, who were randomized to albendazole 400, 800, or 1200 mg, each repeated four times, and 50 randomized to placebo, there were no adverse drug-related events (5C ). In 165 patients with fascioliasis (n = 35) or supposed fascioliasis (based on clinical and laboratory data but without detectable fasciola eggs in stools, n = 130), who were randomly allocated to oral triclabendazole 10 mg/kg for 1, 2, or 3 days, there were mild drug complications, such as nausea, vomiting, weakness, pruritus, epigastric pain, and liver enlargement in five, eight, and five patients who took one, two, and three doses respectively (6C ). In the triple dose group, there was an increase in one or both transaminases in seven patients, which normalized in four of five patients on day 60. Comparative studies In an open study, 57 patients were randomized to metronidazole 500 mg tds for 5 days (n = 29) or albendazole 400 mg/day for 5 days (n = 28) (7C ). Albendazole was better tolerated than metronidazole, especially with respect to anorexia (2 versus 18 patients) and metallic taste (0 versus 9 patients). Placebo-controlled studies In a placebocontrolled, double-blind, crossover study in 99 subjects with Loa loa microfilaremia were given albendazole 400 mg/day or placebo for 3 days and were followed for 180 days, when the groups were crossed over and followed for a further 6 months (8C ). There were few adverse events, the most common being pruritus (30%, similar in the two groups), abdominal discomfort (12%), and urticaria (2%). One patient developed urticaria 14 days after placebo administration, and another developed urticaria and intense pruritus 1 month after albendazole administration. Both responded well to cetirizine. In a double-blind, double-dummy, placebocontrolled trial 120 patients with neurocysticercosis were randomly assigned to either albendazole 800 mg/day plus dexamethasone 6 mg/day for 10 days (n = 60) or placebo (n = 60) (9C ). Significantly more of those who took albendazole had abdominal pain (8 versus 0). The combination of albendazole + diethylcarbamazine has been compared with placebo + diethylcarbamazine in a double blind, randomized, parallel-group, field study in 1396 patients living in an area endemic for lymphatic
filariasis in India (10A ). The combination of albendazole + diethylcarbamazine was as safe as diethylcarbamazine alone. There were 270 adverse events in 693 patients by the 5th day in the placebo arm compared with 238 adverse events in 703 patients with albendazole + diethylcarbamazine. The most common reported adverse event on day 5 was fever, followed by myalgia. The other signs and symptoms that affected daily activity 5 days after administration were headache, nausea, and giddiness in the placebo arm, and abdominal pain, fatigue, and headache in the albendazole + diethylcarbamazine arm. There were no serious adverse events. Liver • In a 17-year-old man severe jaundice, anemia, and edema occurred 20 days after starting albendazole emulsion 12.5 mg/kg/day (3Ac ). After recovery albendazole was re-instituted in a dose of 10 mg/kg/day for 6 months without problems.
Susceptibility factors Age The pharmacokinetics of albendazole/ albendazole sulfoxide and praziquantel have been investigated in 20 Thai school-age children with Giardia intestinalis infections (11c ). They were randomized to a single oral dose of albendazole (400 mg) with or without a single oral dose of praziquantel (20 mg/kg). There was no significant pharmacokinetic interaction and no adverse effects. Drug formulations In a randomized crossover study (12R ) in 10 healthy volunteers (ages 18–41 years, weights 55–110 kg, body mass index 19–34 kg/m2 , four men) the systemic availability of the commercially available tablet of albendazole was compared with three new formulations: 1. an oral suspension in arachis oil and the surfactant polysorbate 80 (aimed at increasing lipid solubility); 2. an oral solution incorporated into hydroxypropyl-β-cyclodextrin (aimed at increasing water solubility); 3. a macrogol suppository (aimed at avoiding intestinal degradation of albendazole).
322 Compared with the results with the tablet, the systemic availability was significantly increased by the oil-surfactant suspension (4.3fold) and the cyclodextrin solution (9.7-fold). Rectal administration of albendazole-containing macrogol suppositories failed. Seven subjects had diarrhea 4–6 hours after the administration of the solution with hydroxypropyl-βcyclodextrin. Drug interactions • A 40-year-old man with HIV infection, taking HAART, developed alveolar echinococcosis (13A ). He was given albendazole 400 mg bd. Within 2 weeks he developed pancytopenia. Zidovudine, lamivudine, nelfinavir, and pyrimethamine/sulfamethoxazole were withdrawn. Full recovery of the bone marrow occurred within 10 weeks. HAART was changed to stavudine, abacavir, and lopinavir/ ritonavir. Instead of albendazole, he was given mebendazole. Since a pharmacokinetic interaction between albendazole and the HIV protease inhibitors was suspected to have contributed to the development of pancytopenia, mebendazole plasma concentrations were carefully monitored. Therapeutic mebendazole plasma concentrations were reached after 6 weeks at a dose of 150 mg bd instead of the usual dosage of 500–1500 mg bd.
These data suggest that there may be a significant pharmacokinetic interaction between benzimidazoles and CYP3A4 inhibitors like protease inhibitors. This may result in significantly increased serum benzimidazole concentrations, when benzimidazole doses are not adjusted under concomitant treatment with HIV protease inhibitors.
Diethylcarbamazine
(SED-15, 1115; SEDA-26, 345; SEDA-27, 328; SEDA-28, 348)
Comparative studies In 58 Egyptian adults with asymptomatic Wuchereria bancrofti microfilaremia single-dose combination therapy with diethylcarbamazine 6 mg/kg and albendazole 400 mg was compared with the same dose combination therapy for 7 consecutive days (14c ). Adverse events of mild-to-moderate severity were common after therapy in both groups, with no significant difference in frequencies between the two groups. These data suggest that the observed adverse events were more likely related to a Mazzotti-like reaction
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to microfilarial killing rather than direct drug or metabolite toxicity. The most frequent adverse events were fever (single dose versus multiple doses 29% versus 27%), headache (25% versus 33%), myalgia (25% versus 37%), and scrotal pain (11% versus 6%). These symptoms usually resolved within 2–3 days. Subjective fever, myalgia, and headache were more common in subjects with high microfilarial counts. Scrotal discomfort peaked at 1 week after treatment, but one man had mild persistent scrotal discomfort after 4 weeks. All adverse events were scored as grade 1 or 2 events. Adverse events in the week after re-treatment of 51 subjects were greatly reduced compared with those after the first round (fever 9%, headache 5%, myalgia 7%, scrotal pain 1 week after treatment 0%). In 150 subjects in whom diethylcarbamazine was used to prevent recurrent attacks of acute lymphadenitis during bancroftian filariasis, divided into those with mild-to-moderate lymphedema (n = 100) and those with severe lymphedema (n = 50), the following treatments were randomly allocated (daily treatment for 12 months): • penicillin G potassium 800 000 U/day (n = 30); • diethylcarbamazine 50 mg/day (n = 30); • daily diethylcarbamazine + penicillin (n = 30); • daily topical antibiotics (n = 30); • daily placebo (n = 30). There were 72 episodes of adverse effects: 25 with diethylcarbamazine, 17 with diethylcarbamazine + penicillin, 10 with local antibiotics, and nine with placebo. No subject withdrew because of adverse effects (15C ). Most subjects reported just one adverse effect each: burning epigastric pain (74%), fever (10%), or headache/drowsiness (10%). The adverse effects were usually mild (60 episodes) but some were moderate (seven episodes) or even severe (six episodes). Five of the six severe events (all epigastric pain) were reported by the subjects who received diethylcarbamazine. Based on these observations the authors recommended a combination of penicillin prophylaxis but not diethylcarbamazine to reduce the risk of acute lymphadenitis in bancroftian filariasis. In 96 subjects with Brugia timori microfilariae, a single oral dose of diethylcarbamazine
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6 mg/kg combined with albendazole 400 mg was not associated with adverse effects (16C ).
Ivermectin
(SED-15, 1946; SEDA-26, 346; SEDA-27, 329; SEDA-28, 349)
Observational studies Of 458 Brazilians with intestinal helminthiasis and parasitic skin diseases treated with ivermectin 200 micrograms/kg and a second dose after 10 days, 24 were also given albendazole and 15 mebendazole (17C ). There were adverse events in 9.4% of treatments (85 individuals). They were all mild to moderate in intensity and were transient. Abdominal pain, the most common adverse event (23 out of 458 first-dose treatments with ivermectin), was probably caused by worms dying and disintegrating, especially Ascaris lumbricoides. Nausea and loose stools were reported after 15 and 12 first-dose treatments respectively. In a 3-year double-blind trial (18C ) in Cameroon the effect of ivermectin, given at 3-monthly intervals and/or in high doses (800 micrograms/kg) on adult Onchocerca volvulus was determined in 643 individuals and compared with the standard annual dose of 150 micrograms/kg. No patient developed a serious adverse reaction, none required hospitalization, and none withdrew because of an adverse reaction. Mild adverse reactions began soon after the start of treatment. Of 1129 consultations for adverse reactions, 367 took place in the a few hours after treatment (day 0); 449, 195, and 118 consultations took place on days 1, 2, and 3 respectively. The incidence of adverse reactions fell steadily over the course of the trial. After the first dose, 3-monthly treatment was associated with a reduced risk of reactions, especially edematous swelling, pruritus, and back pain. Edematous swelling and subjective ocular problems were associated with high doses of ivermectin. Comparative studies In a randomized, double-blind field trial in Tanzania, 1221 children with Wuchereria bancrofti lymphatic filariasis were given a single dose of ivermectin 150–200 micrograms/kg alone or in combination with albendazole 400 mg (19C ). Adverse
reactions were few and mild in both groups, and mainly reported from pre-treatment microfilaria and children positive for circulating filarial antigen. The most common adverse events were headache (n = 25) and fever (n = 19). All adverse events abated within a few days. In a randomized open study, a single dose of oral ivermectin 200 micrograms/kg (n = 17) was compared with oral albendazole 400 mg/ day (n = 14) for 21 days in the treatment of cutaneous gnathostomiasis (20c ). There were no major adverse effects. Drug resistance In an open case-control study, an attempt was made to determine if persistence of Onchocerca volvulus microfilaridermia after multiple treatments with ivermectin was due to drug resistance in the parasite in 21 suboptimal responders matched by age, weight, number of treatments, locality, and skin microfilarial counts, with 7 amicrofilaridermic responders and 14 ivermectin-naïve subjects (21c ). The cases of persistent significant microfilaridermia despite multiple treatments were mainly attributable to non-response of the adult female worms and not to inadequate drug exposure or other factors. The possibility that some adult female worms might have developed resistance to ivermectin could not be excluded. Adverse effects of ivermectin were mild, and were most commonly body pain (n = 8), followed by headache (n = 7), arthralgia, pruritus, gland pain, or limb swelling (n = 6 each) and muscle aches (n = 5). Susceptibility factors HTLV co-infection In Japan co-infection with human T lymphotropic virus type I (HTLV-1) occurs in about 38% of those who are infected with Strongyloides stercoralis, which may limit the efficacy of ivermectin. In a retrospective follow-up study 312 patients with strongyloidiasis were treated with a single dose of ivermectin 6 mg and a repeat dose of 6 mg 2 weeks after the first dose; 121 were HTLV-1 antibodypositive (22C ). Short-term antihelminthic treatment at 4 weeks was 97.9% efficacious in HTLV-1 antibody-negative patients (187 of 191 patients) and 90.1% in HTLV-1 antibodypositive patients (109 of 121 patients). Longterm antihelminthic drug efficacy fell dramatically in HTLV-1 antibody-positive patients
324 (from 90.1% to 50%). Of 97 subsequent patients with strongyloidiasis who were treated with a higher dose of ivermectin (200 micrograms/kg on day 1 and a repeat dose after 2 weeks), 20 were HTLV-1 antibody-positive. Short-term antihelminthic efficacy was 100% in HTLV-1 antibody-positive and 97.1% in HTLV1 antibody-negative patients. Long-term efficacy remained high (90%) in HTLV-1 antibodypositive patients. In those who were given 110 micrograms/kg dose there were subjective adverse effects in 27 patients. The most common adverse effects were dizziness (n = 7), diarrhea (n = 5), and nausea (n = 3). There were liver function test abnormalities in 19 patients. In one patient the second dose of ivermectin was withheld because of a large rise in aspartate transaminase activity. There were adverse effects in six of 93 patients who were given ivermectin 200 micrograms/kg. There were mild liver function test abnormalities in five patients. The frequency of adverse effects was not significantly different between the two treatment groups and neither was the frequency of liver function abnormalities.
Levamisole
(SED-15, 2028; SEDA-26, 347; SEDA-27, 330; SEDA-28, 350)
Placebo-controlled studies In two randomized, double-blind, placebo-controlled trials, in which levamisole 2.5 mg/kg was given alone or with ivermectin 200 micrograms/kg or albendazole 400 mg in 42 healthy male volunteers and in 66 patients with onchocerciasis, the frequencies of adverse events were unrelated to the treatment regimen (23C ). The most common drug-related events were general weakness and headache (n = 9 each), followed by itching (n = 6), rash (n = 5), and joint pain (n = 5). The adverse events were considered mild. The most common drug-related events in the 66 patients with onchocerciasis were itching (n = 36) and rash (n = 31). Other adverse events were headache (n = 20), arthralgia (n = 11), and other body pains (n = 11). None of the adverse events was serious. They occurred more often in patients who took levamisole and ivermectin.
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Hematologic The effects of daily levamisole 2–3 mg/kg have been assessed in 36 children with steroid-sensitive nephrotic syndrome with frequent relapses and/or steroid dependency (24C ). There was transient leukopenia in nine. White blood cell counts returned to normal 1–2 weeks after withdrawal of levamisole in seven cases. Two patients had leukopenia for more than 4 weeks. Leukopenia did not recur after re-institution of levamisole treatment once the white blood cell count had returned to normal. Drug interactions In a pharmacokinetic study, the only clinically relevant drug–drug interactions were levamisole-attributable increases in the AUC and Cmax of ivermectin, and reductions in the AUC and Cmax of the active metabolite of albendazole, albendazole sulfoxide.
Praziquantel
(SED-15, 2911; SEDA-26, 349; SEDA-27, 331; SEDA-28, 351)
Observational studies The effect of a single oral dose of praziquantel 40 mg/kg against Schistosoma mansoni has been studied in a rural community in Côte d’Ivoire (25C ). Among the 200 individuals treated, 25 reported one or more adverse effects within 24 hours after treatment. A significantly higher proportion of individuals with high infection intensities (over 400 Schistosoma mansoni eggs/gram of feces) reported diarrhea and dizziness compared with those with light or moderate infections. None of the other adverse effects, such as itching (n = 5), vomiting (n = 2), headache (n = 2), nausea (n = 2), and urticaria (n = 1) was associated with the severity of the infection, nor with age. Abdominal pain was the only adverse effect associated with (female) sex. Pregnancy In a retrospective study, 88 women who took praziquantel during pregnancy were compared with a control group of 549 women who had not taken praziquantel (26c ). There were no significant differences between the groups in the rates of abortion or preterm deliveries. There were no congenital abnormalities in any of the babies born to either group. These data suggest that praziquantel
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during pregnancy is not associated with an increased risk of congenital abnormalities.
Suramin
(SED-15, 3249; SEDA-26, 350; SEDA-27, 331; SEDA-28, 352) Observational studies Although suramin was developed in the 1920s as a treatment for African trypanosomiasis and was later found to be effective in the treatment of onchocerciasis, it is currently not used for these disorders because of significant adverse effects. Later, suramin received attention as a potential cytostatic agent because of its ability to interfere with the function of a number of peptide growth factors. In 55 patients with newly diagnosed glioblastoma multiforme (27c ) suramin was given in a conventional intermittent fixeddosing regimen for 1 week before and during
cranial radiotherapy (60 Gy in 30 fractions, weeks 2–7) aimed to maintain plasma concentrations in the 150–250 micrograms/ml range. Patients with stable or responsive disease at week 18 received an additional 4 weeks of twice-weekly intravenous infusions of suramin 275 mg/m2 (weeks 19–22). Two patients died of possibly related neurological events (stroke and raised intracranial pressure). Otherwise, adverse effects were generally transient and self-limiting. However, overall survival was not significantly improved when compared with other therapeutic regimens for glioblastoma. In 58 patients with hormone-refractory prostate carcinoma suramin was given in three 1-hour infusions each month (tapering the dose from 2400 mg/m2 on day 1 to 1292 mg/m2 on day 3) (28C ). Grade III fatigue (14%) was the predominant adverse effect. Suramin plasma concentrations were high even 3 months after withdrawal of therapy.
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19. Simonsen PE, Magesa SM, Dunyo SK, MalecelaLazaro MN, Michael E. The effect of single dose ivermectin alone or in combination with albendazole on Wuchereria bancrofti infection in primary school children in Tanzania. Trans R Soc Trop Med Hyg 2004;98:462–72. 20. Kraivichian K, Nuchprayoon S, Sitichalernchai P, Chaicumpa W, Yentakam S. Treatment of cutaneous gnathostomiasis with ivermectin. Am J Trop Med Hyg 2004;71:623–8. 21. Awadzi K, Boakye DA, Edwards G, Opoku NO, Attah SK, Osei-Atweneboana MY, LazdinsHelds JK, Ardrey AE, Addy ET, Quartey BT, Ahmed K, Boatin BA, Soumbey-Alley EW. An investigation of persistent microfilaridermias despite multiple treatments with ivermectin, in two onchocerciasis-endemic foci in Ghana. Ann Trop Med Parasitol 2004;98:231–49. 22. Zaha O, Hirata T, Uchima N, Kinjo F, Saito A. Comparison of anthelmintic effects of two doses of ivermectin on intestinal strongyloidiasis in patients negative or positive for anti-HTLV-1 antibody. J Infect Chemother 2004;10:348–51. 23. Awadzi K, Edwards G, Opoku NO, Ardrey AE, Favager S, Addy ET, Attah SK, Yamuah LK, Quartey BT. The safety, tolerability and pharmacokinetics of levamisole alone, levamisole plus ivermectin, and levamisole plus albendazole, and their efficacy against Onchocerca volvulus. Ann Trop Med Parasitol 2004;98:595–614. 24. Fu LS, Shien CY, Chi CS. Levamisole in steroidsensitive nephrotic syndrome children with frequent relapses and/or steroid dependency: comparison of daily and every-other-day usage. Nephron Clin Pract 2004;97:137–41. 25. Raso G, N’Goran EK, Toty A, Luginbuhl A, Adjoua CA, Tian-Bi NT, Bogoch II, Vounatsou P, Tanner M, Utzinger J. Efficacy and side effects of praziquantel against Schistosoma mansoni in a community of western Côte d’Ivoire. Trans R Soc Trop Med Hyg 2004;98:18–27. 26. Adam I, Elwasila ET, Homeida M. Is praziquantel therapy safe during pregnancy? Trans R Soc Trop Med Hyg 2004;98:540–3. 27. Laterra JJ, Grossman SA, Carson KA, Lesser GJ, Hochberg FH, Gilbert MR. Suramin and radiotherapy in newly diagnosed glioblastoma: phase 2 NABTT CNS Consortium study. NeuroOncology 2004;6:15–20. 28. Vogelzang NJ, Karrison T, Stadler WM, Garcia J, Cohn H, Kugler J, Troeger T, Giannone L, Arrieta R, Ratain MJ, Vokes EE. A phase II trial of suramin monthly × 3 for hormone-refractory prostate carcinoma. Cancer 2004;100:65–71.
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32 Surveillance of adverse events following immunization Standardized case definitions The Brighton collaboration was launched in 2000 as a voluntary international organization to facilitate the development, evaluation, and dissemination of high quality information about the safety of vaccines. The first six standardized case definitions have been developed and published: fever, generalized convulsive seizure, hypotonic–hyporesponsive episodes (HHE), intussusception, nodule at injection site, and persistent crying (SEDA 28, 356). New working groups will soon finalize the work on case definitions for: anaphylaxis, aseptic meningitis, encephalitis, fatigue state, local reactions (abscess, cellulitis, induration, swelling), rash, sudden infant death syndrome, idiopathic thrombocytopenia, myalgia, paresthesia, and smallpox vaccine-associated adverse events following immunization (1r ).
Childhood immunization and diabetes mellitus In a study of all children born in Denmark from 1 January 1990 to 31 December 2000, for whom detailed information on immunizations and type 1 diabetes was available, type 1 diabetes was diagnosed in 681 children during 4 720 517 person-years of follow-up (2C ). The rate ratio for type 1 diabetes among children who received at least one dose of vaccine, compared with unimmunized children, was 0.91 Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29032-9 © 2007 Elsevier B.V. All rights reserved.
Vaccines (95%CI = 0.74, 1.12) for Hemophilus influenzae type b vaccine; 1.02 (0.75, 1.37) for diphtheria, tetanus, and inactivated poliovirus vaccine; 0.96 (0.71, 1.30) for diphtheria, tetanus, acellular pertussis, and inactivated poliovirus vaccine; 1.06 (0.80, 1.40) for whole-cell pertussis vaccine; 1.14 (0.90, 1.45) for measles, mumps, and rubella vaccine; and 1.08 (0.74, 1.57) for oral poliovirus vaccine. Thus, the development of type 1 diabetes in genetically predisposed children (defined as those who had siblings with type 1 diabetes) was not significantly associated with immunization. Furthermore, there was no evidence of any clustering of cases 2–4 years after immunization with any vaccine. The authors concluded that their results did not support a causal relation between childhood immunization and type 1 diabetes.
Multiple immunizations/ combination vaccines Sudden infant deaths shortly after the administration of hexavalent vaccines HEXAVAC® and Infanrix™ hexa are combination vaccines that were authorized in the European Union on 23 October 2000. Both protect infants and children against diphtheria, tetanus, whooping cough (pertussis), hepatitis B virus, polio virus, and Hemophilus influenzae type b. During its April 2003 meeting, the scientific Committee for Proprietary Medicinal Products (CPMP) of the European Agency for the Evaluation of Medicinal Products (EMEA) conducted a detailed review of five reports of unexplained deaths in children within 24 hours of immunization with a hexavalent vaccine (3S ). These reports were received as part of routine postmarketing safety monitoring over 2.5 years. During this time an estimated 8.7 million doses of the vaccines were used world wide, corresponding to the immunization of some 3 million
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Abbreviations BCG Bacillus Calmette Guérin DTaP Diphtheria + tetanus toxoids + acellular pertussis DTaP-Hib-IPV Diphtheria + tetanus toxoids + acellular pertussis + IPV + Hib DTwP Diphtheria + tetanus toxoids + whole cell pertussis HBV Hepatitis B virus HbOC (also called PRP-CRM) Conjugated Hib vaccine (Hib capsular antigen polyribosylphosphate covalently linked to the non-toxic diphtheria toxin variant CRM197) Hib Hemophilus influenzae type b JE vaccine Japanese encephalitis vaccine MMR Measles + mumps + rubella 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 + tetanus toxoids (adult formulation)
children. Participants at the meetings included the pathologists who had conducted the autopsies, pediatricians with experience in vaccines and Sudden Infant Death Syndrome (SIDS), and epidemiologists. On the basis of the available information, the CPMP concluded that: the causes of the deaths remained unexplained, and on the basis of available data it is not possible to establish a cause-and-effect association with the hexavalent vaccines. In several cases SIDS, viral infection, metabolic disorders, allergic reactions, or airway obstruction were plausible, although none of these could be definitely proven to have caused the deaths. The Committee also considered possible risk factors, including a family history of epilepsy or convulsions at an early age, which was reported in three of the five cases. However, they concluded that the clinical description of these individual cases did not provide sufficient evidence to identify a family history of epilepsy as a possible risk factor. In summary, the Committee concluded that there was no change in the benefit/harm balance of these products and that the benefits of immunization far outweigh the possible risks of existing vaccines, including hexavalent vaccines. They recommended that immunization should be continued according to national immunization schedules without changes to the present conditions of use. Since the EMEA Public Statement on 28 April 2003, EMEA’s CPMP has continued to monitor all data submitted and at its November 2003 meeting reviewed the conclusions taken by a number of specialized expert groups and working parties with regard to HEXAVAC® and
Infanrix™ hexa. Since the products were authorized (in 2000) four sudden unexpected deaths in close temporal association with hexavalent immunization have been reported in children during the second year of life (three in Germany, one in Austria) over a period of 3 years. A retrospective analysis based on an epidemiological approach to this problem was performed on data from Germany and showed that the observed number of cases of sudden unexpected death in the second year of life within 48 hours of HEXAVAC® administration exceeded the expected number of cases. This finding was based on three cases amongst more than 700 000 children who were given a booster in the period analysed (November 2000 – June 2003). The CPMP experts considered that this temporal relation raised a possible signal linking HEXAVAC® immunization and sudden unexplained death, but they acknowledged some inevitable limitations of the data sources and methods used to calculate the expected numbers. In any case, a signal only raises a suspicion, and does not prove a cause-and-effect relation. The CPMP has agreed that a possible signal has been generated, but believes that this does not currently constitute a risk to public health. It is known that a very small number of children die in their early years from a number of causes, some of which are unknown. The fact that a child dies shortly after being immunized may lead to the reporting of this event to the responsible health authority as being temporally associated with immunization. Further studies are needed to establish whether or not there is a real risk. Being aware of this possibility, and
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taking into account the findings for HEXAVAC® as suggested by the statistical analysis, the following actions are being undertaken to find out whether the signal is real or not. Prospective and retrospective studies to investigate sudden unexpected deaths will be conducted by independent institutions and will be assessed by regulatory authorities. These active surveillance programs, which started in 2004, should facilitate the collection of further data and monitoring of vaccines by regulatory authorities and the marketing authorization holders. The results will be followed closely, so that timely regulatory action can be taken, if necessary. Based on their review, the CPMP concluded that there was no change in the benefit/harm balance of these products and therefore recommended no changes to the present conditions of use (4S ). In a letter to the editor, Zinka et al. (5r ) described six cases of “sudden infant death” within 48 hours of administration of hexavalent DTaP–Hib–IPV–HBV combination vaccine. While they stated that the causality of immunization and death was uncertain, they aimed to inform physicians, pediatricians, and parents about possibly fatal complications after the use of hexavalent vaccines. In a reply, Schmitt et al. (6r ) suggested that the data given in the letter fell short of providing any scientifically valid evidence. Basic information about the cases was missing; the descriptions of the cases lacked information on any special circumstances or potential risk factors, such as the sleeping position, the type of bed, bedding, or pillows, or the potential for foreign-body aspiration. There was no information about the autopsy protocol, about which tests and examinations had been performed on which of the cases, or whether histology was done on all organs. There was histological evidence of encephalitis, including necrosis, at least in some cases, but there was no information about microbiological tests for non-colonizing microorganisms or tests done to look for intercurrent infections. Zinka et al. had stated that all the children had “extraordinary brain oedema,” but it was not clear if this statement had been based on subjective personal impressions at autopsy, or the weight of the brains relative to a valid reference scale, or histological findings. They also pointed out that neither of the currently available hexavalent vaccines contains hepatitis B serum, but rather recombinant
329 hepatitis B surface antigen protein. Likewise, neither contains “influenza” antigen, but rather Hemophilus influenzae type b polysaccharide conjugated to tetanus toxoid. The recommended schedule for immunization of children in Germany, where the cases were observed, was not 2, 4, 6, and 12–14 months, as described in the letter. In another reply to the letter to the editor, von Kries (7r ) expressed doubt about the conclusions of Zinka et al. and their recommendation to switch from a hexavalent combination vaccine to a pentavalent combination vaccine. The rationale was based on a statement in the discussion: 1/198 cases of sudden infant death shortly after immunization had been observed in 1994–2000 (when tetravalent or pentavalent vaccines were used) compared with six in 74 cases in 2001–2004 (since the launch of hexavalent vaccines). Five of these cases were in close temporal association (“shortly after vaccination”) with the use of HEXAVAC® (four in the first year and one in the second year of life), one with the use of Infanrix™ hexa. Comparing the 1/198 cases and the 4/72 cases (excluding the case in the second year of life and the Infanrix™ hexa case) yields a two-sided Fischer’s exact P value of 0.019. This does not, however, generate a signal for HEXAVAC® in the first year of life. Von Kries added that comparisons with historic control groups are always problematic, since changes in risk factors over time cannot be disentangled from the exposure of interest. Unless there are data to show that the proportion of cases of sudden infant death undergoing autopsy has been constant over time there is a possibility of selection bias. There had been 198 autopsies in cases of sudden infant death in 7 years (1994–2000) compared with only 74 in 4 years (2001–2004), which might be explained by the reduced incidence of sudden infant death in recent years. However, there is also a possibility that cases in temporal association with immunization were more likely to have an autopsy after 2001 than before. Finally, in a systematic analysis of all cases of sudden infant death in temporal association with hexavalent vaccines before June 2003 there was no signal for HEXAVAC® or Infanrix™ hexa in the first year of life. Given the limitations of the data, von Kries doubted that the observations in the Munich Institute for
330 Legal Medicine provided support for an additional empirical signal for HEXAVAC® in the first year of life. He concluded that the observations reported by Zinka et al. justified neither an intimidating “information” policy for immunizing physicians and parents nor a recommendation to switch to pentavalent DTPaP–IPV–Hib vaccines. In a press release (21 April, 2005) the European Agency for the Evaluation of Medicinal Products (EMEA) informed a meeting of the Committee for Medicinal Products for human use as follows: At the request of the German regulatory agency in February 2005 the committee again reviewed the safety of the hexavalent combination vaccine HEXAVAC® and verified its previous position (December 2003) that no regulatory action or changes to the product information are necessary (8S ). During its twelfth meeting (June 9–10, 2005) the Global Advisory Committee on Vaccine Safety (GACVS), an expert clinical and scientific advisory body that reports to the WHO, reviewed the available data concerning a purported association between sudden unexplained death and hexavalent diphtheria, tetanus, acellular pertussis, Haemophilus influenzae type b, poliovirus, and hepatitis B (DTaP–Hib–IPV– HBV) combination vaccines. The Committee concluded that the evidence did not support a causal association, but recommended that additional studies be conducted to extend the observation period to the first 2 years of life. There have been no additional signals from Germany, where the first reports originated. The results from a population-based Italian study on sudden infant deaths and sudden unexplained deaths in five birth cohorts (between 1999 and 2003) have produced no evidence of increased risks in the 48 hours after any immunization in the first year of life. Nor has any increased risk been observed in relation to the number of doses of vaccine administered. In Italy, between 1990 and 2001, infant mortality from any cause fell from 8.1 to 4.8 per 1000 births. Between 1991 and 2002, infant mortality from sudden infant deaths fell in Germany from 1.5 to 0.6 per 1000 births. This happened despite the introduction in both countries of several new vaccines in the infant schedule and increased immunization coverage in both countries. GACVS concluded that these data are inconsistent with any association between
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hexavalent vaccines and sudden infant death or sudden unexplained death (9S ). Hepatitis risk and suspension of marketing authorization for HEXAVAC® At its meeting of 12–15 September 2005, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA) recommended as a precautionary measure the suspension of the marketing authorization for HEXAVAC® because of doubts about its ability to confer long-term protection against hepatitis B (10S ). The recommendation was made after identification of reduced immunogenicity of the hepatitis B component. This is supposed to be due to variability in the production process for the hepatitis B component. There is no immediate concern for children already immunized with HEXAVAC® . However, the Committee asked Sanofi Pasteur MSD, the marketing authorization holder, to design a specific surveillance program to investigate whether infants and children would need to be re-immunized at a later stage, for instance at adolescence, to ensure long-term protection against hepatitis B.
BACTERIAL VACCINES Anthrax vaccine
(SED-15, 260; SEDA-26, 354; SEDA-28, 357)
Observational studies In 2000 the Institute of Medicine of the United States Academy of Sciences encouraged the evaluation of active long-term monitoring studies of large populations to further evaluate the relative safety of anthrax vaccine. The association of anthrax immunization with arthritic, immunological, and gastrointestinal adverse reactions has been evaluated, based on an analysis of the Vaccine Adverse Events Reporting System (VAERS) database (15 December 1997 to 12 April 2000) (11M ). Anthrax vaccine was one of the most reactogenic vaccines included in VAERS. The incidence of adverse reactions reported after anthrax vaccine was higher for every reaction analysed compared with the adult vaccine control groups. The authors concluded that the current anthrax vaccine may be acceptable in military populations in an impending threat of
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anthrax exposure. Civilian anthrax immunization will require a less reactogenic vaccine.
Meningococcal vaccine
(SED-15, 2250; SEDA-27, 337; SEDA-28, 359)
On 14 January 2005, a quadrivalent meningococcal conjugate vaccine (A, C, Y, and W135 ; meningococcal polysaccharide diphtheria toxoid conjugate vaccine, Menactra® , SanofiPasteur, Swiftwater, Pennsylvania) (MCV4) was licensed in the USA for adolescents and adults up to the age of 55 years. MCV4 is a tetravalent vaccine; each dose of 0.5 ml contains 4 micrograms each of capsular polysaccharide from Neisseria meningitidis serogroups A, C, Y, and W135 conjugated to 48 micrograms of diphtheria toxoid. In February 2005, the Advisory Committee on Immunization Practices (ACIP) recommended routine immunization of adolescents at the preadolescent health-care visit (at age 11–12 years). Routine immunization is also indicated for first-year college students living in dormitories and for other people at increased risk. Observational studies Young children have the highest incidence of meningococcal infection. About 50% of cases in US children aged under 2 years of age is caused by serogroups C and Y. MCV-4 has been studied in three groups of 30 infants at 2, 4, and 6 months of age (12c ). The first group was given three doses of a quadrivalent polysaccharide meningococcal vaccine (group A, C, Y, W-135) conjugated to diphtheria toxoid (MCV-4) in a dosage of 1 microgram/ml of each serogroup polysaccharide. The second group was given MCV-4 in a dosage of 4 micrograms/ml, and the last group received 10 micrograms/ml. A subset of these children were immunized at 15–18 months with licensed meningococcal polysaccharide vaccine (A, C, Y, W-135). MCV-4 had a reactogenicity profile that was acceptable to parents and health-care providers. It was only modestly immunogenic in infants, but it primed the immune system of most of the infants who were given three doses in infancy. There was no statistically significant immunological advantage in increasing the dosage beyond 4 micrograms/ml, and local reactions were more frequent after 10 micrograms/ml.
Nervous system As of 4 October 2005, the Vaccine Adverse Event Reporting System (VAERS) had received five reports of Guillain– Barré syndrome after the use of MCV4 vaccine (13c ). All occurred in people aged 17– 18 years who were immunized with MCV4 during 10 June – 25 July 2005 and had onset of symptoms 14–31 days after immunization. One patient reported another acute illness before the onset of the symptoms. The five patients received vaccine from four different lots. About 2.5 million doses of MCV4 had been distributed nationally since March 2005 (Sanofi–Pasteur, unpublished data, 2005). Data (1989–2001) from the Vaccine Safety Datalink in those aged 11–19 years show a background annual incidence of 1–2 cases per 100 000 person-years. This suggests that the rate of Guillain–Barré syndrome based on the number of cases reported within 6 weeks of administration of MCV4 is similar to what might have been expected to occur by chance alone. However, the timing of the onset of neurological symptoms (i.e. within 2–5 weeks of immunization) is of concern. Based on limited experience, it is not yet known whether these cases were caused by the vaccine or were coincidental.
Pertussis vaccines, acellular (including diphtheria-tetanus-acellular pertussis vaccine (DTaP) and other DTaP-based combination vaccines) (SED-15, 2783; SEDA-28, 360) Susceptibility factors Age To evaluate the safety of DTaP–IPV–HIB immunization in premature infants, Pfister et al. (14c ) in an observational study, 78 premature infants of very low birth weights (mean gestational age 28 weeks; mean birth weight 1045 were given DTaP–IPV–HIB vaccine before discharge. The vaccine elicited resurgent or increased cardiorespiratory events in 47% of cases (15% had apnea, 21% had bradycardia, 42% desaturated). Most of the vaccinetriggered events resolved spontaneously or after brief stimulation. The relative risk was 5–8 times higher in infants with a severe clinical course or persistence of cardiorespiratory
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symptoms at the time of immunization. Bag and mask respiratory support was given to five infants, and oxygen requirements increased transiently in four of 21 infants with chronic lung disease; none required re-ventilation. Reintroduction of oxygen, interruption of active oral feeding, or postponing of hospital discharge was not required. The authors concluded that cardiorespiratory events were often problematic after DTaP–IPV–HIB immunization, requiring monitoring and appropriate intervention. However, these episodes did not have a detrimental impact on the infants’ clinical course. Timely immunization is warranted, even in the most vulnerable preterm infants.
Pneumococcal vaccine
(SED-15,
2873; SEDA-28, 360)
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VIRAL VACCINES Hepatitis A vaccine
(SED-15, 1600;
SEDA-26, 357) Nervous system During 1987–2001 there were 12 published cases of Guillain–Barré syndrome after hepatitis A immunization, mainly in adults, but also in a 3-year-old child. • An 18-month-old child developed Guillain–Barré syndrome 10 days after a dose of hepatitis A vaccine (16A ). His neurological status improved slowly, and 4 months after admission the physical examination was normal.
Hepatitis B vaccine (including combination vaccines with HB component) (SED-15, 1600; SEDA-26; 357)
In 2000, the first heptavalent conjugate pneumococcal vaccine, Prevnar (containing polysaccharides of pneumococcal serotypes 4, 6B, 9V, 14, 19F, and 23F, and oligosaccharide of serotype 18C, conjugated to the protein carrier CRM197 , a non-toxic variant of diphtheria toxin), was licensed in the USA, and in 2001 in all EU member states and selected other countries. To have a wide global coverage of the pneumococcal serotypes that are prevalent in young children, the number of serotypes covered by the currently licensed heptavalent pneumococcal conjugate vaccine must be increased. Observational studies An 11-valent pneumococcal conjugate vaccine (including serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F) was given to 117 Finnish and 135 Israeli infants at ages 2, 4, 6, and 12 months together with other vaccines used in the respective national immunization programs (15C ). The authors concluded that the vaccine is safe and immunogenic in infants. There were no severe adverse reactions. After each dose 30% of the vaccinees had local reactions, of which pain was the most common. Fever 38 ◦ C was reported in 33–53% and a high fever ( 40 ◦ C) was reported six times.
The suspension of HEXAVAC® , because of doubts about its ability to protect against hepatitis B, is discussed above. Hematologic Thrombocytopenia purpura after hepatitis B immunization (47 cases) has been reviewed in the context of a new case. • A 45-day-old previously healthy girl developed thrombocytopenia purpura 40 days after receiving hepatitis B and BCG vaccines; she recovered completely within 2 weeks (17AR ).
Influenza vaccine
(SED-15, 1753; SEDA-26, 358; SEDA-28, 361)
The potential influenza H5N1 pandemic The avian influenza virus H5N1 is currently being looked upon as one that might ignite the next human influenza pandemic. The WHO Influenza Surveillance Network has characterized H5N1 influenza viruses isolated from humans and animals from several countries affected by the 2004/2005 H5N1 outbreak in Asia. WHO collaborating centers and reference
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laboratories have developed several recombinant H5N1 prototype vaccine strains, including A/Vietnam/1194/04, A/Vietnam/1203/04, and A/Hongkong/213/03, according to the requirements of several major national and international pharmaceutical licensing agencies for influenza vaccine production. These H5N1 influenza pandemic vaccine prototype strains have already been made available to several institutions and companies, and several different vaccines have been produced for tests of immunogenicity and safety (18S ). Preliminary results have been published, but it is too early to draw firm conclusions. The results of initial clinical trials of a vaccine developed to protect humans against infection with H5N1 avian influenza have been published (19c ). The experimental vaccine evoked an immune response in a small group of healthy adults. However, many problems need to be resolved before vaccines can assume a role in mitigating the effects of the potential H5N1 pandemic. Respiratory The safety of cold-adapted trivalent intranasal influenza virus vaccine (CAIV– FluMist) have been determined in 9689 children and adolescents aged 1–17 years using vaccine or placebo (randomization 2:1) (20C ). Children under 9 years of age received a second dose of CAIV or placebo 28–42 days after the first dose. Of the four prespecified diagnostic categories (acute respiratory tract events, systemic bacterial infection, acute gastrointestinal tract events, and rare events potentially associated with wild-type influenza), none was associated with the vaccine. For reactive airway disease there was a significantly increased relative risk in children aged 18–35 months, with a relative risk of 4.06 (90%CI = 1.29, 17.86). The authors concluded that CAIV was generally safe in children and adolescents. Further studies are planned to evaluate the risk of asthma/reactive airway disease after vaccine. Nervous system After the introduction of an inactivated intranasal influenza vaccine, which was used only in Switzerland, 46 cases of Bell’s palsy were reported. In a matched case-control study and a case-series analysis all primarycare physicians, ear, nose, and throat specialists, and neurologists in German-speaking regions of Switzerland were asked to identify cases
of Bell’s palsy in adults between 1 October 2000 and 30 April 2001 (21C ). Each physician was invited to select three control patients for each patient with Bell’s palsy, matching by age, date of clinic visit, and physician. They identified 773 patients with Bell’s palsy. Of the 412 who could be evaluated, 250 were enrolled and matched with 722 control patients; the other 162 patients had no controls. In the case-control study, 68 patients with Bell’s palsy (27%) and eight controls (1.1%) had received the intranasal vaccine. In contrast to parenteral influenza vaccines, the intranasal vaccine significantly increased the risk of Bell’s palsy (adjusted OR = 84; 95%CI = 20, 352). Even according to conservative assumptions, the relative risk of Bell’s palsy was estimated to be 19 times the risk in the controls, corresponding to 13 excess cases per 10 000 vaccinees within 1–91 days after immunization. In the case-series analysis, the period of highest risk was 31–60 days after immunization. This vaccine is no longer used in Switzerland. The relation of Guillain–Barré syndrome to pericarditis and nephrotic syndrome after influenza immunization has been discussed in the context of a case (22A ). • A 68-year-old woman and a 72-year-old man developed distal weakness of the limbs and numbness within 2 weeks after influenza immunization. Guillain–Barré syndrome was diagnosed in both cases. The first patient also had pericarditis and the second had nephrotic syndrome.
Gastrointestinal Pancolitis has been attributed to influenza immunization (23A ). • Pancolitis occurred in a 70-year-old woman 2 hours after influenza immunization. She developed bloody diarrhea, abdominal cramps, and over the next several days arthralgia of the knees. The diagnosis was confirmed by abdominal CT scan; the patient refused endoscopy and recovered within 10 days.
The authors favored the hypothesis of vasculitis as a delayed hypersensitivity reaction after influenza immunization. The patient had already been given influenza vaccine six times before. Skin rare.
Skin reactions to influenza vaccine are
• Two women, one aged 28 the other 32 years, developed dusky red macules with pain and a burning
334 sensation within 24 hours of receiving influenza vaccine (24A ). One had blisters within the lesion. The clinical feature and histopathology were consistent with the fixed drug eruptions. The lesions subsided within 2 weeks of topical glucocorticoid treatment. The diagnosis was confirmed by a topical provocation prick test with influenza vaccine.
Tumorigenicity The cause of multiple myeloma is unknown. Exposure to chemicals, radiation, viruses, and other systemic factors are likely to interplay in the development of multiple myeloma in specific patients. In a casecontrol study there was no association between immunization and the development of lightchain multiple myeloma. Although there has been a report of multiple myeloma 3 months after influenza immunization (25A ), since multiple myeloma takes many years to develop from the first abnormal cell, this association can be discounted.
Japanese encephalitis vaccine (SED-15, 1957, SEDA-26, 359; SEDA-28, 363) Mouse brain-derived Japanese encephalitis vaccine On 30 May 2005 the Japanese Health, Labor, and Welfare Ministry called a halt to immunization with the mouse brainderived Japanese encephalitis vaccine after a junior high school student developed acute disseminated encephalomyelitis following immunization (26S ). The ministry recognized that Japan now typically has less than 10 cases of Japanese encephalitis each year, and that the number of people who have adverse effects from immunization sometimes surpasses the number of people infected with the virus. During its 12th meeting (9–10 June 2005) the Global Advisory Committee on Vaccine Safety (GACVS) considered the decision taken by the Japanese Government (27S ). It was advised that the Japanese national advisory committee on vaccine adverse events could not rule out a causal link between Japanese encephalitis immunization and the single case of acute disseminated encephalomyelitis, and that there is no definite evidence of an increased risk of acute disseminated encephalomyelitis. It concluded, on currently available information, that there is no good reason for the WHO and national immunization programs to change
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the current recommendations for Japanese encephalitis immunization for residents in and travellers to endemic regions. The Committee will review the problem if further information becomes available. Live attenuated Japanese encephalitis vaccine Researchers in China have attenuated the Japanese encephalitis virus in primary hamster kidney cells and have derived the strain SA 14-14-2, which has proved to be safe and immunogenic in animals and humans (28S ). The vaccine was licensed in China in 1988. The current production of live attenuated SA 14-142 vaccine exceeds 50 million doses annually, most of which are used in China. Neuroattenuation of the SA 14-14-2 strain is reported to be based on 57 nucleotide changes and 24 amino acid substitutions, suggesting that reversion to neurovirulence of the vaccine strain would be highly unlikely. Vaccine production is in accordance with WHO technical specifications, including detailed screening for adventitious viruses. Data reported from several studies have shown vaccine efficacy to be 80–99% following single-dose immunization and 98% or greater with two doses of the vaccine. Preliminary data on co-administration of the SA-14-14-2 vaccine with measles vaccine have been reassuring. SA 14-14-2 has been shown to be 99.3% effective in preventing encephalitis some weeks after immunization. A single dose of SA 14-14-2 was 98.5% effective 12–15 months after immunization. Although important questions about its protective efficacy up to 5 or more years after immunization still need to be answered, this study suggests that a single-dose strategy, which lowers the cost of immunization and increases the supply of the vaccine, should be evaluated. More than 200 million doses of SA 14-142 vaccine have been given to Chinese children without reports of serious adverse events. In large safety studies in China, there were no cases of vaccine-related encephalitis, meningitis, or acute disseminated encephalomyelitis. In a post-licensure study of nearly 183 000 children aged 1–10 years, followed for at least 2 weeks after immunization, there were no serious adverse events. In 26 000 children who were randomized to groups that immediately received SA 1414-2 or had immunization delayed there were
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no cases of encephalitis, meningitis, or anaphylaxis during the 30 days after immunization (28S ). The rates of hospital admissions, seizures, and less serious adverse events (for example fever, rash) did not differ between the groups. In a safety study in South Korea, where SA 14-14-2 vaccine was licensed in 2001, there were no serious adverse events in 522 children who were actively monitored for 4 weeks after immunization; about 10% developed a fever of 38 ◦ C or higher and under 1% had local injection site reactions (redness and swelling) (28S ). During its 12th meeting the Global Advisory Committee on Vaccine Safety (GACVS) considered recent data on the safety profile of live attenuated SA 14-14-2 Japanese encephalitis vaccine (28S ). Data presented to GACVS, covering a 20-year period from 1979 to 1998, contained no reported cases of vaccine-associated Japanese encephalitis. GACVS acknowledged the excellent safety and efficacy profile of the SA 14-14-2 vaccine, but nevertheless recommended more detailed studies of the following: • the safety profile in special risk groups, including immunocompromised people and pregnant women; • whether viral shedding occurs in vaccinees and the potential implications of such shedding; • further analysis of sequential or co-administration of Japanese encephalitis and measles vaccines; • the interchangeability of inactivated and live Japanese encephalitis vaccines; • the safety of vaccine administration to infants aged under 1 year; • the implications for the efficacy and safety of the vaccine in infants with maternal antibodies against Japanese encephalitis virus.
Measles–mumps–rubella (MMR) vaccine (SED-15, 2207; SEDA-26, 359; SEDA-27, 338; SEDA-28, 363)
Subacute sclerosing panencephalitis (SSPE) and measles immunization Subacute sclerosing panencephalitis is a rare complication of measles (SEDA-14, 1077). Re-
335 ported rates vary somewhat, although it is estimated that about 1–4 cases occur per 100 000 reported measles cases. A possible susceptibility factor is measles infection at an early age (at or before the age of 2 years). On average, the symptoms begin 7–10 years after measles infection (range 1 month to 27 years after acute infection). There is no evidence that measles vaccine causes subacute sclerosing panencephalitis, although the issue has been a topic of debate. The long latency period combined with a missed diagnosis of early measles infection can cause parental concern when only the immunization is recalled. It is possible that cases reported without a history of natural measles may have resulted from a subclinical infection that occurred before administration of the vaccine. Even in cases in which the patient had not had measles in the past, wild-type measles sequences have been found in brain tissue of patients with subacute sclerosing panencephalitis (29R , 30A , 31A ). The WHO’s Regional Office for Europe asked the Global Advisory Committee on Vaccine Safety (GACVS) to review the risk of measles vaccine strains causing subacute sclerosing panencephalitis. The US Institute of Medicine statements in its 1994 and 2001 reviews referred to absent or inadequate evidence either to reject or accept any causal relation between measles-containing vaccines and subacute sclerosing panencephalitis in immunocompetent individuals. It is uncertain whether there is enough evidence from viral RNA sequencing and classification to warrant any modification of this conclusion. However, GACVS noted that all reports published since the Institute of Medicine’s review in 2001 containing information on measles virus classification in immunocompetent patients with subacute sclerosing panencephalitis showed the presence of wild (not vaccine) measles strains; and in countries in which measles has been controlled, subacute sclerosing panencephalitis has either declined substantially or no longer occurs. These findings do not suggest an association between measles vaccines and subacute sclerosing panencephalitis. GACVS will commission a review of the epidemiology of subacute sclerosing panencephalitis in relation to measles vaccine, the results of which will be considered at its December 2005 meeting (32S ).
336
Yellow fever vaccine
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(SED-15, 3703;
SEDA-28, 366) Two more recent fatal cases were temporally associated with yellow fever immunization during a mass immunization program to control an outbreak of sylvatic yellow fever in Minas Gerais (2001), in the Southeast region of Brazil (33A ). Virus recovered from blood and post-mortem samples in both cases was identified as yellow fever virus. Partial nucleotide sequence of parts of prM/E and the non-structural 5 genes and 3 non-coding region (3 NCR) was used to characterize the origin of yellow fever virus involved in both cases. Wild-type yellow fever
S. Dittmann
virus was identified as the causative agent. This report underlines the need for careful molecular biological analysis of isolated viruses in case of suspected complication after yellow fever immunization. Kitchener (34C ) carried out an investigation of vaccine surveillance reports from Europe after the distribution of more than 3 million doses of ARILVAX. During 1991–2003 he found four cases each of yellow fever vaccine-associated viscerotropic disease (one death) and yellow fever vaccine-associated neurotropic disease. Since 1996, 29 cases of yellow fever vaccineassociated viscerotropic disease have been reported worldwide.
References 1. Brighton collaboration—working groups. http:// www.brightoncollaboration.org/internet/en/index/ working_groups.html. (Accessed October 17, 2005). 2. Hviid A, Stellfeld M, Wohlfahrt J, Melbye M. Childhood vaccination and type 1 diabetes. N Engl J Med 2004;350:1398–404. 3. EMEA Public statement. EMEA reviews hexavalent vaccines: Hexavac and Infanrix Hexa. London, April 28, 2003. http://www.emea.eu.int. (Accessed October 17, 2005). 4. EMEA Public statement. EMEA update on hexavalent vaccines: Hexavac and Infanrix Hexa. London, December 1, 2003. http://www.emea. eu.int. (Accessed October 17, 2005). 5. Zinka B, Rauch E, Buettner A, Rueff F, Penning R. Unexplained cases of sudden infant death shortly after hexavalent vaccination. Vaccine 2005; doi:10.1016/j.vaccine.2005.03.047. 6. Schmitt HJ, Siegrist CA, Salmaso S, Law B, Booy R. Comment on B. Zinka et al. Unexplained cases of sudden infant death shortly after hexavalent vaccination. Vaccine 2005; doi:10.1016/j.vaccine.2005.03.054. 7. von Kries R. Comment on B. Zinka et al. Unexplained cases of sudden infant death shortly after hexavalent vaccination. Vaccine 2005; doi:10.1016/j.vaccine.2005.03.055. 8. EMEA Public statement: Committee for Medicinal Products for Human Use: Extension of indications and recommendations. London, April 21, 2005. http://www.emea.eu.int. (Accessed October 17, 2005). 9. Global Advisory Committee on Vaccine Safety. Safety of hexavalent vaccines. June 9–10, 2005. Weekly Epidemiol Rec 2005;80:245.
10. EMEA Press release. EMEA recommends suspension of Hexavac. London, September 20, 2005. http://www.emea.eu.int. (Accessed October 17, 2005). 11. Geier MR, Geier DA. Gastrointestinal adverse reactions following anthrax vaccination. HepatoGastroenterology 2004;51:762–7. 12. Rennels M, King J Jr, Ryall R, Papa T, Froeschle J. Dosage escalation, safety and immunogenicity study of four dosages of a tetravalent meninogococcal polysaccharide diphtheria toxoid conjugate vaccine in infants. Ped Infect Dis J 2004;23:429–35. 13. Guillain–Barré syndrome among recipients of Menactra® meningococcal conjugate vaccine— United States, June–July 2005. Morb Mortal Weekly Rep 2005;54:1–3. 14. Pfister RE, Aeschbach V, Niksic-Stuber V, Martin BC, Siegrist C-A. Safety of DTaP-based combined immunization in very-low-birth-weight premature infants: Frequent but mostly benign cardiorespiratory events. J Ped 2004;145:58–66. 15. Dagan R, Käyhty H, Wuorimaa T, Yaich M, Bailleux F, Zamir O, Eskola J. Tolerability and immunogenicity of an eleven-valent mixed carrier Streptococcus pneumoniae capsular polysaccharide-diphtheria toxoid or tetanus protein conjugate vaccine in Finnish and Israeli infants. Ped Infect Dis J 2004;23:91–8. 16. Blumenthal D, Prais D, Bron-Harlev E, Amir J. Possible association of Guillain–Barré syndrome and hepatitis A vaccination. Ped Infect Dis J 2004;23:586–8. 17. Nascimento-Carvalho HNC, Athayde-Oliveira C, Lyra I, Moreira LM. Thrombocytopenia purpura
Vaccines
18.
19. 20.
21.
22.
23. 24. 25.
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after hepatitis B vaccine: case report and review of the literature. Ped Infect Dis J 2004;23:183–4. Availability of H5N1 prototype strains for influenza pandemic vaccine development. Geneva: WHO, February 2005. http://www.who.int/csr/ disease/avian_influenza. (Accessed October 20, 2005). Anonymous. Weekly Epidemiol Rec 2005;80:277–8. Bergen R, Black S, Shinefield H, Lewis E, Ray P, Hansen J, Walker R, Hessel C, Cordova J, Mendelman PM. Safety of cold-adapted live attenuated influenza vaccine in a large cohort of children and adolescents. Ped Infect Dis J 2004;23:138–44. Mutsch M, Zhou W, Rhodes P, Bopp M, Chen RT, Linder T, Spyr C, Steffen R. Use of the inactivated intranasal influenza vaccine and the risk of Bell’s palsy in Switzerland. N Engl J Med 2004;350:896–903. Kao CD, Chen JT, Lin KP, Shan DE, Wu ZA, Liao KK. Guillain–Barré syndrome coexisting with pericarditis or nephritic syndrome after influenza vaccination. Clin Neurol Neurosurg 2004;106:136–8. Luca L, Morisset M, Kanny G, MoneretVautrin DA. Pancolitis after influenza vaccination. Allergy (Copenhagen) 2004;59:367. Al-Mutairi N, Al-Fouzan A, Nour-Eldin O. Fixed drug eruption due to influenza vaccine. J Cutan Med Surg 2004;8:16–8. Schattner A, Berrebi A. Several possible causes for multiple myeloma including a vaccination in a single case study. Vaccine 2004;22:2509–10.
337 26. Xinhua News Agency (05/30/05). 27. Global Advisory Committee on Vaccine Safety. Mouse-brain-derived Japanese encephalitis vaccine. Weekly Epidemiol Rec 2005;80:242. 28. Global Advisory Committee on Vaccine Safety. Safety of SA-14-14-2 Japanese encephalitis vaccine. Weekly Epidemiol Rec 2005;80:242–3. 29. Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases. 8th ed. Atlanta, GA: Centers for Disease Control and Prevention, 2004. (Chapter 10. Measles). 30. Barrero PR, Grippo J, Viegas M, Mistchenko AS. Wild-type measles virus in brain tissue of children with subacute sclerosing panencephalitis, Argentina. Emerg Infect Dis 2003;9:1333–6. 31. Jin L, Beard S, Brown DWG, Miller E. Characterization of measles virus strains causing SSPE: A study of 11 cases. J Neurovirol 2002;8:335–44. 32. Global Advisory Committee on Vaccine Safety. Subacute sclerosing panencephalitis and measles vaccination. Weekly Epidemiol Rec 2005;80:241–9. 33. De Filippis AMB, Nogueira RMR, Jabor AV, Schatzmayr HG, Oliveira JC, Dinis SCM, Galler R. Isolation and characterization of wild type yellow fever virus in cases temporally associated with 17DD vaccination during an outbreak of yellow fever in Brazil. Vaccine 2003;22:1073– 8. 34. Kitchener S. Viscerotropic and neurotropic disease following vaccination with the 17D yellow fever vaccine, ARILVAX® . Vaccine 2004;22:2103–5.
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33 ALBUMIN
Blood, blood components, plasma, and plasma products (SED-15, 54; SEDA-28, 371)
The SAFE study was a randomized, doubleblind study that compared mortality after albumin or saline for fluid resuscitation (1C ). It showed that there are no concerns about the safety of albumin and clearly contradicted the results of a meta-analysis of the use of albumin in critically ill patients performed by the Cochrane Injuries Group in 1998, which showed that albumin was associated with a higher mortality (SEDA-27, 342; SEDA-28, 369). The incidence of adverse effects of albumin is low compared with artificial colloids (2R ). No cases of virus transmission have been reported (2R ).
ANTICOAGULANT PROTEINS (SED-15, 266; SEDA-28, 371) Drotrecogin alfa (recombinant human activated protein C) Drotrecogin alfa (recombinant human activated protein C) has antiinflammatory, anticoagulant, and profibrinolytic properties. It is approved for the treatment of severe sepsis in adults. The only adverse effect, as expected, is an increased risk of serious bleeding (3R –5R , 6C , 7C ). It is therefore contraindicated in patients with an increased risk of bleeding or with active bleeding (5R ). Drotrecogin alfa should be withdrawn 2 hours before a surgical procedure and should not be started until 12 hours after a surgical procedure (5R ). In a selected cohort of 228 surgical patients treated with activated drotrecogin alfa for sepsis Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29033-0 © 2007 Elsevier B.V. All rights reserved.
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from the Protein C World Evaluation in Severe Sepsis (PROWESS) study there was no significant difference in serious bleeding compared with the non-surgical patients (8C ). In this study, drotrecogin alfa (activated) was not administered within 12 hours after surgery. A preliminary analysis of an open, nonrandomized study of activated drotrecogin alfa in 83 children with severe sepsis showed similar safety as in adults (9C ). However, there was one case of fatal intracranial hemorrhage in an adolescent with fulminant meningococcemia, which was assessed as being possibly related to drotrecogin alfa. Four of 83 patients had a serious hemorrhage during or after the infusion, which might have been related to the drotrecogin alfa. • A 4-month-old boy with Gram-negative septic shock was treated with activated drotrecogin alfa 24 micrograms/kg/hour for 76 hours. A brain MRI scan on day 22 showed bilateral small occipital hemorrhages (10A ).
This complication could have been related to the severe sepsis or to treatment with drotrecogin alfa. Death In two recent trials using drotrecogin alfa, there was a higher mortality in patients treated with drotrecogin alfa compared with placebo. While a definitive explanation was not available, these deaths underscore the importance of accurate diagnosis of severe sepsis and assessment of the risk of death when considering patients for drotrecogin alfa therapy (11S ).
BLOOD TRANSFUSION
(SED-15,
529; SEDA-28, 369) Better organized hemovigilance systems have shown that the most common complications of
Blood, blood components, plasma, and plasma products
transfusion are blood group incompatibilities, bacterial contamination, transfusion-related acute lung injury (TRALI), transfusion-associated graft-versus-host disease, and transfusionassociated circulatory overload (12R –16R ). Autologous blood transfusion is associated with fewer complications than allogeneic blood transfusion, but there are still risks of misidentification, bacterial contamination, and circulatory overload. Respiratory Transfusion of plasma-containing blood products can be complicated by life-threatening transfusion-related acute lung injury (TRALI) (SEDA-28, 369) (17R ). The symptoms are dyspnea, hypoxemia, hypotension, fever, and pulmonary infiltrates. Two causative hypotheses have been proposed (12R , 18R ). The first is that TRALI is caused by an immune-mediated reaction due to anti-HLA or anti-neutrophil antibodies, usually of donor origin, but also possibly from the recipient. The other is that TRALI is caused by a twoevent phenomenon, in which damage is caused by specific antibodies or biologically active lipids in the transfusion material in combination with a poor clinical condition. Both mechanisms can occur (12R ). Blood products of multiparous women are often associated with TRALI (SEDA-28, 369) (19C ). A case of TRALI after autologous transfusion (20A ) was probably due to biologically active lipids in the autologous transfusion material, which activated leukocytes within the lung and caused endothelial damage in combination with the patient’s poor clinical condition. Blood transfusion with material from a mother or a child caused TRALI in two cases; these kinds of transfusions might increase the risk, because it is more likely that the HLA antibody and the antigen will both be present (21A ). Hematologic Autoimmune hemolytic anemia, due to auto-antibodies, has been described, associated with a previous allogeneic blood transfusion (22A ). Immunologic Allogeneic blood transfusions are associated with suppression of the immune system (23R ).
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Infection risk Chagas’ disease The protozoon Trypanosoma cruzi, which causes Chagas’ disease, can be transmitted via blood transfusion (23R , 24R ). Variant Creutzfeldt–Jakob disease In two cases transmission of variant Creutzfeldt–Jakob disease (vCJD) may have been associated with previous blood transfusions. In one case the disease may have been transmitted by erythrocytes from a patient who died of variant Creutzfeldt– Jakob disease (25A ). In another case the infection may have been transmitted by blood transfusion from a donor who subsequently developed Creutzfeldt–Jakob disease (26A ). In neither case were the donor blood products leukocyte-depleted. Although leukocyte depletion reduces infectivity, an experimental study with whole blood from scrapie-infected hamsters suggested both leukocyte-associated and plasma-associated transmissible spongiform encephalopathy infectivity (27E ). Another experimental study showed a shorter incubation time after intravenous transmission of bovine spongiform encephalopathy compared with oral infection. Different routes of transmission result in similar distribution patterns of prions in these animals (28E ). From 2004, the UK and some other countries have excluded donors who have received a transfusion in the past (29r ). Current manufacturing processes for plasmaderived products reduce infectivity (SEDA-28, 369) (30R , 31E , 32R ). West Nile virus Seasonal epidemics of West Nile virus can result in an asymptomatic infection in a donor, but can also result in fatal West Nile virus infection in a recipient (33R ). Despite nucleic acid testing of West Nile virus RNA on minipools, transmission of West Nile virus occurred in a patient who received multiple blood components (34A ). Several manufacturing processes, as for example solvent/detergent treatment, eliminate the enveloped West Nile virus (35E ). Tick-borne diseases Different types of tickborne diseases transmitted by blood transfusion have been reported, such as babesiosis and tickborne encephalitis (36A ).
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BLOOD SUBSTITUTES
(SEDA-28,
370) Artificial oxygen carriers can be divided into hemoglobin-based oxygen carriers and perfluorocarbons emulsions, and are in clinical development (37R ).
P.J.M. Vossebeld and P.F.W. Strengers
a perfluorocarbon-based product, perfluorooctyl bromide, was terminated because of an increased incidence of stroke in coronary bypass patients (38R ). Drug interactions An animal study, in which perfluorocarbon emulsion was used in combination with X-ray contrast media, showed a high mortality (44E ). The authors warned that when using perfluorocarbon emulsions one should avoid contrast media.
Hemoglobin-based oxygen carriers Different kinds of modified hemoglobins have been developed, using hemoglobin of bovine or human origin: surface-modified hemoglobin, intramolecular cross-linked hemoglobin, or liposome-encapsulated hemoglobin (SEDA-28, 370). Clinical development of diaspirin crosslinked hemoglobin has been stopped, probably because of increased mortality (SEDA-28, 369) (38R , 39R ). Furthermore, all clinical studies with O-raffinose cross-linked hemoglobin have also been stopped, because of cardiac problems (38R ). A new second generation of hemoglobinbased oxygen carriers is under development, with a re-engineered heme pocket and reduced nitric oxide affinity, which is expected to reduce adverse effects (37R , 38R , 40R ). Cardiovascular Current hemoglobin-based oxygen carriers can cause vasoconstriction, which is probably due to scavenging of nitric oxide or the production of the endogenous vasoconstrictor endothelin-1 (SEDA-28, 369) (41R , 42c ). There was a mild reduction in cardiac output in a study in which 10 patients received diaspirin cross-linked hemoglobin in a dose of 50 mg/kg or 35 ml for a 70 kg patient after repair of an abdominal aortic aneurysm (42c ).
PLASMA PRODUCTS
(SED-15,
2847) Cardiovascular Treatment of patients with factor VII or factor XI deficiency with freshfrozen plasma can cause circulatory overload (45R , 46R ). Immunologic Antibodies to factor V have been reported in a factor V-deficient patient treated with fresh frozen plasma (47C ).
PLASMA SUBSTITUTES (SEDA-26, 374; SEDA-27, 353; SEDA-28, 371) Artificial colloids, such as hydroxyl starch, dextran, or gelatins, are alternatives to human albumin for fluid resuscitation in order to maintain colloid oncotic pressure. All artificial colloids bring increased risks of anaphylactic reactions and renal impairment compared with human albumin (2R , 48R ). A safety analysis of 113 clinical studies from 1944 to 2002 showed that the incidence of anaphylactic reactions was 4.51 per 105 infusions after hydroxyl starch, 2.32 per 105 infusions after dextran, and 12.4 per 105 infusions after gelatin (2R ).
Liver Jaundice has been attributed to hemoglobin-based oxygen carriers (41R ).
Etherified starches Perfluorocarbons
(SED-15, 3544)
Studies of perfluorocarbons have dealt with problems such as complement activation and reduced platelet function (38R , 43R ). A study with
(SED-15, 1237)
Adverse reactions related to hydroxyl starches are anaphylactic reactions, coagulopathy, renal dysfunction, and pruritus (2R , 49R ). A review of safety did not show differences related to the molecular weight or molar substitution of hydroxyl starches (2R ).
Blood, blood components, plasma, and plasma products
Hematologic The dose-related adverse effects of coagulopathy and bleeding are often associated with cardiac surgery (2R ). Hetastarch is therefore not recommended in patients undergoing cardiopulmonary bypass (50r ). Several trials in patients with acute ischemic stroke and other brain injuries have been discontinued prematurely owing to bleeding complications (51r , 52r ). Liver Liver failure has been attributed to hydroxyl starch (2R ). Urinary tract Hydroxyl starches with different molecular weights can cause renal dysfunction (2R , 49R , 53r ). Skin Pruritus due to hydroxyl starch can occur after a delay of days (2R , 49R , 54R ). This adverse effect can occur in patients taking relatively low doses and is unrelated to the molecular weight of the hydroxyl starch (2R , 54R ). Immunologic Anaphylactic reactions can occur after administration of hydroxyl starch (2R ) (49R ).
Polygelines
(SED-15, 2888)
Immunologic Anaphylactic reactions can occur after administration of gelatin (2R ). Although there is probably no cross-reactivity between colloids of different chemical compositions, there is cross-reactivity between urealinked gelatin (Hemaccel) and succinate-linked gelatin (Gelofusin) (SEDA-28, 371) (55r ).
GLOBULINS Antithymocyte globulin Antithymocyte globulin is a polyclonal antibody directed against T lymphocyte surface antigens. It is used to induce immunosuppression and to treat acute rejection after transplantation. Its major adverse effects include sensitization, fever, nausea, and anaphylactic reactions; there is a higher incidence of infections with cytomegalovirus and Epstein–Barr virus.
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Comparative studies A comparison of 5year results between antithymocyte globulin and equine antithymocyte globulin after kidney transplantation showed higher event-free survival (73% versus 33%), graft survival (77% versus 55%), and freedom from rejection (92% versus 66%) with antithymocyte globulin (56C ). There were no additional cases of cytomegalovirus infection after the first year (13% versus 33%). There were two cases of posttransplantation lymphoproliferative disorder (PTLD) with equine antithymocyte globulin, and antithymocyte globulin was associated with profound lymphopenia at 2 years. In an open, randomized, multicenter study, antithymocyte globulin was compared with basiliximab induction therapy followed by delayed introduction of ciclosporin in renal-transplant patients (n = 105) of low immunological risk who were receiving mycophenolate mofetil and glucocorticoids (57C ). One-year patient and graft survival rates were 98% and 94% with basiliximab (n = 52) and 98% and 96% with antithymocyte globulin (n = 53). The incidence of biopsy-confirmed acute rejection was 9.6% with basiliximab and 9.4% with antithymocyte globulin. The number of patients who required dialysis after transplantation was 29% with basiliximab and 30% with antithymocyte globulin. Significantly more patients given antithymocyte globulin had cytomegalovirus infection, leukopenia, and thrombocytopenia. Cardiovascular Rabbit antithymocyte globulin (RATG) is recommended for central venous administration, and there is no evidence to justify the common practice of adding heparin to the infusion bag. However, evaluation of thrombocytopenia may be complicated by coadministration. A total of 330 central or peripheral courses of RATG in 288 patients resulted in nine cases of deep vein thrombosis (58C ). In five there were prior infusion-related reactions and heparin was not used. In most cases the venous thrombosis occurred near the site of the infusion. These results provide justification for adding heparin when RATG is infused, especially peripherally. Hematologic Coagulation status was investigated in 21 patients with hematological malignancies undergoing allogenic stem cell transplantation who received conditioning treatment
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including (n = 11) or not including (n = 10) antithymocyte globulin (59c ). There were no significant differences in mean prothrombin time or partial thromboplastin time, concentrations of fibrinogen, antithrombin, protein C, protein S, thrombin–antithrombin III complex, and homocysteine, the prevalence of genetic markers of thrombophilia, and concentrations of EMP, TMP, or CD40L. There was a significant fall in platelet count in patients who received antithymocyte globulin, but it was not associated with clinical or laboratory evidence of disseminated intravascular coagulation. None of the patients developed thromboembolic events or hepatic veno-occlusive disease.
antithymocyte globulin was administered for a median of 5 days to a total mean dose of 406 mg in combination with prednisolone and tacrolimus (62c ). Survival rate was 100% for patients and 94% for grafts, and the acute rejection rate was 38%, with a median time to acute rejection of 16 days. One patient developed serum sickness. The rate of hepatitis C virus recurrence was 56% and 25% for cytomegalovirus infection. The rate of de novo diabetes that required insulin therapy was 50%. In addition, serum concentrations of hepatitis C virus RNA increased significantly (more than ten-fold) after liver transplantation. The incidence of mediastinitis after heart transplantation is 2.5–7.5%, and most reports have included patients who had not received induction therapy. Of 230 patients treated with rabbit antithymocyte globulin induction, 15 (6.5%) developed mediastinitis (63C ). Only four had a temperature over 38 ◦ C and six had white blood cell counts over 10 × 109 /l. Septicemia (n = 7) and positive cultures from temporary epicardial pacing wires (n = 9) were common. Staphylococcus aureus (n = 5), Staphylococcus epidermidis (n = 5), and Gramnegative bacteria (n = 5) were cultured intraoperatively. The mean duration of mechanical ventilation (2.4 versus 1.6 days) and the use of ventricular assistance (20% versus 0%) were different between cases and controls. One patient died. In the context of immunosuppression after heart transplantation, a high degree of suspicion is necessary to make the diagnosis of mediastinitis. Positive blood cultures and culture of a temporary epicardial pacing wire can be helpful. The use of vancomycin and an aminoglycoside as prophylaxis should be considered, because of the high prevalence of methicillin-resistant Staphylococcus epidermidis and Gram-negative bacteria. Conservative therapy, such as sternal debridement without muscle flap closure and closed-chest drainage, is recommended.
Immunologic Anti-human histocompatibility antigen (HLA) antibodies are deleterious after kidney transplantation and may be increased after the administration of agents that deplete T cells. There was a greater than 10% increase in class I or class II HLA antibodies in six of 27 subjects given antithymocyte globulin versus only one of 27 who were not (60c ). In women the increase occurred in six of 14 treated subjects compared with none of the control subjects. In sensitized subjects the increase occurred in four of 10 treated subjects compared with none of the control subjects. There were no differences in the number or severity of acute rejection episodes or estimated glomerular filtration rate 6 months after transplant between the two treatment groups. Induction with antithymocyte globulin may result in increased HLA antibodies after transplant, particularly in subjects at higher immunologic risk. Prophylactic treatment with equine antithymocyte globulin was associated with deposition of horse IgG and activation of complement in nine patients with cardiac transplants (61c ). Two color stains showed that the horse IgG colocalized with C4d staining. There was no staining for horse IgG or C4d in biopsies obtained before treatment and no staining for horse IgG in seven control patients who had C4d staining. Most patients treated with antithymocyte globulin had no histological evidence of rejection, but did have myocyte damage and macrophage infiltration. Infection risk In 16 liver recipients with hepatitis C virus-related end-stage liver disease
P.J.M. Vossebeld and P.F.W. Strengers
Susceptibility factors Age The choice of induction immunosuppression for kidney transplantation in elderly recipients is dictated by consideration of the risk of infection as well as efficacy in the prevention of acute rejection, thus allowing a reduction in subsequent maintenance immunosuppression and its attendant long-term
Blood, blood components, plasma, and plasma products
adverse effects. Of 183 kidney transplant recipients 60 years of age and over, 29 received equine antithymocyte globulin, 45 received muromonab, 40 received basiliximab with glucocorticoid maintenance therapy, and 69 received basiliximab without glucocorticoids (64C ). There was delayed graft function in 48% with antithymocyte globulin, 36% with muromonab, 36% with basiliximab, and 35% with basiliximab/glucocorticoids. The rejection rate within 3 months was 31% with antithymocyte globulin and muromonab, 18% with basiliximab/glucocorticoids, and 15% with basiliximab. There were significant differences in delayed graft function and acute rejection between patients who received antithymocyte globulin and muromonab, antithymocyte globulin or muromonab, and basiliximab with or without glucocorticoids. Patients who received basiliximab were free of the adverse effects that are typically encountered by patients who receive polyclonal and monoclonal antibodies for induction, and had much shorter hospital stays. Drug formulations Antithymocyte globulin– Fresenius (n = 129) and antithymocyte globulin (n = 65) for induction after kidney transplantation have been compared (65C ). Cytomegalovirus disease occurred in 23% and 37% respectively, post-transplant malignancy in 3.9% and 12%, and death in 3.9% and 14%. Cox regression analysis showed that the use of antithymocyte globulin was an independent predictor of cytomegalovirus disease (RR = 2.16; 95%CI = 1.04, 4.48), malignancy (RR = 2.16; CI = 1.04, 4.48), and death (RR = 4.14; CI = 1.36, 12.6). Drug interactions The increasing number of highly sensitized patients awaiting renal transplantation has prompted the use of induction immunosuppression regimens that include pooled human intravenous immunoglobulin combined with polyclonal antilymphocyte sera. An interaction of antithymocyte globulin with pooled human immunoglobulin might cause acute renal transplant injury (66A ). • A 48-year-old woman received a live donor transplant after prevention of donor-specific positive cytotoxic cross-match by intravenous immunoglobulin. She developed early acute tubular injury associated with intravenous immunoglobulin, mannitol, and hypertonic saline. When she was given an-
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tithymocyte globulin there was an increased number of peripheral CD3(+) lymphocytes after initial rapid lymphodepletion.
In this case nephrotoxicity associated with intravenous immunoglobulin was considered to have been a possible cause of early allograft dysfunction, and intravenous immunoglobulin may have interacted with polyclonal antilymphocyte serum.
Immunoglobulins
(SED-15, 1719;
SEDA-28, 372) Common adverse effects of intravenous immunoglobulins are headache, fever, nausea, chills, dizziness, flushing, backache, rash, arthralgia, myalgia, pruritus, hypotension, diarrhea, dyspnea, and chest pain (SEDA-28, 372) (67R , 68C , 69C , 70R ). A reduced infusion rate often minimizes or prevents these reactions (SEDA-28, 372), and pretreatment with analgesics, NSAIDs, antihistamines, or glucocorticoids can prevent them (71R ). Febrile reactions to intravenous immunoglobulins are sometimes related to an underlying infection (SEDA-28, 373) (68C ). When changing from one formulation to another, the risks of adverse reactions increase. In September 2000, 49 immune-deficient patients switched to a different intravenous immunoglobulin formulation because Intragam was replaced by Intragam P, which had a different manufacturing process. Although neither the patients nor the clinicians knew about the change in formulation, there were increased reports of adverse reactions. The authors suggested that a patient on home therapy should receive the first infusions of a new formulation in hospital (72C ). A dose of 2 g/kg over 2 days, as is often used nowadays in autoimmune diseases, seems not to be associated with more adverse reactions than a dose of 2 g/kg over 5 days (70R ). Cardiovascular Thromboembolic complications, such as stroke and acute myocardial infarction, have been observed after intravenous immunoglobulin in patients with pre-existing susceptibility factors (SEDA-28, 372) (67R , 73A ). Deep venous thrombosis and pulmonary
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embolism have also been reported (74C ). Increased serum viscosity is not always the underlying mechanism, as has been shown retrospectively in seven patients with susceptibility factors who developed such reactions (75c ). Cerebral vasospasm was also excluded as mechanism. The authors suggested that the thromboembolic complications are caused by clotting factors and vasoactive cytokines within specific batches of intravenous immunoglobulin formulations.
especially at risk (SEDA-28, 372) (67R , 78R ). Isometric tubular vacuolization was associated with the use of low-dose sucrose-containing intravenous immunoglobulin formulations to remove donor-specific antibodies in case of an ABO-incompatible transplanted kidney (79C ).
• A 38-year-old woman with multiple sclerosis developed a deep vein thrombosis after a course of intravenous immunoglobulin 2 g over 2 days in combination with methylprednisolone (76A ). She was not immobilized by her multiple sclerosis.
The authors proposed that the combination of intravenous immunoglobulin and methylprednisolone might have been associated with the thrombotic event, because this patient had tolerated several courses of intravenous immunoglobulin without methylprednisolone. They discussed 27 previously reported cases of thrombotic events after intravenous immunoglobulin. In eight cases a glucocorticoid had also been used. In nine cases, there were no data on glucocorticoid usage, but the clinical conditions made it likely that a glucocorticoid had indeed been used. Respiratory Intravenous immunoglobulin can cause transfusion-related acute lung injury (TRALI) (19c ). Nervous system Reversible aseptic meningitis rarely occurs with intravenous immunoglobulin (SEDA-28, 372) (67R ), but has been reported in a patient who received high-dose intravenous immunoglobulin (0.4 g/kg on 5 consecutive days) for idiopathic thrombocytopenic purpura (77C ). The risk of aseptic meningitis is higher in patients with a history of migraine (SEDA-28, 372) (70R ). Urinary tract Intravenous immunoglobulin has been associated with several cases of acute renal insufficiency, with vacuolization of tubular cells. Most cases have occurred after the use of intravenous immunoglobulin formulations that contain sucrose as a stabilizer, and older patients with pre-existing renal impairment, diabetes mellitus, obesity, or dehydration are
P.J.M. Vossebeld and P.F.W. Strengers
Skin Intravenous immunoglobulins can cause skin reactions, such as urticaria, pruritus, and petechiae (70R ). Subcutaneous immunoglobulins are associated with fewer adverse reactions, but local reactions can occur at the injection site (80R ). Local reactions at the infusion site were also observed in 3% of 649 infusions in 108 patients with multiple sclerosis who were given intravenous immunoglobulin (81C ). This kind of reaction is probably not specific to patients with multiple sclerosis. Rashes and eczema after intravenous immunoglobulin occurred in a randomized placebo-controlled trial in 318 patients with secondary progressive multiple sclerosis who received monthly intravenous immunoglobulin 1 g/kg (74C ). Immunologic Intravenous immunoglobulin can interfere with immunization with live virus vaccines, such as measles, mumps, rubella, or varicella (82R , 83R ). Anaphylactic reactions with antibodies against IgA can occur in IgA-deficient patients who receive intravenous immunoglobulin formulations that contain IgA (67R ). • A 17-year-old girl with common variable immunodeficiency developed anaphylactic reactions after intravenous immunoglobulin (84A ). These reactions were probably due to the total absence of IgG2, IgG3, and IgG4.
Infection risk Infections with human parvovirus B19 have been reported in patients who were given intravenous immunoglobulin (SEDA-27, 342). Removal of parvovirus B19 from these formulations requires nanofiltration at 15 nm or liquid heating at 60 ◦ C for 10 hours (85E ). Interference with diagnostic tests Intravenous immunoglobulins containing maltose as a stabilizer can interfere with blood glucose monitoring in systems that use glucose dehydrogenase (86A ). There is no interference with systems that use glucose oxidase.
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COAGULATION PROTEINS (SED-15, 845; SEDA-28, 375) Observational studies During the treatment of 42 surgical events with von Willebrand disease using factor VIII + von Willebrand factor concentrate in 39 patients, there were three unexpected non-serious drug-related adverse reactions (peripheral edema, extremity pain, and pseudothrombocytopenia) (87C ). Cardiovascular Coagulation factors, especially in young children with hemophilia who often require central venous access, can cause thrombus formation or infections near central venous access devices (88R ). Coronary artery disease is less frequent in patients with hemophilia than non-hemophiliacs, but it can occur. • A 62-year-old man with mild hemophilia A received 4000 IU of recombinant factor VIII before coronary angiography. He had an acute myocardial infarction (89A ). • A 50-year-old man with von Willebrand disease type 2A with angiodysplasia and gastrointestinal hemorrhage had a large myocardial infarction when he was given recombinant activated factor VII (90A ).
The second patient had several pre-existing risk factors for thrombosis (hypertension, insulin-dependent diabetes, heavy smoking, and a family history of atherosclerosis). Although acute myocardial infarction is very unusual in patients with hemophilia, it has been associated with the use of intermediate purity factor IX concentrates, owing to the presence of the activated form of factor IX. • A 65-year-old man with severe hemophilia B treated with cryosupernatant had an acute myocardial infarction (91A ).
Recombinant factor VIIa is not approved except in patients with hemophilia with inhibitors, but is also used in cases of excessive bleeding. It is associated with a low incidence of thrombotic complications (18R , 92R –95R ). Activated prothrombin complex concentrate (also called FEIBA), used to bypass factor VIII inhibitors in patients with hemophilia A or acquired hemophilia, can do the same (93R , 96R , 97R , 98c , 99R ).
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Prothrombin complex concentrate also carries the risk of thrombosis, particularly when repeated doses are required. The risk of thrombosis from prothrombin complex concentrate is suggested to be higher in the treatment of factor VII deficiencies, because the other coagulation factors with longer half-lives can accumulate (45R ). Recombinant factor VIIa, prothrombin complex concentrate, and activated prothrombin complex concentrate should be used with caution in patients with a history of thrombotic complications, in patients with established thrombotic disorders, or when there is excessive bleeding (18R , 92R ). Thrombophlebitis at the site of venous access is a common adverse effect of continuous infusion of factor VIII (100C ). Von Willebrand factor concentrates vary in factor VIII content. Although concentrates with a high concentration of factor VIII are more effective in acute surgery, they can produce a high concentration of factor VIII with increased risk of thrombosis (101E ). Liver Treatment of patients with hemophilia with non-virus-inactivated coagulation factors, as occurred in the past, resulted in a high incidence of viral infections with HIV and hepatitis C virus. Nowadays hepatitis C virus still causes complications such as liver failure and liverfailure-associated bleeding (102R , 103R ). Immunologic The most important problem in the treatment of patients with hemophilia, especially in factor VIII deficiency (hemophilia A) is development of antibodies to factor VIII (factor VIII inhibitors) (104R –106R ). The UK Haemophilia Centre Doctors’ Organisation calculated a cumulative risk of inhibitor development of 16% by the age of 5 years and 36% by the age of 75 from data in 6078 patients with hemophilia A, and a cumulative risk of inhibitor development of 6% by the age of 5 years and 8% by the age of 75 from data in 1172 patients with hemophilia B (107C ). The risk of inhibitor development is highest within the first 50 days of exposure to the infused factor (104R , 106R ). Recombinant factor VIII products have probably similar risks of inhibitor development to plasma-derived products (108r ). There is a genetic predisposition to the development of inhibitors, such as a large deletion of the factor VIII gene (106R ). Continuous infusion has been suggested as a risk factor for
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inhibitor development. Other factors, such as a high dose of coagulation factor or the type of bleed can be confounding factors (SEDA-28, 376) (105R ). Treatment of factor VII deficiencies carries the risk of inhibitor development. Two cases of inhibitors of factor VII have been reported (45R , 99R ). Patients with hemophilia A who are treated with recombinant factor VIII sometimes develop antibodies to residual mammalian proteins within the product, but there are no reported cases of clinical relevance (109r ). Inhibitors have been reported in a factor XIII-deficient patient treated with factor XIII concentrate (47C ). Allergic reactions to coagulation factors include rash, pruritus, fever, tachycardia, tachypnea, stomach or intestinal pain, nausea, vomiting, and diarrhea; they are generally mild (88R ). Anaphylactic reactions can occur (88R ). In a study of 12 597 infusions of plasmaand albumin-free recombinant factor VIII there were no serious drug-related adverse reactions. Mild reactions were taste disturbances, headache, fever, diarrhea, dizziness, hot flashes, pain in the upper abdomen, pain in the lower chest, shortness of breath, sweating, nausea, rigors, and itching; these adverse reactions were not different from those of other factor VIII products (110C ).
and hematological abnormalities (113R , 114R ). In another study, a patient with hemophilia B received an adeno-associated viral vector encoding factor IX via the hepatic artery and developed transient increases in serum transaminases. The authors suggested that there had been an immune reaction against the transduced hepatocytes (113R ). The newly developed adeno-associated virus vectors do not have these immunological problems (115R ).
Infection risk Human immunodeficiency virus and hepatitis C virus, which are present in a high number of patients with hemophilia treated before 1990, both worsen the prognosis of the other (111R ).
Coagulation factor gene therapy Gene therapy for hemophilia is still at the experimental stage. It is associated with risks of germ-line transmission, inhibitor formation, insertional mutagenesis, and hepatitis. None of eight patients with hemophilia B enrolled in a study of adeno-associated virusmediated gene therapy developed inhibitors of factor IX (112R ). A study in which patients with hemophilia A were given a high capacity adenovirus encoding full-length factor VIII was stopped, because the first patient developed an inflammatory reaction, hepatotoxicity,
P.J.M. Vossebeld and P.F.W. Strengers
ERYTHROPOIETIN AND DERIVATIVES (SED-15, 1243) Recombinant erythropoietin (epoetin) and its derivative darbepoetin alfa, which has a longer half-life, are used for treatment of anemia in patients with chronic renal insufficiency and anemia in patients with malignant disease. Common adverse effects of epoetin and darbepoetin alfa are injection site reactions, pruritus, headache, influenza-like symptoms (such as arthralgia, myalgia, abdominal pain, and vomiting), peripheral edema, non-specific rashes, dyspnea, and upper respiratory tract infections (SEDA-28, 377) (116R –118R ). Cardiovascular A meta-analysis of 12 randomized controlled studies showed a 1.55 times increased risk of thromboembolic events and a 1.25 times increased risk of hypertension during recombinant erythropoietin treatment in anemic patients with cancers (119M ). Increases in blood pressure are not uncommon after treatment with epoetin or darbepoetin alfa and often require antihypertensive drugs for correction (120c , 121c , 122C ). Thrombotic events have been associated with erythropoietin (123R ). In 312 patients with breast, lung, or gynecological malignancies and chemotherapy-induced anemia who were treated with 2-weekly darbepoetin or weekly epoetin alfa in a randomized study, there were two cases of deep venous thrombosis, one in each treatment group, and one case of pulmonary embolism in those who used epoetin alfa (124C ). There was a high incidence of deep vein thrombosis, related to the use of recombinant human erythropoietin, in seven of 53 anemic
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women with local advanced cervical cancer (125C ). A randomized, controlled trial in 27 patients with metastatic breast cancer and mild anemia was terminated because of four thrombotic events in 14 patients who were treated with erythropoietin compared with no events in 13 patients who were not treated with erythropoietin (126C ). In 1265 hemodialysis patients with cardiac disease randomized to erythropoietin to maintain a hematocrit of 35% or 42%, there was a higher mortality (35%) in the higher hematocrit group compared with 29% in the lower hematocrit group, probably because of a higher incidence of thrombotic events (117C ). Hematologic Pure red cell aplasia is a rare but dangerous adverse effect of erythropoietin, which has been associated with antierythropoietin antibodies (127R , 128r ). Epoetin alfa is contraindicated for subcutaneous use in patients with chronic renal insufficiency because of a higher incidence of pure red cell aplasia (129r , 130R , 127R ), but there have also been reports in patients with normal renal function (131A ). It has also been observed with epoetin beta (131A –133A ). Although antierythropoietin antibodies cross-react with variants of erythropoietin, it has been possible to rechallenge patients with erythropoietin in combination with immunosuppressive drugs (134A , 135A ). Skin Local skin reactions at the injection site, with or without erythema, have been reported (121c ). Some cases of dermatitis have been reported in patients who received 40 000 IU five times in 2 weeks (136c ).
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Tumorigenicity As epoetin or darbepoetin alfa are both growth factors, there are concerns that they may stimulate production of malignant cells that express erythropoietin receptors (116r , 137R ). Susceptibility factors Age Seven children undergoing regular hemodialysis for nephrotic syndrome were switched from epoetin alfa thrice-weekly to darbepoetin alfa once-weekly, following the conversion index for dosing recommended by the manufacturer. There was a large increase in hemoglobin concentration in six of them. Two of the seven had severe hypertension, which required temporary withdrawal of darbepoetin, then a reduced dose of darbepoetin alfa and an increased dose of antihypertensive drugs. Another child required an additional antihypertensive drug. The authors suggested that the conversion index (200 IU of epoetin is equal to 1 microgram of darbepoetin alfa) is not suitable for children (138c ).
STEM CELLS Hemopoietic stem cell transplantation can cause graft-versus-host disease and is associated with an increased incidence of bleeding both after autologous and allogeneic stem cell transplantation (139R ). The incidence of severe bleeding is higher with allogeneic hemopoietic stem cell transplantation.
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associated with methylprednisolone. Thromb Haemost 2004;92(3):662–5. Borte M, Davies SV, Touraine JL, Farber CM, Lipsic T, Adams C, Spath P, Bolli R, Morell A, Andresen I. Clinical properties of a novel liquid intravenous immunoglobulin: studies in patients with immune thrombocytopenic purpura and primary immunodeficiencies. Transfus Med Hemother 2004;31:126–34. Joannidis M. Drug-induced renal failure in the ICU. Int J Artif Organs 2004;27(12):1034–42. Haas M, Sonnenday CJ, Cicone JS, Rabb H, Montgomery RA. Isometric tubular epithelial vacuolization in renal allograft biopsy specimens of patients receiving low-dose intravenous immunoglobulin for a positive crossmatch. Transplantation 2004;78(4):549–56. Berger M. Subcutaneous immunoglobulin replacement in primary immunodeficiencies. Clin Immunol 2004;112(1):1–7. Achiron A, Kishner I, Dolev M, Stern Y, Dulitzky M, Schiff E, Achiron R. Effect of intravenous immunoglobulin treatment on pregnancy and postpartum-related relapses in multiple sclerosis. J Neurol 2004;251(9):1133–7. Burns JC, Glode MP. Kawasaki syndrome. Lancet 2004;364(9433):533–44. Omwandho CO, Gruessner SE, Roberts TK, Tinneberg HR. Intravenous immunoglobulin (IVIG): modes of action in the clinical management of recurrent pregnancy loss (RPL) and selected autoimmune disorders. Clin Chem Lab Med 2004;42(4):359–70. Almeida Barry LR, Forte WC. Common variable immunodeficiency. Allergol Immunopathol (Madr) 2004;32(2):89–91. Yunoki M, Urayama T, Tsujikawa M, Sasaki Y, Abe S, Takechi K, Ikuta K. Inactivation of parvovirus B19 by liquid heating incorporated in the manufacturing process of human intravenous immunoglobulin preparations. Br J Haematol 2005;128(3):401–4. Kannan S, Rowland CH, Hockings GI, Tauchmann PM. Intragam can interfere with blood glucose monitoring. Med J Aust 2004;180(5):251–2. Thompson AR, Gill JC, Ewenstein BM, Mueller-Velten G, Schwartz BA. Successful treatment for patients with von Willebrand disease undergoing urgent surgery using factor VIII/VWF concentrate (Humate-P). Haemophilia 2004;10(1):42–51. Ragni MV. Hemophilia gene transfer: comparison with conventional protein replacement therapy. Semin Thromb Hemost 2004;30(2):239– 47. Kerkhoffs JL, Atsma DE, Oemrawsingh PV, Eikenboom J, van der Meer FJ. Acute myocardial infarction during substitution with recombinant factor VIII concentrate in a patient with mild haemophilia A. Thromb Haemost 2004;92(2):425–6. Basso IN, Keeling D. Myocardial infarction following recombinant activated factor VII in a
Blood, blood components, plasma, and plasma products
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patient with type 2A von Willebrand disease. Blood Coagul Fibrinolysis 2004;15(6):503–4. Najaf SM, Malik A, Quraishi AU, Kazmi K, Kakepoto GN. Myocardial infarction during factor IX infusion in hemophilia B: case report and review of the literature. Ann Hematol 2004;83(9):604–7. Roberts HR, Monroe DM, White GC. The use of recombinant factor VIIa in the treatment of bleeding disorders. Blood 2004;104(13):3858– 64. Aledort LM. Comparative thrombotic event incidence after infusion of recombinant factor VIIa versus factor VIII inhibitor bypass activity. J Thromb Haemost 2004;2(10):1700–8. Abshire T, Kenet G. Recombinant factor VIIa: review of efficacy, dosing regimens and safety in patients with congenital and acquired factor VIII or IX inhibitors. J Thromb Haemost 2004;2(6):899–909. Roberts HR, Monroe DM III, Hoffman M. Safety profile of recombinant factor VIIa. Semin Hematol 2004;41(1 Suppl 1):101–8. Luu H, Ewenstein B. FEIBA safety profile in multiple modes of clinical and home-therapy application. Haemophilia 2004;10(Suppl 2):10– 6. Von Depka M. Immune tolerance therapy in patients with acquired hemophilia. Hematology 2004;9(4):245–57. Tjonnfjord GE, Brinch L, Gedde-Dahl T, Brosstad FR. Activated prothrombin complex concentrate (FEIBA) treatment during surgery in patients with inhibitors to FVIII/IX. Haemophilia 2004;10(2):174–8. Uhlmann EJ, Eby CS. Recombinant activated factor VII for non-hemophiliac bleeding patients. Curr Opin Hematol 2004;11(3):198–204. Stieltjes N, Altisent C, Auerswald G, Negrier C, Pouzol P, Reynaud J, Roussel-Robert V, Savidge GF, Villar A, Schulman S. Continuous infusion of B-domain deleted recombinant factor VIII (ReFacto) in patients with haemophilia A undergoing surgery: clinical experience. Haemophilia 2004;10(5):452–8. Lethagen S, Carlson M, Hillarp A. A comparative in vitro evaluation of six von Willebrand factor concentrates. Haemophilia 2004;10(3):243–9. Goedert JJ, Brown DL, Hoots K, Sherman KE. Human immunodeficiency and hepatitis virus infections and their associated conditions and treatments among people with haemophilia. Haemophilia 2004;10(Suppl 4):205–10. Rumi MG, De Filippi F, Santagostino E, Colombo M. Hepatitis C in haemophilia: lights and shadows. Haemophilia 2004;10(Suppl 4):211– 5. Farrugia A, Manno CS, Evatt BL. Emerging and receding risks of therapeutic regimens for haemophilia. Haemophilia 2004;10(Suppl 4):47–54. DiMichele D, Rivard G, Hay C, Antunes S. Inhibitors in haemophilia: clinical aspects. Haemophilia 2004;10(Suppl 4):140–5.
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106. Saint-Remy JM, Lacroix-Desmazes S, Oldenburg J. Inhibitors in haemophilia: pathophysiology. Haemophilia 2004;10(Suppl 4):146–51. 107. Darby SC, Keeling DM, Spooner RJ, Wan Kan S, Giangrande PL, Collins PW, Hill FG, Hay CR, UK Haemophilia Centre Doctors’ Organisation. The incidence of factor VIII and factor IX inhibitors in the hemophilia population of the UK and their effect on subsequent mortality, 1977–99. J Thromb Haemost 2004;2(7):1047– 54. 108. Lusher JM. Is the incidence and prevalence of inhibitors greater with recombinant products? No. J Thromb Haemost 2004;2(6):863–5. 109. Larson P, Zhang C, Gorina E, Getz EB. IgG formation to mammalian proteins in hemophilia A patients following treatment with a new recombinant human factor VIII. J Thromb Haemost 2004;2(6):1011–2. 110. Tarantino MD, Collins PW, Hay CR, Shapiro AD, Gruppo RA, Berntorp E, Bray GL, Tonetta SA, Schroth PC, Retzios AD, Rogy SS, Sensel MG, Ewenstein BM, RAHF-PFM Clinical Study Group. Clinical evaluation of an advanced category antihaemophilic factor prepared using a plasma/albumin-free method: pharmacokinetics, efficacy, and safety in previously treated patients with haemophilia A. Haemophilia 2004;10(5):428–37. 111. Wilde JT. HIV and HCV coinfection in haemophilia. Haemophilia 2004;10(1):1–8. 112. High KA. Clinical gene transfer studies for hemophilia B. Semin Thromb Hemost 2004;30(2):257–67. 113. Chuah MK, Collen D, Vandendriessche T. Preclinical and clinical gene therapy for haemophilia. Haemophilia 2004;10(Suppl 4):119–25. 114. Chuah MK, Collen D, Vandendriessche T. Clinical gene transfer studies for hemophilia A. Semin Thromb Hemost 2004;30(2):249–56. 115. Nathwani AC, Benjamin R, Nienhuis AW, Davidoff AM. Current status and prospects for gene therapy. Vox Sanguinis 2004;87(2):73–81. 116. Anonymous. Epoetins and darbepoetin alfa in malignant disease. Drug Ther Bull 2004;42(3):21–3. 117. Henry DH, Bowers P, Romano MT, Provenzano R. Epoetin alfa. Clinical evolution of a pleiotropic cytokine. Arch Intern Med 2004;164(3):262–76. 118. Maiese K, Li F, Chong ZZ. Erythropoietin in the brain: can the promise to protect be fulfilled? Trends Pharmacol Sci 2004;25(11):577–83. 119. Bokemeyer C, Aapro MS, Courdi A, Foubert J, Link H, Osterborg A, Repetto L, Soubeyran P. EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. Eur J Cancer 2004;40(15):2201–16. 120. El Haggan W, Vallet L, Hurault de Ligny B, Pujo M, Corne B, Lobbedez T, Levaltier B, Ryckelynck JP. Darbepoetin alfa in the treatment of anemia in renal transplant patients: a single-center report. Transplantation 2004;77(12):1914–5.
352 121. Stasi R, Brunetti M, Terzoli E, Abruzzese E, Amadori S. Once-weekly dosing of recombinant human erythropoietin alpha in patients with myelodysplastic syndromes unresponsive to conventional dosing. Ann Oncol 2004;15(11):1684–90. 122. Gouva C, Nikolopoulos P, Ioannidis JP, Siamopoulos KC. Treating anemia early in renal failure patients slows the decline of renal function: a randomized controlled trial. Kidney Int 2004;66(2):753–60. 123. Ford PA, Mastoris JP. Strategies to optimize the use of erythropoietin and iron therapy in oncology patients. Transfusion 2004;44(s2):S15–25. 124. Schwartzberg LS, Yee LK, Senecal FM, Charu V, Tomita D, Wallace J, Rossi G. A randomized comparison of every-2-week darbepoetin alfa and weekly epoetin alfa for the treatment of chemotherapy-induced anemia in patients with breast, lung, or gynecologic cancer. Oncologist 2004;9(6):696–707. 125. Lavey RS, Liu PY, Greer BE, Robinson WR 3rd, Chang PC, Wynn RB, Conrad ME, Jiang C, Markman M, Alberts DS. Recombinant human erythropoietin as an adjunct to radiation therapy and cisplatin for stage IIB-IVA carcinoma of the cervix: a Southwest Oncology Group study. Gynecol Oncol 2004;95(1):145–51. 126. Rosenzweig MQ, Bender CM, Lucke JP, Yasko JM, Brufsky AM. The decision to prematurely terminate a trial of R-HuEPO due to thrombotic events. J Pain Symptom Manage 2004;27(2):185–90. 127. Casadevall N. Epoetin-induced autoimmune pure red cell aplasia. Hematol J 2004;5(Suppl 3):S104–9. 128. Schonholzer C, Keusch G, Nigg L, Robert D, Wauters JP. High prevalence in Switzerland of pure red-cell aplasia due to anti-erythropoietin antibodies in chronic dialysis patients: report of five cases. Nephrol Dial Transplant 2004;19(8):2121–5. 129. Deray G. Achieving therapeutic targets in renal anaemia: considering cost-efficacy. Curr Med Res Opin 2004;20(7):1095–101. 130. Bennett CL, Luminari S, Nissenson AR, Tallman MS, Klinge SA, McWilliams N,
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131.
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137. 138.
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McKoy JM, Kim B, Lyons EA, Trifilio SM, Raisch DW, Evens AM, Kuzel TM, Schumock GT, Belknap SM, Locatelli F, Rossert J, Casadevall N. Pure red-cell aplasia and epoetin therapy. N Engl J Med 2004;351(14):1403–8. Quint L, Casadevall N, Giraudier S. Pure red cell aplasia in patients with refractory anaemia treated with two different recombinant erythropoietins. Br J Haematol 2004;124(6):842. Macdougall IC. Pure red cell aplasia with antierythropoietin antibodies occurs more commonly with one formulation of epoetin alfa than another. Curr Med Res Opin 2004;20(1):83–6. Tolman C, Duja S, Richardson D, Rashid R, McVerry A, Mooney A, Baker R, Will E. Four cases of pure red cell aplasia secondary to epoetin beta, with strong temporal relationships. Nephrol Dial Transplant 2004;19(8):2133–6. Macdougall IC, Roche A, Rossert J, Casadevall N, Francois P, Kemeny DM. Re-challenging patients who developed pure red cell aplasia with epoetin: can it be done? Nephrol Dial Transplant 2004;19(11):2901–5. Vartia A, Asola MR, Tertti R, Kunelius P, Metsarinne KP. Two haemodialysis patients with epoetin alfa-induced pure red-cell aplasia recovered despite treatment with another epoetin preparation. Nephrol Dial Transplant 2004;19(5):1313–6. Cortesi E, Mancuso A, De Pasquale Ceratti A, Pizzardi N, D’Auria G, Accettura C, Beccaglia P, Bertelletti D, De Marinis F. Effectiveness and safety of an induction therapy with epoetin alfa in anemic cancer patients receiving concomitant chemotherapy. Oncologist 2004;9(4):459–68. Jelkmann W, Wagner K. Beneficial and ominous aspects of the pleiotropic action of erythropoietin. Ann Hematol 2004;83(11):673–86. De Palo T, Giordano M, Palumbo F, Bellantuono R, Messina G, Colella V, Caringella AD. Clinical experience with darbepoietin alfa (NESP) in children undergoing hemodialysis. Pediatr Nephrol 2004;19(3):337–40. Pihusch M. Bleeding complications after hematopoietic stem cell transplantation. Semin Hematol 2004;41(1 Suppl 1):93–100.
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Formulations used in nutrition
PARENTERAL NUTRITION (SED-15, 2700; SEDA-26, 377; SEDA-27, 355; SEDA-28, 383) Metal metabolism Cholestasis is a common complication of parenteral nutrition, particularly in young children. One response is to reduce or discontinue copper and manganese, to avoid accumulation, since both are normally excreted by biliary excretory pathways. If the patient depends mainly or entirely on parenteral nutrition for feeding, deficiency of these elements will ensue. Of particular concern is copper deficiency. Evidence of copper deficiency has emerged in four children, one teenager and three children under 1 year old, all of whom depended entirely on parenteral feeding for maintenance of nutritional well-being (1A ). All were monitored regularly for key markers of nutritional status. After cholestasis developed, all four had signs of copper deficiency. In the teenager, it was clearly manifest 3 months after removing copper from the feeding regimen, although his plasma copper concentrations were almost within his reference range (660 µg/l). His symptoms related principally to pancytenoia. After 6 months, when the copper concentration had fallen to 90 µg/l, copper 20 micrograms/kg every 2 weeks was re-introduced into his diet. His plasma concentrations recovered to between 570 and 920 µg/l. His bone marrow rapidly normalized, with a rise in white cell count, hematocrit, and platelet count to normal. In the three other cases, cholestasis developed at 2–6 weeks after birth, leading to severe cholestasis, when copper was reduced to 10 micrograms/kg/day in one case, or removed completely. In all cases there was Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29034-2 © 2007 Elsevier B.V. All rights reserved.
copper deficiency, based on low plasma concentrations. Reintroduction of copper normalized the plasma concentrations within 1–3 months. In only one case were there effects of copper deficiency, including hypopigmentary changes in the hair and femoral and rib fractures, all of which resolved after re-introduction of copper. Although current guidelines recommend omitting copper (and manganese) from parenteral nutrition regimens in patients with obstructive jaundice (2S ), the authors recommended that copper concentrations should be checked monthly and that re-introduction of copper should be considered when concentrations suggest that there is deficiency. This can be achieved at a dosage of 20 micrograms/kg/ day in children, followed by 10 micrograms/ kg/day after concentrations have returned to normal. Liver Hepatotoxicity associated with parenteral nutrition is probably the most important metabolic complication of intravenous feeding. The literature over the past 5 years has been reviewed (3R ) for evidence about the suspected pathogenesis, commonly used diagnostic tests and procedures, and current methods for preventing and treating it. The authors concluded that, regardless of current advances in research, we are still ignorance in all these areas, with little if any new further information.
Fat emulsions Nervous system Early nutrition is a recognized component of neurosurgical intensive care treatment but it can cause raised intracranial pressure. • A 22-year-old woman with severe traumatic brain injury reproducibly developed raised intracranial pressure when Lipofundin® , a soybean oil-based emulsion for parenteral nutrition, was infused (4A ). When the intracranial pressure rose, the patient remained hemodynamically stable, and so
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an anaphylactic reaction was unlikely. Increased brain tissue oxygenation parallel to the rise in intracranial pressure suggested increased cerebral blood flow as a cause.
Without multimodal monitoring and data storage, the adverse effect of Lipofundin® in this patient would have been difficult to identify. It should be noted that the infusion rate of the fat emulsion was relatively rapid, and also that no other such incidences have been reported, so that the link remains speculative.
VITAMINS OF THE B GROUP (SEDA-26, 419; SEDA-27, 407; SEDA-28, 387)
Vitamin B12 (cobalamins)
(SED-15,
3668) Skin Localized drug-induced injection site reactions are rare. However, sclerodermoid injection site reactions have been reported, most commonly with vitamin K, but also pentazocine, progestin, and vitamin B12 (5A ). • A 31-year-old Caucasian woman who had been receiving monthly injections of vitamin B12 as a nutritional supplement for Crohn’s disease had no local reaction. immediately after receiving an injection in the upper arm, but after 3 years developed a “red spot” which developed into a sclerotic plaque over 1 month. There were no signs of systemic scleroderma. Because the size and extent of the lesion had been stable for several months, excision was performed under local anesthesia. The lesion healed without complications.
While the localized scleroderma was linked directly to the vitamin injection, whether this was due to the vitamin itself or the injection vehicle was unclear.
VITAMIN D ANALOGUES (SED-15, 3669; SEDA-28, 388) Mineral balance The successful treatment of vitamin D-induced hypercalcemia with pamidronate has been reported.
M.C. Allwood and I. Hardy
• A 6-month-old girl who had accidentally been given 300 000 units of oral vitamin D for 10 days was admitted with anorexia, vomiting, polydipsia, polyuria, and constipation (6A ). The serum calcium concentration was 4.2 (reference range 2.2– 2.5) mmol/l and the serum 25-hydroxycolecalciferol concentration was 340 (reference range 10–50) µg/l. She was initially treated with hydration and furosemide (1 mg/kg every 6 hours) followed by three doses of calcitonin (2 U/kg) over 2 days. She also received prednisolone 2 mg/kg/day and oral nifedipine 1 mg/kg/day for hypertension. Despite this the serum calcium concentration remained life-threateningly high (3.9 mmol/l). Calcitonin was withdrawn and pamidronate 1 mg/kg/day was infused over 2 days. The serum calcium fell to 3.4 mmol/l on day 3 and 2.6 mmol/l on day 4. • A 3-month-old boy who had been given a total of 2 560 000 units of vitamin D over 8 days developed constipation, restlessness, anorexia, vomiting, and sweating (7A ). The serum calcium concentration was 4.1 mmol/l and the concentration of 25-hydroxycolecalciferol was 268 µg/l. He was given furosemide 2 mg/kg/day and intravenous hydration. The serum calcium remained high and he was given prednisolone 2 mg/kg/day. The serum calcium remained high and an electrocardiogram showed extra beats. Pamidronate 5 mg/l in 40 ml of isotonic saline was infused over 4 hours. The serum calcium concentration fell to 2.6 mmol/l within 36 hours and the electrocardiogram resolved. The serum calcium 21 days later was 2.9 mmol/l and the pamidronate infusion was repeated; the calcium concentration fell to 2.4 mmol/l. Further infusions of the same dose of pamidronate were given after 30 and 59 days and the calcium concentration was 2.2 mmol/l after 4 months.
Hypercalcemia due to acute vitamin D intoxication is mainly mediated by increased bone resorption, and so drugs that inhibit bone resorption may be more effective than furosemide and intravenous hydration. Calcitonin has the disadvantage of a relatively short duration of action and has been reported to lower the initial serum calcium by only up to 20% (6A ). The bisphosphonate pamidronate is often used in children to treat hypercalcemia due to malignancy and juvenile osteoporosis. The authors of these reports did not report any adverse effects of pamidronate infusion and concluded that it could be a life-saving intervention when calcium concentrations do not respond adequately to conventional management. A recent study of serum 25-hydroxycolecalciferol in 12 very premature infants fed on a specialist formula with a high vitamin D content (2700 IU/l) has shown an increased risk of hypervitaminosis (8c ). Serum 25-hydroxycolecal-
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ciferol concentrations in infants fed exclusively on the premature formula (n = 40) were significantly higher than in infants fed regular formula or breast milk (n = 25) (175 versus 115 nmol/l). However, none of the infants had abnormal serum calcium or phosphorus concentrations. The authors postulated that this was probably because vitamin D-dependent active intestinal calcium resorption is limited in premature infants (9R ), but becomes relevant with intestinal maturation, which seems to be accelerated by premature delivery (10R ). Prolonged feeding of high vitamin D formula in very premature infants therefore poses the risk of hypervitaminosis. Although vitamin D requirements in premature infants are controversial, and a daily intake of 200 IU/kg has been shown to be sufficient (11c ), premature infant formulas marketed in Japan, such as the one used in this study, contain large amounts of vitamin D (2700 IU/l). The preterm formulas that are commonly used in Europe and the USA contain less vitamin D (1010–2200 IU/l) and carry a much reduced risk of hypervitaminosis. Tumorigenicity Vitamin D deficiency has been associated with an increased risk of prostate cancer due to the antiproliferative effect of 1α,25-dihydroxycolecalciferol in vitro (12E ). However, a longitudinal nested case-control study in which serum 25-hydroxycolecalciferol concentrations were measured in 622 men with prostate cancer and 1451 matched controls has shown that both high (80 nmol/l) and low (19 nmol/l) vitamin D blood concentrations carry an increased risk (13C ). The reference range (40–60 nmol/l) was associated with the lowest risk. The finding that high concentrations of vitamin D are related to an increased risk was unexpected and is difficult to explain on the basis of experimental results. The authors speculated that it might be because prostate cells regulate their own vitamin D balance by 24-hydroxylase, an enzyme that inactivates colecalciferol (vitamin D3 ). High concentrations of colecalciferol upregulate the activity of this enzyme, leading to local colecalciferol deficiency and resistance. This means that colecalciferol cannot have its antiproliferative function in prostate tissue despite high serum concentrations. Since these results suggest that even moderately high concentrations of vitamin D may have an adverse effect, care
should be taken before recommending supplementation.
VITAMIN E
(SED-15, 3677)
Death Vitamin E supplementation has been tested in many trials of prevention of cardiovascular disease and cancer. However, a few trials have reported a non-statistically significant increase in total mortality with high-dose vitamin E supplementation. The issue has been reviewed in a meta-analysis (14M ). The purpose was to look for a dose-response relation between vitamin E supplementation and total mortality, using data from randomized controlled trials. Comparing vitamin E with placebo, nine of 11 trials of high-dose vitamin E (over 400 IU/day) showed an increased risk of all-cause mortality, the pooled risk difference being 39 per 10 000 persons (95%CI = 3, 74). In low-dosage vitamin E trials there was no difference. High-dosage vitamin E may therefore be harmful and should be avoided.
Vitamin K1 (phytomenadione) (SED-15, 3681) Hematologic Safe chronic oral anticoagulation is compromised in clinical practice by many factors that cause erratic control and an increased risk of bleeding. One such factor is believed to be dietary vitamin K intake. The potential association between vitamin K intake and coagulation instability has been explored primarily in case reports and small, retrospective, uncontrolled studies. However, there has now been a prospective study of the effects of dietary vitamin K intake on coagulation in 39 out-patients taking oral coumarin derivatives who made 230 visits to one anticoagulation clinic (15C ). In a randomized crossover protocol, 12 patients with stable anticoagulation underwent 4-day in-hospital dietary interventions, 1–2 weeks apart, providing first a 500% increase and then an 80% reduction in vitamin K intake relative to baseline. There was a progressive statistically significant inverse association between vitamin K intake score and different degrees of anticoagulation. Vitamin K
356 intake was independently associated with both overcoagulation and undercoagulation. In the randomized protocol, the INR rose from 2.6 at baseline to 3.3 on day 7 in subjects on the vitamin K-depleted diet and fell from 3.1 at baseline to 2.8 on day 4 in those on the vitamin K-enriched diet. These prospective data strengthen the concept that the interaction between vitamin K and coumarins is a clinically relevant, major independent factor that interferes with anticoagulation stability. Skin Subcutaneous phytomenadione can cause adverse skin reactions, as has been illustrated in an unusual case of an erythematous papulovesicular rash (16A ). • A 21-year-old woman with Wilson’s disease was given fresh frozen plasma and subcutaneous phytomenadione 5 mg/day. On day 12 she started to complain of dryness, pruritus, and an erythematous papulovesicular rash, which was initially localized to several injection sites but eventually increased in size to 5–6 cm. Phytomenadione was withdrawn on day 15, but the rash persisted despite the use of a glucocorticoid cream. The rash finally disappeared shortly after liver transplantation and the start of immunosuppressant treatment.
While skin hypersensitivity to intramuscular phytomenadione is not uncommon, the authors thought that this case was unusual because it involved subcutaneous administration and quickly resolved after immunosuppressive drug therapy. However, it is not perhaps surprising that phytomenadione injection causes similar skin reactions irrespective of the route of injection. Recalcitrant dermatitis after intramuscular phytomenadione responded to treatment with a pulsed dye laser (17A ).
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M.C. Allwood and I. Hardy
• A 25-year-old woman developed pruritic skin lesions on both buttocks laterally while taking several drugs, including phytomenadione. Intradermal testing showed vitamin K-induced allergic contact dermatitis. The symptoms persisted despite the use of a topical glucocorticoid and oral prednisolone 30 mg/day. Because of systemic adverse effects she was then given intralesional glucocorticoid injections and a topical glucocorticoid under an occlusive dressing. After several weeks of unsuccessful treatment she was then given two consecutive pulsed dye laser treatments (450 µsec pulse duration, 585 nm pulse width, fluence of 5 and 7 J/cm2 using a 7 mm hand piece) 3 weeks apart. The skin lesion cleared 1 week after the second laser treatment and she was followed for 7 months without recurrence.
The authors of this report acknowledged that neither the precise mechanism by which the intramuscular phytomenadione could have caused a skin reaction without any apparent systemic or neuromuscular effects, nor the exact mechanism by which the pulsed dye laser treatment improved the condition are known. Laser treatment has been successfully used for psoriatic plaques (18A , 19A ). The beneficial effect has been attributed to destruction of abnormal dermal vasculature. The authors speculated that in this case, which was not associated with abnormal dermal vasculature, the laser may have destroyed dilated vessels, thereby reducing the accumulation of inflammatory cells and cytokine release. Be cause of the high cost the authors suggested that this treatment should be reserved for lesions that are unresponsive to conventional glucocorticoid therapy.
References 1. Hurwitz M, Garcia MG, Poole RL, Kerner JA. Copper deficiency during parenteral nutrition: a report of four pediatric cases. Nutr Clin Pract 2004;19:305–8. 2. Greene HL, Hambridge KM, Schlander R, Tsang RC. Guidelines for the use of vitamins, trace elements, calcium, magnesium, and phosphorus in infants and children receiving TPN.
Report of a subcommittee on pediatric parenteral nutrition requirements from the committee on clinical practice issues of the American Society of Clinical Nutrition. Am J Clin Nutr 1988;48:1324–42. 3. Fulford A, Scolapio JS, Aranda-Michel J. Parenteral nutrition-associated hepatotoxicity. Nutr Clin Pract 2004;19:274–83.
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4. Wolf S, Krammer M, Trost HA, Lumenta CB. Lipofundin® -induced intracranial pressure rise after severe traumatic brain injury—a case report. Z Neurochirurg 2004;65:81–3. 5. Ho J, Rothchild YH, Sengelmann R. Vitamin B12 -associated localized scleroderma and its treatment. Dermatol Surg 2004;30:1252–5. 6. Gurkan F, Davutoglu M, Bosnak M, Ece A, Dikici B, Bilici M, Haspolat K. Pamidronate treatment in acute vitamin D intoxication. J Endocrinol Invest 2004;27:680–2. 7. Ezgu FS, Buyan N, Gündüz M, Tümer L, Ilyas O, Hasanoglu A. Vitamin D intoxication and hypercalcaemia in an infant treated with pamidronate infusions. Eur J Pediatr 2004;163:163–5. 8. Nako Y, Tomomasa T, Morikawa A. Risk of hypervitaminosis D from prolonged feeding of high vitamin D premature infant formula. Pediatr Int 2004;46:439–43. 9. Koo WWK, Steichen JJ. Osteopenia and rickets of prematurity. In: Polin RA, Fox WW, editors. Fetal and Neonatal Physiology, vol. II. Philadelphia: WB Saunders; 1998. p. 2335–49. 10. Senterre J, Salle B. Calcium and phosphorus economy of the preterm infant and its interaction with vitamin D and its metabolites. Acta Paediatr Scand 1982;296(Suppl):85–92. 11. Backström MC, Mäki R, Kuusela A. Randomised controlled trial of vitamin D supplementation on bone density and biochemical indices in preterm infants. Arch Dis Child Fetal Neonatal Ed 1999:F161–6. 12. Ylikomi T, Laaksi I, Lou YR, Martikainen P, Miettinen S, Pennanen P, Purmonen S, Syvala H,
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Vienonen A, Tuohimaa P. Antiproliferative action of vitamin D. Vitam Horm 2002;64:357– 406. Tuohimaa P, Tenkanen L, Ahonen M, Lumme S, Jellum E, Hallmans G, Stattin P, Harvei S, Hakulinen T, Luostarinen T, Dillner J, Lehtinen M, Hakama M. Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: a longitudinal, nested casecontrol study in the Nordic countries. Int J Cancer 2004;108:104–8. Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Metaanalysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37–46. Franco V, Polanczyk CA, Clausell N, Rohde LE. Role of dietary vitamin K intake in chronic oral anticoagulation: prospective evidence from observational and randomized protocols. Am J Med 2004;116:651–6. Bui L, Huynh T, Lam V. Skin reaction to subcutaneous phytonadione injections. Am J HealthSystem Pharm 2004;61:407. Jung J, Cho SB, Chung KY. Recalcitrant adverse reaction to vitamin K: response to pulsed dye laser. Dermatol Surg 2004;30:931–3. Apfelberg D. Psoriasis response to the pulsed dye laser. Plast Reconstr Surg 1998;101:559–60. Ros A, Garden JM, Bakus AD, Hedblad MA. Psoriasis response to the pulsed dye laser. Lasers Surg Med 1996;19:331.
David M. Keeling
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Drugs affecting blood coagulation, fibrinolysis, and hemostasis
Editor’s note: The clotting factors, such as factor VIII, and anticoagulant proteins, such as activated factor C, are included in Chapter 33.
COUMARIN ANTICOAGULANTS (SED-15, 983; SEDA-26, 379; SEDA-27, 358; SEDA-28, 391) Hematologic In a case-control study 170 patients with atrial fibrillation who developed intracranial hemorrhage while taking warfarin were compared with 1020 matched controls who did not (1C ). The cases were significantly older than the controls (median age 78 versus 75 years) and had higher median INRs (2.7 versus 2.3). The risk of intracranial hemorrhage increased at 85 years of age or older (adjusted OR = 2.5; 95%CI = 1.3, 4.7; referent age 70–74 years) and at an INR range of 3.5–3.9 (adjusted OR = 4.6; CI = 2.3, 9.4; referent INR 2.0–3.0). The risk of intracranial hemorrhage at INRs below 2.0 did not differ statistically from the risk at INRs of 2.0–3.0 (adjusted OR = 1.3; CI = 0.8, 2.2). In contrast, an analysis of patients with atrial fibrillation in the Framingham Heart Study did not show age as a risk factor for bleeding (2C ).
Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29035-4 © 2007 Elsevier B.V. All rights reserved.
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Skin necrosis in oral anticoagulation DoTS classification: Reaction: Skin necrosis due to oral anticoagulants Dose-relation: Collateral reaction Time-course: Early Susceptibility factors: Genetic (thrombophilic defects), diseases (obesity, heparin-induced thrombocytopenia) Vitamin K antagonists, such as warfarin, prevent gamma-carboxylation of the vitamin K-dependent procoagulant factors II, VII, IX, and X and the natural anticoagulants protein C and protein S. When therapy is begun these factors fall at rates that depend on their individual half-lives. As the natural anticoagulant protein C has a short half-life and some of the procoagulants (X and particularly II) have longer half-lives, coumarins can be procoagulant until equilibrium is reached. During this induction period thrombosis in the dermal vessels can occur, resulting in skin necrosis. In 2004 there were several reports of this phenomenon (3A – 10A ). • A 50-year-old woman with a left leg deep venous thrombosis and subsequent pulmonary embolism was first anticoagulated with low-molecularweight heparin and subsequently warfarin (3A ). Within 4 days she developed abdominal skin necrosis. She had protein S deficiency and a mutation in the methylenetetrahydrofolate reductase gene (MTHFR). • A 38-year-old obese woman was given heparin and warfarin for a presumed pulmonary embolism (4A ). On day 5 she developed a tender mass in the left breast and was thought to have an inflammatory carcinoma. On the next day irregular greyish blue areas of the skin, ecchymoses,
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•
•
•
•
•
•
and hemorrhagic bullae were noted overlying the mass. Urgent surgical debridement showed extensive necrosis of the skin and breast substance. A 29-year-old woman with an acute pulmonary embolism was given heparin and warfarin and on day 5 developed severe pain, purple discoloration, and swelling in her right breast (5A ). A diagnosis of warfarin-induced skin necrosis was made. Thrombophilia testing showed heterozygosity for factor V Leiden. The concentrations of protein C and S were normal. A 75-year-old man who had taken acenocoumarol for 7 years was given diclofenac for a painful knee (6A ). Two days later, his renal function deteriorated and skin necrosis became evident. Biopsy showed histological changes consistent with coumarin-induced necrosis. Protein C and S concentrations were normal. The authors concluded that acute renal insufficiency could have precipitated a transient defect in the protein C pathway. Six patients with heparin-induced thrombocytopenia (HIT), who developed frank or impending venous limb gangrene (n = 2) or central skin necrosis (n = 5) (one had both) temporally related to warfarin therapy, developed these complications after either taking warfarin alone for 2–7 days (n = 4) or while a direct thrombin inhibitor was being withdrawn (n = 2) (7A ). All had supratherapeutic international normalized ratios. One patient required leg and breast amputations, and another died. A 54-year-old woman had an above knee amputation for limb ischemia due to arteriosclerosis and post-operatively developed subclavian vein thrombosis. She was given enoxaparin and warfarin and after a single dose of 10 mg her INR was 6.7 (8A ). Three days later she developed skin necrosis over her right upper thigh. She was subsequently found to be protein S deficient. An obese woman developed extensive cutaneous necrosis while taking acenocoumarol for a deep venous thrombosis (9A ). She had a heterozygous deficit for protein C. The histopathological findings of vessel thrombi and erythrocyte extravasation were consistent with the clinical picture. A 61-year-old woman with a 12-month history of Raynaud’s phenomenon developed multiple digital necrosis following aortic valve replacement with a mechanical prosthesis for aortic insufficiency caused by non-bacterial thrombotic endocarditis (10A ). Postoperatively she had daily episodes of ischemia of the fingers and toes, which improved with local warming. However, coincident with the occurrence of immune heparin-induced thrombocytopenia, and while undergoing routine warfarin anticoagulation because of the mechanical valve prosthesis, she abruptly developed progression of the digital ischemia to multiple digital necrosis on postoperative day 8, when the international normalized ratio reached its peak value of 4.3. Subsequently, she was found to have metastatic breast adenocarcinoma.
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The authors of the last report suggested that multiple digital gangrene can result from the interaction of various localizing and systemic factors, including compromised microvascular blood flow (Raynaud’s phenomenon), increased thrombin generation (heparin-induced thrombocytopenia, adenocarcinoma), and warfarininduced failure of the protein C natural anticoagulant pathway. These reports re-enforce and add to our knowledge of coumarin induced skin necrosis. In two cases the patient was described as obese (4A , 9A ), and in another three this was apparent from the clinical photographs (3A , 5A , 8A ). Defects of the protein C pathway are a well recognized susceptibility factor, and in these cases two were protein S deficient (3A , 8A ) and one was protein C deficient (9A ). Two patients had factor V Leiden (3A , 5A ), so other thrombophilic defects may also predispose to this adverse effect. There is no other evidence that a mutation in methylene tetrahydrofolate reductase (3A ) or renal impairment (6A ) play a role. Inadequate heparin while starting coumarin therapy is an important factor (5A ), but adequate heparin does not offer complete protection (3A , 4A ). Finally, there is a risk of severe thrombosis when starting warfarin in patients with heparin-induced thrombocytopenia (7A , 10A ).
Susceptibility factors Genetic Variant alleles of CYP2C9, CYP2C9*2 and CYP2C9*3, are associated with an increased response to warfarin. However, an effect on acenocoumarol dose requirements appears to be absent for the CYP2C9*2 allele and the consequences for phenprocoumon metabolism have not yet been established. In 1124 patients from the Rotterdam Study who took acenocoumarol or phenprocoumon there was a statistically significant difference in the first INR between patients with variant genotypes and those with the wild type (11C ). Almost all acenocoumarol-treated patients with a variant genotype had a significantly higher mean INR and a higher risk of an INR of 6.0 or over during the first 6 weeks of treatment and there was a clear genotype–dose relation. Individuals with one or more CYP2C9*2 or CYP2C9*3 alleles required a significantly lower dose of acenocoumarol than wild-type
360 patients. In patients taking phenprocoumon there were no significant differences between variant genotypes and the wild type genotype. The authors concluded that phenprocoumon is a clinically useful alternative in patients carrying the CYP2C9*2 and CYP2C9*3 alleles. Heart failure In a cohort study of all 1077 patients in an outpatient anticoagulation clinic taking acenocoumarol or phenprocoumon between 1 January 1990 and 1 January 2000, 396 developed an INR of 6.0 or over, and the risk of overanticoagulation was increased in patients with heart failure (12C ). Drug interactions Carnitine There was a rise in INR when a 33-year-old man taking acenocoumarol took carnitine 100 mg/day in an over-the-counter product recommended to complement bodybuilding (13A ). No mechanism was suggested. Dicloxacillin An interaction with dicloxacillin resulted in increased warfarin dosage requirements for 2 weeks after dicloxacillin was withdrawn (14A ). The mechanism is probably non-stereoselective induction of warfarin metabolism by dicloxacillin (15Ac , 16R ). Ginseng The possible interaction of warfarin with American ginseng has been studied in a double-blind, randomized, placebo-controlled trial in 20 young healthy subjects (17C ). Warfarin was given for 3 days during weeks 1 and 4 and beginning in week 2, the subjects were assigned to either ginseng or placebo. The peak INR fell significantly after 2 weeks of ginseng administration compared with placebo; the difference between ginseng and placebo was −0.19 (95%CI = −0.36, −0.07). However, in an open, three-way, crossover, randomized study in 12 healthy men who took a single dose of warfarin 25 mg alone or after pretreatment for 7 days with ginseng, there was no change in the pharmacokinetics or pharmacodynamics of either S-warfarin or R-warfarin (18C ). If the mechanism of this interaction is induction of warfarin metabolism by ginseng, the discrepancy between these two studies could be explained by the difference in duration.
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Laxatives In a large population-based cohort study in 1124 patients, 351 developed an International Normalized Ratio of 6.0 or more (19C ). The only laxative with a moderate but significantly increased relative risk of overanticoagulation was lactulose (relative risk 3.4; 95%CI = 2.2, 5.3). Ketolide antibiotics There has been a report that telithromycin increases the effect of warfarin (20A ). The mechanism is unknown, but the authors suggested that it resulted from inhibition of the metabolism of the R-isomer of warfarin, which is metabolized predominantly by CYP1A2 and less by CYP3A4. Macrolide antibiotics There has been a report that azithromycin increases the effect of warfarin (21A ). Azithromycin, unlike erythromycin and clarithromycin, is not known to inhibit cytochrome P450 isozymes and is presumed to be the macrolide of choice in patients already taking warfarin. However, reports of azithromycin–warfarin interactions support the possibility that azithromycin does interact with warfarin, although the exact mechanism is not understood. NSAIDs NSAIDs are reported to increase the risk of bleeding in coumarin users. The mechanism underlying this risk is inhibition of platelet aggregation, but in some cases a pharmacokinetic mechanism, resulting in an increased International Normalized Ratio (INR), has been proposed. In a retrospective cohort study in 112 out-patients stabilized on acenocoumarol 52 had an increase in INR above the target value after they started to take diclofenac, naproxen, or ibuprofen (22c ). In 12 patients the INR increased above 6.0. The INR in the other 60 patients remained constant. There were no statistically significant differences between patients with an increased INR and patients without with regard to age, sex, target range, and average dose of acenocoumarol. Genotyping was performed in 80 patients, of whom 36 had an increased INR as a result of an interaction with an NSAID; there no association between the CYP2C9 genotype and an increased INR. Paracetamol As aspirin and NSAIDs increase the risk of bleeding, paracetamol has become the first choice analgesic for patients taking oral
Drugs affecting blood coagulation, fibrinolysis, and hemostasis
anticoagulants. Whether paracetamol increases the effect of warfarin has been controversial. The authors of a literature review concluded that this was still an unanswered question and recommended that the INR be closely monitored if paracetamol is used (23R ). St John’s wort In an open, three-way, crossover, randomized study in 12 healthy men who took a single dose of warfarin 25 mg alone or after pretreatment for 14 days with St John’s wort, the apparent clearances of S-warfarin were 3.3 ml/minute before St John’s wort was added and 3.7 ml/minute after (18C ). The respective apparent clearances of R-warfarin were 1.8 and 2.4 ml/minute. The mean ratios of the apparent clearances were 1.29 (95%CI = 1.16, 1.46) for S-warfarin and 1.23 (1.11, 1.37) for R-warfarin. St John’s wort did not affect the apparent volume of distribution or protein binding of either enantiomer of warfarin. The authors concluded that St John’s wort induces the clearance of both enantiomers of warfarin. INR was slightly reduced as a result, but platelet aggregation was not altered.
HEPARINS
(SED-15, 1590; SEDA-26, 379; SEDA-27, 358; SEDA-28, 391) Hematologic Heparin can rarely cause acute cardiorespiratory reactions, and some reports relate this to underlying heparin-induced thrombocytopenia. Over 2 years four cardiovascular surgery patients were identified who had eight episodes of cardiorespiratory collapse immediately after heparin administration (24A ). All had underlying heparin-induced thrombocytopenia. They received intravenous boluses of unfractionated heparin. Two had severe respiratory distress within 15 minutes, for which they required endotracheal intubation. Two others had cardiac arrest or a dysrhythmia within minutes of receiving intravenous heparin. Serological tests for heparin-induced antibodies were positive in all cases. In three cases, the platelet count was normal or near normal, but fell dramatically immediately after the heparin bolus. Three patients had prior diagnoses of heparininduced thrombocytopenia, but their prescribers gave them heparin either unaware of the diagnosis or ignorant of its significance. The authors
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noted that heparin administration to patients with heparin-induced antibodies can result in life-threatening pulmonary or cardiac events. Skin Skin necrosis due to low-molecularweight heparin has been reviewed in a systematic review of 20 articles (21 cases) in which skin necrosis occurred locally and distant from the injection site (25M ). Heparin-induced antibodies were common (positive in 9/11 cases, negative in 2/11). However, severe thrombocytopenia (platelet count below 100 × 109 /l) occurred in only four cases, while the platelet count was normal in half of the cases. Recovery after withdrawal was usually benign, but two patients needed reconstructive surgery. The authors concluded that skin necrosis due to low-molecular-weight heparin can occur as part of heparin-induced thrombocytopenia, but that there can be other mechanisms, including allergic reactions and local trauma. When heparin-induced thrombocytopenia is excluded it is safe to switch to unfractionated heparin; otherwise, drugs such as hirudin or fondaparinux should be preferred. Immunologic Heparin has immunomodulatory effects, such as enhancement of cytokine production in monocytes induced by endotoxin (lipopolysaccharide). In whole blood from five healthy volunteers heparin 20 IU/ml or more significantly increased lipopolysaccharide-induced production of interleukin-8; fondaparinux did not (26E ). The authors suggested that fondaparinux is not an immunomodulator like heparin, and may therefore lack adverse effects in patients with endotoxemia. However, in another case there was crossreactivity with fondaparinux after a delayedtype hypersensitivity reaction to heparin (27A ); this is distinct from heparin-induced thrombocytopenia due to IgG antibody against PF4.
THROMBOLYTIC AGENTS (SED-15, 3402; SEDA-28, 392) Susceptibility factors There have been two studies of the susceptibility factors for intracranial hemorrhage in patients with acute coronary syndromes undergoing fibrinolytic therapy (28c , 29C ). FASTRAK II is a prospective
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registry of acute coronary syndromes involving 111 Canadian hospitals, in which trained medical personnel record admission, treatment, and discharge data on patients admitted with acute coronary syndromes (28c ). From 1 January 1998 to 31 December 2000, 12 739 patients received fibrinolytic therapy for acute myocardial infarction. Of these, 146 patients (1.15%) sustained strokes and 82 (0.65%) had an intracranial hemorrhage. Advanced age, female sex, a history of stroke, and systolic hypertension (over 160 mmHg) on arrival were important independent risks factors for intracranial hemorrhage. Patients who received streptokinase had a lower risk of intracranial hemorrhage. Of 592 patients in the Global Utilization of Streptokinase and tPA for Occluded ArteriesI (GUSTO-I) trial who had a stroke during initial hospitalization, the risk of intracranial hemorrhage was significantly greater in those with recent facial or head trauma (OR = 13, 95%CI = 3.4, 86); dementia was also associated with an increased risk for intracranial hemorrhage (OR = 3.4, 95%CI = 1.2, 10) (29c ). Because facial or head trauma can greatly influence treatment decisions, it was suggested that this risk factor should be incorporated into models designed to estimate the benefit to harm balance of fibrinolytic therapy.
SHORT POLYSACCHARIDE INHIBITORS OF COAGULATING FACTORS (SEDA-27, 359; SEDA-28, 392)
Fondaparinux
(SED-15, 1437)
Immunologic Delayed-type hypersensitivity reactions at heparin injection sites, in the form of eczema-like infiltrated plaques, with occasional generalized reactions, are common adverse effects; cross-reactivity with fondaparinux has now been reported (27A ). • An 85-year-old woman developed localized infiltrated plaques followed by a disseminated exanthematous reaction 10 days after the start of dalteparin therapy. Intradermal tests with a comprehensive series of undiluted commercial drugs yielded positive reactions on day 7 to all forms of heparin and
David M. Keeling
the heparinoid danaparoid, whereas fondaparinux and lepirudin were negative. Subcutaneous provocation with lepirudin was tolerated, but there was a positive reaction to fondaparinux at each site of three therapeutic subcutaneous injections. Later, a second intradermal test with fondaparinux was positive.
Cross-reactivity between high- and lowmolecular-weight heparins is well known and the pentasaccharide fondaparinux has been recommended as a safe alternative. However, the authors concluded that in patients with delayed-type hypersensitivity to high- and lowmolecular-weight heparins and danaparoid, fondaparinux cannot reliably be recommended as a therapeutic alternative. In another series of seven women with delayed-type allergy to heparins and semisynthetic heparinoids one also had a delayed-type allergic reaction to fondaparinux (30c ). The authors suggested that the rare cross-reaction between fondaparinux and heparins may be due to differences in the response to haptens. Pregnancy Five pregnant patients in whom anticoagulant therapy was indicated and who had severe cutaneous allergic reactions to low molecular weight heparin were treated with fondaparinux 2.5 mg/day (31c ). There were no allergic reactions at injection sites, thromboembolic events, or abnormal bleeding and no adverse effects in the neonates. In four of the patients, anti-factor Xa activity in umbilical cord blood was increased. The concentration of fondaparinux detected in umbilical cord plasma by the chromogenic assay was about one-tenth the concentration in maternal plasma. The authors concluded that the use of fondaparinux in pregnant women might best be limited to those for whom there are no obvious therapeutic alternatives, such as patients with heparin-induced thrombocytopenia or severe allergic reactions to heparin.
DIRECT THROMBIN INHIBITORS (SED-15, 1142; SEDA-27, 359)
Lepirudin Immunologic About 40% of patients who receive lepirudin for 5–10 days develop anti-
Drugs affecting blood coagulation, fibrinolysis, and hemostasis
hirudin antibodies, which lead to reduced renal elimination of lepirudin, increasing its effects. They also recognize epitopes on bivalirudin (32E ). A few patients with antihirudin antibodies develop hypersensitivity reactions to lepirudin on re-exposure. • A 45-year-old African-American woman received lepirudin for anticoagulation after having type II heparin-induced thrombocytopenia (33A ). She developed supratherapeutic anticoagulation after 10 days, and lepirudin was withheld for 6 days. After it was restarted, she had an anaphylactic reaction. After the reaction had resolved, she was rechallenged with lepirudin, and the anaphylactic reaction recurred.
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a retrospective cohort analysis of 10 093 patients with atrial fibrillation (mean age 77 years), of whom 19% took antiplatelet drugs (37c ). Antiplatelet drugs significantly increased the rates of major bleeding from 1.3% to 1.9%. In a multivariate analysis, the factors associated with bleeding events included anemia (OR = 2.52; 95%CI = 1.64, 3.88), a history of bleeding (OR = 2.40; 95%CI = 1.71, 3.38), and concurrent antiplatelet drug therapy (OR = 1.53; 95%CI = 1.05, 2.22). Although concerns about increased bleeding risk when warfarin and antiplatelet drugs are combined are not unfounded, the risk of bleeding is only increased by 50% and the decision to use concurrent antiplatelet drugs will be tempered by cardiac and bleeding risk factors.
Ximelagatran Drug interactions Alcohol In a randomized, open, two-way, crossover study in 26 men and women, alcohol 0.5 g/kg (women) or 0.6 g/kg (men) did not alter melagatran-induced prolongation of the activated partial thromboplastin time after the administration of a single oral dose of ximelagatran 36 mg (34C ). Atorvastatin In a randomized, two-way, crossover study in 16 healthy men and women, there were no reciprocal pharmacokinetic or pharmacodynamic interactions of a single oral dose of atorvastatin 40 mg and ximelagatran 36 mg bd for 5 days (35C ). Digoxin In a randomized, double-blind, placebo-controlled, two-way, crossover study in 16 healthy men and women, ximelagatran 36 mg for 8 days had no pharmacokinetic or pharmacodynamic effects on a single dose of digoxin 0.5 mg (36C ).
DRUGS THAT ALTER PLATELET FUNCTION (SEDA-25, 412; SEDA-26, 380; SEDA-27, 360; SEDA-28, 396) Drug interactions The impact on major bleeding rates of antiplatelet drug therapy among warfarin users has been examined in
Abciximab
(SED-15, 4; SEDA-23, 377; SEDA-27, 360; SEDA-28, 396) The use of glycoprotein IIb/IIIa inhibitors, such as abciximab, is associated with a mortality benefit, but does not alter the risk of restenosis (38M ).
Hematologic Thrombocytopenia Abciximab is associated with higher incidence of thrombocytopenia (1– 5%) than other glycoprotein IIb/IIIa inhibitors, such as eptifibatide and tirofiban (39AE ). It can occur within hours, and fatal outcomes have been described (40R ). However, it can be delayed and is potentially prothrombotic (41c , 42c ). Five patients with thrombocytopenia that developed 7–12 days after the start of abciximab infusion had IgG antibodies against abciximab-coated platelets, and antibody-containing plasma from three patients induced abciximab-dependent activation and aggregation of normal platelets (41c ). Thrombocytopenia due to abciximab usually resolves 10 days after withdrawal. However, persistent thrombocytopenia has been reported for up to 21 days and in one case was resistant to platelet transfusions and two courses of intravenous gammaglobulin (43A ). Abciximab-induced thrombocytopenia refractory to platelet transfusions has also been observed in a patient with idiopathic thrombocytopenic purpura (44A ).
364 Bleeding In a retrospective chart analysis of 348 patients, 79 who received abciximab (n = 30), eptifibatide (n = 24), or tirofiban (n = 25) were included (45c ). There were 21 bleeding events not related to coronary artery bypass grafting, one major bleed (on tirofiban), and 20 minor bleeds. Bleeding rates were not significantly different between the groups: nine with abciximab, five with eptifibatide, and seven with tirofiban. Significant risk factors for bleeding included weight, infusion duration, and baseline platelet count. In a meta-analysis of randomized comparisons of abciximab and placebo or control therapy in primary percutaneous coronary intervention for acute myocardial infarction in 3266 patients, treatment with abciximab resulted in an increased likelihood of major bleeding (OR = 1.74; 95%CI = 1.11, 2.72) (46M ). In a meta-analysis of randomized controlled trials of abciximab as adjunctive therapy to percutaneous coronary interventions for acute myocardial infarction abciximab was associated with an increased risk of major bleeding (OR = 1.39, 95%CI = 1.03, 1.87), but bleeding was observed only when the heparin bolus was 100 U/kg followed by a maintenance infusion (OR = 1.89, 95%CI = 1.10, 3.28) and not with a bolus of 70 U/kg (OR = 1.22, 95%CI = 0.85, 1.73) (47M ). In the Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes (GUSTO IV-ACS) trial, abciximab (either a 24hour or a 48-hour infusion) was compared with placebo in 7800 patients with an acute coronary syndrome (48c ). There were major bleeds in 98 patients (1.2%), including eight with intracerebral hemorrhage, and 215 patients (2.8%) had a minor bleed. The most significant predictors of spontaneous bleeding were: use of low-molecular weight heparin (OR = 6.6, CI = 5.3–8.4), duration of abciximab infusion (24 hours OR = 3.2, CI = 2.6, 4.1; 48 hours OR = 4.8 CI = 3.8, 6.0), advanced age (over 70 years OR = 1.7, CI = 1.4, 2.0), and female sex (OR = 1.5, CI = 1.3, 1.8). The authors concluded that treatment with abciximab in patients with non-ST-elevation acute coronary syndromes is safe, because major bleeding and stroke are rare and most events are clinically manageable or have few clinical consequences. The ReoPro Readministration Registry found clinically significant bleeding in 31 (2.3%) of 1342 patients given abciximab, in-
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cluding one with intracerebral hemorrhage (49c ). There was thrombocytopenia (less than 100 × 109 /l) in 5% and profound thrombocytopenia (less than 20 × 109 /l) in 2%. In patients who received abciximab within 1 month of a previous treatment (n = 115), the incidences of thrombocytopenia and profound thrombocytopenia were 17% and 12% respectively. Immunologic Because of its antigenic potential, there are theoretical concerns about readministration of abciximab. This has been assessed by the ReoPro Readministration Registry the in 1342 patients who underwent percutaneous coronary intervention and who received abciximab for at least a second time (49c ). There were no cases of anaphylaxis.
Anagrelide Anagrelide was developed as an inhibitor of platelet aggregation and acts by inhibiting phosphodiesterase. It was was later found to reduce the platelet count, in doses lower than those required to inhibit platelet aggregation, by interfering with megakaryocyte differentiation and proliferation. It is used for the treatment of essential thrombocythemia. Observational studies In a long-term study of 39 young patients with essential thrombocythemia treated with anagrelide, 20 had adverse effects: tachycardia (n = 9), gastric distress (n = 6), anemia (n = 4), headache (n = 2), capillary leak syndrome (n = 2), acute fluid retention (n = 1), alopecia (n = 1), and a rash (n = 1) (50c ). In a prospective study of 97 patients the most frequent adverse effects after 1 month were headache (n = 24), diarrhea (n = 8), and bouts of palpitation (n = 8) (51c ). In a prospective study in 120 patients with myeloproliferative disease the adverse effects were bouts of palpitation (n = 84), headache (n = 62), nausea (n = 42), diarrhea or flatulence (n = 38), edema (n = 260), and fatigue (n = 280) (52c ). Psychiatric There has been a single case report of visual hallucinations in a patient taking anagrelide, with recurrence on re-challenge (53c ).
Drugs affecting blood coagulation, fibrinolysis, and hemostasis
Sexual function In a retrospective study of 52 patients with chronic myeloproliferative diseases, 42 had adverse effects and in 15 the adverse effects necessitated withdrawal (54c ). Two patients had erectile dysfunction, which has been described only once before in association with anagrelide.
Clopidogrel
(SED-15, 821; SEDA-26, 380; SEDA-28, 397)
Hematologic Intraoperative and postoperative outcomes have been studied in 505 consecutive patients who underwent isolated coronary artery bypass grafting; some had taken clopidogrel until 72 hours before surgery (n = 136) and others had not taken clopidogrel (n = 369) (55c ). Chest tube fluid drainage was significantly higher during the first 24 hours after bypass in those who had taken clopidogrel (1485 versus 780 ml). These patients also required more transfusion of platelets and fresh frozen plasma. The re-exploration rate because of bleeding was significantly higher in those who had taken clopidogrel (5.9% versus 1.2%). Drug interactions Some have suggested that the antiplatelet effects of clopidogrel are inhibited by atorvastatin. The Interaction of Atorvastatin and Clopidogrel Study included 75 patients undergoing coronary stenting (56c ). All took aspirin 325 mg/day for at least 1 week and clopidogrel 300 mg immediately before stent implantation. They had been taking atorvastatin (n = 25), any other statin (n = 25), or no statin (n = 25) for at least 30 days beforehand. At baseline, the patients in both statin groups had reduced platelet aggregation and reduced platelet expression of G-protein-coupled protease-activated thrombin receptor (PAR)-1. There were no significant differences in measured platelet characteristics among the study groups at 4 and 24 hours after clopidogrel, with the exception of lower collagen-induced aggregation at 24 hours and a constantly reduced expression of PAR-1 in patients taking any statin. The authors concluded that statins in general, and atorvastatin in particular, do not affect the ability of clopidogrel to inhibit platelet function in patients undergoing coronary stenting. These prospective data also suggest that statins
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may inhibit platelets directly via yet unknown mechanisms, possibly related to the regulation of PAR-1 thrombin receptors. Liver Cholestatic clopidogrel-induced liver disease has been reported before, but hepatocellular injury has not. • A 59-year-old man with acute coronary syndrome was given aspirin, clopidogrel, enoxaparin, transdermal nitrates, omeprazole, carvedilol, and captopril (57A ). Four days later his alanine transaminase activity rose to 318 U/l (5–41). Drug-induced liver disease was suspected, and clopidogrel, omeprazole, carvedilol, and captopril were withdrawn and 11 days later the transaminase activity returned to normal. Clopidogrel was reintroduced because of imminent coronary angiography and 4 days later the alanine transaminase activity rose again to 119 UI/l. Clopidogrel was again withdrawn, and the transaminases returned to normal after 7 days. Bilirubin and alkaline phosphatase were normal throughout.
Hematologic Acquired hemophilia A has been attributed to clopidogrel. • Two women aged 70 and 67 years developed excessive bruising and soft tissue bleeding 2– 3 months after starting clopidogrel therapy for peripheral vascular disease (58A ). Their drug therapy had not changed recently. Both had acquired hemophilia A. They had no clinical symptoms or signs of malignancy, antiphospholipid syndrome, or collagen vascular disease. Both were given prednisolone and the inhibitor became undetectable within 8 weeks.
A possible link between autoimmune acquired hemophilia and clopidogrel has not been previously reported.
Dipyridamole (SED-15, 1140; SEDA-26, 380; SEDA-28, 397) Nervous system Dipyridamole, used together with aspirin, has been evaluated in secondary prevention after ischemic stroke in several studies and in a large number of patients. The largest study, the Second European Stroke Prevention Study (59C ), showed that a combination of aspirin and modified-release dipyridamole reduced the risk of stroke or death by 24% (significantly more than the 13% observed with aspirin alone). However, one problem was that
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patients using dipyridamole alone or a combination of dipyridamole and aspirin discontinued treatment because of headache significantly more often than patients taking placebo. More than one-third of the patients who used dipyridamole reported headache as an adverse effect. The headache mostly occurred early, during the initial phase of dipyridamole treatment, and was a reason for early withdrawal. The mechanisms of headache associated with dipyridamole are unknown, although it is a vasodilator and there are similarities with vascular headaches in migraine or in patients who use nitrates. Several different regimens have been suggested to lower the prevalence of headache associated with dipyridamole, for example concurrent treatment with analgesics and an initial titration phase with a low daily dose of dipyridamole (60C ). In healthy individuals, headache is more common during the first days of treatment with dipyridamole and then declines in frequency (61C ). This supports the use of dose titration during the initial period of treatment as a means of reducing the frequency of headache, and could lead to increased adherence to treatment. Drug interactions Cytosine arabinoside is eliminated by deoxycytidine monophosphate deaminase and cytidine deaminase. Severe hepatic failure has been previously reported after the use of cytosine arabinoside but the mechanism is not clear. In reporting the case of a middle-aged man who developed multi-organ failure when treated with cytosine arabinoside and dipyridamole concurrently, the authors suggested that liver toxicity had been caused by inhibition of the extracellular transport of cytosine arabinoside by dipyridamole, thereby increasing retention of cytosine arabinoside in hepatocytes (62A ).
Eptifibatide
(SEDA-28, 398)
Hematologic The risk of hemorrhagic complications after the use of eptifibatide in patients undergoing rescue angiography with or without stenting after failed thrombolysis has been studied in 43 consecutive patients (63c ). There were bleeding complications in 13 patients; four had major bleeding. The predictors of major bleed-
David M. Keeling
ing complications were older age, female sex, lower baseline platelet count, and time to administration of eptifibatide after failed thrombolysis. In one patient thrombocytopenia occurred 2 hours after eptifibatide and resolved within 12 hours (64A ). Susceptibility factors Renal disease The pharmacokinetics of eptifibatide during steady-state infusion have been evaluated in an open study in 31 patients with mild, moderate, or severe renal impairment (65C ). There was a strong correlation between eptifibatide clearance and creatinine clearance, and the break point for the purpose of dosage adjustment was a creatinine clearance of 56 ml/minute. In patients with moderate or severe renal impairment, clearance rates and steady-state concentrations of eptifibatide were respectively about 50% lower and almost twofold higher than in patients with normal renal function or mild renal impairment. Inhibition of platelet aggregation exceeded the clinically significant threshold of 80% in all the groups. Five subjects had a mild bleeding event and four had mild to moderate non-bleeding events; none of the events required intervention. The authors concluded that in patients with renal impairment infusion doses should be adjusted accordingly, but that bolus doses need no adjustment.
Ticlopidine
(SED-15, 3424)
Liver There have been three reports of ticlopidine-induced cholestasis (66A –68A ), in one case associated with pure red cell aplasia (68A ).
Tirofiban Tirofiban is a synthetic, non-peptide inhibitor of platelet glycoprotein IIb/IIIa receptors. It has a rapid onset and short duration of action after intravenous administration, and aggregation returns to normal 4–8 hours after it withdrawn. Respiratory Fatal diffuse alveolar hemorrhage has been reported after the use of tirofiban
Drugs affecting blood coagulation, fibrinolysis, and hemostasis
in a patient with acute coronary syndrome (69A ).
Chapter 35
HEMOSTATIC AGENTS Aprotinin
Hematologic Tirofiban less commonly causes thrombocytopenia than other glycoprotein IIb/ IIIa inhibitors. In the Do Tirofiban and Reopro Give Similar Efficacy Outcomes (TARGET) study, the frequencies of thrombocytopenia (nadir platelet count under 100 × 109 /l) were 2.4% with abciximab and 0.5% with tirofiban (70C ). Acute profound thrombocytopenia occurred on two occasions in the same patient (71A ).
367
(SED-15, 331)
A systematic review of 45 papers that addressed the use of aprotinin in cardiac surgery identified 10 that presented the best evidence to answer the clinical question of whether its use affects graft patency (72M ). The reviewers concluded that aprotinin clearly reduces blood loss, requirements for blood transfusion, and the risk of reoperation for bleeding, but increases the risk of saphenous vein graft occlusion (OR = 1.52; CI = 1.13, 2.03).
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9. Valdivielso M, Longo I, Lecona M, Lazaro P. Cutaneous necrosis induced by acenocoumarol. J Eur Acad Dermatol Venereol 2004;18(2):211– 5. 10. Warkentin TE, Whitlock RP, Teoh KH. Warfarinassociated multiple digital necrosis complicating heparin-induced thrombocytopenia and Raynaud’s phenomenon after aortic valve replacement for adenocarcinoma-associated thrombotic endocarditis. Am J Hematol 2004;75(1):56–62. 11. Visser LE, van Vliet M, van Schaik RH, Kasbergen AA, De Smet PA, Vulto AG, Hofman A, van Duijn CM, Stricker BH. The risk of overanticoagulation in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon. Pharmacogenetics 2004;14(1):27–33. 12. Visser LE, Bleumink GS, Trienekens PH, Vulto AG, Hofman A, Stricker BH. The risk of overanticoagulation in patients with heart failure on coumarin anticoagulants. Br J Haematol 2004;127(1):85–9. 13. Bachmann HU, Hoffmann A. Interaction of food supplement L-carnitine with oral anticoagulant acenocoumarol. Swiss Med Wkly 2004;134(25– 26):385. 14. Lacey CS. Interaction of dicloxacillin with warfarin. Ann Pharmacother 2004;38:898. 15. Mailloux AT, Gidal BE, Sorkness CA. Potential interaction between warfarin and dicloxacillin. Ann Pharmacother 1996;30(12):1402–7. 16. Cropp JS, Bussey HI. A review of enzyme induction of warfarin metabolism with recommendations for patient management. Pharmacotherapy 1997;17(5):917–28. 17. Yuan CS, Wei G, Dey L, Karrison T, Nahlik L, Maleckar S, Kasza K, Ang-Lee M, Moss J.
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in cases of delayed-type allergy to heparins and semisynthetic heparinoids? A study of 7 cases. Contact Dermatitis 2004;51(2):67–72. Dempfle CE. Minor transplacental passage of fondaparinux in vivo. N Engl J Med 2004;350(18):1914–5. Eichler P, Lubenow N, Strobel U, Greinacher A. Antibodies against lepirudin are polyspecific and recognize epitopes on bivalirudin. Blood 2004;103(2):613–6. Badger NO, Butler K, Hallman LC. Excessive anticoagulation and anaphylactic reaction after rechallenge with lepirudin in a patient with heparin-induced thrombocytopenia. Pharmacotherapy 2004;24(12):1800–3. Sarich TC, Johansson S, Schutzer KM, Wall U, Kessler E, Teng R, Eriksson UG. The pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor, are unaffected by a single dose of alcohol. J Clin Pharmacol 2004;44(4):388–93. Sarich TC, Schutzer KM, Dorani H, Wall U, Kalies I, Ohlsson L, Eriksson UG. No pharmacokinetic or pharmacodynamic interaction between atorvastatin and the oral direct thrombin inhibitor ximelagatran. J Clin Pharmacol 2004;44(8):928–34. Sarich TC, Schutzer KM, Wollbratt M, Wall U, Kessler E, Eriksson UG. No pharmacokinetic or pharmacodynamic interaction between digoxin and the oral direct thrombin inhibitor ximelagatran in healthy volunteers. J Clin Pharmacol 2004;44(8):935–41. Shireman TI, Howard PA, Kresowik TF, Ellerbeck EF. Combined anticoagulant-antiplatelet use and major bleeding events in elderly atrial fibrillation patients. Stroke 2004;35(10):2362–7. Rebeiz AG, Adams J, Harrington RA. Interventional cardiovascular pharmacotherapy: current issues. Am J Cardiovasc Drugs 2005;5(2):93– 102. Eryonucu B, Tuncer M, Erkoc R. Repetitive profound thrombocytopenia after treatment with tirofiban: a case report. Cardiovasc Drugs Ther 2004;18(6):503–5. Aster RH, Curtis BR, Bougie DW. Thrombocytopenia resulting from sensitivity to GPIIb-IIIa inhibitors. Semin Thromb Hemost 2004;30(5):569–77. Nurden P, Clofent-Sanchez G, Jais C, Bermejo E, Leroux L, Coste P, Nurden AT. Delayed immunologic thrombocytopenia induced by abciximab. Thromb Haemost 2004;92(4):820–8. Curtis BR, Divgi A, Garritty M, Aster RH. Delayed thrombocytopenia after treatment with abciximab: a distinct clinical entity associated with the immune response to the drug. J Thromb Haemost 2004;2(6):985–92. Lown JA, Hughes AS, Cannell P. Prolonged profound abciximab associated immune thrombocytopenia complicated by transient multispecific platelet antibodies. Heart 2004;90(9):e55. Mendez TC, Diaz O, Enriquez L, Baz JA, Fernandez F, Goicolea J. Severe thrombocytopenia refractory to platelet transfusions, secondary
Drugs affecting blood coagulation, fibrinolysis, and hemostasis
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to abciximab readministration, in a patient previously diagnosed with idiopathic thrombocytopenic purpura. A possible etiopathogenic link. Rev Esp Cardiol 2004;57(8):789–91. Brouse SD, Wiesehan VG. Evaluation of bleeding complications associated with glycoprotein IIb/IIIa inhibitors. Ann Pharmacother 2004;38(11):1783–8. Kandzari DE, Hasselblad V, Tcheng JE, Stone GW, Califf RM, Kastrati A, Neumann FJ, Brener SJ, Montalescot G, Kong DF, Harrington RA. Improved clinical outcomes with abciximab therapy in acute myocardial infarction: a systematic overview of randomized clinical trials. Am Heart J 2004;147(3):457–62. de Queiroz Fernandes Araujo JO, Veloso HH, Braga De Paiva JM, Filho MW, Vincenzo De Paola AA. Efficacy and safety of abciximab on acute myocardial infarction treated with percutaneous coronary interventions: a meta-analysis of randomized, controlled trials. Am Heart J 2004;148(6):937–43. Lenderink T, Boersma E, Ruzyllo W, Widimsky P, Ohman EM, Armstrong PW, Wallentin L, Simoons ML, GUSTO IV-ACS Investigators. Bleeding events with abciximab in acute coronary syndromes without early revascularization: an analysis of GUSTO IV-ACS. Am Heart J 2004;147(5):865–73. Dery JP, Braden GA, Lincoff AM, Kereiakes DJ, Browne K, Little T, George BS, Sane DC, Cines DB, Effron MB, Mascelli MA, Langrall MA, Damaraju L, Barnathan ES, Tcheng JE, ReoPro Readministration Registry Investigators. Final results of the ReoPro readministration registry. Am J Cardiol 2004;93(8):979–84. Mazzucconi MG, Redi R, Bernasconi S, Bizzoni L, Dragoni F, Latagliata R, Santoro C, Mandelli F. A long-term study of young patients with essential thrombocythemia treated with anagrelide. Haematologica 2004;89(11):1306–13. Steurer M, Gastl G, Jedrzejczak WW, Pytlik R, Lin W, Schlogl E, Gisslinger H. Anagrelide for thrombocytosis in myeloproliferative disorders: a prospective study to assess efficacy and adverse event profile. Cancer 2004;101(10):2239–46. Birgegard G, Bjorkholm M, Kutti J, Larfars G, Lofvenberg E, Markevarn B, Merup M, Palmblad J, Mauritzson N, Westin J, Samuelsson J. Adverse effects and benefits of two years of anagrelide treatment for thrombocythemia in chronic myeloproliferative disorders. Haematologica 2004;89(5):520–7. Swords R, Fay M, O’Donnell R, Murphy PT. Anagrelide-induced visual hallucinations in a patient with essential thrombocythemia. Eur J Haematol 2004;73(3):223–4. Penninga E, Jensen BA, Hansen PB, Clausen NT, Mourits-Andersen T, Nielsen OJ, Hasselbalch HC. Anagrelide treatment in 52 patients with chronic myeloproliferative diseases. Clin Lab Haematol 2004;26(5):335–40. Englberger L, Faeh B, Berdat PA, Eberli F, Meier B, Carrel T. Impact of clopidogrel in coro-
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nary artery bypass grafting. Eur J Cardiothorac Surg 2004;26(1):96–101. Serebruany VL, Midei MG, Malinin AI, Oshrine BR, Lowry DR, Sane DC, Tanguay JF, Steinhubl SR, Berger PB, O’Connor CM, Hennekens CH. Absence of interaction between atorvastatin or other statins and clopidogrel: results from the interaction study. Arch Intern Med 2004;164(18):2051–7. Beltran-Robles M, Marquez Saavedra E, Sanchez-Munoz D, Romero-Gomez M. Hepatotoxicity induced by clopidogrel. J Hepatol 2004;40(3):560–2. Haj M, Dasani H, Kundu S, Mohite U, Collins PW. Acquired haemophilia A may be associated with clopidogrel. BMJ 2004;329(7461):323. Diener HC, Cunha L, Forbes C, European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996;143:1–13. Lindgren A. Management of vasodilation headache with dipyridamole. In: Wahlgren NG, editor. Update on Stroke Therapy 2000/2001. Stockholm: Karolinska Stroke Update; 2001. pp. 261–70. Theis JGW, Deichsel G, Marshall S. Rapid development of tolerance to dipyridamole-associated headaches. Br J Clin Pharmacol 1999;48:750–5. Babaoglu MO, Karadag O, Saikawa Y, Altundag K, Elkiran T, Yasar U, Bozkurt A. Hepatotoxicity due to a possible interaction between cytosine arabinoside and dipyridamole: a case report. Eur J Clin Pharmacol 2004;60(6):455–6. Ali A, Rehan A, Ganji J, Munir A, Moser L, Davis T, Khan S, Lalonde T, Schreiber T. Eptifibatide and risk of bleeding after failed thrombolysis. J Invasive Cardiol 2004;16(1):20–2. Gupta N, Kapoor R, Bhandari S. Eptifibatideinduced profound thrombocytopenia. Indian Heart J 2004;56(3):250–1. Gretler DD, Guerciolini R, Williams PJ. Pharmacokinetic and pharmacodynamic properties of eptifibatide in subjects with normal or impaired renal function. Clin Ther 2004;26(3):390–8. Gandolfi A, Mengoli M, Rota E, Tolomelli S, Zanghieri G, Bernini MV, Lusetti L. Epatite acuta colestatica da ticlopidina (Ticlopidineinduced acute cholestatic hepatitis. A case report). Recenti Prog Med 2004;95(2):96–9. Leone N, Giordanino C, Baronio MB, Morgando A, David E, Rizzetto M. Ticlopidineinduced cholestatic hepatitis successfully treated with corticosteroids: a case report. Hepatol Res 2004;28:109–12. Yamamoto N, Shiraki K, Saitou Y, Kawakita T, Okano H, Sugimoto K, Murata K, Nakano T. Ticlopidine induced acute cholestatic hepatitis complicated with pure red cell aplasia. J Clin Gastroenterol 2004;38(1):84. Yilmaz MB, Akin Y, Biyikoglu SF, Guray U, Korkmaz S. Diffuse alveolar hemorrhage following administration of tirofiban in a patient with acute coronary syndrome: a fatal complication. Int J Cardiol 2004;93(1):81–2.
370 70. Merlini PA, Rossi M, Menozzi A, Buratti S, Brennan DM, Moliterno DJ, Topol EJ, Ardissino D. Thrombocytopenia caused by abciximab or tirofiban and its association with clinical outcome in patients undergoing coronary stenting. Circulation 2004;109(18):2203–6. 71. Eryonucu B, Tuncer M, Erkoc R. Repetitive profound thrombocytopenia after treatment with tirofiban: a case report. Cardiovasc Drugs Ther 2004;18(6):503–5.
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72. Kalkat M, Levine A, Dunning J. Does use of aprotinin in coronary artery bypass graft surgery affect graft patency? Interactive Cardiovasc Thorac Surg 2004;3:124–8.
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36
Gastrointestinal drugs
ANTIEMETICS AND DRUGS THAT AFFECT GASTROINTESTINAL MOTILITY Alverine citrate Liver A 34-year-old woman developed hepatotoxicity within 1 month of starting to take alverine citrate 60 mg tds (1A ). This is only the second recorded case of this complication.
Cisapride (SED-15, 789; SEDA-26, 382; SEDA-27, 362; SEDA-28, 401) Comparative studies Cisapride 10 mg tds and levosulpiride 25 mg tds have been compared in a single-blind, randomized, controlled trial for 8 weeks in 140 patients aged 18–65 years with functional dyspepsia meeting the Rome I criteria (2C ). Levosulpiride improves symptoms of dyspepsia and anxiety by 80%, cisapride by 71%. This difference was not statistically significant. There were adverse events in 29 of 69 patients treated with levosulpiride and 29 of 71 patients treated with cisapride. These were amenorrhea, galactorrhea, breast tension, diarrhea, abdominal pain, somnolence, and headache with levosulpiride and diarrhea, abdominal pain, allergy, nervousness, and tachycardia with cisapride. There were no serious adverse events. Significantly more patients taking cisapride (n = 10) dropped out of the trial, because of abdominal pain (n = 3), anxiety (n = 2), tachycardia (n = 1), abdominal bloating (n = 1), headache (n = 1), dizziness (n = 1), or insomnia (n = 1). Three patients taking levosulpiride dropped out, because of abdominal pain, dizziness, and galactorrhea. Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29036-6 © 2007 Published by Elsevier B.V.
Placebo-controlled studies In a double-blind, randomized study in 82 patients with constipation-predominant irritable bowel syndrome patients were given either oral cisapride 5 mg or placebo tds for 12 weeks (3C ). In patients with suboptimal improvement the dose was doubled. Cisapride had the same effect on symptoms as placebo. In the cisapride group one patient had abdominal pain and in one treatment had to be stopped because of severe diarrhea. In the placebo group three patients had abdominal pain. No dysrhythmias were reported. The authors explained the high placebo response rate (70%) as being due to patients’ having received more psychosocial support during a clinical trial. Susceptibility factors Age In 15 children with cerebral palsy (aged 0.22–12 years) with gastroesophageal reflux cisapride 2 mg/kg/day for 3 months improved appetite in six and dysphagia resolved in eight (4c ). There were no adverse events. Electrocardiography in 175 children aged 1.5 months to 17 years showed no changes in QTc interval after 15 days of treatment with cisapride 0.2 mg/kg tds or qds (5c ).
Metoclopramide
(SED-15, 2317; SEDA-27, 362; SEDA-28, 401) Urinary tract A 28-year-old man developed green urine after intravenous administration of metoclopramide 10 mg (6A ). Drug interactions A 52-year-old woman developed tacrolimus toxicity when she was given metoclopramide 20 mg qds; the proposed mechanism was improved gastric motility and delivery of tacrolimus to the small intestine, thus increasing the absorption of tacrolimus (7A ).
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5-HT3 RECEPTOR ANTAGONISTS (SED-15, 1365; SEDA-26, 382; SEDA-27, 363; SEDA-28, 402) Combining a 5HT3 receptor antagonist with either droperidol or dexamethasone is more effective in treating nausea and vomiting than a 5HT3 receptor antagonist alone (8R ). Adverse effects reported were dizziness, headache, and drowsiness. The incidence was similar in the patients treated with the combination and those treated with the 5HT3 receptor antagonist alone.
Alosetron Gastrointestinal Constipation is the most important adverse effect of alosetron; it is dosedependent and more frequent in women and those with an alternating bowel habit (9R ). The long-term safety and efficacy of alosetron 1 mg bd in women with severe, chronic, diarrhea-predominant irritable bowel syndrome has been assessed in a double-blind, randomized, placebo-controlled trial in 714 patients. Alosetron caused constipation in 79/348 patients and withdrawal from the study in 39 (10C ). A meta-analysis of six high-quality clinical trials involving alosetron has confirmed that constipation is common at a dose of 1 mg bd (NNTH = 3.9) (11M ). In these six trials the prevalence of ischemic colitis was 0.1%. Possible causative co-factors in the development of ischemic colitis may have been an infectious gastrointestinal disorder in one patient and protein C deficiency in another. Alosetron is well-known to cause ischemic colitis, and a case has also been reported with the experimental compound cilansetron (12R ). This suggests that this adverse effect may be a class effect of 5HT3 receptor antagonists. Drug interactions The pharmacokinetics and pharmacodynamic markers of efficacy of a lowdose combination oral contraceptive are not altered by alosetron, according to a study in 18 healthy women (13c ). Biochemical markers of thrombosis risk were not altered by alosetron.
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Granisetron Granisetron and ondansetron were equally effective with a similar adverse effects profile in a randomized trial in 96 patients given either ondansetron 0.15 mg/kg every 8 hours or granisetron 10 micrograms/kg/day (14C ). All the patients were undergoing conditioning for hemopoietic stem cell transplantation and also received dexamethasone and lorazepam. Drug dosage regimens In a randomized placebo-controlled study in 100 patients undergoing laparoscopic cholecystectomy granisetron 10 micrograms/kg was equivalent to placebo but significantly more effective at 20 micrograms/kg (15C ). There was no increase in efficacy at doses of 40 or 80 micrograms/kg. Minor adverse effects were headache, dizziness, and constipation, with similar incidences in all groups. Granisetron 20 micrograms/kg was effective in a double-blind, randomized, placebocontrolled dose-ranging study in 100 patients with nausea and vomiting after abdominal hysterectomy; 20 patients in each group were given placebo or granisetron 10, 20, 40, or 100 micrograms/kg (16C ). Granisetron 1 mg and ondansetron 4 mg, given intravenously before induction of anesthesia, were effective in preventing nausea and vomiting after modified radical mastectomy in a randomized placebo-controlled trial in 60 patients (17C ). The incidence of postoperative nausea and vomiting was 25% with ondansetron, 20% with granisetron, and 70% with placebo. Adverse events were headache, dizziness, anxiety, and insomnia; these were mild and similar in all the groups.
Ondansetron Ondansetron 8 mg was more effective than metoclopramide 20 mg in a randomized trial in 80 chemotherapy-naïve patients with cancers (18C ). The patients were randomized to receive either a single dose of cisplatin 60 mg/m2 intravenously (high-dose regimen) or 20 mg/m2 once daily for 3 days (low-dose regimen), and were then randomized to either ondansetron or metoclopramide, given intravenously 30
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minutes before cisplatin and then orally every 8 hours for 5 days; 10 patients in both groups who also received high-dose cisplatin were also given dexamethasone 8 mg intravenously. In patients given the low-dose cisplatin regimen ondansetron suppressed delayed vomiting in 55% of patients and metoclopramide in 30%. In patients given the high-dose regimen vomiting was not completely suppressed in any patient by ondansetron or metoclopramide. The combination of metoclopramide and dexamethasone was as effective as ondansetron monotherapy. Ondansetron was more effective in preventing delayed nausea. Adverse effects may have been due to the chemotherapy as well as the antiemetic. Seven patients had constipation with ondansetron. None reported extrapyramidal effects with metoclopramide.
Infection risk In 102 patients, intragastric pH was reduced and the rate of positive bacterial culture from the gastric aspirate increased in patients taking a proton pump inhibitor; 52 patients were not taking any treatment (group I), 26 were taking an H2 receptor antagonist (group II), and 24 were taking a proton pump inhibitor (group III) (21C ). The mean intragastric pH was 2.91, 4.12, and 5.11 in groups I, II, and III respectively. The positive bacterial culture rates were 29%, 46%, and 67%. The results were significant only between groups I and II. There were no significant differences in the rates of candidal infection (17%, 12%, and 13% respectively).
Esomeprazole
(SED-15, 1252;
SEDA-28, 403)
HISTAMINE H2 RECEPTOR ANTAGONISTS (SED-15, 1629; SEDA-26, 384; SEDA-27, 363; SEDA-28, 403)
Ranitidine
(SED-15, 3022; SEDA-28,
403) Infection risk Ranitidine-induced hypochlorhydria may have resulted in concomitant Clostridium difficile and Giardia lamblia infections in a 49-year-old man (19A ). He had a history of alcohol and cocaine abuse, which may have contributed.
PROTON PUMP INHIBITORS (SED-15, 2973; SEDA-26, 384; SEDA-27, 364; SEDA-28, 403) Observational studies In 676 elderly patients taking aspirin or non-steroidal antiinflammatory drugs and 2435 non-users, concomitant prescription of a proton pump inhibitor was associated with a reduced risk of peptic ulcer in both short-term and longterm users of aspirin or non-steroidal antiinflammatory drugs (20c ). The NNTB to avoid one peptic ulcer in the elderly was 3 in both groups.
Comparative studies Esomeprazole 40 mg/ day maintained intragastric pH above 4 for longer during a 24-hour period than lansoprazole 30 mg/day, omeprazole 20 mg/day, pantoprazole 40 mg/day, and rabeprazole 20 mg/day in 141 patients in four separate crossover studies comparing esomeprazole with lansoprazole (22C ). Esomeprazole 20 mg/day was more effective at maintaining gastric pH below 4 compared with lansoprazole 15 mg/day, rabeprazole 10 mg/day, and pantoprazole 20 mg/day in a study sponsored by a drug company (23C ). The study was a comparison of three standardized, randomized, two-way crossover studies in 108 healthy subjects who were negative for Helicobacter pylori. The proportions of acid suppression in the 24 hours on day 5 of therapy were: esomeprazole 50% versus lansoprazole 43%, esomeprazole 60% versus rabeprazole 52%, esomeprazole 60% versus pantoprazole 40%. In three multicenter, double-blind, randomized, controlled, 4-week acute treatment studies in endoscopy-negative patients with esophageal reflux there was no difference in efficacy between esomeprazole 40 mg/day, esomeprazole 20 mg/day, or omeprazole 20 mg/day (24c ). The proportion of patients in each treatment arm who had resolution of heartburn during the last 7 days, was 57% for esomeprazole 40 mg/day, 61% for esomeprazole 20 mg/day, and 58% for omeprazole 20 mg/day.
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Esomeprazole may be more effective as part of triple therapy (combined with amoxicillin 1 g/day and clarithromycin 500 mg bd) for eradication of Helicobacter pylori in a dose of 40 mg bd, compared with 40 mg/day and omeprazole 20 mg bd (25C ). Eradication rates were 50/52, 42/52, and 37/52 respectively. Minor adverse effects were more common with esomeprazole 40 mg bd compared with 40 mg od. Headache, diarrhea, abdominal pain, flatulence, and nausea occurred in 24/52 patients who took the high dose, compared with 9/52 in the low-dose group. One patient in the highdose group stopped treatment because of abdominal pain. Immunologic There have been few studies of allergic reactions to proton pump inhibitors and only two previous studies have shown crossreactivity in the proton pump inhibitor family by skin prick testing. • IgE-mediated pruritus and urticaria developed in a 24-year-old woman after she took an omeprazole capsule (26A ). She underwent skin prick testing and had positive results with omeprazole, pantoprazole, and lansoprazole.
S. Dar and H.R. Dalton
Drug dosage regimens Rabeprazole 10 mg/ day on demand was effective in the treatment of non-erosive reflux disease in a multicenter, double-blind, randomized, placebo controlled withdrawal study, in which 535 patients were treated for 1 month with rabeprazole 10 mg/day following negative endoscopy and at least 3 days of moderate to severe heartburn symptoms in the week before enrolment (29C ). During the on-demand period of 6 months, 20% (28/139) of those given placebo withdrew because of inadequate symptom relief, while 6% (16/279) withdrew in the rabeprazole group. Drug interactions A detailed review of the pharmacokinetics and pharmacodynamics of rabeprazole has highlighted the fact that its clearance depends less on CYP2C19 than other proton pump inhibitors; it rather undergoes non-enzymatic metabolism with renal excretion. Its metabolism is therefore less affected by polymorphisms of CYP2C19 and there are therefore fewer drug–drug interactions with drugs that are affected by CYP2C19, such as mephenytoin, diazepam, and certain antidepressants (30R ).
Drug interactions In two cases omeprazole caused impaired absorption of oral iron (27A ). • A 51-year-old woman who took omeprazole 20 mg had impaired absorption of oral iron sulfate, demonstrated by an iron absorption test. • An 83-year-old woman continued to have iron deficiency anemia while taking omeprazole, despite taking oral iron for 6 months.
In both cases withdrawal of the proton pump inhibitor resulted in an adequate response to oral iron therapy. A low gastric pH is required to form soluble bivalent ferrous iron for absorption in the small bowel. Hypochlorhydria induced by proton pump inhibitors may therefore impair absorption of iron.
Rabeprazole
(SED-15, 3011; SEDA-28,
ANTIDIARRHEAL AGENTS (SEDA-27, 367; SEDA-28, 406)
Loperamide
(SED-15, 2159; SEDA-28,
406) Nervous system Loperamide is a synthetic opioid and rarely causes neurological adverse effects. A 26-month-old infant developed impaired consciousness due to loperamide and was successfully treated with naloxone (31A ).
LAXATIVES AND ORAL BOWEL PREPARATIONS (SED-15, 2008;
404)
SEDA-26, 387; SEDA-27, 367; SEDA-28, 406)
Rabeprazole 10 mg produces greater acid suppression than omeprazole 10 mg (28C ). The time for which gastric pH was above 4 was 5.8 versus 3.7 hours respectively on day 1 and 10.5 versus 4.6 hours on day 7.
Lactulose and lactitol Lactulose and lactitol, both non-absorbable disaccharides, have been reviewed in a systematic review of randomized control trials of the
Gastrointestinal drugs
treatment of hepatic failure (32M ). There was insufficient evidence to prove that they are beneficial. Adverse effects, such as diarrhea, flatulence, abdominal pain, and nausea, were all related to the gastrointestinal system and were mild. Gastrointestinal Megacolon has been attributed to lactulose in two women aged 88 and 82 years (33A ). In a double-blind, parallel-group, randomized, controlled trial in 16 healthy volunteers, lactulose 10 g/day increased fecal counts of bifidobacteria, which has previously been studied in the context of colon cancer (34c ). There was mild excess flatulence. The authors suggested that lactulose may be considered as a prebiotic.
Mannitol
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(SED-15, 2003)
For patients undergoing magnetic resonance imaging of the small bowel, optimal small bowel distension and tolerability in 10 healthy volunteers were achieved by 1000 ml of mannitol 2.5% in combination with locust bean gum 0.2% (35c ).
Polyethylene glycol
(SED-15, 1516)
The adverse effects of bowel cleansing with polyethylene glycol–electrolyte solution are disagreeable taste, hypothermia, volume-related symptoms (fullness, nausea, bloating), aspiration, reactivation of bleeding, perforation, lavage-induced drug malabsorption, and allergic reactions (36R ). Comparative studies Transipeg® (polyethylene glycol 3350) has been evaluated as a treatment for constipation in 100 children (37C ) aged 6 months to 15 years in a double-blind, randomized, controlled trial. All underwent fecal disimpaction followed by either lactulose or Transipeg. Those aged under 6 years were given 1 sachet/day (Transipeg 2.95 g/sachet, lactulose 6 g/sachet) and those over 6 years were started on 2 sachets/day of either treatment. The maximum dose of Transipeg was 8.85 g/day. Transipeg was more effective at re-
lieving constipation. There were no serious adverse events. Abdominal pain, pain on defecation, and straining occurred significantly more often with lactulose. Bloating, diarrhea, nausea, hard stool consistency, and vomiting were reported more often by those taking lactulose, but the difference was not statistically significant. Transipeg was significantly less palatable; of nine patients who did not complete the study, one withdrew because of the taste of Transipeg.
Phosphates
(SED-15, 2820)
Oral sodium phosphate as a colorectal cleanser (in two 45 ml doses given 10–12 hours apart) has been well tolerated in large randomized trials (38R ). When adults with major co-morbidities were excluded there were no major adverse events. Adverse events were abdominal pain/cramping (19–36%), abdominal fullness and/or bloating (7–46%), nausea (14–66%), vomiting (2–18%), anal and perianal irritation and soreness (4–66%), hunger pains (8–30%), dizziness (1–27%), weakness (8%), fatigue (8%), thirst (17–20%), chest pain (incidence not stated), chills (5–43%), headache (31%), and loss of sleep (13–39%). This profile was similar in children and adults. In the elderly fecal incontinence was also reported (23–55%). The overall tolerability profile was similar to that of polyethylene glycol-based regimens. Some adverse effects occurred significantly less often with sodium phosphate, such as abdominal fullness or bloating, abdominal cramps, abdominal pain, weakness, fatigue, flatulence, sleep disturbance, and dizziness. Sodium phosphate was preferred to a 4 liter volume of polyethylene glycol in terms of ease of completion, acceptability, and willingness to repeat the bowel cleansing regimen. In most studies sodium phosphate was preferred to other cleansing agents (39c ). Comparative studies In a randomized trial in 299 patients, 2 sachets of a sodium phosphate solution achieved better bowel preparation than polyethylene glycol solution and was more acceptable to patients (40C ). Bowel preparation was not as effective when only 1 sachet of sodium phosphate was used. There were no significant differences in nausea, vomiting, abdominal pain, or bloating. Patients given two
376 doses of sodium phosphate had more dizziness and anal irritation. In a randomized trial in 256 patients a threedose regimen of sodium phosphate 45 ml produced better bowel cleansing than a two-dose regimen but was not so well tolerated (41C ).
Abnormalities of electrolyte, mineral, metal, and fluid balance due to polyethylene glycol Electrolytes, minerals, and metals Severe electrolyte disturbances, including hyperphosphatemia, hypernatremia, hypokalemia, hypocalcemia, and hypomagnesemia, have been reported after the administration of sodium phosphate solution and there have been some deaths. In these cases there was evidence that sodium phosphate should have been used with caution or was in fact contraindicated. It should not be used in patients with megacolon, bowel obstruction, ascites, congestive cardiac failure, or kidney disease. In the USA it is contraindicated in children under 5 years of age. It should be used with caution in patients with impaired renal function, heart disease, acute myocardial infarction, unstable angina, and pre-existing electrolyte disturbances, and in debilitated or elderly patients. In at-risk patients who take more than 45 ml in 24 hours, electrolytes should be checked before and after bowel preparation. Serious electrolyte disturbance can occur in patients who exceed the recommended dose and in those taking diuretics. • A 79-year-old woman developed severe hyperphosphatemia, hypocalcemia, and cardiac arrest after the administration of two doses of Soffadex 45 ml (each 5 ml contains monobasic sodium phosphate 2.4 g and dibasic sodium phosphate 0.9 g) (42A ). She was also given Fleet enema twice (each enema contains monobasic sodium phosphate 16 g and dibasic sodium phosphate 6 g). She took the same regimen on the following day because of inadequate bowel cleansing. She became hypotensive and tachycardic and had a cardiac arrest. She was successfully resuscitated, underwent hemofiltration, and recovered.
The authors suspected that this patient had developed severe electrolyte abnormalities because she had chronic renal insufficiency, received a high dose of sodium phosphate, and
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S. Dar and H.R. Dalton
had sluggish intestinal motility. They suggested that patients at risk of hyperphosphatemia from sodium phosphate should undergo bowel cleansing with polyethylene glycol instead. Other factors that may predispose to hyperphosphatemia are intestinal obstruction, reduced intestinal motility, increased intestinal permeability, congestive cardiac failure, and liver cirrhosis. They also suggested that serum phosphate concentrations should be checked at baseline and after the first dose of sodium phosphate. In a randomized controlled trial in 171 patients a combination of one dose of oral sodium phosphate 45 ml, four bisacodyl tablets 5 mg, and one bisacodyl enema 10 mg was better tolerated than 4 liters of PEG solution and as safe (43C ). The cleansing ability was the same and 84% found the sodium phosphate and bisacodyl combination easy to take compared with 33% who used PEG. However, there was hyperphosphatemia in 16% of those who used the combination; all had normal ionized calcium concentrations. Of 15 000 patients who received sodium phosphate over 10 years only four had adverse effects (44AR ). • A 49-year-old man developed paresthesia over the entire face and extremities after two doses of sodium phosphate 45 ml 6 hours apart. Serum calcium was 1.9 mmol/l (reference range 2.15– 2.5 mmol/l). Serum phosphate was mildly raised and magnesium and potassium were reduced. He was successfully treated with calcium gluconate and magnesium intravenously. • A 69-year-old woman with an extensive past history, including ischemic heart disease, congestive cardiac failure, and moderate aortic insufficiency, was given two doses of sodium phosphate 45 ml on 2 days. She had perioral and limb extremity paresthesia and carpal spasm. Serum calcium was 1.62 mmol/l and potassium 2.3 mmol/l (reference range 3.5–5.2 mmol/l). The QTc interval was prolonged to 522 ms from 458 ms. She was successfully treated with intravenous calcium. • A 54-year-old man who required dialysis for renal insufficiency was given two doses of sodium phosphate 45 ml only 2 hours apart. He developed light-headedness and paresthesia and became hypotensive. An electrocardiogram showed a prolonged QTc interval at 604 ms compared with 404 ms before bowel preparation. Serum calcium was 1.27 mmol/l, phosphate 6.3 mmol/l (reference range 0.8–1.5 mmol/l) He was successfully treated by hemodialysis. • A 38-year-old man with suspected enteroenteric fistulae and renal impairment was given two doses of sodium phosphate 45 ml 4 hours apart and
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a sodium phosphate enema, and 12 hours after colonoscopy developed oliguria, carpal spasm, and inferolateral ST segment elevation. The QTc interval was prolonged from 459 to 590 ms. Myocardial infarction was confirmed and he had worse renal impairment, hyperphosphatemia, and hypocalcemia. He required a calcium infusion for 48 hours.
The authors recommended the following absolute contraindications to the use of sodium phosphate: renal insufficiency, an inability to maintain an adequate fluid intake, pre-existing electrolyte disturbances, ascites, symptomatic congestive heart failure, recent (<6 months) symptomatic ischemic heart disease (unstable angina or myocardial infarction), enteric fistulae, and bowel obstruction. Relative contraindications are extremes of age, active inflammatory bowel disease, parathyroidectomy, and delayed bowel transit. They recommended appropriate monitoring of electrolytes and renal function in patients aged over 50 years. Fluid balance Intravascular volume decreases during sodium phosphate bowel cleansing, and in some patients the systolic blood pressure falls by 10–20 mmHg. Renal insufficiency can occur. In one case a renal biopsy showed obstructive calcium-phosphate crystalluria followed by intratubular nephrocalcinosis (45A ). Oral carbohydrate–electrolyte rehydration reduces the degree of intravascular volume depletion (46C ). In a randomized study in 168 patients 43% of those given rehydration had a fall in blood pressure of at least 10 mmHg and/or a rise in heart rate of 10/minute, compared with 65% of those not given rehydration; the changes were not clinically significant and resolved at later endoscopy (47A , 48A ). Gastrointestinal Changes in colonic mucosa can occur after bowel preparation with sodium phosphate. At endoscopy lesions of 1–3 mm with a surrounding halo are seen. They are not friable, not ulcerated, and have preserved crypt architecture and normal background mucosa. A higher incidence of aphthous lesions have been reported with sodium phosphate than with polyethylene glycol or magnesium citrate. The changes do not appear to be clinically significant and resolve at later endoscopy. In a prospective study of 730 patients over 3 years (49C ) 24 (3.3%) had endoscopic lesions possibly due to bowel cleansing; erosions
(n = 3), aphthous lesions (n = 21), and ulceration (n = 1). Histology showed focal active inflammation (n = 14), mucosal disruption and erosion (n = 7), edema of the lamina propria (n = 5), mucosal hyperemia or focal hemorrhage (n = 5), lymphoid nodules (n = 5), and ulceration (n = 1).
Sodium picosulfate A retrospective study of the long-term use of sodium picosulfate in 35 women aged 29–64 years suggested that it may be safe and effective for chronic constipation (50c ). The patients’ medical records did not show any adverse effects. The treatment of chronic constipation with tablets of sodium phosphate has been studied in a randomized trial in 40 patients (51c ), of whom 18 took 4 tablets/day and 25 took 8 tablets/day for 28 days. The dose was adjusted on an individual basis to a minimum of 2 tablets and a maximum of 12 tablets according to the response after 48 hours. The response rate in the first group was 100% and in the second 96%. Four patients in the second group withdrew (one because of worsening migraine, nausea, and diarrhea, another because of nausea, another with abdominal pain, another with bloating and worsening reflux symptoms). Five patients had occasional hypokalemia that did not require treatment. Changes in other electrolytes were not significant. The authors commented that sodium picosulfate has only resulted in fatalities when given in a dose of more than 60 g over less than 12 hours for bowel cleansing. Picoprep3 (sodium picosulfate) has been compared with Fleet (sodium phosphate) in a single-blind, randomized study in 400 patients (52C ). Picoprep3 was better tolerated and tasted better. It caused less nausea, vomiting, dizziness, abdominal pain, and thirst. There was no difference in visualization of the colon.
AMINOSALICYLATES (SED-15, 138; SEDA-26, 387; SEDA-27, 367; SEDA-28, 408) The short-term adverse effects of mesalazine, olsalazine, and balsalazide in 46 randomized
378 trials have been reviewed (53R ). All three agents were deemed safe in the short term.
Mesalazine (5-aminosalicylic acid, mesalamine) (SEDA-28, 408) Respiratory A 36-year-old woman with ulcerative colitis developed pulmonary infiltrates (54A ). She had taken mesalazine 1000 mg bd orally for 2 months, after which time 500 mg tablets were added. She presented 10 months later with respiratory symptoms. There was clinical and radiological resolution on the chest within 2 weeks of withdrawal. Pancreas Three cases of acute pancreatitis due to mesalazine therapy have been reported (55A ). These patients were subsequently treated with rectal 4-aminosalicylic acid which differs from mesalazine (5-aminosalicylic acid) in the position of the NH2 group. No further episodes of acute pancreatitis occurred, and the authors concluded that 4-aminosalicylic acid could be tried in patients with previous suspected hypersensitivity to mesalazine. Mesalazine and sulfasalazine were not identified as causative agents in a retrospective population-based case-control study of 1590 patients with acute pancreatitis, of whom 21 had inflammatory bowel disease (56C ). Urinary tract In an epidemiological study of 19 025 mesalazine users with inflammatory bowel disease, interstitial nephritis or other renal disease was possibly due to mesalazine in 10 cases (five due to mesalazine, four in those taking sulfasalazine, and one taking balsalazide) (57C ). 130 patients developed renal disease (incidence 0.17 cases per 100 patients per year). The authors concluded that users of mesalazine have an increased risk of renal disease, which may be partly attributable to underlying disease. In an observational prospective study in 1529 patients with inflammatory bowel disease over 1 year, there was renal impairment in 2.2% (58C ). End-stage renal insufficiency occurred in 1.3/1000 patients. An association with mesalazine was only suspected in five patients. The authors recommended checking serum creatinine concentrations at the start of therapy
Chapter 36
S. Dar and H.R. Dalton
with mesalazine, 3-monthly for the first year, and then yearly. They recommended that patients with a stoma, those with a low body mass, and those with regular episodes of dehydration should be monitored more closely. Interstitial nephritis occurred in an 18 yearold-man taking mesalazine (59AR ). The authors identified 30 cases reported world wide in the last 10 years and reviewed 23 cases of biopsyproven nephritis published in English over the last 13 years. End-stage renal insufficiency occurred in three patients. Renal disease related to mesalazine may occur 1 in 100–500 patients. It is recommended that renal function be monitored twice a year. Drug formulations Micropellets of mesalazine have compared favorably with the tablet formulation in a phase II, double-blind, activecontrolled, parallel-group, multiple-dose study in 362 patients (60C ). The micropellets were as effective as the tablets. Adverse events occurred in 31% of patients who used the micropellets and 24% of those who used the tablets. They were mostly mild and were attributed to mesalazine. Serious adverse events occurred in nine patients, three taking micropellets and six taking tablets. These were attributed to the underlying disease rather than the medication. Subjective assessments of tolerability were ‘good’ or ‘very good’ in 91.6% and 92.1% according to those who used micropellets or tablets respectively. The authors suggested that patient adherence to therapy may be improved by micropellets, which are easier to swallow.
BILE ACIDS
(SED-15, 515; SEDA-26, 389; SEDA-27, 369; SEDA-28, 409) Comparative studies The combination of ursodeoxycholic acid and metronidazole improved serum alkaline phosphatase and New Mayo Risk Score, compared with ursodeoxycholic alone, in a randomized controlled trial in 80 patients (61C ). There were no statistically significant effects on disease progression (with respect to liver histology or findings at endoscopic retrograde cholangiopancreatography).
Gastrointestinal drugs
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Placebo-controlled studies In a randomized placebo-controlled trial in 166 patients with non-alcoholic steatohepatitis, ursodeoxycholic acid 13–15 mg/kg/day had no effect on liver histology; 126 patients completed 2 years of therapy (62C ). Gastrointestinal In a randomized controlled study in 19 patients with colorectal inflammatory bowel disease, ursodeoxycholic acid may have prevented the progression of low-grade dysplasia (63c ). Two of nine patients in the placebo group developed high grade dysplasia and a dysplasia-associated lesion or mass. None of the 10 patients who took ursodeoxycholic acid had progression of dysplasia.
PREBIOTICS Escherichia coli Nissle 1917 Escherichia coli Nissle 1917 was as effective as mesalazine in maintaining remission of ulcerative colitis in a randomized double-dummy trial in 327 patients (64C ). Relapse occurred in 40/110 patients treated with E. coli Nissle 1917 compared with 38/112 in those given mesalazine after 12 months. Safety and tolerability were equal.
VSL#3 VSL#3 3 g/day in combination with balsalazide 2.25 g/day was more effective than balsalazide 4.5 g/day alone or mesalazine 2.4 g/day in
the treatment of acute mild to moderate ulcerative colitis in a randomized trial in 90 patients (65c ). The combined therapy produced fewer adverse effects, although this was not statistically significant. One patient who took combination therapy had mild adverse effects (such as headache, epigastric pain, and fatigue), compared with three and four patients respectively among those who took balsalazide or mesalazine alone.
OTHER GASTROINTESTINAL AGENTS Hydrogen peroxide Respiratory A 66-year-old man had an oxygen embolism to the pulmonary circulation following injection of 3% hydrogen peroxide 60 ml into a bowel fistula; 10 ml of oxygen are generated by 1 ml of 3% hydrogen peroxide (66A ). The authors recommended caution in the use of hydrogen peroxide. Liver A 6-year-old boy drank a glass of 35% hydrogen peroxide and had an air embolism to the portal circulation (67A ). He was successfully treated using hyperbaric oxygen. The authors stated that a 60 ml volume can liberate 7 liters of oxygen when combined with stomach acid. The oxygen is forced into the portal circulation and can cause infarction of the liver or systemic embolization. The hydrogen peroxide had been procured as a health food additive, to aerate health food drinks at a recommended dose of one drop (which releases 115 ml of oxygen).
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381 43. Hookey LC, Depew WT, Vanner SJ. A prospective randomised trial comparing low-dose oral sodium phosphate plus stimulant laxatives with large volume polyethylene glycol solution for colon cleansing. Am J Gastroenterol 2004;99:2217–22. 44. Hookey LC, Vanner S. Recognising the clinical contraindications to the use of oral sodium phosphate for colon cleansing: a case study. Can J Gastroenterol 2004;18(7):455–8. 45. Desmules S, Bergeron MJ, Isenring P. Acute phosphate nephropathy and renal failure. N Engl J Med 2003;349(10):1006–7. 46. Barclay RL, Depew WT, Vanner SJ. Carbohydrate–electrolyte rehydration protects against intravascular volume contraction during colonic cleansing with orally administered sodium phosphate. Gastrointest Endosc 2002;56(5):633–8. 47. Watts DA, Lessells AM, Penman ID, Ghosh S. Endoscopic and histologic features of sodium phosphate bowel preparation-induced colonic ulceration: case report and review. Gastrointest Endosc 2002;55(4):584–7. 48. Berthelet O, Rolachon A, Papillon E, Fournet J. Lésions rectales induites par la préparation colique Fleet-Phospho-soda® . Gastroenterol Clin Biol 2001;25(4):437–9. 49. Rejchrt S, Bures J, Siroky M, Kopacova M, Slezak L, Langr F. A prospective, observational study of colonic mucosal abnormalities associated with orally administered sodium phosphate for colon cleansing before colonoscopy. Gastrointest Endoscopy 2004;59(6):651–4. 50. Benglsson M, Chisson B. Retrospective study of long-term treatment with sodium picosulphate. Eur J Gastroenterol Hepatol 2004;16:433–4. 51. Medoff J, Katz S, Malik P, Pambianco D, Pruitt R, Poulos J, Rank J, Rose M. Openlabel, dose-ranging pilot study of 4 weeks of low-dose therapy with sodium phosphate tablets in chronically constipated adults. Clin Ther 2004;26:1479–91. 52. Schmidt L-M, Williams P, King D, Perera D. Picoprep-3 is a superior colonoscopy preparation to Fleet: a randomised controlled trial comparing the two bowel preparations. Dis Colon Rectum 2004;47:238–42. 53. Raedler A, Behrens C, Bias P. Mesalazine (5aminosalicylic acid) micropellets show similar efficacy and tolerability to mesalazine tablets in patients with ulcerative colitis—results from a randomized-controlled trial. Aliment Pharmacol Ther 2004;20:1353–63. 54. Nanayakkara PWB, de Jong E, Postmus PE. Bilateral pulmonary infiltrates in a patient with ulcerative colitis receiving mesalazine. Eur J Intern Med 2004;15:470–2. 55. Daniel F, Sekisik P, Cacheux W, Jian R, Marteau P. Tolerance of 4-aminosalicylic acid enemas in patients with inflammatory bowel disease and 5-aminosalicylic-induced acute pancreatitis. Inflamm Bowel Dis 2004;10(3):258–60. 56. Munk EM, Pedersen L, Floyd A, Nørgard B, Rasmussen HH, Sørensen HT. Inflammatory bowel diseases, 5-aminosalicylic acid and sulfasalazine
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Burgart L, Colin P. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 2004;39:770– 8. Sjöqvist U, Tribukait B, Öst A, Einarsson C, Oxelmark L, Löfberg R. Ursodeoxycholic acid treatment in IBD-patients with colorectal dysplasia and/or DNA-aneuploidy: a prospective, double-blind, randomized controlled pilot study. Anticancer Res 2004;24:3121–8. Kruis W, Friˇc P, Pokorotnieks J, Lukáš M, Fixa B, Kašˇcák MA, Weismueller J, Beglinger C, Stolte M, Wolff C, Schulze J. Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine. Gut 2004;53:1617–23. Tursi A, Brandimarte G, Giorgetti GM, Forti G, Modeo ME, Gigliobianco A. Low-dose balsalazide plus a high-potency probiotic preparation is more effective than balsalazide alone or mesalazine in the treatment of acute mildto-moderate ulcerative colitis. Med Sci Monit 2004;10(11):PI126–31. Joes PM, Segal SH, Gelb AW. Venous oxygen embolism produced by injection of hydrogen peroxide into an enterocutaneous fistula. Anesth Analg 2004;99:1861–3. Horowitz BZ. Massive hepatic gas embolism from a health food additive. J Emerg Med 2004;26:229–30.
Thierry Vial, Jacques Descotes, Felix Braun, and Matthias Behrend
37
Drugs that act on the immune system: cytokines and monoclonal antibodies
Editor’s note: In this chapter Drs Vial and Descotes contributed the sections on cytokines and Drs Braun and Behrend the sections on monoclonal antibodies.
COLONY-STIMULATING FACTORS (SEDA-26, 398; SEDA-27, 391; SEDA-28, 415)
Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) (SED-15, 1542) Cardiovascular Aortitis has been attributed to molgramostim in a previously healthy patient (1A ). • A 55-year-old woman was given a 5-day course of G-CSF 5 micrograms/kg/day for peripheral blood stem cell mobilization. Two days after the completion of treatment she developed severe abdominal pain, fever, and vomiting. Acute aortitis of the descending aorta was seen on MRI. Infectious causes, giant cell arteritis, and several systemic diseases were ruled out. She recovered without aneurysm after glucocorticoid treatment. Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29037-8 © 2007 Elsevier B.V. All rights reserved.
As this patient also had a neutrophilia and major leukocyturia with hematuria during the acute episode, a neutrophilic-mediated aortitis was the suggested mechanism. The use of G-CSF, either alone or before intracoronary cell infusion of mobilized peripheral blood stem cells to improve cardiac function in patients with myocardial infarction, has been associated with in-stent restenosis in seven of the first 10 enrolled patients (2c ). This unexpectedly high rate of restenosis led to premature discontinuation of the trial. Hematologic Severe thrombocytopenia and splenomegaly after each dose of G-CSF or GMCSF in a 75-year-old man with myelodysplasiaassociated hemophagocytic syndrome suggested that myeloid growth factors may have exacerbated the thrombophagocytic process of the underlying disease (3R ). Skin Sweet’s syndrome has occasionally been reported with G-CSF. Now the first case attributed to GM-CSF has been described in a 56-year-old man who received sargramostim after chemotherapy for acute myelogenous leukemia (4A ). Sargramostim was probably the cause, because a suspected second episode occurred after another course of sargramostim. Two other cases of Sweet’s syndrome attributed to filgrastim have been reported. • A 48-year-old woman developed an unusual bullous variant of Sweet’s syndrome 3 days after receiving pegfilgrastim (5A ). She had received G-CSF both before and after this episode without incident, suggesting that the particular pharmacokinetics of pegfilgrastim may have played a role. • In a 50-year-old man there were unusual histological features of the cutaneous lesions, with vascular hyperplasia and atypical histiocytes in the neutrophilic infiltrate (6A ).
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384 Acute exacerbation of palmoplantar pustulosis related to G-CSF has been reported (7A ). • A 51-year-old woman with palmoplantar pustulosis and uterine cancer had an acute exacerbation of the cutaneous lesions on the day after filgrastim administration for chemotherapy-induced neutropenia. The lesions disappeared after glucocorticoid therapy, but she had a similar acute exacerbation shortly after lenograstim administration. There was no further exacerbation during chemotherapy alone.
Accumulation of activated neutrophils in the epidermis and dermis may have been the cause. Typical pruritic erythematous maculopapular eruptions with enlarged macrophages in biopsy specimens have been detailed in eight patients following G-CSF (n = 6), GM-CSF (n = 1), or both (n = 1) (8A ). The lesions disappeared despite continuation of the growth factor in six patients. G-CSF is associated with exacerbation of pre-existing psoriasis or de novo psoriasiform skin lesions. • Careful analysis of the pattern of histological lesions, immunochemistry, and the cutaneous cytokine profile in a 56-year-old man who developed de novo psoriasiform dermatitis after filgrastim administration showed a close resemblance to active psoriasis (9A ).
Immunologic Activation of circulating neutrophils and increased numbers of cells were the suspected pathogenic mechanisms in two patients with antineutrophil cytoplasmic antibodyassociated vasculitis whose disease worsened after G-CSF treatment for stem cell mobilization before autologous transplantation (10A ). Tumorigenicity The possible contribution of G-CSF to leukemogenesis has been strongly debated, and long-term data in healthy donors given growth factors for peripheral blood stem cell mobilization are still scarce. The first report of acute myeloid leukemia diagnosed 14 months after G-CSF use in a healthy 61-yearold female donor is therefore of great importance (11A ). Her leukemia cells expressed GCSF receptors with a proliferative response to exogenous G-CSF. According to their estimation of the worldwide number of patient-years of observation, the authors recognized that this unique case may have fallen within the expected incidence of naturally occurring acute leukemia.
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In nine children with severe chronic neutropenia, bone marrow biopsies taken during filgrastim treatment (range 6 months to 7 years) showed a significant increase in bone marrow angiogenesis compared with pre-treatment biopsies and a control group (12c ). Whether these findings are important to consider in relation to the risk of hematologic malignancies is open to question. Drug administration route There were no adverse local or systemic reactions in five patients with sickle cell disease treated with topical molgramostim for leg ulcers (13c ). Interference with diagnostic tests An unexpected increase in serum concentrations of CA 15-3, a widely used tumor marker of breast cancer in Europe, has sometimes been found in patients receiving G-CSF support after chemotherapy (14c ). A G-CSF-induced increase in peripheral blood neutrophil and neutrophil cytoplasmic MUC1 expression probably accounted for these false-positive results.
INTERFERONS
(SED-15, 1841; SEDA-26, 393; SEDA-27, 383; SEDA-28, 416)
Psychological and psychiatric adverse effects of interferons Interferon alfa Depression and mania can both occur in patients taking interferon alfa. The most recent information about interferon alfa-induced psychiatric adverse effects and their recommended management has been comprehensively reviewed (15R –17R ). A past history of psychiatric disorders or substance abuse and a controlled psychiatric disease are no longer considered as contraindications to treatment, provided that patients are closely monitored during treatment. • In a 39-year-old man with chronic hepatitis C, psychotic mania developed within 3 weeks after standard interferon alfa and ribavirin were changed to peginterferon alfa and ribavirin (18AR ).
The authors discussed the management of manic episodes in patients treated with interferon alfa.
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Interferon beta According to data obtained from six controlled and 17 non-controlled studies sponsored by the manufacturer of interferon beta-1a, depression was more frequently reported as an adverse event in the treated patients (19M ). However, this was not associated with an increase in depression scores in the only study that used appropriate rating scales. There was also no significant difference in the rate of suicide attempts or suicide in patients taking interferon compared with placebo. There were 42 cases of serious and non-serious reports of depression and suicide attempts, including only five cases of suicide, in postmarketing experience covering more than 161 000 patient-years. Overall these data suggest that interferon beta1a does not produce typical depression. Cognitive effects A number of mild to moderate frontal–subcortical brain symptoms, including cognitive and behavioral slowing, apathy, impaired executive function, and reduced memory have also been attributed to interferon alfa. These symptoms may alter the quality of life. Of 30 adults treated with interferon-alfa alone (n = 13) or in combination with chemotherapy (low-dose cytarabine arabinoside in 15 or hydroxycarbamide in two), 16 had a significant reduction in one or more cognitive tests compared with baseline (20c ). The combination with chemotherapy was associated with greater risks of impaired cognitive performance, but these patients also took higher cumulative doses of interferon alfa. Although one-third of patients had depressive symptoms, there was no significant correlation between new depressive symptoms and most of the cognitive decline, suggesting that depression alone did not account for cognitive dysfunction. Very similar marked cognitive impairment, assessed by a battery of computer-assisted psychological tests, was also found in 70 patients with chronic hepatitis C treated with interferon alfa and ribavirin; there was no difference in the quality or intensity of the cognitive changes when comparing standard and pegylated interferon alfa, and no correlation with age or education (21c ). An important finding was that cognitive performances returned to pre-treatment values after the end of treatment. Mechanisms Several mechanisms involved in the pathogenesis of interferon alfa-induced psychiatric adverse effects have been hypothesized
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(16R ), but the mechanisms by which interferon alfa enters the brain to produce neurotransmitter changes are unclear. In a prospective study in 48 patients who received adjuvant interferon alfa for malignant melanoma there was a positive correlation between the increase in serum concentration of soluble ICAM-1 and depression scores; the authors suggested that induction of soluble ICAM-1 by interferon alfa increased the permeability of the blood–brain barrier, allowing the drug to enter the brain more readily (22c ). The relation between interferon alfa-induced depressive disorders and the viral response to treatment has been examined in 39 patients with hepatitis C infection and no history of active psychiatric disease (23c ). After treatment with interferon alfa-2b and ribavirin for 6–12 months, 13 developed major depressive disorders requiring treatment with citalopram. The end-of-treatment response rates and sustained viral response rates were significantly greater in patients who developed a major depressive disorder than in those who did not (62% versus 27% and 39% versus 12% respectively). Despite the small sample, these results suggest that interferon alfa-induced depression occurs at doses or concentrations that are associated with a therapeutic effect (i.e. is a collateral adverse reaction) and that antidepressant therapy could allow patients to take an optimal dose. Susceptibility factors The most frequent susceptibility factor for interferon alfa-associated depression is a history of mood and anxiety symptoms before treatment. The roles of a previous history of depression, female sex, and high dose or long duration of interferon alfa treatment have been discussed (17R ). High doses undoubtedly play a role in the development of depression, but the duration of treatment is not a consistently replicated susceptibility factor. Although it was initially found that a past history of depression might be a susceptibility factor, this has not been convincingly associated with an increased risk of interferon alfa-induced depression in further studies. Similar conclusions were reached in patients with a past history of drug or alcohol abuse, provided that patients remain abstinent during treatment. Female sex and age have also not emerged as consistent susceptibility factors. Although depressive symptoms are usually ascribed to interferon alfa alone, ribavirin
386 could also contribute to their occurrence. Among 162 patients with chronic hepatitis C treated with peginterferon alfa-2b (1.5 micrograms/kg once weekly) plus weight-based or standard-dose ribavirin and prospectively evaluated for the incidence and severity of depression, 39% developed moderate to severe depressive symptoms and six patients withdrew because of behavioral symptoms, such as depression, anxiety, or fatigue (24c ). Depressive symptoms developed after 4 weeks of treatment and maximal depression scores were reached after 24 weeks. Baseline depression scores, a history of major depressive disorders, and higher doses of ribavirin were significant predictive factors of depression during treatment, in contrast to sex, age, or a history of substance abuse. In 33 patients with chronic hepatitis C, of whom 10 developed major depressive disorders during interferon alfa treatment, there was no relation between changes in thyroid function and the development of depression (25c ). No patients with depression had clinical hypothyroidism and the sole patient with overt hypothyroidism had no depressive symptoms. A number of other factors, including genetic or biological factors, that are possibly associated with the development of psychiatric disorders, have been explored. In a retrospective study of 110 patients with chronic hepatitis C, those with the apolipoprotein E ε4 allele, the inheritance of which may be associated with several neuropsychiatric outcomes, were more likely than those without this allele to have psychiatric referrals and neuropsychiatric symptoms, in particular irritability, anger, anxiety, or other mood symptoms, during interferon alfa treatment (26c ). In addition, patients with this allele had neuropsychiatric events sooner than patients without it. In another study in 14 patients with chronic hepatitis C, lower baseline serum activities of propylendopeptidase and dipeptyl peptidase IV, which both play a role in the pathophysiology of major depression, were possible predictors of higher depressive and anxiety scores during interferon alfa treatment (27c ). Whether these factors help to predict susceptibility to interferon alfainduced neuropsychiatric disorders in clinical practice needs to be further investigated. Management Some data suggest that selective serotonin reuptake inhibitors (SSRIs) are
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effective in treating interferon-induced depression, allowing patients to continue treatment (15R , 17R ). Because interferon alfa increases serotonin reuptake and reduces serotonin synthesis, the addition of 5-hydroxytryptophan to a selective serotonin reuptake inhibitor has also been suggested to produce a synergistic response, but controlled trials are awaited (28R ). The successful management of psychiatric symptoms during interferon alfa treatment has been detailed in 60 patients with chronic viral hepatitis, treated for 1 year (29c ). A new psychiatric disease developed during treatment in 18 patients (depression in 12, predominant irritability in four, and anxiety in two), and five others had major depression at baseline. Based on the potential mechanisms of interferon alfa-induced psychiatric disorders, and depending on the clinical features, a variety of psychopharmacological treatments were used in 12 of these patients, including selective serotonin reuptake inhibitors in four cases, lowdose pre-synaptic D2 dopamine receptor antagonists (sulpiride and amisulpride) in three, neuroleptic drugs in two, and benzodiazepines or related drugs in three. Only four patients failed to respond to treatment, and one had to be withdrawn from the study because of persistent irritability. During the study, the 12 patients taking psychiatric drugs had significantly less severe psychiatric symptoms than the 11 untreated patients.
Interferon alfa
(SED-15, 1793)
Observational studies The adverse effects of interferon alfa and ribavirin in combination have been reviewed, with particular emphasis on the management of depressive disorders and hematological adverse effects (30M ). Comparative studies In 50 patients treated with peginterferon alfa-2b and ribavirin for 1 year and carefully examined at each 4–6 week visit by a physician trained in pharmacovigilance, 10 patients developed a serious adverse effect (31c ). Compared with clinical trials, blurred vision, injection site reactions, and endocrine adverse effects were more frequent, and depression and insomnia were less frequent with peginterferon; hair loss occurred with similar frequency.
Drugs that act on the immune system: cytokines and monoclonal antibodies
Cardiovascular Pericarditis without the typical features of a lupus-like syndrome has been reported after 4 months of treatment with lowdose interferon alfa-2b in a 40-year-old woman with chronic hepatitis C (32A ). She simultaneously developed a polyneuropathy. Both disorders disappeared after interferon withdrawal. Respiratory Acute pulmonary toxicity from interferon alfa is repeatedly reported and can be fatal. • A 65-year-old man developed bronchiolitis obliterans organizing pneumonia with fulminant respiratory distress 48 hours after starting treatment with interferon alfa, oral cytarabine ocfosfate, and hydroxyurea for chronic myelogenous leukemia (33A ). He died 5 days later. • A 60-year-old man developed the first symptoms of an acute interstitial pneumonia during the second week of interferon alfa and 5-fluorouracil treatment for hepatocellular carcinoma (34A ). He died 3 weeks later.
Although the suspected treatment was promptly withdrawn after the onset of pulmonary symptoms, both patients died despite antibiotic and glucocorticoid pulse administration. As they also received chemotherapeutic agents known to cause interstitial pneumonitis, the exact role of interferon alfa cannot be determined, but there may be an increased risk of very severe pulmonary toxicity attributable to the drug combination. • A 71-year-old woman developed reversible interstitial pneumonia after 5 months of peginterferon alfa and ribavirin treatment for chronic hepatitis C (35AR ). Lung biopsy showed a granulomatous process.
In this patient there was convincing evidence of a causal relation, since her symptoms improved after withdrawal and recurred after readministration. The authors briefly reviewed the spectrum of pulmonary toxicity associated with interferon alfa from 32 other published cases in patients with chronic hepatitis C. Three cases involved peginterferon, but 10 patients had also received ribavirin. There was interstitial pneumonitis in 15 patients, sarcoid-like reactions in 10, bronchiolitis obliterans organizing pneumonia in three, asthma exacerbation in two, pleural effusion in one, and acute respiratory distress in one. All the patients survived after interferon alfa withdrawal, except one who was treated with peginterferon alfa and who died from an acute respiratory distress syndrome.
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Nervous system Extrapyramidal adverse effects of interferons are rare. Interferon alfainduced acute dystonia has been reported (36A ). • A 24-year-old man with chronic hepatitis B who had tolerated interferon alfa for 6 months 9 years before, developed acute involuntary movements with fever and chills 2 hours after his first dose of peginterferon alfa. Electroencephalography and an MRI scan were normal. His symptoms resolved quickly after diazepam injection and he was given peginterferon again uneventfully.
In the context of an acute dystonia, the authors claimed that the development of tolerance to the second injection of interferon alfa further argued for a causal role of the drug. Restless legs syndrome occurred 2 months after a 60-year-old man started to take interferon alfa and ribavirin for chronic hepatitis C (37A ). Evidence for a causal relation was obtained by complete resolution of the syndrome after withdrawal, careful elimination of other causes, and rapid recurrence of the symptoms on rechallenge with peginterferon alfa and ribavirin. Although both interferon alfa and ribavirin may have been the cause of the syndrome, the authors correctly argued that only interferon alfa is thought to affect dopaminergic neurotransmission, which is strongly suspected to be involved in the pathophysiology of restless legs syndrome. Diffuse electroencephalographic slowing, which reversed after the completion of treatment, has previously been found in patients being treated for chronic hepatitis C (SEDA 24, 411). In a prospective study of the effect of age on the electroencephalogram in 98 patients, alterations became more marked as age increased (38c ). Although Bell’s palsy has previously been attributed to interferon alfa, the causal relation remains questionable (SEDA-25, 432; SEDA28, 418). Another three cases have been reported (39A ). • Three men aged 43 to 55 years developed Bell’s palsy after 4 days, 5 weeks, and 4 months of treatment with interferon alfa and ribavirin for chronic hepatitis C. The Bell’s palsy spontaneously resolved within 6 weeks after withdrawal and none of the patients was rechallenged.
Although a coincidental adverse effect was possible, the authors suggested that immunotherapy may have produced a breakdown in peripheral tolerance to myelin sheath antigens.
388 Sensory systems Eyes Retinopathy attributed to interferon alfa is well recognized, and severe visual complications can occur rarely. Whether this complication is more frequent with peginterferon than with standard interferon is still unknown. In one prospective series of 23 patients coinfected with HIV and hepatitis C, who were treated with peginterferon alfa-2b and ribavirin, eight developed classical interferon retinopathy and two had impaired color vision, of whom one was sufficiently severely affected to require drug withdrawal (40c ). Although the incidence of retinopathy in this small study was within the expected range, the occurrence of two symptomatic cases is noteworthy. Isolated reports of ophthalmologic abnormalities continue to appear, most recently visual complaints involving the use of the pegylated form of interferon alfa in patients with chronic viral hepatitis. • A 37-year-old man developed bilateral ischemic retinopathy and blurred vision and recovered promptly after peginterferon alfa-2b withdrawal (41A ). • A 44-year-old woman developed visual difficulties in dim light, with abnormal electro-oculography; she slowly improved after peginterferon alfa withdrawal (42A ). She had previously tolerated standard interferon alfa for 6 months. • A 46-year-old man developed visual complaints with predominant blurry vision and the classical cotton-wool spots of interferon-induced retinopathy after treatment with peginterferon alfa-2b; he recovered after 5 months despite continued treatment (43AR ).
The last report also provided a complete detailed review of 27 reports of interferon alfarelated ocular abnormalities. Vogt–Koyanagi–Harada disease (SEDA-28, 418) has been again observed after 4 months of interferon alfa-2b treatment in a 36-year-old man with chronic hepatitis C (44A ). Withdrawal and methylprednisolone therapy was followed by slow but complete recovery. Ears Standard interferon alfa can cause sudden mostly unilateral sensorineural hearing loss in up to 40% of patients. Sudden hearing loss and tinnitus occurred in six patients treated with peginterferon alfa (mostly alfa-2b); the onset of symptoms after the start of therapy was 1 day in one patient and 4–40 weeks
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in the other five (45c ). The authors estimated that about 1% of patients would experience this event. The ototoxicity was attributed to reversible biochemical and metabolic changes in the cochlea, but could also have been caused by an autoimmune mechanism with antiendothelial cell antibodies, which were found in nearly half of the patients. Autoimmune hearing loss occurs later in the course of treatment than biochemical and metabolic hearing loss, is mostly bilateral, and has a progressive course over the ensuing days and months. In contrast to direct ototoxicity caused by standard interferon, that caused by peginterferon does not recover fully after withdrawal. However, once symptoms appear they do not progress, and so the decision to continue or abandon treatment has to be individualized. Metabolism Interferon alfa-induced diabetes is rare. In a randomized trial in 74 patients with chronic hepatitis C treated with interferon alfa-2b and ribavirin, plus placebo or amantadine, two developed glutamic acid decarboxylase (GAD) autoantibodies, but none developed IA-2 or insulin autoantibodies (46c ). One had an increased titer of GAD autoantibodies during a first sequence of interferon alfa monotherapy, then a further rise during subsequent combination therapy, and finally developed diabetes mellitus after 5 months of treatment. The authors suggested that repetitive treatment with interferon alfa could increase the risk of type 1 diabetes in patients previously positive for islet antibodies. • A 39-year-old man who had received peginterferon alfa-2b and ribavirin for 9 months developed diabetes mellitus 3 months after interferon withdrawal (47A ). He required oral hypoglycemic drugs and insulin, but fasting plasma glucose and glycosylated hemoglobin concentrations later normalized despite withdrawal of antidiabetic treatment.
Severe hypertriglyceridemia (7.5–19 mmol/ l; 653–1644 mg/dl) has been reported in three patients receiving adjuvant high-dose interferon alfa for malignant melanoma (48AR ). The authors reviewed the available literature and proposed a detailed surveillance and management plan for this metabolic disorder in patients with melanoma treated with interferon.
Drugs that act on the immune system: cytokines and monoclonal antibodies
Hematologic Anemia in the course of the combination treatment with interferon and ribavirin is mostly multifactorial, and is due to ribavirin-induced extravascular hemolysis and interferon-induced suppression of bone marrow. The response of erythropoietin is blunted compared with the severity of the anemia. It has been speculated that interferon might cause an inflammatory state severe enough to induce anemia similar that seen in chronic inflammatory disorders (49C ). Interferon alfa can cause pure red cell aplasia (50A ). • A 50-year-old woman with a liver transplant, who had taken interferon alfa-2b for post-transplant recurrence of hepatitis C infection, developed pancytopenia with a severe anemia (hemoglobin: 2.9 g/dl) after 5 months. The leukopenia and thrombocytopenia abated after withdrawal of interferon alfa, but the anemia persisted over the next 3 months. Pure red cell aplasia was confirmed on bone marrow biopsy and no other causes were found. She finally responded to a course of intravenous immunoglobulin.
Pernicious anemia has been associated with interferon alfa (51A ). • During interferon alfa treatment for chronic hepatitis C, a 45-year-old man and a 58-year-old woman developed pernicious anemia, with anti-intrinsic factor antibodies and neurological symptoms. Interferon alfa was continued and both recovered with intramuscular cyanocobalamin.
Although interferon alfa-induced bone marrow aplasia is rare, it can be very severe, as has previously been stressed (SEDA-28, 420). • A 34-year-old woman developed aplastic anemia after 8 months of interferon alfa treatment for chronic myeloid leukemia (52A ). The pancytopenia was transfusion-dependent. There was no hemopoietic recovery 16 months after withdrawal of interferon alfa and no response to two courses of immunosuppressants. Only allogeneic bone marrow transplantation, performed because of recurrent chronic myeloid leukemia, finally restored normal hemopoiesis.
Autoimmune thrombocytopenia is a recognized but rare complication of interferon alfa. • A 55-year-old woman with chronic myelogenous leukemia developed reversible autoimmune thrombocytopenia, which recurred after rechallenge with the same formulation of purified interferon alfa
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(53A ). Further administration with a different purified formulation was well tolerated, suggesting that subtle differences between two types of interferon explained the lack of cross-reactivity.
Tolerance of peginterferon and ribavirin for recurrent hepatitis C after liver transplantation is poor. In a retrospective study of 31 patients, changes in the doses of interferon and peginterferon had to be made in 87% and of ribavirin in 81% of the patients (54c ). Hemopoietic growth factors were often used, for example G-CSF in 88% of patients treated with peginterferon and ribavirin. Gastrointestinal Interferon alfa can unmask celiac disease in predisposed patients. In a retrospective study of 534 patients treated with various formulations of interferon alfa for chronic hepatitis C, 25 developed symptoms consistent with celiac disease and 13 required withdrawal or dosage reduction (55C ). A screen for celiac disease-specific anti-transglutaminase (anti-TG2) antibodies on serum samples obtained before treatment gave positive results in six of 25 patients with interferon alfa-induced symptoms of celiac disease compared with one of 170 patients also treated with interferon-alfa but free of symptoms and one of 225 controls. Liver The rapid growth of a pre-existing liver hemangioma was attributed to a 6-month course of interferon alfa-2b in a 16-year-old girl with chronic hepatitis C (56A ). However, liver enlargement was noted only 12 months after withdrawal of interferon. The authors also recognized that they were unable to determine which factors among puberty, hepatitis C infection, or interferon alfa treatment, could have influenced the rapid progression. Pancreas Among 1706 patients treated with interferon alfa and ribavirin for chronic hepatitis C, acute pancreatitis meeting the criteria of drug-induced pancreatitis was retrospectively found in seven after a median duration of 12 (4–21) weeks (57C ). All promptly recovered after withdrawal and none had recurrent pancreatic symptoms after a median follow-up of 18 months. Only one was rechallenged and did not develop evidence of recurrent pancreatitis, but re-treatment lasted only 1 month because of severe fatigue and diarrhea. Although
390 hypertriglyceridemia is a well-known complication of interferon alfa treatment, only two patients had very mildly raised serum triglyceride concentrations. Because of the association of pancreatitis only with high-dose intravenous ribavirin and the previous experience of recurring pancreatitis after interferon alfa readministration, the authors strongly suspected that interferon alfa had been the cause. • A 52-year-old man with no known risk factors rapidly developed acute pancreatitis after receiving a single injection of peginterferon alfa-2b and ribavirin for 7 days for chronic hepatitis C (58A ). He promptly improved after withdrawal of both interferon and ribavirin.
Urinary tract There have been further reports of acute renal complications attributed to interferon alfa. • A 63-year-old man with Sézary syndrome developed renal thrombotic microangiopathy after 4 years of interferon alfa treatment (59A ). • A 46-year-old woman developed acute irreversible renal insufficiency due to interstitial nephritis during treatment with peginterferon alfa-2a; she had had underlying hepatitis C-associated focal segmental glomerulosclerosis (60C ). • A 54-year-old man developed acute tubular necrosis and worse IgA nephropathy on renal biopsy after treatment for 9 days with peginterferon alfa2a and ribavirin for chronic hepatitis C (61A ).
The last two cases suggest that interferon alfa can exacerbate chronic hepatitis C-related nephropathy in some patients. Skin Of 37 patients with chronic hepatitis C who received double or triple antiviral therapy, including peginterferon alfa-2b, nine developed skin reactions, sufficiently severe in five cases to require withdrawal of treatment (62c ). The skin lesions occurred after a mean of 2 months and consisted of diffuse, erythematous, eczematous, pruritic lesions (n = 2), erythematous papules and desquamative patches (n = 6), and diffuse exacerbation of pre-existing Darier’s disease. Histological findings in five cases showed features resembling contact dermatitis. There was slow recovery of skin lesions in all but one case, and all those who continued interferon required topical glucocorticoids for clinical improvement. Eight of these patients had injection site reactions to peginterferon, as did 14 patients with no cutaneous
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lesions. Apart from a possible synergistic action of amantadine, a pathogenic role of the pegylated formulation of interferon alfa was suggested. There have been other reports of interferon alfa-associated systemic cutaneous adverse effects in patients with chronic hepatitis B or C infections. • A 50-year-old man developed severe, generalized, nummular eczema during treatment with interferon alfa-2b and ribavirin (63A ). His lesions persisted despite withdrawal of treatment and required maintenance therapy with glucocorticoids. • A 41-year-old man treated with peginterferon alfa2b and ribavirin developed generalized exfoliative dermatitis, with recurrence on peginterferon readministration (64A ). • A 44-year-old man developed verrucous psoriasis with ichthyosis hystrix-like plaques after receiving peginterferon for 2 months, with rapid spontaneous healing of the lesions after withdrawal of treatment (65A ). He had a history of inverted psoriasis, but he had not suffered an exacerbation after previous treatment with standard interferon for 1 year. • A 10-year-old girl developed vitiligo after having received interferon alfa-2a for 6 months and received topical glucocorticoids while interferon alfa was continued (66A ). She developed psoriatic lesions 4 months later of treatment and interferon was withdrawn after 1 year of treatment. The depigmented macules and the erythematous lesions continued to evolve and were still present 3 years later. The lesions were resistant to topical glucocorticoids during the next year. • A 44-year-old man had an exacerbation of cryoglobulinemia-associated vasculitis and renal insufficiency 1 month after starting peginterferon alfa; he had tolerated three previous courses of standard interferon alfa (67A ).
Two of these patients developed cutaneous lesions while receiving peginterferon after uneventful previous treatment with standard interferon alfa. This again suggests that pegylated interferon may be associated with more frequent or more severe dermatological adverse effects. • A 52-year-old woman developed dermatitis herpetiformis during treatment with interferon alfa2b and ribavirin for chronic hepatitis C (68A ). Anti-endomysial and anti-gliadin IgA autoantibodies were retrospectively detected in serum samples collected before treatment. As she also had asymptomatic villous atrophy of the duodenum and recovered after a gluten-free diet and dapsone treatment, her skin lesions were attributed to latent gluten hypersensitivity, which could have been unmasked by interferon alfa.
Drugs that act on the immune system: cytokines and monoclonal antibodies
Injection site reactions to subcutaneous interferon alfa can be severe. • A 55-year-old diabetic man developed severe streptococcal cellulitis requiring surgical treatment, despite intensive antibiotic therapy, after receiving injections of peginterferon alfa-2b for 5 months (69A ).
Musculoskeletal Muscle disorders are infrequent. Myopathy has been reported (70A ). • A 33-year-old man without previous muscle disorders was treated for 24 weeks with a combination of peginterferon alfa-2b (1.5 micrograms/kg/ week) and ribavirin (1 g/day) for acute hepatitis C. After 14 weeks he developed weakness and generalized myalgia, with an increase in creatine kinase activity to 904 UI/l and a small rise in CK-MB activity. There were no electromyographic signs of myositis and no inflammatory signs. The dose of peginterferon was halved for the next 10 weeks. The muscle symptoms were unchanged but the creatine kinase activity slowly fell. There was prompt resolution after the end of treatment.
This report suggests that muscle disorders associated with interferon alfa are likely to be collateral reactions. Immunologic Sarcoidosis Further reports of cutaneous or systemic sarcoidosis in patients treated with interferon alfa alone or in association with ribavirin have been published (71A –73A ). The course of the disease was usually benign and there was spontaneous recovery despite continuation of the antiviral treatment in one patient with cutaneous sarcoidosis. In another patient, asymptomatic liver and pulmonary sarcoidosis was diagnosed on a systematic liver biopsy 5 years after interferon alfa withdrawal, with diffuse sarcoid granulomas not found before treatment (74A ). These findings suggest that the incidence of interferon alfa-associated sarcoidosis may have been underestimated. Systemic sclerosis Systemic sclerosis, previously reported (SEDA-27, 388), has again been attributed to interferon alfa (75A ). • A 47-year-old woman without a family or personal history of autoimmune disease developed bilateral Raynaud’s phenomenon after 6 months of treatment with interferon alfa-2b for chronic hepatitis C. Her symptoms worsened over the next 3
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months and she had telangiectasiae, finger edema, diffuse pulmonary fibrosis, raised antinuclear autoantibodies, and a positive rheumatoid factor. There was rapid improvement after withdrawal of interferon and prednisone treatment, but she still had a limited form of systemic sclerosis with Raynaud’s phenomenon, sclerodactyly, and calcinosis on follow-up after 6 years.
The favorable outcome after interferon alfa withdrawal and the absence of detectable hepatitis C-RNA or mixed cryoglobulinemia at the time of diagnosis suggested that interferon alfa was the most likely cause. Organ rejection Recurrence of hepatitis C in liver transplant recipients constitutes a therapeutic challenge, because of accelerated progression in the face of immunosuppression. Up to 28% of transplant recipients will develop cirrhosis within 5 years. So far, induction of rejection by interferons has not been statistically confirmed. In one study of 23 liver transplant recipients treated with pegylatedinterferon alfa-2b for 6 months, 35% had evidence of acute or chronic rejection in liver biopsies within 1–6 months after the start of interferon (76c ). Most of these patients had no history of previous rejection. Two patients had graft loss due to chronic rejection. Only a younger age at transplantation (44 versus 51 years) was a significant susceptibility factor. There was no relation between the time of rejection after transplantation, virological response, length of interferon exposure, history of rejection before interferon treatment, or pretreatment alanine transaminase activity. Persistent elevation of alanine transaminase activity can herald rejection. Unfortunately, rejection episodes can be unresponsive to withdrawal of interferon. Infection risk A higher risk of non-respiratory infections independent of neutropenia has been attributed to peginterferon alfa. In a retrospective study of patients treated with ribavirin plus peginterferon alfa-2a/2b (n = 152) or standard interferon alfa (n = 103), there were 26 infections in the first group and five in the second group (77c ). Although neutropenia (under 1.0× 109 /l) was significantly more frequent in the pegylated interferon group, this was associated only with respiratory infections (n = 8), without a statistical difference between the groups (five cases in the pegylated interferon group
392 versus three in the standard interferon group). In contrast, no non-respiratory infection was observed in patients with neutropenia. Susceptibility factors HIV infection The effectiveness and tolerability of interferon alfa in HIV-infected patients is probably lower than in HIV-negative patients. In an open randomized controlled trial in 180 HIV-infected patients with chronic hepatitis C, interferon alfa-2b 3 MU/day plus ribavirin was compared with interferon alfa-2b 3 MU 3 times weekly plus ribavirin; 42 patients had to discontinue interferon alfa because of an adverse effect related to treatment, with no significant between-group differences (78C ). Although seven adverse effects were serious, no patients died during treatment or developed opportunistic infections. There was no significantly adverse impact of interferon + ribavirin on markers of HIV disease or the effectiveness of antiretroviral treatment. The rate of sustained hepatitis C virus response was only 13%, compared with an expected 42–46% in non HIVinfected patients, with a non-significant higher response in the daily compared with the threetimes weekly group. Liver transplantation The safety of interferon alfa in liver transplant patients with recurrent hepatitis C is a matter of concern. In a retrospective study of 44 such patients treated with standard interferon alfa (n = 11) or pegylated interferon alfa (n = 33), with or without ribavirin, for a mean of 11 months, five developed biopsy-proven acute cellular rejection after a mean of 3.3 months (79c ). Four of 33 patients had received peginterferon alfa and one of 10 standard interferon alfa. Three patients responded to antirejection treatment, but two subsequently developed cirrhosis. The other two failed to respond to treatment: one underwent retransplantation while the other died from sepsis after graft loss. These five patients first received interferon alfa long after transplantation (mean of 42 months) and were correctly stabilized (only one had had a previous episode of rejection 5 years before). Of the remaining 39 patients, 13 had to discontinue interferon alfa prematurely because of another adverse effect (leukopenia in four, refractory anemia in three, thrombocytopenia in one, retinopathy in
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one, and depression in four). Overall, these data suggested poor tolerance of interferon in these patients. There were three cases of late hepatic artery stenosis among 18 liver transplant patients treated with peginterferon alfa-2b and ribavirin for recurrent chronic hepatitis C (80c ). These events occurred after a mean treatment duration of 6 months and a median time of 28 months after transplantation. The authors noted that this rate was higher than expected from large studies in liver transplant patients not receiving interferon alfa and their own experience with non-pegylated interferon alfa. Thus, interferon may have a deleterious effect in transplant patients with recurrent hepatitis C. Any additional effect of pegylated interferon alfa needs to be confirmed. Finally, one of 39 consecutive liver transplant patients treated with peginterferon alfa and ribavirin for recurrent hepatitis C had acute hepatic deterioration with massive ascites and renal insufficiency 1 month after the antiviral treatment had been started (81c ). The patient recovered after withdrawal and aggressive medical treatment. Drug formulations The two currently available formulations of pegylated interferon alfa differ in their chemistry and pharmacokinetic and pharmacodynamic properties, but owing to a lack of direct comparisons, it is as yet unknown whether these differences are relevant in terms of efficacy or adverse effects (82M ). Drug interactions The safety of interferon alfa in opioid-dependent patients with chronic hepatitis C is of major concern. This issue has been explored in 50 stable patients taking methadone maintenance treatment for a median of 21 months (83C ). Compared with a prospectively matched group of 50 chronic controls with hepatitis C, who also received peginterferon alfa-2B and ribavirin for 24–48 weeks, more patients from the methadone group discontinued treatment during the first 8 weeks of the study (4% versus 22%). The discontinuation rates were similar in the two groups after 8 weeks of treatment. Poor compliance, patient request, or treatment failure were the major reasons for discontinuation, and only four patients in the methadone group withdrew because of an adverse effect versus two in the
Drugs that act on the immune system: cytokines and monoclonal antibodies
control group. There were no major psychiatric events in either group and no significant differences in the number of patients who received an antidepressant in the two arms. The sustained viral response at the end of treatment was similar in the methadone group compared with the control group (56% versus 42%), but only 25 patients taking methadone group versus 38 controls were able to complete the study. In addition, interferon alfa treatment did not appear to require changes in the daily dose of methadone. Peginterferon alfa-2a treatment for 4 weeks produced only minimal changes in the pharmacokinetics of methadone maintenance treatment in 24 patients (84c ).
Interferon beta
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(2.8% versus 1.6%), but unfortunately no indepth analysis of these data was provided. Post-marketing surveillance data did not add significant additional information, but there was one convincing case of autoimmune hemolytic anemia, which resolved after interferon beta-1a withdrawal and recurred on readministration. Liver The relevance of liver test abnormalities in patients treated with interferon beta has been discussed at length (87R ). Although rises in transaminase activities occur in about one-third of patients in clinical trials, they are mild and self-limiting in most cases (88C ). The clinical impact, if any, is therefore very small. However, an autoimmune mechanism may be involved in isolated cases, as suggested in a report of autoimmune hepatitis attributed to interferon beta-1a in a 52-year-old woman (89A ).
(SED-15, 1831) Immunologic Systemic hypersensitivity reactions to interferon beta are rare (90A ).
The therapeutic efficacy and adverse effects of subcutaneous interferon beta-1b in the management of relapsing–remitting and secondary progressive multiple sclerosis have been extensively reviewed (85R ). Interferon beta was considered to be a valuable first-line therapy in relapsing–remitting multiple sclerosis, and potentially useful in secondary progressive multiple sclerosis, although its effects on disease progression is uncertain.
• A 36-year-old woman with multiple sclerosis and positive serology for hepatitis C developed biopsyproven non-specific lymphocytic cutaneous vasculitis, with renal involvement marked by proteinuria and hematuria, after 2 years of interferon beta1a treatment. Immunological investigations were negative, except for a previously known positive antinuclear antibody, and serology did not indicate a recent infectious episode. There was complete recovery within 2 weeks after withdrawal.
Hematologic Mild to moderate dose-dependent reductions in leukocyte, neutrophil, and platelet counts are common in patients treated with interferon beta, but most of these changes are without clinical significance. This has been confirmed in an analysis of six controlled clinical trials of interferon beta-1a, in which there was grade 4 toxicity at similar rates in the placebo and treated patients (0.2% in each group) (86M ). Most of the abnormalities occurred within the first 6 months of treatment and resolved despite continued treatment. In the pooled safety database, which also included uncontrolled studies, only 12 of 3995 patients had to stop taking interferon beta-1a. The highest rate of treatment withdrawal was reported with the highest dose (0.8% in those given 44 micrograms 3 times weekly). Although the authors stated that symptomatic events were rare, uncommon infections were more frequent in the highest dose group compared with placebo
Although the long delay in this case suggested a possible coincidental adverse event, this case is reminiscent of reports of vasculitis involving interferon alfa. The clinical impact of neutralizing antibodies to interferon beta is being continually investigated. In an open study in 78 patients treated with various commercially available forms of interferon beta, the highest incidence of persistent neutralizing antibodies was in those who received subcutaneous interferon beta-1b (35%), with an intermediate rate in those who received subcutaneous interferon beta-1a (20%), and the lowest rate in those who received intramuscular interferon beta-1a (3%) (91c ). Patients with persistent neutralizing antibodies had a higher probability of worsening over the 3 years of the study and a shorter time to relapse, again suggesting that these antibodies have a negative influence on disease outcome. There were very similar findings in
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another study in 90 patients, which also suggested that the simultaneous presence of high titers of both binding and neutralizing antibodies correlated with higher degrees of disease activity and progression (92c ). Although both studies involved a limited number of patients, the minimal 3-year length of follow-up allowed accurate analysis of the clinical impact of antibodies.
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granulomatous disease. In addition, his mother had a disease similar to discoid lupus.
INTERLEUKINS
(SED-15, 1842; SEDA-26, 397; SEDA-27, 390; SEDA-28, 424)
Anakinra (interleukin-1 receptor antagonist) (SED-15, 215)
Management of adverse effects In a randomized double-blind trial in 84 patients, ibuprofen, paracetamol, and prednisone were equally effective in controlling the incidence and severity of the flu-like syndrome that occurs during the first month of intramuscular interferon beta-1a (93c ). However, patients who received ibuprofen had less severe symptoms on the day of interferon injection.
Infection risk Septicemia with Staphylococcus aureus, group B and G β-hemolytic streptococci, and Escherichia coli has been reported in a 66-year-old woman 2 months after anakinra was added to prednisolone for rheumatoid arthritis (97A ). This report provides further evidence that anakinra can increase susceptibility to infections.
Interferon gamma
Interleukin-2 (IL-2)
(SED-15, 1838)
Respiratory The safety of interferon gamma in patients with idiopathic pulmonary fibrosis has been previously questioned (SEDA27, 390). In a double-blind study in 330 patients with idiopathic pulmonary fibrosis randomized to receive interferon gamma-1b or placebo, there were no significant differences in progression-free survival or in conventional measures of lung function, gas exchange, or quality of life (94C ). As expected, patients who received interferon gamma-1b had more frequent constitutional symptoms, such as fever, rigors, and flu-like symptoms. They also had more frequent upper respiratory tract infections and non-fatal pneumonias. Interferon gamma-associated lung toxicity has been further supported by a report of acute respiratory insufficiency after 4 months in a 68year-old man with idiopathic pulmonary fibrosis (95A ). Immunologic A 10-year-old boy with chronic granulomatous disease developed systemic lupus erythematosus after treatment with interferon gamma 50 micrograms/m2 three times weekly for 4 years (96A ). The boy was heterozygous for the allelic variants of Fcγ RIIa, which has been linked to an increased risk of autoimmune disorders in patients with chronic
The spectrum of IL-2-induced effects on the immune system and its clinical applications have been reviewed (98R ). Cardiovascular IL-2 therapy has infrequently been associated with myocarditis. Two of 57 patients developed myocarditis during highdose IL-2 treatment for metastatic melanoma and renal cell carcinoma, including one biopsyproven case with eosinophilic and lymphocytic infiltrate (99c ). Both recovered uneventfully. Respiratory Cough and weakness were the main adverse effects in 40 patients who received inhalation of IL-2 for pulmonary metastases of renal cell carcinoma (100c ). Hematologic Severe isolated anemia occurred in a 56-year-old woman who had received interferon alfa and IL-2 for renal cell carcinoma (101A ). As the anemia resolved after IL-2 withdrawal and glucocorticoid pulse therapy, IL-2induced anemia was the suspected cause. There were features of both hemolytic and aplastic anemia, and the pathogenesis was unexplained. Gastrointestinal Gastrointestinal perforation is a rare but serious complication of IL-2 treatment. In a retrospective review of patients treated with high-dose IL-2 (n = 1680) or sub-
Drugs that act on the immune system: cytokines and monoclonal antibodies
cutaneous IL-2 (n = 117), there were 8 cases of gastrointestinal perforation, with an overall incidence of less than 0.5% (102C ). The diagnosis was made after a median number of 8 doses and up to six days after the last dose of IL-2. All the patients required surgical procedures and four underwent uneventful retreatment with IL-2 after recovery. That gastrointestinal perforation can occur throughout the abdominal tract was shown by a review of 12 other published cases. Drug administration route Subcutaneous administration of IL-2 is expected to improve tolerability without deleterious effects on efficacy endpoints. A retrospective comparison of the efficacy and safety of subcutaneous injections (n = 103) or continuous intravenous infusions (n = 225) of IL-2 for metastatic renal cell carcinoma did not show any significant differences in the overall response rate, median response duration, or survival between either method of administration, and confirmed a lower incidence of grade 3 or 4 adverse events, as fewer patients required dose reduction during subcutaneous administration than during continuous intravenous administration (46% versus 76% and 20% versus 82% respectively) (103c ). Cardiovascular, respiratory, urogenital, and metabolic/nutritional symptoms were the most frequent severe adverse effects associated with the continuous intravenous regimen.
TUMOR NECROSIS FACTOR (TNF) ANTAGONISTS (SEDA-26, 399; SEDA-27, 393; SEDA-28, 425) The adverse effects of TNF-alfa antagonists have been comprehensively reviewed, with particular attention to lymphoma, infections, cardiovascular complications, demyelinating disease, autoimmunity, and injection site and skin reactions (104R ). The authors also briefly mentioned several spontaneously reported cases of liver failure, of which seven had no apparent cause, suggesting that TNF-alfa antagonists can cause hepatic failure.
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Infection risk with tumor necrosis factor antagonists The risk of infectious complications associated with TNF-alfa antagonists and current recommendations to be used before and during treatment have been reviewed (105R , 106R ). Comparative incidences TNF plays a key role in granuloma formation, which is an essential component for host control of several infections. Although infliximab and etanercept share the same therapeutic target, differences in their mode of action may account for a differential infection risk (107R ). The general infection rate with etanercept over an entire course of therapy has been estimated to be 35% in placebo-controlled trials (108R ). The data on spontaneous reports received by the FDA’s Adverse Event Reporting System have been analysed to compare the reporting incidence and characteristics of granulomatous infectious diseases associated with etanercept or infliximab (109C , 110C ). A large number of granulomatous infections were selected for this purpose, but tuberculosis, histoplasmosis, candidiasis, and listeriosis accounted for more than 80% of the reported cases. Among 639 episodes of granulomatous infections, 556 were associated with infliximab and 83 with etanercept. According to the estimated number of patients treated in the USA during the reporting period and taking into account only those cases that occurred in there, the calculated reporting rate of granulomatous infections was 130 per 100 000 patients treated with infliximab and 60 per 100 000 patients treated with etanercept. The rates of tuberculosis were 54 per 100 000 and 28 per 100 000 respectively. Overall, there was a significantly higher rate of reporting with infliximab than with etanercept for coccidioidomycosis, histoplasmosis, listeriosis, and tuberculosis. From an analysis of the whole database, extrapulmonary presentation of tuberculosis was more frequent with infliximab (26%) than etanercept (10%), as was meningeal disease (17% versus 7%). In addition, 44% of tuberculosis cases attributed to infliximab were observed within the first 90 days of treatment compared with only 10% in those associated with etanercept. For all types of granulomatous infections, the median time
396 to onset was 40 days for infliximab and 236 days for etanercept. The authors correctly argued that these differences can be explained by the different mechanisms of action of these drugs, with a higher risk of reactivation of latent tuberculosis infection with infliximab than with etanercept. The same conclusion probably applies in other granulomatous infections. Coccidioidomycosis To explore the risk of coccidioidomycosis associated with TNF-alfa antagonists, cases collected from five practices in an endemic area were retrospectively examined (111c ). There were 12 cases associated with infliximab (four with documented dissemination, including two deaths) and one case of resolved pneumonia with etanercept. Two patients had a prior history of coccidioidomycosis, but all of them were also taking other immunosuppressive agents, methotrexate being the most frequent. The disease occurred after a median time of 12.5 weeks (1–48 weeks) after starting infliximab, whereas the time to onset was 96 weeks in the only case involving etanercept. From a cohort of patients with inflammatory arthritis identified in one of these centers, there were seven cases of coccidioidomycosis among 247 patients treated with infliximab and four among 738 patients taking other antirheumatic drugs. The relative risk for infection with infliximab compared with other drugs was 5.2 (CI = 1.5, 18) and remained significant after adjusting for age and use of methotrexate or prednisone. Tuberculosis In a review of 25 cases of tuberculosis following the use of etanercept reported to the voluntary Adverse Event Reporting System of the US Food and Drug Administration, it was reported that the estimated number of cases of tuberculosis reported to the FDA for each person-year of treatment with etanercept among patients with rheumatoid arthritis was about 10 per 100 000 patient-years of exposure (112S ). It is unclear from these data whether etanercept increases the risk of tuberculosis beyond the increased rates already documented among patients with rheumatoid arthritis. Susceptibility factors Patients with psoriatic arthropathy who were being treated with etanercept were able to produce antibodies in response to pneumococcal immunization, whereas
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patients receiving methotrexate had lower mean antibody titers in response to the vaccine (113c ). This suggests that patients treated with etanercept will have normal humoral responses to a T cell-independent antigen. Recent detailed reports in patients treated for rheumatoid arthritis have included: • Late recurrence of Mycobacterium xenopi infection manifesting as Pott’s disease and severe spinal infection in a 49-year-old man taking methotrexate, prednisone, and sulfasalazine about 2 years after etanercept was begun (114A ). • Pulmonary aspergillosis in a 55-year-old woman who had received etanercept alone for 10 months (115A ). • Listeria monocytogenes meningitis in a 45-yearold patient treated with etanercept monotherapy for 20 months (116A ). • Septic arthritis due to Actinobacillus ureae, which necessitated synovectomy and debridement in a 59year-old woman also taking methotrexate (117A ).
All these patients developed their infection after a long course of etanercept and fully recovered from the infectious episode. Two cases of infectious complications associated with the use of adalimumab in patients with rheumatoid arthritis have been reported. • A 61-year-old man with rheumatoid arthritis developed tonsillar tuberculosis after 8 months of adalimumab treatment despite a prophylactic antituberculosis regimen correctly used after an initial screening positive for tuberculosis (118A ). • A 70-year-old man died from fulminant pneumonia with candidal colonies after he had received his third injection of adalimumab together with methotrexate and prednisolone for rheumatoid arthritis (119A ).
Tumorigenicity The potential risk of lymphoma in patients treated with TNF-alfa antagonists has been lengthily discussed (120R ). Whether these agents are independently associated with an increased risk of lymphoma continues to be debated (121r ). This issue was analysed in two large cohorts of rheumatoid arthritis patients. From the data registered in the South Swedish Arthritis Treatment Group, which covered over 90% of arthritic patients treated with anti-TNF-alfa drugs in this area of Sweden, there were 11 cases of tumors and five of lymphomas among 757 patients treated with etanercept or infliximab (1603 person-years of risk) (122C ). Although there was no increase in the overall risk of total tumors, the relative
Drugs that act on the immune system: cytokines and monoclonal antibodies
risk of lymphoma was 11 times higher than that expected in the background population. More importantly, a direct comparison showed that the relative risk of lymphoma was five times higher in patients treated with anti-TNFalfa drugs than in a community-based control group of 800 patients treated with conventional antirheumatic drugs and never exposed to biological agents. This difference persisted after adjustment with the Health Assessment Questionnaire, used as a marker of disease severity. The other cohort consisted of 18 572 patients and included 29 cases of lymphoma, with a standardized incidence ratio of 2.6 for infliximab, 3.8 for etanercept, 1.7 for methotrexate, and 1.0 for patients not receiving methotrexate or anti-TNF-alfa agents (123C ). Although both studies suggested an increased rate of lymphoma in patients treated with infliximab or etanercept, these results should be interpreted with caution, because of the very small number of cases and a possible role of higher disease activity in these patients. Susceptibility factors Age Special attention has been paid to the safety of infliximab and etanercept in children with juvenile idiopathic arthritis, in particular as regards to the possible risk of autoimmune disease and severe infectious disease, such as varicella zoster virus infection or tuberculosis (124R ). Whereas there were no cases of demyelination or lupus in these children, there were two cases of type I diabetes mellitus after etanercept treatment. A genetic predisposition was likely, but accelerated development of diabetes should be also considered, as suggested by experimental data that suggest an important role of TNF suppression in the progression of diabetes.
Adalimumab
(SED-15, 2380)
Immunologic Severe hypersensitivity reactions to adalimumab have not been documented, and it was supposed to be safe in patients previously intolerant to infliximab. Adalimumab was successfully used in a 22-year-old woman who had had a severe anaphylactic-like reaction to infliximab (125A ). Apart from injection
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site reactions, there was good tolerance to adalimumab in seven patients with a history of immediate or delayed hypersensitivity reactions to infliximab, and only one had a pruritic rash after each injection of adalimumab (126c ). One additional patient with infliximab-associated lupus also tolerated adalimumab uneventfully. The previous therapeutic response obtained with infliximab seemed to be unaffected in these patients.
Etanercept
(SED-15, 1279)
Comparative studies In a double-blind study of 682 patients with rheumatoid arthritis randomized to etanercept alone, methotrexate alone, or a combination of the two, the rate of adverse events or study discontinuation related to an adverse event was similar in the three groups (127C ). In particular, there were no differences in the rates of infection and severe infections. There were no cases of tuberculosis, opportunistic infections, demyelinating diseases, or severe blood dyscrasias among the 454 patients who received etanercept, but only 363 completed the 1-year study. One etanercept-treated patient died from heart failure and suspected sepsis. Sensory systems Eye complications with etanercept have rarely been reported. • A 59-year-old woman developed symptomatic bilateral peripheral visual field loss shortly after starting to take etanercept (128A ).
Gastrointestinal Previous clinical trials have shown that etanercept is not effective in Crohn’s disease. This has been indirectly illustrated in a 7-year old boy with juvenile idiopathic arthritis who developed an exacerbation of severe Crohn’s disease after each administration of etanercept (129A ). Infliximab was later successfully used for both diseases. Skin A 55-year-old woman with no previous personal or family history of skin lesions developed clinical and histological features of psoriasis after taking etanercept for 3 months for seronegative rheumatoid arthritis (130A ). Etanercept was continued, but the lesions were poorly controlled by topical steroids and pho-
398 totherapy. Two other patients aged 25 and 34 years had acute exacerbations of palmar and plantar psoriasis 4 and 7 months after starting to take etanercept for ankylosing spondylitis (131A ). Immunologic Giant cell arteritis of the left temporal artery has been attributed to etanercept in a 79-year-old woman with rheumatoid arthritis (132A ). However, the patient had tolerated etanercept for 2 years before the onset of the symptoms and was also taking methotrexate. As the outcome was also unknown, any causal relationship is purely speculative. Severe glomerulonephritis and cutaneous vasculitis have been reported (133A ). • A 28-year-old woman with rheumatoid arthritis and positive antinuclear autoantibodies was given 18 infusions of infliximab because she did not continue to respond to hydroxychloroquine and methotrexate after 10 years of treatment, during which renal function had been normal. When infliximab became ineffective she was given etanercept 35 mg twice a week. Six months later she developed a dot-like eruption, an increase in serum creatinine concentration, and proteinuria. Etanercept was withdrawn. Skin and renal biopsies showed a non-specific lymphocytic vasculitis with a lupus band in the skin and glomerulonephritis. The cutaneous vasculitis resolved within a few days, but she developed status epilepticus and aggravation of renal function and required short-term dialysis. Persistent albuminuria was later noted.
Although anti-double-stranded DNA and antihistone antibodies were negative, a lupuslike syndrome was not completely excluded in this patient. In a case of necrotizing crescentic glomerulonephritis with positive pANCA and progressive renal insufficiency in a 32-year-old woman with rheumatoid arthritis, the authors thought that etanercept given for the previous 11 months had failed to control the development of pANCA-associated vasculitis rather than precipitating or causing the adverse event (134A ). Lactation Etanercept was secreted in breast milk in small amounts in one patient (135A ). The milk to plasma ratio was 0.04 and the calculated amount of etanercept orally ingested by a breast-fed newborn was 50–90 micrograms/ day. Based on these findings, and since the systemic availability of etanercept by the oral route is assumed to be very low, breast-feeding during treatment is probably safe.
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Infliximab
Thierry Vial et al.
(SED-15, 1747)
Centocor has issued a “Dear Healthcare Professional” letter advising of changes to the USA infliximab (Remicade) label, following postmarketing reports of hematological and neurological events (136S ). “A Warning on Hematological Events” has been added to the label to advise of reports of neutropenia, leukopenia, thrombocytopenia, and pancytopenia, some of which were fatal. The “Warning on Neurological Events” has also been updated to detail cases of nervous system manifestations of systemic vasculitis. In addition, pericardial effusion, neutropenia, and cutaneous and systemic vasculitis have been added to the “Adverse Reactions” sections of infliximab prescribing information. Physicians are advised that they should consider withdrawal of infliximab in patients who develop significant adverse nervous system reactions or hematological abnormalities. Observational studies Adverse effects possibly related to infliximab have been retrospectively examined in 500 consecutive patients with Crohn’s disease who had received a median of three infusions (137C ). The median duration of follow-up was 17 months. Serious adverse effects were attributed to infliximab in 30 patients (6%). The most frequent adverse effects were infections (41 patients, of whom 15 had a serious infection), acute infusion reactions (19 patients, of whom two had life-threatening reactions), serum sicknesslike diseases (14 patients, of whom five had severe disease), lupus-like syndrome (three patients, including one with positive rechallenge after a subsequent infusion), malignant disorders (two solid tumors and one case of non-Hodgkin’s lymphoma), worsening of heart failure (one patient with a previously diagnosed cardiomyopathy), and demyelination syndrome (one patient). Among 10 deaths, five were considered to be possibly related to the treatment (four severe infections and one case of lung cancer). Of 217 patients who received infliximab (mean number of infusions 2.6) for inflammatory bowel diseases, 41 had 42 severe adverse events (138C ). Most of these consisted of hypersensitivity reactions (n = 13), infections (n = 11), postoperative complications (n = 7), thromboembolic events (n = 5), or lymphomas
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Table 1. Reports of thrombotic disorders associated with infliximab Age Sex
Disease and risk factors
Time to onset
Adverse reaction
Outcome
Ref.
31 M
Ankylosing spondylitis
(140A )
Crohn’s disease
Recovery
(141A )
63 M
Rheumatoid arthritis Diabetes mellitus Hypertension Hypercholesterolemia Crohn’s disease Non-insulin dependent diabetes
Cerebral thrombophlebitis on day 3 Extensive deep venous thrombosis of the ipsilateral arm Myocardial infarction
Recovery
31 F
Headache rapidly after 1st infusion 1 day after 3rd infusion
Infliximab continued and 2nd myocardial infarction 3 days after 8th infliximab infusion Recovery
(142A )
Recovery
(144A )
63 F
41 M
Ankylosing spondylitis Paroxysmal nocturnal hemoglobinuria
3 days after 1st infusion
Within 30 minutes of the 1st infusion 2 months after 6th infusion
Myocardial infarction
Hepatic vein thrombosis (BuddChiari syndrome)
(n = 3). There was also one case each of lupus-like syndrome, depression, and vestibular neuronitis. Six patients died, and the cause of death was lymphoma in two patients, infections in three, and pulmonary embolism in one. However, it was not stated how the causal relation to infliximab treatment was assessed. The authors noted that the annual incidence of lymphoma in their patients was 1.5%, which is considerably higher than the 0.015% expected from the background population data in their country. They also commented on the unexpectedly 2.8% mortality rate during the 2-year follow-up period. In 100 patients treated with infliximab for inflammatory bowel disease there were adverse events in 10 patients after a median follow-up of 26 months (139C ). There were acute infusion reactions in two patients, a serum sickness-like reaction in one, bacterial or viral infections in four, pancytopenia in one, and surgical complications in two. There were no malignancies, autoimmune diseases, or neurological or cardiovascular adverse events. Cardiovascular Infliximab has previously been associated with venous thrombosis (SEDA-28, 429). Several recent reports have further suggested that infliximab can precipitate thrombotic events in patients with various underlying diseases (140A –144A ) (Table 1).
(143A )
It is not yet known whether infliximab has a negative procoagulant effect, but experimental data suggest that TNF-alpha has a strong antithrombotic activity in mice (145E ). In contrast, prolonged use of infliximab in seven patients with rheumatoid arthritis improved endothelial function assessed by brachial ultrasonography, at least during the first 7 days after infusion (146c ). Respiratory Previous reports have suggested that infliximab can precipitate methotrexateassociated pneumonitis (SEDA-28, 429). Three patients with rheumatoid arthritis and asymptomatic fibrosing alveolitis had acute fatal exacerbations of their lung disease after having received two or three doses of infliximab (147A ). Pulmonary damage in patients without prior pulmonary disease has also been attributed to infliximab. • Two men aged 21 and 71 years developed hypersensitivity pneumonitis after infliximab treatment for Crohn’s disease (148A ). The first developed pulmonary symptoms after a single dose of infliximab, whereas the second had previously tolerated infliximab well for 1 year. The latter had focal interstitial chronic inflammation on transbronchial biopsy. Infectious causes were carefully ruled out in both patients. • An 84-year-old woman with rheumatoid arthritis who had taken leflunomide for 6 months developed severe interstitial pneumonitis 1 week after
400 a second dose of infliximab (149A ). Infliximab was withdrawn and leflunomide was continued. The course of the disease was marked by rapidly progressive end-stage pulmonary fibrosis. • A 35-year-old woman with severe Crohn’s disease that had not responded to hydrocortisone, mercaptopurine, and mesalazine was given infliximab (150A ). Within 48 hours after a second dose she developed fever, a dry cough, and dyspnea, with severe respiratory distress and acute anemia. There was diffuse bilateral alveolar hemorrhage on a chest CT scan and she subsequently developed staphylococcal superinfection. There was full pulmonary recovery 6 months later.
In all cases a causal relation with infliximab treatment was based on a suggestive temporal association and reasonable exclusion of other causes. Possible leflunomide-associated interstitial pneumonitis, possibly aggravated by infliximab, could not be ruled out in the second report. Exacerbation of pre-existing obstructive sleep apnea syndrome concomitant with infliximab infusion has been reported in a 62-yearold woman with rheumatoid arthritis (151A ). Nervous system There have been additional reports of demyelination disorders in patients with Crohn’s disease who received infliximab. • A 19-year-old woman taking azathioprine developed symptoms of multiple sclerosis 2 weeks after a second infusion of infliximab (152A ). An MRI scan confirmed a demyelinating process and there was clinical improvement without a further change in MRI examination. • A 50-year-old woman developed visual loss and ocular pain in the left eye 3 weeks after her last infusion of infliximab (153A ). An MRI scan showed isolated retrobulbar optic neuritis. She recovered spontaneously after withdrawal of infliximab.
Whether these cases occurred by chance or reflected a true relation between infliximab and demyelinating disease is a matter of debate. As reviewed elsewhere, the actual number of reported cases does not appear to exceed the expected incidence in the untreated population (154R ). Several cases of peripheral nerve disorders have emerged. • Two women aged 28 and 45 years had an acute, predominantly motor neuropathy after infliximab for Crohn’s disease and collagenous colitis (155A ). • Multifocal motor neuropathy occurred in a 34year-old woman with rheumatoid arthritis (156A ).
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The hallmark in these patients was the appearance of neurological symptoms after the fourth dose of infliximab and an electromyographic pattern of conduction block. Antiganglioside antibodies were detected in one patient and returned to normal within 6 months after withdrawal of infliximab. A possible autoimmune mechanism was suggested. Sensory neuropathy has also been reported in two women with rheumatoid arthritis aged 41 and 48 years (157A ). The peripheral neuropathy was attributed to necrotizing vasculitis in one patient who first developed symptoms after her sixth infusion of infliximab, and to rapid exacerbation of pre-existing mononeuritis multiplex 8 hours after a first infusion of infliximab in the second patient. Skin Infliximab has rarely been associated with dermatological adverse effects, such as erythema multiforme, leukocytoclastic vasculitis, annular lichenoid eruptions, and bullous skin lesions (108R ). Skin reactions typically occur 1–14 days after the injection. • A 36-year-old man developed a diffuse pruritic rash after treatment for 3 months with oral leflunomide and infliximab for palmoplantar pustular psoriasis (158A ). Withdrawal of both drugs resulted in improvement in the skin condition. Although patch tests to both leflunomide and infliximab were negative, rechallenge with infliximab resulted in recurrence of the eczematous rash. • Alopecia areata occurred in a 51-year-old woman with rheumatoid arthritis and Sjögren’s syndrome who received infliximab for 11 months (159A ). She developed non-scarring hair loss consistent with alopecia areata, which eventually evolved to 100% scalp involvement despite withdrawal of infliximab. • A 23-year-old man with a history of Crohn’s disease developed profuse warts on his penis and perianal region after two doses of infliximab (160A ). A diagnosis of genital condylomata acuminata was made.
Four patients with no previous history of psoriasis experienced psoriasis or psoriasiform cutaneous eruptions (130A , 131A , 161A ) (Table 2). As infliximab can improve severe psoriatic arthritis, a paradoxical adverse reaction to this agent was suggested. Delayed onset of a short-lived maculopapular, urticarial rash has been reported in two children aged 10 and 16 years given infliximab for juvenile rheumatoid arthritis (162A ). They developed cutaneous lesions 13–18 days after
Drugs that act on the immune system: cytokines and monoclonal antibodies
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Table 2. Reports of psoriatic eruption associated with infliximab Age Sex
Disease
Dosage
Time to onset
Outcome
Ref.
47 F
Seronegative rheumatoid arthritis
200 mg
2 months
(130A )
27 F 32 M
Ankylosing spondylitis Ankylosing spondylitis
5 mg/kg
10 months
5 mg/kg
6 weeks
46 F
Crohn’s disease
5 mg/kg
2 weeks
Infliximab continued. Limited improvement with topical steroids and salicylic acid Infliximab continued. No further lesions after topical treatment Infliximab withdrawn. Partial improvement with systemic glucocorticoids Lesions spontaneously cleared, recurred after the third injection, and cleared after infliximab withdrawal
the first or second injection, and later tolerated further infliximab administration well. There was no evidence of vasculitis on skin biopsy. Two patients aged 20 and 56 years treated with infliximab for Behçet’s disease developed multiple lesions of erythema nodosum 3 and 30 days after their third and fourth infusions respectively (163A ). Infliximab-induced exacerbation of previous erythema nodosum was suggested in the first patient. Because new lesions of erythema nodosum subsequently developed despite withdrawal of infliximab in this patient, and because no documentation of the outcome was provided in the other patient, any causal relation should be considered doubtful. A typical nicotinic acid-like reaction, consisting of intense chest tightness and erythematous flushing, occurred within minutes of a first or subsequent infusion of infliximab in three children with refractory juvenile rheumatoid arthritis (164A ). Similar reactions were observed after further infusions despite various prophylactic drug regimens, and only aspirin finally prevented recurrence. Immunologic Treatment with infliximab is associated with the development of neutralizing antibodies to infliximab in about 10% of patients. Patients who were antibody positive were more likely to have an infusion reaction and potential loss of medication efficacy (108c ). The characteristics of infusion reactions to infliximab, defined as adverse events that occur during or within 1–2 hours after infusion, have been studied in 113 patients (1183 infusions) with rheumatoid arthritis (165C ). Although
(131A ) (131A ) (161A )
the rate of reactions per infusion was 8.8%, 60 (53%) patients had at least one reaction during treatment. Nearly half of these reactions occurred during the third and fourth infusions. The symptoms consisted of pruritus, urticaria, and/or facial or generalized swelling in 3.8% of all infusions, cardiopulmonary manifestations (hypotension, hypertension, tachycardia, or shortness of breath) in 3%, and miscellaneous signs (headache, nausea, and/or vomiting) in 2%. There was no increase in the frequency of infusion reactions after the dose of infliximab was increased from 3 to 5 mg/kg. Most of these reactions resolved promptly after discontinuation of the infusion, either spontaneously or after symptomatic treatment, and none was sufficiently severe to require hospitalization. Only three patients had to discontinue infliximab treatment because of infusion reactions. There was no clear benefit from the prophylactic use of diphenhydramine, which may in fact have increased the frequency of adverse reactions. In 59 patients with rheumatoid arthritis a high incidence of autoimmunity, manifesting as an increased number of patients with antinuclear antibodies (69% versus 29% at baseline), anti-double-stranded DNA IgM antibodies (32% versus 0% at baseline), and antihistone IgM antibodies (79% versus 18% at baseline) after 30 weeks of infliximab treatment, has been confirmed (166c ). There were very similar findings in 39 patients with rheumatoid arthritis or ankylosing spondylitis after 2 years of followup; Antiphospholipid autoantibodies also occurred during treatment (23% of patients versus
402
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Table 3. Reports of lupus-like syndrome associated with infliximab Age Sex
Disease
Time to onset
Main symptoms
Ref.
45 M 61 F 54 F 37 F 53 F 43 F 53 F
Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis Crohn’s disease Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis
After 5th infusion
Fever, cough, eruption, arthralgia, pericardial and pleural effusions
(168A )
10 days after 3rd injection 2 weeks after 5th infusion After 5th infusion 4 weeks after 4th infusion 7 weeks after 4th infusion After 2nd, 3rd, and 4th infusions
none at baseline), but vasculitis-associated autoantibodies or organ-specific autoantibodies against the thyroid or the liver were not detected (167c ). None of the patients included in these studies had lupus-like symptoms. Infliximab is a potential cause of lupus-like syndrome (SEDA-28, 431) and cases continue to be reported (168A –173A ) (Table 3). All seven patients had increased antinuclear antibody titers (new occurrences in six), six were positive for anti-double-stranded DNA and three for antihistone antibodies. In contrast, six other patients with moderately active lupus-like syndrome were successfully treated with infliximab without flares of lupus activity despite increased titers of anti-double-stranded DNA and anticardiolipin antibodies in four cases (174c ). Infection risk Bacterial infections There have been reports of severe opportunistic bacterial infections, including disseminated or cutaneous Nocardia infection (175A , 176A ), Legionella pneumophila pneumonia (177A –179A ), and Listeria monocytogenes meningitis (180A ). In three of these six patients, the infection occurred only after the second or third infusion of infliximab, and infliximab was later restarted uneventfully in two cases. Although the incidence of listeriosis is probably very low, there was one case of life-threatening Listeria meningitis pneumonia in a population-based cohort study of 217 patients treated with infliximab for inflammatory bowel disease (138C ).
Fever, myalgia, arthralgia, eruption
(169A )
Fever, myalgia, polyarthritis
(169A )
Arthralgia, myalgia, pericarditis
(170A )
Photosensitive rash, acute polyarthritis, fever, pleural effusion Fever, synovitis, eruption, pleuritic chest pain
(171A )
Cutaneous lesions after each injection Cutaneous discoid lupus later confirmed
(173A )
(172A )
• The first case of disseminated Salmonella typhimurium infection has been reported after 28 weeks of infliximab and methotrexate treatment in a 29year-old man with psoriatic arthropathy (181A ). • Moraxella catarrhalis septic arthritis occurred 1 month after a fourth infusion of infliximab in a 45year-old man with undifferentiated spondyloarthritis (182A ). He was taking no other immunosuppressive drugs at the time of diagnosis. • Fatal staphylococcal sepsis due to adult respiratory distress syndrome has been reported in a 40-yearold woman after a sixth infusion of infliximab for Crohn’s disease (183A ).
De novo tuberculosis or its reactivation in patients treated with infliximab has again been described. • Miliary tuberculosis occurred in a 43-year-old man only 6 weeks after starting infliximab for pyoderma gangrenosum and despite negative pretreatment screening for latent tuberculosis (184A ).
As this patient originated from a country in which tuberculosis is highly endemic and also received glucocorticoids, the authors questioned whether systematic prophylaxis should be proposed in such cases. Testing for tuberculosis with the purified protein derivative test should be completed before starting therapy with infliximab (108R ). Caution should be exercised when considering the use of infliximab or any TNF-alfa antagonists in patients with chronic infections, a history of recurrent or latent infections, or an underlying condition that may predispose them to infections (185R ).
Drugs that act on the immune system: cytokines and monoclonal antibodies
Viral infections In 500 consecutive patients treated with infliximab for Crohn’s disease, viral infections were noted during the first six infusions in six patients and consisted of varicella zoster virus infections in three (primary varicella in one), genital herpes simplex virus infection, infectious mononucleosis due to Epstein– Barr virus, or severe gastroenteritis (one case each) (137C ). • Disseminated primary varicella infection with a fatal outcome has been reported 9 days after a first infusion of infliximab in a 26-year-old man who was also taking 6-mercaptopurine, glucocorticoids, and mesalazine for Crohn’s disease (186A ). • Genital condylomata acuminata occurred after a second dose of infliximab for Crohn’s disease in a 23-year-old man who was also taking glucocorticoids and azathioprine (187A ).
In contrast to these reports, one study suggested that infliximab did not increase the load of Epstein–Barr virus in the short-term in patients with Crohn’s disease (188c ). Fungal infections Recent reports of fungal infections attributed to infliximab have included one case of Cryptococcus neoformans pneumonia due to possible zoonotic transmission from a pet cockatiel (189A ) and two cases of Pneumocystis jiroveci (carinii) pneumonia (190A , 191A ). One of the latter patients, aged 59 years, who was also taking prednisone 40 mg/day, subsequently developed oral candidiasis and invasive aspergillosis. He died from progressive multiorgan failure. As he also had a low CD4 count, the authors wondered whether infliximab may have contributed to this anomaly. In 217 patients treated with infliximab for inflammatory bowel disease, fatal Pneumocystis jiroveci pneumonia was noted once (138C ). Death Health Canada received a total of 697 reports of suspected adverse reactions to infliximab over a 4½ year period (192S ). Of these, 132 (19%) reports were considered serious and 14 (2%) resulted in death. Tumorigenicity Because of two additional case report of lymphoma and a brief review of 33 previously published cases with infliximab, the presence of Epstein–Barr virus infection was sought in four patients and was positive in three (193Ar , 194A ). Owing to the growing number of infections being reported in patients
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treated with anti-TNF-alfa drugs, triggering of Epstein–Barr virus-associated lymphoma by TNF-alfa antagonists should be considered. This is supported by the relatively short time interval between the start of treatment and the diagnosis of lymphoma in most reported cases. Other recent reports of cancer putatively attributed to infliximab include one case of multiple keratoacanthomata and squamous cell cancers in a 76-year-old woman with a history of sun exposure and multiple non-melanoma skin cancers (195A ), a cutaneous T cell lymphoma in a 69-year-old man, and a systemic T cell lymphoma in an 81-year-old woman (196A ). The involvement of infliximab was suggested by rapid development of the cancer after starting infliximab and/or an aggressive course of disease in both of the patients with T cell lymphomas. Teratogenicity The results of the manufacturer’s post-marketing surveillance database, which included infliximab exposure before or during pregnancy, have been made available (192C ). Of 96 pregnancies with a prospectively documented outcome, exposure occurred exclusively before pregnancy in 32 patients or during the first trimester in 58. The time course of exposure was unknown in six. There were 63 live births (67 neonates), one preterm infant who died shortly after birth, 14 miscarriages, and 18 terminations of pregnancy. Three neonates had a congenital anomaly: tetralogy of Fallot, intestinal malrotation with a concomitant exposure to leflunomide, and hypothyroidism with delayed development. Follow-up of pregnancies after paternal exposure was also documented in 10 patients: there were nine healthy live births, and one miscarriage. There were no differences in outcome after maternal infliximab exposure compared with the general population of pregnant women or a historical cohort of patients with Crohn’s disease. However, there were several limitations to this study, such as spontaneous reporting, lack of standardization of outcome ascertainment, a high rate of loss to follow-up, and the small number of patients exposed during the first trimester of pregnancy. Susceptibility factors Surgery Severe postoperative complications in patients who have received infliximab be-
404 fore surgery have sometimes been mentioned in clinical trials or cohort studies. To assess this issue the rate of early and late (up to 3 months) major or minor surgical complications was retrospectively evaluated in patients treated with infliximab for Crohn’s disease and compared with similar patients who had never received infliximab (197C ). Postoperative complications were not more frequent (19 complications) among 40 patients who received infliximab before intestinal resectional surgery compared with 15 complications in 39 patients who did not receive infliximab and who underwent similar surgery. The mean duration of hospital stay was similar in the two groups. The nonsignificant increase in the early infection rate observed with infliximab (six cases versus one) was attributed to more frequent use of other immunosuppressive drugs in these patients.
MONOCLONAL ANTIBODIES (SED-15, 2380; SEDA-26, 402; SEDA-27, 378; SEDA-28, 434)
Abciximab See Chapter 35.
Adalimumab See TNF antagonists above.
Alemtuzumab (Campath-1H® ) (SED-15, 71) Alemtuzumab is an unconjugated, humanized, monoclonal antibody directed against the cell surface antigen CD52 on lymphocytes and monocytes. In 2001, it was approved in the USA and Europe to treat B cell chronic lymphocytic leukemia that had previously been treated with alkylating agents and was refractory to fludarabine. Its adverse effects include acute first-dose reactions, hematological toxicity, and infectious complications. They are usually predictable, manageable, and accept-
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able in the context of chronic lymphocytic leukemia. However, in a significant percentage of patients, cytomegalovirus reactivation occurs during alemtuzumab therapy, and routine weekly monitoring by PCR is indicated. Moreover, antiviral and antibacterial prophylaxis is mandatory (198R ). Comparative studies A regimen of alemtuzumab + low-dose tacrolimus has been compared with prednisolone + tacrolimus as initial immunosuppression after liver transplantation (199c ). Patient and graft survival were similar, but the incidence of acute rejection was significantly lower with alemtuzumab + tacrolimus during the first 2 months after transplantation and slightly less at 12 months. Alemtuzumab + tacrolimus with an average tacrolimus trough concentration below 6.5 ng/ml during the first 2 months after transplantation was associated with a significantly higher rejection rate beyond that time. Cardiovascular Alemtuzumab caused cardiotoxicity in four of eight patients with mycosis fungoides/Sézary syndrome and no prior history of cardiac problems. The effects included congestive heart failure or dysrhythmias that improved after alemtuzumab withdrawal (200A ). Cardiac ischemia has been attributed to alemtuzumab in a man with chronic lymphocytic leukemia (201A ). • A 58 year-old man with B cell chronic lymphocytic leukemia underwent two coronary angioplasties and was asymptomatic thereafter. Chemotherapy before alemtuzumab consisted of fludarabine, melphalan, prednisone, chlorambucil, cyclophosphamide, vincristine, and cladribine. After the second dose of alemtuzumab 10 mg he developed severe chills and a fever, followed by shortness of breath, typical chest pain, hypotension, and hypoxemia. An electrocardiogram showed depressed ST segments laterally. A chest X-ray showed pulmonary edema. The MB fraction of creatine kinase activity was raised. Echocardiography showed segmental hypokinesia but a normal ejection fraction and moderate aortic stenosis. He improved and was given two more doses of alemtuzumab 10 mg subcutaneously, followed a week later by 30 mg; 7 hours after the last infusion he developed chest pain and dyspnea with electrocardiographic changes. He was admitted to the coronary unit where he recovered without complications. He was given further doses of alemtuzumab 10 mg subcutaneously and a glyceryl trinitrate patch with each injection. He had no further symptoms and received six more doses.
Drugs that act on the immune system: cytokines and monoclonal antibodies
Respiratory Alemtuzumab can cause WHO grade 4 bronchospasm, but glucocorticoid comedication during the first four doses with quick tapering can ameliorate the symptoms (202c ). Nervous system There were severe neurological complications in six of 85 patients with a median onset of 151 days (24–334 days) after alemtuzumab-based reduced-intensity conditioning for allogeneic stem cell transplantation (203c ). Five of them presented with progressive peripheral sensorimotor radiculoneuropathy and/or myelitis, preceded by one or more episodes of viral reactivation/infection. Despite treatment with immunoglobulins/plasmapheresis/glucocorticoids, four died of respiratory failure due to progressive peripheral neuropathy. Viral infection was identified as the only risk factor for the development of neurological complications. Patients who are treated in this way may have a lower risk of developing neurological complications, but are more susceptible to peripheral radiculoneuropathy or myelitis. This phenomenon may be related to viral infection associated with delayed immunological recovery or immunological dysregulation caused by alemtuzumab-induced T cell depletion. Hematologic When alemtuzumab 3, 10, and 30 mg was given on sequential days followed by 30 mg 3 times weekly to heavily pretreated patients, median age 62 (range 40–73) years, with B cell chronic lymphocytic leukemia (n = 13), prolymphocytic leukemia (n = 1), mantle cell lymphoma (n = 1), and leukemic immunocytoma (n = 1), recurrent profound leukopenia required withdrawal in 13 patients (202c ). The authors recommended flexible time intervals of administration depending on leukocyte counts. Serious immune thrombocytopenia is rare in patients who receive alemtuzumab and withdrawal is necessary when the platelet count falls below 50 × 109 /l. • A 36-year-old man with refractory chronic lymphocytic leukemia developed relentless progressive cytopenia despite withdrawal of alemtuzumab when the platelet count was over 97×109 /l (204A ). Marrow biopsy showed increased numbers of megakaryocytes. The patient bled uncontrollably and died of cerebral hemorrhage with a platelet count below 10 × 109 /l.
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Immunologic A monocyte-mediated episode of acute renal transplant rejection occurred after combined treatment with preoperative alemtuzumab and postoperative immunosuppression. Alemtuzumab can cause more profound depletion of lymphocytes than monocytes, and the resultant imbalance of lymphocytes and monocytes can lead to acute rejection dominated by monocytes. • A 49-year-old man, the recipient of a kidney of a living non-related donor, was treated with preoperative alemtuzumab and postoperative immunosuppression (205A ). An initial post-transplant renal biopsy showed diffuse mild acute rejection with 95% CD68-positive monocytes, but only 5% CD3-positive T lymphocytes. Inflammatory cells in the renal biopsy were negative for CD34 and CD1a stains, suggesting non-involvement of CD34-derived dendritic cells. After glucocorticoid treatment for 2 weeks, his serum creatinine concentration fell to 142 µmol/l (1.5 mg/dl). The features of acute rejection were absent in a second biopsy of the transplanted kidney.
Infection risk When alemtuzumab 3, 10, and 30 mg was given on sequential days followed by 30 mg 3 times weekly to heavily pretreated patients with chronic lymphocytic leukemia, there were infectious complications due to pulmonary aspergillosis in one case and bacterial pneumonia in another; withdrawal was required in both; one patient with refractory B cell chronic lymphocytic leukemia and Pneumocystis jiroveci pneumonia plus cytomegalovirus reactivation died (202c ). Cytomegalovirus reactivation is common in previously treated patients with chronic lymphocytic leukemia who receive alemtuzumab, but only sporadic cases of cytomegalovirus disease have been reported. Oral ganciclovir results in prompt response to therapy without progression to cytomegalovirus disease and without clinical toxicity. Oral ganciclovir is therefore recommended as pre-emptive therapy in all patients who develop cytomegalovirus reactivation during alemtuzumab treatment (206c ). Adenoviruses are emerging as a major cause of infectious complications after hemopoietic stem cell transplantation. Adenovirus infections occurred in 11 of 86 patients after alemtuzumabbased reduced-intensity conditioning; five died of progressive adenovirus disease (207c ). The probability of non-relapse mortality was 49% in patients with adenovirus disease compared with 26% in those without. The severity of the
406 lymphocytopenia and continuation of immunosuppressive therapy were the most important risk factors for progressive adenovirus disease and death, while patients who were not receiving immunosuppressive therapy or had it reduced or withdrawn cleared the virus. The lack of pre-emptive anti-cytomegalovirus therapy for reactivation correlated with the risk of progressive adenovirus disease. Tumorigenicity Post-transplantation lymphoproliferative disorder is a well-known complication of conventional cell and organ transplantation. It occurred in two of 70 patients after non-myeloablative stem cell transplantation using conditioning with fludarabine, cyclophosphamide, and alemtuzumab (208c ). The pathology in all cases was a donor-origin, Epstein–Barr virus positive, diffuse, large B cell lymphoma. Susceptibility factors Hepatitis C Alemtuzumab 30 mg was given before lung transplantation and then as daily monotherapy in combination with tacrolimus to recipients who were hepatitis C virus negative or positive and compared with tacrolimus + mycophenolate mofetil + prednisolone in 84 non-lymphoid-depleted liver recipients (58 hepatitis C negative, 26 positive) (209c ). The overall incidence of rejection was similar with alemtuzumab and conventional immunosuppression. After 14–22 months, patient survival and primary graft survival in hepatitis C negative (positive) recipients were 97 and 90% (71 and 70%) with alemtuzumab versus 71 and 70% (65 and 54%) with conventional immunosuppression. The adverse effect of pre-existing hepatitis C infection on survival parameters and graft function was significant at 1 year in both groups, but its extent was not evident until the second year. With or without hepatitis C, 62% of the 64 surviving lymphoid-depleted patients were using spaced immunosuppression and four patients were taking no immunosuppression. Drug administration route Intravenous administration of alemtuzumab 30 mg thrice weekly is associated with infusion-related reactions and is inconvenient. The subcutaneous route achieves alemtuzumab concentrations similar to those achieved after intravenous
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administration, although with slightly higher cumulative doses. An antiglobulin response was not detected in 30 patients given intravenous alemtuzumab, whereas two of 32 patients given subcutaneous alemtuzumab had substantial anti-idiotype responses (210c ). Subcutaneous alemtuzumab appears to be more convenient and better tolerated but may be associated with the formation of anti-alemtuzumab antibodies in some patients, particularly those who have been previously untreated. Management of adverse drug reactions Management guidelines for the use of alemtuzumab in B cell chronic lymphocytic leukemia have been recommended by an expert opinion round table in August 2002 (211M ). It was generally accepted that hematological adverse events are transient, manageable, and reversible. Grade 4 neutropenia is an indication to withdraw treatment. Treatment with alemtuzumab should be accompanied by careful monitoring and prophylaxis against infection (212r ). Co-trimoxazole is the prophylaxis of choice against Pneumocystis jiroveci pneumonia. It is given three times a week for at least 4 months after completion of alemtuzumab treatment or until the CD4 count is over 200 × 106 /l. Prophylaxis with aciclovir is recommended against herpes viruses and it should be given in a dosage of 400 or 800 mg bd in patients with previous herpes infection. Alemtuzumab determines cytomegalovirus reactivation in 10–40% of patients with chronic lymphocytic leukemia and in up to 80% who undergo allogenic myeloablative and non-myeloablative bone marrow transplantation. Most patients respond to rapidly to intravenous ganciclovir. Monitoring therapy A simple sensitive enzyme-linked immunosorbent assay has been validated for monitoring alemtuzumab in serum and plasma (213E ). There were similar concentrations in plasma and serum and in fresh samples and samples stored at 4 ◦ C for 24 hours; however, alemtuzumab concentrations were significantly lower in samples stored at room temperature for 24 hours. The limit of detection was 0.05 µg/ml, with a coefficient of variation of 12.5%. There were no false positive results in over 200 samples tested.
Drugs that act on the immune system: cytokines and monoclonal antibodies
Basiliximab
(SED-15, 418)
Basiliximab is a genetically engineered chimeric mouse/human anti-IL-2R (CD25) monoclonal antibody that blocks IL-2R (CD25) without lysis of activated T cells. Its most common adverse effects in adults are constipation, infections, pain, nausea, peripheral edema, hypertension, anemia, headache, hyperkalemia, hypercholesterolemia, increased serum creatinine, and hypophosphatemia (214M ). Placebo-controlled studies In a double-blind comparison of the histological recurrence rate in 140 hepatitis C-positive lung transplant recipients treated with ciclosporin and azathioprine who were given basiliximab plus either glucocorticoids or placebo steroid-free therapy was associated with a significantly lower treatment failure rate (215C ). Although histological recurrence hepatitis C infection was similar in both groups after 12 months (41% basiliximab + glucocorticoids versus 38% basiliximab + placebo), the treatment failure rate was significantly higher with basiliximab + glucocorticoids (29%) than with basiliximab + placebo (16%). The biopsy-proven acute rejection rate was significantly lower in the group treated with glucocorticoids (24% versus 39), while the treated acute rejection rate was similar (30% versus 38%). One-year graft survival and patient survival rates were 73% and 85% with basiliximab + glucocorticoids and 82% and 89% with basiliximab + placebo. Susceptibility factors Age The addition of an intravenous bolus dose of basiliximab on days 0 and 4 to ciclosporinbased immunosuppression did not reduce the incidence of acute rejection in pediatric liver recipients compared with a historical group without basiliximab (216c ). Renal replacement therapy Basiliximab is removed from the body about 64% reduction by plasmapheresis of 2.5 l and also through ascites in patients after lung transplantation (217A , 218c ). There have hitherto been no data on serum concentrations of basiliximab during continuous hemodifiltration.
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• A 57-year-old Japanese man with post-necrotic liver cirrhosis due to hepatitis C virus infection underwent living-donor liver transplantation (219A ). Initial immunosuppression consisted of methylprednisolone tapered from 500 to 20 mg/day, mycophenolate mofetil 2 g/day, and basiliximab 20 mg on days 0 and 4. He was kept on continuous hemodifiltration for pre-existing renal insufficiency until he died on day 30 with MRSA pneumonia. The basiliximab serum concentrations were within the target range of over 200 ng/ml during the complete postoperative period. The percentage of CD25 positive lymphocytes was as low as 0.1% on post-transplant day 4 and 0.2% on posttransplant day 18.
Thus, basiliximab was apparently unaffected by continuous hemodifiltration. Immune status After kidney transplantation, basiliximab combined with sirolimus permits a window of recovery from delayed graft function before the introduction of reduced-dose ciclosporin. Basiliximab-treated high immune responders, such as African-Americans, retransplant recipients, or recipients with panelreactive antibodies of 50% or more, had a significantly greater risk of acute rejection (26%) than either basiliximab-treated low immune responders (10%) or antithymocyte globulintreated high immune responders (3%). Ciclosporin was begun when the serum creatinine concentration was at least 25 mg/l, with a median time to initiation of 12 days. Patients with early return of renal function had a significantly lower incidence of acute rejection episodes than those with later recovery of function. High immune responders treated with basiliximab had significantly higher mean serum creatinine concentrations at 3, 6, and 12 months than either low immune responders treated with basiliximab or high immune responders treated with antithymocyte globulin. A strategy combining sirolimus with basiliximab for recipients at low immunological risk and antithymocyte globulin for high-risk recipients leads to prompt recovery of renal function with a low risk of acute rejection (220C ).
Bevacizumab
(SED-15, 2380)
Bevacizumab is an antibody against vascular endothelial growth factor. It was approved by
408 the FDA in February 2004 for first-line treatment of metastatic colorectal cancer in combination with 5-fluorouracil-based chemotherapy, and is the first approved agent to target tumor angiogenesis (221M ). Thromboembolic events are the most clinically important adverse events, and hypertension, hemorrhage, and gastrointestinal perforation are other potential safety concerns (222c ). Cardiovascular Bevacizumab 5 mg/kg intravenously every 2 weeks can cause mild hypertension (223c ). Respiratory In a phase II trial, 99 patients with advanced or recurrent non-small-cell lung cancer were randomly assigned to bevacizumab 7.5 mg/kg (n = 32) or 15 mg/kg (n = 35) plus carboplatin and paclitaxel 200 mg/m2 every 3 weeks or carboplatin and paclitaxel alone (n = 32) (224c ). Bleeding was the most prominent adverse event and manifested as minor mucocutaneous hemorrhage or major hemoptysis. Major hemoptysis was associated with squamous cell histology, tumor necrosis and cavitation, and disease location close to major blood vessels. Ear, nose, throat Bevacizumab 5 mg/kg intravenously every 2 weeks can cause epistaxis (223c ). Nervous system Bevacizumab 5 mg/kg intravenously every 2 weeks can rarely cause intracranial hemorrhage (223c ). Urinary tract Bevacizumab 5 mg/kg intravenously every 2 weeks can cause mild proteinuria (223c ). Drug dosage regimens Bevacizumab 5 mg/ kg has shown promising efficacy in phase II clinical trials in patients with metastatic colorectal cancer, because its addition to 5-fluorouracil plus leucovorin resulted in a higher objective response rate (40% versus 17%), a longer time to disease progression (9.0 versus 5.2 months), and a longer median survival time (22 versus 14 months). The principle safety concerns, hypertension and thrombosis, were manageable, and phase II/III studies in colorectal cancer of bevacizumab, 5-fluorouracil, and leucovorin, with or without irinotecan and/or oxaliplatin are under way (225M ).
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In a phase II trial in patients with advanced metastatic non-small-cell lung cancer, the addition of bevacizumab to standard carboplatin/paclitaxel chemotherapy produced a significantly longer time to progression (32 versus 18 weeks) and a non-significantly greater response rate (31% versus 19%) than chemotherapy alone (226M ). Bevacizumab was generally well tolerated and did not appear to increase the incidence or severity of nausea/vomiting, neuropathy, and renal toxicity, which are typically associated with carboplatin/paclitaxel chemotherapy. Adverse events in phase I and II studies included hypertension, thrombosis, proteinuria with occasional nephrotic syndrome, and epistaxis. Serious tumor-related bleeding episodes, such as hemoptysis and hematemesis, appear to be the main safety concerns in patients with non-small-cell lung cancer with squamous cell histology.
Daclizumab
(SED-15, 1047)
Daclizumab is a humanized anti-IL2R (CD25) monoclonal antibody that is used to prevent rejection after organ transplantation and in the treatment of inflammatory bowel disease. A Cochrane analysis of IL-2R antagonists in kidney transplant recipients (n = 4893) showed no differences in graft loss at 1 and 3 years compared with placebo, while acute rejection was significantly reduced at 6 months and at 1 year with the use of daclizumab (227M ). Cytomegalovirus infection and malignancy were not significantly different at 1 year. In comparison with other antibody therapies, anti-IL2R monoclonal antibodies did not significantly differ in treatment effects, but adverse effects strongly favored their use. Placebo-controlled studies A combined regimen of methylprednisolone 2 mg/kg/day + daclizumab 1 mg/kg (on days 1, 4, and 8 and then weekly) as initial therapy of acute graft-versus-host disease is not recommended. Compared with placebo, the overall 1-year survival was inferior in the combination arm (29% versus 60%), and relapse contributed to the increased mortality in the combination group (228C ). Reproductive system Alterations in the female reproductive system were studied in 13 re-
Drugs that act on the immune system: cytokines and monoclonal antibodies
cipients of allogenic islet grafts with type 1 diabetes immunosuppressed by daclizumab induction, tacrolimus, and sirolimus. Four patients developed menstrual cycle alterations and clinically significant benign ovarian cysts (229c ). Drug dosage regimens Daclizumab was originally studied as a five-dose regimen, but data are accumulating to suggest that 2 or 3 doses are efficacious and less costly for preventing rejection after transplantation (230R ). A three-dose regimen after lung transplantation (n = 13) in combination with tacrolimus, mycophenolate mofetil and glucocorticoids caused three deaths on postoperative days 14, 19, and 23 due to pulmonary fungal infection, acute hepatic failure, or multiple organ failure resulting from stenosis and thrombosis of the hepatic artery (231c ). Ten recipients developed various infections. Anaphylaxis, PTLD, and other adverse effects were not observed. Monitoring therapy Monitoring soluble IL2 receptor-alfa in the urine and serum of renal transplant recipients taking daclizumab with Immulite IL-2R, a solid-phase enzyme-linked immunosorbent assay, was easier for determining the blockade of IL-2 receptor-alfa than flow cytometric analysis of IL-2 receptor-alfapositive lymphocytes (232c ).
Efalizumab
(SED-15, 2380)
Efalizumab is a humanized anti-LFA-1 (alpha subunit of CD11a) IgG1 monoclonal antibody that inhibits the binding of T lymphocytes to endothelial cells and their subsequent migration. It is used in the treatment of plaque psoriasis with minimal adverse effects (233r , 234C ).
Gemtuzumab ozogamicin
(SED-15,
1488) Gemtuzumab ozogamicin is currently approved to treat CD33-positive acute myeloid leukemia in first relapse in patients aged over 60 years (235c ). Hematologic In elderly patients with acute myeloblastic leukemia (n = 57) aged 61–75
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years, reversible myelosuppression and liver toxicity were the main adverse events during frontline intravenous treatment with gemtuzumab ozogamicin 9 mg/m2 on days 1 and 15 followed by MICE chemotherapy (mitoxantrone + cytarabine + etoposide). Frontline gemtuzumab ozogamicin was associated with modest mucosal and gastrointestinal toxicity, but grade 3–4 pancytopenia was universal and prolonged (236c ). Gemtuzumab ozogamicin caused thrombocytopenia, neutropenia, infections, and raised bilirubin and hepatic transaminases. Severe bleeding occurred in five of 24 cases (21%) of patients with acute myeloblastic leukemia, including five with myeloid sarcomas (237c , 238c ). Gastrointestinal Four of five elderly patients with acute myeloblastic leukemia treated with gemtuzumab ozogamicin in combination with cytarabine developed grade 3/4 bleeding, including gastrointestinal bleeding, epistaxis, intracranial hemorrhage, and ocular bleeding (239c ). Liver Several reports have suggested an association between gemtuzumab ozogamicin and hepatic veno-occlusive disease, but most of the patients in whom this was reported had received high-dose therapy with stem cell transplantation or gemtuzumab ozogamicin in combination with other cytotoxic drugs. Veno-occlusive disease has therefore been studied in 47 patients who received gemtuzumab ozogamicin 9 mg/m2 in two doses 14 days apart, either as initial therapy or in the relapsed and refractory setting. There was liver toxicity in 23 patients, reflected by rises in at least one liver function test (alanine transaminase, aspartate transaminase, total bilirubin, or alkaline phosphatase), with a median onset of 14 (range 7–175) days. Eight of these patients had other co-morbid conditions that could have explained the liver abnormalities, and only one had radiographic and clinical evidence of veno-occlusive disease (240c ). Intravenous gemtuzumab ozogamicin 9 mg/ m2 on days 1 and 15 followed by MICE chemotherapy in 57 elderly patients with acute myeloblastic leukemia resulted in hepatic venoocclusive disease in three patients after gemtuzumab ozogamicin and two after MICE; four patients died from liver failure (236c ).
410 Death The rates of failure due to treatmentrelated mortality or resistant disease were 14% during treatment with intravenous gemtuzumab ozogamicin 9 mg/m2 on days 1 and 15 followed by MICE chemotherapy in 57 elderly patients with acute myeloblastic leukemia. Three died during gemtuzumab ozogamicin therapy and five during MICE. Four of five patients with veno-occlusive disease died from liver failure. One-year survival at follow-up was 34% (236c ).
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Management of adverse drug reactions Late occurrence of hepatic veno-occlusive disease following gemtuzumab ozogamicin can be treated successfully with defibrotide (241A , 242A ).
Infliximab See Tumor necrosis factor (TNF) antagonists.
Susceptibility factors Age The pharmacokinetics of gemtuzumab ozogamicin 6, 7.5, and 9 mg/m2 have been studied in 29 children aged 18 years and under with relapsed or refractory acute myeloblastic leukemia. The mean pharmacokinetic values and interindividual variability were similar to those reported in adults, as were the increases in AUC and decreases in both CL and Vss from the first dose to the second dose (235c ). Changes between dose periods for total calicheamicin derivatives and unconjugated calicheamicin derivatives were consistent with those of hP67.6. These changes in pharmacokinetics between dose periods are attributed to saturation of CD33 binding sites and diminished clearance resulting from a lower peripheral blast burden and antigen. Drug interactions Myeloblasts from patients refractory to gemtuzumab ozogamicin often express the drug transporter P glycoprotein and/or multidrug resistance proteins. Inhibition of drug transport by the P glycoprotein modulator ciclosporin can increase gemtuzumab ozogamicin sensitivity in P glycoprotein positive acute myeloblastic leukemia cells and the peripheral benzodiazepine receptor ligand PK11195 sensitizes acute myeloblastic leukemia cells to standard chemotherapeutic agents both by inhibiting P glycoprotein-mediated efflux and by promoting mitochondrial apoptosis (240E ). PK11195 can overcome multiple resistance mechanisms to increase gemtuzumab ozogamicin sensitivity in myeloblasts, including resistance associated with expression of drug transporters and/or antiapoptotic proteins. PK11195 substantially increases gemtuzumab ozogamicin cytotoxicity in myeloblasts from many different cell lines and primary patient samples, often more effectively than ciclosporin.
Rituximab
(SED-15, 3069)
Rituximab is a chimeric anti-CD20 monoclonal antibody that was approved for the treatment of refractory or relapsed low-grade or follicular non-Hodgkin’s lymphoma in 1997. Adverse effects that are encountered especially during the first infusion are chills, fever, allergic reactions, cardiopulmonary syndrome, and tumor lysis syndrome (243A ). Cardiovascular Acute coronary syndrome has been reported during rituximab therapy. It was speculated that release of cytokines during rituximab infusion caused vasoconstriction, platelet activation, or rupture of an atherosclerotic plaque (244A ). • A 71-year-old man, with a history of type II diabetes mellitus, hypertension, a myocardial infarction 12 years before, and percutaneous transluminal coronary angioplasty 11 years before, was given chlorambucil for B cell chronic lymphocytic leukemia without a response (244A ). Rituximab 375 mg/m2 was therefore, started at a rate of 50 mg/hour intravenously after premedication with paracetamol, diphenhydramine, and methylprednisolone. Four hours later he developed substernal pain radiating to the neck and left arm with a sinus tachycardia; the pain responded to glyceryl trinitrate; the cardiac enzymes were not raised. Rituximab 30 mg/hour was restarted after an interval of 2 hours. He developed identical symptoms and rituximab was withdrawn.
Respiratory Interstitial pneumonitis has been reported after rituximab therapy for immune thrombocytopenic purpura (245A ). • A 77-year-old woman with a 2 year history of immune thrombocytopenic purpura did not respond with a rise in platelet count during a 4-week
Drugs that act on the immune system: cytokines and monoclonal antibodies
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course of rituximab 375 mg/m2 once weekly. Comedication consisted of prednisolone 60 mg/day, danazol 600 mg/day, and warfarin (INR 2–3) because of a mechanical aortic valve. Two weeks after the last infusion of rituximab, elective splenectomy was cancelled because of interstitial pneumonitis. Her pulmonary symptoms improved after the dose of prednisolone was tapered and withdrawn over 2 months.
eyelids and sclerae. Therapy was interrupted, and he was given intravenous hydrocortisone. Rituximab was restarted at a rate of 25 mg/hour after the edema had subsided, and he was given the total dose. One week later, the treatment was repeated, again with diphenhydramine and paracetamol prophylaxis, and was well tolerated. He received six additional doses of rituximab without any adverse events.
Nervous system Reversible posterior leucoencephalopathy has been reported after rituximab infusion (246A ).
Gradual tumor destruction by immune effector cells, leading to local cytokine release and accumulation may have resulted in local edema in this patient.
• A 38-year-old woman with a 13-year history of systemic lupus erythematosus and a small brain infarct with an episode of diplopia and blurring of vision had recurrent occipital headaches, blurring of vision, seizures, and hypertension (210/120 mmHg) after receiving a second weekly course of intravenous rituximab 375 mg/m2 . Concomitant treatment consisted of quarterly infusions of cyclophosphamide and oral anticoagulation (INR 2.5–3.0). Thrombotic microangiopathy and increased lupus activity were diagnosed. Her kidney function deteriorated and she required hemodialysis. After 6 days a third infusion of rituximab was given and she developed an occipital headache, blurring of vision, and seizures 6 hours later. An MRI scan showed high-intensity signals in the cortical and subcortical white matter of the parietal lobes and the lateral posterior and lateral portions of the temporal lobes, consistent with reversible posterior leucoencephalopathy. Hypertensive and anticonvulsant therapy resolved the symptoms within 24 hours. Plasmapheresis, intravenous cyclophosphamide, and methylprednisolone were started. Six weeks later the MRI scan was normal and renal function had improved.
The authors speculated that an interaction with anti-CD20 expressed on activated endothelial cells or systemic lupus erythematosus itself had contributed to the occurrence of reversible posterior leucoencephalopathy. Sensory systems Edema of the eyelids and sclerae occurred after rituximab infusion (247A ). • A 60-year old man with heavily pretreated and refractory mucosa-associated lymphoid tissue (MALT) lymphoma developed bilateral orbital swelling and lymphadenopathy. Given the lack of standard chemotherapy for refractory MALT lymphoma, he was given rituximab 375 mg/m2 (25 mg/hour increasing to 100 mg/hour) plus cladribine and was given intravenous diphenhydramine 50 mg and oral paracetamol 650 mg 30 minutes before the rituximab infusion. Within 2 hours he developed painful bilateral edema of the
Hematologic Late-onset neutropenia occurred in six patients who were given rituximab after stem cell transplantation (248c ). Late-onset neutropenia is a newly recognized adverse effect of rituximab treatment and can last for up to 1 year. • A 30-year-old man with intestinal CD20-positive Burkitt’s lymphoma and retroperitoneal lymphadenopathy was treated with hyper-CVAD chemotherapy (cyclophosphamide, vincristine, doxorubicin, dexamethasone, high-dose methotrexate, and cytarabine) combined with rituximab for eight courses over 5 months (249A ). Four weeks after the end of treatment he developed marked neutropenia and hypogammaglobulinemia, which persisted for 1 year. However, he did not develop any severe infections.
In a phase II study, rituximab 375 mg/m2 , fludarabine 100 mg/m2 , and cyclophosphamide 750 mg/m2 were evaluated in the treatment of relapsed follicular lymphoma. Unexpected severe hematological toxicity with significant prolonged thrombocytopenia WHO grade 3/4 occurred in six of 17 patients and led to early termination of the trial (250c ). Cytology and serology suggested a direct toxic effect. Older patients (mean age 65 versus 57 years) were significantly more likely to develop this toxic effect; no other clinical or hematological parameters differed statistically between those with thrombocytopenia and those without. The addition of rituximab to fludarabine/cyclophosphamide in relapsed follicular lymphoma may have led to this increase in the risk of thrombocytopenia. Caution should therefore be exercised when combining these drugs in patients with relapsed follicular lymphoma, especially older patients. Rituximab-induced thrombocytopenia occurred in a patient with mantle cell lymphoma (251A ).
412 • A 57-year-old man with mantle cell lymphoma stage IV and massive splenomegaly received rituximab 375 mg/m2 as part of induction chemotherapy. The white cell count was 10.8 × 109 /l, hemoglobin 9.4 g/dl, and platelets 151 × 109 /l. After the first infusion of rituximab 638 mg over 4 hours, he developed fever and rigors and was given paracetamol and pethidine. On the next day his white cell count was 6 × 109 /l, hemoglobin 7.7 g/dl, and platelets 8 × 109 /l. After a platelet transfusion, the platelet count increased to 39 × 109 /l. He was given CHOP (cyclophosphamide, hydroxydaunomycin, vincristine, prednisolone) 3 days after the rituximab infusion and the platelet count rose to 82 × 109 /l. After a second cycle of chemotherapy 3 weeks later, the platelet count fell within hours after rituximab infusion from 133 × 109 /l to 8 × 109 /l. Serum sickness was ruled out by C1q and C3d assays within the reference ranges.
The pathophysiology of rituximab-induced thrombocytopenia is unclear. The authors speculated that it was due to a soluble CD20 antigen–antibody reaction and immune-mediated cell lysis by complement activation or CD20 antigen on the platelets themselves, leading to antibody-mediated cell destruction. Immunologic Drug-induced hypersensitivity pneumonia has been attributed to rituximab. Few similar reactions have been described. Two were fatal, but none was associated with pulmonary hemorrhage. A 2.5:1 ratio between the interstitial alveolar T4/T8 lymphocytes in the reported case was similar to the findings in methotrexate-induced pneumonitis and farmers’ lung (252A ). • A 65-year-old man developed a progressive dry cough and digital clubbing after starting rituximab + CHOP chemotherapy for non-Hodgkin’s lymphoma. Lung biopsy showed loose non-necrotic granulomas on a background of mild fibrosis and rare eosinophils, compatible with drug-induced hypersensitivity pneumonia. Associated manifestations were a high eosinophil count, raised serum concentrations of IgE, and a skin rash consistent with pigmented purpuric dermatitis. Glucocorticoids were marginally efficacious in treating this reaction.
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were negative (254A ). She was treated with three courses of rituximab plus anticancer drugs and one course of anticancer drugs. Prednisolone was not given. After the fourth course of chemotherapy with the third dose of rituximab she developed hepatic dysfunction, and the serum titers of HBs and HBc antibodies suddenly fell. After administration of lamivudine she gradually recovered from liver failure.
Management of adverse drug reactions Accurate determination of rituximab plasma concentrations is important for proper dosing of patients and for correlating rituximab concentrations with clinical responses. However, there is currently no assay available that uses easily obtainable commercial reagents. One assay is based on flow cytometry and quantifies immunologically active rituximab based on its ability to bind to CD20 on Raji cells. Two other methods are based on flow cytometry and ELISA and measure rituximab based on its antigenic properties. The assays are accurate, in good agreement with one another, and can all measure rituximab concentrations as low as about 1 µg/ml in both serum and plasma. Patients with chronic lymphocytic leukemia receiving rituximab had lower plasma rituximab concentrations than patients with other B cell lymphomas at all times over the usual 4-week course of therapy. The rituximab plasma concentration in patients with chronic lymphocytic leukemia often falls to below 1 µg/ml 1 week after each infusion, substantially lower than the values found in comparable patient without chronic lymphocytic leukemia. In patients with chronic lymphocytic leukemia who have not previously received rituximab the concentrations of non-cell associated CD20 are not sufficient either to interfere with an in vitro assay of rituximab or to block the potential therapeutic action of rituximab in vivo (255E ).
Infection risk Rituximab can cause reactivation of hepatitis B virus infection (253A , 254A ).
Pregnancy The optimal treatment of nonHodgkin’s lymphoma during pregnancy has not been well defined. The potential teratogenic effects of conventional chemotherapeutic drugs preclude their use during the first trimester. Data on the use of rituximab during pregnancy are scarce.
• A woman with non-Hodgkin’s lymphoma developed hepatitis B virus reactivation after rituximab treatment. HBs antigens and HBs, HBe, and HBc antibodies were positive, but HBe antigens
• A pregnant woman with relapsed indolent follicular non-Hodgkin’s lymphoma was unintentionally treated with rituximab during the first trimester. The treatment stabilized the disease. Following an
Drugs that act on the immune system: cytokines and monoclonal antibodies uncomplicated pregnancy, a healthy child was born at full term and careful hematological and immunological monitoring showed no adverse effects resulting from exposure to rituximab (256A ).
This case suggests that rituximab may be one option for treatment of non-Hodgkin’s lymphoma in early pregnancy. Susceptibility factors Genetic Japanese patients (n = 68) with relapsed or refractory aggressive B cell lym-
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phoma were treated with an infusion of rituximab 375 mg/m2 on 8 consecutive weeks (257c ). Mild to moderate infusion-related toxic effects were common after the first infusion, but all were reversible. Raised lactate dehydrogenase activity and refractoriness to prior chemotherapy were unfavorable factors that affected the overall response rate and progressionfree survival. Serum trough concentrations and AUC of rituximab in responders were significantly higher than in non-responders.
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Drugs that act on the immune system: immunosuppressive and immunostimulatory drugs
IMMUNOSUPPRESSIVE DRUGS Azathioprine (SED-15, 377; SEDA-26, 404; SEDA-27, 373; SEDA-28, 450) [Editor’s note: Azathioprine is a thiopurine; the other thiopurines, mercaptopurine and thioguanine, are covered in the special review in Chapter 45.] Hematologic Myelotoxicity is a well known major adverse effect of azathioprine, and leukocytes are more commonly affected than other bone marrow elements. Megaloblastic change occurs in 16–82% of bone marrow aspirates, but long-term use of azathioprine rarely causes severe anemia. In addition, azathioprine can cause refractory pure red cell aplasia, particularly after kidney transplantation (1A ). Refractory anemia was reported in a patient with 17p- syndrome after heart transplantation (2A ). Azathioprine can cause pancytopenia and subsequent myelodysplasia or secondary leukemia. Complex genetic alterations involving chromosome 7 are characteristic (3A ). • A 49-year-old woman with multiple sclerosis received azathioprine for 5 years (cumulative dose 45 g) (3A ). She developed fatigue and a sinus tachycardia. She had a pancytopenia with a normochromic anemia (hemoglobin 6.2 g/dl), a mild leukopenia (leukocyte count 3.5 × 109 /l), and thrombocytopenia (platelet count 22 × 109 /l) requiring platelet transfusion. A bone marrow aspirate showed dysplasia of all three lineages, with Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29038-X © 2007 Elsevier B.V. All rights reserved.
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reduced thrombopoiesis and ineffective erythropoiesis. Cytogenetic analysis showed a complex aberrant clone, including loss of the critically deleted regions in 5q31 and 7q31, as well as structural changes in 12p. Refractory cytopenia with multilineage dysplasia was diagnosed according to the WHO classification of myelodysplastic syndromes. Allogeneic sibling transplantation was planned, but she developed a spontaneous recurrent subdural hematoma and died due to persistent bleeding refractory to platelet transfusion.
Pancreas Azathioprine-associated acute pancreatitis is strongly associated with Crohn’s disease and occurs less commonly with other underlying conditions (4M ). The incidence of acute pancreatitis was 4.9% in 224 patients with Crohn’s disease, 1.5% in 129 with autoimmune hepatitis, 0.5% in 388 with kidney transplants, and 0.4% in 254 with liver transplants. Skin A febrile diffuse skin eruption occurred in a patient taking azathioprine and a glucocorticoid (5A ). • A 53-year-old man with moderately active ulcerative colitis developed a febrile diffuse skin eruption after taking a glucocorticoid and azathioprine for a few days. Azathioprine was withdrawn. Skin biopsies showed features typical of Sweet’s syndrome (neutrophilic dermatosis). The eruption gradually improved and there was complete regression after further glucocorticoid treatment.
Drug withdrawal In clinical trials, azathioprine is withdrawn in 0–15% of patients because of adverse effects. In patients with Crohn’s disease, azathioprine was preliminary withdrawn in 15 of 50 patients because of adverse events that were probably related to azathioprine in 11 cases (6c ). The rate of azathioprine withdrawal differs between various indications (4M ). Azathioprine withdrawal due
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to drug-related toxicity was significantly higher in patients with rheumatoid arthritis (78/317), ulcerative colitis (20/94), and Crohn’s disease (52/224) compared with systemic lupus erythematosus (5/73), Wegener’s granulomatosis (6/85), autoimmune hepatitis (8/129), after liver transplantation (17/254), and after kidney transplantation (22/388).
with very high TPMT activity are hypermethylators, in whom a beneficial clinical response is less likely. Prior knowledge of TPMT status avoids exposure of individuals with zero TPMT to potentially fatal treatment with azathioprine or mercaptopurine and provides one of the best examples of predictive pharmacogenetics in therapeutics (12R ). Patients with low or deficient TPMT activity are at risk of severe complications and even death, and determination of TPMT is recommended before azathioprine therapy. However, caution must be taken in interpreting TPMT activity in patients who have recently been transfused. Deficient TPMT activity might be missed after erythrocyte or platelet transfusions from patients with normal TPMT activity (13A ).
Drugs that act on the immune system
Tumorigenicity A colon cancer developed after introduction of azathioprine (7A ). Fetotoxicity Out of 57 249 pregnancies, 54 were fathered by men who had filled a prescription for azathioprine or mercaptopurine before conception (8r , 9C ). There were congenital abnormalities in four children (7.4%) compared with 2334 of 57 195 children whose fathers had not taken azathioprine (4.1%), but the odds ratio was not statistically significant. All four congenital abnormalities occurred in boys and consisted of polysyndactyly, esophageal atresia, hydronephrosis with megaloureter, and a ventricular septal defect. Immune function was studied in nine babies from six mothers taking ciclosporin (n = 2), azathioprine (n = 1), and dexamethasone (n = 3) during pregnancy compared with 14 babies from mothers with similar diseases not taking immunosuppressive drugs (10c ). The children were tested at a mean age of 11 (1–17) months. Only a minor proportion of children displayed low values for age, mainly IgA and IgG2. Blood counts, IgA, IgG, IgM, and IgG subclasses, and lymphocyte subpopulations did not differ significantly, and all the children responded satisfactorily to hepatitis B immunization. Prenatal exposure to immunosuppressive drugs had no profound effect on the developing immune system. Azathioprine/mercaptopurine was not associated with poor pregnancy outcomes in 101 women with inflammatory bowel disease (11c ). Susceptibility factors Genetic—TPMT deficiency Allelic polymorphisms in the TPMT gene predict the activity of the enzyme; 1 in 10 of the population are heterozygous and have about 50% of normal activity, while 1 in 300 are completely deficient. These individuals are at high risk of severe myelosuppression. Conversely, individuals
• A woman underwent azathioprine therapy without prior knowledge of TPMT status. Pancytopenia developed over several months. TPMT activity was low at 16 nmol 6-methyl-thioguanine/g Hb/hour, that is within the reference range associated with heterozygosity for TPMT mutant alleles. Three months later, TPMT activity was 2 nmol 6-methylthioguanine/g Hb/hour, consistent with deficient TPMT activity (homozygosity for TPMT mutant alleles). Retrospectively, it was realized that the patient had received erythrocyte and platelet transfusions 6 days before TPMT activity was first measured.
Genetic—ITPase deficiency Adverse drug reactions to azathioprine occur in 15–28% of patients, but often cannot be explained by TPMT deficiency. Inosine triphosphate pyrophosphatase (ITPase) is an enzyme that catalyses the pyrophosphohydrolysis of ITP to IMP. ITPase deficiency is a clinically benign autosomal recessive condition characterized by the abnormal accumulation of ITP in erythrocytes (14C ). Mercaptopurine is activated through a 6thio-IMP intermediate, and in patients deficient in ITPase there will be accumulation of 6-thioITP, which is potentially toxic. Deficiency of ITPase may predict adverse reactions to therapy with the thiopurine drug mercaptopurine and its prodrug azathioprine (15C ). The association between polymorphism in the ITPA gene and adverse drug reactions to azathioprine has been studied in 62 patients with inflammatory bowel disease who had adverse reactions to azathioprine (16C ). The patients were genotyped for ITPA 94C → A and IVS2 plus 21A → C polymorphisms, and
426 TPMT*3A, TPMT*3C, and TPMT*2 polymorphisms. Genotype frequencies were compared with the frequencies in a consecutive control series (n = 68) treated with azathioprine without adverse effects. The ITPA 94C → A allele was significantly associated with adverse drug reactions (OR = 4.2; 95%CI = 1.6, 12). There were significant associations for flu-like symptoms (OR = 4.7; 95%CI = 1.2, 18), rash (OR = 10; 95%CI = 4.7, 63), and pancreatitis (OR = 6.2; CI = 1.1–33). Heterozygous TPMT genotypes did not predict adverse drug reactions but were significantly associated with a subgroup of patients who had nausea and vomiting as the predominant adverse reaction to azathioprine (OR = 5.5; 95%CI = 1.4, 22). Thus, polymorphism in the ITPA gene predicts azathioprine intolerance and alternative immunosuppressive drugs, particularly thioguanine, should be considered for azathioprineintolerant patients with ITPase deficiency (15C , 16C ). There has been another study of the association between azathioprine-associated adverse effects and the A 94C → A mis-sense mutation in the ITPA gene in patients with inflammatory bowel disease intolerant of thiopurine drugs. The ITPA 94C → A, TPMT*2, and TPMT*3 polymorphisms were determined in azathioprine-intolerant (n = 73) and azathioprinetolerant (n = 74) patients. In contrast to the studies described above, this study showed no significant association between the ITPA 94C → A genotype and any adverse effects (OR = 1.0, 95%CI = 0.4, 2.9), flu-like symptoms (OR = 1.5, 95%CI = 0.4, 6.5), rash (no ITPA 94C → A polymorphism identified), or pancreatitis (no ITPA 94C → A polymorphism identified) (17C ). The frequencies of ITPA polymorphisms have been studied in 100 healthy Japanese individuals (14C ). The allele frequency of the 94C → A variant was 0.135 (Caucasian allele frequency = 0.06). The IV2 + 21A→C polymorphism was not found (Caucasian allele frequency = 0.13). Allele frequencies of the 138G → A, 561G → A, and 708G → A polymorphisms were 0.57, 0.18, and 0.06 respectively, similar to the allele frequencies in Caucasians, with the exception of the 138G → A polymorphism (18C ). Drug dosage regimens About 40% of patients with inflammatory bowel disease fail to
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respond to azathioprine 2 mg/kg/day. An increase in dose had no therapeutic benefit in 17 of 40 patients who had been unresponsive to azathioprine 2 mg/kg/day for at least 3 months; dosages over 2.5 mg/kg/day were less likely to be efficacious and were associated with a substantial risk of adverse reactions (19c ). Drug interactions Azathioprine and mercaptopurine are metabolized by xanthine oxidase, which is inhibited by allopurinol. Concomitant administration can result in life-threatening neutropenia unless the dose of allopurinol is reduced by about 75% (20r , 21A ). Interference with diagnostic tests Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) concentrations are widely used as markers of inflammation. There was an unexplained discordance between ESR and CRP in children with asymptomatic inflammatory bowel disease taking azathioprine or mercaptopurine. The ESR was persistently raised in 11 of 120 children but the CRP was normal and there was no clinical evidence of active disease (22c ). Diagnosis of adverse drug reactions Azathioprine-induced drug eruption occurred in two patients with systemic scleroderma and polymyositis (23A ). One presented with Stevens–Johnson syndrome and the other had systemic papular erythema. Stimulation indices of the drug-induced lymphocyte stimulation test (DLST) for azathioprine in these patients were as high as 2180% and 430%, while healthy volunteers had values under 120% without non-specific suppression of lymphocyte proliferation. Other drugs used simultaneously were ruled out by patch and challenge tests. DLST might therefore be useful in testing for azathioprine allergy.
Ciclosporin
(SED-15, 743; SEDA-26, 404; SEDA-27, 374; SEDA-28, 452) Comparative studies In patients taking ciclosporin or tacrolimus, drug-induced hirsutism, gingival hyperplasia, acne, alopecia, or Cushingoid facies were reported in 80% of surveyed
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kidney recipients. Hirsutism (94%) and gingival hyperplasia (51%) occurred more often in patients taking ciclosporin, while alopecia (30%) occurred more often in patients taking tacrolimus (24C ). For every condition the incidence of physical changes reported by the patients significantly exceeded the observations by the professionals; however, 84% of affected patients reported feeling “happy to endure” these changes “for the sake of having a transplant.” They also reported emotional and social effects due to physical changes, an outcome that was underestimated by transplant professionals.
rejection. The incidence of thrombotic microangiopathy was highest with ciclosporin + sirolimus (21%). The relative risk of thrombotic microangiopathy was 16 (95%CI = 4.3, 61) for ciclosporin + sirolimus compared with tacrolimus + mycophenolate mofetil. Ciclosporin + sirolimus was the only regimen that had concomitant pro-necrotic and anti-angiogenic effects on arterial endothelial cells. This suggests that ciclosporin + sirolimus causes thrombotic microangiopathy through dual effects on endothelial cell death and repair.
Drugs that act on the immune system
Cardiovascular Arterial hypertension is common after kidney transplantation. In 3365 adults with a functioning graft after the first year, the prevalence of hypertension increased progressively and significantly during follow-up (25M ). The presence of arterial hypertension at 1 year was significantly associated with recipient sex (male), donor age (under 60 years), immunosuppressive therapy (ciclosporin), serum creatinine, and year of transplantation. Arterial hypertension was not associated with graft survival or cardiovascular mortality. The prevalence and severity of hypertension was significantly lower in patients treated with tacrolimus than with ciclosporin. Drug-induced infusion phlebitis is mainly associated with the use of antibiotics or cytotoxic drugs, and recurrent infusion phlebitis during ciclosporin treatment has not previously been reported (26A ). • A 28-year-old man with ulcerative colitis had acute recurrent infusion phlebitis during administration of intravenous ciclosporin following intravenous hydrocortisone. The intravenous catheter and its site needed to be replaced repeatedly during treatment, which eventually led to complete remission of the ulcerative colitis. After 8 months, he was still in remission, with no permanent signs of damage to the phlebitic veins.
The association between the risk of thrombotic microangiopathy and the use of the combinations ciclosporin + mycophenolate mofetil, ciclosporin + sirolimus, tacrolimus + mycophenolate mofetil, and tacrolimus + sirolimus has been studied in 368 kidney or kidneypancreas transplant recipients (27C ). Biopsyproven thrombotic microangiopathy was detected in 13 patients in the absence of vascular
Nervous system Ciclosporin can cause various neurological disorders, such as tremor, seizures, and central pontine myelinolysis, especially after liver transplantation. In one series of 367 adult and pediatric liver recipients there were 17 cases of new-onset seizures (28C ). However, information on the immunosuppressants they were taking was scanty: three were reported as having ciclosporin toxicity and three as having tacrolimus (FK506) toxicity. The causes were neurotoxicity due to immunosuppressive therapy (n = 6), cerebrovascular disease (n = 4), severe metabolic derangements by sepsis or rejection (n = 3), hyperglycemia (n = 1), brain edema due to fulminant hepatic failure (n = 1), and unknown (n = 2). Seizures recurred in 15 patients, including nine on the same day. The incidence of death or persistent vegetative state in those with seizures was almost 10 times higher than in those without (53% versus 5.7%). The prognosis in patients with seizures due to cerebrovascular disease and severe metabolic derangement due to sepsis or rejection was poorer than in patients with seizures caused by drug neurotoxicity. The eight surviving patients were free of seizures for a follow-up period of 43 (16–58) months. In another study after liver transplantation, 13 of 142 recipients ciclosporin and methylprednisolone (9.2%) had neurological symptoms, including five with central pontine myelinolysis and eight with cerebral hemorrhages or infarcts (29C ). Factors that were associated with central pontine myelinolysis were hyponatremia, a rapid rise in serum sodium concentration, a postoperative increase in plasma osmolality, duration of operation, and high ciclosporin concentrations.
428 Tremor has been studied in patients with severe liver disease without hepatic encephalopathy and after liver transplantation, comparing ciclosporin (n = 29) and tacrolimus (n = 6) (30c ). Compared with controls the patients had significant postural hand tremor before and after liver transplantation. The mean tremor amplitude increased after liver transplantation during treatment with both ciclosporin and tacrolimus. At higher ciclosporin plasma concentrations there was a reduction in the dominant tremor frequency with weight load and an increase in tremor amplitude, suggesting enhanced physiological or toxic tremor. After liver transplantation, a patient developed a chronic inflammatory demyelinating polyradiculoneuropathy while taking ciclosporin + prednisolone (31A ). Treatment with intravenous immunoglobulin significantly improved the neuropathy. Severe headache is an uncommon adverse effect of ciclosporin (32A ). • A 66-year-old woman with no history of headache or adverse drug reactions developed membranous glomerulonephritis and autoimmune noncentral neutropenia. She was given ciclosporin microemulsion 2.5 mg/kg/day. Whole blood ciclosporin concentrations were within the target range. After 5 days she reported a severe, disabling, holocranial headache. A CT scan was normal and other causes of headache were ruled out. The headache subsided when ciclosporin was withdrawn.
Pseudotumor cerebri caused bilateral disk edema with cerebrospinal hypertension in a child treated with ciclosporin (33A ). • An 11-year-old boy with recurrent tubulointerstitial nephritis associated with uveitis (TINU syndrome) was treated with ciclosporin to induce sustained remission. Ciclosporin was introduced as a steroid-sparing drug because of extreme obesity (BMI 32 kg/m2 ). Although he did not complain of any symptoms, eye inspection after 7 months showed bilateral disk edema with retinal bleeding and he developed cerebrospinal hypertension. Pseudotumor cerebri was diagnosed by measuring the intracranial pressure (31 cm H2 O) and normal CT and MRI scans. Ciclosporin was withdrawn, and treatment with mycophenolate mofetil led to resolution within 12 weeks.
Sensory systems Ocular opsoclonus responded to a reduction in the dose of ciclosporin in a liver transplant recipient (34A ).
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• A 17-year-old Caucasian woman underwent liver transplantation for immunological cirrhosis and chronic cellular rejection. She developed ocular symptoms 8 days after transplantation. She also developed a reversible posterior leukoencephalopathy. The ciclosporin trough concentration was 412 ng/ml. The ocular symptoms improved 21 days after reduction of the ciclosporin trough concentration.
This rare condition usually occurs in patients with brain stem encephalitis, neoplasms of the mesencephalon, paraneoplastic syndromes, or intoxication. Endocrine Tacrolimus + sirolimus, tacrolimus + mycophenolate mofetil, and ciclosporin + sirolimus have been compared in recipients of their first kidney transplant (35C ). Oneyear patient and graft survival did not differ. Ciclosporin + sirolimus was associated with increased serum creatinine concentrations, reduced creatinine clearance, more frequent protocol discontinuation, more antihyperlipidemic drug therapy, and a higher incidence of posttransplant diabetes mellitus. Mouth Gingival hyperplasia is a well-known complication of ciclosporin therapy, affecting 21–35% of renal transplant patients. In 18 renal transplant patients taking ciclosporin azithromycin 500 mg/day for 3 consecutive days reduced gingival hyperplasia (36c ). Thus, involvement of micro-organisms is implicated in the pathogenesis of ciclosporin-induced gingival overgrowth. Chlamydia pneumoniae IgG and IgM antibody titers were measured by microimmunofluorescence in the sera of kidney recipients with (n = 11) and without (n = 89) gingival overgrowth (37c ). Chlamydia pneumoniae IgM titers were raised in five of 11 patients with gingival overgrowth and in none without gingival overgrowth. Chlamydia pneumoniaespecific DNA was found in 10 of 11 gingival overgrowth tissue samples before azithromycin therapy, which effectively reduced both gingival overgrowth and Chlamydia pneumoniae IgM titers. Chlamydia pneumoniae infection is highly prevalent in ciclosporin-induced gingival overgrowth. The infection can persist over a long period in residual gingival overgrowth despite short-term azithromycin therapy.
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Gastrointestinal Peptic ulcer disease is a common complication among kidney transplant recipients, with significant morbidity and mortality. After kidney transplantation, 181 of 465 patients (39%) had at least one episode of peptic ulcer disease, including gastritis, gastric ulcer, duodenal ulcer, esophagitis, duodenitis, and esophageal ulceration (38M ). Most of the patients were taking a glucocorticoid + ciclosporin and 156 were taking mycophenolate mofetil. Methylprednisolone pulse therapy (OR = 3.95, 95%CI = 3.15, 18) and a history of pre-transplant peptic ulcer disease (OR = 7.60, 95%CI = 1.21, 13) were independent risk factors for post-transplant peptic ulcer disease by multivariate analysis. Antiulcer prophylaxis is recommended during the use of high-dose glucocorticoids after kidney transplantation, especially in recipients with a history of peptic ulcer disease.
strategies to ameliorate or avoid nephrotoxicity are therefore urgently needed. Chronic interstitial fibrosis is an adverse prognostic feature of chronic allograft nephropathy. It has been analysed in protocol kidney biopsies (n = 959) obtained regularly for 10 years after kidney transplantation (41C ). There was substantial interstitial fibrosis within 1 year after kidney transplantation, with maximum intensity within the first 3 months as a result of early ischemia–reperfusion injury and acute, subacute, or persistent interstitial inflammation. Ciclosporin increased the risk of interstitial fibrosis compared with tacrolimus, and mycophenolate mofetil was protective compared with azathioprine. Ciclosporin-induced renal hypoperfusion was detected by quantitative cine-loop color Doppler imaging after kidney transplantation in 22 patients (42c ). They were taking ciclosporin + mycophenolate mofetil + prednisolone (n = 7), tacrolimus + mycophenolate mofetil + prednisolone (n = 7), or ciclopsorin + a calcium channel blocker (n = 8). The mean effect occurred 1.1 hours after ciclosporin dosing and was prevented by calcium channel blockers. Main renal artery velocities, resistive index, and small vessel perfusion were unchanged, suggesting that medium-sized arteries mediated vasoconstriction. In contrast, tacrolimus did not alter renal vascularity. Withdrawal of ciclosporin increases the risk of rejection, but improves renal function and other forms of ciclosporin-related toxicity. Improvement has also been observed after ciclosporin dosage reduction without an increased risk of acute rejection. Chronic allograft deterioration improved after conversion from ciclosporin to mycophenolate mofetil. Promising results of complete ciclosporin avoidance after kidney transplantation need to be confirmed in larger trials with a longer follow-up (43R ).
Drugs that act on the immune system
Liver Concomitant caspofungin + ciclosporin can cause transiently increased serum transaminase activities. There were rises in serum alanine transaminase and aspartate transaminase in 14 of 40 patients taking concomitant therapy for 18 (1–290) days (39c ). The rises were at least possibly drug-related in five cases, and two patients discontinued therapy because of hepatotoxicity. Urinary tract Ciclosporin-induced nephrotoxicity has been studied in prospective protocol kidney biopsies (n = 888) from 99 patients taken regularly for 10 years after kidney transplantation (40C ). The most sensitive histological marker of ciclosporin-induced nephrotoxicity was arteriolar hyalinosis. Structural nephrotoxicity occurred in two phases, with different clinical and histological characteristics. The acute phase occurred with a median onset of 6 months after kidney transplantation, was usually reversible, and was associated with functional nephrotoxicity, high ciclosporin blood concentrations, and mild arteriolar hyalinosis. The chronic phase persisted over several biopsies and occurred at a median onset of 3 years. It was associated with lower ciclosporin doses and trough concentrations, was largely irreversible, and was accompanied by severe arteriolar hyalinosis and progressive glomerulosclerosis. These pathological changes exacerbated chronic allograft nephropathy and
Skin Folliculodystrophy has again been attributed to ciclosporin (44A ). • A 34-year-old female kidney transplant recipient taking ciclosporin developed an infiltrated appearance to the skin with abundant flesh-colored, follicular papules predominantly affecting the ears, nose, and surrounding areas of the face, but also the trunk and extremities.
430 Musculoskeletal Myositis occurred in a kidney recipient taking ciclosporin, mycophenolate mofetil, and prednisolone (45A ). • A 60-year-old man developed acute polymyositis 4 weeks after receiving a complete HLA mismatch cadaveric renal transplant. Immunosuppression consisted of ciclosporin, mycophenolate mofetil, and prednisolone. The patient developed severe symmetrical proximal muscle weakness associated with a rise in serum creatine kinase to 46 800 U/l. Electromyography confirmed the myopathic changes and muscle biopsy showed extensive muscle fiber necrosis with an inflammatory infiltrate. Viral studies were negative. Prompt initiation of high-dose glucocorticoid therapy led to clinical and biochemical recovery.
This rare complication following kidney transplantation is most commonly the result of drug-mediated myotoxicity. Reproductive system Breast fibroadenomas are the most common solid lesions found in young women, and they have been reported with a high incidence in female kidney transplant recipients taking ciclosporin. It has been suggested that ciclosporin acts on breast fibroblasts by humoral mechanisms and a direct action (46c ). Bilateral fibroadenomas were detected in four female kidney recipients taking ciclosporin (47c ). Symptomatic giant fibroadenomas required bilateral mammoplasty in one patient, while the size of the breasts significantly regressed in three patients after conversion to tacrolimus. Awareness of the association between ciclosporin and fibroadenomas in transplant patients might avoid unnecessary surgical procedures (47c , 48c ). Multiple or bilateral fibroadenomas were detected in 13 of 29 ciclosporin-treated female kidney recipients (age under 55 years), while all 10 female recipients taking glucocorticoids and azathioprine had no abnormal breast findings (46c ). Serum estradiol concentrations were raised in the women with fibroadenomas compared with those with normal breasts, and the FSH concentration was lower. In another series, 22 breast fibroadenomas were detected in 10 of 486 female kidney recipients taking ciclosporin and prednisolone (49c ). These 10 patients were compared with 100 women with fibroadenomas who had never undergone transplantation or immunosuppressive therapy. After kidney transplantation, eight
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patients had multiple fibroadenomas (mean diameter 4.2 cm), and seven were affected bilaterally. The histopathological features of the lesions were generally typical of fibroadenomas, but some were more typical of malignant lesions. The 100 control patients had 146 fibroadenomas. There were multiple lesions (mean diameter 2.1 cm) in 33 patients and 12 were affected bilaterally. Fibroadenomas in female ciclosporin-treated kidney recipients tend to occur multiply and bilaterally and to be of larger diameter than in control patients. The fibroadenomas also had some imaging features that differed from those of typical fibroadenomas; sonographically, the lesions were relatively highly echogenic and had a lower longitudinal to anteroposterior diameter ratio than those in the control group. The control group included 100 women with fibroadenomas who had never undergone organ transplantation or immunosuppressive therapy. Infection risk Immunosuppression due to ciclosporin can result in infection. • A patient with severe aplastic anemia developed hepatitis B virus reactivation on recovery from lymphopenia after ciclosporin and antithymocyte globulin therapy (50A ).
The phenomenon observed in this case supports the prevailing notion that hepatitis B flareup in hepatitis B virus carriers after chemotherapy is caused by an immune-mediated mechanism. Pre-emptive therapy with lamivudine is recommended in SAA/HBsAg(+) patients who receive ciclosporin and antithymocyte globulin. • A man with severe aplastic anemia and chronic hepatitis B virus infection (HbsAg(+), HBeAg(+), HBV-DNA wild-type) received ciclosporin and antithymocyte globulin (50A ). The patient developed lymphopenia over 1 and 2.5 months in response to antithymocyte globulin infusion and ciclosporin. Serum alanine transaminase activity normalized during lymphopenia, but serum hepatitis B viral load increased. The alanine transaminase rose again when his peripheral lymphocyte count recovered. Lamivudine normalized the raised alanine transaminase and suppressed viral replication.
Cryptococcus albidus, a non-neoformans species of the genus Cryptococcus, is generally regarded as a rare cause of disease. Previously, this organism has been isolated as a pathogen in only 14 cases. Recently, the first case of disseminated Cryptococcus albidus infection was reported in a renal transplant recipient (51A ).
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• A 23-year-old male renal transplant recipient taking ciclosporin and prednisolone developed a dry cough, fever, and progressive dyspnea. After 11 days his respiratory status deteriorated dramatically and he developed acute respiratory distress syndrome (ARDS) and fulminant septic shock. A week later tender macules on both of his shins coalesced to form erythematous patches. Cryptococcus albidus was isolated by skin biopsy and tissue culture. Thereafter, the patient was successfully treated with fluconazole monotherapy.
patients who are not taking other immunosuppressants. Nevertheless, two patients developed an explosive basal cell carcinoma and keratoacanthoma within 3 months after starting to take ciclosporin for psoriasis (55A ). Neither had a history of skin cancer or had received PUVA therapy or additional immunosuppressive drugs. The association between Epstein–Barr virus and lymphoma in patients taking immunosuppressive drugs has been well described. Recently, an Epstein–Barr virus-negative lymphoma developed in a ciclosporin-treated patient with refractory anemia (56A ).
Drugs that act on the immune system
Tumorigenicity The molecular effects that lead to the genesis of de novo malignancies during ciclosporin therapy are inhibition of DNA repair, synthesis of TGF-beta, induction of apoptosis of activated T cells, and inhibition of apoptosis through the inhibition of the opening of the mitochondrial permeability transition pore. Ciclosporin can promote the genesis and spread of cancer, not only because of immunosuppression but also because of its ability to facilitate the accumulation of DNA mutations, to reduce the clearance of altered cells, and to transform cancer cells into aggressive cancer cells (52M ). A ciclosporin-treated kidney recipient developed a melanoma metastasis in the allograft (53A ). • A 57-year-old female recipient of a cadaveric renal allograft took ciclosporin, azathioprine, and prednisone. The graft displayed normal renal function for 10 months after transplantation. However, she then developed multiple, large, rapidly growing skin nodules over the lower abdomen. There was metastatic melanoma within the graft and two focal points of melanoma within the skin lesions. She reverted to hemodialysis and received chemotherapy and interferon A, but failed to respond and died 11 days after nephrectomy.
Ciclosporin is effective in the treatment of psoriasis, but is associated with an increased risk of non-melanoma skin cancer, mainly squamous cell carcinoma, when patients have been previously exposed to psoralen-ultraviolet A (PUVA). However, the incidence of non-skin malignancies is not significantly different than in the general population (54M ). In contrast to transplant recipients, patients with autoimmune diseases tend to use lower doses of ciclosporin for shorter times. The current evidence suggests that the risk of cancer is not increased when ciclosporin is used in dermatological doses for less than 2 years in healthy
• A 70-year-old man developed pancytopenia. Bone marrow examination confirmed the diagnosis of refractory anemia. Ciclosporin 3.3 mg/kg/day was begun. He complained of epigastralgia 21 months later, and gastric endoscopic examination showed an ulcer with a cleaved bank. Biopsy showed a diffuse large B cell lymphoma without Epstein–Barr virus analysed by in situ hybridization. Ciclosporin was withdrawn and gastrectomy was performed 31 days later. Histologically, there were no abnormal B cells in the resected stomach. The spontaneous remission observed after withdrawal of ciclosporin treatment suggests that immunosuppressive therapy can be a pathogenic factor in a subset of Epstein–Barr virus-negative lymphomas.
Susceptibility factors Genetic African-American kidney transplant recipients have poorer long-term clinical outcomes and graft survival than Caucasian patients (57M ). Ethnic differences in the pharmacokinetics of immunosuppressants are potentially a key factor. Ciclosporin, tacrolimus, sirolimus, and everolimus all have ethnic-specific differences in systemic availability and/or dose-adjusted systemic exposure. The oral systemic availability of these drugs in AfricanAmericans was 20–50% lower than in Caucasians or non-African-Americans, leading to higher dosage requirements in African-Americans to maintain similar average concentrations. All four drugs undergo extensive metabolism and are substrates for CYP3A4 and CYP3A5 as well as MDR1. Drug dosage regimens Ciclosporin is commonly administered twice daily. A comparison of once and twice daily dosing after kidney transplantation (n = 54) showed higher AUCs with once daily dosing than with twice daily
432 dosing, but there were no differences in survival and rejection rates (58c ). Once daily dosing tended to be associated with lower mean serum creatinine at 1 year after transplantation. Monitoring therapy The use of 2-hour peak ciclosporin blood concentrations has been recommended as an alternative to trough concentration monitoring after kidney transplantation and liver transplantation (59C ). In 928 analyses after 313 heart transplants, the 2-hour concentration correlated better with ciclosporin dose, renal function, and rejection profile, and had less variability between patients than the trough concentration. Trough concentration-adjusted mycophenolate mofetil therapy has been studied in combination with tacrolimus (n = 30) or ciclosporin (n = 30) after heart transplantation (60c ). Target blood trough concentrations were tacrolimus 10–15 ng/ml, ciclosporin 100–300 ng/ml, and mycophenolic acid 1.5–4.0 µg/ml. Glucocorticoids were withdrawn within 6 months after heart transplantation. Tacrolimus + mycophenolate mofetil resulted in a significantly lower incidence of acute rejection than ciclosporin + mycophenolate mofetil, despite similar survival rates. Patients taking tacrolimus required a significantly lower dose of mycophenolate mofetil to achieve target mycophenolic acid blood concentrations compared with ciclosporin. Drug interactions Atorvastatin Atorvastatin is metabolized by the same pathway as ciclosporin. In stable liver transplant recipients, atorvastatin co-administration increased ciclosporin AUC by 9% (range 0–21%) (61c ). There were no other significant changes in ciclosporin pharmacokinetics. One patient developed a two-fold increase in transaminases after 2 weeks of atorvastatin therapy. Etoposide Ciclosporin inhibits P glycoprotein and increases the cytotoxicity of some anticancer drugs, including etoposide. In rats, ciclosporin caused higher tissue concentrations of etoposide as a direct consequence of higher plasma concentrations resulting from a reduced clearance of etoposide rather than as a consequence of changes in the tissue distribution of etoposide (62E ).
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Felix Braun and Matthias Behrend
HAART Highly active antiretroviral therapy (HAART) improves life expectancy in HIVinfected patients. With ritonavir-boosted HAART, ciclosporin concentrations showed markedly altered absorption/elimination characteristics, with more or less constant blood concentrations throughout the dosing interval and prolongation of the half-life up to 38 hours (63c ). Daily ciclosporin doses were reduced to 5–20% of the individual standard doses given before initiation of ritonavir to obtain an equivalent ciclosporin AUC. Irinotecan Ciclosporin allowed an increase in the dose of irinotecan from 25 to 72 mg/m2 / week, and the addition of phenobarbital allowed an increase in dose to 144 mg/m2 (64c ). Doselimiting adverse effects were neutropenia and diarrhea. Irinotecan was well tolerated at the recommended phase II dose of 120 mg/m2 , with a 6% prevalence of grade 4 neutropenia and an 18% prevalence of grade 3 diarrhea. Ciclosporin increased the AUC of the metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) by 23% to 630% and reduced irinotecan clearance by 39% to 64% when compared with historical controls. Phenobarbital increased irinotecan clearance by 27% and reduced the AUC of SN38 by 75% compared with patients treated with ciclosporin alone. Sevelamer The interaction of sevelamer, a new calcium-free phosphate binder, and ciclosporin has been studied (65r , 66A ). After kidney transplantation in 10 adults and eight children sevelamer had no significant effect on ciclosporin AUC, Cmax , or tmax . The AUC of the ciclosporin metabolite AM1 fell by 30% and Cmax by 25% after 4 days of sevelamer treatment. In contrast, mycophenolic acid concentrations were significantly reduced by a mean of 25% (AUC) and 30% (Cmax ) after a single dose of sevelamer (67c ). St John’s wort St John’s wort (Hypericum perforatum) lowers the blood concentrations of ciclosporin and tacrolimus by inducing P glycoprotein and/or CYP3A4 (68R ). It has been suggested that hyperforin is the active compound that produces these interactions, and formulations containing high and low amounts of hyperforin have been studied in patient with kidney transplants (69c ). The AUC0–12 of ciclosporin was 45% lower with high-hyperforin
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St John’s wort co-medication than low-hyperforin St John’s wort. The dose-corrected AUC0–12 of ciclosporin fell significantly from baseline by 52% after 2 weeks of co-medication with high-hyperforin St John’s wort. The peak plasma concentration and the concentration at the end of a dosing interval were similarly affected, with 43% and 55% reductions. In addition, a 65% increase in daily ciclosporin dose was required during high-hyperforin St John’s wort treatment. In contrast, co-administration of low-hyperforin St John’s wort did not significantly affect ciclosporin pharmacokinetics and did not require ciclosporin dose adjustments compared with baseline. Data from 35 double-blind randomized trials showed that dropout and adverse effects rates in patients taking hypericum extracts were similar to placebo, lower than with older antidepressants, and slightly lower than with selective serotonin reuptake inhibitors (70M ). Dropout rates due to adverse effects in 17 observational studies including 35 562 patients were 0–5.7%. Interactions or serious adverse effects were not reported in any study.
of class Vb) received induction therapy with up to seven monthly intravenous boluses of cyclophosphamide 0.5–1.0 g/m2 plus glucocorticoids (72c ). They were subsequently randomized to quarterly intravenous cyclophosphamide, oral azathioprine 1–3 mg/kg/day, or oral mycophenolate mofetil 0.5–3 g/day for 1–3 years. During maintenance therapy, five patients died (four taking cyclophosphamide and one taking mycophenolate mofetil), and five developed chronic renal insufficiency (three taking cyclophosphamide, one taking azathioprine, and one taking mycophenolate mofetil). The 72-month event-free survival rate for the composite end-point of death or chronic renal insufficiency was significantly higher in the mycophenolate mofetil and azathioprine groups than in the cyclophosphamide group. The rate of relapse-free survival was significantly higher in the mycophenolate mofetil group than in the cyclophosphamide group. The incidences of hospitalization, amenorrhea, infections, nausea, and vomiting were significantly lower in the mycophenolate mofetil and azathioprine groups than in the cyclophosphamide group. Therefore, short-term therapy with intravenous cyclophosphamide followed by maintenance therapy with mycophenolate mofetil or azathioprine appears to be more efficacious and safer than long-term therapy with intravenous cyclophosphamide.
Drugs that act on the immune system
Voriconazole The antifungal triazole voriconazole can interact with ciclosporin by inhibiting hepatic CYP450 metabolism. Ciclosporin trough concentrations should therefore be carefully monitored to allow dosage adjustment during and after concomitant voriconazole administration (71A ). • A 14-year-old girl who was taking ciclosporin after bone marrow transplantation also took voriconazole as secondary antifungal prophylaxis. Temporary withdrawal of voriconazole because of worsening liver function tests resulted in a sudden fall in ciclosporin trough blood concentrations, which returned to baseline after normalization of the liver function tests and re-introduction of voriconazole.
Everolimus (SDZ-RAD)
(SED-15, 1306; SEDA-26, 406; SEDA-28, 457)
Cyclophosphamide
Everolimus is an immunosuppressant that blocks growth factor-mediated proliferation of hemopoietic and non-hemopoietic cells. It has been associated with thrombocytopenia, leukopenia, raised serum lipids, and raised serum creatinine (73R ).
Comparative studies The beneficial effects of cyclophosphamide must be weighed against its considerable toxicity during long-term therapy in patients with proliferative lupus nephritis. Patients with lupus nephritis (n = 59; 12 of WHO class III, 46 of class IV, and one
Hematologic The most notably adverse effect of everolimus 10 mg/day in combination with ciclosporin and glucocorticoids in a multicenter, randomized, double-blind, placebocontrolled, dose-escalating phase I study after kidney transplantation was thrombocytopenia (74c ).
(SED-15, 1025; SEDA-26, 406; SEDA-27, 375; SEDA-28, 456)
434 Infection risk Everolimus 1.5 or 3 mg/day has been compared with mycophenolate mofetil 2 g/day in a randomized, multicenter, multinational, 12-month double-blind, double-dummy and 2-year open phase III trial in de novo renal allograft recipients (n = 588) who also took ciclosporin and glucocorticoids (75C ). At 12 months, there were no statistically significant differences across the three groups in the incidence of biopsy-proven acute rejection, graft loss, or death. Everolimus 1.5 mg/day and mycophenolate mofetil were better tolerated than everolimus 3 mg/day. The incidence of cytomegalovirus infection was significantly lower with everolimus 1.5 or 3 mg/day than with mycophenolate mofetil (5.2% and 7.6% versus 19%). Everolimus was also associated with a lower incidence of cytomegalovirus infection than azathioprine and mycophenolate mofetil after heart transplantation (73R ). Endocrine Impairment of bile salt synthesis was implicated in everolimus-induced hypercholesterolemia (76E ). Body temperature Everolimus-induced fever occurred in a patient after heart transplantation (77A ). Drug formulations The systemic availability of everolimus was 2.6-fold higher from tablets than capsules, with evidence of dose proportionality over the dosage range tested (0.75, 2.5, 5, and 10 mg/day) (74c ). Drug dosage regimens Everolimus 3 mg/day has been investigated as a ciclosporin-sparing agent (ciclosporin trough concentrations 125– 250 ng/ml versus 50–100 ng/ml) in combination with basiliximab and glucocorticoids after kidney transplantation (78C ). Efficacy failure was significantly higher in patients with high trough concentrations than in those with reduced trough concentrations at 6, 12, and 36 months. Mean creatinine clearance was higher with reduced ciclosporin trough concentrations at 6, 12, and 36 months. Withdrawals and serious adverse events were more frequent in the patients with high ciclosporin trough concentrations.
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Felix Braun and Matthias Behrend
Monitoring therapy Target trough concentrations of everolimus should be 3–15 µg/l in combination therapy with ciclosporin adjusted to 100–300 µg/l and prednisone (79R ).
FTY720 FTY720 is an immunomodulator that is used in combination therapy with other immunosuppressant drugs in the prophylaxis of acute rejection after solid organ transplantation and for the treatment of multiple sclerosis. It is phosphorylated intracellularly to FTY720-phosphate, which binds to the sphingosine-1-phosphate receptor, and reduces the recirculation of lymphocytes from lymph nodes to blood and peripheral tissue, including the graft site (80R ). Comparative studies In a multicenter phase IIa study, FTY720 (n = 167) was compared with mycophenolate mofetil (n = 41), in combination with ciclosporin and glucocorticoids. The incidence of biopsy-confirmed acute rejection rates at month 3 were 23%, 35%, 18%, and 9.8% with doses of 0.25, 0.5, 1.0, and 2.5 mg versus 17% with mycophenolate mofetil. The incidence for the composite endpoint, defined as biopsy-confirmed acute rejection, graft loss, or death, was lowest with FTY720 in a dose of 2.5 mg at month 3 (15%) compared with FTY720 in doses of 0.25 mg (26%), 0.5 mg (35%), and 1.0 mg (18%), and mycophenolate mofetil (20%). FTY720 2.5 mg was as effective as mycophenolate mofetil in combination with ciclosporin for the prevention of acute rejection after kidney transplantation (81C ). Cardiovascular FTY 720 was associated with a mean 10% reduction in supine heart rate in patients with psoriasis (82c ). Heart rate changes were asymptomatic in all cases. One subject had asymptomatic second-degree type 1 atrioventricular (Wenckebach) block. A mild reduction in heart rate was reported in a phase 2a multicenter study in kidney recipients (81C ). Drug interactions In psoriatic patients (n = 12), FTY720 1 mg was given alone and on day 5 of an 8-day course of ciclosporin 400 mg/day. Ciclosporin co-administration compared with
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FTY720 alone did not significantly alter FTY720 Cmax or AUC (82c ). Likewise for ciclosporin, FTY720 co-administration did not alter the steady-state Cmax or AUC compared with ciclosporin alone.
anti-inflammatory action by inhibition of nuclear factor kappa B (NFκB), tumor necrosis factor alfa (TNF-α), and interleukin 1 beta (IL1β), and increased production of transforming growth factor beta 1 (TGF-β1) (88E –91R ).
Drugs that act on the immune system
Glatiramer acetate
(SEDA-28, 457)
Glatiramer acetate (also known as co-polymer 1 or cop-1), a co-polymer of amino acids, suppresses experimental autoimmune encephalitis, the animal model for multiple sclerosis, in various species, including primates. It binds promiscuously to major histocompatibility complex class II molecules and competes with myelin basic protein and other myelin proteins for binding and presentation to T cells of type Th2 (83R ). The frequency of reported adverse events in a Cochrane review did not support any major toxicity associated with glatiramer acetate (84M ). The most common systemic adverse events were transient and self-limiting flushing, chest tightness, sweating, palpitation, and anxiety. Local injection site reactions caused pain, inflammation, and induration at the injection site and occurred in 20–60% of patients. Another rare adverse effect is lipoatrophy at the site of injection (85A ). The atrophic areas remain unchanged and localized lipoatrophy may be preceded by a subcutaneous panniculitis. Pregnancy Glatiramer acetate should be withdrawn before an anticipated pregnancy until information is available regarding its safety (86M ).
Leflunomide
(SED-15, 2015; SEDA-26, 406; SEDA-28, 457)
The prodrug leflunomide (N-(4 -trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide) is an isoxazole derivative. Its main metabolite is the active compound, A77 1726 (87E ). Mechanism of action A77 1726 inhibits dihydroorate dehydrogenase, the rate-limiting enzyme in pyrimidine synthesis. Besides its immunomodulatory action, A77 1726 also has an
Pharmacokinetics After oral administration, leflunomide undergoes rapid metabolism in the gut wall, plasma, and liver to A77 1726 (M1), peak plasma concentrations of which are reached after 6–12 hours. A77 1726 is highly bound to plasma proteins (99%). Its pharmacokinetics are not affected by food, and dosage requirements are not influenced by age or sex. Enterohepatic recirculation and biliary recycling contribute to its long half-life (2 weeks). About 90% of a single dose of leflunomide is eliminated, 43% in the urine, primarily as leflunomide glucuronides and an oxalinic acid derivative of A77 1726, and 48% in the feces, primarily as A77 1726. Impaired renal function can result in increased plasma concentrations of A77 1726. Elimination of A77 1726 can be dramatically increased by using colestyramine or activated charcoal (92R , 93R ). Indications and clinical efficacy Leflunomide has anti-inflammatory, immunosuppressive, and virustatic effects. Its efficacy has been demonstrated in patients with rheumatoid arthritis and psoriatic arthritis in randomized, double-blind, placebo-controlled trials, and it was approved for treatment of adult rheumatoid arthritis in August 1998 (94R ) (Table 1). In three large phase III trials (US301, n = 482; MN301, n = 358; MN302, n = 999), leflunomide was as effective and well tolerated as methotrexate and sulfasalazine and superior to placebo (113C ). These data were confirmed by a meta-analysis (114M , 115M ). Leflunomide is therefore indicated for patients with rheumatoid arthritis who have failed first-line disease modifying anti-rheumatic drug therapy on the basis of efficacy, safety, and costs (106c , 115M ). It is effective as monotherapy and in combination with methotrexate or infliximab (92R ). Clinical experience with leflunomide in patients with other conditions is limited (Table 2). Extended indications for the use of leflunomide include treatment of Crohn’s disease in patients who are intolerant of standard immunomodulatory therapy (116c ), psoriasis (117C ) (118c ), sarcoidosis (119c ), mild to moderate systemic
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Table 1. The efficacy of leflunomide in controlled trials in rheumatoid arthritis Type of study
Duration
Intervention
Outcome
Reference
Double-blind randomized controlled trial
24 weeks
Leflunomide 10 and 25 mg/day was significantly more effective than placebo
(95C )
Double-blind randomized controlled trial
12 months
Leflunomide 50–100 mg for 1 day, then 5–25 mg/day (n = 300) versus placebo (n = 102) Leflunomide 100 mg for 3 days, thereafter 20 mg/day (n = 182) versus methotrexate 7.5–15 mg/week (n = 180) versus placebo (n = 118)
(96C )
Double-blind randomized controlled trial
24 weeks
Double-blind randomized controlled trial
52 weeks
Double-blind randomized controlled trial
6 months
Follow-up study
2 years
Follow-up study
2 years
Leflunomide 20 mg/day versus sulfasalazine 2 g/day
Single-center experience
32 weeks
Leflunomide 100 mg/day for 3 days, then 20 mg/day plus infliximab 3 mg/kg at 2, 4, 8, 16, and 24 weeks (n = 20)
Double-blind randomized controlled trial
24 weeks
Leflunomide 100 mg/day for 2 days, then 10 mg/day (n = 130) versus placebo (n = 133), both with methotrexate 10–25 mg/day
Follow-up study
5 years
Leflunomide 10–20 mg/day (phase III) continued (n = 214)
American College of Rheumatology response and success rates were: leflunomide 52% and 41%, methotrexate 46% and 35%, and placebo 26% and 19% American College of Rheumatology 20 response rate were: leflunomide 55%, sulfasalazine 56%, and placebo 29% Both drugs effective, although methotrexate resulted in significantly greater improvement in tender and swollen joint counts compared with leflunomide Leflunomide slowed disease progression as early as 6 months, and there was continued retardation of radiographic progression at 2 years American College of Rheumatology 20, 50, and 70 response rates for leflunomide versus methotrexate were 79% versus 67%, 56% versus 43%, and 26% versus 20% American College of Rheumatology 20 response rates were 82% leflunomide versus 60% sulfasalazine after 24 months 11/20 withdrawn (four infliximab infusion reactions, one Stevens–Johnson syndrome); the other patients achieved American College of Rheumatology 20 and 70 response rates in >80% and 46% American College of Rheumatology 20 rates at 24 weeks: leflunomide + methotrexate 46% versus placebo + methotrexate 20%; similar drug withdrawal and adverse events rates American College of Rheumatology 20, 50, and 70 response rates after 1 year were maintained for up to 5 years
Leflunomide 100 mg/day for 3 days, then 20 mg/day (n = 133) versus sulfasalazine 2 g/day (n = 133) versus placebo (n = 92) Leflunomide 100 mg/day for 3 days, then 20 mg/day (n = 501) versus methotrexate 7.5–15 mg/day (n = 498) Leflunomide 100 mg/day for 3 days, then 20 mg/day (n = 133) versus sulfasalazine 0.5–2 g/day (n = 133), versus placebo (n = 92) Leflunomide (n = 98) versus methotrexate (n = 101)
(97C , 98C )
(99C )
(100C )
(101c )
(102c )
(103c )
(104C )
(105c )
Drugs that act on the immune system
437
Chapter 38 Table 1. (Continued)
Type of study
Duration
Intervention
Outcome
Reference
Multicenter experience
24 weeks
Leflunomide 100 mg/day for 3 days, then 20 mg/day (n = 969)
(106c )
Single-center experience
3 months
Single-center experience, open study
24 weeks
Leflunomide 100 mg/day for 3 days, then 20 mg/day plus infliximab 3 mg/kg at 0, 6, and every 8 weeks (n = 17) Leflunomide 100 mg/day for 3 days, then 100 mg/week (n = 50)
191 withdrawn (107 adverse events, 26 lack of efficacy, 58 other reasons); 24% good and 45% moderate responses on the disease activity score, and 61%, 34%, and 9.6% achieved American College of Rheumatology 20, 50, and 70 response rates 20 adverse effects in 13 patients; eight discontinued
(108c )
Single-center experience
6 months
Leflunomide 100 mg/day for 3 days, then 20 mg/day (n = 378)
Extension of double-blind randomized controlled trial
48 weeks
Leflunomide + methotrexate continued (n = 96) and placebo + methotrexate switched to leflunomide 10 mg/day + methotrexate (n = 96)
Double-blind randomized controlled trial
24 weeks
Leflunomide 10 mg/day and 100 mg on day 3 (n = 202) versus 20 mg/day and 100 mg on days 1–3 (n = 200)
Multicenter experience
11–911 days
Leflunomide 100 mg/day for 3 days, then 20 mg/day (n = 136)
American College of Rheumatology 20, 50, and 70 response rates at 24 weeks were 74%, 64%, and 28% (five withdrawn, six lost to follow up) American College of Rheumatology 20, 50, and 70 response rates at 6 months were 48%, 25%, and 12% American College of Rheumatology 20 response rate was 59% at 24 weeks and 55% at 48 weeks in patients maintained on leflunomide + methotrexate, and patients switched from placebo to leflunomide + methotrexate increased their American College of Rheumatology 20 response rates from 25% at 24 weeks to 57% at 48 weeks American College of Rheumatology 20 response rates: leflunomide 10 mg 50% and 20 mg 57%; adverse events: leflunomide 10 mg 15% and 20 mg 12% 76% clinical response after 12 months, but 76/136 (56%) leflunomide withdrawn (29% adverse drug reactions and 13% lack of efficacy)
lupus erythematosus (120C ), and maintenance therapy of complete or partial remission in Wegener’s granulomatosis (121c ). Leflunomide has also been used as an immunosuppressive agent in kidney and liver transplant recipients to spare calcineurin inhibitors and glucocorticoids and to slow progression of chronic kidney graft dysfunction (122c , 123c ).
(107c )
(109c )
(110C )
(111C )
(112c )
In animals, leflunomide has excellent antiviral activity against cytomegalovirus (CMV) and it is currently indicated for second-line therapy of cytomegalovirus disease after solid organ transplantation and in recipients intolerant of ganciclovir (124c ). Leflunomide also reduces HIV replication by about 75% at concentrations that can be obtained with conventional dosing (125E ) and was intended for treatment
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Table 2. The efficacy of leflunomide in controlled trials in conditions other than rheumatoid arthritis Disease
Type of study
Duration Intervention
Crohn’s disease
Single-center experience
3 years
Psoriatic arthropathy, psoriasis
Double-blind randomized controlled trial
24 weeks
Psoriasis
Phase II study
12 weeks
Sarcoidosis
Single-center experience
1 year
Systemic lupus Single-center erythematosus experience, double-blind randomized controlled trial
24 weeks
Wegener’s Phase II study granulomatosis
52 weeks
Outcome
Leflunomide 20 mg/day 8/12 clinical responses; seven (n = 12) continued maintenance therapy and one relapsed after follow-up of 6–78 weeks Leflunomide Leflunomide 59% and placebo 100 mg/day for 3 days, 30% were responders at 24 then 20 mg/day weeks according to the (n = 95) versus placebo psoriatic arthritis response (n = 91) criteria Leflunomide 20 mg/day 6/8 clinical effectiveness (n = 8) (psoriasis area and severity index score 20 at baseline versus 13 at 12 weeks) Leflunomide 13/17 leflunomide and 12/15 100 mg/day for 3 days, leflunomide + methotrexate then 10–20 mg/day complete or partial responses (n = 32, 17 leflunomide and 15 leflunomide + methotrexate) Leflunomide Disease activity fell 100 mg/day for 3 days, significantly in both groups then 100 mg/day after 6 months, and the (n = 6) versus placebo reduction in SLE disease (n = 6) activity index from baseline to 24 weeks was significantly greater with leflunomide than with placebo Leflunomide Maintenance of complete or 20–40 mg/day (n = 20) partial remission after cyclophosphamide + glucocorticoid therapy resulted in one major and eight minor relapses
of patients with HIV/AIDS refractory to HAART (126M ). General adverse drug reactions The major adverse effects of leflunomide are gastrointestinal symptoms (diarrhea and nausea), abnormal liver function tests, skin rashes and pruritus, allergic reactions, alopecia, infections, weight loss, and hypertension (114M , 127M , 128R , 129c , 130c ). Minor adverse effects include musculoskeletal disorders. Rare adverse effects include sepsis, pancytopenia, interstitial lung disease, hypertriglyceridemia, vasculitis, aseptic meningitis, reversible neuropathy, and serious skin reactions (114M , 131A –134A ). In 3325 patients who took leflunomide, the rate of drug withdrawal was 42% within 33 months after approval by the US Food and Drugs Administration, and was more likely in
Reference (116c )
(117C )
(118c )
(119c )
(120C )
(121c )
patients who received a loading dose (135c ). The most common causes of discontinuation were inefficacy (30%), gastrointestinal symptoms (29%), non-adherence to therapy or loss to follow-up (14%), and raised liver enzymes (5%). However, the rate of adverse effects associated with leflunomide was significantly lower than with methotrexate and other disease-modifying antirheumatic drugs (DMARDs) in an analysis of 40 594 patients with rheumatoid arthritis (95C , 136C ). The incidences of adverse events per 1000 patient years were as follows: • • • • •
no DMARDs: 383 methotrexate: 145 leflunomide monotherapy: 94 methotrexate + other DMARDs: 70 leflunomide + other DMARDs: 59
Drugs that act on the immune system
Chapter 38
• leflunomide + methotrexate: 43 • other DMARDs: 143. Leflunomide monotherapy also had the lowest rate of hepatic events in the DMARD monotherapy groups. Cardiovascular The incidence of hypertension in patients with rheumatoid arthritis taking leflunomide 25 mg/day was 11% in a phase II trial (137c ). During phase III trials, there was new-onset hypertension in 2.1–3.7% (96C , 97C ). Increased sympathetic drive has been implicated in its pathogenesis, because leflunomide-induced hypertension is accompanied by an increased heart rate (138c ). However, this hypothesis remains to be tested. Pulmonary hypertension has been described in association with leflunomide (139A ). Respiratory Respiratory symptoms in the MN301, US301, and MN302 trials in patients with rheumatoid arthritis included respiratory infections (21–27%), bronchitis (5–8%), increased cough (4–5%), rhinitis (2–5%), pharyngitis (2–3%), pneumonia (2–3%), and sinusitis (1–5%) (96C , 97C , 99C ). In Japan, acute interstitial pneumonia due to leflunomide has been mentioned as a serious and severe adverse effect, with an incidence of 1.1% and a fatal outcome in 0.36% (140A , 141A , 142r , 143r ). • A 54-year-old woman with rheumatoid arthritis developed an interstitial pneumonia 2 weeks after the end of a 6-week course of treatment with leflunomide (140A ). The onset of the pneumonia was preceded by raised serum liver enzymes and hypertension. The acute respiratory failure improved with prednisolone and colestyramine. • A 49-year-old man with rheumatoid arthritis taking methotrexate developed a skin eruption and a severe non-productive cough after taking leflunomide for 17 days (141A ). He died of respiratory failure 128 days after the diagnosis of acute interstitial pneumonia.
However, clinical trials and subsequent observational studies outside Japan have not suggested that leflunomide causes an excess of pulmonary adverse effects (144r ). A pulmonary abscess occurred during leflunomide therapy in a patient with rheumatoid arthritis (145A ).
439 • A 43-year-old woman who had had rheumatoid arthritis for 5 years complained of fever, arthralgia/myalgia, and night sweating for 1 month. She had been taking only leflunomide 20 mg/day for 5 months. There was no evidence of active arthritis or vasculitic lesions. Her erythrocyte sedimentation rate was 145 mm/hour and C-reactive protein 1.6 g/l. All cultures were negative. A chest X-ray and CT scan showed a pulmonary abscess. Staphylococcus aureus was grown in the culture of a purulent sample obtained from the abscess under ultrasonography. The leflunomide was withdrawn, and sultamicillin 8 g/day was given for 6 weeks. Four weeks later, she had completely recovered and a CT scan showed significant improvement of the pulmonary abscess.
Nervous system Leflunomide can cause a peripheral reversible neuropathy (134A , 146A , 147c –149c ). This neuropathy is usually axonal in nature, affecting multiple sensory or motor nerves of distal extremities. Leflunomideassociated new-onset peripheral neuropathy has been reported in 80 patients (median age 62 years, 61% women) (148c ). The mean time of onset of peripheral neuropathy was 6 months (range 3 days to 3 years) after the start of therapy. Neurological improvement was more likely after drug withdrawal within 30 days after the onset of the symptoms of neuropathy compared with continuous administration. Electrodiagnostic testing in 37 patients was consistent with a distal axonal, sensory, or sensorimotor polyneuropathy in most patients. Withdrawal of leflunomide within 30 days after the onset of symptoms of neuropathy resulted in significant improvement or recovery compared with drug continuation. Peripheral neuropathy attributed to leflunomide was observed in two patients (134A ). • A 76-year-old man, with an 18-month history of seropositive rheumatoid arthritis, chronic emphysema, and pulmonary fibrosis, developed polymyalgia and was treated with glucocorticoids and azathioprine. Azathioprine was withdrawn after a rise in aspartate transaminase. He was then given leflunomide 100 mg over 3 days followed by 10 mg/day as a maintenance dosage. After 2 weeks, he developed a sensory neuropathy with a stocking distribution up to the malleoli and leflunomide was withdrawn 4 weeks later. During this time he had also been taking prednisolone, tramadol, disodium etidronate, indoramin, and celecoxib, none of which is known to cause neuropathy. Glucose, vitamin B12, serum folate, thyroid function, serum proteins, Bence–Jones protein electrophoresis, cryoglobulins, anti-neutrophil cytoplasmic antibodies, antinuclear antibodies,
440 the Venereal Disease Research Laboratory test, and hepatitis B and C serology were all normal or negative. Nerve conduction was consistent with motor sensory axonal peripheral neuropathy of the lower limbs. On review 3 months after withdrawal of leflunomide, there was clear subjective and objective improvement of the neuropathy, confirmed by repeat nerve conduction studies. • A 69-year-old woman with a 10-year history of seropositive erosive rheumatoid arthritis, previously treated with gold salts followed by methotrexate, started to take leflunomide and 3 months later reported numbness in the fingertips and feet bilaterally, with a glove-and-stocking sensory neuropathy involving all fingertips and extending to the mid-shins. Leflunomide was withdrawn. Other medications included prednisolone, lansoprazole, simvastatin, losartan, and amiodarone, which she had been taking for a long time without adverse effects. Screening tests for neuropathy, as in the previous case, were normal or negative. There was no cord or nerve root compression on magnetic resonance imaging of the cervical spine. Nerve conduction studies confirmed a sensory motor peripheral neuropathy. She reported marked improvement in her symptoms 3 months after withdrawal of treatment, and this was confirmed on clinical examination and repeat nerve conduction studies.
One case of leflunomide-induced aseptic meningitis has been reported (133A ). Sensory systems Leflunomide can cause cystoid macular edema (150A ). Metabolism Life-threatening hypertriglyceridemia has been described during treatment with leflunomide (131A ). Hematologic Pancytopenia, thrombocytopenia, and anemia can occur during leflunomide treatment (108c , 151c , 152A , 153A ). The risk of pancytopenia is increased when it is used in combination with methotrexate and in elderly patients. In 18 patients with pancytopenia associated with leflunomide (15 women, 3 men; median age 66 years, range 18–79), the indications for leflunomide were rheumatoid arthritis (n = 17) or systemic lupus erythematosus (n = 1), and 14 of the 18 patients were taking additional methotrexate (151c ). The course of pancytopenia was typically severe, with variable onset ranging from 11 days to 4 years (median 4 months). The patients required withdrawal of the immunosuppressant(s), intensive supportive therapy, and treatment of neutropenic sepsis. Five died, four of whom
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were taking methotrexate. Thus, patients taking methotrexate and elderly patients are at increased risk of pancytopenia during leflunomide therapy. Leflunomide-associated anemia has been reported in renal transplant recipients (121c ). Leflunomide-associated thrombocytosis and leukocytosis resolved after colestyramine washout and withdrawal of leflunomide (154A ). Mouth In the MN301, US301, and MN302 trials, mouth ulceration occurred in 3–5% (96C , 97C , 99C ). Gastrointestinal Leflunomide can cause gastrointestinal symptoms, such as diarrhea, dyspepsia, nausea, abdominal pain, and oral ulcers (106R ). The combination of leflunomide 10 mg/day with methotrexate has been studied in a randomized, double-blind 24-week study in patients with rheumatoid arthritis (110C ). Patients who were switched from placebo to leflunomide had a lower incidence of raised transaminases than patients who were initially treated with leflunomide. Patients who did not receive a loading dose of leflunomide had a lower incidence of diarrhea and nausea. There was a higher rate of diarrhea in the leflunomide group in a double-blind, randomized, placebo-controlled trial in patients with active psoriatic arthropathy and psoriasis taking oral leflunomide. Leflunomide was given in a loading dose of 100 mg/day for 3 days followed by 20 mg/day for 24 weeks (117C ) (Table 2). In the MN301, US301, and MN302 trials, gastrointestinal symptoms consisted of diarrhea (22–27%), nausea (13%), dyspepsia (6–10%), abdominal pain (6–8%), mouth ulceration (3– 5%), vomiting (3–5%), anorexia (3%), and gastroenteritis (1–3%) (96C , 97C , 99C ). Diarrhea and nausea are more common in patients who receive a loading dose, but the onset of action can be delayed without the loading dose (115M ). Gastrointestinal symptoms occur mainly during the first 6 months after initiation of leflunomide. The severity of symptoms was mild. If there is severe diarrhea and/or weight loss, withdrawal of leflunomide and endoscopic examination is advised, since ulcerative and microscopic colitis have been detected under such circumstances (155A ). The pathophysiology of leflunomide-associated diarrhea and
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weight loss is unclear. Weight loss of 9–24 kg was observed in five of 70 patients who took leflunomide, despite normal concentrations of thyroid-stimulating hormone and no other gastrointestinal complaints (130c ).
162A , 163A ), estimated at a rate of 1 in 200 users (164r ). Leflunomide is therefore not recommended in patients with significant liver impairment or evidence of infection with hepatitis B or C virus (165S ). A CYP2C9 polymorphism has been implicated in the pathogenesis of leflunomide hepatotoxicity (162A ).
Drugs that act on the immune system
Liver Raised liver function tests have been reported during treatment with leflunomide (114M ), and close monitoring of liver enzymes is important (156R ). However, the risk of serious and non-serious hepatic adverse events is not higher than with methotrexate (157M ). The risk of hepatic events related to diseasemodifying antirheumatic drugs (DMARDs) has been assessed in 41 885 patients with rheumatoid arthritis (157M ). Overall, 25 patients had serious and 411 patients non-serious hepatic events, an incidence of 4.9 and 80 per 10 000 people per year. Leflunomide did not increase the rate of serious or non-serious hepatic events compared with other DMARDs. Increased alanine transaminase activity was reported in the leflunomide group in a doubleblind, randomized, placebo-controlled trial in 190 patients with active psoriatic arthropathy and psoriasis, who took a loading dose of 100 mg/day for 3 days followed by 20 mg/day orally for 24 weeks (117C ). However, serious liver toxicity did not occur. In a randomized, double-blind, placebocontrolled pilot study over 24 weeks, six of 12 adults (11 women, 1 man; median age 41 years) with mild to moderate active systemic lupus erythematosus took oral leflunomide. Disease activity fell in both groups. Minor adverse events included transient rises in alanine transaminase, hypertension, and transient leukopenia (120c ). In the MN301, US301, and MN302 trials, there were abnormal liver enzymes in 6–10% (96C , 97C , 99C ). The co-administration of methotrexate is a risk factor (104C , 156R , 158C , 159c ). According to the National Cancer Institute Common Toxicity Criteria, 8.9% of patients developed grade 2 or 3 hepatotoxicity within the first year, mainly within 6 months and in combination with methotrexate, after the start of leflunomide therapy based on liver enzyme determinations (158C ). The use of folate was also associated with less frequent changes in liver function tests (96C , 97C , 99C ). Nevertheless, leflunomide can cause severe liver injury (160R , 161R ,
• A 67-year-old woman with rheumatoid arthritis developed diarrhea and raised liver enzymes after taking leflunomide for 15 days. Histologically, the liver showed acute hepatitis. She was homozygous for the CYP2C9*3 allele. The liver damage subsided within a few weeks.
Urinary tract Interstitial nephritis occurred in one case of chronic overdose of leflunomide (166A ) (see Drug overdose). Skin Adverse effects of leflunomide on the skin in patients with rheumatoid arthritis include alopecia (9–17%), rash (11–12%), pruritus (5–6%), dry skin (3%), and eczema (1–3%) (96C , 97C , 99C ). Single cases of an erythema multiforme-like drug eruption (167A ), exfoliative dermatitis (168A ), a lichenoid drug reaction (169A ), and skin ulceration (170A ) have been reported. A photodistributed lichenoid drug eruption with rhabdomyolysis was observed in a patient taking leflunomide (171A ). Subacute cutaneous lupus erythematosus associated with leflunomide has been reported (172A ). Immunologic In the treatment of rheumatoid arthritis leflunomide can occasionally cause a vasculitis (173A , 174A ), and acute necrotizing vasculitis is rare but serious (132A ). Mutagenicity A minor metabolite of leflunomide, 4-trifluoromethylaniline, was mutagenic in vitro (175R ). Tumorigenicity Male mice had an increased incidence of lymphoma at an oral leflunomide dose of 15 mg/kg, and female mice had a doserelated increased incidence of bronchoalveolar adenomas and carcinomas beginning at 1.5 mg/kg (175E ). Fertility Leflunomide did not affect fertility in rats (175E ).
442 Teratogenicity Rheumatic diseases often affect women of childbearing age and drug therapy may be required during pregnancy to control maternal disease activity and to ensure a successful outcome. In oral embryocytotoxicity and teratogenicity studies in rats and rabbits, leflunomide was embryocytotoxic (growth retardation, embryolethality) and teratogenic (malformations of the head, rump, vertebral column, ribs, and limbs) (175R ). Not only is leflunomide teratogenic and fetotoxic in animals, but its active metabolite is detectable in plasma up to 2 years after withdrawal. Therefore, the fetus could have in utero exposure to leflunomide up to 2 years after the end of treatment. Leflunomide has been classified as pregnancy category X by the Food and Drug Administration (175R , 176c ). However, experience in a very small group of pregnant women who took leflunomide and continued their pregnancy to term gave no indication of an increase in teratogenesis (177R ). Nevertheless, the majority of 30 pregnant women elected to interrupt their pregnancies, except three patients (175R ). At present, withdrawal of leflunomide is mandatory before pregnancy, and colestyramine treatment is advised to wash out leflunomide (165S , 175R , 178R , 179R ). Both men and women who want to have a child should discontinue leflunomide and take colestyramine to wash it out. Leflunomide has not been studied in children, possibly because of its cytotoxic nature. In particular, its teratogenic potential may be a concern when treating adolescent girls (179R ). Lactation Breast feeding by nursing mothers is not recommended, because it is unknown if leflunomide is excreted in human milk (165S , 175R ). Drug dosage regimens Leflunomide is taken orally. In most regimens it is begun with a loading dose of 100 mg/day over 3 days followed by a maintenance dosage of 10–20 mg/day. Leflunomide 100 mg/week had similar effectiveness and less toxicity in open trials compared with daily dosing (180c ). The efficacy and safety profile of leflunomide 10 mg (n = 202; loading dose on day 3, 100 mg/day) and 20 mg (n = 200; loading dose on days 1–3, 100 mg/day) have been investigated in patients with active rheumatoid arthritis over 24 weeks (111C ). There was
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no significant difference between the groups regarding the American College of Rheumatology 20% criteria (50 versus 57%). The lower leflunomide dosage regimen resulted in more adverse events requiring withdrawal (15 versus 12%) and a higher rate of serious adverse events (13 versus 10%). Drug overdose Two cases of leflunomide overdose have been reported. • A 70-year-old man with chronic active rheumatoid arthritis was given leflunomide in a loading dose of 100 mg/day followed by 10 mg/day (166A ). The initial response was modest and the dose was increased to 20 mg/day, but the patient actually took 100 mg/week plus 20 mg/day. The serum creatinine concentration increased from 140 µmol/l to 287 µmol/l over 2 years. A renal biopsy showed tubulointerstitial nephritis. Leflunomide was withdrawn immediately and prednisolone 20 mg/day was started. The creatinine returned to 160 µmol/l within 1 month. • A 40-year-old woman with rheumatoid arthritis took leflunomide 100 mg/day for 3 days and 20 mg/day thereafter (181A ). After 28 days it was realized that she had continued to take the 100 mg tablets, resulting in a dosage of 120 mg/day. She was immediately hospitalized and colestyramine washout procedure was performed. She had no adverse effects.
Drug interactions The administration of infliximab after or simultaneously with leflunomide seems to be safe and effective in patients with rheumatoid arthritis (107c , 182c , 183c ). Multiple doses of rifampicin increase leflunomide concentrations (184R ). A case of probable interaction of leflunomide with warfarin has been reported (185A ). • A 49-year-old man with resistant rheumatoid arthritis took leflunomide 100 mg/day for 3 days. His international normalized ratio (INR) had been stable for 1 year while he was taking warfarin, and 2 days before starting treatment with leflunomide it was 3.4. After he took the second dose of leflunomide, he developed gross hematuria. His INR had risen to 11, and warfarin was withdrawn. The hematuria resolved spontaneously several hours later, but his INR remained raised for the next 2 days, even though he had stopped taking warfarin. He was given intravenous vitamin K 1 mg on the third day, and 12 hours later the INR fell to 1.9. Subsequently he began taking warfarin again, but at a lower dose of 1 mg/day, which was sufficient to maintain his INR within the target range.
A77 1726 inhibits CYP2C9 and might increase the systemic availability of CYP2C9 sub-
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strates, such as warfarin and phenytoin (185A , 186R ).
are under way in Europe and the USA to investigate its antiviral properties. Phase I data suggested that food has no substantial effect on the oral systemic availability of FK778, that there is no effect of sex on its pharmacokinetics, and that very little of the unchanged drug is eliminated in the urine; there were no dose-limiting adverse effects, despite escalation of single doses to 1100 mg and repeated doses to 200 mg/day (189R ).
Drugs that act on the immune system
Management of adverse effects Overdosage and adverse events can usually be managed by dosage reduction, the addition of colestyramine, and symptomatic therapy (117M ). However, in one study in patients with rheumatoid arthritis leflunomide 10 mg/day compared with 20 mg/day was associated with less efficacy and more adverse events that led to treatment withdrawal (111C ). Colestyramine 8 g/day tds for 11 days is recommended to wash out leflunomide; if plasma concentrations of A77 1726 do not fall to 0.02 mg/l or less, additional colestyramine is advised. Without this washout procedure, it can take up to 2 years to reach A77 1726 plasma concentrations of 0.02 mg/l. Oral activated charcoal 50 g every 6 hours for 24 hours also reduced plasma concentrations of A77 1726 (165S ). Plasma concentrations of A77 1726 can be measured by high-performance liquid chromatography (187E , 188E ). Monitoring of platelets, white blood cells, hemoglobin, and alanine transaminase activity is advised at baseline, monthly for 6 months, and every 6–8 weeks thereafter. Leflunomide should be withdrawn if pulmonary symptoms such as cough and dyspnea start or worsen (165S ).
Malononitrilamide 715
(FK778)
Synthetic malononitrilamides have been derived from A77 1726, the active metabolite of leflunomide. Of these, FK778 is the most promising derivative, because of its much shorter half-life. It also blocks replication of herpesvirus in vitro and in vivo. FK778 is effective in the prevention of acute allograft rejection in experimental transplant models and vascular remodelling after mechanical intimal injury. In vitro, it blocks herpesvirus, cytomegalovirus, and polyoma virus replication. It is currently been explored in a number of trials in solid organ transplant recipients. Single and repeat dose phase I studies have been completed in Europe and the USA. A phase II concentration controlled trial after kidney transplantation has been completed in Europe. At present, additional clinical studies
Placebo-controlled studies In a phase II trial, kidney recipients were randomized to treatment for 12 weeks with high-dose FK778 (H, n = 49), low-dose FK778 (L, n = 54), or placebo (P, n = 46), in each case with tacrolimus + a glucocorticoid (190C ). Both FK778 arms reduced the incidence of biopsyproven acute rejection (high-dose 27%, lowdose 26%, placebo 39%). Infections, gastrointestinal adverse effects, hepatic function, and renal function were comparable between the groups. Anemia was the most frequently reported adverse effect.
Methotrexate
(SED-15, 2277; SEDA-26, 406; SEDA-27, 376; SEDA-28, 547)
Musculoskeletal Patients with osteosarcoma treated with methotrexate, vincristine, and doxorubicin are at risk of late adverse effects. Of 106 chemotherapy-treated patients with osteosarcoma, 24 died, nine relapsed, and three developed a second malignancy during followup of at least 20 years (191C ). Event-free survival and overall survival were significantly lower than in a previous study with a 3-year follow up period (event-free survival 38% versus 53%; overall survival 44% versus 67%). Susceptibility factors Age Children with Down’s syndrome have a significantly increased risk of leukemia and an increased risk of methotrexate-associated toxicity. Hyperdiploid lymphoblasts with extra copies of chromosome 21 generate higher concentrations of the active methotrexate metabolite. This is because of increased intracellular transport of methotrexate via the reduced folate carrier, whose gene is localized to chromosome 21 and may also account for the
444 increased methotrexate-associated toxicity in patients with Down’s syndrome and acute lymphoblastic leukemia (192R ). Drug dosage regimens Of 106 medication errors reported to the FDA associated with methotrexate there were 25 deaths and 48 other serious outcomes (193M ). The most common types of errors involved confusion about the once-weekly dosage schedule (30%) and other dosage errors (22%). The most frequent indication for use was rheumatoid arthritis (42%). Of the errors, 39 were attributable to the prescriber, 21 to the patient, 20 to dispensing, and 18 to administration by a health-care professional. Drug interactions Benzimidazoles Methotrexate is transported by breast cancer resistance protein (BCRP; ABCG2) and multidrug resistance-associated protein1–4 (MRP1–4; ABCC1–4). In patients with cancer, co-administration of benzimidazoles and methotrexate can result in profound methotrexate-induced toxicity coinciding with an increase in the serum concentrations of methotrexate and its main metabolite 7-hydroxymethotrexate (194E ). Benzimidazoles differentially affect transport of methotrexate mediated by BCRP and MRP2 and competition for BCRP may explain the clinical interaction between methotrexate and benzimidazoles. Carboxypeptidase G2 Carboxypeptidase G2 is used when unexpected toxicity or renal insufficiency occurs during high-dose methotrexate therapy. Leucovorin is used to antagonize the effects of methotrexate on purine metabolism, but its protective effect is antagonized by carboxypeptidase G2. Carboxypeptidase G2 should therefore be administered to patients with caution (195E ). Co-trimoxazole Even low-dose short-course methotrexate therapy can cause a fatal outcome. A patient with rheumatoid arthritis who had taken a low-dose short course of methotrexate developed severe pancytopenia followed by bacterial and monilial sepsis after taking co-trimoxazole for an intercurrent infection (196A ). The proposed mechanisms of this interaction are either protein binding displacement
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of methotrexate by co-trimoxazole or competition between the two drugs for renal tubular excretion. It has also been postulated that methotrexate and co-trimoxazole act synergistically to produce significant folate deficiency, which leads to megaloblastic changes. Cotrimoxazole rarely causes megaloblastic anemia alone; however, this effect is more likely to occur in patients with pre-existing folate deficiency. If this drug combination cannot be avoided, the patient should be closely monitored for signs of hematological toxicity. Calcium leucovorin may be necessary to treat megaloblastic anemia and neutropenia resulting from folic acid deficiency. Etanercept The pharmacokinetics of etanercept 25 mg subcutaneously twice weekly were not altered by concurrent methotrexate 20 mg oral weekly in 682 patients with rheumatoid arthritis in a phase IIIb trial (197C ). Thus, no etanercept dosage adjustment is needed for patients taking concurrent methotrexate. NSAIDs The human organic anion transporters hOAT1 (SLC22A6) and hOAT3 (SLC22A8) are responsible for the renal tubular secretion of methotrexate. Delayed methotrexate elimination occurred in a patient with Hodgkin’s disease who took the NSAID loxoprofen (198A ). Loxoprofen and its trans-hydroxylated metabolite, an active major metabolite, markedly inhibited methotrexate transport by hOAT1 and hOAT3. Co-administration of methotrexate with lumiracoxib, a novel cyclo-oxygenase-2 selective inhibitor, was well tolerated in 18 patients (mean age 49 years) with stable rheumatoid arthritis and had no significant effect on methotrexate pharmacokinetics, protein binding, or urinary excretion (199c ). Sulfasalazine Interaction of sulfasalazine with reduced folate carrier, the dominant cell membrane transporter for natural folates and methotrexate, may limit the efficacy of combination therapy in patients with rheumatoid arthritis. Studies of cellular transport kinetics have shown that sulfasalazine is a potent non-competitive inhibitor of reduced folate carrier-mediated cellular uptake of methotrexate and leucovorin (200E ). There was marked loss of methotrexate efficacy when methotrexate was co-administered with sulfasalazine.
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Along with diminished efficacy of methotrexate, there was evidence of cellular folate depletion by the demonstration of a sulfasalazine dose-dependent reduction in leucovorin accumulation. At clinically relevant plasma concentrations, interactions of sulfasalazine with the reduced folate carrier provide a biochemical rationale for folate deficiency during sulfasalazine treatment as well as the lack of additivity/synergism of the combination of sulfasalazine and methotrexate when these diseasemodifying antirheumatic drugs are given simultaneously. These results provide a rationale for the use of folate supplementation and for staggering the administration of these drugs over time.
munosuppression using sirolimus or mycophenolate mofetil late after kidney transplantation. There was improved renal function in 10 of 13 patients after conversion to sirolimus + mycophenolate mofetil (203c ) with trough concentrations of 4.16 µg/l (sirolimus) and 6.8 and 4.7 mg/l (mycophenolic acid at 1 and 3 months). Adverse events were borderline acute rejection (n = 1), anemia responding to a higher dosage of erythropoietin (n = 3), hyperlipidemia (n = 1), and urinary tract infections (n = 4).
Drugs that act on the immune system
Mizoribine
(SED-15, 2365)
Mizoribine has been implicated in a case of hyperuricemia and renal dysfunction (201A ). • A 64-year-old woman with rheumatoid arthritis took etodolac, actarit, mizoribine, and prednisolone. After 2 years, she developed a fever and nausea, which were treated with diclofenac sodium and clindamycin, nasal bleeding, tarry stools, hyperuricemia, renal dysfunction, and thrombocytopenia. All drugs except prednisolone were withdrawn and hemodialysis was started. The fever and nausea improved over several days and the hyperuricemia and renal dysfunction resolved within 1 month. The platelet count became normal after platelet transfusion.
Mycophenolate mofetil
(SED-15, 2402; SEDA-26, 407; SEDA-27, 376; SEDA-28, 458)
Nervous system Encephalitis occurred in a patient who took mycophenolate mofetil after kidney transplantation (204A ). • After kidney transplantation a 55-year-old woman took ciclosporin, azathioprine, and glucocorticoids; 7 years later, azathioprine was changed to mycophenolate mofetil. One year later, she was developed sulpiride-refractory vertigo and a flulike syndrome. A CT brain scan was normal. Two weeks later, she reported visual hallucinations and impairment of consciousness, and developed a polymorphonuclear leukocytosis, anemia, hyponatremia, and renal insufficiency. A chest X-ray, brain CT, and electroencephalography were normal. The CSF contained 300 cells/ml (79% polymorphonuclear leukocytes), glucose 3.5 mmol/l (63 mg/dl), and protein 450 mg/l. She was given intravenous ampicillin, ceftriaxone, and ganciclovir. She then had seizures on the left side of her body and was mechanical ventilated. A brain MRI scan showed regions of high signal intensity suggesting lesions in the bulb, protuberance, mesencephalon, left thalamus, and parenchyma adjacent to the corpus callosum. Six days later, she started to recover consciousness and had no neurological sequelae. Intubation was terminated. PCR showed Epstein–Barr virus DNA in the CSF and ceftriaxone and ampicillin were withdrawn, but ganciclovir was continued for 8 weeks; 3 weeks later an MRI scan showed reduction of the size of the lesions and the lesions on the brain stem had disappeared.
Mycophenolic acid has an adverse effects profile that includes leukopenia, diarrhea, anemia, and mild hepatotoxicity. Minor mycophenolic acid metabolites have been implicated as a source of adverse effects (202r ).
Hematologic Spontaneously resolving Epstein–Barr virus-associated B cell lymphomas have become more common with the use of immunosuppressive agents in both transplant patients and patients with connective tissue disorders (205A ).
Observational studies Chronic allograft nephropathy and/or calcineurin inhibitor toxicity are common after organ transplantation. It is therefore common to switch from calcineurin inhibitor-based to calcineurin inhibitor-free im-
• A 46-year-old woman with dermatomyositis developed an Epstein–Barr virus-associated B cell lymphoma of the brain while taking oral methotrexate, mycophenolate mofetil, and low-dose prednisone. The lymphoma gradually resolved spontaneously on withdrawal of the methotrexate and mycophenolate mofetil.
446 The potential for such lymphomas to resolve spontaneously should be recognized by the clinician, in order to prevent unnecessary and potentially toxic treatments, including radiation therapy or multidrug chemotherapy. The incidence of anemia in 4263 recipients after kidney transplantation was 39% (206M ). Associated risk factors were serum creatinine concentration over 177 µmol/l (2 mg/dl), the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists, the use of azathioprine or mycophenolate mofetil, kidneys from older donors, and recent infections. Mouth Mycophenolate mofetil can cause oral ulceration (207A ). • A 62-year-old woman received a cadaveric kidney transplant and maintenance immunosuppression with tacrolimus 4 mg/day, mycophenolate mofetil 2 g/day, and prednisolone 7.5 mg/day. After 32 months she developed four mouth ulcers and dysphagia. Histologically, the ulcers showed no specific inflammatory changes or viral inclusions or evidence of malignancy or vasculitis. Serology for Epstein–Barr virus, Herpes simplex, Varicella zoster, and cytomegalovirus was negative. The ulcers deteriorated associated with a fall in white blood cell count from 4.12 to 0.8 × 109 /l. She was treated with granulocyte colony stimulating factor, antibiotics, and nutritional support without any effect on the ulcers. Mycophenolate mofetil was then withdrawn, after which the lesions ameliorated and the white blood cell count rose to 4.0 × 109 /l. The ulcers completely resolved within 6 weeks.
Gastrointestinal Mycophenolate mofetil-related diarrhea is common after kidney transplantation, and villous atrophy has been implicated as a mechanism. It is mandatory to differentiate celiac disease from mycophenolate mofetil-induced villous atrophy, because, in the latter a gluten-free diet is not required (208A ). Liver Liver biopsy in a patient who was switched from azathioprine to mycophenolate mofetil for glucocorticoid-responsive autoimmune hepatitis showed cytoplasmic features of adaptation and nuclear abnormalities in the hepatocytes (209A ).
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mofetil 2 g/day, and prednisolone. After the early postoperative period she complained of myalgia in the legs. The symptoms disappeared within a few days after reduction of the dose of mycophenolate mofetil from 2 to 1.5 g/day. • A 57-year-old male kidney recipient was switched from azathioprine to mycophenolate mofetil to allow allopurinol therapy for severe gouty arthritis. After conversion, diffuse arthromyalgic aches occurred in the legs, with fatigue and ankle edema. The patient was reconverted to azathioprine, followed by relief of symptoms within 1 week.
Infection risk In 869 solid organ recipients the overall incidence of Herpes zoster infection was 5.7% in those with liver transplants, 7.4% in those with kidney transplants, 15% in those with lung transplants, and 17% in those with heart transplants; the median time of onset was 9 months (211C ). Independent organ-specific susceptibility factors for Herpes zoster infection included female sex, mycophenolate mofetil (liver transplantation), and antiviral treatments other than prolonged cytomegalovirus prophylaxis (kidney and heart transplants). Conversion from azathioprine to mycophenolate mofetil 2 g/day during maintenance therapy in 13 liver transplant recipients with hepatitis C infection (12 men and 1 woman, mean age 54 years) did not lead to a decrease in viral load (212c ). Maxillary actinomycosis occurred in an immunocompromised patient taking mycophenolate mofetil (213A ). • A 49-year-old male Caucasian with a 5-year history of unclassified vasculitis treated with mycophenolate mofetil 2 g/day and prednisolone 10 mg/day complained of a watery discharge from his nose after brushing his teeth. An oronasal fistula was detected. An MRI scan showed osteolytic destruction of the left maxillopalatine and histology showed osteomyelitis caused by Actinomyces.
This infection was presumably related to previous extraction of two teeth without antibiotic prophylaxis.
Musculoskeletal Myalgia related to mycophenolate mofetil occurred in two transplant recipients (210A ).
Teratogenicity Mycophenolate mofetil is teratogenic in rats and rabbits and previous human studies have shown an increased rate of fetal loss. Recently, a major fetal malformation has been reported (214A ).
• A 42-year-old woman with type 1 diabetes underwent pancreas transplantation, and immunosuppression consisted of tacrolimus, mycophenolate
• A 27-year-old primiparous Caucasian woman underwent renal transplantation and took mycophenolate mofetil 500 mg/day, tacrolimus 9 mg/
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day, and prednisolone 15 mg/day. When pregnancy was diagnosed at 13 weeks mycophenolate mofetil was replaced by azathioprine 50 mg/day. At 22 weeks gestation, the fetus demonstrated normal growth, but there were multiple malformations, including complete agenesis of the corpus callosum, cleft lip, and cleft palate. Amniocentesis showed a normal male karyotype. The pregnancy was terminated at 22 weeks. There was a cleft lip and palate, micrognathia, ocular hypertelorism, microtia and external auditory duct atresia, and a pelvic ectopic kidney. Midline anomalies included complete agenesis of the corpus callosum. In a subsequent pregnancy 1 year later, she took azathioprine, tacrolimus, and prednisone throughout gestation. She developed chorioamnionitis and delivered a 2640 g live boy at 34 weeks of gestation without congenital malformations.
The pharmacokinetics of a generic formulation of mycophenolate mofetil, MM-Cept 500 mg tablets (Ivax CR) have been compared with those of mycophenolate mofetil 500 mg tablets (Cellcept, Hoffman La Roche) in healthy volunteers (217c ). The products had similar systemic availability.
Drugs that act on the immune system
Susceptibility factors Protein binding Altered protein binding can be associated with severe mycophenolate mofetil toxicity (215A ). • A 58-year-old man with end-stage renal disease developed a raised unbound fraction of mycophenolic acid and associated severe toxicity after cadaveric kidney transplantation. Initial oral immunosuppression consisted of ciclosporin 4 mg/kg bd and mycophenolate mofetil 1 g bd. In the first 5 days after transplantation, the serum creatinine concentration fell, and he developed profound hypoalbuminemia (serum albumin under 20 g/l) and hyperbilirubinemia (serum bilirubin over 150 µmol/l), because of progressive biliary obstruction. On day 5 after transplantation, the concentration of ciclosporin C2 and the mycophenolic acid AUC0–6h were low (837 µg/l and 12.6 h mg/l), while total mycophenolic acid glucuronide AUC0–6h was increased (1317 h mg/l). Mycophenolate mofetil was continued at the same dose, but ciclosporin was switched to tacrolimus. The patient subsequently developed severe nausea, vomiting, hematemesis, and pancytopenia, which abated after withdrawal of mycophenolate mofetil. Retrospective measurement showed that the unbound mycophenolic acid AUC0–6h on day 5 was markedly increased at 2.3 h mg/l, as was the unbound fraction, at 18%.
Drug formulations Enteric-coated mycophenolate sodium, which delivers mycophenolic acid, was designed to prevent upper gastrointestinal adverse events (216R ). At a dose of 720 mg, it produces equivalent mycophenolic acid AUC and Cmax to mycophenolate mofetil 1 g but with a delayed tmax . Enteric-coated mycophenolate 720 mg bd is therapeutically equivalent to mycophenolate mofetil 1 g bd, and as safe, after kidney transplantation.
Drug overdose Mycophenolate mofetil overdose has been reported in a patient with autoimmune disease (218A ). • A 24-year-old woman with lupus nephritis presented 4 hours after taking mycophenolate mofetil 10 g. Her symptoms included mild abdominal cramping and nausea. The mycophenolic acid serum concentration was 44 µg/ml at 5 hours after ingestion. She was treated with oral activated charcoal, promethazine, and intravenous fluids. The mycophenolic acid serum concentrations at 10 and 21 hours were 5.6 and 0.3 µg/ml. She recovered with no adverse effects.
Drug interactions Aciclovir and valaciclovir The interaction of mycophenolate mofetil with aciclovir or valaciclovir has been studied in 15 healthy subjects, who received aciclovir 800 mg, valaciclovir 2 g, mycophenolate mofetil 1 g, intravenous valaciclovir 2 g + mycophenolate mofetil 1 g, or aciclovir 800 mg + mycophenolate mofetil 1 g (219c ). Aciclovir Cmax , tmax , and AUC were significantly increased by 40%, 0.38 hours, and 31% respectively after co-administration mycophenolate mofetil, and the half-life of aciclovir was shortened by 11%. Following co-administration of valaciclovir with mycophenolate mofetil, aciclovir pharmacokinetics were not significantly changed, except for a slight shortening in tmax by about 0.5 hours. The pharmacokinetics of mycophenolic acid and mycophenolic acid glucuronide were not significantly changed by co-administration of mycophenolate mofetil with valaciclovir or aciclovir, except for the AUC of the glucuronide, which was reduced by 12% with valaciclovir. Antiretroviral drugs The interaction of mycophenolate mofetil with antiretroviral drugs has been studied in 19 HIV-1-infected patients (220c ). Antiretroviral-naive men started treatment with didanosine 400 mg/day, lamivudine 300 mg/day, abacavir 600 mg/day, indinavir
448 1600 mg/day, ritonavir 200 mg/day, and nevirapine 400 mg/day and were randomized to mycophenolate mofetil 1000 mg/day (n = 10) or not (n = 9). Mycophenolate mofetil did not alter the clearances of indinavir or abacavir, but increased the clearance of nevirapine. There was no significant difference in the intracellular pools of lamivudine deoxycytidine triphosphate (dCTP), deoxyguanosine triphosphate (dGTP), or triphosphate. Ferrous sulfate Oral ferrous sulfate reduced the intestinal absorption of mycophenolate mofetil in healthy Japanese individuals by 90% but had no effect in Caucasian kidney graft recipients (221c ). In another study oral iron supplements had no significant effect of on mycophenolate mofetil absorption (222c ). Monitoring therapy In 100 kidney transplant recipients, tacrolimus and mycophenolic acid predose trough blood concentration, AUC, Cmax , and dose correlated with efficacy and toxicity (223C ). Initially after grafting, tacrolimus AUC was higher in recipients with infections, whereas mycophenolic acid AUC was not different. From 3 months after kidney transplantation, recipients with anemia or leukopenia had higher mycophenolic acid AUC and trough concentrations. Recipients who did not have a target tacrolimus AUC of 150 h µg/l and mycophenolic acid AUC of 45 h mg/l by day 7, the incidence of acute rejection tended to be higher (26%) compared with patients who reached both target values (7.7%). After liver transplantation (147 adults, 63 children), mycophenolic acid concentrations were related to adverse events, drug dose, and clinical status (224C ). Predose mycophenolic acid concentrations were below 1 mg/l in 12 of 13 acute rejection episodes. The relative risk of infection or leukopenia increased more than three-fold above mycophenolic acid predose concentrations of 3–4 mg/l. Plasma mycophenolic acid concentrations correlated weakly with the dose of mycophenolate mofetil. The dose/concentration relation was variably influenced by age, indication, concentrations of serum albumin and creatinine, and co-medication with tacrolimus or ciclosporin. The median mycophenolate mofetil dose required per unit mycophenolic acid concentration was 50% lower in children than in adults. Dosage requirements were also reduced by renal dysfunction
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(40% adults and 43% children), and in patients who were given mycophenolate mofetil alone rather than with tacrolimus or ciclosporin. Patients with a serum albumin concentration below 35 g/l required higher mycophenolate mofetil doses than those with normal albumin concentrations (2.1-fold in adults and 2.6-fold in children). In adults, 45% achieved clinically acceptable therapeutic mycophenolic acid concentrations at a dose less than 2 g/day and only 6.3% required 3 g/day. Mycophenolic acid predose concentration monitoring appeared to be clinically and cost effective. A therapeutic range of 1–3.5 mg/l monitored by immunoassay is applicable after liver transplantation. Unbound and total mycophenolic acid concentrations and plasma albumin concentrations were determined on day 5 after kidney transplantation in 42 patients (225c ). Low albumin concentrations significantly correlated with an increase in unbound mycophenolic acid. The cut-off value of albumin, determined from receiver operating characteristic (ROC) analysis, that differentiated normal from raised percentage unbound mycophenolic acid (defined as at least 3%) in this population was 31 g/l. At this cut-off value albumin was a good predictor of altered unbound mycophenolic acid, with a sensitivity of 0.75 and a specificity of 0.80, and an area under the ROC curve of 0.79. Monitoring of unbound mycophenolic acid concentration is desirable in patients with a plasma albumin concentration less than 31 g/l. There is substantial inter- and intra-individual variability in mycophenolic acid concentrations and lower mycophenolate mofetil dosage requirements when it is combined with tacrolimus than with ciclosporin (226R ). Patients with autoimmune diseases require an intermediate dose when they are not taking a concomitant calcineurin inhibitor. Combined pharmacokinetic and pharmacodynamic monitoring allows optimization of drug dosing, with maximum efficacy and minimal toxicity. There was wide intra- and interindividual variability in mycophenolic acid concentrations in six adults with psoriasis taking oral mycophenolate mofetil 2 g/day (227c ). There was no significant correlation between mycophenolic acid trough concentrations and the reduction of the Psoriasis Area and Severity Index (PASI)
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or the presence of adverse effects, but there was a good correlation with adherence to therapy.
Tumorigenicity The US FDA Division of Pediatric Drug Development has recommended that a black-box warning be added to the labelling of two eczema treatments, pimecrolimus (Elidel) and tacrolimus (Protopi) to warn of potential carcinogenicity with these products (231S ). This recommendation was based on all available information regarding these agents, including animal carcinogenicity signals in mice and monkeys and postmarketing reports of tumor-related adverse events. The division says that the available data raise “serious safety concerns in children regarding the potential for carcinogenicity in humans” with agents indicated for the treatment of atopic dermatitis, a non-life-threatening condition. In animals, the carcinogenicity signal with the two products is “strong, consistent and dependent on dose and treatment duration.” Furthermore, in humans there have been several post-marketing reports of lymphoma (n = 7), skin cancers (n = 6), and papillomas (n = 2), and the division noted that the increased incidence of specific infections with pimecrolimus and tacrolimus in clinical trials provides additional supportive evidence of immunosuppression in children. The US FDA has advised health-care professionals to prescribe the two products only as directed (minimum dose, for the shortest period of time, and never in children under 2 years of age) and only after other eczema treatments have failed to work.
Drugs that act on the immune system
Pimecrolimus
(SED-15, 2833;
SEDA-28, 460) The most common adverse effects of pimecrolimus in clinical trials have been local, and included burning sensations at the application site and skin infections. Systemic adverse effects, mainly infections, were most marked in infants. In practice, the reference treatment for exacerbations of atopic dermatitis is a topical glucocorticoid. There are concerns about the use of pimecrolimus, especially in children, because it is less active than topical glucocorticoids and its long-term adverse effects are unknown (228c ). Skin Pimecrolimus cream 1% has been compared with topical glucocorticoids in 658 adults with moderate to severe atopic dermatitis (229C ). Efficacy was better with glucocorticoids. The most frequent application site reaction was burning in 26% of patients with pimecrolimus and 11% with glucocorticoids; it was transient and mild to moderate in most cases. Three patients treated with glucocorticoids reported skin striae. There were no treatmentrelated serious systemic adverse events. Infection risk Fungal infection can complicate the topical use of pimecrolimus (230A ). • A 6-year-old boy with a small patch of eczema near his right eye was given pimecrolimus cream bd. After 2–3 days the itching and erythema had completely resolved, but a rough scaly plaque persisted. After 1–2 weeks of treatment, the itching gradually returned, and the lesion began to increase in size. Multiple, similar lesions appeared several centimeters from the initially affected area. Pimecrolimus was withdrawn and topical nystatin + triamcinolone ointment was prescribed. The eruption continued to spread, with multiple annular, scaly papules and plaques with central clearing. There was excoriation and mild inflammation around all the affected areas. Potassium hydroxide examination of the lesions showed numerous hyphae. The nystatin + triamcinolone ointment was withdrawn and oral griseofulvin was prescribed. The eruption improved dramatically after 3 weeks and eventually cleared completely after 5 weeks. Topical ketoconazole cream 2% bd was applied for the final 2 weeks of treatment.
Sirolimus (rapamycin)
(SED-15, 3148; SEDA-26, 408; SEDA-27, 377; SEDA-28, 460) Sirolimus has a range of adverse effects, including altered lipid metabolism, myelosuppression, arthropathy, and impaired wound healing (232R ). A high incidence of complications with sirolimus in two liver transplant trials led to an official warning in the drug information sheet (233S ). Observational studies When sirolimus was given to 40 liver transplant recipients to minimize exposure to calcineurin inhibitors and glucocorticoids, five discontinued sirolimus because of toxicity, and 24 of 35 surviving patients took sirolimus monotherapy (234c ).
450 After liver transplantation, 91 of 175 sirolimus-treated recipients developed a complication other than an increase in serum triglycerides and/or cholesterol (235C ). The most frequent complications were bilateral lower limb edema (57%), dermatitis (25%), oral ulcers (24%), joint pains (23%), pleural effusion (17%), increased abdominal girth (9.9%), generalized edema (5.5%), pericardial effusion (5.5%), facial edema (2.2%), and upper limb edema (1.3%). In addition, two recipients had hepatic artery thrombosis, one had wound dehiscence with evisceration that required surgical repair, and one developed skin cancer. A history of myocardial ischemia correlated with the development of sirolimus adverse effects. Cardiovascular After kidney transplantation or kidney–pancreas transplantation, 13 of 368 recipients (3.5%) developed biopsy-proven thrombotic microangiopathy in the absence of vascular rejection (27C ). The incidence was highest in those who used ciclosporin + sirolimus (21%). The relative risk was 16 (95%CI = 4.3, 61) for patients who used ciclosporin + sirolimus compared with those who used tacrolimus + mycophenolate mofetil. The combination of ciclosporin + sirolimus was the only regimen that had both pronecrotic and antiangiogenic effects on arterial endothelial cells, suggesting that this combination produces thrombotic microangiopathy by dual effects on endothelial cell death and repair. Two intestinal transplant recipients developed thrombotic microangiopathy while taking tacrolimus + sirolimus soon after starting to take sirolimus or increasing the dose; improvement occurred only after withdrawal (236A ). Respiratory Pulmonary toxicity is a serious complication of sirolimus therapy. The symptoms include dyspnea on exertion and a dry cough, followed by fatigue and fever. Chest X-rays and high-resolution CT scans commonly show bilateral patchy or diffuse alveolo-interstitial infiltrates. Bronchoalveolar fluid analysis and lung biopsy in selected cases have shown several distinct histological features, including lymphocytic alveolitis, lymphocytic interstitial pneumonitis, bronchoalveolar obliterans organizing pneumonia, focal fibrosis, and pulmonary alveolar hemorrhage. Sirolimus
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withdrawal or dose reduction results in clinical and radiological improvement within a few weeks (237A ). Alveolar hemorrhage has been observed in association with sirolimus (238A ). Fever, dyspnea, hemoptysis, and lung infiltrates resolved rapidly on withdrawal. Patients can present with lymphocytic alveolitis or macrophage hemosiderosis, suggesting that sirolimus pulmonary toxicity can occur through two separate mechanisms. Sirolimus-induced pneumonitis occurred in two patients who started taking sirolimus to allow ciclosporin withdrawal (239A ). The clinical course ranged from insidious to fulminant, and there was a rapid response to sirolimus withdrawal. Other case reports have confirmed an association between sirolimus and interstitial pneumonitis, which is often difficult to establish as the cause after kidney transplantation (240A –242A ). Sirolimus-associated interstitial pneumonitis has been documented in patients taking at least 5 mg/day and in patients with blood concentration plateaus above 15 ng/ml (243A ). • A 52-year-old male heart transplant recipient died of interstitial pneumonitis after a loading dose of sirolimus 15 mg associated with persistently increased blood concentrations above 20 ng/ml.
After lung transplantation (two single lung transplants, one double lung transplant, and one heart–lung transplant), initial sirolimus and tacrolimus therapy resulted in three cases of Aspergillus infection (244A ). Mean sirolimus trough concentration was 6.2 ng/ml. There was poor wound healing in three patients, resulting in bronchial airway dehiscence in two patients, with a lethal outcome in one. As a result of these complications, the study design was revised. Sirolimus administration is now started only after completion of bronchial wound healing. Endocrine The impact of sirolimus on hormone concentrations involved in the hypothalamus–pituitary–gonad axis has been investigated in 132 male heart transplant recipients (245C ). There was a significant reduction in testosterone and significantly increased follicle stimulating hormone (FSH) and increased luteinizing hormone (LH) in the sirolimus group. The duration of sirolimus treatment correlated
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positively with concentrations of sex hormonebinding globulin, LH, and FSH, and negatively with the unbound androgen index. Sirolimus trough concentrations correlated with LH and FSH concentrations.
eosinophilia, consistent with an allergic drug reaction. Hepatitis C viral load increased slightly, from 600 000 to 700 000 IU/ml. Mean baseline transaminase activities were aspartate transaminase 45 U/l and alanine transaminase 50 U/l, with peak activities of 210 and 180 U/l. The mean time to transaminase increase was 21 days after the addition of sirolimus, and resolution occurred within 27 days after withdrawal. Combination sirolimus and tacrolimus concentrations were maintained at over 10 ng/ml and sirolimus monotherapy at 12 ng/ml. The average duration of sirolimus therapy was 25 weeks. Immediate recognition of sirolimus-related hepatotoxicity is critical, to avoid confusion with other causes of abnormal serum transaminases after liver transplantation, and withdrawal of the drug may be necessary.
Drugs that act on the immune system
Metabolism Hypertriglyceridemia is a common adverse effect of sirolimus, and it often does not respond to dosage reduction or hypolipidemic drugs. After liver transplantation (n = 6), significant hyperlipidemia improved after withdrawal of sirolimus (246c ). The incidence of sirolimus-associated hyperlipidemia is up to 44%. After liver transplantation, there was hypercholesterolemia in 15% and hypertriglyceridemia in 10% of recipients. Sirolimus in combination with tacrolimus and/or mycophenolate mofetil caused no higher incidence of hyperlipidemia than calcineurin inhibitors and mycophenolate mofetil (247c ). After kidney transplantation, at least 60% of adult recipients develop dyslipidemia within 1 month of the start of immunosuppressive therapy; ciclosporin, sirolimus, and prednisone are mainly implicated, and the lipid profile differs between individual agents (248R ). Hematologic Post-transplantation anemia and erythrocytosis have been studied in patients given either sirolimus (n = 87) or mycophenolate mofetil (n = 127) after kidney transplantation or kidney–pancreas transplantation (249C ). Erythrocytosis, defined as a persistent hematocrit above 51%, occurred in 19% with mycophenolate mofetil and 7% with sirolimus. Sirolimus reduced the risk of erythrocytosis compared with mycophenolate mofetil (OR = 0.33; 95%CI = 0.12, 0.89), but was associated with a higher prevalence of anemia (31% at 12 months with mycophenolate mofetil and 57% with sirolimus). Lymphoceles are common in kidney transplantation recipients who receive sirolimus, but lymphedema is rare. Three cases of lymphedema resolved or improved on withdrawal of sirolimus and no other likely causes of lymphedema were discovered (250A ). Liver Putative sirolimus-related hepatotoxicity was studied in 10 patients after liver transplantation (251c ). Sirolimus was given for renal insufficiency (n = 6) or chronic rejection (n = 4). Two of the six patients had changes consistent with sinusoidal congestion and one had
Urinary tract Sirolimus can cause nephrotoxicity in patients with chronic glomerulopathies. Eleven patients with focal segmental glomerulosclerosis, immunoglobulin A nephropathy, membranous nephropathy or membranoproliferative glomerulonephritis and progressive renal insufficiency were given oral sirolimus 5 mg/day (target blood concentrations 7–10 ng/ml) (252c ). All were also taking an angiotensin-converting enzyme inhibitor and/or an angiotensin receptor blocker. Six developed acute renal insufficiency, which improved in four after withdrawal of sirolimus. One patient required hemodialysis and did not recover renal function. In another patient, renal function recovered after withdrawal of the drug and sirolimus was restarted at a lower dose when creatinine returned to baseline; however, this resulted in a second acute increase in serum creatinine and it did not return to baseline when the medication was withdrawn. Four other patients developed skin rash, severe hypertriglyceridemia, diarrhea, and hyperkalemia. None of the patients had sirolimus concentrations over 15 ng/ml. Whether nephrotoxicity is solely related to sirolimus, due to the combination of proteinuria and sirolimus, or due to another unknown factor is not known. Glomerulonephritis developed in four kidney transplant recipients after conversion from calcineurin inhibitors to sirolimus (253A ). All developed proteinuria within 2–9 months. Renal biopsy confirmed membranoproliferative glomerulonephritis type 1 in one case, membranous glomerulonephritis in one, and IgA
452 nephropathy in two. Calcineurin inhibitor-based immunosuppression was reintroduced and resulted in complete remission of proteinuria and stabilized renal function in all four cases. Renal impairment has been attributed to sirolimus (254A ). • A 52-year-old woman underwent kidney transplantation, and immunosuppression included basiliximab, glucocorticoids, and ciclosporin, later switched to sirolimus and mycophenolate mofetil because of biopsy findings of tubular necrosis on day 6 after kidney transplantation. At discharge the serum creatinine was 62 µmol/l (0.7 mg/dl). Four months after transplantation, she developed a fever, anorexia, and weakness. Cultures and other tests for infection were negative. The serum sirolimus concentration was 26 ng/ml. The next day the serum creatinine concentration rose from 150 to 200 µmol/l (1.7 to 2.3 mg/dl) and urine output fell to 20 ml/hour. The bleeding time (Ivy test) before renal biopsy was repeatedly longer than 30 minutes, despite a normal platelet count and normal platelet function studies (there was no spontaneous aggregation and in vitro aggregation was normal to collagen, ADP, adrenaline, and ristocetin). Coagulation studies showed a defect in fibrin formation and reduced fibrinolysis. Withdrawal of sirolimus was followed by remission of fever, improved renal function (serum creatinine 106 µmol/l (1.2 mg/dl)), and normalization of the bleeding time.
Immunologic Angioedema is a previously unrecognized adverse effect of sirolimus that was observed in three African-American primary kidney transplantation recipients taking sirolimus, mycophenolate mofetil, and glucocorticoids (255A ). In two cases, angioedema occurred after sirolimus was restarted after a period of withdrawal. The third case presented on initial exposure to the drug. None of the patients was taking any drug that has been previously associated with angioedema. Complete resolution occurred only after sirolimus was withdrawn. Angioedema did not recur in any of the patients during a follow-up period of up to 21 months. Infection risk When sirolimus was administered to 55 of 116 consecutive liver recipients (61 controls) those who received sirolimus had more infections than controls (47% versus 18%), and this effect persisted across high and low dosage ranges and sirolimus concentrations; those who received even low doses of sirolimus had increased rates of sepsis (256C ).
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Trauma Sirolimus has been associated with an increased risk of wound-healing complications in several retrospective analyses. Rates of wound-healing complications were analysed in a randomized comparison of sirolimus + mycophenolate mofetil + prednisone (n = 64) versus tacrolimus + mycophenolate mofetil + prednisone (n = 59) after kidney transplantation; both groups received antithymocyte globulin induction (257c ). In the early phase of the study, patients (n = 77) were included regardless of body mass index. In the later phase (n = 46), patients with a body mass index greater than 32 kg/m2 were excluded, and the target trough sirolimus concentration was lowered from 15–20 to 10–15 ng/ml. The incidences of complications were 8% with tacrolimus and 47% with sirolimus. Rates of perigraft fluid collections, superficial wound infections, and incisional herniae were significantly higher with sirolimus. Multivariate logistic regression showed that only sirolimus and body mass index correlated independently with complications. In the first and later phases of the study, the wound complication rates in the sirolimus group were 55% and 35% respectively. Drug dosage regimens Primary cadaveric kidney transplant recipients were randomly assigned to receive either standard tacrolimus (10–15 ng/ml) plus reduced sirolimus (5– 10 ng/ml) or reduced tacrolimus (5–10 ng/ml) plus standard sirolimus (10–15 ng/ml) (258c ). All patients received antithymocyte globulin induction and glucocorticoids. Wound complications were the most frequent adverse effect reported in both groups. The combination of tacrolimus + sirolimus was associated with a low risk of acute rejection, but 50% of the patients who received standard tacrolimus + reduced sirolimus had to be withdrawn because of biopsy-proven nephrotoxicity. Drug interactions Sirolimus, ciclosporin, and tacrolimus are all transported by the multidrug transporter P glycoprotein and metabolized by CYP3A4. In healthy volunteers, ciclosporin, diltiazem, erythromycin, ketoconazole, and verapamil significantly increased sirolimus whole blood exposure, and rifampicin significantly reduced it (259c ). However, sirolimus whole blood exposure was not affected by aciclovir,
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atorvastatin, digoxin, ethinylestradiol + norgestrel, glibenclamide, nifedipine, or tacrolimus. Among the 15 drugs studied, sirolimus significantly increased the exposures of only erythromycin and verapamil. In five patients voriconazole, itraconazole, fluconazole, or erythromycin increased sirolimus blood concentrations (260A ). After kidney transplantation, the interaction of voriconazole with sirolimus required a 75–88% reduction in the dose of sirolimus (261A ). In 495 kidney transplant recipients dosenormalized sirolimus trough concentrations were significantly higher in patients who also took ciclosporin (4.15 ng/ml) compared with patients who also took mycophenolate mofetil (3.26 ng/ml) or mycophenolate mofetil + glucocorticoids (2.52 ng/ml) (262C ).
Tacrolimus
(SED-15, 3279; SEDA-26, 408; SEDA-27, 377; SEDA-28, 463)
In the USA, tacrolimus is approved only for kidney transplantation and liver transplantation, but it was used in 67% of kidney transplant recipients, 89% of liver transplant recipients, 81% of kidney–pancreas transplant recipients, 77% of pancreas transplant recipients, 65% of lung transplant recipients, 48% of heart–lung transplant recipients, and 42% of heart transplant recipients in 2003 (263R ). For information on the recommendation of the US FDA Division of Pediatric Drug Development that a black-box warning be added to the labelling of tacrolimus, see above under Pimecrolimus. Cardiovascular Cardiovascular disease is a major cause of morbidity and mortality after kidney transplantation. Ciclosporin was replaced by tacrolimus in 22 adult renal recipients with serum total cholesterol concentrations greater than 5.2 mmol/l (200 mg/dl) more than 1 year after kidney transplantation (264c ). There was a significant improvement in fibrinogen, total cholesterol, and low-density lipoprotein cholesterol after conversion. Low-dose tacrolimus may be preferable to ciclosporin for chronic maintenance immunosuppression because it improves the overall cardiovascular risk profile without any apparent adverse effects.
453 Tacrolimus-associated thrombotic microangiopathy resolved after conversion to sirolimus (265A ). • A 29-year-old man received a kidney–pancreas transplant for end-stage diabetic nephropathy. After induction with basiliximab, immunosuppression consisted of prednisone + tacrolimus + mycophenolate mofetil. Thrombotic microangiopathy occurred 24 days after transplantation. The patient was successfully converted from tacrolimus to sirolimus and was treated with plasma infusion. Allograft biopsy showed focal glomerular and arteriolar acute thrombosis without evidence of rejection.
Respiratory Bronchiolitis obliterans organizing pneumonia (BOOP) has been described after bone marrow transplantation, lung transplantation, heart–lung transplantation, and kidney transplantation, but rarely after liver transplantation (266A ). • A 48-year-old male liver recipient developed dyspnea, cough, and bilateral leg edema 1 month after liver transplantation. Immunosuppression consisted of tacrolimus + prednisone. A chest X-ray showed bilateral infiltrates. A CT scan of the chest showed bilateral diffuse infiltrates with areas of sparing and nodularities. Bronchoscopy was normal and bronchoalveolar lavage was negative. Lung biopsy showed serpiginous plugs of fibroblastic tissue filling the alveolar spaces, focal fibrosis of some alveolar septa, and reactive pneumocytic hyperplasia consistent with BOOP. Methylprednisolone was continued with clinical improvement and weaning from the ventilator, but he developed sepsis and multisystem organ failure and died.
Nervous system A liver transplant recipient developed a chronic inflammatory demyelinating polyradiculoneuropathy while taking tacrolimus (31A ). Two children developed coma and seizures after transplantation, and MRI fluid-attenuated inversion-recovery and diffusion-weighted images allowed diagnosis of drug-induced toxicity (267A ). Unlike other reported patients, in whom all symptoms resolved, the lesions persisted, albeit with some improvement, and both children had learning disabilities after several years of follow-up. Tacrolimus-induced leukoencephalopathy is being increasingly recognized as an important cause of neurological complications after transplantation. It is rare after allogenic stem cell transplantation, but another case has been reported (268A ).
454 • A 46-year-old woman with Hodgkin’s disease underwent non-myeloablative allogenic stem cell transplantation. She received tacrolimus + prednisone for treatment of graft–versus–host disease. At day 100 she developed cortical blindness, seizures, and left hemiparesis. An MRI scan showed multiple changes, mainly in the bilateral occipital lobes. Her symptoms improved after withdrawal of tacrolimus, but cerebral hemorrhage occurred in the left occipital lobe with perforation to the left subdural space 3 days after the episode.
Although tacrolimus-induced leukoencephalopathy with cerebral hemorrhage is considered the more severe form of such leukoencephalopathy, the neurological symptoms in this case almost completely resolved and the radiographic findings improved after withdrawal of tacrolimus, tapering of methylprednisolone, and introduction of mycophenolate mofetil. Encephalopathy associated with ciclosporin + tacrolimus has been studied after bone marrow transplantation for chronic or acute leukemias (n = 311), myelodysplastic syndrome (n = 42), or severe aplastic anemia (n = 25) (269A ). Immunosuppressive drug-associated encephalopathy occurred in 12 patients. The incidence was significantly higher in those with severe aplastic anemia and myelodysplastic syndrome (n = 7/67) than in those with leukemias (n = 5/311). Ten patients died. Five of the seven patients with severe aplastic anemia and myelodysplastic syndrome had taken ciclosporin before bone marrow transplantation, which might have influenced the incidence of encephalopathy. Sensory systems Reversible bilateral internuclear ophthalmoplegia has been attributed to intravenous tacrolimus (270A ). • A 50-year-old man developed tonic–clonic seizures after heart transplantation while taking ciclosporin, prednisone, mycophenolate mofetil, and azathioprine. The seizures resolved after withdrawal of ciclosporin. Thereafter, he received tacrolimus 4 mg/day because of supposed graft rejection. Rejection progressed and he received intravenous tacrolimus aiming at trough concentrations of 10–20 µg/l. Three days later he developed a bilateral internuclear ophthalmoplegia. There was a temporal association between his symptoms and the serum tacrolimus concentration, which rose from 5.2 to 21 µg/l. Withdrawal of intravenous tacrolimus led to prompt resolution of the bilateral internuclear ophthalmoplegia within 2 days and the tacrolimus trough concentration fell to 13 µg/l.
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Endocrine In a meta-analysis of 16 studies of patients who were taking tacrolimus (n = 1636) or ciclosporin (n = 1407) the incidence of type 1 diabetes mellitus was significantly higher among those taking tacrolimus (10% versus 4.5%) (271M ). The effect was observed in those with renal transplants (9.8% versus 2.7%) and those with other organ transplants (11.1% versus 6.2%), and among patients who were taking equal doses of concomitant medications in both treatment arms (12% versus 3%). Further factors associated with diabetes mellitus after kidney transplantation were older recipient age, a cadaveric organ, hepatitis C antibody status, an episode of rejection, and the use of tacrolimus (versus ciclosporin); cumulative glucocorticoid dose and calcineurin inhibitor trough concentration were not associated factors (272C ). Metabolism Hyperuricemia has been reported in association with ciclosporin and tacrolimus. In two cases there was a direct association between tacrolimus and gout after liver transplantation (273A ). • A 31-year-old male liver transplant recipient was given tacrolimus 6 mg/day and prednisolone. After 8 months, he developed acute arthritis of the right wrist and both elbows. The serum uric concentration was 421 µmol/l and creatinine 105 µmol/l. After 16 months a mass was excised from the right forearm; histology was typical for gout. • A 25-year-old liver transplant recipient taking tacrolimus 4 mg/day developed podagra and arthritis of the left wrist. The serum uric acid was 452 µmol/l and creatinine 190 µmol/l. The attacks of gout resolved with allopurinol.
Electrolyte balance The incidences of hyponatremia and hyperkalemia in patients taking ciclosporin (n = 80) and tacrolimus (n = 45) have been studied after kidney transplantation (274c ). Tacrolimus caused a higher incidence of hyponatremia and hyperkalemia than ciclosporin within the first 3 months. Patients with hyponatremia were more likely to experience hyperkalemia. Hematologic After kidney transplantation in 50 patients the overall prevalence of anemia was 60%, including 30% with severe anemia (hemoglobin below 10 g/dl) (275c ). The rate of iron deficiency was 34% and serum iron was the parameter of iron metabolism most closely
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associated with anemia. The hemoglobin concentration in patients with a low serum iron was 9.07 g/dl versus 11.44 g/dl in those with a normal serum iron concentration. The dose of tacrolimus and creatinine clearance were significantly associated with anemia. There was a 1 g/dl reduction in hemoglobin for every increase in dose of tacrolimus of 0.054 mg/kg/ day. The dose of mycophenolate mofetil correlated positively with hemoglobin, but this was probably related to the practice of dose reduction in the setting of anemia. Tacrolimus-induced hematological toxicity can present as thrombotic thrombocytopenic purpura, hemolytic–uremic syndrome, red cell aplasia, and generalized bone marrow suppression (276A ).
Liver Graft dysfunction mimicking autoimmune hepatitis develops only rarely after liver transplantation for non-autoimmune hepatitis. Of 633 tacrolimus-treated patients who underwent live donor liver transplantation, 13 (2 men, 11 women) developed graft dysfunction with interface hepatitis resembling autoimmune hepatitis at a median interval of 3.1 (0.7–9.5) years (278C ). Nine had definite and four probable autoimmune hepatitis. After a median follow-up of 3.5 (0.1–8) years from the time of onset, 11 patients underwent histological evaluation, three underwent repeat liver transplantation, and eight continued to have similar findings on subsequent biopsies, with fluctuations in the amounts of necroinflammatory activity and an increase in fibrosis despite treatment. Acute rejection episodes and recipient age of 11–15 years at time of transplantation independently had predictive value for the development of autoimmune hepatitis; sex mismatch and human leukocyte antigen A, B, and DR mismatches had no effect. Drug-related toxicity has been reported in a liver transplant recipient co-infected with HIV and hepatitis C (279A ).
Drugs that act on the immune system
• A 17-year-old girl underwent liver transplantation for acute toxic hepatitis due to ecstasy. Initial immunosuppression was tacrolimus 0.3 mg/kg/day, azathioprine 50 mg/day, and glucocorticoids. Comedication consisted of ganciclovir 15 mg/kg/day, oral pyrimethamine + sulfadiazine 500 mg/day, and folic acid. A normochromic normocytic anemia (hemoglobin 7.2 g/dl) with a low reticulocyte count developed 13 days after transplantation and the patient required 2–3 red blood cell units over the next 3 months. After 4 months, the leukocyte count (2.2 × 109 /l) and platelet count (105 × 109 /l) fell. A bone marrow biopsy showed reduced cellularity (20%) with depletion of myeloid and erythroid precursors. Viral serologies were negative for hepatitis B, hepatitis C, parvovirus B19, Epstein–Barr virus, and cytomegalovirus. Tacrolimus was replaced by ciclosporin and the hemoglobin concentration increased within 1 month. A bone marrow biopsy 15 months after conversion to ciclosporin showed normal cellularity (over 70%).
In contrast to previous reports of pure red cell aplasia and bone marrow hypoplasia, recovery of hemoglobin and neutrophil numbers was slow after tacrolimus withdrawal. Gastrointestinal Increased tacrolimus trough concentrations were detected in association with severe diarrhea (277A ). • A 32-year-old male renal transplant recipient had increased tacrolimus trough concentrations from 6.7 to 29 ng/ml during an episode of gastroenteritis with severe diarrhea. He was also taking mycophenolate mofetil and prednisone.
The authors suggested that enterocolitis may destroy P glycoprotein in intestinal epithelial cells, thereby reducing first-pass metabolism of tacrolimus.
• A liver transplant recipient co-infected with HIV and hepatitis C took triple antiretroviral therapy consisting of zidovudine, lamivudine, and efavirenz. The CD4+ cell count was stable at over 500 × 106 /l. Immunosuppression was achieved with tacrolimus, azathioprine, and glucocorticoids. Antiretroviral therapy was restarted on the first postoperative day as early graft function was in the reference range. Within a few hours there was rhabdomyolysis with myoglobinuria, and graft function deteriorated rapidly. There was tense ascites and severe hyperbilirubinemia. All drugs were withdrawn except glucocorticoids and riboflavin and glutathione were given empirically for 5 days, when the myoglobinuria disappeared. Tacrolimus trough concentrations remained in the target range for 6 days and tacrolimus was then reintroduced at a reduced dosage of 0.01 mg/kg/day. Liver function normalized after 48 days.
Biliary tract After liver transplantation, immunosuppression affects the rate of recurrent primary biliary cirrhosis. Patients with primary biliary cirrhosis (n = 485) were followed for a median of 79 months after liver transplantation; there was histological evidence of recurrence in 23% (280C ). The only risk factor for recurrence was the type of calcineurin inhibitor used. The odds ratio for recurrence
456 on tacrolimus was 2.73 (95%CI = 1.84, 4.10) compared with ciclosporin. For those taking ciclosporin, the median time to recurrence was 123 months and for those taking tacrolimus 62 months. The reasons for this difference between the two calcineurin inhibitors are not clear. Pancreas Tacrolimus-associated pancreatitis is a rare complication after allogenic bone marrow transplantation (281A ), but has been reported again (282A ). • A 9-year-old boy with chronic granulomatous disease underwent myeloablative bone marrow transplantation. Conditioning included fludarabine, busulfan, and antithymocyte globulin and immunosuppression after transplantation consisted of tacrolimus and mycophenolate mofetil. Other therapy included ursodeoxycholic acid against veno-occlusive disease, aciclovir as prophylaxis against Herpes simplex, and liposomal amphotericin and caspofungin for treatment of aspergillosis. On the 19th day after transplantation, he developed severe abdominal pain, malaise, nausea, and vomiting. Serum lipase and amylase were 1116 U/l and 150 U/l, consistent with a diagnosis of pancreatitis. The tacrolimus trough concentration was 5.4 µg/l. Tacrolimus was converted to ciclosporin and his symptoms improved.
Urinary tract Nephropathy associated with BK polyoma virus can cause allograft dysfunction after kidney transplantation, and specific antiviral therapy is not currently available. Progressive functional deterioration in two kidney recipients, one taking ciclosporin and the other tacrolimus, both in combination with mycophenolate mofetil + prednisolone, suggested BK polyoma virus infection (283A ). There were initially high BK virus loads, which fell in the patient taking ciclosporin when the dose was reduced, but not in the patient taking tacrolimus. Neither patient had received antilymphocyte globulin or muromonab. Of 896 patients with rheumatoid arthritis who took at least one dose of tacrolimus 3 mg, 16% developed tacrolimus-related adverse effects requiring withdrawal and 13% withdrew because of lack of efficacy (284C ). There was a rise in mean creatinine concentration from 67 µmol/l (0.76 mg/dl) at baseline to 75 µmol/l (0.85 mg/dl) at the end of treatment. There was an increase in creatinine by at least 30% from baseline in 351 of 872 patients (40%) and 73 patients (8.4%) exceeded the reference range. At the end of treatment, 177 patients (20%)
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had a 30% or greater increase from baseline in serum creatinine, but serum creatinine remained within the reference range throughout the study in about 90% of patients. Skin Local intolerance reactions, in particular burning sensations, can occur in up to 50% of patients after topical application of tacrolimus. Facial flushing in association with alcohol ingestion has been noted in about 5% of patients treated with 0.1% tacrolimus ointment (285C ). The use of a prostaglandin synthesis inhibitor, such as acetylsalicylic acid 325 mg bd, was effective in reducing this in a pilot study (286c ). Hair After kidney transplantation, alopecia (30%) occurred more frequently in patients taking tacrolimus than in those taking ciclosporin (24C ). Musculoskeletal Severe rhabdomyolysis and acute renal insufficiency occurred in a kidney transplant recipient taking tacrolimus and a chimeric CD25 monoclonal antibody (287A ). • An 18-year-old male kidney transplant recipient who was taking tacrolimus, glucocorticoids, and who received a chimeric CD25 monoclonal antibody on postoperative days 1 and 4, had epileptic seizures 12 hours after the second dose of the antibody. Severe rhabdomyolysis (urine myoglobin 260 000 µg/l) and acute renal insufficiency occurred on the same day. The trough concentration of tacrolimus was 18 µg/l and the dosage was reduced. Tacrolimus was converted to sirolimus and there was complete recovery.
Severe bilateral knee pain within 3 months after kidney transplantation occurred in two patients taking tacrolimus (288A ). Bone scanning with 99m technetium showed increased uptake in the affected areas, and changes on MRI scans were consistent with bone marrow edema. The dosages of tacrolimus were reduced and the symptoms resolved completely within a few months. Tacrolimus can cause myositis (289A ). • A 55-year-old Caucasian man underwent a second kidney transplant and 7 years later immunosuppression was switched from ciclosporin to tacrolimus because of deteriorating renal function. He then developed muscle cramps in both quadriceps muscles, with increased creatine kinase activity and electromyographic evidence of polyneuropathy. Muscle biopsy showed acute myositis.
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Prednisone ameliorated the symptoms, but the creatine kinase activity and myoglobin concentrations remained high. The dose of tacrolimus was reduced to 3 mg/day and mycophenolate mofetil was added. The myositis resolved and the creatine kinase activity fell rapidly.
cutaneous zygomycosis is important. Such infections often present as necrotic-looking lesions and require antifungal therapy and rapid surgical intervention.
Drugs that act on the immune system
Reproductive system Female recipients of allogeneic islets for type 1 diabetes (n = 13) received daclizumab induction and tacrolimus + sirolimus maintenance immunosuppression (290c ). There were frequent menstrual cycle disturbances and clinically significant benign ovarian cysts in these patients, and some required medical or surgical intervention. Infection risk Viruses Infection with West Nile virus occurred in a renal transplant traveller taking tacrolimus (291A ). Polyomavirus-associated nephropathy has emerged as an important cause of renal allograft dysfunction and graft loss after kidney transplantation. Susceptibility appears to be related to the type and intensity of immunosuppression, but some reports have suggested a link between the nephropathy and treatment of rejection or maintenance with a tacrolimus-based immunosuppressive regimen (292A ). BK virus nephritis after kidney transplantation has re-emerged during the past 5 years. Therapeutic options remain limited, and progression of the disease often leads to allograft failure. It is hypothesized that replacement of tacrolimus + mycophenolate mofetil with sirolimus + prednisone can lead to disappearance of the virus without increasing the risk of acute rejection (293A ). Fungi Of 1374 kidney transplant recipients, six (4 men and 2 women, aged 50, range 29– 63, years) developed Nocardia asteroides infections (294A ). Two were taking ciclosporin and four tacrolimus. Three patients had panel reactive antibodies and two had acute rejection episodes. The sites of nocardiosis were pulmonary in five cases, cerebral in two, and mediastinal in one. All recovered following reduction in the doses of immunosuppressive drugs and therapy with co-trimoxazole. Zygomycosis due to Cunninghamella bertholletiae is rare but severe, and the lungs are mainly involved. Only 32 cases have been reported, and 26 were fatal. Early diagnosis of
• A 54-year-old man with insulin-dependent diabetes took tacrolimus + glucocorticoids after kidney transplantation (295A ). He developed primary cutaneous zygomycosis due to Cunninghamella bertholletiae without extracutaneous involvement probably related to insulin injections. He recovered after early surgical excision of the lesion and daily administration of itraconazole for 2 months.
Tumorigenesis Acute lymphoblastic leukemia has been reported in a child with nephrotic syndrome who was switched from ciclosporin to tacrolimus (296A ). • A 5-year-old African-American boy with nephrotic syndrome received standard daily glucocorticoid therapy but became resistant at 5 weeks. A renal biopsy showed focal segmental glomerulosclerosis. The nephrotic syndrome was treated with prednisolone to beign with, but after 6 weeks, he was chushingoid and the prednisolone was withdrawn and ciclosporin given. Ciclosporin was switched to tacrolimus after 20 weeks because of hirsutism. Tacrolimus was stopped after 1 week because of nausea. Six months later he developed acute lymphoblastic leukaemia, which was treated with vincristine, PEG-aspararginase, and dexamethasone. The leukemia went into complete remission and the nephrotic syndrome into partial remission, with continued nephrotic-range proteinuria.
Four other cases of acute lymphoblastic leukemia have been reported in children with nephrotic syndrome. No particular immunosuppressive agent seemed to be causative. Although the exact mechanism for the development of acute lymphoblastic leukemia after nephrotic syndrome is unknown, the incidence of leukemia may be increased after immunosuppressive therapy when used in this context. Acute promyelocytic leukemia occurred in a patient who took tacrolimus after liver transplantation (297A ). • A 12-year-old girl developed acute promyelocytic leukemia 21 months after lung transplantation for ornithine transcarbamylase deficiency. Tacrolimus was administered for prophylaxis against graft– versus–host disease. The bone marrow showed massive infiltration of promyelocytic blasts (M3 by the FAB classification); chromosome 46, XX, t (15; 17) (q22; q12) was the recipient origin. A PML/RAR alpha chimeric gene was detected by reverse transcriptase PCR. Daunorubicin, cytarabine, and tretinoin produced remission.
458 The incidence, risk, and impact of malignant lymphomas in about 200 000 organ transplant recipients have been analysed using the Collaborative Transplant Study database (298M ). Over 10 years the risk in renal transplant recipients was 12 times higher than that in a matched non-transplanted population, and most of the lymphomas were diagnosed after the first post-transplant year. Heart-lung transplants had the highest relative risk (RR = 240). In kidney transplant recipients, immunosuppression with ciclosporin did not confer added risk compared with azathioprine + glucocorticoids, whereas tacrolimus increased the risk about two-fold. Induction and antirejection therapy with muromonab or antithymocyte globulin, but not with anti-IL2 receptor antibodies, increased the risk of lymphoma during the first year. The first-year mortality in kidney and heart transplant recipients with lymphoma was about 40% and 50%. Susceptibility factors Tacrolimus absorption from the gastrointestinal tract is to a large extent determined by both P glycoprotein and CYP3A in the gut wall and liver. The rate of gastric emptying has been studied in 50 renal transplant recipients using a 14 C-octanoic acid breath test and quantifying drug exposure by plasma concentration measurement (299c ). Gastric emptying half-time correlated significantly with tacrolimus tmax (r 2 = 0.30), whereas the gastric emptying coefficient, reflecting overall gastric emptying rate, showed a weak inverse correlation with tmax (r 2 = 0.14). The time-dependent gastric emptying rate correlated strongly with the simultaneously measured blood tacrolimus concentration over the first 4 hours after drug administration (r 2 = 0.96). A comparison of patients with and without delayed gastric emptying confirmed that the tmax occurred significantly later in the former (2.00 versus 1.48 hours), whereas the extent of tacrolimus absorption was not different. Despite a strong association between gastric emptying rate and the timing of tacrolimus absorption from the gut, gastric emptying rate does not affect the total extent of drug absorption and is not responsible for significant alterations in drug exposure, even when gastric emptying is delayed. In a pharmacokinetic study of tacrolimus in 100 renal allograft recipients during the
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first year after kidney transplantation, longterm dose-corrected tacrolimus exposure was characterized by a late significant increase towards the end of the first year as the result of a significant increase in tacrolimus systemic availability and a slow reduction in tacrolimus steady-state clearance (300C ). Consequently, tacrolimus dosage requirements corrected for body weight fell significantly in the first postoperative year, partly related to tapering of the glucocorticoid dose, which significantly affected tacrolimus availability. Other variables that significantly influenced tacrolimus administration, exposure, and systemic availability in a time-related fashion were renal allograft function, liver dysfunction, and diarrhea. Timeunrelated variables were recipient age, sex, donor-recipient sex mismatch, donor hypotension, and cold ischemia time. Multiple stepwise regression analysis showed that classical assessment of tacrolimus exposure by monitoring pre-dose trough blood concentration is not the most reliable method. Abbreviated AUC measurements may be more accurate for therapeutic monitoring of drug exposure. Age The pharmacokinetics of sirolimus (n = 51) and tacrolimus (n = 55) have been studied in 20 boys and 14 girls (23 liver transplants, 11 intestinal transplants), median age 13 (1–24) years (301c ). Neither sirolimus nor tacrolimus dosages correlated with the corresponding AUCs, while trough concentrations correlated well. The short half-life of sirolimus in children may support twice-daily administration early after transplantation. During conversion of subjects from tacrolimus to combined tacrolimus + sirolimus, aggressive plasma concentration monitoring should be used to individualize therapy and avoid serious adverse events. Drug dosage regimens In an attempt to reduce calcineurin inhibitor-induced chronic allograft nephropathy in first cadaver and HLA non-identical live-donor kidney transplantation, sirolimus or mycophenolate mofetil were tested as adjunctive therapy, with planned dose reductions of tacrolimus over the first year postoperatively (30c ). The one-year interim analysis of this randomized study suggested that reducing the maintenance dosage of tacrolimus with adjunctive sirolimus or mycophenolate mofetil
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improved long-term function, with reasonably few adverse events. Alemtuzumab + low-dose tacrolimus (n = 40) has been compared with standard tacrolimus + prednisolone (n = 50) in liver transplant recipients (302c ). Alemtuzumab + low-dose tacrolimus significantly reduced the incidence of acute rejection after 2 and 12 months and was associated with lower tacrolimus trough concentrations, percentage of patients receiving maintenance glucocorticoids, mean creatinine concentrations, and the incidence of nephrotoxicity. Alemtuzumab-treated patients were at risk of rejection if the average tacrolimus trough concentration was under 6.5 µg/l during the first 2 months after liver transplantation. Drug interactions Metoclopramide The effect of metoclopramide on gastrointestinal motility can increase the absorption of tacrolimus, with subsequent toxicity. Caution is indicated when tacrolimus is administered with metoclopramide in patients with gastric dysmotility, and close monitoring of tacrolimus trough concentrations is recommended, as suggested by a recent case report (303A ). • A 52-year-old female liver transplant recipient had subtherapeutic tacrolimus trough concentrations. Tacrolimus was increased from 7 to 28 mg bd and ketoconazole was added. Neither intervention resulted in detectable tacrolimus trough concentrations. Nausea and vomiting were treated with metoclopramide 10 mg qds. Tacrolimus trough concentrations exceeded 30 µg/l within 48 hours of increasing the metoclopramide dosage to 20 mg qds. The patient developed symptoms of tacrolimus nephrotoxicity and neurotoxicity.
Proton pump inhibitors The effects of the proton pump inhibitors lansoprazole (30 mg/day for 4 days) and rabeprazole (10 mg/day for 4 days) on the pharmacokinetics of oral tacrolimus 2 mg have been studied in 19 healthy volunteers (304c ). Co-administration of lansoprazole significantly reduced oral tacrolimus clearance and increased tacrolimus AUC. There was large individual variation in the effects of lansoprazole on tacrolimus AUC, owing to CYP2C19 genotype status. The percent changes in tacrolimus AUC0→8 in subjects with and without CYP2C19 mutant alleles were 81% and 29% respectively. Co-administration of
459 rabeprazole also increased the mean tacrolimus AUC, but the difference was not statistically significant. These observations suggest that there is an interaction of tacrolimus with lansoprazole in subjects with higher lansoprazole blood concentrations, corresponding to CYP2C19 genetic status. In contrast, rabeprazole has a minimal effect on tacrolimus pharmacokinetics regardless of CYP2C19 genotype status. An interaction of lansoprazole with tacrolimus also occurred in a Japanese transplant recipient with CYP2C19 polymorphism (305A ). • A 34-year-old male Japanese kidney transplant recipient took tacrolimus, mycophenolate mofetil, and prednisolone. Lansoprazole was started on postoperative day 4, after which tacrolimus trough concentrations increased markedly while liver function tests were normal. Lansoprazole was stopped on day 15 and replaced with famotidine on day 17. Tacrolimus trough concentrations returned to the target range after withdrawal of lansoprazole. Genetic analysis showed a heterozygous mutation at exon 5 of the CYP2C19 gene (CYP2C19*1/*2).
The CYP2C19 gene mutation in this case may have reduced the hepatic elimination of lansoprazole and caused an interaction via CYP3A4. Sildenafil Sildenafil and tacrolimus are both metabolized by CYP3A4. Nine men aged 29– 52 years took sildenafil 25 mg/day for 9 days in addition to tacrolimus (306A ). The terminal half-lives of tacrolimus did not differ significantly and trough concentrations did not change when sildenafil was co-administered. Monitoring therapy Dosage and target concentration recommendations for tacrolimus vary from center to center, and large pharmacokinetic variability makes it difficult to predict what concentration will be achieved with a particular dose or dosage change (307R ). Target ranges have not been based on statistical approaches. Factors that are reported to influence the pharmacokinetics of tacrolimus include the patient group studied, hepatic dysfunction, hepatitis C status, time after transplantation, patient age, donor liver characteristics, recipient race, hematocrit, albumin concentration, diurnal rhythm, food, glucocorticoid dosage, diarrhea, and the expression of CYP isoenzymes
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and P glycoprotein. Reports have been conflicting as to whether low tacrolimus trough concentrations are related to rejection. Several studies have shown a correlation between high trough concentrations and toxicity, particularly nephrotoxicity.
Temsirolimus (cell cycle inhibitor-779; CCI-779) Temsirolimus is an ester analogue of sirolimus for the treatment of cancers, multiple sclerosis, and rheumatoid arthritis (308R ). Observational studies In a phase I pharmacokinetic study, 24 patients took temsirolimus 7.5–220 mg/m2 (309c ). Dose-limiting thrombocytopenia occurred in two patients at 34 or 45 mg/m2 . At 220 mg/m2 , dose-limiting adverse effects consisted of a manic-depressive syndrome, stomatitis, and weakness in two of nine patients, preventing further dose escalation. The most frequent drug-related adverse effects were acne-like maculopapular rashes and mucositis or stomatitis. All the adverse effects resolved on withdrawal. The efficacy, safety, and pharmacokinetics of multiple doses of temsirolimus (25, 75, or 250 mg/week as a 30-minute intravenous infusion) have been evaluated in 111 patients with advanced refractory renal cell carcinoma (310C ). Temsirolimus produced an objective response rate of 7% and minor responses in 26%. The most frequent adverse effects were maculopapular rash (76%), mucositis (70%), weakness (50%), and nausea (43%). The most frequent grade 3 or 4 adverse events were hyperglycemia (17%), hypophosphatemia (13%), anemia (9%), and hypertriglyceridemia (6%).
IMMUNOENHANCING DRUGS Abetimus sodium
(SED-15, 8)
Drug development of abetimus Abetimus sodium (LJP 394, Rentol, Riquent) is a synthetic toleragen molecule consisting
Felix Braun and Matthias Behrend
of four double-stranded oligodeoxyribonucleotides attached to non-immunogenic polyethylene glycol as a carrier (311R ). It is an immunomodulatory agent and induces tolerance in B cells directed against double-stranded DNA (dsDNA). It does this by cross-linking surface antibodies. These antibodies are thought to be responsible for lupus nephritis. A phase III trial of abetimus was completed in December 2002, and La Jolla Pharmaceuticals established two licensing agreements for abetimus, which have since been terminated. One of the agreements was with Leo Pharmaceutical Products of Denmark. The company was given a licence to abetimus covering Europe and the Middle East. The other agreement was with Abbott Laboratories. Abbott returned all rights to abetimus to La Jolla Pharmaceuticals in September 1999 based on the results of an analysis of a phase II/III trial of abetimus in lupus patients with a history of renal disease. A phase III study, named “PEARL” (Program Enabling Antibody Reduction in Lupus), was conducted in the USA in patients with lupus nephritis. It enrolled 317 patients with a history of systemic lupus erythematosus with lupus nephritis who were treated with abetimus 100 mg/week or placebo. The trial was completed in December 2002 and preliminary results were reported in February 2003. PEARL was designed to determine whether abetimus can significantly delay deterioration in renal function and delay the need for treatment with high-dose glucocorticoids and/or cyclophosphamide in patients with high-affinity IgG antibodies to the double-stranded oligonucleotide epitope in abetimus. Patients with high-affinity antibodies were selected using a surface plasmon resonance-based pharmacoproteomics assay provided by Biacor International. After the completion of PEARL in December 2002, La Jolla Pharmaceuticals began an open follow-on trial. All patients who had completed PEARL were eligible to enrol and receive weekly abetimus. However, in April 2003, La Jolla Pharmaceuticals announced that it was closing this trial, which was designed to collect additional long-term safety data, to conserve resources for the continued development of the drug. Previously, La Jolla Pharmaceuticals and Abbott had begun a phase II/III trial of abetimus in more than 200 patients with lupus nephritis. However, this trial
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was discontinued in May 1999 because the primary end-point (time to deterioration of renal function) was much shorter than expected. After the trial was halted, a new blood test was used to measure the strength of the binding between abetimus and a patient’s antibodies to dsDNA. The number of episodes of deteriorating renal function in the high-affinity patients (responders) treated with abetimus was less than half the number of episodes in the high-affinity patients treated with placebo. The responders also had a significant reduction in the use of highdose glucocorticoids and cyclophosphamide. Being able to screen patients to identify those likely to respond to therapy led La Jolla Pharmaceuticals to initiate PEARL after Abbott’s withdrawal. It is believed that screening patients will help increase the cost-effectiveness of clinical development. In September 2000, the US FDA granted abetimus orphan drug status for treatment of lupus nephritis; the European Union followed suit in November 2001.
109203X, a specific inhibitor of protein kinase C, both completely blocked bryostatin-induced differentiation of the B cells, suggesting that activation of the ERK pathway plays a direct role in this process in a PKC-dependent manner. Bryostatin reduced both spontaneous and drug-induced apoptosis with chlorambucil, fludarabine, and 2-chloro-2 -deoxyadenosine in the B cells. This resistance was associated with early up-regulation of the antiapoptotic protein Mcl-1 and post-translational phosphorylation of Bcl-2 at serine 70. The anti-apoptotic effects of bryostatin were prevented by GF 109203X, and to a lesser extent by LY294002, a reversible inhibitor of phosphatidylinositol 3-kinase. PD98059 inhibited Mcl-1 expression but had little effect on bryostatin-induced survival, suggesting that the ERK pathway predominantly affects differentiation. These results provide an explanation for bryostatininduced B cell survival in chronic lymphocytic leukemia, in which modulation of the PKC pathway couples differentiation to an increase in antiapoptotic protein expression and calls into question the rationale for its use in the treatment of B cell chronic lymphocytic leukemia.
Drugs that act on the immune system
Observational studies When abetimus was given as a weekly infusion in phase 1, 2, and 3 studies in close to 1000 patients, there were no adverse effects (312M ). In patients with lupus nephritis and raised anti-DNA (Farr assay) who had a high affinity for abetimus, it significantly reduced anti-DNA, improved quality of life, and tended to reduce the frequency of episodes of renal function deterioration. Abetimus was well tolerated in 13 controlled and uncontrolled clinical trials in over 800 patients with systemic lupus erythematosus for periods of 22 months and more (313M ).
Bryostatin 1
(SED-15, 563)
The macrocyclic lactone bryostatin is a protein kinase C (PKC) modulator. It has differentiation and anti-tumor activity against several leukemia cell lines in vitro, and has the potential to inhibit tumor invasion, angiogenesis, cell adhesion, and multidrug resistance (314E , 315C ). Bryostatin-induced differentiation in chronic lymphocytic leukemia B cells was characterized by an increase in cell size and marked up-regulation of CD11c expression (314E ). PD98059, a specific inhibitor of the extracellular signal-regulated kinase (ERK), and GF
Observational studies In preclinical experiments, bryostatin-1 induced tumor growth inhibition and enhanced cytotoxicity when combined with other agents, including cisplatin, in cervical cancer cells. Patients (n = 14) with a histological diagnosis of metastatic cervical cancer or recurrent disease not eligible for surgery or radiation were given bryostatin-1 in a dose of 50–65 micrograms/m2 as a 1-hour infusion followed by cisplatin 50 mg/m2 in a phase 2 trial over 21 days; two treatment cycles were completed by 71% of the patients (315c ). Most common grade II–III adverse effects were myalgia, anemia, and nausea or vomiting. One patient developed a hypersensitivity reaction and one developed grade III nephrotoxicity. In 10 patients who were evaluated, tumor progression was documented in eight, stable disease in two, and treatment response in none. The combination of cisplatin and bryostatin-1 was not effective in patients with advanced or recurrent cervical cancer.
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Levamisole
(SED-15, 2028; SEDA-26, 347; SEDA-27, 330; SEDA-28, 350) The adverse affects of levamisole are mild and infrequent and include rashes, nausea, abdominal cramps, taste disturbances, alopecia, arthralgia, and a flu-like syndrome; agranulocytosis is rare (316R ). Levamisole also inhibits alkaline phosphatase and protects from colonic inflammation (317E ). There is little good-quality evidence of the effectiveness of levamisole in steroid-sensitive nephrotic syndrome. This is limited to three clinical trials all of which had methodological limitations. From the available information, no conclusions can be drawn on its steroid-sparing effect, long-term efficacy, safety, or possible differences in efficacy in different subgroups of patients (318R ).
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All the patients received radiotherapy with a three-field technique to a total dose of 45 Gy over 5 weeks. There was no difference in disease-free survival. Adverse effects in the two groups were myelosuppression (leucopenia grade 3, 4% versus 12%), diarrhea (grade 0, 76% versus 60%), and hepatotoxicity (an over three-fold increase in transaminases, 2 versus 12 patients). None stopped chemotherapy because of adverse effects and there were no toxicity-related deaths. Gastrointestinal The combination of levamisole with 5-fluorouracil in 12 patients with colon cancer affected mainly the barrier function of the intestinal mucosa rather than its absorptive capacity, as assessed by the lactulose– mannitol test; however, this effect was mainly attributed to 5-fluorouracil (321c ).
Observational studies Patients (n = 187) with resected colon cancer with tumor adherence or invasion of surrounding structures, or with T3N1 or T3N2 tumors of the ascending or descending colon were randomly assigned to receive fluorouracil and levamisole with or without radiation therapy (45 to 50.4 Gy) (319C ). The overall 5-year patient and diseasefree survival rates were 62 and 51% with chemotherapy and 58 and 51% with chemotherapy plus radiotherapy. Adverse events were grade 3 or 4 toxicity in 42% versus 54% of patients and grade 3 or 4 leukopenia in 10% versus 22%. Thus, those who received chemotherapy had similar overall survival and disease-free survival as those who received chemotherapy plus radiotherapy, but fewer adverse effects.
Hematologic Levamisole 2 mg/kg/day over a mean of 17 months significantly reduced the relapse rate and cumulative glucocorticoid dose in 34 children (21 boys, 13 girls, mean age 5.0 years) with frequently-relapsing nephrotic syndrome (n = 15), steroid-dependent nephrotic syndrome (n = 13), and steroid-resistant nephrotic syndrome (n = 6) during 60 months of follow-up (322c ). There was reversible neutropenia in five patients, but no other adverse effects. Levamisole 2–3 mg/kg/day for 3–24 months was given to 36 children with steroid-sensitive nephrotic syndrome with frequent relapses and/ or steroid dependence (323c ). There was leukopenia in nine and the white blood cell count normalized after withdrawal of levamisole.
Comparative studies In patients with surgically resected rectal carcinoma Duke stage B2 (n = 70) or C (n = 80), the following have been compared (320C ):
Teratogenicity Data on levamisole-induced teratogenicity are rare. Syndactyly, undescended testes, and neural tube defects have been observed, but case-control data have not shown a higher rate of congenital abnormalities in children born to mothers who took oral levamisole treatment once during pregnancy (324C ).
• fluorouracil 450 mg/m2 intravenously on days 1–5 every 4 weeks for 6 cycles plus leucovorin 20 mg/m2 intravenously on each occasion for 6 months; • levamisole 50 mg tds on days in every 2 weeks for 1 year plus 5-fluorouracil 450 mg/ m2 intravenously every week as adjuvant chemotherapy in addition to radiotherapy, total dose 45 Gy over 5 weeks.
Drug interactions Levamisole can increase the systemic availability of ivermectin and reduce the systemic availability of albendazole, perhaps because of effects on CYP3A4 and P glycoprotein (325C ).
Drugs that act on the immune system
OTHER DRUGS Bropirimine
(SED-15, 562)
Bropirimine (2-amino-5-bromo-6-phenyl-4pyrimidinone) has anticancer and interferoninducing properties and is currently under investigation in the management of transitional cell carcinoma of the urinary bladder (326M ).
Lentinan
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(SED-15, 2024)
Lentinan, a branched beta-glucan (beta-1,6;1,3glucan, beta-G, schizophyllan), is an antitumor immunomodulator that is purified from Lentinula edodes (the shiitake mushroom). Observational studies Oral TS-1 has an antineoplastic effect that is potentiated by about 70% by adding cisplatin and lentinan. Nine patients with inoperable advanced gastric cancer were given combination chemotherapy with TS-1 80 mg/m2 for 3 weeks, cisplatin 70 mg/ m2 on day 8, and lentinan 2 mg/week (327c ). Adverse effects (grade 3 or more) were anemia and pigmentation in one patient each. Comparative studies The adverse effects of standardized mistletoe extract (n = 115) and lentinan (n = 109) have been compared in patients with breast cancer (n = 68), ovarian cancer (n = 71), and non-small cell liver cancer (n = 94) (328C ). Quality of life was significantly improved in those who received mistletoe compared with lentinan, as determined by the questionnaires FLIC (Functional Living Index-Cancer), TCMI (Traditional Chinese Medicine Index) and KPI (Karnofsky Performance Index). Adverse events were less frequent with mistletoe than lentinan (all adverse events 52 versus 90, serious adverse events 5 versus 10), but most of the adverse events were attributed to the chemotherapy. Only one serious adverse event (not specified) was allocated to complementary treatment in each group. One patient who took mistletoe had angioedema; the other adverse effects of mistletoe were harmless inflammatory reactions at the subcutaneous injection site (n = 7) and fever (n = 4); these were self-limiting and did not require therapeutic intervention.
Interference with diagnostic tests Measurement of (1 → 3)-beta-D-glucan in the blood is widely used in the diagnosis of deep-seated mycoses, and the administration of lentinan can cause a false positive result (329c ). Plasma concentrations of beta-D-glucan have been measured in 18 samples from seven patients who had taken lentinan and in 86 samples from patients who had not. Lentinan administration markedly increased the plasma concentration of beta-D-glucan, even in patients who had taken it 3 years before. Disparities in betaD-glucan concentrations measured by different methods are due to differences among sample pretreatment methods. The conformation of administered betaG seems to be transformed into a sensitive form to factor G by alkaline pretreatment. The effect of lentinan was much greater after alkaline pretreatment than dilution heating pretreatment. Therefore, in suspected cases, it is important to pay attention to lentinan administration during the previous few years.
Picibanil Picibanil (OK-432) is an immunomodulatory agent prepared from an attenuated strain of Streptococcus pyogenes, which was approved in Japan as an anticancer agent in 1975 (330R ). Sclerotherapy by intralesional injection of picibanil is used as an alternative to surgery in patients with lymphatic malformations (331A , 332c , 333c ). Spontaneous hemorrhage into a cyst due to injection can result in only partial resolution of lymphangiomas. Macrocystic lesions respond well to picibanil, but the response of microcystic or cavernous lesions is disappointing and surgery remains the definitive treatment (332c , 334c ). Observational studies Pleurodesis using picibanil and doxorubicin 30 mg was highly efficacious in controlling malignant pleural effusions caused by liver cancer. The main adverse effects were fever and pain, which responded to non-steroidal anti-inflammatory drugs (335c ). In a phase 2 study, the intrapleural administration of picibanil followed by cisplatin and gemcitabine as systemic chemotherapy prolonged survival but did not reduce tumor size in 15 patients with non-small cell liver cancer
464 with pleural secondaries (336c ). Adverse effects were grade 3 or 4 neutropenia (n = 5), anemia (n = 2), thrombocytopenia (n = 3), grade 3 rises in transaminases (n = 1), and grade 3 nausea (n = 2). Comparative studies In a randomized controlled trial in 760 patients with colon cancer and 669 patients with rectal cancer, combined immunochemotherapy with mitomycin C + 5-fluorouracil + 1-hexylcarbamoyl-5fluorouracil + picibanil for colon cancer and chemotherapy with mitomycin + 5-fluorouracil + uracil/tegafur + picibanil for rectal cancer did not prolong survival in the patients with surgically resected colorectal cancers (337C ). Most of the adverse events occurred in the immunochemotherapy group, followed by the chemotherapy group and the control (surgery alone) group. In particular, the frequencies of leucopenia and skin disorders were significantly higher than in the control groups. Drug dosage regimen In a pilot study, regional immunotherapy for malignant ascites using host-oriented doses of picibanil was studied in 51 patients with gastric cancer and cytologically determined malignant ascites. The dose of picibanil was selected according to the extent of the delayed-type hypersensitivity reaction to picibanil. There was a positive clinical response in 37 patients compared with 53% who were treated with the traditional dosage method. Adverse effects related to picibanil were fever and abdominal pain, but to a significantly lesser extent than with traditional dosing (338c ).
Thymic hormones A family of biologically active molecules with hormone-like properties was first described in 1966 by AL Goldstein and A White. In the early 1970s, preclinical studies established the immunorestorative effects of a partially purified thymosin preparation termed thymosin fraction 5, and were followed by first clinical trials in 1974. Thymosin fraction 5 was effective in turning on the immune system in children with DiGeorge syndrome and other thymic dysplasias. These trials led to further interest in the active components in thymosin fraction 5 and to
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chemical characterization of the biologically active thymosins. Several of these molecules have shown significant clinical promise in the areas of cancer, infectious diseases, and wound healing (339R ). Thymosin beta-4 is a small peptide with actin-sequestering action. It is associated with induction of angiogenesis, accelerated wound healing, and increased metastatic potential of tumor cells. Thymosin beta-4 promotes angiogenesis, wound repair, and hair growth in normal and aged rodents (340E ). It acts by increasing angiogenesis and cell migration and is currently in clinical trials for wound repair. Some NSAIDs induce thymosin beta-4 expression in a time- and concentration-dependent manner. Indometacin and SC-560 [5-(4chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole] induce thymosin beta-4 expression, whereas sulindac sulfide does not. Some NSAIDs induce actin cytoskeletal reorganization, a precursory step to many dynamic processes that regulate growth and motility, including tumorigenesis (341E ). The G-actin sequestering peptide thymosin beta-4 promotes myocardial and endothelial cell migration in the embryonic heart and retains this property in postnatal cardiomyocytes (342E ). Survival of embryonic and postnatal cardiomyocytes in culture was also enhanced by thymosin beta-4. Thymosin beta-4 formed a functional complex with PINCH and integrinlinked kinase (ILK), resulting in activation of the survival kinase Akt (protein kinase B). After coronary artery ligation in mice, thymosin beta-4 treatment resulted in upregulation of ILK and Akt activity in the heart, enhanced early myocyte survival, and improved cardiac function. These findings suggest that thymosin beta4 promotes cardiomyocyte migration, survival, and repair, and the pathway it regulates may be a new therapeutic target in the setting of acute myocardial damage. Thymalfasin (thymosin alpha-1) is an immunomodulatory agent that enhances the Thl immune response. It has been evaluated in chronic hepatitis B and C, AIDS, primary immunodeficiency diseases, depressed responses to immunization, and cancers (343R , 344R ). The combination of thymalfasin with pegylated interferon in patients with chronic hepatitis C virus infection is being investigated in a phase 3 study in the USA (345M ).
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Observational studies The combination of peginterferon alfa-2a, ribavirin, and thymalfasin in 23 previously non-responders resulted in a viral response rate of 61% at week 12 and 47.8% at week 24 (346c ). In naive patients with chronic hepatitis C, after 6 months follow-up, the end-of-treatment virological response rate of combined interferon alfa-2b 3 MU three times per week plus thymalfasin 900 µg/m2 (n = 22) was significantly higher than with interferon alone (n = 19) (347c ).
• group A (n = 18) were treated with hepatectomy plus chemoembolization and thymosin alpha-1; • group B (n = 23) were treated with hepatectomy plus chemoembolization; • group C (n = 16) were treated with hepatectomy alone.
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Comparative studies After resection of hepatocellular carcinoma, transcatheter hepatic arterial chemoembolization with thymalfasin was studied for prevention of recurrence in three groups of patients (348c , 349c ).
The one-year recurrence rates were 83%, 87% and 88% respectively and the median survival times were 10, 7, and 8 months. Thus, the combination of chemoembolization plus thymalfasin may have delayed the time to recurrence and prolonged survival times in patients with hepatocellular carcinoma after hepatectomy, but did not reduce the recurrence rate (348c , 349c ).
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Corticotrophins, corticosteroids, and prostaglandins
Editor’s note: In this chapter adverse effects arising from the oral or intravenous 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 also dealt with in Chapter 16 and topical administration to the skin in Chapter 14.
SYSTEMIC GLUCOCORTICOIDS (SED-15, 906; SEDA-26, 427; SEDA-27, 414; SEDA-28, 471) Observational studies A systematic review of glucocorticoid adjunctive therapy in adults with acute bacterial meningitis has been published (1M ). Five trials involving 623 patients were included (pneumococcal meningitis = 234, meningococcal meningitis = 232, others = 127, unknown = 30). Treatment with glucocorticoids was associated with a significant reduction in mortality (RR = 0.6; 95%CI = 0.4, 0.8) and in neurological sequelae (RR = 0.6; 95%CI = 0.4, 1), and with a reduction in casefatality in pneumococcal meningitis of 21% (RR = 0.5; 95%CI = 0.3, 0.8). In meningococcal meningitis, mortality (RR = 0.9; 95%CI = 0.3, 2.1) and neurological sequelae (RR = 0.5; 95%CI = 0.1, 1.7) were both reduced, but not significantly. Adverse events were similar in the treatment and placebo groups (RR = 1; Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29039-1 © 2007 Elsevier B.V. All rights reserved.
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CI = 0.5, 2), with gastrointestinal bleeding in 1% of glucocorticoid-treated patients and 4% of the rest. The authors recommended the early use of glucocorticoid therapy in adults in whom acute community-acquired bacterial meningitis is suspected. Cardiovascular Long-term systemic administration of glucocorticoids might be expected, because of their effects on vascular fragility and wound healing, to increase the risk of vascular complications during percutaneous coronary intervention. To assess the potential risk of longterm glucocorticoid use in the setting of coronary angioplasty, 114 of 12 883 consecutively treated patients who were taking long-term glucocorticoids were compared with those who were not. Glucocorticoid use was not associated with an increased risk of composite events of major ischemia but was associated with a threefold risk of major vascular complications and a three- to fourfold risk of coronary perforation (2c ). A case report with a review of 27 cases of thromboembolic events after the administration of intravenous globulin with or without glucocorticoids has been published (3AR ). The authors suggested that this combined therapy should be administered with caution because of its potential synergistic thrombotic risk. Nervous system Seventeen patients taking long-term glucocorticoid therapy (16 women, mean age 47 years, mean prednisone dose 16 mg, mean length of current treatment 92 months) and 15 matched controls were assessed with magnetic resonance imaging and proton magnetic resonance spectroscopy, neurocognitive tests (including the Rey Auditory Verbal Learning Test, Stroop Colour Word Test, Trail
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Making Test, and estimated overall intelligent quotient), and psychiatric scales (including the Hamilton Rating Scale for Depression, Young Mania Rating Scale, and Brief Psychiatric Rating Scale) (4c ). Glucocorticoid-treated patients had smaller hippocampal volumes and lower N-acetylaspartate ratios than controls. They had lower scores on the Rey Auditory Verbal Learning Test and Stroop Colour Word Test (declarative memory deficit) and higher scores on the Hamilton Rating Scale for Depression and the Brief Psychiatric Rating Scale (depression). These findings support the idea that chronic glucocorticoid exposure is associated with changes in hippocampal structure and function. Postnatal glucocorticoids have been used to treat or prevent chronic lung disease of prematurity. In a recent systematic review the authors concluded that postnatal dexamethasone at currently recommended doses should be avoided because of long-term neurological adverse effects (5M ). Lower doses of dexamethasone or inhaled glucocorticoids might be indicated for ill ventilator-dependent infants with chronic lung disease after the age of 2 weeks. In 146 children who participated in a placebo-controlled trial of early postnatal dexamethasone therapy for the prevention of the chronic lung disease of prematurity, follow-up at school age (mean age 8 years old) showed that the children who had received dexamethasone were significantly shorter than the controls (mean height 122.8 cm versus 126.4 cm for boys and 121.3 cm versus 124.7 cm for girls) and had a significantly smaller head circumference (49.8 cm versus 50.6 cm) (6c ). They also had significantly poorer motor skills, motor coordination, and visuomotor integration. Compared with the controls, the children who had received dexamethasone had significantly lower IQ scores, including full scores (mean 78.2 versus 84.4), verbal scores (84.1 versus 88.4), and performance scores (76.5 versus 84.5). The frequency of clinically significant disabilities was higher among the children who had received dexamethasone than among the controls (39% versus 22%). The authors did not recommend the routine use of dexamethasone therapy for the prevention or treatment of chronic lung disease.
Effects of glucocorticoids on the eye Ocular hypertension One of the major ophthalmic complications of glucocorticoids is ocular hypertension, which can result in irreversible ocular damage. Previous studies have shown that children have more frequent, more severe, and more rapid ocular hypertensive responses to topical dexamethasone than adults. In one case a systemic glucocorticoid caused significant but asymptomatic ocular hypertension in a child (7A ). • A 9-year-old girl with acute lymphoblastic leukemia received a 5-week course of oral prednisolone 60 mg/day (2.3 mg/kg/day). She did not receive any other systemic medications that have a known effect on intraocular pressure. Her baseline pressures in the right and left eyes were 16 and 17 mmHg with visual acuities of 20/20 and 20/15 respectively. The cup-to-disk ratio was 0.5 in both eyes, with normal visual fields. She was not myopic and had no family history of glaucoma or glucocorticoid responsiveness. After 8 days of systemic glucocorticoid therapy, her intraocular pressures increased to 39 mmHg and 38 mmHg in the right and left eyes respectively. Gonioscopy confirmed an open drainage angle in both eyes. She was given topical betaxolol 0.25% and dorzolamide 2% bd. However, her intraocular pressure continued to increase to 52 mmHg in the right eye and 47 mmHg in the left eye on day 10. Topical latanoprost 0.001% od and brimonidine 0.2% bd were added, and the intraocular pressures fell to 38 mmHg and 36 mmHg. Two days after withdrawal of the prednisolone, the intraocular pressure returned rapidly to 17 mmHg in both eyes. Over the next 6 weeks, this was maintained despite stepwise withdrawal of all glaucoma medications. Four months later, she was given a 4-week course of oral dexamethasone 10 mg/day and had similar patterns of changes in intraocular pressure. Oral acetazolamide was prescribed. She remained largely asymptomatic throughout, except for one episode of reduced visual acuity from 20/20 to 20/40 in the right eye when the intraocular pressure reached 52 mmHg.
Central serous chorioretinopathy Central serous chorioretinopathy is a common disease, characterized by accumulation of subretinal fluid at the posterior pole of the ocular fundus; it typically affects young and middleaged adults, and men are affected more often than women. The exact pathogenesis is unclear, but there is accumulating evidence that both endogenous and exogenous glucocorticoids may be implicated. Regarding the role of exogenous glucocorticoids, central serous
482 chorioretinopathy has been reported as a complication of intravenous, intramuscular, oral, epidural, inhaled, and intranasal glucocorticoids. Two patients developed central serous chorioretinopathy after prolonged treatment with glucocorticoids applied locally to the skin (8A ). • A 32-year-old man complained of reduced vision and metamorphopsia in the right eye. Bestcorrected visual acuity was 20/25 in right eye and 20/20 in left eye. The left fundus was normal but in the right eye there was a well-circumscribed, shallow, serous detachment of the sensory retina. The clinical appearance was consistent with central serous chorioretinopathy, and the diagnosis was confirmed by fluorescein angiography, which showed a leakage point at the superior macula, spreading slowly in an inkblot configuration into the subretinal space. He had had seborrheic dermatitis involving the central face, eyebrows, eyelids, and scalp for 2 years treated with topical hydrocortisone acetate cream 1%. After the initial prescription, he used the cream without further medical consultation when his symptoms got worse and used it for 4 weeks, 3–4 times a day before developing central serous chorioretinopathy. • A 37-year-old man developed blurred vision in the left eye. He had had central serous chorioretinopathy in the contralateral eye 5 years before, for which he had been treated with laser photocoagulation. Best-corrected visual acuity was 20/20 in each eye. There were scars from previous laser photocoagulation at the superior macula in the right eye. In the left eye there was a well-delineated area of serous detachment temporal to the fovea and small yellowish precipitates at the posterior aspect of the detached retina. Fluorescein angiography showed a leakage point at the upper pole of the detachment. He had had pityriasis versicolor, for which he had used local diflucortolone valerate cream 0.1% in combination with isoconazole nitrate 1%. He had used the cream occasionally but had used it for 3 weeks before the onset of symptoms. He also used diflucortolone valerate cream 0.1% during the first episode of central serous chorioretinopathy.
In a prospective, case-control study 38 consecutive patients (28 men and 10 women), aged 28–63 years with central serous chorioretinopathy, were compared with 38 age- and sex-matched controls (28 men and 10 women) aged 27–65 years (9c ). Eleven patients (29%; eight men and three women) with central serous chorioretinopathy were taking glucocorticoids, compared with two patients (5.2%; one man and one woman) in the control group (OR = 7.33, 95%CI = 1.49, 36). Subtenon local injection of a glucocorticoid is effective in the treatment of certain forms of
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uveitis. Central serous chorioretinopathy, confirmed by optical coherence tomography, developed after a single local subtenon glucocorticoid injection to treat HLA-B27-associated iritis (10A ). • A healthy 37-year-old man developed progressive blurred vision, photophobia, and floaters in the left eye. Best-corrected visual acuity was 20/20 in the right eye and 20/50 in the left eye. The intraocular pressures were 21 mmHg in the right eye and 16 mmHg in the left eye. The anterior and posterior segments of the right eye were normal, but the anterior segment of the left eye showed 2+ conjunctival injection and mild keratitic precipitates. There was a 2+ anterior chamber cellular reaction with a 1 mm hypopyon, engorged iris vessels, and fibrinous iris posterior synechiae that were released after pupillary dilatation. Binocular and indirect ophthalmoscopy of the left eye showed a normal optic nerve, macula, retinal vasculature, and periphery. There was no evidence of retinal or vitreous inflammation, vasculitis, or cystoid macular edema. The fovea was well visualized after pupillary dilatation, with a normal and distinct foveal reflex. HLA-B27 iritis was suspected and subsequently confirmed with positive serotyping. He was given prednisolone acetate 1% every hour, cycloplegic eye drops, and a 1.0 ml periocular injection of triamcinolone acetonide (40 mg/ml) into the subtenon space of the left eye. Within 1 week, there was a marked therapeutic response, with complete resolution of the hypopyon and fibrin deposition and partial improvement in acuity to 20/40 in the left eye. There were only occasional residual anterior chamber inflammatory cells. Macular biomicroscopy showed the new development of subretinal fluid and serous pigment epithelial detachment at the fovea. Fluorescein angiography confirmed an enlarging pinpoint spot of hyperfluorescence. Optical coherence tomography confirmed the subretinal location of this fluid collection, consistent with a diagnosis of central serous chorioretinopathy. The topical glucocorticoid drops were rapidly tapered and withdrawn over 5 days. There was progressive reduction in subretinal fluid and gradual improvement in visual acuity. By 12 weeks the fluid had resolved and visual acuity recovered to 20/20 in the left eye.
Intravitreal triamcinolone injection is safe and effective for cystoid macular edema caused by uveitis, diabetic maculopathy, and central retinal vein occlusion, and for pseudophakic cystoid macular edema. Potential risks include glaucoma, cataract, retinal detachment, and endophthalmitis. Hypopyon associated with non-infectious endophthalmitis after intravitreal injection of triamcinolone has been described previously (11A ). Pseudohypopyon and
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sterile endophthalmitis after intravitreal injection of triamcinolone for pseudophakic cystoid macular edema has been reported (12A ).
perhaps it would be appropriate to monitor such patients closely rather than administering intravitreal antibiotics.
• An 88-year-old woman underwent phacoemulsification surgery, which was complicated by posterior capsule rupture. Anterior vitrectomy was performed, with implantation of a silicone intraocular lens into the sulcus. Postoperatively, she developed cystoid macular edema, which failed to respond to topical dexamethasone, topical ketorolac, and posterior subtenon injection of triamcinolone, limiting visual acuity to 6/24 at 7 months after the surgery. An intravitreal injection of triamcinolone acetonide (4 mg in 0.1 ml) (Kenalog®, BristolMyers Squibb, Middlesex, UK) was administered through the pars plana with a 30-gauge needle using a sterile technique. Three days later she reported painless loss of vision, which had developed immediately after the injection. Visual acuity was reduced to perception of hand movements. There was minimal conjunctival injection and the cornea was clear. A 3 mm pseudohypopyon, consisting of refractile crystalline particles, was visible in the anterior chamber, associated with 3+ anterior chamber cells (or particles). Severe vitreous haze prevented visualization of the retina. Because infectious endophthalmitis could not be excluded, she was treated with intravitreal injections of ceftazidime and vancomycin. Vitreous and aqueous taps were performed and the pseudohypopyon was completely aspirated from the anterior chamber. The next day a 2 mm pseudohypopyon had reformed. The position of the pseudohypopyon depended on gravity and shifted with changes in head position. Aqueous and vitreous cultures were negative. Microscopy of the aspirated pseudohypopyon showed triamcinolone particles with no cells. The pseudohypopyon, vitreous haze, and cystoid macular edema (as demonstrated on optical coherence tomography) resolved spontaneously over 6 weeks and visual acuity recovered to 6/12.
Psychiatric High doses of oral glucocorticoids can cause adverse psychiatric effects, including mild euphoria, emotional lability, panic attacks, psychosis, and delirium. There have been sporadic case reports of similar reactions in patients using inhaled glucocorticoids. Of 60 preschool children with a recent diagnosis of asthma taking inhaled budesonide 100– 200 micrograms/day, nine had suspected neuropsychological adverse events after 18 months, according to their parents (13c ). The symptoms reported were irritability, depression, aggressiveness, excitability, and hyperactivity. These adverse events disappeared when the medication was terminated or reduced and recurred when budesonide was restarted at higher doses. Most of the symptoms occurred within 2 days from starting the high dose (200 micrograms 2– 4 times a day). Although mood changes are common during short-term, high-dose, glucocorticoid therapy, there are virtually no data on the mood effects of long-term glucocorticoid therapy. Mood has been evaluated in 20 out-patients (2 men, 18 women), aged 18–65 years taking at least 7.5 mg/day of prednisone for 6 months (mean current dose 19 mg/day; mean duration of current prednisone treatment 129 months) and 14 age-matched controls (1 man, 13 women), using standard clinician-rated measures of mania (Young Mania Rating Scale, YMRS), depression (Hamilton Rating Scale for Depression, HRSD), and global psychiatric symptoms (Brief Psychiatric Rating Scale, BPRS, and the patient-rated Internal State Scale, ISS) (14c ). Syndromal diagnoses were evaluated using a structured clinical interview. The results showed that symptoms and disorders are common in glucocorticoid-dependent patients. Unlike short-term prednisone therapy, longterm therapy is more associated with depressive than manic symptoms, based on the clinicianrated assessments. The Internal State Scale may be more sensitive to mood symptoms than clinician-rated scales. Two women developed secondary bipolar disorder associated with glucocorticoid treatment and deteriorated to depressive–catatonic states without overt hallucinations and delusions (15A ).
The pseudohypopyon was a unique feature of this case and was due to the presence of a posterior capsule defect enabling the passage of triamcinolone from the vitreous cavity into the anterior chamber. The authors commented that presumably the triamcinolone crystals had been carried into the anterior chamber by currents generated by saccadic eye movements in the partially vitrectomized vitreous cavity. In this case the pseudohypopyon was distinguishable from an infective or inflammatory hypopyon by its ground glass appearance, the presence of refractile particles, and its shifting position, which depended on the patient’s head position. The absence of ocular pain, photophobia, ciliary injection, or iris vessel dilatation suggested a non-inflammatory response and
484 • A 21-year-old woman, who had taken prednisolone 60 mg/day for dermatomyositis for 1 year developed a depressed mood, pessimistic thought, irritability, poor concentration, diminished interest, and insomnia. Although the dose of prednisolone was tapered and she was treated with sulpiride, a benzamide with mild antidepressant action, she never completely recovered. After 5 months she had an exacerbation of her dermatomyositis and received two courses of methylprednisolone pulse therapy. Two weeks after the second course, while taking prednisolone 50 mg/day, she became hypomanic and euphoric. She improved substantially with neuroleptic medication and continued to take prednisolone 5 mg/day. About 9 months later she developed depressive stupor without any significant psychological stressor or changes in prednisolone dosage. She had mutism, reduction in contact and reactivity, immobility, and depressed mood. Manic or mixed state and psychotic symptoms were not observed. She was initially treated with intravenous clomipramine 25 mg/day followed by oral clomipramine and lithium carbonate. She improved markedly within 2 weeks with a combination of clomipramine 100 mg/day and lithium carbonate 300 mg/day. Prednisolone was maintained at 5 mg/day. • A 23-year-old woman with ulcerative colitis and no previous psychiatric disorders developed emotional lability, euphoria, persecutory delusions, irritability, and increased motor and verbal activity 3 weeks after starting to take betamethasone 4 mg/day. She improved within a few weeks with bromperidol 3 mg/day. After 10 months she became unable to speak and eat, was mute, depressive, and sorrowful, and responded poorly to questions. There were no neurological signs and betamethasone had been withdrawn 10 months before. She was treated with intravenous clomipramine 25 mg/day and became able to speak. Intravenous clomipramine caused dizziness due to hypotension, and amoxapine 150 mg/day was substituted after 6 days. All of her symptoms improved within 10 days. Risperidone was added for mood lability and mild persecutory ideation.
Gastrointestinal The importance of treatment with glucocorticoids and NSAIDs in the development of sigmoid diverticular abscess perforation has been the subject of a casecontrol study in 64 patients (38 women), median age 70 years (range 39–91) and 320 age- and sex-matched controls (16c ). Independently of rheumatic diagnosis glucocorticoid treatment was strongly associated with sigmoid diverticular abscess perforation (OR = 32; 95%CI = 6.4, 159). Liver Although a direct relation between intravenous glucocorticoids and acute liver damage is yet to be proven, there has been a report
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of seven cases of acute severe liver damage associated with intravenous glucocorticoid pulse therapy in patients with Grave’s ophthalmopathy (17A ). Musculoskeletal Glucocorticoid therapy is associated with bone loss resulting in osteoporosis and an increase in the risk of fractures. These effects have been found after the administration of oral and inhaled glucocorticoids. Dose is an important factor, but these adverse effects have been described after low doses. Three studies add new evidence of the deleterious effects of oral glucocorticoids and high doses of inhaled glucocorticoids on bone mineral density (18c ) and the risk of fractures (19c , 20c ). There have been recent reviews of the mechanisms and adverse effects of glucocorticoids in rheumatoid arthritis (21R ) and the pathogenesis, diagnosis, and treatment of glucocorticoidinduced osteoporosis in patients with pulmonary diseases (22R ). Bone resorption seems to involve the receptor of the activator of the nucleus factor KB ligand (RANK-L) and osteoprotegerin. RANK-L binds to a specific receptor in osteoclasts, and in the presence of the macrophage colony stimulating factor (M-CSF) it induces osteoclastogenesis (the development of mature osteoclasts) and suppression of normal osteoclast apoptosis. Osteoprotegerin is a soluble decoy receptor that binds to and neutralizes RANK-L and so reduces osteoclastogenesis. Glucocorticoids increase the expression of RANK-L and M-CSF and reduce osteoprotegerin production by osteoblasts. The net result is enhanced osteoclastic activity. Other inflammatory mediators, such as tumor necrosis factor-alfa and interleukin-6, have similar biological actions to glucocorticoids. Glucocorticoids reduce osteoblast numbers and function by reducing the replication and differentiation of osteoblasts and by increasing apoptosis in mature osteoblasts. Glucocorticoids inhibit osteoblastic synthesis of type I collagen, the major component of bone extracellular matrix. They can induce apoptosis of osteocytes, and this could be the mechanism of osteonecrosis. Two other factors are involved in bone loss: firstly, glucocorticoids increase renal calcium elimination and reduce intestinal calcium absorption, leading to a negative calcium balance, which can lead to secondary hyperparathyroidism;
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secondly, glucocorticoids reduce the production of gonadal hormones. The histological effects of glucocorticoids are a reduced rate of bone formation, reduced trabecular wall thickness, and apoptosis of bone cells. These effects lead to osteoporosis and fractures. The prevention and treatment of osteoporosis induced by glucocorticoids include the use of bisphosphonates, calcium, vitamin D, salmon calcitonin, and parathyroid hormone (PTH 1– 34). A recent meta-analysis has shown that alfacalcidol and calcitriol prevent bone loss induced by glucocorticoid (effect size = 0.43) but not fractures (23M ). Alfacalcidol and vitamin D3 have been compared in patients with established glucocorticoid-induced osteoporosis with or without vertebral fractures (24c ). Patients taking longterm glucocorticoids were included as matched pairs to receive randomly either alfacalcidol 1 microgram/day plus calcium 500 mg/day (n = 103) or vitamin D3 1000 IU/day plus calcium 500 mg/day (n = 101). The two groups were well matched in terms of mean age, sex ratio, mean height and weight, daily dosage and duration of glucocorticoid therapy, and the percentages of the three underlying diseases (chronic obstructive pulmonary disease, rheumatoid arthritis, and polymyalgia rheumatica). The baseline mean bone mineral density values (T scores) at the lumbar spine were −3.26 (alfacalcidol) and −3.25 (vitamin D3) and at the femoral neck −2.81 and −2.84 respectively. The prevalence rates of vertebral and non-vertebral fractures did not differ. During the 3-year study, the median percentage bone mineral density increased at the lumbar spine by 2.4% with alfacalcidol and decreased by 0.8% with vitamin D3. There also was a significantly larger median increase at the femoral neck with alfacalcidol (1.2%) than with vitamin D3 (0.8%). The 3-year rates of patients with at least one new vertebral fracture were 9.7% with alfacalcidol and 25% with vitamin D3 (RR = 0.61; 95%CI = 0.24, 0.81). The 3-year rates of patients with at least one new non-vertebral fracture were 15% with alfacalcidol and 25% with vitamin D3 (RR = 0.41; 95%CI = 0.06, 0.68). The 3-year rates of patients with at least one new fracture of any kind were 19% with alfacalcidol and 41% with vitamin D3 (RR = 0.52; 95%CI = 0.25, 0.71). Those who took alfacalcidol had a substantially larger reduction in back pain than those who
took vitamin D3. Generally, adverse effects in both groups were mild, and only three patients taking alfacalcidol and two taking vitamin D3 had moderate hypercalcemia. The authors concluded that alfacalcidol plus calcium is greatly superior to vitamin D3 plus calcium in the treatment of established glucocorticoid-induced osteoporosis. Infection risk Patients taking glucocorticoids have an increased risk of infections, including those produced by opportunistic and rare pathogens, and inhaled glucocorticoids can cause oral candidiasis. Fatal cerebral involvement in systemic aspergillosis has been described in a 25-year old woman with severe thrombocytopenia (platelet count 10 × 109 /l) and mild intermittent leukopenia (granulocytes 0.375–3×109 /l) who was taking prednisone 1– 1.5 mg/kg/day and azathioprine 100–200 mg/ day (25A ). Pregnancy Antenatal administration of glucocorticoids to women at risk of preterm delivery can improve neonatal outcomes and reduce mortality. However, there is still controversy about the use of single or repeat courses. It seems that betamethasone is more active in reducing neonatal deaths and produces fewer adverse effects than dexamethasone (26R ). In an Italian prospective study, 201 preterm singleton infants received one or more antenatal courses of a glucocorticoid (27c ). Neurodevelopment was evaluated at 2 years; 138 subjects received at least one complete course of betamethasone (37 multiple) and 63 patients received dexamethasone (33 multiple). The prevalence of infant leukomalacia was 26% after a complete course of glucocorticoid, 40% after one additional course, 42% after two additional courses, and 44% after more than two additional courses. The corresponding prevalences of 2-year infant neurodevelopmental abnormalities, considering the same categories of glucocorticoid exposure, were 18%, 21%, 29%, and 35% respectively. However, most of the risk was related to dexamethasone administration. Compared with betamethasone, exposure to multiple doses of dexamethasone was associated with an increased risk of leukomalacia (OR = 3.21; 95%CI = 1.07, 9.77) and overall 2-year infant neurodevelopmental abnormalities (OR = 3.63; 95%CI = 1.03, 14).
486 In an Australian cohort study, 541 very preterm infants were followed for physical, cognitive, and psychological assessment up to 6 years after administration of glucocorticoids during pregnancy (28c ). Although increasing numbers of antenatal glucocorticoid courses (two intramuscular doses of betamethasone 11.4 mg) were associated with a reduction in the rate of cerebral palsy, three or more courses were also associated with increased rates of aggressive/destructive, distractible, and hyperkinetic behavior, and these effects were present at ages 3 and 6 years. Intelligence quotients were unaffected by antenatal use of a glucocorticoid. In a retrospective study of the benefits and risks of multiple courses of glucocorticoids in patients with preterm premature rupture of membranes, 170 preterm singleton infants were evaluated (29c ). They were divided into three groups: non-use (n = 50), single courses (n = 76), and multiple courses (n = 44). There was a higher incidence of chorioamnionitis those who had received multiple courses. Drug interactions Ciclosporin The AUC of plasma prednisolone has been studied in patients with stable renal transplants (30c ). The prednisolone AUC was significantly higher in women and in those who took ciclosporin. The highest AUC was in women taking estrogen supplements and ciclosporin. A significantly higher proportion of patients taking ciclosporin + azathioprine + prednisolone had glucocorticoid adverse effects compared with those taking azathioprine + prednisolone. Furthermore, more women than men had adverse effects and the prednisone AUC was greater in those with adverse effects than without. Ciclosporin was thought to have increased the systemic availability of prednisolone, most probably by inhibiting P glycoprotein. Because the major contributor to AUC is the maximum post-dose concentration, it may be possible to use single-point monitoring (2 hours after the dose) for routine clinical studies. Itraconazole Most glucocorticoids are metabolized in part by CYP3A4, which can be induced and inhibited in pharmacokinetic interactions (SEDA-25, 470). A case of Cushing’s
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syndrome has been attributed to the combination of itraconazole and inhaled budesonide (31A ). • A 70-year-old white woman taking inhaled budesonide 400 micrograms tds developed multiple, small, purple, non-tender nodules in the subcutaneous tissues of her left leg. Biopsy of a nodule showed fungal hyphae, and Scedosporium apiospermum was isolated. She was treated with itraconazole suspension 200 mg bd, with complete clinical resolution after 4 weeks. Within 8 weeks after starting itraconazole, she developed swollen ankles, shortness of breath, fatigue, lethargy, and progressive severe leg weakness. Her doctor attributed her increased breathlessness to worsening asthma and increased the dose of inhaled budesonide to 800 micrograms bd. She had a Cushingoid appearance, her skin was thin, with multiple bruises over her body, her blood pressure was 170/90 mmHg, and she had proximal muscle weakness in the legs. The plasma cortisol concentration was below 2 (reference range 50–250) µg/l and tetracosactide 250 micrograms produced a rise to 11 µg/l after 60 minutes. The adrenocorticotropic hormone (ACTH) concentration was below 6.8 (9–52) ng/l and the 24-hour urine free cortisol was below 73 (350–1100) µg/l. Itraconazole and inhaled budesonide were withdrawn, and the secondary adrenal insufficiency was treated with hydrocortisone replacement. Inhaled beclomethasone 250 micrograms bd was given by metered-dose inhaler and 4 weeks later she developed a local recurrence of the S. apiospermum infection, which was treated with voriconazole 200 mg bd for 3 months, with complete resolution.
Voriconazole is predominantly metabolized by CYP2C19, and although it is an inhibitor of CYP3A4 its inhibitory effects are much less than those of itraconazole, as shown in this case, in which it appeared not to interact with beclomethasone, while itraconazole did. Diagnosis of adverse drug reactions The short Synacthen (tetracosactide) test is the most commonly used test for assessing adrenal suppression. The potential of a simpler and more cost-effective procedure, the morning salivary cortisol concentration, as an out-patient screening tool to detect adrenal suppression in patients using topical intranasal glucocorticoids for rhinosinusitis has been investigated in 48 patients who were using topical glucocorticoids (32c ). The morning salivary cortisol measurement was a useful screening tool for adrenal suppression in this setting.
Corticotrophins, corticosteroids, and prostaglandins
Chapter 39
Management of adverse drug reactions Mood stabilizers, such as lithium, lamotrigine, and carbamazepine, may be effective in treating glucocorticoid-induced mood symptoms. In an open trial, 12 patients with glucocorticoidinduced manic or mixed symptoms were treated with olanzapine (33c ) 2.5 mg/day initially, increasing to a maximum of 20 mg/day; 11 of the 12 patients had significant improvement.
PROSTAGLANDINS AND ANALOGUES (SED-15, 2955;
NASAL GLUCOCORTICOIDS Musculoskeletal Osteonecrosis of the femoral head after the use of a glucocorticoid nasal spray has been reported (34A ). • A 48-year-old man taking losartan, low-dose amitriptyline, and triamcinolone acetonide nasal spray developed pain in the abdomen and hips. Radiography and magnetic resonance imaging showed rapidly progressive bilateral osteonecrosis of the femoral heads. He had used excessive amounts of nasal glucocorticoids, and during the previous 12 months had used triamcinolone acetonide 110 micrograms qds in each nostril.
INTRA-ARTICULAR GLUCOCORTICOIDS Musculoskeletal An arthropathy induced by glucocorticoid crystals has been reported (35A ). • A 65-year-old man with bilateral osteoarthritis of the knees developed an effusion in the left knee. The swollen joint was treated with an intraarticular injection of triamcinolone hexacetonide 40 mg. The next day, he developed acute arthritis in the injected knee; the joint was swollen and tender and he was unable to walk. Examination of the joint fluid showed 35 ml of a thick, turbid, yellowish synovial fluid with a leukocyte count of 13 × 106 /l (95% neutrophils). Gram and acridine orange stains were negative. Wet preparations of the specimen with polarizing compensated microscopy showed numerous birefringent, pleomorphic intra- and extracellular crystals of glucocorticoid. He underwent joint lavage with 1 l of isotonic saline and recovered, completely within one day.
The conclusive diagnosis in this case was triamcinolone hexacetonide crystal-induced arthropathy.
487
SEDA-26, 430; SEDA-27, 417; SEDA-28, 476)
Alprostadil (prostaglandin E1 ) (SED-15, 94) Skin The harlequin color change is an unusual cutaneous phenomenon observed in neonates as transient benign episodes of sharply demarcated erythema on half of the infant, with simultaneous contralateral blanching. This selfresolving phenomenon usually occurs in the setting of hypoxia, as seen in prematurity or congenital heart disease. Two neonates with congenital heart anomalies demonstrated the harlequin color change (36A ). In one the skin showed a course related to the dose of systemic prostaglandin E1 , suggesting a possible association. • A full-term girl with transposition of the great vessels and an intact intraventricular septum developed a migratory macular erythema on the tenth day of life. The color change was blanchable, with no surface changes, and distributed mostly on the head and neck, with a few patches on the trunk and midline demarcation. There was no correlation between the color change and the position of the child. The event lasted several hours and resolved spontaneously with no skin sequelae. Intravenous diphenhydramine had no effect. At the time of this episode, the child was clinically stable and mechanically ventilated, with normal vital signs and acid-base balance. Medications consisted of PGE1 by continuous infusion, furosemide, midazolam, morphine, and pancuronium (doses not stated). One day later, arterial switch surgery was performed and PGE1 was withdrawn. No further color change or rash occurred after withdrawal of PGE1 . • A full-term girl with pulmonary atresia and an intact intraventricular septum had balloon dilatation of the pulmonary valve performed on the third day of life. Eight days later she developed a macular blanchable erythema involving several areas of the head and neck and on one-half of the trunk with sharp demarcation along the midline. The color change did not respond to intravenous diphenhydramine. The episode lasted 30 minutes and resolved spontaneously. Medications at the time were PGE1 by continuous infusion, furosemide, propranolol, midazolam, morphine, and pancuronium (doses not stated). On the same day as the initial episode of color change, she developed cardiovascular instability with low oxygen saturation. After she had been intubated and ventilated, a bolus of PGE1 was administered (dose not stated). The color change recurred, showing prominent macular erythema in a migratory pattern over the
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face and neck, and on either side of the truncal midline. The erythema was brighter and more extensive than in the previous episode, and was not affected by position. The colour change was not responsive to intravenous diphenhydramine or topical hydrocortisone. This second episode recurred intermittently over the next 8 days, becoming significantly less prominent as PGE1 was gradually weaned. After the withdrawal of PGE1 , no further color change was noted.
As this adverse effect is not serious, PGE1 should be continued until surgical correction is performed. Recognition of the association between systemic PGE1 infusion and the harlequin color change may assist the clinician to manage neonates with cyanotic heart disease and to avoid unnecessary exposure to pharmacological agents given to treat the rash.
Epoprostenol
(SED-15, 1228; SEDA-25,
474) Respiratory Interstitial pneumonia has been reported in a patient taking epoprostenol for primary pulmonary hypertension (37A ). • A 25-year-old woman with primary pulmonary hypertension, dyspnea, and exacerbation of edema was given an infusion of epoprostenol 0.5 ng/kg/ minute with incremental increases of 0.5 ng/kg/ minute every 12 hours. After 5 days she was receiving 4.5 ng/kg/minute. Her chest X-ray showed rapid changes in bilateral infiltrates and her respiration gradually deteriorated so that she required tracheal intubation and inhaled nitric oxide 10–20 ppm. Despite intensive antibiotic therapy, her oxygenation did not improve. The flow rate of nitric oxide was increased and she was given methylprednisolone 500 mg/day for 3 days and then weaned to oral prednisolone 40 mg/day. Her oxygenation improved and the dose of prednisolone was reduced to 20 mg/day. Ten days after intubation, she had massive bleeding from a gastric ulcer, which required a blood transfusion and endoscopic hemostasis. Prednisolone was withdrawn. One week later, her chest X-ray began to show bilateral infiltrates and a CT scan showed diffuse nodular interstitial changes, consistent with interstitial pneumonia. She was given methylprednisolone 500 mg/day for 3 days followed by prednisolone 40 mg/day, which resulted in significant improvement. Because the cause of her respiratory failure was unknown a lymphocyte stimulation test was conducted with epoprostenol and was positive (273% compared with control). She was given prostaglandin E1 (PGE1 ) instead of epoprostenol, after which her oxygenation, chest X-ray, and CT scan became stable.
J. Costa and M. Farré
Skin Common dose-limiting adverse effects of epoprostenol (including flushing) are attributed to vasodilatation. However, patients can develop a persistent rash distinct from the flushing associated with epoprostenol. The clinical and pathological findings have been described in 12 patients who developed a persistent rash while receiving long-term epoprostenol for pulmonary arterial hypertension (38c ). Management of adverse drug reactions Long-term therapy with epoprostenol, a potent prostacyclin and short-acting vasodilator, improves hemodynamics, exercise capacity, and survival in adults and children with pulmonary hypertension. However, epoprostenol has several inherent drawbacks (SEDA-24, 463). Bosentan, a dual endothelin receptor antagonist, lowers pulmonary artery pressure and resistance and improves exercise tolerance in adults with pulmonary arterial hypertension. Based on a case series that suggested that epoprostenol can be withdrawn from a select group of adults with normal pulmonary pressures, it has been shown that bosentan facilitates the reduction of epoprostenol dosages and the severity of its associated adverse effects, without adversely affecting hemodynamic parameters in selected children (39c ). Further randomized studies are required to determine if use of bosentan concomitantly with epoprostenol improves hemodynamics and may allow safe weaning or discontinuation of epoprostenol. In a double-blind, placebo-controlled study, the Bosentan Randomized trial of Endothelin Antagonist Therapy for Pulmonary Arterial Hypertension (BREATHE-2), 33 patients took epoprostenol (2 ng/kg/min initially, increasing to a mean dosage of 14 ng/kg/min at week 16) and were then randomized for 16 weeks in a 2:1 ratio to bosentan (62.5 mg bd for 4 weeks then 125 mg bd) or placebo (40c ). There was a non-significant trend towards hemodynamic and clinical improvement with to the combination. There were several early and late major complications (four withdrawals with bosentan + epoprostenol: two deaths due to cardiopulmonary failure, one clinical worsening, and one increase in hepatic transaminases; and one withdrawal due to increased hepatic transaminases with placebo + epoprostenol. Power was the major limitation of this study, in which only 33 patients were enrolled, and the results should
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be interpreted with caution. Additional information is needed to evaluate the benefit to harm balance of combined bosentan + epoprostenol therapy in pulmonary arterial hypertension.
oped iris pigmentation, 89% had a baseline eye color known to be susceptible to color change (mixed-color irises containing brown areas). Patient with blue-grey eyes and no brown pigment did not develop increased iris pigmentation. In the 127 patients who developed iris pigmentation, it occurred during the first 8 months of the study in 94, during the first 12 months in 103, and during the first 24 months in 103. All developed the condition after 36 months. There was hypertrichosis in 14%. Seven patients using different topical prostaglandin F2a analogues developed bilateral poliosis, which appeared at 1.5–6 months after the start of therapy (44A ). Four used latanoprost, two used bimatoprost, and one used travaprost. The use of latanoprost after trabeculectomy can cause shallowing of the anterior chamber, choroidal effusion, and choroidal detachment. A new case of the last of these has been reported (45A ).
Iloprost
(SED-15, 1716)
Comparative studies The effects of PGE1 and iloprost on microcirculation have been investigated in a randomized crossover study in 36 patients with peripheral arterial occlusive disease stage III and IV according to Fontaine (41c ). They received PGE1 and iloprost by single 3-hour intravenous infusions on two different days at doses recommended by the manufacturers or as have been used in previous studies (PGE1 : first hour 20 micrograms, next 2 hours 30 micrograms each; iloprost: first hour 0.5 ng/kg/minute, next 2 hours 1.0 ng/kg/minute). Adverse effects occurred in 19% (PGE1 ) and 31% (iloprost). Dosage reduction was required in three patients receiving iloprost (hypotension, nausea, irritation of the infused vein), and in none in those receiving PGE1 .
Latanoprost
(SED-15, 2002)
Sensory systems Latanoprost can cause darkening of the iris and hypertrichosis (including lengthening and darkening of the eyelashes). The long-term safety of topical latanoprost in the long-term treatment of open-angle glaucoma has been assessed in two studies. To investigate the possible appearance of trabecular pigmentation, 50 subjects who used latanoprost were evaluated by gonioscopic photography of the inferior quadrant at baseline and every 3 months during the first year and every 6 months during the second and third years (42c ). In all 41 subjects (79 eyes) completed the 3-year followup and none had any increase in the grade of trabecular pigmentation, including 10 subjects (20 eyes) in whom iris pigment increased. The safety of latanoprost after 5 years of treatment has been reported in 380 subjects, of whom 353 were evaluated at 4 years and 344 completed the 5th year (43C ). In 127 (33%) there was increased iris pigmentation in one or both eyes after 5 years. Of the patients who devel-
• A 36-year-old man with juvenile open-angle glaucoma in both eyes and traumatic glaucoma in the left eye had extensive iridodialysis and angle recession of about 180◦ in the left eye. He was treated with topical timolol 0.5% bd and later daily latanoprost 0.005% to both eyes. Immediately after surgery for cataract extraction and intraocular lens implantation combined with trabeculectomy he had a large fall in intraocular pressure and 2 days later developed severe pain, gross impairment of vision, and intense congestion in the left eye. Indirect ophthalmoscopy showed an inferior choroidal detachment. Topical latanoprost was immediately stopped in the left eye and systemic prednisolone 1.5 mg/kg/day was continued. Within 7 days, the choroidal detachment settled.
The authors suggested that the drastic fall in intraocular pressure after trabeculectomy had resulted from an unusually large increase in uveoscleral outflow because of latanoprost. This was because of the additive effect of two factors: trabeculectomy-associated ciliary body detachment and the pre-existing cleft between the ciliary body stroma and the sclera, evidenced by extensive angle recession. The latter was perhaps responsible for the large fall in intraocular pressure (from 32 to 16 mmHg) when latanoprost was first introduced. Although the patient did not have uveitis, prostaglandinmediated damage to the blood retinal barrier could also have contributed to choroidal detachment. They cautioned against the use of latanoprost as an adjunctive pressure-lowering agent after glaucoma filtration surgery.
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Teratogenicity Latanoprost exposure has been reported in 11 pregnancies (46A ). All the women used latanoprost in the first trimester, and embryo exposure lasted from a minimum of 4 days to a maximum of 70 days. There was complete follow-up in 10 cases: nine women delivered normal fetuses without malformations and one pregnancy was complicated by early spontaneous abortion 2 weeks after treatment was completed in a 46-year-old primigravida. The children were considered normal at followup within 2 years.
Misoprostol
(SED-15, 2357)
Placebo-controlled studies The adverse effects of misoprostol have been evaluated in a large double-blind randomized placebo-controlled trial sponsored by the WHO in 15 clinics in 11 countries in 2219 healthy pregnant women requesting medical abortion after up to 63 days of amenorrhea (47C ). They were given oral mifepristone 200 mg on day 1, followed by 800 micrograms either orally or vaginally on day 3. The oral group and one of the vaginal groups continued taking oral misoprostol 400 micrograms bd for 7 days and the vaginal-only group took oral placebo. Pregnancy-related symptoms abated in all the groups after misoprostol and breast tenderness was reduced by mifepristone. Oral misoprostol was associated with a higher frequency of nausea and vomiting than vaginal administration at 1 hour after administration. With oral misoprostol, diarrhea was more frequent at 1, 2, and 3 hours after administration. Misoprostol caused fever during at least 3 hours after administration in up to 6% of the women, the peak being slightly higher and later with
J. Costa and M. Farré
vaginal administration. Lower abdominal pain peaked at 1 and 2 hours after oral misoprostol and at 2 and 3 hours after vaginal misoprostol. In the two groups of women who continued to take misoprostol, 27% had diarrhea between the misoprostol visit and the 2-week follow up visit, compared with 9% in the placebo group. Drug administration route In a randomized controlled trial, 74 primigravidae who were undergoing surgical abortion were randomly assigned to misoprostol 400 micrograms sublingually or vaginally 2–4 hours before surgery (48c ). Efficacy was similar in the two groups. Women who took sublingual misoprostol had significantly more nausea (63% versus 32%), vomiting (29% versus 6%), diarrhea (6% versus 0%), and unpleasant taste in the mouth (39% versus 3%) compared with the women who used vaginal misoprostol. In another study, 100 pregnant women who opted for termination of pregnancy at 6–12 weeks gestation were randomly allocated to misoprostol 400 micrograms sublingually or vaginally 2 hours before suction evacuation (49c ). There was a significant difference between the sublingual and vaginal misoprostol groups with respect to mean cervical dilatation (8.6 mm versus 6.8 mm). However, the durations of the procedures (3.03 versus 3.16 minutes) and the amounts of blood loss (29 versus 31.2 ml) were not different. The women who used sublingual misoprostol had significantly more shivering and preoperative vaginal bleeding (68% versus 56%). Sublingual misoprostol is an effective alternative to vaginal administration for cervical priming before surgical abortion, despite a higher incidence of adverse effects.
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liver damage associated with intravenous glucocorticoid pulse therapy in patients with Graves’ ophthalmopathy. Thyroid 2004;14:403–6. Langhammer A, Norjavaara E, de Verdier MG, Johnsen R, Bjermer L. Use of inhaled corticosteroids and bone mineral density in a population based study: the Nord–Trondelag Health Study (the HUNT Study). Pharmacoepidemiol Drug Saf 2004;13:569–79. Suissa S, Baltzan M, Kremer R, Ernst P. Inhaled and nasal corticosteroid use and the risk of fracture. Am J Respir Crit Care Med 2004;169:83–8. Steinbuch M, Youket TE, Cohen S. Oral glucocorticoid use is associated with an increased risk of fracture. Osteoporos Int 2004;15:323–8. Townsend HB, Saag KG. Glucocorticoid use in rheumatoid arthritis: benefits, mechanisms, and risks. Clin Exp Rheumatol 2004;22(Suppl 35):S77–82. Gluck O, Colice G. Recognizing and treating glucocorticoid-induced osteoporosis in patients with pulmonary diseases. Chest 2004;125:1859– 76. Richy F, Ethgen O, Bruyere O, Reginster JY. Efficacy of alphacalcidol and calcitriol in primary and corticosteroid-induced osteoporosis: a metaanalysis of their effects on bone mineral density and fracture rate. Osteoporos Int 2004;15:301– 10. Ringe JD, Dorst A, Faber H, Schacht E, Rahlfs VW. Superiority of alfacalcidol over plain vitamin D in the treatment of glucocorticoid-induced osteoporosis. Rheumatol Int 2004;24:63–70. Buchheidt D, Hummel M, Diehl S, Hehlmann R. Fatal cerebral involvement in systemic aspergillosis: a rare complication of steroidtreated autoimmune bicytopenia. Eur J Haematol 2004;72:375–6. Jobe AH, Soll RF. Choice and dose of corticosteroid for antenatal treatments. Am J Obstet Gynecol 2004;190:878–81. Spinillo A, Viazzo F, Colleoni R, Chiara A, Maria Cerbo R, Fazzi E. Two-year infant neurodevelopmental outcome after single or multiple antenatal courses of corticosteroids to prevent complications of prematurity. Am J Obstet Gynecol 2004;191:217–24. French NP, Hagan R, Evans SF, Mullan A, Newnham JP. Repeated antenatal corticosteroids: effects on cerebral palsy and childhood behavior. Am J Obstet Gynecol 2004;190:588–95. Yang SH, Choi SJ, Roh CR, Kim JH. Multiple courses of antenatal corticosteroid therapy in patients with preterm premature rupture of membranes. J Perinat Med 2004;32:42–8. Potter JM, McWhinney BC, Sampson L, Hickman PE. Area-under-the-curve monitoring of prednisolone for dose optimization in a stable renal transplant population. Ther Drug Monit 2004;26:408–14. Bolland MJ, Bagg W, Thomas MG, Lucas JA, Ticehurst R, Black PN. Cushing’s syndrome due to interaction between inhaled corticosteroids and itraconazole. Ann Pharmacother 2004;38:46–9.
492 32. Patel RS, Shaw SR, McIntyre HE, McGarry GW, Wallace AM. Morning salivary cortisol versus short Synacthen test as a test of adrenal suppression. Ann Clin Biochem 2004;41:408–10. 33. Brown ES, Chamberlain W, Dhanani N, Paranjpe P, Carmody TJ, Sargeant M. An open-label trial of olanzapine for corticosteroid-induced mood symptoms. J Affect Disord 2004;83(2– 3):277–81. 34. Mistlin A, Gibson T. Osteonecrosis of the femoral head resulting from excessive corticosteroid nasal spray use. J Clin Rheumatol 2004;10:45–6. 35. Selvi E, De Stefano R, Lorenzini S, Marcolongo R. Arthritis induced by corticosteroid crystals. J Rheumatol 2004;31:622. 36. Rao J, Campbell ME, Krol A. The harlequin color change and association with prostaglandin E1. Pediatr Dermatol 2004;21:573–6. 37. Morimatsu H, Goto K, Matsusaki T, Katayama H, Matsubara H, Ohe T, Morita K. Rapid development of severe interstitial pneumonia caused by epoprostenol in a patient with primary pulmonary hypertension. Anesth Analg 2004;99:1205–7. 38. Myers SA, Ahearn GS, Selim MA, Tapson VF. Cutaneous findings in patients with pulmonary arterial hypertension receiving longterm epoprostenol therapy. J Am Acad Dermatol 2004;51:98–102. 39. Ivy DD, Doran A, Clausen L, Bingaman D, Yetman A. Weaning and discontinuation of epoprostenol in children with idiopathic pulmonary arterial hypertension receiving concomitant bosentan. Am J Cardiol 2004;93:943–6. 40. Humbert M, Barst RJ, Robbins IM, Channick RN, Galie N, Boonstra A, Rubin LJ, Horn EM, Manes A, Simonneau G. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J 2004;24:353–9. 41. Schellong S, Altmann E, Von Bilderling P, Rudofsky G, Waldhausen P, Rogatti W. Microcirculation and tolerability following i.v. infusion of PGE1 and iloprost: a randomized
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cross-over study in patients with critical limb ischemia. Prostaglandins Leukot Essent Fatty Acids 2004;70:503–9. Nakamura Y, Nakamura Y, Morine-Shinjo S, Sakai H, Sawaguchi S. Assessment of chamber angle pigmentation during longterm latanoprost treatment for open-angle glaucoma. Acta Ophthalmol Scand 2004;82:158–60. Alm A, Schoenfelder J, McDermott J. A 5-year, multicenter, open-label, safety study of adjunctive latanoprost therapy for glaucoma. Arch Ophthalmol 2004;122:957–65. Chen CS, Wells J, Craig JE. Topical prostaglandin F(2alpha) analog induced poliosis. Am J Ophthalmol 2004;137:965–6. Sodhi PK, Sachdev MS, Gupta A, Verma LK, Ratan SK. Choroidal detachment with topical latanoprost after glaucoma filtration surgery. Ann Pharmacother 2004;38:510–1. De Santis M, Lucchese A, Carducci B, Cavaliere AF, De Santis L, Merola A, Straface G, Caruso A. Latanoprost exposure in pregnancy. Am J Ophthalmol 2004;138:305–6. Honkanen H, Piaggio G, Hertzen H, Bartfai G, Erdenetungalag R, Gemzell-Danielsson K, Gopalan S, Horga M, Jerve F, Mittal S, Thi Nhu Ngoc N, Peregoudov A, Prasad RN, PretnarDarovec A, Shah RS, Song S, Tang OS, Wu SC, WHO Research Group on Post-Ovulatory Methods for Fertility Regulation. WHO multinational study of three misoprostol regimens after mifepristone for early medical abortion. BJOG 2004;111:715–25. Hamoda H, Ashok PW, Flett GM, Templeton A. A randomized controlled comparison of sublingual and vaginal administration of misoprostol for cervical priming before first-trimester surgical abortion. Am J Obstet Gynecol 2004;190:55– 9. Vimala N, Mittal S, Kumar S, Dadhwal V, Sharma Y. A randomized comparison of sublingual and vaginal misoprostol for cervical priming before suction termination of first-trimester pregnancy. Contraception 2004;70:117–20.
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Editor’s note: It is not possible to be definitive in separating reports on adverse reactions to estrogens in hormone replacement therapy from those that occur when estrogens are used for other purposes. Information on particular types of adverse effects should be sought under both headings.
GONADOTROPINS AND OVULATION-INDUCING DRUGS (SED-15, 1536; SEDA-26, 434; SEDA-27, 420; SEDA-28, 480) Reproductive system Further attempts have been made to reduce the risk of severe ovarian hyperstimulation by “coasting,” i.e. withdrawing exogenous gonadotropins and delaying the use of human chorionic gonadotropin (hCG) should the patient’s serum cholesterol concentration become dangerously high (SEDA-28, 480). The effects of this technique have been examined objectively in women at risk of hyperstimulation by measurement of both follicular size and vascular endothelial growth factor (VEGF) in 22 women who had been coasted and 26 women who had not (1C ). Average follicular size was significantly less and VEGF concentrations significantly lower. It is possible that coasting alters the capacity of granulosa cells to produce VEGF and/or their response to Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29040-8 © 2007 Published by Elsevier B.V.
hCG and in this way acts to reduce the severity and incidence of severe hyperstimulation. Various other low-dose approaches have been tested in an attempt to reduce the risk of complications. Recombinant FSH (rhFSH, Gonal-F) has been compared with urinary human FSH (uhFSH, Metrodin) in a randomized study in a low-dose step-up protocol for ovulation induction in 20 infertile clomipheneresistant patients with polycystic ovaries (2C ). The starting dose was 75 IU of rhFSH or uhFSH. Human chorionic gonadotropin (hCG) 10 000 IU was administered if 1–3 follicles achieved a diameter of 16 mm or more, and both sonographic and hormonal monitoring were carried out. All the six pregnancies induced were in the rhFSH group, but two of them ended in miscarriage. There were no differences between the two groups concerning the intensity or duration of treatment or the hormonal response. Three patients had grade II and one patient grade III hyperstimulation. These results support earlier evidence that rhFSH is superior to uhFSH regarding pregnancy rates when using this low-dose protocol. There is ever more evidence that the results obtained with low doses can equal those earlier obtained with larger doses, while in principle reducing the risk of overstimulation. Where human chorionic gonadotropin is concerned, a dose of 3300 IU now appears to be sufficient, at least in high responders, to provide adequate oocyte maturation and fertilization (3C ), whereas doses of 5000 or 10 000 U have often been used. Attempts to identify hyper-responders continue. There is a significant predictive association between serum estradiol (E2) concentrations measured on stimulation days 3 and 5 and both ovarian hyper-responses and “extreme
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responses” in in vitro fertilization. However, the practical clinical value of stimulated serum estradiol (E2) concentrations for the prediction of hyper-responses is low, because of modest sensitivity and a high false-positive rate. For prediction of “extreme responses” the clinical value of stimulated E2 concentrations is moderate (4cr ). A mesothelial cyst in the round ligament has been attributed to ovarian stimulation (5A ).
gonadotropins, and no substantial relations to dosage or cycles of use. There were slight and non-significant increases in risk for both drugs after 20 years or more of follow-up (RR = 1.39 for clomiphene and 1.54 for gonadotropins). However, the risk associated with clomiphene for invasive breast cancers was statistically significant (RR = 1.60, 95%CI = 1.0, 2.5).
• A 31-year-old woman developed left lower quadrant pain after gonadotropin stimulation for IUI and a tender left inguinal mass after increasing ovarian stimulation for IVF/intracytoplasmic sperm injection. The mass was successfully removed.
ESTROGENS
Tumorigenicity The possibility that fertility treatment of one type or another might increase the risk of breast cancer has been raised but not finally settled. Data from the French E3N prospective cohort study have now been analysed in the hope of throwing light on the question (6M ). Of 92 555 women in the study population, 6602 were treated for infertility. During the 10-year follow-up period, 2571 cases of primary invasive breast cancer were diagnosed (183 in treated women). Analysis showed no significant overall association between the risk of breast cancer and treatment of any type for infertility (RR = 0.95, 95%CI = 0.82, 1.11). However, in the subgroup of women with a family history of breast cancer, infertility treatment was associated with a very slight further increase, of borderline significance, in the risk of breast cancer. There is, however, a possibility that an increased risk of breast cancer might be associated with the state of infertility itself and not with the agents administered to treat it. In a retrospective study of data on 12 193 women evaluated for infertility between 1965 and 1988 at five clinical sites, 292 were identified and followed up to the end of 1999. The standardized incidence ratios for in situ and invasive breast cancers in these women were compared with the breast cancer risks in a cohort from the general population (7C ). Infertile patients as a group had a significantly higher risk of breast cancer (RR = 1.29, 95%CI = 1.1, 1.4). Analyses for types of treatment within the cohort showed adjusted relative risks of 1.02 for clomiphene citrate and 1.07 for
(SED-15, 1253; SEDA-26, 436; SEDA-27, 422; SEDA-28, 481) Cardiovascular Because any possible effect of estrogens, favourable or unfavourable, on atherosclerosis is difficult to detect without very long-term experience, some workers have sought to use indirect measures that might be relevant. A Greek group set out to determine in a randomized, double-blind study the effect of hormonal or antihormonal therapy on serum VE-cadherin in 28 healthy postmenopausal women, who received either 17beta-estradiol (2 mg/day) with norethisterone acetate (1 mg/day) or alternatively raloxifene HCl alone (60 mg/day) for 6 months (8C ). Serum VE-cadherin, which was estimated at baseline and at month 6, fell significantly in both groups. These findings suggest that these drugs may preserve interendothelial junction integrity and control vascular permeability. Although this effect may favorably influence the progress of an atheromatous lesion, its clinical impact, for example on coronary artery disease, remains uncertain. Reproductive system Because in some societies excessive height in women is considered a social disadvantage, a minority of physicians have long used estrogens to arrest rapid growth in adolescent girls. The question has always been whether this might adversely affect reproductive function in later life. A retrospective cohort study, based on 371 women who had undergone such treatment (with diethylstilbestrol or ethinylestradiol) and 409 controls, has been published (9c ). After adjustment for age, the treated women were more likely than the controls to have tried at some time for 12 months or more to become pregnant without success (RR = 1.80), more likely to have seen a doctor because they were having difficulty becoming
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pregnant (RR = 1.80; CI = 1.39, 2.32), and more likely to have taken fertility drugs at some time (RR = 2.05; CI = 1.39, 3.04). The treated group was 40% less likely to conceive in any given menstrual cycle of unprotected intercourse. These striking findings raise much doubt as to the wisdom of using estrogens to arrest growth in girls. Drug formulations Alternative means of administering estrogens continue to be investigated, particularly in the hope of reducing unwanted effects. If it is necessary to give estrogens shortly after delivery, one concern will be whether this will suppress lactation, the other whether undesirable amounts of estrogen may enter the milk and thus pass to the infant. A Finnish group has reported that by using transdermal estrogen a sufficient effect can be obtained to compensate for a hypoestrogenic state without significant passage into the milk (10c ). In 21 healthy breastfeeding women who had delivered 20 weeks earlier, all of whom had received transdermal estradiol (E2) 50, 75, or 100 micrograms/day or placebo for 2 weeks, none of the breast milk samples contained any measurable concentrations of estradiol. Serum estradiol concentrations were increased dose-dependently. Both serum FSH and LH concentrations were reduced in all treatment groups, with more pronounced suppression in those who took 75 and 100 micrograms/day. Serum inhibin B concentrations were not significantly suppressed. In some instances, transdermal estrogens appear less likely to cause problems than other forms of administration. One group studied the treatment of polycystic ovary syndrome in 24 women, using transdermal or peroral administration of a combination of estradiol and cyproterone acetate in doses comparable to those used in oral contraceptives (11c ). The peroral treatment led to a significant impairment in insulin secretion and action whereas the transdermal application of estrogens did not significantly influence insulin sensitivity. Another group has tested the hypothesis that continuous transdermal hormone replacement therapy with estrogen/progestogen combinations could have beneficial effects on risk markers for coronary heart disease without eliciting serious adverse effects. In a randomized study, 60 postmenopausal women received either transdermal oestradiol-17-beta 0.05 mg/
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day with norethisterone acetate 0.125 mg/day or an identical placebo (12c ). After 6 months, HRT resulted in highly significant reductions in E-selectin, angiotensin-converting enzyme, cholesterol, low-density lipoproteins, high-density lipoprotein 3, apolipoproteins AII, and fasting insulin. Factor VII coagulation activity fell, while plasminogen activator inhibitor-1 and fibrin D-dimer increased in the HRT group, while prothrombin fragments 1 + 2 fell, more so in the placebo group. There were no changes in matrix metalloproteinase (MMP)-2, or in LDL particle size. Transdermal HRT was therefore considered to have beneficial effects on vascular function and CHD risk markers. It is unfortunate that in this work there was no direct therapeutic comparison between effective doses of the transdermal and the oral forms.
Diethylstilbestrol (stilbestrol, DES) (SED-15, 1119) Tumorigenicity It is only 30 years since the use of diethylstilbestrol in pregnancy was discontinued, and reports of second-generation complications will no doubt continue to be reported for some time. The difficulty in many cases will be to determine, after this lapse of time, whether the mother actually took diethylstilbestrol during her pregnancy. In a recent case of a very large clear-cell carcinoma of the cervix in a teenager with no known history of maternal use of diethylstilbestrol, in view of the dates it was likely to have been non-drugrelated, but the possibility of third-generation effects must also be borne in mind (13A ). Clear cell adenocarcinomas of the vagina and cervix induced by prenatal exposure to this drug metastasize to the lungs. The secondaries generally appear within 2–3 years of the initial diagnosis. Unusually, a case has been reported in which pulmonary metastases occurred more than 15 years after presentation of the primary tumor (14A ). This makes it clear that patients of this type should be followed up in the very long term.
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Hormone replacement therapy (HRT) (SED-15, 1684, 1686, 1692; SEDA-26, 436; SEDA-27, 423; SEDA-28, 483) The evidence of adverse effects emerging from randomized trials in and around 2002 has resulted in a dramatic fall in the use of hormone replacement therapy, the use of some formulations falling by two-thirds (15R ). Continuing debate on the benefit to harm balance of hormonal therapy at the time of the menopause or subsequently has in the recent past hardly yielded new conclusions (16R ). Unresolved questions remain, and with the decline in usage and changes in patterns and intensity of treatment it is doubtful whether these issues will ever be finally settled (17R ). Cardiovascular The continuing debate about the relation, if any, between HRT and coronary heart disease is still no nearer a solution (18r , 19r ). Respiratory Since female reproductive hormones appear to influence respiratory disease in some as yet poorly defined way, a prospective cohort study over 8 years sought to determine whether postmenopausal hormone use was associated with an increased rate of newly diagnosed asthma or chronic obstructive pulmonary disease (20C ). During 546 259 person-years of follow-up, current use of estrogen alone was associated with an increased rate of asthma (multivariate rate ratio = 2.29; 95%CI = 1.59, 3.29) compared with those who never used hormones. Current users of estrogen + progestogen had a similarly increased rate of newly diagnosed asthma. Rate ratios increased with certainty of diagnosis of asthma. In contrast, rates of newly diagnosed obstructive pulmonary disease were the same among hormone users and non-users. Metabolism The effects of therapeutic doses of estrogens on glucose tolerance are probably only slight, although the available data are inconsistent. In a study of the effects of transdermal and peroral oestrogen in conjunction with cyproterone acetate on metabolic and hormonal parameters in 24 women with polycystic ovary syndrome, peroral estrogens (at doses comparable to those currently used in combined
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oral contraceptives) significantly impaired insulin secretion and action (21c ). In contrast, transdermal estrogens did not significantly alter insulin sensitivity. It is doubtful whether these effects are of clinical importance. Hematologic The effects of hormonal replacement therapy on blood coagulation, fibrinolysis, and thrombosis are still remarkably uncertain after much epidemiological and laboratory study. The essential problem is the multiplicity of products, dosage schedules, and study criteria that have been used. The Women’s Health Initiative in the USA, based on 5 years of experience in more than 16 000 women, primarily using an estrogen + progestogen combination, seemed to indicate mean increases of coronary artery disease by 29%, stroke by 41%, and pulmonary embolism by 113% (SEDA27, 423), but other work at the time concluded that it might be another decade before the picture became clearer. That is probably still the only valid conclusion, although the fact that there is a significant hematological risk, perhaps outweighing the benefits of treatment, is now widely accepted. In the meantime, individual studies can only be regarded as helpful with respect to the particular treatment regimens to which they relate. The effect of continuously administered low-dose 17-beta-estradiol (E2) + norethisterone acetate (NETA) on coagulation and fibrinolytic factors has been studied in 120 menopausal women, using two dosage variations (1 mg of E2 with 0.25 mg or 0.5 mg of NETA) compared with placebo over a year (22C ). In either dose, the combination significantly lowered plasma concentrations of factor VII, fibrinogen, antithrombin, and plasminogen activator inhibitor-1 (PAI-1) compared with placebo. These changes appear favorable, since they may lead to increased fibrinolytic activity and could reduce the risk of coronary heart disease. However, antithrombin activity was also reduced, which may increase the risk of venous thromboembolism. The overall benefit to harm balance for medium-term hormone (estrogen + progestogen) replacement therapy (2 years) has been assessed in a novel although theoretical study using a Markov model. Data from the Women’s Health Initiative were used to simulate the effect of short-term treatment on life expectancy
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and quality-adjusted life expectancy (QALE) in 50-year-old menopausal women with intact uteri (23M ). Quality-of-life (QOL) utility scores were derived from the literature. The investigators assumed that HRT affected quality of life only during the perimenopause, when it reduced symptoms by 80%. Among asymptomatic women, short-term therapy was associated with net reductions in life expectancy and QALE of 1–3 months, depending on the risk of cardiovascular disease. Women with mild or severe menopausal symptoms gained 3–4 months or 7–8 months of QALE respectively. Among women at low risk of cardiovascular complications, HRT extended QALE, even if menopausal symptoms lowered quality of life by as little as 4%. Among women at increased risk of cardiovascular disease, HRT extended QALE only if symptoms lowered quality of life by at least 12%. The authors’ conclusion was that hormone therapy is associated with reduced survival but gains in QALE for women with menopausal symptoms, and that women who are expected to benefit from short-term HRT can be identified by the severity of their menopausal symptoms and their risk of cardiovascular disease. Biliary tract Hormone replacement therapy is associated with an increased risk of gallstones. In 16 postmenopausal women with no history of gallstones, fasting and residual gallbladder volumes increased and the ejection fraction fell significantly were examined after 3 months of treatment with HRT (conjugated estrogen 0.625 mg/day+medroxyprogesterone acetate 2.5 mg/day) (24C ). There was no change in measures of lithogenicity, such as nucleation time. Reproductive system Many physicians and clinics still choosing to continue HRT in spite of debates as to its safety have reconsidered the controls that they should perform in order to detect emergent risks. In particular, when abnormal bleeding occurs the cause needs to be diagnosed so that further courses of treatment can be decided on. Several groups have successfully used transvaginal ultrasonography to examine the state of the endometrium, although experience is still limited (25r ). In one series of 702 women measurements of endometrial thickness, using transvaginal ultrasound, provided a helpful but not infallible indication of
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those women in whom hysterectomy may be advisable; increased endometrial thickness (in excess of 4.5 mm) during HRT tends to run parallel with other endometrial abnormalities, such as polyps or endocavitary fibroids (26C ). In interpreting these findings it is important to bear in mind that medical and female attitudes to hysterectomy differ markedly between countries; for example, the operation is performed and accepted much more readily in the USA than in Europe. Immunologic Allergy to steroids of any type is unusual, but it has been reported with both corticosteroids and sex hormones, and crossallergy can occur. • A woman with a persistent dermatitis of the hands and feet developed multiple contact allergies to topical steroids (27A ). She had a past history of allergic contact dermatitis to a hormone replacement patch containing both estrogen and progesterone. Patch testing showed positive reactions to hydroxyprogesterone, progesterone, estradiol, and multiple corticosteroids.
Tumorigenicity There is continuing confusion between the effects of short-term lowdose treatment to relieve the symptoms of the climacteric and the much more fundamental and questionable attempt to counter postmenopausal changes by hormonal treatment over a period of years. Neither new research nor extensive reviews (28R ) have further clarified existing knowledge on the ability of HRT to modify the risks of certain malignancies. The main concern relates to the increased risk of breast cancer. HRT is thought to increase the risk in about 6 per 1000 users aged 50–59 and 12 per 1000 in older women, the risk being further increased when combined estrogen + progestogen regimens are used. The risk of endometrial cancer is unaltered or very slightly reduced; randomized trials examining other important but rarer malignancies, like ovarian, gall-bladder, and urinary bladder cancer, are either non-existent or too small to detect any effect reliably (29R ). Breast cancer It would be helpful if there were a reliable means of identifying women at an increased risk of breast cancer when taking decisions on HRT. The possibility that the androgen receptor gene might provide a clue, in view of earlier evidence that women with a
498 higher number of CAG repeat lengths on this gene have increased breast cancer rates, has been studied in 404 women with breast cancer (30c ). Among postmenopausal users of estrogen + progestogen treatment, carriers of the less active AR-CAG had a statistically significantly higher mean percentage breast density (41%) than carriers of the more active ARCAG. It is thus possible that the number of AR-CAG repeats will ultimately be helpful in predicting the breast cancer risk in women taking HRT. The pathological spectrum of breast cancers that develop in users of HRT is not necessarily the same as that of cancers that develop spontaneously. In a retrospective study of 10 874 postmenopausal Danish Nurses over 10 years, using data retrieved from the National Cancer Registry, there were breast cancers in 244 women, 172 being invasive ductal carcinomas (31M ). Compared with never users, current users of HRT had an increased risk of a hormone receptor-positive breast cancer, but no increased risk of receptor-negative breast cancer (RR = 3.29; 95%CI = 2.27, 4.77). The risk of a diagnosis of a “low histological malignancy” grade of cancer was higher than that of high malignancy grade (RR = 4.13). For breast cancers with other prognostic characteristics, the risk was increased equally for the favorable and non-favorable types. Current users of HRT had a two- to four-fold increased risk of breast cancer with various prognostic characteristics, both the favorable and non-favorable types. As regards receptor status, the risk with HRT was statistically significantly higher for hormone receptor-positive breast cancer than with receptor-negative breast cancer. It is widely considered that women who have already suffered breast cancer and have been treated for it should not receive estrogen therapy, but some workers express doubts as to whether this is indeed risky. The influential results of the Women’s Health Initiative study concerning the risks of HRT did not address this specific subgroup of users. A recent review has examined more than 30 studies of the issue, involving in all 1558 breast cancer survivors treated with estrogen or estrogen + progestogen replacement therapy (32r ). Overall, the recurrence rate accrued from the uncontrolled studies was 7.3% (53 of 728). The average rate culminating from 11 case-controlled studies was 11%
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(99 of 830) in treated patients versus 20% (739 of 3640) in their untreated counterparts. There was no increase in recurrent disease among treated patients but the study was not conclusive because of deficiencies in some of the studies reviewed. Endometrial cancer It has long been considered that the risk of endometrial carcinoma may be somewhat reduced by HRT, but that the risk is affected by the dose of progestogen used, if any. In a recent population-based case-control study covering 647 cases and 1209 controls, users of estrogen + medroxyprogesterone acetate (MPA) given for 10–24 days monthly in a dose of 100 mg/month or more showed the same risk of endometrial cancer as women not using HRT (33C ). However, the relative risk was only 0.8 (95%CI 0.5–1.5) in those who used a lower monthly MPA dose. Among users of a continuous combined hormone regimen, the risk of endometrial cancer was low relative to untreated women, regardless of the MPA dose. These findings hardly suggest that the dose of progestogen has very much effect on the risk of endometrial cancer. HRT after gynecological malignancies The possible effects of hormonal therapy on women who have been treated for endometrial or other malignancies have been reviewed (16R ). Data derived from 537 women involved in four case-control studies showed that early use of estrogens very greatly reduces the incidence of recurrences. The impact of estrogen on other gynecological malignancies is not as clear. Incomplete data in the literature suggest a slight increase in recurrence of ovarian cancer but indicate that there is no effect on most other gynecological malignancies. However, a previous history of cervical adenocarcinoma definitely excludes the use of these hormonal regimens. Susceptibility factors There is evidence that in women who have been treated with allogeneic stem cell transplantation for hematological malignancies, hormone replacement therapy may introduce particular risks. Premature ovarian failure in 30 women who were followed up in a single center 12–120 months after stem cell transplantation was treated with HRT (estrogen + progestogen) (34C ). Three of the women who were affected by chronic graft versus host
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disease (cGVHD) developed hemocolpometra after hormonal treatment. Local application of estrogens consistently improved the gynecological complication, but the vaginal synechiae tended to relapse when local treatment was interrupted, despite the apparent absence of other evidence of active cGVHD. These workers urged that all women with cGVHD should undergo gynecological examination before the introduction of HRT, in order to avoid the risk of inducing hemocolpometra. Vaginal and cervical synechiae should be treated with prolonged local treatments, and temporary use of continuous HRT regimens may be advisable. Moreover, close monitoring by pelvic examination and ultrasonography is advisable during the initial cycles to detect any complication caused by possible intrauterine adhesions undetected during gynecological examination. Drug formulations Throughout the 40-year history of HRT efforts have been made to improve the benefit to harm balance by modifications in the pattern of drug administration. In most cases it is not clear that improved tolerance to a particular drug, when this is claimed, is due to anything other than a reduction in total dosage or circulating concentrations, although there are exceptions. Vaginal rings loaded with estrogen and/or progestogen, as they are currently produced, provide steady delivery of the steroid over a period of up to 3 months; they have been used primarily as a means of treating menopausal symptoms. Resting on the pelvic floor muscles in a nearly horizontal position, the rings are as a rule imperceptible and cause no local symptoms. Over 5700 healthy US women who evaluated an unmedicated ring as a drug delivery platform found it very acceptable independent of age or prior use of barrier contraceptives (35R ). The fact that the estrogen can in this way be delivered directly into the systemic circulation is thought to result from there being less interference with the processes of coagulation and fibrinolysis than when estrogens are given transdermally. When progesterone is administered in this form, there are fewer adverse effects than with other routes of use, possibly due to lower serum concentrations of metabolites such as alloprenanolone.
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Pulsed intranasal therapy “Pulsed” (i.e. intermittent) estrogen treatment, given by the intranasal route, has been examined as a means of reducing the risk or rate of postmenopausal bone loss and hence osteoporosis. In a 2-year randomized, placebo-controlled study, in 386 women, hysterectomized patients received 17beta-estradiol, 150 or 300 micrograms/day for 2 years, and women with an intact uterus received micronized progesterone 200 mg/day over 14 days of each 28-day cycle (36C ). Bone marrow density, measured at two sites, increased significantly in women who used the active treatment in a dose-related manner, the differences compared with placebo were 5.2% and 6.7% at the spine and 3.2% and 4.7% at the hip with 150 and 300 micrograms/day respectively. On the other hand, there were reductions versus baseline of −3.2% and −3.3% at the spine and hip respectively in women who took placebo. In the patients with at least one risk factor for osteoporotic fractures, the difference between placebo and estradiol was even higher. Tolerance was good in all cases. One would wish to see a side-by-side comparison of this and other routes and patterns of estrogen use before concluding whether there is indeed any dissociation of wanted and unwanted effects; in view of current concern regarding estrogen use after the menopause, comparisons with non-hormonal treatment for osteoporosis (e.g. alendronate) would also be desirable.
HORMONAL CONTRACEPTIVES (SED-15, 1642 et seq; SEDA-26, 442; SEDA-27, 426; SEDA-28, 487) Cardiovascular Despite the vast literature on thromboembolic complications of oral contraceptives, little attention has been paid to factors that may determine the ultimate prognosis and risk of death. Data from the Swedish Adverse Reactions Monitoring Bureau and other sources have now been used to study this question in regard to pulmonary embolism, as well as estimating the incidence (37M ). Over 36 years (during which the spectrum and usage of oral contraceptives naturally changed) 248 cases of suspected pulmonary embolism were
500 reported. The presence of thromboembolism was confirmed in all fatal cases and 83% of non-fatal cases. The medical records showed that the presence of nausea or abdominal pain, age above 35 years, concomitant treatment with other drugs that increase the risk of thromboembolism, vein or lymph vessel malformations, and a deep vein thrombosis above the knee were positively associated with a fatal outcome. Chest pain and previous use of a combined oral contraceptive were negatively associated with a fatal outcome. Using pharmacy records to estimate sales, the incidence of verified pulmonary embolism was calculated as 1.72 per 100 000 treatment years; the figure for fatal cases was 0.25 per 100 000 treatment years. Nervous system Chorea has occasionally been seen during oral contraceptive treatment. Although it has been suggested that in such cases the contraceptive simply triggered the reactivation of latent Sydenham’s chorea, there has been a report of a case with no evidence of pre-existing chorea or recent streptococcal infection (38A ). However, the patient had positive antibasal ganglia antibodies, which supports an immunological basis for the pathophysiology of this complication. Musculoskeletal The various oral contraceptives currently available, although they differ in their qualitative and quantitative composition, do not appear to cause a reduction in bone density. In one study of combinations of levonorgestrel 100 micrograms with ethinylestradiol 20 or 30 micrograms there was no change in bone mineral density over 3 years (39C ), and it is possible that formulations with even lower estrogen contents would be satisfactory in this respect, although not necessarily in others (such as cycle control). Tumorigenicity The link, if there is one, between female sex hormones and hepatic hemangioma is not clear. In 1992, Stricker noted that there had been references to the occurrence or accelerated growth of hemangiomata (or their recurrence after resection) in scattered reports on oral contraception (40r ). The same had from time to time been reported as a consequence of pregnancy, so an association would not be entirely surprising. The impact of female sex hormones on the natural history of liver hemangiomas has now
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been prospectively evaluated over 1–17 years in 94 women with 181 hemangiomas diagnosed by ultrasound (41C ). There was an increase in the size of the lesions in 5 of 22 patients exposed to hormone therapy compared with 7 of 72 controls. Three variables (ultrasonographic pattern, number of hemangiomas, and hormone therapy) predicted whether or not a given hemangioma would increase in size. Hormone therapy significantly increased the risk of hemangioma enlargement but there was significant enlargement only in a minority of women. It would seem that in women with existing hepatic hemangiomas who are to receive hormone therapy (oral contraception or HRT) periodic ultrasound examination is advisable to detect any tendency to enlargement. The risk of a de novo hemangioma as a result of exposure to female sex hormone therapy is probably negligible. Drug formulations After nearly 50 years, new variants on the theme of two-component oral contraceptives continue to appear in an attempt to improve tolerance. Especially when these involve the use of lower doses than hitherto, one may be skirting the limits of efficacy in the cause of safety. When assessing studies of these newer combinations it can therefore be relevant to consider the average body weight of participants. For example, in Thailand there were therapeutically excellent contraceptive results with a daily combination of drospirenone 3 mg and ethinylestradiol 30 micrograms compared with a combination of levonorgestrel 150 micrograms and ethinylestradiol 30 micrograms (42c ). The rates of spotting and breakthrough bleeding were low and not different between the two regimens. There were no pregnancies and no menorrhea in either group. The most common adverse events in both groups were nausea, headache, and breast tenderness. Drospirenone + ethinylestradiol had a more favorable effect on body weight and blood pressure: mean body weight and mean blood pressure remained lower than baseline mean. However, all of these findings have to be read in the light of the fact that the body weight of Thai women is substantially less than that of women in Europe or the USA, and that both the efficacy and adverse reaction pattern could differ between such populations.
Sex hormones and related compounds, including hormonal contraceptives
Drug interactions Isotretinoin Isotretinoin is a potent teratogen, and when it is prescribed it is vital to use one or more reliable contraceptive methods. It is therefore important to determine whether isotretinoin itself might interfere with the efficacy of hormonal contraception. In 26 women who were to be treated with isotretinoin and expected to use oral contraceptives, serum concentrations of the two components of Ortho Novum (ethinylestradiol and norethindrone) were used as markers for any direct kinetic effect of isotretinoin, while concentrations of serum progesterone, luteinizing hormone, and follicle-stimulating hormone were taken as indicators of hormonal effectiveness) (43C ). Adding isotretinoin to the oral contraceptive regimen resulted in small and inconsistent, but statistically significant, reductions in the concentrations of both ethinylestradiol (9% reduction in AUC) from time 0 to 24 hours after the dose on day 6) and norethindrone (11% reduction in Cmax on day 20). Isotretinoin did not cause any statistically significant increases in pharmacodynamic markers. One woman in each study phase (one before and one during isotretinoin treatment) had a rise in progesterone consistent with possible ovulation. There were no serious or unexpected adverse events. These findings do not indicate any substantial ability of isotretinoin in therapeutic doses to render oral contraception less reliable, but the variability of the figures recorded underlines once more the need to use two contraceptive methods during isotretinoin treatment. Implantable contraceptives While the Norplant device has lost favor in some countries because of local intolerance and difficulties with removal, it continues to be widely used elsewhere. The difference in usage of Norplant between countries seems to reflect in part the degree of sophistication of users. Where, as in many western countries, low-dose oral contraceptives are very widely used and have become the standard by which users judge the acceptability of other means of contraception, the Norplant method has remained popular where expectations are somewhat lower. Reproductive system Of 756 Norplant users (mean duration of use 3.08 years) most had
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previously used coitus interruptus as a contraceptive method and chose Norplant because of its effectiveness, despite the fact that adverse effects were detected in 80% (44C ). There were bleeding problems in 70%. Pregnancy occurred in only one case. Discontinuation because of bleeding problems occurred in 38%. It has been reported that the irregular bleeding or spotting that may be experienced with this device is to some extent alleviated by intermittent administration of mifepristone, based on a double-blind, randomized, placebo-controlled trial in 120 Norplant users (45C ). From the second to the seventh month one group of users received intermittent mifepristone (100 mg/day on 2 consecutive days in every month). Women who used mifepristone recorded the same frequency of bleeding/spotting episodes as controls, but the bleeding episodes were significantly less prolonged, the total number of bleeding days being reduced by 35%. After the end of mifepristone use, bleeding patterns were similar in both groups. One pregnancy occurred in the mifepristone-treated group, in month 6 of treatment; the outcome was a healthy male baby. The authors concluded that intermittent administration of mifepristone can offer a clinically significant improvement in the vaginal bleeding pattern in Norplant users. Clearly, more experience is needed if mifepristone is to be used over long periods for this purpose.
Emergency contraception Gastrointestinal Nausea and vomiting, which are common after use of the “morning after” pill, appear to be influenced by the timing of food and medication. With the standard Yuzpe regimen or modifications of it (substituting norethindrone as the progestogen or eliminating the second dose), taking the first dose within 1 hour of a meal or snack was associated with increased nausea and vomiting; while taking the second dose within 1 hour of a meal or snack was associated with decreased nausea and vomiting (46c ). At present many of these women use antiemetics; it is possible that the need for these drugs could be reduced by better timing of medication and food intake, but this is at present no more than a hypothesis.
502
Cyproterone acetate + ethinylestradiol Cardiovascular Cyproterone acetate in combination with ethinylestradiol is indicated for the treatment of women with severe acne and moderately severe hirsutism. This product has been associated with a greater risk of venous thromboembolism than oral contraceptives. However, in a rigorous case-control study the risk of venous thromboembolism with cyproterone acetate + ethinylestradiol was not significantly greater than the risk in women who took conventional oral contraceptives (47C ).
ANTIESTROGENS AND SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs) (SEDA-26, 445; SEDA-27, 429; SEDA-28, 490) Cardiovascular Evidence of the wanted or unwanted effects of antiestrogens on the cardiovascular system has been sought in an extensive literature study (48R ). Earlier papers had suggested that selective estrogen receptor modulators might have cardioprotective effects and could lower the risk of atherosclerotic disease, but both tamoxifen and raloxifene had also been shown to increase the risk of thromboembolic events (SEDA-26, 445, 446). The situation is still unclear, but raloxifene is currently being studied in a prospective, randomized, controlled trial (RUTH = Raloxifene Use for the Heart) to assess its effects on coronary heart disease and to set these alongside whatever adverse effects are observed. There is much evidence that when tamoxifen is used to prevent and treat breast cancer it significantly increases the risk of venous thromboembolism, but there has been doubt as to whether the risk is greater than with other treatments for this condition. An extensive literature survey published in 2004 and covering a 7-year period sought to resolve these doubts, taking careful account of other susceptibility factors that might distort the picture (49R ). Accurate determination of the rate of thromboembolism was impaired by the lack in most studies of routine assessments to detect asymptomatic
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cases. However, based on symptomatic cases the risk of thromboembolism was increased two- to three-fold during use of either tamoxifen or raloxifene to prevent breast carcinoma. It is not known whether the risk is increased further in women with inherited hypercoagulable states. In the case of early-stage breast carcinoma, the risk of thromboembolism is increased with both tamoxifen and anastrozole, although the problem appeared to be somewhat less when using anastrozole. Susceptibility factors Age There is a very proper reluctance today to interfere with hormonal processes during puberty and adolescence for fear of producing adverse long-term changes. Just as the use of estrogens in rapidly growing girls has largely fallen out of favor in most countries, so the safety of attempts to treat pubertal gynecomastia in boys is being questioned. However, this can be a distressing condition at a sensitive age, and some workers have cautiously used tamoxifen and raloxifene for this purpose. The results of different approaches have been compared in 38 patients with persistent pubertal gynecomastia at an average age of 14 years (50C ). They received reassurance alone or a 3- to 9-month course of an estrogen receptor modifier (tamoxifen 60 mg/day or raloxifene 10–20 mg bd). There were significant reductions in breast nodule size with both drugs, although the effect was more marked with raloxifene. In these doses, there were no adverse effects. If further work is to be performed it will be important to provide long-term follow-up to detect any unwanted later effects. Idoxifene Idoxifene is one of the newer selective oestrogen receptor modulators, which in the light of animal studies is stated to have greater binding affinity for estrogen receptors and less partial agonist activity than tamoxifen. The clinical evidence is still very limited, but the hope has been expressed that it might prove effective in women with breast cancers that are resistant to tamoxifen. In a randomized phase II trial in 47 such women in whom tamoxifen 20 mg/day had ceased to be effective, idoxifene showed only very slight evidence of activity; possible drug-related adverse effects were similar in frequency to those with tamoxifen (hot
Sex hormones and related compounds, including hormonal contraceptives
flushes/flashes 13% versus 15%, mild nausea 20% versus 15%) (51C ). Endocrine and lipid analysis in both groups showed similar changes.
Raloxifene
(SED-15, 3019)
Comparative studies Since both raloxifene and the non-hormonal drug alendronate reduce the incidence of osteoporotic fractures in postmenopausal women it is relevant to determine which approach is better tolerated and thus most likely to promote long-term adherence to therapy. Adverse effects and compliance have been studied in a direct randomized comparison over 12 months in 902 women attending 154 treatment centres in Spain (52C ). They took either raloxifene 60 mg/day or alendronate 10 mg/day. Those who took raloxifene reported significantly better compliance than those who took alendronate; more patients discontinued alendronate prematurely than raloxifene (26% versus 16%). The main reason for premature discontinuation was adverse reactions, particularly gastrointestinal reactions (9.9% with alendronate, 3.4% with raloxifene). Alendronate 70 mg once weekly and raloxifene 60 mg/day for 12 months have been compared in an international multicenter blinded trial in 487 women with low bone density (53C ). Bone mineral density increased much more with alendronate. Overall tolerability was similar, but the proportion of patients who reported vasomotor events was significantly higher with raloxifene (9.5%) than with alendronate (3.7%); the proportions of patients who reported gastrointestinal events were similar. Endocrine Some studies have suggested that raloxifene has a relatively favorable safety profile among the antiestrogens, notably as regards cardiovascular risk factors (SEDA27, 431), but when used therapeutically it is generally considered likely to produce an increase in hot flushes/flashes, very much like tamoxifen. This has now been disputed on the basis of a double-blind study in 487 postmenopausal women who took raloxifene drug for 8 months to counter the development of osteoporosis (54C ). Treated patients took either raloxifene 60 mg/day throughout or raloxifene by slow-dose escalation for the first 2 months,
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followed by the standard dose for the rest of the study; another group took placebo. The baseline incidence of hot flushes/flashes (3–5 per week) was low. During treatment it increased by an average of less than one episode per week in both active treatment groups and reduced by less than one per week with placebo. The high proportion (about 60%) of asymptomatic patients at baseline had increased further by the end of treatment in all groups. The proportion of women whose pre-existing episodes abated during treatment was significantly greater with slow dose escalation and placebo but not with standard doses of raloxifene, when compared with the proportion with treatment-related episodes. There were no statistically significant between-group differences in the distribution of the number of episodes after 2 months. However one analyses these figures, it would seem that the effect of raloxifene in increasing hot flushes/flashes is not dramatic, although it exists; if it does prove problematical, slow dose escalation may reduce it.
Tamoxifen
(SED-15, 3296)
In women believed to be at high risk of breast cancer, chemoprevention with tamoxifen and the newer selective estrogen receptor modulators is promising but still has to be weighed adequately against possible risks (55R ). This form of chemoprophylaxis has not been widely adopted; in the population as a whole the proportion of women who stand to benefit is low, and the risks of unnecessary drug treatment in the remainder have to be taken into account. In a survey in North Carolina 10% or less of women in all age groups were potentially eligible for chemoprevention while the maximum proportion of breast cancers prevented in eligible women was estimated at 6.0–8.3% (56C ). Clearly, the most desirable key to future policy on prophylaxis would be a means of selecting the subgroup at the highest risk, so that drug treatment could be limited to them. Nervous system It is unclear what effects tamoxifen might have on brain function and the nervous system as a whole. In the past there has been a suspicion that it might be associated with stroke (SEDA-25, 490), and it has been suggested that it might influence brain metabolism
504 or function or actually cause cognitive impairment (SEDA-27, 432). On the other hand, other work showed that tamoxifen had precisely the same effect on myoinositol concentrations in the basal ganglia as estrogen replacement therapy did (SEDA-17, 432), which could suggest that there is no risk to brain function. The effects of estrogen and tamoxifen on positron emission tomography (PET) measures of brain glucose metabolism and magnetic resonance imaging (MRI) have been evaluated as measures of hippocampal atrophy in three groups of postmenopausal women, women taking estrogen, women with breast cancer taking tamoxifen, and women not taking estrogen or tamoxifen (57C ). In those taking tamoxifen there were widespread areas of hypometabolism in the inferior and dorsal lateral frontal lobes relative to the other two groups. The untreated women had lower metabolism in the inferior frontal cortex and temporal cortex compared with those taking estrogen. Those taking tamoxifen also had significantly lower semantic memory scores than the other two groups. Finally, those taking tamoxifen had smaller right hippocampal volumes than those taking estrogen, an effect that was of borderline significance. Both right and left hippocampal volumes were significantly smaller than in those taking estrogen when a single outlier was removed. Those taking estrogen had hippocampal volumes that were intermediate to the other two groups. The authors concluded that these findings provide physiological and anatomical evidence for neuroprotective effects of estrogen. Biochemical changes are difficult to interpret in clinical terms, and there is now an evident need for longer-term controlled work correlating tamoxifen use and cognitive performance. Special senses Estrogen receptors are present in the retina, and tamoxifen has been stated to affect color vision. In a further study of this phenomenon in 24 middle-aged women who were taking tamoxifen 20 mg/day as adjuvant therapy for early stage breast cancer, visual fields were measured using both short wavelength automated perimetry and frequency doubling perimetry (58c ). The visual fields were affected, the changes being detectable within 2 years. The effects of tamoxifen were more readily detected with short wavelength automated perimetry, suggesting that it affects some
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types of visual pathways preferentially, presumably the cone pathways, which are measured with this technique. Some older work pointed to an increased risk of other ophthalmic complications, including cataract in patients with cancer who took tamoxifen for a longer period. The issue was later examined in Britain using a case-control study design and data collected in the General Practice Research Database relating to women taking tamoxifen for breast cancer, the comparators being women with other cancers who were not taking tamoxifen (59M ). Current tamoxifen users were not at increased risk of cataract and there was no evidence of an increased risk with increasing cumulative dose (AOR = 1.0, 95%CI = 0.7, 1.4). Pancreas Severe acute pancreatitis has been attributed to tamoxifen (60A ). • A woman with hypertriglyceridemia and breast cancer was given tamoxifen and various lipidregulating agents after mastectomy. She stopped the latter of her own accord after 2 years and had a recurrence of hypertriglyceridemia and pancreatitis.
In this instance there were other possible precipitating factors, particularly hypertriglyceridemia, and it is hard to see why tamoxifen should have been held responsible. Tumorigenicity Although it has been suggested that tamoxifen-associated endometrial carcinoma has a distinct gene expression profile, this has not been confirmed. There are two types of this cancer, with extremely different molecular profiles, but the distinction is not related to tamoxifen exposure (61c ). Much other work is being done to determine the characteristics of tamoxifen-associated endometrial tumors, in particular as regards their content of estrogen receptors (ER) and progesterone receptors. The pathological features and expression of ERα, ERβ, and progesterone receptors in these tumors have been compared with matched cases of non-tamoxifen-associated endometrial cancers (62C ). Compared with spontaneous tumors the drug-associated tumors were characterized by a lower expression of ERα, higher expression of progesterone receptors, and more frequent expression of ERβ. Differential expression of ERα and ERβ may alter the expression of key target genes (such as those
Sex hormones and related compounds, including hormonal contraceptives
induced by AP-1-dependent gene transcription) and contribute to the pathogenesis and clinical behavior of these tumors. Survival was significantly poorer in women with drug-associated tumors than in those with non-drug associated tumors. Susceptibility factors Drug metabolism Whether the adverse effects of tamoxifen when used to treat breast cancer recurrence correlate with the quantities of circulating tamoxifen and its metabolites (Ndesmethyltamoxifen and 4-hydroxytamoxifen) has been studied in 99 women with breast cancer, who had been taking tamoxifen for at least 30 days (63C ). Women who had at least one tamoxifen-related adverse effect had significantly higher concentrations of tamoxifen than women not did not. Women who reported visual problems had significantly higher concentrations of both tamoxifen and N-desmethyltamoxifen compared with others. However, concentrations of 4-hydroxytamoxifen were negatively associated with vaginal discharge. The authors suggested that that patterns of tamoxifen metabolism and its adverse effects are in some respects related and that studies of the metabolism of tamoxifen could be of value in choosing better tolerated schemes of treatment for individual patients. Drug–procedure interactions The use of tamoxifen in combination with radiotherapy appears to increase the risk of breast fibrosis, which is a known effect of irradiation. In a retrospective study of the records of 147 women with breast cancer who had taken part in a major prospective study of tamoxifen 20 mg/day and who had also received adjuvant radiotherapy, 90 were hormone receptor-positive (64c ). There was a statistically significant difference in terms of mean complication-relapse-free survival rates at 3 years (48% versus 66%) and at 2 years (51% versus 80%) in the tamoxifen and control groups respectively. In each group the mean complication-relapse-free survival rates were significantly lower in patients with low levels of CD8 radiation-induced apoptosis (20%, 66%, and 79% for CD8 16%, 16–24%, and >24% respectively). There were similar results for the complication-free survival rates. These findings pointed suggest that
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concomitant use of tamoxifen with irradiation is significantly associated with an increased incidence of grade 2 or higher subcutaneous fibrosis. Many patients who take tamoxifen for breast cancer take other drugs for co-existing illnesses, and the possibility of interactions with these drugs has so far been incompletely studied. In a study of 98 treated women I was shown that co-medication can influence plasma concentrations of tamoxifen and its metabolites (Ndesmethyltamoxifen and 4-hydroxytamoxifen) (65C ). Those taking diuretics had significantly higher plasma concentrations of tamoxifen and N-desmethyltamoxifen than others. Analgesics and anti-inflammatory drugs were negatively associated with plasma tamoxifen concentrations. Chemotherapeutic agents, allergy drugs, antidepressants, and medications for diabetes did not significantly alter plasma concentrations of tamoxifen or its metabolites. There is an impression, in the light of clinical experience, that antidepressants might reduce the clinical efficacy of tamoxifen (66A ), but more evidence is needed to confirm or reject this view. Management of adverse drug reactions Hot flushes/flashes remain a problem when tamoxifen is used to treat breast cancer. In a 4-week study in 22 women with this problem considerable relief was obtained by simultaneous use of oral gabapentin 300 mg tds (67c ). Occasional adverse effects were nausea, rash, and excessive sleepiness.
PROGESTOGENS
(SED-15, 2930; SEDA-26, 447; SEDA-27, 433; SEDA-28, 493) Immunologic Autoimmune progesterone-induced dermatitis with purpura and petechiae has been reported (68A ).
Drug interactions It is unusual to find a study in which the use of a medicinal treatment is found to interact with “street drugs” or other agents used illicitly. The effects of progesterone on the drug experience of cocaine users have been studied (69c ). Ten adult cocaine users entered two experimental sessions. Before each session, they took either two oral doses of
506 progesterone 200 mg or placebo. Two hours after the second dose, they received cocaine 0.3 mg/kg intravenously and started the selfadministration period, in which five optional doses of cocaine were available. Progesterone attenuated the cocaine-induced increase in diastolic blood pressure without affecting the increases in systolic blood pressure and heart rate. Progesterone also attenuated the subjective ratings of the “high” and “feel” responses but did not affect cocaine self-administration behavior.
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oral group, in which 28% withdrew, were hormonal (72C ). LNG-IUS has also been used for contraception immediately after termination of pregnancy in 20 nulliparous young women and was well accepted, although irregular vaginal bleeding was not uncommon (73c ). When exposure to LNG-IUS continued for up to 4 years the system was well tolerated throughout, with a high continuation rate; in women with heavy menstrual bleeding some irregular bleeding and spotting can occur, but this is much more acceptable than the menorrhagia for which the treatment is used (74C ).
Levonorgestrel PROGESTERONE ANTAGONISTS Skin Sweet’s syndrome has been reported several times in women taking oral contraceptives, but a well-documented recent case concerned the use of the Mirena uterine system for the administration of menorrhagia, where the complication could only have been due to levonorgestrel (70A ). • A 54-year-old woman fitted with a Mirena system soon developed fever and progressive skin lesions. A skin biopsy confirmed Sweet’s syndrome. She was treatment with topical and oral glucocorticoids, but the condition relapsed on reduction of the dose. Her symptoms finally resolved on removal of the intrauterine system and she remained symptom free after 9 months.
Drug formulations Levonorgestrel is now often administered in an intrauterine system (often LNG-IUS, Mirena) for endometriosis and other conditions. In a prospective noncomparative 6-month study of 34 women with mild to moderate endometriosis this approach gave marked relief of symptoms, and two-thirds of the women elected to continue treatment after the trial was completed (71C ). The staging of the disease was favorably affected. Administration of low doses in this manner seems to provide a means of avoiding significant systemic adverse effects while maintaining efficacy, but longer-term experience is required. In another study of the LNG-IUS in 200 young nulliparous women, half of whom received the intrauterine system and the remainder an oral contraceptive for 1 year, 20% of those in the LNG-IUS group withdrew, onethird because of pain; the adverse effects in the
(SEDA-26, 448; SEDA-27, 433; SEDA-28, 494)
Mifepristone
(SED-15, 2344)
Controversy surrounding the use of mifepristone as an abortifacient has continued, particularly in the USA. Many of the objections raised reflect ethical or religious views, but various papers have stressed the risks involved, such as the fact that in the USA at least two preventable deaths have occurred, as well as other life-threatening complications. It has also been argued that approval of mifepristone as an abortifacient breached the FDA’s procedural rules. In 2002 a Citizen Petition to the Congress called for a revocation of the drug’s approval (75R ). Observational studies A Chinese group has sought to compare the efficacy and safety of different dosage schemes and dosage forms of mifepristone with misoprostol for early termination (76C ). In a randomized double-blind trial in 480 women, one group took two mifepristone 150 mg tablets in the morning and 150 mg 12 hours later for 2 days, while another group took three 75 mg capsules orally twice daily for 2 days. In both groups, misoprostol 600 micrograms was given 48 hours later. There were no significant differences between the two groups in the rates of complete abortion (95% or more) or incomplete abortion (3.3% or more), vaginal bleeding, or the incidence of adverse effects, such as vomiting, nausea, headache, diarrhea, and lower abdominal pain.
Sex hormones and related compounds, including hormonal contraceptives
However, there are still groups who have concluded that higher doses are required, and alternative schemes of treatment with mifepristone are being compared to attain an optimal efficacy/safety balance in different circumstances. In a prospective study in 104 women, the best means of using mifepristone combined with oral misoprostol in the management of first trimester miscarriage (missed abortion and blighted ovum) was investigated (77c ). The women took either oral mifepristone 600 mg (n = 44) or 200 mg (n = 60), in both groups followed after 48 hours by oral misoprostol. Successful treatment (i.e. an empty uterus on scan and no bleeding after 10 days) was attained in some two-thirds of the women in both groups. In the high-dose group, the adverse effects were nausea in 25% and diarrhea in 16%; in the low-dose group, there was nausea in 7% and diarrhea in 7%. Since the therapeutic effects were similar the low-dose regimen seems preferable, and the method as a whole may provide a valid alternative to surgery in these cases. The adverse effects of these medicinal approaches to abortion have been studied in 15 clinics in 11 countries in 2219 healthy women requesting medical abortion within 63 days of the onset of amenorrhea (78C ). Mifepristone 200 mg was given orally on day 1, followed by misoprostol 0.8 mg either orally or vaginally on day 3. Oral of misoprostol was associated with a higher frequency of nausea and vomiting than vaginal administration at 1 hour after administration. With oral misoprostol, diarrhea was more frequent at 1, 2, and 3 hours after administration than with vaginal administration. Misoprostol induced fever during at least 3 hours after administration in up to 6% of the women; the peak occurred slightly higher and later with the vaginal route. Lower abdominal pain peaked at 1 and 2 hours after oral misoprostol, and at 2 and 3 hours after vaginal misoprostol. In the two groups that continued misoprostol, 27% of the women had diarrhea between the misoprostol visit and the two-week follow up visit, compared with 9% in the placebo group. Among the women studied, 84% would have chosen medical abortion again, 9% would have chosen surgical abortion, and 7% did not know. Comparative studies No doubt in part because of ethical controversies it has sometimes
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been difficult to mount adequate controlled studies, especially in the USA. Many women and practitioners have retained a preference for dilatation and evacuation as a means of performing abortion rather than using a medicinal technique. In a pilot study at Chapel Hill, North Carolina oral mifepristone 200 mg followed 2 days later by vaginal and oral misoprostol was compared with the surgical method (79c ). Of 47 women eligible for the trial, 29 declined to participate, primarily because of a preference for dilatation and evacuation. Of the 18 participants enrolled, nine were randomized to treatment with mifepristone + misoprostol and 9 to dilatation and evacuation. Mifepristone + misoprostol caused more pain and adverse events, although none was serious. As so often happens in the hormonal field, drugs of this class have commonly been given in excessive doses, no doubt because of the overriding need to ensure efficacy; as time goes by lower doses are proving effective and are better tolerated. For emergency contraception, for example, mifepristone 10 mg now appears to be as effective as the 25 mg that was recommended before (80c ). Reproductive system From time to time mifepristone causes uterine rupture, sometimes even in unscarred uterus (81c ). Infection risk The frequency of infection after medical abortion is quite low. A major systematic review of the literature up to mid2003 showed that in a total population of 46 421 cases, infection occurred only in 0.92%, with little variation between the various medical techniques used (82R ).
ANABOLIC STEROIDS, ANDROGENS, AND RELATED COMPOUNDS (SED-15, 216; SEDA-26, 449; SEDA-27, 434; SEDA-28, 495) The notion that many men in later life require androgen supplementation to counter the effects of the “andropause” is more widespread in some countries than others, both among practitioners and the public, and it is heavily debated (83R , 84R ). Proponents of this therapy
508 call for the development of more specific formulations for this purpose, while others argue that such treatment is rarely justified and should be strictly limited to a minority of men with severe and evident hypogonadism. It has, after all, to quote a sober review, “never been definitively established that the decline in testosterone seen in most aging men results in an androgen deficient state with health-related outcomes that can be improved by androgen therapy” (85r ). In that situation it is indefensible to run risks. A thorough review of present knowledge has concluded that there is no place for such treatment in healthy older men (86R ). It is not clear to what extent the less favorable aspects of ageing are really attributable to androgen decline; nor is it clear that aged tissues remain androgen sensitive, nor that such treatment is necessarily safe. However, certain idiosyncratic adverse effects of androgen treatment, which can include disordered sleep and breathing, as well as polycythemia, are clearly dose related, suggesting that dose escalation to increase efficacy may create or aggravate undesirable adverse effects. Furthermore, the safety of androgen therapy for cardiovascular and prostatic disease is uncertain. Kraus, after a careful review of the literature from a German perspective, has pointed out that androgen substitution must be approached with caution; even if the hazards are dubious, the need for such treatment is even more doubtful: “. . . The lack of clear hazards from testosterone substitution in the aging male does not indicate unrestricted treatment safety. Until all doubts are cleared, each treatment should be carefully documented and monitored” (87R ). While opinions are many and varied, only a few groups have made an adequate effort to acquire firm data on relative benefits and harms. In a randomized study using the anabolic androgen oxandrolone, 32 men aged 60– 87 took oxandrolone 20 mg/day for 12 weeks or placebo (88c ). Oxandrolone produced significant increases in lean body mass and muscle strength during treatment, but 12 weeks after the treatment had ended these measures were no long different from baseline; however, there was some improvement in fat mass during the study, which was largely discernible 12 weeks later. These modest short-term effects hardly seem to provide a justification for anabolic treatment of the elderly in view of the risks involved.
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Anabolic steroids are also still used in refractory anemias, although with recombinant human erythropoietin now widely available they appear to be seen mainly as a means of increasing the response to erythropoietin in highly resistant cases; combination treatment with erythropoietin, a glucocorticoid, and nandrolone has also been recommended for treating myelodysplastic syndromes (89Cr ). Again, in such exceptional situations the risks of anabolic steroids have to be accepted. Metabolism Data regarding the effect of androgen substitution therapy on blood lipids are conflicting, but are interpreted by proponents of this treatment as favorable. A small reduction in high-density lipoprotein cholesterol tends to be accompanied by a significant reduction in total cholesterol and low-density lipoprotein cholesterol, which is consistent with an absence of added cardiovascular risk (90r ). Hematologic Polycythemia as a complication of androgen treatment seems to be directly related to the intensity and duration of treatment. There is a little evidence that should it occur (for example after treatment with intramuscular androgens) it can be reversed by changing to the use of transdermal testosterone. However it remains unclear whether this is related to the mode of administration or simply to the fact that a lower dose is used (91c ). Liver One of the few valid uses remaining for anabolic androgens is temporary relief of Fanconi anemia while awaiting hemopoietic cell transplantation. However, a known risk is hepatic adenoma and this is not always readily detectable. In one case a large adenoma it ruptured shortly after transplantation, with a fatal result (92A ).
Abuse of anabolic steroids in sport Illegal use of anabolic androgenic steroids in sport continues, and is thought to be extensive. The risks have been documented for many years, but since it is uncertain what doses are in use, the extent of the dangers cannot be measured; from incidental cases it is suspected
Sex hormones and related compounds, including hormonal contraceptives
that the quantities administered are often much higher than those that were studied scientifically when anabolic drugs were developed for medical use 50 years ago. According to an extensive review published in 2004 (93R ), the main untoward effects that male athletes most often self-report are an increase in sexual drive, acne vulgaris, increased body hair, and increased aggressive and hostile behavior. Mood disturbances (for example depression, mania and hypomania, and psychotic features) are likely to be dose- and drugdependent. Anabolic dependence or withdrawal effects (such as depression) seem to occur only in a small number of users. Drug intake will derange endogenous production of testosterone and gonadotropins, and this effect may persist for months after drug withdrawal. Cardiovascular risk factors may undergo deleterious alterations, including raised blood pressure and depression of serum high-density lipoprotein (HDL), HDL2, and HDL3 cholesterol concentrations. In echocardiographic studies in male athletes, anabolic drugs did not seem to affect cardiac structure and function, although in animal studies they have hazardous effects on heart structure and function, while in other studies they did not damage the liver. Many other adverse effects have been associated with misuse, including disturbance of endocrine and immune function, alterations of the sebaceous system and skin, hemostatic changes, and changes in the urogenital tract. The conclusions of this review generally correspond to those advanced in previous volumes in the present series, although case reports in the course of the last 30 years seem to have thrown doubt on these relatively optimistic statements regarding cardiac and hepatic function. Cardiomegaly and heart failure have repeatedly been described; both hepatic enlargement and liver tumors seem to occur more often than one would expect in sportsmen generally and have long been documented as adverse effects of these drugs. The reversibility of the long-term physical effects of these drugs, notably cardiac hypertrophy, has been studied in 32 bodybuilders or powerlifters, including 15 athletes who had not been using anabolic drugs for at least 12 months and 17 current abusers; there was also a control group of 15 weightlifters who were
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non-users (94C ). The mean systolic blood pressure was higher in users (mean 140 mmHg) than in ex-users (130 mmHg) or weightlifters (125 mmHg). Left ventricular muscle mass related to fat-free body mass and the ratio of mean left ventricular wall thickness to internal diameter were not significantly higher in users and ex-users than in controls. Left ventricular wall thickness related to fat-free body mass was also lower in non-user weightlifters, but did not differ between users and ex-users. In all groups, systolic left ventricular function was within the reference range. The maximum late transmitral Doppler flow velocity was higher in users than in non-user controls. One has to conclude that several years after discontinuation of anabolic steroid abuse, strength athletes still show slight concentric left ventricular hypertrophy in comparison with anabolic-free strength athletes. There is more than sufficient reason to discourage firmly the use of anabolic drugs in sportsmen. Drug formulations Small-scale work with a bioadhesive buccal tablet of testosterone has shown that adequate serum concentrations can be obtained and that the buccal tablet (administered twice daily) is well tolerated (95c ). Other work has confirmed that twice-daily buccal application is optimal to maintain therapeutic serum concentrations of testosterone and its metabolites (96c –98c ); however, it appears that about one patient in six initially has a degree of oral discomfort from the presence of the “mucoadhesive” tablet, although this fades after a few days and does not seriously affect compliance. Transdermal testosterone (for example in the form of a 1% gel) provides a therapeutically adequate means of attaining and maintaining serum hormone concentrations in hypogonadal men, but nothing is known about the incidence of adverse effects, for example unwanted effects on the prostate or the risk of erythrocytosis. Of 123 men who used “AndroGel 1%” for periods up to 42 months, 12 had some local skin irritation, but only one discontinued treatment as a result (99c ). However, one needs to be cautious when faced with claims that topical hormonal products are better tolerated than those administered orally or by other routes. Topical testosterone
510 has sometimes been used in women as a treatment for different vulvar conditions, and hirsutism and other signs of virilization have been described by several authors. Clearly, close monitoring is needed (100cr ). Susceptibility factors Transsexuals When androgens are used to treat female-to-male transsexuals, a minor problem is the tendency for them to develop male pattern baldness, while a greater problem appears to be an increase in the risk of coronary heart disease. It has been suggested that the development of baldness might in these subjects actually serve as an early indicator for the risk of coronary complications, but a retrospective study in 81 transsexuals seems to show that the two effects simply occur coincidentally. Thinning of hair was related to the duration of androgen administration and present in about 50% of Frightward arrow M transsexuals after 13 years. None of the coronary risk factors at follow-up, nor proportional changes, was associated with the degree of baldness, except that there was an unexpected tendency to lower fasting glucose concentrations in balding subjects (101c ). Women In women, as well as men, androgens have effects on sexual function, bone health, muscle mass, body composition, mood, energy, and the sense of well-being. Androgen insufficiency has clearly been demonstrated in women with hypopituitarism, after adrenalectomy and oophorectomy, and in some women who take oral estrogen therapy, which increases sex hormone-binding globulin. The indications for administering androgens to women are not well-defined, nor is it clear which doses can be safely used; both testosterone and dehydroepiandrosterone (DHEA) have been used. The risks of rash or poorly dosed androgen treatment are evident, but the literature provides little guidance; further study is clearly needed (102R ). The effect of androgens on cardiovascular function and prognosis, breast and endometrial tissues, and mood and anger need careful investigation, and this is still largely lacking (103R ). There is still disagreement as to whether the concept of “female sexual dysfunction” is a genuine pathological entity or a concept artificially constructed to promote the sale of
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particular drugs. In a thorough review published by the Mayo Clinic it was stressed that failure of sexual performance in women can have many causes (for example psychological and marital) and that it demands an individualized therapeutic approach, which is not necessarily medicinal. However, for certain patients androgens may prove useful, especially in strengthening libido. The risks are evident, notably manifestations of virilization of the user and masculinization of a female fetus should pregnancy occur (104R ). Children In just a few medical situations, the marginal benefits of “anabolic” androgens may still outweigh their risks. The need to treat life-threatening episodes of severe hereditary angioma in children may for example justify use of oxandrolone or other anabolic drugs, but the doses required are likely to cause marked virilization (105c ). The long-term use of oxandrolone has been studied in children with very severe burns (covering 40% or more of the body surface). Under controlled conditions, 84 children (56 girls and 28 boys; mean age 8 years) received treatment for 1 year with placebo or oral oxandrolone 0.1 mg/kg bd (106c ). At discharge (95% healed) and at 6, 9, and 12 months after the burn, oxandrolone improved lean body mass, bone mineral content, and bone mineral density compared with placebo and there was no adverse effect on hepatic transaminases. The latter finding, and the absence of other adverse effects, suggests that this treatment of very severely burnt children is defensible.
ANTIANDROGENS
(SEDA-26, 451; SEDA-27, 435; SEDA-28, 497) Choice of antiandrogen Steroidal antiandrogens, such as cyproterone acetate and the various non-steroidal agents now widely used, have different endocrine effects and therefore different adverse effects (107R ). Cyproterone acetate tends to result in a loss of sexual interest and erectile dysfunction, whereas most men experience this only moderately or not at all during non-steroidal treatment. The most common adverse effects of the non-steroidal agents are
Sex hormones and related compounds, including hormonal contraceptives
gynecomastia and breast pain. Although the incidence of these events varies considerably between studies, and it is tempting for a reviewer to revise his preferences as new work appears, there is probably no real difference in the incidence of hormonal adverse effects between the three non-steroidal agents. However, there are important differences between them in other respects. Cyproterone acetate has been linked to adverse changes in serum lipids as well as significant, and in some cases fatal, cardiovascular events; it can also induce hepatotoxic effects. Nilutamide is associated with delayed adaptation to darkness, alcohol intolerance, and interstitial pneumonitis. Flutamide is associated with a greater risk of serious hepatotoxicity than bicalutamide or nilutamide. Diarrhea is also more likely to occur during therapy with flutamide than the other antiandrogens. In contrast, no specific non-pharmacological complications have been linked to bicalutamide, while diarrhea and abnormal liver function occur less often than with flutamide. It could be that bicalutamide will in a longer perspective prove to be the best tolerated of the present series. Musculoskeletal Androgen deprivation therapy for prostatic cancer, whether it is carried out surgically or medicinally, carries a substantial risk of osteoporosis and spinal fractures. These risks have been quantified to some extent (108C ). In 87 elderly men treated in this way over a long period, 38 had radiographic evidence of spinal fractures. They had an initial mean prostate specific antigen of 53 ng/ml and had received androgen deprivation therapy for a mean of 40 months. Mean spinal and femoral neck bone mineral densities were significantly lower than in men without spinal fractures. The duration of androgen deprivation therapy, low serum 25-hydroxycolecalciferol concentrations, and a history of alcohol excess (defined as more than four standard drinks daily) were the main determinants of spinal fractures.
Finasteride Observational studies In 41 men with advanced prostatic cancer treated over a longer period (mean 3.9 years) the effect of adding finasteride 5 mg/day to high-dose bicalutamide
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150 mg/day has been studied (109C ). Serum prostate-specific antigen (PSA) concentration was measured every 2 weeks until disease progression. At the first nadir of PSA, the median fall in PSA from baseline was 96.5%. Thirty of 41 patients (73%) achieved a second nadir and median fall of 98.5% from baseline. The median times to each nadir were 3.7 and 5.8 weeks respectively. The median time to treatment failure was 21 months. Adverse effects were minor, including gynecomastia. In 17 of 29 men at baseline and 12 of 24 men at the second PSA nadir sex drive was normal. Onethird of the men had spontaneous erections at both time points. The authors concluded that finasteride provided additional intracellular androgen blockade when added to bicalutamide. The duration of control was comparable to that achieved with castration, with preserved sexual function in some patients. Comparative studies In an open comparative study of androgenetic alopecia in 90 men oral finasteride (1 mg/day for 12 months; n = 65) was compared with 5% topical minoxidil solution twice daily (n = 25) (110c ). The cure rates were 80% for oral finasteride and 52% for topical minoxidil. The adverse effects were all mild, and did not lead to withdrawal of treatment. Of the 65 men given oral finasteride, six had loss of libido, and one had an increase in body hair at other sites; irritation of the scalp was seen in one of those who used minoxidil. These adverse events disappeared as soon as the treatment was withdrawn. The laboratory data did not show any statistically or clinically significant changes from baseline values to the endpoint, except for the serum total testosterone concentration, which was increased, and free testosterone and serum prostate-specific antigen in the finasteride group which were reduced from baseline values. The herbal preparation saw palmetto (Serenoa repens) has in the past been compared with finasteride in the treatment of benign prostatic hyperplasia, and in short-term studies it seems to give a similar degree of relief. However, long-term comparisons of efficacy and safety have been lacking. In a prospective 1-year comparative randomized trial in 64 men with category III prostatitis or chronic pelvic pain syndrome, finasteride was 5 mg/day was compared with saw palmetto 325 mg/day (111C ). At 1
512 year the mean NIH Chronic Prostatitis Symptom Index score fell from 24 to 18 in the finasteride group, but scarcely or not at all in the saw palmetto group. Adverse events included headache (n = 3) in the saw palmetto group and reduced libido (n = 2) in the finasteride group. Although one might envisage even more prolonged studies these findings hardly suggest that saw palmetto is a serious replacement for finasteride even though it is well tolerated. Special senses Cataract has been associated with finasteride therapy (112A ). • A 43-year-old man developed impaired vision in both eyes over 3 months. Anterior subcapsular opacities were found in both eyes, necessitating cataract extraction. He had been taking finasteride 1 mg/day for 3 years to treat the early stage of androgenic alopecia. It was suspected that the drug was responsible and the treatment was therefore withdrawn.
Pancreas The incidence of acute pancreatitis as a suspected complication of finasteride treatment has been examined in a case-control study in a Danish regional population of 490 000 over 7 years. Of 302 men aged 60 and older with incident acute pancreatitis, three had been exposed to finasteride; of 2994 controls 37 had been exposed to finasteride. After adjustment for alcohol-related diseases, gallstone disease, hyperlipidemia, hypercalcemia, and hyperparathyroidism, the authors found no evidence of an increased risk of acute pancreatitis in users of finasteride (113M ). Sexual function The use of finasteride to treat male pattern hair loss is based on its ability to inhibit the conversion of testosterone to dihydrotestosterone, the latter being involved in the development of baldness in some men. In the doses needed for this purpose it is generally well tolerated, but there are repeated reports of reduced libido, decreased ejaculate volume, and gynecomastia, and incidentally reports of other apparent complications appear (114R ). In recent years various clinical studies have shown that the doses of finasteride needed to treat androgenetic alopecia commonly lead to impairment of sexual and erectile function, but this has not as a rule been the principal topic of such studies. A recent Italian investigation of this issue, using questionnaires directed to 186 patients treated at various centers with finas-
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teride 1 mg/day for 4–6 months has challenged the accepted wisdom; the authors concluded that (as judged by the five-item International Index of Erectile Function) there was no adverse effect on erection after this period of time (115c ). Tumorigenicity Striking evidence of the association of finasteride with male breast cancer comes from the Medical Therapy of Prostatic Symptoms (MTOPS) study, a National Institutes of Health (NIH)-sponsored study of about 3047 men that compared finasteride, doxazosin, and the combination for the treatment of benign prostatic hyperplasia. The rate of breast cancer in this trial for men taking finasteride either alone or with doxazosin was four in 1554, or nearly 200 times that of the general population; one man in the finasteride + doxazosin group and three in the finasteride-alone group developed male breast cancer (116cr ). Dosage regimens Many of the problems seen with finasteride have undoubtedly been due to its use in unnecessarily high doses. Particularly when used for cosmetic ends there has been doubt as to how far dosage can be reduced while maintaining an acceptable effect. Finasteride continues to be used to treat hirsutism in women and is effective, although long-term information on safety is sparse, and in principle it might adverse affect an unborn child (117R ). The dose should certainly be kept as low as possible. In a randomized study in 38 hirsute women finasteride 2.5 mg every 3 days was as effective as the higher daily dose formerly used and better tolerated (118C ).
Bicalutamide As a non-steroidal antiandrogen, bicalutamide continues to provide a promising alternative to castration in men with prostatic cancer, especially since it appears somewhat less likely to cause impotence or loss of libido (119c , 120r , 121C ). Placebo-controlled studies The effects of bicalutamide 150 mg/day, in addition to standard non-medicinal care, have been tested in an internationally co-ordinated series of randomized placebo-controlled studies in more than 8000 patients with localized or locally advanced prostate cancer (122C ). At this dosage, sufficient to increase the length of progression-free
Sex hormones and related compounds, including hormonal contraceptives
survival, patients with locally advanced disease gained most benefit from bicalutamide. Overall survival was similar with bicalutamide and placebo. Survival appeared to be improved by bicalutamide in those with locally advanced disease, whereas it was reduced by bicalutamide in those with localized disease. The most common adverse events with bicalutamide were gynecomastia and breast pain.
Flutamide
(SED-15, 1427)
Comparative studies Although flutamide is sufficiently well tolerated in prostatic cancer, the much older drug cyproterone acetate continues to show up favorably. In a direct comparison between the two drugs in 310 men the two were equally effective in delaying progression of the cancer and prolonging survival; however, adverse effect profiles were more favorable for cyproterone acetate overall and in particular with respect to gynecomastia, diarrhea, and nausea (123C ). Respiratory An 88-year-old man developed interstitial pneumonitis while taking flutamide 375 mg/day for prostatic cancer (124A ). After 3 weeks he developed dyspnea and bilateral pulmonary interstitial infiltrates; glucocorticoid therapy and withdrawal of flutamide resulted in clinical improvement. Gastrointestinal Gastrointestinal effects are common when flutamide is used to treat advanced cases of prostate cancer. At doses of 250 mg every 8 hours or 500 mg/day, 23 of 106 men had gastrointestinal problems, irrespective of the dosage regimen (125c ). There was no difference in the incidence of these effects in the 56 men who had previously received external beam radiation and 50 others who had undergone radical prostatectomy. This suggests that the gastrointestinal adverse effects of flutamide are not due to a local toxic effect. Enterocolic lymphocytic phlebitis has been temporally associated with flutamide treatment (126Ar ). Although the association could have been coincidental, the facts suggest that the report should be taken seriously. • A 53-year-old man developed ileocecal intussusception due to an edematous ischemic cecum, due
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to enterocolic lymphocytic phlebitis, with numerous associated thrombi. The phlebitis involved not only the ischemic area but also other sites, notably the entire right colon, terminal ileum, and appendix. All layers of the bowel wall were involved. The mesenteric veins were also prominently affected, but the arteries were spared. There was a marked lymphocytic infiltrate involving the epithelium of the entire right colon, ileum, and appendix.
This is the first reported case of enterocolic lymphocytic phlebitis, a rare form of vasculitis, in conjunction with lymphocytic colitis, lymphocytic enteritis, and lymphocytic appendicitis. The fact that the patient was taking flutamide at the same time suggests that this peculiar form of lymphocytic inflammation of the veins and mucosa could represent a drug reaction. It should be recalled that diarrhea is a common complication of flutamide use, and perhaps occurs in severe degree in some 15% of men taking full-dose treatment. Skin Photosensitivity as a complication of flutamide treatment has been described before; in one unusually severe recent case, erythroderma ensued and proceeded to extensive vitiligo (127A ). Tumorigenicity An elderly man with prostatic cancer took long-term flutamide and developed adenocarcinoma of the breast (128Ar ). There could have been several reasons for this complication. Unlike LH-releaser-based hormonal therapy for prostatic cancer, antiandrogens cause hyperestrogenemia owing to suppressed negative feedback of androgens on LHRH and LH production, stimulation of testicular androgen production, and transformation to estrogens in peripheral target tissues. It is true that, in this particular individual, there were other susceptibility factors, namely BRCA-1 mutation and chromosome 9 inversion, which has been previously shown to impinge upon testicular function and intracrine balance of androgens versus estrogens. However, the authors stressed that men with prostate cancer who take antiandrogens may be at risk of breast cancer and they advised caution in the use of the treatment in men with risk factors for male breast cancer. Drug interactions Sequential administration of flutamide and cyproterone acetate has been associated with toxic hepatitis (129A ).
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MISCELLANEOUS COMPOUNDS Danazol
(SEDA-24, 479; SEDA-28, 496)
Danazol is a weak androgen and can thus exert the adverse effects of androgens, but because it inhibits LH and FSH secretion it can also elicit menopausal-like symptoms. However, from time to time it has other types of adverse effect. Respiratory A patient developed pulmonary fibrosis after having taken danazol for 2 months for idiopathic thrombocytopenic purpura (130Ar ). He developed bilateral pneumothoraces and pneumomediastinum and died. An association between danazol and lung fibrosis has been reported only once before; here it could have been coincidental or a reflection of a pathological process underlying the originally diagnosed disorder.
Tibolone
(SEDA-27, 437; SEDA-28, 499)
It is still difficult to form an objective view of this compound and its usefulness. Studies and reviews sponsored by the manufacturer have over many decades argued that, as one reviewer puts it, tibolone “may provide a safer alternative to traditional hormone replacement therapy”, but even this review adds that “the impact of tibolone on the risk of breast cancer or cardiovascular and thromboembolic events is not well defined” (131R ). Bearing in mind that these are precisely the questions that have cast a shadow over other forms of hormone replacement therapy, this is a serious defect in the evidence about the drug’s safety; it is possible that the extent of use of tibolone has been insufficient to provide well-documented answers.
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Metabolism The effects of 5 years of therapy with tibolone 2.5 mg/day on the lipid profile in 82 postmenopausal women with mild hypercholesterolemia have been examined (132C ). Total, low-density, and high-density lipoprotein cholesterol and lipoprotein(a) were very significantly reduced by tibolone group (n = 53) compared with controls (n = 29), by 18%, 32%, 16% and 12% respectively; triglycerides did not change. At this dose, which was sufficient to relieve menopausal symptoms, there were some adverse effects on hormone-dependent tissues (vaginal spotting in 11% and febrile hemorrhagic cystic mastopathy in 3.8%), but long-term therapy with tibolone was well tolerated and its effect on the concentrations of serum lipids appeared to be beneficial. Musculoskeletal A 2-year randomized controlled study in 90 women compared the effects of oral tibolone doses of 1.25 mg/day and 2.5 mg/day on bone loss in the early postmenopausal period; all took calcium 1000 mg/ day. Vertebral and femoral bone density rose in both treated groups but fell in the control group, and bone turnover markers (urinary excretion of hydroxyproline/creatinine and plasma osteocalcin concentrations) were similarly affected favorably in the treated groups, as was the incidence of hot flushes/flashes (133c ). Studies such as this still leave open the question of the advisability of continuing tibolone treatment over a longer period. While tibolone has indeed been shown to benefit mineral bone density, few data are available to show whether it lowers fracture incidence; nor is it clear whether there is a link between tibolone and breast cancer (134R ).
References 1. Tozer AJ, Iles RK, Iammarrone E, Gillott CMY, Al-Shawaf T, Grudzinskas JG. The effects of “coasting” on follicular fluid concentrations of vascular endothelial growth factor in women at risk of developing ovarian hyperstimulation syndrome. Hum Reprod 2004;19:522–8.
2. Szilagyi A, Bartfai G, Manfai A, Koloszar S, Pal A, Szabo I. Low-dose ovulation induction with urinary gonadotropins or recombinant follicle stimulating hormone in patients with polycystic ovary syndrome. Gynecol Endocrinol 2004;18:17–22.
Sex hormones and related compounds, including hormonal contraceptives 3. Schmidt DW, Maier DB, Nulsen JC, Benadiva CA. Reducing the dose of human chorionic gonadotropin in high responders does not affect the outcomes of in vitro fertilization. Fertil Steril 2004;82:841–6. 4. Hendriks DJ, Klinkert ER, Bancsi LFJMM, Looman CWN, Habbema JDF, Te Velde ER, Broekmans FJ. Use of stimulated serum estradiol measurements for the prediction of hyperresponse to ovarian stimulation in in vitro fertilization (IVF). J Assist Reprod Genet 2004;21:65–72. 5. Ryley DA, Moorman DW, Hecht JL, Alper MM. A mesothelial cyst of the round ligament presenting as an inguinal hernia after gonadotropin stimulation for in vitro fertilization. Fertil Steril 2004;82:944–6. 6. Gauthier E, Paoletti X, Clavel-Chapelon F, Fangon M, Follain Y, Hoang L, Niravong M, Evans G. Breast cancer risk associated with being treated for infertility: results from the French E3N cohort study. Hum Reprod 2004;19:2216–21. 7. Brinton LA, Scoccia B, Moghissi KS, Westhoff CL, Althuis MD, Mabie JE, Lamb EJ. Breast cancer risk associated with ovulationstimulating drugs. Hum Reprod 2004;19:2005– 13. 8. Christodoulakos G, Lambrinoudaki I, Panoulis C, Papadias C, Economou E, Creatsas G. Effect of hormone therapy and raloxifene on serum VE-cadherin in postmenopausal women. Fertil Steril 2004;82:634–8. 9. Venn A, Bruinsma F, Werther PG, Pyett P, Baird D, Jones P, Rayner J, Lumley PJ. Oestrogen treatment to reduce the adult height of tall girls: long-term effects on fertility. Lancet 2004;364:1513–8. 10. Perheentupa A, Ruokonen A, Tapanainen JS. Transdermal estradiol treatment suppresses serum gonadotropins during lactation without transfer into breast milk. Fertil Steril 2004;82:903–7. 11. Vrbikova J, Stanicka S, Dvorakova K, Hill M, Vondra K, Bendlova B, Starka L. Metabolic and endocrine effects of treatment with peroral or transdermal oestrogens in conjunction with peroral cyproterone acetate in women with polycystic ovary syndrome. Eur J Endocrinol 2004;150:215–23. 12. Stevenson JC, Oladipo A, Manassiev N, Whitehead MI, Guilford S, Proudler AJ. Randomized trial of effect of transdermal continuous combined hormone replacement therapy on cardiovascular risk markers. Br J Haematol 2004;124:802–8. 13. Ding D-C, Chang F-W, Yu M-H. Huge clear cell carcinoma of the cervix in teenager not associated with diethylstilbestrol: a brief case report. Eur J Obstet Gynecol Reprod Biol 2004;117:115–6. 14. Hall WB, Detterbeck FC, Livasy CA, Fowler WC Jr. Endobronchial clear cell adenocarcinoma occurring in a patient 15 years after treatment for DES-associated vaginal
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41
Thyroid hormones and antithyroid drugs
THYROID HORMONES (SED-15, 3409; SEDA-26, 45; SEDA-27, 442; SEDA-28, 505)
ANTITHYROID DRUGS
Thyroid hormones are prescribed for about 1% of the adult population in developed countries, and the prevalence of prescription rises to 5– 10% in those aged over 60 years (1c , 2c ). Since it is clear that about 25% of those who use levothyroxine (T4) take doses sufficient to suppress serum TSH (2c , 3C ), much attention has focused on potential adverse effects of this degree of over-treatment.
Hematologic
Musculoskeletal There have been many studies of the effects of levothyroxine in TSHsuppressive doses on measurements of bone mineral density. Data from more than 30 studies of the effect of thyroid hormone on bone have been reviewed (4R ). The results have supported the view, expressed before (5M ), that there is a small, but statistically significant, adverse effect on bone mineral density, especially in postmenopausal women. However, these and other authors have noted that data on the risk of fractures associated with levothyroxine are so far scanty.
Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29041-X © 2007 Elsevier B.V. All rights reserved.
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(SED-15, 3387; SEDA-26, 458; SEDA-27, 442; SEDA -28, 506)
DoTS classification: Reaction: Agranulocytosis due to thionamides Dose-relation: Collateral Time-course: Intermediate Susceptibility factors: None known Drug-induced agranulocytosis remains the most feared and indeed life-threatening disorder associated with thionamide therapy, with a reported mortality of 5–15%. A previously described but still important study in the UK used drug prescribing data recorded on the General Practice Research Database to identify the incidence of idiosyncratic neutropenia and agranulocytosis (6C ). The incidences of neutropenia and agranulocytosis in England and Wales were estimated to be 120 and 7 cases per million per year respectively. Current users of drugs classed as “thyroid inhibitors” had the highest adjusted odds ratios for neutropenia (adjusted OR = 35; 95%CI = 12, 100) and for agranulocytosis (OR = 21; 95%CI = 3.3, ∞) compared with other classes of drug associated with this complication. The increased risk of neutropenia was highest in those who had received two or three prior prescriptions (OR = 58; CI = 7.4, 454), compared with one prior prescription (OR = 14; CI = 1.6, 119) or those who had received four or more prior prescriptions (OR = 34; 7.7, 154). The increased risk of neutropenia associated specifically with carbimazole was higher in those taking 20 mg/day or more (OR = 33; CI = 8.0, 136), compared with those taking 5– 15 mg/day (OR = 17; CI = 4.2, 72).
Thyroid hormones and antithyroid drugs
Chapter 41
Another important UK study has examined data spontaneously reported to the Medicines and Healthcare products Regulatory Agency through the Yellow Card system (7C ). Between 1981 and 2003 there were 5.23 million prescriptions for thionamide drugs in England and Scotland, 94% of which were for carbimazole. Neutrophil dyscrasias (agranulocytosis and neutropenia) accounted for 49% of all deaths ascribed to these drugs. They were more frequently fatal in those over 65 years, and since 1981 reports of neutrophil dyscrasias were significantly more frequent per prescription of propylthiouracil than carbimazole. The latter finding may reflect a genuine difference in risk, relative unfamiliarity with the use of propylthiouracil, or higher use of this drug in certain patient groups. The findings from these two UK studies support the view that agranulocytosis remains the most important complication of antithyroid drugs, remembering that neutropenia may in part reflect underlying hyperthyroidism rather than an adverse drug effect. A study of 109 cases of antithyroid drug-induced agranulocytosis has introduced the concept of “normal white cell count agranulocytosis” by describing a significant number of cases in whom total white cell counts were normal despite the presence of symptomatic agranulocytosis (8c ). This observation highlights the importance of measuring neutrophil counts in addition to total white cell count if there is clinical suspicion of bone marrow suppression. Agranulocytosis is not the only hematological complication of thionamide therapy. • A 53-year-old took methimazole 30 mg/day for 3 weeks and developed aplastic anemia associated with an increased peripheral blood lymphocyte count and a hypocellular bone marrow with plasmacytosis (9A ).
Immunologic It is well recognized that antithyroid drugs, and especially propylthiouracil, can be associated with development of antineutrophil cytoplasmic antibody (ANCA)positive vasculitis, often manifesting as renal disease. Atypical presentations, with pyoderma gangrenosum (10A ) and progressive bilateral sensorineural hearing loss (11A ), have been described in separate case reports of subjects taking propylthiouracil.
521 The prevalence of ANCAs and their relation to drug therapy have been examined in a consecutive series of 407 patients with Graves’ disease compared with 200 cases of autoimmune hypothyroidism and 649 controls (12C ). The prevalence of ANCA, as measured by immunofluorescence, was significantly increased in those with Graves’ disease (20%) compared with euthyroid controls (4.6%), as was the prevalence of specific myeloperoxidase (MPO)ANCA, measured by ELISA. The prevalence of ANCA was more strongly associated with propylthiouracil (RR = 7.3; CI = 4.2, 12.9) than carbimazole (RR = 2.2; CI = 1.8, 2.8) when compared with controls, although there was still a positive association with carbimazole. ANCA positivity was not increased in patients with autoimmune thyroiditis. These findings suggest that the altered immune environment associated with autoimmune thyroid disease is not itself sufficient to increase the risk of development of ANCAs, but that thionamide therapy is required; the risk is higher with propylthiouracil than with carbimazole. Anti-MPO antibodies have been studied in subjects with propylthiouracil-induced vasculitis or primary systemic vasculitis; there was a potential difference in epitope recognition (13c ). Teratogenicity The issue of whether antithyroid drug administration in early pregnancy is associated with congenital abnormalities remains unclear. Aplasia cutis congenita and choanal atresia have been reported in association with maternal carbimazole therapy, suggesting a causative link either with the drug or with underlying hyperthyroidism. A further case of aplasia cutis has been described in an infant of a mother with Graves’ disease exposed to methimazole (40 mg/day) for the first 6 weeks of gestation (14c ). Three further cases of choanal atresia have also been described in association with methimazole exposure in early fetal life (15c ). These cases continue to highlight a possible link between carbimazole, or its active metabolite methimazole, and congenital abnormalities, and they reinforce the view that propylthiouracil is the drug of choice in early pregnancy. However, it should be noted that one of the major hazards of antithyroid drug use in pregnancy is over-treatment, and hence induction of fetal hypothyroidism and goiter.
522 • Fetal hydrops and goiter occurred at 29 weeks of gestation after the mother had taken propylthiouracil 200 mg/day for Graves’ disease (16c ). Although the mother was biochemically euthyroid, fetal blood sampling showed hypothyroidism, with a raised serum TSH. Both the fetal hydrops and goiter regressed after withdrawal of maternal propylthiouracil and intra-amniotic administration of levothyroxine.
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It is important to monitor maternal thyroid status carefully and to use the lowest possible dose of antithyroid drug sufficient to maintain maternal euthyroidism.
References 1. Kaufman SC, Gross TP, Kennedy DL. Thyroid hormone use: trends in the United States from 1960 through 1988. Thyroid 1991;1(4):285–91. 2. Parle JV, Franklyn JA, Cross KW, Jones SR, Sheppard MC. Thyroxine prescription in the community: serum thyroid stimulating hormone level assays as an indicator of under treatment or over treatment. Br J Gen Pract 1993;43(368):107–9. 3. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med 2000;160(4):526– 34. 4. Stathatos NWL. Effects of thyroid hormone on bone. Clin Rev Bone Mineral Metab 2005;2:135– 50. 5. Uzzan B, Campos J, Cucherat M, Nony P, Boissel JP, Perret GY. Effects on bone mass of long term treatment with thyroid hormones: a meta-analysis. J Clin Endocrinol Metab 1996;81(12):4278–89. 6. Van Staa TP, Boulton F, Cooper C, Hagenbeek A, Inskip H, Leufkens HG. Neutropenia and agranulocytosis in England and Wales: incidence and risk factors. Am J Hematol 2003;72(4):248– 54. 7. Pearce SH. Spontaneous reporting of adverse reactions to carbimazole and propylthiouracil in the UK. Clin Endocrinol (Oxf) 2004;61(5):589–94. 8. Tajiri J, Noguchi S. Antithyroid drug-induced agranulocytosis: special reference to normal white blood cell count agranulocytosis. Thyroid 2004;14(6):459–62. 9. Yamamoto A, Katayama Y, Tomiyama K, Hosoai H, Hirata F, Kimura F, Fujita K, Yasuda H. Methimazole-induced aplastic anemia
10.
11.
12.
13.
14.
15.
16.
caused by hypocellular bone marrow with plasmacytosis. Thyroid 2004;14(3):231–5. Hong SB, Lee MH. A case of propylthiouracilinduced pyoderma gangrenosum associated with antineutrophil cytoplasmic antibody. Dermatology 2004;208(4):339–41. Sano M, Kitahara N, Kunikata R. Progressive bilateral sensorineural hearing loss induced by an antithyroid drug. ORL J Otorhinolaryngol Relat Spec 2004;66(5):281–5. Harper L, Chin L, Daykin J, Allahabadia A, Heward J, Gough SC, Savage CO, Franklyn JA. Propylthiouracil and carbimazole associatedantineutrophil cytoplasmic antibodies (ANCA) in patients with Graves’ disease. Clin Endocrinol (Oxf) 2004;60(6):671–5. Ye H, Zhao MH, Gao Y, Guo XH, Wang HY. Anti-myeloperoxidase antibodies in sera from patients with propylthiouracil-induced vasculitis might recognize restricted epitopes on myeloperoxidase molecule. Clin Exp Immunol 2004;138(1):179–82. Barbero P, Ricagni C, Mercado G, Bronberg R, Torrado M. Choanal atresia associated with prenatal methimazole exposure: three new patients. Am J Med Genet A 2004;129(1):83–6. Karg E, Bereg E, Gaspar L, Katona M, Turi S. Aplasia cutis congenita after methimazole exposure in utero. Pediatr Dermatol 2004;21(4):491– 4. Yanai N, Shveiky D. Fetal hydrops, associated with maternal propylthiouracil exposure, reversed by intrauterine therapy. Ultrasound Obstet Gynecol 2004;23(2):198–201.
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Insulin, other hypoglycemic drugs, and glucagon
INSULIN (SED-15, 1761; SEDA-26, 461; SEDA-27, 446; SEDA-28, 509) Respiratory Pulmonary edema secondary to hypoglycemia was reported particularly in the 1930s when insulin shock treatment was used for schizophrenia. It is less common nowadays, but has been reported after insulin overdose (1A ). Metabolism Hypoglycemia In a 12-month open study of 64 patients with type 2 diabetes (mean age 58 years) who used either once-daily bedtime NPH insulin + tablets or twice-daily 30% soluble + 70% NPH, there was less hypoglycemia in the former (2.7 hypoglycemic events per person compared with 4.3); the improvement in HBA1c was similar (2c ). Weight gain was also less in those who used once-daily NPH (1.3 kg compared with 4.2 kg). The use of insulin during intensive therapy for critically ill patients has been reviewed (3R ). In a safety study from the GIST (poststroke hyperglycemic management) trial in 25 patients using a GKI (glucose, potassium, insulin) infusion one patient required therapy for symptomatic hypoglycemia (4c ). Of 452 patients, mean age 75 years, 20 had blood glucose concentrations below 4 mmol/l within 30 minutes of stopping the GKI infusion and required intravenous dextrose. The patients had been randomized to GKI infusion or saline to maintain blood glucose concentrations at 4– 7 mmol/l, and only 69 of the 452 had type 2 diabetes. Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29042-1 © 2007 Published by Elsevier B.V.
In 1500 patients in intensive care, there was hypoglycemia (4 mmol/l and less) in 5.2% of the intensively treated group and 0.8% of those who received conventional therapy (3R ). It has been reported that 11% of drug errors are from insulin administration errors and it has been recommended that frequent checks be made of infusion systems (3R ). Electrolyte balance Hypokalemia occurred in 29 children undergoing insulin tolerance tests; the mean serum potassium concentration at the start was 4.1 mmol/l, falling to a mean of 3 mmol/l at 30 minutes (5Ac ). Ten children had a serum potassium concentration below 2.9 mmol/l and one had a concentration of 2.2 mmol/l. There were no cardiac events. • An 8-year-old girl had an insulin tolerance test with 0.05 IU/kg to assess growth hormone concentrations. The blood glucose concentration fell to 0.9 mmol/l and she was given intravenous dextrose. She had a generalized seizure and developed ventricular flutter. The serum potassium concentration was 2.6 mmol/l. Catecholaminergic polymorphous ventricular tachycardia was later diagnosed.
Fluid balance Insulin edema, a syndrome of unidentified origin that occurs in patients with either type 1 or type 2 diabetes after the introduction or intensification of insulin treatment, has been reviewed (6R ). In studies in the 1970s peripheral edema developed in 15 of 86 middleaged insulin-treated patients (7C ) and between 4 and 10% of intensively treated people with type I diabetes (8C ). In more recent studies of patients with type 2 diabetes, 5.4% of 408 patients treated with insulin developed edema compared with 15% of those who received insulin and a glitazone. In a further study edema occurred in 4.8% of patients who used rosiglitazone alone (9S ). Insulin can cause edema that can become clinically significant, particularly when it is combined with other therapies that cause edema.
523
524 • A 39-year-old man developed type 1 diabetes and lost 9 kg over 6 months (10AR ). He was treated with intravenous fluids and insulin. Within 1 month he developed bilateral edema to the knees. The jugular venous pressure was not raised.
Liver Four girls aged 11–14 years with poorly controlled type 1 diabetes had hepatomegaly and raised transaminase activities up to 30 times the upper limit of the reference range (11A ). Their diabetes was poorly controlled (HBA1c 9.2–15%) despite high doses of insulin (1.3–2.2 units/kg/day). After admission for diabetes control their insulin requirements fell to 0.9–1.2 units/day and their liver function normalized within days. A biopsy in one case showed abundant deposits of glycogen. In these patients diabetes was poorly controlled, as shown by the HbA1c , but the doses of insulin were high. Because insulin promotes glycogenesis, the authors suggested that when high blood glucose concentrations are treated intermittently with high doses of insulin, glucose is driven into the liver, which then promotes abnormal liver function. When insulin is used regularly, less insulin is needed and the liver problem resolves. This is in contrast to nonalcoholic steatohepatitis (NASH), which does not resolve promptly. Susceptibility factors Renal disease In renal insufficiency the renal metabolism of insulin is impaired and generation of glucose reduced (12A ). • A 64-year-old man who had had type 2 diabetes for 15 years used insulin 35 units/day without problematic hypoglycemia, but within 2 weeks had three episodes. He was found to have developed renal insufficiency secondary to diclofenac and his serum creatinine concentration had increased to 440 µmol/l.
Drug administration route Subcutaneous Injection of insulin into abnormal subcutaneous tissues can result in poor control of blood glucose (13A ). • A 42-year-old man who had had type 1 diabetes for 24 years had deteriorating blood glucose control despite increasing insulin doses (HBA1c increased from 11% to 17%). He was injecting into two areas that contained 4 cm hard woody nodules. Biopsy showed collagen with fibroblasts and necrosis. When he avoided the areas his blood glucose improved with reduced insulin doses.
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The authors went on to audit 73 consecutive patients; 32 had clinical lipohypertrophy and a further two had hard nodular lumps. Continuous subcutaneous insulin infusion (CSII) Continuous subcutaneous insulin infusion (CSII) has been compared with multiple daily injections of insulin in a randomized study in 32 patients, mean age 13 years, over 16 weeks (14C ). Of the 16 patients who used CSII one returned the pump twice and one returned the pump once, in both cases for pump software errors. Medtronic MiniMed 508 or Paradigm 511 pumps were used in the study. In two randomized crossover trials metabolic deterioration occurred earlier and was of greater amplitude with insulin lispro than with regular insulin when a pump was discontinued (15R ). However, when the pump was restarted, insulin lispro was more effective than regular insulin in correcting metabolic deterioration. CSII is associated with infections at the site of infusion, about 40 episodes per 100 patient years (15c ). One-third required oral antibiotics. Surgical drainage was very rarely needed (16r ). Lipoatrophy, although rare, has been reported in patients using both regular and lispro insulin in CSII pumps (17A , 18A ). Inhalation Insulin-binding IgG antibodies are found in about 75% of patients with type 2 diabetes using inhaled insulin (19r ). This is more than one would expect from the use of subcutaneous insulin. The antibodies appear to plateau after 1 year. There are no obvious clinical effects. In an open study of 107 patients with type 2 diabetes using the AERx insulin diabetes management system (n = 54) or subcutaneous insulin (n = 53), the number of people with insulin antibodies increased from 6% to 35% in those who used the AERx insulin diabetes management system (20c ). The number of patients with antibodies remained stable at about 10% in those who used subcutaneous insulin. There were no obvious clinical consequences. Similar results were found in a study of patients with type 1 diabetes: 29% of those who used inhaled insulin compared with 3% of those who used subcutaneous insulin (21c ). Most trials of inhaled insulin exclude smokers and patients with severe asthma or chronic obstructive pulmonary disease. Mild to moderate cough is a common adverse effect (19r ).
Insulin, other hypoglycemic drugs, and glucagon
Smoking can reduce the dosage requirements of inhaled insulin, because of increased permeability of the alveolar capillary barrier (22R ). A reduction in carbon monoxide diffusion capacity has been reported in phase III trials with an insulin aerosol delivery system, Exubera. In further studies to investigate this, the changes in lung function were transient or reversible. In patients who used AERx for 12 weeks there were no changes in lung function (23R ). The risk of hypoglycemia with inhaled insulin has been reported to be similar to that with subcutaneous insulin (22R ). In an open study of 107 patients with type 2 diabetes, mean age 58 years, using liquid insulin aerosol droplets + subcutaneous NPH insulin (n = 54) compared with Actrapid + NPH (n = 53) for 24 weeks, there were three major episodes of hypoglycemia in two patients using inhaled insulin and none in the other group (20c ). Of 335 patients with type 1 diabetes randomized to receive preprandial inhaled insulin as a dry powder formulation via an aerosol delivery system (Exubera) plus bedtime subcutaneous Ultralente insulin, or to continue NPH and regular insulins subcutaneously, 170 received inhaled insulin (mean age 33 years) (21c ). Six discontinued inhaled insulin, one because of mild cough, two because of hypoglycemia, and three because of insufficient responses. The risk of hypoglycemia was slightly lower in those who used inhaled insulin, at 8.6 events per month compared with 9.0 events per month in the conventional insulin group. Both powdered insulin formulations and liquid inhaled insulin formulations are being developed. There have been no direct comparisons of these formulations, and it is therefore difficult to make definitive statements about whether one is superior to the other (23R ). Further information will need to be obtained about the possible long-term adverse effects of inhaled insulin.
525
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Weakness, headache, ataxia, thirst, dry mouth, and nausea were reported, among other symptoms.
NEW ULTRASHORT-ACTING INSULINS (SEDA-26, 463; SEDA-27, 449; SEDA-28, 512)
Insulin lispro
(SED-15, 1788)
Skin Lipoatrophy has previously been reported with lispro (SEDA-27, 449). • A 35-year-old woman with type 1 diabetes was transferred after 7 years to lispro subcutaneously tds and NPH twice daily (25A ). Within 2 years she developed lipoatrophy and further lipoatrophy at another site 6 months later.
Pregnancy Maternal and fetal outcomes have been investigated when insulin lispro has been used during pregnancy (15R ). Insulin lispro is unlikely to cross the placenta when used in a single standard dose. Lispro was not found in the cord blood of neonates whose mothers had received a continuous intravenous infusion of lispro. These data and data from controlled studies showing similar outcomes in women treated with conventional insulin are reassuring. In a prospective comparison in 69 pregnant women of lispro (n = 36) with conventional insulin (n = 33), there was no adverse impact on the progression of diabetic retinopathy (15R ).
LONG-ACTING INSULINS (SEDA-26, 463; SEDA-27, 450; SEDA-28, 513)
Insulin detemir Oral In a phase I trial of oral modified insulin (HIM 2), 16 patients (mean age 37 years) with type 1 diabetes using CSII over 2 separate days used basal CSII on one day and basal CSII and oral insulin on another (24c ). There were 58 adverse events in 15 patients, although it was not clear whether they were drug-related.
(SED-15, 1785;
SEDA-28, 513) Metabolism Phase 3 trials have suggested that insulin detemir is associated with less weight gain (0.4 kg) than NPH insulin (1.3 kg); the mechanism is uncertain (26R ).
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OTHER HYPOGLYCEMIC DRUGS (SEDA-26, 466; SEDA-27, 452; SEDA-28, 514)
ALPHA GLUCOSIDASE INHIBITORS (SED-15, 85; SEDA-26, 466; SEDA-27, 452; SEDA-28, 514)
Acarbose Gastrointestinal A meta-analysis of seven double-blind, randomized, placebo-controlled studies in which acarbose was used for a minimum of 52 weeks for the management of type 2 diabetes has shown that the frequency of the most common adverse events of flatulence, diarrhea, and abdominal pain varied from country to country: 53% of those taking acarbose reported symptoms in Germany compared with 73% in Canada (27M ). The frequency of adverse effects with placebo was also higher in Canada (39%) than in Germany (29%).
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co-administered with insulin. It received FDA approval in 2005 for both type 1 and type 2 diabetes. Placebo-controlled studies In 18 subjects with type 1 diabetes, mean age 37 years, who received in random order on separate days pramlintide 60 micrograms or placebo plus their usual doses of regular insulin, hypoglycemia (pramlintide 28% versus 16%) and mild nausea (17% versus 11%) were the most common adverse effects (30c ). Nausea has also occurred in other long-term studies (29R ). Weight loss rather than weight gain has been reported in association with reductions in HBA1c concentrations in patients with type 2 diabetes. Whether this relates to a reduction in insulin dose while using pramlintide, especially in those who are more obese, is uncertain.
BIGUANIDES
(SED-15, 506; SEDA-26, 467; SEDA-27, 453; SEDA-28, 514)
Metformin Miglitol Gastrointestinal In 33 patients with type 2 diabetes treated with sulfonylureas and insulin who took miglitol 50 mg bd for 1 week and then over the next month increased the dose to 50 mg tds, 15% developed adverse effects (6% diarrhea, 6% abdominal distension), which disappeared within 3 weeks of continuing therapy (28c ).
Metabolism Hypoglycemia is uncommon with metformin. When it does occur it should lead to a search for other potential problems. • A 72-year-old man taking metformin 1 g bd for type 2 diabetes began to have episodes of hypoglycemia, which resolved on stopping the metformin; he also had anterior pituitary failure (31A ).
Metformin and lactic acidosis AMYLIN ANALOGUES
(SEDA-27,
453; SEDA-28, 514)
Pramlintide Amylin is a peptide hormone that is co-secreted with insulin from pancreatic beta cells. Its actions include delayed gastric emptying, inhibition of glucagon secretion, and reduced food intake. Pramlintide is an amylin analogue (29R ). It is administered subcutaneously, but it precipitates above pH 5.5 and therefore cannot be
Case reports Further cases of lactic acidosis attributed to metformin have been reported. • A 42-year-old man developed nausea and vomiting and felt suicidal. He had type 2 diabetes and was taking metformin (32A ). His blood lactate concentration was 8.9 mmol/l, bicarbonate 16 mmol/l, and pH 7.2. Severe hypotension required intensive care. The lactate concentration rose to 22 mmol/l and the bicarbonate fell to 6.7 mmol/l and the pH to 6.89. The metformin concentration was high at 191 mg/l. He survived, having been treated with intermittent hemodialysis.
Insulin, other hypoglycemic drugs, and glucagon • A 61-year-old woman developed a bradydysrhythmia after a cardiac arrest (33AM ). Her lactate concentration was 18 mmol/l, pH 6.60, blood glucose 19 mmol/l, and creatinine 1136 µmol/l. She had a 5-year history of type 2 diabetes treated with glimepiride 3 mg/day and metformin 850 mg tds, and 4 months before admission had had a serum creatinine concentration of 1.1 mg/dl. In the few days before admission she had had abdominal pain, nausea, and a speech disorder. She was treated with hemodialysis, and 6 weeks later the creatinine was 0.54 mg/dl. Further information about events leading to the acute renal insufficiency was not given, but a diagnosis of metforminassociated lactic acidosis was made.
There is no doubt from reports such as this in people who take overdoses that metformin can cause lactic acidosis. In a review of enquires to a poison center relating to metformin between 1995 and 2003 there were 109 enquires, of which 62 were for attempted suicide and 47 for adverse effects; 14 patients had had lactic acidosis (33AM ). Eight were taking metformin as regular therapy, of whom one died; of six who had attempted suicide, three died. Reviews The questions “Does metformin cause lactic acidosis?” (34r ) and “What is the risk of lactic acidosis accompanying metformin therapy for patients with type 2 diabetes?” (35r ) have been posed and answered using data from a Cochrane review (SEDA-28, 516). The reports suggested that there was no evidence of an association between metformin and lactic acidosis. In another review it was suggested that the risk of lactic acidosis when metformin is used as recommended is close to zero (36r ). The author discussed the COSMIC study, which compared metformin treatment for 1 year (n = 7227) with usual care with other antidiabetic agents (n = 1505). There were no cases of lactic acidosis. The findings in controlled trials contrast with case reports of lactic acidosis. About one million patients have received metformin in the USA and the FDA has received 47 reports of lactic acidosis (20 fatal). Of these, 43 patients had renal insufficiency or susceptibility factors for lactic acidosis, such as congestive cardiac failure. Only four cases appeared to have no other susceptibility factors, one of which may have been precipitated by urinary sepsis; none of these four died. Six experts in intensive care or metabolic disease reviewed all case reports of lactic acidosis from 1957 to 1999—37 articles reporting
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80 cases (37M ). To be assessed the reports had to meet strict criteria, including: a diagnosis of type 2 diabetes, metformin therapy before lactic acidosis, a pH of 7.35 or less, or a plasma bicarbonate concentration below 22 mmol/l and a lactic acid concentration of at least 5 mmol/l. Because of lack of information, 33 cases were excluded. There were other susceptibility factors for lactic acidosis besides metformin in 46 of 47 cases. Only 13 of the 47 cases were classified as probably due to metformin by at least three experts. The authors suggested a rethink about the relation between lactic acidosis and metformin. However, they still recommended withdrawing therapy in acute renal insufficiency and when contrast dyes are used for radiological investigation. In a review of reports to the Australian Adverse Drugs Reactions Advisory Committee between 1985 and 2001 there were 48 cases of lactic acidosis with metformin (38r ). In 35 of the 48 cases known susceptibility factors were identified. The estimated frequency was one case of lactic acidosis in 30 000 patients taking metformin. The authors discussed the arbitrary cut-off point of a creatinine concentration of 150 µmol/l often set for withdrawal of metformin. They suggest that the concentration should be individualized and that age, muscle mass, and protein turnover should also be considered. They recommended using the Cockcroft–Gault equation to estimate creatinine clearance, and an absolute cut-off point of 30 ml/minute, below which metformin should be withdrawn. In patients with a creatinine clearance of 30–50 ml/minute there should be caution. Metformin should be withdrawn during significant intercurrent illnesses and when using iodinated contrast agents. Skin Erythema multiforme has been attributed to metformin after 4 days of therapy in a 58year-old man with type 2 diabetes; the rash resolved within 2 weeks of stopping the drug (39A ). Pregnancy Metformin crosses the placenta, and although there is no evidence that it is not safe in pregnancy there are insufficient data to say that it is (40r ). In an audit in Auckland there was no increase in perinatal mortality or pre-eclampsia (41c ). The MIG (metformin in gestational diabetes) prospective randomized
528 comparison of metformin and insulin aims to recruit 750 women; 70 have been recruited so far without serious adverse events in the metformin arm. In a review of 60 publications on metformin and pregnancy malabsorption of vitamin B12 , which occurs in non-pregnant women, was thought to be a potential problem (42R ). The data did not suggest an increased risk of teratogenesis. Teratogenicity In 126 infants born to 109 mothers with polycystic ovary syndrome who conceived while taking metformin and continued to take it during pregnancy, there were no differences in infant growth up to 18 months of age or in motor and social development (43c ). The doses during pregnancy were 2.55 g/day (n = 74), 1.5–2 g/day (n = 43), and 1 g/day (n = 5). In 18 pregnancies the metformin was stopped at a median of 12 weeks because the obstetrician did not want it to continue. Preeclampsia occurred in five of 122 pregnancies (4.1%), which was no different to community controls (nine of 252 (3.6%)). Drug formulations Adverse effects are more likely to occur with metformin at the start of therapy. In retrospective case note review comparison of modified-release and immediaterelease metformin 9.2% of those newly started on modified-release metformin (n = 65) had gastrointestinal adverse effects compared with 20% of those who started on immediate-release metformin (n = 363) (44c ). The main gastrointestinal adverse effect was diarrhea. The mean doses were 1258 mg/day for modified-release metformin and 1282 mg/day for immediaterelease metformin.
Incretin mimetics Incretins are compounds that increase insulin secretion from the pancreas in a glucose-dependent manner; they are therefore potential therapies for the treatment of diabetes mellitus. Glucagon-like peptide-1 (GLP-1) (30 amino acids) is a naturally occurring incretin. It is largely produced in the distal ileum and colon in response to food that contains carbohydrate and fat. Other incretins include gastric
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inhibitory polypeptide (GIP). The half-life of GLP-1 is only minutes, as it is rapidly metabolized by dipeptidyl peptase IV, which is another therapeutic target. Other actions of GLP-1 include delayed gastric emptying, appetite suppression, and increased beta cell mass. There is suppression of raised glucagon concentrations, but the counter-regulatory response remains intact. Subcutaneous GLP-1 also has a short halflife (about 30 minutes) and so longer-acting GLP-1 receptor agonists are being developed. These drugs are known as incretin mimetics. Exenatide (39 amino acids) is the first to have received FDA approval. Liraglutide (32 amino acids) is undergoing trials. Exenatide is injected subcutaneously into the thigh, abdomen, or upper arm. It is administered twice daily. The pharmacokinetics of exenatide 10 micrograms subcutaneously are: Cmax 211 pg/ml, tmax median 2.1 hours, apparent volume of distribution 28 liters, clearance 9.1 l/hour, terminal half-life 2.4 hours. Elimination is by glomerular filtration followed by proteolytic degradation. The clearance is not affected by mild or moderate renal impairment. However, clearance is reduced in end-stage renal insufficiency and dialysis. It is recommended that exenatide should not be used in such patients. Liraglutide is also injected subcutaneously, but once daily because of its longer half-life. Incretin mimetics are an exciting development, because when used alone they do not promote hypoglycemia, as their actions on insulin and glucagon are strictly glucose dependent. They are accompanied by weight loss, and they may preserve beta cell mass. Reviews of incretin mimetics (45R , 46R ) have suggested that nausea and vomiting are adverse effects common to all those currently in clinical trials. The adverse effects occur transiently and in association with peak plasma concentrations of glucagon-like peptide (GLP)-1. The doses of both exenatide and liraglutide that have maximum glucose lowering effects are similar to the doses that are associated with these adverse effects. Metabolism Hypoglycemia is more common when incretin mimetics are taken with sulfonylureas but not metformin. Many of the actions of GLP-1 and incretin mimetics are glucose dependent and do not on their own provoke hypoglycemia. However, it is thought that because
Insulin, other hypoglycemic drugs, and glucagon
of the ability of sulfonylureas to open KATP channels at low blood glucose concentrations, GLP-1 can augment insulin secretory responses at lower concentrations than it would normally. The same problem may occur when incretin mimetics are combined with meglitinides. Gastrointestinal Both exenatide and liraglutide cause slowed gastric emptying; this may have an effect on the speed of absorption of other drugs (45R ).
Exenatide Patients with type 2 diabetes treated with a sulfonylurea alone, aged 22–76 years, were randomized to placebo (n = 123) or subcutaneous exenatide 5 micrograms bd (n = 254); after 4 weeks 129 patients increased their dose to 10 micrograms bd (47C ). During the 30 weeks of the study 12 subjects had mild to moderate transient abnormalities of creatine kinase. Serious adverse events were no more frequent with exenatide (4% with 10 micrograms and 3% with 5 micrograms) than with placebo (8%). The adverse events that were related to treatment included nausea, which occurred in 49 patients (39%) of those who used 5 micrograms and 66 (51%) of those who used 10 micrograms, compared with 9 (7%) of those who used placebo. The nausea was worst during the first 8 weeks then abated. Other adverse effects included hypoglycemia, dizziness, and a jittery feeling. There was hypoglycemia in 36% of those taking 10 micrograms, 14% of those taking 5 micrograms, and 3% of those using placebo. One subject withdrew owing to hypoglycemia. Weight loss was progressive over 30 weeks and was most apparent in those taking 10 micrograms (−1.6 kg). Those who did not report nausea also lost weight.
Liraglutide Liraglutide is a long-acting incretin mimetic designed for once-daily subcutaneous injection. Phase II trials have been completed and phase III trials are planned. In 190 patients, mean age 57 years, randomized to different doses of liraglutide (0.045–0.75 mg/day) for 12 weeks,
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gastrointestinal events increased with increasing doses; 10 of 135 patients exposed to liguratide reported nausea (five in the highest dose group), compared with 1 of 29 who took placebo (48c ). Diarrhea, vomiting, and constipation also occurred. Most (two-thirds) of the gastrointestinal symptoms resolved within 3 days. Headache was also reported.
MEGLITINIDES (SED-15, 2238; SEDA-26, 468; SEDA-27, 455; SEDA-28, 518) Comparative studies Repaglinide has been compared with nateglinide in an open 16-week study (49c ). Repaglinide was started in a dose of 0.5 mg per meal and increased up to 4 mg per meal if necessary. Nateglinide was started in a dose of 60 mg per meal and increased up to 120 mg per meal. Of those who used repaglinide, 54% achieved an HBA1c concentration of less than 7%, compared with 42% of those who used nateglinide. There were 0.016 hypoglycemic events per patient in those who used repaglinide compared with none in those who used nateglinide. Weight gain was 1.8 kg with repaglinide and 0.7 kg with nateglinide. There were no noticeable differences in the pattern of adverse events, which included constipation, arthralgia, and headache.
Nateglinide Susceptibility factors Age Of 358 patients aged 35–84 years who were given nateglinide over 12 weeks, 115 took 120 mg before main meals (group 1) and 214 took metformin and nateglinide in combination (group 2) (50c ). There were no differences in rates of hypoglycemia. Three patients in group 2 had serious adverse events, one of which was thought to be related to the study drug (details not given). Adverse events included nausea, vomiting, and headache. There was no information about how these events related to age.
Repaglinide Liver Hepatotoxicity has been attributed to repaglinide (51A ).
530 • A 70-year-old man developed diabetes and started to take repaglinide 1 mg tds. After 2 weeks he developed malaise, anorexia, and jaundice. Liver function tests, including bilirubin, were raised. Repaglinide was withdrawn and the liver function tests returned to normal. There were no other obvious causes.
Drug interactions Gemfibrozil has previously been reported to increase plasma concentrations of repaglinide (SEDA-27, 456). However, in a formal study bezafibrate and fenofibrate did not affect the pharmacokinetics or pharmacodynamics of a single dose of repaglinide 0.25 mg (52c ). Rifampicin Studies involving rifampicin and repaglinide have yielded conflicting results, perhaps because of timing and dosages. In one study rifampicin had no effect on the pharmacokinetics and pharmacodynamics of a single dose repaglinide given after 7 days of rifampicin (53C ). In contrast, in another study there was a 57% reduction in the AUC of repaglinide, with a reduction in its effect on blood glucose (54C ). These studies differed in timing and doses. In a more recent study, 12 male volunteers took rifampicin 600 mg/day for 7 days followed by two doses of repaglinide 4 mg 24 hours apart; the AUC for repaglinide was reduced by 50% on day 7, and by 80% on day 8 (55c ). Timing of the drugs may alter the clinical effects. Trimethoprim CYP2C8 and CYP3A4 are involved in the metabolism of repaglinide (56c ). Trimethoprim is a selective inhibitor of CYP2C8. When nine healthy volunteers aged 19–23 years, 8 men) took placebo or trimethoprim 160 mg bd for 3 days followed by 0.25 mg of repaglinide 1 hour after the last dose of trimethoprim, the AUC of repaglinide increased by 61% and the Cmax increased by 41% compared with placebo.
SULFONYLUREAS
(SED-15, 3230; SEDA-26, 469; SEDA-27, 456; SEDA-28, 518)
Glibenclamide Cardiovascular In a randomized study of 48 patients with type 2 diabetes, mean age
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58 years, those who took glibenclamide for 8 weeks had a mean increase in systolic blood pressure of 3.1 mmHg (57c ). In the same study the systolic and diastolic blood pressures fell in those who took rosiglitazone. The authors speculated whether changes in insulin concentrations and sympathetic activity were responsible. Hematologic Anemia has been attributed to glibenclamide (58A ). • After taking metformin 850 mg tds and glibenclamide 5 mg bd for 5 days, a 58-year-old woman of Burkina Faso origin became anemic. The hemoglobin concentration was 9.4 g/dl, the reticulocyte count was 6.6%, and the glucose-6-phsophate dehydrogenase (G6PD) activity was low (0.4 UI/g Hb, reference range 4.0–6.8). Glibenclamide was withdrawn and metformin continued. The hemoglobin rose to 11.5 g/dl.
There have been rare reports of autoimmune hemolytic anemia attributed to glibenclamide and the manufacturer’s product leaflet also mentions reports of pancytopenia. Immunologic Hypersensitivity reactions have been described with glibenclamide. • A 67-year-old man developed Stevens–Johnson syndrome after taking glibenclamide 20 mg/day for 4 weeks, having previously used insulin. He died from hemorrhagic bronchopneumonia. Post mortem examination also showed features of granulomatous arteritis and cholestatic interface hepatitis, suggestive of a hypersensitivity reaction (59A ).
Pregnancy Of 197 patients with gestational diabetes, 73 took glibenclamide, and 59 (81%) achieved satisfactory blood glucose control (60c ). Of these 59, nine had adverse effects, including malaise and weakness (n = 4), nausea (n = 2), lightheadedness (n = 1), and hypoglycemia (n = 2). Glibenclamide was withdrawn in one patient because of adverse effects; 11 of the 59 had babies who weighed over 4 kg. No anomalies were identified, but glibenclamide was started at a mean of 30 weeks. Drug interactions Ciprofloxacin can precipitate hypoglycemia in patients taking glibenclamide. • A 68-year-old man with type 2 diabetes, who was taking glibenclamide 1.25 mg bd, warfarin, furosemide 40 mg/day, fosinopril 10 mg/day,
Insulin, other hypoglycemic drugs, and glucagon clopidogrel 75 mg/day, lovastatin 40 mg/day, and metoprolol XL 50 mg/day, took ciprofloxacin 250 mg bd for 1 day (61A ). He had renal impairment (creatinine 203 µmol/l). On admission he was hypoglycemic with a capillary blood glucose concentration of 1.1 mmol/l (20 mg/dl). The hypoglycemia continued for 24 hours.
There has been a previous report of hypoglycemia in a patient taking glibenclamide and ciprofloxacin (62A ). A similar effect has been reported with another fluoroquinolone, gatifloxacin (63R ). • A 79-year-old man with type 2 diabetes taking glibenclamide 10 mg/day and metformin 2.5 g/day became hypoglycemic after taking one dose of gatifloxacin 400 mg. The hypoglycemia continued for 24–48 hours. • An 84-year-old woman taking glibenclamide 5 mg/day and metformin 2 g/day became hypoglycemic after taking gatifloxacin 400 mg. The hypoglycemia continued for 24–36 hours.
In 48 patients with type 2 diabetes on diet, gatifloxacin reduced blood glucose concentration by 1.1 mmol/l (20 mg/dl) (64C ). In Japan gatifloxacin is contraindicated in patients with diabetes. Low blood glucose concentrations were reported in 75 patients, 58 of who had diabetes (63R ).
Gliclazide Metabolism In a 2-year study in 507 patients, mean age 61 years, the incidence of symptoms suggestive of hypoglycemia was 4.8 per 100 patient years (65c ). Seven patients withdrew after 1 year because of adverse events, which were thought to be unrelated to the gliclazide.
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the hydroxymetabolite was detectable 4–8 hours longer than glimepiride itself. This may be useful in suspected poisoning. The clinical relevance of the hydoxymetabolite is uncertain (68r ). In a meta-analysis of 1444 patients who took glimepiride for a year there was no change in weight (69M ).
Glipizide Drug dosage regimens Continuous exposure to high concentrations of sulfonylureas impairs rather than improves therapeutic efficacy (70R ). The authors suggested that the sulfonylurea receptor is desensitized during long-term therapy. This suggests either that the concentration– effect curve of sulfonylurea drugs is shifted to the right with time or that it is not sigmoidal but bell-shaped. The optimum dosage for a specific drug should not be exceeded. It has been suggested that this might be 10 mg/day for glipizide and 7–10 mg/day for glibenclamide (70R ). In a 3-month crossover study of placebo or glipizide 10, 20, or 40 mg in randomized order, glipizide 10 mg/day produced higher insulin concentrations and lower glucose concentrations than 20 or 40 mg/day (71C ). Drug interactions Drugs that potentiate the actions of sulfonylureas and the mechanisms responsible have been reviewed (72R ). Mechanisms include: • displacement from plasma proteins, e.g. salicylates; • reduced hepatic metabolism, e.g. monoamine oxidase inhibitors; • reduced urinary excretion, e.g. allopurinol; • intrinsic hypoglycemic activity, e.g. alcohol.
Glimepiride Glimepiride has been reviewed (66R , 67R ). It is metabolized by the liver and its active metabolites are excreted by the kidneys. It should be used with caution in patients with renal or liver disease. Metabolism Hypoglycemia appears to be less of a problem with glimepiride than with other sulfonylurea drugs. In nine patients who had severe hypoglycemia associated with glimepiride
THIAZOLIDINEDIONES (GLITAZONES) (SED-15, 3380; SEDA-26, 471; SEDA-27, 457; SEDA-28, 519)
Peripheral edema due to thiazolidinediones In patients who had taken either rosiglitazone (n = 96) or pioglitazone (n = 107) for at least
532 2 months, adverse effects included peripheral edema (33% and 21% respectively), and 7% and 4% respectively had treatment withdrawn (73c ). The edema was not related to dose. Pulmonary edema occurred in two patients taking pioglitazone and three taking rosiglitazone. In another study the combination of a thiazolidinedione with insulin increased the prevalence of edema and the dose of thiazolidinedione was important (74c ). Of 319 patients taking insulin, 13% developed edema when taking rosiglitazone 4 mg/day compared with 16% taking 8 mg/day and 4.7% taking placebo (75C ). In 556 patients taking insulin, edema developed in 18% of those who took pioglitazone 30 mg/day, 13% of those who took 15 mg/day, and 7.0% of those who took placebo (76C ). The authors undertook a retrospective review of 79 subjects taking thiazolidinediones and insulin; 20 had developed edema. The mean dose of pioglitazone was 24 mg/day and rosiglitazone 6 mg/day. The mean time to edema was 135 days. They reported a 77% resolution rate with various interventions. Whether thiazolidinediones need to be withdrawn in patients with edema has been discussed in several papers. • A 58-year-old man with type 2 diabetes and angina, weight 106 kg, taking metformin and insulin took rosiglitazone 2 mg bd, increased to 4 mg bd 4 months later (77A ). HbA1c improved from 9.6% to 8% after a further 2 months, although his weight had increased to 113 kg and he had developed ankle edema. Therapy was continued and furosemide 20 mg/day was added. After a further 2 months the edema had increased, his weight was 115 kg, and HbA1c had improved to 7.5%. The furosemide was increased to 20 mg bd. Two months later his weight had increased further to 117 kg and he was short of breath on exertion. Metformin was withdrawn, furosemide was increased to 80 mg bd, and irbesartan 75 mg bd was added. However, his symptoms worsened. Two weeks later the rosiglitazone was stopped and his symptoms gradually improved. • A 73-year-old man with angina and hypertension had an HbA1c concentration of 16% while taking insulin (77A ). He weighed 114 kg. Since he was unable to take a sulfonylurea or metformin, he was given rosiglitazone 2 mg bd with an increased dose of insulin. Two months later his HbA1c had improved to 11%, his weight had risen to 120 kg, and there was a trace of edema. After 7 months he de-
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veloped paroxysmal dyspnea and bilateral edema. The rosiglitazone was withdrawn and the dose of furosemide was increased. His symptoms improved within 3 months.
There have been other reports of resolution of edema while continuing therapy with thiazolidinediones (78A ). • A 54-year-old obese woman with type 2 diabetes had rosiglitazone 4 mg bd added to insulin and metformin. Five months later she reported shortness of breath on exertion, paroxysmal nocturnal dyspnea, and peripheral edema. One month later a chest X-ray confirmed bilateral pulmonary edema. The dose of rosiglitazone was reduced to 4 mg/day and furosemide 20 mg/day was added. Her symptoms improved. • Ten months after adding rosiglitazone 4 mg bd to insulin and metformin a 68-year-old woman developed shortness of breath on exertion and edema. The rosiglitazone was continued in the same dosage, and her symptoms resolved. • An 80-year-old man taking insulin developed edema 10 months after starting to take rosiglitazone. The rosiglitazone was withdrawn and pioglitazone 30 mg/day started instead. The edema initially improved but then worsened. Furosemide was given and the pioglitazone withdrawn.
These reports suggest that edema can improve with continued therapy of thiazolidinediones, but in some patients reducing or withdrawing therapy is necessary for resolution of symptoms. The time of onset of symptoms suggests that in some patients the edema can occur as part of the natural disease process and that the thiazolidinedione can exacerbate symptoms and impairs the response to diuretic therapy. Fluid retention with thiazolidinediones may be dose-dependent and a class effect (79R ). There is little or no evidence to suggest a direct negative effect on cardiac performance. Because the symptoms may be due to increased permeability of the microcirculation, they may respond more quickly to drug withdrawal than to diuretic therapy. In a retrospective cohort study of interventions for chronic heart failure before and after the use of rosiglitazone in 139 patients aged 66–75 years (mainly men), 20 had received treatment for heart failure before therapy with rosiglitazone and 50 needed it within 6 months of starting therapy (80c ).
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The pre-treatment plasma concentration of natriuretic peptide type B may be a good marker for pioglitazone-induced congestive heart failure but this needs confirmation (79R ).
Pioglitazone Metabolism Weight gain occurs with thiazolidinediones, which cause recruitment and conversion of pre-adipocytes into adipocytes and are therefore adipogenic (79R ). In 18 patients without diabetes, mean age 46 years, who took pioglitazone 30 mg/day for 48 weeks for non-alcoholic steatohepatitis, there was a mean weight gain of 3.5 kg in 72% (81c ). Similarly, in 91 patients with type 2 diabetes who took pioglitazone 30 or 45 mg/day for 1 year there was a mean weight gain of 3 kg, compared with 1.1 kg in the 109 who took glibenclamide (82c ). Liver Hepatotoxicity has been reported with pioglitazone. • A 42-year-old man took pioglitazone 30 mg/day for 6 weeks and developed abnormal liver function tests, which returned to normal 1 month after withdrawal (83A ). • A 63-year-old man was given pioglitazone instead of gliclazide and within 3 months developed jaundice and malaise (84A ). Liver function was deranged, with aspartate transaminase activity of 1984 IU/l, alanine transaminase 455 IU/l, alkaline phosphatase 1053 IU/l, and bilirubin 522 µmol/l. He died 9 days later. Histology showed parenchymal damage with steatohepatitis, including Mallory bodies superimposed on a severely fibrotic liver.
The authors of the second report speculated that this patient had pioglitazone-induced acute liver damage superimposed on chronic liver disease related to diabetes. Susceptibility factors Age Pioglitazone was as effective in those aged over 65 years as in those under 65 years. Adverse events were also similar, with similar numbers of cardiovascular and hypoglycemic events in the studies reviewed (85R ).
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Rosiglitazone Endocrine It has been suggested that thiazolidinediones may be novel candidates for redifferentiation therapy of various cancers. Five patients with papillary or follicular thyroid cancer took rosiglitazone 4 mg/day for 1 month and 8 mg/day for 2 months (86c ). There were increased thyroglobulin concentrations in four. The significance of this increase was uncertain. Although the authors suggested that redifferentiation might have been the cause, thyroglobulin concentrations also increase with increased tumor mass. Metabolism Lipoma formation has been attributed to rosiglitazone. • A 58-year-old HIV-positive man with type 2 diabetes was given rosiglitazone and over the next 3 months developed several dozen lipomas measuring 1–4 cm in diameter. Biopsy showed well circumscribed tumors of normal appearing fat cells, beneath normal-looking skin. The rosiglitazone was withdrawn and the lipomas resolved (87A ).
In a placebo-controlled study in 108 nondiabetic adults with HIV-1 infection and lipoatrophy, rosiglitazone 4 mg/day for 48 weeks had no beneficial effect on the lipoatrophy (88c ). However 30 of those who took rosiglitazone developed hypertriglyceridemia, compared with 20 taking placebo, and 11 developed hypercholesterolemia, compared with four taking placebo. Triglycerides have been reported to increase by a mean of 0.99 mmol/l in patients taking rosiglitazone, with no change in those taking pioglitazone (73c ). A more profound change in triglycerides has also been reported with rosiglitazone, although this is likely to be rare (89A ). • A 64-year-old woman who had taken metformin for 3 years had a high-density lipoprotein concentration of 1.2 mmol/l, which fell to 0.26 mmol/l when she took rosiglitazone. The HbA1c fell from 10.1% to 7.9%. Fenofibrate was added and the HDL concentration fell further to 0.11 mmol/l. Triglycerides, 2.7 mmol/l before treatment, increased to 4.7 mmol/l. Apolipoprotein A1 concentrations were low at 0.14 g/l (reference range 1.1–2.05 g/l). On withdrawing both the rosiglitazone and the fenofibrate the HDL concentration rose to 0.95 mmol/l.
534 • A 64-year-old man took metformin and glipizide. The HbA1c concentration was 11.4%, HDL 0.99 mmol/l, and triglycerides 3.8 mmol/l. Bezafibrate was added and the HbA1c fell to 8.7%, HDL was unchanged at 0.98 mmol/l, and triglycerides fell to 1.9 mmol/l. After starting rosiglitazone 4 mg/day the HDL fell to 0.44 mmol/l, and on increasing the dose of rosiglitazone to 8 mg/day the HDL fell to 0.26 mmol/l, triglycerides rose to 5.2 mmol/l and apo-1 concentrations were 0.27 g/l. On withdrawal of rosiglitazone the HDL returned to 0.98 mmol/l. • A 64-year-old man had rosiglitazone added to his therapy and the HDL concentration fell from 0.90 to 0.31 mmol/l. Triglycerides rose from 4.0 to 8.0 mmol/l. Apo-1 concentrations were reduced (0.57 g/l).
Hypolipoproteinemia is likely to be a rare adverse effect. The measurement of HDL cholesterol and triglycerides before and after staring thiazolidinedione therapy will allow its detection. On withdrawing therapy concentrations return to normal. This effect may be specific to rosiglitazone, as it is becoming apparent that the PPAR-γ agonists vary in their effects. Liver In a review it has been suggested that hepatotoxicity with pioglitazone and rosiglitazone may not be causal but due to confounding medical factors (66R ). For example, hepatotoxicity has been attributed to rosiglitazone, secondary to cardiac failure (90A ). • An 84-year-old man took rosiglitazone 4 mg/day for 11 months in combination with metformin 1 g bd and gliclazide 160 mg bd. He developed abnormal liver function tests, with alanine transaminase activity of 4336 IU/l, which later increased to 7776 IU/l, alkaline phosphatase activity of 358 IU/l, and a normal bilirubin. Serum lactate was high at 8.59 mmol/l. Rosiglitazone was withdrawn and his diabetes was treated with insulin. His liver function normalized within 4 weeks, but he died after developing a chest infection.
The authors speculated about the role of rosiglitazone, suggesting that it may have precipitated congestive cardiac failure, which then led to ischemic hepatitis. A direct hepatotoxic effect was thought to be unlikely. Drug interactions Rosiglitazone is metabolized by CYP2C8 and to a lesser extent by CYP2C9. No unchanged drug is excreted in the urine. Rifampicin induces hepatic and intestinal CYP isozymes. When 10 healthy Korean men aged 22–26 years were given rifampicin
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600 mg/day for 6 days and then rosiglitazone 8 mg on day 7 the plasma AUC was reduced to 65% and the half-life shortened from 3.9 to 1.5 hours compared with placebo (91c ). Similar studies have shown increased plasma concentrations of rosiglitazone after the addition of ketoconazole (92c ) and trimethoprim (93c ).
COMBINATIONS OF ORAL HYPOGLYCEMIC DRUGS Sulfonylureas + metformin Death In the United Kingdom Prospective Diabetes Study a subgroup of patients taking sulfonylurea therapy to which metformin was added appeared to have had excess mortality. Data from 263 general practices in the UK were analysed; 8488 patients took a sulfonylurea initially, to which metformin was added in 1868 (94c ). The crude mortality rates per 1000 person years were 59 and 40 respectively. Metformin was used initially in 3099 patients and a sulfonylurea was added in 867. The crude mortality rates per 1000 person years were 25 and 20 respectively. These results suggest there is no increased mortality risk with a combination of a sulfonylurea and metformin.
Glibenclamide + metformin + rosiglitazone Metabolism Glibenclamide 2.5 mg/day + metformin 500 mg/day in a combination tablet was increased to a maximum of 10 mg/day + 2000 mg/day in patients with type 2 diabetes, mean age 57 years and weight 93 kg; 181 patients also took rosiglitazone and 184 took placebo for 24 weeks (95c ). Rosiglitazone was added to a maximum of 8 mg/day aiming to reduce the HBA1c concentration to less than 7.0%. There was hypoglycemia in 140 patients; 95 (53%) of those who took rosiglitazone reported hypoglycemia compared with 45 (25%) of those who took placebo. One patient taking rosiglitazone withdrew owing to hypoglycemia.
Insulin, other hypoglycemic drugs, and glucagon
HbA1c concentrations were less than 7% in 42% of those taking rosiglitazone compared with 14% of those taking placebo. Weight gain was
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greater in those taking rosiglitazone, 3 kg compared with 0.03 kg.
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45. Nauck MA. Glucagon-like peptide 1 (GLP-1) and incretin mimetics for the treatment of diabetes. Pract Diabetes Int 2005;22:171–9. 46. Gryskiewicz K, Coleman CI. Exenatide. A novel incretin mimetic hormone for the treatment of type 2 diabetes. Formulary 2005;40:86–90. 47. Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD, for the Exenatide-113 Clinical Study Group. Effects of exenatide (exendin4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 2004;27:2628–35. 48. Madsbad S, Schmitz O, Ranstam J, Jakobsen G, Matthews DR, on behalf of the NN2211-1310 International Study Group. Improved glycemic control with no weight increase in patients with type 2 diabetes after once daily treatment with the long acting glucagons like peptide 1 analog liraglutide (NN2211). Diabetes Care 2004;27:1335–42. 49. Rosenstock J, Hassman DR, Maddere RD, Brazinsky SA, Farrell J, Khutoryansky N, Hale PM, for the Repaglinide Versus Nateglinide Comparison Study Group. Diabetes Care 2004;27:1265–70. 50. Weaver JU, Robertson D, Atkin SL, on behalf of the Nateglinide Glycaemic Control Investigators. Nateglinide alone or with metformin safely improves glycaemia to target in patients up to an age of 84. Diabetes Obesity Metab 2004;6:344–52. 51. Nan DN, Hernandez JL, Fernandez-Ayala M, Carrascosa M. Acute hepatoxicity caused by repaglinide. Ann Intern Med 2004;141:823. 52. Kajosaari LI, Backman JT, Neuvonen M, Laitila J, Neuvonen PJ. Lack of effect of bezafibrate and fenofibrate on the pharmacokinetics and pharmacodynamics of repaglinide. Br J Clin Pharmacol 2004;58:390–6. 53. Hartop V, Hansen KT, Thomsen MK. Influence of drugs interacting with CYP3A4 on the pharmacokinetics, pharmacodynamics and safety of the prandial glucose regulator repaglinide. J Clin Pharmacol 2003;43:649–60. 54. Niemi M, Backman JT, Neuvonen M, Neuvonen PJ, Kivisto KT. Rifampicin decreases the plasma concentrations and effects of repaglinide. Clin Pharmacol Ther 2000;68:495–500. 55. Bidstrup TB, Stilling N, Damkier P, Scharling B, Thomsen MS, Brøsen K. Rifampicin seems to act as both an inducer and inhibitor of the metabolism of repaglinide. Eur J Clin Pharmacol 2004;60:109–14. 56. Neimi M, Kajosaari LI, Neuvonen M, Backman JT, Neuvonen PJ. The CYP2C8 inhibitor trimethoprim increases the plasma concentrations of repaglinide in healthy subjects. Br J Clin Pharmacol 2004;57:441–7. 57. Yosefy C, Magen E, Kiselevich A, Priluk R, London D, Volchek L, Viskoper JR. Rosiglitazone improves, while glibenclamide worsens blood pressure control in treated hypertensive diabetic and dyslipidemic subjects via modulation of insulin resistance and sympathetic activity. J Cardiovasc Pharmacol 2004;44:215–22.
Insulin, other hypoglycemic drugs, and glucagon 58. Vinzio S, Andres E, Perrin A-E, Schlienger J-L, Goichot B. Glibenclamide-induced acute haemolytic anaemia revealing a G6PD-deficiency. Diabetes Res Clin Pract 2004;64:181–3. 59. Duncan C, Sommerfield AJ, Nawroz I, Campbell IW. Stevens–Johnson syndrome with visceral arteritis due to sulphonylurea therapy. Pract Diabetes Int 2004;21:195–8. 60. Kremer CJ, Duff P. Glyburide for the treatment of gestational diabetes. Am J Obstet Gynecol 2004;190:1438–9. 61. Lin G, Hays DP, Spillane L. Refractory hypoglycaemia from ciprofloxacin and glyburide interaction. J Toxicol Clin Toxicol 2004;42:295–7. 62. Roberge RJ, Kaplan R, Frank R, Fore C. Glyburide–ciprofloxacin interaction with resistant hypoglycaemia. Ann Emerg Med 2000;36:160–3. 63. Leblanc M, Belanger C, Cossette P. Severe and resistant hypoglycaemia associated with concomitant gatifloxacin and glyburide therapy. Pharmacotherapy 2004;24:926–31. 64. Gajjar DA, LaCreta FP, Kollia GD, Stolz RR, Berger S, Smith WB, Swingle M, Grasela DM. Effect of multiple-dose gatifloxacin or ciprofloxacin on glucose homeostasis and insulin production in patients with non-insulindependent diabetes mellitus maintained with diet and exercise. Pharmacotherapy 2000;20(6 pt 2):S76–86. 65. Drouin P, Standl E, for the diamicron MR study group. Gliclazide modified release: results of a 2 year study in patients with type 2 diabetes. Diabetes Obesity Metab 2004;6:414–21. 66. Korytkowski MT. Sulfonylurea treatment of type 2 diabetes mellitus focus on glimepiride. Pharmacotherapy 2004;24:606–20. 67. Davis SN. The role of glimepiride in the effective management of type 2 diabetes. J Diabetes Comp 2004;18:367–76. 68. Holstein A, Plaschke A, Ptak M, Egberts E-H, Tenberken O, Maurer H. The diagnostic value of determining the hydroxymetabolite of glimepiride in the blood serum in cases of severe hypoglycaemia associated with glimepiride therapy. Diabetes Obesity Metab 2004;6:391–3. 69. Bugos M, Austin T, Atherton T, Viereck C. Long-term treatment of type 2 diabetes mellitus with glimepiride is weight neutral: a meta-analysis. Diabetes Res Clin Pract 2000;50(Suppl 1):S47. 70. Melander A. Kinetics-effect relations of insulinreleasing drugs in patients with type 2 diabetes. Diabetes 2004;53:S151–5. 71. Stenman S, Melander A, Groop P-H, Groop L. What is the benefit of increasing the sulphonylurea dose? Ann Intern Med 1993;118:169–72. 72. Chelliah A, Burge MR. Hypoglycaemia in elderly patients with diabetes mellitus causes and strategies for prevention. Drugs Aging 2004;21:511–30. 73. Hussein Z, Wentworth JM, Nankervis AJ, Proietto J, Colman PG. Effectiveness and side effects of thiazolidinediones for type 2 diabetes: real-life
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experience from a tertiary hospital. Med J Aust 2004;181:536–9. King KA, Levi VE. Prevalence of edema in patients receiving combination therapy with insulin and thiazolidinedione. Am J Health-Syst Pharm 2004;61:390–3. Raskin P, Rendell M, Riddle MC, Dole JF, Freed MI, Rosenstock J, Rosiglitazone Clinical Trials Study Group. A randomised trial of rosiglitazone therapy in patients with inadequately controlled insulin-treated type 2 diabetes. Diabetes Care 2001;24:1226–32. Rosenstock J, Einhorn D, Hershon K, Glazer NB, Yu S, Pioglitazone 014 Study Group. Efficacy and safety of pioglitazone in type 2 diabetes: a randomised placebo controlled study in patients receiving stable insulin therapy. Int J Clin Pract 2002;56:251–7. Singh N. Rosiglitazone and heart failure: long term vigilance. J Cardiovasc Pharmacol Ther 2004;9:21–5. Wang F, Vergara C, Carbino J, Desilets A, Vasquez R. Continuation of thiazolidinedione therapy in patients without left ventricular dysfunction who developed edema and congestive heart failure symptoms. Am J Health-Syst Pharm 2004;61:1604–8. Scheen AJ. Combined thiazolidinedione-insulin therapy should we be concerned about safety? Drug Saf 2004;27:841–56. Marceille JR, Goins JA, Soni R, Biery JC, Lee TA. Chronic heart failure-related interventions after starting rosiglitazone in patients receiving insulin. Pharmacotherapy 2004;24:1317– 22. Promrat K, Lutchman G, Uwaifo GI, Freedman RJ, Soza A, Heller T, Doo E, Ghany M, Premkumar A, Park Y, Liang J, Yanovski JA, Kleiner DE, Hoofnagle JH. A pilot study of pioglitazone treatment for non-alcoholic steatohepatitis. Hepatology 2004;39:188–96. Tan MH, Johns D, Strand J, Hlse J, Madsbad S, Eriksson JW, Clausen J, Konkoy CS, Herz M, for the GLAC Study Group. Sustained effects of pioglitazone vs. glibenclamide on insulin sensitivity, glycaemic control and lipid profiles in patients with type 2 diabetes. Diabetic Med 2004;21:859–66. Arotcarena R, Bigue J-P, Etcharry F, Pariente A. Hepatite aiguë sevère à la pioglitazone. Gastroenterol Clin Biol 2004;28:610–1. Farley-Hills E, Sivasankar R, Martin M. Fatal liver failure associated with pioglitazone. BMJ 2004;329:429. Rajagopalan R, Rerez A, Khan M, Murray FT. Pioglitazone is effective therapy for elderly patients with type 2 diabetes mellitus. Drugs Aging 2004;21:259–71. Philips J-C, Petite C, Willi J-P, Buchegger F, Meier CA. Effect of peroxisome proliferatoractivated receptor δ agonist rosiglitazone on dedifferentiated thyroid cancers. Nucl Med Comm 2004;25:1183–6. Mafong DD, Lee GA, Yu S, Tien P, Mauro T, Grunfeld C. Development of multiple lipomas
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during treatment with rosiglitazone in a patient with HIV-associated lipoatrophy. AIDS 2004;18:1742–4. Carr A, Workman C, Carey D, Rogers G, Martin A, Baker D, Wand H, Law M, Samaras K, Emery S, Cooper DA, for the Rosey investigators. No effect of rosiglitazone for treatment of HIV-1 lipoatrophy: randomised, double-blind placebo-controlled trial. Lancet 2004;363:429– 38. Sarker A, Semple RK, Dinneen SF, O’Rahilly S, Martin SC. Sever hypo-α-lipoproteinemia during treatment with rosiglitazone. Diabetes Care 2004;27:2577–80. Berry P. Severe congestive cardiac failure and ischaemic hepatitis associated with rosiglitazone. Pract Diabetes Int 2004;21:199–200. Park J-Y, Kim K-A, Kang M-H, Kim S-L, Shin JG. Pharmacokinetics and drug disposition. Effect of rifampicin on the pharmacokinetics of rosigli-
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tazone in healthy subjects. Clin Pharmacol Ther 2004;75:157–62. Park J-Y, Kim K-A, Shin J-G, Lee K-Y. Effect of ketoconazole on the pharmacokinetics of rosiglitazone in healthy subjects. Br J Clin Pharmacol 2004;58:397–402. Niemi M, Backman JT, Neuvonen PJ. Effects of trimethoprim and rifampicin on the pharmacokinetics of the cytochrome P450 2C8 substrate rosiglitazone. Clin Pharmacol Ther 2004;76:239–49. Gulliford M, Latinovic R. Mortality in type 2 diabetic subjects prescribed metformin and sulphonylurea drugs in combination: cohort study. Diabetes Metab Res Rev 2004;20:239–45. Dailey GE III, Noor MA, Park J-S, Bruce S, Fiedorek FT. Glycemic control with glyburide/metformin tablets in combination with rosiglitazone in patients with type 2 diabetes: a randomised double-blind trial. Am J Med 2004;116:223–9.
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43 Calcitonin
Miscellaneous hormones (SED-15, 595; SEDA-26, 477;
SEDA-27, 465) Drug formulations The adverse effects of parenteral and intranasal calcitonin have been compared (1R ). Parenteral salmon calcitonin is commonly associated with flushing of the face, ears, hands, and feet within minutes of the injection. Nausea and vomiting can occur within 30 minutes. The flushing needs to be distinguished from the less common but serious and potentially fatal hypersensitivity reactions that have been reported. The nausea, which is mild, usually abates with continued therapy. Intranasal calcitonin is better tolerated; rhinitis of mild or moderate severity is the most frequent adverse effect.
Gonadorelin antagonists (SED-15, 1535; SEDA-26, 478; SEDA-27, 466) The adverse effects of cetrorelix and ganirelix have been reviewed (2R ). Those most commonly reported are headache, fatigue, and injection site reactions. In the development of LHRH antagonists one problem was their ability to induce systemic histamine release; however, structural changes solved this problem (3R ) and no symptoms attributed to systemic histamine release have been reported so far.
Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29043-3 © 2007 Published by Elsevier B.V.
Gonadotropins (gonadorelin and analogues) (SED-15, 1536; SEDA-26, 477; SEDA-27, 465; SEDA-28, 528) Metabolism Premenopausal women who received leuprolide acetate depot 3.75 mg every 28 days for 6 cycles had slightly but statistically significant higher concentrations of total cholesterol, LDL-cholesterol, and HDLcholesterol, and increased insulin resistance (4c ). Whether these changes are clinically significant is not known. Skin Epithelioid granulomata have been attributed to leuprorelin (5A ). • A 73-year-old man with prostate cancer received leuprorelin acetate injections and developed a subcutaneous nodule at the injection site. Histology showed epithelioid granulomata with multinuclear giant cells.
These lesions were suggested to have been caused by a type IV allergic response to the copolymer of lactic and glycolic acids used as a vehicle. Drug dosage regimens Of 247 men with prostate cancer who received goserelin 3.6 mg subcutaneously every 28 days or 10.8 mg every 84 days, 27% and 18% respectively had a rise in serum testosterone concentration to above the castrate range (6c ). Only 1.7% had a testosterone concentration within the age-specific reference range. There were no clinical symptoms of tumor flare reaction. Management of adverse drug reactions The use of gonadorelin analogues is commonly associated with reduced bone mineral density. In 50 premenopausal women with uterine leiomyomas who received leuprolide acetate depot 3.75 mg every 28 days for 18 cycles with raloxifene 60 mg/day, there was a reduction in leiomyoma size with no significant change
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540 in bone mineral density or markers of bone metabolism (7c ). Psychological In 20 women (mean age 67 years) who received intramuscular triptorelin 3.75 mg 6-weekly for endometriosis, nine developed mood disturbance after the second injection and appeared to be cumulative, since the symptoms only started after the second injection and worsened with successive injections (8c ). One woman withdrew after the third injection because of severe irritability.
Somatropin (human growth hormone, hGH) (SED-15, 3163; SEDA-26, 479; SEDA- 27, 466; SEDA-28, 528) Nervous system The National Cooperative Growth Study Multicentre Observational Surveillance Registry started in 1985. It is a postmarketing surveillance programme in children treated with biosynthetic growth hormone from Genentech. Data collected up to January 2002 have shown that the risk of intracranial hypertension is related to the indication for growth hormone (9c ). There were 62 cases per 1000 patient years in children with renal insufficiency, 3.7 cases per 1000 patient years in children with Turner’s syndrome, 1.6 cases per 1000 patient years in children with growth hormone deficiency, and no cases in children with idiopathic short stature. This suggests that a prior condition may be required for the development of intracranial hypertension. Most cases are reversible after withdrawal of growth hormone. • A 13-month-old girl with Turner’s syndrome developed mild papilledema (10A ). At the age of 4 years she was considered for growth hormone therapy and investigation showed intracranial hypertension before therapy was started. • A 6-year-old girl with Turner’s syndrome was treated with growth hormone. There was no papilledema before therapy, but intracranial hypertension was diagnosed at the age of 10 years (10A ).
Metabolism Growth hormone is a counterregulatory hormone and can cause diabetes mellitus. • A 13-year-old boy with Prader–Willi syndrome and steatohepatitis was given growth hormone
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0.23 mg/kg/week (11A ). His HbA1c concentration before treatment was 5.6%. Four weeks later he developed diabetic ketoacidosis. He was given insulin and the growth hormone was withdrawn. Insulin was then gradually withdrawn and blood glucose concentrations remained normal for the next 6 months.
The KIGS/KIMS (Pharmacia International Growth Database) has reported 233 patients with Prader–Willi syndrome, of whom three developed carbohydrate intolerance. Death Nine deaths have been reported in children with Prader–Willi syndrome receiving growth hormone. Pfizer issued a safety warning for growth hormone and Prader–Willi syndrome after reviewing seven deaths in male subjects (12cS ). There was an association with severe obesity and severe respiratory impairment. • A 4-year-old, severely obese boy with Prader– Willi syndrome received growth hormone 0.3 mg/ day for 2 weeks, 0.6 mg/day for 2 further weeks, and then 1 mg/day (0.16 mg/kg/week actual body weight and 0.41 mg/kg/week ideal body weight) (13A ). He started to have headaches within a few weeks of using the highest dosage, which was reduced. The dosage was then increased without recurrence of symptoms to 1 mg/day, but he was found dead 3 days later, 67 days after starting growth hormone.
Tumorigenicity Diamond–Blackfan anemia is rare: only about 400 cases have been reported world wide. Six patients have developed an osteosarcoma, three after receiving growth hormone (14cR ). • A Caucasian girl with Diamond–Blackfan anemia received growth hormone to treat short stature, and 6 weeks later developed pain in the right thigh; an osteosarcoma was diagnosed.
The short time period in this case makes the tumor less likely to have been induced by growth hormone. It is also unlikely that the growth hormone hastened the growth of a preexisting tumor; the mean survival of the other five patients was 1.6 years from the time of diagnosis and this patient was alive 1.6 years after the diagnosis.
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Susceptibility factors Age The use of growth hormone in adults over the age of 60 years without growth hormone deficiency has been reviewed (15R ). The adverse effects were the same as those found in adults deficient in growth hormone: peripheral edema, paresthesia, carpal tunnel syndrome, glucose intolerance, and gynecomastia in men. The adverse effects were dose-related. There were no long-term data available about safety, in particular the risk of cancer. Sex In 47 men and 37 women aged 18–70 years, who received growth hormone 0.0125 mg/kg/day for 1 month and then 0.025 mg/ kg/day in a placebo-controlled trial for 12 months, the dose was adjusted if adverse effects occurred (16c ). The mean serum IGF-1 concentration in women rose into the reference range. In contrast the mean serum IGF-1 concentration in men exceeded the age-adjusted reference range. Arthralgia was more common in men who received growth hormone than placebo (34% versus 10%) and edema in was more common in women (70% versus 40%). Ring size increased in both men (5.4% versus 0.7%) and women (3.5 versus −1.7%). Drug formulations Human growth hormone with a molecular mass of 20 kDa comprises 6– 7% of circulating growth hormone. Rat studies have suggested that 20 kDa growth hormone may have fewer adverse effects than the commonly prescribed 22 kDa variety. In 56 subjects aged 20–64 years with growth hormone deficiency, who received 20 kDa growth hormone, 0.006 mg/kg/day (n = 19), 0.012 mg/kg/day (n = 18), or 0.024 mg/kg/day (n = 19) for 16 weeks, adverse effects were similar to those that occur with 22 kDa growth hormone (17c ). Peripheral edema developed in six patients (31%) who received the lowest dose and in 15 patients (79%) who received the highest dose. Arthralgia, headache, and glucose intolerance also occurred. There were no significant advantages of 20 kDa growth hormone.
SOMATOSTATIN (GROWTH HORMONE RELEASEINHIBITING HORMONE) AND ANALOGUES (SED-15, 3160; SEDA-26, 480; SEDA-27, 467; SEDA-28, 530)
Octreotide Cardiovascular Bradycardia, hypotension, and heart block have been attributed to octreotide (18A ). • A 67-year-old man who was receiving subcutaneous octreotide 100 micrograms bd underwent abdominal laparotomy for metastatic carcinoid. He was given an intravenous bolus of octreotide 100 micrograms 10 minutes after induction and immediately after surgical incision. His heart rate fell to 35/minute and his blood pressure to 85/40 mmHg. He was given ephedrine 20 mg intravenously and recovered. He was given a further bolus of octreotide 100 micrograms 30 minutes later. His heart rate immediately fell to 45/minute and he developed complete heart block. He was given ephedrine 20 mg and glycopyrrolate 0.2 mg intravenously and recovered.
There have been previous reports of bradycardia with octreotide. The authors suggested that intravenous octreotide should be infused slowly when possible. The records of 21 children who received infusions of octreotide (1–2 micrograms/kg/ hour) for 35 gastrointestinal bleeds have been reviewed (19c ). There was one case of asymptomatic bradycardia and one case of a sudden unexplained cardiac event in a patient who appeared to be hemodynamically stable just before the event 5 hours after starting octreotide. Octreotide increases systemic vascular resistance, and bradycardia may be a baroreceptorinduced response. Octreotide also has direct effects on the heart, the main effects being reduced heart rate, reduced myocardial contractility, and slowing of the propagation velocity along the cardiac conduction system. Body temperature Of 12 patients (7 men, 5 women) with malignant mid-gut carcinoid tumors, median age 50 years, who received intramuscular octreotide pamoate 160 mg every 2 weeks for 2 months and then every month for 12 months, six developed unexplained episodic fever (20c ). No infection or cause was found.
542
Melatonin
(SED-15, 2245; SEDA-25, 523; SEDA-28, 531) Melatonin is primarily used as an aid for sleep disorders and to treat circadian rhythm problems, such as jet lag and shift work (21R ).
Drug overdose The Texas Poison Center Network has received reports of 779 cases of exposure to melatonin during 1998–2003 (22S ). The annual number of cases was 114–146 with no annual trend. Melatonin was the only reported exposure in 644 (83%) of the cases. Of the patients whose ages were known, 59% were under 6 years, 14% were 6–19 years, and 27% were over 19 years. The majority of preschool age patients were male, while more of the older patients were female. Most of the exposures to melatonin among children under 6 years were unintentional, while most of the exposures among the older age groups were intentional. Exposure was more likely to occur in the patient’s home than anywhere else. Of the cases with a known outcome, the proportion with at least minor effects rose with increasing age. There were no deaths. The most common effects among the 394 cases during 2000–2003 in whom melatonin was the only exposure were drowsiness or lethargy, which affected 58 (18%). No other categories of clinical effects were reported in more than four cases. These included chest pain, tachycardia, abdominal pain, nausea, vomiting, hypothermia, agitation/irritability, ataxia, confusion, vertigo/dizziness, headache, slurred speech, and tremor.
Parathyroid hormone (PTH) and analogues (SED-15, 2689; SEDA-26, 481; SDA-27, 468; SEDA-28, 531) Reviews of parathyroid hormone have suggested that it is generally well tolerated (23R – 25R ). Nausea, headache, and dizziness are the most frequently reported adverse effects. Hypercalcemia, which is common, is usually mild and asymptomatic. Adverse effects, including hypercalcemia, appear to be dose related in the therapeutic range.
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Tumorigenicity The risk of osteosarcoma in animals receiving parathyroid hormone has been reviewed (25E ). Bone tumors, mainly osteosarcomata, have been reported in rats receiving parathyroid hormone (1–34), but not with parathyroid hormone (1–84). Whether this is a true difference between the drugs is not known.
VASOPRESSIN AND ANALOGUES (SED-15, 3609; SEDA-26, 482; SEDA-27, 469; SEDA-28, 531) Skin Multiple logistic regression analysis has shown that the presence of septic shock and pre-existing peripheral arterial occlusive disease are significant independent risk factors for the development of ischemic skin lesions during vasopressin infusion (26R ). The authors of a review have suggested that low-dose vasopressin should not be given peripherally when treating septic shock owing to the risk of severe skin necrosis that can occur after extravasation (27R ). Drug dosage regimens A review of trials has suggested that vasopressin is more likely to cause adverse effects at doses of 0.04 U/minute or more when it is used to treat septic shock; mesenteric ischemia and cardiac dysfunction and ischemia were particularly associated with high doses (28R ). The authors suggested that limiting the dosage to 0.03 U/minute may minimize these effects. This suggestion has been supported by a retrospective audit of the effects of continuous vasopressin infusion in septic shock in 102 men and women, mean age 53 years (29c ). There were adverse events that may have been linked to vasopressin in 18 patients: cardiac arrest (n = 9); ischemic/mottled digits (n = 8); myocardial infarction (n = 1); and hyponatremia (n = 1). Adverse events occurred with doses of vasopressin of 0.04 units/ minute and over, except in one patient (dose not stated). Further data have come from a review of the use of high doses of vasopressin (mean dose 0.47 U/minute) to replace noradrenaline (26R ). There were reductions in heart rate, cardiac index, and oxygen delivery. The authors recommended that the dose of vasopressin should
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not exceed 0.04 U/minute and that vasopressin should not be used as a single vasopressor agent in septic shock.
Desmopressin (N-deamino-8-D-arginine vasopressin, DDAVP) (SED-15, 1076) Cardiovascular People with hemophilia can develop atherosclerosis, but they are usually protected from ischemic coronary events. However, such events can occur when desmopressin is given. • A 59-year-old man with mild hemophilia A was given a test dose of desmopressin 30 micrograms (0.19 micrograms/kg) in 100 ml of saline by intravenous infusion over 30 minutes (30A ). Shortly afterwards, having had a cigarette, he developed chest pain. An electrocardiogram showed ST elevation, and a myocardial infarction was confirmed.
Cardiovascular evaluation may be appropriate before using desmopressin. Nervous system In 64 women mean age 53 years enrolled in a randomized, placebocontrolled, crossover study of desmopressin 40 micrograms by nasal spray for the treatment of severe daytime urinary incontinence, there were drug-related adverse events in 25 women taking desmopressin and 24 adverse drug reactions in 15 women taking placebo (31c ). The most common adverse event with desmopressin was headache (36%). Nausea occurred in 10%. Electrolyte balance About 900 000 children with primary nocturnal enuresis are treated with tablets and 400 000 with spray annually. Hyponatremia is rare (32r ), possibly as low as 1 per 20 000 patients exposed. • An 11-year-old girl was given desmopressin 10 micrograms by nasal spray per nostril for nocturnal enuresis (33A ). On the second night she took 3 puffs and at 3 a.m. awoke with a tonic–clonic fit. Her serum sodium concentration was 115 mmol/l.
This case highlights the importance of clear guidance for the use of desmopressin when taken for bedwetting: • the prescribed dose should never be exceeded;
543 • if using a nasal spray and uncertain if the spray was successful, never repeat the dose; • fluid intake should be kept to a minimum from one hour before taking the desmopressin and for the following 8 hours; • if there is vomiting or diarrhea desmopressin should be withdrawn; • inform the doctor if starting any other drugs. An analysis of trials reporting the risk of hyponatremia in older adults using desmopressin for nocturia has suggested that the risk is much higher in this group, estimated at 7.6% (34M ). However, the analysis was limited by problems with definitions of hyponatremia, varying ages studied, and the lengths of the studies. This is a similar incidence to another report of 5% (32r ). In this report it was suggested that the highest risk was in those over the age of 65 years, in whom sodium monitoring was recommended. Mineral balance There was a slight but significant increase in calcium excretion in 15 girls and 17 boys, median age 9.8 years, who received desmopressin 30 micrograms by intranasal spray for 4 weeks, withdrawn for 2 weeks, and then continued for at least 3 further weeks (35c ). This is unlikely to be significant in the short term and whether it would have any significance in the long term is uncertain. Hematologic Desmopressin induces factor VIII and von Willebrand factor (vWF) activity, resulting in an increase in ultra-large vWF multimers. In thrombotic thrombocytopenic purpura there is a deficiency in the von Willebrand factor-cleaving protease (ADAMTS13), which is responsible for degradation of vWF multimers. These ultra-large vWF multimers accumulate and facilitate platelet adhesion. • A 42-year-old woman with thrombotic thrombocytopenic purpura received a number of therapies, including desmopressin 20 micrograms in 100 ml of saline over 1 hour. One hour later she developed a fever of 38.4 ◦ C, headache, and an expressive aphasia (36A ).
Pancreas A scientific registry of transplant recipients has been used to determine the effect of cadaveric organ donor treatment with desmopressin on the incidence of pancreas graft thrombosis in clinical pancreas transplantation
544 (37c ). Of 2804 cases with sufficient information between 5 April 1994 and 27 September 2002, 1287 (46%) had received desmopressin. The mean follow up was 1.5 years (1 month to 8.4 years). There was pancreatic graft thrombosis in 4.3%, of whom 5.1% had received desmopressin and 3.5% had not; this was just statistically significant. There was no information about dose, time-course, or duration of desmopressin use. It is not known whether this finding is clinically significant. Susceptibility factors Age Participants in a short-term study were invited to continue in an open study of the longterm use of desmopressin for nocturia (38c ). The study was completed by 95 men aged 24– 88 years and 87 women aged 21–85 years, who took therapy for 11–13 months. The dosage was the dose (0.1, 0.2, or 0.4 mg orally at bedtime) that was found to be optimal during the shortterm study by dose titration. Adverse events were more common in those aged 65 years or
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older, 27% versus 21% in men and 41% versus 19% in women. Hyponatremia was more common, but it was unclear which other events occurred more commonly. The authors recommended monitoring of sodium concentrations, particularly when starting therapy and when changing dose.
Terlipressin Nervous system Six unselected patients (four women), mean age 27 years, with acute liver failure and grade IV hepatic encephalopathy received terlipressin 0.005 mg/kg as a single intravenous bolus (39c ). There was an increase in cerebral blood flow 1 hour after the bolus, which returned to baseline at 5 hours, and an increase in intracranial pressure at 1 hour, which returned to baseline at 2 hours. The authors speculated that terlipressin could have a deleterious effect on cerebral hemodynamics in patients with severe hepatic encephalopathy.
References 1. Munoz-Torres M, Alonso G, Raya PM. Calcitonin therapy in osteoporosis. Treat Endocrinol 2004;3:117–32. 2. Griesinger G, Felberbaum RE, SchultzeMosgau A, Diedrich K. Gonadotropin-releasing hormone antagonists for assisted reproductive techniques. Are there clinical differences between agents? Drugs 2004;64:563–75. 3. Reissman T, Schally AV, Bouchard P, Riethmuller H, Engel J. The LHRH antagonist cetrorelix: a review. Hum Reprod Update 2000;6:322– 31. 4. Palomba S, Russo T, Orio F Jr, Sammartino A, Sbano FM, Nappi C, Colao A, Mastantonio P, Lombardi G, Zullo F. Lipid, glucose and homocysteine metabolism in women treated with GnRH agonist with or without raloxifene. Hum Reprod 2004;19:415–21. 5. Yamano Z, Kusuda Y, Hara S, Shimogaki H, Hamani G. Cutaneous epithelioid granulomas caused by subcutaneous infusion of leuprorelin acetate. A case report. Acta Urol Japan 2004;50:199–202.
6. Zinner NR, Bidair M, Ceneno A, Tomera K. Similar frequency of testosterone surge after repeat injections of goserelin (Zoladex) 3.6 mg and 10.8 mg: results of a randomised open-label trial. Urology 2004;64:1177–81. 7. Palomba S, Orio F Jr, Russo T, Falbo A, Cascella T, Doldo P, Nappi C, Mastrantonio P, Zullo F. Long-term effectiveness and safety of GnRH agonist plus raloxifene administration in women with uterine leiomyomas. Hum Reprod 2004;6:1308–14. 8. Wong AYK, Tang L. An open and randomised study comparing the efficacy of standard danazol and modified triptorelin regimens for postoperative disease management of moderate to severe endometriosis. Fertil Steril 2004;81:1522–7. 9. Wyatt D. Lessons from the National Cooperative Growth Study. Eur J Endocrinol 2004;151:S55– 9. 10. Bala P, McKiernan J, Gardiner C, O’Connor G, Murray A. Turner’s syndrome and benign intracranial hypertension with or without growth hormone treatment. J Ped Endocrinol Metab 2004;17:1243–4.
Miscellaneous hormones
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11. Yigit S, Estrada E, Bucci K, Hyams J, Rosengren S. Diabetic ketoacidosis secondary to growth hormone treatment in a boy with Prader– Willi syndrome and steatohepatitis. J Ped Endocrinol Metab 2004;17:361–4. 12. Allen DB, Carrel AL. Growth hormone therapy for Prader–Willi syndrome: a critical appraisal. J Ped Endocrinol Metab 2004;17:1297–306. 13. Van Vliet G, Deal CL, Crock PA, Robitaille Y, Oligny LL. Sudden death in growth hormonetreated children with Prader–Willi syndrome. J Pediatr 2004;144:129–31. 14. Lee RS, Higgs D, Haddo O, Pringle J, Briggs TWR. Osteosarcoma associated with Diamond–Blackfan anaemia: a case of a child receiving growth hormone therapy. Sarcoma 2004;8:47–9. 15. Toogood AA. The somatopause. An indication for growth hormone therapy. Treat Endocrinol 2004;3:201–9. 16. Hoffman AR, Kuntze JE, Baptista J, Baum HBA, Baumann GP, Biller BMK, Clark RV, Cook D, Inzucchi SE, Kleinberg D, Klibanski A, Phillips LS, Ridgway EC, Robbins RJ, Schlechte J, Sharma M, Thorner MO, Vance ML. Growth hormone (GH) replacement therapy in adult-onset GH deficiency: effects on body composition in men and women in a double-blind, randomised, placebo-controlled trial. J Clin Endocrinol Metab 2004;89:2048–56. 17. Hayakawa M, Shimazaki Y, Tsushima T, Kato Y, Takano K, Chihara K, Shimatsu A, Irie M. Metabolic effects of 20-kilodalton human growth hormone (20k-hGH) for adults with growth hormone deficiency: results of an exploratory uncontrolled multicenter clinical trial of 20k-hGH. J Clin Endocrinol Metab 2004;89:1562–71. 18. Dilger JA, Rho EH, Que FG, Sprung J. Octreotide-induced bradycardia and heart block during surgical resection of a carcinoid tumour. Anesth Analg 2004;98:318–20. 19. Eroglu Y, Emerick KM, Whitingon PF, Alonso EM. Octreotide therapy for control of acute gastrointestinal bleeding in children. J Ped Gastroenterol Nutr 2004;38:41–7. 20. Welin SV, Janson ET, Sundin A, Stridsberg M, Lavenius E, Granberg D, Skogseid B, Oberg KE, Eriksson BK. High-dose treatment with a longacting somatostatin analogue in patients with advanced midgut carcinoid tumours. Eur J Endocrinol 2004;151:107–12. 21. Lamberg L. Melatonin potentially useful, but safety, efficacy remain uncertain. JAMA 1996;276:1011–4. 22. Forrester MB. Melatonin exposures reported to Texas Poison Centers in 1998–2003. Vet Hum Toxicol 2004;46:345–6. 23. Olszynski WP, Davison KS, Adachi JD, Brown JP, Cummings SR, Hanley DA, Harris ST, Hodsman AB, Kendler D, McClumg MR, Miller PD, Yuen CK. Osteoporosis in men: epidemiology, diagnosis, prevention and treatment. Clin Ther 2004;26:15–28.
545 24. Keam SJ, Plosker GL. Prevention and treatment of osteoporosis in postmenopausal women. Dis Manage Health Outcomes 2004;12:19–37. 25. McClung M. Parathyroid hormone for the treatment of osteoporosis. Obstet Gynaecol Surv 2004;59:826–32. 26. Holmes CL, Walley KR. Vasopressin in the ICU. Curr Opin Crit Care 2004;10:442–8. 27. Kam PCA, Williams S, Yoong FFY. Vasopressin and terlipressin: pharmacology and its clinical relevance. Anaesthesia 2004;59:993–1001. 28. Obritsch MD, Bestul DJ, Jung R, Fish DN, MacLaren R. The role of vasopressin in vasodilatory septic shock. Pharmacotherapy 2004;24:1050– 63. 29. Obritsch MD, Jung R, Fish DN, MacLaren R. Effects of continuous vasopressin infusion in patients with septic shock. Ann Pharmacother 2004;38:1117–22. 30. Virtanen R, Kauppila M, Itala M. Percutaneous coronary intervention with stenting in a patient with haemophilia A an acute myocardial infarction following a single dose of desmopressin. Thromb Haemost 2004;92:1154–6. 31. Robinson D, Cardozo L, Akeson M, Hvistendahl G, Riis A, Norgaard JP. Antidiuresis: a new concept in managing female daytime urinary incontinence. BJU Int 2004;93:996–1000. 32. Norgaard JP. Hyponatremia in desmopressin treated patients—what is evidence based? J Urol Urogynäkol 2004;11:7. 33. Passi GR, Shad R. Seizures and coma after desmopressin for nocturnal enuresis. Indian Pediatr 2004;41:1276–7. 34. Weatherall M. The risk of hyponatremia in older adults using desmopressin for nocturia: a systematic review and meta-analysis. Neurourol Urodyn 2004;23:302–5. 35. Muller D, Kuehnle K, Eggert P. Increased urinary calcium excretion in enuretic children treated with desmopressin. J Urol 2004;171:2618–20. 36. Overman M, Brass E. Worsening of thrombotic thrombocytopenic purpura symptoms associated with desmopressin administration. Thromb Haemost 2004;92:886–7. 37. Marques RG, Rogers J, Chavin KD, Baliga PK, Lin A, Emovon O, Afzal F, Baillie GM, Taber DJ, Ashcraft EE, Rajagopalan PR. Does treatment of cadaveric organ donors with desmopressin increase the likelihood of pancreas graft thrombosis? Results of a preliminary study. Transplant Proc 2004;36:1048–9. 38. Lose G, Mattiasson A, Walter S, Lalos O, van Kerrerbroeck P, Abrams P, Freeman R. Clinical experiences with desmopressin for long-term treatment of nocturia. J Urol 2004;172:1021–5. 39. Shawcross DL, Davies NA, Mookerjee RP, Hayes PC, Williams R, Lee A, Jalan R. Worsening of cerebral hyperemia by the administration of terlipressin in acute liver failure with severe encephalopathy. Hepatology 2004;39:471–5.
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44
Drugs that affect lipid metabolism
Ezetimibe (SED-15, 1308; SEDA-27, 473; SEDA-28, 534) Ezetimibe selectively and potently blocks intestinal absorption of dietary and biliary cholesterol and has an adverse event profile similar to that of placebo. Musculoskeletal Myotoxicity linked to ezetimibe has been described in a 45-year-old overweight man with McArdle disease, which is the most common disorder of muscle carbohydrate metabolism, caused by mutations in the gene that encodes myophosphorylase (1A ).
while not taking lipid-lowering drugs and hypertriglyceridemia (4r ). An interaction of ezetimibe with statins was suspected in two men aged 43 and 53 years, both of whom had raised creatine kinase activity and one of whom also had myalgia (5r ). However, co-administration of ezetimibe and lovastatin in 48 healthy men resulted in no significant changes in laboratory test results, including enzymes indicative of muscle or liver damage (6c ). Vitamins Ezetimibe has no major effect on the absorption of fat-soluble vitamins (7R ).
Drug interactions
Fibrates
Fibrates Co-administration of ezetimibe and fenofibrate in 32 healthy subjects with hypercholesterolemia (2c ) resulted in no significant changes in laboratory test results, including enzymes indicative of muscle or liver injury. In a randomized, open, three-way crossover, multiple-dose study in 12 healthy adult men there was no clinically significant interaction of ezetimibe with gemfibrozil (3c ). Statins Ezetimibe given with simvastatin and atorvastatin is well tolerated, with a safety profile similar to the statin alone and to placebo (SEDA-28, 534). However, there are concerns about the use of ezetimibe in patients with impaired oxidation of fatty acids, as in familial combined hyperlipidemia. Of more than 300 patients with intolerance of lipid-lowering therapies a subgroup had common features, including raised fasting respiratory exchange ratios Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29044-5 © 2007 Elsevier B.V. All rights reserved.
546
(SED-15, 1358; SEDA-26, 486; SEDA-27, 473; SEDA-28, 534) Musculoskeletal Rhabdomyolysis and acute renal insufficiency associated with gemfibrozil monotherapy has been reported (8A ). • A 30-year-old white man with hypertension, type 1 diabetes mellitus, and hyperlipidemia developed myalgias, nausea, and vomiting, which began 4 days after he started working as a jackhammer operator. His medications were lisinopril, aspirin, insulin, and gemfibrozil. Creatine kinase and creatinine, which had previously been respectively mildly raised and normal, were markedly raised, consistent with rhabdomyolysis with acute renal insufficiency.
Gemfibrozil monotherapy of hyperlipidemia may predispose to rhabdomyolysis with acute renal insufficiency. Patients using gemfibrozil should be cautioned regarding strenuous exertion, dehydration, and the need for prompt evaluation of myalgia. Urinary tract Reversible acute renal allograft dysfunction occurred in three patients taking fenofibrate (9A ). Serum concentrations
Drugs that affect lipid metabolism
Chapter 44
of immunosuppressant agents remained within the target ranges throughout. On withdrawal of fenofibrate the renal dysfunction resolved. The pathological changes in the proximal tubules in all three biopsy specimens were in keeping with a toxic rather than an ischemic etiology. Although the control of hyperlipidemia is crucial in patients with transplants, the authors suggested that caution should be exercised and serum creatinine concentrations be closely monitored in patients who start to take fibrates.
HMG-CoA reductase inhibitors (SED-15, 1632; SEDA-26, 487; SEDA-27, 473; SEDA-28, 535) Nervous system A 58-year-old man developed a disorder resembling Guillain–Barré syndrome at the start of simvastatin therapy (10A ). He had had a similar but milder episode after taking pravastatin 6 months before. This case suggests that acute polyradiculoneuropathy may represent a rare but serious adverse effect of statin treatment. The pathophysiology of acute neuropathy on statin exposure is unknown; a hypersensitivity reaction resulting in an immune-mediated process has been suggested. It is possible that this patient had relapsing Guillain–Barré syndrome unrelated to the use of statins. The possible link between statins and peripheral neuropathy, has been evaluated (11R ). Based on epidemiologic studies and case reports, there may be a risk of peripheral neuropathy associated with statins; however, the risk appears to be minimal. These findings should alert prescribers to a potential risk of peripheral neuropathy in patients taking any statin; that is, statins should be considered the cause of peripheral neuropathy when other causes have been excluded. Psychiatric The risk of Alzheimer’s disease has previously been mentioned (SEDA-28, 535). In 308 hypercholesterolemic adults aged 35–70 years, daily treatment with placebo, simvastatin 10 mg, or simvastatin 40 mg for 6 months was associated with decremental effects of simvastatin on tests previously observed to be sensitive to statins and on tests not previously administered, but not on tests previously
547 observed to be insensitive to statins (12C ). For the three tests specifically affected by simvastatin, effects on cognitive performance were small, manifesting only as a failure to improve during the 6 months of treatment, and were confounded by baseline differences on one test. This study provides partial support for minor decrements in cognitive functioning with statins. Whether such effects have any longterm sequelae or occur with other cholesterollowering interventions is not known. Metabolism Co-enzyme Q10 concentrations were measured in blood from hypercholesterolemic subjects before and after exposure to atorvastatin 80 mg/day for 14 and 30 days in 34 subjects eligible for statin treatment (13c ). The mean blood concentration of co-enzyme Q10 was 1.26 µg/ml at baseline, and fell to 0.62 after 30 days of atorvastatin therapy. There was a statistically significant fall detectable after 14 days of treatment. The authors concluded that widespread inhibition of co-enzyme Q10 synthesis could explain the exercise intolerance, myalgia, and myoglobinuria that are observed with statin treatment. In 14 asymptomatic patients statin therapy worsened left ventricular diastolic function; co-enzyme Q10 supplementation produced improvement. There were several limitations of this study, including a small sample size and the lack of a control arm, but the patients did serve as contemporary controls for themselves. Because baseline concentrations of co-enzyme Q10 do not predict dysfunction, routine concomitant co-enzyme Q10 administration, especially in patients at risk, may be prudent (14c ). Skin A 59-year-old woman developed a lichenoid eruption while taking a statin (15A ). Musculoskeletal A few cases of dermatomyositis and polymyositis due to cholesterollowering drugs have previously been reported. Symptoms in four men and one woman, median age 68 years, were compatible with a diagnosis of polymyositis. Antinuclear antibodies were positive in four cases and muscle biopsies showed polymyositic infiltrates in four cases. Treatment (four statins and one fibrates) was withdrawn, with partial clinical improvement in three cases. Clinical remission was
548 obtained with glucocorticoids. Antinuclear antibody screening, especially in cases of proximal muscular weakness and increased muscle enzyme activity, is warranted (16A ). The incidence of rhabdomyolysis in patients taking different statins and fibrates, alone and in combination, has been estimated using data from 11 managed health care plans across the USA (17M ). The incidences of rhabdomyolysis were 0.44 per 10 000 person-years of treatment with atorvastatin, pravastatin, or simvastatin, 5.34 with cerivastatin, and 2.82 with fibrates. The incidence increased to 5.98 when atorvastatin, pravastatin, or simvastatin was with a fibrate, and to 1035 when cerivastatin was combined with a fibrate. The clinical course and muscle biopsy findings have been described in eight patients with hyperlipoproteinemia taking lipid-lowering drugs who developed myalgias or proximal muscle weakness (18c ). All became asymptomatic after withdrawal of the drug, although creatine kinase activity remained high. Muscle biopsy in six cases from 3 months to 2 years after withdrawal of the drug showed variation in fiber diameters in all cases, with necrosis of fibers in five cases, inflammatory infiltration in one, vacuolated fibers in one, and raggedred fibers in three. Although the muscle biopsy findings were not specific, the authors concluded that prolonged use of statins or fibrates might cause a chronic myopathy, even in the absence of symptoms.
Chapter 44
serum concentration of simvastatin and simvastatin acid by 83%, through induction of CYP3A4 (20c ). CYP3A4 activates clopidogrel, and atorvastatin competitively inhibits this activation. Some authors have suggested that the use of a statin that is not metabolized by CYP3A4 may be warranted in patients taking clopidogrel (SEDA-27, 536). However, in 45 patients with acute coronary syndrome randomized to receive either atorvastatin 10 mg/day or pravastatin 40 mg/day neither atorvastatin nor pravastatin significantly affected clopidogrel-induced inhibition of platelet activation; nor did clopidogrel affect the therapeutic efficacy of atorvastatin (21c ). Platelet biomarkers were studied 4 and 24 hours after clopidogrel in 75 patients taking statins or placebo before coronary stenting (22c ). There were no significant differences in measured platelet characteristics among the study groups, with the exception of a lower collagen-induced aggregation at 24 hours and a constantly reduced expression of G-proteincoupled protease-activated thrombin receptor in patients treated with statins. Thus statins do not affect the ability of clopidogrel to inhibit platelet function in patients undergoing coronary stenting.
Atorvastatin Immunologic There have been reports of lupus-like symptoms in patients taking statins (SEDA 23, 473). • A 59-year-old patient (sex not specified) developed anti-dsDNA antibodies in the serum while taking a statin (19A ).
Statin-induced lupus-like syndrome is characterized by a long delay between the start of therapy and the skin eruption. Antinuclear antibodies can persist for many months after drug withdrawal. The causal relation may be therefore difficult to establish, and probably many cases are unrecognized. Early diagnosis may avoid unnecessary immunosuppressive therapy. Drug interactions In twelve Caucasian men concomitant use of carbamazepine reduced the
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(SED-15, 366)
Liver Acute hepatitis has been associated with statins and in one patient with autoimmune hepatitis it was suggested that atorvastatin may have unmasked the underlying disease (SEDA-28, 536). Based on the low frequency of raised alanine transaminase activity and the lack of clinical evidence of hepatotoxicity, some clinicians are calling for a change in the current practice of monitoring liver function tests. However, a 71-year-old woman taking atorvastatin had raised transaminase activity on two occasions and developed pruritus on rechallenge. Thus, clinicians should be aware of asymptomatic rises in liver function tests in patients taking atorvastatin who do not have known susceptibility factors for liver damage (23A ).
Drugs that affect lipid metabolism
Simvastatin
Chapter 44
(SED-15, 3145)
Drug interactions Amiodarone An interaction of simvastatin with amiodarone has been described. • A 63-year-old white man with insulin-dependent diabetes and recent coronary artery bypass surgery developed diffuse muscle pain with generalized muscular weakness after taking amiodarone 1 g/ day for 10 days then 200 mg/day plus simvastatin 40 mg/day (24A ). He had a significant increase in creatine kinase activity, peaking at 40 392 U/l.
Amiodarone may be another drug that necessitates special caution if used with statins metabolized by CYP3A4.
549 Clarithromycin A 49-year-old man developed rhabdomyolysis after taking simvastatin 80 mg/day combined with clarithromycin 500 mg bd for 6 weeks (25A ). This effect was probably causal according to the Naranjo algorithm. Grapefruit juice In a randomized, two-phase, controlled, crossover study in 10 healthy volunteers one glass of grapefruit juice, taken daily for 3 days considerably increased the plasma concentrations of simvastatin and simvastatin acid (26A ).
References 1. Perez-Calvo J, Civeira-Murillo F, Cabello A. Worsening myopathy associated with ezetimibe in a patient with McArdle disease. Q J Med 2005;98(6):461–2. 2. Kosoglou T, Statkevich P, Fruchart JC, Pember LJ, Reyderman L, Cutler DL, Guillaume M, Maxwell SE, Veltri EP. Pharmacodynamic and pharmacokinetic interaction between fenofibrate and ezetimibe. Curr Med Res Opin 2004;20(8):1197–207. 3. Reyderman L, Kosoglou T, Statkevich P, Pember L, Boutros T, Maxwell SE, Affrime M, Batra V. Assessment of a multiple-dose drug interaction between ezetimibe, a novel selective cholesterol absorption inhibitor and gemfibrozil. International J Clin Pharmacol Ther 2004;42(9):512–8. 4. Phillips PS. Ezetimibe and statin-associated myopathy. Ann Intern Med 2004;141(8):649. 5. Fux R, Mörike K, Gundel UF, Hartmann R, Gleiter CH. Ezetimibe and statin-associated myopathy. Ann Intern Med 2004;140(8):671–2. 6. Kosoglou T, Statkevich P, Meyer I, Cutler DL, Musiol B, Yang B, Zhu Y, Maxwell SE, Veltri EP. Effects of ezetimibe on the pharmacodynamics and pharmacokinetics of lovastatin. Curr Med Res Opin 2004;20(6):955–65. 7. Murdoch D, Scott LJ. Ezetimibe/simvastatin: a review of its use in the management of hypercholesterolemia. Am J Cardiovasc Drugs 2004;4(6):405–22. 8. Layne RD, Sehbai AS, Stark LJ. Rhabdomyolysis and renal failure associated with gemfibrozil monotherapy. Ann Pharmacother 2004;38(2):232–4.
9. Angeles C, Lane BP, Miller F, Nord EP. Fenofibrate-associated reversible acute allograft dysfunction in 3 renal transplant recipients: biopsy evidence of tubular toxicity. Am J Kidney Dis 2004;44(3):543–50. 10. Rajabally YA, Varakantam V, Abbott RJ. Disorder resembling Guillain–Barré syndrome on initiation of statin therapy. Muscle Nerve 2004;30(5):663–6. 11. Chong PH, Boskovich A, Stevkovic N, Bartt RE. Statin-associated peripheral neuropathy: review of the literature. Pharmacotherapy 2004;24(9):1194–203. 12. Muldoon MF, Ryan CM, Sereika SM, Flory JD, Manuck SB. Randomized trial of the effects of simvastatin on cognitive functioning in hypercholesterolemic adults. Am J Med 2004;117(11):823–9. 13. Rundek T, Naini A, Sacco R, Coates K, DiMauro S. Atorvastatin decreases the coenzyme Q10 level in the blood of patients at risk for cardiovascular disease and stroke. Arch Neurol 2004;61(6):889–92. 14. Silver MA, Langsjoen PH, Szabo S, Patil H, Zelinger A. Effect of atorvastatin on left ventricular diastolic function and ability of coenzyme Q10 to reverse that dysfunction. Am J Cardiol 2004;94(10):1306–10. 15. Sebök B, Toth M, Anga B, Harangi F, Schneider I. Lichenoid drug eruption with HMG-CoA reductase inhibitors (fluvastatin and lovastatin). Acta Derm Venereol 2004;84(3):229–30. 16. Fauchais AL, Iba Ba J, Maurage P, Kyndt X, Bataille D, Hachulla E, Parent D, Queyrel V, Lambert M, Michon Pasturel U, Hatron PY,
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18.
19. 20.
21.
Vanhille P, Devulder B. Polymyosites induites ou associées aux traitements hypolipémiants? A propos de cinq cas. Rev Med Interne 2004;25(4):294–8. Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, Grenade LL, Gurwitz JH, Chan KA, Goodman MJ, Platt R. Incidence of hospitalized rhabdomyolysis in patients treated with lipidlowering drugs. JAMA 2004;292(21):2585–90. Carvalho AA, Lima UW, Valiente RA. Statin and fibrate associated myopathy: study of eight patients. Arq Neuro-Psiquiatria 2004;62(2A):257– 61. Noel B, Panizzon RG. Lupus-like syndrome associated with statin therapy. Dermatology 2004;208(3):276–7. Ucar M, Neuvonen M, Luurila H, Dahlqvist R, Neuvonen PJ, Mjorndal T. Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid. Eur J Clin Pharmacol 2004;59(12):879–82. Mitsios JV, Papathanasiou AI, Rodis FI, Elisaf M, Goudevenos JA, Tselepis AD. Atorvastatin does not affect the antiplatelet potency of clopidogrel when it is administered concomi-
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22.
23.
24.
25.
26.
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tantly for 5 weeks in patients with acute coronary syndromes. Circulation 2004;109(11):1335–8. Serebruany VL, Midei MG, Malinin AI, Oshrine BR, Lowry DR, Sane DC, Tanguay JF, Steinhubl SR, Berger PB, O’Connor CM, Hennekens CH. Absence of interaction between atorvastatin or other statins and clopidogrel: results from the interaction study. Arch Intern Med 2004;164(18):2051–7. Gershovich OE, Lyman AE Jr. Liver function test abnormalities and pruritus in a patient treated with atorvastatin: case report and review of the literature. Pharmacotherapy 2004;24:150–4. Roten L, Schoenenberger RA, Krahenbuhl S, Schlienger RG. Rhabdomyolysis in association with simvastatin and amiodarone. Ann Pharmacother 2004;38(6):978–81. Kahri AJ, Valkonen MM, Vuoristo MK, Pentikainen PJ. Rhabdomyolysis associated with concomitant use of simvastatin and clarithromycin. Ann Pharmacother 2004;38(4):719. Lilja JJ, Neuvonen M, Neuvonen PJ. Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin. Br J Clin Pharmacol 2004;58(1):56–60.
Hans-Peter Lipp and Jörg Thomas Hartmann
45 Editor’s note: The wide range of cytostatic 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 the adverse effects of all the drugs in this field as the Annual gives in others. This year most of this chapter is devoted to a special review of the adverse effects of the various anticancer drugs that are antimetabolites. Previous special reviews in this chapter have been as follows: • Anthracyclines (SEDA-25, 533) • Fluorouracil (SEDA-23, 476) • Inhibitors of topoisomerase I and topoisomerase II (SEDA-27, 477) • Paclitaxel (SEDA-21, 463) • Platinum compounds (SEDA-26, 490) • Vinca alkaloids (SEDA-28, 538)
Anticancer antimetabolites Anticancer drugs that are classified as antimetabolites can be further grouped as follows: • purine antagonists (clofarabine, mercaptopurine, tioguanine); • pyrimidine antagonists (azacytidine, capecitabine, cytarabine, decitabine, fluorouracil, gemcitabine, tegafur, troxacitabine); • antifolate drugs (lometrexol, methotrexate, pemetrexed, raltitrexed, trimetrexate); • phosphatidylcholine antagonists (miltefosine); • adenosine deaminase inhibitors (cladribine, fludarabine, pentostatin) Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29045-7 © 2007 Elsevier B.V. All rights reserved.
Cytostatic drugs PURINE ANTAGONISTS Clofarabine Clofarabine (Clolar® ) is a purine nucleoside analogue, which has been approved for the treatment of relapsed or refractory acute lymphoblastic leukemia in children after at least two prior regimens. The active 5 -triphosphate metabolite inhibits DNA synthesis by reducing cellular pools of deoxynucleotide triphosphate. In addition, drug-related inhibition of ribonucleotide reductase and termination of DNA chain elongation contribute to clofarabine’s antineoplastic activity. After intravenous administration of 52 mg/m2 /day for 5 days the half-life averages 5.2 hours. More than 50% of the dose is excreted in the urine unchanged, and the dosage must be modified in patients with reduced renal function (1c ). Severe myelosuppression, including neutropenia, anemia, and thrombocytopenia, has been described as a dose-limiting adverse effect. The risk of severe infection may therefore be increased. In addition, dose-limiting nonhematological adverse effects, including rashes and reversible hyperbilirubinemia and raised transaminases, have been described (2R ). Metabolism Tumor lysis syndrome together with increased cytokine release can occur. Therefore, besides intensified hydration, allopurinol should be given if hyperuricemia is expected (1c ). Skin Clofarabine has been associated with acral erythema in two patients after infusion of clofarabine (3A ). One patient had a myelodysplastic syndrome and the other had acute lymphoblastic leukemia.
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Mercaptopurine and tioguanine (thioguanine) (SED-15, 377, 3429) Mercaptopurine (6-mercaptopurine) and tioguanine are thiopurines that undergo three important metabolic pathways within cells: 1. Oxidation to 6-thiouric acid, which does not have significant antineoplastic activity. 2. Metabolism to thioinosine monophosphate, which is further metabolized to highly active 6-tioguanine nucleotides. 3. S-methylation, which is catalysed by the enzyme thiopurine S-methyltransferase (TPMT). Both 6-thiouric acid and its S-methyl derivative lack clinically significant antineoplastic activity (4R ). Regarding the first metabolic pathway, there is a clinically important difference between tioguanine and mercaptopurine. In contrast to tioguanine, the metabolic catabolism of mercaptopurine is exclusively mediated by the enzyme xanthine oxidase, resulting in 6-thiouric acid. In contrast, the first step of metabolic degradation of tioguanine to 6-thiouric acid is catalysed by the enzyme guanase, whereas xanthine oxidase is responsible for the second step (5E ). In consequence, inhibition of xanthine oxidase (for example by allopurinol) will result in severe forms of mercaptopurine toxicity, particularly myelosuppression, when dosage modification of concomitant mercaptopurine is neglected, whereas in the case of tioguanine dosage modification is not warranted, because the first step of drug inactivation is not affected by allopurinol. Because azathioprine is a prodrug of mercaptopurine, allopurinol coadministration will have a profound negative effect on white blood cell count, if the dosage of azathioprine is not modified (6A ). Considering thiopurine inactivation by the enzyme S-methyltransferase (thiopurine methyltransferase, TPMT), a genetic polymorphism has been identified to be the reason for high interindividual variability among cancer patients. According to population studies, about 89% of patients express normal constitutive TPMT activity, whereas 11% and 0.3% have intermediate and very low enzyme activity respectively (7E , 8A , 9C ). Patients with genetically
Hans-Peter Lipp and Jörg Thomas Hartmann
low and absent TPMT activity are predisposed to severe bone marrow toxicity, even at conventional dosages, whereas individual hepatotoxicity does not appear to co-segregate with abnormal TPMT activity (9C , 10E ). Patients who have intermediate TPMT activity accumulate about 50% more active tioguanine nucleotides than patients with normal TPMT activity. Most of these patients are identified only after an unexpected episode of severe myelosuppression. The risk of very severe subacute and potentially fatal hemopoietic toxicity is greatly increased in patients with deficient TPMT activity (autosomal recessive trait) (9C , 10E ). Drugs such as benzoic acid derivatives (including the aminosalicylates, sulfasalazine, olsalazine, and 5-aminosalicylic acid) have some inhibitory action on TPMT activity. Thus, coadministration with mercaptopurine increases the risk of severe bone marrow toxicity, particularly in patients with low constitutive TPMT enzyme activity (11A ). Hematologic Myelosuppression during treatment with 6-mercaptopurine (mercaptopurine) is dose-related. Daily oral doses of 2.5 mg/kg of mercaptopurine can be associated with a fall in leukocyte count, with a moderate fall within 1–2 weeks. If myelosuppression is more severe than expected, one has to consider the possible contribution of co-administered drugs or pharmacogenetic abnormalities (6A , 11A ). • A 16-year-old white student with Crohn’s disease took mercaptopurine 50 mg/day and olsalazine 500 mg/day (11A ). The white cell count was 8.8 × 109 /l. About 1 month later, the dosages were increased to olsalazine 1000 mg/day and mercaptopurine 75 mg/day. Concomitant prednisone was tapered to 5 mg/day. Within 3–4 weeks she developed leukopenia (white cell count 1.7 × 109 /l). The dosage of mercaptopurine was reduced to 50 mg/day but the white cell count remained low. The dosage of mercaptopurine was reduced to 25 mg/day, and the white cell count increased slowly to 5.2 × 109 /l.
Liver Mercaptopurine can cause liver damage, and hepatic function has to be carefully monitored. Jaundice has also been observed during tioguanine administration, but a causal relation has not been clearly established. The underlying mechanisms of hepatotoxicity have not been elucidated, but they include direct hepatotoxicity and hypersensitivity reactions. The
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incidence of hepatotoxicity during administration of conventional dosages is 0–6%, but it can be higher at dosages exceeding 2.5 mg/kg/day. In most patients, hepatotoxicity is reversible when mercaptopurine is withdrawn (10E ). Mercaptopurine caused cholestatic liver disease in two patients after liver transplantation (12A ). Thiopurine methyltransferase (TPMT) alleles and 6-tioguanine (6-TG) concentrations were normal, but 6-methyl-mercaptopurine concentrations were in the toxic range. The cholestasis resolved within a few weeks after drug withdrawal. Mercaptopurine-associated hepatotoxicity can present with a variety of clinical, biochemical, and histological manifestations after liver transplantation and should be considered as a cause of rises in liver enzymes. Tioguanine-related hepatotoxicity, including raised liver function tests, sinusoidal collagen deposition on electron microscopy, and venoocclusive disease, have been related to its use in neoplastic disease (13c ). There was histological nodular liver regeneration in 20 of 37 patients with inflammatory bowel disease who took tioguanine for 1–3 years; one patient had venous outflow obstruction. There was minimal fibrosis in 13 of 38 liver biopsies and 14 of 23 biopsies showed sinusoidal collagen deposition on electron microscopy. The natural history of these changes in patients taking tioguanine is unknown. Periodical follow-up liver biopsies are required to determine the histological and clinical sequelae. Susceptibility factors Genetic—ITPase deficiency Inosine triphosphate pyrophosphatase (ITPase) is an enzyme that catalyses the pyrophosphohydrolysis of ITP to IMP. ITPase deficiency is a clinically benign autosomal recessive condition characterized by the abnormal accumulation of ITP in erythrocytes (14C ). Mercaptopurine is activated through a 6-thio-IMP intermediate, and in patients deficient in ITPase there will be accumulation of 6-thio-ITP, which is potentially toxic. Deficiency of ITPase may predict adverse reactions to therapy with mercaptopurine and its prodrug azathioprine (14C ). Tumorigenesis Both mercaptopurine and tioguanine can cause chromosomal aberrations in animals and humans. There is increasing
evidence that there is a substantial risk of secondary myelodysplastic syndrome/acute myeloblastic leukemia in a minority of patients treated with an intensified regimen consisting of mercaptopurine + methotrexate as maintenance treatment. Patients with lower constitutive TPMT activity are at a higher risk (15E ). Fetotoxicity Out of 57 249 pregnancies, 54 were fathered by men who had filled a prescription for azathioprine or mercaptopurine before conception (16r , 17C ). There were congenital abnormalities in four children (7.4%) compared with 2334 of 57 195 children whose fathers had not taken azathioprine (4.1%), but the odds ratio was not statistically significant. All four congenital abnormalities occurred in boys and consisted of polysyndactyly, esophageal atresia, hydronephrosis with megaloureter, and a ventricular septal defect. Azathioprine/mercaptopurine was not associated with poor pregnancy outcomes in 101 women with inflammatory bowel disease (18c ). Drug interactions Mercaptopurine is metabolized by xanthine oxidase, which is inhibited by allopurinol. Concomitant administration can result in life-threatening neutropenia unless the dose of allopurinol is reduced by about 75% (19r ). Interference with diagnostic tests Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) concentrations are widely used as markers of inflammation. There was an unexplained discordance between ESR and CRP in children with asymptomatic inflammatory bowel disease taking azathioprine or mercaptopurine. The ESR was persistently raised in 11 of 120 children but the CRP was normal and there was no clinical evidence of active disease (20c ).
PYRIMIDINE ANTAGONISTS Among the approved pyrimidine antagonists used in clinical oncology, cytarabine, gemcitabine, and fluorouracil and related compounds are of great clinical importance. Azacytidine has recently been approved for treatment of myelodysplastic syndrome, and decitabine and troxacitabine are still under investigation.
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Azacitidine Azacitidine has been recently approved for the treatment of myelodysplastic syndrome. It inhibits DNA methyltransferase, resulting in hypomethylation of DNA and direct cytotoxicity in abnormal hemopoietic cells in the bone marrow. The recommended dosage is 75 mg/m2 /day given subcutaneously for 7 days every 4 weeks (21C ). The absolute systemic availability after subcutaneous administration is about 89%. After intravenous and subcutaneous administration the half-life is 0.36 and 0.69 hours respectively (22c ). Respiratory Azacitidine can cause pulmonary dysfunction (23A ). • A 71-year-old man developed bilateral perihilar airspace disease after a 7-day course of azacitidine. Bronchoscopy showed scattered petechiae, but cultures and microscopic examinations of bronchoalveolar lavage fluid were negative. Progression of the diffuse, bilateral, interstitial, alveolar process was documented by radiography and chest CT scanning and was interpreted as acute and chronic interstitial and alveolar fibrosis with chronic inflammation consistent with organizing pneumonitis.
The authors hypothesized that azacitidine and gemcitabine, which are structurally similar, may share adverse effects, since the latter has been associated with respiratory distress and acute interstitial pneumonitis (23A ). Liver Hepatotoxicity has been reported after subcutaneous azacitidine, which makes it mandatory to monitor liver function before and during treatment cycles. Whether patients who receive the drug intravenously are at a lower risk of hepatotoxicity has not yet been clearly evaluated. There is some evidence that concomitant low serum albumin concentrations (for example below 28 g/l) predispose to druginduced hepatotoxicity, but a causal relation has not yet been shown. Urinary tract Renal tubular dysfunction is characterized by raised serum creatinine concentrations, glycosuria (up to 8 g/day), polyuria, and transient changes in serum bicarbonate. Polyuria (4–16 l) begins about 4 days after the start of azacitidine treatment and resolves after the end of treatment. However, polyuria
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may continue despite drug withdrawal. Thus, renal function has to be assessed before the start of azacitidine therapy. If there is an unexplained reduction in serum bicarbonate concentrations to less than 20 mmol/l or raised blood urea nitrogen and serum creatinine concentrations, the next cycle containing azacitidine should be delayed and a 50% dosage reduction should be considered. The mechanism of azacitidine-induced renal dysfunction has not been elucidated, but it may involve focal renal tubular necrosis (21C ).
Capecitabine Capecitabine is a prodrug of fluorouracil, which has been developed as a tumor-selective fluoropyrimidine carbamate in order to achieve high cytotoxic concentrations of fluorouracil within tumor cells. In addition, during daily oral administration, capecitabine mimics continuous fluorouracil administration. The systemic availability of oral fluorouracil is unacceptably highly variable (0–80%). More consistent availability could be achieved by the concomitant use of reversible or irreversible inhibitors of dihydropyrimidine dehydrogenase, such as 5-chloro-2,4-dihydroxypyridine (reversible) or eniluracil (irreversible). However, phase II/III trials have given disappointing results compared with fluorouracil + leucovorin. In contrast, the fluorouracil prodrug capecitabine has achieved better response rates and equivalent overall survival and time to disease progression compared with fluorouracil + leucovorin in patients with advanced colorectal cancer. Capecitabine has therefore been approved in the USA and Europe as first-line therapy for metastatic colorectal cancer (24R , 25C , 26c , 27R ). Diarrhea is the second most common adverse effect of capecitabine. Less frequently, adverse effects such as mucositis, leopard-like vitiligo, peripheral neuropathy, and onycholysis have been reported (25C , 28A ). Cardiovascular The incidence of symptomatic cardiotoxicity with capecitabine has been estimated to average 3%, based on two phase III trials, which is similar to intravenous fluorouracil (29A ).
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Nervous system Signs of sensorimotor peripheral neuropathy (for example, right leg weakness, perioral and arm weakness) can develop after treatment with capecitabine for about 28 days, resolving several weeks after withdrawal without further intervention (30Ar ). Skin Oral capecitabine and fluorouracil by continuous infusion share a common adverse effect: palmar–plantar erythrodysesthesia. Hand–foot syndrome of any grade occurs in up to 68% of patients taking capecitabine (for example 2500 mg/m2 /day for 2 weeks followed by 1 weeks’ rest, with cycles repeated every 3 weeks); the most severe episodes follow the second treatment cycle (31r ). Susceptibility factors Genetic Capecitabine can cause fatal adverse effects in patients with absent dihydropyrimidine dehydrogenase activity because of a pharmacogenetic disorder or concomitant use of a potent dihydropyrimidine dehydrogenase inhibitor, such as brivudine (32A ). Drug interactions Capecitabine should not be combined with leucovorin, because of an increased incidence of intolerable adverse effects (32A ).
Cytarabine
(SED-15, 1034)
Cytarabine is rapidly converted intracellularly to its active metabolite, cytarabine triphosphate (ara-CTP), which inhibits DNA polymerase by competing with physiological substrates. In addition, a small amount of cytarabine triphosphate is incorporated into DNA and RNA. After intravenous administration, cytarabine has a half-life of about 1–3 hours. It undergoes extensive intrahepatic and extrahepatic metabolism catalysed by the enzyme cytidine deaminase. The resulting metabolite, 1-β-D-arabinofuranosyluracil (ara-U) lacks any significant cytotoxic activity. Both cytarabine and ara-U are excreted in the urine. Whereas during conventional dosages, about 90% of the dose is recovered as ara-U in the urine, intensified cytarabine regimens are associated with a lower percentage ara-U excretion
555 (33c ). Cytarabine can also be administered intrathecally or subcutaneously in patients with a higher risk of brain metastases or hypoplastic myelodysplastic syndrome respectively. Cytarabine syndrome Some patients may develop symptoms such as myalgia, bone pain, chest pain, maculopapular rash, conjunctivitis, malaise, and fever simultaneously about 6–12 hours after intravenous cytarabine administration (“cytarabine syndrome”). Glucocorticoids can be used to prevent as well as to treat this syndrome (34A ). Cardiovascular Acute pericarditis has been described during high-dose cytarabine treatment. Interruption of high-dose therapy and the use of glucocorticoids were effective in resolving the pericardial effusion. Besides direct toxic effects on the pericardium, mechanisms mediated by the immune system may be involved (35A ). • A 37-year-old patient with acute myeloblastic leukemia and nervous system involvement received a first consolidation course of chemotherapy containing mitoxantrone and cytarabine 3 g/m2 (once daily on days 1–5) after remission with daunorubicin and cytarabine (36A ). On day 3, after the fifth dose of subsequent consolidation treatment containing high-dose cytarabine, the patient suddenly complained of dyspnea and sharp anterior chest pain worsened by inspiration. His temperature was 37.8 ◦ C, blood pressure 100/60 mm Hg, pulse 120/minute. Echocardiography showed a small circumferential pericardial effusion. On day 4, fever was still present, and a pericardial friction rub was heard. The pericardial effusion had increased in size and there was paradoxical septal movement. Cytarabine was withdrawn and oral methyprednisolone 0.5 mg/kg/day was given together with morphine. The fever and chest pain resolved.
Respiratory Bronchiolitis obliterans organizing pneumonia has been attributed to a combination of cytarabine and interferon alfa (37A ). • Shortly after the start of combination treatment including interferon alfa and cytarabine, a 59year-old man developed fever, shortness of breath, persistent cough, and weight loss, which was interpreted as bronchiolitis obliterans organizing pneumonia (BOOP). His symptoms resolved when treatment was withdrawn.
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Nervous system In about 1% of patients treated with high-dose cytarabine, drug-related demyelinating polyneuropathy can be expected, with severe motor disability as a consequence (38c , 39A ). In addition to direct neurotoxic effects to Schwann cells, drug-induced immunosuppression may contribute to immunemediated neuropathic effects. Neurological deficits can be described as quadriplegia, distal weakness, and sensory loss (40E , 41c , 42A , 43A ). Patients who are at risk of brain metastases, for example from gestational trophoblastic tumors, are candidates for intrathecal cytarabine, particularly when the tumor is likely to be resistant to methotrexate. Occasional dose-related neurological effects have been described during intrathecal administration of cytarabine and may be more frequent with concomitant radiotherapy or repeated intrathecal administration within a period of a few days. A very few patients develop pronounced muscle weakness and epileptic seizures (44A ). Sensory systems Acute anterior uveitis has been attributed to high-dose cytarabine in a 21-year-old-woman with a diffuse large B cell lymphoma; there was complete resolution of symptoms within a few days of treatment with topical glucocorticoids (45A ). Hematologic The major dose-limiting adverse effect of cytarabine is myelosuppression, with megaloblastosis, reticulocytopenia, leukopenia, thrombocytopenia, and anemia. The severity of toxicity depends on the dosage regimen. If it is given daily intravenously as intermittent bolus injections or continuous infusions, almost all patients will develop myelosuppression. After a 5-day continuous infusion, the first nadir of leukopenia occurs on days 7–9, followed by a more severe nadir on days 15–24. Liver and urinary tract Raised hepatic enzymes and serum creatinine have been described as frequent adverse effects during highdose cytarabine administration. However, a case report has suggested that hepatic and renal dysfunction can occur during low-dose subcutaneous drug administration (46A ). • A 45-year-old Japanese woman with therapyrelated hypoplastic myelodysplastic syndrome received low-dose subcutaneous cytarabine 10 mg/
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m2 every 12 hours. She complained of a high-grade fever on the second day during consolidation therapy, with concomitant dyspnea, hepatic dysfunction, and acute renal insufficiency on day 4 of chemotherapy. C-reactive protein increased to 264 mg/l, alanine transaminase to 232 U/l, and serum creatinine to 387 µmol/l. After withdrawal of low-dose cytarabine and treatment with diuretics, the laboratory abnormalities rapidly improved. When subcutaneous cytarabine was restarted, hepatic and renal dysfunction recurred on the next day.
Skin Skin reactions occur in more than half of all patients after high-dose cytarabine. The most common reactions include morbilliform eruptions on the trunk and limbs, acral erythema, and severe swelling and generalized urticaria. Most reactions clear spontaneously without medical intervention (47A ). Recurrent, increasingly severe episodes of palmar–plantar erythrodysesthesia have been reported after subsequent cycles containing high-dose cytarabine for the treatment of acute lymphoblastic leukemia (48A ). Based on the observation that severe bullous eruptions developed during re-exposure, the authors proposed that one should be cautious about the further use of high-dose cytarabine in patients who develop signs of drug-related palmar–plantar erythrodysesthesia. Drug formulations DepoCyt® (25–50 mg every 14 days intrathecally) is a modifiedrelease formulation containing cytarabine (49c ). It maintains therapeutic drug concentrations for at least 14 days in the lumbar and ventricular fluid after a single intrathecal injection. Headache (grade 2–3), fatigue, and back/neck pain are common adverse effects after DepoCyt® despite concomitant administration of intravenous or oral dexamethasone 0.15 mg/kg bd for 5 days. However, the incidence of drug-related arachnoiditis has been described to be dramatically higher if dexamethasone prophylaxis is omitted. Systemic adverse effects, including hypersensitivity reactions, hepatic or renal toxicity, cardiac adverse events, or myelosuppression, were related to concomitant systemic chemotherapy rather than DepoCyt® .
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Decitabine Decitabine (5-aza-2 -deoxycytidine) is structurally very similar to azacitidine. Both drugs have promising activity against acute myeloblastic leukemia and myelodysplastic syndrome. In addition, decitabine has significant activity against chronic myeloid leukemia. It is rapidly metabolized in the liver by cytidine deaminase, which explains its short half-life of 8–30 minutes. In an intravenous dose of 100 mg/m2 over 6 hours every 12 hours for 5 days (1000 mg/m2 per course), the only adverse effect was dose-dependent myelosuppression, with a delayed onset and a prolonged course. Other adverse effects, such as cardiovascular effects (for example acute myocardial infarction and acute heart failure), nephrotoxicity, or nervous system effects, were rare, and it is unclear whether these adverse effects were drug-related or whether the underlying condition was a more likely cause (50C ).
Fluorouracil
(SED-15, 1407)
Fluorouracil (5-fluorouracil) is one of the most commonly used anticancer drugs worldwide. It is of particular importance in the treatment of colorectal cancer, followed by other indications, including esophageal cancer, head and neck cancers, and breast cancer (51R ). In colorectal cancer, it has two modes of action, depending on the mode of administration. Bolus administration (for example injection over 3 minutes) appears to mediate its antineoplastic activity, primarily through effects on RNA, whereas the critical enzyme thymidylate synthase is targeted by continuous drug infusion. Thus, synchronous use of continuous and bolus administration may be effective in patients with colorectal cancer who develop progression during one form of administration only (52R , 53c , 54c , 55r ). Cardiovascular About 3% (range 2–10%) of patients experience fluorouracil-related cardiovascular complications, with symptoms that include angina-like chest pain and to a lesser extent hypotension, cardiac dysrhythmias, and left ventricular dysfunction. Angina-like symptoms are often noticed during infusion or with
557 a delay of 3–18 hours after administration. Patients with pre-existing ischemic heart disease are at a higher risk of severe complications, including sudden death or cardiogenic shock. Higher fluorouracil dosages confer a higher risk of cardiotoxicity (56A , 57R ). Among several hypotheses, including formulation impurities (58E , 59E ), fluorouracil-induced arterial vasoconstriction has been identified as an important first step in cardiotoxicity (60E , 61r ). In the case of vessel contractions related to bolus injection, glyceryl trinitrate reportedly protects against further events in successive cycles. Transdermal glyceryl trinitrate has been recommended as prophylaxis in patients with fluorouracilrelated angina-like symptoms (59E , 60E ). Nervous system Neurotoxicity, in the form of a cerebellar syndrome, occurs in 2–4% of patients treated with fluorouracil, but peripheral neuropathy is very rare (30Ar ). The pathogenesis of fluorouracil-induced neurotoxicity is still unclear, but it may involve drug-induced thiamine deficiency, particularly in patient with low thiamine stores. This theory has been strengthened by the observation that the symptoms of Wernicke–Korsakoff syndrome (ataxia, nystagmus, mental confusion, cognitive changes) are similar to the neurotoxic effects of fluorouracil. Early thiamine supplementation may therefore prevent drug-induced neurotoxicity. • A 50-year-old Caucasian man with recurrent hepatocellular carcinoma and pleural metastases received combination chemotherapy consisting of paclitaxel (175 mg/m2 on day 1) fluorouracil (370 mg/m2 on days 2–5 by bolus injection), and leucovorin (500 mg/m2 on days 1–4) (62A ). On the eight day of cycle 1, he complained of diarrhea, nausea and vomiting, dehydration, confusion, and disorientation. However, his mental status gradually improved over the next days. • A 73-year-old white man with esophageal carcinoma received a continuous intravenous infusion of fluorouracil 1500 mg/m2 /day for 4 days in combination with cisplatin (130 mg on day 1) (62A ). Other medications included ondansetron and dexamethasone. He became confused 48 hours after the completion of therapy. He had cognitive abnormalities, including disorientation in place and time and impaired memory and calculation, horizontal jerk nystagmus, and limb ataxia. Over the next 8–10 hours, he had three generalized tonic–clonic seizures, which resolved with phenytoin. He was given thiamine 50 mg/day and 72 hours later his confusional state and seizures resolved. However, he continued to have limb and gait ataxia.
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Gastrointestinal Stomatitis is one of the most common adverse effects of fluorouracil, and esophagitis, diarrhea, proctitis, and gastrointestinal ulceration can also occur (63c ). The symptoms start about 5–8 days after administration. The risk of gastrointestinal adverse effects is higher when fluorouracil is combined with leucovorin. In addition, severe forms of diarrhea are more frequent when the drug is administered as bolus injection weekly or during a 5-day regimen than during continuous drug infusion.
those who are extensive metabolizers of fluorouracil.
Skin About 28% of patients develop grade 1 or grade 2 skin reactions classified as palmar– plantar erythema (also known as hand–foot syndrome, acral erythema, or palmar–plantar erythrodysesthesia). This is a localized skin reaction, which begins with dysesthesia and is followed by painful, symmetrical, sharply demarcated swelling and erythema of the palms and soles, followed by local desquamation. The lesions usually progress for 1–2 weeks once chemotherapy has been stopped, and they can recur when fluorouracil is re-administered. The pathogenesis has not yet been elucidated, but it may involve drug elimination by eccrine secretion. The histological findings include vacuolar degeneration of the basal-cell layer, necrotic or dyskeratotic keratinocytes, papillary dermal edema, and mild mononuclear perivascular infiltrates. Supportive management includes the empirical use of oral pyridoxine 50–150 mg/day (64r ).
• A 42-year-old woman with advanced ovarian carcinoma and liver metastases received palliative treatment with fluorouracil and leucovorin. The once-weekly regimen contained leucovorin 80 mg/m2 as a 1-hour infusion, followed by fluorouracil 400 mg/m2 as an intravenous bolus dose. On day 4 she developed grade 4 mucositis, on day 6 grade 4 thrombocytopenia and grade 3 anemia and on day 12 grade 4 leukopenia, total alopecia, scaling, and erythroderma. Despite intensive anti-infective treatment, she developed infiltrative lesions in the lung and died on day 21, with continuing mucositis and alopecia and no signs of bone marrow recovery. Further analysis showed a novel nonsense mutation in exon 2 of the dihydropyrimidine dehydrogenase gene, creating a translation stop codon leading to a non-functional protein without residual activity.
Susceptibility factors Genetic The enzymatic catabolism of fluorouracil to inactive metabolites is mediated by dihydropyrimidine dehydrogenase (65E ). However, population analysis has shown that dihydropyrimidine dehydrogenase is under pharmacogenetic control, and there are large pharmacokinetic variations in individual patients. The frequency of heterozygotes with constitutively reduced dihydropyrimidine dehydrogenase activity has been estimated to average 3%, and these patients are at higher risk of severe fluorouracil toxicity despite conventional dosages. In 0.5% of patients, functionally active dihydropyrimidine dehydrogenase is totally absent (66r –68r , 69A , 70A ). Patients with partial or total dihydropyrimidine dehydrogenase deficiency suffer more severe adverse effects than
Sex The risk of more severe forms of stomatitis and myelosuppression is inversely correlated with the constitutive activity of the enzyme dihydropyrimidine dehydrogenase in patients with cancer. Women therefore develop more severe forms of mucositis and myelosuppression than men, despite similar doses, because they express generally lower constitutive dihydropyrimidine dehydrogenase activity (71C , 72C ).
Drug administration route Following bolus injection (over less than 5 minutes), about 14% of patients with colorectal cancer will develop grade 2 neutropenia and 11% and 6% grade 2 and grade 3 stomatitis respectively; skin reactions are of minor importance. In contrast, 24-hour drug infusion regimens rarely result in myelosuppression grade 2–3, whereas hand– foot syndrome is very common (64r ). The peak time for severe hand–foot syndrome is at between weeks 8 and 17. Important risk factors for skin toxicity include older age, female sex, impaired liver function, and renal dysfunction. Diarrhea, stomatitis, and nausea occur with both regimens in 30–40% of patients (73A ). Management of adverse drug reactions The half-life of fluorouracil averages 16 minutes after intravenous administration. The corresponding metabolites do not have cytotoxic activity. It has been proposed that defined fluorouracil plasma concentrations should be maintained over several hours in order to increase therapeutic effectiveness by avoiding
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subtherapeutic concentrations; however, this strategy has not yet been established (74C ). Although chronomodulation of fluorouracil has been suggested to be beneficial, in order to increase the therapeutic index of the drug, this strategy is not associated with a significant survival benefit, which limits its use in everyday clinical practice (75r ).
Gemcitabine
(SED-15, 1484)
Respiratory Gemcitabine should be withdrawn immediately in patients who develop severe pulmonary adverse effects. In addition, acute intervention with supportive agents, such as diuretics and glucocorticoids, appears to be highly effective (76A , 77A , 78E ). • A 55-year-old woman with debulked stage IIIC epithelial ovarian carcinoma progressed during two cycles of carboplatin and cyclophosphamide. She was a non-smoker with no history of respiratory disease and had no radiological evidence of pulmonary metastases. She received three cycles of gemcitabine 1250 mg/m2 on days 1, 8, and 15 every 4 weeks, with clinical improvement and a partial response on CT scan. The most obvious adverse effects during treatment were a grade 2 skin rash and flu-like symptoms with fever (38.5◦ for 24–48 hours) after each infusion. One week after day 15 of cycle 3 she developed rapidly progressive dyspnea. She had a fever, tachypnea (24/minute), and bilateral basal crackles. She was given antibiotics without success. Serial X-rays showed progressive bilateral pulmonary infiltrates throughout both lungs, with areas of peribronchial consolidation and collapse; however, blood cultures were negative for micro-organisms. Over the next 5 days, her condition deteriorated, with persistent fever, worsening oxygen saturation (71% on air), and arterial hypoxemia. A biopsy showed non-specific interstitial pneumonitis consistent with drug-induced lung toxicity. After dexamethasone (16 mg/day) there was clinical and functional improvement. After 1 week, the glucocorticoid was changed to prednisolone 60 mg/day. A repeat chest CT scan after 2 weeks of glucocorticoid therapy showed that the air space infiltrate had resolved, but there were persistent abnormalities in the right lung which were thought to be fibrotic. No further gemcitabine was given, and over the next 2 months the glucocorticoid therapy was progressively tapered and ultimately withdrawn with no recurrence of respiratory symptoms.
Hematologic The most common adverse effect of gemcitabine is myelosuppression. Highdose regimens (for example 2200 mg/m2 intravenously on days 1 and 15 for 6 months)
559 cause grade 3 leukopenia in 12% of patients and leukopenia of all grades in 74%. However, the time to white cell count recovery is generally short (for example about 7 days). In contrast, thrombocytopenia does not appear to be severe after gemcitabine administration (79R , 80c , 81r ). Urinary tract Hemolytic–uremic syndrome has been previously reported to be a rare adverse effect of gemcitabine. However, the incidence may be higher than originally reported (82A , 83A ). Based on systematic screening of this adverse effect, it has been concluded that the frequency averages 2.2% which is higher than previously reported (0.015– 0.072%). Early signs of hemolytic–uremic syndrome include new-onset hypertension or exacerbation of underlying hypertension and peripheral edema; the extent of mild anemia or thrombocytopenia is often variable. • A 57-year-old woman with axillary and supraclavicular nodal metastases received gemcitabine 1000 mg/m2 , increased after the second cycle to 1250 mg/m2 , when she developed a partial response (82A ). A few days after one of the next cycles, she was anemic, with a hemoglobin concentration of 7.4 g/dl. Blood urea (24 mmol/l) and creatinine (205 µmol/l) were both raised, both values having been normal at the time of drug administration. There was no erythrocyte fragmentation in the blood smear, so the diagnosis of hemolytic– uremic syndrome could not be confirmed. She was treated with blood transfusion, antibiotics, glucocorticoids, diuretics, and antihypertensive drugs. Both renal function and blood pressure slowly returned to normal over a period of 6–8 weeks and remained normal without further treatment.
Skin Gemcitabine-related radiation recall dermatitis, resulting in extensive desquamation, is rare. • A 67-year-old woman was treated with whole pelvic radiation for palliation of leg swelling and pain due to recurrent ovarian carcinoma (83A ). Three months later, she received three courses of chemotherapy containing gemcitabine. However, treatment had to be interrupted when she developed severe cellulitis and edema of the skin of the anterior abdominal wall in the field of her prior radiation therapy.
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Susceptibility factors Liver disease If gemcitabine is used in patients with isolated raised aspartate transaminase activity, dose reduction is not necessary in order to avoid drug-induced hepatotoxicity (84C ). However, in patients with raised serum bilirubin concentrations, an empirical reduction in dosage to 800 mg/m2 intravenously is highly recommended, in order to avoid an increased risk of hepatotoxicity. If this is well tolerated, the dose of gemcitabine can be increased. Renal disease In patients with raised serum creatinine concentrations, gemcitabine dosages should be chosen cautiously. However, empirical dosage modifications have not been so far recommended (84C ).
Tegafur A mixture of tegafur + uracil in molar proportions of 1:4, UFT, was studied about 20 years ago as an alternative to intravenous fluorouracil. The combination has since been approved in several countries for the treatment of solid tumors, particularly advanced colorectal cancer. In contrast to capecitabine, UFT is regularly combined with oral leucovorin in order to increase its activity in patients with advanced colorectal cancer. Its predominant adverse effects include myelosuppression, alopecia, nausea, weakness, hyperbilirubinemia, diarrhea, and mucositis, whereas significant hand–foot syndrome has surprisingly not yet been observed.
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cellular DNA polymerases in vitro. Because troxacitabine has a stereochemically unnatural structure, deoxycytidine deaminase cannot deaminate it to its inactive form. The half-life of troxacitabine is therefore rather long (about 80 hours). Troxacitabine has modest activity in advanced and/or metastatic renal cell carcinoma. In a phase II trial (10 mg/m2 intravenously once every 3 weeks) granulocytopenia grade 4 was the major dose-limiting adverse effect, followed by anemia and thrombocytopenia. The most common drug-related non-hematological adverse effects were rash (77%), hand–foot syndrome (69%), alopecia (51%), fatigue (51%), and nausea (57%). Without glucocorticoid premedication, the incidence of skin reactions was higher. Whether pyridoxine and topical dimethylsulfoxide (DMSO) can alleviate the incidence and severity of hand–foot syndrome needs further investigation (86C –88C ). Skin Skin reactions, including palmar–plantar erythrodysesthesia syndrome, occurred in six patients who had previously received troxacitabine, but developed recall reactions by various other chemotherapy regimens. The recall palmar–plantar erythrodysesthesia was mild to moderate with a minimal need for medical intervention (89r ).
ANTIFOLATE DRUGS Lometrexol
Drug interactions There is great similarity between capecitabine and UFT, for example in relation to the concomitant use of brivudine and related compounds. UFT aggravates leflunomide-associated peripheral neuropathy; however, the underlying mechanism has not been elucidated (85A ).
Lometrexol is a novel antifolate drug that targets de novo purine synthesis in tumor cells by inhibiting glycinamide ribonucleotide formyltransferase (GARFT), a folate-dependent enzyme. There have been phase II trials of intravenous lometrexol 10.4 mg/m2 weekly together with oral folic acid 3 mg/m2 /day. Without folic acid supplementation, severe cumulative toxicity on the bone marrow and the mucosa is likely. The role of lometrexol in clinical oncology has not been elucidated (90c ).
Troxacitabine
Methotrexate
Troxacitabine is a novel L-nucleoside analogue, a potent inhibitor and chain terminator for
Methotrexate is a folic acid antagonist used in a broad spectrum of indications, including
(SED-15, 2277)
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Chapter 45
rheumatoid arthritis, psoriasis, ectopic pregnancy, and selected solid tumors (e.g. CMF and breast cancer), osteogenic sarcoma, choriocarcinoma, and acute leukemias. After intravenous administration, 60–85% of a dose of methotrexate is excreted in the urine unchanged. Methotrexate is metabolized to 7hydroxymethotrexate, which is inactive. Less hydroxymethotrexate is formed when methotrexate is given as infusion, for example over 30 minutes, possibly because of saturation of aldehyde oxidase at higher methotrexate plasma concentrations. The elimination of methotrexate is competitively inhibited by penicillins (91A ). Nervous system Methotrexate-associated neurotoxicity has been classified into three forms: acute, subacute, and late (92R , 93E ). Acute neurotoxicity is characterized by an early onset (within 24 hours of administration) with symptoms of nausea, headache, somnolence, confusion, and seizures. In contrast, subacute forms occur at 7–9 days after exposure and cause affective disturbances and focal neurological deficits, including transient paresis, pseudobulbar palsy, and visual disorders. Finally, chronic or late methotrexate-related neurotoxicity develops weeks or months after administration and involves impairment of higher cognitive functions. Whereas the severity of the acute form correlates with the pharmacokinetics of methotrexate and its nervous system distribution (94A ), the subacute form has been proposed to be result from a metabolic disorder. There is some evidence that methotrexate increases plasma homocysteine concentrations, causing increased formation of sulphur-containing excitatory amino acids as endogenous agonists at NMDA receptors. Therefore, the supportive use of betaine as a methyl donor for homocysteine, or supportive intervention with NMDA receptor antagonists (for example dextromethorphan) could alleviate the severity of methotrexateinduced subacute neurotoxicity (93E ). Sensory systems Ocular discomfort (for example burning, dry eyes) during high-dose methotrexate therapy has been suggested to correlate with drug concentrations in the tears. Patients who are predisposed to acidic lacrimal secretions may develop more severe symptoms because of reduced solubility of methotrexate at lower pH values (94A ).
561 Respiratory Pulmonary fibrosis and acute or chronic interstitial pneumonitis have been described after methotrexate treatment. These adverse effects can occur at any time and any dose during methotrexate administration. Therefore, early signs such as fever, a dry and non-productive cough, dyspnea, and chest pain, together with radiographic evidence of pulmonary infiltrates, have to be considered as potential methotrexate-related pulmonary adverse effects. Besides withdrawing methotrexate, high dosages of glucocorticoids can be beneficial (95R ). Gastrointestinal Stomatitis, gingivitis, glossitis, pharyngitis, and gastrointestinal ulceration (any grade) are common after intravenous and oral methotrexate. Other gastrointestinal adverse effects include abdominal distress, dosedependent nausea and vomiting, anorexia, and diarrhea. Mucositis usually begins 3–5 days after methotrexate administration and lasts for about 4 days. Liver Acute and chronic liver toxicity can occur during methotrexate treatment. Acute effects include increased serum transaminase activities, usually asymptomatic and transient. In contrast, chronic hepatotoxicity is associated with liver fibrosis and histological changes. Based on the severity of this adverse effect, which can result in fatal forms of liver dysfunction, intermittent measurement of liver enzymes is mandatory during administration of methotrexate over 2 years or more and after cumulative doses exceeding 1500 mg. Other risk factors include obesity, alcoholism, other potential hepatotoxins, advanced patient age, and diabetes mellitus (96A ). 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 highly recommended that the urine be alkalinized (target urinary pH above 7.5) before intensive
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methotrexate regimens are started. Supportive agents include sodium bicarbonate orally or intravenously, acetazolamide 500 mg qds, or both in combination (97A –99A ). 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 (100A , 101A ). • 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 (99A ). 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 µmol/l. During the sixth cycle, methotrexate plasma concentrations were 657 µmol/l (compared with 3.3 µmol/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 sill abnormal, with a creatinine clearance of 10 ml/minute. The next day, he was given carboxypeptidase G2 50 units/kg, which resulted in a reduction in methotrexate plasma concentrations from 614 µmol/l to 24 µmol/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 6hourly 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.
Dosage regimens Care must be taken with the once-weekly regimen used in rheumatoid arthritis, which has repeatedly resulted in the use of a higher dosage frequency than recommended, highlighting the need for appropriate patient information (102A ). Management of adverse drug reactions Because methotrexate-related inhibition of dihydrofolate reductase is responsible for gastrointestinal and bone marrow toxicity, leucovorin (5-formyltetrahydrofolate) is highly recommended and replenishes the cellular pool of reduced folate in normal cells. However, leucovorin must not be started too early after the end of the methotrexate infusion because there is a risk of a “tumor rescue effect”. Usually,
Hans-Peter Lipp and Jörg Thomas Hartmann
the dose of leucovorin is adapted to the serum methotrexate concentrations and ranges from 10 to 1000 mg/m2 6-hourly intravenously if methotrexate concentrations are extremely high over time (103R ).
Pemetrexed Pemetrexed (LY231514, MTA) is a novel antifolate congener. It is transported into cells by the reduced folate carrier and undergoes intracellular polyglutamylation, resulting in a persistent cytotoxic metabolite, which targeting several enzymes simultaneously, including dihydrofolate reductase, thymidylate synthase, GARFT, and AICARFT (104r ). Pemetrexed has been approved as monotherapy for the treatment of advanced non-small cell lung cancer and in combination with cisplatin for the treatment of pleural mesothelioma (105r , 106C ). Further indications may include the treatment of other solid tumors, for example metastatic breast cancer (107C ). Following the recommended dosage of 500 mg/m2 intravenously every 3 weeks, hematological toxicity has been reported to be the most severe adverse effect, with grade 4 neutropenia in about 24% of treated patients. Under conditions of folate and/or cobalamin deficiency, there is an increase in total plasma homocysteine concentrations, which is a highly significant predictor of febrile neutropenia, grade 4 thrombocytopenia, and grade 4 diarrhea (106C ). As a consequence, folic acid and vitamin B12 supplements reduce the risk of severe myelosuppression, because both vitamins reduce homocysteine concentrations. Folic acid 350–1000 micrograms/day should be taken orally, starting at least 5 consecutive days before pemetrexed is begun and continuing throughout the course of therapy and for 21 days after the end of treatment. In addition, intramuscular vitamin B12 1000 micrograms every 9 weeks is highly recommended, starting 1–3 weeks before and continuing during treatment cycles (104r ). Grade 3 and 4 non-hematological adverse effects related to pemetrexed include stomatitis, diarrhea, vomiting, and skin reactions. However, the last can be significantly reduced by the prophylactic use of dexamethasone on the day
Cytostatic drugs
before chemotherapy and for 3 subsequent days (104r ).
Raltitrexed
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(SED-15, 3021)
The quinazoline antifolate drug raltitrexed (Tomudex® ) is a potent inhibitor of thymidylate synthase after polyglutamylation within cells (108R ). In a dosage of 3 mg/m2 intravenously every 3 weeks, it has been suggested to be a promising agent for first-line treatment of advanced colorectal cancer. However, during comparative phase 3 trials there was some evidence that bolus fluorouracil + leucovorin may be more effective in regard to survival advantage. Compared with bolus fluorouracil + leucovorin, raltitrexed has been associated with a lower incidence of leukopenia and mucositis. However, compared with continuous infusion fluorouracil + leucovorin, the incidences of neutropenia, thrombocytopenia, diarrhea, and lethargy were higher. A high percentage of the dose is excreted renally unchanged, and dosage modification is required in patients with impaired renal function, reducing the dose by 25% or 50% if the creatinine clearance is 55–65 or 25–54 ml/minute respectively (109R ). Liver The most common adverse effect of raltitrexed is a transient rise in liver enzymes (110R ). Although serious hepatic toxicity is very rare, there have been reports of fatal liver failure that was not preceded by transient increases in transaminases during earlier cycles (111A ). The most highly predictive factors of drug-induced hepatotoxicity are increases in transaminases, the number of chemotherapy cycles, the cumulative dose, unprolonged intervals between courses, and regimens that contain raltitrexed + oxaliplatin. Both oral glutathione (median dose 600 mg/day) and Sadenosylmethionine (median dose 800 mg/day) have been suggested to be promising hepatoprotective agents, without impairing the antineoplastic activity of the antifolate drug (110R ).
does not use the reduced folate transport to enter cells and does not need to be activated by polyglutamylation. It has a broader spectrum of antineoplastic activity than methotrexate, but has not yet been approved for the treatment of solid tumors. Trimetrexate can cause gastrointestinal toxicity, for example grade 3 and 4 diarrhea and nausea, and its myelosuppressive adverse effects appear to be moderate. In order to alleviate drug-induced toxicity in rapidly proliferating normal cells, oral leucovorin 15 mg 6-hourly is highly recommended, starting 24 hours after the administration of trimetrexate (112C , 113c ).
PHOSPHATIDYLCHOLINE ANTAGONISTS Miltefosine
(SED-15, 2348)
Miltefosine, the active ingredient of 6% miltefosine solution (Miltex® ), is an alkylphosphocholine derivative with a long-chain fatty acidlike backbone, which is structurally related to physiologically occurring phospholipids. Its cytotoxic drug effects appear to be linked to phospholipid turnover and signal transduction through cell membranes, including inhibition of protein kinase C, phospholipase C, and phosphoinositidase. Oral miltefosine has not yet been approved for anticancer treatment, but it has been used with some success in the eradication of leishmaniasis. In contrast, topical miltefosine is effective in the palliative treatment of cutaneous metastases. Systemic adverse effects of miltefosine are very rare during topical application, but local skin reactions, including erythema, pruritus, desquamation, skin dryness, itching, burning, and local pain, are common, although rarely severe (114c , 115C ).
ADENOSINE DEAMINASE INHIBITORS Trimetrexate
(SED-15, 3524)
Trimetrexate is a lipophilic inhibitor of dihydrofolate reductase. In contrast to methotrexate, it
Compounds such as fludarabine, 2-chlorodeoxyadenosine, and 2 -deoxycoformycin (pentostatin) are impressive agents for the treatment
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of indolent lymphoproliferative disorders, including hairy-cell leukemia, chronic lymphatic leukemia, and low-grade non-Hodgkin’s lymphoma. In contrast, they lack activity against common solid tumors (116R ).
Cladribine Cladribine is an adenosine deaminase inhibitor that has been approved for the treatment of hairy cell leukemia (116R ). It is usually given intravenously (for example 0.15 mg/kg/day for 7 days), although subcutaneous administration is generally feasible. Its systemic availability after oral administration is 37–55%, which is lower than fludarabine (55–70%) (117R , 118C ). About 30–50% of a dose is excreted unchanged in the urine within 24 hours, which highlights the need for appropriate dosage modification in patients with impaired renal function. Some of the adverse effects of cladribine are similar to those of fludarabine, including myelosuppression, immunodeficiency, and a risk of opportunistic infections (119R ). Nervous system and renal adverse effects particularly occur at high doses (4–9 times those currently recommended) (120R ). About 27% of patients developed a rash during the first 2 weeks of treatment, but skin and local reactions are generally mild. Accidental drug extravasation is non-irritant (121A ).
Fludarabine
(SED-15, 1391)
Because fludarabine is insoluble in aqueous solutions, its derivative fludarabine monophosphate is formulated for intravenous administration, after which it is rapidly converted to fludarabine. Fludarabine is generally well tolerated; transient myelosuppression is its major adverse effect. Cardiovascular Conditioning with fludarabine (25 mg/m2 /day on 5 consecutive days) and melphalan (70 mg/m2 on 2 consecutive days) has been associated with cardiotoxicity as a unique complication (122c ). However, analysis of the benefit to harm balance showed that the regimen led to durable remissions in patients with hematological malignancies.
Hans-Peter Lipp and Jörg Thomas Hartmann
Respiratory In a case-control study more patients than expected developed pulmonary toxicity, including fever, dyspnea, hypoxemia, and radiographic infiltrates after treatment with fludarabine (123A ). The authors calculated an incidence of 8.6%; however, patients with chronic lymphatic leukemia appeared to have a 13-fold higher risk than patients with other diseases treated with fludarabine. Intervention with glucocorticoids often led to objective and subjective improvement. The true incidence of fludarabine-related pulmonary dysfunction may need further revaluation. Fludarabine caused an eosinophilic pneumonia in a patient with stage IV follicular lymphoma (124A ). Nervous system Nervous system vulnerability related to standard-dose fludarabine appears to be multifactorial in origin, but it may involve immunodepression-related opportunistic infections, including JC virus, which has been associated with infection of oligodendroglial cells, causing demyelination. Progressive multifocal leukoencephalitis during standard-dose fludarabine treatment may be secondary to immunodeficiency rather than a direct toxic effect (120R , 125A –127A ). Hematologic Adverse hematological effects of fludarabine include a reduced total lymphocyte count, prolonged reductions in CD4 and B cell counts, transient monocytopenia, and a transient reduction in NK cell count. Predisposing factors include older age, poor performance status, advanced disease, bone marrow involvement, hypogammaglobulinemia, higher than recommended doses, and concurrent glucocorticoid therapy. Liver Sequential use of fludarabine and rituximab was a susceptibility factor in the development of fulminant hepatitis B virus reactivation and listeriosis in a female carrier of hepatitis B with acute prolymphocytic leukemia (128A ). Reactivation of hepatitis B resulted in severe liver failure 3 months after the end of treatment. Listeria monocytogenes was also identified as a pathogen. These complications can be regarded as being due to deleterious effects on T cells. Infection risk Because life-threatening infections with unusual opportunistic pathogens can
Cytostatic drugs
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occur, early diagnostic evaluation is mandatory. Important pathogens include Pneumocystis jiroveci, Aspergillus, Torulopsis glabrata, and disseminated cytomegalovirus. Several investigators have recommended the use of co-trimoxazole with or without aciclovir and antimycotic agents as prophylaxis. However, the many possible infections limit routine antimicrobial drug therapy. Patients should be treated with the fewest number of courses of fludarabine necessary for an optimal response, and continuous treatment cycles that exceed 6– 9 months should be avoided whenever possible (125A –127A ). Susceptibility factors Renal disease Whether fludarabine is given intravenously or orally, a high percentage is excreted unchanged by the kidneys and the halflife of fludarabine, normally up to 30 hours, can be significantly prolonged in patients with impaired renal function (129R , 118C ). Appropriate dosage modification is therefore highly recommended in patients with renal dysfunction, for example 15 mg/m2 /day instead of 25 mg/m2 /day intravenously in patients with creatinine clearance values below 40 ml/min (129R ). Abnormal fluid spaces Fludarabine is distributed into third spaces, for example pleural effusions. Therefore, prolonged drug exposure based on third compartment effects has to be kept in mind in relation to the risk of severe forms of neutropenia and septicemia. Pleural fluid and ascites should be drained before administration of fludarabine, in order to reduce the risk of accumulation (130A ).
Pentostatin Pentostatin (2 -deoxycoformycin) is a natural product isolated from Streptomyces antibioticus. It is a potent and irreversible inhibitor of adenosine deaminase, which is widely distributed in mammalian tissues, with particularly high constitutive activity in lymphocytes (T cells more than B cells). Pentostatin-related inhibition of adenosine deaminase results in accumulation of deoxyadenosine and its nucleotides,
which in turn results in a negative regulatory effect on ribonucleotide reductase as well as DNA replication and repair. Proliferative lymphocytes are predominantly targeted by pentostatin and related compounds, which is of particular interest in the treatment of lymphoproliferative disorders. Pentostatin is used in the treatment of hairy-cell leukemia (131R , 132r ). Hematologic Neutropenia occurs in up to 70% of patients. In addition, several weeks after pentostatin treatment, patients develop a significant reduction in the number of CD4 and B cells, which favors the occurrence of bacterial, viral, and fungal infections. Most patients are lymphophenic rather than neutropenic at the start of the infection (132r ). Nervous system Inhibition of adenosine deaminase in the CSF can result in accumulation of adenosine and deoxyadenosine, which both have significant depressant effects in the nervous system, which may explain the increased incidence of lethargy during repeated cycles of pentostatin. In contrast, increasing the interval between doses reduces the incidence. Other nervous system adverse effects included depression, paresthesia, and mild drowsiness (120R , 132r ). Urinary tract A fall in creatinine clearance of more than 20 ml/minute can occur in up to 50% of patients 10–12 days after the start of pentostatin therapy. However, this effect appears to resolve completely after withdrawal in patients with normal baseline renal function. Hydration with 500–1000 ml of fluids before and at least 500 ml after drug administration has been recommended (131R , 132r ). Susceptibility factors A high percentage of pentostatin is excreted unchanged via the kidneys after intravenous administration, and dosage adjustment is warranted in patients with impaired renal function (133c , 117R ).
GENERAL Anthracyclines
(SED-15, 245)
Cardiovascular Pretreatment with anthracyclines is a risk factor for prolongation of
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the QTc interval during isoflurane anesthesia (134E ). In 40 women undergoing surgery for breast cancer, who were pretreated with anthracyclines (n = 20) or who were chemotherapy naive, there was significantly greater prolongation of the QTc interval in those who had previously received an anthracycline (135c ). Although relatively modest cumulative doses of anthracyclines were given to 111 children with acute lymphoblastic leukemia, there were subclinical abnormalities of left ventricular performance. Continuous drug administration by 6-hourly infusion did not appear to be advantageous compared with bolus injection in respect to the development of late cardiotoxicity (136c ). Cardiac failure and severe cardiac abnormalities (mainly conduction abnormalities) were of major clinical importance in 229 childhood survivors who had received doxorubicin, even after follow-up of 15 years or more (137C ). The cardiotoxic risk increases with the dose of doxorubicin and the amount of radiation received by the heart, without evidence of a threshold.
Oxazaphosphorines
(SED-15, 1025,
1714) The oxazaphosphorine trofosfamide is being increasingly used in the treatment of several solid and hematological tumors. It is mainly metabolized to ifosfamide and to a smaller extent to cyclophosphamide. Respiratory Although oxazaphosphorines are beneficial in the treatment of autoimmune lung disease, there are case reports of interstitial pneumonitis secondary to both ifosfamide and cyclophosphamide in patients with cancers. • A 83-year-old woman with a malignant peripheral nerve sheath tumor of the right femur that had metastasized to multiple sites, including mesenteric, retroperitoneal, and mediastinal lymph nodes, as well as the abdominal wall and the right pleura, was given palliative treatment with oral trofosfamide 300 mg/day for 7 days, followed by a
Hans-Peter Lipp and Jörg Thomas Hartmann
maintenance dose of 150 mg/day (138A ). She developed progressive dyspnea on exertion. A CT scan showed excellent partial remission (over 80% tumor reduction) at all sites, but high resolution CT imaging of the chest also showed bilateral fibrosis compatible with exogenous allergic alveolitis. Trofosfamide was withdrawn and she was given prednisolone 1 mg/kg, which resulted in rapid subjective improvement of the dyspnea and partial remission of the alveolitis.
Drug interactions In a randomized comparison of itraconazole and fluconazole as preventive agents in patients undergoing allogenic stem cell transplantation, there was an interaction between high-dose cyclophosphamide and itraconazole (139C ). Exposure to toxic metabolites was greater among those who received itraconazole than those who received fluconazole. Inhibition of CYP isozymes by itraconazole was probably responsible.
Taxanes
(SED-15, 1172, 2663)
Cardiovascular During a phase 2 study, a weekly regimen containing paclitaxel and trastuzumab had beneficial activity in anthracycline- and taxane-pretreated patients with HER2 overexpression. Since cardiac dysfunction (grade 3) was observed frequently, monitoring of cardiac function is warranted during combined use of these two drugs (140C ). Skin Stevens–Johnson syndrome occurred in a 53-year-old patient with advanced squamous cell carcinoma who received systemic chemotherapy containing carboplatin and paclitaxel (141A ). The authors concluded that the taxane was the likely cause of this cutaneous complication. Immunologic Hypersensitivity reactions to paclitaxel can occur in spite of adequate premedication regimens. Short-course premedication with dexamethasone given once intravenously within 1 hour before paclitaxel administration did not prevent a fatal hypersensitivity reaction in a middle-aged man (142A ).
Cytostatic drugs
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Radiological contrast agents
TYPES OF CONTRAST AGENTS Iodinated water soluble contrast media are of four types: (a) high-osmolar ionic monomers (e.g. diatrizoate, iothalamate, metrizoate); (b) low-osmolar ionic dimers (e.g. ioxaglate); (c) low-osmolar non-ionic monomers (e.g. iopitridole, iohexol, iomeprole, iopamidole, iopromide, ioversol); (d) iso-osmolar non-ionic dimers (e.g. iodixonal, iotrolan). They are mainly used intravascularly, but can also be injected into body cavities, particularly the low-osmolar contrast agents. They are also suitable for oral or rectal administration. The high-osmolar water-soluble contrast agent Gastrografin (diatrizoate preparation) is suitable only for oral or rectal administration. Barium formulations, widely used for imaging different parts of the gastrointestinal tract, are based on barium sulfate, which is not absorbed. Several additives are used in commercial barium formulations to enhance the properties of the suspension to image the gastrointestinal tract and improve taste for oral use. The barium formulations are generally safe, with a low incidence of adverse effects. There are also contrast agents to enhance the diagnostic information provided by ultrasound scanning and magnetic resonance imaging. The latter are mainly gadolinium-based, but new non-gadolinium paramagnetic contrast agents have recently become available. Ultrasound contrast agents are microbubbles that provide acoustic enhancement. Adverse reactions to contrast media are generally few, and serious reactions are uncommon. Ultrasound contrast agents are particularly safe. Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29046-9 © 2007 Elsevier B.V. All rights reserved.
Water-soluble intravascular iodinated contrast agents (SED-15, 1848; SEDA-26, 512; SEDA-27, 496; SEDA-28, 552) Adverse reaction to intravascular iodinated contrast agents can be minor, intermediate or severe life threatening. All types of reactions to low osmolar contrast media (LOCM) are at least five times less common than reactions to high osmolar contrast media (HOCM). The benefits of using contrast media must be weighed against the potential risks for each individual undergoing radiological examination. In a review of acute reactions to contrast agents the susceptibility factors for these reactions have been highlighted and methods for reducing their incidence in patients at risk discussed (1CR ). These issues have been well covered in previous Annuals (SEDA 27, 497; SEDA-28, 552). Nervous system Status epilepticus can complicate myelography with water-soluble lowosmolar non-ionic iodinated contrast media, particularly in patients with epilepsy. The incidence of status epilepticus after myelography with non-ionic contrast medium iopamidol has been retrospectively investigated in 1350 patients over 5 years (2C ). Two non-epileptic patients (0.15%) had a first generalized tonic– clonic seizure and a 67-year-old woman with symptomatic epilepsy after a remote ischemic stroke developed a generalized tonic–clonic seizure evolving into a dialeptic and right nystagmus status epilepticus (i.e. complex focal status) lasting 5 hours. The authors concluded that iopamidol myelography is associated with a risk of seizures in non-epileptic individuals and can induce status epilepticus in patients with epilepsy. Patients should be informed about the risk of seizure induction.
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Table 1. Simple guidelines on iodinated contrast media and thyroid function in adults (http://www.esur.org) • Iodinated contrast media should not be given to patients with manifest hyperthyroidism Development of thyrotoxicosis after iodinated contrast media • Patients with normal thyroid function No risk • Patients with Graves’ disease At risk • Patients with multinodular goiter and thyroid autonomy, especially if they are elderly and/or live in areas of dietary iodine deficiency • Prophylaxis is generally not necessary Recommendations • Patients at risk should be closely monitored by endocrinologists after iodinated contrast medium injection • In selected high-risk patients prophylactic treatment may be given by an endocrinologist; this is more relevant in areas of dietary iodine deficiency • Intravenous cholangiographic contrast media should not be given to patients at risk Radioactive iodine treatment • Patients undergoing therapy with radioactive iodine should not have received Recommendation iodinated contrast media for at least 2 months before treatment Isotope imaging of the thyroid • Isotope imaging of the thyroid should be avoided for 2 months after iodiRecommendation nated contrast medium injection Absolute contraindication
Ascending tonic–clonic syndrome can complicate myelography with water-soluble nonionic contrast media (3A ). • A 52-year-old man had progressive tonic–clonic activity 30 minutes after myelography with Omnipaque (a low-osmolar non-ionic contrast medium). The activity progressed to seizures, hyperthermia, and acidosis. He was intubated, cooled, and treated symptomatically. His creatine kinase activity rose to 60 000 IU/l. He eventually recovered completely.
Although this syndrome superficially resembles malignant hyperthermia, the pathophysiology is different. Survival depends on prompt recognition and rapid symptomatic treatment. Treatment with dantrolene sodium is not necessary. Endocrine Hyperthyroidism and hypothyroidism have both been reportedly precipitated by the administration of iodinated contrast media (SEDA-21, 478; SEDA-23, 497; SEDA-25, 559, SEDA-26, 515, SEDA-28, 554). Thyrotoxic crisis has been reported after intravascular administration of iodinated contrast media in patients with Graves’ disease (4A ). • A 41-year-old man had CT pulmonary angiography and developed a tachycardia of 209/minute and hypertension of 220/100 mmHg, which resolved after sublingual and intravenous glyceryl trinitrate and intravenous metoprolol. On further
assessment he was found to have thyromegaly with bruit, a fine tremor, and brisk reflexes. He also had a 1-year history of intermittent anxiety, bouts of palpitation, and weight loss. The free thyroxine concentration was 53 ng/l and TSH was less than 0.5 µU/ml. The diagnosis was Graves’ disease and thyrotoxicosis triggered by the administration of iodinated contrast medium.
The Contrast Media Safety Committee of the European Society of Urogenital Radiology (ESUR) has produced guidelines on the effects of iodinated contrast media on thyroid function in adults (Table 1) (5CR ). Hematologic The effects of contrast media on hemostasis have been a subject of interest and debate for many years (SEDA-27, 499; SEDA-28, 555). It has been inaccurately suggested that non-ionic radiographic contrast media could be thrombogenic. Some clinicians therefore add heparin to the contrast media solution during percutaneous angioplasty to avoid a risk of thrombosis. Bivalirudin, used to replace heparin during percutaneous coronary intervention, is reported to be associated with reduced bleeding complications. The effect of adding heparin to contrast medium during percutaneous coronary intervention and stent implantation has been evaluated in 664 patients, who were treated with either bivalirudin only (0.75 mg/kg bolus + 1.75 mg/kg/hour, n = 323) or the same dose
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plus low-dose heparin added to the contrast medium solution (mean dose 2102 U, n = 341) (6C ). Periprocedural, in-hospital, and 1-month clinical outcomes, including thrombotic complications, were similar. There was no difference in the periprocedural thrombosis rate between the groups. However, in the heparin group, the overall incidence of hematoma was significantly higher (8.5% versus 3.8%), there were trends toward higher rates of blood transfusion (6.6% versus 2.6%) and overall vascular complications (5.3% versus 0.01%), including pseudoaneurysm (2.6% versus 0%), and patients who required surgical repair (1.8% versus 0.3%). The authors concluded that routine addition of low-dose heparin to contrast media during contemporary percutaneous coronary intervention does not add any protection and is associated with higher rates of bleeding and vascular complications.
Nephrotoxicity due to contrast media DoTS classification: Reaction: Contrast medium nephrotoxicity Dose-relation: Collateral Time-course: Intermediate Susceptibility factors: Endogenous factors (pre-existing renal insufficiency, particularly if it is secondary to diabetes mellitus congestive heart failure, dehydration); drugs (nephrotoxic drugs, such as non-steroidal anti-inflammatory drugs; metformin; mannitol and diuretics, particularly loop diuretics); multiple repeat exposures to contrast media within a short period of time (72 hours) Contrast medium nephrotoxicity is a condition in which impaired renal function (an increase in serum creatinine concentration of more than 25% or 44 µmol/l) occurs within 3 days after intravascular administration of a contrast medium in the absence of an alternative cause (SEDA-27, 500; SEDA-28, 556). Susceptibility factors The susceptibility factors for contrast medium nephrotoxicity are listed above.
The possible nephrotoxicity of non-ionic monomeric contrast media has been investigated in patients with cirrhosis (7C ). Firstly, renal function was evaluated before and 48 hours after the administration of contrast media in 31 patients with cirrhosis (20 with ascites, 5 with renal insufficiency); glomerular filtration rate using iothalamate 125 I clearance, renal plasma flow using iodohippurate 131 I clearance, solute-free water clearance, urine sodium, prostaglandins, and markers of tubular damage were measured. Non-ionic monomeric contrast media (mean dose 202, range 110– 400, ml) did not significantly change renal function; urinary prostaglandin E2 and N-acetylbeta-D-glucosaminidase rose significantly, but sodium and solute-free water excretion were unchanged. Secondly, a different group of 60 patients with cirrhosis and renal insufficiency were examined prospectively; none had renal insufficiency due to contrast media. Only in one patient with septic shock was the contrast medium a possible contributing factor. In conclusion, non-ionic monomeric contrast media do not have adverse effects on renal function in patients with cirrhosis. The cumulative risk of combinations of susceptibility factors is not known. A simple risk score of nephrotoxicity has been devised in 8357 patients who had percutaneous coronary intervention, who are at higher risk of nephrotoxicity because of hemodynamic instability and the non-feasibility of adequate prophylaxis (8C ). In 5571 patients eight variables were assigned a weighted integer: • • • • • • • •
hypotension 5; intra-aortic balloon pump 5; congestive heart failure 5; chronic kidney disease 4; diabetes 4; age over 75 years 4; anemia 3; volume of contrast 1 for each 100 ml.
The sum of the integers was the total risk score for each patient. The overall occurrence of nephrotoxicity was 13%. The frequency was 7.5% for low scores (5 or less) and 57% for high scores (16 and more). The frequency of nephrotoxicity increased exponentially with increasing risk score. The model was then tested in 2786 patients and had good discriminative power;
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the increasing risk score was again strongly associated with nephrotoxicity: 8.4% for a low score and 56% for a high score. In another study a time-insensitive score was derived to predict the risk of nephrotoxicity after percutaneous coronary intervention, which occurred in 2% of 20 479 patients and was associated with a 15-fold increase in adverse cardiac events (9C ). Independent variables (with weighted scores) included:
• use of an intra-aortic balloon (15.5; 4.65, 52).
• estimated creatinine clearance <60 ml/minute 2; • urgent percutaneous coronary intervention 2; • intra-aortic balloon pump use 2; • diabetes mellitus 1; • congestive heart failure 1; • hypertension 1; • peripheral vascular disease 1; • contrast volume >260 ml 1.
Prevention Several strategies have been advocated to reduce the incidence of nephrotoxicity due to contrast media. The lowest possible dose of a low-osmolar or iso-osmolar non ionic-contrast medium should be used in highrisk patients. The use of high-osmolar contrast media and large doses should be avoided. Intravenous hydration with saline (1 ml/kg/ hour for 4–6 hours before contrast injection and for 12 hours afterwards) should be given (SEDA-27, 501; SEDA-28, 557). The value of pharmacological manipulation using renal vasodilators, such as fenoldopam, or cytoprotective drugs, such as N-acetylcysteine, in preventing contrast nephropathy remains uncertain, in spite of large number of publications in this field. The results of these studies have been conflicting; some have reported a protective effect while others have failed to detect any benefit. In a recent study two doses of N-acetylcysteine have been compared in 224 consecutive patients with chronic renal insufficiency (creatinine concentration over 130 µmol/l and/or creatinine clearance under 60 ml/minute), who were randomly assigned to receive N-acetylcysteine in the standard dose (600 mg orally bd; n = 110) or in a double dose (1200 mg orally bd; n = 114) for 2 days starting 24 hours before contrast administration (low-osmolar contrast media) (11C ). All received intravenous hydration with 0.45% saline for 12 hours before and after the procedure. There were increases of at least 0.44 µmol/l in creatinine concentration 48 hours after the procedure in 12/109 patients (11%) in the standard dose group and 4/114 patients (3.5%) in the double dose group (OR = 0.29; 95%CI = 0.09, 0.94). In the subgroup given a low dose of contrast (under 140 ml), there was no significant difference in renal function deterioration between the two groups. However, in the subgroup given a high
The incidence of nephrotoxicity after percutaneous coronary intervention increased with each unit increase in score. No patient with a score of 1 or less developed nephropathy, whereas 26% of patients with a score of 9 or more did. Propensity score analysis showed that patients who developed nephrotoxicity after percutaneous coronary intervention, irrespective of the need for hemodialysis, had higher in-hospital rates of major adverse cardiac events (OR = 15; 95%CI = 11, 20). In another study the incidence, clinical predictors, and outcome of contrast media-induced nephrotoxicity were assessed after primary percutaneous coronary intervention for acute myocardial infarction in 208 consecutive patients (10C ). There was nephrotoxicity in 40 patients (19%). Of the 160 patients with a baseline creatinine clearance of 60 ml/minute or more, only 21 (13%) developed nephrotoxicity, whereas it occurred in 19 (40%) of those with a creatinine clearance of under 60 ml/minute. The following factors (with odds ratios and 95% confidence intervals) were significant independent correlates of nephrotoxicity in a multivariate analysis: • age over 75 years (5.28; 1.98, 14); • anterior infarction (2.17; 0.88. 5.34); • time to reperfusion over 6 h (2.51; 1.01, 6.16); • contrast agent volume over 300 ml (2.80; 1.17, 6.68);
Patients who developed nephrotoxicity had longer hospital stays (13 versus 8 days), more complicated clinical courses, and significantly higher mortality rate (31% versus 0.6%). The authors concluded that preventive strategies are needed, particularly in high-risk patients.
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dose of contrast (140 ml or more), nephrotoxicity was significantly more common after the single dose (19%) than the double dose (5.4%). The same authors have also compared fenoldopam mesylate (an agonist at dopamine D1 receptors) with double dose of N-acetylcysteine in 192 consecutive patients with chronic renal insufficiency, who were randomly assigned to receive 0.45% saline intravenously and Nacetylcysteine 1200 mg orally bd; n = 97) or fenoldopam (0.10 micrograms/kg/minute; n = 95) before and after a non-ionic, iso-osmolar contrast medium (iodixanol) (12C ). The baseline creatinine concentrations were similar (152 µmol/l and 155 µmol/l respectively). There was an increase of at least 44 µmol/l in creatinine concentration 48 hours after the procedure in 4 (4.1%) of 97 patients who were given N-acetylcysteine and in 13 (14%) of 95 patients who were given fenoldopam (OR = 0.27; 95%CI = 0.08, 0.85). The amount of contrast medium used in the two groups was similar (160 and 168 ml respectively). Thus, high-dose N-acetylcysteine may be more effective than fenoldopam. The benefit of oral acetylcysteine as an adjunct to saline hydration has been prospectively studied in 80 patients with chronic renal insufficiency (mean serum creatinine 177 µmol/l) who underwent coronary angiography (mean dose of non-ionic contrast medium 115 ml), with or without intervention (13C ). They were randomly assigned to either acetylcysteine (600 mg orally tds) or placebo, in addition to intravenous 0.45% saline (1 ml/kg/hour) 12 hours before and after coronary angiography. The serum creatinine concentration increased by over 44 µmol/l in the 48 hours after coronary angiography in 7 (9%) of the 80 patients: in 4 (10%) of the 41 patients who were given acetylcysteine and in 3 (8%) of the 39 patients who were given placebo. The incidence of in-hospital adverse events (acetylcysteine 5%, placebo 8%) and the median length of hospital stay (acetylcysteine 4 days, placebo 2 days) did not differ significantly. These findings do not support routine prophylactic administration of oral acetylcysteine as an adjunct to saline hydration in preventing nephropathy in patients with chronic renal insufficiency undergoing coronary angiography. Considering all the published studies, including systematic reviews, consistent protec-
577 tion by acetylcysteine against contrast nephropathy has not been proven (SEDA-28, 557). In addition, the nephroprotective effect of acetylcysteine that was observed in some studies might have been spurious, as most studies used serum creatinine as a surrogate marker of renal function. A recent study has shown that acetylcysteine can cause a reduction in serum creatinine concentration independent of altered GFR (14C ). It was suggested that acetylcysteine may enhance the tubular secretion of creatinine, causing the serum creatinine concentration to fall. The authors concluded that the use of creatinine concentration measurement alone in assessing renal function in studies of the renoprotective effect of acetylcysteine is questionable, and that direct measurement of GFR or another marker of renal function, such as cystatin C, should be considered. Thus, although acetylcysteine has several attractive advantages, being inexpensive and easy to administer and having few adverse effects, further studies are required before its routine use can be endorsed unreservedly (15CR ). In animal models of acute ischemic renal failure pretreatment with sodium bicarbonate was more renoprotective than sodium chloride. This protective effect is thought to be due to antioxidant effects and scavenging reactive free radicals and not secondary to better volume expansion compared with saline infusion (15CR ). The efficacy of sodium bicarbonate infusion compared with hydration with sodium chloride for prevention of contrast medium induced nephrotoxicity has recently been investigated prospectively in 119 patients with stable serum creatinine concentrations, who were randomized to a 154 mmol/l infusion of either sodium chloride (n = 59) or sodium bicarbonate (n = 60) (16C ). The fluid was given as a bolus of 3 ml/kg/hour for 1 hour before contrast (iopamidol “low-osmolar non-ionic contrast medium,” 370 mg iodine/ml) followed by an infusion of 1 ml/kg/hour for 6 hours after the procedure. The two groups were matched, and mean baseline serum creatinine concentrations were 151 and 167 µmol/l respectively. There was nephrotoxicity in 8 (14%) of those who received sodium chloride but in only one (1.7%) who received sodium bicarbonate. In a follow-up registry of 191 consecutive patients who received prophylactic sodium bicarbonate contrast nephropathy developed in only 3
578 cases (1.6%). The protective effect of sodium bicarbonate in this study was impressive, and there were no important adverse effects. Furthermore, this approach could be suitable for out-patient cases, as fluid administration can begin an hour before the procedure and need only continue for 6 hours afterwards. However, further studies are required to establish the consistency of sodium bicarbonate in reducing the incidence of contrast nephropathy in high-risk patients. Conclusions Several review articles on this subject have been published over the last few years, reflecting a high degree of interest and appreciation of its clinical importance, particularly in patients undergoing life-saving cardioangiographic procedures. Most authors agree on the following approach to minimize the risk: • if administration of an iodinated contrast medium is deemed necessary in high-risk patients, volume expansion should be offered; • the smallest possible dose of contrast medium should be used; • the choice of agent should be either a nonionic iso-osmolar dimeric contrast medium or a non-ionic low-osmolar monomeric contrast medium. Prophylactic administration of fenoldopam or acetylcysteine has not offered consistent protection. Newer data suggest benefit from high-dose N-acetylcysteine (1200 mg bd) for patients who receive high doses (over 140 ml) of contrast agent, or in those with advanced renal insufficiency (serum creatinine over 220 µmol/l). Sodium bicarbonate infusion reduces the risk, but further studies are required to confirm its protective effect (15CR , 16C , 17CR ).
Immunologic Severe non-IgE-mediated anaphylactic (i.e. anaphylactoid) reactions to contrast media can be associated with edema of the bowel wall (18A ). • A 21-year-old woman underwent a CT scan of the abdomen with oral barium sulfate suspension and an injection of iothalamate meglumine (a high osmolar ionic contrast medium, 282 mg I/ml at a rate of 1.5 ml/second), with no contraindications. About 70 seconds after the start of the injection,
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she became breathless and developed severe itching, with swelling of the face, lips, and eyelids. The heart rate was 80/minute and the blood pressure 130/90 mmHg. She was given intravenous fluids and oxygen and the dyspnea improved rapidly, as did the itching and swelling. The CT scan was performed and showed thickened bowel wall, particularly of the cecum and colon.
MRI CONTRAST MEDIA Gadolinium salts (SED-15, 1469; SEDA-26, 520, SEDA-27, 504; SEDA-28, 561) Drug interactions The Contrast Media Safety Committee of the European Society of Urogenital Radiology has introduced useful guidelines on interactions between contrast media and other drugs and interference with biochemical tests (Table 2) (19S ). Interference with diagnostic tests Gadodiamide and gadoversetamide can cause spurious hypocalcemia, particularly in doses of 0.2 mmol/kg or higher in patients with renal insufficiency (20C –22C ). These contrast media interfere with calcium measurements obtained by assay using the ortho-cresolphthalein complexone (OOC) method but not with assays that use the Arsenazo III method (23C , 24C ). False measurements of serum calcium did not occur with gadopentetate dimeglumine (Gd-DTPA) or gadoteridol (19C ). In very high concentrations Gd-DTPA can interfere with calcium determination when methylthymol blue is used (25C ). Awareness of this effect on calcium measurements by some MRI contrast agents is important to avoid incorrect and potentially hazardous treatment (20C ). Biochemical assays are better performed before injection of the contrast medium or delayed for at least 24 hours afterwards, or longer in patients with renal impairment. Urgent laboratory tests performed on specimens collected shortly after injection should be carefully assessed. The accuracy of unexpected abnormal results should be questioned and discussed with colleagues from the laboratory.
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Table 2. Simple guidelines for avoiding interactions between contrast media and other drugs (the ESUR guidelines can be found at http://www.esur.org) Do
Be aware of the patient’s drug history Keep proper records of the contrast medium injection (time, dose, name)
Drugs that need special attention
Metformin
Refer to ESUR guidelines on metformin
Ciclosporin Cisplatin Aminoglycosides Non-steroidal anti-inflammatory drugs Beta-blockers
Refer to ESUR guidelines on nephrotoxicity
Interleukin-2 Hydralazine
Refer to ESUR guidelines on prevention and management of adverse reactions Refer to ESUR guidelines on delayed reactions Avoid contrast medium injection if possible
Do not
Mix contrast media with other drugs in tubes or syringes Make non-emergency biochemical analysis on blood or urine collected within 24 hours of contrast medium injection
Isotope studies
Thyroid Bone Erythrocyte labelling
Sulfur hexafluoride The use of sulfur hexafluoride (SonoVue) in echocardiography has been temporarily suspended by the EMEA pending further evaluation of it benefit to harm balance (26S ). The EMEA issued a public statement to inform health-care professionals that SonoVue • should not be used in echocardiography; • is contraindicated in patients with cardiac disorders; • is still indicated for use in non-cardiac imaging; • should be given under close medical supervision, and supervision should be continued for at least 30 minutes after administration.
Refer to ESUR guidelines on thyroid function in adults Avoid contrast medium injection for at least 24 hours before the isotope study
This regulatory action comes after reports of adverse events, including severe hypotension, bradycardia, cardiac arrest, and acute myocardial infarction, most of which occurred in patients undergoing echocardiography in the context of an idiosyncratic hypersensitivity reaction. There were three deaths in patients with severe coronary artery disease. The EMEA will continue to review information relating to the safety of SonoVue and will take further action as appropriate. The labelling has been updated accordingly.
References 1. Hagan JB. Anaphylactoid and adverse reactions to radiocontrast agents. Immunol Allergy Clin N Am 2004;24:507–19. 2. Klein KM, Shiratori K, Knake S, Hamer HM, Fritsch B, Todorova-Rudolph A, Rosenow F. Sta-
tus epilepticus and seizures induced by iopamidol myelography. Seizure 2004;13:196–9. 3. Rosenberg H, Grant M. Ascending tonic–clonic syndrome secondary to intrathecal Omnipaque. J Clin Anesth 2004;16:299–300.
580 4. Kulstad CE, Carlson A. Contrast-induced thyrotoxicosis. Ann Emerg Med 2004;44:281–2. 5. van der Molen AJ, Thomsen HS, Morcos SK, Contrast Media Safety Committee, European Society of Urogenital Radiology (ESUR). Effect of iodinated contrast media on thyroid function in adults. Eur Radiol 2004;14:902–7. 6. Rha S-W, Kuchulakanti PK, Pakala R, Cheneau E, Pinnow E, Guevara M, FernandezEsparrach G, Alessandria C, Torre A, Terra C, Montana X, Piera C, Alvarez ML, Jimenez W, Gines P, Arroyo V. Effects of contrast media on renal function in patients with cirrhosis: a prospective study. Hepatology 2004;40:646– 51. 7. Mehran R, Aymong ED, Nikolsky E, Lasic Z, Iakovou I, Fahy M, Mintz GS, Lansky AJ, Moses JW, Stone GW, Leon MB, Dangas G. A simple risk score for prediction of contrastinduced nephropathy after percutaneous coronary intervention: Development and initial validation. J Am Coll Cardiol 2004;44:1393–9. 8. Bartholomew BA, Harjai KJ, Dukkipati S, Boura JA, Yerkey MW, Glazier S, Grines CL, O’Neill WW. Impact of nephropathy after percutaneous coronary intervention and a method for risk stratification. Am J Cardiol 2004;93:1515–9. 9. Marenzi G, Lauri G, Assanelli E, Campodonico J, De Metrio M, Marana I, Grazi M, Veglia F, Bartorelli AL. Contrast-induced nephropathy in patients undergoing primary angioplasty for acute myocardial infarction. J Am Coll Cardiol 2004;44:1780–5. 10. Briguori C, Colombo A, Violante A, Balestrieri P, Manganelli F, Paolo Elia P, Golia B, Lepore S, Riviezzo G, Scarpato P, Focaccio A, Librera M, Bonizzoni E, Ricciardelli B. Standard vs double dose of N-acetylcysteine to prevent contrast agent associated nephrotoxicity. Eur Heart J. 2004;25:206–11. 11. Briguori C, Colombo A, Airoldi F, Violante A, Castelli A, Balestrieri P, Paolo Elia P, Golia B, Lepore S, Riviezzo G, Scarpato P, Librera M, Focaccio A, Ricciardelli B. N-acetylcysteine versus fenoldopam mesylate to prevent contrast agentassociated nephrotoxicity. J Am Coll Cardiol 2004;44:762–5. 12. Goldenberg I, Shechter M, Matetzky S, Jonas M, Adam M, Pres H, Elian D, Agranat O, Schwammenthal E, Guetta V. Oral acetylcysteine as an adjunct to saline hydration for the prevention of contrast-induced nephropathy following coronary angiography. A randomized controlled trial and review of the current literature. Eur Heart J 2004;25:212–8. 13. Hoffmann U, Fischereder M, Kruger B, Drobnik W, Kramer BK. The value of Nacetylcysteine in the prevention of radiocontrast
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agent-induced nephropathy seems questionable. J Am Soc Nephrol 2004;15:407–10. Morcos SK. Prevention of contrast media nephrotoxicity following angiographic procedures. J Vasc Interv Radiol 2005;16:13–23. Merten GJ, Burgess WP, Gray LV, Holleman JH, Roush TS, Kowalchuk GJ, Bersin RM, Moore AV, Simonton CA, Rittase RA, Norton HJ, Kennedy TP. Prevention of contrastinduced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA 2004;291:2328–34. Maeder M, Klein M, Fehr T, Rickli H. Contrast nephropathy: review focusing on prevention. J Am Coll Cardiol 2004;44:1763–71. Blake SP, McNicholas MM. Hypersensitivity to intravenous contrast material causing CT appearance of bowel wall thickening. Clin Radiol 2004;59:638–40. Morcos SK, Thomsen HS, Exley CM, Members of Contrast Media Safety Committee of European Society of Urogenital Radiology (ESUR). Contrast media: interaction with other drugs and clinical tests. Eur Radiol 2005;15:1463–8. Kefalas CH, Murray NG, Aguanno JJ, Dockery WD, Weinstein JS, Anderson K, Klintmalm GB. Pseudohypocalcemia after magnetic resonance imaging with gadolinium in patients with cirrhosis. Liver Transpl 2004;10:136–40. Prince MR, Erel HE, Lent RW, Blumenfeld J, Kent KC, Bush HL, Wang Y. Gadodiamide administration causes spurious hypocalcemia. Radiology 2003;227:639–46. Choyke PL, Knopp MV. Pseudohypocalcemia with MR imaging contrast agents: a cautionary tale. Radiology 2003;227:627–8. Proctor KAS, Rao LV, Roberts WL. Gadolinium magnetic resonance contrast agents produce analytic interference in multiple serum assays. Am J Clin Pathol 2004;121:282–92. Normann PT, Frøysa A, Svaland M. Interference of gadodiamide injection (OMNISCAN® ) on the colorimetric determination of serum calcium. Scand J Clin Lab Invest 1995;55:421–6. Junge W, Troge B. Kontrastmittel als Störfaktoren in der laborchemischen Analytik. In: Peters PE, Zetler F, editors. Röntgen Kontrastmittel. Berlin: Springer-Verlag; 1991. p. 76–82. Anonymous. Sulphur hexafluoride. Use in echocardiography suspended. WHO Pharmaceutical Newslett 2004;4:3. GebreEyesus A, Aggrey G, Pichard AD, Satler LF, Kent KM, Lindsa J, Waksman R. Addition of heparin to contrast media is associated with increased bleeding and peripheral vascular complications during percutaneous coronary intervention with bivalirudin and drug-eluting stents. Cardiovasc Radiation Med 2004;5:64–70.
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47 Drugs used in ocular treatment Intravitreal and parabulbar injection of drugs Both new angiostatic drugs and traditional glucocorticoids are currently undergoing evaluation in the treatment of diabetic retinopathy, diabetic macular edema, age-related macular degeneration (AMD), and other diseases of the posterior segment of the eye. New delivery techniques, such as intravitreal injections and intraocular sustained-release devices, facilitate high local concentrations of angiostatic and antipermeability drugs while minimizing intraocular and extraocular toxicity (1R –3R ). The risk of serious adverse events after intravitreal injection is low. Nevertheless, careful attention to injection technique and appropriate monitoring after injection are essential, because uncommon injection-related complications can be associated with permanent vision loss. A systematic research of the literature via PubMed from 1966 to 1 March 2004 was conducted to identify studies of the safety of intravitreal injection. Data submitted in New Drug Applications to the US Food and Drug Administration (FDA) for drugs administered into the vitreous were included where available. Serious adverse events reported in each study were included and risk per eye and risk per injection were calculated for the following serious adverse events: endophthalmitis, retinal detachment, iritis/uveitis, intraocular hemorrhage, ocular hypertension, cataract, and hypotony. Data from 14 866 intravitreal injections in 4382 eyes were analysed. There were 38 cases of endophthalmitis, a prevalence of 0.3% per injection and 0.9% per eye. Excluding cases reported specifically as pseudoendophSide Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29047-0 © 2007 Elsevier B.V. All rights reserved.
thalmitis, the prevalence of endophthalmitis was 0.2% per injection and 0.5% per eye. Retinal detachment, iritis/uveitis, ocular hypertension, cataract, intraocular hemorrhage, and hypotony were generally associated with intravitreal injection of specific compounds and were infrequently attributed by the investigators to the injection procedure itself. Retinal vascular occlusions were rare after intravitreal injection, and it was unclear in most cases whether these represented true injection-related complications or chance associations (4M ). Glucocorticoids are traditionally used in the eye for inflammatory disorders, such as keratitis and uveitis, because of their ability to diminish neutrophil transmigration, limit access to sites of inflammation, and reduce cytokine production. More recently investigators have focused on the angiostatic and antipermeability properties of glucocorticoids for posterior segment diseases, such as age related macular degeneration, diabetic retinopathy, and macular edema. Intravitreal glucocorticoid injections potently inhibit experimental choroidal neovascular membranes in primates and rats and have shown promise in some early human pilot trials. In proliferative diabetic retinopathy they may directly inhibit growth factors, such as vascular endothelial derived growth factor, and inhibit leukocytes, which play an important role in early microvascular alterations. In addition, the effect of glucocorticoids on vascular permeability has led to their use for macular edema from many causes, such as diabetes and venous occlusive disease. The apparent short-term success must be balanced by the fact that long-term safety and efficacy have yet to be determined for any of these approaches (5R ). Intravitreal triamcinolone In 15 patients with bilateral diabetic macular edema unresponsive to laser photocoagulation, one intravitreal injection of triamcinolone acetonide 4 mg was injected into one eye, under subconjunctival anesthesia, while the other eye served as a control. The main outcome measure was cen-
581
582 tral macular thickness at 1, 3, and 6 months, measured by optical coherence tomography. Secondary outcomes were Early Treatment Diabetic Retinopathy Study (ETDRS) scores, intraocular pressure, and cataract progression. Intravitreal injection of triamcinolone reduced macular thickening due to diffuse macular edema after 3 months. However, after 6 months the difference between the central macular thickness of injected and control eyes was no longer significant, because of recurrence of macular edema. In six of 12 injected eyes intraocular pressure exceeded 25 mmHg, and was controlled by topical medication (6c ). In another study, three patients developed a significant rise in intraocular pressure within 1 week after intravitreal injection of triamcinolone for refractory macular edema (7c ). In one patient a white material was found in the chamber angle on gonioscopy. All three patients required surgical intervention to reduce the intraocular pressure. Parabulbar triamcinolone Increased intraocular pressure has been reported after parabulbar triamcinolone. • A 53-year-old woman had been treated with glucocorticoid eye drops for continuous bilateral uveitis (8A ). For cystoid macular edema triamcinolone acetonide 32 mg was applied by bilateral subTenon’s capsule injection. Cystoid macular edema
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was reduced in both eyes 20 days after injection, but intraocular pressure was increased in both eyes (right eye 26 mmHg, left eye 37 mmHg). Because intraocular pressure continued to rise and visual field defects developed despite administration of antiglaucomatous medications, trabeculectomy was performed in both eyes. After surgery the intraocular pressure stabilized at about 10 mmHg.
In a double-blind, double-placebo study in 100 patients undergoing uncomplicated cataract surgery (phacoemulsification and intraocular posterior chamber lens implantation) intraoperative triamcinolone acetonide 40 mg by sub-Tenon’s capsule injection was compared with postoperative 1% prednisolone acetate eye drops (1 drop qds in week 1, tds in week 2, bd in week 3, and once daily in week 4) (9C ). Triamcinolone had anti-inflammatory efficacy equivalent to conventional 1% prednisolone eye drops in reducing intraocular inflammation and was as safe in terms of adverse effects, changes in visual acuity, and intraocular pressure. The intraocular pressure was significantly lower after triamcinolone than prednisolone.
Ocular dyes See Chapter 49 (p. 606).
References 1. Thompson MJ, Ip MS. Diabetic macular edema: a review of past, present and future therapies. Int Ophthalmol Clin 2004;44:51–67. 2. Kim RW, Heier JS. Innovative treatments for exudative age-related macular degeneration. Int Ophthalmol 2004;44:41–50. 3. Tranos PG, Wickremasinghe SS, Stangos NT, Topouzis F, Tsinopoulos I, Pavesio CE. Macular edema. Surv Ophthalmol 2004;49:470–90. 4. Jager RD, Aiello LP, Patel SC, Cunningham ET. Risks of intravitreous injection: a comprehensive review. Retina 2004;24:676–98. 5. Ciulla TA, Walker JD, Fong DS, Criswel MH. Corticosteroids in posterior segment disease: an update on new delivery systems and new indications. Curr Opin Ophthalmol 2004;15:211–20. 6. Massin P, Audren F, Haouchine B, Erginay A, Bergmann JF, Benosman R, Caulin C, Gau-
dric A. Intravitreal triamcinolone acetonide for diabetic diffuse macular edema: preliminary results of a prospective controlled trial. Ophthalmology 2004;111:218–24. 7. Singh IP, Ahmad SI, Yeh D, Challa P, Herndon LW, Allingham RR, Lee PP. Early rapid rise in intraocular pressure after intravitreal triamcinolone acetonide injection. Am J Ophthalmol 2004;138:286–7. 8. Konomi K, Nagasawa A, Mori A, Nomura M. A case of steroid-induced glaucoma caused by a sub-Tenon’s capsule injection of triamcinolone acetonide. Folia Ophthalmol Jap 2004;55:50–3. 9. Paganelli F, Cardillo JA, Melo LAS, Oliveira AG, Skaf M, Costa RA. A single intraoperative subTenon’s capsule triamcinolone acetonide injection for the treatment of post-cataract surgery inflammation. Ophthalmology 2004;111:2102–8.
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Complementary and alternative medicine (CAM) remains popular with consumers and patients. The often-voiced assumption that CAM is natural and therefore safe (1c ) has for a long time hindered systematic research of its risks. However, surveys suggest that adverse effects undoubtedly do occur (1c , 2c ). As patients often do not discuss their use of CAM with doctors (3c ) and as it is often not documented in medical records (4c ), the risks are somewhat of a blind spot to both doctors and patients (1c ).
HERBAL MEDICINES
Asian herbal medicines Multiple adverse effects can occur when mixtures of herbs are used, as is common in Asian formulations • A 37-year-old woman developed toxic hepatitis and a vaginal vault hematoma after hysterectomy (25A ). She had been taking a Chinese herbal mixture containing 61 different ingredients for 6 weeks. Her prothrombin time and liver enzymes were abnormal. No other reason for her medical problems was identified. Her herbal prescription included ingredients known to have hepatotoxic and anticoagulant properties. The remedy was withdrawn and she made an uneventful recovery.
(SED-15, 1609; SEDA-26, 528; SEDA-27, 512; SEDA-28, 573)
Drug contamination Asian herbal remedies have repeatedly been adulterated with prescription drugs.
A plethora of review articles have focused on the safety issues of herbal medicines, mostly self-prescribed, either in general (5r –8r ) or related to specific herbal traditions (9r –11r ). Other reviews have addressed the potential of herbal medicines to damage specific organs, for example the liver (12r –14r ) and the kidneys (15r ), or their potential for harm in defined populations, for example patients with cancer (16r ), pregnant women (17r ), or children (18r ). Several reviews have addressed the issue of herb–drug interactions (19r –23r , 24R ).
• A 48-year-old diabetic patient from London was initially managed with metformin and gliclazide, but because of poor metabolic control treatment was switched to insulin plus oral metformin (26A ). His metabolic control remained poor and he developed microvascular and macrovascular complications. He returned to his native India for a visit and on returning his metabolic control was improved. He attributed this to treatment that he had received in India, three different ‘herbal balls’ to be taken three times a day with meals. The remedies contained chlorpropamide in a dose equivalent to 200 mg/day. It was agreed that the patient should continue with this treatment. One year later, while still taking the ‘herbal balls’, his metabolic control deteriorated. The herbal therapy was withdrawn and bolus insulin treatment was restarted.
Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29048-2 © 2007 Published by Elsevier B.V.
Jackyakamcho-tang Jackyakamcho-tang is a Korean herbal mixture of Paeoniae radix and Glycyrrhizae radix, used for its alleged analgesic and spasmolytic properties. In 81 patients treated with this remedy there were adverse effects in 11%. Indigestion, diarrhea, and edema
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584 were the most common complaints; in 3.7% of cases they were rated as severe (27A ).
Nu Bao Infection risk The patient information leaflet for a traditional Chinese medicine named Nu Bao lists human placenta, deer antler (Corna cervi oantotrichum), and donkey skin (Colla cori astini) as ingredients of capsules of the product (28S ). Although information about the sources of these ingredients is limited, the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK has advised that all animal and human tissue derivatives carry a risk of infectious diseases, because of transmission of infective agents. The MHRA has therefore advised that consumers should not take this product. Current users should stop taking it and should consult their doctor if they feel unwell. The MHRA has written to suppliers to stop marketing Nu Bao with immediate effect.
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Qing zhisan tain shou The UK Medicines and Healthcare products Regulatory Agency (MHRA) has become aware of the supply of a traditional Chinese medicine slimming aid called Qing zhisan tain shou, which contains the prescription-only medicine sibutramine (30S ). The MHRA has warned consumers that sibutramine should only be prescribed under specific circumstances and requires the supervision of a registered doctor, as it can cause increased blood pressure. Qing zhisan tain shou is supplied in a bicolored cream and a brown capsule formulation. The capsules are contained within blister packs and are presented in a white and green carton with various lettering and imagery. Two other Chinese slimming products, Li da dai dai hua and Meizitang have been seized by the Netherlands’ authorities and have been found to contain sibutramine.
Quilinggao Phu Chee and Lin Chee/Active Rheuma Plus Drug contamination The Norwegian Medicines Agency (NoMA) has banned the sale of two herbal medicines, Phu Chee and Lin Chee/Active Rheuma plus, which were found to contain high doses of undeclared dexamethasone (Phu Chee) and prednisolone (Lin Chee/Active Rheuma plus) (29S ). Physicians from a hospital in northern Norway reported that several patients taking Phu Chee or Lin Chee/Active Rheuma Plus developed symptoms similar to those observed with prolonged use, or high doses, of glucocorticoids, along with subsequent withdrawal symptoms. Laboratory analysis showed that Phu Chee contains dexamethasone 0.4–0.5 mg per tablet and that Lin Chee/Active Rheuma Plus contains an unknown quantity of prednisolone. As the recommended dosage of Phu Chee was 3–9 tablets/day, patients could have been exposed to a daily dose of dexamethasone of 1.2–4.5 mg. NoMA sent a letter to all of the distributors’ customers, with a warning about use and rapid discontinuation of the herbal medicines, as well as advice to see a doctor.
Hematologic Quilinggao is a popular herbal mixture. Different brands contain different mixtures of herbs, some of which have antithrombotic effects. • A 61-year-old man had been stable on warfarin treatment when his INR was noted to be above 6.0 (31A ). There was no obvious reason for this and it turned out that he has been self-medicating with Quilinggao. The herbal remedy and warfarin were withdrawn. After normalization of the INR, warfarin was restarted and the INR was stable until he tried another brand of Quilinggao whereupon the same cycle occurred.
Shubao slimming capsules Liver Globally, the illegal adulteration of slimming products with nitrosofenfluramine and fenfluramine has been associated with a large number of reports of liver toxicity (32S ). There was one report of liver failure requiring liver transplantation in a patient taking Shubao Slimming Capsules in the UK. The MHRA directed that the supply and sale of Shubao capsules should be stopped immediately and requested cooperation from the herbal sector in
Treatments used in complementary and alternative medicine
minimizing the risks to consumers posed by the illegal inclusion of fenfluramine and nitrosofenfluramine in these capsules.
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Skin In two double-blind placebo-controlled studies of Andrographis paniculata in a total of 225 patients there were two cases of urticaria (37C ).
Allium sativum (Liliaceae)
(SED-15, 2061; SEDA-26, 529; SEDA-27, 515; SEDA-28, 574)
Skin Raw Allium sativum (garlic) is commonly applied to the skin as a poultice. However, it can cause burns on the skin (33A ). • A 60-year-old Eastern European man developed partial thickness burns to both feet after having applied crushed raw garlic to his feet for 12 hours. He was initially treated with Silvadene cream and sent home, but 3 days later developed a low-grade fever and wound erythema. He was treated with intravenous nafcillin and Accuzyme debridement. He recovered uneventfully within 3 days.
Garlic contact dermatitis is a type IV allergic reaction limited to the epidermis, thought to be due to diallyldisulfide, allicin, and allylpropyldisulfide (34C ). However, partial or full thickness skin injury due to garlic is less common and is probably not a true allergic reaction.
Andrographis paniculata (Acanthaceae) Andrographis paniculata is a shrub that is found throughout India and other Asian countries and is sometimes called Indian Echinacea. In China it is known as Chuan Xin Lian and Kan Jang. Its constituents include diterpenoid lactones (andrographolides), paniculides, farnesols, and flavonoids. It has been used to treat viral infections, such as colds and influenza. In a double-blind, placebo-controlled study of the use of andrographis 1200 mg/day in 61 patients there were no changes in liver or kidney function, blood counts, or other laboratory measures (35C ). A systematic review of all clinical reports of adverse events resulting from treatment of upper respiratory tract infections with Andrographis paniculata found only mild, infrequent and reversible adverse events (36M ). The most frequent ones included pruritus, fatigue, headache, and diarrhea.
Aristolochia species (Aristolochiaceae) (SED-15, 336; SEDA-26, 529; SEDA-27, 515; SEDA-28, 575) In 2001, severe adverse events among users of herbal and dietary formulations containing aristolochic acid led to bans or consumer warnings in different parts of the world (38S ). China’s State FDA has banned two commonly used herbs containing aristolochic acid, a toxin that is linked to renal insufficiency and cancer (39S ). Manufacturers were directed to replace Aristolochia fangchi and Aristolochia debilis with Staphania tetrandra and Inula helenium respectively in their traditional medicine formulations by 30 September 2004. The Provincial Drug Bureau was instructed to carry out inspections to ensure compliance with the ban by 31 October. Medicines found to contain either Aristolochia fangchi or Aristolochia debilis after 30 September were to be treated as fake under Chinese law. By a previous order, special restrictions were imposed on four other potentially harmful aristolochic acid-containing herbs in China (Fructus aristolochiae, Aristolochia mollissima Hance, Herba aristolochiae, and Aristolochia tuberose); however, there was no outright ban on these products. Several countries withdrew formulations containing aristolochic acid in 1981 after the demonstration of carcinogenicity in a 3-month toxicity study in rats. A consolidated list of products whose consumption and/or sale have been banned, withdrawn, severally restricted or not approved by governments has been published (40S ). Urinary tract The nephrotoxicity of Aristolochia is well-documented. • A 43-year-old Korean woman developed Fanconi’s syndrome after taking a Chinese herbal mixture containing Aristolochia for 10 days, hoping to lose weight (41A ). Despite withdrawal of the remedy, she rapidly progressed to renal insufficiency. A renal biopsy showed typical findings of aristolochic acid-induced neuropathy.
586 An animal study has suggested that the nephrotoxicity of Aristolochia can be reduced by combining it with an extract of Rhizoma coptidis (Huanglian) (42E ).
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The authors believed that a casual relation was likely but no brand or dose or any other characterization of the herbal remedy was obtained. Causality in this case may therefore have been related to something in the tablets but not necessarily to black cohosh itself.
Cannabis sativa (Cannabaceae) (SED-15, 613) See Chapter 4.
Caulophyllum thalictroides (Berberidaceae) (SED-15, 447) Drug contamination Caulophyllum thalictroides (blue cohosh) has been reportedly adulterated with cocaine (43A ). • A 24-year-old woman who had taken blue cohosh for induction of labor was delivered by cesarean section of an apparently healthy female infant weighing 3860 g, but 26 hours later the infant had focal motor seizures of the right arm, which turned out to be due to an infarct in the distribution of the left middle cerebral artery. The seizures were managed with phenobarbital and phenytoin. There were no clotting abnormalities and the family history was negative. The infant’s urine tested positive for the cocaine metabolic benzoylecgonine and so did the mother’s blue cohosh tablets.
The authors pointed out that maternal cocaine use is a recognized cause of perinatal stroke and speculated that either benzoylecgonine is a metabolite of both cocaine and blue cohosh or the tablets had been contaminated with cocaine.
Cimicifuga racemosa (Ranunculaceae) (SED-15, 3025;
Cinnamonum camphora (Lauraceae) (SED-15, 2006) Skin Besides other components, cinnamon, which is derived from the bark of the Cinnamonum camphora tree, contains about 1–3% ethereal oils, cinnamic aldehyde being the main constituent, and about 35 other constituents, such as eugenol and cinnamic alcohol. The constituents of oil of cinnamon are common allergens or irritants, and occupational allergic contact dermatitis from oil of cinnamon has often been reported in bakers, confectioners, and cooks (45c , 46c ). • Contact with insoles containing cinnamon has been reported as having caused allergic contact dermatitis in a 47-year-old man, consistent with podopompholyx, 2 days after he had started to use new insoles containing cinnamon powder as an odor-neutralizing agent (47A ). There was no past history of plantar eczema. Treatment with topical glucocorticoids initially failed to clear the lesions. He developed erysipelas on the left foot 5 days after the onset of the eczema and was therefore given intravenous antibiotics. There was marked improvement in the eczema and clearance of the erysipelas within 2 weeks. Patch testing with the European standard series showed positive reactions to fragrance mix (+++ at D2, further testing stopped), balsam of Peru (Myroxylon pereirae resin; + at D2 and D3), and thiomersal (+ at D2 and D3). Testing with components of the fragrance mix showed reactions to cinnamic aldehyde (cinnamal; ++ at D2 and +++ at D3) and cinnamic alcohol (+ at D2 and +++ at D3). There was also a strongly positive reaction with both the inside and the outside of the cinnamon insole (each +++ at D2, further testing stopped).
SEDA-27, 516; SEDA-28, 575) Liver Cimicifuga racemosa (or Actaea racemosa, common name black cohosh or black bugbane) is popular for menopausal problems. It has been reported to cause hepatitis (44A ). • A 57-year-old woman developed autoimmune hepatitis 3 weeks after taking black cohosh tablets.
Citrus aurantium (Rutaceae) (SED-15, 3087) Citrus aurantium (bitter orange) contains synephrine, which has ephedrine-like effects on the cardiovascular system.
Treatments used in complementary and alternative medicine • A 55-year-old woman suffered an acute lateral wall myocardial infarction after taking a herbal supplement containing bitter orange (Edita’s Skinny Pill) 300 mg (48A ). She had no relevant past medical history and had been free of cardiovascular risk factors.
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tests do not reflect in vivo effects under all circumstances, or the previous anecdotal reports have been in patients who are in some way specifically susceptible.
Hypericum perforatum (Clusiaceae) Echinacea species (Asteraceae) (SED-15, 363; SEDA-26, 531, SEDA-27, 516; SEDA-28, 576) Skin Echinacea is recommended for the prevention and treatment of the common cold through its immunostimulatory effects. It has been reported to have caused a flare up of pemphigus vulgaris (49A ). • A 55-year-old man with pemphigus vulgaris in remission self-administered Echinacea for an upper respiratory tract infection. Within 1 week he developed an acute exacerbation of the pemphigus vulgaris. Withdrawal of Echinacea resulted in improvement of his symptoms, but he had to be treated with prednisolone, azathioprine, and dapsone to achieve a partial remission.
The authors suggested that the immunostimulatory properties of Echinacea may have caused this flare up.
Ephedra
(SED-15, 1221)
See Chapter 13.
Ginkgo biloba (Ginkgoaceae) (SED-15, 1507; SEDA-26, 531; SEDA-27, 517; SEDA-28, 576) Hematologic Bleeding complications have been reported in patients taking extracts of Ginkgo biloba (50A , 51A ) (SEDA-28, 576), attributed to the antiplatelet properties of the extracts. In a placebo-controlled study in volunteers a special extract of Ginkgo biloba, EGb 761, was compared with placebo; there was no evidence of any effect on tests of primary hemostasis, coagulation, or platelet function (52c ). This particular extract could lack an effect on bleeding tendency, or routine laboratory
(SED-15, 842; SEDA-26, 532; SEDA-27, 517; SEDA-28, 577) In a meta-analysis of three randomized, placebo-controlled studies with very similar methods in 594 patients with mild to moderate depression, who took 900 mg/day of a standardized hypericum extract for 6 weeks, the numbers of patients who had adverse effects were similar with hypericum and placebo (53M ). Specifically, hypericum was devoid of sedative or anticholinergic effects and did not cause gastrointestinal or sexual problems, which can be a problem with conventional antidepressants. Psychiatric The clinical evidence associating Hypericum with psychotic events has been summarized in a systematic review of 17 case reports (54M ). In 12 instances the diagnosis was mania or hypomania. In most of these cases, causality between the herbal remedy and the adverse effect was rated as possible; in no instance was there a positive re-challenge. Drug interactions All pharmacokinetic trials in which interactions between hypericum and conventional drugs were examined have been evaluated in a systematic review (22 studies in all) (55M ). In 17 trials there was a reduction in the systemic availability of a range of conventional drugs. The drugs that were affected included amitriptyline, ciclosporin, digoxin, indinavir, irinotecan, mycophenolic acid, omeprazole, oral contraceptives, tacrolimus, theophylline, and warfarin.
Illicium verum/anisatum (Iliciaceae) (SED-15, 1715) Nervous system Chinese star anise (Illicium verum) is used as a tea for a range of conditions. Seven cases have been reported of infants aged 2 weeks to 3 months who developed
588 neurological symptoms (clonus, myoclonus, increased deep tendon reflexes, nystagmus, vomiting, seizures) after ingesting the tea (56A ). All the symptoms resolved within 24 hours of dechallenge. Analyses of the herbal ingredients showed that most contained Japanese star anise (Illicium anisatum), which is known to be neurotoxic. The authors suggested that the problems could have been due to an overdose of Illicium verum, contamination with Illicium anisatum, or both.
Larrea tridentata (Zygophyllaceae) (SED-15, 3732) The name chaparral (Larrea tridentata, creosote bush) is also sometimes used for other desert plants such as Larrea mexicana, Larrea glutinosa, Larrea nitida, and Larrea caneifolia, which are all widely used, for instance to cure colds, diarrhea, urinary tract infections, rheumatism, and skin problems, or to reduce body weight. Liver Liver damage has been repeatedly associated with chaparral. • A 22-year-old, previously healthy Finnish woman developed toxic hepatitis after taking chaparral tablets (57A ). She recovered after dechallenge but again developed toxic hepatitis after re-starting the herbal remedy against the advice of her doctors. Her liver function normalized 6 months after this re-challenge but she still had hepatic fibrosis.
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Phytoestrogens Breasts Phytoestrogens can cause breast changes in men, including gynecomastia. • A 58-year-old otherwise healthy man developed gynecomastia and breast cancer, which was positive for androgen, estrogen, and progesterone receptors (59A ). He had taken herbal mixtures high in phytoestrogen content for 6 years, estimated to amount to the equivalent of estriol 6000 IU/day. There was no family history of breast cancer or BRCA1/BRCA2 mutation. He had breast surgery, but the clinical outcome was not reported.
Teucrium polium (Lamiaceae) (SED-15, 1986) Liver Teucrium polium is hepatotoxic. • A 67-year-old man consumed large amounts of Teucrium polium tea daily for 6 months to normalize his blood lipids and developed acute cholestatic hepatitis (60A ). After withdrawal of the herbal remedy, his liver function returned to normal.
NON-HERBAL SUPPLEMENTS Co-enzyme Q10 A systematic review of co-enzyme Q10 found no evidence of adverse effects in clinical trials (61M ). However, the authors pointed out that because of its structural similarity to vitamin K, concurrent use of this popular supplement with anticoagulants might cause impaired anticoagulation.
Panax ginseng (Amaranthaceae) (SED-15, 107; SEDA-28, 578)
Fish oils Cardiovascular A 64-year-old previously normotensive man presented with amaurosis fugax and hypertension (blood pressure 220/130 mmHg) after taking Ginseng Forte-Dietisa 500 mg/day for 13 days (58A ). All other tests were normal. He was advised to stop taking ginseng, and 1 week later his blood pressure was normal (140/90 mmHg).
(SED-15, 1364)
Drug interactions A 67-year-old woman had been stable on warfarin prescribed for recurrent transient ischemic attacks (62M ). When she decided to double her intake of fish oil from 1000 to 2000 mg/day her INR increased from 2.8 to 4.3 within 1 month. After withdrawal it returned to normal.
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Usnic acid Usnic acid is an oxidative uncoupler, with similar properties to 2,4-dinitrophenol, which is promoted as a weight loss supplement. Liver Usnic acid is hepatotoxic. • A 28-year-old woman developed fulminant liver failure requiring transplantation 1 month after starting to take usnic acid 500 mg/day (63A ). She had taken the supplement for 2 weeks and stopped when she began to feel ill. There were no other risk factors.
ACUPUNCTURE
(SED-15, 890; SEDA-26, 535; SEDA-27, 520; SEDA-28, 581)
Incidence of adverse effects of acupuncture The author of a Chinese overview has pointed out that complications, even deaths, after acupuncture were first described in the early Qin dynasty (64r ). Physicians of subsequent dynasties also reported such events regularly. The author suggested that acupuncture has become safer today, not least because most practitioners are aware of human anatomy. However, because of its worldwide popularity “acupuncture accidents due to improper application are increasing.” A review of the literature included a total of 715 adverse events (65r ). The most common were pneumothorax, central nervous system damage, and infections. There were 12 primary reports of deaths associated with acupuncture. In 12 prospective studies with more than one million treatments, the risk of a serious adverse event was 5 per 200 000 treatments and 11 per 200 000 individual patients. The author concluded that the risk of acupuncture is lower than that of many common medical interventions. In a survey of 9404 patients of 638 UK nonmedically trained acupuncturists, 3% of the therapists gave advice about conventional/prescription medications (66r ). Six patients reported adverse consequences after taking such advice. Similarly, advice provided by the staff of health food stores (67r ) or on internet sites
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(68r ) regarding complementary medicines is often inadequate and can endanger the health of consumers who follow it. The Dutch government has introduced regulatory measures after a much-publicized case of the death of an actress who was treated with “alternative” treatments for her cancer (69A ). In a prospective study of 97 733 patients treated with acupuncture by 7050 German doctors there were mild adverse effects (needling pain or hematoma) in 7.1% (70R ). The authors also described five potentially serious adverse events, including two cases of pneumothorax in a 47-year-old man and a 73-year-old woman; both made a full recovery after conventional treatment. A further German study included 190 924 patients with chronic pain (71r ). There were 24 serious adverse events per 100 000 patients. However, the authors suspected that this figure had been distorted through under-reporting. In their series, only 5% of the average death rate in the German population was reported. Assuming therefore that under-reporting was 95%, the true incidence of serious adverse events after acupuncture could be as high as 480 per 100 000 patients. Infection risk The main type of infection that can be introduced by acupuncture needles is hepatitis (72R , 73M ), but other infections can occur, including mycobacterial infections (74A ) and infections with more common organisms. • A 44-year-old man had regular acupuncture for his chronic neck pain (75A ). He subsequently developed left elbow soreness and weakening of grip strength in the left hand, followed by left hemiparesis and intermittent fever. He was admitted to hospital where a cervical subdural empyema was diagnosed. At laminectomy multiple subdural abscesses were found between C6 and T11. Cultures were positive for Staphylococcus aureus. After surgery and antibiotic treatment he recovered and was left with only a mild residual hand paresis. • A 64-year-old Korean woman experienced gastrointestinal pain after having had abdominal acupuncture for several weeks during which gold needles were inserted into the abdominal wall, their ends being broken off, leaving multiple fragments in situ (76A ). A CT scan showed a round abdominal mass with acupuncture needles surrounding it. The abscess was removed surgically. Cultures tested positive for Bacteroides fragilis and Escherichia coli. She made a full recovery after antibacterial drug treatment.
590 • A 48-year-old man who had received acupuncture for his back pain developed increasing pain over 2 weeks (77A ). Bone and MRI scans showed septic arthritis in the right L5/S1 facet joint, due to Staphylococcus aureus. Antibacterial drug therapy was initially not successful, and surgical debridement of the facet joint resulted in a full recovery. • A 55-year-old diabetic woman who had received acupuncture for her knee osteoarthritis (78A ) developed life-threatening necrotizing fasciitis, which did not respond to intravenous antibacterial drugs. Pseudomonas was cultured from the wound. Repeated extensive debridement and skin grafting was required. She eventually made a satisfactory recovery.
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•
•
Traumatic adverse effects of acupuncture •
Anecdotal reports Adverse effects that have been reported from the traumatic effects of acupuncture needles have included cardiac tamponade (79A , 80A ), pneumothorax (79A , 81A –84A ), sometimes fatal (85A , 86A ), nervous system damage (87A –89A ), and scarring (90A ). • A 25-year-old woman had a bilateral pneumothorax with pericardial and peritoneal effusions during acupuncture treatment (79A ). She was successfully resuscitated and made a full recovery. • An 83-year-old woman developed syncope and cardiogenic shock shortly after an acupuncture needle had been inserted into the sternum (80A ). Echocardiography showed cardiac tamponade, and pericardiocentesis showed hemopericardium. At thoracotomy a small bleeding perforation of the right ventricle was found and successfully closed. • A slender 38-year-old woman received acupuncture from a German doctor in the subacromial area and paravertebral region of the third thoracic vertebra (81A ). During one session, she had breathing problems, which turned out to be due to a tension pneumothorax caused by a penetrating acupuncture needle. • A 31-year-old man developed breathlessness and chest pain directly after receiving acupuncture in the shoulder region (82A ). A right apical pneumothorax was diagnosed. He made a swift, full recovery. • A patient developed dyspnea and chest pain directly after the treatment and died before adequate medical help was available (83A ). At autopsy ecchymoses were noted on the parietal pleura, suggesting that needles had been inserted into the thoracic cavity and had perforated the lungs. Microscopically many black spots were seen on the parietal pleura along the vertebral column. The
•
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authors interpreted them as traces from previous acupuncture treatments, which had been dangerously close to causing pneumothorax. A 30-year-old woman developed bilateral chest pain and dyspnea after paraspinal acupuncture resulted in bilateral pneumothorax; she recovered fully within 2 days (84A ). A 71-year-old woman without a relevant medical history decided to try acupuncture for persistent shoulder pains (85A ). Immediately after the treatment, she developed severe breathing problem due to bilateral tension pneumothorax. She died in cardiopulmonary arrest soon after. The autopsy findings were consistent with pneumothorax caused by penetrating acupuncture needles. A 70-year-old man was referred to radiologists for evaluation of an acupuncture needle that had been accidentally broken 3 weeks earlier (87A ). A CT scan showed a needle in the cervical spinal cord penetrating the medulla oblongata. Initially there were no neurological deficits and it was decided not to remove the needle surgically. Later he developed left facial paresthesia. Again the neurosurgeons decided not to remove the needle. A 62-year-old woman developed left drop foot, anterior leg pain, and numbness (88A ). The symptoms occurred after acupuncture for sciatica. Radiographs showed a needle-like object near the fibular head; it was removed surgically. A 68-year-old woman developed symptoms consistent with spinal stenosis (89A ). Microscopic examination showed a chronic inflammatory epidural granuloma compressing the lumbar fourth nerve and dural sac. Her history suggested that it had been caused by acupuncture. Surgical excision of the granuloma led to a full recovery. A 36-year-old woman presented with unusual bilateral round scars, two of which were atrophic (90A ). It turned out that she had received a series of acupuncture treatments from a Chinese acupuncturist. The practitioner had treated her around 20 times with hot needles. The woman had permanent, visible, unesthetic scars due to these interventions. When a 67-year-old woman was investigated for pancytopenia, multiple needle fragments were noted on an X-ray along the anterior and posterior thoracic and abdominal walls (91A ). They had probably originated from acupuncture 17 years before, when she had had “Hari” acupuncture, which involves leaving small gold needles permanently at acupuncture points. She did not seem to have had any symptoms from these remnants.
Reviews The authors of a review of the risks associated with acupuncture concluded that serious complications are rare (72R ). The traumatic complications included pneumothorax (more than 90 cases on record at that time), cardiac tamponade (six cases), and injuries to the spinal cord (10 cases). A systematic review of all prospective studies of adverse effects associated with acupunc-
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ture included nine primary investigations (92M ). Pneumothorax was the only serious complication in these studies; it was reported twice in about 250 000 patients. A systematic review of all adverse events associated with acupuncture in the Japanese medical literature located 124 cases (93M ). These included 25 cases of pneumothorax and 18 cases of spinal cord injury. In a survey of 1100 Australian providers of traditional Chinese medicine the adverse events of acupuncture were also monitored (94M ). There were 3222 events, including 64 cases of pneumothorax; no deaths were recorded. A systematic review of case reports from the Japanese literature yielded 105 cases of suspected acupuncture adverse effects not previously reported in Western publications (95M ). The traumatic complications included 21 spinal lesions, 21 cases of pneumothorax, 15 cases of foreign bodies in organs, ten neural injuries, and two cases of cardiac tamponade. A review of serious complications included one case of cardiac tamponade (with full recovery of the patient after surgery), one case of peripheral nerve damage (foot drop with residual weakness after 6 years), and three cases of pneumothorax (all with full recovery) (96r ).
COLONIC IRRIGATION Gastrointestinal In colonic irrigation large volumes of fluid are introduced into the colon via the rectum. It is used to empty the bowel, often with a view to prevent so-called “autointoxication”. Recognized risks include electrolyte imbalance, bowel perforation, and communicable diseases such as amebiasis. Australian authors have reported three cases in which colonic irrigation caused perforation of the rectum. All three patients survived after adequate surgical treatment (97A ).
HOMEOPATHY
(SED-15, 892;
SEDA-28, 582) According to homeopathic teaching, “homeopathic aggravations” or “remedy reactions”
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occur in 20–25% of patients with any complaint when treated by homeopaths for the first time. To a homeopath, such aggravations of the presenting symptom indicate that the optimal homeopathic remedy has been found; it is seen therefore as a “healing crisis” on the road to eventual recovery. For the patient, however, such an aggravation is undoubtedly an adverse event. In an audit of 116 homeopathic patients, 11% reported an adverse event, 27% described new symptoms, and 18% reported a return of old symptoms after starting homeopathic treatments (98r ). The authors concluded that “remedy reactions are common in clinical practice; some patients experience them as adverse events.” Skin Allergic skin reactions can occur to homeopathic remedies. • A 45-year-old woman developed widespread dermatitis after applying homeopathic “mother tincture” of Rhus toxicodendron and ingesting globuli of the same remedy in 7CH dilution to treat a herpesvirus infection (99A ). Skin testing showed an allergy to this plant.
Drug contamination A 29-year-old Belgian woman presented with extreme agitation after using “speed”, alcohol and “Loco X112”, a homeopathic slimming remedy (100A ). Analysis of the remedy revealed the presence of thyroid extract and diethylpropion, an amphetamine-like noradrenergic agent.
SPINAL MANIPULATION (SED-15, 893; SEDA-26, 536; SEDA-27, 521; SEDA-28, 582)
Adverse effects of spinal manipulation In a systematic review of the recent literature (1995–2003) numerous case reports, case series, and retrospective and prospective studies were found in which spinal manipulation was associated with cerebrovascular complications (101M ). More than 300 patients were affected. The most frequently reported complication was stroke, due to arterial dissection after cervical
592 spinal manipulation. No reliable incidence figures could be generated. Another systematic review focused on the risk of spinal manipulation for lumbar disc herniation (102M ). Based on published data, an estimate was derived of the risk of worsening disc herniation or cauda equine syndrome; it turned out to be less than 1 in 3.7 million. The authors pointed out that this compares favorably with other treatments of lumbar disc herniation. In a prospective study in Belgium the authors recruited 59 manipulation therapists (chiropractors, osteopaths, and physiotherapists), each of whom had to enrol 15 consecutive patients attending for their first spinal manipulation (103R ). These patients then completed a questionnaire about the adverse effects of their first treatment. In all 61% of them reported at least one adverse event after spinal manipulation, most commonly headache (20%), stiffness (20%), local discomfort (15%), radiating discomfort (12%), and fatigue (12%). Most of the events began within 4 hours after manipulation and had subsided 24 hours later. Upper spinal manipulation was three times more likely to cause these problems than other treatments.
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In a randomized comparison of the effects of cervical manipulation with cervical mobilization in 336 patients with neck pain 30% of them reported at least one adverse event (104r ). Manipulation was more likely than mobilization to cause such events (adjusted OR = 1.44; 95%CI = 0.85, 2.43). The authors concluded that therapists should consider using mobilization instead of manipulation when treating the upper spine. In a retrospective review of data from the Californian Board of Chiropractic Examiners the disciplinary categories included fraud (44%), sexual boundary issues (22%), other offences (13%), drug or alcohol abuse (10%), negligence or incompetence (6%), poor supervision (2%), and mental impairment (0.3%) (105r ). Trauma A previously healthy patient received cervical manipulation by a chiropractor for neck pain and experienced multiple cervical spine disc herniations during treatment (106A ). The author suggested that lack of medical training is in part responsible for such complications.
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61. Roffe L, Schmidt K, Ernst E. Efficacy of coenzyme Q10 for improved tolerability of cancer treatments: a systematic review. J Clin Oncol 2004;22:4418–24. 62. Buckley MS, Goff AD, Knapp WE. Fish oil interaction with warfarin. Ann Pharmacother 2004;38:50–3. 63. Durazo FA, Lassman C, Han SHB, Saab S, Lee NP, Kawano M, Saggi B, Gordon S, Farmer DG, Yersiz H, Goldstein LI, Ghobrial M, Busuttil RW. Fulminant liver failure due to usnic acid for weight loss. Am J Gastroenterol 2004;99:950–2. 64. Zhang R. Accidents in acupuncture treatment: history and current state. Zhong Xi Yi Jie He Xue Bao 2004;2:306–13. 65. White A. A cumulative review of the range and incidence of significant adverse events associated with acupuncture. Acupunc Med 2004;22:122–3. 66. MacPherson H, Scullion A, Thomas KJ, Walters S. Patient reports of adverse events associated with acupuncture treatment: a prospective national survey. Qual Saf Health Care 2004;13:349–55. 67. Mills E, Singh R, Ross C, Ernst E, Wilson K. Impact of federal safety advisories on health food store advice. J Gen Intern Med 2004;19:269–72. 68. Schmidt K, Ernst E. Assessing websites on complementary and alternative medicine for cancer. Ann Oncol 2004;15:733–42. 69. Van Dam FSAM. De voorgestelde maatregelen van de Inspectie voor de Gezondheidszorg naar aanleiding van de dood van Sylvia Millecam en haar behandeling door alternatieve genezers (The measures proposed by the Dutch Healthcare Inspectorate after the death of Sylvia Millecam and her treatment by practitioners of alternative medicine). Ned Tijdschr Geneeskd 2004;148:629–30. 70. Melchart D, Weidenhammer W, Streng A, Reitmayr S, Hoppe A, Ernst E, Linde K. Prospective investigation of adverse effects of acupuncture in 97,733 patients. Arch Intern Med 2004;164:104–5. 71. Endres HG, Molsberger A, Lungenhausen M, Trampisch HJ. An internal standard for verifying the accuracy of serious adverse event reporting: the example of an acupuncture study of 190,924 patients. Eur J Res Med 2004;9:545– 51. 72. White AR, Ernst E. Risks associated with acupuncture. Perfusion 2002;15:153–8. 73. Ernst E, Sherman KJ. Is acupuncture a risk factor for hepatitis? Systematic review of epidemiological studies. J Gastroenterol Hepatol 2003;18:1231–6. 74. Woo PCY, Leung K-W, Wong SSY, Chong KTK, Cheung EYL, Yuen K-Y. Relatively alcohol-resistant mycobacteria are merging pathogens in patients receiving acupuncture treatment. J Clin Microbiol 2002;40:1219–24.
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93. Yamashita H, Tsukayama H, White AR, Tanno Y, Sugishita C, Ernst E. Systematic review of adverse events following acupuncture: the Japanese literature. Complement Ther Med 2001;9:98–104. 94. Bensoussan A, Myers SP, Carlton AL. Risks associated with the practice of traditional Chinese medicine: an Australian study. Arch Fam Med 2000;9:1071–8. 95. Yamashita H, Tsukayama H, White AR, Ernst E, Tanno Y, Sugishita C. Systematic review of case reports on acupuncture adverse events in the Japanese literature. Forsch Komplementarmed 2000;7:57. 96. Ernst E, White AR. Indwelling needles carry greater risks than acupuncture techniques. Br Med J 1999;318:536. 97. Handley DV, Rieger NA, Rodda DJ. Rectal perforation from colonic irrigation administered by alternative practitioners. MJA 2004;181:575–6. 98. Thompson E, Barron S, Spence D. A preliminary audit investigating remedy reactions including adverse events in routine homeopathic practice. Homeopathy 2004;93:203–9. 99. Cardinali C, Francalanci S, Giomi B, Caproni M, Sertoli A, Fabbri F. Contact dermatitis from Rhus toxicodendron in a homeopathic remedy. J Am Acad Dermatol 2004;50:150–1. 100. Mortelmans LJM, Biesemans L, Van Rossom P. Homeopathic products, not as innocent and safe as they seem? A case report. Eur J Emerg Med 2004;11:242–3. 101. Ernst E. Cerebrovascular complications associated with spinal manipulation. Phys Ther Rev 2004;9:5–15. 102. Oliphant D. Safety of spinal manipulation in the treatment of lumbar disk herniations: a systematic review and risk assessment. J Manip Physiol Ther 2004;27:197–210. 103. Cagnie B, Vinck E, Beernaert A, Cambier D. How common are side effects of spinal manipulation and can these side effects be predicted? Man Ther 2004;9:151–6. 104. Hurwitz EL, Morgenstern H, Vassilaki M, Chiang LM. Adverse reactions to chiropractic treatment and their effects on satisfaction and clinical outcomes among patients enrolled in the UCLA Neck Pain Study. J Manip Physiol Ther 2004;27:16–25. 105. Foreman SM, Stahl MJ. Chiropractors disciplined by a state chiropractic board and a comparison with disciplined medical physicians. J Manip Physiol Ther 2004;27:472–7. 106. Tomé F, Barriga A, Espejo L. Multiple disc herniation after chiropractic manipulation. Rev Med Univ Navarra 2004;48:39–41.
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Medication errors Sources of errors Understanding the classification of medication errors is important in understanding their genesis. The psychological classification of medication errors is shown in Table 1 (1R ). In a UK report, the causes and frequency of medication errors have been reviewed (2S ). The causes of errors are complex, involving both errors by the actions of individuals and systems weaknesses that predisposed to error. The authors recommended checks and error traps that should be built into all medication processes, including prescribing, dispensing, and drug administration. They also called for improved information management and technology. They made practical recommendations for specific groups of patients and drugs that pose particular risks, including clear procedures and electronic prescribing systems for documenting and alerting prescribers to drug allergies. Training and assessment of competence in pediatric drug therapy was also emphasized. Over a period of 2 years, surgical residents in a US hospital made 75 prescribing errors, of which 33 involved orders for antimicrobial drugs (3C ). Errors that could not be directly attributed to deficits in knowledge were responsible for 36 errors (48%), and specific deficits in knowledge were responsible for the other 39. Problems arising from drug names have been reviewed and strategies for prevention suggested (4R ). Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29049-4 © 2007 Elsevier B.V. All rights reserved.
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In French hospitals in 2000–1, adverse effects due to errors during drug use or spotted before any incident, 319 in all, were characterized by type, cause, contributing factors, and consequences (5E ). All stages of the drug use process were implicated in errors: prescription, transcription, preparation, dispensing, administration, and drug monitoring. Dosing errors (often overdose) were the most common. The main causes were poor practices and inadequate knowledge, followed by problems of communication, packaging, and confusion over drug names. Contributing factors included failure to follow rules and procedures, inadequate communication or training, interruptions and distractions, and drug storage on wards. The patterns and causes of medication errors have been studied in a major tertiary care teaching hospital over 3 months (6E ). Of 321 medication errors, 240 were analysed; 95 were actual errors and the rest near misses. Most actual errors involved uncontrolled infections associated with prescribed underdoses of anti-infective drugs (23%), renal insufficiency associated with prescribed overdoses of anti-infective drugs (4%), nervous system drug intoxication after prescribed overdoses (4%), or uncontrolled pain associated with prescribed underdoses (4%). Most errors were initiated during prescribing (72%) and were associated with deficits in knowledge about drug therapy (39%) or with failure to consider critical patient information (18%). Errors initiated during dispensing and administration were mostly associated with performance deficits (for example accidental slips and lapses). The incidence, nature, and causes of dispensing errors have been studied over 4 weeks in 35 community pharmacies in England and Wales (7E ). Of 125 395 dispensed items there
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Table 1. A psychological classification of medication errors, with examples in each category (from 1R ) Type of error∗ Mistakes Knowledge-based Rule-based mistakenly applying a good rule applying a bad rule Skill-based errors Action-based (slips)
technical errors Memory-based (lapses)
Examples Giving penicillin, without having established whether the patient is allergic Injecting diclofenac into the lateral thigh (the usually preferred site for intramuscular injection) rather than the buttock (which is preferred for diclofenac) Using excessive doses of captopril (as or failing to apply was done during early use of the drug) Intending to write ‘chlorpromazine,’ but instead writing ‘chlorpropamide;’ scrawling ‘chlorpromazine,’ which is misread as ‘chlorpropamide;’ picking a bottle containing chlorpromazine from the pharmacy shelf when intending to take one containing chlorpropamide Putting the wrong amount of acetylcysteine into an infusion bottle Giving penicillin, knowing the patient to be allergic, but forgetting
∗ Mnemonic: KRAM (knowledge, rule, action, memory).
were 330 incidents relating to 310 prescriptions. Of these, 280 (85%) were classified as a near miss (22.33 per 10 000 items dispensed), while the other 50 (15%) were classified as dispensing errors (3.99 per 10 000 items dispensed). Selection errors were the most common types of incidents (199, 60.3%), followed by labelling (109, 33%) and bagging errors (22, 6.6%). Most of the incidents were caused either by misreading the prescription (90, 25%), similar drug names (62, 17%), selecting the previous drug or dose from the patient’s medication record on the pharmacy computer (42, 11%) or similar packaging (28, 7.6%). Dispensing error reports for the Central Arkansas Veteran’s Healthcare System have been obtained for October 1997 to September 2001 and classified by type of error (wrong drug, wrong dose, wrong patient, and ‘other’) and severity (minor, significant, major, and unrated) (8C ). In all, 82 dispensing errors were reported from eight different pharmacy sections, including 31 wrong drugs, 21 wrong doses, 24 wrong patients, and six other errors. By severity 29 were unrated, 30 minor, 21 significant, and two major (both due to wrong drug selection). The authors suggested that focusing efforts on selecting the correct drug and correct patient would probably yield the best results in reducing dispensing errors. The factors that cause nurses to make drug errors in their practice have been reviewed
(9R ). They include calculation errors, overdosing/underdosing, covert drug administration in food and drink, and an increasingly relaxed attitude among professional nurses with regard to ensuring that drugs are administered to the standards required by law. The author suggested that nurses may breach the legal duty of care they owe patients by being complacent in their drug administration practices. The risk of medication errors that surgical patients experience can be partly attributed to the many processes that patients encounter as they move from preadmission, to preoperative areas, to the operating room, to postoperative care units, and then back to a clinical unit or discharge. In an analysis of 645 medication error records in Post Anesthesia Care Units (PACUs) the errors resulted in a higher than expected threshold of harm (6.8%), and most errors occurred during administration (59%) (10c ). Nearly a quarter of the errors involved the wrong dose. Three quarters of the errors were influenced by distractions. More than 130 different products were involved. Problem areas identified involved epidural analgesia, patientcontrolled analgesia, and duplicate doses. Frequency of errors In 2002 the US Pharmacopeia’s MEDMARX database of medication errors received 192 477 reports from 482 institutions, an 82% increase from 2001 (11c ). Errors that did not reach the patient occurred in 35% of the records, errors that reached the
598 patient in 49%, and errors that may have contributed to or resulted in harm in 2%. The incidence of detectable medication errors in a unit dose drug distribution and control system has been studied prospectively using an observational method confined to the Pharmacy Department and a voluntary anonymous reporting system (12C ). Prescription errors were the most common (1.12%), followed by dispensing errors (1.04%), transcription errors (0.42%), and administration errors (0.69%). Voluntary reports involved only 4.25% of all detected errors. The frequency and characteristics of medication errors have been studied in medical inpatients (13C ). Events were first categorized by whether they occurred during the hospital stay or had occurred before admission. They were then categorized as error-associated events (indication error, missed contraindication, wrong dosage regimen, or inadequate surveillance) and adverse drug reactions (indication established, no contraindications, appropriate dosage regimen, and adequate surveillance). Of 6383 patients 481 (7.5%) had at least one event. These were adverse drug reactions in 457 (7.2%). There were error-associated events in 28 patients, an incidence of 0.4% (95%CI = 0.2, 0.7). Error types were missing/inappropriate indication (n = 4), missed contraindications (n = 9), relative overdoses (n = 8), absolute overdoses (n = 3), and inadequate clinical surveillance (n = 4). The drugs incriminated included antithrombotic drugs (n = 6), cardiovascular drugs (n = 5), antibiotics (n = 5), hypnotics (n = 4), and non-steroidal anti-inflammatory drugs (n = 3). There were event-related hospital admissions in 262 patients (4.1%); 183 (2.9%) were classified as adverse drug reactions and 79 (1.2%) as errors. The authors concluded that medication errors in hospital occurred in 1 of 250 patients and accounted for about 6% of events. In contrast, medication errors accounted for 30% of drug event-related hospital admissions. The occurrence and types of medical errors have been studied in a 19-bed intensive care unit using a voluntary reporting method (14c ). Over 6 months: • there were 232 medical events involving 147 patients; • there were 89.3 medical events per 1000 intensive care unit days;
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• most of the reports came from nurses (59%), followed by physicians-in-training (27%) and intensive care unit attending physicians (2.6%); • 130 (56%) events were judged to involve patient care providers who were working in the intensive care unit area; • 102 (448%) events were commissions or omissions that occurred outside the intensive care unit during transport or in the emergency department and hospital floors; • 23 (9.9%) events that led to a medical error resulted in the need for additional lifesustaining treatment, and seven (3.0%) errors may have contributed to patient deaths. Anesthesia The incidence and outcomes of drug administration errors have been studied in operating theaters in Japan (15C ). In 4 291 925 cases of anesthetic delivery the rate of critical incidents due to drug administration error was 18/100 000 anesthetics. Cardiac arrest occurred in 2.21 patients per 100 000 anesthetics. The causes were: overdose or selection error involving non-anesthetic drugs, 42%; overdose of anesthetics, 29%; inadvertent high spinal anesthesia, 18%; local anesthetic intoxication, 6.4%; ampoule or syringe swap, 4.3%; blood mismatch, 0.6%. Deaths occurred in 0.44/100 000. The causes of death were: overdose or selection error involving non-anesthetic drugs, 47%; overdose of anesthetics, 26%; inadvertent high spinal anesthesia, 16%; local anesthetic intoxication, 5.3%. Death following inadvertent high-spinal anesthesia and local anesthetic intoxication was reported only in patients who had had a cardiac arrest. The authors suggested that education, adequate supervision, and improved organization are necessary and that bar-code technology might be useful in preventing drug administration error, as has been suggested elsewhere (16r , 17R ). Infusions In an evaluation of 202 continuous infusions in 71 patients in a 16-bed surgical intensive care unit errors occurred at a rate of 106 per 1000 patient days (18c ). For nonweight-based infusions, 94% of doses were delivered correctly. Slightly more than 10% of the doses administered for weight-based infusions were incorrect. There were no severe consequences. When 22 nurses gave intravenous drugs, one or more errors occurred in the preparation and administration of 58 of 122 drug doses; four
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were potentially major errors (3%), 38 (31%) potentially moderate, and 16 (13%) potentially minor (19c ). Common errors included multiple step preparations and the co-administration of potentially incompatible drugs as intermittent infusions. Anticoagulants In a 3-year study of the extent and severity of medication errors anticoagulation in hospital 130 medication errors were identified (20C ). There were 1.67 medication errors for every 1000 patients treated. These were most often associated with unfractionated heparin (66%), followed by warfarin (22%), lowmolecular-weight heparin (9.2%), argatroban (1.5%), and lepirudin (1.5%). No deaths were attributed to errors, but 6.2% of patients required medical intervention and 1.5% needed prolonged hospitalization. Insulin It has been reported that 11% of drug errors are from insulin administration errors and it has been recommended that frequent checks be made of infusion systems (21R ). Methotrexate In a study of 106 medication errors associated with methotrexate reported to the FDA between November 1997 and December 2001, there were 25 deaths (24%) and 48 other serious outcomes (45%) (22C ). The most common types of errors involved confusion about the once-weekly dosage schedule (30%) and other dosage errors (22%). The most frequent indication for use was rheumatoid arthritis (42%). Of the errors, 39 (37%) were attributable to the prescriber, 21 (20%) to the patient, 20 (19%) to dispensing, and 18 (17%) to administration by a health-care professional. Vincristine Three types of medication errors associated with the use of vincristine sulfate have been described: overdosage (wrong dose), name confusion (wrong drug), and incorrect administration (wrong route) (23r ). These errors are preventable, usually result in serious patient harm, and are often lethal. Specific strategies are needed to prevent them. Reporting errors Nurses The processes that are used to report medication errors and nursing staff’s perceptions about such errors have been studied (24E ).
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There was an average of 4.7 medication error reports per month. The staff felt that half of all medication errors were identified and communicated informally through change-of-shift reports rather than through medication error reports. Most (85%) believed that disciplinary action was taken against the person who committed an error. Reasons why nurses do not report medication errors include fear of reactions by managers and peers (25R ). Pharmacists In a telephone survey of awareness of medication errors among 113 community pharmacists in Vermont and their use of the United States Pharmacopeia Medication Errors Reporting (USP MER) program, although 62% had heard of USP MER, only 21% had ever submitted a report (26C ). Significantly more pharmacists employed by independent pharmacies had submitted a report than pharmacists from other types of pharmacy (chain, supermarket, mass merchandiser). Submitting reports through a corporate hierarchy or to a corporate program was the reason most frequently cited by pharmacists for not submitting reports directly to USP MER (37%). The barriers to submitting reports are unclear. Detecting errors It has been estimated that voluntary reporting systems seriously underestimate the number of medication errors and suspected adverse drug reactions by as much as 90%. In a review of the causes and impact of medication errors and suspected adverse drug reactions the authors concluded that significant improvement requires systemic implementation of information technology, with integration of the different components of health-care information systems (27R ). Preventing errors Strategies that can be adopted to reduce medication errors have been reviewed (28R , 29R ), including the role of the pharmacist (30R , 31R ) and the implementation of computers (32R ). It has been suggested that the best way to enhance patient safety is by being honest when errors occur, reporting them to a national clearing house, objectively searching for root causes, avoiding arbitrary blame, and when possible implementing safeguards to minimize the occurrence of future errors (33R ). The importance of clear naming, labelling, and packaging has also been stressed (34R ).
600 Successful strategies for prevention of medication errors include participation of pharmacists in medical rounds, the use of computerized physician order entry, and improved communication between physicians, nurses, and pharmacists. Computerized medication administration records, unit dose dispensing, and pharmacist monitoring of order transcribing tended to prevent non-harmful errors more than serious errors. The following general steps have been suggested: • make errors a top priority of the institution rather than the responsibility of one or two departments; • treat them as symptoms of system errors and not simply individual human errors; • design non-punitive reporting mechanisms that accurately report errors and near misses and give information on the potential causes; • use the information to re-design the process with emphasis on high-risk drugs or highrisk diagnoses identified in reports; • use this information to target educational and training programmes or system designs to reduce the incidence of these types of errors. Pharmacists are encouraged to promote a number of simple but proven strategies for reducing errors, such as approved lists of abbreviations, reducing verbal orders, use of preprinted chemotherapy orders, and patient counseling. Providing drug information at the time of prescribing is a proven strategy for reducing medication errors. Automated dispensing systems may reduce dispensing and administration errors, but only if incorporated into a well designed system that includes pharmacist review of orders before dispensing and proper packaging and access to the system. Voluntary medication error reporting can overcome barriers to learning about and correcting system failures in hospital (35E ). The use of computerized physician order entry (CPOE) systems to reduce medication errors has been studied in a prospective study in 514 children in a pediatric critical care unit (36C ). In all 13 828 medication orders were reviewed. Before implementation, medication prescribing errors occurred at a rate of 301 per 1000 orders, and rule violations at a rate of 68 per 1000 orders. After implementation, the rate of medication prescribing errors was reduced to 2 per
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1000 orders and rule violations to 1 per 1000 orders. Methods for preventing errors in intravenous drug administration have been reviewed focusing on “smart” infusion technology, particularly in relation to heparin (37R ). An intravenous medication safety system designed to prevent high-risk infusion medication errors and to capture continuous quality improvement data for best practice improvement has been tested with 50 systems in 2 units at Vanderbilt University Medical Center (38E ). Even in the presence of a fully mature computerized prescriber order-entry system, the new safety system averted 99 potential infusion errors in 8 months. Medication errors in a neonatal intensive care unit over 1 year have been described and the impact of a combined risk management/clinical pharmacist-led education programme assessed (39E ). There were 105 errors; four were serious, 45 potentially serious, and 56 minor. The four serious errors included two ten-fold dose miscalculations. Most (71%) of the errors were due to poor prescribing. After the interventions were introduced, monthly medication errors fell from a mean of 24 per 1000 neonatal activity days to 5.1 per 1000 days. The subsequent change over of junior medical staff was associated with a significant increase in medication errors to 12 per 1000 neonatal activity days. Proper drug storage and labelling is important in order to avoid drug administration errors (40A ). • An 82-year-old man receiving regular line flushing with heparin died of hypoglycemia. He had had raised insulin concentrations and a low C-peptide. The bottles of insulin had been kept with those of heparin and saline.
A systematic review that identified 98 relevant references (14 with experimental designs or incident reports and 19 with reports of cases or case series) has led to recommendations for minimizing errors in intravenous drug administration in anesthesia (41M ): • the label on any drug ampoule or syringe should be read carefully before a drug is drawn up or injected; • the legibility and contents of labels on ampoules and syringes should be optimized according to agreed standards;
Miscellaneous drugs and materials, medical devices, and techniques
• syringes should (almost) always be labelled; • formal organization of drug drawers and workspaces should be used; • labels should be checked by a second person or a device before a drug is drawn up or administered. It has been reported that 11% of drug errors are from insulin administration errors and it has been recommended that frequent checks be made of infusion systems (42R ). In a 66-bed hospital with 8.5 hours/day of pharmacy staffing, 34% of all medication errors during 2 years involved selection of the wrong drug from stock after pharmacy hours, as detected by a webcam (43E ). The authors suggested that using webcam/e-mail image transmission and video verification by a pharmacist improved patient safety. Six sigma is a quality management method that was originally developed by companies such as Motorola and General Electric. It involves the use of statistical data to redesign faulty systems and defines manufacturing of ultra-high quality, in which only 3.4 defects occur per 1 million products (44R ). It has been adapted to problems of health care (45R ), including reducing the risks of medication errors (46R ). In Taiwan, because of financial difficulties, pharmacists are being required to care for more patients, use fewer resources, and work faster, better, and more efficiently than before (47C ). Dispensing errors by pharmacists ranked second in the list of errors, and an effort to reduce this has been made by implementing the six sigma method. The analysis involved the following steps (DMAIC): • Define the problem: identify the project, review historical data, and define expectations. • Measure current standards. • Analyse current capabilities and sources of variability. • Improve: institute changes and observe their effects. • Control: implement process controls. Dispensing errors were reduced from a mean of 335 per million in 2000 to 200 per million in 2003. Anecdotal reports Medication errors in emergency departments have been reviewed in the light of 15 cases in adults and children (48cr ).
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Packaging continues to provide an important source of medication errors (49r , 50A , 51A ). • A 71-year-old woman with chronic renal insufficiency developed hypotension and bradycardia after having been given generic acebutolol instead of generic amiodarone, which were packaged in similar blister packs; she responded to dobutamine (52A ).
The French Health Products Safety Agency (AFSSAPS) has asked companies that produce generic medications to modify the packaging and labelling of their blister packs. Susceptibility factors Children The sources of medication errors in children have been reviewed (53R ). The authors recommended that it is critical to have personnel trained in pediatric therapeutics to prescribe, prepare, dispense, and administer medications, to institute a quality review system to review drug use and medication errors, and to implement computerized physician order entry with decision support. The perceptions of 57 pediatric and 227 adult hospital nurses regarding the proportion of medication errors reported on their units, why medication errors occur, and why medication errors are not always reported have been studied (54c ). Pediatric nurses indicated that a higher proportion of errors were reported (67%) than adult nurses (56%). The medication error rates per 1000 patient-days computed from actual occurrence reports were also higher on pediatric units (14.80) compared with adult units (5.66). Pediatric nurses identified distractions/interruptions and nurse-to-patient ratios as the major reasons for medication errors. The propensity for nurse administrators to focus on the individual rather than the system and the fear of reprimand were primary reasons identified for not reporting medication errors. In a prospective observational study of mock resuscitations in children the participants gave 125 orders for medications (55E ). In 21 (17%) of the orders the exact dose was not specified. There were nine dosing errors during the ordering phase. Of these, five were intercepted before the drug reached the patient. Four 10fold errors were identified. In nine (16%) of 58 syringes analysed, measured drug concentrations deviated by at least 20% from the ordered
602 dose. There was a large deviation (at least 50%) from the expected dose in four (7%) cases. The authors concluded that many errors could be detected only by analysing syringe contents, suggesting that such errors may be a major source of morbidity and mortality in resuscitated children.
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These results suggested that she was probably reacting to the benzyl alcohol but could not rule out the possibility of sensitization to both the benzyl alcohol and cyanocobalamin. The patient was therefore skin tested with a nasal gel formulation of cyanocobalamin and did not react. Hypersensitivity reactions to benzyl alcohol have been documented in patients treated with a variety of medications containing benzyl alcohol as a preservative (58A , 59A ).
Ayurvedic medicines Drug contamination Health Canada has warned that according to a study in the USA, as many as 14 Ayurvedic preparations have been reported to contain high concentrations of lead, mercury, and/or arsenic (56S ). Three products are suspected to be available in various parts of Canada, although none has been authorized for sale. Ayurvedic medicinal products are used in the traditional Indian healing paradigm. According to the principles of Ayurvedic medicines, heavy metals are used in a detoxified state in these medicinal products because of their reputed therapeutic properties. However, should the detoxification process not be strictly followed during manufacturing, it is possible for the resulting product to contain large amounts of heavy metals. Health Canada is currently determining the availability of the listed products in Canada to ascertain appropriate action. In the meantime, consumers are being warned not to use any of these products. Those who have used the preparations in the past and are concerned about their health are advised to consult their physicians.
Benzyl alcohol Immunologic An anaphylactic reaction has been attributed to benzyl alcohol, used as an antimicrobial preservative in vitamin B12 (57A ). • A 16-year-old girl developed anaphylactic reactions after using vitamin B12 injections. The symptoms included pain at the injection site, a sensation of substernal burning and pleuritic pain, and pruritus of the arms and legs, but no rash. She was skin tested to three commercial formulations of injectable cyanocobalamin and to the benzyl alcohol (0.9%) preservative in each. Prick testing was negative but intradermal testing was positive to all the cyanocobalamin formulations and benzyl alcohol.
Bisphosphonates
(SED-15, 523;
SEDA-28, 590) The bisphosphonates alendronate, risedronate, tiludronate, etidronate, pamidronate, and zoledronic acid- are approved by the Food and Drug Administration for the treatment and prevention of osteoporosis and heterotopic ossification, the treatment of Paget’s disease and hypercalcemia of malignancy, and the prevention of osteolytic lesions and metastases in patients with cancer. Although they are generally well tolerated, bisphosphonates can be associated with adverse drug reactions (60C ). Nausea, diarrhea, dyspepsia, and esophageal ulceration and bleeding are well documented adverse effects of oral bisphosphonates (61C ). Intravenous bisphosphonates can cause anorexia, nausea, vomiting, and electrolyte abnormalities. Less commonly, they can cause anemia, hypertension, and impaired renal function (60C ). Psychological Bisphosphonates, regardless of route of administration, have also been associated with hallucinations (auditory and olfactory) and visual disturbances (62C ). • A 79-year-old Caucasian woman who had been taking alendronate 10 mg/day for over 2 years to prevent osteoporosis reported hearing “voices in her head” along with red-colored visual disturbances (63A ). These disturbances began shortly after her regimen had been changed from alendronate 10 mg/day to 70 mg once/week. Assessment of causality revealed “probable” and “highly probable” relationships respectively between the adverse events and the switch from daily to weekly alendronate therapy.
Other bisphosphonates, such as etidronate and pamidronate, have caused both reversible
Miscellaneous drugs and materials, medical devices, and techniques
and irreversible auditory, visual, and olfactory hallucinations beginning 2 hours to 1 week after drug administration. The mechanism of these adverse effects is unknown but is thought to be independent of calcium homeostasis. Sensory systems The Australian Adverse Drug Reactions Advisory Committee (ADRAC) has reported that inflammatory ocular disorders are rare adverse effects of bisphosphonates (64S ). To date, there have been 28 cases of bisphosphonate-associated ocular inflammation reported to ADRAC, including uveitis (13 reports), iritis (6), scleritis/episcleritis (7), and optic neuritis (2). The median time to onset of these reactions was 3 weeks, but ranged from 2 days to over 3 years. Of the 21 patients who had a documented outcome, 15 had recovered at the time of submission of the report, four were improving (although one required a trabeculectomy), and one had reduced visual acuity. • An elderly man with low bone mineral density of the hip developed uveitis 3 weeks after starting to take risedronic acid 35 mg once weekly. He developed eye pain again after restarting risedronic acid and the pain recurred after he switched to alendronic acid 70 mg once weekly.
Skin Lesions mimicking pemphigus vulgaris have been attributed to alendronate (65A ). • A 77-year-old woman taking long-term coumarin (1 mg/day orally), alendronate (10 mg/day orally), and calcium (500 mg/day orally) developed easily bleeding erosive and ulcerative oral lesions, which caused significant distress and pain when eating. The lesions were partly covered by yellowish and hematogenous crusts, extending to the whole mucosa of the lower lip. There was a 1 cm erythematous erosion on the hard palate. A biopsy from the lower lip was showed extensive epithelial necrosis, dermal perivascular and dispersed inflammatory infiltrates consisting of lymphomononuclear cells and neutrophils, focal formation of granulation tissue, and in some sites preserved hyperplastic epithelium; these findings were not consistent with pemphigus vulgaris. Because alendronate has been reported to cause esophageal and gastric erosions and ulcers, she was questioned again and revealed that she used to disperse her medication before taking it. Withdrawal resulted in rapid healing of the erosions and ulcers within 2 weeks, without relapse, even when alendronate was reintroduced with proper instructions about its administration.
Collagen
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(SED-15, 885)
Voice Injection laryngoplasty is one of the most commonly performed procedures in patients with voice complaints. Various biomaterials have been used to medialize vocal folds or to treat symptoms of vocal fold scarring. The ideal biomaterial would be easily injected through a fine-gauge needle, well tolerated, and long lasting. Injectable collagen preparations fulfil at least two of these criteria, and collagen has been widely used in vocal fold injections. Although collagen injections of the vocal fold rarely result in complications, physicians using collagen must be familiar with the types of complications that can occur. Proper diagnosis and prompt management of complications can result in good outcomes. • A 40-year-old male professional rock singer complained of voice fatigue, weakness, and cracking in the midrange. He had a mild left superior laryngeal nerve palsy, mild failure of glottic closure, and bilateral vocal fold stiffness (66A ). He underwent bilateral collagen injections, and despite a deep injection location and a reportedly good immediate appearance after injection, he slowly developed increased hoarseness and dysphonia. Strobovideolaryngoscopy showed firm submucosal deposits of collagen throughout the anterior two-thirds of the musculomembranous vocal folds, which produced stiffness and a mass effect. No superficial collagen was noted in the right true vocal fold. The superficial collagen was removed surgically and at microlaryngoscopy. The deeper collagen was left intact to maintain some medialization. Postoperatively, the lesions healed well, with some residual stiffness of the mid vocal fold at 2 weeks.
Other complications of collagen injection include hypersensitivity reactions to bovine collagen, local abscess formation at injection sites, and possibly induction of collagen vascular disease in some patients.
Cosmetic fillers The injection of various substances in orofacial tissues have been increasingly used during the past 40 years (67C ). Mostly performed in the perioral, periocular, and cheek areas of middle-aged women, the aim is to smoothen out wrinkles or creases and to produce artificial
604 augmentation of lip or cheek volume for cosmetic and rejuvenation purposes. In the 1960s and 1970s, after unsuccessful attempts with various oils, the earliest injected substances were liquid silicone and, since 1981, purified bovine dermal collagen. Increasing demand, in imitation of movie stars, led to the development an amazing number and variety of commercial “cosmetic fillers,” of which only a few, and not necessarily the same ones, have been approved either by the European Community (EC) or by the Food and Drug Administration (FDA) in the USA. Most of the new fillers seem to be well tolerated, but various adverse reactions are possible, especially with permanent products. Among them, foreign-body granulomas are held by manufacturers to be rare and not always clearly distinguished from “nodules.” The latter term seems to be meant to describe little bumps that appear rapidly after the injection, as a result of uneven distribution of the product in the tissues. The histological features of filler-induced granulomas are poorly documented, although some recent cases have been reported mainly in the dermatological literature (68c ). In 11 patients orofacial foreign-body granulomas developed after injection of various cosmetic fillers (69c ). All were women, mean age 55 years. There was slight pain or mild discomfort in five patients, with transient facial edema in three. The lesion was not clinically visible in one case and there were variably sized nodules bulging under the skin or lip vermilion in four cases. In all, 12 biopsy specimens were taken from the lips (upper three, lower two, commissure one), the cheeks (2), the nasolabial grooves (1), the glabella (2) and the lower eyelid (1). Almost every histological section showed a poorly limited foreignbody granuloma, either superficial in the facial or labial dermis, or more deeply situated in the hypodermis. Some granulomas extended through the muscle from the dermis to the submucosa of the lip or cheek. Two main types of granulomas were identified: the classic foreignbody granuloma type, featuring numerous giant cells around the foreign bodies, and the cystic and macrophagic granuloma type, characterized by extracellular microcysts surrounded by a mainly mononuclear infiltrate of vacuolated macrophages.
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Cresols Skin p-chloro-m-cresol is well recognized as a rare cause of allergic contact dermatitis and is a recommended allergen in the British Contact Dermatitis Society standard series. It is used as a preservative in a wide number of topical formulations. • A 42-year-old woman with psoriasis developed severe pruritus and redness within 30 minutes of applying certain topical formulations containing emollients and glucocorticoids creams (70A ). She was also aware that perfumes and some cosmetics induced similar effects. She found this distressing and disabling. Standard face series and her own medicaments and cosmetics were applied in the usual way bur left in place for only 30 minutes. On removal there were marked urticarial reactions to fragrance mix, cinnamaldehyde, eugenol, and p-chloro-m-cresol. There were also marked urticarial reactions to all medicaments containing p-chloro-m-cresol that had been prescribed for her psoriasis (Diprobase, Betnovate, and Eumovate creams) and a brand of aqueous cream containing p-chloro-m-cresol. However, contact urticaria was demonstrated only at a concentration of 10%.
This case highlights the fact that p-chlorom-cresol can cause contact urticaria.
C31G C31G is a mixture of two synthetic amphoteric surface-active compounds, cetyl betaine and myristamine oxide, and has being studied as a contraceptive and microbicide. In in vitro testing C31G reduces total sperm count and sperm motility (71E ). It has broad-spectrum in vitro activity against both Gram-positive and Gram-negative bacteria, including a range of antibiotic-resistant strains, a wide range of fungi and yeasts, and HIV and Herpes simplex virus (72E ). Comparative studies There has been a randomized, double-blind, single-center Phase I study in circumcised and uncircumcised men, to assess penile irritation, safety, and acceptability of seven consecutive daily doses of 1.0% C31G compared with a marketed spermicide, Extra Strength Gynol II® (3% nonoxynol-9; ES Gynol II). Each participant was instructed to apply the product to his penis at bedtime, to
Miscellaneous drugs and materials, medical devices, and techniques
wash it off 6–10 hours later, and to record any symptoms on a diary card. A genital examination was performed at the follow-up visit, and participants were again asked about adverse events and to complete an acceptability questionnaire (73C ). All 36 men completed all seven uses of gel on 7 consecutive days and completed the study. The C31G gel was left on for an average of 8.6 hours, and the ES Gynol II gel for an average of 8.9 hours before being washed off. There were no protocol violations to do with engaging in intercourse, masturbation, or other activities potentially traumatic to the genitalia during the 7 days of product use. Three men in the C31G group reported a total of five product-related adverse events: stinging dryness, irritation, mild dysuria, and rash. Two men in the ES Gynol II group reported a total of four adverse events, of which dryness, stinging, and irritation/sensitivity were the most common. Two participants, both in the C31G group, had a laboratory result that was normal at enrolment and abnormal at follow-up (one mild rise in eosinophils and one mild rise in monocytes). There were two participants, again both in the C31G group, who had an abnormal result at enrolment that was more abnormal at followup (a slight rise in monocytes in one user and rises in transaminases in another).
Disulfiram and dithiocarbamate (SED-15, 1148; SEDA-26, 541; SEDA-28, 592) Nervous system Disulfiram produces a peripheral neuropathy in humans and experimental animals. N,N-diethyldithiocarbamate is a proximate toxic species of disulfiram. In rats, DEDC increased copper concentrations in peripheral nerves. Lipid peroxidation also appears to contribute to demyelination, possibly through an increase in redox active copper or a consequence of direct myelin injury (74E ). Liver Disulfiram rarely causes hepatitis and liver failure (75A , 76A ). Liver transplantation should be considered early in the management of disulfiram-induced fulminant hepatic failure (77A , 78A ). • A 16-year-old white girl, who had taken disulfiram 500 mg twice a week for 5 weeks in order to discourage excess drinking, developed intermittent,
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right-sided, upper abdominal pain, nausea, vomiting, and malaise, because of which disulfiram was withdrawn (79A ). She then developed jaundice and had mild right upper quadrant tenderness. Her serum liver enzymes before starting disulfiram were abnormal. A liver biopsy showed 80– 90% hepatic necrosis, a mild portal infiltrate with a moderate to severe eosinophilia, and only a few plasma cells. The damage was predominantly hepatocellular with minimal ductal involvement. She developed grade III hepatic encephalopathy and marked deterioration of synthetic liver function. She was given fresh frozen plasma and vitamin K to correct the coagulopathy, which nevertheless worsened. There was no improvement in the encephalopathy. She underwent successful orthotopic liver transplantation.
Drug interactions Dithiocarbamate is a metabolite of disulfiram, and its metabolites can inhibit P glycoprotein. The disulfiram metabolites S-methyl N,N-diethylthiocarbamate sulfoxide and S-methyl N,N-diethylthiocarbamate sulfone inhibit the verapamil-stimulated ATPase activity of P glycoprotein, with IC50 values of 9 and 4.8 µmol/l respectively (80E ). They also inhibit the activity of aldehyde dehydrogenase with IC50 values of 3.2 and 1.7 µmol/l. Inhibition of P glycoprotein by these metabolites was not reversed by the addition of dithiothreitol, a reducing compound. Treatment of P glycoprotein mutants containing a single cysteine residue showed that inactivation was primarily due to modification of Cys1074 in NBD2. These results suggest that metabolites of disulfiram can covalently inactivate P glycoprotein, which has implications for drug interactions and the treatment of multidrug resistant cancers. Tretinoin Diethyldithiocarbamate is a more powerful in vitro inhibitor of the metabolism of tretinoin (all-trans-retinoic acid, ATRA) than the well-established cytochrome P450 inhibitor ketoconazole (81E ). The effects of diethyldithiocarbamate, ketoconazole, and grapefruit juice on the pharmacokinetics of tretinoin have been studied in rats. A high dose of diethyldithiocarbamate caused a marked reduction in plasma tretinoin concentrations. Ketoconazole increased the AUC of tretinoin. Grapefruit juice had no effect. The authors concluded that the in vivo effects of CYP inhibitors on the pharmacokinetics of tretinoin are qualitatively different from those expected from in vitro studies.
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Ethylenediamine
(SED-15, 1300; SEDA-24, 544; SEDA-25, 586) Ethylenediamine is an aliphatic amine with many applications in industry. Some topical medicaments contain ethylenediamine as a stabilizer. Aminophylline is a mixture of theophylline and ethylenediamine, which renders the theophylline more water soluble. Skin Ethylenediamine was first reported as a cause of allergic contact dermatitis in 1959 (82c ). Skin reactions have been reported following parenteral administration of aminophylline in individuals who have subsequently been shown to have positive patch test reactions to ethylenediamine but not theophylline. These reactions include exanthems, the baboon syndrome, exfoliative dermatitis, urticaria, and erythroderma (83c , 84c ). • A 68-year-old woman developed an intensely itchy erythematous eruption over the left scapular area 3 days after starting to take oral aminophylline and the mucolytic carbocisteine for an exacerbation of chronic airways disease (85A ). She had an impetiginized eczematous plaque over the left scapular area and dusky erythematous macules on the trunk, thighs, and upper limbs. The carbocisteine was withdrawn, but the rash worsened despite oral prednisolone. She stopped taking aminophylline. Patch tests in 2001 showed a ++ reaction to ethylenediamine. She was treated with intramuscular triamcinolone 80 mg and betamethasone 0.025% cream.
DYESTUFFS Ocular dyes
N.H. Choulis and J.K. Aronson
Table 2. Distribution of patients according to the use of eyelash dyes (from 88c ) Eyelash dyes
Cases (%)
Controls (%)
Total
Used Not used
172 (63) 100 (37)
110 (40) 162 (60)
282 262
Total
272
272
544
past 14 days was taken. A history of episodes of itching and redness of the eyes before starting to use eyelash dye was sought, and the reasons for using the dye were determined. A thorough eye examination was carried out on every patient. The patients were regarded as having been exposed if they had used eye cosmetics at any time in the past 14 days or if the dye was found on the eyes or lids. Of the 544 patients, 282 (52%) had used eyelash dyes. Home-made dyes were used by 71% of all dye users; the remainder used industrially manufactured dyes. Of the 282 dye users, 276 (98%) were women and 165 (59%) users (cases and controls) were aged 21–50 years. More than 60% of cases involved eyelash dyes, while 40% of controls used such dyes; this difference was statistically significant (Table 2). Some women use eyelash dyes as a treatment for eye diseases, following advice given by traditional herbalists, a practice that is very common in many parts of Africa. In this study, almost one-third of dye users used dyes based on traditional herbalists’ advice.
FD & C Blue No. 1 dye (SED-15, 2596)
Immunologic Allergic eye diseases are commonly encountered in clinical practice. Some commercial preparations cause not only allergic eye diseases but also chemical keratitis. In the USA some eyelash dyes have been reported to cause argyria of the cornea (86C ). Others can cause conjunctival pigmentation (87c ). In a case-control study 272 patients who came to the eye clinic with allergic eye disease were compared with 272 controls who attended the same clinic with non-allergic eye diseases. The cases were sex- and age-matched with controls at ±5 years (88c ). A detailed history regarding the use of eye cosmetics in the
Food Drug and Cosmetic Blue No. 1 dye (FD & C Blue No. 1) is commonly added to enteral nutrition formulations in order to facilitate the detection of gastric aspirate in tracheal secretions in critically ill patients. However, reports of systemic blue dye absorption and associated adverse outcomes are emerging. • A 57-year-old man with a history of cadaveric renal transplant developed Gram-negative sepsis related to an infected vascular catheter (89A ). Despite removal of the catheter and treatment with appropriate antibiotics, he had persistent fever, leukocytosis, tachycardia, hypotension, and progressive inflammation, pain, and palpable crepitus in the left hand. An X-ray of the left arm showed gas in
Miscellaneous drugs and materials, medical devices, and techniques the soft tissues, consistent with necrotizing fasciitis. He had urgent surgical debridement and amputation at the left wrist. His condition was further complicated by respiratory failure and acute renal insufficiency requiring hemodialysis. Postoperatively he needed continuous enteral feeding and FD & C Blue No. 1 100 mg was added to 1000 ml of enteral formula in order to facilitate the detection of gastric aspiration. The total dose of FD & C Blue No. 1 did not exceed 0.7 mg/kg/day. On day 32, a bluish discoloration of both the skin and dialysis ultrafiltrate was noted. Spectrophotometric analysis of serum and dialysate confirmed the presence of FD & C Blue No. 1. Enteral feeding was immediately discontinued, but his condition rapidly deteriorated. Despite aggressive volume resuscitation and maximal vasopressor therapy, he developed lactic acidosis, respiratory failure, and refractory shock. No source of infection was identified. Multiple organ failure developed, and he died on day 35.
Fluorescein dye
(SEDA-26, 542)
Sensory systems The technique of fundus fluorescein angiography was introduced by Novotny and Alvis in 1961 (90E ). Since then, it has become an invaluable diagnostic and therapeutic adjunct and is regarded as a relatively safe procedure, although the reported incidence of adverse effects after intravenous administration of fluorescein dye is 4–20% (91C , 92C ). Adverse effects are usually categorized as mild, moderate, or severe, depending on their duration, the need for medical intervention, and the final outcome. Two patients with pre-existing ocular inflammatory disease had unusual ocular reactions after intravenous fluoresce administration (93A ). • A 43-year-old healthy man, with a history of Toxoplasma retinochoroiditis in his right eye 11 years before, developed reduced vision in his right eye. Visual acuity was 20/20 in both eyes, and the left eye was completely unremarkable. Slitlamp biomicroscopy and indirect ophthalmoscopy showed a moderate vitreous cellular reaction, although there did not appear to be any obvious reactivation of the retinochoroiditis. Fluorescein angiography was performed to further evaluate the posterior segment because of the active vitreitis. About 5 ml of 10% sodium fluorescein was injected intravenously into the right arm. Within several minutes, he had a burning sensation in his right eye. Although he became slightly lightheaded and sweaty, his vital signs remained stable. There was a yellowish discoloration and chemosis of the conjunctiva of the right eye only. The left eye was
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unaffected. The reaction in the right eye abated shortly after without specific treatment. • A 66-year-old man, with a history of mild central retinal vein occlusion, reported worsening vision in his left eye. Visual acuity was 20/400, and there was a trace of conjunctival injection and a mild cellular reaction in the anterior chamber. Dilated fundus examination showed a large exudative retinal detachment with shifting fluid. Ultrasonography confirmed exudative retinal detachment and also showed a markedly thickened sclera, consistent with posterior scleritis. He underwent intravenous fluorescein angiography and several minutes later had an ocular burning sensation, which was accompanied by increased tearing in the left eye. His vital signs remained stable, and he had no other ill effects. Examination showed markedly worse conjunctival injection and moderate chemosis in the left eye, although the right eye was unaffected. He was given oral prednisone to treat the posterior scleritis. Two weeks later the retinal detachment was resolving.
Hair dyes
(SED-15, 1572)
Immunologic Although p-phenylenediamine (PPD) and toluene-2,5-diamine are the most frequently reported hair dye allergens, allergic contact dermatitis from direct dyes for hair coloration is unusual. Two patients, with a history of PPD allergic contact dermatitis had positive patch tests to HC Yellow 7,4 amino3-nitrophenol and HC Red B54 in hair dyes (94A ).
Isosulfan blue dye Isosulfan blue (Lymphazurin 1%) is a vital blue dye that is being used in the operating room with increasing frequency. After injection into tissues, isosulfan blue binds to albumin in the interstitial fluid and travels with it through the lymphatic vessels to the regional lymph nodes that drain the area. Vessels and nodes are therefore stained with a deep blue color that is readily seen after surgical exposure. The term intraoperative lymphatic mapping (IOLM) has been used to describe this procedure. Observational studies In 1852 patients (724 male and 1128 female; mean age 53, median 53, range 3–92 years), isosulfan blue was used for sentinel node biopsy in 1850 procedures
608 and to identify lymphatic vessels for lymphatic grafting in the other two (95C ). There were adverse events potentially attributable to isosulfan blue in 28 procedures (1.5%), as follows: skin reactions (n = 21), hypotension (n = 14), edema (n = 1), and an unspecified reaction (n = 1). The edema was described as “severe facial edema.” There were no episodes of bronchospasm or upper airway edema. Seven patients had hypotension combined with skin reactions, and one had hypotension, a skin reaction, and edema. The skin reactions included urticaria (n = 13), erythema/flushing (n = 4), and unspecified rashes (n = 6). Two patients had erythema/flushing plus one of the other types of skin reaction. In two patients with urticaria and one with an unspecified rash, the lesions were characterized by a bluish color. The skin reactions were described as either diffuse or involving more than two areas of the body in 11 patients. In patients with hypotension, the duration was 82 (median 40; range 10–365) minutes. In one patient, the initial episode of hypotension resolved within 165 minutes, but recurred 7.25 hours later; it was successfully treated with a single 100 microgram intravenous bolus of adrenaline and 1 liter of intravenous crystalloid solution. In the eight patients with skin reactions in addition to hypotension, the duration of the skin reactions was poorly defined. In five cases, the skin reaction was only described at onset, and not in any subsequent notes. In the other three, the event was noted at onset and at one later time at least.
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of anesthesia with propofol 2.5 mg/kg, sufentanil, and sevoflurane (99A ). Ephedrine was ineffective and she was given adrenaline, clemastine, and intravenous hydrocortisone. Serum tryptase activity was increased (74 µg/l; reference range <10 µg/l), IgE latex was negative and an anaphylactic reaction to patent blue, which had been used to outline sentinel lymph nodes, was assumed to be the most probable cause. Re-exposure to patent blue was considered too dangerous.
Shoe dyes Drug overdose Emergency physicians often encounter patients who ingest non-food products with the intent of harming themselves. Information provided either on the product label or from the poison center database is usually helpful in determining the contents of a particular product and therefore the potential effects after ingestion. • A previously healthy, 39-year-old woman intentionally took 125 ml of AmberesTM Mexican shoe dye in a suicide attempt (100A ). The product stated only “contiene methanol” on the packaging. Information regarding the specific product contents could not be obtained through standard poison center databases. In addition to the initially anticipated methanol toxicity, the patient subsequently developed severe methemoglobinemia, sulfhemoglobinemia, and hemolytic anemia from aniline contained in the shoe dye (101c ).
Fluoride salts and derivatives (SED-15, 1395)
Patent blue Immunologic Patent blue is a dye that is often used in textiles, cosmetics, and agricultural and medical products. In the 1970s and 1980s it was often used in lymphangiography, and skinprick testing was advocated to predict allergic reactions, as 2.7% of the population was sensitized to the dye (96R ). Currently, patent blue is used in multiple oncological surgical sentinel node procedures (97C ), and an increasing number of cases of severe anaphylaxis have been reported (98c ). • A 49-year-old woman with an atopic constitution developed severe hypotension, mild bronchospasm, and a rash 20 minutes after induction
Hydrofluoric acid is widely used in industrial settings, but also in domestic products, such as cleaning solutions and rust removers. On the other hand, it is one of the most corrosive inorganic acids because of its strong affinity for protein (102E ). Moreover, the dissociated fluoride ions cause systemic poisoning owing to their high affinity for cellular enzymes and divalent cations, mainly calcium and magnesium. • A 65-year-old skilled worker was in the process of cleaning iron pipes associated with a cooling apparatus by using a high-pressure stream of water, in which hydrofluoric acid gas was liquefied into hydrofluoric acid (103A ). About 5 minutes later, he was heard crying for help and was found crouching, his face gray in color. He complained
Miscellaneous drugs and materials, medical devices, and techniques of chest pain. At the time he was wearing a helmet, goggles, rubber gloves, and a raincoat. It was not clear whether during the accident he had been wearing a plastic face shield that was found nearby. When an ambulance arrived about 30 minutes after the accident, he was in cardiopulmonary arrest. Despite aggressive cardiopulmonary resuscitation and the intravenous administration of adrenaline, atropine, and sodium bicarbonate, he died about 1.5 hours after the accident. Subsequent police investigation showed that one of the iron pipes had been clogged with crystallized hydrofluoric acid. It was therefore surmised that a solution containing hydrofluoric acid and vapor was unexpectedly expelled on to his face from the pipe by the application of a high-pressure stream of water while it was being cleaned. At post-mortem there was a third-degree chemical burn to his face, extending to both ears. The affected area was greenish-gray in color, and the upper and lower lips had turned black. Both temporal bones were dyed greenishgray. Both lungs were edematous, with diffuse parenchymatous hemorrhage. Although a frothy fluid containing blood was found inside the trachea and both of the main bronchi, there was no definite evidence of burning in the upper airway.
Limonene Since the 1980s limonene has been used as an alternative to traditional solvents and degreasing agents. It is a monoterpene found in a variety of fruits, vegetables, herbs, trees, and bushes. Limonene constitutes the main volatile component of some citrus oils and represents a small fraction of the terpenes in pine needle oils and turpentine. Biogenic and anthropogenic sources release large amounts of limonene into the atmosphere, and biogenic emissions may meet or exceed anthropogenic sources (104E ). Limonene is used as a substitute for chlorinated hydrocarbons, chlorofluorocarbons, and other solvents. In concentrations of 30–100%, it is used as a metal degreaser before painting, as a paint solvent, and as a cleaner in the printing and electronic industries. It is also used in numerous other products, such as home cleaning products, disinfectants, industrial hand cleansers, odorants, rubber, wax and paint strippers, adhesives, lubricating oils, essential oils, cosmetics, fire extinguishers, and wetting and dispersing agents. For more that 50 years, it has been used as a fragrance and flavoring additive to perfumes, soaps, food, and beverages. Medicinal uses include chemopreventive and chemotherapeutic properties (105c , 106c ).
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Although data are limited, limonene, linoleic acid, and oleic acid are probably of low toxicity. Human dietary and in vitro studies of linoleic and oleic acids have shown alterations in erythrocyte membranes, platelet activity, sperm motility, and thyroxine binding; however, these findings have not been extended to potential hazards in exposed workers. Until more data are available, conclusions regarding occupational health effects remain difficult to determine. Human exposure to these products is common and almost certainly occurs during daily food intake. Medical management of exposure is symptomatic and supportive. Mild skin irritation can occur, and oxidative products of limonene can produce skin sensitization. Patients with skin or ocular exposure should be decontaminated with water or saline respectively. Treatment of dermal effects involves removal and symptomatic skin care, such as antihistamines for allergic effects. An ophthalmologist should see patients with ocular complaints that do not resolve with irrigation or who have abnormal ocular findings on examination (107c ). Respiratory Limonene, and possibly linoleic and oleic acids, can have irritative and bronchoconstrictive airway effects. Patients with significant inhalational exposure should be removed from the environment and undergo appropriate decontamination. Inhaled beta2 adrenoceptor agonists can be used for bronchoconstriction. Urinary tract Limonene ingested in sufficient quantity can cause proteinuria. However, nephropathy and renal tumors are not expected in humans.
Lipiocis Lipiocis is a radiopharmaceutical product that contains 131 I-labelled iodized oil, indicated for the treatment of hepatocellular carcinomas with thrombosis of the portal vein. Respiratory CIS Bio (a subsidiary company of the Schering group), in agreement with the French agency for medical safety of health products (AFSSAPS) has informed health professionals that the incidence of interstitial pneumopathy associated with the use of Lipiocis
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appears to be higher (2%) than was initially observed in clinical trials (0.5%) (108S ). A total of 13 cases of interstitial pneumopathy have been reported to the French reference centre for the treatment of hepatocellular carcinomas. The pneumopathy occur about a month after injection of Lipiocis, generally after the second injection. The symptoms include dyspnea, sometimes associated with a dry cough and bilateral crackles. Pneumopathy can lead to serious complications, with a high death rate. AFSSAPS has recommended that thoracic radiography must be carried out before administering Lipiocis and if respiratory symptoms are observed. The Summary of Product Characteristics has been updated to reflect this information.
(112R ). Fatal delayed hemolysis has been described when methylthioninium chloride was used to treat toxic methemoglobinemia resulting from exposure to aniline-based compounds (113C ).
Menthol
Nicotine
(SED-15, 2254; SEDA-26, 543)
Menthol, 2-isopropyl-5-methylcyclohexanol, is a non-aromatic cyclic alcohol widely used in preparations such as cigarettes, cough drops, and perfumes. Menthol, administered orally, is hydroxylated in the liver, conjugated with glucuronide, and excreted in the urine (109R ). In 1976, the Food and Agriculture Organization of the United Nations World Health Organization (FAO/WHO) established an acceptable daily intake of 0.2 mg/kg/day for menthol, because adverse events are unlike to occur below this threshold (110S ). • A 54-year-old man took 20 extra-strong lozenges, each containing 19.8 mg of menthol, every day for 5 years (5.82 mg/kg/day) and developed abnormal liver function tests and a low platelet count (111A ). Diagnostic evaluation for all principal causes of liver disease was negative.
Methylthioninium chloride (methylene blue) (SED-15, 2314; SEDA-27, 531; SEDA-28, 595) Hematologic Methylthioninium chloride, a phenothiazine dye, is conventionally used to treat methemoglobinemia. It acts through the NADPH reductase pathway and can cause oxidant hemolysis when there is glucose-6phosphate dehydrogenase (G6PD) deficiency
• An 18-year-old school drop-out took employment in a printing press, cleaning printing plates with a solvent. It was not clear whether he inhaled the solvent or drank it, possibly the latter. He developed an unsteady gait, drowsiness, and vomiting over 2–3 hours, became comatose, and was deeply cyanosed. His vital signs were stable. Arterial blood gases were normal. All samples of freshly drawn venous and arterial blood were dark chocolate brown in color (114A ). He was given two units of packed cells but developed acute renal insufficiency and had repeated cardiac arrests, from which he could not be resuscitated.
(SED-15, 2508; SEDA-28, 596)
Drug overdose Although 15–39% of the population smoke nicotine-containing products, acute nicotine toxicity is rare and can be difficult to recognize; it can produce rapid and dramatic toxicity (115C ). • A 15-year-old boy, who was in generally good health, had a cardiopulmonary arrest with a generalized seizure at home, while resting on a couch, and stopped breathing (116A ). On arrival in hospital, he was unresponsive, with a Glasgow Coma Scale score of 4, a rectal temperature of 33.8 ◦ C, a heart rate of 157/minute, a blood pressure of 170/108 mmHg, and a respiratory rate of 6/minute. The breath sounds were clear but the cardiac rhythm was irregular, with normal heart sounds and normal capillary refill. He had midline fixed pupils, the right slightly larger than the left, with weak corneal reflexes. There was no gag reflex. He was globally hypotonic, with decerebrate posturing to painful stimuli and extensor plantar responses. He had intermittent stiffening of the limbs and arching of the back, with spontaneous resolution, and diaphragmatic spasm. MRI scanning of the brain showed severe hypoxic-ischemic encephalopathy, with multiple areas of cortical and basal ganglia infarction. Despite aggressive intensive care support, he improved minimally and remained dependent on gastric tube feedings and full-time care providers.
He had a history of depression and was known to smoke cigarettes and marijuana. In his attic there was a bottle that was nearly empty and had contained an insecticide with the trade name Black Leaf 40, with nicotine sulfate 40%
Miscellaneous drugs and materials, medical devices, and techniques
as the active ingredient. A presumptive diagnosis of nicotine ingestion was made. Laboratory analysis of residual liquid in the bottle showed that it contained nicotine 357 mg/ml.
Silicone
(SED-15, 3137)
Various surgical techniques have been developed to augment and rejuvenate the lips and perioral region and to give them a younger and fuller appearance. Filling procedures for this purpose include autologous tissues and different alloplastic materials, such as liquid silicone, collagen, polymethylmethacrylate microspheres, polyacrylamide hydrophilic gel, and gold threads, although local and systemic toxicity limits the use of some of these substances (117C ). • A 56-year-old woman had her lower lip augmented with suspended silicone particles of unknown origin (118A ). During the next year she developed a painful swelling of the central part of the lip and a yellowish nodule of about 6 × 6 mm. Submandibular and cervical lymph nodes were not palpable. A biopsy specimen of 10 × 9 × 3 mm was taken under local anesthesia. During surgery a fibrotic capsule was dissected and accidentally ruptured with extrusion of pus. Wound healing after excision was uneventful. One month later her lip was still slightly deformed and a biopsy showed spherical homogeneous foreign body inclusions of 0.02–0.05 mm in diameter in fibrotic connective tissue. The inclusions were surrounded by moderate infiltration of lymphocytes in several areas and multinuclear giant cells. • A 30-year-old male-to-female transsexual was referred for evaluation of progressive lymphedema of both legs (119A ). In 1997, he had had injections of nearly 3 liters of “silicone oil” of unknown quality and origin into the hips and buttocks to obtain a female body form. There were no problems during the first few months, but then the skin became indurated and discolored. Painful subcutaneous nodules developed in the treated regions and also in the inguinal region and thighs, i.e. outside the original injection location. During the next 5 years there was progressive painful swelling of the feet and legs. However, there were no problems with silicone breast prostheses, which had been implanted in 1999. There were large areas of brownish pigmentation, brawny indurated skin, and non-movable subcutaneous nodules of different sizes in the hips, buttocks, groins, and thighs. There was tender edema of the feet, ankles, and lower legs. A biopsy of the right buttock showed numerous optically clear vacuoles of varying sizes in the dermis and subcutaneous tissues, surrounded by a granulomatous histiocytoid cell infiltrate.
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Sodium metabisulfite Skin Contact allergy to sodium metabisulfite is not often encountered; there are about 20 case reports to date. These involve individuals who are employed in the pharmaceutical industry, the food industry, or the photographic industry. There have also been several case reports of patients who were allergic to sodium metabisulfite in creams such as hydrocortisone and ketoconazole creams (120A ). However, in one case contact allergy to sodium metabisulfite appeared not to be so rare (121A ). Of 2894 patch tests with sodium metabisulfite (1% in petrolatum) in patients with eczema there were positive reactions in 50 (1.7%). The positive reaction to sodium metabisulfite was considered to be clinically relevant in 12 cases. Immunologic Sodium metabisulfite (sodium pyrosulfite) is included as an antioxidant in various oral, topical, and parenteral medicines. It is used as an additive to inhibit oxidation of active components. Sodium metabisulfite is also used as a food additive (E223) in the food industry. Oral or nasal administration of sulfites can cause various hypersensitivity reactions such as bronchospasm (in asthmatic patients), rhinoconjunctivitis, urticaria, and even anaphylactic shock. There is no unequivocal explanation of the pathogenic mechanism of hypersensitivity to sulfite. Clear proof of an immunological (IgE mediated) cause is still lacking (122E ).
Sodium morrhuate Venous malformations are common vascular anomalies, with a propensity for the head and neck. In the oral and facial regions, the diagnosis of vascular malformation may be easy, but their management remains difficult. Venous malformations have been treated by various methods over the years, including surgical resection, lasers, sclerotherapy, and others. Sclerotherapy is an effective method for the treatment of venous malformations. Comparative studies In a study of sclerotherapy with pingyangmycin and/or sodium morrhuate in 260 patients (131 men and 159 women), the most common sites of malformation were the tongue and lips (123C ). Previous
612 ineffective treatment included sclerotherapy (n = 11), surgical resection (n = 13), laser therapy (n = 5), and cryotherapy (n = 2). Among the 11 sclerotherapy patients, nine had received one to three injections of sodium morrhuate and two had had one to two injections of pingyangmycin. Swelling and pain were the most common adverse effects of sodium morrhuate, and were recorded in 93% of patients after 441 injections of the sclerosant. Increased swelling of the lesion lasted for 3– 5 days after treatment. Fever was sometimes noted on the day after the intralesional injection of pingyangmycin. There were no hematological or lymphatic changes. Ulceration and subsequent scarring occurred in seven patients given sodium morrhuate. Ulceration often occurred at sites of bluish and discolored mucosa or skin where venous malformation involved the dermis. In five patients the ulcer became infected, requiring local treatment and oral or intravenous antibiotics. Clinical and laboratory examinations showed no other abnormalities or long-term complications.
Talc
(SED-15, 3292; SEDA-26, 544; SEDA-27, 531) Talc (magnesium silicate) widely used in the ceramics, paper, plastics, rubber, paint, construction, and cosmetics industries.
Respiratory Four different forms of pulmonary disease caused by talc have been recognized. Three are related to inhalation of magnesium silicate and include inhalation of pure talc (talcosis), talc associated with silica particles (talco-silicosis), and talc associated with asbestos fibers (talco-asbestosis). The fourth form of talcosis is caused by the endovenous administration of talc and is seen in intravenous drug users (124C ). Of three patients with inhalation talcosis (two men one woman, aged 45–52 years) two had occupational exposure to talc (125A ). One had worked for 2 years in a talc factory and one had worked for 8 years in a magnesium silicate mineral processing company where the end product was used for polishing rice. The third patient was a ballerina, who had used talcum powder in abundance for cosmetic reasons
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for more than 10 years, at times using an entire can (250 g of talc) every 2 days. The three patients presented with a history of progressive dyspnea. Two had a dry cough. All three had small nodules and conglomerate masses. The nodules were predominately centrilobular and subpleural in distribution and were present in all lobes but involved mainly the upper and middle zones, with relative sparing of the bases. The subpleural nodules looked like pleural plaques (pseudoplaques). Soft-tissue windows showed focal areas of high attenuation, consistent with talc deposition within the conglomerate masses. There were linear areas of attenuation and architectural distortion adjacent to the conglomerate masses. • A 55-year-old woman was admitted for pleurodesis for recurrent bilateral exudative pleural effusions that had required repeated thoracenteses for 2 years (126A ). She had a history of esophageal cancer treated with radiotherapy and chemotherapy without evidence of recurrence. During videoassisted thoracoscopy a pleural biopsy was obtained and right pleurodesis was performed with aerosolization of 4 g of talc and 12 hours later began to complain about shortness of breath and mild pain at the chest tube insertion site. She developed hypoxemia refractory to high concentrations of oxygen. A chest X-ray showed a dense right lung infiltrate. A C T scan of the chest excluded a proximal pulmonary embolism but showed a diffuse alveolar infiltrate involving the entire right lung.
MEDICAL DEVICES Catheters
(SED-15, 677; SEDA-26, 545)
Infection risk Catheter-related sepsis is a common complication of long-term parenteral nutrition. Conventional antibiotic therapy is often effective in the short term but, because of poor activity against intraluminal microbial biofilms, may not prevent relapse. Ethanol is an effective antiseptic. • A 31-year-old man with Crohn’s disease had been receiving parenteral nutrition for 9 years, during which time he had had 22 admissions for fever and bacteremia secondary to catheter-related infections, including four instances of catheter replacement (127A ). He received systemic antibiotics through the line during all episodes of infection, and during later episodes the antibiotics (van-
Miscellaneous drugs and materials, medical devices, and techniques comycin or gentamicin) were instilled into catheter daily for up to 3 months. Infections recurred soon after discontinuation of these antibiotic locks. After the last infection, due to Escherichia coli, he was given amoxicillin, along with a catheter lock of 70% ethanol, after each infusion, left in situ for 2 hours. This was then continued with the ethanol lock left in the line for the entire period between
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each daily infusion. There were no further episodes of catheter-related sepsis during the next 3 years.
This is not the first time that antiseptic locks have been used, but it confirms their usefulness in dealing with recurrent catheter-related sepsis.
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Address list of national centres that participate in the WHO Drug Monitoring Programme Editor’s note: The details given here were correct at the time of going to press in February 2007. However, details of this sort often change, and readers should contact the WHO Monitoring Programme at Uppsala if they are unable to reach any of the agencies listed using the information given. Countries whose names are in italics are provisional members.
Algeria Prof Abdelkader Helali Tel: +213-21-96 5059 E-mail: pharmacomateriovigilancedz@hotmail. com Argentina Dr Inés Bignone Tel: +54-11-4340-0800, ext 1154 E-mail:
[email protected] Armenia Dr Anahit Ayvazyan Tel: +374-1-584020, 584120 Fax: +374-1-542406 E-mail:
[email protected] Website: www.pharm.am
Centre National de Pharmacovigilance et Matériovigilance Ministère de la Santé et de la Population BP 247, CHU de Bab El Oued DA-16009 Alger, Algeria Departamento de Farmacovigilancia (ANMAT) Avenida de Mayo 869, piso 11o 1084 Buenos Aires, Argentina Department of Rational Therapy, Monitoring of Adverse Reactions, and Professional Information Scientific Centre of Drug & Medical Technology Expertise 15 Moskovyan Street Yerevan 375001, Armenia
Australia Dr Kerri Mackay Tel: +61-2-6232 8310 Fax: +61-2-6232 8392 E-mail:
[email protected]
Adverse Drug Reactions Unit Therapeutics Goods Administration PO Box 100 Woden, ACT 2606, Australia
Austria Dr Bettina Schade Tel: +43-50555 36240 Fax: +43-50555 36207 E-mail:
[email protected]
AGES PharmMed Institut Pharmakovigilanz Schnirchgasse 9 A-1030 Vienna, Austria
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Address list of national centres
Bahrain Ms Layla Abdur-Rahman Tel: +973-25 86 68 Fax: +973-25 93 57 E-mail:
[email protected]
Ministry of Health Pharmacy and Drug Control PO Box 28136 Riffa, Bahrain
Belarus Dr Gennady V Godovalnicov Tel: +375-17-299 55 10 Fax: +375-17-299 53 58 E-mail:
[email protected] Website: www.rceth.nsys.by
Ministry of Health Center for Examinations and Test Health Service Republican Unitary Enterprise 2-a Tovarishcheskij Per 22 0037 Minsk, Belarus
Belgium Johan Van Calster Tel: +32-2-227 5500 Fax: +32-2-227 5528 E-mail:
[email protected] Website: afigp.fgov.be
National Centre for Pharmacovigilance Federal Public Service, Public Health Protection Directorate – General Medicinal Products Boulevard Bischoffsheim 33, 1st floor B-1000 Brussels, Belgium
Bhutan Mr Tashi Tobgay Tel: +975-2-58668 Fax: +975-2-59357 E-mail:
[email protected]
National Pharmacovigilance Centre Ministry of Health Pharmacy Department JDWNR Hospital, Thimphu, Bhutan
Bhutan Mr Ugyen Dendup Tel: +975-2-321 686 Fax: +975-2-324 215 E-mail:
[email protected]
Traditional Medicines Pharmacovigilance Centre Pharmaceutical and Research Unit Institute of Traditional Medicine Service Post Box 297, Thimphu, Bhutan
Botswana Ms Motshegwana Olenkie Tebogo Tel: +267-3632383 Fax: +267-3170169 E-mail:
[email protected]
Drug Regulatory Unit Ministry of Health Private Bag 00355 Gaborone, Botswana
Brazil Dr Anthony Wong Tel: +55-11-3088 9431 Fax: +55-11-3088 9431 E-mail:
[email protected] Website: ceatox.com.br
Brazil Mr Murilo Freitas Dias Tel: +55-61-448 1219 Fax: +55-61-448 1275 E-mail:
[email protected] Website: anvisa.gov.br/farmacovigilancia
CEATOX Sao Paulo Regional Poison and Pharmacovigilance Centre Inst. Crianca Reference Centre Av. Dr Enéas de Carvalho Aguiar 647 05403-903 Sao Paulo SP, Brazil
Unidade de Farmacovigilância – UFARM Agênica Nacional de Vigilânica Sanitária – ANVISA SEPN 515 Bl.B Ed. Omega 2 Andar, Sala 2 CEP 70770-502 Brasilia DF, Brazil
620 Brunei Darussalam Ms Asma A’tiyah Haji Abdul Hamid Tel: +673-2-2242424, ext 569 Fax: +673-2-230001 E-mail:
[email protected]
Bulgaria Dr Kapka Kaneva Tel: +359-2-9446 999, ext 356 Fax: +359-2-9434 487 E-mail:
[email protected] Website: www.bda.bg Canada Dr Barbara Law Tel: +1-613-952 9730 Fax: +1-613-998 6413 E-mail:
[email protected]
Canada Ms Heather Sutcliffe Tel: +1-613-946 1138 or 957 0337 Fax: +1-613-957 0335 E-mail:
[email protected] Website: hc-sc.gc.ca/hpb-dgps/therapeut/
Chile Dra Q F Cecilia Morgado-Cadiz Tel: +56-2-239 8769 Fax: +56-2-239 8760 E-mail:
[email protected]
China Dr Shaohong Jin E-mail:
[email protected]
Colombia Dr José Rodrigo Valcárcel Vela E-mail:
[email protected]
Address list of national centres
Drug and Poison Information Section Ministry of Health RIPAS Hospital Commonwealth Drive Jalan Menteri Besar BB3910 Brunei Darussalam
Pharmacovigilance Unit Bulgarian Drug Agency 26 Yanko Sakazov Boulevard BG-1504 Sofia Bulgaria
Immunization & Respiratory Infections Division Centre for Infectious Disease Prevention & Control, Public Health Agency of Canada PL 0602C Bldg # 6, Tunney’s Pasture 0603EI Ottawa, Ontario K1A OK9, Canada
Marketed Health Products Safety & Effectiveness Information Division Marketed Health Products Directorate Health Canada Tunney’s Pasture, A/L 0701C Ottawa, Ontario K1A OK9, Canada
Instituto de Salud Publica de Chile CENIMEF – National Drug Information and Pharmacovigilance Centre Avenida Marathon 1000, 3 piso, Nuñoa-Casilla 48 Santiago, Chile
Division of ADR Monitoring Center for Drug Reevaluation State Food and Drug Administration Building 11, Fa-Hua-Nan-Li Chongwen District, Beijing 100061, China
Grupo de Farmacovigilancia, Subdirección de Medicamentos y Productos Biológicos Instituto Nacional de Vigilancia de Medicamentos y Alimentos – INVIMA Carrera 68 D No. 17-11/21 Bogota, DC, Colombia
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Address list of national centres
Congo, the Democratic Republic of the Mr Franck Biayi Kanumpepa Tel: +242-81-812 5838 E-mail:
[email protected]
Focal Point for Pharmacovigilance National Programme on Essential Medicines Ministry of Health Boulevard dy 30 Juin no 4310 BP 3088 Kin 1 Kinshasa Gombe Democratic Republic of the Congo
Costa Rica Dr Adolfo Ortiz Barboza Tel: +506-221 1662 Fax: +506-221 1167 E-mail:
[email protected]
Ministero de Salud Oficinas Centrales Dirección de Vigilancia de Salud Centro Nacional de Farmacovigilancia PO Box 10123-1000, San José, Costa Rica
Croatia Dr Sinisa Tomic Tel: +385-146 93 830 Fax: +385-146 73 175 E-mail:
[email protected] Website: www.almp.hr
Croatian Agency for Medicinal Products and Medical Devices Ksaverska Cesta 4 H 10000 Zagreb Croatia
Cuba Dra Giset Jiménez López Tel: +53-7-2023 513 Fax: +53-7-24 7227 E-mail:
[email protected] Website: cdf.sld.cu Cyprus Ms Xenia Ashikales Tel: +357-22-407 100 Fax: +357-22-407 149 E-mail:
[email protected] Czech Republic Dr Jana Mladá Tel: +420-272-182 729 Fax: +420-272-182 816 E-mail:
[email protected] Website: www.sukl.cz Denmark Ms Elin Andersen Tel: +45-44-88 92 87 Fax: +45-44-88 95 99 E-mail:
[email protected] Website: dkma.dk Egypt Dr Radwa Abou-Zeid Tel: +20-354 5151 Fax: +20-354 5159 E-mail:
[email protected]
Pharmacovigilance Department Pharmacoepidemiology Development Center Calle 44 esq. 5ta Ave No 502 Miramar, Playa, Havana CP 11300, Cuba
Pharmaceutical Services Ministry of Health 1475 Lefkosia Cyprus State Institute for Drug Control Srobarova 48 10041 Prague 10 Czech Republic
Danish Medicines Agency Medicines Control Division Axel Heides gade 1 DK-2300 Köbenhavn Denmark Technical Research & Training Department Central Administration of Pharmaceutical Affairs, Ministry of Health and Population 22 Falky street, Magles el Shaab-Cairo Cairo, Egypt
622
Address list of national centres
Eritrea Mr Seare Ghebreyesus Tel: +291-1-120297/122429 Fax: +291-1-122899 E-mail:
[email protected]
Drug Information Unit Ministry of Health PO Box 212 Asmara, Eritrea
Estonia Dr Maia Uusküla Tel: +372-7-374 140 Fax: +372-7-374 142 E-mail:
[email protected] Website: sam.ee
Ravimiamet State Agency of Medicines 1 Nooruse Street 50411 Tartu Estonia
Ethiopia Mr Abraham Geberegiorgis Kahsay Tel: +251-1-52 41 22 Fax: +251-1-52 13 92 E-mail:
[email protected]
Fiji Ms Vasiti Nawadra-Taylor Fax: +679-33 88 003 E-mail:
[email protected]
Drug Administration and Control Authority of Ethiopia ADR Monitoring & Promotion Control Division PO Box 5681 Addis Ababa, Ethiopia
Pharmacy Department Fiji Pharmaceutical Services PO Box 106 Suva, Fiji
Finland Prof Erkki Palva Tel: +358-9-4733 4288 Fax: +358-9-4733 4297 E-mail:
[email protected] Website: www.nam.fi
National Agency for Medicines – Lääkelaitos Department of Safety & Drug Information PO Box 55 Mannerheimintie 103B SF-00301 Helsinki, Finland
France Dr Carmen Kreft-Jaïs Tel: +33-1-5587 3533 Fax: +33-1-5587 3532 E-mail:
[email protected] Website: afssaps.sante.fr
Unité de Pharmacovigilance Agence Francaise de Securité Sanitaire des Produits de Sonti (AFSSAPS) 143-147 Boulevard Anatole France F-93285 Saint-Denis, Cedex, France
Georgia Pharmacological Committee Tel: +995-99-563 451 Fax: +995-99-399 947 E-mail:
[email protected] Germany Dr Ulrich Hagemann Tel: +49-21-67 30 90 Fax: +49-21-66 03 89 E-mail:
[email protected]
Pharmacological Committee 29a Mitskevich Street 380060 Tbilisi, Georgia
Federal Institute for Drugs and Medical Devices Bundesinstitut für Arzneimittel und Medizinprodukte Kurt-Georg-Kiesinger-Allee 3 DE-53175, Bonn, Germany
623
Address list of national centres
Germany Dr Dirk Mentzer Tel: +49-6103771011 E-mail:
[email protected]
Pharmacovigilance Unit Facharzt für Kinderheilkunde Paul Ehrlich Institut Bundesamt für Sera und Impfstoffe Paul Ehrlich Strasse 51-59 D-66235, Langen, Germany
Ghana Mr Benjamin Kwame Botwe Tel: +233-21-67 30 90 Fax: +233-21-66 0389 E-mail:
[email protected]
Food and Drugs Board PO Box CT 2783 Cantonments Accra, Ghana
Greece Ms Georgia Terzi-Vaslamatzi Tel: +30-210-6507337 Fax: +30-210-6549585 E-mail:
[email protected]
Adverse Drug Reactions Department National Organization for Medicines 284 Mesogeion Av GR-155 62 Athens-Holargos, Greece
Guatemala Dr José María Del Valle Tel: +502-24752121-5, ext 136 Fax: +502-24406454 E-mail:
[email protected] Website: www.mspas.gob.gt/farmacovigilancia Hungary Dr Mariann Virányi Tel: +36-1-266 6073 Fax: +36-1-266 6073 E-mail:
[email protected]
Programa Nacional de Farmacovigilancia Asesoría de Medicamentos, MSPAS 6a. Avenida. 3-45 zona 11 Guatemala
National Institute of Pharmacy Adverse Drug Reactions Monitoring Centre Zrínyi u. 3-1051 PO Box 450 H-1372 Budapest, Hungary
Iceland Prof. Magnús Jóhannsson Tel: +354-5-20 2114 Fax: +354-5-61 2170 E-mail:
[email protected] Website: ww.lyfjastofnun.is
Lyfjastofnun The Icelandic Medicines Control Agency Box 180 172 Seltjarnarnes Iceland
India Tel: +91-11-3018806 Fax: +91-11-23012648 E-mail:
[email protected]
Central Drugs Standard Control Organization Nirman Bhawan New Delhi 110011, India
Indonesia Dra Engko Sosialine M Tel: +62-21-4245 459 Fax: +62-21-4243 605 E-mail:
[email protected] Website: pom.go.id
Surveillance and Risk Analysis of Therapeutic Products Directorate of Distribution Control of Therapeutic Products National Agency for Drug and Food Control Jalan Percetakan Negara 23 Jakarta 10560, Indonesia
624 Iran, Islamic Republic of Dr Kheirollah Gholami Tel: +98-21-640 4223 Fax: +98-21-641 7252 E-mail:
[email protected]
Ireland Ms Niamh Arthur Tel: +353-1-676 4971 Fax: +353-1-676 2517 E-mail:
[email protected] Website: www.imb.ie Israel Dr Dina Hemo Tel: +972-2-568 1219 Fax: +972-2-672 58 20 E-mail:
[email protected]
Italy Dr Mauro Venegoni Tel: +39-6-596 841 16 Fax: +39-6-597 841 42 E-mail:
[email protected] Japan Mr Tamaki Fushimi E-mail:
[email protected]
Jordan Ms Nidaa Bawaresh E-mail:
[email protected]
Address list of national centres
Ministry of Health and Medical Education Research and Development Office Iranian ADR Centre Building no. 3, Fakhr-e-Razi Street, Enghlab Ave Teheran 13145, Islamic Republic of Iran
Pharmacovigilance Unit Irish Medicines Board Earlsfort Terrace Earlsfort Centre Dublin 2, Ireland
Drug Monitoring Center Department of Clinical Pharmacology Ministry of Health 29 Rivka Street, PO Box 1176 Jerusalem 91010, Israel
Ufficio Farmacovigilanza AIFA Via Sierra Nevada 60 IT-00144 Roma, Italy
Safety Division Pharmaceutical and Food Safety Bureau Ministry of Health, Labour, and Welfare 1-2-2 Kasumigaseki, Chiyoda-Ku Tokyo 100-8916, Japan
Jordanian Pharmacovigilance Centre PO Box 86 0096 Amman, Jordan
Kazakhstan Dr Shinara Kulieva Tel: +7-3172-317414 Fax: +7-3172-317594 E-mail:
[email protected]
Pharmacy Committee Ministry of Health of the Republic of Kazakhstan 66 Moskovskaya St 437000 Astana, Kazakhstan
Korea, Republic of Ms Kyoung-Min Myoung Tel: +82-2-382 1658 60 Fax: +82-2-382-2870 E-mail:
[email protected] Website: www.kfda.go.kr
Pharmaceutical Management Team Korean FDA 231 Jinheungno Eunpyeong-gu Seoul 122-704, Republic of Korea
625
Address list of national centres
Kyrgyzstan Dr Zamir Akaev Tel: +996-312-54 29 10 Fax: +996-312-54 29 10 E-mail:
[email protected] Website: www.pharm.med.kg
Drug Information Centre Department of Drug Provision & Medical Equipment Ministry of Health Tretiya Liniya Street 25 720044 Bishkek, Kyrgyzstan
Latvia Dr Inese Studere Tel: +371-707 8442 Fax: +371-707 8428 E-mail:
[email protected] Website: www.zva.gov.lv
ADR Monitoring Department State Agency of Medicine of Latvia (SAM) Jersikas St. 15 LV-1003 Riga Latvia
Lithuania Ms Rita Kalvelyte Tel: +370-5-269 1895 Fax: +370-5-263 9265 E-mail:
[email protected] Website: www.vvkt.lt
Post Authorisation Evaluation Unit State Medicines Control Agency 9/1 Traku Street Vilnius, LT 01132 Lithuania
Macedonia, the Former Yugoslav Republic of Ms Vesna Nasteska-Nedanovska Tel: +389-2-311 25 00 Fax: +389-2-323 08 57 E-mail:
[email protected]
Ministry of Health UL 50 Divizija br 6 1000 Skopje The Former Yugoslav Republic of Macedonia
Madagascar Dr Donat P.E. Rakotomanana Tel: +261-20-22 365 22 Fax: +261-20-22 365 22 E-mail:
[email protected]
Agence du Médicament Ex-Pharmacie Centrale Tsaralalana BP 8145 Antananarivo 101, Madagascar
Malaysia Mrs Tan Lie Sie
Pharmacovigilance National Pharmaceutical Control Bureau Ministry of Health Malaysia
Malta Dr Patricia Vella Bonanno Tel: +356-23-43 91 10/12 Fax: +356-23-43 91 61/58 E-mail:
[email protected]
Medicines Authority 198 Rue D’Argens Gzira GZR 03 Malta
Mexico Dra Ma. Del Carmen Becerril Martinez Tel: +52-55-551 485 81 Fax: +52-55-5080 5451 E-mail:
[email protected] Website: www.cofepris.gob.mx
Ministry of Health Río Rhin No. 57 Col. Cuauhtémoc Del. Cuauhtémoc 06700 Mexico City 06500, DF Mexico
626 Moldova, Republic of Dr Lucia Turcan Tel: +373-22-73 7000 Fax: +373-22-73 7000 E-mail:
[email protected] Website: www.amed.md Mongolia Mrs Nanjaa Tsogzolmaa Tel: +976-11-321 093 Fax: +976-11-320 633 E-mail:
[email protected]
Morocco Prof Rachida Soulaymani-Bencheikh Tel: +212-37-6110 47 45 (gsm) Fax: +212-37-77 71 79 E-mail:
[email protected] Mozambique Dr Esperanca Julia Sevene Tel: +258-1-32 52 27 / 32 42 10 Fax: +258-1-32 52 55 E-mail:
[email protected]
Nepal Mr Gajendra Bahadur Bhuju Tel: +977-1-4780 432 Fax: +977-1-4780 572 E-mail:
[email protected] Website: www.dda.gov.np Netherlands Dr Adrianus C van Grootheest Tel: +31-73-646 9700 Fax: +31-73-642 6136 E-mail:
[email protected] Website: lareb.nl New Zealand Dr Michael Tatley Tel: +64-3-479 7247 Fax: +64-3-479 0509 E-mail:
[email protected] Website: www.otago.ac.nz/carm Nigeria Mrs Adeline Osakwe Tel: +234-01-2671635 Fax: +234-01-2671635 E-mail:
[email protected]
Address list of national centres
Drug Authorization, Evaluation, and Pharmacovigilance Department of the Republic of Moldova Medicines Agency Str. Korolenko 2/1 Chisinau 2028, Republic of Moldavia Department of Pharmacy and Medical Equipment Government Building 8 Ministry of Health Olimpic Street 2 Sukhbaatar district Ulaanbaatar 210648, Mongolia Centre Anti Poisons et de Pharmacovigilance Rue Lamfedel Cherkaoui Rabat Institute Al Irfane, BP 6671 Rabat, Morocco Drug Information Center (CIMed) Faculty of Medicine, Department of Pharmacology Eduardo Mondlane University Av. Salvador Allende n. 702 PO Box 257, Maputo, Mozambique Department of Drug Administration Ministry of Health and Population Bijulibazar, Nayabaneshwor Kathmandu Nepal Netherlands Pharmacovigilance Centre LAREB Goudsbloemvallei 7 NL-5237 MH’s-Hertogenbosch The Netherlands
New Zealand Pharmacovigilance Centre (N2 PhuC) Department of Preventive & Social Medicine University of Otago PO Box 913, Dunedin 9000 New Zealand National Agency for Food & Drug Administration and Control (NAFDAC) Pharmacovigilance/Food and Drug Information Centre Abuja, Nigeria
627
Address list of national centres
Norway Ms Ingebjorg Buajordet Tel: +47-22-89 77 00 Fax: +47-22-89 77 99 E-mail: Ingebjorg.Buajordet@ legemiddelverket.no Website: legemiddelverket.no
Norwegian Medicines Agency Statens Legemiddelverk Pharmacovigilance Section Sven Oftedals vei 8 N-0950 Oslo Norway
Oman Dr Sawsan Ahmad Jaffar Tel: +968-24-600 016 Fax: +968-24-602 287 E-mail:
[email protected] Website: moh.gov.om
Directorate General of Pharmaceutical Affairs and Drug Control Ministry of Health PO Box 393 Muscat, PC-113, Sultanate of Oman, Oman
Pakistan Prof Akhlaque Un-Nabi Khan Tel: +92-21-588 2997/589 2801 Fax: +92-21-588 1444/589 3062
Panama Indira Credidio Tel: +507-2129404 Fax: +507-2129196 E-mail:
[email protected] Peru Dra Susana Vasquez Lezcano Tel: +51-1-471 62 46 Fax: +51-1-470 59 97 E-mail:
[email protected] Philippines Ms Maria Lourdes C Santiago Tel: +63-2-8070700 E-mail:
[email protected]
Poland Dr Agata Maciejczyk Tel: +48-22-4921 300 Fax: +48-22-4921 309 E-mail:
[email protected] Website: www.urpl.gov.pl Portugal Dr Regina Carmona Tel: +351-21-798 7153 Fax: +351-21-798 7155 E-mail:
[email protected] Website: infarmed.pt
College of Physicians & Surgeons Pakistan (CPSP) Department of Clinical Pharmacology 7th Central Street Phase II, Defence Housing Authority Karachi 75500, Pakistan Ministerio de Salud Calle Gorgas. Edificio 237 PO Box 2048 Panama, Panama Centro Nacional de Farmacovigilancia Equipo de Farmacoepidemiologia Coronel E odriozola N 103 – San Isidro (Alt Cdra 32 Av Arequipa) Lima 11, Peru Product Service Division Bureau of Food and Drugs Department of Health Filinvest Corporate City, Alabang Muntinlupa 1770, Philippines Urzad Rejestracji Produktów Leczniczych Wyrobów Medycznych i Produktów Biobójczych ul. Zabkowska 41 PL-03736 Warsaw, Poland
National Pharmacovigilance Centre INFARMED Parque de Saúde de Lisboa Avenida do Brasil, no. 53 1749-004 Lisboa, Portugal
628 Romania Dr Iuliana Daniela Stanciu Tel: +40-1-224 1102/224 1710 Fax: +40-1-2243 497 E-mail:
[email protected] Website: www.anm.ro Russian Federation Prof Victor Cheltsov Tel: +7-095-1905 427/1903 490 Fax: +7-095-434 02 92 E-mail:
[email protected] Serbia Ms Milena Miljkovic Tel: +381-11-395 1145 Fax: +381-11-395 1130 E-mail:
[email protected] Website: www.alims.sr.gov.yu Sierra Leone Mr Wiltshire C.N. Johnson Tel: +x-22-225983/228497 Fax: +x-22-224526 E-mail:
[email protected] Singapore Ms Cheng Leng Chan Tel: +65-6-866 3528 Fax: +65-6-478 9069 E-mail:
[email protected] Website: hsa.gov.sg/hsa/cpa/CPA_pharma_about.htm Slovak Republic Dr Pavol Gibala Tel: +421-2-5293 1735/5293 1732 Fax: +421-2-5293 1734 E-mail:
[email protected] Website: sukl.sk South Africa Mr Mukesh Dheda Tel: +27-12-3120526 E-mail:
[email protected]
Spain Dr Francisco José de Abajo Tel: +34-91-822 5330 Fax: +34-91-822 5386 E-mail:
[email protected] Website: www.agemed.es
Address list of national centres
Adverse Reactions Section National Medicines Agency Str Aviator Sanatescu no 48, Sector 1 R-71 324 Bucuresti, Romania
Department of Clinical Pharmacology Miklukho-Maklay Street 8 117198 Moscow Russian Federation Medicines and Medical Devices Agency of Serbia National Pharmacovigilance Center Vojvode Stepe 458 11152 Belgrade, Serbia
Drug Information and Pharmacovigilance Unit Pharmacy Board of Sierra Leone PO Box 322 Freetown, Sierra Leone Pharmacovigilance Unit Centre for Drug Administration Health Sciences Authority 11 Biopolis Way, #11-03 Helios Singapore 138667
National Centre for Monitoring Adverse Reactions to Drugs State Institute for Drug Control Kvetná 11 825 08 Bratislava 26, Slovak Republic Pharmacovigilance Unit Medicine Regulatory Affairs National Department of Health Private Bag X828 Pretoria 0001, South Africa Agencia Española de Medicamentos y Productos Sanitarios División de Farmacoepidemiología y Farmacovigilancia Parque Empresarial Las Mercedes Edificio 8, 3a planta-oeste, c/ Campezo 1 E-28022 Madrid, Spain
629
Address list of national centres
Sri Lanka Dr Shalini Sri Ranganathan Tel: +94-1-695 300 ext 41 03 17 Fax: +94-1-695 300 E-mail:
[email protected] Suriname Ms Naomi T Jessurun Tel: +597-597 422 222, ext 376 Fax: +597-1-597 440 331 E-mail:
[email protected]
Sweden Dr Gunilla Sjölin-Forsberg Tel: +46-18-17 47 98 Fax: +46-18-54 85 66 E-mail:
[email protected] Website: mpa.se Switzerland Mr Ruedi Stoller Tel: +41-31-322 0348 Fax: +41-31-322 0418 E-mail:
[email protected] Website: swissmedic.ch Tanzania, United Republic of Ms Mary Masanja Tel: +255-22-245 0512 / 245 07 51 Fax: +255-22-245 0793 E-mail:
[email protected]
Faculty of Medicine University of Colombo Kynsey Road, PO Box 271 Colombo 8, Sri Lanka
Academic Hospital Paramaribo Academisch Ziehenhuis Paramaribo Flustraat PO Box 389 Paramaribo, Suriname
Pharmacovigilance Unit Medical Products Agency Box 26 S-751 03 Uppsala, Sweden
Swissmedic Schweizerisches Heilmittelinstitut Pharmacovigilance Zentrum Erlachstrasse 8 CH-3000 Bern 9, Switzerland
Section, Postmarketing Product Risk Analysis National ADR Monitoring Centre The Tanzania Food and Drug Authority PO Box 77150 Dar Es Salaam, United Republic of Tanzania
Thailand Mrs Wimon Suwankesawong Tel: +66-2-590 7261/53 Fax: +66-2-590 7269/591 8459 E-mail:
[email protected] Website: www.fda.moph.go.th
Thai National ADRM Centre Food and Drug Administration Ministry of Public Health Ti-wa-nondh Road Nonthaburi 11000, Thailand
Tunisia Professor Chalbi Belkahia Tel: +216-71-56 47 63/57 84 88 Fax: +216-71-57 13 90 E-mail:
[email protected]
Centre National de Pharmacovigilance 9, Avenue Dr Zouheïr Essafi 1006 Tunis Tunisia
Turkey Mrs Demet Aydinkarahaliloglu Tel: +90-312-309 1141/1192 Fax: +90-312-309 7118 E-mail:
[email protected]
Turkish Pharmacovigilance Center, TUFAM Department of Quality Control General Directorate of Pharmaceutical and Pharmacy, Ministry of Health Cankiri Caddesi, No 57 06060 Diskapi, Ankara, Turkey
630
Address list of national centres
Uganda Ms Helen Byomire-Ndagije Tel: +256-41-347391/2 Fax: +256-41-342921/222469/222881 E-mail:
[email protected] Website: www.nda.or.ug
National Drug Authority Plot 46/48 Lumumba Avenue PO Box 23096 Kampala Uganda
Ukraine Prof Alexey Victorov Tel: +380-44249 7001 Fax: +380-44249 7001 E-mail:
[email protected] Website: www.pharma-center.kiev.ua
Pharmacovigilance Department State Pharmacological Center Ministry of Health of Ukraine 18 Chygorina Street, 01042 Kiev Ukraine
United Kingdom Dr June Raine Tel: +44-20-7084 2400 Fax: +44-20-7084 2675 E-mail:
[email protected] Website: mhra.gov.uk United States of America Dr M Miles Braun Tel: +1-301-827 3974 Fax: +1-301-827 3529 E-mail:
[email protected] United States of America Dr Gerald Dal Pan Tel: +1-301-827 3172 E-mail:
[email protected]
Uruguay Dra Carolina Seade Fournie Tel: +598-2-409 78 00 Fax: +598-2-401 38 70 E-mail:
[email protected] Uzbekistan Dr Bakhtiyor Shoislamov Tel: +998-711-444823 Fax: +998-711-444825 E-mail:
[email protected]
Venezuela Drs María Aguilar Tel: +58-212-662 4797 Fax: +58-212-693 1455 E-mail:
[email protected]
Post-licensing Division Medicines and Healthcare products Regulatory Agency Market Towers 1 Nine Elms Lane London SW8 5NQ, UK Division of Epidemiology, HFM-222 Center for Biologics Evaluation and Research Food and Drug Administration 1401 Rockville Pike Rockville, MD 20852, USA Office of Drug Safety Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane, Room 15 B33 Rockville, MD 20857, USA Ministerio de Salud Publica Direccion General de la Salud Avenida 18 de Julio 1892, P. 2, Of. 219 CP 11.200 Montevideo, Uruguay Pharmacological Committee of HDDMEQC Curator of Adverse Reaction Monitoring Commission Usmankhodjaev St K Umarov passage 16 700002 Tashkent, Uzbekistan Instituto Nacional de Higiene “Rafael Rangel” Centro Nacional de Vigilancia Farmacológia (CENAVIF) Ciudad Universitaria Caracas 1010, Venezuela
631
Address list of national centres
Vietnam Dr Mai Haong Thanh Tel: +84-4-823 5812 Fax: +84-4-823 1253 E-mail:
[email protected]
Centre of ADR Monitoring of Viet Nam 138 A – Gian Vo – Ba Dinh Hanoi Vietnam
Zambia Dr Oscar O Simooya Tel: +260-2-222206/231850/230562 Fax: +260-2-228319/222469/222881 E-mail:
[email protected]
Copperbelt University Health Services PO Box 21692 Kitwe Zambia
Zimbabwe Mr Rutendo Kuwana Tel: +263-4-736981-5 Fax: +263-4-736980 E-mail:
[email protected]
Pharmacovigilance and Clinical Trials Medicines Control Authority of Zimbabwe 106 Baines Ave Harare, Zimbabwe
Index of drugs Notes. See both classes and specific drugs. Boldface page numbers refer to main discussions. A abacavir, 303 abciximab, 363–364 abetimus sodium, 460–461 acarbose, 526 ACE inhibitors, 207–209 see also specific drugs, such as captopril; perindopril acetaminophen see paracetamol acetazolamide, 220 acetylsalicylic acid (aspirin), 124 aciclovir clearance, +mycophenolate mofetil, 447 during pregnancy, 301 acitretin, 158 acupuncture adverse effects incidence, 589–590 infection risk, 589–590 traumatic adverse effects, 590–591 adalimumab, 397 adenosine, 185 adrenaline (epinephrine), 148 albendazole availability, +levamisole, 462 bradycardia, 320 clearance, +levamisole, 324 general effects, 320 pancytopenia, 322 albumin, 338 albuterol see salbutamol alcohol (ethanol) concomitant sildenafil, 204 concomitant ximelagatran, 363 alemtuzumab administration route, 406 adverse reactions management, 406 bronchospasm, 405 comparative studies, 404 hematologic effects, 405 infection risk, 405 lymphoproliferative disorder, 406 monitoring therapy, 406 nervous system effects, 405 renal transplant rejection, 405 susceptibility factors, 406 alendronate, 603 alfuzosin, 214 Allium sativum (garlic), 584 allopurinol
632
mercaptopurine concentration, 552 neutropenia, +azathioprine, 426 alosetron, 372 alprazolam cortisol reduction, 51–52 interactions, 52 overdose, 52 psychiatric effects, 51 alprostadil (prostaglandin E1 ), 487–488 aluminium administration route, 226 macrophagic myofasciitis, 225 respiratory effects, 225 skin effects, 225 susceptibility factors, 226 alverine citrate, 371 amfebutamone (bupropion) hypertension, +linezolid, 268 interactions, 24 serum sickness-like reaction, 24 sexual dysfunction, 24 amfetamines, 2, 52 amikacin, 253 aminoglycosides, 253 aminolevulinic acid, 158 amiodarone basal cell carcinoma, 187 bone marrow granulomata, 186 cardiovascular effects, 185 death, 187 digoxin clearance, 182 endocrine effects, 186 fetotoxicity, 187 interactions, 187 liver effects, 186 monitoring therapy, 187 optic neuropathy, 186 phototoxicity, 187 respiratory effects, 185–186 simvastatin concentration, 549 amisulpride comparative studies, 65 hyperprolactinemia, 65–66 vs. olanzapine, 70–71 placebo-controlled studies, 65 amlodipine, 195–196 amphotericin concomitant caspofungin, 289 urinary tract effects, 280 amphotericin, liposomal (L-amB), 282
amphotericin B deoxycholate (DAMB), 281 amphotericin B lipid complex (ABLC), 281 ampicillin, 247 amprenavir, 307 anabolic steroids abuse, 508–509 formulations, 509–510 susceptibility factors, 510 anagrelide erectile dysfunction, 365 hallucinations, visual, 364 observational studies, 364 anakinra (interleukin-1 receptor antagonist), 394 androgens general effects, 507–508 metabolism, 508 polycythemia, 508 Andrographis paniculata, 585 anesthesia, 598 see also specific agents, such as benzocaine; ropivacaine anesthesia, dental, 138 anesthesia, epidural hypotension, 135–136 nervous system effects, 136–137 respiratory effects, 136 anesthesia, infiltration, 138 anesthesia, intrathecal (spinal) cardiovascular effects, 137 fetotoxicity, 138 nervous system effects, 137–138 anesthesia, intravenous regional, 138–139 anesthesia, ocular, 139 anesthesia, topical airway obstruction, 140 cerebellar ataxia, 140 formulations, 139 methemoglobinemia, 140 misdiagnosis, 140 anesthetic vapors see specific gases, such as halothane; nitrous oxide anesthetics concomitant risperidone, 79 special circumstances, 128–129 angiotensin converting enzyme inhibitors see ACE inhibitors
633
Index of drugs angiotensin II receptor antagonists see specific drugs, such as irbesartan; telmisartan anidulafungin, 289 antacids azithromycin concentration, 264 concomitant posaconazole, 282 prulifloxacin absorption, 259 anthracyclines, 565–566 anthrax vaccine, 330 antiandrogens, 510–511 antibiotics see specific drugs and classes, such as monobactams; minocycline anticholinergics, 153 anticoagulants, 599 antidepressants, 18–19 antidysrhythmics, 184 antiepileptics see specific drugs and classes, such as benzodiazepines; gabapentin antiestrogens, 502 antifungal azoles comparative studies, 282 interactions, 282–286 antihistamines (H1 ), 265 see also specific drugs, such as cetirizine; hydroxyzine antihypertensives, 206 antimetabolites, classification, 551 antimony, 226–227 antiplatelet drugs, 363 antipsychotics cardiovascular effects, 62 comparative studies, 60–61 dysphoria, 63 hyperprolactinemia, 63–64 nervous system effects, 63 observational studies, 60 placebo-controlled studies, 61–62 during pregnancy, 64 susceptibility factors, 64–65 weight gain, 64 antiretrovirals, 447–448 antithymocyte globulin comparative studies, 341 deep vein thrombosis, 341 drug formulations, 343 hematologic effects, 341–342 immunologic effects, 342 infection risk, 342 lymphocytopenia, +pooled human immunoglobulin, 343 susceptibility factors, 342–343 aprotinin, 367 Aristolochia species, 585 arsenic, 227 artemisinin derivatives comparative studies, 297 observational studies, 297, 320 articaine, 140
ASA see acetylsalicylic acid Asian herbal medicines, 583 aspirin see acetylsalicylic acid atazanavir, 307 atorvastatin concomitant ximelagatran, 363 hepatitis, 548 avoparcin, 244–245 Ayurvedic medicines, 602 azacitidine, 554 azathioprine diagnostic test interference, 425 fetotoxicity, 425 hematologic effects, 424 neutropenia, +allopurinol, 426 pancreatitis, 424 skin effects, 424 susceptibility factors, 425–426 withdrawal, 424–425 azithromycin, 264 B barbiturates, 220 basiliximab, 407 benazepril, 209 benzimidazoles comparative studies, 321 formulations, 321–322 observational studies, 320 placebo-controlled studies, 321 susceptibility factors, 321 benzocaine, 140–141 benzodiazepines, 51 benzyl alcohol, 602 beta2 -adrenoceptor agonists comparative studies, 171 general effects, 176 beta2 -adrenoceptor agonists+anticholinergics, 176–177 beta-adrenoceptor antagonists (beta-blockers) cardiovascular effects, 194 concomitant cocaine, 39 metabolic effects, 194 musculoskeletal effects, 194–195 beta-lactam antibiotics, 245 betamethasone see glucocorticoids bevacizumab dosage regimens, 408 epistaxis, 408 general effects, 407–408 hemoptysis, 408 hypertension, 408 intracranial hemorrhage, 408 proteinuria, 408 bicalutamide, 512–513 bile acids, 378–379 bismuth, 228 bisphosphonates general effects, 602
psychological effects, 602–603 vision, 603 black cohosh see Cimicifuga racemosa blood transfusion autoimmune hemolytic anemia, 339 general effects, 338–339 immune system suppression, 339 infection risk, 339 transfusion-related acute lung injury (TRALI), 339 bosentan, 213 botulinum toxin A, 156 brachial plexus anesthetics, 135 brinzolamide, 221 bropirimine, 463 brotizolam, 282 bryostatin 1, 461 budesonide, 486 buflomedil, 202 bupivacaine, 141 buprenorphine, 111 bupropion see amfebutamone buspirone, 51 C cabergoline, 152 caffeine clozapine concentration, 68 serotonin syndrome, +paroxetine, 1 calcipotriol, 156 calcitonin, 539 calcium channel blockers see specific drugs, such as felodipine; verapamil calcium dobesilate, 202 candesartan, 212 cannabinoids arteritis, 36 cognitive impairment, 37–38 hyperemesis, 38 nervous system effects, 36–37 observational studies, 35 placebo-controlled studies, 35–36 pneumothorax, 36 psychiatric effects, 37–38 capecitabine cardiotoxicity, 554 comparative studies, 554 concomitant leucovorin, 555 palmar–plantar erythrodysesthesia, 555 peripheral neuropathy, 555 susceptibility factors, 555 weakness, 555 captopril, 210 carbamazepine adverse reactions, 88–89 concentration, +fluconazole, 282 immunoglobin deficiency, 88
634 interactions, 88 myasthenia, 87–88 myoclonus, 87 pitch perception alteration, 87 simvastatin concentration, 548 sperm abnormalities, 88 carbonic anhydrase inhibitors, 220 carboxypeptidase G2, 444 cardiac glycosides interactions, 182 management of toxicity, 183 mesenteric ischemia, 182 nervous system effects, 182 carisoprodol, 146 carnitine, 360 carvedilol, 194 caspofungin, 289 catheters, 612–613 Caulophyllum thalictroides, 586 cefazolin, 246 ceftriaxone, 246–247 celecoxib, 121 cetacaine, 141 cetirizine, 161–162 C31G, 604–605 chloramphenicol, 254 chlordiazepoxide, 52 chlorhexidine, 241–242 chloroprocaine cardiotoxicity, 141 vs. lidocaine, 137 chloroquine cardiomyopathy, 294 general effects, 294 gluteal abscess, 295 overdose, 295 psychiatric effects, 294–295 skin effects, 295 chlorphenamine, 162 chromium, 228 ciclosporin alopecia, +tacrolimus, 427 breast fibroadenomas, 430 cardiovascular effects, 427 clearance, +atorvastatin, 432 clearance, +etoposide, 432 clearance, +HAART, 432 clearance, +prednisolone, 486 clearance, +sevelamer, 432 clearance, +St John’s wort, 432–433 comparative studies, 426–427 concentration, +quinupristin/dalfopristin, 269 concentration, +voriconazole, 282, 433 concomitant caspofungin, 289 dosage regimens, 431–432 endocrine effects, 428 gingival hyperplasia, 428 infection risk, 430 interactions, 432
Index of drugs liver, 429 monitoring therapy, 432 myositis, 430 nephrotoxicity, 429 nervous system effects, 427–428 ocular opsoclonus, 428 peptic ulcer disease, 429 susceptibility factors, 431 tumorigenicity, 431 cidofovir, 300 cilostazol, 202 cimetidine clearance, +itraconazole, 283 prulifloxacin absorption, 259 Cimicifuga racemosa (black cohosh), 586 Cinnamonum camphora (cinnamon), 586 ciprofloxacin cardiovascular effects, 255 fibroblast activity reduction, 255 hypoglycemia, +glibenclamide, 255, 530–531 interstitial pneumonitis, 255 leukocytoclastic vasculitis, 255 liver damage, 255 observational studies, 255 propriospinal myoclonus, 255 tizanidine clearance, 146–147 toxic epidermal necrolysis, 255 cisapride, 371 Citrus aurantium (bergamot), 586–587 cladribine, 564 clarithromycin digoxin clearance, 182 gastrointestinal effects, 265 interactions, 265 simvastatin concentration, 549 clindamycin, 263 clobazam, 52–53 clofarabine, 551 clonazepam glucose concentration, 53 psychiatric effects, 53 teratogenicity, 53–54 urinary retention, 53 clonidine, 214 clopidogrel bleeding, +acetylsalicylic acid, 124 concomitant statins, 365, 548 hematologic effects, 365 hemophilia, acquired, 365 hepatocellular injury, 365 clorazepate, 54 clozapine general effects, 66–67 hypersalivation, 68 interactions, 68–69 lupus erythematosus, 68 metabolic effects, 67
monitoring therapy, 69 myocarditis, 62 nervous system, 67 neutropenia, 67–68 vs. olanzapine, 71 pericardial effusions, 67 susceptibility factors, 68 co-trimoxazole aseptic meningitis, 297–298 folate deficiency, +methotrexate, 444 methemoglobinemia, 298 pancytopenia, +methotrexate, 444 systemic response syndrome, 298 coagulation proteins, 345–346 cocaine administration route, 43 cardiovascular system, 38–39 concomitant beta-blockers, 39 concomitant progestogens, 505–506 death, 41 fetotoxicity, 41–43 genitoperineal numbness, 141 hepatotoxicity, 40–41 interactions, 44 overdose, 43–44 penile necrosis, 41, 141 pneumoperitoneum, 40 respiratory system, 40 rhinitis, destructive, 40 splenic infarction, 40 stroke, 40 coenzyme Q10, 588 colchicine clearance, +clarithromycin, 265 paresis, +verapamil, 125 colistin, 268 collagen, 603 colonic irrigation, 591 colophony, 156–157 contraceptives, emergency, 501 contraceptives, hormonal, 499–500 contraceptives, implantable, 501 contraceptives, oral concomitant alosetron, 372 concomitant isotretinoin, 500 contrast agents interactions, 579 nephrotoxicity, 575–578 nephrotoxicity prevention, 576–578 types, 573 usage guidelines, 574 contrast agents, water-soluble iodinated anaphylactoid reaction, 578 endocrine effects, 574 nervous system, 573–574 thrombosis, 574–575 copper, 228
635
Index of drugs coumarin anticoagulants hematologic effects, 358 interactions, 360–361 skin necrosis, 358–359 susceptibility factors, 359–360 COX-2 inhibitors (coxibs) cardiovascular effects, 116, 117, 123–124 concomitant gentamicin, 254 “crack” see cocaine cyclophosphamide clearance, +itraconazole, 566 comparative studies, 433 metabolism, +azole antifungals, 283 cyproterone acetate general effects, 510 hepatitis, +flutamide, 513 cyproterone acetate +ethinylestradiol, 502 cytarabine anterior uveitis, 556 described, 555 formulations, 556 hematologic effects, 556 liver, 556 metabolism, +caspofungin, 290 metabolism, +itraconazole, 283 nervous system effects, 556 pericarditis, 555 respiratory effects, 555 skin, 556 cytosine arabinoside, 366 D daclizumab dosage regimens, 409 general effects, 408 monitoring therapy, 409 placebo-controlled studies, 408 reproductive system effects, 409 dalbavancin, 260 danazol, 514 dapsone clearance, +fluconazole, 316 clearance, +rifabutin, 316 hypersensitivity syndromes, 315–316 interactions, 316 metabolism, +fluconazole, 283 daptomycin, 271–272 data mining conclusions, xliv–xlv described, xxxiii–xxxiv efficacy, xxxviii–xli future directions, xliii–xliv indications, xli–xlii innovations, xxxvi–xxxviii purpose, xxxiv–xxxv techniques, xxxv–xxxvi warnings, xlii–xliii daunorubicin see anthracyclines DDAVP see desmopressin
decitabine, 557 deferasirox, 236 deferiprone arthropathy, 237 efficacy, 235–236 hematologic effects, 237 observational studies, 237 deferoxamine efficacy, 235–236 mucormycosis, 237 observational studies, 237 retinopathy, 237–238 deflazacort see glucocorticoids desloratadine, 162 desmopressin calcium excretion, 543 cardiovascular effects, 543 hematologic effects, 543 hyponatremia, 543 nervous system, 543 pancreas graft thrombosis, 543–544 susceptibility factors, 544 dexamethasone see glucocorticoids dexchlorpheniramine, 162 dexmedetomidine, 129 dextromethorphan clearance, +quinidine, 190 placebo-controlled studies, 105 diamorphine see heroin diazepam, 54–55 diazoxide, 215 dicloxacillin, 360 didanosine concentration, +clarithromycin, 265 concentration, +tenofovir, 303–304 diethylcarbamazine, 322 diethyldithiocarbamate, 605 diethylstilbestrol, 495 digoxin, 363 diltiazem, 196 diphenhydramine delirium, 163 delirium, +linezolid, 268 overdose, 163 dipyridamole, 365–366 dirithromycin, 265 disulfiram, 605 diuretics, 219–220 divalproex, 28 dobutamine, 150–151 docetaxel, 283 dofetilide, 187–188 donepezil, 12–13 dorzolamide, 221 doxapram, 9 doxazosin, 214 doxepin, 19 doxorubicin see anthracyclines dronabinol, 36 droperidol
comparative studies, 69 death, 70 nervous system effects, 70 placebo-controlled studies, 69 QT interval prolongation, 69–70 drotrecogin alfa, 338 duloxetine, 23 Dyastat see diazepam E ebastine, 163 Echinacea species, 587 echinocandins, 288–289 ecstasy see methylenedioxymetamfetamine efalizumab, 409 efavirenz, 305 emtricitabine, 304 enalapril, 210 enfuvirtide, 310 entacapone, 153 Ephedra and ephedrine administration route, 149 cardiovascular effects, 148–149 interactions, 149 liver damage, 149 overdose, 149 vs. sibutramine, 11 stroke, 149 epinephrine see adrenaline epirubicin see anthracyclines epoetin see erythropoietin epoprotenol, 488–489 ergot alkaloids, 202–203 ertapenem, 246 erythromycin, 265–266 erythropoietin and derivatives cardiovascular effects, 346–347 pure red cell aplasia, 347 skin effects, 347 susceptibility factors, 347 tumorigenicity, 347 Escherichia coli Nissle 1917, 379 esomeprazole, 373–374 estrogens cardiovascular effects, 494 formulations, 495 infertility, 494–495 etanercept comparative studies, 397 concomitant digoxin, 182 concomitant methotrexate, 444 Crohn’s disease, 397 immunologic effects, 398 infection risk, 395–396 during lactation, 398 psoriasis, 397–398 susceptibility factors, 397 visual field loss, 397 ethambutol, 316–317 ethanol see alcohol etherified starches, 341 ethmozine see moricizine ethyl alcohol see alcohol
636 ethylene oxide, 242 ethylenediamine, 606 etizolam, 283–284 etoricoxib, 123 everolimus dosage regimens, 434 fever, 434 formulations, 434 hematologic effects, 433 hypercholesterolemia, 434 infection risk, 434 monitoring therapy, 434 exenatide, 529 ezetimibe, 546 F famciclovir, 301 FD and C Blue No. 1, 606–607 felodipine, 197 fenfluramines, 11 fentanyl, 106, 190 fibrates concomitant ezetimibe, 546 renal allograft dysfunction, 546–547 rhabdomyolysis, 546 filgrastim see granulocyte colony-stimulating factor finasteride breast cancer, males, 512 cataracts, 157, 512 comparative studies, 511–512 dosage regimens, 512 gynecomastia, 157–158 observational studies, 511 pancreatitis, 512 sexual function, 157, 512 fish oils, 588 flecainide, 188 fluconazole adrenal dysfunction, 286 carbamazepine metabolism, 88 observational studies, 286 fludarabine cardiovascular effects, 564 hematologic effects, 564 infection risk, 564–565 liver, 564 nervous system, 564 respiratory effects, 564 susceptibility factors, 565 fluorescein dye, 607 fluoroquinolones gastrointestinal effects, 254 musculoskeletal effects, 255 nervous system effects, 254 skin effects, 254–255 fluorouracil (5-fluorouracil) administration routes, 558 adverse reaction management, 558–559 cardiovascular effects, 557 gastrointestinal effects, 558 neurotoxicity, 557
Index of drugs palmar–plantar erythrodysesthesia, 558 susceptibility factors, 558 fluoxetine, 162 fluphenazine, 71 flutamide adenocarcinoma of the breast, 513 comparative studies, 513 enterocolic lymphocytic phlebitis, 513 general effects, 511 hepatitis, +cyproterone acetate, 513 interstitial pneumonitis, 513 skin, 513 fluticasone, 171 fluvoxamine clozapine concentration, 68 haloperidol concentration, 22, 70 olanzapine availability, 75 tizanidine clearance, 147 folinic acid see leucovorin fondaparinux, 362 formoterol, 171–172 foscarnet, 300 fosmidomycin, 272–273 fosphenytoin see phenytoin FTY720, 434 furosemide, 222 fusidic acid (sodium fusidate), 259 G gabapentin, 89 gadolinium salts, 578 gallium, 228 ganciclovir, 300 garlic see Allium sativum gatifloxacin, 256, 531 gemcitabine hematologic effects, 559 hemolytic-uremic syndrome, 559 respiratory effects, 559 skin, 559 susceptibility factors, 560 urinary tract, 559 gemfibrozil, 530 gemifloxacin availability, +concomitant cations, 256–257 food–drug interactions, 257 gastrointestinal effects, 256 liver effects, 256 phototoxicity, 256 QT interval prolongation, 256 gemtuzumab ozogamicin adverse reactions management, 410 death, 410 gastrointestinal effects, 409 hematologic effects, 409
hepatic veno-occlusive disease, 409 interactions, 410 susceptibility factors, 410 gentamicin adverse reactions management, 254 concomitant COX-2-selective inhibitors, 254 death, 254 digoxin concentration, 182–183 sensory systems effects, 253 Ginkgo biloba (maidenhair tree), 587 ginseng see Panax ginseng glatiramer acetate, 435 glibenclamide (glyburide) anemia, 530 blood pressure increase, 530 hypersensitivity reaction, 530 hypoglycemia, +ciprofloxacin, 255 interactions, 530–531 during pregnancy, 530 glibenclamide+metformin +rosiglitazone, 534–535 gliclazide, 531 glimepiride, 531 glipizide, 531 glucocorticoids, 284 glucocorticoids, inhaled adrenal suppression, 169, 171 formulations, 171 musculoskeletal effects, 170 oral effects, 168–169 skin effects, 169–170 susceptibility factors, 170–171 glucocorticoids, intra-articular, 487 glucocorticoids, nasal, 487 glucocorticoids, systemic adverse reactions diagnosis, 486 adverse reactions management, 487 cardiovascular effects, 480 diverticular abscess perforation, 484 gastrointestinal effects, 484 infection risk, 485 interactions, 486 liver damage, 484 musculoskeletal effects, 484–485 nervous system effects, 480–481 observational studies, 480 during pregnancy, 485–486 psychiatric effects, 483–484 vision, 481–483 glyburide see glibenclamide glyceryl trinitrate, 195 gold and gold salts, 228–229 gonadorelin antagonists, 539
637
Index of drugs gonadotropins adverse reactions management, 539 breast cancer, 494 metabolism, 539 psychological effects, 540 reproductive system effects, 493–494 goserelin, 539 granisetron, 372 granulocyte-colony stimulating factor (G-CSF) administration route, 384 diagnostic test interference, 384 hematologic effects, 383 myeloid leukemia, 384 restenosis, in-stent, 383 vasculitis, 384 grapefruit juice itraconazole clearance, 284 methadone availability, 107 simvastatin concentration, 549 grepafloxacin, 257 H hair dyes, 607 haloperidol concentration, +fluvoxamine, 22, 70 vs. olanzapine, 71–72 vs. risperidone, 77 tardive Tourette’s syndrome, 70 hemoglobin-based oxygen carriers, 340 heparins, 361 hepatitis A vaccine, 332 hepatitis B vaccine, 332 see also HEXAVAC herbal medicines, 9 heroin (diamorphine) fetotoxicity, 47 gastric emptying delay, 106 infection risk, 46–47 nervous system, 46 nutrition, 46 psychiatric effects, 46 HEXAVAC, 330 hexavalent vaccines, and sudden infant death, 327–330 HMG coenzyme-A reductase inhibitors see statins homeopathy, 591 hormone replacement therapy (HRT) allergy, 497 asthma, 496 bleeding, 497 cardiovascular effects, 496 formulations, 499 gallstones, 497 glucose tolerance, 496 after gynecological malignancies, 498
hematologic effects, 496–497 susceptibility factors, 498–499 tumorigenicity, 497–498 hydrochlorothiazide, 88 hydrocodone, 106 hydrofluoric acid, 608–609 hydrogen peroxide, 379 hydromorphone, 107 hydroxychloroquine see chloroquine hydroxyzine, 163 Hypericum perforatum (St. John’s wort) digoxin concentration, 183 hypomania, 587 INR decrease, +coumarin anticoagulants, 361 interactions, 587 quazepam concentration, 56–57 I ibuprofen, 124–125 ICL670A, 238 idarubicin, 284 idoxifene, 502–503 Illicium verum/anisatum (Chinese/Japanese star anise), 587–588 iloprost, 489 imatinib, 284 immunoglobulins aseptic meningitis, 344 cardiovascular effects, 343–344 human parvovirus B19 infection, 344 immunologic effects, 344 skin, 344 transfusion-related acute lung injury (TRALI), 344 urinary tract, 344 incretin mimetics described, 528 gastrointestinal effects, 529 hypoglycemia, 528–529 indinavir concentration, +rifampicin, 308 insulin resistance, 307–308 susceptibility factors, 308 infliximab cardiovascular effects, 399 concomitant leflunomide, 442 death, 403 hematologic effects, 398 immunologic effects, 401–402 infection risk, 395–396, 402–403 nervous system effects, 400 observational studies, 398 respiratory effects, 399–400 skin effects, 400–401 susceptibility factors, 403–404 teratogenicity, 403 tumorigenicity, 403 influenza vaccine
H5N1 pandemic, 332–333 nervous system effects, 333 respiratory effects, 333 skin effects, 333–334 tumorigenicity, 334 infusions, 598–599 insulin administration errors, 599 administration route, 524 edema, 523–524 hepatomegaly, 524 hypoglycemia, 523 hypokalemia, 523 pulmonary edema, 523 susceptibility factors, 524 insulin detemir, 525 insulin lispro, 525 insulin pumps, 524 interferon alfa celiac disease, 389 comparative studies, 386 formulations, 392 hematologic effects, 389 immunologic effects, 391 infection risk, 391–392 interactions, 392 liver hemangioma, 389 metabolic effects, 388 myopathy, 391 nervous system effects, 387 observational studies, 386 pancreatitis, 389–390 pericarditis, 387 psychiatric effects, 384 respiratory effects, 387 sensory systems effects, 388 skin effects, 390–391 susceptibility factors, 392 urinary tract effects, 390 interferon beta adverse reactions management, 394 hematologic effects, 393 immunologic effects, 393–394 liver effects, 393 psychiatric effects, 385 interferon gamma, 394 interferons cognitive effects, 385 psychiatric effects management, 386 psychiatric effects mechanisms, 385 psychiatric effects susceptibility factors, 385–386 interleukin-2 (IL-2) administration route, 395 anemia, 394 gastrointestinal perforation, 394–395 myocarditis, 394 respiratory effects, 394 intraocular injection, 581
638 iodine see contrast agents, water-soluble iodinated iptifibatide, 366 irbesartan, 212 irinotecan, 432 iron chelators, 235, 236 iron salts, 229–230 isoniazid chloramphenicol concentration, 254 hepatitis, 317 isosulfan blue, 607–608 isotretinoin concomitant oral contraceptives, 501 Guillain-Barré syndrome, 158 hyperostosis, 159 itraconazole concentration, +clarithromycin, 265 concomitant lidocaine, 188 Cushing’s syndrome, +budesonide, 486 cyclophosphamide clearance, 566 susceptibility factors, 286 toxic epidermal necrolysis, 286 ivermectin availability, +levamisole, 462 clearance, +levamisole, 324 comparative studies, 323 drug resistance, 323 observational studies, 323 J Jackyakamcho-tang, 583 Japanese encephalitis vaccine, 334–335 K ketamine, 131–132 ketoconazole, 534 ketogenic diet, 89 ketolides blurred vision, 262 gastrointestinal effects, 262 INR increase, +telithromycin, 360 interactions, 262 interstitial nephritis, 262 susceptibility factors, 262–263 torsade de pointes, 262 ketotifen, 163 L lactulose and lactitol, 375 lamotrigine adverse reactions management, 91 hemophagocytic syndrome, 90 immune deficiency, 90 interactions, 91 vs. lithium, 28
Index of drugs monitoring therapy, 91–92 nervous system effects, 90 observational studies, 90 overdose, 91 during pregnancy, 90–91 Larrea tridentata (chaparral), 588 latanoprost, 490 laxatives, 360 leflunomide adverse reactions management, 443 cardiovascular effects, 439 concomitant rifampicin, 442 dosage regimens, 442 efficacy, 436–438 fertility effects, 441 gastrointestinal effects, 440–441 general effects, 438–439 hematologic effects, 440 hypertriglyceridemia, 440 indications, 435, 437 INR increase, +warfarin, 442 interstitial nephritis, 441 during lactation, 442 liver, 441 macular edema, 440 mechanism of action, 435 mutagenicity, 441 nephritis, 441 overdose, 442 peripheral neuropathy, 439–440 pharmacokinetics, 435 respiratory effects, 439 skin, 441 teratogenicity, 442 tumorigenicity, 441 leg block, 139 lentinan, 463 lepirudin, 362–363 lercanidipine, 197 leucovorin (folinic acid), 555 leukotriene receptor antagonists, 174–175 leuprorelin, 539 levalbuterol see levosalbutamol levamisole comparative studies, 462 gastrointestinal effects, 462 general effects, 462 hematologic effects, 462 interactions, 324, 462 leukopenia, 324 observational studies, 462 placebo-controlled studies, 324 teratogenicity, 462 levetiracetam enterocolitis, 92 hyponatremia, 93 interactions, 93 jaundice, 92–93 nervous system effects, 92 overdose, 93 psychiatric effects, 92
sperm abnormalities, 93 thrombocytopenia, 92 levocetirizine, 164 levodopa, 151–152 levofloxacin, 257 levonorgestrel, 506 levosalbutamol (levalbuterol), 172 lidocaine (lignocaine) administration route, 188 vs. chloroprocaine, 137 concomitant itraconazole, 188, 284 death, 188 euphoria, 142 interactions, 188 susceptibility factors, 188 lignocaine see lidocaine limonene, 609 Lin Chee/Active Rheuma Plus, 584 linezolid 5-HT neurotoxicity, +SSRIs, 22 adverse reactions management, 268 cardiovascular effects, 267 delirium, +diphenhydramine, 268 hypertension, +bupropion, 268 myelosuppression, 267 observational studies, 267 optic neuropathy, 267 pressor response, +MAO inhibitors, 268 serotonin syndrome, +venlafaxine, 268 susceptibility factors, 267–268 lipiocis, 609–610 liraglutide, 529 lisinopril hypotension, +tizanidine, 211 pancreatitis, 210 pemphigus foliaceus, 210–211 lithium comparative studies, 28–29 concentration, +clozapine, 68–69 concentration, +topiramate, 96–97 dysrhythmias, 30 hypotension, 29–30 interactions, 33 monitoring therapy, 33 nephrogenic diabetes insipidus, 31 observational studies, 29 overdose, 33 placebo-controlled studies, 28 skin effects, 31–32 susceptibility factors, 32–33 local anesthetics, 135 lometrexol, 560 loperamide, 374 lopinavir+ritonavir cholesterol concentration, 308
639
Index of drugs concentration, +NNRTIs, 308–309 hepatoxicity, 308 monitoring therapy, 309 triglyceride concentration, 308 loratadine, 164 lorazepam, 55 lormetazepam, 55–56 lumiracoxib cardiovascular effects, 122–123 concomitant fluconazole, 284–285 M Ma-huang see Ephedra/ephedrine macrolides see also specific drugs, such as josamycin; spiramycin cardiovascular effects, 263 immunologic effects, 263 INR increase, +azithromycin, 360 sensory systems effects, 263 susceptibility factors, 263–264 malononitrilamide 715, 443 manganese, 230 mannitol general effects, 375 hyperkalemia, 222–223 renal insufficiency, 223 marijuana see cannabinoids MDMA see methylenedioxymetamfetamine measles-mumps-rubella (MMR) vaccine, 335 meclozine, 165 mefloquine, 295 meglitinides, 529 melatonin, 542 meningococcal vaccine, 331 menthol, 610 meperidine see pethidine mercaptopurine concentration, +allopurinol, 552 diagnostic test interference, 553 fetotoxicity, 553 general effects, 552 hepatotoxicity, 552–553 leukopenia, 552 susceptibility factors, 553 tumorigenesis, 553 mercury and mercurial salts, 230 mesalazine, 378 metamfetamine cardiac hyposensitivity, 3 cognitive impairment, 3–6 intracerebral hemorrhage, 3 metformin erythema multiforme, 527 formulations, 528 hypoglycemia, 526 lactic acidosis, 526–527
during pregnancy, 527–528 teratogenicity, 528 metformin+sulfonylureas, 534 methadone availability, +quinidine, 190 concomitant interferon alfa, 392–393 edema, 47 interactions, 107 QT interval prolongation, 107 withdrawal, 107 methotrexate administration errors, 599 adverse effects management, 562 availability, +sulfasalazine, 444–445 clearance, +NSAIDs, 444 concentration, +benzimidazoles, 444 described, 560–561 dosage regimens, 444 folate deficiency, +co-trimoxazole, 444 gastrointestinal effects, 561 general effects, 443 hepatotoxicity, 561 interactions, 444 nervous system, 561 pancytopenia, +co-trimoxazole, 444 regimens, 562 renal insufficiency, 561–562 respiratory effects, 561 susceptibility factors, 443–444 vision, 561 methylene blue see methylthioninium chloride methylenedioxymetamfetamine (MDMA, ecstasy) death, 8–9 drug adulteration, 9 drug overdose, 9 fever, 8 guttate psoriasis, 8 hemopneumothorax, 6–7 hyperkalemia, 8 memory deficit, 7–8 mood disorders, 7 methylphenidate, 10 methylprednisolone see glucocorticoids methylthioninium chloride (methylene blue), 610 metoclopramide, 371 metoprolol bradycardia, +amfebutamone, 24 concentration, +amiodarone, 187 mexiletine, 188–189 micafungin, 290 midazolam, 56 mifepristone (RU486)
comparative studies, 507 general effects, 506 infection risk, 507 observational studies, 506–507 uterine rupture, 507 miglitol, 526 milrinone, 183 miltefosine, 563 minocycline brain injury, 248 hyperpigmentation, 248–249 musculoskeletal effects, 249 polyarteritis nodosa, 249 thyroid pigmentation, 249–250 minoxidil, 215 misoprostol, 490 mizoribine, 445 moclobemide, 19 modafinil, 10–11 molgramostim, 383 mometasone furoate, 171 monoamine oxidase inhibitors, 268 monobactams, 247 montelukast, 175 moricizine, 189 morphine, 107–108 moxifloxacin clearance, +itraconazole, 285 concomitant antidiabetics, 258 gastrointestinal effects, 257 hypersensitivity reaction, 258 metabolic effects, 257 observational studies, 257 tendinopathy, 258 moxonidine, 214–215 mumps vaccine see measles-mumps-rubella (MMR) vaccine mycophenolate mofetil absorption ferrous sulfate, 448 B cell lymphoma, 445–446 diarrhea, 446 formulations, 447 infection risk, 446 liver, 446 lymphoma, 445–446 monitoring therapy, 448 myalgia, 446 nervous system effects, 445 observational studies, 445 overdose, 447 susceptibility factors, 447 teratogenicity, 446–447 N N-deamino-8-d-arginine vasopressin see desmopressin nalbuphine, 111 nalmefene, 111–112 naltrexone, 112 nateglinide, 529 nefopam, 112
640 nelfinavir concomitant caspofungin, 290 metabolism, 309 neuromuscular blockers, 149 nevirapine hepatoxicity, 306 hypersensitivity reaction, 305–306 during pregnancy, 306 Stevens–Johnson syndrome, 306 nicardipine, 197–198 nickel, 230, 231 nicotine, 610–611 nifedipine adverse reactions management, 199 cardiovascular effects, 198 during pregnancy, 198 nilutamide, 511 nimodipine, 199 nitrofurantoin liver damage, 266 neutropenia, 266 pulmonary toxicity, +fluconazole, 285 respiratory effects, 266 susceptibility factors, 266 nitroglycerin see glyceryl trinitrate nitrous oxide, 131 non-nucleoside reverse transcriptase inhibitors (NNRTIs), 305 nonsteroidal anti-inflammatory drugs (NSAIDs), 360 see also specific drugs, such as ketoprofen norfloxacin, 258 NSAIDs see nonsteroidal anti-inflammatory drugs (NSAIDs) Nu Bao, 584 nystatin, 290–291 O octreotide, 541 ocular dyes, 606 ofloxacin, 258 olanzapine vs. amisulpride, 65 comparative studies, 70–72 endocrine effects, 73–74 general effects, 61 hematologic effects, 75 interactions, 75 metabolic effects, 74–75 overdose, 75 placebo-controlled studies, 72–73 priapism, 75 psychiatric effects, 73 QT interval prolongation, 73 tardive dyskinesia, 73
Index of drugs olopatadine, 165 omeprazole, 374 ondansetron, 372–373 opioids death, 44–46 susceptibility factors, 105 oritavancin, 260 orlistat, 11 oxatomide, 165 oxazaphosphorines, 566 oxycodone, 108 oxymorphone, 108 P p-chloro-m-cresol, 604 paclitaxel, 566 Panax ginseng hypertension, 588 INR decrease, +coumarin anticoagulants, 360 paracetamol (acetaminophen) chloramphenicol concentration, 254 concomitant coumarin anticoagulants, 360–361 parathyroid hormone (PTH), 542 parecoxib, 122 parenteral nutrition, 353–354 paroxetine concomitant alprazolam, 52 mania, 18 serotonin syndrome, +caffeine, 1 patent blue, 608 pazufloxacin, 258 pefloxacin, 258 pegfilgrastim see granulocyte colony-stimulating factor (G-CSF) pemetrexed, 562 penicillamine, 239 pentostatin described, 565 nervous system, 565 neutropenia, 565 susceptibility factors, 565 urinary tract, 565 perfluorocarbons, 340 pergolide, 152–153 perphenazine, 75 pertussis vaccines, acellular, 331–332 pethidine, 108–109 phenobarbital anticonvulsant hypersensitivity syndrome, 93–94 chloramphenicol concentration, 254 overdose, 94 teratogenicity, 94 phenylpropanolamine, 150 phenytoin administration route, 95
anticonvulsant hypersensitivity syndrome, 94 chloramphenicol concentration, 254 gingival overgrowth, 94 pharmacoeconomics, 94 psychological effects, 94 skin effects, 94 susceptibility factors, 95 phosphate, 375–376 phosphodiesterase type V inhibitors interactions, 204 nervous system effects, 203 reproductive system effects, 204 serous chorioretinopathy, 203–204 urticaria, 204 Phu Chee, 584 phytoestrogens, 588 picibanil, 463–464 pimecrolimus, 449 pioglitazone hepatotoxicity, 533 peripheral edema, 531–533 susceptibility factors, 533 weight gain, 533 piperacillin, 247–248 pneumococcal vaccine, 332 polyethylene glycol, 375 polygelines, 341 polystyrene sulfonates, 239 polyvinylpyrrolidone, 242–243 posaconazole, 286–287 potassium salts, 230 pramlintide, 526 praziquantel, 324 prednisolone, 486 see also glucocorticoids prednisone see glucocorticoids pristinamycin, 269 progestogens, 505–506 promazine, 61 propofol during endoscopy, 128–129 injection site pain, 132 pancreatitis, 132 propofol infusion syndrome, 132, 132–133 propylthiouracil antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis, 520–521 hearing loss, 521 hydrops, 522 pyoderma gangrenosum, 521 prostaglandin E see alprostadil protease inhibitors comparative studies, 307 formulations, 307 pancytopenia, 322 tacrolimus concentration, +diltiazem, 196
641
Index of drugs proton pump inhibitors, 373 prulifloxacin cardiovascular effects, 259 gastric pain, 259 general effects, 258–259 pseudoephedrine see also Ephedra/ephedrine cardiovascular effects, 149–150 skin effects, 150 psychotherapy, 29 PTH see parathyroid hormone (PTH) pulsed intranasal therapy, 499 PUVA, 158 pyrimethamine+dapsone, 296 pyrimethamine+sulfadoxine, 296 Q Qing zhisan tain shou, 584 quazepam, 56–57 quetiapine, 75–76 Quilinggao, 584 quinapril, 211 quinidine comparative studies, 189 interactions, 190 observational studies, 189 thrombocytopenia, 190 quinine and congeners, 296 quinupristin/dalfopristin, 269 R rabeprazole, 374 raloxifene, 503 raltitrexed, 563 ramipril, 211 ramoplanin, 273 ranitidine, 373 rapamycin see sirolimus remifentanil cardiovascular effects, 109 fetotoxicity, 110 respiratory depression, 109 tonic–clonic seizure, 109 repaglinide hepatotoxicity, 529–530 interactions, 530 ribavirin, 301 rifabutin concentration, +efavinrenz, 305 concomitant azithromycin, 265 rifampicin caspofungin clearance, 290 chloramphenicol concentration, 254 concentration, +indinavir, 308 concomitant repaglinide, 530 fluconazole clearance, 285 rosiglitazone clearance, 534 susceptibility factors, 317–318 risperidone vs. amisulpride, 65 comparative studies, 77 concentration, +SSRIs, 23
extrapyramidal symptoms, 77 formulations, 79–80 general effects, 61 hematologic effects, 78–79 hyperprolactinemia, 78 hypotension, 77 interactions, 79 during lactation, 79 observational studies, 76 sexual dysfunction, 79 weight gain, 78 ritonavir see lopinavir+ritonavir rituximab adverse reactions management, 411 interstitial pneumonitis, 410–411 during pregnancy, 411–412 susceptibility factors, 412 rocuronium, 145–146 rofecoxib, cardiovascular effects, 116–121 ropivacaine, 142 rosiglitazone interactions, 534 liver, 534 metabolism, 533–534 peripheral edema, 531–533 thyroglobulin concentration increase, 533 rosin see colophony roxithromycin, 266 RU 486 see mifepristone rubella vaccine see measles-mumps-rubella (MMR) vaccine rufloxacin, 259 S salbutamol formulations, 174 genotypic variation, 173–174 hypoglycemia, 173 myocardial infarction, 172 tremor, 173 saquinavir, 309 selective serotonin re-uptake inhibitors (SSRIs) 5-HT neurotoxicity, +linezolid, 22 5-HT neurotoxicity, +tramadol, 23 electrolyte balance, 21 hepatotoxicity, 21 hyponatremia, 21 interactions, 22–23 during lactation, 22 overdose, 22 risperidone concentration, 23 serotonin syndrome, +tramadol, 111 sexual dysfunction, 21–22 suicide, 19–21 selenium, 231
sertraline, 12 sevoflurane hepatitis, 130 nervous system effects, 129–130 QT interval prolongation, 129 renal insufficiency, 130 visual pathway abnormality, 130 shoe dyes, 608 Shubao slimming capsules, 584 sibutramine, 11–12 sildenafil, 459 silicone, 611 silver, 231 simvastatin clearance, +diltiazem, 196 concentration, +carbamazepine, 88, 548 interactions, 549 rhabdomyolysis, +amiodarone, 187 sirolimus (rapamycin) angioedema, 452 concentration, +fluconazole, 285 dosage regimens, 452 endocrine effects, 450–451 hematologic effects, 451 hepatoxicity, 451 interactions, 452–453 metabolism, 451 observational studies, 449–450 respiratory effects, 450 sepsis, 452 urinary tract, 451–452 sitaxsentan, 213–214 sodium fusidate see fusidic acid sodium metabisulfite, 611 sodium morrhuate, 611–612 sodium phosphate electrolyte imbalance, 376 fluid balance, 377 gastrointestinal effects, 377 sodium picosulfate, 377 somatropin death, 540 diabetes mellitus, 540 formulations, 541 intracranial hypertension, 540 osteosarcoma, 540 susceptibility factors, 541 sotalol, 190, 195 sparfloxacin, 259 spinal manipulation, 591–592 spironolactone, 222 SSRIs see selective serotonin re-uptake inhibitors statins (HMG-CoA reductase inhibitors) cognitive impairment, 547 concomitant clopidogrel, 365 concomitant ezetimibe, 546 lichenoid eruptions, 547 lupus-like syndrome, 548
642 metabolism, 547 musculoskeletal system, 547–548 nervous system effects, 547 stem cells, 347 streptomycin, 254 strychnine, 9 sufentanil, 110 sulfamethoxazole, 285–286 see also co-trimoxazole sulfur hexafluoride, 579 sultiame, 95 suramin, 325 T tacrolimus absorption, +metoclopramide, 371 alopecia, 456 biliary cirrhosis, 455–456 bronchiolitis obliterans organizing pneumonia (BOOP), 454 cardiovascular effects, 453 clearance, +proton pump inhibitors, 459 concentration, +diltiazem, 196–197 concentration, +diltiazem +protease inhibitors, 196 diabetes mellitus, type 1, 454 diarrhea, 455 dosage regimens, 458–459 electrolyte balance, 454 hematologic effects, 454–455 interactions, 459 internuclear ophthalmoplegia, 454 liver, 455 metabolism, 454 metoclopramide absorption, 459 monitoring therapy, 459–460 musculoskeletal effects, 456–457 nervous system effects, 453–454 ophthalmoplegia, 454 pancreatitis, 456 reproductive system effects, 457 skin, 456 susceptibility factors, 458 tumorigenicity, 457–458 talc, 612 tamoxifen adverse reactions management, 505 concentration, +anti-inflammatory drugs, 505 concentration, +diuretics, 505 drug-procedure interactions, 505
Index of drugs endometrial carcinoma, 504–505 nervous system effects, 503–504 pancreatitis, 504 susceptibility factors, 505 vision, 504 tamsulosin, 214 taxanes, 566 tegafur, 560 teicoplanin drug hypersensitivity syndrome, 261 hematologic effects, 260–261 sensory systems effects, 260 telmisartan, 212 temocapril, 211 temsirolimus, 460 tenofovir bone density loss, 305 clearance, +atazanavir, 307 lichenoid eruption, 304–305 metabolism, 304 skin effects, 304–305 urinary tract, 304 tenoxicam, 125 terbinafine, 280 terlipressin, 544 tetracaine, 142 Teucrium polium, 588 thalidomide, 253 theophylline availability, +prulifloxacin, 259 chloramphenicol concentration, 254 nephroprotection, 1 thiazide diuretics, 221 thiazolidinediones, 531–533 thionamides, 520–521 thioridazine, 80 thrombolytic agents, 361–362 thymic hormones, 465 tiagabine, 95 tibolone, 514 ticlopidine, 366 tigecycline, 250 tioguanine, 552–553 tiotropium bromide, 174 tirofiban, 367 titanium, 231 tizanidine hypotension, +lisinopril, 211 interactions, 146 tobramycin, 254 tocopherols see vitamin E topiramate appetite loss, 95 hypersensitivity, 96 hypokalemia, 96 interactions, 96–97 leukopenia, +clozapine, 69 lithium toxicity, +lithium, 33 nephrolithiasis, 96 overdose, 96
psychiatric effects, 95–96 vision effects, 96 tosufloxacin, 259 tramadol 5-HT neurotoxicity, +SSRIs, 23 5-HT toxicity, +venlafaxine, 24 abuse, 111 comparative studies, 110 gastric pH increase, 110–111 interactions, 111 observational studies, 110 trazodone, 24 tretinoin concentration, +diethyldithiocarbamate, 605 hemophagocytic syndrome, 159 retinoic acid syndrome, 159 triamcinolone, intravitreal, 581–582 triamcinolone, parabulbar, 582 tribavirin see ribavirin trichloroethylene liver effects, 130 teratogenicity, 130 tumorigenicity, 131 triclabendazole, 321 trientine, 239 trimethoprim see also co-trimoxazole anaphylaxis, 271 fixed drug eruption, 271 gastrointestinal effects, 270 hematologic effects, 270 hepatic toxicity, 270 hyperkalemia, 270 myoclonus, 270 renal tubular acidosis, 270–271 rosiglitazone concentration, 534 susceptibility factors, 271 trimetrexate, 563 triptans, 203 troxacitabine, 560 tumor necrosis factor-alfa antagonists infection risk, 395–396 lymphoma, 396–397 susceptibility factors, infection, 396 U usnic acid, 589 V vaccines, standardized case definitions, 327 vaginal rings, 499 valaciclovir, 301 valdecoxib, 122 valganciclovir, 300 valproate sodium/semisodium administration route, 99 bone marrow loss, 98
643
Index of drugs factor XIII deficiency, 98 Fanconi syndrome, 98 fatty liver disease, non-alcoholic, 98 hyperammonemia, 97–98 interactions, 99 vs. lithium, 28–29 nervous system effects, 97 overdose, 99 sperm abnormalities, 98–99 teratogenicity, 99 valproic acid hypersensitivity syndrome, 99 valproic acid encephalopathy, +topiramate, 97 lamotrigine concentration, 91 valsartan, 213 vancomycin anaphylactic reactions, 261 antimicrobial drug resistance, 244–245 hematologic effects, 261 observational studies, 261 overdose, 262 skin effects, 261 susceptibility factors, 261 vasopressin, 542 venlafaxine, 24, 268
verapamil atrioventricular block, 200 comparative studies, 199 concentration, +telithromycin, 262 lymphomatoid papulosis, 200 paresis, +colchicine, 125 placebo-controlled studies, 199–200 vesnarinone, 183 vigabatrin, 99–100 virginiamycin, 273 vitamin B12 (cobalamins), 354 vitamin D analogues, 354–355 vitamin E, 355 vitamin K1 , 355–356 vitamins, 546 voriconazole concentration, +ciclosporin, 433 concomitant caspofungin, 290 hallucinations, auditory, 287 hallucinations, visual, 287 monitoring therapy, 288 QT interval prolongation, 287 retinoid-like photosensitivity, 287 susceptibility factors, 288 visual disturbances, 287 VP-eicosene copolymer, 157 VSL#3, 379
W warfarin INR increase, +azithromycin, 265 INR increase, +telithromycin, 262 INR increase, +tramadol, 111 potentiation, +amiodarone, 187 X X-ray contrast media, 340 xenon, 131 ximelagatran concomitant digoxin, 183 interactions, 363 Y yellow fever vaccine, 336 Z zafirlukast, 176 zaleplon, 57 zidovudine, 301 zinc, 232 ziprasidone, 81 zolpidem, 57 zonisamide body temperature, 100 concomitant carbamazepine, 88 observational studies, 100
Index of adverse effects 5-HT toxicity linezolid+SSRIs, 22 moclobemide, 19 SSRIs+tramadol, 23 tramadol+venlafaxine, 24 trazodone+venlafaxine, 25 A abdominal discomfort chloroquine, 294 methotrexate, 561 abdominal distension miglitol, 526 abdominal fullness phosphate, 375 abdominal girth, increased sirolimus (rapamycin), 450 abdominal pain acarbose, 526 albendazole, 321 artemisinin derivatives, 320 azithromycin, 264 cisapride, 371 clarithromycin, 265 dirithromycin, 265 disulfiram, 605 erythromycin, 265 esomeprazole, 374 ethambutol, 317 fluoroquinolones, 254 fosmidomycin, 272 ivermectin, 323 lactulose and lactitol, 375 leflunomide, 440 levosulpride, 371 melatonin, 542 micafungin, 290 mifepristone, 506, 507 misoprostol, 490 naltrexone, 112 phosphate, 375 praziquantel, 324 risperidone, 61 sodium picosulfate, 377 terbinafine, 280 thiabendazole, 320 abscess formation collagen, 603 accommodation disturbance chloroquine, 294 Achilles tendon avulsion leg block, 139 acidosis ketogenic diet, 89 acne ciclosporin, 426–427
644
fluoroquinolones, 255 lithium, 31 acne vulgaris anabolic steroids, 509 acral erythema cytarabine, 556 actinomycosis mycophenolate mofetil, 446 acute coronary syndrome rituximab, 410 acute disseminated encephalomyelitis Japanese encephalitis vaccine, 334 acute respiratory distress syndrome (ARDS) ciclosporin, 431 interferon alfa, 387 addiction zolpidem, 57 adenocarcinoma of the breast flutamide, 513 Adenovirus infection alemtuzumab, 405–406 adrenal dysfunction fluconazole, 286 glucocorticoids, inhaled, 169, 171 adult respiratory distress syndrome amiodarone, 187 infliximab, 402 affective disorder levetiracetam, 92 aggressive behavior anabolic steroids, 509 levetiracetam, 92 paroxetine, 18 systemic glucocorticoids, 483 topiramate, 96 agitation carisoprodol, 146 diazepam, 54 diuretics, 219 levetiracetam, 92 melatonin, 542 risperidone, 76, 77, 79 sevoflurane, 129–130 agranulocytosis antipsychotics, 60 deferiprone, 237 levamisole, 462 thiabendazole, 320 thionamides, 520–521 zonisamide, 100
airway obstruction topical anesthesia, 140 akathisia antipsychotics, 60 dexchlorpheniramine, 162 fluphenazine, 71 haloperidol, 61, 77 olanzapine, 61 pyrimethamine+sulfadoxine, 296 risperidone, 76 alcohol intolerance nilutamide, 511 allergic contact dermatitis ethylenediamine, 606 hair dyes, 607 p-chloro-m-cresol, 604 allergic reaction beta-lactam antibiotics, 245 cefazolin, 246 ciprofloxacin, 255 cisapride, 371 coagulation proteins, 346 erythromycin, 265 esomeprazole+omeprazole, 374 fondaparinux, 362 homeopathy, 591 hormone replacement therapy (HRT), 497 leflunomide, 438 nickel, 230, 231 polyethylene glycol, 375 rituximab, 410 vancomycin, 261 alopecia albendazole, 320 anagrelide, 364 ciclosporin+tacrolimus, 427 fluorouracil, 558 leflunomide, 438, 441 levamisole, 462 lisinopril, 210 tacrolimus, 456 tegafur, 560 troxacitabine, 560 alopecia areata infliximab, 400 alveolar hemorrhage sirolimus (rapamycin), 450 tirofiban, 366 amaurosis ocular anesthesia, 139 amaurosis fugax Panax ginseng, 588 amebiasis colonic irrigation, 591
645
Index of adverse effects amenorrhea amisulpride, 71 ciclosporin, 433 gabapentin, 89 levosulpride, 371 olanzapine, 73 anaphylactic reaction antithymocyte globulin, 341 benzyl alcohol, 602 coagulation proteins, 346 diazepam, 55 etherified starches, 341 immunoglobulins, 344 iron, 229 plasma substitutes, 340 polygelines, 341 vancomycin, 261 anaphylactic shock sodium metabisulfite, 611 anaphylactoid reaction water-soluble iodinated contrast agents, 578 anaphylaxis dental anesthesia, 138 patent blue, 608 rocuronium, 145–146 trimethoprim, 271 ANCA see antineutrophil cytoplasmic antibodies (ANCA) anemia albendazole, 321 anagrelide, 364 basiliximab, 407 bisphosphonates, 602 bryostatin 1, 461 clofarabine, 551 glibenclamide, 530 infliximab, 400 interferon alfa, 389, 392 interleukin-2 (IL-2), 394 itraconazole, 286 leflunomide, 440 lentinan, 463 linezolid, 267 malononitrilamide 715, 443 mycophenolate mofetil, 445 picibanil, 463 ribavirin, 301 sirolimus (rapamycin), 451 teicoplanin, 260 temsirolimus, 460 troxacitabine, 560 zidovudine, 301 anger levetiracetam, 92 angina see also cardiac ischemia adenosine, 185 azithromycin, 264 fluorouracil, 557 angioedema ACE inhibitors, 207–209 angiotensin II receptor antagonists, 211
azithromycin, 264 fluoroquinolones, 255 lentinan, 463 naltrexone, 112 sirolimus (rapamycin), 452 water-soluble iodinated contrast agents, 578 anhidrosis diphenhydramine, 163 anhydramnios valsartan, 213 anorexia see appetite loss (anorexia) anorgasmia amfebutamone, 24 SSRIs, 21–22 anosmia zinc, 232 anterior uveitis cytarabine, 556 anti-hirudin antibodies lepirudin, 363 anti-human histocompatibility antigen (HLA) antibodies antithymocyte globulin, 342 anticonvulsant hypersensitivity syndrome phenytoin, 94 antimicrobial drug resistance development, 244–245 antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis propylthiouracil, 521 antisocial personality disorder heroin, 46 anxiety cannabinoids, 35, 36 cisapride, 371 duloxetine, 23 glatiramer acetate, 435 mefloquine, 295 olanzapine, 72 risperidone, 80 zonisamide, 100 aortic dissection cocaine, 41 aortitis molgramostimin, 383 apathy diuretics, 219 interferons, 385 aphasia desmopressin, 543 aphthous lesions sodium phosphate, 377 aplasia cutis congenita carbimazole, 521 aplastic anemia thionamides, 521 apnea pertussis vaccines, acellular, 331
appetite increase lamotrigine, 90 appetite loss (anorexia) albendazole, 320 bisphosphonates, 602 calcipotriol, 156 diuretics, 219 erythromycin, 265 leflunomide, 440 methotrexate, 561 metronidazole, 321 olanzapine, 73 sirolimus (rapamycin), 452 sultiame, 95 topiramate, 95 vitamin D analogues, 354 zonisamide, 100 arachnoiditis cytarabine, 556 ARDS see acute respiratory distress syndrome argyria of the cornea ocular dyes, 606 argyrosis silver, 231 arrhythmia propofol, 133 arterial dissection ergot alkaloids, 202 spinal manipulation, 591 arterial hypertension ciclosporin, 427 arteritis cannabinoids, 36 arthralgia calcium dobesilate, 202 immunoglobulins, 343 influenza vaccine, 333 ivermectin, 323 leflunomide, 439 levamisole, 462 meglitinides, 529 quinupristin/dalfopristin, 269 somatropin, 541 arthropathy deferiprone, 237 intra-articular glucocorticoids, 487 sirolimus (rapamycin), 449 ascending tonic–clonic syndrome water-soluble iodinated contrast agents, 574 ascites interferon beta, 392 tacrolimus, 455 aseptic meningitis co-trimoxazole, 297–298 immunoglobulins, 344 leflunomide, 438, 440 aspergillosis alemtuzumab, 405 systemic glucocorticoids, 485
646 Aspergillus infection sirolimus (rapamycin), 450 aspiration polyethylene glycol, 375 asterixis gabapentin, 89 asthma aluminium, 225 dobutamine, 151 hormone replacement therapy (HRT), 496 asthma exacerbation beta2 -adrenoceptor agonists+anticholinergics, 177 ataxia fluorouracil, 557 melatonin, 542 tiagabine, 95 zonisamide, 100 atherosclerosis cocaine, 38–39 atrial extra beats antipsychotics, 60 atrioventricular block adenosine, 185 FTY720, 434 verapamil, 200 atrioventricular junctional rhythm adrenaline, 148 atrium, heart see entries at heart– auditory disturbance see entries at hearing– B B cell lymphoma mycophenolate mofetil, 445–446 babesiosis blood transfusion, 339 baboon syndrome ethylenediamine, 606 back pain clozapine, 71 cytarabine, 556 ivermectin, 323 backache immunoglobulins, 343 bacterial contamination blood transfusion, 339 bacterial infection infliximab, 402 bacterial pneumonia enfuvirtide, 310 balance impairment zaleplon, 57 basal cell carcinoma amiodarone, 187 ciclosporin, 431 behavior, abnormal anticholinergic drugs, 153
Index of adverse effects behavioral deficit cocaine, 43 Bell’s palsy influenza vaccine, 333 interferon alfa, 387 biliary cholesterol saturation thiazide diuretics, 221 biliary cirrhosis tacrolimus, 455–456 biliary sludge ceftriaxone, 246 bipolar disorder systemic glucocorticoids, 483 BK virus nephritis tacrolimus, 457–458 bleeding abciximab, 364 anagrelide, 365 antiplatelet drugs, 363 clopidogrel+acetylsalicylic acid, 124 drotrecogin alfa, 338 etherified starches, 341 gemtuzumab ozogamicin, 409 Ginkgo biloba, 587 hormone replacement therapy (HRT), 497 implantable contraceptives, 501 iptifibatide, 366 levonorgestrel, 506 misoprostol, 490 polyethylene glycol, 375 stem cells, 347 vitamin K1 , 355–356 blepharoptosis botulinum toxin A, 156 blindness see vision loss bloating sodium picosulfate, 377 blood glucose monitoring immunoglobulins, 344 blood group incompatibility blood transfusion, 339 blood pressure increase glibenclamide, 530 body pain ivermectin, 323 levamisole, 324 bone marrow aplasia interferon alfa, 389 thiabendazole, 320 bone marrow granuloma amiodarone, 186 bone marrow loss valproate, 98 bone marrow suppression tacrolimus, 455 bone mineral loss glucocorticoids, inhaled, 170 gonadotropins, 539 systemic glucocorticoids, 484–485 tenofovir, 305
thyroid hormones, 520 bone pain aluminium, 226 cytarabine, 555 borderline personality disorder heroin, 46 bowel perforation colonic irrigation, 591 polyethylene glycol, 375 bradycardia glyceryl trinitrate, 195 linezolid, 267 octreotide, 541 pertussis vaccines, acellular, 331 remifentanil, 109 sulfur hexafluoride, 579 thiabendazole, 320 bradycardia, fetal intrathecal (spinal) anesthesia, 138 bradydysrhythmia metformin, 527 brain injury minocycline, 248 brain structure deterioration metamfetamine, 4 brawny skin heroin, 47 breast cancer gonadotropins, 494 hormone replacement therapy (HRT), 497–498 breast cancer, male finasteride, 512 phytoestrogens, 588 breast fibroadenoma ciclosporin, 430 breast fibrosis tamoxifen+radiotherapy, 505 breast pain antiandrogens, 511 bicalutamide, 513 breast tenderness hormonal contraceptives, 500 breast tension levosulpride, 371 breathlessness water-soluble iodinated contrast agents, 578 bronchiolitis obliterans organizing pneumonia (BOOP) cytarabine, 555 interferon alfa, 387 sirolimus (rapamycin), 450 tacrolimus, 453 bronchitis leflunomide, 439 bronchospasm alemtuzumab, 404 patent blue, 608 sodium metabisulfite, 611
647
Index of adverse effects Brugada syndrome cocaine, 39, 44 flecainide, 188 bruising botulinum toxin A, 156 glucocorticoids, inhaled, 169–170 bullae coumarin anticoagulants, 359 heroin, 47 burning clindamycin, 263 pimecrolimus, 449 tacrolimus, 456 burns garlic, 585 C calcinosis interferon alfa, 391 calcium excretion desmopressin, 543 cancer Aristolochia species, 585 candidiasis systemic glucocorticoids, 485 Capgras syndrome diazepam, 54 capillary leak syndrome acitretin, 158 anagrelide, 364 cardiac see also entries at coronary–; heart– cardiac arrest see also myocardial infarction heparins, 361 iron, 229 sulfur hexafluoride, 579 vasopressin, 542 cardiac depression remifentanil, 109 cardiac dysfunction nimodipine, 199 vasopressin, 542 cardiac failure anthracyclines, 566 cardiac hypokinesis Ephedra and ephedrine, 149 cardiac hyposensitivity metamfetamine, 3 cardiac ischemia alemtuzumab, 404 cardiac output reduction hemoglobin-based oxygen carriers, 340 cardiac tamponade acupuncture, 590 cardiogenic shock acupuncture, 590 fluorouracil, 557 cardiomegaly anabolic steroids, 509
cardiomyopathy chloroquine, 294 Ephedra and ephedrine, 149 cardiopulmonary arrest nicotine, 610 cardiopulmonary syndrome rituximab, 410 cardiotoxicity bupivacaine, 141 capecitabine, 554 chloroprocaine, 141 cardiovascular events celecoxib, 121 carpal spasm sodium phosphate, 377 carpal tunnel syndrome somatropin, 541 cataract chlorhexidine, 242 finasteride, 157, 512 tamoxifen, 504 catheter phlebitis vancomycin, 261 celiac disease interferon alfa, 389 cellulite infiltration anesthesia, 138 central pontine myelinolysis ciclosporin, 427 central serous chorioretinopathy systemic glucocorticoids, 481–482 cerebellar ataxia topical anesthesia, 140 cerebral blood flow deficit doxapram, 9 intrathecal (spinal) anesthesia, 137 cerebral hemorrhage phosphodiesterase type V inhibitors, 203 tacrolimus, 454 cerebral infarction methylphenidate, 10 Chagas’ disease blood transfusion, 339 chest pain acupuncture, 590 adenosine, 185 alemtuzumab, 404 cytarabine, 555 dapsone, 316 desmopressin, 543 fluorouracil, 557 immunoglobulins, 343 melatonin, 542 methotrexate, 561 phosphate, 375 chest tightness glatiramer acetate, 435 Cheyne–Stokes respiration diuretics, 219
chills alemtuzumab, 404 co-trimoxazole, 298 immunoglobulins, 343 nystatin, 290 phosphate, 375 rituximab, 410 choanal atresia carbimazole, 521 cholangitis tenoxicam, 125 cholestasis parenteral nutrition, 353 ticlopidine, 366 cholestatic hepatitis erythromycin, 265 Teucrium polium, 588 cholestatic jaundice amiodarone, 186 cholestatic liver disease mercaptopurine, 553 cholesterol concentration increase basiliximab, 407 doxepin, 19 everolimus, 434 gonadotropins, 539 lopinavir+ritonavir, 308 saquinavir, 309 sirolimus (rapamycin), 451 chorea amphetamines, 2 hormonal contraceptives, 500 choroidal detachment latanoprost, 489 chromonychia telmisartan, 212 chronic obstructive pulmonary disease aluminium, 225 Churg–Strauss syndrome leukotriene receptor antagonists, 174–175 circulatory failure quinine, 297 clear-cell carcinoma of the cervix diethylstilbestrol, 495 clonus Illicium anisatum, 588 Clostridium difficile infection ranitidine, 373 coagulopathy etherified starches, 341 levofloxacin, 257 coccidioidomycosis infliximab, 396 coenzyme Q10 inhibition statins, 547 cognitive impairment cannabinoids, 37–38 interferons, 385 lithium, 32 metamfetamine, 3–6
648 methotrexate, 561 promazine, 61 statins, 547 tamoxifen, 504 cogwheel rigidity antipsychotics, 63 collagen vascular disease collagen, 603 colon cancer azathioprine, 425 color vision impairment deferoxamine, 238 tamoxifen, 504 coma diuretics, 219 tacrolimus, 453 combativeness topiramate, 96 complement activation antithymocyte globulin, 342 perfluorocarbons, 340 confusion diazepam, 55 fluorouracil, 557 melatonin, 542 methotrexate, 561 nalmefene, 112 promazine, 61 congestive heart failure alemtuzumab, 404 conjuctival pigmentation ocular dyes, 606 conjunctivitis cytarabine, 555 dapsone, 315 consciousness, impaired loperamide, 374 constipation aciclovir, 301 alosetron, 372 amisulpride, 71 anidulafungin, 289 antipsychotics, 60 basiliximab, 407 clozapine, 66 diazepam, 55 ephedrine, 12 granisetron, 373 liraglutide, 529 lormetazepam, 56 meglitinides, 529 olanzapine, 61 promazine, 61 risperidone, 61 vitamin D analogues, 354 contact allergy aminolevulinic acid, 158 local anesthetics, 135 sodium metabisulfite, 611 VP-eicosene copolymer, 157 contact dermatitis azithromycin, 264 Cinnamonum camphora, 586 colophony, 156–157
Index of adverse effects dorzolamide, 221 gold, 228–229 contact stomatitis manganese, 230 convulsions diazepam, 55 MDMA, 9 ropivacaine, 142 copper deficiency parenteral nutrition, 353 zinc, 232 corneal chrysiasis gold, 229 corneal edema brinzolamide, 221 coronary see also entries at cardi–; heart– coronary artery disease coagulation proteins, 345 coronary artery rupture amfetamine, 2 coronary artery spasm sotalol, 195 coronary heart disease anabolic steroids, 510 coronary perforation systemic glucocorticoids, 480 cortical blindness tacrolimus, 454 cortisol reduction alprazolam, 51–52 cotton–wool spots interferon alfa, 388 cough angiotensin II receptor antagonists, 211 benazepril, 209 beta2 -adrenoceptor agonists+ anticholinergics, 177 colistin, 268 cytarabine, 555 dapsone, 316 emtricitabine, 304 fluconazole+nitrofurantoin, 285 glucocorticoids, inhaled, 168 infliximab, 400 insulin, inhaled, 524 interleukin-2 (IL-2), 394 leflunomide, 439 lidocaine, 188 methotrexate, 561 nitrofurantoin, 266 rituximab, 412 tacrolimus, 453 talc, 612 crackles gemcitabine, 559 cramps, abdominal influenza vaccine, 333 levamisole, 462 mycophenolate mofetil, 447
cramps, leg valsartan, 213 Crohn’s disease etanercept, 397 cryoglobulinemia-associated vasculitis interferon alfa, 390 Cryptococcus albidus infection ciclosporin, 430–431 Cryptococcus neoformans pneumonia infliximab, 403 Cunninghamella bertholletiae infection tacrolimus, 457 Cushingoid facies ciclosporin, 426–427 cutaneous lupus erythematosus terbinafine, 280 cutaneous vasculitis etanercept, 398 cutis laxa penicillamine, 239 cytarabine syndrome cytarabine, 555 cytomegalovirus infection antithymocyte globulin, 341, 343 cytomegalovirus reactivation alemtuzumab, 404, 405 D dapsone hypersensitivity syndrome dapsone+pyrimethamine, 296 Darier’s disease interferon alfa, 390 deafness azithromycin, 264 deferoxamine, 237 death antithymocyte globulin, 343 buflomedil, 202 cocaine, 41 drotrecogin alfa, 338 erythromycin, 266 fentanyl, 106 fluorouracil, 557 gentamicin, 254 iron, 229 lithium, 30 metformin+sulfonylureas, 534 methylenedioxymetamfetamine, 8–9 opioids, 44–46 risperidone, 80 somatropin, 540 vesnarinone, 183 vitamin E, 355 deep tendon reflex increase Illicium anisatum, 588 deep vein thrombosis antithymocyte globulin, 341
649
Index of adverse effects erythropoietin and derivatives, 346 immunoglobulins, 344 parecoxib, 122 dehydration fluorouracil, 557 delirium diphenhydramine, 163 diphenhydramine+linezolid, 268 ketamine, 131 sevoflurane, 129 systemic glucocorticoids, 483 delusions zonisamide, 100 demyelinating polyneuropathy cytarabine, 556 demyelinating polyradiculoneuropathy ciclosporin, 428 demyelination fludarabine, 564 infliximab, 398, 400 depression anabolic steroids, 509 fluoroquinolones, 254 heroin, 46 infliximab, 399 interferon alfa, 384, 392 interferon beta, 385 metamfetamine, 4 pentostatin, 565 perphenazine, 75 risperidone, 76, 80 systemic glucocorticoids, 481, 483 valsartan, 213 vancomycin, 261 zonisamide, 100 depressive–catatonic state systemic glucocorticoids, 483 dermatitis see also contact dermatitis; eczematous dermatitis; exfoliative dermatitis aluminium, 225 amlodipine, 196 erythropoietin and derivatives, 347 progestogens, 505 sirolimus (rapamycin), 450 vitamin K1 , 356 dermatomyositis statins, 547 desquamation interferon alfa, 390 miltefosine, 563 voriconazole, 287 diabetes insipidus lithium, 31 olanzapine, 75 tenofovir, 304 diabetes mellitus antithymocyte globulin, 342
ciclosporin, 428 interferon alfa, 388 mexiletine, 189 olanzapine, 74 somatropin, 540 thiazide diuretics, 221 diabetes mellitus, type 1 childhood immunization, 327 tacrolimus, 454 diarrhea acarbose, 526 anagrelide, 364 Andrographis paniculata, 585 azithromycin, 264 bisphosphonates, 602 ciprofloxacin, 255 cisapride, 371 clarithromycin, 265 coagulation proteins, 346 diazepam, 55 donepezil+sertraline, 12 duloxetine, 23 entacapone, 153 erythromycin, 265 fluoroquinolones, 254 fluorouracil, 557, 558 flutamide, 511, 513 fosmidomycin, 272 fusidic acid, 259 gatifloxacin, 256 gemifloxacin, 256 immunoglobulins, 343 influenza vaccine, 333 ivermectin, 324 Jackyakamcho-tang, 583 ketolides, 262 lactulose and lactitol, 375 leflunomide, 438, 440 levamisole, 462 liraglutide, 529 macrolide antibiotics, 264 methotrexate, 561 micafungin, 290 mifepristone, 506, 507 miglitol, 526 misoprostol, 490 moxifloxacin, 257 mycophenolate mofetil, 446 pemetrexed, 562 praziquantel, 324 quinidine, 189, 190 raltitrexed, 563 sirolimus (rapamycin), 451 sodium picosulfate, 377 tacrolimus, 455 tegafur, 560 digital clubbing rituximab, 412 diplopia see double vision disagreeable taste polyethylene glycol, 375 disc herniation spinal manipulation, 592
discomfort spinal manipulation, 592 disequilibrium zonisamide, 100 disorientation cannabinoids, 35 diazepam, 55 diuretics, 219 fluorouracil, 557 lorazepam, 55 disseminated encephalomyelitis Japanese encephalitis vaccine, 334 diverticular abscess perforation systemic glucocorticoids, 484 dizziness 5-HT3 receptor antagonists, 372 adenosine, 185 azithromycin, 264 cannabinoids, 35 chloroquine, 294 cisapride, 371 clozapine, 66, 71 coagulation proteins, 346 daptomycin, 271 dronabinol, 36 droperidol, 69 duloxetine, 23 ephedrine, 12 exenitide, 529 fluoroquinolones, 254 gabapentin, 89 gatifloxacin, 256 granisetron, 372 immunoglobulins, 343 ivermectin, 324 lamotrigine, 92 levetiracetam, 92 lorazepam, 55 mefloquine, 295 melatonin, 542 moxifloxacin, 257 nalbuphine, 111 nalmefene, 112 olanzapine, 61 parathyroid hormone, 542 phosphate, 375 risperidone, 77, 80 sitaxsentan, 214 spironolactone, 222 tiagabine, 95 tramadol, 110 valproate, 99 zonisamide, 100 double vision (diplopia) cannabinoids, 36 carbamazepine+fluconazole, 282 lamotrigine, 90 lidocaine, 142 ocular anesthesia, 139 dream disturbance ketamine, 131
650 dreams, abnormal efavirenz, 305 dreams, bad fluoroquinolones, 254 driving ability impairment carisoprodol, 146 lorazepam, 55 drooling clozapine, 66 drowsiness 5-HT3 receptor antagonists, 372 cannabinoids, 35, 36 dextromethorphan, 105 diethylcarbamazine, 322 droperidol, 69 lamotrigine, 92 levetiracetam, 92 lormetazepam, 56 melatonin, 542 methylene blue, 610 nalbuphine, 111 pentostatin, 565 pethidine, 109 risperidone, 76 sultiame, 95 zaleplon, 54 drug hypersensitivity syndrome teicoplanin, 261 drug malabsorption polyethylene glycol, 375 drug resistance ivermectin, 323 drug tolerance virginiamycin, 273 dry mouth antipsychotics, 60 cannabinoids, 35 duloxetine, 23 ephedrine, 12 haloperidol, 66 lormetazepam, 56 naltrexone, 112 nefopam, 112 olanzapine, 72 promazine, 61 quetiapine, 29, 76 tiotropium bromide, 174 dry skin amlodipine, 196 leflunomide, 441 miltefosine, 563 duodenitis ciclosporin, 429 dysgeusia clarithromycin, 265 ketolides, 262 dyskinesia haloperidol, 61 dyslipidemia thiazide diuretics, 221 dyspepsia azithromycin, 264 bisphosphonates, 602
Index of adverse effects clarithromycin, 265 leflunomide, 440 risperidone, 61, 77 dysphagia mycophenolate mofetil, 446 dysphonia beta2 -adrenoceptor agonists, 176 collagen, 603 glucocorticoids, inhaled, 168 mometasone furoate, 171 dysphoria antipsychotics, 63 cannabinoids, 36 naltrexone, 112 dyspnea acupuncture, 590 adenosine, 185 alemtuzumab, 404 amiodarone, 186 blood transfusion, 339 cytarabine, 555, 556 dapsone, 316 diazepam, 55 fluconazole+nitrofurantoin, 285 fludarabine, 564 flutamide, 513 gemcitabine, 559 immunoglobulins, 343 infliximab, 400 methotrexate, 561 nitrofurantoin, 266 oxazaphosphorines, 566 tacrolimus, 453 talc, 612 dysrhythmia alemtuzumab, 404 amiodarone, 185 Ephedra and ephedrine, 149 fluorouracil, 557 heparins, 361 hydroxyzine, 163 lithium, 30 milrinone, 183 quinidine, 190 dystonia antipsychotics, 63 haloperidol, 61, 72 interferon alfa, 387 dysuria C31G, 605 E ecchymoses coumarin anticoagulants, 358 eczema gold, 228 immunoglobulins, 344 infliximab, 400 interferon alfa, 390 leflunomide, 441 edema see also angioedema
acitretin, 158 albendazole, 321 amlodipine, 195 anagrelide, 364 basiliximab, 407 dapsone, 315 enfuvirtide, 310 insulin, 523–524 interferon alfa, 391 isosulfan blue dye, 608 ivermectin, 323 Jackyakamcho-tang, 583 lercanidipine, 197 methadone, 47 mexiletine, 189 nifedipine, 199 rituximab, 411 sirolimus (rapamycin), 450 sitaxsentan, 213 somatropin, 541 tacrolimus, 453 ejaculate volume reduction finasteride, 157, 512 ejaculatory dysfunction risperidone, 79 elastoma penicillamine, 239 electrocardiographic changes see QT interval prolongation electrolyte imbalance bisphosphonates, 602 colonic irrigation, 591 sodium phosphate, 376 emesis see vomiting emotional lability diazepam, 55 levetiracetam, 92 systemic glucocorticoids, 483, 484 encephalitis blood transfusion, 339 mycophenolate mofetil, 445 encephalomyelitis Japanese encephalitis vaccine, 334 encephalopathy tacrolimus, 454 topiramate+valproic acid, 97 valproate, 97 end-stage renal disease diuretics, 220 endometrial cancer hormone replacement therapy (HRT), 498 tamoxifen, 504–505 enervation zonisamide, 100 enterocholic lymphocytic phlebitis flutamide, 513 enterocolitis levetiracetam, 92 enuresis
651
Index of adverse effects clobazam, 53 zonisamide, 100 eosinophilia disulfiram, 605 dobutamine, 151 erythromycin, 265 teicoplanin, 261 terbinafine, 280 eosinophilic pneumonia levofloxacin epidermal necrolysis chloroquine, 295 epigastralgia lercanidipine, 197 epigastric pain diethylcarbamazine, 322 irbesartan, 212 triclabendazole, 321 VSL#3, 379 epistaxis see nosebleed epithelioid granulomata leuprorelin, 539 Epstein–Barr virus infection antithymocyte globulin, 341 erectile dysfunction anagrelide, 365 cyproterone acetate, 510 finasteride, 157 erectile failure SSRIs, 21–22 erosions, gastrointestinal sodium phosphate, 377 erythema alprostadil (prostaglandin E1 ), 487–488 amlodipine, 196 azathioprine, 426 captopril, 210 chlorhexidine, 241 clindamycin, 263 clofarabine, 551 enfuvirtide, 310 interferon alfa, 390 isosulfan blue dye, 608 mexiletine, 189 miltefosine, 563 voriconazole, 287 erythema multiforme amlodipine, 196 candesartan, 212 fluoroquinolones, 255 metformin, 527 phenytoin, 94 terbinafine, 280 trimethoprim, 271 erythema multiforme-like eruption leflunomide, 441 erythema nodosum infliximab, 401 erythema toxicum terbinafine, 280 erythrocytosis
sirolimus (rapamycin), 451 erythroderma ethylenediamine, 606 fluoroquinolones, 255 flutamide, 513 esophagitis ciclosporin, 429 fluorouracil, 558 tamsulosin, 214 euphoria cannabinoids, 36 diazepam, 54 lidocaine, 142 systemic glucocorticoids, 483, 484 exanthematous pustulosis pseudoephedrine, 150 exanthems ethylenediamine, 606 fluoroquinolones, 255 excitability systemic glucocorticoids, 483 executive function impairment interferons, 385 exercise intolerance statins, 547 exfoliative dermatitis ethylenediamine, 606 leflunomide, 441 extrapyramidal symptoms amisulpride, 71 antipsychotics, 63 haloperidol, 66 perphenazine, 75 promazine, 61 pyrimethamine+sulfadoxine, 296 risperidone, 61, 77 tiagabine, 95 valproate, 97 extremity pain coagulation proteins, 345 F facial edema sirolimus (rapamycin), 450 factor VIII antibodies coagulation proteins, 345–346 factor XIII deficiency valproate, 98 Fanconi syndrome Aristolochia species, 585 tenofovir, 304 valproate, 98 fat embolism amphotericin B lipid complex (ABLC), 281 fatigue albendazole, 321 aluminium, 226 anagrelide, 364 Andrographis paniculata, 585 azithromycin, 264 cannabinoids, 35
cytarabine, 556 fluconazole+nitrofurantoin, 285 gonadorelin antagonists, 539 mefloquine, 295 nitrofurantoin, 266 phosphate, 375 spinal manipulation, 592 suramin, 325 troxacitabine, 560 VSL#3, 379 fatty liver disease, non-alcoholic valproate, 98 fear sensation sultiame, 95 febrile neutrophilic dermatosis norfloxacin, 258 feeling of intoxication cannabinoids, 35 fetal malformation valproate, 99 fever albendazole, 321 alemtuzumab, 404 antithymocyte globulin, 341 antituberculosis drugs, 315 artemisinin derivatives, 320 blood transfusion, 339 calcium dobesilate, 202 cladribine, 564 co-trimoxazole, 298 coagulation proteins, 346 cytarabine, 555, 556 dapsone, 316 daptomycin, 271 desmopressin, 543 diethylcarbamazine, 322 erythromycin, 265 everolimus, 434 heroin, 47 immunoglobulins, 343 infliximab, 400 interferon gamma, 394 ivermectin, 323 leflunomide, 439 lentinan, 463 methotrexate, 561 methylenedioxymetamfetamine, 8 micafungin, 290 mifepristone, 507 misoprostol, 490 norfloxacin, 258 octreotide, 541 picibanil, 463 pneumococcal vaccine, 332 pyrimethamine+dapsone, 296 rituximab, 410 sirolimus (rapamycin), 452 teicoplanin, 261 tretinoin, 159 zonisamide, 100
652 fibroblast activity reduction ciprofloxacin, 255 fibrosis nitrofurantoin, 266 fibrotic reaction cabergoline, 152 fingernail clubbing telmisartan, 212 fixed drug eruption articaine, 140 clarithromycin, 265 fluoroquinolones, 255 influenza vaccine, 333 trimethoprim, 271 vancomycin, 261 flank pain polyvinylpyrrolidone, 243 flatulence acarbose, 526 anagrelide, 364 azithromycin, 264 esomeprazole, 374 lactulose and lactitol, 375 flu-like symptoms gemcitabine, 559 interferon gamma, 394 levamisole, 462 mycophenolate mofetil, 445 fluid retention anagrelide, 364 flushing adenosine, 185 aluminium, 225 calcitonin, 539 epoprotenol, 488 glatiramer acetate, 435 immunoglobulins, 343 isosulfan blue dye, 608 tacrolimus, 456 focal fibrosis sirolimus (rapamycin), 450 follicle stimulating hormone (FSH) increase sirolimus (rapamycin), 450 folliculitis lithium, 31 folliculodystrophy ciclosporin, 429 foreign-body granuloma cosmetic fillers, 604 fractures antiandrogens, 511 systemic glucocorticoids, 484–485 fungal infection daclizumab, 409 infliximab, 403 pimecrolimus, 449 tacrolimus, 457 G gait instability carbamazepine+fluconazole, 282
Index of adverse effects methylene blue, 610 galactorrhea antipsychotics, 60 divalproex+lithium, 28 levosulpride, 371 olanzapine, 73 gallstones hormone replacement therapy (HRT), 497 gangrene coumarin anticoagulants, 359 garlic smell selenium, 231 gasping syndrome clindamycin, 263 gastric distress anagrelide, 364 gastric emptying delay diamorphine, 106 gastric pain albendazole, 320 prulifloxacin, 259 gastric pH increase tramadol, 110–111 gastritis ciclosporin, 429 gastroenteritis infliximab, 403 leflunomide, 440 gastrointestinal damage polystyrene sulfonates, 239 gastrointestinal discomfort fusidic acid, 259 gastrointestinal hemorrhage terbinafine, 280 gastrointestinal intolerance sparfloxacin, 259 gastrointestinal perforation bevacizumab, 408 interleukin-2 (IL-2), 394–395 genital condylomata acuminata infliximab, 400, 403 genitoperineal numbness cocaine, 141 germ-line transmission coagulation proteins, 346 giant cell arteritis etanercept, 398 Giardia lamblia infection ranitidine, 373 gingival hyperplasia diltiazem, 196 gingival overgrowth ciclosporin, 426–427, 428 phenytoin, 94 gingivitis methotrexate, 561 gland pain ivermectin, 323 glaucoma topiramate, 96 global amnesia cannabinoids, 37
glomerulonephritis etanercept, 398 sirolimus (rapamycin), 451–452 glossitis methotrexate, 561 glottal edema loratadine, 164 glucose concentration clobazam, 53 glucose intolerance hormone replacement therapy (HRT), 496 somatropin, 541 gluteal abscess chloroquine, 295 glycosuria tenofovir, 304 glycosylated hemoglobin increase metoprolol, 194 gout tacrolimus, 454 graft dysfunction tacrolimus, 455 graft-vs.-host disease blood transfusion, 339 stem cells, 347 granulocytopenia clozapine, 68 deferiprone, 237 troxacitabine, 560 green urine levosulpride, 371 growth restriction systemic glucocorticoids, 481 growth velocity reduction glucocorticoids, inhaled, 170 Guillain–Barré syndrome hepatitis A vaccine, 332 influenza vaccine, 333 isotretinoin, 158 meningococcal vaccine, 331 statins, 547 guttate psoriasis methylenedioxymetamfetamine, 8 gynecomastia antiandrogens, 511 bicalutamide, 513 cetirizine, 162 efavirenz, 305 finasteride, 157–158, 511, 512 flutamide, 513 phytoestrogens, 588 somatropin, 541 H hair loss see alopecia hallucinations bisphosphonates, 602–603 cannabinoids, 35 fluoroquinolones, 254
653
Index of adverse effects zonisamide, 100 hallucinations, auditory meclozine, 165 voriconazole, 287 hallucinations, kinesthetic chloroquine, 294 hallucinations, tactile methylphenidate, 10 hallucinations, visual anagrelide, 364 methylphenidate, 10 mycophenolate mofetil, 445 voriconazole, 287 harlequin color change alprostadil (prostaglandin E1 ), 487–488 headache 5-HT3 receptor antagonists, 372 adenosine, 185 albendazole, 320, 321 anagrelide, 364 Andrographis paniculata, 585 artemisinin derivatives, 320 azithromycin, 264 basiliximab, 407 beta2 -adrenoceptor agonists+ anticholinergics, 176 botulinum toxin A, 156 chloroquine, 294 ciclosporin, 428 cisapride, 371 clarithromycin, 265 cytarabine, 556 daptomycin, 271 desmopressin, 543 diethylcarbamazine, 322 dipyridamole, 365–366 dronabinol, 36 droperidol, 69 ephedrine, 12 esomeprazole, 374 fluoroquinolones, 254 gatifloxacin, 256 gonadorelin antagonists, 539 granisetron, 372 hormonal contraceptives, 500 immunoglobulins, 343 infliximab, 401 irbesartan, 212 ivermectin, 323 lamotrigine, 90, 92 lercanidipine, 197 levamisole, 324 levosulpride, 371 liraglutide, 529 lormetazepam, 56 meglitinides, 529 melatonin, 542 methotrexate, 561 micafungin, 290 mifepristone, 506 mometasone furoate, 171 naltrexone, 112
nateglinide, 529 olanzapine, 72 parathyroid hormone, 542 phosphate, 375 phosphodiesterase type V inhibitors, 203 praziquantel, 324 quinine, 297 risperidone, 76, 80 rituximab, 411 saw palmetto, 512 sitaxsentan, 213 somatropin, 541 spinal manipulation, 592 sultiame, 95 tramadol, 110 VSL#3, 379 zafirlukast, 176 zonisamide, 100 hearing loss erythromycin, 265 gentamicin, 253 interferon alfa, 388 propylthiouracil, 521 heart see also coronary–; entries at cardi– heart beat see cardiac dysrhythmias; tachycardia; specific conditions, such as sinus node dysfunction heart block amiodarone, 185 octreotide, 541 heart failure anabolic steroids, 509 etanercept, 397 infliximab, 398 heart rate increase ephedrine, 12 heart rate reduction epidural anesthesia, 136 FTY720, 434 heartburn azithromycin, 264 hemangioma hormonal contraceptives, 500 hematemesis mycophenolate mofetil, 447 selenium, 231 hematological abnormalities coagulation proteins, 346 hematoma acupuncture, 589 hemiparesis acupuncture, 589 cannabinoids, 36 tacrolimus, 454 hemocolpometra hormone replacement therapy (HRT), 499 hemolysis methylene blue, 610
teicoplanin, 260 hemolytic anemia, autoimmune blood transfusion, 339 glibenclamide, 530 hemolytic–uremic syndrome gemcitabine, 559 tacrolimus, 455 hemopericardium acupuncture, 590 hemophagocytic syndrome lamotrigine, 90 tretinoin, 159 hemophilia chlorphenamine, 162 hemophilia, acquired anagrelide, 365 hemopneumothorax methylenedioxymetamfetamine, 6–7 hemoptysis bevacizumab, 408 hemorrhage bevacizumab, 408 drotrecogin alfa, 338 hemorrhagic cystic mastopathy tibolone, 514 hepat– see also entries at liver– hepatic artery stenosis interferon alfa, 392 hepatic artery thrombosis sirolimus (rapamycin), 450 hepatic cirrhosis amiodarone, 186 hepatic dysfunction cytarabine, 556 hepatic enlargement anabolic steroids, 509 hepatic failure daclizumab, 409 hepatic insufficiency dapsone, 316 hepatic toxicity trimethoprim, 270 hepatic veno-occlusive disease gemtuzumab ozogamicin, 409 hepatitis acupuncture, 589 alfuzosin, 214 Asian herbal medicines, 583 atorvastatin, 548 cetirizine, 161–162 Cimicifuga racemosa, 586 coagulation proteins, 346 disulfiram, 605 HEXAVAC, 330 isoniazid, 317 nevirapine, 305 quinidine, 189 sevoflurane, 130 thiabendazole, 320 trichloroethylene, 130
654 hepatitis, autoimmune tacrolimus, 455 hepatitis B reactivation ciclosporin, 430 fludarabine, 564 rituximab, 412 hepatocellular injury anagrelide, 365 hepatomegaly insulin, 524 hepatosplenomegaly dapsone, 315 hepatotoxicity alverine citrate, 371 amiodarone, 186 amlodipine, 196 azacitadine, 554 caspofungin, 289 coagulation proteins, 346 cocaine, 40–41 cytosine arabinoside+dipyridamole, 366 fenfluramines, 11 flutamide, 511 levamisole, 462 lopinavir+ritonavir, 308 mercaptopurine, 552–553 methotrexate, 561 nevirapine, 306 parenteral nutrition, 353 pioglitazone, 533 repaglinide, 529–530 SSRIs, 21 sirolimus (rapamycin), 451 trimethoprim, 271 herpes simplex virus infection infliximab, 403 herpes zoster infection arsenic, 227 mycophenolate mofetil, 446 hidradenitis aluminium, 225 hippocampal stroke cocaine, 40 hirsutism anabolic steroids, 509 ciclosporin, 426–427 H5N1 pandemic influenza vaccine, 332 hoarding behavior antipsychotics, 60 hoarseness beta2 -adrenoceptor agonists, 176 collagen, 603 glucocorticoids, inhaled, 168 homocysteine concentration levodopa, 152 hospitalization ciclosporin, 433 hostility anabolic steroids, 509 levetiracetam, 92
Index of adverse effects hot flashes coagulation proteins, 346 idoxifene, 502–503 raloxifene, 503 tamoxifen, 505 human parvovirus B19 infections immunoglobulins, 344 hunger ketogenic diet, 89 hunger pains phosphate, 375 hydrops propylthiouracil, 522 hyper-reflexia tramadol+venlafaxine, 24 hyperactivity paroxetine, 18 systemic glucocorticoids, 483 hyperammonemia valproate, 97–98 hyperbilirubinemia amphotericin B lipid complex (ABLC), 281 clofarabine, 551 mycophenolate mofetil, 447 tacrolimus, 455 tegafur, 560 hypercalcemia calcipotriol, 156 parathyroid hormone, 542 vitamin D analogues, 354 hyperglycemia clozapine, 67 gatifloxacin, 256 temsirolimus, 460 thiazide diuretics, 221 hyperkalemia aluminium, 226 basiliximab, 407 mannitol, 222–223 methylenedioxymetamfetamine, 8 sirolimus (rapamycin), 451 spironolactone, 222 tacrolimus, 454 trimethoprim, 270 hyperkinesia diazepam, 54 risperidone, 77, 80 hyperlactatemia NRTIs, 302–303 hyperlipidemia mycophenolate mofetil, 445 propofol, 133 hypernatremia sodium phosphate, 376 hyperostosis isotretinoin, 159 hyperparathyroidism lithium, 31 hyperphosphatemia sodium phosphate, 376, 377
hyperpigmentation amlodipine, 196 minocycline, 248–249 hyperprolactinemia amisulpride, 65–66 antipsychotics, 63–64 olanzapine, 73 risperidone, 78 hypersalivation antipsychotics, 60 clozapine, 66, 68 haloperidol, 72 hypersensitivity topiramate, 96 hypersensitivity pneumonia rituximab, 412 hypersensitivity pneumonitis dapsone, 316 infliximab, 399 hypersensitivity reaction abacavir, 303 adalimumab, 397 bryostatin 1, 461 calcitonin, 539 clarithromycin, 265 collagen, 603 enfuvirtide, 310 fondaparinux, 362 glibenclamide, 530 infliximab, 398 interferon beta, 393 lepirudin, 363 levofloxacin, 257 mexiletine, 188–189 moxifloxacin, 258 nevirapine, 305–306 paclitaxel, 566 trimethoprim, 271 hypersensitivity syndrome azithromycin, 264 dapsone, 315–316 valproate, 99 hypertension amlodipine, 195 basiliximab, 407 bevacizumab, 408 bisphosphonates, 602 bupropion+linezolid, 268 carisoprodol, 146 ciclosporin, 427 Ephedra and ephedrine, 149 ephedrine, 11 erythropoietin and derivatives, 346 infliximab, 401 leflunomide, 438, 439 linezolid, 267 Panax ginseng, 588 pseudoephedrine, 149 Qing zhisan tain shou, 584 sibutramine, 11 water-soluble iodinated contrast agents, 574
655
Index of adverse effects hyperthermia caffeine+paroxetine, 1 water-soluble iodinated contrast agents, 574 zonisamide, 100 hyperthyroidism amiodarone, 186 water-soluble iodinated contrast agents, 574 hypertonia fluphenazine, 71 haloperidol, 72 hypertrichosis latanoprost, 489 hyperuricemia itraconazole, 286 mizoribine, 445 tacrolimus, 454 hyperventilation sultiame, 95 hypoalbuminemia mycophenolate mofetil, 447 hypocalcemia gadolinium salts, 578 nifedipine, 198 sodium phosphate, 376, 377 hypochondria zonisamide, 100 hypochromic anemia aluminium, 226 hypogammaglobulinemia rituximab, 411 hypoglycemia ciprofloxacin+glibenclamide, 255, 530–531 exenitide, 529 gatifloxacin, 256 glibenclamide, 530 gliclazide, 531 incretin mimetics, 528 insulin, 523 insulin, inhaled, 525 levofloxacin, 257 metformin, 526 pramlintide, 526 salbutamol, 173 hypohidrosis zonisamide, 100 hypokalemia chloroquine, 295 insulin, 523 itraconazole, 286 sodium phosphate, 376 sodium picosulfate, 377 topiramate, 96 hypolipoproteinemia rosiglitazone, 534 hypomagnesemia sodium phosphate, 376 hypomania olanzapine, 73 St. John’s wort, 587 systemic glucocorticoids, 484
hyponatremia carbamazepine+ hydrochlorothiazide, 88 citalopram, 21 desmopressin, 543 diuretics, 219–220 heroin, 47 levetiracetam, 93 mycophenolate mofetil, 445 SSRIs, 21 tacrolimus, 454 vasopressin, 542 hypophosphatemia basiliximab, 407 temsirolimus, 460 tenofovir, 304 hypopyon systemic glucocorticoids, 482 hypospadias loratadine, 164 hypotension adenosine, 185 alemtuzumab, 404 amiodarone, 185 anidulafungin, 289 blood transfusion, 339 chloroquine, 295 co-trimoxazole, 298 diazepam, 55 epidural anesthesia, 135–136 fluorouracil, 557 glyceryl trinitrate, 195 iloprost, 489 immunoglobulins, 343 infliximab, 401 intrathecal (spinal) anesthesia, 137 isosulfan blue dye, 608 lercanidipine, 197 lisinopril+tizanidine, 211 lithium, 29–30 lormetazepam, 56 metformin, 526 octreotide, 541 patent blue, 608 promazine, 61 propofol, 128 remifentanil, 109 risperidone, 61, 77 ropivacaine, 142 sodium phosphate, 376 sulfur hexafluoride, 579 hypothermia melatonin, 542 polyethylene glycol, 375 hypothyroidism amiodarone, 186, 187 infliximab, 403 lithium, 31, 32 water-soluble iodinated contrast agents, 574 hypotonia nicotine, 610
hypoxemia alemtuzumab, 404 blood transfusion, 339 dapsone, 316 fludarabine, 564 propofol, 128 talc, 612 hypoxia co-trimoxazole, 298 nifedipine, 198 I ichthyosis hystrix-like plaque interferon alfa, 390 imbalance lamotrigine, 92 immobility systemic glucocorticoids, 484 immune deficiency lamotrigine, 90 immune reconstruction disease antituberculosis drugs, 315 immunization interference immunoglobulins, 344 immunoglobin deficiency antiepileptic drugs, 88 immunosuppression blood transfusion, 339 ciclosporin, 430 impotence risperidone, 76 incoherence topiramate, 96 incontinence, urinary donepezil, 12–13 olanzapine, 73 zonisamide, 100 indigestion Jackyakamcho-tang, 583 induration enfuvirtide, 310 naltrexone, 112 infarctions see cerebral infarction; myocardial infarction infection basiliximab, 407 ciclosporin, 433 gemtuzumab ozogamicin, 409 infliximab, 399 leflunomide, 438 medication errors, 596 infection risk Nu Bao, 584 infectious mononucleosis infliximab, 403 infertility estrogens, 494–495 inflammatory reaction coagulation proteins, 346 infusion reaction infliximab, 398, 399, 401 infusion site reactions immunoglobulins, 344
656 inhibitor formation coagulation proteins, 346 injection site inflammation micafungin, 290 injection site pain amiodarone, 185 propofol, 132 injection site reaction daptomycin, 271 enfuvirtide, 310 erythropoietin and derivatives, 347 glatiramer acetate, 435 gonadorelin antagonists, 539 interferon alfa, 386, 391 Japanese encephalitis vaccine, 335 vitamin B12 (cobalamins), 354 INR decrease coumarin anticoagulants+ dicloxacillin, 360 coumarin anticoagulants+ ginseng, 360 coumarin anticoagulants+ St John’s wort, 361 INR increase azithromycin+macrolide antibiotics, 360 carnitine+coumarin anticoagulants, 360 coumarin anticoagulants+ laxatives, 360 coumarin anticoagulants+ NSAIDs, 360 fish oils, 588 ketolide antibiotics+ telithromycin, 360 Quilinggao, 584 warfarin+tramadol, 111 insertional mutagenesis coagulation proteins, 346 insomnia amisulpride, 71 cisapride, 371 daptomycin, 271 duloxetine, 23 efavirenz, 305 fluoroquinolones, 254 fluphenazine, 71 lamotrigine, 90, 92 lormetazepam, 56 mefloquine, 295 nalmefene, 112 paroxetine, 18 risperidone, 61, 79 insulin resistance gonadotropins, 539 indinavir, 307–308 internuclear ophthalmoplegia tacrolimus, 454 interstitial fibrosis ciclosporin, 429 interstitial lung disease leflunomide, 438
Index of adverse effects interstitial nephritis azithromycin, 264 interferon alfa, 390 leflunomide, 441 mesalazine, 378 interstitial pneumonia epoprotenol, 488 gemcitabine, 559 interferon alfa, 387 leflunomide, 439 lipiocis, 609–610 interstitial pneumonitis ciprofloxacin, 255 flutamide, 513 infliximab, 399–400 methotrexate, 561 nilutamide, 511 nitrofurantoin, 266 oxazaphosphorines, 566 rituximab, 410–411 sirolimus (rapamycin), 450 intestinal malrotation infliximab, 403 intestinal pain coagulation proteins, 346 intracerebral hemorrhage metamfetamine, 3 intracranial hemorrhage bevacizumab, 408 coumarin anticoagulants, 358 drotrecogin alfa, 338 gemtuzumab ozogamicin, 409 thrombolytic agents, 362 intracranial hypertension isotretinoin, 159 somatropin, 540 intracranial pressure increase parenteral nutrition, 353–354 suramin, 325 terlipressin, 544 intrahepatic cholestasis azithromycin, 264 intraocular pressure increase triamcinolone, intravitreal, 582 intrastromal deposits gatifloxacin, 256 iris atrophy chlorhexidine, 242 iris pigmentation increase latanoprost, 489 iritis bisphosphonates, 603 iron absorption esomeprazole+omeprazole, 374 iron deposition iron, 229 irritability gonadotropins, 540 ketogenic diet, 89 lamotrigine, 90 levetiracetam, 92 melatonin, 542 naltrexone, 112 systemic glucocorticoids, 483
zonisamide, 100 irritation C31G, 605 colistin, 268 ischemic colitis alosetron, 372 triptans, 203 ischemic digits vasopressin, 542 ischemic skin lesions vasopressin, 542 isometric tubular vacuolization immunoglobulins, 344 itching azithromycin, 264 chlorhexidine, 241 levamisole, 324 praziquantel, 324 zonisamide, 100 J jaundice albendazole, 321 azithromycin, 264 dapsone, 315 disulfiram, 605 erythromycin, 265 ethambutol, 317 hemoglobin-based oxygen carriers, 340 levetiracetam, 92–93 pioglitazone, 533 JC virus infection fludarabine, 564 jitteriness exenitide, 529 joint pain levamisole, 324 sirolimus (rapamycin), 450 K keratitis ocular dyes, 606 keratoacanthoma ciclosporin, 431 infliximab, 403 keratoconjunctivitis sicca acitretin, 158 kidney see also entries at nephro–; renal– kidney stones see nephrolithiasis knee pain tacrolimus, 456 koro-like syndrome amfetamine, 2 L lactic acidosis propofol, 132, 133 language delay cocaine, 43
657
Index of adverse effects left ventricular dysfunction anthracyclines, 566 leg pain acupuncture, 590 Legionella pnuemophila pneumonia infliximab, 402 lentigines PUVA, 158 lethargy diuretics, 219 ketogenic diet, 89 melatonin, 542 pentostatin, 565 raltitrexed, 563 leukemia azathioprine, 424 clofarabine, 551 leukocytoclastic vasculitis ciprofloxacin, 255 clarithromycin, 265 leukocytosis itraconazole, 286 leflunomide, 440 mycophenolate mofetil, 445 leukoencephalopathy tacrolimus, 453–454 leukopenia alemtuzumab, 405 antithymocyte globulin, 341 clozapine, 71 clozapine+topiramate, 69 cytarabine, 556 deferiprone, 237 doxazosin, 214 everolimus, 433 fluorouracil, 558 gemcitabine, 559 interferon alfa, 392 levamisole, 324, 462 linezolid, 267 mercaptopurine, 552 micafungin, 290 picibanil, 463 risperidone, 78 teicoplanin, 260 libido increase risperidone, 61 libido loss cyproterone acetate, 510 finasteride, 157, 511, 512 SSRIs, 21–22 lichen planus amlodipine, 196 copper, 228 mercury and mercurial salts, 230 lichenoid eruption lisinopril, 210 statins, 547 tenofovir, 304–305 lichenoid reaction leflunomide, 441
lightheadedness dextromethorphan, 105 fluorescein dye, 607 glibenclamide, 530 sodium phosphate, 376 limb swelling ivermectin, 323 linear immunoglobulin A bullous disease vancomycin, 261 lipid concentration antipsychotics, 64 lipid metabolism, altered sirolimus (rapamycin), 449 lipoatrophy glatiramer acetate, 435 insulin, 524 insulin lispro, 525 NRTIs, 302–303 lipoma rosiglitazone, 533 Listeria monocytogenes meningitis infliximab, 402 listeriosis fludarabine, 564 listlessness ketogenic diet, 89 lithium toxicity furosemide+lithium, 32 liver see also entries at hepat– liver damage bosentan, 213 ciprofloxacin, 255 Ephedra and ephedrine, 149 Larrea tridentata, 588 nitrofurantoin, 266 quinidine, 190 systemic glucocorticoids, 484 liver enlargement triclabendazole, 321 liver failure disulfiram, 605 etherified starches, 341 moxifloxacin, 258 raltitrexed, 563 Shubao slimming capsules, 584 trichloroethylene, 130 usnic acid, 589 liver hemangioma interferon alfa, 389 liver pain albendazole, 320 loose stools fosmidomycin, 272 ivermectin, 323 lupus erythematosus clozapine, 68 lupus-like syndrome infliximab, 398, 399, 402 minocycline, 249 statins, 548
luteinizing hormone (LH) increase sirolimus (rapamycin), 450 lymph node enlargement mexiletine, 189 lymphadenopathy antituberculosis drugs, 315 dapsone, 315 teicoplanin, 261 lymphedema silicone, 611 sirolimus (rapamycin), 451 lymphoblastic leukemia clofarabine, 551 tacrolimus, 457 lymphocytic alveolitis sirolimus (rapamycin), 450 lymphocytic dermatitis valsartan, 213 lymphocytic interstitial pneumonitis sirolimus (rapamycin), 450 lymphocytopenia antithymocyte globulin+pooled human immunoglobulin, 343 lymphoma ciclosporin, 431 infliximab, 398, 399, 403 leflunomide, 441 mycophenolate mofetil, 445–446 pimecrolimus, 449 tacrolimus, 458 tumor necrosis factor-alfa antagonists, 396–397 lymphomatoid papulosis verapamil, 200 lymphopenia antithymocyte globulin, 341 lymphoproliferative disorder alemtuzumab, 406 M macrophagic myofasciitis aluminium, 225 macular edema leflunomide, 440 macular exanthems terbinafine, 280 maculopapular eruptions azithromycin, 264 lithium, 31 maculopapular rash amlodipine, 196 mexiletine, 189 malaise cytarabine, 555 disulfiram, 605 glibenclamide, 530 pioglitazone, 533 zonisamide, 100 male pattern baldness anabolic steroids, 510
658 malignancy antithymocyte globulin, 343 malignant hyperthermia water-soluble iodinated contrast agents, 574 mania clarithromycin, 265 interferon alfa, 384 olanzapine, 73 risperidone, 77 St. John’s wort, 587 manic-depressive syndrome temsirolimus, 460 masturbation, compulsive gabapentin, 89 mediastinitis antithymocyte globulin, 342 medication errors anecdotal reports, 601 classification, 597 detection of, 599 prevention of, 599–601 reporting of, 599 sources of errors, 596–597 susceptibility factors, 601–602 megacolon lactulose and lactitol, 375 megaloblastic anemia trientine, 239 megaloblastosis cytarabine, 556 melanoma ciclosporin, 431 melena azithromycin, 264 memory impairment benzodiazepines, 51 cannabinoids, 37 diazepam, 55 fluorouracil, 557 interferons, 385 methylenedioxymetamfetamine, 7–8 systemic glucocorticoids, 481 zaleplon, 57 menstrual cycle alteration daclizumab, 409 tacrolimus, 457 mental status alteration amphotericin B lipid complex (ABLC), 281 mesenteric ischemia cardiac glycosides, 182 vasopressin, 542 mesothelial cyst gonadotropins, 494 metallic taste metronidazole, 321 metaphysis metaplasia deferoxamine, 237 metastasis ciclosporin, 431
Index of adverse effects methemoglobinemia benzocaine, 140–141 cetacaine, 141 co-trimoxazole, 298 topical anesthesia, 140 trimethoprim, 270 MI see myocardial infarction microalbuminuria metoprolol, 194 migraine sodium picosulfate, 377 miliary tuberculosis infliximab, 402 mineral balance sodium phosphate, 376 misdiagnosis piperacillin, 248 topical anesthesia, 140 mitochondrial toxicity NRTIs, 302–303 stavudine, 304 Möbius sequence ergot alkaloids, 203 monocytopenia fludarabine, 564 mood changes systemic glucocorticoids, 483 mood disturbance gonadotropins, 540 levetiracetam, 92 methylenedioxymetamfetamine, 7 Moraxella catarrhalis septic arthritis infliximab, 402 motor neuropathy infliximab, 400 motor slowing antiepileptic drugs, 87 motor vehicle accident cannabinoids, 37 lithium, 30 mucormycosis deferoxamine, 237 mucositis fluorouracil, 558 methotrexate, 561 tegafur, 560 temsirolimus, 460 multiple organ failure daclizumab, 409 muscle aches ivermectin, 323 muscle discomfort naltrexone, 112 muscle pain daptomycin, 272 muscle spasms carisoprodol, 146 muscle trauma ocular anesthesia, 139 mutism systemic glucocorticoids, 484
myalgia acitretin, 158 albendazole, 321 bryostatin 1, 461 cytarabine, 555 diethylcarbamazine, 322 dronabinol, 36 immunoglobulins, 343 interferon alfa, 391 leflunomide, 439 minocycline, 249 mycophenolate mofetil, 446 norfloxacin, 258 quinupristin/dalfopristin, 269 statins, 547, 548 valsartan, 213 myasthenia antiepileptic drugs, 87–88 mydriasis tramadol+venlafaxine, 24 myelitis alemtuzumab, 405 myeloblastic leukemia mercaptopurine, 553 myelodysplasia azathioprine, 424 clofarabine, 551 myelodysplastic syndrome mercaptopurine, 553 myeloid leukemia G-CSF, 384 myelopathy zinc, 232 myelosuppression cladribine, 564 decitabine, 557 fludarabine, 564 fluorouracil, 558 gemtuzumab ozogamicin, 409 levamisole, 462 linezolid, 267 mercaptopurine, 552 sirolimus (rapamycin), 449 tegafur, 560 myelotoxicity azathioprine, 424 myocardial infarction see also cardiac arrest adenosine, 185 bergamot, 586 clonidine, 214 coagulation proteins, 345 cocaine, 38 desmopressin, 543 Ephedra and ephedrine, 149 immunoglobulins, 343 parecoxib, 122 pseudoephedrine, 149–150 rofecoxib, 116–121 salbutamol, 172 sodium phosphate, 377 sulfur hexafluoride, 579 vasopressin, 542
659
Index of adverse effects myocarditis clozapine, 62 myoclonus antiepileptic drugs, 87 caffeine+paroxetine, 1 cannabinoids, 36 carisoprodol, 146 ciprofloxacin, 255 clozapine+lithium, 30 dobutamine, 150–151 Illicium anisatum, 588 tramadol+venlafaxine, 24 trimethoprim, 270 myofasciitis aluminium, 225 myoglobinuria statins, 547 myopathy interferon alfa, 391 myopia topiramate, 96 myositis ciclosporin, 430 tacrolimus, 456–457 myotoxicity ezetimibe, 546 N nasal congestion sitaxsentan, 214 nausea, 501 adenosine, 185 albendazole, 320 anagrelide, 364 anidulafungin, 289 antithymocyte globulin, 341 azithromycin, 264 basiliximab, 407 bisphosphonates, 602 bryostatin 1, 461 calcitonin, 539 carbamazepine+fluconazole, 282 ciclosporin, 433 ciprofloxacin, 255 clarithromycin, 265 clozapine, 66 coagulation proteins, 346 desmopressin, 543 disulfiram, 605 diuretics, 219 duloxetine, 23 emergency contraceptives, 501 enfuvirtide, 310 entacapone, 153 erythromycin, 265 exenitide, 529 fentanyl, 106 fluoroquinolones, 254 fluorouracil, 557, 558 flutamide, 513 fosmidomycin, 272 gatifloxacin, 256 gemifloxacin, 256
glibenclamide, 530 hormonal contraceptives, 500 idoxifene, 503 iloprost, 489 immunoglobulins, 343 infliximab, 401 irbesartan, 212 itraconazole, 286 ivermectin, 323, 324 ketogenic diet, 89 ketolides, 262 lactulose and lactitol, 375 leflunomide, 438, 440 levamisole, 462 liraglutide, 529 lormetazepam, 56 macrolide antibiotics, 264 melatonin, 542 metformin, 526 methotrexate, 561 micafungin, 290 mifepristone, 506, 507 misoprostol, 490 morphine, 108 moxifloxacin, 257 mycophenolate mofetil, 447 nalbuphine, 111 nalmefene, 112 naltrexone, 112 nateglinide, 529 nefopam, 112 parathyroid hormone, 542 phosphate, 375 picibanil, 463 pramlintide, 526 praziquantel, 324 promazine, 61 quinine, 297 raltitrexed, 563 risperidone, 77 sevoflurane, 129 sodium picosulfate, 377 tacrolimus, 457 tegafur, 560 temsirolimus, 460 tigecycline, 250 triclabendazole, 321 troxacitabine, 560 necrosis infiltration anesthesia, 138 naltrexone, 112 necrotizing fasciitis heroin, 46–47 necrotizing leukocytoclastic vasculitis bosentan, 213 necrotizing vasculitis leflunomide, 441 minocycline, 249 nephr– see also entries at kidney–; renal– nephritis azithromycin, 264
nephrogenic diabetes insipidus lithium, 31 tenofovir, 304 nephrolithiasis (kidney stones) ceftriaxone, 246–247 ketogenic diet, 89 topiramate, 96 zonisamide, 100 nephropathy cidofovir, 300 foscarnet, 300 tacrolimus, 456 nephrotoxicity aminoglycoside antibiotics, 253 Aristolochia species, 585–586 bryostatin 1, 461 caspofungin, 289 ciclosporin, 429 contrast agents, 575–578 liposomal amphotericin (L-amB), 282 sirolimus (rapamycin), 451 thalidomide+amikacin, 253 nervousness beta2 -adrenoceptor agonists+ anticholinergics, 176 cisapride, 371 diazepam, 54, 55 lamotrigine, 90 neuroleptic malignant syndrome antipsychotics, 60 clozapine, 67 ziprasidone, 81 neurological deficits diuretics, 219 neuropathy infliximab, 400 leflunomide, 438 neurotoxicity bismuth, 228 fluorouracil, 557 neurotropic disease yellow fever vaccine, 336 neutralizing antibodies to infliximab infliximab, 401 neutralizing antibodies to interferon beta interferon beta, 393–394 neutropenia allopurinol+azathioprine, 426 antipsychotics, 60 azathioprine+allopurinol, 426 clofarabine, 551 clozapine, 66, 67–68 fluorouracil, 558 ganciclovir, 300 gemtuzumab ozogamicin, 409 infliximab, 398 levamisole, 462 nitrofurantoin, 266 olanzapine, 75
660 pemetrexed, 562 pentostatin, 565 picibanil, 463 piperacillin, 247–248 raltitrexed, 563 risperidone, 78 rituximab, 411 thionamides, 520 trimethoprim, 270 valganciclovir, 300 vancomycin, 261 vesnarinone, 183 neutropenic fever anidulafungin, 289 nicotinic acid-like reaction infliximab, 401 night sweats leflunomide, 439 lormetazepam, 56 nightmares chloroquine, 294 valsartan, 213 NK cell count reduction fludarabine, 564 Nocardia infection infliximab, 402 non-melanoma skin cancer PUVA, 158 nosebleed (epistaxis) bevacizumab, 408 gemtuzumab ozogamicin, 409 risperidone, 78–79 numbness acupuncture, 590 nystagmus fluorouracil, 557 Illicium anisatum, 588 O obstructive sleep apnea syndrome infliximab, 400 occipital hemorrhage drotrecogin alfa, 338 occipital stroke cannabinoids, 36–37 ocular bleeding gemtuzumab ozogamicin, 409 ocular damage chloroquine, 294 ocular dryness loratadine, 164 ocular hypertension systemic glucocorticoids, 481 ocular opsoclonus ciclosporin, 428 oculogyric crisis antipsychotics, 60 ziprasidone, 81 oligohydrosis zonisamide, 100 oliguria calcipotriol, 156 ethambutol, 317
Index of adverse effects sodium phosphate, 377 ophthalmoplegia tacrolimus, 454 optic neuritis bisphosphonates, 603 optic neuropathy amiodarone, 186 linezolid, 267 organ rejection interferon alfa, 391 orofacial dyskinesia ofloxacin, 258 oropharyngeal candidiasis glucocorticoids, inhaled, 168–169 oscillopsia carbamazepine fluconazole, 282 osteonecrosis of the femoral head nasal glucocorticoids, 487 osteoporosis antiandrogens, 511 systemic glucocorticoids, 484–485 osteosarcoma parathyroid hormone, 542 somatropin, 540 otitis media diazepam, 55 ototoxicity amikacin, 253 aminoglycoside antibiotics, 253 ovarian cysts daclizumab, 409 tacrolimus, 457 ovarian hyperstimulation gonadotropins, 493–494 over-talkativeness paroxetine, 18 oxygen embolism hydrogen peroxide, 379 P pain basiliximab, 407 diazepam, 55 medication errors, 596 picibanil, 463 risperidone, 80 sodium morrhuate, 612 palmar–plantar erythrodysesthesia cytarabine, 556 fluorouracil, 558 troxacitabine, 560 palmar–plantar pustulosis G-CSF, 384 palpebral edema phosphodiesterase type V inhibitors, 204 palpitation anagrelide, 364
azithromycin, 264 cannabinoids, 35 clozapine, 66 Ephedra and ephedrine, 12, 148 glatiramer acetate, 435 hydroxyzine, 163 palsy methotrexate, 561 pancolitis influenza vaccine, 333 pancreas graft thrombosis desmopressin, 543–544 pancreatic cancer acetylsalicylic acid, 124 pancreatitis azathioprine, 424 interferon alfa, 389–390 lisinopril, 210 mesalazine, 378 propofol, 132 ramipril, 211 tacrolimus, 456 tamoxifen, 504 telmisartan, 212 pancytopenia albendazole, 322 azathioprine, 424 captopril, 210 glibenclamide, 530 infliximab, 398, 399 leflunomide, 438, 440 linezolid, 267 mycophenolate mofetil, 447 protease inhibitors, 322 panic cannabinoids, 36 panic attacks mefloquine, 295 systemic glucocorticoids, 483 papillomas pimecrolimus, 449 paralysis botulinum toxin A, 156 epidural anesthesia, 136 paranoia cannabinoids, 35 paranoid syndrome zolpidem, 57 paresis colchicine+verapamil, 125 epidural anesthesia, 136–137 methotrexate, 561 paresthesia azithromycin, 264 pentostatin, 565 sodium phosphate, 376 somatropin, 541 sultiame, 95 parkinsonism clozapine, 66 heroin, 46 risperidone, 76 valproate, 97 pemphigus foliaceus
661
Index of adverse effects lisinopril, 210–211 pemphigus vulgaris alendronate, 603 Echinacea species, 587 penile necrosis cocaine, 41, 141 peptic ulcer disease ciclosporin, 429 perianal irritation phosphate, 375 pericardial effusion acupuncture, 590 clozapine, 67 cytarabine, 555 sirolimus (rapamycin), 450 pericarditis cytarabine, 555 interferon alfa, 387 perihilar airspace disease azacitadine, 554 perioral dermatitis glucocorticoids, inhaled, 168 periorbital edema topiramate, 96 peripheral edema coagulation proteins, 345 somatropin, 541 thiazolidinediones, 531–533 peripheral neuropathy capecitabine, 555 disulfiram, 605 leflunomide, 439–440 linezolid, 267 statins, 547 pernicious anemia interferon alfa, 386 petechiae immunoglobulins, 344 progestogens, 505 pharyngitis leflunomide, 439 methotrexate, 561 phlebitis ciclosporin, 427 photosensitivity azithromycin, 264 flutamide, 513 quinapril, 211 thioridazine, 80 phototoxicity amiodarone, 187 fluoroquinolones, 254 gemifloxacin, 256 pigmentation lentinan, 463 pitch perception alteration antiepileptic drugs, 87 pityriasis rosea-like dermatitis lisinopril, 210 lithium, 32 platelet count reduction antithymocyte globulin, 342 platelet function reduced perfluorocarbons, 340
pleural effusion amiodarone, 186 minoxidil, 215 nitrofurantoin, 266 sirolimus (rapamycin), 450 pleuritic pain fluconazole+nitrofurantoin, 285 Pneumocystis jiroveci (carinii) pneumonia infliximab, 403 pneumonia amiodarone, 186 interferon gamma, 394 leflunomide, 439 pneumonitis carvedilol, 194 infliximab, 399 sirolimus (rapamycin), 450 pneumoperitoneum cocaine, 40 pneumothorax acupuncture, 589, 590 cannabinoids, 36 polyarteritis nodosa minocycline, 249 polycythemia androgens, 508 polydipsia vitamin D analogues, 354 polymyositis statins, 547 polyneuropathy cytarabine, 556 epidural anesthesia, 136 polyradiculoneuropathy ciclosporin, 428 statins, 547 tacrolimus, 453 polyuria lithium+risperidone, 28 vitamin D analogues, 354 popliteal artery entrapment cannabinoids, 36 post-hypoxic action myoclonus trimethoprim, 270 post-transplantation lymphoproliferative disorder (PTLD) antithymocyte globulin, 341 post traumatic stress disorder heroin, 46 posterior leukoencephalopathy rituximab, 411 postural hypotension olanzapine, 61 quetiapine, 29, 76 pressor response linezolid+monoamine oxidase inhibitors, 268 priapism methylphenidate, 10 olanzapine, 75 risperidone, 79
proctitis fluorouracil, 558 progressive multifocal leukoencephalitis fludarabine, 564 prolactinoma amisulpride, 66 prolonged QT interval see QT interval prolongation promyelocytic leukemia tacrolimus, 457 propofol infusion syndrome propofol, 132–133 propriospinal myoclonus cannabinoids, 36 ciprofloxacin, 255 proteinuria bevacizumab, 408 limonene, 609 tenofovir, 304 proximal tubulopathy tenofovir, 304 pruritus adalimumab, 397 albendazole, 320, 321 Andrographis paniculata, 585 chloroquine, 294 ciprofloxacin, 255 clindamycin, 263 coagulation proteins, 346 diazepam, 54 etherified starches, 341 immunoglobulins, 343, 344 infliximab, 400 interferon alfa, 390 ivermectin, 323 leflunomide, 438, 441 mexiletine, 189 miltefosine, 563 morphine, 108 p-chloro-m-cresol, 604 triclabendazole, 321 pseudoathetosis nitrous oxide, 131 pseudohypopyon systemic glucocorticoids, 482–483 pseudoporphyria ampicillin, 247 pseudothrombocytopenia coagulation proteins, 345 levofloxacin, 257 pseudotumor cerebri ciclosporin, 428 minocycline, 248 psoriasis etanercept, 397–398 G-CSF, 384 interferon alfa, 390 psoriatic eruptions infliximab, 401 psychosis chloroquine, 294 mefloquine, 295
662 risperidone, 80 systemic glucocorticoids, 483 topiramate, 95–96 psychotic reaction fluoroquinolones, 254 pulmonary aspergillosis alemtuzumab, 405 pulmonary edema alemtuzumab, 404 insulin, 523 nicardipine, 197–198 quinine, 296 pulmonary embolism erythropoietin and derivatives, 346 hormonal contraceptives, 499–500 immunoglobulins, 343–344 infliximab, 399 parecoxib, 122 pulmonary fibrosis amiodarone, 186 danazol, 514 interferon alfa, 391 methotrexate, 561 pulmonary hypertension leflunomide, 439 pulmonary infiltration blood transfusion, 339 mesalazine, 378 pulmonary toxicity fluconazole+nitrofurantoin, 285 pupils, dilated diphenhydramine, 163 pure red cell aplasia azathioprine, 424 erythropoietin and derivatives, 347 interferon alfa, 386 ribavirin, 301 pustular eruptions terbinafine, 280 pustulosis G-CSF, 384 pyoderma gangrenosum propylthiouracil, 521 pyrexia anidulafungin, 289 Q QT interval prolongation anthracyclines, 565–566 antipsychotics, 62 azithromycin, 264 ciprofloxacin, 255 cocaine, 39 dofetilide, 187–188 droperidol, 69–70 Ephedra and ephedrine, 148 gatifloxacin, 256 gemifloxacin, 256 macrolide antibiotics, 263 methadone, 107
Index of adverse effects olanzapine, 73 pazufloxacin, 258 quinidine, 189 sevoflurane, 129 sodium phosphate, 376 sparfloxacin, 259 voriconazole, 287 quadriplegia cytarabine, 556 R radiation-recall dermatitis gemcitabine, 559 radiculoneuropathy alemtuzumab, 405 rash adalimumab, 397 albendazole, 320 amfebutamone, 25 amlodipine, 195 anabolic steroids, 510 anagrelide, 364 C31G, 605 ciprofloxacin, 255 cladribine, 564 clofarabine, 551 coagulation proteins, 346 cytarabine, 555 dapsone, 315 daptomycin, 271 diazepam, 54, 55 epoprotenol, 488 gemcitabine, 559 gemifloxacin, 256 ICL670A, 238 immunoglobulins, 343, 344 infliximab, 400 lamotrigine, 90, 91, 92 leflunomide, 438, 441 levamisole, 324, 462 lisinopril, 210 naltrexone, 112 nevirapine, 305 patent blue, 608 phenytoin, 94 pyrimethamine+dapsone, 296 sirolimus (rapamycin), 451 temsirolimus, 460 terbinafine, 280 thiabendazole, 320 trimethoprim, 271 troxacitabine, 560 vitamin K1 , 356 zonisamide, 100 Raynaud’s phenomenon interferon alfa, 391 rectal irritation diazepam, 54 red cell aplasia tacrolimus, 455 redness p-chloro-m-cresol, 604 rejection antithymocyte globulin, 341
rejection graft antithymocyte globulin, 341 renal see also entries at nephr– renal allograft dysfunction fibrates, 546 renal damage vancomycin, 261 renal dysfunction etherified starches, 341 mizoribine, 445 renal failure tenofovir, 304 renal hepatic insufficiency dapsone, 316 renal hypoperfusion ciclosporin, 429 renal impairment mesalazine, 378 plasma substitutes, 340 sirolimus (rapamycin), 452 sodium phosphate, 377 renal insufficiency aluminium, 226 Aristolochia species, 585 calcipotriol, 156 ciclosporin, 433 cytarabine, 556 ethambutol, 316–317 ibuprofen, 124 immunoglobulins, 344 interferon alfa, 390, 392 mannitol, 223 medication errors, 596 methotrexate, 561–562 mycophenolate mofetil, 445 roxithromycin, 266 sirolimus (rapamycin), 451 sodium phosphate, 377 tacrolimus, 456 telmisartan, 212 thiabendazole, 320 tosufloxacin, 259 renal thrombotic microangiopathy interferon alfa, 390 renal toxicity amphotericin B lipid complex (ABLC), 281 renal transplant rejection alemtuzumab, 405 renal tubular acidosis trimethoprim, 270–271 renal tubular damage tenofovir, 304 renal tubular dysfunction azacitadine, 554 respiratory arrest ropivacaine, 142 respiratory depression clobazam, 53 diazepam, 55 iron, 229 propofol, 128 remifentanil, 109
663
Index of adverse effects sufentanil, 110 respiratory distress heparins, 361 infliximab, 400 interferon alfa, 387 nifedipine, 198 tretinoin, 159 respiratory failure alemtuzumab, 405 amphotericin B lipid complex (ABLC), 281 ciprofloxacin, 255 respiratory infection beta2 -adrenoceptor agonists, 176 restless legs syndrome interferon alfa, 387 restlessness vitamin D analogues, 354 reticulocytopenia cytarabine, 556 quinupristin/dalfopristin, 269 retinoid-like photosensitivity voriconazole, 287 retinopathy deferoxamine, 237–238 interferon alfa, 388, 392 retrobulbular neuritis thiabendazole, 320 rhabdomyolysis amiodarone+simvastatin, 187 fibrates, 546 leflunomide, 441 ofloxacin, 258 propofol, 133 statins, 548 tacrolimus, 455, 456 rhinitis calcitonin, 539 leflunomide, 439 risperidone, 76, 80 rhinitis, destructive cocaine, 40 rhinoconjunctivitis sodium metabisulfite, 611 rigidity remifentanil, 110 rigors co-trimoxazole, 298 coagulation proteins, 346 interferon gamma, 394 S Salmonella typhimurium infection infliximab, 402 saphenous vein graft occlusion aprotinin, 367 sarcoidosis interferon alfa, 391 scaling clindamycin, 263 fluorouracil, 558
scarring sodium morrhuate, 612 scleritis bisphosphonates, 603 topiramate, 96 sclerochorioretinal necrosis gentamicin, 253 sclerodactyly interferon alfa, 391 scrotal discomfort diethylcarbamazine, 322 sedation clonidine, 214 diazepam, 54 droperidol, 69 lamotrigine, 91 levetiracetam, 92 lorazepam, 55 pethidine, 109 seizure worsening diazepam, 54 seizures amfebutamone, 25 anidulafungin, 289 ciclosporin, 427 clozapine, 66 cytarabine, 556 diuretics, 219 ertapenem, 246 fluoroquinolones, 254 Illicium anisatum, 588 intravenous regional anesthesia, 138–139 lamotrigine, 90 levetiracetam, 92 lidocaine, 142 methotrexate, 561 mycophenolate mofetil, 445 nicotine, 610 rituximab, 411 sevoflurane, 130 sultiame, 95 tacrolimus, 453, 454 venlafaxine, 22 zonisamide, 100 self-harm risperidone, 76 sensitization antithymocyte globulin, 341 sensorineural hearing loss interferon alfa, 388 propylthiouracil, 521 sensory loss cytarabine, 556 sensory neuropathy infliximab, 400 sepsis catheters, 612–613 leflunomide, 438 sirolimus (rapamycin), 452 septic shock ciclosporin, 431 septicemia antithymocyte globulin, 342
serotonin syndrome caffeine+paroxetine, 1 SSRIs+tramadol, 111 serotonin transporter density methylenedioxymetamfetamine, 7 serous chorioretinopathy phosphodiesterase type V inhibitors, 203–204 serum sickness antithymocyte globulin, 342 serum sickness-like reaction amfebutamone, 24 infliximab, 398, 399 sexual dysfunction duloxetine, 23 risperidone, 79 shivering carisoprodol, 146 misoprostol, 490 nystatin, 290 tramadol+venlafaxine, 24 shortness of breath alemtuzumab, 404 coagulation proteins, 346 cytarabine, 555 infliximab, 401 SIADH see syndrome of inappropriate antidiuretic hormone secretion sialadenitis captopril, 210 terbinafine, 280 sicca syndrome terbinafine, 280 sideroblastic anemia fusidic acid, 259 sinus node dysfunction cilostazol, 202 sinus tachycardia diphenhydramine, 163 Ephedra and ephedrine, 148 promazine, 61 skin cancer pimecrolimus, 449 sirolimus (rapamycin), 450 skin discoloration amlodipine, 196 emtricitabine, 304 skin eruption norfloxacin, 258 skin infections pimecrolimus, 449 skin irritation chlorhexidine, 241 skin necrosis coumarin anticoagulants, 358–359 heparins, 361 skin pain PUVA, 158 skin sloughing infiltration anesthesia, 138
664 skin striae pimecrolimus, 449 sleep attack levodopa, 151–152 sleep disorders androgens, 508 sleep disturbances efavirenz, 305 sleep loss phosphate, 375 sleepiness cetirizine, 161 droperidol, 69 topiramate, 96 zonisamide, 100 sleepwalking zaleplon, 57 somnolence azithromycin, 264 clobazam, 53 clozapine, 66, 71 diazepam, 54, 55 duloxetine, 23 lamotrigine, 90 levosulpride, 371 methotrexate, 561 olanzapine, 61, 72 promazine, 61 quetiapine, 29, 76 risperidone, 61, 76, 77 sultiame, 95 tramadol, 110 valproate, 99 ziprasidone, 81 speech disturbances aluminium, 226 speech slurring melatonin, 542 sperm abnormalities antiepileptic drugs, 88 levetiracetam, 93 valproate, 98–99 spinal cord damage nitrous oxide, 131 spinal cord lesion intrathecal (spinal) anesthesia, 137 spinal fracture antiandrogens, 511 splenic infarction cocaine, 40 splenomegaly G-CSF, 383 spongiform leukoencephalopathy heroin, 46 spotting implantable contraceptives, 501 tibolone, 514 squamous cell cancer infliximab, 403 ST segment depression adenosine, 185
Index of adverse effects ST segment elevation sodium phosphate, 377 sotalol, 195 staphylococcal sepsis infliximab, 402 staphylococcal wound infection infiltration anesthesia, 138 status epilepticus water-soluble iodinated contrast agents, 573 steatohepatitis pioglitazone, 533 Stevens–Johnson syndrome azathioprine, 426 azithromycin, 264 chloroquine, 295 fluoroquinolones, 255 nevirapine, 306 paclitaxel, 566 phenytoin, 94 terbinafine, 280 trimethoprim, 271 valdecoxib, 122 stiffness spinal manipulation, 592 stinging C31G, 605 stomach pain coagulation proteins, 346 stomatitis fluorouracil, 558 methotrexate, 561 pemetrexed, 562 temsirolimus, 460 stomatodynia enalapril, 210 stroke acetazolamide, 220 cannabinoids, 36–37 cocaine, 40 Ephedra and ephedrine, 149 immunoglobulins, 343 parecoxib, 122 perfluorocarbons, 340 phenylpropanolamine, 150 risperidone, 77 spinal manipulation, 591 suramin, 325 tamoxifen, 503–504 thrombolytic agents, 362 stupor diazepam, 55 systemic glucocorticoids, 484 stuttering aluminium, 226 clozapine, 67 olanzapine, 73 subacute sclerosing panencephalitis (SSPE) measles-mumps-rubella (MMR) vaccine, 335 subcutaneous fibrosis deferoxamine, 237
sudden infant death hexavalent vaccines, 327 suicide quinine, 296 risperidone, 80 suicide attempts risperidone, 76 suprachoroidal effusions topiramate, 96 supraventricular tachycardia adenosine, 185 hydroxyzine, 163 sweating caffeine+paroxetine, 1 coagulation proteins, 346 fluorescein dye, 607 glatiramer acetate, 435 nefopam, 112 tramadol+venlafaxine, 24 vitamin D analogues, 354 Sweet syndrome azathioprine, 424 furosemide, 222 G-CSF, 383 levonorgestrel, 506 swelling cytarabine, 556 sodium morrhuate, 612 syncope acupuncture, 590 quinidine, 189 syndrome of inappropriate antidiuretic hormone secretion (SIADH) amiodarone, 186 systemic lupus erythematosus interferon gamma, 394 systemic response syndrome co-trimoxazole, 298 systemic sclerosis interferon alfa, 391 T T cell lymphoma infliximab, 403 tachycardia amphotericin B lipid complex (ABLC), 281 anagrelide, 364 beta2 -adrenoceptor agonists, 176 carisoprodol, 146 cisapride, 371 co-trimoxazole, 298 coagulation proteins, 346 diphenhydramine, 163 duloxetine, 23 Ephedra and ephedrine, 148 heroin, 47 hydroxyzine, 163 infliximab, 401 lercanidipine, 197 melatonin, 542 risperidone, 61
665
Index of adverse effects water-soluble iodinated contrast agents, 574 tachypnea amphotericin B lipid complex (ABLC), 281 co-trimoxazole, 298 coagulation proteins, 346 talcosis talc, 612 tardive dermopathy penicillamine, 239 tardive dyskinesia antipsychotics, 60 olanzapine, 73 ziprasidone, 81 tardive dystonia olanzapine, 73 tardive Tourette’s syndrome haloperidol, 70 taste, abnormal clarithromycin, 265 taste disturbance candesartan, 211–212 coagulation proteins, 346 enalapril, 210 levamisole, 462 taste unpleasantness misoprostol, 490 telangiectasia interferon alfa, 391 tendinopathy levofloxacin, 257 moxifloxacin, 258 tendon rupture fluoroquinolones, 255 tendonitis fluoroquinolones, 255 testosterone increase goserelin, 539 testosterone reduction sirolimus (rapamycin), 450 tetralogy of Fallot infliximab, 403 thiamin deficiency fluorouracil, 557 third nerve palsy ocular anesthesia, 139 thirst glucocorticoids, inhaled, 168 phosphate, 375 thrombocytopenia abciximab, 363 alemtuzumab, 405 amphotericin B lipid complex (ABLC), 281 antithymocyte globulin, 341 caspofungin, 289 clofarabine, 551 cytarabine, 556 enfuvirtide, 310 everolimus, 433 fluorouracil, 558 G-CSF, 383 gemcitabine, 559
gemtuzumab ozogamicin, 409 heparins, 361 infliximab, 398 interferon alfa, 392 iptifibatide, 366 leflunomide, 440 levetiracetam, 92 linezolid, 267 olanzapine, 75 pemetrexed, 562 picibanil, 463 quinidine, 190 raltitrexed, 563 rituximab, 411–412 teicoplanin, 261 temsirolimus, 460 tirofiban, 367 trientine, 239 trimethoprim, 270 troxacitabine, 560 vancomycin, 261 thrombocytopenia, autoimmune interferon alfa, 389 thrombocytopenia purpura hepatitis B vaccine, 332 tacrolimus, 455 thrombocytosis leflunomide, 440 thromboembolic events bevacizumab, 408 erythropoietin and derivatives, 346–347 etoricoxib, 123 infliximab, 398 systemic glucocorticoids, 480 thromboembolism antiestrogens, 502 thrombophlebitis amiodarone, 185 coagulation proteins, 345 thrombosis coagulation proteins, 345 water-soluble iodinated contrast agents, 574–575 thrombotic disorders infliximab, 399 thrombotic microangiopathy ciclosporin, 427 sirolimus (rapamycin), 450 tacrolimus, 453 thyroglobulin concentration increase rosiglitazone, 533 thyroid enlargement minocycline, 250 thyroid pigmentation minocycline, 249–250 thyrotoxic crisis water-soluble iodinated contrast agents, 574 tick-borne encephalitis blood transfusion, 339
time perception alteration cannabinoids, 35 tinnitus lidocaine, 142 quinine, 297 tiredness dronabinol, 36 tiagabine, 95 tongue hypertrophy glucocorticoids, inhaled, 168 tongue numbness lidocaine, 142 tonic-clonic seizure pethidine, 109 remifentanil, 109 torsade de pointes amiodarone, 185 antidysrhythmics, 184 antipsychotics, 62 ciprofloxacin, 255 gatifloxacin, 256 grepafloxacin, 257 ketolides, 262 levofloxacin, 257 macrolide antibiotics, 263 roxithromycin, 266 sotalol, 190 torticollis pyrimethamine+sulfadoxine, 296 Tourette’s syndrome haloperidol, 70 toxic epidermal necrolysis ciprofloxacin, 255 fluoroquinolones, 255 itraconazole, 286 lamotrigine, 91 streptomycin, 254 tenoxicam, 125 terbinafine, 280 trimethoprim, 271 valdecoxib, 122 toxic pustuloderma azithromycin, 264 tracheal pain fluconazole+nitrofurantoin, 285 transfusion-related acute lung injury (TRALI) blood transfusion, 339 immunoglobulins, 344 transient global amnesia cannabinoids, 37 tremor aluminium, 226 antipsychotics, 60, 63 beta2 -adrenoceptor agonists, 176 beta2 -adrenoceptor agonists+ anticholinergics, 176 carisoprodol, 146 ciclosporin, 427–428 Ephedra and ephedrine, 148 fluphenazine, 71
666 lamotrigine, 90, 92 lithium, 32 melatonin, 542 salbutamol, 173 triglyceride concentration increase interferon alfa, 388 leflunomide, 438, 440 lopinavir+ritonavir, 308 rosiglitazone, 533–534 saquinavir, 309 sirolimus (rapamycin), 451 temsirolimus, 460 trismus pyrimethamine+sulfadoxine, 296 tuberculosis etanercept, 396 tubular necrosis interferon alfa, 390 tenofovir, 304 tubulointerstitial nephritis ethambutol, 316 tumor lysis syndrome clofarabine, 551 rituximab, 410 U ulcer, duodenal ciclosporin, 429 ulcer, esophageal bisphosphonates, 602 ciclosporin, 429 clindamycin, 263 ulcer, gastric ciclosporin, 429 sodium phosphate, 377 ulcer, genital minoxidil, 215 ulcer, mouth cannabinoids, 35 leflunomide, 440 lormetazepam, 55 ulcer, oral mycophenolate mofetil, 446 sirolimus (rapamycin), 450 ulcer, skin leflunomide, 441 sodium morrhuate, 612 voriconazole, 287 unsteadiness lorazepam, 55 upper-airway obstruction loratadine, 164 urinary retention amfetamine, 2 clobazam, 53 fentanyl, 106 morphine, 108 urinary tract infection mycophenolate mofetil, 445 urticaria albendazole, 321 amlodipine, 196
Index of adverse effects Andrographis paniculata, 585 cytarabine, 556 ethylenediamine, 606 immunoglobulins, 344 infliximab, 400, 401 linezolid, 267 lisinopril, 210 montelukast, 175 p-chloro-m-cresol, 604 phenytoin, 94 phosphodiesterase type V inhibitors, 204 praziquantel, 324 sodium metabisulfite, 611 trimethoprim, 271 uterine rupture mifepristone, 507 uveitis bisphosphonates, 603 cytarabine, 556 V vaginal candidiasis azithromycin, 264 vaginal vault hematoma Asian herbal medicines, 583 vaginitis azithromycin, 264 valproic acid hypersensitivity syndrome valproate, 99 valvular fibrotic changes pergolide, 152–153 vanishing bile duct syndrome ibuprofen, 124 tenoxicam, 125 variant Creutzfeldt–Jakob disease blood transfusion, 339 varicella zoster virus infection infliximab, 403 vascular complications systemic glucocorticoids, 480 vascular insufficiency brachial plexus anesthesia, 135 vasculitis candesartan, 212 etanercept, 398 G-CSF, 384 interferon alfa, 390 leflunomide, 438, 441 vasoconstriction hemoglobin-based oxygen carriers, 340 vasodilatation diazepam, 55 venous thromboembolism cyproterone acetate+ ethinylestradiol, 502 ventricular arrhythmia propofol, 133 ventricular dysfunction fluorouracil, 557
ventricular dysrhythmia chloroquine, 295 ventricular extra beats amlodipine, 195 ventricular trigeminy beta2 -adrenoceptor agonists, 171 vertigo azithromycin, 264 melatonin, 542 mycophenolate mofetil, 445 spironolactone, 222 tramadol, 110 zonisamide, 100 vestibular dysfunction gentamicin, 253 vestibular neuronitis infliximab, 399 viral infection infliximab, 403 tacrolimus, 457 visceral angioedema telmisartan, 212 viscerotropic disease yellow fever vaccine, 336 vision, abnormal diazepam, 55 vision blurring interferon alfa, 386, 388 ketolides, 262 rituximab, 411 systemic glucocorticoids, 482 vision disorders methotrexate, 561 vision loss nitrous oxide, 131 quinine, 297 systemic glucocorticoids, 483 visual changes fluoroquinolones, 254 visual disturbance bisphosphonates, 602 dextromethorphan, 105 lamotrigine, 92 voriconazole, 287 visual field loss etanercept, 397 vigabatrin, 99–100 visual pathway abnormality sevoflurane, 130 vitiligo flutamide, 513 interferon alfa, 390 Vogt–Koyanagi–Harada disease interferon alfa, 388 vomiting (emesis) albendazole, 320 anidulafungin, 289 azithromycin, 264 bisphosphonates, 602 bryostatin 1, 461 calcitonin, 539 carbamazepine fluconazole, 282
667
Index of adverse effects ciclosporin, 433 ciprofloxacin, 255 coagulation proteins, 346 diazepam, 55 disulfiram, 605 emergency contraceptives, 501 enfuvirtide, 310 erythromycin, 265 fentanyl, 106 fluoroquinolones, 254 fluorouracil, 557 fosmidomycin, 272 Illicium anisatum, 588 infliximab, 401 irbesartan, 212 itraconazole, 286 ketogenic diet, 89 lamotrigine, 90 leflunomide, 440 liraglutide, 529 melatonin, 542 metformin, 526 methotrexate, 561 methylene blue, 610 mifepristone, 506, 507 misoprostol, 490 mycophenolate mofetil, 447 nalbuphine, 111 naltrexone, 112 nateglinide, 529 nefopam, 112 pemetrexed, 562 phosphate, 375 praziquantel, 324 quinine, 297
selenium, 231 sevoflurane, 129 tigecycline, 250 tramadol, 110 triclabendazole, 321 vitamin D analogues, 354 W weakness cytarabine, 556 daptomycin, 272 dronabinol, 36 glibenclamide, 530 interferon alfa, 391 interleukin-2 (IL-2), 394 levamisole, 324 lorazepam, 55 phosphate, 375 quetiapine, 76 risperidone, 61 sirolimus (rapamycin), 452 statins, 548 tegafur, 560 temsirolimus, 460 triclabendazole, 321 zonisamide, 100 weight gain acitretin, 158 antipsychotics, 63, 64 clobazam, 53 clozapine, 66, 67 meglitinides, 529 olanzapine, 61, 71, 72, 73, 74–75 pioglitazone, 533
risperidone, 76, 78 rosiglitazone, 534 tretinoin, 159 ziprasidone, 81 weight loss cytarabine, 555 ketogenic diet, 89 leflunomide, 438, 441 pramlintide, 526 stavudine, 304 zonisamide, 100 West Nile virus infection blood transfusion, 339 tacrolimus, 457 West syndrome oxatomide, 165 wheezing azithromycin, 264 lidocaine, 188 macrolide antibiotics, 264 wind see flatulence wound dehiscence sirolimus (rapamycin), 450 wound healing, impaired sirolimus (rapamycin), 449 wound healing complications sirolimus (rapamycin), 452 wound infections infiltration anesthesia, 138 Z zygomycosis tacrolimus, 457
