! " # ! "# $ %!! "%!& '(')'( (( *+!, ! " #$ % &'# ( )! * +, - . "., / 0, % , / 1 - , 2 * 3 4 ' ! " 45 * 1 , 3 , 6, 7$ , , "89 &#:6:$%&#:;, " )"4"+ )34+ . . :. . , - ". 3 4 3 < . #&$, " #&= . 34, #&$7 . 34 > / 2 1 , 34 : :5 , 3 ? 5 1 , / . 34 34 : . 34 . 34 5 ) + , ( 5 . 34 , "4" 34 . @ . . . . . 5 , "4" 34 ) 34 + 5 34 34 34 . . , " "4" ,, : 5 . , 2. . "4" 5 ? : 5 , ! ! "# # $#! ! %&'()*( ! A 0 / % ""9 #$#:$% $ "89 &#:6:$%&#:; ' ''' :7$$ ) 'BB ,5,B C D ' ''' :7$$+ To my parents. To Marko, Victoria, Astrid and Eric List of Papers I. Hedenmalm K, Spigset O. Peripheral sensory disturbances related to treatment with fluoroquinolones. J Antimicrob.Chemother. 1996;37(4):831-7. II. Spigset O, Hedenmalm K. Hyponatremia in relation to treatment with antidepressants: a survey of reports in the World Health Organization data base for spontaneous reporting of adverse drug reactions. Pharmacotherapy 1997;17(2):348-52. III. Hedenmalm K, Spigset O. Agranulocytosis and other blood dyscrasias associated with dipyrone (metamizole). Eur J Clin Pharmacol 2002;58(4):265-74. IV. Hedenmalm K, Hägg S, Ståhl M, Mortimer O, Spigset O. Glucose intolerance with atypical antipsychotics. Drug Saf 2002;25(15):1107-16. V. Hedenmalm K, Samuelsson E, Spigset O. Pulmonary embolism associated with combined oral contraceptives: reporting incidences and potential risk factors for a fatal outcome. Acta Obstet Gynecol Scand 2004;83:576-85. VI. Hedenmalm K, Yue QY, Dahl M-L, Spigset O. Risk factors for extrapyramidal symptoms during treatment with selective serotonin reuptake inhibitors, including cytochrome P-450 enzyme and serotonin and dopamine transporter and receptor mutations. Manuscript in preparation. Contents Introduction...................................................................................................11 Short historical background of three drug disasters of major importance12 Thalidomide.........................................................................................12 Diethylstilbestrol .................................................................................12 Cerivastatin..........................................................................................13 Drug regulation: Requirement of efficacy and acceptable safety.............15 Development of spontaneous reporting systems, WHO initiative, Eudravigilance..........................................................................................17 The ‘spontaneous’ reporting system in Sweden.......................................18 Pharmacovigilance responsibilities of marketing authorization holders..20 Mechanisms of adverse drug reactions, pharmacogenomics ...................22 ADRs due to direct effects of the drug molecule.................................23 ADRs resulting from hypersensitivity (immunological) reactions......28 Signal detection........................................................................................32 Signal evaluation......................................................................................35 Causality evaluation.............................................................................35 Frequency estimation...........................................................................35 Further characterization of risk............................................................38 Aims..............................................................................................................40 Materials and methods ..................................................................................41 Study subjects...........................................................................................41 Methods....................................................................................................41 Signal detection ...................................................................................41 Characterization of the clinical picture................................................42 Identification of risk factors.................................................................42 Risk quantification...............................................................................42 Statistical methods...............................................................................42 Results and discussion ..................................................................................43 Study 1. Peripheral sensory disturbances (PSD) related to treatment with fluoroquinolones.......................................................................................43 Study 2. Hyponatremia in relation to treatment with antidepressants: A survey of reports in the World Health Organization database for spontaneous reporting of adverse drug reactions .....................................45 Study 3. Agranulocytosis and other blood dyscrasias associated with dipyrone (metamizole) .............................................................................46 Study 4. Glucose intolerance with atypical antipsychotics ......................51 Study 5. Pulmonary embolism associated with combined oral contraceptives: reporting incidences and potential risk factors for a fatal outcome ....................................................................................................58 Study 6. Risk factors for extrapyramidal symptoms during treatment with selective serotonin reuptake inhibitors (SSRIs) .......................................60 General discussion ........................................................................................62 Pros and cons with spontaneous reporting ...............................................62 Strengths and merits ............................................................................62 Underreporting, selective reporting, causality.....................................63 Other methodological considerations ..................................................65 Risk management .....................................................................................66 Dipyrone (metamizole)........................................................................69 Nefazodone..........................................................................................70 Risk minimization strategies ....................................................................72 Conclusions and future perspectives.............................................................74 Acknowledgements.......................................................................................76 Reference List ...............................................................................................77 Abbreviations ACE Angiotensin Converting Enzyme ADH Anti-Diuretic Hormone ADR Adverse Drug Reaction ALAT Alanine-Aminotransferase APC Antigen Presenting Cell ASAT Aspartate-Aminotransferase BCPNN Bayesian Confidence Propagation Neural Network CD Cluster of Differentiation molecules on the cell surface CD4+ Cells expressing CD4 on the cell surface (T helper cells) CD8+ Cells expressing CD8 on the cell surface (cytotoxic T cells) CI Cumulative Incidence CIOMS Council for International Organizations of Medical Sciences CNS Central Nervous System COC Combined Oral Contraceptive COX Cyclo-Oxygenase CPMP Committee for Proprietary Medicinal Products CYP Cytochrome P-450 DAT1 Dopamine Transporter gene DDD Defined Daily Dose DES Diethylstilbestrol DNA Dioxyribonucleic Acid DRD2 Dopamine D2-receptor gene DRD3 Dopamine D3-receptor gene EF Etiologic Fraction EFPIA European Federation of Pharmaceutical Industries Association EFTA European Free Trade Area EMG Electromyography EPS Extra-Pyramidal Symptoms FDA Food and Drug Administration G6PD Glucose-6-Phosphate Dehydrogenase HIV Human Immunodeficiency Virus HMG-CoA 3-Hydroxy-3-Methylglutaryl Coenzyme A HOMA-IR Homeostasis Model Assessment for Insulin Resistance 5HTTLPR 5-Hydroxytryptamine Transporter gene Linked Polymorphic Region IAAA International Agranulocytosis and Aplastic Anemia study IC Information Component ICH International Conference of Harmonization IFPMA International Federation of Pharmaceutical Manufacturers Association Ig Immunoglobulin INR International Normalized Ratio INTDIS International Drug Information System IR Incidence Rate JPMA Japan Pharmaceutical Manufacturers Association MAH Marketing Authorization Holder MHC Major Histocompatibility Complex MHW Ministry of Health and Welfare Msc1 Micrococcus species restriction enzyme Na+ Natrium (sodium) ion NADPH Nicotinamide Adenine Dinucleotide Phosphate NSAID Non-Steroidal Anti-Inflammatory Agent PAHA Procaine-Amide Hydroxyl-Amine PhRMA Pharmaceutical Research and Manufacturers of America PSD Peripheral Sensory Disturbance PSUR Periodic Safety Update Report RFLP Restriction Fragment Length Polymorphism RR Relative Risk RYR1 Ryanodine Receptor gene SG Glucose Sensitivity = insulin-independent