Safety of clozapine use during pregnancy: Analysis of international pharmacovigilance data.

PURPOSE: Safety data on clozapine use during pregnancy are limited. The aim of this study was to determine disproportionality in case safety reports on adverse pregnancy outcomes between clozapine and other antipsychotics (OAP) used during pregnancy. METHODS: We included all reports of suspected adverse drug reactions (ADRs) to antipsychotics registered in the World Health Organization global individual case safety report (ICSR) database (VigiBase) in children younger than 2 years and women aged 12-45 years. A case/non-case approach was used to evaluate the association between several pregnancy-related ADRs and clozapine exposure during pregnancy, using 2×2 contingency tables to investigate disproportionality and Standard MedDRA Queries to select cases. Clozapine exposure was defined as all ICSR-ADR combinations with clozapine as (one of) the suspected drug(s). Non-exposure was defined as all ICSR-ADR combinations with OAP as (one of) the suspected drug(s). RESULTS: We identified 42 236 unique ICSR-ADR combinations related with clozapine exposure and 170 710 with OAP exposure. Of these, 494 and 4645 ICSR-ADR combinations involved adverse pregnancy outcomes related with clozapine exposure and OAP exposure respectively. Overall, no signal of disproportionate reporting associating clozapine with the studied adverse pregnancy outcomes was found compared with OAP exposure. CONCLUSION: Based on global pharmacovigilance data, we did not find any evidence that clozapine is less safe during pregnancy than OAP. Although this is not automatically equivalent to the relative safety of clozapine during pregnancy, these findings add to the convergence of proofs to allow final conclusions and decisions regarding the treatment of pregnant women with clozapine.

Cyclo-oxygenase selectivity and chemical groups of nonsteroidal anti-inflammatory drugs and the frequency of reporting hypersensitivity reactions: a case/noncase study in VigiBase.

To date, no reports of hypersensitivity reactions (HSRs) among nonsteroidal anti-inflammatory drugs (NSAIDs) according to cyclo-oxygenase (COX) selectivity and chemical groups have been published in a single study. The present study assessed the reporting frequency of HSRs for NSAIDs based on their relative inhibitory potency toward COX enzymes and chemical groups, including the presence/absence of a functional sulfonamide group, in strata observed 5 years after market authorization. A case/noncase study was performed among individual case safety reports (ICSRs) with NSAIDs as suspected drugs in VigiBase, the WHO spontaneous reporting database. Cases were ICSRs mentioning angioedema and anaphylactic/anaphylactoid shock conditions, while noncases were ICSRs without HSRs. NSAIDs were categorized into (i) NSAIDs with high COX-2 selectivity (coxibs), (ii) noncoxib NSAIDs with COX-2 preference, (iii) NSAIDs with poor selectivity, or (iv) NSAIDs with unknown selectivity. Chemical groups were defined based on the Anatomical Therapeutic Chemical classification system and the presence/absence of a functional sulfonamide group. Reporting odds ratios (RORs) and 95% confidence intervals (95% CIs) were calculated using logistic regression analysis. We identified 13 229 cases and 106 444 noncases. In the first 5 years after marketing, poor-selectivity NSAIDs and acetic acid derivatives were associated with the highest ROR of HSRs (age- and sex-adjusted ROR 2.12, 95% CI 1.98-2.28; and ROR 2.21, 95% CI 1.83-2.66, respectively) compared with coxibs, and sulfonamide NSAIDs were associated with the highest ROR of HSRs compared with nonsulfonamide NSAIDs (age- and sex-adjusted ROR 1.38, 95% CI 1.29-1.47). After the first 5 years of marketing, most of the RORs returned to approximately 1.

The impact of age and sex on the reporting of cough and angioedema with renin-angiotensin system inhibitors: a case/noncase study in VigiBase.

The purpose of this study was to assess the impact of age and sex on the reporting of cough and angioedema related to renin-angiotensin system (RAS) inhibitors. A case/noncase study was performed in VigiBase. Two case groups were identified, reports of cough and reports of angioedema, and noncases were all reports of all other adverse events. Logistic regression analysis was used to assess the association between reporting of cough and angioedema with each class of RAS inhibitors stratified by age/sex and to control for confounding. The reporting of cough with angiotensin-converting enzyme (ACE) inhibitors was significantly higher in women than in men [adjusted reporting odds ratio (ROR): 44.0, 95% CI (43.2-44.8) for women vs. 29.2, 95% CI (28.5-29.9) for men]. There was no difference in reporting of cough linked to angiotensin receptor blockers (ARBs) and aliskiren between men and women. In contrast, the reporting of angioedema with ACE inhibitors and ARBs was significantly higher in men than in women, but for aliskiren, women had a significantly higher ROR than men [adjusted ROR: 5.20, 95% CI (4.18-6.46) for women vs. 3.04, 95% CI (2.30-4.02) for men]. The reporting of cough with ACE inhibitors was increased with age until reaching a plateau at middle adulthood (40-59 years) and the reporting of angioedema with ACE inhibitors was increased with age until elderly (60-79 years). Age had only a slight effect on the reporting of cough and angioedema with ARBs and aliskiren. Both age and sex have substantial effects on the reporting of cough and angioedema with RAS inhibitors and in particular ACE inhibitors. Further study is needed to determine whether these differences mainly express different adverse drug reaction risks in subgroups or also can be explained by factors influencing reporting.

Allergy-like immediate reactions with herbal medicines in children: A retrospective study using data from VigiBase®.

BACKGROUND: The use of herbal medicines in children and the general population is continually on the rise with an overall herbal lifetime and current use ranging between 0.8%-85.5% and 2.2%-8.9%, respectively. Although acute hypersensitivity reactions are generally considered to be rare, little knowledge exists on the frequency and type of these reactions especially in specific populations like children. OBJECTIVES: To assess the patterns of acute hypersensitivity reactions to herbal medicines reported to the WHO global individual case safety report (ICSR) database VigiBase® in children. STUDY DESIGN: From the original VigiBase® extract for the time between 1968 and 2014, we included all reports with adverse drug reactions (ADR) associated with herbal medicines in children where WHO-ART reaction terms were indicative of acute hypersensitivity reactions. RESULTS: VigiBase® contained 2646 ICSRs with 14 860 distinct adverse reactions reported in association with herbal medicine in children. Among those, 79 cases with 107 allergy-like reactions met our inclusion criteria. The most commonly reported WHO-ART terms were urticaria or rash/rash erythematous (59.8%), and allergic reaction (8.4%). The most frequently reported suspected herbal medicines were mixed herbal products (51.4%), Hedera helix (15.0%), and Echinacea purpurea (5.6%). Most frequent routes of administration were oral (75.9%), topical (8.9%), and rectal (3.8%). Over 30% of cases were reported in the age group from 7 to 12 years. The majority of reports were received from Germany (29.1%), Thailand (21.5%), and Australia (11.4%). CONCLUSION: VigiBase® contains a considerable number of acute hypersensitivity reactions in children associated with herbal medicines, including life-threatening reactions such as anaphylactic shock.

Allergy-Like Immediate Reactions with Herbal Medicines: A Retrospective Study Using Data from VigiBase®.

INTRODUCTION: Herbal medicines are used worldwide and with an increasing popularity in Western countries. Although often perceived as 'naturally safe', herbals may cause severe adverse drug reactions (ADRs), with immediate allergic reactions being particularly life threatening. OBJECTIVES: The aim of this study was to analyse immediate allergy-like ADRs to herbals documented in VigiBase®, the WHO international pharmacovigilance database. METHODS: The documentation of all suspected ADRs in association with herbal exposure reported to VigiBase® from 1969 to August 2014 was retrieved. Among all reports in which WHO-ART reaction terms were indicative of acute allergic reactions, those classified as 'suspect' with a documented causality assessment and latency time of ≤1 day were selected. For the most frequent specific herbal-ADR combinations, the information component (IC) as a measure of disproportionality based on Bayesian statistics was calculated. RESULTS: We identified 757 reports out of 1039 ADRs. Products with mixed herbals (36.0 %) as well as those administered orally (63.2 %) were predominant. The most frequent reactions were urticaria and rash (49.2 %). Anaphylactic reactions accounted for 9.5 %. Disproportionally frequent reporting of mouth edema (IC = 1.81) and anaphylactic reactions (IC = 1.24) to Phleum pretense were noted. CONCLUSION: Our findings indicate that herbal medicines for oral use carry a risk of causing immediate allergy-like ADRs. Studies using the Vigibase® database can identify specific combinations of particular herbs and adverse reactions. Healthcare professionals and patients should be aware of these risks and report any serious adverse experiences.

Quick assessment of drug-related admissions over time (QUADRAT study).

PURPOSE: To develop a computerized prescreening procedure for the identification of possible/probably Hospital Admissions potential Related to Medications (HARMs). METHOD: Pairs of drugs and reasons for hospitalization (generated automatically from the PHARMO record linkage database by using two data mining techniques) were assessed manually to determine whether they represented pharmacologically plausible adverse drug events (PP-ADEs). Two crude samples of these PP-ADEs (from 2005 and 2008) were examined manually to establish causality and preventability on the basis of hospital discharge letters plus medication dispensing data. The results were used to calculate the positive predictive value (PPV) of the crude causality PP-ADEs, the net percentage of possible/probably HARMs, and their potential preventability. RESULTS: Data mining by Gamma Poisson Shrinkage and trend analysis produced 1330 and 2941 significant drug-event pairs, respectively. After manual assessment, 307 different PP-ADEs remained. The annual prevalence of these PP-ADEs was stable at approximately 8% throughout 2000-2009. Manual assessment of two samples of crude PP-ADEs showed that their causality PPV was 53.7% (95%CI: 52.7%-54.7%) in 2005 and 47.9% (95%CI: 46.9%-49.0%) in 2008. The net contribution of possible/probably HARMs to all acute admissions was 4.6% (95%CI: 4.5%-4.8%) in 2005 and 3.9% (95%CI: 3.8%-4.0%) in 2008. The potential preventability of all possible/probably HARMs in the two samples was 19.3% (95%CI: 18.5-20.1). CONCLUSION: Automated pre-selection of PP-ADEs is an efficient way to monitor crude trends. Further validation and manual assessment of the automatically selected hospitalizations is necessary to get a more detailed and precise picture.

Statin-associated polymyalgia rheumatica. An analysis using WHO global individual case safety database: a case/non-case approach.

OBJECTIVE: To assess whether there is an association between statin use and the occurrence of polymyalgia rheumatic (PMR) in the spontaneous reporting database of the World Health Organisation (WHO). METHODS: We conducted a case/non-case study based on individual case safety reports (ICSR) in the WHO global ICSR database (VigiBase). Case reports containing the adverse event term polymyalgia rheumatica (WHOART or MedDRA Preferred Term) were defined as cases. Non-cases were all case reports containing other adverse event terms. Each case was matched to five non-cases by age, gender, and time of reporting. Case reports regarding a statin as suspected or concomitant drug were identified using the Anatomical Therapeutic Chemical (ATC) classification. Multivariate logistic regression was used to calculate reporting odds ratios (RORs) with 95% confidence intervals (CI). RESULTS: We identified 327 reports of PMR as cases and 1635 reports of other ADRs as non-cases. Among cases, statins were more frequently reported as suspected agent (29.4%) compared to non-cases (2.9%). After adjustment for several covariates, statins were significantly associated with reports of PMR (ROR 14.21; 95% CI 9.89-20.85). CONCLUSION: The results of this study lends support to previous anecdotal case reports in the literature suggesting that the use of a statin may be associated with the occurrence of PMR. Further studies are needed to study the strength of the association in more detail and to elucidate the underlying mechanism.

Association between statin use and lupus-like syndrome using spontaneous reports.

OBJECTIVES: Several case reports of lupus-like syndrome suggest that statins could have triggered the development of this rare autoimmune disease. However, data on the association between statin use and lupus-like syndrome are scarce. We assessed whether there was an association between statin use and the occurrence of lupus-like syndrome. METHODS: A case/noncase study based on individual case safety reports listed in the World Health Organization global individual case safety reports database (VigiBase) was conducted. According to World Health Organization adverse reaction terminology, cases were defined as reports of lupus-like syndrome. Each case was matched with 5 noncases by age, gender, and time of reporting. Use of statins was classified according to the Anatomical Therapeutic Chemical classification code system. Covariates, ie, use of corticosteroids, immunosuppressive drugs, nonsteroidal anti-inflammatory drugs, antidepressants, antiepileptics, proton pump inhibitors, and cardiovascular drugs, were determined. Multivariate logistic regression was used to calculate the reporting odds ratios with 95% confidence intervals. RESULTS: We identified 3362 reports of lupus-like syndrome as cases and 27,092 reports of other adverse drug reactions as noncases. Statins were more frequently reported as suspected drug in cases (3.2%) than in noncases (1.5%). After adjustment for several covariates, statins were associated with the reporting of lupus-like syndrome (reporting odds ratios 2.01; 95% confidence intervals 1.61-2.51). CONCLUSIONS: We found an association between reporting of statins and lupus-like syndrome. Further studies are needed to confirm this finding in more detail and establish causality.

Mapping the safety profile of biologicals: a disproportionality analysis using the WHO adverse drug reaction database, VigiBase.

BACKGROUND: Biologicals have specific characteristics, as compared with the small molecule drugs, and carry specific risks. Safety problems, for example infliximab and the risk for tuberculosis, have been identified via spontaneous reports of suspected adverse drug reactions (ADRs). However, in general there is limited data on the nature of spontaneously reported suspected ADRs for biologicals. OBJECTIVE: To map the safety profile of biologicals as compared with all other drugs. In addition, mechanistic classes of biologicals will be compared. METHODS: Data was obtained from the ADR database (VigiBase) maintained by the WHO Collaborating Centre for International Drug Monitoring. A disproportionality analysis was performed in which case reports for biologicals and all other drugs (the reference group), reported between January 1995 and December 2008, were selected. Vaccines were not included in the analysis. Suspected ADRs were classified according to Medical Dictionary for Regulatory Activities (MedDRA) version 12.0 at the System Organ Class (SOC) level. Biologicals were classified into mechanistic classes: antibodies, cytokines, enzymes, growth factors, hormones (reference group), interferons, receptors and others/various. The safety profile of the biologicals versus all other drugs in the database and of the various mechanistic classes of biologicals was compared using the proportional reporting ratio (PRR). RESULTS: 191,004 case reports containing 546,474 suspected ADRs were reported for 62 different biologicals, and 2,556,209 case reports containing 8,761,522 suspected ADRs were reported for all other drugs (the reference group). It was found that two-thirds of all suspected ADRs reported for biologicals were reported for five active substances: etanercept (20.3%), interferon-beta-1a (15.6%), infliximab (11.6%), teriparatide (10.7%) and adalimumab (9.0%). Comparison of the safety profile of biologicals and the reference group showed that suspected ADRs for biologicals were more frequently reported in the SOCs 'Infections and infestations' (PRR 4.5), 'Surgical and medical procedures' (PRR 2.4) and 'Neoplasms benign, malignant and unspecified' (PRR 2.1), and less frequently reported in the SOCs 'Psychiatric disorders' (PRR 0.4), 'Vascular disorders' (PRR 0.4) and 'Pregnancy, puerperium and perinatal conditions' (PRR 0.4). Regarding the differences in safety profile between various mechanistic classes of biologicals, compared with hormones (reference group), 'Infections and infestations' were more frequently reported for receptors and antibodies. 'Neoplasms benign, malignant and unspecified' were more frequently reported for antibodies, cytokines, interferons and receptors, and less frequently for enzymes as compared with the reference group. CONCLUSIONS: In VigiBase, five biologicals comprise two-thirds of the suspected ADRs reported for biologicals, which might distort the relation found between a specific biological and a specific adverse event in case of quantitative signal detection. Therefore the choice of reference group to be used in case of quantitative signal detection should be considered very carefully. This study confirmed that biologicals have a different safety profile compared with all other drugs in the database and, within the group of biologicals, differences exist between mechanistic classes. Infections are, for example, frequently reported for receptors and antibodies, which often have an immune compromising effect. Such predictable safety issues should be specifically studied by preregistration clinical trials and/or targeted pharmacovigilance. In addition, since not all adverse reactions can be predicted or detected during development, spontaneous reporting remains an important tool for the early detection of signals.

Medication errors: problems and recommendations from a consensus meeting.

Here we discuss 15 recommendations for reducing the risks of medication errors: 1. Provision of sufficient undergraduate learning opportunities to make medical students safe prescribers. 2. Provision of opportunities for students to practise skills that help to reduce errors. 3. Education of students about common types of medication errors and how to avoid them. 4. Education of prescribers in taking accurate drug histories. 5. Assessment in medical schools of prescribing knowledge and skills and demonstration that newly qualified doctors are safe prescribers. 6. European harmonization of prescribing and safety recommendations and regulatory measures, with regular feedback about rational drug use. 7. Comprehensive assessment of elderly patients for declining function. 8. Exploration of low-dose regimens for elderly patients and preparation of special formulations as required. 9. Training for all health-care professionals in drug use, adverse effects, and medication errors in elderly people. 10. More involvement of pharmacists in clinical practice. 11. Introduction of integrated prescription forms and national implementation in individual countries. 12. Development of better monitoring systems for detecting medication errors, based on classification and analysis of spontaneous reports of previous reactions, and for investigating the possible role of medication errors when patients die. 13. Use of IT systems, when available, to provide methods of avoiding medication errors; standardization, proper evaluation, and certification of clinical information systems. 14. Nonjudgmental communication with patients about their concerns and elicitation of symptoms that they perceive to be adverse drug reactions. 15. Avoidance of defensive reactions if patients mention symptoms resulting from medication errors.

Intranasally administered corticosteroids and neuropsychiatric disturbances: a review of the international pharmacovigilance programme of the World Health Organization.

BACKGROUND: The systemic use of corticosteroids is connected with a variety of psychiatric and neurologic effects. Corticosteroids for intranasal administration (INCs) are considered to act locally and to exert minimal systemic effects. An unexpected cluster of case reports of neuropsychiatric disorders during intranasal corticosteroid use was reported to the World Health Organization Uppsala Monitoring Centre. OBJECTIVE: To investigate the possible connection between intranasal corticosteroid use and the development of neuropsychiatric disorders, as reported to the International Pharmacovigilance Programme. METHODS: All reports containing adverse event terms indicating neuropsychiatric disturbances in suspected connection with intranasal corticosteroids were retrieved from Vigibase and evaluated (April 2006). The case reports are heterogeneous and vary regarding source, documentation quality, and relationship likelihood. RESULTS: A total of 429 reports were received from 16 countries (1980-April 2006), of neuropsychiatric events occurring in patients using INCs, representing 7.6% of the total of reports regarding these drugs in the same period. Frequently reported events were nervousness, anxiety, agitation, insomnia, emotional lability, depression, somnolence, confusion, convulsions, and migraine. Most reports concerned fluticasone propionate, beclometasone dipropionate, mometasone furoate, or budesonide. In 370 reports (86.2%), the INC was the sole suspect drug and in 220 (51.3%) it was the only drug used. In 97 of 108 patients who had discontinued use of the intranasal corticosteroid, the reaction abated. Of 41 patients, 32 had a relapse when the drug was reintroduced. CONCLUSIONS: The data collected by the International Pharmacovigilance Programme suggest that the intranasal use of corticosteroids can be complicated by neuropsychiatric adverse reactions. Further study is needed to confirm the connection and to determine the frequency and risk factors of such reactions.

The association between antidepressant use and disturbances in glucose homeostasis: evidence from spontaneous reports.

OBJECTIVES: Depression is common in patients with diabetes, and the use of antidepressants may impair glycaemic control. We assessed the association between antidepressant use and hyper- and hypoglycaemia. METHODS: Based on spontaneous reports listed in the World Health Organization (WHO) Adverse Drug Reaction Database, a case-control study was conducted. The study base consisted of all adverse drug reactions (ADRs) ascribed to antidepressants, antipsychotics and benzodiazepines between 1969 and 2005. Cases were defined as reported ADRs classified as hyper- or hypoglycaemia and separated in different study populations. All other reports were considered as controls. Exposure to antidepressants was the primary determinant investigated. Benzodiazepines and antipsychotics were chosen as reference groups. Potential confounding factors, namely, age, gender, use of antidiabetic medication, use of hyper- or hypoglycaemia-inducing comedication and reporting year, were determined on the index date. Multivariate logistic regression was used to evaluate the strength of the association, which was expressed as reporting odds ratios (RORs) with 95% confidence intervals (95% CI). RESULTS: Overall, the use of antidepressants was associated with hyperglycaemia [ROR 1.52 (95% CI: 1.20-1.93)] and of hypoglycaemia [ROR 1.84 (95% CI: 1.40-2.42)]. The association with hyperglycaemia was most pronounced for antidepressants with affinity for the 5-HT(2c) receptor, histamine-(1) receptor and norepinephrinic (NE) reuptake transporter. The association with hypoglycaemia was most pronounced for antidepressants with affinity for the serotonin reuptake transporter. CONCLUSION: The results of this study strengthen the findings in individual case reports that the use of antidepressants is associated with disturbances in glucose homeostasis.

An analysis of Vigimed, a global e-mail system for the exchange of pharmacovigilance information.

BACKGROUND AND AIM: The Internet provides novel ways for communication and data exchange between national regulators. One innovation was the introduction of Vigimed, an e-mail discussion forum for national pharmacovigilance centres (NPCs). We reviewed a sample of Vigimed messages to learn more about this new tool and about the problems encountered in everyday pharmacovigilance and how these are handled. METHODS: We analysed the contents of 100 subsequent questions and the corresponding responses as stored in the Vigimed datafile. RESULTS: To the 100 questions circulated through Vigimed, 575 answers were received; mean number of answers per question 6, range 0-20. Fifty-five (77%) of the 71 collaborating countries and 88 (43%) of the 204 individuals who had access in the study period had submitted at least one question or answer. These countries were in all parts of the world and in various phases of development. A total of 38% of the questions concerned the regulatory status of a drug; 30% safety issues; 13% regulatory actions under consideration; and 10% drug use-related problems (more than one category possible). Of the questions, 89% concerned established drugs; 11% were classified as new. A total of 90% of the questions concerned specific active substances or drug groups. Of the drugs, 73% were classified as 'orthodox' and 9% as herbal; 4% were vaccines and 4% excipients. Emerging drug groups (anatomical therapeutic chemical codes) were NSAIDs and analgesics (M01, N02), antibacterials (J01), antiobesity drugs (A08), psychotropic drugs (N05) and antihistamines (R06). DISCUSSION: NPCs operate in a restricted environment and there is little published information about the daily practices and experiences at NPCs. Our study concerned a sample in a limited period in time. In the meantime, the use of Vigimed has greatly expanded. The data in the Vigimed records are subjected to confidentiality in regard to the identities of countries, staff members, drug products and pharmaceutical companies, which limits the presentation of data in a publication. For information about the actions taken to manage the matters and problems raised in Vigimed it would have been necessary to contact the NPCs and acquire follow-up data. CONCLUSIONS: The Vigimed e-mail discussion group was rapidly incorporated into the routines at NPCs in many countries around the world. When two or more persons per country have access, participation increases. The matters raised predominantly refer to regulatory policy, safety concerns and drug use-related problems, and mainly concern established drugs. The latter emphasises the need for persistent monitoring of all drugs. New safety concerns are often sensitive and uncertain; the timely and efficient communication of such suspicions benefits from an environment of confidentiality. The Vigimed records give a unique view of real-life pharmacovigilance, of the matters addressed, the problems encountered, the data needed and the ways in which NPCs help each other. Such information can help make pharmacovigilance more efficient and effective.

Allergic reactions to medicines derived from Pelargonium species.

Pelargonium (Pelargonium sidoides DC and P. reniforme Curtis) is reported to have immune modulating properties and antibacterial activity, and Pelargonium extracts have been used for the treatment of respiratory tract and gastrointestinal infections. Introduced in the early 1980s in Germany, Umckaloabo (ISO Arzneimittel), an ethanolic extract of the roots of P. sidoides and P. reniforme, was the first Pelargonium-derived product to be commonly used in a country in the EU. According to the Umckaloabo product information, this extract has no known adverse effects. However, there is a theoretical risk of interactions with anticoagulants such as warfarin, and antiplatelet drugs, such as aspirin (acetylsalicylic acid). To date, the Uppsala Monitoring Centre has, through the WHO international pharmacovigilance programme, received 34 case reports of allergic reactions suspected to be associated with the use of Pelargonium extract, all originating from Germany. In a number of these reports, the description and timing of the event was indicative of an acute Coombs and Gell Type I hypersensitivity reaction; two of these patients needed treatment for circulatory failure. So far, the experience of such reactions is limited to Germany. Since Pelargonium-containing herbal products have recently been approved in a number of other countries, the possibility of the occurrence of allergic reactions has become of more general interest and further information regarding these products is needed.

Risk of aplastic anemia in patients using antiepileptic drugs.

PURPOSE: To assess the association between exposure to antiepileptic drugs (AEDs) and the occurrence of aplastic anemia. METHODS: A retrospective case-control study was conducted using data from the U.K. General Practitioners Research Database (GPRD). Cases were defined as patients diagnosed with aplastic anemia. For each case, up to three control patients were matched on age, sex, and medical practice. Cases and controls were compared with respect to AED use. The effects of duration of AED use were assessed. Characteristics of individual cases with AED use were reviewed. RESULTS: The study population comprised 173 cases and 497 controls. AED use was more prevalent among cases (9.2%) than among controls (0.8%). After adjustment for confounders, the use of AEDs was significantly associated with aplastic anemia (adjusted odds ratio (OR), 9.5; 95% confidence interval (CI), 3.0-39.7). The most frequently used AEDs were carbamazepine (CBZ), valproic acid (VPA), and phenytoin. The 16 exposed cases were heterogeneous with respect to patient and exposure characteristics: the age of these patients varied from 1 to 92 years, and the duration of AED use varied from 17 days to 6.8 years. CONCLUSIONS: This study indicates that use of AEDs, in particular CBZ and VPA, is associated with a ninefold increased risk of aplastic anemia. Physicians should be alert to the possibility of AED-associated aplastic anemia.

Drug-induced immune thrombocytopenia.

Thrombocytopenia can have several causes, including the use of certain drugs. The mechanism behind drug-induced thrombocytopenia is either a decrease in platelet production (bone marrow toxicity) or an increased destruction (immune-mediated thrombocytopenia). In addition, pseudothrombocytopenia, an in vitro effect, has to be distinguished from true drug-induced thrombocytopenia. This article reviews literature on drug-induced immune thrombocytopenia, with the exception of thrombo-haemorrhagic disorders such as thrombotic thrombocytopenic purpura and heparin-induced thrombocytopenia and thrombosis. A literature search in PubMed combined with a check of the reference lists of all the retrieved articles resulted in 108 articles relevant to the subject. The drug classes that are most often associated with drug-induced immune thrombocytopenia are cinchona alkaloid derivatives (quinine, quinidine), sulfonamides, NSAIDs, anticonvulsants, disease modifying antirheumatic drugs and diuretics. Several other drugs are occasionally described in case reports of thrombocytopenia; an updated review of these case reports can be found on the internet. A small number of epidemiological studies, differing largely in the methodology used, describe incidences in the magnitude of 10 cases per 1 000 000 inhabitants per year. No clear risk factors could be identified from these studies. The underlying mechanism of drug-induced immune thrombocytopenia is not completely clarified, but at least three different types of antibodies appear to play a role (hapten-dependent antibodies, drug-induced, platelet-reactive auto-antibodies and drug-dependent antibodies). Targets for drug-dependent antibodies are glycoproteins on the cell membrane of the platelets, such as glycoprotein (GP) Ib/IX and GPIIb/IIIa. Diagnosis of drug-induced immune thrombocytopenia may consist of identifying clinical symptoms (bruising, petechiae, bleeding), a careful evaluation of the causal relationship of the suspected causative drug, general laboratory investigation, such as total blood count and peripheral blood smear (to rule out pseudothrombocytopenia), and platelet serology tests. The sensitivity of these tests is dependent on factors such as the concentration of the drug in the test and the potential sensitisation of the patient by metabolites instead of the parent drug. Drug-induced immune thrombocytopenia can be treated by withholding the causative drug and, in severe cases associated with bleeding, by platelet transfusion. Although drug-induced thrombocytopenia is a relatively rare adverse drug reaction, its consequences may be severe. Therefore it is important to extend our knowledge on this subject. Future research should focus on the identification of potential risk factors, as well as the exact mechanism underlying drug-induced thrombocytopenia.