Drugs and dilated cardiomyopathies: a case/noncase study in the French PharmacoVigilance Database

AIMS

To evaluate putative associations between drugs and dilated cardiomyopathy.

METHODS

We used the case/noncase method in the French PharmacoVigilance Database (FPVD). Cases were all the observations with dilated cardiomyopathy registered into the FPVD between 1 January 1990 and 30 June 2007. Noncases were all other reports other than those studied. Anthracyclines were used as positive controls. Data were expressed as reporting odds ratio (ROR) with their 95% confidence intervals.

RESULTS

Out of the 258 729 adverse drug reaction (ADR) reports recorded in the FPVD between 1 January 1990 and 30 June 2007, 47 (22 men, mean age 49 years) were defined as dilated cardiomyopathy. In these 47 patients, 67 drugs were ‘suspect’. A significant ROR was found with cytotoxic (epirubicin, mitoxantrone, cyclophosphamide, gemcitabine, fluorouracil) and antiretroviral (lamividune, zidovudine, abacavir) but also with isotretinoin, prednisone, appetite suppressant (clobenzorex) and psychotropic [antipsychotic (clozapine, olanzapine), lithium, antidepressant (clomipramine, amitriptyline, fluvoxamine)] drugs.

CONCLUSIONS

The present study describes an association between some drugs and reports of dilated cardiomyopathies. This relationship involves not only some already suspected drugs (anthracyclines, antiretrovirals), but also other drugs (antipsychotics, lithium, antidepressants, retinoids) less known to induce such an ADR. Despite the mandatory limits of this kind of study (underreporting, confounding factors …), these data represent a pharmacovigilance signal and could contribute to establish further prospective studies in order to confirm such signals.     

Prescribed drugs and violence: a case/noncase study in the French PharmacoVigilance Database

Aim  

Our aim was to identify prescribed drugs associated with violent behaviours using the French PharmacoVigilance Database (FPVD).     

Trends of reporting of 'serious'vs. 'non-serious' adverse drug reactions over time: a study in the French PharmacoVigilance Database

AIM

To investigate trends in spontaneous reporting to the French Pharmacovigilance system of ‘serious’ (SADRs) and ‘non-serious’ (NSADRs) adverse drug reactions over time.

METHODS

Annual SADR : NSADR ratios were calculated for each drug and their evolution tested with linear trend tests.

RESULTS

Among the 39 new active substances commercialized in France in 2000, 16 had sufficient data to perform linear trend tests. An increasing linear relation was found for five widely prescribed drugs, a non-significant increasing trend for eight others, i.e. drugs mostly used in hospitals.

CONCLUSION

ADR reports mainly concern NSADRs during first years of marketing. Reports of SADRs are proportionally more frequent later.     

Hospital admissions for 'drug-induced' disorders in England: a study using the Hospital Episodes Statistics (HES) database

AIMS: To review Hospital Episode Statistics (HES) data for England coded as being 'drug induced' during 1996-2000 and to consider their potential utility for assessing the public health burden of adverse drug reactions (ADRs) and studying drug safety. METHODS: ICD-10 codes including the words 'drug-induced' or 'due to' a medicine or which are recognized to be invariably caused by a drug were extracted along with external cause codes indicating that a drug was implicated (i.e. Y40-59 in ICD-10). We also calculated the proportions of patients with each 'drug-induced' code for whom an external cause code had been applied. RESULTS: During the 5-year study period there were almost 53.8 million hospital admissions in England, of which 44 411 (0.083%) were coded as 'drug-induced' and 168 958 (0.314%) were associated with a relevant external cause code. The numbers of patients with 'drug-induced' codes used were generally stable during the study period (range 7454-8860 per year) but the application of external cause codes increased in each year and by 40% overall (from 24 786 in 1996 to 34 843 in 2000). The overall proportion of 'drug-induced' codes associated with a relevant external cause code was quite low (12-15%) but there was considerable variation between codes. CONCLUSIONS: Comparisons with published studies indicate that HES data grossly underestimate the burden of drug-induced disorders as a cause of hospital admission. There are likely to be multiple underlying reasons including under-recognition, under-recording and limitations of the coding system. The potential of these data for identifying previously unrecognized serious ADRs is limited by constraints on the availability of detailed data regarding individual cases.     

A prediction model‐based algorithm for computer‐assisted database screening of adverse drug reactions in the Netherlands

Purpose

The statistical screening of pharmacovigilance databases containing spontaneously reported adverse drug reactions (ADRs) is mainly based on disproportionality analysis. The aim of this study was to improve the efficiency of full database screening using a prediction model‐based approach.

Methods

A logistic regression‐based prediction model containing 5 candidate predictors was developed and internally validated using the Summary of Product Characteristics as the gold standard for the outcome. All drug‐ADR associations, with the exception of those related to vaccines, with a minimum of 3 reports formed the training data for the model. Performance was based on the area under the receiver operating characteristic curve (AUC). Results were compared with the current method of database screening based on the number of previously analyzed associations.

Results

A total of 25 026 unique drug‐ADR associations formed the training data for the model. The final model contained all 5 candidate predictors (number of reports, disproportionality, reports from healthcare professionals, reports from marketing authorization holders, Naranjo score). The AUC for the full model was 0.740 (95% CI; 0.734–0.747). The internal validity was good based on the calibration curve and bootstrapping analysis (AUC after bootstrapping = 0.739). Compared with the old method, the AUC increased from 0.649 to 0.740, and the proportion of potential signals increased by approximately 50% (from 12.3% to 19.4%).

Conclusions

A prediction model‐based approach can be a useful tool to create priority‐based listings for signal detection in databases consisting of spontaneous ADRs.     

The nature of the scientific evidence leading to drug withdrawals for pharmacovigilance reasons in France

INTRODUCTION: Because of design, objectives and number of included subjects, clinical studies are insufficient to assess the safety of new drugs. Sometimes, serious adverse drug reactions (ADRs) led to withdrawal of the drug from the market after their approval. The objective of our study was to determine the scientific evidences leading to drug withdrawal for pharmacovigilance reasons in France. METHODS: Data coming from French Health Products Safety Agency, literature and Toulouse Pharmacovigilance Center allowed to identify all drugs withdrawn from the French market for pharmacovigilance reasons from 1998 to 2004. We classified data according to their study design (Randomized Clinical Trial [RCT], case serie or case report, case-control study, cohort study, observational study, animal study), the organ/system affected and the type of ADR. RESULTS: A total of 21 drugs were withdrawn for safety reasons between 1998 and 2004 in France. The most frequent ADRs were hepatic (n = 7), cardiovascular (n = 4) or neurological (n = 3) ones. Eleven withdrawals were due to type-B ('unexpected') reactions (52%). For 19 out of 21 drugs, scientific evidence leading to drug withdrawal came from spontaneous case reports (or case series). Among these, case reports were the sole evidence in 12 cases. Withdrawals were based on evidence from case reports in combination with case-control or cohort study in four cases, in combination with observational study in two cases or in combination with animal study in two other cases. In only one case, a RCT supported the decision. CONCLUSIONS: This study underlines the importance of spontaneous case reports in detecting signals and supporting withdrawal of drug for pharmacovigilance reasons in France. Health authorities suffer from lack of comparative data resource. In this perspective, a pharmaco-epidemiological population-based database could represent a helpful tool to both generate and test safety hypotheses.     

Reporting rate of adverse drug reactions to the French pharmacovigilance system with three step 2 analgesic drugs: dextropropoxyphene, tramadol and codeine (in combination with paracetamol)

AIMS

Three ‘weak’ opioid analgesics in association with paracetamol are marketed in France as step 2 analgesics: dextropropoxyphene, tramadol and codeine. These combinations are involved in several adverse drug reactions (ADRs), but no data are available about their comparative reporting rate. The aim was to compare the reporting rate of ADRs between tramadol/paracetamol (TRM+P), codeine/paracetamol (COD+P) and dextropropoxyphene/paracetamol (DXP+P).

METHODS

All spontaneous reports submitted to the French Pharmacovigilance Database from 1 January 1987 to 31 December 2006 suspected to be induced by one of the three step 2 analgesic combinations (DXP+P, TRM+P, COD+P) were extracted. Their consumption for the same period was obtained from the French Drug Agency. The number of ADRs, serious ADRs and different organ classes of ADRs were compared according to their consumption. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each variable using DXP+P as reference.

RESULTS

The reporting rate of ADRs was calculated as 24.9/100 000 person-years for DXP+P, 44.5/100 000 person-years for TRM+P and 12.5/100 000 person-years for COD+P. The reporting rate (OR 0.56, 95% CI 0.50, 0.63) and ‘seriousness»’ (OR 0.65, 95% CI 0.53, 0.80) of ADRs were significantly higher with TRM+P than with DXP+P. However, hepatobiliary ADRs were significantly more frequent with the DXP+P combination (OR 2.62, 95% CI 1.59, 4.37). In contrast, the reporting rate (OR 1.99, 95% CI 1.82, 2.18) and ‘seriousness’ (OR 2.64, 95% CI 2.24, 3.11) of ADRs were significantly higher with DXP+P than with COD+P.

CONCLUSIONS

Among the three step 2 analgesic combinations, reporting rate and ‘seriousness’ of ADRs are the highest with TRM+P and the lowest with COD+P. Our study suggests that the safety profile of DXP+P is worst than that of COD+P.