Background Pharmacovigilance uses data mining algorithms on spontaneous reporting databases to assess significant associations between adverse drug reactions (ADR) and drugs. These pharmacovigilance databases provide early warnings of hazards that were missed before marketing a drug, mainly because of the limitations of clinical trials. In July 2013, tetrazepam marketing was suspended, after four decades on the market, due to serious skin and subcutaneous tissue disorders (SSTD-ADR).
Purpose To detect possible pharmacovigilance signals between SSTD-ADR and benzodiazepines, by applying data mining on the American Pharmacovigilance Database (FAERS) whose data were public.
Material and methods We calculated data mining algorithms (PRR: proportional reporting ratio; ROR: reporting odds ratio; IC: information component, and EBGM: empiric Bayesian geometric mean) on spontaneous reports of SSTD-ADR due to benzodiazepines commercialised in the USA, registered in FAERS. All statistical algorithms were calculated from 2 × 2 contingency tables, according to the literature: PRR–1.96 SE (standard error) (with χ2 and p value associated), ROR–1.96 SE, IC–2 SD (standard deviation) and EBGM–2 SD precision algorithms were calculated. A signal was considered when: PRR ≥2 (with χ2 value ≥4); lower band of 95% two sided confidence interval (95% CI) of ROR >1; 95% CI two sided of IC >0; or 95% CI one sided of EBGM ≥2. All calculations were done using Excel 2011 14.4.1.
Results We found 3957 SSTD-ADR (3.05% of all benzodiazepine ADR reports). ROR yielded signals for 8 drugs (clobazam, clonazepam, clorazepate, midazolam, oxazepam, quazepam, tetrazepam and triazolam), PRR and IC for 4 (clobazam, midazolam, quazepam and tretrazepam), while EBGM detected only a signal for tetrazepam.
Midazolam, clobazam and quazepam originated a signal by 3 algorithms. Tetrazepam was the only one which generated a signal by 4 algorithms. Clobazam originated a signal for Stevens-Johnson Syndrome and Blister; midazolam for toxic epidermal necrolysis, DRESS Syndrome and erythema; quazepam for erythema multiform and drug eruption; and tetrazepam for dermatitis bullous, toxic skin eruption, rash maculopapular and rash erythematous. (All of these terms are ‘preferred term’ level of the MedDRA classification).
Conclusion Our pharmacovigilance data mining revealed the existence of potential signals for benzodiazepine and SSTD-ADR. However, to establish causality, larger studies providing new clinical evaluation on these associations will be required.
No conflict of interest.
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