Serious skin reactions and selective COX-2 inhibitors: a case series from prescription-event monitoring in England.

Background: The erythema multiforme (EM) spectrum of bullous eruptions (toxic epidermal necrolysis [TEN] and Stevens-Johnson syndrome [SJS]) are rare and serious skin reactions that have been reported for cyclo-oxygenase (COX)-2 selective inhibitors. Our objectives were to identify and describe cases of serious skin reactions reported during postmarketing studies of COX-2 selective inhibitors.

Methods: A retrospective review of information from reports of serious skin reactions reported during prescription-event monitoring (PEM) studies of rofecoxib, celecoxib, etoricoxib and valdecoxib conducted in England since 1999. Exposure data were derived from dispensed prescriptions written by primary care physicians for each study drug. Outcome data were derived from questionnaires posted to prescribers at least 9 months after the date of the first prescription for each patient (valdecoxib data collection ongoing at the time of this study). Reports of EM, exfoliative dermatitis, SJS, TEN and symptoms associated with EM (EM syndrome) were identified from the PEM database. Additional data on diagnosis, relevant risk factors and management were requested for each case from the prescriber. A causality assessment was undertaken by a Drug Safety Research Unit research fellow and referred for expert review to a consultant dermatologist.

Results: Nine cases of serious skin reactions and two cases of symptoms associated with EM (EM syndrome) were identified. No reports of TEN were recorded. Six skin reaction questionnaires were returned. Of the nine cases of serious skin reactions, four cases (all SJS; one for each COX-2 selective inhibitor studied) were assessed as possibly related to use of the study drug (for combined cohorts: incidence risk 0.008%, 4 of 52,644 patients; rate 0.019 per 1000 patient-months of treatment). These four cases (two male, two female; age range 54-64 years) occurred within 2 weeks of starting treatment; the patient prescribed rofecoxib had reported risk factors (history of allergy, adverse reaction [asthma] to ibuprofen). The two cases from the EM syndrome search (one female, 35 years; one male, 80 years) occurred within 2 weeks of starting treatment; both were assessed as possibly related to use of celecoxib but considered suggestive of angio-oedema/urticaria and hypersensitivity reactions.

Conclusions: This case series provides useful and complementary information to other published studies about serious skin reactions reported during treatment with COX-2 selective inhibitors. The crude incidence of cases of SJS possibly related to the use of a COX-2 selective inhibitor in this case series is very low (0.008% for all four cohorts combined). Prescribers and patients should be aware of the severe and life-threatening risk of EM potentially associated with NSAIDs, including COX-2 selective inhibitors.