Abstracts

Rationale: In 2007, stiripentol was granted a conditional marketing authorisation throughout European Union (EU). Given the limited amount of systematic safety assessment, the European Medicines Agency (EMA) required a post-marketing surveillance study. The aim was to prospectively collect real-world safety information on stiripentol use in patients with Dravet syndrome (DS), but also in any other epilepsies, with special focus on neutropenia, hepatotoxic potential, failure to thrive, behavior issues, and psychomotor development.

Methods: DIAVEY was a non-interventional EU-wide post-marketing study conducted in countries where stiripentol was marketed. All patients with refractory generalized tonic-clonic or clonic seizures newly prescribed stiripentol were eligible. The study covered the period from January 2007 till May 2012, and patients were evaluated at least yearly. Patients were included in the trial for a minimum of 1 year and patients in whom stiripentol treatment was discontinued were followed-up for one year after discontinuation.

Results: 227 patients in 57 centers from 11 European countries were enrolled. 152 had DS and 75 other epilepsies, mainly focal refractory epilepsies or epileptic encephalopathies other than DS. Mean age at inclusion was 7.2 years, 6.4 years in DS and 8.6 years in non-Dravet. 16 DS patients were less than 1 year-old, and 46 were between 1 and 3 years of age.

At stiripentol start, 79% of DS patients were receiving valproate, 71% clobazam, and 24% topiramate, while 56% of non-Dravet patients were receiving clobazam, 36% valproate, and 25% carbamazepine. Mean ± standard deviation (SD) stiripentol dosage at inclusion was 38.9 ± 16.8 mg/kg/d in DS and 33.5 ± 17.6 mg/kg/d in non-Dravet.

Mean ± SD treatment duration was 22.4 ± 13.8 months in DS and 15.9 ± 13.7 in non-Dravet. 83 patients (36.6%) discontinued stiripentol: 41 (27.0%) Dravet and 42 (56%) with other epilepsies. The main reasons for discontinuation were lack of efficacy and/or adverse drug reactions (ADRs).

Overall, 130 patients (57%) experienced 387 ADRs, mainly increased γ-glutamyl transferase levels (17%), increased aspartate aminotransferase levels (14%), decreased appetite (13%), somnolence (9%), fatigue (8%), and neutropenia (7%). All these events were already known. Also, 9 thrombopenia were reported in 7 patients, and further a cumulative review by the EMA thrombocytopenia was added as rare undesirable effects in the Summary of Product Characteristics (SmPC).

No negative impact of stiripentol on patients’ growth in height or weight was observed, nor on their development or behavior.

Despite this study was not intended to evaluate stiripentol efficacy, a decrease in tonic-clonic and clonic seizures frequency was observed in most patients.

Conclusions: DIAVEY didn’t identify new ADRs, and only thrombocytopenia was added in the SmPC. Lack of efficacy and/or ADRS were the main reasons for stiripentol discontinuation, which occurred more frequently in non-Dravet patients or when stiripentol dosage was notably lower than the 50 mg/kg/day recommended dose.

Funding: The DIAVEY study was sponsored by Biocodex