Rationale: Following its market authorization in Japan (November 2012), a post-marketing surveillance
study in all Dravet syndrome (DS) patients that initiated stiripentol (STP) was conducted.
Methods: In the present surveillance study analysis, we report an observation period up to 156 weeks after STP initiation. Here, STP’s safety and effectiveness were prospectively investigated in all DS patients in Japan who were administrated the drug from November 2012 to August 2017. Patients administered STP for the first time were defined as “new patients”, and those who continued to take STP after domestic clinical studies were defined as “continuous patients”.
All adverse reactions were reported by the treating physicians, who also comprehensively assessed and compared patients’ condition before and after STP’s initiation.
Overall improvement was rated on a 5-point scale (marked, moderate, mild, unchanged, or worsened) or as undetermined based on the evaluations for frequency of seizures, duration and intensity of seizures, and ability to undertake activities of daily living. Additionally, the percentage change in seizure frequency was calculated.
Results: Data were collected in 521 patients, of whom 520 (486 new and 34 continuous) were included in the safety analysis set (SAS), and 515 (482 new and 33 continuous) were included in the effectiveness analysis set (EAS). Adverse drug reactions occurred in 69.2 % of the 520 SAS patients; the most common were somnolence (37.3 %), loss of appetite (26.5 %), dizziness (12.5%), weight reduction (8.5%), and drug concentration increase (6.2%). No new safety concerns due to STP were observed.
Overall, 12 deaths were reported: 2 cardiopulmonary arrests, 2 near drownings, 1 encephalopathy, 1 hypoxic-ischemic encephalopathy, 1 sudden death, 1 status epilepticus, 1 generalised tonic-clonic seizure 1 acute circulatory failure, 1 liver injury, and 1 hepatobiliary cancer
.
After 156 weeks or at the time of drug discontinuation, 37.9% of new patients were markedly or moderately improved, and 60.1% were at least mildly improved. None of the continuous patients were considered as “worsened”. Also, after 156 weeks, the median percent change from baseline in tonic-clonic and/or clonic seizure frequency ranged from -46.43% to -75.00%. After 4 weeks of treatment, the median percent change from baseline in seizure frequency was -64.29% for
focal impaired awareness seizures, and -61.03% for
generalized myoclonic seizures and/or generalized atypical absence seizures. Then seizure frequency gradually decreased and reached -100% after 57 weeks and 49 weeks of treatment respectively.
Conclusions: The present analysis reports the largest cohort of patients in a real-world setting, followed for 3 years. Here, we did not identify new adverse drug reactions and confirmed the long-term efficacy of STP in decreasing tonic-clonic/clonic seizures. Additionally, we report efficacy of stiripentol on focal impaired awareness seizures as well as generalized myoclonic/generalized atypical absence seizures.
Funding: Sponsored by Meiji Seika Pharma