The approval is backed by the effectiveness established in 2, 12-week studies in patients with Dravet syndrome, and open-label long-term studies.
The FDA has approved stiripentol (Diacomit), as capsules and powder, for the treatment of seizures associated with Dravet syndrome in patients 2 years of age and older taking clobazam, announced Biocodex, the company marketing the medication.
The approval was backed by the effectiveness established in two, 12-week multicenter placebo-controlled, double-blind studies in patients with Dravet syndrome (Study 1 and Study 2), and open-label long-term studies. Participants enrolled in the study were required to be 2 to 18 years of age, to have Dravet syndrome that was inadequately controlled on clobazam and valproate with at least 4 generalized clonic or tonic-clonic seizures per month, despite optimized therapy. Approximately 53% of study participants were female and the mean age was 9.2 years. In both studies, the demographic and baseline clinical characteristics were similar between treatment groups.
In Study 1 and Study 2, participants were randomly allocated to receive either a fixed dose of 50 mg/kg/day in divided doses with no dose titration of stiripentol, or placebo, added to participants’ treatment with clobazam and valproate. Stiripentol was administered to 21 participants in Study 1 and 12 participants in Study 2, while 20 participants were randomized to placebo in Study 1 and 11 in Study 2, for a treatment duration of 8 weeks.
The primary endpoint for both studies was the responder rate, which researchers defined as participants who experienced greater than a 50% decrease in the frequency (per 30 days) of generalized clonic or tonic-clonic seizures throughout the double-blind treatment period compared to the 4-week baseline period. Researchers also evaluated the mean change from baseline in frequency of generalized clonic or tonic-clonic seizures.
In both studies, the primary efficacy endpoint was significantly greater for stiripentol than placebo. The results also demonstrated that stiripentol was superior to placebo in the reduction in mean frequency of generalized clonic or tonic-clonic seizures. There were no reports of generalized clonic or tonic-clonic seizure for the duration of the study in 43% and 25% of participants in Study 1 and Study 2, respectively.
Adverse reactions that occurred in at least 10% of stiripentol-treated patients include somnolence (67%), decreased appetite (45%), agitation (27%), ataxia (27%), weight loss (27%), hypotonia (24%), nausea (15%), tremor (15%), dysarthria (12%) and insomnia (12%).
Reported adverse reactions that occurred in 5% or more of stiripentol-treated patients and at a rate greater than in patients on placebo included nausea (15%), vomiting (9%), salivary hypersecretion (6%), fatigue (9%), pyrexia (6%), bronchitis (6%), nasopharyngitis (6%), weight decreased (27%), weight increased (6%), decreased appetite (46%), somnolence (67%), ataxia (27%), hypotonia (18%), tremor (15%), dysarthria (12%), agitation (27%), insomnia (12%) and aggression (9%).
Two patients were reported to discontinue stiripentol treatment because of adverse reactions: 1 patient had an adverse reaction of status epilepticus; the second patient had drowsiness, balance impairment and sialorrhea.
The recommended oral dosage of stiripentol is 50 mg/kg/day, administered in 2 or 3 divided doses. If the exact dosage is not achievable in the available strengths, the prescribing information advises rounding to the nearest possible dosage, which is usually within 50 mg to 150 mg of the recommended 50 mg/kg/day. The maximum recommended total dosage is 3000 mg/day.
If stiripentol is discontinued, the drug should be withdrawn gradually to minimize the risk of increased seizure frequency and status epilepticus.
The safety and efficacy of stiripentol is unknown in children under 2 years of age, and there is also limited information on safety in patients 6 months and older in non-pivotal trials.
The FDA advises that stiripentol be dispensed with a patient Medication Guide describing important information about the drug’s uses and risk.
Diacomit [prescribing information]. Beauvais, France: Biocodex; 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206709s000,207223s000lbl.pdf. Accessed August, 21, 2018.