How do stiripentol and fenfluramine work for seizure control?
Stiripentol acts as an allosteric modulator of GABAA receptors, boosting inhibitory signaling in the brain, and inhibits CYP450 enzymes to raise levels of other antiseizure drugs like clobazam. Fenfluramine, a serotonin-releasing agent and sigma-1 receptor agonist, reduces seizure activity through enhanced serotonergic neurotransmission and possibly AMPA receptor modulation. Both target Dravet syndrome primarily, but stiripentol emphasizes GABAergic effects while fenfluramine leverages serotonin pathways.[1][2]
Seizure reduction rates in Dravet syndrome trials
In randomized controlled trials for Dravet syndrome patients (ages 6 months+), stiripentol added to clobazam and valproate cut monthly drop seizures by 53-71% versus 30% placebo reduction (p<0.001). Fenfluramine (0.4 mg/kg/day) reduced convulsive seizures by 63-74% versus 20-38% placebo (p<0.001). Head-to-head data is absent; stiripentol shows stronger effects when combined with clobazam, while fenfluramine works independently.[3][4]
Responder rates and seizure freedom
Over 50% of stiripentol patients achieve ≥50% seizure reduction, with 8-12% seizure-free at 3 months. Fenfluramine yields 50-74% responders (≥50% reduction), with 2-6% seizure-free. Fenfluramine edges out in some long-term extensions (up to 57% responders at 2 years), but stiripentol sustains responses better in cofactor-dependent regimens.[3][5]
Onset of action and long-term efficacy
Stiripentol reduces seizures within 2-4 weeks, with peak effects by month 1. Fenfluramine shows reductions in 1-2 weeks, maintaining efficacy up to 3 years in open-label studies. Both lose some initial gains over time, but fenfluramine has more extended data (median treatment 2.7 years).[4][6]
Use in different epilepsy types
Stiripentol is FDA/EMA-approved only for Dravet syndrome (ages 2+), with off-label use in other refractory epilepsies. Fenfluramine is approved for Dravet (ages 2+) and Lennox-Gastaut syndrome (LGS, ages 2+), showing 26-40% convulsive seizure reductions in LGS trials versus 15% placebo. Stiripentol lacks LGS approval or robust data there.[1][2]
Side effect profiles affecting seizure control
Stiripentol commonly causes sedation (30%), appetite loss (25%), and agitation, potentially limiting dosing and adherence. Fenfluramine leads to diarrhea (30-40%), decreased appetite (40%), and rare cardiac risks (monitored via echocardiograms), but less sedation. Weight loss is steeper with fenfluramine (up to 10% body weight), which can impact long-term tolerability.[3][5]
Dosing, combinations, and practical differences
Stiripentol doses at 50 mg/kg/day (max 3000 mg), always with clobazam for synergy. Fenfluramine starts at 0.2 mg/kg/day titrated to 0.7 mg/kg (max 30 mg/day), usable as monotherapy or add-on. Stiripentol requires fat-rich food for absorption; both need gradual titration to minimize side effects.[1][2]
[1]: FDA Label: Diacomit (stiripentol)
[2]: FDA Label: Fintepla (fenfluramine)
[3]: Chiron C, et al. Lancet Neurol 2000; Stiripentol study.
[4]: Lagae L, et al. Lancet Neurol 2018; Fenfluramine Dravet trial.
[5]: Nabbout R, et al. Epilepsia 2020; Fenfluramine long-term.
[6]: Bialer M, et al. Drugs 2022; Comparative review.