Fenfluramine for seizures in Dravet syndrome and Lennox-Gastaut syndrome: Mechanisms, clinical evidence, safety, and practical integration

Developmental and epileptic encephalopathies such as Dravet syndrome and Lennox–Gastaut syndrome remain highly drug resistant and are associated with substantial neurodevelopmental, behavioral, and caregiver burdens. Fenfluramine, repurposed at low antiseizure doses, is approved as adjunctive therapy for both syndromes and has a distinct multimodal mechanism that combines serotonergic modulation with positive allosteric activity at the sigma-1 receptor. This narrative review summarizes key translational insights and the pivotal clinical trial evidence in Dravet syndrome and Lennox–Gastaut syndrome, including long-term open-label extension and emerging real-world data. Across randomized studies, fenfluramine reduces convulsive seizures in Dravet syndrome and drop seizures in Lennox–Gastaut syndrome, with clinically meaningful responder rates and durability over time. Particular attention is given to neurocognitive and behavioral outcomes, as caregiver-reported improvements in executive function have been observed in Dravet cohorts and may not be fully explained by seizure reduction alone. Given historical associations between high-dose fenfluramine and cardiopulmonary adverse effects, we also review cardiovascular safety findings at antiseizure doses and the rationale for baseline and periodic echocardiographic monitoring. Finally, practical dosing, drug–drug interaction considerations, and an integration algorithm are provided to support routine clinical implementation across pediatric and adult care pathways.