Fenfluramine and Comparative Antiseizure Therapies in Drug-Resistant Epilepsy: A Systematic Review of Efficacy, Cardiometabolic Safety, and Clinical Outcomes.

Fenfluramine has emerged as a promising adjunctive antiseizure medication for treatment-resistant epilepsy syndromes such as Dravet and Lennox-Gastaut. This systematic review synthesized evidence from seven studies, including randomized controlled trials and open-label extensions, evaluating fenfluramine's efficacy, cardiovascular and metabolic safety, and long-term outcomes across pediatric and adult populations. The findings consistently demonstrated substantial reductions in seizure frequency, particularly for drop and generalized tonic-clonic seizures. Safety monitoring revealed no cases of valvular heart disease or pulmonary arterial hypertension, and treatment-emergent adverse events such as decreased appetite and fatigue were generally mild to moderate. In parallel, selected studies evaluating other commonly used antiseizure medications provided comparative insights into metabolic risks, identifying concerns such as vitamin D deficiency, hyponatremia, and weight fluctuations, alongside mitigation strategies through supplementation and lifestyle interventions. Integrating these data contextualizes fenfluramine's favorable profile within the broader antiseizure therapy landscape and underscores the importance of individualized risk-benefit assessment. Overall, the evidence supports fenfluramine as an effective and well-tolerated option for drug-resistant epilepsy, while emphasizing the need for systematic metabolic monitoring to optimize long-term care. Future research should prioritize head-to-head comparative trials, standardized cardiovascular and metabolic safety protocols, and long-term real-world studies to strengthen clinical guidance and advance precision therapy in epilepsy management.