Fenfluramine in refractory epileptic encephalopathies: multi-mechanistic insights and future directions—a comprehensive review

Abstract Refractory epileptic encephalopathies are defined as the severe, childhood-onset epilepsies associated with drug-resistant periodic seizures, neurodevelopmental disability, behavioral problems, and escalate the risk of sudden unexpected death in epilepsy (SUDEP), especially in Lennox-Gastaut syndrome and Dravet syndrome. Although several anti-seizure drugs are offered, about 20–30% of the patients do not respond well to the treatment, indicating the necessity of new methods of treatment. This is an in-depth analysis of the pharmacology, pharmacokinetics, pharmacodynamics, clinical effectiveness, safety profile, and pharmacokinetic status of the drug, fenfluramine, in refractory developmental and epileptic encephalopathies The mechanism of action of fenfluramine is primarily associated with enhancing serotonergic neurotransmission and modulating sigma-1 receptors, as well as restoring the excitatory-inhibitory balance in neural networks. Other processes of GABAergic enhancement, regulation of glutamatergic signalling, Nrf2, ROS, and possible neuroendocrine effects are discussed. Various Clinical trials have shown that convulsive seizures are reduced significantly by fenfluramine in Dravet syndrome and drop seizures in Lennox-Gastaut syndrome, and cognitive and behavioral and improve the quality of life are emerging. Although echocardiographic monitoring remains a mandatory requirement due to past safety concerns, modern low-dose regimens demonstrate a satisfactory tolerability rate. Fenfluramine is a novel multi-mechanistic anti-seizure drug that has disease-modifying and multi-mechanistic activity. The purpose of this review is to highlights the additional long-term safety evaluation and larger clinical trials are justified in order to establish its place in the management of refractory epilepsy further and to treat the various types of seizures.