Comprehensive Monograph: Cenobamate (DB06119)

Executive Summary and Core Drug Profile

Cenobamate is a third-generation antiseizure medication (ASM) representing a significant therapeutic advancement for adult patients with refractory partial-onset (focal) epilepsy.[1] It is distinguished by a novel, dual mechanism of action that involves both the inhibition of voltage-gated sodium channels and the positive allosteric modulation of

γ-aminobutyric acid type A (GABAA​) receptors.[2] This combined approach to reducing neuronal hyperexcitability and enhancing synaptic inhibition has translated into unprecedented efficacy in clinical trials, particularly in achieving high rates of seizure freedom in a difficult-to-treat patient population that has failed multiple prior therapies.[3]

The clinical use of cenobamate is defined by a characteristic safety and tolerability profile that necessitates a specific, slow-titration protocol. This regimen, which involves initiating treatment at a low dose of 12.5 mg daily and escalating every two weeks, was developed to mitigate the risk of serious adverse events, most notably Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).[4] Common adverse effects are primarily related to the central nervous system and include somnolence, dizziness, and fatigue.[1] Furthermore, cenobamate possesses a complex pharmacokinetic profile characterized by a long elimination half-life of 50-60 hours, which supports convenient once-daily dosing but also necessitates a gradual withdrawal period.[1] Its metabolism involves both UGT and CYP enzymes, leading to significant potential for drug-drug interactions that require active management of concomitant medications.[6]