Effectiveness and safety of cenobamate after conversion to monotherapy or dual therapy in real‐world clinical practice

Abstract Objective Patients with drug‐resistant epilepsy (DRE) typically take multiple anti‐seizure medications (ASMs) and are at risk of treatment‐related adverse events (AEs). This study assessed the impact of cenobamate monotherapy or dual therapy in patients with drug‐resistant epilepsy. Methods This was a multicenter (six Spanish epilepsy units), retrospective, observational study in patients with drug‐resistant epilepsy who had received treatment with cenobamate as monotherapy (after conversion from polytherapy) or in dual therapy for at least three consecutive months, between April 2017 and November 2024. Results In total, 125 patients (mean age 46 ± 15.9 years; median epilepsy duration 16 years, range: 1–65) were included. Median follow‐up was 11 months (range 3–80). Patients had received a median of 5 (range 2–19) previous anti‐seizure medications and were receiving a median of 2 (range 0–3) concomitant anti‐seizure medications at cenobamate initiation; the most common concomitant anti‐seizure medications were lacosamide (36%), brivaracetam (29.6%), and clobazam (26.4%). The median cenobamate dose at the last visit was 200 mg/day (range 100–400 mg/day). By the last visit, 31.5% of patients had achieved seizure freedom, and 75.8%, 58.1%, and 49.2% had achieved ≥50%, ≥75%, and ≥90% reductions in seizure frequency, respectively. During cenobamate treatment, 52% of patients discontinued one, 32% discontinued two, and 4% discontinued three concomitant anti‐seizure medications. In total, 63/125 patients (50.4%) had adverse events during cenobamate treatment, all mild or moderate; 40.8% of patients had adverse events at the last visit. The most reported adverse events were somnolence (22.4%), dizziness (10.4%), fatigue (7.2%), and instability (4.8%). Significance This study highlights the real‐world effectiveness and safety of cenobamate, either as monotherapy (after conversion from polytherapy) or in dual therapy, in patients with drug‐resistant epilepsy. Cenobamate allows for a significant treatment simplification, resulting in fewer treatment‐related adverse events without compromising seizure reduction.