Early sedation-related adverse events with the cenobamate–clobazam combination in drug-resistant epilepsy: real-world preliminary observations

Background: Cenobamate is increasingly used as adjunctive treatment in adults with drug-resistant focal epilepsy. In clinical practice, the combination with clobazam is common and sedation-related adverse events (SRAEs) have been reported. Methods: We conducted a retrospective single-centre analysis of adult patients with drug-resistant epilepsy treated with cenobamate between January and September 2025. Clinical data, concomitant antiseizure medications, and adverse events were collected during routine follow-up. SRAEs occurring within three months of cenobamate initiation were classified as early. Particular attention was paid to patients receiving concomitant clobazam. Pharmacogenetic data were available as part of routine clinical assessment. Results: SRAEs were observed more frequently among patients receiving the cenobamate–clobazam combination and were mostly reported within the first three months of treatment. Among affected patients, clobazam doses ranged between 10 and 30 mg/day. When pharmacogenetic data were considered, a higher proportion of SRAEs was observed among intermediate CYP2C19 metabolizers compared with other phenotypes, although the sample size was limited. Conclusions: In this real-world cohort, early SRAEs were observed in a subset of patients receiving the cenobamate–clobazam combination, particularly among individuals with reduced CYP2C19 metabolic activity. Further prospective studies are needed to clarify the pharmacokinetic and pharmacogenetic contributions to these adverse events.