Effect of Concomitant Medications on Adverse Event Frequency, Severity, and Time to Resolution in a Cenobamate Open-Label Trial

Background and Purpose: Polytherapy in epilepsy is associated with a higher risk of adverse events, poorer adherence, and impaired quality of life. Thus, reducing concomitant antiseizure medications (ASMs) and/or using a newly added ASM such as cenobamate with only 1 other ASM (i.e., bitherapy) may improve tolerability. This post hoc analysis evaluated the impact of the number and type of concomitant ASMs on treatment-emergent adverse events (TEAEs) that occurred in the cenobamate C021 open-label clinical trial. Methods: Adjunctive cenobamate was initiated in adults (aged 18–70 years) with uncontrolled focal seizures who were taking 1 to 3 ASMs. The number and type of concomitant ASMs and the frequency, severity, and time to resolution of TEAEs were assessed. Results: The most frequently reported (≥ 10%) TEAEs in the overall population (n = 1340) were somnolence, dizziness, fatigue, and headache. The percentage of patients with dizziness, somnolence, and fatigue increased with increasing numbers of concomitant ASMs, especially when combined with benzodiazepines, chiefly clobazam, and in patients taking ≥ 2 sodium channel blockers. Median time to resolution of frequently reported TEAEs was shorter in patients taking fewer concomitant ASMs, with the exception of fatigue. The proportion of patients experiencing more severe TEAEs (except for headache) also increased with increasing numbers of concomitant ASMs. Conclusions: Patients taking fewer concomitant ASMs reported better tolerability as evidenced by fewer and less severe AEs and faster time to resolution. These findings emphasize the importance of optimizing concomitant ASM regimens through dose adjustments, ASM substitution, and treatment simplification to improve tolerability.