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

Oct 5, 2026

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Background and Purpose: Polytherapy in epilepsy increases the risk of adverse events, worsens adherence, and impairs quality of life. Reducing concomitant antiseizure medications (ASMs), or using cenobamate with only one other ASM, may improve tolerability. This post hoc analysis assessed how the number and type of concomitant ASMs affected treatment-emergent adverse events (TEAEs) in the cenobamate C021 open-label trial. Methods: Adjunctive cenobamate was given to adults with uncontrolled focal seizures taking 1–3 ASMs. Results: Common TEAEs (≥10%) included somnolence, dizziness, fatigue, and headache; dizziness, somnolence, and fatigue increased with more concomitant ASMs, especially with benzodiazepines/clobazam and with ≥2 sodium channel blockers. Median time to resolution was shorter with fewer concomitant ASMs (except fatigue), and more severe TEAEs increased with more concomitant ASMs (except headache). Conclusions: Fewer concomitant ASMs correlated with fewer and less severe AEs and faster resolution, supporting optimization of concomitant ASM regimens.

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European Journal of Neurology ORIGINAL ARTICLE OPEN ACCESS Effect of Concomitant Medications on Adverse Event Frequency, Severity, and Time to Resolution ina Cenobamate Open-Label Trial Bernhard J. Steinhoff1,2 | Antonio Gil-Nagel3 | Elena Alvarez-Baron4 | John Paul Leach4 | Karthinathan Thangavelu5 | Yaroslav Winter6 | Vicente Villanueva7 1Department for Adults, Kork Epilepsy Center, Kehl-Kork, Germany | 2Clinic for Neurology and Neurophysiology, University of Freiburg, Freiburg, Germany | 3Department of Neurology, Hospital Ruber Internacional, Madrid, Spain | 4Global Medical Department, Angelini Pharma S.p.A, Rome, Italy | 5MeDaStats LLC, Florida, USA | 6Department of Neurology, Saarland University Medical Center, University of Saarland, Homburg, Germany | 7Refractory Epilepsy Unit, Neurology Service, Hospital Universitari i Politècnic La Fe, Member of ERN Epicare, Valencia, Spain Correspondence: Bernhard J. Steinhoff (bsteinhoff@epilepsiezentrum.de) Received: 19 December 2025 | Revised: 11 June 2026 | Accepted: 3 July 2026 Keywords: adverse drug event | antiseizure medications | clinical trial | epilepsy | focal seizures ABSTRACT 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 ascenobamate 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. 1 | Introduction Nearly half of people with newly-diagnosed epilepsy will achieve seizure freedom with the first antiseizure medication (ASM); ultimately, those continuing to experience uncontrolled seizures will most likely receive polytherapy [1, 2]. As the drug load increases, treatment-emergent adverse events (TEAEs) tend to increase, necessitating medication and dose adjustments to maximize efficacy and minimize tolerability issues [3] . Newer ASMs such as cenobamate offer This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2026 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology. European Journal of Neurology, 2026; 33:e70705 1 of 8 [https://doi.org/10.1111/ene.70705](https://doi.org/10.1111/ene.70705) increased seizure control [4, 5] and improved

FAQs

What was the main aim of this post hoc analysis in the C021 trial?

To evaluate how the number and type of concomitant antiseizure medications (ASMs) influenced treatment-emergent adverse events, including their frequency, severity, and time to resolution, during cenobamate open-label treatment.

Which TEAEs were most frequently reported in the overall population?

Somnolence, dizziness, fatigue, and headache were the most frequently reported TEAEs, each occurring in at least 10% of participants in the overall population.

How did the number of concomitant ASMs relate to tolerability outcomes?

Patients taking fewer concomitant ASMs reported better tolerability, with fewer and less severe adverse events and a faster time to resolution for commonly reported TEAEs (except fatigue), while the proportion of more severe TEAEs increased with more concomitant ASMs (except headache).

Oct 5, 2026

Uploaded by Kyle