Dose Adjustment of Concomitant Antiseizure Medications During Cenobamate Treatment: Expert Opinion Consensus Recommendations

Michael C Smith; Pavel Klein; Gregory L Krauss; Samiya Rashid; Lawrence G Seiden; John M Stern; William E Rosenfeld

doi:10.1007/s40120-022-00400-5

Dose Adjustment of Concomitant Antiseizure Medications During Cenobamate Treatment: Expert Opinion Consensus Recommendations

Neurol Ther. 2022 Dec;11(4):1705-1720. doi: 10.1007/s40120-022-00400-5. Epub 2022 Sep 3.

Authors

Michael C Smith¹, Pavel Klein², Gregory L Krauss³, Samiya Rashid⁴, Lawrence G Seiden⁵, John M Stern⁶, William E Rosenfeld⁷

Affiliations

¹ Department of Neurological Sciences, Section of Clinical Neurophysiology and Epilepsy, Rush Medical College, 1725 W. Harrison Street, Suite 885, Chicago, IL, 60612, USA. [email protected].
² Mid-Atlantic Epilepsy and Sleep Center, Bethesda, MD, USA.
³ Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Epilepsy and Neurology Specialists of San Diego, Encinitas, CA, USA.
⁵ Atlanta Neuroscience Institute/MS Center of Atlanta, Atlanta, GA, USA.
⁶ University of California at Los Angeles, Los Angeles, CA, USA.
⁷ Comprehensive Epilepsy Care Center for Children and Adults, St. Louis, MO, USA.

Abstract

Introduction: Our objective was to provide expert consensus recommendations to improve treatment tolerability through dose adjustments of concomitant antiseizure medications (ASMs) during addition of cenobamate to existing ASM therapy in adult patients with uncontrolled focal seizures.

Methods: A panel of seven epileptologists experienced in the use of ASMs, including cenobamate, used a modified Delphi process to reach consensus. The panelists discussed tolerability issues with concomitant ASMs during cenobamate titration and practical strategies for dose adjustments that may prevent or mitigate adverse effects. The resulting recommendations consider concomitant ASM dose level and specify proactive (prior to report of an adverse effect) and reactive (in response to report of an adverse effect) dose adjustment suggestions based on concomitant ASM pharmacokinetic and pharmacodynamic interactions with cenobamate. Specific dose adjustment recommendations are provided.

Results: We recommend proactively lowering the dose of clobazam, phenytoin, and phenobarbital due to their known drug-drug interactions with cenobamate, and lacosamide due to a pharmacodynamic interaction with cenobamate, to prevent adverse effects during cenobamate titration. Reactive lowering of a concomitant ASM dose is sufficient for other ASMs at standard dosing owing to quick resolution of adverse effects. For carbamazepine and lamotrigine doses exceeding the upper end of standard dosing (e.g., carbamazepine, greater than 1200 mg/day; lamotrigine, greater than 500 mg/day), we encourage consideration of proactive dose reduction at cenobamate 200 mg/day to prevent potential adverse effects. All dose reductions for adverse effects can be repeated every 2 weeks as dictated by the adverse effects. At cenobamate 200 mg/day, we recommend that patients be evaluated for marked improvement of seizures and further dose reductions be considered to reduce potentially unnecessary polypharmacy.

Conclusion: The primary goal of the recommended dose reductions of concomitant ASMs is to prevent or resolve adverse effects, thereby allowing cenobamate to reach the optimal dose to achieve the maximal potential of improving seizure control.

Keywords: Antiseizure medications; Cenobamate; Dose reduction; Drug-refractory epilepsy; Focal seizures; Polytherapy; Tolerability.

Plain language summary

Some people with epilepsy need to take more than one seizure medicine as part of their treatment. Taking more than one seizure medicine, however, can increase the risk of unwanted side effects. One approach to preventing side effects when adding a new seizure medicine is to lower the amount (dose) of existing seizure medicines. Cenobamate is a newer seizure medicine available in the USA for adults with focal seizures (also referred to as partial-onset seizures). Cenobamate, like many seizure medicines, must be titrated over time to a target dose. A group of epilepsy specialists met and developed recommendations for when and how to change the doses of existing seizure medicines when adding cenobamate. The goal of these recommendations is to prevent or reduce side effects like sleepiness or dizziness. The authors recommend that the dose of specific seizure medicines, including clobazam, lacosamide, phenytoin, and phenobarbital, be lowered as cenobamate is started or as cenobamate’s dose is being increased (but before side effects occur). Regular doses of other seizure medicines can be lowered if a side effect occurs because reducing the dose of the other seizure medications can often stop the side effect. These recommendations may help patients successfully reach their optimal dose of cenobamate with fewer side effects, potentially improving their seizure control. Video Abstract: Dose Adjustment of Concomitant Antiseizure Medications During Cenobamate Treatment: Expert Opinion Consensus Recommendations.