Cenobamate in refractory epilepsy: Overview of treatment options and practical considerations

Abstract

Management of drug resistant epilepsy (DRE) represents a challenge to the treating clinician. This manuscript addresses DRE and provides an overview of treatment options, medical, surgical, and dietary. It addresses treatment strategies in polytherapy, then focuses on the role cenobamate (CNB) may play in reducing the burden of DRE while providing practical advice for its introduction. CNB is a recently approved, third generation, anti‐seizure medication (ASM), a tetrazole‐derived carbamate, thought to have a dual mechanism of action, through its effect on sodium channels as well as on GABAA receptors at a non‐benzodiazepine site. CNB, having a long half‐life, is an effective add‐on ASM in refractory focal epilepsy with a higher response rate and a higher seizure‐freedom rate than is usually seen in regulatory clinical trials. Experience post‐licensing, though still limited, supports the findings of clinical trials and is encouraging. Its spectrum of action in relation to generalized epilepsies and seizures remains to be established, and there are no data on its efficacy in monotherapy. At the time of writing, CNB has been prescribed for some 50,000 individuals with DRE and focal epilepsy. A larger number is needed to fully establish its safety profile. It should at all times be introduced slowly to minimize the risk of serious allergic drug reactions. It has clinically meaningful interactions which must be anticipated and managed to maximize tolerability and likelihood of successful treatment. Despite the above, it may well prove to be of major benefit in the treatment of many patients with drug resistant epilepsy.

The cenobamate KORK study—A prospective monocenter observational study investigating cenobamate as an adjunctive therapy in refractory epilepsy, with comparisons to historical cohorts treated with add‐on lacosamide, perampanel, and brivaracetam

“…However, since the study settings and the circumstances were similar, we still conclude that the high efficacy of CNB that was indicated by the pivotal trials 9,12 and confirmed by other real-world studies [18][19][20][23][24][25][26][27][28]35,38 was also obvious in our data.…”

“…Several expert recommendations proposed how to deal with such tolerability issues, especially considering pharmacokinetic and pharmacodynamic interactions with concomitant ASMs such as CLB, LTG, PHT, PB, OXC, or LCM. 34 , 35 , 36 , 37 , 38 Our study was initiated immediately after the introduction of CNB to the free market following the conclusion of the compassionate use program offered by the manufacturer in Germany. It is worth noting that we did not adhere to certain recommendations, such as proactive reductions of baseline ASMs under certain clinical conditions.…”

“…This finding supports the recommendations to consider early reduction of sodium channel blockers with sedating profiles during titration. [34][35][36][37][38] On the other hand, CNB was well tolerated among most PWE despite unfavorable prerequisites. In our study, proactive modifications of the drug regimen were not necessary.…”

Cenobamate Plasma Levels in Patients with Epilepsy: Correlation with Efficacy and Tolerability?

“…From the pivotal trials and the published real-world evidence, it has been claimed that combinations of cenobamate with sodium-channel-blocking agents (for pharmacodynamic reasons) or with clobazam (for pharmacokinetic reasons) are associated with a higher risk of AEs [32]. We could not confirm this assumption from our data because these AEs were more common under combinations with levetiracetam and lamotrigine, although the plasma level of the latter usually drops under the influence of cenobamate [5,11,15,16].…”

Cenobamate Plasma Levels in Patients with Epilepsy: Correlation with Efficacy and Tolerability

“…From the pivotal trials and the published real-world evidence, it has been claimed that combinations of cenobamate with sodium-channel-blocking agents (for pharmacodynamic reasons) or with clobazam (for pharmacokinetic reasons) are associated with a higher risk of adverse events [33,34]. We could not confirm this assumption from our data because these adverse events were more common under combinations with levetiracetam and lamotrigine, although the plasma level of the latter usually drops under the influence of cenobamate [5,11,15,16].…”