Cenobamate Can Be Used Either as Monotherapy or in Combination with Other Antiseizure Medications
Cenobamate is FDA-approved as adjunctive (add-on) therapy, but real-world evidence and pharmacokinetic data strongly support its use as monotherapy after conversion from polytherapy, with many patients successfully reducing or eliminating concomitant antiseizure medications while maintaining or improving seizure control. 1
FDA-Approved Indication vs. Real-World Practice
The FDA label indicates cenobamate pharmacokinetics are similar when used as monotherapy or adjunctive therapy for partial-onset seizures 1. Population pharmacokinetic modeling demonstrates that cenobamate monotherapy produces comparable drug exposures to those proven safe and effective in adjunctive therapy trials 2. This provides the pharmacologic foundation for monotherapy use.
Evidence for Treatment Simplification
Real-world data demonstrates that cenobamate enables significant treatment simplification:
- In a Spanish multicenter study of 125 patients with drug-resistant epilepsy, 52% discontinued one concomitant medication, 32% discontinued two, and 4% discontinued three medications during cenobamate treatment 3
- At 2-year follow-up, patients reduced their mean number of concomitant antiseizure medications significantly, with the mean defined daily dose dropping from 3.2 at baseline to 1.2 4
- 31.5% achieved seizure freedom and 75.8% had ≥50% seizure reduction after conversion to monotherapy or dual therapy 3
Practical Approach to Medication Management
Starting as Adjunctive Therapy
Begin cenobamate as add-on therapy with existing medications, then systematically reduce concomitant drugs based on:
Proactive dose reduction during cenobamate titration for:
- Clobazam at high doses
- Phenytoin or phenobarbital
- Sodium channel blockers at high doses
- Two or more sodium channel blockers simultaneously 5
Reactive dose reduction only if moderate/severe adverse events occur for:
- Other antiseizure medications not listed above 5
Optimal Combination Partners
When maintaining combination therapy, cenobamate demonstrates:
- Best efficacy when combined with valproate and broad-spectrum agents 6
- Suboptimal efficacy when combined with sodium channel blockers 6
- Lower treatment discontinuation rates with SV2A ligands, valproate, or carbonic anhydrase inhibitors 6
Key Drug Interactions
Cenobamate increases levels of:
- Phenytoin (Cmax and AUC by 70% and 84%) 1
- Phenobarbital (Cmax and AUC by 34% and 37%) 1
- Omeprazole (Cmax and AUC by 83% and 107%) 1
Cenobamate decreases levels of:
Phenytoin decreases cenobamate levels by 27-28% 1
Common Pitfalls to Avoid
Failing to proactively reduce sodium channel blockers: This increases risk of adverse events (somnolence, dizziness, fatigue) without improving efficacy 5
Rapid titration without co-medication adjustment: The most common adverse events (somnolence 22.4%, dizziness 10.4%, fatigue 7.2%) often reflect excessive total drug load rather than cenobamate alone 3
Assuming higher doses are always better: Substantial seizure improvements often occur at moderate cenobamate doses (median 200 mg/day), emphasizing individualized titration 3, 6
Bottom Line Algorithm
Start: Cenobamate as adjunctive therapy with existing medications
During titration: Proactively reduce high-dose clobazam, phenytoin, phenobarbital, and sodium channel blockers
At maintenance: Continue simplifying to monotherapy or dual therapy if seizure control permits, prioritizing retention of valproate or broad-spectrum agents over sodium channel blockers
Target: Minimum effective cenobamate dose (often 200 mg/day) with fewest concomitant medications that maintains seizure control 3, 4