When starting Xcopri (cenobamate), when can other antiseizure medications be decreased?

When to Decrease Concomitant Antiseizure Medications with Xcopri (Cenobamate)

Concomitant antiseizure medications should be reduced during the cenobamate maintenance phase (after completing the 12-week titration), not during the initial titration period, with adjustments individualized based on tolerability and drug interactions.

Timing of ASM Reductions

During Titration Phase (Weeks 1-12)

• Do not reduce concomitant ASMs during the initial 12-week titration period unless specifically required for drug interactions or intolerable adverse effects 1, 2
• The cenobamate starter pack increases doses slowly (12.5 mg → 25 mg → 50 mg → 100 mg → 150 mg → 200 mg over 12 weeks at 2-week intervals) to minimize severe treatment-emergent adverse events 1, 2
• Early seizure reduction often occurs during titration (48.1% responder rate at weeks 1-4 on 12.5-25 mg/day; 61.7% at weeks 5-8 on 50-100 mg/day), but this does not indicate readiness to reduce other ASMs 1

During Maintenance Phase (After Week 12)

• Begin considering ASM reductions once cenobamate reaches maintenance dosing (typically 200 mg/day or higher) and therapeutic effect is established 1, 3
• Real-world data shows that 67.4% of treatment responders required cenobamate doses ≥250 mg/day for optimal seizure control 3
• Adverse events most commonly emerge at doses ≥250 mg/day, making this the critical window for comedication adjustments 3, 4

Priority ASMs for Reduction

High-Priority Reductions (Drug Interactions)

• Clobazam, eslicarbazepine, and perampanel should be reduced first as these are most commonly adjusted in clinical practice to manage adverse effects 3
• Cenobamate is metabolized primarily by CYP3A4 and can interact with other medications using this pathway 5
• Enzyme-inducing ASMs (carbamazepine, phenytoin, phenobarbital) may require dose adjustments due to metabolic interactions 5, 6

Reduction Strategy

• Reduce the overall ASM burden gradually when adverse effects emerge, particularly fatigue, somnolence, dizziness, or ataxia 1, 7, 3
• Three-fourths of patients experience at least one side effect, most manageable through comedication reduction rather than cenobamate discontinuation 3
• In pediatric patients, ataxia (23.8%) and sedation (9.5%) are the most common adverse events requiring comedication adjustment 7

Clinical Monitoring Points

Efficacy Assessment

• Evaluate seizure response at 3-month intervals after reaching maintenance dosing 4
• At 3 months on median 100 mg/day: expect 46% responder rate (≥50% seizure reduction), 26% with ≥75% reduction, 9% seizure-free 4
• At 12 months: responder rates increase to 55% (≥50%), 35% (≥75%), and 19% (seizure-free) 4

Safety Monitoring

• Monitor for treatment-emergent adverse events most closely when cenobamate reaches ≥250 mg/day, as this is when side effects most commonly emerge 3, 4
• Common adverse events include fatigue (34.6%), dizziness (32.1%), and somnolence (29.6%) 1
• No correlation exists between cenobamate daily dose and adverse event incidence at the group level, suggesting individual variability 4

Critical Pitfalls to Avoid

• Never reduce ASMs prematurely during titration as cenobamate's full therapeutic effect requires adequate dosing and time 1, 2
• Do not discontinue cenobamate for adverse effects without first attempting comedication reduction, as 32% of patients successfully manage side effects through this approach 3
• Avoid abrupt discontinuation of enzyme-inducing ASMs (carbamazepine, phenytoin, phenobarbital) as this may alter cenobamate levels through metabolic changes 5, 6
• Remember that seizure freedom or high response rates (≥75% reduction) may take 6-12 months to achieve, so patience with the titration and maintenance phases is essential 1, 4