What is the recommended dosing and titration schedule of cenobamate for pediatric patients with focal drug‑resistant epilepsy?

Cenobamate is NOT approved for pediatric use, but emerging real-world evidence supports off-label use with specific dosing protocols

Cenobamate (XCOPRI) has not been approved by the FDA for pediatric patients, and safety and effectiveness in children have not been established 1. However, multiple recent real-world studies from 2022-2026 demonstrate that cenobamate can be used off-label in children with drug-resistant focal epilepsy with careful dosing and monitoring.

Current Regulatory Status

The FDA label explicitly states: "Safety and effectiveness in pediatric patients have not been established" 1. Additionally, juvenile animal studies showed concerning findings including mortality, delayed sexual maturation, neurobehavioral impairment, and decreased brain weight at plasma exposures less than those achieved at the maximum recommended human dose of 400 mg 1.

Real-World Pediatric Dosing Evidence

Despite lack of FDA approval, substantial real-world data has emerged supporting off-label use:

Initiation Dosing

• Start at 12.5 mg/day (approximately 0.25-0.3 mg/kg/day) 2, 3, 4
• The most common starting dose across multiple studies was 12.5 mg or 0.25-0.3 mg/kg/day
• Some centers used weight-based initiation at 0.12-0.47 mg/kg/day 5, 6

Titration Schedule

• Increase by approximately 0.47 mg/kg/day every 2 weeks 5
• Alternative approach: gradual increases to clinical effect using a reduced dosage schedule compared to adults 4
• The titration is slower and more conservative than adult protocols to minimize adverse effects

Maintenance Dosing

• Target maintenance dose: 2.34-3.7 mg/kg/day 3, 6, 4
• Range reported across studies: 0.3-10 mg/kg/day (median 3.1-3.57 mg/kg/day) 2, 5
• Total daily doses typically 50-400 mg depending on weight and tolerance
• Final dosing should be individualized based on seizure control and tolerability

Efficacy Data Supporting Use

The real-world evidence is remarkably consistent:

• ≥50% seizure reduction: 41-75% of patients 2, 3, 6, 4
• Seizure freedom: 12-31% of patients 2, 5, 3, 4
• Median seizure frequency reduction: from 30 to 9 per month 2
• Response rates improved from 41% at 6 months to 54% at 12 months 6

The largest multicenter European study (n=108) showed 52.8% achieved ≥50% seizure reduction with 18.5% becoming seizure-free 2.

Safety and Tolerability

Common adverse events (reported in 24-57% of patients):

• Fatigue/somnolence (most common, 42%) 5, 4
• Dizziness/vertigo 2
• Behavioral symptoms 2
• Ataxia (4%) 4
• Nausea/vomiting (4%) 4
• Appetite loss 3

Critical safety points:

• No cases of DRESS syndrome reported in pediatric studies 2
• Most adverse events were mild, well-tolerated, and self-limiting 3
• Retention rates at 12 months: 82-86.8% 2, 4
• Higher retention in patients without adverse events (93.5% vs 81.6%) 2

Additional Considerations

Polypharmacy reduction:

• 44-55% of patients had dose reductions of concomitant ASMs 2, 6
• 35-51% discontinued at least one other ASM 2, 6
• Median concomitant ASM count decreased from 3 to 2 2

Patient characteristics in studies:

• Median age: 11.5-15 years (range 1.2-21.8 years) 5, 3, 6
• Included patients as young as 3 years 2, 3
• Patients had failed median of 5-10 previous ASMs 5, 3, 6
• 72% had developmental delay 6

Clinical Algorithm for Off-Label Pediatric Use

If considering cenobamate off-label in a child with drug-resistant focal epilepsy:

1. Ensure appropriate patient selection: Drug-resistant focal epilepsy after failure of multiple ASMs
2. Obtain informed consent discussing off-label use and lack of FDA approval
3. Start at 12.5 mg/day or 0.25-0.3 mg/kg/day
4. Titrate by 0.47 mg/kg/day every 2 weeks (slower than adult protocols)
5. Target maintenance: 2.5-3.5 mg/kg/day (adjust based on response and tolerability)
6. Monitor closely for: somnolence, behavioral changes, ataxia, gastrointestinal symptoms
7. Consider reducing concomitant ASMs once seizure control improves
8. Assess response at 6 and 12 months (efficacy may continue to improve)

Important Caveats

• All pediatric data comes from retrospective, real-world studies—no prospective controlled trials exist 2, 5, 3, 6, 4
• Juvenile animal toxicity data raises concerns about developmental effects 1
• Long-term safety data in children are lacking
• Best responses observed in structural or unknown etiology epilepsy, particularly without developmental and epileptic encephalopathy 3
• Cenobamate reduces effectiveness of oral contraceptives—counsel adolescent females about alternative contraception 1

The decision to use cenobamate in pediatric patients must weigh the substantial real-world evidence of efficacy (50-75% responder rates) against the lack of FDA approval and concerning juvenile animal data, making it appropriate primarily for children with severe drug-resistant epilepsy who have exhausted other options.