Section 01 · Monograph
Cenobamate
Reviewed Nov 2026FDA label
XcopriNa+/GABA-A modulator
- Forms
- Tab: 12.5, 25, 50, 100, 150, 200mg
- Dose
- 200-400mg/day
- MOA
- Na+ blockade + GABA-A positive modulation
Indications
- Treatment of partial-onset (focal) seizures in adultsFDA-labeled
Mechanism of Action
- Believed to reduce repetitive neuronal firing by inhibiting voltage-gated sodium currents, particularly the persistent sodium current
- Also acts as a positive allosteric modulator of the GABA-A ion channel (at a site distinct from the benzodiazepine site)
- Dual mechanism (Na+ channel blockade + GABAergic potentiation) is thought to underlie its high efficacy relative to many other ASMs
Full Dosing
Adult / usual
- Adults: initiate 12.5mg once daily for weeks 1-2
- Weeks 3-4: increase to 25mg once daily
- Weeks 5-6: increase to 50mg once daily
- Weeks 7-8: increase to 100mg once daily
- Weeks 9-10: increase to 150mg once daily
- Week 11 onward: increase to the recommended maintenance dose of 200mg once daily
- May be further titrated in 50mg increments no more than every 2 weeks up to a max of 400mg/day if needed
- This slow, weeks-long titration schedule is specifically required to reduce the risk of DRESS (drug reaction with eosinophilia and systemic symptoms) and other serious rash
- Schedule V controlled substance (CV) — has abuse and dependence potential
Hepatic
- Mild-moderate hepatic impairment: max dose 200mg/day
Contraindications
- Known hypersensitivity to cenobamate or any component of the formulation
- Familial Short QT syndrome
Drug Interactions
- Strong inhibitor of CYP2C19 and inducer of CYP3A4 — numerous interactions with other AEDs and hormonal contraceptives
- Phenytoin: cenobamate can increase phenytoin levels by 70-84%; reduce phenytoin dose
- Clobazam and phenobarbital levels may increase — reduce dosing as needed
- Lamotrigine and carbamazepine levels may decrease — dose adjustment may be needed
- Reduces efficacy of hormonal contraceptives via CYP3A4 induction — use additional/alternative contraception
- Additive QT-shortening effect with other QT-shortening drugs (e.g., some antiarrhythmics) — avoid combination
- Additive CNS depression with alcohol, opioids, and other CNS depressants
Adverse Effects
- Common (≥10%, more than placebo): somnolence, dizziness, fatigue, diplopia, headache
- Dose-related: balance disorder, gait disturbance, nystagmus, cognitive slowing, blurred/double vision
- DRESS (drug reaction with eosinophilia and systemic symptoms) — serious, potentially fatal multiorgan hypersensitivity reaction; risk mitigated by slow titration
- QT interval shortening — avoid use with other QT-shortening drugs and in familial Short QT syndrome
- ALT elevations
- Suicidal ideation/behavior (class effect of ASMs)
Monitoring Parameters
- Monitor closely for signs/symptoms of DRESS (fever, rash, lymphadenopathy, facial edema, organ involvement) especially during titration
- Baseline and periodic ECG in patients with risk factors for QT shortening or on other QT-shortening drugs
- Liver transaminases if clinically indicated
- Serum potassium (elevations reported)
- Monitor for suicidal thoughts/behavior
- Assess sedation/CNS effects before driving or operating machinery
Pregnancy & Lactation
- Limited human data; based on animal data may cause fetal harm
- Encourage enrollment in the North American Antiepileptic Drug (NAAED) Pregnancy Registry (1-888-233-2334)
- Unknown whether cenobamate is present in human milk; present in milk of lactating rats