CENOBAMATE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for CENOBAMATE (CENOBAMATE).
Cenobamate is a tetrazole-derived anticonvulsant that modulates GABA A receptors, preferentially inhibiting the persistent sodium current and activating potassium currents (M-current). It also enhances GABA-mediated inhibition and reduces excitatory neurotransmitter release.
| Metabolism | Primarily metabolized by glucuronidation via UGT2B7 and UGT1A9, with minor contributions from UGT2B4 and CYP2E1. Unchanged drug and metabolites are excreted renally. |
| Excretion | Renal excretion accounts for approximately 92% of the administered dose, with 62% as unchanged drug and 30% as metabolites. Fecal excretion is minimal (<2%). |
| Half-life | The terminal elimination half-life is approximately 10-17 hours in adults. Steady-state is achieved within 2-3 days. In patients with moderate to severe hepatic impairment, half-life may be prolonged. |
| Protein binding | Approximately 95% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Approximately 0.7 L/kg, indicating distribution into total body water. |
| Bioavailability | Oral bioavailability is approximately 100% (well absorbed, minimal first-pass metabolism). |
| Onset of Action | Oral administration: Onset of anticonvulsant effect is observed within 1-2 weeks of dose titration. |
| Duration of Action | Duration of action is approximately 12 hours, supporting twice-daily dosing. Clinical effect is maintained with regular dosing. |
Cenobamate 200 mg orally once daily initially, titrated weekly by 50 mg to a target dose of 400 mg once daily; maximum 400 mg/day.
| Dosage form | TABLET |
| Renal impairment | eGFR ≥30 mL/min/1.73 m²: no adjustment required. eGFR <30 mL/min/1.73 m²: not recommended due to lack of data. Hemodialysis: not recommended. |
| Liver impairment | Child-Pugh Class A: no adjustment required. Child-Pugh Class B: maximum dose 200 mg daily. Child-Pugh Class C: not recommended. |
| Pediatric use | Safety and efficacy in pediatric patients (<18 years) have not been established. |
| Geriatric use | No specific dose adjustment is required solely based on age; however, caution in patients with renal or hepatic impairment is advised. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for CENOBAMATE (CENOBAMATE).
| Breastfeeding | No human data on cenobamate in breast milk. Animal studies indicate excretion into milk. M/P ratio is unknown. Potential for infant toxicity (somnolence, poor feeding). Caution advised; consider alternative therapies or avoid breastfeeding. |
| Teratogenic Risk | Cenobamate is Pregnancy Category C. First trimester: Animal studies show fetal harm (increased malformations, growth retardation) at clinically relevant doses, but no adequate human data. Risk of neural tube defects or cleft palate cannot be excluded. Second/third trimester: Potential for adverse neurobehavioral effects; risk of fetal hemorrhage if used near delivery. Use only if benefit outweighs risk. |
■ FDA Black Box Warning
Cenobamate can cause serious or life-threatening reactions including drug reaction with eosinophilia and systemic symptoms (DRESS), which can be fatal. This risk is highest in the first few weeks of treatment. Close monitoring is required.
| Serious Effects |
Hypersensitivity to cenobamate or any component of the formulation. Family history of short QT syndrome or concurrent use with other drugs known to shorten QT interval.
| Precautions | Risk of DRESS syndrome, suicidal ideation/behavior, QT shortening, hepatic injury, and angioedema. Requires gradual dose titration to reduce risk of hypersensitivity reactions. Monitor liver function tests and ECG. |
| Food/Dietary | No specific food restrictions, but cenobamate should be taken with food to improve tolerability (reduces nausea). Avoid excessive consumption of grapefruit or grapefruit juice as it may alter drug metabolism (CYP3A4 interaction). Maintain adequate fluid intake to reduce risk of kidney stones; avoid high-sodium diets if hyponatremia is a concern. |
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| Fetal Monitoring | Monitor: Seizure control (frequency and severity), drug serum levels (if available), liver function (ALT, AST), sodium levels (risk of hyponatremia). Fetal: Ultrasound for structural anomalies if exposed in first trimester; fetal growth monitoring in later pregnancy. Newborn: Observe for sedation, withdrawal, or bleeding signs. |
| Fertility Effects | No specific human studies. Animal data suggest potential for reduced fertility (altered estrous cycle, decreased conception rates) at high doses. Clinical significance unknown. Counsel patients on potential reversible effects. |
| Clinical Pearls | Cenobamate is a novel antiseizure medication with a unique dual mechanism: it enhances slow inactivation of voltage-gated sodium channels and acts as a positive allosteric modulator of GABA-A receptors. Due to risk of drug reaction with eosinophilia and systemic symptoms (DRESS) and QT shortening, strict dose titration is required: start at 12.5 mg/day, titrate every 2 weeks over 6-12 weeks to target maintenance of 200 mg/day (max 400 mg/day). It is a strong CYP2C19 inducer and a moderate-to-strong CYP3A4 inducer, potentially reducing efficacy of hormonal contraceptives, warfarin, and many other drugs. Monitor for hyponatremia, especially in elderly or those on other hyponatremic agents. Contraindicated in patients with familial short QT syndrome. CBC and LFTs should be monitored due to risk of DRESS. |
| Patient Advice | Take cenobamate exactly as prescribed; do not stop suddenly without doctor guidance to avoid withdrawal seizures. · May cause dizziness, drowsiness, or coordination problems; avoid driving or operating heavy machinery until you know how this medicine affects you. · Report any signs of allergic reaction: rash, fever, swollen lymph nodes, or yellowing of skin/eyes (possible DRESS syndrome). · This drug can reduce effectiveness of hormonal birth control (pills, patches, rings, implants); use additional non-hormonal contraception during treatment and for 4 weeks after stopping. · Avoid alcohol and marijuana; can worsen dizziness and drowsiness. · Tell your doctor if you are pregnant, planning pregnancy, or breastfeeding. · Cenobamate may cause low sodium levels; report symptoms such as headache, confusion, weakness, or muscle cramps. · Do not increase or decrease dose without consulting your doctor; follow the prescribed titration schedule. |