Cenobamate

• Partial-Onset Seizures in Adults:
  Approved as adjunctive therapy for the treatment of partial-onset seizures with or without secondary generalization in adults with epilepsy.
• Off-label Uses:
  Occasionally used off-label in refractory epilepsy or other seizure types under specialist guidance.

Adults:

• Initial Dose:
  Start at 12.5 mg once daily for 2 weeks.
• Titration:
  Increase to 25 mg once daily for 2 weeks, then 50 mg once daily for 1 week. Further increase by 50 mg weekly as tolerated.
• Maintenance Dose:
  Typically 200 mg to 400 mg daily, given once daily.
• Maximum Dose:
  Up to 400 mg per day.

Special Populations:

• Renal Impairment:
  No specific dosage adjustment required; monitor clinically.
• Hepatic Impairment:
  Use caution in moderate to severe impairment; start at lower dose and titrate slowly.

Administration:

• Oral tablets taken once daily, with or without food.

Cenobamate exerts its antiseizure effects through a dual mechanism. It enhances the inactivation of voltage-gated sodium channels, stabilizing neuronal membranes and reducing repetitive neuronal firing. Additionally, cenobamate is a positive allosteric modulator of GABA_A receptors, increasing inhibitory GABAergic neurotransmission. These combined actions decrease excitatory neuronal activity, thereby reducing the frequency and severity of partial seizures.

• Absorption:
  Rapidly absorbed with peak plasma concentrations reached within 1 to 4 hours.
• Bioavailability:
  Approximately 88%.
• Distribution:
  Volume of distribution ~40 L. Plasma protein binding is about 60%.
• Metabolism:
  Primarily metabolized in the liver via glucuronidation (UGT2B7) and oxidation by CYP2E1, CYP2A6, and CYP2B6.
• Elimination:
  Excreted mainly in urine as metabolites; less than 6% excreted unchanged.
• Half-life:
  Approximately 50 to 60 hours, allowing once-daily dosing.

• Pregnancy:
  Classified as FDA Pregnancy Category C. Animal studies have shown some adverse effects on fetal development at high doses; human data are limited. Use only if potential benefits justify the risk.
• Lactation:
  Unknown if excreted in human milk. Caution is advised when administered to breastfeeding women.

• Antiepileptic drug (AED)
• Voltage-gated sodium channel blocker and GABA_A receptor modulator

• Known hypersensitivity to cenobamate or any formulation components.
• History of drug reaction with eosinophilia and systemic symptoms (DRESS) with cenobamate.

• Serious Skin Reactions:
  Risk of DRESS syndrome; monitor for rash, fever, lymphadenopathy, or systemic symptoms. Discontinue immediately if suspected.
• Suicidal Thoughts and Behavior:
  Like other AEDs, monitor for mood changes and suicidal ideation.
• Central Nervous System Depression:
  May cause somnolence, dizziness, and coordination issues; caution when operating machinery.
• Hypersensitivity Reactions:
  Includes severe cutaneous adverse reactions.
• Withdrawal:
  Gradual dose reduction recommended to avoid increased seizure frequency.

Common:

• CNS: Dizziness, somnolence, headache, fatigue, diplopia, ataxia
• Gastrointestinal: Nausea, constipation

Serious/Rare:

• DRESS syndrome (potentially fatal)
• Suicidal ideation or behavior
• Severe hypersensitivity reactions (e.g., Stevens-Johnson syndrome)

• CYP Enzymes:
  Cenobamate is both a substrate and inducer/inhibitor of CYP enzymes. It induces CYP3A4 and CYP2B6 and inhibits CYP2C19.
• Effect on Other Drugs:
  May decrease plasma concentrations of CYP3A4 substrates (e.g., midazolam) and increase concentrations of CYP2C19 substrates (e.g., phenytoin, phenobarbital).
• Concomitant AEDs:
  Dose adjustments of other antiepileptics may be necessary.
• Oral Contraceptives:
  May reduce effectiveness; alternative contraception recommended.

• FDA approval granted in 2019 as adjunctive treatment for partial-onset seizures in adults.
• Updated warnings emphasize early recognition of serious skin reactions and slow titration.
• Recent epilepsy guidelines incorporate cenobamate as a treatment option for refractory partial seizures.

• Store at 20°C to 25°C (68°F to 77°F).
• Protect from moisture and light.
• Keep in original container tightly closed.
• Keep out of reach of children.