Xcopri - Drug Monograph

Introduction

Xcopri (cenobamate) is a novel antiepileptic drug (AED) approved by the FDA in November 2019 for the treatment of partial-onset seizures in adults. Developed by SK Life Science, Inc., it represents a significant advancement in epilepsy management, particularly for patients who have not achieved adequate seizure control with existing therapies.

Mechanism of Action

Cenobamate demonstrates a dual mechanism of action:

• Enhances GABAergic inhibition by positive allosteric modulation of GABAA receptors (preferentially targeting non-δ-containing subtypes)
• Inhibits voltage-gated sodium currents by stabilizing the fast-inactivated state of sodium channels

This unique dual mechanism results in reduced neuronal excitability and suppression of seizure activity through both enhanced inhibition and reduced excitation.

Indications

FDA-approved for:

• Treatment of partial-onset (focal) seizures in adults

Dosage and Administration

• Start at 12.5 mg once daily
• Increase by 12.5 mg increments at 2-week intervals
• Recommended maintenance dose: 200 mg once daily (range: 100-400 mg daily)

• Moderate hepatic impairment: Maximum 200 mg daily
• Severe hepatic impairment: Not recommended
• Renal impairment: No dosage adjustment needed for mild to moderate impairment
• Use with strong CYP3A4 or CYP2C19 inducers: May require dosage adjustment
• Elderly patients: Consider lower starting dose due to potential decreased clearance

• Administer once daily with or without food
• Tablets should be swallowed whole
• If missed dose, take as soon as possible unless next dose is due within 4 hours

Pharmacokinetics

• Time to peak concentration (Tmax): 1-4 hours
• Bioavailability: >88%
• Food effect: None clinically significant

• Protein binding: ~60% (primarily albumin)
• Volume of distribution: ~40-50 L

• Primarily metabolized by UGT2B7, UGT1A9, and UGT2B4
• Minor pathways include CYP2E1, CYP2A6, and CYP2C19
• Forms inactive metabolites

• Half-life: ~50-60 hours (allows once-daily dosing)
• Excretion: Primarily urine (82%, mostly as metabolites), feces (14%)
• Clearance: ~0.5 L/hour

Contraindications

• Hypersensitivity to cenobamate or any component of the formulation
• Familial short QT syndrome

Warnings and Precautions

• Dose-dependent shortening of QTc interval
• Avoid in patients with familial short QT syndrome
• Use with caution in patients with conditions that predispose to ventricular arrhythmias

• Also known as multiorgan hypersensitivity
• Has been reported with cenobamate use
• Monitor for fever, rash, lymphadenopathy, and systemic involvement

• AEDs increase risk of suicidal thoughts and behavior
• Monitor for emergence or worsening of depression, suicidal thoughts, or behavior changes

• Somnolence, dizziness, fatigue, and coordination difficulties
• Caution patients about operating machinery or driving

• Gradually withdraw to minimize risk of increased seizure frequency

Drug Interactions

• Rifampin: May decrease cenobamate concentrations
• Consider dosage adjustment

• Carbamazepine, phenytoin: May decrease cenobamate concentrations
• Consider dosage adjustment

• Weak inducer of CYP3A4 and CYP2B6
• May decrease concentrations of drugs metabolized by these enzymes:

- Oral contraceptives (effectiveness may be reduced) - CYP3A4 substrates (e.g., simvastatin, midazolam) - CYP2B6 substrates

• Enhanced sedative effects with alcohol, benzodiazepines, opioids

Adverse Effects

• Somnolence (24%)
• Dizziness (20%)
• Fatigue (16%)
• Diplopia (8%)
• Headache (7%)

• DRESS/multiorgan hypersensitivity
• QT shortening
• Suicidal behavior and ideation
• Neurological effects (ataxia, gait disturbance)

Monitoring Parameters

• Seizure frequency and characteristics
• ECG monitoring (baseline and periodic) for QT interval
• Signs of hypersensitivity reactions (especially during first 4 months)
• Mental status changes, depression, suicidal ideation
• Neurological function (somnolence, dizziness, coordination)
• Liver function tests (baseline and periodic)
• Complete blood count
• Pregnancy testing in women of childbearing potential
• Therapeutic drug monitoring (though not routinely required)

Patient Education

• Take medication exactly as prescribed at the same time each day
• Do not abruptly discontinue medication
• Be aware of potential dizziness, drowsiness, and coordination problems
• Avoid alcohol and other CNS depressants
• Use effective contraception (as cenobamate may reduce effectiveness of hormonal contraceptives)
• Report any skin rash, fever, or swollen lymph nodes immediately
• Monitor for mood changes, depression, or suicidal thoughts
• Inform all healthcare providers about Xcopri use
• Keep regular follow-up appointments with neurologist
• Carry seizure identification information

References

1. Krauss GL, Klein P, Brandt C, et al. Safety and efficacy of adjunctive cenobamate (YKP3089) in patients with uncontrolled focal seizures: a multicentre, double-blind, randomised, placebo-controlled, dose-response trial. Lancet Neurol. 2020;19(1):38-48.

2. Sperling MR, Abou-Khalil B, Harvey J, et al. Efficacy of adjunctive cenobamate based on number of concomitant antiseizure medications: A post hoc analysis of a randomized clinical trial. Epilepsia. 2020;61(3):440-450.

3. Xcopri® (cenobamate) prescribing information. SK Life Science, Inc.; 2021.

4. Lattanzi S, Trinka E, Zaccara G, et al. Adjunctive cenobamate for focal-onset seizures in adults: a systematic review and meta-analysis. CNS Drugs. 2020;34(11):1105-1120.

5. Chung SS, French JA, Kowalski J, et al. Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures. Neurology. 2020;94(22):e2311-e2322.

6. FDA Drug Approval Package: Xcopri. U.S. Food and Drug Administration. Accessed January 2023.