FDA Approves XCOPRI (Cenobamate) for Partial-Onset Seizures in Adult Patients

On November 21, 2019, the U.S. Food and Drug Administration (FDA) approved XCOPRI (cenobamate) for the treatment of partial-onset seizures in adult patients. The approved recommended dosage of XCOPRI is 12.5 mg orally once daily, titrated to the recommended maintenance dosage of 200 mg orally once daily. The maximum dosage is 400 mg orally once daily. The recommended dosage and titration should not be exceeded because of the potential for serious adverse reactions. If XCOPRI is discontinued, the dosage should be gradually reduced over a period of at least 2 weeks, unless safety concerns require abrupt withdrawal. 

XCOPRI is contraindicated in patients with hypersensitivity to cenobamate or any of the inactive ingredients in XCOPRI or familial short QT syndrome. Caution should be used when administering XCOPRI and other drugs that shorten the QT interval. Concomitant use of XCOPRI with other CNS depressants, including alcohol, may have additive effects. Additional information regarding dosage and administration as well as important warnings and precautions related drug reaction with eosinophilia and systemic symptoms (DRESS)/multiorgan hypersensitivity, QT shortening, suicidal behavior and ideation, neurological adverse reactions, and withdrawal of antiepileptic drugs can be found in the full prescribing information linked below.  

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD)  

  • MOA: The precise mechanism by which cenobamate exerts its therapeutic effects in patients with partial-onset seizures is unknown. Cenobamate reduces repetitive neuronal firing by inhibiting voltage-gated sodium currents and is a positive allosteric modulator of the γ-aminobutyric acid (GABAA) ion channel. 

  • General PK: Cenobamate AUC increases in a greater than dose-proportional manner following single doses from 5 to 750 mg (0.0125 to 1.88 times the approved maximum recommended dosage). Cenobamate Cmax increases in a dose proportional manner. Steady-state plasma concentrations are attained after approximately two weeks of once daily dosing. 

  • Absorption: At least 88% of XCOPRI is absorbed following oral administration, with median Tmax ranging from 1 to 4 hours. 

  • Distribution: The apparent volume of distribution of cenobamate is approximately 40-50 L. Plasma protein binding is 60%, primarily to human albumin, and independent of concentration in vitro. 

  • Elimination: The apparent terminal half-life of cenobamate is 50-60 hours and apparent oral clearance is approximately 0.45-0.63 L/hour over a dose range from 100 mg/day to 400 mg/day. 

  • Metabolism: Cenobamate undergoes glucuronidation via UGT2B7 and to a lesser extent by UGT2B4, and oxidation via CYP2E1, CYP2A6, CYP2B6 and to a lesser extent by CYP2C19 and CYP3A4/5. Following administration of radiolabeled cenobamate, unchanged cenobamate accounted for > 98% of the total AUC of radioactivity in plasma. 

  • Excretion: Following administration of radiolabeled cenobamate, a mean of 87.8% of the total dose was recovered in urine and 5.2% in feces. Unchanged cenobamate accounted for 6.8% of the dose which was mainly excreted in the urine (6.4%). More than 50% of the radioactivity was excreted within 72 hours of dosing. 

  • PD: No clinically significant differences on objective attention, psychomotor performance, and memory tests, in addition to other subjective CNS tests, were observed following concomitant use of XCOPRI and ethanol (preparation of 40% ethanol in orange juice dosed at 0.7 g/kg for males and 0.57 g/kg for females) in healthy subjects. 

  • Cardiac Electrophysiology: In a placebo-controlled QT study in healthy volunteers, dose-dependent shortening of the QTcF interval has been observed with XCOPRI. The mean ΔΔQTc is -11 [-13, -8] msec for 200 mg once daily and -18 [-22, -15] msec for 500 mg once daily (1.25 times the maximum recommended dosage). A higher percentage of XCOPRI-treated subjects (31% at 200 mg and 66% at 500 mg) had a QT shortening of greater than 20 msec compared to placebo (6-17%). Reductions of the QTc interval below 300 msec were not observed. 

Drug Interactions 

Due to the effect of XCOPRI on the drugs listed below, the following is recommended when used concomitantly with XCOPRI: 

  • Phenytoin: Gradually decrease dosage by up to 50% as XCOPRI is being titrated. 

  • Phenobarbital and Clobazam: Reduce dosage as needed. 

  • Lamotrigine and Carbamazepine: Increase dosage as needed. 

  • CYP2B6 and CYP3A Substrates: Increase dosage as needed. 

  • CYP2C19 Substrates: Reduce dosage as needed. 

  • Oral Contraceptives: Effectiveness of hormonal oral contraceptives may be reduced when used concomitantly with XCOPRI. Women should use additional or alternative non-hormonal birth control. 

Use in Specific Populations 

No clinically significant differences in the pharmacokinetics of cenobamate were observed based on age (18 to 77 years), sex, or race/ethnicity (Asian, Black, Caucasian, Hispanic, or Other). 

Renal Impairment 

XCOPRI should be used with caution and dosage reduction may be considered in patients with mild, moderate, or severe renal impairment (CLcr 15 to < 90 mL/min). Use of XCOPRI in patients with end-stage renal disease (CLcr < 15 mL/min) undergoing dialysis is not recommended. 

Hepatic Impairment 

XCOPRI should be used with caution in patients with mild to moderate (Child-Pugh A or B) hepatic impairment. In these patients, the maximum recommended dosage is 200 mg once daily and additional dosage reduction may be considered. Use of XCOPRI in patients with severe (Child-Pugh C) hepatic impairment is not recommended. 

Efficacy and Safety 

Efficacy of XCOPRI was demonstrated in two multicenter, randomized, double-blind, placebo-controlled studies in adult patients who had partial-onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant AEDs. Additional information regarding efficacy trial(s) can be found in the full prescribing information linked below. 

The most common adverse reactions in patients receiving XCOPRI (at least 10% for XCOPRI and more frequently than placebo) include somnolence, dizziness, fatigue, diplopia, and headache.

Full prescribing information is available at https://go.usa.gov/xp5y4. 

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. 

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C. 

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at https://www.fda.gov/safety/medwatch/default.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088). 

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.