Clinical Overview: Cenobamate (Xcopri) for Partial-Onset Seizures

Introduction
The FDA approved cenobamate (Xcopri) in 2019 for the treatment of partial-onset seizures in adult patients 18 years of age or older.¹ A partial-onset seizure is an uncontrolled activation of neurons in a limited area of the brain. Many patients require up to 3 concomitant anti-epileptic medications and may still experience breakthrough seizures.

Cenobamate is a once daily anti-epileptic medication with a recommended maintenance dose of 200 mg once daily that can be prescribed as monotherapy or adjunctive therapy.² Cenobamate was evaluated in 2 multicenter studies and was shown to cause a statistically significant 2 times greater reduction in seizures compared to placebo in as many as 1 in 5 patients.²

Mechanism of Action³
Cenobamate is a positive allosteric modulator of the γ-aminobutyric acid (GABA_A) ion channel.

The drug’s precise mechanism of action is unknown; however, it has been shown to inhibit voltage gated sodium channels causing a reduction in repetitive neuronal firing.

Dosage and Administration³

Cenobamate is taken orally once daily with or without food. Patients should swallow tablets whole and never crush or chew them.

• Initial Dosing
  • Weeks 1 and 2: 12.5 mg once per day
• Titration Dosing
  • Weeks 3 and 4: 5 mg once per day
  • Weeks 5 and 6: 50 mg once per day
  • Weeks 7 and 8: 100 mg once per day
  • Weeks 9 and 10: 150 mg once per day
• Maintenance Dosing
  • Weeks 11 and onward: 200 mg once per day

The FDA-approved labeling recommends a maximum dose of 400 mg once per day if determined necessary based on the patient’s response to the medication. It also indicates clinicians should increase doses in increments of no more than 50 mg daily every 2 weeks to a maximum dose of 400 mg.

Discontinuation

Cenobamate dosage should be gradually reduced over the course of at least 2 weeks to decrease the risk of seizure and status epilepticus. Rapid discontinuation can be considered in instances of serious adverse events (AEs).

AEs²
The most common AEs were somnolence, dizziness, fatigue, double vision, and headache.

Warnings and Precautions³
Drug Reaction with Eosinophilia and Systemic Syndrome (DRESS), including one fatality has been reported when patients taking cenobamate are titrated too quickly. No DRESS cases were reported when prescribers initiated cenobamate at 12.5 mg per day and titrated at the appropriate 2-week interval.

Prescribers should monitor patients for signs and symptoms of DRESS. Such symptoms include fever, rash, and lymphadenopathy, in association with other organ involvement.

Cenobamate can shorten the QT interval. Prescribers should monitor patients taking other QT interval shortening medications in addition to cenobamate closely.

Various antiepileptic drugs may increase the risk of suicidal thoughts and behavior. Patients treated with cenobamate are also at risk and prescribers should monitor patients for worsening of depression and suicidal thoughts or behavior.

Cenobamate is contraindicated in patients with Familial Short QT syndrome as well as patients with a known hypersensitivity to any of the components of the drug

Pregnancy and Lactation^1,3

Cenobamate should be avoided in pregnancy due to lack of adequate data regarding developmental risk. There are currently no data regarding the presence of the medication in human breast milk.

Prescribers and patients should discuss the developmental and health benefits of breastfeeding, the mother’s need for cenobamate, and any potential effects on the infant should be considered before breast feeding.

About the Author
Connor Walker, PharmD, is a clinical pharmacist at Yale New Haven Health in Connecticut.

References
1. Drug Trial Snapshots: Xcopri. U.S. Food and Drug Administration. Accessed May 14, 2022. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-xcopri

2. Xcopri (Healthcare Professionals). SK Life Science. Accessed May 12, 2022 https://www.xcoprihcp.com/

3. Xcopri prescribing information. April 2021. Accessed May 12, 2022 https://www.xcopri.com/wp-content/uploads/2021/05/SK_Prescribing_Information_Med_ Guide_Combined.pdf