What is Xcopri (cenobamate) used for in adults with a history of epilepsy or seizure disorders?

What is Xcopri (Cenobamate)?

Xcopri (cenobamate) is an oral antiseizure medication approved for the treatment of partial-onset seizures (also called focal-onset seizures) in adults with epilepsy. 1

FDA-Approved Indication

• Xcopri is specifically indicated for the treatment of partial-onset seizures in adult patients. 1
• The medication is not approved for use in children, and its safety and effectiveness in pediatric populations have not been established. 1

Mechanism of Action

Cenobamate works through two primary mechanisms to control seizures:

• Enhancement of the inactivated state of voltage-gated sodium channels, which blocks the persistent sodium current that can contribute to abnormal neuronal firing. 2
• Positive allosteric modulation of GABAA receptors at a non-benzodiazepine binding site, which enhances inhibitory neurotransmission in the brain. 2

Clinical Efficacy Profile

Cenobamate has demonstrated substantial efficacy in reducing seizure frequency in adults with drug-resistant focal epilepsy:

• In randomized controlled trials, cenobamate significantly reduced seizure frequency compared to placebo, with a greater proportion of patients achieving ≥50% reduction in seizure frequency. 3, 4
• Seizure freedom rates were notably improved, with sustained benefits observed over treatment periods extending up to 48 months in clinical studies. 4
• Real-world data from highly refractory epilepsy patients showed that 5.3% achieved complete seizure freedom, 42.1% had 75-99% seizure reduction, and 28.1% had 50-74% seizure reduction. 5
• Cenobamate abolished focal to bilateral tonic-clonic seizures in 55.6% of patients in real-world studies of ultra-refractory epilepsy. 5

Dosing and Administration

• Cenobamate requires a slow titration schedule starting at 12.5 mg/day over 12 weeks, which appears to reduce the risk of severe treatment-emergent adverse events during the titration period. 4
• The medication can be taken once daily at any time, with or without food. 1
• Tablets can be taken whole or crushed and mixed with water for oral administration or via nasogastric tube. 1
• Most treatment responders in real-world studies required doses of ≥250 mg/day for optimal seizure control. 5

Safety and Tolerability

The most serious safety concern with cenobamate is the risk of drug reaction with eosinophilia and systemic symptoms (DRESS):

• Three cases of DRESS occurred during early clinical development, leading to implementation of the slow titration protocol. 2
• With the start-low and go-slow approach in 1,339 patients, no serious idiosyncratic adverse reactions were subsequently observed. 2
• Patients should be monitored for signs of serious allergic reactions including swelling, rash, fever, swollen glands, painful mouth sores, yellowing of skin/eyes, unusual bruising/bleeding, and severe fatigue. 1

Common adverse events include:

• Somnolence, dizziness, and fatigue (most frequently reported). 4, 5
• Headache and diplopia. 2
• Adverse events most commonly emerged at cenobamate doses ≥250 mg/day and were partially manageable by reducing concomitant antiseizure medication burden. 5

Critical Drug Interactions

Cenobamate has significant drug interaction potential:

• Cenobamate is a CYP2C19 inhibitor and an inducer of CYP3A4 and CYP2B6, leading to multiple drug-drug interactions with other antiseizure medications. 3, 2
• Cenobamate may reduce the effectiveness of hormonal contraceptives, requiring discussion of alternative birth control methods. 1
• Adjustments to concomitant ASMs, most often clobazam, eslicarbazepine, and perampanel, may be necessary to manage adverse effects. 5

Important Warnings

• Like all antiseizure medications, cenobamate carries a risk of suicidal thoughts or actions (approximately 1 in 500 patients), requiring monitoring for new or worsening depression, anxiety, agitation, or suicidal ideation. 1
• Cenobamate is a federally controlled substance (Schedule V) due to potential for abuse or dependence. 1
• Abrupt discontinuation can cause serious problems including status epilepticus (seizures that will not stop), so cenobamate must be tapered under medical supervision. 1
• Cenobamate is contraindicated in patients with familial short QT syndrome. 1

Place in Therapy

Cenobamate represents a valuable adjunctive treatment option for adults with uncontrolled focal-onset seizures:

• It is particularly useful in highly active and ultra-refractory epilepsy cases where patients have failed multiple prior treatments including other ASMs, epilepsy surgery, and vagus nerve stimulation. 5
• Real-world effectiveness and adverse event profiles are consistent with clinical trial data. 4
• The medication's high efficacy rates, including meaningful seizure freedom rates, make it an attractive option despite the need for careful monitoring and slow titration. 3, 4