Introduction

• Cenobamate is an anticonvulsant medication used primarily for the treatment of partial-onset seizures in adults.
• It was first approved by the U.S. Food and Drug Administration (FDA) in November 2019.

Mechanism of Action

• Cenobamate acts by enhancing inhibitory neurotransmission via positive allosteric modulation of GABA_A receptors (Sharma et al., 2020).
• It also reduces excitatory neurotransmission by inhibiting voltage-gated sodium channels, leading to stabilization of hyperexcitable neuronal membranes.

Pharmacokinetics

• Absorption: Cenobamate is well absorbed orally, with peak plasma concentrations occurring approximately 1-4 hours after administration.
• Distribution: The drug is widely distributed throughout the body, with a high volume of distribution.
• Metabolism: Cenobamate is primarily metabolized in the liver via glucuronidation and oxidation.
• Elimination: The elimination half-life ranges from 50 to 60 hours, allowing for once-daily dosing. It is excreted primarily via the urine (Roberti et al., 2021).

Indications

• Cenobamate is indicated for the treatment of partial-onset seizures in adult patients.
• It is used as an adjunctive therapy for patients who do not achieve adequate seizure control with other medications.

Dosage and Administration

• The initial dosage typically starts at 12.5 mg once daily, gradually increasing to a target dose of 200 mg once daily over several weeks.
• The dosage may be adjusted based on patient response and tolerability, with a maximum recommended dose of 400 mg per day.

Use in Children

• Makridis et al (2022) reported their experience with CNB in 16 pediatric patients with Drug Resistant Epilepsy (DRE).
• CNB was initiated in pediatric patients at 12.5 mg once a day (0.22 mg/kg/d) and then titrated-up by 0.47 ± 0.27 mg/kg/d every 2 weeks.
• Treatment with CNB resulted in seizure-free or a significant seizure reduction of > 50% in more than two thirds of their patients.
• The rates of seizure freedom or strong reduction of seizure frequency were in line with data published for adults
• No serious adverse events occurred in their cohort.

Most frequent adverse effects in their cohort were somnolence/fatigue which occurred during up-titration, in line with other reports^[4]. Less frequently vertigo, nausea, balance disorder, diplopia, increased impulsive/agitated behavior, increased appetite with weight gain and impaired sleep quality were reported.

Side Effects

• Common side effects include dizziness, fatigue, somnolence, headache, and diplopia.
• Serious side effects can include hypersensitivity reactions, drug rash with eosinophilia and systemic symptoms (DRESS), QT shortening, and suicidal behavior or ideation (Sperling et al., 2020).

Contraindications and Precautions

• Cenobamate is contraindicated in patients with a history of hypersensitivity to the drug or its components.
• Caution should be exercised in patients with hepatic or renal impairment.
• Regular monitoring of liver enzymes and mental health is recommended during treatment.

Drug Interactions

• Cenobamate can interact with other central nervous system depressants, leading to additive sedative effects.
• It may also affect the plasma levels of other antiepileptic drugs, necessitating dose adjustments.

Special Populations

• Pregnancy: There is limited data on the use of cenobamate in pregnant women. It should only be used if the potential benefits justify the potential risks.
• Lactation: It is unknown whether cenobamate is excreted in human milk. Caution is advised when administering to breastfeeding women.
• Elderly: Dose adjustments may be necessary due to the increased likelihood of hepatic, renal, or cardiac impairment in elderly patients.

Clinical Studies

• Clinical trials have demonstrated the efficacy of cenobamate in reducing the frequency of partial-onset seizures in patients with epilepsy.
• In pivotal trials, patients receiving cenobamate experienced significant reductions in seizure frequency compared to placebo.

Patient Counseling Information

• Patients should be informed about the potential side effects and the importance of adherence to the prescribed dosing regimen.
• They should also be advised to avoid activities requiring mental alertness, such as driving or operating heavy machinery, until they know how cenobamate affects them.

Conclusion

• Cenobamate represents a valuable addition to the treatment options for partial-onset seizures in adults, offering a new mechanism of action and the potential for improved seizure control. Regular monitoring and patient education are essential to ensure safe and effective use.

References