Cenobamate for treating focal onset seizures in epilepsy

NICE state (1):

• Cenobamate is recommended as an option for treating focal onset seizures with or without secondary generalised seizures in adults with drug-resistant epilepsy that has not been adequately controlled with at least 2 antiseizure medicines. It is recommended only if:
  • it is used as an add-on treatment, after at least 1 other add-on treatment has not controlled seizures, and
  • treatment is started in a tertiary epilepsy service

Notes:

• Cenobamate is an antiseizure medication (ASM) approved by the US Food and Drug Administration on November 21, 2019, for the treatment of partial- (focal-) onset seizures in adults
  • is a novel tetrazole alkyl carbamate derivative, structurally different from carisbamate
  • reduces repetitive neuronal firing by inhibiting voltage-gated sodium currents
    • enhances the fast and slow inactivation of sodium channels and potently inhibits the noninactivating persistent component of the sodium channel current (INaP) by which many ASMs, notably lacosamide, are believed to work
    • is a positive allosteric modulator of the gamma-aminobutyric acid (GABAA) ion channel
      • cenobamate acts as a positive allosteric modulator of the GABAA ion channels and is effective in reducing repetitive neuronal firing by inhibition of voltage-gated sodium channels, but the complete mechanism of action is currently unknown (3)
  • most common adverse effects in cenobamate-treated patients reported were somnolence, dizziness, fatigue, and headache (2)
    • adverse effects occurred in the greatest number of subjects at the highest dose - side effects associated with cenobamate use were dose-dependent increases in somnolence, fatigue, dizziness, gait disturbance, coordination disturbance, cognitive dysfunction, confusion, and visual changes
    • serious adverse effects associated with cenobamate are drug reaction with eosinophilia and systemic symptoms, QT shortening, suicidal behavior, and suicidal ideation (3)
  • initiation of CNB in patient's taking multiple medication should be carefully considered because some of the most commonly prescribed medications (SSRIs, methadone, macrolides) can cause QT prolongation and arrhythmias can occur
    • is crucial to monitor other drugs or drug interactions that can cause QT interval shortening and CNS depression, including alcohol
  • Cenobamate must be renally dosed and is not recommended in those with end-stage renal disease (3)
  • Cenobamate should be used with caution in patients with mild to moderate hepatic impairment and is not recommended in patients with severe hepatic impairment (3)
  • Cenobamate memory and impairment
    • reported that in a pooled analysis of 2 studies involving cenobamate memory impairment was seen in 1.8% of patients treated with this medicine compared with 0.5% of placebo treated patients. Similarly confusion was detected in 2.5% vs 0% respectively (4)

Reference:

• NICE (December 2021). Cenobamate for treating focal onset seizures in epilepsy
• Vossler DG. Remarkably High Efficacy of Cenobamate in Adults With Focal-Onset Seizures: A Double-Blind, Randomized, Placebo-Controlled Trial. Epilepsy Curr. 2020;20(2):85-87. Published 2020 Feb 24. doi:10.1177/1535759720903032
• Latimer DR, Edinoff AN, Ruff RD, et al. Cenobamate, a Sodium Channel Inhibitor and Positive Allosteric Modulator of GABAA Ion Channels, for Partial Onset Seizures in Adults: A Comprehensive Review and Clinical Implications. Neurol Int. 2021;13(2):252-265. Published 2021 Jun 9. doi:10.3390/neurolint13020026
• SK life science Presents Long-term Data on Cognitive and Psychiatric Adverse Events Associated with XCOPRI (R) (cenobamate tablets) CV in Adults with Partial-Onset (Focal) Seizures at the AAN 2022 Annual Meeting (March 2022)