Chemistry:Cenobamate

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Cenobamate, sold under the brand names Xcopri (US) and Ontozry (EU), is a medication used for the treatment of focal onset seizures, a kind of epilepsy, in adults.[1][2][3] It is taken by mouth.[1]

Cenobamate was approved for medical use in the United States in November 2019,[1][2][3][4] and placed in Schedule V of the Controlled Substances Act in March 2020.[5] Cenobamate was authorized for medical use in the European Union in March 2021,[6] approved for use in the UK in December 2021,[7] and approved for use in Canada in June 2023.[8]

Medical uses

In the United States, cenobamate is indicated for the treatment of focal onset seizures in adults.[1] Cenobamate may have superior efficacy in patients with drug resistant epilepsy compared to other anti-seizure medications.[9] A meta-analysis found that it reduced seizures by more than 50% in 68% of drug resistant patients and resulted in seizure freedom in 16%.[10]

In the European Union, it is indicated for the adjunctive treatment of focal-onset seizures with or without secondary generalization in adults with epilepsy who have not been adequately controlled despite a history of treatment with at least two anti-epileptic medications.[6]

In the UK, it is used as an add-on treatment, after at least 1 other add-on treatment has not controlled seizures and only when treatment is started in a specialised epilepsy service (tertiary care).[7]

Studies evaluating the safety and efficacy of cenobamate for generalized epilepsies are ongoing.[citation needed]

Contraindications

Cenobamate shortens the QT interval of the heart rhythm. It is therefore contraindicated in people with familial short QT syndrome, a very rare disease of the electrical system of the heart.[11][12]

Adverse effects

The most common side effects are drowsiness (in 37% of people taking the drug), dizziness (33%), and fatigue (24%). Sight disorders, headache and elevated potassium levels in the blood (over 5 mmol/L) are also common.[11] Hypersensitivity occurs in fewer than 1% of patients, drug reaction with eosinophilia and systemic symptoms (DRESS) in fewer than 0.1%.[12]

Overdose

There is little data regarding cenobamate overdose. It is expected that the described adverse effects such as drowsiness, dizziness and fatigue would occur, as well as possibly problems with the heart rhythm. No specific antidote exists.[11][12]

Interactions

Using cenobamate together with other central nervous system depressants such as barbiturates, benzodiazepines or alcohol may result in increased drowsiness and other central nervous system symptoms.[11][12]

Cenobamate induces the enzymes CYP3A4 and CYP2B6 and can therefore decrease blood concentrations of drugs that are metabolized by these enzymes (for example midazolam and bupropion, respectively). Conversely, it inhibits the enzyme CYP2C19, potentially increasing concentrations of drugs metabolized by this enzyme (for example clobazam and phenytoin).[11][12]

Pharmacology

Mechanism of action

Cenobamate is a voltage-gated sodium channel (VGSC) blocker.[13] It is a selective blocker of the inactivated state of VGSCs, preferentially inhibiting persistent sodium current while sparing transient sodium current.[13] This is unique compared to other anti-seizure medications. It has been proposed that cenobamate additionally enhances presynaptic release of γ-aminobutyric acid (GABA), thereby increasing inhibitory GABAergic neurotransmission.[13] The dual mechanism of action may account for the unique efficacy of cenobamate.[14]

Pharmacokinetics

Cenobamate is absorbed from the gut to at least 88% and reaches highest concentrations in the blood plasma after one to four hours. When in the bloodstream, 60% of the substance are bound to plasma proteins, mostly to albumin. Cenobamate is inactivated mainly by glucuronidation via the enzyme UGT2B7 and to a lesser extent UGT2B4. The enzymes CYP2E1, CYP2A6, CYP2B6, CYP2C19 and CYP3A4 play smaller roles in the drug's metabolism.[12]

Steady state conditions are reached after 14 days. Cenobamate and its metabolites are mostly eliminated via the urine and only to 5.2% via the faeces. The terminal half-life is 50 to 60 hours.[12]

History

The safety and efficacy of cenobamate to treat partial-onset seizures was established in two randomized, double-blind, placebo-controlled studies that enrolled 655 adults. In these studies, patients had partial-onset seizures with or without secondary generalization for an average of approximately 24 years and median seizure frequency of 8.5 seizures per 28 days during an 8-week baseline period. During the trials, doses of 100, 200, and 400 milligrams (mg) daily reduced the number of seizures per 28 days compared with the placebo group.[2]

Society and culture

The US Food and Drug Administration (FDA) approved cenobamate in November 2019, and granted the application for Xcopri to SK Life Science Inc.[2][3][4][15]

In January 2021, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization.[16] The applicant for this medicinal product is Arvelle Therapeutics Netherlands B.V.[16] Ontozry was authorized for medical use in the European Union in March 2021.[6][17]

References

  1. ↑ 1.0 1.1 1.2 1.3 Cite error: Invalid <ref> tag; no text was provided for refs named Xcopri FDA label
  2. ↑ 2.0 2.1 2.2 2.3 "FDA approves new treatment for adults with partial-onset seizures". U.S. Food and Drug Administration (FDA) (Press release). 21 November 2019. Archived from the original on 22 November 2019. Retrieved 21 November 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  3. ↑ 3.0 3.1 3.2 "Drug Trials Snapshots: Xcopri". 3 December 2019. https://www.fda.gov/drugs/drug-trials-snapshots-xcopri.  Public Domain This article incorporates text from this source, which is in the public domain.
  4. ↑ 4.0 4.1 "Drug Approval Package: Xcopri". 10 December 2019. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212839Orig1s000TOC.cfm.  Public Domain This article incorporates text from this source, which is in the public domain.
  5. ↑ "2020 - Placement of Cenobamate in Schedule V". 10 March 2020. https://www.deadiversion.usdoj.gov/fed_regs/rules/2020/fr0310_9.htm. 
  6. ↑ 6.0 6.1 6.2 Cite error: Invalid <ref> tag; no text was provided for refs named Ontozry EPAR
  7. ↑ 7.0 7.1 "Information for the public - Technology appraisal guidance [TA753"]. 15 December 2021. https://www.nice.org.uk/guidance/ta753/informationforpublic. 
  8. ↑ "Health Canada approves Endo's anti-seizure pills". 30 June 2023. https://www.pharmaceutical-technology.com/news/health-canada-approves-endos-anti-seizure-pills/. 
  9. ↑ "Cenobamate in refractory epilepsy: Overview of treatment options and practical considerations". Epilepsia Open 8 (4): 1241–1255. December 2023. doi:10.1002/epi4.12830. PMID 37743544. 
  10. ↑ "Real-world experience with cenobamate: A systematic review and meta-analysis". Seizure 112: 1–10. November 2023. doi:10.1016/j.seizure.2023.09.006. PMID 37713961. 
  11. ↑ 11.0 11.1 11.2 11.3 11.4 Xcopri FDA Professional Drug Information. Accessed 28 July 2021.
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 "Ontozry: EPAR – Product information". European Medicines Agency. 2 June 2021. https://www.ema.europa.eu/en/documents/product-information/ontozry-epar-product-information_en.pdf. 
  13. ↑ 13.0 13.1 13.2 "A resurging boom in new drugs for epilepsy and brain disorders". Expert Review of Clinical Pharmacology 11 (1): 27–45. January 2018. doi:10.1080/17512433.2018.1386553. PMID 28956955. 
  14. ↑ "Exploration of the mechanism of action of cenobamate". Seizure 134: 79–85. January 2026. doi:10.1016/j.seizure.2025.11.010. PMID 41285102. 
  15. ↑ "Cenobamate FDA Approval Status". 13 November 2019. https://www.drugs.com/history/cenobamate.html. 
  16. ↑ 16.0 16.1 "Ontozry: Pending EC decision". 29 January 2021. https://www.ema.europa.eu/en/medicines/human/summaries-opinion/ontozry.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  17. ↑ "Ontozry". https://ec.europa.eu/health/documents/community-register/html/h1530.htm. 



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