Cenobamate

Cenobamate
Names
Trade namesXcopri, Ontozry
Other namesYKP3089
IUPAC name
  • [(1R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl] carbamate
Clinical data
Main usesFocal-onset seizures[1]
Side effectsSleepiness, dizziness, tiredness, double vision, headache[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Routes of
use		By mouth
External links
AHFS/Drugs.comMonograph
MedlinePlusa620021
Legal
License data
Legal status
Pharmacokinetics
Bioavailability≥88%
Protein binding60%
MetabolismMainly glucuronidation via UGT2B7
Elimination half-life50–60 hours
ExcretionMainly via urine
Chemical and physical data
FormulaC10H10ClN5O2
Molar mass267.67 g·mol−1
3D model (JSmol)
SMILES
  • C1=CC=C(C(=C1)C(CN2N=CN=N2)OC(=O)N)Cl
InChI
  • InChI=1S/C10H10ClN5O2/c11-8-4-2-1-3-7(8)9(18-10(12)17)5-16-14-6-13-15-16/h1-4,6,9H,5H2,(H2,12,17)/t9-/m0/s1
  • Key:GFHAXPJGXSQLPT-VIFPVBQESA-N

Cenobamate, sold under the brand name Xcopri and Ontozry, is a medication used to treat epilepsy, specifically focal-onset seizures.[1] It may be used together with other medication.[3] It is taken by mouth.[1]

Common side effects include sleepiness, dizziness, tiredness, double vision, and headache.[1] Other side effects may include short QT, DRESS, and suicide.[1] Use in pregnancy may harm the baby.[1] How it works is not entirely clear; however, it alters ion channels.[1]

Cenobamate was approved for medical use in the United States in 2019 and Europe in 2021.[4][3] It is on Schedule V of the Controlled Substances Act.[5] In the United States 30 pills of 100 mg costs about 1,000 USD as of 2022.[6]

Medical uses

In the United States, cenobamate is indicated for the treatment of partial-onset seizures in adults.[1]

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.[3]

Dosage

It is generally started at a dose of 12.5 mg once per day and than gradually increased to 200 mg once per day.[3] Up to 400 mg once per day may be used.[3]

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.[7][8]

Side effects

The most common side effects are drowsiness (in 37% of people taking the drug), dizziness (33%), and fatigue (24%). Sight disorders, headache and hyperkalaemia (high potassium levels in the blood) are also common.[7] Hypersensitivity occurs in fewer than 1% of patients, drug reaction with eosinophilia and systemic symptoms (DRESS) in fewer than 0.1%.[8]

Overdose

There are few 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.[7][8]

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.[7][8]

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 omeprazole).[7][8]

Pharmacology

Mechanism of action

Cenobamate is a voltage-gated sodium channel (VGSC) blocker.[9] It is a selective blocker of the inactivated state of VGSCs, preferentially inhibiting persistent sodium current.[9] It has been proposed that cenobamate additionally enhances presynaptic release of γ-aminobutyric acid (GABA), thereby increasing inhibitory GABAergic neurotransmission.[9]

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.[8]

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.[8]

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.[10]

Society and culture

The U.S. Food and Drug Administration (FDA) approved cenobamate in November 2019, and granted the application for Xcopri to SK Life Science Inc.[10][11][12][13]

On 28 January 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization.[14] The applicant for this medicinal product is Arvelle Therapeutics Netherlands B.V.[14] Ontozry was approved on 26 March 2021.[3][15]

References

  1. 1 2 3 4 5 6 7 8 9 10 "Xcopri Titration Pack- cenobamate kit Xcopri- cenobamate tablet, film coated Xcopri Maintenance Pack- cenobamate kit". DailyMed. Archived from the original on 11 August 2020. Retrieved 1 February 2021.
  2. ↑ "Schedules of Controlled Substances: Placement of Cenobamate in Schedule V". Federal Register. 10 March 2020. Archived from the original on 3 April 2021. Retrieved 4 August 2021.
  3. 1 2 3 4 5 6 7 "Ontozry EPAR". European Medicines Agency (EMA). 25 January 2021. Archived from the original on 4 June 2021. Retrieved 4 June 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  4. ↑ "Cenobamate Monograph for Professionals". Drugs.com. Retrieved 3 January 2022.
  5. ↑ "2020 - Placement of Cenobamate in Schedule V". DEA Diversion Control Division. 10 March 2020. Archived from the original on 19 April 2020. Retrieved 11 March 2020.
  6. ↑ "Xcopri Prices, Coupons & Savings Tips - GoodRx". GoodRx. Archived from the original on 19 October 2021. Retrieved 3 January 2022.
  7. 1 2 3 4 5 Xcopri FDA Professional Drug Information. Accessed 2021-07-28.
  8. 1 2 3 4 5 6 7 "Ontozry: EPAR – Product information" (PDF). European Medicines Agency. 2 June 2021. Archived (PDF) from the original on 28 July 2021. Retrieved 4 August 2021.
  9. 1 2 3 Younus I, Reddy DS (January 2018). "A resurging boom in new drugs for epilepsy and brain disorders". Expert Review of Clinical Pharmacology. 11 (1): 27–45. doi:10.1080/17512433.2018.1386553. PMID 28956955. S2CID 5598471.
  10. 1 2 "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.
  11. ↑ "Drug Trials Snapshots: Xcopri". U.S. Food and Drug Administration (FDA). 3 December 2019. Archived from the original on 19 December 2019. Retrieved 18 December 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  12. ↑ "Drug Approval Package: Xcopri". U.S. Food and Drug Administration (FDA). 10 December 2019. Archived from the original on 19 December 2019. Retrieved 18 December 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  13. ↑ "Cenobamate FDA Approval Status". Drugs.com. 13 November 2019. Retrieved 22 November 2019.
  14. 1 2 "Ontozry: Pending EC decision". European Medicines Agency (EMA). 29 January 2021. Archived from the original on 1 February 2021. Retrieved 1 February 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  15. ↑ "Ontozry". Union Register of medicinal products. Archived from the original on 2 August 2021. Retrieved 3 August 2021.
Identifiers:
  • "Cenobamate". Drug Information Portal. U.S. National Library of Medicine (NLM). Archived from the original on 1 November 2021. Retrieved 4 August 2021.
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