|Trade names||Xcopri, Ontozry|
|Main uses||Focal-onset seizures|
|Side effects||Sleepiness, dizziness, tiredness, double vision, headache|
|Metabolism||Mainly glucuronidation via UGT2B7|
|Elimination half-life||50–60 hours|
|Excretion||Mainly via urine|
|Chemical and physical data|
|Molar mass||267.67 g·mol−1|
|3D model (JSmol)|
Cenobamate, sold under the brand name Xcopri and Ontozry, is a medication used to treat epilepsy, specifically focal-onset seizures. It may be used together with other medication. It is taken by mouth.
Common side effects include sleepiness, dizziness, tiredness, double vision, and headache. Other side effects may include short QT, DRESS, and suicide. Use in pregnancy may harm the baby. How it works is not entirely clear; however, it alters ion channels.
Cenobamate was approved for medical use in the United States in 2019 and Europe in 2021. It is on Schedule V of the Controlled Substances Act. In the United States 30 pills of 100 mg costs about 1,000 USD as of 2022.
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.
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. Hypersensitivity occurs in fewer than 1% of patients, drug reaction with eosinophilia and systemic symptoms (DRESS) in fewer than 0.1%.
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.
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.
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).
Mechanism of action
Cenobamate is a voltage-gated sodium channel (VGSC) blocker. It is a selective blocker of the inactivated state of VGSCs, preferentially inhibiting persistent sodium current. It has been proposed that cenobamate additionally enhances presynaptic release of γ-aminobutyric acid (GABA), thereby increasing inhibitory GABAergic neurotransmission.
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.
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.
Society and culture
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. The applicant for this medicinal product is Arvelle Therapeutics Netherlands B.V. Ontozry was approved on 26 March 2021.
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