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Cenobamate

Brand name: Xcopri
Drug class: Anticonvulsants, Miscellaneous
VA class: CN400
Chemical name: [(1R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl] carbamate
Molecular formula: C10H10ClN5O2
CAS number: 913088-80-9

Medically reviewed by Drugs.com on May 3, 2022. Written by ASHP.

Introduction

Anticonvulsant; a tetrazole alkyl carbamate derivative.

Uses for Cenobamate

Partial Seizures

Management of partial-onset seizures in adults.

Cenobamate Dosage and Administration

General

Patient Monitoring

  • Monitor patients for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression.

Other General Considerations

  • Cenobamate dosage must be titrated slowly according to the manufacturer's recommended dosage titration schedule; more rapid titration has resulted in serious adverse effects.

Administration

Oral Administration

Administer orally once daily without regard to food.

Swallow tablets whole with liquid; do not crush or chew.

Dosage

Adults

Partial Seizures
Oral

Initially, 12.5 mg once daily for the first 2 weeks; titrate to the recommended dosage of 200 mg once daily according to the manufacturer's titration schedule (see Table 1).

If needed, dosage may be further increased by increments of 50 mg once daily every 2 weeks up to a maximum dosage of 400 mg once daily based on clinical response and tolerability. Do not exceed the recommended titration schedule because of potential for serious adverse effects.

Table 1. Recommended Dosage Titration Schedule for Cenobamate1

Week

Dosage

Weeks 1 and 2

12.5 mg once daily

Weeks 3 and 4

25 mg once daily

Weeks 5 and 6

50 mg once daily

Weeks 7 and 8

100 mg once daily

Weeks 9 and 10

150 mg once daily

Week 11 and thereafter

200 mg once daily

If therapy is discontinued, reduce dosage gradually over a period of at least 2 weeks unless safety concerns require abrupt withdrawal.

Prescribing Limits

Adults

Partial Seizures
Oral

Maximum 400 mg once daily.

Special Populations

Hepatic Impairment

Partial Seizures
Oral

Mild or moderate hepatic impairment (Child-Pugh class A or B): Maximum recommended dosage is 200 mg once daily.

Severe hepatic impairment: Use not recommended.

Renal Impairment

Partial Seizures
Oral

Consider dosage reduction in patients with mild to moderate (Clcr 30 to <90 mL/minute) or severe (Clcr <30 mL/minute) renal impairment.

Geriatric Patients

Oral

Manufacturer recommends cautious dosage selection (usually starting at the low end of the dosage range).

Cautions for Cenobamate

Contraindications

  • Known hypersensitivity to cenobamate or any ingredients in the formulation.

  • Familial short QT syndrome.

Warnings/Precautions

Sensitivity Reactions

Multi-organ Hypersensitivity

Multi-organ hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]) reported; can be fatal or life-threatening. Clinical presentation is variable but typically includes fever, rash, lymphadenopathy, and/or facial swelling associated with other organ system involvement (e.g., eosinophilia, hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis).

Initiate therapy at a low dosage and titrate every 2 weeks as recommended.

If manifestations of multi-organ hypersensitivity reaction occur, evaluate patient immediately. If an alternative cause cannot be identified, permanently discontinue cenobamate.

Shortening of QT Interval

Shortening of QT interval reported.

Familial short QT syndrome is associated with an increased risk of sudden death and ventricular arrhythmias, particularly ventricular fibrillation; such events are thought to occur primarily when corrected QT (QTc) interval <300 msec.

Avoid use in patients with familial short QT syndrome. Exercise caution when administered concomitantly with other drugs that shorten QT interval.

Suicidality Risk

Increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%). Increased suicidality risk was observed as early as 1 week after beginning therapy and continued through 24 weeks. Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.

Closely monitor all patients currently receiving or beginning therapy with any anticonvulsant for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.

Balance risk of suicidality with risk of untreated illness. Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality. If suicidal thoughts or behavior emerge during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.

Neurologic Effects

Cenobamate can cause a variety of adverse neurologic effects including dizziness, disturbances in gait or coordination (e.g., vertigo, nystagmus, balance disorder, ataxia, abnormal coordination), cognitive dysfunction, somnolence, and fatigue.

Monitor patients for these adverse effects and advise patients not to drive or operate machinery until the effects of the drug are known.

Carefully observe patients for signs of CNS depression (e.g., somnolence and sedation) when used with other drugs with sedative properties.

Ophthalmologic Effects

Adverse ophthalmologic effects (e.g., diplopia, blurred vision, and impaired vision) reported.

Discontinuance of Therapy

Abrupt withdrawal of anticonvulsants may increase seizure frequency and risk of status epilepticus. In general, gradually withdraw therapy (i.e., over ≥2 weeks); however, prompt withdrawal may be considered if discontinuance of cenobamate is necessary because of serious adverse effects.

Abuse Potential and Dependence

Cenobamate is subject to control as a schedule V (C-V) drug. Euphoric effects, confusional state, and sedation reported.

May cause physical dependence and withdrawal syndrome characterized by insomnia, decreased appetite, depressed mood, tremor, and amnesia. In general, withdraw therapy gradually.

Specific Populations

Pregnancy

North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 or [Web].

No adequate data in humans; in animal studies, developmental toxicity (i.e., increased embryofetal mortality, decreased fetal and offspring body weight, neurobehavioral and reproductive impairment in offspring) observed at clinically relevant doses.

Females and Males of Reproductive Potential

Females of reproductive potential who are receiving oral contraceptives should use additional or alternative nonhormonal birth control.

Lactation

Not known whether cenobamate is distributed into milk; effects on milk production or on breast-fed infant also not known.

Consider benefits of breast-feeding and importance of cenobamate to the woman; also consider any potential adverse effects on breast-fed infant from the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy in pediatric patients not established.

Geriatric Use

Insufficient experience in geriatric patients to determine whether they respond differently than younger patients. Consider greater frequency of decreased hepatic, renal, and/or cardiac function, and other concomitant medical conditions and drug therapy in this population.

Hepatic Impairment

Systemic exposure is increased in patients with hepatic impairment.

Use with caution in patients with mild to moderate (Child-Pugh class A or B) hepatic impairment. Maximum recommended dosage in such patients is 200 mg once daily; consider additional dosage reduction.

Not studied in patients with severe hepatic impairment; use not recommended.

Renal Impairment

Systemic exposure is increased in patients with renal impairment.

Use with caution and consider dosage reduction in patients with mild to moderate renal impairment (Clcr 30 to <90 mL/minute) or severe renal impairment (Clcr<30 mL/minute).

Effect of hemodialysis on cenobamate pharmacokinetics not studied; use not recommended in patients with end-stage renal disease undergoing dialysis.

Common Adverse Effects

Adverse effects (≥10%): somnolence, dizziness, fatigue, diplopia, headache.

Interactions for Cenobamate

Extensively metabolized by glucuronidation via UGT2B7 and to a lesser extent by UGT2B4. Also metabolized by CYP isoenzymes 2E1, 2A6, and 2B6, and to a lesser extent by CYP2C19 and CYP3A4/5.

In vitro, inhibits CYP isoenzymes 2B6, 2C19, and 3A, but does not inhibit CYP1A2, CYP2C8, CYP2C9, or CYP2D6. Induces CYP2B6, CYP2C8, and CYP3A4, but does not induce CYP1A2, CYP2C9, or CYP2C19.

Not a substrate of the efflux transporter P-glycoprotein (P-gp). Also not a substrate of breast cancer resistance protein (BCRP), multidrug and toxin extrusion transporters (MATE) 1 or MATE2/K, organic ion transporters (OAT) 1 and OAT3, or organic cation transporter (OCT) 2. Does not inhibit P-gp, OAT1, OAT3, OCT1, OCT2, organic anion transport proteins (OATP) 1B1 and OATP1B3, or bile salt extrusion protein (BSEP).

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP2B6 and CYP3A Substrates: Cenobamate may decrease plasma concentrations and efficacy of substrate drug. Consider increasing dosage of substrate drug as needed.

CYP2C19 Substrates: Cenobamate may increase plasma concentrations of the CYP2C19 substrate, potentially increasing risk of adverse reactions. Consider decreasing dosage of substrate drug as clinically appropriate if adverse reactions are observed.

Drugs that Shorten QT Interval

Potential additive effect on QT interval; use concomitantly with caution.

Specific Drugs

Drug

Interaction

Comments

Alcohol

May increase risk of somnolence and sedation

No clinically important pharmacokinetic effects observed

Bupropion

Decrease in bupropion peak plasma concentration and AUC by 23 and 39%, respectively

Increase bupropion dosage as needed

Carbamazepine

Peak plasma concentration and AUC of carbamazepine each decreased by 23%

Increase carbamazepine dosage as clinically appropriate

Clobazam

Increased plasma concentration of desmethylclobazam (active metabolite of clobazam)

Consider reduction in clobazam dosage

CNS depressants

May increase risk of adverse neurologic effects, including somnolence and sedation

Lacosamide

Clinically important effects on lacosamide pharmacokinetics not observed

Lamotrigine

Lamotrigine concentrations expected to decrease by 21–52%

Possible additive effect on shortening of QT interval

Increase lamotrigine dosage as clinically appropriate

Use concomitantly with caution

Levetiracetam

Clinically important effects on levetiracetam pharmacokinetics not observed

Midazolam

Midazolam peak plasma concentration and AUC decreased by 61 and 72%, respectively

Increase midazolam dosage as needed

Omeprazole

Omeprazole peak plasma concentration and AUC increased by 83 and 107%, respectively

Decrease omeprazole dosage as clinically appropriate if adverse effects occur

Oral contraceptives

May decrease concentrations and efficacy of oral contraceptives

Use additional or alternative nonhormonal contraception

Oxcarbazepine

Interaction unlikely

Phenobarbital

Increased phenobarbital peak plasma concentration and AUC by 34 and 37%, respectively

Consider dosage reduction of phenobarbital as clinically appropriate

Phenytoin

Increased phenytoin peak plasma concentration and AUC by 70 and 84%, respectively; cenobamate exposure decreased by 27–28%

Gradually reduce phenytoin dosage by up to 50% as cenobamate is being titrated

Primidone

Possible additive effect on shortening of QT interval

Use concomitantly with caution

Rufinamide

Possible additive effect on shortening of QT interval

Use concomitantly with caution

Valproic acid

No effect on pharmacokinetics of valproic acid

Warfarin

No clinically important effects on pharmacokinetics of warfarin (CYP2C9 substrate)

Cenobamate Pharmacokinetics

Absorption

Bioavailability

AUC increases in a greater than dose-proportional manner following single oral doses of 5–750 mg; however, peak plasma concentrations increase in a dose-proportional manner.

Steady-state plasma concentrations attained following approximately 2 weeks of daily dosing.

≥88% absorbed following oral administration.

Median time to peak plasma concentrations 1–4 hours.

Food

Administration with a high-fat meal does not affect pharmacokinetics.

Special Populations

Exposure increased 2.1- or 2.3-fold in individuals with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, respectively, following a single 200-mg dose.

AUC increased 1.4-fold to 1.5-fold in subjects with mild (ClCr 60 to <90 mL/minute) or moderate (ClCr 30 to <60 mL/minute) renal impairment following a single 200-mg dose.

Distribution

Plasma Protein Binding

60% (primarily albumin).

Elimination

Metabolism

Extensively metabolized by glucuronidation via UGT2B7 and to a lesser extent by UGT2B4.

Also metabolized by CYP isoenzymes 2E1, 2A6, and 2B6, and to a lesser extent by CYP2C19 and CYP3A4/5.

Elimination Route

Approximately 93% of a radioactive dose was recovered in urine (87.8%) and feces (5.2%); >50% of radioactivity was excreted within 72 hours.

Half-life

50–60 hours.

Stability

Storage

Oral

Tablets

25°C (excursions permitted to 15–30°C).

Actions

  • Precise mechanism of anticonvulsant action unknown.

  • Reduces repetitive neuronal firing by inhibiting voltage-gated sodium currents; also a positive allosteric modulator of the γ-aminobutyric acid (GABAA) ion channel.

Advice to Patients

  • Importance of advising patients to read the manufacturer's patient information (medication guide).

  • Importance of informing patients that cenobamate may be taken with or without food and that tablets should be swallowed whole with liquid and not chewed or crushed.

  • Risk of multi-organ hypersensitivity (or DRESS). Importance of advising patients and caregivers that a fever or rash associated with signs of other organ system involvement (e.g., lymphadenopathy, hepatic dysfunction) may be drug-related and should be reported to their clinician immediately. Importance of immediately discontinuing cenobamate if a serious hypersensitivity reaction is suspected.

  • Importance of informing patients that cenobamate may be associated with shortening of the QT interval. Importance of instructing patients to inform their clinician if they have any symptoms (e.g., heart palpitations, loss of consciousness).

  • Anticonvulsants, including cenobamate, may increase the risk of suicidal thoughts or behavior. Importance of patients, family members, and caregivers being alert to and immediately reporting emergence or worsening of depression; any unusual changes in mood or behavior; or emergence of suicidal thoughts, behavior, or thoughts about self-harm.

  • Risk of adverse neurologic effects (e.g., somnolence, fatigue, dizziness, gait disturbance); such effects are more likely to occur early in treatment but can occur at any time. Importance of advising patients not to drive or operate machinery until the effects of the drug are known. Concomitant use of other CNS depressants, including alcohol, may result in additive effects.

  • Importance of advising patients not to discontinue cenobamate therapy without consulting with their clinician. Cenobamate generally should be gradually withdrawn to minimize the risk of increased seizure frequency and status epilepticus.

  • Importance of advising patients that cenobamate is a federally controlled substance because it has the potential to be abused or lead to dependence. Advise patients to keep their medication secure.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Counsel females of reproductive potential that cenobamate may decrease the efficacy of oral contraceptives and advise them to use additional or alternative nonhormonal birth control. Encourage patients who become pregnant while taking the drug to enroll in the North American Antiepileptic Drug Pregnancy Registry.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Cenobamate is subject to control under the Federal Controlled Substances Act of 1970 as a schedule V (C-V) drug.

Cenobamate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Kit

14 tablets, uncoated cenobamate 12.5 mg

14 tablets, film-coated cenobamate 25 mg

Xcopri 28-Day Titration Blister Pack

SK Life Science

14 tablets, film-coated cenobamate 50 mg

14 tablets, film-coated cenobamate 100 mg

Xcopri 28-Day Titration Blister Pack

SK Life Science

14 tablets, film-coated cenobamate 150 mg

14 tablets, film-coated cenobamate 200 mg

Xcopri 28-Day Titration Blister Pack

SK Life Science

28 tablets, film-coated cenobamate 100 mg

28 tablets, film-coated cenobamate 150 mg

Xcopri 28-Day Maintenance Blister Pack

SK Life Science

28 tablets, film-coated cenobamate 150 mg

28 tablets, film-coated cenobamate 200 mg

Xcopri 28-Day Maintenance Blister Pack

SK Life Science

Tablets, film-coated

50 mg

Xcopri

SK Life Science

100 mg

Xcopri

SK Life Science

150 mg

Xcopri

SK Life Science

200 mg

Xcopri

SK Life Science

AHFS DI Essentials™. © Copyright 2022, Selected Revisions May 3, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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