cenobamate (Rx)

Brand and Other Names:Xcopri
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet (pending FDA scheduling)

  • 12.5mg
  • 25mg
  • 50mg
  • 100mg
  • 150mg
  • 200mg

Partial-onset Seizures

Indicated for treatment of partial-onset seizures as either monotherapy or adjunctive therapy

Dose and titration schedule

  • Do not exceed recommended dosage and titration, owing to potential for serious adverse reactions
  • Weeks 1-2: 12.5 mg PO qDay initially
  • Titration dose
    • Weeks 3-4: 25 mg PO qDay
    • Weeks 5-6: 50 mg PO qDay
    • Weeks 7-8: 100 mg PO qDay
    • Weeks 9-10 150 mg PO qDay
  • Maintenance dose
    • Week 11 and thereafter: 200 mg PO qDay
  • Maximum dose
    • Based on clinical response and tolerability, dose may be increased above 200 mg by increments of 50 mg/day q2week to 400 mg PO qDay if needed

Dosage Modifications

Renal impairment

  • Mild, moderate, or severe: Caution advised; consider dosage reduction
  • End-stage renal disease: Not recommended

Hepatic impairment

  • Mild-to-moderate (Child-Pugh 5-9): Not to exceed 200 mg/day; additional dosage reduction may be necessary
  • Severe: Not recommended

<18 years: Safety and efficacy not established

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Interactions

Interaction Checker

and cenobamate

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    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            Somnolence (19-37%)

            Dizziness (18-33%)

            Fatigue (12-24%)

            Diplopia (6-15%)

            Headache (10-12%)

            Serum potassium increased; K+ >5 mEq/L (8.3-10.8%)

            1-10%

            Nausea (6-9%)

            Balance disorder (3-9%)

            Constipation (2-8%)

            Gait disturbance (1-8%)

            Nystagmus (3-7%)

            Dysarthria (1-7%)

            Ataxia (2-6%)

            Vertigo (1-6%)

            Vomiting (2-5%)

            Nasopharyngitis (2-5%)

            Urinary tract infection (2-5%)

            Back pain (2-5%)

            Diarrhea (1-5%)

            Appetite decreased (1-5%)

            Vision blurred (2-4%)

            ALT increased (1-4%)

            Aphasia (1-4%)

            Dyspnea (3%)

            Confusional state (2-3%)

            Asthenia (1-3%)

            AST increased (1-3%)

            Dry mouth (1-3%)

            Tremor (1-3%)

            Palpitations (2%)

            Dyspepsia (2%)

            Dysgeusia (2%)

            Migraine (2%)

            Euphoric mood (2%)

            Papular rash (2%)

            Abdominal pain (1-2%)

            Pharyngitis (1-2%)

            Head injury (1-2%)

            Weight decreased (1-2%)

            Musculoskeletal chest pain (1-2%)

            Memory impairment (1-2%)

            Sedation (1-2%)

            Irritability (1-2%)

            Suicidal ideation (1-2%)

            Dysmenorrhea (1-2%)

            Pruritus (1-2%)

            Pollakiuria (1%)

            Hiccups (1%)

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            Warnings

            Contraindications

            Hypersensitivity

            Familial short QT syndrome (SQTS)

            Cautions

            Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity, reported; DRESS has occurred, including 1 fatality, when cenobamate was titrated rapidly (weekly or faster titration)

            QT shortening >20 msec (31-66%) observed in clinical trials compared with placebo (6-17%); QTc reduction <300 msec not observed; contraindicated in patients with familial SQTS

            Antiepileptic drugs (AEDs), including cenobamate, increase risk of suicidal thoughts or behavior in patients taking these drugs for any indication; monitor for emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior

            Similar to most AEDs, discontinue cenobamate gradually, owing to risk of increased seizure frequency and status epilepticus; may consider rapid discontinuation because of a serious adverse event

            Neurological adverse reactions

            • Dose-dependent increases in somnolence and fatigue-related adverse reactions (somnolence, fatigue, asthenia, malaise, hypersomnia, sedation, and lethargy) observed in approximately one third of patients during clinical trials
            • Dose-dependent adverse reactions related to dizziness and disturbance in gait and coordination (dizziness, vertigo, balance disorder, ataxia, nystagmus, gait disturbance, abnormal coordination) observed in up to ~50% of patients observed in clinical trials
            • Cognitive dysfunction (ie, memory impairment, disturbance in attention, amnesia, confusional state, aphasia, speech disorders, slowness of thought, disorientation, psychomotor retardation) observed
            • Visual changes (eg, diplopia, blurred vision, and impaired vision) observed
            • Warn patients against engaging in hazardous activities requiring mental alertness until the effects of cenobamate are known

            Drug interaction overview

            • Effect of cenobamate on other drugs
              • Lamotrigine or carbamazepine: Plasma levels decreased; potential for reduced efficacy of these drugs; increase dosage of lamotrigine or carbamazepine, as needed
              • Phenytoin: Plasma levels increased; owing to potential 2-fold increase in phenytoin levels, gradually decrease phenytoin dosage by up to 50% as cenobamate is being titrated
              • Phenobarbital, clobazam (ie, desmethyl-clobazam active metabolite): Plasma levels increased; potential for increased adverse reactions from these drugs; consider dose reduction of phenobarbital or clobazam, as clinically appropriate
              • CYP2B6 or CYP3A substrates: Plasma levels decreased; potential for reduced efficacy of these drugs; increase dosage of CYP2B6 or CYP3A4 substrates, as needed
              • Oral contraceptives: Plasma levels decreased; potential for reduced efficacy of oral contraceptives; women should use additional contraceptive or a nonhormonal birth control method while taking cenobamate
              • CYP2C19 substrates: Plasma levels increased; potential for increased risk of adverse reactions from these drugs; consider dosage reduction of CYP2C19 substrates, as clinically appropriate
            • Drugs that shorten QT interval
              • Cenobamate can shorten QT interval; therefore, caution when administering with other drugs that shorten QT interval (eg, rufinamide)
            • CNS depressants and alcohol
              • Coadministration with other CNS depressants, including alcohol, may increase risk of neurological adverse reactions, including sedation and somnolence
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            Pregnancy & Lactation

            Pregnancy

            Data are unavailable on the developmental risk associated with use of cenobamate in pregnant women

            Encourage women to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry 1-888-233-2334 or http://www.aedpregnancyregistry.org

            Animal studies

            • Administration during pregnancy or throughout pregnancy and lactation resulted in adverse effects on development (increased embryofetal mortality, decreased fetal and offspring body weights, neurobehavioral and reproductive impairment in offspring) at clinically relevant drug exposures

            Contraception

            • Cenobamate may decrease plasma concentrations of oral contraceptives
            • Women of reproductive potential concomitantly using oral contraceptives should use additional or alternative nonhormonal birth control

            Lactation

            Data are unavailable on the presence in human milk, effects on breastfed infants, or effects on milk production

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Exact mechanism of action unknown

            It is thought to work by reducing repetitive neuronal firing by inhibiting voltage-gated sodium currents; it is also a positive allosteric modulator of the GABA ion channel

            Absorption

            Bioavailability: 88%

            Peak plasma time: 1-4 hr

            Distribution

            Protein bound: 60%; primarily to albumin

            Vd: 40-50 L

            Metabolism

            Extensively metabolized; primarily by glucuronidation via UGT2B7 and to a lesser extent by UGT2B4, and by oxidation via CYP2E1, CYP2A6, CYP2B6, and to a lesser extent by CYP2C19 and CYP3A4/5

            Elimination

            Half-life: 50-60 hr

            Oral clearance: 0.45-9.63 L/hr

            Excretion: Urine 87.8%; feces 5.2%

            Pharmacogenomics

            Short QT syndrome

            • Genotype-phenotype correlations of congenital SQTS are presently not well characterized
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            Administration

            Oral Administration

            Administer at any time with or without food

            Swallow tablet whole with liquid; do not crush or chew

            Discontinuation

            • If discontinued, gradually reduce dose over at least 2 weeks, unless safety concerns require abrupt withdrawal
            • Abrupt withdrawal associated with increased seizure frequency and status epilepticus

            Storage

            Store at controlled room temperature of 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.