(XCOPRI)- Cenobamate- (Nov 2019)
Drug Name:(XCOPRI)- Cenobamate- (Nov 2019)
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
DRUG INTERACTIONS
• Phenytoin: Gradually decrease phenytoin dosage by up to 50%
• Phenobarbital and Clobazam: Reduce dosage as needed when used concomitantly with XCOPRI.
• Lamotrigine, Carbamazepine: Increase dosage as needed when used concomitantly with XCOPRI.
• CYP2B6 and CYP3A Substrates: Increase dosage as needed when used concomitantly with XCOPRI.
• CYP2C19 Substrates: Reduce dosage as needed when used concomitantly with XCOPRI.
• Oral Contraceptives: Effectiveness of hormonal oral contraceptives may be reduced when administered concomitantly with XCOPRI. Women should use additional or alternative non-hormonal birth control.
Indication:
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use XCOPRI safely and effectively.
See full prescribing information for XCOPRI. XCOPRI® (cenobamate tablets), for oral use, [controlled substance schedule pending]
Initial U.S. Approval: XXXX [pending controlled substance scheduling]
INDICATIONS AND USAGE-
XCOPRI is indicated for the treatment of partial-onset seizures in adult patients.
Adverse Reaction:
ADVERSE REACTIONS-
The most common adverse reactions in patients receiving XCOPRI (at least 10% for XCOPRI and more frequently than placebo) include somnolence, dizziness, fatigue, diplopia, and headache.
Contra-Indications:
CONTRAINDICATIONS
• Hypersensitivity to cenobamate or any of the inactive ingredients in XCOPRI.
• Familial Short QT syndrome.
WARNINGS AND PRECAUTIONS
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/ Multi-Organ Hypersensitivity: Discontinue if no alternate etiology.
• QT Shortening: Use caution when administering XCOPRI with other drugs that shorten the QT interval
• Suicidal Behavior and Ideation: Monitor patients for suicidal behavior and ideation.
• Neurological Adverse Reactions: Monitor for somnolence and fatigue and advise patients not to drive or operate machinery until they have gained sufficient experience on XCOPRI. Concomitant use with other CNS depressants or alcohol may have additive effects.
Withdrawal of Antiepileptic Drugs: XCOPRI should be gradually withdrawn to minimize the potential of increased seizure frequency.
___________________ DRUG INTERACTIONS____________________ • Phenytoin: Gradually decrease phenytoin dosage by up to 50% (7.1) • Phenobarbital and Clobazam: Reduce dosage as needed when used concomitantly with XCOPRI. (7.1) • Lamotrigine, Carbamazepine: Increase dosage as needed when used concomitantly with XCOPRI. (7.1) • CYP2B6 and CYP3A Substrates: Increase dosage as needed when used concomitantly with XCOPRI. (7.1) • CYP2C19 Substrates: Reduce dosage as needed when used concomitantly with XCOPRI. (7.1) • Oral Contraceptives: Effectiveness of hormonal oral contraceptives may be reduced when administered concomitantly with XCOPRI. Women should use additional or alternative non-hormonal birth control.
(7.1) USE IN SPECIFIC POPULATIONS • Pregnancy: Based on animal data, may cause fetal harm. (8.1) • Renal Impairment: Use with caution and dosage reduction may be considered in patients with mild to moderate (CLcr 30 to < 90 mL/min) and severe (CLcr < 30 mL/min) renal impairment. Use not recommended in end-stage renal disease (CLcr < 15 mL/min) undergoing dialysis. (8.6) • Hepatic Impairment: Use with caution in patients with mild to moderate hepatic impairment; lower maximum dosage and additional dosage reduction may be considered. Use of XCOPRI in patients with severe hepatic impairment is not recommended. (2.3, 8.7) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Dosages/ Overdosage Etc:
DOSAGE AND ADMINISTRATION-
• Swallow tablets whole. Do not crush or chew.
• The recommended initial dosage of XCOPRI is 12.5 mg once daily, titrated to the recommended maintenance dosage of 200 mg once daily. The recommended titration schedule should not be exceeded. The maximum dosage is 400 mg once daily.
• Hepatic impairment: For patients with mild or moderate hepatic impairment, the maximum recommended dosage is 200 mg once daily.
DOSAGE FORMS AND STRENGTHS
• Tablets: 12.5 mg, 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg.
Patient Information:
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
DRESS/Multi-organ Hypersensitivity- Instruct 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 healthcare provider immediately.
XCOPRI should be discontinued immediately if a serious hypersensitivity reaction is suspected [
QT Shortening-
Instruct patients to inform their healthcare provider of all of the medications, over-the-counter medications, and herbal supplements that they are taking. Instruct patients to notify their healthcare provider if they have any symptoms of shortening of the QT interval, including prolonged heart palpitations or a loss of consciousness
Suicidal Behavior and Ideation- Counsel patients, their caregivers, and/or families that antiepileptic drugs, including XCOPRI, may increase the risk of suicidal thoughts and behavior, and advise patients to be alert for the emergence or worsening of symptoms of depression; unusual changes in mood or behavior; or suicidal thoughts, behavior, or thoughts about self-harm.
Advise patients, their caregivers, and/or families to report behaviors of concern immediately to a healthcare provider
Neurological Adverse Reactions- Counsel patients that XCOPRI causes somnolence, fatigue, dizziness, and gait disturbance. These adverse reactions, if observed, are more likely to occur early in treatment but can occur at any time.
Advise patients not to drive or operate machinery until they have gained sufficient experience on XCOPRI to gauge whether it adversely affects their ability to drive or operate machinery and that other CNS depressants or alcohol may have additive effects
Withdrawal of XCOPRI- Advise patients not to discontinue use of XCOPRI without consulting with their healthcare provider. XCOPRI should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus
Contraceptives- Counsel females of reproductive potential that XCOPRI may decrease the efficacy of oral contraceptives and advise them to use additional or alternative non-hormonal birth control
Pregnancy- Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during XCOPRI therapy.
Encourage patients to enroll in the North American Antiepileptic Drug Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy
.
Dosing Instructions- Counsel patients that XCOPRI may be taken any time with or without food. Instruct patients that XCOPRI tablets should be swallowed whole with liquid and not chewed or crushed
Abuse and Dependence - There is a pending DEA decision for control of XCOPRI (cenobamate) under the Controlled Substances Act. A statement about abuse and dependence risks cannot be completed at this time.
Manufactured for: SK Life Science, Inc. Paramus, NJ 07652 Phone: 1-866-657-5574 © 2019 SK Life Science, Inc. XCOPRI® is a registered trademark of SK Life Science, Inc. or its affiliates and protected by U.S. Patent
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action-
The precise mechanism by which cenobamate exerts its therapeutic effects in patients with partialonset seizures is unknown. Cenobamate has been demonstrated to reduce repetitive neuronal firing by inhibiting voltage-gated sodium currents.
It is also a positive allosteric modulator of the ?-aminobutyric acid (GABAA) ion channel.
2. Pharmacodynamics- Interactions with Alcohol No clinically significant differences on objective attention, psychomotor performance, and memory tests, in addition to other subjective CNS tests, were observed following concomitant use of XCOPRI and ethanol (preparation of 40% ethanol in orange juice dosed at 0.7 g/kg for males and 0.57 g/kg for females) in healthy subjects.
Cardiac Electrophysiology In a placebo-controlled QT study in healthy volunteers, dose-dependent shortening of the QTcF interval has been observed with XCOPRI
3. Pharmacokinetics - Cenobamate AUC increases in a greater than dose-proportional manner following single oral doses from 5 to 750 mg (0.0125 to 1.88 times the maximum recommended dosage).
Cenobamate Cmax increases in a dose proportional manner. Steady-state plasma concentrations are attained after approximately two weeks of once daily dosing.
Absorption- At least 88% of XCOPRI is absorbed following oral administration, with median Tmax ranging from 1 to 4 hours.
Effect of Food- No clinically significant differences in cenobamate pharmacokinetics were observed following administration of a high-fat meal (800-1000 calories with 50% fat).
Distribution - The apparent volume of distribution (Vd/F) of cenobamate after oral administration of XCOPRI is approximately 40-50 L.
Plasma protein binding of cenobamate is 60% and independent of concentration in vitro. Cenobamate primarily binds with human albumin protein.
Elimination- The apparent terminal half-life of cenobamate is 50-60 hours and apparent oral clearance is approximately 0.45-0.63 L/hour over a dose range from 100 mg/day to 400 mg/day.
Metabolism - Cenobamate is extensively metabolized. The primary metabolic pathways are 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.
Following administration of radiolabeled cenobamate, unchanged cenobamate accounted for greater than 98% of the total AUC of radioactivity in plasma. Unchanged cenobamate accounted for 6.8% of the dose which was mainly excreted in the urine (6.4%).
Excretion-
Following administration of radiolabeled cenobamate, a mean of 93.0% of the total radioactive dose was recovered in urine (87.8%) and feces (5.2%). More than 50% of the radioactivity was excreted within 72 hours of dosing.
Specific Populations- No clinically significant differences in the pharmacokinetics of cenobamate were observed based on age based on data from subjects age 18 years to 77 years, sex, or race/ethnicity based on data from subjects categorized as Asian, Black, Caucasian, Hispanic, or Other.
Patients with Renal Impairment Cenobamate plasma AUC was 1.4 fold to 1.5 fold higher in subjects with mild (CLcr 60 to less than 90 mL/min) and moderate (CLcr 30 to less than 60 mL/min) following a single oral 200 mg dose of XCOPRI compared to healthy controls.
IThe effect of hemodialysis on cenobamate pharmacokinetics has not been studied.
Patients with Hepatic Impairment - Cenobamate plasma AUC was 2.1-fold and 2.3-fold higher in subjects with mild (5-6 points on Child-Pugh assessment) and moderate (7-9 points on Child-Pugh assessment) hepatic impairment, respectively, following a single oral 200 mg dose of XCOPRI compared to matched healthy controls ].
The effect of severe hepatic impairment on cenobamate pharmacokinetics has not been studied.
Drug Interaction Studies- Clinical Studies Alcohol No clinically significant pharmacokinetic differences were observed for either cenobamate or alcohol when administered concomitantly. Reference ID: 4523384 AEDs
Multiple doses of concomitant XCOPRI 200 mg once daily increased phenytoin mean Cmax and AUC by 70% and 84%, respectively, and phenobarbital mean Cmax and AUC by 34% and 37%, respectively [
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1 Pregnancy-
Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as XCOPRI, during pregnancy.
Encourage women who are taking XCOPRI during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling the toll-free number 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/.
Risk Summary-
There are no adequate data on the developmental risk associated with the use of XCOPRI in pregnant women.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
The background risk of major birth defects and miscarriage for the indicated population is unknown.
2. Lactation Risk Summary- There are no data available on the presence of cenobamate in human milk, the effects on the breastfed infant, or the effects of the drug on milk production.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XCOPRI and any potential adverse effects on the breastfed infant from XCOPRI or from the underlying maternal condition.
3 Females and Males of Reproductive Potential-
Contraception Women of reproductive potential concomitantly using oral contraceptives should use additional or alternative non-hormonal birth control
4. Pediatric Use- Safety and effectiveness in pediatric patients have not been established.
5. Geriatric Use - Clinical studies of XCOPRI did not include sufficient numbers of patients aged 65 and over to determine the safety and efficacy of XCOPRI in the elderly population. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].
6 Renal Impairment - XCOPRI should be used with caution and dosage reduction may be considered in patients with mild to moderate (CLcr 30 to less than 90 mL/min) and severe (CLcr less than 30 mL/min) renal Reference ID: 4523384 impairment.
7. Hepatic Impairment - XCOPRI should be used with caution and in patients with mild to moderate (5-9 points on ChildPugh assessment; Class A or B) hepatic impairment. In these patients, the maximum recommended dosage is 200 mg once daily and additional dosage reduction may be considered [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. Use of XCOPRI in patients with severe hepatic impairment is not recommended.
8. DRUG ABUSE AND DEPENDENCE
1. Controlled Substance XCOPRI contains cenobamate. (Controlled substance schedule to be determined after review by the Drug Enforcement Administration).
.2. Abuse Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. In a human abuse potential study conducted in recreational sedative abusers (n=39), single doses of XCOPRI (200 mg and 400 mg) were compared to placebo.
OVERDOSAGE
There is limited clinical experience with XCOPRI overdose in humans. Reference ID: 4523384
There is no specific antidote for overdose with XCOPRI. In the event of overdose, standard medical practice for the management of any overdose should be used