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. 

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. 

• Withdrawal of Antiepileptic Drugs:                                                                     XCOPRI should be gradually withdrawn to minimize the potential of increased seizure frequency. 

 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 7,598,279 Reference ID: 4523384

MEDICATION GUIDE XCOPRI® (ex-koh-pree) (cenobamate) tablets, for oral use, [symbol pending DEA decision] What is the most important information I should know about XCOPRI? XCOPRI can cause serious side effects, including: 1. Serious or life threatening allergic reactions which may affect organs and other parts of your body like the liver or blood cells. You may or may not have a rash with these types of reactions. Call your healthcare provider right away and go to the nearest emergency room if you have any of the following: • swelling of your face, eyes, lips, or tongue • painful sores in the mouth or around your eyes • trouble swallowing or breathing • yellowing of your skin or eyes • a skin rash • unusual bruising or bleeding • hives • severe fatigue or weakness • fever, swollen glands, or sore throat that does not go away or comes and goes • severe muscle pain • frequent infections that do not go away These symptoms may be the first signs of a serious reaction. A healthcare provider should examine you to decide if you should continue taking XCOPRI. 2. Like other antiepileptic drugs, XCOPRI may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare p

 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 

The mean QTc is -11 [-13, -8] msec for 200 mg once daily and -18 [-22, -15] msec for 500 mg once daily (1.25 times the maximum recommended dosage).

A higher percentage of XCOPRI-treated subjects (31% at 200 mg and 66% at 500 mg) had a QT shortening of greater than 20 msec compared to placebo (6-17%).

Reductions of the QTc interval below 300 msec were not observed.

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. The pharmacokinetics of cenobamate are similar when used as monotherapy or as adjunctive therapy for the treatment of partial-onset seizures, except plasma cenobamate multiple-dose exposure (Cmax, AUC) decreased with co-administration of phenytoin by 27-28%.

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.

In subjects with severe (CLcr less than 30 mL/min) renal impairment, cenobamate plasma AUC did not change significantly compared to healthy controls following single oral 100 mg dose of XCOPRI

Use in Specific Populations  The 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.

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 

Multiple doses of concomitant XCOPRI 200 mg once daily decreased carbamazepine mean Cmax and AUC each by 23% 

. No clinically significant differences in the pharmacokinetics of the following drugs were observed when used concomitantly with cenobamate: valproic acid, levetiracetam or lacosamide.

Based on population PK analyses, during treatment within the 100-400 mg/day XCOPRI dose range, lamotrigine concentrations are expected to decrease by 21-52% ; and levetiracetam concentrations are expected to decrease by 4-13%, which is not expected to be clinically significant. In subjects treated with XCOPRI in Study 1 and Study 2, there was no clear relationship between efficacy and concomitant oxcarbazepine use.

As such, the efficacy data from Study 1 and Study 2 do not support the existence of a clinically relevant interaction perpetrated by XCOPRI against oxcarbazepine.

CYP Substrates Multiple doses of concomitant XCOPRI 200 mg once daily decreased total bupropion (CYP2B6 substrate) mean Cmax and AUC by 23% and 39%, respectively, and decreased midazolam (CYP3A substrate) mean Cmax and AUC by 61% and 72%, respectively 

Multiple doses of concomitant XCOPRI 200 mg once daily increased the omeprazole (CYP2C19 substrate) mean Cmax and AUC by 83% and 107%, respectively .              No clinically significant differences in the pharmacokinetics of warfarin (CYP2C9 substrate) were observed when used concomitantly with cenobamate.

The effects of concomitant AEDs on cenobamate PK Plasma cenobamate multiple-dose exposure (Cmax, AUC) decreased with co-administration of phenytoin by 27-28%.

However, repeated dosing of valproate, phenobarbital, and carbamazepine did not have any significant impact on plasma cenobamate multiple-dose exposure.

Summary

USE IN SPECIFIC POPULATIONS

• Pregnancy: Based on animal data, may cause fetal harm. 

• 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. 

• 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.

 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 animal studies, administration of cenobamate 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 

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 impairment.

Use in patients with end-stage renal disease undergoing dialysis is not recommended 

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 

Use of XCOPRI in patients with severe hepatic impairment is not recommended. 

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. XCOPRI at single doses of 400 mg produced responses on positive subjective measures such as “Drug Liking,” “Overall Drug Liking,” “Take Drug Again,” and “Good Drug Effects” that were statistically greater than the responses produced on these measures by placebo.

3. Dependence                                                                                                       Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Clinical studies in healthy subjects indicate that XCOPRI may cause physical dependence and lead to a withdrawal syndrome characterized by insomnia, decreased appetite, depressed mood, tremor, and amnesia. XCOPRI should be withdrawn gradually 

 OVERDOSAGE

There is limited clinical experience with XCOPRI overdose in humans.

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.

An adequate airway, oxygenation and ventilation should be ensured; monitoring of cardiac rate and rhythm and vital signs is recommended.

A certified poison control center should be contacted for updated information on the management of overdose with XCOPRI. There are no data on the removal of XCOPRI using dialysis.