DRUG INTERACTIONS

1. Effect of XCOPRI on Other Drugs

1 Pharmacokinetic Drug Interactions Drug or Substrate Type Effect of XCOPRI on Drug or Substrate Clinical Recommendation  

Antiepileptic Drugs lamotrigine - plasma concentrations-

Because f a potential  for reduced efficacy of these drugs, increase the dosage of lamotrigine or carbamazepine, as needed, when used concomitantly with XCOPRI. carbamazepine ? plasma concentrations phenytoin ? plasma concentrations

Because of a potential 2-fold increase in phenytoin levels, gradually decrease phenytoin dosage by up to 50% as XCOPRI is being titrated. phenobarbital ? plasma concentrations 

Because of a potential for an increase in the risk of adverse reactions from these drugs, desmethylclobazam, the active metabolite of clobazam ? plasma concentrations Reference ID: 4523384 Drug or Substrate Type Effect of XCOPRI on Drug or Substrate Clinical Recommendation consider a reduction in dosage of phenobarbital or clobazam, as clinically appropriate, when used concomitantly with XCOPRI.

CYP2B6 Substrates ? plasma concentrations                                                        Because of a potential for reduced efficacy of these drugs, increase the dosage of CYP2B6 or CYP3A4 substrates, as needed, when used concomitantly with XCOPRI.

CYP3A Substrates  Oral contraceptives ? plasma concentrations                                      Because of the potential for reduced efficacy of oral contraceptives, women should use additional or alternative non-hormonal birth control while taking XCOPRI.

CYP2C19 Substrates concentrations Because of a potential for an increase in the risk of adverse reactions from these drugs, consider a reduction in dosage of CYP2C19 substrates, as clinically appropriate, when used concomitantly with XCOPRI.

2. Drug that Shorten the QT Interval XCOPRI can shorten the QT interval; therefore, caution should be used when administering XCOPRI and other drugs that shorten the QT interval 

3 CNS Depressants and Alcohol                                                                    Concomitant use of XCOPRI with other CNS depressants, including alcohol, may increase the risk of neurological adverse reactions, including sedation and somnolence [

• Withdrawal of Antiepileptic Drugs: XCOPRI should be gradually withdrawn to minimize the potential of increased seizure frequency.

(5.5) 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. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact SK Life Science, Inc. at 1-866-657-5574 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

___________________ 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 PAT

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 [see Warnings and Precautions (5.1)].

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 [see Warnings and Precautions (5.2)].

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 [see Warnings and Precautions (5.3)].

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 [see Warnings and Precautions (5.4)].

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 [see Warnings and Precautions (5.5)].

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 [see Drug Interactions (7.1)].

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 [see Use in Specific Populations (8.1)].

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 [see Dosage and Administration (2.1)].

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

12 CLINICAL PHARMACOLOGY 12.1 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 Reference ID: 4523384 by inhibiting voltage-gated sodium currents. It is also a positive allosteric modulator of the ?-aminobutyric acid (GABAA) ion channel. 12.2 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 [see Warnings and Precautions (5.2)]. 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. 12.3 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 Reference ID: 4523384 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 [see Dosage and Administration (2.4) and Use in Specific Populations (8.6)]. 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 [see Dosage and Administration (2.5) and Use in Specific Populations (8.7)].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 [see Drug Interactions (7.1)]. Multiple doses of concomitant XCOPRI 200 mg once daily decreased carbamazepine mean Cmax and AUC each by 23% [see Drug Interactions (7.1]. 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% [see Drug Interactions (7.1)]; 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 [see Drug Interactions (7.1)]. Multiple doses of concomitant XCOPRI 200 mg once daily increased the omeprazole (CYP2C19 substrate) mean Cmax and AUC by 83% and 107%, respectively [see Drug Interactions (7.1)]. 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. In Vitro Studies CYP Enzymes Cenobamate inhibits CYP2B6, CYP2C19, and CYP3A, but cenobamate does not inhibit CYP1A2, CYP2C8, CYP2C9, or CYP2D6. Cenobamate induces CYP2B6, CYP2C8, and CYP3A4, but cenobamate does not induce CYP1A2, CYP2C9, or CYP2C19. Transporters Systems Cenobamate was not a substrate of P-gp, BCRP, OAT1, OAT3, OCT2, MATE1, or MATE2-K, and cenobamate did not inhibit P-gp, OAT1, OCT1, OCT2, OATP1B3, BSEP, OAT3, or OATP1B1. Reference ID: 4523384 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Oral administration of cenobamate (0, 5, 15, or 35 mg/kg/day) to Tg.rasH2 mice for up to 26 weeks did not result in an increase in tumors. Oral administration of cenobamate (0, 4, 8, or 20 mg/kg/day) to male and female rats for up to 87 or 90 weeks, respectively, did not result in an increase in tumors. Plasma exposure at the highest dose tested in rats was less than that in humans at the maximum recommended human dose (MRHD) of 400 mg/day. Mutagenesis Cenobamate was negative for genotoxicity in in vitro (Ames, mouse lymphoma) and in vivo (rat bone marrow micronucleus) assays. Impairment of Fertility Oral administration of cenobamate (0, 11, 22, or 44 mg/kg/day) to male and female rats prior to and throughout mating and continuing in females to Gestation Day 6 did not produce adverse effects on fertility, general reproductive performance, or early embryonic development. Plasma exposure (AUC) at the highest dose tested in rats was less than that in humans at the MRHD.

14 CLINICAL STUDIES The efficacy of XCOPRI for the treatment of partial-onset seizures was established in two multicenter, randomized, double-blind, placebo-controlled studies in adult patients (Study 1 and Study 2). Patients enrolled in the studies had partial-onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant AEDs. During an 8­ week baseline period, patients were required to have at least 3 or 4 partial-onset seizures per 28 days on average with no seizure-free period exceeding 3 to 4 weeks. In these studies, patients had a mean duration of epilepsy of approximately 24 years and median baseline seizure frequency of 8.5 seizures per 28 days. More than 80% of patients were taking 2 or more concomitant AEDs. Study 1 (NCT01866111) compared doses of XCOPRI 200 mg/day with placebo. Study 2 (NCT01397968) compared doses of XCOPRI 100 mg/day, 200 mg/day, and 400 mg/day with place

8 USE IN SPECIFIC POPULATIONS 8.1 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 [see Data]. 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. Data Animal Data Oral administration of cenobamate (0, 10, 30, or 60 mg/kg/day) to pregnant rats during the period of organogenesis resulted in increased embryofetal mortality, reduced fetal body weights, and incomplete fetal skeletal ossification at the highest dose tested, which was associated with maternal toxicity. There was a small increase in visceral malformations at the high dose; however, teratogenic potential could not be fully evaluated because of the high rate of embryofetal deaths, which resulted in an inadequate number of fetuses examined. Maternal plasma exposure (AUC) at the no-effect dose for adverse effects on embryofetal development (30 mg/kg/day) was less than that in humans at the maximum recommended human dose (MRHD) of 400 mg. Oral administration of cenobamate (0, 4, 12, or 36 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality at the highest dose tested, which was associated with maternal toxicity. Maternal plasma exposure at the no-effect dose (12 mg/kg/day) for adverse effects on embryofetal development was less than that in humans at the MRHD. When cenobamate (0, 11, 22, or 44 mg/kg/day) was orally administered to female rats throughout pregnancy and lactation, neurobehavioral impairment (learning and memory deficit and increased auditory startle response) was observed in the offspring at all doses and decreased preweaning body weight gain and adverse effects on reproductive function (decreased numbers of corpora lutea, implantations, and live fetuses) were seen in the offspring at the high dose. Maternal plasma Reference ID: 4523384 exposure at the lowest effect dose (11 mg/kg/day) for adverse effects on pre- and postnatal development was less than that in humans at the MRHD. 8.2 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. 8.3 Females and Males of Reproductive Potential Contraception Women of reproductive potential concomitantly using oral contraceptives should use additional or alternative non-hormonal birth control [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Juvenile Animal Toxicity Data Cenobamate was administered orally to juvenile rats from postnatal day (PND) 7 to 70. To maintain consistent plasma drug exposures, doses were increased during the dosing period, up to 120 and 80 mg/kg/day in males and females, respectively. Adverse effects included mortality, delayed sexual maturation, neurological (decreased grip strength) and neurobehavioral (learning and memory deficits) impairment, decreased sperm count, decreased brain weight, and ocular histopathology. Recovery from these effects was observed following discontinuation of dosing. Overall, a no-effect dose for adverse effects on postnatal development was not identified. At the lowest doses tested, plasma cenobamate exposures (AUC) were less than that in humans at the maximum recommended human dose (MRHD) of 400 mg. 8.5 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)]. 8.6 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. Use in patients with end-stage renal disease undergoing dialysis is not recommended [see Clinical Pharmacology (12.3)]. 8.7 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. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance XCOPRI contains cenobamate. (Controlled substance schedule to be determined after review by the Drug Enforcement Administration). 9.2 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. In this study, euphoric mood occurred at greater extent with XCOPRI (400 mg) (8%) than with placebo (0%). Phase 1 multiple ascending dose studies in healthy subjects showed rates of euphoria and feeling drunk of about 3% and disturbance in attention of about 5% in subjects who received supratherapeutic doses of cenobamate, but these adverse events were absent in the placebo group. In Phase 2 and 3 studies in subjects with epilepsy, euphoric mood, confusional state, and sedation occurred at low rates in subjects who received XCOPRI (0.5-2.5%). 9.3 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 [see Warnings and Precautions (5.5)]. 10 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. 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. 11

DESCRIPTION The chemical name of XCOPRI (cenobamate) is [(1R)-1-(2-Chlorophenyl)-2-(tetrazol-2-yl) ethyl] carbamate. Its molecular formula is C10H10ClN5O2 and its molecular weight is 267.67 g/mol. The chemical structure is: N Cl O N N H