Xcopri

1 INDICATIONS AND USAGE XCOPRI is indicated for the treatment of partial-onset seizures in adult patients. XCOPRI is indicated for the treatment of partial-onset seizures in adult patients. ( 1 )

2 DOSAGE AND ADMINISTRATION Prior to initiating XCOPRI, obtain serum transaminases (ALT and AST) and total bilirubin, if not recently available (i.e., within 3 months), to establish baseline liver function. ( 2.1 , 5.4 ) 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. ( 2.2 ) Hepatic impairment: For patients with mild or moderate hepatic impairment, the maximum recommended dosage is 200 mg once daily. ( 2.3 , 8.7 , 12.3 ) XCOPRI can be taken whole or the tablets can be crushed. The crushed tablet can be mixed with water and either administered by mouth as an oral suspension or administered via a nasogastric tube. ( 2.4 ) 2.1 Assessments Prior to Initiating XCOPRI Liver Function Tests Prior to initiating XCOPRI, obtain serum transaminases (ALT and AST) and total bilirubin, if not recently available (i.e., within 3 months), to establish baseline liver function [see Warnings and Precautions ( 5.4 )] . For patients with baseline hepatic impairment, dosage modifications are recommended [see Dosage and Administration ( 2.3 )] . 2.2 Recommended Dosage Monotherapy and Adjunctive Therapy XCOPRI is administered orally once daily with or without food. The recommended dosage and titration, which should not be exceeded because of the potential for serious adverse reactions [see Warnings and Precautions ( 5.2 )] , is included in Table 1 . Table 1: Recommended Dosage for Partial-Onset Seizures in Adults Initial Dosage Week 1 and 2 12.5 mg once daily Titration Regimen Week 3 and 4 25 mg once daily Week 5 and 6 50 mg once daily Week 7 and 8 100 mg once daily Week 9 and 10 150 mg once daily Maintenance Dosage Week 11 and thereafter 200 mg once daily Maximum Dosage If needed based on clinical response and tolerability, dose may be increased above 200 mg by increments of 50 mg once daily every two weeks to 400 mg. 400 mg once daily 2.3 Recommended Dosage in Patients with Hepatic Impairment For patients with mild to moderate (Child-Pugh Class A to B) hepatic impairment, the maximum recommended dosage is 200 mg once daily [see Use in Specific Populations ( 8.7 )] . XCOPRI is not recommended for use in patients with severe (Child-Pugh Class C) hepatic impairment [see Dosage and Administration ( 2.1 ) and see Clinical Pharmacology ( 12.3 )] . 2.4 Administration Instructions XCOPRI can be taken whole or the tablets can be crushed. The crushed tablet can be mixed with water and either administered by mouth as an oral suspension or administered via a nasogastric tube, as described below [see Clinical Pharmacology ( 12.3 )]. Administration of Crushed Tablets by Mouth as Oral Suspension Crush the appropriate number of tablet(s) for the prescribed dose. In a cup, combine the crushed tablet(s) and 25 mL of water. Swirl to suspend the crushed tablet(s). Drink the suspension immediately. Do not store the tablet-water mixture for later use. To ensure no tablet residue is left in the container, rinse the container with 25 mL of water and drink. Visually confirm that no particles are left in the container. If particles remain, repeat step 5. Administration of Crushed Tablets via Nasogastric (NG) Tube Crush the appropriate number of tablet(s) for the prescribed dose. In an appropriate container, combine the crushed tablet(s) and 25 mL of water. Swirl to suspend the crushed tablet(s). Ensuring no particles are left in the container, instill the suspension with a syringe into the NG tube. Refill the catheter-tip syringe again with 10 mL of water, swirl gently, and administer. Visually confirm that no particles are left in the syringe. If particles remain, repeat step 5. 2.5 Discontinuation of XCOPRI If XCOPRI is discontinued, the dosage should be gradually reduced over a period of at least 2 weeks, unless safety concerns require abrupt withdrawal [see Warnings and Precautions ( 5.1 ,…

5 WARNINGS AND PRECAUTIONS Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity: Discontinue if no alternate etiology. ( 5.1 ) QT Shortening: Use caution when administering XCOPRI with other drugs that shorten the QT interval ( 5.2 ) Suicidal Behavior and Ideation: Monitor patients for suicidal behavior and ideation. ( 5.3 ) Liver Injury: Clinically significant liver injury has occurred. Obtain serum transaminases (ALT and AST) and total bilirubin before initiating XCOPRI, and during treatment if clinically indicated. Discontinue XCOPRI in patients with evidence of liver injury in the absence of an alternative etiology. ( 5.4 ) 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. ( 5.5 ) Withdrawal of Antiepileptic Drugs: XCOPRI should be gradually withdrawn to minimize the potential of increased seizure frequency. ( 5.6 ) 5.1 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking XCOPRI. DRESS has occurred, including one fatality, when XCOPRI was titrated rapidly (weekly or faster titration). No cases of DRESS were reported in an open-label safety study of 1339 partial-onset seizure patients when XCOPRI was initiated at 12.5 mg once daily and titrated every two weeks. This finding does not establish that the risk of DRESS is prevented by a slower titration; however, XCOPRI should be initiated at 12.5 mg once daily and titrated every two weeks [see Dosage and Administration ( 2.2 )] . DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. XCOPRI should be discontinued immediately and not restarted if an alternative etiology for the signs or symptoms cannot be established [see Contraindications ( 4 )] . 5.2 QT Shortening In a placebo-controlled study of the QT interval, a higher percentage of subjects who took XCOPRI (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 [see Clinical Pharmacology ( 12.2 )] . Familial Short QT syndrome is associated with an increased risk of sudden death and ventricular arrhythmias, particularly ventricular fibrillation. Such events in this syndrome are believed to occur primarily when the corrected QT interval falls below 300 msec. Nonclinical data also indicate that QT shortening is associated with ventricular fibrillation. Patients with Familial Short QT syndrome should not be treated with XCOPRI [see Contraindications ( 4 )] . Caution should be used when administering XCOPRI and other drugs that shorten the QT interval as there may be a synergistic effect on the QT interval that would increase the QT shortening risk. 5.3 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including XCOPRI, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes i…

4 CONTRAINDICATIONS XCOPRI is contraindicated in patients with: Hypersensitivity to cenobamate or any of the inactive ingredients in XCOPRI [see Warnings and Precautions ( 5.1 ) and Description ( 11 )] Familial Short QT syndrome [see Warnings and Precautions ( 5.2 )] Hypersensitivity to cenobamate or any of the inactive ingredients in XCOPRI. ( 4 ) Familial Short QT syndrome. ( 4 )

7 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 ) 7.1 Effect of XCOPRI on Other Drugs Table 5 summarizes the effect of XCOPRI on other drugs [see Clinical Pharmacology ( 12.3 )] . Table 5: Pharmacokinetic Drug Interactions Drug or Substrate Type Effect of XCOPRI on Drug or Substrate Clinical Recommendation Antiepileptic Drugs lamotrigine ↓ plasma concentrations Because of 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, consider a reduction in dosage of phenobarbital or clobazam, as clinically appropriate, when used concomitantly with XCOPRI. desmethylclobazam, the active metabolite of clobazam ↑ plasma concentrations 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 ↓ plasma concentrations 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 ↑ plasma 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. 7.2 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 [see Warnings and Precautions ( 5.2 ) and Clinical Pharmacology ( 12.2 )]. 7.3 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 [see Warnings and Precautions ( 5.5 )] .

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 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.

6 ADVERSE REACTIONS The following serious adverse reactions are described in more detail in the Warnings and Precautions section of the labeling: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions ( 5.1 )] QT Shortening [see Warnings and Precautions ( 5.2 )] Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.3 )] Liver Injury [see Warnings and Precautions ( 5.4 )] Neurological Adverse Reactions [see Warnings and Precautions ( 5.5 )] Withdrawal of Antiepileptic Drugs [see Warnings and Precautions ( 5.6 )] 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 . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions and for varying durations, adverse reaction frequencies observed in the clinical trials of a drug cannot be directly compared with frequencies in the clinical trials of another drug and may not reflect the frequencies observed in practice. In all controlled and uncontrolled trials performed in adult partial-onset seizure patients, XCOPRI was administered as adjunctive therapy to 1944 patients. Of these patients, 1575 were treated for at least 6 months, 710 for at least 12 months, 349 for at least 24 months, and 320 for at least 36 months. A total of 658 patients (442 patients treated with XCOPRI and 216 patients treated with placebo) constituted the safety population in the pooled analysis of placebo-controlled studies in patients with partial-onset seizures (Studies 1 and 2) [see Clinical Studies ( 14 )] . The adverse reactions presented in Table 4 are based on this safety population; the median length of treatment in these studies was 18 weeks. Of the patients in those studies, approximately 49% were male, 76% were Caucasian, and the mean age was 39 years. In Study 1 and Study 2, adverse events occurred in 77% of patients treated with XCOPRI and 68% treated with placebo. Table 4 gives the incidence of adverse reactions that occurred in subjects with partial-onset seizures in any XCOPRI treatment group and for which the incidence was greater than placebo during the controlled clinical trials. The most common adverse reactions that occurred in XCOPRI-treated patients (incidence at least 10% and greater than placebo) were somnolence, dizziness, fatigue, diplopia, and headache. The discontinuation rates because of adverse events were 11%, 9%, and 21% for patients randomized to receive XCOPRI at doses of 100 mg/day, 200 mg/day, and 400 mg/day, respectively, compared to 4% in patients randomized to receive placebo. The adverse reactions most commonly (1% or greater in any XCOPRI treatment group, and greater than placebo) leading to discontinuation, in descending order of frequency, were ataxia, dizziness, somnolence, diplopia, nystagmus, and vertigo. Table 4: Adverse Reactions in Pooled Placebo-Controlled Adjunctive Therapy Studies in Patients with Partial-Onset Seizures with XCOPRI Frequency in Any Treatment Arm Greater Than 1% Over Placebo * Reported as an adverse reaction; see Laboratory Abnormalities for ALT changes from collected laboratory values Adverse Reaction XCOPRI Placebo 100mg 200mg 400mg n = 108 % n= 223 % n=111 % n=216 % Cardiac Disorders Palpitations 0 0 2 0 Ear and Labyrinth Disorders Vertigo 1 1 6 1 Eye Disorders Diplopia 6 7 15 2 Vision Blurred 2 2 4 0 Gastrointestinal Disorders Nausea 6 6 9 3 Constipation 2 4 8 0 Diarrhea 1 3 5 0 Vomiting 2 4 5 0 Dry Mouth 1 1 3 0 Abdominal Pain 2 2 1 0 Dyspepsia 2 2 0 0 Infections and Infestations Nasopharyngitis 2 4 5 3 Pharyngitis 1 2 0 0 Urinary Tract Infection 2 5 0 2 Injury, Poisoning and Procedural Complications Head Injury 1 0 2 0 Investigations Alanine Aminotrans…