Xcopri

Dosage and Administration ( 2.1 ) 8/2025 Dosage and Administration ( 5.4 ) 8/2025

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 , …

3 DOSAGE FORMS AND STRENGTHS XCOPRI tablets are available in the following strengths, shapes, colors, and tablet markings (Table 2). Table 2: XCOPRI Tablet Presentations Tablet Strength Tablet Color/Shape Tablet Markings 12.5 mg Uncoated round white to off-white tablets SK on one side and 12 on the other side 25 mg Film coated round brown tablets SK on one side and 25 on the other side 50 mg Film coated round yellow tablets SK on one side and 50 on the other side 100 mg Film coated round brown tablets SK on one side and 100 on the other side 150 mg Film coated round light orange tablets SK on one side and 150 on the other side 200 mg Film coated modified oval light orange tablets SK on one side and 200 on the other side Tablets: 12.5 mg, 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg. ( 3 )

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 )

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 …

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 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. ( 2.2 , 8.7 , 12.3 ) 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. 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. Cenobamate was present in rat milk at concentrations similar to those in maternal plasma. 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 …

12.1 Mechanism of Action The precise mechanism by which cenobamate exerts its therapeutic effects in patients with partial-onset 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 γ-aminobutyric acid (GABA A ) ion channel.

11 DESCRIPTION The chemical name of XCOPRI (cenobamate) is [(1 R )-1-(2-Chlorophenyl)-2-(tetrazol-2-yl) ethyl] carbamate. Its molecular formula is C 10 H 10 ClN 5 O 2 and its molecular weight is 267.67 g/mol. The chemical structure is: Cenobamate is a white to off-white crystalline powder. It is slightly soluble in aqueous solutions (water 1.7 mg/mL) and has higher solubility in organic solvents like ethanol (209.4 mg/mL). XCOPRI tablets are for oral administration and contain the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate and film coating agents specified below: 12.5 mg tablets: Not applicable, since 12.5 mg tablets are uncoated. 25 mg and 100 mg tablets: FD&C Blue# 2/indigo carmine aluminum lake, iron oxide red, iron oxide yellow, polyethylene glycol 3350, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide. 50 mg tablets: iron oxide yellow, polyethylene glycol 3350, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide. 150 mg and 200 mg tablets: iron oxide red, iron oxide yellow, polyethylene glycol 3350, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide. Chemical Structure

10 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied XCOPRI tablets are supplied in the following configurations: Bottles; 30 count Strength NDC Number Tablet Description (Color, Shape, Markings) 25 mg 71699-025-30 Film coated round brown tablets with SK on one side and 25 on the other side 50 mg 71699-050-30 Film coated round yellow tablets with SK on one side and 50 on the other side 100 mg 71699-100-30 Film coated round brown tablets with SK on one side and 100 on the other side 150 mg 71699-150-30 Film coated round light orange tablets with SK on one side and 150 on the other side 200 mg 71699-200-30 Film coated modified oval light orange tablets with SK on one side and 200 on the other side Titration Blister Packs; 14-Day Daily Dose NDC Number Supplied As [strength(quantity)] Tablet Description (Color, Shape, Markings) 12.5 mg per day for 14 days 71699-204-14 12.5 mg (14-count) Uncoated round white to off-white tablets with SK on one side and 12 on the other side Titration Blister Packs; 28-Day Daily Dose NDC Number Supplied As [strength(quantity)] Tablet Description (Color, Shape, Markings) 12.5 mg per day for 14 days, then 25 mg per day for 14 days 71699-201-28 12.5 mg (14-count) Uncoated round white to off-white tablets with SK on one side and 12 on the other side 25 mg (14-count) Film coated round brown tablets with SK on one side and 25 on the other side 50 mg per day for 14 days, then 100 mg per day for 14 days 71699-202-28 50 mg (14-count) Film coated round yellow tablets with SK on one side and 50 on the other side 100 mg (14-count) Film coated round brown tablets with SK on one side and 100 on the other side 150 mg per day for 14 days, then 200 mg per day for 14 days 71699-203-28 150 mg (14-count) Film coated round light orange tablets with SK on one side and 150 on the other side 200 mg (14-count) Film coated modified oval light orange tablets with SK on one side and 200 on the other side Maintenance Blister Packs; 28-Day Daily Dose NDC Number Supplied As [strength(quantity)] Tablet Description (Color, Shape, Markings) 250 mg per day 71699-104-56 100 mg (28-count) Film coated round brown tablets with SK on one side and 100 on the other side 150 mg (28-count) Film coated round light orange tablets with SK on one side and 150 on the other side 350 mg per day 71699-103-56 150 mg (28-count) Film coated round light orange tablets with SK on one side and 150 on the other side 200 mg (28-count) Film coated modified oval light orange tablets with SK on one side and 200 on the other side 16.2 Storage and Handling Store XCOPRI tablets at 20°C to 25°C (68°F to 77°F) with excursions permitted to 15°C to 30°C (59°F to 86°F) (See USP Controlled Room Temperature) .