Eslicarbazepine Acetate

1 INDICATIONS AND USAGE Eslicarbazepine acetate tablets are indicated for the treatment of partial-onset seizures in patients 4 years of age and older. Eslicarbazepine acetate tablets are indicated for the treatment of partial-onset seizures in patients 4 years of age and older. ( 1 )

2 DOSAGE AND ADMINISTRATION · Adult Patients: The recommended initial dosage of eslicarbazepine acetate tablet is 400 mg once daily. For some patients, treatment may be initiated at 800 mg once daily if the need for seizure reduction outweighs an increased risk of adverse reactions. Increase the dose in weekly increments of 400 mg to 600 mg once daily, based on clinical response and tolerability, to a recommended maintenance dosage of 800 mg to 1,600 mg once daily. ( 2.2 ) · Pediatric Patients: The recommended dosage of eslicarbazepine acetate tablets is based on body weight and is administered orally once daily. Increase the dose in weekly intervals based on clinical response and tolerability, to the recommended maintenance dosage ( 2.2 ). · Patients with Moderate or Severe Renal Impairment: Reduce dosage by 50%. ( 2.4 ) 2.1 Important Administration Instructions Instruct patients to administer eslicarbazepine acetate tablets either as whole or as crushed tablets. Instruct patients to take eslicarbazepine acetate tablets either with or without food. The eslicarbazepine acetate tablets dosing regimen depends on age, weight, and renal function. 2.2 General Dosing Recommendations Monotherapy and Adjunctive Therapy Adult Patients The recommended initial dosage of eslicarbazepine acetate tablet is 400 mg administered orally once daily. For some patients, treatment may be initiated at 800 mg once daily if the need for seizure reduction outweighs an increased risk of adverse reactions during initiation [see Adverse Reactions (6.1)]. Dosage should be increased in weekly increments of 400 mg to 600 mg, based on clinical response and tolerability, to a recommended maintenance dosage of 800 mg to 1,600 mg once daily. For patients on eslicarbazepine acetate tablets monotherapy, the 800 mg once daily maintenance dose should generally be considered in patients who are unable to tolerate a 1,200 mg daily dose. For patients on eslicarbazepine acetate tablets adjunctive therapy, the 1,600 mg daily dose should generally be considered in patients who did not achieve a satisfactory response with a 1,200 mg daily dose. Pediatric Patients (4 to 17 Years of Age) In pediatric patients 4 to 17 years of age, the recommended dosing regimen is dependent upon body weight and is administered orally once daily. The recommended initial dosage of eslicarbazepine acetate tablets is shown in Table 1. Dosage should be increased based on clinical response and tolerability, no more frequently than once per week. Titration increments should not exceed those shown in Table 1. The daily maintenance dosage should not exceed the maintenance dosage for each body weight range shown in Table 1. Table 1: Eslicarbazepine Acetate Tablets Once Daily Dosage Schedule for Pediatric Patients 4 to 17 Years of Age Body Weight Range Initial and Maximum Titration Increment Dosage (mg/day) Maintenance Dosage (mg/day) 11 to 21 kg 200 400 to 600 22 to 31 kg 300 500 to 800 32 to 38 kg 300 600 to 900 more than 38 kg 400 800 to 1,200 2.3 Dosage Modifications with Other Antiepileptic Drugs Some adverse reactions occur more frequently when patients take eslicarbazepine acetate tablets adjunctively with carbamazepine [see Warnings and Precautions (5.6)]. However, carbamazepine reduces the plasma concentration of eslicarbazepine [see Drug Interactions (7.1)]. When eslicarbazepine acetate tablets and carbamazepine are taken concomitantly, the dose of eslicarbazepine acetate tablets or carbamazepine may need to be adjusted based on efficacy and tolerability. For patients taking other enzyme-inducing AEDs (i.e., phenobarbital, phenytoin, and primidone), higher doses of eslicarbazepine acetate tablets may be needed [see Drug Interactions ( 7.1 )]. Eslicarbazepine acetate tablets should not be taken as an adjunctive therapy with oxcarbazepine. 2.4 Dosage Modifications in Patients with Renal Impairment In patients with moderate and severe renal impairment (i.e., creatinine clearance < 50 mL/min), th …

3 DOSAGE FORMS AND STRENGTHS Eslicarbazepine acetate tablets are available in the following shapes and color (Table 2) with respective two-sided debossing: Table 2: Eslicarbazepine Acetate Tablet Presentations Tablet Strength Tablet Color/Shape Tablet Markings Functional Score 200 mg White to off-white oblong bi-convex ‘E’ on the left side and ‘T’ on the right side of score line on one side and ‘200’ on the other side Yes 400 mg White to off-white round bi-convex ‘ET’ on one side and ‘400’ on the other side No 600 mg White to off-white oblong bi-convex ‘E’ on the left side and ‘T’ on the right side of score line on one side and ‘600’ on the other side Yes 800 mg White to off-white oblong bi-convex ‘E’ on the left side and ‘T’ on the right side of score line on one side and ‘800’ on the other side Yes Tablets: 200 mg, 400 mg, 600 mg, 800 mg ( 3 )

4 CONTRAINDICATIONS Eslicarbazepine acetate tablets are contraindicated in patients with a hypersensitivity to eslicarbazepine acetate or oxcarbazepine [see Warnings and Precautions ( 5.2 , 5.3 , and 5.4 )] . Hypersensitivity to eslicarbazepine acetate or oxcarbazepine. ( 4 )

6 ADVERSE REACTIONS The following adverse reactions are described in more detail in the Warnings and Precautions section of the label: Suicidal Behavior and Ideation [see Warnings and Precautions (5.1) ] Serious Dermatologic Reactions [see Warnings and Precautions (5.2) ] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.3) ] Anaphylactic Reactions and Angioedema [see Warnings and Precautions (5.4) ] Hyponatremia [see Warnings and Precautions (5.5) ] Neurological Adverse Reactions [see Warnings and Precautions (5.6) ] Drug Induced Liver Injury [see Warnings and Precautions (5.8) ] Abnormal Thyroid Function Tests [see Warnings and Precautions (5.9) ] Pancytopenia, Agranulocytosis, and Leukopenia [see Warnings and Precautions (5.10) ] Most common adverse reactions in adult patients receiving eslicarbazepine acetate tablets (≥4% and ≥2% greater than placebo): dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor. ( 6.1 ) Adverse reactions in pediatric patients are similar to those seen in adult patients. To report SUSPECTED ADVERSE REACTIONS, contact Jubilant Cadista Pharmaceuticals Inc. at 1-800-313-4623 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, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Patients In monotherapy trials in patients with partial-onset seizures [Study 1 and Study 2, see Clinical Studies (14.1) ] , 365 patients received eslicarbazepine acetate tablets, of whom 225 were treated for longer than 12 months and 134 for longer than 24 months. Of the patients in those trials, 95% were between 18 and 65 years old; 48% were male, and 84% were Caucasian. Across controlled and uncontrolled trials in patients receiving adjunctive therapy for partial-onset seizures, 1,195 patients received eslicarbazepine acetate tablets, of whom 586 were treated for longer than 6 months and 462 for longer than 12 months. In the placebo controlled adjunctive therapy trials in patients with partial-onset seizures (Study 3, Study 4 and Study 5), 1,021 patients received eslicarbazepine acetate tablets. Of the patients in those trials, approximately 95% were between 18 and 60 years old, approximately 50% were male, and approximately 80% were Caucasian. Monotherapy Historical Control Trials In the monotherapy epilepsy trials (Study 1 and Study 2), 13% of patients randomized to receive eslicarbazepine acetate tablets at the recommended doses of 1,200 mg and 1,600 mg once daily discontinued from the trials as a result of an adverse event. The adverse reaction most commonly (≥1% on eslicarbazepine acetate tablets) leading to discontinuation was hyponatremia. Adverse reactions observed in these studies were generally similar to those observed and attributed to drug in adjunctive placebo-controlled studies. Because these studies did not include a placebo control group, causality could not be established. Dizziness, nausea, somnolence, and fatigue were all reported at lower incidences during the AED Withdrawal Phase and Monotherapy Phase compared with the Titration Phase. Adjunctive Therapy Controlled Trials In the controlled adjunctive therapy epilepsy trials (Study 3, Study 4, and Study 5) , the rate of discontinuation as a result of any adverse reaction was 14% for the 800 mg dose, 25% for the 1,200 mg dose, and 7% in subjects randomized to placebo. The adverse reactions most commonly (≥1% in any eslicarbazepine acetate tablets treatment group, and greater than placebo) leading to discontinuation, in descending order of frequency, were dizziness, nausea, vomiting, ataxia, diplopia, somnolence, headache, blurred vision, vertigo, asthenia, fatigue, rash, dysarthria …

7 DRUG INTERACTIONS · Carbamazepine: May need dose adjustment for eslicarbazepine acetate tablets or carbamazepine. ( 2.3 , 5.6 , 7 .1 ) · Phenytoin: Higher dosage of eslicarbazepine acetate tablets may be necessary and dose adjustment may be needed for phenytoin. ( 2.3 , 7.1 , 7.2 ) · Phenobarbital or Primidone: Higher dosage of eslicarbazepine acetate tablets may be necessary. ( 2.3 , 7. 1) · Hormonal Contraceptives: Eslicarbazepine acetate tablets may decrease the effectiveness of hormonal contraceptives. ( 7.4 , 8.3 ) 7.1 Other Antiepileptic Drugs Several AEDs (e.g., carbamazepine, phenobarbital, phenytoin, and primidone) can induce enzymes that metabolize eslicarbazepine acetate tablets and can cause decreased plasma concentrations of eslicarbazepine [see Clinical Pharmacology ( 12.3 )] . Higher doses of eslicarbazepine acetate tablets may be needed [see Dosage and Administration ( 2.4 )]. 7.2 CYP2C19 Substrates Eslicarbazepine acetate tablets can inhibit CYP2C19, which can cause increased plasma concentrations of drugs that are metabolized by this isoenzyme (e.g., phenytoin, clobazam, and omeprazole) [see Clinical Pharmacology ( 12.3 )]. Dose adjustment may be needed. 7.3 CYP3A4 Substrates In vivo studies suggest that eslicarbazepine acetate tablets can induce CYP3A4, decreasing plasma concentrations of drugs that are metabolized by this isoenzyme (e.g., simvastatin, lovastatin) [see Clinical Pharmacology ( 12.3 )] . Dose adjustment of simvastatin and lovastatin may be needed if a clinically significant change in lipids is noted. 7.4 Oral Contraceptives Because concomitant use of eslicarbazepine acetate tablets and ethinylestradiol and levonorgestrel is associated with lower plasma levels of these hormones, females of reproductive potential should use additional or alternative non-hormonal birth control.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as eslicarbazepine acetate tablets, during pregnancy. Encourage women who are taking eslicarbazepine acetate tablets during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org. Risk Summary Limited available data with eslicarbazepine acetate tablets use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. In oral studies conducted in pregnant mice, rats, and rabbits, eslicarbazepine acetate demonstrated developmental toxicity, including increased incidence of malformations (mice), embryolethality (rats), and fetal growth retardation (all species), at clinically relevant doses (see Data). Advise a pregnant woman of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data When eslicarbazepine acetate was orally administered (150, 350, 650 mg/kg/day) to pregnant mice throughout organogenesis, increased incidences of fetal malformations was observed at all doses and fetal growth retardation was observed at the mid and high doses. A no-effect dose for adverse developmental effects was not identified. At the lowest dose tested, plasma eslicarbazepine exposure (C max , AUC) is less than that in humans at the maximum recommended human dose (MRHD, 1,600 mg/day). Oral administration of eslicarbazepine acetate (40, 160, 320 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in fetal growth retardation and increased incidences of skeletal variations at the mid and high doses. The no-effect dose (40 mg/kg/day) is less than the MRHD on a mg/m 2 basis. Oral administration to pregnant rats (65, 125, 250 mg/kg/day) throughout organogenesis resulted in embryolethality at all doses, increased incidences of skeletal variations at the mid and high doses, and fetal growth retardation at the high dose. The lowest dose tested (65 mg/kg/day) is less than the MRHD on a mg/m 2 basis. When eslicarbazepine acetate was orally administered to female mice during pregnancy and lactation (150, 350, 650 mg/kg/day), the gestation period was prolonged at the highest dose tested. In offspring, a persistent reduction in offspring body weight and delayed physical development and sexual maturation were observed at the mid and high doses. The lowest dose tested (150 mg/kg/day) is less than the MRHD on a mg/m 2 basis. When eslicarbazepine acetate was orally administered (65, 125, 250 mg/kg/day) to rats during pregnancy and lactation, reduced offspring body weight was seen at the mid and high doses. Delayed sexual maturation and a neurological deficit (decreased motor coordination) were observed at the highest dose tested. The no-effect dose for adverse developmental effects (65 mg/kg/day) is less than the MRHD on a mg/m 2 basis. The rat data are of uncertain relevance to humans because of differences in metabolic profile between species. 8.2 Lactation Eslicarbazepine is present in human milk. The effects of eslicarbazepine acetate tablets on the breastfed infant or on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for eslicarbazepine acetate tablets and any potential adverse effects on the breastfed infant from eslicarbazepine acetate tablets or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Contraception Use of eslicarbazepine acetate tablets with hormonal contracep …

12.1 Mechanism of Action Eslicarbazepine acetate tablets is extensively converted to eslicarbazepine, which is considered to be responsible for therapeutic effects in humans. The precise mechanism(s) by which eslicarbazepine exerts anticonvulsant activity is unknown but is thought to involve inhibition of voltage-gated sodium channels.

11 DESCRIPTION The chemical name of eslicarbazepine acetate is (S)-10-Acetoxy-10,11-dihydro-5H-dibenz[b,f]-azepine-5-carboxamide. Eslicarbazepine acetate is a dibenz[b,f]azepine-5-carboxamide derivative. Its molecular formula is C 17 H 16 N 2 O 3 and its molecular weight is 296.32. The chemical structure is: Eslicarbazepine acetate is a white to off-white powder. It is insoluble in hexane, very slightly soluble in aqueous solvents and soluble in organic solvents such as acetone, acetonitrile, and methanol. Each eslicarbazepine acetate tablet contains 200 mg, 400 mg, 600 mg or 800 mg of eslicarbazepine acetate and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, low substituted hydroxypropyl cellulose and magnesium stearate Figure 1

10 OVERDOSAGE 10.1 Signs, Symptoms, and Laboratory Findings of Acute Overdose in Humans Symptoms of overdose are consistent with the known adverse reactions of eslicarbazepine acetate tablets and include hyponatremia (sometimes severe), dizziness, nausea, vomiting, somnolence, euphoria, oral paraesthesia, ataxia, walking difficulties, and diplopia. The maximum dosage studied in open-label adult monotherapy treatment following withdrawal of concomitant AEDs was 2,400 mg once daily. 10.2 Treatment or Management of Overdose There is no specific antidote for overdose with eslicarbazepine acetate tablets. Symptomatic and supportive treatment should be administered as appropriate. Removal of the drug by gastric lavage and/or inactivation by administering activated charcoal should be considered. Standard hemodialysis procedures result in partial clearance of eslicarbazepine acetate tablets. Hemodialysis may be considered based on the patient's clinical state or in patients with significant renal impairment.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Eslicarbazepine acetate tablets are white to off-white, oblong and with functional scoring on one side (200 mg, 600 mg, and 800 mg) or white to off-white, circular bi-convex and plain on one side (400 mg) and identified with strength-specific one-sided engraving on the other side, "V1" (200 mg), "V2" (400 mg), "V3" (600 mg), or "V7" (800 mg). Tablets are supplied in the following strengths and package configurations (Table 6): Table 6: Package Configuration for Eslicarbazepine Acetate Tablets Tablet Strength Package Configuration NDC Code 200 mg Bottles of 30 13668-538-30 Bottles of 60 13668-538-60 Bottles of 500 13668-538-05 400 mg Bottles of 30 13668-539-30 Bottles of 60 13668-539-60 Bottles of 500 13668-539-05 600 mg Bottles of 30 13668-540-30 Bottles of 60 13668-540-60 Bottles of 500 13668-540-05 800 mg Bottles of 30 13668-541-30 Bottles of 60 13668-541-60 Bottles of 500 13668-541-05 16.2 Storage and Handling Store eslicarbazepine acetate tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

16.1 How Supplied Eslicarbazepine acetate tablets are white to off-white, oblong and with functional scoring on one side (200 mg, 600 mg, and 800 mg) or white to off-white, circular bi-convex and plain on one side (400 mg) and identified with strength-specific one-sided engraving on the other side, "V1" (200 mg), "V2" (400 mg), "V3" (600 mg), or "V7" (800 mg). Tablets are supplied in the following strengths and package configurations (Table 6): Table 6: Package Configuration for Eslicarbazepine Acetate Tablets Tablet Strength Package Configuration NDC Code 200 mg Bottles of 30 13668-538-30 Bottles of 60 13668-538-60 Bottles of 500 13668-538-05 400 mg Bottles of 30 13668-539-30 Bottles of 60 13668-539-60 Bottles of 500 13668-539-05 600 mg Bottles of 30 13668-540-30 Bottles of 60 13668-540-60 Bottles of 500 13668-540-05 800 mg Bottles of 30 13668-541-30 Bottles of 60 13668-541-60 Bottles of 500 13668-541-05