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.

2 DOSAGE AND ADMINISTRATION Adult Patients: The recommended initial dosage of eslicarbazepine acetate tablets 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 tablets 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 image description 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), the initial, titration, and maintenance dosages should generally be reduced by 50%. Titration and maintenance dosages may be adjusted according to clinical response [see Use in Specific Populations (8.6)…

5 WARNINGS AND PRECAUTIONS Suicidal Behavior and Ideation: Monitor for suicidal thoughts or behavior. ( 5.1 ) Serious Dermatologic Reactions, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Anaphylactic Reactions and Angioedema: Monitor and discontinue if another cause cannot be established. ( 5.2 , 5.3 , 5.4 ) Hyponatremia: Monitor sodium levels in patients at risk or patients experiencing hyponatremia symptoms. ( 5.5 ) Neurological Adverse Reactions: Monitor for dizziness, disturbance in gait and coordination, somnolence, fatigue, cognitive dysfunction, and visual changes. Use caution when driving or operating machinery. ( 5.6 ) Withdrawal of eslicarbazepine acetate tablets: Withdraw eslicarbazepine acetate tablets gradually to minimize the risk of increased seizure frequency and status epilepticus. ( 2.6 , 5.7 , 8.1 ) Drug Induced Liver Injury: Discontinue eslicarbazepine acetate tablets in patients with jaundice or evidence of significant liver injury. ( 5.8 ) Hematologic Adverse Reactions: Consider discontinuing. ( 5.10 ) 5.1 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including eslicarbazepine acetate, 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 in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% confidence interval [CI]: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 3 shows absolute and relative risk by indication for all evaluated AEDs. Table 3: Risk of Suicidal Thoughts or Behaviors by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1,000 Patients Drug Patients with Events Per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Differences: Additional Drug Patients with Events Per 1,000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials in patients with epilepsy than in clinical trials in patients with psychiatric or other conditions, but the absolute risk differences were similar for epilepsy and psychiatric indications. Anyone considering prescribing eslicarbazepine acetate or any other AED must balance this risk with the risk of untreated illness. Epilepsy and …

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.

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 and can cause decreased plasma concentrations of eslicarbazepine [see Clinical Pharmacology (12.3)] . Higher doses of eslicarbazepine acetate may be needed [see Dosage and Administration (2.4)]. 7.2 CYP2C19 Substrates Eslicarbazepine acetate 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 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 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.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as eslicarbazepine acetate, during pregnancy. Encourage women who are taking eslicarbazepine acetate 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 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 (Cmax, 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.

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 Torrent Pharma Inc., at 1-800-912-9561 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, 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, 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. 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 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) 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 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, and tremor. The most frequently reported adverse r…