Eslicarbazepine Acetate Drug Information

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.

• 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 (≥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 Dr. Reddy’s Laboratories, Inc., at 1-888-375-3784 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 reactions in patients receiving eslicarbazepine acetate at doses of 800 mg or 1,200 mg (≥4% and ≥2% greater than placebo) were dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor. Table 4 gives the incidence of adverse reactions that occurred in ≥2% of subjects with partial-onset seizures in any eslicarbazepine acetate treatment group and for which the incidence was greater than placebo during the controlled clinical trials. Adverse reactions during titration were less frequent for patients who began therapy at an initial dose of 400 mg for 1 week and then increased to 800 mg compared to patients who initiated therapy at 800 mg. Table 4: Adverse Reactions Incidence in Pooled Controlled Clinical Trials of Adjunctive Therapy in Adults (Events ≥2% of Patients in the Eslicarbazepine Acetate Tablets 800 mg or 1,200 mg Dose Group and More Frequent Than in the Placebo Group) Placebo Eslicarbazepine Acetate Tablets 800 mg 1,200 mg (N=426) % (N=415) % (N=410) % Ear and labyrinth disorders Vertigo <1 2 6 Eye disorders Diplopia Blurred vision Visual impairment 2 1 1 9 6 2 11 5 1 Gastrointestinal disorders Nausea Vomiting Diarrhea Constipation Abdominal pain Gastritis 5 3 3 1 1 <1 10 6 4 2 2 2 16 10 2 2 2 <1 General disorders and administration site conditions Fatigue Asthenia Gait disturbance Peripheral edema 4 2 <1 1 4 2 2 2 7 3 2 1 Infections and Infestations Urinary tract infections 1 2 2 Injury, poisoning and procedural complications Fall 1 3 1 Metabolism and nutrition disorders Hyponatremia <1 2 2 Nervous system disorders Dizziness Somnolence Headache Ataxia Balance disorder Tremor Dysarthria Memory impairment Nystagmus 9 8 9 2 <1 1 0 <1 <1 20 11 13 4 3 2 1 1 1 28 18 15 6 3 4 2 2 2 Psychiatric disorders Depression Insomnia 2 1 1 2 3 2 Respiratory, thoracic and mediastinal disorders Cough 1 2 1 Skin and subcutaneous tissue disorders Rash 1 1 3 Vascular disorders Hypertension 1 1 2 Pediatric Patients (4 to 17 Years of Age) Clinical studies of pediatric patients 4 to 17 years of age were conducted which support the safety and tolerability of eslicarbazepine acetate for the treatment of partial-onset seizures. Across studies in pediatric patients with partial-onset seizures, 393 patients ages 4 to 17 years received eslicarbazepine acetate, of whom 265 received eslicarbazepine acetate for at least 1 year. Adverse reactions reported in clinical studies of pediatric patients 4 to 17 years of age were similar to those seen in adult patients. Other Adverse Reactions with Eslicarbazepine Acetate Use Compared to placebo, eslicarbazepine acetate use was associated with slightly higher frequencies of decreases in hemoglobin and hematocrit, increases in total cholesterol, triglycerides, and LDL, and increases in creatine phosphokinase. Adverse Reactions Based on Gender and Race No significant gender differences were noted in the incidence of adverse reactions. Although there were few non-Caucasian patients, no differences in the incidences of adverse reactions compared to Caucasian patients were observed. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of eslicarbazepine acetate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Hematologic and Lymphatic Systems: leukopenia, agranulocytosis, thrombocytopenia, megaloblastic anemia, and pancytopenia [see Warnings and Precautions ( 5.10 )] Metabolism and Nutrition Disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH) [see Warnings and Precautions ( 5.5 )]

• Carbamazepine: May need dose adjustment for eslicarbazepine acetate or carbamazepine. ( 2.3 , 5.6 , 7.1 )
• Phenytoin: Higher dosage of eslicarbazepine acetate 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 may be necessary. ( 2.3 , 7.1 )
• Hormonal Contraceptives: Eslicarbazepine acetate 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.

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 (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.

Pediatric Use Safety and effectiveness of eslicarbazepine acetate have been established in the age groups 4 to 17 years. Use of eslicarbazepine acetate in these age groups is supported by evidence from adequate and well-controlled studies of eslicarbazepine acetate in adults with partial-onset seizures, pharmacokinetic data from adult and pediatric patients, and safety data from clinical studies in 393 pediatric patients 4 to 17 years of age. Safety and effectiveness in pediatric patients below the age of 4 years have not been established.

Animal Data In a juvenile animal study in which eslicarbazepine acetate (40, 80, 160 mg/kg/day) was orally administered to young dogs for 10 months starting on postnatal day 21, adverse effects on bone growth (decreased bone mineral content and density) were seen in females at all doses at the end of the dosing period, but not at the end of a 2 month recovery period. Convulsions were seen at the highest dose tested. A no-effect dose for adverse effects in juvenile dogs was not identified.

The lowest dose tested is less than the maximum recommended pediatric dose (1,200 mg/day) on a body surface area (mg/m 2 ) basis. A separate juvenile animal study was conducted to assess possible adverse effects on the immune system. Eslicarbazepine acetate (10, 40, 80 mg/kg/day) was orally administered to young dogs for 17 weeks starting on postnatal day 21. No effects on the immune system were observed.

Eslicarbazepine acetate tablets are contraindicated in patients with a hypersensitivity to eslicarbazepine acetate or oxcarbazepine. Hypersensitivity to eslicarbazepine acetate or oxcarbazepine.

Signs, Symptoms, and Laboratory Findings of Acute Overdose in Humans Symptoms of

overdose are consistent with the known adverse reactions of eslicarbazepine acetate 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.

Treatment or Management of Overdose

There is no specific antidote for overdose with eslicarbazepine acetate. 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. Hemodialysis may be considered based on the patient’s clinical state or in patients with significant renal impairment.