Oxcarbazepine

1 INDICATIONS AND USAGE Oxcarbazepine extended-release tablets are indicated for the treatment of partial-onset seizures in patients 6 years of age and older. Oxcarbazepine extended-release tablets are indicated for the treatment of partial-onset seizures in patients 6 years of age and older. ( 1 )

2 DOSAGE AND ADMINISTRATION Adult Patients: The recommended initial dosage is 600 mg once per day. Increase the dosage in weekly increments of 600 mg once per day, based on clinical response and tolerability, to a recommended maintenance dosage of 1,200 mg to 2,400 mg once per day. ( 2.2 ) In adult patients with a creatinine clearance < 30 mL/min, initiate at one-half the usual starting dosage and increase slowly. ( 2.3 ) Pediatric Patients: The recommended dosage is based on body weight and is administered orally once per day. Increase the dosage in weekly intervals based on clinical response and tolerability, to the recommended dosage. ( 2.2 ) Geriatric Patients: Start at lower dosage (300 mg or 450 mg/day) and increase slowly. ( 2.4 ) In conversion of oxcarbazepine immediate-release to oxcarbazepine extended-release tablets, higher dosages of oxcarbazepine extended-release tablets may be necessary. ( 2.7 , 12.3 ) 2.1 Important Administration Instructions Administer oxcarbazepine extended-release tablets as a single daily dose taken on an empty stomach (at least 1 hour before or at least 2 hours after meals) [see Clinical Pharmacology ( 12.3 )]. If oxcarbazepine extended-release tablets are taken with food, adverse reactions are more likely to occur because of increased peak levels [see Clinical Pharmacology ( 12.3 )]. Swallow oxcarbazepine extended-release tablets whole. Do not cut, crush, or chew the tablets. For ease of swallowing in pediatric patients or patients with difficulty swallowing, achieve daily dosages with multiples of appropriate lower strength tablets (e.g., 150 mg tablets). 2.2 General Dosing Recommendations Monotherapy or Adjunctive Therapy Adult Patients Initiate treatment at a dosage of 600 mg/day given orally once daily for one week. Subsequent dosage increases can be made at weekly intervals in 600 mg/day increments to achieve the recommended daily dosage. The recommended daily dosage of oxcarbazepine extended-release tablets are 1,200 mg to 2,400 mg/day, given once daily. The dosage of 2,400 mg/day showed slightly greater efficacy than 1,200 mg/day, but was associated with an increase in adverse reactions [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14.1 )]. Dosage adjustment is recommended with concomitant use of strong CYP3A4 enzyme inducers or UGT inducers, which include certain antiepileptic drugs (AEDs) [see Drug Interactions ( 7.1 , 7.2 )]. Pediatric Patients (6 to Less than 17 Years of Age) In pediatric patients 6 to less than 17 years of age, initiate treatment at a daily dosage of 8 mg/kg to 10 mg/kg orally once daily, not to exceed 600 mg per day in the first week. Subsequent dosage increases can be made at weekly intervals in 8 mg/kg to 10 mg/kg increments once daily, not to exceed 600 mg, to achieve the target daily dosage. The target maintenance dosage, achieved over two to three weeks, is displayed in Table 1. Table 1: Target Daily Dosage in Pediatric Patients (6 to Less Than 17 Years of Age) Weight Target Daily Dosage 20 kg to 29 kg 900 mg/day 29.1 kg to 39 kg 1,200 mg/day Greater than 39 kg 1,800 mg/day Dosage adjustment is recommended with concomitant use of strong CYP3A4 enzyme inducers or UGT inducers, which include certain antiepileptic drugs (AEDs) [see Drug Interactions ( 7.1 , 7.2 )]. 2.3 Dosage Modifications in Adult Patients with Renal Impairment In adult patients with severe renal impairment (creatinine clearance less than 30 mL/minute), initiate oxcarbazepine extended-release tablets at one-half the usual starting dosage (300 mg/day). Subsequent dosage increases can be made at weekly intervals in increments of 300 mg to 450 mg/day to achieve the desired clinical response [see Use in Specific Populations ( 8.6 )]. 2.4 Dosage Modifications in Geriatric Patients In geriatric patients, consider starting at a lower dosage (300 mg or 450 mg/day). Subsequent dosage increases can be made at weekly intervals in increments of 300 mg to 450 mg/day to achieve the desired clinic …

3 DOSAGE FORMS AND STRENGTHS Extended-release tablets : 150 mg: pink colored, modified-oval shaped, film coated tablet debossed with "ING" on one side and "203" on another side 300 mg: pink colored, modified-oval shaped, film coated tablet debossed with "ING" on one side and "204" on another side 600 mg: pink colored, modified-oval shaped, film coated tablet debossed with "ING" on one side and "205" on another side Extended-release tablets : 150 mg, 300 mg and 600 mg ( 3 )

4 CONTRAINDICATIONS Oxcarbazepine extended-release tablets are contraindicated in patients with a known hypersensitivity to oxcarbazepine, to any of the components of oxcarbazepine extended-release tablets, or to eslicarbazepine acetate. Reactions have included anaphylaxis and angioedema [see Warnings and Precautions ( 5.2 , 5.3 )]. Known hypersensitivity to oxcarbazepine, any of the components of oxcarbazepine extended-release tablets, or to eslicarbazepine acetate. ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are described in other sections of the labeling: Hyponatremia [see Warnings and Precautions ( 5.1 )] Anaphylactic Reactions and Angioedema [see Warnings and Precautions ( 5.2 )] Cross Hypersensitivity Reaction to Carbamazepine [see Warnings and Precautions ( 5.3 )] Serious Dermatological Reactions [see Warnings and Precautions ( 5.4 )] Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.5 )] Withdrawal of AEDs [see Warnings and Precautions ( 5.6 )] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity [see Warnings and Precautions ( 5.7 )] Hematologic Reactions [see Warnings and Precautions ( 5.8 )] Risk of Seizures in the Pregnant Patient [see Warnings and Precautions ( 5.9 )] Most commonly observed (≥ 5% and more frequent than placebo) adverse reactions in adults were dizziness, somnolence, headache, balance disorder, tremor, vomiting, diplopia, asthenia, and fatigue. ( 6.1 ) Adverse reactions in pediatric patients are similar to those seen in adult patients. To report SUSPECTED ADVERSE REACTIONS, contact Ajanta Pharma USA Inc. at 855-664-7744 or contact 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 clinical practice. The safety data presented below are from 384 patients with partial-onset seizures who received oxcarbazepine extended-release tablets (366 adults and 18 pediatric patients) with concomitant AEDs. In addition, safety data presented below are from a total of 2,288 patients with seizure disorders treated with immediate-release oxcarbazepine; 1,832 were adults and 456 were pediatric patients. Most Common Adverse Reactions Reported by Adult Patients Receiving Concomitant AEDs in Oxcarbazepine Extended-Release Tablets Clinical Studies Table 3 lists adverse reactions that occurred in at least 2% of adult patients with epilepsy treated with oxcarbazepine extended-release tablets or placebo and concomitant AEDs and that were numerically more common in the patients treated with any dosage of oxcarbazepine extended release tablets than in patients receiving placebo. Table 3: Adverse Reaction Incidence in a Controlled Clinical Study of Oxcarbazepine Extended-Release Tablets with Concomitant AEDs in Adults* Oxcarbazepine Extended-Release Tablets 2,400 mg/day N=123 % Oxcarbazepine Extended-Release Tablets 1,200 mg/day N=122 % Placebo N=121 % Any System / Any Term 69 57 55 Nervous System Disorders Dizziness 41 20 15 Somnolence 14 12 9 Headache 15 8 7 Balance Disorder 7 5 5 Tremor 1 5 2 Nystagmus 3 3 1 Ataxia 1 3 1 Gastrointestinal Disorders Vomiting 15 6 9 Abdominal Pain Upper 0 3 1 Dyspepsia 0 3 1 Gastritis 0 3 2 Eye Disorders Diplopia 13 10 4 Vision Blurred 1 4 3 Visual Impairment 1 3 0 General Disorders and Administration Site Conditions Asthenia 7 3 1 Fatigue 3 6 1 Gait Disturbance 0 3 1 Drug Intolerance 2 0 0 Infections and Infestations Nasopharyngitis 0 3 0 Sinusitis 0 3 2 * Reported by ≥ 2% of patients treated with oxcarbazepine extended-release tablets and numerically more frequent than in the placebo group The overall incidence of adverse reactions appeared to be dose related, particularly during the titration period. The most commonly observed (≥ 5%) adverse reactions seen in association with oxcarbazepine extended-release tablets and more frequent than in placebo-treated patients were: dizziness, somnolence, headache, balance disorder, tremor, vomiting, diplopia, and asthenia. Adverse Reactions Associated with Discontinuation of Oxcarbazepine Extended-Release Tablets Treatment: Approximately 23.3% of the 366 adult patients receiving oxcarbazepine extended-release tablets in clinical studies discontinued treatment because of an …

7 DRUG INTERACTIONS Phenytoin, Carbamazepine, and Phenobarbital: Coadministration decreased blood levels of an active metabolite of oxcarbazepine extended-release tablets: Greater dosage of oxcarbazepine extended-release tablets may be required. ( 2.5 , 7.2 ) Oral Contraceptives: Advise patients that oxcarbazepine extended-release tablets may decrease the effectiveness of hormonal contraceptives. Additional non-hormonal forms of contraception are recommended. ( 7.3 ) 7.1 Effect of Oxcarbazepine Extended-Release Tablets on Other Drugs It is recommended that the plasma levels of phenytoin be monitored during the period of oxcarbazepine extended-release tablets titration and dosage modification [see Clinical Pharmacology ( 12.3 )]. A decrease in the dosage of phenytoin may be required. 7.2 Effect of Other Drugs on Oxcarbazepine Extended-Release Tablets If oxcarbazepine extended-release tablets and strong CYP3A4 inducers or UGT inducers (e.g., rifampin, carbamazepine, phenytoin and phenobarbital) are administered concurrently, it is recommended that the plasma levels of MHD be monitored during the period of oxcarbazepine extended-release tablets titration [see Clinical Pharmacology ( 12.3 )]. Dosage adjustment of oxcarbazepine extended-release tablets may be required after initiation, dosage modification, or discontinuation of such inducers [see Dosage and Administration ( 2.5 )]. 7.3 Hormonal Contraceptives Concurrent use of immediate-release oxcarbazepine with hormonal contraceptives may render these contraceptives less effective [see Clinical Pharmacology ( 12.3 )]. Studies with other oral or implant contraceptives have not been conducted.

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. ( 5.9, 8.1 ). Severe Hepatic Impairment: Not recommended. ( 8.7 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as oxcarbazepine extended-release tablets, during pregnancy. Encourage women who are taking oxcarbazepine extended-release 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 There are no adequate data on the developmental risks associated with the use of oxcarbazepine extended-release tablets in pregnant women; however, oxcarbazepine is closely related structurally to carbamazepine, which is considered to be teratogenic in humans. Data on a limited number of pregnancies from pregnancy registries suggest that oxcarbazepine monotherapy use is associated with congenital malformations (e.g., craniofacial defects such as oral clefts, and cardiac malformations such as ventricular septal defects). Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity (embryolethality, growth retardation) were observed in the offspring of animals treated with either oxcarbazepine or its active 10-hydroxy metabolite (MHD) during pregnancy at doses similar to the maximum recommended human dose (MRHD). 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. Clinical Considerations An increase in seizure frequency may occur during pregnancy because of altered levels of the active metabolite of oxcarbazepine. Monitor patients carefully during pregnancy and through the postpartum period [see Warnings and Precautions (5.9) ] Data Human Data Data from published registries have reported craniofacial defects such as oral clefts and cardiac malformations such as ventricular septal defects in children with prenatal oxcarbazepine exposure. Animal Data When pregnant rats were given oxcarbazepine (30, 300, or 1000 mg/kg/day) orally throughout the period of organogenesis, increased incidences of fetal malformations (craniofacial, cardiovascular, and skeletal) and variations were observed at the intermediate and high doses (approximately 1.2 and 4 times, respectively, the MRHD on a mg/m 2 basis). Increased embryofetal death and decreased fetal body weights were seen at the high dose. Doses ≥ 300 mg/kg were also maternally toxic (decreased body weight gain, clinical signs), but there is no evidence to suggest that teratogenicity was secondary to the maternal effects. In a study in which pregnant rabbits were orally administered MHD (20, 100, or 200 mg/kg/day) during organogenesis, embryofetal mortality was increased at the highest dose (1.5 times the MRHD on a mg/m 2 basis). This dose produced only minimal maternal toxicity. In a study in which female rats were dosed orally with oxcarbazepine (25, 50, or 150 mg/kg/day) during the latter part of gestation and throughout the lactation period, a persistent reduction in body weights and altered behavior (decreased activity) were observed in offspring exposed to the highest dose (0.6 times the MRHD on a mg/m 2 basis). Oral administration of MHD (25, 75, or 250 mg/kg/day) to rats during gestation and lactation resulted in a persistent reduction in offspring weights at the highest dose (equivalent to the MRHD on a mg/m 2 basis). 8.2 Lactation Risk Summary Oxcarbazepine and its active metabolite (MHD) are present in human milk after oxcarbazepine administration. The effects of oxcarbazepine and its active metabolite (MHD) on the breastfed infant or on milk production are unknown. The developmental and health benefits of breastfeeding should be considered al …

12.1 Mechanism of Action The pharmacological activity of oxcarbazepine extended-release tablets are primarily exerted through the 10-monohydroxy metabolite (MHD) of oxcarbazepine [see Clinical Pharmacology ( 12.3 )]. The precise mechanism by which oxcarbazepine and MHD exert their antiseizure effect is unknown; however, in vitro electrophysiological studies indicate that they produce blockade of voltage-sensitive sodium channels, resulting in stabilization of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and diminution of propagation of synaptic impulses. These actions are thought to be important in the prevention of seizure spread in the intact brain. In addition, increased potassium conductance and modulation of high-voltage activated calcium channels may contribute to the anticonvulsant effects of the drug. No significant interactions of oxcarbazepine or MHD with brain neurotransmitter or modulator receptor sites have been demonstrated.

11 DESCRIPTION Oxcarbazepine is an antiepileptic drug (AED). Oxcarbazepine extended-release tablets contain oxcarbazepine for once-a-day oral administration. Oxcarbazepine is 10,11-Dihydro-10-oxo-5H-dibenz[b,f]-azepine-5-carboxamide, and its structural formula is Oxcarbazepine is white or faintly orange, crystalline powder. Oxcarbazepine USP is sparingly soluble in chloroform (30 g/L to 100 g/L). In aqueous media over pH range 1 to 8, oxcarbazepine is practically insoluble and its solubility is 40 mg/L (0.04 g/L) at pH 7.0, 25°C. The molecular formula is C 15 H 12 N 2 O 2 and its molecular weight is 252.27. Oxcarbazepine extended-release tablets contain the following inactive ingredients: colloidal silicon dioxide, hypromellose, hydroxypropyl cellulose, yellow iron oxide, red iron oxide (300 mg, 600 mg tablets only), black iron oxide (150 mg, 300 mg tablets only), magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, povidone, sodium lauryl sulfate, talc, and titanium dioxide. structure

10 OVERDOSAGE 10.1 Human Overdose Experience Isolated cases of overdose with immediate-release oxcarbazepine have been reported. The maximum dose taken was approximately 48,000 mg. All patients recovered with symptomatic treatment. Nausea, vomiting, somnolence, aggression, agitation, hypotension, and tremor each occurred in more than one patient. Coma, confusional state, convulsion, dyscoordination, depressed level of consciousness, diplopia, dizziness, dyskinesia, dyspnea, QT prolongation, headache, miosis, nystagmus, overdose, decreased urine output, and blurred vision also occurred. 10.2 Treatment and Management There is no specific antidote for oxcarbazepine extended-release tablets overdose. Administer symptomatic and supportive treatment as appropriate. Options include removal of the drug by gastric lavage and/or inactivation by administering activated charcoal.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 150 mg (yellow oval shaped, biconvex tablet debossed with "XC1" on one side and plain on other side). Bottles of 100 tablets with child-resistant closure....................................NDC 27241-237-01 300 mg (brown oval shaped, biconvex tablet debossed with "XC2" on one side and plain on other side). Bottles of 100 tablets with child-resistant closure....................................NDC 27241-238-01 600 mg (brownish red oval shaped, biconvex tablet debossed with "XC3" on one side and plain on other side). Bottles of 100 tablets with child-resistant closure....................................NDC 27241-239-01 16.2 Storage and Handling Store 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]. Protect from light and moisture. Dispense in a tight, light-resistant container.