Oxcarbazepine

1 INDICATIONS & USAGE Oxcarbazepine Tablets are indicated for use as monotherapy or adjunctive therapy in the treatment of partial-onset seizures in adults and as monotherapy in the treatment of partial-onset seizures in pediatric patients aged 4 years and above, and as adjunctive therapy in pediatric patients aged 2 years and above with partial-onset seizures. Oxcarbazepine Tablets are indicated for: Adults: Monotherapy or adjunctive therapy in the treatment of partial-onset seizures Pediatrics Monotherapy in the treatment of partial-onset seizures in children 4 to 16 years Adjunctive therapy in the treatment of partial-onset seizures in children 2 to 16 years (1)

2 DOSAGE & ADMINISTRATION Adults: Initiate with a dose of 600 mg/day, given twice a day Adjunctive Therapy: Maximum increment of 600 mg/day at approximately weekly intervals. The recommended daily dose is 1200 mg/day (2.1) Conversion to Monotherapy: Withdrawal concomitant over 3 to 6 weeks; reach maximum dose of oxcarbazepine tablets in 2 to 4 weeks with increments of 600 mg/day at weekly intervals to a recommended daily dose of 2400 mg/day (2.2) Initiation of Monotherapy: Increments of 300 mg/day every third day to a dose of 1200 mg/day (2.3) Initiate at one-half the usual starting dose and increase slowly in patients with a creatinine clearance < 30 mL/min (2.7) Pediatrics: Initiation with 8 to 10 mg/kg/day, given twice a day. For patients aged 2 to < 4 years and under 20 kg, a starting dose of 16 to 20 mg/kg/day may be considered. Recommended daily dose is dependent upon patient weight. Adjunctive Patients (Aged 2 to 16 Years): For patients aged 4 to 16 years, target maintenance dose should be achieved over 2 weeks (2.4). For patients aged 2 to < 4 years, maximum maintenance dose should be achieved over 2 to 4 weeks and should not exceed 60 mg/kg/day (2.4) Conversion to Monotherapy for Patients (Aged 4 to 16 Years): Maximum increment of 10 mg/kg/day at weekly intervals, concomitant antiepileptic drugs (AEDs) can be completely withdrawn over 3 to 6 weeks (2.5) Initiation of Monotherapy for Patients (Aged 4 to 16 Years): Increments of 5 mg/kg/day every third day (2.6) 2.1 Adjunctive Therapy for Adults Initiate oxcarbazepine tablets with a dose of 600 mg/day, given twice a day. If clinically indicated, the dose may be increased by a maximum of 600 mg/day at approximately weekly intervals; the maximum recommended daily dose is 1200 mg/day. Daily doses above 1200 mg/day show somewhat greater effectiveness in controlled trials, but most patients were not able to tolerate the 2400 mg/day dose, primarily because of central nervous (CNS) effects. Dosage adjustment is recommended with concomitant use of strong CYP3A4 enzyme inducers or UDP- glucuronosyltransferases (UGT) inducers, which include certain antiepileptic drugs (AEDs) [see Drug Interactions (7.1, 7.2)] . 2.2 Conversion to Monotherapy for Adults Patients receiving concomitant AEDs may be converted to monotherapy by initiating treatment with oxcarbazepine tablets at 600 mg/day (given in a twice a day regimen) while simultaneously initiating the reduction of the dose of the concomitant AEDs. The concomitant AEDs should be completely withdrawn over 3 to 6 weeks, while the maximum dose of oxcarbazepine tablets should be reached in about 2 to 4 weeks. Oxcarbazepine tablets may be increased as clinically indicated by a maximum increment of 600 mg/day at approximately weekly intervals to achieve the maximum recommended daily dose of 2400 mg/day. A daily dose of 1200 mg/day has been shown in one study to be effective in patients in whom monotherapy has been initiated with oxcarbazepine. Patients should be observed closely during this transition phase. 2.3 Initiation of Monotherapy for Adults Patients not currently being treated with AEDs may have monotherapy initiated with oxcarbazepine tablets. In these patients, initiate oxcarbazepine tablets at a dose of 600 mg/day (given twice a day); the dose should be increased by 300 mg/day every third day to a dose of 1200 mg/day. Controlled trials in these patients examined the effectiveness of a 1200 mg/day dose; a dose of 2400 mg/day has been shown to be effective in patients converted from other AEDs to oxcarbazepine monotherapy (see above). 2.4 Adjunctive Therapy for Pediatric Patients (Aged 2 to 16 Years) In pediatric patients aged 4 to 16 years, initiate oxcarbazepine tablets at a daily dose of 8 to 10 mg/kg generally not to exceed 600 mg/day, given twice a day. The target maintenance dose of oxcarbazepine tablets should be achieved over 2 weeks, and is dependent upon patient weight, according to the following chart: 20 to 29 kg-900 …

5 WARNINGS AND PRECAUTIONS Hyponatremia: Monitor serum sodium levels (5.1) Cross Hypersensitivity Reaction to Carbamazepine: Discontinue immediately if hypersensitivity occurs (5.3) Serious Dermatological Reactions: If occurs, consider discontinuation (5.4) Suicidal Behavior and Ideation: Monitor for suicidal thoughts/behavior (5.5) Withdrawal of AEDs: Withdraw oxcarbazepine tablets gradually (5.6) Cognitive/Neuropsychiatric Adverse Reactions: May cause cognitive dysfunction, somnolence, and coordination abnormalities. Use caution when operating machinery (5.7) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi- Organ Hypersensitivity: Monitor and discontinue if another cause cannot be established (5.8) Hematologic Events: Consider discontinuing (5.9) Seizure Control During Pregnancy: Active metabolite may decrease (5.10) Risk of Seizure Aggravation: Discontinue if occurs (5.11) 5.1 Hyponatremia Clinically significant hyponatremia (sodium < 125 mmol/L) can develop during oxcarbazepine use. In the 14 controlled epilepsy studies, 2.5% of oxcarbazepine-treated patients (38/1524) had a sodium of less than 125 mmol/L at some point during treatment, compared to no such patients assigned placebo or active control (carbamazepine and phenobarbital for adjunctive and monotherapy substitution studies, and phenytoin and valproate for the monotherapy initiation studies). Clinically significant hyponatremia generally occurred during the first 3 months of treatment with oxcarbazepine, although there were patients who first developed a serum sodium < 125 mmol/L more than 1 year after initiation of therapy. Most patients who developed hyponatremia were asymptomatic, but patients in the clinical trials were frequently monitored and some had their oxcarbazepine dose reduced, discontinued, or had their fluid intake restricted for hyponatremia. Whether or not these maneuvers prevented the occurrence of more severe events is unknown. Cases of symptomatic hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported during postmarketing use. In clinical trials, patients whose treatment with oxcarbazepine was discontinued due to hyponatremia generally experienced normalization of serum sodium within a few days without additional treatment. Measurement of serum sodium levels should be considered for patients during maintenance treatment with oxcarbazepine, particularly if the patient is receiving other medications known to decrease serum sodium levels (e.g., drugs associated with inappropriate ADH secretion), or if symptoms possibly indicating hyponatremia develop (e.g., nausea, malaise, headache, lethargy, confusion, obtundation, or increase in seizure frequency or severity). 5.2 Anaphylactic Reactions and Angioedema Rare cases of anaphylaxis and angioedema involving the larynx, glottis, lips and eyelids have been reported in patients after taking the first or subsequent doses of oxcarbazepine. Angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions after treatment with oxcarbazepine, the drug should be discontinued and an alternative treatment started. These patients should not be rechallenged with the drug [see Warnings and Precautions (5.3)] . 5.3 Cross Hypersensitivity Reaction to Carbamazepine Approximately 25% to 30% of patients who have had hypersensitivity reactions to carbamazepine will experience hypersensitivity reactions with oxcarbazepine. For this reason, patients should be specifically questioned about any prior experience with carbamazepine, and patients with a history of hypersensitivity reactions to carbamazepine should ordinarily be treated with oxcarbazepine only if the potential benefit justifies the potential risk. If signs or symptoms of hypersensitivity develop, oxcarbazepine should be discontinued immediately [see Warnings and Precautions (5.2, 5.8)] . 5.4 Serious Dermatological Reactions Serious dermatological reactions, inc…

4 CONTRAINDICATIONS Oxcarbazepine tablets are contraindicated in patients with a known hypersensitivity to oxcarbazepine or to any of its components, or to eslicarbazepine acetate [see Warnings and Precautions (5.2, 5.3)] . Known hypersensitivity to oxcarbazepine or to any of its components, or to eslicarbazepine acetate (4, 5.2)

7 DRUG INTERACTIONS Phenytoin: Increased phenytoin levels. Reduced dose of phenytoin may be required (7.1) Carbamazepine, Phenytoin, and Phenobarbital: Decreased plasma levels of MHD (the active metabolite). Dose adjustments may be necessary (7.1) Oral Contraceptive: Oxcarbazepine may decrease the effectiveness of hormonal contraceptives (7.3) 7.1 Effect of Oxcarbazepine on Other Drugs Phenytoin levels have been shown to increase with concomitant use of oxcarbazepine at doses greater than 1200 mg/day [see Clinical Pharmacology (12.3)] . Therefore, it is recommended that the plasma levels of phenytoin be monitored during the period of oxcarbazepine titration and dosage modification. A decrease in the dose of phenytoin may be required . 7.2 Effect of Other Drugs on Oxcarbazepine Strong inducers of cytochrome P450 enzymes and/or inducers of UGT (e.g., rifampin, carbamazepine, phenytoin and phenobarbital) have been shown to decrease the plasma/serum levels of MHD, the active metabolite of oxcarbazepine (25% to 49%) [see Clinical Pharmacology (12.3)]. If oxcarbazepine and strong CYP3A4 inducers, or UGT inducers are administered concurrently, it is recommended that the plasma levels of MHD be monitored during the period of oxcarbazepine titration. Dose adjustment of oxcarbazepine may be required after initiation, dosage modification, or discontinuation of such inducers. 7.3 Hormonal Contraceptives Concurrent use of oxcarbazepine with hormonal contraceptives may render these contraceptives less effective [see Use in Specific Populations (8.3) and Clinical Pharmacology (12.3)] . Studies with other oral or implant contraceptives have not been conducted.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as oxcarbazepine tablets, during pregnancy. Encourage women who are taking oxcarbazepine 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 Although oxcarbazepine tablets is closely related structurally to carbamazepine, which is considered to be teratogenic in humans, available human data from published literature and ongoing pregnancy registry studies on use of oxcarbazepine during pregnancy have not demonstrated an increased prevalence of major congenital malformations with first trimester exposure. However, all published studies reviewed have important methodological limitations, including unmeasured confounding and a small number of exposed cases (see Data). There are risks to the mother and fetus associated with partial onset seizures (see Clinical Considerations ). There are no data on the risks associated with the use of oxcarbazepine tablets and miscarriage or other adverse maternal outcomes. 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% to 4% and 15% to 20%, respectively. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. Clinical Considerations Disease-associated Maternal and/or Embryofetal Risk Epilepsy, with or without exposure to antiepileptic drugs, has been associated with several adverse outcomes during pregnancy, including preeclampsia, preterm labor, antepartum and postpartum hemorrhage, placental abruption, poor fetal growth, prematurity, fetal death, and maternal mortality. The risk of maternal or fetal injury may be greatest for patients with untreated or poorly controlled convulsive seizures. Women with epilepsy who become pregnant should not abruptly discontinue antiepileptic drugs, including oxcarbazepine tablets, due to the risk of status epilepticus or severe seizures, which may be life-threatening [see Warnings and Precautions (5.6)]. Maternal Adverse Reactions 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 (5.10)]. Data Human Data Data from a published retrospective cohort study and ongoing pregnancy registry studies on the use of oxcarbazepine during pregnancy have not demonstrated an increased prevalence of major congenital malformations with first trimester exposure. A retrospective cohort study conducted in Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) from 1996-2020 found that there was no increased prevalence of major congenital malformations when pregnancies exposed to oxcarbazepine during the first trimester were compared to pregnancies exposed to lamotrigine (adjusted risk ratio =1.09; 95% CI 0.83 to 1.44; n pregnancies exposed to oxcarbazepine= 1,313, n exposed cases = 58). In an ongoing pregnancy registry that included data from over 40 countries from 1999 to 2022 and 443 pregnancies exposed to oxcarbazepine, oxcarbazepine exposure during the first trimester was not associated with major congenital malformations (adjusted odds ratio =1.09; 95% CI 0.56 to 2.13, n exposed cases = 10). However, there are important methodological limitations of these studies including unmeasured confounding factors and a small number of exposed cases in …

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in 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)] Cognitive/Neuropsychiatric Adverse Reactions [see Warnings and Precautions (5.7)] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity [see Warnings and Precautions (5.8)] Hematologic Events [see Warnings and Precautions (5.9)] The most common ( > 10% more than placebo for adjunctive or low dose for monotherapy) adverse reactions in adults and pediatrics were: dizziness, somnolence, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision, headache, nystagmus, tremor, and abnormal gait (6.1) To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-855-204-1431 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. Most Common Adverse Reactions in All Clinical Studies Adjunctive Therapy/Monotherapy in Adults Previously Treated With Other AEDs The most common ( > 10% more than placebo for adjunctive or low dose for monotherapy) adverse reactions with oxcarbazepine: dizziness, somnolence, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision, headache, nystagmus tremor, and abnormal gait. Approximately 23% of these 1537 adult patients discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were: dizziness (6.4%), diplopia (5.9%), ataxia (5.2%), vomiting (5.1%), nausea (4.9%), somnolence (3.8%), headache (2.9%), fatigue (2.1%), abnormal vision (2.1%), tremor (1.8%), abnormal gait (1.7%), rash (1.4%), and hyponatremia (1.0%). Monotherapy in Adults Not Previously Treated With Other AEDs The most common ( > 5%) adverse reactions with oxcarbazepine in these patients were similar to those in previously treated patients. Approximately 9% of these 295 adult patients discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were: dizziness (1.7%), nausea (1.7%), rash (1.7%), and headache (1.4%). Adjunctive Therapy/Monotherapy in Pediatric Patients 4 Years Old and Above Previously Treated With Other AEDs The most common ( > 5%) adverse reactions with oxcarbazepine in these patients were similar to those seen in adults. Approximately 11% of these 456 pediatric patients discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were: somnolence (2.4%), vomiting (2.0%), ataxia (1.8%), diplopia (1.3%), dizziness (1.3%), fatigue (1.1%), and nystagmus (1.1%). Monotherapy in Pediatric Patients 4 Years Old and Above Not Previously Treated With Other AEDs The most common ( > 5%) adverse reactions with oxcarbazepine in these patients were similar to those in adults. Approximately 9.2% of 152 pediatric patients discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated ( > 1%) with discontinuation were rash (5.3%) and maculopapular rash (1.3%). Adjunctive Therapy/Monotherapy in Pediatric Patients 1 Month to < 4 Years Old Previously Treated or Not Previously Treated with Other AEDs: The most common ( > 5%) adverse reactions with oxcarbazepine in these patients were similar to those seen in older children and adults, except for infections and infestations which were more frequently seen in these younger children. …