Oxcarbazepine

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 Breckenridge Pharmaceutical, Inc. at 1-800-367-3395 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 tablets: dizziness, somnolence, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision, headache, nystagmus tremor, and abnormal gait. Approximately 23% of these 1,537 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%), hyponatremia (1.0%). Monotherapy in Adults Not Previously Treated with Other AEDs The most common (≥5%) adverse reactions with oxcarbazepine tablets 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%), 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 tablets 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%), 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 tablets 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 tablets 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. Approximately 11% of these 241 pediatric patients discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were: convulsions (3.7%), status epilepticus (1.2%), and ataxia (1.2%). Controlled Clinical Studies of Adjunctive Therapy/Monotherapy in Adults Previously Treated with Other AEDs Table 3 lists adverse reactions that occurred in at least 2% of adult patients with epilepsy, treated with oxcarbazepine tablets or placebo as adjunctive treatment and were numerically more common in the patients treated with any dose of oxcarbazepine tablets. Table 4 lists adverse reactions in patients converted from other AEDs to either high-dose oxcarbazepine tablets (2400 mg/day) or low-dose (300 mg/day) oxcarbazepine tablets. Note that in some of these monotherapy studies patients who dropped out during a preliminary tolerability phase are not included in the tables. Table 3: Adverse Reactions in a Controlled Clinical Study of Adjunctive Therapy with Oxcarbazepine Tablets in Adults Oxcarbazepine tablets Dosage (mg/day) Body System/ Adverse Reaction OXC 600 N=163 % OXC 1200 N=171 % OXC 2400 N=126 % Placebo N=166 % Body as a Whole Fatigue 15 12 15 7 Asthenia 6 3 6 5 Leg Edema 2 1 2 1 Increased Weight 1 2 2 1 Feeling Abnormal 0 1 2 0 Cardiovascular System Hypotension 0 1 2 0 Digestive System Nausea 15 25 29 10 Vomiting 13 25 36 5 Abdominal Pain 10 13 11 5 Diarrhea 5 6 7 6 Dyspepsia 5 5 6 2 Constipation 2 2 6 4 Gastritis 2 1 2 1 Metabolic and Nutritional Disorders Hyponatremia 3 1 2 1 Musculoskeletal System Muscle Weakness 1 2 2 0 Sprains and Strains 0 2 2 1 Nervous System Headache 32 28 26 23 Dizziness 26 32 49 13 Somnolence 20 28 36 12 Ataxia 9 17 31 5 Nystagmus 7 20 26 5 Abnormal Gait 5 10 17 1 Insomnia 4 2 3 1 Tremor 3 8 16 5 Nervousness 2 4 2 1 Agitation 1 1 2 1 Abnormal Coordination 1 3 2 1 Abnormal EEG 0 0 2 0 Speech Disorder 1 1 3 0 Confusion 1 1 2 1 Cranial Injury NOS 1 0 2 1 Dysmetria 1 2 3 0 Abnormal Thinking 0 2 4 0 Respiratory System Rhinitis 2 4 5 4 Skin and Appendages Acne 1 2 2 0 Special Senses Diplopia 14 30 40 5 Vertigo 6 12 15 2 Abnormal Vision 6 14 13 4 Abnormal Accommodation 0 0 2 0 Table 4: Adverse Reactions in Controlled Clinical Studies of Monotherapy with Oxcarbazepine Tablets in Adults Previously Treated with Other AEDs Body System/ Adverse Reaction Oxcarbazepine tablets 2400 mg/day N=86 % Oxcarbazepine tablets 300 mg/day N=86 % Body as a Whole Fatigue 21 5 Fever 3 0 Allergy 2 0 Generalized Edema 2 1 Chest Pain 2 0 Digestive System Nausea 22 7 Vomiting 15 5 Diarrhea 7 5 Dyspepsia 6 1 Anorexia 5 3 Abdominal Pain 5 3 Mouth Dry 3 0 Hemorrhage Rectum 2 0 Toothache 2 1 Hemic and Lymphatic System Lymphadenopathy 2 0 Infections and Infestations Viral Infection 7 5 Infection 2 0 Metabolic and Nutritional Disorders Hyponatremia 5 0 Thirst 2 0 Nervous System Headache 31 15 Dizziness 28 8 Somnolence 19 5 Anxiety 7 5 Ataxia 7 1 Confusion 7 0 Nervousness 7 0 Insomnia 6 3 Tremor 6 3 Amnesia 5 1 Aggravated Convulsions 5 2 Emotional Lability 3 2 Hypoesthesia 3 1 Abnormal Coordination 2 1 Nystagmus 2 0 Speech Disorder 2 0 Respiratory System Upper Respiratory Tract Infection 10 5 Coughing 5 0 Bronchitis 3 0 Pharyngitis 3 0 Skin and Appendages Hot Flushes 2 1 Purpura 2 0 Special Senses Abnormal Vision 14 2 Diplopia 12 1 Taste Perversion 5 0 Vertigo 3 0 Earache 2 1 Ear Infection NOS 2 0 Urogenital and Reproductive System Urinary Tract Infection 5 1 Micturition Frequency 2 1 Vaginitis 2 0 Controlled Clinical Study of Monotherapy in Adults Not Previously Treated with Other AEDs Table 5 lists adverse reactions in a controlled clinical study of monotherapy in adults not previously treated with other AEDs that occurred in at least 2% of adult patients with epilepsy treated with oxcarbazepine tablets or placebo and were numerically more common in the patients treated with oxcarbazepine tablets. Table 5: Adverse Reactions in a Controlled Clinical Study of Monotherapy with Oxcarbazepine Tablets in Adults Not Previously Treated with Other AEDs Body System/ Adverse Reaction Oxcarbazepine tablets N=55 % Placebo N=49 % Body as a Whole Falling Down NOS 4 0 Digestive System Nausea 16 12 Diarrhea 7 2 Vomiting 7 6 Constipation 5 0 Dyspepsia 5 4 Musculoskeletal System Back Pain 4 2 Nervous System Dizziness 22 6 Headache 13 10 Ataxia 5 0 Nervousness 5 2 Amnesia 4 2 Abnormal Coordination 4 2 Tremor 4 0 Respiratory System Upper Respiratory Tract Infection 7 0 Epistaxis 4 0 Infection Chest 4 0 Sinusitis 4 2 Skin and Appendages Rash 4 2 Special Senses Vision Abnormal 4 0 Controlled Clinical Studies of Adjunctive Therapy/Monotherapy in Pediatric Patients Previously Treated with Other AEDs Table 6 lists adverse reactions that occurred in at least 2% of pediatric patients with epilepsy treated with oxcarbazepine tablets or placebo as adjunctive treatment and were numerically more common in the patients treated with oxcarbazepine tablets. Table 6: Adverse Reactions in Controlled Clinical Studies of Adjunctive Therapy/Monotherapy with Oxcarbazepine Tablets in Pediatric Patients Previously Treated with Other AEDs Body System/ Adverse Reaction Oxcarbazepine tablets N=171 % Placebo N=139 % Body as a Whole Fatigue 13 9 Allergy 2 0 Asthenia 2 1 Digestive System Vomiting 33 14 Nausea 19 5 Constipation 4 1 Dyspepsia 2 0 Nervous System Headache 31 19 Somnolence 31 13 Dizziness 28 8 Ataxia 13 4 Nystagmus 9 1 Emotional Lability 8 4 Abnormal Gait 8 3 Tremor 6 4 Speech Disorder 3 1 Impaired Concentration 2 1 Convulsions 2 1 Involuntary Muscle Contractions 2 1 Respiratory System Rhinitis 10 9 Pneumonia 2 1 Skin and Appendages Bruising 4 2 Increased Sweating 3 0 Special Senses Diplopia 17 1 Abnormal Vision 13 1 Vertigo 2 0 Other Events Observed in Association with the Administration of Oxcarbazepine Tablets In the paragraphs that follow, the adverse reactions, other than those in the preceding tables or text, that occurred in a total of 565 children and 1,574 adults exposed to oxcarbazepine tablets and that are reasonably likely to be related to drug use are presented. Events common in the population, events reflecting chronic illness and events likely to reflect concomitant illness are omitted particularly if minor. They are listed in order of decreasing frequency. Because the reports cite events observed in open label and uncontrolled trials, the role of oxcarbazepine tablets in their causation cannot be reliably determined. Body as a Whole: fever, malaise, pain chest precordial, rigors, weight decrease. Cardiovascular System: bradycardia, cardiac failure, cerebral hemorrhage, hypertension, hypotension postural, palpitation, syncope, tachycardia. Digestive System: appetite increased, blood in stool, cholelithiasis, colitis, duodenal ulcer, dysphagia, enteritis, eructation, esophagitis, flatulence, gastric ulcer, gingival bleeding, gum hyperplasia, hematemesis, hemorrhage rectum, hemorrhoids, hiccup, mouth dry, pain biliary, pain right hypochondrium, retching, sialoadenitis, stomatitis, stomatitis ulcerative. Hematologic and Lymphatic System: thrombocytopenia. Laboratory Abnormality: gamma-GT increased, hyperglycemia, hypocalcemia, hypoglycemia, hypokalemia, liver enzymes elevated, serum transaminase increased. Musculoskeletal System: hypertonia muscle. Nervous System: aggressive reaction, amnesia, anguish, anxiety, apathy, aphasia, aura, convulsions aggravated, delirium, delusion, depressed level of consciousness, dysphonia, dystonia, emotional lability, euphoria, extrapyramidal disorder, feeling drunk, hemiplegia, hyperkinesia, hyperreflexia, hypoesthesia, hypokinesia, hyporeflexia, hypotonia, hysteria, libido decreased, libido increased, manic reaction, migraine, muscle contractions involuntary, nervousness, neuralgia, oculogyric crisis, panic disorder, paralysis, paroniria, personality disorder, psychosis, ptosis, stupor, tetany. Respiratory System: asthma, dyspnea, epistaxis, laryngismus, pleurisy. Skin and Appendages : acne, alopecia, angioedema, bruising, dermatitis contact, eczema, facial rash, flushing, folliculitis, heat rash, hot flushes, photosensitivity reaction, pruritus genital, psoriasis, purpura, rash erythematous, rash maculopapular, vitiligo, urticaria. Special Senses: accommodation abnormal, cataract, conjunctival hemorrhage, edema eye, hemianopia, mydriasis, otitis externa, photophobia, scotoma, taste perversion, tinnitus, xerophthalmia. Surgical and Medical Procedures: procedure dental oral, procedure female reproductive, procedure musculoskeletal, procedure skin. Urogenital and Reproductive System: dysuria, hematuria, intermenstrual bleeding, leukorrhea, menorrhagia, micturition frequency, pain renal, pain urinary tract, polyuria, priapism, renal calculus. Other: Systemic lupus erythematosus. Laboratory Tests Serum sodium levels below 125 mmol/L have been observed in patients treated with oxcarbazepine tablets [see Warnings and Precautions ( 5.1 )]. Experience from clinical trials indicates that serum sodium levels return toward normal when the oxcarbazepine tablets dosage is reduced or discontinued, or when the patient was treated conservatively (e.g., fluid restriction). Laboratory data from clinical trials suggest that oxcarbazepine tablets use was associated with decreases in T 4 , without changes in T 3 or TSH. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of oxcarbazepine tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: multi-organ hypersensitivity disorders characterized by features such as rash, fever, lymphadenopathy, abnormal liver function tests, eosinophilia and arthralgia [see Warnings and Precautions ( 5.8 )] Cardiovascular System: atrioventricular block Immune System Disorders: anaphylaxis [see Warnings and Precautions ( 5.2 )] Digestive System: pancreatitis and/or lipase and/or amylase increase Hematologic and Lymphatic Systems: aplastic anemia [see Warnings and Precautions ( 5.9 ) ] Metabolism and Nutrition Disorders: hypothyroidism and syndrome of inappropriate antidiuretic hormone secretion (SIADH) Skin and Subcutaneous Tissue Disorders: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis [see Warnings and Precautions ( 5.4 ) ], Acute Generalized Exanthematous Pustulosis (AGEP) Musculoskeletal, connective tissue and bone disorders: There have been reports of decreased bone mineral density, osteoporosis and fractures in patients on long-term therapy with oxcarbazepine tablets. Injury, Poisoning, and Procedural Complications: fall Nervous System Disorders: dysarthria

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 )

11 DESCRIPTION Oxcarbazepine is an antiepileptic drug available as 150 mg, 300 mg, and 600 mg film-coated tablets for oral administration. Oxcarbazepine is 10,11-Dihydro-10-oxo-5 H- dibenz[b,ƒ]azepine-5-carboxamide, and its structural formula is: Oxcarbazepine is a white to faintly orange crystalline powder. It is slightly soluble in chloroform, dichloromethane, acetone, and methanol and practically insoluble in ethanol, ether and water. Its molecular weight is 252.27. Oxcarbazepine film-coated tablets contain the following inactive ingredients: microcrystalline cellulose, crospovidone, hypromellose, colloidal silicon dioxide, magnesium stearate, talc. Coating: polyvinyl alcohol, talc, titanium dioxide, polyethylene glycol, Contains FD&C Yellow No. 6 as a color additive. FD&C Yellow No. 6 aluminum lake, lecithin, FD&C Blue No. 2 aluminum lake, Contains FD&C Yellow No. 5 as a color additive. [See WARNINGS AND PRECAUTIONS (5.12)]. FD&C Yellow No. 5 aluminum lake. Allergen Statement: This product contains soy. Oxcarbazepine Tablets, USP complies with USP Dissolution Test 2. Chemical Structure

2 DOSAGE AND 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 2-16 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 to exceed 60 mg/kg/day ( 2.4 ) • Conversion to Monotherapy for Patients (Aged 4-16 Years): Maximum increment of 10 mg/kg/day at weekly intervals, concomitant antiepileptic drugs can be completely withdrawn over 3 to 6 weeks ( 2.5 ) • Initiation of Monotherapy for Patients (Aged 4-16 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 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 CNS effects. 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 )]. 2.2 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 tablets. 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 tablets monotherapy (see above). 2.4 Adjunctive Therapy for Pediatric Patients (Aged 2-16 Years) In pediatric patients aged 4-16 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 mg/day 29.1 to 39 kg - 1200 mg/day >39 kg - 1800 mg/day In the clinical trial, in which the intention was to reach these target doses, the median daily dose was 31 mg/kg with a range of 6 to 51 mg/kg. In pediatric patients aged 2 to <4 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. For patients less than 20 kg, a starting dose of 16 to 20 mg/kg may be considered [see Clinical Pharmacology ( 12.3 ) ]. The maximum maintenance dose of oxcarbazepine tablets should be achieved over 2 to 4 weeks and should not exceed 60 mg/kg/day in a twice-a-day regimen. In the clinical trial in pediatric patients (2 to 4 years of age) in which the intention was to reach the target dose of 60 mg/kg/day, 50% of patients reached a final dose of at least 55 mg/kg/day. Under adjunctive therapy (with and without enzyme-inducing AEDs), when normalized by body weight, apparent clearance (L/hr/kg) decreased when age increased such that children 2 to <4 years of age may require up to twice the oxcarbazepine dose per body weight compared to adults; and children 4 to ≤12 years of age may require a 50% higher oxcarbazepine dose per body weight compared to adults. 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 )]. 2.5 Conversion to Monotherapy for Pediatric Patients (Aged 4-16 Years) Patients receiving concomitant antiepileptic drugs may be converted to monotherapy by initiating treatment with oxcarbazepine tablets at approximately 8 to 10 mg/kg/day given twice-a-day, while simultaneously initiating the reduction of the dose of the concomitant antiepileptic drugs. The concomitant antiepileptic drugs can be completely withdrawn over 3 to 6 weeks while oxcarbazepine tablets may be increased as clinically indicated by a maximum increment of 10 mg/kg/day at approximately weekly intervals to achieve the recommended daily dose. Patients should be observed closely during this transition phase. The recommended total daily dose of oxcarbazepine tablets is shown in Table 1. 2.6 Initiation of Monotherapy for Pediatric Patients (Aged 4-16 Years) Patients not currently being treated with antiepileptic drugs may have monotherapy initiated with oxcarbazepine tablets. In these patients, initiate oxcarbazepine tablets at a dose of 8 to 10 mg/kg/day given twice-a-day. The dose should be increased by 5 mg/kg/day every third day to the recommended daily dose shown in the table below. Table 1: Range of Maintenance Doses of Oxcarbazepine Tablets for Pediatrics by Weight During Monotherapy From To Weight in kg Dose (mg/day) Dose (mg/day) 20 600 900 25 900 1200 30 900 1200 35 900 1500 40 900 1500 45 1200 1500 50 1200 1800 55 1200 1800 60 1200 2100 65 1200 2100 70 1500 2100 2.7 Dosage Modification for Patients with Renal Impairment In patients with impaired renal function (creatinine clearance <30 mL/min) initiate oxcarbazepine tablets at one-half the usual starting dose (300 mg/day, given twice-a-day) and increase slowly to achieve the desired clinical response [see Clinical Pharmacology ( 12.3 ) ]. 2.8 Administration Information Oxcarbazepine tablets can be taken with or without food [see Clinical Pharmacology ( 12.3 ) ].

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

9.2 Abuse The abuse potential of oxcarbazepine tablets has not been evaluated in human studies.

9.3 Dependence Intragastric injections of oxcarbazepine to 4 cynomolgus monkeys demonstrated no signs of physical dependence as measured by the desire to self-administer oxcarbazepine by lever pressing activity.

9 DRUG ABUSE AND DEPENDENCE 9.2 Abuse The abuse potential of oxcarbazepine tablets has not been evaluated in human studies. 9.3 Dependence Intragastric injections of oxcarbazepine to 4 cynomolgus monkeys demonstrated no signs of physical dependence as measured by the desire to self-administer oxcarbazepine by lever pressing activity.

10 OVERDOSAGE 10.1 Human Overdose Experience Isolated cases of overdose with oxcarbazepine tablets 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, blurred vision also occurred. 10.2 Treatment and Management There is no specific antidote. 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.

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

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The pharmacological activity of oxcarbazepine tablets is 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 anti-seizure 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. 12.2 Pharmacodynamics Oxcarbazepine and its active metabolite (MHD) exhibit anticonvulsant properties in animal seizure models. They protected rodents against electrically induced tonic extension seizures and, to a lesser degree, chemically induced clonic seizures, and abolished or reduced the frequency of chronically recurring focal seizures in Rhesus monkeys with aluminum implants. No development of tolerance (i.e., attenuation of anticonvulsive activity) was observed in the maximal electroshock test when mice and rats were treated daily for 5 days and 4 weeks, respectively, with oxcarbazepine or MHD. 12.3 Pharmacokinetics Following oral administration of oxcarbazepine tablets, oxcarbazepine is completely absorbed and extensively metabolized to its pharmacologically active 10-monohydroxy metabolite (MHD). In a mass balance study in people, only 2% of total radioactivity in plasma was due to unchanged oxcarbazepine, with approximately 70% present as MHD, and the remainder attributable to minor metabolites. The half-life of the parent is about 2 hours, while the half-life of MHD is about 9 hours, so that MHD is responsible for most antiepileptic activity. Absorption Based on MHD concentrations, oxcarbazepine tablets and suspension were shown to have similar bioavailability. After single-dose administration of oxcarbazepine tablets to healthy male volunteers under fasted conditions, the median t max was 4.5 (range 3 to 13) hours. Steady-state plasma concentrations of MHD are reached within 2 to 3 days in patients when oxcarbazepine tablets is given twice a day. At steady state the pharmacokinetics of MHD are linear and show dose proportionality over the dose range of 300 to 2400 mg/day. Food has no effect on the rate and extent of absorption of oxcarbazepine from oxcarbazepine tablets. Therefore, oxcarbazepine tablets can be taken with or without food. Distribution The apparent volume of distribution of MHD is 49 L. Approximately 40% of MHD is bound to serum proteins, predominantly to albumin. Binding is independent of the serum concentration within the therapeutically relevant range. Oxcarbazepine and MHD do not bind to alpha-1-acid glycoprotein. Metabolism and Excretion Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to its 10-monohydroxy metabolite, MHD, which is primarily responsible for the pharmacological effect of oxcarbazepine tablets. MHD is metabolized further by conjugation with glucuronic acid. Minor amounts (4% of the dose) are oxidized to the pharmacologically inactive 10,11-dihydroxy metabolite (DHD). Oxcarbazepine is cleared from the body mostly in the form of metabolites which are predominantly excreted by the kidneys. More than 95% of the dose appears in the urine, with less than 1% as unchanged oxcarbazepine. Fecal excretion accounts for less than 4% of the administered dose. Approximately 80% of the dose is excreted in the urine either as glucuronides of MHD (49%) or as unchanged MHD (27%); the inactive DHD accounts for approximately 3% and conjugates of MHD and oxcarbazepine account for 13% of the dose. The half-life of the parent is about 2 hours, while the half-life of MHD is about 9 hours. Specific Populations Geriatrics Following administration of single (300 mg) and multiple (600 mg/day) doses of oxcarbazepine tablets to elderly volunteers (60 to 82 years of age), the maximum plasma concentrations and AUC values of MHD were 30% to 60% higher than in younger volunteers (18 to 32 years of age). Comparisons of creatinine clearance in young and elderly volunteers indicate that the difference was due to age-related reductions in creatinine clearance. Pediatrics Weight-adjusted MHD clearance decreases as age and weight increases, approaching that of adults. The mean weight- adjusted clearance in children 2 years to <4 years of age is approximately 80% higher on average than that of adults. Therefore, MHD exposure in these children is expected to be about one-half that of adults when treated with a similar weight-adjusted dose. The mean weight-adjusted clearance in children 4 to 12 years of age is approximately 40% higher on average than that of adults. Therefore, MHD exposure in these children is expected to be about three-quarters that of adults when treated with a similar weight-adjusted dose. As weight increases, for patients 13 years of age and above, the weight-adjusted MHD clearance is expected to reach that of adults. Gender No gender-related pharmacokinetic differences have been observed in children, adults, or the elderly. Race No specific studies have been conducted to assess what effect, if any, race may have on the disposition of oxcarbazepine. Renal Impairment There is a linear correlation between creatinine clearance and the renal clearance of MHD. When oxcarbazepine tablets is administered as a single 300 mg dose in renally-impaired patients (creatinine clearance <30 mL/min), the elimination half-life of MHD is prolonged to 19 hours, with a 2-fold increase in AUC [see Dosage and Administration ( 2.7 ) and Use in Specific Populations ( 8.6 )]. Hepatic Impairment The pharmacokinetics and metabolism of oxcarbazepine and MHD were evaluated in healthy volunteers and hepatically-impaired subjects after a single 900-mg oral dose. Mild-to-moderate hepatic impairment did not affect the pharmacokinetics of oxcarbazepine and MHD [see Dosage and Administration ( 2.8 )]. Pregnancy Due to physiological changes during pregnancy, MHD plasma levels may gradually decrease throughout pregnancy [see Use in Specific Populations ( 8.1 )] Drug Interactions: • In Vitro Oxcarbazepine can inhibit CYP2C19 and induce CYP3A4/5 with potentially important effects on plasma concentrations of other drugs. In addition, several AEDs that are cytochrome P450 inducers can decrease plasma concentrations of oxcarbazepine and MHD. No autoinduction has been observed with oxcarbazepine tablets. Oxcarbazepine was evaluated in human liver microsomes to determine its capacity to inhibit the major cytochrome P450 enzymes responsible for the metabolism of other drugs. Results demonstrate that oxcarbazepine and its pharmacologically active 10-monohydroxy metabolite (MHD) have little or no capacity to function as inhibitors for most of the human cytochrome P450 enzymes evaluated (CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, CYP4A9 and CYP4A11) with the exception of CYP2C19 and CYP3A4/5. Although inhibition of CYP3A4/5 by oxcarbazepine and MHD did occur at high concentrations, it is not likely to be of clinical significance. The inhibition of CYP2C19 by oxcarbazepine and MHD can cause increased plasma concentrations of drugs that are substrates of CYP2C19, which is clinically relevant. In vitro , the UDP-glucuronyl transferase level was increased, indicating induction of this enzyme. Increases of 22% with MHD and 47% with oxcarbazepine were observed. As MHD, the predominant plasma substrate, is only a weak inducer of UDP-glucuronyl transferase, it is unlikely to have an effect on drugs that are mainly eliminated by conjugation through UDP-glucuronyl transferase (e.g., valproic acid, lamotrigine). In addition, oxcarbazepine and MHD induce a subgroup of the cytochrome P450 3A family (CYP3A4 and CYP3A5) responsible for the metabolism of dihydropyridine calcium antagonists, oral contraceptives and cyclosporine resulting in a lower plasma concentration of these drugs. As binding of MHD to plasma proteins is low (40%), clinically significant interactions with other drugs through competition for protein binding sites are unlikely. • In Vivo Other Antiepileptic Drugs Potential interactions between oxcarbazepine tablets and other AEDs were assessed in clinical studies. The effect of these interactions on mean AUCs and C min are summarized in Table 7 [see Drug Interactions ( 7.1 , 7.2 )]. Table 7: Summary of AED Interactions with Oxcarbazepine Tablets AED Coadministered Dose of AED (mg/day) Oxcarbazepine tablets Dose (mg/day) Influence of Oxcarbazepine tablets on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval) Carbamazepine 400-2000 900 nc nc denotes a mean change of less than 10% 40% decrease [CI: 17% decrease, 57% decrease] Phenobarbital 100-150 600-1800 14% increase [CI: 2% increase, 24% increase] 25% decrease [CI: 12% decrease, 51% decrease] Phenytoin 250-500 600-1800 >1200-2400 nc Pediatrics up to 40% increase Mean increase in adults at high oxcarbazepine tablets doses [CI: 12% increase, 60% increase] 30% decrease [CI: 3% decrease, 48% decrease] Valproic acid 400-2800 600-1800 nc 18% decrease [CI: 13% decrease, 40% decrease] Lamotrigine 200 1200 nc nc Hormonal Contraceptives Coadministration of oxcarbazepine tablets with an oral contraceptive has been shown to influence the plasma concentrations of the two hormonal components, ethinylestradiol (EE) and levonorgestrel (LNG) [see Drug Interactions ( 7.3 )]. The mean AUC values of EE were decreased by 48% [90% CI: 22 to 65] in one study and 52% [90% CI: 38 to 52] in another study. The mean AUC values of LNG were decreased by 32% [90% CI: 20 to 45] in one study and 52% [90% CI: 42 to 52] in another study. Other Drug Interactions Calcium Antagonists: After repeated coadministration of oxcarbazepine tablets, the AUC of felodipine was lowered by 28% [90% CI: 20 to 33]. Verapamil produced a decrease of 20% [90% CI: 18 to 27] of the plasma levels of MHD. Cimetidine, erythromycin and dextropropoxyphene had no effect on the pharmacokinetics of MHD. Results with warfarin show no evidence of interaction with either single or repeated doses of oxcarbazepine tablets.

12.1 Mechanism of Action The pharmacological activity of oxcarbazepine tablets is 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 anti-seizure 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.

12.2 Pharmacodynamics Oxcarbazepine and its active metabolite (MHD) exhibit anticonvulsant properties in animal seizure models. They protected rodents against electrically induced tonic extension seizures and, to a lesser degree, chemically induced clonic seizures, and abolished or reduced the frequency of chronically recurring focal seizures in Rhesus monkeys with aluminum implants. No development of tolerance (i.e., attenuation of anticonvulsive activity) was observed in the maximal electroshock test when mice and rats were treated daily for 5 days and 4 weeks, respectively, with oxcarbazepine or MHD.

12.3 Pharmacokinetics Following oral administration of oxcarbazepine tablets, oxcarbazepine is completely absorbed and extensively metabolized to its pharmacologically active 10-monohydroxy metabolite (MHD). In a mass balance study in people, only 2% of total radioactivity in plasma was due to unchanged oxcarbazepine, with approximately 70% present as MHD, and the remainder attributable to minor metabolites. The half-life of the parent is about 2 hours, while the half-life of MHD is about 9 hours, so that MHD is responsible for most antiepileptic activity. Absorption Based on MHD concentrations, oxcarbazepine tablets and suspension were shown to have similar bioavailability. After single-dose administration of oxcarbazepine tablets to healthy male volunteers under fasted conditions, the median t max was 4.5 (range 3 to 13) hours. Steady-state plasma concentrations of MHD are reached within 2 to 3 days in patients when oxcarbazepine tablets is given twice a day. At steady state the pharmacokinetics of MHD are linear and show dose proportionality over the dose range of 300 to 2400 mg/day. Food has no effect on the rate and extent of absorption of oxcarbazepine from oxcarbazepine tablets. Therefore, oxcarbazepine tablets can be taken with or without food. Distribution The apparent volume of distribution of MHD is 49 L. Approximately 40% of MHD is bound to serum proteins, predominantly to albumin. Binding is independent of the serum concentration within the therapeutically relevant range. Oxcarbazepine and MHD do not bind to alpha-1-acid glycoprotein. Metabolism and Excretion Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to its 10-monohydroxy metabolite, MHD, which is primarily responsible for the pharmacological effect of oxcarbazepine tablets. MHD is metabolized further by conjugation with glucuronic acid. Minor amounts (4% of the dose) are oxidized to the pharmacologically inactive 10,11-dihydroxy metabolite (DHD). Oxcarbazepine is cleared from the body mostly in the form of metabolites which are predominantly excreted by the kidneys. More than 95% of the dose appears in the urine, with less than 1% as unchanged oxcarbazepine. Fecal excretion accounts for less than 4% of the administered dose. Approximately 80% of the dose is excreted in the urine either as glucuronides of MHD (49%) or as unchanged MHD (27%); the inactive DHD accounts for approximately 3% and conjugates of MHD and oxcarbazepine account for 13% of the dose. The half-life of the parent is about 2 hours, while the half-life of MHD is about 9 hours. Specific Populations Geriatrics Following administration of single (300 mg) and multiple (600 mg/day) doses of oxcarbazepine tablets to elderly volunteers (60 to 82 years of age), the maximum plasma concentrations and AUC values of MHD were 30% to 60% higher than in younger volunteers (18 to 32 years of age). Comparisons of creatinine clearance in young and elderly volunteers indicate that the difference was due to age-related reductions in creatinine clearance. Pediatrics Weight-adjusted MHD clearance decreases as age and weight increases, approaching that of adults. The mean weight- adjusted clearance in children 2 years to <4 years of age is approximately 80% higher on average than that of adults. Therefore, MHD exposure in these children is expected to be about one-half that of adults when treated with a similar weight-adjusted dose. The mean weight-adjusted clearance in children 4 to 12 years of age is approximately 40% higher on average than that of adults. Therefore, MHD exposure in these children is expected to be about three-quarters that of adults when treated with a similar weight-adjusted dose. As weight increases, for patients 13 years of age and above, the weight-adjusted MHD clearance is expected to reach that of adults. Gender No gender-related pharmacokinetic differences have been observed in children, adults, or the elderly. Race No specific studies have been conducted to assess what effect, if any, race may have on the disposition of oxcarbazepine. Renal Impairment There is a linear correlation between creatinine clearance and the renal clearance of MHD. When oxcarbazepine tablets is administered as a single 300 mg dose in renally-impaired patients (creatinine clearance <30 mL/min), the elimination half-life of MHD is prolonged to 19 hours, with a 2-fold increase in AUC [see Dosage and Administration ( 2.7 ) and Use in Specific Populations ( 8.6 )]. Hepatic Impairment The pharmacokinetics and metabolism of oxcarbazepine and MHD were evaluated in healthy volunteers and hepatically-impaired subjects after a single 900-mg oral dose. Mild-to-moderate hepatic impairment did not affect the pharmacokinetics of oxcarbazepine and MHD [see Dosage and Administration ( 2.8 )]. Pregnancy Due to physiological changes during pregnancy, MHD plasma levels may gradually decrease throughout pregnancy [see Use in Specific Populations ( 8.1 )] Drug Interactions: • In Vitro Oxcarbazepine can inhibit CYP2C19 and induce CYP3A4/5 with potentially important effects on plasma concentrations of other drugs. In addition, several AEDs that are cytochrome P450 inducers can decrease plasma concentrations of oxcarbazepine and MHD. No autoinduction has been observed with oxcarbazepine tablets. Oxcarbazepine was evaluated in human liver microsomes to determine its capacity to inhibit the major cytochrome P450 enzymes responsible for the metabolism of other drugs. Results demonstrate that oxcarbazepine and its pharmacologically active 10-monohydroxy metabolite (MHD) have little or no capacity to function as inhibitors for most of the human cytochrome P450 enzymes evaluated (CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, CYP4A9 and CYP4A11) with the exception of CYP2C19 and CYP3A4/5. Although inhibition of CYP3A4/5 by oxcarbazepine and MHD did occur at high concentrations, it is not likely to be of clinical significance. The inhibition of CYP2C19 by oxcarbazepine and MHD can cause increased plasma concentrations of drugs that are substrates of CYP2C19, which is clinically relevant. In vitro , the UDP-glucuronyl transferase level was increased, indicating induction of this enzyme. Increases of 22% with MHD and 47% with oxcarbazepine were observed. As MHD, the predominant plasma substrate, is only a weak inducer of UDP-glucuronyl transferase, it is unlikely to have an effect on drugs that are mainly eliminated by conjugation through UDP-glucuronyl transferase (e.g., valproic acid, lamotrigine). In addition, oxcarbazepine and MHD induce a subgroup of the cytochrome P450 3A family (CYP3A4 and CYP3A5) responsible for the metabolism of dihydropyridine calcium antagonists, oral contraceptives and cyclosporine resulting in a lower plasma concentration of these drugs. As binding of MHD to plasma proteins is low (40%), clinically significant interactions with other drugs through competition for protein binding sites are unlikely. • In Vivo Other Antiepileptic Drugs Potential interactions between oxcarbazepine tablets and other AEDs were assessed in clinical studies. The effect of these interactions on mean AUCs and C min are summarized in Table 7 [see Drug Interactions ( 7.1 , 7.2 )]. Table 7: Summary of AED Interactions with Oxcarbazepine Tablets AED Coadministered Dose of AED (mg/day) Oxcarbazepine tablets Dose (mg/day) Influence of Oxcarbazepine tablets on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval) Carbamazepine 400-2000 900 nc nc denotes a mean change of less than 10% 40% decrease [CI: 17% decrease, 57% decrease] Phenobarbital 100-150 600-1800 14% increase [CI: 2% increase, 24% increase] 25% decrease [CI: 12% decrease, 51% decrease] Phenytoin 250-500 600-1800 >1200-2400 nc Pediatrics up to 40% increase Mean increase in adults at high oxcarbazepine tablets doses [CI: 12% increase, 60% increase] 30% decrease [CI: 3% decrease, 48% decrease] Valproic acid 400-2800 600-1800 nc 18% decrease [CI: 13% decrease, 40% decrease] Lamotrigine 200 1200 nc nc Hormonal Contraceptives Coadministration of oxcarbazepine tablets with an oral contraceptive has been shown to influence the plasma concentrations of the two hormonal components, ethinylestradiol (EE) and levonorgestrel (LNG) [see Drug Interactions ( 7.3 )]. The mean AUC values of EE were decreased by 48% [90% CI: 22 to 65] in one study and 52% [90% CI: 38 to 52] in another study. The mean AUC values of LNG were decreased by 32% [90% CI: 20 to 45] in one study and 52% [90% CI: 42 to 52] in another study. Other Drug Interactions Calcium Antagonists: After repeated coadministration of oxcarbazepine tablets, the AUC of felodipine was lowered by 28% [90% CI: 20 to 33]. Verapamil produced a decrease of 20% [90% CI: 18 to 27] of the plasma levels of MHD. Cimetidine, erythromycin and dextropropoxyphene had no effect on the pharmacokinetics of MHD. Results with warfarin show no evidence of interaction with either single or repeated doses of oxcarbazepine tablets.

20221219

3

3 DOSAGE FORMS AND STRENGTHS 150 mg Film-Coated Tablets: beige, film-coated, modified oval shaped tablet, scored on both sides, debossed “B2 | 92” on one side and plain on the other side. 300 mg Film-Coated Tablets: beige, film-coated, modified oval shaped tablet, scored on both sides, debossed “B | 293” on one side and plain on the other side. 600 mg Film-Coated Tablets: beige, film-coated, modified oval shaped tablet, scored on both sides, debossed “B | 294” on one side and plain on the other side.. • Film-coated tablets: 150 mg, 300 mg and 600 mg ( 3 )

Oxcarbazepine Oxcarbazepine MICROCRYSTALLINE CELLULOSE CROSPOVIDONE (120 .MU.M) HYPROMELLOSE, UNSPECIFIED SILICON DIOXIDE MAGNESIUM STEARATE TALC POLYVINYL ALCOHOL, UNSPECIFIED TITANIUM DIOXIDE POLYETHYLENE GLYCOL, UNSPECIFIED FD&C YELLOW NO. 6 LECITHIN, SOYBEAN FD&C BLUE NO. 2 FD&C YELLOW NO. 5 OXCARBAZEPINE OXCARBAZEPINE Beige B2;92 Oxcarbazepine Oxcarbazepine MICROCRYSTALLINE CELLULOSE CROSPOVIDONE (120 .MU.M) HYPROMELLOSE, UNSPECIFIED SILICON DIOXIDE MAGNESIUM STEARATE TALC POLYVINYL ALCOHOL, UNSPECIFIED TITANIUM DIOXIDE POLYETHYLENE GLYCOL, UNSPECIFIED FD&C YELLOW NO. 6 LECITHIN, SOYBEAN FD&C BLUE NO. 2 FD&C YELLOW NO. 5 OXCARBAZEPINE OXCARBAZEPINE Beige B;293

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In 2-year carcinogenicity studies, oxcarbazepine was administered in the diet at doses of up to 100 mg/kg/day to mice and by gavage at doses of up to 250 mg/kg/day to rats, and the pharmacologically active 10-hydroxy metabolite (MHD) was administered orally at doses of up to 600 mg/kg/day to rats. In mice, a dose-related increase in the incidence of hepatocellular adenomas was observed at oxcarbazepine doses ≥70 mg/kg/day or approximately 0.1 times the maximum recommended human dose (MRHD) on a mg/m 2 basis. In rats, the incidence of hepatocellular carcinomas was increased in females treated with oxcarbazepine at doses ≥25 mg/kg/day (0.1 times the MRHD on a mg/m 2 basis), and incidences of hepatocellular adenomas and/or carcinomas were increased in males and females treated with MHD at doses of 600 mg/kg/day (2.4 times the MRHD on a mg/m 2 basis) and ≥250 mg/kg/day (equivalent to the MRHD on a mg/m 2 basis), respectively. There was an increase in the incidence of benign testicular interstitial cell tumors in rats at 250 mg oxcarbazepine/kg/day and at ≥250 mg MHD/kg/day, and an increase in the incidence of granular cell tumors in the cervix and vagina in rats at 600 mg MHD/kg/day. Mutagenesis Oxcarbazepine increased mutation frequencies in the in vitr o Ames test in the absence of metabolic activation. Both oxcarbazepine and MHD produced increases in chromosomal aberrations and polyploidy in the Chinese hamster ovary assay in vitro in the absence of metabolic activation. MHD was negative in the Ames test, and no mutagenic or clastogenic activity was found with either oxcarbazepine or MHD in V79 Chinese hamster cells in vitro . Oxcarbazepine and MHD were both negative for clastogenic or aneugenic effects (micronucleus formation) in an in vivo rat bone marrow assay. Impairment of Fertility In a fertility study in which rats were administered MHD (50, 150, or 450 mg/kg) orally prior to and during mating and early gestation, estrous cyclicity was disrupted and numbers of corpora lutea, implantations, and live embryos were reduced in females receiving the highest dose (approximately 2 times the MRHD on a mg/m 2 basis).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In 2-year carcinogenicity studies, oxcarbazepine was administered in the diet at doses of up to 100 mg/kg/day to mice and by gavage at doses of up to 250 mg/kg/day to rats, and the pharmacologically active 10-hydroxy metabolite (MHD) was administered orally at doses of up to 600 mg/kg/day to rats. In mice, a dose-related increase in the incidence of hepatocellular adenomas was observed at oxcarbazepine doses ≥70 mg/kg/day or approximately 0.1 times the maximum recommended human dose (MRHD) on a mg/m 2 basis. In rats, the incidence of hepatocellular carcinomas was increased in females treated with oxcarbazepine at doses ≥25 mg/kg/day (0.1 times the MRHD on a mg/m 2 basis), and incidences of hepatocellular adenomas and/or carcinomas were increased in males and females treated with MHD at doses of 600 mg/kg/day (2.4 times the MRHD on a mg/m 2 basis) and ≥250 mg/kg/day (equivalent to the MRHD on a mg/m 2 basis), respectively. There was an increase in the incidence of benign testicular interstitial cell tumors in rats at 250 mg oxcarbazepine/kg/day and at ≥250 mg MHD/kg/day, and an increase in the incidence of granular cell tumors in the cervix and vagina in rats at 600 mg MHD/kg/day. Mutagenesis Oxcarbazepine increased mutation frequencies in the in vitr o Ames test in the absence of metabolic activation. Both oxcarbazepine and MHD produced increases in chromosomal aberrations and polyploidy in the Chinese hamster ovary assay in vitro in the absence of metabolic activation. MHD was negative in the Ames test, and no mutagenic or clastogenic activity was found with either oxcarbazepine or MHD in V79 Chinese hamster cells in vitro . Oxcarbazepine and MHD were both negative for clastogenic or aneugenic effects (micronucleus formation) in an in vivo rat bone marrow assay. Impairment of Fertility In a fertility study in which rats were administered MHD (50, 150, or 450 mg/kg) orally prior to and during mating and early gestation, estrous cyclicity was disrupted and numbers of corpora lutea, implantations, and live embryos were reduced in females receiving the highest dose (approximately 2 times the MRHD on a mg/m 2 basis).

ANDA078069

Oxcarbazepine

Oxcarbazepine

55154-8198

HUMAN PRESCRIPTION DRUG

ORAL

Package/Label Display Panel Oxcarbazepine Tablets, USP 150 mg 10 Tablets Bag

Dosage and Administration ( 2.1 , 2.4 ) 11/2017 Contraindications ( 4 ) 3/2017 Warnings and Precautions ( 5.1 , 5.3 , 5.4 , 5.6 , 5.7 , 5.8 , 5.11 ) 3/2017

PACKAGING INFORMATION Distributed by: Cardinal Health Dublin, OH 43017 L56460211220 L57056600421 8284501/0119

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Administration Information Counsel patients that oxcarbazepine tablets may be taken with or without food. Hyponatremia Advise patients that oxcarbazepine tablets may reduce the serum sodium concentrations especially if they are taking other medications that can lower sodium. Instruct patients to report symptoms of low sodium like nausea, tiredness, lack of energy, confusion, and more frequent or more severe seizures [see Warnings and Precautions ( 5.1 ) ]. Anaphylactic Reactions and Angioedema Anaphylactic reactions and angioedema may occur during treatment with oxcarbazepine tablets. Advise patients to report immediately signs and symptoms suggesting angioedema (swelling of the face, eyes, lips, tongue or difficulty in swallowing or breathing) and to stop taking the drug until they have consulted with their physician [see Warnings and Precautions ( 5.2 ) ]. Cross Hypersensitivity Reaction to Carbamazepine Inform patients who have exhibited hypersensitivity reactions to carbamazepine that approximately 25% to 30% of these patients may experience hypersensitivity reactions with oxcarbazepine tablets. Patients should be advised that if they experience a hypersensitivity reaction while taking oxcarbazepine tablets they should consult with their physician immediately [see Warnings and Precautions ( 5.3 )]. Serious Dermatological Reactions Advise patients that serious skin reactions have been reported in association with oxcarbazepine tablets. In the event a skin reaction should occur while taking oxcarbazepine tablets, patients should consult with their physician immediately [see Warnings and Precautions ( 5.4 ) ]. Suicidal Behavior and Ideation Patients, their caregivers, and families should be counseled that AEDs, including oxcarbazepine tablets, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers [see Warnings and Precautions ( 5.5 )]. Driving and Operating Machinery Advise patients that oxcarbazepine tablets may cause adverse reactions such as dizziness, somnolence, ataxia, visual disturbances, and depressed level of consciousness. Accordingly, advise patients not to drive or operate machinery until they have gained sufficient experience on oxcarbazepine tablets to gauge whether it adversely affects their ability to drive or operate machinery [see Warnings and Precautions ( 5.7 ) and Adverse Reactions ( 6 )]. Multi-Organ Hypersensitivity Instruct patients that a fever associated with other organ system involvement (e.g., rash, lymphadenopathy, hepatic dysfunction) may be drug-related and should be reported to their healthcare provider immediately [see Warnings and Precautions ( 5.8 )]. Hematologic Events Advise patients that there have been rare reports of blood disorders reported in patients treated with oxcarbazepine tablets. Instruct patients to immediately consult with their physician if they experience symptoms suggestive of blood disorders [see Warnings and Precautions ( 5.9 )]. Drug Interactions Caution female patients of reproductive potential that the concurrent use of oxcarbazepine tablets with hormonal contraceptives may render this method of contraception less effective [see Drug Interactions ( 7.2 )]. Additional non-hormonal forms of contraception are recommended when using oxcarbazepine tablets. Caution should be exercised if alcohol is taken in combination with oxcarbazepine tablets, due to a possible additive sedative effect. Pregnancy Registry Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. [see Use in Specific Populations ( 8.1 )].

MEDICATION GUIDE 8284501/0119 Oxcarbazepine Tablets, USP (ox kar baz' e peen) film-coated tablets, for oral use Oxcarbazepine Tablets, USP contains FD&C yellow no. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C yellow no. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity. Read this Medication Guide before you start taking oxcarbazepine tablets and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. What is the most important information I should know about oxcarbazepine tablets? Do not stop taking oxcarbazepine tablets without first talking to your healthcare provider. Stopping oxcarbazepine tablets suddenly can cause serious problems. Oxcarbazepine tablets can cause serious side effects, including: 1. Oxcarbazepine tablets may cause the level of sodium in your blood to be low. Symptoms of low blood sodium include: • nausea • tiredness (lack of energy) • headache • confusion • more frequent or more severe seizures Similar symptoms that are not related to low sodium may occur from taking oxcarbazepine tablets. You should tell your healthcare provider if you have any of these side effects and if they bother you or they do not go away. Some other medicines can also cause low sodium in your blood. Be sure to tell your healthcare provider about all the other medicines that you are taking. Your healthcare provider may do blood tests to check your sodium levels during your treatment with oxcarbazepine tablets. 2. Oxcarbazepine tablets may also cause allergic reactions or serious problems which may affect organs and other parts of your body like the liver or blood cells. You may or may not have a rash with these types of reactions. Call your healthcare provider right away if you have any of the following: • swelling of your face, eyes, lips, or tongue • trouble swallowing or breathing • a skin rash • hives • fever, swollen glands, or sore throat that do not go away or come and go • frequent infections or infections that do not go away • painful sores in the mouth or around your eyes • yellowing of your skin or eyes • unusual bruising or bleeding • severe fatigue or weakness • severe muscle pain Many people who are allergic to carbamazepine are also allergic to oxcarbazepine tablets. Tell your healthcare provider if you are allergic to carbamazepine. 3. Like other antiepileptic drugs, oxcarbazepine tablets may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: • thoughts about suicide or dying • trouble sleeping (insomnia) • attempts to commit suicide • new or worse irritability • new or worse depression • acting aggressive, being angry, or violent • new or worse anxiety • acting on dangerous impulses • feeling agitated or restless • an extreme increase in activity and talking (mania) • panic attacks • other unusual changes in behavior or mood How can I watch for early symptoms of suicidal thoughts and actions? • Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. • Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. Do not stop taking oxcarbazepine tablets without first talking to a healthcare provider. • Stopping oxcarbazepine tablets suddenly can cause serious problems. • Stopping a seizure medicine suddenly in a patient who has epilepsy may cause seizures that will not stop (status epilepticus). Suicidal thoughts or actions may be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. What are oxcarbazepine tablets? Oxcarbazepine tablets are a prescription medicine used: • alone or with other medicines to treat partial seizures in adults • alone to treat partial seizures in children 4 years and older • with other medicines to treat partial seizures in children 2 years and older It is not known if oxcarbazepine tablets is safe and effective for use alone to treat partial seizures in children less than 4 years of age or for use with other medicines to treat partial seizures in children less than 2 years of age. Do not take oxcarbazepine tablets if you are allergic to oxcarbazepine tablets or any of the other ingredients in oxcarbazepine tablets or to eslicarbazepine acetate. See the end of this Medication Guide for a complete list of ingredients in oxcarbazepine tablets. Many people who are allergic to carbamazepine are also allergic to oxcarbazepine tablets. Tell your healthcare provider if you are allergic to carbamazepine. Before taking oxcarbazepine tablets, tell your healthcare provider about all your medical conditions, including if you: • have or have had suicidal thoughts or actions, depression or mood problems • have liver problems • have kidney problems • are allergic to carbamazepine. Many people who are allergic to carbamazepine are also allergic to oxcarbazepine tablets. • use birth control medicine. Oxcarbazepine tablets may cause your birth control medicine to be less effective. Talk to your healthcare provider about the best birth control method to use. • are pregnant or plan to become pregnant. Oxcarbazepine tablets may harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking oxcarbazepine tablets. You and your healthcare provider will decide if you should take oxcarbazepine tablets while you are pregnant. If you become pregnant while taking oxcarbazepine tablets, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this registry is to collect information about the safety of antiepileptic medicine during pregnancy. You can enroll in this registry by calling 1-888-233-2334. • are breastfeeding or plan to breastfeed. Oxcarbazepine tablets passes into breast milk. You and your healthcare provider should discuss whether you should take oxcarbazepine tablets or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking oxcarbazepine tablets with certain other medicines may cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take Oxcarbazepine tablets? • Do not stop taking oxcarbazepine tablets without talking to your healthcare provider. Stopping oxcarbazepine tablets suddenly can cause serious problems, including seizures that will not stop (status epilepticus). • Take oxcarbazepine tablets exactly as prescribed. Your healthcare provider may change your dose. Your healthcare provider will tell you how much oxcarbazepine tablets to take. • Take oxcarbazepine tablets 2 times a day. • Take oxcarbazepine tablets with or without food. • If you take too many oxcarbazepine tablets, call your healthcare provider right away. What should I avoid while taking Oxcarbazepine tablets? • Do not drive or operate machinery until you know how oxcarbazepine tablets affects you. Oxcarbazepine tablets may slow your thinking and motor skills. • Do not drink alcohol or take other drugs that make you sleepy or dizzy while taking oxcarbazepine tablets until you talk to your healthcare provider. Oxcarbazepine tablets taken with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse. What are the possible side effects of oxcarbazepine tablets? See "What is the most important information I should know about oxcarbazepine tablets?" Oxcarbazepine tablets may cause other serious side effects including: • trouble concentrating • problems with your speech and language • feeling confused • feeling sleepy and tired • trouble walking and with coordination • seizures that can happen more often or become worse, especially in children Get medical help right away if you have any of the symptoms listed above or listed in "What is the most important information I should know about oxcarbazepine tablets?" 1. The most common side effects of oxcarbazepine tablets include: • dizziness • sleepiness • double vision • tiredness • nausea • vomiting • problems with vision • trembling • problems with walking and coordination (unsteadiness) • rash These are not all the possible side effects of oxcarbazepine tablets. Tell your healthcare provider if you have any side effect that bothers you or does not go away Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store oxcarbazepine tablets? • Store Oxcarbazepine Tablets between 20°C to 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F). • Keep oxcarbazepine tablets dry. Keep oxcarbazepine tablets and all medicines out of the reach of children. General Information about the safe and effective use of oxcarbazepine tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use oxcarbazepine tablets for a condition for which it was not prescribed. Do not give oxcarbazepine tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about oxcarbazepine tablets that is written for health professionals. For more information, go to www.bpirx.com or call 1-800-367-3395. What are the ingredients in oxcarbazepine tablets? Active ingredient: oxcarbazepine Inactive ingredients: • Film-coated tablets: microcrystalline cellulose, crospovidone, hypromellose, colloidal silicon dioxide, magnesium stearate, talc. Coating: polyvinyl alcohol, talc, titanium dioxide, polyethylene glycol, Contains FD&C Yellow No. 6 as a color additive. FD&C Yellow No. 6 aluminum lake, lecithin, FD&C Blue No. 2 aluminum lake, This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity. FD&C Yellow No. 5 aluminum lake. Allergen Statement: This product contains soy. This Medication Guide has been approved by the U.S. Food and Drug Administration. Distributed by: Cardinal Health Dublin, OH 43017 L56460211220 L57056600421 8284501/0119

14 CLINICAL STUDIES The effectiveness of oxcarbazepine tablets as adjunctive and monotherapy for partial seizures in adults, and as adjunctive therapy in children aged 2 to 16 years was established in seven multicenter, randomized, controlled trials. The effectiveness of oxcarbazepine tablets as monotherapy for partial seizures in children aged 4 to 16 years was determined from data obtained in the studies described, as well as by pharmacokinetic/pharmacodynamic considerations. 14.1 Oxcarbazepine Tablets Monotherapy Trials Four randomized, controlled, double-blind, multicenter trials, conducted in a predominately adult population, demonstrated the efficacy of oxcarbazepine tablets as monotherapy. Two trials compared oxcarbazepine tablets to placebo and 2 trials used a randomized withdrawal design to compare a high dose (2400 mg) with a low dose (300 mg) of oxcarbazepine tablets, after substituting oxcarbazepine tablets 2400 mg/day for 1 or more antiepileptic drugs (AEDs). All doses were administered on a twice-a-day schedule. A fifth randomized, controlled, rater-blind, multicenter study, conducted in a pediatric population, failed to demonstrate a statistically significant difference between low and high dose oxcarbazepine tablets treatment groups. One placebo-controlled trial was conducted in 102 patients (11 to 62 years of age) with refractory partial seizures who had completed an inpatient evaluation for epilepsy surgery. Patients had been withdrawn from all AEDs and were required to have 2 to 10 partial seizures within 48 hours prior to randomization. Patients were randomized to receive either placebo or oxcarbazepine tablets given as 1500 mg/day on Day 1 and 2400 mg/day thereafter for an additional 9 days, or until 1 of the following 3 exit criteria occurred: 1) the occurrence of a fourth partial seizure, excluding Day 1, 2) 2 new-onset secondarily generalized seizures, where such seizures were not seen in the 1-year period prior to randomization, or 3) occurrence of serial seizures or status epilepticus. The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria. There was a statistically significant difference in favor of oxcarbazepine tablets (see Figure 1), p=0.0001. Figure 1 Kaplan-Meier Estimates of Exit Rate by Treatment Group The second placebo-controlled trial was conducted in 67 untreated patients (8 to 69 years of age) with newly-diagnosed and recent-onset partial seizures. Patients were randomized to placebo or oxcarbazepine tablets, initiated at 300 mg twice a day and titrated to 1200 mg/day (given as 600 mg twice a day) in 6 days, followed by maintenance treatment for 84 days. The primary measure of effectiveness was a between-group comparison of the time to first seizure. The difference between the 2 treatments was statistically significant in favor of oxcarbazepine tablets (see Figure 2), p=0.046. Figure 2 Kaplan-Meier Estimates of First Seizure Event Rate by Treatment Group A third trial substituted oxcarbazepine tablets monotherapy at 2400 mg/day for carbamazepine in 143 patients (12 to 65 years of age) whose partial seizures were inadequately controlled on carbamazepine (CBZ) monotherapy at a stable dose of 800 to 1600 mg/day, and maintained this oxcarbazepine tablets dose for 56 days (baseline phase). Patients who were able to tolerate titration of oxcarbazepine tablets to 2400 mg/day during simultaneous carbamazepine withdrawal were randomly assigned to either 300 mg/day of oxcarbazepine tablets or 2400 mg/day oxcarbazepine tablets. Patients were observed for 126 days or until 1 of the following 4 exit criteria occurred: 1) a doubling of the 28-day seizure frequency compared to baseline, 2) a 2-fold increase in the highest consecutive 2-day seizure frequency during baseline, 3) a single generalized seizure if none had occurred during baseline, or 4) a prolonged generalized seizure. The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria. The difference between the curves was statistically significant in favor of the oxcarbazepine tablets 2400 mg/day group (see Figure 3), p=0.0001. Figure 3 Kaplan-Meier Estimates of Exit Rate by Treatment Group Another monotherapy substitution trial was conducted in 87 patients (11 to 66 years of age) whose seizures were inadequately controlled on 1 or 2 AEDs. Patients were randomized to either oxcarbazepine tablets 2400 mg/day or 300 mg/day and their standard AED regimen(s) were eliminated over the first 6 weeks of double-blind therapy. Double-blind treatment continued for another 84 days (total double-blind treatment of 126 days) or until 1 of the 4 exit criteria described for the previous study occurred. The primary measure of effectiveness was a between-group comparison of the percentage of patients meeting exit criteria. The results were statistically significant in favor of the oxcarbazepine tablets 2400 mg/day group (14/34; 41.2%) compared to the oxcarbazepine tablets 300 mg/day group (42/45; 93.3%) (p<0.0001). The time to meeting one of the exit criteria was also statistically significant in favor of the oxcarbazepine tablets 2400 mg/day group (see Figure 4), p=0.0001. Figure 4 Kaplan-Meier Estimates of Exit Rate by Treatment Group A monotherapy trial was conducted in 92 pediatric patients (1 month to 16 years of age) with inadequately-controlled or new-onset partial seizures. Patients were hospitalized and randomized to either oxcarbazepine tablets 10 mg/kg/day or were titrated up to 40 to 60 mg/kg/day within 3 days while withdrawing the previous AED on the second day of oxcarbazepine tablets. Seizures were recorded through continuous video-EEG monitoring from Day 3 to Day 5. Patients either completed the 5-day treatment or met 1 of the 2 exit criteria: 1) three study-specific seizures (i.e., electrographic partial seizures with a behavioral correlate), 2) a prolonged study-specific seizure. The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria in which the difference between the curves was not statistically significant (p=0.904). The majority of patients from both dose groups completed the 5-day study without exiting. Although this study failed to demonstrate an effect of oxcarbazepine as monotherapy in pediatric patients, several design elements, including the short treatment and assessment period, the absence of a true placebo, and the likely persistence of plasma levels of previously administered AEDs during the treatment period, make the results uninterpretable. For this reason, the results do not undermine the conclusion, based on pharmacokinetic/pharmacodynamic considerations, that oxcarbazepine is effective as monotherapy in pediatric patients 4 years old and older. Figure 1 Figure 2 Figure 3 Figure 4 14.2 Oxcarbazepine Tablets Adjunctive Therapy Trials The effectiveness of oxcarbazepine tablets as an adjunctive therapy for partial seizures was established in 2 multicenter, randomized, double-blind, placebo-controlled trials, one in 692 patients (15 to 66 years of age) and one in 264 pediatric patients (3 to 17 years of age), and in one multicenter, rater-blind, randomized, age-stratified, parallel-group study comparing 2 doses of oxcarbazepine in 128 pediatric patients (1 month to <4 years of age). Patients in the 2 placebo-controlled trials were on 1 to 3 concomitant AEDs. In both of the trials, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least 8 (minimum of 1 to 4 per month) partial seizures during the baseline phase were randomly assigned to placebo or to a specific dose of oxcarbazepine tablets in addition to their other AEDs. In these studies, the dose was increased over a 2-week period until either the assigned dose was reached, or intolerance prevented increases. Patients then entered a 14- (pediatrics) or 24-week (adults) maintenance period. In the adult trial, patients received fixed doses of 600, 1200 or 2400 mg/day. In the pediatric trial, patients received maintenance doses in the range of 30 to 46 mg/kg/day, depending on baseline weight. The primary measure of effectiveness in both trials was a between-group comparison of the percentage change in partial seizure frequency in the double-blind treatment phase relative to baseline phase. This comparison was statistically significant in favor of oxcarbazepine tablets at all doses tested in both trials (p=0.0001 for all doses for both trials). The number of patients randomized to each dose, the median baseline seizure rate, and the median percentage seizure rate reduction for each trial are shown in Table 8. It is important to note that in the high-dose group in the study in adults, over 65% of patients discontinued treatment because of adverse events; only 46 (27%) of the patients in this group completed the 28-week study [see Adverse Reactions ( 6 ) ], an outcome not seen in the monotherapy studies. Table 8 Summary of Percentage Change in Partial Seizure Frequency from Baseline for Placebo-Controlled Adjunctive Therapy Trials Trial Treatment Group N Baseline Median Seizure Rate = number of seizures per 28 days Median % Reduction 1 (pediatrics) Oxcarbazepine tablets 136 12.5 34.8 p=0.0001 Placebo 128 13.1 9.4 2 (adults) Oxcarbazepine tablets 2400 mg/day 174 10.0 49.9 Oxcarbazepine tablets 1200 mg/day 177 9.8 40.2 Oxcarbazepine tablets 600 mg/day 168 9.6 26.4 Placebo 173 8.6 7.6 Subset analyses of the antiepileptic efficacy of oxcarbazepine tablets with regard to gender in these trials revealed no important differences in response between men and women. Because there were very few patients over the age of 65 years in controlled trials, the effect of the drug in the elderly has not been adequately assessed. The third adjunctive therapy trial enrolled 128 pediatric patients (1 month to <4 years of age) with inadequately-controlled partial seizures on 1 to 2 concomitant AEDs. Patients who experienced at least 2 study-specific seizures (i.e., electrographic partial seizures with a behavioral correlate) during the 72-hour baseline period were randomly assigned to either oxcarbazepine tablets 10 mg/kg/day or were titrated up to 60 mg/kg/day within 26 days. Patients were maintained on their randomized target dose for 9 days and seizures were recorded through continuous video-EEG monitoring during the last 72 hours of the maintenance period. The primary measure of effectiveness in this trial was a between-group comparison of the change in seizure frequency per 24 hours compared to the seizure frequency at baseline. For the entire group of patients enrolled, this comparison was statistically significant in favor of oxcarbazepine tablets 60 mg/kg/day. In this study, there was no evidence that oxcarbazepine tablets were effective in patients below the age of 2 years (N=75).

8.5 Geriatric Use There were 52 patients over age 65 in controlled clinical trials and 565 patients over the age of 65 in other trials. Following administration of single (300 mg) and multiple (600 mg/day) doses of oxcarbazepine tablets in elderly volunteers (60 to 82 years of age), the maximum plasma concentrations and AUC values of MHD were 30% to 60% higher than in younger volunteers (18 to 32 years of age). Comparisons of creatinine clearance in young and elderly volunteers indicate that the difference was due to age-related reductions in creatinine clearance. Close monitoring of sodium levels is required in elderly patients at risk for hyponatremia [seeWarnings and Precautions ( 5.1 )].

8.3 Nursing Mothers Oxcarbazepine and its active metabolite (MHD) are excreted in human milk. A milk-to-plasma concentration ratio of 0.5 was found for both. Because of the potential for serious adverse reactions to oxcarbazepine tablets in nursing infants, a decision should be made about whether to discontinue nursing or to discontinue the drug in nursing women, taking into account the importance of the drug to the mother.

8.4 Pediatric Use Oxcarbazepine tablets is indicated for use as adjunctive therapy for partial seizures in patients aged 2 to 16 years. The safety and effectiveness for use as adjunctive therapy for partial seizures in pediatric patients below the age of 2 have not been established. Oxcarbazepine tablets is also indicated as monotherapy for partial seizures in patients aged 4 to 16 years. The safety and effectiveness for use as monotherapy for partial seizures in pediatric patients below the age of 4 have not been established. Oxcarbazepine tablets has been given to 898 patients between the ages of 1 month to 17 years in controlled clinical trials (332 treated as monotherapy) and about 677 patients between the ages of 1 month to 17 years in other trials [see Warnings and Precautions ( 5.11 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), and Clinical Studies ( 14 )].

8.1 Pregnancy Clinical Considerations Oxcarbazepine tablets levels may decrease during pregnancy [see Warnings and Precautions ( 5.10 ) ]. Pregnancy Category C Fetal Risk Summary There are no adequate and well-controlled clinical studies of oxcarbazepine tablets in pregnant women; however, oxcarbazepine tablets 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 congenital malformations associated with oxcarbazepine tablets monotherapy use (e.g., craniofacial defects such as oral clefts and cardiac malformations such as ventricular septal defects). Oxcarbazepine tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Data Animal 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). When pregnant rats were given oxcarbazepine (30, 300, or 1000 mg/kg) 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) 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) 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) 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). Pregnancy Registry To provide information regarding the effects of in utero exposure to oxcarbazepine tablets, physicians are advised to recommend that pregnant patients taking oxcarbazepine tablets enroll in the NAAED Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/ .

Pregnancy Category C Fetal Risk Summary There are no adequate and well-controlled clinical studies of oxcarbazepine tablets in pregnant women; however, oxcarbazepine tablets 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 congenital malformations associated with oxcarbazepine tablets monotherapy use (e.g., craniofacial defects such as oral clefts and cardiac malformations such as ventricular septal defects). Oxcarbazepine tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Data Animal 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). When pregnant rats were given oxcarbazepine (30, 300, or 1000 mg/kg) 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) 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) 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) 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). Pregnancy Registry To provide information regarding the effects of in utero exposure to oxcarbazepine tablets, physicians are advised to recommend that pregnant patients taking oxcarbazepine tablets enroll in the NAAED Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/ .

8 USE IN SPECIFIC POPULATIONS • Pregnancy: May cause fetal harm. ( 8.1 ) 8.1 Pregnancy Clinical Considerations Oxcarbazepine tablets levels may decrease during pregnancy [see Warnings and Precautions ( 5.10 ) ]. Pregnancy Category C Fetal Risk Summary There are no adequate and well-controlled clinical studies of oxcarbazepine tablets in pregnant women; however, oxcarbazepine tablets 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 congenital malformations associated with oxcarbazepine tablets monotherapy use (e.g., craniofacial defects such as oral clefts and cardiac malformations such as ventricular septal defects). Oxcarbazepine tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Data Animal 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). When pregnant rats were given oxcarbazepine (30, 300, or 1000 mg/kg) 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) 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) 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) 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). Pregnancy Registry To provide information regarding the effects of in utero exposure to oxcarbazepine tablets, physicians are advised to recommend that pregnant patients taking oxcarbazepine tablets enroll in the NAAED Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/ . 8.3 Nursing Mothers Oxcarbazepine and its active metabolite (MHD) are excreted in human milk. A milk-to-plasma concentration ratio of 0.5 was found for both. Because of the potential for serious adverse reactions to oxcarbazepine tablets in nursing infants, a decision should be made about whether to discontinue nursing or to discontinue the drug in nursing women, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Oxcarbazepine tablets is indicated for use as adjunctive therapy for partial seizures in patients aged 2 to 16 years. The safety and effectiveness for use as adjunctive therapy for partial seizures in pediatric patients below the age of 2 have not been established. Oxcarbazepine tablets is also indicated as monotherapy for partial seizures in patients aged 4 to 16 years. The safety and effectiveness for use as monotherapy for partial seizures in pediatric patients below the age of 4 have not been established. Oxcarbazepine tablets has been given to 898 patients between the ages of 1 month to 17 years in controlled clinical trials (332 treated as monotherapy) and about 677 patients between the ages of 1 month to 17 years in other trials [see Warnings and Precautions ( 5.11 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), and Clinical Studies ( 14 )]. 8.5 Geriatric Use There were 52 patients over age 65 in controlled clinical trials and 565 patients over the age of 65 in other trials. Following administration of single (300 mg) and multiple (600 mg/day) doses of oxcarbazepine tablets in elderly volunteers (60 to 82 years of age), the maximum plasma concentrations and AUC values of MHD were 30% to 60% higher than in younger volunteers (18 to 32 years of age). Comparisons of creatinine clearance in young and elderly volunteers indicate that the difference was due to age-related reductions in creatinine clearance. Close monitoring of sodium levels is required in elderly patients at risk for hyponatremia [seeWarnings and Precautions ( 5.1 )]. 8.6 Renal Impairment Dose adjustment is recommended for renally impaired patients (CLcr <30 mL/min) [see Dosage and Administration ( 2.7 ) and Clinical Pharmacology ( 12.3 )].

16 HOW SUPPLIED/STORAGE AND HANDLING Oxcarbazepine Tablets, USP are provided as: 150 mg Film-Coated Tablets: beige, film-coated, modified oval shaped tablet, scored on both sides, debossed "B2 | 92" on one side and plain on the other side. Available: Overbagged with 10 tablets per bag, NDC 55154-8187-0 300 mg Film-Coated Tablets : beige, film-coated, modified oval shaped tablet, scored on both sides, debossed "B | 293" on one side and plain on the other side. Available: Overbagged with 10 tablets per bag, NDC 55154-8198-0 Store at 20°-25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. FOR YOUR PROTECTION: Do not use if blister is torn or broken.

Store at 20°-25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. FOR YOUR PROTECTION: Do not use if blister is torn or broken.