ADVERSE REACTIONS SECTION.

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 Annora Pharma Private Limited at 1-866-495-1995 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 drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Most Common Adverse Reactions in All Clinical Studies Adjunctive Therapy/Monotherapy in Adults Previously Treated with Other AEDs The most common (>=10% more than placebo for adjunctive or low dose for monotherapy) adverse reactions with oxcarbazepine: dizziness, somnolence, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision, headache, nystagmus tremor, and abnormal gait. Approximately 23% of these 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 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 Years Old and Above Previously Treated with Other AEDs The most common (>=5%) adverse reactions with oxcarbazepine in these patients were similar to those seen in adults. Approximately 11% of these 456 pediatric patients discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were: somnolence (2.4%), vomiting (2.0%), ataxia (1.8%), diplopia (1.3%), dizziness (1.3%), fatigue (1.1%), nystagmus (1.1%). Monotherapy in Pediatric Patients Years Old and Above Not Previously Treated with Other AEDs The most common (>=5%) adverse reactions with oxcarbazepine in these patients were similar to those in adults. Approximately 9.2% of 152 pediatric patients discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated (>=1%) with discontinuation were rash (5.3%) and maculopapular rash (1.3%). Adjunctive Therapy/Monotherapy in Pediatric Patients Month to <4 Years Old Previously Treated or Not Previously Treated with Other AEDs: The most common (>=5%) adverse reactions with oxcarbazepine in these patients were similar to those seen in older children and adults except for infections and infestations which were more frequently seen in these younger children. 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 lists adverse reactions that occurred in at least 2% of adult patients with epilepsy, treated with oxcarbazepine or placebo as adjunctive treatment and were numerically more common in the patients treated with any dose of oxcarbazepine. Table lists adverse reactions in patients converted from other AEDs to either high-dose oxcarbazepine (2400 mg/day) or low-dose (300 mg/day) oxcarbazepine. Note that in some of these monotherapy studies patients who dropped out during preliminary tolerability phase are not included in the tables. Table 3: Adverse Reactions in Controlled Clinical Study of Adjunctive Therapy with Oxcarbazepine in Adults Body System/ Adverse Reaction Oxcarbazepine Dosage (mg/day) Oxcarbazepine 600 N=163 Oxcarbazepine 1200 N=171 Oxcarbazepine 2400 N=126 Placebo N=166 Body as Whole Fatigue 15 12 15 Asthenia 3 5 Leg Edema 1 1 Increased Weight 2 1 Feeling Abnormal 1 0 Cardiovascular System Hypotension 1 0 Digestive System Nausea 15 25 29 10 Vomiting 13 25 36 Abdominal Pain 10 13 11 Diarrhea 6 6 Dyspepsia 5 2 Constipation 2 4 Gastritis 1 1 Metabolic and Nutritional Disorders Hyponatremia 1 1 Musculoskeletal System Muscle Weakness 2 0 Sprains and Strains 2 1 Nervous System Headache 32 28 26 23 Dizziness 26 32 49 13 Somnolence 20 28 36 12 Ataxia 17 31 Nystagmus 20 26 Abnormal Gait 10 17 Insomnia 2 1 Tremor 8 16 Nervousness 4 1 Agitation 1 1 Abnormal Coordination 3 1 Abnormal EEG 0 0 Speech Disorder 1 0 Confusion 1 1 Cranial Injury NOS 0 1 Dysmetria 2 0 Abnormal Thinking 2 0 Respiratory System Rhinitis 4 4 Skin and Appendages Acne 2 0 Special Senses Diplopia 14 30 40 Vertigo 12 15 Abnormal Vision 14 13 Abnormal Accommodation 0 0 Table 4: Adverse Reactions in Controlled Clinical Studies of Monotherapy with Oxcarbazepine in Adults Previously Treated with Other AEDs Body System/ Adverse Reaction Oxcarbazepine 2400 mg/day N=86 Oxcarbazepine 300 mg/day N=86 Body as Whole Fatigue 21 Fever 0 Allergy 0 Generalized Edema 1 Chest Pain 0 Digestive System Nausea 22 Vomiting 15 Diarrhea 5 Dyspepsia 1 Anorexia 3 Abdominal Pain 3 Dry Mouth 0 Hemorrhage Rectum 0 Toothache 1 Hemic and Lymphatic System Lymphadenopathy 0 Infections and Infestations Viral Infection 5 Infection 0 Metabolic and Nutritional Disorders Hyponatremia 0 Thirst 0 Nervous System Headache 31 15 Dizziness 28 Somnolence 19 Anxiety 5 Ataxia 1 Confusion 0 Nervousness 0 Insomnia 3 Tremor 3 Amnesia 1 Aggravated Convulsions 2 Emotional Lability 2 Hypoesthesia 1 Abnormal Coordination 1 Nystagmus 0 Speech Disorder 0 Respiratory System Upper Respiratory Tract Infection 10 Coughing 0 Bronchitis 0 Pharyngitis 0 Skin and Appendages Hot Flushes 1 Purpura 0 Special Senses Abnormal Vision 14 Diplopia 12 Taste Perversion 0 Vertigo 0 Earache 1 Ear Infection NOS 0 Urogenital and Reproductive System Urinary Tract Infection 1 Micturition Frequency 1 Vaginitis 0 Controlled Clinical Study of Monotherapy in Adults Not Previously Treated with Other AEDs Table lists adverse reactions in 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 or placebo and were numerically more common in the patients treated with oxcarbazepine. Table 5: Adverse Reactions in Controlled Clinical Study of Monotherapy with Oxcarbazepine in Adults Not Previously Treated with Other AEDs Body System/ Adverse Reaction Oxcarbazepine N=55 Placebo N=49 Body as Whole Falling Down NOS 0 Digestive System Nausea 16 12 Diarrhea 2 Vomiting 6 Constipation 0 Dyspepsia 4 Musculoskeletal System Back Pain 2 Nervous System Dizziness 22 Headache 13 10 Ataxia 0 Nervousness 2 Amnesia 2 Abnormal Coordination 2 Tremor 0 Respiratory System Upper Respiratory Tract Infection 0 Epistaxis 0 Infection Chest 0 Sinusitis 2 Skin and Appendages Rash 2 Special Senses Vision Abnormal 0 Controlled Clinical Studies of Adjunctive Therapy/Monotherapy in Pediatric Patients Previously Treated with Other AEDs Table lists adverse reactions that occurred in at least 2% of pediatric patients with epilepsy treated with oxcarbazepine or placebo as adjunctive treatment and were numerically more common in the patients treated with oxcarbazepine. Table 6: Adverse Reactions in Controlled Clinical Studies of Adjunctive Therapy/Monotherapy with Oxcarbazepine in Pediatric Patients Previously Treated with Other AEDs Body System/ Adverse Reaction Oxcarbazepine N=171 Placebo N=139 Body as Whole Fatigue 13 Allergy 0 Asthenia 1 Digestive System Vomiting 33 14 Nausea 19 Constipation 1 Dyspepsia 0 Nervous System Headache 31 19 Somnolence 31 13 Dizziness 28 Ataxia13 Nystagmus 1 Emotional Lability 4 Abnormal Gait 3 Tremor 4 Speech Disorder 1 Impaired Concentration 1 Convulsions 1 Involuntary Muscle Contractions 1 Respiratory System Rhinitis 10 Pneumonia 1 Skin and Appendages Bruising 2 Increased Sweating 0 Special Senses Diplopia 17 Abnormal Vision 13 Vertigo 0Other Events Observed in Association with the Administration of Oxcarbazepine In the paragraphs that follow, the adverse reactions, other than those in the preceding tables or text, that occurred in total of 565 children and 1,5 74 adults exposed to oxcarbazepine 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 in their causation cannot be reliably determined. Body as 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 [see Warnings and Precautions 5.1)]. Experience from clinical trials indicates that serum sodium levels return toward normal when the oxcarbazepine dosage is reduced or discontinued, or when the patient was treated conservatively (e.g., fluid restriction). Laboratory data from clinical trials suggest that oxcarbazepine use was associated with decreases in 4, without changes in 3 or TSH. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of oxcarbazepine. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Body as 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. Injury, Poisoning, and Procedural Complications: fall Nervous System Disorders: dysarthria.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The pharmacological activity of oxcarbazepine 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 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 days and 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 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 hours, while the half-life of MHD is about 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 max was 4.5 (range to 13) hours. After single-dose administration of oxcarbazepine oral suspension to healthy male volunteers under fasted conditions, the median max was hours. Steady-state plasma concentrations of MHD are reached within to days in patients when oxcarbazepine is given twice 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. Although not directly studied, the oral bioavailability of the oxcarbazepine suspension is unlikely to be affected under fed conditions. Therefore, oxcarbazepine tablets and suspension 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. 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 hours, while the half-life of MHD is about hours. Specific Populations Geriatrics Following administration of single (300 mg) and multiple (600 mg/day) doses of oxcarbazepine 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 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 similar weight-adjusted dose. The mean weight-adjusted clearance in children 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 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 linear correlation between creatinine clearance and the renal clearance of MHD. When oxcarbazepine is administered as 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 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 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. 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 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 subgroup of the cytochrome P450 3A family (CYP3A4 and CYP3A5) responsible for the metabolism of dihydropyridine calcium antagonists, oral contraceptives and cyclosporine resulting in 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 and other AEDs were assessed in clinical studies. The effect of these interactions on mean AUCs and min are summarized in Table [see Drug Interactions 7.1, 7.2)]. Table 7: Summary of AED Interactions with Oxcarbazepine AED Coadministered Dose of AED (mg/day) Oxcarbazepine Dose (mg/day) Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval) Carbamazepine 400-2000 900 nc 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 1,2 up to 40% increase [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 1nc denotes mean change of less than 10% 2Pediatrics 3Mean increase in adults at high oxcarbazepine doses Hormonal Contraceptives Coadministration of oxcarbazepine 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, the AUC of felodipine was lowered by 28% [90% CI: 20 to 33]. Verapamil produced 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The effectiveness of oxcarbazepine as adjunctive and monotherapy for partial-onset seizures in adults, and as adjunctive therapy in children aged to 16 years was established in seven multicenter, randomized, controlled trials. The effectiveness of oxcarbazepine as monotherapy for partial-onset seizures in children aged to 16 years was determined from data obtained in the studies described, as well as by pharmacokinetic/pharmacodynamic considerations. 14.1 Oxcarbazepine Monotherapy Trials. Four randomized, controlled, double-blind, multicenter trials, conducted in predominately adult population, demonstrated the efficacy of oxcarbazepine as monotherapy. Two trials compared oxcarbazepine to placebo and trials used randomized withdrawal design to compare high dose (2400 mg) with low dose (300 mg) of oxcarbazepine, after substituting oxcarbazepine 2400 mg/day for or more antiepileptic drugs (AEDs). All doses were administered on twice-a-day schedule. fifth randomized, controlled, rater-blind, multicenter study, conducted in pediatric population, failed to demonstrate statistically significant difference between low and high dose oxcarbazepine treatment groups. One placebo-controlled trial was conducted in 102 patients (11 to 62 years of age) with refractory partial-onset seizures who had completed an inpatient evaluation for epilepsy surgery. Patients had been withdrawn from all AEDs and were required to have to 10 partial-onset seizures within 48 hours prior to randomization. Patients were randomized to receive either placebo or oxcarbazepine given as 1500 mg/day on Day and 2400 mg/day thereafter for an additional days, or until of the following exit criteria occurred: 1) the occurrence of fourth partial-onset seizure, excluding Day 1, 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 between-group comparison of the time to meet exit criteria. There was statistically significant difference in favor of oxcarbazepine (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, initiated at 300 mg twice day and titrated to 1200 mg/day (given as 600 mg twice day) in days, followed by maintenance treatment for 84 days. The primary measure of effectiveness was between-group comparison of the time to first seizure. The difference between the treatments was statistically significant in favor of oxcarbazepine (see Figure 2), p=0.046. Figure 2: Kaplan-Meier Estimates of First Seizure Event Rate by Treatment Group third trial substituted oxcarbazepine monotherapy at 2400 mg/day for carbamazepine in 143 patients (12 to 65 years of age) whose partial-onset seizures were inadequately controlled on carbamazepine (CBZ) monotherapy at stable dose of 800 to 1600 mg/day, and maintained this oxcarbazepine dose for 56 days (baseline phase). Patients who were able to tolerate titration of oxcarbazepine to 2400 mg/day during simultaneous carbamazepine withdrawal were randomly assigned to either 300 mg/day of oxcarbazepine or 2400 mg/day oxcarbazepine. Patients were observed for 126 days or until of the following exit criteria occurred: 1) doubling of the 28-day seizure frequency compared to baseline, 2) 2-fold increase in the highest consecutive 2-day seizure frequency during baseline, 3) single generalized seizure if none had occurred during baseline, or 4) prolonged generalized seizure. The primary measure of effectiveness was between-group comparison of the time to meet exit criteria. The difference between the curves was statistically significant in favor of the oxcarbazepine 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 or AEDs. Patients were randomized to either oxcarbazepine 2400 mg/day or 300 mg/day and their standard AED regimen(s) were eliminated over the first weeks of double-blind therapy. Double-blind treatment continued for another 84 days (total double-blind treatment of 126 days) or until of the exit criteria described for the previous study occurred. The primary measure of effectiveness was between-group comparison of the percentage of patients meeting exit criteria. The results were statistically significant in favor of the oxcarbazepine 2400 mg/day group (14/34; 41.2%) compared to the oxcarbazepine 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 2400 mg/day group (see Figure 4), p=0.0001. Figure 4: Kaplan-Meier Estimates of Exit Rate by Treatment Group 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 10 mg/kg/day or were titrated up to 40 to 60 mg/kg/day within days while withdrawing the previous AED on the second day of oxcarbazepine. Seizures were recorded through continuous video-EEG monitoring from Day to Day 5. Patients either completed the 5- day treatment or met of the exit criteria: 1) three study-specific seizures (i.e., electrographic partial-onset seizures with behavioral correlate), 2) prolonged study-specific seizure. The primary measure of effectiveness was 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 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 years old and older. oxcarbazepinetabfig1. oxcarbazepinetabfig2. oxcarbazepinetabfig3. oxcarbazepinetabfig4. 14.2 Oxcarbazepine Adjunctive Therapy Trials. The effectiveness of oxcarbazepine as an adjunctive therapy for partial-onset seizures was established in 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 doses of oxcarbazepine in 128 pediatric patients (1 month to <4 years of age). Patients in the placebo-controlled trials were on to 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 (minimum of to per month) partial-onset seizures during the baseline phase were randomly assigned to placebo or to specific dose of oxcarbazepine in addition to their other AEDs. In these studies, the dose was increased over 2-week period until either the assigned dose was reached, or intolerance prevented increases. Patients then entered 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 between-group comparison of the percentage change in partial-onset seizure frequency in the double-blind treatment phase relative to baseline phase. This comparison was statistically significant in favor of oxcarbazepine 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-Onset Seizure Frequency from Baseline for Placebo-Controlled Adjunctive Therapy Trials Trial Treatment Group Baseline Median Seizure Rate Median Reduction (pediatrics) Oxcarbazepine 136 12.5 34.8 Placebo 128 13.1 9.4 (adults) Oxcarbazepine 2400 mg/day 174 10.0 49.9 Oxcarbazepine 1200 mg/day 177 9.8 40.2 Oxcarbazepine 600 mg/day 168 9.6 26.4 Placebo 173 8.6 7.6 p=0.0001; number of seizures per 28 days Subset analyses of the antiepileptic efficacy of oxcarbazepine 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-onset seizures on to concomitant AEDs. Patients who experienced at least study-specific seizures (i.e., electrographic partial-onset seizures with behavioral correlate) during the 72-hour baseline period were randomly assigned to either oxcarbazepine 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 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 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 60 mg/kg/day. In this study, there was no evidence that oxcarbazepine was effective in patients below the age of years (N=75).

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Adults: initiate with 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 to weeks; reach maximum dose of oxcarbazepine tablets in to weeks with increments of 600 mg/day at weekly intervals to recommended daily dose of 2400 mg/day 2.2) Initiation of Monotherapy: Increments of 300 mg/day every third day to dose of 1200 mg/day 2.3) Initiate at one-half the usual starting dose and increase slowly in patients with creatinine clearance <30 mL/min, 2.7) Pediatrics: initiation with to 10 mg/kg/day, given twice-a-day. For patients aged to <4 years and under 20 kg, starting dose of 16 to 20 mg/kg/day may be considered. Recommended daily dose is dependent upon patient weight. Adjunctive Patients (Aged to 16 Years): For patients aged to 16 years, target maintenance dose should be achieved over weeks 2.4). For patients aged to <4 years, maximum maintenance dose should be achieved over to weeks and should not to exceed 60 mg/kg/day 2.4) Conversion to Monotherapy for Patients (Aged to 16 Years) Maximum increment of 10 mg/kg/day at weekly intervals, concomitant antiepileptic drugs can be completely withdrawn over to weeks 2.5) Initiation of Monotherapy for Patients (Aged to 16 Years) Increments of mg/kg/day every third day 2.6) 2.1 Adjunctive Therapy for Adults. Initiate oxcarbazepine tablets with dose of 600 mg/day, given twice-a-day. If clinically indicated, the dose may be increased by maximum of 600 mg/day at approximately weekly intervals; the maximum recommended daily dose is 1200 mg/day. Daily doses above 1200 mg/day show somewhat greater effectiveness in controlled trials, but most patients were not able to tolerate the 2400 mg/day dose, primarily because of 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 twice-a-day regimen) while simultaneously initiating the reduction of the dose of the concomitant AEDs. The concomitant AEDs should be completely withdrawn over to weeks, while the maximum dose of oxcarbazepine tablets should be reached in about to weeks. Oxcarbazepine tablets may be increased as clinically indicated by maximum increment of 600 mg/day at approximately weekly intervals to achieve the maximum recommended daily dose of 2400 mg/day. 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 dose of 600 mg/day (given twice-a-day); the dose should be increased by 300 mg/day every third day to dose of 1200 mg/day. Controlled trials in these patients examined the effectiveness of 1200 mg/day dose; 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 to 16 Years). In pediatric patients aged to 16 years, initiate oxcarbazepine tablets at daily dose of 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 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 range of to 51 mg/kg. In pediatric patients aged to <4 years, initiate oxcarbazepine tablets at daily dose of to 10 mg/kg generally not to exceed 600 mg/day, given twice-a-day. For patients less than 20 kg, 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 to weeks and should not exceed 60 mg/kg/day in twice-a-day regimen. In the clinical trial in pediatric patients (2 to years of age) in which the intention was to reach the target dose of 60 mg/kg/day, 50% of patients reached 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 to <4 years of age may require up to twice the oxcarbazepine dose per body weight compared to adults; and children to <=12 years of age may require 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 to 16 Years). Patients receiving concomitant antiepileptic drugs may be converted to monotherapy by initiating treatment with oxcarbazepine tablets at approximately 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 to weeks while oxcarbazepine tablets may be increased as clinically indicated by 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 to 16 Years). Patients not currently being treated with antiepileptic drugs may have monotherapy initiated with oxcarbazepine tablets. In these patients, initiate oxcarbazepine tablets at dose of to 10 mg/kg/day given twice-a-day. The dose should be increased by 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 Weight in kg From To 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) ]. Oxcarbazepine oral suspension and oxcarbazepine tablets may be interchanged at equal doses.

PHARMACOKINETICS SECTION.

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 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 hours, while the half-life of MHD is about 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 max was 4.5 (range to 13) hours. After single-dose administration of oxcarbazepine oral suspension to healthy male volunteers under fasted conditions, the median max was hours. Steady-state plasma concentrations of MHD are reached within to days in patients when oxcarbazepine is given twice 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. Although not directly studied, the oral bioavailability of the oxcarbazepine suspension is unlikely to be affected under fed conditions. Therefore, oxcarbazepine tablets and suspension 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. 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 hours, while the half-life of MHD is about hours. Specific Populations Geriatrics Following administration of single (300 mg) and multiple (600 mg/day) doses of oxcarbazepine 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 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 similar weight-adjusted dose. The mean weight-adjusted clearance in children 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 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 linear correlation between creatinine clearance and the renal clearance of MHD. When oxcarbazepine is administered as 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 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 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. 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 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 subgroup of the cytochrome P450 3A family (CYP3A4 and CYP3A5) responsible for the metabolism of dihydropyridine calcium antagonists, oral contraceptives and cyclosporine resulting in 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 and other AEDs were assessed in clinical studies. The effect of these interactions on mean AUCs and min are summarized in Table [see Drug Interactions 7.1, 7.2)]. Table 7: Summary of AED Interactions with Oxcarbazepine AED Coadministered Dose of AED (mg/day) Oxcarbazepine Dose (mg/day) Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval) Carbamazepine 400-2000 900 nc 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 1,2 up to 40% increase [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 1nc denotes mean change of less than 10% 2Pediatrics 3Mean increase in adults at high oxcarbazepine doses Hormonal Contraceptives Coadministration of oxcarbazepine 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, the AUC of felodipine was lowered by 28% [90% CI: 20 to 33]. Verapamil produced 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.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure Registry There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as oxcarbazepine, during pregnancy. Encourage women who are taking oxcarbazepine during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/. Risk Summary There are no adequate data on the developmental risks associated with the use of oxcarbazepine in pregnant women; however, oxcarbazepine is closely related structurally to carbamazepine, which is considered to be teratogenic in humans. Data on limited number of pregnancies from pregnancy registries suggest that oxcarbazepine monotherapy use is associated with congenital malformations (e.g., craniofacial defects such as oral clefts, and cardiac malformations such as ventricular septal defects). Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity (embryolethality, growth retardation) were observed in the offspring of animals treated with either oxcarbazepine or its active 10-hydroxy metabolite (MHD) during pregnancy at doses similar to the maximum recommended human dose (MRHD). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations An increase in seizure frequency may occur during pregnancy because of altered levels of the active metabolite of oxcarbazepine. Monitor patients carefully during pregnancy and through the postpartum period [see Warnings and Precautions 5.10)]. Data Human Data Data from published registries have reported craniofacial defects such as oral clefts and cardiac malformations such as ventricular septal defects in children with prenatal oxcarbazepine exposure. Animal Data When pregnant rats were given oxcarbazepine (0, 30, 300, or 1000 mg/kg/day) orally throughout the period of organogenesis, increased incidences of fetal malformations (craniofacial, cardiovascular, and skeletal) and variations were observed at the intermediate and high doses (approximately 1.2 and times, respectively, the MRHD on mg/m basis). Increased embryofetal death and decreased fetal body weights were seen at the high dose. Doses >=300 mg/kg/day 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 study in which pregnant rabbits were orally administered MHD (0, 20, 100, or 200 mg/kg/day) during organogenesis, embryofetal mortality was increased at the highest dose (1.5 times the MRHD on mg/m2 basis). This dose produced only minimal maternal toxicity. In study in which female rats were dosed orally with oxcarbazepine (0, 25, 50, or 150 mg/kg/day) during the latter part of gestation and throughout the lactation period, persistent reduction in body weights and altered behavior (decreased activity) were observed in offspring exposed to the highest dose (less than the MRHD on mg/m basis). Oral administration of MHD (0, 25, 75, or 250 mg/kg/day) to rats during gestation and lactation resulted in persistent reduction in offspring weights at the highest dose (equivalent to the MRHD on mg/m basis).

INFORMATION FOR PATIENTS SECTION.

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 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 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 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) and Use in Specific Populations 8.1)] 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 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)]. Manufactured for: Camber Pharmaceuticals, Inc. Piscataway, NJ 08854 By: Annora Pharma Pvt. Ltd. Sangareddy 502313, Telangana, India. Revised: 01/2022. oxcarbazipinetabcamberlogo1.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. o Pregnancy: May cause fetal harm 8.1) 8.1 Pregnancy. Pregnancy Exposure Registry There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as oxcarbazepine, during pregnancy. Encourage women who are taking oxcarbazepine during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/. Risk Summary There are no adequate data on the developmental risks associated with the use of oxcarbazepine in pregnant women; however, oxcarbazepine is closely related structurally to carbamazepine, which is considered to be teratogenic in humans. Data on limited number of pregnancies from pregnancy registries suggest that oxcarbazepine monotherapy use is associated with congenital malformations (e.g., craniofacial defects such as oral clefts, and cardiac malformations such as ventricular septal defects). Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity (embryolethality, growth retardation) were observed in the offspring of animals treated with either oxcarbazepine or its active 10-hydroxy metabolite (MHD) during pregnancy at doses similar to the maximum recommended human dose (MRHD). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations An increase in seizure frequency may occur during pregnancy because of altered levels of the active metabolite of oxcarbazepine. Monitor patients carefully during pregnancy and through the postpartum period [see Warnings and Precautions 5.10)]. Data Human Data Data from published registries have reported craniofacial defects such as oral clefts and cardiac malformations such as ventricular septal defects in children with prenatal oxcarbazepine exposure. Animal Data When pregnant rats were given oxcarbazepine (0, 30, 300, or 1000 mg/kg/day) orally throughout the period of organogenesis, increased incidences of fetal malformations (craniofacial, cardiovascular, and skeletal) and variations were observed at the intermediate and high doses (approximately 1.2 and times, respectively, the MRHD on mg/m basis). Increased embryofetal death and decreased fetal body weights were seen at the high dose. Doses >=300 mg/kg/day 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 study in which pregnant rabbits were orally administered MHD (0, 20, 100, or 200 mg/kg/day) during organogenesis, embryofetal mortality was increased at the highest dose (1.5 times the MRHD on mg/m2 basis). This dose produced only minimal maternal toxicity. In study in which female rats were dosed orally with oxcarbazepine (0, 25, 50, or 150 mg/kg/day) during the latter part of gestation and throughout the lactation period, persistent reduction in body weights and altered behavior (decreased activity) were observed in offspring exposed to the highest dose (less than the MRHD on mg/m basis). Oral administration of MHD (0, 25, 75, or 250 mg/kg/day) to rats during gestation and lactation resulted in persistent reduction in offspring weights at the highest dose (equivalent to the MRHD on mg/m basis). 8.2 Lactation. Risk Summary Oxcarbazepine and its active metabolite (MHD) are present in human milk after oxcarbazepine administration. The effects of oxcarbazepine and its active metabolite (MHD) on the breastfed infant or on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for oxcarbazepine and any potential adverse effects on the breastfed infant from oxcarbazepine or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential. Contraception Use of oxcarbazepine with hormonal contraceptives containing ethinylestradiol or levonorgestrel is associated with decreased plasma concentrations of these hormones and may result in failure of the therapeutic effect of the oral contraceptive drug. Advise women of reproductive potential taking oxcarbazepine who are using contraceptive containing ethinylestradiol or levonorgestrel to use additional or alternative non-hormonal birth control [see Drug interactions 7.3) and Clinical Pharmacology 12.3)]. 8.4 Pediatric Use. Oxcarbazepine is indicated for use as adjunctive therapy for partial-onset seizures in patients aged to 16 years. The safety and effectiveness for use as adjunctive therapy for partial-onset seizures in pediatric patients below the age of have not been established. Oxcarbazepine is also indicated as monotherapy for partial-onset seizures in patients aged to 16 years. The safety and effectiveness for use as monotherapy for partial-onset seizures in pediatric patients below the age of have not been established. Oxcarbazepine has been given to 898 patients between the ages of month to 17 years in controlled clinical trials (332 treated as monotherapy) and about 677 patients between the ages of 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 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 see Warnings 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) ].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. o Hyponatremia: Monitor serum sodium levels 5.1) Cross Hypersensitivity Reaction to Carbamazepine: Discontinue immediately if hypersensitivity occurs 5.3) Serious Dermatological Reactions: If occurs consider discontinuation 5.4) Suicidal Behavior and Ideation: Monitor for suicidal thoughts/ behavior 5.5) Withdrawal of AEDs: Withdraw oxcarbazepine gradually 5.6) Cognitive/Neuropsychiatric Adverse Reactions: May cause cognitive dysfunction, somnolence, coordination abnormalities. Use caution when operating machinery 5.7) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity: Monitor and discontinue if another cause cannot be established 5.8) Hematologic Events: Consider discontinuing 5.9) Seizure Control During Pregnancy: Active metabolite may decrease 5.10) Risk of Seizure Aggravation: Discontinue if occurs. 5.11) 5.1 Hyponatremia. Clinically significant hyponatremia (sodium <125 mmol/L) can develop during oxcarbazepine use. In the 14 controlled epilepsy studies 2.5% of oxcarbazepine-treated patients (38/1,524) had sodium of less than 125 mmol/L at some point during treatment, compared to no such patients assigned placebo or active control (carbamazepine and phenobarbital for adjunctive and monotherapy substitution studies, and phenytoin and valproate for the monotherapy initiation studies). Clinically significant hyponatremia generally occurred during the first months of treatment with oxcarbazepine, although there were patients who first developed serum sodium <125 mmol/L more than year after initiation of therapy. Most patients who developed hyponatremia were asymptomatic but patients in the clinical trials were frequently monitored and some had their oxcarbazepine dose reduced, discontinued, or had their fluid intake restricted for hyponatremia. Whether or not these maneuvers prevented the occurrence of more severe events is unknown. Cases of symptomatic hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported during postmarketing use. In clinical trials, patients whose treatment with oxcarbazepine was discontinued due to hyponatremia generally experienced normalization of serum sodium within few days without additional treatment. Measurement of serum sodium levels should be considered for patients during maintenance treatment with oxcarbazepine, particularly if the patient is receiving other medications known to decrease serum sodium levels (e.g., drugs associated with inappropriate ADH secretion) or if symptoms possibly indicating hyponatremia develop (e.g., nausea, malaise, headache, lethargy, confusion, obtundation, or increase in seizure frequency or severity). 5.2 Anaphylactic Reactions and Angioedema. Rare cases of anaphylaxis and angioedema involving the larynx, glottis, lips and eyelids have been reported in patients after taking the first or subsequent doses of oxcarbazepine. Angioedema associated with laryngeal edema can be fatal. If patient develops any of these reactions after treatment with oxcarbazepine, the drug should be discontinued and an alternative treatment started. These patients should not be rechallenged with the drug [see Warnings and Precautions 5.3)]. 5.3 Cross Hypersensitivity Reaction to Carbamazepine. Approximately 25% to 30% of patients who have had hypersensitivity reactions to carbamazepine will experience hypersensitivity reactions with oxcarbazepine. For this reason patients should be specifically questioned about any prior experience with carbamazepine, and patients with history of hypersensitivity reactions to carbamazepine should ordinarily be treated with oxcarbazepine only if the potential benefit justifies the potential risk. If signs or symptoms of hypersensitivity develop, oxcarbazepine should be discontinued immediately [see Warnings and Precautions 5.2, 5.8)]. 5.4 Serious Dermatological Reactions. Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both children and adults in association with oxcarbazepine use. Such serious skin reactions may be life threatening, and some patients have required hospitalization with very rare reports of fatal outcome. The median time of onset for reported cases was 19 days after treatment initiation. Recurrence of the serious skin reactions following rechallenge with oxcarbazepine has also been reported. The reporting rate of TEN and SJS associated with oxcarbazepine use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate estimates by factor of 3- to 10-fold. Estimates of the background incidence rate for these serious skin reactions in the general population range between 0.5 to cases per million-person years. Therefore, if patient develops skin reaction while taking oxcarbazepine, consideration should be given to discontinuing oxcarbazepine use and prescribing another antiepileptic medication. Association with HLA-B1502 Patients carrying the HLA-B1502 allele may be at increased risk for SJS/TEN with oxcarbazepine treatment. Human Leukocyte Antigen (HLA) allele B1502 increases the risk for developing SJS/TEN in patients treated with carbamazepine. The chemical structure of oxcarbazepine is similar to that of carbamazepine. Available clinical evidence, and data from nonclinical studies showing direct interaction between oxcarbazepine and HLA-B1502 protein, suggest that the HLA-B1502 allele may also increase the risk for SJS/TEN with oxcarbazepine. The frequency of HLA-B1502 allele ranges from to 12% in Han Chinese populations, is about 8% in Thai populations, and above 15% in the Philippines and in some Malaysian populations. Allele frequencies up to about 2% and 6% have been reported in Korea and India, respectively. The frequency of the HLA-B1502 allele is negligible in people from European descent, several African populations, indigenous peoples of the Americas, Hispanic populations, and in Japanese (<1%). Testing for the presence of the HLA-B1502 allele should be considered in patients with ancestry in genetically at-risk populations, prior to initiating treatment with oxcarbazepine. The use of oxcarbazepine should be avoided in patients positive for HLA-B1502 unless the benefits clearly outweigh the risks. Consideration should also be given to avoid the use of other drugs associated with SJS/TEN in HLA-B1502 positive patients, when alternative therapies are otherwise equally acceptable. Screening is not generally recommended in patients from populations in which the prevalence of HLAB 1502 is low, or in current oxcarbazepine users, as the risk of SJS/TEN is largely confined to the first few months of therapy, regardless of HLA B1502 status. The use of HLA-B1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been well characterized. 5.5 Suicidal Behavior and Ideation. Antiepileptic drugs (AEDs), including oxcarbazepine, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table shows absolute and relative risk by indication for all evaluated AEDs. Table 2: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1,000 Patients Drug Patients with Events Per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1,000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.Anyone considering prescribing oxcarbazepine or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and 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. 5.6 Withdrawal of AEDs. As with most antiepileptic drugs, oxcarbazepine should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus see Dosage and Administration 2.4) and Clinical Studies 14) ]. But if withdrawal is needed because of serious adverse event, rapid discontinuation can be considered. 5.7 Cognitive/Neuropsychiatric Adverse Reactions. Use of oxcarbazepine has been associated with central nervous system-related adverse reactions. The most significant of these can be classified into general categories: 1) cognitive symptoms including psychomotor slowing, difficulty with concentration, and speech or language problems, 2) somnolence or fatigue, and 3) coordination abnormalities, including ataxia and gait disturbances. Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on oxcarbazepine to gauge whether it adversely affects their ability to drive or operate machinery. Adult Patients In one large, fixed-dose study, oxcarbazepine was added to existing AED therapy (up to three concomitant AEDs). By protocol, the dosage of the concomitant AEDs could not be reduced as oxcarbazepine was added, reduction in oxcarbazepine dosage was not allowed if intolerance developed, and patients were discontinued if unable to tolerate their highest target maintenance doses. In this trial, 65% of patients were discontinued because they could not tolerate the 2400 mg/day dose of oxcarbazepine on top of existing AEDs. The adverse events seen in this study were primarily CNS related and the risk for discontinuation was dose related. In this trial, 7.1% of oxcarbazepine-treated patients and 4% of placebo-treated patients experienced cognitive adverse reaction. The risk of discontinuation for these events was about 6.5 times greater on oxcarbazepine than on placebo. In addition, 26% of oxcarbazepine-treated patients and 12% of placebo-treated patients experienced somnolence. The risk of discontinuation for somnolence was about 10 times greater on oxcarbazepine than on placebo. Finally, 28.7% of oxcarbazepine-treated patients and 6.4% of placebo-treated patients experienced ataxia or gait disturbances. The risk for discontinuation for these events was about times greater on oxcarbazepine than on placebo. In single placebo-controlled monotherapy trial evaluating 2400 mg/day of oxcarbazepine, no patients in either treatment group discontinued double-blind treatment because of cognitive adverse events, somnolence, ataxia, or gait disturbance. In the dose-controlled conversion to monotherapy trials comparing 2400 mg/day and 300 mg/day oxcarbazepine, 1.1% of patients in the 2400 mg/day group discontinued double-blind treatment because of somnolence or cognitive adverse reactions compared to 0% in the 300 mg/day group. In these trials, no patients discontinued because of ataxia or gait disturbances in either treatment group. Pediatric Patients study was conducted in pediatric patients (3 to 17 years old) with inadequately controlled partial-onset seizures in which oxcarbazepine was added to existing AED therapy (up to concomitant AEDs). By protocol, the dosage of concomitant AEDs could not be reduced as oxcarbazepine was added. Oxcarbazepine was titrated to reach target dose ranging from 30 mg/kg to 46 mg/kg (based on patients body weight with fixed doses for predefined weight ranges). Cognitive adverse events occurred in 5.8% of oxcarbazepine-treated patients (the single most common event being concentration impairment, of 138 patients) and in 3.1% of patients treated with placebo. In addition, 34.8% of oxcarbazepine-treated patients and 14.0% of placebo-treated patients experienced somnolence. (No patient discontinued due to cognitive adverse reaction or somnolence.). Finally, 23.2% of oxcarbazepine-treated patients and 7.0% of placebo-treated patients experienced ataxia or gait disturbances. Two (1.4%) oxcarbazepine-treated patients and (0.8%) placebo-treated patient discontinued due to ataxia or gait disturbances. 5.8 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, has occurred with oxcarbazepine. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Oxcarbazepine should be discontinued if an alternative etiology for the signs or symptoms cannot be established.. 5.9 Hematologic Events. Rare reports of pancytopenia, agranulocytosis, and leukopenia have been seen in patients treated with oxcarbazepine during postmarketing experience. Discontinuation of the drug should be considered if any evidence of these hematologic events develops.. 5.10 Seizure Control During Pregnancy. Due to physiological changes during pregnancy, plasma levels of the active metabolite of oxcarbazepine, the 10-monohydroxy derivative (MHD), may gradually decrease throughout pregnancy. It is recommended that patients be monitored carefully during pregnancy. Close monitoring should continue through the postpartum period because MHD levels may return after delivery.. 5.11 Risk of Seizure Aggravation. Exacerbation of or new onset primary generalized seizures has been reported with oxcarbazepine. The risk of aggravation of primary generalized seizures is seen especially in children but may also occur in adults. In case of seizure aggravation, oxcarbazepine should be discontinued.