Topiramate

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more detail in other sections of the labeling: Acute Myopia and Secondary Angle Closure Glaucoma [see Warnings and Precautions ( 5.1 )] Visual Field Defects [see Warnings and Precautions ( 5.2 )] Oligohydrosis and Hyperthermia [see Warnings and Precautions ( 5.3 )] Metabolic Acidosis [see Warnings and Precautions ( 5.4 )] Interaction With Alcohol [see Warnings and Precautions ( 5.5 )] Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.6 )] Cognitive/Neuropsychiatric Adverse Reactions [see Warnings and Precautions ( 5.7 )] Fetal Toxicity [see Warnings and Precautions ( 5.8 )] Withdrawal of Antiepileptic Drugs [see Warnings and Precautions ( 5.9 )] Decrease of Bone Mineral Density [see Warnings and Precautions ( 5.10 )] Negative Effects on Growth (Height and Weight) [see Warnings and Precautions ( 5.11 )] Serious Skin Reactions [see Warnings and Precautions ( 5.12 )] Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use) [see Warnings and Precautions ( 5.13 )] Kidney Stones [see Warnings and Precautions ( 5.14 )] Hypothermia With Concomitant Valproic Acid Use [see Warnings and Precautions ( 5.15 )] The data described in the following sections were obtained using immediate-release topiramate tablets. Topiramate extended-release capsules have not been studied in a randomized, placebo-controlled Phase III clinical study; however, it is expected that topiramate extended-release capsules would produce a similar adverse reaction profile as immediate-release topiramate. Epilepsy: Most common (greater than or equal to 10% more frequent than placebo or low-dose topiramate) adverse reactions in adult and pediatric patients were paresthesia, anorexia, weight loss, speech disorders/related speech problems, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, abnormal vision, and fever ( 6.1 ). Migraine: Most common (greater than or equal to 5% more frequent than placebo) adverse reactions in adult and pediatric patients were: paresthesia, anorexia, weight loss, difficulty with memory, taste perversion, diarrhea, hypoesthesia, nausea, abdominal pain, and upper respiratory track infection ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Ajanta Pharma USA, Inc., at 1-855-664-7744 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. Monotherapy Epilepsy Adults 16 Years of Age and Older The most common adverse reactions in the controlled trial (Study 1) that occurred in adults in the 400 mg/day topiramate group and at an incidence higher (greater than or equal to 10%) than in the 50 mg per day group were: paresthesia, weight loss, and anorexia (see Table 3). Approximately 21% of the 159 adult patients in the 400 mg/day group who received topiramate as monotherapy in Study 1 discontinued therapy due to adverse reactions. The most common (greater than or equal to 2% more frequent than low- dose 50 mg/day topiramate) adverse reactions causing discontinuation were difficulty with memory, fatigue, asthenia, insomnia, somnolence, and paresthesia. Pediatric Patients 6 Years to 15 Years of Age The most common adverse reactions in the controlled trial (Study 1) that occurred in pediatric patients in the 400 mg/day topiramate group and at an incidence higher (greater than or equal to 10%) than in the 50 mg/day group were fever and weight loss (see Table 3). Approximately 14% of the 77 pediatric patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. The most common (greater than or equal to 2% more frequent than in the 50 mg/day group) adverse reactions resulting in discontinuation in this trial were difficulty with concentration/attention, fever, flushing, and confusion. Table 3 represents the incidence of adverse reactions occurring in at least 3% of adult and pediatric patients treated with 400 mg/day immediate-release topiramate and occurring with greater incidence than 50 mg/day topiramate. Table 3: Adverse Reactions in the High Dose Group as Compared to the Low Dose Group, in Monotherapy Epilepsy Trial in Adult and Pediatric Patients Age Group Pediatric Adult (6 to 15 Years) (Age greater than or equal to 16 Years) Immediate-release Topiramate Daily Dosage Group (mg/day) 50 400 50 400 Body System/ Adverse Reaction (N=74) % (N=77) % (N=160) % (N=159) % Body as a Whole-General Disorders Asthenia 0 3 4 6 Fever 1 12 Leg pain 2 3 Central & Peripheral Nervous System Disorders Paresthesia 3 12 21 40 Dizziness 13 14 Ataxia 3 4 Hypoesthesia 4 5 Hypertonia 0 3 Involuntary Muscle contraction 0 3 Vertigo 0 3 Gastro-intestinal System Disorders Constipation 1 4 Diarrhea 8 9 Gastritis 0 3 Dry mouth 1 3 Liver and Biliary System Disorders Increase in Gamma-GT 1 3 Metabolic and Nutritional Disorders Weight loss 7 17 6 17 Platelet, Bleeding & Clotting Disorders Epistaxis 0 4 Psychiatric Disorders Anorexia 4 14 Anxiety 4 6 Cognitive problems 1 6 1 4 Confusion 0 3 Depression 0 3 7 9 Difficulty with concentration or attention 7 10 7 8 Difficulty with memory 1 3 6 11 Insomnia 8 9 Decrease in libido 0 3 Mood problems 1 8 2 5 Personality disorder (behavior problems) 0 3 Psychomotor slowing 3 5 Somnolence 10 15 Red Blood Cell Disorders Anemia 1 3 Reproductive Disorders, Female Intermenstrual bleeding 0 3 Vaginal hemorrhage 0 3 Resistance Mechanism Disorders Infection 3 8 2 3 Viral infection 3 6 6 8 Respiratory System Disorders Bronchitis 1 5 3 4 Upper respiratory tract infection 16 18 Rhinitis 5 6 2 4 Sinusitis 1 4 Skin and Appendages Disorders Alopecia 1 4 3 4 Pruritus 1 4 Rash 3 4 1 4 Acne 2 3 Special Senses Other, Disorders Taste perversion 3 5 Urinary System Disorders Cystitis 1 3 Micturition frequency 0 3 0 2 Renal calculus 0 3 Urinary incontinence 1 3 Vascular (Extracardiac) Disorders Flushing 0 5 Ajunctive Therapy Epilepsy Adults 16 Years of Age and Older In pooled controlled clinical trials in adults with partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, 183 patients received adjunctive therapy with immediate-release topiramate at dosages of 200 mg/day to 400 mg/day (recommended dosage range), and 291 patients received placebo. Patients in these trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to immediate-release topiramate or placebo. The most common adverse reactions in the controlled clinical trial that occurred in adult patients in the 200 mg/day to 400 mg/day topiramate group with an incidence higher (greater than or equal to 10%) than in the placebo group were: dizziness, speech disorders/related speech problems, somnolence, nervousness, psychomotor slowing, and vision abnormal (see Table 4) [see Clinical Studies ( 14.3 )] . Table 4 presents the incidence of adverse reactions occurring in at least 3% of adult patients treated with 200 mg/day to 400 mg/day topiramate and was greater than placebo incidence. The incidence of some adverse reactions (e.g., fatigue, dizziness, paresthesia, language problems, psychomotor slowing, depression, difficulty with concentration/attention, mood problems) was dose-related and much greater at higher than recommended topiramate dosing (i.e., 600 mg/day to 1000 mg/day) compared to the incidence of these adverse reactions at the recommended dosing (200 mg/day to 400 mg/day) range. Table 4: Most Common Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trials in Adults *,† * Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo † Values represent the percentage of patients reporting a given reaction. Patient may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category. Body System/ Adverse Reaction Placebo (N=291) % Topiramate Dosage (mg/day) 200-400 (N=183) % Body as a Whole-General Disorders Fatigue 13 15 Asthenia 1 6 Back pain 4 5 Chest pain 3 4 Influenza-like symptoms 2 3 Central & Peripheral Nervous System Disorders Dizziness 15 25 Ataxia 7 16 Speech disorders/Related speech problems 2 13 Paresthesia 4 11 Nystagmus 7 10 Tremor 6 9 Language problems 1 6 Coordination abnormal 2 4 Gait abnormal 1 3 Gastro-Intestinal System Disorders Nausea 8 10 Dyspepsia 6 7 Abdominal pain 4 6 Constipation 2 4 Metabolic and Nutritional Disorders Weight loss 3 9 Psychiatric Disorders Somnolence 12 29 Nervousness 6 16 Psychomotor slowing 2 13 Difficulty with memory 3 12 Confusion 5 11 Anorexia 4 10 Difficulty with concentration/attention 2 6 Mood problems 2 4 Agitation 2 3 Aggressive reaction 2 3 Emotional liability 1 3 Cognitive problems 1 3 Reproductive Disorders, Female Breast pain 2 4 Respiratory System Disorders Rhinitis 6 7 Pharyngitis 2 6 Sinusitis 4 5 Vision Disorders Vision abnormal 2 13 Diplopia 5 10 In controlled clinical trials in adults, 11% of patients receiving immediate-release topiramate 200 to 400 mg per day as adjunctive therapy discontinued due to adverse reactions. This rate appeared to increase at dosages above 400 mg per day. Adverse reactions associated with discontinuing therapy included somnolence, dizziness, anxiety, difficulty with concentration or attention, fatigue, and paresthesia. Pediatric Patients 2 Years to 15 Years of Age In pooled, controlled clinical trials in pediatric patients (2 years to 15 years of age) with partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, 98 patients received adjunctive therapy with immediate-release topiramate at dosages of 5 mg to 9 mg/kg/day (recommended dosage range) and 101 patients received placebo. The most common adverse reactions in the controlled clinical trial that occurred in pediatric patients in the 5 mg to 9 mg/kg/day immediate-release topiramate group with an incidence higher (greater than or equal to 10%) than in the placebo group were: fatigue and somnolence (see Table 5). Table 5 presents the incidence of adverse reactions that occurred in at least 3% of pediatric patients 2 to 15 years of age receiving 5 mg to 9 mg/kg/day (recommended dosage range) of immediate-release topiramate and was greater than placebo incidence. Table 5: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trial in Pediatric Patients 2 to 15 Years of Age *,† * Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo † Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category Body System/ Adverse Reaction Placebo (N=101) % Topiramate (N=98) % Body as a Whole-General Disorders Fatigue 5 16 Injury 13 14 Central & Peripheral Nervous System Disorders Gait abnormal 5 8 Ataxia 2 6 Hyperkinesia 4 5 Dizziness 2 4 Speech disorders/Related speech problems 2 4 Gastro-Intestinal System Disorders Nausea 5 6 Saliva increased 4 6 Constipation 4 5 Gastroenteritis 2 3 Metabolic and Nutritional Disorders Weight loss 1 9 Platelet, Bleeding & Clotting Disorders Purpura 4 8 Epistaxis 1 4 Psychiatric Disorders Somnolence 16 26 Anorexia 15 24 Nervousness 7 14 Personality disorder (Behavior Problems) 9 11 Difficulty with concentration/attention 2 10 Aggressive reaction 4 9 Insomnia 7 8 Difficulty with memory 0 5 Confusion 3 4 Psychomotor slowing 2 3 Resistance Mechanism Disorders Infection viral 3 7 Respiratory System Disorders Pneumonia 1 5 Skin and Appendages Disorders Skin Disorder 2 3 Urinary System Disorders Urinary incontinence 2 4 None of the pediatric patients who received topiramate adjunctive therapy at 5 mg/kg/day to 9 mg/kg/day in controlled clinical trials discontinued due to adverse reactions. Migraine Adults In the four multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trials for the preventive treatment of migraine (which included 35 pediatric patients 12 to 15 years of age), most adverse reactions occurred more frequently during the titration period than during the maintenance period. The most common adverse reactions with immediate-release topiramate 100mg in the clinical trials for the preventive treatment of migraineof predominantly adults that were seen at an incidence higher (greater than or equal to 5%) than in the placebo group were: paresthesia, anorexia, weight loss, taste perversion, diarrhea, difficulty with memory, hypoesthesia, and nausea (see Table 6). Table 6 includes those adverse reactions that occurred in the placebo-controlled trials where the incidence in any immediate-release topiramate group was at least 3% and was greater than that for placebo patients. The incidence of some adverse reactions (e.g., fatigue, dizziness, somnolence, difficulty with memory, difficulty with concentration/attention) was dose-related and greater at higher than recommended topiramate dosing (200 mg/day) compared to the incidence of these adverse reactions at the recommended dosing (100 mg/day). Table 6: Adverse Reactions in Pooled, Placebo-Controlled, Migraine Trials in Adults *,†,‡ * Includes 35 adolescent patients age 12 to 15 years † Values represent the percentage of patients reporting a given reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category. ‡ Blurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for more than 50% of reactions coded as vision abnormal, a preferred term Topiramate Dosage (mg/day) Body System/ Adverse Reaction Placebo (N=445) % 50 (N=235) % 100 (N=386) % Body as a Whole-General Disorders Fatigue 11 14 15 Injury 7 9 6 Central & Peripheral Nervous System Disorders Paresthesia 6 35 51 Dizziness 10 8 9 Hypoaesthesia 2 6 7 Language problems 2 7 6 Gastro-Intestinal System Disorders Nausea 8 9 13 Diarrhea 4 9 11 Abdominal pain 5 6 6 Dyspepsia 3 4 5 Dry mouth 2 2 3 Gastroenteritis 1 3 3 Metabolic and Nutritional Disorders Weight loss 1 6 9 Musculoskeletal System Disorders Arthralgia 2 7 3 Psychiatric Disorders Anorexia 6 9 15 Somnolence 5 8 7 Difficulty with memory 2 7 7 Insomnia 5 6 7 Difficulty with concentration/attention 2 3 6 Mood problems 2 3 6 Anxiety 3 4 5 Depression 4 3 4 Nervousness 2 4 4 Confusion 2 2 3 Psychomotor slowing 1 3 2 Reproductive Disorders, Female Menstrual disorder 2 3 2 Reproductive Disorders, Male Ejaculation premature 0 3 0 Resistance Mechanism Disorders Viral Infection 3 4 4 Respiratory System Disorders Upper respiratory tract infection 12 13 14 Sinusitis 6 10 6 Pharyngitis 4 5 6 Coughing 2 2 4 Bronchitis 2 3 3 Dyspnea 2 1 3 Skin and Appendages Disorders Pruritis 2 4 2 Special Sense Other, Disorders Taste perversion 1 15 8 Urinary System Disorders Urinary tract infection 2 4 2 Vision Disorders Blurred vision 2 4 2 Of the 1135 patients exposed to immediate-release topiramate in the adult placebo-controlled studies, 25% discontinued due to adverse reactions, compared to 10% of the 445 placebo patients. The adverse reactions associated with discontinuing therapy in the immediate-release topiramate-treated patients in these studies included paresthesia (7%), fatigue (4%), nausea (4%), difficulty with concentration/attention (3%), insomnia (3%), anorexia (2%), and dizziness (2%). Patients treated in these studies experienced mean percent reductions in body weight that were dose-dependent. This change was not seen in the placebo group. Mean changes of 0%, -2%, -3%, and -4% were seen for the placebo group, immediate-release topiramate 50 mg, 100 mg, and 200 mg groups, respectively. Pediatric Patients 12 Years to 17 Years of Age In five randomized, double-blind, placebo-controlled, parallel group clinical trials for the preventive treatment of migraine, most of the adverse reactions occurred more frequently during the titration period than during the maintenance period. Among adverse reactions with onset during titration, approximately half persisted into the maintenance period. In four, fixed-dose, double-blind clinical trials for the preventive treatment of migraine in pediatric patients 12 to 17 years of age, the most common adverse reactions with immediate-release topiramate 100 mg that were seen at an incidence higher (greater than or equal to 5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain (see Table 7). Table 7 shows adverse reactions from the pediatric trial (Study 13 [see Clinical Studies (14.4)] ) in which 103 pediatric patients were treated with placebo or 50 mg or 100 mg of immediate- release topiramate, and three predominantly adult trials in which 49 pediatric patients (12 to 17 years of age) were treated with placebo or 50 mg, 100 mg or 200 mg of immediate-release topiramate [see Clinical Studies (14.4)]. Table 7 also shows adverse reactions in pediatric patients in controlled migraine trials when the incidence in an immediate-release topiramate dose group was at least 5% or higher and greater than the incidence of placebo. Many adverse reactions shown in Table 7 indicate a dose-dependent relationship. The incidence of some adverse reactions (e.g., allergy, fatigue, headache, anorexia, insomnia, somnolence, and viral infection) was dose-related and greater at higher than recommended immediate-release topiramate dosing (200 mg daily) compared to the incidence of these adverse reactions at the recommended dosing (100 mg daily). Table 7: Adverse Reactions in Pooled Double-Blind Studies for the Preventive Treatment of Migraine in Pediatric Patients 12 to 17 Years of Age) *† * 35 adolescent patients aged 12 to less than 16 years were also included in adverse reaction assessment for adults † Incidence is based on the number of subjects experiencing at least 1 adverse event, not the number of events. Placebo (N=45) % Immediate-Release Topiramate Dosage Body System/ Adverse Reaction 50 mg/day (N=46) % 100 mg/day (N=48) % Body as a Whole – General Disorders Fatigue 7 7 8 Fever 2 4 6 Central & Peripheral Nervous System Disorders Paresthesia 7 20 19 Dizziness 4 4 6 Gastrointestinal System Disorders Abdominal pain 9 7 15 Nausea 4 4 8 Metabolic and Nutritional Disorders Weight loss 2 7 4 Psychiatric Disorders Anorexia 4 9 10 Somnolence 2 2 6 Insomnia 2 9 2 Resistance Mechanism Disorders Infection viral 4 4 8 Respiratory System Disorders Upper respiratory tract infection 11 26 23 Rhinitis 2 7 6 Sinusitis 2 9 4 Coughing 0 7 2 Special Senses Other, Disorders Taste perversion 2 2 6 Vision Disorders Conjunctivitis 4 7 4 In the double-blind placebo-controlled studies, adverse reactions led to discontinuation of treatment in 8% of placebo patients compared with 6% of immediate-release topiramate-treated patients. Adverse reactions associated with discontinuing therapy that occurred in more than one immediate-release topiramate-treated patient were fatigue (1%), headache (1%), and somnolence (1%). Increased Risk for Bleeding Topiramate is associated with an increased risk for bleeding. In a pooled analysis of placebo-controlled studies of approved and unapproved indications, bleeding was more frequently reported as an adverse reaction for topiramate than for placebo (4.5% versus 3% in adult patients, and 4.4% versus 2.3% in pediatric patients). In this analysis, the incidence of serious bleeding events for topiramate and placebo was 0.3% versus 0.2% for adult patients, and 0.4% versus 0% for pediatric patients. Adverse bleeding reactions reported with topiramate ranged from mild epistaxis, ecchymosis, and increased menstrual bleeding to life-threatening hemorrhages. In patients with serious bleeding events, conditions that increased the risk for bleeding were often present, or patients were often taking drugs that cause thrombocytopenia (other antiepileptic drugs) or affect platelet function or coagulation (e.g., aspirin, nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, or warfarin or other anticoagulants). Other Adverse Reactions Observed During Clinical Trials Other adverse reactions seen during clinical trials were: abnormal coordination, eosinophilia, gingival bleeding, hematuria, hypotension, myalgia, myopia, postural hypotension, scotoma, suicide attempt, syncope, and visual field defect. Laboratory Test Abnormalities Adult Patients In addition to changes in serum bicarbonate (i.e., metabolic acidosis), sodium chloride, and ammonia, immediate-release topiramate was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies [see Warnings and Precautions ( 5.4 , 5.13 )]. Controlled trials of adjunctive topiramate treatment of adults for partial-onset seizures showed an increased incidence of markedly decreased serum phosphorus (6% topiramate versus 2% placebo), markedly increased serum alkaline phosphatase (3% topiramate versus 1% placebo), and decreased serum potassium (0.4% topiramate versus 0.1% placebo). Pediatric Patients In pediatric patients (1 to 24 months) receiving adjunctive topiramate for partial-onset seizures, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with immediate-release topiramate (vs placebo) for the following clinical laboratory analytes: creatinine, BUN, alkaline phosphatase, and total protein. The incidence was also increased for a decreased result for bicarbonate (i.e., metabolic acidosis) and potassium with immediate-release topiramate (vs. placebo) [see Use in Specific Populations ( 8.4 )]. Topiramate extended-release capsules are not indicated for partial-onset seizures in pediatric patients less than 6 years of age. In pediatric patients (ranging from 6 years to 17 years of age) receiving immediate-release topiramate for the preventive treatment of migraine, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with immediate-release topiramate (vs placebo) for the following clinical laboratory analytes: creatinine, BUN, uric acid, chloride, ammonia, alkaline phosphatase, total protein, platelets, and eosinophils. The incidence was also increased for a decreased result for phosphorus, bicarbonate, total white blood count, and neutrophils [see Use in Specific Populations ( 8.4 )]. Topiramate extended-release capsules are not indicated for the preventive treatment of migraine in pediatric patients less than 12 years of age. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of immediate-release topiramate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole-General Disorders: oligohydrosis and hyperthermia [see Warnings and Precautions ( 5.3 )], hyperammonemia, hyperammonemic encephalopathy [see Warnings and Precautions ( 5.13 )] , hypothermia with concomitant valproic acid [see Warnings and Precautions 5.15 )]. Gastrointestinal System Disorders: hepatic failure (including fatalities), hepatitis, pancreatitis Skin and Appendage Disorders: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis) [see Warnings and Precautions ( 5.12 )], pemphigus Urinary System Disorders: kidney stones, nephrocalcinosis [see Warnings and Precautions ( 5.14 )] Vision disorders: acute myopia, secondary angle closure glaucoma [see Warnings and Precautions ( 5.1 )], maculopathy Hematological Disorders: decrease of the International Normalized Ratio (INR) or prothrombin time when given concomitantly with vitamin K antagonist anticoagulant medications such as warfarin.

4 CONTRAINDICATIONS Topiramate extended-release capsules are contraindicated in patients: With recent alcohol use ( i.e., within 6 hours prior to and 6 hours after topiramate extended-release capsules use) [see Warnings and Precautions ( 5.5 )] With recent alcohol use, i.e, within 6 hours prior to and 6 hours after topiramate extended-release capsules use ( 4 , 5.5 )

11 DESCRIPTION Topiramate, USP, is a sulfamate-substituted monosaccharide. Topiramate extended-release capsules are available as 25 mg, 50 mg, 100 mg, and 200 mg capsules for oral administration. Topiramate is a white to off-white powder. Topiramate is freely soluble in Dichloromethane. Topiramate has the molecular formula C 12 H 21 NO 8 S and a molecular weight of 339.4. Topiramate is designated chemically as 2,3:4,5-Di- O -isopropylidene-β-D-fructopyranose sulfamate and has the following structural formula: Topiramate extended-release capsules contain the following inactive ingredients: sugar spheres, hypromellose, ethyl cellulose, ammonium hydroxide, triglyceride, oleic acid, polyethylene glycol, povidone, glyceryl dibehenate, polyvinyl alcohol, titanium dioxide, talc, lecithin, xanthan gum. The capsule shell contains: gelatin, titanium dioxide, (25 mg, 50 mg, 100 mg and 200 mg), sodium lauryl sulfate (100 mg). FD & C Blue 1, FD & C Red 3, FD & C Red 40 (25 mg, 100 mg and 200 mg), iron oxide yellow, iron oxide red (50 mg). For 25 mg, 50 mg, 100 mg (body & cap) and 200 mg (body only) strengths, imprinting black ink contains: shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide and potassium hydroxide. For 200 mg (cap only) strength, imprinting white ink contains: shellac, ethanol, isopropyl alcohol, n-butanol, propylene glycol, ammonia solution, potassium hydroxide and titanium dioxide. structure

2 DOSAGE AND ADMINISTRATION Topiramate extended-release capsules initial dose, titration, and recommended maintenance dose varies by indication and age group. See Full Prescribing Information for recommended dosage, and dosing considerations in patients with renal impairment, geriatric patients, and patients undergoing hemodialysis ( 2.1 , 2.2 , 2.3 , 2.4 , 2.5 , 2.6 ) Swallow capsule whole and intact. Do not sprinkle on food, chew, or crush ( 2.7 ) 2.1 Dosing in Monotherapy Epilepsy Adults and Pediatric Patients 10 Years of Age and Older with Partial Onset or Primary Generalized Tonic- Clonic Seizures The recommended dose for topiramate extended-release capsules monotherapy in adults and in pediatric patients 10 years of age and older is 400 mg orally once daily. Titrate topiramate extended-release capsules according to the following schedule: Week 1: 50 mg once daily Week 2: 100 mg once daily Week 3: 150 mg once daily Week 4: 200 mg once daily Week 5: 300 mg once daily Week 6: 400 mg once daily Pediatric Patients Ages 6 to 9 Years of Age Dosing in patients 6 to 9 years of age is based on weight. During the titration period, the initial dose of topiramate extended-release capsules are 25 mg/day nightly for the first week. Based upon tolerability, the dosage can be increased to 50 mg/day in the second week. Dosage can be increased by 25 mg to 50 mg/day each subsequent week as tolerated. Titration to the minimum maintenance dose should be attempted over 5 to 7 weeks of the total titration period. Based upon tolerability and clinical response, additional titration to a higher dose (up to the maximum maintenance dose) can be attempted at 25 mg to 50 mg/day weekly increments. The total daily dose should not exceed the maximum maintenance dose for each range of body weight (see Table 1). Table 1: Monotherapy Target Total Daily Maintenance Dosing for Patients 6 to 9 Years of Age Weight (kg) Total Daily Dose (mg/day) Minimum Maintenance Dose Total Daily Dose (mg/day) Maximum Maintenance Dose Up to 11 150 250 12 - 22 200 300 23 - 31 200 350 32 - 38 250 350 Greater than 38 250 400 2.2 Dosing in Adjunctive Therapy Epilepsy Adults (17 Years of Age and Older) The recommended total daily dose of topiramate extended-release capsules as adjunctive therapy in adults with partial-onset seizures or Lennox-Gastaut Syndrome is 200 mg to 400 mg orally once daily and with primary generalized tonic-clonic seizures is 400 mg orally once daily. Initiate therapy at 25 mg to 50 mg once daily followed by titration to an effective dose in increments of 25 mg to 50 mg every week. Titrating in increments of 25 mg/day every week may delay the time to reach an effective dose. Doses above 400 mg/day have not been shown to improve responses in adults with partial-onset seizures. Pediatric Patients 6 to 16 Years of Age The recommended total daily dose of topiramate extended-release capsules as adjunctive therapy for patients 6 to 16 years of age with partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox- Gastaut syndrome is approximately 5 mg/kg to 9 mg/kg orally once daily. Begin titration at 25 mg once daily (or less, based on a range of 1 mg/kg/day to 3 mg/kg/day) given nightly for the first week. Subsequently, increase the dosage at 1- or 2-week intervals by increments of 1 mg/kg/day to 3 mg/kg/day to achieve optimal clinical response. Dose titration should be guided by clinical outcome. The total daily dose should not exceed 400 mg/day. 2.3 Dosing for the Preventive Treatment of Migraine The recommended total daily dose of topiramate extended-release capsules as treatment for the preventive treatment of migraine in patients 12 years of age and older is 100 mg once daily. Titrate topiramate extended-release capsules for the preventive treatment of migraine according to the following schedule: Week 1: 25mg once daily Week 2: 50mg once daily Week 3: 75mg once daily Week 4: 100mg once daily Dose and titration rate should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used. 2.4 Administration With Alcohol Alcohol use should be completely avoided within 6 hours prior to and 6 hours after topiramate extended-release capsules administration [see Warnings and Precautions ( 5.5 )] . 2.5 Dose Modifications in Patients With Renal Impairment In patients with renal impairment (creatinine clearance less than 70 mL/min/1.73 m 2 ), one-half of the usual adult dose of topiramate extended-release capsules are recommended [see Use in Specific Populations ( 8.5 , 8.6 ), Clinical Pharmacology ( 12.3 )] . 2.6 Dosage Modifications in Patients Undergoing Hemodialysis To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate extended-release capsules may be required. The actual adjustment should take into account 1) the duration of dialysis period, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of topiramate in the patient being dialyzed [see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )] . 2.7 Administration Instructions Topiramate extended-release capsules can be taken without regard to meals. Swallow capsule whole and intact. Do not sprinkle on food, chew, or crush.

1 INDICATIONS AND USAGE Topiramate extended-release capsules are indicated for: Epilepsy: initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 6 years of age and older ( 1.1 ); adjunctive therapy for the treatment of partial-onset, primary generalized tonic-clonic seizures, or seizures associated with Lennox- Gastaut syndrome (LGS) in patients 6 years of age and older ( 1.2 ) Preventive treatment of migraine in patients 12 years of age and older ( 1.3 ) 1.1 Monotherapy Epilepsy Topiramate extended-release capsules are indicated as initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 6 years of age and older [ see Clinical Studies ( 14.2 ) ]. 1.2 Adjunctive Therapy Epilepsy Topiramate extended-release capsules are indicated as adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome in patients 6 years of age and older [ see Clinical Studies ( 14.3 ) ]. 1.3 Migraine Topiramate extended-release capsules are indicated for the preventive treatment of migraine in patients 12 years of age and older [ see Clinical Studies ( 14.4 ) ].

10 OVERDOSAGE Overdoses of topiramate have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbance, blurred vision, diplopia, impaired mentation, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness, and depression. The clinical consequences were not severe in most cases, but deaths have been reported after overdoses involving topiramate. Topiramate overdose has resulted in severe metabolic acidosis [see Warnings and Precautions ( 5.4 )] . A patient who ingested a dose of immediate-release topiramate between 96 g and 110 g was admitted to a hospital with a coma lasting 20 years to 24 hours followed by full recovery after 3 days to 4 days. Similar signs, symptoms, and clinical consequences are expected to occur with overdosage of topiramate extended-release capsules. In the event of overdose, topiramate extended-release capsules should be discontinued and general supportive treatment given until clinical toxicity has been diminished or resolved. Hemodialysis is an effective means of removing topiramate from the body.

7 DRUG INTERACTIONS Oral contraceptives: Decreased contraceptive efficacy and increased breakthrough bleeding, especially at doses greater than 200 mg per day ( 7.5 ) Monitor lithium levels if lithium is used with high-dose topiramate extended-release capsules ( 7.8 ) 7.1 Alcohol Alcohol use is contraindicated within 6 hours prior to and 6 hours after topiramate extended-release capsules administration [see Contraindications ( 4 ) and Warnings and Precautions ( 5.5 )]. 7.2 Antiepileptic Drugs Concomitant administration of phenytoin or carbamazepine with topiramate resulted in a clinically significant decrease in plasma concentrations of topiramate when compared to topiramate given alone. A dosage adjustment may be needed [see Dosage and Administration ( 2.1 ), Clinical Pharmacology ( 12.3 )]. Concomitant administration of valproic acid and topiramate has been associated with hypothermia and hyperammonemia with and without encephalopathy. Examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions ( 5.13 , 5.15 ) and Clinical Pharmacology ( 12.3 )] . 7.3 Other Carbonic Anhydrase Inhibitors Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide or acetazolamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Patients should be monitored for the appearance or worsening of metabolic acidosis when topiramate extended-release capsules are given concomitantly with another carbonic anhydrase inhibitor [see Clinical Pharmacology ( 12.3 )] . 7.4 CNS Depressants Concomitant administration of topiramate with other CNS depressant drugs or alcohol has not been evaluated in clinical studies. Because of the potential of topiramate to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse reactions, topiramate extended-release capsules should be used with extreme caution if used in combination with alcohol and other CNS depressants [see Contraindications ( 4 ) and Warnings and Precautions ( 5.7 )]. 7.5 Oral Contraceptives The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking combination oral contraceptive products with topiramate extended-release capsules. Patients taking estrogen-containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding [see Clinical Pharmacology ( 12.3 )] . 7.6 Hydrochlorothiazide (HCTZ) Topiramate C max and AUC increased when HCTZ was added to immediate-release topiramate. The clinical significance of this change is unknown. The addition of HCTZ to topiramate extended-release capsules may require a decrease in the topiramate extended-release capsules dose [see Clinical Pharmacology ( 12.3 )] . 7.7 Pioglitazone A decrease in the exposure of pioglitazone and its active metabolites were noted with the concurrent use of pioglitazone and immediate-release topiramate in a clinical trial. The clinical relevance of these observations is unknown; however, when topiramate extended-release capsules are added to pioglitazone therapy or pioglitazone is added to topiramate extended-release capsules therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state [see Clinical Pharmacology ( 12.3 )] . 7.8 Lithium An increase in systemic exposure of lithium following topiramate doses of up to 600 mg/day can occur. Lithium levels should be monitored when co-administered with high-dose topiramate extended-release capsules [see Clinical Pharmacology ( 12.3 )]. 7.9 Amitriptyline Some patients may experience a large increase in amitriptyline concentration in the presence of topiramate extended-release capsules and any adjustments in amitriptyline dose should be made according to the patients’ clinical response and not on the basis of plasma levels [see Clinical Pharmacology ( 12.3 )].

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The precise mechanisms by which topiramate exerts its anticonvulsant and preventive migraine effects are unknown; however, preclinical studies have revealed four properties that may contribute to topiramate's efficacy for epilepsy and the preventive treatment of migraine. Electrophysiological and biochemical evidence suggests that topiramate, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV. 12.2 Pharmacodynamics Topiramate has anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests. Topiramate is only weakly effective in blocking clonic seizures induced by the GABA-A receptor antagonist, pentylenetetrazole. Topiramate is also effective in rodent models of epilepsy, which include tonic and absence- like seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in rats by kindling of the amygdala or by global ischemia. Changes (increases and decreases) from baseline in vital signs (systolic blood pressure-SBP, diastolic blood pressure-DBP, pulse) occurred more frequently in pediatric patients (6 years to 17 years) treated with various daily doses of topiramate (50 mg, 100 mg, 200 mg, 2 mg/kg to 3 mg/kg) than in patients treated with placebo in controlled trials for the preventive treatment of migraine. The most notable changes were SBP less than 90 mm Hg, DBP less than 50 mm Hg, SBP or DBP increases or decreases greater than or equal to 20 mm Hg, and pulse increases or decreases greater than or equal to 30 beats per minute. These changes were often dose-related, and were most frequently associated with the greatest treatment difference at the 200 mg dose level. Systematic collection of orthostatic vital signs has not been conducted. The clinical significance of these various changes in vital signs has not been clearly established. 12.3 Pharmacokinetics Absorption and Distribution Linear pharmacokinetics of topiramate from topiramate extended-release capsules were observed following a single oral dose over the range of 50 mg to 200 mg. At 25 mg, the pharmacokinetics of topiramate extended-release capsules are nonlinear possibly due to the binding of topiramate to carbonic anhydrase in red blood cells. The peak plasma concentrations (C max ) of topiramate occurred at approximately 24 hours following a single 200 mg oral dose of topiramate extended-release capsules. At steady-state, the (AUC 0-24 , C max , and C min ) of topiramate from topiramate extended-release capsules administered once-daily and the immediate-release tablet administered twice-daily were shown to be bioequivalent. Fluctuation of topiramate plasma concentrations at steady-state for topiramate extended-release capsules administered once-daily was approximately 26% and 42% in healthy subjects and in epileptic patients, respectively, compared to approximately 40% and 51%, respectively, for immediate-release topiramate [see Clinical Pharmacology ( 12.6 ) ]. Compared to the fasted state, high-fat meal increased the C max of topiramate by 37% and shortened the T max to approximately 8 hours following a single dose of topiramate extended-release capsules, while having no effect on the AUC. Modeling of the observed single dose fed data with simulation to steady state showed that the effect on C max is significantly reduced following repeat administrations. Topiramate extended-release capsules can be taken without regard to meals. Topiramate is 15% to 41% bound to human plasma proteins over the blood concentration range of 0.5 mcg/mL to 250 mcg/mL. The fraction bound decreased as blood concentration increased. Carbamazepine and phenytoin do not alter the binding of immediate-release topiramate. Sodium valproate, at 500 mcg/mL (a concentration 5 to 10 times higher than considered therapeutic for valproate) decreased the protein binding of immediate-release topiramate from 23% to 13%. Immediate-release topiramate does not influence the binding of sodium valproate. Metabolism and Excretion Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption of topiramate. In rats, given probenecid to inhibit tubular reabsorption, along with topiramate, a significant increase in renal clearance of topiramate was observed. This interaction has not been evaluated in humans. Overall, oral plasma clearance (CL/F) is approximately 20 mL/min to 30 mL/min in adults following oral administration. The mean elimination half-life of topiramate was approximately 31 hours following repeat administration of topiramate extended-release capsules. Specific Populations Renal Impairment The clearance of topiramate was reduced by 42% in subjects with moderate renal impairment (creatinine clearance 30 mL/min/1.73m 2 to 69 mL/min/1.73m 2 ) and by 54% in subjects with severe renal impairment (creatinine clearance less than 30 mL/min/1.73m 2 ) compared to subjects with normal renal function (creatinine clearance greater than 70 mL/min/1.73m 2 ) [see Dosage and Administration ( 2.5 )] . Hemodialysis Topiramate is cleared by hemodialysis. Using a high-efficiency, counterflow, single pass-dialysate hemodialysis procedure, topiramate dialysis clearance was 120 mL/min with blood flow through the dialyzer at 400 mL/min. This high clearance (compared to 20 mL/min to 30 mL/min total oral clearance in healthy adults) will remove a clinically significant amount of topiramate from the patient over the hemodialysis treatment period [see Dosage and Administration ( 2.6 ) and Use in Specific Populations ( 8.7 )] . Hepatic Impairment Plasma clearance of topiramate decreased a mean of 26% in patients with moderate to severe hepatic impairment. Age, Gender and Race The pharmacokinetics of topiramate in elderly subjects (65 years to 85 years of age, N=16) were evaluated in a controlled clinical study. The elderly subject population had reduced renal function (creatinine clearance [-­20%]) compared to young adults. Following a single oral 100 mg dose, maximum plasma concentration for elderly and young adults was achieved at approximately 1 hours to 2 hours. Reflecting the primary renal elimination of topiramate, topiramate plasma and renal clearance were reduced 21% and 19%, respectively, in elderly subjects, compared to young adults. Similarly, topiramate half-life was longer (13%) in the elderly. Reduced topiramate clearance resulted in slightly higher maximum plasma concentration (23%) and AUC (25%) in elderly subjects than observed in young adults. Topiramate clearance is decreased in the elderly only to the extent that renal function is reduced [see Dosage and Administration ( 2.4 ) and Use in Specific Populations ( 8.5 )]. In a study of 13 healthy elderly subjects and 18 healthy young adults who received topiramate extended-release capsules, 30% higher mean C max and 44% higher AUC values were observed in elderly compared to young subjects. Elderly subjects exhibited shorter median T max at 16 hours versus 24 hours in young subjects. The apparent elimination half-life was similar across age groups. As recommended for all patients, dosage adjustment is indicated in elderly patients with a creatinine clearance rate less than 70 mL/min/1.73 m 2 ) [see Dosage and Administration ( 2.5 ) and Use in Specific Populations ( 8.5 )] . Clearance of topiramate in adults was not affected by gender or race. Pediatric Pharmacokinetics Pharmacokinetics of immediate-release topiramate were evaluated in patients ages 2 to less than 16 years of age. Patients received either no or a combination of other antiepileptic drugs. A population pharmacokinetic model was developed on the basis of pharmacokinetic data from relevant topiramate clinical studies. This dataset contained data from 1217 subjects including 258 pediatric patients age 2 years to less than 16 years of age (95 pediatric patients less than 10 years of age). Pediatric patients on adjunctive treatment exhibited a higher oral clearance (L/h) of topiramate compared to patients on monotherapy, presumably because of increased clearance from concomitant enzyme-inducing antiepileptic drugs. In comparison, topiramate clearance per kg is greater in pediatric patients than in adults and in young pediatric patients (down to 2 years of age) than in older pediatric patients. Consequently, the plasma drug concentration for the same mg/kg/day dose would be lower in pediatric patients compared to adults and also in younger pediatric patients compared to older pediatric patients. Clearance was independent of dose. As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations of topiramate. Drug-Drug Interaction Studies In vitro studies indicate that topiramate does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4/5 isozymes. In vitro studies indicate that immediate-release topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4. The same drug interactions can be expected with the use of topiramate extended-release capsules. Antiepileptic Drugs Potential interactions between immediate-release topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in Table 9. Interaction of topiramate extended-release capsules and standard AEDs is not expected to differ from the experience with immediate-release topiramate products. In Table 9, the second column (AED concentration) describes what happens to the concentration of the co- administered AED listed in the first column when topiramate is added. The third column (topiramate concentration) describes how the co-administration of a drug listed in the first column modifies the concentration of topiramate when compared to topiramate given alone. Table 9: Summary of AED Interactions with Topiramate AED Coadministered AED Concentration Topiramate Concentration Phenytoin NC or 25% increase * 48% decrease Carbamazepine (CBZ) NC 40% decrease CBZ epoxide † NC NE Valproic acid 11% decrease 14% decrease Phenobarbital NC NE Primidone NC NE Lamotrigine NC at TPM doses up to 400mg per day 13% decrease NC=Less than 10% change in plasma concentration AED=Antiepileptic drug NE=Not evaluated TPM=topiramate * =Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin † =Is not administered but is an active metabolite of carbamazepine Oral Contraceptives In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), immediate-release topiramate, given in the absence of other medications at doses of 50 to 200 mg/day, was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg per day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in patients taking valproic acid. In both studies, topiramate (50 mg per day to 800 mg per day) did not significantly affect exposure to NET, and there was no significant dose-dependent change in EE exposure for doses of 50 to 200 mg/day. The clinical significance of the changes observed is not known [ see Drug Interactions (7.5) ]. Digoxin In a single-dose study, serum digoxin AUC was decreased by 12% with concomitant topiramate administration. The clinical relevance of this observation has not been established. Hydrochlorothiazide A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg every 24 hours) and topiramate (96 mg every 12 hours) when administered alone and concomitantly. The results of this study indicate that topiramate C max increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination [see Drug Interactions ( 7.6 )]. Metformin A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin (500 mg every 12 hours) and topiramate in plasma when metformin was given alone and when metformin and topiramate (100 mg every 12 hours) were given simultaneously. The results of this study indicated that the mean metformin C max and AUC 0-12h increased by 17% and 25%, respectively, when topiramate was added. Topiramate did not affect metformin Tmax. The clinical significance of the effect of topiramate on metformin pharmacokinetics is not known. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect of metformin on topiramate or topiramate extended-release capsules pharmacokinetics is unclear. Pioglitazone A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15% decrease in the AUC τ,ss of pioglitazone with no alteration in C max,ss was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in C max,ss and AUC τ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in C max,ss and AUC τ,ss of the active keto-metabolite. The clinical significance of these findings is not known [see Drug Interactions ( 7.7 )]. Glyburide A drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg per day) alone and concomitantly with topiramate (150 mg per day). There was a 22% decrease in C max and 25% reduction in AUC 24 for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4- trans -hydroxy glyburide (M1) and 3- cis -hydroxyglyburide (M2), was also reduced by 13% and 15%, reduced C max by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide. Lithium In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg per day; however, there was an observed increase in systemic exposure of lithium (27% for C max and 26% for AUC) following topiramate doses up to 600 mg per day [see Drug Interactions ( 7.8 )]. Haloperidol The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hr) in 13 healthy adults (6 males, 7 females). Amitriptyline There was a 12% increase in AUC and C max for amitriptyline (25 mg per day) in 18 healthy subjects (9 males, 9 females) receiving 200 mg per day of immediate-release topiramate [see Drug Interactions ( 7.9 )]. Sumatriptan Multiple dosing of topiramate (100 mg every 12 hours) in 24 healthy volunteers (14 males, 10 females) did not affect the pharmacokinetics of single-dose sumatriptan either orally (100 mg) or subcutaneously (6 mg). Risperidone When administered concomitantly with topiramate at escalating doses of 100, 250, and 400 mg per day, there was a reduction in risperidone systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg per day doses of topiramate). No alterations of 9-hydroxyrisperidone levels were observed. Coadministration of topiramate 400 mg per day with risperidone resulted in a 14% increase in C max and a 12% increase in AUC 12 of topiramate. There were no clinically significant changes in the systemic exposure of risperidone plus 9­ hydroxyrisperidone or of topiramate; therefore, this interaction is not likely to be of clinical significance. Propranolol Multiple dosing of topiramate (200 mg per day) in 34 healthy volunteers (17 males, 17 females) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg per day in 39 volunteers (27 males, 12 females) had no effect on the exposure to topiramate at a dose of 200 mg/day of topiramate. Dihydroergotamine Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (12 males, 12 females) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg/day dose of topiramate in the same study. Diltiazem Co-administration of diltiazem (240 mg Cardizem CD ® ) with topiramate (150 mg/day) resulted in a 10% decrease in C max and 25% decrease in diltiazem AUC, 27% decrease in C max and 18% decrease in des-acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem resulted in a 16% increase in C max and a 19% increase in AUC 12 of topiramate. Venlafaxine Multiple dosing of topiramate (150 mg/day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg) did not affect the pharmacokinetics of topiramate. 12.6 Relative Bioavailability of Topiramate Extended-Release Capsules Compared to Immediate-Release Topiramate Study in Healthy Normal Volunteers Topiramate extended-release capsules taken once a day provides steady state plasma levels comparable to immediate-release topiramate taken every 12 hours, when administered at the same total 200-mg daily dose. In a crossover study, 33 healthy subjects were titrated to a 200-mg dose of either topiramate extended-release capsules or immediate-release topiramate and were maintained at 200 mg per day for 10 days. The 90% CI for the ratios of AUC 0-24 , C max and C min , as well as partial AUC (the area under the concentration- time curve from time 0 to time p (post dose) for multiple time points were within the 80 to 125% bioequivalence limits, indicating no clinically significant difference between the two formulations. In addition, the 90% CI for the ratios of topiramate plasma concentration at each of multiple time points over 24 hours for the two formulations were within the 80 to 125% bioequivalence limits, except for the initial time points before 1.5 hours post-dose. Study in Patients with Epilepsy In a study in epilepsy patients treated with immediate-release topiramate alone or in combination with either enzyme-inducing or neutral AEDs who were switched to an equivalent daily dose of topiramate extended-release capsules, there was a 10% decrease in AUC 0-24 , C max , and C min on the first day after the switch in all patients. At steady state, AUC 0-24 and C max were comparable to immediate-release topiramate in all patients. While patients treated with topiramate extended-release capsules alone or in combination with neutral AEDs showed comparable C min at steady state, patients treated with enzyme-inducers showed a 10% decrease in C min . This difference is likely not clinically significant and probably due to the small number of patients on enzyme-inducers.

12.1 Mechanism of Action The precise mechanisms by which topiramate exerts its anticonvulsant and preventive migraine effects are unknown; however, preclinical studies have revealed four properties that may contribute to topiramate's efficacy for epilepsy and the preventive treatment of migraine. Electrophysiological and biochemical evidence suggests that topiramate, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV.

12.2 Pharmacodynamics Topiramate has anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests. Topiramate is only weakly effective in blocking clonic seizures induced by the GABA-A receptor antagonist, pentylenetetrazole. Topiramate is also effective in rodent models of epilepsy, which include tonic and absence- like seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in rats by kindling of the amygdala or by global ischemia. Changes (increases and decreases) from baseline in vital signs (systolic blood pressure-SBP, diastolic blood pressure-DBP, pulse) occurred more frequently in pediatric patients (6 years to 17 years) treated with various daily doses of topiramate (50 mg, 100 mg, 200 mg, 2 mg/kg to 3 mg/kg) than in patients treated with placebo in controlled trials for the preventive treatment of migraine. The most notable changes were SBP less than 90 mm Hg, DBP less than 50 mm Hg, SBP or DBP increases or decreases greater than or equal to 20 mm Hg, and pulse increases or decreases greater than or equal to 30 beats per minute. These changes were often dose-related, and were most frequently associated with the greatest treatment difference at the 200 mg dose level. Systematic collection of orthostatic vital signs has not been conducted. The clinical significance of these various changes in vital signs has not been clearly established.

12.3 Pharmacokinetics Absorption and Distribution Linear pharmacokinetics of topiramate from topiramate extended-release capsules were observed following a single oral dose over the range of 50 mg to 200 mg. At 25 mg, the pharmacokinetics of topiramate extended-release capsules are nonlinear possibly due to the binding of topiramate to carbonic anhydrase in red blood cells. The peak plasma concentrations (C max ) of topiramate occurred at approximately 24 hours following a single 200 mg oral dose of topiramate extended-release capsules. At steady-state, the (AUC 0-24 , C max , and C min ) of topiramate from topiramate extended-release capsules administered once-daily and the immediate-release tablet administered twice-daily were shown to be bioequivalent. Fluctuation of topiramate plasma concentrations at steady-state for topiramate extended-release capsules administered once-daily was approximately 26% and 42% in healthy subjects and in epileptic patients, respectively, compared to approximately 40% and 51%, respectively, for immediate-release topiramate [see Clinical Pharmacology ( 12.6 ) ]. Compared to the fasted state, high-fat meal increased the C max of topiramate by 37% and shortened the T max to approximately 8 hours following a single dose of topiramate extended-release capsules, while having no effect on the AUC. Modeling of the observed single dose fed data with simulation to steady state showed that the effect on C max is significantly reduced following repeat administrations. Topiramate extended-release capsules can be taken without regard to meals. Topiramate is 15% to 41% bound to human plasma proteins over the blood concentration range of 0.5 mcg/mL to 250 mcg/mL. The fraction bound decreased as blood concentration increased. Carbamazepine and phenytoin do not alter the binding of immediate-release topiramate. Sodium valproate, at 500 mcg/mL (a concentration 5 to 10 times higher than considered therapeutic for valproate) decreased the protein binding of immediate-release topiramate from 23% to 13%. Immediate-release topiramate does not influence the binding of sodium valproate. Metabolism and Excretion Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption of topiramate. In rats, given probenecid to inhibit tubular reabsorption, along with topiramate, a significant increase in renal clearance of topiramate was observed. This interaction has not been evaluated in humans. Overall, oral plasma clearance (CL/F) is approximately 20 mL/min to 30 mL/min in adults following oral administration. The mean elimination half-life of topiramate was approximately 31 hours following repeat administration of topiramate extended-release capsules. Specific Populations Renal Impairment The clearance of topiramate was reduced by 42% in subjects with moderate renal impairment (creatinine clearance 30 mL/min/1.73m 2 to 69 mL/min/1.73m 2 ) and by 54% in subjects with severe renal impairment (creatinine clearance less than 30 mL/min/1.73m 2 ) compared to subjects with normal renal function (creatinine clearance greater than 70 mL/min/1.73m 2 ) [see Dosage and Administration ( 2.5 )] . Hemodialysis Topiramate is cleared by hemodialysis. Using a high-efficiency, counterflow, single pass-dialysate hemodialysis procedure, topiramate dialysis clearance was 120 mL/min with blood flow through the dialyzer at 400 mL/min. This high clearance (compared to 20 mL/min to 30 mL/min total oral clearance in healthy adults) will remove a clinically significant amount of topiramate from the patient over the hemodialysis treatment period [see Dosage and Administration ( 2.6 ) and Use in Specific Populations ( 8.7 )] . Hepatic Impairment Plasma clearance of topiramate decreased a mean of 26% in patients with moderate to severe hepatic impairment. Age, Gender and Race The pharmacokinetics of topiramate in elderly subjects (65 years to 85 years of age, N=16) were evaluated in a controlled clinical study. The elderly subject population had reduced renal function (creatinine clearance [-­20%]) compared to young adults. Following a single oral 100 mg dose, maximum plasma concentration for elderly and young adults was achieved at approximately 1 hours to 2 hours. Reflecting the primary renal elimination of topiramate, topiramate plasma and renal clearance were reduced 21% and 19%, respectively, in elderly subjects, compared to young adults. Similarly, topiramate half-life was longer (13%) in the elderly. Reduced topiramate clearance resulted in slightly higher maximum plasma concentration (23%) and AUC (25%) in elderly subjects than observed in young adults. Topiramate clearance is decreased in the elderly only to the extent that renal function is reduced [see Dosage and Administration ( 2.4 ) and Use in Specific Populations ( 8.5 )]. In a study of 13 healthy elderly subjects and 18 healthy young adults who received topiramate extended-release capsules, 30% higher mean C max and 44% higher AUC values were observed in elderly compared to young subjects. Elderly subjects exhibited shorter median T max at 16 hours versus 24 hours in young subjects. The apparent elimination half-life was similar across age groups. As recommended for all patients, dosage adjustment is indicated in elderly patients with a creatinine clearance rate less than 70 mL/min/1.73 m 2 ) [see Dosage and Administration ( 2.5 ) and Use in Specific Populations ( 8.5 )] . Clearance of topiramate in adults was not affected by gender or race. Pediatric Pharmacokinetics Pharmacokinetics of immediate-release topiramate were evaluated in patients ages 2 to less than 16 years of age. Patients received either no or a combination of other antiepileptic drugs. A population pharmacokinetic model was developed on the basis of pharmacokinetic data from relevant topiramate clinical studies. This dataset contained data from 1217 subjects including 258 pediatric patients age 2 years to less than 16 years of age (95 pediatric patients less than 10 years of age). Pediatric patients on adjunctive treatment exhibited a higher oral clearance (L/h) of topiramate compared to patients on monotherapy, presumably because of increased clearance from concomitant enzyme-inducing antiepileptic drugs. In comparison, topiramate clearance per kg is greater in pediatric patients than in adults and in young pediatric patients (down to 2 years of age) than in older pediatric patients. Consequently, the plasma drug concentration for the same mg/kg/day dose would be lower in pediatric patients compared to adults and also in younger pediatric patients compared to older pediatric patients. Clearance was independent of dose. As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations of topiramate. Drug-Drug Interaction Studies In vitro studies indicate that topiramate does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4/5 isozymes. In vitro studies indicate that immediate-release topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4. The same drug interactions can be expected with the use of topiramate extended-release capsules. Antiepileptic Drugs Potential interactions between immediate-release topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in Table 9. Interaction of topiramate extended-release capsules and standard AEDs is not expected to differ from the experience with immediate-release topiramate products. In Table 9, the second column (AED concentration) describes what happens to the concentration of the co- administered AED listed in the first column when topiramate is added. The third column (topiramate concentration) describes how the co-administration of a drug listed in the first column modifies the concentration of topiramate when compared to topiramate given alone. Table 9: Summary of AED Interactions with Topiramate AED Coadministered AED Concentration Topiramate Concentration Phenytoin NC or 25% increase * 48% decrease Carbamazepine (CBZ) NC 40% decrease CBZ epoxide † NC NE Valproic acid 11% decrease 14% decrease Phenobarbital NC NE Primidone NC NE Lamotrigine NC at TPM doses up to 400mg per day 13% decrease NC=Less than 10% change in plasma concentration AED=Antiepileptic drug NE=Not evaluated TPM=topiramate * =Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin † =Is not administered but is an active metabolite of carbamazepine Oral Contraceptives In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), immediate-release topiramate, given in the absence of other medications at doses of 50 to 200 mg/day, was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg per day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in patients taking valproic acid. In both studies, topiramate (50 mg per day to 800 mg per day) did not significantly affect exposure to NET, and there was no significant dose-dependent change in EE exposure for doses of 50 to 200 mg/day. The clinical significance of the changes observed is not known [ see Drug Interactions (7.5) ]. Digoxin In a single-dose study, serum digoxin AUC was decreased by 12% with concomitant topiramate administration. The clinical relevance of this observation has not been established. Hydrochlorothiazide A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg every 24 hours) and topiramate (96 mg every 12 hours) when administered alone and concomitantly. The results of this study indicate that topiramate C max increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination [see Drug Interactions ( 7.6 )]. Metformin A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin (500 mg every 12 hours) and topiramate in plasma when metformin was given alone and when metformin and topiramate (100 mg every 12 hours) were given simultaneously. The results of this study indicated that the mean metformin C max and AUC 0-12h increased by 17% and 25%, respectively, when topiramate was added. Topiramate did not affect metformin Tmax. The clinical significance of the effect of topiramate on metformin pharmacokinetics is not known. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect of metformin on topiramate or topiramate extended-release capsules pharmacokinetics is unclear. Pioglitazone A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15% decrease in the AUC τ,ss of pioglitazone with no alteration in C max,ss was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in C max,ss and AUC τ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in C max,ss and AUC τ,ss of the active keto-metabolite. The clinical significance of these findings is not known [see Drug Interactions ( 7.7 )]. Glyburide A drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg per day) alone and concomitantly with topiramate (150 mg per day). There was a 22% decrease in C max and 25% reduction in AUC 24 for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4- trans -hydroxy glyburide (M1) and 3- cis -hydroxyglyburide (M2), was also reduced by 13% and 15%, reduced C max by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide. Lithium In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg per day; however, there was an observed increase in systemic exposure of lithium (27% for C max and 26% for AUC) following topiramate doses up to 600 mg per day [see Drug Interactions ( 7.8 )]. Haloperidol The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hr) in 13 healthy adults (6 males, 7 females). Amitriptyline There was a 12% increase in AUC and C max for amitriptyline (25 mg per day) in 18 healthy subjects (9 males, 9 females) receiving 200 mg per day of immediate-release topiramate [see Drug Interactions ( 7.9 )]. Sumatriptan Multiple dosing of topiramate (100 mg every 12 hours) in 24 healthy volunteers (14 males, 10 females) did not affect the pharmacokinetics of single-dose sumatriptan either orally (100 mg) or subcutaneously (6 mg). Risperidone When administered concomitantly with topiramate at escalating doses of 100, 250, and 400 mg per day, there was a reduction in risperidone systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg per day doses of topiramate). No alterations of 9-hydroxyrisperidone levels were observed. Coadministration of topiramate 400 mg per day with risperidone resulted in a 14% increase in C max and a 12% increase in AUC 12 of topiramate. There were no clinically significant changes in the systemic exposure of risperidone plus 9­ hydroxyrisperidone or of topiramate; therefore, this interaction is not likely to be of clinical significance. Propranolol Multiple dosing of topiramate (200 mg per day) in 34 healthy volunteers (17 males, 17 females) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg per day in 39 volunteers (27 males, 12 females) had no effect on the exposure to topiramate at a dose of 200 mg/day of topiramate. Dihydroergotamine Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (12 males, 12 females) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg/day dose of topiramate in the same study. Diltiazem Co-administration of diltiazem (240 mg Cardizem CD ® ) with topiramate (150 mg/day) resulted in a 10% decrease in C max and 25% decrease in diltiazem AUC, 27% decrease in C max and 18% decrease in des-acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem resulted in a 16% increase in C max and a 19% increase in AUC 12 of topiramate. Venlafaxine Multiple dosing of topiramate (150 mg/day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg) did not affect the pharmacokinetics of topiramate.

20230719

5

3 DOSAGE FORMS AND STRENGTHS Topiramate extended-release capsules are available in the following strengths and colors: 25 mg: Pink opaque/white opaque, hard gelatin size "4" capsules imprinted with "ap" logo on cap and "TP4" on body in black color ink containing white to off white colored pellets. 50 mg: Light brown opaque/white opaque, hard gelatin size "3" capsules imprinted with "ap" logo on cap and "TP3" on body in black color ink containing white to off white colored pellets. 100 mg: Blue opaque/white opaque, hard gelatin size "1" capsules imprinted with "ap" logo on cap and "TP2" on body in black color ink containing white to off white colored pellets. 200 mg: Blue opaque/pink opaque, hard gelatin size "0 el" capsules imprinted with "ap" logo on cap in white color ink and "TP1" on body in black color ink containing white to off white colored pellets. Extended-release capsules: 25 mg, 50 mg, 100 mg, and 200 mg ( 3 )

Topiramate Topiramate TOPIRAMATE TOPIRAMATE SUCROSE HYPROMELLOSE, UNSPECIFIED ETHYLCELLULOSE, UNSPECIFIED AMMONIA MEDIUM-CHAIN TRIGLYCERIDES OLEIC ACID POLYETHYLENE GLYCOL, UNSPECIFIED POVIDONE, UNSPECIFIED GLYCERYL DIBEHENATE POLYVINYL ALCOHOL, UNSPECIFIED TITANIUM DIOXIDE TALC LECITHIN, SOYBEAN XANTHAN GUM GELATIN, UNSPECIFIED FD&C BLUE NO. 1 FD&C RED NO. 3 FD&C RED NO. 40 SHELLAC ALCOHOL ISOPROPYL ALCOHOL BUTYL ALCOHOL PROPYLENE GLYCOL FERROSOFERRIC OXIDE POTASSIUM HYDROXIDE Pink opaque white opaque ap;TP4 Topiramate Topiramate TOPIRAMATE TOPIRAMATE SUCROSE HYPROMELLOSE, UNSPECIFIED ETHYLCELLULOSE, UNSPECIFIED AMMONIA MEDIUM-CHAIN TRIGLYCERIDES OLEIC ACID POLYETHYLENE GLYCOL, UNSPECIFIED POVIDONE, UNSPECIFIED GLYCERYL DIBEHENATE POLYVINYL ALCOHOL, UNSPECIFIED TITANIUM DIOXIDE TALC LECITHIN, SOYBEAN XANTHAN GUM GELATIN, UNSPECIFIED FERRIC OXIDE YELLOW FERRIC OXIDE RED SHELLAC ALCOHOL ISOPROPYL ALCOHOL BUTYL ALCOHOL PROPYLENE GLYCOL FERROSOFERRIC OXIDE POTASSIUM HYDROXIDE Light brown opaque white opaque ap;TP3 Topiramate Topiramate TOPIRAMATE TOPIRAMATE SUCROSE HYPROMELLOSE, UNSPECIFIED ETHYLCELLULOSE, UNSPECIFIED AMMONIA MEDIUM-CHAIN TRIGLYCERIDES OLEIC ACID POLYETHYLENE GLYCOL, UNSPECIFIED POVIDONE, UNSPECIFIED GLYCERYL DIBEHENATE POLYVINYL ALCOHOL, UNSPECIFIED TITANIUM DIOXIDE TALC LECITHIN, SOYBEAN XANTHAN GUM GELATIN, UNSPECIFIED SODIUM LAURYL SULFATE SHELLAC ALCOHOL ISOPROPYL ALCOHOL BUTYL ALCOHOL PROPYLENE GLYCOL FERROSOFERRIC OXIDE POTASSIUM HYDROXIDE Blue opaque white opaque ap;TP2 Topiramate Topiramate TOPIRAMATE TOPIRAMATE SUCROSE HYPROMELLOSE, UNSPECIFIED ETHYLCELLULOSE, UNSPECIFIED AMMONIA MEDIUM-CHAIN TRIGLYCERIDES OLEIC ACID POLYETHYLENE GLYCOL, UNSPECIFIED POVIDONE, UNSPECIFIED GLYCERYL DIBEHENATE POLYVINYL ALCOHOL, UNSPECIFIED TITANIUM DIOXIDE TALC LECITHIN, SOYBEAN XANTHAN GUM GELATIN, UNSPECIFIED FD&C BLUE NO. 1 FD&C RED NO. 3 FD&C RED NO. 40 SHELLAC ALCOHOL ISOPROPYL ALCOHOL BUTYL ALCOHOL PROPYLENE GLYCOL FERROSOFERRIC OXIDE POTASSIUM HYDROXIDE Blue opaque pink opaque ap;TP1

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis An increase in urinary bladder tumors was observed in mice given topiramate (0, 20, 75, and 300 mg/kg/day) in the diet for 21 months. An increase in the incidence of bladder tumors in males and females receiving 300 mg/kg was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. The higher of the doses not associated with an increase in tumors (75 mg/kg/day) is equivalent to the maximum recommended human dose (MRHD) for epilepsy and approximately 4 times the MRHD for migraine (100 mg) on a mg/m 2 basis. The relevance of this finding to human carcinogenic risk is uncertain. No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/kg/day (approximately 3 times the MRHD for epilepsy and 12 times the MRHD for migraine on a mg/m 2 basis). Mutagenesis Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitro and in vivo assays. Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increase unscheduled DNA synthesis in rat hepatocytes in vitro; and it did not increase chromosomal aberrations in human lymphocytes in vitro or in rat bone marrow in vivo . Impairment of Fertility No adverse effects on male or female fertility were observed in rats administered oral doses of up to 100 mg/kg/day (2.5 times the MRHD for epilepsy and 10 times the MRHD for migraine on a mg/m 2 basis) prior to and during mating and early pregnancy.

13 NON-CLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis An increase in urinary bladder tumors was observed in mice given topiramate (0, 20, 75, and 300 mg/kg/day) in the diet for 21 months. An increase in the incidence of bladder tumors in males and females receiving 300 mg/kg was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. The higher of the doses not associated with an increase in tumors (75 mg/kg/day) is equivalent to the maximum recommended human dose (MRHD) for epilepsy and approximately 4 times the MRHD for migraine (100 mg) on a mg/m 2 basis. The relevance of this finding to human carcinogenic risk is uncertain. No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/kg/day (approximately 3 times the MRHD for epilepsy and 12 times the MRHD for migraine on a mg/m 2 basis). Mutagenesis Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitro and in vivo assays. Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increase unscheduled DNA synthesis in rat hepatocytes in vitro; and it did not increase chromosomal aberrations in human lymphocytes in vitro or in rat bone marrow in vivo . Impairment of Fertility No adverse effects on male or female fertility were observed in rats administered oral doses of up to 100 mg/kg/day (2.5 times the MRHD for epilepsy and 10 times the MRHD for migraine on a mg/m 2 basis) prior to and during mating and early pregnancy.

ANDA215663

Topiramate

Topiramate

27241-227

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL NDC 27241-227-30 30 Capsules Topiramate Extended-Release Capsules 25 mg PHARMACIST: Dispense the accompanying Medication Guide to each patient. Rx Only ajanta NDC 27241-228-30 30 Capsules Topiramate Extended-Release Capsules 50 mg PHARMACIST: Dispense the accompanying Medication Guide to each patient. Rx Only ajanta NDC 27241-229-30 30 Capsules Topiramate Extended-Release Capsules 100 mg PHARMACIST: Dispense the accompanying Medication Guide to each patient. Rx Only ajanta NDC 27241-230-30 30 Capsules Topiramate Extended-Release Capsules 200 mg PHARMACIST: Dispense the accompanying Medication Guide to each patient. Rx Only ajanta 25mg 50mg 100mg 200mg

Warnings and Precautions ( 5.1 , 5.4 , 5.10 , 5.11 , 5.14 ) 10/2022

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Administration Instructions Counsel patients to swallow topiramate extended-release capsules whole and intact. Topiramate extended-release capsules should not be sprinkled on food, chewed, or crushed [see Dosage and Administration ( 2.7 )]. Consumption of Alcohol Advise patients to completely avoid consumption of alcohol at least 6 hours prior to and 6 hours after taking topiramate extended-release capsules [see Warnings and Precautions ( 5.5 )] . Eye Disorders Advise patients taking topiramate extended-release capsules to seek immediate medical attention if they experience blurred vision, visual disturbances or periorbital pain [see Warnings and Precautions ( 5.1 , 5.2 )]. Oligohydrosis and Hyperthermia Counsel patients that topiramate extended-release capsules, especially pediatric patients, can cause decreased sweating and increased body temperature, especially in hot weather, and they should seek medical attention if this is noticed [see Warnings and Precautions ( 5.3 )]. Metabolic Acidosis Inform patients about the potentially significant risk for metabolic acidosis that may be asymptomatic and may be associated with adverse effects on kidneys (e.g., kidney stones, nephrocalcinosis), bones (e.g., osteoporosis, osteomalacia, and/or rickets in children), and growth (e.g., growth delay/retardation) in pediatric patients, and on the fetus [see Warnings and Precautions ( 5.4 )]. Suicidal Behavior and Ideation Counsel patients, their caregivers, and families that AEDs, including topiramate extended-release capsules, may increase the risk of suicidal thoughts and behavior and they 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 [see Warnings and Precautions ( 5.6 )]. Interference With Cognitive and Motor Performance Warn patients about the potential for somnolence, dizziness, confusion, difficulty concentrating, or visual effects and advise them not to drive or operate machinery until they have gained sufficient experience on topiramate extended-release capsules to gauge whether it adversely affects their mental performance, motor performance, and/or vision [see Warnings and Precautions ( 5.7 )] . Advise patients that even when taking topiramate extended-release capsules or other anticonvulsants, some patients with epilepsy will continue to have unpredictable seizures. Therefore, counsel all patients taking topiramate extended-release capsules for epilepsy to exercise appropriate caution when engaging in any activities where loss of consciousness could result in serious danger to themselves or those around them (including swimming, driving a car, climbing in high places, etc.). Some patients with refractory epilepsy will need to avoid such activities altogether. Physicians should discuss the appropriate level of caution with their patients, before patients with epilepsy engage in such activities. Fetal Toxicity Counsel pregnant women and women of childbearing potential that use of topiramate extended-release capsules during pregnancy can cause fetal harm, including an increased risk for cleft lip and/or cleft palate (oral clefts), which occur early in pregnancy before many women know they are pregnant. Also inform patients that infants exposed to topiramate monotherapy in utero may be small for their gestational age [see Use in Specific Populations ( 8.1 )] . There may also be risks to the fetus from chronic metabolic acidosis with use of topiramate extended-release capsules during pregnancy [see Warnings and Precautions ( 5.4 , 5.8 )]. When appropriate, prescribers should counsel pregnant women and women of childbearing potential about alternative therapeutic options. Advise women of childbearing potential who are not planning a pregnancy to use effective contraception while using topiramate, keeping in mind that there is a potential for decreased contraceptive efficacy when using estrogen-containing birth control with topiramate [see Warnings and Precautions ( 5.8 ) and Drug Interactions ( 7.5 )]. Encourage pregnant women using topiramate extended-release capsules to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations ( 8.1 )]. Decrease in Bone Mineral Density Inform the patient or caregiver that long-term treatment with Topiramate extended-release capsules can decrease bone formation and increase bone resorption in children [see Warnings and Precautions ( 5.10 )]. Negative Effects on Growth (Height and Weight) Discuss with the patient or caregiver that long-term Topiramate extended-release capsules treatment may attenuate growth as reflected by slower height increase and weight gain in pediatric patients [see Warnings and Precautions ( 5.11 )]. Serious Skin Reactions Inform patients about the signs of serious skin reactions. Instruct patients to immediately inform their healthcare provider at the first appearance of skin rash [see Warnings and Precautions ( 5.12 )] . Hyperammonemia and Encephalopathy Warn patients about the possible development of hyperammonemia with or without encephalopathy. Although hyperammonemia may be asymptomatic, clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. This hyperammonemia and encephalopathy can develop with topiramate treatment alone or with topiramate treatment with concomitant valproic acid (VPA). Patients should be instructed to contact their physician if they develop unexplained lethargy, vomiting, or changes in mental status [see Warnings and Precautions ( 5.13 )]. Kidney Stones Instruct patients, particularly those with predisposing factors, to maintain an adequate fluid intake in order to minimize the risk of kidney stone formation [see Warnings and Precautions ( 5.14 )]. Hypothermia Counsel patients that topiramate extended-release capsules can cause a reduction in body temperature, which can lead to alterations in mental status. If they note such changes, they should call their health care professional and measure their body temperature. Patients taking concomitant valproic acid should be specifically counseled on this potential adverse reaction [see Warnings and Precautions ( 5.15 )]. #All trademarks are the properties of their respective owners. Marketed by: Ajanta Pharma USA Inc. Bridgewater, NJ 08807. Made in INDIA Revised: 07/2023

MEDICATION GUIDE Topiramate (toe pir′ a mate) Extended-Release Capsules What is the most important information I should know about topiramate extended-release capsules? Take topiramate extended-release capsules whole. Do not sprinkle topiramate extended-release capsules on food, or break, crush, dissolve, or chew topiramate extended-release capsules before swallowing. If you cannot swallow topiramate extended-release capsules whole, tell your healthcare provider. You may need a different medicine. Do not drink alcohol within 6 hours prior to and 6 hours after topiramate extended-release capsules administration. Topiramate extended-release capsules may cause eye problems. Serious eye problems include: any sudden decrease in vision with or without eye pain and redness, a blockage of fluid in the eye causing increased pressure in the eye (secondary angle closure glaucoma). These eye problems can lead to permanent loss of vision if not treated. You should call your healthcare provider right away if you have any new eye symptoms, including any new problems with your vision. Topiramate extended-release capsules may cause decreased sweating and increased body temperature (fever). People, especially children, should be watched for signs of decreased sweating and fever, especially in hot temperatures. Some people may need to be hospitalized for this condition. If a high fever, a fever that does not go away, or decreased sweating develops, call your healthcare provider right away. Topiramate extended-release capsules can increase the level of acid in your blood (metabolic acidosis). If left untreated, metabolic acidosis can cause brittle or soft bones (osteoporosis, osteomalacia, osteopenia), kidney stones, can slow the rate of growth in children, and may possibly harm your baby if you are pregnant. Metabolic acidosis can happen with or without symptoms. Sometimes people with metabolic acidosis will: feel tired not feel hungry (loss of appetite) feel changes in heartbeat have trouble thinking clearly Your healthcare provider should do a blood test to measure the level of acid in your blood before and during your treatment with topiramate extended-release capsules. If you are pregnant, you should talk to your healthcare provider about whether you have metabolic acidosis. Like other antiepileptic drugs, topiramate extended-release capsules 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 attempts to commit suicide new or worse depression new or worse anxiety feeling agitated or restless panic attacks trouble sleeping (insomnia) new or worse irritability acting aggressive, being angry, or violent acting on dangerous impulses an extreme increase in activity and talking (mania) other unusual changes in behavior or mood Do not stop topiramate extended-release capsules without first talking to a healthcare provider. Stopping topiramate extended-release capsules suddenly can cause serious problems. Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. 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. Topiramate extended-release capsules can harm your unborn baby. If you take topiramate extended-release capsules during pregnancy, your baby has a higher risk for birth defects called cleft lip and cleft palate. These defects can begin early in pregnancy, even before you know you are pregnant. Cleft lip and cleft palate may happen even in children born to women who are not taking any medicines and do not have other risk factors. There may be other medicines to treat your condition that have a lower chance of birth defects. All women of childbearing age should talk to their healthcare providers about using other possible treatments instead of topiramate extended-release capsules. If the decision is made to use topiramate extended-release capsules, you should use effective birth control (contraception) unless you are planning to become pregnant. You should talk to your doctor about the best kind of birth control to use while you are taking topiramate extended-release capsules. Tell your healthcare provider right away if you become pregnant while taking topiramate extended-release capsules. You and your healthcare provider should decide if you will continue to take topiramate extended-release capsules while you are pregnant. If you take topiramate extended-release capsules during pregnancy, your baby may be smaller than expected at birth. The long-term effects of this are not known. Talk to your healthcare provider if you have questions about this risk during pregnancy. Metabolic acidosis may have harmful effects on your baby. Talk to your healthcare provider if topiramate extended-release capsules has caused metabolic acidosis during your pregnancy. Pregnancy Registry: If you become pregnant while taking topiramate extended-release capsules, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1­888-233-2334. The purpose of this registry is to collect information about the safety of topiramate extended-release capsules and other antiepileptic drugs during pregnancy. Topiramate extended-release capsules may decrease the density of bones when used over a long period. Topiramate extended-release capsules may slow height increase and weight gain in children and adolescents when used over a long period. What is Topiramate extended-release capsules? Topiramate extended-release capsules are a prescription medicine used: to treat certain types of seizures (partial onset seizures and primary generalized tonic-clonic seizures) in people 6 years and older, with other medicines to treat certain types of seizures (partial onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome) in adults and children 6 years and older to prevent migraine headaches in adults and adolescents 12 years of age and older. Before taking topiramate extended-release capsules, tell your healthcare provider about all of your medical conditions, including if you: have or have had depression, mood problems, or suicidal thoughts or behavior have kidney problems, kidney stones, or are getting kidney dialysis have a history of metabolic acidosis (too much acid in the blood) have liver problems have weak, brittle or soft bones (osteomalacia, osteoporosis, osteopenia, or decreased bone density) have lung or breathing problems have eye problems, especially glaucoma have diarrhea have a growth problem are on a diet high in fat and low in carbohydrates, which is called a ketogenic diet are having surgery are pregnant or plan to become pregnant are breastfeeding. Topiramate passes into your breast milk. Breastfed babies may be sleepy or have diarrhea. It is not known if the topiramate that passes into breast milk can cause other serious harm to your baby. Talk to your healthcare provider about the best way to feed your baby if you take topiramate extended-release capsules. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially, tell your healthcare provider if you take: Valproic acid (such as DEPAKENE or DEPAKOTE) any medicines that impair or decrease your thinking, concentration, or muscle coordination birth control pills. Topiramate extended-release capsules may make your birth control pills less effective. Tell your healthcare provider if your menstrual bleeding changes while you are taking birth control pills and Topiramate extended-release capsules. Ask your healthcare provider if you are not sure if your medicine is listed above. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time you get a new medicine. Do not start a new medicine without talking with your healthcare provider. How should I take topiramate extended-release capsules? Take topiramate extended-release capsules exactly as prescribed. Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider. Take topiramate extended-release capsules whole. Do not sprinkle topiramate extended-release capsules on food, or break, crush, dissolve, or chew topiramate extended-release capsules before swallowing. Topiramate extended-release capsules can be taken before, during, or after a meal. Drink plenty of fluids during the day. This may help prevent kidney stones while taking topiramate extended-release capsules. If you take too much topiramate extended-release capsules, call your healthcare provider right away or go to the nearest emergency room. Talk to your health care provider on what you should do if you miss a dose. Do not stop taking topiramate extended-release capsules without talking to your healthcare provider. Stopping topiramate extended-release capsules suddenly may cause serious problems. If you have epilepsy and you stop taking topiramate extended-release capsules suddenly, you may have seizures that do not stop. Your healthcare provider will tell you how to stop taking topiramate extended-release capsules slowly. Your healthcare provider may do blood tests while you take topiramate extended-release capsules. What should I avoid while taking topiramate extended-release capsules? Do not drink alcohol within 6 hours before or 6 hours after taking topiramate extended-release capsules. Topiramate extended-release capsules and alcohol can cause serious side effects such as severe sleepiness and dizziness and an increase in seizures. Do not drive a car or operate heavy machinery until you know how topiramate extended-release capsules affect you. Topiramate extended-release capsules can slow your thinking and motor skills and may affect vision. What are the possible side effects of topiramate extended-release capsules? Topiramate extended-release capsules may cause serious side effects, including: See “What is the most important information I should know about topiramate extended-release capsules?” Serious skin reactions. Topiramate extended-release capsules may cause a severe rash with blisters and peeling skin, especially around the mouth, nose, eyes, and genitals (Stevens-Johnson syndrome). Topiramate extended-release capsules may also cause a rash with blisters and peeling skin over much of the body that may cause death (toxic epidermal necrolysis). Call your healthcare provider right away if you develop a skin rash or blisters. High blood ammonia levels. High ammonia in the blood can affect your mental activities, slow your alertness, make you feel tired, or cause vomiting. This has happened when topiramate extended-release capsules are taken with a medicine called valproic acid (DEPAKENE and DEPAKOTE). Kidney stones. Drink plenty of fluids when taking topiramate extended-release capsules to decrease your chances of getting kidney stones. Low body temperature. Taking topiramate extended-release capsules when you are also taking valproic acid cause a drop in body temperature to less than 95ºF, feeling tired, confusion, or coma. Effects on thinking and alertness. Topiramate extended-release capsules may affect how you think, and cause confusion, problems with concentration, attention, memory, or speech. Topiramate extended-release capsules may cause depression or mood problems, tiredness, and sleepiness. Dizziness or loss of muscle coordination. Call your healthcare provider right away if you have any of the symptoms above. The most common side effects of topiramate extended-release capsules include: tingling of the arms and legs (paresthesia) not feeling hungry nausea weight loss abnormal vision a change in the way foods taste nervousness speech problems dizziness slow reactions upper respiratory tract infection fever tiredness sleepiness/drowsiness difficulty with memory diarrhea pain in abdomen decreased feeling or sensitivity, especially in the skin Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of topiramate extended-release capsules. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Ajanta Pharma USA, Inc., at 1-855-664-7744. How should I store topiramate extended-release capsules? Store topiramate extended-release capsules at room temperature between 59°F to 86°F (15°C to 30°C). This package is child-resistant. Keep topiramate extended-release capsules in a tightly closed container. Keep topiramate extended-release capsules dry and away from moisture and light. Keep topiramate extended-release capsules and all medicines out of the reach of children. General information about the safe and effective use of topiramate extended-release capsules. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use topiramate extended-release capsules for a condition for which it was not prescribed. Do not give topiramate extended-release capsules 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 topiramate extended-release capsules that is written for health professionals. What are the ingredients in topiramate extended-release capsules? Active ingredient: topiramate Inactive ingredients: sugar spheres, hypromellose, ethyl cellulose, ammonium hydroxide, triglyceride, oleic acid, polyethylene glycol, povidone, glyceryl dibehenate, polyvinyl alcohol, titanium dioxide, talc, lecithin, xanthan gum. The capsule shell contains: gelatin, titanium dioxide, (25 mg, 50 mg, 100 mg and 200 mg), sodium lauryl sulfate (100 mg). FD & C Blue 1, FD & C Red 3, FD & C Red 40 (25 mg, 100 mg and 200 mg), iron oxide yellow, iron oxide red (50 mg). For 25 mg, 50 mg, 100 mg (body & cap) and 200 mg (body only) strengths, imprinting black ink contains: shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide and potassium hydroxide. For 200 mg (cap only) strength, imprinting white ink contains: shellac, ethanol, isopropyl alcohol, n-butanol, propylene glycol, ammonia solution, potassium hydroxide and titanium dioxide. #All trademarks are the properties of their respective owners. This Medication Guide has been approved by the U.S. Food and Drug Administration Marketed by: Ajanta Pharma USA Inc. Bridgewater, NJ 08807. Made in INDIA Revised: 07/2023

14 CLINICAL STUDIES 14.1 Bridging Study to Demonstrate Pharmacokinetic Equivalence between Extended-Release and Immediate-Release Topiramate Formulations The basis for approval of the extended-release formulation (topiramate extended-release capsules) included the studies described below using an immediate-release formulation and the demonstration of the pharmacokinetic equivalence of topiramate extended-release capsules to immediate-release topiramate through the analysis of concentrations and cumulative AUCs at multiple time points [see Clinical Pharmacology ( 12.6 )]. The clinical studies described in the following sections were conducted using immediate-release topiramate. 14.2 Monotherapy Epilepsy Patients With Partial-Onset or Primary Generalized Tonic-Clonic Seizures Adults and Pediatric Patients 10 Years of Age and Older The effectiveness of topiramate as initial monotherapy in adults and pediatric patients 10 years of age and older with partial onset or primary generalized tonic-clonic seizures was established in a multicenter, randomized, double-blind, dose-controlled, parallel-group trial (Study 1). Study 1 was conducted in 487 patients diagnosed with epilepsy (6 years to 83 years of age) who had 1 or 2 well- documented seizures during the 3-month retrospective baseline phase who then entered the study and received topiramate 25 mg per day for 7 days in an open-label fashion. Forty-nine percent of subjects had no prior AED treatment and 17% had a diagnosis of epilepsy for greater than 24 months. Any AED therapy used for temporary or emergency purposes was discontinued prior to randomization. In the double-blind phase, 470 patients were randomized to titrate up to 50 mg/day or 400 mg/day of topiramate. If the target dose could not be achieved, patients were maintained on the maximum tolerated dose. Fifty-eight percent of patients achieved the maximal dose of 400 mg/day for greater than 2 weeks, and patients who did not tolerate 150 mg/day were discontinued. The primary efficacy assessment was a between-group comparison of time to first seizure during the double- blind phase. Comparison of the Kaplan-Meier survival curves of time to first seizure favored the topiramate 400 mg/day group over the topiramate 50 mg/day group (Figure 1). The treatment effects with respect to time to first seizure were consistent across various patient subgroups defined by age, sex, geographic region, baseline body weight, baseline seizure type, time since diagnosis, and baseline AED use. Figure 1: Kaplan-Meier Estimates of Cumulative Rates for Time to First Seizure in Study 1 Pediatric Patients 6 to 9 Years of Age The conclusion that topiramate is effective as initial monotherapy in pediatric patients 6 years to 9 years of age with partial-onset or primary generalized tonic-clonic seizures was based on a pharmacometric bridging approach using data from the controlled epilepsy trials conducted with immediate-release topiramate described in labeling. The approach consisted of first showing a similar exposure response relationship between pediatric patients down to 2 years of age and adults when immediate-release topiramate was given as adjunctive therapy [see Use in Specific Populations ( 8.4 )] . Similarity of exposure-response was demonstrated in pediatric patients 6 years to less than 16 years of age and adults when topiramate was given as initial monotherapy. Specific dosing in pediatric patients 6 years to 9 years of age was derived from simulations utilizing plasma exposure ranges observed in pediatric and adult patients treated with immediate-release topiramate initial monotherapy [see Dosage and Administration ( 2.1 )] . figure1 14.3 Adjunctive Therapy Epilepsy Adult Patients With Partial-Onset Seizures The effectiveness of topiramate as an adjunctive treatment for adults with partial-onset seizures was established in six multicenter, randomized, double-blind, placebo-controlled trials (Studies 2, 3, 4, 5, 6, and 7), two comparing several dosages of topiramate and placebo and four comparing a single dosage with placebo, in patients with a history of partial onset seizures, with or without secondarily generalized seizures. Patients in these studies were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In each study, patients were stabilized on optimum dosages of their concomitant AEDs during baseline phase lasting between 4 and 12 weeks. Patients who experienced a pre-specified minimum number of partial-onset seizures, with or without secondary generalization, during the baseline phase (12 seizures for 12-week baseline, 8 for 8-week baseline or 3 for 4-week baseline) were randomly assigned to placebo or a specified dose of topiramate tablets in addition to their other AEDs. Following randomization, patients began the double-blind phase of treatment. In five of the six studies, patients received active drug beginning at 100 mg per day; the dose was then increased by 100 mg or 200 mg/day increments weekly or every other week until the assigned dose was reached, unless intolerance prevented increases. In Study 7, the 25 or 50 mg/day initial doses of topiramate were followed by respective weekly increments of 25 or 50 mg/day until the target dose of 200 mg/day was reached. After titration, patients entered a 4, 8 or 12-week stabilization period. The numbers of patients randomized to each dose, and the actual mean and median doses in the stabilization period are shown in Table 10. Pediatric Patients 6 Years to 16 Years of Age With Partial-Onset Seizures The effectiveness of topiramate as an adjunctive treatment for pediatric patients 6 years to 16 years of age with partial-onset seizures was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 8), comparing topiramate and placebo in patients with a history of partial-onset seizures, with or without secondarily generalized seizures. Patients in Study 8 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In Study 8, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least six partial onset seizures, with or without secondarily generalized seizures, during the baseline phase were randomly assigned to placebo or topiramate in addition to their other AEDs. Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 25 or 50 mg/day; the dose was then increased by 25 mg to 150 mg/day increments every other week until the assigned dosage of 125, 175, 225 or 400 mg/day based on patients' weight to approximate a dosage of 6 mg/kg/day per day was reached, unless intolerance prevented increases. After titration, patients entered an 8-week stabilization period. Patients With Primary Generalized Tonic-Clonic Seizures The effectiveness of topiramate as an adjunctive treatment for primary generalized tonic-clonic seizures in patients 6 years of age and older was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 9), comparing a single dosage of topiramate and placebo (see Table 11). Patients in Study 9 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least three primary generalized tonic-clonic seizures during the baseline phase were randomly assigned to placebo or topiramate in addition to their other AEDs. Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 50 mg/day for four weeks; the dose was then increased by 50 mg to 150 mg/day increments every other week until the assigned dose of 175, 225 or 400 mg/day based on patients' body weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered a 12-week stabilization period. Patients With Lennox-Gastaut Syndrome The effectiveness of topiramate as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome in patients 6 years of age and older was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 10), comparing a single dosage of topiramate with placebo (see Table 11). Patients in Study 10 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients who were experiencing at least 60 seizures per month before study entry were stabilized on optimum dosages of their concomitant AEDs during a 4 week baseline phase. Following baseline, patients were randomly assigned to placebo or topiramate in addition to their other AEDs. Active drug was titrated beginning at 1 mg/kg/day for a week; the dose was then increased to 3 mg/kg/day for one week then to 6 mg/kg/day. After titration, patients entered an 8-week stabilization period. The primary measures of effectiveness were the percent reduction in drop attacks and a parental global rating of seizure severity. Table 10: Immediate Release Topiramate Dose Summary During the Stabilization Periods of Each of Six Double-Blind, Placebo-Controlled, Adjunctive Trials in Adults With Partial-Onset Seizures* * Dose-response studies were not conducted for other indications or pediatric partial-onset seizure † Placebo dosages are given as the number of tablets. Placebo target dosages were as follows: Study 4 (4 tablets/day); Studies 2 and 5 (6 tablets/day); Studies 6 and 7 (8 tablets/day); Study 3 (10 tablets/day) Target Topiramate Dosage (mg per day) Study Stabilization Dose Placebo † 200 400 600 800 1,000 2 N 42 42 40 41 -­ -­ Mean Dose 5.9 200 390 556 -­ -­ Median Dose 6.0 200 400 600 -­ -­ 3 N 44 -­ -­ 40 45 40 Mean Dose 9.7 -­ -­ 544 739 796 Median Dose 10.0 -­ -­ 600 800 1,000 4 N 23 -­ 19 -­ -­ -­ Mean Dose 3.8 -­ 395 -­ -­ -­ Median Dose 4.0 -­ 400 -­ -­ -­ 5 N 30 -­ -­ 28 -­ -­ Mean Dose 5.7 -­ -­ 522 -­ -­ Median Dose 6.0 -­ -­ 600 -­ -­ 6 N 28 -­ -­ -­ 25 -­ Mean Dose 8.0 -­ -­ -­ 568 -­ Median Dose 8.0 -­ -­ -­ 600 -­ 7 N 90 157 -­ -­ -­ -­ Mean Dose 8 200 -­ -­ -­ -­ Median Dose 8 200 -­ -­ -­ -­ In all adjunctive topiramate trials, the reduction in seizure rate from baseline during the entire double-blind phase was measured. The median percent reductions in seizure rates and the responder rates (fraction of patients with at least a 50% reduction) by treatment group for each study are shown below in Table 11. As described above, a global improvement in seizure severity was also assessed in the Lennox-Gastaut trial. Table 11: Efficacy Results in Double-Blind, Placebo-Controlled, Adjunctive Epilepsy Trials Target Topiramate Dosage (mg per day) Study # # Placebo 200 400 600 800 1,000 ≈6mg/ kg/day* Partial Onset Seizures Studies in Adults 2 N 45 45 45 46 -­ -­ -­ Median % Reduction 12 27 † 48 ‡ 45 § -­ -­ -­ % Responders 18 24 44 ¶ 46 ¶ -­ -­ -­ 3 N 47 -­ -­ 48 48 47 -­ Median % Reduction 2 -­ -­ 41 § 41 § 36 § % Responders 9 -­ -­ 40 § 41 § 36 ¶ 4 N 24 -­ 23 -­ -­ -­ -­ Median % Reduction 1 -­ 41 # -­ -­ -­ -­ % Responders 8 -­ 35 ¶ -­ -­ -­ -­ 5 N 30 -­ -­ 30 -­ -­ -­ Median % Reduction -12 -­ -­ 46 Þ -­ -­ -­ % Responders 10 -­ -­ 47 § -­ -­ -­ 6 N 28 -­ -­ -­ 28 -­ -­ Median % Reduction -21 -­ -­ -­ 24 § -­ -­ % Responders 0 -­ -­ -­ 43 § -­ -­ 7 N 91 168 -­ -­ -­ -­ -­ Median % Reduction 20 44 § -­ -­ -­ -­ -­ % Responders 24 45 § Partial Onset Seizures Studies in Pediatric Patients ß 8 N 45 -­ -­ -­ -­ -­ 41 Median % Reduction 11 -­ -­ -­ -­ -­ 33 ¶ % Responders 20 -­ -­ -­ -­ -­ 39 Primary Generalized Tonic-Clonic à, ß 9 N 40 -­ -­ -­ -­ -­ 39 Median % Reduction 9 -­ -­ -­ -­ -­ 57 ¶ % Responders 20 -­ -­ -­ -­ -­ 56 § Lennox-Gastaut Syndrome è, ß 10 N 49 -­ -­ -­ -­ -­ 46 Median % Reduction -5 -­ -­ -­ -­ -­ 15 ¶ % Responders 14 28 ð Improvement in Seizure Severity ø 28 52 ¶ Comparisons with placebo: * For Studies 8 and 9, specified target dosages (less than 9.3 mg/kg/day) were assigned based on subject's weight to approximate a dosage of 6mg/kg per day; these dosages corresponded to mg/day dosages of 125, 175, 225, and 400 mg/day † p=0.080; ‡ p less than or equal to 0.010; § p less than or equal to 0.001; ¶ p less than or equal to 0.050; # p=0.065; Þ p less than or equal to 0.005; ß Studies included pediatric patients 2 years of age and older, an age group for which topiramate is not indicated [see Indications and Usage (1.2) and Use in Specific Populations (8.4)] à Median % reduction and % responders are reported for PGTC seizures; è Median % reduction and % responders for drop attacks, i.e., tonic or atonic seizures ð p=0.071; ø Percentage of subjects who were minimally, much, or very much improved from baseline. Subset analyses of the antiepileptic efficacy of topiramate tablets in these studies showed no differences as a function of gender, race, age, baseline seizure rate, or concomitant AED. In clinical trials for epilepsy, daily dosages were decreased in weekly intervals by 50 mg per day to 100 mg per day in adults and over a 2- to 8-week period in pediatric patients; transition was permitted to a new antiepileptic regimen when clinically indicated. 14.4 Preventive Treatment of Migraine Adult Patients The results of 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trials conducted in US (Study 11) or the US and Canada (Study 12) established the effectiveness of immediate-release topiramate in the preventive treatment of migraine. The design of both trials was identical, enrolling patients with a history of migraine with or without aura, for at least 6 months, according to the International Headache Society (IHS) diagnostic criteria. Patients with a history of cluster headaches or basilar, opthalmoplegic, hemiplegic, or transformed migraine headaches were excluded from the trials. Patients were required to have completed up to a 2-week washout of any prior migraine preventative medications before starting the baseline phase. Patients who experienced 3 to 12 migraine headaches over the 4 weeks in the baseline phase were randomized to either immediate-release topiramate 50 mg/day, 100 mg/day, 200 mg/day (twice the recommended daily dosage for migraine prophylaxis) or placebo, and treated for a total of 26 weeks (8-week titration period and 18­ week maintenance period.). Treatment was initiated at 25 mg/day for one week, and then the daily dosage was increased by 25 mg increments each week until reaching the assigned target dose or maximum tolerated dose (administered twice daily). Effectiveness of treatment was assessed by the reduction in migraine headache frequency, as measured by the change in 4-week migraine rate (according to migraines classified by IHS criteria) from the baseline phase to double-blind treatment period in each immediate-release topiramate treatment group compared to placebo in the Intent-To-Treat (ITT) population. In Study 11, a total of 469 patients (416 females, 53 males) ranging in age from 13 years to 70 years, were randomized and provided efficacy data. Two hundred sixty-five patients completed the entire 26-week double- blind phase. The median average daily dosages were 48 mg/day, 88 mg/day, and 132 mg/day in the target dose groups of topiramate 50, 100 and 200 mg/day, respectively. The mean migraine headache frequency rate at baseline was approximately 5.5 migraine headaches per 28 days, and was similar across treatment groups. The change in the mean 4-week migraine headache frequency from baseline to the double-blind phase was -1.3, -2.1, and -2.2 in the immediate-release topiramate 50, 100, and 200 mg/day groups, respectively, versus -0.8 in the placebo group (see Figure 2). The treatment differences between the immediate release topiramate 100 and 200 mg/day groups versus placebo were similar and statistically significant (p less than 0.001 for both comparisons). In Study 12, a total of 468 patients (406 females, 62 males) ranging in age from 12 years to 65 years, were randomized and provided efficacy data. Two hundred fifty-five patients completed the entire 26-week double- blind phase. The median average daily dosages were 47 mg/day, 86 mg/day, and 150 mg/day in the target dose groups of immediate-release topiramate 50, 100, and 200 mg/day, respectively. The mean migraine headache frequency rate at baseline was approximately 5.5 migraine headaches per 28 days and was similar across treatment groups. The change in the mean 4-week migraine headache period frequency from baseline to the double-blind phase was -1.4, -2.1, and -2.4 in the immediate-release topiramate 50, 100, and 200 mg/day groups, respectively, versus -1.1 in the placebo group (see Figure 2). The differences between the immediate-release topiramate 100 and 200 mg per day groups versus placebo were similar and statistically significant (p = 0.008 and p less than 0.001, respectively). In both studies there were no apparent differences in treatment effect within age or gender subgroups. Because most patients were Caucasian, there were insufficient numbers of patients from different races to make a meaningful comparison of race. For patients withdrawing from immediate-release topiramate, daily dosages were decreased in weekly intervals by 25 mg/day to 50 mg/day. Figure 2: Reduction in 4-Week Migraine Headache Frequency (Studies 11 and 12 for Adults and Adolescents) Pediatric Patients 12 Years to 17 Years of Age The effectiveness of immediate-release topiramate for the preventive treatment of migraine in pediatric patients 12 years to 17 years of age was established in a multicenter, randomized, double-blind, parallel-group trial (Study 13). The study enrolled 103 patients (40 male, 63 female) 12 to 17 years of age with episodic migraine headaches with or without aura. Patient selection was based on IHS criteria for migraines (using proposed revisions to the 1988 IHS pediatric migraine criteria [IHS-R criteria]). Patients who experienced 3 to 12 migraine attacks (according to migraines classified by patient reported diaries) and less than or equal to 14 headache days (migraine and non-migraine) during the 4-week prospective baseline period were randomized to either immediate-release topiramate 50 mg/day, 100 mg/day, or placebo and treated for a total of 16 weeks (4-week titration period followed by a 12 week maintenance period). Treatment was initiated at 25 mg/day for one week, and then the daily dosage was increased by 25 mg increments each week until reaching the assigned target dose or maximum tolerated dose (administered twice daily). Approximately 80% or more patients in each treatment group completed the study. The median average daily dosages were 45 and 79 mg/day in the target dose groups of immediate-release topiramate 50 and 100 mg/day, respectively. Effectiveness of treatment was assessed by comparing each immediate-release topiramate treatment group to placebo (ITT population) for the percent reduction from baseline to the last 12 weeks of the double-blind phase in the monthly migraine attack rate (primary endpoint). The percent reduction from baseline to the last 12 weeks of the double-blind phase in average monthly migraine attack rate is shown in Table 12. The 100 mg immediate-release topiramate dose produced a statistically significant treatment difference relative to placebo of 28% reduction from baseline in the monthly migraine attack rate. The mean reduction from baseline to the last 12 weeks of the double-blind phase in average monthly attack rate, a key secondary efficacy endpoint in Study 13 (and the primary efficacy endpoint in Studies 11 and 12, of adults) was 3 for 100 mg immediate-release topiramate dose and 1.7 for placebo. This 1.3 treatment difference in mean reduction from baseline of monthly migraine rate was statistically significant (p=0.0087). Table 12: Percent Reduction from Baseline to the Last 12 Weeks of Double-Blind Phase in Average Monthly Attack Rate: Study 13 (Intent-to-Treat Analysis Set) * P-values (two-sided) for comparisons relative to placebo are generated by applying an ANCOVA model on ranks that includes subject’s stratified age at baseline, treatment group, and analysis center as factors and monthly migraine attack rate during baseline period as a covariate. † P-values for the dose groups are the adjusted p-value according to the Hochberg multiple comparison procedure. ‡ Indicates p-value is less than 0.05 (two-sided). Category Placebo (N=33) Immediate-Release Topiramate 50 mg/day (N=35) Immediate-Release Topiramate 100 mg/day (N=35) Baseline Median 3.6 4.0 4.0 Last 12 Weeks of Double-Blind Phase Median 2.3 2.3 1.0 Percent Reduction (%) Median 44.4 44.6 72.2 P-value versus Placebo *,† 0.7975 0.0164 ‡ figure2

8.5 Geriatric Use Clinical studies of immediate-release topiramate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Dosage adjustment may be necessary for elderly with creatinine clearance less than 70 mL/min/1.73 m 2 . Estimate GFR should be measured prior to dosing [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )] .

8.2 Lactation Risk Summary Topiramate is excreted in human milk [see Data]. The effects of topiramate on milk production are unknown. Diarrhea and somnolence have been reported in breastfed infants whose mothers receive topiramate treatment. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for topiramate extended-release capsules and any potential adverse effects on the breastfed infant from topiramate extended-release capsules or from the underlying maternal condition. Data Limited data from 5 women with epilepsy treated with topiramate during lactation showed drug levels in milk similar to those in maternal plasma.

8.3 Females and Males of Reproductive Potential Contraception Women of childbearing potential who are not planning a pregnancy should use effective contraception because of the risks to the fetus of oral clefts and of being small for gestational age [ see Drug Interactions ( 7.5 ) and Use in Specific Populations ( 8.1 ) ].

8.4 Pediatric Use Seizures in Pediatric Patients 6 Years of Age and Older The safety and effectiveness of topiramate extended-release capsules for treatment of partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndromes in pediatric patients at least 6 years of age is based on controlled trials with immediate-release topiramate [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14.2 , 14.3 )]. The adverse reactions in pediatric patients treated for partial onset seizure, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome are similar to those seen in adults [see Warnings and Precautions ( 5 ) and Adverse Reactions ( 6 )]. These include, but are not limited to: oligohydrosis and hyperthermia [see Warnings and Precautions ( 5.3 )] dose-related increased incidence of metabolic acidosis [see Warnings and Precautions ( 5.4 )] dose-related increased incidence of hyperammonemia [see Warnings and Precautions ( 5.13 )] Not Recommended for Pediatric Patients Younger than 6 Years of Age The safety and effectiveness of topiramate extended-release capsules for treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndromes in pediatric patients younger than 6 years of age has not been established. Because the capsule must be swallowed whole, and may not be sprinkled on food, crushed or chewed, topiramate extended-release capsules are recommended only for children age 6 or older. The following pediatric use information for adjunctive treatment for partial onset epilepsy in infants and toddlers (1 to 24 months) is based on studies conducted with immediate-release topiramate, which failed to demonstrate efficacy. Safety and effectiveness of immediate-release topiramate in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome. In a single randomized, double-blind, placebo-controlled investigational trial, the efficacy, safety, and tolerability of immediate-release topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in pediatric patients 1 to 24 months of age with refractory partial-onset seizures were assessed. After 20 days of double-blind treatment, immediate-release topiramate (at fixed doses of 5, 15, and 25 mg/kg per day) did not demonstrate efficacy compared with placebo in controlling seizures. In general, the adverse reaction profile for immediate-release topiramate in this population was similar to that of older pediatric patients, although results from the above controlled study, and an open-label, long-term extension study in these pediatric patients 1 to 24 months old suggested some adverse reactions not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions that occurred with a greater frequency and/or greater severity than had been recognized previously from studies in older pediatric patients or adults for various indications. These very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%). The following adverse reactions were observed in at least 3% of patients on immediate-release topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm. A generally similar profile was observed in older pediatric patients [see Adverse Reactions ( 6.1 )]. Immediate-release topiramate resulted in an increased incidence of patients with increased creatinine (any topiramate dose 5%, placebo 0%), BUN (any topiramate dose 3%, placebo 0%), and protein (any topiramate dose 34%, placebo 6%), and an increased incidence of decreased potassium (any topiramate dose 7%, placebo 0%). This increased frequency of abnormal values was not dose related. Creatinine was the only analyte showing a noteworthy increased incidence (topiramate 25 mg/kg/day 5%, placebo 0%) of a markedly abnormal increase [see Adverse Reactions ( 6.1 )]. The significance of these findings is uncertain. Immediate-release topiramate treatment also produced a dose-related increase in the percentage of patients who had a shift from normal at baseline to high/increased (above the normal reference range) in total eosinophil count at the end of treatment. The incidence of these abnormal shifts was 6 % for placebo, 10% for 5 mg/kg/day, 9% for 15 mg/kg/day, 14% for 25 mg/kg/day, and 11% for any topiramate dose [see Adverse Reactions ( 6.1 )]. There was a mean dose-related increase in alkaline phosphatase. The significance of these findings is uncertain. Topiramate produced a dose-related increased incidence of hyperammonemia [see Warnings and Precautions ( 5.13 )]. Treatment with immediate-release topiramate for up to 1 year was associated with reductions in Z SCORES for length, weight, and head circumference [see Warnings and Precautions ( 5.4 ) and Adverse Reactions ( 6 )]. In open-label, uncontrolled experience, increasing impairment of adaptive behavior was documented in behavioral testing over time in this population. There was a suggestion that this effect was dose-related. However, because of the absence of an appropriate control group, it is not known if this decrement in function was treatment related or reflects the patient’s underlying disease (e.g., patients who received higher doses may have more severe underlying disease) [see Warnings and Precautions ( 5.7 )]. In this open-label, uncontrolled study, the mortality was 37 deaths/1000 patient years. It is not possible to know whether this mortality rate is related to immediate-release topiramate treatment, because the background mortality rate for a similar, significantly refractory, young pediatric population (1 month to 24 months) with partial epilepsy is not known. Other Pediatric Studies Topiramate treatment produced a dose-related increased shift in serum creatinine from normal at baseline to an increased value at the end of 4 months treatment in adolescent patients (ages 12 years to 16 years) in a double- blind, placebo-controlled study [see Adverse Reactions ( 6.1 )]. A one-year, active-controlled, open-label study with blinded assessments of bone mineral density (BMD) and growth in pediatric patients 4 to 15 years of age, including 63 patients with recent or new onset of epilepsy, was conducted to assess effects of immediate-release topiramate (N=28, 6 to 15 years of age) versus levetiracetam (N=35, 4 to 15 years of age) monotherapy on bone mineralization and on height and weight, which reflect growth. Effects on bone mineralization were evaluated via dual-energy X-ray absorptiometry and blood markers. Table 8 summarizes effects of immediate-release topiramate at 12 months for key safety outcomes including BMD, height, height velocity, and weight. All Least Square Mean values for immediate-release topiramate and the comparator were positive. Therefore, the Least Square Mean treatment differences shown reflect an immediate-release topiramate-induced attenuation of the key safety outcomes. Statistically significant effects were observed for decreases in BMD (and bone mineral content) in lumbar spine and total body less head and in weight. Subgroup analyses according to age demonstrated similar negative effects for all key safety outcomes (i.e., BMD, height, weight). Table 8 Summary of Immediate-release Topiramate Treatment Difference Results at 12 Months for Key Safety Outcomes * TBLH=total body less head ** Whereas no patients were randomized to 2 to 5 year age subgroup for immediate-release topiramate, 5 patients (4 to 5 years) were randomized to the active control group. Safety Parameter Treatment Difference in Least Square Means (95 % Confidence Interval) Annual Change in BMD Lumbar Spine (g/cm 2 ) -0.036 (-0.058, -0.014) Annual Change in BMD TBLH* (g/cm 2 ) -0.026 (-0.039, -0.012) Annual Change in Height (cm) (4-9 years, Primary Analysis Population for Height) ** -0.84 (-2.67,0.99) Annual Change in Height (cm) (4-15 years) -0.75 (-2.21, 0.71) Annual Change in Height (cm) (10-15 years) -1.01 (-3.64, 1.61) Height Velocity (cm/year) (4-9 years) -1.00 (-2.76, 0.76) Height Velocity (cm/year) (4-15 years) -0.98 (-2.33, 0.37) Height Velocity (cm/year) (10-15 years) -0.96 (-3.24, 1.32) Annual Change in Weight (kg) -2.05 (-3.66, -0.45) Metabolic acidosis (serum bicarbonate less than 20 mEq/L) was observed in all immediate-release topiramate-­treated patients at some time in the study [see Warnings and Precautions ( 5.4 )]. Over the whole study, 76% more immediate-release topiramate-treated patients experienced persistent metabolic acidosis (i.e., 2 consecutive visits with or final serum bicarbonate less than 20 mEq/L) compared to levetiracetam-treated patients. Over the whole study, 35% more immediate-release topiramate-treated patients experienced a markedly abnormally low serum bicarbonate (i.e., absolute value less than17 mEq/L and greater than or equal to 5mEq/L decrease from pre-treatment), indicating the frequency of more severe metabolic acidosis, compared to levetiracetam-treated patients. The decrease in BMD at 12 months was correlated with decreased serum bicarbonate, suggesting that metabolic acidosis was at least a partial factor contributing to this adverse effect on BMD. Immediate-release topiramate-treated patients exhibited an increased risk for developing an increased serum creatinine and an increased serum glucose above the normal reference range compared to control patients. Preventive Treatment of Migraine in Pediatric Patients 12 Years to 17 Years of Age Safety and effectiveness of topiramate for the preventive treatment of migraine was studied in 5 double-blind, randomized, placebo-controlled, parallel-group trials in a total of 219 pediatric patients, at doses of 50 mg/day to 200 mg/day, or 2 mg/kg/day to 3 mg/kg/day. These comprised a fixed dose study in 103 pediatric patients 12 years to 17 years of age [see Clinical Studies (14.4)], a flexible dose (2 mg/kg/day to 3 mg/kg/day), placebo-controlled study in 157 pediatric patients 6 years to 16 years of age (including 67 pediatric patients 12 years to 16 years of age), and a total of 49 pediatric patients 12 years to 17 years of age in 3 studies for the preventive treatment of migraine primarily in adults. Open-label extension phases of 3 studies enabled evaluation of long-term safety for up to 6 months after the end of the double-blind phase. Efficacy of topiramate for the preventive treatment of migraine in pediatric patients 12 years to 17 years of age is demonstrated for a 100 mg daily dose in Study 3 [see Clinical Studies ( 14.4 )] . Efficacy of topiramate (2 mg/kg/day to 3 mg/kg/day) for the preventive treatment of migraine was not demonstrated in a placebo-controlled trial of 157 pediatric patients (6 years to 16 years of age) that included treatment of 67 pediatric patients 12 years to 16 years of age) for 20 weeks. In the pediatric trials (12 years to 17 years of age) in which patients were randomized to placebo or a fixed daily dose of immediate-release topiramate, the most common adverse reactions with immediate-release topiramate that were seen at an incidence higher (greater than or equal to 5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain [see Adverse Reactions ( 6.1 )] . The most common cognitive adverse reaction in pooled double-blind studies in pediatric patients 12 years to 17 years of age was difficulty with concentration/attention [see Warnings and Precautions ( 5.7 )] . Markedly abnormally low serum bicarbonate values indicative of metabolic acidosis were reported in topiramate-treated pediatric migraine patients [see Warnings and Precautions ( 5.4 )] . In topiramate-treated pediatric patients (12 years to 17 years of age) compared to placebo-treated patients, abnormally increased results were more frequent for creatinine, BUN, uric acid, chloride, ammonia, total protein, and platelets. Abnormally decreased results were observed with topiramate vs placebo treatment for phosphorus and bicarbonate [see Adverse Reactions ( 6.1 )] . Notable changes (increases and decreases) from baseline in systolic blood pressure, diastolic blood pressure, and pulse that were observed occurred more commonly in pediatric patients treated with topiramate compared to pediatric patients treated with placebo [see Clinical Pharmacology ( 12.2 )] . Preventive Treatment of Migraine in Pediatric Patients 6 Years to 11 Years of Age Safety and effectiveness in pediatric patients below the age of 12 years have not been established for the preventive treatment of migraine. In a double-blind study in 90 pediatric patients 6 years to 11 years of age (including 59 topiramate-treated and 31 placebo patients), the adverse reaction profile was generally similar to that seen in pooled double-blind studies of pediatric patients 12 years to 17 years of age. The most common adverse reactions that occurred in immediate- release topiramate-treated pediatric patients 6 years to 11 years of age, and at least twice as frequently than placebo, were gastroenteritis (12% topiramate, 6% placebo), sinusitis (10% topiramate, 3% placebo), weight loss (8% topiramate, 3% placebo) and paresthesia (7% topiramate, 0% placebo). Difficulty with concentration/attention occurred in 3 topiramate-treated patients (5%) and 0 placebo-treated patients. The risk for cognitive adverse reactions was greater in younger patients (6 years to 11 years of age) than in older patients (12 years to 17 years of age) [see Warnings and Precautions ( 5.7 )] . Juvenile Animal Studies When topiramate (30, 90, and 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose, which is approximately 5 to 8 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m 2 ) basis.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as topiramate extended-release capsules, during pregnancy. Patients should be encouraged 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. To enroll, patients can call the toll-free number 1-888-233-2334. Information about the North American Drug Pregnancy Registry can be found at http://www.aedpregnancyregistry.org/. Risk Summary Topiramate extended-release capsules can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have increased risk for cleft lip and/or cleft palate (oral clefts) and for being small for gestational age (SGA) [see Human Data] . SGA has been observed at all doses and appears to be dose-dependent. The prevalence of SGA is greater in infants of women who received higher doses of topiramate during pregnancy. In addition, the prevalence of SGA in infants of women who continued topiramate use until later in pregnancy is higher compared to the prevalence in infants of women who stopped topiramate use before the third trimester. In multiple animal species, topiramate demonstrated developmental toxicity, including increased incidences of fetal malformations, in the absence of maternal toxicity at clinically relevant doses [see Animal Data]. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse reactions Consider the benefits and risks of topiramate when prescribing this drug to women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death. Because of the risk of oral clefts to the fetus, which occur in the first trimester of pregnancy before many women know they are pregnant, all women of childbearing potential should be informed of the potential risk to the fetus from exposure to topiramate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of topiramate use during pregnancy, and alternative therapeutic options should be considered for these patients. Labor or Delivery Although the effect of topiramate on labor and delivery in humans has not been established, the development of topiramate-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus’ ability to tolerate labor. Topiramate extended-release capsules treatment can cause metabolic acidosis [see Warnings and Precautions ( 5.4 )] . The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus’ ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state [see Warnings and Precautions ( 5.4 )] . Newborns of mothers treated with topiramate extended-release capsules should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic acidosis following birth. Based on limited information, topiramate has also been associated with pre-term labor and premature delivery. Data Human Data Data from pregnancy registries indicate an increased risk of oral clefts in infants exposed to topiramate during the first trimester of pregnancy. In the NAAED pregnancy registry, the prevalence of oral clefts among topiramate-exposed infants (1.1%) was higher than the prevalence of infants exposed to reference AEDs (0.36%) , or the prevalence in infants of mothers without epilepsy and without exposure to AEDs (0.12%). It was also higher than the background prevalence in United States (0.17%) as estimated by the Centers for Disease Control and Prevention (CDC). The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 9.6 (95% Confidence Interval=[CI] 4 to 23) as compared to the risk in a background population of untreated women. The UK Epilepsy and Pregnancy Register reported a prevalence of oral clefts among infants exposed to topiramate monotherapy (3.2%) that was 16 times higher than the background rate in the UK (0.2%). Data from the NAAED pregnancy registry and a population-based birth registry cohort indicate that exposure to topiramate in utero is associated with an increased risk of SGA newborns (birth weight less than 10th percentile). In the NAAED pregnancy registry, 19.7% of topiramate-exposed newborns were SGA compared to 7.9% of newborns exposed to a reference AED, and 5.4% of newborns of mothers without epilepsy and without AED exposure. In the Medical Birth Registry of Norway (MBRN), a population-based pregnancy registry, 25% of newborns in the topiramate monotherapy exposure group were SGA compared to 9% in the comparison group who were unexposed to AEDs. The long-term consequences of the SGA findings are not known. Animal Data When topiramate (0, 20, 100, or 500 mg/kg/day) was administered orally to pregnant mice during the period of organogenesis, incidences of fetal malformations (primarily craniofacial defects) were increased at all doses. Fetal body weights and skeletal ossification were reduced at the highest dose tested in conjunction with decreased maternal body weight gain. A no-effect dose for embryofetal developmental toxicity in mice was not identified. The lowest dose tested, which was associated with an increased incidence of malformations, is less than the maximum recommended human dose (MRHD) for epilepsy (400 mg/day) or migraine (100 mg/day) on a body surface area (mg/m 2 ) basis. In pregnant rats administered topiramate (0, 20, 100, and 500 mg/kg/day or 0, 0.2, 2.5, 30, and 400 mg/kg/day) orally during the period of organogenesis, the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased in fetuses at 400 and 500 mg/kg/day. Embryotoxicity (reduced fetal body weights, increased incidences of structural variations) was observed at doses as low as 20 mg/kg/day. Clinical signs of maternal toxicity were seen at 400 mg/kg/day and above, and maternal body weight gain was reduced at doses of 100 mg/kg/day or greater. The no-effect dose (2.5 mg/kg/day) for embryofetal developmental toxicity in rats is less than the MRHD for epilepsy or migraine on a mg/m 2 basis. In pregnant rabbits administered topiramate (0, 20, 60, and 180 mg/kg/day or 0, 10, 35, and 120 mg/kg/day) orally during organogenesis, embryofetal mortality was increased at 35 mg/kg/day and an increased incidence of fetal malformations (primarily rib and vertebral malformations) was observed at 120 mg/kg/day. Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg/day and above. The no-effect dose (20 mg/kg/day) for embryofetal developmental toxicity in rabbits is equivalent to the MRHD for epilepsy and approximately 4 times the MRHD for migraine on a mg/m 2 basis. When topiramate (0, 0.2, 4, 20, and 100 mg/kg/day or 0, 2, 20, and 200 mg/kg/day) was administered orally to female rats during the latter part of gestation and throughout lactation, offspring exhibited decreased viability and delayed physical development at 200 mg/kg/day and reductions in pre-and/or postweaning body weight gain at 2 mg/kg/day and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg/day or greater. In a rat embryofetal development study which included postnatal assessment of offspring, oral administration of topiramate (0, 0.2, 2.5, 30, and 400 mg/kg/day) to pregnant animals during the period of organogenesis resulted in delayed physical development in offspring at 400 mg/kg/day and persistent reductions in body weight gain in offspring at 30 mg/kg/day and higher. The no-effect dose (0.2 mg/kg/day) for pre- and postnatal developmental toxicity is less than the MRHD for epilepsy or migraine on a mg/m 2 basis.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as topiramate extended-release capsules, during pregnancy. Patients should be encouraged 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. To enroll, patients can call the toll-free number 1-888-233-2334. Information about the North American Drug Pregnancy Registry can be found at http://www.aedpregnancyregistry.org/. Risk Summary Topiramate extended-release capsules can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have increased risk for cleft lip and/or cleft palate (oral clefts) and for being small for gestational age (SGA) [see Human Data] . SGA has been observed at all doses and appears to be dose-dependent. The prevalence of SGA is greater in infants of women who received higher doses of topiramate during pregnancy. In addition, the prevalence of SGA in infants of women who continued topiramate use until later in pregnancy is higher compared to the prevalence in infants of women who stopped topiramate use before the third trimester. In multiple animal species, topiramate demonstrated developmental toxicity, including increased incidences of fetal malformations, in the absence of maternal toxicity at clinically relevant doses [see Animal Data]. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse reactions Consider the benefits and risks of topiramate when prescribing this drug to women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death. Because of the risk of oral clefts to the fetus, which occur in the first trimester of pregnancy before many women know they are pregnant, all women of childbearing potential should be informed of the potential risk to the fetus from exposure to topiramate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of topiramate use during pregnancy, and alternative therapeutic options should be considered for these patients. Labor or Delivery Although the effect of topiramate on labor and delivery in humans has not been established, the development of topiramate-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus’ ability to tolerate labor. Topiramate extended-release capsules treatment can cause metabolic acidosis [see Warnings and Precautions ( 5.4 )] . The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus’ ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state [see Warnings and Precautions ( 5.4 )] . Newborns of mothers treated with topiramate extended-release capsules should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic acidosis following birth. Based on limited information, topiramate has also been associated with pre-term labor and premature delivery. Data Human Data Data from pregnancy registries indicate an increased risk of oral clefts in infants exposed to topiramate during the first trimester of pregnancy. In the NAAED pregnancy registry, the prevalence of oral clefts among topiramate-exposed infants (1.1%) was higher than the prevalence of infants exposed to reference AEDs (0.36%) , or the prevalence in infants of mothers without epilepsy and without exposure to AEDs (0.12%). It was also higher than the background prevalence in United States (0.17%) as estimated by the Centers for Disease Control and Prevention (CDC). The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 9.6 (95% Confidence Interval=[CI] 4 to 23) as compared to the risk in a background population of untreated women. The UK Epilepsy and Pregnancy Register reported a prevalence of oral clefts among infants exposed to topiramate monotherapy (3.2%) that was 16 times higher than the background rate in the UK (0.2%). Data from the NAAED pregnancy registry and a population-based birth registry cohort indicate that exposure to topiramate in utero is associated with an increased risk of SGA newborns (birth weight less than 10th percentile). In the NAAED pregnancy registry, 19.7% of topiramate-exposed newborns were SGA compared to 7.9% of newborns exposed to a reference AED, and 5.4% of newborns of mothers without epilepsy and without AED exposure. In the Medical Birth Registry of Norway (MBRN), a population-based pregnancy registry, 25% of newborns in the topiramate monotherapy exposure group were SGA compared to 9% in the comparison group who were unexposed to AEDs. The long-term consequences of the SGA findings are not known. Animal Data When topiramate (0, 20, 100, or 500 mg/kg/day) was administered orally to pregnant mice during the period of organogenesis, incidences of fetal malformations (primarily craniofacial defects) were increased at all doses. Fetal body weights and skeletal ossification were reduced at the highest dose tested in conjunction with decreased maternal body weight gain. A no-effect dose for embryofetal developmental toxicity in mice was not identified. The lowest dose tested, which was associated with an increased incidence of malformations, is less than the maximum recommended human dose (MRHD) for epilepsy (400 mg/day) or migraine (100 mg/day) on a body surface area (mg/m 2 ) basis. In pregnant rats administered topiramate (0, 20, 100, and 500 mg/kg/day or 0, 0.2, 2.5, 30, and 400 mg/kg/day) orally during the period of organogenesis, the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased in fetuses at 400 and 500 mg/kg/day. Embryotoxicity (reduced fetal body weights, increased incidences of structural variations) was observed at doses as low as 20 mg/kg/day. Clinical signs of maternal toxicity were seen at 400 mg/kg/day and above, and maternal body weight gain was reduced at doses of 100 mg/kg/day or greater. The no-effect dose (2.5 mg/kg/day) for embryofetal developmental toxicity in rats is less than the MRHD for epilepsy or migraine on a mg/m 2 basis. In pregnant rabbits administered topiramate (0, 20, 60, and 180 mg/kg/day or 0, 10, 35, and 120 mg/kg/day) orally during organogenesis, embryofetal mortality was increased at 35 mg/kg/day and an increased incidence of fetal malformations (primarily rib and vertebral malformations) was observed at 120 mg/kg/day. Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg/day and above. The no-effect dose (20 mg/kg/day) for embryofetal developmental toxicity in rabbits is equivalent to the MRHD for epilepsy and approximately 4 times the MRHD for migraine on a mg/m 2 basis. When topiramate (0, 0.2, 4, 20, and 100 mg/kg/day or 0, 2, 20, and 200 mg/kg/day) was administered orally to female rats during the latter part of gestation and throughout lactation, offspring exhibited decreased viability and delayed physical development at 200 mg/kg/day and reductions in pre-and/or postweaning body weight gain at 2 mg/kg/day and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg/day or greater. In a rat embryofetal development study which included postnatal assessment of offspring, oral administration of topiramate (0, 0.2, 2.5, 30, and 400 mg/kg/day) to pregnant animals during the period of organogenesis resulted in delayed physical development in offspring at 400 mg/kg/day and persistent reductions in body weight gain in offspring at 30 mg/kg/day and higher. The no-effect dose (0.2 mg/kg/day) for pre- and postnatal developmental toxicity is less than the MRHD for epilepsy or migraine on a mg/m 2 basis. 8.2 Lactation Risk Summary Topiramate is excreted in human milk [see Data]. The effects of topiramate on milk production are unknown. Diarrhea and somnolence have been reported in breastfed infants whose mothers receive topiramate treatment. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for topiramate extended-release capsules and any potential adverse effects on the breastfed infant from topiramate extended-release capsules or from the underlying maternal condition. Data Limited data from 5 women with epilepsy treated with topiramate during lactation showed drug levels in milk similar to those in maternal plasma. 8.3 Females and Males of Reproductive Potential Contraception Women of childbearing potential who are not planning a pregnancy should use effective contraception because of the risks to the fetus of oral clefts and of being small for gestational age [ see Drug Interactions ( 7.5 ) and Use in Specific Populations ( 8.1 ) ]. 8.4 Pediatric Use Seizures in Pediatric Patients 6 Years of Age and Older The safety and effectiveness of topiramate extended-release capsules for treatment of partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndromes in pediatric patients at least 6 years of age is based on controlled trials with immediate-release topiramate [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14.2 , 14.3 )]. The adverse reactions in pediatric patients treated for partial onset seizure, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome are similar to those seen in adults [see Warnings and Precautions ( 5 ) and Adverse Reactions ( 6 )]. These include, but are not limited to: oligohydrosis and hyperthermia [see Warnings and Precautions ( 5.3 )] dose-related increased incidence of metabolic acidosis [see Warnings and Precautions ( 5.4 )] dose-related increased incidence of hyperammonemia [see Warnings and Precautions ( 5.13 )] Not Recommended for Pediatric Patients Younger than 6 Years of Age The safety and effectiveness of topiramate extended-release capsules for treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndromes in pediatric patients younger than 6 years of age has not been established. Because the capsule must be swallowed whole, and may not be sprinkled on food, crushed or chewed, topiramate extended-release capsules are recommended only for children age 6 or older. The following pediatric use information for adjunctive treatment for partial onset epilepsy in infants and toddlers (1 to 24 months) is based on studies conducted with immediate-release topiramate, which failed to demonstrate efficacy. Safety and effectiveness of immediate-release topiramate in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome. In a single randomized, double-blind, placebo-controlled investigational trial, the efficacy, safety, and tolerability of immediate-release topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in pediatric patients 1 to 24 months of age with refractory partial-onset seizures were assessed. After 20 days of double-blind treatment, immediate-release topiramate (at fixed doses of 5, 15, and 25 mg/kg per day) did not demonstrate efficacy compared with placebo in controlling seizures. In general, the adverse reaction profile for immediate-release topiramate in this population was similar to that of older pediatric patients, although results from the above controlled study, and an open-label, long-term extension study in these pediatric patients 1 to 24 months old suggested some adverse reactions not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions that occurred with a greater frequency and/or greater severity than had been recognized previously from studies in older pediatric patients or adults for various indications. These very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%). The following adverse reactions were observed in at least 3% of patients on immediate-release topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm. A generally similar profile was observed in older pediatric patients [see Adverse Reactions ( 6.1 )]. Immediate-release topiramate resulted in an increased incidence of patients with increased creatinine (any topiramate dose 5%, placebo 0%), BUN (any topiramate dose 3%, placebo 0%), and protein (any topiramate dose 34%, placebo 6%), and an increased incidence of decreased potassium (any topiramate dose 7%, placebo 0%). This increased frequency of abnormal values was not dose related. Creatinine was the only analyte showing a noteworthy increased incidence (topiramate 25 mg/kg/day 5%, placebo 0%) of a markedly abnormal increase [see Adverse Reactions ( 6.1 )]. The significance of these findings is uncertain. Immediate-release topiramate treatment also produced a dose-related increase in the percentage of patients who had a shift from normal at baseline to high/increased (above the normal reference range) in total eosinophil count at the end of treatment. The incidence of these abnormal shifts was 6 % for placebo, 10% for 5 mg/kg/day, 9% for 15 mg/kg/day, 14% for 25 mg/kg/day, and 11% for any topiramate dose [see Adverse Reactions ( 6.1 )]. There was a mean dose-related increase in alkaline phosphatase. The significance of these findings is uncertain. Topiramate produced a dose-related increased incidence of hyperammonemia [see Warnings and Precautions ( 5.13 )]. Treatment with immediate-release topiramate for up to 1 year was associated with reductions in Z SCORES for length, weight, and head circumference [see Warnings and Precautions ( 5.4 ) and Adverse Reactions ( 6 )]. In open-label, uncontrolled experience, increasing impairment of adaptive behavior was documented in behavioral testing over time in this population. There was a suggestion that this effect was dose-related. However, because of the absence of an appropriate control group, it is not known if this decrement in function was treatment related or reflects the patient’s underlying disease (e.g., patients who received higher doses may have more severe underlying disease) [see Warnings and Precautions ( 5.7 )]. In this open-label, uncontrolled study, the mortality was 37 deaths/1000 patient years. It is not possible to know whether this mortality rate is related to immediate-release topiramate treatment, because the background mortality rate for a similar, significantly refractory, young pediatric population (1 month to 24 months) with partial epilepsy is not known. Other Pediatric Studies Topiramate treatment produced a dose-related increased shift in serum creatinine from normal at baseline to an increased value at the end of 4 months treatment in adolescent patients (ages 12 years to 16 years) in a double- blind, placebo-controlled study [see Adverse Reactions ( 6.1 )]. A one-year, active-controlled, open-label study with blinded assessments of bone mineral density (BMD) and growth in pediatric patients 4 to 15 years of age, including 63 patients with recent or new onset of epilepsy, was conducted to assess effects of immediate-release topiramate (N=28, 6 to 15 years of age) versus levetiracetam (N=35, 4 to 15 years of age) monotherapy on bone mineralization and on height and weight, which reflect growth. Effects on bone mineralization were evaluated via dual-energy X-ray absorptiometry and blood markers. Table 8 summarizes effects of immediate-release topiramate at 12 months for key safety outcomes including BMD, height, height velocity, and weight. All Least Square Mean values for immediate-release topiramate and the comparator were positive. Therefore, the Least Square Mean treatment differences shown reflect an immediate-release topiramate-induced attenuation of the key safety outcomes. Statistically significant effects were observed for decreases in BMD (and bone mineral content) in lumbar spine and total body less head and in weight. Subgroup analyses according to age demonstrated similar negative effects for all key safety outcomes (i.e., BMD, height, weight). Table 8 Summary of Immediate-release Topiramate Treatment Difference Results at 12 Months for Key Safety Outcomes * TBLH=total body less head ** Whereas no patients were randomized to 2 to 5 year age subgroup for immediate-release topiramate, 5 patients (4 to 5 years) were randomized to the active control group. Safety Parameter Treatment Difference in Least Square Means (95 % Confidence Interval) Annual Change in BMD Lumbar Spine (g/cm 2 ) -0.036 (-0.058, -0.014) Annual Change in BMD TBLH* (g/cm 2 ) -0.026 (-0.039, -0.012) Annual Change in Height (cm) (4-9 years, Primary Analysis Population for Height) ** -0.84 (-2.67,0.99) Annual Change in Height (cm) (4-15 years) -0.75 (-2.21, 0.71) Annual Change in Height (cm) (10-15 years) -1.01 (-3.64, 1.61) Height Velocity (cm/year) (4-9 years) -1.00 (-2.76, 0.76) Height Velocity (cm/year) (4-15 years) -0.98 (-2.33, 0.37) Height Velocity (cm/year) (10-15 years) -0.96 (-3.24, 1.32) Annual Change in Weight (kg) -2.05 (-3.66, -0.45) Metabolic acidosis (serum bicarbonate less than 20 mEq/L) was observed in all immediate-release topiramate-­treated patients at some time in the study [see Warnings and Precautions ( 5.4 )]. Over the whole study, 76% more immediate-release topiramate-treated patients experienced persistent metabolic acidosis (i.e., 2 consecutive visits with or final serum bicarbonate less than 20 mEq/L) compared to levetiracetam-treated patients. Over the whole study, 35% more immediate-release topiramate-treated patients experienced a markedly abnormally low serum bicarbonate (i.e., absolute value less than17 mEq/L and greater than or equal to 5mEq/L decrease from pre-treatment), indicating the frequency of more severe metabolic acidosis, compared to levetiracetam-treated patients. The decrease in BMD at 12 months was correlated with decreased serum bicarbonate, suggesting that metabolic acidosis was at least a partial factor contributing to this adverse effect on BMD. Immediate-release topiramate-treated patients exhibited an increased risk for developing an increased serum creatinine and an increased serum glucose above the normal reference range compared to control patients. Preventive Treatment of Migraine in Pediatric Patients 12 Years to 17 Years of Age Safety and effectiveness of topiramate for the preventive treatment of migraine was studied in 5 double-blind, randomized, placebo-controlled, parallel-group trials in a total of 219 pediatric patients, at doses of 50 mg/day to 200 mg/day, or 2 mg/kg/day to 3 mg/kg/day. These comprised a fixed dose study in 103 pediatric patients 12 years to 17 years of age [see Clinical Studies (14.4)], a flexible dose (2 mg/kg/day to 3 mg/kg/day), placebo-controlled study in 157 pediatric patients 6 years to 16 years of age (including 67 pediatric patients 12 years to 16 years of age), and a total of 49 pediatric patients 12 years to 17 years of age in 3 studies for the preventive treatment of migraine primarily in adults. Open-label extension phases of 3 studies enabled evaluation of long-term safety for up to 6 months after the end of the double-blind phase. Efficacy of topiramate for the preventive treatment of migraine in pediatric patients 12 years to 17 years of age is demonstrated for a 100 mg daily dose in Study 3 [see Clinical Studies ( 14.4 )] . Efficacy of topiramate (2 mg/kg/day to 3 mg/kg/day) for the preventive treatment of migraine was not demonstrated in a placebo-controlled trial of 157 pediatric patients (6 years to 16 years of age) that included treatment of 67 pediatric patients 12 years to 16 years of age) for 20 weeks. In the pediatric trials (12 years to 17 years of age) in which patients were randomized to placebo or a fixed daily dose of immediate-release topiramate, the most common adverse reactions with immediate-release topiramate that were seen at an incidence higher (greater than or equal to 5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain [see Adverse Reactions ( 6.1 )] . The most common cognitive adverse reaction in pooled double-blind studies in pediatric patients 12 years to 17 years of age was difficulty with concentration/attention [see Warnings and Precautions ( 5.7 )] . Markedly abnormally low serum bicarbonate values indicative of metabolic acidosis were reported in topiramate-treated pediatric migraine patients [see Warnings and Precautions ( 5.4 )] . In topiramate-treated pediatric patients (12 years to 17 years of age) compared to placebo-treated patients, abnormally increased results were more frequent for creatinine, BUN, uric acid, chloride, ammonia, total protein, and platelets. Abnormally decreased results were observed with topiramate vs placebo treatment for phosphorus and bicarbonate [see Adverse Reactions ( 6.1 )] . Notable changes (increases and decreases) from baseline in systolic blood pressure, diastolic blood pressure, and pulse that were observed occurred more commonly in pediatric patients treated with topiramate compared to pediatric patients treated with placebo [see Clinical Pharmacology ( 12.2 )] . Preventive Treatment of Migraine in Pediatric Patients 6 Years to 11 Years of Age Safety and effectiveness in pediatric patients below the age of 12 years have not been established for the preventive treatment of migraine. In a double-blind study in 90 pediatric patients 6 years to 11 years of age (including 59 topiramate-treated and 31 placebo patients), the adverse reaction profile was generally similar to that seen in pooled double-blind studies of pediatric patients 12 years to 17 years of age. The most common adverse reactions that occurred in immediate- release topiramate-treated pediatric patients 6 years to 11 years of age, and at least twice as frequently than placebo, were gastroenteritis (12% topiramate, 6% placebo), sinusitis (10% topiramate, 3% placebo), weight loss (8% topiramate, 3% placebo) and paresthesia (7% topiramate, 0% placebo). Difficulty with concentration/attention occurred in 3 topiramate-treated patients (5%) and 0 placebo-treated patients. The risk for cognitive adverse reactions was greater in younger patients (6 years to 11 years of age) than in older patients (12 years to 17 years of age) [see Warnings and Precautions ( 5.7 )] . Juvenile Animal Studies When topiramate (30, 90, and 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose, which is approximately 5 to 8 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m 2 ) basis. 8.5 Geriatric Use Clinical studies of immediate-release topiramate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Dosage adjustment may be necessary for elderly with creatinine clearance less than 70 mL/min/1.73 m 2 . Estimate GFR should be measured prior to dosing [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )] . 8.6 Renal Impairment The clearance of topiramate is reduced in patients with moderate (creatinine clearance 30 mL/min/1.73m 2 to 69 mL/min/1.73m 2 ) and severe (creatinine clearance less than 30 mL/min/1.73m 2 ) renal impairment. A dosage adjustment is recommended in patients with moderate or severe renal impairment [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )] . 8.7 Patients Undergoing Hemodialysis Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than in a normal individual. A dosage adjustment may be required [see Dosage and Administration ( 2.6 ) and Clinical Pharmacology ( 12.3 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Topiramate extended-release capsules are available in the following strengths and colors: 25 mg: Pink opaque/white opaque, hard gelatin size "4" capsules imprinted with "ap" logo on cap and "TP4" on body in black color ink containing white to off white colored pellets: Bottle of 30’s with child resistant closures (NDC 27241-227-30) Bottle of 100’s with child resistant closures (NDC 27241-227-01) 50 mg: Light brown opaque/white opaque, hard gelatin size "3" capsules imprinted with "ap" logo on cap and "TP3" on body in black color ink containing white to off white colored pellets: Bottle of 30’s with child resistant closures (NDC 27241-228-30) Bottle of 100’s with child resistant closures (NDC 27241-228-01) 100 mg: Blue opaque/white opaque, hard gelatin size "1" capsules imprinted with "ap" logo on cap and "TP2" on body in black color ink containing white to off white colored pellets: Bottle of 30’s with child resistant closures (NDC 27241-229-30) Bottle of 100’s with child resistant closures (NDC 27241-229-01) 200 mg: Blue opaque/pink opaque, hard gelatin size "0 el" capsules imprinted with "ap" logo on cap in white color ink and "TP1" on body in black color ink containing white to off white colored pellets: Bottle of 30’s with child resistant closures (NDC 27241-230-30) Bottle of 100’s with child resistant closures (NDC 27241-230-01) 16.2 Storage and Handling Topiramate extended-release capsules should be stored in well closed containers at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Protect from moisture and light.