TOPIRAMATE

Topiramate is a sulfamate-substituted monosaccharide. Topiramate tablets USP are available as 25mg, 50 mg and 100 mg circular tablets and 200 mg capsule shaped tablets for oral administration. Topiramate USP is a white crystalline powder with a bitter taste. Topiramate USP is most soluble in alkaline solutions containing sodium hydroxide or sodium phosphate and having a pH of 9 to 10. It is freely soluble in acetone, chloroform, dimethylsulfoxide, and ethanol. The solubility in water is 9.8 mg/mL. Its saturated solution has a pH of 6.3. Topiramate has the molecular formula C 12 H 21 NO 8 S and a molecular weight of 339.36. Topiramate is designated chemically as 2,3:4,5Di- O -isopropylidene-ß-D-fructopyranose sulfamate and has the following structural formula: Each tablet, for oral administration, contains 25 mg, 50 mg, 100 mg and 200 mg topiramate and has the following inactive ingredients: hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, pregelatinized starch, sodium starch glycolate and titanium dioxide. In addition, the 25 mg also contains FD&C Blue #2; the 50 mg and 100 mg also contain red iron oxide and yellow iron oxide; and the 200 mg also contains red iron oxide. topi

Topiramate tablets USP is an antiepileptic (AED) agent indicated for: Monotherapy epilepsy: Initial monotherapy in patients ≥ 2 years of age with partial onset or primary generalized tonic-clonic seizures ( 1.1 ) Adjunctive therapy epilepsy: Adjunctive therapy for adults and pediatric patients (2 to 16 years of age) with partial onset seizures or primary generalized tonic-clonic seizures, and in patients ≥2 years of age with seizures associated with Lennox-Gastaut syndrome (LGS) ( 1.2 ) 1.1 Monotherapy Epilepsy Topiramate tablets USP are indicated as initial monotherapy in patients 2 years of age and older with partial onset or primary generalized tonic-clonic seizures. Safety and effectiveness in patients who were converted to monotherapy from a previous regimen of other anticonvulsant drugs have not been established in controlled trials [see Clinical Studies (14.1) ] . 1.2 Adjunctive Therapy Epilepsy Topiramate tablets USP are indicated as adjunctive therapy for adults and pediatric patients ages 2 to 16 years with partial onset seizures or primary generalized tonic-clonic seizures, and in patients 2 years of age and older with seizures associated with Lennox-Gastaut syndrome [see Clinical Studies (14.2) ] .

See DOSAGE AND ADMINISTRATION, Epilepsy: Monotherapy and Adjunctive Therapy Use for additional details Initial Dose Titration Recommended Dose Epilepsy monotherapy: children 2to<10years (2.1 ) 25mg/day administered nightly for the first week The dosage should betitratedover5–7 weeks Daily doses in two divided doses based on weight(Table2) Epilepsy monotherapy: adults and pediatric patients≥10years (2.1 ) 50mg/day in two divided doses The dosage should be increased weekly by increments of 50mg for the first 4 weeks then100mgfor weeks 5to6. 400 mg/day in two divided doses Epilepsy adjunctive therapy :adults with partial onset seizures or LGS( 2.1 ) 25to50mg/day The dosage should be increased weekly to an effective dose by incrementsof25to50mg. 200–400 mg/day in two divided doses Epilepsy adjunctive therapy: adults with primary generalized tonic- clonic seizures (2.1 ) 25to50mg/day The dosage should be increased weekly to an effective dose by incrementsof25to50mg. 400 mg/day in two divided doses Epilepsy adjunctive therapy: pediatric Patients with partial onset seizures, primary generalized tonic-clonic seizures or LGS(186 2.1) 25mg/day(or less, based on a range of1to3mg/kg/day) nightly for the first week The dosage should beincreasedat1-or 2-weekintervalsby incrementsof1to3 mg/kg/day(administered in two divided doses).Dose titration should be guided by clinical outcome. 5to9mg/kg/day in two divided doses 2.1 Epilepsy It is not necessary to monitor topiramate plasma concentrations to optimize topiramate therapy. On occasion, the addition of topiramate to phenytoin may require an adjustment of the dose of phenytoin to achieve optimal clinical outcome. Addition or withdrawal of phenytoin and/or carbamazepine during adjunctive therapy with topiramate may require adjustment of the dose of topiramate. Because of the bitter taste, tablets should not be broken. Topiramate tablets USP can be taken without regard to meals. Monotherapy Use Adults and Pediatric Patients 10 Years and Older The recommended dose for topiramate monotherapy in adults and pediatric patients 10 years of age and older is 400 mg/day in two divided doses. Approximately 58% of patients randomized to 400 mg/day achieved this maximal dose in the monotherapy controlled trial; the mean dose achieved in the trial was 275 mg/day. The dose should be achieved by titration according to the following schedule (Table 1): Table 1: Monotherapy Titration Schedule for Adults and Pediatric Patients 10 years and older Morning Dose Evening Dose Week 1 25 mg 25 mg Week 2 50 mg 50 mg Week 3 75 mg 75 mg Week 4 100 mg 100 mg Week 5 150 mg 150 mg Week 6 200 mg 200 mg Children Ages 2 to <10 Years Dosing of topiramate as initial monotherapy in children 2 to < 10 years of age with partial onset or primary generalized tonic-clonic seizures was based on a pharmacometric bridging approach [see Clinical Studies ( 14.1 ) ] Dosing in patients 2 to <10 years is based on weight. During the titration period, the initial dose of topiramate should be 25 mg/day administered nightly for the first week. Based upon tolerability, the dosage can be increased to 50 mg/day (25 mg twice daily) in the second week. Dosage can be increased by 25–50 mg/day each subsequent week as tolerated. Titration to the minimum maintenance dose should be attempted over 5–7 weeks of the total titration period. Based upon tolerability and seizure control, additional titration to a higher dose (up to the maximum maintenance dose) can be attempted at 25–50 mg/day weekly increments. The total daily dose should not exceed the maximum maintenance dose for each range of body weight (Table 2). Table 2: Monotherapy Target Total Daily Maintenance Dosing for Patients 2 to <10 Years * Administered in two equally divided doses 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 Adjunctive Therapy Use Adults 17 Years of Age and Over - Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome The recommended total daily dose of topiramate as adjunctive therapy in adults with partial onset seizures is 200 to 400 mg/day in two divided doses, and 400 mg/day in two divided doses as adjunctive treatment in adults with primary generalized tonic-clonic seizures. It is recommended that therapy be initiated at 25 to 50 mg/day followed by titration to an effective dose in increments of 25 to 50 mg/day 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 (600, 800 or 1,000 mg/day) have not been shown to improve responses in dose-response studies in adults with partial onset seizures. Daily doses above 1,600 mg have not been studied. In the study of primary generalized tonic-clonic seizures, the initial titration rate was slower than in previous studies; the assigned dose was reached at the end of 8 weeks [see Clinical Studies ( 14.1 )] Pediatric Patients Ages 2 – 16 Years – Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome The recommended total daily dose of Topiramate as adjunctive therapy for pediatric patients with partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome is approximately 5 to 9 mg/kg/day in two divided doses. Titration should begin at 25 mg/day (or less, based on a range of 1 to 3 mg/kg/day) nightly for the first week. The dosage should then be increased at 1- or 2-week intervals by increments of 1 to 3 mg/kg/day (administered in two divided doses), to achieve optimal clinical response. Dose titration should be guided by clinical outcome. In the study of primary generalized tonic-clonic seizures, the initial titration rate was slower than in previous studies; the assigned dose of 6 mg/kg/day was reached at the end of 8 weeks [see Clinical Studies ( 14.1 )] . 2.4 Patients with Renal Impairment In renally impaired subjects (creatinine clearance less than 70 mL/min/1.73 m 2 ), one-half of the usual adult dose is recommended. Such patients will require a longer time to reach steady-state at each dose. 2.5 Geriatric Patients (Ages 65 Years and Over) Dosage adjustment may be indicated in the elderly patient when impaired renal function (creatinine clearance rate <70 mL/min/1.73 m2) is evident [see Clinical Pharmacology ( 12.3 )] . 2.6 Patients Undergoing Hemodialysis Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than a normal individual. Accordingly, a prolonged period of dialysis may cause topiramate concentration to fall below that required to maintain an anti-seizure effect. To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate 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. 2.7 Patients with Hepatic Disease In hepatically impaired patients, topiramate plasma concentrations may be increased. The mechanism is not well understood.

None None

The most common (>10% more frequent than placebo or low-dose topiramate in monotherapy) adverse reactions at recommended dosing in adult and pediatric controlled, epilepsy clinical trials were paresthesia, anorexia, weight decrease, speech disorder related speech problem, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, abnormal vision, and fever.( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Cipla Ltd, at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch The following adverse reactions are discussed in more detail in other sections of the labeling: Acute Myopia and Secondary Angle Closure [see Warnings and Precautions ( 5.1 )] Visual Field Defects [see Warnings and Precautions ( 5.2 )] Oligohidrosis and Hyperthermia [see Warnings and Precautions ( 5.3 )] Metabolic Acidosis [see Warnings and Precautions ( 5.4 )] Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.5 )] Cognitive/Neuropsychiatric Adverse Reactions [see Warnings and Precautions ( 5.6 )] Fetal Toxicity [see Warnings and Precautions ( 5.7 ) and Use in Specific Populations ( 8.1 )] Withdrawal of Antiepileptic Drugs (AEDs) [see Warnings and Precautions ( 5.8 )] Sudden Unexplained Death in Epilepsy (SUDEP) [see Warnings and Precautions ( 5.9 )] Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid [VPA] Use) [see Warnings and Precautions ( 5.10 )] Kidney Stones [see Warnings and Precautions ( 5.11 )] Hypothermia with Concomitant Valproic Acid (VPA) Use [see Warnings and Precautions ( 5.12 )] Paresthesia [see Warnings and Precautions ( 5.13 )] The data described in the following sections were obtained using topiramate tablets. 6.1 Clinical Trial Experience Monotherapy Epilepsy Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions observed in the clinical trials of a drug cannot be directly compared to the incidence of adverse reactions in the clinical trials of another drug, and may not reflect the incidence of adverse reactions observed in practice. Increased Risk for Bleeding Topiramate tablets treatment 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 event for topiramate tablets than for placebo (4.5% versus 3.0% in adult patients, and 4.4% versus 2.3% in pediatric patients). In this analysis, the incidence of serious bleeding events for topiramate tablets 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 tablets 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). Monotherapy Epilepsy Adults ≥16 Years The adverse reactions in the controlled trial that occurred most commonly in adults in the 400 mg/day topiramate group and at a rate higher (≥ 5 %) than in the 50 mg/day group were: paresthesia, weight decrease, anorexia, somnolence, and difficulty with memory (see Table 5 ). Approximately 21% of the 159 adult 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 (≥ 2% more frequent than low-dose 50 mg/day topiramate) adverse reactions causing discontinuation in this trial were difficulty with memory, fatigue, asthenia, insomnia, somnolence, and paresthesia. Pediatric Patients 6 to <16 Years of Age The adverse reactions in the controlled trial that occurred most commonly in pediatric patients in the 400 mg/day topiramate tablets group and at a rate higher (≥ 5%) than in the 50 mg/day group were fever, weight decrease, mood problems, cognitive problems, infection, flushing, and paresthesia (see Table 5 ). Table 5 also presents the incidence of adverse reactions occurring in at least 2% of adult and pediatric patients treated with 400 mg/day topiramate tablets and occurring with greater incidence than 50 mg/day topiramate tablets. Approximately 14% of the 77 pediatric patients in the 400 mg/day group who received topiramate tablets as monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. The most common ( > 2% more frequent than low-dose 50 mg/day topiramate) adverse reactions resulting in discontinuation in this trial were difficulty with concentration/attention, fever, flushing, and confusion. Table 5: Incidence of Treatment-Emergent Adverse Reactions in Monotherapy Epilepsy Where the Rate Was at Least 2% in Any Topiramate Tablets Group and the Rate in the 400 mg/day Topiramate Tablets Group Was Greater Than the Rate in the 50 mg/day Topiramate Tablets Group for Adults (≥16 Years) and Pediatric (6 to <16 Years) Patients in Study TOPMAX-EPMN-106 * Percentages calculated with the number of subjects in each group as denominator † N with Female Reproductive Disorders – Incidence calculated relative to the number of females; Pediatric TPM 50 mg n=40; Pediatric TPM 400 mg n=33; Adult TPM 50 mg n=84; TPM 400 mg n=80 Age Group Pediatric ( 6 to < 16 Years ) Adult ( Age ≥ 16 Years ) Topiramate Tablets Daily Dosage Group ( mg / day ) 50 400 50 400 Body System ( N = 74 ) ( N = 77 ) ( N = 160 ) ( N = 159 ) Adverse Reaction % * % * % * % * Body as a Whole - General Disorders Asthenia 0 3 4 6 Chest pain 1 2 Fever 1 12 Leg pain 2 3 Central & Peripheral Nervous System Disorders Ataxia 3 4 Dizziness 13 14 Hypertonia 0 3 Hypoesthesia 4 5 Muscle contractions involuntary 0 3 Paresthesia 3 12 21 40 Vertigo 0 3 Gastro - Intestinal System Disorders Constipation 1 4 Diarrhea 8 9 Gastritis 0 3 Gastroesophageal reflux 1 2 Dry mouth 1 3 Liver and Biliary System Disorders Gamma-GT increased 1 3 Metabolic and Nutritional Disorders Weight decrease 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/attention 7 10 7 8 Difficulty with memory 1 3 6 11 Insomnia 8 9 Libido decreased 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 Infection viral 3 6 6 8 Respiratory System Disorders Bronchitis 1 5 3 4 Dyspnea 1 2 Rhinitis 5 6 2 4 Sinusitis 1 4 Upper respiratory tract infection 16 18 Skin and Appendages Disorders Acne 2 3 Alopecia 1 4 3 4 Pruritus 1 4 Rash 3 4 1 4 Special Senses Other , Disorders Taste perversion 3 5 Urinary System Disorders Cystitis 1 3 Dysuria 0 2 Micturition frequency 0 3 0 2 Renal calculus 0 3 Urinary incontinence 1 3 Urinary tract infection 1 2 Vascular ( Extracardiac ) Disorders Flushing 0 5 Adjunctive Therapy Epilepsy The most commonly observed adverse reactions associated with the use of topiramate tablets at dosages of 200 to 400 mg/day (recommended dose range) in controlled trials in adults with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, that were seen at an incidence higher (≥ 5%) than in the placebo group were : somnolence, weight decrease, anorexia, dizziness, ataxia, speech disorders and related speech problems, language problems, psychomotor slowing, confusion, abnormal vision, difficulty with memory, paresthesia, diplopia, nervousness, and asthenia (see Table 6). Dose-related adverse reactions at dosages of 200 to 1,000 mg/day are shown in Table 8. The most commonly observed adverse reactions associated with the use of topiramate tablets at dosages of 5 to 9 mg/kg/day in controlled trials in pediatric patients with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, that were seen at an incidence higher (≥ 5%) than in the placebo group were : fatigue, somnolence, anorexia, nervousness, difficulty with concentration/attention, difficulty with memory, aggressive reaction, and weight decrease (see Table 9). Table 9 also presents the incidence of adverse reactions occurring in at least 1% of pediatric patients treated with topiramate tablets and occurring with greater incidence than placebo. In controlled clinical trials in adults, 11% of patients receiving topiramate tablets 200 to 400 mg/day as adjunctive therapy discontinued due to adverse reactions. This rate appeared to increase at dosages above 400 mg/day. Adverse reactions associated with discontinuing therapy included somnolence, dizziness, anxiety, difficulty with concentration or attention, fatigue, and paresthesia and increased at dosages above 400 mg/day. None of the pediatric patients who received topiramate tablets adjunctive therapy at 5 to 9 mg/kg/day in controlled clinical trials discontinued due to adverse reactions. Approximately 28% of the 1757 adults with epilepsy who received topiramate tablets at dosages of 200 to 1,600 mg/day in clinical studies discontinued treatment because of adverse reactions; an individual patient could have reported more than one adverse reaction. These adverse reactions were psychomotor slowing (4.0%), difficulty with memory (3.2%), fatigue (3.2%), confusion (3.1%), somnolence (3.2%), difficulty with concentration/attention (2.9%), anorexia (2.7%), depression (2.6%), dizziness (2.5%), weight decrease (2.5%), nervousness (2.3%), ataxia (2.1%), and paresthesia (2.0%). Approximately 11% of the 310 pediatric patients who received topiramate tablets at dosages up to 30 mg/kg/day discontinued due to adverse reactions. Adverse reactions associated with discontinuing therapy included aggravated convulsions (2.3%), difficulty with concentration/attention (1.6%), language problems (1.3%), personality (1.3%), and somnolence (1.3%). Incidence in Epilepsy Controlled Clinical Trials – Adjunctive Therapy – Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, and Lennox-Gastaut Syndrome Table 6 lists treatment-emergent adverse reactions that occurred in at least 1% of adults treated with 200 to 400 mg/day topiramate tablets in controlled trials that were numerically more common at this dose than in the patients treated with placebo. In general, most patients who experienced adverse reactions during the first eight weeks of these trials no longer experienced them by their last visit. Table 9 lists treatment-emergent adverse reactions that occurred in at least 1% of pediatric patients treated with 5 to 9 mg/kg topiramate tablets in controlled trials that were numerically more common than in patients treated with placebo. The prescriber should be aware that these data were obtained when topiramate tablets was added to concurrent antiepileptic drug therapy and cannot be used to predict the frequency of adverse reactions in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with data obtained from other clinical investigations involving different treatments, uses, or investigators. Inspection of these frequencies, however, does provide the prescribing physician with a basis to estimate the relative contribution of drug and non-drug factors to the adverse reaction incidences in the population studied. Other Adverse Reactions Observed During Double-Blind Epilepsy Adjunctive Therapy Trials Other adverse reactions that occurred in more than 1% of adults treated with 200 to 400 mg of topiramate in placebo-controlled epilepsy trials but with equal or greater frequency in the placebo group were headache, injury, anxiety, rash, pain, convulsions aggravated, coughing, fever, diarrhea, vomiting, muscle weakness, insomnia, personality disorder, dysmenorrhea, upper respiratory tract infection, and eye pain. Table 6: Incidence of Treatment-Emergent Adverse Reactions in Placebo-Controlled, Add-On Epilepsy Trials in Adults * , † Where Incidence Was >1% in Any Topiramate Tablets Group and Greater Than the Rate in Placebo-Treated Patients * Patients in these add-on/ adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate tablets 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. ‡ Adverse reactions reported by at least 1% of patients in the topiramate tablets 200–400 mg/day group and more common than in the placebo group are listed in this table. Topiramate Dosage ( mg / day ) Body System / Placebo 200 – 400 600 – 1 , 000 Adverse Reaction ‡ ( N = 291 ) ( N = 183 ) ( N = 414 ) Body as a Whole - General Disorders Fatigue 13 15 30 Asthenia 1 6 3 Back pain 4 5 3 Chest pain 3 4 2 Influenza-like symptoms 2 3 4 Leg pain 2 2 4 Hot flushes 1 2 1 Allergy 1 2 3 Edema 1 2 1 Body odor 0 1 0 Rigors 0 1 <1 Central & Peripheral Nervous System Disorders Dizziness 15 25 32 Ataxia 7 16 14 Speech disorders/Related speech problems 2 13 11 Paresthesia 4 11 19 Nystagmus 7 10 11 Tremor 6 9 9 Language problems 1 6 10 Coordination abnormal 2 4 4 Hypoesthesia 1 2 1 Gait abnormal 1 3 2 Muscle contractions involuntary 1 2 2 Stupor 0 2 1 Vertigo 1 1 2 Gastro - Intestinal System Disorders Nausea 8 10 12 Dyspepsia 6 7 6 Abdominal pain 4 6 7 Constipation 2 4 3 Gastroenteritis 1 2 1 Dry mouth 1 2 4 Gingivitis <1 1 1 GI disorder <1 1 0 Hearing and Vestibular Disorders Hearing decreased 1 2 1 Metabolic and Nutritional Disorders Weight decrease 3 9 13 Muscle - Skeletal System Disorders Myalgia 1 2 2 Skeletal pain 0 1 0 Platelet , Bleeding , & Clotting Disorders Epistaxis 1 2 1 Psychiatric Disorders Somnolence 12 29 28 Nervousness 6 16 19 Psychomotor slowing 2 13 21 Difficulty with memory 3 12 14 Anorexia 4 10 12 Confusion 5 11 14 Depression 5 5 13 Difficulty with concentration/attention 2 6 14 Mood problems 2 4 9 Agitation 2 3 3 Aggressive reaction 2 3 3 Emotional lability 1 3 3 Cognitive problems 1 3 3 Libido decreased 1 2 <1 Apathy 1 1 3 Depersonalization 1 1 2 Reproductive Disorders , Female Breast pain 2 4 0 Amenorrhea 1 2 2 Menorrhagia 0 2 1 Menstrual disorder 1 2 1 Reproductive Disorders , Male Prostatic disorder <1 2 0 Resistance Mechanism Disorders Infection 1 2 1 Infection viral 1 2 <1 Moniliasis <1 1 0 Respiratory System Disorders Pharyngitis 2 6 3 Rhinitis 6 7 6 Sinusitis 4 5 6 Dyspnea 1 1 2 Skin and Appendages Disorders Skin disorder <1 2 1 Sweating increased <1 1 <1 Rash erythematous <1 1 <1 Special Sense Other , Disorders Taste perversion 0 2 4 Urinary System Disorders Hematuria 1 2 <1 Urinary tract infection 1 2 3 Micturition frequency 1 1 2 Urinary incontinence <1 2 1 Urine abnormal 0 1 <1 Vision Disorders Vision abnormal 2 13 10 Diplopia 5 10 10 White Cell and RES Disorders Leukopenia 1 2 1 Incidence in Study 119 – Add-On Therapy– Adults with Partial Onset Seizures Study 119 was a randomized, double-blind, add-on/adjunctive, placebo-controlled, parallel group study with 3 treatment arms: 1) placebo; 2) topiramate tablets 200 mg/day with a 25 mg/day starting dose, increased by 25 mg/day each week for 8 weeks until the 200 mg/day maintenance dose was reached; and 3) topiramate tablets 200 mg/day with a 50 mg/day starting dose, increased by 50 mg/day each week for 4 weeks until the 200 mg/day maintenance dose was reached. All patients were maintained on concomitant carbamazepine with or without another concomitant antiepileptic drug. The most commonly observed adverse reactions associated with the use of topiramate tablets that were seen at an incidence higher (≥ 5%) than in the placebo group were : paresthesia, nervousness, somnolence, difficulty with concentration/attention, and fatigue (see Table 7). Because these topiramate tablets treatment difference incidence (Topiramate Tablets % -Placebo %) of many adverse reactions reported in this study were markedly lower than those reported in the previous epilepsy studies, they cannot be directly compared with data obtained in other studies Table 7: Incidence of Treatment-Emergent Adverse Reactions in Study 119 * , † Where Incidence Was ≥ 2% in the Topiramate Tablets Group and Greater Than the Rate in Placebo-Treated Patients * Patients in these add-on/adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate tablets 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. ‡ Adverse reactions reported by at least 2% of patients in the topiramate tablets 200 mg/day group and more common than in the placebo group are listed in this table. Topiramate Tablets Dosage ( mg / day ) Body System / Placebo 200 Adverse Reaction ‡ ( N = 92 ) ( N = 171 ) Body as a Whole - General Disorders Fatigue 4 9 Chest pain 1 2 Cardiovascular Disorders , General Hypertension 0 2 Central & Peripheral Nervous System Disorders Paresthesia 2 9 Dizziness 4 7 Tremor 2 3 Hypoesthesia 0 2 Leg cramps 0 2 Language problems 0 2 Gastro - Intestinal System Disorders Abdominal pain 3 5 Constipation 0 4 Diarrhea 1 2 Dyspepsia 0 2 Dry mouth 0 2 Hearing and Vestibular Disorders Tinnitus 0 2 Metabolic and Nutritional Disorders Weight decrease 4 8 Psychiatric Disorders Somnolence 9 15 Anorexia 7 9 Nervousness 2 9 Difficulty with concentration/attention 0 5 Insomnia 3 4 Difficulty with memory 1 2 Aggressive reaction 0 2 Respiratory System Disorders Rhinitis 0 4 Urinary System Disorders Cystitis 0 2 Vision Disorders Diplopia 0 2 Vision abnormal 0 2 Table 8: Incidence (%) of Dose-Related Adverse Reactions From Placebo-Controlled, Add-On Trials in Adults With Partial Onset Seizures * * Dose-response studies were not conducted for other adult indications or for pediatric indications. Topiramate Tablets Dosage ( mg / day ) Placebo 200 400 600 – 1 , 000 Adverse Reaction ( N = 216 ) ( N = 45 ) ( N = 68 ) ( N = 414 ) Fatigue 13 11 12 30 Nervousness 7 13 18 19 Difficulty with concentration/attention 1 7 9 14 Confusion 4 9 10 14 Depression 6 9 7 13 Anorexia 4 4 6 12 Language problems <1 2 9 10 Anxiety 6 2 3 10 Mood problems 2 0 6 9 Weight decrease 3 4 9 13 Table 9: Incidence (%) of Treatment-Emergent Adverse Reactions in Placebo-Controlled, Add-On Epilepsy Trials in Pediatric Patients (Ages 2 –16 Years) * , † (Reactions That Occurred in at Least 1% of Topiramate Tablets-Treated Patients and Occurred More Frequently in Topiramate Tablets -Treated Than Placebo-Treated Patients) * Patients in these add-on/adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate tablets 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 / Placebo Topiramate Adverse Reaction ( N = 101 ) ( N = 98 ) Body as a Whole - General Disorders Fatigue 5 16 Injury 13 14 Allergic reaction 1 2 Back pain 0 1 Pallor 0 1 Cardiovascular Disorders , General Hypertension 0 1 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 Hyporeflexia 0 2 Convulsions grand mal 0 1 Fecal incontinence 0 1 Paresthesia 0 1 Gastro - Intestinal System Disorders Nausea 5 6 Saliva increased 4 6 Constipation 4 5 Gastroenteritis 2 3 Dysphagia 0 1 Flatulence 0 1 Gastroesophageal reflux 0 1 Glossitis 0 1 Gum hyperplasia 0 1 Heart Rate and Rhythm Disorders Bradycardia 0 1 Metabolic and Nutritional Disorders Weight decrease 1 9 Thirst 1 2 Hypoglycemia 0 1 Weight increase 0 1 Platelet , Bleeding , & Clotting Disorders Purpura 4 8 Epistaxis 1 4 Hematoma 0 1 Prothrombin increased 0 1 Thrombocytopenia 0 1 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 Appetite increased 0 1 Neurosis 0 1 Reproductive Disorders , Female Leukorrhea 0 2 Resistance Mechanism Disorders Infection viral 3 7 Respiratory System Disorders Pneumonia 1 5 Respiratory disorder 0 1 Skin and Appendages Disorders Skin disorder 2 3 Alopecia 1 2 Dermatitis 0 2 Hypertrichosis 1 2 Rash erythematous 0 2 Eczema 0 1 Seborrhea 0 1 Skin discoloration 0 1 Urinary System Disorders Urinary incontinence 2 4 Nocturia 0 1 Vision Disorders Eye abnormality 1 2 Vision abnormal 1 2 Diplopia 0 1 Lacrimation abnormal 0 1 Myopia 0 1 White Cell and RES Disorders Leukopenia 0 2 Other Adverse Reactions Observed During All Epilepsy Clinical Trials Topiramate tablets has been administered to 2246 adults and 427 pediatric patients with epilepsy during all clinical studies, only some of which were placebo-controlled. During these studies, all adverse reactions were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse reactions, similar types of reactions were grouped into a smaller number of standardized categories using modified WHOART dictionary terminology. The frequencies presented represent the proportion of patients who experienced a reaction of the type cited on at least one occasion while receiving topiramate tablets. Reported reactions are included except those already listed in the previous tables or text, those too general to be informative, and those not reasonably associated with the use of the drug. Reactions are classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent occurring in at least 1/100 patients; infrequent occurring in 1/100 to 1/1000 patients; rare occurring in fewer than 1/1000 patients. Autonomic Nervous System Disorders: Infrequent: vasodilation. Body as a Whole: Frequent: syncope. Infrequent : abdomen enlarged. Rare: alcohol intolerance. Cardiovascular Disorders, General: Infrequent: hypotension, postural hypotension, angina pectoris. Central & Peripheral Nervous System Disorders: Infrequent : neuropathy, apraxia, hyperesthesia, dyskinesia, dysphonia, scotoma, ptosis, dystonia, visual field defect, encephalopathy, EEG abnormal. Rare: upper motor neuron lesion, cerebellar syndrome, tongue paralysis. Gastrointestinal System Disorders: Infrequent: hemorrhoids, stomatitis, melena, gastritis, esophagitis. Rare: tongue edema. Heart Rate and Rhythm Disorders: Infrequent: AV block. Liver and Biliary System Disorders: Infrequent: SGPT increased, SGOT increased. Metabolic and Nutritional Disorders: Infrequent: dehydration, hypocalcemia, hyperlipemia, hyperglycemia, xerophthalmia, diabetes mellitus. Rare: hypernatremia, hyponatremia, hypocholesterolemia, creatinine increased. Musculoskeletal System Disorders: Frequent: arthralgia. Infrequent: arthrosis. Neoplasms: Infrequent: thrombocythemia. Rare: polycythemia. Platelet, Bleeding, and Clotting Disorders: Infrequent: gingival bleeding, pulmonary embolism. Psychiatric Disorders: Frequent: impotence, hallucination, psychosis, suicide attempt. Infrequent: euphoria, paranoid reaction, delusion, paranoia, delirium, abnormal dreaming. Rare: libido increased, manic reaction. Red Blood Cell Disorders: Frequent: anemia. Rare: marrow depression, pancytopenia. Reproductive Disorders, Male: Infrequent: ejaculation disorder, breast discharge. Skin and Appendages Disorders: Infrequent: urticaria, photosensitivity reaction, abnormal hair texture. Rare: chloasma. Special Senses Other, Disorders: Infrequent: taste loss, parosmia. Urinary System Disorders: Infrequent: urinary retention, face edema, renal pain, albuminuria, polyuria, oliguria. Vascular (Extracardiac) Disorders: Infrequent: flushing, deep vein thrombosis, phlebitis. Rare: vasospasm. Vision Disorders: Frequent: conjunctivitis. Infrequent: abnormal accommodation, photophobia, strabismus. Rare: mydriasis, iritis. White Cell and Reticuloendothelial System Disorders: Infrequent: lymphadenopathy, eosinophilia, lymphopenia, granulocytopenia. Rare: lymphocytosis. 6.2 Postmarketing and Other Experience In addition to the adverse experiences reported during clinical testing of topiramate tablets, the following adverse experiences have been reported worldwide in patients receiving topiramate tablets post-approval. These adverse experiences have not been listed above and data are insufficient to support an estimate of their incidence or to establish causation. The listing is alphabetized: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), hepatic failure (including fatalities), hepatitis, maculopathy, pancreatitis, and pemphigus.

Summary of antiepileptic drug (AED) interactions with topiramate tablets ( 7.1 ) AED Co - administered AED Concentration Topiramate Concentration Phenytoin NCor25%increase a 48%decrease Carbamazepine(CBZ) NC 40%decrease CBZepoxide b NC NE Valproic acid 11%decrease 14%decrease Phenobarbital NC NE Primidone NC NE Lamotrigine NCatTPM dosesupto400 mg/day 13%decrease Oral contraceptives: Decreased contraceptive efficacy and increased breakthrough bleeding should be considered, especially at doses greater than 200 mg/day ( 7.3 ) Metformin is contraindicated with metabolic acidosis, an effect of topiramate tablets ( 7.4 ) Lithium levels should be monitored when co-administered with high-dose topiramate tablets ( 7.5 ) Other carbonic anhydrase inhibitors: Monitor the patient for the appearance or worsening of metabolic acidosis ( 7.6 ) In vitro studies indicate that topiramate does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4/5 isozymes. In vitro studies indicate that topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4. Drug interactions with some antiepileptic drugs, CNS depressants and oral contraceptives are described here. For other drug interactions, please refer to Clinical Pharmacology ( 12.3 ) . 7.1 Antiepileptic Drugs Potential interactions between topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. Concomitant administration of phenytoin or carbamazepine with topiramate decreased plasma concentrations of Topiramate by 48% and 40%, respectively when compared to topiramate given alone [see Clinical Pharmacology ( 12.3 ).] Concomitant administration of valproic acid and topiramate tablets has been associated with hyperammonemia with and without encephalopathy. Concomitant administration of topiramate tablets with valproic acid has also been associated with hypothermia (with and without hyperammonemia) in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions ( 5.10 ), ( 5.12 ) or Clinical Pharmacology ( 12.3 )] . 7.2 CNS Depressants Concomitant administration of topiramate tablets and alcohol or other CNS depressant drugs 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 tablets should be used with extreme caution if used in combination with alcohol and other CNS depressants. 7.3 Oral Contraceptives Exposure to ethinyl estradiol was statistically significantly decreased at doses of 200, 400, and 800 mg/day (18%, 21%, and 30%, respectively) when topiramate tablets was given as adjunctive therapy in patients taking valproic acid. However, norethindrone exposure was not significantly affected. In another 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), topiramate tablets, 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. The possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking combination oral contraceptive products with topiramate tablets. 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 )]. 7.4 Metformin Topiramate treatment can frequently cause metabolic acidosis, a condition for which the use of metformin is contraindicated [ see Clinical Pharmacology ( 12.3 )] . 7.5 Lithium In patients, lithium levels were unaffected during treatment with topiramate at doses of 200 mg/day; however, there was an observed increase in systemic exposure of lithium (27% for Cmax and 26% for AUC) following topiramate doses of up to 600 mg/day. Lithium levels should be monitored when co-administered with high-dose topiramate tablets [see Clinical Pharmacology ( 12.3 )] . 7.6 Other Carbonic Anhydrase Inhibitors Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide, acetazolamide, or dichlorphenamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, if topiramate tablets is given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis [see Clinical Pharmacology ( 12.3 )] .

16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F) [See USP controlled room temperature]. Protect from moisture.