FDA label bb2afcb1-4412-4841-a449-7feff8f10da0

WARNINGS Metabolic Acidosis Hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) is associated with topiramate treatment. This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of topiramate on carbonic anhydrase. Such electrolyte imbalance has been observed with the use of topiramate in placebo-controlled clinical trials and in the post-marketing period. Generally,topiramate-induced metabolic acidosis occurs early in treatment although cases can occur at any time during treatment. Bicarbonate decrements are usually mild moderate(average decrease of 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, surgery, ketogenic diet, or drugs) may be additive to the bicarbonate lowering effects of topiramate. In adults, the incidence of persistent treatment-emergent decreases in serum bicarbonate (levels of <20 mEq/L at two consecutive visits or at the final visit) in controlled clinical trials for adjunctive treatment of epilepsy was 32% for 400 mg/day, and 1% for placebo. Metabolic acidosis has been observed at doses as low as 50 mg/day. The incidence of persistent treatment-emergent decreases in serum bicarbonate in adults in the epilepsy controlled clinical trial for monotherapy was 15% for 50 mg/day and 25% for 400 mg/day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and >5 mEq/L decrease from pretreatment) in the adjunctive therapy trials was 3% for 400 mg/day,and 0% for placebo and in the monotherapy trial was 1% for 50 mg/day and 7% for 400 mg/day. Serum bicarbonate levels have not been systematically evaluated at daily doses greater than 400 mg/day. In pediatric patients (<16 years of age), the incidence of persistent treatment emergent decreases in serum bicarbonate in placebo-controlled trials for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures was 67% for topiramate (at approximately 6 mg/kg/day), and 10% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and >5 mEq/L decrease from pretreatment) in these trials was 11% for topiramate and 0% for placebo. Cases of moderately severe metabolic acidosis have been reported in patients as young as 5 months old, especially at daily doses above 5 mg/kg/day. In pediatric patients (10 years up to 16 years of age), the incidence of persistent treatment-emergent decreases in serum bicarbonate in the epilepsy controlled clinical trial for monotherapy was 7% for 50 mg/day and 20% for 400 mg/day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and >5 mEq/L decrease from pretreatment) in this trial was 4% for 50 mg/day and 4% for 400 mg/day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and >5 mEq/L decrease from pretreatment) in these trials was 11% for 200 mg/day, 9% for 100 mg/day, 2% for 50 mg/day, and <1% for placebo. Some manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis, and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures. Chronic metabolic acidosis in pediatric patients may also reduce growth rates. A reduction in growth rate may eventually decrease the maximal height achieved. The effect of topiramate on growth and bone-related sequelae has not been systematically investigated. Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering). If the decision is made to continue patients on topiramate in the face of persistent acidosis, alkali treatment should be considered. Acute Myopia and Secondary Angle Closure Glaucoma A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving Topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness) and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating Topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of Topiramate as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of Topiramate, may be helpful. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss. Oligohidrosis and Hyperthermia Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with Topiramate use. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases were reported after exposure to elevated environmental temperatures. The majority of the reports have been in children. Patients, especially pediatric patients, treated with Topiramate should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when Topiramate is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity. Withdrawal of AEDs Antiepileptic drugs, including Topiramate should be withdrawn gradually to minimize the potential of increased seizure frequency. Cognitive/Neuropsychiatric Adverse Events Adults Adverse events most often associated with the use of Topiramate were related to the central nervous system and were observed in the epilepsy populations. In adults, the most frequent of these can be classified into three general categories: 1) Cognitive-related dysfunction (e.g. confusion, psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or language problems, particularly word-finding difficulties); 2) Psychiatric/behavioral disturbances (e.g. depression or mood problems); and 3) Somnolence or fatigue. Cognitive-Related Dysfunction The majority of cognitive-related adverse events were mild to moderate in severity,and they frequently occurred in isolation. Rapid titration rate and higher initial dose were associated with higher incidences of these events. Many of these events contributed to withdrawal from treatment [see ADVERSE REACTIONS , Table 4 and Table 6 ]. In the original add-on epilepsy controlled trials (using rapid titration such as 100 to200 mg/day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse events was 42% for 200 mg/day, 41% for 400 mg/day, 52% for 600 mg/day, 56% for 800 and 1000 mg/day, and 14% for placebo. These dose-related adverse reactions began with a similar frequency in the titration or in the maintenance phase, although in some patients the events began during titration and persisted into the maintenance phase. Some patients who experienced one or more cognitive-related adverse events in the titration phase had a dose-related recurrence of these events in the maintenance phase. In the monotherapy epilepsy controlled trial, the proportion of patients who experienced one or more cognitive-related adverse events was 19% for Topiramate 50 mg/day and 26% for 400 mg/day. Psychiatric/Behavioral Disturbances Psychiatric/behavioral disturbances (depression or mood problems) were dose-related for the epilepsy populations. Somnolence/Fatigue Somnolence and fatigue were the adverse events most frequently reported during clinical trials of Topiramate for adjunctive epilepsy. For the adjunctive epilepsy population, the incidence of somnolence did not differ substantially between 200 mg/day and 1000 mg/day, but the incidence of fatigue was dose-related and increased at dosages above 400 mg/day. For the monotherapy epilepsy population in the 50 mg/day and 400 mg/day groups, the incidence of somnolence was dose-related (9% for the 50 mg/day group and 15% for the 400 mg/day group) and the incidence of fatigue was comparable in both treatment groups (14% each). Additional nonspecific CNS events commonly observed with topiramate in the add-on epilepsy population include dizziness or ataxia. Pediatric Patients In double-blind adjunctive therapy and monotherapy epilepsy clinical studies, the incidences of cognitive/neuropsychiatric adverse events in pediatric patients were generally lower than observed in adults. These events included psychomotor slowing,difficulty with concentration/attention, speech disorders/related speech problems and language problems. The most frequently reported neuropsychiatric events in pediatric patients during adjunctive therapy double-blind studies were somnolence and fatigue. The most frequently reported neuropsychiatric events in pediatric patients in the 50 mg/day and 400 mg/day groups during the monotherapy double-blind study were headache, dizziness anorexia, and somnolence. No patients discontinued treatment due to any adverse events in the adjunctive epilepsy double-blind trials. In the monotherapy epilepsy double-blind trial, 1 pediatric patient (2%) in the 50 mg/day group and 7 pediatric patients (12%) in the 400 mg/day group discontinued treatment due to any adverse events. The most common adverse event associated with discontinuation of therapy was difficulty with concentration/attention; all occurred in the 400 mg/day group. Sudden Unexplained Death in Epilepsy (SUDEP) During the course of premarketing development of Topiramate Tablets, 10 sudden and unexplained deaths were recorded among a cohort of treated patients (2,796 subject years of exposure). This represents an incidence of 0.0035 deaths per patient year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving Topiramate (ranging from 0.0005 for the general population of patients with epilepsy, to 0.003 for a clinical trial population similar to that in the Topiramate program, to 0.005 for patients with refractory epilepsy).

ADVERSE REACTIONS The data described in the following section were obtained using Topiramate Tablets. Monotherapy Epilepsy The adverse events in the controlled trial that occurred most commonly in adults in the 400 mg/day group and at a rate higher than the 50 mg/day group were: paresthesia, weight decrease, somnolence, anorexia, dizziness, and difficulty with memory NOS [see Table 4]. The adverse events in the controlled trial that occurred most commonly in children (10 years up to 16 years of age) in the 400 mg/day group and at a rate higher than the 50 mg/day group were: weight decrease, upper respiratory tract infection, paresthesia, anorexia, diarrhea, and mood problems [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 events. Adverse events associated with discontinuing therapy (≥2%) included depression, insomnia, difficulty with memory (NOS), somnolence, paresthesia, psychomotor slowing, dizziness, and nausea. Approximately 12% of the 57 pediatric patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse events. Adverse events associated with discontinuing therapy (≥5%) included difficulty with concentration/attention. The prescriber should be aware that these data cannot be used to predict the frequency of adverse events in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during the clinical study. 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 event incidences in the population studied. Table 4: Incidence of Treatment-Emergent Adverse Events in the Monotherapy Epilepsy Trial in Adults a Where Rate Was at Least 2% in the 400 mg/day Topiramate Group and Greater Than the Rate in the 50 mg/day Topiramate Group a Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category Body System/ Adverse Event Topiramate Dosage (mg/day) 50 (N=160) 400 (N=159) Body as a Whole- General Disorders Asthenia Leg Pain Chest Pain 4 2 1 6 3 2 Central & Peripheral Nervous system Disorders Paresthesia Dizziness Hypoaesthesia Ataxia Hypertonia 21 13 4 3 0 40 14 5 4 3 Gastro-Intestinal System Disorders Diarrhea Constipation Gastritis Dry Mouth Gastroesophageal Reflux 5 1 0 1 1 6 4 3 3 2 Liver and Biliary System Disorders Gamma-GT Increased 1 3 Metabolic and nutritional Disorders Weight Decrease 6 16 Psychiatric Disorders Somnolence Anorexia Difficulty with Memory NOS Insomnia Depression Difficulty with Concentration/Attention Anxiety Psychomotor Slowing Mood Problems Confusion Cognitive Problem NOS Libido Decreased 9 4 5 8 7 7 4 3 2 3 1 0 15 14 10 9 9 8 6 5 5 4 4 3 Reproductive Disorders, female Vaginal Hemorrhage 0 3 Red Blood Cell disorders Anemia 1 2 Table 5: Incidence of Treatment-Emergent Adverse Events in the Monotherapy Epilepsy Trail in Children Ages 10 up to 16 Yearsa where Rate was at least 5% in the 400 mg/day Topiramate Group and Greater Than the Rate in the 50 mg/day Topiramate Group a Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category Body System/ Adverse Event Topiramate Dosage (mg/day) b 50 (N=57) 400 (N=57) Body as a Whole-General Disorders Fever 0 9 Central & Peripheral Nervous system Disorders Paresthesia 2 16 Gastro-Intestinal System Disorders Diarrhea 5 11 Metabolic and nutritional Disorders Weight Decrease 7 21 Psychiatric Disorders Anorexia Mood Problems Difficulty with Concentration/Attention Cognitive Problem NOS Nervousness 11 2 4 0 4 14 11 9 7 5 Resistance Mechanism Disorders Infection Viral Infection 4 2 9 7 Respiratory System Disorders Upper Respiratory Tract Infection Rhinitis Bronchitis Sinusitis 16 2 2 2 18 7 7 5 Skin and Appendages Disorders Alopecia 2 5 Adjunctive Therapy Epilepsy The most commonly observed adverse events associated with the use of topiramate at dosages of 200 to 400 mg/day in controlled trials in adults with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, that were seen at greater frequency in topiramate-treated patients and did not appear to be doserelated were: somnolence, dizziness, ataxia, speech disorders and related speech problems, psychomotor slowing, abnormal vision, difficulty with memory, paresthesia and diplopia [see Table 6]. The most common dose-related adverse events at dosages of 200 to 1,000 mg/day were: fatigue, nervousness, difficulty with concentration or attention, confusion, depression, anorexia, language problems, anxiety, mood problems, and weight decrease [see Table 8]. Adverse events associated with the use of topiramate 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 greater frequency in topiramate-treated patients were: fatigue, somnolence, anorexia, nervousness, difficulty with concentration/attention, difficulty with memory, aggressive reaction, and weight decrease [see Table 9]. In controlled clinical trials in adults, 11% of patients receiving topiramate 200 to 400 mg/day as adjunctive therapy discontinued due to adverse events. This rate appeared to increase at dosages above 400 mg/day. Adverse events 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 adjunctive therapy at 5 to 9 mg/kg/day in controlled clinical trials discontinued due to adverse events. Approximately 28% of the 1,757 adults with epilepsy who received topiramate at dosages of 200 to 1,600 mg/day in clinical studies discontinued treatment because of adverse events; an individual patient could have reported more than one adverse event. These adverse events 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 at dosages up to 30 mg/kg/day discontinued due to adverse events. Adverse events associated with discontinuing therapy included aggravated convulsions (2.3%), difficulty with concentration/attention (1.6%), language problems (1.3%), personality disorder (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 events that occurred in at least 1% of adults treated with 200 to 400 mg/day topiramate 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 events during the first eight weeks of these trials no longer experienced them by their last visit. Table 9 lists treatment-emergent adverse events that occurred in at least 1% of pediatric patients treated with 5 to 9 mg/kg topiramate 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 was added to concurrent antiepileptic drug therapy and cannot be used to predict the frequency of adverse events 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 event incidences in the population studied. Other Adverse Events Observed During Double-Blind Adjunctive Therapy Epilepsy Trials Other events 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 Events in Placebo-Controlled, Add-On Epilepsy Trials in Adults a,b Where Rate Was >1% in Any Topiramate Group and Greater Than the Rate in Placebo-Treated Patients Body System/ Adverse Eventc Placebo (N=291) Topiramate Dosage (mg/day) 200-400 (N=183) 600-1,000 (N=414) Body as a Whole- General Disorders Fatigue Asthenia Back Pain Chest Pain Influenza-Like Symptoms Leg Pain Hot Flushes Allergy Edema Body Odor Rigors 13 1 4 3 2 2 1 1 1 0 0 15 6 5 4 3 2 2 2 2 1 1 30 3 3 2 4 4 1 3 1 0 <1 Central & Peripheral Nervous system Disorders Dizziness Ataxia Speech Disorders/ Related Speech Problems Paresthesia Nystagmus Tremor Language problems Coordination Abnormal Hypoaesthesia Gait Abnormal Muscle Contractions Involuntary Stupor Vertigo 15 7 2 4 7 6 1 2 1 1 1 0 1 25 16 13 11 10 9 6 4 2 3 2 2 1 32 14 11 19 11 9 10 4 1 2 2 1 2 Gastro-Intestinal System Disorders Nausea Dyspepsia Abdominal Pain Constipation Gastroenteritis Dry Mouth Gingivitis GI Disorder 8 6 4 2 1 1 <1 <1 10 7 6 4 2 2 1 1 12 6 7 3 1 4 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 Skeletal Pain 1 0 2 1 2 0 Platelet, Bleeding, & Clotting Disorders Epistaxis 1 2 1 Psychiatric Disorders Somnolence Nervousness Psychomotor Slowing Difficulty with Memory Anorexia Confusion Depression Difficulty with Concentration/ Attention Mood Problems Agitation Aggressive Reaction Emotional Liability Cognitive Problems Libido Decreased Apathy Depersonalization 12 6 2 3 4 5 5 2 2 2 2 1 1 1 1 1 29 16 13 12 10 11 5 6 4 3 3 3 3 2 1 1 28 19 21 14 12 14 13 14 9 3 3 3 3 <1 3 2 Reproductive Disorders, female Breast Pain Amenorrhea Menorrhagia Menstrual Disorder 2 1 0 1 4 2 2 2 0 2 1 1 Reproductive Disorders, male Prostatic Disorder <1 2 0 Resistance Mechanism Disorders Infection Infection Viral Moniliasis 1 1 <1 2 2 1 1 <1 0 Respiratory System Disorders Pharyngitis Rhinitis Sinusitis Dyspnea 2 6 4 1 6 7 5 1 3 6 6 2 Skin and Appendages Disorders Skin Disorder Sweating Increased Rash Erythematous <1 <1 <1 2 1 1 1 <1 <1 Special Senses Other, Disorders Taste Perversion 0 2 4 Urinary System Disorders Hematuria Urinary Tract Infection Micturition Frequency Urinary Incontinence Urine Abnormal 1 1 1 <1 0 2 2 1 2 1 <1 3 2 1 <1 Vision Disorders Vision Abnormal Diplopia 2 5 13 10 10 10 White Cell and RES Disorders Leukopenia 1 2 1 a Patients in these add-on trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to Topiramate or placebo. b Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category. c Adverse events reported by at least 1% of patients in the Topiramate 200-400 mg/day group and more common than in the placebo group are listed in this table. Incidence in Study 119 – Add-On Therapy– Adults with Partial Onset Seizures Study 119 was a randomized, double-blind, placebo-controlled, parallel group study with 3 treatment arms: 1) placebo; 2) topiramate 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 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 incidence of adverse events (Table 7) did not differ significantly between the 2 topiramate regimens. Because the frequencies of adverse events 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 Events in Study 119 a,b Where Rate Was ≥2% in the Topiramate Group and Greater Than the Rate in Placebo-Treated Patients Body System/ Adverse Eventc Placebo (N=92) Topiramate Dosage (mg/day) 200 (N=171) Body as a Whole-General Disorders Fatigue Chest Pain 4 1 9 2 Cardiovascular Disorders, General Hypertension 0 2 Central & Peripheral Nervous system Disorders Paresthesia Dizziness Tremor Hypoasthesia Leg Cramps Language Problems 2 4 2 0 0 0 9 7 3 2 2 2 Gastro-Intestinal System Disorders Abdominal Pain Constipation Diarrhea Dyspepsia Dry Mouth 3 0 1 0 0 5 4 2 2 2 Hearing and Vestibular Disorders Tinnitus 0 2 Metabolic and Nutritional Disorders Weight Decrease 4 8 Psychiatric Disorders Somnolence Anorexia Nervousness Difficulty with Concentration/Attention Insomnia Difficulty with Memory Aggressive Reaction 9 7 2 0 3 1 0 15 9 9 5 4 2 2 Respiratory System Disorders Rhinitis 0 4 Urinary System Disorders Cystitis 0 2 Vision Disorders Diplopia Vision Abnormal 0 0 2 2 a Patients in these add-on trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to Topiramate or placebo. b Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category. c Adverse events reported by at least 2% of patients in the Topiramate 200 mg/day group and more common than in the placebo group are listed in this table. Table 8: Incidence (%) of Dose-Related Adverse Events From Placebo-Controlled, Add-On Trials in Adults with Partial Onset Seizures a Adverse Event Placebo (N=216) Topiramate Dosage (mg/day) 200 (N=45) 400 (N=68) 600-1,000 (N=414) Fatigue Nervousness Difficulty with Concentration/ Attention Confusion Depression Anorexia Language problems Anxiety Mood problems Weight decrease 13 7 1 4 6 4 <1 6 2 3 11 13 7 9 9 4 2 2 0 4 12 18 9 10 7 6 9 3 6 9 30 19 14 14 13 12 10 10 9 13 a Dose-response studies were not conducted for other adult indications or for pediatric indications. Table 9: Incidence (%) of Treatment-Emergent Adverse Events in Placebo-Controlled, Add-On Epilepsy Trials in Pediatric Patients Ages 2-16 Years a,b (Events that Occurred in at Least 1% of Topiramate-Treated Patients and Occurred More Frequently in Topiramate-Treated Than Placebo-Treated Patients) Body System/ Adverse Event Placebo (N=101) Topiramate (N=98) Body as a Whole-General Disorders Fatigue Injury Allergic Reaction Back Pain Pallor 5 13 1 0 0 16 14 2 1 1 Cardiovascular Disorders, General Hypertension 0 1 Central & Peripheral Nervous system Disorders Gait Abnormal Ataxia Hyperkinesia Dizziness Speech Disorders/Related Speech Problems Hyporeflexia Convulsions Grand Mal Fecal Incontinence Paresthesia 5 2 4 2 2 0 0 0 0 8 6 5 4 4 2 1 1 1 Gastro-Intestinal System Disorders Nausea Saliva Increased Constipation Gastroenteritis Dysphagia Flatulence Gastroesophageal Reflux Glossitis Gum Hyperplasia 5 4 4 2 0 0 0 0 0 6 6 5 3 1 1 1 1 1 Heart Rate and Rhythm Disorders Bradycardia 0 1 Metabolic and Nutritional Disorders Weight Decrease Thirst Hypoglycemia Weight Increase 1 1 0 0 9 2 1 1 Platelet, Bleeding, & Clotting Disorders Purpura Epistaxis Hematoma Prothrombin Increased Thrombocyotopenia 4 1 0 0 0 8 4 1 1 1 Psychiatric Disorders Somnolence Anorexia Nervousness Personality Disorder (Behavior Problems) Difficulty with Concentration/Attention Aggressive Reaction Insomnia Difficulty with Memory NOS Confusion Psychomotor Slowing Appetite Increased Neurosis 16 15 7 9 2 4 7 0 3 2 0 0 26 24 14 11 10 9 8 5 4 3 1 1 Reproductive Disorders, female Leukorrhoea 0 2 Resistance Mechanism Disorders Infection Viral 3 7 Respiratory System Disorders Pneumonia Respiratory Disorder 1 0 5 1 Body System/ Adverse Event Placebo(N=101) Topiramate(N=98) Skin and Appendages Disorders Skin Disorder Alopecia Dermatitis Hypertrichosis Rash Erythematous Eczema Seborrhoea Skin Discoloration 2 1 0 1 0 0 0 0 3 2 2 2 2 1 1 1 Urinary System Disorders Urinary Incontinence Nocturia 2 0 4 1 Vision Disorders Eye Abnormality Vision Abnormal Diplopia Lacrimation Abnormal Myopia 1 1 0 0 0 2 2 1 1 1 White Cell and RES Disorders Leukopenia 0 2 a Patients in these add-on trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to Topiramate or placebo. b Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category. Other Adverse Events Observed During All Epilepsy Clinical Trials Topiramate has been administered to 2,246 adults and 427 pediatric patients with epilepsy during all clinical studies, only some of which were placebo controlled. During these studies, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified WHOART dictionary terminology. The frequencies presented represent the proportion of patients who experienced an event of the type cited on at least one occasion while receiving topiramate. Reported events 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. Events 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, hyperaesthesia, 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, hypokalemia, alkaline phosphatase increased, hypocalcemia, hyperlipemia, hyperglycemia, xerophthalmia, diabetes mellitus. Rare: hyperchloremia, hypernatremia, hyponatremia, hypocholesterolemia, hypophosphatemia, 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. Postmarketing and Other Experience In addition to the adverse experiences reported during clinical testing of Topiramate, the following adverse experiences have been reported worldwide in patients receiving topiramate 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, pancreatitis, pemphigus, and renal tubular acidosis.

<table> <col/> <col/> <col/> <tfoot> <tr> <td valign="top" colspan="3"> ^a Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category </td> </tr> </tfoot> <tbody> <tr> <td valign="top" rowspan="2" styleCode=" Botrule Toprule "> <content styleCode="bold"> </content> <content styleCode="bold">Body System/</content> <content styleCode="bold"> </content> Adverse Event</td> <td valign="top" colspan="2" styleCode=" Botrule Toprule "> Topiramate Dosage (mg/day)</td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule "> 50 (N=160)</td> <td valign="top" styleCode=" Botrule Toprule "> 400 (N=159)</td> </tr> <tr> <td valign="top" styleCode=" Toprule "> <content styleCode="bold">Body as a Whole-</content> <content styleCode="bold"> </content> <content styleCode="bold">General Disorders</content>Asthenia Leg Pain Chest Pain</td> <td valign="top" styleCode=" Toprule "> 4 2 1</td> <td valign="top" styleCode=" Toprule "> 6 3 2</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Central &amp; Peripheral Nervous system Disorders</content> Paresthesia Dizziness Hypoaesthesia Ataxia Hypertonia</td> <td valign="top"> 21 13 4 3 0</td> <td valign="top"> 40 14 5 4 3</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Gastro-Intestinal System Disorders</content> Diarrhea Constipation Gastritis Dry Mouth Gastroesophageal Reflux</td> <td valign="top"> 5 1 0 1 1</td> <td valign="top"> 6 4 3 3 2</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Liver and Biliary System Disorders</content> Gamma-GT Increased</td> <td valign="top"> 1</td> <td valign="top"> 3</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Metabolic and nutritional Disorders</content> Weight Decrease</td> <td valign="top"> 6</td> <td valign="top"> 16</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Psychiatric Disorders</content> Somnolence Anorexia Difficulty with Memory NOS Insomnia Depression Difficulty with Concentration/Attention Anxiety Psychomotor Slowing Mood Problems Confusion Cognitive Problem NOS Libido Decreased</td> <td valign="top"> 9 4 5 8 7 7 4 3 2 3 1 0</td> <td valign="top"> 15 14 10 9 9 8 6 5 5 4 4 3</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Reproductive Disorders, female</content> Vaginal Hemorrhage</td> <td valign="top"> 0</td> <td valign="top"> 3</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Red Blood Cell disorders</content> Anemia</td> <td valign="top"> 1</td> <td valign="top"> 2</td> </tr> </tbody> </table>

<table> <col/> <col/> <col/> <tfoot> <tr> <td valign="top" colspan="3" styleCode=" Botrule "> ^aValues represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category </td> </tr> </tfoot> <tbody> <tr> <td valign="top" rowspan="2" styleCode=" Botrule Toprule "> <content styleCode="bold">Body System/</content> Adverse Event</td> <td valign="top" colspan="2" styleCode=" Botrule Toprule "> Topiramate Dosage (mg/day)^b </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule "> 50 (N=57)</td> <td valign="top" styleCode=" Botrule Toprule "> 400 (N=57)</td> </tr> <tr> <td valign="top" styleCode=" Toprule "> <content styleCode="bold">Body as a Whole-General Disorders</content> Fever</td> <td valign="top" styleCode=" Toprule "> 0</td> <td valign="top" styleCode=" Toprule "> 9</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Central &amp; Peripheral Nervous system Disorders</content> Paresthesia </td> <td valign="top"> 2</td> <td valign="top"> 16</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Gastro-Intestinal System Disorders</content> Diarrhea</td> <td valign="top"> 5</td> <td valign="top"> 11</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Metabolic and nutritional Disorders</content> Weight Decrease</td> <td valign="top"> 7</td> <td valign="top"> 21</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Psychiatric Disorders</content> Anorexia Mood Problems Difficulty with Concentration/Attention Cognitive Problem NOS Nervousness</td> <td valign="top"> 11 2 4 0 4</td> <td valign="top"> 14 11 9 7 5</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Resistance Mechanism Disorders</content> Infection Viral Infection</td> <td valign="top"> 4 2</td> <td valign="top"> 9 7</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Respiratory System Disorders</content> Upper Respiratory Tract Infection Rhinitis Bronchitis Sinusitis</td> <td valign="top"> 16 2 2 2</td> <td valign="top"> 18 7 7 5</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Skin and Appendages Disorders</content> Alopecia</td> <td valign="top"> 2</td> <td valign="top"> 5</td> </tr> </tbody> </table>

<table> <col/> <col/> <col/> <col/> <tbody> <tr> <td valign="top" rowspan="2" styleCode=" Botrule Toprule "> <content styleCode="bold">Body System/</content> Adverse Eventc</td> <td valign="top" rowspan="2" styleCode=" Botrule Toprule "> Placebo (N=291)</td> <td align="right" valign="top" colspan="2" styleCode=" Botrule Toprule "> Topiramate Dosage (mg/day)</td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule "> 200-400 (N=183)</td> <td valign="top" styleCode=" Botrule Toprule "> 600-1,000 (N=414)</td> </tr> <tr> <td valign="top" styleCode=" Toprule "> <content styleCode="bold">Body as a Whole-</content> <content styleCode="bold"> </content> <content styleCode="bold">General Disorders</content> Fatigue Asthenia Back Pain Chest Pain Influenza-Like Symptoms Leg Pain Hot Flushes Allergy Edema Body Odor Rigors</td> <td valign="top" styleCode=" Toprule "> 13 1 4 3 2 2 1 1 1 0 0</td> <td valign="top" styleCode=" Toprule "> 15 6 5 4 3 2 2 2 2 1 1</td> <td valign="top" styleCode=" Toprule "> 30 3 3 2 4 4 1 3 1 0 &lt;1</td> </tr> <tr> <td valign="top" colspan="4"> <content styleCode="bold">Central &amp; Peripheral Nervous system Disorders</content> </td> </tr> <tr> <td valign="top"> Dizziness Ataxia Speech Disorders/ Related Speech Problems Paresthesia Nystagmus Tremor Language problems Coordination Abnormal Hypoaesthesia Gait Abnormal Muscle Contractions Involuntary Stupor Vertigo</td> <td valign="top"> 15 7 2 4 7 6 1 2 1 1 1 0 1</td> <td valign="top"> 25 16 13 11 10 9 6 4 2 3 2 2 1</td> <td valign="top"> 32 14 11 19 11 9 10 4 1 2 2 1 2</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Gastro-Intestinal System Disorders</content> <content styleCode="bold"> </content> Nausea<content styleCode="bold"> </content> Dyspepsia<content styleCode="bold"> </content> Abdominal Pain Constipation<content styleCode="bold"> </content> Gastroenteritis Dry Mouth<content styleCode="bold"> </content> Gingivitis GI Disorder</td> <td valign="top"> 8 6 4 2 1 1 &lt;1 &lt;1</td> <td valign="top"> 10 7 6 4 2 2 1 1</td> <td valign="top"> 12 6 7 3 1 4 1 0</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Hearing and Vestibular Disorders</content> <content styleCode="bold"> </content> Hearing Decreased</td> <td valign="top"> 1</td> <td valign="top"> 2</td> <td valign="top"> 1</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Metabolic and nutritional Disorders</content> Weight Decrease</td> <td valign="top"> 3</td> <td valign="top"> 9</td> <td valign="top"> 13</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Muscle-Skeletal System Disorders</content> <content styleCode="bold"> </content> Myalgia<content styleCode="bold"> </content> Skeletal Pain</td> <td valign="top"> 1 0</td> <td valign="top"> 2 1</td> <td valign="top"> 2 0</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Platelet, Bleeding, &amp; Clotting Disorders</content> Epistaxis </td> <td valign="top"> 1</td> <td valign="top"> 2</td> <td valign="top"> 1</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Psychiatric Disorders</content> Somnolence Nervousness Psychomotor Slowing Difficulty with Memory Anorexia Confusion Depression Difficulty with Concentration/ Attention Mood Problems Agitation Aggressive Reaction Emotional Liability Cognitive Problems Libido Decreased Apathy Depersonalization</td> <td valign="top"> 12 6 2 3 4 5 5 2 2 2 2 1 1 1 1 1</td> <td valign="top"> 29 16 13 12 10 11 5 6 4 3 3 3 3 2 1 1</td> <td valign="top"> 28 19 21 14 12 14 13 14 9 3 3 3 3 &lt;1 3 2</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Reproductive Disorders, female</content> <content styleCode="bold"> </content> Breast Pain Amenorrhea Menorrhagia Menstrual Disorder</td> <td valign="top"> 2 1 0 1</td> <td valign="top"> 4 2 2 2</td> <td valign="top"> 0 2 1 1</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Reproductive Disorders, male</content> Prostatic Disorder</td> <td valign="top"> &lt;1</td> <td valign="top"> 2</td> <td valign="top"> 0</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Resistance Mechanism Disorders</content> <content styleCode="bold"> </content> Infection<content styleCode="bold"> </content> Infection Viral<content styleCode="bold"> </content> Moniliasis</td> <td valign="top"> 1 1 &lt;1</td> <td valign="top"> 2 2 1</td> <td valign="top"> 1 &lt;1 0</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Respiratory System Disorders</content> <content styleCode="bold"> </content>Pharyngitis<content styleCode="bold"> </content>Rhinitis<content styleCode="bold"> </content>Sinusitis<content styleCode="bold"> </content>Dyspnea </td> <td valign="top"> 2 6 4 1</td> <td valign="top"> 6 7 5 1</td> <td valign="top"> 3 6 6 2</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Skin and Appendages Disorders</content> <content styleCode="bold"> </content> Skin Disorder<content styleCode="bold"> </content> Sweating Increased<content styleCode="bold"> </content> Rash Erythematous</td> <td valign="top"> &lt;1 &lt;1 &lt;1</td> <td valign="top"> 2 1 1</td> <td valign="top"> 1 &lt;1 &lt;1</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Special Senses Other, Disorders</content> <content styleCode="bold"> </content> Taste Perversion</td> <td valign="top"> 0</td> <td valign="top"> 2</td> <td valign="top"> 4</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Urinary System Disorders</content> <content styleCode="bold"> </content>Hematuria<content styleCode="bold"> </content>Urinary Tract Infection<content styleCode="bold"> </content>Micturition Frequency <content styleCode="bold"> </content>Urinary Incontinence<content styleCode="bold"> </content>Urine Abnormal</td> <td valign="top"> 1 1 1 &lt;1 0</td> <td valign="top"> 2 2 1 2 1</td> <td valign="top"> &lt;1 3 2 1 &lt;1</td> </tr> <tr> <td valign="top"> <content styleCode="bold">Vision Disorders</content> <content styleCode="bold"> </content>Vision Abnormal<content styleCode="bold"> </content>Diplopia</td> <td valign="top"> 2 5</td> <td valign="top"> 13 10</td> <td valign="top"> 10 10</td> </tr> <tr> <td valign="top" styleCode=" Botrule "> <list listType="unordered" styleCode="Square"> <item> <content styleCode="bold">White Cell and RES Disorders </content>Leukopenia</item> </list> </td> <td valign="top" styleCode=" Botrule "> 1</td> <td valign="top" styleCode=" Botrule "> 2</td> <td valign="top" styleCode=" Botrule "> 1</td> </tr> </tbody> </table>