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adverse reactions
ADVERSE REACTIONS The data described in the following section were obtained using TOPAMAX ® (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: Incidenceof 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 TOPAMAX ® Dosage (mg/day) Body System/ Adverse Event 50 (N= 160) 400 (N=159) 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 as a Whole-General Disorders Asthenia 4 6 Leg Pain 2 3 Chest Pain 1 2 Central & Peripheral Nervous System Disorders Paresthesia 21 40 Dizziness 13 14 Hypoaesthesia 4 5 Ataxia 3 4 Hypertonia 0 3 Gastro-Intestinal System Disorders Diarrhea 5 6 Constipation 1 4 Gastritis 0 3 Dry Mouth 1 3 Gastroesophageal Reflux 1 2 Liver and Biliary System Disorders Gamma-GT Increased 1 3 Metabolic and Nutritional Disorders Weight Decrease 6 16 Psychiatric Disorders Somnolence 9 15 Anorexia 4 14 Difficulty with Memory NOS 5 10 Insomnia 8 9 Depression 7 9 Difficulty with Concentration/Attention 7 8 Anxiety 4 6 Psychomotor Slowing 3 5 Mood Problems 2 5 Confusion 3 4 Cognitive Problem NOS 1 4 Libido Decreased 0 3 Reproductive Disorders, Female Vaginal Hemorrhage 0 3 Red Blood Cell Disorders Anemia 1 2 Resistance Mechanism Disorders Infection Viral 6 8 Infection 2 3 Respiratory System Disorders Bronchitis 3 4 Rhinitis 2 4 Dyspnea 1 2 Skin and Appendages Disorders Rash 1 4 Pruritus 1 4 Acne 2 3 Special Senses Other, Disorders Taste Perversion 3 5 Urinary System Disorders Cystitis 1 3 Renal Calculus 0 3 Urinary Tract Infection 1 2 Dysuria 0 2 Micturition Frequency 0 2 Table 5: Incidence of Treatment-Emergent Adverse Events in the Monotherapy Epilepsy Trial in Children Ages 10 up to 16 Years a 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 TOPAMAX ® Dosage (mg/day) Body System/ Adverse Event 50 (N=57) 400 (N=57) 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 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 11 14 Mood Problems 2 11 Difficulty with Concentration/Attention 4 9 Cognitive Problems NOS 0 7 Nervousness 4 5 Resistance Mechanism Disorders Infection Viral 4 9 Infection 2 7 Respiratory System Disorders Upper Respiratory Tract Infection 16 18 Rhinitis 2 7 Bronchitis 2 7 Sinusitis 2 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 dose-related 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 TOPAMAX ® 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 Epilepsy Adjunctive Therapy 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 TOPAMAX ® Dosage (mg/day) Body System/ Adverse Event c Placebo (N=291) 200-400 (N=183) 600-1,000 (N=414) a Patients in these add-on trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to TOPAMAX ® 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 TOPAMAX ® 200-400 mg/day group and more common than in the placebo group are listed in this table. 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 Hypoaesthesia 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, 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 TOPAMAX ® Dosage (mg/day) Body System/ AdverseEvent c Placebo (N=92) 200 (N=171) a Patients in these add-on trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to TOPAMAX ® 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 TOPAMAX ® 200 mg/day group and more common than in the placebo group are listed in this table. 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 Hypoasthesia 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 Events From Placebo-Controlled, Add-On Trials in Adults with Partial Onset Seizures a TOPAMAX ® Dosage (mg/day) Adverse Event Placebo (N = 216) 200 (N = 45) 400 (N = 68) 600 - 1,000 (N = 414) a Dose-response studies were not conducted for other adult indications or for pediatric indications. 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 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) a Patients in these add-on trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to TOPAMAX ® 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. 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 NOS 0 5 Confusion 3 4 Psychomotor Slowing 2 3 Appetite Increased 0 1 Neurosis 0 1 Reproductive Disorders, Female Leukorrhoea 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 Seborrhoea 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 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. Migraine In the four multicenter, randomized, double-blind, placebo-controlled, parallel group migraine prophylaxis clinical trials, most of the adverse events with topiramate were mild or moderate in severity. Most adverse events occurred more frequently during the titration period than during the maintenance period. Table 10 includes those adverse events reported for patients in the placebo-controlled trials where the incidence rate in any topiramate treatment group was at least 2 % and was greater than that for placebo patients. Table 10: Incidence of Treatment-Emergent Adverse Events in Placebo-Controlled, Migraine Trials Where Rate Was ≥2 % in Any Topiramate Group and Greater than the Rate in Placebo-Treated Patients a TOPAMAX ® Dosage (mg/day) Body System/ Adverse Event Placebo (N=445) 50 (N=235) 100 (N=386) 200 (N=514) 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. b Blurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for > 50 % of events coded as vision abnormal, a preferred term. Body as a Whole-General Disorders Fatigue 11 14 15 19 Injury 7 9 6 6 Asthenia 1 <1 2 2 Fever 1 1 1 2 Influenza-Like Symptoms <1 <1 <1 2 Allergy <1 2 <1 <1 Central & Peripheral Nervous System Disorders Paresthesia 6 35 51 49 Dizziness 10 8 9 12 Hypoaesthesia 2 6 7 8 Language Problems 2 7 6 7 Involuntary Muscle Contractions 1 2 2 4 Ataxia <1 1 2 1 Speech Disorders/Related Speech Problems <1 1 <1 2 Gastro-Intestinal System Disorders Nausea 8 9 13 14 Diarrhea 4 9 11 11 Abdominal Pain 5 6 6 7 Dyspepsia 3 4 5 3 Dry Mouth 2 2 3 5 Vomiting 2 1 2 3 Gastroenteritis 1 3 3 2 Hearing and Vestibular Disorders Tinnitus 1 <1 1 2 Metabolic and Nutritional Disorders Weight Decrease 1 6 9 11 Thirst <1 2 2 1 Musculoskeletal System Disorders Arthralgia 2 7 3 1 Neoplasms Neoplasm NOS <1 2 <1 <1 Psychiatric Disorders Anorexia 6 9 15 14 Somnolence 5 8 7 10 Difficulty with Memory NOS 2 7 7 11 Difficulty with Concentration/Attention 2 3 6 10 Insomnia 5 6 7 6 Anxiety 3 4 5 6 Mood Problems 2 3 6 5 Depression 4 3 4 6 Nervousness 2 4 4 4 Confusion 2 2 3 4 Psychomotor Slowing 1 3 2 4 Libido Decreased 1 1 1 2 Aggravated Depression 1 1 2 2 Agitation 1 2 2 1 Cognitive Problems NOS 1 <1 2 2 Reproductive Disorders, Female Menstrual Disorder 2 3 2 2 Reproductive Disorders, Male Ejaculation Premature 0 3 0 0 Resistance Mechanism Disorders Viral Infection 3 4 4 3 Otitis Media <1 2 1 1 Respiratory System Disorders Upper Respiratory Tract Infection 12 13 14 12 Sinusitis 6 10 6 8 Pharyngitis 4 5 6 2 Coughing 2 2 4 3 Bronchitis 2 3 3 3 Dyspnea 2 1 3 2 Rhinitis 1 1 2 2 Skin and Appendages Disorders Pruritis 2 4 2 2 Special Sense Other, Disorders Taste Perversion 1 15 8 12 Taste Loss <1 1 1 2 Urinary System Disorders Urinary Tract Infection 2 4 2 4 Renal Calculus 0 0 1 2 Vision Disorders Vision Abnormal <1 1 2 3 Blurred Vision b 2 4 2 4 Conjunctivitis 1 1 2 1 Of the 1,135 patients exposed to topiramate in the placebo-controlled studies, 25% discontinued due to adverse events, compared to 10% of the 445 placebo patients. The adverse events associated with discontinuing therapy in the topiramate-treated patients included paresthesia (7%), fatigue (4%), nausea (4%), difficulty with concentration/attention (3%), insomnia (3%), anorexia (2%), and dizziness (2%). Patients treated with topiramate 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, topiramate 50, 100, and 200 mg groups, respectively. Table 11 shows adverse events that were dose-dependent. Several central nervous system adverse events, including some that represented cognitive dysfunction, were dose-related. The most common dose-related adverse events were paresthesia, fatigue, nausea, anorexia, dizziness, difficulty with memory, diarrhea, weight decrease, difficulty with concentration/attention, and somnolence. Table 11: Incidence (%) of Dose-Related Adverse Events From Placebo-Controlled, Migraine Trials a TOPAMAX ® Dosage (mg/day) Adverse Event Placebo (N =445) 50 (N = 235) 100 (N = 386) 200 (N = 514 ) a The incidence rate of the adverse event in the 200 mg/day group was ≥2% than the rate in both the placebo group and the 50 mg/day group. Paresthesia 6 35 51 49 Fatigue 11 14 15 19 Nausea 8 9 13 14 Anorexia 6 9 15 14 Dizziness 10 8 9 12 Weight decrease 1 6 9 11 Difficulty with Memory NOS 2 7 7 11 Diarrhea 4 9 11 11 Difficulty with Concentration/Attention 2 3 6 10 Somnolence 5 8 7 10 Hypoaesthesia 2 6 7 8 Anxiety 3 4 5 6 Depression 4 3 4 6 Mood Problems 2 3 6 5 Dry Mouth 2 2 3 5 Confusion 2 2 3 4 Involuntary Muscle Contractions 1 2 2 4 Abnormal Vision <1 1 2 3 Renal Calculus 0 0 1 2 Other Adverse Events Observed During Migraine Clinical Trials Topiramate, for the treatment of prophylaxis of migraine headache, has been administered to 1,367 patients in all clinical studies (includes double-blind and open-label extension). 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 following additional adverse events that were not described earlier were reported by greater than 1% of the 1,367 topiramate-treated patients in the controlled clinical trials: Body as a Whole: Pain, chest pain, allergic reaction. Central & Peripheral Nervous System Disorders: Headache, vertigo, tremor, sensory disturbance, migraine aggravated. Gastrointestinal System Disorders: Constipation, gastroesophageal reflux, tooth disorder. Musculoskeletal System Disorders: Myalgia. Platelet, Bleeding, and Clotting Disorders: Epistaxis. Reproductive Disorders, Female: Intermenstrual bleeding. Resistance Mechanism Disorders: Infection, genital moniliasis. Respiratory System Disorders: Pneumonia, asthma. Skin and Appendages Disorders: Rash, alopecia. Vision Disorders: Abnormal accommodation, eye pain. Postmarketing and Other Experience In addition to the adverse experiences reported during clinical testing of TOPAMAX ® , the following adverse experiences have been reported worldwide in patients receiving TOPAMAX ® 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, pemphigus and renal tubular acidosis.