FDA label 31508051-c9ce-149b-e054-00144ff88e88

WARNINGS

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 (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 (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 Adultsa 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 Topiramate Dosage (mg/day) Body System/ Adverse Event50400 (N=160)(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 categoryBody as a Whole-General DisordersAsthenia46Leg Pain23Chest Pain12Central & Peripheral Nervous System DisordersParesthesia2140Dizziness1314Hypoaesthesia45Ataxia34Hypertonia03Gastro-Intestinal System DisordersDiarrhea56Constipation14Gastritis03Dry Mouth13Gastroesophageal Reflux12Liver and Biliary System DisordersGamma-GT Increased13Metabolic and Nutritional DisordersWeight Decrease616Psychiatric DisordersSomnolence915Anorexia414Difficulty with Memory NOS510Insomnia89Depression79Difficulty with Concentration/Attention78Anxiety46Psychomotor Slowing35Mood Problems25Confusion34Cognitive Problem NOS14Libido Decreased03Reproductive Disorders, femaleVaginal Hemorrhage03Red Blood Cell DisordersAnemia12Resistance Mechanism DisordersInfection Viral68Infection23Respiratory System DisordersBronchitis34Rhinitis24Dyspnea12Skin and Appendages DisordersRash14Pruritus14Acne23Special Senses Other, DisordersTaste Perversion35Urinary System DisordersCystitis13Renal Calculus03Urinary Tract Infection12Dysuria02Micturition Frequency02 Table 5: Incidence of Treatment-Emergent Adverse Events in the Monotherapy Epilepsy Trial 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 Topiramate Dosage (mg/day)b Body System/ Adverse Event50400 (N=57)(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 categoryBody as a Whole-General DisordersFever09Central & Peripheral Nervous System DisordersParesthesia216Gastro-Intestinal System DisordersDiarrhea511Metabolic and Nutritional DisordersWeight Decrease721Psychiatric DisordersAnorexia1114Mood Problems211Difficulty with Concentration/Attention49Cognitive Problem NOS07Nervousness45Resistance Mechanism DisordersInfection Viral49Infection27Respiratory System DisordersUpper Respiratory Tract Infection1618Rhinitis27Bronchitis27Sinusitis25Skin and Appendages DisordersAlopecia25 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 TherapyPartial 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 treatmentemergent 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 Adultsa,b Where Rate Was >1% in Any Topiramate Group and Greater Than the Rate in Placebo-Treated Patients Topiramate Dosage (mg/day) Body System/ Adverse EventcPlacebo (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 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.Body as a Whole- General DisordersFatigue131530Asthenia163Back Pain453Chest Pain342Influenza-Like Symptoms234Leg Pain224Hot Flushes121Allergy123Edema121Body Odor010Rigors01<1Central & Peripheral Nervous System DisordersDizziness152532Ataxia71614Speech Disorders/Related Speech Problems21311Paresthesia41119Nystagmus71011Tremor699Language Problems1610Coordination Abnormal244Hypoaesthesia121Gait Abnormal132Muscle Contractions Involuntary122Stupor021Vertigo112Gastro-Intestinal System DisordersNausea81012Dyspepsia676Abdominal Pain467Constipation243Gastroenteritis121Dry Mouth124Gingivitis<111GI Disorder<110Hearing and Vestibular DisordersHearing Decreased121Metabolic and Nutritional DisordersWeight Decrease3913Muscle-Skeletal System DisordersMyalgia122Skeletal Pain010Platelet, Bleeding, & Clotting DisordersEpistaxis121Psychiatric DisordersSomnolence122928Nervousness61619Psychomotor Slowing21321Difficulty with Memory31214Anorexia41012Confusion51114Depression5513Difficulty with Concentration/Attention2614Mood Problems249Agitation233Aggressive Reaction233Emotional Liability133Cognitive Problems133Libido Decreased12<1Apathy113Depersonalization112Reproductive Disorders, femaleBreast Pain240Amenorrhea122Menorrhagia021Menstrual Disorder121Reproductive Disorders, maleProstatic Disorder<120Resistance Mechanism DisordersInfection121Infection Viral12<1Moniliasis<110Respiratory System DisordersPharyngitis263Rhinitis676Sinusitis456Dyspnea112Skin and Appendages DisordersSkin Disorder<121Sweating Increased<11<1Rash Erythematous<11<1Special Senses Other, DisordersTaste Perversion024Urinary System DisordersHematuria12<1Urinary Tract Infection123Micturition Frequency112Urinary Incontinence<121Urine Abnormal01<1Vision DisordersVision Abnormal21310Diplopia51010White Cell and RES DisordersLeukopenia121 Incidence in Study 119Add-On TherapyAdults with Partial Onset Seizures 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 119a,b Where Rate was2% in the Topiramate Group and Greater Than the Rate in Placebo- Treated Patients Body System/Adverse EventcTopiramate Dosage (mg/day) Placebo (N=92)200 (N=171) 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.Body as a Whole-General DisordersFatigue49Chest Pain12Cardiovascular Disorders, GeneralHypertension02Central & Peripheral Nervous System DisordersParesthesia29Dizziness47Tremor23Hypoasthesia02Leg Cramps02Language Problems02Gastro-Intestinal System DisordersAbdominal Pain35Constipation04Diarrhea12Dyspepsia02Dry Mouth02Hearing and Vestibular DisordersTinnitus02Metabolic and Nutritional DisordersWeight Decrease48Psychiatric DisordersSomnolence915Anorexia79Nervousness29Difficulty with Concentration/ Attention05Insomnia34Difficulty with Memory12Aggressive Reaction02Respiratory System DisordersRhinitis04Urinary System DisordersCystitis02Vision DisordersDiplopia02Vision Abnormal02 Table 8: Incidence (%) of Dose-Related Adverse Events From Placebo-Controlled, Add-On Trials in Adults with Partial Onset Seizuresa Topiramate Dosage (mg/day) Adverse EventPlacebo (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.Fatigue13111230Nervousness7131819Difficulty with Concentration/Attention17914Confusion491014Depression69713Anorexia44612Language Problems<12910Anxiety62310Mood Problems2069Weight Decrease34913 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 EventPlacebo (N=101)Topiramate (N=98) 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.Body as a Whole-General DisordersFatigue516Injury1314Allergic Reaction12Back Pain01Pallor01Cardiovascular Disorders, GeneralHypertension01Central & Peripheral Nervous System DisordersGait Abnormal58Ataxia26Hyperkinesia45Dizziness24Speech Disorders/Related Speech Problems24Hyporeflexia02Convulsions Gran Mal01Fecal Incontinence01Paresthesia01Gastro-Intestinal System DisordersNausea56Saliva Increased46Constipation45Gastroenteritis23Dysphagia01Flatulence01Gastroesophageal Reflux01Glossitis01Gum Hyperplasia01Heart Rate and Rhythm DisordersBradycardia01Metabolic and Nutritional DisordersWeight Decrease19Thirst12Hypoglycemia01Weight Increase01Platelet, Bleeding, & Clotting DisordersPurpura48Epistaxis14Hematoma01Prothrombin Increased01Thrombocyotopenia01Psychiatric DisordersSomnolence1626Anorexia1524Nervousness714Personality Disorder (Behavior Problems)911Difficulty with Concentration/Attention210Aggressive Reaction49Insomnia78Difficulty with Memory NOS05Confusion34Psychomotor Slowing23Appetite Increased01Neurosis01Reproductive Disorders, femaleLeukorrhoea02Resistance Mechanism DisordersInfection Viral37Respiratory System DisordersPneumonia15Respiratory Disorder01Skin and Appendages DisordersSkin Disorder23Alopecia12Dermatitis02Hypertrichosis12Rash Erythematous02Eczema01Seborrhoea01Skin Discoloration01Urinary System DisordersUrinary Incontinence24Nocturia01Vision DisordersEye Abnormality12Vision Abnormal12Diplopia01Lacrimation Abnormal01Myopia01White Cell and RES DisordersLeukopenia02 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.