FDA label 40183d1e-5279-3c85-e054-00144ff88e88

WARNINGS 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. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including topiramate, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 3 shows absolute and relative risk by indication for all evaluated AEDs. Table 3 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis IndicationPlacebo Patients with Events Per 1000 PatientsDrug Patients with Events Per 1000 PatientsRelative Risk: Incidence of Events in Drug Patients/Incidence in Placebo PatientsRisk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy1.03.43.52.4Psychiatric5.78.51.52.9Other1.01.81.90.9Total2.44.31.81.9The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing topiramate or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior or the emergence of suicidal thoughts, behavior or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Metabolic Acidosis 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. 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. Cognitive/Neuropsychiatric Adverse Events Adults 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 5 and Table 7 ]. In the original add-on epilepsy controlled trials (using rapid titration such as 100 to 200 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 population. 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. Withdrawal of AEDs Antiepileptic drugs, including topiramate, should be withdrawn gradually to minimize the potential of increased seizure frequency. 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 5 ]. 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 6 ]. 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 5: 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 Event50 (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 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 6: 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)Body System/ Adverse Event50 (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 DisordersFever09Central & Peripheral Nervous System DisordersParesthesia216Gastro-Intestinal System DisordersDiarrhea511Metabolic and Nutritional DisordersWeight Decrease721Psychiatric DisordersAnorexia1114Mood Problems211Difficulty with Concentration/Attention49Cognitive Problems 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 7 ]. 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 9 ]. 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 10 ]. 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%), 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%). 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 7 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 10 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 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 7: 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 to 400 (N=183)600 to 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 to 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 Lability133Cognitive 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 Sense 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 8 ) 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 8: 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 Topiramate Dosage (mg/day)Body System/ Adverse EventcPlacebo (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 9: 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 to 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 10: Incidence (%) of Treatment-Emergent Adverse Events in Placebo-Controlled, Add-On Epilepsy Trials in Pediatric Patients Ages 2 to 16 Yearsa,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 Grand Mal01Fecal Incontinence01Paresthesia01Gastro-Intestinal System DisordersNausea56Saliva Increased46Constipation45Gastroenteritis23Dysphagia01Flatulence01Gastroesophageal Reflux01Glossitis01Gum Hyperplasia01Heart Rate and Rhythm DisordersBradycardia01Metabolic and Nutritional DisordersWeight Decrease19Thirst12Hypoglycemia01Weight Increase01Platelet, Bleeding, & Clotting DisordersPurpura48Epistaxis14Hematoma01Prothrombin Increased01Thrombocytopenia01Psychiatric 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: 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: 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, maculopathy, pancreatitis, pemphigus, and renal tubular acidosis.