FDA label 31505ab0-ba71-0e3d-e054-00144ff88e88

WARNINGS AND PRECAUTIONS 5. WARNINGS AND PRECAUTIONS 5.1 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 tablets 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 tablets as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of topiramate tablets, may be helpful. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss. 5.2 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 pediatric patients. 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. 5.3 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 1 shows absolute and relative risk by indication for all evaluated AEDs. Table 1 : Risk by Indication for Antiepileptic Drugs in Pooled Analysis IndicationPlacebo PatientsDrug PatientsRelative Risk: Incidence ofRisk Difference:with Events perwith Events perEvents in Drug Patients/Additional Drug1000 Patients1000 PatientsIncidence in Placebo PatientsPatients with Eventsper 1000 PatientsEpilepsy1.03.43.52.4Psychiatric5.78.51.52.9Other1.01.81.90.9Total2.44.31.81.9The 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. 5.4 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 (2-16 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. Although not approved for use in patients under 2 years of age with partial onset seizures, a controlled trial that examined this population revealed that topiramate produced a metabolic acidosis that is notably greater in magnitude than that observed in controlled trials in older children and adults. The mean treatment difference (25 mg/kg/d topiramate-placebo) was -5.9 mEq/L for bicarbonate. The incidence of metabolic acidosis (defined by a serum bicarbonate < 20 mEq/L) was 0% for placebo, 30% for 5 mg/kg/d, 50% for 15 mg/kg/d, and 45% for 25 mg/kg/d [see Pediatric Use ( 8.4 )]. 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 persistent treatment-emergent decreases in serum bicarbonate in placebo-controlled trials for adults for another indication was 44% for 200 mg/day, 39% for 100 mg/day, 23% for 50 mg/day, and 7% 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 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 in long-term, placebo-controlled trials. Long-term, open-label treatment of infants/toddlers, with intractable partial epilepsy, for up to 1 year, showed reductions from baseline in Z SCORES for length, weight, and head circumference compared to age and sex-matched normative data, although these patients with epilepsy are likely to have different growth rates than normal infants. Reductions in Z SCORES for length and weight were correlated to the degree of acidosis [see Pediatric Use ( 8.4 )]. 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. 5.5 Cognitive/Neuropsychiatric Adverse Reactions Adult Patients Cognitive-Related Dysfunction The majority of cognitive-related adverse reactions 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 reactions. Many of these reactions contributed to withdrawal from treatment [see Adverse Reactions ( 6 )]. In the add-on epilepsy controlled trials (using rapid titration such as 100-200 mg/day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions 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 reactions in the titration phase had a dose-related recurrence of these reactions in the maintenance phase. In the monotherapy epilepsy controlled trial, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg/day and 26% for 400 mg/day. In the 6-month controlled trials for another indication using a slower titration regimen (25 mg/day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg/day, 22% for 100 mg/day (the recommended dose), 28% for 200 mg/day, and 10% for placebo. These dose-related adverse reactions typically began in the titration phase and often persisted into the maintenance phase, but infrequently began in the maintenance phase. Some patients experienced a recurrence of one or more of these cognitive adverse reactions and this recurrence was typically in the titration phase. A relatively small proportion of topiramate-treated patients experienced more than one concurrent cognitive adverse reaction. The most common cognitive adverse reactions occurring together included difficulty with memory along with difficulty with concentration/attention, difficulty with memory along with language problems, and difficulty with concentration/attention along with language problems. Rarely, topiramate-treated patients experienced three concurrent cognitive reactions. Psychiatric/Behavioral Disturbances Psychiatric/behavioral disturbances (depression or mood) were dose-related for both the epilepsy and other populations [see Warnings and Precautions ( 5.3 )]. Somnolence/Fatigue Somnolence and fatigue were the adverse reactions 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). For another population, fatigue and somnolence were dose-related and more common in the titration phase. 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 reactions in pediatric patients were generally lower than observed in adults. These reactions included psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems and language problems. The most frequently reported neuropsychiatric reactions in pediatric patients during adjunctive therapy double-blind studies were somnolence and fatigue. The most frequently reported neuropsychiatric reactions 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 reaction associated with discontinuation of therapy was difficulty with concentration/attention; all occurred in the 400 mg/day group. 5.6 Withdrawal of Antiepileptic Drugs (AEDs) In patients with or without a history of seizures or epilepsy, antiepileptic drugs including topiramate should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency [see Clinical Studies ( 14 )]. In situations where rapid withdrawal of topiramate is medically required, appropriate monitoring is recommended. 5.7 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). >5.8 Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid [VPA] Use) Hyperammonemia/Encephalopathy Without Concomitant Valproic Acid (VPA) Hyperammonemia/Encephalopathy Without Concomitant Valproic Acid (VPA) Topiramate treatment has produced hyperammonemia (in some instances dose-related) in clinical investigational programs of adolescents (12-16 years) who were treated with topiramate monotherapy for another indication (incidence above normal, 22% for placebo, 26 % for 50 mg/day, 41% for 100 mg daily) and in very young pediatric patients (1-24 months) who were treated with adjunctive topiramate for partial onset epilepsy (8% for placebo, 10 % for 5 mg/kg/day, 0 % for 15 mg/kg/day, 9 % for 25 mg/kg/day). Topiramate is not approved as monotherapy for another indication in adolescent patients or as adjunctive treatment of partial onset seizures in pediatric patients less than 2 years old. In some patients, ammonia was markedly increased (> 50 % above upper limit of normal). In the adolescent patients, the incidence of markedly increased hyperammonemia was 6 % for placebo, 6 % for 50 mg, and 12 % for 100 mg topiramate daily. The hyperammonemia associated with topiramate treatment occurred with and without encephalopathy in placebo-controlled trials, and in an open-label, extension trial. Dose-related hyperammonemia was also observed in the extension trial in pediatric patients up to 2 years old. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. Hyperammonemia with and without encephalopathy has also been observed in post-marketing reports in patients who were taking topiramate without concomitant valproic acid (VPA). Hyperammonemia/Encephalopathy With Concomitant Valproic Acid (VPA) Concomitant administration of topiramate and valproic acid (VPA) has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone based upon post-marketing reports. Although hyperammonemia may be asymptomatic, clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is not due to a pharmacokinetic interaction. Although topiramate is not indicated for use in infants/toddlers (1-24 months) VPA clearly produced a dose-related increased in the incidence of treatment-emergent hyperammonemia (above the upper limit of normal, 0% for placebo, 12% for 5 mg/kg/day, 7% for 15 mg/kg/day, 17% for 25 mg/kg/day) in an investigational program. Markedly increased, dose-related hyperammonemia (0% for placebo and 5 mg/kg/day, 7% for 15 mg/kg/day, 8 % for 25 mg/kg/day) also occurred in these infants/toddlers. Dose-related hyperammonemia was similarly observed in a long-term, extension trial in these very young, pediatric patients [see Use in Specific Populations ( 8.4 )]. Hyperammonemia with and without encephalopathy has also been observed in post-marketing reports in patients taking topiramate with valproic acid (VPA). The hyperammonemia associated with topiramate treatment appears to be more common when topiramate is used concomitantly with VPA. Monitoring for Hyperammonemia Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, topiramate treatment or an interaction of concomitant topiramate and valproic acid treatment may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status associated with any topiramate treatment, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. 5.9 Kidney Stones A total of 32/2,086 (1.5%) of adults exposed to topiramate during its adjunctive epilepsy therapy development reported the occurrence of kidney stones, an incidence about 2 to 4 times greater than expected in a similar, untreated population. In the double-blind monotherapy epilepsy study, a total of 4/319 (1.3%) of adults exposed to topiramate reported the occurrence of kidney stones. As in the general population, the incidence of stone formation among topiramate treated patients was higher in men. Kidney stones have also been reported in pediatric patients. During long-term (up to 1 year) topiramate treatment in an open-label extension study of 284 pediatric patients 1-24 months old with epilepsy, 7% developed kidney or bladder stones that were diagnosed clinically or by sonogram. Topiramate is not approved for pediatric patients less than 2 years old [see Pediatric Use ( 8.4 )]. An explanation for the association of topiramate and kidney stones may lie in the fact that topiramate is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) can promote stone formation by reducing urinary citrate excretion and by increasing urinary pH [see Warnings and Precautions ( 5.4 )]. The concomitant use of topiramate with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided. Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation. 5.10 Paresthesia Paresthesia (usually tingling of the extremities), an effect associated with the use of other carbonic anhydrase inhibitors, appears to be a common effect of topiramate. Paresthesia was more frequently reported in the monotherapy epilepsy trials and trials for another indication than in the adjunctive therapy epilepsy trials. In the majority of instances, paresthesia did not lead to treatment discontinuation. 5.11 Adjustment of Dose in Renal Failure The major route of elimination of unchanged topiramate and its metabolites is via the kidney. Dosage adjustment may be required in patients with reduced renal function [see Dosage and Administration ( 2 )]. 5.12 Decreased Hepatic Function In hepatically impaired patients, topiramate should be administered with caution as the clearance of topiramate may be decreased. 5.13 Monitoring: Laboratory Tests Topiramate treatment was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies. Topiramate treatment causes non-anion gap, hyperchloremic, metabolic acidosis manifested by a decrease in serum bicarbonate and increase in serum chloride. Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended [see Warnings and Precautions ( 5.4 )]. Controlled trials of adjunctive topiramate treatment of adults for partial onset seizures showed an increased incidence of markedly decreased serum phosphorus (6% topiramate, 2% placebo), markedly increased serum alkaline phosphatase (3% topiramate, 1% placebo), and decreased serum potassium (0.4 % topiramate, 0.1 % placebo). The clinical significance of these abnormalities has not been clearly established. Changes in several clinical laboratory laboratories (increased creatinine, BUN, alkaline phosphatase, total protein, total eosinophil count and decreased potassium) have been observed in a clinical investigational program in very young (<2 years) pediatric patients who were treated with adjunctive topiramate for partial onset seizures [see Pediatric Use ( 8.4 )]. Topiramate treatment produced a dose-related increased shift in serum creatinine from normal at baseline to an increased value at the end of 4 months treatment in adolescent patients (ages 12-16 years) who were treated for another indication in a double-blind, placebo-controlled study. Topiramate treatment with or without concomitant valproic acid (VPA) can cause hyperammonemia with or without encephalopathy [see Warnings and Precautions ( 5.8 )].

ADVERSE REACTIONS 6. ADVERSE REACTIONS The data described in the following section were obtained using topiramate tablets. 6.1 Monotherapy Epilepsy The adverse reactions 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 2 ]. The adverse reactions 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 3 ]. Approximately 21% of the 159 adult patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. Adverse reactions 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 reactions. Adverse reactions 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 reactions 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 reactions incidences in the population studied. Table 2: Incidence of Treatment-Emergent Adverse Reaction in the Monotherapy Epilepsy Trial in Adultsa Where Incidence Was at Least 2% in the 400 mg/day Topiramate Group and Greater Than the Rate in the 50 mg/day Topiramate Group Topiramate Tablets Dosage (mg/day) Body System 50400Adverse Reaction(N = 160)(N = 159) Body as a Whole - General Disorders Asthenia46Leg Pain23Chest Pain12 Central & Peripheral Nervous System Disorders Paresthesia2140Dizziness1314Hypoaesthesia45Ataxia34Hypertonia03 Gastro-Intestinal System Disorders Diarrhea56Constipation14Gastritis03Dry Mouth13Gastroesophageal Reflux12 Liver and Biliary System Disorders Gamma-GT Increased13 Metabolic and Nutritional Disorders Weight Decrease616 Psychiatric Disorders Somnolence915Anorexia414Difficulty with Memory NOS510Insomnia89Depression79Difficulty with Concentration/78AttentionAnxiety46Psychomotor Slowing35Mood Problems25Confusion34Cognitive Problem NOS14Libido Decreased03 Reproductive Disorders, Female Vaginal Hemorrhage03 Red Blood Cell Disorders Anemia12 Resistance Mechanism Disorders Infection Viral68Infection23 Respiratory System Disorders Bronchitis34Rhinitis24Dyspnea12 Skin and Appendages Disorders Rash14Pruritus14Acne23 Special Senses Other, Disorders Taste Perversion35 >Urinary System Disorders Cystitis13Renal Calculus03Urinary Tract Infection12Dysuria02Micturition Frequency02a Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category. Table 3: Incidence of Treatment-Emergent Adverse Reactions in the Monotherapy Epilepsy Trial in Pediatric Patients (Ages 10 up to 16 years)a Where Incidence Was at Least 5% in the 400 mg/day Topiramate Group and Greater Than the Rate in the 50 mg/day Topiramate Group Topiramate Tablets Dosage (mg/day) Body System/ 50400Adverse Reaction(N = 57)(N = 57) Body as a Whole-General Disorders Fever09 Central & Peripheral Nervous System Disorders Paresthesia216 Gastro-Intestinal System Disorders Diarrhea511 Metabolic and Nutritional Disorders Weight Decrease721 Psychiatric Disorders Anorexia1114Mood Problems211Difficulty with Concentration/49AttentionCognitive Problems NOS07Nervousness45 Resistance Mechanism Disorders Infection Viral49Infection27 Respiratory System Disorders Upper Respiratory Tract Infection 1618Rhinitis27Bronchitis27Sinusitis25 Skin and Appendages Disorders Alopecia25a Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category. 6.2 Adjunctive Therapy Epilepsy The most commonly observed adverse reactions 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 4 ]. The most common dose-related adverse reactions 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 6 ]. Adverse reactions 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 7 ]. In controlled clinical trials in adults, 11% of patients receiving topiramate 200 to 400 mg/day as adjunctive therapy discontinued due to adverse reactions. This rate appeared to increase at dosages above 400 mg/day. Adverse 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 reactions. 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 reactions; an individual patient could have reported more than one adverse reaction. These adverse reactions were: psychomotor slowing (4.0%), difficulty with memory (3.2%), fatigue (3.2%), confusion (3.1%), somnolence (3.2%), difficulty with concentration/attention (2.9%), anorexia (2.7%), depression (2.6%), dizziness (2.5%), weight decrease (2.5%), nervousness (2.3%), ataxia (2.1%), and paresthesia (2.0%). Approximately 11% of the 310 pediatric patients who received topiramate at dosages up to 30 mg/kg/day discontinued due to adverse reactions. Adverse reactions associated with discontinuing therapy included aggravated convulsions (2.3%), difficulty with concentration/attention (1.6%), language problems (1.3%), personality disorder (1.3%), and somnolence (1.3%). 6.3 Incidence in Epilepsy Controlled Clinical TrialsAdjunctive TherapyPartial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, and Lennox-Gastaut Syndrome Table 4 lists treatment-emergent adverse reactions 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 reactions during the first eight weeks of these trials no longer experienced them by their last visit. Table 7 lists treatment-emergent adverse reactions 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 reactions in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with data obtained from other clinical investigations involving different treatments, uses, or investigators. Inspection of these frequencies, however, does provide the prescribing physician with a basis to estimate the relative contribution of drug and non-drug factors to the adverse reaction incidences in the population studied. 6.4 Other Adverse Reactions Observed During Double-Blind Epilepsy Adjunctive Therapy Trials Other adverse reactions that occurred in more than 1% of adults treated with 200 to 400 mg of topiramate in placebo-controlled epilepsy trials but with equal or greater frequency in the placebo group were: headache, injury, anxiety, rash, pain, convulsions aggravated, coughing, fever, diarrhea, vomiting, muscle weakness, insomnia, personality disorder, dysmenorrhea, upper respiratory tract infection, and eye pain. Table 4: Incidence of Treatment-Emergent Adverse Reactions in Placebo-Controlled, Add-On Epilepsy Trials in Adultsa,b Where Incidence Was >1% in Any Topiramate Group and Greater Than the Rate in Placebo-Treated Patients Topiramate Tablets Dosage (mg/day) Body System/ Placebo200-400600-1,000Adverse Reaction c(N = 291)(N = 183)(N = 414) Body as a Whole-General Disorders Fatigue131530Asthenia163Back Pain453Chest Pain342Influenza-Like Symptoms 2344Leg Pain224Hot Flushes121Allergy123Edema121Body Odor010Rigors01<1 Central & Peripheral Nervous System Disorders Dizziness152532Ataxia71614Speech Disorders/Related2131111Speech ProblemsParesthesia41119Nystagmus71011Tremor699Language Problems1610Coordination Abnormal244Hypoaesthesia121Gait Abnormal132Muscle Contractions122InvoluntaryStupor021Vertigo112 Gastro-Intestinal System Disorders Nausea81012Dyspepsia676Abdominal Pain467Constipation243Gastroenteritis121Dry Mouth124Gingivitis<111GI Disorder<110 Hearing and Vestibular Disorders Hearing Decreased121 Metabolic and Nutritional Disorders Weight Decrease3913 Muscle-Skeletal System Disorders Myalgia122Skeletal pain010 Platelet, Bleeding, & Clotting Disorders Epistaxis121 Psychiatric Disorders Somnolence122928Nervousness61619Psychomotor Slowing21321Difficulty with Memory31214Anorexia41012Confusion51114Depression5513Difficulty with2614Concentration/AttentionMood Problems249Agitation233Aggressive Reaction233Emotional Lability133Cognitive Problems133Libido Decreased12<1Apathy113Depersonalization112 Reproductive Disorders, Female Breast Pain240Amenorrhea122Menorrhagia021Menstrual Disorder121 Reproductive Disorders, Male Prostatic Disorder<120 Resistance Mechanism Disorders Infection121Infection Viral12<1Moniliasis<110 Respiratory System Disorders Pharyngitis263Rhinitis676Sinusitis456Dyspnea112 Skin and Appendages Disorders Skin Disorder<121Sweating Increased<11<1Rash Erythematous<11<1 Special Sense Other, Disorders Taste Perversion024 Urinary System Disorders Hematuria12<1Urinary Tract Infection123Micturition Frequency112Urinary Incontinence<121Urine Abnormal01<1 Vision Disorders Vision Abnormal21310Diplopia51010 White Cell and RES Disorders Leukopenia121 6.5 Incidence in Study 119Add-On TherapyAdults with Partial Onset Seizures The incidence of adverse reactions (Table 5) did not differ significantly between the 2 topiramate regimens. Because the frequencies of adverse reactions reported in this study were markedly lower than those reported in the previous epilepsy studies, they cannot be directly compared with data obtained in other studies. Table 5: Incidence of Treatment-Emergent Adverse Reactions in Study 119a,b Where Incidence Wasin the Topiramate Group and Greater Than the Rate in Placebo-Treated Patients Topiramate Tablets Dosage(mg/day)Body System/Placebo200Adverse Reaction c(N = 92)(N = 171)Body as a Whole-General Disorders Fatigue49Chest Pain12 Cardiovascular Disorders, General Hypertension02 Central & Peripheral Nervous System Disorders Paresthesia29Dizziness47Tremor23Hypoasthesia02Leg Cramps02Language Problems02 Gastro-Intestinal System Disorders Abdominal Pain35Constipation04Diarrhea12Dyspepsia02Dry Mouth02 Hearing and Vestibular Disorders Tinnitus02 Metabolic and Nutritional Disorders Weight Decrease48Psychiatric DisordersSomnolence915Anorexia79Nervousness29Difficulty with Concentration/05AttentionInsomnia34Difficulty with Memory12Aggressive Reaction02 Respiratory System Disorders Rhinitis04 Urinary System Disorders Cystitis02 Vision Disorders Diplopia02Vision Abnormal02Table 6: Incidence (%) of Dose-Related Adverse Reactions From Placebo-Controlled, Add-On Trials in Adults with Partial Onset Seizuresa Topiramate Tablets Dosage (mg/day)Adverse ReactionPlacebo200400600-1,000(N = 216)(N = 45)(N = 68)(N = 414)Fatigue13111230Nervousness7131819Difficulty with Concentration/17914AttentionConfusion491014Depression69713Anorexia44612Language Problems<12910Anxiety62310Mood problems2069Weight decrease34913a Dose-response studies were not conducted for other adult indications or for pediatric indications. Table 7: Incidence (%) of Treatment-Emergent Adverse Reaction in Placebo-Controlled, Add-On Epilepsy Trials in Pediatric Patients (Ages 2-16 Years)a,b (Reaction that Occurred in at Least 1% of Topiramate-Treated Patients and Occurred More Frequently in Topiramate-Treated Than Placebo-Treated Patients) Body System/ PlaceboTopiramateAdverse Reaction(N = 101)(N = 98) Body as a Whole - General Disorders Fatigue516Injury1314Allergic Reaction12Back Pain01Pallor01 Cardiovascular Disorders, General Hypertension01 Central & Peripheral Nervous System Disorders Gait Abnormal58Ataxia26Hyperkinesia45Dizziness24Speech Disorders/Related24Speech ProblemsHyporeflexia02Convulsions Grand Mal01Fecal Incontinence01Paresthesia01 Gastro-Intestinal System Disorders Nausea56Saliva Increased46Constipation45Gastroenteritis23Dysphagia01Flatulence01Gastroesophageal Reflux01Glossitis01Gum Hyperplasia01Heart Rate and Rhythm01Disorders Bradycardia Metabolic and Nutritional Disorders Weight Decrease19Thirst12Hypoglycemia01Weight Increase01 Platelet, Bleeding, & Clotting Disorders Purpura48Epistaxis14Hematoma01Prothrombin Increased01Thrombocytopenia01 Psychiatric Disorders Somnolence1626Anorexia1524Nervousness714Personality Disorders911(Behavior Problems)Difficulty with Concentration/210AttentionAggressive Reaction49Insomnia78Difficulty with Memory NOS05Confusion34Psychomotor Slowing23Appetite Increased01Neurosis01 Reproductive Disorders, Female Leukorrhoea02 Resistance Mechanism Disorders Infection Viral37 Respiratory System Disorders Pneumonia15Respiratory Disorder01 Skin and Appendages Disorders Skin Disorder23Alopecia12Dermatitis02Hypertrichosis12Rash Erythematous02Eczema01Seborrhoea01Skin Discoloration01 Urinary System Disorders Urinary Incontinence24Nocturia01 Vision Disorders Eye Abnormality12Vision Abnormal12Diplopia01Lacrimation Abnormal01Myopia01 White Cell and RES Disorders Leukopenia02 6.6 Other Adverse Reactions 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 reactions were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse reaction, similar types of reactions were grouped into a smaller number of standardized categories using modified WHOART dictionary terminology. The frequencies presented represent the proportion of patients who experienced a reaction of the type cited on at least one occasion while receiving topiramate. Reported reactions are included except those already listed in the previous tables or text, those too general to be informative, and those not reasonably associated with the use of the drug. Reactions are classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent occurring in at least 1/100 patients; infrequent occurring in 1/100 to 1/1000 patients; rare occurring in fewer than 1/1000 patients. Autonomic Nervous System Disorders: Infrequent: vasodilation. Body as a Whole: Frequent: syncope. Infrequent: abdomen enlarged. Rare: alcohol intolerance. Cardiovascular Disorders, General: Infrequent: hypotension, postural hypotension, angina pectoris. Central & Peripheral Nervous System Disorders: Infrequent: neuropathy, apraxia, 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, hypocalcemia, hyperlipemia, hyperglycemia, xerophthalmia, diabetes mellitus. Rare: hypernatremia, hyponatremia, hypocholesterolemia, creatinine increased. Musculoskeletal System Disorders: Frequent: arthralgia. Infrequent: arthrosis. Neoplasms: Infrequent: thrombocythemia. Rare: polycythemia. Platelet, Bleeding, and Clotting Disorders: Infrequent: gingival bleeding, pulmonary embolism. Psychiatric Disorders: Frequent: impotence, hallucination, psychosis, suicide attempt. Infrequent: euphoria, paranoid reaction, delusion, paranoia, delirium, abnormal dreaming. Rare: libido increased, manic reaction. Red Blood Cell Disorders: Frequent: anemia. Rare: marrow depression, pancytopenia. Reproductive Disorders, Male: Infrequent: ejaculation disorder, breast discharge. Skin and Appendages Disorders: Infrequent: urticaria, photosensitivity reaction, abnormal hair texture. Rare: chloasma. Special Senses Other, Disorders: Infrequent: taste loss, parosmia. Urinary System Disorders: Infrequent: urinary retention, face edema, renal pain, albuminuria, polyuria, oliguria. Vascular (Extracardiac) Disorders: Infrequent: flushing, deep vein thrombosis, phlebitis. Rare: vasospasm. Vision Disorders: Frequent: conjunctivitis. Infrequent: abnormal accommodation, photophobia, strabismus. Rare: mydriasis, iritis. White Cell and Reticuloendothelial System Disorders: Infrequent: lymphadenopathy, eosinophilia, lymphopenia, granulocytopenia. Rare: lymphocytosis. 6.9 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, and pemphigus.