FDA label 7bc5d9dd-ee17-5d36-e053-2a91aa0a5e91

5 WARNINGS AND PRECAUTIONS Acute myopia and secondary angle closure glaucoma: Untreated elevated intraocular pressure can lead to permanent visual loss. Discontinue topiramate extended-release capsules if it occurs ( 5.1 ) Visual field defects: These have been reported independent of elevated intraocular pressure. Consider discontinuation of topiramate extended-release capsules ( 5.2 ) Oligohydrosis and hyperthermia: Monitor decreased sweating and increased body temperature, especially in pediatric patients ( 5.3 ) Metabolic acidosis: Measure baseline and periodic measurement of serum bicarbonate. Consider dose reduction or discontinuation of topiramate extended-release capsules if clinically appropriate ( 5.4 ) Suicidal behavior and ideation: Antiepileptic drugs increase the risk of suicidal behavior or ideation ( 5.5 ) Cognitive/neuropsychiatric: Topiramate extended-release capsules may cause cognitive dysfunction. Use caution when operating machinery including automobiles. Depression and mood problems may occur ( 5.6 ) Fetal toxicity: Topiramate use during pregnancy can cause cleft lip and/or palate and increases the risk of being small for gestational age ( 5.7 ) Withdrawal of AEDs: Withdrawal of topiramate extended-release capsules should be done gradually ( 5.8 ) Hyperammonemia and encephalopathy: Patients with inborn errors of metabolism or reduced mitochondrial activity may have an increased risk of hyperammonemia. Measure ammonia if encephalopathic symptoms occur ( 5.9 ) Kidney stones: Avoid use with other carbonic anhydrase inhibitors, other drugs causing metabolic acidosis, or in patients on a ketogenic diet ( 5.10 ) Hypothermia: Reported with concomitant valproic acid use ( 5.11 ) 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 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 extended-release capsules as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of topiramate extended-release capsules, may be helpful. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss. 5.2 Visual Field Defects Visual field defects have been reported in patients receiving topiramate independent of elevated intraocular pressure. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during treatment with topiramate extended-release capsules, consideration should be given to discontinuing the drug. 5.3 Oligohydrosis and Hyperthermia Oligohydrosis (decreased sweating), resulting in hospitalization in some cases, 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 extended-release capsules should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when topiramate extended-release capsules are 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 [see Drug Interactions (7.4) ] . 5.4 Metabolic Acidosis Hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) is associated with topiramate treatment. This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of topiramate on carbonic anhydrase. Such electrolyte imbalance has been observed with the use of topiramate in placebo-controlled clinical trials and in the post-marketing period. Generally, topiramate-induced metabolic acidosis occurs early in treatment although cases can occur at any time during treatment. Bicarbonate decrements are usually mild-moderate (average decrease of 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose patients to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet or specific drugs) may be additive to the bicarbonate lowering effects of topiramate. Manifestations of Metabolic Acidosis 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 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 Use in Specific Populations (8.4) ] . Topiramate treatment that causes metabolic acidosis during pregnancy can possibly produce adverse effects on the fetus and might also cause metabolic acidosis in the neonate from possible transfer of topiramate to the fetus [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1) ] . Epilepsy Adult Patients In adults, the incidence of persistent decreases in serum bicarbonate (levels of less than 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 per day, and 1% for placebo. Metabolic acidosis has been observed at doses as low as 50 mg per day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in the adjunctive therapy trials was 3% for 400 mg per day and 0% for placebo. The incidence of persistent decreases in serum bicarbonate in adult patients (≥16 years of age) in the epilepsy controlled clinical trial for monotherapy was 14% for 50 mg per day and 25% for 400 mg per day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in this trial for adults was 1% for 50 mg per day and 6% for 400 mg per day. Serum bicarbonate levels have not been systematically evaluated at daily doses greater than 400 mg per day. Pediatric Patients (2 years to 16 years of age) The incidence of persistent decreases in serum bicarbonate in placebo-controlled trials for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures in patients age 2 years to 16 years 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 less than 17 mEq/L and greater than 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 (6 years to 15 years of age), the incidence of persistent decreases in serum bicarbonate in the epilepsy controlled clinical trial for monotherapy performed with topiramate was 9% for 50 mg per day and 25% for 400 mg per day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in this trial was 1% for 50 mg per day and 6% for 400 mg per day. Pediatric Patients (under 2 years of age) Although topiramate extended-release capsules are not approved for use in patients less than 2 years of age, a study of topiramate as adjunctive use in patients under 2 years of age with partial onset seizures 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/day topiramate-placebo) was -5.9 mEq/L for bicarbonate. The incidence of metabolic acidosis (defined by a serum bicarbonate less than 20 mEq/L) was 0% for placebo, 30% for 5 mg/kg/day, 50% for 15 mg/kg/day, and 45% for 25 mg/kg/day. The incidence of markedly abnormal changes (i.e., less than 17 mEq/L and greater than 5 mEq/L decrease from baseline of greater than or equal to 20 mEq/L) was 0% for placebo, 4% for 5 mg/kg/day, 5% for 15 mg/kg/day and 5% for 25 mg/kg/day [see Use in Specific Populations (8.4) ] . Migraine Adult Patients The incidence of persistent decreases in serum bicarbonate in placebo-controlled trials in adults for the prophylaxis of migraine was 44% for 200 mg/day, 39% for 100 mg/day, 23% for 50 mg/day, and 7% for placebo. The incidence of markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 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. Adolescent Patients In pooled, double-blind migraine prophylaxis studies in adolescent patients (12 to 17 years of age), the incidence of persistent decreases in serum bicarbonate was 77% for 200 mg/day, 27% for 100 mg/day, 30% for 50 mg/day, and 9% for placebo. The incidence of markedly low serum bicarbonate (i.e., absolute value <17 mEq/L and >5 mEq/L decrease from pretreatment) was 6% for 100 mg/day, 2% for 50 mg/day, and 2% for placebo. This bicarbonate criterion was not met by any patients in the 200 mg/day group, which had a low number of subjects (n=13). Measurement of Serum Bicarbonate in Epilepsy and Migraine Patients 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.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 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED, including topiramate extended-release capsules, 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 4 shows absolute and relative risk by indication for all evaluated AEDs. Table 4: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events per 1,000 Patients Drug Patients with Events per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/ Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1,000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The 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 extended-release capsules 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. 5.6 Cognitive/Neuropsychiatric Adverse Reactions Adverse reactions most often associated with the use of topiramate, and therefore expected to be associated with the use of topiramate extended-release capsules, were related to the central nervous system and were observed in both the epilepsy and migraine populations. In adults, the most frequent of these can be classified into three general categories: 1) Cognitive-related dysfunction (e.g. confusion, psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or language problems, particularly word-finding difficulties), 2) Psychiatric/behavioral disturbances (e.g. depression or mood problems), and 3) Somnolence or fatigue. 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 . 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 (6.1) ] . In the adjunctive epilepsy controlled trials conducted with topiramate (using rapid titration such as 100 mg per day to 200 mg per day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions was 42% for 200 mg per day, 41% for 400 mg per day, 52% for 600 mg per day, 56% for 800 and 1,000 mg per 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 adjunctive epilepsy controlled trials conducted with topiramate (using rapid titration such as 100 mg per day to 200 mg per day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions was 42% for 200 mg per day, 41% for 400 mg per day, 52% for 600 mg per day, 56% for 800 and 1,000 mg per 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 conducted with topiramate, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg per day and 26% for 400 mg per day.In the monotherapy epilepsy controlled trial conducted with topiramate, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg per day and 26% for 400 mg per day. In the 6-month migraine prophylaxis controlled trials 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 migraine populations treated with topiramate [see Warnings and Precautions (5.5) and Adverse Reactions (6.1) ] . 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 per day and 1,000 mg per day, but the incidence of fatigue was dose-related and increased at dosages above 400 mg per day. For the monotherapy epilepsy population in the 50 mg per day and 400 mg per day groups, the incidence of somnolence was dose-related (9% for the 50 mg per day group and 15% for the 400 mg per day group) and the incidence of fatigue was comparable in both treatment groups (14% each). 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 per day and 1,000 mg per day, but the incidence of fatigue was dose-related and increased at dosages above 400 mg per day. For the monotherapy epilepsy population in the 50 mg per day and 400 mg per day groups, the incidence of somnolence was dose-related (9% for the 50 mg per day group and 15% for the 400 mg per day group) and the incidence of fatigue was comparable in both treatment groups (14% each). For the migraine population, somnolence and fatigue were dose-related and more common in the titration phase. Additional nonspecific CNS events commonly observed with topiramate in the adjunctive epilepsy population include dizziness or ataxia.Additional nonspecific CNS events commonly observed with topiramate in the adjunctive epilepsy population include dizziness or ataxia. Pediatric Patients Epilepsy In double-blind adjunctive therapy and monotherapy epilepsy clinical studies conducted with topiramate, 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 per day and 400 mg per day groups during the monotherapy double-blind study were headache, dizziness, anorexia, and somnolence. No patients discontinued treatment due to any adverse reactions in the adjunctive epilepsy double-blind trials. In the monotherapy epilepsy double-blind trial conducted with immediate-release topiramate product, 1 pediatric patient (2%) in the 50 mg per day group and 7 pediatric patients (12%) in the 400 mg per day group discontinued treatment due to any adverse reactions. The most common adverse reaction associated with discontinuation of therapy was difficulty with concentration/attention; all occurred in the 400 mg per day group. Migraine The incidence of cognitive adverse reactions was increased in topiramate-treated patients (7%) versus placebo (4%) in pooled, double-blind placebo-controlled studies in which adolescent patients (12 to 17 years) were randomized to placebo or one of several fixed daily doses of topiramate (50 mg, 100 mg, 200 mg). The incidence of cognitive adverse reactions was also increased in a placebo-controlled study of pediatric patients (6 to 16 years) treated with 2 to 3 mg/kg/day of topiramate (10%) versus placebo treatment (2%). Topiramate extended-release capsules are not approved for prophylaxis of migraine in pediatric patients under 12 years of age. The risk for cognitive adverse reactions was dose-dependent, and was particularly evident at the 200 mg dose. This risk for cognitive adverse reactions was also greater in younger patients (6 to 11 years) than in older patients (12 to 17 years). The most common cognitive adverse reaction in these trials was difficulty with concentration/attention. Cognitive adverse reactions most commonly developed in the titration period and sometimes persisted into the maintenance period. These adverse reactions typically occurred in isolation as single type of cognitive adverse reaction. Cognitive adverse reactions that led to study discontinuation occurred in one patient (difficulty with concentration/attention and language problems). The Cambridge Neuropsychological Test Automated Battery (CANTAB) was administered to adolescents (12 to 17 years) to assess the effects of topiramate on cognitive function at baseline and at the end of the Study 3 [see Clinical Studies (14.7) ] . Mean change from baseline in certain CANTAB tests suggests that topiramate treatment may result in psychomotor slowing and decreased verbal fluency. 5.7 Fetal Toxicity Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or cleft palate (oral clefts) and for being small for gestational age. In multiple species, oral administration of topiramate to pregnant animals at clinically relevant doses resulted in structural malformations, including craniofacial defects, and reduced body weights in offspring [see Use in Specific Populations (8.1) ] . Consider the benefits and risks of topiramate when administering the drug in women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death . Topiramate should be used during pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus . Consider the benefits and risks of topiramate when administering the drug in women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death [see Use in Specific Populations (8.1) ] . Topiramate should be used during pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus [see Use in Specific Populations (8.1) ] . 5.8 Withdrawal of Antiepileptic Drugs In patients with or without a history of seizures or epilepsy, antiepileptic drugs including topiramate extended-release capsules, 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 extended-release capsules is medically required, appropriate monitoring is recommended. 5.9 Hyperammonemia and Encephalopathy Hyperammonemia/Encephalopathy Without Concomitant Valproic Acid (VPA) Topiramate treatment has produced hyperammonemia (in some instances dose-related) in a clinical investigational program in adolescent patients (12 to 17 years) who were treated with topiramate for migraine prophylaxis. The incidence of hyperammonemia (above the upper limit of normal reference) at any time in the trial was 9% for placebo, 14% for 50 mg, and 26% for 100 mg topiramate daily. In some patients, hyperammonemia was observed at the end of the trial at the final visit. The incidence of markedly increased hyperammonemia (at least 50% or higher above upper limit of normal) at any time in the trial in adolescent patients was also increased at 100 mg/day (9%) compared to 50 mg topiramate (0%) or placebo (3%). During this trial, markedly increased ammonia levels returned to normal in all but one patient (in whom the ammonia level fell to high instead of markedly abnormal). Topiramate treatment has produced hyperammonemia in a clinical investigational program in very young pediatric patients (1 month to 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 extended-release capsules are not approved as adjunctive treatment of partial onset seizures in pediatric patients less than 2 years old. In some patients, ammonia was markedly increased (greater than 50% above upper limit of normal). The hyperammonemia associated with topiramate treatment occurred with and without encephalopathy in placebo-controlled trials, and in an open-label, extension trial of infants with refractory epilepsy. 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 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 extended-release capsules are not indicated for use in infants/toddlers (1 month to 24 months), topiramate with concomitant VPA clearly produced a dose-related increase in the incidence of 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 using topiramate. Markedly increased, dose-related hyperammonemia (0% for placebo and 5 mg/kg/day, 7% for 15 mg/kg/day, and 8% for 25 mg/kg/day) also occurred in these infants/toddlers. Dose-related hyperammonemia was similarly observed in a long-term, extension trial utilizing topiramate 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 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 or topiramate extended-release capsules treatment or an interaction of concomitant topiramate-based product 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. 5.10 Kidney Stones A total of 32/2086 (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 taking topiramate for epilepsy or migraine. During long-term (up to 1 year) topiramate treatment in an open-label extension study of 284 pediatric patients 1 month to 24 months old with epilepsy, 7% developed kidney or bladder stones that were diagnosed clinically or by sonogram. Topiramate extended-release capsules are not approved for pediatric patients less than 2 years old . During long-term (up to 1 year) topiramate treatment in an open-label extension study of 284 pediatric patients 1 month to 24 months old with epilepsy, 7% developed kidney or bladder stones that were diagnosed clinically or by sonogram. Topiramate extended-release capsules are not approved for pediatric patients less than 2 years old [see Use in Specific Populations (8.4) ] . Kidney stones have also been reported in pediatric patients taking topiramate for migraine prophylaxis. For the double-blind migraine prophylaxis studies, one adverse event (renal calculus) occurred in a topiramate-treated subject in the age 12 to 17 years group. The overall experience with open-label, long-term, topiramate treatment for migraine prophylaxis is limited in pediatric patients. Topiramate extended-release capsules would be expected to have the same effect as topiramate on the formation of kidney stones. An explanation for the association of topiramate and kidney stones may lay 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 . The concomitant use of topiramate extended-release capsules 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. Topiramate extended-release capsules would be expected to have the same effect as topiramate on the formation of kidney stones. An explanation for the association of topiramate and kidney stones may lay 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) , Drug Interactions (7.4) and Clinical Pharmacology (12.3) ] . The concomitant use of topiramate extended-release capsules 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.Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation. 5.11 Hypothermia with Concomitant Valproic Acid Use Hypothermia, defined as an unintentional drop in body core temperature to less than 35°C (95°F) has been reported in association with topiramate use with concomitant valproic acid (VPA) both in the presence and in the absence of hyperammonemia. This adverse reaction in patients using concomitant topiramate and valproate can occur after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.2) and Clinical Pharmacology (12.3) ] . Consideration should be given to stopping topiramate or valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels. 5.12 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 in adult and pediatric patients. Paresthesia was more frequently reported in the monotherapy epilepsy trials and migraine prophylaxis trials conducted with immediate-release topiramate than in the adjunctive therapy epilepsy trials conducted with the same product. In the majority of instances, paresthesia did not lead to treatment discontinuation [see Adverse Reactions (6.1) ] . 5.13 Interaction with Other CNS Depressants Topiramate is a CNS depressant. Concomitant administration of topiramate with other CNS depressant drugs or alcohol can result in significant CNS depression. Patients should be watched carefully when topiramate extended-release capsules are co-administered with other CNS depressant drugs [see Drug Interactions (7.3) and Clinical Pharmacology (12.3) ] .

<table ID="table4" width="75%"> <caption>Table 4: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis</caption> <col width="20%" align="left" valign="top"/> <col width="20%" align="center" valign="top"/> <col width="20%" align="center" valign="top"/> <col width="20%" align="center" valign="top"/> <col width="20%" align="center" valign="top"/> <thead> <tr> <th valign="bottom">Indication</th> <th valign="bottom">Placebo Patients with Events per 1,000 Patients</th> <th valign="bottom">Drug Patients with Events per 1,000 Patients</th> <th valign="bottom">Relative Risk: Incidence of Events in Drug Patients/ Incidence in Placebo Patients</th> <th valign="bottom">Risk Difference: Additional Drug Patients with Events per 1,000 Patients</th> </tr> </thead> <tbody> <tr> <td>Epilepsy</td> <td>1.0</td> <td>3.4</td> <td>3.5</td> <td>2.4</td> </tr> <tr> <td>Psychiatric</td> <td>5.7</td> <td>8.5</td> <td>1.5</td> <td>2.9</td> </tr> <tr styleCode="Botrule"> <td>Other</td> <td>1.0</td> <td>1.8</td> <td>1.9</td> <td>0.9</td> </tr> <tr> <td>Total</td> <td>2.4</td> <td>4.3</td> <td>1.8</td> <td>1.9</td> </tr> </tbody> </table>

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more detail in other sections of the labeling: Acute Myopia and Secondary Angle Closure Glaucoma [see Warnings and Precautions (5.1) ] Visual Field Defects [see Warnings and Precautions (5.2) ] Oligohydrosis and Hyperthermia [see Warnings and Precautions (5.3) ] Metabolic Acidosis [see Warnings and Precautions (5.4) ] Suicidal Behavior and Ideation [see Warnings and Precautions (5.5) ] Cognitive/Neuropsychiatric Adverse Reactions [see Warnings and Precautions (5.6) ] Fetal Toxicity [see Warnings and Precautions (5.7) ] Hyperammonemia and Encephalopathy [see Warnings and Precautions (5.9) ] Kidney Stones [see Warnings and Precautions (5.10) ] Hypothermia with Concomitant Valproic Acid Use [see Warnings and Precautions (5.11) ] Paresthesia [see Warnings and Precautions (5.12) ] The most common (≥10% more frequent than placebo or low-dose topiramate in monotherapy) adverse reactions in adult and pediatric controlled, epilepsy clinical trials of immediate release topiramate were paresthesia, anorexia, weight decrease, speech disorders and related speech problems, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, abnormal vision, and fever. The most common (≥5% more frequent than placebo) adverse reactions at recommended dosing in adult and adolescent controlled, migraine clinical trials were paresthesia, anorexia, weight decrease, difficulty with memory, taste perversion, upper respiratory tract infection, abdominal pain, diarrhea, hypoesthesia, and nausea ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Upsher-Smith Laboratories, Inc. at 1-855-899-9180 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience with Immediate-Release Topiramate Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Increased Risk for Bleeding Topiramate treatment is associated with an increased risk for bleeding. In a pooled analysis of placebo-controlled studies of approved and unapproved indications, bleeding was more frequently reported as an adverse event for topiramate than for placebo (4.5% versus 3.0% in adult patients, and 4.4% versus 2.3% in pediatric patients). In this analysis, the incidence of serious bleeding events for topiramate and placebo was 0.3% versus 0.2% for adult patients, and 0.4% versus 0% for pediatric patients. Adverse bleeding reactions reported with topiramate ranged from mild epistaxis, ecchymosis, and increased menstrual bleeding to life-threatening hemorrhages. In patients with serious bleeding events, conditions that increased the risk for bleeding were often present, or patients were often taking drugs that cause thrombocytopenia (other antiepileptic drugs) or affect platelet function or coagulation (e.g., aspirin, nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, or warfarin or other anticoagulants). Adverse Reactions Observed in Monotherapy Epilepsy Trial Adult Patients 16 Years of Age and Older The adverse reactions in the monotherapy controlled trial (Study 1) that occurred most commonly in adults in the 400 mg per day topiramate group and at an incidence ≥ 5% higher than the 50 mg per day group were paresthesia, weight decrease, somnolence, anorexia, and difficulty with memory [see Table 5 ] . Approximately 21% of the 159 adult patients in the 400 mg per day group who received topiramate as monotherapy in Study 1 discontinued therapy due to adverse reactions. The most common (≥ 2% more frequent than for topiramate 50 mg per day) adverse reactions causing discontinuation in this trial were difficulty with memory, fatigue, asthenia, insomnia, somnolence, and paresthesia. Pediatric Patients 6 to less than 16 Years of Age The adverse reactions in Study 1 that occurred most commonly in pediatric patients in the 400 mg per day topiramate group and at an incidence ≥ 5% higher than in the 50 mg per day group were fever, weight decrease, mood problems, cognitive problems, infection, flushing, and paresthesia [see Table 5 ]. Approximately 14% of the 77 pediatric patients in the 400 mg per day group who received topiramate as monotherapy in Study 1 discontinued therapy due to adverse reactions. The most common (≥ 2% more frequent than for topiramate 50 mg per day) adverse reactions resulting in discontinuation in this trial were difficulty with concentration/attention, fever, flushing, and confusion. Table 5: Adverse Reactions in the Immediate-Release Topiramate Monotherapy Trial with Incidence ≥2% in Any Topiramate Group and Incidence in the 400 mg per Day Group Greater Than in the 50 mg per Day Group Age Group Pediatric (6 to <16 Years) Adult (Age ≥16 Years) Immediate-release Topiramate Daily Dosage Group (mg per day) 50 400 50 400 Body System/ (N=74) (N=77) (N=160) (N=159) Adverse Reaction % Percentages calculated with the number of subjects in each group as denominator % % % Body as a Whole-General Disorders Asthenia 0 3 4 6 Chest pain 1 2 Fever 1 12 Leg pain 2 3 Central & Peripheral Nervous System Disorders Ataxia 3 4 Dizziness 13 14 Hypertonia 0 3 Hypoesthesia 4 5 Muscle contractions involuntary 0 3 Paresthesia 3 12 21 40 Vertigo 0 3 Gastro-Intestinal System Disorders Constipation 1 4 Diarrhea 8 9 Gastritis 0 3 Gastroesophageal reflux 1 2 Dry mouth 1 3 Liver and Biliary System Disorders Gamma-GT increased 1 3 Metabolic and Nutritional Disorders Weight Decrease 7 17 6 17 Platelet, Bleeding & Clotting Disorders Epistaxis 0 4 Psychiatric Disorders Anorexia 4 14 Anxiety 4 6 Cognitive problems 1 6 1 4 Confusion 0 3 Depression 0 3 7 9 Difficulty with concentration/attention 7 10 7 8 Difficulty with memory 1 3 6 11 Insomnia 8 9 Libido decreased 0 3 Mood problems 1 8 2 5 Personality disorder (behavior problems) 0 3 Psychomotor slowing 3 5 Somnolence 10 15 Red Blood Cell Disorders Anemia 1 3 Reproductive Disorders, Female N with Female Reproductive Disorders – Incidence calculated relative to the number of females; Pediatric TPM 50 mg n=40; Pediatric TPM 400 mg n=33; Adult TPM 50 mg n=84; TPM 400 mg n=80 Intermenstrual bleeding 0 3 Vaginal hemorrhage 0 3 Resistance Mechanism Disorders Infection 3 8 2 3 Infection viral 3 6 6 8 Respiratory System Disorders Bronchitis 1 5 3 4 Dyspnea 1 2 Rhinitis 5 6 2 4 Sinusitis 1 4 Upper respiratory tract infection 16 18 Skin and Appendages Disorders Acne 2 3 Alopecia 1 4 3 4 Pruritus 1 4 Rash 3 4 1 4 Special Senses Other, Disorders Taste perversion 3 5 Urinary System Disorders Cystitis 1 3 Dysuria 0 2 Micturition frequency 0 3 0 2 Renal calculus 0 3 Urinary incontinence 1 3 Urinary tract infection 1 2 Vascular (Extracardiac) Disorders Flushing 0 5 Adverse Reactions Observed in Adjunctive Therapy Epilepsy Trials The most commonly observed adverse reactions associated with the use of topiramate at dosages of 200 to 400 mg per day (recommended dose range) in controlled trials in adults with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, that were seen at an incidence of higher (≥5%) than in the placebo group were: somnolence, weight decrease, anorexia, dizziness, ataxia, speech disorders and related speech problems, language problems, psychomotor slowing, confusion, abnormal vision, difficulty with memory, paresthesia, diplopia, nervousness, and asthenia [see Table 6 ] . Dose-related adverse reactions at dosages of 200 mg to 1,000 mg per day are shown in Table 8. The most commonly observed adverse reactions associated with the use of topiramate at dosages of 5 mg/kg/day 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 an incidence higher (≥5%) than in the placebo group were: fatigue, somnolence, anorexia, nervousness, difficulty with concentration/attention, difficulty with memory, aggressive reaction, and weight decrease [see Table 9 ]. Table 9 also presents the incidence of adverse reactions occurring in at least 1% of pediatric patients treated with topiramate and occurring with greater incidence than placebo. In controlled clinical trials in adults, 11% of patients receiving topiramate 200 to 400 mg per day as adjunctive therapy discontinued due to adverse reactions. This rate appeared to increase at dosages above 400 mg per 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 per day. None of the pediatric patients who received topiramate adjunctive therapy at 5 mg/kg/day to 9 mg/kg/day in controlled clinical trials discontinued due to adverse reactions. Approximately 28% of the 1757 adults with epilepsy who received topiramate at dosages of 200 mg to 1,600 mg per 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%). Incidence in Epilepsy Controlled Clinical Trials – Adjunctive Therapy – Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, and Lennox-Gastaut Syndrome Table 6 lists the incidence of adverse reactions that occurred in at least 1% of adults treated with 200 to 400 mg per day topiramate (and also higher daily dosing of 600 mg to 1,000 mg) in controlled trials that was numerically greater with topiramate than 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 9 lists the incidence of adverse reactions that occurred in at least 1% of pediatric patients treated with 5 to 9 mg/kg topiramate in controlled trials and that was numerically greater than the incidence in patients treated with placebo. 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 mg 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 Adverse Reactions in Placebo-Controlled, Adjunctive Epilepsy Trials in Adults Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo , Values represent the percentage of patients reporting a given reaction. Patient may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category. , Adverse reactions reported by at least 1% of patients in the topiramate 200 mg to 400 mg per day group and more common than in the placebo group Topiramate Dosage (mg per day) Body System/ Placebo 200 to 400 600 to 1,000 Adverse Reaction (N=291) (N=183) (N=414) Body as a Whole-General Disorders Fatigue 13 15 30 Asthenia 1 6 3 Back pain 4 5 3 Chest pain 3 4 2 Influenza-like symptoms 2 3 4 Leg pain 2 2 4 Hot flushes 1 2 1 Allergy 1 2 3 Edema 1 2 1 Body odor 0 1 0 Rigors 0 1 <1 Central & Peripheral Nervous System Disorders Dizziness 15 25 32 Ataxia 7 16 14 Speech disorders/Related speech problems 2 13 11 Paresthesia 4 11 19 Nystagmus 7 10 11 Tremor 6 9 9 Language problems 1 6 10 Coordination abnormal 2 4 4 Hypoesthesia 1 2 1 Gait abnormal 1 3 2 Muscle contractions involuntary 1 2 2 Stupor 0 2 1 Vertigo 1 1 2 Gastro-Intestinal System Disorders Nausea 8 10 12 Dyspepsia 6 7 6 Abdominal pain 4 6 7 Constipation 2 4 3 Gastroenteritis 1 2 1 Dry mouth 1 2 4 Gingivitis <1 1 1 GI disorder <1 1 0 Hearing and Vestibular Disorders Hearing decreased 1 2 1 Metabolic and Nutritional Disorders Weight decrease 3 9 13 Musculo-Skeletal System Disorders Myalgia 1 2 2 Skeletal pain 0 1 0 Platelet, Bleeding & Clotting Disorders Epistaxis 1 2 1 Psychiatric Disorders Somnolence 12 29 28 Nervousness 6 16 19 Psychomotor slowing 2 13 21 Difficulty with memory 3 12 14 Anorexia 4 10 12 Confusion 5 11 14 Depression 5 5 13 Difficulty with concentration/attention 2 6 14 Mood problems 2 4 9 Agitation 2 3 3 Aggressive reaction 2 3 3 Emotional lability 1 3 3 Cognitive problems 1 3 3 Libido decreased 1 2 <1 Apathy 1 1 3 Depersonalization 1 1 2 Reproductive Disorders, Female Breast pain 2 4 0 Amenorrhea 1 2 2 Menorrhagia 0 2 1 Menstrual disorder 1 2 1 Reproductive Disorders, Male Prostatic disorder <1 2 0 Resistance Mechanism Disorders Infection 1 2 1 Infection viral 1 2 <1 Moniliasis <1 1 0 Respiratory System Disorders Pharyngitis 2 6 3 Rhinitis 6 7 6 Sinusitis 4 5 6 Dyspnea 1 1 2 Skin and Appendages Disorders Skin disorder <1 2 1 Sweating increased <1 1 <1 Rash, erythematous <1 1 <1 Special Senses Other, Disorders Taste perversion 0 2 4 Urinary System Disorders Hematuria 1 2 <1 Urinary tract infection 1 2 3 Micturition frequency 1 1 2 Urinary incontinence <1 2 1 Urine abnormal 0 1 <1 Vision Disorders Vision abnormal 2 13 10 Diplopia 5 10 10 White Cell and RES Disorders Leukopenia 1 2 1 Adverse Reactions Observed in Adjunctive Therapy Trial in Adults with Partial Onset Seizures (Study 7) Study 7 was a randomized, double-blind, adjunctive, placebo-controlled, parallel group study with 3 treatment arms: 1) placebo; 2) topiramate 200 mg per day with a 25 mg per day starting dose, increased by 25 mg per day each week for 8 weeks until the 200 mg per day maintenance dose was reached; and 3) topiramate 200 mg per day with a 50 mg per day starting dose, increased by 50 mg per day each week for 4 weeks until the 200 mg per day maintenance dose was reached. All patients were maintained on concomitant carbamazepine with or without another concomitant antiepileptic drug. The most commonly observed adverse reactions associated with the use of topiramate that were seen at an incidence higher (≥5%) than in the placebo group were: paresthesia, nervousness, somnolence, difficulty with concentration/attention, and fatigue (Table 7). Because these topiramate treatment difference incidence (topiramate % - placebo %) of many 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 7: Incidence of Adverse Reactions in Study 7 Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo , 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 , Adverse reactions reported by at least 2% of patients in the topiramate 200 mg per day group and more common than in the placebo group Topiramate Dosage (mg per day) Body System/ Placebo 200 Adverse Reaction (N=92) (N=171) Body as a Whole-General Disorders Fatigue 4 9 Chest pain 1 2 Cardiovascular Disorders, General Hypertension 0 2 Central & Peripheral Nervous System Disorders Paresthesia 2 9 Dizziness 4 7 Tremor 2 3 Hypoesthesia 0 2 Leg cramps 0 2 Language problems 0 2 Gastro-Intestinal System Disorders Abdominal pain 3 5 Constipation 0 4 Diarrhea 1 2 Dyspepsia 0 2 Dry mouth 0 2 Hearing and Vestibular Disorders Tinnitus 0 2 Metabolic and Nutritional Disorders Weight decrease 4 8 Psychiatric Disorders Somnolence 9 15 Anorexia 7 9 Nervousness 2 9 Difficulty with concentration/attention 0 5 Insomnia 3 4 Difficulty with memory 1 2 Aggressive reaction 0 2 Respiratory System Disorders Rhinitis 0 4 Urinary System Disorders Cystitis 0 2 Vision Disorders Diplopia 0 2 Vision abnormal 0 2 Table 8: Incidence (%) of Dose-Related Adverse Reactions From Placebo-Controlled, Adjunctive Trials in Adults With Partial Onset Seizures (Studies 2 through 7) Dose-response studies were not conducted for other adult indications or for pediatric indications Topiramate Dosage (mg per day) Adverse Reaction Placebo (N=216) 200 (N=45) 400 (N=68) 600 to 1,000 (N=414) Fatigue 13 11 12 30 Nervousness 7 13 18 19 Difficulty with concentration/attention 1 7 9 14 Confusion 4 9 10 14 Depression 6 9 7 13 Anorexia 4 4 6 12 Language Problems <1 2 9 10 Anxiety 6 2 3 10 Mood Problems 2 0 6 9 Weight Decrease 3 4 9 13 Table 9: Incidence (%) of Adverse Reaction in Placebo-Controlled, Adjunctive Epilepsy Trial in Pediatric Patients (Ages 2 Years to 16 Years) Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo , 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 , Reactions that Occurred in at Least 1% of Topiramate-Treated Patients and Occurred More Frequently in Topiramate-Treated Than Placebo-Treated Patients (Study 8) Body System/ Placebo Topiramate Adverse Reaction (N=101) (N=98) Body as a Whole-General Disorders Fatigue 5 16 Injury 13 14 Allergic reaction 1 2 Back pain 0 1 Pallor 0 1 Cardiovascular Disorders, General Hypertension 0 1 Central & Peripheral Nervous System Disorders Gait abnormal 5 8 Ataxia 2 6 Hyperkinesia 4 5 Dizziness 2 4 Speech disorders/Related speech problems 2 4 Hyporeflexia 0 2 Convulsions grand mal 0 1 Fecal incontinence 0 1 Paresthesia 0 1 Gastro-Intestinal System Disorders Nausea 5 6 Saliva increased 4 6 Constipation 4 5 Gastroenteritis 2 3 Dysphasia 0 1 Flatulence 0 1 Gastroesophageal reflux 0 1 Glossitis 0 1 Gum hyperplasia 0 1 Heart Rate and Rhythm Disorders Bradycardia 0 1 Metabolic and Nutritional Disorders Weight decrease 1 9 Thirst 1 2 Hypoglycemia 0 1 Weight increase 0 1 Platelet, Bleeding & Clotting Disorders Purpura 4 8 Epistaxis 1 4 Hematoma 0 1 Prothrombin increased 0 1 Thrombocytopenia 0 1 Psychiatric Disorders Somnolence 16 26 Anorexia 15 24 Nervousness 7 14 Personality disorder (Behavior Problems) 9 11 Difficulty with concentration/attention 2 10 Aggressive reaction 4 9 Insomnia 7 8 Difficulty with memory 0 5 Confusion 3 4 Psychomotor slowing 2 3 Appetite increased 0 1 Neurosis 0 1 Reproductive Disorders, Female Leukorrhea 0 2 Resistance Mechanism Disorders Infection viral 3 7 Respiratory System Disorders Pneumonia 1 5 Respiratory disorder 0 1 Skin and Appendages Disorders Skin Disorder 2 3 Alopecia 1 2 Dermatitis 0 2 Hypertrichosis 1 2 Rash erythematous 0 2 Eczema 0 1 Seborrhea 0 1 Skin discoloration 0 1 Urinary System Disorders Urinary incontinence 2 4 Nocturia 0 1 Vision Disorders Eye abnormality 1 2 Vision abnormal 1 2 Diplopia 0 1 Lacrimation abnormal 0 1 Myopia 0 1 White Cell and RES Disorders Leukopenia 0 2 Migraine Adults In the four multicenter, randomized, double-blind, placebo-controlled, parallel group migraine prophylaxis clinical trials (which included 35 adolescent patients age 12 to 15 years), most of the adverse reactions with topiramate were mild or moderate in severity. Most adverse reactions occurred more frequently during the titration period than during the maintenance period. The most common (≥5% more frequent than placebo) adverse reactions associated with the use of the 100 mg topiramate dose in controlled, migraine clinical trials of predominantly adults were paresthesia, anorexia, weight decrease, taste perversion, diarrhea, difficulty with memory, hypoesthesia, and nausea. Table 10 includes those adverse reactions reported for patients in the placebo-controlled trials where the incidence in any topiramate treatment group was at least 2% and was greater than that for placebo patients. Table 10: Incidence (%) of Adverse Reactions in Placebo-Controlled, Migraine Trials Where Incidence Was ≥2% in Any Topiramate Group and Greater Than the Rate in Placebo-Treated Patients Includes 35 adolescent patients age 12 to 15 years. , 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. Topiramate Dosage (mg per day) Placebo 50 100 200 Body System/ (N=445) (N=235) (N=386) (N=514) Adverse Reaction % % % % Body as a Whole-General Disorders Fatigue 11 14 15 19 Injury 7 9 6 6 Asthenia 1 <1 2 2 Fever 1 1 1 2 Influenza-like symptoms <1 <1 <1 2 Allergy <1 2 <1 <1 Central & Peripheral Nervous System Disorders Paresthesia 6 35 51 49 Dizziness 10 8 9 12 Hypoesthesia 2 6 7 8 Language problems 2 7 6 7 Involuntary muscle contractions 1 2 2 4 Ataxia <1 1 2 1 Speech disorders/Related speech problems <1 1 <1 2 Gastro-Intestinal System Disorders Nausea 8 9 13 14 Diarrhea 4 9 11 11 Abdominal pain 5 6 6 7 Dyspepsia 3 4 5 3 Dry mouth 2 2 3 5 Vomiting 2 1 2 3 Gastroenteritis 1 3 3 2 Hearing and Vestibular Disorders Tinnitus 1 <1 1 2 Metabolic and Nutritional Disorders Weight decrease 1 6 9 11 Thirst <1 2 2 1 Musculoskeletal System Disorders Arthralgia 2 7 3 1 Neoplasms Neoplasm <1 2 <1 <1 Psychiatric Disorders Anorexia 6 9 15 14 Somnolence 5 8 7 10 Difficulty with memory 2 7 7 11 Difficulty with concentration/attention 2 3 6 10 Insomnia 5 6 7 6 Anxiety 3 4 5 6 Mood problems 2 3 6 5 Depression 4 3 4 6 Nervousness 2 4 4 4 Confusion 2 2 3 4 Psychomotor slowing 1 3 2 4 Libido decreased 1 1 1 2 Aggravated depression 1 1 2 2 Agitation 1 2 2 1 Cognitive problems 1 <1 2 2 Reproductive Disorders, Female Menstrual disorder 2 3 2 2 Reproductive Disorders, Male Ejaculation premature 0 3 0 0 Resistance Mechanism Disorders Viral infection 3 4 4 3 Otitis media <1 2 1 1 Respiratory System Disorders Upper respiratory tract infection 12 13 14 12 Sinusitis 6 10 6 8 Pharyngitis 4 5 6 2 Coughing 2 2 4 3 Bronchitis 2 3 3 3 Dyspnea 2 1 3 2 Rhinitis 1 1 2 2 Skin and Appendages Disorders Pruritus 2 4 2 2 Special Senses Other, Disorders Taste perversion 1 15 8 12 Taste loss <1 1 1 2 Urinary System Disorders Urinary tract infection 2 4 2 4 Renal calculus 0 0 1 2 Vision Disorders Vision abnormal <1 1 2 3 Blurred vision Blurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for >50% of reactions coded as vision abnormal, a preferred term. 2 4 2 4 Conjunctivitis 1 1 2 1 Of the 1135 patients exposed to topiramate in the adult placebo-controlled studies, 25% discontinued due to adverse reactions, compared to 10% of the 445 placebo patients. The adverse reactions associated with discontinuing therapy in the topiramate-treated patients included paresthesia (7%), fatigue (4%), nausea (4%), difficulty with concentration/attention (3%), insomnia (3%), anorexia (2%), and dizziness (2%). Patients treated with topiramate experienced mean percent reductions in body weight that were dose-dependent. This change was not seen in the placebo group. Mean changes of 0%, -2%, -3%, and -4% were seen for the placebo group, topiramate 50 mg, 100 mg, and 200 mg groups, respectively. Table 11 shows adverse reactions that were dose-dependent. Several central nervous system adverse reactions, including some that represented cognitive dysfunction, were dose-related. The most common dose-related adverse reactions (treatment difference ≥5% for the 100 mg dose) were paresthesia, nausea, anorexia, difficulty with memory, diarrhea, weight decrease, and hypoesthesia. Table 11: Incidence (%) of Dose-Related Adverse Reactions From Placebo-Controlled, Migraine Trials Includes 35 adolescent patients age 12 to <16 years. , The incidence of adverse reactions in the 200 mg/day group was ≥ 2% than the incidence in both the placebo group and the 50% mg/day group. Topiramate Dosage (mg per day) Placebo 50 100 200 (N=445) (N=235) (N=386) (N=514) Adverse Reaction % % % % Paresthesia 6 35 51 49 Fatigue 11 14 15 19 Nausea 8 9 13 14 Anorexia 6 9 15 14 Dizziness 10 8 9 12 Weight decrease 1 6 9 11 Difficulty with memory 2 7 7 11 Diarrhea 4 9 11 11 Difficulty with concentration/ attention 2 3 6 10 Somnolence 5 8 7 10 Hypoesthesia 2 6 7 8 Anxiety 3 4 5 6 Depression 4 3 4 6 Mood problems 2 3 6 5 Dry mouth 2 2 3 5 Confusion 2 2 3 4 Involuntary muscle contractions 1 2 2 4 Abnormal vision <1 1 2 3 Renal calculus 0 0 1 2 Adolescents 12 to 17 Years of Age In five, randomized, double-blind, placebo-controlled, parallel group migraine prophylaxis clinical trials, most of the adverse reactions with topiramate were mild or moderate in severity. Most adverse reactions occurred more frequently during the titration period than during the maintenance period. Among adverse reactions with onset during titration, approximately half persisted into the maintenance period. In four, fixed-dose, double-blind migraine prophylaxis clinical trials in topiramate-treated adolescent patients, the most commonly observed adverse reactions associated with the use of 100 mg of topiramate that were seen at an incidence higher (≥ 5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain (see Table 12 ). Table 12 shows adverse reactions from the adolescent pivotal trial (Study 3 demonstrating the efficacy of topiramate) in which there were 103 adolescent patients who were treated with placebo or 50 mg or 100 mg of topiramate and three predominantly adult trials in which there were 49 adolescent patients (12 to 17 years) who were treated with placebo or 50 mg, 100 mg or 200 mg of topiramate [see Clinical Studies (14.7) ] . Table 12 also shows adverse reactions in adolescents in the controlled migraine trials when the incidence in a topiramate dose group was at least 5% or higher than the incidence of placebo. Many adverse reactions shown in Table 12 indicated a dose-dependent relationship. Table 12: Incidence (%) of Adverse Reactions in Pooled Placebo-Controlled, Migraine Trials in Adolescent Patients (12 to 17 Years of Age) Where Incidence Was ≥5% or Greater Than the Placebo Incidence in Any Topiramate Group 35 adolescent patients aged 12 to <16 years were also included in adverse reaction assessment for adults (Tables 10 and 11). , Incidence based on the number of subjects experiencing at least 1 adverse event, not the number of events. Topiramate Dosage (mg per day) Placebo 50 100 200 Body System/ (N=45) (N=46) (N=48) (N=13) Adverse Reaction % % % % Body as a Whole-General Disorders Allergy 0 0 4 8 Fatigue 7 7 8 15 Fever 2 4 6 0 Leg Pain 0 2 2 8 Central & Peripheral Nervous System Disorders Dizziness 4 4 6 0 Headache 2 2 4 8 Language problems 2 0 0 15 Muscle contractions involuntary 0 0 0 8 Paresthesia 7 20 19 38 Endocrine Disorders Hyperthyroidism 0 0 0 8 Gastro-Intestinal System Disorders Abdominal pain 9 7 15 15 Diarrhea 0 2 2 8 Nausea 4 4 8 0 Metabolic and Nutritional Disorders Edema pharynx 0 0 0 8 Weight decrease 2 7 4 31 Platelet, Bleeding & Clotting Disorders Epistaxis 0 2 2 8 Psychiatric Disorders Anorexia 4 9 10 15 Anxiety 0 0 0 8 Difficulty with concentration/attention 0 0 2 15 Difficulty with memory 2 0 0 8 Insomnia 2 09 2 0 Mood problems 4 2 2 8 Psychomotor slowing 0 2 0 8 Somnolence 2 2 6 15 Resistance Mechanism Disorders Infection viral 4 4 8 15 Otitis media 0 0 0 8 Respiratory System Disorders Coughing 0 7 2 0 Laryngitis 0 0 0 8 Rhinitis 2 7 6 8 Sinusitis 2 9 4 15 Upper respiratory tract infection 11 26 23 23 Skin and Appendages Disorders Rash erythematous 0 0 0 8 Special Senses Other, Disorders Taste perversion 2 2 6 8 Vision Disorders Conjunctivitis 4 7 4 0 In the double-blind placebo-controlled studies, adverse reactions led to discontinuation of treatment in 8% of placebo patients compared with 6% of topiramate-treated patients. Adverse reactions associated with discontinuing therapy that occurred in more than one topiramate-treated patient were fatigue (1%), headache (1%), and somnolence (1%). Laboratory Abnormalities Topiramate decreases serum bicarbonate [see Warnings and Precautions (5.4) ] . Immediate-release topiramate treatment was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies. Similar effects should be anticipated with use of topiramate extended-release capsules. Topiramate treatment with or without concomitant valproic acid (VPA) can cause hyperammonemia with or without encephalopathy [see Warnings and Precautions (5.9) ] . Epilepsy 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). Changes in several clinical laboratory analytes (i.e., 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 and younger) pediatric patients who were treated with adjunctive topiramate for partial onset seizures [see Use in Specific Populations (8.4) ] . Migraine In pooled double-blind studies in pediatric patients (6 to 17 years), an increased risk for certain abnormalities (value outside normal reference range) in selected clinical laboratory analytes measured in blood has been observed during topiramate treatment of pediatric patients compared to placebo-treated patients. In some instances, abnormalities were also observed at the end of the trial at the final visit and the changes were considered markedly abnormal. For patients 12 to 17 years, the following were noted to be abnormally increased more frequently with topiramate than with placebo: BUN, creatinine, uric acid, chloride, ammonia, total protein, and platelets [see Warnings and Precautions (5.4 , 5.9) ]. The following were abnormally decreased in some subjects: phosphorus and bicarbonate [see Warnings and Precautions (5.4) ] . For patients 6 to 11 years, the following were noted to be abnormally increased more frequently with topiramate than with placebo: alkaline phosphatase, creatinine and eosinophils. Analytes abnormally decreased were: total white count and neutrophils. There was no testing for serum bicarbonate, chloride, ammonia, or phosphorus in these younger patients. 6.2 Clinical Trials Experience with Topiramate Extended-Release Capsules Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In the topiramate extended-release capsules study, a dose of 200 mg per day was administered to a limited number of patients; therefore, these results cannot be directly compared to immediate-release topiramate experience. The safety data presented below are from 249 patients with partial epilepsy on concomitant AEDs who participated in the topiramate extended-release capsules study [see Clinical Studies (14.6) ] . Table 13 displays the incidence of adverse reactions that occurred in ≥2% of patients and numerically greater than placebo. Table 13: Incidence (≥2%) of Adverse Reactions in Placebo-Controlled Adjunctive Therapy Clinical Trial in Patients With Partial Onset Seizures Body System/ Placebo Topiramate Extended-release Capsules (200 mg) Adverse Reaction (N=125) (N=124) General Disorders Fatigue 5 6 Asthenia 1 2 Irritability 1 2 Nervous System Disorders Somnolence 2 12 Dizziness 6 7 Paresthesia 2 7 Aphasia 0 2 Dysarthria 1 2 Memory impairment 1 2 Psychiatric Disorder Psychomotor retardation 0 2 Cardiovascular Disorders, General Hypertension 1 3 Metabolic and Nutritional Disorders Weight decrease 0 7 Decreased appetite 2 4 Anorexia 1 2 In the controlled clinical study using topiramate extended-release capsules, 8.9% of patients who received topiramate extended-release capsules and 4.0% who received placebo discontinued as a result of adverse reactions. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of topiramate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 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.

<table ID="table5" width="75%"> <caption>Table 5: Adverse Reactions in the Immediate-Release Topiramate Monotherapy Trial with Incidence &#x2265;2% in Any Topiramate Group and Incidence in the 400 mg per Day Group Greater Than in the 50 mg per Day Group </caption> <col width="40%" align="left" valign="top"/> <col width="15%" align="center" valign="top"/> <col width="15%" align="center" valign="top"/> <col width="15%" align="center" valign="top"/> <col width="15%" align="center" valign="top"/> <thead> <tr> <th/> <th colspan="4">Age Group</th> </tr> <tr> <th/> <th colspan="2" styleCode="Botrule">Pediatric (6 to &lt;16 Years) </th> <th colspan="2" styleCode="Botrule">Adult (Age &#x2265;16 Years) </th> </tr> <tr> <th/> <th colspan="4">Immediate-release Topiramate Daily Dosage Group (mg per day)</th> </tr> <tr> <th/> <th styleCode="Botrule">50</th> <th styleCode="Botrule">400</th> <th styleCode="Botrule">50</th> <th styleCode="Botrule">400</th> </tr> <tr> <th>Body System/</th> <th>(N=74)</th> <th>(N=77)</th> <th>(N=160)</th> <th>(N=159)</th> </tr> <tr> <th> Adverse Reaction</th> <th>% <footnote ID="t5f1">Percentages calculated with the number of subjects in each group as denominator</footnote> </th> <th>% <footnoteRef IDREF="t5f1"/> </th> <th>% <footnoteRef IDREF="t5f1"/> </th> <th>% <footnoteRef IDREF="t5f1"/> </th> </tr> </thead> <tbody> <tr> <td> <content styleCode="bold">Body as a Whole-General Disorders</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td> Asthenia</td> <td>0</td> <td>3</td> <td>4</td> <td>6</td> </tr> <tr> <td> Chest pain</td> <td/> <td/> <td>1</td> <td>2</td> </tr> <tr> <td> Fever</td> <td>1</td> <td>12</td> <td/> <td/> </tr> <tr> <td> Leg pain</td> <td/> <td/> <td>2</td> <td>3</td> </tr> <tr> <td> <content styleCode="bold">Central &amp; Peripheral Nervous System Disorders</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td> Ataxia</td> <td/> <td/> <td>3</td> <td>4</td> </tr> <tr> <td> Dizziness</td> <td/> <td/> <td>13</td> <td>14</td> </tr> <tr> <td> Hypertonia</td> <td/> <td/> <td>0</td> <td>3</td> </tr> <tr> <td> Hypoesthesia</td> <td/> <td/> <td>4</td> <td>5</td> </tr> <tr> <td> Muscle contractions involuntary</td> <td>0</td> <td>3</td> <td/> <td/> </tr> <tr> <td> Paresthesia</td> <td>3</td> <td>12</td> <td>21</td> <td>40</td> </tr> <tr> <td> Vertigo</td> <td>0</td> <td>3</td> <td/> <td/> </tr> <tr> <td> <content styleCode="bold">Gastro-Intestinal System Disorders</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td> Constipation</td> <td/> <td/> <td>1</td> <td>4</td> </tr> <tr> <td> Diarrhea</td> <td>8</td> <td>9</td> <td/> <td/> </tr> <tr> <td> Gastritis</td> <td/> <td/> <td>0</td> <td>3</td> </tr> <tr> <td> Gastroesophageal reflux </td> <td/> <td/> <td>1</td> <td>2</td> </tr> <tr> <td> Dry mouth</td> <td/> <td/> <td>1</td> <td>3</td> </tr> <tr> <td> <content styleCode="bold">Liver and Biliary System Disorders</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td> Gamma-GT increased</td> <td/> <td/> <td>1</td> <td>3</td> </tr> <tr> <td> <content styleCode="bold">Metabolic and Nutritional Disorders</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td> Weight Decrease</td> <td>7</td> <td>17</td> <td>6</td> <td>17</td> </tr> <tr> <td> <content styleCode="bold">Platelet, Bleeding &amp; Clotting Disorders</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td> Epistaxis</td> <td>0</td> <td>4</td> <td/> <td/> </tr> <tr> <td> <content styleCode="bold">Psychiatric Disorders</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td> Anorexia</td> <td/> <td/> <td>4</td> <td>14</td> </tr> <tr> <td> Anxiety</td> <td/> <td/> <td>4</td> <td>6</td> </tr> <tr> <td> Cognitive problems</td> <td>1</td> <td>6</td> <td>1</td> <td>4</td> </tr> <tr> <td> Confusion</td> <td>0</td> <td>3</td> <td/> <td/> </tr> <tr> <td> Depression</td> <td>0</td> <td>3</td> <td>7</td> <td>9</td> </tr> <tr> <td> Difficulty with concentration/attention</td> <td>7</td> <td>10</td> <td>7</td> <td>8</td> </tr> <tr> <td> Difficulty with memory</td> <td>1</td> <td>3</td> <td>6</td> <td>11</td> </tr> <tr> <td> Insomnia</td> <td/> <td/> <td>8</td> <td>9</td> </tr> <tr> <td> Libido decreased</td> <td/> <td/> <td>0</td> <td>3</td> </tr> <tr> <td> Mood problems</td> <td>1</td> <td>8</td> <td>2</td> <td>5</td> </tr> <tr> <td> Personality disorder (behavior problems)</td> <td>0</td> <td>3</td> <td/> <td/> </tr> <tr> <td> Psychomotor slowing</td> <td/> <td/> <td>3</td> <td>5</td> </tr> <tr> <td> Somnolence</td> <td/> <td/> <td>10</td> <td>15</td> </tr> <tr> <td> <content styleCode="bold">Red Blood Cell Disorders</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td> Anemia</td> <td>1</td> <td>3</td> <td/> <td/> </tr> <tr> <td> <content styleCode="bold">Reproductive Disorders, Female <footnote ID="t5f2">N with Female Reproductive Disorders &#x2013; Incidence calculated relative to the number of females; Pediatric TPM 50 mg n=40; Pediatric TPM 400 mg n=33; Adult TPM 50 mg n=84; TPM 400 mg n=80</footnote> </content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td> Intermenstrual bleeding</td> <td>0</td> <td>3</td> <td/> <td/> </tr> <tr> <td> Vaginal hemorrhage</td> <td/> <td/> <td>0</td> <td>3</td> </tr> <tr> <td> <content styleCode="bold">Resistance Mechanism Disorders</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td> Infection</td> <td>3</td> <td>8</td> <td>2</td> <td>3</td> </tr> <tr> <td> Infection viral</td> <td>3</td> <td>6</td> <td>6</td> <td>8</td> </tr> <tr> <td> <content styleCode="bold">Respiratory System Disorders</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td> Bronchitis</td> <td>1</td> <td>5</td> <td>3</td> <td>4</td> </tr> <tr> <td> Dyspnea</td> <td/> <td/> <td>1</td> <td>2</td> </tr> <tr> <td> Rhinitis</td> <td>5</td> <td>6</td> <td>2</td> <td>4</td> </tr> <tr> <td> Sinusitis</td> <td>1</td> <td>4</td> <td/> <td/> </tr> <tr> <td> Upper respiratory tract infection</td> <td>16</td> <td>18</td> <td/> <td/> </tr> <tr> <td> <content styleCode="bold">Skin and Appendages Disorders</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td> Acne</td> <td/> <td/> <td>2</td> <td>3</td> </tr> <tr> <td> Alopecia</td> <td>1</td> <td>4</td> <td>3</td> <td>4</td> </tr> <tr> <td> Pruritus</td> <td/> <td/> <td>1</td> <td>4</td> </tr> <tr> <td> Rash</td> <td>3</td> <td>4</td> <td>1</td> <td>4</td> </tr> <tr> <td> <content styleCode="bold">Special Senses Other, Disorders</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td> Taste perversion</td> <td/> <td/> <td>3</td> <td>5</td> </tr> <tr> <td> <content styleCode="bold">Urinary System Disorders</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td> Cystitis</td> <td/> <td/> <td>1</td> <td>3</td> </tr> <tr> <td> Dysuria</td> <td/> <td/> <td>0</td> <td>2</td> </tr> <tr> <td> Micturition frequency</td> <td>0</td> <td>3</td> <td>0</td> <td>2</td> </tr> <tr> <td> Renal calculus</td> <td/> <td/> <td>0</td> <td>3</td> </tr> <tr> <td> Urinary incontinence</td> <td>1</td> <td>3</td> <td/> <td/> </tr> <tr> <td> Urinary tract infection</td> <td/> <td/> <td>1</td> <td>2</td> </tr> <tr> <td> <content styleCode="bold">Vascular (Extracardiac) Disorders</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td> Flushing</td> <td>0</td> <td>5</td> <td/> <td/> </tr> </tbody> </table>

<table ID="table6" width="75%"> <caption>Table 6: Incidence of Adverse Reactions in Placebo-Controlled, Adjunctive Epilepsy Trials in Adults <footnote ID="t6f1">Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo</footnote> ^, <footnote ID="t6f2">Values represent the percentage of patients reporting a given reaction. Patient may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category.</footnote> ^, <footnote ID="t6f3">Adverse reactions reported by at least 1% of patients in the topiramate 200 mg to 400 mg per day group and more common than in the placebo group </footnote> </caption> <col width="40%" align="left" valign="top"/> <col width="20%" align="center" valign="top"/> <col width="20%" align="center" valign="top"/> <col width="20%" align="center" valign="top"/> <thead> <tr> <th/> <th/> <th colspan="2" styleCode="Botrule">Topiramate Dosage (mg per day) </th> </tr> <tr> <th>Body System/</th> <th>Placebo</th> <th>200 to 400 </th> <th>600 to 1,000 </th> </tr> <tr> <th> Adverse Reaction <footnoteRef IDREF="t6f3"/> </th> <th>(N=291)</th> <th>(N=183)</th> <th>(N=414)</th> </tr> </thead> <tbody> <tr> <td> <content styleCode="bold">Body as a Whole-General Disorders</content> </td> <td/> <td/> <td/> </tr> <tr> <td> Fatigue</td> <td>13</td> <td>15</td> <td>30</td> </tr> <tr> <td> Asthenia</td> <td>1</td> <td>6</td> <td>3</td> </tr> <tr> <td> Back pain</td> <td>4</td> <td>5</td> <td>3</td> </tr> <tr> <td> Chest pain</td> <td>3</td> <td>4</td> <td>2</td> </tr> <tr> <td> Influenza-like symptoms</td> <td>2</td> <td>3</td> <td>4</td> </tr> <tr> <td> Leg pain</td> <td>2</td> <td>2</td> <td>4</td> </tr> <tr> <td> Hot flushes</td> <td>1</td> <td>2</td> <td>1</td> </tr> <tr> <td> Allergy</td> <td>1</td> <td>2</td> <td>3</td> </tr> <tr> <td> Edema</td> <td>1</td> <td>2</td> <td>1</td> </tr> <tr> <td> Body odor</td> <td>0</td> <td>1</td> <td>0</td> </tr> <tr> <td> Rigors</td> <td>0</td> <td>1</td> <td>&lt;1</td> </tr> <tr> <td> <content styleCode="bold">Central &amp; Peripheral Nervous System Disorders</content> </td> <td/> <td/> <td/> </tr> <tr> <td> Dizziness</td> <td>15</td> <td>25</td> <td>32</td> </tr> <tr> <td> Ataxia</td> <td>7</td> <td>16</td> <td>14</td> </tr> <tr> <td> Speech disorders/Related speech problems</td> <td>2</td> <td>13</td> <td>11</td> </tr> <tr> <td> Paresthesia</td> <td>4</td> <td>11</td> <td>19</td> </tr> <tr> <td> Nystagmus</td> <td>7</td> <td>10</td> <td>11</td> </tr> <tr> <td> Tremor</td> <td>6</td> <td>9</td> <td>9</td> </tr> <tr> <td> Language problems</td> <td>1</td> <td>6</td> <td>10</td> </tr> <tr> <td> Coordination abnormal</td> <td>2</td> <td>4</td> <td>4</td> </tr> <tr> <td> Hypoesthesia</td> <td>1</td> <td>2</td> <td>1</td> </tr> <tr> <td> Gait abnormal</td> <td>1</td> <td>3</td> <td>2</td> </tr> <tr> <td> Muscle contractions involuntary</td> <td>1</td> <td>2</td> <td>2</td> </tr> <tr> <td> Stupor</td> <td>0</td> <td>2</td> <td>1</td> </tr> <tr> <td> Vertigo</td> <td>1</td> <td>1</td> <td>2</td> </tr> <tr> <td> <content styleCode="bold">Gastro-Intestinal System Disorders</content> </td> <td/> <td/> <td/> </tr> <tr> <td> Nausea</td> <td>8</td> <td>10</td> <td>12</td> </tr> <tr> <td> Dyspepsia</td> <td>6</td> <td>7</td> <td>6</td> </tr> <tr> <td> Abdominal pain</td> <td>4</td> <td>6</td> <td>7</td> </tr> <tr> <td> Constipation</td> <td>2</td> <td>4</td> <td>3</td> </tr> <tr> <td> Gastroenteritis</td> <td>1</td> <td>2</td> <td>1</td> </tr> <tr> <td> Dry mouth</td> <td>1</td> <td>2</td> <td>4</td> </tr> <tr> <td> Gingivitis</td> <td>&lt;1</td> <td>1</td> <td>1</td> </tr> <tr> <td> GI disorder</td> <td>&lt;1</td> <td>1</td> <td>0</td> </tr> <tr> <td> <content styleCode="bold">Hearing and Vestibular Disorders</content> </td> <td/> <td/> <td/> </tr> <tr> <td> Hearing decreased</td> <td>1</td> <td>2</td> <td>1</td> </tr> <tr> <td> <content styleCode="bold">Metabolic and Nutritional Disorders</content> </td> <td/> <td/> <td/> </tr> <tr> <td> Weight decrease</td> <td>3</td> <td>9</td> <td>13</td> </tr> <tr> <td> <content styleCode="bold">Musculo-Skeletal System Disorders</content> </td> <td/> <td/> <td/> </tr> <tr> <td> Myalgia</td> <td>1</td> <td>2</td> <td>2</td> </tr> <tr> <td> Skeletal pain</td> <td>0</td> <td>1</td> <td>0</td> </tr> <tr> <td> <content styleCode="bold">Platelet, Bleeding &amp; Clotting Disorders</content> </td> <td/> <td/> <td/> </tr> <tr> <td> Epistaxis</td> <td>1</td> <td>2</td> <td>1</td> </tr> <tr> <td> <content styleCode="bold">Psychiatric Disorders</content> </td> <td/> <td/> <td/> </tr> <tr> <td> Somnolence</td> <td>12</td> <td>29</td> <td>28</td> </tr> <tr> <td> Nervousness</td> <td>6</td> <td>16</td> <td>19</td> </tr> <tr> <td> Psychomotor slowing</td> <td>2</td> <td>13</td> <td>21</td> </tr> <tr> <td> Difficulty with memory</td> <td>3</td> <td>12</td> <td>14</td> </tr> <tr> <td> Anorexia</td> <td>4</td> <td>10</td> <td>12</td> </tr> <tr> <td> Confusion</td> <td>5</td> <td>11</td> <td>14</td> </tr> <tr> <td> Depression</td> <td>5</td> <td>5</td> <td>13</td> </tr> <tr> <td> Difficulty with concentration/attention</td> <td>2</td> <td>6</td> <td>14</td> </tr> <tr> <td> Mood problems</td> <td>2</td> <td>4</td> <td>9</td> </tr> <tr> <td> Agitation</td> <td>2</td> <td>3</td> <td>3</td> </tr> <tr> <td> Aggressive reaction</td> <td>2</td> <td>3</td> <td>3</td> </tr> <tr> <td> Emotional lability</td> <td>1</td> <td>3</td> <td>3</td> </tr> <tr> <td> Cognitive problems</td> <td>1</td> <td>3</td> <td>3</td> </tr> <tr> <td> Libido decreased</td> <td>1</td> <td>2</td> <td>&lt;1</td> </tr> <tr> <td> Apathy</td> <td>1</td> <td>1</td> <td>3</td> </tr> <tr> <td> Depersonalization</td> <td>1</td> <td>1</td> <td>2</td> </tr> <tr> <td> <content styleCode="bold">Reproductive Disorders, Female</content> </td> <td/> <td/> <td/> </tr> <tr> <td> Breast pain</td> <td>2</td> <td>4</td> <td>0</td> </tr> <tr> <td> Amenorrhea</td> <td>1</td> <td>2</td> <td>2</td> </tr> <tr> <td> Menorrhagia</td> <td>0</td> <td>2</td> <td>1</td> </tr> <tr> <td> Menstrual disorder</td> <td>1</td> <td>2</td> <td>1</td> </tr> <tr> <td> <content styleCode="bold">Reproductive Disorders, Male</content> </td> <td/> <td/> <td/> </tr> <tr> <td> Prostatic disorder</td> <td>&lt;1</td> <td>2</td> <td>0</td> </tr> <tr> <td> <content styleCode="bold">Resistance Mechanism Disorders</content> </td> <td/> <td/> <td/> </tr> <tr> <td> Infection</td> <td>1</td> <td>2</td> <td>1</td> </tr> <tr> <td> Infection viral</td> <td>1</td> <td>2</td> <td>&lt;1</td> </tr> <tr> <td> Moniliasis</td> <td>&lt;1</td> <td>1</td> <td>0</td> </tr> <tr> <td> <content styleCode="bold">Respiratory System Disorders</content> </td> <td/> <td/> <td/> </tr> <tr> <td> Pharyngitis</td> <td>2</td> <td>6</td> <td>3</td> </tr> <tr> <td> Rhinitis</td> <td>6</td> <td>7</td> <td>6</td> </tr> <tr> <td> Sinusitis</td> <td>4</td> <td>5</td> <td>6</td> </tr> <tr> <td> Dyspnea</td> <td>1</td> <td>1</td> <td>2</td> </tr> <tr> <td> <content styleCode="bold">Skin and Appendages Disorders</content> </td> <td/> <td/> <td/> </tr> <tr> <td> Skin disorder</td> <td>&lt;1</td> <td>2</td> <td>1</td> </tr> <tr> <td> Sweating increased</td> <td>&lt;1</td> <td>1</td> <td>&lt;1</td> </tr> <tr> <td> Rash, erythematous</td> <td>&lt;1</td> <td>1</td> <td>&lt;1</td> </tr> <tr> <td> <content styleCode="bold">Special Senses Other, Disorders</content> </td> <td/> <td/> <td/> </tr> <tr> <td> Taste perversion</td> <td>0</td> <td>2</td> <td>4</td> </tr> <tr> <td> <content styleCode="bold">Urinary System Disorders</content> </td> <td/> <td/> <td/> </tr> <tr> <td> Hematuria</td> <td>1</td> <td>2</td> <td>&lt;1</td> </tr> <tr> <td> Urinary tract infection</td> <td>1</td> <td>2</td> <td>3</td> </tr> <tr> <td> Micturition frequency</td> <td>1</td> <td>1</td> <td>2</td> </tr> <tr> <td> Urinary incontinence</td> <td>&lt;1</td> <td>2</td> <td>1</td> </tr> <tr> <td> Urine abnormal</td> <td>0</td> <td>1</td> <td>&lt;1</td> </tr> <tr> <td> <content styleCode="bold">Vision Disorders</content> </td> <td/> <td/> <td/> </tr> <tr> <td> Vision abnormal</td> <td>2</td> <td>13</td> <td>10</td> </tr> <tr> <td> Diplopia</td> <td>5</td> <td>10</td> <td>10</td> </tr> <tr> <td> <content styleCode="bold">White Cell and RES Disorders</content> </td> <td/> <td/> <td/> </tr> <tr> <td> Leukopenia</td> <td>1</td> <td>2</td> <td>1</td> </tr> </tbody> </table>

<table ID="table7" width="60%"> <caption>Table 7: Incidence of Adverse Reactions in Study 7 <footnote ID="t7f1">Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo</footnote> ^, <footnote ID="t7f2">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</footnote> ^, <footnote ID="t7f3">Adverse reactions reported by at least 2% of patients in the topiramate 200 mg per day group and more common than in the placebo group </footnote> </caption> <col width="50%" align="left" valign="top"/> <col width="25%" align="center" valign="top"/> <col width="25%" align="center" valign="top"/> <thead> <tr> <th/> <th/> <th>Topiramate Dosage (mg per day) </th> </tr> <tr> <th>Body System/</th> <th>Placebo</th> <th>200</th> </tr> <tr> <th> Adverse Reaction <footnoteRef IDREF="t7f3"/> </th> <th>(N=92)</th> <th>(N=171)</th> </tr> </thead> <tbody> <tr> <td> <content styleCode="bold">Body as a Whole-General Disorders</content> </td> <td/> <td/> </tr> <tr> <td> Fatigue</td> <td>4</td> <td>9</td> </tr> <tr> <td> Chest pain</td> <td>1</td> <td>2</td> </tr> <tr> <td> <content styleCode="bold">Cardiovascular Disorders, General</content> </td> <td/> <td/> </tr> <tr> <td> Hypertension</td> <td>0</td> <td>2</td> </tr> <tr> <td> <content styleCode="bold">Central &amp; Peripheral Nervous System Disorders </content> </td> <td/> <td/> </tr> <tr> <td> Paresthesia</td> <td>2</td> <td>9</td> </tr> <tr> <td> Dizziness</td> <td>4</td> <td>7</td> </tr> <tr> <td> Tremor</td> <td>2</td> <td>3</td> </tr> <tr> <td> Hypoesthesia</td> <td>0</td> <td>2</td> </tr> <tr> <td> Leg cramps</td> <td>0</td> <td>2</td> </tr> <tr> <td> Language problems</td> <td>0</td> <td>2</td> </tr> <tr> <td> <content styleCode="bold">Gastro-Intestinal System Disorders</content> </td> <td/> <td/> </tr> <tr> <td> Abdominal pain</td> <td>3</td> <td>5</td> </tr> <tr> <td> Constipation</td> <td>0</td> <td>4</td> </tr> <tr> <td> Diarrhea</td> <td>1</td> <td>2</td> </tr> <tr> <td> Dyspepsia</td> <td>0</td> <td>2</td> </tr> <tr> <td> Dry mouth</td> <td>0</td> <td>2</td> </tr> <tr> <td> <content styleCode="bold">Hearing and Vestibular Disorders</content> </td> <td/> <td/> </tr> <tr> <td> Tinnitus</td> <td>0</td> <td>2</td> </tr> <tr> <td> <content styleCode="bold">Metabolic and Nutritional Disorders</content> </td> <td/> <td/> </tr> <tr> <td> Weight decrease</td> <td>4</td> <td>8</td> </tr> <tr> <td> <content styleCode="bold">Psychiatric Disorders</content> </td> <td/> <td/> </tr> <tr> <td> Somnolence</td> <td>9</td> <td>15</td> </tr> <tr> <td> Anorexia</td> <td>7</td> <td>9</td> </tr> <tr> <td> Nervousness</td> <td>2</td> <td>9</td> </tr> <tr> <td> Difficulty with concentration/attention</td> <td>0</td> <td>5</td> </tr> <tr> <td> Insomnia</td> <td>3</td> <td>4</td> </tr> <tr> <td> Difficulty with memory</td> <td>1</td> <td>2</td> </tr> <tr> <td> Aggressive reaction</td> <td>0</td> <td>2</td> </tr> <tr> <td> <content styleCode="bold">Respiratory System Disorders</content> </td> <td/> <td/> </tr> <tr> <td> Rhinitis</td> <td>0</td> <td>4</td> </tr> <tr> <td> <content styleCode="bold">Urinary System Disorders</content> </td> <td/> <td/> </tr> <tr> <td> Cystitis</td> <td>0</td> <td>2</td> </tr> <tr> <td> <content styleCode="bold">Vision Disorders</content> </td> <td/> <td/> </tr> <tr> <td> Diplopia</td> <td>0</td> <td>2</td> </tr> <tr> <td> Vision abnormal</td> <td>0</td> <td>2</td> </tr> </tbody> </table>