Adults and Pediatric Patients 10 Years of Age and Older with Partial Onset or Primary Generalized Tonic-Clonic Seizures

The recommended dose for TROKENDI XR monotherapy in adults and in pediatric patients 10 years of age and older is 400 mg orally once daily. Titrate TROKENDI XR ®according to the following schedule:

Pediatric Patients Ages 6 to 9 Years of Age

Dosing in patients 6 to 9 years of age is based on weight. During the titration period, the initial dose of TROKENDI XR ®is 25 mg/day nightly for the first week. Based upon tolerability, the dosage can be increased to 50 mg/day in the second week. Dosage can be increased by 25 mg to 50 mg/day each subsequent week as tolerated. Titration to the minimum maintenance dose should be attempted over 5-7 weeks of the total titration period. Based upon tolerability and clinical response, additional titration to a higher dose (up to the maximum maintenance dose) can be attempted at 25 mg to 50 mg/day weekly increments. The total daily dose should not exceed the maximum maintenance dose for each range of body weight (see Table 1).

Adults (17 Years of Age and Older)

The recommended total daily dose of TROKENDI XR ®as adjunctive therapy in adults with partial-onset seizures or Lennox-Gastaut Syndrome is 200 mg to 400 mg orally once daily and with primary generalized tonic-clonic seizures is 400 mg orally once daily. Initiate therapy at 25 mg to 50 mg once daily followed by titration to an effective dose in increments of 25 mg to 50 mg every week. Titrating in increments of 25 mg/day every week may delay the time to reach an effective dose. Doses above 400 mg/day have not been shown to improve responses in adults with partial-onset seizures.

Pediatric Patients 6 to 16 Years of Age

The recommended total daily dose of TROKENDI XR ®as adjunctive therapy for patients 6 to 16 years of age with partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome is approximately 5 mg/kg to 9 mg/kg orally once daily. Begin titration at 25 mg once daily (or less, based on a range of 1 mg/kg/day to 3 mg/kg/day) given nightly for the first week. Subsequently, increase the dosage at 1- or 2-week intervals by increments of 1 mg/kg/day to 3 mg/kg/day to achieve optimal clinical response. Dose titration should be guided by clinical outcome. The total daily dose should not exceed 400 mg/day.

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 TROKENDI XR (using dose tapering). If the decision is made to continue patients on TROKENDI XR in the face of persistent acidosis, alkali treatment should be considered.

Adult Patients

Pediatric Patients

In pediatric epilepsy trials (adjunctive and monotherapy) conducted with topiramate, the incidence of cognitive/neuropsychiatric adverse reactions in pediatric patients was generally lower than that 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 epilepsy patients during adjunctive therapy double-blind studies were somnolence and fatigue. The most frequently reported cognitive/neuropsychiatric reactions in pediatric epilepsy patients in the 50 mg/day and 400 mg/day groups during the monotherapy double-blind study were headache, dizziness, anorexia, and somnolence.

In pediatric migraine patients, the incidence of cognitive/neuropsychiatric adverse reactions was increased in immediate-release topiramate-treated patients compared to placebo.

The risk for cognitive/neuropsychiatric adverse reactions was dose-dependent, and was greatest at the highest dose (200 mg). This risk for cognitive/neuropsychiatric adverse reactions was also greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age). The most common cognitive/neuropsychiatric adverse reaction in these trials was difficulty with concentration/attention. Cognitive adverse reactions most commonly developed during titration and sometimes persisted for various durations after completion of titration. The Cambridge Neuropsychological Test Automated Battery (CANTAB) was administered to adolescents (12 to 17 years of age) to assess the effects of topiramate on cognitive function at baseline at the end of the Study 3 [see Clinical Studies (14.4)]. Mean change from baseline in certain CANTAB tests suggests that topiramate treatment may result in psychomotor slowing and decreased verbal fluency.

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 TROKENDI XR ®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.

Monotherapy Epilepsy

Adjunctive Therapy Epilepsy

Migraine

Increased Risk for Bleeding

Topiramate 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 reaction 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).

Other Adverse Reactions Observed During Clinical Trials

Other adverse reactions seen during clinical trials were: abnormal coordination, eosinophilia, gingival bleeding, hematuria, hypotension, myalgia, myopia, postural hypotension, scotoma, suicide attempt, syncope, and visual field defect.

Laboratory Test Abnormalities

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as TROKENDI XR, during pregnancy. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334. Information about the North American Drug Pregnancy Registry can be found at http://www.aedpregnancyregistry.org/.

Risk Summary

TROKENDI XR can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in uterohave increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA) [see Human Data] . SGA has been observed at all doses and appears to be dose-dependent. The prevalence of SGA is greater in infants of women who received higher doses of topiramate during pregnancy. In addition, the prevalence of SGA in infants of women who continued topiramate use until later in pregnancy is higher compared to the prevalence in infants of women who stopped topiramate use before the third trimester.

In multiple animal species, topiramate demonstrated developmental toxicity, including increased incidences of fetal malformations, in the absence of maternal toxicity at clinically relevant doses [see Animal Data] .

All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.

Clinical Considerations

Data

Risk Summary

Topiramate is excreted in human milk [see Data]. The effects of topiramate on milk production are unknown. Diarrhea and somnolence have been reported in breastfed infants whose mothers receive topiramate treatment.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for TROKENDI XR and any potential adverse effects on the breastfed infant from TROKENDI XR or from the underlying maternal condition.

Data

Limited data from 5 women with epilepsy treated with topiramate during lactation showed drug levels in milk similar to those in maternal plasma.

Contraception

Women of childbearing potential who are not planning a pregnancy should use effective contraception because of the risk of major congenital malformations, including oral clefts, and the risk of infants being SGA [see Drug Interactions (7.5)and Use in Specific Populations (8.1)] .

Seizures in Pediatric Patients 6 Years of Age and Older

The safety and effectiveness of TROKENDI XR ®for treatment of partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndromes in pediatric patients at least 6 years of age is based on controlled trials with immediate-release topiramate [see Adverse Reactions (6.1), Clinical Studies (14.2, 14.3)] .

The adverse reactions in pediatric patients treated for partial onset seizure, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome are similar to those seen in adults [see Warnings and Precautions (5)and Adverse Reactions (6)] .

These include, but are not limited to:

• oligohydrosis and hyperthermia [see Warnings and Precautions (5.3)]
• dose-related increased incidence of metabolic acidosis [see Warnings and Precautions (5.4)]
• dose-related increased incidence of hyperammonemia [see Warnings and Precautions (5.13)]

Not Recommended for Pediatric Patients Younger than 6 Years of Age

The safety and effectiveness of TROKENDI XR for treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndromes in pediatric patients younger than 6 years of age has not been established.

Because the capsule must be swallowed whole, and may not be sprinkled on food, crushed or chewed, TROKENDI XR ®is recommended only for children age 6 or older.

The following pediatric use information for adjunctive treatment for partial onset epilepsy in infants and toddlers (1 to 24 months) is based on studies conducted with immediate-release topiramate, which failed to demonstrate efficacy.

Safety and effectiveness of immediate-release topiramate in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome. In a single randomized, double-blind, placebo-controlled investigational trial, the efficacy, safety, and tolerability of immediate-release topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in pediatric patients 1 to 24 months of age with refractory partial-onset seizures were assessed. After 20 days of double-blind treatment, immediate-release topiramate (at fixed doses of 5, 15, and 25 mg/kg per day) did not demonstrate efficacy compared with placebo in controlling seizures.

In general, the adverse reaction profile for immediate-release topiramate in this population was similar to that of older pediatric patients, although results from the above controlled study, and an open-label, long-term extension study in these pediatric patients 1 to 24 months old suggested some adverse reactions not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions that occurred with a greater frequency and/or greater severity than had been recognized previously from studies in older pediatric patients or adults for various indications.

These very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%). The following adverse reactions were observed in at least 3% of patients on immediate-release topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm. A generally similar profile was observed in older pediatric patients [see Adverse Reactions (6.1)].

Immediate-release topiramate resulted in an increased incidence of patients with increased creatinine (any topiramate dose 5%, placebo 0%), BUN (any topiramate dose 3%, placebo 0%), and protein (any topiramate dose 34%, placebo 6%), and an increased incidence of decreased potassium (any topiramate dose 7%, placebo 0%). This increased frequency of abnormal values was not dose related. Creatinine was the only analyte showing a noteworthy increased incidence (topiramate 25 mg/kg/day 5%, placebo 0%) of a markedly abnormal increase [see Adverse Reactions (6.1)] . The significance of these findings is uncertain.

Immediate-release topiramate treatment also produced a dose-related increase in the percentage of patients who had a shift from normal at baseline to high/increased (above the normal reference range) in total eosinophil count at the end of treatment. The incidence of these abnormal shifts was 6 % for placebo, 10% for 5 mg/kg/day, 9% for 15 mg/kg/day, 14% for 25 mg/kg/day, and 11% for any topiramate dose [see Adverse Reactions (6.1)] . There was a mean dose-related increase in alkaline phosphatase. The significance of these findings is uncertain.

Topiramate produced a dose-related increased incidence of hyperammonemia [see Warnings and Precautions (5.13)] .

Treatment with immediate-release topiramate for up to 1 year was associated with reductions in Z SCORES for length, weight, and head circumference [see Warnings and Precautions (5.4)and Adverse Reactions (6)] .

In open-label, uncontrolled experience, increasing impairment of adaptive behavior was documented in behavioral testing over time in this population. There was a suggestion that this effect was dose-related. However, because of the absence of an appropriate control group, it is not known if this decrement in function was treatment related or reflects the patient's underlying disease (e.g., patients who received higher doses may have more severe underlying disease) [see Warnings and Precautions (5.7)] .

In this open-label, uncontrolled study, the mortality was 37 deaths/1000 patient years. It is not possible to know whether this mortality rate is related to immediate-release topiramate treatment, because the background mortality rate for a similar, significantly refractory, young pediatric population (1 month to 24 months) with partial epilepsy is not known.

Other Pediatric Studies

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 years to 16 years) in a double-blind, placebo-controlled study [see Adverse Reactions (6.1)] .

A one-year, active-controlled, open-label study with blinded assessments of bone mineral density (BMD) and growth in pediatric patients 4 to 15 years of age, including 63 patients with recent or new onset of epilepsy, was conducted to assess effects of immediate-release topiramate (N=28, 6-15 years of age) versus levetiracetam (N=35, 4-15 years of age) monotherapy on bone mineralization and on height and weight, which reflect growth. Effects on bone mineralization were evaluated via dual-energy X-ray absorptiometry and blood markers. Table 8 summarizes effects of immediate-release topiramate at 12 months for key safety outcomes including BMD, height, height velocity, and weight. All Least Square Mean values for immediate-release topiramate and the comparator were positive. Therefore, the Least Square Mean treatment differences shown reflect an immediate-release topiramate-induced attenuation of the key safety outcomes. Statistically significant effects were observed for decreases in BMD (and bone mineral content) in lumbar spine and total body less head and in weight. Subgroup analyses according to age demonstrated similar negative effects for all key safety outcomes (i.e., BMD, height, weight).

Metabolic acidosis (serum bicarbonate <20 mEq/L) was observed in all immediate-release topiramate-treated patients at some time in the study [see Warnings and Precautions (5.4)]. Over the whole study, 76% more immediate-release topiramate-treated patients experienced persistent metabolic acidosis (i.e., 2 consecutive visits with or final serum bicarbonate < 20 mEq/L) compared to levetiracetam-treated patients. Over the whole study, 35% more immediate-release topiramate-treated patients experienced a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and ≥ 5mEq/L decrease from pre-treatment), indicating the frequency of more severe metabolic acidosis, compared to levetiracetam-treated patients. The decrease in BMD at 12 months was correlated with decreased serum bicarbonate, suggesting that metabolic acidosis was at least a partial factor contributing to this adverse effect on BMD.

Immediate-release topiramate-treated patients exhibited an increased risk for developing an increased serum creatinine and an increased serum glucose above the normal reference range compared to control patients.

Preventive Treatment of Migraine in Pediatric Patients 12 to 17 Years of Age

Safety and effectiveness of topiramate for the preventive treatment of migraine was studied in 5 double-blind, randomized, placebo-controlled, parallel-group trials in a total of 219 pediatric patients, at doses of 50 mg/day to 200 mg/day, or 2 to 3 mg/kg/day. These comprised a fixed dose study in 103 pediatric patients 12 to 17 years of age [see Clinical Studies (14.4)], a flexible dose (2 to 3 mg/kg/day), placebo-controlled study in 157 pediatric patients 6 to 16 years of age (including 67 pediatric patients 12 to 16 years of age), and a total of 49 pediatric patients 12 to 17 years of age in 3 studies for the preventive treatment of migraine primarily in adults. Open-label extension phases of 3 studies enabled evaluation of long-term safety for up to 6 months after the end of the double-blind phase.

Efficacy of topiramate for the preventive treatment of migraine in pediatric patients 12 to 17 years of age is demonstrated for a 100 mg daily dose in Study 3 [see Clinical Studies (14.4)]. Efficacy of topiramate (2 to 3 mg/kg/day) for the preventive treatment of migraine was not demonstrated in a placebo-controlled trial of 157 pediatric patients (6 to 16 years of age) that included treatment of 67 pediatric patients 12 to 16 years of age) for 20 weeks.

In the pediatric trials (12 to 17 years of age) in which patients were randomized to placebo or a fixed daily dose of immediate-release topiramate, the most common adverse reactions with immediate-release 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 Adverse Reactions (6.1)] .

The most common cognitive adverse reaction in pooled double-blind studies in pediatric patients 12 to 17 years of age was difficulty with concentration/attention [see Warnings and Precautions (5.7)] .

Markedly abnormally low serum bicarbonate values indicative of metabolic acidosis were reported in topiramate-treated pediatric migraine patients [see Warnings and Precautions (5.4)] .

In topiramate-treated pediatric patients (12 to 17 years of age) compared to placebo-treated patients, abnormally increased results were more frequent for creatinine, BUN, uric acid, chloride, ammonia, total protein, and platelets. Abnormally decreased results were observed with topiramate vs placebo treatment for phosphorus and bicarbonate [see Adverse Reactions (6.1)] .

Notable changes (increases and decreases) from baseline in systolic blood pressure, diastolic blood pressure, and pulse that were observed occurred more commonly in pediatric patients treated with topiramate compared to pediatric patients treated with placebo [see Clinical Pharmacology (12.2)] .

Preventive Treatment of Migraine in Pediatric Patients 6 to 11 Years of Age

Safety and effectiveness in pediatric patients below the age of 12 years have not been established for the preventive treatment of migraine.

In a double-blind study in 90 pediatric patients 6 to 11 years of age (including 59 topiramate-treated and 31 placebo patients), the adverse reaction profile was generally similar to that seen in pooled double-blind studies of pediatric patients 12 to 17 years of age. The most common adverse reactions that occurred in immediate-release topiramate-treated pediatric patients 6 to 11 years of age, and at least twice as frequently than placebo, were gastroenteritis (12% topiramate, 6% placebo), sinusitis (10% topiramate, 3% placebo), weight loss (8% topiramate, 3% placebo) and paresthesia (7% topiramate, 0% placebo). Difficulty with concentration/attention occurred in 3 topiramate-treated patients (5%) and 0 placebo-treated patients.

The risk for cognitive adverse reactions was greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age) [see Warnings and Precautions (5.7)] .

Juvenile Animal Studies

When topiramate (30, 90, and 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose, which is approximately 5-8 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m 2) basis.

Absorption and Distribution

Linear pharmacokinetics of topiramate from TROKENDI XR ®were observed following a single oral dose over the range of 50 mg to 200 mg. At 25 mg, the pharmacokinetics of TROKENDI XR ®is nonlinear possibly due to the binding of topiramate to carbonic anhydrase in red blood cells.

The peak plasma concentrations (C max) of topiramate occurred at approximately 24 hours following a single 200 mg oral dose of TROKENDI XR ®. At steady-state, the (AUC 0-24, C max, and C min) of topiramate from TROKENDI XR ®administered once-daily and the immediate-release tablet administered twice-daily were shown to be bioequivalent. Fluctuation of topiramate plasma concentrations at steady-state for TROKENDI XR ®administered once-daily was approximately 26% and 42% in healthy subjects and in epileptic patients, respectively, compared to approximately 40% and 51%, respectively, for immediate-release topiramate [see Clinical Pharmacology (12.6)] .

Compared to the fasted state, high-fat meal increased the C maxof topiramate by 37% and shortened the T maxto approximately 8 hours following a single dose of TROKENDI XR ®, while having no effect on the AUC. Modeling of the observed single dose fed data with simulation to steady state showed that the effect on C maxis significantly reduced following repeat administrations. TROKENDI XR ®can be taken without regard to meals.

Topiramate is 15% to 41% bound to human plasma proteins over the blood concentration range of 0.5 mcg/mL to 250 mcg/mL. The fraction bound decreased as blood concentration increased.

Carbamazepine and phenytoin do not alter the binding of immediate-release topiramate. Sodium valproate, at 500 mcg/mL (a concentration 5 to 10 times higher than considered therapeutic for valproate) decreased the protein binding of immediate-release topiramate from 23% to 13%. Immediate-release topiramate does not influence the binding of sodium valproate.

Metabolism and Excretion

Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption of topiramate. In rats, given probenecid to inhibit tubular reabsorption, along with topiramate, a significant increase in renal clearance of topiramate was observed. This interaction has not been evaluated in humans. Overall, oral plasma clearance (CL/F) is approximately 20 mL/min to 30 mL/min in adults following oral administration. The mean elimination half-life of topiramate was approximately 31 hours following repeat administration of TROKENDI XR ®.

Specific Populations

Drug-Drug Interaction Studies

In vitrostudies indicate that topiramate does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4/5 isozymes. In vitrostudies indicate that immediate-release topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4. The same drug interactions can be expected with the use of TROKENDI XR ®.

Study in Healthy Normal Volunteers

TROKENDI XR ®taken once a day provides steady state plasma levels comparable to immediate-release topiramate taken every 12 hours, when administered at the same total 200-mg daily dose. In a crossover study, 33 healthy subjects were titrated to a 200-mg dose of either TROKENDI XR ®or immediate-release topiramate and were maintained at 200 mg per day for 10 days.

The 90% CI for the ratios of AUC 0-24, C maxand C min, as well as partial AUC (the area under the concentration-time curve from time 0 to time p (post dose) for multiple time points were within the 80 to 125% bioequivalence limits, indicating no clinically significant difference between the two formulations. In addition, the 90% CI for the ratios of topiramate plasma concentration at each of multiple time points over 24 hours for the two formulations were within the 80 to 125% bioequivalence limits, except for the initial time points before 1.5 hours post-dose.

Study in Patients with Epilepsy

In a study in epilepsy patients treated with immediate-release topiramate alone or in combination with either enzyme-inducing or neutral AEDs who were switched to an equivalent daily dose of TROKENDI XR ®, there was a 10% decrease in AUC 0-24, C max, and C minon the first day after the switch in all patients. At steady state, AUC 0-24and C maxwere comparable to immediate-release topiramate in all patients. While patients treated with TROKENDI XR ®alone or in combination with neutral AEDs showed comparable C minat steady state, patients treated with enzyme-inducers showed a 10% decrease in C min. This difference is likely not clinically significant and probably due to the small number of patients on enzyme-inducers.

Carcinogenesis

An increase in urinary bladder tumors was observed in mice given topiramate (0, 20, 75, and 300 mg/kg/day) in the diet for 21 months. An increase in the incidence of bladder tumors in males and females receiving 300 mg/kg was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. The higher of the doses not associated with an increase in tumors (75 mg/kg/day) is equivalent to the maximum recommended human dose (MRHD) for epilepsy and approximately 4 times the MRHD for migraine (100 mg) on a mg/m 2basis. The relevance of this finding to human carcinogenic risk is uncertain. No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/kg/day (approximately 3 times the MRHD for epilepsy and 12 times the MRHD for migraine on a mg/m 2basis).

Mutagenesis

Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitroand in vivoassays. Topiramate was not mutagenic in the Ames test or the in vitromouse lymphoma assay; it did not increase unscheduled DNA synthesis in rat hepatocytes in vitro;and it did not increase chromosomal aberrations in human lymphocytes in vitroor in rat bone marrow in vivo.

Impairment of Fertility

No adverse effects on male or female fertility were observed in rats administered oral doses of up to 100 mg/kg/day (2.5 times the MRHD for epilepsy and 10 times the MRHD for migraine on a mg/m 2basis) prior to and during mating and early pregnancy.

Patients With Partial-Onset or Primary Generalized Tonic-Clonic Seizures

Adult Patients With Partial-Onset Seizures

The effectiveness of topiramate as an adjunctive treatment for adults with partial-onset seizures was established in six multicenter, randomized, double-blind, placebo-controlled trials (Studies 2, 3, 4, 5, 6, and 7), two comparing several dosages of topiramate and placebo and four comparing a single dosage with placebo, in patients with a history of partial onset seizures, with or without secondarily generalized seizures.

Patients in these studies were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In each study, patients were stabilized on optimum dosages of their concomitant AEDs during baseline phase lasting between 4 and 12 weeks. Patients who experienced a pre-specified minimum number of partial-onset seizures, with or without secondary generalization, during the baseline phase (12 seizures for 12-week baseline, 8 for 8-week baseline or 3 for 4-week baseline) were randomly assigned to placebo or a specified dose of topiramate tablets in addition to their other AEDs.

Following randomization, patients began the double-blind phase of treatment. In five of the six studies, patients received active drug beginning at 100 mg per day; the dose was then increased by 100 mg or 200 mg/day increments weekly or every other week until the assigned dose was reached, unless intolerance prevented increases. In Study 7, the 25 or 50 mg/day initial doses of topiramate were followed by respective weekly increments of 25 or 50 mg/day until the target dose of 200 mg/day was reached. After titration, patients entered a 4, 8 or 12-week stabilization period. The numbers of patients randomized to each dose, and the actual mean and median doses in the stabilization period are shown in Table 10.

Pediatric Patients 6 to 16 Years of Age With Partial-Onset Seizures

The effectiveness of topiramate as an adjunctive treatment for pediatric patients 6 to 16 years of age with partial-onset seizures was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 8), comparing topiramate and placebo in patients with a history of partial-onset seizures, with or without secondarily generalized seizures.

Patients in Study 8 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In Study 8, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least six partial onset seizures, with or without secondarily generalized seizures, during the baseline phase were randomly assigned to placebo or topiramate in addition to their other AEDs.

Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 25 or 50 mg/day; the dose was then increased by 25 mg to 150 mg/day increments every other week until the assigned dosage of 125, 175, 225 or 400 mg/day based on patients' weight to approximate a dosage of 6 mg/kg/day per day was reached, unless intolerance prevented increases. After titration, patients entered an 8-week stabilization period.

Patients With Primary Generalized Tonic-Clonic Seizures

The effectiveness of topiramate as an adjunctive treatment for primary generalized tonic-clonic seizures in patients 6 years of age and older was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 9), comparing a single dosage of topiramate and placebo (see Table 11).

Patients in Study 9 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least three primary generalized tonic-clonic seizures during the baseline phase were randomly assigned to placebo or topiramate in addition to their other AEDs.

Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 50 mg/day for four weeks; the dose was then increased by 50 mg to 150 mg/day increments every other week until the assigned dose of 175, 225 or 400 mg/day based on patients' body weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered a 12-week stabilization period.

Patients With Lennox-Gastaut Syndrome

The effectiveness of topiramate as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome in patients 6 years of age and older was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 10), comparing a single dosage of topiramate with placebo (see Table 11).

Patients in Study 10 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients who were experiencing at least 60 seizures per month before study entry were stabilized on optimum dosages of their concomitant AEDs during a 4 week baseline phase. Following baseline, patients were randomly assigned to placebo or topiramate in addition to their other AEDs. Active drug was titrated beginning at 1 mg/kg/day for a week; the dose was then increased to 3 mg/kg/day for one week then to 6 mg/kg/day. After titration, patients entered an 8-week stabilization period. The primary measures of effectiveness were the percent reduction in drop attacks and a parental global rating of seizure severity.

In all adjunctive topiramate trials, the reduction in seizure rate from baseline during the entire double-blind phase was measured. The median percent reductions in seizure rates and the responder rates (fraction of patients with at least a 50% reduction) by treatment group for each study are shown below in Table 11. As described above, a global improvement in seizure severity was also assessed in the Lennox-Gastaut trial.

Subset analyses of the antiepileptic efficacy of topiramate tablets in these studies showed no differences as a function of gender, race, age, baseline seizure rate, or concomitant AED.

In clinical trials for epilepsy, daily dosages were decreased in weekly intervals by 50 mg per day to 100 mg per day in adults and over a 2- to 8-week period in pediatric patients; transition was permitted to a new antiepileptic regimen when clinically indicated.

Adult Patients

The results of 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trials conducted in US (Study 11) or the US and Canada (Study 12) established the effectiveness of immediate-release topiramate in the preventive treatment of migraine. The design of both trials was identical, enrolling patients with a history of migraine with or without aura, for at least 6 months, according to the International Headache Society (IHS) diagnostic criteria. Patients with a history of cluster headaches or basilar, opthalmoplegic, hemiplegic, or transformed migraine headaches were excluded from the trials. Patients were required to have completed up to a 2-week washout of any prior migraine preventative medications before starting the baseline phase.

Patients who experienced 3 to 12 migraine headaches over the 4 weeks in the baseline phase were randomized to either immediate-release topiramate 50 mg/day, 100 mg/day, 200 mg/day (twice the recommended daily dosage for migraine prophylaxis) or placebo, and treated for a total of 26 weeks (8-week titration period and 18-week maintenance period.). Treatment was initiated at 25 mg/day for one week, and then the daily dosage was increased by 25 mg increments each week until reaching the assigned target dose or maximum tolerated dose (administered twice daily).

Effectiveness of treatment was assessed by the reduction in migraine headache frequency, as measured by the change in 4-week migraine rate (according to migraines classified by IHS criteria) from the baseline phase to double-blind treatment period in each immediate-release topiramate treatment group compared to placebo in the Intent-To-Treat (ITT) population.

In Study 11, a total of 469 patients (416 females, 53 males) ranging in age from 13 to 70 years, were randomized and provided efficacy data. Two hundred sixty-five patients completed the entire 26-week double-blind phase. The median average daily dosages were 48 mg/day, 88 mg/day, and 132 mg/day in the target dose groups of topiramate 50, 100 and 200 mg/day, respectively.

The mean migraine headache frequency rate at baseline was approximately 5.5 migraine headaches per 28 days and was similar across treatment groups. The change in the mean 4-week migraine headache frequency from baseline to the double-blind phase was -1.3, -2.1, and -2.2 in the immediate-release topiramate 50, 100, and 200 mg/day groups, respectively, versus -0.8 in the placebo group (see Figure 2). The treatment differences between the immediate release topiramate 100 and 200 mg/day groups versus placebo were similar and statistically significant (p < 0.001 for both comparisons).

In Study 12, a total of 468 patients (406 females, 62 males) ranging in age from 12 to 65 years, were randomized and provided efficacy data. Two hundred fifty-five patients completed the entire 26-week double-blind phase. The median average daily dosages were 47 mg/day, 86 mg/day, and 150 mg/day in the target dose groups of immediate-release topiramate 50, 100, and 200 mg/day, respectively.

The mean migraine headache frequency rate at baseline was approximately 5.5 migraine headaches per 28 days and was similar across treatment groups. The change in the mean 4-week migraine headache period frequency from baseline to the double-blind phase was -1.4, -2.1, and -2.4 in the immediate-release topiramate 50, 100, and 200 mg/day groups, respectively, versus -1.1 in the placebo group (see Figure 2). The differences between the immediate-release topiramate 100 and 200 mg per day groups versus placebo were similar and statistically significant (p = 0.008 and p < 0.001, respectively).

In both studies there were no apparent differences in treatment effect within age or gender subgroups. Because most patients were Caucasian, there were insufficient numbers of patients from different races to make a meaningful comparison of race.

For patients withdrawing from immediate-release topiramate, daily dosages were decreased in weekly intervals by 25 to 50 mg/day.

Figure 2: Reduction in 4-Week Migraine Headache Frequency (Studies 11 and 12 for Adults and Adolescents)

Pediatric Patients 12 to 17 Years of Age

The effectiveness of immediate-release topiramate for the preventive treatment of migraine in pediatric patients 12 to 17 years of age was established in a multicenter, randomized, double-blind, parallel-group trial (Study 13). The study enrolled 103 patients (40 male, 63 female) 12 to 17 years of age with episodic migraine headaches with or without aura. Patient selection was based on IHS criteria for migraines (using proposed revisions to the 1988 IHS pediatric migraine criteria [IHS-R criteria]).

Patients who experienced 3 to 12 migraine attacks (according to migraines classified by patient reported diaries) and ≤14 headache days (migraine and non-migraine) during the 4-week prospective baseline period were randomized to either immediate-release topiramate 50 mg/day, 100 mg/day, or placebo and treated for a total of 16 weeks (4-week titration period followed by a 12 week maintenance period). Treatment was initiated at 25 mg/day for one week, and then the daily dosage was increased by 25 mg increments each week until reaching the assigned target dose or maximum tolerated dose (administered twice daily). Approximately 80% or more patients in each treatment group completed the study. The median average daily dosages were 45 and 79 mg/day in the target dose groups of immediate-release topiramate 50 and 100 mg/day, respectively.

Effectiveness of treatment was assessed by comparing each immediate-release topiramate treatment group to placebo (ITT population) for the percent reduction from baseline to the last 12 weeks of the double-blind phase in the monthly migraine attack rate (primary endpoint). The percent reduction from baseline to the last 12 weeks of the double-blind phase in average monthly migraine attack rate is shown in Table 12. The 100 mg immediate-release topiramate dose produced a statistically significant treatment difference relative to placebo of 28% reduction from baseline in the monthly migraine attack rate.

The mean reduction from baseline to the last 12 weeks of the double-blind phase in average monthly attack rate, a key secondary efficacy endpoint in Study 13 (and the primary efficacy endpoint in Studies 11 and 12, of adults) was 3.0 for 100 mg immediate-release topiramate dose and 1.7 for placebo. This 1.3 treatment difference in mean reduction from baseline of monthly migraine rate was statistically significant (p=0.0087).