PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION. 3 INDICATIONS AND CLINICAL USE. 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 10 DRUG INTERACTIONS 27 DOSAGE AND ADMINISTRATION. 32 OVERDOSAGE 34 ACTION AND CLINICAL PHARMACOLOGY 35 STORAGE AND STABILITY 37 DOSAGE FORMS, COMPOSITION AND PACKAGING 37

PART II: SCIENTIFIC INFORMATION 39

PHARMACEUTICAL INFORMATION. 39 CLINICAL TRIALS. 39 DETAILED PHARMACOLOGY. 47 TOXICOLOGY. 49 REFERENCES. 54

PART III: CONSUMER INFORMATION. 59

Pr

GEN-TOPIRAMATE

topiramate 25 mg, 100 mg and 200 mg Tablets Antiepileptic/Migraine Prophylaxis

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics

There is limited information in patients over 65 years of age (see

).

CONTRAINDICATIONS

• Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph.

WARNINGS AND PRECAUTIONS

General

Antiepileptic drugs, including topiramate, should be withdrawn gradually to minimize the potential of increased seizure frequency. In adult clinical trials, dosages were decreased by 100 mg/day at weekly intervals.

Carcinogenesis and Mutagenesis

Product Monograph Part II: TOXICOLOGY - Carcinogenicitv and Mutagenicity

See

for discussion on animal data.

Endocrine and Metabolism

Oligohidrosis and Hyperthermia

Oligohidrosis (decreased sweating) and hyperthermia, infrequently resulting in hospitalization, including fatalities, have been reported in patients treated with topiramate. Oligohidrosis and hyperthermia may have potentially serious sequelae and may be preventable by prompt recognition of symptoms and appropriate treatment. Decreased sweating and elevation of body temperature above normal characterized the cases reported in patients treated with topiramate. Some of the cases were reported after exposure to elevated environmental temperatures. These reports have primarily involved children. Patients treated with topiramate, especially pediatric patients, should be monitored closely for evidence of decreased sweating and increased body temperature, particularly in hot weather. Proper hydration before and during activities such as exercise or exposure to warm temperatures is recommended.

ADVERSE REACTIONS, Post-Market Adverse Drug Reactions)

Caution should be used when topiramate is prescribed with other drugs that predispose patients to heat- related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity. (See

Metabolic Acidosis

Hyperchloremic, non-anion gap, metabolic acidosis (i.e. decreased serum bicarbonate below the normal reference range in the absence of respiratory alkalosis) is associated with topiramate treatment. This decrease in serum bicarbonate is due to the inhibitory effect of topiramate on renal carbonic anhydrase. Generally, the decrease in bicarbonate occurs early in treatment although it can occur at any time during treatment. These decreases are usually mild to moderate (average decrease of 4 mmol/L at doses of 100 mg/day or above in adults and at approximately 6 mg/kg/day in pediatric patients). Rarely, patients have experienced decreases to values below 10 mmol/L. Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, surgery, ketogenic diet, or certain drugs) may be additive to the bicarbonate lowering effects of topiramate. In adults, the incidence of persistent treatment-emergent decreases in serum bicarbonate (levels of <20 mmol/L at two consecutive visits or at the final visit) in controlled clinical trials for adjunctive treatment of epilepsy was 32% for 400 mg/day, and 1% for placebo. Metabolic acidosis has been observed at doses as low as 50 mg/day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mmol/L and >5 mmol/L decrease from pretreatment) in these trials was 3% for 400 mg/day, and 0% for placebo. Serum bicarbonate levels have not been systematically evaluated at daily doses greater than 400 mg/day. In pediatric patients (<16 years of age), the incidence of persistent treatment-emergent decreases in serum bicarbonate in placebo-controlled trials for adjunctive treatment of Lennox-Gastaut Syndrome or refractory partial onset seizures was 67% for topiramate (at approximately 6 mg/kg/day), and 10% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mmol/L and >5 mmol/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. The incidence of persistent treatment-emergent decreases in serum bicarbonate in placebo-controlled trials for adults for 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 a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mmol/L and >5 mmol/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. Safety and effectiveness in patients below the age of 2 years have not been established. Topiramate is associated with metabolic acidosis. Chronic untreated metabolic acidosis in pediatric patients may cause osteomalacia (rickets) and may 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. Chronic metabolic acidosis in pediatric patients can reduce growth rates. The effect of topiramate on growth and bone-related sequelae has not been systematically investigated in pediatric or adult populations. 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.

Decreases in Serum Potassium with Concomitant Treatment with Hydrochlorothiazide (HCTZ)

In a drug interaction study, a greater decrease from baseline in serum potassium values was seen with concomitant treatment than for either drug alone. At the end of each treatment period, 27% (3/12) of subjects on topiramate treatment alone and 25% (3/12) of subjects on HCTZ treatment alone showed a serum potassium value of <3.6 mEq/L, compared to 61% (14/23) of subjects on concomitant drug treatment. One of the subjects who had hypokalemia with concomitant treatment also had an abnormal

ECG (nonspecific ST-T wave changes), which may have been related to the decrease in plasma potassium levels. Caution should be used when treating patients who are receiving topiramate and hydrochlorothiazide concomitantly. (See DRUG INTERACTIONS.)

Nutritional Supplementation

A dietary supplement or increased food intake may be considered if the patient is losing weight while on this medication.

Hepatic/Biliary/Pancreatic

Decreased Hepatic Function

In hepatically impaired patients, topiramate should be administered with caution as the clearance of topiramate was decreased compared with normal subjects.

Neurologic

Central Nervous System Effects

Adverse events most often associated with the use of topiramate were central nervous system related and were observed in both the epilepsy and migraine populations. In adults, the most significant of these can be classified into three general categories: psychomotor slowing, difficulty with concentration and speech or language problems, in particular, word-finding difficulties, somnolence or fatigue and mood disturbances including irritability and depression. In the controlled epilepsy adjunctive therapy trials, these events were generally mild to moderate, and generally occurred early in therapy. While the incidence of psychomotor slowing does not appear to be dose related, both language problems and difficulty with concentration or attention increased in frequency with increasing dosage in the six double-blind trials, suggesting that these events are dose related (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions). Central nervous system and psychiatric-related events were also more frequently reported in topiramate- treated subjects in the migraine prophylaxis trials. These included: anorexia, dizziness, difficulty with memory, somnolence, language problems, and difficulty with concentration and attention. Most of the events were mild or moderate in severity, some of which led to withdrawal from treatment. (See ADVERSE REACTIONS, MIGRAINE.)

In the double-blind phases of clinical trials with topiramate in approved and investigational indications, suicide attempts occurred at an incidence of 0.2% (13 reports/7,999 patients) on topiramate versus 0% (0 reports/3,150 patients) on placebo. One completed suicide was reported in a bipolar disorder trial in a patient on topiramate (see ADVERSE REACTIONS, Less Common Clinical Trial Adverse Drug Reactions (<2%) and Post-Market Adverse Drug Reactions). Additional nonspecific CNS effects occasionally observed with topiramate as add-on epilepsy therapy include dizziness or imbalance, confusion and memory problems. Although the duration of the epilepsy monotherapy studies was considerably longer than the epilepsy adjunctive therapy studies, these adverse events were reported at lower incidences in the monotherapy trials.

Paresthesia

Paresthesia, an effect associated with the use of other carbonic anhydrase inhibitors, appears to be a common effect of topiramate. Paresthesia was more frequently reported in the migraine prophylaxis and epilepsy monotherapy trials versus the adjunctive therapy trials in epilepsy. The higher incidence in the epilepsy monotherapy studies may have been related to the higher topiramate plasma concentrations achieved in the monotherapy studies. In the majority of instances, paresthesia did not lead to treatment discontinuation.

Ophthalmologic

Acute Myopia and Secondary Angle Closure Glaucoma

WARNINGS AND PRECAUTIONS, Neurologic, Central Nervous System Effects

There have been rare spontaneous postmarketing reports of suicide attempts and suicide-related adverse events, including fatalities, in patients treated with topiramate alone or in combination with other medications (see

).

DRUG INTERACTIONS

Drug-Drug Interactions

In all of the studies below, except where noted, the maximum topiramate dose administered was 200 mg/day.

Antiepileptic Drugs

Potential interactions between topiramate and standard AEDs were measured in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on plasma concentrations are summarized in Table 8.

Table 8:

Drug Interactions with Topiramate Therapy

AED AED

Co-administered Concentration

Topiramate Concentration

Phenytoin o * * 959%

Carbamazepine (CBZ) o 940%

CBZ epoxide * o NS

Valproic acid 911% 914%

Phenobarbital o NS

Primidone o NS

Lamotrigine o 15% decrease

at topiramate doses up to 400 mg/day

* Is not administered but is an active metabolite of carbamazepine

o

No effect on plasma concentration (< 15% change)

* *

Plasma concentrations increased 25% in some patients, generally those on a b.i.d. dosing regimen of phenytoin

Plasma concentrations decrease in individual patients NS Not studied

AED Antiepileptic drug

Effects of Topiramate on Other Antiepileptic Drugs

The addition of topiramate to other antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, primidone) has no effect on their steady-state plasma concentrations, except in the occasional patient, where the addition of topiramate to phenytoin may result in an increase of plasma concentrations of phenytoin. The effect of topiramate on steady-state pharmacokinetics of phenytoin may be related to the frequency of phenytoin dosing. A slight increase in steady-state phenytoin plasma concentrations was observed, primarily in patients receiving phenytoin in two divided doses. The slight increase may be due to the saturable nature of phenytoin pharmacokinetics and inhibition of phenytoin metabolism (CYP2Cmeph). The addition of topiramate therapy to phenytoin should be guided by clinical outcome. In general, as evidenced in clinical trials, patients do not require dose adjustments. However, any patient on phenytoin showing clinical signs or symptoms of toxicity should have phenytoin levels monitored.

Effects of Other Antiepileptic Drugs on Topiramate

Phenytoin and carbamazepine decrease the plasma concentration of topiramate. The addition or withdrawal of phenytoin and/or carbamazepine during adjunctive therapy with topiramate may require adjustment of the dose of topiramate. This should be done by titrating to clinical effect. The addition or withdrawal of valproic acid does not produce clinically significant changes in plasma concentrations of topiramate, and therefore, does not warrant dosage adjustment of topiramate.

DOSAGE AND ADMINISTRATION

Dosing Considerations

• Patients with renal impairment

• Patients undergoing hemodialysis

• Patients with hepatic disease

Recommended Dose and Dosage Adjustment

Topiramate Tablets can be taken without regard to meals.

Epilepsy

Monotherapy

Adults and Children (Age 6 years and older)

The recommended initial target dose for topiramate monotherapy in adults and children 6 years of age and older is 100 mg/day and the maximum recommended dose is 400 mg/day, administered in two divided doses, as needed and tolerated. The recommended titration rate for topiramate monotherapy to 100 mg/day is:

OVERDOSAGE

Overdoses of topiramate have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbances, blurred vision, diplopia, mentation impaired, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness and depression. The clinical consequences were not severe in most cases but deaths have been reported after polydrug overdoses involving topiramate.

WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Metabolic Acidosis

Topiramate overdose can result in severe metabolic acidosis (see

).

A patient who ingested a dose calculated to be between 96 and 110 g topiramate was admitted to hospital with coma lasting 20-24 hours followed by full recovery after 3 to 4 days. In acute topiramate overdose, if the ingestion is recent, the stomach should be emptied immediately by lavage or by induction of emesis. Activated charcoal has been shown to adsorb topiramate in vitro. Treatment should be appropriately supportive. Hemodialysis has been shown to be an effective means of removing topiramate from the body. The patient should be well hydrated.

ACTION AND CLINICAL PHARMACOLOGY

Pharmacodynamics

Topiramate is a novel agent classified as a sulfamate substituted monosaccharide. Three pharmacological properties of topiramate are believed to contribute to its anticonvulsant activity. First, topiramate reduces the frequency at which action potentials are generated when neurons are subjected to a sustained depolarization indicative of a state-dependent blockade of voltage-sensitive sodium channels. Second, topiramate markedly enhances the activity of GABA at some types of GABA receptors. Because the antiepileptic profile of topiramate differs markedly from that of the benzodiazepines, it may modulate a benzodiazepine-insensitive subtype of GABAA receptor. Third, topiramate antagonizes the ability of kainate to activate the kainate/AMPA subtype of excitatory amino acid (glutamate) receptors but has no apparent effect on the activity of N-methyl-D-aspartate (NMDA) at the NMDA receptor subtype. In addition, topiramate inhibits some isoenzymes of carbonic anhydrase. This pharmacologic effect is much weaker than that of acetazolamide, a known carbonic anhydrase inhibitor, and is not thought to be a major component of topiramate *s antiepileptic activity.

Pharmacokinetics

Topiramate exhibits low intersubject variability in plasma concentrations and therefore has predictable pharmacokinetics. The pharmacokinetics of topiramate are linear with plasma clearance remaining constant and area under the plasma concentration curve increasing in a dose-proportional manner over a 100 to 400 mg single oral dose range in healthy subjects. Patients with normal renal function may take 4 to 8 days to reach steady-state plasma concentrations. The mean Cmax following multiple twice- a-day oral doses of 100 mg to healthy subjects was 6.76 :g/mL. The mean plasma elimination half- lives from multiple 50 mg and 100 mg q12h doses of topiramate were approximately 21 hours. The elimination half-life did not significantly change when switching from single dose to multiple dose. In well-controlled add-on trials, no correlation has been demonstrated between trough plasma concentrations and its clinical efficacy. It is not necessary to monitor topiramate plasma concentrations to optimize therapy with topiramate. No evidence of tolerance requiring increased dosage has been demonstrated in patients during 5 years of use. Concomitant multiple-dose administration of topiramate, 100 to 400 mg q12h, with phenytoin or carbamazepine shows dose-proportional increases in plasma concentrations of topiramate. Absorption: Topiramate is rapidly and well absorbed. Following oral administration of 100 mg topiramate to healthy subjects, a mean peak plasma concentration (Cmax) of 1.5 :g/mL was achieved within 2 to 3 hours (Tmax). The mean extent of absorption from a 100 mg oral dose of was at least 81% based on the recovery of radioactivity from the urine. There was no clinically significant effect of food on the bioavailability of topiramate. C-topiramate

Distribution:

Approximately 13% to 17% of topiramate is bound to plasma proteins. A low capacity

binding site for topiramate in/on erythrocytes that is saturable above plasma concentrations of 4

:

g/mL has been observed.

The volume of distribution varied inversely with the dose. The mean apparent volume of distribution was 0.80 to 0.55 L/kg for a single-dose range of 100 to 1200 mg. Metabolism: Topiramate is not extensively metabolized (~20%) in healthy volunteers. It is metabolized up to 50% in patients receiving concomitant antiepileptic therapy with known inducers of drug metabolizing enzymes. Six metabolites formed through hydroxylation, hydrolysis and glucuronidation, have been isolated, characterized and identified from plasma, urine and feces of humans. Each metabolite represents less than 3% of the total radioactivity excreted following administration of 14C-topiramate. Two metabolites, which retained most of the structure of topiramate, were tested and found to have little or no pharmacological activity. Excretion: In humans, the major route of elimination of unchanged topiramate and its metabolites is via the kidney (at least 81% of the dose). Approximately 66% of a dose of 14C-topiramate was excreted unchanged in the urine within 4 days. The mean renal clearance for 50 mg and 100 mg of topiramate, following q12h dosing, was approximately 18 mL/min and 17 mL/min, respectively. Evidence exists for renal tubular reabsorption of topiramate. This is supported by studies in rats where topiramate was co-administered with probenecid, and a significant increase in renal clearance of topiramate was observed. This interaction has not been evaluated in humans. Overall, plasma clearance (CL/F) is approximately 20 to 30 mL/min in humans following oral administration.

Special Populations and Conditions

Pediatrics:

Pharmacokinetics of topiramate were evaluated in patients ages 4 to 17 years receiving one or two other antiepileptic drugs. Pharmacokinetic profiles were obtained after one week at doses of 1, 3, and 9 mg/kg/day. As in adults, topiramate pharmacokinetics were linear with clearance independent of dose and steady-state plasma concentrations increasing in proportion to dose. Compared with adult epileptic patients, mean topiramate clearance is approximately 50% higher in pediatric patients. Steady-state plasma topiramate concentrations for the same mg/kg dose are expected to be approximately 33% lower in children compared to adults. As with adults, hepatic enzyme-inducing antiepileptic drugs (AEDs) decrease the plasma concentration of topiramate.

Geriatrics:

Plasma clearance of topiramate is unchanged in elderly subjects in the absence of underlying renal disease.

Race, Gender and Age:

Although direct comparison studies of pharmacokinetics have not been conducted, analysis of plasma concentration data from clinical efficacy trials have shown that race, gender and age appear to have no effect on the plasma clearance of topiramate. In addition, based on pooled analyses, race and gender appear to have no effect on the efficacy of topiramate.

Hepatic Insufficiency:

The plasma clearance of topiramate is decreased in patients with moderate to severe hepatic impairment.

Renal Insufficiency:

The plasma and renal clearance of topiramate are decreased in patients with

CR

impaired renal function (CL < 70 mL/min/1.73 m2), and the plasma clearance is decreased in patients with end-stage renal disease. As a result, higher steady-state topiramate plasma concentrations are expected for a given dose in renally impaired patients as compared to those with normal renal function.

Hemodialysis: DOSAGE AND ADMINISTRATION

Topiramate is effectively removed from plasma by hemodialysis (see

).

STORAGE AND STABILITY

Topiramate Tablets should be stored in tightly closed containers at controlled room temperature (15 to 30/C). Protect from moisture.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Availability of Dosage Forms

Gen-Topiramate (topiramate) is available as embossed tablets in the following strengths as described below: 25 mg: white, round, biconvex, coated tablet with "G" on one side and "TO" over "25" on the other side 100 mg: yellow, round, biconvex, coated tablet with "G" on one side and "TO" over "100" on the other side 200 mg: salmon-coloured, round, biconvex, coated tablet with "G" on one side and "TO" over "200" on the other side Supplied: 25 mg Tablets: Bottles of 60, 100, and 500 with dessicant. 100 mg Tablets: Bottles of 60, 100, and 500 with desiccant. 200 mg Tablets: Bottles of 60 and 100 with desiccant.

Composition

Gen-Topiramate (topiramate) Tablets contain the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, and titanium dioxide. The 25 mg tablets also contain hypromellose, polyethylene glycol 400 and polysorbate 80. The 100 mg tablets also contain hypromellose, iron oxide yellow, lactose monohydrate, and triacetin. The 200 mg tablets also contain iron oxide red, polyethylene glycol, polyvinyl alcohol, and talc. Product Monograph available upon request. Genpharm Inc. 85 Advance Rd. Toronto, Ontario M8Z 2S6 Last Revised: August 29, 2005 Rev. 000-xxx

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: topiramate Chemical name: 2,3:4,5-bis-O-(1-methylethylidene)-$-D-fructopyranose sulfamate Molecular formula and molecular mass: C12H21NO8S, 339.36 Structural formula:

O H3C

O

CH2OSO2NH2 O

O

CH3

CH3 Physicochemical properties: Topiramate is a white crystalline powder having a bitter taste. Topiramate is most soluble in alkaline solutions containing sodium hydroxide or sodium phosphate with a pH of 9 to 10. It is freely soluble in acetone, chloroform, dimethylsulfoxide and ethanol. The solubility in water is 9.8 mg/mL. Its saturated solution has a pH of 6.3.

CLINICAL TRIALS

Epilepsy

Monotherapy Controlled Trials

The effectiveness of topiramate as monotherapy in adults and children 6 years of age and older with newly diagnosed epilepsy was established in a multicentre, randomized, double-blind, parallel-group trial that compared the safety and efficacy of 2 doses of topiramate as monotherapy for the treatment of newly diagnosed or recurrent epilepsy. The trial was conducted in 487 patients (6 to 83 years of age) who had a new diagnosis of epilepsy (partial onset or generalized) or a diagnosis of recurrent epilepsy while not taking antiepileptic drugs (AEDs). Patients who had either 1 or 2 well-documented seizures during the 3-month retrospective baseline phase entered the study and received topiramate 25 mg/day for 7 days in an open-label fashion. Any AED therapy used for temporary or emergency purposes was discontinued prior to randomization. Following that phase, patients were randomized to receive topiramate 50 mg/day or topiramate 400 mg/day. Patients remained in the double-blind phase until they experienced a first partial onset or generalized tonic-clonic seizure, until termination of the double-blind phase 6 months after randomization of the last subject, or until withdrawal for protocol-specified reasons. The primary efficacy assessment was based on the comparison between topiramate dose groups with respect to time to first partial onset or generalized tonic-clonic seizure during the double-blind phase. Comparison of the Kaplan-Meier survival curves of time to first seizure favoured topiramate 400 mg/day over topiramate 50 mg/day (p=0.0002, log rank test). The separation between the groups in favour of the higher dose group occurred early in the titration phase and was statistically significant as early as 2 weeks post randomization (p = 0.046), when, by following the weekly titration schedule, the subjects in the higher dose group had achieved a maximum topiramate dose of 100 mg/day. The higher dose group was also superior to the lower dose group with respect to the proportion of subjects who remained seizure-free, based on the Kaplan-Meier estimates, for a minimum of 6 months of therapy (82.9% vs. 71.4%; p = 0.005), and for a minimum of 1 year of therapy (75.7% vs. 58.8%; p = 0.001). The ratio of hazard rates for time to first seizure was 0.516 (95% confidence interval, 0.364 to 0.733). The treatment effects with respect to time to first seizure were consistent across various subject subgroups defined by age, sex, geographic region, baseline body weight, baseline seizure type, time since diagnosis, and baseline AED use.

Adjunctive Therapy Controlled Trials in Adults with Partial Onset Seizures

The effectiveness of topiramate as adjunctive therapy in adults with refractory partial onset seizures with or without secondarily generalized seizures was established in six multicentre, outpatient, randomized, double-blind, placebo-controlled trials. Patients in all six studies were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate therapy (target doses of 200, 400, 600, 800, or 1,000 mg/day) or placebo. In all six add-on trials, the primary efficacy measurement was reduction in seizure rate from baseline during the entire double-blind phase; responder rate (fraction of patients with at least a 50% reduction) was also measured. The median percent reductions in seizure rates and the responder rates by treatment group for each study are shown in Table 9.

Table 9: Median Percent Seizure Rate Reduction and Percent Responders in Six Double-Blind, Placebo-Controlled, Add-On Trials in Adults with Partial Onset Seizures

Comparisons with placebo: ap > 0.05; bp < 0.05; cp # 0.01; dp # 0.001 Across the six efficacy trials in adults, 232 of the 527 topiramate patients (44%) responded to treatment with at least a 50% seizure reduction during the double-blind phase; by comparison, only 25 of the 216 placebo-treated patients (12%) showed the same level of treatment response. When the treatment response was defined more rigorously as a 75% or greater decrease from baseline in seizure rate during double- blind treatment, 111 of the 527 topiramate patients (21%) in the 200 to 1,000 mg/day groups, but only 8 of the 216 placebo patients (4%), demonstrated this level of efficacy. In addition, 24 (5%) of the patients treated with topiramate became seizure-free, compared with 0% in the placebo group (p #0.01). At target dosages of 400 mg/day and higher, the percent of treatment responders was statistically greater for patients treated with topiramate than placebo-treated patients. Pooled analyses of secondarily generalized seizure rates for all patients who had this seizure type during the studies show statistically significant percent reductions in the topiramate groups when compared with placebo. The median percent reduction in the rate of generalized seizures was 57% for patients treated with topiramate compared with -4% for placebo-treated patients. Among patients treated with topiramate, 109 (55%) of 198 had at least a 50% reduction in generalized seizure rate compared with 24 (27%) of 88 placebo-treated patients. The dose titration in the original clinical trials was 100 mg/day the first week, 100 mg b.i.d. the second week, and 200 mg b.i.d. the third week. In a 12-week, double-blind trial, this titration rate was compared to a less rapid rate beginning at 50 mg/day. There were significantly fewer adverse experiences leading to discontinuation and/or dosage adjustment in the group titrated at the less rapid rate. Seizure rate reductions were comparable between the groups at all time points measured.

Adjunctive Therapy Controlled Trials in Children with Partial Onset Seizures

The effectiveness of topiramate as an adjunctive treatment for children with partial onset seizures was established in a multicentre, randomized, double-blind, placebo-controlled trial comparing topiramate and placebo in patients with a history of partial onset seizures, with or without secondarily generalized seizures. Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients were stabilized on optimal dosages of their concomitant AEDs during an 8-week baseline phase. Included were patients who experienced at least six partial onset seizures, with or without secondarily generalized seizures, during the baseline phase. 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 to 150 mg/day increments every other week until the assigned dosage of 125, 175, 225, or 400 mg/day, based on patient *s weight to approximate a dosage of 6 mg/kg per day, was reached. After titration, patients entered an 8-week stabilization period. The reduction in seizure rate from baseline during the entire double-blind phase was measured. The median percent reduction in seizure rate and the responder rate (fraction of patients with at least a 50% reduction) were also measured and the key results are shown in Table 10.

Table 10: Median Percent Seizure Rate Reduction and Percent Responders in a Double-Blind, Placebo-

Controlled, Add-On Trial in Pediatric Patients with Partial Onset Seizures

Target Topiramate Dosage

Protocol Efficacy results

Placebo 6 mg/kg/day * p value

YP N

45 41

Median % Reduction

% Responders

0.034

0.08

* For Protocol YP, protocol-specified target dosages (<9.3 mg/kg/day) were assigned based on subject's

weight to approximate a dosage of 6 mg/kg/day; these dosages corresponded to mg/day dosages of 125, 175, 225, and 400 mg/day.

Forty patients received topiramate during the double-blind study and continued topiramate treatment in the open-label study. During the open-label study, dose escalation was permitted if required. The percent responders increased to 53% at a median average dose of 7.5 mg/kg/day.

Additional Adjunctive Therapy Clinical Data

Some data demonstrating efficacy of topiramate as adjunctive therapy in adults and a small number of pediatric patients for primary generalized tonic-clonic seizures and seizures associated with Lennox- Gastaut syndrome are available from randomized, double-blind, placebo-controlled trials.

Migraine

Controlled Trials in the Prophylactic Treatment of Migraine

The results of 2 multicentre, randomized, double-blind, placebo-controlled, parallel-group clinical trials established the effectiveness of topiramate in the prophylactic treatment of migraine headache. 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 diagnostic criteria. Patients with a history of cluster headaches or basilar, ophthalmoplegic, hemiplegic, or transformed migraine headaches were excluded from the trials. Patients were required to have completed a washout of any prior migraine preventive medications before starting the baseline phase. Patients who experienced 3 to 12 migraine periods (each migraine period was defined as any occurrence of migraine headache that started and ended, or recurred within a 24-hour interval) over the 4 weeks in the baseline phase were equally randomized to either topiramate 50 mg/day, 100 mg/day, 200 mg/day, 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). Up to 2 dose adjustments were allowed after the second week of treatment during the double-blind phase if unacceptable tolerability problems occurred. When needed, rescue medications were allowed for the acute treatment of headache or migraine-associated symptoms. Effectiveness of treatment was assessed through the reduction in migraine headache frequency, as measured by the change in 4-week migraine period rate from the baseline phase to double-blind treatment in each topiramate treatment group compared to placebo. In the first study, 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 47.8 mg/day, 88.3 mg/day, and 132.1 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/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 topiramate 50, 100, and 200 mg/day groups, respectively, versus -0.8 in the placebo group (see Figure 1). The differences between the topiramate 100 and 200 mg/day groups versus placebo were statistically significant (p<0.001 for both comparisons; confidence intervals vs. placebo: topiramate 100 mg/day [-1.93, -0.55], and topiramate 200 mg/day [-2.04, -0.62]). The changes in migraine frequency represent a median percent reduction of 31%, 53%, and 55% in the topiramate 50, 100, and 200 mg/day groups, respectively, versus 21% in the placebo group. In the second study, 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 and fifty-five patients completed the entire 26-week double-blind phase. The median average daily dosages were 46.5 mg/day, 85.6 mg/day, and 150.2 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/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 topiramate 50, 100, and 200 mg/day groups, respectively, versus -1.1 in the placebo group (see Figure 1). The differences between the topiramate 100 and 200 mg/day groups versus placebo were statistically significant (p=0.008 and p<0.001, respectively; confidence intervals vs. placebo: topiramate 100 mg/day [-1.76, -0.27], and topiramate 200 mg/day [-2.06, -0.57]). The changes in migraine frequency represent a median percent reduction of 35%, 49%, and 48% in the topiramate 50, 100, and 200 mg/day groups, respectively, versus 19% in the placebo group. In both studies, there were no apparent differences in treatment effect within age, gender, or racial subgroups.

Figure 1:

Reduction in 4-Week Migraine Headache Frequency

Topiramate Topiramate Topiramate

Additional efficacy measures that were assessed, in both studies, included responder rate, cumulative response rate, change in average monthly migraine attack rate, change in the average monthly rate of rescue medication use, change in the average number of monthly migraine days and onset of action defined as the earliest month that there was a statistically significant difference between each topiramate treatment group and placebo with respect to the primary efficacy endpoint that was maintained for the remainder of the double-blind phase.

Bioequivalency Study

A bioequivalence study was performed to compare Gen-Topiramate tablets against Topamax(r) tablets. The study was a randomized, 2-period, 2-sequence, single-dose, crossover, comparative bioavailability study. The pharmacokinetic data are presented in Table 11.

TABLE 11: SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

* * expressed as arithmetic mean (CV%) only.

+ Brand leader Topamax, manufactured by Ortho-McNeil Pharmaceutical, U.S.A.

DETAILED PHARMACOLOGY

Preclinical

In Vitro Studies

Electrophysiological and biochemical studies on cultured neurons have revealed three properties that may contribute to the antiepileptic efficacy of topiramate. Action potentials elicited repetitively by a sustained depolarization of the neurons were blocked by topiramate in a time-dependent manner, suggestive of a state-dependent sodium channel blocking action. Topiramate increased the frequency at which (- aminobutyrate (GABA) activated GABAA receptors, and enhanced the ability of GABA to induce a flux of chloride ions into neurons, suggesting that topiramate potentiates the activity of this inhibitory neurotransmitter. Because the antiepileptic profile of topiramate differs markedly from that of the benzodiazepines, it may modulate a benzodiazepine-insensitive subtype of GABAA receptor. Topiramate antagonized the ability of kainate to activate the kainate/AMPA ("-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) subtype of excitatory amino acid (glutamate) receptor, but had no apparent effect on the activity of N- methyl-D-aspartate (NMDA) at the NMDA receptor subtype. These effects of topiramate were concentration-dependent over a range of 1 :M to 200 :M, with minimum activity observed at 1 :M to 10

:M. In addition, topiramate inhibits some isoenzymes of carbonic anhydrase. This pharmacologic effect is much weaker than that of acetazolamide, a known carbonic anhydrase inhibitor, and is not thought to be a major component of topiramate *s antiepileptic activity.

In Vivo Studies

Pharmacodynamics

Topiramate was initially found to possess anticonvulsant activity in the maximal electroshock seizure (MES) test in mice. Subsequent studies revealed that topiramate was also highly effective in the MES test in rats. In both species, anticonvulsant activity was evident within 30 minutes after oral administration, reached a peak 1 to 6 hours after dosing, and gradually declined thereafter. Topiramate *s anticonvulsant activity in rodents was further evaluated using chemical convulsants (pentylenetetrazole, bicuculline, picrotoxin, strychnine) to induce clonic or tonic seizures. Topiramate was either weak or inactive in blocking chemically induced seizures. Topiramate was found to effectively block seizures in mouse and rat models of hereditary epilepsy, in some animal models of kindled epilepsy, and in a rat model of stroke-induced epilepsy. In the spontaneous epileptic rat (SER) model of hereditary epilepsy, topiramate blocked the clonic motor seizures and the absence-like seizures monitored by EEG recordings. The potency of topiramate in blocking MES seizures is similar to that of phenytoin and carbamazepine, and much greater than that of valproate. The oral ED50 of topiramate at the time of peak activity was 20 to 50 mg/kg in mice and 5 to 15 mg/kg in rats. Studies in mice receiving concomitant administration of topiramate and carbamazepine or phenobarbital showed synergistic anticonvulsant activity, while combination with phenytoin showed additive anticonvulsant activity. An investigation of the possible development of tolerance to the anticonvulsant activity revealed no tolerance in rats dosed orally with topiramate for 14 days at twice the ED50 value. When mice were dosed orally for 5 days at four times the ED50 value, a small but significant degree of tolerance did occur. Topiramate was examined for effects on central nervous system (CNS) function, particularly reflex activity and motor co-ordination. A quantitative measure of CNS impairment was obtained by calculating the dose required to cause a loss of righting reflex (LRR) in either 3% (TD3) or 50% (TD50) of mice tested, or the dose that caused 50% (TD50) of mice or rats to be unable to remain ambulatory on a rotating rod or reel. A protective index (PI) was obtained by calculating the ratio of the TD50 dose to the ED50 dose in the MES test (or the TD3 dose to the ED97 dose). The calculated PI values for topiramate compared favourably to those of the reference anticonvulsants phenytoin, carbamazepine, valproate (divalproex), and phenobarbital, particularly in rats. An evaluation of acute effects in dogs indicated that impairment of CNS function occurred only at doses several times the ED50 dose in the MES test in rats and mice. Topiramate was evaluated for effects on general behaviour in mice, rats, and dogs at doses ranging from 10 to 1,000 mg/kg. Dose-related effects in mice and rats included a decrease in spontaneous motor activity, and a decrease in body tone and respiratory activity. In dogs, emesis occurred in one of three dogs at 100 mg/kg (p.o. ), and at 500 mg/kg (p.o.) one of three dogs exhibited preconvulsant activity and one of three convulsed. Recovery was complete at six hours after dosing. When administered i.v. to rats at doses ranging from 1 mg/kg to 10 mg/kg, topiramate had no effect on EEG activity, cerebral pH, spinal reflexes, or neuromuscular conduction. In mice, topiramate at doses of 30 mg/kg (p.o.) or greater prolonged pentobarbital-induced sleep time threefold to eightfold in a dose-dependent manner. In rats pretreated with topiramate at 60 mg/kg or 200 mg/kg (p.o.) one hour prior to inducing sleep with ethanol, sleep time was prolonged 38% and 54%, respectively. When rats were pretreated with these doses of topiramate four hours prior to inducing sleep with ethanol, there was no prolongation of sleep time. In cardiovascular studies, topiramate, when given i.v. to anesthetized dogs at doses up to 10 mg/kg, caused a small, dose-related increase in blood pressure, which was associated with a slight decrease in heart rate. There was no effect on electrocardiographic measures at these doses. Topiramate, when administered to spontaneously hypertensive rats at doses of 30 mg/kg i.p. and 100 mg/kg p.o. caused a biphasic response in mean arterial pressure; an initial transient increase was followed by a modest decrease in blood pressure that persisted for about 12 hours. Topiramate, at concentrations up to 10 :M, elicited no biologically significant effects on coronary flow, contractile force, or flow rate in the isolated guinea pig heart. In GI studies, topiramate at concentrations up to 100 :M had no effect on basal or pentagastrin-stimulated gastric acid secretion in the isolated mouse stomach assay. Topiramate weakly inhibited gastric acid secretion in rats and dogs. Topiramate and acetazolamide were examined for effects on renal function using rats anesthetized with pentobarbital. Both compounds were infused i.v. at 9 or 90 :M/kg/h. At each dose, both compounds produced changes in renal function, including an increase in urinary flow rate, solute clearance and urinary pH. Also, a decrease in urinary osmolality and decreases in arterial blood pH and plasma bicarbonate concentration were observed. The effects of both dosage levels of topiramate were similar to, but less than, those of acetazolamide. Renal vascular resistance, heart rate, and glomerular filtration rate did not differ from pretreatment control values.

Pharmacokinetics

Studies performed in rats and dogs employing 14C-topiramate show that topiramate is rapidly and well absorbed after oral administration and that unchanged topiramate is the major component in plasma for several hours after dosing. The absolute bioavailability of topiramate is approximately 100% in male and female rats. Topiramate is poorly bound to plasma proteins (9% to 17%) in the mouse, rat, rabbit, dog, and monkey, but there appears to be a low capacity erythrocyte binding site for the drug in all species studied. Studies in rats show that following oral administration of 14C-topiramate total radioactivity does not accumulate in any tissue. Topiramate did distribute across the blood-brain barrier, with brain tissue concentrations of total radioactivity being about 40% of plasma concentrations 6 hours after a single oral dose. The metabolism of topiramate has been investigated in mice, rats, rabbits and dogs. The metabolic pathways, primarily hydroxylation or hydrolysis of the isopropylidene groups and subsequent conjugation, were qualitatively similar in all species studied. The major route of elimination of unchanged topiramate and its metabolites in all species studied is via the kidney. All species excreted a significant proportion of the dose in urine as intact topiramate; however the proportion of metabolites excreted tended to be higher in species with shorter plasma half-lives.

TOXICOLOGY

In acute and long-term studies conducted in mice, rats, dogs, and rabbits, exposure to topiramate was well tolerated.

Acute Toxicity

Table 12:

Acute Toxicity Studies Performed with Topiramate

Chronic Toxicity

Table 13:

Multiple-Dose Toxicity Studies

recovery periods

associated with tumor formation in the presence of high gastrin levels). During recovery phase, all changes were reversible.

Species/Strain Sex

Route of administra- tion

No. Animals/ Group

M/F

Dosage (mg/kg/day)

Duration Results

Dog/Beagle Male & Female

p.o 4/4 10, 40, 150 3 months

Lower

weight gain, food

consumption, and food efficiency;

hemodilution; lower transaminases and urine specific gravity; higher urine pH, serum alkaline phosphatase and chloride; and higher liver weights. No significant morphological changes. Observations essentially at 40 and 150 mg/kg per day only.

Dog/Beagle Male & Female

p.o 4/4 10, 30, 100 12 months S

poradic emesis at all dosage levels.

Lower body weight gain;

hemodilution; higher urine pH, serum alkaline phosphatase and chloride; and higher liver weights. No significant morphologic changes. Only findings seen below 100 mg/kg per day were emesis, and higher alkaline phosphatase and chloride.

Reproductive Toxicity

Despite maternal and paternal toxicity as low as 8 mg/kg/day, no effects on fertility were observed in male or female rats dosed up to 100 mg/kg/day. As with other antiepileptic drugs, topiramate was teratogenic in mice, rats and rabbits. In mice, fetal weights and skeletal ossification were reduced at 500 mg/kg/day in conjunction with maternal toxicity. Overall numbers of fetal malformations in mice were increased for all drug-treated groups (20, 100, and 500 mg/kg/day), but no significant differences or dosage-response relationships were observed for overall or specific malformations, suggesting that other factors such as maternal toxicity may be involved. In rats, dosage-related maternal and embryo/fetal toxicity (reduced fetal weights and/or skeletal ossification) were observed down to 20 mg/kg/day with teratogenic effects (limb and digit defects) at 400 mg/kg/day and above. In rabbits, dosage-related maternal toxicity was noted down to 10 mg/kg/day with embryo/fetal toxicity (increased lethality) down to 35 mg/kg/day, and teratogenic effects (rib and vertebral malformations) at 120 mg/kg/day. The teratogenic effects seen in rats and rabbits were similar to those seen with carbonic anhydrase inhibitors, which have not been associated with malformations in humans. Effects on growth were also indicated by lower weights at birth and during lactation for pups from female rats treated with 20 or 100 mg/kg/day during gestation and lactation. In rats, topiramate crosses the placental barrier. In studies of rats where dams were allowed to deliver pups naturally, no drug-related effects on gestation length or parturition were observed at dosage levels up to 100 mg/kg/day.

Carcinogenicity

Tumours of smooth muscle origin in the urinary bladder were seen only in mice (oral dosages up to 300 mg/kg for 21 months) and appear to be unique to the species. Since no human counterpart exists, they were not considered clinically relevant. No such findings occurred in the rat carcinogenicity study (oral dosages up to 120 mg/kg/day for 24 months).

Mutagenicity

In a battery of in vitro and in vivo mutagenicity assays, topiramate did not show genotoxic potential.

REFERENCES

1. Rangel RJ, Penry JK, Wilder BJ, et al. Topiramate: A new antiepileptic drug for complex partial seizures - first use in epileptic patients. Neurology 1988; 38:234.

2. Ostergaard L, Dam M, Mikkelsen M. Topiramate as add-on therapy in refractory partial epilepsy.

Epilepsia 1992; 33(Suppl 3):105. Anon. Topiramate, MCN-4853, RWJ-17021-000, EN=105605. Drugs of the Future. 1990; 15:432. Aranguiz C, McJilton J, Vega M, Ramsay RE. Safety and effectiveness of three oral doses of topiramate in the treatment of patients with refractory partial epilepsy. Epilepsia 1991; 32:11. Fincham R, Schottelius D, Faught E, Kuzniecky R, Thompson G. Efficacy and safety of topiramate (TPM) as adjunctive therapy in adults with refractory partial epilepsy (RPE). Neurology 1992; 42:311. Rosenfeld WE, Holmes GB, Hunt TL, Schaefer P. Topiramate-effective dosaging enhances potential for success. Epilepsia 1992; 33:118. Ben-Menachem E. Double-blind placebo-controlled trial of topiramate as add-on therapy for the treatment of complex partial seizures. Epilepsia 1992; 33:105. Ben-Menachem E, Mikkelsen M, Dam M, Engelskjon T, Henriksen O, Johanessen SI, Schmidt D, Ried S, Proest G. Topiramate add-on treatment in patients with intractable partial epilepsy: a multicenter study. Epilepsia 1993; 34:109. Faught E, Wilder BJ, Ramsay RE, et al. Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy using 200-, 400-, and 600-mg daily dosages. Neurology 1996; 46: 1684- 1696. Ben-Menachem E. Topiramate: European studies in partial epilepsy. Abstract of a paper presented at the 20th International Epilepsy Congress, Oslo, Norway, July 4, 1993. Ben-Menachem E. Double-blind placebo-controlled study of topiramate for the treatment of complex partial seizures. Abstract of a paper presented at the European Epilepsy Mtg., Glasgow, Scotland, September 1-5, 1992. Engelskjon T, Johannessen SI, Kloster R, Lossius R, Nakken KO, Henriksen O. Topiramate in the treatment of refractory partial epilepsy - an efficacy and tolerance study. Abstract of a paper presented at the European Epilepsy Mtg., Glasgow, Scotland, September 1-5, 1992. Henriksen O . The safety and clinical tolerability of topiramate. Abstract of a paper presented at the 20th International Epilepsy Congress, Oslo, Norway, July 4, 1993. Doose DR, Scott VV, Marchgul BL, et al. Multiple-dose pharmacokinetics of topiramate in healthy male subjects. Epilepsia 1988; 29(5):662. Easterling DE, Zakszewski T, Moyer MD, et al. Plasma pharmacokinetics of topiramate, a new anticonvulsant in humans. Epilepsia 1988; 29(5):662. Wilder BJ, Penry JK, Rangel RJ, et al. Topiramate: Efficacy, toxicity, and dose/plasma concentrations. Epilepsia 1988; 29(5):698. Wilensky AJ, Ojemann LM, Chmelir T, et al. Topiramate pharmacokinetics in epileptic patients receiving carbamazepine. Epilepsia 1989; 30(5): 645-646. Floren KL, Graves NM, Leppik IE, et al. Pharmacokinetics of topiramate in patients with partial epilepsy receiving phenytoin or valproate. Epilepsia 1989; 30(5):646. Levy RH. The clinical pharmacokinetics of topiramate. 20th International Epilepsy Congress, Oslo, Norway, July 4, 1993. Marchyanoff BE, Marchgul BL. Topiramate. Drugs of the Future 1989; 14(4):342-344. Nakamura J, Tamura S, Ishii A. Inhibition of tonic and absence-like seizures in spontaneously epileptic rats by a novel antiepileptic drug topiramate (KW6485). Jap J Pharmacol 1992; 58:321. Tanabe K, Wang Y, Kimishima K. Anticonvulsant activities and properties of topiramate. J Yonago Medical Assoc 1991; 42(6):330-346. Edmonds H, Jiang D, Zhang P, Vaught JL. Topiramate in a rat model of post-traumatic epilepsy. Epilepsia 1991; 32:15. Kanda T, Nakamura J, Kurokawa M, et al. Inhibition of excessive releases of excitatory amino acids in hippocampus of spontaneously epileptic rat (SER) by topiramate (KW-6485). Jap J Pharmacol 1992; 58:92. Coulter DA, Sombati S, DeLorenzo RJ. Selective effects of topiramate on sustained repetitive firing and spontaneous bursting in cultured hippocampal neurons. Epilepsia 1993; 34(Suppl 2):123. Brown SD, Wolf HH, Swinyard EA, Twyman RE, White HS. The novel anticonvulsant topiramate enhances GABA-mediated chloride flux. Epilepsia 1993; 34(Suppl 2):122-3. Vaught JL, Marchyanoff BE, Shank R. The pharmacological profile of topiramate: A structurally novel, clinically effective anticonvulsant. Epilepsia 1991; 32:19. Shank RP, Vaught JL, Raffa RB, Marchyanoff BE. Investigation of the mechanism of topiramate *s anticonvulsant activity. Epilepsia 1991; 32:7-8. Edmonds HL, Jiang D, Zhang YP, Shank RP. Topiramate as a neuroprotectant and anticonvulsant in post-ischemic injury. Epilepsia, December 6-9, 1992; 33:118-119. No Authors listed in citation. Topiramate. Drugs of the Future 1993; 18:4:398. Kramer LD. The preclinical profile of topiramate: a structurally novel antiepileptic drug. In: Abstracts. Topiramate: a promising new agent for the treatment of epilepsy (a satellite symposium of the 20th International Epilepsy Congress), Oslo, Norway, July 4, 1993. Privitera M, Fincham R, Penny J, et al. Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy using 600-, 800- and 1,000- mg daily dosages. Neurology 1996; 46: 1678- 1683. Ben-Menachem E, Henriksen O, Dam M, et al. Double-blind, placebo-controlled trial of topiramate as add-on therapy in patients with refractory partial seizures. Epilepsia 1996; 37:539-543. Tassinari CA, Michelucci R, Chauvel P, et al. Double-blind, placebo-controlled trial of topiramate (600 mg daily) for the treatment of refractory partial epilepsy. Epilepsia 1996; 37:763-768. Rosenfeld B, Abou-Khalil B, Reife R, et al. Placebo-controlled trial of topiramate as adjunctive therapy to carbamazepine or phenytoin for partial-onset epilepsy. Epilepsia 1996; 37 (Suppl 5): 153. Special Advisory Committee on Reproductive Physiology to the Drugs Directorate, Health Protection Branch, Health Canada. Oral Contraceptives 1994. Dulac O, N *Guyen T. The Lennox-Gastaut syndrome. Epilepsia 1993; 34 (Suppl 7): S7-S17. Reife RA. Topiramate: a novel antiepileptic agent. In: Shorvon S, Dreifuss F, Fish D, and Thomas D (eds), The Treatment of Epilepsy. Cambridge, MA: Blackwell Science Ltd.; 1996:1-11. Dodson WE, Bourgeois BFD. Pharmacology and therapeutic aspects of antiepileptic drugs in paediatrics. J Child Neurol 1994; 9 (Suppl):2S1-2S7. Biton V, Reife R, Kamin M, Bobroshy K. Topiramate (TOPAMAX) as add-on therapy for patients with primary generalized epilepsy. Neurology 1996; 46:A176. Glauser TA. Topiramate. Seminars in Pediatric Neurology 1997; 4(1):34-42. Elterman RD, Glauser RA, Wyllie E. et al. A double-blind, randomized trial of topiramate as adjunctive therapy for partial-onset seizures in children (Study YP). Neurology April 1999; 52(7): 1338-1344. Topiramate Clinical Trial in Children with Partial Onset Seizures (Study YP) Open-Label Extension. The R.W. Johnson Pharmaceutical Research Institute, Data on file, 1998. Sachdeo RC, Glauser TA, Ritter F et al. A Double-Blind, randomized trial of topiramate in Lennox- Gastaut Syndrome (Study YL). Neurology June 1999; 52(9): 1882-1887. A Double-Blind Trial of Topiramate in Subjects with Lennox-Gastaut Syndrome (Study YL) Open- Label Extension. The R.W. Johnson Pharmaceutical Research Institute, Data on file, 1998. Biton V, Montouris GD, Ritter R et al. A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic (Study YTC). Neurology April 1999; 52(7):1330-1337. Topiramate Clinical Trial in Primary Generalized Tonic-Clonic Seizures (Study YTCE) Open-Label Extension. The R.W. Johnson Pharmaceutical Research Institute, Data on file, 1998. JWAS Sander. Practical aspects of the use of topiramate in patients with epilepsy. Epilepsia 1997; 38 (Suppl 1): S56-S58. Banta J, Hoffman K, Budenz D, Ceballos E, Greenfield D. Presumed topiramate-induced bilateral acute angle-closure glaucoma. American Journal of Ophthalmology 2001; 132(1): 112-114. Sen H, O *Halloran H, Lee W. Topiramate-induced acute myopia and retinal striae. Arch. Ophthalmol. 2001; 119(5): 775-777. Aldenkamp AP, Baker G, Mulder OG, et al. A multicenter, randomized clinical study to evaluate the effect on cognitive function of topiramate compared with valproate as add-on therapy to carbamazepine in patients with partial-onset seizures. Epilepsia 2000; 41(9):1167-1178. Baker GA, Currie NG, Light MJ, Schneiderman JH. The effects of adjunctive topiramate therapy on seizure severity and health-related quality of life in patients with refractory epilepsy - a Canadian study. Seizure 2002; 11(1): 6-15. Stephen LJ, Sills GJ, Brodie MJ. Topiramate in refractory epilepsy: a prospective observational study. Epilepsia 2000; 41(8): 977-980. Rosenfeld, WE, Slater, J. Characterization of topiramate-associated weight changes in adults with epilepsy. AES Proceedings. Epilepsia 2001; 42(7):252. Naritoku DK, Hulihan JF, Kamin M et al. Reduction of AED Co-therapy improves tolerability of add-on therapy with topiramate: A novel randomized study. AES Proceedings. Epilepsia 2001; 42(7):258. Ben-Menachem E, Smith U, Hellstrom K et al. Predictors of weight loss in patients with epilepsy treated with topiramate. AES Proceedings. Epilepsia 2002; 43(7):220-221.

International Headache Society. The international classification of headache

disorders.

Cephalgia 2004; 24(Supplement 1):1-160. Silberstein SD, Neto W, Schmitt J, Jacobs DJ. Topiramate in migraine prevention: Results of a large controlled trial. Arch Neurol 2004; 61:490-495. Brandes JL, Saper JR, Diamond M et al. Topiramate for migraine prevention: A randomized controlled trial. JAMA 2004; 291:965-973. Diener H-C, Tfelt-Hansen P, Dahlof C et al. Topiramate in migraine prophylaxis: Results from a placebo-controlled trial with propranolol as an active control. J Neurol 2004; 251:943-950. Product Monograph for TOPAMAX, May 9, 2005. Janssen-Ortho Inc. IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION

Pr

Gen-Topiramate

topiramate

This leaflet is part III of a three-part "Product Monograph" published when Gen-Topiramate was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about Gen-Topiramate. Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

Gen-Topiramate has been prescribed to you/your child to control epilepsy.

Gen-Topiramate may also be prescribed to you to prevent your migraine headaches if you are an adult patient (over 18 years of age) with 4 or more attacks per month and are not responding to acute treatment.

What it does:

Gen-Topiramate affects chemicals in the brain that are involved in sending signals to the nerves. Gen-Topiramate belongs to a group of medicines used to treat epilepsy.

When it should not be used:

You/your child should not use Gen-Topiramate if you are allergic to any of the ingredients in the product. Contact your doctor immediately if you experience an allergic reaction

(e.g. skin rash, hives) or any severe or unusual side effects.

Topiramate should not be used for:

• the prevention of other types of headaches that are different from migraine attacks.

• the acute treatment of migraine headache.

What the medicinal ingredient is

: topiramate

What the nonmedicinal ingredients are:

Gen-Topiramate (topiramate) Tablets contain the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, and titanium dioxide. The 25 mg tablets also contain hypromellose, polyethylene glycol 400 and polysorbate 80. The 100 mg tablets also contain

hypromellose, iron oxide yellow, lactose monohydrate, and triacetin. The 200 mg tablets also contain iron oxide red, polyethylene glycol, polyvinyl alcohol, and talc.

What dosage forms it comes in

: 25 mg, 100 mg and 200 mg tablets

WARNINGS AND PRECAUTIONS

BEFORE you use Gen-Topiramate talk to your doctor or pharmacist if:

• you drive a vehicle, use machines, perform hazardous tasks during your work or do anything else that could be dangerous if you are not alert.

• if you/your child have or have had kidney stones or kidney disease. Your doctor may want you to increase the amount of fluids you/your child drink(s) while you are taking this medicine.

• any medical problems and any allergies you/your child have or have had in the past.

you are pregnant, or if you are planning to become pregnant.

you are breast-feeding (nursing).

you/your child are taking medicines that slow down the nervous system (CNS depressants).

you/your child are taking oral contraceptives and Gen-Topiramate Tablets, tell your doctor about any changes in your bleeding patterns (breakthrough bleeding/spotting).

you are taking a ketogenic diet (a diet high in fat and low in protein and sugar)

your consume alcohol regularly

Other Precautions:

Gen-Topiramate may cause some people to be less

alert than normal. Make sure you know how you/your child are affected by this medication before you drive, use machines, or do anything else that could be dangerous if you are not alert.

Gen-Topiramate may reduce the efficacy of oral contraceptives even in the absence of breakthrough bleeding. Therefore, oral contraceptives containing not less than 30 :g of estrogen should be used.

A very small number of people may have thoughts of suicide. Rarely, blood tests have shown a slight increase in acidity. In

many cases, there are no symptoms from this increased

acidity but some people may experience symptoms such as rapid breathing, persistent lack of energy and loss of appetite. Some people may experience more serious symptoms such as heart problems, confused thinking or reduced consciousness.

INTERACTIONS WITH THIS MEDICATION

Tell your doctor about all medications (prescription and non- prescription) and dietary supplements you/your child are using. It is especially important that your doctor know if you/your child are taking digoxin, oral contraceptives, or any other antiepileptic drugs, such as phenytoin, valproate or carbamazepine.

PROPER USE OF THIS MEDICATION

Gen-Topiramate is usually taken twice a day; however, your doctor may tell you to take it once a day or at a higher or lower dose. Never increase or decrease the amount of Gen- Topiramate you are taking unless your doctor tells you to.

Swallow the Tablets and take with plenty of water. You/your child can take the Tablets with or without food. Do not break or crush your tablets.

Always check that you have enough Tablets and do not run out. Do not suddenly stop taking this medicine without first checking with your doctor.

Epilepsy

It is important that you take Gen-Topiramate exactly as your doctor has instructed. Your doctor will start with a low dose and slowly increase the dose to the lowest amount needed to control your/your child *s epilepsy.

Usual dose:

Gen-Topiramate taken alone:

The usual maintenance dose in adults and children (6 years of age and older) is between 100 mg/day and 400 mg/day.

Gen-Topiramate is usually taken twice a day.

Gen-Topiramate taken in combination with other antiepileptic drugs:

The usual adult maintenance dose is 200 mg to 400 mg per day.

In children, dosing is based on weight and the dose is approximately 5 to 9 mg/kg/day.

Migraine

It is important that you follow your doctor's instructions carefully to help reduce the chances of getting a migraine headache. Your doctor will start treatment with a dose of 25 mg to be taken at night. Your doctor will then increase your dose to the lowest amount needed to prevent migraine headaches.

Usual dose:

The usual adult dose is 100 mg per day. Topiramate is taken twice a day (50 mg in the morning and 50 mg at night). Your doctor may tell you to use a lower or higher dose.

Remember: This medicine has been prescribed for you/your child. Do not give it to anybody else.

Overdose:

If you/your child accidentally take(s) an overdose of Gen-Topiramate, contact your doctor or the nearest hospital or Emergency Room, even though you/your child may not feel sick.

Missed Dose:

If you/your child miss a dose, take it as soon as you remember. But, if it is almost time for the next dose, do not take the missed dose. Instead, take the next scheduled dose. Do not try to make up for the missed dose by taking a double dose next time.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Any medicine may have unwanted effects. Tell your doctor or pharmacist about any unusual sign or symptom whether listed or not.

Contact your doctor immediately or go to the Emergency Room if you/your child experience(s) sudden worsening of vision, blurred vision or painful/red eye(s).

Decreased sweating may occur while taking Gen-

Topiramate. Make sure you/your child increase and maintain fluid intake prior to and during activities such as exercise and exposure to warm temperatures. Contact your doctor if you/your child are not sweating as usual or show signs of increased body temperature.

• Side effects reported most often in adults were: co- ordination problems, difficulty concentrating, slow thinking, confusion and forgetfulness, dizziness, tiredness, tingling, headache, upper respiratory tract infection (e.g., colds, bronchitis) and drowsiness. Less frequently reported side effects are: agitation, decrease in appetite, speech disorders (e.g. hesitancy or word- finding difficulty), depression, emotional lability, vision disorders (e.g. double vision), mood swings, nausea, taste changes, weight loss and kidney stones (may include symptoms such as blood in the urine, or low back pain or pain in the genital area).

In children, the following side effects were associated with the use of topiramate: difficulty concentrating, forgetfulness, tiredness, drowsiness, nervousness, decrease in appetite, weight loss, upper respiratory tract infection (e.g., colds, bronchitis), headache, fever, tingling and aggressive behaviour.

This is not a complete list of side effects. If you have any unexpected effects while taking this drug, contact your doctor or pharmacist.

HOW TO STORE IT

• Do not use this product after the expiry date written on the package.

• Store between 15-30degC in a dry place.

• Keep this and all medicines in a safe place away from children.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Health Canada by:

toll-free telephone: 866-234-2345

toll-free fax: 866-678-6789

By email: cadrmp @hc-sc.gc.ca

By regular mail:

Canadian Adverse Drug Reaction Monitoring Program (CADRMP)

Health Canada

Address Locator: 0701C Ottawa, ON K1A 0K9

NOTE: Before contacting Health Canada, you should contact your physician or pharmacist.

MORE INFORMATION

This leaflet was prepared by: Genpharm Inc.

Toronto, Ontario M8Z 2S6

The sponsor, Genpharm Inc., can be contacted at: 1-800-575-1397

Email: customerservice @genpharm.ca Last revised: August 29, 2005

Rev. 000-xxx