PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 11 DRUG INTERACTIONS 30 DOSAGE AND ADMINISTRATION 38 OVERDOSAGE 40 ACTION AND CLINICAL PHARMACOLOGY 41 STORAGE AND STABILITY 43 DOSAGE FORMS, COMPOSITION AND PACKAGING 44

PART II: SCIENTIFIC INFORMATION 45

PHARMACEUTICAL INFORMATION 45 CLINICAL TRIALS 45 DETAILED PHARMACOLOGY 52 TOXICOLOGY 54 REFERENCES 58

PART III: CONSUMER INFORMATION 63

Pr

CO

Topiramate

Topiramate

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Antiepileptic drugs, including CO Topiramate (topiramate), should be withdrawn gradually to minimize the potential of increased seizure frequency.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.

Hyperammonemia and Encephalopathy

ADVERSE REACTIONS, Post-Market Adverse Drug Reactions DRUG INTERACTIONS, Drug- Drug Interactions

There have been rare reports of patients, with or without previous history, experiencing hyperammonemia with or without encephalopathy while receiving topiramate alone or in combination with other antiepileptic medications. The majority of these cases indicate that concomitant administration of topiramate and valproic acid is associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse event is not due to a pharmacokinetic interaction. 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, an interaction of topiramate and valproic acid may exacerbate existing defects or unmask deficiencies in susceptible persons (see

and

).

In patients who develop unexplained vomiting, lethargy, confusion or other changes in mental status, hyperammonemic encephalopathy should be considered and serum ammonia levels should be measured.

Carcinogenesis and Mutagenesis

See Product Monograph Part II: TOXICOLOGY, Carcinogenicity and Mutagenicity 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 CO 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. Caution should be used when CO 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 ADVERSE REACTIONS, Post-Market Adverse Drug Reactions).

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 CO 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, CO 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:

1. psychomotor slowing, difficulty with concentration and speech or language problems, in particular, word-finding difficulties

2. somnolence or fatigue and

3. mood disturbances including irritability and depression.

WARNINGS AND PRECAUTIONS, Endocrine and Metabolism).

It has been observed in clinical trials that topiramate treated subjects experienced an average decrease in serum bicarbonate level of 4 mmol/L and an average increase in serum chloride level of 4 mmol/L (See

Hypokalemia Observed During Concomitant Treatment with HydrochlorothiazideWARNINGS AND PRECAUTIONS, Endocrine and Metabolism DRUG INTERACTIONS

: In a drug interaction study with the diuretic hydrochlorothiazide (HCTZ), the percentage of patients with a serum potassium measurement of <3.6 mEq/L was greater at the end of concomitant treatment than at the end of treatment for either drug alone: 27% (3/11) of subjects on topiramate treatment alone and 25% (3/12) of subjects on HCTZ alone versus 61% (14/22) of subjects on concomitant drug treatment. (See

and

).

WARNINGS AND PRECAUTIONS, Endocrine and Metabolism

Oligohidrosis (decreased sweating) has been rarely reported with the use of topiramate. The majority of spontaneous post-marketing reports have been in children. Adverse events that may be related to potential cases of oligohidrosis include dehydration, hyperthermia, and heat intolerance. Adequate hydration prior to activities such as exercise or exposure to warm temperatures is recommended (see

).

To date, there have been rare spontaneous, post-marketing reports of metabolic acidosis. In some cases, acidosis resolved after dosage reduction or upon discontinuation of topiramate (see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism). Rare reports of encephalopathy with or without hyperammonemia have been received for patients treated with topiramate while also taking valproate or other antiepileptic medications (see DRUG INTERACTIONS, General and DRUG INTERACTIONS, Drug-Drug Interactions). Reports of increases in liver function tests in patients taking topiramate with and without other medications have been received. Isolated reports have been received of hepatitis and hepatic failure occurring in patients taking multiple medications while being treated with topiramate. Very rare reports have also been received for bullous skin and mucosal reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme and pemphigus). The majority of these reports have occurred in patients taking other medications that can be associated with bullous skin and mucosal reactions.

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 1.8.

Table 1.8: Drug Interactions with Topiramate Therapy

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 CYP2C19. 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. The effects of these interactions on plasma concentrations are summarized in Table 1.8.

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 of dose 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. The effects of these interactions on plasma concentrations are summarized in Table 1.8. Rare post-marketing reports of encephalopathy with or without hyperammonemia have been received for patients treated with topiramate alone or in combination with valproate or other antiepileptic medications. The majority of the cases reported concomitant administration of topiramate and valproic acid. Thus, caution is advised when polytherapy is necessary (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions and WARNINGS AND PRECAUTIONS, General).

Other Drug Interactions

Digoxin:

In a single-dose study, serum digoxin AUC decreased 12% due to concomitant topiramate administration (200 mg/day). Multiple-dose studies have not been performed. When topiramate is added or withdrawn in patients on digoxin therapy, careful attention should be given to the routine monitoring of serum digoxin.

CNS Depressants:

Concomitant administration of topiramate and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. It is recommended that topiramate not be used concomitantly with alcohol or other CNS depressant drugs.

Oral Contraceptives: Topiramate (50-200 mg/day) in Healthy Volunteers: In a pharmacokinetic interactions study in healthy volunteers, subjects were stratified into obese versus non-obese (n=12 versus n=12) with both groups concomitantly administered a combination oral contraceptive product containing 1 mg norethindrone plus 35 ug ethinyl estradiol and topiramate (50 to 200 mg/day) given in the absence of other medications. For the ethinyl estradiol component, both obese and non-obese volunteers showed a decrease in mean AUC and Cmax at 200 mg/day (-10.7% and -9.4% versus - 15.2% and -11.3%, respectively) that were not statistically significant. Changes in individual subjects ranged from decreases of approximately 35% to 90% in 5 individuals to increases of approximately 35% to 60% in 3 individuals. At the 50 and 100 mg/day topiramate doses, similar changes in mean Cmax and AUC were observed for non-obese volunteers. The clinical significance of these changes is unknown. For the norethindrone component, only the non-obese group showed a decrease (-11.8%). In view of the dose-dependent decreases seen in the ethinyl estradiol component in epileptic patients receiving topiramate as adjunctive therapy (below), and the fact that the recommended dose is up to 400 mg/day, there may be greater decreases seen at doses above 200 mg/day as monotherapy.

Topiramate as Adjunctive Therapy with Valproic Acid in Epileptic Patients:

In a pharmacokinetic interaction study, epileptic patients received topiramate as adjunctive therapy with valproic acid and a combination oral contraceptive product containing norethindrone (1 mg) plus ethinyl estradiol (35 ug ). In this study, topiramate did not significantly affect the oral clearance of norethindrone. The serum levels of the estrogenic component decreased by 18%, 21% and 30% at daily doses of 200, 400 and 800 mg of topiramate, respectively. There are minimal clinical data regarding interaction of valproic acid and oral contraceptives.

In view of both of the above study findings, the efficacy of low-dose (e.g., 20 ug) oral contraceptives may be reduced in both the monotherapy and adjunctive therapy situation with topiramate. For topiramate doses up to 200 mg/day, which includes the recommended dose for migraine prophylaxis of 100 mg/day, the mean reduction in norethindrone and ethinyl estradiol exposure from topiramate treatment is not significant, although marked changes in individual patients are possible. In the treatment of epilepsy at doses greater than 200 mg/day, significant dose-dependent decreases in ethinyl estradiol exposure are expected. Patients on topiramate doses greater than 200 mg/day who are taking oral contraceptives should receive a preparation containing not less than 30 ug of estrogen. Patients taking oral contraceptives should be asked to report any changes in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding. Hydrochlorothiazide (HCTZ): A parallel-arm drug-drug interaction study conducted in healthy volunteers (12 males, 11 females) evaluated the steady-state pharmacokinetics of the diuretic HCTZ (25 mg q24h) and topiramate (96 mg q12h) when administered alone and concomitantly. The results of this study indicate that mean topiramate Cmax increased by 27% and mean AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this statistically significant change is unknown. Thus, the concomitant use of topiramate and HCTZ may require a downward adjustment of the topiramate dose. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. In addition, greater decreases in serum potassium were seen with concomitant treatment than with either drug alone, both in terms of percentage of patients with a serum potassium measurements of <3.6 mEq/L at the end of each treatment period [61% (14/23) with concomitant treatment versus 27% (3/11) with topiramate alone versus 25% (3/12) with HCTZ alone] and in mean change from baseline (approximately -0.60 mEq/L for concomitant treatment versus -0.25 mEq/L for topiramate alone versus -0.12 mEq/L for HCTZ alone). One of the subjects who had hypokalemia with concomitant treatment also had an abnormal ECG (non-specific ST-T wave changes), which may have been related to the decrease in plasma potassium levels. See also WARNINGS AND PRECAUTIONS, Endocrine and Metabolism. Metformin: A drug-drug interaction study conducted in 18 healthy volunteers, ages 18-37, evaluated the steady-state pharmacokinetics of metformin and topiramate in plasma when metformin (500 mg b.i.d.) was given alone and when metformin and topiramate (50, 75 and 100 mg) were given simultaneously for 6 consecutive days. The results of this study indicated that metformin mean Cmax and mean AUC0-12h increased by 18% and 25%, respectively, while mean CL/F decreased 20% when metformin was co-administered with topiramate (up-titrated to 100 mg b.i.d. ). Topiramate did not affect metformin tmax. The effects of higher doses of topiramate (>100 mg b.i.d) on metformin are unknown. The clinical significance of the effect of topiramate on metformin pharmacokinetics is unclear. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The extent of change in the clearance is unknown. The clinical significance of the effect of metformin on topiramate pharmacokinetics is unclear. When topiramate is added or withdrawn in patients on metformin therapy, careful attention should be given to the routine monitoring for adequate control of their diabetic disease state. Glyburide: A drug-drug interaction study conducted in 28 patients with type 2 diabetes, ages 38- 68 years and BMIs 25-40 kg/m2, evaluated the steady-state pharmacokinetics of glyburide and topiramate in plasma when glyburide (5 mg/day) was given alone and when glyburide and topiramate (150 mg/day) were given concomitantly for 48 consecutive days. Glyburide systemic exposure was statistically significantly reduced when combined with topiramate such that mean Cmax and mean AUC24 decreased by 22% and 25%, respectively, while mean CL/F increased by 21%. Systemic exposure of the active metabolites, 4-trans-hydroxyglyburide and 3-cis-hydroxyglyburide, was also statistically significantly reduced by 13% and 15%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide. The clinical significance of the effect of glyburide on topiramate pharmacokinetics is unclear. Mild to moderate declines in serum bicarbonate without metabolic acidosis were associated with the addition of topiramate (see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Metabolic Acidosis). The effects of higher doses of topiramate (>150 mg/day) on glyburide are unknown. When topiramate is added to glyburide therapy or glyburide is added to topiramate therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state. Pioglitazone: A drug-drug interaction study conducted in healthy volunteers (26 males, 26 females) evaluated the steady-state pharmacokinetics of topiramate and the antidiabetic agent, pioglitazone, when administered alone and concomitantly. The pharmacokinetic parameters of topiramate were not affected; mean pioglitazone AUC decreased by 15%, mean Cmax increased non-significantly by 10% but with individual subjects showing large increases, and 3 of the 4 highest values were recorded by males. In addition, each of the active hydroxy-metabolite and the active keto-metabolite showed mean decreases in Cmax and AUC (approximately 15% for the hydroxy-metabolite and 60% for the keto-metabolite). The clinical significance of these findings is not known. When topiramate is added to pioglitazone therapy or pioglitazone is added to topiramate therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.

Lithium:

Healthy Volunteers

A drug-drug interaction study conducted in twelve healthy volunteers, ages 20-40 years, evaluated the steady-state pharmacokinetics of lithium in plasma when lithium (300 mg q8h) was administered for 14 days and topiramate (up-titrated to 100 mg q12h) was given concomitantly for the last 6 days. Based on the data analysis of twelve subjects, systemic exposure of lithium was statistically significantly reduced in the presence of topiramate such that Cmax and AUC 0-8h decreased by 20% and 18%, respectively, while mean CL/F and CLR increased by 36% and 12%, respectively. One subject did not have measurable trough lithium concentrations on Day 14, potentially indicating missed dose administration. By excluding this subject from the analyses, systemic exposure of lithium was slightly reduced in the presence of topiramate (12% for Cmax, 10% for AUC0-8) while mean CL/F and CLR increased by 11% and 16%, respectively. The clinical significance of the effect of topiramate on lithium pharmacokinetics is unclear. The effects of higher doses of topiramate (>200 mg/day) on the pharmacokinetics of lithium are unknown.

Patients with Bipolar Disorder

A drug-drug interaction study conducted in 31 patients with various types of bipolar disorder, ages 20-60 years, evaluated the steady-state pharmacokinetics of lithium and topiramate when administered concomitantly. Subjects were randomized to receive either low doses of topiramate of up to 200 mg/day or high doses of topiramate of up to 600 mg/day. Pharmacokinetic profiles for lithium were obtained following 1 week and 3 weeks of continuous lithium dosing. The pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of up to 200 mg/day, and were unaffected by short-term treatment with topiramate (1 week) at doses up to 600 mg/day. Following treatment with topiramate at doses of up to 600 mg/day for 3 weeks, there was an observed statistically significant increase in systemic exposure of lithium (about 27% for both Cmax and AUC). Topiramate exposure for both the low and high dose groups was similar following 1 week and 3 weeks of continuous treatment in the presence of lithium. The effects of higher doses of topiramate (>600 mg/day) on lithium have not been studied and are unknown. Lithium levels should be monitored when co-administered with topiramate and dose adjustments for lithium should be based on both lithium levels and clinical outcome for the patient.

Risperidone

: Healthy Volunteers

A drug-drug interaction study was conducted in 12 healthy volunteers (6 males, 6 females), ages 28-40 years, with single-dose administration of risperidone (2 mg) and multiple doses of topiramate (titrated up to 200 mg/day). In the presence of topiramate, systemic exposure of the total active moiety (risperidone + 9-hydroxyrisperidone) was reduced such that the mean AUC0-4 was 11% lower and mean Cmax was statistically significantly (18%) lower. In the presence of topiramate, systemic exposure of risperidone was statistically significantly reduced such that mean Cmax and AUC 0-4 were 29% and 23% lower, respectively. The pharmacokinetics of 9- hydroxyrisperidone were unaffected. The effects of a single dose (2 mg/day) of risperidone on the pharmacokinetics of multiple doses of topiramate have not been studied. Therefore, patients receiving risperidone in combination with topiramate should be closely monitored for clinical response to risperidone.

Patients with Bipolar Disorder

A drug-drug interaction study conducted in 52 patients with various types of bipolar disorder (24 males, 28 females), ages 19-56 years, evaluated the steady-state pharmacokinetics of risperidone and topiramate when administered concomitantly. Eligible subjects were stabilized on a risperidone dose of 1 - 6 mg/day for 2 to 3 weeks. Topiramate was then titrated up to escalating doses of 100, 250 and 400 mg/day along with risperidone for up to 6 weeks. Risperidone was then tapered and discontinued over 4 weeks while maintaining topiramate (up to 400 mg/day). There was a statistically significant reduction in risperidone systemic exposure (16% and 33% for AUC12 and 13% and 34% for Cmax at the 250 and 400 mg/day doses, respectively). Minimal alterations were observed in the pharmacokinetics of the total active moiety (risperidone plus 9- hydroxyrisperidone) and 9-hydroxyrisperidone. Topiramate systemic exposure was slightly reduced (12.5% for mean Cmax and 11% for mean AUC12) in the presence of risperidone, which achieved statistical significance. There were no clinically significant changes in the systemic exposure of the risperidone total active moiety or of topiramate. The effects of higher doses of topiramate (>400 mg/day) are unknown. Patients with bipolar disorder receiving risperidone in combination with topiramate should be closely monitored for clinical response to risperidone.

Haloperidol:

The pharmacokinetics of a single dose of the antipsychotic haloperidol (5 mg) were not affected following multiple dosing of topiramate (200 mg/day) in 13 healthy adults (6 males, 7 females).

Venlafaxine: A drug-drug interaction study was conducted in 26 healthy volunteers (16 males / 10 females, ages 18-40 years, BMI ranging from 25 to 30 kg/m2) to evaluate the interaction between venlafaxine and topiramate. Subjects received single 150-mg doses of extended release venlafaxine and multiple doses of topiramate titrated up to 150 mg/day. The single-dose pharmacokinetics of venlafaxine were unaffected by treatment with topiramate. While the Cmax, AUC4 and CL/F of the active metabolite O-desmethylvenlafaxine were unaffected, the renal clearance of the active metabolite was increased by 53% during treatment with topiramate. These observed increases in urinary excretion of O-desmethylvenlafaxine during treatment with topiramate did not affect systemic exposure. The steady-state pharmacokinetics of topiramate were unaffected by repeated daily-dose administration of venlafaxine for 5 days. The effects of higher doses of topiramate (>150 mg/day) on the pharmacokinetics of venlafaxine and higher doses of venlafaxine up to the maximum dose of 375 mg/day on the pharmacokinetics of topiramate are unknown. Amitriptyline: There was a 12% increase in both AUC and Cmax for the tricyclic antidepressant amitriptyline (25 mg/day) in 18 normal subjects (9 males, 9 females) receiving 200 mg/day of topiramate. Individual subjects experienced large changes in amitriptyline concentration, either up or down, in the presence of topiramate; any adjustments in amitriptyline dose should be made according to patient's clinical response and not on the basis of plasma levels.

Pizotifen:

Multiple dosing of topiramate (200 mg/day) in 19 healthy volunteers (12 males, 7 females) had little effect on the pharmacokinetics of the anti-histamine pizotifen following daily

1.5 mg doses. There was a mean 12% and 15% decrease respectively in topiramate Cmax and AUC in the volunteers (12 males and 7 females) receiving 200 mg/day topiramate and 1.5 mg/day pizotifen. This is not considered to be clinically significant.

Dihydroergotamine:

Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (12

males, 12 females) had little effect on the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine and a 1 mg subcutaneous dose of dihydroergotamine similarly had little effect on the pharmacokinetics of a 200 mg/day dose of topiramate.

Sumatriptan:

Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (14 males, 10 females) had little effect on the pharmacokinetics of single doses of the anti-migraine medication, sumatriptan, either orally (100 mg) or subcutaneously (6 mg).

Propranolol: Multiple dosing of topiramate (100, then 200, mg/day) in 34 healthy volunteers (17 males, 17 females) had little effect on the pharmacokinetics of propranolol following daily 160 mg doses. There was a 17% increase in Cmax of the metabolite 4-OH propranolol at 100 mg/day topiramate. Propranolol doses of 80, then 160 mg/day in 39 volunteers (27 males, 12 females) had a dose-dependent effect on exposure to topiramate (200 mg/day), reaching approximately 16% increases for each of Cmax and AUC at 160 mg/day propranolol. Diltiazem: A drug-drug interaction study was conducted in 28 healthy volunteers (13 males / 15 females, ages 18-45 years and BMIs 25-35 kg/m2) to evaluate the interaction between topiramate and diltiazem. Eligible subjects received single 240-mg doses of extended-release diltiazem and multiple doses of topiramate titrated to 150 mg/day. Systemic exposure of diltiazem was statistically significantly reduced during topiramate treatment, where Cmax and AUC4 were 10% and 25% lower, respectively, following single-dose administration. There was an increase in diltiazem CL/F by approximately 30%. Systemic exposure of the active metabolite, desacetyl diltiazem, was statistically significantly reduced during treatment with topiramate where Cmax and AUC36 were 27% and 18% lower, respectively. The single-dose pharmacokinetics of the active metabolite, N-demethyl-diltiazem, were unaffected by topiramate. Following repeated daily-dose administration of diltiazem for 5 days, steady-state systemic exposure of topiramate was greater during treatment with diltiazem, where Cmax and AUC12 were approximately 17% and 20% higher, respectively, and CL/F was 16% lower. The effects of higher doses of topiramate (>150 mg/day) on the pharmacokinetics of diltiazem or its metabolites have not been studied. Overall, the clinical significance of these observations is unclear.

Agents Predisposing to Nephrolithiasis: WARNINGS AND PRECAUTIONS, Renal).

Topiramate, when used concomitantly with other agents predisposing to nephrolithiasis, such as carbonic anhydrase inhibitors, e.g. acetazolamide, may increase the risk of nephrolithiasis. While using topiramate, agents like these should be avoided since they may create a physiological environment that increases the risk of renal stone formation (see

Drug-Food Interactions

There was no clinically significant effect of food on the bioavailability of topiramate.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

There are no known interactions of topiramate with commonly used laboratory tests.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Patients with renal impairment Patients undergoing hemodialysis Patients with hepatic disease

Recommended Dose and Dosage Adjustment

CO

Topiramate tablets can be taken without regard to meals.

Epilepsy

Monotherapy

Adults and Children (Age 6 years and older)

The recommended initial 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:

ADVERSE REACTIONS, EPILEPSY, Clinical Trial Adverse Drug Reactions, Table 1.2).

If doses above 100 mg/day are required, the dose may be increased at weekly intervals in increments of 50 mg/day to a maximum of 400 mg/day. Dose and titration rate should be guided by clinical outcome. Some patients may benefit from a slower titration schedule. Daily doses above 400 mg/day have not been adequately studied. Only 14 pediatric patients have received 500 mg/day topiramate in controlled clinical trials (see

Adjunctive Therapy

Adults (Age 17 years and older)

It is recommended that CO Topiramate as adjunctive therapy be initiated at 50 mg/day, followed by titration as needed and tolerated to an effective dose. At weekly intervals, the dose may be increased by 50 mg/day and taken in two divided doses. Some patients may benefit from lower initial doses, e.g. 25 mg and/or a slower titration schedule. Some patients may achieve efficacy with once-a-day dosing. The recommended total daily maintenance dose is 200-400 mg/day in two divided doses. Doses above 400 mg/day have not been shown to improve responses and have been associated with a greater incidence of adverse events. The maximum recommended dose is 800 mg/day. Daily doses above 1,600 mg have not been studied.

Children (Ages 2-16 years)

It is recommended that CO Topiramate as adjunctive therapy be initiated at 25 mg (or less, based on a range of 1 to 3 mg/kg/day) nightly for the first week followed by titration as needed and tolerated to an effective dose. The dosage should then be increased at 1- or 2-week intervals by increments of 1 to 3 mg/kg/day (administered in two divided doses). Some patients may benefit from lower initial doses and/or a slower titration schedule. The recommended total daily maintenance dose is approximately 5 to 9 mg/kg/day in two divided doses.

Migraine

Adults

The usual total daily dose of CO Topiramate as treatment for prophylaxis of migraine headache is 100 mg/day administered in two divided doses. Dose and titration rate should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used. No extra benefit has been demonstrated from the administration of doses higher than 100 mg/day and the incidence of some adverse events increases with increasing dose (see ADVERSE REACTIONS, MIGRAINE, Table 1.7). The recommended titration rate for topiramate for migraine prophylaxis to 100 mg/day is:

Pediatrics

The safety and efficacy of topiramate in the management or prevention of migraine in pediatrics have not been established.

Patients with Renal Impairment

In renally impaired subjects (creatinine clearance less than 70 mL/min/1.73 m2), one-half of the usual adult dose is recommended. Such patients will require a longer time to reach steady-state at each dose.

Patients Undergoing Hemodialysis

Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than a normal individual. Accordingly, a prolonged period of dialysis may cause topiramate concentration to fall below that required to maintain an antiseizure effect. To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of CO Topiramate may be required. The actual adjustment should take into account 1) the duration of dialysis, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of topiramate in the patient being dialyzed.

Patients with Hepatic Disease

In hepatically impaired patients, topiramate plasma concentrations are increased approximately 30%. This moderate increase is not considered to warrant adjustment of the CO Topiramate dosing regimen. Initiate topiramate therapy with the same dose and regimen as for patients with normal hepatic function. The dose titration in these patients should be guided by clinical outcome, i.e. seizure control, and avoidance of adverse effects. Such patients will require a longer time to reach steady-state at each dose.

Geriatrics

See WARNINGS AND PRECAUTIONS section.

Missed Dose

The missed dose should be taken as soon as possible. If it is almost time for the next dose, the missed dose should not be taken. Instead, the next scheduled dose should be taken. Doses should not be doubled.

Administration

Tablets should not be broken.

OVERDOSAGE

Overdoses of topiramate have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbances, blurred vision, diplopia, mentation impaired, lethargy, abnormal co-ordination, 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 ug/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 CO 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 ug/mL was achieved within 2 to 3 hours (Tmax). The mean extent of absorption from a 100 mg oral dose of 14C-topiramate 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.

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 ug/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.

CR

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

CO

Topiramate tablets should be stored in tightly closed containers at room temperature (15 to 30degC). Protect from moisture.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Availability of Dosage Forms

25 mg tablet: White to off-white, round, biconvex, film-coated tablet with " " on one side and "25" on the other side. 100 mg tablet: Yellow, round, biconvex, film-coated tablet with " " on one side and "100" on the other side. 200 mg tablet: Pink, round, biconvex, film-coated tablet with " " on one side and "200" on the other side.

Composition

CO Topiramate tablets contain 25 mg, 50 mg or 200 mg of topiramate as the active medicinal ingredient. In addition, CO Topiramate contains the following inactive ingredients: lactose, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate The tablet coatings contain the following inactive ingredients: White (25mg): hydroxypropyl methyl cellulose, PEG 400, polysorbate 80 and titanium dioxide. Yellow (100 mg): hydroxypropyl methyl cellulose, PEG 400, polysorbate 80, iron oxide yellow, iron oxide red and titanium dioxide. Pink (200mg): hydroxypropyl methyl cellulose, PEG 400, polysorbate 80, iron oxide yellow, iron oxide red and titanium dioxide

Packaging

CO

Topiramate is available in HDPE bottles of 100 and 500 tablets.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

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

O H3C

H3C O

O O

O

O

CH3 O

NH2 O

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.

CLINICAL TRIALS

Safety and Efficacy 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 2.1.

Table 2.1: Median Percent Seizure Rate Reduction and Percent Responders in Six Double-Blind, Placebo- Controlled, Add-On Trials in Adults with Partial Onset Seizures.

Target Topiramate Dosage (mg/day) Protocol Efficacy results Placebo 200 400 600 800 1,000

YD n

Median % Reduction

% Responders

13.1

29.6a

47.8c

47b

46 -- --

44.7d -- --

46b -- --

YE n

Median % Reduction

% Responders

47 --

1.2 --

9 --

-- 48

-- 40.7d

-- 44d

41.0d

40c

37.5d

38c

Y1 n

Median % Reduction

% Responders

1.1

-- 23 --

-- 40.7a --

-- 35b --

-- --

-- --

-- --

Y2 n

Median % Reduction

% Responders

30 --

-12.2 --

10 --

-- 30 -- --

-- 46.4c -- --

-- 47c -- --

Y3 n

Median % Reduction

% Responders

28 -- --

-17.8 -- --

0 -- --

-- 28 --

-- 35.8c --

-- 43c --

YF/YG n

Median % Reduction

% Responders

42 -- --

1.2 -- --

19 -- --

-- --

-- --

-- --

50.8d

52d

Comparisons with placebo: a p > 0.05; b p < 0.05; c p # 0.01; d p # 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 has 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 2.2.

Table 2.2: 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 10.5 33.1 0.034

% Responders 20 39 0.08

• For Protocol YP, protocol-specific 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 seizure 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 many occurrence of migraine headache that started and ended, or recurred within a 24-hour interval) over the 4 weeks of 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 nd 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 2.1). 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 2.1: Reduction in 4-Week Migraine Headache Frequency (Studies TOPMAT- MIGR-001 and TOPMAT-MIGR-002)

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.

Comparative Bioavailability Studies

A comparative bioavailability study under fasting conditions was performed on CO Topiramate against the Canadian Reference Product, Topamax(r) (Janssen Ortho Inc.). The study was a blinded, single-dose, randomized, 2-period, 2-sequence, cross-over bioequivalence study on the 200 mg tablets and was performed on 20 healthy adult male volunteers. The pharmacokinetic data are presented in Table 2.3 below.

Table 2.3:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

TOPIRAMATE

(1 x 200 mg) From measured data

Geometric Mean Arithmetic Mean (CV %)

T

MAX

T1/2

*

Topiramate 200 mg tablets (Cobalt Pharmaceuticals Inc., Canada).

+

Topamax(r) 200 mg tablets (Janssen-Ortho Inc., Canada)

SS

Expressed as median (range) only

++

Expressed as the arithmetic mean (CV%) only

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 uM to 200 uM, with minimum activity observed at 1 uM to 10 uM. 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 seizure 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 uM, 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 uM 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 uM/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 14 C-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 2.4: Acute Toxicity Studies Performed with Topiramate

Species/ Strain

Route of Administration

No. Animals/Group M/F [Age]

Dose Range (mg/kg)

Estimated LD50 (mg/kg)

Mouse Crl:COBS CD(r)-1 (ICR)BR

Oral gavage

2/2 or 5/5 [6-8 weeks]

1000-3375 M 2338

F 2915

Mouse Crl:COBS CD(r)-1 (ICR)BR

i.p 5/5 or 2/2

500-1700 M 605

F 710

Rat Crl:COBS(r) (WI)BR

Oral gavage

5/5 or 2/2 [7-8 weeks]

1500-4220 M 3745

F 2436

Rat Crl:COBS(r) (WI)BR

i.p. 5/5 or 2/2

750-2550 M 1633

F 1227

Dog Beagle

p.o. 1/1 or 2/2

[approx. 1 yr.]

270-400 No deaths

Chronic Toxicity

Table 2.5: Multiple-Dose Toxicity Studies

Table 2.5 (cont'd. ): Multiple-Dose Toxicity Studies

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. Topriamate as add-on therapy in refractory partial epilepsy. Epilepsia 1992; 33(Suppl 3):105

3. Anon. Topiramate, MCN-4853, RWJ-17021-000, EN=105605. Drugs of the Future. 1990; 15:432.

4. 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.

5. 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.

6. Rosenfeld WE, Holmes GB, Hunt TL, Schaefer P. Topiramate-effective dosaging enhances potential for success. Epilepsia 1992; 33:118.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. Doose DR, Scott VV, Marchgul BL, et al. Multiple-dose pharmacokinetics of topiramate in healthy male subjects. Epilepsia 1988; 29(5):662.

15. Easterling DE, Zakszewski T, Moyer MD, et al. Plasma pharmacokinetics of topiramate, a new anticonvulsant in humans. Epilepsia 1988; 29(5):662.

16. Wilder BJ, Penry JK, Rangel RJ, et al. Topiramate: Efficacy, toxicity, and dose/plasma concentrations. Epilepsia 1988; 29(5):698.

17. Wilensky AJ, Ojemann LM, Chmelir T, et al. Topiramate pharmacokinetics in epileptic patients receiving carbamazepine. Epilepsia 1989; 30(5)645-646.

18. 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.

19. Levy RH. The clinical pharmacokinetics of topiramate. 20th International Epilepsy Congress, Oslo, Norway, July 4, 1993.

20. Marchyanoff BE, Marchgul BL. Topiramate. Drugs of the Future 1989; 14(4):342-344.

21. 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.

22. Tanabe K, Wang Y, Kimishima K. Anticonvulsant activities and properties of topiramate. J Yonago Medical Assoc 1991; 42(6):330-346.

23. Edmonds H, Jiang D, Zhang P, Vaught JL. Topiramate in a rat model of post-traumatic epilepsy. Epilepsia 1991; 32:15.

24. 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

25. 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.

26. 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.

27. Vaught JL, Marchyanoff BE, Shank R. The pharmacological profile of topiramate: A structurally novel, clinically effective anticonvulsant. Epilepsia 1991; 32:19.

28. Shank RP, Vaught JL, Raffa RB, Marchyanoff BE. Investigation of the mechanism of topiramate's anticonvulsant activity. Epilepsia 1991; 32:7-8.

29. 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.

30. No Authors listed in citation. Topiramate. Drugs of the Future 1993; 18(4):398.

31. 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.

32. 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 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 PrTOPAMAX (Topiramate), manufactured by Janssen-Ortho Inc. Control No. 100073, date of Revision: February 8, 2006. IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION

Pr

CO

Topiramate

Topiramate

This leaflet is part III of a three-part "Product Monograph" published when CO 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 CO Topiramate. Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

CO

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

CO

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:

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

When it should not be used:

You/your child should not use CO 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.

CO 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 important nonmedicinal ingredients are:

Lactose, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate.

The tablet coatings contain the following inactive ingredients:

25 mg: hydroxypropyl methyl cellulose, PEG 400, polysorbate 80, and titanium dioxide.

100 mg and 200 mg: hydroxypropyl methyl cellulose, PEG 400, polysorbate 80, iron oxide yellow, iron oxide red and titanium dioxide.

What dosage forms it comes in:

25, 100, and 200 mg tablets

WARNINGS AND PRECAUTIONS

BEFORE you use CO 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.

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/is taking medicines that slow down the nervous system (CNS depressants).

you/your child are taking oral contraceptives and CO 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).

you consume alcohol regularly.

Other Precautions:

CO

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

CO

Topiramate may reduce the efficacy of oral contraceptives even in the absence of breakthrough bleeding. Therefore, oral contraceptives containing not less than 30 ug 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/is using. It is especially important that your doctor know if you/your child are/is taking digoxin, oral contraceptives, glyburide, lithium, risperidone, diltiazem, or any other antiepileptic drugs, such as phenytoin, valproate or carbamazepine.

PROPER USE OF THIS MEDICATION

CO

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 CO Topiramate you are taking unless your doctor tells you to.

Swallow the Tablets and take it 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 CO 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:

CO Topiramate taken alone:

The usual maintenance dose in adults and children (6 years of age or older) is between 100 mg/day to 400 mg/day. CO Topiramate is usually taken twice a day.

CO 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. CO 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 CO 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/misses 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 usual sign or symptom whether listed or not.

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

Decreased sweating may occur while taking CO Topiramate .

Make sure you/your child increases/increases and maintain/maintains fluid intake prior to and during activities such as exercise and exposure to warm temperatures. Contact your doctor if you/your child are/is 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. For any unexpected effects while taking CO Topiramate, contact your doctor or pharmacist.

HOW TO STORE IT

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

Store in a tightly closed container at room temperature (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: National AR Centre

Marketed Health Products Safety and Effectiveness Information Division

Marketed Health Products Directorate Tunney's Pasture, AL 0701C

Ottawa ON K1A 0K9

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

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be found by contacting the sponsor, Cobalt Pharmaceuticals Inc., at: 1-866-254-6111

This leaflet was prepared by:

Cobalt Pharmaceuticals, Inc

6500 Kitimat Road, Mississauga, ON, L5N 2B8, Canada Last revised: November 02, 2006