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 28 DOSAGE AND ADMINISTRATION 36 OVERDOSAGE 39 ACTION AND CLINICAL PHARMACOLOGY 40 STORAGE AND STABILITY 42 DOSAGE FORMS, COMPOSITION AND PACKAGING 42

PART II: SCIENTIFIC INFORMATION 44

PHARMACEUTICAL INFORMATION 44 CLINICAL TRIALS 44 DETAILED PHARMACOLOGY 50 TOXICOLOGY 53 REFERENCES 56

PART III: CONSUMER INFORMATION. 61

Pr

TOPAMAX *

topiramate tablets 25, 100 and 200 mg topiramate sprinkle capsules 15, and 25 mg Antiepileptic/Migraine Prophylaxis

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics

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

).

CONTRAINDICATIONS

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

WARNINGS AND PRECAUTIONS

General

Antiepileptic drugs, including TOPAMAX (topiramate), should be withdrawn gradually to minimize the potential for seizures or increased seizure frequency. In clinical trials in adult patients with epilepsy, dosages were decreased by 50-100 mg/day at weekly intervals. In clinical trials of children, TOPAMAX was gradually withdrawn over a 2-8 week period. (See DOSAGE and ADMINISTRATION, General and Epilepsy) In patients without a history of seizures or epilepsy, Topamax (topiramate) should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency. In clinical trials in adult patients receiving Topamax for migraine prophylaxis dosages were decreased by 25-50 mg/day at weekly intervals (See DOSAGE and ADMINISTRATION, General and Migraine) In situations where rapid withdrawal of TOPAMAX is medically required, appropriate monitoring is recommended. (See DOSAGE and ADMINISTRATION, General).

Hyperammonemia and Encephalopathy

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 ADVERSE REACTIONS, Post-Market Adverse Drug Reactions and DRUG INTERACTIONS, Drug- Drug Interactions). 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 TOPAMAX, 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 TOPAMAX 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 pre-treatment) 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 TOPAMAX (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 pre-treatment) in these trials was 11% for TOPAMAX 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 pre-treatment) 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% (3/11) 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 (non-specific 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 TOPAMAX 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, TOPAMAX 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 TOPAMAX 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.

In the controlled epilepsy adjunctive therapy trials, these events were generally mild to moderate and generally occurred early in therapy. While the incidence of psychomotor slowing does not appear to be dose related, both language problems and difficulty with concentration or attention increased in frequency with increasing dosage in the six double-blind trials, suggesting that these events are dose related (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions). Central nervous system and psychiatric-related events were also more frequently reported in topiramate-treated subjects in the migraine prophylaxis trials. These included: anorexia, dizziness, difficulty with memory, somnolence, language problems, and difficulty with concentration and attention. Most of the events were mild or moderate in severity, some of which led to withdrawal from treatment (see ADVERSE REACTIONS, MIGRAINE).

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

Paresthesia

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

Ophthalmologic

Acute Myopia and Secondary Angle Closure Glaucoma

WARNINGS AND PRECAUTIONS, Endocrine and Metabolism DRUG INTERACTIONS

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 TOPAMAX. 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 TOPAMAX while also taking valproate or other antiepileptic medications (see WARNINGS AND PRECAUTIONS, General and DRUG INTERACTIONS, Drug-Drug

Interactions).

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

).

The following adverse experiences have not been listed above and data are insufficient to support an estimate of their incidence or to establish causation. Reports of increases in liver function tests in patients taking TOPAMAX 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 TOPAMAX. Isolated 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.

DRUG INTERACTIONS

Drug-Drug Interactions

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

Antiepileptic Drugs

Potential interactions between TOPAMAX 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 1.9.

Table 1.9: Drug Interactions with TOPAMAX Therapy

AED

AED

Topiramate

Co-administered Concentration Concentration

Phenytoin : * * 959%

Carbamazepine (CBZ) : 940%

CBZ epoxide * : NS

Valproic acid 911% 914%

Phenobarbital : NS

Primidone : NS

Lamotrigine :

13% decrease

at TOPAMAX doses up to 400 mg/day

* Is not administered but is an active metabolite of carbamazepine

- 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 TOPAMAX on Other Antiepileptic Drugs

The addition of TOPAMAX 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 TOPAMAX to phenytoin may result in an increase of plasma concentrations of phenytoin. The effect of TOPAMAX on the 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 TOPAMAX 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 1.9.

Effects of Other Antiepileptic Drugs on TOPAMAX

Phenytoin and Carbamazepine

Phenytoin and carbamazepine decrease the plasma concentration of topiramate. The addition or withdrawal of phenytoin and/or carbamazepine during adjunctive therapy with TOPAMAX may require adjustment of the dose of TOPAMAX. This should be done by titrating to clinical effect.

Valproic Acid

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 TOPAMAX. The effects of these interactions on plasma concentrations are summarized in Table 1.9. Rare post-marketing reports of encephalopathy with or without hyperammonemia have been received for patients treated with TOPAMAX alone or in combination with valproic acid 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 TOPAMAX administration (200 mg/day). Multiple-dose studies have not been performed. When TOPAMAX 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 TOPAMAX and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. It is recommended that TOPAMAX not be used concomitantly with alcohol or other CNS depressant drugs.

Oral Contraceptives:

TOPAMAX (50-200 mg/day) in Healthy Volunteers

In a pharmacokinetic interaction 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 TOPAMAX (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 TOPAMAX 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 TOPAMAX 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.

TOPAMAX as Adjunctive Therapy with Valproic Acid in Epileptic Patients

In a pharmacokinetic interaction study, epileptic patients received TOPAMAX as adjunctive therapy with valproic acid and a combination oral contraceptive product containing norethindrone (1 mg) plus ethinyl estradiol (35 ug). In this study, TOPAMAX 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 change 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 measurement 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 TOPAMAX (up-titrated to 100 mg b.i.d. ). TOPAMAX 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 TOPAMAX 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%, and mean Cmax increased non-significantly by 10%, but with individual subjects showing large increases and 3 of the 4 highest values 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 TOPAMAX is added to pioglitazone therapy or pioglitazone is added to TOPAMAX 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 AUC0-8h 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 mean AUC0-[?] 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 AUC0-[?] 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, AUC[?] 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 patients' 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 antihistamine 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 AUC[?] 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.

Flunarizine:

Patients with Migraine - Effects of topiramate on the pharmacokinetics of flunarizine

The dose of flunarizine used in this study is one-half of the recommended daily dose. A drug- drug interaction study was conducted in forty seven patients with a history migraine (13 males, 34 females), ages 20-53 years, evaluated the steady-state pharmacokinetics of flunarizine when topiramate was administered concomitantly. Subjects were taking flunarizine for at least 4 weeks before study start. One subgroup was administered only flunarizine (5 mg q24h) for 81 days, and, a second subgroup received flunarizine (5 mg q24h) for 81 days and topiramate (up-titrated to 50 mg/day and then to 100 mg/day) from Day 4 to a.m. dose on Day 82 concomitantly. Mean Cmax of flunarizine decreased by 22% with concomitant administration of topiramate at 50 mg/day. During concomitant treatment with topiramate at 100 mg/day, Cmax estimates returned to those observed during treatment with flunarizine alone Mean AUC0-24 for flunarizine was similar with concomitant administration of topiramate at 50 mg/day and 16% higher with topiramate at 100mg/day compared to treatment with flunarizine alone Mean CL/F of flunarizine was unaffected by treatment with topiramate. Systemic exposure of topiramate (Cmax and AUC0-12) doubled with increasing topiramate dose from 50 mg/day to 100 mg/day. Mean CL/F was similar during both dose periods and was consistent with previously observed estimates in healthy volunteers. These alterations are unlikely to be of clinical significance. However, there are no data on the effects of higher doses of topiramate on flunarizine levels. There is also no information on the interaction of topiramate and flunarizine in patients with history of seizure or epilepsy. ,Agents Predisposing to Nephrolithiasis: TOPAMAX, 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 TOPAMAX, agents like these should be avoided since they may create a physiological environment that increases the risk of renal stone formation (see WARNINGS AND PRECAUTIONS, Renal).

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 TOPAMAX with commonly used laboratory tests.

DOSAGE AND ADMINISTRATION

General

In patients with or without a history of seizures or epilepsy, Topamax (topiramate) should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency. (See WARNINGS and PRECAUTIONS, General). In clinical trials in adult patients with epilepsy, dosages were decreased by 50-100 mg/day at weekly intervals. In clinical trials of children, TOPAMAX was gradually withdrawn over a 2-8 week period. In clinical trials in adult patients receiving Topamax for migraine prophylaxis dosages were decreased by 25-50 mg/day at weekly intervals (See WARNINGS and PRECAUTIONS, General). In situations where rapid withdrawal of TOPAMAX is medically required, appropriate monitoring is recommended. . (See WARNINGS and PRECAUTIONS, General).

Dosing Considerations

• Patients with renal impairment

• Patients undergoing hemodialysis

• Patients with hepatic disease

Recommended Dose and Dosage Adjustment

TOPAMAX (topiramate) Tablets or Sprinkle Capsules can be taken without regard to meals.

EPILEPSY

Monotherapy

Adults and Children (Age 6 years and older)

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

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 have not been adequately studied. Only 14 pediatric patients have received 500 mg/day topiramate in controlled clinical trials (see ADVERSE REACTIONS, EPILEPSY,

Clinical Trial Adverse Drug Reactions).

, Table 1.2

Adjunctive Therapy

Adults (Age 17 years and older)

It is recommended that TOPAMAX 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 TOPAMAX 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.

Drug Discontinuation

In patients with a history of seizures or epilepsy, TOPAMAX should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency. In clinical trials, daily dosages were decreased in weekly intervals by 50-100 mg in adults with epilepsy. In clinical trials of children, TOPAMAX was gradually withdrawn over a 2-8 week period. In situations where rapid withdrawal of TOPAMAX is medically required, appropriate monitoring is recommended.

MIGRAINE

Adults

The usual total daily dose of TOPAMAX 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:

Drug Discontinuation

In patients without a history of seizures or epilepsy, TOPAMAX should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency. In clinical trials, daily dosages were decreased in weekly intervals by 25-50 mg in adults receiving TOPAMAX at doses up to 100 mg/day for migraine prophylaxis. In situations where rapid withdrawal of TOPAMAX is medically required, appropriate monitoring is recommended.

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 TOPAMAX 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 TOPAMAX 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. TOPAMAX Sprinkle Capsules may be swallowed whole or may be administered by carefully opening the capsule and sprinkling the entire contents on a small amount (teaspoon) of soft food. This drug/food mixture should be swallowed immediately and not chewed. It should not be stored for future use. The sprinkle formulation is provided for those patients who cannot swallow tablets, e.g. pediatric and the elderly.

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

TOPAMAX (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 TOPAMAX. No evidence of tolerance requiring increased dosage has been demonstrated in patients during 5 years of use. Concomitant multiple-dose administration of TOPAMAX, 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 aged 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 has 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 TOPAMAX.

Hepatic Insufficiency:

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

Renal Insufficiency: The plasma and renal clearance of topiramate are decreased in patients with impaired renal function (CLCR < 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

TOPAMAX Tablets or Sprinkle Capsules should be stored in tightly closed containers at controlled room temperature (15 to 30oC). Protect from moisture.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Availability of Dosage Forms

TOPAMAX (topiramate) is available as embossed, round, coated tablets in the following strengths and colours: 25 mg white, 100 mg yellow and 200 mg salmon. They are marked as follows: 25 mg: "TOP" on one side; "25" on the other. 100 mg: "TOP" on one side; "100" on the other. 200 mg: "TOP" on one side; "200" on the other. Supplied: 25 mg tablets in bottles of 100 with desiccant. 100 and 200 mg tablets in bottles of 60 with desiccant. TOPAMAX (topiramate) Sprinkle Capsules contain small white to off-white spheres. The gelatin capsules are white and clear. They are marked as follows: 15 mg: "TOP" and "15 mg" on the side. 25 mg: "TOP" and "25 mg" on the side. Supplied: Bottles of 60 capsules without desiccant.

Composition

TOPAMAX (topiramate) Tablets contain the following inactive ingredients: carnauba wax, hypromellose, lactose monohydrate, magnesium stearate, pregelatinized starch, microcrystalline cellulose, polyethylene glycol, polysorbate 80, purified water, sodium starch glycolate, titanium dioxide, and may contain synthetic iron oxide. TOPAMAX (topiramate) Sprinkle Capsules contain topiramate-coated beads in a hard gelatin capsule. The inactive ingredients are black pharmaceutical ink, cellulose acetate, gelatin, povidone, sorbitan monolaurate, sodium lauryl sulfate, sugar spheres (sucrose and starch), and titanium dioxide. Product Monograph available upon request. Janssen-Ortho Inc. Toronto, Ontario M3C 1L9 Last revised: (Component #) (c) 2007 JANSSEN-ORTHO Inc. *All trademark rights used under license JOI Logo