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TOPAMAX®(topiramate)
Tablets
TOPAMAX®(topiramate capsules)
Sprinkle Capsules

Rx Only

DESCRIPTION

Topiramate is a sulfamate-substituted monosaccharide. TOPAMAX® (topiramate) Tablets are available as 25 mg, 50 mg, 100 mg, and 200 mg round tablets for oral administration. TOPAMAX® (topiramate capsules) Sprinkle Capsules are available as 15 mg and 25 mg sprinkle capsules for oral administration as whole capsules or opened and sprinkled onto soft food.

Topiramate is a white crystalline powder with a bitter taste. Topiramate is most soluble in alkaline solutions containing sodium hydroxide or sodium phosphate and having a pH of 9 to 10. It is freely soluble in acetone, chloroform, dimethylsulfoxide, and ethanol. The solubility in water is 9.8 mg/mL. Its saturated solution has a pH of 6.3. Topiramate has the molecular formula C12H21NO8S and a molecular weight of 339.36. Topiramate is designated chemically as 2,3:4,5-Di-O-isopropylidene-β-D-fructopyranose sulfamate and has the following structural formula:

TOPAMAX® (topiramate) Tablets contain the following inactive ingredients: lactose monohydrate, pregelatinized starch, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, purified water, carnauba wax, hypromellose, titanium dioxide, polyethylene glycol, synthetic iron oxide (50, 100, and 200 mg tablets) and polysorbate 80.

TOPAMAX® (topiramate capsules) Sprinkle Capsules contain topiramate coated beads in a hard gelatin capsule. The inactive ingredients are: sugar spheres (sucrose and starch), povidone, cellulose acetate, gelatin, sorbitan monolaurate, sodium lauryl sulfate, titanium dioxide, and black pharmaceutical ink.

CLINICAL PHARMACOLOGY

Mechanism of Action:

The precise mechanisms by which topiramate exerts its anticonvulsant and migraine prophylaxis effects are unknown; however, preclinical studies have revealed four properties that may contribute to topiramate's efficacy for epilepsy and migraine prophylaxis. Electrophysiological and biochemical evidence suggests that topiramate, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV.

Pharmacodynamics:

Topiramate has anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests. Topiramate is only weakly effective in blocking clonic seizures induced by the GABAA receptor antagonist, pentylenetetrazole. Topiramate is also effective in rodent models of epilepsy, which include tonic and absence-like seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in rats by kindling of the amygdala or by global ischemia.

Pharmacokinetics:

The sprinkle formulation is bioequivalent to the immediate release tablet formulation and, therefore, may be substituted as a therapeutic equivalent.

Absorption of topiramate is rapid, with peak plasma concentrations occurring at approximately 2 hours following a 400 mg oral dose. The relative bioavailability of topiramate from the tablet formulation is about 80% compared to a solution. The bioavailability of topiramate is not affected by food.

The pharmacokinetics of topiramate are linear with dose proportional increases in plasma concentration over the dose range studied (200 to 800 mg/day). The mean plasma elimination half-life is 21 hours after single or multiple doses. Steady state is thus reached in about 4 days in patients with normal renal function. Topiramate is 15-41% bound to human plasma proteins over the blood concentration range of 0.5 -250 μg/mL. The fraction bound decreased as blood concentration increased.

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

Metabolism and Excretion:

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

Pharmacokinetic Interactions

(see also Drug Interactions):

Special Populations:

CLINICAL STUDIES

The studies described in the following sections were conducted using TOPAMAX® (topiramate) Tablets.

Epilepsy

Monotherapy Controlled Trial

The effectiveness of topiramate as initial monotherapy in adults and children 10 years of age and older with partial onset or primary generalized seizures was established in a multicenter, randomized, double-blind, parallel-group trial.

The trial was conducted in 487 patients diagnosed with epilepsy (6 to 83 years of age) who had 1 or 2 well-documented seizures during the 3-month retrospective baseline phase who then entered the study and received topiramate 25 mg/day for 7 days in an open-label fashion. Forty-nine percent of subjects had no prior AED treatment and 17% had a diagnosis of epilepsy for greater than 24 months. Any AED therapy used for temporary or emergency purposes was discontinued prior to randomization. In the double-blind phase, 470 patients were randomized to titrate up to 50 mg/day or 400 mg/day. If the target dose could not be achieved, patients were maintained on the maximum tolerated dose. Fifty eight percent of patients achieved the maximal dose of 400 mg/day for≥ 2 weeks, and patients who did not tolerate 150 mg/day were discontinued. The primary efficacy assessment was a between group comparison of time to first seizure during the double-blind phase. Comparison of the Kaplan-Meier survival curves of time to first seizure favored the topiramate 400 mg/day group over the topiramate 50 mg/day group (p=0.0002, log rank test; Figure 1). The treatment effects with respect to time to first seizure were consistent across various patient subgroups defined by age, sex, geographic region, baseline body weight, baseline seizure type, time since diagnosis, and baseline AED use.

Figure 1: Kaplan-Meier Estimates of Cumulative Rates for Time to First Seizure

Adjunctive Therapy Controlled Trials in Patients With Partial Onset Seizures

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

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

Following randomization, patients began the double-blind phase of treatment. In five of the six studies, patients received active drug beginning at 100 mg per day; the dose was then increased by 100 mg or 200 mg/day increments weekly or every other week until the assigned dose was reached, unless intolerance prevented increases. In the sixth study (119), the 25 or 50 mg/day initial doses of topiramate were followed by respective weekly increments of 25 or 50 mg/day until the target dose of 200 mg/day was reached. After titration, patients entered a 4, 8, or 12-week stabilization period. The numbers of patients randomized to each dose, and the actual mean and median doses in the stabilization period are shown in Table 1.

Adjunctive Therapy Controlled Trial in Pediatric Patients Ages 2 - 16 Years With Partial Onset Seizures

The effectiveness of topiramate as an adjunctive treatment for pediatric patients ages 2 - 16 years with partial onset seizures was established in a multicenter, 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 TOPAMAX® Tablets or placebo. In this study, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least six partial onset seizures, with or without secondarily generalized seizures, during the baseline phase were randomly assigned to placebo or TOPAMAX® Tablets in addition to their other AEDs.

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

Adjunctive Therapy Controlled Trial in Patients With Primary Generalized Tonic-Clonic Seizures

The effectiveness of topiramate as an adjunctive treatment for primary generalized tonic-clonic seizures in patients 2 years old and older was established in a multicenter, randomized, double-blind, placebo-controlled trial, comparing a single dosage of topiramate and placebo.

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

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

Adjunctive Therapy Controlled Trial in Patients With Lennox-Gastaut Syndrome

The effectiveness of topiramate as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome was established in a multicenter, randomized, double-blind, placebo-controlled trial comparing a single dosage of topiramate with placebo in patients 2 years of age and older.

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

Table 1: Topiramate Dose Summary During the Stabilization Periods of Each of Six Double-Blind, Placebo-Controlled, Add-On Trials in Adults with Partial Onset Seizuresb
Target Topiramate Dosage (mg/day)
ProtocolStabilization DosePlaceboa2004006008001,000

a Placebo dosages are given as the number of tablets. Placebo target dosages were as follows: Protocol Y1, 4 tablets/day; Protocols YD and Y2, 6 tablets/day; Protocol Y3 and 119, 8 tablets/day; Protocol YE, 10 tablets/day.

b Dose-response studies were not conducted for other indications or pediatric partial onset seizures.

YDN42424041----
Mean Dose5.9200390556----
Median Dose6.0200400600----
YE N44----404540
Mean Dose9.7----544739796
Median Dose10.0----6008001,000
Y1 N23--19------
Mean Dose3.8--395------
Median Dose4.0--400------
Y2 N30----28----
Mean Dose5.7----522----
Median Dose6.0----600----
Y3 N28------25--
Mean Dose7.9------568--
Median Dose8.0------600--
119 N90157--------
Mean Dose8200--------
Median Dose8200--------

In all add-on trials, the reduction in seizure rate from baseline during the entire double-blind phase was measured. The median percent reductions in seizure rates and the responder rates (fraction of patients with at least a 50% reduction) by treatment group for each study are shown below in Table 2. As described above, a global improvement in seizure severity was also assessed in the Lennox-Gastaut trial.

Table 2: Efficacy Results in Double-Blind, Placebo-Controlled, Add-On Epilepsy Trials
Target Topiramate Dosage (mg/day)
ProtocolEfficacy ResultsPlacebo2004006008001,000≈6
mg/kg/day*

Comparisons with placebo: a p=0.080; b p≤0.010; c p≤0.001; d p≤0.050; e p=0.065; f p≤0.005;g p=0.071;

h Median % reduction and % responders are reported for PGTC Seizures;

i Median % reduction and % responders for drop attacks, i.e., tonic or atonic seizures;

j Percent of subjects who were minimally, much, or very much improved from baseline

* For Protocols YP and YTC, protocol-specified target dosages (<9.3 mg/kg/day) were assigned based on subject's weight to approximate a dosage of 6 mg/kg per day; these dosages corresponded to mg/day dosages of 125, 175, 225, and 400 mg/day.

Partial Onset Seizures
Studies in Adults
YD N45454546------
Median % Reduction11.627.2a47.5b44.7c------
% Responders182444d46d------
YE N47----484847--
Median % Reduction1.7----40.8c41.0c36.0c--
% Responders9----40c41c36d--
Y1 N24--23--------
Median % Reduction1.1--40.7e--------
% Responders8--35d--------
Y2 N30----30------
Median % Reduction-12.2----46.4f------
% Responders10----47c------
Y3 N28------28----
Median % Reduction-20.6------24.3c----
% Responders0------43c----
119 N91168----------
Median % Reduction20.044.2c----------
% Responders2445c----------
Studies in Pediatric Patients
YP N45----------41
Median % Reduction10.5----------33.1d
% Responders20----------39
Primary Generalized Tonic-Clonich
YTC N40----------39
Median % Reduction9.0----------56.7d
% Responders20----------56c
Lennox-Gastaut Syndromei
YL N49----------46
Median % Reduction-5.1----------14.8d
% Responders14----------28g
Improvement in Seizure Severityj28----------52d

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

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

Migraine

The results of 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trials established the effectiveness of TOPAMAX® in the prophylactic treatment of migraine headache. The design of both trials (one study was conducted in the U.S. and one study was conducted in the U.S. and Canada) 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 up to a 2 week washout of any prior migraine preventive medications before starting the baseline phase.

Patients who experienced 3 to 12 migraine headaches over the 4-weeks in the baseline phase were equally randomized to either TOPAMAX® 50 mg/day, 100 mg/day, 200 mg/day, or placebo and treated for a total of 26 weeks (8-week titration period and18-week maintenance period). Treatment was initiated at 25 mg/day for one week, and then the daily dosage was increased by 25-mg increments each week until reaching the assigned target dose or maximum tolerated dose (administered twice daily).

Effectiveness of treatment was assessed by the reduction in migraine headache frequency, as measured by the change in 4-week migraine rate from the baseline phase to double-blind treatment period in each TOPAMAX® treatment group compared to placebo in the intent to treat (ITT) population.

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 TOPAMAX® 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 TOPAMAX® 50, 100, and 200 mg/day groups, respectively, versus -0.8 in the placebo group (see Figure 2). The differences between the TOPAMAX® 100 and 200 mg/day groups versus placebo were statistically significant (p<0.001 for both comparisons).

In the second study a total of 468 patients (406 females, 62 males), ranging in age from 12 to 65 years, were randomized and provided efficacy data. Two hundred 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 TOPAMAX® 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 TOPAMAX® 50, 100, and 200 mg/day groups, respectively, versus –1.1 in the placebo group (see Figure 2). The differences between the TOPAMAX® 100 and 200 mg/day groups versus placebo were statistically significant (p=0.008 and <0.001, respectively).

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

For patients withdrawing from TOPAMAX®, daily dosages were decreased in weekly intervals by 25 to 50 mg.

Figure 2: Reduction in 4-Week Migraine Headache Frequency (Studies TOPMAT-MIGR-001 and TOPMAT-MIGR-002)

INDICATIONS AND USAGE

Monotherapy Epilepsy

TOPAMAX® (topiramate) Tablets and TOPAMAX® (topiramate capsules) Sprinkle Capsules are indicated as initial monotherapy in patients 10 years of age and older with partial onset or primary generalized tonic-clonic seizures .

Effectiveness was demonstrated in a controlled trial in patients with epilepsy who had no more than 2 seizures in the 3 months prior to enrollment. Safety and effectiveness in patients who were converted to monotherapy from a previous regimen of other anticonvulsant drugs have not been established in controlled trials.

Adjunctive Therapy Epilepsy

TOPAMAX® (topiramate) Tablets and TOPAMAX® (topiramate capsules) Sprinkle Capsules are indicated as adjunctive therapy for adults and pediatric patients ages 2 - 16 years with partial onset seizures, or primary generalized tonic-clonic seizures, and in patients 2 years of age and older with seizures associated with Lennox-Gastaut syndrome.

Migraine

TOPAMAX® (topiramate) Tablets and TOPAMAX® (topiramate capsules) Sprinkle Capsules are indicated for adults for the prophylaxis of migraine headache. The usefulness of TOPAMAX® in the acute treatment of migraine headache has not been studied.

CONTRAINDICATIONS

TOPAMAX® is contraindicated in patients with a history of hypersensitivity to any component of this product.

WARNINGS

Metabolic Acidosis

Hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) is associated with topiramate treatment. This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of topiramate on carbonic anhydrase. Such electrolyte imbalance has been observed with the use of topiramate in placebo-controlled clinical trials and in the post-marketing period. Generally, topiramate-induced metabolic acidosis occurs early in treatment although cases can occur at any time during treatment. Bicarbonate decrements are usually mild-moderate (average decrease of 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, surgery, ketogenic diet, or 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 mEq/L at two consecutive visits or at the final visit) in controlled clinical trials for adjunctive treatment of epilepsy was 32% for 400 mg/day, and 1% for placebo. Metabolic acidosis has been observed at doses as low as 50 mg/day. The incidence of persistent treatment-emergent decreases in serum bicarbonate in adults in the epilepsy controlled clinical trial for monotherapy was 15% for 50 mg/day and 25% for 400 mg/day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and >5 mEq/L decrease from pretreatment) in the adjunctive therapy trials was 3% for 400 mg/day, and 0% for placebo and in the monotherapy trial was 1% for 50 mg/day and 7% for 400 mg/day. 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 mEq/L and >5 mEq/L decrease from pretreatment) 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.

In pediatric patients (10 years up to 16 years of age), the incidence of persistent treatment-emergent decreases in serum bicarbonate in the epilepsy controlled clinical trial for monotherapy was 7% for 50 mg/day and 20% for 400 mg/day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and >5 mEq/L decrease from pretreatment) in this trial was 4% for 50 mg/day and 4% for 400 mg/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 mEq/L and >5 mEq/L decrease from pretreatment) in these trials was 11% for 200 mg/day, 9% for 100 mg/day, 2% for 50 mg/day, and <1% for placebo.

Some manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis, and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures. Chronic metabolic acidosis in pediatric patients may also reduce growth rates. A reduction in growth rate may eventually decrease the maximal height achieved. The effect of topiramate on growth and bone-related sequelae has not been systematically investigated.

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.

Acute Myopia and Secondary Angle Closure Glaucoma

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving TOPAMAX®. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness) and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating TOPAMAX® therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of TOPAMAX® as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of TOPAMAX®, may be helpful.

Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss.

Oligohidrosis and Hyperthermia

Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with TOPAMAX® use. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases were reported after exposure to elevated environmental temperatures.

The majority of the reports have been in children. Patients, especially pediatric patients, treated with TOPAMAX® should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. 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.

Withdrawal of AEDs

In patients with or without a history of seizures or epilepsy, antiepileptic drugs including TOPAMAX® should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency (see CLINICAL STUDIES, Epilepsy and Migraine). In situations where rapid withdrawal of TOPAMAX® is medically required, appropriate monitoring is recommended.

Cognitive/Neuropsychiatric Adverse Events

Sudden Unexplained Death in Epilepsy (SUDEP)

During the course of premarketing development of TOPAMAX® (topiramate) Tablets, 10 sudden and unexplained deaths were recorded among a cohort of treated patients (2,796 subject years of exposure). This represents an incidence of 0.0035 deaths per patient year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving TOPAMAX® (ranging from 0.0005 for the general population of patients with epilepsy, to 0.003 for a clinical trial population similar to that in the TOPAMAX® program, to 0.005 for patients with refractory epilepsy).

PRECAUTIONS

Hyperammonemia and Encephalopathy Associated with Concomitant Valproic Acid Use

Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse event is not due to a pharmacokinetic interaction.

It is not known if topiramate monotherapy is associated with hyperammonemia.

Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, an interaction of topiramate and valproic acid may exacerbate existing defects or unmask deficiencies in susceptible persons.

In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured.

Kidney Stones

A total of 32/2,086 (1.5%) of adults exposed to topiramate during its adjunctive epilepsy therapy development reported the occurrence of kidney stones, an incidence about 2-4 times greater than expected in a similar, untreated population. In the double-blind monotherapy epilepsy study, a total of 4/319 (1.3%) of adults exposed to topiramate reported the occurrence of kidney stones. As in the general population, the incidence of stone formation among topiramate treated patients was higher in men. Kidney stones have also been reported in pediatric patients.

An explanation for the association of TOPAMAX® and kidney stones may lie in the fact that topiramate is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors, e.g., acetazolamide or dichlorphenamide, promote stone formation by reducing urinary citrate excretion and by increasing urinary pH. The concomitant use of TOPAMAX® with other carbonic anhydrase inhibitors or potentially in patients on a ketogenic diet may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided.

Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation.

Paresthesia

Paresthesia (usually tingling of the extremities), an effect associated with the use of other carbonic anhydrase inhibitors, appears to be a common effect of TOPAMAX®. Paresthesia was more frequently reported in the monotherapy epilepsy trials and migraine prophylaxis trials versus the adjunctive therapy epilepsy trials. In the majority of instances, paresthesia did not lead to treatment discontinuation.

Adjustment of Dose in Renal Failure

The major route of elimination of unchanged topiramate and its metabolites is via the kidney. Dosage adjustment may be required in patients with reduced renal function (see DOSAGE AND ADMINISTRATION).

Decreased Hepatic Function

In hepatically impaired patients, topiramate should be administered with caution as the clearance of topiramate may be decreased.

Information for Patients

Patients should read the Patient Information before starting treatment with TOPAMAX® and each time their prescription is renewed.

Patients taking TOPAMAX® should be told to seek immediate medical attention if they experience blurred vision, visual disturbances or periorbital pain.

Patients, especially pediatric patients, treated with TOPAMAX® should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather.

Patients, particularly those with predisposing factors, should be instructed to maintain an adequate fluid intake in order to minimize the risk of renal stone formation (see PRECAUTIONS: Kidney Stones, for support regarding hydration as a preventative measure).

Patients should be warned about the potential for somnolence, dizziness, confusion, difficulty concentrating, and visual effects and advised not to drive or operate machinery until they have gained sufficient experience on topiramate to gauge whether it adversely affects their mental performance, motor performance, and/or vision.

Additional food intake may be considered if the patient is losing weight while on this medication.

Even when taking TOPAMAX® or other anticonvulsants, some patients with epilepsy will continue to have unpredictable seizures. Therefore, all patients taking TOPAMAX® for epilepsy should be told to exercise appropriate caution when engaging in any activities where loss of consciousness could result in serious danger to themselves or those around them (including swimming, driving a car, climbing in high places, etc.). Some patients with refractory epilepsy will need to avoid such activities altogether. Physicians should discuss the appropriate level of caution with their patients, before patients with epilepsy engage in such activities.

Please refer to the end of the product labeling for important information on how to take TOPAMAX® (topiramate capsules) Sprinkle Capsules.

Laboratory Tests:

Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended (see WARNINGS).

In double-blind trials hypokalemia defined as serum potassium decline below 3.5 mmol/L has been observed in 0.4% of subjects treated with topiramate compared to 0.1% of subjects treated with placebo.

Drug Interactions:

In vitro studies indicate that topiramate does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4/5 isozymes. In vitro studies indicate that topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4.

Antiepileptic Drugs

Potential interactions between topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in Table 3.

In Table 3, the second column (AED concentration) describes what happens to the concentration of the AED uled in the first column when topiramate is added.

The third column (topiramate concentration) describes how the coadministration of a drug uled in the first column modifies the concentration of topiramate in experimental settings when TOPAMAX® was given alone.

Table 3: Summary of AED Interactions with TOPAMAX®
AED
Co-administered
AED
Concentration
Topiramate
Concentration

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

b = Is not administered but is an active metabolite of carbamazepine.

NC = Less than 10% change in plasma concentration.

AED = Antiepileptic drug.

NE = Not Evaluated.

TPM = Topiramate

PhenytoinNC or 25% increasea48% decrease
Carbamazepine (CBZ)NC40% decrease
CBZ epoxidebNCNE
Valproic acid11% decrease14% decrease
PhenobarbitalNCNE
PrimidoneNCNE
LamotrigineNC at TPM doses up to 400 mg/day13% decrease

In addition to the pharmacokinetic interaction described in the above table, concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with and without encephalopathy (see PRECAUTIONS, Hyperammonemia and Encephalopathy Associated with Concomitant Valproic Acid Use).

Other Drug Interactions

Carcinogenesis, Mutagenesis, Impairment of Fertility:

An increase in urinary bladder tumors was observed in mice given topiramate (20, 75, and 300 mg/kg) in the diet for 21 months. The elevated bladder tumor incidence, which was statistically significant in males and females receiving 300 mg/kg, was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. Plasma exposures in mice receiving 300 mg/kg were approximately 0.5 to 1 times steady-state exposures measured in patients receiving topiramate monotherapy at the recommended human dose (RHD) of 400 mg, and 1.5 to 2 times steady-state topiramate exposures in patients receiving 400 mg of topiramate plus phenytoin. The relevance of this finding to human carcinogenic risk is uncertain. No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/kg (approximately 3 times the RHD on a mg/m2 basis).

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

No adverse effects on male or female fertility were observed in rats at doses up to 100 mg/kg (2.5 times the RHD on a mg/m2 basis).

Pregnancy: Pregnancy Category C.

Topiramate has demonstrated selective developmental toxicity, including teratogenicity, in experimental animal studies. When oral doses of 20, 100, or 500 mg/kg were administered to pregnant mice during the period of organogenesis, the incidence of fetal malformations (primarily craniofacial defects) was increased at all doses. The low dose is approximately 0.2 times the recommended human dose (RHD=400 mg/day) on a mg/m2 basis. Fetal body weights and skeletal ossification were reduced at 500 mg/kg in conjunction with decreased maternal body weight gain.

In rat studies (oral doses of 20, 100, and 500 mg/kg or 0.2, 2.5, 30, and 400 mg/kg), the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased among the offspring of dams treated with 400 mg/kg (10 times the RHD on a mg/m2 basis) or greater during the organogenesis period of pregnancy. Embryotoxicity (reduced fetal body weights, increased incidence of structural variations) was observed at doses as low as 20 mg/kg (0.5 times the RHD on a mg/m2 basis). Clinical signs of maternal toxicity were seen at 400 mg/kg and above, and maternal body weight gain was reduced during treatment with 100 mg/kg or greater.

In rabbit studies (20, 60, and 180 mg/kg or 10, 35, and 120 mg/kg orally during organogenesis), embryo/fetal mortality was increased at 35 mg/kg (2 times the RHD on a mg/m2 basis) or greater, and teratogenic effects (primarily rib and vertebral malformations) were observed at 120 mg/kg (6 timesthe RHD on a mg/m2 basis). Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg and above.

When female rats were treated during the latter part of gestation and throughout lactation (0.2, 4, 20, and 100 mg/kg or 2, 20, and 200 mg/kg), offspring exhibited decreased viability and delayed physical development at 200 mg/kg (5 times the RHD on a mg/m2 basis) and reductions in pre- and/or postweaning body weight gain at 2 mg/kg (0.05 times the RHD on a mg/m2 basis) and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg or greater.

In a rat embryo/fetal development study with a postnatal component (0.2, 2.5, 30, or 400 mg/kg during organogenesis; noted above), pups exhibited delayed physical development at 400 mg/kg (10 times the RHD on a mg/m2 basis) and persistent reductions in body weight gain at 30 mg/kg (1 times the RHD on a mg/m2 basis) and higher.

There are no studies using TOPAMAX® in pregnant women. TOPAMAX® should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

In post-marketing experience, cases of hypospadias have been reported in male infants exposed in utero to topiramate, with or without other anticonvulsants; however, a causal relationship with topiramate has not been established.

Labor and Delivery:

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 200 mg/kg/day.

The effect of TOPAMAX® on labor and delivery in humans is unknown.

Nursing Mothers:

Topiramate is excreted in the milk of lactating rats. The excretion of topiramate in human milk has not been evaluated in controlled studies. Limited observations in patients suggest an extensive secretion of topiramate into breast milk. Since many drugs are excreted in human milk, and because the potential for serious adverse reactions in nursing infants to TOPAMAX® is unknown, the potential benefit to the mother should be weighed against the potential risk to the infant when considering recommendations regarding nursing.

Pediatric Use:

Safety and effectiveness in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome. Safety and effectiveness in patients below the age of 10 years have not been established for the monotherapy treatment of epilepsy. 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 (see WARNINGS).

Safety and effectiveness in pediatric patients have not been established for the prophylaxis treatment of migraine headache.

Geriatric Use:

In clinical trials, 3% of patients were over 60. No age related difference in effectiveness or adverse effects were evident. However, clinical studies of topiramate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Dosage adjustment may be necessary for elderly with impaired renal function (creatinine clearance rate≤70 mL/min/1.73 m2) due to reduced clearance of topiramate (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Race and Gender Effects:

Evaluation of effectiveness and safety in clinical trials has shown no race or gender related effects.

ADVERSE REACTIONS

The data described in the following section were obtained using TOPAMAX® (topiramate) Tablets.

Monotherapy Epilepsy

The adverse events in the controlled trial that occurred most commonly in adults in the 400 mg/day group and at a rate higher than the 50 mg/day group were: paresthesia, weight decrease, somnolence, anorexia, dizziness, and difficulty with memory NOS [see Table 4].

The adverse events in the controlled trial that occurred most commonly in children (10 years up to 16 years of age) in the 400 mg/day group and at a rate higher than the 50 mg/day group were: weight decrease, upper respiratory tract infection, paresthesia, anorexia, diarrhea, and mood problems [see Table 5].

Approximately 21% of the 159 adult patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse events. Adverse events associated with discontinuing therapy (≥2%) included depression, insomnia, difficulty with memory (NOS), somnolence, paresthesia, psychomotor slowing, dizziness, and nausea.

Approximately 12% of the 57 pediatric patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse events. Adverse events associated with discontinuing therapy (≥5%) included difficulty with concentration/attention.

The prescriber should be aware that these data cannot be used to predict the frequency of adverse events in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during the clinical study. Similarly, the cited frequencies cannot be directly compared with data obtained from other clinical investigations involving different treatments, uses, or investigators. Inspection of these frequencies, however, does provide the prescribing physician with a basis to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied.

Table 4: Incidence of Treatment-Emergent Adverse Events in the Monotherapy Epilepsy Trial in Adultsa Where Rate Was at Least 2% in the 400 mg/day Topiramate Group and Greater Than the Rate in the 50 mg/day Topiramate Group
TOPAMAX® Dosage (mg/day)
Body System/
Adverse Event
50
(N= 160)
400
(N=159)

a Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category

Body as a Whole-General Disorders
   Asthenia46
   Leg Pain23
   Chest Pain12
Central & Peripheral Nervous System Disorders
   Paresthesia2140
   Dizziness1314
   Hypoaesthesia45
   Ataxia34
   Hypertonia03
Gastro-Intestinal System Disorders
   Diarrhea56
   Constipation14
   Gastritis03
   Dry Mouth13
   Gastroesophageal Reflux12
Liver and Biliary System Disorders
   Gamma-GT Increased13
Metabolic and Nutritional Disorders
   Weight Decrease616
Psychiatric Disorders
   Somnolence915
   Anorexia414
   Difficulty with Memory NOS510
   Insomnia89
   Depression79
   Difficulty with Concentration/Attention78
   Anxiety46
   Psychomotor Slowing35
   Mood Problems25
   Confusion34
   Cognitive Problem NOS14
   Libido Decreased03
Reproductive Disorders, Female
   Vaginal Hemorrhage03
Red Blood Cell Disorders
   Anemia12
Resistance Mechanism Disorders
   Infection Viral68
   Infection23
Respiratory System Disorders
   Bronchitis34
   Rhinitis24
   Dyspnea12
Skin and Appendages Disorders
   Rash14
   Pruritus14
   Acne23
Special Senses Other, Disorders
   Taste Perversion35
Urinary System Disorders
   Cystitis13
   Renal Calculus03
   Urinary Tract Infection12
   Dysuria02
   Micturition Frequency02
Table 5: Incidence of Treatment-Emergent Adverse Events in the Monotherapy Epilepsy Trial in Children Ages 10 up to 16 Yearsa Where Rate Was at Least 5% in the 400 mg/day Topiramate Group and Greater Than the Rate in the 50 mg/day Topiramate Group
TOPAMAX® Dosage (mg/day)
Body System/
Adverse Event
50
(N=57)
400
(N=57)

a Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category.

Body as a Whole-General Disorders
   Fever09
Central & Peripheral Nervous System Disorders
   Paresthesia216
Gastro-Intestinal System Disorders
   Diarrhea511
Metabolic and Nutritional Disorders
   Weight Decrease721
Psychiatric Disorders
   Anorexia1114
   Mood Problems211
   Difficulty with Concentration/Attention49
   Cognitive Problems NOS07
   Nervousness45
Resistance Mechanism Disorders
   Infection Viral49
   Infection27
Respiratory System Disorders
   Upper Respiratory Tract Infection1618
   Rhinitis27
   Bronchitis27
   Sinusitis25
Skin and Appendages Disorders
   Alopecia25

Adjunctive Therapy Epilepsy

The most commonly observed adverse events associated with the use of topiramate at dosages of 200 to 400 mg/day in controlled trials in adults with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, that were seen at greater frequency in topiramate-treated patients and did not appear to be dose-related were: somnolence, dizziness, ataxia, speech disorders and related speech problems, psychomotor slowing, abnormal vision, difficulty with memory, paresthesia and diplopia [see Table 6]. The most common dose-related adverse events at dosages of 200 to 1,000 mg/day were: fatigue, nervousness, difficulty with concentration or attention, confusion, depression, anorexia, language problems, anxiety, mood problems, and weight decrease [see Table 8].

Adverse events associated with the use of topiramate at dosages of 5 to 9 mg/kg/day in controlled trials in pediatric patients with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, that were seen at greater frequency in topiramate-treated patients were: fatigue, somnolence, anorexia, nervousness, difficulty with concentration/attention, difficulty with memory, aggressive reaction, and weight decrease [see Table 9].

In controlled clinical trials in adults, 11% of patients receiving topiramate 200 to 400 mg/day as adjunctive therapy discontinued due to adverse events. This rate appeared to increase at dosages above 400 mg/day. Adverse events associated with discontinuing therapy included somnolence, dizziness, anxiety, difficulty with concentration or attention, fatigue, and paresthesia and increased at dosages above 400 mg/day. None of the pediatric patients who received topiramate adjunctive therapy at 5 to 9 mg/kg/day in controlled clinical trials discontinued due to adverse events.

Approximately 28% of the 1,757 adults with epilepsy who received topiramate at dosages of 200 to 1,600 mg/day in clinical studies discontinued treatment because of adverse events; an individual patient could have reported more than one adverse event. These adverse events were: psychomotor slowing (4.0%), difficulty with memory (3.2%), fatigue (3.2%), confusion (3.1%), somnolence (3.2%), difficulty with concentration/attention (2.9%), anorexia (2.7%), depression (2.6%), dizziness (2.5%), weight decrease (2.5%), nervousness (2.3%), ataxia (2.1%), and paresthesia (2.0%). Approximately 11% of the 310 pediatric patients who received topiramate at dosages up to 30 mg/kg/day discontinued due to adverse events. Adverse events associated with discontinuing therapy included aggravated convulsions (2.3%), difficulty with concentration/attention (1.6%), language problems (1.3%), personality disorder (1.3%), and somnolence (1.3%).

Incidence in Epilepsy Controlled Clinical Trials – Adjunctive Therapy – Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, and Lennox-Gastaut Syndrome

Table 6 uls treatment-emergent adverse events that occurred in at least 1% of adults treated with 200 to 400 mg/day topiramate in controlled trials that were numerically more common at this dose than in the patients treated with placebo. In general, most patients who experienced adverse events during the first eight weeks of these trials no longer experienced them by their last visit. Table 9 uls treatment-emergent adverse events that occurred in at least 1% of pediatric patients treated with 5 to 9 mg/kg topiramate in controlled trials that were numerically more common than in patients treated with placebo.

The prescriber should be aware that these data were obtained when TOPAMAX® was added to concurrent antiepileptic drug therapy and cannot be used to predict the frequency of adverse events in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with data obtained from other clinical investigations involving different treatments, uses, or investigators.Inspection of these frequencies, however, does provide the prescribing physician with a basis to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied.

Other Adverse Events Observed During Double-Blind Epilepsy Adjunctive Therapy Trials

Other events that occurred in more than 1% of adults treated with 200 to 400 mg of topiramate in placebo-controlled epilepsy trials but with equal or greater frequency in the placebo group were: headache, injury, anxiety, rash, pain, convulsions aggravated, coughing, fever, diarrhea, vomiting, muscle weakness, insomnia, personality disorder, dysmenorrhea, upper respiratory tract infection, and eye pain.

Table 6: Incidence of Treatment-Emergent Adverse Events in Placebo-Controlled, Add-On Epilepsy Trials in Adultsa,b Where Rate Was > 1% in Any Topiramate Group and Greater Than the Rate in Placebo-Treated Patients
TOPAMAX® Dosage (mg/day)
Body System/
Adverse Eventc
Placebo
(N=291)
200-400
(N=183)
600-1,000
(N=414)

a Patients in these add-on trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to TOPAMAX® or placebo.

b Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category.

c Adverse events reported by at least 1% of patients in the TOPAMAX® 200-400 mg/day group and more common than in the placebo group are uled in this table.

Body as a Whole-General Disorders
   Fatigue131530
   Asthenia163
   Back Pain453
   Chest Pain342
   Influenza-Like Symptoms234
   Leg Pain224
   Hot Flushes121
   Allergy123
   Edema121
   Body Odor010
   Rigors01<1
Central & Peripheral Nervous System Disorders
   Dizziness152532
   Ataxia71614
   Speech Disorders/Related Speech Problems21311
   Paresthesia41119
   Nystagmus71011
   Tremor699
   Language Problems1610
   Coordination Abnormal244
   Hypoaesthesia121
   Gait Abnormal132
   Muscle Contractions Involuntary122
   Stupor021
   Vertigo112
Gastro-Intestinal System Disorders
   Nausea81012
   Dyspepsia676
   Abdominal Pain467
   Constipation243
   Gastroenteritis121
   Dry Mouth124
   Gingivitis<111
   GI Disorder<110
Hearing and Vestibular Disorders
   Hearing Decreased121
Metabolic and Nutritional Disorders
   Weight Decrease3913
Muscle-Skeletal System Disorders
   Myalgia122
   Skeletal Pain010
Platelet, Bleeding,& Clotting Disorders
   Epistaxis121
Psychiatric Disorders
   Somnolence122928
   Nervousness61619
   Psychomotor Slowing21321
   Difficulty with Memory31214
   Anorexia41012
   Confusion51114
   Depression5513
   Difficulty with Concentration/Attention2614
   Mood Problems249
   Agitation233
   Aggressive Reaction233
   Emotional Lability133
   Cognitive Problems133
   Libido Decreased12<1
   Apathy113
   Depersonalization112
Reproductive Disorders, Female
   Breast Pain240
   Amenorrhea122
   Menorrhagia021
   Menstrual Disorder121
Reproductive Disorders, Male
   Prostatic Disorder<120
Resistance Mechanism Disorders
   Infection121
   Infection Viral12<1
   Moniliasis<110
Respiratory System Disorders
   Pharyngitis263
   Rhinitis676
   Sinusitis456
   Dyspnea112
Skin and Appendages Disorders
   Skin Disorder<121
   Sweating Increased<11<1
   Rash Erythematous<11<1
Special Sense Other, Disorders
   Taste Perversion024
Urinary System Disorders
   Hematuria12<1
   Urinary Tract Infection123
   Micturition Frequency112
   Urinary Incontinence<121
   Urine Abnormal01<1
Vision Disorders
   Vision Abnormal21310
   Diplopia51010
White Cell and RES Disorders
   Leukopenia121

Incidence in Study 119 – Add-On Therapy– Adults with Partial Onset Seizures

Study 119 was a randomized, double-blind, placebo-controlled, parallel group study with 3 treatment arms: 1) placebo; 2) topiramate 200 mg/day with a 25 mg/day starting dose, increased by 25 mg/day each week for 8 weeks until the 200 mg/day maintenance dose was reached; and 3) topiramate 200 mg/day with a 50 mg/day starting dose, increased by 50 mg/day each week for 4 weeks until the 200 mg/day maintenance dose was reached. All patients were maintained on concomitant carbamazepine with or without another concomitant antiepileptic drug.

The incidence of adverse events (Table 7) did not differ significantly between the 2 topiramate regimens. Because the frequencies of adverse events reported in this study were markedly lower than those reported in the previous epilepsy studies, they cannot be directly compared with data obtained in other studies.

Table 7: Incidence of Treatment-Emergent Adverse Events in Study 119a,b Where Rate Was ≥ 2% in the Topiramate Group and Greater Than the Rate in Placebo-Treated Patients
TOPAMAX® Dosage (mg/day)
Body System/
AdverseEventc
Placebo
(N=92)
200
(N=171)

a Patients in these add-on trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to TOPAMAX® or placebo.

b Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category.

c Adverse events reported by at least 2% of patients in the TOPAMAX® 200 mg/day group and more common than in the placebo group are uled in this table.

Body as a Whole-General Disorders
   Fatigue49
   Chest Pain12
Cardiovascular Disorders, General
   Hypertension02
Central & Peripheral Nervous System Disorders
   Paresthesia29
   Dizziness47
   Tremor23
   Hypoasthesia02
   Leg Cramps02
   Language Problems02
Gastro-Intestinal System Disorders
   Abdominal Pain35
   Constipation04
   Diarrhea12
   Dyspepsia02
   Dry Mouth02
Hearing and Vestibular Disorders
   Tinnitus02
Metabolic and Nutritional Disorders
   Weight Decrease48
Psychiatric Disorders
   Somnolence915
   Anorexia79
   Nervousness29
   Difficulty with Concentration/Attention05
   Insomnia34
   Difficulty with Memory12
   Aggressive Reaction02
Respiratory System Disorders
   Rhinitis04
Urinary System Disorders
   Cystitis02
Vision Disorders
   Diplopia02
   Vision Abnormal02
Table 8: Incidence (%) of Dose-Related Adverse Events From Placebo-Controlled, Add-On Trials in Adults with Partial Onset Seizuresa
TOPAMAX® Dosage (mg/day)

Adverse Event
Placebo
(N = 216)
200
(N = 45)
400
(N = 68)
600 - 1,000
(N = 414)

a Dose-response studies were not conducted for other adult indications or for pediatric indications.

Fatigue13111230
Nervousness7131819
Difficulty with Concentration/Attention17914
Confusion491014
Depression69713
Anorexia44612
Language problems<12910
Anxiety62310
Mood problems2069
Weight decrease34913
Table 9: Incidence (%) of Treatment-Emergent Adverse Events in Placebo-Controlled, Add-On Epilepsy Trials in Pediatric Patients Ages 2 -16 Yearsa,b (Events that Occurred in at Least 1% of Topiramate-Treated Patients and Occurred More Frequently in Topiramate-Treated Than Placebo-Treated Patients)
Body System/
Adverse Event
Placebo
(N=101)
Topiramate
(N=98)

a Patients in these add-on trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to TOPAMAX® or placebo.

b Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category.

Body as a Whole - General Disorders
    Fatigue516
    Injury1314
    Allergic Reaction12
    Back Pain01
    Pallor01
Cardiovascular Disorders, General
    Hypertension01
Central & Peripheral Nervous System Disorders
    Gait Abnormal58
    Ataxia26
    Hyperkinesia45
    Dizziness24
    Speech Disorders/Related Speech Problems24
    Hyporeflexia02
    Convulsions Grand Mal01
    Fecal Incontinence01
    Paresthesia01
Gastro-Intestinal System Disorders
    Nausea56
    Saliva Increased46
    Constipation45
    Gastroenteritis23
    Dysphagia01
    Flatulence01
    Gastroesophageal Reflux01
    Glossitis01
    Gum Hyperplasia01
Heart Rate and Rhythm Disorders
    Bradycardia01
Metabolic and Nutritional Disorders
    Weight Decrease19
    Thirst12
    Hypoglycemia01
    Weight Increase01
Platelet, Bleeding,& Clotting Disorders
    Purpura48
    Epistaxis14
    Hematoma01
    Prothrombin Increased01
    Thrombocytopenia01
Psychiatric Disorders
    Somnolence1626
    Anorexia1524
    Nervousness714
    Personality Disorder (Behavior Problems)911
    Difficulty with Concentration/Attention210
    Aggressive Reaction49
    Insomnia78
    Difficulty with Memory NOS05
    Confusion34
    Psychomotor Slowing23
    Appetite Increased01
    Neurosis01
Reproductive Disorders, Female
    Leukorrhoea02
Resistance Mechanism Disorders
    Infection Viral37
Respiratory System Disorders
    Pneumonia15
    Respiratory Disorder01
Skin and Appendages Disorders
    Skin Disorder23
    Alopecia12
    Dermatitis02
    Hypertrichosis12
    Rash Erythematous02
    Eczema01
    Seborrhoea01
    Skin Discoloration01
Urinary System Disorders
    Urinary Incontinence24
    Nocturia01
Vision Disorders
    Eye Abnormality12
    Vision Abnormal12
    Diplopia01
    Lacrimation Abnormal01
    Myopia01
White Cell and RES Disorders
    Leukopenia02

Other Adverse Events Observed During All Epilepsy Clinical Trials

Topiramate has been administered to 2,246 adults and 427 pediatric patients with epilepsy during all clinical studies, only some of which were placebo controlled. During these studies, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified WHOART dictionary terminology. The frequencies presented represent the proportion of patients who experienced an event of the type cited on at least one occasion while receiving topiramate. Reported events are included except those already uled in the previous tables or div, those too general to be informative, and those not reasonably associated with the use of the drug.

Events are classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent occurring in at least 1/100 patients; infrequent occurring in 1/100 to 1/1000 patients; rare occurring in fewer than 1/1000 patients.

Autonomic Nervous System Disorders: Infrequent: vasodilation.

Body as a Whole:Frequent: syncope. Infrequent: abdomen enlarged. Rare: alcohol intolerance.

Cardiovascular Disorders, General:Infrequent: hypotension, postural hypotension, angina pectoris.

Central& Peripheral Nervous System Disorders:Infrequent: neuropathy, apraxia, hyperaesthesia, dyskinesia, dysphonia, scotoma, ptosis, dystonia, visual field defect, encephalopathy, EEG abnormal. Rare: upper motor neuron lesion, cerebellar syndrome, tongue paralysis.

Gastrointestinal System Disorders:. Infrequent: hemorrhoids, stomatitis, melena, gastritis, esophagitis. Rare: tongue edema.

Heart Rate and Rhythm Disorders:Infrequent: AV block.

Liver and Biliary System Disorders:Infrequent: SGPT increased, SGOT increased.

Metabolic and Nutritional Disorders:Infrequent: dehydration, hypokalemia, alkaline phosphatase increased, hypocalcemia, hyperlipemia, hyperglycemia, xerophthalmia, diabetes mellitus,. Rare: hyperchloremia, hypernatremia, hyponatremia, hypocholesterolemia, hypophosphatemia, creatinine increased.

Musculoskeletal System Disorders:Frequent: arthralgia. Infrequent: arthrosis.

Neoplasms:Infrequent: thrombocythemia. Rare: polycythemia.

Platelet, Bleeding, and Clotting Disorders:Infrequent: gingival bleeding, pulmonary embolism.

Psychiatric Disorders:Frequent: impotence, hallucination, psychosis, suicide attempt. Infrequent: euphoria, paranoid reaction, delusion, paranoia, delirium, abnormal dreaming. Rare: libido increased, manic reaction.

Red Blood Cell Disorders:Frequent: anemia. Rare: marrow depression, pancytopenia.

Reproductive Disorders, Male:Infrequent: ejaculation disorder, breast discharge.

Skin and Appendages Disorders:Infrequent: urticaria, photosensitivity reaction, abnormal hair divure. Rare: chloasma.

Special Senses Other, Disorders:Infrequent: taste loss, parosmia.

Urinary System Disorders:Infrequent: urinary retention, face edema, renal pain, albuminuria, polyuria, oliguria.

Vascular (Extracardiac) Disorders:Infrequent: flushing, deep vein thrombosis, phlebitis. Rare: vasospasm.

Vision Disorders:Frequent: conjunctivitis. Infrequent: abnormal accommodation, photophobia, strabismus. Rare: mydriasis, iritis.

White Cell and Reticuloendothelial System Disorders:Infrequent: lymphadenopathy, eosinophilia, lymphopenia, granulocytopenia. Rare: lymphocytosis.

Migraine

In the four multicenter, randomized, double-blind, placebo-controlled, parallel group migraine prophylaxis clinical trials, most of the adverse events with topiramate were mild or moderate in severity. Most adverse events occurred more frequently during the titration period than during the maintenance period.

Table 10 includes those adverse events reported for patients in the placebo-controlled trials where the incidence rate in any topiramate treatment group was at least 2 % and was greater than that for placebo patients.

Table 10: Incidence of Treatment-Emergent Adverse Events in Placebo-Controlled, Migraine Trials Where Rate Was ≥2 % in Any Topiramate Group and Greater than the Rate in Placebo-Treated Patients a
TOPAMAX®  Dosage (mg/day)
Body System/
Adverse Event
Placebo
(N=445)
50
(N=235)
100
(N=386)
200
(N=514)

a Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category.

b Blurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for > 50 % of events coded as vision abnormal, a preferred term.

Body as a Whole-General Disorders
    Fatigue11141519
    Injury7966
    Asthenia1<122
    Fever1112
    Influenza-Like Symptoms<1<1<12
    Allergy<12<1<1
Central & Peripheral Nervous System Disorders
    Paresthesia6355149
    Dizziness108912
    Hypoaesthesia2678
    Language Problems2767
    Involuntary Muscle Contractions1224
    Ataxia<1121
    Speech Disorders/Related Speech Problems<11<12
Gastro-Intestinal System Disorders
    Nausea891314
    Diarrhea491111
    Abdominal Pain5667
    Dyspepsia3453
    Dry Mouth2235
    Vomiting2123
    Gastroenteritis1332
Hearing and Vestibular Disorders
    Tinnitus1<112
Metabolic and Nutritional Disorders
    Weight Decrease16911
    Thirst<1221
Musculoskeletal System Disorders
    Arthralgia2731
Neoplasms
    Neoplasm NOS<12<1<1
Psychiatric Disorders
    Anorexia691514
    Somnolence58710
    Difficulty with Memory NOS27711
    Difficulty with Concentration/Attention23610
    Insomnia5676
    Anxiety3456
    Mood Problems2365
    Depression4346
    Nervousness2444
    Confusion2234
    Psychomotor Slowing1324
    Libido Decreased1112
    Aggravated Depression1122
    Agitation1221
    Cognitive Problems NOS1<122
Reproductive Disorders, Female
    Menstrual Disorder2322
Reproductive Disorders, Male
    Ejaculation Premature0300
Resistance Mechanism Disorders
    Viral Infection3443
    Otitis Media<1211
Respiratory System Disorders
    Upper Respiratory Tract Infection12131412
    Sinusitis61068
    Pharyngitis4562
    Coughing2243
    Bronchitis2333
    Dyspnea2132
    Rhinitis1122
Skin and Appendages Disorders
    Pruritis2422
Special Sense Other, Disorders
    Taste Perversion115812
    Taste Loss<1112
Urinary System Disorders
    Urinary Tract Infection2424
    Renal Calculus0012
Vision Disorders
    Vision Abnormal<1123
    Blurred Vision b2424
    Conjunctivitis1121

Of the 1,135 patients exposed to topiramate in the placebo-controlled studies, 25% discontinued due to adverse events, compared to 10% of the 445 placebo patients. The adverse events associated with discontinuing therapy in the topiramate-treated patients included paresthesia (7%), fatigue (4%), nausea (4%), difficulty with concentration/attention (3%), insomnia (3%), anorexia (2%), and dizziness (2%).

Patients treated with topiramate experienced mean percent reductions in body weight that were dose-dependent. This change was not seen in the placebo group. Mean changes of 0%, –2%, – 3%, and – 4% were seen for the placebo group, topiramate 50, 100, and 200 mg groups, respectively.

Table 11 shows adverse events that were dose-dependent. Several central nervous system adverse events, including some that represented cognitive dysfunction, were dose-related. The most common dose-related adverse events were paresthesia, fatigue, nausea, anorexia, dizziness, difficulty with memory, diarrhea, weight decrease, difficulty with concentration/attention, and somnolence.

Table 11: Incidence (%) of Dose-Related Adverse Events From Placebo-Controlled, Migraine Trialsa
TOPAMAX® Dosage (mg/day)

Adverse Event
Placebo
(N =445)
50
(N = 235)
100
(N = 386)
200
(N = 514 )

a The incidence rate of the adverse event in the 200 mg/day group was ≥2% than the rate in both the placebo group and the 50 mg/day group.

Paresthesia6355149
Fatigue11141519
Nausea891314
Anorexia691514
Dizziness108912
Weight decrease16911
Difficulty with Memory NOS27711
Diarrhea491111
Difficulty with Concentration/Attention23610
Somnolence58710
Hypoaesthesia2678
Anxiety3456
Depression4346
Mood Problems2365
Dry Mouth2235
Confusion2234
Involuntary Muscle Contractions1224
Abnormal Vision<1123
Renal Calculus0012

Other Adverse Events Observed During Migraine Clinical Trials

Topiramate, for the treatment of prophylaxis of migraine headache, has been administered to 1,367 patients in all clinical studies (includes double-blind and open-label extension). During these studies, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified WHOART dictionary terminology.

The following additional adverse events that were not described earlier were reported by greater than 1% of the 1,367 topiramate-treated patients in the controlled clinical trials:

Body as a Whole: Pain, chest pain, allergic reaction.

Central & Peripheral Nervous System Disorders: Headache, vertigo, tremor, sensory disturbance, migraine aggravated.

Gastrointestinal System Disorders: Constipation, gastroesophageal reflux, tooth disorder.

Musculoskeletal System Disorders: Myalgia.

Platelet, Bleeding, and Clotting Disorders: Epistaxis.

Reproductive Disorders, Female: Intermenstrual bleeding.

Resistance Mechanism Disorders: Infection, genital moniliasis.

Respiratory System Disorders: Pneumonia, asthma.

Skin and Appendages Disorders: Rash, alopecia.

Vision Disorders: Abnormal accommodation, eye pain.

Postmarketing and Other Experience

In addition to the adverse experiences reported during clinical testing of TOPAMAX®, the following adverse experiences have been reported worldwide in patients receiving TOPAMAX® post-approval. Adverse drug reactions from spontaneous reports during the worldwide postmarketing experience with TOPAMAX® are included in Table 12. The adverse drug reactions are ranked by frequency, using the following convention (all calculated per patient-years of estimated exposure):

Very common≥1/10
Common≥1/100 and <1/10
Uncommon≥1/1,000 and <1/100
Rare≥1/10,000 and <1/1000
Very rare<1/10,000

The frequencies provided below reflect reporting rates for adverse drug reactions from spontaneous reports, and do not represent more precise estimates that might be obtained in clinical or experimental studies.

Table 12: Postmarketing Reports of Adverse Drug Reactions
Blood and Lymphatic System DisordersVery rare: leucopenia and neutropenia, thrombocytopenia
Metabolism and Nutrition DisordersRare: anorexia
Very rare: metabolic acidosis (see Warnings), decreased appetite, hyperammonemia (see Precautions)
Psychiatric DisordersRare: depression agitation; somnolence (see Warnings)
Very rare: insomnia, confusional state, psychotic disorder, aggression, hallucination, suicidal ideation, attempts, and suicide, expressive language disorder (see Warnings)
Nervous System DisordersRare: paresthesia (see Precautions), convulsion, headache
Very rare: speech disorder, dysgeusia, amnesia, memory impairment, drug withdrawal convulsion (see Warnings)
Eye DisordersRare: visual disturbance, vision blurred
Very rare: myopia and angle closure glaucoma (see Warnings), eye pain, blindness transient
Gastrointestinal DisordersRare: nausea
Very rare: diarrhea, abdominal pain , vomiting, acute pancreatitis
Skin and Subcutaneous Tissue Disorders Rare: alopecia
Very rare: rash
Renal and Urinary DisordersRare: nephrolithiasis (see Warnings)
Very rare: renal tubular acidosis
General Disorders and Administration Site ConditionsRare: fatigue, oligohydrosisThe majority of these reports have been in children. (see Warnings)
Very rare: pyrexia, feeling abnormal, asthenia
InvestigationsRare: weight decreased
Very rare: hepatic enzymes increased

In addition, the following adverse experiences have been reported very rarely worldwide in patients receiving TOPAMAX® post-approval. These adverse experiences have not been uled above and data are insufficient to support an estimate of their incidence or to establish causation. The uling is alphabetized: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), hepatic failure (including fatalities), hepatitis, pancreatitis, and pemphigus.

DRUG ABUSE AND DEPENDENCE

The abuse and dependence potential of TOPAMAX® has not been evaluated in human studies.

OVERDOSAGE

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

Topiramate overdose has resulted in severe metabolic acidosis (see WARNINGS).

A patient who ingested a dose 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 TOPAMAX® 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 is an effective means of removing topiramate from the body.

DOSAGE AND ADMINISTRATION

Epilepsy

In the controlled add-on trials, no correlation has been demonstrated between trough plasma concentrations of topiramate and clinical efficacy. No evidence of tolerance has been demonstrated in humans. Doses above 400 mg/day (600, 800, or 1,000 mg/day) have not been shown to improve responses in dose-response studies in adults with partial onset seizures.

It is not necessary to monitor topiramate plasma concentrations to optimize TOPAMAX® therapy. On occasion, the addition of TOPAMAX® to phenytoin may require an adjustment of the dose of phenytoin to achieve optimal clinical outcome. Addition or withdrawal of phenytoin and/or carbamazepine during adjunctive therapy with TOPAMAX® may require adjustment of the dose of TOPAMAX®. Because of the bitter taste, tablets should not be broken.

TOPAMAX® can be taken without regard to meals.

Adjunctive Therapy Use

Migraine

The recommended total daily dose of TOPAMAX® as treatment for prophylaxis of migraine headache is 100 mg/day administered in two divided doses. The recommended titration rate for topiramate for migraine prophylaxis to 100 mg/day is:

 Morning DoseEvening Dose
Week 1None25 mg
Week 225 mg25 mg
Week 325 mg50 mg
Week 450 mg50 mg

Dose and titration rate should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used.

Administration of TOPAMAX® Sprinkle Capsules

TOPAMAX® (topiramate capsules) Sprinkle Capsules may be swallowed whole or may be administered by carefully opening the capsule and sprinkling the entire spans 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.

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.

Geriatric Patients (Ages 65 Years and Over):

Dosage adjustment may be indicated in the elderly patient when impaired renal function (creatinine clearance rate≤70 mL/min/1.73 m2) is evident (see DOSAGE AND ADMINISTRATION: Patients with Renal Impairment and CLINICAL PHARMACOLOGY: Special Populations: Age, Gender, and Race).

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 anti-seizure effect. To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate may be required. The actual adjustment should take into account 1) the duration of dialysis period, 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 may be increased. The mechanism is not well understood.

HOW SUPPLIED

TOPAMAX® (topiramate) Tablets are available as debossed, coated, round tablets in the following strengths and colors:

25 mg white (coded "TOP" on one side; "25" on the other)
50 mg light-yellow (coded "TOPAMAX" on one side; "50" on the other)
100 mg yellow (coded "TOPAMAX" on one side; "100" on the other)
200 mg salmon (coded "TOPAMAX" on one side; "200" on the other)

They are supplied as follows:
25 mg tablets – bottles of 60 count with desiccant (NDC 0045-0639-65)
50 mg tablets – bottles of 60 count with desiccant (NDC 0045-0640-65)
100 mg tablets – bottles of 60 count with desiccant (NDC 0045-0641-65)
200 mg tablets – bottles of 60 count with desiccant (NDC 0045-0642-65)

TOPAMAX® (topiramate capsules) Sprinkle Capsules contain small, white to off white spheres. The gelatin capsules are white and clear.

They are marked as follows:
15 mg capsule with “TOP” and “15 mg” on the side
25 mg capsule with “TOP” and “25 mg” on the side

The capsules are supplied as follows:
15 mg capsules – bottles of 60 (NDC 0045-0647-65)
25 mg capsules – bottles of 60 (NDC 0045-0645-65)

TOPAMAX® (topiramate) Tablets should be stored in tightly-closed containers at controlled room temperature (59 to 86°F, 15 to 30°C). Protect from moisture.

TOPAMAX® (topiramate capsules) Sprinkle Capsules should be stored in tightly-closed containers at or below 25°C (77°F). Protect from moisture.

TOPAMAX® (topiramate) and TOPAMAX® (topiramate capsules) are trademarks of Ortho-McNeil Neurologics, Inc.


SPL Patient Package Insert

PATIENT INFORMATION

TOPAMAX® [ Toe-pa-max.]

(topiramate) Tablets/(topiramate capsules) Sprinkle Capsules

What do TOPAMAX Tablets and Sprinkle Capsules look like?

TOPAMAX® (topiramate) Tablets
25 mg 50 mg100 mg200 mg
WhiteLight-YellowYellowSalmon

Topamax (topiramate capsules) Sprinkle Capsules

Capsules are white and clear.

Note: The pictures above show the shapes and lettering of TOPAMAX tablets and sprinkle capsules. The wording describes the strength and colors of the medication. Before taking your medicine, it is important to compare the tablets or sprinkle capsules you receive from your healthcare professional or pharmacist with these pictures to make sure you have received the correct medicine.

Please read this patient information carefully before you take TOPAMAX and each time you obtain a refill, in case any information has changed. This summary does not contain all the information about TOPAMAX and is not meant to take the place of talking with your healthcare professional. If you have any questions about TOPAMAX, discuss them with your healthcare professional or pharmacist.

What is TOPAMAX?

TOPAMAX is a prescription medicine used:

  • alone to treat seizures in patients 10 years and older

  • with other medicines to treat seizures in adults and children over age 2

  • to prevent migraine headaches in adults

Who Should Not Take TOPAMAX?

Do not take TOPAMAX if you are allergic to anything in it. See the end of this leaflet for a complete ul of ingredients in TOPAMAX.

What Should I Tell My Healthcare Professional Before Taking TOPAMAX?

Tell your healthcare professional about all of your medical conditions, including if you:

  • have kidney problems, especially kidney stones, or are getting kidney dialysis

  • have a history of metabolic acidosis (blood and body fluid abnormality)

  • have liver problems

  • have osteoporosis (weak or brittle bones) and/or soft bones (osteomalacia) or decreased bone density (osteopenia)

  • have lung or breathing problems

  • have eye problems, especially glaucoma

  • have diarrhea

  • have a growth problem

  • are on a diet high in fat called a ketogenic diet

  • are having surgery

  • are pregnant or planning to become pregnant. It is not known if TOPAMAX can harm your unborn baby.

  • are breastfeeding. TOPAMAX may pass into your milk. Talk to your healthcare professional about the best way to feed your baby while taking TOPAMAX.

  • suffer from depression, mood problems or suicidal thoughts or behavior

Tell your healthcare professional about all the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. TOPAMAX and certain other medicines can affect each other. Sometimes the dose of some of your other medicines or TOPAMAX will have to be adjusted. Especially, tell your healthcare professional if you are taking:

  • other medicines that impair or decrease your thinking, concentration, or muscle coordination (e.g. central nervous system depressant medicines).

  • birth control pills. TOPAMAX may make your birth control pills less effective. Tell your healthcare professional if your menstrual bleeding changes while you are taking birth control pills and TOPAMAX.

Keep a ul of all the medicines you take. Show this ul to your healthcare professionals and pharmacists before you start a new medicine.

How Should I Take TOPAMAX?

  • Take TOPAMAX exactly as prescribed. Your healthcare professional will usually start you on a low dose of TOPAMAX and slowly increase your dose until the best dose is found for you.

  • TOPAMAX Tablets should be swallowed whole. Avoid, chewing the tablets as they may leave a bitter taste.

  • TOPAMAX Sprinkle Capsules may be swallowed whole or may be opened and sprinkled on a teaspoon of soft food of any type. Examples are applesauce, custard, ice cream, oatmeal, pudding or yogurt. Drink fluids right after to make sure all of the food and medicine mixture is swallowed.

  • Never store any medicine and food mixture for use at a later time.

  • TOPAMAX can be taken before, during, or after a meal. Drink plenty of fluids during the day to prevent kidney stones while taking TOPAMAX.

  • If you take too much TOPAMAX, call your healthcare professional or poison control center right away or go to an emergency room.

  • If you miss a single dose of TOPAMAX, take it as soon as you can. However, if you are within 6 hours of taking your next scheduled dose, wait until then to take your usual dose of TOPAMAX, and skip the missed dose. Do not double your dose. If you have missed more than one dose, you should call your healthcare professional for advice.

  • Do not stop taking TOPAMAX unless a healthcare professional tells you to stop taking TOPAMAX. Your healthcare professional will tell you how to slowly stop taking TOPAMAX.

What Should I Avoid While Taking TOPAMAX?

  • If you are taking Topamax or other antiepileptic drugs for epilepsy or seizures, you may need to avoid activities where loss of consciousness (passing out) could result in serious danger to yourself or those around you (including swimming, driving a car, climbing in high places, etc.). Talk to your doctor before engaging in such activities.

  • Unless prescribed by your healthcare professional, you should avoid other medicines that also impair or decrease your thinking, concentration, or muscle coordination (e.g. central nervous system depressant medicines).

  • You should avoid drinking alcohol while taking TOPAMAX. Alcohol with TOPAMAX can make side effects such as sleepiness and dizziness worse.

  • Do not drive a car or operate heavy machinery until you know how TOPAMAX affects you. TOPAMAX can impair your thinking, motor skills, and/or vision.

What are the Possible Side Effects of TOPAMAX?

TOPAMAX may cause the following side effects which can be serious :

  • metabolic acidosis. Metabolic acidosis is a condition that happens when there is too much acid in your blood. Metabolic acidosis can cause symptoms such as tiredness, loss of appetite, irregular heartbeat, and impaired consciousness. Call your healthcare professional right away if you get these symptoms with TOPAMAX. Your healthcare professional should do a blood test (measurement of serum bicarbonate) to monitor your bicarbonate level while you are taking TOPAMAX.

  • eye problems. Serious eye problems include:

    • a sudden decrease in vision (acute myopia) with or without eye pain and

    • a blockage of fluid in the eye causing increased pressure in the eye (secondary angle closure glaucoma).

Call your healthcare professional right away if you have a loss in vision or get eye pain. These problems can lead to blindness if not treated right away. Your healthcare professional will probably stop TOPAMAX and may recommend other therapy.

  • decreased sweating (oligohidrosis) and increased body temperature (fever). Patients, especially children, should be watched closely for signs of decreased sweating and fever (increased body temperature), especially in hot temperatures. Some patients may need hospital treatment for this condition.

  • effects on thinking and alertness. TOPAMAX may affect thinking skills and cause confusion, problems with concentration, attention, memory, and/or speech. TOPAMAX may cause depression or mood problems, tiredness, and sleepiness. Call your healthcare professional right away if you experience any of these side effects.

  • dizziness or loss of muscle coordination in patients who take TOPAMAX alone or with other seizure medicines.

  • high blood ammonia levels and effects on mental activities. High ammonia in the blood can affect your mental activities and decrease alertness, can make you feel tired or fatigued, or can cause vomiting. This has happened when TOPAMAX has been used with a medicine called valproic acid (DEPAKENE® and DEPAKOTE®).

  • kidney stones. Drink plenty of fluids when taking TOPAMAX to decrease your chances of getting kidney stones.

  • tingling of the arms and legs (paresthesia) is a common side effect of TOPAMAX.

Other side effects with TOPAMAX include loss of appetite, nausea, a change in the way foods taste, diarrhea, weight loss, nervousness, aggression, upper respiratory tract infection.

Call your healthcare professional if you have any symptoms that concern you or that do not go away.

These are not all the side effects with TOPAMAX. For more information, ask your healthcare professional or pharmacist.

What Should I Do If I Get Pregnant While Taking TOPAMAX?

It is not clear if there is a risk to the fetus/baby if you are exposed to TOPAMAX and you are pregnant. Various abnormalities have been described in the offspring of animals exposed to TOPAMAX during pregnancy. If you use TOPAMAX while you are pregnant, ask your healthcare professional about reporting your experience to the North American Drug Pregnancy Registry at Massachusetts General Hospital (Boston, MA). This registry collects information about the babies born to women who are taking drugs to treat various conditions. Information about the North American Drug Pregnancy Registry can be found at http://www.massgeneral.org/aed/. You can also join the registry by calling 1-877-376-3872.

How Should I Store TOPAMAX?

  • Store TOPAMAX tablets in tightly-closed containers at room temperature, 59°F to 86°F (15°C to 30°C). Protect from moisture.

  • Store TOPAMAX Sprinkle Capsules in tightly-closed containers at or below 77°F (25°C). Protect from moisture.

  • Keep TOPAMAX and all medicines out of the reach of children.

General Information About TOPAMAX.

Medicines are sometimes prescribed for purposes other than those uled in Patient Information leaflets. Do not use TOPAMAX for a condition for which it was not prescribed. Do not give TOPAMAX to other people, even if they have the same symptoms that you have. It may harm them.

This leaflet summarizes the most important information about TOPAMAX. If you would like more information, talk to your healthcare professional. You can ask your health care professional or pharmacist for information about TOPAMAX that is written for health professionals. You can also visit www.topamax.com or call 1-800-526-7736 for more information.

What Are the Ingredients of TOPAMAX?

Active Ingredient: topiramate

Inactive Ingredients:

  • Tablets - contain lactose monohydrate, pregelatinized starch, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, purified water, carnauba wax, hypromellose, titanium dioxide, polyethylene, glycol, synthetic iron oxide (50, 100 and 200 mg tablets) and polysorbate 80.

  • Sprinkle Capsules - contain sugar spheres (sucrose and starch), povidone, cellulose acetate, gelatin, sorbitan monolaurate, sodium lauryl sulfate, titanium dioxide, and black pharmaceutical ink.

DEPAKENE® and DEPAKOTE® are registered trademarks of Abbott Laboratories

ORTHO-McNEIL NEUROLOGICS, INC.
Titusville, NJ 08560
© OMN 2005 December 2006
7517114

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