Topamax 200 MG Oral Tablet

Generic Name: TOPIRAMATE
Brand Name: Topamax
  • Substance Name(s):
  • TOPIRAMATE

DRUG INTERACTIONS

7 Oral contraceptives: decreased contraceptive efficacy and increased breakthrough bleeding, especially at doses greater than 200 mg/day (7.3) Monitor lithium levels if lithium is used with high-dose TOPAMAX® (7.4) 7.1 Antiepileptic Drugs Concomitant administration of phenytoin or carbamazepine with TOPAMAX® resulted in a clinically significant decrease in plasma concentrations of topiramate when compared to TOPAMAX® given alone.

A dosage adjustment may be needed [see Dosage and Administration (2.1), Clinical Pharmacology (12.3).] Concomitant administration of valproic acid and TOPAMAX® has been associated with hypothermia and hyperammonemia with and without encephalopathy.

Examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.9, 5.11), Clinical Pharmacology (12.3)].

7.2 CNS Depressants Concomitant administration of TOPAMAX® and alcohol or other CNS depressant drugs has not been evaluated in clinical studies.

Because of the potential of topiramate to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse reactions, TOPAMAX® should be used with extreme caution if used in combination with alcohol and other CNS depressants.

7.3 Oral Contraceptives The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking combination oral contraceptive products with TOPAMAX®.

Patients taking estrogen-containing contraceptives should be asked to report any change in their bleeding patterns.

Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding [see Clinical Pharmacology (12.3)].

7.4 Lithium An increase in systemic exposure of lithium following TOPAMAX® doses of up to 600 mg/day can occur.

Lithium levels should be monitored when co-administered with high-dose TOPAMAX® [see Clinical Pharmacology (12.3)].

7.5 Other Carbonic Anhydrase Inhibitors Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide or acetazolamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation.

Therefore, patients given TOPAMAX® concomitantly with another carbonic anhydrase inhibitor should be monitored particularly closely for the appearance or worsening of metabolic acidosis [see Clinical Pharmacology (12.3)].

7.6 Hydrochlorothiazide (HCTZ) Topiramate Cmax and AUC increased when HCTZ was added to TOPAMAX®.

The clinical significance of this change is unknown.

The addition of HCTZ to TOPAMAX® may require a decrease in the TOPAMAX® dose [see Clinical Pharmacology (12.3)].

7.7 Pioglitazone A decrease in the exposure of pioglitazone and its active metabolites were noted with the concurrent use of pioglitazone and TOPAMAX® in a clinical trial.

The clinical relevance of these observations is unknown; however, 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 [see Clinical Pharmacology (12.3)].

7.8 Amitriptyline Some patients may experience a large increase in amitriptyline concentration in the presence of TOPAMAX® and any adjustments in amitriptyline dose should be made according to the patient’s clinical response and not on the basis of plasma levels [see Clinical Pharmacology (12.3)].

OVERDOSAGE

10 Overdoses of TOPAMAX® have been reported.

Signs and symptoms included convulsions, drowsiness, speech disturbance, blurred vision, diplopia, impaired mentation, 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 overdoses involving TOPAMAX®.

TOPAMAX® overdose has resulted in severe metabolic acidosis [see Warnings and Precautions (5.4)].

A patient who ingested a dose of TOPAMAX® between 96 and 110 g was admitted to a hospital with a coma lasting 20 to 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.

Hemodialysis is an effective means of removing topiramate from the body.

DESCRIPTION

11 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® Tablets contain the following inactive ingredients: carnauba wax, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, pregelatinized starch, purified water, sodium starch glycolate, synthetic iron oxide, and titanium dioxide.

TOPAMAX® Sprinkle Capsules contain topiramate-coated beads in a hard gelatin capsule.

The inactive ingredients are black pharmaceutical ink, cellulose acetate, gelatin, povidone, sodium lauryl sulfate, sorbitan monolaurate, sugar spheres (sucrose and starch) and titanium dioxide.

Chemical Structure

CLINICAL STUDIES

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

14.1 Monotherapy Epilepsy Patients with Partial Onset or Primary Generalized Tonic-Clonic Seizures Adults and Pediatric Patients 10 Years of Age and Older The effectiveness of TOPAMAX® as initial monotherapy in adults and pediatric patients 10 years of age and older with partial onset or primary generalized tonic-clonic 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 TOPAMAX® 25 mg/day for 7 days in an open-label fashion.

Forty-nine percent of patients 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 TOPAMAX® 400 mg/day group over the TOPAMAX® 50 mg/day group (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 Figure 1 Pediatric Patients 2 to 9 Years of Age The conclusion that TOPAMAX® is effective as initial monotherapy in pediatric patients 2 to 9 years of age with partial onset or primary generalized tonic-clonic seizures was based on a pharmacometric bridging approach using data from the controlled epilepsy trials described in labeling.

This approach consisted of first showing a similar exposure response relationship between pediatric patients down to 2 years of age and adults when TOPAMAX® was given as adjunctive therapy.

Similarity of exposure-response was also demonstrated in pediatric patients 6 to less than 16 years of age and adults when TOPAMAX® was given as initial monotherapy.

Specific dosing in pediatric patients 2 to 9 years of age was derived from simulations utilizing plasma exposure ranges observed in pediatric and adult patients treated with TOPAMAX® initial monotherapy [see Dosage and Administration (2.1)] .

14.2 Adjunctive Therapy Epilepsy Adult Patients With Partial Onset Seizures The effectiveness of TOPAMAX® 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 TOPAMAX® 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 pre-specified minimum number of partial onset seizures, with or without secondary generalization, during the baseline phase (12 seizures for 12-week baseline, 8 for 8-week baseline or 3 for 4-week baseline) were randomly assigned to placebo or a specified dose of 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 (Study 6), 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 11.

Pediatric Patients 2 to 16 Years of Age with Partial Onset Seizures The effectiveness of TOPAMAX® as an adjunctive treatment for pediatric patients 2 to 16 years of age with partial onset seizures was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 7), comparing TOPAMAX® and placebo in patients with a history of partial onset seizures, with or without secondarily generalized seizures (see Table 12).

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/day; the dose was then increased by 25 mg to 150 mg/day increments every other week until the assigned dosage of 125, 175, 225, or 400 mg/day based on patients’ weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases.

After titration, patients entered an 8-week stabilization period.

Patients With Primary Generalized Tonic-Clonic Seizures The effectiveness of TOPAMAX® as an adjunctive treatment for primary generalized tonic-clonic seizures in patients 2 years of age and older was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 8), comparing a single dosage of TOPAMAX® and placebo (see Table 12).

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/day for four weeks; the dose was then increased by 50 mg to 150 mg/day increments every other week until the assigned dose of 175, 225, or 400 mg/day based on patients’ body weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases.

After titration, patients entered a 12-week stabilization period.

Patients With Lennox-Gastaut Syndrome The effectiveness of TOPAMAX® as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 9) comparing a single dosage of TOPAMAX® with placebo in patients 2 years of age and older (see Table 12).

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/day for a week; the dose was then increased to 3 mg/kg/day for one week, then to 6 mg/kg/day.

After titration, patients entered an 8-week stabilization period.

The primary measures of effectiveness were the percent reduction in drop attacks and a parental global rating of seizure severity.

Table 11: TOPAMAX® Dose Summary During the Stabilization Periods of Each of Six Double-Blind, Placebo-Controlled, Add-On Trials in Adults with Partial Onset SeizuresDose-response studies were not conducted for other indications or pediatric partial onset seizures.

Target TOPAMAX® Dosage (mg/day) Protocol Stabilization Dose PlaceboPlacebo dosages are given as the number of tablets.

Placebo target dosages were as follows: Protocol 3 4 tablets/day; Protocols 1 and 4, 6 tablets/day; Protocols 5 and 6, 8 tablets/day; Protocol 2, 10 tablets/day.

200 400 600 800 1,000 1 N Mean Dose Median Dose 42 5.9 6.0 42 200 200 40 390 400 41 556 600 — — — — — — 2 N Mean Dose Median Dose 44 9.7 10.0 — — — — — — 40 544 600 45 739 800 40 796 1,000 3 N Mean Dose Median Dose 23 3.8 4.0 — — — 19 395 400 — — — — — — — — — 4 N Mean Dose Median Dose 30 5.7 6.0 — — — — — — 28 522 600 — — — — — — 5 N Mean Dose Median Dose 28 7.9 8.0 — — — — — — — — — 25 568 600 — — — 6 N Mean Dose Median Dose 90 8 8 157 200 200 — — — — — — — — — — — — 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 12.

As described above, a global improvement in seizure severity was also assessed in the Lennox-Gastaut trial.

Table 12: Efficacy Results in Double-Blind, Placebo-Controlled, Add-On Epilepsy Trials Target TOPAMAX® Dosage (mg/day) Placebo 200 400 600 800 1,000 ≈6 mg/kg/dayFor Protocols 7 and 8, 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.

Protocol Efficacy Results 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; Partial Onset Seizures Studies in Adults 1 N 45 45 45 46 — — — Median % Reduction 12 27a 48b 45c — — — % Responders 18 24 44d 46d — — — 2 N 47 — — 48 48 47 — Median % Reduction 2 — — 41c 41c 36c — % Responders 9 — — 40c 41c 36d — 3 N 24 — 23 — — — — Median % Reduction 1 — 41e — — — — % Responders 8 — 35d — — — — 4 N 30 — — 30 — — — Median % Reduction -12 — — 46f — — — % Responders 10 — — 47c — — — 5 N 28 — — — 28 — — Median % Reduction -21 — — — 24c — — % Responders 0 — — — 43c — — 6 N 91 168 — — — — — Median % Reduction 20 44c — — — — — % Responders 24 45c — — — — — Studies in Pediatric Patients 7 N 45 — — — — — 41 Median % Reduction 11 — — — — — 33d % Responders 20 — — — — — 39 Primary Generalized Tonic-ClonicMedian % reduction and % responders are reported for PGTC Seizures; 8 N 40 — — — — — 39 Median % Reduction 9 — — — — — 57d % Responders 20 — — — — — 56c Lennox-Gastaut SyndromeMedian % reduction and % responders for drop attacks, i.e., tonic or atonic seizures; 9 N 49 — — — — — 46 Median % Reduction -5 — — — — — 15d % Responders 14 — — — — — 28g Improvement in Seizure SeverityPercent of patients who were minimally, much, or very much improved from baseline 28 — — — — — 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/day in adults and over a 2- to 8-week period in pediatric patients; transition was permitted to a new antiepileptic regimen when clinically indicated.

14.3 Migraine Prophylaxis Adult Patients 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 (Study 10 was conducted in the U.S.

and Study 11 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 (IHS) 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 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 and 18-week maintenance period).

Treatment was initiated at 25 mg/day for one week, and then the daily dosage was increased by 25 mg increments each week until reaching the assigned target dose or maximum tolerated dose (administered twice daily).

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

In Study 10, a total of 469 patients (416 females, 53 males), ranging in age from 13 to 70 years, were randomized and provided efficacy data.

Two hundred sixty-five patients completed the entire 26-week double-blind phase.

The median average daily dosages were 48 mg/day, 88 mg/day, and 132 mg/day in the target dose groups of 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 treatment differences between the TOPAMAX® 100 and 200 mg/day groups versus placebo were similar and statistically significant (p<0.001 for both comparisons).

In Study 11, a total of 468 patients (406 females, 62 males), ranging in age from 12 to 65 years, were randomized and provided efficacy data.

Two hundred fifty-five patients completed the entire 26-week double-blind phase.

The median average daily dosages were 47 mg/day, 86 mg/day, and 150 mg/day in the target dose groups of 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 similar and statistically significant (p=0.008 and p <0.001, respectively).

In both studies, there were no apparent differences in treatment effect within age or gender subgroups.

Because most patients were Caucasian, there were insufficient numbers of patients from different races to make a meaningful comparison of race.

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

Figure 2: Reduction in 4-Week Migraine Headache Frequency (Studies 10 and 11 for Adults and Adolescents) Figure 2 Pediatric Patients 12 to 17 Years of Age The effectiveness of TOPAMAX® as prophylaxis for migraine headache in pediatric patients 12 to 17 years of age was established in a multicenter, randomized, double-blind, parallel-group trial.

The study enrolled 103 patients (40 male, 63 female) 12 to 17 years of age with episodic migraine headaches with or without aura.

Patient selection was based on IHS criteria for migraines (using proposed revisions to the 1988 IHS pediatric migraine criteria [IHS-R criteria]).

Patients who experienced 3 to 12 migraine attacks (according to migraines classified by patient reported diaries) and ≤14 headache days (migraine and non-migraine) during the 4-week prospective baseline period were randomized to either TOPAMAX® 50 mg/day, 100 mg/day, or placebo and treated for a total of 16 weeks (4-week titration period followed by a 12-week maintenance period).

Treatment was initiated at 25 mg/day for one week, and then the daily dosage was increased by 25 mg increments each week until reaching the assigned target dose or maximum tolerated dose (administered twice daily).

Approximately 80% or more patients in each treatment group completed the study.

The median average daily dosages were 45 and 79 mg/day in the target dose groups of TOPAMAX® 50 and 100 mg/day, respectively.

Effectiveness of treatment was assessed by comparing each TOPAMAX® treatment group to placebo (ITT population) for the percent reduction from baseline to the last 12 weeks of the double-blind phase in the monthly migraine attack rate (primary endpoint).

The percent reduction from baseline to the last 12 weeks of the double-blind phase in average monthly migraine attack rate is shown in Table 13.

The 100 mg TOPAMAX® dose produced a statistically significant treatment difference relative to placebo of 28% reduction from baseline in the monthly migraine attack rate.

The mean reduction from baseline to the last 12 weeks of the double-blind phase in average monthly attack rate, a key secondary efficacy endpoint in Study 12 (and the primary efficacy endpoint in Studies 10 and 11, of adults) was 3.0 for 100 mg TOPAMAX® dose and 1.7 for placebo.

This 1.3 treatment difference in mean reduction from baseline of monthly migraine rate was statistically significant (p = 0.0087).

Table 13: Percent Reduction from Baseline to the Last 12 Weeks of Double-Blind Phase in Average Monthly Attack Rate: Study 12 (Intent-to-Treat Analysis Set) Placebo TOPAMAX® 50 mg/day TOPAMAX® 100 mg/day Category (N=33) (N=35) (N=35) Baseline Median 3.6 4.0 4.0 Last 12 Weeks of Double-Blind Phase Median 2.3 2.3 1.0 Percent Reduction (%) Median 44.4 44.6 72.2 P-value versus 0.7975 0.0164 Indicates p-value is <0.05 (two-sided).

Placebo P-values (two-sided) for comparisons relative to placebo are generated by applying an ANCOVA model on ranks that includes subject’s stratified age at baseline, treatment group, and analysis center as factors and monthly migraine attack rate during baseline period as a covariate.

, P-values for the dose groups are the adjusted p-value according to the Hochberg multiple comparison procedure.

HOW SUPPLIED

16 /STORAGE AND HANDLING 16.1 How Supplied TOPAMAX® Tablets TOPAMAX® (topiramate) Tablets are available as debossed, coated, round tablets in the following strengths and colors: 25 mg cream tablet (debossed “OMN” on one side; “25” on the other) and are available in bottles of 60 count with desiccant (NDC 50458-639-65) 50 mg light yellow tablet (debossed “OMN” on one side; “50” on the other) and are available in bottles of 60 count with desiccant (NDC 50458-640-65) 100 mg yellow tablet (debossed “OMN” on one side; “100” on the other) and are available in bottles of 60 count with desiccant (NDC 50458-641-65) 200 mg salmon tablet (debossed “OMN” on one side; “200” on the other) and are available in bottles of 60 count with desiccant (NDC 50458-642-65) TOPAMAX® Sprinkle Capsules TOPAMAX® (topiramate capsules) Sprinkle Capsules contain small, white to off-white spheres.

The gelatin capsules are white and clear and are marked as follows: 15 mg capsule with “TOP” and “15 mg” on the side and are available in bottles of 60 (NDC 50458-647-65) 25 mg capsule with “TOP” and “25 mg” on the side and are available in bottles of 60 (NDC 50458-645-65) 16.2 Storage and Handling TOPAMAX® Tablets TOPAMAX® Tablets should be stored in tightly-closed containers at controlled room temperature (59° to 86°F, 15° to 30°C).

Protect from moisture.

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

Protect from moisture.

GERIATRIC USE

8.5 Geriatric Use In clinical trials, 3% of patients were over age 60.

No age-related differences in effectiveness or adverse effects were evident.

However, clinical studies of topiramate did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently than younger subjects.

Dosage adjustment may be necessary for elderly with age-related renal impairment (creatinine clearance rate <70 mL/min/1.73 m2) resulting in reduced clearance [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].

DOSAGE FORMS AND STRENGTHS

3 TOPAMAX® Tablets are available as debossed, coated, round tablets in the following strengths and colors: 25 mg cream (debossed “OMN” on one side; “25” on the other) 50 mg light-yellow (debossed “OMN” on one side; “50” on the other) 100 mg yellow (debossed “OMN” on one side; “100” on the other) 200 mg salmon (debossed “OMN” on one side; “200” on the other) TOPAMAX® 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 Tablets: 25 mg, 50 mg, 100 mg, and 200 mg (3) Sprinkle Capsules: 15 mg and 25 mg (3)

MECHANISM OF ACTION

12.1 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.

INDICATIONS AND USAGE

1 TOPAMAX® is indicated for: Epilepsy: initial monotherapy in patients ≥2 years of age with partial onset or primary generalized tonic-clonic seizures (1.1); adjunctive therapy for adults and pediatric patients (2 to 16 years of age) with partial onset seizures or primary generalized tonic-clonic seizures, and for patients ≥2 years of age with seizures associated with Lennox-Gastaut syndrome (1.2) Prophylaxis of migraine in patients 12 years of age and older (1.3) 1.1 Monotherapy Epilepsy TOPAMAX® is indicated as initial monotherapy in patients 2 years of age and older with partial onset or primary generalized tonic-clonic seizures.

1.2 Adjunctive Therapy Epilepsy TOPAMAX® is indicated as adjunctive therapy for adults and pediatric patients 2 to 16 years of age 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.

1.3 Migraine TOPAMAX® is indicated for patients 12 years of age and older for the prophylaxis of migraine headache.

PEDIATRIC USE

8.4 Pediatric Use Adjunctive Treatment for Partial Onset Epilepsy in Pediatric Patients 1 to 24 months 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.

In a single randomized, double-blind, placebo-controlled investigational trial, the efficacy, safety, and tolerability of topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in pediatric patients 1 to 24 months of age with refractory partial onset seizures were assessed.

After 20 days of double-blind treatment, topiramate (at fixed doses of 5, 15, and 25 mg/kg/day) did not demonstrate efficacy compared with placebo in controlling seizures.

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

These very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%).

The following adverse reactions were observed in at least 3% of patients on topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm.

A generally similar profile was observed in older pediatric patients [see Adverse Reactions (6)].

Topiramate resulted in an increased incidence of patients with increased creatinine (any topiramate dose 5%, placebo 0%), BUN (any topiramate dose 3%, placebo 0%), and protein (any topiramate dose 34%, placebo 6%), and an increased incidence of decreased potassium (any topiramate dose 7%, placebo 0%).

This increased frequency of abnormal values was not dose-related.

Creatinine was the only analyte showing a noteworthy increased incidence (topiramate 25 mg/kg/day 5%, placebo 0%) of a markedly abnormal increase.

The significance of these findings is uncertain.

Topiramate treatment also produced a dose-related increase in the percentage of patients who had a shift from normal at baseline to high/increased (above the normal reference range) in total eosinophil count at the end of treatment.

The incidence of these abnormal shifts was 6 % for placebo, 10% for 5 mg/kg/day, 9% for 15 mg/kg/day, 14% for 25 mg/kg/day, and 11% for any topiramate dose.

There was a mean dose-related increase in alkaline phosphatase.

The significance of these findings is uncertain.

Topiramate produced a dose-related increased incidence of hyperammonemia [see Warnings and Precautions (5.9)].

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

In open-label, uncontrolled experience, increasing impairment of adaptive behavior was documented in behavioral testing over time in this population.

There was a suggestion that this effect was dose-related.

However, because of the absence of an appropriate control group, it is not known if this decrement in function was treatment-related or reflects the patient’s underlying disease (e.g., patients who received higher doses may have more severe underlying disease) [see Warnings and Precautions (5.6)].

In this open-label, uncontrolled study, the mortality was 37 deaths/1000 patient years.

It is not possible to know whether this mortality rate is related to topiramate treatment, because the background mortality rate for a similar, significantly refractory, young pediatric population (1–24 months) with partial epilepsy is not known.

Monotherapy Treatment in Partial Onset Epilepsy in Patients <2 Years Old Safety and effectiveness in patients below the age of 2 years have not been established for the monotherapy treatment of epilepsy.

Migraine Prophylaxis in Pediatric Patients 12 to 17 Years of Age Safety and effectiveness of topiramate in the prophylaxis of migraine was studied in 5 double-blind, randomized, placebo-controlled, parallel-group trials in a total of 219 pediatric patients, at doses of 50 to 200 mg/day, or 2 to 3 mg/kg/day.

These comprised a fixed dose study in 103 pediatric patients 12 to 17 years of age [see Clinical Studies (14.3)], a flexible dose (2 to 3 mg/kg/day), placebo-controlled study in 157 pediatric patients 6 to 16 years of age (including 67 pediatric patients 12 to 16 years of age), and a total of 49 pediatric patients 12 to 17 years of age in 3 studies of migraine prophylaxis primarily in adults.

Open-label extension phases of 3 studies enabled evaluation of long-term safety for up to 6 months after the end of the double-blind phase.

Efficacy of topiramate for migraine prophylaxis in pediatric patients 12 to 17 years of age is demonstrated for a 100 mg daily dose in Study 12 [see Clinical Studies (14.3)].

Efficacy of topiramate (2 to 3 mg/kg/day) for migraine prophylaxis was not demonstrated in a placebo-controlled trial of 157 pediatric patients (6 to 16 years of age) that included treatment of 67 pediatric patients (12 to 16 years of age) for 20 weeks.

In the pediatric trials (12 to 17 years of age) in which patients were randomized to placebo or a fixed daily dose of TOPAMAX®, the most common adverse reactions with TOPAMAX® that were seen at an incidence higher (≥5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain [see Adverse Reactions (6)].

The most common cognitive adverse reaction in pooled double-blind studies in pediatric patients 12 to 17 years of age was difficulty with concentration/attention [see Warnings and Precautions (5.6)].

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

In topiramate-treated pediatric patients (12 to 17 years of age) compared to placebo-treated patients, abnormally increased results were more frequent for creatinine, BUN, uric acid, chloride, ammonia, total protein, and platelets.

Abnormally decreased results were observed with topiramate vs placebo treatment for phosphorus and bicarbonate [see Clinical Trials Experience (6.1)].

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

Migraine Prophylaxis in Pediatric Patients 6 to 11 Years of Age Safety and effectiveness in pediatric patients below the age of 12 years have not been established for the prophylaxis treatment of migraine headache.

In a double-blind study in 90 pediatric patients 6 to 11 years of age (including 59 topiramate-treated and 31 placebo patients), the adverse reaction profile was generally similar to that seen in pooled double-blind studies of pediatric patients 12 to 17 years of age.

The most common adverse reactions that occurred in TOPAMAX®-treated pediatric patients 6 to 11 years of age, and at least twice as frequently than placebo, were gastroenteritis (12% topiramate, 6% placebo), sinusitis (10% topiramate, 3% placebo), weight loss (8% topiramate, 3% placebo) and paresthesia (7% topiramate, 0% placebo).

Difficulty with concentration/attention occurred in 3 topiramate-treated patients (5%) and 0 placebo-treated patients.

The risk for cognitive adverse reaction was greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age) [see Warnings and Precautions (5.6)].

Juvenile Animal Studies When topiramate (30, 90, or 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose, which is approximately 5–8 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m2) basis.

PREGNANCY

8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.7)] TOPAMAX® can cause fetal harm when administered to a pregnant woman.

Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or cleft palate (oral clefts) and for being small for gestational age.

When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring.

TOPAMAX® should be used during pregnancy only if the potential benefit outweighs the potential risk.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.8)].

Pregnancy Registry Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant.

This registry is collecting information about the safety of antiepileptic drugs during pregnancy.

To enroll, patients can call the toll-free number 1-888-233-2334.

Information about the North American Drug Pregnancy Registry can be found at http://www.aedpregnancyregistry.org/.

Human Data Data from pregnancy registries indicate an increased risk of oral clefts in infants exposed to topiramate during the first trimester of pregnancy.

In the NAAED pregnancy registry, the prevalence of oral clefts among topiramate-exposed infants (1.1%) was higher than the prevalence of infants exposed to a reference AED (0.36%) or the prevalence of infants in mothers without epilepsy and without exposure to AEDs (0.12%).

It was also higher than the background prevalence in United States (0.17%) as estimated by the Centers for Disease Control and Prevention (CDC).

The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 9.6 (95% Confidence Interval [CI] 4.0 – 23.0) as compared to the risk in a background population of untreated women.

The UK Epilepsy and Pregnancy Register reported a prevalence of oral clefts among infants exposed to topiramate monotherapy (3.2%) that was 16 times higher than the background rate in the UK (0.2%).

Data from the NAAED pregnancy registry and a population-based birth registry cohort indicate that exposure to topiramate in utero is associated with an increased risk of small for gestational age (SGA) newborns (birth weight <10th percentile).

In the NAAED pregnancy registry, 19.7% of topiramate-exposed newborns were SGA compared to 7.9% of newborns exposed to a reference AED and 5.4% of newborns of mothers without epilepsy and without AED exposure.

In the Medical Birth Registry of Norway (MBRN), a population-based pregnancy registry, 25% of newborns in the topiramate monotherapy exposure group were SGA compared to 9 % in the comparison group unexposed to AEDs.

The long term consequences of the SGA findings are not known.

TOPAMAX® treatment can cause metabolic acidosis [see Warnings and Precautions (5.4)].

The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus’ ability to tolerate labor.

Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state [see Warnings and Precautions (5.4)].

Newborns of mothers treated with TOPAMAX® should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic acidosis following birth.

Animal Data Topiramate has demonstrated selective developmental toxicity, including teratogenicity, in multiple animal species at clinically relevant doses.

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 times the 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.

NUSRING MOTHERS

8.3 Nursing Mothers Limited data on 5 breastfeeding infants exposed to topiramate showed infant plasma topiramate levels equal to 10–20% of the maternal plasma level.

The effects of this exposure on infants are unknown.

Caution should be exercised when administered to a nursing woman.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Acute myopia and secondary angle closure glaucoma: can lead to permanent visual loss; discontinue TOPAMAX® as soon as possible (5.1) Visual field defects: consider discontinuation of TOPAMAX® (5.2) Oligohidrosis and hyperthermia: monitor decreased sweating and increased body temperature, especially in pediatric patients (5.3) Metabolic acidosis: baseline and periodic measurement of serum bicarbonate is recommended; consider dose reduction or discontinuation of TOPAMAX® if clinically appropriate (5.4) Suicidal behavior and ideation: antiepileptic drugs increase the risk of suicidal behavior or ideation (5.5) Cognitive/neuropsychiatric adverse reactions: use caution when operating machinery including cars; depression and mood problems may occur (5.6) Fetal Toxicity: use during pregnancy can cause cleft lip and/or palate and being small for gestational age (5.7) Withdrawal of AEDs: withdraw TOPAMAX® gradually (5.8) Hyperammonemia/encephalopathy: measure ammonia if encephalopathic symptoms occur (5.9) Kidney stones: avoid use with other carbonic anhydrase inhibitors, drugs causing metabolic acidosis, or in patients on a ketogenic diet (5.10) Hypothermia has been reported with and without hyperammonemia during topiramate treatment with concomitant valproic acid use (5.11) 5.1 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.

5.2 Visual Field Defects Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate.

In clinical trials, most of these events were reversible after topiramate discontinuation.

If visual problems occur at any time during topiramate treatment, consideration should be given to discontinuing the drug.

5.3 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 pediatric patients.

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 given 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.

5.4 Metabolic Acidosis TOPAMAX® can cause hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis).

This metabolic acidosis is caused by renal bicarbonate loss due to carbonic anhydrase inhibition by TOPAMAX®.

TOPAMAX®-induced metabolic acidosis 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 patients to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet, or specific drugs) may be additive to the bicarbonate lowering effects of TOPAMAX®.

Metabolic acidosis was commonly observed in adult and pediatric patients treated with TOPAMAX® in clinical trials.

The incidence of decreased serum bicarbonate in pediatric trials, for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures was as high as 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 5 mEq/L decrease from pretreatment) in these trials was up to 11%, compared to ≤ 2% for placebo.

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, which may decrease the maximal height achieved.

The effect of TOPAMAX® on growth and bone-related sequelae has not been systematically investigated in long-term, placebo-controlled trials.

Long-term, open-label treatment of pediatric patients 1 to 24 months old with intractable partial epilepsy, for up to 1 year, showed reductions from baseline in length, weight, and head circumference compared to age and sex-matched normative data, although these patients with epilepsy are likely to have different growth rates than normal 1 to 24 month old pediatrics.

Reductions in length and weight were correlated to the degree of acidosis [see Use in Specific Populations (8.4)].

TOPAMAX® treatment that causes metabolic acidosis during pregnancy can possibly produce adverse effects on the fetus and might also cause metabolic acidosis in the neonate from possible transfer of topiramate to the fetus [see Warnings and Precautions (5.7), Use in Specific Populations (8.1)].

Measurement of Serum Bicarbonate in Epilepsy and Migraine Patients Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended.

If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing TOPAMAX® (using dose tapering).

If the decision is made to continue patients on TOPAMAX® in the face of persistent acidosis, alkali treatment should be considered.

5.5 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including TOPAMAX®, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.

Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo.

In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated.

There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed.

Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.

The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication.

The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.

Table 4 shows absolute and relative risk by indication for all evaluated AEDs.

Table 4: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events per 1000 Patients Drug Patients with Events per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing TOPAMAX® or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness.

Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.

Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

5.6 Cognitive/Neuropsychiatric Adverse Reactions TOPAMAX® can cause cognitive/neuropsychiatric adverse reactions.

The most frequent of these can be classified into three general categories: 1) Cognitive-related dysfunction (e.g., confusion, psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or language problems, particularly word-finding difficulties); 2) Psychiatric/behavioral disturbances (e.g., depression or mood problems); and 3) Somnolence or fatigue.

Adult Patients Cognitive-Related Dysfunction Rapid titration rate and higher initial dose were associated with higher incidences of cognitive-related dysfunction.

In adult epilepsy add-on controlled trials, which used rapid titration (100–200 mg/day weekly increments), and target TOPAMAX® doses of 200 mg – 1000 mg/day, 56% of patients in the 800 mg/day and 1000 mg/day dose groups experienced cognitive-related dysfunction compared to approximately 42% of patients in the 200–400 mg/day groups and 14% for placebo.

In this rapid titration regimen, these dose-related adverse reactions began in the titration or in the maintenance phase, and in some patients these events began during titration and persisted into the maintenance phase.

In the monotherapy epilepsy controlled trial, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for TOPAMAX® 50 mg/day and 26% for 400 mg/day.

In the 6-month migraine prophylaxis controlled trials, which used a slower titration regimen (25 mg/day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for TOPAMAX® 50 mg/day, 22% for 100 mg/day (the recommended dose), 28% for 200 mg/day, and 10% for placebo.

Cognitive adverse reactions most commonly developed during titration and sometimes persisted after completion of titration.

Psychiatric/Behavioral Disturbances Psychiatric/behavioral disturbances (e.g., depression, mood) were dose-related for both the adjunctive epilepsy and migraine populations [see Warnings and Precautions (5.5)].

Somnolence/Fatigue Somnolence and fatigue were the adverse reactions most frequently reported during clinical trials of TOPAMAX® for adjunctive epilepsy.

For the adjunctive epilepsy population, the incidence of fatigue, appeared dose related.

For the monotherapy epilepsy population, the incidence of somnolence was dose-related.

For the migraine population, the incidences of both fatigue and somnolence were dose-related and more common in the titration phase.

Pediatric Patients In pediatric epilepsy trials (adjunctive and monotherapy), the incidence of cognitive/neuropsychiatric adverse reactions was generally lower than that observed in adults.

These reactions included psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems, and language problems.

The most frequently reported cognitive/neuropsychiatric reactions in pediatric epilepsy patients during adjunctive therapy double-blind studies were somnolence and fatigue.

The most frequently reported cognitive/neuropsychiatric reactions in pediatric epilepsy patients in the 50 mg/day and 400 mg/day groups during the monotherapy double-blind study were headache, dizziness, anorexia, and somnolence.

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

The risk for cognitive/neuropsychiatric adverse reactions was dose-dependent, and was greatest at the highest dose (200 mg).

This risk for cognitive/neuropsychiatric adverse reactions was also greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age).

The most common cognitive/neuropsychiatric adverse reaction in these trials was difficulty with concentration/attention.

Cognitive adverse reactions most commonly developed during titration and sometimes persisted for various durations after completion of titration.

The Cambridge Neuropsychological Test Automated Battery (CANTAB) was administered to adolescents (12 to 17 years) to assess the effects of topiramate on cognitive function at baseline and at the end of the Study 12 [see Clinical Studies (14.3)].

Mean change from baseline in certain CANTAB tests suggests that topiramate treatment may result in psychomotor slowing and decreased verbal fluency.

5.7 Fetal Toxicity TOPAMAX® can cause fetal harm when administered to a pregnant woman.

Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or cleft palate (oral clefts) and for being small for gestational age.

When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring [see Use in Specific Populations (8.1)].

Consider the benefits and the risks of TOPAMAX® when administering this drug in women of childbearing potential, particularly when TOPAMAX® is considered for a condition not usually associated with permanent injury or death [see Use in Specific Populations (8.8), Patient Counseling Information (17)].

TOPAMAX® should be used during pregnancy only if the potential benefit outweighs the potential risk.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1, 8.8)].

5.8 Withdrawal of Antiepileptic Drugs 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 (14)].

In situations where rapid withdrawal of TOPAMAX® is medically required, appropriate monitoring is recommended.

5.9 Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use) Topiramate treatment can cause hyperammonemia with or without encephalopathy [see Adverse Reactions (6.2)].

The risk for hyperammonemia with topiramate appears dose-related.

Hyperammonemia has been reported more frequently when topiramate is used concomitantly with valproic acid.

Postmarketing cases of hyperammonemia with or without encephalopathy have been reported with topiramate and valproic acid in patients who previously tolerated either drug alone [see Drug Interactions (7.1)].

Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy and/or vomiting.

In most cases, hyperammonemic encephalopathy abated with discontinuation of treatment.

The incidence of hyperammonemia in pediatric patients 12 to 17 years of age in migraine prophylaxis trials was 26% in patients taking TOPAMAX® monotherapy at 100 mg/day, and 14% in patients taking TOPAMAX® at 50 mg/day, compared to 9% in patients taking placebo.

There was also an increased incidence of markedly increased hyperammonemia at the 100 mg dose.

Dose-related hyperammonemia was also seen in pediatric patients 1 to 24 months of age treated with TOPAMAX® and concomitant valproic acid for partial onset epilepsy and this was not due to a pharmacokinetic interaction.

In some patients, hyperammonemia can be asymptomatic.

Monitoring for Hyperammonemia Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy.

Although not studied, topiramate treatment or an interaction of concomitant topiramate and valproic acid treatment may exacerbate existing defects or unmask deficiencies in susceptible persons.

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

5.10 Kidney Stones TOPAMAX® increases the risk of kidney stones.

During adjunctive epilepsy trials, the risk for kidney stones in TOPAMAX®-treated adults was 1.5%, an incidence about 2 to 4 times greater than expected in a similar, untreated population.

As in the general population, the incidence of stone formation among TOPAMAX®-treated patients was higher in men.

Kidney stones have also been reported in pediatric patients taking TOPAMAX® for epilepsy or migraine.

During long-term (up to 1 year) TOPAMAX® treatment in an open-label extension study of 284 pediatric patients 1–24 months old with epilepsy, 7% developed kidney or bladder stones.

TOPAMAX® is not approved for treatment of epilepsy in pediatric patients less than 2 years old [see Use in Specific Populations (8.4)].

TOPAMAX® is a carbonic anhydrase inhibitor.

Carbonic anhydrase inhibitors can promote stone formation by reducing urinary citrate excretion and by increasing urinary pH [see Warnings and Precautions (5.4)].

The concomitant use of TOPAMAX® with any other drug producing metabolic acidosis, 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.

5.11 Hypothermia with Concomitant Valproic Acid Use Hypothermia, defined as a drop in body core temperature to <35°C (95°F), has been reported in association with topiramate use with concomitant valproic acid both in conjunction with hyperammonemia and in the absence of hyperammonemia.

This adverse reaction in patients using concomitant topiramate and valproate can occur after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.1)].

Consideration should be given to stopping TOPAMAX® or valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems.

Clinical management and assessment should include examination of blood ammonia levels.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Eye Disorders Instruct patients taking TOPAMAX® to seek immediate medical attention if they experience blurred vision, visual disturbances, or periorbital pain [see Warnings and Precautions (5.1, 5.2)].

Oligohidrosis and Hyperthermia Closely monitor TOPAMAX®-treated patients, especially pediatric patients, for evidence of decreased sweating and increased body temperature, especially in hot weather.

Counsel patients to contact their healthcare professionals immediately if they develop a high or persistent fever, or decreased sweating [see Warnings and Precautions (5.3)].

Metabolic Acidosis Warn patients about the potential significant risk for metabolic acidosis that may be asymptomatic and may be associated with adverse effects on kidneys (e.g., kidney stones, nephrocalcinosis), bones (e.g., osteoporosis, osteomalacia, and/or rickets in children), and growth (e.g., growth delay/retardation) in pediatric patients, and on the fetus [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].

Suicidal Behavior and Ideation Counsel patients, their caregivers, and families that AEDs, including TOPAMAX®, may increase the risk of suicidal thoughts and behavior, and advise of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior or the emergence of suicidal thoughts, or behavior or thoughts about self-harm.

Instruct patients to immediately report behaviors of concern to their healthcare providers [see Warnings and Precautions (5.5)].

Interference with Cognitive and Motor Performance Warn patients about the potential for somnolence, dizziness, confusion, difficulty concentrating, or visual effects, and advise patients not to drive or operate machinery until they have gained sufficient experience on TOPAMAX® to gauge whether it adversely affects their mental performance, motor performance, and/or vision [see Warnings and Precautions (5.6)].

Even when taking TOPAMAX® or other anticonvulsants, some patients with epilepsy will continue to have unpredictable seizures.

Therefore, advise all patients taking TOPAMAX® for epilepsy 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.

Discuss the appropriate level of caution with patients, before patients with epilepsy engage in such activities.

Fetal Toxicity Inform pregnant women and women of childbearing potential that use of TOPAMAX® during pregnancy can cause fetal harm, including an increased risk for cleft lip and/or cleft palate (oral clefts), which occur early in pregnancy before many women know they are pregnant.

Also inform patients that infants exposed to topiramate monotherapy in utero may be small for their gestational age [see Use in Specific Populations (8.1)].

There may also be risks to the fetus from chronic metabolic acidosis with use of TOPAMAX® during pregnancy [see Warnings and Precautions (5.7), Use in Specific Populations (8.1, 8.8)].

When appropriate, counsel pregnant women and women of childbearing potential about alternative therapeutic options.

This is particularly important when TOPAMAX® use is considered for a condition not usually associated with permanent injury or death.

Advise women of childbearing potential who are not planning a pregnancy to use effective contraception while using TOPAMAX®, keeping in mind that there is a potential for decreased contraceptive efficacy when using estrogen-containing birth control with topiramate [see Drug Interactions (7.3)].

Encourage pregnant women using TOPAMAX®, to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry.

The registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1)].

Hyperammonemia and Encephalopathy Warn patients about the possible development of hyperammonemia with or without encephalopathy.

Although hyperammonemia may be asymptomatic, clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy and/or vomiting.

This hyperammonemia and encephalopathy can develop with TOPAMAX® treatment alone or with TOPAMAX® treatment with concomitant valproic acid (VPA).

Instruct patients to contact their physician if they develop unexplained lethargy, vomiting, or changes in mental status [see Warnings and Precautions (5.9)].

Kidney Stones Instruct patients, particularly those with predisposing factors, to maintain an adequate fluid intake in order to minimize the risk of kidney stone formation [see Warnings and Precautions (5.10)].

Instructions for a Missing Dose Instruct patients that if they miss a single dose of TOPAMAX®, it should be taken as soon as possible.

However, if a patient is within 6 hours of taking the next scheduled dose, tell the patient to wait until then to take the usual dose of TOPAMAX®, and to skip the missed dose.

Tell patients that they should not take a double dose in the event of a missed dose.

Advise patients to contact their healthcare provider if they have missed more than one dose.

DOSAGE AND ADMINISTRATION

2 TOPAMAX® initial dose, titration, and recommended maintenance dose varies by indication and age group.

See Full Prescribing Information for recommended dosage, and dosing considerations in patients with renal impairment, geriatric patients, and patients undergoing hemodialysis (2.1, 2.2, 2.3, 2.4, 2.5, 2.6) 2.1 Dosing in Monotherapy Epilepsy Adults and Pediatric Patients 10 Years of Age and Older The recommended dose for TOPAMAX® monotherapy in adults and pediatric patients 10 years of age and older is 400 mg/day in two divided doses.

The dose should be achieved by titration according to the following schedule (Table 1): Table 1: Monotherapy Titration Schedule for Adults and Pediatric Patients 10 years and older Morning Dose Evening Dose Week 1 25 mg 25 mg Week 2 50 mg 50 mg Week 3 75 mg 75 mg Week 4 100 mg 100 mg Week 5 150 mg 150 mg Week 6 200 mg 200 mg Pediatric Patients 2 to 9 Years of Age Dosing in patients 2 to 9 years of age is based on weight.

During the titration period, the initial dose of TOPAMAX® is 25 mg/day nightly for the first week.

Based upon tolerability, the dosage can be increased to 50 mg/day (25 mg twice daily) in the second week.

Dosage can be increased by 25–50 mg/day each subsequent week as tolerated.

Titration to the minimum maintenance dose should be attempted over 5–7 weeks of the total titration period.

Based upon tolerability and clinical response, additional titration to a higher dose (up to the maximum maintenance dose) can be attempted at 25–50 mg/day weekly increments.

The total daily dose should not exceed the maximum maintenance dose for each range of body weight (Table 2).

Table 2: Monotherapy Target Total Daily Maintenance Dosing for Patients 2 to 9 Years of Age Weight (kg) Total Daily Dose (mg/day)Administered in two equally divided doses Minimum Maintenance Dose Total Daily Dose (mg/day) Maximum Maintenance Dose Up to 11 150 250 12 – 22 200 300 23 – 31 200 350 32 – 38 250 350 Greater than 38 250 400 2.2 Dosing in Adjunctive Therapy Epilepsy Adults (17 Years of Age and Over) The recommended total daily dose of TOPAMAX® as adjunctive therapy in adults with partial onset seizures or Lennox-Gastaut Syndrome is 200 to 400 mg/day in two divided doses, and 400 mg/day in two divided doses as adjunctive treatment in adults with primary generalized tonic-clonic seizures.

TOPAMAX® should be initiated at 25 to 50 mg/day, followed by titration to an effective dose in increments of 25 to 50 mg/day every week.

Titrating in increments of 25 mg/day every week may delay the time to reach an effective dose.

Doses above 400 mg/day have not been shown to improve responses in adults with partial onset seizures.

Pediatric Patients 2 to 16 Years of Age The recommended total daily dose of TOPAMAX® as adjunctive therapy for pediatric patients 2 to 16 years of age with partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome is approximately 5 to 9 mg/kg/day in two divided doses.

Titration should begin at 25 mg/day (or less, based on a range of 1 to 3 mg/kg/day) nightly for the first week.

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), to achieve optimal clinical response.

Dose titration should be guided by clinical outcome.

The total daily dose should not exceed 400 mg/day.

2.3 Dosing in Migraine Prophylaxis The recommended total daily dose of TOPAMAX® as treatment for patients 12 years of age and older for prophylaxis of migraine headache is 100 mg/day administered in two divided doses (Table 3).

The recommended titration rate for TOPAMAX® for migraine prophylaxis is as follows: Table 3: Migraine Prophylaxis Titration Schedule for Patients 12 Years of Age and Older Morning Dose Evening Dose Week 1 None 25 mg Week 2 25 mg 25 mg Week 3 25 mg 50 mg Week 4 50 mg 50 mg Dose and titration rate should be guided by clinical outcome.

If required, longer intervals between dose adjustments can be used.

2.4 Administration Information TOPAMAX® can be taken without regard to meals.

TOPAMAX® Tablets Because of the bitter taste, tablets should not be broken.

TOPAMAX® Sprinkle Capsules 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.

2.5 Dosing in Patients with Renal Impairment In patients with renal impairment (creatinine clearance less than 70 mL/min/1.73 m2), one-half of the usual adult dose of TOPAMAX® is recommended [see Use in Specific Populations (8.5, 8.6), Clinical Pharmacology (12.3)].

2.6 Dosing in Patients Undergoing Hemodialysis 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 period, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of topiramate in the patient being dialyzed [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].