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Name:Topiramate
Manufacturer:Zydus Pharmaceuticals (usa) Inc.
Category:Prescription Marketed Drugs


Topiramate Tablets

TOPIRAMATE - topiramate tablet, film coated 
Zydus Pharmaceuticals (USA) Inc.

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Topiramate Tablets

DESCRIPTION

Topiramate is a sulfamate-substituted monosaccharide.

Topiramate, USP is a white to off-white crystalline powder with bitter taste. It is soluble in 10 % ethanol. Topiramate has the molecular formula C12H21NO8S and a molecular weight of 339.37. Topiramate is designated chemically as 2,3:4,5-Di-O-isopropylidene-β-D-fructopyranose sulfamate and has the following structural formula:

Structured formula for topiramate

Each topiramate tablet intended for oral administration contains 25 mg or 50 mg or 100 mg or 200 mg of topiramate. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose anhydrous, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, talc and titanium dioxide.

CLINICAL PHARMACOLOGY

Mechanism of Action:

The precise mechanisms by which topiramate exerts its anticonvulsant effects are unknown; however, preclinical studies have revealed four properties that may contribute to topiramate’s efficacy for epilepsy. 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:

Dosing must be individualized. The usual starting dose of losartan is 50 mg once daily, with 25 mg recommended for patients with intravascular volume depletion (e.g., patients treated with diuretics) (see WARNINGS, Hypotension — Volume-Depleted Patients) and patients with a history of hepatic impairment (see WARNINGS, Impaired Hepatic Function). Losartan can be administered once or twice daily at total daily doses of 25 to 100 mg. If the antihypertensive effect measured at trough using once-a-day dosing is inadequate, a twice-a-day regimen at the same total daily dose or an increase in dose may give a more satisfactory response.

Hydrochlorothiazide is effective in doses of 12.5 to 50 mg once daily and can be given at doses of 12.5 to 25 mg as losartan potassium and hydrochlorothiazide tablets.

To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy.

The side effects (see WARNINGS) of losartan are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of losartan and hydrochlorothiazide will be associated with both sets of dose-independent side effects.

Replacement Therapy:

The combination may be substituted for the titrated components.

Dose Titration by Clinical Effect:

A patient whose blood pressure is not adequately controlled with losartan monotherapy (see above) or hydrochlorothiazide alone, may be switched to losartan potassium and hydrochlorothiazide tablets (50 mg/ 12.5 mg) once daily. If blood pressure remains uncontrolled after about 3 weeks of therapy, the dose may be increased to two tablets of losartan potassium and hydrochlorothiazide tablets (50 mg/ 12.5 mg) once daily or one tablet of losartan potassium and hydrochlorothiazide tablets (100 mg/ 25 mg) once daily. A patient whose blood pressure is not adequately controlled with losartan 100 mg monotherapy (see above) may be switched to losartan potassium and hydrochlorothiazide tablets (100 mg/ 12.5 mg) once daily. If blood pressure remains uncontrolled after about 3 weeks of therapy, the dose may be increased to two tablets of losartan potassium and hydrochlorothiazide tablets (50 mg/ 12.5 mg) once daily or one tablet of losartan potassium and hydrochlorothiazide tablets (100 mg/ 25 mg) once daily.

A patient whose blood pressure is inadequately controlled by 25 mg once daily of hydrochlorothiazide, or is controlled but who experiences hypokalemia with this regimen, may be switched to losartan potassium and hydrochlorothiazide tablets (50 mg/ 12.5 mg) once daily, reducing the dose of hydrochlorothiazide without reducing the overall expected antihypertensive response. The clinical response to losartan potassium and hydrochlorothiazide tablets (50 mg/ 12.5 mg) should be subsequently evaluated, and if blood pressure remains uncontrolled after about 3 weeks of therapy, the dose may be increased to two tablets of losartan potassium and hydrochlorothiazide tablets (50 mg/ 12.5 mg) once daily or one tablet of losartan potassium and hydrochlorothiazide tablets (100 mg/ 25 mg) once daily.

The usual dose of losartan potassium and hydrochlorothiazide tablets is one tablet of losartan potassium and hydrochlorothiazide tablets (50 mg/ 12.5 mg) once daily. More than two tablets of losartan potassium and hydrochlorothiazide tablets (50 mg/ 12.5 mg) once daily or more than one tablet of losartan potassium and hydrochlorothiazide tablets (100 mg/ 25 mg) once daily is not recommended. The maximal antihypertensive effect is attained about 3 weeks after initiation of therapy.

Use in Patients with Renal Impairment:

The usual regimens of therapy with  losartan potassium and hydrochlorothiazide tablets may be followed as long as the patient’s creatinine clearance is >30 mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so losartan potassium and hydrochlorothiazide tablets are not recommended.

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 Interaction

(see also Drug Interactions):

Antiepileptic Drugs:

Potential interactions between topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effect of these interactions on mean plasma AUCs are summarized under PRECAUTIONS (Table 4).

Special Populations:

Renal Impairment:

The clearance of topiramate was reduced by 42% in moderately renally impaired (creatinine clearance 30-69 mL/min/1.73m2) and by 54% in severely renally impaired subjects (creatinine clearance < 30 mL/min/1.73m2) compared to normal renal function subjects (creatinine clearance > 70 mL/min/1.73m2). Since topiramate is presumed to undergo significant tubular reabsorption, it is uncertain whether this experience can be generalized to all situations of renal impairment. It is conceivable that some forms of renal disease could differentially affect glomerular filtration rate and tubular reabsorption resulting in a clearance of topiramate not predicted by creatinine clearance. In general, however, use of one-half the usual starting and maintenance dose is recommended in patients with moderate or severe renal impairment (see PRECAUTIONS: Adjustment of Dose in Renal Failure and DOSAGE AND ADMINISTRATION).

Hemodialysis:

Topiramate is cleared by hemodialysis. Using a high efficiency, counterflow, single pass-dialysate hemodialysis procedure, topiramate dialysis clearance was 120 mL/min with blood flow through the dialyzer at 400 mL/min. This high clearance (compared to 20-30 mL/min total oral clearance in healthy adults) will remove a clinically significant amount of topiramate from the patient over the hemodialysis treatment period. Therefore, a supplemental dose may be required (see DOSAGE AND ADMINISTRATION).

Hepatic Impairment:

In hepatically impaired subjects, the clearance of topiramate may be decreased; the mechanism underlying the decrease is not well understood.

Age, Gender, and Race:

The pharmacokinetics of topiramate in elderly subjects (65-85 years of age, N=16) were evaluated in a controlled clinical study. The elderly subject population had reduced renal function [creatinine clearance (-20%)] compared to young adults. Following a single oral 100 mg dose, maximum plasma concentration for elderly and young adults was achieved at approximately 1-2 hours. Reflecting the primary renal elimination of topiramate, topiramate plasma and renal clearance were reduced 21% and 19%, respectively, in elderly subjects, compared to young adults. Similarly, topiramate half-life was longer (13%) in the elderly. Reduced topiramate clearance resulted in slightly higher maximum plasma concentration (23%) and AUC (25%) in elderly subjects than observed in young adults. Topiramate clearance is decreased in the elderly only to the extent that renal function is reduced. As recommended for all patients, dosage adjustment may be indicated in the elderly patient when impaired renal function (creatinine clearance rate ≤ 70 mL/min/1.73 m2) is evident. It may be useful to monitor renal function in the elderly patient (see Special Populations: Renal Impairment, PRECAUTIONS: Adjustment of Dose in Renal Failure and DOSAGE AND ADMINISTRATION).

Clearance of topiramate in adults was not affected by gender or race.

Pediatric Pharmacokinetics:

Pharmacokinetics of topiramate were evaluated in patients ages 4 to 17 years receiving one or two other antiepileptic drugs. Pharmacokinetic profiles were obtained after one week at doses of 1, 3, and 9 mg/kg/day. Clearance was independent of dose.

Pediatric patients have a 50% higher clearance and consequently shorter elimination half-life than adults. Consequently, the plasma concentration for the same mg/kg dose may be lower in pediatric patients compared to adults. As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations of topiramate.

CLINICAL STUDIES

The studies described in the following sections were conducted using 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.

Structured formula for topiramate

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 topiramate 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 topiramate 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 topiramate 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 topiramate 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 topiramate tablets 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 topiramate tablets 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 topiramate tablets 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 topiramate tablets 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
Protocol
Stabilization Dose
Target Topiramate Dosage (mg/day)

Placeboa
200
400
600
800
1,000

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.

YD
N
42
42
40
41
-
-

Mean Dose
5.9
200
390
556
-
-

Median Dose
6.0
200
400
600
-
-








YE
N
44
-
-
40
45
40

Mean Dose
9.7
-
-
544
739
796

Median Dose
10.0
-
-
600
800
1,000








Y1
N
23
-
19
-
-
-

Mean Dose
3.8
-
395
-
-
-

Median Dose
4.0
-
400
-
-
-








Y2
N
30
-
-
28
-
-

Mean Dose
5.7
-
-
522
-
-

Median Dose
6.0
-
-
600
-
-








Y3
N
28
-
-
-
25
-

Mean Dose
7.9
-
-
-
568
-

Median Dose
8.0
-
-
-
600
-








119
N
90
157
-
-
-
-

Mean Dose
8
200
-
-
-
-

Median Dose
8
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 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
Protocol Efficacy Results 
Target Topiramate Dosage (mg/day

Placebo
200 
400 
600 
800 
1,000 
≈ 6
mgkgday*

Comparisons with placebo: ap=0.080; bp< 0.010; cp< 0.001; dp< 0.050;ep=0.065; fp< 0.005; gp=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 

45 
45 
45 
46 




Median % Reduction 
11.6 
27.2a
47.5b
44.7c




% Responders 
18 
24 
44d
46d



YE 

47 


48 
48 
47 


Median % Reduction 
1.7 


40.8c
41.0c
36.0c


% Responders 



40c
41c
36d

Y1 

24 

23 





Median % Reduction 
1.1 

40.7e





% Responders 


35d




Y2 

30 


30 




Median % Reduction 
-12.2 


46.4f




% Responders 
10 


47c



Y3 

28 



28 



Median % Reduction 
-20.6 



24.3c



% Responders 




43c


119 

91 
168 






Median % Reduction 
20.0 
44.2c






% Responders 
24 
45c





Studies in Pediatric Patients 
YP 

45 





41 

Median % Reduction 
10.5 





33.1d

% Responders 
20 





39 
Primary Generalized Tonic-Clonich
YTC 

40 





39 

Median % Reduction 
9.0 





56.7d

% Responders 
20 





56c
Lennox-Gastaut Syndromei
YL 

49 





46 

Median % Reduction 
-5.1 





14.8d

% Responders 
14 





28g

Improvement in Seizure Severityj
28 





52d

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

INDICATIONS AND USAGE

Monotherapy Epilepsy:

Topiramate tablets 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:

Topiramate tablets 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.

CONTRAINDICATIONS

Topiramate tablets are contraindicated in patients with a history of hypersensitivity to any component of this product.

WARNINGS

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 topiramate tablets. 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 topiramate tablets 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 topiramate tablets as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of topiramate tablets, 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 topiramate tablets 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 topiramate tablets should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when topiramate tablets are 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.

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including topiramate tablets, 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 3 shows absolute and relative risk by indication for all evaluated AEDs.

Table 3 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 topiramate tabletsor 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.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised 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, behavior or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

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 treatmentemergent decreases in serum bicarbonate in placebo-controlled trials for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures was 67% for topiramate tablets  (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 topiramate tablets 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.

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.

Cognitive/Neuropsychiatric Adverse Events:

Adults:

Adverse events most often associated with the use of topiramate tablets were related to the central nervous system and were observed in the epilepsy populations. In adults, 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.

Cognitive-Related Dysfunction:

The majority of cognitive-related adverse events were mild to moderate in severity, and they frequently occurred in isolation. Rapid titration rate and higher initial dose were associated with higher incidences of these events. Many of these events contributed to withdrawal from treatment (see ADVERSE REACTIONS, Table 5 and Table 7).

In the original add-on epilepsy controlled trials (using rapid titration such as 100-200 mg/day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse events was 42% for 200 mg/day, 41% for 400 mg/day, 52% for 600 mg/day, 56% for 800 and 1000 mg/day, and 14% for placebo. These dose-related adverse reactions began with a similar frequency in the titration or in the maintenance phase, although in some patients the events began during titration and persisted into the maintenance phase. Some patients who experienced one or more cognitive-related adverse events in the titration phase had a dose-related recurrence of these events in the maintenance phase.

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

Psychiatric/Behavioral Disturbances:

Psychiatric/behavioral disturbances (depression or mood problems) were dose-related for the epilepsy populations.

Somnolence/Fatigue:

Somnolence and fatigue were the adverse events most frequently reported during clinical trials of topiramate tablets for adjunctive epilepsy. For the adjunctive epilepsy population, the incidence of somnolence did not differ substantially between 200 mg/day and 1000 mg/day, but the incidence of fatigue was dose-related and increased at dosages above 400 mg/day. For the monotherapy epilepsy population in the 50 mg/day and 400 mg/day groups, the incidence of somnolence was dose-related (9% for the 50 mg/day group and 15% for the 400 mg/day group) and the incidence of fatigue was comparable in both treatment groups (14% each).

Additional nonspecific CNS events commonly observed with topiramate in the add-on epilepsy population include dizziness or ataxia.

Pediatric Patients:

In double-blind adjunctive therapy and monotherapy epilepsy clinical studies, the incidences of cognitive/neuropsychiatric adverse events in pediatric patients were generally lower than observed in adults. These events included psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems and language problems. The most frequently reported neuropsychiatric events in pediatric patients during adjunctive therapy double-blind studies were somnolence and fatigue. The most frequently reported neuropsychiatric events in pediatric patients in the 50 mg/day and 400 mg/day groups during the monotherapy double-blind study were headache, dizziness, anorexia, and somnolence.

No patients discontinued treatment due to any adverse events in the adjunctive epilepsy double-blind trials. In the monotherapy epilepsy double-blind trial, 1 pediatric patient (2%) in the 50 mg/day group and 7 pediatric patients (12%) in the 400 mg/day group discontinued treatment due to any adverse events. The most common adverse event associated with discontinuation of therapy was difficulty with concentration/attention; all occurred in the 400 mg/day group.

Withdrawal of AEDs:

Antiepileptic drugs, including topiramate tablets, should be withdrawn gradually to minimize the potential of increased seizure frequency.

Sudden Unexplained Death in Epilepsy (SUDEP):

During the course of premarketing development of 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 topiramate tablets (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 topiramate tablets 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 topiramate tablets 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 topiramate tablets 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 topiramate tablets. Paresthesia was more frequently reported in the monotherapy epilepsy 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 and their caregivers should be informed of the availability of a Medication Guide, and they should be instructed to read the Medication Guide prior to taking topiramate tablets. Patients should be instructed to take topiramate tablets only as prescribed.

Patients taking topiramate tablets should be told to seek immediate medical attention if they experience blurred vision or periorbital pain.

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

Patients, their caregivers, and families should be counseled that AEDs, including topiramate tablets, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior or the emergence of suicidal thoughts, behavior or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

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, and difficulty concentrating 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 and/or motor performance.

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

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 (see PRECAUTIONS: Pregnancy: Pregnancy Category C).

Laboratory Tests:

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

Drug Interactions:

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

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 4.

In Table 4, the second column (AED concentration) describes what happens to the concentration of the AED listed in the first column when topiramate is added.

The third column (topiramate concentration) describes how the coadministration of a drug listed in the first column modifies the concentration of topiramate in experimental settings when topiramate tablets were given alone.

Table 4 Summary of AED Interactions with Topiramate Tablets
AED
Co-administered 
AED
Concentration
Topiramate
Concentration

NC = Less than 10% change in plasma concentration.

AED = Antiepileptic drug.

NE = Not Evaluated.

TPM – Topiramate

*
Is not administered but is an active metabolite of carbamazepine.
Plasma concentration increased 25% in some patients, generally those on a b.i.d. dosing regimen of phenytoin.
Phenytoin
Carbamazepine (CBZ)
CBZ epoxide*
Valproic acid
Phenobarbital
Primidone
Lamotrigine
NC or 25 % increase
NC
NC
11% decrease
NC
NC
NC at TPM doses up to 400 mg/day
48% decrease
40% decrease
NE
14% decrease
NE
NE
15% increase   

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:

Digoxin:

In a single-dose study, serum digoxin AUC was decreased by 12% with concomitant topiramate tablets administration. The clinical relevance of this observation has not been established.

CNS Depressants:

Concomitant administration of topiramate tablets 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 events, topiramate should be used with extreme caution if used in combination with alcohol and other CNS depressants.

Oral Contraceptives:

In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), topiramate tablets given in the absence of other medications at doses of 50 to 200 mg/day was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg/day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in patients taking valproic acid. In both studies, topiramate tablets (50 mg/day to 800 mg/day) did not significantly affect exposure to NET. Although there was a dose dependent decrease in EE exposure for doses between 200-800 mg/day, there was no significant dose dependent change in EE exposure for doses of 50-200 mg/day. The clinical significance of the changes observed is not known. The possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking combination oral contraceptive products with topiramate tablets. 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.

Hydrochlorothiazide (HCTZ):

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of HCTZ (25 mg q24h) and topiramate (96 mg q12h) when administered alone and concomitantly. The results of this study indicate that topiramate Cmax increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The addition of HCTZ to topiramate therapy may require an adjustment of the topiramate dose. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination.

Pioglitazone:

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15% decrease in the AUCτ,ss of pioglitazone with no alteration in Cmax,ss was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in Cmax,ss and AUCτ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in Cmax,ss and AUCτ,ss of the active keto-metabolite. The clinical significance of these findings is not known. When topiramate tablets are added to pioglitazone therapy or pioglitazone is added to topiramate tablets therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.

Lithium:

Multiple dosing of topiramate 100 mg every 12 hrs decreased the AUC and Cmax of Lithium (300 mg every 8 hrs) by 20% (N=12, 6 M; 6 F).

Haloperidol:

The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hr) in 13 healthy adults (6 M, 7 F).

Amitriptyline:

There was a 12% increase in AUC and Cmax for amitriptyline (25 mg per day) in 18 normal subjects (9 male; 9 female) receiving 200 mg/day of topiramate. Some subjects may experience a large increase in amitriptyline concentration in the presence of topiramate and any adjustments in amitriptyline dose should be made according to the patient’s clinical response and not on the basis of plasma levels.

Sumatriptan:

Multiple dosing of topiramate (100 mg every 12 hrs) in 24 healthy volunteers (14 M, 10 F) did not affect the pharmacokinetics of single dose sumatriptan either orally (100 mg) or subcutaneously (6 mg).

Risperidone:

There was a 25% decrease in exposure to risperidone (2 mg single dose) in 12 healthy volunteers (6 M, 6 F) receiving 200 mg/day of topiramate. Therefore, patients receiving risperidone in combination with topiramate should be closely monitored for clinical response.

Propranolol:

Multiple dosing of topiramate (200 mg/day) in 34 healthy volunteers (17 M, 17 F) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg/day in 39 volunteers (27M, 12F) had no effect on the exposure to topiramate at a dose of 200 mg/day of topiramate.

Dihydroergotamine:

Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (12 M, 12 F) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg/day dose of topiramate in the same study.

Others:

Concomitant use of topiramate tablets, a carbonic anhydrase inhibitor, with other carbonic anhydrase inhibitors, e.g., acetazolamide or dichlorphenamide, may create a physiological environment that increases the risk of renal stone formation, and should therefore be avoided.

Drug/Laboratory Tests Interactions:

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

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 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.

There are no studies using topiramate tablets in pregnant women. Topiramate tablets 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.

To provide information regarding the effects of in utero exposure to topiramate tablets, physicians are advised to recommend that pregnant patients taking topiramate tablets enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number, 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

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 topiramate tablets 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 topiramate tablets 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).

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 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 5).

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 6).

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 5 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

Body System/
Adverse Event
Topiramate Tablets  Dosage (mg/day)

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.


50
(N=160)
400
(N=159)
Body as Whole-General Disorders


Asthenia
4
6
Leg Pain
2
3
Chest Pain
1
2
Central Peripheral Nervous System Disorders


Paresthesia
21
40
Dizziness
13
14
Hypoaesthesia
4
5
Ataxia
3
4
Hypertonia
0
3
Gastro-Intestinal System Disorders


Diarrhea
5
6
Constipation
1
4
Gastritis
0
3
Dry Mouth
1
3
Gastroesophageal Reflux
1
2
Liver and Biliary System Disorders


Gamma-GT Increased
1
3
Metabolic and Nutritional Disorders


Weight Decreased
6
16
Psychiatric Disorders


Somnolence
9
15
Anorexia
4
14
Difficulty with Memory NOS
5
10
Insomnia
8
9
Depression
7
9
Difficulty with Concentration/Attention
7
8
Anxiety
4
6
Psychomotor Slowing
3
5
Mood Problems
2
5
Confusion
3
4
Cognitive Problem NOS
1
4
Libido Decreased
0
3
Reproductive DisordersFemale


Vaginal Hemorrhage
0
3
Red Blood Cell Disorders


    Anemia
1
2
Resistance Mechanism Disorders


    Infection Viral
6
8
    Infection
2
3
Respiratory System Disorders


Bronchitis
3
4
Rhinitis
2
4
Dyspnea
1
2
Skin and Appendages Disorders


Rash
1
4
Pruritis
1
4
Acne
2
3
Special Senses OtherDisorders


Taste Perversion
3
5
Urinary System Disorders


Cystitis
1
3
Renal Calculus
0
3
Urinary Tract Infection
1
2
Dysuria
0
2
Micturition Frequency
0
2
Table 6 Incidence of Treatment-Emergent Adverse Events in the Monotherapy EpilepsyTrial in Children Ages 10 up to 16 Years* 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
Body System/
Adverse Event 
Topiramate Tablets Dosage (mg/day

50 
(N=57
400 
(N=57
*
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 Whole-General Disorders 


     Fever 


Central Peripheral Nervous System Disorders 


     Paresthesia 

16 
Gastro-Intestinal System Disorders 


     Diarrhea   

11 
Metabolic and Nutritional Disorders 


     Weight decrease 

21 
Psychiatric Disorders 


     Anorexia 
11 
14 
     Mood Problems 

11 
     Difficulty with Concentration/Attention 


     Cognitive Problems NOS 


     Nervousness 


Resistance Mechanism Disorders 


     Infection Viral 


     Infection 


Respiratory System Disorders 


     Upper Respiratory Tract Infection 
16 
18 
     Rhinitis 


     Bronchitis 


     Sinusitis 


Skin and Appendages Disorders 


     Alopecia 


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 7). 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 9).

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 10).

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 7 lists 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 10 lists 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 topiramate tablets were 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 7 Incidence of Treatment-Emergent Adverse Events in Placebo-Controlled, Add-On Epilepsy Trials in Adults *, Where Rate Was > 1% in Any Topiramate Group and Greater Than the Rate in Placebo-Treated Patients
Body System/
 Adverse Event
Topiramate Tablets Dosage (mg/day)

Placebo
(N=291)
200-400
(N=183)
600-1,000
(N=414)
*
Patients in these add-on trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate tablets or placebo.
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.
Adverse events reported by at least 1 % of patients in the topiramate tablets 200-400 mg/day group and more common than in the placebo group are listed in this table.
Body as Whole-General Disorders



     Fatigue 
13 
15 
30 
     Asthenia 



     Back Pain 



     Chest Pain 



     Influenza-Like Symptoms 



     Leg Pain  



     Hot Flushes 



     Allergy 



     Edema 



     Body Odor 



     Rigors 


<1 
Central Peripheral Nervous System Disorders 



     Dizziness 
15 
25 
32 
     Ataxia 

16 
14 
     Speech Disorders/Related Speech Problems

13 
11 
     Paresthesia 

11 
19 
     Nystagmus 

10 
11 
     Tremor 



     Language Problems


10 
     Coordination Abnormal



     Hypoaesthesia 



     Gait Abnormal 



     Muscle Contractions Involuntary



     Stupor 



     Vertigo 



Gastro-Intestinal System Disorders



     Nausea 

10 
12 
     Dyspepsia 



     Abdominal Pain 



     Constipation 



     Gastroenteritis 



     Dry Mouth 



     Gingivitis  
<1 


     GI Disorder 
<1 


Hearing and Vestibular Disorders



     Hearing Decreased 



Metabolic and Nutritional Disorders



     Weight Decrease 


13 
Muscle-Skeletal System Disorders



     Myalgia 



     Skeletal Pain 



PlateletBleedingClotting Disorders



     Epitaxis 



Psychiatric Disorders 



     Somnolence 
12 
29 
28 
     Nervousness 

16 
19 
     Psychomotor Slowing 

13 
21 
     Difficulty with Memory  

12 
14 
     Anorexia 

10 
12 
     Confusion 

11 
14 
     Depression 


13 
     Difficulty with Concentration/Attention 


14 
     Mood Problems 



     Agitation   



     Aggressive Reaction 



     Emotional Lability 



     Cognitive Problems 



     Libido Decreased 


<1 
     Apathy 



     Depersonalization 



Reproductive DisordersFemale 



      Breast Pain 



      Amenorrhea 



      Menorrhagia 



      Menstrual Disorder 



Reproductive DisordersMale



     Prostatic Disorders 
<1 


Resistance Mechanism Disorders



     Infection 



     Infection Viral  


<1 
     Moniliasis 
<1 


Respiratory System Disorders



     Pharyngitis   



      Rhinitis 



     Sinusitis 



     Dyspnea 



Skin and Appendages Disorders



     Skin Disorder 
<1 


     Sweating Increased 
<1 

<1 
     Rash Erythematous 
<1 

<1 
Special Sense OtherDisorders



     Taste Perversion 



Urinary System Disorders 



     Hematuria 


<1 
     Urinary Tract Infection 



     Micturition Frequency 



     Urinary Incontinence 
<1 


     Urine Abnormal 


<1 
Vision Disorders 



     Vision Abnormal 

13 
10 
     Diplopia 

10 
10 
White Cell and RES Disorders 



     Leukopenia 



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 8) 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 8 Incidence of Treatment-Emergent Adverse Events in Study 119*, Where Rate Was ≥ 2% in the Topiramate Group and Greater Than the Rate inPlacebo-Treated Patients
Body System/
Adverse Event

Topiramate Tablets Dosage
(mg/day

Placebo
(N=92
200
(N=171)
*
Patients in these add-on trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate tablets or placebo.
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.
Adverse events reported by at least 2 % of patients in the topiramate tablets 200 mg/day group and more common than in the placebo group are listed in this table.
Body as Whole-General Disorders 


     Fatigue 


     Chest Pain 


Cardiovascular DisordersGeneral 


     Hypertension 


Central Peripheral Nervous System Disorders 


     Paresthesia 


     Dizziness 


     Tremor   


     Hypoaesthesia 


     Leg Cramps 


     Language Problems 


Gastro-Intestinal System Disorders  


     Abdominal Pain 


     Constipation 


     Diarrhea 


     Dyspepsia 


     Dry Mouth   


Hearing and Vestibular Disorders 


     Tinnitus 


Metabolic and Nutritional Disorders 


     Weight Decrease 


Psychiatric Disorders   


     Somnolence 

15 
     Anorexia 


     Nervousness 


     Difficulty with Concentration/Attention 


     Insomnia 


     Difficulty with Memory 


     Aggressive Reaction 


Respiratory System Disorders 


     Rhinitis 


Urinary System Disorders 


     Cystitis 


Vision Disorders 


     Diplopia 


     Vision Abnormal 


Table 9 Incidence (%) of Dose-Related Adverse Events From Placebo-Controlled, Add-On Trials in Adults with Partial Onset Seizures*


Topiramate Tablets Dosage (mg/day)

Placebo
200
400
600 1,000
Adverse Event
(N=216)
(45)
(68)
(414)
*
Dose-response studies were not conducted for other adult indications or for pediatric indications.
Fatigue
13
11
12
30
Nervousness
7
13
18
19
Difficulty with Concentration/Attention
1
7
9
14
Confusion
4
9
10
14
Depression
6
9
7
13
Anorexia
4
4
6
12
Language problems
<1
2
9
10
Anxiety
6
2
3
10
Mood problems
2
0
6
9
Weight decrease
3
4
9
13
Table 10 Incidence (%) of Treatment-Emergent Adverse Events in Placebo-Controlled, Add-On Epilepsy Trials in Pediatric Patients Ages 2-16 Years*, (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)
*
Patients in these add-on trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate tablets or placebo.
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 Whole-General Disorders


     Fatigue
5
16
     Injury
13
14
     Allergic Reaction
1
2
     Back Pain
0
1
     Pallor
0
1
Cardiovascular DisordersGeneral


     Hypertension
0
1
Central Peripheral Nervous System Disorders


     Gait Abnormal
5
8
     Ataxia
2
6
     Hyperkinesia
4
5
     Dizziness
2
4
     Speech Disorders/Related Speech Problems
2
4
     Hyporeflexia
0
2
     Convulsions Grand Mal
0
1
     Fecal Incontinence
0
1
     Paresthesia
0
1
Gastro-Intestinal System Disorders


     Nausea
5
6
     Saliva Increased
4
6
     Constipation
4
5
     Gastroenteritis
2
3
     Dysphagia
0
1
     Flatulence
0
1
     Gastroesophageal Reflux
0
1
     Glossitis
0
1
     Gum Hyperplasia     
0
1
Heart Rate and Rhythm Disorders


     Bradycardia
0
1
Metabolic and Nutritional Disorders


     Weight Decrease
1
9
     Thirst
1
2
     Hypoglycemia
0
1
     Weight Increase
0
1
PlateletBleeding Clotting Disorders


     Purpura
4
8
     Epistaxis
1
4
     Hematoma
0
1
     Prothrombin Increased
0
1
     Thrombocytopenia
0
1
Psychiatric Disorders


     Somnolence
16
26
     Anorexia
15
24
     Nervousness
7
14
     Personality Disorder (Behavior Problems)
9
11
     Difficulty with Concentration/Attention
2
10
     Aggressive Reaction
4
9
     Insomnia
7
8
     Difficulty with Memory NOS
0
5
     Confusion
3
4
     Psychomotor Slowing
2
3
     Appetite Increased
0
1
     Neurosis
0
1
Reproductive DisordersFemale


     Leukorrhoea
0
2
Resistance Mechanism Disorders


     Infection Viral
3
7
Respiratory System Disorders


     Pneumonia
1
5
     Respiratory Disorder
0
1
Skin and Appendages Disorders


     Skin Disorder
2
3
     Alopecia
1
2
     Dermatitis
0
2
     Hypertrichosis
1
2
     Rash Erythematous
0
2
     Eczema
0
1
     Seborrhoea
0
1
     Skin Discoloration  
0
1
Urinary System Disorders


     Urinary Incontinence
2
4
     Nocturia
0
1
Vision Disorders


     Eye Abnormality
1
2
     Vision Abnormal
1
2
     Diplopia
0
1
     Lacrimation Abnormal
0
1
     Myopia
0
1
White Cell and RES Disorders


     Leukopenia
0
2

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 listed in the previous tables or text, 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 texture.

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.

Postmarketing and Other Experience:

In addition to the adverse experiences reported during clinical testing of topiramate tablets, the following adverse experiences have been reported worldwide in patients receiving topiramate post-approval. These adverse experiences have not been listed above and data are insufficient to support an estimate of their incidence or to establish causation. The listing is alphabetized: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), hepatic failure (including fatalities), hepatitis, pancreatitis, pemphigus, and renal tubular acidosis.

These adverse experiences have not been listed above and data are insufficient to support an estimate of their incidence or to establish causation. The listing is alphabetized: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), hepatic failure (including fatalities), hepatitis, maculopathy, pancreatitis, pemphigus, and renal tubular acidosis.

DRUG ABUSE AND DEPENDENCE

The abuse and dependence potential of topiramate tablets has not been evaluated in human studies.

OVERDOSAGE

Overdoses of topiramate tablets 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 topiramate tablets.

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 topiramate tablets 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 topiramate tablets therapy. On occasion, the addition of topiramate tablets 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 topiramate tablets may require adjustment of the dose of topiramate tablets. Because of the bitter taste, tablets should not be broken.

Topiramate tablets can be taken without regard to meals.

Monotherapy Use:

The recommended dose for topiramate monotherapy in adults and children 10 years of age and older is 400 mg/day in two divided doses. Approximately 58% of patients randomized to 400 mg/day achieved this maximal dose in the monotherapy controlled trial; the mean dose achieved in the trial was 275 mg/day. The dose should be achieved by titrating according to the following schedule:


Morning Dose
Evening Dose
Week1
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

Adjunctive Therapy Use:

Adults (17 Years of Age and Over) - Partial Seizures, Primary Generalized Tonic- Clonic Seizures, or Lennox-Gastaut Syndrome:

The recommended total daily dose of topiramate tablets as adjunctive therapy in adults with partial seizures is 200-400 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. It is recommended that therapy be initiated at 25-50 mg/day followed by titration to an effective dose in increments of 25-50 mg/week. Titrating in increments of 25 mg/week may delay the time to reach an effective dose. Daily doses above 1,600 mg have not been studied.

In the study of primary generalized tonic-clonic seizures the initial titration rate was slower than in previous studies; the assigned dose was reached at the end of 8 weeks (see CLINICAL STUDIES, Adjunctive Therapy Controlled Trials in Patients with Primary Generalized Tonic-Clonic Seizures).

Pediatric Patients (Ages 2-16 Years) - Partial Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome:

The recommended total daily dose of topiramate tablets as adjunctive therapy for patients with partial 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 (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.

In the study of primary generalized tonic-clonic seizures the initial titration rate was slower than in previous studies; the assigned dose of 6 mg/kg/day was reached at the end of 8 weeks (see CLINICAL STUDIES, Adjunctive Therapy Controlled Trial in Patients with Primary Generalized Tonic-Clonic Seizures).

Patients with Renal Impairment:

In renally impaired subjects (creatinine clearance less than 70 mL/min/1.73m2), 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

Topiramate Tablets, 25 mg are white to off-white, round-shaped, biconvex, beveled-edge, film-coated tablets debossed with "ZD 16" on one side and plain on the other side and are supplied as follows:

NDC 68382-138-14 in bottle of 60 tablets

NDC 68382-138-16 in bottle of 90 tablets

NDC 68382-138-01 in bottle of 100 tablets

NDC 68382-138-05 in bottle of 500 tablets

Topiramate Tablets, 50 mg are white to off-white, round-shaped, biconvex, beveled-edge, film-coated tablets debossed with "ZD 15" on one side and plain on the other side and are supplied as follows:

NDC 68382-139-14 in bottle of 60 tablets

NDC 68382-139-16 in bottle of 90 tablets

NDC 68382-139-01 in bottle of 100 tablets

NDC 68382-139-05 in bottle of 500 tablets

Topiramate Tablets, 100 mg are white to off-white, round-shaped, biconvex, beveled-edge, film-coated tablets debossed with "ZD 14" on one side and plain on the other side and are supplied as follows:

NDC 68382-140-14 in bottle of 60 tablets

NDC 68382-140-16 in bottle of 90 tablets

NDC 68382-140-01 in bottle of 100 tablets

NDC 68382-140-05 in bottle of 500 tablets

Topiramate Tablets, 200 mg are white to off-white, round-shaped, biconvex, beveled-edge, film-coated tablets debossed with "ZD 13" on one side and plain on the other side and are supplied as follows:

NDC 68382-141-14 in bottle of 60 tablets

NDC 68382-141-16 in bottle of 90 tablets

NDC 68382-141-01 in bottle of 100 tablets

NDC 68382-141-05 in bottle of 500 tablets

STORAGE AND HANDLING

Store at 20o to 25o C (68o to 77o F) [See USP Controlled Room Temperature]. Protect from moisture.

Dispense in a tight container.

SPL MEDGUIDE

Topiramate Tablets

Rx only

Read this Medication Guide before you start taking topiramate tablets and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about topiramate tablets, talk to your healthcare provider or pharmacist.

What is the most important information I should know about topiramate tablets?

•   Topiramate tablets may cause eye problems. Serious eye problems include:

  • any sudden decrease in vision with or without eye pain and redness
  • a blockage of fluid in the eye causing increased pressure in the eye (secondary angle closure glaucoma).
  • These eye problems can lead to permanent loss of vision if not treated. You should call your healthcare provider right away if you have any new eye symptoms.

•   Topiramate tablets may cause decreased sweating and increased body temperature (fever). People, especially children, should be watched for signs of decreased sweating and fever, especially in hot temperatures. Some people may need to be hospitalized for this condition.

•   Like other antiepileptic drugs, topiramate tablets may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.

Call a healthcare provider right away if you have any of these symptoms,

especially if they are new, worse, or worry you:

  • thoughts about suicide or dying
  • attempts to commit suicide
  • new or worse depression
  • new or worse anxiety
  • feeling agitated or restless
  • panic attacks
  • trouble sleeping (insomnia)
  • new or worse irritability
  • acting aggressive, being angry, or violent
  • acting on dangerous impulses
  • an extreme increase in activity and talking (mania)
  • other unusual changes in behavior or mood

Do not stop topiramate tablets without first talking to a healthcare provider.

  • Stopping topiramate tablets suddenly can cause serious problems.
  • Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

How can I watch for early symptoms of suicidal thoughts and actions?

  • Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
  • Keep all follow-up visits with your healthcare provider as scheduled.
  • Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

What is topiramate tablets?

Topiramate tablet is a prescription medicine used:

  • to treat certain types of seizures (partial onset seizures and primary generalized tonic-clonic seizures) in people 10 years and older
  • with other medicines to treat certain types of seizures (partial onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome) in adults and children 2 years and older

What should I tell my healthcare provider before taking topiramate tablets?

Before taking topiramate tablets, tell your healthcare provider about all your medical conditions, including if you:

  • have or have had depression, mood problems or suicidal thoughts or behavior
  • have kidney problems, kidney stones, or are getting kidney dialysis
  • have a history of metabolic acidosis (too much acid in the blood)
  • have liver problems
  • have osteoporosis, soft bones, or decreased bone density
  • have lung or breathing problems
  • have eye problems, especially glaucoma
  • have diarrhea
  • have a growth problem
  • are on a diet high in fat and low in carbohydrates, which is called a ketogenic diet
  • are having surgery
  • are pregnant or plan to become pregnant. It is not known if topiramate tablets will harm your unborn baby. If you become pregnant while taking topiramate tablets, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic medicine during pregnancy.
  • are breastfeeding. It is not known if topiramate tablets passes into breast milk and if it can harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take topiramate tablets.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Topiramate tablets and other medicines may affect each other causing side effects.

Especially, tell your healthcare provider if you take:

  • Valproic acid (Depakene®*, Depakote®*)
  • any medicines that impair or decrease your thinking, concentration, or muscle coordination.
  • birth control pills. Topiramate tablets may make your birth control pills less effective.  Tell your healthcare provider if your menstrual bleeding changes while you are taking birth control pills and topiramate tablets.

Ask you healthcare provider if you are not sure if your medicine is listed above.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time you get a new medicine. Do not start a new medicine without talking with your healthcare provider.

How should I take topiramate tablets?

  • Take topiramate tablets exactly as prescribed.
  • Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider.
  • Topiramate tablets should be swallowed whole. Do not chew the tablets. They may leave a bitter taste.
  • Do not store any medicine and food mixture for later use.
  • Topiramate tablets can be taken before, during, or after a meal. Drink plenty of fluids during the day. This may help prevent kidney stones while taking topiramate tablets.
  • If you take too much topiramate tablets, call your healthcare provider or poison control center right away or go to the nearest emergency room.
  • If you miss a single dose of topiramate tablets, 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 topiramate tablets, 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 topiramate tablets without talking to your healthcare provider. Stopping topiramate tablets suddenly may cause serious problems. If you have epilepsy and you stop taking topiramate tablets suddenly, you may have seizures that do not stop. Your healthcare provider will tell you how to stop taking topiramate tablets slowly.
  • Your healthcare provider may do blood tests while you take topiramate tablets.

What should I avoid while taking topiramate tablets?

  • Do not drink alcohol while taking topiramate tablets. Topiramate tablets and alcohol can affect each other causing side effects such as sleepiness and dizziness.
  • Do not drive a car or operate heavy machinery until you know how topiramate tablets affect you. Topiramate tablets can slow your thinking and motor skills.

What are the possible side effects of topiramate tablets?

Topiramate tablets may cause serious side effects including:

See "What is the most important information I should know about topiramate tablets?"

•   Metabolic Acidosis. Metabolic acidosis can cause:

  • tiredness
  • loss of appetite
  • irregular heartbeat
  • impaired consciousness

•   High blood ammonia levels. High ammonia in the blood can affect your mental activities, slow your alertness, make you feel tired, or cause vomiting. This has happened when topiramate tablets is taken with a medicine called valproic acid (DEPAKENE®* and DEPAKOTE®*).

•   Kidney stones. Drink plenty of fluids when taking topiramate tablets to decrease your chances of getting kidney stones.

•   Effects on Thinking and Alertness. Topiramate tablets may affect how you think, and cause confusion, problems with concentration, attention, memory, or speech. Topiramate tablets may cause depression or mood problems, tiredness, and sleepiness.

•   Dizziness or Loss of Muscle Coordination.

Call your healthcare provider right away if you have any of the symptoms above.

The most common side effects of topiramate tablets include:

  • tingling of the arms and legs (paresthesia)
  • not feeling hungry
  • nausea
  • a change in the way foods taste
  • diarrhea
  • weight loss
  • nervousness
  • upper respiratory tract infection

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all the possible side effects of topiramate tablets. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store topiramate tablets?

  • Store topiramate tablets at 20o to 25o C (68o to 77o F) [See USP Controlled Room Temperature].
  • Keep topiramate tablets in a tightly closed container
  • Keep topiramate tablets dry and away from moisture
  • Keep topiramate tablets out of the reach of children.

General information about topiramate tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use topiramate tablets for a condition for which it was not prescribed. Do not give topiramate tablets to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about topiramate tablets. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about topiramate tablets that is written for health professionals.

Please address medical inquiries to, (MedicalAffairs@zydususa.com) Tel.: 1-877-993-8779.

What are the ingredients in topiramate tablets?

Active ingredient: topiramate

Inactive ingredients: colloidal silicon dioxide, hypromellose, lactose anhydrous, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, talc and titanium dioxide.

*DEPAKENE® and DEPAKOTE® are registered trademarks of Abbott Laboratories.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured by:

Cadila Healthcare Ltd.

Ahmedabad, India

Distributed by:

Zydus Pharmaceuticals USA Inc.

Pennington, NJ 08534

Rev.: 09/10

Revision Date: 09/22/2010

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC 68382-138-05 in bottle of 500 Tablets

Topiramate Tablets, 25 mg

Rx only

500 Tablets

ZYDUS

Structured formula for topiramate

NDC 68382-139-05 in bottle of 500 Tablets

Topiramate Tablets, 50 mg

Rx only

500 Tablets

ZYDUS

Structured formula for topiramate

NDC 68382-140-05 in bottle of 500 Tablets

Topiramate Tablets, 100 mg

Rx only

500 Tablets

ZYDUS

Structured formula for topiramate

NDC 68382-141-05 in bottle of 500 Tablets

Topiramate Tablets, 200 mg

Rx only

500 Tablets

ZYDUS

Structured formula for topiramate

TOPIRAMATE  
topiramate tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68382-138
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
TOPIRAMATE (TOPIRAMATE) TOPIRAMATE 25 mg
Inactive Ingredients
Ingredient Name Strength
HYPROMELLOSE  
MAGNESIUM STEARATE  
POLYETHYLENE GLYCOL  
SODIUM STARCH GLYCOLATE TYPE A POTATO  
TALC  
TITANIUM DIOXIDE  
SILICON DIOXIDE  
CELLULOSE, MICROCRYSTALLINE  
LACTOSE, ANHYDROUS  
Product Characteristics
Color WHITE (WHITE TO OFF-WHITE) Score no score
Shape ROUND (ROUND) Size 6mm
Flavor Imprint Code ZD;16
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:68382-138-14 60 TABLET, FILM COATED (60 TABLET) in 1 BOTTLE None
2 NDC:68382-138-16 90 TABLET, FILM COATED (90 TABLET) in 1 BOTTLE None
3 NDC:68382-138-01 100 TABLET, FILM COATED (100 TABLET) in 1 BOTTLE None
4 NDC:68382-138-05 500 TABLET, FILM COATED (500 TABLET) in 1 BOTTLE None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA078235 03/27/2009

TOPIRAMATE  
topiramate tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68382-139
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
TOPIRAMATE (TOPIRAMATE) TOPIRAMATE 50 mg
Inactive Ingredients
Ingredient Name Strength
HYPROMELLOSE  
MAGNESIUM STEARATE  
POLYETHYLENE GLYCOL  
SODIUM STARCH GLYCOLATE TYPE A POTATO  
TALC  
TITANIUM DIOXIDE  
SILICON DIOXIDE  
CELLULOSE, MICROCRYSTALLINE  
LACTOSE, ANHYDROUS  
Product Characteristics
Color WHITE (WHITE TO OFF-WHITE) Score no score
Shape ROUND (ROUND) Size 7mm
Flavor Imprint Code ZD;15
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:68382-139-14 60 TABLET, FILM COATED (60 TABLET) in 1 BOTTLE None
2 NDC:68382-139-16 90 TABLET, FILM COATED (90 TABLET) in 1 BOTTLE None
3 NDC:68382-139-01 100 TABLET, FILM COATED (100 TABLET) in 1 BOTTLE None
4 NDC:68382-139-05 500 TABLET, FILM COATED (500 TABLET) in 1 BOTTLE None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA078235 03/27/2009

TOPIRAMATE  
topiramate tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68382-140
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
TOPIRAMATE (TOPIRAMATE) TOPIRAMATE 100 mg
Inactive Ingredients
Ingredient Name Strength
HYPROMELLOSE  
MAGNESIUM STEARATE  
POLYETHYLENE GLYCOL  
SODIUM STARCH GLYCOLATE TYPE A POTATO  
TALC  
TITANIUM DIOXIDE  
SILICON DIOXIDE  
CELLULOSE, MICROCRYSTALLINE  
LACTOSE, ANHYDROUS  
Product Characteristics
Color WHITE (WHITE TO OFF-WHITE) Score no score
Shape ROUND (ROUND) Size 10mm
Flavor Imprint Code ZD;14
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:68382-140-14 60 TABLET, FILM COATED (60 TABLET) in 1 BOTTLE None
2 NDC:68382-140-16 90 TABLET, FILM COATED (90 TABLET) in 1 BOTTLE None
3 NDC:68382-140-01 100 TABLET, FILM COATED (100 TABLET) in 1 BOTTLE None
4 NDC:68382-140-05 500 TABLET, FILM COATED (500 TABLET) in 1 BOTTLE None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA078235 03/27/2009

TOPIRAMATE  
topiramate tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68382-141
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
TOPIRAMATE (TOPIRAMATE) TOPIRAMATE 200 mg
Inactive Ingredients
Ingredient Name Strength
HYPROMELLOSE  
MAGNESIUM STEARATE  
POLYETHYLENE GLYCOL  
SODIUM STARCH GLYCOLATE TYPE A POTATO  
TALC  
TITANIUM DIOXIDE  
SILICON DIOXIDE  
CELLULOSE, MICROCRYSTALLINE  
LACTOSE, ANHYDROUS  
Product Characteristics
Color WHITE (WHITE TO OFF-WHITE) Score no score
Shape ROUND (ROUND) Size 12mm
Flavor Imprint Code ZD;13
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:68382-141-14 60 TABLET, FILM COATED (60 TABLET) in 1 BOTTLE None
2 NDC:68382-141-16 90 TABLET, FILM COATED (90 TABLET) in 1 BOTTLE None
3 NDC:68382-141-01 100 TABLET, FILM COATED (100 TABLET) in 1 BOTTLE None
4 NDC:68382-141-05 500 TABLET, FILM COATED (500 TABLET) in 1 BOTTLE None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA078235 03/27/2009

Labeler - Zydus Pharmaceuticals (USA) Inc. (156861945)
Registrant - Zydus Pharmaceuticals (USA) Inc. (156861945)
Establishment
Name Address ID/FEI Operations
Cadila Healthcare Limited 918596198 Analysis, Manufacture

Revised: 09/2010 Zydus Pharmaceuticals (USA) Inc.



Source: http://dailymed.nlm.nih.gov
Reproduced with permission of U.S. National Library of Medicine


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