NDC 54868-6016 Topiramate

NDC Product Code 54868-6016

NDC 54868-6016-0

Package Description: 60 TABLET, FILM COATED in 1 BOTTLE

NDC 54868-6016-1

Package Description: 30 TABLET, FILM COATED in 1 BOTTLE

NDC 54868-6016-2

Package Description: 90 TABLET, FILM COATED in 1 BOTTLE

NDC 54868-6016-3

Package Description: 120 TABLET, FILM COATED in 1 BOTTLE

This product is EXCLUDED from the official NDC directory because the listing data was inactivated by the FDA.

NDC Product Information

Topiramate with NDC 54868-6016 is a product labeled by Physicians Total Care, Inc. The generic name of Topiramate is . The product's dosage form is and is administered via form.

Labeler Name: Physicians Total Care, Inc

Dosage Form: -

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Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)
  • CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)
  • STARCH, CORN (UNII: O8232NY3SJ)
  • SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • POLYVINYL ALCOHOL (UNII: 532B59J990)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • POLYETHYLENE GLYCOLS (UNII: 3WJQ0SDW1A)
  • TALC (UNII: 7SEV7J4R1U)
  • FERRIC OXIDE YELLOW (UNII: EX438O2MRT)
  • ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)
  • CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)
  • STARCH, CORN (UNII: O8232NY3SJ)
  • SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • POLYVINYL ALCOHOL (UNII: 532B59J990)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • POLYETHYLENE GLYCOLS (UNII: 3WJQ0SDW1A)
  • TALC (UNII: 7SEV7J4R1U)
  • FERRIC OXIDE YELLOW (UNII: EX438O2MRT)
  • D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)
  • ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)
  • CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)
  • STARCH, CORN (UNII: O8232NY3SJ)
  • SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • POLYVINYL ALCOHOL (UNII: 532B59J990)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • POLYETHYLENE GLYCOLS (UNII: 3WJQ0SDW1A)
  • TALC (UNII: 7SEV7J4R1U)
  • FERRIC OXIDE RED (UNII: 1K09F3G675)
  • LECITHIN, SOYBEAN (UNII: 1DI56QDM62)
  • FERROSOFERRIC OXIDE (UNII: XM0M87F357)
  • ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)
  • CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)
  • STARCH, CORN (UNII: O8232NY3SJ)
  • SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • POLYVINYL ALCOHOL (UNII: 532B59J990)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • POLYETHYLENE GLYCOLS (UNII: 3WJQ0SDW1A)
  • TALC (UNII: 7SEV7J4R1U)

Product Labeler Information

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Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Physicians Total Care, Inc
Labeler Code: 54868
Start Marketing Date: 04-13-2009 What is the Start Marketing Date?
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Listing Expiration Date: 12-31-2017 What is the Listing Expiration Date?
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Exclude Flag: I What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

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Information for Patients

Topiramate

Topiramate is pronounced as (toe pyre' a mate)

Why is topiramate medication prescribed?
Topiramate is used alone or with other medications to treat certain types of seizures including primary generalized tonic-clonic seizures (formerly known as a grand mal s...
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Topiramate Product Label Images

Topiramate Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Description

Topiramate is a sulfamate-substituted monosaccharide. Topiramate
tablets are available as 25 mg, 50 mg, 100 mg, and 200 mg circular tablets for
oral administration.Topiramate is a white crystalline powder with a bitter taste. Topiramate USP
is most soluble in alkaline solutions containing sodium hydroxide or sodium
phosphate and having a pH of 9 to 10. It is freely soluble in acetone,
chloroform, dimethylsulfoxide, and ethanol. The solubility in water is 9.8
mg/mL. Its saturated solution has a pH of 6.3. Topiramate has the molecular
formula C12H21NO8S and a molecular weight of 339.37. Topiramate is designated
chemically as 2,3:4,5-Di-O-isopropylidene-β-D-fructopyranose sulfamate and has the
following structural formula:Topiramate tablets contain the following inactive ingredients: anhydrous
lactose, microcrystalline cellulose, pregelatinized starch, sodium starch
glycolate, magnesium stearate, purified water, polyvinyl alcohol, titanium
dioxide, polyethylene glycol and talc.In addition, individual tablets contain:50 mg tablets: iron oxide yellow100 mg tablets: iron oxide yellow, and
D&C Yellow # 10 Aluminum Lake200 mg tablets: iron oxide red, lecithin
(soya), and iron oxide black

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: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 to 41% bound to human plasma proteins
over the blood concentration range of 0.5 to 250 mcg/mL. The fraction bound
decreased as blood concentration increased. Carbamazepine and phenytoin do not alter the binding of topiramate. Sodium
valproate, at 500 mcg/mL (a concentration 5 to 10 times higher than considered
therapeutic for valproate) decreased the protein binding of topiramate from 23%
to 13%. Topiramate does not influence the binding of sodium valproate.Metabolism and Excretion:Topiramate is not extensively metabolized and is primarily
eliminated unchanged in the urine (approximately 70% of an administered dose).
Six metabolites have been identified in humans, none of which constitutes more
than 5% of an administered dose. The metabolites are formed via hydroxylation,
hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption
of topiramate. In rats, given probenecid to inhibit tubular reabsorption, along
with topiramate, a significant increase in renal clearance of topiramate was
observed. This interaction has not been evaluated in humans. Overall, oral
plasma clearance (CL/F) is approximately 20 to 30 mL/min in humans following
oral administration.Pharmacokinetic Interactions(see also Drug Interactions):Antiepileptic DrugsPotential 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 to 69 mL/min/1.73m2) and by 54% in severely renally impaired subjects (creatinine
clearance less than 30 mL/min/1.73m2) compared to normal renal
function subjects (creatinine clearance greater than 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 to 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 to 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 to
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.EpilepsyMonotherapy Controlled TrialThe effectiveness of topiramate as initial monotherapy in adults
and children 10 years of age and older with partial onset or primary generalized
seizures was established in a multicenter, randomized, double-blind,
parallel-group trial.The trial was conducted in 487 patients diagnosed with epilepsy (6 to 83
years of age) who had 1 or 2 well-documented seizures during the 3-month
retrospective baseline phase who then entered the study and received topiramate
25 mg/day for 7 days in an open-label fashion. Forty-nine percent of subjects
had no prior AED treatment and 17% had a diagnosis of epilepsy for greater than
24 months. Any AED therapy used for temporary or emergency purposes was
discontinued prior to randomization. In the double-blind phase, 470 patients
were randomized to titrate up to 50 mg/day or 400 mg/day. If the target dose
could not be achieved, patients were maintained on the maximum tolerated dose.
Fifty eight percent of patients achieved the maximal dose of 400 mg/day for ≥ 2
weeks, and patients who did not tolerate 150 mg/day were discontinued. The
primary efficacy assessment was a between group comparison of time to first
seizure during the double-blind phase. Comparison of the Kaplan-Meier survival
curves of time to first seizure favored the topiramate 400 mg/day group over the
topiramate 50 mg/day group (p=0.0002, log rank test; Figure 1). The treatment effects with respect to time to
first seizure were consistent across various patient subgroups defined by age,
sex, geographic region, baseline body weight, baseline seizure type, time since
diagnosis, and baseline AED use.Figure 1: Kaplan-Meier Estimates of Cumulative Rates
for Time to First SeizureAdjunctive Therapy Controlled Trials in Patients With
Partial Onset SeizuresThe 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 to 16 Years With Partial Onset SeizuresThe effectiveness of topiramate as an adjunctive treatment for
pediatric patients ages 2 to 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 SeizuresThe 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 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 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 SyndromeThe 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 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 in addition
to their other AEDs. Active drug was titrated beginning at 1 mg/kg per day for a
week; the dose was then increased to 3 mg/kg per day for one week then to 6
mg/kg per day. After titration, patients entered an 8-week stabilization period.
The primary measures of effectiveness were the percent reduction in drop attacks
and a parental global rating of seizure severity.Table 1: Topiramate Dose Summary During the Stabilization Periods of Each of Six Double-Blind, Placebo-Controlled, Add-On Trials in Adults with Partial Onset Seizuresb Target TopiramateDosage (mg/day)ProtocolStabilization DosePlaceboa               200                                     400            600800            1,000           YDNMean DoseMedian Dose425.96.0422002004039040041556600------YENMean DoseMedian Dose449.710.0------4054460045739800407961,000Y1NMean DoseMedian Dose233.84.0---19395400---------Y2NMean DoseMedian Dose305.76.0------28522600------Y3NMean DoseMedian Dose287.98.0---------25568600---119 NMean DoseMedian Dose9088157200200------------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 seizure.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 TrialsTargetProtocol    Efficacy Results                                                                              Placebo               200               400               600               800               1,000                ≈6mg/kg/day*      Partial Onset Seizures Studies in Adults                YDMedian % Reduction% RespondersN4511.6184527.2a244547.5b44d4644.7c46d---------YEMedian % Reduction% RespondersN1.7924------4840.8c40c4841.0c41c4736.0c36d---Y1Median % Reduction% RespondersN241.18---2340.7e35d------------Y2Median % Reduction% RespondersN30-12.210------3046.4f47c---------Y3Median % Reduction% RespondersN28-20.60---------2824.3c43c------119NMedian % Reduction% Responders9116820.024-44.2c45c--------------Studies in Pediatric PatientsYPMedian T Reduction% RespondersN4510.520---------------4133.1d39Primary Generalized Tonic-ClonichYTCMedian % Reduction% RespondersN409.020---------------3956.7d56cLennox-Gastuat SyndromeiYLMedian % Reduction% RespondersN49-5.114---------------4614.8d28gImprovement in Seizure Severityj28------52dComparisons with placebo: a
p=0.080; b p less than 0.010; c
p less than 0.001; d p less than 0.050; e
p=0.065; f p less than 0.005;g
p=0.071;h Median % reduction and %
responders are reported for PGTC Seizures;i Median % reduction and %
responders for drop attacks, i.e., tonic or atonic seizures;j Percent of subjects who were
minimally, much, or very much improved from baseline* For Protocols YP and YTC, protocol-specified target
dosages (less than 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.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 EpilepsyTopiramate 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 EpilepsyTopiramate tablets are indicated as adjunctive therapy for adults
and pediatric patients ages 2 to 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
GlaucomaA syndrome consisting of acute myopia associated with secondary
angle closure glaucoma has been reported in patients receiving topiramate.
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
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 as rapidly as possible,
according to the judgment of the treating physician. Other measures, in
conjunction with discontinuation of topiramate, may be helpful.Elevated intraocular pressure of any etiology, if left untreated, can lead to
serious sequelae including permanent vision loss.Oligohidrosis and HyperthermiaOligohidrosis (decreased sweating), infrequently resulting in
hospitalization, has been reported in association with topiramate 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 should be monitored closely for
evidence of decreased sweating and increased body temperature, especially in hot
weather. Caution should be used when topiramate is prescribed with other drugs
that predispose patients to heat-related disorders; these drugs include, but are
not limited to, other carbonic anhydrase inhibitors and drugs with
anticholinergic activity.Suicidal Behavior and IdeationAntiepileptic drugs (AEDs), including topiramate, 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
AnalysisIndicationPlacebo Patients with Events Per 1000 PatientsDrug Patients with Events Per 1000 PatientsRelative Risk: Incidence of Events in Drug Patients/Incidence
in Placebo PatientsRisk Difference: Additional Drug Patients with Events Per 1000
PatientsEpilepsy1.03.43.52.4Psychiatric5.78.51.52.9Other1.01.81.90.9Total2.44.31.81.9The 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 or any other AED must balance the
risk of suicidal thoughts or behavior with the risk of untreated illness.
Epilepsy and many other illnesses for which AEDs are prescribed are themselves
associated with morbidity and mortality and an increased risk of suicidal
thoughts and behavior. Should suicidal thoughts and behavior emerge during
treatment, the prescriber needs to consider whether the emergence of these
symptoms in any given patient may be related to the illness being treated. 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 AcidosisHyperchloremic, 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 less than 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
less than 17 mEq/L and greater than 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 (less than 16 years of age), the incidence of persistent
treatment-emergent decreases in serum bicarbonate in placebo-controlled trials
for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset
seizures was 67% for topiramate (at approximately 6 mg/kg/day), and 10% for
placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e.,
absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in these
trials was 11% for topiramate and 0% for placebo. Cases of moderately severe
metabolic acidosis have been reported in patients as young as 5 months old,
especially at daily doses above 5 mg/kg/day.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 less than 17 mEq/L and greater than 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 EventsAdults Adverse events most often associated with the use of topiramate
were related to the central nervous system and were observed in the epilepsy
population. 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
DysfunctionThe 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 to 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
50 mg/day and 26% for 400 mg/day.Psychiatric/Behavioral
DisturbancesPsychiatric/behavioral disturbances (depression or mood problems)
were dose-related for the epilepsy population.Somnolence/FatigueSomnolence and fatigue were the adverse events most frequently
reported during clinical trials of topiramate 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 PatientsIn 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 AEDsAntiepileptic drugs, including topiramate, 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 (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 program, to 0.005 for patients with refractory epilepsy).

Precautions

Hyperammonemia and Encephalopathy Associated with
Concomitant Valproic Acid UseConcomitant 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 StonesA 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 to 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 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 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.ParesthesiaParesthesia (usually tingling of the extremities), an effect
associated with the use of other carbonic anhydrase inhibitors, appears to be a
common effect of topiramate. 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 FailureThe 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 FunctionIn hepatically impaired patients, topiramate should be
administered with caution as the clearance of topiramate may be decreased.Information for PatientsPatients 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 should be told to seek immediate medical attention
if they experience blurred vision or periorbital pain.Patients, especially pediatric patients, treated with topiramate 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, 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 DrugsPotential 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 was given alone.Table 4: Summary of AED Interactions with TopiramateAEDCo-administeredAEDConcentrationTopiramateConcentrationPhenytoinCarbamazepine (CBZ)CBZ epoxidebValproic acidPhenobarbitalPrimidoneLamatrigineNC or 25% increaseaNCNC11% decreaseNCNCNC at TPM doses up to400 mg/day48% decrease40% decreaseNE14% decreaseNENE15% increasea = Plasma concentration increased 25% in some patients, generally those on a b.i.d.
dosing regimen of phenytoin.b = Is not administered but is an active metabolite of carbamazepine.NC = Less than 10% change in plasma concentration.AED = Antiepileptic drug.NE = Not Evaluated.TPM = TopiramateIn 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 InteractionsDigoxinIn a single-dose study, serum digoxin AUC was decreased by 12%
with concomitant topiramate administration. The clinical relevance of this
observation has not been established.CNS DepressantsConcomitant administration of topiramate 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 ContraceptivesIn 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 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 (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 to 800 mg/day, there was no
significant dose dependent change in EE exposure for doses of 50 to 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. 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.PioglitazoneA 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 is added to pioglitazone therapy or pioglitazone is added to
topiramate therapy, careful attention should be given to the routine monitoring
of patients for adequate control of their diabetic disease state.LithiumMultiple 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).HaloperidolThe 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).AmitriptylineThere 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.SumatriptanMultiple 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).RisperidoneThere 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.PropranololMultiple 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.DihydroergotamineMultiple 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.OthersConcomitant use of topiramate, 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 InteractionsThere 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 in pregnant women. Topiramate 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 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 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 less than or equal to 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 EpilepsyThe 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 (greater than or equal to 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 (greater than or equal to 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 GroupBody System/Adverse EventTopiramate Dosage50(N = 160)(mg/day)400(N = 159)Body as a Whole-General Disorders   Asthenia   Leg Pain   Chest PainCentral and Peripheral Nervous System Disorders   Paresthesa   Dizziness   Hypoaesthesia   Ataxia   HypertoniaGastro-Intestinal System Disorders   Diarrhea   Constipation   Gastritis   Dry Mouth   Gastroesophageal RefluxLiver and Biliary System Disorders   Gamma-GT IncreasedMetabolic and Nutritional Disorders   Weight DecreasePsychiatric Disorders   Somnolence   Anorexia   Difficulty with Memory NOS   Insomnia   Depression   Difficulty with Concentration/Attention   Anxiety   Psychomotor Slowing   Mood Problems   Confusion   Cognitive Problem NOS   Libido DecreasedReproductive Disorders, Female   Vaginal HemorrhageRed Blood Cell Disorders   AnemiaResistance Mechanism Disorders   Infection Viral   InfectionRespiratory System Disorders   Bronchitis   Rhinitis   DyspneaSkin and Appendages Disorders   Rash   Pruritus   AcneSpecial Senses Other, Disorders   Taste PerversionUrinary System Disorders   Cystitis   Renal Calculus   Urinary Tract Infection   Dysuria   Micturition Frequency4212113430510111694587743231001623211123101006324014543643323161514109986554433283442443533222a   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.Table 6: Incidence of Treatment-Emergent Adverse Events in the Monotherapy Epilepsy Trial in Children Ages 10 up to 16 Yearsa Where Rate Was at Least 5% in the 400 mg/day Topiramate Group and Greater Than the Rate in the 50 mg/day Topiramate GroupBody System/Adverse EventTopiramate Dosage

50
(N = 57)(mg/day)

400
(N = 57)Body as a Whole-General Disorders
   FeverCentral and Peripheral Nervous System Disorders
   ParesthesaGastro-Intestinal System Disorders
   DiarrheaMetabolic and Nutritional Disorders
   Weight DecreasePsychiatric Disorders
   Anorexia
   Mood Problems   Difficulty with Concentration/Attention
   Cognitive Problem NOS
   NervousnessResistance Mechanism Disorders
   Infection Viral
   InfectionRespiratory System Disorders
   Upper Respiratory Tract Infection   Rhinitis   Bronchitis
   SinusitisSkin and Appendages Disorders
   Alopecia0257112404421622229161121141197597187755a  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.Adjunctive Therapy EpilepsyThe 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%),
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%). 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 SyndromeTable 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
was added to concurrent antiepileptic drug therapy and cannot be used to predict
the frequency of adverse events in the course of usual medical practice where
patient characteristics and other factors may differ from those prevailing
during clinical studies. Similarly, the cited frequencies cannot be directly
compared with data obtained from other clinical investigations involving
different treatments, uses, or investigators. Inspection of these frequencies,
however, does provide the prescribing physician with a basis to estimate the
relative contribution of drug and non-drug factors to the adverse event
incidences in the population studied.

Other

Other Adverse Events Observed During Double-Blind
Epilepsy Adjunctive Therapy TrialsOther 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 Adultsa,b Where Rate Was Greater Than 1% in Any Topiramate Group and Greater Than the Rate in Placebo-Treated PatientsTopiramate Dosage (mg/day)Body System/Adverse
EventcPlacebo(N=291)200 to 400(N=183)600 to
1,000(N=414)Body as a Whole-General
Disorders   Fatigue131530   Asthenia163   Back Pain453   Chest Pain342   Influenza-Like Symptoms234   Leg Pain224   Hot Flushes121   Allergy123   Edema121   Body Odor010   Rigors01less than 1Central & Peripheral Nervous
System Disorders   Dizziness152532   Ataxia71614   Speech Disorders/Related Speech Problems21311   Paresthesia41119   Nystagmus71011   Tremor699   Language Problems1610   Coordination Abnormal244   Hypoaesthesia121   Gait Abnormal132   Muscle Contractions Involuntary122   Stupor021   Vertigo112Gastro-Intestinal System
Disorders   Nausea81012   Dyspepsia676   Abdominal Pain467   Constipation243   Gastroenteritis121   Dry Mouth124   Gingivitisless than 111   GI Disorderless than 110Hearing and Vestibular
Disorders   Hearing Decreased121Metabolic and Nutritional
Disorders   Weight Decrease3913Muscle-Skeletal System
Disorders   Myalgia122   Skeletal Pain010Platelet, Bleeding, & Clotting
Disorders   Epistaxis121Psychiatric Disorders    Somnolence122928   Nervousness61619   Psychomotor Slowing21321   Difficulty with Memory31214   Anorexia41012   Confusion51114   Depression5513   Difficulty with Concentration/Attention2614   Mood Problems249   Agitation233   Aggressive Reaction233   Emotional Lability133   Cognitive Problems133   Libido Decreased12less than 1   Apathy113   Depersonalization112Reproductive Disorders,
Female   Breast Pain240   Amenorrhea122   Menorrhagia021   Menstrual Disorder121Reproductive Disorders,
Male   Prostatic Disorderless than 120Resistance Mechanism
Disorders   Infection121   Infection Viral12less than 1   Moniliasisless than 110Respiratory System
Disorders   Pharyngitis263   Rhinitis676   Sinusitis456   Dyspnea112Skin and Appendages
Disorders   Skin Disorderless than 121   Sweating Increasedless than 11less than 1   Rash Erythematousless than 11less than 1Special Sense Other,
Disorders   Taste Perversion024Urinary System Disorders    Hematuria12less than 1   Urinary Tract Infection123   Micturition Frequency112   Urinary Incontinenceless than 121   Urine Abnormal01less than 1Vision Disorders   Vision Abnormal21310   Diplopia51010White Cell and RES
Disorders   Leukopenia121a  Patients in these add-on trials were receiving 1 to 2 concomitant antiepileptic
drugs in addition to topiramate or placebo.b  Values represent the percentage of patients reporting a given adverse event.
Patients may have reported more than one adverse event during the study and can
be included in more than one adverse event category.c  Adverse events reported by at least 1% of patients in the topiramate 200 to 400
mg/day group and more common than in the placebo group are listed in this table.

Incidence in Study 119 – Add-On Therapy– Adults with
Partial Onset SeizuresStudy 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 119a,b Where Rate Was Greater Than or Equal To 2% in the Topiramate Group and Greater
Than the Rate in Placebo-Treated PatientsTopiramate Dosage (mg/day)Body System/Adverse
EventcPlacebo(N=92)200(N=171)Body as a Whole-General
Disorders   Fatigue49   Chest Pain12Cardiovascular Disorders,
General   Hypertension02Central & Peripheral Nervous
System Disorders   Paresthesia29   Dizziness47   Tremor23   Hypoasthesia02   Leg Cramps02   Language Problems02Gastro-Intestinal System
Disorders   Abdominal Pain35   Constipation04   Diarrhea12   Dyspepsia02   Dry Mouth02Hearing and Vestibular
Disorders   Tinnitus02Metabolic and Nutritional
Disorders   Weight Decrease48Psychiatric Disorders    Somnolence915   Anorexia79   Nervousness29   Difficulty with Concentration/Attention05   Insomnia34   Difficulty with Memory12   Aggressive Reaction02Respiratory System
Disorders   Rhinitis04Urinary System Disorders    Cystitis02Vision Disorders   Diplopia02   Vision Abnormal02a  Patients in these add-on trials were receiving 1 to 2 concomitant antiepileptic
drugs in addition to topiramate or placebo.b  Values represent the percentage of patients reporting a given adverse event.
Patients may have reported more than one adverse event during the study and can
be included in more than one adverse event category.c  Adverse events reported by at least 2% of patients in the topiramate 200 mg/day
group and more common than in the placebo group are listed in this table.

Table 9: Incidence (%) of Dose-Related Adverse Events From Placebo-Controlled,
Add-On Trials in Adults with Partial Onset SeizuresaTopiramate Dosage (mg/day)Adverse EventPlacebo(N = 216)200(N = 45)400(N = 68)600 to 1,000(N =
414)Fatigue13111230Nervousness7131819Difficulty with Concentration/Attention17914Confusion491014Depression69713Anorexia44612Language problemsless than 12910Anxiety62310Mood problems2069Weight decrease34913a  Dose-response studes were not conducted for otehr adult indications or for pediatric indications.Table 10: Incidence (%) of Treatment-Emergent Adverse Events in
Placebo-Controlled, Add-On Epilepsy Trials in Pediatric Patients Ages 2 to 16
Yearsa,b (Events that Occurred in at Least 1% of
Topiramate-Treated Patients and Occurred More Frequently in Topiramate-Treated
Than Placebo-Treated Patients)Body System/Adverse
EventPlacebo(N=101)Topiramate(N=98)Body as a Whole - General
Disorders    Fatigue516    Injury1314    Allergic Reaction12    Back Pain01    Pallor01Cardiovascular Disorders,
General    Hypertension01Central & Peripheral Nervous
System Disorders    Gait Abnormal58    Ataxia26    Hyperkinesia45    Dizziness24    Speech Disorders/Related Speech Problems24    Hyporeflexia02    Convulsions Grand Mal01    Fecal Incontinence01    Paresthesia01Gastro-Intestinal System
Disorders    Nausea56    Saliva Increased46    Constipation45    Gastroenteritis23    Dysphagia01    Flatulence01    Gastroesophageal Reflux01    Glossitis01    Gum Hyperplasia01Heart Rate and Rhythm
Disorders    Bradycardia01Metabolic and Nutritional
Disorders    Weight Decrease19    Thirst12    Hypoglycemia01    Weight Increase01Platelet, Bleeding, & Clotting
Disorders    Purpura48    Epistaxis14    Hematoma01    Prothrombin Increased01    Thrombocytopenia01Psychiatric Disorders     Somnolence1626    Anorexia1524    Nervousness714    Personality Disorder (Behavior Problems)911    Difficulty with Concentration/Attention210    Aggressive Reaction49    Insomnia78    Difficulty with Memory NOS05    Confusion34    Psychomotor Slowing23    Appetite Increased01    Neurosis01Reproductive Disorders,
Female    Leukorrhoea02Resistance Mechanism
Disorders    Infection Viral37Respiratory System
Disorders    Pneumonia15    Respiratory Disorder01Skin and Appendages
Disorders    Skin Disorder23    Alopecia12    Dermatitis02    Hypertrichosis12    Rash Erythematous02    Eczema01    Seborrhoea01    Skin Discoloration01Urinary System Disorders     Urinary Incontinence24    Nocturia01Vision Disorders    Eye Abnormality12    Vision Abnormal12    Diplopia01    Lacrimation Abnormal01    Myopia01White Cell and RES
Disorders    Leukopenia02a  Patients in these add-on trials were receiving 1 to 2 concomitant antiepileptic
drugs in addition to topiramate or placebo.b  Values represent the percentage of patients reporting a given adverse event.
Patients may have reported more than one adverse event during the study and can
be included in more than one adverse event category.Other Adverse Events Observed During All Epilepsy
Clinical TrialsTopiramate 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 ExperienceIn addition to the adverse experiences reported during clinical
testing of topiramate, 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, maculopathy, pancreatitis,
pemphigus, and renal tubular acidosis.

Drug Abuse And Dependence

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

Overdosage

Overdoses of topiramate 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.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 to 24 hours followed by full recovery after 3 to 4
days.In acute topiramate overdose, if the ingestion is recent, the stomach should
be emptied immediately by lavage or by induction of emesis. Activated charcoal
has been shown to adsorb topiramate in vitro.
Treatment should be appropriately supportive. Hemodialysis is an effective means
of removing topiramate from the body.

Dosage And Administration

EpilepsyIn 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 1000 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 therapy. On occasion, the addition of topiramate 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 may require adjustment of the dose of
topiramate. Because of the bitter taste, tablets should not be broken.Topiramate tablets can be taken without regard to meals.Monotherapy UseThe 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 DoseEvening
DoseWeek 125 mg25 mgWeek 250 mg50 mgWeek 375 mg75 mgWeek 4100 mg100 mgWeek 5150 mg150 mgWeek 6200 mg200 mgAdjunctive Therapy UseAdults (17 Years of Age and Over) - Partial Seizures,
Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut SyndromeThe recommended total daily dose of topiramate as adjunctive
therapy in adults with partial seizures is 200 to 400 mg/day in two divided
doses, and 400 mg/day in two divided doses as adjunctive treatment in adults
with primary generalized tonic-clonic seizures. It is recommended that therapy
be initiated at 25 to 50 mg/day followed by titration to an effective dose in
increments of 25 to 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 to 16 Years)– Partial
Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut
SyndromeThe recommended total daily dose of topiramate 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 Trials in
Patients With Primary Generalized Tonic-Clonic Seizures).Patients with Renal Impairment:In renally impaired subjects (creatinine clearance less than
70 mL/min/1.73 m2), one half of the usual adult dose is
recommended. Such patients will require a longer time to reach steady-state at
each dose.Geriatric Patients (Ages 65 Years and Over):Dosage adjustment may be indicated in the elderly patient when
impaired renal function (creatinine clearance rate ≤70 mL/min/1.73 m2) is evident (see DOSAGE AND ADMINISTRATION: Patients with Renal
Impairment and CLINICAL PHARMACOLOGY: Special Populations: Age, Gender,
and Race).Patients Undergoing Hemodialysis:Topiramate is cleared by hemodialysis at a rate that is 4 to 6
times greater than a normal individual. Accordingly, a prolonged period of
dialysis may cause topiramate concentration to fall below that required to
maintain an anti-seizure effect. To avoid rapid drops in topiramate plasma
concentration during hemodialysis, a supplemental dose of topiramate may be
required. The actual adjustment should take into account 1) the duration of
dialysis period, 2) the clearance rate of the dialysis system being used, and 3)
the effective renal clearance of topiramate in the patient being dialyzed.Patients with Hepatic Disease:In hepatically impaired patients topiramate plasma concentrations
may be increased. The mechanism is not well understood.

How Supplied

Topiramate tablets are available as debossed, film-coated,
circular tablets in the following strengths and colors:25 mg white (coded "S" on one side; "707" on the other)50 mg yellow
(coded "S" on one side; "710" on the other)100 mg yellow (coded "S" on one
side; "711" on the other)200 mg brown (coded "S" on one side; "712" on the
other)They are supplied as follows:25 mg tablets    Bottles of 30NDC 54868-6016-1Bottles of 60NDC 54868-6016-0Bottles of 90NDC 54868-6016-2Bottles of 120NDC 54868-6016-350 mg tablets   
Bottles of 30NDC 54868-6017-1Bottles of 60NDC 54868-6017-0Bottles of 90NDC 54868-6017-2                            100 mg tablets  Bottles of 30NDC 54868-6014-1Bottles of 60NDC 54868-6014-0Bottles of 90NDC 54868-6014-2200 mg tablets  Bottles of 30NDC 54868-6015-1Bottles of 60NDC 54868-6015-0Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59°
to 86°F) [See USP Controlled Room Temperature]. Protect from moisture. Dispense
in a tight container.

Medication Guide

  • Topiramate TabletsRead 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 rednessa 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 dyingattempts to commit suicidenew or worse depressionnew or worse anxietyfeeling agitated or restlesspanic attackstrouble sleeping (insomnia)new or worse irritabilityacting aggressive, being angry, or violentacting on dangerous impulsesan extreme increase in activity and talking (mania)other unusual changes in behavior or moodDo 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 tablet?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 olderwith 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
  • OlderWhat 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
  • Behaviorhave kidney problems, kidney stones, or are getting kidney dialysishave a history of metabolic acidosis (too much acid in the blood)have liver problemshave osteoporosis, soft bones, or decreased bone densityhave lung or breathing problemshave eye problems, especially glaucomahave diarrheahave a growth problemare on a diet high in fat and low in carbohydrates, which is called a
  • Ketogenic dietare having surgeryare 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 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 acidany 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 many 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:tirednessloss of appetiteirregular heartbeatimpaired consciousnessHigh 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 are taken with a
  • Medicine called valproic acid.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 hungrynauseaa change in the way foods tastediarrheaweight lossnervousnessupper respiratory tract infectionTell 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 20° to 25°C (68° to 77°F); excursions permitted
  • To 15° to 30°C (59° to 86°F).Keep topiramate tablets in a tightly closed containerKeep topiramate tablets dry and away from moistureKeep topiramate tablets and all medicines 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 tablet 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.For more information, call 1-800-818-4555What are the ingredients in topiramate tablets?Active ingredient: topiramateInactive ingredients: anhydrous lactose,
  • Microcrystalline cellulose, pregelatinized starch, sodium starch glycolate,
  • Magnesium stearate, purified water, polyvinyl alcohol, titanium dioxide,
  • Polyethylene glycol and talc.In addition, individual tablets contain:50 mg tablets: iron oxide yellow100 mg tablets: iron oxide yellow, and
  • D&C Yellow # 10 Aluminum Lake200 mg tablets: iron oxide red, lecithin
  • (soya), and iron oxide blackThis Medication Guide has been approved by the U.S. Food and
  • Drug Administration.Distributed by:Caraco Pharmaceutical
  • Laboratories, Ltd.1150 Elijah McCoy Drive, Detroit, MI 48202Manufactured by:Sun Pharmaceutical Industries
  • Ltd.Acme Plaza, Andheri-Kurla Road,Andheri (East), Mumbai - 400
  • 059, India.ISS. 07/2009PGPI0101ARepackaging and Relabeling by:Physicians Total Care, Inc.Tulsa, OK      74146

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