Topiramate tablet, film coated

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 C H NO S and a molecular weight of 339.37. Topiramate is designated chemically as 2,3:4,5-Di- -isopropylidene--D-fructopyranose sulfamate and has the following structural formula: 12 21 8 O

topiramate-structure

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 yellow 100 mg tablets: iron oxide yellow, and D&C Yellow # 10 Aluminum Lake 200 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 Drugs

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

Special populations:


Renal impairment:

The clearance of topiramate was reduced by 42% in moderately renally impaired (creatinine clearance 30 to 69mL/min/1.73m ) and by 54% in severely renally impaired subjects (creatinine clearance <30mL/min/1.73m ) compared to normal renal function subjects (creatinine clearance >70mL/min/1.73m ). 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 and . 2 2 2 PRECAUTIONS: Adjustment of Dose in Renal Failure ) DOSAGE AND ADMINISTRATION

Hemodialysis:

Topiramate is cleared by hemodialysis. Using a high efficiency, counterflow, single pass-dialysate hemodialysis procedure, topiramate dialysis clearance was 120mL/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 2hours. 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 70mL/min/1.73 m ) is evident. It may be useful to monitor renal function in the elderly patient (see , and ). 2 Special Populations: Renal Impairment PRECAUTIONS: Adjustment of Dose in Renal Failure DOSAGE AND ADMINISTRATION

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

Pediatric pharmacokinetics:

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

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

Clinical studies

The studies described in the following sections were conducted using topiramate tablets.

Epilepsy

Monotherapy controlled trial

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

The trial was conducted in 487patients diagnosed with epilepsy (6 to 83 years of age) who had 1 or 2 well-documentedseizures during the 3-month retrospective baseline phase who then enteredthe 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 diagnosisof epilepsy for greater than 24 months. Any AED therapy used for temporaryor emergency purposes was discontinued prior to randomization. In the double-blindphase, 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 themaximum tolerated dose. Fifty eight percent of patients achieved the maximaldose of 400 mg/day for 2 weeks, and patients who did not tolerate150 mg/day were discontinued. The primary efficacy assessment was a betweengroup comparison of time to first seizure during the double-blind phase. Comparisonof the Kaplan-Meier survival curves of time to first seizure favored the topiramate400 mg/day group over the topiramate 50 mg/day group (p=0.0002, log rank test; ). Thetreatment effects with respect to time to first seizure were consistent acrossvarious patient subgroups defined by age, sex, geographic region, baselinebody weight, baseline seizure type, time since diagnosis, and baseline AEDuse. Figure 1

Figure1: Kaplan-Meier Estimates of Cumulative Rates for Time to First Seizure
topiramate-fig01

Adjunctive therapy controlled trials in patients with partial onset seizures

The effectiveness of topiramate as an adjunctive treatmentfor adults with partial onset seizures was established in six multicenter,randomized, double-blind, placebo-controlled trials, two comparing severaldosages of topiramate and placebo and four comparing a single dosage withplacebo, in patients with a history of partial onset seizures, with or withoutsecondarily generalized seizures.

Patients in thesestudies were permitted a maximum of two antiepileptic drugs (AEDs) in additionto topiramate tablets or placebo. In each study, patients werestabilized on optimum dosages of their concomitant AEDs during baseline phaselasting between 4 and 12 weeks. Patients who experienced a prespecified minimumnumber of partial onset seizures, with or without secondary generalization,during the baseline phase (12 seizures for 12-week baseline, 8 for 8-weekbaseline, or 3 for 4-week baseline) were randomly assigned to placebo or aspecified dose of topiramate tablets in addition to their otherAEDs.

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

Adjunctive therapy controlled trialin pediatric patients ages 2 to 16 years with partial onset seizures

The effectiveness of topiramate as an adjunctive treatmentfor pediatric patients ages 2 to 16 years with partial onset seizures was establishedin a multicenter, randomized, double-blind, placebo-controlled trial, comparingtopiramate and placebo in patients with a history of partial onset seizures,with or without secondarily generalized seizures.

Patientsin this study were permitted a maximum of two antiepileptic drugs (AEDs) inaddition to topiramate tablets or placebo. In this study, patientswere stabilized on optimum dosages of their concomitant AEDs during an 8-weekbaseline phase. Patients who experienced at least six partial onset seizures,with or without secondarily generalized seizures, during the baseline phasewere randomly assigned to placebo or topiramate tablets in additionto their other AEDs.

Following randomization, patientsbegan the double-blind phase of treatment. Patients received active drug beginningat 25 or 50mg per day; the dose was then increased by 25mg to150mg/day increments every other week until the assigned dosage of 125,175, 225, or 400mg/day based on patients' weight to approximate a dosageof 6mg/kg per day was reached, unless intolerance prevented increases.After titration, patients entered an 8-week stabilization period.

Adjunctive therapy controlled trialin patients with primary generalized tonic-clonic seizures

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

Patientsin this study were permitted a maximum of two antiepileptic drugs (AEDs) inaddition to topiramate or placebo. Patients were stabilizedon optimum dosages of their concomitant AEDs during an 8-week baseline phase.Patients who experienced at least three primary generalized tonic-clonic seizuresduring the baseline phase were randomly assigned to placebo or topiramate inaddition to their other AEDs.

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

Adjunctive therapy controlled trialin patients with lennox-gastaut syndrome

The effectiveness of topiramate as an adjunctive treatmentfor seizures associated with Lennox-Gastaut syndrome was established in amulticenter, randomized, double-blind, placebo-controlled trial comparinga single dosage of topiramate with placebo in patients 2 years of age andolder.

Patients in this study were permitted a maximumof two antiepileptic drugs (AEDs) in addition to topiramate orplacebo. Patients who were experiencing at least 60seizures per monthbefore study entry were stabilized on optimum dosages of their concomitantAEDs during a 4-week baseline phase. Following baseline, patients were randomlyassigned to placebo or topiramate in addition to their otherAEDs. Active drug was titrated beginning at 1 mg/kg per day for a week; thedose was then increased to 3 mg/kg per day for one week then to 6 mg/kg perday. After titration, patients entered an 8-week stabilization period. Theprimary measures of effectiveness were the percent reduction in drop attacksand a parental global rating of seizure severity.

Table 1: Topiramate Dose Summary During the StabilizationPeriods of Each of Six Double-Blind, Placebo-Controlled, Add-On Trials inAdults with Partial Onset Seizures b
Target TopiramateDosage (mg/day)
Protocol Stabilization Dose Placebo a 200 400 600 800 1,000

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

Dose-responsestudies were not conducted for other indications or pediatric partial onsetseizures. b

YD N 42 42 40 41 -- --
Mean Dose 5.9 200 390 556 -- --
Median Dose 6.0 200 400 600 -- --
YE N 44 -- -- 40 45 40
Mean Dose 9.7 -- -- 544 739 796
Median Dose 10.0 -- -- 600 800 1,000
Y1 N 23 -- 19 -- -- --
Mean Dose 3.8 -- 395 -- -- --
Median Dose 4.0 -- 400 -- -- --
Y2 N 30 -- -- 28 -- --
Mean Dose 5.7 -- -- 522 -- --
Median Dose 6.0 -- -- 600 -- --
Y3 N 28 -- -- -- 25 --
Mean Dose 7.9 -- -- -- 568 --
Median Dose 8.0 -- -- -- 600 --
119 N 90 157 -- -- -- --
Mean Dose 8 200 -- -- -- --
Median Dose 8 200 -- -- -- --

In all add-on trials, the reduction in seizure rate frombaseline during the entire double-blind phase was measured. The median percentreductions in seizure rates and the responder rates (fraction of patientswith at least a 50% reduction) by treatment group for each study are shownbelow in . As described above, a global improvement in seizure severity wasalso assessed in the Lennox-Gastaut trial. Table 2

Table 2: Efficacy Results in Double-Blind, Placebo-Controlled, Add-On Epilepsy Trials
TargetTopiramate Dosage (mg/day)
Protocol Efficacy Results Placebo 200 400 600 800 1,000 6 mg/kg/day*

Comparisonswith placebo: p=0.080; p<0.010; p<0.001; p<0.050; p=0.065; p<0.005; p=0.071; a b c d e f g

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

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

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

*For Protocols YP and YTC, protocol-specified target dosages (<9.3 mg/kg/day)were assigned based on subject's weight to approximate a dosage of 6 mg/kgper day; these dosages corresponded to mg/day dosages of 125, 175, 225, and400 mg/day.

Partial Onset Seizures
Studies in Adults
YD N 45 45 45 46 -- -- --
Median % Reduction 11.6 27.2 a 47.5 b 44.7 c -- -- --
% Responders 18 24 44 d 46 d -- -- --
YE N 47 -- -- 48 48 47 --
Median % Reduction 1.7 -- -- 40.8 c 41.0 c 36.0 c --
% Responders 9 -- -- 40 c 41 c 36 d --
Y1 N 24 -- 23 -- -- -- --
Median % Reduction 1.1 -- 40.7 e -- -- -- --
% Responders 8 -- 35 d -- -- -- --
Y2 N 30 -- -- 30 -- -- --
Median % Reduction -12.2 -- -- 46.4 f -- -- --
% Responders 10 -- -- 47 c -- -- --
Y3 N 28 -- -- -- 28 -- --
Median % Reduction -20.6 -- -- -- 24.3 c -- --
% Responders -- -- -- 43 c -- --
119 N 91 168 -- -- -- -- --
Median % Reduction 20.0 44.2 c -- -- -- -- --
% Responders 24 45 c -- -- -- -- --
Studies in Pediatric Patients
YP N 45 -- -- -- -- -- 41
Median % Reduction 10.5 -- -- -- -- -- 33.1 d
% Responders 20 -- -- -- -- -- 39
Primary Generalized Tonic-Clonic h
YTC N 40 -- -- -- -- -- 39
Median % Reduction 9.0 -- -- -- -- -- 56.7 d
% Responders 20 -- -- -- -- -- 56 c
Lennox-Gastaut Syndrome i
YL N 49 -- -- -- -- -- 46
Median % Reduction -5.1 -- -- -- -- -- 14.8 d
% Responders 14 -- -- -- -- -- 28 g
Improvement in Seizure Severity j 28 -- -- -- -- -- 52 d

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

Indications and usage

Monotherapy epilepsy

Topiramate tablets are indicated as initial monotherapy in patients 10 years of age and older with partial onset or primary generalized tonic-clonic seizures.

Effectiveness was demonstrated in a controlledtrial in patients with epilepsy who had no more than 2 seizures in the 3 monthsprior to enrollment. Safety and effectiveness in patients who were convertedto monotherapy from a previous regimen of other anticonvulsant drugs havenot been established in controlled trials.

Adjunctive therapy epilepsy

Topiramate tablets are indicated as adjunctive therapy for adultsand pediatric patients ages 2to16 years with partial onset seizures,or primary generalized tonic-clonic seizures, and in patients 2 years of ageand older with seizures associated with Lennox-Gastaut syndrome.

Contraindications

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

Warnings

Acute myopia and secondary angle closureglaucoma

A syndrome consisting of acute myopia associated with secondaryangle 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, ocularhyperemia (redness) and increased intraocular pressure. Mydriasis may or maynot be present. This syndrome may be associated with supraciliary effusionresulting in anterior displacement of the lens and iris, with secondary angleclosure glaucoma. Symptoms typically occur within 1 month of initiating topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 yearsof age, secondary angle closure glaucoma associated with topiramate has beenreported in pediatric patients as well as adults. The primary treatment toreverse symptoms is discontinuation of topiramate as rapidlyas possible, according to the judgment of the treating physician. Other measures,in conjunction with discontinuation of topiramate, may be helpful.

Elevatedintraocular pressure of any etiology, if left untreated, can lead to serioussequelae including permanent vision loss.

Oligohidrosis and hyperthermia

Oligohidrosis (decreased sweating), infrequently resultingin hospitalization, has been reported in association with topiramate use.Decreased sweating and an elevation in body temperature above normal characterizedthese cases. Some of the cases were reported after exposure to elevated environmentaltemperatures.

The majority of the reports have beenin children. Patients, especially pediatric patients, treated with topiramate should be monitored closely for evidence of decreased sweating and increased bodytemperature, especially in hot weather. Caution should be used when topiramate isprescribed with other drugs that predispose patients to heat-related disorders;these drugs include, but are not limited to, other carbonic anhydrase inhibitorsand drugs with anticholinergic activity.

Suicidal behavior and ideation

Antiepileptic 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 Analysis
Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients
Epilepsy 1.0 3.4 3.5 2.4
Psychiatric 5.7 8.5 1.5 2.9
Other 1.0 1.8 1.9 0.9
Total 2.4 4.3 1.8 1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing topiramate 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 acidosis

Hyperchloremic, non-anion gap, metabolic acidosis (i.e.,decreased serum bicarbonate below the normal reference range in the absenceof chronic respiratory alkalosis) is associated with topiramate treatment.This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitoryeffect of topiramate on carbonic anhydrase. Such electrolyte imbalance hasbeen observed with the use of topiramate in placebo-controlled clinical trialsand in the post-marketing period. Generally, topiramate-induced metabolicacidosis occurs early in treatment although cases can occur at any time duringtreatment. Bicarbonate decrements are usually mild-moderate (average decreaseof 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/dayin pediatric patients); rarely, patients can experience severe decrementsto 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 bicarbonatelowering effects of topiramate.

In adults, the incidenceof persistent treatment-emergent decreases in serum bicarbonate (levels of <20mEq/L at two consecutive visits or at the final visit) in controlled clinicaltrials for adjunctive treatment of epilepsy was 32% for 400mg/day, and1% for placebo. Metabolic acidosis has been observed at doses as low as 50mg/day. The incidence of persistent treatment-emergent decreases in serumbicarbonate in adults in the epilepsy controlled clinical trial for monotherapywas 15% for 50 mg/day and 25% for 400 mg/day. The incidence of a markedlyabnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and >5mEq/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% for50 mg/day and 7% for 400 mg/day. Serum bicarbonate levels have not been systematicallyevaluated at daily doses greater than 400 mg/day.

Inpediatric patients (<16 years of age), the incidence of persistent treatment-emergentdecreases in serum bicarbonate in placebo-controlled trials for adjunctivetreatment of Lennox-Gastaut syndrome or refractory partial onset seizureswas 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 <17mEq/L and >5 mEq/L decrease from pretreatment)in these trials was 11% for topiramate and 0% for placebo. Casesof moderately severe metabolic acidosis have been reported in patients asyoung 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 persistenttreatment-emergent decreases in serum bicarbonate in the epilepsy controlledclinical 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., absolutevalue <17 mEq/L and >5 mEq/L decrease from pretreatment) in this trialwas 4% for 50 mg/day and 4% for 400 mg/day.

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

Measurementof baseline and periodic serum bicarbonate during topiramate treatment isrecommended. If metabolic acidosis develops and persists, consideration shouldbe given to reducing the dose or discontinuing topiramate (using dose tapering).If the decision is made to continue patients on topiramate in the face ofpersistent acidosis, alkali treatment should be considered.

Cognitive/neuropsychiatric adverseevents

Adults

Adverse events most often associated with the use of topiramate were related to the central nervous system and were observed in the epilepsypopulation. In adults, the most frequent of these can be classifiedinto three general categories: 1)Cognitive-related dysfunction (e.g.confusion, psychomotor slowing, difficulty with concentration/attention, difficultywith memory, speech or language problems, particularly word-finding difficulties);2) Psychiatric/behavioral disturbances (e.g. depression or mood problems);and 3) Somnolence or fatigue.

Cognitive-related dysfunction

The majority of cognitive-related adverse events were mildto moderate in severity, and they frequently occurred in isolation. Rapidtitration rate and higher initial dose were associated with higher incidencesof these events. Many of these events contributed to withdrawal from treatment [see , and ]. ADVERSEREACTIONS Table5 Table 7

In the originaladd-on epilepsy controlled trials (using rapid titration such as 100 to 200mg/dayweekly increments), the proportion of patients who experienced one or morecognitive-related adverse events was 42% for 200 mg/day, 41% for 400mg/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 thetitration or in the maintenance phase, although in some patients the eventsbegan during titration and persisted into the maintenance phase. Some patientswho experienced one or more cognitive-related adverse events in the titrationphase had a dose-related recurrence of these events in the maintenance phase.

Inthe monotherapy epilepsy controlled trial, the proportion of patients whoexperienced one or more cognitive-related adverse events was 19% for topiramate 50mg/dayand 26% for 400 mg/day.

Psychiatric/behavioral disturbances

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

Somnolence/fatigue

Somnolence and fatigue were the adverse events most frequentlyreported during clinical trials of topiramate for adjunctiveepilepsy.For the adjunctive epilepsy population, the incidence of somnolencedid not differ substantially between 200 mg/day and 1000 mg/day, but the incidenceof fatigue was dose-related and increased at dosages above 400mg/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 and15% for the 400 mg/day group) and the incidence of fatigue was comparablein both treatment groups (14% each).

Additionalnonspecific CNS events commonly observed with topiramate in the add-on epilepsypopulation include dizziness or ataxia.

Pediatric patients

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

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

Withdrawal of aeds

Antiepileptic drugs, including topiramate, 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 oftreated patients (2,796 subject years of exposure). This represents an incidenceof 0.0035deaths per patient year. Although this rate exceeds that expectedin a healthy population matched for age and sex, it is within the range ofestimates for the incidence of sudden unexplained deaths in patients withepilepsy not receiving topiramate (ranging from 0.0005 for thegeneral population of patients with epilepsy, to 0.003 for a clinical trialpopulation similar to that in the topiramate program, to 0.005for patients with refractory epilepsy).

Precautions

Hyperammonemia and encephalopathyassociated with concomitant valproic acid use

Concomitant administration of topiramate and valproic acidhas been associated with hyperammonemia with or without encephalopathy inpatients who have tolerated either drug alone. Clinical symptoms of hyperammonemicencephalopathy often include acute alterations in level of consciousness and/orcognitive function with lethargy or vomiting. In most cases, symptoms andsigns abated with discontinuation of either drug. This adverse event is notdue to a pharmacokinetic interaction.

It is not knownif topiramate monotherapy is associated with hyperammonemia.

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

Inpatients who develop unexplained lethargy, vomiting, or changes in mentalstatus, hyperammonemic encephalopathy should be considered and an ammonialevel should be measured.

Kidney stones

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

An explanationfor the association of topiramate and kidney stones may liein the fact that topiramate is a carbonic anhydrase inhibitor. Carbonic anhydraseinhibitors, e.g., acetazolamide or dichlorphenamide, promote stone formationby reducing urinary citrate excretion and by increasing urinary pH. The concomitantuse of topiramate with other carbonic anhydrase inhibitors orpotentially in patients on a ketogenic diet may create a physiological environmentthat increases the risk of kidney stone formation, and should therefore beavoided.

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

Paresthesia

Paresthesia (usually tingling of the extremities), an effectassociated with the use of other carbonic anhydrase inhibitors, appears tobe a common effect of topiramate. Paresthesia was more frequentlyreported in the monotherapy epilepsy trials versus the adjunctive therapy epilepsy trials. In the majority of instances,paresthesia did not lead to treatment discontinuation.

Adjustment of dose in renal failure

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

Decreased hepatic function

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

Information for patients

Patients and their caregivers should be informed of the availability of a Medication Guide, and they should be instructed to read the Medication Guide prior to taking topiramate tablets. Patients should be instructed to take topiramate tablets only as prescribed.

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

Patients, especiallypediatric patients, treated with topiramate should be monitoredclosely 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 thosewith predisposing factors, should be instructed to maintain an adequate fluidintake in order to minimize the risk of renal stone formation (see , for support regarding hydration as a preventative measure). PRECAUTIONS: Kidney Stones

Patients should be warned about the potential for somnolence, dizziness, confusion, anddifficulty concentrating, and advised not to drive or operatemachinery until they have gained sufficient experience on topiramate to gaugewhether it adversely affects their mental performance and/or motor performance.

Additional food intake may be consideredif 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 duringtopiramate treatment is recommended (see ). WARNINGS

Drug interactions:

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

Antiepileptic drugs

Potential interactions between topiramate and standard AEDswere assessed in controlled clinical pharmacokinetic studies in patients withepilepsy. The effects of these interactions on mean plasma AUCs are summarizedin . Table 4

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

The third column (topiramateconcentration) describes how the coadministration of a drug listed in thefirst column modifies the concentration of topiramate in experimental settingswhen topiramate was given alone.

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

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

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

NC= Less than 10% change in plasma concentration.

AED= Antiepileptic drug.

NE= Not Evaluated.

TPM= Topiramate

Phenytoin NC or 25% increase a 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide b NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 15% increase

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

Other drug interactions

Digoxin

In a single-dose study, serum digoxin AUC was decreased by12% with concomitant topiramate administration. The clinicalrelevance of this observation has not been established.

Cns depressants

Concomitant administration of topiramate andalcohol or other CNS depressant drugs has not been evaluated in clinical studies.Because of the potential of topiramate to cause CNS depression, as well asother cognitive and/or neuropsychiatric adverse events, topiramate shouldbe used with extreme caution if used in combination with alcohol and otherCNS depressants.

Oral contraceptives

In a pharmacokinetic interaction study in healthy volunteerswith a concomitantly administered combination oral contraceptive product containing1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), topiramate givenin the absence of other medications at doses of 50 to 200 mg/day was not associatedwith statistically significant changes in mean exposure (AUC) to either componentof the oral contraceptive. In another study, exposure to EE was statisticallysignificantly decreased at doses of 200, 400, and 800 mg/day (18%, 21%, and30%, respectively) when given as adjunctive therapy in patients taking valproicacid. In both studies, topiramate (50 mg/day to 800 mg/day)did not significantly affect exposure to NET. Although there was a dose dependentdecrease in EE exposure for doses between 200 to 800 mg/day, there was no significantdose dependent change in EE exposure for doses of 50 to 200 mg/day. The clinicalsignificance of the changes observed is not known. The possibility of decreasedcontraceptive efficacy and increased breakthrough bleeding should be consideredin patients taking combination oral contraceptive products with topiramate.Patients taking estrogen containing contraceptives should be asked to reportany change in their bleeding patterns. Contraceptive efficacy can be decreasedeven in the absence of breakthrough bleeding.

Hydrochlorothiazide (hctz)

A drug-drug interaction study conducted in healthy volunteersevaluated the steady-state pharmacokinetics of HCTZ (25 mg q24h) and topiramate(96 mg q12h) when administered alone and concomitantly. The results of thisstudy indicate that topiramate C increased by 27% and AUC increasedby 29% when HCTZ was added to topiramate. The clinical significance of thischange is unknown. The addition of HCTZ to topiramate therapy may requirean adjustment of the topiramate dose. The steady-state pharmacokinetics ofHCTZ were not significantly influenced by the concomitant administration oftopiramate. Clinical laboratory results indicated decreases in serum potassiumafter topiramate or HCTZ administration, which were greater when HCTZ andtopiramate were administered in combination. max

Pioglitazone

A drug-drug interaction study conducted in healthy volunteersevaluated the steady-state pharmacokinetics of topiramate and pioglitazonewhen administered alone and concomitantly. A 15% decrease in the AUC ofpioglitazone with no alteration in C was observed. Thisfinding was not statistically significant. In addition, a 13% and 16% decreasein C and AUC respectively, of the activehydroxy-metabolite was noted as well as a 60% decrease in C andAUC of the active keto-metabolite. The clinical significanceof these findings is not known. When topiramate is added topioglitazone therapy or pioglitazone is added to topiramate therapy,careful attention should be given to the routine monitoring of patients foradequate control of their diabetic disease state. ,ss max,ss max,ss ,ss max,ss ,ss

Lithium

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

Haloperidol

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

Amitriptyline

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

Sumatriptan

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

Risperidone

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

Propranolol

Multiple dosing of topiramate (200 mg/day) in 34 healthyvolunteers (17 M, 17 F) did not affect the pharmacokinetics of propranololfollowing daily 160mg 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/dayof topiramate.

Dihydroergotamine

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

Others

Concomitant use of topiramate, a carbonic anhydraseinhibitor, with other carbonic anhydrase inhibitors, e.g., acetazolamide ordichlorphenamide, may create a physiological environment that increases therisk of renal stone formation, and should therefore be avoided.

Drug/laboratory tests interactions

There are no known interactions of topiramate with commonlyused laboratory tests.

Carcinogenesis, mutagenesis, impairmentof fertility:

An increase in urinary bladder tumors was observed in micegiven topiramate (20,75,and 300 mg/kg) in the diet for 21 months.The elevated bladder tumor incidence, which was statistically significantin males and females receiving 300mg/kg, was primarily due to the increasedoccurrence of a smooth muscle tumor considered histomorphologically uniqueto mice. Plasma exposures in mice receiving 300 mg/kg were approximately 0.5to 1 times steady-state exposures measured in patients receiving topiramatemonotherapy at the recommended human dose (RHD) of 400mg, and 1.5 to2 times steady-state topiramate exposures in patients receiving 400 mg oftopiramate plus phenytoin. The relevance of this finding to human carcinogenicrisk is uncertain. No evidence of carcinogenicity was seen in rats followingoral administration of topiramate for 2 years at doses up to 120mg/kg(approximately 3 times the RHD on a mg/m basis). 2

Topiramatedid not demonstrate genotoxic potential when tested in a battery of and assays. Topiramate was not mutagenic in the Ames test or the mouse lymphoma assay; it did not increaseunscheduled DNA synthesis in rat hepatocytes ; and it did not increase chromosomal aberrations in humanlymphocytes or in rat bonemarrow . invitro invivo in vitro invitro in vitro in vivo

Noadverse effects on male or female fertility were observed in rats at dosesup to 100mg/kg (2.5 times the RHD on a mg/m basis). 2

Pregnancy: . pregnancycategory c

Topiramate has demonstrated selective developmental toxicity,including teratogenicity, in experimental animal studies. When oral dosesof 20, 100, or 500mg/kg were administered to pregnant mice during theperiod of organogenesis, the incidence of fetal malformations (primarily craniofacialdefects) was increased at all doses. The low dose is approximately 0.2 timesthe recommended human dose (RHD=400 mg/day) on a mg/m basis. Fetalbody weights and skeletal ossification were reduced at 500 mg/kg in conjunctionwith decreased maternal body weight gain. 2

In rat studies(oral doses of 20, 100, and 500 mg/kg or 0.2, 2.5, 30, and 400mg/kg),the frequency of limb malformations (ectrodactyly, micromelia, and amelia)was increased among the offspring of dams treated with 400 mg/kg (10timesthe RHD on a mg/m basis) or greater during the organogenesis periodof pregnancy. Embryotoxicity (reduced fetal body weights, increased incidenceof structural variations) was observed at doses as low as 20mg/kg (0.5times the RHD on a mg/m basis). Clinical signs of maternaltoxicity were seen at 400mg/kg and above, and maternal body weight gainwas reduced during treatment with 100 mg/kg or greater. 2 2

Inrabbit studies (20, 60, and 180 mg/kg or 10, 35, and 120mg/kg orallyduring organogenesis), embryo/fetal mortality was increased at 35 mg/kg (2timesthe RHD on a mg/m basis) or greater, and teratogenic effects (primarilyrib and vertebral malformations) were observed at 120 mg/kg (6times theRHD on a mg/m basis). Evidence of maternal toxicity (decreasedbody weight gain, clinical signs, and/or mortality) was seen at 35mg/kgand above. 2 2

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

In a rat embryo/fetal development studywith 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 (10times the RHD on a mg/m basis) and persistent reductions in bodyweight gain at 30 mg/kg (1 times the RHD on a mg/m basis) andhigher. 2 2

There are no studies using topiramate inpregnant women. Topiramate should be used during pregnancy onlyif the potential benefit outweighs the potential risk to the fetus.

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

To provide information regarding the effects of 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/. in utero

Labor and delivery:

In studies of rats where dams were allowed to deliver pupsnaturally, no drug-related effects on gestation length or parturition wereobserved at dosage levels up to 200mg/kg/day.

Theeffect of topiramate on labor and delivery in humans is unknown.

Nursing mothers:

Topiramate is excreted in the milk of lactating rats. Theexcretion of topiramate in human milk has not been evaluated in controlledstudies. Limited observations in patients suggest an extensive secretion oftopiramate into breast milk. Since many drugs are excreted in human milk,and because the potential for serious adverse reactions in nursing infantsto topiramate is unknown, the potential benefit to the mothershould be weighed against the potential risk to the infant when consideringrecommendations regarding nursing.

Pediatric use:

Safety and effectiveness in patients below the age of 2 yearshave not been established for the adjunctive therapy treatment of partialonset seizures, primary generalized tonic-clonic seizures, or seizures associatedwith Lennox-Gastaut syndrome. Safety and effectiveness in patients below theage of 10 years have not been established for the monotherapy treatment ofepilepsy. Topiramate is associated with metabolic acidosis. Chronic untreatedmetabolic acidosis in pediatric patients may cause osteomalacia/rickets andmay reduce growth rates. A reduction in growth rate may eventually decreasethe maximal height achieved. The effect of topiramate on growth and bone-relatedsequelae has not been systematically investigated (see ). WARNINGS

Geriatric use:

In clinical trials, 3% of patients were over 60. No age relateddifference in effectiveness or adverse effects were evident. However, clinicalstudies of topiramate did not include sufficient numbers of subjects aged65 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 70mL/min/1.73m )due to reduced clearance of topiramate (see and ). 2 CLINICAL PHARMACOLOGY DOSAGE AND ADMINISTRATION

Race and gender effects:

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

Adverse reactions

The data described in the following section were obtainedusing topiramate tablets.

Monotherapy epilepsy

The adverse events in the controlled trial that occurredmost commonly in adults in the 400 mg/day group and at a rate higher thanthe 50 mg/day group were: paresthesia, weight decrease, somnolence, anorexia,dizziness, and difficulty with memory NOS [see ]. Table5

The adverse events in the controlledtrial that occurred most commonly in children (10 years up to 16 years ofage) in the 400 mg/day group and at a rate higher than the 50 mg/day groupwere: weight decrease, upper respiratory tract infection, paresthesia, anorexia,diarrhea, and mood problems [see ]. Table 6

Approximately21% of the 159 adult patients in the 400 mg/day group who received topiramateas monotherapy in the controlled clinical trial discontinued therapy due toadverse events. Adverse events associated with discontinuing therapy (2%)included depression, insomnia, difficulty with memory (NOS), somnolence, paresthesia,psychomotor slowing, dizziness, and nausea.

Approximately12% of the 57 pediatric patients in the 400 mg/day group who received topiramateas monotherapy in the controlled clinical trial discontinued therapy due toadverse events. Adverse events associated with discontinuing therapy (5%)included difficulty with concentration/attention.

Theprescriber should be aware that these data cannot be used to predict the frequencyof adverse events in the course of usual medical practice where patient characteristicsand other factors may differ from those prevailing during the clinical study.Similarly, the cited frequencies cannot be directly compared with data obtainedfrom other clinical investigations involving different treatments, uses, orinvestigators. Inspection of these frequencies, however, does provide theprescribing physician with a basis to estimate the relative contribution ofdrug and non-drug factors to the adverse event incidences in the populationstudied.

Table 5: Incidence of Treatment-Emergent Adverse Events in the Monotherapy Epilepsy Trial inAdults Where Rate Was at Least 2% in the 400 mg/day TopiramateGroup and Greater Than the Rate in the 50 mg/day Topiramate Group a
Topiramate Dosage(mg/day)
/ AdverseEvent Body System
50 (N= 160)
400 (N=159)

Valuesrepresent the percentage of patients reporting a given adverse event. Patientsmay have reported more than one adverse event during the study and can beincluded in more than one adverse event category. a

Body as a Whole-GeneralDisorders
Asthenia 4 6
Leg Pain 2 3
Chest Pain 1 2
Central & PeripheralNervous System Disorders
Paresthesia 21 40
Dizziness 13 14
Hypoaesthesia 4 5
Ataxia 3 4
Hypertonia 3
Gastro-IntestinalSystem Disorders
Diarrhea 5 6
Constipation 1 4
Gastritis 3
Dry Mouth 1 3
Gastroesophageal Reflux 1 2
Liver and BiliarySystem Disorders
Gamma-GT Increased 1 3
Metabolic and NutritionalDisorders
Weight Decrease 6 16
Psychiatric Disorders
Somnolence 9 15
Anorexia 4 14
Difficulty with Memory NOS 5 10
Insomnia 8 9
Depression 7 9
Difficulty with Concentration/Attention 7 8
Anxiety 4 6
Psychomotor Slowing 3 5
Mood Problems 2 5
Confusion 3 4
Cognitive Problem NOS 1 4
Libido Decreased 3
Reproductive Disorders,Female
Vaginal Hemorrhage 3
Red Blood Cell Disorders
Anemia 1 2
Resistance MechanismDisorders
Infection Viral 6 8
Infection 2 3
Respiratory SystemDisorders
Bronchitis 3 4
Rhinitis 2 4
Dyspnea 1 2
Skin and AppendagesDisorders
Rash 1 4
Pruritus 1 4
Acne 2 3
Special Senses Other,Disorders
Taste Perversion 3 5
Urinary System Disorders
Cystitis 1 3
Renal Calculus 3
Urinary Tract Infection 1 2
Dysuria 2
Micturition Frequency 2
Table 6: Incidence of Treatment-EmergentAdverse Events in the Monotherapy Epilepsy Trial in Children Ages 10 up to16 Years Where Rate Was at Least 5% in the 400 mg/day TopiramateGroup and Greater Than the Rate in the 50 mg/day Topiramate Group a
Topiramate Dosage(mg/day)
/ AdverseEvent Body System
50 (N=57)
400 (N=57)

Valuesrepresent the percentage of patients reporting a given adverse event. Patientsmay have reported more than one adverse event during the study and can beincluded in more than one adverse event category. a

Body as a Whole-GeneralDisorders
Fever 9
Central & PeripheralNervous System Disorders
Paresthesia 2 16
Gastro-IntestinalSystem Disorders
Diarrhea 5 11
Metabolic and NutritionalDisorders
Weight Decrease 7 21
Psychiatric Disorders
Anorexia 11 14
Mood Problems 2 11
Difficulty with Concentration/Attention 4 9
Cognitive Problems NOS 7
Nervousness 4 5
Resistance MechanismDisorders
Infection Viral 4 9
Infection 2 7
Respiratory SystemDisorders
Upper Respiratory Tract Infection 16 18
Rhinitis 2 7
Bronchitis 2 7
Sinusitis 2 5
Skin and AppendagesDisorders
Alopecia 2 5

Adjunctive therapy epilepsy

The most commonly observed adverse events associated withthe use of topiramate at dosages of 200 to 400 mg/day in controlled trialsin adults with partial onset seizures, primary generalized tonic-clonic seizures,or Lennox-Gastaut syndrome, that were seen at greater frequency in topiramate-treatedpatients 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 ]. The most common dose-related adverse eventsat dosages of 200 to 1,000 mg/day were: fatigue, nervousness, difficulty withconcentration or attention, confusion, depression, anorexia, language problems,anxiety, mood problems, and weight decrease [see ]. Table 7 Table9

Adverse events associated with the useof topiramate at dosages of 5 to 9mg/kg/day in controlled trials inpediatric patients with partial onset seizures, primary generalized tonic-clonicseizures, or Lennox-Gastaut syndrome, that were seen at greater frequencyin topiramate-treated patients were: fatigue, somnolence, anorexia, nervousness,difficulty with concentration/attention, difficulty with memory, aggressivereaction, and weight decrease [see ]. Table 10

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

Approximately 28%of the 1,757 adults with epilepsy who received topiramate at dosages of 200to 1,600 mg/day in clinical studies discontinued treatment because of adverseevents; 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 withconcentration/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 topiramateat dosages up to 30 mg/kg/day discontinued due to adverse events. Adverseevents 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 clinicaltrials - adjunctive therapy partial onset seizures, primarygeneralized tonic-clonic seizures, and lennox-gastaut syndrome

lists treatment-emergent adverse events that occurredin at least 1% of adults treated with 200 to 400 mg/day topiramate in controlledtrials that were numerically more common at this dose than in the patientstreated with placebo. In general, most patients who experienced adverse eventsduring the first eight weeks of these trials no longer experienced them bytheir last visit. lists treatment-emergent adverse events that occurredin at least 1% of pediatric patients treated with 5 to 9 mg/kg topiramatein controlled trials that were numerically more common than in patients treatedwith placebo. Table7 Table10

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

Other adverse events observed during double-blind epilepsy adjunctive therapy trials

Other events that occurred in more than 1% of adults treatedwith 200 to 400 mg of topiramate in placebo-controlled epilepsy trials butwith 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 respiratorytract infection, and eye pain.

Table7: Incidence of Treatment-Emergent Adverse Events in Placebo-Controlled, Add-OnEpilepsy Trials in Adults Where Rate Was > 1% in Any TopiramateGroup and Greater Than the Rate in Placebo-Treated Patients a,b
Topiramate Dosage(mg/day)
/ AdverseEvent Body System
c
Placebo (N=291)
200 to 400 (N=183)
600 to 1,000 (N=414)

Patientsin these add-on trials were receiving 1 to 2 concomitant antiepileptic drugsin addition to topiramate or placebo. a

Valuesrepresent the percentage of patients reporting a given adverse event. Patientsmay have reported more than one adverse event during the study and can beincluded in more than one adverse event category. b

Adverseevents reported by at least 1% of patients in the topiramate 200 to 400mg/day group and more common than in the placebo group are listed in thistable. c

Body as a Whole-GeneralDisorders
Fatigue 13 15 30
Asthenia 1 6 3
Back Pain 4 5 3
Chest Pain 3 4 2
Influenza-Like Symptoms 2 3 4
Leg Pain 2 2 4
Hot Flushes 1 2 1
Allergy 1 2 3
Edema 1 2 1
Body Odor 1
Rigors 1 <1
Central & PeripheralNervous System Disorders
Dizziness 15 25 32
Ataxia 7 16 14
Speech Disorders/Related SpeechProblems 2 13 11
Paresthesia 4 11 19
Nystagmus 7 10 11
Tremor 6 9 9
Language Problems 1 6 10
Coordination Abnormal 2 4 4
Hypoaesthesia 1 2 1
Gait Abnormal 1 3 2
Muscle Contractions Involuntary 1 2 2
Stupor 2 1
Vertigo 1 1 2
Gastro-IntestinalSystem Disorders
Nausea 8 10 12
Dyspepsia 6 7 6
Abdominal Pain 4 6 7
Constipation 2 4 3
Gastroenteritis 1 2 1
Dry Mouth 1 2 4
Gingivitis <1 1 1
GI Disorder <1 1
Hearing and VestibularDisorders
Hearing Decreased 1 2 1
Metabolic and NutritionalDisorders
Weight Decrease 3 9 13
Muscle-Skeletal SystemDisorders
Myalgia 1 2 2
Skeletal Pain 1
Platelet, Bleeding, &Clotting Disorders
Epistaxis 1 2 1
Psychiatric Disorders
Somnolence 12 29 28
Nervousness 6 16 19
Psychomotor Slowing 2 13 21
Difficulty with Memory 3 12 14
Anorexia 4 10 12
Confusion 5 11 14
Depression 5 5 13
Difficulty with Concentration/Attention 2 6 14
Mood Problems 2 4 9
Agitation 2 3 3
Aggressive Reaction 2 3 3
Emotional Lability 1 3 3
Cognitive Problems 1 3 3
Libido Decreased 1 2 <1
Apathy 1 1 3
Depersonalization 1 1 2
Reproductive Disorders,Female
Breast Pain 2 4
Amenorrhea 1 2 2
Menorrhagia 2 1
Menstrual Disorder 1 2 1
Reproductive Disorders,Male
Prostatic Disorder <1 2
Resistance MechanismDisorders
Infection 1 2 1
Infection Viral 1 2 <1
Moniliasis <1 1
Respiratory SystemDisorders
Pharyngitis 2 6 3
Rhinitis 6 7 6
Sinusitis 4 5 6
Dyspnea 1 1 2
Skin and AppendagesDisorders
Skin Disorder <1 2 1
Sweating Increased <1 1 <1
Rash Erythematous <1 1 <1
Special Sense Other,Disorders
Taste Perversion 2 4
Urinary System Disorders
Hematuria 1 2 <1
Urinary Tract Infection 1 2 3
Micturition Frequency 1 1 2
Urinary Incontinence <1 2 1
Urine Abnormal 1 <1
Vision Disorders
Vision Abnormal 2 13 10
Diplopia 5 10 10
White Cell and RESDisorders
Leukopenia 1 2 1

Incidence in study 119 add-ontherapy adults with partial onset seizures

Study 119 was a randomized, double-blind, placebo-controlled,parallel group study with 3 treatment arms: 1) placebo; 2) topiramate 200mg/day with a 25 mg/day starting dose, increased by 25 mg/day each week for8 weeks until the 200 mg/day maintenance dose was reached; and 3) topiramate200 mg/day with a 50 mg/day starting dose, increased by 50 mg/day each weekfor 4 weeks until the 200 mg/day maintenance dose was reached. All patientswere maintained on concomitant carbamazepine with or without another concomitantantiepileptic drug.

The incidence of adverse events( )did not differ significantly between the 2topiramate regimens. Becausethe frequencies of adverse events reported in this study were markedly lowerthan those reported in the previous epilepsy studies, they cannot be directlycompared with data obtained in other studies. Table 8

Table 8: Incidence of Treatment-Emergent Adverse Events in Study119 Where Rate Was 2% in the Topiramate Groupand Greater Than the Rate in Placebo-Treated Patients a,b
Topiramate Dosage (mg/day)
Adverse Event Body System/
c
Placebo (N=92)
200 (N=171)

Patientsin these add-on trials were receiving 1 to 2 concomitant antiepileptic drugsin addition to topiramate or placebo. a

Values representthe percentage of patients reporting a given adverse event. Patients may havereported more than one adverse event during the study and can be includedin more than one adverse event category. b

Adverseevents reported by at least 2% of patients in the topiramate 200mg/day group and more common than in the placebo group are listed in thistable. c

Body as a Whole-GeneralDisorders
Fatigue 4 9
Chest Pain 1 2
Cardiovascular Disorders,General
Hypertension 2
Central & PeripheralNervous System Disorders
Paresthesia 2 9
Dizziness 4 7
Tremor 2 3
Hypoasthesia 2
Leg Cramps 2
Language Problems 2
Gastro-IntestinalSystem Disorders
Abdominal Pain 3 5
Constipation 4
Diarrhea 1 2
Dyspepsia 2
Dry Mouth 2
Hearing and VestibularDisorders
Tinnitus 2
Metabolic and NutritionalDisorders
Weight Decrease 4 8
Psychiatric Disorders
Somnolence 9 15
Anorexia 7 9
Nervousness 2 9
Difficulty with Concentration/Attention 5
Insomnia 3 4
Difficulty with Memory 1 2
Aggressive Reaction 2
Respiratory SystemDisorders
Rhinitis 4
Urinary System Disorders
Cystitis 2
Vision Disorders
Diplopia 2
Vision Abnormal 2
Table 9: Incidence (%) of Dose-RelatedAdverse Events From Placebo-Controlled, Add-On Trials in Adults with PartialOnset Seizures a
Topiramate Dosage(mg/day)
Adverse Event
Placebo (N = 216)
200 (N = 45)
400 (N = 68)
600 to 1,000 (N = 414)

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

Fatigue 13 11 12 30
Nervousness 7 13 18 19
Difficulty with Concentration/Attention 1 7 9 14
Confusion 4 9 10 14
Depression 6 9 7 13
Anorexia 4 4 6 12
Language problems <1 2 9 10
Anxiety 6 2 3 10
Mood problems 2 6 9
Weight decrease 3 4 9 13
Table 10: Incidence (%) of Treatment-EmergentAdverse Events in Placebo-Controlled, Add-On Epilepsy Trials in PediatricPatients Ages 2 to 16 Years (Events that Occurred in at Least1% of Topiramate-Treated Patients and Occurred More Frequently in Topiramate-TreatedThan Placebo-Treated Patients) a,b
AdverseEvent Body System/
Placebo (N=101)
Topiramate (N=98)

Patientsin these add-on trials were receiving 1 to 2 concomitant antiepileptic drugsin addition to topiramate or placebo. a

Valuesrepresent the percentage of patients reporting a given adverse event. Patientsmay have reported more than one adverse event during the study and can beincluded in more than one adverse event category. b

Body as a Whole -General Disorders
Fatigue 5 16
Injury 13 14
Allergic Reaction 1 2
Back Pain 1
Pallor 1
Cardiovascular Disorders,General
Hypertension 1
Central & PeripheralNervous System Disorders
Gait Abnormal 5 8
Ataxia 2 6
Hyperkinesia 4 5
Dizziness 2 4
Speech Disorders/RelatedSpeech Problems 2 4
Hyporeflexia 2
Convulsions Grand Mal 1
Fecal Incontinence 1
Paresthesia 1
Gastro-IntestinalSystem Disorders
Nausea 5 6
Saliva Increased 4 6
Constipation 4 5
Gastroenteritis 2 3
Dysphagia 1
Flatulence 1
Gastroesophageal Reflux 1
Glossitis 1
Gum Hyperplasia 1
Heart Rate and RhythmDisorders
Bradycardia 1
Metabolic and NutritionalDisorders
Weight Decrease 1 9
Thirst 1 2
Hypoglycemia 1
Weight Increase 1
Platelet, Bleeding, &Clotting Disorders
Purpura 4 8
Epistaxis 1 4
Hematoma 1
Prothrombin Increased 1
Thrombocytopenia 1
Psychiatric Disorders
Somnolence 16 26
Anorexia 15 24
Nervousness 7 14
Personality Disorder (BehaviorProblems) 9 11
Difficulty with Concentration/Attention 2 10
Aggressive Reaction 4 9
Insomnia 7 8
Difficulty with Memory NOS 5
Confusion 3 4
Psychomotor Slowing 2 3
Appetite Increased 1
Neurosis 1
Reproductive Disorders,Female
Leukorrhoea 2
Resistance MechanismDisorders
Infection Viral 3 7
Respiratory SystemDisorders
Pneumonia 1 5
Respiratory Disorder 1
Skin and AppendagesDisorders
Skin Disorder 2 3
Alopecia 1 2
Dermatitis 2
Hypertrichosis 1 2
Rash Erythematous 2
Eczema 1
Seborrhoea 1
Skin Discoloration 1
Urinary System Disorders
Urinary Incontinence 2 4
Nocturia 1
Vision Disorders
Eye Abnormality 1 2
Vision Abnormal 1 2
Diplopia 1
Lacrimation Abnormal 1
Myopia 1
White Cell and RESDisorders
Leukopenia 2

Other adverse events observed duringall epilepsy clinical trials

Topiramate has been administered to 2,246 adults and 427pediatric patients with epilepsy during all clinical studies, only some ofwhich were placebo controlled. During these studies, all adverse events wererecorded by the clinical investigators using terminology of their own choosing.To provide a meaningful estimate of the proportion of individuals having adverseevents, similar types of events were grouped into a smaller number of standardizedcategories using modified WHOART dictionary terminology. The frequencies presentedrepresent the proportion of patients who experienced an event of the typecited on at least one occasion while receiving topiramate. Reported eventsare included except those already listed in the previous tables or text, thosetoo general to be informative, and those not reasonably associated with theuse of the drug.

Events are classified within body systemcategories and enumerated in order of decreasing frequency using the followingdefinitions: occurring inat least 1/100 patients; occurringin 1/100 to 1/1000 patients; occurringin fewer than 1/1000 patients. frequent infrequent rare

: vasodilation. AutonomicNervous System Disorders Infrequent:

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

hypotension,postural hypotension, angina pectoris. CardiovascularDisorders, General: Infrequent:

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

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

AV block. HeartRate and Rhythm Disorders: Infrequent:

SGPT increased, SGOT increased. Liverand Biliary System Disorders: Infrequent:

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

arthralgia. arthrosis. MusculoskeletalSystem Disorders: Frequent: Infrequent:

thrombocythemia. polycythemia. Neoplasms: Infrequent: Rare:

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

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

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

ejaculationdisorder, breast discharge. ReproductiveDisorders, Male: Infrequent:

urticaria, photosensitivity reaction, abnormal hair texture. chloasma. Skinand Appendages Disorders: Infrequent: Rare:

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

urinaryretention, face edema, renal pain, albuminuria, polyuria, oliguria. UrinarySystem Disorders: Infrequent:

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

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

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

Postmarketing and other experience

In addition to the adverse experiences reported during clinicaltesting of topiramate, the following adverse experiences havebeen reported worldwide in patients receiving topiramate post-approval.

Theseadverse experiences have not been listed above and data are insufficient tosupport an estimate of their incidence or to establish causation. The listingis alphabetized: bullous skin reactions (including erythema multiforme, Stevens-Johnsonsyndrome, 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 hasnot been evaluated in human studies.

Overdosage

Overdoses of topiramate have been reported.Signs and symptoms included convulsions, drowsiness, speech disturbance, blurredvision, diplopia, mentation impaired, lethargy, abnormal coordination, stupor,hypotension, abdominal pain, agitation, dizziness and depression. The clinicalconsequences were not severe in most cases, but deaths have been reportedafter poly-drug overdoses involving topiramate.

Topiramateoverdose has resulted in severe metabolic acidosis (see ). WARNINGS

Apatient who ingested a dose between 96 and 110 g topiramate was admitted tohospital with coma lasting 20 to 24 hours followed by full recovery after 3 to4 days.

In acute topiramate overdose,if the ingestion is recent, the stomach should be emptied immediately by lavageor by induction of emesis. Activated charcoal has been shown to adsorb topiramate . Treatment should be appropriatelysupportive. Hemodialysis is an effective means of removing topiramate fromthe body. in vitro

Dosage and administration

Epilepsy

In the controlled add-on trials, no correlation has beendemonstrated between trough plasma concentrations of topiramate and clinicalefficacy. No evidence of tolerance has been demonstrated in humans. Dosesabove 400 mg/day (600, 800, or 1000 mg/day) have not been shown to improveresponses in dose-response studies in adults with partial onset seizures.

Itis not necessary to monitor topiramate plasma concentrations to optimize topiramate therapy.On occasion, the addition of topiramate to phenytoin may requirean adjustment of the dose of phenytoin to achieve optimal clinical outcome.Addition or withdrawal of phenytoin and/or carbamazepine during adjunctivetherapy with topiramate may require adjustment of the dose oftopiramate. Because of the bitter taste, tablets should notbe broken.

Topiramate tablets can be taken withoutregard to meals.

Monotherapy use

The recommended dose for topiramate monotherapy in adultsand 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 maximaldose in the monotherapy controlled trial; the mean dose achieved in the trialwas 275 mg/day. The dose should be achieved by titrating according to thefollowing schedule:

Morning Dose Evening Dose
Week 1 25 mg 25 mg
Week 2 50 mg 50 mg
Week 3 75 mg 75 mg
Week 4 100 mg 100 mg
Week 5 150 mg 150 mg
Week 6 200 mg 200 mg

Adjunctive therapy use

Adults (17 years of age and over)- partial seizures, primary generalized tonic-clonic seizures, or lennox-gastautsyndrome

The recommended total daily dose of topiramate asadjunctive therapy in adults with partial seizures is 200 to 400 mg/day in twodivided doses, and 400 mg/day in two divided doses as adjunctive treatmentin adults with primary generalized tonic-clonic seizures. It is recommendedthat therapy be initiated at 25 to 50 mg/day followed by titration to an effectivedose in increments of 25 to 50 mg/week. Titrating in increments of 25 mg/weekmay delay the time to reach an effective dose. Daily doses above 1,600 mghave not been studied.

In the study of primary generalizedtonic-clonic seizures the initial titration rate was slower than in previousstudies; the assigned dose was reached at the end of 8 weeks (see ). CLINICAL STUDIES, AdjunctiveTherapy Controlled Trials in Patients With Primary Generalized Tonic-ClonicSeizures

Pediatric patients (ages 2 to 16 years)partial seizures, primary generalized tonic-clonic seizures, or lennox-gastautsyndrome

The recommended total daily dose of topiramate as adjunctive therapy for patients with partial seizures, primary generalizedtonic-clonic seizures, or seizures associated with Lennox-Gastaut syndromeis approximately 5 to 9 mg/kg/day in two divided doses. Titration should beginat 25 mg (or less, based on a range of 1to 3 mg/kg/day) nightly forthe first week. The dosage should then be increased at 1- or 2-week intervalsby increments of 1 to 3 mg/kg/day (administered in two divided doses), toachieve optimal clinical response. Dose titration should be guided by clinicaloutcome.

In the study of primary generalized tonic-clonicseizures the initial titration rate was slower than in previous studies; theassigned dose of 6 mg/kg/day was reached at the end of 8 weeks (see ). CLINICAL STUDIES, AdjunctiveTherapy Controlled Trials in Patients With Primary Generalized Tonic-ClonicSeizures

Patients with renal impairment:

In renally impaired subjects (creatinine clearance less than70mL/min/1.73 m ), one half of the usual adult dose is recommended.Such patients will require a longer time to reach steady-state at each dose. 2

Geriatric patients (ages 65 yearsand over):

Dosage adjustment may be indicated in the elderly patientwhen impaired renal function (creatinine clearance rate 70 mL/min/1.73m ) is evident (see and ). 2 DOSAGE AND ADMINISTRATION: Patients with Renal Impairment CLINICALPHARMACOLOGY: Special Populations: Age, Gender, and Race

Patients undergoing hemodialysis:

Topiramate is cleared by hemodialysis at a rate that is 4to 6 times greater than a normal individual. Accordingly, a prolonged periodof dialysis may cause topiramate concentration to fall below that requiredto maintain an anti-seizure effect. To avoid rapid drops in topiramate plasmaconcentration during hemodialysis, a supplemental dose of topiramate may berequired. The actual adjustment should take into account 1) the duration ofdialysis 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 concentrationsmay be increased. The mechanism is not well understood.

How supplied

NDC:64725-0710-1 in a BOTTLE of 60 TABLET, FILM COATEDS

Medication guide


Topiramate tablets

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

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

  • Serious eye problems include: Topiramate tablets may cause eye problems.
    • any sudden decrease in vision with or without eye pain and redness
    • a blockage of fluid in the eye causing increased pressure in the eye (secondary angle closure glaucoma).
    • These eye problems can lead to permanent loss of vision if not treated. You should call your healthcare provider right away if you have any new eye symptoms.
  • 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. Topiramate tablets may cause decreased sweating and increased body temperature (fever).
  • Like other antiepileptic drugs, topiramate tablets may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.

Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

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

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

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

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

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

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

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

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

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

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

Especially, tell your healthcare provider if you take:

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

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

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

How should I take topiramate tablets?

  • Take topiramate tablets exactly as prescribed.
  • Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider.
  • Topiramate tablets should be swallowed whole. Do not chew the tablets. They may leave a bitter taste.
  • Do not store any medicine and food mixture for later use.
  • Topiramate tablets can be taken before, during, or after a meal. Drink plenty of fluids during the day. This may help prevent kidney stones while taking topiramate tablets.
  • If you take too 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 can cause: Metabolic Acidosis.
    • tiredness
    • loss of appetite
    • irregular heartbeat
    • impaired consciousness
  • 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. High blood ammonia levels.
  • Drink plenty of fluids when taking topiramate tablets to decrease your chances of getting kidney stones. Kidney stones.
  • 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. Effects on Thinking and Alertness.
  • Dizziness or Loss of Muscle Coordination.

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

The most common side effects of topiramate tablets include:

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

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

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

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

How should I store topiramate tablets?

  • Store topiramate tablets at 20 to 25C (68 to 77F); excursions permitted to 15 to 30C (59 to 86F).
  • Keep topiramate tablets in a tightly closed container
  • Keep topiramate tablets dry and away from moisture
  • Keep 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 1-800-818-4555

What are the ingredients in topiramate tablets?

topiramate Active ingredient:

anhydrous lactose, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, magnesium stearate, purified water, polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc. Inactive ingredients:

In addition, individual tablets contain:

50 mg tablets: iron oxide yellow 100 mg tablets: iron oxide yellow, and D&C Yellow # 10 Aluminum Lake 200 mg tablets: iron oxide red, lecithin (soya), and iron oxide black

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

Spl unclassified section

Distributed by: 1150 Elijah McCoy Drive, Detroit, MI 48202
Caraco Pharmaceutical Laboratories, Ltd.

Manufactured by: Acme Plaza, Andheri-Kurla Road, Andheri (East), Mumbai - 400 059, India.
Sun Pharmaceutical Industries Ltd.

ISS. 07/2009 PGPI0101A

Ingredients and appearance - Product information

Topiramate tablet, film coated- Topiramate

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 64725-0710
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Topiramate ( UNII: 0H73WJJ391)( Topiramate - UNII: 0H73WJJ391 ) 50 mgin 1

Inactive Ingredients

Ingredient Name Code
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)

Product Characteristics

Color yellow Score 1
Shape ROUND (circular) Imprint Code S;710
Size 7 mm

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
ANDA ANDA090278 USA

Topiramate tablet, film coated- Topiramate

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 64725-0707
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Topiramate ( UNII: 0H73WJJ391)( Topiramate - UNII: 0H73WJJ391 ) 25 mgin 1

Inactive Ingredients

Ingredient Name Code
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 Characteristics

Color white Score 1
Shape ROUND (circular) Imprint Code S;707
Size 6 mm

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
ANDA ANDA090278 USA

Labeler - TYA Pharmaceuticals( 938389038)

Establishment

Name ID/FEI Business Operations
TYA Pharmaceuticals 938389038 RELABEL( 64725-0710, 64725-0707), REPACK( 64725-0710)

Topiramate tablet, film coated

Topiramate tablet, film coated