TOPAMAX®
`(topiramate)
`
`Tablets
`
`
`TOPAMAX®
`(topiramate capsules)
`Sprinkle Capsules
`
`
`Rx only
`
`DESCRIPTION
`Topiramate is a sulfamate-substituted monosaccharide. TOPAMAX® (topiramate)
`
`Tablets are available as 25 mg, 50 mg, 100 mg, and 200 mg round tablets for oral
`administration. TOPAMAX® (topiramate capsules) Sprinkle Capsules are available as
`
`15 mg and 25 mg sprinkle capsules for oral administration as whole capsules or
`opened and sprinkled onto soft food.
`
`
`
`Topiramate is a white crystalline powder with a bitter taste. Topiramate is most
`soluble in alkaline solutions containing sodium hydroxide or sodium phosphate and
`having a pH of 9 to 10. It is freely soluble in acetone, chloroform, dimethylsulfoxide,
`and ethanol. The solubility in water is 9.8 mg/mL. Its saturated solution has a pH of
`6.3. Topiramate has the molecular formula C12H21NO8S and a molecular weight of
`339.37. Topiramate is designated chemically as 2,3:4,5-Di-O-isopropylidene-β­
`D-fructopyranose sulfamate and has the following structural formula:
`
`O
`
`CH2OSO2NH2
`O
`
`O
`
`CH3
`H3C
`H3C
`CH3
`
`TOPAMAX®(topiramate) Tablets contain the following inactive ingredients: lactose
`monohydrate, pregelatinized starch, microcrystalline cellulose, sodium starch
`glycolate, magnesium stearate, purified water, carnauba wax, hypromellose, titanium
`dioxide, polyethylene glycol, synthetic iron oxide (50, 100, and 200 mg tablets) and
`polysorbate 80.
`
`O
`
`O
`
`TOPAMAX® (topiramate capsules) Sprinkle Capsules contain topiramate coated
`beads in a hard gelatin capsule. The inactive ingredients are: sugar spheres (sucrose
`and starch), povidone, cellulose acetate, gelatin, silicone dioxide, sodium lauryl
`sulfate, titanium dioxide, and black pharmaceutical ink.
`
`
`
`ARGENTUM Exhibit 1137
` Argentum Pharmaceuticals LLC v. Research Corporation Technologies, Inc.
`IPR2016-00204
`
`1
`
`
`Page 00001
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`

`
`CLINICAL PHARMACOLOGY
`Mechanism of Action
`The precise mechanisms by which topiramate exerts its anticonvulsant and migraine
`
` prophylaxis effects are unknown; however, preclinical studies have revealed four
`properties that may contribute to topiramate's efficacy for epilepsy and migraine
`prophylaxis. Electrophysiological and biochemical evidence suggests that topiramate,
`at pharmacologically relevant concentrations, blocks voltage-dependent sodium
`channels, augments the activity of the neurotransmitter gamma-aminobutyrate at
`some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of
`the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly
`isozymes II and IV.
`
`Pharmacodynamics
`Topiramate has anticonvulsant activity in rat and mouse maximal electroshock
`seizure (MES) tests. Topiramate is only weakly effective in blocking clonic seizures
`induced by the GABAA receptor antagonist, pentylenetetrazole. Topiramate is also
`
`effective in rodent models of epilepsy, which include tonic and absence-like seizures
`in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in rats by
`kindling of the amygdala or by global ischemia.
`
`Pharmacokinetics
` The sprinkle formulation is bioequivalent to the immediate release tablet formulation
`
` and, therefore, may be substituted as a therapeutic equivalent.
`
`
`
`Absorption of topiramate is rapid, with peak plasma concentrations occurring at
`approximately 2 hours following a 400 mg oral dose. The relative bioavailability of
`topiramate from the tablet formulation is about 80% compared to a solution. The
`bioavailability of topiramate is not affected by food.
`
`The pharmacokinetics of topiramate are linear with dose proportional increases in
`plasma concentration over the dose range studied (200 to 800 mg/day). The mean
`plasma elimination half-life is 21 hours after single or multiple doses. Steady state is
`thus reached in about 4 days in patients with normal renal function. Topiramate is
`15-41% bound to human plasma proteins over the blood concentration range of
`0.5 -250 µg/mL. The fraction bound decreased as blood concentration increased.
`
`
`Carbamazepine and phenytoin do not alter the binding of topiramate. Sodium
`valproate, at 500 µg/mL (a concentration 5-10 times higher than considered
`therapeutic for valproate) decreased the protein binding of topiramate from 23% to
`13%. Topiramate does not influence the binding of sodium valproate.
`
`
`
`2
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`Page 00002
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`

`
`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 3).
`
`Special Populations
`Renal Impairment
`The clearance of topiramate was reduced by 42% in moderately renally impaired
`
`(creatinine clearance 30-69 mL/min/1.73m2) and by 54% in severely renally impaired
`subjects (creatinine clearance <30 mL/min/1.73m2) compared to normal renal
`function subjects (creatinine clearance >70 mL/min/1.73m2). Since topiramate is
`presumed to undergo significant tubular reabsorption, it is uncertain whether this
`experience can be generalized to all situations of renal impairment. It is conceivable
`that some forms of renal disease could differentially affect glomerular filtration rate
`and tubular reabsorption resulting in a clearance of topiramate not predicted by
`
` creatinine clearance. In general, however, use of one-half the usual starting and
`maintenance dose is recommended in patients with moderate or severe renal
`impairment (see PRECAUTIONS: Adjustment of Dose in Renal Failure and
`DOSAGE AND ADMINISTRATION).
`
`Hemodialysis
`Topiramate is cleared by hemodialysis. Using a high efficiency, counterflow, single
`pass-dialysate hemodialysis procedure,
`topiramate dialysis clearance was
`120 mL/min with blood flow through the dialyzer at 400 mL/min. This high clearance
`(compared to 20-30 mL/min total oral clearance in healthy adults) will remove a
`clinically significant amount of topiramate from the patient over the hemodialysis
`
`
`
`
`
`3
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`Page 00003
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`

`
`
`
` treatment period. Therefore, a supplemental dose may be required (see DOSAGE
`AND ADMINISTRATION).
`
`Hepatic Impairment
`In hepatically impaired subjects, the clearance of topiramate may be decreased; the
`mechanism underlying the decrease is not well understood.
`
`Age, Gender, and Race
`The pharmacokinetics of topiramate in elderly subjects (65-85 years of age, N=16)
`were evaluated in a controlled clinical study. The elderly subject population had
`reduced renal function [creatinine clearance (-20%)] compared to young adults.
`Following a single oral 100 mg dose, maximum plasma concentration for elderly and
`young adults was achieved at approximately 1-2 hours. Reflecting the primary renal
`elimination of topiramate, topiramate plasma and renal clearance were reduced
`
` 21% and 19%, respectively, in elderly subjects, compared to young adults. Similarly,
`topiramate half-life was longer (13%) in the elderly. Reduced topiramate clearance
`resulted in slightly higher maximum plasma concentration (23%) and AUC (25%) in
`elderly subjects than observed in young adults. Topiramate clearance is decreased in
`the elderly only to the extent that renal function is reduced. As recommended for all
`patients, dosage adjustment may be indicated in the elderly patient when impaired
`renal function (creatinine clearance rate ≤70 mL/min/1.73 m2) is evident. It may be
`useful to monitor renal function in the elderly patient (see Special Populations:
`Renal Impairment, PRECAUTIONS: Adjustment of Dose in Renal Failure and
`
`DOSAGE AND ADMINISTRATION).
`
`Clearance of topiramate in adults was not affected by gender or race.
`
`Pediatric Pharmacokinetics
`
`Pharmacokinetics of topiramate were evaluated in patients ages 4 to 17 years
`receiving one or two other antiepileptic drugs. Pharmacokinetic profiles were
`obtained after one week at doses of 1, 3, and 9 mg/kg/day. Clearance was
`independent of dose.
`
`
`Pediatric patients have a 50% higher clearance and consequently shorter elimination
`half-life than adults. Consequently, the plasma concentration for the same mg/kg dose
`may be lower in pediatric patients compared to adults. As in adults, hepatic
`enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations
`of topiramate.
`
`
`
`4
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`Page 00004
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`
`
`
` CLINICAL STUDIES
`
` The studies described in the following sections were conducted using TOPAMAX®
`(topiramate) Tablets.
`
` Epilepsy
`
`Monotherapy Controlled Trial
`The effectiveness of topiramate as initial monotherapy in adults and children 10 years
`of age and older with partial onset or primary generalized seizures was established in
`a multicenter, randomized, double-blind, parallel-group trial.
`
`
`
`The trial was conducted in 487 patients diagnosed with epilepsy (6 to 83 years of age)
`who had 1 or 2 well-documented seizures during the 3-month retrospective baseline
`phase who then entered the study and received topiramate 25 mg/day for 7 days in an
`open-label fashion. Forty-nine percent of subjects had no prior AED treatment and
`17% had a diagnosis of epilepsy for greater than 24 months. Any AED therapy used
`
`for temporary or emergency purposes was discontinued prior to randomization. In the
`
`double-blind phase, 470 patients were randomized to titrate up to 50 mg/day or 400
`mg/day. If the target dose could not be achieved, patients were maintained on the
`maximum tolerated dose. Fifty eight percent of patients achieved the maximal dose
`of 400 mg/day for > 2 weeks, and patients who did not tolerate 150 mg/day were
`discontinued. The primary efficacy assessment was a between group comparison of
`time to first seizure during the double-blind phase. Comparison of the Kaplan-Meier
`survival curves of time to first seizure favored the topiramate 400 mg/day group over
`the topiramate 50 mg/day group (p=0.0002, log rank test; Figure 1). The treatment
`effects with respect to time to first seizure were consistent across various patient
`subgroups defined by age, sex, geographic region, baseline body weight, baseline
`seizure type, time since diagnosis, and baseline AED use.
`
`
`
`
`
` Figure 1:
`
`Kaplan-Meier Estimates of Cumulative Rates for Time to First Seizure
`
`Topiramate 50 mg/day (N=234)
`
`
`Topiramate 400 mg/day (N=236)
`
`
`p = 0.0002
`
`0.50
`
`0.40
`
`0.30
`
`0.20
`
`0.10
`
`0.00
`
`Cumulative Rates for Time to First Seizure
`
`
`
`0
`
`50
`
`100
`
`150
`
`200
`
`250
`
`300
`
`350
`
`400
`
`450
`
`500
`
`
`
` Time (Days)
`
`
`
`
`
`5
`
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`Page 00005
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`

`
`Adjunctive Therapy Controlled Trials in Patients With Partial Onset
`Seizures
`The effectiveness of topiramate as an adjunctive treatment for adults with partial
`onset seizures was established in six multicenter, randomized, double-blind,
`
` placebo-controlled trials, two comparing several dosages of topiramate and placebo
`and four comparing a single dosage with placebo, in patients with a history of partial
`onset seizures, with or without secondarily generalized seizures.
`
`Patients in these studies were permitted a maximum of two antiepileptic drugs
`
` (AEDs) in addition to TOPAMAX® Tablets or placebo. In each study, patients were
`stabilized on optimum dosages of their concomitant AEDs during baseline phase
`lasting between 4 and 12 weeks. Patients who experienced a prespecified minimum
`number of partial onset seizures, with or without secondary generalization, during the
`baseline phase (12 seizures for 12-week baseline, 8 for 8-week baseline, or 3 for
`
` 4-week baseline) were randomly assigned to placebo or a specified dose of
`TOPAMAX® Tablets in addition to their other AEDs.
`
`Following randomization, patients began the double-blind phase of treatment. In five
`
`of the six studies, patients received active drug beginning at 100 mg per day; the dose
`was then increased by 100 mg or 200 mg/day increments weekly or every other week
`until the assigned dose was reached, unless intolerance prevented increases. In the
`
`sixth study (119), the 25 or 50 mg/day initial doses of topiramate were followed by
`respective weekly increments of 25 or 50 mg/day until the target dose of 200 mg/day
`was reached. After titration, patients entered a 4, 8, or 12-week stabilization period.
`The numbers of patients randomized to each dose, and the actual mean and median
`doses in the stabilization period are shown in Table 1.
`
`Adjunctive Therapy Controlled Trial in Pediatric Patients Ages 2 - 16
`Years With Partial Onset Seizures
`
`The effectiveness of topiramate as an adjunctive treatment for pediatric patients ages
`2 - 16 years with partial onset seizures was established in a multicenter, randomized,
`double-blind, placebo-controlled trial, comparing topiramate and placebo in patients
`with a history of partial onset seizures, with or without secondarily generalized
`seizures.
`
`
`
`Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in
`addition to TOPAMAX® Tablets or placebo. In this study, patients were stabilized on
`optimum dosages of their concomitant AEDs during an 8-week baseline phase.
`Patients who experienced at least six partial onset seizures, with or without
`secondarily generalized seizures, during the baseline phase were randomly assigned
`to placebo or TOPAMAX® Tablets in addition to their other AEDs.
`
`
`
`6
`
`
`Page 00006
`
`

`
`Following randomization, patients began the double-blind phase of treatment.
`Patients received active drug beginning at 25 or 50 mg per day; the dose was then
`increased by 25 mg to 150 mg/day increments every other week until the assigned
`dosage of 125, 175, 225, or 400 mg/day based on patients' weight to approximate a
`dosage of 6 mg/kg per day was reached, unless intolerance prevented increases. After
`titration, patients entered an 8-week stabilization period.
`
`
`Adjunctive Therapy Controlled Trial in Patients With Primary
`Generalized Tonic-Clonic Seizures
`The effectiveness of topiramate as an adjunctive treatment for primary generalized
`
` tonic-clonic seizures in patients 2 years old and older was established in a
`multicenter, randomized, double-blind, placebo-controlled trial, comparing a single
`dosage of topiramate and placebo.
`
`Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in
`addition to TOPAMAX® or placebo. Patients were stabilized on optimum dosages of
`their concomitant AEDs during an 8-week baseline phase. Patients who experienced
`
` at least three primary generalized tonic-clonic seizures during the baseline phase were
`randomly assigned to placebo or TOPAMAX® in addition to their other AEDs.
`
`Following randomization, patients began the double-blind phase of treatment.
`Patients received active drug beginning at 50 mg per day for four weeks; the dose was
`then increased by 50 mg to 150 mg/day increments every other week until the
`assigned dose of 175, 225, or 400 mg/day based on patients' body weight to
`approximate a dosage of 6 mg/kg per day was reached, unless intolerance prevented
`increases. After titration, patients entered a 12-week stabilization period.
`
`Adjunctive Therapy Controlled Trial in Patients With Lennox-Gastaut
`Syndrome
`The effectiveness of topiramate as an adjunctive treatment for seizures associated
`with Lennox-Gastaut syndrome was established in a multicenter, randomized, double-
`blind, placebo-controlled trial comparing a single dosage of topiramate with placebo
`in patients 2 years of age and older.
`
`Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in
`addition to TOPAMAX® or placebo. Patients who were experiencing at least
`60 seizures per month before study entry were stabilized on optimum dosages of their
`concomitant AEDs during a 4-week baseline phase. Following baseline, patients were
`randomly assigned to placebo or TOPAMAX® in addition to their other AEDs.
`Active drug was titrated beginning at 1 mg/kg per day for a week; the dose was then
`increased to 3 mg/kg per day for one week then to 6 mg/kg per day. After titration,
`
`
`
`
`
`7
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`Page 00007
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`

`
`patients entered an 8-week stabilization period. The primary measures of
`
`effectiveness were the percent reduction in drop attacks and a parental global rating
`of seizure severity.
`
`Table 1:
`
`
`200
`
`N
`Mean Dose
`Median Dose
`
`N
`Mean Dose
`Median Dose
`
`N
`Mean Dose
`Median Dose
`
`N
`Mean Dose
`Median Dose
`
`N
`Mean Dose
`Median Dose
`
` Topiramate Dose Summary During the Stabilization Periods of Each of Six Double-
`
`
` Blind, Placebo-Controlled, Add-On Trials in Adults with Partial Onset Seizuresb
`Target Topiramate Dosage (mg/day)
`
`
`
`
`Placeboa
`Protoco Stabilization
`1,000
`
`400
`600
`800
`l
`Dose
`
`
`
`
`
`
`
`--
`--
`41
`40
`42
`42
`YD
`--
`--
`556
`390
`200
`5.9
`
`--
`--
`600
`400
`200
`6.0
`
`
`
`
`
`
`
`
`40
`45
`40
`--
`--
`44
`YE
`796
`739
`544
`--
`--
`9.7
`
`1,000
`800
`600
`--
`--
`10.0
`
`
`
`
`
`
`
`
`--
`--
`--
`19
`--
`23
`Y1
`--
`--
`--
`395
`--
`3.8
`
`--
`--
`--
`400
`--
`4.0
`
`
`
`
`
`
`
`
`--
`--
`28
`--
`--
`30
`Y2
`--
`--
`522
`--
`--
`5.7
`
`--
`--
`600
`--
`--
`6.0
`
`
`
`
`
`
`
`
`--
`25
`--
`--
`--
`28
`Y3
`--
`568
`--
`--
`--
`7.9
`
`--
`600
`--
`--
`--
`8.0
`
`
`
`
`
`
`
`
`--
`--
`--
`--
`157
`90
`119 N
`--
`--
`--
`--
`200
`8
`Mean Dose
`
`--
`--
`--
`--
`200
`8
`Median Dose
`
`a Placebo dosages are given as the number of tablets. Placebo target dosages were as follows:
`
`
`
`Protocol Y1, 4 tablets/day; Protocols YD and Y2, 6 tablets/day; Protocol Y3 and 119, 8
`
`tablets/day; Protocol YE, 10 tablets/day.
`
`
`
`
`b Dose-response studies were not conducted for other indications or pediatric partial onset
`
`seizures.
`
`
`
`
`In all add-on trials, the reduction in seizure rate from baseline during the entire
`
`double-blind phase was measured. The median percent reductions in seizure rates and
`the responder rates (fraction of patients with at least a 50% reduction) by treatment
`
`group for each study are shown below in Table 2. As described above, a global
`improvement in seizure severity was also assessed in the Lennox-Gastaut trial.
`
`
`
`8
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`Page 00008
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`

`
`
`
`
`
`
`
`
`
`46
`44.7c
`46d
`48
`40.8c
`40c
`--
`--
`--
`30
`46.4f
`47c
`--
`--
`--
`--
`--
`--
`
`--
`--
`--
`
`
` Table 2:
`Efficacy Results in Double-Blind, Placebo-Controlled, Add-On Epilepsy Trials
`
`
`
`
`
` Target Topiramate Dosage (mg/day)
`1,000 ≈6 mg/kg/day*
`Protocol Efficacy Results Placebo
`200
`400
`600
`800
`
`Partial Onset Seizures
`
`
`
`
`
`
`Studies in Adults
`
`
`
`
`
`
`
`45
`45
`--
`--
`45
`--
`N
`YD
`27.2a
`47.5b
`--
`--
`--
`Median % Reduction
`11.6
`44d
`--
`--
`--
`% Responders
`18
`24
`YE
`N
`47
`--
`--
`48
`47
`--
`41.0c 36.0c
`--
`Median % Reduction
`1.7
`--
`--
`41c
`36d
`--
`% Responders
`9
`--
`--
`Y1
`N
`24
`--
`23
`--
`--
`--
`40.7e
`--
`--
`--
`Median % Reduction
`1.1
`--
`35d
`--
`--
`--
`% Responders
`8
`--
`
`Y2
`N
`30
`--
`--
`--
`--
`--
`--
`--
`--
`Median % Reduction
`-12.2
`--
`--
`--
`--
`--
`% Responders
`10
`--
`--
`Y3
`N
`28
`--
`--
`28
`--
`--
`24.3c
`--
`--
`Median % Reduction
`-20.6
`--
`--
`43c
`--
`--
`% Responders
`0
`--
`--
`119 N
`91
`168
`--
`--
`--
`--
`44.2c
`
`--
`--
`--
`--
`Median % Reduction
`20.0
`45c
`
`
`--
`--
`--
`--
`% Responders
`24
`
`
`
`
`
`
`
`Studies in Pediatric Patients
`
`N
`YP
`--
`45
`--
`--
`--
`41
`33.1d
`
`Median % Reduction
`10.5
`--
`--
`--
`--
`
`% Responders
`20
`--
`--
`--
`--
`39
`
`
`
`
`
`
`Primary Generalized
`Tonic-Clonich
`
`YTC N
`Median % Reduction
`
`% Responders
`Lennox-Gastaut Syndromei
`
`
` YL
`N
`Median % Reduction
`% Responders
`
`Improvement in Seizure
`
`Severityj
`
`
`
`
`
`
`
`
`
`Comparisons with placebo: a p=0.080; b p<0.010; c p<0.001; d p<0.050; e p=0.065; f p<0.005;g p=0.071;
`
`h Median % reduction and % responders are reported for PGTC Seizures;
`
`i Median % reduction and % responders for drop attacks, i.e., tonic or atonic seizures;
`
`j Percent of subjects who were minimally, much, or very much improved from baseline
`
`
`* For Protocols YP and YTC, protocol-specified target dosages (<9.3 mg/kg/day) were assigned based on
`
`subject's weight to approximate a dosage of 6 mg/kg per day; these dosages corresponded to mg/day dosages of
`125, 175, 225, and 400 mg/day.
`
`40
`9.0
`20
`
`49
`-5.1
`14
`28
`
`--
`--
`--
`
`--
`--
`--
`--
`
`--
`--
`--
`
`--
`--
`--
`--
`
`--
`--
`--
`
`--
`--
`--
`--
`
`--
`--
`--
`
`--
`--
`--
`--
`
`--
`--
`--
`
`--
`--
`--
`--
`
`39
`56.7d
`
`56c
`
`46
`
` 14.8d
`28g
`
`52d
`
`
`
`Subset analyses of the antiepileptic efficacy of TOPAMAX®. Tablets in these studies
`
` showed no differences as a function of gender, race, age, baseline seizure rate, or
`concomitant AED.
`
`Migraine
`The results of 2 multicenter, randomized, double-blind, placebo-controlled,
`parallel-group clinical trials established the effectiveness of TOPAMAX® in the
`9
`
`
`
`
`Page 00009
`
`

`
`prophylactic treatment of migraine headache. The design of both trials (one study was
`conducted in the U.S. and one study was conducted in the U.S. and Canada) was
`identical, enrolling patients with a history of migraine, with or without aura, for at
`least 6 months, according to the International Headache Society diagnostic criteria.
`Patients with a history of cluster headaches or basilar, ophthalmoplegic, hemiplegic,
`or transformed migraine headaches were excluded from the trials. Patients were
`
`required to have completed up to a 2 week washout of any prior migraine preventive
`medications before starting the baseline phase.
`
`
`
`Patients who experienced 3 to 12 migraine headaches over the 4-weeks in the
`baseline phase were equally randomized to either TOPAMAX® 50 mg/day,
`100 mg/day, 200 mg/day, or placebo and treated for a total of 26 weeks (8-week
`titration period and 18-week maintenance period). Treatment was initiated at
`25 mg/day for one week, and then the daily dosage was increased by 25-mg
`increments each week until reaching the assigned target dose or maximum tolerated
`dose (administered twice daily).
`
`Effectiveness of treatment was assessed by the reduction in migraine headache
`frequency, as measured by the change in 4-week migraine rate from the baseline
`phase to double-blind treatment period in each TOPAMAX® treatment group
`compared to placebo in the intent to treat (ITT) population.
`
`In the first study a total of 469 patients (416 females, 53 males), ranging in age from
`13 to 70 years, were randomized and provided efficacy data. Two hundred sixty five
`patients completed the entire 26-week double-blind phase. The median average daily
`dosages were 47.8 mg/day, 88.3 mg/day, and 132.1 mg/day in the target dose groups
`of TOPAMAX® 50, 100, and 200 mg/day, respectively.
`
`The mean migraine headache frequency rate at baseline was approximately
`5.5 migraine headaches/28 days and was similar across treatment groups. The change
`in the mean 4-week migraine headache frequency from baseline to the double-blind
`phase was -1.3, -2.1, and -2.2 in the TOPAMAX® 50, 100, and 200 mg/day groups,
`
`respectively, versus -0.8 in the placebo group (see Figure 2). The differences between
`the TOPAMAX® 100 and 200 mg/day groups versus placebo were statistically
`significant (p<0.001 for both comparisons).
`
`
`
`In the second study a total of 468 patients (406 females, 62 males), ranging in age
`from 12 to 65 years, were randomized and provided efficacy data. Two hundred fifty
`five patients completed the entire 26-week double-blind phase. The median average
`daily dosages were 46.5 mg/day, 85.6 mg/day, and 150.2 mg/day in the target dose
`groups of TOPAMAX® 50, 100, and 200 mg/day, respectively.
`
`
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`

`
` The mean migraine headache frequency rate at baseline was approximately
`
`5.5 migraine headaches/28 days and was similar across treatment groups. The change
`in the mean 4-week migraine headache period frequency from baseline to the double-
`blind phase was -1.4, -2.1, and -2.4 in the TOPAMAX® 50, 100, and 200 mg/day
`groups, respectively, versus –1.1 in the placebo group (see Figure 2). The differences
`between the TOPAMAX® 100 and 200 mg/day groups versus placebo were
`statistically significant (p=0.008 and <0.001, respectively).
`
`In both studies, there were no apparent differences in treatment effect within age, or
`gender, subgroups. Because most patients were Caucasian, there were insufficient
`numbers of patients from different races to make a meaningful comparison of race.
`
`
`
` Figure 2:
`
` Reduction in 4-Week Migraine Headache Frequency (Studies TOPMAT-MIGR-001
`
`
`and TOPMAT-MIGR-002)
`
`
`
`
`
`
`
`INDICATIONS AND USAGE
`
`Monotherapy Epilepsy
`TOPAMAX® (topiramate) Tablets and TOPAMAX® (topiramate capsules) Sprinkle
`Capsules are indicated as initial monotherapy in patients 10 years of age and older
`with partial onset or primary generalized tonic-clonic seizures.
`
`Effectiveness was demonstrated in a controlled trial in patients with epilepsy who had
`no more than 2 seizures in the 3 months prior to enrollment. Safety and effectiveness
`in patients who were converted to monotherapy from a previous regimen of other
`anticonvulsant drugs have not been established in controlled trials.
`
`Adjunctive Therapy Epilepsy
`
`TOPAMAX® (topiramate) Tablets and TOPAMAX® (topiramate capsules) Sprinkle
`Capsules are indicated as adjunctive therapy for adults and pediatric patients ages
`
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`
`2 - 16 years with partial onset seizures, or primary generalized tonic-clonic seizures,
`and in patients 2 years of age and older with seizures associated with Lennox-Gastaut
`syndrome.
`
`Migraine
`TOPAMAX® (topiramate) Tablets and TOPAMAX® (topiramate capsules) Sprinkle
`Capsules are indicated for adults for the prophylaxis of migraine headache. The
`usefulness of TOPAMAX® in the acute treatment of migraine headache has not been
`
`studied.
`
`CONTRAINDICATIONS
`TOPAMAX® is contraindicated in patients with a history of hypersensitivity to any
`
`component of this product.
`
`WARNINGS
`Acute Myopia and Secondary Angle Closure Glaucoma
`A syndrome consisting of acute myopia associated with secondary angle closure
`glaucoma has been reported in patients receiving TOPAMAX®. Symptoms include
`acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings
`can include myopia, anterior chamber shallowing, ocular hyperemia (redness) and
`increased intraocular pressure. Mydriasis may or may not be present. This syndrome
`may be associated with supraciliary effusion resulting in anterior displacement of the
`lens and iris, with secondary angle closure glaucoma. Symptoms typically occur
`within 1 month of initiating TOPAMAX® therapy. In contrast to primary narrow
`angle glaucoma, which is rare under 40 years of age, secondary angle closure
`glaucoma associated with topiramate has been reported in pediatric patients as well as
`adults. The primary
`treatment
`to reverse symptoms
`is discontinuation of
`TOPAMAX® as rapidly as possible, according to the judgment of the treating
`physician. Other measures, in conjunction with discontinuation of TOPAMAX®, may
`be helpful.
`
`
`
`
`
`Elevated intraocular pressure of any etiology, if left untreated, can lead to serious
`sequelae including permanent vision loss.
`
`Oligohidrosis and Hyperthermia
`Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been
`reported in association with TOPAMAX® use. Decreased sweating and an elevation
`in body temperature above normal characterized these cases. Some of the cases were
`reported after exposure to elevated environmental temperatures.
`
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`
`The majority of the reports have been in children. Patients, especially pediatric
`patients, treated with TOPAMAX® should be monitored closely for evidence of
`decreased sweating and increased body temperature, especially in hot weather.
`Caution should be used when TOPAMAX® is prescribed with other drugs that
`predispose patients to heat-related disorders; these drugs include, but are not limited
`to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity.
`
` Suicidal Behavior and Ideation
`
`Antiepileptic drugs (AEDs), including TOPAMAX®, increase the risk of suicidal
`thoughts or behavior in patients taking these drugs for any indication. Patients treated
`with any AED for any indication should be monitored for the emergence or
`worsening of depression, suicidal thoughts or behavior, and/or any unusual changes
`in mood or behavior.
`
`Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive
`
` therapy) of 11 different AEDs showed that patients randomized to one of the AEDs
`had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of
`suicidal thinking or behavior compared to patients randomized to placebo. In these
`trials, which had a median treatment duration of 12 weeks, the estimated incidence
`rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%,
`compared to 0.24% among 16,029 placebo-treated patients, representing an increase
`of approximately one case of suicidal thinking or behavior for every 530 patients
`treated. There were four suicides in drug-treated patients in the trials and none in
`placebo-treated patients, but the number is too small to allow any conclusion about
`drug effect on suicide.
`
`The increased risk of suicidal thoughts or behavior with AEDs was observed as early
`as one week after starting drug treatment with AEDs and persisted for the duration of
`
` treatment assessed. Because most trials included in the analysis did not extend
`beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could
`not be assessed.
`
`The risk of suicidal thoughts or behavior was generally consistent among drugs in the
`data analyzed. The finding of increased risk with AEDs of varying mechanisms of
`
` action and across a range of indications suggests that the risk applies to all AEDs
`used for any indication. The risk did not vary substantially by age (5 to 100 years) in
`the clinical trials analyzed.
`
`Table 3 shows absolute and relative risk by indication for all evaluated AEDs.
`
`
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`
`
`Placebo Patients
`with Events per
`1000 Patients
`
`Drug Patients with
`Events per 1000
`Patients
`
`1.0
`5.7
`1.0
`2.4
`
`3.4
`8.5
`1.8
`4.3
`
`Epilepsy
`Psychiatric
`Other
`Total
`
`The relative risk for suicidal thoughts or behavior was higher in clinical trials for
`epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk
`differences were similar for the epilepsy and psychiatric indications.
`
`Anyone considering prescribing TOPAMAX® or any other AED must balance the
`risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and
`many other illnesses for which AEDs are prescribed are themselves associated with
`morbidity and mortality and an increased risk of suicidal thoughts and behavior.
`
` Should suicidal thoughts and behavior emerge during treatment, the prescriber needs
`to consider whether the emergence of these symptoms in any given patient may be
`related to the illness being treated.
`
` 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
`(i.e., decreased serum
`Hyperchloremic, non-anion gap, metabolic acidosis
`bicarbonate below the normal reference range in the absence of chronic respiratory
`alkalosis) is associated with topiramate treatment. This metabolic acidosis is caused
`by renal bicarbonate loss due to the inhibitory effect of topiramate on carbonic
`anhydrase. Such electrolyte imbalance has been observed with the use of topiramate
`in placebo-controlled clinical trials and in the post-marketing period.