DrugLib.com — Drug Information Portal

Rx drug information, pharmaceutical research, clinical trials, news, and more

Topamax (Topiramate) - Description and Clinical Pharmacology

 
 



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 339.36. Topiramate is designated chemically as 2,3:4,5-Di-O-isopropylidene-β-D-fructopyranose sulfamate and has the following structural formula:

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

TOPAMAX® Sprinkle Capsules contain topiramate-coated beads in a hard gelatin capsule. The inactive ingredients are sugar spheres (sucrose and starch), povidone, cellulose acetate, gelatin, sorbitan monolaurate, sodium lauryl sulfate, titanium dioxide, and black pharmaceutical ink.

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% to 41% bound to human plasma proteins over the blood concentration range of 0.5 to 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 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 adults following oral administration.

Special Populations

Renal Impairment

The clearance of topiramate was reduced by 42% in moderately renally impaired (creatinine clearance 30 to 69 mL/min/1.73m2) and by 54% in severely renally impaired subjects (creatinine clearance <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 Dosage and Administration and and Warnings and Precautions].

Hemodialysis

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

Hepatic Impairment

In hepatically impaired subjects, the clearance of topiramate may be decreased; the mechanism underlying the decrease is not well understood [see Dosage and Administration].

Age, Gender, and Race

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

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

Pediatric Pharmacokinetics

Pharmacokinetics of topiramate were evaluated in patients aged 2 to <16 years. Patients received either no or a combination of other antiepileptic drugs. A population pharmacokinetic model was developed on the basis of pharmacokinetic data from relevant topiramate clinical studies. This dataset contained data from 1217 subjects including 258 pediatric patients aged 2 to <16 years (95 pediatric patients <10 years of age).

Pediatric patients on adjunctive treatment exhibited a higher oral clearance (L/h) of topiramate compared to patients on monotherapy, presumably because of increased clearance from concomitant enzyme-inducing antiepileptic drugs. In comparison, topiramate clearance per kg is greater in pediatric patients than in adults and in young pediatric patients (down to 2 years) than in older pediatric patients. Consequently, the plasma drug concentration for the same mg/kg/day dose would be lower in pediatric patients compared to adults and also in younger pediatric patients compared to older pediatric patients. Clearance was independent of dose.

As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations of topiramate.

Drug-Drug Interactions

Antiepileptic Drugs

Potential interactions between topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in Table 12.

In Table 12, the second column (AED concentration) describes what happens to the concentration of the AED listed in the first column when topiramate is added. The third column (topiramate concentration) describes how the co-administration of a drug listed in the first column modifies the concentration of topiramate in experimental settings when TOPAMAX® was given alone.

Table 12: Summary of AED Interactions with TOPAMAX®
AED
Co-administered
AED
Concentration
Topiramate
Concentration
NC = Less than 10% change in plasma concentration.
AED = Antiepileptic drug.
NE = Not Evaluated.
TPM = Topiramate
Phenytoin NC or 25% increase 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease

In addition to the pharmacokinetic interaction described in the above table, concomitant administration of valproic acid and TOPAMAX® has been associated with hyperammonemia with and without encephalopathy and hypothermia [see Warnings and Precautions, and Drug Interactions].

CNS Depressants

Concomitant administration of TOPAMAX® and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. Because of the potential of TOPAMAX® to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse reactions, TOPAMAX® should be used with extreme caution if used in combination with alcohol and other CNS depressants [see Drug Interactions].

Oral Contraceptives

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

Digoxin

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

Hydrochlorothiazide

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

Metformin

Topiramate treatment can frequently cause metabolic acidosis, a condition for which the use of metformin is contraindicated.

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin (500 mg every 12 hr) and topiramate in plasma when metformin was given alone and when metformin and topiramate (100 mg every 12 hr) were given simultaneously. The results of this study indicated that the mean metformin Cmax and AUC0–12h increased by 17% and 25%, respectively, when topiramate was added. Topiramate did not affect metformin tmax. The clinical significance of the effect of topiramate on metformin pharmacokinetics is not known. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect of metformin on topiramate pharmacokinetics is unclear [see Drug Interactions].

Pioglitazone

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

Glyburide

A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg/day) alone and concomitantly with topiramate (150 mg/day). There was a 22% decrease in Cmax and a 25% reduction in AUC24 for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4-trans-hydroxy-glyburide (M1) and 3-cis-hydroxyglyburide (M2), was also reduced by 13% and 15%, and Cmax was reduced by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide.

Lithium

In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg/day; however, there was an observed increase in systemic exposure of lithium (27% for Cmax and 26% for AUC) following topiramate doses up to 600 mg/day. Lithium levels should be monitored when co-administered with high-dose TOPAMAX® [see Drug Interactions].

Haloperidol

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

Amitriptyline

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

Sumatriptan

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

Risperidone

When administered concomitantly with topiramate at escalating doses of 100, 250, and 400 mg/day, there was a reduction in risperidone systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg/day doses of topiramate). No alterations of 9-hydroxyrisperidone levels were observed. Co-administration of topiramate 400 mg/day with risperidone resulted in a 14% increase in Cmax and a 12% increase in AUC12 of topiramate. There were no clinically significant changes in the systemic exposure of risperidone plus 9-hydroxyrisperidone or of topiramate; therefore, this interaction is not likely to be of clinical significance.

Propranolol

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

Dihydroergotamine

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

Diltiazem

Co-administration of diltiazem (240 mg Cardizem CD®) with topiramate (150 mg/day) resulted in a 10% decrease in Cmax and a 25% decrease in diltiazem AUC, a 27% decrease in Cmax and an 18% decrease in des-acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem resulted in a 16% increase in Cmax and a 19% increase in AUC12 of topiramate.

Venlafaxine

Multiple dosing of topiramate (150 mg/day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg Effexor XR®) did not affect the pharmacokinetics of topiramate.

Other Carbonic Anhydrase Inhibitors

Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide, acetazolamide, or dichlorphenamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, if TOPAMAX® is given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis [see Drug Interactions ].

Drug/Laboratory Tests Interactions

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

NON-CLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis

An increase in urinary bladder tumors was observed in mice given topiramate (20, 75, and 300 mg/kg) in the diet for 21 months. The elevated bladder tumor incidence, which was statistically significant in males and females receiving 300 mg/kg, was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. Plasma exposures in mice receiving 300 mg/kg were approximately 0.5 to 1 times steady-state exposures measured in patients receiving topiramate monotherapy at the recommended human dose (RHD) of 400 mg, and 1.5 to 2 times steady-state topiramate exposures in patients receiving 400 mg of topiramate plus phenytoin. The relevance of this finding to human carcinogenic risk is uncertain. No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/kg (approximately 3 times the RHD on a mg/m2 basis).

Mutagenesis

Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitro and in vivo assays. Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increase unscheduled DNA synthesis in rat hepatocytes in vitro; and it did not increase chromosomal aberrations in human lymphocytes in vitro or in rat bone marrow in vivo.

Impairment of Fertility

No adverse effects on male or female fertility were observed in rats at doses up to 100 mg/kg (2.5 times the RHD on a mg/m2 basis).

CLINICAL STUDIES

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

Monotherapy Epilepsy Controlled Trial

Patients with Partial Onset or Primary Generalized Tonic-Clonic Seizures

Adults and Pediatric Patients 10 Years of Age and Older

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

The trial was conducted in 487 patients diagnosed with epilepsy (6 to 83 years of age) who had 1 or 2 well-documented seizures during the 3-month retrospective baseline phase who then entered the study and received 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

Children 2 to <10 Years of Age

The conclusion that topiramate is effective as initial monotherapy in children 2 to <10 years of age with partial onset or primary generalized tonic-clonic seizures was based on a pharmacometric bridging approach using data from the controlled epilepsy trials described in labeling. This approach consisted of first showing a similar exposure response relationship between pediatric patients down to 2 years of age and adults when topiramate was given as adjunctive therapy. Similarity of exposure-response was also demonstrated in pediatric patients ages 6 to <16 years and adults when topiramate was given as initial monotherapy. Specific dosing in children 2 to <10 years of age was derived from simulations utilizing plasma exposure ranges observed in pediatric and adult patients treated with topiramate initial monotherapy [see Dosage and Administration] .

Adjunctive Therapy Epilepsy Controlled Trials

Adult 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 13.

Pediatric Patients Ages 2 to 16 Years with Partial Onset Seizures

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

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

Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 25 or 50 mg/day; the dose was then increased by 25 mg to 150 mg/day increments every other week until the assigned dosage of 125, 175, 225, or 400 mg/day based on patients' weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered an 8-week stabilization period.

Patients With Primary Generalized Tonic-Clonic Seizures

The effectiveness of 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/day for four weeks; the dose was then increased by 50 mg to 150 mg/day increments every other week until the assigned dose of 175, 225, or 400 mg/day based on patients' body weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered a 12-week stabilization period.

Patients With Lennox-Gastaut Syndrome

The effectiveness of 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/day for a week; the dose was then increased to 3 mg/kg/day for one week, then to 6 mg/kg/day. After titration, patients entered an 8-week stabilization period. The primary measures of effectiveness were the percent reduction in drop attacks and a parental global rating of seizure severity.

Table 13: Topiramate Dose Summary During the Stabilization Periods of Each of Six Double-Blind, Placebo-Controlled, Add-On Trials in Adults with Partial Onset SeizuresDose-response studies were not conducted for other indications or pediatric partial onset seizures.
Target Topiramate Dosage (mg/day)
Protocol Stabilization Dose PlaceboPlacebo 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; Protocols Y3 and 119, 8 tablets/day; Protocol YE, 10 tablets/day. 200 400 600 800 1,000
YD N 42 42 40 41 -- --
Mean Dose 5.9 200 390 556 -- --
Median Dose 6.0 200 400 600 -- --
 
YE N 44 -- -- 40 45 40
Mean Dose 9.7 -- -- 544 739 796
Median Dose 10.0 -- -- 600 800 1,000
 
Y1 N 23 -- 19 -- -- --
Mean Dose 3.8 -- 395 -- -- --
Median Dose 4.0 -- 400 -- -- --
 
Y2 N 30 -- -- 28 -- --
Mean Dose 5.7 -- -- 522 -- --
Median Dose 6.0 -- -- 600 -- --
 
Y3 N 28 -- -- -- 25 --
Mean Dose 7.9 -- -- -- 568 --
Median Dose 8.0 -- -- -- 600 --
 
119 N 90 157 -- -- -- --
Mean Dose 8 200 -- -- -- --
Median Dose 8 200 -- -- -- --

In all add-on trials, the reduction in seizure rate from baseline during the entire double-blind phase was measured. The median percent reductions in seizure rates and the responder rates (fraction of patients with at least a 50% reduction) by treatment group for each study are shown below in Table 14. As described above, a global improvement in seizure severity was also assessed in the Lennox-Gastaut trial.

Table 14: Efficacy Results in Double-Blind, Placebo-Controlled, Add-On Epilepsy Trials
Target Topiramate Dosage (mg/day)
Protocol Efficacy Results Placebo 200 400 600 800 1,000 ≈6 mg/kg/dayFor 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.
Comparisons with placebo:
Partial Onset Seizures
Studies in Adults
YD N 45 45 45 46 -- -- --
Median % Reduction 11.6 27.2 47.5 44.7 1 -- -- --
% Responders 18 24 44 2 46 -- -- --
YE N 47 -- -- 48 48 47 --
Median % Reduction 1.7 -- -- 40.8 41.0 36.0 --
% Responders 9 -- -- 40 41 36 --
Y1 N 24 -- 23 -- -- -- --
Median % Reduction 1.1 -- 40.7 -- -- -- --
% Responders 8 -- 35 -- -- -- --
Y2 N 30 -- -- 30 -- -- --
Median % Reduction -12.2 -- -- 46.4p≤0.005; -- -- --
% Responders 10 -- -- 47 -- -- --
Y3 N 28 -- -- -- 28 -- --
Median % Reduction -20.6 -- -- -- 24.3 -- --
% Responders 0 -- -- -- 43 -- --
119 N 91 168 -- -- -- -- --
Median % Reduction 20.0 44.2 -- -- -- -- --
% Responders 24 45 -- -- -- -- --
Studies in Pediatric Patients
YP N 45 -- -- -- -- -- 41
Median % Reduction 10.5 -- -- -- -- -- 33.1
% Responders 20 -- -- -- -- -- 39
Primary Generalized Tonic-ClonicMedian % reduction and % responders are reported for PGTC Seizures;
YTC N 40 -- -- -- -- -- 39
Median % Reduction 9.0 -- -- -- -- -- 56.7
% Responders 20 -- -- -- -- -- 56
Lennox-Gastaut SyndromeMedian % reduction and % responders for drop attacks, i.e., tonic or atonic seizures;
YL N 49 -- -- -- -- -- 46
Median % Reduction -5.1 -- -- -- -- -- 14.8
% Responders 14 -- -- -- -- -- 28p=0.071;
Improvement in Seizure SeverityPercent of subjects who were minimally, much, or very much improved from baseline 28 -- -- -- -- -- 52

1 p≤0.001;
2 p≤0.050;

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

In clinical trials for epilepsy, daily dosages were decreased in weekly intervals by 50 to 100 mg/day in adults and over a 2- to 8-week period in children; transition was permitted to a new antiepileptic regimen when clinically indicated.

Migraine Prophylaxis

The results of 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trials established the effectiveness of TOPAMAX® in the prophylactic treatment of migraine headache. The design of both trials (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.

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 p <0.001, respectively).

In both studies, there were no apparent differences in treatment effect within age or gender subgroups. Because most patients were Caucasian, there were insufficient numbers of patients from different races to make a meaningful comparison of race.

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

Figure 2: Reduction in 4-Week Migraine Headache Frequency
(Studies TOPMAT-MIGR-001 and TOPMAT-MIGR-002)

-- advertisement -- The American Red Cross
 
Home | About Us | Contact Us | Site usage policy | Privacy policy

All Rights reserved - Copyright DrugLib.com, 2006-2017