"The U.S. Food and Drug Administration today approved a device to help reduce the frequency of seizures in epilepsy patients who have not responded well to medications.
The RNS Stimulator consists of a small neurostimulator implanted within "...
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.
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 GABA-A 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.
Absorption and Distribution
The pharmacokinetics of QUDEXY XR are linear with dose proportional increases in plasma concentration when administered as a single oral dose over the range of 50 mg to 1,400 mg. At 25 mg, the pharmacokinetics of QUDEXY XR are nonlinear, possibly due to the binding of topiramate to carbonic anhydrase in red blood cells.
QUDEXY XR sprinkled on a spoonful of soft food is bioequivalent to the intact capsule formulation.
Following a single 200 mg oral dose of QUDEXY XR, peak plasma concentrations (Tmax) occurred approximately 20 hours after dosing. Steady-state was reached in about 5 days following daily dosing of QUDEXY XR in subjects with normal renal function, with a Tmax of approximately 6 hours.
At steady-state, the plasma exposure (AUC0-24hr, Cmax, and Cmin) of topiramate from QUDEXY XR administered once daily and the immediate-release topiramate tablets administered twice-daily were shown to be bioequivalent. Fluctuation of topiramate plasma concentrations at steady-state for QUDEXY XR administered once daily was approximately 40% in healthy subjects, compared to approximately 53% for immediate-release topiramate [see Relative Bioavailability of QUDEXY XR Compared to Immediate- Release Topiramate in Healthy Volunteers below].
Compared to the fasted state, high-fat meal had no effect on bioavailability (AUC and Cmax) but delayed the Tmax by approximately 4 hours following a single dose of QUDEXY XR. QUDEXY XR can be taken without regard to meals.
Topiramate is 15% to 41% bound to human plasma proteins over the blood concentration range of 0.5 mcg/mL to 250 mcg/mL. The fraction bound decreased as blood concentration increased.
Carbamazepine and phenytoin do not alter the binding of immediate-release topiramate. Sodium valproate, at 500 mcg/mL (a concentration 5 to 10 times higher than considered therapeutic for valproate) decreased the protein binding of immediate-release topiramate from 23% to 13%. Immediate-release 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 mL/min to 30 mL/min in adults following oral administration. The mean effective half-life of QUDEXY XR is approximately 56 hours. Steady-state is reached in about 5 days after QUDEXY XR dosing in subjects with normal renal function.
The clearance of topiramate was reduced by 42% in subjects with moderate renal impairment (creatinine clearance 30 to 69 mL/min/1.73 m²) and by 54% in subjects with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m²) compared to subjects with normal renal function (creatinine clearance greater than70 mL/min/1.73 m²). 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 creatinine clearance less than 70 mL/min/1.73 m² [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].
Topiramate is cleared by hemodialysis. Using a high-efficiency, counterflow, single passdialysate 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 mL/min 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 and Use In Specific Populations].
In subjects with hepatic impairment, the clearance of topiramate may be decreased; the mechanism underlying the decrease is not well understood.
Age, Gender and Race
The pharmacokinetics of topiramate in elderly subjects (65 to 85 years of age, N=16) were evaluated in a controlled clinical study. The elderly subject population had reduced renal function (creatinine clearance [-20%]) compared to young adults. Following a single oral 100 mg dose, maximum plasma concentration for elderly and young adults was achieved at approximately 1 to 2 hours. Reflecting the primary renal elimination of topiramate, topiramate plasma and renal clearance were reduced 21% and 19%, respectively, in elderly subjects, compared to young adults. Similarly, topiramate half-life was longer (13%) in the elderly. Reduced topiramate clearance resulted in slightly higher maximum plasma concentration (23%) and AUC (25%) in elderly subjects than observed in young adults. Topiramate clearance is decreased in the elderly only to the extent that renal function is reduced. Because of this, dosage adjustment may be necessary [see DOSAGE AND ADMINISTRATION, Use in Specific Populations and CLINICAL PHARMACOLOGY].
Clearance of topiramate in adults was not affected by gender or race.
Pharmacokinetics of immediate-release topiramate were evaluated in patients ages 2 years to less than 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 years to less than 16 years (95 pediatric patients less than 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 Interaction Studies
Potential interactions between immediate-release 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 9. Interaction of QUDEXY XR and standard AEDs is not expected to differ from the experience with immediate-release topiramate products.
In Table 10, the second column (AED concentration) describes what happened to the concentration of the AED listed in the first column when topiramate was added. The third column (topiramate concentration) describes how the co-administration of a drug listed in the first column modified the concentration of topiramate in experimental settings when topiramate was given alone.
Table 10: Summary of AED
Interactions with topiramate
|AED Co-administered||AED Concentration||Topiramate Concentration|
|Phenytoin||NC or 25% increasea||48% decrease|
|Carbamazepine (CBZ)||NC||40% decrease|
|Valproic acid||11% decrease||14% decrease|
|Lamotrigine||NC at TPM doses up to 400 mg per day||13% decrease|
|NC=Less than 10% change in
AED=Antiepileptic drug NE=Not evaluated TPM=topiramate
aPlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin
bIs not administered, but is an active metabolite of carbamazepine
In addition to the pharmacokinetic interaction described in the above table, concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with and without encephalopathy and hypothermia [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
CNS Depressants or Alcohol
In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), topiramate, given in the absence of other medications at doses of 50 to 200 mg per 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 per day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in patients taking valproic acid. In both studies, topiramate (50 mg per day to 800 mg per day) did not significantly affect exposure to NET. Although there was a dose-dependent decrease in EE exposure for doses between 200 to 800 mg per day, there was no significant dose-dependent change in EE exposure for doses of 50 to 200 mg per 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 QUDEXY XR. 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].
In a single-dose study, serum digoxin AUC was decreased by 12% with concomitant topiramate administration. The clinical relevance of this observation has not been established.
A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg every 24 hours) and topiramate (96 mg every 12 hours) 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 QUDEXY XR therapy may require an adjustment of the QUDEXY XR 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.
Topiramate treatment can frequently cause metabolic acidosis, a condition for which the use of metformin is contraindicated. QUDEXY XR is expected to exhibit the same degree of metabolic acidosis as topiramate.
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 18% 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 QUDEXY XR pharmacokinetics is unclear [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
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 QUDEXY XR is added to pioglitazone therapy or pioglitazone is added to QUDEXY XR therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.
A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg per day) alone and concomitantly with topiramate (150 mg per day). There was a 22% decrease in Cmax and 25% reduction in AUC24 for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4-transhydroxy glyburide (M1) and 3-cis-hydroxyglyburide (M2), was also reduced by 13% and 15%, reduced Cmax by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide.
In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg per 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 per day. Lithium levels should be monitored when co-administered with high-dose QUDEXY XR [see DRUG INTERACTIONS].
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).
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 per day of topiramate. Some subjects may experience a large increase in amitriptyline concentration in the presence of QUDEXY XR and any adjustments in amitriptyline dose should be made according to the patient's clinical response and not on the basis of plasma levels.
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).
When administered concomitantly with topiramate at escalating doses of 100, 250, and 400 mg per day, there was a reduction in risperidone systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg per day doses of topiramate). No alterations of 9hydroxyrisperidone levels were observed. Coadministration of topiramate 400 mg per 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 9hydroxyrisperidone or of topiramate; therefore, this interaction is not likely to be of clinical significance.
Multiple dosing of topiramate (200 mg per 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 per day in 39 volunteers (27 males, 12 females) had no effect on the exposure to topiramate at a dose of 200 mg per day of topiramate.
Multiple dosing of topiramate (200 mg per 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 per day dose of topiramate in the same study.
Co-administration of diltiazem (240 mg) with topiramate (150 mg per day) resulted in a 10% decrease in Cmax and 25% decrease in diltiazem AUC, 27% decrease in Cmax and 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.
Multiple dosing of topiramate (150 mg per day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg) did not affect the pharmacokinetics of topiramate.
Other Carbonic Anhydrase Inhibitors
Concomitant use of QUDEXY XR, 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 QUDEXY XR 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 QUDEXY XR with commonly used laboratory tests.
Relative Bioavailability Of QUDEXY XR Compared To Immediate-Release Topiramate In Healthy Volunteers
QUDEXY XR, taken once daily, provides similar steady-state topiramate concentrations to immediate-release topiramate taken every 12 hours, when administered at the same total daily dose. In a healthy volunteer, multiple-dose crossover study, the 90% CI for the ratios of AUC024, Cmax and Cmin, as well as partial AUC (the area under the concentration-time curve from time 0 to time p (post dose)) for multiple time points were within the 80 to 125% bioequivalence limits, indicating no clinically significant difference between the two formulations. In addition, the 90% CI for the ratios of topiramate plasma concentration at each of multiple time points over 24 hours for the two formulations were within the 80 to 125% bioequivalence limits, except for the initial time points before 3 hours and at 8 hours post-dose, which is not expected to have a significant clinical impact.
The effects of switching between QUDEXY XR and immediate-release topiramate were also evaluated in the same multiple-dose, crossover, comparative bioavailability study. In healthy subjects switched from immediate-release topiramate given every 12 hours to QUDEXY XR given once daily, similar concentrations were maintained immediately after the formulation switch. On the first day following the switch, there were no significant differences in AUC0-24, Cmax, and Cmin, as the 90% CI for the ratios were contained within the 80 to 125% equivalence limits.
Extended-Release: Bridging Study To Demonstrate Pharmacokinetic Equivalence between Extended-Release (QUDEXY XR) And Immediate-Release Topiramate Formulations
Although a controlled clinical trial was performed (Study 11), the basis for approval of the extended-release formulation (QUDEXY XR) included the studies described below using an immediate-release formulation and the demonstration of the pharmacokinetic equivalence of QUDEXY XR to immediate-release topiramate through the analysis of concentrations and cumulative AUCs at multiple time points [see CLINICAL PHARMACOLOGY].
Immediate-Release: Monotherapy Treatment In 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 pediatric patients 10 years of age and older with partial onset or primary generalized tonic-clonic seizures was established in a multicenter, randomized, double-blind, dose-controlled, parallel-group trial (Study 1).
Study 1 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 per 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 per day or 400 mg per day of topiramate. 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 per day for greater than 2 weeks, and patients who did not tolerate 150 mg per 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 per day group over the topiramate 50 mg per 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.
Pediatric Patients 2 to less than 10 Years of Age
The conclusion that topiramate is effective as initial monotherapy in pediatric patients 2 to less than 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 less than 16 years and adults when topiramate was given as initial monotherapy. Specific dosing in pediatric patients 2 to less than 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].
Figure 1: Kaplan-Meier Estimates of Cumulative Rates
for Time to First Seizure in Study 1
Immediate-Release: Adjunctive Therapy In Patients With Partial Onset Seizures
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 (Studies 2, 3, 4, 5, 6, and 7), two comparing several dosages of topiramate and placebo and four comparing a single dosage with placebo, in patients with a history of partial onset seizures, with or without secondarily generalized seizures.
Patients in these studies were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In each study, patients were stabilized on optimum dosages of their concomitant AEDs during baseline phase lasting between 4 and 12 weeks. Patients who experienced a prespecified minimum number of partial onset seizures, with or without secondary generalization, during the baseline phase (12 seizures for 12-week baseline, 8 for 8-week baseline or 3 for 4-week baseline) were randomly assigned to placebo or a specified dose of topiramate tablets in addition to their other AEDs.
Following randomization, patients began the double-blind phase of treatment. In five of the six studies, patients received active drug beginning at 100 mg per day; the dose was then increased by 100 mg or 200 mg per day increments weekly or every other week until the assigned dose was reached, unless intolerance prevented increases. In Study 7, the 25 or 50 mg per day initial doses of topiramate were followed by respective weekly increments of 25 or 50 mg per day until the target dose of 200 mg per 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 11.
Table 11: Immediate Release Topiramate Dose Summary
During the Stabilization Periods of Each of Six Double-Blind,
Placebo-Controlled, Adjunctive Trials in Adults with Partial Onset Seizuresa
|Study||Stabilization Dose||Placebob||Target Topiramate Dosage (mg per day)|
|aDose-response studies were not conducted for other
indications or pediatric partial-onset seizures
bPlacebo dosages are given as the number of tablets. Placebo target dosages were as follows: Study 4 (4 tablets/day); Studies 2 and 5 (6 tablets/day); Studies 6 and 7 (8 tablets/day); Study 3 (10 tablets/day)
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 (Study 8), comparing topiramate and placebo in patients with a history of partial onset seizures, with or without secondarily generalized seizures.
Patients in Study 8 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In Study 8, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least six partial onset seizures, with or without secondarily generalized seizures, during the baseline phase were randomly assigned to placebo or topiramate in addition to their other AEDs.
Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 25 or 50 mg per day; the dose was then increased by 25 mg to 150 mg per day increments every other week until the assigned dosage of 125, 175, 225 or 400 mg per 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.
Immediate-Release: Adjunctive Therapy 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 (Study 9), comparing a single dosage of topiramate and placebo.
Patients in Study 9 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least three primary generalized tonic-clonic seizures during the baseline phase were randomly assigned to placebo or topiramate in addition to their other AEDs.
Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 50 mg per day for four weeks; the dose was then increased by 50 mg to 150 mg per day increments every other week until the assigned dose of 175, 225 or 400 mg per 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.
Immediate-Release: Adjunctive Therapy 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 (Study 10).
Patients in Study 10 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients who were experiencing at least 60 seizures per month before study entry were stabilized on optimum dosages of their concomitant AEDs during a 4 week baseline phase. Following baseline, patients were randomly assigned to placebo or topiramate in addition to their other AEDs. Active drug was titrated beginning at 1 mg/kg/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.
In all adjunctive topiramate 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 12. As described above, a global improvement in seizure severity was also assessed in the Lennox-Gastaut trial.
Table 12: Efficacy Results in Double-Blind,
Placebo-Controlled, Adjunctive Epilepsy Trials
|Study #||#||Placebo||Target Topiramate Dosage (mg per day)|
|200||400||600||800||1,000||≈6 mg/ kg/day*|
|Partial Onset Seizures Studies in Adults|
|Median % Reduction||11.6||27.2a||47.5b||44.7c||--||--||--|
|Median % Reduction||1.7||--||--||40.8c||41.0c||36.0c|
|Median % Reduction||1.1||--||40.7e||--||--||--||--|
|Median % Reduction||-12.2||--||--||46.4f||--||--||--|
|Median % Reduction||-20.6||--||--||--||24.3c||--||--|
|Reduction % Responders||24||45c||--||--||--||--||--|
|Studies in Pediatric Patients|
|Median % Reduction||10.5||--||--||--||--||--||33.1d|
|Primary Generalized Tonic-Clonich|
|Median % Reduction||9.0||--||--||--||--||--||56.7d|
|Median % Reduction||-5.1||--||--||--||--||--||14.8d|
|Improvement in Seizure Severityj||28||--||--||--||--||--||52d|
|Comparisons with placebo: ap=0.080; bp ≤ 0.010; cp ≤ 0.001; dp ≤
0.050; ep=0.065; fp
≤ 0.005; gp=0.071;
hMedian % reduction and % responders are reported for PGTC seizures;
iMedian % reduction and % responders for drop attacks, i.e., tonic or atonic seizures
jPercent of subjects who were minimally, much, or very much improved from baseline.
*For Studies 8 and 9, specified target dosages (less than 9.3 mg/kg/day) were assigned based on subject's weight to approximate a dosage of 6mg/kg/day; these dosages corresponded to mg per day dosages of 125 mg per day, 175 mg per day, 225 mg per day, and 400 mg per day
Subset analyses of the antiepileptic efficacy of topiramate tablets in these studies showed no differences as a function of gender, race, age, baseline seizure rate, or concomitant AED.
In clinical trials for epilepsy, daily dosages were decreased in weekly intervals by 50 mg per day to 100 mg per day in adults and over a 2-to 8-week period in children; transition was permitted to a new antiepileptic regimen when clinically indicated.
Extended-Release: Adjunctive Therapy In Adult Patients With Partial Onset Seizures With QUDEXY XR (Study 11)
The effectiveness of QUDEXY XR as an adjunctive treatment for adults (18 to 75 years of age) was evaluated in Study 11, a randomized, international, multi-center, double-blind, parallel-group, placebo-controlled trial in patients with a history of partial onset seizures, with or without secondary generalization.
Patients with partial onset seizures on a stable dose of 1 to 3 AEDs entered into an 8 week baseline period. Patients who experienced at least 8 partial onset seizures, with or without secondary generalization, and no more than 21 consecutive seizure free days during the 8 week baseline phase were randomly assigned to placebo or QUDEXY XR administered once daily in addition to their concomitant AEDs. Following randomization, 249 patients began the double-blind treatment phase, which consisted of an initial 3 week titration period followed by an 8 week maintenance period. During the titration period, patients received QUDEXY XR or placebo beginning at 50 mg once daily; the dose was increased at weekly intervals by 50 mg once daily, or the placebo equivalent, until a final dose of 200 mg once daily was achieved. Patients than entered the maintenance period at the assigned dose of 200 mg once daily, or its placebo equivalent.
The percent reduction in the frequency of partial-onset seizure, baseline period compared to the treatment phase, was the primary endpoint. Data was analyzed by the Wilcoxon rank-sum test, with the criteria of statistical significance of p < 0.05. The results of the analysis are presented in Table 13. The median percent reduction in seizure rate was 39.5% in patients taking QUDEXY XR (N=124) and 21.7% in patients taking placebo (N=125). This difference was statistically significant.
Table 13: Percent Reduction From Baseline in
Partial-Onset Seizure Frequency During 11-week Treatment Period in Study 11
|Study End Point||QUDEXY XR
|Median Percent Reduction from Baselinea||39.5%||21.7%|
|aStatistically Significant by the Wilcoxon rank-sum test|
Figure 2 shows the change from baseline during titration plus maintenance (11 weeks) in partial-onset seizure frequency by category for patients treated with QUDEXY XR and placebo. Patients in whom the seizure frequency increased are shown as “worse.” Patients in whom the seizure frequency decreased are shown in four categories of reduction in seizure frequency.
Figure 2: Proportion of
Patients by Category of Seizure Response to QUDEXY XR and Placebo
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