DESCRIPTION

Topiramate is a sulfamate-substituted monosaccharide. Topiramate tablets are available as 25 mg, 50 mg, 100 mg, and 200 mg circular tablets for oral administration.

Topiramate is a white crystalline powder with a bitter taste. Topiramate USP is most soluble in alkaline solutions containing sodium hydroxide or sodium phosphate and having a pH of 9 to 10. It is freely soluble in acetone, chloroform, dimethylsulfoxide, and ethanol. The solubility in water is 9.8 mg/mL. Its saturated solution has a pH of 6.3. Topiramate has the molecular formula C12H21NO8S and a molecular weight of 339.37. Topiramate is designated chemically as 2,3:4,5-Di-O-isopropylidene-β-D-fructopyranose sulfamate and has the following structural formula:

Topiramate tablets contain the following inactive ingredients: anhydrous lactose, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, magnesium stearate, purified water, polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc.

In addition, individual tablets contain:

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

CLINICAL PHARMACOLOGY

Mechanism of Action:

The precise mechanisms by which topiramate exerts its anticonvulsant effects are unknown; however, preclinical studies have revealed four properties that may contribute to topiramate's efficacy for epilepsy. Electrophysiological and biochemical evidence suggests that topiramate, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV.

Pharmacodynamics:

Topiramate has anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests. Topiramate is only weakly effective in blocking clonic seizures induced by the GABAA receptor antagonist, pentylenetetrazole. Topiramate is also effective in rodent models of epilepsy, which include tonic and absence-like seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in rats by kindling of the amygdala or by global ischemia.

Pharmacokinetics:

The sprinkle formulation is bioequivalent to the immediate release tablet formulation and, therefore, may be substituted as a therapeutic equivalent.

Absorption of topiramate is rapid, with peak plasma concentrations occurring at approximately 2 hours following a 400 mg oral dose. The relative bioavailability of topiramate from the tablet formulation is about 80% compared to a solution. The bioavailability of topiramate is not affected by food.

The pharmacokinetics of topiramate are linear with dose proportional increases in plasma concentration over the dose range studied (200 to 800 mg/day). The mean plasma elimination half-life is 21 hours after single or multiple doses. Steady state is thus reached in about 4 days in patients with normal renal function. Topiramate is 15 to 41% bound to human plasma proteins over the blood concentration range of 0.5 to 250 mcg/mL. The fraction bound decreased as blood concentration increased.

Carbamazepine and phenytoin do not alter the binding of topiramate. Sodium valproate, at 500 mcg/mL (a concentration 5 to 10 times higher than considered therapeutic for valproate) decreased the protein binding of topiramate from 23% to 13%. Topiramate does not influence the binding of sodium valproate.

Metabolism and Excretion:

Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption of topiramate. In rats, given probenecid to inhibit tubular reabsorption, along with topiramate, a significant increase in renal clearance of topiramate was observed. This interaction has not been eva luated in humans. Overall, oral plasma clearance (CL/F) is approximately 20 to 30 mL/min in humans following oral administration.

Pharmacokinetic Interactions

(see also Drug Interactions):

Antiepileptic Drugs

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

Special Populations:

Renal Impairment:

The clearance of topiramate was reduced by 42% in moderately renally impaired (creatinine clearance 30 to 69mL/min/1.73m2) and by 54% in severely renally impaired subjects (creatinine clearance <30mL/min/1.73m2) compared to normal renal function subjects (creatinine clearance >70mL/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 120mL/min with blood flow through the dialyzer at 400 mL/min. This high clearance (compared to 20 to 30 mL/min total oral clearance in healthy adults) will remove a clinically significant amount of topiramate from the patient over the hemodialysis treatment period. Therefore, a supplemental dose may be required (see DOSAGE AND ADMINISTRATION).

Hepatic Impairment:

In hepatically impaired subjects, the clearance of topiramate may be decreased; the mechanism underlying the decrease is not well understood.

Age, Gender, and Race:

The pharmacokinetics of topiramate in elderly subjects (65 to 85 years of age, N=16) were eva luated in a controlled clinical study. The elderly subject population had reduced renal function [creatinine clearance (-20%)] compared to young adults. Following a single oral 100 mg dose, maximum plasma concentration for elderly and young adults was achieved at approximately 1 to 2hours. Reflecting the primary renal elimination of topiramate, topiramate plasma and renal clearance were reduced 21%and 19%, respectively, in elderly subjects, compared to young adults. Similarly, topiramate half-life was longer (13%) in the elderly. Reduced topiramate clearance resulted in slightly higher maximum plasma concentration (23%) and AUC (25%) in elderly subjects than observed in young adults. Topiramate clearance is decreased in the elderly only to the extent that renal function is reduced. As recommended for all patients, dosage adjustment may be indicated in the elderly patient when impaired renal function (creatinine clearance rate ≤70mL/min/1.73 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 eva luated in patients ages 4 to 17 years receiving one or two other antiepileptic drugs. Pharmacokinetic profiles were obtained after one week at doses of 1, 3, and 9 mg/kg/day. Clearance was independent of dose.

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

CLINICAL STUDIES

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

Epilepsy

Monotherapy Controlled Trial

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

The trial was conducted in 487patients diagnosed with epilepsy (6 to 83 years of age) who had 1 or 2 well-documentedseizures during the 3-month retrospective baseline phase who then enteredthe study and received topiramate 25 mg/day for 7 days in an open-label fashion.Forty-nine percent of subjects had no prior AED treatment and 17% had a diagnosisof epilepsy for greater than 24 months. Any AED therapy used for temporaryor emergency purposes was discontinued prior to randomization. In the double-blindphase, 470 patients were randomized to titrate up to 50 mg/day or 400 mg/day.If the target dose could not be achieved, patients were maintained on themaximum tolerated dose. Fifty eight percent of patients achieved the maximaldose of 400 mg/day for ≥ 2 weeks, and patients who did not tolerate150 mg/day were discontinued. The primary efficacy assessment was a betweengroup comparison of time to first seizure during the double-blind phase. Comparisonof the Kaplan-Meier survival curves of time to first seizure favored the topiramate400 mg/day group over the topiramate 50 mg/day group (p=0.0002, log rank test; Figure 1). Thetreatment effects with respect to time to first seizure were consistent acrossvarious patient subgroups defined by age, sex, geographic region, baselinebody weight, baseline seizure type, time since diagnosis, and baseline AEDuse.

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

Adjunctive Therapy Controlled Trials in Patients With Partial Onset Seizures

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

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

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

Adjunctive Therapy Controlled Trialin Pediatric Patients Ages 2 to 16 Years With Partial Onset Seizures

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

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

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

Adjunctive Therapy Controlled Trialin Patients With Primary Generalized Tonic-Clonic Seizures

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

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

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

Adjunctive Therapy Controlled Trialin Patients With Lennox-Gastaut Syndrome

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

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

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

Tags： 责任编辑：admin
【大 中 小】【打印】 【繁体】【投稿】【收藏】 【推荐】【举报】【评论】 【关闭】 【返回顶部】
分享到:
上一篇：TOPIRAMATEtablet, film coated	下一篇：TOPIRAMATEtablet, film coated