pms-Topiramate

pms-Topiramate Mechanism of Action

topiramate

Manufacturer:

Pharmascience

Distributor:

T-BOMA
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Pharmacology: Pharmacodynamics: Topiramate is a novel agent classified as a sulfamate substituted monosaccharide. Three pharmacological properties of topiramate are believed to contribute to its anticonvulsant activity. First, topiramate reduces the frequency at which action potentials are generated when neurons are subjected to a sustained depolarization indicative of a state-dependent blockade of voltage-sensitive sodium channels. Second, topiramate markedly enhances the activity of GABA at some types of GABA receptors. Because the antiepileptic profile of topiramate differs markedly from that of the benzodiazepines, it may modulate a benzodiazepine-insensitive subtype of GABAA receptor. Third, topiramate antagonizes the ability of kainate to activate the kainate/AMPA subtype of excitatory amino acid (glutamate) receptors but has no apparent effect on the activity of N-methyl-D-aspartate (NMDA) at the NMDA receptor subtype.
In addition, topiramate inhibits some isoenzymes of carbonic anhydrase. This pharmacologic effect is much weaker than that of acetazolamide, a known carbonic anhydrase inhibitor, and is not thought to be a major component of topiramate's antiepileptic activity.
Clinical Trials: Comparative Bioavailability Studies: A single dose, randomized 2-way crossover study was conducted in 19 healthy male volunteers under fasting conditions with Pharmascience Inc., pms-TOPIRAMATE tablets (1 x 100 mg topiramate), vs. the reference product, TOPAMAX, Janssen-Ortho Inc., (1 x 100 mg topiramate). The results are summarized in the following table: See Table 1.

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A single dose, randomized 2-way crossover study was also conducted in 20 healthy male volunteers under fasting conditions with Pharmascience Inc., pms-TOPIRAMATE tablets (1 x 200 mg topiramate), vs. the reference product, TOPAMAX, Janssen-Ortho Inc., (1 x 200 mg topiramate). The results are summarized in the following table: See Table 2.

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Epilepsy: Monotherapy Controlled Trials: The effectiveness of topiramate as monotherapy in adults and children 6 years of age and older with newly diagnosed epilepsy was established in a multicentre, randomized, double-blind, parallel-group trial that compared the safety and efficacy of 2 doses of topiramate as monotherapy for the treatment of newly diagnosed or recurrent epilepsy.
The trial was conducted in 487 patients (6 to 83 years of age) who had a new diagnosis of epilepsy (partial onset or generalized) or a diagnosis of recurrent epilepsy while not taking AEDs. Patients who had either 1 or 2 well-documented seizures during the 3-month retrospective baseline phase entered the study and received topiramate 25 mg/day for 7 days in an open-label fashion. Any AED therapy used for temporary or emergency purposes was discontinued prior to randomization. Following that phase, patients were randomized to receive topiramate 50 mg/day or topiramate 400 mg/day. Patients remained in the double-blind phase until they experienced a first partial onset or generalized tonic-clonic seizure, until termination of the double-blind phase 6 months after randomization of the last subject, or until withdrawal for protocol-specified reasons. The primary efficacy assessment was based on the comparison between topiramate dose groups with respect to time to first partial onset or generalized tonic-clonic seizure during the double-blind phase. Comparison of the Kaplan-Meier survival curves of time to first seizure favoured topiramate 400 mg/day over topiramate 50 mg/day (p = 0.0002, log rank test). The separation between the groups in favour of the higher dose group occurred early in the titration phase and was statistically significant as early as 2 weeks post-randomization (p = 0.046), when, by following the weekly titration schedule, the subjects in the higher dose group had achieved a maximum topiramate dose of 100 mg/day. The higher dose group was also superior to the lower dose group with respect to the proportion of subjects who remained seizure-free, based on the Kaplan-Meier estimates, for a minimum of 6 months of therapy (82.9% vs. 71.4%; p = 0.005), and for a minimum of 1 year of therapy (75.7% vs. 58.8%; p = 0.001). The ratio of hazard rates for time to first seizure was 0.516 (95% confidence interval, 0.364 to 0.733). The treatment effects with respect to time to first seizure were consistent across various subject subgroups defined by age, sex, geographic region, baseline body weight, baseline seizure type, time since diagnosis, and baseline AED use.
Adjunctive Therapy Controlled Trials in Adults with Partial Onset Seizures: The effectiveness of topiramate as adjunctive therapy in adults with refractory partial onset seizures, with or without secondarily generalized seizures, was established in six multicentre, outpatient, randomized, double-blind, placebo-controlled trials. Patients in all six studies were permitted a maximum of two AEDs in addition to topiramate therapy (target doses of 200, 400, 600, 800, or 1,000 mg/day) or placebo.
In all six add-on trials, the primary efficacy measurement was reduction in seizure rate from baseline during the entire double-blind phase; responder rate (fraction of patients with at least a 50% reduction) was also measured. The median percent reductions in seizure rates and the responder rates by treatment group for each study are shown in Table 3. (See Table 3.)

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Across the six efficacy trials in adults, 232 of the 527 topiramate patients (44%) responded to treatment with at least a 50% seizure reduction during the double-blind phase; by comparison, only 25 of the 216 placebo-treated patients (12%) showed the same level of treatment response. When the treatment response was defined more rigorously as a 75% or greater decrease from baseline in seizure rate during double-blind treatment, 111 of the 527 topiramate patients (21%) in the 200 to 1,000 mg/day groups, but only 8 of the 216 placebo patients (4%), demonstrated this level of efficacy. In addition, 24 (5%) of the patients treated with topiramate became seizure-free, compared with 0% in the placebo group (p ≤ 0.01). At target dosages of 400 mg/day and higher, the percent of treatment responders was statistically greater for patients treated with topiramate than placebo-treated patients.
Pooled analyses of secondarily generalized seizure rates for all patients who had this seizure type during the studies show statistically significant percent reductions in the topiramate groups when compared with placebo. The median percent reduction in the rate of generalized seizures was 57% for patients treated with topiramate compared with -4% for placebo-treated patients. Among patients treated with topiramate, 109 (55%) of 198 had at least a 50% reduction in generalized seizure rate compared with 24 (27%) of 88 placebo-treated patients.
The dose titration in the original clinical trials was 100 mg/day the first week, 100 mg b.i.d. the second week, and 200 mg b.i.d. the third week. In a 12-week, double-blind trial, this titration rate was compared to a less rapid rate beginning at 50 mg/day.
There were significantly fewer adverse experiences leading to discontinuation and/or dosage adjustment in the group titrated at the less rapid rate. Seizure rate reductions were comparable between the groups at all time points measured.
Adjunctive Therapy Controlled Trials in Children with Partial Onset Seizures: The effectiveness of topiramate as an adjunctive treatment for children with partial onset seizures was established in a multicentre, 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 AEDs in addition to topiramate or placebo. Patients were stabilized on optimal dosages of their concomitant AEDs during an 8-week baseline phase. Included were patients who experienced at least six partial onset seizures, with or without secondarily generalized seizures, during the baseline phase.
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 to 150 mg/day increments every other week until the assigned dosage of 125, 175, 225 or 400 mg/day, based on patient's weight to approximate a dosage of 6 mg/kg per day, was reached. After titration, patients entered an 8-week stabilization period.
The reduction in seizure rate from baseline during the entire double-blind phase was measured. The median percent reduction in seizure rate and the responder rate (fraction of patients with at least a 50% reduction) were also measured and the key results are shown in Table 4. (See Table 4.)

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Forty patients received topiramate during the double-blind study and continued topiramate treatment in the open-label study. During the open-label study, dose escalation was permitted if required. The percent responders increased to 53% at a median average dose of 7.5 mg/kg/day.
Additional Adjunctive Therapy Clinical Data: Some data demonstrating efficacy of topiramate as adjunctive therapy in adults and a small number of pediatric patients for primary generalized tonic-clonic seizures and seizures associated with Lennox-Gastaut syndrome are available from randomized, double-blind, placebo-controlled trials.
In the epilepsy clinical trials in approximately 1,300 patients, daily dosages were decreased when required in weekly intervals by 50 to 100 mg 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: Controlled Trials in the Prophylactic Treatment of Migraine: The results of two multicentre, randomized, double-blind, placebo-controlled, parallel-group clinical trials established the effectiveness of topiramate in the prophylactic treatment of migraine headache. The design of both trials 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 a washout of any prior migraine preventive medications before starting the baseline phase.
Patients who experienced 3 to 12 migraine periods (each migraine period was defined as any occurrence of migraine headache that started and ended, or recurred within a 24-hour interval) over the 4 weeks in the baseline phase were equally randomized to either topiramate 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). Up to 2 dose adjustments were allowed after the second week of treatment during the double-blind phase if unacceptable tolerability problems occurred. When needed, rescue medications were allowed for the acute treatment of headache or migraine-associated symptoms.
Effectiveness of treatment was assessed through the reduction in migraine headache frequency, as measured by the change in 4-week migraine period rate from the baseline phase to double-blind treatment in each topiramate treatment group compared to placebo.
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 and 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 topiramate 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 topiramate 50, 100, and 200 mg/day groups, respectively, vs. -0.8 in the placebo group (see figure). The differences between the topiramate 100 and 200 mg/day groups vs. placebo were statistically significant (p < 0.001 for both comparisons; confidence intervals vs. placebo: topiramate 100 mg/day [-1.93, -0.55], and topiramate 200 mg/day [-2.04, -0.62]). The changes in migraine frequency represent a median percent reduction of 31%, 53%, and 55% in the topiramate 50, 100, and 200 mg/day groups, respectively, vs. 21% in the placebo group.
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 and 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 topiramate 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 topiramate 50, 100, and 200 mg/day groups, respectively, vs. -1.1 in the placebo group (see figure). The differences between the topiramate 100 and 200 mg/day groups vs. placebo were statistically significant (p = 0.008 and p < 0.001, respectively; confidence intervals vs. placebo: topiramate 100 mg/day [-1.76, -0.27], and topiramate 200 mg/day [-2.06, -0.57]). The changes in migraine frequency represent a median percent reduction of 35%, 49%, and 48% in the topiramate 50, 100, and 200 mg/day groups, respectively, vs. 19% in the placebo group.
In both studies, there were no apparent differences in treatment effect within age, gender or racial subgroups.
In the migraine prophylaxis clinical trials in approximately 900 patients, daily dosages were decreased when required in weekly intervals by 25 to 50 mg in adults receiving topiramate at doses up to 100 mg/day. (See figure.)

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Additional efficacy measures that were assessed, in both studies, included responder rate, cumulative response rate, change in average monthly migraine attack rate, change in the average monthly rate of rescue medication use, change in the average number of monthly migraine days and onset of action defined as the earliest month that there was a statistically significant difference between each topiramate treatment group and placebo with respect to the primary efficacy endpoint that was maintained for the remainder of the double-blind phase.
Detailed Pharmacology: Preclinical: In Vitro Studies: Electrophysiological and biochemical studies on cultured neurons have revealed three properties that may contribute to the antiepileptic efficacy of topiramate. Action potentials elicited repetitively by a sustained depolarization of the neurons were blocked by topiramate in a time-dependent manner, suggestive of a state-dependent sodium channel blocking action. Topiramate increased the frequency at which γ-aminobutyrate (GABA) activated GABAA receptors, and enhanced the ability of GABA to induce a flux of chloride ions into neurons, suggesting that topiramate potentiates the activity of this inhibitory neurotransmitter.
Because the antiepileptic profile of topiramate differs markedly from that of the benzodiazepines, it may modulate a benzodiazepine-insensitive subtype of GABAA receptor. Topiramate antagonized the ability of kainate to activate the kainate/AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) subtype of excitatory amino acid (glutamate) receptor, but had no apparent effect on the activity of N-methyl-D-aspartate (NMDA) at the NMDA receptor subtype. These effects of topiramate were concentration-dependent over a range of 1 mcM to 200 mcM, with minimum activity observed at 1 mcM to 10 mcM.
In addition, topiramate inhibits some isoenzymes of carbonic anhydrase. This pharmacologic effect is much weaker than that of acetazolamide, a known carbonic anhydrase inhibitor, and is not thought to be a major component of topiramate's antiepileptic activity.
In Vivo Studies: Pharmacodynamics: Topiramate was initially found to possess anticonvulsant activity in the maximal electroshock seizure (MES) test in mice. Subsequent studies revealed that topiramate was also highly effective in the MES test in rats. In both species, anticonvulsant activity was evident within 30 minutes after oral administration, reached a peak 1 to 6 hours after dosing, and gradually declined thereafter.
Topiramate's anticonvulsant activity in rodents was further evaluated using chemical convulsants (pentylenetetrazole, bicuculline, picrotoxin, strychnine) to induce clonic or tonic seizures. Topiramate was either weak or inactive in blocking chemically induced seizures. Topiramate was found to effectively block seizures in mouse and rat models of hereditary epilepsy, in some animal models of kindled epilepsy, and in a rat model of stroke-induced epilepsy. In the spontaneous epileptic rat (SER) model of hereditary epilepsy, topiramate blocked the clonic motor seizures and the absence-like seizures monitored by EEG recordings.
The potency of topiramate in blocking MES seizures is similar to that of phenytoin and carbamazepine, and much greater than that of valproate. The oral ED50 of topiramate at the time of peak activity was 20 to 50 mg/kg in mice and 5 to 15 mg/kg in rats.
Studies in mice receiving concomitant administration of topiramate and carbamazepine or phenobarbital showed synergistic anticonvulsant activity, while combination with phenytoin showed additive anticonvulsant activity.
An investigation of the possible development of tolerance to the anticonvulsant activity revealed no tolerance in rats dosed orally with topiramate for 14 days at twice the ED50 value. When mice were dosed orally for 5 days at four times the ED50 value, a small but significant degree of tolerance did occur.
Topiramate was examined for effects on central nervous system (CNS) function, particularly reflex activity and motor co-ordination. A quantitative measure of CNS impairment was obtained by calculating the dose required to cause a loss of righting reflex (LRR) in either 3% (TD3) or 50% (TD50) of mice tested, or the dose that caused 50% (TD50) of mice or rats to be unable to remain ambulatory on a rotating rod or reel. A protective index (PI) was obtained by calculating the ratio of the TD50 dose to the ED50 dose in the MES test (or the TD3 dose to the ED97 dose). The calculated PI values for topiramate compared favourably to those of the reference anticonvulsants phenytoin, carbamazepine, valproate (divalproex), and phenobarbital, particularly in rats. An evaluation of acute effects in dogs indicated that impairment of CNS function occurred only at doses several times the ED50 dose in the MES test in rats and mice.
Topiramate was evaluated for effects on general behaviour in mice, rats, and dogs at doses ranging from 10 to 1,000 mg/kg. Dose-related effects in mice and rats included a decrease in spontaneous motor activity, and a decrease in body tone and respiratory activity. In dogs, emesis occurred in one of three dogs at 100 mg/kg (p.o.), and at 500 mg/kg (p.o.) one of three dogs exhibited preconvulsant activity and one of three convulsed. Recovery was complete at six hours after dosing. When administered IV to rats at doses ranging from 1 mg/kg to 10 mg/kg, topiramate had no effect on EEG activity, cerebral pH, spinal reflexes, or neuromuscular conduction. In mice, topiramate at doses of 30 mg/kg (p.o.) or greater prolonged pentobarbital-induced sleep time threefold to eightfold in a dose-dependent manner. In rats pretreated with topiramate at 60 mg/kg or 200 mg/kg (p.o.) one hour prior to inducing sleep with ethanol, sleep time was prolonged 38% and 54%, respectively. When rats were pretreated with these doses of topiramate four hours prior to inducing sleep with ethanol, there was no prolongation of sleep time.
In cardiovascular studies, topiramate, when given IV to anesthetized dogs at doses up to 10 mg/kg, caused a small, dose-related increase in blood pressure, which was associated with a slight decrease in heart rate. There was no effect on electrocardiographic measures at these doses. Topiramate, when administered to spontaneously hypertensive rats at doses of 30 mg/kg i.p. and 100 mg/kg p.o. caused a biphasic response in mean arterial pressure; an initial transient increase was followed by a modest decrease in blood pressure that persisted for about 12 hours. Topiramate, at concentrations up to 10 mcM, elicited no biologically significant effects on coronary flow, contractile force, or flow rate in the isolated guinea pig heart.
In GI studies, topiramate at concentrations up to 100 mcM had no effect on basal or pentagastrin-stimulated gastric acid secretion in the isolated mouse stomach assay. Topiramate weakly inhibited gastric acid secretion in rats and dogs.
Topiramate and acetazolamide were examined for effects on renal function using rats anesthetized with pentobarbital. Both compounds were infused IV at 9 or 90 mcM/kg/h. At each dose, both compounds produced changes in renal function, including an increase in urinary flow rate, solute clearance and urinary pH. Also, a decrease in urinary osmolality and decreases in arterial blood pH and plasma bicarbonate concentration were observed. The effects of both dosage levels of topiramate were similar to, but less than, those of acetazolamide. Renal vascular resistance, heart rate, and glomerular filtration rate did not differ from pre-treatment control values.
Pharmacokinetics: Topiramate exhibits low inter-subject variability in plasma concentrations and therefore has predictable pharmacokinetics. The pharmacokinetics of topiramate are linear with plasma clearance remaining constant and area under the plasma concentration curve increasing in a dose-proportional manner over a 100 to 400 mg single oral dose range in healthy subjects. Patients with normal renal function may take four to eight days to reach steady-state plasma concentrations. The mean Cmax following multiple twice-a-day oral doses of 100 mg to healthy subjects was 6.76 mcg/mL. The mean plasma elimination half-lives from multiple 50 mg and 100 mg q12h doses of topiramate were approximately 21 hours. The elimination half-life did not significantly change when switching from single dose to multiple dose.
In well-controlled add-on trials, no correlation has been demonstrated between trough plasma concentrations and its clinical efficacy. It is not necessary to monitor topiramate plasma concentrations to optimize therapy with topiramate.
No evidence of tolerance requiring increased dosage has been demonstrated in patients during five years of use.
Concomitant multiple-dose administration of topiramate, 100 to 400 mg q12h, with phenytoin or carbamazepine shows dose-proportional increases in plasma concentrations of topiramate.
Absorption: Topiramate is rapidly and well-absorbed. Following oral administration of 100 mg topiramate to healthy subjects, a mean peak plasma concentration (Cmax) of 1.5 mcg/mL was achieved within two to three hours (Tmax). The mean extent of absorption from a 100 mg oral dose of 14C-topiramate was at least 81% based on the recovery of radioactivity from the urine.
There was no clinically significant effect of food on the bioavailability of topiramate.
Distribution: Approximately 13% to 17% of topiramate is bound to plasma proteins. A low capacity binding site for topiramate in/on erythrocytes that is saturable above plasma concentrations of 4 mcg/mL has been observed.
The volume of distribution varied inversely with the dose. The mean apparent volume of distribution was 0.80 to 0.55 L/kg for a single-dose range of 100 to 1,200 mg.
Metabolism: Topiramate is not extensively metabolized (≈20%) in healthy volunteers. It is metabolized up to 50% in patients receiving concomitant antiepileptic therapy with known inducers of drug-metabolizing enzymes. Six metabolites formed through hydroxylation, hydrolysis and glucuronidation have been isolated, characterized and identified from plasma, urine and feces of humans. Each metabolite represents less than 3% of the total radioactivity excreted following administration of 14C-topiramate.
Two metabolites which retained most of the structure of topiramate were tested and found to have little or no pharmacological activity.
Excretion: In humans, the major route of elimination of unchanged topiramate and its metabolites is via the kidney (at least 81% of the dose). Approximately 66% of a dose of 14C-topiramate was excreted unchanged in the urine within four days. The mean renal clearance for 50 mg and 100 mg of topiramate, following q12h dosing, was approximately 18 mL/min and 17 mL/min, respectively. Evidence exists for renal tubular reabsorption of topiramate. This is supported by studies in rats where topiramate was coadministered with probenecid, and a significant increase in renal clearance of topiramate was observed. This interaction has not been evaluated in humans. Overall, plasma clearance (CL/F) is approximately 20 to 30 mL/min in humans following oral administration.
Special Populations and Conditions: Pediatrics: Pharmacokinetics of topiramate were evaluated in patients aged 4 to 17 years receiving one or two other AEDs. Pharmacokinetic profiles were obtained after one week at doses of 1, 3, and 9 mg/kg/day. As in adults, topiramate pharmacokinetics were linear with clearance independent of dose and steady-state plasma concentrations increasing in proportion to dose. Compared with adult epileptic patients, mean topiramate clearance is approximately 50% higher in pediatric patients. Steady-state plasma topiramate concentrations for the same mg/kg dose are expected to be approximately 33% lower in children compared to adults. As with adults, hepatic enzyme-inducing AEDs decrease the plasma concentration of topiramate.
Geriatrics: Plasma clearance of topiramate is unchanged in elderly subjects in the absence of underlying renal disease.
Race, Gender and Age: Although direct comparison studies of pharmacokinetics have not been conducted, analysis of plasma concentration data from clinical efficacy trials has shown that race, gender and age appear to have no effect on the plasma clearance of topiramate. In addition, based on pooled analyses, race and gender appear to have no effect on the efficacy of topiramate.
Hepatic Insufficiency: The pharmacokinetics of a single 100 mg oral dose of topiramate were evaluated in subjects with moderate to severe hepatic impairment (n = 5) and in six healthy subjects in which five of the healthy subjects were demographically matched to the five hepatically impaired subjects. Plasma topiramate concentrations in the hepatically impaired group increased (Cmax 28.9% and AUC(0-∞) 29.2%) with respect to the healthy subjects, due to an approximate 26% decrease in topiramate oral plasma clearance. The decrease in topiramate oral plasma clearance (CL/F) was primarily due to a 49% decrease in renal clearance. The reason for this decrease in renal clearance in hepatically impaired subjects is not known. Therefore, pms-TOPIRAMATE should be administered with caution in patients with hepatic impairment (see Patients with Hepatic Disease under Dosage & Administration).
Renal Insufficiency: The pharmacokinetics of a single 100 mg oral dose of topiramate were evaluated in patients with moderate or severe renal impairment (seven patients per group) and were compared to seven demographically matched subjects with normal renal function. Compared to normal subjects, the overall oral plasma clearance (CL/F) of topiramate was reduced by 42% and 54% in patients with moderate and severe renal impairment, respectively. The respective renal clearance values decreased by 54% and 77%. As a result, mean plasma exposure (AUC) values in moderate and severe renal impairment increased by 1.9- and 2.2-fold, respectively. Overall, higher steady-state topiramate plasma AUC is expected for a given dose in renally impaired patients as compared to those with normal renal function. In addition, patients with renal impairment will require a longer time to reach steady-state at each dose. In patients with moderate and severe renal impairment, half of the usual starting and maintenance dose is recommended (see Patients with Renal Impairment under Dosage & Administration; Renal: Adjustment of Dose in Renal Failure under Precautions).
Hemodialysis: Topiramate is effectively removed from plasma by hemodialysis (see Patients Undergoing Hemodialysis under Dosage & Administration).
Detailed Pharmacology: Preclinical: In Vivo Studies: Pharmacokinetics: Studies performed in rats and dogs employing 14C-topiramate show that topiramate is rapidly and well-absorbed after oral administration and that unchanged topiramate is the major component in plasma for several hours after dosing. The absolute bioavailability of topiramate is approximately 100% in male and female rats.
Topiramate is poorly bound to plasma proteins (9% to 17%) in the mouse, rat, rabbit, dog and monkey, but there appears to be a low capacity erythrocyte binding site for the drug in all species studied. Studies in rats show that following oral administration of 14C-topiramate, total radioactivity does not accumulate in any tissue. Topiramate did distribute across the blood-brain barrier, with brain tissue concentrations of total radioactivity being about 40% of plasma concentrations 6 hours after a single oral dose.
The metabolism of topiramate has been investigated in mice, rats, rabbits and dogs. The metabolic pathways, primarily hydroxylation or hydrolysis of the isopropylidene groups and subsequent conjugation, were qualitatively similar in all species studied.
The major route of elimination of unchanged topiramate and its metabolites in all species studied is via the kidney. All species excreted a significant proportion of the dose in urine as intact topiramate; however, the proportion of metabolites excreted tended to be higher in species with shorter plasma half-lives.
Toxicology: In acute and long-term studies conducted in mice, rats, dogs and rabbits, exposure to topiramate was well-tolerated.
Acute Toxicity: See Table 5.

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Chronic Toxicity: See Table 6.

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Reproductive Toxicity: Topiramate has demonstrated selective developmental toxicity, including teratogenicity, in multiple animal species at clinically relevant doses. When oral doses of 20, 100, or 500 mg/kg were administered to pregnant mice during the period of organogenesis, the incidence of fetal malformations (primarily craniofacial defects) was increased at all doses. The low dose is approximately 0.2 times the recommended human dose (RHD) 400 mg/day on a mg/m2 basis. Fetal body weights and skeletal ossification were reduced at 500 mg/kg in conjunction with decreased maternal body weight gain.
In rat studies (oral doses of 20, 100, and 500 mg/kg or 0.2, 2.5, 30, and 400 mg/kg), the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased among the offspring of dams treated with 400 mg/kg (10 times the RHD on a mg/m2 basis) or greater during the organogenesis period of pregnancy. Embryotoxicity (reduced fetal body weights, increased incidence of structural variations) was observed at doses as low as 20 mg/kg (0.5 times the RHD on a mg/m2 basis). Clinical signs of maternal toxicity were seen at 400 mg/kg and above, and maternal body weight gain was reduced during treatment with 100 mg/kg or greater.
In rabbit studies (20, 60, and 180 mg/kg or 10, 35, and 120 mg/kg orally during organogenesis), embryo/fetal mortality was increased at 35 mg/kg (2 times the RHD on a mg/m2 basis) or greater, and teratogenic effects (primarily rib and vertebral malformations) were observed at 120 mg/kg (6 times the RHD on a mg/m2 basis). Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg and above.
When female rats were treated during the latter part of gestation and throughout lactation (0.2, 4, 20, and 100 mg/kg or 2, 20, and 200 mg/kg), offspring exhibited decreased viability and delayed physical development at 200 mg/kg (5 times the RHD on a mg/m2 basis) and reductions in pre- and/or post-weaning body weight gain at 2 mg/kg (0.05 times the RHD on a mg/m2 basis) and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg or greater.
In a rat embryo/fetal development study with a postnatal component (0.2, 2.5, 30, or 400 mg/kg during organogenesis; noted previously), pups exhibited delayed physical development at 400 mg/kg (10 times the RHD on a mg/m2 basis) and persistent reductions in body weight gain at 30 mg/kg (1 times the RHD on a mg/m2 basis) and higher.
Carcinogenicity: Tumours of smooth muscle origin in the urinary bladder were seen only in mice (oral dosages up to 300 mg/kg for 21 months) and appear to be unique to the species. Since no human counterpart exists, they were not considered clinically relevant. No such findings occurred in the rat carcinogenicity study (oral dosages up to 120 mg/kg/day for 24 months).
Mutagenicity: In a battery of in vitro and in vivo mutagenicity assays, topiramate did not show genotoxic potential.
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