Topamax

Topamax

topiramate

Manufacturer:

Janssen

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Topiramate.
Description
Each tablet contains the following excipients: Lactose monohydrate, pregelatinized starch, carnauba wax, magnesium stearate, microcrystalline cellulose, Opadry (white, yellow, pink), sodium starch glycollate.
Each sprinkle capsule contains the following excipients: Sprinkle Beads: Sugar spheres, povidone, cellulose acetate. Gelatin Capsules: Gelatin, titanium dioxide (for the white, opaque body), black pharmaceutical ink.
Topiramate is designated chemically as 2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate. Its empirical formula is C12H21NO8S and has a molecular weight of 339.36.
Topiramate is a white crystalline powder having a bitter taste. It is most soluble in alkaline solutions containing sodium hydroxide or sodium phosphate and having a pH of 9-10. 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.
Action
Pharmacology: Pharmacodynamics: Topiramate is classified as a sulfamate-substituted monosaccharide. The precise mechanism by which topiramate exerts its antiseizure and migraine prophylaxis effects are unknown. Electrophysiological and biochemical studies on cultured neurons have identified 3 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.
This effect was not blocked by flumazenil, a benzodiazepine antagonist, nor did topiramate increase the duration of the channel open time, differentiating topiramate from barbiturates that modulate GABAA receptors.
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 1-200 mcM, with minimum activity observed at 1-10 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 animal studies, topiramate exhibits anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests and is 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 ischaemia. Topiramate is only weakly effective in blocking clonic seizures induced by the GABAA receptor antagonist, pentylenetetrazole.
Studies in mice receiving concomitant administration of topiramate and carbamazepine or phenobarbital showed synergistic anticonvulsant activity, while combination with phenytoin showed additive anticonvulsant activity. In well-controlled add-on trials, no correlation has been demonstrated between trough and plasma concentrations of topiramate and its clinical efficacy. No evidence of tolerance has been demonstrated in man.
Epilepsy Clinical Trials: The results of controlled clinical trials established the efficacy of Topamax (topiramate) tablets and (topiramate capsules) sprinkle capsules as monotherapy for adults and children ages ≥6 with epilepsy, adjunctive therapy in adults and pediatric patients 2-16 years with partial onset seizures or primary generalized tonic-clonic seizures, and in patients ≥2 years with seizures associated with Lennox-Gastaut syndrome.
Monotherapy: The effectiveness of topiramate as monotherapy in adults and children ≥6 years with newly diagnosed epilepsy was established in 4 randomized, double-blind, parallel-group trials. Study EPMN-106 was conducted in 487 patients 6-83 years who had a new diagnosis of epilepsy (partial onset or generalized) or a diagnosis of recurrent epilepsy while not taking antiepileptic drugs (AEDs). Patients were randomized to receive topiramate 50 or 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 favored topiramate 400 mg/day over topiramate 50 mg/day (p=0.0002, log rank test). The separation between the groups in favor 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, 0.364-0.733). 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.
In study YI, a single center study, patients 15-63 years with refractory partial onset seizures (n=48) were converted from their existing treatment to Topamax 100 mg/day or 1000 mg/day as monotherapy. The high dose group was statistically superior to the low dose group for efficacy variables. Fifty four percent (54%) of high dose patients achieved monotherapy compared with 17% in the low dose group with the difference between the doses being statistically significant (p=0.005). The mean time to exit was significantly greater in the high dose group (p=0.002). The investigator and subject global evaluations of clinical response statistically favoured the high dose group (≤0.002).
In study EPMN-104, adult and paediatric patients 6-85 years with recently diagnosed epilepsy (n=252) were randomised into the low dose (25 or 50 mg/day) or the high dose group (200 or 500 mg/day) based on their body weight. Overall, 54% of high dose patients and 39% of low dose patients were reported to be seizure free during the double-blind phase (p=0.022). The high dose group was also superior to the low dose group with respect to seizure frequency distribution (p=0.008) and the difference in time to first seizure across 3 plasma topiramate concentration strata (p=0.015).
In study EPMN-105, patients 6-84 years with newly diagnosed epilepsy (n=613) were randomised to receive either 100 or 200 mg/day of Topamax or standard antiepileptic treatment (carbamazepine or valproate). Topamax was at least as efficacious as carbamazepine or valproate in reducing seizures in these patients. The 95% confidence intervals for the difference between the 2 treatment groups were narrow and included 0, indicating that there were no statistically significant between group difference. The 2 treatment groups were also comparable with respect to all clinical utility and efficacy endpoints including time to exit, proportion of seizure-free subjects and time to first seizure.
Patients (n=207; 32 were ≤16 years of age) who completed the double-blind phase of study YI and EPMN-104 were enrolled in long-term extension studies with the majority of patients receiving Topamax for 2-5 years. In these studies, sustained efficacy was demonstrated with long-term administration of Topamax as monotherapy. There was no significant change in dosage during the extension period and no indication that effectiveness of Topamax monotherapy diminished with continued exposure.
Adjunctive Therapy: Controlled Trials in Patients with Partial Onset Seizures: Adults: The effectiveness of topiramate as an adjunctive treatment for adults with partial onset seizures was established in 6 multicenter, randomized, double-blind, placebo-controlled trials, 2 comparing several dosages of topiramate and placebo and 4 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 2 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 5 of the 6 studies, patients received active drug beginning at 100 mg/day; the dose was then increased by 100 or 200 mg/day increments weekly or every other week until the assigned dose was reached, unless intolerance prevented increases. In the 6th 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 number of patients randomized to each dose, and the actual mean and median doses in the stabilization period are shown in Tables 2 and 3 under Adverse Reactions.
Pediatric Patients 2-16 years: The effectiveness of topiramate as an adjunctive treatment for pediatric patients 2-16 years with partial onset seizures was established in a multicenter, randomized, double-blind, placebo-controlled trial, comparing topiramate and placebo in patients with a history of partial onset seizures, with or without secondarily generalized seizures.
Patients in this study were permitted a maximum of 2 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 6 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 25-150 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.
Controlled Trials 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 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 2 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 3 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 4 weeks; the dose was then increased by 50-150 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.
Controlled Trial in Patients with Lennox-Gastaut Syndrome: The effectiveness of topiramate as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome was established in a multicenter, randomized, double-blind, placebo-controlled trial comparing a single dosage of topiramate with placebo in patients ≥2 years.
Patients in this study were permitted a maximum of 2 AEDs in addition to Topamax or placebo. Patients who were experiencing at least 60 seizures/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 1 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 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 in Table 1. As described previously, a global improvement in seizure severity was also assessed in the Lennox-Gastaut trial.

Click on icon to see table/diagram/image

Subset analyses of the antiepileptic efficacy of Topamax tablets in these studies showed no differences as a function of gender, race, age, baseline seizure rate or concomitant AED.
Migraine Clinical Trials: The clinical development program to evaluate the efficacy of Topamax in prophylaxis of migraine included 2 multicenter, randomized, double-blind, placebo-controlled, parallel group pivotal trials conducted in North America (MIGR-001 and MIGR-002). The primary efficacy endpoint was the reduction in migraine headache frequency, as measured by the change in 4-week migraine rate from the baseline phase to the double-blind treatment phase in each Topamax treatment group compared to placebo in the intent to treat (ITT) population.
The pooled results of the 2 pivotal trials evaluating Topamax doses of 50 (N=233), 100 (N=244) and 200 mg/day (N=228) found a median percent reduction in average monthly migraine period rate of 35%, 51% and 49% respectively, compared to 21% for the placebo group (N=229). The 100 and 200 mg/day of Topamax were statistically better than placebo. Notably, 27% of patients administered Topamax 100 mg/day achieved at least a 75% reduction in migraine frequency, while 52% achieved at least a 50% reduction.
An additional supportive study, MIGR-003, demonstrated that Topamax 100 mg/day was comparable in terms of efficacy to propranolol 160 mg/day. There was no statistically significant difference between the 2 groups in the primary efficacy endpoint.
Pharmacokinetics: The tablet and sprinkle formulations are bioequivalent.
The pharmacokinetic profile of topiramate compared to other antiepileptic drugs shows a long plasma half-life, linear pharmacokinetics, predominantly renal clearance, absence of significant protein-binding and lack of clinically relevant active metabolites.
Topiramate is not a potent inducer of drug metabolizing enzymes, can be administered without regard to meals, and routine monitoring of plasma topiramate concentrations is not necessary. In clinical studies, there was no consistent relationship between plasma concentrations and efficacy or adverse events.
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 2-3 hrs (Tmax). Based on the recovery of radioactivity from the urine, the mean extent of absorption of a 100-mg oral dose of 14C-topiramate was at least 81%. There was no clinically significant effect of food on the bioavailability of topiramate. Generally, 13-17% of topiramate is bound to plasma protein. 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 to varied inversely with the dose. The mean apparent volume of distribution was 0.8 to 0.55 L/kg for a single dose range of 100-1200 mg. An effect of gender on the volume of distribution was detected, with values for females circa 50% of those for males. This was attributed to the higher percent body fat in female patients and is of no clinical consequence.
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 faeces of humans. Each metabolite represents <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 anticonvulsant activity.
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 4 days. Following twice-a-day dosing with 50 and 100 mg of topiramate, the mean renal clearance was approximately 18 and 17 mL/min, respectively. There is evidence of renal tubular reabsorption of topiramate. This is supported by studies in rats where topiramate was co-administered with probenecid, and a significant increase in renal clearance of topiramate was observed. Overall, plasma clearance is approximately 20-30 mL/min in humans following oral administration.
Topiramate exhibits low intersubject 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 100-400 mg single oral dose range in healthy subjects. Patients with normal renal function may take 4-8 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. Following administration of multiple doses of 50 and 100 mg of topiramate twice a day, the mean plasma elimination half-life was approximately 21 hrs.
Concomitant multiple-dose administration of topiramate, 100-400 mg twice a day, with phenytoin or carbamazepine shows dose proportional increases in plasma concentrations of topiramate.
The plasma and renal clearance of topiramate are decreased in patients with impaired renal function (CrCl ≤60 mL/min), and the plasma clearance is decreased in patients with end-stage renal disease. As a result, higher steady-state topiramate plasma concentrations are expected for a given dose in renally-impaired patients as compared to those with normal renal function. Topiramate is effectively removed from plasma by haemodialysis.
Plasma clearance of topiramate is decreased in patients with moderate to severe hepatic impairment.
Plasma clearance of topiramate is unchanged in elderly subjects in the absence of underlying renal disease.
Pediatric Patients Up To 12 years: The pharmacokinetics of topiramate in children, as in adults receiving add-on therapy are linear, with clearance independent of dose and steady-state plasma concentrations increasing in proportion to dose. Children, however, have a higher clearance and a shorter elimination half-life. Consequently, the plasma concentrations of topiramate for the same mg/kg dose may be lower in children compared to adults. As in adults, hepatic enzyme inducing antiepileptic drugs decrease the steady-state plasma concentrations.
Toxicology: Preclinical Safety Data: Acute and long-term exposure of mice, rats, dogs and rabbits to topiramate was well tolerated. Hyperplasia of the gastric epithelial cells was observed only in rodents and in rats was reversible after 9 weeks without treatment.
Tumors 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). Other toxicologic and pathologic effects of topiramate observed in these studies may be related to the weak induction of drug-metabolizing enzymes or weak carbonic anhydrase inhibition.
Despite maternal and paternal toxicity as low as 8 mg/kg/day, no effects on fertility were observed in male or female rats with up to 100 mg/kg/day.
In preclinical studies, topiramate has been shown to have teratogenic effects in the species studied (mice, rats and rabbits). In mice, fetal weights and skeletal ossification were reduced at 500 mg/kg/day in conjunction with maternal toxicity. Overall numbers of fetal malformations in mice were increased for all drug-treated groups (20, 100 and 500 mg/kg/day), but no significant differences or dosage-response relationships were observed for overall or specific malformations, suggesting that other factors eg, maternal toxicity, may be involved.
In rats, dosage-related maternal and embryo/fetal toxicity (reduced fetal weights and/or skeletal ossification) were observed down to 20 mg/kg/day with teratogenic effects (limb and digit defects) at ≥400 mg/kg/day. In rabbits, dosage-related maternal toxicity was noted down to 10 mg/kg/day with embryo/fetal toxicity (increased lethality) down to 35 mg/kg/day and teratogenic effects (rib and vertebral malformations) at 120 mg/kg/day.
The teratogenic effects seen in rats and rabbits were similar to those seen with carbonic anhydrase inhibitors, which have not been associated with malformations in humans. Effects on growth were also indicated by lower weights at birth and during lactation for pups from female rats treated with 20 or 100 mg/kg/day during gestation and lactation. In rats, topiramate crosses the placental barrier.
In juvenile rats, daily oral administration of topiramate at doses up to 300 mg/kg/day during the period of development corresponding to infancy, childhood, and adolescence resulted in toxicities similar to those in adult animals (decreased food consumption with decreased body weight gain, centrolobullar hepatocellular hypertrophy and slight urothelial hyperplasia in the urinary bladder). There were no relevant effects on long bone (tibia) growth or bone (femur) mineral density, preweaning and reproductive development, neurological development (including assessments on memory and learning), mating and fertility or hysterotomy parameters.
In a battery of in vitro and in vivo mutagenicity assays, topiramate did not show genotoxic potential.
Indications/Uses
Monotherapy in patients with newly diagnosed epilepsy or for conversion to monotherapy in patients with epilepsy.
Adjunctive therapy for adults and children ≥2 years with partial onset seizures or generalized tonic-clonic seizures and treatment of seizures associated with Lennox Gastaut syndrome.
Prophylaxis of migraine headache in adult patients. The usefulness of Topamax in the acute treatment of migraine headache has not been studied.
Dosage/Direction for Use
It is recommended that therapy be initiated at a low dose followed by titration to an effective dose.
Topamax is available in tablets and a sprinkle capsule formulation. It is recommended that tablets not be broken. The sprinkle formulation is provided for those patients who cannot swallow tablets eg, pediatric and the elderly.
Topamax sprinkle capsules may be swallowed whole or may be administered by carefully opening the capsule and sprinkling the entire contents on a small amount (teaspoon) of soft food. This drug/food mixture should be swallowed immediately and not chewed. It should not be stored for future use.
It is not necessary to monitor topiramate plasma concentrations to optimize Topamax therapy. On rare occasions, the addition of Topamax to phenytoin may require an adjustment of the dose of phenytoin to achieve optimal clinical outcome. Addition or withdrawal of phenytoin and carbamazepine to adjunctive therapy with Topamax may require adjustment of the dose of Topamax.
Topamax can be taken without regard to meals.
Adjunctive Therapy Epilepsy: Adults: Therapy should begin at 25-50 mg nightly for 1 week. Use of lower initial doses has been reported, but has not been studied systematically. Subsequently, at weekly or bi-weekly intervals, the dose should be increased by 25-50 to 100 mg/day and taken in 2 divided doses. Dose titration should be guided by clinical outcome. Some patients may achieve efficacy with once-a-day dosing.
In clinical trials, as adjunctive therapy, 200 mg was effective and was the lowest dosage studied. This is therefore considered the minimum effective dose. The usual daily dose is 200-400 mg in 2 divided doses. Individual patients have received doses as high as 1600 mg/day.
Since Topamax is removed from plasma by haemodialysis, a supplemental dose of Topamax equal to approximately ½ of the daily dose should be administered on haemodialysis days. The supplemental dose should be administered in divided doses at the beginning and completion of the haemodialysis procedure. The supplemental dose may differ based on the characteristics of the dialysis equipment being used.
These dosing recommendations apply to adults, including the elderly, in the absence of underlying renal disease (see Precautions).
Children ≥2 years: The recommended total daily dose of Topamax as adjunctive therapy is approximately 5-9 mg/kg/day in 2 divided doses. Titration should begin at 25 mg (or less, based on a range of 1-3 mg/kg/day) nightly for the 1st week. The dosage should then be increased at 1- or 2-week intervals by increments of 1-3 mg/kg/day (administered in 2 divided doses) to achieve optimal clinical response. Dose titration should be guided by clinical outcome.
Daily doses up to 30 mg/kg/day have been studied and were generally well tolerated.
Monotherapy Epilepsy: When concomitant AEDs are withdrawn to achieve monotherapy with topiramate, consideration should be given to the effects this may have on seizure control. Unless safety concerns require an abrupt withdrawal of the concomitant AED, a gradual discontinuation at the rate of approximately 1/3 of the concomitant AED dose every 2 weeks is recommended.
When enzyme-inducing drugs are withdrawn, topiramate levels will increase. A decrease in Topamax dosage may be required if clinically indicated.
Adults: Titration should begin at 25 mg nightly for 1 week. The dosage should then be increased at 1- or 2-week intervals by increments of 25 or 50 mg/day, administered in 2 divided doses. If the patient is unable to tolerate the titration regimen, smaller increments or longer intervals between increments can be used. Dose and titration rate should be guided by clinical outcome.
The recommended initial target dose for topiramate monotherapy in adults is 100 mg/day and the maximum recommended daily dose is 500 mg. Some patients with refractory forms of epilepsy have tolerated topiramate monotherapy at doses of 1000 mg/day. These dosing recommendations apply to all adults including the elderly in the absence of underlying renal disease.
Children: Treatment of children ≥2 years should begin at 0.5-1 mg/kg nightly for the 1st week. The dosage should then be increased at 1- or 2-week intervals by increments of 0.5-1 mg/kg/day, administered in 2 divided doses. If the child is unable to tolerate the titration regimen, smaller increments or longer intervals between dose increments can be used. Dose and dose titration rate should be guided by clinical outcome.
The recommended initial target dose range for topiramate monotherapy in children ≥2 years is 3-6 mg/kg/day. Children with recently diagnosed partial onset seizures have received doses of up to 500 mg/day.
Migraine: The recommended total daily dose of topiramate for prophylaxis of migraine headache is 100 mg/day administered in 2 divided doses. Titration should begin at 25 mg nightly for 1 week. The dosage should then be increased in increments of 25 mg/day administered at 1-week intervals. If the patient is unable to tolerate the titration regimen, longer intervals between dose adjustments can be used.
Some patients may experience a benefit at a total daily dose of 50 mg/day. Patients have received a total daily dose up to 200 mg/day. Dose and titration rate should be guided by clinical outcome (see Actions).
Overdosage
Symptoms: Overdoses of topiramate have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbances, blurred vision, diplopia, impaired mentation, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness and depression. The clinical consequences were not severe in most cases, but deaths have been reported after polydrug overdoses involving topiramate.
Topiramate overdose can result in severe metabolic acidosis (see Precautions).
The highest topiramate overdose reported was calculated to be between 96 and 110 g and resulted in coma lasting 20-24 hrs followed by full recovery after 3-4 days.
Treatment: In acute topiramate overdose, if the ingestion is recent, the stomach should be emptied immediately by lavage or by induction of emesis. Activated charcoal has been shown to adsorb topiramate in vitro. Treatment should be appropriately supportive. Hemodialysis has been shown to be an effective means of removing topiramate from the body. The patient should be well hydrated.
Contraindications
Hypersensitivity to any component of Topamax.
Special Precautions
In patients with or without a history of seizures or epilepsy, antiepileptic drugs, including Topamax, should be withdrawn gradually to minimize the potential for seizures or increased seizure frequency. In clinical trials, daily dosages were decreased in weekly intervals by 50-100 mg in adults with epilepsy and by 25-50 mg in adults receiving Topamax at doses up to 100 mg/day for migraine prophylaxis. In clinical trials of children, Topamax was gradually withdrawn over a 2-8 week period. In situations where rapid withdrawal of Topamax is medically required, appropriate monitoring is recommended.
The major route of elimination of unchanged topiramate and its metabolites is via the kidney. Renal elimination is dependent on renal function and is independent of age. Patients with moderate or severe renal impairment may take 10-15 days to reach steady-state plasma concentrations as compared to 4-8 days in patients with normal renal function.
As with all patients, the titration schedule should be guided by clinical outcome (ie, seizure control, avoidance of side effects) with the knowledge that subjects with known renal impairment may require a longer time to reach steady state at each dose.
Adequate hydration while using topiramate is very important. Hydration can reduce the risk of nephrolithiasis. Proper hydration prior to and during activities eg, exercise or exposure to warm temperatures may reduce the risk of heat-related adverse events (see Adverse Reactions).
Mood Disturbances/Depression: An increased incidence of mood disturbances and depression has been observed during topiramate treatment.
Suicide/Suicidal Ideation: AEDs, including Topamax, increased the risk of suicidal thoughts or behaviour in patients taking these drugs for any indication. A meta-analysis of randomised placebo-controlled trials of antiepileptic drugs has shown an increased risk of suicidal ideation and behaviour (0.43% on antiepileptic drugs vs 0.24% on placebo). The mechanism of this risk is not known.
In double-blind clinical trials, suicide-related events (suicidal ideation, suicide attempts and suicide) occurred at a frequency of 0.5% in topiramate-treated patients (46 out of 8652 patients treated) compared to 0.2% treated with placebo (8 out of 4045 patients treated). One completed suicide was reported in a bipolar disorder double-blind trial in a patient on topiramate.
Therefore, patients should be monitored for signs of suicidal ideation and behaviour and appropriate treatment should be considered. Patients (and, when appropriate, caregivers of patients) should be advised to seek immediate medical advice should signs of suicidal ideation or behaviour emerge.
Nephrolithiasis: Some patients, especially those with a predisposition to nephrolithiasis, may be at increased risk for renal stone formation and associated signs and symptoms eg, renal colic, renal pain or flank pain.
Risk factors for nephrolithiasis include prior stone formation, a family history of nephrolithiasis and hypercalciuria. None of these risk factors can reliably predict stone formation during topiramate treatment. In addition, patients taking other medication associated with nephrolithiasis may be at an increased risk.
Decreased Hepatic Function: In hepatically-impaired patients, topiramate should be administered with caution as the clearance of topiramate may be decreased.
Acute Myopia and Secondary Angle Closure Glaucoma: A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving Topamax. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shalowing, ocular hyperemia (redness) and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating Topamax therapy. In contrast to primary narrow angle glaucoma, which is rare in patients <40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. Treatment includes discontinuation of Topamax, as rapidly as possible in the judgment of the treating physician, and appropriate measures to reduce intraocular pressure. These measures generally result in a decrease in intraocular pressure.
Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent loss of vision.
Metabolic Acidosis: Hyperchloremic, non-anion gap, metabolic acidosis (ie, decreased serum bicarbonate below the normal reference range in the absence of respiratory alkalosis) is associated with topiramate treatment. This decrease in serum bicarbonate is due to the inhibitory effect of topiramate on renal carbonic anhydrase. Generally, the decrease in bicarbonate occurs early in the treatment although it can occur at any time during treatment. These decreases are usually mild to moderate (average decrease of 4 mmol/L at doses of ≥100 mg/day) in adults and at approximately 6 mg/kg/day in pediatric patients. Rarely, patients have experienced decreases to values <10 mmol/L. Conditions or therapies that predispose to acidosis (eg, renal disease, severe respiratory disorders, status epilepticus, diarrhea, surgery, ketogenic diet or certain drugs) may be additive to the bicarbonate lowering effects of topiramate.
Chronic metabolic acidosis in pediatric patients can reduce growth rates. The effect of topiramate on growth and bone-related sequelae has not been systematically investigated in pediatric or adult populations.
Depending on underlying conditions, appropriate evaluation including serum bicarbonate levels is recommended with topiramate therapy. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering).
Nutritional Supplementation: A dietary supplement or increased food intake may be considered if the patient is losing weight while on this medication.
Effects on the Ability to Drive or Operate Machinery: Topamax acts on the central nervous system and may produce drowsiness, dizziness or other related symptoms. It may also cause visual disturbances and/or blurred vision. These adverse events could potentially be dangerous in patients driving a vehicle or operating machinery, particularly until such time as the individual patient's experience with Topamax is established.
Use in pregnancy: Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology under Actions). In rats, topiramate crosses the placental barrier.
There are no adequate and well-controlled studies using Topamax in pregnant women.
Pregnancy registry data suggest that there may be an association between the use of Topamax during pregnancy and congenital malformations (eg, craniofacial defects eg, cleft lip/palate, hypospadias, and anomalies involving various body systems). This has been reported with topiramate monotherapy and topiramate as part of a polytherapy regimen.
In addition, data from these registries and other studies suggest that, compared with monotherapy, there may be an increased risk of teratogenic effects associated with the use of antiepileptic drugs in combination therapy.
Topamax should be used during pregnancy only if potential benefit justifies the potential risk to the fetus. In treating and counseling women of childbearing potential, the prescribing physician should weigh the benefits of therapy against the risks. If Topamax is used during pregnancy or if the patient becomes pregnant while taking Topamax, the patient should be apprised of the potential hazard to the fetus.
Topiramate is excreted in the milk of lactating rats. The excretion of topiramate in human milk has not been evaluated in controlled studies. Limited observations in patients suggest an extensive excretion of topiramate into breast milk. Since many drugs are excreted in human milk, a decision should be made whether to discontinue nursing or to discontinue Topamax taking into account the importance of the drug to the mother.
Use In Pregnancy & Lactation
Use in pregnancy: Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology under Actions). In rats, topiramate crosses the placental barrier.
There are no adequate and well-controlled studies using Topamax in pregnant women.
Pregnancy registry data suggest that there may be an association between the use of Topamax during pregnancy and congenital malformations (eg, craniofacial defects eg, cleft lip/palate, hypospadias, and anomalies involving various body systems). This has been reported with topiramate monotherapy and topiramate as part of a polytherapy regimen.
In addition, data from these registries and other studies suggest that, compared with monotherapy, there may be an increased risk of teratogenic effects associated with the use of antiepileptic drugs in combination therapy.
Topamax should be used during pregnancy only if potential benefit justifies the potential risk to the fetus. In treating and counseling women of childbearing potential, the prescribing physician should weigh the benefits of therapy against the risks. If Topamax is used during pregnancy or if the patient becomes pregnant while taking Topamax, the patient should be apprised of the potential hazard to the fetus.
Topiramate is excreted in the milk of lactating rats. The excretion of topiramate in human milk has not been evaluated in controlled studies. Limited observations in patients suggest an extensive excretion of topiramate into breast milk. Since many drugs are excreted in human milk, a decision should be made whether to discontinue nursing or to discontinue Topamax taking into account the importance of the drug to the mother.
Adverse Reactions
Clinical Trial Data: The safety of Topamax was evaluated from a clinical trial database consisting of 4111 patients (3182 on Topamax and 929 on placebo) who participated in 20 double-blind trials and 2847 patients who participated in 34 open-label trials, respectively, for the treatment of primary generalized tonic-clonic seizures, partial onset seizures, seizures associated with Lennox-Gastaut syndrome, newly or recently diagnosed epilepsy or migraine. The information presented in this section was derived from pooled data.
The majority of all adverse reactions were mild to moderate in severity.
Double-Blind, Placebo-Controlled Data, Adjunctive Epilepsy Trials in Adult Patients: Adverse drug reactions (ADRs) reported in ≥1% of Topamax-treated adult patients in double-blind, placebo-controlled adjunctive epilepsy trials are shown in Table 2. ADRs that had an incidence >5% in the recommended dose range (200-400 mg/day) in adults in double-blind, placebo-controlled, adjunctive epilepsy studies in descending order of frequency included somnolence, dizziness, fatigue, irritability, decreased weight, bradyphrenia, paresthesias, diplopia, abnormal coordination, nausea, nystagmus, lethargy, anorexia, dysarthria, blurred vision, decreased appetite, memory impairment and diarrhoea.

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The recommended dose for adjunctive epilepsy therapy in adults is 200-400 mg daily.
Double-Blind, Placebo-Controlled Data, Adjunctive Epilepsy Trials in Pediatric Patients: ADRs reported in >2% of Topamax-treated pediatric patients 2-16 years in double-blind, placebo-controlled adjunctive epilepsy trials are shown in Table 3. ADRs that had an incidence >5% in the recommended dose range (5-9 mg/kg/day) in descending order of frequency included decreased appetite, fatigue, somnolence, lethargy, irritability, disturbance in attention, decreased weight, aggression, rash, abnormal behavior, anorexia, balance disorder and constipation.

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The recommended dose for adjunctive epilepsy therapy in children (2-16 years of age) is 5-9 mg/kg/day.
Double-Blind, Controlled Data, Monotherapy Epilepsy Trials in Adult Patients: ADRs reported in ≥1% of Topamax-treated adult patients in double-blind, controlled monotherapy epilepsy trials are shown in Table 4. ADRs that had an incidence >5% at the recommended dose (400 mg/day) in descending order of frequency included paraesthesia, decreased weight, fatigue, anorexia, depression, memory impairment, anxiety, diarrhea, asthenia, dysgeusia and hypoesthesia.

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The recommended dose for monotherapy therapy in adults is 400 mg daily.
Double-Blind, Controlled Data, Monotherapy Epilepsy Trials in Pediatric Patients: ADRs reported in ≥2% of Topamax-treated pediatric patients 10-16 years in double-blind, controlled monotherapy epilepsy trials are shown in Table 5. ADRs that had an incidence >5% at the recommended dose (400 mg/day) in descending order of frequency included decreased weight, paraesthesia, diarrhoea, disturbance in attention, pyrexia and alopecia.

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The recommended dose for monotherapy therapy in children ≥10 years is 400 mg daily.
Double-Blind, Placebo-Controlled Data, Migraine Prophylaxis Trials in Adult Patients: ADRs reported in ≥1% of Topamax-treated adult patients in double-blind, placebo-controlled migraine prophylaxis trials are shown in Table 6. ADRs that had an incidence >5% at the recommended dose (100 mg/day) in descending order of frequency included paraesthesia, fatigue, nausea, diarrhoea, decreased weight, dysgeusia, anorexia, decreased appetite, insomnia, hypoesthesia, disturbance in attention, anxiety, somnolence and expressive language disorder.

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The recommended dose for migraine prophylaxis is 100 mg daily.
Other Clinical Trial Data: ADRs reported in double-blind controlled clinical trials in <1% of Topamax-treated adult patients or at any rate in open-label clinical trials of Topamax-treated adult patients are as follows: Blood and Lymphatic System Disorders: Leukopenia, lymphadenopathy, thrombocytopenia.
Immune System Disorders: Hypersensitivity.
Metabolism and Nutrition Disorders: Hyperchloraemic acidosis, hypokalaemia, increased appetite, metabolic acidosis, polydipsia.
Psychiatric Disorders: Abnormal behaviour, anorgasmia, apathy, crying, distractibility, disturbance in sexual arousal, dysphemia, early morning awakening, elevated mood, euphoric mood, flat affect, hallucination, auditory and visual hallucination, hallucination-visual, hypomania, initial insomnia, lack of spontaneous speech, decreased libido, listless, loss of libido, mania, middle insomnia, decreased orgasmic sensation, panic attack, panic disorder, panic reaction, paranoia, perseveration, reading disorder, restlessness, sleep disorder, suicidal ideation, suicide attempt, tearfulness, abnormal thinking.
Nervous System Disorders: Ageusia, akinesia, anosmia, aphasia, apraxia, aura, burning sensation, cerebellar syndrome, circadian rhythm sleep disorder, clumsiness, complex partial seizure convulsion, depressed level of consciousness, postural dizziness, drooling, dysaesthesia, dysgraphia, dyskinesia, dysphasia, dystonia, essential tremor, formication, grand mal convulsion, hyperaesthesia, hypersomnia, hypogeusia, hypokinesia, hyposmia, peripheral neuropathy, parosmia, poor sleep quality, presyncope, repetitive speech, sensory disturbance, sensory loss, stupor, syncope, unresponsive to stimuli.
Eye Disorders: Accommodation disorder, altered visual depth perception, amblyopia, blepharospasm, transient blindness, unilateral blindness, glaucoma, increased lacrimation, mydriasis, night blindness, photopsia, presbyopia, scintillating scotoma, scotoma, reduced visual acuity.
Ear and Labyrinth Disorders: Deafness, neurosensory and unilateral deafness, ear discomfort, impaired hearing.
Cardiac Disorders: Bradycardia, sinus bradycardia, palpitations.
Vascular Disorders: Flushing, hot flush, orthostatic hypotension, Raynaud's phenomenon.
Respiratory, Thoracic and Mediastinal Disorders: Dysphonia, exertional dyspnoea, nasal congestion, paranasal sinus hypersecretion.
Gastrointestinal Disorders: Abdominal discomfort, lower abdominal pain, abdominal tenderness, breath odour, epigastric discomfort, flatulence, glossodynia, oral hypoaesthesia, oral pain, pancreatitis, salivary hypersecretion.
Skin and Subcutaneous Tissue Disorders: Anhidrosis, allergic dermatitis, erythema, macular rash, skin discolouration, abnormal skin odour, swelling face, urticaria, localised urticaria.
Musculoskeletal and Connective Tissue Disorders: Flank pain, muscle fatigue, muscular weakness, musculoskeletal stiffness.
Renal and Urinary Disorders: Ureteric calculus, urinary calculus, haematuria, incontinence, micturition urgency, renal colic, renal pain, urinary incontinence.
Reproductive System and Breast Disorders: Sexual dysfunction.
General Disorders: Calcinosis, face oedema, feeling abnormal, feeling drunk, feeling jittery, malaise, peripheral coldness, sluggishness.
Investigations: Decreased blood bicarbonate, presence of crystal urine, abnormal tandem gait test, decreased white blood cell count.
Adverse Drug Reactions reported in double-blind controlled clinical trials in <2% of Topamax-treated pediatric patients or at any rate in open-label clinical trials of Topamax-treated pediatric patients are as follows: Blood and Lymphatic System Disorders: Eosinophilia, leukopenia, lymphadenopathy, thrombocytopenia.
Immune System Disorders: Hypersensitivity.
Metabolism and Nutrition Disorders: Hyperchloraemic disorders, hypokalaemia, increased appetite.
Psychiatric Disorders: Anger, apathy, crying, distractibility, expressive language disorder, initial insomnia, insomnia, middle insomnia, mood swings, perseveration, sleep disorder, suicidal ideation, suicide attempt.
Nervous System Disorders: Circadian rhythm sleep disorder, convulsion, dysarthria, dysgeusia, grand mal convulsion, hypoaesthesia, mental impairment, nystagmus, parosmia, poor sleep quality, psychomotor hyperactivity, impaired psychomotor skills, syncope, tremor.
Eye Disorders: Diplopia, increased lacrimation, blurred vision.
Ear and Labyrinth Disorders: Ear pain.
Cardiac Disorders: Palpitations, sinus bradycardia.
Vascular Disorders: Orthostatic hypotension.
Respiratory, Thoracic and Mediastinal Disorders: Nasal congestion, paranasal sinus hypersecretion, rhinorrhoea.
Gastrointestinal Disorders: Abdominal discomfort, abdominal pain, dry mouth, flatulence, gastritis, gastroesophageal reflux disease, gingival bleeding, glossodynia, pancreatitis, oral paraesthesia, stomach discomfort.
Musculoskeletal and Connective Tissue Disorders: Arthralgia, musculoskeletal stiffness, myalgia.
Renal and Urinary Disorders: Incontinence, micturition urgency, pollakiuria.
General Disorders: Feeling abnormal, hyperthermia, malaise, sluggishness.
Post-Marketing Data: Adverse events first identified as ADRs during post-marketing experience with Topamax are listed as follows. The frequencies are provided according to the following convention: Very common: ≥1/10; common: ≥1/100 to <1/10; uncommon: ≥1/1000 to <1/100; rare: ≥1/10,000 to <1/1000; very rare: <1/10,000, including isolated reports.
Adverse Drug Reactions are presented by frequency category based on incidence in clinical trials, when known.
Infections and Infestations: Very Common: Nasopharyngitis*.
Blood and Lymphatic System Disorders: Rare: Neutropenia.
Immune System Disorders: Unknown: Allergic oedema, conjunctival oedema.
Psychiatric Disorders: Rare: Feeling of despair.
Eye Disorders: Rare: Abnormal sensation in the eye, eyelid oedema, myopia. Unknown: Angle closure glaucoma, eye movement disorder, maculopathy.
Skin and Subcutaneous Tissue Disorders: Rare: Erythema multiforme, periorbital oedema, Stevens-Johnson syndrome. Unknown: Toxic epidermal necrolysis.
Musculoskeletal and Connective Tissue Disorders: Uncommon: Joint swelling. Rare: Limb discomfort.
Renal and Urinary Disorders: Rare: Renal tubular acidosis.
General Disorders and Administration Site Conditions: Uncommon: Influenza-like illness. Unknown: Generalised oedema.
Investigations: Common: Increased weight.
*Nasopharyngitis in the clinical trial database was attributed to infectious or other causes, and was deemed a non-ADR. Note: The frequency of these events in the post-marketing database was very rare.
Drug Interactions
Effects of Topamax on Other Antiepileptic Drugs: The addition of Topamax to other antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, primidone) has no effect on their steady-state plasma concentrations, except in the occasional patient, where the addition of Topamax to phenytoin may result in an increase of plasma concentrations of phenytoin. This is possibly due to inhibition of a specific enzyme polymorphic isoform (CYP2C19). Consequently, any patient on phenytoin showing clinical signs or symptoms of toxicity should have phenytoin levels monitored.
A pharmacokinetic interaction study of patients with epilepsy indicated the addition of topiramate to lamotrigine had no effect on steady-state plasma concentration of lamotrigine at topiramate doses of 100-400 mg/day. In addition, there was no change in steady-state plasma concentration during or after removal of lamotrigine treatment (mean dose of 327 mg/day).
Effects of Other Antiepileptic Drugs on Topamax: Phenytoin and carbamazepine decrease the plasma concentration of Topamax. The addition or withdrawal of phenytoin or carbamazepine to Topamax therapy may require an adjustment in dosage of the latter. This should be done by titrating to clinical effect. The addition or withdrawal of valproic acid does not produce clinically significant changes in plasma concentrations of Topamax and, therefore, does not warrant dosage adjustment of Topamax.
The results of these interactions are summarized in Table 7.

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Other Drug Interactions: Digoxin: In a single-dose study, serum digoxin area under plasma concentration curve (AUC) decreased 12% due to concomitant administration of Topamax. The clinical relevance of this observation has not been established. When Topamax is added or withdrawn in patients on digoxin therapy, careful attention should be given to the routine monitoring of serum digoxin.
CNS Depressants: Concomitant administration of Topamax and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. It is recommended that Topamax not be used concomitantly with alcohol or other CNS depressant drugs.
Oral Contraceptives: In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptives containing norethindrone (NET) 1 mg plus ethinyl estradiol (EE) 35 mcg, Topamax given in the absence of other medications at doses of 50-200 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 (50-800 mg/day) did not significantly affect exposure to NET. Although there was a dose-dependent decrease in EE exposure for doses between 200-800 mg/day, there was no significant dose-dependent change in EE exposure for doses of 50-200 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 contraceptives 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.
Lithium: In healthy volunteers, there was an observed reduction (18% for AUC) in systemic exposure for lithium during concomitant administration with topiramate 200 mg/day. In patients with bipolar disorder, 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 (26% for AUC) following topiramate doses of up to 600 mg/day. Lithium levels should be monitored when co-administered with topiramate.
Risperidone: Drug-drug interaction studies conducted under single and multiple dose conditions in healthy volunteers and patients with bipolar disorder yielded similar results. When administered concomitantly with topiramate at escalating doses of 100, 250 and 400 mg/day, there was a reduction in risperidone (administered at doses ranging from 1-6 mg/day) systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg/day doses, respectively). Minimal alterations in the pharmacokinetics of the total active moiety (risperidone plus 9-hydroxyrisperidone) and no alterations for 9-hydroxyrisperidone were observed. There were no clinically significant changes in the systemic exposure of the risperidone total active moiety or of topiramate, therefore this interaction is not likely to be of clinical significance.
Hydrochlorothiazide (HCTZ): A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of HCTZ (25 mg every 24 hrs) and topiramate (96 mg every 12 hrs) 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: A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin and topiramate in plasma when metformin was given alone and when metformin and topiramate were given simultaneously. The results of this study indicated that metformin mean Cmax and mean AUC0-12 hrs increased by 18% and 25%, respectively, while mean CL/F decreased 20% when metformin was co-administered with topiramate. Topiramate did not affect metformin tmax. The clinical significance of the effect of topiramate on metformin pharmacokinetics is unclear. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The extent of change in the clearance is unknown. The clinical significance of the effect of metformin on topiramate pharmacokinetics is unclear. When Topamax is added or withdrawn in patients on metformin therapy, careful attention should be given to the routine monitoring for adequate control of their diabetic disease state.
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 AUCss 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 AUCss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in Cmax,ss and AUCss 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 25% reduction in glyburide AUC24 during topiramate administration. Systemic exposure of the active metabolites, 4-trans-hydroxy-glyburide (M1) and 3-cis-hydroxyglyburide (M2), were also reduced by 13% and 15%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide. When topiramate is added to glyburide therapy or glyburide is added to topiramate therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.
Others: Agents Predisposing to Nephrolithiasis: Topamax when used concomitantly with other agents predisposing to nephrolithiasis, may increase the risk of nephrolithiasis. While using Topamax, agents like these should be avoided since they may create a physiological environment that increases the risk of renal stone formation.
Valproic Acid: Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse event is not due to a pharmacokinetic interaction. An association of hyperammonemia with topiramate monotherapy or concomitant treatment with other antiepileptics has not been established.
Additional Pharmacokinetic Drug Interaction Studies: Clinical studies have been conducted to assess the potential pharmacokinetic drug interaction between topiramate and other agents. The changes in Cmax or AUC as a result of the interactions are summarized in Table 8. The 2nd column (concomitant drug concentration) describes what happens to the concentration of the concomitant drug listed in the 1st column when topiramate is added. The 3rd column (topiramate concentration) describes how the co-administration of a drug listed in the 1st column modifies the concentration of topiramate.

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Incompatibilities: None known.
Storage
Tablet: Store in a dry place at or below 30°C.
Sprinkle Capsule: Store at or below 25°C. Protect from moisture.
ATC Classification
N03AX11 - topiramate ; Belongs to the class of other antiepileptics.
Presentation/Packing
Tab 25 mg (embossed, round, coated, white, imprinted 'TOP' on one side, '25' on the other) x 60's. 50 mg (embossed, round, coated, light yellow, imprinted 'TOP' on one side, '50' on the other) x 60's. 100 mg (embossed, round, coated, yellow, imprinted 'TOP' on one side, '100 on the other) x 60's. Sprinkle cap 15 mg (small, white to off-white spheres in gelatin cap, white body with clear cap, printed with black ink, 'TOP' on the cap and '15 mg' on the body) x 60's. 25 mg (small, white to off-white spheres gelatin cap, white body with clear cap, printed with black ink, 'TOP' on the cap and '25 mg' on the body) x 60's.
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