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topiramate 25 mg tablet generic topamax

Out of Stock Manufacturer CIPLA USA, INC. 69097012212
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Uses

Seizure Disorders

Topiramate is used as initial monotherapy or as adjunctive therapy in the management of seizure disorders. Efficacy of the drug in the management of seizure disorders was evaluated using topiramate immediate-release tablets.

Initial Monotherapy

Partial Seizures or Primary Generalized Tonic-Clonic Seizures

Topiramate is used as initial monotherapy in the management of partial seizures or primary generalized tonic-clonic seizures in adults and pediatric patients 2 years of age and older. Safety and efficacy of topiramate monotherapy in patients who previously received a regimen of other anticonvulsant agents have not been established in controlled trials.

Safety and efficacy of topiramate as initial monotherapy were established in a randomized, double-blind study in 487 patients (age range: 6-83 years) with epilepsy who had 1 or 2 well-documented seizures within 3 months prior to enrollment and were not receiving anticonvulsant therapy at the time of randomization. Of those enrolled, 49% had no prior treatment with anticonvulsant drugs. During the initial open-label phase, any anticonvulsant being used for temporary or emergency purposes was withdrawn before the patients were randomized. During this phase, all patients received an initial topiramate dosage of 25 mg daily for 7 days. This was followed by a double-blind phase, in which 470 patients were randomized to receive topiramate titrated to a target maintenance dosage of 50 mg or 400 mg daily for a median of 9 months; if the target dosage could not be achieved, patients were maintained on the maximum tolerated dosage. Patients randomized to the target dosage of 400 mg daily received a mean of 275 mg daily; 58% of patients achieved the maximum dosage of 400 mg daily for at least 2 weeks. In this study, the 400-mg daily dosage was superior to the 50-mg daily dosage in delaying time to first seizure. Substantial differences in efficacy between the 2 treatment groups were observed at day 14, when patients randomized to receive target dosages of 400 or 50 mg daily were actually receiving 100 or 25 mg daily, respectively. At 6 months following initiation of treatment, 83% of patients randomized to the 400-mg daily dosage target were seizure free, compared with 71% of those randomized to the 50-mg daily dosage target. At 12 months, 76 or 59% of patients randomized to the 400- or 50-mg daily dosage targets, respectively, were seizure free. Treatment effects were consistent across various patient subgroups defined by age, gender, geographic region, baseline body weight, baseline seizure type, time since diagnosis, and baseline anticonvulsant use.

Topiramate's efficacy as initial monotherapy in children 2 to younger than 10 years of age with partial seizures or primary generalized tonic-clonic seizures was concluded based on a pharmacometric bridging approach using data from controlled epilepsy studies. This approach consisted of first demonstrating that the exposure-response relationship in pediatric patients 6 to younger than 16 years of age was similar to that in adults when topiramate was used as initial monotherapy. Specific dosage recommendations in children 2 to younger than 10 years of age were derived from simulations using plasma exposure ranges observed in pediatric and adult patients receiving topiramate as initial monotherapy.(See Dosage and Administration: Dosage.)

Adjunctive Therapy

Partial Seizures

Topiramate is used in combination with other anticonvulsant agents in the management of partial seizures in adults and children 2-16 years of age. Efficacy of topiramate as adjunctive therapy in adult patients with partial (including simple and complex partial) seizures with or without secondarily generalized tonic-clonic seizures was established in 6 controlled clinical studies. In these studies, patients initially were stabilized with optimum dosages of 1 or 2 conventional anticonvulsant drugs (e.g., carbamazepine, clonazepam, phenobarbital, phenytoin, primidone, valproic acid) during a 4- to 12-week baseline period; those experiencing a prespecified minimum number of partial seizures (with or without secondary generalization) during this baseline phase (12 seizures for a 12-week baseline, 8 for an 8-week baseline, or 3 for a 4-week baseline) were randomized to receive topiramate or placebo during a dosage titration period of 3-6 weeks followed by a 4-, 8-, or 12-week stabilization period during which the maximally achieved dosage of topiramate or placebo was maintained. Efficacy of topiramate in these studies principally was evaluated in terms of the change in seizure frequency and the responder rate. The change in seizure frequency with the addition of topiramate or placebo to the existing anticonvulsant regimen was the median percentage decrease (or increase) in average monthly (28 day) seizure rate. The responder rate was the percentage of patients with a reduction in seizure frequency of 50% or greater compared with baseline values.

Patients receiving topiramate 200 mg daily or placebo in 2 of the studies experienced a decrease in seizure frequency of 27-44 or 12-20%, respectively, and the responder rate was 24-45 or 18-24%, respectively. In 2 of the studies, patients receiving topiramate 400 mg daily or placebo experienced a decrease in seizure frequency of 41-48 or 1-13%, respectively, and the responder rate was 35-47 or 8-18%, respectively. Patients receiving 600 mg of topiramate daily in 3 of the studies experienced a decrease in seizure frequency of 41-46%, and patients receiving placebo experienced a decrease in seizure frequency of 1-13% in 2 of the studies, and an increase in seizure frequency of 12% in the third study. In the 3 studies in which patients received topiramate 600 mg daily or placebo, 40-47 or 9-18%, respectively, were considered responders. Patients receiving topiramate 800 mg daily in 2 studies experienced a decrease in seizure frequency of 24-41%, and patients receiving placebo experienced a decrease in monthly seizure rate of 1-2% in one study or an 18-21% increase in seizure frequency in the other study. In the studies of patients receiving topiramate 800 mg daily or placebo, 40-43 or 0-9%, respectively, were considered responders. Patients receiving 1 g of topiramate or placebo daily in one study experienced a decrease in seizure frequency of 36-38 or 1-2%, respectively, and 36-38 or 8-9% of patients, respectively, were reported to be responders. Overall, topiramate dosages exceeding 600 mg daily did not result in substantially improved efficacy, although individual patients may have benefited from such relatively high dosages.

Efficacy of topiramate as adjunctive therapy in pediatric patients (2-16 years of age) with partial seizures with or without secondarily generalized seizures was established in a multicenter, randomized, controlled trial. In this study, patients initially were stabilized with optimum dosages of 1 or 2 conventional anticonvulsant drugs; patients who experienced 6 or more partial seizures with or without secondarily generalized seizures during an 8-week baseline period were randomized either to topiramate or to placebo. Patients received topiramate initially at a dosage of 25 or 50 mg daily, after which the daily dosage was increased in increments of 25-150 mg every other week until the assigned dosage of 125, 175, 225, or 400 mg daily (approximately 6 mg/kg of topiramate daily, based on the patient's body weight) was reached, or until the development of adverse effects precluded increases in dosage. The 8-week dosage titration period was then followed by an 8-week maintenance period. Patients receiving topiramate 6 mg/kg daily or placebo experienced a decrease in seizure frequency of 33.1 or 10.5%, respectively, and the responder rate was 39 or 20%, respectively.

Primary Generalized Tonic-Clonic Seizures

Topiramate is used in combination with other anticonvulsant agents in the management of primary generalized tonic-clonic seizures in adults and children 2 years of age or older. Efficacy of topiramate as adjunctive therapy in patients with primary generalized tonic-clonic seizures was established in a multicenter, randomized, controlled trial. In this study, patients (age range: 3-59 years) initially were stabilized with optimum dosages of 1 or 2 conventional anticonvulsant drugs; patients who experienced 3 or more primary generalized tonic-clonic seizures during an 8-week baseline period were randomized either to topiramate or to placebo. Therapy was targeted to a dosage of 6 mg/kg daily during an 8-week dosage titration period; patients received topiramate initially at a dosage of 50 mg daily for 4 weeks, after which the daily dosage was increased in increments of 50-150 mg every other week until the assigned dosage of 175, 225, or 400 mg daily (approximately 6 mg/kg of topiramate daily, based on the patient's body weight) was reached, or until the development of adverse effects precluded increases in dosage. The dosage titration period was then followed by a 12-week maintenance period. Efficacy of topiramate was evaluated in terms of the change in seizure frequency (i.e., median percent reduction in primary generalized tonic-clonic seizures) and by the responder rate (i.e., percentage of patients with a reduction in primary generalized tonic-clonic seizure frequency of 50% or greater compared with baseline values). Patients receiving topiramate 6 mg/kg daily or placebo experienced a decrease in seizure frequency of 56.7 or 9%, respectively, and the responder rate was 56 or 20%, respectively. Preliminary data from the open-label extension period of a double-blind, placebo-controlled study in a limited number of patients with resistant primary generalized seizures indicate that 92% of patients experienced a 50% or greater decrease in seizures, while 58% of patients were seizure-free during this extension period.

Seizures Associated with Lennox-Gastaut Syndrome

Topiramate is used in combination with other anticonvulsant agents in the management of seizures associated with Lennox-Gastaut syndrome in adults and children 2 years of age or older. Efficacy of topiramate as adjunctive therapy in patients with Lennox-Gastaut syndrome was established in a multicenter, randomized, controlled trial. In this study, patients (age range: 2-42 years) who experienced 60 or more seizures per month prior to study entry were stabilized with optimum dosages of 1 or 2 conventional anticonvulsant drugs for 4 weeks. Following the 4-week baseline period, patients were randomized either to topiramate or to placebo. Patients received topiramate initially at a dosage of 1 mg/kg daily for 1 week, after which the dosage was increased to 3 mg/kg daily for 1 week, and then to the target dosage of 6 mg/kg daily. The dosage titration period was then followed by an 8-week maintenance period. Efficacy of topiramate was evaluated in terms of the change in seizure frequency (i.e., median percent reduction in drop attacks), the responder rate (i.e., percentage of patients with a reduction in seizure frequency of 50% or greater compared with baseline values), and the overall improvement in seizure severity (i.e., percentage of patients who were improved from baseline). Patients receiving topiramate 6 mg/kg daily experienced a decrease in seizure frequency of 14.8%, while those receiving placebo experienced an increase of 5.1%. Overall improvement in seizure severity was reported in more patients receiving topiramate (52%) than in those receiving placebo (28%). Responder rates were not significantly different between patients receiving topiramate (28%) and those receiving placebo (14%).

Migraine Prophylaxis

Topiramate is used in the prophylaxis of migraine headache in adults; efficacy of the drug in the acute treatment of migraine headache has not been established.

Topiramate was shown to be effective in the prophylaxis of migraine headache in 2 randomized, double-blind, placebo-controlled trials in over 900 patients with at least a 6-month history of migraine, with or without associated aura. Patients also had to experience 3-12 migraines over 4 weeks in the baseline phase; patients were excluded if they had cluster headaches or basilar, ophthalmoplegic, hemiplegic, or transformed migraine headaches. In both studies, after a 4-week baseline placebo period, patients were randomized to receive either topiramate or placebo during a 26-week treatment period consisting of an 8-week titration period and an 18-week maintenance period. Patients randomized to receive topiramate were given an initial dosage of 25 mg daily for 1 week, after which the dosage was increased by 25-mg increments every week until the target dosage of 50, 100, or 200 mg daily was achieved or the maximum tolerated dosage was reached (administered twice daily). Efficacy of prophylaxis was assessed by the reduction in migraine headache frequency, as measured by the change in the 4-week migraine headache rate from the baseline phase to the 26-week treatment period in each topiramate treatment group compared with placebo. The mean migraine headache frequency at baseline in all treatment groups in both studies was approximately 5.5 migraines per 28 days. In the first study, the reduction in the mean 4-week migraine headache frequency from baseline was 1.3, 2.1, or 2.2 for topiramate dosages of 50, 100, or 200 mg daily, respectively, and 0.8 for placebo. In the second study, the reduction in the mean 4-week migraine headache frequency from baseline was 1.4, 2.1, or 2.4 for topiramate dosages of 50, 100, or 200 mg daily, respectively, and 1.1 for placebo. In both studies, there were no apparent differences in treatment effect with respect to age or gender. Because most patients were Caucasian, there were insufficient numbers of patients from different races to make a meaningful comparison of the effectiveness of topiramate with respect to race.

Alcohol Dependence

Topiramate has been used successfully in adults for the management of alcohol dependence. Efficacy of the drug in this condition has been evaluated in 2 randomized, double-blind, placebo-controlled studies in adults who met DSM-IV criteria for alcohol dependence; the initial trial was of 12 weeks' duration and was conducted at a single site, while the subsequent trial was of 14 weeks' duration and was conducted at multiple sites. Patients in both studies received escalating dosages of topiramate (initially, 25 mg daily and gradually increased up to 300 mg daily) or placebo in conjunction with a weekly medication compliance intervention. Topiramate was found to be more effective than placebo in improving self-reported drinking outcomes (e.g., number of drinks per day, number of drinks per drinking day, percentage of heavy drinking days, percentage of days abstinent) as well as the objective laboratory measure of alcohol consumption (reduced plasma γ-glutamyltransferase) in both of these studies. In addition, topiramate was shown to reduce self-reported alcohol craving to a greater extent than placebo in the 12-week study. Additional analyses of these 2 studies found topiramate to be more effective than placebo at improving physical and psychosocial well-being and some aspects of quality of life in these alcoholic individuals. In an open-label, longer-term study comparing topiramate with naltrexone in alcohol-dependent patients, topiramate was found to be at least as effective at reducing drinking behaviors as naltrexone during 6 months of therapy and appeared superior to naltrexone at reducing alcohol-related cravings.

Topiramate is one of several drugs currently recommended by the National Institute of Alcohol Abuse and Alcoholism (NIAAA) for treating alcohol dependence; however, unlike the other recommended drugs (naltrexone, acamprosate, disulfiram), topiramate has not been approved by the US Food and Drug Administration (FDA) for this indication. Topiramate also differs from the other recommended drug therapies because it has been administered to patients who were still drinking alcohol, and a period of abstinence from alcohol does not appear to be necessary before starting therapy with the drug. Additional studies, including longer-term trials, are needed to more clearly determine topiramate's efficacy, safety, and potential role in treating alcohol dependence, including its use in different populations and alcoholic subtypes, its potential use in combination with other drugs, and the optimal dosage and duration of therapy. For further information on the use of topiramate and other medications in the management of alcohol dependence, the NIAAA's web site at http://www.niaaa.nih.gov/Publications/EducationTrainingMaterials/guide.htm should be consulted.

Topiramate has been effective in the management of alcohol withdrawal in a limited number of patients in uncontrolled studies; however, larger, well-controlled studies are needed to confirm these initial findings.

Dosage and Administration

Administration

Topiramate is administered orally. The manufacturer states that the capsule/sprinkle formulation of topiramate is bioequivalent to the immediate-release tablet and may be substituted as a therapeutic equivalent. The bioavailability of topiramate is not affected by food, and the drug may be administered as either the capsule/sprinkle formulation or immediate-release tablets without regard to meals.

Because of the bitter taste, immediate-release tablets of topiramate preferably should be swallowed intact and not broken or chewed. If the tablets are broken, they should be used immediately since stability of exposed drug beyond a brief period cannot be ensured; any unused portion should be discarded. For patients experiencing difficulty in swallowing the tablets, contents of the capsule/sprinkle formulation may be sprinkled on a small amount of food as described below.

The capsule/sprinkle formulation of topiramate may be taken whole, or it may be opened and the entire contents sprinkled on a small amount (e.g., a teaspoonful) of soft food (e.g., applesauce, custard, ice cream, oatmeal, pudding, yogurt). The patient should swallow the entire spoonful of the sprinkle/food mixture immediately; chewing should be avoided. It may be helpful to have the patient drink fluids immediately in order to make sure that all of the mixture is swallowed. The sprinkle/food mixture must not be stored for use at a later time.

Patients who are currently receiving or beginning therapy with topiramate and/or any other anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.(See Cautions: Adverse Effects and see Cautions: Precautions and Contraindications.)

Dispensing and Administration Precautions

Because of similarity in spelling between Topamax (the trade name for topiramate) and Toprol-XL (a trade name for metoprolol succinate, a β-adrenergic blocking agent), the potential exists for dispensing or prescribing errors involving these drugs. According to medication error reports, the overlapping tablet strengths (25, 50, 100, and 200 mg) between Topamax and Toprol-XL and the fact that these drugs were stored closely together in pharmacies also may have been contributing factors in causing these errors. Another contributing factor to dispensing errors may be the use of mnemonic abbreviations in computerized listings incorporating the first 3 letters and dose of Topamax and Toprol-XL (e.g., ''TOP25''). Extra care should be exercised to ensure the accuracy of both oral and written prescriptions for these drugs. The manufacturers of Topamax and Toprol-XL also recommend that pharmacists assess various measures of avoiding dispensing errors and implement them as appropriate (e.g., by verifying all orders for these drugs by citing both the trade and generic names to prescribers, attaching reminders to pharmacy shelves, separating the drugs on pharmacy shelves, counseling patients).(See Cautions: Precautions and Contraindications.)

Dosage

Dosage of topiramate must be adjusted carefully and individualized according to patient response and tolerance and the condition being treated. The manufacturer states that titration of topiramate dosages too rapidly (e.g., over 3-6 weeks) to achieve target dosages and/or excessive target dosages may have contributed to an unnecessarily high incidence of adverse effects in clinical studies.

In patients with or without a history of seizures or epilepsy, anticonvulsant drugs, including topiramate, should be withdrawn gradually to minimize the risk of seizures or increased seizure frequency. In clinical studies for seizure disorders, daily dosages of topiramate were decreased in weekly intervals by 50-100 mg in adults and over a 2-8 week period in pediatric patients; transition to a new anticonvulsant regimen was permitted when clinically indicated. In clinical studies for migraine prophylaxis, daily dosages were decreased in weekly intervals by 25-50 mg. However, in situations where more rapid withdrawal of topiramate is clinically necessary, the manufacturers recommend appropriate monitoring.

Seizure Disorders

The manufacturers state that it is not necessary to monitor plasma topiramate concentrations to achieve optimal clinical effect with the drug.

Addition or withdrawal of phenytoin and/or carbamazepine during adjunctive therapy may require adjustment of topiramate dosage. Addition of topiramate to an anticonvulsant regimen containing phenytoin may require adjustment of the dosage of phenytoin.(See Drug Interactions: Anticonvulsants.)

Initial Monotherapy

The recommended total daily dosage of topiramate as initial monotherapy for management of partial seizures or primary generalized tonic-clonic seizures in adults and pediatric patients 10 years of age and older is 400 mg daily, administered in 2 divided doses. The dosage of topiramate should be titrated using the schedule in Table 1.

Table 1. Topiramate Dosage Titration Schedule for Monotherapy of Partial Seizures or Primary Generalized Tonic-Clonic Seizures in Adults and Pediatric Patients 10 Years of Age or Older[1 ]
Morning Dose Evening Dose
Week 1 25 mg 25 mg
Week 2 50 mg 50 mg
Week 3 75 mg 75 mg
Week 4 100 mg 100 mg
Week 5 150 mg 150 mg
Week 6 200 mg 200 mg

In a controlled study evaluating safety and efficacy of topiramate (titrated up to 50 or 400 mg daily) as initial monotherapy, approximately 58% of patients randomized to receive the 400-mg daily dosage achieved this maximum dosage; the mean dosage achieved was 275 mg daily. Because a therapeutic effect emerges during titration, the investigators of this study recommend that topiramate dosages should be titrated in a stepwise fashion with intermediate stopping points (e.g., 100 mg daily) to evaluate patient response and achieve the optimal maintenance dosage, and to avoid possibly exceeding an appropriate dosage for an individual patient.

The dosage of topiramate as initial monotherapy for management of partial seizures or primary generalized tonic-clonic seizures in pediatric patients 2 to younger than 10 years of age is based on body weight. The dosing strategy in this population is derived from pharmacokinetic and pharmacodynamic modeling data from adult and pediatric patients using a pharmacometric bridging approach. During the titration period, the recommended initial dosage of topiramate is 25 mg daily (administered in the evening) for the first week. Based on tolerability, the total daily dosage can be increased to 50 mg (given as 25 mg twice daily) during the second week. The total daily dosage can then be increased by 25-50 mg daily each subsequent week as tolerated. Titration to the minimum recommended dosage (see Table 2) should be attempted over 5-7 weeks of the total titration period. Based upon tolerability and seizure control, additional titration to a higher dosage (up to the maximum recommended maintenance dosage) can be attempted in weekly increments of 25-50 mg daily. The total daily dosage of topiramate should not exceed the maximum recommended maintenance dosage for each range of body weight (see Table 2).

Table 2. Target Maintenance Topiramate Dosage for Monotherapy of Partial Seizures or Primary Generalized Tonic-Clonic Seizures in Pediatric Patients 2 to Younger than 10 Years of Age[1 ]
Weight (kg) Minimum Total Daily Dosage (mg/day)* Maximum Total Daily Dosage (mg/day)*
Up to 11 150 250
12-22 200 300
23-31 200 350
32-38 250 350
>38 250 400

* Administered in 2 equally divided doses.

Adjunctive Therapy

In adults 17 years of age or older, the recommended total daily dosage of topiramate as adjunctive therapy for management of partial seizures is 200-400 mg, administered in 2 divided doses. The recommended total daily adult dosage for management of primary generalized tonic-clonic seizures is 400 mg, administered in 2 divided doses. Topiramate therapy should be initiated at 25-50 mg daily, titrating the daily dosage upward in increments of 25-50 mg at weekly intervals to an optimal level, but generally not exceeding 400 mg daily. Limited data indicate that upward titration in increments of 25 mg per week may delay the time to reach an effective dosage; however, such a titration schedule appears to be associated with a lower incidence of neurocognitive and/or psychiatric adverse effects and a lower discontinuance rate. In the clinical trial of topiramate for the adjunctive management of primary generalized tonic-clonic seizures, the titration period was longer than that used in trials of the drug for partial seizures and lasted 8 weeks. Maintenance dosages less than 400 mg daily may be optimally effective in some patients and therefore should be individualized; however, results from clinical studies in adults with partial onset seizures indicate that a daily dosage of 200 mg may produce inconsistent effects and appears to be less effective than a daily dosage of 400 mg. Dosages exceeding 400 mg daily have not improved response to topiramate substantially, although seizure control may be improved in some patients from such relatively high dosages if tolerated. Dosages exceeding 1.6 g daily have not been studied.

The manufacturers do not make specific dosage recommendations for management of Lennox-Gastaut syndrome in adults 17 years of age or older. However, in one controlled trial, dosage of topiramate was initiated at 1 mg/kg and titrated over 2 weeks to a target dosage of approximately 6 mg/kg daily.(See Uses: Seizures Associated with Lennox-Gastaut Syndrome.)

In pediatric patients 2-16 years of age, the recommended total daily dosage of topiramate as adjunctive therapy for the management of partial seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome is approximately 5-9 mg/kg daily, administered in 2 divided doses. Dosage titration should begin at 25 mg (or less, based on a range of 1-3 mg/kg daily) given nightly for the first week. The dosage should then be increased at 1- or 2-week intervals in increments of 1-3 mg/kg daily (administered in 2 divided doses) to achieve optimal clinical response. Dosage titration should be guided by clinical outcome. Some clinicians recommend that the initial topiramate dosage should range from 0.5-1 mg/kg daily and that the drug should be titrated slowly (e.g., followed by incremental increases of 1-3 mg/kg every other week or incremental increases of 0.5-1 mg/kg per week) to obtain optimal efficacy with minimal adverse effects.

Pharmacokinetic data from one controlled clinical study have revealed a decreased clearance of topiramate in geriatric patients with reduced renal function (i.e., creatinine clearance reduced by 20% compared with that in younger adults).(See Cautions: Geriatric Precautions.) Therefore, the manufacturers state that it may be useful to monitor renal function in geriatric patients receiving topiramate therapy; dosage adjustment may be necessary in geriatric patients with impaired renal function (i.e., creatinine clearance less than 70 mL/minute per 1.73 m).(See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Migraine Prophylaxis

The recommended total daily dosage of topiramate for prophylaxis of migraine headache in adults is 100 mg, administered in 2 divided doses. The dosage of topiramate should be titrated using the schedule in Table 3.

Table 3. Topiramate Dosage Titration Schedule for Migraine Prophylaxis in Adults
Morning Dose Evening Dose
Week 1 None 25 mg
Week 2 25 mg 25 mg
Week 3 25 mg 50 mg
Week 4 50 mg 50 mg

Titration of topiramate dosage should be guided by clinical outcome. If required, longer intervals between dosage adjustments can be used.

Alcohol Dependence

The optimal dosage regimen of topiramate for the management of alcohol dependence remains to be established; however, initial dosages of 25 mg given once daily in the afternoon or evening (e.g., at bedtime) followed by gradual dosage titration (e.g., increasing dosage in increments of 25-50 mg daily each week, given in 2 divided doses) to target maintenance dosages of 200-300 mg daily were found to be effective in short-term, controlled clinical trials in adults and have been recommended by some authorities. Patients who are unable to tolerate the target dosage may respond to lower dosages.

Results from clinical studies in alcohol dependence suggest that a more gradual titration (e.g., over 8 weeks) to achieve target dosages of 200-300 mg daily may be better tolerated than more rapid titration (e.g., over 6 weeks). A period of abstinence from alcohol prior to initiating topiramate therapy for alcohol dependence does not appear to be necessary.

Although the optimal duration of topiramate therapy for the management of alcohol dependence remains to be established, some authorities recommend an initial period of at least 3 months to prevent relapse in alcohol-dependent patients. These authorities also recommend continuing drug therapy for 12 months or longer if the patient responds to the medication during this initial period when the risk of relapse is highest.

Dosage in Renal and Hepatic Impairment

Dosage of topiramate should be adjusted according to the degree of renal impairment. In patients with a creatinine clearance less than 70 mL/minute per 1.73 m, the daily dosage of topiramate should be decreased by 50%, and such patients will require a longer time to reach steady-state plasma concentrations of the drug at each dosage increase during titration. In patients undergoing hemodialysis, clearance of topiramate is 4-6 times more rapid than in healthy individuals, and prolonged hemodialysis may result in plasma topiramate concentrations below those required for anticonvulsant activity. Therefore, to avoid rapid decreases of plasma topiramate concentrations in patients undergoing hemodialysis, a supplemental dose of the drug may be required; selection of the supplemental dose should take into account the duration of dialysis, clearance rate of the dialysis system being used, and the patient's effective renal clearance of topiramate.

Although topiramate clearance may decrease in patients with hepatic impairment, the manufacturers make no specific recommendations for dosage adjustment in such patients.

Cautions

Adverse Effects

Nervous system effects are the most frequently reported adverse effects of topiramate in adults and generally can be classified into 3 categories: cognitive-related dysfunction (e.g., confusion, psychomotor slowing, difficulty with concentration or attention, difficulty with memory, speech or language problems, particularly word-finding difficulties); psychiatric or behavioral disturbances (e.g., depression, mood problems); and somnolence or fatigue. Cognitive-related adverse effects frequently occur in isolation and often in association with a rapid titration rate and higher initial dosages. Although generally mild or moderate in severity, many of these cognitive-related adverse effects have resulted in discontinuance of topiramate therapy.

Psychiatric or behavioral disturbances appear to be dose-related in patients receiving topiramate for seizure disorders as well as for migraine prophylaxis. Suicide attempts were reported frequently (i.e., with an incidence of 1% or more) in patients receiving topiramate in clinical trials.(See Cautions: Precautions and Contraindications.)

Somnolence and fatigue are the most commonly reported adverse effects in patients receiving topiramate for seizure disorders. In patients receiving topiramate as initial monotherapy for seizure disorders, the frequency of somnolence (but not fatigue) appears to be dose related. In patients receiving topiramate as adjunctive therapy for seizure disorders, the frequency of somnolence does not appear to be dose related; however, fatigue tends to occur with increasing frequency in patients receiving topiramate at dosages exceeding 400 mg daily. In patients receiving topiramate for migraine prophylaxis, somnolence and fatigue appear to be dose related and occur more frequently during the titration phase.

Other common dose-related adverse nervous system effects of topiramate (at dosages of 200-1000 mg daily) include nervousness and anxiety. Frequently reported adverse nervous system effects that do not appear to be dose related include dizziness, ataxia, and paresthesia. Paresthesia occurred more frequently in patients receiving topiramate as initial monotherapy for management of seizure disorders or for migraine prophylaxis than for adjunctive therapy of seizure disorders; however, in most instances, this adverse effect did not result in discontinuance of therapy.

Other common dose-related adverse effects of topiramate, in addition to adverse nervous system effects, include anorexia and weight loss. Frequently reported adverse effects that do not appear to be dose related include abnormal vision and diplopia.

In controlled clinical trials evaluating topiramate for alcohol dependence, paresthesia, taste perversion, fatigue, anorexia, insomnia, concentration and attention difficulties, memory impairment, nervousness, somnolence, diarrhea, dizziness, and pruritus were reported more frequently in patients receiving topiramate than in patients receiving placebo.

Precautions and Contraindications

Hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate concentrations to below the normal reference range in the absence of chronic respiratory alkalosis) has been reported in clinical trials and during postmarketing surveillance of topiramate. Such electrolyte imbalance generally occurs early in topiramate therapy, although cases can occur at any time. Metabolic acidosis, which has been observed at topiramate dosages as low as 50 mg daily, is caused by renal bicarbonate loss because of the inhibitory effect of topiramate on carbonic anhydrase. Decreases in serum bicarbonate concentrations usually are mild to moderate (average decrease of 4 mEq/L at daily topiramate dosages of 400 mg in adults and at approximately 6 mg/kg daily in pediatric patients); marked decreases in serum bicarbonate concentrations (to below 10 mEq/L) may rarely occur. In clinical trials, persistent treatment-emergent decreases in serum bicarbonate concentrations (defined as concentrations of less than 20 mEq/L at 2 consecutive visits or at the final visit) occurred in 7-67% of patients receiving topiramate and in 1-10% of those receiving placebo.Markedly abnormally low serum bicarbonate concentrations (defined as concentrations of less than 17 mEq/L and a decrease from pretreatment values exceeding 5 mEq/L) were observed in 1-11% of patients receiving topiramate and in 0 to less than 1% of those receiving placebo. Manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Because chronic, untreated metabolic acidosis may have potentially serious sequelae (e.g., increased risk of nephrolithiasis or nephrocalcinosis, development of osteomalacia and/or osteoporosis with an increased risk for fractures), the manufacturers state that serum bicarbonate concentrations should be measured at baseline and periodically during topiramate therapy. If metabolic acidosis develops and persists, consideration should be given to reducing the dosage or discontinuing topiramate therapy (by gradually tapering the dosage). If a decision is made to continue topiramate therapy in the presence of persistent acidosis, alkali treatment should be considered.

A syndrome consisting of acute myopia associated with secondary angle-closure glaucoma has been reported in some patients receiving topiramate. This syndrome may be associated with supraciliary effusion, resulting in anterior displacement of the lens and iris and, subsequently, secondary angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity and/or ocular pain and typically occur within 1 month of initiating topiramate therapy. Ophthalmologic findings include myopia, anterior chamber shallowing, ocular hyperemia, and increased intraocular pressure; mydriasis may or may not be present. Patients receiving topiramate should be advised to seek immediate medical attention if they experience blurred vision, visual disturbances, or periorbital pain during therapy with the drug. If adverse ocular signs or symptoms are detected during topiramate therapy, the drug should be discontinued immediately and appropriate measures instituted.

Oligohidrosis, which rarely may require hospitalization, has been reported in clinical trials or during postmarketing surveillance of topiramate. Manifestations include decreased sweating and an elevation in body temperature above normal (hyperthermia). Most cases of oligohidrosis were reported in children, and some occurred following exposure to elevated environmental temperatures and/or vigorous activity. Topiramate therapy has been continued in most patients who experienced oligohidrosis and hyperthermia. Because oligohidrosis and hyperthermia may have potentially serious sequelae, the manufacturers state that patients, particularly pediatric patients, receiving topiramate should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Proper hydration is recommended before and during activities (e.g., exercise) or exposure to warm temperatures. Caution is advised if topiramate is used concomitantly with other drugs that predispose patients to heat-related disorders (e.g., carbonic anhydrase inhibitors, drugs with anticholinergic activity).

In patients with or without a history of seizures or epilepsy, anticonvulsant drugs, including topiramate, should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency.(See Dosage and Administration: Dosage.) The manufacturers recommend appropriate monitoring in situations where more rapid withdrawal of topiramate is required.

Patients should be informed that topiramate may cause adverse nervous system effects (e.g., somnolence, dizziness, confusion, difficulty concentrating, visual disturbances) and that they should not drive a motor vehicle or operate other complex machinery until they have gained sufficient experience with the drug to determine whether it has adverse effects on their mental performance, motor performance, and/or vision.

Patients with seizure disorders who are receiving anticonvulsant agents, including topiramate, may continue to experience unpredictable seizures. Therefore, the manufacturers recommend that all patients receiving topiramate for seizure disorders be advised to exercise caution when engaging in any activities where loss of consciousness could result in serious danger to themselves or those around them (including swimming, driving a motor vehicle, and climbing in high places). Some patients with refractory seizure disorders may need to avoid such activities altogether.

The US Food and Drug Administration (FDA) has informed healthcare professionals about an increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants compared with placebo. FDA's analysis included 199 randomized, placebo-controlled studies of 11 anticonvulsants (carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide) involving over 43,000 patients 5 years of age or older; the studies evaluated the effectiveness of the anticonvulsants in epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain). The analysis revealed that patients receiving these anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%); this increased suicidality risk was observed as early as one week after beginning therapy and continued through 24 weeks. The results were generally consistent among the 11 drugs studied. In addition, patients who were treated for epilepsy, psychiatric disorders, and other conditions were all found to be at increased risk for suicidality when compared with placebo; there did not appear to be a specific demographic subgroup of patients to which the increased risk could be attributed. However, the relative risk for suicidality was found to be higher in patients with epilepsy compared with patients who were given one of the drugs for psychiatric or other conditions.

Based on the current analysis of the available data, FDA recommends that all patients who are currently receiving or beginning therapy with any anticonvulsant for any indication be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or unusual changes in mood or behavior. Symptoms such as anxiety, agitation, hostility, mania, and hypomania may be precursors to emerging suicidality. Clinicians should inform patients, their families, and caregivers of the potential for an increased risk of suicidality so that they are aware and able to notify their clinician of any unusual behavioral changes. Patients, family members, and caregivers also should be advised not to make any changes to the anticonvulsant regimen without first consulting with the responsible clinician. They should pay close attention to any day-to-day changes in mood, behavior, and actions; since changes can happen very quickly, it is important to be alert to any sudden differences. In addition, patients, family members, and caregivers should be aware of common warning signs that may signal suicide risk (e.g., talking or thinking about wanting to hurt oneself or end one's life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions). If these or any new and worrisome behaviors occur, the responsible clinician should be contacted immediately. FDA also recommends that clinicians who prescribe topiramate or any other anticonvulsant balance the risk for suicidality with the risk of untreated illness. Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with an increased risk of morbidity and mortality and an increased risk of suicidal thoughts and behavior. If suicidal thoughts and behavior emerge during anticonvulsant therapy, the clinician must consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Hyperammonemia and associated encephalopathy have been reported in adults and pediatric patients receiving topiramate (with and without concomitant valproic acid) in clinical studies and during postmarketing experience. In investigational protocols, hyperammonemia with or without encephalopathy (in some cases dose related) was reported in 26-41% of adolescents 12-16 years of age who received topiramate monotherapy for migraine prophylaxis and in 0-10% of children 1-24 months of age who received adjunctive topiramate therapy for partial seizures. In some cases, ammonia concentrations were markedly increased (defined as concentrations of 50% or greater above the upper limit of normal). Concomitant administration of topiramate and valproic acid also has been associated with hyperammonemia with or without encephalopathy in patients who have previously tolerated either drug alone. Although topiramate is not labeled for use in infants and toddlers, dose-related hyperammonemia was observed in infants and toddlers 1-24 months of age receiving topiramate and valproic acid concomitantly in a placebo-controlled study and a long-term extension trial; in some cases, ammonia concentrations were markedly increased in these patients. Topiramate-associated hyperammonemia appears to be more common when topiramate is used concomitantly with valproic acid. Although patients may be asymptomatic, manifestations of hyperammonemic encephalopathy include acute alterations in the level of consciousness and/or cognitive function with lethargy or vomiting. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although it has not been studied, it is possible that an interaction between topiramate and valproic acid may exacerbate existing defects or unmask deficiencies in susceptible individuals. If unexplained lethargy, vomiting, or changes in mental status occur, hyperammonemic encephalopathy should be considered, and an ammonia concentration should be measured.

Formation of kidney stones has been reported in approximately 1.5% of adults receiving topiramate in clinical trials. As in the general population, the incidence of kidney stone formation among topiramate-treated patients appears to be higher in men than in women; kidney stones also have been reported in pediatric patients receiving topiramate. Although the mechanism of this adverse effect has not been fully elucidated, it has been suggested that topiramate exhibits weak inhibition of carbonic anhydrase and, similar to other carbonic anhydrase inhibitors (e.g., acetazolamide), may promote stone formation by reducing urinary citrate excretion and increasing urinary pH. The manufacturers state that use of topiramate in patients on a ketogenic diet or concomitant use of the drug with other carbonic anhydrase inhibitors may increase the risk of kidney stone formation and, therefore, should be avoided. Because increased fluid intake may increase urinary output and reduce the concentration of substances involved in stone formation, patients receiving topiramate, particularly those with predisposing factors, should be instructed to maintain adequate fluid intake to prevent kidney stone formation.

Hypothermia (defined as an unintentional drop in body core temperature to less than 35°C), both in conjunction with and in the absence of hyperammonemia, has been reported in patients receiving concurrent topiramate and valproic acid therapy. Hypothermia may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and substantial alterations in other major organ systems such as the cardiovascular and respiratory systems. Hypothermia may occur after initiating topiramate therapy or following a dosage increase. Discontinuance of topiramate or valproic acid therapy should be considered in patients who develop hypothermia. Since hypothermia also may be a manifestation of hyperammonemia, clinical management and assessment of hypothermia should include determination of plasma ammonia concentrations.

Serum electrolyte abnormalities have been reported in controlled clinical trials of adults with partial onset seizures receiving topiramate. Hypokalemia and hypophosphatemia were reported in 0.4 and 6% of topiramate-treated patients, respectively, compared with 0.1 and 2 % of placebo-treated patients in double-blind clinical trials. Markedly increased serum alkaline phosphatase concentrations were reported in 3% of patients receiving topiramate compared with 1% of placebo recipients in these studies. The clinical importance of these abnormalities has not been clearly established.

Because of similarity in spelling between Topamax (the trade name for topiramate) and Toprol-XL (a trade name for metoprolol succinate, a β-adrenergic blocking agent), the potential exists for dispensing or prescribing errors involving these drugs. These medication errors have been associated with serious adverse events sometimes requiring hospitalization as a result of either lack of the intended medication (e.g., seizure or hypertension recurrence) or exposure to the wrong drug (e.g., bradycardia in a patient erroneously receiving metoprolol). Therefore, extra care should be exercised to ensure the accuracy of both oral and written prescriptions for these drugs. Patients should be advised to carefully check their medications and to bring any questions or concerns to the attention of the dispensing pharmacist. Dispensing errors involving Topamax (topiramate) and Toprol-XL (metoprolol succinate) should be reported to the manufacturers, the USP/ISMP (Institute for Safe Medication Practices) Medication Errors Reporting Program by phone (800-233-7767), or directly to the FDA MedWatch program by phone (800-FDA-1088), fax (800-FDA-0178), or internet (http://www.fda.gov/Safety/MedWatch/default.htm).

During the premarketing development of topiramate, 10 sudden and unexplained deaths were reported among a cohort of patients receiving adjunctive therapy with the drug (2796 patient-years of exposure). Although the rate of these deaths exceeds that expected to occur in a healthy (nonepileptic) population matched for age and gender, this rate was similar to that occurring in a similar population of epileptic patients not receiving topiramate.

There are no known contraindications to topiramate therapy.

Pediatric Precautions

Safety and efficacy of topiramate as initial monotherapy or as adjunctive therapy for the management of seizure disorders have not been established in children younger than 2 years of age. Efficacy, safety, and tolerability of topiramate as adjunctive therapy in infants 1-24 months of age with refractory partial seizures were evaluated in a randomized, double-blind, placebo-controlled study; after 20 days of treatment, topiramate in fixed dosages of 5, 15, and 25 mg/kg daily was not shown to be more effective than placebo in controlling seizures. Results of this study in addition to a long-term open-label study in infants and toddlers suggest that very young children may experience adverse effects not previously observed in older pediatric patients and adults or that occur with greater frequency or severity than in these older age groups. Such adverse effects included growth/length retardation, changes in certain laboratory parameters (e.g., increased serum creatinine concentrations, increased BUN, increased protein concentrations, decreased potassium concentrations, increased eosinophil count, increased alkaline phosphatase concentrations), and impairment of adaptive behavior.

Safety and efficacy of topiramate for migraine prophylaxis have not been established in pediatric patients. Topiramate produced a dose-related increase in serum creatinine concentrations in a controlled study of adolescents 12-16 years of age who received 4 months of treatment with the drug for migraine prophylaxis; elevated serum creatinine concentrations occurred in 4-18% of the adolescents who received topiramate in this study versus 4% of placebo-treated patients.

The incidence of nervous system effects in pediatric patients appears to be lower than that observed in adults. The most common adverse nervous system effects reported in pediatric patients receiving topiramate as initial monotherapy for seizure disorders include paresthesia, somnolence, dizziness, headache, confusion, and mood problems. The most common adverse nervous system effects reported in pediatric patients receiving the drug as adjunctive therapy for seizure disorders include fatigue; somnolence; psychomotor slowing; nervousness; difficulty with concentration, attention span, and memory; speech disorders and related speech problems; language problems; and aggressive reaction. Other adverse effects reported in these populations include anorexia, weight loss, upper respiratory tract infection, fever, flushing, and diarrhea.

Hyperchloremic, non-anion gap, metabolic acidosis (i.e. decreased serum bicarbonate concentrations to below the normal reference range in the absence of chronic respiratory alkalosis) has been reported in clinical trials and during postmarketing surveillance of topiramate.(See Cautions: Precautions and Contraindications.) In clinical trials in pediatric patients 6-15 years of age receiving topiramate as initial monotherapy, the incidence of treatment-emergent decreases in serum bicarbonate concentrations was 25% for patients receiving topiramate 400 mg daily and 9% for those receiving topiramate 50 mg daily. In clinical trials in pediatric patients 2-16 years of age in which topiramate was used as adjunctive therapy, the incidence of persistent treatment-emergent decreases in serum bicarbonate concentrations was 67 or 10% for patients receiving topiramate (approximately 6 mg/kg daily) or placebo, respectively. Cases of moderately severe metabolic acidosis have been reported in infants as young as 5 months of age, especially at daily dosages exceeding 5 mg/kg daily. Although not labeled for use in this age group, a controlled trial in children younger than 2 years of age with partial onset seizures found that topiramate produced a metabolic acidosis of greater magnitude than that observed in controlled trials of older children and adults; the incidence of metabolic acidosis ranged from 30 to 50% following treatment with topiramate in dosages of 5-25 mg/kg daily. Chronic, untreated metabolic acidosis may have potentially serious sequelae, including development of osteomalacia (rickets), reduction of growth rates, and a decrease in maximal height achieved in pediatric patients. Although the effects of topiramate on growth and bone-related sequelae have not been systematically evaluated in long-term, placebo-controlled trials, results of an open-label study demonstrated that infants and toddlers who received topiramate for up to 1 year had reduced length, weight, and head circumference compared with age- and sex-matched normative data; reductions in length and weight were correlated with the degree of acidosis. Because of the potential risk of metabolic acidosis, the manufacturers state that serum bicarbonate concentrations should be measured at baseline and periodically during topiramate therapy.(See Cautions: Precautions and Contraindications.)

Oligohidrosis (decreased sweating) and hyperthermia have been reported in clinical trials and during postmarketing surveillance of topiramate. Because oligohidrosis and hyperthermia typically occurred in children and may have potentially serious sequelae, the manufacturers state that patients, particularly pediatric patients, receiving topiramate should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather.(See Cautions: Precautions and Contraindications.)

Clearance of topiramate is higher in pediatric patients than in adults, and also higher in younger versus older pediatric patients, presumably because of age-related changes in the rate of drug metabolism. Pediatric patients (2 to younger than 16 years of age) receiving adjunctive therapy with topiramate exhibited higher oral topiramate clearance than those receiving topiramate monotherapy; the observed difference was presumably due to concomitant use of enzyme-inducing anticonvulsant agents.

Geriatric Precautions

While clinical studies evaluating topiramate did not include sufficient numbers of adults 65 years of age or older to determine whether geriatric patients respond differently than younger adults, approximately 3% of patients receiving the drug in clinical trials were older than 60 years of age. Although no age-related differences in efficacy or safety were evident in these patients, pharmacokinetic data from one controlled clinical study have revealed a decreased clearance of topiramate in geriatric patients with reduced renal function (i.e., creatinine clearance reduced by 20% compared with that in younger adults). Following administration of a single 100-mg dose of topiramate in these patients, plasma clearance and renal clearance of topiramate were reduced by 21 and 19%, respectively; half-life was prolonged by 13%; and peak plasma concentrations and area under the plasma concentration-time curve (AUC) were increased by 23 or 25%, respectively, compared with younger adults. Therefore, the manufacturers state that it may be useful to monitor renal function in geriatric patients; dosage adjustment may be necessary in geriatric patients with impaired renal function (i.e., creatinine clearance less than 70 mL/minute per 1.73 m).(See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Pregnancy and Lactation

Pregnancy

Topiramate can cause fetal harm when administered to pregnant women. Use of the drug during the first trimester of pregnancy is associated with an increased risk of the development of oral clefts (cleft lip and/or palate). Data from pregnancy registries, including the North American Antiepileptic Drug (NAAED) pregnancy registry, indicate that infants exposed to topiramate in utero have a higher prevalence of oral cleft birth defects than those with no such exposure. The prevalence of oral clefts among infants in the NAAED registry who were exposed to topiramate during the first trimester of pregnancy was 1.2% compared with a prevalence of 0.39-0.46% in infants exposed to other anticonvulsant agents in utero and a prevalence of 0.12% in infants of women without epilepsy or treatment with other anticonvulsant agents. For comparison, the US Centers for Disease Control and Prevention (CDC) reviewed available data on oral clefts in the US and found a similar background rate of 0.17%. Based on NAAED data, the relative risk of developing an oral cleft defect in topiramate-exposed pregnancies was 9.6 compared with the risk in a background population of untreated women. The United Kingdom Epilepsy and Pregnancy Registry reported a similarly increased prevalence of oral clefts of 3.2% among infants exposed in utero to topiramate monotherapy; the reported rate was 16 times higher than the background rate in the United Kingdom, which is approximately 0.2%.

Topiramate has demonstrated selective developmental toxicity, including teratogenicity and embryotoxicity, in multiple species of animals (rats, rabbits, mice). Structural malformations, including craniofacial defects, and reduced fetal weights have occurred in offspring of pregnant animals that received topiramate at clinically relevant dosages. There also was some evidence of maternal toxicity (e.g., decreased maternal body weight gain, increased mortality).

Topiramate therapy can cause metabolic acidosis (see Cautions: Precautions and Contraindications). The effect of topiramate-induced metabolic acidosis has not been specifically studied during pregnancy; however, metabolic acidosis from other causes during pregnancy can result in decreased fetal growth, decreased fetal oxygenation, and fetal death, and also may affect the ability of the fetus to tolerate labor. Therefore, pregnant women receiving topiramate should be monitored and treated for metabolic acidosis in the same manner as nonpregnant patients. In addition, neonates born to women treated with topiramate should be monitored for metabolic acidosis because of possible drug transfer to the fetus and possible occurrence of transient metabolic acidosis following birth.

The benefits and risks of topiramate therapy should be carefully considered when use of the drug in women of childbearing potential is contemplated, particularly for conditions not usually associated with permanent injury or death. Alternative drugs that have a lower risk of oral clefts and other adverse birth outcomes should be considered in such patients. If a decision is made to use topiramate in a woman of childbearing potential, clinicians should recommend use of effective contraception for those who are not planning a pregnancy. The potential for decreased efficacy of estrogen-containing oral contraceptives should be considered.(See Drug Interactions: Oral Contraceptives.) Topiramate should be used during pregnancy only when the potential benefits outweigh the possible risks. If topiramate is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.

Women who become pregnant while receiving topiramate should be encouraged to enroll in the NAAED pregnancy registry; patients can enroll by calling 888-233-2334. Information on the registry also can be found on the website http://www.aedpregnancyregistry.org.

Lactation

Limited data indicate that topiramate distributes into human milk at concentrations equal to approximately 10-20% of maternal plasma concentrations. Because the effects of this exposure on infants are unknown, caution should be exercised when topiramate is used in nursing women.

Drug Interactions

Drugs Metabolized by Hepatic Microsomal Enzymes

In vitro studies indicate that topiramate is a mild inhibitor of cytochrome P-450 (CYP) isoenzyme 2C19 and a mild inducer of CYP3A4. Pharmacokinetic interactions with drugs metabolized by these isoenzymes, including some anticonvulsants, CNS depressants, and oral contraceptives, are therefore possible.

Amitriptyline

In healthy individuals, concomitant administration of topiramate (200 mg daily) and amitriptyline (25 mg daily) increased both peak plasma concentrations and area under the plasma concentration-time curve (AUC) of amitriptyline by 12%. Because some patients may experience a large increase in amitriptyline concentrations in the presence of topiramate, any adjustments in amitriptyline dosage should be made according to the patient's clinical response and not on the basis of plasma concentrations.

Anticonvulsants

Plasma concentrations of topiramate were reduced by 48% with concomitant administration of phenytoin and topiramate compared with topiramate given alone. Plasma concentrations of phenytoin increased by 25% in some patients (generally in those receiving a twice-daily dosage regimen of phenytoin) and did not change substantially in others who received these drugs in combination. Phenytoin does not alter protein binding of topiramate.

Concomitant administration of carbamazepine and topiramate decreased plasma concentrations of topiramate by 40% compared with topiramate given alone, but did not substantially alter plasma concentrations of carbamazepine or its active metabolite, carbamazepine-10,11-epoxide. Carbamazepine does not alter protein binding of topiramate.

Concomitant administration of valproic acid and topiramate altered the pharmacokinetics of both drugs (decreased topiramate plasma concentrations by 14% and valproic acid plasma concentrations by 11%). In addition, concomitant use of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have previously tolerated either drug alone.(See Cautions: Precautions and Contraindications.) In most cases, manifestations resolved with discontinuance of either drug. Although not studied, the interaction between valproic acid and topiramate may exacerbate existing defects or unmask deficiencies in susceptible patients. Concomitant use of topiramate with valproic acid also has been associated with hypothermia (with and without hyperammonemia) (see Cautions: Precautions and Contraindications). Discontinuance of topiramate or valproic acid therapy should be considered in patients who develop hypothermia. Valproic acid (at concentrations 5-10 times higher than therapeutic concentrations) decreases protein binding of topiramate from 23% to 13%; topiramate does not affect protein binding of valproic acid.

Concomitant administration of topiramate and phenobarbital or primidone altered plasma concentrations of the concomitantly administered anticonvulsant by less than 10%; the effects of phenobarbital or primidone on the pharmacokinetics of topiramate were not evaluated.

Lamotrigine pharmacokinetics are unlikely to be substantially affected by concurrent topiramate administration at dosages of up to 400 mg daily; however, plasma topiramate concentrations decreased by 13% during concurrent lamotrigine administration.

Antidiabetic Agents

Concomitant administration of topiramate and glyburide (5 mg daily) in patients with type 2 diabetes mellitus decreased steady-state peak plasma concentrations and AUC of glyburide by 22 and 25%, respectively, compared with administration of glyburide alone. Systemic exposure of the active metabolites, 4-trans-hydroxyglyburide and 3-cis-hydroxyglyburide, also were reduced by 18 and 25%, respectively. Steady-state pharmacokinetics of topiramate were not affected by concomitant glyburide administration.

Concurrent administration of topiramate and pioglitazone in healthy individuals resulted in a nonsignificant decrease in steady-state pioglitazone AUC with no change in peak plasma concentrations. Decreases in systemic exposure to the active hydroxy- and keto-metabolites of pioglitazone also were observed; however, the clinical importance of these findings is not known. When topiramate therapy is initiated in patients receiving pioglitazone or vice versa, careful attention should be given to the routine monitoring of patients for adequate glycemic control.

In a drug interaction study in healthy individuals, mean peak plasma concentrations and AUC of metformin were increased by 17 and 25%, respectively, following concomitant administration of topiramate; however, time to reach peak plasma concentrations of metformin was not affected. Oral clearance of topiramate appears to be reduced when administered in conjunction with metformin. The clinical importance of these pharmacokinetic interactions is not known. However, topiramate can cause metabolic acidosis, a condition for which the use of metformin is contraindicated.

Drugs Predisposing to Heat-related Disorders

Increased risk of hyperthermia is possible with concomitant use of topiramate and drugs that predispose patients to heat-related disorders (e.g., carbonic anhydrase inhibitors, drugs with anticholinergic activity); caution is advised when topiramate is used in combination with such drugs.

Carbonic Anhydrase Inhibitors

Concomitant use of topiramate with other carbonic anhydrase inhibitors (e.g., acetazolamide, dichlorphenamide, zonisamide) may increase the risk or severity of metabolic acidosis and may also increase the risk of kidney stone formation. If topiramate is used concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the onset or worsening of metabolic acidosis.

Alcohol and Other CNS Depressants

Concomitant administration of topiramate and alcohol or other CNS depressants has not been evaluated in clinical studies. Because of the potential for topiramate to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse effects, the drug should be used with extreme caution if administered concurrently with alcohol or other CNS depressants.

Digoxin

Serum digoxin AUC was decreased by 12% with concomitant use of topiramate in a single-dose study; however, the clinical importance of this interaction is unknown.

Dihydroergotamine

Concomitant administration of topiramate (200 mg daily) and a single dose of dihydroegotamine (1 mg subcutaneously) in healthy individuals did not affect the pharmacokinetics of either drug.

Diltiazem

Concomitant administration of topiramate (150 mg daily) and diltiazem (240 mg as extended-release capsules [Cardizem CD]) decreased peak plasma concentrations and AUC of diltiazem by 10 and 25%, respectively. Systemic exposure to deacetyldiltiazem also was decreased, but there was no effect on N-monodesmethyldiltiazem. Diltiazem increased peak plasma concentrations and AUC of topiramate by 16 and 19%, respectively.

Haloperidol

Pharmacokinetics of haloperidol (administered as a single 5-mg dose) were not affected by multiple doses of topiramate (100 mg every 12 hours) in healthy individuals.

Hydrochlorothiazide

In a drug interaction study in healthy individuals, peak plasma concentrations and AUC of topiramate increased by 27 and 29%, respectively, following the addition of hydrochlorothiazide (25 mg daily). Steady-state pharmacokinetics of hydrochlorothiazide were not substantially altered by concomitant administration of topiramate. Although the clinical importance of this interaction is not known, topiramate dosage adjustment may be necessary when hydrochlorothiazide is initiated.

In addition, both topiramate and hydrochlorothiazide have been shown to decrease serum potassium concentrations, and the decrease is greater when hydrochlorothiazide and topiramate are given in combination.

Lithium

Although the pharmacokinetics of lithium were not affected during concurrent topiramate therapy at a dosage of 200 mg daily, an increase in lithium exposure (peak concentrations and AUC increased by 27 and 26%, respectively) has been reported in patients concurrently receiving topiramate dosages of up to 600 mg daily. Serum lithium concentrations should therefore be monitored in patients receiving concurrent lithium and high-dose topiramate therapy.

Oral Contraceptives

In a pharmacokinetic study in healthy individuals, mean exposure to either component of an oral contraceptive containing 35 mcg of ethinyl estradiol and 1 mg of norethindrone was not substantially altered by concomitant administration of topiramate (given in the absence of other drugs). However, substantially decreased exposure to ethinyl estradiol was observed in patients receiving an oral contraceptive containing ethinyl estradiol and norethindrone in conjunction with topiramate and valproic acid therapy; exposure to norethindrone was not substantially affected. The possibility of contraceptive failure and increased breakthrough bleeding should be considered in patients receiving combination oral contraceptives with topiramate. Such patients should be advised to report any changes in bleeding patterns to a clinician; contraceptive efficacy can be decreased even in the absence of breakthrough bleeding.(See Cautions: Pregnancy and Lactation.)

Propranolol

Concomitant administration of topiramate (200 mg daily) and propranolol (160 mg daily) in healthy individuals did not affect the pharmacokinetics of either drug.

Risperidone

Risperidone systemic exposure was decreased by 16 and 33% during concomitant topiramate therapy at dosages of 250 and 400 mg daily, respectively; no alterations of 9-hydroxyrisperidone (the active metabolite of risperidone; paliperidone) concentrations were observed. Concurrent administration of topiramate and risperidone increased peak plasma concentrations and AUC of topiramate by 14 and 12%, respectively. There were no clinically important changes in the systemic exposure of risperidone plus 9-hydroxyrisperidone or of topiramate; therefore, this interaction is unlikely to be clinically important.

Sumatriptan

In healthy individuals, topiramate (100 mg every 12 hours) did not affect the pharmacokinetics of single-dose sumatriptan (100 mg orally or 6 mg subcutaneously).

Venlafaxine

Concomitant multiple-dose administration of topiramate (150 mg daily) and venlafaxine (150 mg as extended-release capsules) in healthy individuals did not affect pharmacokinetics of venlafaxine, its active metabolite (O-desmethylvenlafaxine), or topiramate.

Pharmacokinetics

Absorption

Topiramate is rapidly absorbed with peak plasma concentrations occurring about 2 hours following an oral dose of 400 mg. The capsule/sprinkle formulation of the drug is bioequivalent to the immediate-release tablet and, therefore, may be substituted as a therapeutic equivalent. The relative bioavailability of topiramate from the tablet formulation is about 80% compared with a solution. Topiramate exhibits linear, dose-proportional increases in plasma concentration over a dosage range of 200-800 mg daily. Food does not appear to affect bioavailability of the drug.

Distribution

Topiramate crosses the placenta and is distributed into breast milk. Approximately 15-41% of topiramate is bound to plasma proteins, with the fraction of protein binding decreasing as blood concentration increases.

Elimination

The mean elimination half-life of topiramate is 21 hours following single or multiple doses of the drug. Approximately 70% of an administered dose is eliminated principally in urine as unchanged drug. Topiramate is not extensively metabolized; six minor metabolites have been identified, none of which constitutes more than 5% of an administered dose.

In patients with moderate renal impairment (creatinine clearance 30-69 mL/minute per 1.73 m) or severe renal impairment (creatinine clearance less than 30 mL/minute per 1.73 m), clearance of topiramate was reduced by 42 or 54%, respectively. However, since topiramate also undergoes substantial tubular reabsorption, the manufacturers state that creatinine clearance may not always predict clearance of topiramate. Geriatric patients with renal impairment also exhibited reduced clearance of the drug.(See Cautions: Geriatric Precautions.) In patients undergoing hemodialysis, clearance of topiramate is 4-6 times more rapid than in healthy individuals. (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Although the mechanism is not well understood, patients with hepatic impairment may have decreased clearance of topiramate.

Changes in topiramate clearance also have been observed in pediatric patients.(See Cautions: Pediatric Precautions.)

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