Uses
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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.
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Initial Monotherapy
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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 During the initial open-label phase, any anticonvulsant being used for temporary or emergency purposes was withdrawn before the patients were randomized.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.)
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Adjunctive Therapy
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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.
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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.
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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%).
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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.
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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.