AHFS Class:

• Anticonvulsants, Miscellaneous 28:12.92

Generic Name(s):

• Topiramate

Topiramate, a sulfamate-substituted derivative of d-fructose, is an anticonvulsant and antimigraine agent.1,3,5,17,18

Seizure Disorders

Topiramate is used as initial monotherapy or as adjunctive therapy (i.e., in combination with other anticonvulsants) in the management of seizure disorders.1,51 Efficacy of the drug in the management of seizure disorders has been evaluated principally using topiramate immediate-release tablets.1,51 Efficacy of the extended-release capsules is based on experience with immediate-release topiramate and studies demonstrating pharmacokinetic equivalence between the formulations.87,88 Efficacy of topiramate oral solution is based on experience with topiramate tablets and sprinkle capsules and studies demonstrating comparable bioavailability between these dosage forms.90

Initial Monotherapy

Partial Seizures or Primary Generalized Tonic-Clonic Seizures

Topiramate is used as initial monotherapy in the management of partial-onset seizures or primary generalized tonic-clonic seizures in adults and pediatric patients 2 years of age or older (6 years of age or older for Trokendi XR^® only).1,87,88,90

Safety and efficacy of topiramate as initial monotherapy of seizures in adults and pediatric patients 10 years of age or older have been 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.1,51 Of those enrolled, 49% had no prior treatment with anticonvulsant drugs.1 During an initial open-label phase, all patients received an initial topiramate dosage of 25 mg daily for 7 days (as an immediate-release preparation).1,51 This was followed by a double-blind phase, in which patients were randomized to receive topiramate (titrated to a target maintenance dosage of 50 or 400 mg daily or the maximum tolerated dosage) for a median of 9 months.1,51 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.1 In this study, the 400-mg daily dosage was superior to the 50-mg daily dosage in delaying time to first seizure.1,51 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.51 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.51 At 12 months, 76 or 59% of patients randomized to the 400- or 50-mg daily dosage targets, respectively, were seizure free.51 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.1

Topiramate's efficacy as initial monotherapy in pediatric patients 2-9 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 conducted with an immediate-release formulation of the drug.1,87,88,90 This approach consisted of first demonstrating that the exposure-response relationships in pediatric patients (as young as 2 years of age) and adults were similar when immediate-release topiramate was given as adjunctive therapy; similarity of the exposure-response was then demonstrated in pediatric patients (6 to younger than 16 years of age) and adults when topiramate was used as initial monotherapy.1,87,88,90 Specific dosage recommendations in children 2-9 years of age were derived from simulations using plasma exposure ranges observed in pediatric and adult patients receiving topiramate as initial monotherapy.1,87,88,90

Adjunctive Therapy

Partial Seizures

Topiramate is used as adjunctive therapy (i.e., in combination with other anticonvulsants) in the management of partial-onset seizures in adults and pediatric patients 2 years of age or older (6 years of age or older for Trokendi XR^® only).1,5,6,7,8,9,10,22,25,87,88,90,91,96

Efficacy of topiramate as adjunctive therapy in adults with partial seizures with or without secondarily generalized tonic-clonic seizures has been established in 6 controlled clinical studies.1,6,7,8,9,10,22,25,87,91 In these studies, patients initially were stabilized with optimum dosages of 1 or 2 anticonvulsant drugs (e.g., carbamazepine, clonazepam, phenobarbital, phenytoin, primidone, valproic acid) during a 4- to 12-week baseline period;1,6,7,8,9,10,22 those experiencing a prespecified minimum number of partial seizures during this baseline period were randomized to receive topiramate (as an immediate-release preparation) 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.1,6,7,8,9,10,22 Efficacy of topiramate in these studies principally was evaluated in terms of the change in seizure frequency (i.e., median percent decrease or increase in average monthly seizure rate) and the responder rate (i.e., percentage of patients with at least a 50% reduction in seizure frequency).1,6,7,8,9,10,22,25

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.1,6 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.1,6,8 Patients receiving 600 mg of topiramate daily in 3 of the studies experienced a decrease in seizure frequency of 41-46%,1,6,7,9 and patients receiving placebo experienced a decrease in seizure frequency of 1-13% in 2 of the studies,1,6,7 and an increase in seizure frequency of 12% in the third study.1,9 In the 3 studies in which patients received topiramate 600 mg daily or placebo, 40-47 or 9-18%, respectively, were considered responders.1,6,7,9 Patients receiving topiramate 800 mg daily in 2 studies experienced a decrease in seizure frequency of 24-41%,1,7,10 and patients receiving placebo experienced a decrease in monthly seizure rate of 1-2% in one study1,7 and an 18-21% increase in seizure frequency in the other study.1,10 In the studies of patients receiving topiramate 800 mg daily or placebo, 40-43 or 0-9%, respectively, were considered responders.1,7,10 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,1,7 and 36-38 or 8-9% of patients, respectively, were reported to be responders.1,7 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.7,25

Efficacy of topiramate as adjunctive therapy in pediatric patients (2-16 years of age) with partial seizures with or without secondarily generalized seizures has been established in a multicenter, randomized controlled trial.1,35,87 In this study, patients initially were stabilized with optimum dosages of 1 or 2 anticonvulsant drugs; patients who experienced 6 or more partial seizures with or without secondary generalization during an 8-week baseline period were randomized to receive topiramate (as an immediate-release preparation) or placebo.1,35 Target dosages were assigned based on the patient's body weight to approximate a dosage of 6 mg/kg daily (corresponding to daily dosages of 125, 175, 225, or 400 mg daily); after titration to the target dosage, patients were treated for an additional 8 weeks.1,35 Patients receiving topiramate 6 mg/kg daily or placebo experienced a decrease in seizure frequency of 33 or 11%, respectively, and the responder rate was 39 or 20%, respectively.1,35

Efficacy of topiramate extended-release capsules (Qudexy^® XR) was evaluated in a double-blind, placebo-controlled study (PREVAIL) in adults with partial-onset seizures with or without secondary generalization who were experiencing at least 8 partial seizures during an 8-week baseline period while receiving stable dosages of 1-3 anticonvulsant agents.87,91 Topiramate was administered at an initial dosage of 50 mg once daily (as extended-release capsules) and increased at weekly intervals during a 3-week titration period up to a dosage of 200 mg daily; the maintenance dosage was continued for an additional 8 weeks.87,91 Patients receiving topiramate experienced a substantial reduction in seizure frequency from baseline compared with those receiving placebo (mean percent reduction of 40 versus 22%).87,91 This reduction in seizure frequency was sustained over 1 year in an open-label extension study of PREVAIL (PREVAIL OLE).96

Primary Generalized Tonic-Clonic Seizures

Topiramate is used as adjunctive therapy (i.e., in combination with other anticonvulsants) in the management of primary generalized tonic-clonic seizures in adults and pediatric patients 2 years of age or older (6 years of age or older for Trokendi XR^®).1,39,87,88,90

Efficacy of topiramate for this seizure type has been established in a multicenter, double-blind, randomized controlled trial.1,39,87 In this study, patients (age range: 3-59 years) initially were stabilized on optimum dosages of 1 or 2 anticonvulsant drugs during an 8-week baseline period; patients who experienced 3 or more primary generalized tonic-clonic seizures were randomized to receive topiramate (as an immediate-release preparation) or placebo.1,39 Target dosages were assigned based on the patient's body weight to approximate a dosage of 6 mg/kg daily (corresponding to daily dosages of 175, 225, or 400 mg daily); after titration to the target dosage, patients were treated for an additional 12 weeks.1,39 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 at least a 50% reduction in seizure frequency).1 Patients receiving topiramate 6 mg/kg daily or placebo experienced a decrease in seizure frequency of 57 or 9%, respectively, and the responder rate was 56 or 20%, respectively.1 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.40

Seizures Associated with Lennox-Gastaut Syndrome

Topiramate is used as adjunctive therapy (i.e., in combination with other anticonvulsants) in the management of seizures associated with Lennox-Gastaut syndrome in adults and pediatric patients 2 years of age or older (6 years of age or older for Trokendi XR^® only).1,87,88,90,97,98

Efficacy of topiramate for this seizure type has been established in a multicenter, double-blind, randomized controlled trial.1,97 In this study, patients (age range: 2-42 years) who were experiencing 60 or more seizures per month prior to study entry were stabilized on optimum dosages of 1 or 2 anticonvulsant drugs during a 4-week baseline period.1,97 Patients were then randomized to receive adjunctive therapy with topiramate (administered as an immediate-release preparation and titrated to a target dosage of 6 mg/kg daily) or placebo; after titration to the target dosage, patients were treated for an additional 8 weeks.1,97 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 at least a 50% reduction in seizure frequency), and the overall improvement in seizure severity as rated by the caregiver.1,97 Patients receiving topiramate 6 mg/kg daily experienced a median reduction in seizure frequency of 15%, while those receiving placebo experienced an increase of 5%.1,97 Overall improvement in seizure severity was reported in more patients receiving topiramate (52%) than in those receiving placebo (28%).1,97 Responder rates were not significantly different between patients receiving topiramate (28%) and those receiving placebo (14%).1,97 An open-label, long-term extension study of this trial found sustained efficacy of topiramate for 3 or more years.98

Seizures Associated with Dravet Syndrome

Topiramate has been used as adjunctive therapy in the treatment of seizures associated with Dravet syndrome†.310,311,312,314 Although evidence from controlled studies is limited,311,314,315 experts generally recommend initial treatment with either clobazam† or valproic acid†, followed by a combination of both drugs; however, adequate seizure control is rarely achieved with these drugs alone, and most patients will require additional anticonvulsant agents.310,311,312,314 Topiramate has been recommended as a second-line anticonvulsant option in patients with Dravet syndrome.310,312,314 Results of several small, open-label prospective and retrospective studies indicate that about 35-78% of patients respond with a greater than 50% reduction in seizures and about 8-17% of patients achieve seizure freedom.311,312,314

Clinical Perspective

Current drugs or drug classes used in the management of focal (partial onset) and/or generalized seizures include benzodiazepines, lamotrigine, levetiracetam, perampanel, phenobarbital, topiramate, sodium valproate, zonisamide, brivaracetam, carbamazepine, eslicarbazepine, gabapentin, lacosamide, oxcarbazepine, phenytoin, pregabalin, tiagabine, and vigabatrin.6000 Selection of appropriate treatment should be individualized and consider factors such as the specific seizure type, epilepsy syndrome, drug efficacy and adverse effects, and comorbid conditions.6000

In a joint 2018 guideline from the American Academy of Neurology (AAN) and the American Epilepsy Society, topiramate is classified as possibly effective for the management of adults with new-onset epilepsy with focal epilepsy or unclassified generalized tonic-clonic seizures; however, the guideline states that efficacy should be further evaluated in randomized controlled studies with doses commonly used in clinical practice.6001 For pediatric patients with new-onset epilepsy with focal epilepsy or unclassified generalized tonic-clonic seizures, the guideline states that no recommendations can be made regarding the use of topiramate monotherapy due to inappropriate dosing of the drug in clinical trials.6001

Guidelines on management of treatment-resistant epilepsy from the AAN and the American Epilepsy Society include recommendations for use of topiramate as monotherapy for focal epilepsy in adults and as adjunctive treatment for focal epilepsy in adults and pediatric patients in addition to use for treatment of idiopathic generalized epilepsy and Lennox-Gastaut syndrome.6002 No recommendation is made for use of monotherapy to manage treatment-resistant focal epilepsy in pediatric patients due to a lack of data.6002

Migraine Prophylaxis

Topiramate is used for the prevention of migraine headaches in adults and adolescents 12 years of age or older.1,44,84,87,88 90,99

Efficacy of topiramate for migraine prophylaxis in adults has been established in 2 randomized, double-blind, placebo-controlled trials in over 900 patients with at least a 6-month history of migraine headaches, with or without associated aura, who were experiencing 3-12 migraines over a 4-week baseline period; patients with cluster headaches or basilar, ophthalmoplegic, hemiplegic, or transformed migraine headaches were excluded from the studies.1,44,84 In both studies, patients were randomized to receive topiramate (as an immediate-release preparation and titrated to a target dosage of 50, 100, or 200 mg daily or the maximum tolerated dosage) or placebo for 26 weeks.1,44,84 Efficacy of topiramate was evaluated in terms of the reduction in migraine headache frequency, as measured by the change in 4-week migraine headache rate from baseline to the double-blind treatment period in each topiramate treatment group compared with placebo.1,44,84 The mean migraine headache frequency at baseline in all treatment groups in both studies was approximately 5.5 migraines per 28 days.1,44,84 In the first study, the reduction in 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.1 In the second study, the reduction in 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.1,44 In both studies, there were no apparent differences in treatment effect with respect to age or gender.1 Because most patients were white, there are insufficient data to determine whether there are any treatment differences based on race.1 A long-term, open-label extension study that included patients from both randomized controlled trials of topiramate for migraine prophylaxis found the reduction in migraine frequency to be sustained for up to 14 months.99

Efficacy of topiramate for the prevention of migraine headaches in adolescents has been established in a randomized, double-blind, parallel-group study in patients 12-17 years of age with episodic migraine headaches with or without aura.1,86 Patients who experienced 3-12 migraines with no more than 14 headache days (including nonmigraine headaches) over a 4-week baseline period were randomized to receive topiramate (administered as an immediate-release preparation and titrated to a dosage of 50 or 100 mg daily) or placebo for 16 weeks.1,86 Patients receiving topiramate 100 mg daily experienced a substantially greater reduction in monthly migraine attacks from baseline compared with placebo (median reduction of 72 versus 44%); however, there was no difference in the monthly attack rate between topiramate 50 mg daily and placebo.1,86

Clinical Perspective

Preventive treatment of migraine should be considered in patients with frequent attacks or attacks that interfere with daily life; patients with adverse effects or contraindications to acute treatments; and those who fail or overuse acute treatments.6009 Patient preference should also factor into the decision-making process.6009 Prior to establishing a preventive treatment plan, appropriate use of acute treatments should be evaluated and lifestyle modifications initiated.6009 Several guidelines on the management of migraines have been published by experts including the American Academy of Neurology (AAN) and the American Headache Society (AHS).6003,6009 Drugs with established efficacy for migraine prevention based on reliable evidence supporting efficacy and safety include several oral agents (e.g., divalproex sodium, sodium valproate, topiramate, metoprolol, propranolol, timolol, frovatriptan) and parenteral agents (e.g., eptinezumab, erenumab, fremanezumab, galcanezumab, onabotulinumtoxinA).6009 The existing evidence is not sufficient to support superiority of one agent over another; therefore, selection of an appropriate agent should be individualized and take into consideration drug efficacy, tolerability, cost, patient comorbidities, and other patient-specific factors.6003,6009 Combining preventive drugs from different classes may be useful when there is a suboptimal response or dose-limiting adverse effects of a particular agent.6009

Guidelines on pediatric migraine prevention from the AAN and AHS suggest that preventive treatments may be considered in pediatric patients with frequent headaches, disability related to migraine, or medication overuse; however, the existing evidence is limited and many trials failed to show a benefit with preventive treatments over placebo.6004 Although topiramate has been shown to decrease the frequency of migraine, it is not clear whether the effects achieved are clinically meaningful in children and adolescents.6004

Alcohol Dependence

Topiramate has been used successfully in adults for the management of alcohol dependence†.52,53,54,55,56,57,60,61,73,74,75,76,77,78 Efficacy of the drug in this condition has been evaluated in 2 randomized, double-blind, placebo-controlled studies in adults who met Diagnostic and Statistical Manual of Mental Disorders (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.52,55 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.52,55,62 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.52,53,55,56 In addition, topiramate was shown to reduce self-reported alcohol craving to a greater extent than placebo in the 12-week study.52,53 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.54,74 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.75

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 FDA for this indication.78 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.52,55,56,57,74,77 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.53,57,60,61,65,74,75

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.61,65,66,76

Antipsychotic-induced Weight Gain

Topiramate has been effective for moderate weight loss and prevention of weight gain from second-generation antipsychotics in patients with schizophrenia†.92,93,6005 Guidelines from the American Psychiatric Association (APA) state that pharmacologic weight management with topiramate can be considered in such patients based on a modest benefit seen in several small studies evaluating the efficacy of topiramate for this indication; however, this benefit should be weighed against the potential risk of adverse effects.6005

Binge Eating Disorder

Topiramate has been evaluated in randomized controlled trials and found to be effective for the treatment of binge eating disorder†, by reducing the number of binge episodes and binge days per week; however, its use may be precluded by the potential for adverse effects.94,6006 Guidelines from the APA support the use of topiramate for this indication.6006

Essential Tremor

Topiramate has been found to be effective for the treatment of essential tremor (ET)†, by improving functional disability, based on low-quality evidence from randomized controlled trials.95,6007,6008 Patients receiving topiramate for this indication were also significantly more likely to withdraw from treatment due to adverse effects including paresthesia, weight loss, decreased appetite, and cognitive dysfunction.95

Guidelines from the AAN recommend primidone and propranolol as first-line treatments for limb tremor in ET based on established evidence of efficacy; topiramate is listed among agents that are probably effective for this condition based on a lower level of evidence.6007 Recommendations from the International Parkinson and Movement Disorder Society also conclude that topiramate (when dosed higher than 200 mg per day), primidone, and propranolol are all efficacious and clinically useful for treatment of limb tremor.6008

General

Pretreatment Screening

• Measure serum bicarbonate prior to initiating treatment with topiramate.1

Patient Monitoring

• Closely monitor patients who are currently receiving or beginning therapy with topiramate and/or any other anticonvulsant for any indication for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.1,68,80
• Monitor height and weight in pediatric patients receiving long-term treatment with topiramate.1
• Measure serum bicarbonate periodically during treatment with topiramate.1
• Closely monitor patients, particularly pediatric patients, for evidence of decreased sweating and increased body temperature, especially in hot weather.1,87,88,90
• Monitor for seizures/increased seizure frequency when rapid withdrawal of topiramate is medically required.1
• Monitor for signs of hyperammonemic encephalopathy in patients who develop unexplained lethargy, vomiting, or changes in mental status.1

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.47,48,49,50 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).47,48,49,50 Therefore, extra care should be exercised to ensure the accuracy of both oral and written prescriptions for these drugs.47,48,49,50 Patients should be advised to carefully check their medications and to bring any questions or concerns to the attention of the dispensing pharmacist.50
• 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 ([Web]).48,49,50

Administration

Topiramate is administered orally; the drug is commercially available in various dosage forms for oral administration, including immediate-release tablets, sprinkle capsules, extended-release capsules, and an oral solution.1,87,88,90

Store topiramate tablets at 15-30°C and topiramate sprinkle capsules at or below 25°C.1 Store Qudexy^® XR extended-release capsules at 20-25°C (excursions permitted between 15-30°C).87 Store Trokendi XR^® extended-release capsules at 25°C (excursions permitted between 15-30°C).88 Store Eprontia^® oral solution at 20-25°C (excursions permitted between 15-30°C).90 Protect topiramate tablets, sprinkle capsules, and extended-release capsules from moisture during stora 1,87,88 additionally, protect Trokendi XR^® from light during storage.88

Oral Administration

Topiramate is administered orally as immediate-release tablets, sprinkle capsules, extended-release capsules, or an oral solution.1,87,88,90 The immediate-release tablets, sprinkle capsules, and oral solution are administered in 2 divided doses; the extended-release capsules are administered once daily.1,87,88,90

The manufacturer states that the sprinkle capsule formulation of topiramate is bioequivalent to the immediate-release tablet and may be substituted as a therapeutic equivalent.1 At steady state, the extended-release capsules administered once daily are bioequivalent to the immediate-release tablets administered twice daily.87,88 Because the bioavailability of topiramate is not affected by food, the drug may be administered without regard to meals.1,87,88,90

Because of the bitter taste, immediate-release tablets of topiramate should be swallowed intact and not broken or chewed.1 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.1

The sprinkle capsule formulation of topiramate may be taken whole, or may be administered by opening the capsule and sprinkling the entire contents on a small amount (e.g., a teaspoonful) of soft food (e.g., applesauce, custard, ice cream, oatmeal, pudding, yogurt).1 The patient should swallow the entire spoonful of the sprinkle/food mixture immediately; chewing should be avoided.1 It may be helpful to have the patient drink fluids immediately after administration in order to make sure that all of the mixture is swallowed.1 The sprinkle/food mixture must not be stored for use at a later time.1

Qudexy^® XR extended-release capsules may be swallowed whole or may be administered by opening the capsule and sprinkling the contents on a small amount of soft food; the sprinkle/food mixture should be swallowed immediately and not chewed, crushed, or stored for later use.87

Trokendi XR^® extended-release capsules must be swallowed whole and may not be sprinkled on food, crushed, or chewed; because of these limitations, Trokendi XR^® is not recommended for use in children younger than 6 years of age.88 The manufacturer of Trokendi XR^® states that patients should completely avoid consumption of alcohol at least 6 hours prior to and 6 hours after administration of the drug.88

A calibrated measuring device is recommended for use with Eprontia^® to ensure accurate measurement of the dose.90 A household tablespoon or teaspoon should not be used to measure the dose.90 Discard any unused portion of Eprontia^® oral solution within 30 days after opening.90

Extemporaneously Compounded Oral Liquid

An extemporaneously compounded oral liquid formulation of topiramate has been prepared.252

Standardize 4 Safety

Standardized concentrations for an extemporaneously prepared oral liquid preparation of topiramate has been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 252Multidisciplinary expert panels were convened to determine recommended standard concentrations. Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 252 For additional information on S4S (including updates that may be available), see [Web].252

Dosage

Dosage of topiramate must be adjusted carefully and individualized according to patient response and tolerance and the condition being treated.1 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.1

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.1 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;1 transition to a new anticonvulsant regimen was permitted when clinically indicated.1 In clinical studies for migraine prophylaxis, daily dosages were decreased in weekly intervals by 25-50 mg.1 However, in situations where more rapid withdrawal of topiramate is clinically necessary, the manufacturers recommend appropriate monitoring.1

Seizure Disorders

The manufacturers state that it is not necessary to monitor plasma topiramate concentrations to achieve optimal clinical effect with the drug.1

Addition or withdrawal of phenytoin and/or carbamazepine during adjunctive therapy may require adjustment of topiramate dosage.1,11 Addition of topiramate to an anticonvulsant regimen containing phenytoin may require adjustment of the dosage of phenytoin.1

Initial Monotherapy

The recommended dosage of topiramate as initial monotherapy for management of partial-onset seizures or primary generalized tonic-clonic seizures in adults and pediatric patients 10 years of age or older is 400 mg daily (administered in 2 divided doses as immediate-release tablets, sprinkle capsules, or oral solution, or once daily as extended-release capsules).1,87,88 The dosage of topiramate should be titrated using the schedule in Table 1 or 2 depending on the dosage form used.

In a controlled study evaluating safety and efficacy of topiramate (titrated up to 50 or 400 mg daily as an immediate-release preparation) as initial monotherapy, approximately 58% of patients randomized to receive the 400-mg daily dosage achieved this maximum dosage.1 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.51

Dosage of topiramate as initial monotherapy for the management of partial-onset seizures or primary generalized tonic-clonic seizures in pediatric patients 2-9 years of age (or 6-9 years of age if using Trokendi XR^®) is based on body weight.1,83,87,88,90 During the titration period, the recommended initial dosage of topiramate is 25 mg daily (administered in the evening) for the first week.1,87,88,90 Based on tolerability, dosage can be increased to 50 mg daily (administered in 2 divided doses as immediate-release tablets, sprinkle capsules, or oral solution, or once daily as extended-release capsules) during the second week.1,87,88,90 The total daily dosage can then be increased by 25-50 mg daily each subsequent week as tolerated.1,87,88,90 Titration to the minimum recommended dosage (see Table 3) should be attempted over 5-7 weeks of the total titration period.1,87,88,90 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.1,87,88,90 The total daily dosage of topiramate should not exceed the maximum recommended maintenance dosage for each range of body weight (see Table 3).1,87,88,90

Adjunctive Therapy

In adults, the recommended dosage of topiramate as adjunctive therapy for management of partial-onset seizures or Lennox-Gastaut Syndrome is 200-400 mg daily (administered in 2 divided doses as immediate-release tablets, sprinkle capsules, or oral solution, or once daily as extended-release capsules).1,87,88,90 The recommended adult dosage for adjunctive management of primary generalized tonic-clonic seizures is 400 mg daily (administered in 2 divided doses as immediate-release tablets, sprinkle capsules, or oral solution, or once daily as extended-release capsules).1,87,88,90 Topiramate therapy should be initiated at 25-50 mg daily,1,87,88,90 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 dosa 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.41 Maintenance dosages less than 400 mg daily may be optimally effective in some patients and therefore dosage should be individualized;1 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.1 Dosages exceeding 400 mg daily have not been shown to improve responses in adults with partial-onset seizures.1,87,88,90

In pediatric patients 2-16 years of age (or 6-16 years of age if using Trokendi XR^®), the recommended dosage of topiramate as adjunctive therapy for the management of partial-onset 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 as immediate-release tablets, sprinkle capsules, or oral solution, or once daily as extended-release capsules).1,87,88,90 An initial dose of 25 mg (or less, based on a range of 1-3 mg/kg daily) should be given nightly for the first week.1,87,88,90 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 as immediate-release tablets, sprinkle capsules, or oral solution, or once daily as extended-release capsules) to achieve optimal clinical response.1,87,88,90 Dosage titration should be guided by clinical outcome; some manufacturers recommend that the total daily dose should not exceed 400 mg.1,87,88,90 Alternatively, 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.36

Dravet Syndrome

For the adjunctive treatment of seizures associated with Dravet syndrome† in children, dosages of topiramate are similar to those of other epilepsy types; typical starting dosage ranges from 0.5 to 2 mg/kg daily (in divided doses) and is increased to a target dosage of 5-12 mg/kg daily.311,314

Migraine Prophylaxis

The recommended dosage of topiramate for prophylaxis of migraine headache in adults and adolescents 12 years of age or older is 100 mg daily (administered in 2 divided doses as immediate-release tablets, sprinkle capsules, or oral solution, or once daily as extended-release capsules).1,87,88,90 The dosage of topiramate should be titrated using the schedule in Table 4 or 5 depending on the dosage form used.1,87,88,90

Titration of topiramate dosage should be guided by clinical outcome.1,87,88,90 If required, longer intervals between dosage adjustments can be used.1,87,88,90

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.52,53,54,55,60,74,76,78

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).52,55,74,76,77,78 A period of abstinence from alcohol prior to initiating topiramate therapy for alcohol dependence does not appear to be necessary.52,55,56,57,74,77

Special Populations

Hepatic Impairment

Although topiramate clearance may decrease in patients with hepatic impairment, the manufacturers make no specific recommendations for dosage adjustment in such patients.1

Renal Impairment

Dosage of topiramate should be adjusted according to the degree of renal impairment.1 In patients with creatinine clearance less than 70 mL/minute per 1.73 m², the daily dosage of topiramate should be decreased by 50%.1,87,88,90 Dosage adjustment also may be required in patients undergoing hemodialysis since clearance of topiramate is 4-6 times faster in such patients.1,87,88,90 To avoid rapid decreases in 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.1,87,88,90

Geriatric Patients

The manufacturers make no specific dosage recommendations for geriatric patients.1

Contraindications

• There are no known contraindications to the use of immediate-release topiramate and Qudexy^® XR extended-release topiramate capsules.1,87,90 Trokendi XR^® extended-release topiramate capsules are contraindicated in patients with recent alcohol use (i.e., within 6 hours prior to or 6 hours after topiramate use).88

Warnings/Precautions

Acute Myopia and Secondary Closure Glaucoma Syndrome

A syndrome consisting of acute myopia associated with secondary angle-closure glaucoma has been reported in some adults and pediatric patients receiving topiramate.1,74,87,88,90 This syndrome may be associated with supraciliary effusion, resulting in anterior displacement of the lens and iris and, subsequently, secondary angle-closure glaucoma.1,87,88,90 Symptoms include acute onset of decreased visual acuity and/or ocular pain and typically occur within one month of initiating topiramate therapy.1,87,88,90 Ophthalmologic findings include myopia, mydriasis, anterior chamber shallowing, ocular hyperemia, choroidal detachments, retinal pigment epithelial detachments, macular striae, and increased intraocular pressure.1,87,88,90 Untreated elevations in intraocular pressure can lead to serious sequelae including permanent vision loss.1,87,88,90

If any adverse ocular effects or visual problems occur during topiramate therapy, discontinue the drug as rapidly as possible; additional supportive measures may also be indicated.1,87,88,90

Visual Field Defects

Visual field defects not associated with elevated intraocular pressure also have been reported in patients receiving topiramate in clinical trials and during postmarketing experience.1,87,88,90 If visual problems occur during treatment with topiramate, consider discontinuing the drug.1,87,88,90 Manifestations generally resolve after drug is discontinued.1,87,88,90

Oligohidrosis and Hyperthermia

Oligohidrosis, which rarely may require hospitalization, has been reported in patients receiving topiramate; most cases have occurred in pediatric patients.1,87,88,90 Manifestations include decreased sweating and an elevation in body temperature above normal (hyperthermia).1,87,88,90 Some cases occurred following exposure to elevated environmental temperatures.1,87,88,90 Closely monitor patients, particularly pediatric patients, receiving topiramate for evidence of decreased sweating and increased body temperature, especially in hot weather.1,87,88,90 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).1,87,88,90

Metabolic Acidosis

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 adults and pediatric patients receiving immediate-release topiramate.1,87 Such electrolyte imbalance can occur at any time during therapy.1,87,88,90 Metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of topiramate on carbonic anhydrase.1,87,88,90 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 approximately 6 mg/kg daily in pediatric patients); marked decreases in serum bicarbonate concentrations (to below 10 mEq/L) may rarely occur.1,87,88,90 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.1,87,88,90

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, reduced growth rates in pediatric patients), the manufacturers state that serum bicarbonate concentrations should be measured at baseline and periodically during topiramate therapy.1,87,88,90 If metabolic acidosis develops and persists, consider reducing the dosage or discontinuing topiramate therapy (by gradually tapering the dosage).1,87,88,90 If a decision is made to continue topiramate therapy in the presence of persistent acidosis, consider alkali treatment.1,87,88,90

Interaction with Alcohol

Use of Trokendi XR^® is contraindicated in patients with recent alcohol use (i.e., within 6 hours prior to or 6 hours after topiramate use).88 In vitro data indicate that in the presence of alcohol, plasma concentrations of Trokendi XR^® extended-release topiramate capsules may be markedly increased soon after dosing and become subtherapeutic later in the day.88

Suicidal Behavior and Ideation

An increased risk of suicidality (suicidal behavior or ideation) was observed in an analysis of studies using various anticonvulsants compared with placebo.1,68,80,87,88,90 The analysis of suicidality reports from 199 placebo-controlled studies involving 11 anticonvulsants (carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide) in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain) found that patients receiving 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 1 week after beginning therapy and continued through 24 weeks.1,68,87,88,90 Although patients treated with an anticonvulsant for epilepsy, psychiatric disorders, and other conditions were all found to be at increased risk for suicidality compared with those receiving placebo, the relative risk for suicidality was found to be higher in patients with epilepsy compared with those receiving anticonvulsants for other conditions.1,68,87,88,90

Clinicians who prescribe topiramate or any other anticonvulsant should balance the risk for suicidality with the risk of untreated illness.1,68,87,88,90 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.1,87,88,90 If suicidal thoughts and behavior emerge during anticonvulsant therapy, the clinician should consider whether these symptoms may be related to the illness being treated.1,87,88,90

Cognitive/Neuropsychiatric Adverse Events

Immediate-release formulations of topiramate have been associated with cognitive and neuropsychiatric adverse effects; thus, these adverse effects are also expected to be associated with extended-release preparations of topiramate.1,87,88,90 Adverse CNS effects are frequently reported with topiramate 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.1,87,88,90

The risk of adverse cognitive effects is increased with rapid titration and higher initial dosages of topiramate.1,87,88,90

Somnolence and fatigue were the most commonly reported adverse effects in patients receiving topiramate for adjunctive therapy of seizure disorders.1,87,88,90 In patients receiving topiramate as initial monotherapy for seizure disorders, the incidence of somnolence appeared to be dose related.1,87,88,90 In patients receiving topiramate as adjunctive therapy for seizure disorders, the incidence of fatigue appeared to be dose related.1,87,88,90 In patients receiving topiramate for migraine prophylaxis, both somnolence and fatigue appeared to be dose related and occurred more frequently during the titration phase.1,87,88,90

Psychiatric or behavioral disturbances reported with topiramate in the adjunctive epilepsy and migraine populations were dose related.1,87,88,90 Suicide attempts also have been reported in patients receiving the drug.1,87,88,90

Other common adverse psychiatric effects reported with topiramate include nervousness, anxiety, aggression, insomnia, decreased libido, personality disorder, and anorexia; other frequently reported CNS effects include dizziness, ataxia, paresthesia, hypoesthesia, nystagmus, tremor, and abnormal gait or coordination.1,87,88,90

Fetal/Neonatal Morbidity and Mortality

Topiramate can cause fetal harm when administered to pregnant patients.1,87,88,90 Exposure to the drug in utero has been associated with an increased risk of oral clefts (cleft lip and/or palate) and for neonates being small for gestational age (SGA).1,87,88,90 Structural malformations, including craniofacial defects, and reduced fetal weights have occurred in the offspring of pregnant animals exposed to topiramate at clinically relevant dosages.1,87,88,90

Carefully consider the benefits and risks of topiramate therapy when use of the drug in females of reproductive potential is contemplated, particularly for conditions not usually associated with permanent injury or death.1,87,88,90 Inform all females of reproductive potential of the potential risks to the fetus from exposure to topiramate.1,87,88,90

Withdrawal of Antiepileptic Drugs

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.1,87,88,90 The manufacturers recommend appropriate monitoring in situations where more rapid withdrawal of topiramate is required.1,87,88,90

Decrease in Bone Mineral Density

The results from a one-year, active-controlled trial in pediatric patients treated with topiramate monotherapy found statistically significant decreases in bone mineral density in both the lumbar spine and total body less head among patients treated with topiramate.1 Of 63 pediatric patients in the trial, 21% of patients treated with topiramate experienced decreases in Z score of at least -0.5 from baseline compared with 0% of patients in the control group.1 These bone mineral density changes occurred most commonly among patients aged 6-9 years, although they occurred across all age groups in the trial.1 The potential impact of topiramate on fracture risk cannot be determined due to the small sample size and short duration of the trial.1 Decreases in bone mineral density in the lumbar spine were correlated with decreases in serum bicarbonate; these decreases are reflective of metabolic acidosis, which is known to occur during treatment with topiramate and is associated with increased resorption of bone.1 Patients treated with topiramate also had small reductions in markers of bone metabolism (e.g., alkaline phosphatase, calcium, phosphorus, and 1,25-dihydroxyvitamin D), larger reductions in markers of bone metabolism (e.g., parathyroid hormone and 25-hydroxyvitamin D), and increased urinary calcium excretion.1

Negative Effects on Growth (Height and Weight)

A one-year, active-controlled study of 63 pediatric patients treated with topiramate found statistically significant reductions in mean annual change from baseline in body weight compared to control; similar reductions in height velocity and change in height from baseline were also observed.1 These negative effects on height and weight were observed across all included age groups.1 Carefully monitor height and weight in pediatric patients receiving long-term therapy with topiramate.1

Serious Skin Reactions

Serious skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in patients treated with topiramate.1,87,88,90 Discontinue topiramate at the first sign of a rash, unless it is clearly unrelated to the drug.1,87,88,90 If signs or symptoms of Stevens-Johnson syndrome or toxic epidermal necrolysis occur, do not resume therapy with topiramate and consider alternative treatment.1,87,88,90

Hyperammonemia and Encephalopathy (without and with Concomitant Valproic Acid)

Dose-related hyperammonemia with or without encephalopathy has been reported in patients receiving topiramate in clinical studies and during postmarketing experience.1,87,88,90 In adolescents 12-17 years of age who received topiramate monotherapy in migraine prophylaxis studies, hyperammonemia was reported in 26, 14, or 9% of those receiving topiramate 100 mg daily, topiramate 50 mg daily, or placebo, respectively.1,87,88,90 In some cases, ammonia concentrations were markedly increased in patients receiving the highest dosage of 100 mg daily.1,87,88,90 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.1,87,88,90 Although topiramate is not labeled for use in pediatric patients 1-24 months of age, dose-related hyperammonemia was observed in such patients who were receiving topiramate and valproic acid concomitantly in partial-onset seizure studies.1,87,88,90 Although some patients may be asymptomatic, manifestations of hyperammonemic encephalopathy include acute alterations in the level of consciousness and/or cognitive function with lethargy or vomiting; in most cases, manifestations abated after discontinuance of therapy.1,87,88,90 Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy.1,87,88,90 Although not studied, it is possible that an interaction between topiramate and valproic acid may exacerbate existing defects or unmask deficiencies in susceptible individuals.1,87,88,90 If unexplained lethargy, vomiting, or changes in mental status occur, hyperammonemic encephalopathy should be considered, and an ammonia concentration should be measured.1,87,88,90

Kidney Stones

Formation of kidney stones has been reported in approximately 1.5% of adults receiving topiramate in clinical trials.1,87,88,90 As in the general population, the incidence of kidney stone formation among topiramate-treated patients appears to be higher in men than in women;1,87,88,90 kidney stones also have been reported in pediatric patients receiving topiramate.1,87,88,90 Because topiramate is a carbonic anhydrase inhibitor, the drug may promote stone formation by reducing urinary citrate excretion and increasing urinary pH.1,87,88,90 The manufacturers state that use of topiramate in patients on a ketogenic diet or concomitant use of the drug with other drugs that produce metabolic acidosis may increase the risk of kidney stone formation and, therefore, should be avoided.1,87,88,90 Increased fluid intake may increase urinary output and reduce the concentration of substances involved in stone formation.1,87,88,90 Instruct patients receiving topiramate, particularly those with predisposing factors, to maintain adequate hydration to prevent kidney stone formation.1,87,88,90 In a one-year, active controlled trial of pediatric patients, an increase in urinary calcium and a marked decrease in urinary citrate were observed among patients treated with topiramate; this increased ratio increases the risk for kidney stones and nephrocalcinosis.1

Hypothermia with Concomitant Valproic Acid

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.1,87,88,90 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.1,87,88,90 Hypothermia may occur after initiating topiramate therapy or following a dosage increase.1,87,88,90 Consider discontinuance of topiramate or valproic acid therapy in patients who develop hypothermia.1,87,88,90 Since hypothermia also may be a manifestation of hyperammonemia, clinical management and assessment of hypothermia should include determination of plasma ammonia concentrations.1,87,88,90

Specific Populations

Pregnancy

Topiramate can cause fetal harm when administered to pregnant patients.1,81,82 Exposure to the drug in utero has been associated with an increased risk of oral clefts (cleft lip and/or palate) and for neonates being SGA (i.e., birth weight less than 10th percentile).1,81,82 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.1,81,82 The prevalence of oral clefts among infants in the NAAED registry who were exposed to topiramate in utero was 1.1% compared with a prevalence of 0.36% in infants exposed to a reference anticonvulsant and a prevalence of 0.12% in infants born to women without epilepsy and without exposure to anticonvulsant agents.1 For comparison, the estimated background rate of oral clefts in the US as estimated by the US Centers for Disease Control and Prevention (CDC) is 0.17%.1 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.1 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;1,82 the reported rate was 16 times higher than the background rate in the United Kingdom, which is approximately 0.2%.1

Data from the NAAED registry indicate that 19.7% of infants who were exposed to topiramate in utero were SGA compared with 7.9% of infants exposed to a reference anticonvulsant and 5.4% of infants born to women without epilepsy and without exposure to anticonvulsant agents.1 In another population-based birth registry, 25% of topiramate-exposed infants were SGA compared with 9% of infants who were not exposed to anticonvulsants.1 The prevalence of this adverse effect is higher in infants born to women who received higher dosages of topiramate during pregnancy or who continued to receive topiramate through the third trimester.1 SGA has been observed at all dosages of topiramate and appears to be dose dependent; however, the long-term consequences of these findings are not known.1

Topiramate has demonstrated selective developmental toxicity, including teratogenicity and embryotoxicity, in multiple species of animals (rats, rabbits, mice).1 Structural malformations, including craniofacial defects, and reduced fetal weights have occurred in the offspring of pregnant animals exposed to topiramate at clinically relevant dosages in the absence of maternal toxicity.1 However, there also was some evidence of maternal toxicity (e.g., decreased maternal body weight gain, increased mortality).1

Topiramate therapy can cause metabolic acidosis.1 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.1 Therefore, pregnant women receiving topiramate should be monitored and treated for metabolic acidosis in the same manner as nonpregnant patients.1 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.1

The benefits and risks of topiramate therapy should be carefully considered when use of the drug in females of reproductive potential is contemplated, particularly for conditions not usually associated with permanent injury or death.1,81 All females of reproductive potential should be informed of the potential risks to the fetus from exposure to topiramate.1 Alternative options should be considered in patients who are planning a pregnancy.1,81 If a decision is made to use topiramate in a female of reproductive potential who is not planning a pregnancy, clinicians should recommend use of effective contraception.1,81 The potential for decreased efficacy of estrogen-containing oral contraceptives should be considered.1,81

Women who become pregnant while receiving topiramate should be encouraged to enroll in the NAAED pregnancy registry; patients can enroll by calling 888-233-2334.1 Information on the registry also can be found on the website [Web].1

Lactation

Limited data indicate that topiramate distributes into human milk at concentrations similar to those in maternal plasma.1,81 The effects of topiramate on milk production are not known.1,87,88,90 Diarrhea and somnolence have been reported in breast-fed infants whose mothers were receiving topiramate treatment.1,87,88,90 The known benefits of breast-feeding should be considered along with the clinical importance of the drug to the mother and any potential adverse effects on the breast-fed infant from topiramate or the underlying maternal condition.1,81,87,88,90

Females and Males of Reproductive Potential

All females of reproductive potential should be informed of the potential risks to the fetus from exposure to topiramate.1 Alternative options should be considered in patients who are planning a pregnancy.1,81 If a decision is made to use topiramate in a female of reproductive potential who is not planning a pregnancy, clinicians should recommend use of effective contraception.1,81 The potential for decreased efficacy of estrogen-containing oral contraceptives should be considered.1,81

Pediatric Use

Safety and efficacy of topiramate for the management of seizure disorders have not been established in children younger than 2 years of age.1,87,90 In a randomized, double-blind, placebo-controlled study in infants 1-24 months of age, topiramate in fixed dosages of 5, 15, and 25 mg/kg daily was not shown to be more effective than placebo in controlling seizures after 20 days of treatment.1 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.1 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.1 Although other preparations of topiramate may be used in children as young as 2 years of age for the management of seizure disorders,1,87,90 use of Trokendi XR^® extended-release capsules is recommended only in children 6 years of age or older because this capsule formulation must be swallowed whole and cannot be sprinkled on food, crushed, or chewed.88

Safety and efficacy of topiramate for migraine prophylaxis have not been established in pediatric patients younger than 12 years of age.1,87,88,90 In a controlled study in pediatric patients 6-16 years of age, topiramate 2-3 mg/kg daily was not more effective than placebo for preventing migraine headaches.1

As in adults, cognitive/neuropsychiatric effects are commonly reported in pediatric patients receiving topiramate, although the incidence appears to be lower than that observed in adults.1 Such effects include psychomotor slowing, difficulty with concentration or attention, speech disorders, and language problems.1 The most common adverse CNS effects reported in pediatric patients receiving topiramate as initial monotherapy for seizure disorders include dizziness, headache, anorexia, and somnolence.1 The most common adverse CNS effects reported in pediatric patients receiving the drug as adjunctive therapy for seizure disorders include somnolence and fatigue.1 In migraine prophylaxis studies in pediatric patients 12-17 years of age, difficulty with concentration/attention was the most commonly reported adverse CNS effect.1 Adverse cognitive effects observed in pediatric migraine studies were dose dependent and occurred with greater frequency in younger (6-11 years of age) compared with older (12-17 years of age) children.1 Topiramate may cause psychomotor slowing and decreased verbal fluency based on results of a standard neuropsychological test that was administered to adolescents 12-17 years of age.1

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 pediatric patients receiving topiramate.1 In pediatric studies evaluating topiramate as adjunctive therapy for refractory partial-onset seizures or Lennox-Gastaut syndrome, the incidence of decreased serum bicarbonate concentrations was as high as 67 or 10% for patients receiving topiramate (approximately 6 mg/kg daily) or placebo, respectively.1 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 up to 11% of patients receiving topiramate in these studies compared with no more than 2% of those receiving placebo.1 Similar reductions in serum bicarbonate were reported in an open-label, active-controlled study of pediatric patients treated with topiramate monotherapy for partial-onset seizures.1 Markedly low serum bicarbonate concentrations and persistent metabolic acidosis were reported in 35 and 76% of patients treated with topiramate, respectively.1 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.1 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 pediatric patients 1-24 months old 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.1 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.1

Reductions in bone mineral density and growth have been reported in a 1-year active-controlled study of pediatric patients receiving monotherapy with topiramate for treatment of partial-onset seizures.1 In an open-label, active-controlled study of pediatric patients aged 4-15 years with partial-onset seizures, statistically significant reductions in weight and bone mineral density in the lumbar spine and total body less head were reported among patients treated with topiramate monotherapy compared to those treated with levetiracetam monotherapy.1

Oligohidrosis (decreased sweating) and hyperthermia have been reported in clinical trials and during postmarketing surveillance of topiramate.1 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.1

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.1,83 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.1

Geriatric Use

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.1 Although no age-related differences in efficacy or safety were evident in these patients, pharmacokinetic data from one controlled clinical study 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).1 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.1 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 m²).1

Hepatic Impairment

Pharmacokinetic studies have shown that plasma clearance of topiramate decreases by an average of 26% in patients with moderate to severe hepatic impairment; however, the manufacturer does not make specific recommendations for dosage adjustment in patients with hepatic impairment.1,87,88,90

Renal Impairment

Pharmacokinetic studies have shown a decrease in clearance of topiramate by 42 and 54% in patients with moderate (creatinine clearance of 30 to less than 70 mL/minute per 1.73 m²), and severe (creatinine clearance less than 30 mL/minute per 1.73 m²) renal impairment, respectively, compared to patients with normal renal function.1,87,88,90 Administration of hemodialysis with a high-efficiency, counterflow, single pass-dialysate procedure cleared topiramate at a rate of 120 mL/minute with blood flow through the dialyzer at 400 mL/minute; this rate of clearance will remove a substantial amount of topiramate over a typical hemodialysis session.1 In patients with creatinine clearance less than 70 mL/minute per 1.73 m², the daily dosage of topiramate should be decreased by 50%.1,87,88,90 Dosage adjustment also may be required in patients undergoing hemodialysis since clearance of topiramate is 4-6 times faster in such patients.1,87,88,90

Common Adverse Effects

The most common adverse effects reported in adults and pediatric patients receiving topiramate for epilepsy (≥10% incidence and occurring more frequently with the drug than placebo) include paresthesia, anorexia, weight loss, speech disorders or other related speech problems, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, abnormal vision, and fever.1

The most common adverse effects reported in adults and pediatric patients receiving topiramate for migraine prophylaxis (5% or greater incidence and occurring more frequently with the drug than with placebo) include paresthesia, anorexia, weight loss, difficulty with memory, taste perversion, diarrhea, hypoesthesia, nausea, abdominal pain, and upper respiratory tract infection.1

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.52,54,55,60,74,78

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 CYP3A4.1 Pharmacokinetic interactions with drugs metabolized by these isoenzymes, including some anticonvulsants, CNS depressants, and oral contraceptives, are therefore possible.1 Topiramate does not inhibit CYP1A2, 2A6, 2B6, 2C9, 2D6, 2E1, or 3A4/5.1

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%.1 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.1

Anticonvulsants

Clinically important decreases in plasma concentrations of topiramate have been observed in patients receiving concomitant therapy with phenytoin or carbamazepine.1 Plasma concentrations of topiramate were reduced by 48% when administered concomitantly with phenytoin.1 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.1 Concomitant administration of carbamazepine and topiramate decreased plasma concentrations of topiramate by 40%, but did not substantially alter plasma concentrations of carbamazepine or its active metabolite, carbamazepine epoxide.1 Neither phenytoin nor carbamazepine alters the protein binding of topiramate.1

Concomitant administration of valproic acid and topiramate decreased topiramate plasma concentrations by 14% and valproic acid plasma concentrations by 11%.1 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.1 . Although not studied, the interaction between valproic acid and topiramate may exacerbate existing defects or unmask deficiencies in susceptible patients.1 Concomitant use of topiramate with valproic acid also has been associated with hypothermia (with and without hyperammonemia).1 Discontinuance of topiramate or valproic acid therapy should be considered in patients who develop hypothermia.1 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.1

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.1

Plasma concentrations of lamotrigine were altered by less than 10% when topiramate was dosed at up to 400 mg per day; plasma topiramate concentrations were decreased by 13% when the drugs were administered concomitantly.1,71,72

Antidiabetic Agents

Concomitant administration of topiramate and glyburide in patients with type 2 diabetes mellitus decreased steady-state peak plasma concentrations and AUC of glyburide by 22 and 25%, respectively.1 Systemic exposure of the active metabolites, 4- trans -hydroxyglyburide and 3- cis -hydroxyglyburide, also were reduced by 13 and 15%, respectively.1 Steady-state pharmacokinetics of topiramate were not affected by concomitant glyburide administration.1

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.1 Decreases in systemic exposure to the active hydroxy- and keto-metabolites of pioglitazone were observed; however, the clinical importance of these findings is not known.1 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.1

In healthy individuals, mean peak plasma concentrations and AUC of metformin were increased by 18 and 25%, respectively, following concomitant administration of topiramate; however, time to reach peak plasma concentrations of metformin was not affected.1 Oral clearance of topiramate appears to be reduced when administered in conjunction with metformin.1 The clinical importance of these pharmacokinetic interactions is not known.1 However, topiramate can cause metabolic acidosis, a condition for which the use of metformin is contraindicated.1

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.1

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.1 If topiramate is used concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the onset or worsening of metabolic acidosis.1

CNS Depressants

Concomitant administration of topiramate and CNS depressants (including alcohol) has not been evaluated in clinical studies.1 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.1

In vitro data indicate that in the presence of alcohol, plasma concentrations of Trokendi XR^® extended-release topiramate capsules may be markedly increased soon after dosing and become subtherapeutic later in the day.88 Use of Trokendi XR^® is contraindicated in patients with recent alcohol use (i.e., within 6 hours prior to or 6 hours after topiramate use).88

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.1

Dihydroergotamine

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

Diltiazem

Concomitant administration of topiramate and diltiazem decreased peak plasma concentrations and AUC of diltiazem by 10 and 25%, respectively.1 Systemic exposure to deacetyldiltiazem also was decreased, but there was no effect on N -monodesmethyldiltiazem.1 Diltiazem increased peak plasma concentrations and AUC of topiramate by 16 and 19%, respectively.1

Haloperidol

Pharmacokinetics of haloperidol were not affected by topiramate in healthy individuals.1

Hydrochlorothiazide

In healthy individuals, peak plasma concentrations and AUC of topiramate increased by 27 and 29%, respectively, following concomitant administration of hydrochlorothiazide.1 Steady-state pharmacokinetics of hydrochlorothiazide were not substantially altered by topiramate.1 Although the clinical importance of this interaction is not known, a reduction in topiramate dosage may be necessary when hydrochlorothiazide is initiated.1

In addition, both topiramate and hydrochlorothiazide have been shown to decrease serum potassium concentrations, and the decrease is greater when the drugs are given in combination.1

Lithium

Although the pharmacokinetics of lithium were not affected during concurrent administration of topiramate at a dosage of 200 mg daily, peak concentrations and AUC of lithium increased by 27 and 26%, respectively during concurrent administration of topiramate dosages up to 600 mg daily.1 Serum lithium concentrations should therefore be monitored in patients receiving concurrent lithium and high-dose topiramate therapy.1

Oral Contraceptives

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).1 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.1

The possibility of contraceptive failure and increased breakthrough bleeding should be considered in patients receiving combination oral contraceptives with topiramate.1 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.1

Propranolol

Concomitant administration of topiramate and propranolol in healthy individuals did not affect the pharmacokinetics of either drug.1

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 (active metabolite) concentrations were observed.1 Concurrent administration of topiramate and risperidone increased peak plasma concentrations and AUC of topiramate by 14 and 12%, respectively.1 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.1

Sumatriptan

In healthy individuals, topiramate did not affect the pharmacokinetics of single-dose sumatriptan.1

Venlafaxine

Concomitant administration of topiramate and venlafaxine in healthy individuals did not affect the pharmacokinetics of venlafaxine, O-desmethylvenlafaxine (active metabolite), or topiramate.1

Warfarin

Concomitant use of topiramate and warfarin has resulted in decreased international normalized ratio (INR) or prothrombin time (PT).1

Description

Topiramate, a sulfamate-substituted derivative of the monosaccharide d-fructose, is an anticonvulsant agent that is also used for prophylaxis of migraine headache and management of alcohol dependence.1,3,5,17,18,52,53,54,55,56,57,60,61,73,74,75,76,77,78 The drug differs structurally from other currently available anticonvulsant agents.1,3,5,17,18 The spectrum of topiramate's anticonvulsant activity resembles that of carbamazepine and phenytoin, although differences in certain animal models have been observed and additive effects appear to occur when the drug is combined with these anticonvulsants.1,5,15,17,18,20

Although the precise mechanism of action of topiramate is unknown, data from electrophysiologic and biochemical studies have revealed 4 properties that may contribute to the drug's efficacy for seizure disorders and migraine prophylaxis.1 At pharmacologically relevant concentrations, topiramate blocks voltage-dependent sodium channels; augments the activity of γ-aminobutyric acid (GABA) at some subtypes of the GABA-A receptor; antagonizes the AMPA/kainate subtype of the glutamate receptor; and inhibits carbonic anhydrase (particularly the CA-II and CA-IV isoenzymes).1,15,16,17,18,19

Topiramate exhibits effects on cultured neurons similar to those observed with phenytoin and carbamazepine, and such effects are suggestive of an inactive state-dependent block of voltage-dependent sodium channels.1,5 Topiramate reduces the duration of epileptiform bursts of neuronal firing and decreases the number of action potentials in studies of cultured rat hippocampal neurons with spontaneous epileptiform burst activity.1 Topiramate also decreases the frequency of action potentials elicited by depolarizing electric current in cultured rat hippocampal neurons.1 During a partial seizure, neurons characteristically undergo high-frequency depolarization and firing of action potentials which is uncommon during normal physiologic neuronal activity.12 Some anticonvulsant drugs (e.g., phenytoin, carbamazepine) preferentially bind to voltage-dependent sodium channels during their inactivated state, slow the rate of recovery of sodium channels from their period of inactivation, and limit the ability of the neuron to depolarize and fire at high frequencies.5,12

Topiramate enhances the activity of the inhibitory neurotransmitter GABA at a nonbenzodiazepine site on GABA_A receptors.1,19,52,54,55,57 Activation of the postsynaptic GABA_A receptor by GABA causes inhibition by increasing the inward flow of chloride ions, resulting in hyperpolarization of the postsynaptic cell;12 in chloride ion-depleted murine cerebellar granule cells, therapeutic concentrations of topiramate (in combination with GABA) enhance GABA-evoked inward flux of chloride ions in a concentration-dependent manner.1 Benzodiazepines act at GABA_A receptors to enhance GABA-evoked inward flow of chloride ions,12 but the benzodiazepine antagonist flumazenil does not appear to inhibit topiramate enhancement of GABA-evoked currents in GABA_A cortical neuronal receptors.1 Topiramate also does not appear to increase duration of chloride ion channel opening.1 Therefore, topiramate may potentiate GABA_A-evoked chloride ion flux by a mechanism other than GABA_A-receptor modulation.15

Topiramate antagonizes a non- N -methyl-d-aspartate (NMDA) glutamate receptor and the kainate/α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subtype.1,15,19,52,54,55,57 Although topiramate had no apparent effect on glutamate receptors of the NMDA subtype in cultured rat hippocampal neurons, topiramate antagonized the ability of kainate to activate the kainate/AMPA glutamate receptor subtype,1,15 and these effects were shown to be concentration dependent.1 Glutamate, the principal excitatory neurotransmitter amino acid in the brain, interacts with specific neuronal membrane receptors, including ion channel coupled (ionotropic) (e.g., NMDA, kainate/AMPA, kainate) receptor subtypes14,58 and with G-protein coupled (metabotropic) receptors that modulate intracellular second-messengers.14 The pathogenesis of seizures is thought to be mediated at least in part through excessive stimulation of glutamate receptors.14 In spontaneously epileptic rats, topiramate has reduced extracellular hippocampal concentrations of both glutamate and aspartate, and a correlation existed between reduction in glutamate concentrations and suppression of tonic seizures.21

In animals, topiramate exhibits anticonvulsant activity in the maximal electroshock seizure (MES) test, suggesting that, like phenytoin, it may be effective in the management of partial and tonic-clonic (grand mal) seizures in humans.1,5 Topiramate also exhibited dose-dependent inhibition of absence-like seizures, which was antagonized by pretreatment with haloperidol.20 In animals, topiramate was ineffective5 or weakly effective1,17 in blocking clonic seizures induced by pentylenetetrazole,1,5 indicating that the drug may not enhance GABA inhibitory activity substantially.5

Although the precise mechanism(s) of action of topiramate in the management of alcohol dependence is unclear, topiramate enhances GABA-mediated inhibitory neurotransmission and inhibits glutamatergic stimulatory neurotransmission; such changes appear to decrease dopaminergic activity in the mesocorticolimbic areas of the brain, which have been associated with alcohol dependence.1,52,54,55,57,58,60,61,62,63,64,74,75,77

Topiramate is rapidly absorbed; peak plasma concentrations occur about 2 hours following an oral dose of 400 mg (as an immediate-release formulation) or approximately 20-24 hours following a single oral dose of 200 mg (as an extended-release formulation).1,87,88,90 The sprinkle capsule formulation of the drug is bioequivalent to the immediate-release tablet and, therefore, may be substituted as a therapeutic equivalent.1 The relative bioavailability of topiramate from the tablet formulation is about 80% compared with a solution.1 At steady state, the extended-release capsules administered once daily are bioequivalent to the immediate-release tablets administered twice daily.87,88 Topiramate exhibits linear, dose-proportional increases in plasma concentration over the dosage ranges evaluated (50 mg to 1.4 g daily depending on the formulation).1,87,88,90 Food may affect time to peak concentrations of the drug (depending on the formulation), but does not appear to affect systemic exposure.1,87,88,90 Approximately 15-41% of topiramate is bound to plasma proteins, with the fraction of protein binding decreasing as blood concentration increases.1

The mean elimination half-life of topiramate is 21 hours following single or multiple doses of the drug as immediate-release formulations; the mean elimination half-life of Trokendi XR^® extended-release capsules is approximately 31 hours following multiple doses, and the mean effective half-life of Qudexy^® XR extended-release capsules is 56 hours.1,46,87,88,90 Approximately 70% of an administered dose is eliminated principally in urine as unchanged drug.1 Topiramate is not extensively metabolized; six minor metabolites have been identified, none of which constitutes more than 5% of an administered dose.1

In patients with moderate (creatinine clearance 30-69 mL/minute per 1.73 m²) or severe (creatinine clearance less than 30 mL/minute per 1.73 m²) renal impairment, clearance of topiramate was reduced by 42 or 54%, respectively.1 However, since topiramate also undergoes substantial tubular reabsorption, the manufacturers state that creatinine clearance may not always predict clearance of topiramate.1 Geriatric patients with age-related renal impairment also may exhibit reduced clearance of the drug.1 In patients undergoing hemodialysis, clearance of topiramate is 4-6 times more rapid than in healthy individuals. 1

Although the mechanism is not well understood, patients with hepatic impairment may have decreased clearance of topiramate.1

Changes in topiramate clearance also have been observed in pediatric patients.1

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Medication Guide).1,87,88,90
• Counsel patients to swallow Qudexy^® XR capsules whole or carefully open and sprinkle the entire contents on a spoonful of soft food.87 The drug/food mixture should be swallowed immediately and not chewed.87 Do not store drug/food mixture for future use.87 Counsel patients to swallow Trokendi XR^® capsules whole and intact.88 Trokendi XR^® should not be sprinkled on food, chewed or crushed.88
• Counsel patients that Eprontia^® may be taken with or without food.90 Advise patients that the dosage of Eprontia^® should be measured using a calibrated measuring device and not a household teaspoon and an oral dosing syringe may be obtained from their pharmacist.90 Instruct patients to discard any unused Eprontia^® after 30 days of first opening the bottle.90
• Advise patients to completely avoid consumption of alcohol at least 6 hours prior to and 6 hours after taking Trokendi XR^®.88
• Instruct patients taking topiramate to seek immediate medical attention if they experience blurred vision, visual disturbances, or periorbital pain.1,87,88,90
• Closely monitor patients treated with topiramate, especially pediatric patients, for evidence of decreased sweating and increased body temperature, especially in hot weather.1,87,88,90 Counsel patients to contact their healthcare professionals immediately if they develop a high or persistent fever, or decreased sweating.1,87,88,90
• Warn patients about the potential significant risk for metabolic acidosis that may be asymptomatic and may be associated with adverse effects on kidneys (e.g., kidney stones, nephrocalcinosis), bones (e.g., osteoporosis, osteomalacia, and/or rickets in children), and growth (e.g., growth delay/retardation) in pediatric patients, and on the fetus.1,87,88,90
• Counsel patients, their caregivers, and families that antiepileptic drugs, including topiramate, may increase the risk of suicidal thoughts and behavior, and advise of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior or the emergence of suicidal thoughts, or behavior or thoughts about self-harm.1,87,88,90 Instruct patients to immediately report behaviors of concern to their healthcare providers.1,87,88,90
• Warn patients about the potential for somnolence, dizziness, confusion, difficulty concentrating, or visual effects, and advise patients not to drive or operate machinery until they have gained sufficient experience on topiramate to gauge whether it adversely affects their mental performance, motor performance, and/or vision.1,87,88,90
• Even when taking topiramate or other anticonvulsants, some patients with epilepsy will continue to have unpredictable seizures.1,87,88,90 Therefore, advise all patients taking topiramate for epilepsy to exercise appropriate 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 car, climbing in high places, etc.).1,87,88,90 Some patients with refractory epilepsy will need to avoid such activities altogether.1,87,88,90 Discuss the appropriate level of caution with patients, before patients with epilepsy engage in such activities.1,87,88,90
• Inform pregnant patients and females of reproductive potential that use of topiramate during pregnancy can cause fetal harm, including an increased risk for cleft lip and/or cleft palate (oral clefts), which occur early in pregnancy before many people know they are pregnant.1,87,88,90 Also inform patients that infants exposed to topiramate monotherapy in utero may be small for gestational age.1,87,88,90 There may also be risks to the fetus from chronic metabolic acidosis with use of topiramate during pregnancy.1,87,88,90 When appropriate, counsel pregnant patients and females of reproductive potential about alternative therapeutic options.1,87,88,90
• Advise females of reproductive potential who are not planning a pregnancy to use effective contraception while using topiramate, keeping in mind that there is a potential for decreased contraceptive efficacy when using estrogen-containing birth control with topiramate.1,87,88,90
• Encourage pregnant patients using topiramate to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry.1,87,88,90 The registry is collecting information about the safety of antiepileptic drugs during pregnancy.1,87,88,90
• Inform the patient or caregiver that long-term treatment with topiramate can decrease bone formation and increase bone resorption in children.1
• Discuss with the patient or caregiver that long-term topiramate treatment may attenuate growth as reflected by slower height increase and weight gain in pediatric patients.1
• Inform patients about the signs of serious skin reactions.1,87,88,90 Instruct patients to immediately inform their healthcare provider at the first appearance of skin rash.1,87,88,90
• Warn patients about the possible development of hyperammonemia with or without encephalopathy.1,87,88,90 Although hyperammonemia may be asymptomatic, clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy and/or vomiting.1,87,88,90 This hyperammonemia and encephalopathy can develop with topiramate treatment alone or with topiramate treatment with concomitant valproic acid.1,87,88,90 Instruct patients to contact their physician if they develop unexplained lethargy, vomiting, or changes in mental status.1,87,88,90
• Instruct patients, particularly those with predisposing factors, to maintain an adequate fluid intake in order to minimize the risk of kidney stone formation.1,87,88,90
• Counsel patients taking extended-release forms of topiramate that these formulations can cause a reduction in body temperature, which can lead to alterations in mental status. If they note such changes, they should call their health care professional and measure their body temperature. Patients taking concomitant valproic acid should be specifically counseled on this potential adverse reaction.87,88
• Instruct patients that if they miss a single dose of immediate-release topiramate, it should be taken as soon as possible.1,90 However, if a patient is within 6 hours of taking the next scheduled dose, tell the patient to wait until then to take the usual dose of topiramate and to skip the missed dose.1,90 Tell patients that they should not take a double dose in the event of a missed dose.1,90 Advise patients to contact their healthcare provider if they have missed more than one dose.1,90
• Advise female patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed.
• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.
• Advise patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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