Topiramate

Introduction

C12H21NO8S

• Topiramate is an anticonvulsant.1, 2, 3, 4, 5, 17, 18

Uses

• Partial Seizures

Topiramate is used in combination with other anticonvulsant agents in the management of partial
seizures in adults and children 2-16 years of age.1, 2, 4, 5, 6, 7, 8, 9, 10, 22, 25, 29, 30, 31, 32, 33, 34, 37,
38 Efficacy of topiramate as adjunctive therapy in adult patients with partial (including simple and
complex partial) seizures with or without secondarily generalized tonic-clonic seizures was established in
several controlled clinical studies.1, 2, 4, 6, 7, 8, 9, 10, 22, 25, 29 In these studies, patients initially were
stabilized with optimum dosages of 1 or 2 conventional anticonvulsant drugs (e.g., carbamazepine,
clonazepam, phenobarbital, phenytoin, primidone, valproic acid) during an 8- to 12-week baseline
period;1, 2, 4, 6, 7, 8, 9, 10, 22 those experiencing an average of at least one partial seizure (with or
without secondary generalization) per week during this phase were randomized to receive topiramate
or placebo during a dosage titration period of 3-6 weeks followed by an 8- to 12-week stabilization
period during which the maximally achieved dosage of topiramate or placebo was maintained.1, 2, 6, 7,
8, 9, 10, 22 Efficacy of topiramate in these studies prinicipally was evaluated in terms of the change in
seizure frequency and the responder rate.1, 2, 4, 6, 7, 8, 9, 10, 22, 25 The change in seizure frequency
with the addition of topiramate or placebo to the existing anticonvulsant regimen was the median
percentage decrease (or increase) in average monthly (28 day) seizure rate.1, 2, 4, 6, 7, 8, 9, 10 The
responder rate was the percentage of patients with a reduction in seizure frequency of 50% or greater
compared with baseline values.1, 2, 4, 6, 7, 8, 9, 10, 25

Patients receiving topiramate 200 mg daily or placebo in one of the studies experienced a decrease in
seizure frequency of 27-30 or 12-13%, respectively, and the responder rate was 24-27 or 18%,
respectively.1, 2, 4, 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, 2, 4, 6, 8 Patients receiving 600 mg of topiramate daily in 3 of the
studies experienced a decrease in seizure frequency of 41-46%,1, 2, 4, 6, 7, 9 and patients receiving
placebo experienced a decrease in seizure frequency of 1-13% in 2 of the studies,1, 2, 4, 6, 7 and an
increase in seizure frequency of 12% in the third study.1, 2, 4, 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, 2, 4, 6, 7, 9 Patients receiving topiramate 800 mg daily in 2 studies experienced a decrease
in seizure frequency of 24-41%,1, 2, 4, 7, 10 and patients receiving placebo experienced a decrease in
monthly seizure rate of 1-2% in one study1, 2, 7 or an 18-21% increase in seizure frequency in the other
study.1, 2, 4, 10 In the studies of patients receiving topiramate 800 mg daily or placebo, 40-43 or 0-9%,
respectively, were considered responders.1, 2, 4, 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, 2, 7 and
36-38 or 8-9% of patients, respectively, were reported to be responders.1, 2, 4, 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 was established in a multicenter, randomized,
controlled trial.1, 31, 35 In this study, patients initially were stabilized with optimum dosages of 1 or 2
conventional anticonvulsant drugs; patients who experienced 6 or more partial seizures with or without
secondarily generalized seizures during an 8-week baseline period were randomized either to
topiramate or to placebo.1, 35 Patients received topiramate initially at a dosage of 25 or 50 mg daily,
after which the daily dosage was increased in increments of 25-150 mg every other week until the
assigned dosage of 125, 175, 225, or 400 mg daily (approximately 6 mg/kg of topiramate daily, based on
the patient's body weight) was reached, or until the development of adverse effects precluded increases
in dosage.1, 35 The 8-week dosage titration period was then followed by an 8-week maintenance
period.1, 35 Patients receiving topiramate 6 mg/kg daily or placebo experienced a decrease in seizure
frequency of 33.1 or 10.5%, respectively, and the responder rate was 39 or 20%, respectively.1, 35

• Primary Generalized Tonic-Clonic Seizures

Topiramate is used in combination with other anticonvulsant agents in the management of primary
generalized tonic-clonic seizures in adults and children 2 years of age or older.1, 30, 31, 39 Efficacy of
topiramate as adjunctive therapy in patients with primary generalized tonic-clonic seizures was
established in a multicenter, randomized, controlled trial.1, 39 In this study, patients (age range: 3-59
years) initially were stabilized with optimum dosages of 1 or 2 conventional anticonvulsant drugs;
patients who experienced 3 or more primary generalized tonic-clonic seizures during an 8-week baseline
period were randomized either to topiramate or to placebo.1, 39 Therapy was targeted to a dosage of 6
mg/kg daily during an 8-week dosage titration period; patients received topiramate initially at a dosage
of 50 mg daily for 4 weeks, after which the daily dosage was increased in increments of 50-150 mg every
other week until the assigned dosage of 175, 225, or 400 mg daily (approximately 6 mg/kg of topiramate
daily, based on the patient's body weight) was reached, or until the development of adverse effects
precluded increases in dosage.1 The dosage titration period was then followed by a 12-week
maintenance period.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 a reduction in primary generalized tonic-clonic seizure
frequency of 50% or greater compared with baseline values).1 Patients receiving topiramate 6 mg/kg
daily or placebo experienced a decrease in seizure frequency of 56.7 or 9%, respectively, and the
responder rate was 56 or 20%, respectively.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 in combination with other anticonvulsant agents in the management of seizures
associated with Lennox-Gastaut syndrome in adults and children 2 years of age or older.1 Efficacy of
topiramate as adjunctive therapy in patients with Lennox-Gastaut syndrome was established in a
multicenter, randomized, controlled trial.1 In this study, patients (age range: 2-42 years)24 who
experienced 60 or more seizures per month prior to study entry were stabilized with optimum dosages
of 1 or 2 conventional anticonvulsant drugs for 4 weeks.1 Following the 4-week baseline period, patients
were randomized either to topiramate or to placebo.1 Patients received topiramate initially at a dosage
of 1 mg/kg daily for 1 week, after which the dosage was increased to 3 mg/kg daily for 1 week, and then
to the target dosage of 6 mg/kg daily.1 The dosage titration period was then followed by an 8-week
maintenance period.1 Efficacy of topiramate was evaluated in terms of the change in seizure frequency
(i.e., median percent reduction in drop attacks), the responder rate (i.e., percentage of patients with a
reduction in seizure frequency of 50% or greater compared with baseline values), and the overall
improvement in seizure severity (i.e., percentage of patients who were improved from baseline).1
Patients receiving topiramate 6 mg/kg daily experienced a decrease in seizure frequency of 14.8%, while
those receiving placebo experienced an increase of 5.1%.1 Overall improvement in seizure severity was
reported in more patients receiving topiramate (52%) than in those receiving placebo (28%).1
Responder rates were not significantly different between patients receiving topiramate (28%) and those
receiving placebo (14%).1

Dosage and Administration

• Administration
Topiramate is administered orally.1, 2 The manufacturer states that the capsule/sprinkle formulation of
topiramate is bioequivalent to the immediate-release tablet and may be substituted as a therapeutic
equivalent.1 The bioavailability of topiramate is not affected by food, and the drug may be administered
without regard to meals.1, 2, 4 Because of the bitter taste, tablets of topiramate preferably should be
swallowed intact and not broken or chewed.1, 2, 4, 24 If the tablets are broken, they should be used
immediately since stability of exposed drug beyond a brief period cannot be ensured; any unused
portion should be discarded.24 For patients experiencing difficulty in swallowing the tablets, the tablets
can be crushed, mixed with applesauce or oatmeal, and administered immediately.24

The capsule formulation of topiramate may be taken whole, or it may be opened and the entire
contents sprinkled on 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 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

• Dosage

Safety and efficacy of topiramate in children younger than 2 years of age have not been established.1

The manufacturer states that it is not necessary to monitor plasma topiramate concentrations to
achieve optimal clinical effect with the drug when it is added to an existing anticonvulsant regimen.1, 2,
4 However, addition and withdrawal of phenytoin and/or carbamazepine during adjunctive therapy may
require adjustment of topiramate dosage.1, 2, 4, 11 Decreases of 48 or 40% in mean area under the
plasma topiramate concentration-time curve (AUC) during concomitant administration of topiramate
with phenytoin or carbamazepine, respectively, have been reported.1, 2, 4Alterations in the
pharmacokinetics of topiramate and valproic acid appear to be small during concomitant use.26

Addition of topiramate to an anticonvulsant regimen containing phenytoin may require adjustment of

the dosage of the latter anticonvulsant.1, 2, 4 Increases of about 25% in the plasma AUC of phenytoin in
50% of patients receiving phenytoin (generally those receiving phenytoin twice daily) have been
reported.1, 2, 4, 11

Dosage of topiramate must be adjusted carefully and individualized according to patient response and
tolerance.1, 2, 4 The manufacturer states that in clinical studies, too rapid titration (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.1, 2, 4 Because of the possibility of increasing seizure frequency,
anticonvulsant drugs, including topiramate, should not be discontinued abruptly.1, 2

In adults 17 years of age or older, the recommended total daily dosage of topiramate as adjunctive
therapy for management of partial seizures with or without secondary generalization is 200-400 mg,
administered in 2 divided doses.1 The recommended total daily adult dosage for management of
primary generalized tonic-clonic seizures is 400 mg, administered in 2 divided doses.1 Topiramate
therapy should be initiated at 25-50 mg daily,1, 2, 4, 24 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.2, 4, 24
Limited data indicate that upward titration in increments of 25 mg per week may delay the time to
reach an effective dose; 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.24, 41 In
the clinical trial of topiramate for the adjunctive management of primary generalized tonic-clonic
seizures, the titration period was longer than that used in trials of the drug for partial seizures and lasted
8 weeks.1 Maintenance dosages less than 400 mg daily may be optimally effective in some patients and
therefore should be individualized;1, 2 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, 24 Dosages exceeding 400 mg daily have not improved
response to topiramate substantially, although seizure control may be improved in some patients from
such relatively high dosages if tolerated.1, 2, 4, 7, 24, 25 Dosages exceeding 1.6 g daily have not been
studied.1, 2, 4

The manufacturer does not make specific dosage recommendations for management of Lennox-Gastaut
syndrome in adults 17 years of age or older.1 However, in one controlled trial, dosage of topiramate was
initiated at 1 mg/kg and titrated over 2 weeks to a target dosage of approximately 6 mg/kg daily.1, 24
(See Uses: Seizures Associated with Lennox-Gastaut Syndrome.)

In pediatric patients aged 2-16 years, the recommended total daily dosage of topiramate as adjunctive
therapy for the management of partial seizures with or without secondary generalization, primary
generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome is approximately
5-9 mg/kg daily in 2 divided doses.1 Dosage titration should begin at 25 mg (or less, based on a range of
1-3 mg/kg daily) given nightly for the first week.1 The dosage should then be increased at 1- or 2-week
intervals by increments of 1-3 mg/kg daily (administered in 2 divided doses) to achieve optimal clinical
response.1 Dosage titration should be guided by clinical outcome.1 Some clinicians recommend that the
initial topiramate dosage range from 0.5-1 mg/kg daily and that it 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.33, 36
Pharmacokinetic data from one controlled clinical study have revealed a decreased clearance of
topiramate in geriatric patients with reduced renal function (i.e., creatinine clearance reduced by 20%
compared with that in younger adults).1 (See Cautions: Geriatric Precautions.) Therefore, the
manufacturer states that it may be useful to monitor renal function in geriatric patients receiving
topiramate therapy; dosage adjustment may be necessary in geriatric patients with impaired renal
function (i.e., creatinine clearance less than 70 mL/minute per 1.73 m2).1 (See Dosage and
Administration: Dosage in Renal and Hepatic Impairment.)

• Dosage in Renal and Hepatic Impairment

Dosage of topiramate should be adjusted according to the degree of renal impairment.1, 2, 4 In patients
with a creatinine clearance less than 70 mL/minute per 1.73 m2), the daily dosage of topiramate should
be decreased by 50%,1, 2, 4 and such patients will require a longer time to reach steady-state plasma
concentrations of the drug at each dosage increase during titration.1, 2, 4 In patients undergoing
hemodialysis, clearance of topiramate is 4-6 times more rapid than in healthy individuals,1, 2, 4 and
prolonged hemodialysis may result in plasma topiramate concentrations below those required for
anticonvulsant activity.1, 2, 4 Therefore, to avoid rapid decreases of plasma topiramate concentrations
in patients undergoing hemodialysis, a supplemental dose of the drug may be required, the amount of
which takes into account the duration of dialysis, clearance rate of the dialysis system being used, and
the patient's effective renal clearance of topiramate.1, 2, 4

Although topiramate clearance may decrease in patients with hepatic impairment and therefore caution
should be exercised, the manufacturer makes no specific recommendations for dosage adjustment in
such patients.1

Cautions

• Adverse Effects

Nervous system effects are the most frequently reported adverse effects of topiramate and generally
can be classified into 2 categories: language and coordination difficulties and somnolence and fatigue.1
Somnolence and fatigue are the most common adverse nervous system effects of topiramate, occurring
in about 26-29 and 11-30%, respectively, of patients receiving the drug in clinical trials.1 These adverse
effects generally are mild to moderate in severity and occur early in therapy.1 Although the frequency of
somnolence does not appear to be dose related, fatigue tends to occur with increasing frequency in
patients receiving topiramate at dosages exceeding 400 mg daily.1 Other common dose-related adverse
nervous system effects of topiramate (at dosages of 200-1000 mg daily) include nervousness, difficulty
with concentration or attention, confusion, depression, language problems, anxiety, and mood
problems.1 Frequently reported adverse nervous system effects that do not appear to be dose related
include somnolence, dizziness, ataxia, speech disorders and related speech problems, psychomotor
slowing, difficulty with memory, and paresthesia.1

Other common dose-related adverse effects of topiramate, in addition to adverse nervous system
effects, include anorexia and weight loss.1 Frequently reported adverse effects that do not appear to be
dose related include abnormal vision and diplopia.1

• Precautions and Contraindications

Hyperchloremic, non-anion gap, metabolic acidosis (i.e. decreased serum bicarbonate concentrations to
below the normal reference range in the absence of chronic respiratory alkalosis) has been reported in
clinical trials and during postmarketing surveillance of topiramate.1, 43 Such electrolyte imbalance
generally occurs early in topiramate therapy, although cases can occur at any time.1, 43 Metabolic
acidosis, which has been observed at topiramate dosages as low as 50 mg daily, is caused by renal
bicarbonate loss because of the inhibitory effect of topiramate on carbonic anhydrase.1 Decreases in
serum bicarbonate concentrations usually are mild to moderate (average decrease of 4 mEq/L at daily
dosages of 400 mg in adults and at approximately 6 mg/kg daily in pediatric patients); marked decreases
in serum bicarbonate concentrations (to below 10 mEq/L) may rarely occur.1, 43 In clinical trials,
persistent treatment-emergent decreases in serum bicarbonate concentrations (defined as
concentrations of less than 20 mEq/L at 2 consecutive visits or at the final visit) occurred in 23-67% of
patients receiving topiramate and in 1-10% of those receiving placebo.1, 43 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 3-11% of patients receiving topiramate
and in 0 to less than 1% of those receiving placebo.1, 43 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, 43 Because chronic, untreated metabolic
acidosis may have potentially serious sequelae (e.g., increased risk of nephrolithiasis or
nephrocalcinosis, development of osteomalacia and/or osteoporosis with an increased risk for
fractures), the manufacturer states that serum bicarbonate concentrations should be measured at
baseline and periodically during topiramate therapy.1, 43 If metabolic acidosis develops and persists,
consideration should be given to reducing the dosage or discontinuing topiramate therapy (by gradually
tapering the dose).1, 43 If a decision is made to continue topiramate therapy in the presence of
persistent acidosis, alkali treatment should be considered.1, 43
A syndrome consisting of acute myopia associated with secondary angle-closure glaucoma has been
reported in some patients receiving topiramate.1 This syndrome may be associated with supraciliary
effusion, resulting in anterior displacement of the lens and iris and, subsequently, secondary angle-
closure glaucoma.1 Symptoms include acute onset of decreased visual acuity and/or ocular pain and
typically occur within 1 month of initiating topiramate therapy.1 Ophthalmologic findings include
myopia, anterior chamber shallowing, ocular hyperemia, and increased intraocular pressure;1 mydriasis
may or may not be present.1 Patients receiving topiramate should be advised to seek immediate
medical attention if they experience blurred vision or periorbital pain during therapy with the drug.1 If
adverse ocular signs or symptoms are detected during topiramate therapy, the drug should be
discontinued immediately and appropriate measures instituted.1

Oligohidrosis, which rarely may require hospitalization, has been reported in clinical trials or during
postmarketing surveillance of topiramate.1, 42 Manifestations include decreased sweating and an
elevation in body temperature above normal (hyperthermia).1, 42 Most cases of oligohidrosis were
reported in children, and some occurred following exposure to elevated environmental temperatures
and/or vigorous activity.1, 42 Topiramate therapy has been continued in most patients who experienced
oligohidrosis and hyperthermia.42 Because oligohidrosis and hyperthermia may have potentially serious
sequelae,42 the manufacturer states 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 Proper hydration is recommended before and during activities (e.g.,
exercise) or exposure to warm temperatures.42 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

Because of the possibility of increased seizure frequency, anticonvulsant drugs, including topiramate,
should not be discontinued suddenly.1

Patients should be informed that topiramate may cause adverse nervous system effects (e.g.,
somnolence, dizziness, confusion, difficulty with concentration) and that they should not drive a motor
vehicle or operate other complex machinery until they have gained sufficient experience with the drug
to determine whether it has adverse effects on their mental and/or motor performance.1

Formation of kidney stones has been reported in approximately 1.5% of adults receiving topiramate in
clinical trials.1 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 kidney stones also have been reported in
pediatric patients receiving topiramate.1 Although the mechanism of this adverse effect has not been
fully elucidated, it has been suggested that topiramate exhibits weak inhibition of carbonic anhydrase
and, similar to other carbonic anhydrase inhibitors (e.g., acetazolamide), may promote stone formation
by reducing urinary citrate excretion and increasing urinary pH.1 The manufacturer states that use of
topiramate in patients on a ketogenic diet or concomitant use of the drug with other carbonic
anhydrase inhibitors may increase the risk of kidney stone formation and, therefore, should be
avoided.1 Because increased fluid intake may increase urinary output and reduce the concentration of
substances involved in stone formation, patients receiving topiramate, particularly those with
predisposing factors, should be instructed to maintain adequate fluid intake to prevent kidney stone
formation.1

During the premarketing development of topiramate, 10 sudden and unexplained deaths were reported
among a cohort of patients receiving adjunctive therapy with the drug (2796 patient-years of
exposure).1 Although the rate of these deaths exceeds that expected to occur in a healthy (nonepileptic)
population matched for age and gender, this rate was similar to that occurring in a similar population of
epileptic patients not receiving topiramate.1

Topiramate is contraindicated in patients with known hypersensitivity to the drug or any ingredient in
the formulation.1

• Pediatric Precautions

Safety and efficacy of topiramate in children younger than 2 years of age have not been established.1
The incidence of nervous system effects in pediatric patients appears to be lower than that observed in
adults.1 The most common adverse nervous system effects reported in pediatric patients receiving
topiramate include fatigue; somnolence; psychomotor slowing; nervousness; difficulty with
concentration, attention span, and memory; speech disorders and related speech problems; language
problems; and aggressive reaction.1 Other adverse effects reported in this population include anorexia
and weight loss.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
clinical trials and during postmarketing surveillance of topiramate.1, 43 (See Cautions: Precautions and
Contraindications.) In clinical trials in pediatric patients younger than 16 years of age, the incidence of
persistent treatment-emergent decreases in serum bicarbonate concentrations was 67 or 10% for
patients receiving topiramate (approximately 6 mg/kg daily) or placebo, respectively.1, 43 Cases of
moderately severe metabolic acidosis have been reported in infants as young as 5 months of age,
especially at daily dosages exceeding 5 mg/kg daily.1 Because chronic, untreated metabolic acidosis may
have potentially serious sequelae (e.g., development of osteomalacia [rickets], reduction of growth
rates, decrease in maximal height achieved), the manufacturer states that serum bicarbonate
concentrations should be measured at baseline and periodically during topiramate therapy.1, 43 (See
Cautions: Precautions and Contraindications.)

Oligohidrosis (decreased sweating) and hyperthermia have been reported in clinical trials or during
postmarketing surveillance of topiramate.1, 42 Because oligohidrosis and hyperthermia typically
occurred in children and may have potentially serious sequelae,42 the manufacturer states 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 (See Cautions:
Precautions and Contraindications.)

• Geriatric Precautions

While clinical studies evaluating topiramate did not include sufficient numbers of adults 65 years of age
or older to determine whether geriatric patients respond differently than younger adults, approximately
3% of patients receiving the drug in clinical trials were older than 60 years of age.1 Although no age-
related differences in efficacy or safety were evident in these patients, pharmacokinetic data from one
controlled clinical study have revealed a decreased clearance of topiramate in geriatric patients with
reduced renal function (i.e., creatinine clearance reduced by 20% compared with that in younger
adults).1 Following administration of a single 100-mg dose of topiramate in these patients, plasma 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 manufacturer
states 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 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

• Pregnancy and Lactation

Although there are no adequate and controlled studies to date in humans, topiramate has been shown
to be teratogenic and embryotoxic in mice or rabbits when given at dosages 0.2 or 2 times, respectively,
the recommended human dosage on a mg/m2 basis.1 Several cases of hypospadias have been reported
during postmarketing surveillance in infants exposed to topiramate (alone or concomitantly with other
anticonvulsant agents) in utero; however, a causal relationship to the drug has not been established.1
Topiramate should be used during pregnancy only when the potential benefits justify the possible risks
to the fetus.1
Topiramate is distributed into milk in rats.1 Distribution of topiramate into human milk has not been
evaluated in controlled studies; however, limited data indicate that the drug may distribute extensively
into milk in humans.1 Because many drugs are distributed into human milk and because of the potential
for serious adverse effects in nursing infants, the potential benefits to the mother should be weighed
against the potential risks to the infant when considering topiramate therapy in nursing women.1

Description

Topiramate, a sulfamate-substituted derivative of the monosaccharide d-fructose, is an anticonvulsant

agent.1, 2, 3, 4, 5, 17, 18 The drug differs structurally from other currently available anticonvulsant
agents.1, 2, 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, 2, 4, 5, 15, 17,
18, 20

Although the precise mechanism of action of topiramate is unknown, the drug has demonstrated
properties in electrophysiologic and biochemical studies that may contribute to its anticonvulsant
activity, including blocking sodium channels, enhancing the inhibitory action of ?-aminobutyric acid
(GABA) by acting at an apparently novel modulatory site, and attenuating kainate-induced responses.1,
2, 4, 15, 16, 17, 18, 19 In general, anticonvulsant drugs are thought to act by one or more of the
following mechanisms: modulating voltage-dependent ion (e.g., sodium) channels involved in action
potential propagation or burst generation, enhancement of GABA inhibitory activity, and/or inhibition of
excitatory amino acid neurotransmitter (e.g., glutamate, aspartate) activity.2, 5, 12, 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, 2, 4, 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, 2, 4 Topiramate also decreases the frequency of
action potentials elicited by depolarizing electric current in cultured rat hippocampal neurons.1, 2, 4
Depolarization and firing of an action potential results from the rapid inflow of sodium ions through
voltage-dependent sodium channels in the neuronal cell membrane.5, 13 After firing, a neuron enters a
period of inactivation during which it is unable to fire again even if the sodium channel is open.12, 13 A
slow action potential firing rate allows the neuron sufficient time to recover from inactivation, and the
normal period of inactivation has a minimal effect on low-frequency firing.12 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 GABAA receptors.1, 2, 4, 19 Activation of the postsynaptic GABAA 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, 2, 4 Benzodiazepines act at GABAA 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 GABAA cortical neuronal receptors.1, 2, 4
Topiramate also does not appear to increase duration of chloride ion channel opening.1, 2, 4 Therefore,
topiramate may potentiate GABAA-evoked chloride ion flux by a mechanism other than GABAA-receptor
modulation.2, 15

Topiramate antagonizes a non-N-methyl-d-aspartate (NMDA) glutamate receptor and the kainate/a-

amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subtype.1, 2, 4, 15, 19 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, 2, 4, 15 and these effects were shown to be concentration dependent.1,
2 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 and with G-protein coupled (metabotropic) receptors that modulate
intracellular second-messengers.14 Glutamate is responsible for a variety of neurologic functions,
including cognition, memory, movement, and sensation, and excessive activation of glutamate receptors
may mediate injury or destruction of neurons in some acute neurologic disorders and chronic
neurodegenerative diseases.14 The pathogenesis of seizures is thought to be meditated 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, 2, 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, 2, 17 in blocking clonic seizures induced by pentylenetetrazole,1, 2, 5
indicating that the drug may not enhance GABA inhibitory activity substantially.5

Although topiramate weakly inhibits carbonic anhydrase CA-II and CA-IV isoenzymes,1, 2, 17 and other
carbonic anhydrase inhibitors (e.g., acetazolamide) are used adjunctively as anticonvulsants, the drug is
considerably less potent than acetazolamide, and this effect is not thought to contribute substantially to
the anticonvulsant activity of topiramate.1, 2, 17 However, like other carbonic anhydrase inhibitors (e.g.,
acetazolamide, dichlorphenamide), topiramate may promote the formation of renal calculi by increasing
urinary pH and decreasing the excretion of urinary citrates.1, 2, 15 In premarketing studies, renal calculi
were reported to occur in 1.5% of patients receiving topiramate, an incidence 2-4 times that expected in
a similar untreated population,1, 2, 23, 27, 28 but most patients who developed calculi elected to
continue therapy with the drug.23, 24 Use of topiramate with other carbonic anhydrase inhibitors may
increase the risk of renal calculi and therefore should be avoided.1, 2, 4

SumMon® (see Users Guide). For additional information on this drug until a more detailed monograph is
developed and published, the manufacturer's labeling should be consulted. It is essential that the
labeling be consulted for information on the usual cautions, precautions, and contraindications
concerning potential drug interactions and/or laboratory test interferences and for information on acute
toxicity.

Preparations

Topiramate

Oral

Capsules 15 mg Topamax® Sprinkle, (with

povidone) Ortho-McNeil

25 mg Topamax® Sprinkle, (with

 povidone) Ortho-McNeil

Tablets, film- 25 mg Topamax®, Ortho-

coated McNeil

50 mg Topamax®, Ortho-

McNeil

100 mg Topamax®, Ortho-

McNeil

200 mg Topamax®, Ortho-

McNeil

References

1. Ortho-McNeil. Topamax® (topiramate) tablets and capsules prescribing information. Raritan, NJ; 2003
Dec.

2. Ortho-McNeil. Topamax® (topiramate) clinical review. Raritan, NJ: undated.

3. Pugh CB, Garnett WR, Current issues in the treatment of epilepsy. Clin Pharm. 1991; 10:335-58.
4. Ortho-McNeil. Topamax® (topiramate) tablets product information reference source. Raritan, NJ;
1997 Jan.

5. Rogawski MA, Porter RJ: Antiepileptic drugs: Pharmacological mechanisms and clinical efficacy with
consideration of promising developmental stage compounds, Pharmacol Rev 1990 42: 223-86

6. Faught E, Wilder BJ, Ramsay RE et al: Topiramate placebo-controlled dose-ranging trial in refractory
partial epilepsy using 200-, 400-, and 600-mg daily dosages, Neurology 1996 46: 1684-90

7. Privitera M, Fincham R, Penry J et al: Topiramate placebo-controlled dose-ranging trial in refractory

partial epilepsy using 600-, 800-, and 1,000-mg daily dosages, Neurology 1996 46: 1678-83

8. Sharief M, Viteri C, Ben-Menachem E: Double-blind, placebo-controlled study of topiramate in

patients with refractory partial epilepsy, Epilepsy Res 1996 25: 217-24

9. Tassinari CA, Michelucci R, Chauvel P: Double-blind, placebo-controlled trial of topiramate (600 mg

daily) for the treatment of refractory partial epilepsy, Epilepsia 1996 37: 763-8

10. Ben-Menachem E, Henriksen O, Dam M: Double-blind, placebo-controlled trial of topiramate as add-

on therapy in patients with refractory partial seizures, Epilepsia 1996 37: 539-43

11. Bourgeois BFD: Drug interaction profile of topiramate, Epilepsia 1996 37: Suppl 2 S14-17

12. McNamara JO. Drugs effective in the treatment of the epilepsies. In: Hardman JG, Limbird LE,
Molinoff PB et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 9th ed. New
York: Macmillan Publishing Company; 1996:461-86.

13. Membrane potentials and action potentials. In: Guyton AC. Textbook of medical physiology. 8th ed.
Philadelphia: WB Saunders; 1991:51-66.
14. Lipton SA, Rosenberg PA: Excitatory amino acids as a final common pathway for neurologic
disorders, N Engl J Med 1994 330: 613-22

15. Dichter MA, Brodie MJ: New antiepileptic drugs, N Engl J Med 1996 334: 1583-90

16. White HS, Brown SD, Wolf HH: The anticonvulsant topiramate potentiates GABA-evoked chloride
current in mouse cortical neurons, Epilepsia 1994 35: Suppl 8 S67

17. Shank RP, Gardocki JF, Vaught JL: Topiramate: preclinical evaluation of structurally novel
anticonvulsant, Epilepsia 1994 35: 450-60

18. Edmonds HL Jr, Jiang YD, Zhang PY: Anticonvulsant activity of topiramate and phenytoin in a rat
model of ischemia-induced epilepsy, Life Sci 1996 59: PL127-31

19. White HS: Clinical significance of animal seizure models and mechanism of action studies of potential
antiepileptic drugs, Epilepsia 1997 38: Suppl 1 S9-17

20. Nakamura J, Tamura S, Kanda T: Inhibition by topiramate of seizures in spontaneously epileptic rats
and DBA/2 mice, Eur J Pharmacol 1994 254: 83-9

21. Kanda T, Kurokawa M, Tamura S: Topiramate reduces abnormally high extracellular levels of
glutamate and aspartate in the hippocampus of spontaneously epileptic rats (SER), Life Sci 1996 59:
1607-16

22. Reife RA, Pledger GW: Topiramate as adjunctive therapy in refractory partial epilepsy: pooled
analysis of data from five double-blind, placebo-controlled trials, Epilepsia 1997 38: Suppl 1 S31-3
23. Wasserstein AG, Rak I, Reife RA: Nephrolithiasis during treatment with topiramate, Epilepsia 1995
36: Suppl 3 S153

24. Ortho-McNeil, Raritan, NJ: Personal communication.

25. Marson AG, Kadir ZA, Chadwick DW: New antiepileptic drugs: a systematic review of their efficacy
and tolerability, BMJ 1996 313: 1169-74

26. Rosenfeld WE, Liao S, Kramer LD: Comparison of the steady-state pharmacokinetics of topiramate
and valproate in patients with epilepsy during monotherapy and concomitant therapy, Epilepsia 1997
38: 324-33

27. Wallace SJ: A comparative review of the adverse effects of anticonvulsants in children with epilepsy,
Drug Saf 1996 15: 378-93

28. Shorvon SD: Safety of topiramate: adverse events and relationships to dosing, Epilepsia 1996 37:
Suppl 2 S18-22

29. Privitera MD: Topiramate: a new antiepileptic drug, Ann Pharmacother 1997 31: 1164-73

30. Langtry HD, Gillis JC, Davis R: Topiramate: a review of its pharmacodynamic and pharmacokinetic
properties and clinical efficacy in the management of epilepsy, Drugs 1997 354: 5 752-73

31. Sachdeo RC: Topiramate: clinical profile in epilepsy, Clin Pharmacokinet 1998 34: 5 335-46

32. Markind JE: Topiramate: a new antiepileptic drug, Am J Health-Syst Pharm 1998 55: 554-62

33. Glauser TA: Topiramate use in pediatric patients, Can J Neurol Sci 1998 25: 3 S8-12
34. Moreland EC, Griesemer DA, Holden KR: Topiramate for intractable childhood epilepsy, Seizure 1999
8: 1 38-40

35. Elterman RD, Glauser TA, Wyllie E: A double-blind, randomized trial of topiramate as adjunctive
therapy for partial-onset seizures in children: Topiramate YP Study Group, Neurology 1999 52: 7 1338-44

36. Uldall P, Buchholt JM: Clinical experiences with topiramate in children with intractable epilepsy,
Europ J Paediatr Neurol 1999 3: 3 105-11

37. Glauser TA: Preliminary observations on topiramate in pediatric epilepsies, Epilepsia 1997 38: Suppl
1 S37-41

38. Ben-Menachem E: Clinical efficacy of topiramate as add-on therapy in refractory partial epilepsy: the
European experience, Epilepsia 1997 38: Suppl 1 S28-30

39. Biton V, Montouris GD, Ritter F: A randomized, placebo-controlled study of topiramate in primary
generalized tonic-clonic seizures: Topiramate YTC Study Group, Neurology 1999 52: 7 1330-7

40. Biton V: Preliminary open-label experience with topiramate in primary generalized seizures,
Epilepsia 1997 38: Suppl 1 S42-4

41. Alapati A, Faught E: Side effect profile on two different starting doses of topiramate, Epilepsia 1999
40: Suppl 7 141-2

42. Hulihan J, Ortho-McNeil Pharmaceutical Inc. Dear healthcare professional letter regarding
oligohidrosis and hyperthermia. Raritan, NJ; 2003 Jul. From FDA web site
(http://www.fda.gov/medwatch/SAFETY/2003/Topamax_deardoc.pdf).
BR>43. Hulihan J, Ortho-McNeil Pharmaceutical Inc. Dear healthcare professional letter regarding
metabolic acidosis. Raritan, NJ; 2003 Dec. From FDA web site
(http://www.fda.gov/medwatch/SAFETY/2003/topamax_dhcp.pdf).

Location In Book:

AHFS DRUG INFORMATION® (2004)

28:00 Central Nervous System Agents

28:12 Anticonvulsants

28:12.92 Miscellaneous Anticonvulsants

Topiramate
Topiramate

pengantar

C12H21NO8S

• Topiramate adalah antikonvulsan.1, 2, 3, 4, 5, 17, 18

Kegunaan

• Kejang parsial

Topiramate digunakan dalam kombinasi dengan agen antikonvulsan lainnya dalam

pengelolaan kejang parsial pada orang dewasa dan anak-anak berusia 2-16 tahun.1,
2, 4, 5, 6, 7, 8, 9, 10, 22, 25, 29, Khasiat topiramate sebagai terapi tambahan pada
pasien dewasa dengan kejang parsial (termasuk yang sederhana dan kompleks
parsial) dengan atau tanpa serangan klonik klonik umum sekunder ditemukan pada
beberapa penelitian klinis terkontrol.1 Dalam penelitian ini, pasien awalnya
distabilkan dengan dosis optimum 1 atau 2 obat antikonvulsan konvensional
(misalnya karbamazepin, klonazepam, fenobarbital, fenitoin, primidona , asam
valproik) selama periode baseline 8- sampai 12 minggu; 1, 2, 4, 6, 7, 8, 9, 10, 22
yang mengalami rata-rata setidaknya satu kejang parsial (dengan atau tanpa
generalisasi sekunder) per minggu selama fase ini diacak untuk menerima
topiramate atau plasebo selama periode titrasi dosis 3-6 minggu diikuti oleh
periode stabilisasi 8- sampai 12 minggu di mana dosis topiramate atau plasebo
maksimal dicapai.1 Khasiat topiramate dalam penelitian ini secara prinicipally
dievaluasi berdasarkan perubahan frekuensi kejang dan tingkat responder.1, 2, 4, 6,
7, 8, 9, 10, 22, 25 Perubahan frekuensi kejang dengan penambahan topiramate atau
plasebo pada rejimen antikonvulsan yang ada adalah persentase median yang
menurun. (atau meningkat) rata-rata tingkat kejenuhan bulanan (28 hari ).1, 2, 4, 6,
7, 8, 9, 10 Tingkat tanggapan responden adalah persentase pasien dengan
penurunan frekuensi kejang 50% atau lebih besar dibandingkan dengan nilai
dasar.1, 2, 4, 6, 7, 8, 9, 10, 25

Pasien yang menerima topiramate 200 mg setiap hari atau plasebo pada salah satu
penelitian mengalami penurunan frekuensi kejang masing-masing 27-30 atau 12-
13%, dan tingkat tanggapan masing-masing adalah 24-27 atau 18% .1, 2, 4 , 6
Dalam 2 penelitian, pasien yang menerima topiramate 400 mg setiap hari atau
plasebo mengalami penurunan frekuensi kejang masing-masing 41-48 atau 1-13%,
dan tingkat tanggapan masing-masing adalah 35-47 atau 8-18%. 1, 2, 4, 6, 8 Pasien
yang menerima 600 mg topiramate setiap hari dalam 3 penelitian mengalami
penurunan frekuensi kejang 41-46%, 1, 2, 4, 6, 7, 9 dan pasien yang menerima
plasebo mengalami penurunan frekuensi kejang 1-13% pada 2 penelitian, 1, 2, 4, 6,
7 dan peningkatan frekuensi kejang 12% pada penelitian ketiga.1, 2, 4, 9 Dalam 3
penelitian di pasien yang menerima topiramate 600 mg per hari atau plasebo, 40-47
atau 9-18%, masing-masing, dianggap sebagai responden.1, 2, 4, 6, 7, 9 Pasien
yang menerima topiramate 800 mg setiap hari dalam 2 penelitian mengalami
penurunan se dengan frekuensi kejang 24-41%, 1, 2, 4, 7, 10 dan pasien yang
menerima plasebo mengalami penurunan tingkat kejang bulanan 1-2% pada satu
penelitian1, 2, 7 atau peningkatan 18-21% pada frekuensi kejang dalam penelitian
lainnya.1, 2, 4, 10 Dalam penelitian pasien yang menerima topiramate 800 mg
setiap hari atau plasebo, 40-43 atau 0-9%, masing-masing, dianggap sebagai
responden.1, 2, 4, 7, 10 Pasien yang menerima 1 g topiramate atau plasebo setiap
hari dalam satu penelitian mengalami penurunan frekuensi kejang masing-masing
36-38 atau 1-2%, 1, 2, 7 dan 36-38 atau 8-9% pasien, dilaporkan sebagai
responden. 2, 4, 7 Secara keseluruhan, dosis topiramate yang melebihi 600 mg
setiap hari tidak menghasilkan efikasi yang jauh lebih baik, walaupun setiap pasien
mungkin mendapat manfaat dari dosis yang relatif tinggi.7, 25

Khasiat topiramate sebagai terapi tambahan pada pasien anak-anak (usia 2-16
tahun) dengan kejang parsial dengan atau tanpa serangan umum sekunder
dilakukan pada percobaan multisenter, acak, terkontrol.1, 31, 35 Dalam penelitian
ini, pasien pada awalnya distabilkan dengan dosis optimum 1 atau 2 obat
antikonvulsan konvensional; pasien yang mengalami 6 atau lebih kejang parsial
dengan atau tanpa kejang umum sekunder selama periode baseline 8 minggu secara
acak baik untuk topiramate atau placebo.1, 35 Pasien menerima topiramate pada
awalnya dengan dosis 25 atau 50 mg setiap hari, setelah itu dosis harian meningkat
dengan penambahan 25-150 mg setiap minggu sampai dosis yang ditetapkan 125,
175, 225, atau 400 mg setiap hari (sekitar 6 mg / kg topiramate setiap hari,
berdasarkan berat tubuh pasien) tercapai, atau sampai perkembangan efek samping
menghalangi kenaikan dosis.1, 35 Periode titrasi dosis 8 minggu kemudian diikuti
oleh periode pemeliharaan 8 minggu.1, 35 Pasien yang menerima topiramate 6 mg
/ kg setiap hari atau plasebo mengalami penurunan kejang. masing-masing 33,1
atau 10,5%, dan tingkat tanggapan masing-masing 39 atau 20%. 35

• Kejang-kejang Tonik Klonik Generalized Umum

Topiramate digunakan dalam kombinasi dengan agen antikonvulsan lainnya dalam

pengelolaan generalisata primer