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TOPIRAMATEtablet, film coated
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HIGHLIGHTS OF PRESCRIBING INFORMATION |
These highlights do not include all the information needed to use topiramate safely and effectively. See full prescribing information for topiramate tablets.
topiramate tablets for oral use
Initial U.S. Approval – 1996
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INDICATIONS AND USAGE
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Topiramate tablets are an antiepileptic (AED) agent indicated for:
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Monotherapy epilepsy: Initial monotherapy in patients ≥10 years of age with partial onset or primary generalized tonic-clonic seizures (1.1).
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Adjunctive therapy epilepsy: Adjunctive therapy for adults and pediatric patients (2 to 16 years of age) with partial onset seizures or primary generalized tonic-clonic seizures, and in patients ≥2 years of age with seizures associated with Lennox-Gastaut syndrome (LGS) (1.2).
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DOSAGE AND ADMINISTRATION
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See DOSAGE AND ADMINISTRATION, Epilepsy: Adjunctive Therapy Use for additional details (2.1).
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Initial Dose |
Titration |
Recommended Dose |
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Epilepsy monotherapy: adults and pediatric patients ≥10 years (2.1) |
50 mg/day in two divided doses |
The dosage should be increased weekly by increments of50 mg for the first 4 weeks then 100 mg for weeks 5 to 6. |
400 mg/day in two divided doses |
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Epilepsy adjunctive therapy: adults with partial onset seizures or LGS (2.1) |
25 to
50 mg/day |
The dosage should be increased weekly to an effective dose by increments of 25 to 50 mg. |
200 to 400 mg/day in two divided doses |
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Epilepsy adjunctive therapy: adults with primary generalized tonic-clonic seizures (2.1) |
25 to
50 mg/day |
The dosage should be increased weekly to an effective dose by increments of 25 to 50 mg. |
400 mg/day in two divided doses |
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Epilepsy adjunctive therapy: pediatric patients with partial onset seizures, primary generalized tonic-clonic seizures or LGS (2.1) |
25 mg/day (or less, based on a range of 1 to 3 mg/ kg/day) nightly for the first week |
The dosage should be increased at 1- or 2-week intervals by increments of 1 to 3 mg/kg/day (administered in two divided doses). Dose titration should be guided by clinical outcome. |
5 to 9 mg/ kg/day in two divided doses |
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DOSAGE FORMS AND STRENGTHS
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Tablets: 25 mg, 50 mg, 100 mg, and 200 mg (3)
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WARNINGS AND PRECAUTIONS
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Acute myopia and secondary angle closure glaucoma: Untreated elevated intraocular pressure can lead to permanent visual loss. The primary treatment to reverse symptoms is discontinuation of topiramate as rapidly as possible (5.1).
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Oligohydrosis and hyperthermia: Monitor decreased sweating and increased body temperature, especially in pediatric patients (5.2).
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Suicidal behavior and ideation: Antiepileptic drugs increase the risk of suicidal behavior or ideation (5.3).
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Metabolic acidosis: Baseline and periodic measurement of serum bicarbonate is recommended. Consider dose reduction or discontinuation of topiramate if clinically appropriate (5.4).
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Cognitive/neuropsychiatric: Topiramate may cause cognitive dysfunction. Patients should use caution when operating machinery including automobiles. Depression and mood problems may occur in epilepsy and other populations (5.5).
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Fetal Toxicity: Topiramate use during pregnancy can cause cleft lip and/or palate (5.6).
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Withdrawal of AEDs: Withdrawal of topiramate should be done gradually (5.7).
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Hyperammonemia and encephalopathy associated with or without concomitant valproic acid use: Patients with inborn errors of metabolism or reduced mitochondrial activity may have an increased risk of hyperammonemia. Measure ammonia if encephalopathic symptoms occur (5.9).
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Kidney stones: Use with other carbonic anhydrase inhibitors, other drugs causing metabolic acidosis, or in patients on a ketogenic diet should be avoided (5.10).
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ADVERSE REACTIONS
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The most common (>5% more frequent than placebo or low dose topiramate in monotherapy) adverse reactions in controlled, epilepsy clinical trials were paresthesia, anorexia, weight decrease, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, difficulty with memory, difficulty with concentration/attention, and confusion (6).
To report SUSPECTED ADVERSE REACTIONS, contact Greenstone LLC at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. |
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DRUG INTERACTIONS
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Summary of antiepileptic drug (AED) interactions with topiramate (7.1).
a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not eva luated. |
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AED Co-administered |
AED Concentration |
Topiramate Concentration |
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Phenytoin |
NC or 25% increasea |
48% decrease |
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Carbamazepine (CBZ) |
NC |
40% decrease |
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CBZ epoxideb |
NC |
NE |
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Valproic acid |
11% decrease |
14% decrease |
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Phenobarbital |
NC |
NE |
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Primidone |
NC |
NE |
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Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
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Concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with and without encephalopathy (5.7).
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Oral contraceptives: Decreased contraceptive efficacy and increased breakthrough bleeding should be considered, especially at doses greater than 200 mg/day (7.3).
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Metformin is contraindicated with metabolic acidosis, a possible effect of topiramate (7.4).
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Lithium levels should be monitored when co-administered with high-dose topiramate (7.5).
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Other Carbonic Anhydrase Inhibitors: Monitor the patient for the appearance or worsening of metabolic acidosis (7.6).
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USE IN SPECIFIC POPULATIONS
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Renal Impairment: In renally impaired patients (creatinine clearance less than 70 mL/min/1.73 m2), one half of the adult dose is recommended (2.4).
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Patients Undergoing Hemodialysis: Topiramate is cleared by hemodialysis.
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Dosage adjustment is necessary to avoid rapid drops in topiramate plasma concentration during hemodialysis (2.6).
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Pregnancy: Increased risk of cleft lip and/or palate. Pregnancy registry available (8.1).
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Nursing Mothers: Caution should be exercised when administered to a nursing mother (8.3).
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Geriatric Use: Dosage adjustment may be necessary for elderly with impaired renal function (8.5).
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See 17 for PATIENT COUNSELING INFORMATION and Medication Guide |
Revised: 07/2011 |
Back to Highlights and Tabs
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FULL PRESCRIBING INFORMATION: CONTENTS* |
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1 INDICATIONS AND USAGE
1.1 Monotherapy Epilepsy
1.2 Adjunctive Therapy Epilepsy
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
2.4 Patients with Renal Impairment
2.5 Geriatric Patients (Ages 65 Years and Over)
2.6 Patients Undergoing Hemodialysis
2.7 Patients with Hepatic Disease
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Acute Myopia and Secondary Angle Closure Glaucoma
5.2 Oligohydrosis and Hyperthermia
5.3 Suicidal Behavior and Ideation
5.4 Metabolic Acidosis
5.5 Cognitive/Neuropsychiatric Adverse Reactions
5.6 Fetal Toxicity
5.7 Withdrawal of Antiepileptic Drugs (AEDs)
5.8 Sudden Unexplained Death in Epilepsy (SUDEP)
5.9 Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid [VPA] Use)
5.10 Kidney Stones
5.11 Paresthesia
5.12 Adjustment of Dose in Renal Failure
5.13 Decreased Hepatic Function
5.14 Monitoring: Laboratory Tests
6 ADVERSE REACTIONS
6.1 Monotherapy Epilepsy
6.2 Adjunctive Therapy Epilepsy
6.3 Incidence in Epilepsy Controlled Clinical Trials – Adjunctive Therapy – Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, and Lennox-Gastaut Syndrome
6.4 Other Adverse Reactions Observed During Double-Blind Epilepsy Adjunctive Therapy Trials
6.5 Incidence in Study 119 – Add-On Therapy – Adults with Partial Onset Seizures
6.6 Other Adverse Reactions Observed During All Epilepsy Clinical Trials
6.9 Postmarketing and Other Experience
7 DRUG INTERACTIONS
7.1 Antiepileptic Drugs
7.2 CNS Depressants
7.3 Oral Contraceptives
7.4 Metformin
7.5 Lithium
7.6 Other Carbonic Anhydrase Inhibitors
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Labor and Delivery
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Race and Gender Effects
8.7 Renal Impairment
8.8 Patients Undergoing Hemodialysis
8.9 Women of Childbearing Potential
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
9.2 Abuse
9.3 Dependence
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.4 Special Populations
12.5 Drug-Drug Interactions
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Monotherapy Epilepsy Controlled Trial
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Eye Disorders
17.2 Oligohydrosis and Hyperthermia
17.3 Suicidal Behavior and Ideation
17.4 Metabolic Acidosis
17.5 Interference with Cognitive and Motor Performance
17.6 Hyperammonemia and Encephalopathy
17.7 Kidney Stones
17.8 Fetal Toxicity
MEDICATION GUIDE
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 25 mg (60 Tablet Bottle)
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 50 mg (60 Tablet Bottle)
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 100 mg (60 Tablet Bottle)
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 200 mg (60 Tablet Bottle)
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FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
1.1 Monotherapy Epilepsy
Topiramate tablets are indicated as initial monotherapy in patients 10 years of age and older with partial onset or primary generalized tonic-clonic seizures. Effectiveness was demonstrated in a controlled trial in patients with epilepsy who had no more than 2 seizures in the 3 months prior to enrollment. Safety and effectiveness in patients who were converted to monotherapy from a previous regimen of other anticonvulsant drugs have not been established in controlled trials [see Clinical Studies (14.1)].
1.2 Adjunctive Therapy Epilepsy
Topiramate tablets are indicated as adjunctive therapy for adults and pediatric patients ages 2 to 16 years with partial onset seizures or primary generalized tonic-clonic seizures, and in patients 2 years of age and older with seizures associated with Lennox-Gastaut syndrome [see Clinical Studies (14.1)].
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
In the controlled adjunctive (i.e., add-on) trials, no correlation has been demonstrated between trough plasma concentrations of topiramate and clinical efficacy. No evidence of tolerance has been demonstrated in humans. Doses above 400 mg/day (600, 800 or1,000 mg/day) have not been shown to improve responses in dose-response studies in adults with partial onset seizures.
It is not necessary to monitor topiramate plasma concentrations to optimize topiramate tablets therapy. On occasion, the addition of topiramate tablets to phenytoin may require an adjustment of the dose of phenytoin to achieve optimal clinical outcome. Addition or withdrawal of phenytoin and/or carbamazepine during adjunctive therapy with topiramate tablets may require adjustment of the dose of topiramate tablets. Because of the bitter taste, tablets should not be broken.
Topiramate tablets can be taken without regard to meals.
Monotherapy Use
The recommended dose for topiramate monotherapy in adults and pediatric patients 10 years of age and older is 400 mg/day in two divided doses. Approximately 58% of patients randomized to 400 mg/day achieved this maximal dose in the monotherapy controlled trial; the mean dose achieved in the trial was 275 mg/day. The dose should be achieved by titration according to the following schedule:
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Morning Dose |
Evening Dose |
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Week 1 |
25 mg |
25 mg |
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Week 2 |
50 mg |
50 mg |
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Week 3 |
75 mg |
75 mg |
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Week 4 |
100 mg |
100 mg |
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Week 5 |
150 mg |
150 mg |
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Week 6 |
200 mg |
200 mg |
Adjunctive Therapy Use
Adults (17 Years of Age and Over) - Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome
The recommended total daily dose of topiramate tablets as adjunctive therapy in adults with partial onset seizures is 200 to 400 mg/day in two divided doses, and 400 mg/day in two divided doses as adjunctive treatment in adults with primary generalized tonic-clonic seizures. It is recommended that therapy be initiated at 25 to 50 mg/day followed by titration to an effective dose in increments of 25 to 50 mg/day every week. Titrating in increments of 25 mg/day every week may delay the time to reach an effective dose. Daily doses above 1,600 mg have not been studied.
In the study of primary generalized tonic-clonic seizures the initial titration rate was slower than in previous studies; the assigned dose was reached at the end of 8 weeks [see Clinical Studies (14.1)].
Pediatric Patients (Ages 2 to 16 Years) – Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome
The recommended total daily dose of topiramate tablets as adjunctive therapy for pediatric patients with partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome is approximately 5 to 9 mg/kg/day in two divided doses. Titration should begin at 25 mg/day (or less, based on a range of 1 to 3 mg/kg/day) nightly for the first week. The dosage should then be increased at 1- or 2-week intervals by increments of 1 to 3 mg/kg/day (administered in two divided doses), to achieve optimal clinical response. Dose titration should be guided by clinical outcome.
In the study of primary generalized tonic-clonic seizures the initial titration rate was slower than in previous studies; the assigned dose of 6 mg/kg/day was reached at the end of 8 weeks [see Clinical Studies (14.1)].
2.4 Patients with Renal Impairment
In renally impaired subjects (creatinine clearance less than 70 mL/min/1.73 m2), one-half of the usual adult dose is recommended. Such patients will require a longer time to reach steady-state at each dose.
2.5 Geriatric Patients (Ages 65 Years and Over)
Dosage adjustment may be indicated in the elderly patient when impaired renal function (creatinine clearance rate <70 mL/min/1.73 m2) is evident [see Clinical Pharmacology (12.4)].
2.6 Patients Undergoing Hemodialysis
Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than a normal individual. Accordingly, a prolonged period of dialysis may cause topiramate concentration to fall below that required to maintain an anti-seizure effect. To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate may be required. The actual adjustment should take into account 1) the duration of dialysis period, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of topiramate in the patient being dialyzed.
2.7 Patients with Hepatic Disease
In hepatically impaired patients, topiramate plasma concentrations may be increased. The mechanism is not well understood.
3 DOSAGE FORMS AND STRENGTHS
Topiramate tablets are available as debossed, coated, circular tablets in the following strengths and colors:
25 mg white, circular, biconvex, film-coated tablets debossed with ‘E’ on one side and ‘22’ on the other side.
50 mg light yellow colored, circular, biconvex, film-coated tablets debossed with ‘E’ on one side and ‘33’ on the other side.
100 mg dark yellow colored, circular, biconvex, beveled edge, film-coated tablets debossed with ‘E’ on one side and ‘23’ on the other side.
200 mg pink colored, circular, biconvex, beveled edge, film-coated tablets debossed with ‘E’ on one side and ‘24’ on the other side.
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Acute Myopia and Secondary Angle Closure Glaucoma
A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness) and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of topiramate as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of topiramate, may be helpful.
Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss.
5.2 Oligohydrosis and Hyperthermia
Oligohydrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with topiramate use. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases were reported after exposure to elevated environmental temperatures.
The majority of the reports have been in pediatric patients. Patients, especially pediatric patients, treated with topiramate should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when topiramate is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity.
5.3 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including topiramate, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.
Table 1 shows absolute and relative risk by indication for all eva luated AEDs.
Table 1: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
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Indication |
Placebo Patients with Events per 1000 Patients |
Drug Patients with Events per 1000 Patients |
Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients |
Risk Difference: Additional Drug Patients with Events per 1000 Patients |
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Epilepsy |
1 |
3.4 |
3.5 |
2.4 |
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Psychiatric |
5.7 |
8.5 |
1.5 |
2.9 |
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Other |
1 |
1.8 |
1.9 |
0.9 |
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Total |
2.4 |
4.3 |
1.8 |
1.9 |
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing topiramate or any other AED must balance the risk of suicidal thoughts or behavior with the r |
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