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TOPAMAX(topiramate) tablet, coated

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use TOPAMAX® safely and effectively. See full prescribing information for TOPAMAX® TOPAMAX® (topiramate) TABLETSTOPAMAX® (topiramate capsules) SPRINKLE CAPSULESInitial U.S. Approval – 1996

RECENT MAJOR CHANGES

• Warnings and Precautions (5.8)

[12/2009]

INDICATIONS AND USAGE

TOPAMAX® is an antiepileptic (AED) agent indicated for:

Monotherapy epilepsy: Initial monotherapy in patients ≥10 years of age with partial onset or primary generalized tonic-clonic seizures (1.1).
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).
Migraine: Treatment for adults for prophylaxis of migraine headache (1.3).

DOSAGE AND ADMINISTRATION

See DOSAGE AND ADMINISTRATION, Epilepsy: Adjunctive Therapy Use for additional details (2.1).

	Initial Dose	Titration	Recommended Dose
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 of 50 mg for the first 4 weeks then 100 mg for weeks 5 to 6.	400 mg/day in two divided doses
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.	200–400 mg/day in two divided doses
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
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
Migraine (2.3)	25 mg/day administered nightly for the first week	The dosage should be increased weekly by increments of 25 mg. Dose and titration should be guided by clinical outcome.	100 mg/day administered in two divided doses

DOSAGE FORMS AND STRENGTHS

Tablets: 25 mg, 50 mg, 100 mg, and 200 mg (3)
Sprinkle Capsules: 15 mg and 25 mg (3)

CONTRAINDICATIONS

None.

WARNINGS AND PRECAUTIONS

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 TOPAMAX® as rapidly as possible (5.1).
Oligohidrosis and hyperthermia: Monitor decreased sweating and increased body temperature, especially in pediatric patients (5.2).
Suicidal behavior and ideation: Antiepileptic drugs increase the risk of suicidal behavior or ideation (5.3).
Metabolic acidosis: Baseline and periodic measurement of serum bicarbonate is recommended. Consider dose reduction or discontinuation of TOPAMAX® if clinically appropriate (5.4).
Cognitive/neuropsychiatric: TOPAMAX® may cause cognitive dysfunction. Patients should use caution when operating machinery including automobiles. Depression and mood problems may occur in epilepsy and migraine populations (5.5).
Withdrawal of AEDs: Withdrawal of TOPAMAX® should be done gradually (5.6).
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 hyper-ammonemia. Measure ammonia if encephalopathic symptoms occur (5.8).
Kidney stones: Use with other carbonic anhydrase inhibitors, other drugs causing metabolic acidosis, or in patients on a ketogenic diet should be avoided (5.9).

ADVERSE REACTIONS

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. The most common (≥5% more frequent than placebo) adverse reactions in controlled, migraine clinical trials were paresthesia and taste perversion.

TO REPORT SUSPECTED ADVERSE REACTIONS, CONTACT ORTHO-MCNEIL NEUROLOGICS AT 1-888-526-7736 OR FDA AT 1-800-FDA-1088 OR WWW.FDA.GOV/MEDWATCH.

DRUG INTERACTIONS

Summary of antiepileptic drug (AED) interactions with TOPAMAX® (7.1).

AED Co-administered	AED Concentration	TOPAMAX Concentration
Phenytoin	NC or 25% increase*	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide†	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

NC = Less than 10% change in plasma concentration.
NE = Not eva lutated
*= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.†= Is not administered but is an active metabolite of carbamazepine.

Concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with and without encephalopathy (5.7).
Oral contraceptives: Decreased contraceptive efficacy and increased breakthrough bleeding should be considered, especially at doses greater than 200 mg/day (7.3).
Metformin is contraindicated with metabolic acidosis, a possible effect of topiramate (7.4)
Lithium levels should be monitored when co-administered with high-dose topiramate (7.5)
Other Carbonic Anhydrase Inhibitors: monitor the patient for the appearance or worsening of metabolic acidosis (7.6)

USE IN SPECIFIC POPULATIONS

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).
Patients Undergoing Hemodialysis: Topiramate is cleared by hemodialysis. Dosage adjustment is necessary to avoid rapid drops in topiramate plasma concentration during hemodialysis (2.6).
Pregnancy: based on animal data, may cause fetal harm. To enroll in the North American Antiepileptic Drug Pregnancy Registry call 1-888-233-2334 (toll free) (8.1).
Geriatric Use: Dosage adjustment may be necessary for elderly with impaired renal function (8.5).

See 17 for PATIENT COUNSELING INFORMATION and the FDA-approved Medication Guide

Revised: 01/2011

Back to Highlights and Tabs

FULL PRESCRIBING INFORMATION: CONTENTS*

*Sections or subsections omitted from the full prescribing information are not listed

1 INDICATIONS AND USAGE

1.1 Monotherapy Epilepsy

1.2 Adjunctive Therapy Epilepsy

1.3 Migraine

2 DOSAGE AND ADMINISTRATION

2.1 Epilepsy

2.2 Migraine

2.3 Administration of TOPAMAX® Sprinkle Capsules

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 Oligohidrosis and Hyperthermia

5.3 Suicidal Behavior and Ideation

5.4 Metabolic Acidosis

5.5 Cognitive/Neuropsychiatric Adverse Reactions

5.6 Withdrawal of Antiepileptic Drugs (AEDs)

5.7 Sudden Unexplained Death in Epilepsy (SUDEP)

5.8 Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid [VPA] Use)

5.9 Kidney Stones

5.10 Paresthesia

5.11 Adjustment of Dose in Renal Failure

5.12 Decreased Hepatic Function

5.13 Monitoring: Laboratory Tests

6 ADVERSE REACTIONS

6.1 Monotherapy Epilep

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

6.7 Migraine

6.8 Other Adverse Reactions Observed During Migraine 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

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, and Impairment of Fertility

14 CLINICAL STUDIES

14.1 Monotherapy Epilepsy Controlled Trial

14.2 Migraine Prophylaxis

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Eye Disorders

17.2 Oligohydrosis and Hypeerthermia

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

PRINCIPAL DISPLAY PANEL

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Enter section text here

1.1 Monotherapy Epilepsy

TOPAMAX® (topiramate) Tablets and TOPAMAX® (topiramate capsules) Sprinkle Capsules 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

TOPAMAX® (topiramate) Tablets and TOPAMAX® (topiramate capsules) Sprinkle Capsules 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 (14.2)].

1.3 Migraine

TOPAMAX® (topiramate) Tablets and TOPAMAX® (topiramate capsules) Sprinkle Capsules are indicated for adults for the prophylaxis of migraine headache [see Clinical Studies (14.3)]. The usefulness of TOPAMAX® in the acute treatment of migraine headache has not been studied.

2 DOSAGE AND ADMINISTRATION

Enter section text here

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 or 1,000 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 TOPAMAX® therapy. On occasion, the addition of TOPAMAX® 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 TOPAMAX® may require adjustment of the dose of TOPAMAX®. Because of the bitter taste, tablets should not be broken.

TOPAMAX® 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:

	Morning Dose	Evening Dose
Week 1	25 mg	25 mg
Week 2	50 mg	50 mg
Week 3	75 mg	75 mg
Week 4	100 mg	100 mg
Week 5	150 mg	150 mg
Week 6	200 mg	200 mg

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 TOPAMAX® 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 – 16 Years) – Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome

The recommended total daily dose of TOPAMAX® (topiramate) 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)].

2.2 Migraine

The recommended total daily dose of TOPAMAX® as treatment for adults for prophylaxis of migraine headache is 100 mg/day administered in two divided doses. The recommended titration rate for topiramate for migraine prophylaxis to 100 mg/day is:

	Morning Dose	Evening Dose
Week 1	None	25 mg
Week 2	25 mg	25 mg
Week 3	25 mg	50 mg
Week 4	50 mg	50 mg

Dose and titration rate should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used.

TOPAMAX® can be taken without regard to meals.

2.3 Administration of TOPAMAX® Sprinkle Capsules

TOPAMAX® (topiramate capsules) Sprinkle Capsules may be swallowed whole or may be administered by carefully opening the capsule and sprinkling the entire contents on a small amount (teaspoon) of soft food. This drug/food mixture should be swallowed immediately and not chewed. It should not be stored for future use.