TOPIRAMATE - topiramate tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
TOPIRAMATE (UNII: 0H73WJJ391) (TOPIRAMATE - UNII:0H73WJJ391)
Available from:
H.J. Harkins Company, Inc.
INN (International Name):
TOPIRAMATE
Composition:
TOPIRAMATE 25 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
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)]. 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 (14.2)]. None. Pregnancy Category C. Topiramate may cause serious adverse fetal effects, based on clinical and nonclinical data.   Topiramate treatment is associated with metabolic acidosis [see Warnings and Precau
Product summary:
Topiramate Tablets 25 mg are white to off white, round, biconvex, film coated tablets debossed with ‘1031’ on one side and ‘25’ on other side. Topiramate Tablets 25 mg are supplied as follows: Package                                                                                                                 NDC Number Topiramate Tablets 50 mg are yellow colored, round, biconvex, film coated tablets debossed with ‘1032’ on one side and ‘50’ on other side. Topiramate Tablets 50 mg are supplied as follows: Package                                                                                                                 NDC Number Topiramate tablets should be stored in tightly-closed containers at 20° - 25°C (68° - 77°F); excursions permitted to 15° - 30°C (59° - 86°F) [see USP Controlled Room Temperature]. PROTECT FROM MOISTURE.
Authorization status:
Abbreviated New Drug Application
Authorization number:
52959-441-01, 52959-441-30, 52959-441-60, 52959-994-02, 52959-994-30, 52959-994-60, 52959-994-90

TOPIRAMATE - topiramate tablet

H.J. Harkins Company, Inc.

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MEDICATION GUIDE

Topiramate tablets

Rx Only

Read this Medication Guide before you start taking topiramate tablets and each time you get a refill.

There may be new information. This information does not take the place of talking to your healthcare

provider about your medical condition or treatment. If you have any questions about topiramate tablets,

talk to your healthcare provider or pharmacist.

What is the most important information I should know about topiramate tablets?

Topiramate tablets may cause eye problems. Serious eye problems include:

any sudden decrease in vision with or without eye pain and redness,

a blockage of fluid in the eye causing increased pressure in the eye (secondary angle closure

glaucoma).

These eye problems can lead to permanent loss of vision if not treated. You should call your

healthcare provider right away if you have any new eye symptoms.

Topiramate tablets may cause decreased sweating and increased body temperature (fever). People,

especially children, should be watched for signs of decreased sweating and fever, especially in hot

temperatures. Some people may need to be hospitalized for this condition.

Like other antiepileptic drugs, topiramate tablets may cause suicidal thoughts or actions in a very small

number of people, about 1 in 500.

Call a healthcare provider right away if you have any of these symptoms, especially if they are new,

worse, or worry you:

thoughts about suicide or dying

attempts to commit suicide

new or worse depression

new or worse anxiety

feeling agitated or restless

panic attacks

trouble sleeping (insomnia)

new or worse irritability

acting aggressive, being angry, or violent

acting on dangerous impulses

an extreme increase in activity and talking (mania)

other unusual changes in behavior or mood

Do not stop topiramate tablets without first talking to a healthcare provider.

Stopping topiramate tablets suddenly can cause serious problems.

Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal

thoughts or actions, your healthcare provider may check for other causes.

How can I watch for early symptoms of suicidal thoughts and actions?

Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or

feelings.

Keep all follow-up visits with your healthcare provider as scheduled.

Call your healthcare provider between visits as needed, especially if you are worried about

symptoms.

What are topiramate tablets?

Topiramate tablets are a prescription medicine used:

to treat certain types of seizures (partial onset seizures and primary generalized tonic-clonic

seizures) in people 10 years and older,

with other medicines to treat certain types of seizures (partial onset seizures, primary generalized

tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome) in adults and

children 2 years and older.

What should I tell my healthcare provider before taking topiramate tablets?

Before taking topiramate tablets, tell your healthcare provider about all your medical conditions,

including if you:

have or have had depression, mood problems or suicidal thoughts or behavior

have kidney problems, kidney stones or are getting kidney dialysis

have a history of metabolic acidosis (too much acid in the blood)

have liver problems

have osteoporosis, soft bones, or decreased bone density

have lung or breathing problems

have eye problems, especially glaucoma

have diarrhea

have a growth problem

are on a diet high in fat and low in carbohydrates, which is called a ketogenic diet

are having surgery

are pregnant or plan to become pregnant. It is not known if topiramate tablets will harm your

unborn baby. If you become pregnant while taking topiramate tablets, talk to your healthcare

provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You

can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect

information about the safety of antiepileptic medicine during pregnancy.

are breastfeeding. It is not known if topiramate tablets passes into breast milk and if it can harm

your baby. Talk to your healthcare provider about the best way to feed your baby if you take

topiramate tablets.

Tell your healthcare provider about all the medicines you take, including prescription and non-

prescription medicines, vitamins, and herbal supplements. Topiramate tablets and other medicines may

affect each other causing side effects.

Especially, tell your healthcare provider if you take:

Valproic acid

any medicines that impair or decrease your thinking, concentration, or muscle coordination.

birth control pills. Topiramate tablets may make your birth control pills less effective. Tell your

healthcare provider if your menstrual bleeding changes while you are taking birth control pills and

topiramate tablets.

Ask your healthcare provider if you are not sure if your medicine is listed above.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each

time you get a new medicine. Do not start a new medicine without talking with your healthcare provider.

How should I take topiramate tablets?

Take topiramate tablets exactly as prescribed.

Your healthcare provider may change your dose. Do not change your dose without talking to your

healthcare provider.

Topiramate tablets should be swallowed whole. Do not chew the tablets. They may leave a bitter

taste.

Do not store any medicine and food mixture for later use.

Topiramate tablets can be taken before, during, or after a meal. Drink plenty of fluids during the

day. This may help prevent kidney stones while taking topiramate tablets.

If you take too much topiramate tablets, call your healthcare provider or poison control center

right away or go to the nearest emergency room.

If you miss a single dose of topiramate tablets, take it as soon as you can. However, if you are

within 6 hours of taking your next scheduled dose, wait until then to take your usual dose of

topiramate tablets, and skip the missed dose. Do not double your dose. If you have missed more

than one dose, you should call your healthcare professional for advice.

Do not stop taking topiramate tablets without talking to your healthcare provider. Stopping

topiramate tablets suddenly may cause serious problems. If you have epilepsy and you stop taking

topiramate tablets suddenly, you may have seizures that do not stop. Your healthcare provider will

tell you how to stop taking topiramate tablets slowly.

Your healthcare provider may do blood tests while you take topiramate tablets.

What should I avoid while taking topiramate tablets?

Do not drink alcohol while taking topiramate tablets. Topiramate tablets and alcohol can affect

each other causing side effects such as sleepiness and dizziness.

Do not drive a car or operate heavy machinery until you know how topiramate tablet affects you.

Topiramate tablets can slow your thinking and motor skills, and/or vision.

What are the possible side effects of topiramate tablets?

Topiramate tablets may cause serious side effects including:

See "What is the most important information I should know about topiramate tablets?"

Metabolic Acidosis. Metabolic acidosis can cause:

tiredness

loss of appetite

irregular heartbeat

impaired consciousness

High blood ammonia levels. High ammonia in the blood can affect your mental activities, slow your

alertness, make you feel tired, or cause vomiting. This has happened when topiramate tablets is taken with

a medicine called valproic acid.

Kidney stones. Drink plenty of fluids when taking topiramate tablets to decrease your chances of

getting kidney stones.

Effects on Thinking and Alertness. Topiramate tablets may affect how you think, and cause confusion,

problems with concentration, attention, memory, or speech. Topiramate tablets may cause depression or

mood problems, tiredness, and sleepiness.

Dizziness or Loss of Muscle Coordination.

Call your healthcare provider right away if you have any of the symptoms above.

The most common side effects of topiramate tablets include:

tingling of the arms and legs (paresthesia)

not feeling hungry

nausea

a change in the way foods taste

diarrhea

weight loss

nervousness

upper respiratory tract infection

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all the possible side effects of topiramate tablets. For more information, ask your healthcare

provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-

FDA-1088.

How should I store topiramate tablets?

Store topiramate tablets at 20° - 25°C (68° - 77°F); excursions permitted to 15° - 30°C (59° -

86°F) [see USP Controlled Room Temperature]. PROTECT FROM MOISTURE.

Keep topiramate tablets in a tightly closed container.

Keep topiramate tablets and all medicines out of the reach of children.

General information about topiramate tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not

use topiramate tablets for a condition for which it was not prescribed. Do not give topiramate tablets to

other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about topiramate tablets. If you

would like more information, talk with your healthcare provider. You can ask your pharmacist or

healthcare provider for information about topiramate tablets that is written for health professionals.

For more information, call 1-269-544-2299.

What are the ingredients in topiramate tablets?

Active ingredient: topiramate, USP

Inactive ingredients: colloidal silicon dioxide, ferric oxide red (200 mg tablets), ferric oxide yellow (50,

100, and 200 mg tablets), HYPROMELLOSES, lactose monohydrate, magnesium stearate,

microcrystalline cellulose, polyethylene glycol, pregelatinized starch, sodium starch glycolate, talc and

titanium dioxide.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured by:

TORRENT PHARMACEUTICALS LTD., Indrad-382 721

Dist. Mehsana, INDIA.

For:

TORRENT PHARMA INC., 5380 Holiday Terrace, Suite 40, Kalamazoo, Michigan 49009.

8021903 Revised January 2010

Revised: 1/2012

Document Id: 7e3a6da2-f432-4a62-ab53-c305587b7726

Set id: 546130a3-e5f2-422d-88f0-66de19540ecb

Version: 3

Effective Time: 20120119

H.J. Harkins Company, Inc.

TOPIRAMATE - topiramate tablet

H.J. Harkins Company, Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use topiramate tablets safely and effectively. See

full prescribing information for topiramate tablets

Topiramate Tablets

Rx Only

Initial U.S. Approval - 1996

RECENT MAJOR CHANGES

Warnings and Precautions (5.3) [04/2009]

Warnings and Precautions (5.8) [12/2009]

INDICATIONS AND USAGE

Topiramate 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).

DOSAGE AND ADMINISTRATION

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

Initial Dose

T itration

Recommended Dose

Epilepsy monotherapy:

adults and

pediatric patients

≥10 years (2.1)

50 mg/day

in two

divided

dose s

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

dose s

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

dose s

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

dose s

DOSAGE FORMS AND STRENGTHS

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

CONTRAINDICATIONS

None. (4)

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 topiramate 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 topiramate if clinically appropriate (5.4).

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).

Withdrawal of AEDs: Withdrawal of topiramate 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 hyperammonemia. 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. (6)

TO REPORT SUSPECTED ADVERSE REACTIONS, CONTACT TORRENT PHARMA INC. AT 1-269-544-2299 OR FDA

AT 1-800-FDA-1088 OR WWW.FDA.GOV/MEDWATCH. (6)

DRUG INTERACTIONS

Summary of antiepileptic drug (AED) interactions with topiramate (7.1).

= 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.

NC = Less than 10% change in plasma concentration.

NE = Not Evaluated

AED Co-administered

AED Concentration

Topiramate Concentration

Phenytoin

NC or 25% increase

48% decrease

Carbamazepine (CBZ)

40% decrease

CBZ epoxide

Valproic acid

11% decrease

14% decrease

Phe nobarbital

Primidone

Lamotrigine

NC at TPM doses up to 400 mg/day

13% decrease

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 m ), 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 1-800-233-2334 (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 Medication Guide.

Revised: 1/2012

FULL PRESCRIBING INFORMATION: CONTENTS*

1. INDICATIONS AND USAGE

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 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) Hyperammonemia/Encephalopathy Without Concomitant Valproic Acid (VPA)

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 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

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

16. HOW SUPPLIED/STORAGE AND HANDLING

Topiramate tablets

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 Use in Pregnancy

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 (14.2)].

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

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

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 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:

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 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 - 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 m ), 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 m ) is evident [see Clinical Pharmacology 12.3].

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, round tablets in the following strengths and

colors:

25 mg white to off white (debossed "1031" on one side; "25" on the other)

50 mg yellow (debossed "1032" on one side; "50" on the other)

100 mg light yellow (debossed "1033" on one side; "100" on the other)

200 mg peach (debossed "1034" on one side; "200" on the other)

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 tablets 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

tablets as rapidly as possible, according to the judgment of the treating physician. Other measures, in

conjunction with discontinuation of topiramate tablets, may be helpful.

Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including

permanent vision loss.

5.2 Oligohidrosis and Hyperthermia

Oligohidrosis (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 evaluated AEDs.

Table 1 : Risk by Indication for Antiepileptic Drugs in Pooled Analysis

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

Epilepsy

Psychiatric

Other

Total

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.

epilepsy and psychiatric indications.

Anyone considering prescribing topiramate or any other AED must balance the risk of suicidal thoughts

or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are

prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal

thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber

needs to consider whether the emergence of these symptoms in any given patient may be related to the

illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal

thoughts and behavior and should be advised 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, behavior or thoughts about self-harm. Behaviors of concern should be reported

immediately to healthcare providers.

5.4 Metabolic Acidosis

Hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the

normal reference range in the absence of chronic respiratory alkalosis) is associated with topiramate

treatment. This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of

topiramate on carbonic anhydrase. Such electrolyte imbalance has been observed with the use of

topiramate in placebo-controlled clinical trials and in the post-marketing period. Generally, topiramate-

induced metabolic acidosis occurs early in treatment although cases can occur at any time during

treatment. Bicarbonate decrements are usually mild-moderate (average decrease of 4 mEq/L at daily

doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can

experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose

patients to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea,

ketogenic diet or specific drugs) may be additive to the bicarbonate lowering effects of topiramate.

In adults, the incidence of persistent treatment-emergent decreases in serum bicarbonate (levels of <20

mEq/L at two consecutive visits or at the final visit) in controlled clinical trials for adjunctive treatment

of epilepsy was 32% for 400 mg/day, and 1% for placebo. Metabolic acidosis has been observed at

doses as low as 50 mg/day. The incidence of persistent treatment-emergent decreases in serum

bicarbonate in adults in the epilepsy controlled clinical trial for monotherapy was 15% for 50 mg/day

and 25% for 400 mg/day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute

value <17 mEq/L and >5 mEq/L decrease from pretreatment) in the adjunctive therapy trials was 3% for

400 mg/day, and 0% for placebo and in the monotherapy trial was 1% for 50 mg/day and 7% for 400

mg/day. Serum bicarbonate levels have not been systematically evaluated at daily doses greater than 400

mg/day.

In pediatric patients (2-16 years of age), the incidence of persistent treatment-emergent decreases in

serum bicarbonate in placebo-controlled trials for adjunctive treatment of Lennox-Gastaut syndrome or

refractory partial onset seizures was 67% for topiramate (at approximately 6 mg/kg/day), and 10% for

placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17

mEq/L and >5 mEq/L decrease from pretreatment) in these trials was 11% for topiramate and 0% for

placebo. Cases of moderately severe metabolic acidosis have been reported in patients as young as 5

months old, especially at daily doses above 5 mg/kg/day.

Although not approved for use in patients under 2 years of age with partial onset seizures, a controlled

trial that examined this population revealed that topiramate produced a metabolic acidosis that is notably

greater in magnitude than that observed in controlled trials in older children and adults. The mean

treatment difference (25 mg/kg/d topiramate-placebo) was -5.9 mEq/L for bicarbonate. The incidence of

metabolic acidosis (defined by a serum bicarbonate < 20 mEq/L) was 0% for placebo, 30% for 5

mg/kg/d, 50% for 15 mg/kg/d, and 45% for 25 mg/kg/d [see Pediatric Use (8.4)].

In pediatric patients (10 years up to 16 years of age), the incidence of persistent treatment-emergent

decreases in serum bicarbonate in the epilepsy controlled clinical trial for monotherapy was 7% for 50

mg/day and 20% for 400 mg/day. The incidence of a markedly abnormally low serum bicarbonate (i.e.,

absolute value <17 mEq/L and >5 mEq/L decrease from pretreatment) in this trial was 4% for 50 mg/day

and 4% for 400 mg/day. The incidence of persistent treatment-emergent decreases in serum bicarbonate

in placebo-controlled trials for adults for another indication was 44% for 200 mg/day, 39% for 100

mg/day, 23% for 50 mg/day, and 7% for placebo. The incidence of a markedly abnormally low serum

bicarbonate (i.e., absolute value <17 mEq/L and >5 mEq/L decrease from pretreatment) in these trials

was 11% for 200 mg/day, 9% for 100 mg/day, 2% for 50 mg/day, and <1% for placebo.

Some 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. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or

nephrocalcinosis, and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or

osteoporosis with an increased risk for fractures. Chronic metabolic acidosis in pediatric patients may

also reduce growth rates. A reduction in growth rate may eventually decrease the maximal height

achieved. The effect of topiramate on growth and bone-related sequelae has not been systematically

investigated in long-term, placebo-controlled trials. Long-term, open-label treatment of infants/toddlers,

with intractable partial epilepsy, for up to 1 year, showed reductions from baseline in Z SCORES for

length, weight, and head circumference compared to age and sex-matched normative data, although

these patients with epilepsy are likely to have different growth rates than normal infants. Reductions in Z

SCORES for length and weight were correlated to the degree of acidosis [see Pediatric Use (8.4)].

Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended.

If metabolic acidosis develops and persists, consideration should be given to reducing the dose or

discontinuing topiramate (using dose tapering). If the decision is made to continue patients on topiramate

in the face of persistent acidosis, alkali treatment should be considered.

5.5 Cognitive/Neuropsychiatric Adverse Reactions

Adverse reactions most often associated with the use of topiramate were related to the central nervous

system and were observed in both the epilepsy and other populations. In adults, the most frequent of

these can be classified into three general categories: 1) Cognitive-related dysfunction (e.g. confusion,

psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or

language problems, particularly word-finding difficulties); 2) Psychiatric/behavioral disturbances (e.g.

depression or mood problems); and 3) Somnolence or fatigue.

Adult Patients

Cognitive-Related Dysfunction

The majority of cognitive-related adverse reactions were mild to moderate in severity, and they

frequently occurred in isolation. Rapid titration rate and higher initial dose were associated with higher

incidences of these reactions. Many of these reactions contributed to withdrawal from treatment [see

Adverse Reactions (6)].

In the add-on epilepsy controlled trials (using rapid titration such as 100-200 mg/day weekly

increments), the proportion of patients who experienced one or more cognitive-related adverse

reactions was 42% for 200 mg/day, 41% for 400 mg/day, 52% for 600 mg/day, 56% for 800 and 1000

mg/day, and 14% for placebo. These dose-related adverse reactions began with a similar frequency in

the titration or in the maintenance phase, although in some patients the events began during titration and

persisted into the maintenance phase. Some patients who experienced one or more cognitive-related

adverse reactions in the titration phase had a dose-related recurrence of these reactions in the

maintenance phase.

In the monotherapy epilepsy controlled trial, the proportion of patients who experienced one or more

cognitive-related adverse reactions was 19% for topiramate 50 mg/day and 26% for 400 mg/day.

In the 6-month controlled trials for another indication using a slower titration regimen (25 mg/day

weekly increments), the proportion of patients who experienced one or more cognitive-related adverse

reactions was 19% for topiramate 50 mg/day, 22% for 100 mg/day (the recommended dose), 28% for

200 mg/day, and 10% for placebo. These dose-related adverse reactions typically began in the titration

phase and often persisted into the maintenance phase, but infrequently began in the maintenance phase.

Some patients experienced a recurrence of one or more of these cognitive adverse reactions and this

recurrence was typically in the titration phase. A relatively small proportion of topiramate-treated

patients experienced more than one concurrent cognitive adverse reaction. The most common cognitive

adverse reactions occurring together included difficulty with memory along with difficulty with

concentration/attention, difficulty with memory along with language problems, and difficulty with

concentration/attention along with language problems. Rarely, topiramate-treated patients experienced

three concurrent cognitive reactions.

Psychiatric/Behavioral Disturbances

Psychiatric/behavioral disturbances (depression or mood) were dose-related for both the epilepsy and

other populations [see Warnings and Precautions (5.3)].

Somnolence/Fatigue

Somnolence and fatigue were the adverse reactions most frequently reported during clinical trials of

topiramate for adjunctive epilepsy. For the adjunctive epilepsy population, the incidence of somnolence

did not differ substantially between 200 mg/day and 1000 mg/day, but the incidence of fatigue was

dose-related and increased at dosages above 400 mg/day. For the monotherapy epilepsy population in

the 50 mg/day and 400 mg/day groups, the incidence of somnolence was dose-related (9% for the 50

mg/day group and 15% for the 400 mg/day group) and the incidence of fatigue was comparable in both

treatment groups (14% each). For another population, fatigue and somnolence were dose-related and

more common in the titration phase.

Additional nonspecific CNS events commonly observed with topiramate in the add-on epilepsy

population include dizziness or ataxia.

Pediatric Patients

In double-blind adjunctive therapy and monotherapy epilepsy clinical studies, the incidences of

cognitive/neuropsychiatric adverse reactions in pediatric patients were generally lower than observed

in adults. These reactions included psychomotor slowing, difficulty with concentration/attention, speech

disorders/related speech problems and language problems. The most frequently reported

neuropsychiatric reactions in pediatric patients during adjunctive therapy double-blind studies were

somnolence and fatigue. The most frequently reported neuropsychiatric reactions in pediatric patients in

the 50 mg/day and 400 mg/day groups during the monotherapy double-blind study were headache,

dizziness, anorexia, and somnolence.

No patients discontinued treatment due to any adverse events in the adjunctive epilepsy double-blind

trials. In the monotherapy epilepsy double-blind trial, 1 pediatric patient (2%) in the 50 mg/day group

and 7 pediatric patients (12%) in the 400 mg/day group discontinued treatment due to any adverse events.

The most common adverse reaction associated with discontinuation of therapy was difficulty with

concentration/attention; all occurred in the 400 mg/day group.

5.6 Withdrawal of Antiepileptic Drugs (AEDs)

In patients with or without a history of seizures or epilepsy, antiepileptic drugs including topiramate

should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency

[see Clinical Studies (14)]. In situations where rapid withdrawal of topiramate is medically required,

appropriate monitoring is recommended.

5.7 Sudden Unexplained Death in Epilepsy (SUDEP)

During the course of premarketing development of topiramate tablets, 10 sudden and unexplained deaths

were recorded among a cohort of treated patients (2,796 subject years of exposure). This represents an

incidence of 0.0035 deaths per patient year. Although this rate exceeds that expected in a healthy

population matched for age and sex, it is within the range of estimates for the incidence of sudden

unexplained deaths in patients with epilepsy not receiving topiramate (ranging from 0.0005 for the

general population of patients with epilepsy, to 0.003 for a clinical trial population similar to that in the

topiramate program, to 0.005 for patients with refractory epilepsy).

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

Use) Hyperammonemia/Encephalopathy Without Concomitant Valproic Acid (VPA)

Hyperammonemia/Encephalopathy Without Concomitant Valproic Acid (VPA)

Topiramate treatment has produced hyperammonemia (in some instances dose-related) in clinical

investigational programs of adolescents (12-16 years) who were treated with topiramate monotherapy

for another indication (incidence above normal, 22% for placebo, 26 % for 50 mg/day, 41% for 100 mg

daily) and in very young pediatric patients (1-24 months) who were treated with adjunctive topiramate

for partial onset epilepsy (8% for placebo, 10 % for 5 mg/kg/day, 0 % for 15 mg/kg/day, 9 % for 25

mg/kg/day). Topiramate is not approved as monotherapy for another indication in adolescent patients or

as adjunctive treatment of partial onset seizures in pediatric patients less than 2 years old. In some

patients, ammonia was markedly increased (> 50 % above upper limit of normal). In the adolescent

patients, the incidence of markedly increased hyperammonemia was 6 % for placebo, 6 % for 50 mg,

and 12 % for 100 mg topiramate daily. The hyperammonemia associated with topiramate treatment

occurred with and without encephalopathy in placebo-controlled trials, and in an open-label, extension

trial. Dose-related hyperammonemia was also observed in the extension trial in pediatric patients up to 2

years old. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in

level of consciousness and/or cognitive function with lethargy or vomiting.

Hyperammonemia with and without encephalopathy has also been observed in post-marketing reports in

patients who were taking topiramate without concomitant valproic acid (VPA).

Hyperammonemia/Encephalopathy With Concomitant Valproic Acid (VPA)

Concomitant administration of topiramate and valproic acid (VPA) has been associated with

hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone based

upon post-marketing reports. Although hyperammonemia may be asymptomatic, clinical symptoms of

hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or

cognitive function with lethargy or vomiting. In most cases, symptoms and signs abated with

discontinuation of either drug. This adverse reaction is not due to a pharmacokinetic interaction.

Although topiramate is not indicated for use in infants/toddlers (1-24 months) VPA clearly produced a

dose-related increased in the incidence of treatment-emergent hyperammonemia (above the upper limit

of normal, 0% for placebo, 12% for 5 mg/kg/day, 7% for 15 mg/kg/day, 17% for 25 mg/kg/day) in an

investigational program. Markedly increased, dose-related hyperammonemia (0% for placebo and 5

mg/kg/day, 7% for 15 mg/kg/day, 8 % for 25 mg/kg/day) also occurred in these infants/toddlers. Dose-

related hyperammonemia was similarly observed in a long-term, extension trial in these very young,

pediatric patients [see Use in Specific Populations (8.4)].

Hyperammonemia with and without encephalopathy has also been observed in post-marketing reports in

patients taking topiramate with valproic acid (VPA).

The hyperammonemia associated with topiramate treatment appears to be more common when topiramate

is used concomitantly with VPA.

Monitoring for Hyperammonemia

Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an

increased risk for hyperammonemia with or without encephalopathy. Although not studied, topiramate

treatment or an interaction of concomitant topiramate and valproic acid treatment may exacerbate existing

defects or unmask deficiencies in susceptible persons.

In patients who develop unexplained lethargy, vomiting, or changes in mental status associated with any

topiramate treatment, hyperammonemic encephalopathy should be considered and an ammonia level

should be measured.

5.9 Kidney Stones

A total of 32/2,086 (1.5%) of adults exposed to topiramate during its adjunctive epilepsy therapy

development reported the occurrence of kidney stones, an incidence about 2 to 4 times greater than

expected in a similar, untreated population. In the double-blind monotherapy epilepsy study, a total of

4/319 (1.3%) of adults exposed to topiramate reported the occurrence of kidney stones. As in the

general population, the incidence of stone formation among topiramate treated patients was higher in

men. Kidney stones have also been reported in pediatric patients. During long-term (up to 1 year)

topiramate treatment in an open-label extension study of 284 pediatric patients 1-24 months old with

epilepsy, 7% developed kidney or bladder stones that were diagnosed clinically or by sonogram.

Topiramate is not approved for pediatric patients less than 2 years old [see Pediatric Use (8.4)].

An explanation for the association of topiramate and kidney stones may lie in the fact that topiramate is a

carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or

dichlorphenamide) can promote stone formation by reducing urinary citrate excretion and by increasing

urinary pH [see Warnings and Precautions (5.4)]. The concomitant use of topiramate with any other drug

producing metabolic acidosis, or potentially in patients on a ketogenic diet may create a physiological

environment that increases the risk of kidney stone formation, and should therefore be avoided.

Increased fluid intake increases the urinary output, lowering the concentration of substances involved in

stone formation. Hydration is recommended to reduce new stone formation.

5.10 Paresthesia

Paresthesia (usually tingling of the extremities), an effect associated with the use of other carbonic

anhydrase inhibitors, appears to be a common effect of topiramate. Paresthesia was more frequently

reported in the monotherapy epilepsy trials and trials for another indication than in the adjunctive therapy

epilepsy trials. In the majority of instances, paresthesia did not lead to treatment discontinuation.

5.11 Adjustment of Dose in Renal Failure

The major route of elimination of unchanged topiramate and its metabolites is via the kidney. Dosage

adjustment may be required in patients with reduced renal function [see Dosage and Administration (2)].

5.12 Decreased Hepatic Function

In hepatically impaired patients, topiramate should be administered with caution as the clearance of

topiramate may be decreased.

5.13 Monitoring: Laboratory Tests

Topiramate treatment was associated with changes in several clinical laboratory analytes in randomized,

double-blind, placebo-controlled studies.

Topiramate treatment causes non-anion gap, hyperchloremic, metabolic acidosis manifested by a

decrease in serum bicarbonate and increase in serum chloride. Measurement of baseline and periodic

serum bicarbonate during topiramate treatment is recommended [see Warnings and Precautions (5.4)].

Controlled trials of adjunctive topiramate treatment of adults for partial onset seizures showed an

increased incidence of markedly decreased serum phosphorus (6% topiramate, 2% placebo), markedly

increased serum alkaline phosphatase (3% topiramate, 1% placebo), and decreased serum potassium (0.4

% topiramate, 0.1 % placebo). The clinical significance of these abnormalities has not been clearly

established.

Changes in several clinical laboratory laboratories (increased creatinine, BUN, alkaline phosphatase,

total protein, total eosinophil count and decreased potassium) have been observed in a clinical

investigational program in very young (<2 years) pediatric patients who were treated with adjunctive

topiramate for partial onset seizures [see Pediatric Use (8.4)].

Topiramate treatment produced a dose-related increased shift in serum creatinine from normal at

baseline to an increased value at the end of 4 months treatment in adolescent patients (ages 12-16 years)

who were treated for another indication in a double-blind, placebo-controlled study. Topiramate

treatment with or without concomitant valproic acid (VPA) can cause hyperammonemia with or without

encephalopathy [see Warnings and Precautions (5.8)].

6. ADVERSE REACTIONS

The data described in the following section were obtained using topiramate tablets.

6.1 Monotherapy Epilepsy

The adverse reactions in the controlled trial that occurred most commonly in adults in the 400 mg/day

group and at a rate higher than the 50 mg/day group were: paresthesia, weight decrease, somnolence,

anorexia, dizziness, and difficulty with memory NOS [see Table 2 ].

The adverse reactions in the controlled trial that occurred most commonly in children (10 years up to 16

years of age) in the 400 mg/day group and at a rate higher than the 50 mg/day group were: weight

decrease, upper respiratory tract infection, paresthesia, anorexia, diarrhea, and mood problems [see

Table 3 ].

Approximately 21% of the 159 adult patients in the 400 mg/day group who received topiramate as

monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. Adverse

reactions associated with discontinuing therapy (>2%) included depression, insomnia, difficulty with

memory (NOS), somnolence, paresthesia, psychomotor slowing, dizziness, and nausea.

Approximately 12% of the 57 pediatric patients in the 400 mg/day group who received topiramate as

monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. Adverse

reactions associated with discontinuing therapy (>5%) included difficulty with concentration/attention.

The prescriber should be aware that these data cannot be used to predict the frequency of adverse

reactions in the course of usual medical practice where patient characteristics and other factors may

differ from those prevailing during the clinical study. Similarly, the cited frequencies cannot be directly

compared with data obtained from other clinical investigations involving different treatments, uses, or

investigators. Inspection of these frequencies, however, does provide the prescribing physician with a

basis to estimate the relative contribution of drug and non-drug factors to the adverse reactions

incidences in the population studied.

Table 2: Incidence of Treatment-Emergent Adverse Reaction in the Monotherapy Epilepsy Trial in

Adults Where Incidence Was at Least 2% in the 400 mg/day Topiramate Group and Greater Than the

Rate in the 50 mg/day Topiramate Group

Topiramate Tablets Dosage

(mg/day)

Body System/

Adverse Reaction

(N=160)

(N=159)

Body as a Whole - General Disorders

Asthenia

Leg Pain

Chest Pain

Central & Peripheral Nervous System Disorders

Paresthesia

Dizziness

Hypoaesthesia

Ataxia

Hypertonia

Gastro-Intestinal System Disorders

Diarrhea

Constipation

Gastritis

Dry Mouth

Gastroesophageal Reflux

Liver and Biliary System Disorders

Gamma-GT Increased

Metabolic and Nutritional Disorders

Weight Decrease

Psychiatric Disorders

Somnolence

Anorexia

Difficulty with Memory NOS

Insomnia

Depression

Difficulty with Concentration/Attention

Anxiety

Psychomotor Slowing

Mood Problems

Confusion

Cognitive Problem NOS

Libido Decreased

Reproductive Disorders, Female

Vaginal Hemorrhage

Red Blood Cell Disorders

Anemia

Resistance Mechanism Disorders

Infection Viral

Infection

Respiratory System Disorders

Bronchitis

Rhinitis

Dyspnea

Skin and Appendages Disorders

Rash

Pruritus

Acne

Special Senses Other, Disorders

Taste Perversion

Urinary System Disorders

Cystitis

Renal Calculus

Urinary Tract Infection

Dysuria

Micturition Frequency

Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more

than one adverse reaction during the study and can be included in more than one adverse reaction category.

Micturition Frequency

Table 3: Incidence of Treatment-Emergent Adverse Reactions in the Monotherapy Epilepsy Trial in

Pediatric Patients (Ages 10 up to 16 years) Where Incidence Was at Least 5% in the 400 mg/day

Topiramate Group and Greater Than the Rate in the 50 mg/day Topiramate Group

Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more

than one adverse reaction during the study and can be included in more than one adverse reaction category.

Topiramate Tablets Dosage

(mg/day)

Body System/

Adverse Reaction

(N=57)

(N=57)

Body as a Whole-General Disorders

Fever

Central & Peripheral Nervous System Disorders

Paresthesia

Gastro-Intestinal System Disorders

Diarrhea

Metabolic and Nutritional Disorders

Weight Decrease

Psychiatric Disorders

Anorexia

Mood Problems

Difficulty with Concentration/Attention

Cognitive Problems NOS

Nervousness

Resistance Mechanism Disorders

Infection Viral

Infection

Respiratory System Disorders

Upper Respiratory Tract Infection

Rhinitis

Bronchitis

Sinusitis

Skin and Appendages Disorders

Alopecia

6.2 Adjunctive Therapy Epilepsy

The most commonly observed adverse reactions associated with the use of topiramate at dosages of

200 to 400 mg/day in controlled trials in adults with partial onset seizures, primary generalized tonic-

clonic seizures, or Lennox-Gastaut syndrome, that were seen at greater frequency in topiramate-treated

patients and did not appear to be dose-related were: somnolence, dizziness, ataxia, speech disorders and

related speech problems, psychomotor slowing, abnormal vision, difficulty with memory, paresthesia

and diplopia [see Table 4 ]. The most common dose-related adverse reactions at dosages of 200 to

1,000 mg/day were: fatigue, nervousness, difficulty with concentration or attention, confusion,

depression, anorexia, language problems, anxiety, mood problems, and weight decrease [see Table 6 ].

Adverse reactions associated with the use of topiramate at dosages of 5 to 9 mg/kg/day in controlled

trials in pediatric patients with partial onset seizures, primary generalized tonic-clonic seizures, or

Lennox-Gastaut syndrome, that were seen at greater frequency in topiramate-treated patients were:

fatigue, somnolence, anorexia, nervousness, difficulty with concentration/attention, difficulty with

memory, aggressive reaction, and weight decrease [see Table 7 ].

In controlled clinical trials in adults, 11% of patients receiving topiramate 200 to 400 mg/day as

adjunctive therapy discontinued due to adverse reactions. This rate appeared to increase at dosages

above 400 mg/day. Adverse events associated with discontinuing therapy included somnolence,

dizziness, anxiety, difficulty with concentration or attention, fatigue, and paresthesia and increased at

dosages above 400 mg/day. None of the pediatric patients who received topiramate adjunctive therapy

at 5 to 9 mg/kg/day in controlled clinical trials discontinued due to adverse reactions.

Approximately 28% of the 1,757 adults with epilepsy who received topiramate at dosages of 200 to

1,600 mg/day in clinical studies discontinued treatment because of adverse reactions; an individual

patient could have reported more than one adverse reaction. These adverse reactions were:

psychomotor slowing (4.0%), difficulty with memory (3.2%), fatigue (3.2%), confusion (3.1%),

somnolence (3.2%), difficulty with concentration/attention (2.9%), anorexia (2.7%), depression (2.6%),

dizziness (2.5%), weight decrease (2.5%), nervousness (2.3%), ataxia (2.1%), and paresthesia (2.0%).

Approximately 11% of the 310 pediatric patients who received topiramate at dosages up to 30

mg/kg/day discontinued due to adverse reactions. Adverse reactions associated with discontinuing

therapy included aggravated convulsions (2.3%), difficulty with concentration/attention (1.6%),

language problems (1.3%), personality disorder (1.3%), and somnolence (1.3%).

6.3 Incidence in Epilepsy Controlled Clinical Trials – Adjunctive Therapy – Partial Onset

Seizures, Primary Generalized Tonic-Clonic Seizures, and Lennox-Gastaut Syndrome

Table 4 lists treatment-emergent adverse reactions that occurred in at least 1% of adults treated with 200

to 400 mg/day topiramate in controlled trials that were numerically more common at this dose than in the

patients treated with placebo. In general, most patients who experienced adverse reactions during the

first eight weeks of these trials no longer experienced them by their last visit. Table 7 lists treatment-

emergent adverse reactions that occurred in at least 1% of pediatric patients treated with 5 to 9 mg/kg

topiramate in controlled trials that were numerically more common than in patients treated with placebo.

The prescriber should be aware that these data were obtained when topiramate was added to concurrent

antiepileptic drug therapy and cannot be used to predict the frequency of adverse reactions in the course

of usual medical practice where patient characteristics and other factors may differ from those

prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with data

obtained from other clinical investigations involving different treatments, uses, or investigators.

Inspection of these frequencies, however, does provide the prescribing physician with a basis to

estimate the relative contribution of drug and non-drug factors to the adverse reaction incidences in the

population studied.

6.4 Other Adverse Reactions Observed During Double-Blind Epilepsy Adjunctive Therapy Trials

Other adverse reactions that occurred in more than 1% of adults treated with 200 to 400 mg of

topiramate in placebo-controlled epilepsy trials but with equal or greater frequency in the placebo

group were: headache, injury, anxiety, rash, pain, convulsions aggravated, coughing, fever, diarrhea,

vomiting, muscle weakness, insomnia, personality disorder, dysmenorrhea, upper respiratory tract

infection, and eye pain.

Table 4: Incidence of Treatment-Emergent Adverse Reactions in Placebo-Controlled, Add-On Epilepsy

Trials in Adults

Where Incidence Was >1% in Any Topiramate Group and Greater Than the Rate in

Placebo-Treated Patients

Topiramate Tablets Dosage (mg/day)

Body System/

Adverse Reaction

Placebo

(N=291)

200-400

(N=183)

600-1,000

(N=414)

Body as a Whole-General Disorders

Fatigue

Asthenia

Back Pain

Chest Pain

Influenza-Like Symptoms

Leg Pain

Hot Flushes

Allergy

Edema

Body Odor

Rigors

<1

Central & Peripheral Nervous System Disorders

Dizziness

Ataxia

Speech Disorders/Related Speech Problems

Paresthesia

Nystagmus

Tremor

Language Problems

Coordination Abnormal

Hypoaesthesia

Gait Abnormal

Muscle Contractions Involuntary

Stupor

Vertigo

Gastro-Intestinal System Disorders

Nausea

Dyspepsia

Abdominal Pain

Constipation

Gastroenteritis

Dry Mouth

Gingivitis

<1

GI Disorder

<1

Hearing and Vestibular Disorders

Hearing Decreased

Metabolic and Nutritional Disorders

Weight Decrease

Muscle-Skeletal System Disorders

Myalgia

Skeletal pain

Platelet, Bleeding, & Clotting Disorders

Epistaxis

Psychiatric Disorders

Somnolence

Nervousness

Psychomotor Slowing

Patients in these add-on/adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to

Difficulty with Memory

Anorexia

Confusion

Depression

Difficulty with Concentration/Attention

Mood Problems

Agitation

Aggressive Reaction

Emotional Lability

Cognitive Problems

Libido Decreased

<1

Apathy

Depersonalization

Reproductive Disorders, Female

Breast Pain

Amenorrhea

Menorrhagia

Menstrual Disorder

Reproductive Disorders, Male

Prostatic Disorder

<1

Resistance Mechanism Disorders

Infection

Infection Viral

<1

Moniliasis

<1

Respiratory System Disorders

Pharyngitis

Rhinitis

Sinusitis

Dyspnea

Skin and Appendages Disorders

Skin Disorder

<1

Sweating Increased

<1

<1

Rash Erythematous

<1

<1

Special Sense Other, Disorders

Taste Perversion

Urinary System Disorders

Hematuria

<1

Urinary Tract Infection

Micturition Frequency

Urinary Incontinence

<1

Urine Abnormal

<1

Vision Disorders

Vision Abnormal

Diplopia

White Cell and RES Disorders

Leukopenia

topiramate or placebo.

Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more

than one adverse reaction during the study and can be included in more than one adverse reaction category.

Adverse reactions reported by at least 1% of patients in the topiramate 200-4 00 mg/day group and more common

than in the placebo group are listed in this table.

6.5 Incidence in Study 119 – Add-On Therapy– Adults with Partial Onset Seizures

Study 119 was a randomized, double-blind, add-on/adjunctive, placebo-controlled, parallel group study

with 3 treatment arms: 1) placebo; 2) topiramate 200 mg/day with a 25 mg/day starting dose, increased by

25 mg/day each week for 8 weeks until the 200 mg/day maintenance dose was reached; and 3) topiramate

200 mg/day with a 50 mg/day starting dose, increased by 50 mg/day each week for 4 weeks until the 200

mg/day maintenance dose was reached. All patients were maintained on concomitant carbamazepine with

or without another concomitant antiepileptic drug.

The incidence of adverse reactions (Table 5) did not differ significantly between the 2 topiramate

regimens. Because the frequencies of adverse reactions reported in this study were markedly lower

than those reported in the previous epilepsy studies, they cannot be directly compared with data

obtained in other studies.

Table 5: Incidence of Treatment-Emergent Adverse Reactions in Study 119

Where Incidence Was

≥2% in the Topiramate Group and Greater Than the Rate in Placebo-Treated Patients

Topiramate Tablets Dosage

(mg/day)

Body System/

Adverse Reaction

Placebo

(N=92)

200

(N=171)

Body as a Whole-General Disorders

Fatigue

Chest Pain

Cardiovascular Disorders, General

Hypertension

Central & Peripheral Nervous System Disorders

Paresthesia

Dizziness

Tremor

Hypoasthesia

Leg Cramps

Language Problems

Gastro-Intestinal System Disorders

Abdominal Pain

Constipation

Diarrhea

Dyspepsia

Dry Mouth

Hearing and Vestibular Disorders

Tinnitus

Metabolic and Nutritional Disorders

Weight Decrease

Psychiatric Disorders

Somnolence

c

Patients in these add-on/adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to

topiramate or placebo.

Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more

than one adverse reaction during the study and can be included in more than one adverse reaction category.

Adverse reactions reported by at least 2% of patients in the topiramate 200 mg/day group and more common than

in the placebo group are listed in this table.

Anorexia

Nervousness

Difficulty with Concentration/Attention

Insomnia

Difficulty with Memory

Aggressive Reaction

Respiratory System Disorders

Rhinitis

Urinary System Disorders

Cystitis

Vision Disorders

Diplopia

Vision Abnormal

Table 6: Incidence (%) of Dose-Related Adverse Reactions From Placebo-Controlled, Add-On

Trials in Adults with Partial Onset Seizures

Dose-response studies were not conducted for other adult indications or for pediatric indications.

Topiramate Tablets Dosage (mg/day)

Adverse Reaction

Placebo

(N=216)

(N=45)

(N=68)

600-1,000

(N=414)

Fatigue

Nervousness

Difficulty with Concentration/Attention

Confusion

Depression

Anorexia

Language Problems

<1

Anxiety

Mood problems

Weight decrease

Table 7: Incidence (%) of Treatment-Emergent Adverse Reaction in Placebo-Controlled, Add-On

Epilepsy Trials in Pediatric Patients (Ages 2-16 Years)

(Reaction that Occurred in at Least 1% of

Topiramate-Treated Patients and Occurred More Frequently in Topiramate-Treated Than Placebo-

Treated Patients)

Body System/

Adverse Reaction

Placebo

(N=101)

Topiramate

(N=98)

Body as a Whole - General Disorders

Fatigue

Injury

Allergic Reaction

Back Pain

Pallor

Cardiovascular Disorders, General

Hypertension

Central & Peripheral Nervous System Disorders

Gait Abnormal

Ataxia

Hyperkinesia

Dizziness

Speech Disorders/Related Speech Problems

Hyporeflexia

Convulsions Grand Mal

Fecal Incontinence

Paresthesia

Gastro-Intestinal System Disorders

Nausea

Saliva Increased

Constipation

Gastroenteritis

Dysphagia

Flatulence

Gastroesophageal Reflux

Glossitis

Gum Hyperplasia

Heart Rate and Rhythm Disorders

Bradycardia

Metabolic and Nutritional Disorders

Weight Decrease

Thirst

Hypoglycemia

Weight Increase

Platelet, Bleeding, & Clotting Disorders

Purpura

Epistaxis

Hematoma

Prothrombin Increased

Thrombocytopenia

Psychiatric Disorders

Somnolence

Anorexia

Nervousness

Personality Disorders (Behavior Problems)

Difficulty with Concentration/Attention

Aggressive Reaction

Insomnia

Difficulty with Memory NOS

Patients in these add-on/adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to

topiramate or placebo.

Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more

than one adverse reaction during the study and can be included in more than one adverse reaction category.

Confusion

Psychomotor Slowing

Appetite Increased

Neurosis

Reproductive Disorders, Female

Leukorrhoea

Resistance Mechanism Disorders

Infection Viral

Respiratory System Disorders

Pneumonia

Respiratory Disorder

Skin and Appendages Disorders

Skin Disorder

Alopecia

Dermatitis

Hypertrichosis

Rash Erythematous

Eczema

Seborrhoea

Skin Discoloration

Urinary System Disorders

Urinary Incontinence

Nocturia

Vision Disorders

Eye Abnormality

Vision Abnormal

Diplopia

Lacrimation Abnormal

Myopia

White Cell and RES Disorders

Leukopenia

6.6 Other Adverse Reactions Observed During All Epilepsy Clinical Trials

Topiramate has been administered to 2,246 adults and 427 pediatric patients with epilepsy during all

clinical studies, only some of which were placebo-controlled. During these studies, all adverse

reactions were recorded by the clinical investigators using terminology of their own choosing. To

provide a meaningful estimate of the proportion of individuals having adverse reaction, similar types of

reactions were grouped into a smaller number of standardized categories using modified WHOART

dictionary terminology. The frequencies presented represent the proportion of patients who

experienced a reaction of the type cited on at least one occasion while receiving topiramate. Reported

reactions are included except those already listed in the previous tables or text, those too general to be

informative, and those not reasonably associated with the use of the drug.

Reactions are classified within body system categories and enumerated in order of decreasing

frequency using the following definitions: frequent occurring in at least 1/100 patients; infrequent

occurring in 1/100 to 1/1000 patients; rare occurring in fewer than 1/1000 patients.

Autonomic Nervous System Disorders: Infrequent: vasodilation.

Body as a Whole: Frequent: syncope. Infrequent: abdomen enlarged. Rare: alcohol intolerance.

Cardiovascular Disorders, General: Infrequent: hypotension, postural hypotension, angina pectoris.

Central & Peripheral Nervous System Disorders: Infrequent: neuropathy, apraxia, hyperaesthesia,

dyskinesia, dysphonia, scotoma, ptosis, dystonia, visual field defect, encephalopathy, EEG abnormal.

Rare: upper motor neuron lesion, cerebellar syndrome, tongue paralysis.

Gastrointestinal System Disorders: Infrequent: hemorrhoids, stomatitis, melena, gastritis, esophagitis.

Rare: tongue edema.

Heart Rate and Rhythm Disorders: Infrequent: AV block.

Liver and Biliary System Disorders: Infrequent: SGPT increased, SGOT increased.

Metabolic and Nutritional Disorders: Infrequent: dehydration, hypocalcemia, hyperlipemia,

hyperglycemia, xerophthalmia, diabetes mellitus. Rare: hypernatremia, hyponatremia,

hypocholesterolemia, creatinine increased.

Musculoskeletal System Disorders: Frequent: arthralgia. Infrequent: arthrosis.

Neoplasms: Infrequent: thrombocythemia. Rare: polycythemia.

Platelet, Bleeding, and Clotting Disorders: Infrequent: gingival bleeding, pulmonary embolism.

Psychiatric Disorders: Frequent: impotence, hallucination, psychosis, suicide attempt. Infrequent:

euphoria, paranoid reaction, delusion, paranoia, delirium, abnormal dreaming. Rare: libido increased,

manic reaction.

Red Blood Cell Disorders: Frequent: anemia. Rare: marrow depression, pancytopenia.

Reproductive Disorders, Male: Infrequent: ejaculation disorder, breast discharge.

Skin and Appendages Disorders: Infrequent: urticaria, photosensitivity reaction, abnormal hair texture.

Rare: chloasma.

Special Senses Other, Disorders: Infrequent: taste loss, parosmia.

Urinary System Disorders: Infrequent: urinary retention, face edema, renal pain, albuminuria, polyuria,

oliguria.

Vascular (Extracardiac) Disorders: Infrequent: flushing, deep vein thrombosis, phlebitis. Rare:

vasospasm.

Vision Disorders: Frequent: conjunctivitis. Infrequent: abnormal accommodation, photophobia,

strabismus. Rare: mydriasis, iritis.

White Cell and Reticuloendothelial System Disorders: Infrequent: lymphadenopathy, eosinophilia,

lymphopenia, granulocytopenia. Rare: lymphocytosis.

6.9 Postmarketing and Other Experience

In addition to the adverse experiences reported during clinical testing of topiramate, the following

adverse experiences have been reported worldwide in patients receiving topiramate post-approval.

These adverse experiences have not been listed above and data are insufficient to support an estimate of

their incidence or to establish causation. The listing is alphabetized: bullous skin reactions (including

erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), hepatic failure (including

fatalities), hepatitis, maculopathy, pancreatitis, and pemphigus.

7. DRUG INTERACTIONS

In vitro studies indicate that topiramate does not inhibit enzyme activity for CYP1A2, CYP2A6,

CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4/5 isozymes. In vitro studies indicate that

topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4. Drug interactions with some

antiepileptic drugs, CNS depressants and oral contraceptives are described here. For other drug

interactions, please refer to Clinical Pharmacology (12.5).

7.1 Antiepileptic Drugs

Potential interactions between topiramate and standard AEDs were assessed in controlled clinical

pharmacokinetic studies in patients with epilepsy. Concomitant administration of phenytoin or

carbamazepine with topiramate decreased plasma concentrations of topiramate by 48% and 40%

respectively when compared to topiramate given alone [Clinical Pharmacology (12.5)]. In addition,

concomitant administration of valproic acid and topiramate has been associated with hyperammonemia

with and without encephalopathy [see Warnings and Precautions (5.8) or Clinical Pharmacology (12.5)].

7.2 CNS Depressants

Concomitant administration of topiramate and alcohol or other CNS depressant drugs has not been

evaluated in clinical studies. Because of the potential of topiramate to cause CNS depression, as well as

other cognitive and/or neuropsychiatric adverse events, topiramate should be used with extreme caution

if used in combination with alcohol and other CNS depressants.

7.3 Oral Contraceptives

Exposure to ethinyl estradiol was statistically significantly decreased at doses of 200, 400, and 800

mg/day (18%, 21%, and 30%, respectively) when topiramate was given as adjunctive therapy in patients

taking valproic acid). However, norethindrone exposure was not significantly affected. In another

pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination

oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE),

topiramate, given in the absence of other medications at doses of 50 to 200 mg/day, was not associated

with statistically significant changes in mean exposure (AUC) to either component of the oral

contraceptive. The possibility of decreased contraceptive efficacy and increased breakthrough

bleeding should be considered in patients taking combination oral contraceptive products with

topiramate. Patients taking estrogen-containing contraceptives should be asked to report any change in

their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough

bleeding [see Clinical Pharmacology (12.5)].

7.4 Metformin

Topiramate treatment can frequently cause metabolic acidosis, a condition for which the use of

metformin is contraindicated [see Clinical Pharmacology (12.5)].

7.5 Lithium

In patients, lithium levels were unaffected during treatment with topiramate at doses of 200 mg/day;

however, there was an observed increase in systemic exposure of lithium (27% for C

and 26% for

AUC) following topiramate doses of up to 600 mg/day. Lithium levels should be monitored when co-

administered with high-dose topiramate [see Clinical Pharmacology (12.5)].

7.6 Other Carbonic Anhydrase Inhibitors

Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase

inhibitor (e.g., zonisamide, acetazolamide or dichlorphenamide), may increase the severity of metabolic

acidosis and may also increase the risk of kidney stone formation. Therefore, if topiramate is given

concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the

appearance or worsening of metabolic acidosis [see Clinical Pharmacology (12.5)].

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C.

Topiramate may cause serious adverse fetal effects, based on clinical and nonclinical data.

Topiramate treatment is associated with metabolic acidosis [see Warnings and Precautions (5.4)]. The

effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic

acidosis in pregnancy (due to other causes) may be associated with decreased fetal growth, decreased

fetal oxygenation, and fetal death, and may affect the fetus’ ability to tolerate labor. Pregnant patients

should be monitored for metabolic acidosis and treated as in the nonpregnant state [see Warnings and

Precautions (5.4)]. Newborns of mothers treated with topiramate should be monitored for metabolic

acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic

acidosis following birth.

There are no studies using topiramate in pregnant women. Topiramate should be used during pregnancy

only if the potential benefit outweighs the potential risk to the fetus.

Topiramate has demonstrated selective developmental toxicity, including teratogenicity, in multiple

animal species at clinically relevant doses. When oral doses of 20, 100 or 500 mg/kg were

administered to pregnant mice during the period of organogenesis, the incidence of fetal malformations

(primarily craniofacial defects) was increased at all doses. The low dose is approximately 0.2 times the

recommended human dose (RHD) 400 mg/day on a mg/m basis. Fetal body weights and skeletal

ossification were reduced at 500 mg/kg in conjunction with decreased maternal body weight gain.

In rat studies (oral doses of 20, 100, and 500 mg/kg or 0.2, 2.5, 30, and 400 mg/kg), the frequency of

limb malformations (ectrodactyly, micromelia, and amelia) was increased among the offspring of dams

treated with 400 mg/kg (10 times the RHD on a mg/m basis) or greater during the organogenesis

period of pregnancy. Embryotoxicity (reduced fetal body weights, increased incidence of structural

variations) was observed at doses as low as 20 mg/kg (0.5 times the RHD on a mg/m basis). Clinical

signs of maternal toxicity were seen at 400 mg/kg and above, and maternal body weight gain was

reduced during treatment with 100 mg/kg or greater.

In rabbit studies (20, 60, and 180 mg/kg or 10, 35, and 120 mg/kg orally during organogenesis),

embryo/fetal mortality was increased at 35 mg/kg (2 times the RHD on a mg/m basis) or greater, and

teratogenic effects (primarily rib and vertebral malformations) were observed at 120 mg/kg (6 times the

RHD on a mg/m basis). Evidence of maternal toxicity (decreased body weight gain, clinical signs,

and/or mortality) was seen at 35 mg/kg and above.

When female rats were treated during the latter part of gestation and throughout lactation (0.2, 4, 20, and

100 mg/kg or 2, 20, and 200 mg/kg), offspring exhibited decreased viability and delayed physical

development at 200 mg/kg (5 times the RHD on a mg/m basis) and reductions in pre-and/or postweaning

body weight gain at 2 mg/kg (0.05 times the RHD on a mg/m basis) and above. Maternal toxicity

(decreased body weight gain, clinical signs) was evident at 100 mg/kg or greater.

In a rat embryo/fetal development study with a postnatal component (0.2, 2.5, 30 or 400 mg/kg during

organogenesis; noted above), pups exhibited delayed physical development at 400 mg/kg (10 times the

RHD on a mg/m basis) and persistent reductions in body weight gain at 30 mg/kg (1 times the RHD on a

mg/m basis) and higher.

Pregnancy Registry

The North American Drug Pregnancy Registry has been established to collect information and provide

scientific knowledge about safety and outcomes associated with pregnant women being treated with

antiepileptic drugs. It is desirable that the experience from patients who are exposed to topiramate

during pregnancy be reported to this registry. Such information can be reported to the North American

Drug Pregnancy Registry by either a healthcare provider or the patient by calling 1-888-233-2334.

Information about the North American Drug Pregnancy Registry can be found at

http://www.massgeneral.org/aed/ .

8.2 Labor and Delivery

Although the effect of topiramate on labor and delivery in humans has not been established, the

development of topiramate-induced metabolic acidosis in the mother and/or in the fetus might affect the

fetus’ ability to tolerate labor [see Pregnancy (8.1)].

8.3 Nursing Mothers

Limited data on 5 breastfeeding infants exposed to topiramate showed infant plasma topiramate levels

equal to 10-20% of the maternal plasma level. The effects of this exposure on infants are unknown.

Caution should be exercised when administered to a nursing woman.

8.4 Pediatric Use

Adjunctive Treatment for Partial Onset Epilepsy in Infants and Toddlers (1 to 24 months)

Safety and effectiveness in patients below the age of 2 years have not been established for the

adjunctive therapy treatment of partial onset seizures, primary generalized tonic-clonic seizures, or

seizures associated with Lennox-Gastaut syndrome. In a single randomized, double-blind placebo-

controlled investigational trial, the efficacy, safety, and tolerability of topiramate oral liquid and

sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in infants 1 to 24 months of

age with refractory partial onset seizures, was assessed. After 20 days of double-blind treatment,

topiramate (at fixed doses of 5, 15, and 25 mg/kg per day) did not demonstrate efficacy compared with

placebo in controlling seizures.

In general, the adverse reaction profile in this population was similar to that of older pediatric patients,

although results from the above controlled study, and an open-label long-term extension study in these

infants/toddlers (1 to 24 months old) suggested some adverse reactions/toxicities (not previously

observed in older pediatric patients and adults; i.e, growth/length retardation, certain clinical laboratory

abnormalities, and other adverse reactions/toxicities that occurred with a greater frequency and/or

greater severity than had been recognized previously from studies in older pediatric patients or adults

for various indications.

These very young pediatric patients appeared to experience an increased risk for infections (any

topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo

16%). The following adverse reactions were observed in at least 3% of patients on topiramate and were

3% to 7% more frequent then in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis,

otitis media, upper respiratory infection, cough, and bronchospasm. A generally similar profile was

observed in older children [see Adverse Reactions (6)].

Topiramate resulted in an increased incidence of patients with increased creatinine (any topiramate dose

5%, placebo 0%), BUN (any topiramate dose 3%, placebo 0%), and protein (any topiramate dose 34%,

placebo 6%), and an increased incidence of decreased potassium (any topiramate dose 7%, placebo

0%). This increased frequency of abnormal values was not dose-related. Creatinine was the only analyte

showing a noteworthy increased incidence (topiramate 25 mg/kg/d 5%, placebo 0%) of a markedly

abnormal increase [see Warnings and Precautions (5.13)]. The significance of these finding is uncertain.

Topiramate treatment also produced a dose-related increase in the percentage of patients who had a

shift from normal at baseline to high/increased (above the normal reference range) in total eosinophil

count at the end of treatment. The incidence of these abnormal shifts was 6 % for placebo, 10% for 5

mg/kg/d, 9% for 15 mg/kg/d, 14% for 25 mg/kg/d, and 11% for any topiramate dose [see Warnings and

Precautions (5.13)]. There was a mean dose-related increase in alkaline phosphatase. The significance

of these finding is uncertain.

Topiramate produced a dose-related increased incidence of treatment-emergent hyperammonemia. [see

Warnings and Precautions (5.8)].

Treatment with topiramate for up to 1 year was associated with reductions in Z SCORES for length,

weight, and head circumference. [see Warnings and Precautions (5.4) and Adverse Reactions (6)].

In open-label, uncontrolled experience, increasing impairment of adaptive behavior was documented in

behavioral testing over time in this population. There was a suggestion that this effect was dose-

related. However, because of the absence of an appropriate control group, it is not known if this

decrement in function was treatment related or reflects the patient’s underlying disease (e.g., patients

who received higher doses may have more severe underlying disease) [see Warnings and Precautions

(5.5)].

In this open-label, uncontrolled study, the mortality was 37 deaths/1000 patient years. It is not possible

to know whether this mortality rate is related to topiramate treatment, because the background mortality

rate for a similar, significantly refractory, young pediatric population (1-24 months) with partial

epilepsy is not known.

Monotherapy Treatment in Partial Onset Epilepsy in Patients <10 Years Old

Safety and effectiveness in patients below the age of 10 years have not been established for the

monotherapy treatment of epilepsy.

Juvenile Animal Studies

When topiramate (30, 90 or 300 mg/kg/day) was administered orally to rats during the juvenile period of

development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest

dose, which is approximately 5-8 times the maximum recommended pediatric dose (9 mg/kg/day) on a

body surface area (mg/m ) basis.

8.5 Geriatric Use

In clinical trials, 3% of patients were over 60. No age related difference in effectiveness or adverse

effects were evident. However, clinical studies of topiramate did not include sufficient numbers of

subjects aged 65 and over to determine whether they respond differently than younger subjects. Dosage

adjustment may be necessary for elderly with impaired renal function (creatinine clearance rate <70

mL/min/1.73 m ) due to reduced clearance of topiramate [see Clinical Pharmacology (12.3) and Dosage

and Administration (2.5)].

8.6 Race and Gender Effects

Evaluation of effectiveness and safety in clinical trials has shown no race or gender related effects.

8.7 Renal Impairment

The clearance of topiramate was reduced by 42% in moderately renally impaired (creatinine clearance

30 to 69 mL/min/1.73 m ) and by 54% in severely renally impaired subjects (creatinine clearance <30

mL/min/1.73 m ) compared to normal renal function subjects (creatinine clearance >70 mL/min/1.73 m ).

One-half the usual starting and maintenance dose is recommended in patients with moderate or severe

renal impairment [see Dosage and Administration (2.6) and Clinical Pharmacology (12.4)].

8.8 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 the duration of dialysis period, the clearance rate of the dialysis system being used,

and the effective renal clearance of topiramate in the patient being dialyzed [see Dosage and

Administration (2.4) and Clinical Pharmacology (12.4)].

9. DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Topiramate is not a controlled substance.

9.2 Abuse

The abuse and dependence potential of topiramate has not been evaluated in human studies.

9.3 Dependence

Topiramate has not been systematically studied in animals or humans for its potential for tolerance or

physical dependence.

10. OVERDOSAGE

Overdoses of topiramate have been reported. Signs and symptoms included convulsions, drowsiness,

speech disturbance, blurred vision, diplopia, mentation impaired, lethargy, abnormal coordination,

stupor, hypotension, abdominal pain, agitation, dizziness and depression. The clinical consequences

were not severe in most cases, but deaths have been reported after poly-drug overdoses involving

topiramate.

Topiramate overdose has resulted in severe metabolic acidosis [see Warnings and Precautions (5.4)].

A patient who ingested a dose between 96 and 110 g topiramate was admitted to hospital with coma

lasting 20 to 24 hours followed by full recovery after 3 to 4 days.

In acute topiramate overdose, if the ingestion is recent, the stomach should be emptied immediately by

lavage or by induction of emesis. Activated charcoal has been shown to adsorb topiramate in vitro.

Treatment should be appropriately supportive. Hemodialysis is an effective means of removing

topiramate from the body.

11. DESCRIPTION

Topiramate is a sulfamate-substituted monosaccharide. Topiramate tablets are available as 25 mg, 50

mg, 100 mg, and 200 mg round tablets for oral administration.

Topiramate, USP is a white crystalline powder with a bitter taste. Topiramate is most soluble in alkaline

solutions containing sodium hydroxide or sodium phosphate and having a pH of 9 to 10. It is freely

soluble in acetone, chloroform, dimethylsulfoxide, and ethanol. The solubility in water is 9.8 mg/mL.

Its saturated solution has a pH of 6.3. Topiramate has the molecular formula C

H NO S and a

molecular weight of 339.36. Topiramate is designated chemically as 2,3:4,5-Di-O-isopropylidene-β-D-

fructopyranose sulfamate and has the following structural formula:

Topiramate tablets contain the following inactive ingredients: colloidal silicon dioxide, ferric oxide

red (200 mg tablets), ferric oxide yellow (50, 100, and 200 mg tablets), HYPROMELLOSES, lactose

monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, pregelatinized

starch, sodium starch glycolate, talc and titanium dioxide.

12. CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The precise mechanisms by which topiramate exerts its anticonvulsant and other effects are unknown;

however, preclinical studies have revealed four properties that may contribute to topiramate's efficacy

for epilepsy and other indications. Electrophysiological and biochemical evidence suggests that

topiramate, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels,

augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA-A

receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic

anhydrase enzyme, particularly isozymes II and IV.

12.2 Pharmacodynamics

Topiramate has anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests.

Topiramate is only weakly effective in blocking clonic seizures induced by the GABA receptor

antagonist, pentylenetetrazole. Topiramate is also effective in rodent models of epilepsy, which include

tonic and absence-like seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures

induced in rats by kindling of the amygdala or by global ischemia.

12.3 Pharmacokinetics

Absorption of topiramate is rapid, with peak plasma concentrations occurring at approximately 2 hours

following a 400 mg oral dose. The relative bioavailability of topiramate from the tablet formulation is

about 80% compared to a solution. The bioavailability of topiramate is not affected by food.

The pharmacokinetics of topiramate are linear with dose proportional increases in plasma concentration

over the dose range studied (200 to 800 mg/day). The mean plasma elimination half-life is 21 hours

after single or multiple doses. Steady state is thus reached in about 4 days in patients with normal renal

function. Topiramate is 15% to 41% bound to human plasma proteins over the blood concentration range

of 0.5 to 250 µg/mL. The fraction bound decreased as blood concentration increased.

Carbamazepine and phenytoin do not alter the binding of topiramate. Sodium valproate, at 500 µg/mL (a

concentration 5 to 10 times higher than considered therapeutic for valproate) decreased the protein

binding of topiramate from 23% to 13%. Topiramate does not influence the binding of sodium valproate.

Metabolism and Excretion

Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine

(approximately 70% of an administered dose). Six metabolites have been identified in humans, none of

which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation,

hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption of topiramate. In rats,

given probenecid to inhibit tubular reabsorption, along with topiramate, a significant increase in renal

clearance of topiramate was observed. This interaction has not been evaluated in humans. Overall, oral

plasma clearance (CL/F) is approximately 20 to 30 mL/min in humans following oral administration.

12.4 Special Populations

Renal Impairment

The clearance of topiramate was reduced by 42% in moderately renally impaired (creatinine clearance

30 to 69 mL/min/1.73 m ) and by 54% in severely renally impaired subjects (creatinine clearance <30

mL/min/1.73 m ) compared to normal renal function subjects (creatinine clearance >70 mL/min/1.73 m ).

Since topiramate is presumed to undergo significant tubular reabsorption, it is uncertain whether this

experience can be generalized to all situations of renal impairment. It is conceivable that some forms of

renal disease could differentially affect glomerular filtration rate and tubular reabsorption resulting in a

clearance of topiramate not predicted by creatinine clearance. In general, however, use of one-half the

usual starting and maintenance dose is recommended in patients with moderate or severe renal

impairment [see Dosage and Administration (2.4 and 2.5) and Warnings and Precautions (5.11)].

Hemodialysis

Topiramate is cleared by hemodialysis. Using a high efficiency, counterflow, single pass-dialysate

hemodialysis procedure, topiramate dialysis clearance was 120 mL/min with blood flow through the

dialyzer at 400 mL/min. This high clearance (compared to 20 to 30 mL/min total oral clearance in

healthy adults) will remove a clinically significant amount of topiramate from the patient over the

hemodialysis treatment period. Therefore, a supplemental dose may be required [see Dosage and

Administration (2.6)].

Hepatic Impairment

In hepatically impaired subjects, the clearance of topiramate may be decreased; the mechanism

underlying the decrease is not well understood [see Dosage and Administration (2.7)].

Age, Gender, and Race

The pharmacokinetics of topiramate in elderly subjects (65 to 85 years of age, N=16) were evaluated in

a controlled clinical study. The elderly subject population had reduced renal function (creatinine

clearance [-20%]) compared to young adults. Following a single oral 100 mg dose, maximum plasma

concentration for elderly and young adults was achieved at approximately 1 to 2 hours. Reflecting the

primary renal elimination of topiramate, topiramate plasma and renal clearance were reduced 21% and

19%, respectively, in elderly subjects, compared to young adults. Similarly, topiramate half-life was

longer (13%) in the elderly. Reduced topiramate clearance resulted in slightly higher maximum plasma

concentration (23%) and AUC (25%) in elderly subjects than observed in young adults. Topiramate

clearance is decreased in the elderly only to the extent that renal function is reduced. As recommended

for all patients, dosage adjustment may be indicated in the elderly patient when impaired renal function

(creatinine clearance rate ≤70 mL/min/1.73 m ) is evident. It may be useful to monitor renal function in

the elderly patient [see Dosage and Administration (2.4) and Warnings and Precautions (5.11)].

Clearance of topiramate in adults was not affected by gender or race.

Pediatric Pharmacokinetics

Pharmacokinetics of topiramate were evaluated in patients ages 4 to 17 years receiving one or two other

antiepileptic drugs. Pharmacokinetic profiles were obtained after one week at doses of 1, 3, and 9

mg/kg/day. Clearance was independent of dose.

Pediatric patients have a 50% higher clearance and consequently shorter elimination half-life than

adults. Consequently, the plasma concentration for the same mg/kg dose may be lower in pediatric

patients compared to adults. As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the

steady state plasma concentrations of topiramate.

12.5 Drug-Drug Interactions

Antiepileptic Drugs

Potential interactions between topiramate and standard AEDs were assessed in controlled clinical

pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma

AUCs are summarized in the Table 8.

In Table 8, the second column (AED concentration) describes what happens to the concentration of the

AED listed in the first column when topiramate is added. The third column (topiramate concentration)

describes how the coadministration of a drug listed in the first column modifies the concentration of

topiramate in experimental settings when topiramate tablets were given alone.

Table 8: Summary of AED Interactions with Topiramate

= 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.

NC = Less than 10% change in plasma concentration.

AED = Antiepileptic drug.

NE = Not Evaluated.

TPM = Topiramate

Co-administered

Concentration

Topiramate

Concentration

Phenytoin

NC or 25% increase

48% decrease

Carbamazepine (CBZ)

CBZ epoxide

40% decrease

Valproic acid

11% decrease

14% decrease

Phenobarbital

Primidone

Lamotrigine

NC at TPM doses up

13% decrease

to 400 mg/day

In addition to the pharmacokinetic interaction described in the above table, concomitant administration of

valproic acid and topiramate has been associated with hyperammonemia with and without

encephalopathy [see Warnings and Precautions (5.8) and Drug Interactions (7.1)].

CNS Depressants

Concomitant administration of topiramate and alcohol or other CNS depressant drugs has not been

evaluated in clinical studies. Because of the potential of topiramate to cause CNS depression, as well as

other cognitive and/or neuropsychiatric adverse reactions, topiramate should be used with extreme

caution if used in combination with alcohol and other CNS depressants [see Drug Interactions (7.2)].

Oral Contraceptives

In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered

combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl

estradiol (EE), topiramate, given in the absence of other medications at doses of 50 to 200 mg/day, was

not associated with statistically significant changes in mean exposure (AUC) to either component of the

oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of

200, 400, and 800 mg/day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in

patients taking valproic acid. In both studies, topiramate (50 mg/day to 800 mg/day) did not significantly

affect exposure to NET. Although there was a dose dependent decrease in EE exposure for doses

between 200 to 800 mg/day, there was no significant dose dependent change in EE exposure for doses

of 50 to 200 mg/day. The clinical significance of the changes observed is not known. The possibility of

decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients

taking combination oral contraceptive products with topiramate. Patients taking estrogen-containing

contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy

can be decreased even in the absence of breakthrough bleeding [see Drug Interactions (7.3)].

Digoxin

In a single-dose study, serum digoxin AUC was decreased by 12% with concomitant topiramate

administration. The clinical relevance of this observation has not been established.

Hydrochlorothiazide

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state

pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg q24h) and topiramate (96 mg q12h) when

administered alone and concomitantly. The results of this study indicate that topiramate C

increased

by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of

this change is unknown. The addition of HCTZ to topiramate therapy may require an adjustment of the

topiramate dose. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the

concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum

potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate

were administered in combination.

Metformin

Topiramate treatment can frequently cause metabolic acidosis, a condition for which the use of

metformin is contraindicated.

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state

pharmacokinetics of metformin (500 mg every 12 hr) and topiramate in plasma when metformin was

given alone and when metformin and topiramate (100 mg every 12 hr) were given simultaneously. The

results of this study indicated that the mean metformin C

and AUC

increased by 17% and 25%,

respectively, when topiramate was added. Topiramate did not affect metformin t

. The clinical

significance of the effect of topiramate on metformin pharmacokinetics is not known. Oral plasma

clearance of topiramate appears to be reduced when administered with metformin. The clinical

significance of the effect of metformin on topiramate pharmacokinetics is unclear. [See Drug

Interactions (7.4)].

Pioglitazone

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state

pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15%

decrease in the AUC

of pioglitazone with no alteration in C

was observed. This finding was

not statistically significant. In addition, a 13% and 16% decrease in C

and AUC

respectively, of

the active hydroxy-metabolite was noted as well as a 60% decrease in C

and AUC

of the active

keto-metabolite. The clinical significance of these findings is not known. When topiramate is added to

pioglitazone therapy or pioglitazone is added to topiramate therapy, careful attention should be given to

the routine monitoring of patients for adequate control of their diabetic disease state.

Glyburide

A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state

pharmacokinetics of glyburide (5 mg/day) alone and concomitantly with topiramate (150 mg/day). There

was a 22% decrease in C

and 25% reduction in AUC

for glyburide during topiramate

administration. Systemic exposure (AUC) of the active metabolites, 4-trans-hydroxy-glyburide (M1) and

3-cis-hydroxyglyburide (M2), was also reduced by 13% and 15%, reduced C

by 18% and 25%,

respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant

administration of glyburide.

Lithium

In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of

200 mg/day; however, there was an observed increase in systemic exposure of lithium (27% for C

and 26% for AUC) following topiramate doses up to 600 mg/day. Lithium levels should be monitored

when co-administered with high-dose topiramate [See Drug Interactions (7.5)].

Haloperidol

The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple

0-12h

τ,ss

max,ss

max,ss

τ,ss

max,ss

τ,s s

dosing of topiramate (100 mg every 12 hr) in 13 healthy adults (6 males, 7 females).

Amitriptyline

There was a 12% increase in AUC and C

for amitriptyline (25 mg per day) in 18 normal subjects (9

males; 9 females) receiving 200 mg/day of topiramate. Some subjects may experience a large increase

in amitriptyline concentration in the presence of topiramate and any adjustments in amitriptyline dose

should be made according to the patient's clinical response and not on the basis of plasma levels.

Sumatriptan

Multiple dosing of topiramate (100 mg every 12 hrs) in 24 healthy volunteers (14 males, 10 females) did

not affect the pharmacokinetics of single dose sumatriptan either orally (100 mg) or subcutaneously (6

mg).

Ris peridone

When administered concomitantly with topiramate at escalating doses of 100, 250 and 400 mg/day, there

was a reduction in risperidone (systemic exposure (16% and 33% for steady-state AUC at the 250 and

400 mg/day doses of topiramate). No alterations of 9-hydroxyrisperidone levels were observed.

Coadministration of topiramate 400 mg/day with risperidone resulted in a 14% increase in C

and a

12% increase in AUC

of topiramate. There were no clinically significant changes in the systemic

exposure of risperidone plus 9-hydroxyrisperidone or of topiramate, therefore this interaction is not

likely to be of clinical significance.

Propranolol

Multiple dosing of topiramate (200 mg/day) in 34 healthy volunteers (17 males, 17 females) did not

affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160

mg/day in 39 volunteers (27 males, 12 females) had no effect on the exposure to topiramate at a dose of

200 mg/day of topiramate.

Dihydroergotamine

Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (12 males, 12 females) did not

affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg

subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg/day dose of

topiramate in the same study.

Diltiazem

Co-administration of diltiazem (240 mg Cardizem CD ) with topiramate (150 mg/day) resulted in a 10%

decrease in C

and 25% decrease in diltiazem AUC, 27% decrease in C

and 18% decrease in des-

acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem, Coadministration of topiramate with

diltiazem resulted in a 16% increase in C

and a 19% increase in AUC

of topiramate.

Venlafaxine

Multiple dosing of topiramate (150 mg/day) in healthy volunteers did not affect the pharmacokinetics of

venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg Effexor XR ) did not

affect the pharmacokinetics of topiramate.

Other Carbonic Anhydrase Inhibitors

Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase

inhibitor (e.g., zonisamide, acetazolamide or dichlorphenamide), may increase the severity of metabolic

acidosis and may also increase the risk of kidney stone formation. Therefore, if topiramate is given

concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the

appearance or worsening of metabolic acidosis [see Drug Interactions (7.5)].

Drug/Laboratory Tests Interactions

There are no known interactions of topiramate with commonly used laboratory tests.

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis

An increase in urinary bladder tumors was observed in mice given topiramate (20, 75, and 300 mg/kg) in

the diet for 21 months. The elevated bladder tumor incidence, which was statistically significant in

males and females receiving 300 mg/kg, was primarily due to the increased occurrence of a smooth

muscle tumor considered histomorphologically unique to mice. Plasma exposures in mice receiving

300 mg/kg were approximately 0.5 to 1 times steady-state exposures measured in patients receiving

topiramate monotherapy at the recommended human dose (RHD) of 400 mg, and 1.5 to 2 times steady-

state topiramate exposures in patients receiving 400 mg of topiramate plus phenytoin. The relevance of

this finding to human carcinogenic risk is uncertain. No evidence of carcinogenicity was seen in rats

following oral administration of topiramate for 2 years at doses up to 120 mg/kg (approximately 3 times

the RHD on a mg/m basis).

Mutagenesis

Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitro and in vivo assays.

Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increase

unscheduled DNA synthesis in rat hepatocytes in vitro; and it did not increase chromosomal aberrations

in human lymphocytes in vitro or in rat bone marrow in vivo.

Impairment of Fertility

No adverse effects on male or female fertility were observed in rats at doses up to 100 mg/kg (2.5 times

the RHD on a mg/m basis).

14. CLINICAL STUDIES

The studies described in the following sections were conducted using topiramate tablets.

14.1 Monotherapy Epilepsy Controlled Trial

The effectiveness of topiramate as initial monotherapy in adults and children 10 years of age and older

with partial onset or primary generalized seizures was established in a multicenter, randomized, double-

blind, parallel-group trial.

The trial was conducted in 487 patients diagnosed with epilepsy (6 to 83 years of age) who had 1 or 2

well-documented seizures during the 3-month retrospective baseline phase who then entered the study

and received topiramate 25 mg/day for 7 days in an open-label fashion. Forty-nine percent of subjects

had no prior AED treatment and 17% had a diagnosis of epilepsy for greater than 24 months. Any AED

therapy used for temporary or emergency purposes was discontinued prior to randomization. In the

double-blind phase, 470 patients were randomized to titrate up to 50 mg/day or 400 mg/day. If the target

dose could not be achieved, patients were maintained on the maximum tolerated dose. Fifty eight percent

of patients achieved the maximal dose of 400 mg/day for >2 weeks, and patients who did not tolerate

150 mg/day were discontinued. The primary efficacy assessment was a between group comparison of

time to first seizure during the double-blind phase. Comparison of the Kaplan-Meier survival curves of

time to first seizure favored the topiramate 400 mg/day group over the topiramate 50 mg/day group

(p=0.0002, log rank test; Figure 1). The treatment effects with respect to time to first seizure were

consistent across various patient subgroups defined by age, sex, geographic region, baseline body

weight, baseline seizure type, time since diagnosis, and baseline AED use.

Figure 1: Kaplan-Meier Estimates of Cumulative Rates for Time to First Seizure

Adjunctive Therapy Controlled Trials in Patients With Partial Onset Seizures

The effectiveness of topiramate as an adjunctive treatment for adults with partial onset seizures was

established in six multicenter, randomized, double-blind, placebo controlled trials, two comparing

several dosages of topiramate and placebo and four comparing a single dosage with placebo, in patients

with a history of partial onset seizures, with or without secondarily generalized seizures.

Patients in these studies were permitted a maximum of two antiepileptic drugs (AEDs) in addition to

topiramate tablets or placebo. In each study, patients were stabilized on optimum dosages of their

concomitant AEDs during baseline phase lasting between 4 and 12 weeks. Patients who experienced a

prespecified minimum number of partial onset seizures, with or without secondary generalization,

during the baseline phase (12 seizures for 12-week baseline, 8 for 8-week baseline or 3 for 4-week

baseline) were randomly assigned to placebo or a specified dose of topiramate tablets in addition to

their other AEDs.

Following randomization, patients began the double-blind phase of treatment. In five of the six studies,

patients received active drug beginning at 100 mg per day; the dose was then increased by 100 mg or

200 mg/day increments weekly or every other week until the assigned dose was reached, unless

intolerance prevented increases. In the sixth study (119), the 25 or 50 mg/day initial doses of topiramate

were followed by respective weekly increments of 25 or 50 mg/day until the target dose of 200 mg/day

was reached. After titration, patients entered a 4, 8 or 12-week stabilization period. The numbers of

patients randomized to each dose, and the actual mean and median doses in the stabilization period are

shown in Table 9.

Adjunctive Therapy Epilepsy Controlled Trials in Adults and Pediatric Patients (Ages 2 to 16

Years )

The effectiveness of topiramate as an adjunctive treatment for pediatric patients ages 2 to 16 years with

partial onset seizures was established in a multicenter, randomized, double-blind, placebo-controlled

trial, comparing topiramate and placebo in patients with a history of partial onset seizures, with or

without secondarily generalized seizures.

Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in addition to

topiramate tablets or placebo. In this study, patients were stabilized on optimum dosages of their

concomitant AEDs during an 8-week baseline phase. Patients who experienced at least six partial onset

seizures, with or without secondarily generalized seizures, during the baseline phase were randomly

assigned to placebo or topiramate tablets in addition to their other AEDs.

Following randomization, patients began the double-blind phase of treatment. Patients received active

drug beginning at 25 or 50 mg per day; the dose was then increased by 25 mg to 150 mg/day increments

every other week until the assigned dosage of 125, 175, 225 or 400 mg/day based on patients' weight to

approximate a dosage of 6 mg/kg per day was reached, unless intolerance prevented increases. After

titration, patients entered an 8-week stabilization period.

Adjunctive Therapy Controlled Trial in Patients With Primary Generalized Tonic-Clonic Seizures

The effectiveness of topiramate as an adjunctive treatment for primary generalized tonic-clonic seizures

in patients 2 years old and older was established in a multicenter, randomized, double-blind, placebo-

controlled trial, comparing a single dosage of topiramate and placebo.

Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in addition to

topiramate or placebo. Patients were stabilized on optimum dosages of their concomitant AEDs during

an 8-week baseline phase. Patients who experienced at least three primary generalized tonic-clonic

seizures during the baseline phase were randomly assigned to placebo or topiramate in addition to their

other AEDs.

Following randomization, patients began the double-blind phase of treatment. Patients received active

drug beginning at 50 mg per day for four weeks; the dose was then increased by 50 mg to 150 mg/day

increments every other week until the assigned dose of 175, 225 or 400 mg/day based on patients' body

weight to approximate a dosage of 6 mg/kg per day was reached, unless intolerance prevented

increases. After titration, patients entered a 12-week stabilization period.

Adjunctive Therapy Controlled Trial in Patients With Lennox-Gastaut Syndrome

The effectiveness of topiramate as an adjunctive treatment for seizures associated with Lennox-Gastaut

syndrome was established in a multicenter, randomized, double-blind, placebo-controlled trial

comparing a single dosage of topiramate with placebo in patients 2 years of age and older.

Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in addition to

topiramate or placebo. Patients who were experiencing at least 60 seizures per month before study

entry were stabilized on optimum dosages of their concomitant AEDs during a 4-week baseline phase.

Following baseline, patients were randomly assigned to placebo or topiramate in addition to their other

AEDs. Active drug was titrated beginning at 1 mg/kg per day for a week; the dose was then increased to

3 mg/kg per day for one week then to 6 mg/kg per day. After titration, patients entered an 8-week

stabilization period. The primary measures of effectiveness were the percent reduction in drop attacks

and a parental global rating of seizure severity.

Table 9:Topiramate Dose Summary During the Stabilization Periods of Each of Six Double-

Blind, Placebo-Controlled, Add-On Trials in Adults with Partial Onset Seizures

Target Topiramate Dosage (mg/day)

Protocol

Stabilization Dose Placebo

200

400

600

800

1,000

Mean Dose

Median Dose

Mean Dose

Median Dose

10.0

1,000

b

a

Placebo dosages are given as the number of tablets. Placebo target dosages were as follows: Protocol Y1, 4

tablets/day; Protocols YD and Y2, 6 tablets/day; Protocol Y3 and 119, 8 tablets/day; Protocol YE, 10

tablets/day.

Dose-response studies were not conducted for other indications or pediatric partial onset seizures.

Mean Dose

Median Dose

Mean Dose

Median Dose

Mean Dose

Median Dose

Mean Dose

Median Dose

In all add-on trials, the reduction in seizure rate from baseline during the entire double-blind phase was

measured. The median percent reductions in seizure rates and the responder rates (fraction of patients

with at least a 50% reduction) by treatment group for each study are shown below in Table 10. As

described above, a global improvement in seizure severity was also assessed in the Lennox-Gastaut

trial.

Table 10: Efficacy Results in Double-Blind, Placebo-Controlled, Add-On Epilepsy Trials

Target Topiramate Dosage (mg/day)

Protocol Efficacy Results

Placebo

200

400

600

800

1,000

≈6

mg/kg/day*

Partial Onset Seizures

Studies in Adults

Median % Reduction

11.6

27.2

47.5

44.7

% Responders

Median % Reduction

40.8

41.0

36.0

% Responders

Median % Reduction

40.7

% Responders

Median % Reduction

-12.2

46.4

% Responders

Comparisons with placebo:

p=0.080;

p≤0.010;

p≤0.001;

p≤0.050;

p=0.065; p≤0.005;

p=0.071;

Median % reduction and % responders are reported for PGTC Seizures;

Median % reduction and % responders for drop attacks, i.e., tonic or atonic seizures;

Percent of subjects who were minimally, much, or very much improved from baseline

* For Protocols YP and YTC, protocol-specified target dosages (<9.3 mg/kg/day) were assigned based on

subject’s weight to approximate a dosage of 6 mg/kg per day; these dosages corresponded to mg/day dosages

of 125, 175, 225, and 4 00 mg/day.

Median % Reduction

-20.6

24.3

% Responders

Median % Reduction

20.0

44.2

% Responders

Studies in Pediatric Patients

Median % Reduction

10.5

33.1

% Responders

Primary Generalized Tonic-Clonic

Median % Reduction

56.7

% Responders

Lennox-Gastaut Syndrome

Median % Reduction

-5.1

14.8

% Responders

Improvement in Seizure

severity

Subset analyses of the antiepileptic efficacy of topiramate tablets in these studies showed no

differences as a function of gender, race, age, baseline seizure rate, or concomitant AED. In clinical

trials for epilepsy, daily dosages were decreased in weekly intervals by 50 to 100 mg per day in adults

and over a 2 to 8 week period in children; transition was permitted to a new antiepileptic regimen when

clinically indicated.

16. HOW SUPPLIED/STORAGE AND HANDLING

Topiramate Tablets 25 mg are white to off white, round, biconvex, film coated tablets debossed with

‘1031’ on one side and ‘25’ on other side. Topiramate Tablets 25 mg are supplied as follows:

Package NDC Number

Bottles of 30

NDC 13668-031-30

Bottles of 60

NDC 13668-031-60

Bottles of 100

NDC 13668-031-01

Bottles of 500

NDC 13668-031-05

Bottles of 9000

NDC 13668-031-53

100 unit dose tablets

NDC 13668-031-74

Topiramate Tablets 50 mg are yellow colored, round, biconvex, film coated tablets debossed with

‘1032’ on one side and ‘50’ on other side. Topiramate Tablets 50 mg are supplied as follows:

Package NDC Number

Bottles of 30

NDC 13668-032-30

Bottles of 60

NDC 13668-032-60

Bottles of 100

NDC 13668-032-01

Bottles of 500

NDC 13668-032-05

Bottles of 6000

NDC 13668-032-42

100 unit dose tablets

NDC 13668-032-74

Topiramate tablets

Storage and Handling

Topiramate tablets should be stored in tightly-closed containers at 20° - 25°C (68° - 77°F); excursions

permitted to 15° - 30°C (59° - 86°F) [see USP Controlled Room Temperature]. PROTECT FROM

MOISTURE.

17. PATIENT COUNSELING INFORMATION

Patients and their caregivers should be informed of the availability of a Medication Guide, and they

should be instructed to read the Medication Guide prior to taking topiramate tablets. Patients should be

instructed to take topiramate tablets only as prescribed. See FDA approved Medication Guide.

17.1 Eye Disorders

Patients taking topiramate should be told to seek immediate medical attention if they experience blurred

vision, visual disturbances or periorbital pain [see Warnings and Precautions (5.1)].

17.2 Oligohydrosis and Hyperthermia

Patients, especially pediatric patients, treated with topiramate should be monitored closely for evidence

of decreased sweating and increased body temperature, especially in hot weather [see Warnings and

Precautions (5.2)].

17.3 Suicidal Behavior and Ideation

Patients, their caregivers, and families should be counseled that AEDs, including topiramate, may

increase the risk of suicidal thoughts and behavior and should be advised 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, behavior or thoughts about self-harm. Behaviors of

concern should be reported immediately to healthcare providers.

17.4 Metabolic Acidosis

Patients should be warned 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 [see Warnings and Precautions (5.4)].

17.5 Interference with Cognitive and Motor Performance

Patients should be warned about the potential for somnolence, dizziness, confusion, difficulty

concentrating, visual effects and advised 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. [see Warnings and Precautions (5.5)].

Even when taking topiramate or other anticonvulsants, some patients with epilepsy will continue to have

unpredictable seizures. Therefore, all patients taking topiramate for epilepsy should be told 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.). Some patients with refractory epilepsy will need to avoid such activities altogether. Physicians

should discuss the appropriate level of caution with their patients, before patients with epilepsy engage

in such activities.

17.6 Hyperammonemia and Encephalopathy

Patients should be warned about the possible development of hyperammonemia with or without

encephalopathy. Although hyperammonemia may be asymptomatic, clinical symptoms of

hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or

cognitive function with lethargy or vomiting. This hyperammonemia and encephalopathy can develop

with topiramate treatment alone or with topiramate treatment with concomitant valproic acid (VPA).

Patients should be instructed to contact their physician if they develop unexplained lethargy, vomiting,

or changes in mental status [see Warnings and Precautions (5.8)].

17.7 Kidney Stones

Patients, particularly those with predisposing factors, should be instructed to maintain an adequate fluid

intake in order to minimize the risk of kidney stone formation [see Warnings and Precautions (5.9)].

17.8 Use in Pregnancy

Patients should be instructed to notify their physician if they become pregnant or intend to become

pregnant during therapy and to notify their physician if they are breastfeeding or intend to breastfeed

during therapy with topiramate [see Use in Specific Populations (8.1) and (8.3). Patients should be

encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they

become pregnant. The registry is collecting information about the safety of antiepileptic drugs during

pregnancy. To enroll, patients can call the toll free number, 1-888-233-2334 [see Use in Specific

Populations (8.1)].

Manufactured by:

TORRENT PHARMACEUTICALS LTD., Indrad-382 721

Dist. Mehsana, INDIA.

For:

TORRENT PHARMA INC., 5380 Holiday Terrace, Suite 40, Kalamazoo, Michigan 49009.

8021903 Revised January 2010

MEDICATION GUIDE

Topiramate tablets

Rx Only

Read this Medication Guide before you start taking topiramate tablets and each time you get a refill.

There may be new information. This information does not take the place of talking to your healthcare

provider about your medical condition or treatment. If you have any questions about topiramate tablets,

talk to your healthcare provider or pharmacist.

What is the most important information I should know about topiramate tablets?

Topiramate tablets may cause eye problems. Serious eye problems include:

any sudden decrease in vision with or without eye pain and redness,

a blockage of fluid in the eye causing increased pressure in the eye (secondary angle closure

glaucoma).

These eye problems can lead to permanent loss of vision if not treated. You should call your

healthcare provider right away if you have any new eye symptoms.

Topiramate tablets may cause decreased sweating and increased body temperature (fever).

People, especially children, should be watched for signs of decreased sweating and fever, especially

in hot temperatures. Some people may need to be hospitalized for this condition.

Like other antiepileptic drugs, topiramate tablets may cause suicidal thoughts or actions in a

very small number of people, about 1 in 500.

Call a healthcare provider right away if you have any of these symptoms, especially if they are

new, worse, or worry you:

thoughts about suicide or dying

attempts to commit suicide

new or worse depression

new or worse anxiety

feeling agitated or restless

panic attacks

trouble sleeping (insomnia)

new or worse irritability

acting aggressive, being angry, or violent

acting on dangerous impulses

an extreme increase in activity and talking (mania)

other unusual changes in behavior or mood

Do not stop topiramate tablets without first talking to a healthcare provider.

Stopping topiramate tablets suddenly can cause serious problems.

Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal

thoughts or actions, your healthcare provider may check for other causes.

How can I watch for early symptoms of suicidal thoughts and actions?

Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.

Keep all follow-up visits with your healthcare provider as scheduled.

Call your healthcare provider between visits as needed, especially if you are worried about

symptoms.

What are topiramate tablets?

Topiramate tablets are a prescription medicine used:

to treat certain types of seizures (partial onset seizures and primary generalized tonic-clonic

seizures) in people 10 years and older,

with other medicines to treat certain types of seizures (partial onset seizures, primary generalized

tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome) in adults and children

2 years and older.

What should I tell my healthcare provider before taking topiramate tablets?

Before taking topiramate tablets, tell your healthcare provider about all your medical conditions,

including if you:

have or have had depression, mood problems or suicidal thoughts or behavior

have kidney problems, kidney stones or are getting kidney dialysis

have a history of metabolic acidosis (too much acid in the blood)

have liver problems

have osteoporosis, soft bones, or decreased bone density

have lung or breathing problems

have eye problems, especially glaucoma

have diarrhea

have a growth problem

are on a diet high in fat and low in carbohydrates, which is called a ketogenic diet

are having surgery

are pregnant or plan to become pregnant. It is not known if topiramate tablets will harm your unborn

baby. If you become pregnant while taking topiramate tablets, talk to your healthcare provider about

registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this

registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the

safety of antiepileptic medicine during pregnancy.

are breastfeeding. It is not known if topiramate tablets passes into breast milk and if it can harm your

baby. Talk to your healthcare provider about the best way to feed your baby if you take topiramate

tablets.

Tell your healthcare provider about all the medicines you take, including prescription and non-

prescription medicines, vitamins, and herbal supplements. Topiramate tablets and other medicines may

affect each other causing side effects.

Especially, tell your healthcare provider if you take:

Valproic acid

any medicines that impair or decrease your thinking, concentration, or muscle coordination.

birth control pills. Topiramate tablets may make your birth control pills less effective. Tell your

healthcare provider if your menstrual bleeding changes while you are taking birth control pills and

topiramate tablets.

Ask your healthcare provider if you are not sure if your medicine is listed above.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each

time you get a new medicine. Do not start a new medicine without talking with your healthcare provider.

How should I take topiramate tablets?

Take topiramate tablets exactly as prescribed.

Your healthcare provider may change your dose. Do not change your dose without talking to your

healthcare provider.

Topiramate tablets should be swallowed whole. Do not chew the tablets. They may leave a bitter

taste.

Do not store any medicine and food mixture for later use.

Topiramate tablets can be taken before, during, or after a meal. Drink plenty of fluids during the day.

This may help prevent kidney stones while taking topiramate tablets.

If you take too much topiramate tablets, call your healthcare provider or poison control center right

away or go to the nearest emergency room.

If you miss a single dose of topiramate tablets, take it as soon as you can. However, if you are

within 6 hours of taking your next scheduled dose, wait until then to take your usual dose of

topiramate tablets, and skip the missed dose. Do not double your dose. If you have missed more than

one dose, you should call your healthcare professional for advice.

Do not stop taking topiramate tablets without talking to your healthcare provider. Stopping

topiramate tablets suddenly may cause serious problems. If you have epilepsy and you stop taking

topiramate tablets suddenly, you may have seizures that do not stop. Your healthcare provider will

tell you how to stop taking topiramate tablets slowly.

Your healthcare provider may do blood tests while you take topiramate tablets.

What should I avoid while taking topiramate tablets?

Do not drink alcohol while taking topiramate tablets. Topiramate tablets and alcohol can affect each

other causing side effects such as sleepiness and dizziness.

Do not drive a car or operate heavy machinery until you know how topiramate tablet affects you.

Topiramate tablets can slow your thinking and motor skills, and/or vision.

What are the possible side effects of topiramate tablets?

Topiramate tablets may cause serious side effects including:

See "What is the most important information I should know about topiramate tablets?"

Metabolic Acidosis. Metabolic acidosis can cause:

tiredness

loss of appetite

irregular heartbeat

impaired consciousness

High blood ammonia levels. High ammonia in the blood can affect your mental activities, slow your

alertness, make you feel tired, or cause vomiting. This has happened when topiramate tablets is taken

with a medicine called valproic acid.

Kidney stones. Drink plenty of fluids when taking topiramate tablets to decrease your chances of

getting kidney stones.

Effects on Thinking and Alertness. Topiramate tablets may affect how you think, and cause

confusion, problems with concentration, attention, memory, or speech. Topiramate tablets may cause

depression or mood problems, tiredness, and sleepiness.

Dizziness or Loss of Muscle Coordination.

Call your healthcare provider right away if you have any of the symptoms above.

The most common side effects of topiramate tablets include:

tingling of the arms and legs (paresthesia)

not feeling hungry

nausea

a change in the way foods taste

diarrhea

weight loss

nervousness

upper respiratory tract infection

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all the possible side effects of topiramate tablets. For more information, ask your

healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-

FDA-1088.

How should I store topiramate tablets?

Store topiramate tablets at 20° - 25°C (68° - 77°F); excursions permitted to 15° - 30°C (59° - 86°F)

[see USP Controlled Room Temperature]. PROTECT FROM MOISTURE.

Keep topiramate tablets in a tightly closed container.

Keep topiramate tablets and all medicines out of the reach of children.

General information about topiramate tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not

use topiramate tablets for a condition for which it was not prescribed. Do not give topiramate tablets to

other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about topiramate tablets. If you

would like more information, talk with your healthcare provider. You can ask your pharmacist or

healthcare provider for information about topiramate tablets that is written for health professionals.

For more information, call 1-269-544-2299.

What are the ingredients in topiramate tablets?

Active ingredient: topiramate, USP

Inactive ingredients: colloidal silicon dioxide, ferric oxide red (200 mg tablets), ferric oxide yellow

(50, 100, and 200 mg tablets), HYPROMELLOSES, lactose monohydrate, magnesium stearate,

microcrystalline cellulose, polyethylene glycol, pregelatinized starch, sodium starch glycolate, talc and

titanium dioxide.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured by:

TORRENT PHARMACEUTICALS LTD., Indrad-382 721

Dist. Mehsana, INDIA.

For:

TORRENT PHARMA INC., 5380 Holiday Terrace, Suite 40, Kalamazoo, Michigan 49009.

8021903 Revised January 2010

PRINCIPAL DISPLAY PANEL

25 mg : label

50 mg : label

TOPIRAMATE

topiramate tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:529 59 -441(NDC:136 6 8 -0 31)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

TO PIRAMATE (UNII: 0 H73WJJ39 1) (TOPIRAMATE - UNII:0 H73WJJ39 1)

TOPIRAMATE

25 mg

Inactive Ingredients

Ingredient Name

Stre ng th

CO LLO IDAL SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

PO LYETHYLENE GLYCO L 4 0 0 (UNII: B6 9 78 9 4SGQ)

SO DIUM STARCH GLYCO LATE TYPE A PO TATO (UNII: 58 56 J3G2A2)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

Product Characteristics

Color

WHITE (white to o ff white)

S core

no sco re

S hap e

ROUND (Ro und, bico nvex film co ated)

S iz e

Flavor

Imprint Code

10 31;25

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:529 59 -441-0 1

120 in 1 BOTTLE

2

NDC:529 59 -441-30

30 in 1 BOTTLE

3

NDC:529 59 -441-6 0

6 0 in 1 BOTTLE

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 79 153

0 3/27/20 0 9

TOPIRAMATE

topiramate tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:529 59 -9 9 4(NDC:136 6 8 -0 32)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

TO PIRAMATE (UNII: 0 H73WJJ39 1) (TOPIRAMATE - UNII:0 H73WJJ39 1)

TOPIRAMATE

50 mg

H.J. Harkins Company, Inc.

Inactive Ingredients

Ingredient Name

Stre ng th

CO LLO IDAL SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

PO LYETHYLENE GLYCO L 4 0 0 (UNII: B6 9 78 9 4SGQ)

SO DIUM STARCH GLYCO LATE TYPE A PO TATO (UNII: 58 56 J3G2A2)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

Product Characteristics

Color

YELLOW

S core

no sco re

S hap e

ROUND (Ro und, bico nvex film co ated)

S iz e

6 mm

Flavor

Imprint Code

10 32;50

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:529 59 -9 9 4-30

30 in 1 BOTTLE

2

NDC:529 59 -9 9 4-6 0

6 0 in 1 BOTTLE

3

NDC:529 59 -9 9 4-9 0

9 0 in 1 BOTTLE

4

NDC:529 59 -9 9 4-0 2

120 in 1 BOTTLE

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 79 153

0 3/27/20 0 9

Labeler -

H.J. Harkins Company, Inc. (147681894)

Registrant -

H.J. Harkins Company, Inc. (147681894)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

H.J. Harkins Co mpany, Inc.

1476 8 18 9 4

repack, relabel

Revised: 1/2012

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