TOPIRAMATE tablet, film coated

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

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Active ingredient:
TOPIRAMATE (UNII: 0H73WJJ391) (TOPIRAMATE - UNII:0H73WJJ391)
Available from:
PD-Rx Pharmaceuticals, Inc.
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Topiramate tablets are indicated as initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 2 years of age and older. Topiramate tablets are indicated as adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome in patients 2 years of age and older. Topiramate tablets are indicated for the preventive treatment of migraine in patients 12 years of age and older. None. Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to topiramate during pregnancy. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This 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. Information about the North American Drug Pregnancy
Product summary:
Topiramate tablets, USP are available as debossed, film-coated, circular tablets in the following strengths and colors: 25 mg white (coded “S” on one side; “707” on the other) They are supplied as follows: 25 mg tablets Bottles of 30's .................NDC 43063-998-30 Bottles of 60’s …………...NDC 43063-998-60 Store topiramate tablets at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Protect from moisture. Dispense in a tight container.
Authorization status:
Abbreviated New Drug Application
Authorization number:
43063-998-30, 43063-998-60

PD-Rx Pharmaceuticals, Inc.

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MEDICATION GUIDE

Topiramate Tablets, USP

(toe-PEER-uh-mate )

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

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, including any new

problems with your vision.

Topiramate tablet 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. If a high fever, a fever that does not go away, or

decreased sweating develops, call your healthcare provider right away.

Topiramate tablet can increase the level of acid in your blood (metabolic acidosis). If left untreated,

metabolic acidosis can cause brittle or soft bones (osteoporosis, osteomalacia, osteopenia), kidney stones, can

slow the rate of growth in children, and may possibly harm your baby if you are pregnant. Metabolic acidosis

can happen with or without symptoms.

Sometimes people with metabolic acidosis will:

feel tired

not feel hungry (loss of appetite)

feel changes in heartbeat

have trouble thinking clearly

Your healthcare provider should do a blood test to measure the level of acid in your blood before and during

your treatment with topiramate tablets. If you are pregnant, you should talk to your healthcare provider about

whether you have metabolic acidosis.

Like other antiepileptic drugs, topiramate tablet 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.

Topiramate can harm your unborn baby.

If you take topiramate tablets during pregnancy, your baby has a higher risk for birth defects called cleft lip

and cleft palate. These defects can begin early in pregnancy, even before you know you are pregnant.

Cleft lip and cleft palate may happen even in children born to women who are not taking any medicines and

do not have other risk factors.

There may be other medicines to treat your condition that have a lower chance of birth defects.

All women of childbearing age should talk to their healthcare providers about using other possible

treatments instead of topiramate tablets. If the decision is made to use topiramate tablets, you should use

effective birth control (contraception) unless you are planning to become pregnant. You should talk to your

doctor about the best kind of birth control to use while you are taking topiramate tablets.

Tell your healthcare provider right away if you become pregnant while taking topiramate. You and your

healthcare provider should decide if you will continue to take topiramate tablets while you are pregnant.

If you take topiramate during pregnancy, your baby may be smaller than expected at birth. The long-term

effects of this are not known. Talk to your healthcare provider if you have questions about this risk during

pregnancy.

Metabolic acidosis may have harmful effects on your baby. Talk to your healthcare provider if topiramate

tablets have caused metabolic acidosis during your pregnancy.

Pregnancy Registry: 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 topiramate and other antiepileptic drugs during pregnancy.

What is topiramate tablet?

Topiramate tablet is prescription medicine used:

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

adults and children 2 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,

to prevent migraine headaches in adults and adolescents 12 years and older.

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

if you:

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

have kidney problems, have kidney stones, or are getting kidney dialysis.

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

have liver problems.

have weak, brittle, or soft bones (osteomalacia, osteoporosis, osteopenia, 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.

are breastfeeding or plan to breastfeed. Topiramate passes into breast milk. Breastfed babies may be sleepy

or have diarrhea. It is not known if the topiramate that passes into breast milk can cause other serious harm to

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 over-the-counter

medicines, vitamins, and herbal supplements. Topiramate and other medicines may affect each other causing

side effects.

Especially tell your healthcare provider if you take:

Valproic acid (such as DEPAKENE or DEPAKOTE).

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.

Take topiramate tablets whole. Do not chew the tablets. They may leave a bitter taste.

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 many topiramate tablets, call your healthcare provider 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 provider 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?

You should 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 machinery until you know how topiramate tablets affect you. Topiramate

tablets can slow your thinking and motor skills, and may affect vision.

What are the possible side effects of topiramate tablet?

Topiramate tablets may cause serious side effects including:

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

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 are taken with a

medicine called valproic acid (DEPAKENE and DEPAKOTE).

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.

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

kidney stones.

Low body temperature. Taking topiramate tablets when you are also taking valproic acid can cause a drop

in body temperature to less than 95°F, or can cause tiredness, confusion, or coma.

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

The most common side effects of topiramate tablet include:

tingling of the arms and legs (paresthesia)

nervousness

slow reactions

upper respiratory tract infection

difficulty with memory

not feeling hungry

pain in the abdomen

nausea

speech problems

fever

a change in the way foods taste

tiredness

abnormal vision

dizziness

decreased feeling or sensitivity, especially in the skin

diarrhea

sleepiness/drowsiness

weight loss

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 tablet. Call your doctor for medical advice about side

effects. You may report side effects to FDA at 1-800-FDA-1088.

You may also report side effects to Sun Pharmaceutical Industries, Inc. at 1-800-818-4555.

How should I store topiramate tablets?

Store topiramate tablets at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).

Keep topiramate tablets in a tightly closed container.

Keep topiramate tablets dry and away from moisture.

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

General information about the safe and effective use of topiramate tablets.

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

topiramate tablet for a condition for which it was not prescribed. Do not give topiramate tablet to other

people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist

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

What are the ingredients in topiramate tablets?

Active ingredient: topiramate

Inactive ingredients:

Anhydrous lactose, microcrystalline cellulose, pregelatinized maize starch, sodium starch glycolate type A

potato, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc.

In addition, individual tablets contain:

50 mg tablets: iron oxide yellow

100 mg tablets: iron oxide yellow, and D&C Yellow # 10 Aluminum Lake

200 mg tablets: iron oxide red, lecithin (soya), and iron oxide black

For more information, call 1-800-818-4555

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

* All trademark names are the property of their respective owners.

Distributed by:

Sun Pharmaceutical Industries, Inc.

Cranbury, NJ 08512

Manufactured by:

Sun Pharmaceutical Industries Ltd.

Survey No. 259/15,

Dadra-396 191(U.T. of D & NH), India.

ISS. 05/2019

PGPI0305G

Revised: 6/2020

Document Id: a70ceece-9d3e-e75c-e053-2995a90a3646

34391-3

Set id: 021005ab-6a00-40d8-9aee-20c91613b4d5

Version: 15

Effective Time: 20200601

PD-Rx Pharmaceuticals, Inc.

TOPIRAMATE- topiramate tablet, film coated

PD-Rx Pharmaceuticals, 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, for oral use

Initial U.S. Approval: 1996

INDICATIONS AND USAGE

Topiramate is indicated for: (1)

Epilepsy: initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 2

years of age and older (1.1); adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-

clonic seizures, or seizures associated with Lennox- Gastaut syndrome in patients 2 years of age and older (1.2)

Preventive treatment of migraine in patients 12 years of age and older (1.3)

DOSAGE AND ADMINISTRATION

Topiramate initial dose, titration, and recommended maintenance dose varies by indication and age group. See Full

Prescribing Information for recommended dosage, and dosing considerations in patients with renal impairment, geriatric

patients, and patients undergoing hemodialysis (2.1, 2.2, 2.3, 2.4, 2.5, 2.6) (2)

DOSAGE FORMS AND STRENGTHS

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

CONTRAINDICATIONS

None (4) (4)

WARNINGS AND PRECAUTIONS

Acute myopia and secondary angle closure glaucoma: can lead to permanent visual loss; discontinue topiramate as soon

as possible (5.1)

Visual field defects: consider discontinuation of topiramate (5.2)

Oligohidrosis and hyperthermia: monitor decreased sweating and increased body temperature, especially in pediatric

patients (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)

Suicidal behavior and ideation: antiepileptic drugs increase the risk of suicidal behavior or ideation (5.5)

Cognitive/neuropsychiatric adverse reactions: use caution when operating machinery including cars; depression and

mood problems may occur (5.6)

Fetal Toxicity: use during pregnancy can cause cleft lip and/or palate and being small for gestational age (5.7)

Withdrawal of AEDs: withdraw topiramate gradually (5.8)

Hyperammonemia/encephalopathy: measure ammonia if encephalopathic symptoms occur (5.9)

Kidney stones: avoid use with other carbonic anhydrase inhibitors, drugs causing metabolic acidosis, or in patients on a

ketogenic diet (5.10)

Hypothermia has been reported with and without hyperammonemia during topiramate treatment with concomitant

valproic acid use (5.11) (5)

ADVERSE REACTIONS

Epilepsy: Most common (≥10% more frequent than placebo

or low-dose topiramate) adverse reactions in adult and pediatric patients were: paresthesia, anorexia, weight loss, speech

disorders/related speech problems, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, abnormal vision

and fever (6.1)

Migraine: Most common (≥5% more frequent than placebo) adverse reactions in adult and pediatric patients were:

paresthesia, anorexia, weight loss, difficulty with memory, taste perversion, diarrhea, hypoesthesia, nausea, abdominal pain

and upper respiratory tract infection (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555

or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Oral contraceptives: decreased contraceptive efficacy and increased breakthrough bleeding, especially at doses greater

than 200 mg/day (7.4)

Monitor lithium levels if lithium is used with high-dose topiramate (7.7)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 5/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Monotherapy Epilepsy

1.2 Adjunctive Therapy Epilepsy

1.3 Migraine

2 DOSAGE AND ADMINISTRATION

2.1 Dosing in Monotherapy Epilepsy

2.2 Dosing in Adjunctive Therapy Epilepsy

2.3 Dosing for the Preventive Treatment of Migraine

2.4 Administration Information

2.5 Dosing in Patients with Renal Impairment

2.6 Dosing in Patients Undergoing Hemodialysis

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Acute Myopia and Secondary Angle Closure Glaucoma

5.2 Visual Field Defects

5.3 Oligohidrosis and Hyperthermia

5.4 Metabolic Acidosis

5.5 Suicidal Behavior and Ideation

5.6 Cognitive/Neuropsychiatric Adverse Reactions

5.7 Fetal Toxicity

5.8 Withdrawal of Antiepileptic Drugs

5.9 Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use)

5.10 Kidney Stones

5.11 Hypothermia with Concomitant Valproic Acid Use

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Antiepileptic Drugs

7.2 Other Carbonic Anhydrase Inhibitors

7.3 CNS Depressants

7.4 Oral Contraceptives

7.5 Hydrochlorothiazide (HCTZ)

7.6 Pioglitazone

7.7 Lithium

7.8 Amitriptyline

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Patients Undergoing Hemodialysis

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NON-CLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Monotherapy Epilepsy

14.2 Adjunctive Therapy Epilepsy

14.3 Preventive Treatment of Migraine

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

16.2 Storage and Handling

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Monotherapy Epilepsy

Topiramate tablets are indicated as initial monotherapy for the treatment of partial-onset or primary

generalized tonic-clonic seizures in patients 2 years of age and older.

1.2 Adjunctive Therapy Epilepsy

Topiramate tablets are indicated as adjunctive therapy for the treatment of partial-onset seizures, primary

generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome in patients 2

years of age and older.

1.3 Migraine

Topiramate tablets

are indicated for the preventive treatment of migraine in patients 12 years of age and older.

2 DOSAGE AND ADMINISTRATION

2.1 Dosing in Monotherapy Epilepsy

Adults and Pediatric Patients 10 Years of Age and Older

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. The dose should be achieved by titration according to the

following schedule (Table 1):

Table 1: Monotherapy Titration Schedule for Adults and Pediatric Patients 10

years and older

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

Pediatric Patients 2 to 9 Years of Age

Dosing in patients 2 to 9 years of age is based on weight. During the titration period, the initial dose of

topiramate is 25 mg/day nightly for the first week. Based upon tolerability, the dosage can be increased

to 50 mg/day (25 mg twice daily) in the second week. Dosage can be increased by 25 to 50 mg/day each

subsequent week as tolerated. Titration to the minimum maintenance dose should be attempted over 5 to

7 weeks of the total titration period. Based upon tolerability and clinical response, additional titration to

a higher dose (up to the maximum maintenance dose) can be attempted at 25 to 50 mg/day weekly

increments. The total daily dose should not exceed the maximum maintenance dose for each range of

body weight (Table 2).

Table 2: Monotherapy Target Total Daily Maintenance Dosing for Patients 2 to 9 Years of Age

Weight (kg)

Total Daily Dose (mg/day)*

Minimum Maintenance Dose

Total Daily Dose (mg/day)*

Maximum Maintenance Dose

Up to 11

12 to 22

23 to 31

32 to 38

Greater than 38

* Administered in two equally divided doses

2.2 Dosing in Adjunctive Therapy Epilepsy

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

Adults (17 Years of Age and Older)

The recommended total daily dose of topiramate as adjunctive therapy in adults with partial onset

seizures or Lennox-Gastaut Syndrome 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.

Topiramate should 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. Doses above 400 mg/day have not been shown to improve

responses in adults with partial-onset seizures.

Pediatric Patients 2 to 16 Years of Age

The recommended total daily dose of topiramate tablets as adjunctive therapy for pediatric patients 2 to

16 years of age 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. The total daily dose should not exceed 400 mg/day.

2.3 Dosing for the Preventive Treatment of Migraine

The recommended total daily dose of topiramate as treatment for patients 12 years of age and older

for the preventive treatment of migraine is 100 mg/day administered in two divided doses (Table 3). The

recommended titration rate for topiramate for the preventive treatment of migraine is as follows:

Table 3: Preventive Treatment of Migraine Titration Schedule for Patients 12 Years

of Age and Older

Morning Dose

Evening Dose

Week 1

None

25 mg

Week 2

25 mg

25 mg

Week 3

25 mg

50 mg

Week 4

50 mg

50 mg

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

dose adjustments can be used.

2.4 Administration Information

Topiramate tablets can be taken without regard to meals.

Because of the bitter taste, tablets should not be broken.

2.5 Dosing in Patients with Renal Impairment

In patients with renal impairment (creatinine clearance less than 70 mL/min/1.73 m2), one-half of the

usual adult dose of topiramate is recommended [see Use in Specific Populations (8.5, 8.6), Clinical

Pharmacology (12.3)].

2.6 Dosing in Patients Undergoing Hemodialysis

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 [see Use in Specific Populations (8.7), Clinical Pharmacology

(12.3)].

3 DOSAGE FORMS AND STRENGTHS

Topiramate tablets, USP are available as debossed, film-coated, circular tablets in the following

strengths and colors:

25 mg white (coded “S” on one side; “707” on the other)

50 mg yellow (coded “S” on one side; “710” on the other)

100 mg yellow (coded “S” on one side; “711” on the other)

200 mg brown (coded “S” on one side; “712” 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 therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age,

secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as

well as adults. The primary treatment to reverse symptoms is discontinuation of topiramate as rapidly as

possible, according to the judgment of the treating physician. Other measures, in conjunction with

discontinuation of topiramate, may be helpful.

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

permanent vision loss.

5.2 Visual Field Defects

Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials

and in postmarketing experience in patients receiving topiramate. In clinical trials, most of these events

were reversible after topiramate discontinuation. If visual problems occur at any time during topiramate

treatment, consideration should be given to discontinuing the drug.

5.3 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 given 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.

5.4 Metabolic Acidosis

Topiramate can cause hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum

bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis). This

metabolic acidosis is caused by renal bicarbonate loss due to carbonic anhydrase inhibition by

topiramate. Topiramate-induced metabolic acidosis 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.

Metabolic acidosis was commonly observed in adult and pediatric patients treated with topiramate in

clinical trials. The incidence of decreased serum bicarbonate in pediatric trials, for adjunctive treatment

of Lennox-Gastaut syndrome or refractory partial-onset seizures was as high as 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 up to 11%, compared to < 2% for placebo.

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 [see Warnings and Precautions (5.10)]. Chronic

metabolic acidosis in pediatric patients may also reduce growth rates, which may 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

pediatric patients 1 to 24 months old with intractable partial epilepsy, for up to 1 year, showed

reductions from baseline in 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 1 to 24 month old pediatrics. Reductions in length and weight were correlated to the degree of

acidosis [see Use in Specific Populations (8.4)]. Topiramate treatment that causes metabolic acidosis

during pregnancy can possibly produce adverse effects on the fetus and might also cause metabolic

acidosis in the neonate from possible transfer of topiramate to the fetus [see Warnings and Precautions

(5.7), Use in Specific Populations (8.1)].

Measurement of Serum Bicarbonate in Epilepsy and Migraine Patients

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 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 4 shows absolute and relative risk by indication for all evaluated AEDs.

Table 4: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

Indication

Placebo Patients

Relative Risk:

Risk Difference:

with Events per

1000 Patients

Drug Patients

with Events

per 1000 Patients

Incidence of Events

in Drug

Patients/Incidence in

Placebo Patients

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.

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.

5.6 Cognitive/Neuropsychiatric Adverse Reactions

Topiramate can cause cognitive/neuropsychiatric adverse reactions. 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

Rapid titration rate and higher initial dose were associated with higher incidences of cognitive- related

dysfunction.

In adult epilepsy adjunctive controlled trials, which used rapid titration (100 to 200 mg/day weekly

increments), and target topiramate doses of 200 mg to 1000 mg/day, 56% of patients in the 800 mg/day

and 1000 mg/day dose groups experienced cognitive-related dysfunction compared to approximately

42% of patients in the 200 to 400 mg/day groups and 14% for placebo. In this rapid titration regimen,

these dose-related adverse reactions began in the titration or in the maintenance phase, and in some

patients these events began during titration and persisted into

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 the preventive treatment of migraine, which used 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. Cognitive adverse reactions most

commonly developed during titration and sometimes persisted after completion of titration.

Psychiatric/Behavioral Disturbances

Psychiatric/behavioral disturbances (e.g., depression, mood) were dose-related for both the adjunctive

epilepsy and migraine populations [see Warnings and Precautions (5.5)].

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 fatigue,

appeared dose related. For the monotherapy epilepsy population, the incidence of somnolence was

dose-related. For the migraine population, the incidences of both fatigue and somnolence were dose-

related and more common in the titration phase.

Pediatric Patients

In pediatric epilepsy trials (adjunctive and monotherapy), the incidence of cognitive/neuropsychiatric

adverse reactions was generally lower than that observed in adults. These reactions included

psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech

problems, and language problems. The most frequently reported cognitive/neuropsychiatric reactions in

pediatric epilepsy patients during adjunctive therapy double-blind studies were somnolence and fatigue.

The most frequently reported cognitive/neuropsychiatric reactions in pediatric epilepsy patients in the

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

dizziness, anorexia, and somnolence.

In pediatric migraine patients, the incidence of cognitive/neuropsychiatric adverse reactions was

increased in topiramate-treated patients compared to placebo.

The risk for cognitive/neuropsychiatric adverse reactions was dose-dependent, and was greatest at the

highest dose (200 mg). This risk for cognitive/neuropsychiatric adverse reactions was also greater in

younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age). The most common

cognitive/neuropsychiatric adverse reaction in these trials was difficulty with concentration/attention.

Cognitive adverse reactions most commonly developed during titration and sometimes persisted for

various durations after completion of titration.

The Cambridge Neuropsychological Test Automated Battery (CANTAB) was administered to

adolescents (12 to 17 years) to assess the effects of topiramate on cognitive function at baseline and at

the end of the Study 13 [see Clinical Studies (14.3)]. Mean change from baseline in certain CANTAB

tests suggests that topiramate treatment may result in psychomotor slowing and decreased verbal

fluency.

5.7 Fetal Toxicity

Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy

registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or

cleft palate (oral clefts) and for being small for gestational age (SGA). When multiple species of

pregnant animals received topiramate at clinically relevant doses, structural malformations, including

craniofacial defects, and reduced fetal weights occurred in offspring [see Use in Specific Populations

(8.1)].

Consider the benefits and the risks of topiramate when administering this drug in women of childbearing

potential, particularly when topiramate is considered for a condition not usually associated with

permanent injury or death [see Use in Specific Populations (8.1), Patient Counseling Information (17)].

Topiramate should be used during pregnancy only if the potential benefit outweighs the potential risk. If

this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient

should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

5.8 Withdrawal of Antiepileptic Drugs

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.

5.9 Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use)

Topiramate treatment can cause hyperammonemia with or without encephalopathy [see Adverse Reactions

(6.2)]. The risk for hyperammonemia with topiramate appears dose-related. Hyperammonemia has been

reported more frequently when topiramate is used concomitantly with valproic acid. Postmarketing

cases of hyperammonemia with or without encephalopathy have been reported with topiramate and

valproic acid in patients who previously tolerated either drug alone [see Drug Interactions (7.1)].

Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of

consciousness and/or cognitive function with lethargy and/or vomiting. In most cases, hyperammonemic

encephalopathy abated with discontinuation of treatment.

The incidence of hyperammonemia in pediatric patients 12 to 17 years of age in the preventive treatment

of migraine trials was 26% in patients taking topiramate monotherapy at 100 mg/day, and 14% in

patients taking topiramate at 50 mg/day, compared to 9% in patients taking placebo. There was also an

increased incidence of markedly increased hyperammonemia at the 100 mg dose.

Dose-related hyperammonemia was also seen in pediatric patients 1 to 24 months of age treated with

topiramate and concomitant valproic acid for partial-onset epilepsy and this was not due to a

pharmacokinetic interaction.

In some patients, hyperammonemia can be asymptomatic.

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.

5.10 Kidney Stones

Topiramate increases the risk of kidney stones. During adjunctive epilepsy trials, the risk for kidney

stones in topiramate-treated adults was 1.5%, an incidence about 2 to 4 times greater than expected in a

similar, untreated population. 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 taking topiramate for epilepsy or migraine. During long-term (up to 1 year) topiramate

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

7% developed kidney or bladder stones. Topiramate is not approved for treatment of epilepsy in

pediatric patients less than 2 years old [see Use in Specific Populations (8.4)].

Topiramate is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors 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.

5.11 Hypothermia with Concomitant Valproic Acid Use

Hypothermia, defined as a drop in body core temperature to <35°C (95°F), has been reported in

association with topiramate use with concomitant valproic acid both in conjunction with

hyperammonemia and in the absence of hyperammonemia. This adverse reaction in patients using

concomitant topiramate and valproate can occur after starting topiramate treatment or after increasing the

daily dose of topiramate [see Drug Interactions (7.1)]. Consideration should be given to stopping

topiramate or valproate in patients who develop hypothermia, which may be manifested by a variety

of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other

major organ systems such as the cardiovascular and respiratory systems. Clinical management and

assessment should include examination of blood ammonia levels.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in more detail in other sections of the labeling:

Acute Myopia and Secondary Angle Closure Glaucoma [see Warnings and Precautions

(5.1)]

Visual Field Defects [see Warnings and Precautions (5.2)]

Oligohidrosis and Hyperthermia [see Warnings and Precautions (5.3)]

Metabolic Acidosis [see Warnings and Precautions (5.4)]

Suicidal Behavior and Ideation [see Warnings and Precautions (5.5)]

Cognitive/Neuropsychiatric Adverse Reactions [see Warnings and Precautions (5.6)]

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

[see Warnings and Precautions (5.9)]

Kidney Stones [see Warnings and Precautions (5.10)]

Hypothermia with Concomitant Valproic Acid (VPA) Use [see Warnings and Precautions (5.11)]

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

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the incidence of adverse

reactions observed in the clinical trials of a drug cannot be directly compared to the incidence of

adverse reactions in the clinical trials of another drug, and may not reflect the incidence of adverse

reactions observed in practice.

Monotherapy Epilepsy

Adults 16 Years of Age and Older

The most common adverse reactions in the controlled clinical trial (Study 1) that occurred in adults in

the 400 mg/day topiramate group and at an incidence higher (≥ 10 %) than in the 50 mg/day group

were: paresthesia, weight loss and anorexia (see Table 5).

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

monotherapy in Study 1 discontinued therapy due to adverse reactions. The most common (≥ 2% more

frequent than low-dose 50 mg/day topiramate) adverse reactions causing discontinuation were difficulty

with memory, fatigue, asthenia, insomnia, somnolence, and paresthesia.

Pediatric Patients 6 to 15 Years of Age

The most common adverse reactions in the controlled clinical trial (Study 1) that occurred in pediatric

patients in the 400 mg/day topiramate group and at an incidence higher (≥10%) than in the 50 mg/day

group were fever and weight loss (see Table 5).

Approximately 14% of the 77 pediatric patients in the 400 mg/day group who received topiramate as

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

common (≥2% more frequent than low-dose 50 mg/day topiramate) adverse reactions resulting in

discontinuation were difficulty with concentration/attention, fever, flushing, and confusion.

Table 5 presents the incidence of adverse reactions occurring in at least 3% of adult and pediatric

patients treated with 400 mg/day topiramate and occurring with greater incidence than 50 mg/day

topiramate.

Table 5: Adverse Reactions in the High Dose Group As Compared to the Low Dose Group, in Monotherapy Epilepsy

Trial (Study 1) in Adult and Pediatric Patients

Body System

Adverse Reaction

Age Group

Pediatric

(6 to 15 Years)

Adult

(Age ≥16 Years)

Topiramate Daily Dosage Group (mg/day)

50

400

50

400

(N=74) %

(N=77) %

(N=160) %

(N=159) %

Body as a Whole - General Disorders

Asthenia

Fever

Leg pain

Central & Peripheral Nervous System Disorders

Paresthesia

Dizziness

Ataxia

Hypoesthesia

Hypertonia

Involuntary muscle contractions

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