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TOPAMAX (topiramate) is an FDA-approved antiepileptic medication indicated for monotherapy and adjunctive therapy for various types of seizures and for migraine prophylaxis. The document outlines the drug's indications, dosage, administration, contraindications, warnings, and potential adverse reactions. It also emphasizes the importance of consulting the FDA website for the most current labeling information.

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14 views71 pages

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This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

NDA 020505-S-050 Topamax (topiramate) oral tablets (25mg, 50mg, 100mg and 200mg)
NDA 020844-S-041 Topamax (topiramate) sprinkle capsules (15mg, and 25mg)
FDA Approved Labeling Text dated October 2012
Page 1 of 71

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

HIGHLIGHTS OF PRESCRIBING INFORMATION
• Sprinkle Capsules: 15 mg and 25 mg (3)
These highlights do not include all the information needed to use
TOPAMAX® safely and effectively. See full prescribing information for --------------------------------CONTRAINDICATIONS------------------------------
TOPAMAX® None.
TOPAMAX (topiramate) TABLETS for oral use
---------------------------WARNINGS AND PRECAUTIONS--------------------
TOPAMAX (topiramate capsules) SPRINKLE CAPSULES for oral use • Acute myopia and secondary angle closure glaucoma: Untreated elevated
Initial U.S. Approval – 1996 intraocular pressure can lead to permanent visual loss. The primary
treatment to reverse symptoms is discontinuation of TOPAMAX� as
----------------------------INDICATIONS AND USAGE----------------------------
rapidly as possible (5.1)
TOPAMAX® is an antiepileptic (AED) agent indicated for:
• Oligohidrosis and hyperthermia: Monitor decreased sweating and increased
• Monotherapy epilepsy: Initial monotherapy in patients � 2 years of age body temperature, especially in pediatric patients (5.2)
with partial onset or primary generalized tonicclonic seizures (1.1)
• Metabolic acidosis: Baseline and periodic measurement of serum
• Adjunctive therapy epilepsy: Adjunctive therapy for adults and pediatric bicarbonate is recommended. Consider dose reduction or discontinuation of
patients (2 to 16 years of age) with partial onset seizures or primary
TOPAMAX� if clinically appropriate (5.3)
generalized tonicclonic seizures, and in patients �2 years of age with
• Suicidal behavior and ideation: Antiepileptic drugs increase the risk of
seizures associated with LennoxGastaut syndrome (LGS) (1.2)
suicidal behavior or ideation (5.4)
• Migraine: Treatment for adults for prophylaxis of migraine headache (1.3)
• Cognitive/neuropsychiatric: TOPAMAX� may cause cognitive
-----------------------DOSAGE AND ADMINISTRATION----------------------- dysfunction. Patients should use caution when operating machinery
See DOSAGE AND ADMINISTRATION, Epilepsy: Monotherapy and including automobiles. Depression and mood problems may occur in
Adjunctive Therapy Use for additional details (2.1) epilepsy and migraine populations (5.5)
Recommended • Fetal Toxicity: TOPAMAX� use during pregnancy can cause cleft lip
Initial Dose Titration Dose and/or palate (5.6)
Epilepsy 25 mg/day The dosage should be Daily doses in • Withdrawal of AEDs: Withdrawal of TOPAMAX� should be done
monotherapy: administered titrated over 57 weeks two divided gradually (5.7)
children 2 to <10 nightly for the doses based on • Hyperammonemia and encephalopathy associated with or without
years (2.1) first week weight (Table concomitant valproic acid use: Patients with inborn errors of metabolism or
2) reduced mitochondrial activity may have an increased risk of hyper
Epilepsy 50 mg/day in The dosage should be 400 mg/day in ammonemia. Measure ammonia if encephalopathic symptoms occur (5.9)
monotherapy: two divided increased weekly by two divided • Kidney stones: Use with other carbonic anhydrase inhibitors, other drugs
adults and doses increments of 50 mg doses causing metabolic acidosis, or in patients on a ketogenic diet should be
pediatric patients for the first 4 weeks avoided (5.10)
�10 years (2.1) then 100 mg for • Hypothermia has been reported with and without hyperammonemia during
weeks 5 to 6. topiramate treatment with concomitant valproic acid use (5.11)
Epilepsy 25 to The dosage should be 200400
adjunctive 50 mg/day increased weekly to an mg/day in two ------------------------------ADVERSE REACTIONS------------------------------
therapy: adults effective dose by divided doses The most common (>5% more frequent than placebo or lowdose
with partial onset increments of 25 to TOPAMAX� in monotherapy) adverse reactions in controlled, epilepsy
seizures or LGS 50 mg. clinical trials were paresthesia, anorexia, weight decrease, fatigue, dizziness,
(2.1) somnolence, nervousness, psychomotor slowing, difficulty with memory,
Epilepsy 25 to The dosage should be 400 mg/day in difficulty with concentration/attention, cognitive problems, confusion, mood
adjunctive 50 mg/day increased weekly to an two divided problems, fever, infection, and flushing. The most common (>5% more
therapy: adults effective dose by doses frequent than placebo) adverse reactions in controlled, migraine clinical trials
with primary increments of 25 to were paresthesia and taste perversion (6) .
generalized tonic 50 mg. To report SUSPECTED ADVERSE REACTIONS, contact Janssen
clonic seizures Pharmaceuticals, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-
(2.1) 800-FDA-1088 or WWW.FDA.GOV/MEDWATCH.
Epilepsy 25 mg/day (or The dosage should be 5 to -------------------------------DRUG INTERACTIONS----------------------------
adjunctive less, based on a increased at 1 or 9 mg/kg/day in Summary of antiepileptic drug (AED) interactions with TOPAMAX� (7.1)
therapy: pediatric range of 1 to 2week intervals by two divided
AED Coadministered AED Concentration Topiramate
patients with 3 mg/kg/day) increments of 1 to doses Concentration
partial onset nightly for the 3 mg/kg/day Phenytoin NC or 25% increasea 48% decrease
seizures, primary first week (administered in two Carbamazepine (CBZ) NC 40% decrease
generalized tonic divided doses). Dose CBZ epoxideb NC NE
clonic seizures or titration should be Valproic acid 11% decrease 14% decrease
LGS (2.1) guided by clinical Phenobarbital NC NE
outcome. Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease
Migraine (2.2) 25 mg/day The dosage should be 100 mg/day a
= Plasma concentration increased 25% in some patients, generally those on a twice
administered increased weekly by administered a day dosing regimen of phenytoin.
nightly for the increments of 25 mg. in two divided b
= Is not administered but is an active metabolite of carbamazepine.
first week Dose and titration doses NC = Less than 10% change in plasma concentration.
should be guided by NE = Not Evaluated
clinical outcome.
---------------------DOSAGE FORMS AND STRENGTHS----------------------

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• Oral contraceptives: Decreased contraceptive efficacy and increased • Patients undergoing hemodialysis: Topiramate is cleared by hemodialysis.
breakthrough bleeding should be considered, especially at doses greater Dosage adjustment is necessary to avoid rapid drops in topiramate plasma
than 200 mg/day (7.3) concentration during hemodialysis (2.6)
• Metformin is contraindicated with metabolic acidosis, an effect of • Pregnancy: Increased risk of cleft lip and/or palate. Pregnancy registry
TOPAMAX� (7.4) available (8.1)
• Lithium levels should be monitored when coadministered with highdose • Nursing mothers: Caution should be exercised when administered to a
TOPAMAX� (7.5) nursing mother (8.3)
• Other carbonic anhydrase inhibitors: Monitor the patient for the appearance • Geriatric use: Dosage adjustment may be necessary for elderly with
or worsening of metabolic acidosis (7.6) impaired renal function (8.5)

-----------------------USE IN SPECIFIC POPULATIONS----------------------- See 17 for PATIENT COUNSELING INFORMATION and FDA-
• Renal impairment: In renally impaired patients (creatinine clearance less approved Medication Guide.
than 70 mL/min/1.73 m2), onehalf of the adult dose is recommended (2.4) Revised: 10/2012

6.8 Other Adverse Reactions Observed During

FULL PRESCRIBING INFORMATION: CONTENTS* Migraine Clinical Trials
6.9 Postmarketing and Other Experience
1 INDICATIONS AND USAGE 7 DRUG INTERACTIONS
1.1 Monotherapy Epilepsy 7.1 Antiepileptic Drugs
1.2 Adjunctive Therapy Epilepsy 7.2 CNS Depressants
1.3 Migraine 7.3 Oral Contraceptives
2 DOSAGE AND ADMINISTRATION 7.4 Metformin
2.1 Epilepsy 7.5 Lithium
2.2 Migraine 7.6 Other Carbonic Anhydrase Inhibitors
2.3 Administration of TOPAMAX® Sprinkle Capsules 8 USE IN SPECIFIC POPULATIONS
2.4 Patients with Renal Impairment 8.1 Pregnancy
2.5 Geriatric Patients (Ages 65 Years and Over) 8.2 Labor and Delivery
2.6 Patients Undergoing Hemodialysis 8.3 Nursing Mothers
2.7 Patients with Hepatic Disease 8.4 Pediatric Use
3 DOSAGE FORMS AND STRENGTHS 8.5 Geriatric Use
4 CONTRAINDICATIONS 8.6 Race and Gender Effects
5 WARNINGS AND PRECAUTIONS 8.7 Renal Impairment
5.1 Acute Myopia and Secondary Angle Closure 8.8 Patients Undergoing Hemodialysis
Glaucoma 8.9 Women of Childbearing Potential
5.2 Oligohidrosis and Hyperthermia 9 DRUG ABUSE AND DEPENDENCE
5.3 Metabolic Acidosis 9.1 Controlled Substance
5.4 Suicidal Behavior and Ideation 9.2 Abuse
5.5 Cognitive/Neuropsychiatric Adverse Reactions 9.3 Dependence
5.6 Fetal Toxicity 10 OVERDOSAGE
5.7 Withdrawal of Antiepileptic Drugs (AEDs) 11 DESCRIPTION
5.8 Sudden Unexplained Death in Epilepsy (SUDEP) 12 CLINICAL PHARMACOLOGY
5.9 Hyperammonemia and Encephalopathy (Without 12.1 Mechanism of Action
and With Concomitant Valproic Acid [VPA] Use) 12.2 Pharmacodynamics
5.10 Kidney Stones 12.3 Pharmacokinetics
5.11 Hypothermia with Concomitant Valproic Acid 13 NON-CLINICAL TOXICOLOGY
(VPA) Use 13.1 Carcinogenesis, Mutagenesis, and Impairment of
5.12 Paresthesia Fertility
5.13 Adjustment of Dose in Renal Failure 14 CLINICAL STUDIES
5.14 Decreased Hepatic Function 14.1 Monotherapy Epilepsy Controlled Trial
5.15 Monitoring: Laboratory Tests 14.2 Adjunctive Therapy Epilepsy Controlled Trials
6 ADVERSE REACTIONS 14.3 Migraine Prophylaxis
6.1 Monotherapy Epilepsy 16 HOW SUPPLIED/STORAGE AND HANDLING
6.2 Adjunctive Therapy Epilepsy 17 PATIENT COUNSELING INFORMATION
6.3 Incidence in Epilepsy Controlled Clinical Trials – 17.1 Eye Disorders
Adjunctive Therapy – Partial Onset Seizures, 17.2 Oligohidrosis and Hyperthermia
Primary Generalized Tonic-Clonic Seizures, and 17.3 Metabolic Acidosis
Lennox-Gastaut Syndrome 17.4 Suicidal Behavior and Ideation
6.4 Other Adverse Reactions Observed During 17.5 Interference with Cognitive and Motor
Double-Blind Epilepsy Adjunctive Therapy Trials Performance
6.5 Incidence in Study 119 – Add-On Therapy– 17.6 Fetal Toxicity
Adults with Partial Onset Seizures 17.7 Hyperammonemia and Encephalopathy
6.6 Other Adverse Reactions Observed During All 17.8 Kidney Stones
Epilepsy Clinical Trials
6.7 Migraine

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

Reference ID: 3197087

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FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE
1.1 Monotherapy Epilepsy
TOPAMAX® (topiramate) Tablets and TOPAMAX® (topiramate capsules) Sprinkle Capsules
are indicated as initial monotherapy in patients 2 years of age and older with partial onset or
primary generalized tonicclonic seizures. Safety and effectiveness in patients who were
converted to monotherapy from a previous regimen of other anticonvulsant drugs have not been
established in controlled trials [see Clinical Studies (14.1)].

1.2 Adjunctive Therapy Epilepsy

TOPAMAX� Tablets and TOPAMAX� Sprinkle Capsules are indicated as adjunctive therapy
for adults and pediatric patients ages 2 to 16 years with partial onset seizures or primary
generalized tonicclonic seizures, and in patients 2 years of age and older with seizures
associated with LennoxGastaut syndrome [see Clinical Studies (14.2)].

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

2 DOSAGE AND ADMINISTRATION

2.1 Epilepsy
It is not necessary to monitor topiramate plasma concentrations to optimize TOPAMAX�
(topiramate) therapy.

On occasion, the addition of TOPAMAX� to phenytoin may require an adjustment of the dose of
phenytoin to achieve optimal clinical outcome. Addition or withdrawal of phenytoin and/or
carbamazepine during adjunctive therapy with TOPAMAX� may require adjustment of the dose
of TOPAMAX�.

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

TOPAMAX� can be taken without regard to meals.

Monotherapy Use
Adults and Pediatric Patients 10 Years and Older

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The recommended dose for TOPAMAX® 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 (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

Children Ages 2 to <10 Years

Dosing of topiramate as initial monotherapy in children 2 to < 10 years of age with partial onset
or primary generalized tonicclonic seizures was based on a pharmacometric bridging approach
[see Clinical Studies (14.1)].

Dosing in patients 2 to <10 years is based on weight. During the titration period, the initial dose
of TOPAMAX� should be 25 mg/day administered 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 2550 mg/day each subsequent week as tolerated. Titration to the
minimum maintenance dose should be attempted over 57 weeks of the total titration period.
Based upon tolerability and seizure control, additional titration to a higher dose (up to the
maximum maintenance dose) can be attempted at 2550 mg/day weekly increments. The total
daily dose should not exceed the maximum maintenance dose for each range of body weight
(Table 2).

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Table 2: Monotherapy Target Total Daily Maintenance

Dosing for Patients 2 to <10 Years
Total Daily Dose Total Daily Dose
(mg/day)* (mg/day)*
Weight (kg)
Minimum Maximum
Maintenance Dose Maintenance Dose
Up to 11 150 250
12 22 200 300
23 31 200 350
32 38 250 350
Greater than 38 250 400
* Administered in two equally divided doses

Adjunctive Therapy Use

Adults 17 Years of Age and Over - Partial Onset Seizures, Primary Generalized Tonic-
Clonic Seizures, or Lennox-Gastaut Syndrome
The recommended total daily dose of TOPAMAX� as adjunctive therapy in adults with partial
onset seizures is 200 to 400 mg/day in two divided doses, and 400 mg/day in two divided doses
as adjunctive treatment in adults with primary generalized tonicclonic 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. Doses above 400 mg/day (600, 800 or
1,000 mg/day) have not been shown to improve responses in doseresponse studies in adults with
partial onset seizures. Daily doses above 1,600 mg have not been studied.

In the study of primary generalized tonicclonic seizures, the initial titration rate was slower than
in previous studies; the assigned dose was reached at the end of 8 weeks [see Clinical Studies
(14.1)].

Pediatric Patients Ages 2 - 16 Years – Partial Onset Seizures, Primary Generalized

Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome
The recommended total daily dose of TOPAMAX® as adjunctive therapy for pediatric patients
with partial onset seizures, primary generalized tonicclonic seizures, or seizures associated with
LennoxGastaut 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 2week 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.

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In the study of primary generalized tonicclonic seizures, the initial titration rate was slower than
in previous studies; the assigned dose of 6 mg/kg/day was reached at the end of 8 weeks [see
Clinical Studies (14.1)].

2.2 Migraine
The recommended total daily dose of TOPAMAX® as treatment for adults for prophylaxis of
migraine headache is 100 mg/day administered in two divided doses (Table 3). The
recommended titration rate for topiramate for migraine prophylaxis to 100 mg/day is:

Table 3: Migraine Prophylaxis Titration Schedule for Adults

Morning Dose Evening Dose
Week 1 None 25 mg
Week 2 25 mg 25 mg
Week 3 25 mg 50 mg
Week 4 50 mg 50 mg
Dose and titration rate should be guided by clinical outcome. If required, longer intervals
between dose adjustments can be used.

TOPAMAX® can be taken without regard to meals.

2.3 Administration of TOPAMAX® Sprinkle Capsules

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

2.4 Patients with Renal Impairment

In renally impaired subjects (creatinine clearance less than 70 mL/min/1.73 m2), onehalf of the
usual adult dose is recommended. Such patients will require a longer time to reach steadystate at
each dose.

2.5 Geriatric Patients (Ages 65 Years and Over)

Dosage adjustment may be indicated in the elderly patient when impaired renal function
(creatinine clearance rate <70 mL/min/1.73 m2) is evident [see Clinical Pharmacology (12.3)].

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 antiseizure effect. To avoid rapid drops in topiramate
7

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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

TOPAMAX� (topiramate) Tablets are available as debossed, coated, round tablets in the
following strengths and colors:

25 mg cream (debossed “OMN” on one side; "25" on the other)

50 mg lightyellow (debossed “OMN” on one side; "50" on the other)

100 mg yellow (debossed “OMN” on one side; "100" on the other)

200 mg salmon (debossed “OMN” on one side; "200" on the other)

TOPAMAX� (topiramate capsules) Sprinkle Capsules contain small, white to offwhite spheres.
The gelatin capsules are white and clear.

They are marked as follows:

15 mg capsule with “TOP” and “15 mg” on the side

25 mg capsule with “TOP” and “25 mg” on the side

4 CONTRAINDICATIONS
None.

5 WARNINGS AND PRECAUTIONS

5.1 Acute Myopia and Secondary Angle Closure Glaucoma
A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has
been reported in patients receiving TOPAMAX� (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
8

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effusion resulting in anterior displacement of the lens and iris, with secondary angle closure
glaucoma. Symptoms typically occur within 1 month of initiating TOPAMAX� 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 TOPAMAX® as rapidly
as possible, according to the judgment of the treating physician. Other measures, in conjunction
with discontinuation of TOPAMAX�, 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 TOPAMAX� 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 TOPAMAX� should be monitored closely for evidence of decreased sweating and
increased body temperature, especially in hot weather. Caution should be used when
TOPAMAX� is prescribed with other drugs that predispose patients to heatrelated disorders;
these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with
anticholinergic activity.

5.3 Metabolic Acidosis

Hyperchloremic, nonanion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the
normal reference range in the absence of chronic respiratory alkalosis) is associated with
TOPAMAX� 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 placebocontrolled clinical trials and in the post
marketing period. Generally, topiramateinduced metabolic acidosis occurs early in treatment
although cases can occur at any time during treatment. Bicarbonate decrements are usually
mildmoderate (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,

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

In adults, the incidence of persistent treatmentemergent 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 to 16 years of age), the incidence of persistent treatmentemergent

decreases in serum bicarbonate in placebocontrolled trials for adjunctive treatment of Lennox
Gastaut syndrome or refractory partial onset seizures was 67% for TOPAMAX� (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 TOPAMAX� 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/day topiramateplacebo) 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/day, 50% for 15 mg/kg/day, and 45% for
25 mg/kg/day. The incidence of markedly abnormal changes (i.e., <17 mEq/L and >5 mEq/L
decrease from baseline of >20 mEq/L) was 0% for placebo, 4% for 5 mg/kg/day, 5% for
15 mg/kg/day, and 5% for 25 mg/kg/day [see Use in Special Populations (8.4)].

In pediatric patients (6 to 15 years of age), the incidence of persistent treatmentemergent

decreases in serum bicarbonate in the epilepsy controlled clinical trial for monotherapy was 9%
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 this
10

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trial was 1% for 50 mg/day and 6% for 400 mg/day. In adult patients (>16 years of age), the
incidence of persistent treatmentemergent decreases in serum bicarbonate in the epilepsy
controlled clinical trial for monotherapy was 14% 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 this trial for adults was 1% for 50 mg/day and 6% for
400 mg/day.

The incidence of persistent treatmentemergent decreases in serum bicarbonate in placebo

controlled trials for adults for prophylaxis of migraine 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
bonerelated sequelae has not been systematically investigated in longterm, placebocontrolled
trials. Longterm, openlabel 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 sexmatched 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 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 (5.6) and Use in
Specific Populations (8.1)].

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

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considered.

5.4 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including TOPAMAX�, 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 placebocontrolled 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 placebotreated patients,
representing an increase of approximately one case of suicidal thinking or behavior for every
530 patients treated. There were four suicides in drugtreated patients in the trials and none in
placebotreated 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.

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

Indication Placebo Patients Drug Patients Relative Risk: Risk Difference:
with Events per with Events per Incidence of Additional Drug
1000 Patients 1000 Patients Events in Drug Patients with
Patients/Incidence Events per 1000
in Placebo Patients
Patients
Epilepsy 1.0 3.4 3.5 2.4
Psychiatric 5.7 8.5 1.5 2.9
Other 1.0 1.8 1.9 0.9
Total 2.4 4.3 1.8 1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.

Anyone considering prescribing TOPAMAX� 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, or behavior or thoughts about selfharm. Behaviors of
concern should be reported immediately to healthcare providers.

5.5 Cognitive/Neuropsychiatric Adverse Reactions

Adverse reactions most often associated with the use of TOPAMAX� were related to the central
nervous system and were observed in both the epilepsy and migraine populations. In adults, the
most frequent of these can be classified into three general categories: 1) Cognitiverelated
dysfunction (e.g., confusion, psychomotor slowing, difficulty with concentration/attention,
difficulty with memory, speech or language problems, particularly wordfinding difficulties); 2)
Psychiatric/behavioral disturbances (e.g., depression or mood problems); and 3) Somnolence or
fatigue.

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Adult Patients
Cognitive-Related Dysfunction
The majority of cognitiverelated 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 addon epilepsy controlled trials (using rapid titration such as 100200 mg/day weekly
increments), the proportion of patients who experienced one or more cognitiverelated adverse
reactions was 42% for 200 mg/day, 41% for 400 mg/day, 52% for 600 mg/day, 56% for 800 and
1,000 mg/day, and 14% for placebo. These doserelated 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 cognitiverelated adverse reactions in the titration phase had a doserelated recurrence of
these reactions in the maintenance phase.

In the monotherapy epilepsy controlled trial, the proportion of patients who experienced one or
more cognitiverelated adverse reactions was 19% for TOPAMAX® 50 mg/day and 26% for 400
mg/day.

In the 6month migraine prophylaxis controlled trials using a slower titration regimen
(25 mg/day weekly increments), the proportion of patients who experienced one or more
cognitiverelated adverse reactions was 19% for TOPAMAX� 50 mg/day, 22% for 100 mg/day
(the recommended dose), 28% for 200 mg/day, and 10% for placebo. These doserelated 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 topiramatetreated 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, topiramatetreated patients
experienced three concurrent cognitive reactions.

Psychiatric/Behavioral Disturbances
Psychiatric/behavioral disturbances (depression or mood) were doserelated for both the epilepsy
and migraine populations [see Warnings and Precautions (5.4)].

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Somnolence/Fatigue
Somnolence and fatigue were the adverse reactions most frequently reported during clinical trials
of TOPAMAX� for adjunctive epilepsy. For the adjunctive epilepsy population, the incidence of
somnolence did not differ substantially between 200 mg/day and 1,000 mg/day, but the incidence
of fatigue was doserelated 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
doserelated (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 the migraine population,
fatigue and somnolence were doserelated and more common in the titration phase.

Additional nonspecific CNS events commonly observed with topiramate in the addon epilepsy
population included dizziness or ataxia.

Pediatric Patients
In doubleblind 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 doubleblind 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 doubleblind study were headache, dizziness, anorexia, and somnolence.

No patients discontinued treatment due to any adverse reactions in the adjunctive epilepsy
doubleblind trials. In the monotherapy epilepsy doubleblind 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 reactions. 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 Fetal Toxicity

TOPAMAX� 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). 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 TOPAMAX� when administering this drug in women of

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childbearing potential, particularly when TOPAMAX� is considered for a condition not usually
associated with permanent injury or death [see Use in Specific Populations (8.9) and Patient
Counseling Information (17.8)]. TOPAMAX� 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) and (8.9)].

5.7 Withdrawal of Antiepileptic Drugs (AEDs)

In patients with or without a history of seizures or epilepsy, antiepileptic drugs, including
TOPAMAX®, should be gradually withdrawn to minimize the potential for seizures or increased
seizure frequency [see Clinical Studies (14)]. In situations where rapid withdrawal of
TOPAMAX® is medically required, appropriate monitoring is recommended.

5.8 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 (2796 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
TOPAMAX® (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 TOPAMAX� program, to 0.005 for patients
with refractory epilepsy).

5.9 Hyperammonemia and Encephalopathy (Without and With Concomitant

Valproic Acid [VPA] Use)
Hyperammonemia/Encephalopathy Without Concomitant Valproic Acid (VPA)
Topiramate treatment has produced hyperammonemia (in some instances doserelated) in clinical
investigational programs of adolescents (1216 years) who were treated with topiramate
monotherapy for migraine prophylaxis (incidence above the upper limit of normal, 22% for
placebo, 26% for 50 mg/day, 41% for 100 mg/day) 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). TOPAMAX� is not
approved as monotherapy for migraine prophylaxis 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 adolescent patients,

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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 placebocontrolled trials and in an openlabel,
extension trial. Doserelated 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 postmarketing
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 postmarketing 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 TOPAMAX� is not indicated for use in infants/toddlers (124 months), TOPAMAX®
with concomitant VPA clearly produced a doserelated increase 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, doserelated 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. Doserelated
hyperammonemia was similarly observed in a longterm 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 postmarketing
reports in patients taking topiramate with 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,
17

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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

A total of 32/2086 (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 doubleblind 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 topiramatetreated patients
was higher in men. Kidney stones have also been reported in pediatric patients. During longterm
(up to 1 year) topiramate treatment in an openlabel 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. TOPAMAX� is not approved for pediatric patients less than 2 years
old [see Use in Specific Populations (8.4)].

An explanation for the association of TOPAMAX� 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 (5.3)]. The concomitant
use of TOPAMAX® 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 (VPA) Use

Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has
been reported in association with topiramate use with concomitant valproic acid (VPA) 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

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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.

5.12 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 TOPAMAX�. Paresthesia was
more frequently reported in the monotherapy epilepsy trials and migraine prophylaxis trials than
in the adjunctive therapy epilepsy trials. In the majority of instances, paresthesia did not lead to
treatment discontinuation.

5.13 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 (2.4)].

5.14 Decreased Hepatic Function

In hepatically impaired patients, TOPAMAX� should be administered with caution as the
clearance of topiramate may be decreased [see Dosage and Administration (2.7)].

5.15 Monitoring: Laboratory Tests

Topiramate treatment was associated with changes in several clinical laboratory analytes in
randomized, doubleblind, placebocontrolled studies.

Topiramate treatment causes nonanion gap, hyperchloremic metabolic acidosis manifested by a

decrease in serum bicarbonate and an increase in serum chloride. Measurement of baseline and
periodic serum bicarbonate during TOPAMAX� treatment is recommended [see Warnings and
Precautions (5.3)].

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 values (i.e., increased creatinine, BUN, alkaline

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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 Use in Specific Populations (8.4)].

Topiramate treatment produced a doserelated increased shift in serum creatinine from normal at
baseline to an increased value at the end of 4 months treatment in adolescent patients (ages 1216
years) who were treated for migraine prophylaxis in a doubleblind, placebocontrolled study.

TOPAMAX� treatment with or without concomitant valproic acid (VPA) can cause
hyperammonemia with or without encephalopathy [see Warnings and Precautions (5.9)].

6 ADVERSE REACTIONS
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed in practice.

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

• Acute Myopia and Secondary Angle Closure [see Warnings and Precautions (5.1)]
• Oligohidrosis and Hyperthermia [see Warnings and Precautions (5.2)]
• Metabolic Acidosis [see Warnings and Precautions (5.3)]
• Suicidal Behavior and Ideation [see Warnings and Precautions (5.4)]
• Cognitive/Neuropsychiatric Adverse Reactions [see Warnings and Precautions (5.5)]
• Fetal Toxicity [see Warnings and Precautions (5.6) and Use in Specific Populations
(8.1)]
• Withdrawal of Antiepileptic Drugs (AEDs) [see Warnings and Precautions (5.7)]
• Sudden Unexplained Death in Epilepsy (SUDEP) [see Warnings and Precautions (5.8)]
• 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)]
• Paresthesia [see Warnings and Precautions (5.12)]

The data described in the following sections were obtained using TOPAMAX� (topiramate)
Tablets.

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6.1 Monotherapy Epilepsy

Adults ≥16 Years
The adverse reactions in the controlled trial that occurred most commonly in adults in the 400
mg/day TOPAMAX� group and at a rate higher (> 5 %) than in the 50 mg/day group were:
paresthesia, weight decrease, anorexia, somnolence, and difficulty with memory (see Table 5).

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. The
most common (> 2% more frequent than lowdose 50 mg/day TOPAMAX� ) adverse reactions
causing discontinuation in this trial were difficulty with memory, fatigue, asthenia, insomnia,
somnolence, and paresthesia.

Pediatric Patients 6 to <16 Years of Age

The adverse reactions in the controlled trial that occurred most commonly in pediatric patients in
the 400 mg/day TOPAMAX� group and at a rate higher (> 5%) than in the 50 mg/day group
were fever, weight decrease, mood problems, cognitive problems, infection, flushing, and
paresthesia (see Table 5).

Approximately 14% of the 77 pediatric patients in the 400 mg/day group who received
TOPAMAX® as monotherapy in the controlled clinical trial discontinued therapy due to adverse
reactions. The most common (> 2% more frequent than lowdose 50 mg/day TOPAMAX� )
adverse reactions resulting in discontinuation in this trial were difficulty with
concentration/attention, fever, flushing, and confusion.

Table 5: Incidence of TreatmentEmergent Adverse Reactions in Monotherapy Epilepsy Where the

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Table 5: Incidence of TreatmentEmergent Adverse Reactions in Monotherapy Epilepsy Where the

Rate Was at Least 2% in Any TOPAMAX® Group and the Rate in the 400 mg/day TOPAMAX®
Group Was Greater Than the Rate in the 50 mg/day TOPAMAX® Group for Adults (>16 Years) and
Pediatric (6 to <16 Years) Patients in Study TOPMAXEPMN106
Age Group
Pediatric Adult
(6 to <16 Years) (Age ≥16 Years)
TOPAMAX® Daily Dosage Group (mg/day)
50 400 50 400
Body System (N=74) (N=77) (N=160) (N=159)
Adverse Reaction %* %* %* %*
Central & Peripheral Nervous System Disorders
Ataxia 3 4
Dizziness 13 14
Hypertonia 0 3
Hypoesthesia 4 5
Muscle contractions involuntary 0 3
Paresthesia 3 12 21 40
Vertigo 0 3
Gastro-Intestinal System Disorders
Constipation 1 4
Diarrhea 8 9
Gastritis 0 3
Gastroesophageal reflux 1 2
Dry mouth 1 3
Liver and Biliary System Disorders
GammaGT increased 1 3
Metabolic and Nutritional Disorders
Weight decrease 7 17 6 17
Platelet, Bleeding & Clotting Disorders
Epistaxis 0 4
Psychiatric Disorders
Anorexia 4 14
Anxiety 4 6
Cognitive problems 1 6 1 4
Confusion 0 3
Depression 0 3 7 9
Difficulty with 7 10 7 8
concentration/attention
Difficulty with memory 1 3 6 11
Insomnia 8 9
Libido decreased 0 3
Mood problems 1 8 2 5
Personality disorder(behavior 0 3
problems)
Psychomotor slowing 3 5
Somnolence 10 15
Red Blood Cell Disorders
Anemia 1 3
Reproductive Disorders, Female†
Intermenstrual Bleeding 0 3
Vaginal Hemorrhage 0 3
Resistance Mechanism Disorders
Infection 3 8 2 3
Infection viral 3 6 6 8
Respiratory System Disorders
Bronchitis 1 5 3 4

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Table 5: Incidence of TreatmentEmergent Adverse Reactions in Monotherapy Epilepsy Where the

Rate Was at Least 2% in Any TOPAMAX® Group and the Rate in the 400 mg/day TOPAMAX®
Group Was Greater Than the Rate in the 50 mg/day TOPAMAX® Group for Adults (>16 Years) and
Pediatric (6 to <16 Years) Patients in Study TOPMAXEPMN106
Age Group
Pediatric Adult
(6 to <16 Years) (Age ≥16 Years)
TOPAMAX® Daily Dosage Group (mg/day)
50 400 50 400
Body System (N=74) (N=77) (N=160) (N=159)
Adverse Reaction %* %* %* %*
Dyspnea 1 2
Rhinitis 5 6 2 4
Sinusitis 1 4
Upper respiratory tract infection 16 18
Skin and Appendages Disorders
Acne 2 3
Alopecia 1 4 3 4
Pruritus 1 4
Rash 3 4 1 4
Special Senses Other, Disorders
Taste perversion 3 5
Urinary System Disorders
Cystitis 1 3
Dysuria 0 2
Micturition frequency 0 3 0 2
Renal calculus 0 3
Urinary incontinence 1 3
Urinary tract infection 1 2
Vascular (Extracardiac) Disorders
Flushing 0 5
*Percentages calculated with the number of subjects in each group as denominator
†
N with Female Reproductive Disorders – Incidence calculated relative to the number of females;
Pediatric TPM 50 mg n=40; Pediatric TPM 400 mg n=33; Adult TPM 50 mg n=84; TPM 400 mg
n=80

6.2 Adjunctive Therapy Epilepsy

The most commonly observed adverse reactions associated with the use of TOPAMAX® at
dosages of 200 to 400 mg/day in controlled trials in adults with partial onset seizures, primary
generalized tonicclonic seizures, or LennoxGastaut syndrome, that were seen at greater
frequency in TOPAMAX®treated patients and did not appear to be doserelated were
somnolence, dizziness, ataxia, speech disorders and related speech problems, psychomotor
slowing, abnormal vision, difficulty with memory, paresthesia and diplopia (see Table 6). The
most common doserelated 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 8).

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

controlled trials in pediatric patients with partial onset seizures, primary generalized tonicclonic

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seizures, or LennoxGastaut syndrome, that were seen at greater frequency in TOPAMAX®

treated patients were fatigue, somnolence, anorexia, nervousness, difficulty with
concentration/attention, difficulty with memory, aggressive reaction, and weight decrease (see
Table 9).

In controlled clinical trials in adults, 11% of patients receiving TOPAMAX® 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 reactions 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 TOPAMAX® adjunctive therapy at 5 to 9 mg/kg/day in controlled clinical trials
discontinued due to adverse reactions.

Approximately 28% of the 1757 adults with epilepsy who received TOPAMAX® 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
TOPAMAX® 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 6 lists treatmentemergent adverse reactions that occurred in at least 1% of adults treated
with 200 to 400 mg/day TOPAMAX� 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 9 lists treatmentemergent adverse reactions that occurred in at least 1% of
pediatric patients treated with 5 to 9 mg/kg TOPAMAX� in controlled trials that were
numerically more common than in patients treated with placebo.

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The prescriber should be aware that these data were obtained when TOPAMAX� 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 nondrug
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
TOPAMAX� in placebocontrolled 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 6: Incidence of TreatmentEmergent Adverse Reactions in PlaceboControlled,

AddOn Epilepsy Trials in Adultsa,b Where Incidence Was >1% in Any
TOPAMAX� Group and Greater Than the Rate in PlaceboTreated Patients
TOPAMAX� Dosage (mg/day)
Body System/ Placebo 200400 6001,000
Adverse Reactionc (N=291) (N=183) (N=414)
Body as a Whole-General Disorders
Fatigue 13 15 30
Asthenia 1 6 3
Back pain 4 5 3
Chest pain 3 4 2
Influenzalike symptoms 2 3 4
Leg pain 2 2 4
Hot flushes 1 2 1
Allergy 1 2 3
Edema 1 2 1
Body odor 0 1 0
Rigors 0 1 <1
Central & Peripheral Nervous System Disorders
Dizziness 15 25 32
Ataxia 7 16 14
Speech disorders/Related speech problems 2 13 11
Paresthesia 4 11 19
Nystagmus 7 10 11
Tremor 6 9 9
Language problems 1 6 10
Coordination abnormal 2 4 4
Hypoesthesia 1 2 1
Gait abnormal 1 3 2
Muscle contractions involuntary 1 2 2

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TOPAMAX� Dosage (mg/day)

Body System/ Placebo 200400 6001,000
Adverse Reactionc (N=291) (N=183) (N=414)
Stupor 0 2 1
Vertigo 1 1 2
Gastro-Intestinal System Disorders
Nausea 8 10 12
Dyspepsia 6 7 6
Abdominal pain 4 6 7
Constipation 2 4 3
Gastroenteritis 1 2 1
Dry mouth 1 2 4
Gingivitis <1 1 1
GI disorder <1 1 0
Hearing and Vestibular Disorders
Hearing decreased 1 2 1
Metabolic and Nutritional Disorders
Weight decrease 3 9 13
Muscle-Skeletal System Disorders
Myalgia 1 2 2
Skeletal pain 0 1 0
Platelet, Bleeding, & Clotting Disorders
Epistaxis 1 2 1
Psychiatric Disorders
Somnolence 12 29 28
Nervousness 6 16 19
Psychomotor slowing 2 13 21
Difficulty with memory 3 12 14
Anorexia 4 10 12
Confusion 5 11 14
Depression 5 5 13
Difficulty with concentration/attention 2 6 14
Mood problems 2 4 9
Agitation 2 3 3
Aggressive reaction 2 3 3
Emotional lability 1 3 3
Cognitive problems 1 3 3
Libido decreased 1 2 <1
Apathy 1 1 3
Depersonalization 1 1 2
Reproductive Disorders, Female
Breast pain 2 4 0
Amenorrhea 1 2 2
Menorrhagia 0 2 1
Menstrual disorder 1 2 1
Reproductive Disorders, Male
Prostatic disorder <1 2 0
Resistance Mechanism Disorders
Infection 1 2 1
Infection viral 1 2 <1
Moniliasis <1 1 0
Respiratory System Disorders
Pharyngitis 2 6 3
Rhinitis 6 7 6
Sinusitis 4 5 6
Dyspnea 1 1 2
Skin and Appendages Disorders
Skin disorder <1 2 1

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TOPAMAX� Dosage (mg/day)

Body System/ Placebo 200400 6001,000
Adverse Reactionc (N=291) (N=183) (N=414)
Sweating increased <1 1 <1
Rash erythematous <1 1 <1
Special Sense Other, Disorders
Taste perversion 0 2 4
Urinary System Disorders
Hematuria 1 2 <1
Urinary tract infection 1 2 3
Micturition frequency 1 1 2
Urinary incontinence <1 2 1
Urine abnormal 0 1 <1
Vision Disorders
Vision abnormal 2 13 10
Diplopia 5 10 10
White Cell and RES Disorders
Leukopenia 1 2 1
a
Patients in these addon/ adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs
in addition to TOPAMAX® or placebo.
b
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.
c
Adverse reactions reported by at least 1% of patients in the TOPAMAX® 200400 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, doubleblind, addon/adjunctive, placebocontrolled, parallel group
study with 3 treatment arms: 1) placebo; 2) TOPAMAX� 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) TOPAMAX� 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 7) did not differ significantly between the 2
TOPAMAX� 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 7: Incidence of TreatmentEmergent Adverse Reactions in Study 119a,b Where

Incidence Was � 2% in the TOPAMAX� Group and Greater Than the Rate in
PlaceboTreated Patients
TOPAMAX�
Dosage (mg/day)

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Body System/ Placebo 200

Adverse Reactionc (N=92) (N=171)
Body as a Whole-General Disorders
Fatigue 4 9
Chest pain 1 2
Cardiovascular Disorders, General
Hypertension 0 2
Central & Peripheral Nervous System Disorders
Paresthesia 2 9
Dizziness 4 7
Tremor 2 3
Hypoesthesia 0 2
Leg cramps 0 2
Language problems 0 2
Gastro-Intestinal System Disorders
Abdominal pain 3 5
Constipation 0 4
Diarrhea 1 2
Dyspepsia 0 2
Dry mouth 0 2
Hearing and Vestibular Disorders
Tinnitus 0 2
Metabolic and Nutritional Disorders
Weight decrease 4 8
Psychiatric Disorders
Somnolence 9 15
Anorexia 7 9
Nervousness 2 9
Difficulty with concentration/attention 0 5
Insomnia 3 4
Difficulty with memory 1 2
Aggressive reaction 0 2
Respiratory System Disorders
Rhinitis 0 4
Urinary System Disorders
Cystitis 0 2
Vision Disorders
Diplopia 0 2
Vision abnormal 0 2
a
Patients in these addon/adjunctive trials were receiving 1 to 2 concomitant
antiepileptic drugs in addition to TOPAMAX® or placebo.
b
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.
c
Adverse reactions reported by at least 2% of patients in the TOPAMAX® 200 mg/day
group and more common than in the placebo group are listed in this table.

Table 8: Incidence (%) of DoseRelated Adverse Reactions From PlaceboControlled, AddOn

Trials in Adults With Partial Onset Seizuresa
TOPAMAX® Dosage (mg/day)
Placebo 200 400 600 1,000

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Adverse Reaction (N = 216) (N = 45) (N = 68) (N = 414)

Fatigue 13 11 12 30
Nervousness 7 13 18 19
Difficulty with 1 7 9 14
concentration/attention
Confusion 4 9 10 14
Depression 6 9 7 13
Anorexia 4 4 6 12
Language problems <1 2 9 10
Anxiety 6 2 3 10
Mood problems 2 0 6 9
Weight decrease 3 4 9 13
a
Doseresponse studies were not conducted for other adult indications or for pediatric
indications.

Table 9: Incidence (%) of TreatmentEmergent Adverse Reactions in PlaceboControlled, AddOn

Epilepsy Trials in Pediatric Patients (Ages 2 16 Years)a,b (Reactions That Occurred in at
Least 1% of TOPAMAX�Treated Patients and Occurred More Frequently in
TOPAMAX®Treated Than PlaceboTreated Patients)

Body System/ Placebo TOPAMAX®

Adverse Reaction (N=101) (N=98)
Body as a Whole - General Disorders
Fatigue 5 16
Injury 13 14
Allergic reaction 1 2
Back pain 0 1
Pallor 0 1
Cardiovascular Disorders, General
Hypertension 0 1
Central & Peripheral Nervous System Disorders
Gait abnormal 5 8
Ataxia 2 6
Hyperkinesia 4 5
Dizziness 2 4
Speech disorders/Related speech problems 2 4
Hyporeflexia 0 2
Convulsions grand mal 0 1
Fecal incontinence 0 1
Paresthesia 0 1
Gastro-Intestinal System Disorders
Nausea 5 6
Saliva increased 4 6
Constipation 4 5
Gastroenteritis 2 3
Dysphagia 0 1
Flatulence 0 1
Gastroesophageal reflux 0 1
Glossitis 0 1
Gum hyperplasia 0 1
Heart Rate and Rhythm Disorders
Bradycardia 0 1

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Body System/ Placebo TOPAMAX®

Adverse Reaction (N=101) (N=98)
Metabolic and Nutritional Disorders
Weight decrease 1 9
Thirst 1 2
Hypoglycemia 0 1
Weight increase 0 1
Platelet, Bleeding, & Clotting Disorders
Purpura 4 8
Epistaxis 1 4
Hematoma 0 1
Prothrombin increased 0 1
Thrombocytopenia 0 1
Psychiatric Disorders
Somnolence 16 26
Anorexia 15 24
Nervousness 7 14
Personality disorder (behavior problems) 9 11
Difficulty with concentration/attention 2 10
Aggressive reaction 4 9
Insomnia 7 8
Difficulty with memory 0 5
Confusion 3 4
Psychomotor slowing 2 3
Appetite increased 0 1
Neurosis 0 1
Reproductive Disorders, Female
Leukorrhea 0 2
Resistance Mechanism Disorders
Infection viral 3 7
Respiratory System Disorders
Pneumonia 1 5
Respiratory disorder 0 1
Skin and Appendages Disorders
Skin disorder 2 3
Alopecia 1 2
Dermatitis 0 2
Hypertrichosis 1 2
Rash erythematous 0 2
Eczema 0 1
Seborrhea 0 1
Skin discoloration 0 1
Urinary System Disorders
Urinary incontinence 2 4
Nocturia 0 1
Vision Disorders
Eye abnormality 1 2
Vision abnormal 1 2
Diplopia 0 1
Lacrimation abnormal 0 1
Myopia 0 1

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Body System/ Placebo TOPAMAX®

Adverse Reaction (N=101) (N=98)
White Cell and RES Disorders
Leukopenia 0 2
a
Patients in these addon/adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in
addition to TOPAMAX® or placebo.
b
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.

6.6 Other Adverse Reactions Observed During All Epilepsy Clinical Trials
TOPAMAX� has been administered to 2246 adults and 427 pediatric patients with epilepsy
during all clinical studies, only some of which were placebocontrolled. 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
reactions, 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 TOPAMAX�. 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, hyperesthesia,
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.

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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.

6.7 Migraine
In the four multicenter, randomized, doubleblind, placebocontrolled, parallel group migraine

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prophylaxis clinical trials, most of the adverse reactions with TOPAMAX� were mild or
moderate in severity. Most adverse reactions occurred more frequently during the titration period
than during the maintenance period.

Table 10 includes those adverse reactions reported for patients in the placebocontrolled trials
where the incidence in any TOPAMAX� treatment group was at least 2% and was greater than
that for placebo patients.

Table 10: Incidence of TreatmentEmergent Adverse Reactions in PlaceboControlled,

Migraine Trials Where Incidence Was �2 % in Any TOPAMAX� Group and
Greater Than the Rate in PlaceboTreated Patients a
TOPAMAX� Dosage (mg/day)
Body System/ Placebo 50 100 200
Adverse Reaction (N=445) (N=235) (N=386) (N=514)
Body as a Whole-General Disorders
Fatigue 11 14 15 19
Injury 7 9 6 6
Asthenia 1 <1 2 2
Fever 1 1 1 2
Influenzalike symptoms <1 <1 <1 2
Allergy <1 2 <1 <1
Central & Peripheral Nervous System Disorders
Paresthesia 6 35 51 49
Dizziness 10 8 9 12
Hypoesthesia 2 6 7 8
Language problems 2 7 6 7
Involuntary muscle contractions 1 2 2 4
Ataxia <1 1 2 1
Speech disorders/Related speech <1 1 <1 2
problems
Gastro-Intestinal System Disorders
Nausea 8 9 13 14
Diarrhea 4 9 11 11
Abdominal pain 5 6 6 7
Dyspepsia 3 4 5 3
Dry mouth 2 2 3 5
Vomiting 2 1 2 3
Gastroenteritis 1 3 3 2
Hearing and Vestibular Disorders
Tinnitus 1 <1 1 2
Metabolic and Nutritional Disorders
Weight decrease 1 6 9 11
Thirst <1 2 2 1
Musculoskeletal System Disorders
Arthralgia 2 7 3 1
Neoplasms
Neoplasm <1 2 <1 <1
Psychiatric Disorders
Anorexia 6 9 15 14

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TOPAMAX� Dosage (mg/day)

Body System/ Placebo 50 100 200
Adverse Reaction (N=445) (N=235) (N=386) (N=514)
Somnolence 5 8 7 10
Difficulty with memory 2 7 7 11
Difficulty with concentration/ 2 3 6 10
attention
Insomnia 5 6 7 6
Anxiety 3 4 5 6
Mood problems 2 3 6 5
Depression 4 3 4 6
Nervousness 2 4 4 4
Confusion 2 2 3 4
Psychomotor slowing 1 3 2 4
Libido decreased 1 1 1 2
Aggravated depression 1 1 2 2
Agitation 1 2 2 1
Cognitive problems 1 <1 2 2
Reproductive Disorders, Female
Menstrual disorder 2 3 2 2
Reproductive Disorders, Male
Ejaculation premature 0 3 0 0
Resistance Mechanism Disorders
Viral infection 3 4 4 3
Otitis media <1 2 1 1
Respiratory System Disorders
Upper respiratory tract infection 12 13 14 12
Sinusitis 6 10 6 8
Pharyngitis 4 5 6 2
Coughing 2 2 4 3
Bronchitis 2 3 3 3
Dyspnea 2 1 3 2
Rhinitis 1 1 2 2
Skin and Appendages Disorders
Pruritis 2 4 2 2
Special Sense Other, Disorders
Taste perversion 1 15 8 12
Taste loss <1 1 1 2
Urinary System Disorders
Urinary tract infection 2 4 2 4
Renal calculus 0 0 1 2
Vision Disorders
Vision abnormal <1 1 2 3
Blurred vision b 2 4 2 4
Conjunctivitis 1 1 2 1
a
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.
b
Blurred vision was the most common term considered as vision abnormal. Blurred
vision was an included term that accounted for >50% of reactions coded as vision
abnormal, a preferred term.
Of the 1135 patients exposed to TOPAMAX® in the placebocontrolled studies, 25%
34

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discontinued due to adverse reactions, compared to 10% of the 445 placebo patients. The adverse
reactions associated with discontinuing therapy in the TOPAMAX® treated patients included
paresthesia (7%), fatigue (4%), nausea (4%), difficulty with concentration/attention (3%),
insomnia (3%), anorexia (2%), and dizziness (2%).

Patients treated with TOPAMAX® experienced mean percent reductions in body weight that
were dosedependent. This change was not seen in the placebo group. Mean changes of 0%, 2%,
3%, and 4% were seen for the placebo group, TOPAMAX® 50, 100, and 200 mg groups,
respectively.

Table 11 shows adverse reactions that were dosedependent. Several central nervous system
adverse reactions, including some that represented cognitive dysfunction, were doserelated. The
most common doserelated adverse reactions were paresthesia, fatigue, nausea, anorexia,
dizziness, difficulty with memory, diarrhea, weight decrease, difficulty with
concentration/attention, and somnolence.

Table 11: Incidence (%) of DoseRelated Adverse Reactions From PlaceboControlled,

Migraine Trialsa
TOPAMAX® Dosage (mg/day)
Placebo 50 100 200
Adverse Reaction (N=445) (N=235) (N=386) (N=514)
Paresthesia 6 35 51 49
Fatigue 11 14 15 19
Nausea 8 9 13 14
Anorexia 6 9 15 14
Dizziness 10 8 9 12
Weight decrease 1 6 9 11
Difficulty with memory 2 7 7 11
Diarrhea 4 9 11 11
Difficulty with concentration/ 2 3 6 10
attention
Somnolence 5 8 7 10
Hypoesthesia 2 6 7 8
Anxiety 3 4 5 6
Depression 4 3 4 6
Mood problems 2 3 6 5
Dry mouth 2 2 3 5
Confusion 2 2 3 4
Involuntary muscle 1 2 2 4
contractions
Abnormal vision <1 1 2 3
Renal calculus 0 0 1 2
a
The incidence of adverse reactions in the 200 mg/day group was � 2% than the
incidence in both the placebo group and the 50 mg/day group.

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6.8 Other Adverse Reactions Observed During Migraine Clinical Trials

TOPAMAX�, for the treatment of prophylaxis of migraine headache, has been administered to
1367 patients in all clinical studies (includes doubleblind and openlabel extension). 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 reactions, similar types of reactions were grouped into a smaller number of standardized
categories using modified WHOART dictionary terminology.

The following additional adverse reactions that were not described earlier were reported by
greater than 1% of the 1367 TOPAMAX�treated patients in the controlled clinical trials:

Body as a Whole: Pain, chest pain, allergic reaction.

Central & Peripheral Nervous System Disorders: Headache, vertigo, tremor, sensory
disturbance, migraine aggravated.

Gastrointestinal System Disorders: Constipation, gastroesophageal reflux.

Musculoskeletal System Disorders: Myalgia.

Platelet, Bleeding, and Clotting Disorders: Epistaxis.

Reproductive Disorders, Female: Intermenstrual bleeding.

Resistance Mechanism Disorders: Infection, genital moniliasis.

Respiratory System Disorders: Pneumonia, asthma.

Skin and Appendages Disorders: Rash, alopecia.

Vision Disorders: Abnormal accommodation, eye pain.

6.9 Postmarketing and Other Experience

In addition to the adverse experiences reported during clinical testing of TOPAMAX�, the
following adverse experiences have been reported worldwide in patients receiving TOPAMAX�
postapproval.

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, StevensJohnson syndrome, toxic epidermal

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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 (12.3).

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 TOPAMAX® given alone [see Clinical Pharmacology (12.3).]

Concomitant administration of valproic acid and TOPAMAX® has been associated with
hyperammonemia with and without encephalopathy. Concomitant administration of
TOPAMAX® with valproic acid has also been associated with hypothermia (with and without
hyperammonemia) in patients who have tolerated either drug alone. It may be prudent to
examine blood ammonia levels in patients in whom the onset of hypothermia has been reported
[see Warnings and Precautions (5.9), (5.11) or Clinical Pharmacology (12.3)].

7.2 CNS Depressants

Concomitant administration of TOPAMAX� 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, TOPAMAX�
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 TOPAMAX® 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), TOPAMAX®, given in the absence of other medications at doses
37

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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 TOPAMAX®. Patients taking estrogencontaining
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 (12.3)].

7.4 Metformin
Topiramate treatment can frequently cause metabolic acidosis, a condition for which the use of
metformin is contraindicated [see Clinical Pharmacology (12.3)].

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
Cmax and 26% for AUC) following topiramate doses of up to 600 mg/day. Lithium levels should
be monitored when coadministered with highdose TOPAMAX® [see Clinical Pharmacology
(12.3)].

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 TOPAMAX� is given concomitantly with another carbonic anhydrase inhibitor, the
patient should be monitored for the appearance or worsening of metabolic acidosis [see Clinical
Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy
Pregnancy Category D. [see Warnings and Precautions (5.6)]
TOPAMAX� (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). When multiple species of pregnant animals
received topiramate at clinically relevant doses, structural malformations, including craniofacial
defects, and reduced fetal weights occurred in offspring. TOPAMAX� should be used during
pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during

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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 (8.9)].

Pregnancy Registry
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 tollfree number 1
8882332334. Information about the North American Drug Pregnancy Registry can be found at
http://www.massgeneral.org/aed/.

Human Data
Data from the NAAED Pregnancy Registry indicate an increased risk of oral clefts in infants
exposed to topiramate monotherapy during the first trimester of pregnancy. The prevalence of
oral clefts was 1.2% compared to a prevalence of 0.39% 0.46% in infants exposed to other
AEDs, and a prevalence of 0.12% in infants of mothers without epilepsy or treatment with other
AEDs. For comparison, the Centers for Disease Control and Prevention (CDC) reviewed
available data on oral clefts in the United States and found a similar background rate of 0.17%.
The relative risk of oral clefts in topiramateexposed pregnancies in the NAAED Pregnancy
Registry was 9.6 (95% Confidence Interval = CI 3.6 – 25.7) as compared to the risk in a
background population of untreated women. The UK Epilepsy and Pregnancy Register reported
a similarly increased prevalence of oral clefts of 3.2% among infants exposed to topiramate
monotherapy. The observed rate of oral clefts was 16 times higher than the background rate in
the UK, which is approximately 0.2%.

TOPAMAX® treatment can cause metabolic acidosis [see Warnings and Precautions (5.3)]. The
effect of topiramateinduced metabolic acidosis has not been studied in pregnancy; however,
metabolic acidosis in pregnancy (due to other causes) can cause 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 (5.3)]. Newborns of mothers treated with TOPAMAX®
should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and
possible occurrence of transient metabolic acidosis following birth.

Animal Data
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

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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/m2 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/m2 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/m2 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/m2 basis) or
greater, and teratogenic effects (primarily rib and vertebral malformations) were observed at
120 mg/kg (6 times the RHD on a mg/m2 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/m2 basis) and reductions in pre
and/or postweaning body weight gain at 2 mg/kg (0.05 times the RHD on a mg/m2 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/m2 basis) and persistent reductions in body weight gain at 30 mg/kg
(1 times the RHD on a mg/m2 basis) and higher.

8.2 Labor and Delivery

Although the effect of TOPAMAX� on labor and delivery in humans has not been established,
the development of topiramateinduced metabolic acidosis in the mother and/or in the fetus
might affect the fetus’ ability to tolerate labor [see Use in Specific Populations (8.1)].

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8.3 Nursing Mothers

Limited data on 5 breastfeeding infants exposed to topiramate showed infant plasma topiramate
levels equal to 1020% 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 tonicclonic seizures,
or seizures associated with LennoxGastaut syndrome. In a single randomized, doubleblind,
placebocontrolled 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 were assessed. After 20 days of
doubleblind treatment, topiramate (at fixed doses of 5, 15, and 25 mg/kg/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 openlabel, longterm 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 than 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
41

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related. Creatinine was the only analyte showing a noteworthy increased incidence (topiramate
25 mg/kg/day 5%, placebo 0%) of a markedly abnormal increase [see Warnings and Precautions
(5.15)]. The significance of these findings is uncertain.

Topiramate treatment also produced a doserelated 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/day, 9% for 15 mg/kg/day, 14% for 25 mg/kg/day, and 11% for any
topiramate dose [see Warnings and Precautions (5.15)]. There was a mean doserelated increase
in alkaline phosphatase. The significance of these findings is uncertain.

Topiramate produced a doserelated increased incidence of treatmentemergent

hyperammonemia [see Warnings and Precautions (5.9)].

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 (5.3) and Adverse
Reactions (6)].

In openlabel, 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 doserelated. However, because of the absence of an appropriate control group, it is
not known if this decrement in function was treatmentrelated 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 openlabel, 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 <2 Years Old

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

Migraine Prophylaxis in Pediatrics

Safety and effectiveness in pediatric patients have not been established for the prophylaxis
treatment of migraine headache.

Topiramate treatment produced a doserelated increased shift in serum creatinine from normal at
42

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baseline to an increased value at the end of 4 months treatment in adolescent patients (ages 12
16 years) who were treated for migraine prophylaxis in a doubleblind, placebocontrolled study.
The incidence of these abnormal shifts was 4% for placebo, 4% for 50 mg, and 18% for 100 mg
[see Warnings and Precautions (5.15)].

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 58 times the maximum recommended
pediatric dose (9 mg/kg/day) on a body surface area (mg/m2) basis.

8.5 Geriatric Use

In clinical trials, 3% of patients were over 60. No agerelated differences 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 m2) 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 genderrelated
effects.

8.7 Renal Impairment

The clearance of topiramate was reduced by 42% in moderately renally impaired (creatinine
clearance 30 to 69 mL/min/1.73m2) and by 54% in severely renally impaired subjects (creatinine
clearance <30 mL/min/1.73m2) compared to normal renal function subjects (creatinine clearance
>70 mL/min/1.73m2). Onehalf 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 (12.3)].

8.8 Patients Undergoing Hemodialysis

Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than in a normal
individual. Accordingly, a prolonged period of dialysis may cause topiramate concentration to
fall below that required to maintain an antiseizure effect. To avoid rapid drops in topiramate
plasma concentration during hemodialysis, a supplemental dose of TOPAMAX® may be
required.
43

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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 (12.3)].

8.9 Women of Childbearing Potential

Data from pregnancy registries indicate that infants exposed to TOPAMAX� in utero have an
increased risk for cleft lip and/or cleft palate (oral clefts) [see Warnings and Precautions (5.6)
and Use in Specific Populations (8.1)]. Consider the benefits and the risks of TOPAMAX� when
prescribing this drug to women of childbearing potential, particularly when TOPAMAX� is
considered for a condition not usually associated with permanent injury or death. Because of the
risk of oral clefts to the fetus, which occur in the first trimester of pregnancy before many
women know they are pregnant, all women of childbearing potential should be apprised of the
potential hazard to the fetus from exposure to TOPAMAX�. If the decision is made to use
TOPAMAX�, women who are not planning a pregnancy should use effective contraception [see
Drug Interactions (7.3)]. Women who are planning a pregnancy should be counseled regarding
the relative risks and benefits of TOPAMAX� use during pregnancy, and alternative therapeutic
options should be considered for these patients [see Patient Counseling Information (17.6)].

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance
TOPAMAX� (topiramate) is not a controlled substance.

9.2 Abuse
The abuse and dependence potential of TOPAMAX� has not been evaluated in human studies.

9.3 Dependence
TOPAMAX� has not been systematically studied in animals or humans for its potential for
tolerance or physical dependence.

10 OVERDOSAGE
Overdoses of TOPAMAX� 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 TOPAMAX�.

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Topiramate overdose has resulted in severe metabolic acidosis [see Warnings and Precautions
(5.3)].

A patient who ingested a dose between 96 and 110 g topiramate was admitted to a hospital with a
coma lasting 20 to 24 hours followed by full recovery after 3 to 4 days.

In acute TOPAMAX® 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 sulfamatesubstituted monosaccharide. TOPAMAX� (topiramate) Tablets are
available as 25 mg, 50 mg, 100 mg, and 200 mg round tablets for oral administration.
TOPAMAX� (topiramate capsules) Sprinkle Capsules are available as 15 mg and 25 mg sprinkle
capsules for oral administration as whole capsules or opened and sprinkled onto soft food.

Topiramate 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
C12H21NO8S and a molecular weight of 339.36. Topiramate is designated chemically as 2,3:4,5
DiOisopropylidene�Dfructopyranose sulfamate and has the following structural formula:

O CH2OSO2NH2
O O
H3C CH3
O O
H3C CH3

TOPAMAX� Tablets contain the following inactive ingredients: lactose monohydrate,

pregelatinized starch, microcrystalline cellulose, sodium starch glycolate, magnesium stearate,
purified water, carnauba wax, hypromellose, titanium dioxide, polyethylene glycol, synthetic
iron oxide, and polysorbate 80.

TOPAMAX� Sprinkle Capsules contain topiramatecoated beads in a hard gelatin capsule. The
inactive ingredients are sugar spheres (sucrose and starch), povidone, cellulose acetate, gelatin,

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sorbitan monolaurate, sodium lauryl sulfate, titanium dioxide, and black pharmaceutical ink.

12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The precise mechanisms by which topiramate exerts its anticonvulsant and migraine prophylaxis
effects are unknown; however, preclinical studies have revealed four properties that may
contribute to topiramate's efficacy for epilepsy and migraine prophylaxis. Electrophysiological
and biochemical evidence suggests that topiramate, at pharmacologically relevant
concentrations, blocks voltagedependent sodium channels, augments the activity of the
neurotransmitter gammaaminobutyrate at some subtypes of the GABAA 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 GABAA
receptor antagonist, pentylenetetrazole. Topiramate is also effective in rodent models of epilepsy,
which include tonic and absencelike 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
The sprinkle formulation is bioequivalent to the immediaterelease tablet formulation and,
therefore, may be substituted as a therapeutic equivalent.

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
halflife is 21 hours after single or multiple doses. Steadystate 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

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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
adults following oral administration.

Special Populations
Renal Impairment
The clearance of topiramate was reduced by 42% in moderately renally impaired (creatinine
clearance 30 to 69 mL/min/1.73m2) and by 54% in severely renally impaired subjects (creatinine
clearance <30 mL/min/1.73m2) compared to normal renal function subjects (creatinine clearance
>70 mL/min/1.73m2). 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 onehalf 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 (5.13)].

Hemodialysis
Topiramate is cleared by hemodialysis. Using a highefficiency, 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

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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 halflife 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 m2) is evident. It may be useful to monitor renal
function in the elderly patient [see Dosage and Administration (2.4) and Warnings and
Precautions (5.13)].

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

Pediatric Pharmacokinetics
Pharmacokinetics of topiramate were evaluated in patients aged 2 to <16 years. Patients received
either no or a combination of other antiepileptic drugs. A population pharmacokinetic model was
developed on the basis of pharmacokinetic data from relevant topiramate clinical studies. This
dataset contained data from 1217 subjects including 258 pediatric patients aged 2 to <16 years
(95 pediatric patients <10 years of age).

Pediatric patients on adjunctive treatment exhibited a higher oral clearance (L/h) of topiramate
compared to patients on monotherapy, presumably because of increased clearance from
concomitant enzymeinducing antiepileptic drugs. In comparison, topiramate clearance per kg is
greater in pediatric patients than in adults and in young pediatric patients (down to 2 years) than
in older pediatric patients. Consequently, the plasma drug concentration for the same mg/kg/day
dose would be lower in pediatric patients compared to adults and also in younger pediatric
patients compared to older pediatric patients. Clearance was independent of dose.

As in adults, hepatic enzymeinducing antiepileptic drugs decrease the steady state plasma
concentrations of topiramate.

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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 Table 12.

In Table 12, 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 TOPAMAX�
was given alone.

Table 12: Summary of AED Interactions with TOPAMAX�

AED AED Topiramate
Coadministered Concentration Concentration
Phenytoin NC or 25% increasea 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxideb NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up 13% decrease
to 400 mg/day
a
= Plasma concentration increased 25% in some patients, generally those on a twice a day
dosing regimen of phenytoin.
b
= Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
AED = Antiepileptic drug.
NE = Not Evaluated.
TPM = Topiramate
In addition to the pharmacokinetic interaction described in the above table, concomitant
administration of valproic acid and TOPAMAX® has been associated with hyperammonemia
with and without encephalopathy and hypothermia [see Warnings and Precautions (5.9), (5.11)
and Drug Interactions (7.1)].

CNS Depressants
Concomitant administration of TOPAMAX� and alcohol or other CNS depressant drugs has not
been evaluated in clinical studies. Because of the potential of TOPAMAX� to cause CNS
depression, as well as other cognitive and/or neuropsychiatric adverse reactions, TOPAMAX®
should be used with extreme caution if used in combination with alcohol and other CNS
depressants [see Drug Interactions (7.2)].

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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), TOPAMAX�, 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,
TOPAMAX� (50 mg/day to 800 mg/day) did not significantly affect exposure to NET. Although
there was a dosedependent decrease in EE exposure for doses between 200 and 800 mg/day,
there was no significant dosedependent 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 TOPAMAX�. 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 singledose study, serum digoxin AUC was decreased by 12% with concomitant
TOPAMAX� administration. The clinical relevance of this observation has not been established.

Hydrochlorothiazide
A drugdrug interaction study conducted in healthy volunteers evaluated the steadystate
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
Cmax 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 steadystate 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

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metformin is contraindicated.

A drugdrug interaction study conducted in healthy volunteers evaluated the steadystate

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 Cmax and AUC012h
increased by 17% and 25%, respectively, when topiramate was added. Topiramate did not affect
metformin tmax. 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 drugdrug interaction study conducted in healthy volunteers evaluated the steadystate
pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A
15% decrease in the AUC�,ss of pioglitazone with no alteration in Cmax,ss was observed. This
finding was not statistically significant. In addition, a 13% and 16% decrease in Cmax,ss and
AUC�,ss respectively, of the active hydroxymetabolite was noted as well as a 60% decrease in
Cmax,ss and AUC�,ss of the active ketometabolite. The clinical significance of these findings is not
known. When TOPAMAX� is added to pioglitazone therapy or pioglitazone is added to
TOPAMAX� therapy, careful attention should be given to the routine monitoring of patients for
adequate control of their diabetic disease state.

Glyburide
A drugdrug 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 Cmax and a 25% reduction in AUC24 for glyburide during
topiramate administration. Systemic exposure (AUC) of the active metabolites, 4transhydroxy
glyburide (M1) and 3cishydroxyglyburide (M2), was also reduced by 13% and 15%, and Cmax
was reduced by 18% and 25%, respectively. The steadystate 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 Cmax and 26% for AUC) following topiramate doses up to 600 mg/day. Lithium levels
should be monitored when coadministered with highdose TOPAMAX� [see Drug Interactions
51

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(7.5)].

Haloperidol
The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following
multiple 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 Cmax 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 singledose sumatriptan either orally (100 mg)
or subcutaneously (6 mg).

Risperidone
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
9hydroxyrisperidone levels were observed. Coadministration of topiramate 400 mg/day with
risperidone resulted in a 14% increase in Cmax and a 12% increase in AUC12 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

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200 mg/day dose of topiramate in the same study.

Diltiazem
Coadministration of diltiazem (240 mg Cardizem CD�) with topiramate (150 mg/day) resulted
in a 10% decrease in Cmax and a 25% decrease in diltiazem AUC, a 27% decrease in Cmax and an
18% decrease in desacetyl diltiazem AUC, and no effect on Ndesmethyl diltiazem. Co
administration of topiramate with diltiazem resulted in a 16% increase in Cmax and a 19%
increase in AUC12 of topiramate.

Venlafaxine
Multiple dosing of topiramate (150 mg/day) in healthy volunteers did not affect the
pharmacokinetics of venlafaxine or Odesmethyl 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 TOPAMAX® is given concomitantly with another carbonic anhydrase inhibitor, the
patient should be monitored for the appearance or worsening of metabolic acidosis [see Drug
Interactions (7.6)].

Drug/Laboratory Tests Interactions

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

13 NON-CLINICAL 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 steadystate
exposures measured in patients receiving topiramate monotherapy at the recommended human
dose (RHD) of 400 mg, and 1.5 to 2 times steadystate 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

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topiramate for 2 years at doses up to 120 mg/kg (approximately 3 times the RHD on a mg/m2
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/m2 basis).

14 CLINICAL STUDIES
The studies described in the following sections were conducted using TOPAMAX� (topiramate)
Tablets.

14.1 Monotherapy Epilepsy Controlled Trial

Patients with Partial Onset or Primary Generalized Tonic-Clonic Seizures
Adults and Pediatric Patients 10 Years of Age and Older
The effectiveness of topiramate as initial monotherapy in adults and children 10 years of age and
older with partial onset or primary generalized tonicclonic seizures was established in a
multicenter, randomized, doubleblind, parallelgroup trial.

The trial was conducted in 487 patients diagnosed with epilepsy (6 to 83 years of age) who had 1
or 2 welldocumented seizures during the 3month retrospective baseline phase who then entered
the study and received topiramate 25 mg/day for 7 days in an openlabel fashion. Fortynine
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 doubleblind 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. Fiftyeight 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 betweengroup comparison of time to first seizure during the
doubleblind phase. Comparison of the KaplanMeier 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

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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: KaplanMeier Estimates of Cumulative Rates for Time to First Seizure

0.50
Cumulative Rates for Time to First Seizure Topiramate 50 mg/day (N=234)
Topiramate 400 mg/day (N=236)

0.40

0.30

0.20

0.10
p = 0.0002

0.00
0 50 100 150 200 250 300 350 400 450 500

Time (Days)

Children 2 to <10 Years of Age

The conclusion that topiramate is effective as initial monotherapy in children 2 to <10 years of
age with partial onset or primary generalized tonicclonic seizures was based on a
pharmacometric bridging approach using data from the controlled epilepsy trials described in
labeling. This approach consisted of first showing a similar exposure response relationship
between pediatric patients down to 2 years of age and adults when topiramate was given as
adjunctive therapy. Similarity of exposureresponse was also demonstrated in pediatric patients
ages 6 to <16 years and adults when topiramate was given as initial monotherapy. Specific
dosing in children 2 to <10 years of age was derived from simulations utilizing plasma exposure
ranges observed in pediatric and adult patients treated with topiramate initial monotherapy [see
Dosage and Administration (2.1)].

14.2 Adjunctive Therapy Epilepsy Controlled Trials

Adult 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, doubleblind, placebocontrolled 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.

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Patients in these studies were permitted a maximum of two antiepileptic drugs (AEDs) in
addition to TOPAMAX® 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 12week baseline, 8
for 8week baseline or 3 for 4week baseline) were randomly assigned to placebo or a specified
dose of TOPAMAX® tablets in addition to their other AEDs.

Following randomization, patients began the doubleblind 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 13.

Pediatric Patients Ages 2 to 16 Years with Partial Onset Seizures

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, doubleblind,
placebocontrolled 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 TOPAMAX� tablets or placebo. In this study, patients were stabilized on optimum dosages of
their concomitant AEDs during an 8week 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 TOPAMAX� tablets in addition to their other AEDs.

Following randomization, patients began the doubleblind phase of treatment. Patients received
active drug beginning at 25 or 50 mg/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/day was reached, unless intolerance
prevented increases. After titration, patients entered an 8week stabilization period.

Patients With Primary Generalized Tonic-Clonic Seizures

The effectiveness of topiramate as an adjunctive treatment for primary generalized tonicclonic

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seizures in patients 2 years old and older was established in a multicenter, randomized, double
blind, placebocontrolled 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 TOPAMAX� or placebo. Patients were stabilized on optimum dosages of their concomitant
AEDs during an 8week baseline phase. Patients who experienced at least three primary
generalized tonicclonic seizures during the baseline phase were randomly assigned to placebo or
TOPAMAX� in addition to their other AEDs.

Following randomization, patients began the doubleblind phase of treatment. Patients received
active drug beginning at 50 mg/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/day was reached, unless
intolerance prevented increases. After titration, patients entered a 12week stabilization period.

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, doubleblind, 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 TOPAMAX� 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
TOPAMAX� in addition to their other AEDs. Active drug was titrated beginning at 1 mg/kg/day
for a week; the dose was then increased to 3 mg/kg/day for one week, then to 6 mg/kg/day.
After titration, patients entered an 8week stabilization period. The primary measures of
effectiveness were the percent reduction in drop attacks and a parental global rating of seizure
severity.

Table 13: Topiramate Dose Summary During the Stabilization Periods of Each of Six Double-
Blind, Placebo-Controlled, Add-On Trials in Adults with Partial Onset Seizuresa
Target Topiramate Dosage (mg/day)
Protocol Stabilization Placebob 200 400 600 800 1,000
Dose

YD N 42 42 40 41
Mean Dose 5.9 200 390 556
Median Dose 6.0 200 400 600

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YE N 44 40 45 40
Mean Dose 9.7 544 739 796
Median Dose 10.0 600 800 1,000

Y1 N 23 19
Mean Dose 3.8 395
Median Dose 4.0 400

Y2 N 30 28
Mean Dose 5.7 522
Median Dose 6.0 600

Y3 N 28 25
Mean Dose 7.9 568
Median Dose 8.0 600

119 N 90 157
Mean Dose 8 200
Median Dose 8 200
a
Doseresponse studies were not conducted for other indications or pediatric partial onset seizures.
b
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; Protocols Y3 and 119, 8 tablets/day; Protocol YE, 10
tablets/day.

In all addon trials, the reduction in seizure rate from baseline during the entire doubleblind
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 14. As described above, a global improvement in seizure severity was also
assessed in the LennoxGastaut trial.

Table 14: Efficacy Results in Double-Blind, Placebo-Controlled, Add-On Epilepsy Trials

Target Topiramate Dosage (mg/day)
Placebo 200 400 600 800 1,000 �6
Protocol Efficacy Results mg/kg/day*
Partial Onset Seizures
Studies in Adults
YD N 45 45 45 46
Median % Reduction 11.6 27.2a 47.5b 44.7c
% Responders 18 24 44d 46d
YE N 47 48 48 47
Median % Reduction 1.7 40.8c 41.0c 36.0c
% Responders 9 40c 41c 36d
Y1 N 24 23
Median % Reduction 1.1 40.7e
% Responders 8 35d
Y2 N 30 30
Median % Reduction 12.2 46.4f
% Responders 10 47c
Y3 N 28 28
Median % Reduction 20.6 24.3c
% Responders 0 43c
119 N 91 168
Median % Reduction 20.0 44.2c
% Responders 24 45c

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Studies in Pediatric Patients

YP N 45 41
Median % Reduction 10.5 33.1d
% Responders 20 39
Primary Generalized
TonicClonich
YTC N 40 39
Median % Reduction 9.0 56.7d
% Responders 20 56c
LennoxGastaut Syndromei
YL N 49 46
Median % Reduction 5.1 14.8d
% Responders 14 28g
Improvement in Seizure 28 52d
j
Severity
Comparisons with placebo: a p=0.080; b p<0.010; c p<0.001; d p<0.050; e p=0.065; f p<0.005;g p=0.071;
h
Median % reduction and % responders are reported for PGTC Seizures;
i
Median % reduction and % responders for drop attacks, i.e., tonic or atonic seizures;
j
Percent of subjects who were minimally, much, or very much improved from baseline

* For Protocols YP and YTC, protocolspecified 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 400 mg/day.

Subset analyses of the antiepileptic efficacy of TOPAMAX� 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/day in adults and over a 2 to 8week period in children; transition was permitted to a
new antiepileptic regimen when clinically indicated.

14.3 Migraine Prophylaxis

The results of 2 multicenter, randomized, doubleblind, placebocontrolled, parallelgroup
clinical trials established the effectiveness of TOPAMAX� in the prophylactic treatment of
migraine headache. The design of both trials (one study was conducted in the U.S. and one study
was conducted in the U.S. and Canada) was identical, enrolling patients with a history of
migraine, with or without aura, for at least 6 months, according to the International Headache
Society diagnostic criteria. Patients with a history of cluster headaches or basilar,
ophthalmoplegic, hemiplegic, or transformed migraine headaches were excluded from the trials.
Patients were required to have completed up to a 2week washout of any prior migraine
preventive medications before starting the baseline phase.

Patients who experienced 3 to 12 migraine headaches over the 4 weeks in the baseline phase
were equally randomized to either TOPAMAX� 50 mg/day, 100 mg/day, 200 mg/day, or
placebo and treated for a total of 26 weeks (8week titration period and 18week maintenance

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period). Treatment was initiated at 25 mg/day for one week, and then the daily dosage was
increased by 25 mg increments each week until reaching the assigned target dose or maximum
tolerated dose (administered twice daily).

Effectiveness of treatment was assessed by the reduction in migraine headache frequency, as

measured by the change in 4week migraine rate from the baseline phase to doubleblind
treatment period in each TOPAMAX� treatment group compared to placebo in the IntentTo
Treat (ITT) population.

In the first study, a total of 469 patients (416 females, 53 males), ranging in age from 13 to
70 years, were randomized and provided efficacy data. Two hundred sixtyfive patients
completed the entire 26week doubleblind phase. The median average daily dosages were 47.8
mg/day, 88.3 mg/day, and 132.1 mg/day in the target dose groups of TOPAMAX® 50, 100, and
200 mg/day, respectively.

The mean migraine headache frequency rate at baseline was approximately 5.5 migraine
headaches/28 days and was similar across treatment groups. The change in the mean 4week
migraine headache frequency from baseline to the doubleblind phase was 1.3, 2.1, and 2.2 in
the TOPAMAX� 50, 100, and 200 mg/day groups, respectively, versus 0.8 in the placebo group
(see Figure 2). The differences between the TOPAMAX� 100 and 200 mg/day groups versus
placebo were statistically significant (p<0.001 for both comparisons).

In the second study, a total of 468 patients (406 females, 62 males), ranging in age from 12 to
65 years, were randomized and provided efficacy data. Two hundred fiftyfive patients
completed the entire 26week doubleblind phase. The median average daily dosages were
46.5 mg/day, 85.6 mg/day, and 150.2 mg/day in the target dose groups of TOPAMAX� 50, 100,
and 200 mg/day, respectively.

The mean migraine headache frequency rate at baseline was approximately 5.5 migraine
headaches/28 days and was similar across treatment groups. The change in the mean 4week
migraine headache period frequency from baseline to the doubleblind phase was 1.4, 2.1, and
2.4 in the TOPAMAX� 50, 100, and 200 mg/day groups, respectively, versus 1.1 in the
placebo group (see Figure 2). The differences between the TOPAMAX� 100 and 200 mg/day
groups versus placebo were statistically significant (p=0.008 and p <0.001, respectively).

In both studies, there were no apparent differences in treatment effect within age or gender
subgroups. Because most patients were Caucasian, there were insufficient numbers of patients

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from different races to make a meaningful comparison of race.

For patients withdrawing from TOPAMAX�, daily dosages were decreased in weekly intervals
by 25 to 50 mg/day.

Figure 2: Reduction in 4Week Migraine Headache Frequency

(Studies TOPMATMIGR001 and TOPMATMIGR002)

16 HOW SUPPLIED/STORAGE AND HANDLING

TOPAMAX� Tablets
TOPAMAX� (topiramate) Tablets are available as debossed, coated, round tablets in the
following strengths and colors:

25 mg cream tablet (debossed “OMN” on one side; "25" on the other) and are available in bottles
of 60 count with desiccant (NDC 5045863965)

50 mg light yellow tablet (debossed “OMN” on one side; "50" on the other) and are available in
bottles of 60 count with desiccant (NDC 5045864065)

100 mg yellow tablet (debossed “OMN” on one side; "100" on the other) and are available in
bottles of 60 count with desiccant (NDC 5045864165)

200 mg salmon tablet (debossed “OMN” on one side; "200" on the other) and are available in
bottles of 60 count with desiccant (NDC 5045864265)

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TOPAMAX� Sprinkle Capsules

TOPAMAX� (topiramate capsules) Sprinkle Capsules contain small, white to offwhite spheres.
The gelatin capsules are white and clear and are marked as follows:

15 mg capsule with “TOP” and “15 mg” on the side and are available in bottles of 60 (NDC
5045864765)

25 mg capsule with “TOP” and “25 mg” on the side and are available in bottles of 60 (NDC
5045864565)

Storage and Handling

TOPAMAX� Tablets should be stored in tightlyclosed containers at controlled room
temperature (59° to 86°F, 15° to 30°C). Protect from moisture.

TOPAMAX� Sprinkle Capsules should be stored in tightlyclosed containers at or below 25°C

(77°F). 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 TOPAMAX�. Patients
should be instructed to take TOPAMAX� only as prescribed. See FDAapproved Medication
Guide.

17.1 Eye Disorders

Patients taking TOPAMAX� 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 Oligohidrosis and Hyperthermia

Patients, especially pediatric patients, treated with TOPAMAX� should be monitored closely for
evidence of decreased sweating and increased body temperature, especially in hot weather.
Patients should be counseled to contact their healthcare professionals immediately if they
develop a high or persistent fever, or decreased sweating [see Warnings and Precautions (5.2)].

17.3 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

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growth (e.g., growth delay/retardation) in pediatric patients, and on the fetus [see Warnings and
Precautions (5.3) and Use in Specific Populations (8.1)].

17.4 Suicidal Behavior and Ideation

Patients, their caregivers, and families should be counseled that AEDs, including TOPAMAX�,
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, or behavior or thoughts
about selfharm. Behaviors of concern should be reported immediately to healthcare providers
[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, or visual effects and should be advised not to drive or operate machinery until
they have gained sufficient experience on TOPAMAX� to gauge whether it adversely affects
their mental performance, motor performance, and/or vision [see Warnings and Precautions
(5.5)].

Even when taking TOPAMAX� or other anticonvulsants, some patients with epilepsy will
continue to have unpredictable seizures. Therefore, all patients taking TOPAMAX� 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 Fetal Toxicity

Inform pregnant women and women of childbearing potential that use of TOPAMAX� during
pregnancy can cause fetal harm, including an increased risk for cleft lip and/or cleft palate (oral
clefts), which occur early in pregnancy before many women know they are pregnant. There may
also be risks to the fetus from chronic metabolic acidosis with use of TOPAMAX� during
pregnancy [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1), (8.9)].
When appropriate, prescribers should counsel pregnant women and women of childbearing
potential about alternative therapeutic options. This is particularly important when TOPAMAX�
use is considered for a condition not usually associated with permanent injury or death.

Reference ID: 3197087

This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda

Prescribers should advise women of childbearing potential who are not planning a pregnancy to
use effective contraception while using TOPAMAX�, keeping in mind that there is a potential
for decreased contraceptive efficacy when using estrogencontaining birth control with
topiramate [see Drug Interactions (7.3)].

Encourage pregnant women using TOPAMAX�, to enroll in the North American Antiepileptic
Drug (NAAED) Pregnancy Registry. The registry is collecting information about the safety of
antiepileptic drugs during pregnancy. To enroll, patients can call the tollfree number, 1888
2332334. Information about the North American Drug Pregnancy Registry can be found at
http://www.massgeneral.org/aed/ [see Use in Specific Populations (8.1)].

17.7 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 TOPAMAX� treatment alone or with TOPAMAX� 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 (5.9)].

17.8 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 (5.10)].

Manufactured by: Janssen Ortho, LLC, Gurabo, Puerto Rico 00778

Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560

Revised October 2012

Reference ID: 3197087

This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda

MEDICATION GUIDE
TOPAMAX® (TOE-PA-MAX)
(topiramate)
Tablets and Sprinkle Capsules
Read this Medication Guide before you start taking TOPAMAX® 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
TOPAMAX®, talk to your healthcare provider or pharmacist.

What is the most important information I should know about TOPAMAX®?

TOPAMAX® 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.
TOPAMAX® 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. Call
your healthcare provider right away if you have a high fever, a fever that does not go away, or
decreased sweating.
TOPAMAX® 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 TOPAMAX®. If you are pregnant, you should talk to your
healthcare provider about whether you have metabolic acidosis.

Reference ID: 3197087

This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda

Like other antiepileptic drugs, TOPAMAX® 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 TOPAMAX® without first talking to a healthcare provider.

• Stopping TOPAMAX® 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 followup visits with your healthcare provider as scheduled.
• Call your healthcare provider between visits as needed, especially if you are worried about
symptoms.

TOPAMAX® can harm your unborn baby.

• If you take TOPAMAX® 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.

Reference ID: 3197087

This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda

• 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 TOPAMAX®. If the decision is made to use TOPAMAX®, 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 TOPAMAX®.
• Tell your healthcare provider right away if you become pregnant while taking TOPAMAX®.
You and your healthcare provider should decide if you will continue to take TOPAMAX®
while you are pregnant.
• Metabolic acidosis may have harmful effects on your baby. Talk to your healthcare provider
if TOPAMAX® has caused metabolic acidosis during your pregnancy.
• Pregnancy Registry: If you become pregnant while taking TOPAMAX®, talk to your
healthcare provider about registering with the North American Antiepileptic Drug Pregnancy
Registry. You can enroll in this registry by calling 18882332334. The purpose of this
registry is to collect information about the safety of antiepileptic drugs during pregnancy.

What is TOPAMAX®?
TOPAMAX® is a prescription medicine used:
• to treat certain types of seizures (partial onset seizures and primary generalized tonicclonic
seizures) in adults and children 2 years and older,
• with other medicines to treat certain types of seizures (partial onset seizures, primary
generalized tonicclonic seizures, and seizures associated with LennoxGastaut syndrome) in
adults and children 2 years and older,
• to prevent migraine headaches in adults.

What should I tell my healthcare provider before taking TOPAMAX®?

Before taking TOPAMAX®, 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, have kidney stones, or are getting kidney dialysis
• have a history of metabolic acidosis (too much acid in the blood)
• have liver problems

Reference ID: 3197087

This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda

• 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. TOPAMAX® passes into breast milk. It is not known if the TOPAMAX®
that passes into breast milk can harm your baby. Talk to your healthcare provider about the
best way to feed your baby if you take TOPAMAX®.

Tell your healthcare provider about all the medicines you take, including prescription and non
prescription medicines, vitamins, and herbal supplements. TOPAMAX® 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. TOPAMAX® 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 TOPAMAX®.
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 TOPAMAX®?

• Take TOPAMAX® exactly as prescribed.
• Your healthcare provider may change your dose. Do not change your dose without talking to
your healthcare provider.
• TOPAMAX® Tablets should be swallowed whole. Do not chew the tablets. They may leave a
bitter taste.
68

Reference ID: 3197087

This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda

• TOPAMAX® Sprinkle Capsules may be swallowed whole or may be opened and sprinkled
on a teaspoon of soft food. Drink fluids right after eating the food and medicine mixture to
make sure it is all swallowed.
• Do not store any medicine and food mixture for later use.
• TOPAMAX® can be taken before, during, or after a meal. Drink plenty of fluids during the
day. This may help prevent kidney stones while taking TOPAMAX®.
• If you take too much TOPAMAX®, call your healthcare provider or poison control center
right away or go to the nearest emergency room.
• If you miss a single dose of TOPAMAX®, 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
TOPAMAX®, 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 TOPAMAX® without talking to your healthcare provider. Stopping
TOPAMAX® suddenly may cause serious problems. If you have epilepsy and you stop
taking TOPAMAX® suddenly, you may have seizures that do not stop. Your healthcare
provider will tell you how to stop taking TOPAMAX® slowly.
• Your healthcare provider may do blood tests while you take TOPAMAX®.

What should I avoid while taking TOPAMAX®?

• Do not drink alcohol while taking TOPAMAX®. TOPAMAX® 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 TOPAMAX® affects you.
TOPAMAX® can slow your thinking and motor skills, and may affect vision.

What are the possible side effects of TOPAMAX®?

TOPAMAX® may cause serious side effects including:
See “What is the most important information I should know about TOPAMAX®?”
• Metabolic acidosis. Metabolic acidosis can cause:
o tiredness
o loss of appetite
o irregular heartbeat
o 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

Reference ID: 3197087

This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda

TOPAMAX® is taken with a medicine called valproic acid (DEPAKENE® and

DEPAKOTE®).
• Low body temperature. Taking TOPAMAX® when you are also taking valproic acid can
cause a drop in body temperature to less than 95°F, feeling tired, confusion, or coma.
• Kidney stones. Drink plenty of fluids when taking TOPAMAX® to decrease your chances of
getting kidney stones.
• Effects on thinking and alertness. TOPAMAX® may affect how you think and cause
confusion, problems with concentration, attention, memory, or speech. TOPAMAX® 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 TOPAMAX® 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 TOPAMAX®. 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
800FDA1088.

You may also report side effects to Janssen Pharmaceuticals, Inc. at 1800JANSSEN (1800
5267736).

How should I store TOPAMAX®?

• Store TOPAMAX® Tablets at room temperature, 59°F to 86°F (15°C to 30°C).
• Store TOPAMAX® Sprinkle Capsules at or below 77°F (25°C).
70

Reference ID: 3197087

This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda

• Keep TOPAMAX® in a tightly closed container.

• Keep TOPAMAX® dry and away from moisture.
• Keep TOPAMAX® and all medicines out of the reach of children.

General information about TOPAMAX®.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use TOPAMAX® for a condition for which it was not prescribed. Do not give
TOPAMAX® 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 TOPAMAX®. If you
would like more information, talk with your healthcare provider. You can ask your pharmacist or
healthcare provider for information about TOPAMAX® that is written for health professionals.

For more information, go to www.topamax.com or call 1800JANSSEN (18005267736).

What are the ingredients in TOPAMAX®?

Active ingredient: topiramate

Inactive ingredients:
• Tablets - lactose monohydrate, pregelatinized starch, microcrystalline cellulose, sodium
starch glycolate, magnesium stearate, purified water, carnauba wax, hypromellose, titanium
dioxide, polyethylene glycol, synthetic iron oxide, and polysorbate 80.

• Sprinkle Capsules - sugar spheres (sucrose and starch), povidone, cellulose acetate, gelatin,
sorbitan monolaurate, sodium lauryl sulfate, titanium dioxide, and black pharmaceutical ink.

Revised October 2012

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

Manufactured by: Janssen Ortho, LLC, Gurabo, Puerto Rico 00778

Manufactured for: Janssen Pharmaceuticals, Inc., Titusville, NJ 08560

Reference ID: 3197087

RFQ - Mexamic Spas - Mexamic Forte - Mexamic - 07-07-2025
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