TOPIRAMATE tablet

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

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Active ingredient:
TOPIRAMATE (UNII: 0H73WJJ391) (TOPIRAMATE - UNII:0H73WJJ391)
Available from:
REMEDYREPACK INC.
INN (International Name):
TOPIRAMATE
Composition:
TOPIRAMATE 100 mg
Prescription type:
PRESCRIPTION DRUG
Authorization status:
Abbreviated New Drug Application

TOPIRAMATE- topiramate tablet

REMEDYREPACK INC.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use topiramate tablets, USP safely and

effectively. See full prescribing information for topiramate tablets, USPTopiramate Tablets, USP for oral use

Initial U.S. Approval: 1996

RECENT MAJOR CHANGES

Warnings and Precautions, Visual Field Defects ( 5.2) 01/2014

INDICATIONS AND USAGE

Topiramate is indicated for:

Monotherapy epilepsy: Initial monotherapy in patients ≥ 2 years of age with partial onset or primary generalized tonic-

clonic seizures ( 1.1).

Adjunctive therapy epilepsy: Adjunctive therapy for adults and pediatric patients (2 to 16 years of age) with partial

onset seizures or primary generalized tonic-clonic seizures, and in patients ≥2 years of age with seizures associated

with Lennox-Gastaut syndrome (LGS) ( 1.2)

DOSAGE AND ADMINISTRATION

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

Initial Dose

Titration

Recommended Dose

Epilepsy monotherapy: children 2 to

<10 years ( 2.1)

25 mg/day

administered nightly

for the first week

The dosage should be

titrated over 5 to 7 weeks

Daily doses in two

divided doses based

on weight (Table 2)

Epilepsy monotherapy: adults and

pediatric patients ≥10 years ( 2.1)

50 mg/day in two

divided doses.

The dosage should be increased

weekly by increment of 50 mg for

the first 4 weeks then 100 mg for

weeks 5 to 6.

400 mg/day in two

divided doses

Epilepsy adjunctive therapy: adults

with partial onset seizures or LGS ( 2.1)

25 to 50 mg/day

The dosage should be incrased

weekly to an effective dose by

increments of 25 to 50 mg.

200 to 400

mg/day in two

divided doses

Epilepsy adjunctive therapy: adults

with primary generalized tonic-clonic

seizures ( 2.1)

25 to 50 mg/day

The dosage should be increased

weekly to an effective dose by

increments of 25 to 50 mg.

400 mg/day in

two divided doses

Epilepsy adjunctive therapy: pediatric

patients with partial onset

seizures, primary generalized tonic-

clonic seizures or LGS ( 2.1)

25 mg/day (or less,

based on a range of

1 to 3 mg/kg/day)

nightly for the first

week

The dosage should be increased

at 1- or 2- week intervals by

increments of 1 to 3

mg/kg/day

(administered in two divided doses).

Dose titration should be guided by

clinical outcome.

5 to 9 mg/kg/day in

two divided

dose s

DOSAGE FORMS AND STRENGTHS

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

CONTRAINDICATIONS

None ( 4)

WARNINGS AND PRECAUTIONS

Acute myopia and secondary angle closure glaucoma: Untreated elevated intraocular pressure can lead to permanent

visual loss. The primary treatment to reverse symptoms is discontinuation of topiramate as rapidly as possible ( 5.1).

Visual field defects: These have been reported independent of elevated intraocular pressure. Consider discontinuation

of topiramate ( 5.2)

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

patients ( 5.3).

Metabolic acidosis: Baseline and periodic measurement of serum bicarbonate is recommended. Consider dose

reduction or discontinuation of topiramate if clinically appropriate ( 5.4)

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

Cognitive/neuropsychiatric: Topiramate may cause cognitive dysfunction. Patients should use caution when operating

machinery including automobiles. Depression and mood problems may occur in epilepsy populations ( 5.6)

Fetal Toxicity: Topiramate use during pregnancy can cause cleft lip and/or palate ( 5.7)

Withdrawal of AEDs: Withdrawal of topiramate should be done gradually ( 5.8)

Hyperammonemia and encephalopathic associated with or without concomitant valproic acid use: Patients with inborn

errors of metabolism or reduced mitochondrial activity may have an increased risk of hyperammonemia. Measure

ammonia if encephalopathic symptoms occur ( 5.10)

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

ketogenic diet should be avoided ( 5.11).

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

valproic acid use ( 5.12)

ADVERSE REACTIONS

The most common (≥10% more frequent than placebo or low-dose topiramate in monotherapy) adverse reactions at

recommended dosing in adult and pediatric controlled, epilepsy clinical trials were paresthesia, anorexia, weight decrease,

speech disorder related speech problem, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, abnormal

vision, and fever. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Camber Pharmaceuticals, Inc. at 1-866-495-8330 or

FDA at 1-800-FDA-1088 ORwww.fda.gov/medwatch. (6)

DRUG INTERACTIONS

Summary of (AED) interactions with topiramate ( 7.1)

AED Coadministered

AED Concentration

Topiramate Concentration

Phe nytoin

NC or 25% increase

48% decrease

Carbamazepine (CBZ)

40% decrease

CBZ epoxide

Valproic acid

11% decrease

14% decrease

Phe nobarbital

Primidone

Lamotrigine

NC at TPM doses up to 400 mg/day

13% decrease

a= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.

b= Is not administered but is an active metabolite of carbamazepine.

NC= Less than 10% change in plasma concentration.

NE= Not Evaluated.

Oral contraceptives: Decreased contraceptive efficacy and increased breakthrough bleeding should be considered,

especially at doses greater than 200 mg/day ( 7.3)

Metformin is contraindicated with metabolic acidosis, an effect of topiramate ( 7.4)

Lithium levels should be monitored when co-administered with high-dose topiramate ( 7.5)

Other carbonic anhydrase inhibitors: Monitor the patient for the appearance or worsening of metabolic acidosis ( 7.6)

USE IN SPECIFIC POPULATIONS

Renal Impairment: In renally impaired patients (creatinine clearance less than 70 mL/min/1.73 m

), one-half of the

adult dose is recommended ( 2.4)

Patients undergoing hemodialysis: Topiramate is cleared by hemodialysis. Dosage adjustment is necessary to avoid

rapid drops in topiramate plasma concentration during hemodialysis ( 2.6)

Pregnancy: Increased risk of cleft lip and/or palate ( 8.1)

Nursing Mothers: Caution should be exercised when administered to a nursing mother ( 8.3)

Geriatric Use: Dosage adjustment may be necessary for elderly with impaired renal function ( 8.5)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 11/2016

FULL PRESCRIBING INFORMATION: CONTENTS*

1. INDICATIONS AND USAGE

1.1 Monotherapy Epilepsy

1.2 Adjunctive Therapy Epilepsy

2. DOSAGE AND ADMINISTRATION

2.1 Epilepsy

2.4 Patients with Renal Impairment

2.5 Geriatric Patients (Ages 65 Years and Over)

2.6 Patients Undergoing Hemodialysis

2.7 Patients with Hepatic Disease

3. DOSAGE FORMS AND STRENGTHS

4. CONTRAINDICATIONS

5. WARNINGS AND PRECAUTIONS

5.1 Acute Myopia and Secondary Angle Closure Glaucoma

5.2 Visual Field Defects

5.3 Oligohidrosis and Hyperthermia

5.4 Metabolic Acidosis

5.5 Suicidal Behavior and Ideation

5.6 Cognitive/Neuropsychiatric Adverse Reactions

5.7 Fetal Toxicity

5.8 Withdrawal of Antiepileptic Drugs (AEDs)

5.9 Sudden Unexplained Death in Epilepsy (SUDEP)

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

Use)

5.11 Kidney Stones

5.12 Hypothermia with Concomitant Valproic Acid (VPA) Use

5.13 Paresthesia

5.14 Adjustment of Dose in Renal Failure

5.15 Decreased Hepatic Function

5.16 Monitoring: Laboratory Tests

6. ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing and Other Experience

7. DRUG INTERACTIONS

7.1 Antiepileptic Drugs

7.2 CNS Depressants

7.3 Oral Contraceptives

7.4 Metformin

7.5 Lithium

7.6 Other Carbonic Anhydrase Inhibitors

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Labor and Delivery

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Race and Gender Effects

8.7 Renal Impairment

8.8 Patients Undergoing Hemodialysis

8.9 Women of Childbearing Potential

10. OVERDOSAGE

11. DESCRIPTION

12. CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13. NON-CLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

14. CLINICAL STUDIES

14.1 Monotherapy Epilepsy Controlled Trial

14.2 Adjunctive Therapy Epilepsy Controlled Trials

16. HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

16.2 Storage and Handling

17. PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1. INDICATIONS AND USAGE

1.1 Monotherapy Epilepsy

Topiramate tablets, USP are indicated as initial monotherapy in patients 2 years of age and older with

partial onset or primary generalized tonic-clonic 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

Topiramate tablets, USP are indicated as adjunctive therapy for adults and pediatric patients ages 2 to 16

years with partial onset seizures or primary generalized tonic-clonic seizures, and in patients 2 years of

age and older with seizures associated with Lennox-Gastaut syndrome [ see Clinical Studies ( 14.2) ].

2. DOSAGE AND ADMINISTRATION

2.1 Epilepsy

It is not necessary to monitor topiramate plasma concentrations to optimize topiramate tablets therapy.

On occasion, the addition of topiramate tablets to phenytoin may require an adjustment of the dose of

phenytoin to achieve optimal clinical outcome. Addition or withdrawal of phenytoin and/or

carbamazepine during adjunctive therapy with topiramate tablets may require adjustment of the dose of

topiramate tablets.

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

Topiramate tablets can be taken without regard to meals.

Monotherapy Use

Adults and Pediatric Patients 10 Years and Older

The recommended dose for topiramate tablet 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 ):

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

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 tonic-clonic 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

topiramate tablets 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 25 to 50 mg/day each subsequent week as tolerated. Titration to the minimum maintenance

dose should be attempted over 5 to 7 weeks of the total titration period. Based upon tolerability and

clinical response, additional titration to a higher dose (up to the maximum maintenance dose) can be

attempted at 25 to 50 mg/day weekly increments. The total daily dose should not exceed the maximum

maintenance dose for each range of body weight (Table 2).

Adjunctive Therapy Use

Adults (17 Years of Age and Over) - Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, or

Lennox-Gastaut Syndrome

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

seizures is 200 to 400 mg/day in two divided doses, and 400 mg/day in two divided doses as adjunctive

treatment in adults with primary generalized tonic-clonic seizures. It is recommended that therapy be

initiated at 25 to 50 mg/day followed by titration to an effective dose in increments of 25 to 50 mg/day

every week. Titrating in increments of 25 mg/day every week may delay the time to reach an effective

dose. Doses above 400 mg/day (600 mg, 800 mg or 1,000 mg/day) have not been shown to improve

responses in dose-response studies in adults with partial onset seizures. Daily doses above 1,600 mg

have not been studied.

In the study of primary generalized tonic-clonic seizures the initial titration rate was slower than in

previous studies; the assigned dose was reached at the end of 8 weeks [ see Clinical Studies ( 14.1) ].

Pediatric Patients (Ages 2 to 16 Years) – Partial Onset Seizures, Primary Generalized Tonic-Clonic

Seizures, or Lennox-Gastaut Syndrome

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

partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-

Gastaut syndrome is approximately 5 to 9 mg/kg/day in two divided doses. Titration should begin at 25

mg/day (or less, based on a range of 1 to 3 mg/kg/day) nightly for the first week. The dosage should

then be increased at 1- or 2-week intervals by increments of 1 to 3 mg/kg/day (administered in two

divided doses), to achieve optimal clinical response. Dose titration should be guided by clinical

outcome.

In the study of primary generalized tonic-clonic seizures the initial titration rate was slower than in

previous studies; the assigned dose of 6 mg/kg/day was reached at the end of 8 weeks [ see Clinical

Studies ( 14.1) ].

2.4 Patients with Renal Impairment

In renally impaired subjects (creatinine clearance less than 70 mL/min/1.73 m

), one-half of the usual

adult dose is recommended. Such patients will require a longer time to reach steady-state at each dose.

2.5 Geriatric Patients (Ages 65 Years and Over)

Dosage adjustment may be indicated in the elderly patient when impaired renal function (creatinine

clearance rate <70 mL/min/1.73 m

)) is evident [ see Clinical Pharmacology ( 12.3)].

2.6 Patients Undergoing Hemodialysis

Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than a normal individual.

Accordingly, a prolonged period of dialysis may cause topiramate concentration to fall below that

required to maintain an anti-seizure effect. To avoid rapid drops in topiramate plasma concentration

during hemodialysis, a supplemental dose of topiramate may be required. The actual adjustment should

take into account 1) the duration of dialysis period, 2) the clearance rate of the dialysis system being

used, and 3) the effective renal clearance of topiramate in the patient being dialyzed.

2.7 Patients with Hepatic Disease

In hepatically impaired patients, topiramate plasma concentrations may be increased. The mechanism is

not well understood.

3. DOSAGE FORMS AND STRENGTHS

Topiramate tablets are available containing 25 mg, 50 mg, 100 mg or 200 mg of topiramate, USP.

The 25 mg tablets are white, film coated, round, biconvex tablets debossed with IG on one side and 278

on other.

The 50 mg tablets are yellow, film coated, round, biconvex tablets debossed with IG on one side and

279 on other.

The 100 mg tablets are light yellow, film coated, round, biconvex tablets debossed with IG on one side

and 280 on other.

The 200 mg tablets are pink, film coated, round, biconvex tablets debossed with IG on one side and 281

on other.

4. CONTRAINDICATIONS

None.

5. WARNINGS AND PRECAUTIONS

5.1 Acute Myopia and Secondary Angle Closure Glaucoma

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been

reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity

and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular

hyperemia (redness) and increased intraocular pressure. Mydriasis may or may not be present. This

syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and

iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating

topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age,

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

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

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

with discontinuation of topiramate, may be helpful.

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

permanent vision loss.

5.2 Visual Field Defects

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

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

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

treatment, consideration should be given to discontinuing the drug.

5.3 Oligohidrosis and Hyperthermia

Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in

association with topiramate use. Decreased sweating and an elevation in body temperature above normal

characterized these cases. Some of the cases were reported after exposure to elevated environmental

temperatures.

The majority of the reports have been in pediatric patients. Patients, especially pediatric patients, treated

with topiramate should be monitored closely for evidence of decreased sweating and increased body

temperature, especially in hot weather. Caution should be used when topiramate is prescribed with

other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to,

other carbonic anhydrase inhibitors and drugs with anticholinergic activity.

5.4 Metabolic Acidosis

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

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

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

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

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

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

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

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

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

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

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

Some manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific

symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or

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

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

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

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

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

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

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

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

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

SCORES for length and weight were correlated to the degree of acidosis [ see Use in

SpecificPopulations ( 8.4) ]. Topiramate treatment that causes metabolic acidosis during pregnancy can

possibly produce adverse effects on the fetus and might also cause metabolic acidosis in the neonate

from possible transfer of topiramate to the fetus [ see Warnings and Precautions ( 5.7) and Use in Special

Populations ( 8.1) ].

Epilepsy

Adult patients

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

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

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

doses as low as 50 mg/day. The incidence of 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.

The incidence of persistent treatment-emergent decreases in serum bicarbonate in adult patients (≥ 16

years of age) 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% for400 mg/day. Serum bicarbonate levels have not been systematically evaluated at daily doses

greater than 400 mg/day.

Pediatric patients

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

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

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

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

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

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

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

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

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

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

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

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

mg/kg/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 to15 years of age), the incidence of persistent treatment-emergent 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 trial was 1 % for 50 mg/day and 6 %

400 mg/day.

Measurement of Serum Bicarbonate in Epilepsy Patients

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

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

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

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

5.5 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including topiramate, increase the risk of suicidal thoughts or behavior in

patients taking these drugs for any indication. Patients treated with any AED for any indication should be

monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any

unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different

AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted

Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to

placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate

of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24%

among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal

thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in

the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about

drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week

after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because

most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or

behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.

The finding of increased risk with AEDs of varying mechanisms of action and across a range of

indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary

substantially by age (5 to 100 years) in the clinical trials analyzed.

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

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in

clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the

epilepsy and psychiatric indications.

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

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

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

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

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

illness being treated.

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

thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of

the signs and symptoms of depression, any unusual changes in mood or behavior or the emergence of

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

immediately to healthcare providers.

5.6 Cognitive/Neuropsychiatric Adverse Reactions

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

system and were observed in the epilepsy population. In adults, the most frequent of these can be

classified into three general categories:

1) Cognitive-related dysfunction (e.g., confusion, psychomotor slowing, difficulty with

concentration/attention, difficulty with memory, speech or language problems, particularly word-finding

difficulties);

2) Psychiatric/behavioral disturbances (e.g., depression or mood problems); and

3) Somnolence or fatigue.

Adult Patients

Cognitive-Related Dysfunction

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

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

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

Adverse Reactions ( 6) ].

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

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

reactions was 42% for 200 mg/day, 41% for 400 mg/day, 52% for 600 mg/day, 56% for 800 and 1,000

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

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

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

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

maintenance phase.

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

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

Psychiatric/Behavioral Disturbances

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

population [ see Warnings and Precautions ( 5.5) ].

Somnolence/Fatigue

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

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

did not differ substantially between 200 mg/day and 1,000 mg/day, but the incidence of fatigue was

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

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

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

treatment groups (14% each).

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

population include dizziness or ataxia.

Pediatric Patients

Epilepsy

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

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

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

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

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

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

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

dizziness, anorexia, and somnolence.

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

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

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

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

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

5.7 Fetal Toxicity

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

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

cleft palate (oral clefts). When multiple species of pregnant animals received topiramate at clinically

relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights

occurred in offspring [ see Use in Specific Populations ( 8.1) ].

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

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

permanent injury or death [ see Use in Specific Populations ( 8.9) and Patient Counseling Information ( 17)

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

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

should be apprised of the potential hazard to a fetus [ see Use in Specific Populations ( 8.1) and ( 8.9) ]

5.8 Withdrawal of Antiepileptic Drugs (AEDs)

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

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

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

appropriate monitoring is recommended.

5.9 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 topiramate (ranging from 0.0005 for the

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

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

5.10 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 dose-related) in a clinical

investigational program in adolescent patients (12 to 17 years) given topiramate. The incidence of

hyperammonemia (above the upper limit of normal reference) at any time in the trial was 9% for

placebo, 14% for 50 mg, and 26% for 100 mg topiramate daily. In some patients, hyperammonemia was

observed at the end of the trial at the final visit. The incidence of markedly increased hyperammonemia

(at least 50% or higher above upper limit of normal) at any time in the trial in adolescent patients was

also increased at 100 mg/day (9%) compared to 50 mg topiramate (0%) or placebo (3%). During this

trial, markedly increased ammonia levels returned to normal in all but one patient (in whom the ammonia

level fell to high instead of markedly abnormal).

Topiramate treatment has produced hyperammonemia in a clinical investigational program in very young

pediatric patients (1 to 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). In some patients,

ammonia was markedly increased (≥ 50% above upper limit of normal). The hyperammonemia

associated with topiramate treatment occurred with and without encephalopathy in placebo-controlled

trials and in an open-label, extension trial of infants with refractory epilepsy. Dose-related

hyperammonemia was 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. Topiramate is not approved as adjunctive treatment

of partial onset seizures in pediatric patients less than 2 years old.

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

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

Hyperammonemia/Encephalopathy With Concomitant Valproic Acid (VPA)

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

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

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

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

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

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

Although topiramate is not indicated for use in infants/toddlers (1 to 24 months) topiramate with VPA

clearly produced a dose-related to 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, dose-related hyperammonemia (0%

for placebo and 5 mg/kg/day, 7% for 15 mg/kg/day, 8% for 25 mg/kg /day) also occurred in these

infants/toddlers. Dose-related hyperammonemia was similarly observed in a long-term, extension trial in

these very young, pediatric patients [s ee Use in Specific Populations ( 8.4) ].

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

5.11 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 double-blind monotherapy epilepsy study, a total of

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

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

men. Kidney stones have also been reported in pediatric patients taking topiramate for epilepsy.

During long-term (up to 1 year) topiramate treatment in an open-label extension study of 284 pediatric

patients 1 to 24 months old with epilepsy, 7% developed kidney or bladder stones that were diagnosed

clinically or by sonogram. Topiramate is not approved for treatment of epilepsy in pediatric patients

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

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

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

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

urinary pH [ see Warnings and Precautions ( 5.3) ]. The concomitant use of topiramate with any other

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

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

avoided.

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

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

5.12 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 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.

5.13 Paresthesia

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

anhydrase inhibitors, appears to be a common effect of topiramate in adult and pediatric patients.

Paresthesia was more frequently reported in the monotherapy epilepsy trials than in the adjunctive

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

5.14 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)

5.15 Decreased Hepatic Function

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

topiramate may be decreased. [ see Dosage and Administration ( 2.7) ].

5.16 Monitoring: Laboratory Tests

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

double-blind, placebo-controlled studies.

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

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

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

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

or without encephalopathy [ see Warnings and Precautions ( 5.10) ].

The clinical significance of decreased serum bicarbonate and associated increased serum chloride

reflecting metabolic acidosis and of increased ammonia reflecting hyperammonemia which may be

associated with encephalopathy is described [ see Warnings and Precautions ( 5.4 and 5.10) ]. However,

the clinical significance of these other various abnormalities in other clinical laboratory analytes

described here has not been clearly established.

Epilepsy

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).

Changes in several clinical laboratory analytes (i.e., increased creatinine, BUN, alkaline phosphatase,

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

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

topiramate for partial onset seizures [ see Use in Specific Populations ( 8.4) ].

Other Use

In pooled double-blind studies in pediatric patients (6 to 17 years), an increased risk for certain

abnormalities (value outside normal reference range) in selected clinical laboratory analytes measured

in blood has been observed during topiramate treatment of pediatric patients compared to placebo-

treated patients. In some instances, abnormalities were also observed at the end of the trial at the final

visit and the changes were considered markedly abnormal.

For patients 12 to 17 years, the following were noted to be abnormally increased more frequently with

topiramate than with placebo: BUN, creatinine, uric acid, chloride [ see Warnings and Precautions ( 5.4)

], ammonia [see Warnings and Precautions ( 5.10)], total protein, and platelets. The following were

abnormally decreased in some subjects: phosphorus, and bicarbonate [ see Warnings and Precautions (

5.4) ].

For patients 6 to 11 years, the following were noted to be abnormally increased more frequently with

topiramate than with placebo: alkaline phosphatase, creatinine and eosinophils. Analytes abnormally

decreased were: total white count and neutrophils. There was no testing for serum bicarbonate,

chloride, ammonia, or phosphorus in these younger patients.

6. ADVERSE REACTIONS

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)]

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

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

Metabolic Acidosis [see Warnings and Precautions ( 5.4)]

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

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

Fetal Toxicity [see Warnings and Precautions ( 5.7) and Use in Specific Populations ( 8.1)]

Sudden Unexplained Death in Epilepsy (SUDEP) [see Warnings and Precautions ( 5.9)]

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

[see Warnings and Precautions ( 5.10)]

Kidney Stones [see Warnings and Precautions ( 5.11)]

Hypothermia with Concomitant Valproic Acid (VPA) Use [see Warnings and Precautions ( 5.12)]

Paresthesia [see Warnings and Precautions ( 5.13)]

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

6.1 Clinical Trials Experience

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

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

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

reactions observed in practice.

Increased Risk for Bleeding Topiramate treatment is associated with an increased risk for bleeding. In a

pooled analysis of placebo-controlled studies of approved and unapproved indications, bleeding was

more frequently reported as an adverse event for topiramatethan for placebo (4.5% versus 3.0% in adult

patients, and 4.4% versus 2.3% in pediatric patients). In this analysis, the incidence of serious bleeding

events for topiramateand placebo was 0.3% versus 0.2% for adult patients, and 0.4% versus 0% for

pediatric patients.

Adverse bleeding reactions reported with topiramateranged from mild epistaxis, ecchymosis, and

increased menstrual bleeding to life-threatening hemorrhages. In patients with serious bleeding events,

conditions that increased the risk for bleeding were often present, or patients were often taking drugs

that cause thrombocytopenia (other antiepileptic drugs) or affect platelet function or coagulation (e.g.,

aspirin, nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, or warfarin or

other anticoagulants).

Monotherapy Epilepsy

Adults ≥16 Years

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

topiramate 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 low-dose 50 mg/day topiramate) 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 topiramate 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). Table

5 also presents the incidence of adverse reactions occurring in at least 2% of adult and pediatric patients

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

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

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

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

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

Adjunctive Therapy Epilepsy

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

200 to 400 mg/day (recommended dose range) in controlled trials in adults with partial onset seizures,

primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, that were seen at an incidence

higher (≥ 5%) than in the placebo group were : somnolence, weight decrease, anorexia, dizziness,

ataxia, speech disorders and related speech problems, language problems, psychomotor slowing,

confusion, abnormal vision, difficulty with memory, paresthesia, diplopia, nervousness, and asthenia

(see Table 6). Dose-related adverse reactions at dosages of 200 to 1,000 mg/day are shown in Table 8.

The most commonly observed adverse reactions associated with the use of topiramate at dosages of 5

to 9 mg/kg/day in controlled trials in pediatric patients with partial onset seizures, primary generalized

tonic-clonic seizures, or Lennox-Gastaut syndrome, that were seen at an incidence higher (≥ 5%) than in

the placebo group were: fatigue, somnolence, anorexia, nervousness, difficulty with

concentration/attention, difficulty with memory, aggressive reaction, and weight decrease (see Table 9).

Table 9 also presents the incidence of adverse reactions occurring in at least 1% of pediatric patients

treated with topiramate and occurring with greater incidence than placebo.

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

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

above 400 mg/day. Adverse 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 topiramate 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 topiramate at dosages of 200 to

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

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

slowing (4%), 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%). Approximately 11%

of the 310 pediatric patients who received topiramate at dosages up to 30 mg/kg/day discontinued due to

adverse reactions. Adverse reactions associated with discontinuing therapy included aggravated

convulsions (2.3%), difficulty with concentration/attention (1.6%), language problems (1.3%),

personality disorder (1.3%), and somnolence (1.3%). Incidence in Epilepsy Controlled Clinical Trials –

Adjunctive Therapy – Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, and Lennox-

Gastaut Syndrome

Table 6 lists the incidence of adverse reactions that occurred in at least 1% of adults treated with 200 to

400 mg/day topiramate (and also higher daily dosing of 600 mg to 1000 mg) in controlled trials that was

numerically greater with topiramate than 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 the incidence of treatment-emergent adverse reactions that occurred in at least 1% of

pediatric patients treated with 5 to 9 mg/kg topiramate in controlled trials and that was numerically

greater than the incidence in patients treated with placebo.

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

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

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

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

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

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

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

population studied.

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

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

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

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

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

infection, and eye pain.

Table 6:Incidence of Treatment-Emergent Adverse Reactions in Placebo-Controlled, Add-On

Epilepsy Trials in Adults

Where Incidence Was ≥1% in Any Topiramate Group and Greater

Than the Rate in Placebo-Treated Patients

a, b

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

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

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

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

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

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

or without another concomitant antiepileptic drug.

The most commonly observed adverse reactions associated with the use of topiramate that were seen at

an incidence higher (≥ 5%) than in the placebo group were: paresthesia, nervousness, somnolence,

difficulty with concentration/attention, and fatigue (see Table 7). Because these topiramate treatment

difference incidence (topiramate % - Placebo %) of many 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.

Other Adverse Reactions Observed During All Epilepsy Clinical Trials

Topiramate has been administered to 2246 adults and 427 pediatric patients with epilepsy during all

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

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

provide a meaningful estimate of the proportion of individuals having adverse 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 topiramate. Reported

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

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

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

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

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

Autonomic Nervous System Disorders: Infrequent: vasodilation.

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

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

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

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.

6.2 Postmarketing and Other Experience

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

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

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

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

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

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

7. DRUG INTERACTIONS

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

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

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

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

interactions, please refer to Clinical Pharmacology ( 12.3).

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 topiramate given alone [ see Clinical Pharmacology ( 12.3) ].

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

with and without encephalopathy. Concomitant administration of topiramate 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 ( 5.10) ( 5.12) or Clinical Pharmacology (

12.3) ].

7.2 CNS Depressants

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

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

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

caution if used in combination with alcohol and other CNS depressants.

7.3 Oral Contraceptives

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

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

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

another pharmacokinetic interaction study in healthy volunteers with a concomitantly administered

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

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

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

oral contraceptive. The possibility of decreased contraceptive efficacy and increased breakthrough

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

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

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

bleeding [ see Clinical Pharmacology ( 12.3) ].

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 C

and 26% for

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

coadministered with high-dose topiramate [ 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 topiramate is given

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

appearance or worsening of metabolic acidosis [ see Clinical Pharmacology ( 12.3) ].

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D. [ see Warnings and Precautions ( 5.7) ]

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

outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant

while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in

Specific Populations ( 8.9)].

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 toll free number 1-888-233-2334.

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 (425 prospective topiramate monotherapy-exposed

pregnancies) indicate an increased risk of oral clefts in infants exposed during the first trimester of

pregnancy. The prevalence of oral clefts among topiramate-exposed infants was 1.2% compared to a

prevalence of 0.39% for infants exposed to a reference AED. In infants of mothers without epilepsy or

treatment with other AEDs, the prevalence was 0.12%. For comparison, the Centers for Disease

Control and Prevention (CDC) reviewed available data on oral clefts in the United States and found a

background rate of 0.17%.

The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry

was 9.6 (95% Confidence Interval[CI] 4 to 23) 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%.

Topiramate treatment can cause metabolic acidosis [see Warnings and Precautions ( 5.4)]. The effect of

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

in pregnancy (due to other causes) 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 ( 5.4)].

Newborns of mothers treated with topiramate should be monitored for metabolic acidosis because of

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

birth.

Animal Data

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

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

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

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

recommended human dose (RHD) 400 mg/day on a mg/ m

basis. Fetal body weights and skeletal

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

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

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

offspring of dams treated with 400 mg/kg (10 times the RHD on a mg/ m

basis) or greater during the

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

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

basis). Clinical signs of maternal toxicity were seen at 400 mg/kg and above, and maternal body weight

gain was reduced during treatment with 100 mg/kg or greater.

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

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

basis)

or greater, and teratogenic effects (primarily rib and vertebral malformations) were observed at 120

mg/kg (6 times the RHD on a mg/ m

basis). Evidence of maternal toxicity (decreased body weight gain,

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

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

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

delayed physical development at 200 mg/kg (5 times the RHD on a mg/ m

basis) and reductions in pre-

and/or postweaning body weight gain at 2 mg/kg (0.05 times the RHD on a mg/ m

basis) and above.

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

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

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

times the RHD on a mg/ m

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

RHD on a mg/ m

basis) and higher.

8.2 Labor and Delivery

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

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

fetus’ ability to tolerate labor [ see Use in Specific Populations ( 8.1) ].

8.3 Nursing Mothers

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

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

Caution should be exercised when administered to a nursing woman.

8.4 Pediatric Use

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

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

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

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

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

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

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

topiramate (at fixed doses of 5 mg, 15 mg, 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 open-label, long-term extension study in these

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

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

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

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

for various indications.

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

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

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

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

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

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

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

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

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

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

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

abnormal increase [ see Warnings and Precautions ( 5.16) ]. The significance of these finding is

uncertain.

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

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

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

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

Warnings and Precautions ( 5.16)]. There was a mean dose-related increase in alkaline phosphatase. The

significance of these findings is uncertain.

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

Warnings and Precautions ( 5.10) ].

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

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

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

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

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

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

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

5.6) ].

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

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

rate for a similar, significantly refractory, young pediatric population (1 to 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.

Juvenile Animal Studies

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

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

the highest dose, which is approximately 5 to 8 times the maximum recommended pediatric dose (9

mg/kg/day) on a body surface area (mg/ m

) basis.

8.5 Geriatric Use

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

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

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

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

mL/min/1.73 m

) due to reduced clearance of topiramate [ see Clinical Pharmacology ( 12.3) and Dosage

and Administration ( 2.5) ].

8.6 Race and Gender Effects

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

8.7 Renal Impairment

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

30 to 69 mL/min/1.73 m

) and by 54% in severely renally impaired subjects (creatinine clearance <30

mL/min/1.73 m

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

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

renal impairment [ see Dosage and Administration ( 2.6) and Clinical Pharmacology ( 12.3) ].

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 anti-seizure effect. To avoid rapid drops in topiramate plasma concentration

during hemodialysis, a supplemental dose of topiramate may be required.

The actual adjustment should take into account the duration of dialysis period, the clearance rate of the

dialysis system being used, and the effective renal clearance of topiramate in the patient being dialyzed [

see Dosage and Administration ( 2.4) and Clinical Pharmacology ( 12.3) ].

8.9 Women of Childbearing Potential

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) [see Warnings and Precautions ( 5.7) and Use in Specific

Populations ( 8.1) ]. Consider the benefits and the risks of topiramate when prescribing this drug to

women of childbearing potential, particularly when topiramate 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 topiramate. If the

decision is made to use topiramate, 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 topiramate use during pregnancy, and alternative therapeutic

options should be considered for these patients

10. OVERDOSAGE

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

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

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

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

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

topiramate.

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

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

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

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

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

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

topiramate from the body.

11. DESCRIPTION

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

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

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

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

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

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

S and a

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

D-fructopyranose sulfamate and has the following structural formula:

Topiramate tablets contain the following inactive ingredients: lactose monohydrate, microcrystalline

cellulose, pre-gelatinized starch (maize), sodium starch glycolate, magnesium stearate, opadry white

(titanium dioxide, hypromellose 3cp, hypromellose 6cp, PEG 400, polysorbate 80) for 25 mg tablets,

opadry yellow (titanium dioxide, hypromellose 3cp, hypromellose 6cp, PEG 400, polysorbate 80, iron

oxide yellow) for 50 mg tablets, opadry yellow (hypromellose 3cp, hypromellose 6cp, titanium

dioxide, PEG 400, iron oxide yellow, polysorbate 80, iron oxide red) for 100 mg tablets and, opadry

pink (titanium dioxide, hypromellose 6cp, PEG 400,iron oxide red) for 200 mg tablets.

12. CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

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

for epilepsy. Electrophysiological and biochemical evidence suggests that topiramate, at

pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the

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

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

enzyme, particularly isozymes II and IV.

12.2 Pharmacodynamics

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

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

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

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

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

Changes (increases and decreases) from baseline in vital signs (systolic blood pressure-SBP, diastolic

blood pressure-DBP, pulse) occurred more frequently in pediatric patients (6 to 17 years) treated with

various daily doses of topiramate (50 mg, 100 mg, 200 mg, 2 to 3 mg/kg) than in patients treated with

placebo in controlled trials for another indication. The most notable changes were SBP < 90 mm Hg,

DBP < 50 mm Hg, SBP or DBP increases or decreases ≥ 20 mm Hg, and pulse increases or decreases ≥

30 beats per minute. These changes were often dose-related, and were most frequently associated with

the greatest treatment difference at the 200 mg dose level. When a position was specified for

measurement of vital signs in a trial, measurements were made in a sitting position. Systematic collection

of orthostatic vital signs has not been conducted. The clinical significance of these various changes in

vital signs has not been clearly established.

12.3 Pharmacokinetics

The sprinkle formulation is bioequivalent to the immediate-release 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 half-life is 21 hours

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

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

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

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

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

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

Metabolism and Excretion

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

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

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

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

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

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

plasma clearance (CL/F) is approximately 20 to 30 mL/min in 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/1.73 m

) and by 54% in severely renally impaired subjects (creatinine clearance <30

mL/min/1.73 m

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

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

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

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

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

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

impairment [ see Dosage and Administration ( 2.4 ) and ( 2.5) and Warnings and Precautions ( 5.14) ].

impairment [ see Dosage and Administration ( 2.4 ) and ( 2.5) and Warnings and Precautions ( 5.14) ].

Hemodialysis

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

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

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

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

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

Administration (2.6)].

Hepatic Impairment

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

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

Age, Gender, and Race

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

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

clearance

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

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

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

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

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

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

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

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

(creatinine clearance rate ≤70 mL/min/1.73 m

) is evident. It may be useful to monitor renal function in

the elderly patient [ see Dosage and Administration ( 2.4) and Warnings and Precautions ( 5.14) ].

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 enzyme-

inducing 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 enzyme-inducing antiepileptic drugs decrease the steady state plasma

concentrations of topiramate.

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 13.

In Table 13, 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 co-administration of a drug listed in the first column modifies the concentration of

topiramate in experimental settings when topiramate tablets were given alone.

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

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

encephalopathy and hypothermia [see Warnings and Precautions ( 5.10) ( 5.12) and Drug Interactions (

7.1)].

CNS Depressants

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

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

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

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

Oral Contraceptives

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

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

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

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

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

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

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

significantly affect exposure to NET. Although there was a dose-dependent decrease in EE exposure

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

exposure for doses of 50 to 200 mg/day. The clinical significance of the changes observed is not

known. The possibility of decreased contraceptive efficacy and increased breakthrough bleeding

should be considered in patients taking combination oral contraceptive products with topiramate.

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

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

bleeding [see Drug Interactions ( 7.3)].

Digoxin

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

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

Hydrochlorothiazide

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

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

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

increased

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

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

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

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

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

were administered in combination.

Metformin

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

metformin is contraindicated.

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

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

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

results of this study indicated that the mean metformin C

and AUC

increased by 18% and 25%,

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

. The clinical

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

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

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

Interactions ( 7.4)].

Pioglitazone

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

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

decrease in the AUC ,

of pioglitazone with no alteration in C

was observed. This finding was

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

and AUCτ,ss respectively,

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

and AUCτ,ss of the

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

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

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

Glyburide

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

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

was a 22% decrease in C

and a 25% reduction in AUC

for glyburide during topiramate

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

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

was reduced by 18% and

25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant

administration of glyburide.

Lithium

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

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

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

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

Haloperidol

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

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

Amitriptyline

There was a 12% increase in AUC and C

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

0-12h

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

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

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

Sumatriptan

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

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

mg).

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 9-hydroxyrisperidone levels were observed. Co-

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

and a 12%

increase in AUC

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

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

likely to be of clinical significance.

Propranolol

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

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

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

200 mg/day of topiramate.

Dihydroergotamine

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

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

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

topiramate in the same study.

Diltiazem

Co-administration of diltiazem (240 mg Cardizem CD

) with topiramate (150 mg/day) resulted in a 10%

decrease in C

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

and an 18% decrease

in des-acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Coadministration of topiramate

with diltiazem resulted in a 16% increase in C

and a 19% increase in AUC

of topiramate.

Venlafaxine

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

venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg Effexor XR

) did not

affect the pharmacokinetics of topiramate.

Other Carbonic Anhydrase Inhibitors

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

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

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

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

appearance or worsening of metabolic acidosis [ see Drug Interactions ( 7.6) ].

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 mg, 75 mg, and 300

mg/kg) in the diet for 21 months. The elevated bladder tumor incidence, which was statistically

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

a smooth muscle tumor considered histomorphologically unique to mice. Plasma exposures in mice

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

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

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

relevance of this finding to human carcinogenic risk is uncertain. No evidence of carcinogenicity was

seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/kg

(approximately 3 times the RHD on a mg/ m

basis).

Mutagenesis

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

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

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

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

Impairment of Fertility

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

the RHD on a mg/ m

basis).

14. CLINICAL STUDIES

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

14.1 Monotherapy Epilepsy Controlled Trial

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 tonic-clonic seizures was established in a multicenter,

randomized, double-blind, parallel-group trial.

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

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

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

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

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

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

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

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

tolerate 150 mg/day were discontinued. The primary efficacy assessment was a between-group

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

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

mg/day group (p=0.0002, log rank test; Figure 1). The treatment effects with respect to time to first

seizure were consistent across various patient subgroups defined by age, sex, geographic region,

baseline body weight, baseline seizure type, time since diagnosis, and baseline AED use.

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 tonic-clonic 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 exposure-response 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, double-blind, placebo-controlled trials, two comparing

several dosages of topiramate and placebo and four comparing a single dosage with placebo, in patients

with a history of partial onset seizures, with or without secondarily generalized seizures.

Patients in these studies were permitted a maximum of two antiepileptic drugs (AEDs) in addition to

topiramate tablets or placebo. In each study, patients were stabilized on optimum dosages of their

concomitant AEDs during baseline phase lasting between 4 and 12 weeks. Patients who experienced a

prespecified minimum number of partial onset seizures, with or without secondary generalization,

during the baseline phase (12 seizures for 12-week baseline, 8 for 8-week baseline or 3 for 4-week

baseline) were randomly assigned to placebo or a specified dose of topiramate tablets in addition to

their other AEDs.

Following randomization, patients began the double-blind phase of treatment. In five of the six studies,

patients received active drug beginning at 100 mg per day; the dose was then increased by 100 mg or

200 mg/day increments weekly or every other week until the assigned dose was reached, unless

intolerance prevented increases. In the sixth study (119), the 25 or 50 mg/day initial doses of topiramate

were followed by respective weekly increments of 25 or 50 mg/day until the target dose of 200 mg/day

was reached. After titration, patients entered a 4, 8 or 12-week stabilization period. The numbers of

patients randomized to each dose and the actual mean and median doses in the stabilization period are

shown in Table 14.

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, double-blind, placebo-controlled

trial, comparing topiramate and placebo in patients with a history of partial onset seizures, with or

without secondarily generalized seizures(see Table 14)

Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in addition to

topiramate tablets or placebo. In this study, patients were stabilized on optimum dosages of their

concomitant AEDs during an 8-week baseline phase. Patients who experienced at least six partial onset

seizures, with or without secondarily generalized seizures, during the baseline phase were randomly

assigned to placebo or topiramate tablets in addition to their other AEDs.

Following randomization, patients began the double-blind phase of treatment. Patients received active

drug beginning at 25 or 50 mg per day; the dose was then increased by 25 mg to 150 mg/day increments

every other week until the assigned dosage of 125 mg, 175 mg, 225 mg, or 400 mg/day based on

patients' weight to approximate a dosage of 6 mg/kg per day was reached, unless intolerance prevented

increases. After titration, patients entered an 8-week stabilization period.

Patients With Primary Generalized Tonic-Clonic Seizures

The effectiveness of topiramate as an adjunctive treatment for primary generalized tonic-clonic seizures

in patients 2 years old and older was established in a multicenter, randomized, double-blind, placebo-

controlled trial, comparing a single dosage of topiramate and placebo(see Table 14).

Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in addition to

topiramate or placebo. Patients were stabilized on optimum dosages of their concomitant AEDs during

an 8-week baseline phase. Patients who experienced at least three primary generalized tonic-clonic

seizures during the baseline phase were randomly assigned to placebo or topiramate in addition to their

other AEDs.

Following randomization, patients began the double-blind phase of treatment. Patients received active

drug beginning at 50 mg/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 mg, 225 mg, 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 12-week 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, double-blind, placebo-controlled trial

comparing a single dosage of topiramate with placebo in patients 2 years of age and older(see Table

14).

Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in addition to

topiramate or placebo. Patients who were experiencing at least 60 seizures per month before study

entry were stabilized on optimum dosages of their concomitant AEDs during a 4-week baseline phase.

Following baseline, patients were randomly assigned to placebo or topiramate in addition to their other

AEDs. Active drug was titrated beginning at 1 mg/kg/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 8-week stabilization

period. The primary measures of effectiveness were the percent reduction in drop attacks and a parental

global rating of seizure severity.

In all add-on trials, the reduction in seizure rate from baseline during the entire double-blind phase was

measured. The median percent reductions in seizure rates and the responder rates (fraction of patients

with at least a 50% reduction) by treatment group for each study are shown below in Table 10. As

described above, a global improvement in seizure severity was also assessed in the Lennox-Gastaut

trial.

Subset analyses of the antiepileptic efficacy of topiramate tablets in these studies showed no

differences as a function of gender, race, age, baseline seizure rate, or concomitant AED.

In clinical trials for epilepsy, daily dosages were decreased in weekly intervals by 50 to 100 mg/day in

adults and over a 2- to 8- week period in children; transition was permitted to a new antiepileptic

regimen when clinically indicated.

16. HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Topiramate tablets, USP are available containing 25 mg, 50 mg, 100 mg or 200 mg of topiramate USP.

The 25 mg tablets are white, film coated, round, biconvex tablets debossed with IG on one side and 278

on other.

They are available as follows:

NDC 31722-278-60 bottles of 60 tablets

NDC 31722-278-05 bottles of 500 tablets

NDC 31722-278-10 bottles of 1000 tablets

The 50 mg tablets are yellow, film coated, round, biconvex tablets debossed with IG on one side and

279 on other.

They are available as follows:

NDC 31722-279-60 bottles of 60 tablets

NDC 31722-279-05 bottles of 500 tablets

NDC 31722-279-10 bottles of 1000 tablets

The 100 mg tablets are light yellow, film coated, round, biconvex tablets debossed with IG on one side

and 280 on other.

They are available as follows:

NDC 31722-280-60 bottles of 60 tablets

NDC 31722-280-05 bottles of 500 tablets

NDC 31722-280-10 bottles of 1000 tablets

The 200 mg tablets are pink, film coated, round, biconvex tablets debossed with IG on one side and 281

on other. They are available as follows:

NDC 31722-281-60 bottles of 60 tablets

NDC 31722-281-05 bottles of 500 tablets

NDC 31722-281-10 bottles of 1000 tablets

16.2 Storage and Handling

Topiramate tablets

Store at 20° to 25°C (68° to 77°F); [see USP Controlled Room Temperature]. Protect from moisture.

17. PATIENT COUNSELING INFORMATION

Advise the patients to read FDA-approved patient labeling (Medication Guide).

Eye Disorders

Instruct patients taking topiramate to seek immediate medical attention if they experience blurred vision,

visual disturbances or periorbital pain [ see Warnings and Precautions ( 5.1), ( 5.2) ].

Oligohydrosis and Hyperthermia

Closely monitor topiramate-treated patients, especially pediatric patients, for evidence of decreased

sweating and increased body temperature, especially in hot weather. Counsel patients to contact their

healthcare professionals immediately if they develop a high or persistent fever, or decreased sweating

[ see Warnings and Precautions ( 5.3) ].

Metabolic AcidosisWarn patients about the potential significant risk for metabolic acidosis that may be

asymptomatic and may be associated with adverse effects on kidneys (e.g., kidney stones,

nephrocalcinosis), bones (e.g., osteoporosis, osteomalacia, and/or rickets in children), and growth (e.g.,

growth delay/retardation) in pediatric patients, and on the fetus [see Warnings and Precautions ( 5.4) and

Use in Specific Populations (8.1)] .

Suicidal Behavior and Ideation

Counsel patients, their caregivers, and families that AEDs, including topiramate, may increase the risk

of suicidal thoughts and behavior, and advise 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 self-harm. Instruct patients to immediately report

behaviors of concern to their healthcare providers [ see Warnings and Precautions ( 5.5) ].

Interference with Cognitive and Motor Performance

Warn patients about the potential for somnolence, dizziness, confusion, difficulty concentrating, or

visual effects, and advise patients not to drive or operate machinery until they have gained sufficient

experience on topiramate to gauge whether it adversely affects their mental performance, motor

performance, and/or vision [ see Warnings and Precautions ( 5.6) ].

Even when taking topiramate or other anticonvulsants, some patients with epilepsy will continue to have

unpredictable seizures. Therefore, advise all patients taking topiramate for epilepsy 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. Discuss the

appropriate level of caution with patients, before patients with epilepsy engage in such activities.

Fetal Toxicity

Inform pregnant women and women of childbearing potential that use of topiramate 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 topiramate during pregnancy [ see Warnings and

Precautions ( 5.7) 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 topiramate use is considered for a condition not usually associated with

permanent injury or death.

Advise women of childbearing potential who are not planning a pregnancy to use effective

contraception while using topiramate, keeping in mind that there is a potential for decreased

contraceptive efficacy when using estrogen-containing birth control with topiramate [ see Drug

Interactions ( 7.3)] .

Encourage pregnant women using topiramate 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 toll free-number, 1-888-233-2334. Information

about the North American Drug Pregnancy Registry can be found at http://www.massgeneral.org/aed/. [

see Use in Specific Populations ( 8.1) ].

Hyperammonemia and Encephalopathy

Warn patients about the possible development of hyperammonemia with or without encephalopathy.

Although hyperammonemia may be asymptomatic, clinical symptoms of hyperammonemic

encephalopathy often include acute alterations in level of consciousness and/or cognitive function with

lethargy or vomiting. This hyperammonemia and encephalopathy can develop with topiramate treatment

alone or with topiramate treatment with concomitant valproic acid (VPA).

Instruct patients to contact their physician if they develop unexplained lethargy, vomiting, or changes in

mental status [ see Warnings and Precautions ( 5.10) ].

Kidney Stones

Instruct patients, particularly those with predisposing factors, to maintain an adequate fluid intake in

order to minimize the risk of kidney stone formation [ see Warnings and Precautions ( 5.11) ].

Instructions for a Missing DoseInstruct patients that if they miss a single dose of topiramate, it should

be taken as soon as possible. However, if a patient is within 6 hours of taking the next scheduled dose,

tell the patient to wait until then to take the usual dose of topiramate, and to skip the missed dose. Tell

patients that they should not take a double dose in the event of a missed dose. Advise patients to contact

their healthcare provider if they have missed more than one dose.

Rev:10/15

MEDICATION GUIDE

Topiramate Tablets, USP

(toe pir’a mate).

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

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

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

talk to your healthcare provider or pharmacist.

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

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

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

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

glaucoma).

These eye problems can lead to permanent loss of vision if not treated.

You should call your healthcare provider right away if you have any new eye symptoms, including

any new problems with your vision.

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

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

in hot temperatures. Some people may need to be hospitalized for this condition. Call your healthcare

provider right away if you have a high fever, a fever that does not go away, or decreased sweating.

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

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

kidney stones, can slow the rate of growth in children, and may possibly harm your baby if you are

pregnant. Metabolic acidosis can happen with or without symptoms.

Sometimes people with metabolic acidosis will:

feel tired

not feel hungry (loss of appetite)

feel changes in heartbeat

have trouble thinking clearly

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

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

provider about whether you have metabolic acidosis.

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

small number of people, about 1 in 500.

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

new, worse, or worry you:

thoughts about suicide or dying

attempts to commit suicide

new or worse depression

new or worse anxiety

feeling agitated or restless

panic attacks

trouble sleeping (insomnia)

new or worse irritability

acting aggressive, being angry, or violent

acting on dangerous impulses

an extreme increase in activity and talking (mania)

other unusual changes in behavior or mood

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

Stopping topiramate tablets suddenly can cause serious problems.

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

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

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

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

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

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

symptoms.

Topiramate tablets can harm your unborn baby.

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

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

pregnant.

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

medicines and do not have other risk factors.

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

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

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

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

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

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

You and your healthcare provider should decide if you will continue to take topiramate tablets while

you are pregnant.

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

topiramate tablets have caused metabolic acidosis during your pregnancy.

Pregnancy Registry: If you become pregnant while taking topiramate tablets, talk to your healthcare

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

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

information about the safety of antiepileptic drugs during pregnancy.

What are topiramate tablets?

Topiramate tablets are a prescription medicine used:

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

seizures) in adults and children 2 years and older,

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

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

2 years and older

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

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

including if you:

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

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

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

have liver problems

have weak, brittle, or soft bones (osteomalacia, osteoporosis, osteopenia, or decreased bone

density)

have lung or breathing problems

have eye problems, especially glaucoma

have diarrhea

have a growth problem

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

are having surgery

are pregnant or plan to become pregnant

are breastfeeding. Topiramate passes into breast milk. It is not known if the topiramate 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 topiramate tablets.

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

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

affect each other causing side effects.

Especially tell your healthcare provider if you take:

Valproic acid (such as DEPAKENE

or DEPAKOTE

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

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

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

topiramate tablets.

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

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

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

How should I take topiramate tablets?

Take topiramate tablets exactly as prescribed.

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

healthcare provider.

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

taste.

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

This may help prevent kidney stones while taking topiramate tablets.

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

away or go to the nearest emergency room.

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

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

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

one dose, you should call your healthcare provider for advice.

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

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

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

tell you how to stop taking topiramate tablets slowly.

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

What should I avoid while taking topiramate tablets?

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

other causing side effects such as sleepiness and dizziness.

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

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

What are the possible side effects of topiramate tablets?

Topiramate tablets may cause serious side effects including:

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

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

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

with a medicine called valproic acid (DEPAKENE

and DEPAKOTE

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

getting kidney stones.

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

a drop in body temperature to less then 95

F, feeling tired, confusion, or coma.

Effects on thinking and alertness. Topiramate tablets may affect how you think and cause confusion,

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

mood problems, tiredness, and sleepiness.

Dizziness or loss of muscle coordination.

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

The most common side effects of topiramate tablets include:

tingling of the arms and legs (paresthesia)

not feeling hungry

nausea

a change in the way foods taste

diarrhea

weight loss

nervousness

upper respiratory tract infection

speech problems

tiredness

dizziness

sleepiness/drowsiness

slow reactions

difficulty with memory

pain in the abdomen

fever

abnormal vision

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

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

healthcare provider or pharmacist.

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

FDA-1088.

How should I store topiramate tablets?

Store at 20° to 25°C (68°F to 77°F); [see USP Controlled Room Temperature]. Protect from

moisture.

Keep topiramate tablets in a tightly closed container.

Keep topiramate tablets dry and away from moisture.

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

General information about topiramate tablets.

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

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

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

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

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

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

For more information, go to www.camberpharma.com or call Camber Pharmaceuticals, Inc at 1-866-

495-8330.

What are the ingredients in topiramate tablets?

Active ingredient: topiramate, USP

Inactive ingredients: Topiramate tablets contain the following inactive ingredients: lactose monohydrate,

microcrystalline cellulose, pre-gelatinized starch (maize), sodium starch glycolate, magnesium

stearate, opadry white (titanium dioxide, hypromellose 3cp, hypromellose 6cp, PEG 400, polysorbate

80) for 25 mg tablets, opadry yellow (titanium dioxide, hypromellose 3cp, hypromellose 6cp, PEG 400,

polysorbate 80, iron oxide yellow) for 50 mg tablets, opadry yellow (hypromellose 3cp, hypromellose

6cp, titanium dioxide, PEG 400, iron oxide yellow, polysorbate 80, iron oxide red) for 100 mg tablets

and, opadry pink (titanium dioxide, hypromellose 6cp, PEG 400,iron oxide red) for 200 mg tablets.

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

All brands names listed are the registered trademarks of their respective owners and are not trademarks

of Camber Pharmaceuticals, Inc

Manufactured by:

Ascent Pharmaceuticals, Inc.

Central Islip, NY 11722

Manufactured for:

Camber Pharmaceuticals, Inc.

Piscataway, NJ 08854

Rev: 10/15

Barcode: 281-10-2015

DRUG: Topiramate

GENERIC: Topiramate

DOSAGE: TABLET

ADMINSTRATION: ORAL

NDC: 49349-802-02

COLOR: yellow

SHAPE: ROUND

SCORE: No score

SIZE: 10 mm

IMPRINT: IG;280

PACKAGING: 30 in 1 BLISTER PACK

ACTIVE INGREDIENT(S):

TOPIRAMATE 100mg in 1

INACTIVE INGREDIENT(S):

FERRIC OXIDE RED

HYPROMELLOSE 2910 (6 MPA.S)

POLYETHYLENE GLYCOL 400

FERRIC OXIDE YELLOW

HYPROMELLOSE 2910 (3 MPA.S)

POLYSORBATE 80

CELLULOSE, MICROCRYSTALLINE

LACTOSE MONOHYDRATE

STARCH, CORN

MAGNESIUM STEARATE

SILICON DIOXIDE

SODIUM STARCH GLYCOLATE TYPE A POTATO

TOPIRAMATE

topiramate tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:49 349 -8 0 2(NDC:31722-28 0 )

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

TO PIRAMATE (UNII: 0 H73WJJ39 1) (TOPIRAMATE - UNII:0 H73WJJ39 1)

TOPIRAMATE

10 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

STARCH, CO RN (UNII: O8 232NY3SJ)

SO DIUM STARCH GLYCO LATE TYPE A PO TATO (UNII: 58 56 J3G2A2)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

HYPRO MELLO SE 2 9 10 ( 3 MPA.S) (UNII: 0 VUT3PMY8 2)

HYPRO MELLO SE 2 9 10 ( 6 MPA.S) (UNII: 0 WZ8 WG20 P6 )

REMEDYREPACK INC.

PO LYETHYLENE GLYCO L 4 0 0 (UNII: B6 9 78 9 4SGQ)

PO LYSO RBATE 8 0 (UNII: 6 OZP39 ZG8 H)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

Product Characteristics

Color

yello w (Light yello w)

S core

no sco re

S hap e

ROUND

S iz e

10 mm

Flavor

Imprint Code

IG;28 0

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date Marketing End Date

1

NDC:49 349 -8 0 2-

30 in 1 BLISTER PACK; Type 0 : No t a Co mbinatio n

Pro duc t

10 /31/20 11

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 79 16 2

10 /31/20 11

Labeler -

REMEDYREPACK INC. (829572556)

Revised: 11/2016

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