Topiramate ER Capsules

Epilepsy

Monotherapy Use

Adults and Pediatric Patients 10 Years and Older with Partial Onset or Primary Generalized Tonic-Clonic Seizures

The recommended dose for topiramate monotherapy in adults and pediatric patients 10 years of age and older is 400 mg orally once daily. Titrate topiramate extended-release capsules according to the following schedule [Table 1]:

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

	Topiramate Extended-release Capsules Once Daily Dose
Week 1	50 mg
Week 2	100 mg
Week 3	150 mg
Week 4	200 mg
Week 5	300 mg
Week 6	400 mg

Pediatric Patients 2 to less than 10 Years with Partial Onset or Primary Generalized Tonic-Clonic Seizures

Dosing in patients 2 to less than 10 years is based on weight. During the titration period, the initial dose of topiramate extended-release capsules should be 25 mg once daily given at nighttime for the first week. Based upon tolerability, the dosage can be increased to 50 mg once daily in the second week. Dosage can be increased by 25 mg to 50 mg once daily each subsequent week, as tolerated. Titration to the minimum maintenance dose should be attempted over 5 to 7 weeks. Based upon tolerability and clinical response, additional titration to a higher dose (up to the maximum maintenance dose) can be attempted in weekly increments by 25 mg to 50 mg once daily, up to the maximum recommended maintenance dose for each range of body weight [see Table 2].

Table 2: Monotherapy Target Once Daily Maintenance Dosing for Patients 2 to Less Than 10 Years

Weight (kg)	Once Daily Dose (mg per day) Minimum Maintenance Dose	Once Daily Dose (mg per day) Maximum Maintenance Dose
Up to 11	150	250
12 to 22	200	300
23 to 31	200	350
32 to 38	250	350
Greater than 38	250	400

Adjunctive Therapy Use

Adults (17 Years of Age and Older) - Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome

The recommended total daily dose of topiramate extended-release capsules as adjunctive therapy in adults with partial onset seizures or Lennox-Gastaut Syndrome is 200 mg to 400 mg orally once daily. The recommended total dose for adults with primary generalized tonic-clonic seizures is 400 mg orally once daily.

Initiate therapy at 25 mg to 50 mg once daily followed by titration to an effective dose in increments of 25 mg to 50 mg every week. Daily topiramate doses above 1,600 mg have not been studied.

In the study of primary generalized tonic-clonic seizures using topiramate, the assigned dose was reached at the end of 8 weeks [see Clinical Studies (14.4)].

Pediatric Patients (Ages 2 Years to 16 Years) - Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome

The recommended total daily dose of topiramate extended-release capsules 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 mg/kg to 9 mg/kg orally once daily. Begin titration at 25 mg once daily (based on a range of 1 mg/kg/day to 3 mg/kg/day) given nightly for the first week. Subsequently, increase the dosage at 1 or 2 week intervals by increments of 1 mg/kg to 3 mg/kg to achieve optimal clinical response. Dose titration should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used.

In the study of primary generalized tonic-clonic seizures, the assigned dose of 6 mg/kg once daily was reached at the end of 8 weeks [see Clinical Studies (14.3, 14.4, and 14.5)].

Migraine

The recommended total daily dose of topiramate extended-release capsules as treatment for prophylaxis of migraine headache in adults and adolescents 12 years of age and older is 100 mg once daily. The recommended titration rate for topiramate extended-release capsules for migraine prophylaxis to 100 mg/day is:

Table 3: Migraine Prophylaxis Titration Schedule for Adults and Adolescents 12 years of Age and Older

	Topiramate Extended-release Capsules Once Daily Dose
Week 1	25 mg
Week 2	50 mg
Week 3	75 mg
Week 4	100 mg

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

Dose Modifications in Patients with Renal Impairment

In patients with renal impairment (creatinine clearance less than 70 mL/min/1.73 m2), one-half of the usual adult dose is recommended. Such patients will require a longer time to reach steady-state at each dose [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

Prior to dosing, obtain an estimated creatinine clearance (CrCl) in patients at high risk for renal insufficiency (e.g., older patients, or those with diabetes mellitus, hypertension, or autoimmune disease). CrCl can be estimated using the following equation (multiply by 0.85 for women):

CrCl =	(140 - age) × weight(kg)
	SerumCr(mg / dl) × 72

Dosage Modifications in Patients Undergoing Hemodialysis

Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than in patients with normal renal function. 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
• clearance rate of the dialysis system being used
• effective renal clearance of topiramate in the patient being dialyzed [see Use in Specific Populations (8.8) and Clinical Pharmacology (12.3)].

Laboratory Testing Prior to Treatment Initiation

Measurement of baseline and periodic serum bicarbonate during topiramate extended-release capsules treatment is recommended [see Warnings and Precautions (5.4)].

Dosing Modifications in Patients Taking Phenytoin and/or Carbamazepine

The co-administration of topiramate extended-release capsules with 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 extended-release capsules may require adjustment of the dose of topiramate extended-release capsules [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

Monitoring for Therapeutic Blood Levels

It is not necessary to monitor topiramate plasma concentrations to optimize topiramate extended-release capsules therapy.

Administration Instructions

Topiramate extended-release capsules may be swallowed whole or may be administered by carefully opening the capsule and sprinkling the entire contents on a small amount (teaspoon) of soft food. This drug/food mixture should be swallowed immediately and not chewed or crushed. Do not store drug/food mixture for further use. Topiramate extended-release capsules can be taken without regard to meals [see Clinical Pharmacology (12.3)].

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 extended-release capsules as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of topiramate extended-release capsules, may be helpful.

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

Visual Field Defects

Visual field defects have been reported in patients receiving topiramate independent of elevated intraocular pressure. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during treatment with topiramate extended-release capsules, consideration should be given to discontinuing the drug.

Oligohydrosis and Hyperthermia

Oligohydrosis (decreased sweating), resulting in hospitalization in some cases, 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 extended-release capsules should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when topiramate extended-release capsules are 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 [see Drug Interactions (7.4)].

Metabolic Acidosis

Hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) is associated with topiramate treatment. This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of topiramate on carbonic anhydrase. Such electrolyte imbalance has been observed with the use of topiramate in placebo-controlled clinical trials and in the post-marketing period. Generally, topiramate-induced metabolic acidosis occurs early in treatment although cases can occur at any time during treatment. Bicarbonate decrements are usually mild-moderate (average decrease of 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose patients to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet or specific drugs) may be additive to the bicarbonate lowering effects of topiramate.

Manifestations of Metabolic Acidosis

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 are likely to have different growth rates than normal infants. Reductions in Z SCORES for length and weight were correlated to the degree of acidosis [see Use in Specific Populations (8.4)]. Topiramate treatment that causes metabolic acidosis during pregnancy can possibly produce adverse effects on the fetus and might also cause metabolic acidosis in the neonate from possible transfer of topiramate to the fetus [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1)].

Epilepsy

Adult Patients

In adults, the incidence of persistent decreases in serum bicarbonate (levels of less than 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 per day, and 1% for placebo. Metabolic acidosis has been observed at doses as low as 50 mg per day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in the adjunctive therapy trials was 3% for 400 mg per day and 0% for placebo. The incidence of persistent decreases in serum bicarbonate in adult patients (≥16 years of age) in the epilepsy controlled clinical trial for monotherapy was 14% for 50 mg per day and 25% for 400 mg per day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in this trial for adults was 1% for 50 mg per day and 6% for 400 mg per day. Serum bicarbonate levels have not been systematically evaluated at daily doses greater than 400 mg per day.

Pediatric Patients (2 years to 16 years of age)

The incidence of persistent decreases in serum bicarbonate in placebo-controlled trials for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures in patients age 2 years to 16 years 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 less than 17 mEq/L and greater than 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.

In pediatric patients (6 years to 15 years of age), the incidence of persistent decreases in serum bicarbonate in the epilepsy controlled clinical trial for monotherapy performed with topiramate was 9% for 50 mg per day and 25% for 400 mg per day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in this trial was 1% for 50 mg per day and 6% for 400 mg per day.

Pediatric Patients (under 2 years of age)

Although topiramate extended-release capsules are not approved for use in patients less than 2 years of age, a study of topiramate as adjunctive use in patients under 2 years of age with partial onset seizures 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 less than 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., less than 17 mEq/L and greater than 5 mEq/L decrease from baseline of greater than or equal to 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 Specific Populations (8.4)].

Migraine

Adult Patients

The incidence of persistent decreases in serum bicarbonate in placebo-controlled trials in adults for the prophylaxis of migraine was 44% for 200 mg/day, 39% for 100 mg/day, 23% for 50 mg/day, and 7% for placebo. The incidence of markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in these trials was 11% for 200 mg/day, 9% for 100 mg/day, 2% for 50 mg/day, and <1% for placebo.

Adolescent Patients

In pooled, double-blind migraine prophylaxis studies in adolescent patients (12 to 17 years of age), the incidence of persistent decreases in serum bicarbonate was 77% for 200 mg/day, 27% for 100 mg/day, 30% for 50 mg/day, and 9% for placebo. The incidence of markedly low serum bicarbonate (i.e., absolute value <17 mEq/L and >5 mEq/L decrease from pretreatment) was 6% for 100 mg/day, 2% for 50 mg/day, and 2% for placebo. This bicarbonate criterion was not met by any patients in the 200 mg/day group, which had a low number of subjects (n=13).

Measurement of Serum Bicarbonate in Epilepsy and Migraine Patients

Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering). If the decision is made to continue patients on topiramate in the face of persistent acidosis, alkali treatment should be considered.

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED, including topiramate extended-release capsules, for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.

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

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

Indication	Placebo Patients with Events per 1,000 Patients	Drug Patients with Events per 1,000 Patients	Relative Risk: Incidence of Events in Drug Patients/ Incidence in Placebo Patients	Risk Difference: Additional Drug Patients with Events per 1,000 Patients
Epilepsy	1.0	3.4	3.5	2.4
Psychiatric	5.7	8.5	1.5	2.9
Other	1.0	1.8	1.9	0.9
Total	2.4	4.3	1.8	1.9

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

Anyone considering prescribing topiramate extended-release capsules 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.

Cognitive/Neuropsychiatric Adverse Reactions

Adverse reactions most often associated with the use of topiramate, and therefore expected to be associated with the use of topiramate extended-release capsules, were related to the central nervous system and were observed in both the epilepsy and migraine populations. In adults, the most frequent of these can be classified into three general categories: 1) 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 (6.1)].

In the adjunctive epilepsy controlled trials conducted with topiramate (using rapid titration such as 100 mg per day to 200 mg per day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions was 42% for 200 mg per day, 41% for 400 mg per day, 52% for 600 mg per day, 56% for 800 and 1,000 mg per 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 conducted with topiramate, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg per day and 26% for 400 mg per day.

In the 6-month migraine prophylaxis controlled trials using a slower titration regimen (25 mg/day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg/day, 22% for 100 mg/day (the recommended dose), 28% for 200 mg/day, and 10% for placebo. These dose-related adverse reactions typically began in the titration phase and often persisted into the maintenance phase, but infrequently began in the maintenance phase. Some patients experienced a recurrence of one or more of these cognitive adverse reactions and this recurrence was typically in the titration phase. A relatively small proportion of topiramate-treated patients experienced more than one concurrent cognitive adverse reaction. The most common cognitive adverse reactions occurring together included difficulty with memory along with difficulty with concentration/attention, difficulty with memory along with language problems, and difficulty with concentration/attention along with language problems. Rarely, topiramate-treated patients experienced three concurrent cognitive reactions.

Psychiatric/Behavioral Disturbances

Psychiatric/behavioral disturbances (depression or mood) were dose-related for both the epilepsy and migraine populations treated with topiramate [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].

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 per day and 1,000 mg per day, but the incidence of fatigue was dose-related and increased at dosages above 400 mg per day. For the monotherapy epilepsy population in the 50 mg per day and 400 mg per day groups, the incidence of somnolence was dose-related (9% for the 50 mg per day group and 15% for the 400 mg per day group) and the incidence of fatigue was comparable in both treatment groups (14% each).

For the migraine population, somnolence and fatigue were dose-related and more common in the titration phase.

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

Pediatric Patients

Epilepsy

In double-blind adjunctive therapy and monotherapy epilepsy clinical studies conducted with topiramate, 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 per day and 400 mg per 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 conducted with immediate-release topiramate product, 1 pediatric patient (2%) in the 50 mg per day group and 7 pediatric patients (12%) in the 400 mg per 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 per day group.

Migraine

The incidence of cognitive adverse reactions was increased in topiramate-treated patients (7%) versus placebo (4%) in pooled, double-blind placebo-controlled studies in which adolescent patients (12 to 17 years) were randomized to placebo or one of several fixed daily doses of topiramate (50 mg, 100 mg, 200 mg).

The incidence of cognitive adverse reactions was also increased in a placebo-controlled study of pediatric patients (6 to 16 years) treated with 2 to 3 mg/kg/day of topiramate (10%) versus placebo treatment (2%). Topiramate extended-release capsules are not approved for prophylaxis of migraine in pediatric patients under 12 years of age.

The risk for cognitive adverse reactions was dose-dependent, and was particularly evident at the 200 mg dose. This risk for cognitive adverse reactions was also greater in younger patients (6 to 11 years) than in older patients (12 to 17 years). The most common cognitive adverse reaction in these trials was difficulty with concentration/attention. Cognitive adverse reactions most commonly developed in the titration period and sometimes persisted into the maintenance period. These adverse reactions typically occurred in isolation as single type of cognitive adverse reaction. Cognitive adverse reactions that led to study discontinuation occurred in one patient (difficulty with concentration/attention and language problems). The Cambridge Neuropsychological Test Automated Battery (CANTAB) was administered to adolescents (12 to 17 years) to assess the effects of topiramate on cognitive function at baseline and at the end of the Study 3 [see Clinical Studies (14.7)]. Mean change from baseline in certain CANTAB tests suggests that topiramate treatment may result in psychomotor slowing and decreased verbal fluency.

Fetal Toxicity

Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or cleft palate (oral clefts) and for being small for gestational age. In multiple species, oral administration of topiramate to pregnant animals at clinically relevant doses resulted in structural malformations, including craniofacial defects, and reduced body weights in offspring [see Use in Specific Populations (8.1)].

Consider the benefits and risks of topiramate when administering the drug in women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death [see Use in Specific Populations (8.1)]. 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 informed of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

Withdrawal of Antiepileptic Drugs

In patients with or without a history of seizures or epilepsy, antiepileptic drugs including topiramate extended-release capsules, 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 extended-release capsules is medically required, appropriate monitoring is recommended.

Hyperammonemia and Encephalopathy

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) who were treated with topiramate for migraine prophylaxis. 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 month 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). Topiramate extended-release capsules are not approved as adjunctive treatment of partial onset seizures in pediatric patients less than 2 years old. In some patients, ammonia was markedly increased (greater than 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 also observed in the extension trial in pediatric patients up to 2 years old. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting.

Hyperammonemia with and without encephalopathy has also been observed in post-marketing reports in patients who were taking topiramate without concomitant valproic acid (VPA).

Hyperammonemia/Encephalopathy With Concomitant Valproic Acid (VPA)

Concomitant administration of topiramate and valproic acid (VPA) has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone based upon post-marketing reports. Although hyperammonemia may be asymptomatic, clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is not due to a pharmacokinetic interaction.

Although topiramate extended-release capsules are not indicated for use in infants/toddlers (1 month to 24 months), topiramate with concomitant VPA clearly produced a dose-related increase in the incidence of 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 using topiramate. Markedly increased, dose-related hyperammonemia (0% for placebo and 5 mg/kg/day, 7% for 15 mg/kg/day, and 8% for 25 mg/kg/day) also occurred in these infants/toddlers. Dose-related hyperammonemia was similarly observed in a long-term, extension trial utilizing topiramate in these very young, pediatric patients [see Use in Specific Populations (8.4)].

Hyperammonemia with and without encephalopathy has also been observed in post-marketing reports in patients taking topiramate with valproic acid (VPA).

The hyperammonemia associated with topiramate treatment appears to be more common when 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 or topiramate extended-release capsules treatment or an interaction of concomitant topiramate-based product 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.

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 or migraine.

During long-term (up to 1 year) topiramate treatment in an open-label extension study of 284 pediatric patients 1 month to 24 months old with epilepsy, 7% developed kidney or bladder stones that were diagnosed clinically or by sonogram. Topiramate extended-release capsules are not approved for pediatric patients less than 2 years old [see Use in Specific Populations (8.4)].

Kidney stones have also been reported in pediatric patients taking topiramate for migraine prophylaxis. For the double-blind migraine prophylaxis studies, one adverse event (renal calculus) occurred in a topiramate-treated subject in the age 12 to 17 years group. The overall experience with open-label, long-term, topiramate treatment for migraine prophylaxis is limited in pediatric patients.

Topiramate extended-release capsules would be expected to have the same effect as topiramate on the formation of kidney stones. An explanation for the association of topiramate and kidney stones may lay in the fact that topiramate is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) can promote stone formation by reducing urinary citrate excretion and by increasing urinary pH [see Warnings and Precautions (5.4), Drug Interactions (7.4) and Clinical Pharmacology (12.3)]. The concomitant use of topiramate extended-release capsules 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.

Hypothermia with Concomitant Valproic Acid Use

Hypothermia, defined as an unintentional drop in body core temperature to less than 35°C (95°F) has been reported in association with topiramate use with concomitant valproic acid (VPA) both in the presence 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 (7.2) and Clinical Pharmacology (12.3)]. 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.

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 and migraine prophylaxis trials conducted with immediate-release topiramate than in the adjunctive therapy epilepsy trials conducted with the same product. In the majority of instances, paresthesia did not lead to treatment discontinuation [see Adverse Reactions (6.1)].

Interaction with Other CNS Depressants

Topiramate is a CNS depressant. Concomitant administration of topiramate with other CNS depressant drugs or alcohol can result in significant CNS depression. Patients should be watched carefully when topiramate extended-release capsules are co-administered with other CNS depressant drugs [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].

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

• Acute Myopia and Secondary Angle Closure Glaucoma [see Warnings and Precautions (5.1)]
• Visual Field Defects [see Warnings and Precautions (5.2)]
• Oligohydrosis 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)]
• Hyperammonemia and Encephalopathy [see Warnings and Precautions (5.9)]
• Kidney Stones [see Warnings and Precautions (5.10)]
• Hypothermia with Concomitant Valproic Acid Use [see Warnings and Precautions (5.11)]
• Paresthesia [see Warnings and Precautions (5.12)]

Clinical Trials Experience with Immediate-Release Topiramate

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical 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 topiramate than 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 topiramate and placebo was 0.3% versus 0.2% for adult patients, and 0.4% versus 0% for pediatric patients.

Adverse bleeding reactions reported with topiramate ranged 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).

Adverse Reactions Observed in Monotherapy Epilepsy Trial

Adult Patients 16 Years of Age and Older

The adverse reactions in the monotherapy controlled trial (Study 1) that occurred most commonly in adults in the 400 mg per day topiramate group and at an incidence ≥ 5% higher than the 50 mg per day group were paresthesia, weight decrease, somnolence, anorexia, and difficulty with memory [see Table 5].

Approximately 21% of the 159 adult patients in the 400 mg per day group who received topiramate as monotherapy in Study 1 discontinued therapy due to adverse reactions. The most common (≥ 2% more frequent than for topiramate 50 mg per day) adverse reactions causing discontinuation in this trial were difficulty with memory, fatigue, asthenia, insomnia, somnolence, and paresthesia.

Pediatric Patients 6 to less than 16 Years of Age

The adverse reactions in Study 1 that occurred most commonly in pediatric patients in the 400 mg per day topiramate group and at an incidence ≥ 5% higher than in the 50 mg per day group were fever, weight decrease, mood problems, cognitive problems, infection, flushing, and paresthesia [see Table 5].

Approximately 14% of the 77 pediatric patients in the 400 mg per day group who received topiramate as monotherapy in Study 1 discontinued therapy due to adverse reactions. The most common (≥ 2% more frequent than for topiramate 50 mg per day) adverse reactions resulting in discontinuation in this trial were difficulty with concentration/attention, fever, flushing, and confusion.

Table 5: Adverse Reactions in the Immediate-Release Topiramate Monotherapy Trial with Incidence ≥2% in Any Topiramate Group and Incidence in the 400 mg per Day Group Greater Than in the 50 mg per Day Group

	Age Group
	Pediatric (6 to <16 Years)		Adult (Age ≥16 Years)
	Immediate-release Topiramate Daily Dosage Group (mg per day)
	50	400	50	400
Body System/	(N=74)	(N=77)	(N=160)	(N=159)
Adverse Reaction	%*	%*	%*	%*
* Percentages calculated with the number of subjects in each group as denominator † N with Female Reproductive Disorders – Incidence calculated relative to the number of females; Pediatric TPM 50 mg n=40; Pediatric TPM 400 mg n=33; Adult TPM 50 mg n=84; TPM 400 mg n=80
Body as a Whole-General Disorders
Asthenia	0	3	4	6
Chest pain			1	2
Fever	1	12
Leg pain			2	3
Central & Peripheral Nervous System Disorders
Ataxia			3	4
Dizziness			13	14
Hypertonia			0	3
Hypoesthesia			4	5
Muscle contractions involuntary	0	3
Paresthesia	3	12	21	40
Vertigo	0	3
Gastro-Intestinal System Disorders
Constipation			1	4
Diarrhea	8	9
Gastritis			0	3
Gastroesophageal reflux			1	2
Dry mouth			1	3
Liver and Biliary System Disorders
Gamma-GT increased			1	3
Metabolic and Nutritional Disorders
Weight Decrease	7	17	6	17
Platelet, Bleeding & Clotting Disorders
Epistaxis	0	4
Psychiatric Disorders
Anorexia			4	14
Anxiety			4	6
Cognitive problems	1	6	1	4
Confusion	0	3
Depression	0	3	7	9
Difficulty with concentration/attention	7	10	7	8
Difficulty with memory	1	3	6	11
Insomnia			8	9
Libido decreased			0	3
Mood problems	1	8	2	5
Personality disorder (behavior problems)	0	3
Psychomotor slowing			3	5
Somnolence			10	15
Red Blood Cell Disorders
Anemia	1	3
Reproductive Disorders, Female†
Intermenstrual bleeding	0	3
Vaginal hemorrhage			0	3
Resistance Mechanism Disorders
Infection	3	8	2	3
Infection viral	3	6	6	8
Respiratory System Disorders
Bronchitis	1	5	3	4
Dyspnea			1	2
Rhinitis	5	6	2	4
Sinusitis	1	4
Upper respiratory tract infection	16	18
Skin and Appendages Disorders
Acne			2	3
Alopecia	1	4	3	4
Pruritus			1	4
Rash	3	4	1	4
Special Senses Other, Disorders
Taste perversion			3	5
Urinary System Disorders
Cystitis			1	3
Dysuria			0	2
Micturition frequency	0	3	0	2
Renal calculus			0	3
Urinary incontinence	1	3
Urinary tract infection			1	2
Vascular (Extracardiac) Disorders
Flushing	0	5

Adverse Reactions Observed in Adjunctive Therapy Epilepsy Trials

The most commonly observed adverse reactions associated with the use of topiramate at dosages of 200 to 400 mg per 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 of 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 mg to 1,000 mg per day are shown in Table 8.

The most commonly observed adverse reactions associated with the use of topiramate at dosages of 5 mg/kg/day 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 per day as adjunctive therapy discontinued due to adverse reactions. This rate appeared to increase at dosages above 400 mg per day. Adverse events associated with discontinuing therapy included somnolence, dizziness, anxiety, difficulty with concentration or attention, fatigue, and paresthesia and increased at dosages above 400 mg per day. None of the pediatric patients who received topiramate adjunctive therapy at 5 mg/kg/day 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 mg to 1,600 mg per day in clinical studies discontinued treatment because of adverse reactions; an individual patient could have reported more than one adverse reaction. These adverse reactions were: psychomotor slowing (4.0%), difficulty with memory (3.2%), fatigue (3.2%), confusion (3.1%), somnolence (3.2%), difficulty with concentration/attention (2.9%), anorexia (2.7%), depression (2.6%), dizziness (2.5%), weight decrease (2.5%), nervousness (2.3%), ataxia (2.1%), and paresthesia (2.0%). Approximately 11% of the 310 pediatric patients who received topiramate at dosages up to 30 mg/kg/day discontinued due to adverse reactions. Adverse reactions associated with discontinuing therapy included aggravated convulsions (2.3%), difficulty with concentration/attention (1.6%), language problems (1.3%), personality disorder (1.3%), and somnolence (1.3%).

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 per day topiramate (and also higher daily dosing of 600 mg to 1,000 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 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.

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 mg 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 Adverse Reactions in Placebo-Controlled, Adjunctive Epilepsy Trials in Adults*,†,‡

		Topiramate Dosage (mg per day)
Body System/	Placebo	200 to 400	600 to 1,000
Adverse Reaction‡	(N=291)	(N=183)	(N=414)
* Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo † Values represent the percentage of patients reporting a given reaction. Patient may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category. ‡ Adverse reactions reported by at least 1% of patients in the topiramate 200 mg to 400 mg per day group and more common than in the placebo group
Body as a Whole-General Disorders
Fatigue	13	15	30
Asthenia	1	6	3
Back pain	4	5	3
Chest pain	3	4	2
Influenza-like symptoms	2	3	4
Leg pain	2	2	4
Hot flushes	1	2	1
Allergy	1	2	3
Edema	1	2	1
Body odor	0	1	0
Rigors	0	1	<1
Central & Peripheral Nervous System Disorders
Dizziness	15	25	32
Ataxia	7	16	14
Speech disorders/Related speech problems	2	13	11
Paresthesia	4	11	19
Nystagmus	7	10	11
Tremor	6	9	9
Language problems	1	6	10
Coordination abnormal	2	4	4
Hypoesthesia	1	2	1
Gait abnormal	1	3	2
Muscle contractions involuntary	1	2	2
Stupor	0	2	1
Vertigo	1	1	2
Gastro-Intestinal System Disorders
Nausea	8	10	12
Dyspepsia	6	7	6
Abdominal pain	4	6	7
Constipation	2	4	3
Gastroenteritis	1	2	1
Dry mouth	1	2	4
Gingivitis	<1	1	1
GI disorder	<1	1	0
Hearing and Vestibular Disorders
Hearing decreased	1	2	1
Metabolic and Nutritional Disorders
Weight decrease	3	9	13
Musculo-Skeletal System Disorders
Myalgia	1	2	2
Skeletal pain	0	1	0
Platelet, Bleeding & Clotting Disorders
Epistaxis	1	2	1
Psychiatric Disorders
Somnolence	12	29	28
Nervousness	6	16	19
Psychomotor slowing	2	13	21
Difficulty with memory	3	12	14
Anorexia	4	10	12
Confusion	5	11	14
Depression	5	5	13
Difficulty with concentration/attention	2	6	14
Mood problems	2	4	9
Agitation	2	3	3
Aggressive reaction	2	3	3
Emotional lability	1	3	3
Cognitive problems	1	3	3
Libido decreased	1	2	<1
Apathy	1	1	3
Depersonalization	1	1	2
Reproductive Disorders, Female
Breast pain	2	4	0
Amenorrhea	1	2	2
Menorrhagia	0	2	1
Menstrual disorder	1	2	1
Reproductive Disorders, Male
Prostatic disorder	<1	2	0
Resistance Mechanism Disorders
Infection	1	2	1
Infection viral	1	2	<1
Moniliasis	<1	1	0
Respiratory System Disorders
Pharyngitis	2	6	3
Rhinitis	6	7	6
Sinusitis	4	5	6
Dyspnea	1	1	2
Skin and Appendages Disorders
Skin disorder	<1	2	1
Sweating increased	<1	1	<1
Rash, erythematous	<1	1	<1
Special Senses Other, Disorders
Taste perversion	0	2	4
Urinary System Disorders
Hematuria	1	2	<1
Urinary tract infection	1	2	3
Micturition frequency	1	1	2
Urinary incontinence	<1	2	1
Urine abnormal	0	1	<1
Vision Disorders
Vision abnormal	2	13	10
Diplopia	5	10	10
White Cell and RES Disorders
Leukopenia	1	2	1

Adverse Reactions Observed in Adjunctive Therapy Trial in Adults with Partial Onset Seizures (Study 7)

Study 7 was a randomized, double-blind, adjunctive, placebo-controlled, parallel group study with 3 treatment arms: 1) placebo; 2) topiramate 200 mg per day with a 25 mg per day starting dose, increased by 25 mg per day each week for 8 weeks until the 200 mg per day maintenance dose was reached; and 3) topiramate 200 mg per day with a 50 mg per day starting dose, increased by 50 mg per day each week for 4 weeks until the 200 mg per 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 (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.

Table 7: Incidence of Adverse Reactions in Study 7*,†,‡

		Topiramate Dosage (mg per day)
Body System/	Placebo	200
Adverse Reaction‡	(N=92)	(N=171)
* Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo † Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category ‡ Adverse reactions reported by at least 2% of patients in the topiramate 200 mg per day group and more common than in the placebo group
Body as a Whole-General Disorders
Fatigue	4	9
Chest pain	1	2
Cardiovascular Disorders, General
Hypertension	0	2
Central & Peripheral Nervous System Disorders
Paresthesia	2	9
Dizziness	4	7
Tremor	2	3
Hypoesthesia	0	2
Leg cramps	0	2
Language problems	0	2
Gastro-Intestinal System Disorders
Abdominal pain	3	5
Constipation	0	4
Diarrhea	1	2
Dyspepsia	0	2
Dry mouth	0	2
Hearing and Vestibular Disorders
Tinnitus	0	2
Metabolic and Nutritional Disorders
Weight decrease	4	8
Psychiatric Disorders
Somnolence	9	15
Anorexia	7	9
Nervousness	2	9
Difficulty with concentration/attention	0	5
Insomnia	3	4
Difficulty with memory	1	2
Aggressive reaction	0	2
Respiratory System Disorders
Rhinitis	0	4
Urinary System Disorders
Cystitis	0	2
Vision Disorders
Diplopia	0	2
Vision abnormal	0	2

Table 8: Incidence (%) of Dose-Related Adverse Reactions From Placebo-Controlled, Adjunctive Trials in Adults With Partial Onset Seizures (Studies 2 through 7)*

		Topiramate Dosage (mg per day)
Adverse Reaction	Placebo (N=216)	200 (N=45)	400 (N=68)	600 to 1,000 (N=414)
* Dose-response studies were not conducted for other adult indications or for pediatric indications
Fatigue	13	11	12	30
Nervousness	7	13	18	19
Difficulty with concentration/attention	1	7	9	14
Confusion	4	9	10	14
Depression	6	9	7	13
Anorexia	4	4	6	12
Language Problems	<1	2	9	10
Anxiety	6	2	3	10
Mood Problems	2	0	6	9
Weight Decrease	3	4	9	13

Table 9: Incidence (%) of Adverse Reaction in Placebo-Controlled, Adjunctive Epilepsy Trial in Pediatric Patients (Ages 2 Years to 16 Years)*,†,‡ (Study 8)

Body System/	Placebo	Topiramate
Adverse Reaction	(N=101)	(N=98)
* Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo † Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category ‡ Reactions that Occurred in at Least 1% of Topiramate-Treated Patients and Occurred More Frequently in Topiramate-Treated Than Placebo-Treated Patients
Body as a Whole-General Disorders
Fatigue	5	16
Injury	13	14
Allergic reaction	1	2
Back pain	0	1
Pallor	0	1
Cardiovascular Disorders, General
Hypertension	0	1
Central & Peripheral Nervous System Disorders
Gait abnormal	5	8
Ataxia	2	6
Hyperkinesia	4	5
Dizziness	2	4
Speech disorders/Related speech problems	2	4
Hyporeflexia	0	2
Convulsions grand mal	0	1
Fecal incontinence	0	1
Paresthesia	0	1
Gastro-Intestinal System Disorders
Nausea	5	6
Saliva increased	4	6
Constipation	4	5
Gastroenteritis	2	3
Dysphasia	0	1
Flatulence	0	1
Gastroesophageal reflux	0	1
Glossitis	0	1
Gum hyperplasia	0	1
Heart Rate and Rhythm Disorders
Bradycardia	0	1
Metabolic and Nutritional Disorders
Weight decrease	1	9
Thirst	1	2
Hypoglycemia	0	1
Weight increase	0	1
Platelet, Bleeding & Clotting Disorders
Purpura	4	8
Epistaxis	1	4
Hematoma	0	1
Prothrombin increased	0	1
Thrombocytopenia	0	1
Psychiatric Disorders
Somnolence	16	26
Anorexia	15	24
Nervousness	7	14
Personality disorder (Behavior Problems)	9	11
Difficulty with concentration/attention	2	10
Aggressive reaction	4	9
Insomnia	7	8
Difficulty with memory	0	5
Confusion	3	4
Psychomotor slowing	2	3
Appetite increased	0	1
Neurosis	0	1
Reproductive Disorders, Female
Leukorrhea	0	2
Resistance Mechanism Disorders
Infection viral	3	7
Respiratory System Disorders
Pneumonia	1	5
Respiratory disorder	0	1
Skin and Appendages Disorders
Skin Disorder	2	3
Alopecia	1	2
Dermatitis	0	2
Hypertrichosis	1	2
Rash erythematous	0	2
Eczema	0	1
Seborrhea	0	1
Skin discoloration	0	1
Urinary System Disorders
Urinary incontinence	2	4
Nocturia	0	1
Vision Disorders
Eye abnormality	1	2
Vision abnormal	1	2
Diplopia	0	1
Lacrimation abnormal	0	1
Myopia	0	1
White Cell and RES Disorders
Leukopenia	0	2

Migraine

Adults

In the four multicenter, randomized, double-blind, placebo-controlled, parallel group migraine prophylaxis clinical trials (which included 35 adolescent patients age 12 to 15 years), most of the adverse reactions with topiramate were mild or moderate in severity. Most adverse reactions occurred more frequently during the titration period than during the maintenance period.

The most common (≥5% more frequent than placebo) adverse reactions associated with the use of the 100 mg topiramate dose in controlled, migraine clinical trials of predominantly adults were paresthesia, anorexia, weight decrease, taste perversion, diarrhea, difficulty with memory, hypoesthesia, and nausea. Table 10 includes those adverse reactions reported for patients in the placebo-controlled trials where the incidence in any topiramate treatment group was at least 2% and was greater than that for placebo patients.

Table 10: Incidence (%) of Adverse Reactions in Placebo-Controlled, Migraine Trials Where Incidence Was ≥2% in Any Topiramate Group and Greater Than the Rate in Placebo-Treated Patients*,†

	Topiramate Dosage (mg per day)
	Placebo	50	100	200
Body System/	(N=445)	(N=235)	(N=386)	(N=514)
Adverse Reaction	%	%	%	%
* Includes 35 adolescent patients age 12 to 15 years. † Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category. ‡ Blurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for >50% of reactions coded as vision abnormal, a preferred term.
Body as a Whole-General Disorders
Fatigue	11	14	15	19
Injury	7	9	6	6
Asthenia	1	<1	2	2
Fever	1	1	1	2
Influenza-like symptoms	<1	<1	<1	2
Allergy	<1	2	<1	<1
Central & Peripheral Nervous System Disorders
Paresthesia	6	35	51	49
Dizziness	10	8	9	12
Hypoesthesia	2	6	7	8
Language problems	2	7	6	7
Involuntary muscle contractions	1	2	2	4
Ataxia	<1	1	2	1
Speech disorders/Related speech problems	<1	1	<1	2
Gastro-Intestinal System Disorders
Nausea	8	9	13	14
Diarrhea	4	9	11	11
Abdominal pain	5	6	6	7
Dyspepsia	3	4	5	3
Dry mouth	2	2	3	5
Vomiting	2	1	2	3
Gastroenteritis	1	3	3	2
Hearing and Vestibular Disorders
Tinnitus	1	<1	1	2
Metabolic and Nutritional Disorders
Weight decrease	1	6	9	11
Thirst	<1	2	2	1
Musculoskeletal System Disorders
Arthralgia	2	7	3	1
Neoplasms
Neoplasm	<1	2	<1	<1
Psychiatric Disorders
Anorexia	6	9	15	14
Somnolence	5	8	7	10
Difficulty with memory	2	7	7	11
Difficulty with concentration/attention	2	3	6	10
Insomnia	5	6	7	6
Anxiety	3	4	5	6
Mood problems	2	3	6	5
Depression	4	3	4	6
Nervousness	2	4	4	4
Confusion	2	2	3	4
Psychomotor slowing	1	3	2	4
Libido decreased	1	1	1	2
Aggravated depression	1	1	2	2
Agitation	1	2	2	1
Cognitive problems	1	<1	2	2
Reproductive Disorders, Female
Menstrual disorder	2	3	2	2
Reproductive Disorders, Male
Ejaculation premature	0	3	0	0
Resistance Mechanism Disorders
Viral infection	3	4	4	3
Otitis media	<1	2	1	1
Respiratory System Disorders
Upper respiratory tract infection	12	13	14	12
Sinusitis	6	10	6	8
Pharyngitis	4	5	6	2
Coughing	2	2	4	3
Bronchitis	2	3	3	3
Dyspnea	2	1	3	2
Rhinitis	1	1	2	2
Skin and Appendages Disorders
Pruritus	2	4	2	2
Special Senses Other, Disorders
Taste perversion	1	15	8	12
Taste loss	<1	1	1	2
Urinary System Disorders
Urinary tract infection	2	4	2	4
Renal calculus	0	0	1	2
Vision Disorders
Vision abnormal	<1	1	2	3
Blurred vision‡	2	4	2	4
Conjunctivitis	1	1	2	1

Of the 1135 patients exposed to topiramate in the adult placebo-controlled studies, 25% discontinued due to adverse reactions, compared to 10% of the 445 placebo patients. The adverse reactions associated with discontinuing therapy in the topiramate-treated patients included paresthesia (7%), fatigue (4%), nausea (4%), difficulty with concentration/attention (3%), insomnia (3%), anorexia (2%), and dizziness (2%).

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

Table 11 shows adverse reactions that were dose-dependent. Several central nervous system adverse reactions, including some that represented cognitive dysfunction, were dose-related. The most common dose-related adverse reactions (treatment difference ≥5% for the 100 mg dose) were paresthesia, nausea, anorexia, difficulty with memory, diarrhea, weight decrease, and hypoesthesia.

Table 11: Incidence (%) of Dose-Related Adverse Reactions From Placebo-Controlled, Migraine Trials*,†

	Topiramate Dosage (mg per day)
	Placebo	50	100	200
	(N=445)	(N=235)	(N=386)	(N=514)
Adverse Reaction	%	%	%	%
* Includes 35 adolescent patients age 12 to <16 years. † The incidence of adverse reactions in the 200 mg/day group was ≥ 2% than the incidence in both the placebo group and the 50% mg/day group.
Paresthesia	6	35	51	49
Fatigue	11	14	15	19
Nausea	8	9	13	14
Anorexia	6	9	15	14
Dizziness	10	8	9	12
Weight decrease	1	6	9	11
Difficulty with memory	2	7	7	11
Diarrhea	4	9	11	11
Difficulty with concentration/ attention	2	3	6	10
Somnolence	5	8	7	10
Hypoesthesia	2	6	7	8
Anxiety	3	4	5	6
Depression	4	3	4	6
Mood problems	2	3	6	5
Dry mouth	2	2	3	5
Confusion	2	2	3	4
Involuntary muscle contractions	1	2	2	4
Abnormal vision	<1	1	2	3
Renal calculus	0	0	1	2

Adolescents 12 to 17 Years of Age

In five, randomized, double-blind, placebo-controlled, parallel group migraine prophylaxis clinical trials, most of the adverse reactions with topiramate were mild or moderate in severity. Most adverse reactions occurred more frequently during the titration period than during the maintenance period. Among adverse reactions with onset during titration, approximately half persisted into the maintenance period.

In four, fixed-dose, double-blind migraine prophylaxis clinical trials in topiramate-treated adolescent patients, the most commonly observed adverse reactions associated with the use of 100 mg of topiramate that were seen at an incidence higher (≥ 5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain (see Table 12). Table 12 shows adverse reactions from the adolescent pivotal trial (Study 3 demonstrating the efficacy of topiramate) in which there were 103 adolescent patients who were treated with placebo or 50 mg or 100 mg of topiramate and three predominantly adult trials in which there were 49 adolescent patients (12 to 17 years) who were treated with placebo or 50 mg, 100 mg or 200 mg of topiramate [see Clinical Studies (14.7)]. Table 12 also shows adverse reactions in adolescents in the controlled migraine trials when the incidence in a topiramate dose group was at least 5% or higher than the incidence of placebo. Many adverse reactions shown in Table 12 indicated a dose-dependent relationship.

Table 12: Incidence (%) of Adverse Reactions in Pooled Placebo-Controlled, Migraine Trials in Adolescent Patients (12 to 17 Years of Age) Where Incidence Was ≥5% or Greater Than the Placebo Incidence in Any Topiramate Group*,†

	Topiramate Dosage (mg per day)
	Placebo	50	100	200
Body System/	(N=45)	(N=46)	(N=48)	(N=13)
Adverse Reaction	%	%	%	%
* 35 adolescent patients aged 12 to <16 years were also included in adverse reaction assessment for adults (Tables 10 and 11). † Incidence based on the number of subjects experiencing at least 1 adverse event, not the number of events.
Body as a Whole-General Disorders
Allergy	0	0	4	8
Fatigue	7	7	8	15
Fever	2	4	6	0
Leg Pain	0	2	2	8
Central & Peripheral Nervous System Disorders
Dizziness	4	4	6	0
Headache	2	2	4	8
Language problems	2	0	0	15
Muscle contractions involuntary	0	0	0	8
Paresthesia	7	20	19	38
Endocrine Disorders
Hyperthyroidism	0	0	0	8
Gastro-Intestinal System Disorders
Abdominal pain	9	7	15	15
Diarrhea	0	2	2	8
Nausea	4	4	8	0
Metabolic and Nutritional Disorders
Edema pharynx	0	0	0	8
Weight decrease	2	7	4	31
Platelet, Bleeding & Clotting Disorders
Epistaxis	0	2	2	8
Psychiatric Disorders
Anorexia	4	9	10	15
Anxiety	0	0	0	8
Difficulty with concentration/attention	0	0	2	15
Difficulty with memory	2	0	0	8
Insomnia	2	09	2	0
Mood problems	4	2	2	8
Psychomotor slowing	0	2	0	8
Somnolence	2	2	6	15
Resistance Mechanism Disorders
Infection viral	4	4	8	15
Otitis media	0	0	0	8
Respiratory System Disorders
Coughing	0	7	2	0
Laryngitis	0	0	0	8
Rhinitis	2	7	6	8
Sinusitis	2	9	4	15
Upper respiratory tract infection	11	26	23	23
Skin and Appendages Disorders
Rash erythematous	0	0	0	8
Special Senses Other, Disorders
Taste perversion	2	2	6	8
Vision Disorders
Conjunctivitis	4	7	4	0

In the double-blind placebo-controlled studies, adverse reactions led to discontinuation of treatment in 8% of placebo patients compared with 6% of topiramate-treated patients. Adverse reactions associated with discontinuing therapy that occurred in more than one topiramate-treated patient were fatigue (1%), headache (1%), and somnolence (1%).

Laboratory Abnormalities

Topiramate decreases serum bicarbonate [see Warnings and Precautions (5.4)].

Immediate-release topiramate treatment was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies. Similar effects should be anticipated with use of topiramate extended-release capsules.

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

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 and younger) pediatric patients who were treated with adjunctive topiramate for partial onset seizures [see Use in Specific Populations (8.4)].

Migraine

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, ammonia, total protein, and platelets [see Warnings and Precautions (5.4, 5.9)]. 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.

Clinical Trials Experience with Topiramate Extended-Release Capsules

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In the topiramate extended-release capsules study, a dose of 200 mg per day was administered to a limited number of patients; therefore, these results cannot be directly compared to immediate-release topiramate experience.

The safety data presented below are from 249 patients with partial epilepsy on concomitant AEDs who participated in the topiramate extended-release capsules study [see Clinical Studies (14.6)].

Table 13 displays the incidence of adverse reactions that occurred in ≥2% of patients and numerically greater than placebo.

Table 13: Incidence (≥2%) of Adverse Reactions in Placebo-Controlled Adjunctive Therapy Clinical Trial in Patients With Partial Onset Seizures

Body System/	Placebo	Topiramate Extended-release Capsules (200 mg)
Adverse Reaction	(N=125)	(N=124)
General Disorders
Fatigue	5	6
Asthenia	1	2
Irritability	1	2
Nervous System Disorders
Somnolence	2	12
Dizziness	6	7
Paresthesia	2	7
Aphasia	0	2
Dysarthria	1	2
Memory impairment	1	2
Psychiatric Disorder
Psychomotor retardation	0	2
Cardiovascular Disorders, General
Hypertension	1	3
Metabolic and Nutritional Disorders
Weight decrease	0	7
Decreased appetite	2	4
Anorexia	1	2

In the controlled clinical study using topiramate extended-release capsules, 8.9% of patients who received topiramate extended-release capsules and 4.0% who received placebo discontinued as a result of adverse reactions.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of topiramate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 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.

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to topiramate during pregnancy. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334. Information about the North American Drug Pregnancy Registry can be found at http://www.aedpregnancyregistry.org/.

Risk Summary

Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have increased risk for cleft lip and/or cleft palate (oral clefts) and for being small for gestational age [see Human Data].

In multiple animal species, topiramate demonstrated developmental toxicity, including teratogenicity, in the absence of maternal toxicity at clinically relevant doses [see Animal Data].

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse reactions

Consider the benefits and 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 informed of the potential risk to the fetus from exposure to topiramate. 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.

Labor or 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.

Topiramate treatment can cause metabolic acidosis [see Warnings and Precautions (5.3)]. 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 (5.3)]. 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.

Data

Human Data

Data from the NAAED Pregnancy Registry indicate an increased risk of oral clefts in infants exposed to topiramate monotherapy during the first trimester of pregnancy. The prevalence of oral clefts was 1.2% compared to a prevalence of 0.39% to 0.46% in infants exposed to other AEDs, and a prevalence of 0.12% in infants of mothers without epilepsy or treatment with other AEDs. For comparison, the Centers for Disease Control and Prevention (CDC) reviewed available data on oral clefts in the United States and found a similar background rate of 0.17%. The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 9.6 (95% Confidence Interval=[CI] 4.0 to 23.0) 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%.

Data from the NAAED pregnancy registry and a population-based birth registry cohort indicate that exposure to topiramate in utero is associated with an increased risk of small for gestational age (SGA) newborns (birth weight <10th percentile). In the NAAED pregnancy registry, 18% of topiramate-exposed newborns were SGA compared to 7% of newborns exposed to a reference AED, and 5% of newborns of mothers without epilepsy and without AED exposure. In the Medical Birth Registry of Norway (MBRN), a population-based pregnancy registry, 25% of newborns in the topiramate monotherapy exposure group were SGA compared to 9% in the comparison group who were unexposed to AEDs. The long-term consequences of the SGA findings are not known.

Animal Data

When topiramate (20, 100, and 500 mg/kg/day) was administered orally to pregnant mice during the period of organogenesis, the incidence of fetal malformations (primarily craniofacial defects) was increased at all doses. Fetal body weights and skeletal ossification were reduced at the highest dose tested in conjunction with decreased maternal body weight gain. A no-effect dose for embryofetal developmental toxicity in mice was not identified. The lowest dose tested, which was associated with teratogenic effects, is less than the maximum recommended human dose (MRHD) of 400 mg/day on a body surface area (mg/m2) basis.

In pregnant rats administered topiramate (20, 100, and 500 mg/kg/day or 0.2, 2.5, 30, and 400 mg/kg/day) orally during the period of organogenesis, the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased in fetuses at 400 or 500 mg/kg/day. Embryotoxicity (reduced fetal body weights, increased incidences of structural variations) was observed at doses as low as 20 mg/kg/day. Clinical signs of maternal toxicity were seen at 400 mg/kg/day and above, and maternal body weight gain was reduced at doses of 100 mg/kg/day or greater. The no-effect dose for embryofetal developmental toxicity in rats is less than the MRHD on a mg/m2 basis.

In pregnant rabbits administered topiramate (20, 60, and 180 mg/kg/day or 10, 35, and 120 mg/kg/day) orally during organogenesis, embryofetal mortality was increased at 35 mg/kg/day and teratogenic effects (primarily rib and vertebral malformations) were observed at 120 mg/kg/day. Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg/day and above. The no-effect dose (20 mg/kg/day) for embryofetal developmental toxicity in rabbits is equivalent to the MRHD on a mg/m2 basis.

When topiramate (0.2, 4, 20, and 100 mg/kg/day or 2, 20, and 200 mg/kg/day) was administered orally to female rats during the latter part of gestation and throughout lactation, offspring exhibited decreased viability and delayed physical development at 200 mg/kg/day and reductions in pre- and/or postweaning body weight gain at 2 mg/kg/day and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg or greater. In a rat embryofetal development study which included postnatal assessment of offspring, oral administration of topiramate (0.2, 2.5, 30, and 400 mg/kg/day) to pregnant animals during the period of organogenesis resulted in delayed physical development at 400 mg/kg/day and persistent reductions in body weight gain at 30 mg/kg/day and higher in the offspring. The no-effect dose (0.2 mg/kg/day) for pre- and postnatal developmental toxicity is less than the MRHD on a mg/m2 basis.

Lactation

Risk Summary

Topiramate is excreted in human milk [see Data]. The effects of topiramate exposure in breastfed infants are unknown.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for topiramate extended-release capsules and any potential adverse effects on the breastfed infant from topiramate extended-release capsules or from the underlying maternal condition.

Data

Limited data from 5 women with epilepsy treated with topiramate during lactation showed drug levels in milk similar to those in maternal plasma.

Females and Males of Reproductive Potential

Contraception

Women of childbearing potential who are not planning a pregnancy should use effective contraception because of the risks to the fetus of oral clefts and of being small for gestational age [see Drug Interactions (7.1) and Use in Specific Populations (8.1)].

Pediatric Use

Seizures in Pediatric Patients 2 Years of Age and Older

The safety and effectiveness of topiramate extended-release capsules in pediatric patients is based on controlled trials with immediate-release topiramate [see Clinical Studies (14.2, 14.3, 14.4 and 14.5)].

The adverse reactions (both common and serious) in pediatric patients are similar to those seen in adults [see Warnings and Precautions (5) and Adverse Reactions (6)].

These include, but are not limited to:

• oligohydrosis and hyperthermia [see Warnings and Precautions (5.3)]
• dose-related increased incidence of metabolic acidosis [see Warnings and Precautions (5.4)]
• dose-related increased incidence of hyperammonemia [see Warnings and Precautions (5.9)]

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

The following pediatric use information is based on studies conducted with immediate-release topiramate.

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 immediate-release topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in infants 1 to 24 months of age with refractory partial onset seizures, was assessed. After 20 days of double-blind treatment, immediate-release topiramate (at fixed doses of 5 mg/kg, 15 mg/kg, 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 not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions 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 immediate-release topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm. A generally similar profile was observed in older children [see Adverse Reactions (6.1)].

Immediate-release 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 Adverse Reactions (6.1)]. The significance of these findings is uncertain.

Immediate-release 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 Adverse Reactions (6.1)]. 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 hyperammonemia [see Warnings and Precautions (5.9)].

Treatment with immediate-release 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)].

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 immediate-release topiramate treatment, because the background mortality rate for a similar, significantly refractory, young pediatric population (1 month 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.

Migraine Prophylaxis in Adolescents 12 to 17 Years

Safety and effectiveness of topiramate in the prophylaxis of migraine was studied in 5 double-blind, randomized, placebo-controlled, parallel-group trials in a total of 219 pediatric patients, at doses of 50 to 200 mg/day, or 2 to 3 mg/kg/day. These comprised a fixed dose study in 103 adolescents age 12 to 17 years [see Clinical Studies (14.7)], a flexible dose (2 to 3 mg/kg/day), placebo-controlled study in 157 pediatric patients age 6 to 16 years (including 67 adolescent patients age 12 to 16 years), and a total of 49 adolescents age 12 to 17 years in 3 studies of migraine prophylaxis primarily in adults. Open-label extension phases of 3 studies enabled evaluation of long-term safety for up to 6 months after the end of the double-blind phase.

Efficacy of topiramate for migraine prophylaxis in adolescents is demonstrated for a 100 mg daily dose in Study 3 [see Clinical Studies (14.7)]. Efficacy of topiramate (2 to 3 mg/kg/day) for migraine prophylaxis was not demonstrated in a placebo-controlled trial of 157 pediatric patients (6 to 16 years) that included treatment of 67 adolescents (12 to 16 years) for 20 weeks.

In the adolescent trials (12 to 17 years) in which patients were randomized to placebo or a fixed daily dose of topiramate, 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, upper respiratory tract infection, anorexia, and abdominal pain [see Adverse Reactions (6.1)].

The most common cognitive adverse reaction in pooled double-blind studies in adolescent patients age 12 to 17 years was difficulty with concentration/attention [see Warnings and Precautions (5.6)].

Markedly abnormally low serum bicarbonate values indicative of metabolic acidosis were reported in topiramate-treated adolescent migraine patients [see Warnings and Precautions (5.4)].

In topiramate-treated adolescent patients (12 to 17 years) compared to placebo-treated patients, abnormally increased results were more frequent for creatinine, BUN, uric acid, chloride, ammonia, total protein, and platelets. Abnormally decreased results were observed with topiramate vs placebo treatment for phosphorus and bicarbonate [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

Notable changes (increases and decreases) from baseline in systolic blood pressure, diastolic blood pressure, and pulse that were observed occurred more commonly in adolescents treated with topiramate compared to adolescents treated with placebo [see Clinical Pharmacology (12.2)].

Migraine Prophylaxis in Children 6 to 11 Years Old

Safety and effectiveness in pediatric patients below the age of 12 years have not been established for the prophylaxis treatment of migraine headache.

In a double-blind study in 90 children age 6 to 11 years (including 59 topiramate-treated and 31 placebo patients), the adverse reaction profile was generally similar to that in pooled double-blind studies of adolescents age 12 to 17 years. The adverse reactions that occurred most commonly in topiramate-treated children age 6 to 11 years, and at least twice as frequently than placebo, were gastroenteritis (12% topiramate, 6% placebo), sinusitis (10% topiramate, 3% placebo), weight decrease (8% topiramate, 3% placebo) and paresthesia (7% topiramate, 0% placebo). Difficulty with concentration/attention occurred in 3 topiramate-treated patients (5%) and 0 placebo patients.

The risk for cognitive adverse reaction was greater in younger patients (6 to 11 years) than in older patients (12 to 17 years) [see Warnings and Precautions (5.6)].

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 [see Adverse Reactions (6.1)].

Serum bicarbonate, chloride, phosphorus, and ammonia data were not collected for pediatric patients 6 to 11 years of age.

Juvenile Animal Studies

When topiramate (30 mg/kg/day, 90 mg/kg/day 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/m2) basis.

Geriatric Use

Clinical studies of immediate-release topiramate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Dosage adjustment is necessary for elderly with creatinine clearance less than 70 mL/min/1.73 m2. Estimate CrCl prior to dosing [see Dosage and Administration (2.3), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

Race and Gender Effects

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

Renal Impairment

The clearance of topiramate was reduced by 42% in moderately renally impaired (creatinine clearance 30 to 69 mL/min/1.73m2) and by 54% in severely renally impaired subjects (creatinine clearance less than 30 mL/min/1.73m2) compared to normal renal function subjects (creatinine clearance greater than 70 mL/min/1.73m2). One-half the usual starting and maintenance dose is recommended in patients with moderate or severe renal impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

Patients Undergoing Hemodialysis

Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than a normal individual. Accordingly, a prolonged period of dialysis may cause topiramate concentration to fall below that required to maintain an anti-seizure effect. To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate may be required. The actual adjustment should take into account the duration of dialysis period, the clearance rate of the dialysis system being used, and the effective renal clearance of topiramate in the patient being dialyzed [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

Topiramate Extended-release Capsules

Topiramate extended-release capsules contain beads of topiramate in a capsule and are available in the following strengths and colors:

25 mg: light pink and grey capsules, printed with "UPSHER-SMITH" on the cap in black ink and "25 mg" on the body in black ink. 25 mg capsules are available in the following package configurations:

• Bottle of 30 count with desiccant (NDC 0832-1071-30)
• Bottle of 90 count with desiccant (NDC 0832-1071-90)
• Bottle of 500 count with desiccant (NDC 0832-1071-15)

50 mg: golden yellow and grey capsules, printed with "UPSHER-SMITH" on the cap in black ink and "50 mg" on the body in black ink. 50 mg capsules are available in the following package configurations:

• Bottle of 30 count with desiccant (NDC 0832-1072-30)
• Bottle of 90 count with desiccant (NDC 0832-1072-90)
• Bottle of 500 count with desiccant (NDC 0832-1072-15)

100 mg: reddish brown and grey capsules, printed with "UPSHER-SMITH" on the cap in black ink and "100 mg" on the body in black ink. 100 mg capsules are available in the following package configurations:

• Bottle of 30 count with desiccant (NDC 0832-1074-30)
• Bottle of 90 count with desiccant (NDC 0832-1074-90)
• Bottle of 500 count with desiccant (NDC 0832-1074-15)

150 mg: pale yellow and grey capsules, printed with "UPSHER-SMITH" on the cap in black ink and "150 mg" on the body in black ink. 150 mg capsules are available in the following package configurations:

• Bottle of 30 count with desiccant (NDC 0832-1075-30)
• Bottle of 90 count with desiccant (NDC 0832-1075-90)
• Bottle of 500 count with desiccant (NDC 0832-1075-15)

200 mg: brown and grey capsules, printed with "UPSHER-SMITH" on the cap in white ink and "200 mg" on the body in black ink. 200 mg capsules are available in the following package configurations:

• Bottle of 30 count with desiccant (NDC 0832-1073-30)
• Bottle of 90 count with desiccant (NDC 0832-1073-90)
• Bottle of 500 count with desiccant (NDC 0832-1073-15)

Storage and Handling

Topiramate extended-release capsules should be stored in a tightly-closed container at 20 to 25°C (68 to 77°F). Excursions permitted between 15 to 30°C (59 to 86°F). [See USP Controlled Room Temperature]. Protect from moisture.

Advise patients and caregivers to read the FDA-approved patient labeling (Medication Guide).

Administration Instructions

Counsel patients to swallow topiramate extended-release capsules whole or carefully open and sprinkle the entire contents on a spoonful of soft food. This drug/food mixture should be swallowed immediately and not chewed. Do not store drug/food mixture for future use [See Dosage and Administration (2.8)].

Eye Disorders

Instruct patients taking topiramate extended-release capsules to seek immediate medical attention if they experience blurred vision, visual disturbances or periorbital pain [see Warnings and Precautions (5.1 and 5.2)].

Oligohydrosis and Hyperthermia

Closely monitor topiramate extended-release capsules-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 Acidosis

Warn patients about the potentially 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 and 8.4)].

Suicidal Behavior and Ideation

Counsel patients, their caregivers, and families that AEDs, including topiramate extended-release capsules, may increase the risk of suicidal thoughts and behavior and they 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. 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, visual effects, and advise patients not to drive or operate machinery until they have gained sufficient experience on topiramate extended-release capsules to gauge whether it adversely affects their mental performance, motor performance, and/or vision [see Warnings and Precautions (5.6)].

Even when taking topiramate extended-release capsules, or other anticonvulsants, some patients with epilepsy will continue to have unpredictable seizures. Therefore, advise all patients taking topiramate extended-release capsules 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 their patients, before patients with epilepsy engage in such activities.

Fetal Toxicity

Counsel 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. Also inform patients that infants exposed to topiramate monotherapy in utero may be small for their gestational age. There may also be risks to the fetus from chronic metabolic acidosis with use of topiramate extended-release capsules during pregnancy [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1)].

When appropriate, prescribers should counsel pregnant women and women of childbearing potential about alternative therapeutic options. This is particularly important when topiramate extended-release capsules 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 (7.1)].

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.aedpregnancyregistry.org [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 (5.9)].

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 (5.10)].

Hypothermia

Counsel patients that topiramate extended-release capsules can cause a reduction in body temperature, which can lead to alterations in mental status. If they note such changes, they should call their health care professional and measure their body temperature. Patients taking concomitant valproic acid should be specifically counseled on this potential adverse reaction [see Warnings and Precautions (5.11)].

Paresthesia

Counsel patients that they may experience tingling in the arms and legs. If this symptom occurs, they should consult with their physician [see Warnings and Precautions (5.12)].

Manufactured for
USL PHARMA, INC.
Denver, CO 80223

Revised 0317

MEDICATION GUIDE Topiramate (toe pir' a mate) Extended-release Capsules
This Medication Guide has been approved by the U.S. Food and Drug Administration      Revised 03/2017
What is the most important information I should know about Topiramate Extended-release Capsules? Topiramate Extended-release Capsules 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 Extended-release Capsules may cause decreased sweating and increased body temperature (fever). People, especially children, should be watched for signs of decreased sweating and fever, especially in hot temperatures. Some people may need to be hospitalized for this condition. If a high fever, a fever that does not go away, or decreased sweating develops, call your healthcare provider right away. Topiramate Extended-release Capsules 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 Extended-release Capsules. If you are pregnant, you should talk to your healthcare provider about whether you have metabolic acidosis. Like other antiepileptic drugs, Topiramate Extended-release Capsules 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 Extended-release Capsules without first talking to a healthcare provider. Stopping Topiramate Extended-release Capsules 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 Extended-release Capsules can harm your unborn baby. If you take Topiramate Extended-release Capsules 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. Also, if you take Topiramate Extended-release Capsules during pregnancy, your baby may be smaller than expected at birth. The long-term effects of this are not known. 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 Extended-release Capsules. If the decision is made to use Topiramate Extended-release Capsules, you should use effective birth control (contraception) unless you are planning to become pregnant. You should talk to your healthcare provider about the best kind of birth control to use while you are taking Topiramate Extended-release Capsules. Tell your healthcare provider right away if you become pregnant while taking Topiramate Extended-release Capsules. You and your healthcare provider should decide if you will continue to take Topiramate Extended-release Capsules while you are pregnant. If you take Topiramate Extended-release Capsules during pregnancy, your baby may be smaller than expected at birth. Talk to your healthcare provider if you have any questions about this risk during pregnancy. Metabolic acidosis may have harmful effects on your baby. Talk to your healthcare provider if Topiramate Extended-release Capsules has caused metabolic acidosis during your pregnancy. Pregnancy Registry: If you become pregnant while taking Topiramate Extended-release Capsules, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of Topiramate Extended-Release Capsules and other antiepileptic drugs during pregnancy.
What are Topiramate Extended-release Capsules? Topiramate Extended-release Capsules is 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 of age 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 of age and older. to prevent migraine headaches in adults and adolescents 12 years of age and older.
Do not take Topiramate Extended-release Capsules if you have been told you have a problem with your blood called metabolic acidosis and are taking a medicine called metformin at the same time.
Before taking Topiramate Extended-release Capsules, tell your healthcare provider about all of your medical conditions, including if you: have or have had depression, mood problems or suicidal thoughts or behavior have kidney problems, 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 Extended-release Capsules passes into your breast milk. It is not known if the Topiramate Extended-release Capsules 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 Extended-release Capsules. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Topiramate Extended-release Capsules and other medicines may affect each other causing side effects. Especially tell your healthcare provider if you take: Metformin (such as GLUCOPHAGE®) Valproic acid (such as DEPAKENE® or DEPAKOTE®) any medicines that impair or decrease your thinking, concentration, or muscle coordination birth control pills. Topiramate Extended-release Capsules 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 Extended-release Capsules. medicines used to prevent seizures any other carbonic anhydrase inhibitors like Topiramate Extended-release Capsules (such as zonisamide, acetazolamide, or dichlorphenamide). 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 Extended-release Capsules? Take Topiramate Extended-release Capsules exactly as your healthcare provider tells you to. Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider. Topiramate Extended-release Capsules may be swallowed whole or, if you cannot swallow the capsule whole, you may carefully open the Topiramate Extended-release Capsules and sprinkle the medicine on a spoonful of soft food like applesauce. Swallow the food and medicine mixture right away. Do not store the food and medicine mixture to use later. Drink fluids right after eating the food and medicine mixture to make sure it is all swallowed. Do not crush or chew the food and medicine mixture before swallowing. Do not crush or chew Topiramate Extended-release Capsules before swallowing. Topiramate Extended-release Capsules 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 Extended-release Capsules. If you take too much Topiramate Extended-release Capsules, 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 Extended-release Capsules, take it as soon as you can. 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 Extended-release Capsules without talking to your healthcare provider. Stopping Topiramate Extended-release Capsules suddenly may cause serious problems. If you have epilepsy and you stop taking Topiramate Extended-release Capsules suddenly, you may have seizures that do not stop. Your healthcare provider will tell you how to stop taking Topiramate Extended-release Capsules slowly. Your healthcare provider may do blood tests while you take Topiramate Extended-release Capsules.
What should I avoid while taking Topiramate Extended-release Capsules? Do not drink alcohol while taking Topiramate Extended-release Capsules. Topiramate Extended-release Capsules and alcohol can cause serious side effects such as severe sleepiness and dizziness and an increase in seizures. Do not drive a car or operate heavy machinery until you know how Topiramate Extended-release Capsules affects you. Topiramate Extended-release Capsules can slow your thinking and motor skills, and may affect vision.
What are the possible side effects of Topiramate Extended-release Capsules? Topiramate Extended-release Capsules may cause serious side effects, including: See "What is the most important information I should know about Topiramate Extended-release Capsules?" 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 Extended-release Capsules are taken with a medicine called valproic acid (DEPAKENE® and DEPAKOTE®). Kidney stones. Drink plenty of fluids when taking Topiramate Extended-release Capsules to decrease your chances of getting kidney stones. Low body temperature. Taking Topiramate Extended-release Capsules when you are also taking valproic acid can cause a drop in body temperature to less than 95ºF, feeling tired, confusion, or coma. Effects on thinking and alertness. Topiramate Extended-release Capsules may affect how you think, and cause confusion, problems with concentration, attention, memory, or speech. Topiramate Extended-release Capsules 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 Extended-release Capsules include:
tingling of the arms and legs (paresthesia) not feeling hungry weight loss nervousness nausea	speech problems tiredness dizziness sleepiness/drowsiness a change in the way foods taste upper respiratory tract infection	slow reactions difficulty with memory fever abnormal vision diarrhea pain in the abdomen
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 Extended-release Capsules. 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 Extended-release Capsules? Store Topiramate Extended-release Capsules at room temperature between 68° to 77°F (20° to 25°C). Keep Topiramate Extended-release Capsules in a tightly-closed container. Keep Topiramate Extended-release Capsules dry and away from moisture. Keep Topiramate Extended-release Capsules and all medicines out of the reach of children.
General information about the safe and effective use of Topiramate Extended-release Capsules. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Topiramate Extended-release Capsules for a condition for which it was not prescribed. Do not give Topiramate Extended-release Capsules to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Topiramate Extended-release Capsules that is written for health professionals.
What are the ingredients in Topiramate Extended-release Capsules? Active ingredient: topiramate Inactive ingredients: microcrystalline cellulose, hypromellose 2910, ethylcellulose, diethyl phthalate, titanium dioxide, black iron oxide, red iron oxide and/or yellow iron oxide, black pharmaceutical ink, and white pharmaceutical ink (200 mg only). Manufactured for: USL Pharma, INC. Denver, CO 80223 All marks are owned by their respective owners. This product may be covered by one or more U.S. patent(s). See www.uslpatents.com For more information, go to www.upsher-smith.com or call UPSHER-SMITH LABORATORIES, INC. at 1-888-650-3789.

NDC 0832-1072-30

Once-Daily Dosing
Topiramate Extended-
Release Capsules

50 mg

PHARMACIST: Dispense the Medication
Guide provided separately to each patient.

30 Capsules
Rx only

NDC 0832-1073-30

Once-Daily Dosing
Topiramate
Extended-Release
Capsules

200 mg

PHARMACIST: Dispense the Medication
Guide provided separately to each patient.

30 Capsules
Rx only

TOPIRAMATE  topiramate capsule, extended release

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0832-1071 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Topiramate (Topiramate) Topiramate 25 mg

Inactive Ingredients Ingredient Name Strength cellulose, microcrystalline   hypromellose 2910 (6 MPA.S)   ethylcellulose (10 MPA.S)   diethyl phthalate   titanium dioxide   ferrosoferric oxide   ferric oxide red

Product Characteristics Color PINK (light pink) , GRAY Score no score Shape CAPSULE Size 7mm Flavor Imprint Code UPSHER;SMITH;25mg Contains

Packaging # Item Code Package Description 1 NDC:0832-1071-30 1 BOTTLE in 1 CARTON 1 30 CAPSULE, EXTENDED RELEASE in 1 BOTTLE 2 NDC:0832-1071-90 1 BOTTLE in 1 CARTON 2 90 CAPSULE, EXTENDED RELEASE in 1 BOTTLE 3 NDC:0832-1071-15 500 CAPSULE, EXTENDED RELEASE in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA authorized generic NDA205122 07/07/2014

TOPIRAMATE  topiramate capsule, extended release

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0832-1072 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Topiramate (Topiramate) Topiramate 50 mg

Inactive Ingredients Ingredient Name Strength cellulose, microcrystalline   hypromellose 2910 (6 MPA.S)   ethylcellulose (10 MPA.S)   diethyl phthalate   titanium dioxide   ferrosoferric oxide   ferric oxide yellow

Product Characteristics Color YELLOW (golden yellow) , GRAY Score no score Shape CAPSULE Size 8mm Flavor Imprint Code UPSHER;SMITH;50mg Contains

Packaging # Item Code Package Description 1 NDC:0832-1072-30 1 BOTTLE in 1 CARTON 1 30 CAPSULE, EXTENDED RELEASE in 1 BOTTLE 2 NDC:0832-1072-90 1 BOTTLE in 1 CARTON 2 90 CAPSULE, EXTENDED RELEASE in 1 BOTTLE 3 NDC:0832-1072-15 500 CAPSULE, EXTENDED RELEASE in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA authorized generic NDA205122 07/07/2014

TOPIRAMATE  topiramate capsule, extended release

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0832-1074 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Topiramate (Topiramate) Topiramate 100 mg

Inactive Ingredients Ingredient Name Strength cellulose, microcrystalline   hypromellose 2910 (6 MPA.S)   ethylcellulose (10 MPA.S)   diethyl phthalate   titanium dioxide   ferrosoferric oxide   ferric oxide red   ferric oxide yellow

Product Characteristics Color BROWN (reddish brown) , GRAY Score no score Shape CAPSULE Size 10mm Flavor Imprint Code UPSHER;SMITH;100mg Contains

Packaging # Item Code Package Description 1 NDC:0832-1074-30 1 BOTTLE in 1 CARTON 1 30 CAPSULE, EXTENDED RELEASE in 1 BOTTLE 2 NDC:0832-1074-90 1 BOTTLE in 1 CARTON 2 90 CAPSULE, EXTENDED RELEASE in 1 BOTTLE 3 NDC:0832-1074-15 500 CAPSULE, EXTENDED RELEASE in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA authorized generic NDA205122 07/07/2014

TOPIRAMATE  topiramate capsule, extended release

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0832-1075 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Topiramate (Topiramate) Topiramate 150 mg

Inactive Ingredients Ingredient Name Strength cellulose, microcrystalline   hypromellose 2910 (6 MPA.S)   ethylcellulose (10 MPA.S)   diethyl phthalate   titanium dioxide   ferrosoferric oxide   ferric oxide yellow

Product Characteristics Color YELLOW (pale yellow) , GRAY Score no score Shape CAPSULE Size 11mm Flavor Imprint Code UPSHER;SMITH;150mg Contains

Packaging # Item Code Package Description 1 NDC:0832-1075-30 1 BOTTLE in 1 CARTON 1 30 CAPSULE, EXTENDED RELEASE in 1 BOTTLE 2 NDC:0832-1075-90 1 BOTTLE in 1 CARTON 2 90 CAPSULE, EXTENDED RELEASE in 1 BOTTLE 3 NDC:0832-1075-15 500 CAPSULE, EXTENDED RELEASE in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA authorized generic NDA205122 07/07/2014

TOPIRAMATE  topiramate capsule, extended release

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0832-1073 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Topiramate (Topiramate) Topiramate 200 mg

Inactive Ingredients Ingredient Name Strength cellulose, microcrystalline   hypromellose 2910 (6 MPA.S)   ethylcellulose (10 MPA.S)   diethyl phthalate   titanium dioxide   ferrosoferric oxide   ferric oxide red   ferric oxide yellow

Product Characteristics Color BROWN, GRAY Score no score Shape CAPSULE Size 12mm Flavor Imprint Code UPSHER;SMITH;200mg Contains

Packaging # Item Code Package Description 1 NDC:0832-1073-30 1 BOTTLE in 1 CARTON 1 30 CAPSULE, EXTENDED RELEASE in 1 BOTTLE 2 NDC:0832-1073-90 1 BOTTLE in 1 CARTON 2 90 CAPSULE, EXTENDED RELEASE in 1 BOTTLE 3 NDC:0832-1073-15 500 CAPSULE, EXTENDED RELEASE in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA authorized generic NDA205122 07/07/2014

Labeler - Upsher-Smith Laboratories, Inc. (809088862)

Establishment
Name	Address	ID/FEI	Operations
Upsher-Smith Laboratories, Inc.		047251004	ANALYSIS(0832-1071, 0832-1072, 0832-1074, 0832-1075, 0832-1073), LABEL(0832-1071, 0832-1072, 0832-1074, 0832-1075, 0832-1073), PACK(0832-1071, 0832-1072, 0832-1074, 0832-1075, 0832-1073)

Establishment
Name	Address	ID/FEI	Operations
Catalent Pharma Solutions, LLC		829672745	MANUFACTURE(0832-1071, 0832-1072, 0832-1074, 0832-1075, 0832-1073)

Establishment
Name	Address	ID/FEI	Operations
Upsher-Smith Laboratories, Inc.		079111820	LABEL(0832-1071, 0832-1072, 0832-1074, 0832-1075, 0832-1073), PACK(0832-1071, 0832-1072, 0832-1074, 0832-1075, 0832-1073)

Revised: 05/2017   Upsher-Smith Laboratories, Inc.