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Topiramate Extended-Release Capsules

TABLE OF CONTENTS

1. DESCRIPTION 8. USE IN SPECIFIC POPULATIONS
2. INDICATIONS AND USAGE 9. OVERDOSAGE
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 12. PHARMACOKINETICS
6. ADVERSE REACTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING
7. DRUG INTERACTIONS

 

1. DESCRIPTION

Topiramate, USP, is a sulfamate-substituted monosaccharide. Topiramate is designated chemically as 2,3:4,5-Di-O-isopropylidene-β-D-fructopyranose sulfamate and has the following structural formula:

Empirical formula: C12H21NO8S - Molecular weight: 339.4

Topiramate is a white to off-white powder. Topiramate is freely soluble in polar organic solvents such as acetonitrile and acetone; and very slightly soluble to practically insoluble in non-polar organic solvents such as hexanes.

Topiramate extended-release capsules are available as:

QUDEXY XR®: 25 mg, 50 mg, 100 mg, 150 mg and 200 mg capsules for oral administration.

Inactive ingredients: microcrystalline cellulose, hypromellose 2910, ethylcellulose, diethyl phthalate.

In addition, the capsule shells for all strengths contain hypromellose 2910, titanium dioxide, black iron oxide, red iron oxide and/or yellow iron oxide, black pharmaceutical ink, and white pharmaceutical ink (200 mg only).

TROKENDI XR®: 25 mg, 50 mg, 100 mg and 200 mg capsules for oral administration.

Inactive ingredients: Sugar spheres, hypromellose (type 2910), mannitol, docusate sodium, sodium benzoate, ethylcellulose, oleic acid, medium chain triglycerides, polyethylene glycol, polyvinyl alcohol, titanium dioxide, talc, lecithin, xanthan gum.

The capsule shells contain gelatin, titanium dioxide, and colorants.

The colorants are: FD&C blue #1 (all strength capsules), yellow iron oxide (25 mg and 50 mg capsules), FD&C red #3 (50 mg, 100 mg and 200 mg capsules), FD&C yellow #6 (50 mg, 100 mg and 200 mg capsules), riboflavin (25 mg capsules).

All capsule shells are imprinted with black print that contains shellac, NF, and black iron oxide, NF.

2. INDICATIONS AND USAGE

2.1 Partial Onset Seizure and Primary Generalized Tonic-Clonic Seizures

Topiramate extended-release (ER) capsules are indicated as initial monotherapy in patients 10 years of age and older with partial onset or primary generalized tonic-clonic seizures and adjunctive therapy in patients 6 years of age and older with partial onset or primary generalized tonic-clonic seizures. Safety and effectiveness in patients who were converted to monotherapy from a previous regimen of other anticonvulsant drugs have not been established in controlled trials.

2.2 Lennox-Gastaut Syndrome

Topiramate ER capsules are indicated as adjunctive therapy in patients 6 years of age and older with seizures associated with Lennox-Gastaut syndrome.

3. DOSAGE AND ADMINISTRATION

3.1 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 ER according to the following schedule:

Week 1: 50 mg once daily

Week 2: 100 mg once daily

Week 3: 150 mg once daily

Week 4: 200 mg once daily

Week 5: 300 mg once daily

Week 6: 400 mg once daily

3.2 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 ER as adjunctive therapy in adults with partial onset seizures or Lennox-Gaustaut Syndrome is 200 mg to 400 mg orally once daily 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 50mg 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.

Pediatric Patients (Ages 6 years to 16 Years) - Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome

The recommended total daily dose of topiramate ER 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.

3.3 Administration with Alcohol

Alcohol use should be completely avoided within 6 hours prior to and 6 hours after topiramate ER administration [see Warnings and Precautions (5.4)].

3.4 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.

Prior to dosing, obtain an estimated GFR measurement in patients at high risk for renal insufficiency (e.g., older patients, or those with diabetes mellitus, hypertension, or autoimmune disease).

3.5 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.

3.6 Laboratory Testing Prior to Treatment Initiation

Measurement of baseline and periodic serum bicarbonate during topiramate ER treatment is recommended [see Warnings and Precautions (5.3)].

3.7 Dosing Modifications in Patients Taking Phenytoin and/or Carbamazepine

The co-administration of topiramate ER 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 ER may require adjustment of the dose of topiramate ER.

3.8 Monitoring for Therapeutic Blood Levels

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

3.9 Administration Instructions

Topiramate ER can be taken without regard to meals.

Swallow capsule whole and intact. Do not sprinkle on food, chew or crush.

4. CONTRAINDICATIONS

Topiramate ER is contraindicated in patients:

• With recent alcohol use (i.e., within 6 hours prior to and 6 hours after topiramate ER use) [see Warnings and Precautions (5. 4)]

• With metabolic acidosis who are taking concomitant metformin [see Warnings and Precautions (5.3) and Drug Interactions (7.6)]

5. WARNINGS AND PRECAUTIONS

5.1 Acute Myopia and Secondary Angle Closure Glaucoma

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness) and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of topiramate ER as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of topiramate ER, may be helpful.

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

5.2 Visual Field Defects

Visual field defects 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 topiramate treatment, consideration should be given to discontinuing the drug.

5.3 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 ER should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when topiramate ER is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity.

5.4 Metabolic Acidosis

Hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) is associated with topiramate, and can be expected with treatment with topiramate ER. 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.

Adults

In adults, the incidence of persistent treatment-emergent 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 persistent treatment-emergent decreases in serum bicarbonate in adults in the epilepsy controlled clinical trial for monotherapy was 15% 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 the adjunctive therapy trials was 3% for 400 mg per day, and 0% for placebo and in the monotherapy trial was 1% for 50 mg per day and 7% 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)

Although topiramate ER is not approved for use in patients below the age of 6, the incidence of persistent treatment-emergent decreases in serum bicarbonate in placebo-controlled trials for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures 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 than17 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 treatment-emergent 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 ER is not approved for use in patients less than 6 years of age with partial onset seizures, a study of topiramate as adjunctive use in patients under 2 years of age 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 [see Use in Specific Populations(8.4)].

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 with epilepsy are likely to have different growth rates than normal infants. Reductions in Z SCORES for length and weight were correlated to the degree of acidosis [see Pediatric Use (8.4)]. 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)].

Risk Mitigation Strategies

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

5.5 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED, including topiramate ER 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 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 ER or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior or the emergence of suicidal thoughts, behavior or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

5.6 Cognitive/Neuropsychiatric Adverse Reactions

Adverse reactions most often associated with the use of topiramate, and therefore expected to be associated with the use of topiramate ER were related to the central nervous system and were observed in the epilepsy population. In adults, the most frequent of these can be classified into three general categories: 1) Cognitive-related dysfunction (e.g. confusion, psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or language problems, particularly word-finding difficulties), 2) Psychiatric/behavioral disturbances (e.g. depression or mood problems), and 3) Somnolence or fatigue.

Adult Patients

Cognitive Related Dysfunction

The majority of cognitive-related adverse reactions were mild to moderate in severity, and they frequently occurred in isolation. Rapid titration rate and higher initial dose were associated with higher incidences of these reactions. Many of these reactions contributed to withdrawal from treatment [see Adverse Reactions (6.1)].

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

Psychiatric/Behavioral Disturbances

Psychiatric/behavioral disturbances (depression or mood) were dose-related for the epilepsy population treated with topiramate [see Warnings and Precautions (5.6)].

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 other uses not approved for topiramate ER, somnolence and fatigue were 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

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 events 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 events. The most common adverse reaction associated with discontinuation of therapy was difficulty with concentration/attention; all occurred in the 400 mg per day group.

5.7 Fetal Toxicity

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

Consider the benefits and 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 (8.9)]. 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) and (8.9)].

5.8 Withdrawal of Antiepileptic Drugs

In patients with or without a history of seizures or epilepsy, antiepileptic drugs including topiramate ER should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency. In situations where rapid withdrawal of topiramate ER is medically required, appropriate monitoring is recommended.

5.9 Hyperammonemia and Encephalopathy

Hyperammonemia/Encephalopathy Without Concomitant Valproic Acid (VPA)

Topiramate treatment has produced hyperammonemia (in some instances dose-related) in clinical investigational programs 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 ER is not approved as adjunctive treatment of partial onset seizures in pediatric patients less than 6 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. 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 ER is not indicated for use in infants/toddlers (1month to 24 months), topiramate with concomitant VPA clearly produced a dose-related increase in the incidence of treatment-emergent hyperammonemia (above the upper limit of normal, 0% for placebo, 12% for 5 mg/kg/day, 7% for 15 mg/kg/day, 17% for 25 mg/kg/day) in an investigational program 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 ER 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.

5.10 Kidney Stones

A total of 32/2086 (1.5%) of adults exposed to topiramate during its adjunctive epilepsy therapy development reported the occurrence of kidney stones, an incidence about 2 to 4 times greater than expected in a similar, untreated population. In the double-blind monotherapy epilepsy study, a total of 4/319 (1.3%) of adults exposed to topiramate reported the occurrence of kidney stones. As in the general population, the incidence of stone formation among topiramate treated patients was higher in men. Kidney stones have also been reported in pediatric patients. During long-term (up to 1 year) topiramate treatment in an open-label extension study of 284 pediatric patients 1 month to 24 months old with epilepsy, 7% developed kidney or bladder stones that were diagnosed clinically or by sonogram. Topiramate ER is not approved for pediatric patients less than 6 years old [see Use in Specific Populations (8.4)].

Topiramate ER 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 (5.9)]. The concomitant use of topiramate ER with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided.

Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation.

5.11 Hypothermia with Concomitant Valproic Acid Use

Hypothermia, defined as an unintentional drop in body core temperature to less than 35ºC (95ºF) 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 (7.5)]. Consideration should be given to stopping topiramate or valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.

5.12 Paresthesia

Paresthesia (usually tingling of the extremities), an effect associated with the use of other carbonic anhydrase inhibitors, appears to be a common effect of topiramate. Paresthesia was more frequently reported in the monotherapy epilepsy trials conducted with 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.

5.13 Interaction with Other CNS Depressants

Topiramate is a CNS depressant. Concomitant administration of topiramate with other CNS depressant drugs can result in significant CNS depression. Patients should be watched carefully when topiramate ER is co-administered with other CNS depressant drugs.

6. ADVERSE REACTIONS

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

• Acute Myopia and Secondary Angle Closure [see Warnings and Precautions (5.1)]

• Oligohydrosis and Hyperthermia [see Warnings and Precautions (5.2)]

• Metabolic Acidosis [see Warnings and Precautions (5.3)]

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

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

• Fetal Toxicity [see Warnings and Precautions (5.7)]

• Withdrawal of Antiepileptic Drugs [see Warnings and Precautions (5.8)]

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

The data described in the following sections were obtained using immediate-release topiramate tablets in studies of patients with epilepsy. Topiramate ER has not been studied in a randomized, placebo-controlled Phase III clinical study in the epilepsy patient population. However, it is expected that topiramate ER would produce a similar adverse reaction profile as immediate-release topiramate.

6.1 Clinical Trials Experience

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.

Adverse Reactions Observed in Monotherapy Trial

Adults 17 Years and Older

The adverse reactions in the controlled trial (Study 1) that occurred most commonly in adults in the 400 mg per day group (incidence greater than or equal to 5%) and at a rate higher than the 50 mg per day group were paresthesia, weight decrease, somnolence, anorexia, dizziness, and difficulty with memory (see Table 1).

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 (greater than or equal to 2% more frequent than low-dose 50 mg per day topiramate) adverse reactions causing discontinuation in this trial were difficulty with memory, fatigue, asthenia, insomnia, somnolence and paresthesia.

Pediatric Patients 10 Years to 16 Years of Age

The adverse reactions in the controlled trial (Study 1) that occurred most commonly in children (10 years up to 16 years of age) in the 400 mg per day topiramate group (incidence greater than or equal to 5%) and at a rate higher than in the 50 mg per day group were weight decrease, upper respiratory tract infection, paresthesia, anorexia, diarrhea, and mood problems (see Table 2).

Approximately 12% of the 57 pediatric patients in the 400 mg per day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. The most common (greater than 5%) adverse reactions resulting in discontinuation in this trial were difficulty with concentration/attention.

Table 1: Incidence of Treatment-Emergent Adverse Reaction in the Monotherapy Epilepsy Trial in Adultsa Where Incidence Was at Least 2% in the 400 mg/day Immediate-Release Topiramate Group and Greater Than the Rate in the 50 mg/day Immediate-Release Topiramate Group

a Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category

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Table 2: Incidence of Treatment-Emergent Adverse Reactions in the Monotherapy Epilepsy Trial in Pediatric Patients (Ages 10 up to 16 Years)a Where Incidence Was at Least 5% in the 400 mg/day Immediate-Release Topiramate Group and Greater than the Rate in the 50mg/day Immediate-Release Topiramate Group

a Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category

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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 in controlled trials in adults with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome that were seen at greater frequency in topiramate-treated patients and did not appear to be dose-related were: somnolence, ataxia, speech disorders and related speech problems, psychomotor slowing, abnormal vision, difficulty with memory, paresthesia and diplopia [see Table 3]. The most common dose-related adverse reactions at dosages of 200 mg to 1,000 mg per day were: fatigue, nervousness, difficulty with concentration or attention, confusion, depression, anorexia, language problems, anxiety, mood problems, and weight decrease [see Table 5].

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 greater frequency in topiramate-treated patients were: fatigue, somnolence, anorexia, nervousness, difficulty with concentration/attention, difficulty with memory, aggressive reaction, and weight decrease [see Table 6].

In controlled clinical trials in adults, 11% of patients receiving topiramate 200 to 400mg per day as adjunctive therapy discontinued due to adverse reactions. This rate appeared to increase at dosages above 400mg 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 3 lists adverse reactions that occurred in at least 1% of adults treated with 200 to 400 mg per day topiramate in controlled trials that were numerically more common at this dose than in the patients treated with placebo. In general, most patients who experienced adverse reactions during the first eight weeks of these trials no longer experienced them by their last visit. Table 6 lists adverse reactions that occurred in at least 1% of pediatric patients treated with 5 mg/kg to 9 mg/kg topiramate in controlled trials that were numerically more common than 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 3: Incidence of Adverse Reactions in Placebo-Controlled, Adjunctive Epilepsy Trials in Adultsa,b,c

a Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo

b 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.

c 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

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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 incidence of adverse reactions (Table 4) did not differ significantly between the 2 topiramate regimens. Because the frequencies of adverse reactions reported in this study were markedly lower than those reported in the previous epilepsy studies, they cannot be directly compared with data obtained in other studies.

Table 4: Incidence of Adverse Reactions in Study 7a,b,c

a Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo

b Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category

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

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Table 5: Incidence (%) of Dose-Related Adverse Reactions From Placebo-Controlled, Adjunctive Trials in Adults With Partial Onset Seizures (Studies 2 through 7)a

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

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Table 6: Incidence (%) of Adverse Reaction in Placebo-Controlled, Adjunctive Epilepsy Trial in Pediatric Patients (Ages 2 Years to 16 Years)a,b,c (Study 8)

a Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo

b Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category

c Reactions that Occurred in at Least 1% of Topiramate-Treated Patients and Occurred More Frequently in Topiramate-Treated Than Placebo-Treated Patients

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Laboratory Abnormalities

Topiramate decreases serum bicarbonate [see Warnings and Precautions (5.3)]

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 ER.

Controlled trials of adjunctive topiramate treatment of adults for partial onset seizures showed an increased incidence of markedly decreased serum phosphorus (6% topiramate, 2% placebo), markedly increased serum alkaline phosphatase (3% topiramate, 1% placebo), and decreased serum potassium (0.4 % topiramate, 0.1 % placebo). The clinical significance of these abnormalities has not been clearly established.

Changes in several clinical laboratory results (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)].

Topiramate treatment produced a dose-related increased shift in serum creatinine from normal at baseline to an increased value at the end of 4 months treatment in adolescent patients (ages 12 years to 16 years) in a double-blind, placebo-controlled study. The incidence of these abnormal shifts was 4% for placebo, 4% for 50 mg, and 18% for 100 mg.

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

6.2 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.

7. DRUG INTERACTIONS

7.1 Alcohol

Alcohol use is contraindicated within 6 hours prior to and 6 hours after topiramate ER administration [see Contraindications (4) and Warnings and Precautions (5.4)].

7.2 Oral Contraceptives

Exposure to ethinyl estradiol was statistically significantly decreased when topiramate (at doses above 200 mg) was given as adjunctive therapy in patients taking valproic acid. However, norethindrone exposure was not significantly affected.

In another pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), topiramate, given in the absence of other medications at doses of 50 to 200 mg per day, was not associated with statistically significant changes in mean exposure to either component of the oral contraceptive.

The possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking combination oral contraceptive products with topiramate ER. Patients taking estrogen-containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding.

7.3 Antiepileptic Drugs

Concomitant administration of phenytoin or carbamazepine with topiramate decreased plasma concentrations of topiramate.

Concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with and without encephalopathy. Concomitant administration of topiramate with valproic acid has also been associated with hypothermia (with and without hyperammonemia) in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.8), (5.10)].

Numerous AEDs are substrates of the CYP enzyme system. In vitro studies indicate that topiramate does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4/5 isozymes. In vitro studies indicate that immediate-release topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4. The same drug interactions can be expected with the use of topiramate ER.

7.4 CNS Depressants

Topiramate is a CNS depressant. Concomitant administration of topiramate with other CNS depressant drugs or alcohol can result in significant CNS depression [see Warnings and Precautions (5.13)].

7.5 Other Carbonic Anhydrase Inhibitors

Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide, acetazolamide or dichlorphenamide), may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Patient should be monitored for the appearance or worsening of metabolic acidosis when topiramate ER is given concomitantly with another carbonic anhydrase inhibitor.

7.6 Metformin

Topiramate treatment can frequently cause metabolic acidosis, a condition for which the use of metformin is contraindicated. The concomitant use of topiramate ER and metformin is contraindicated in patients with metabolic acidosis.

7.7 Lithium

In patients, there was an observed increase in systemic exposure of lithium following topiramate doses of up to 600 mg per day. Lithium levels should be monitored when co-administered with high-dose topiramate ER.

8. USE IN SPECIFIC POPULATIONS

8.1 Usage in Pregnancy

Pregnancy Category D

[see Warnings and Precautions (5.7)]

Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have increased risk for cleft lip and/or cleft palate (oral clefts). When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring. Topiramate should be used during pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to the fetus [see Use in Specific Populations (8.9)].

Pregnancy Registry

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

Human Data

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

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.

Animal Data

Topiramate has demonstrated selective developmental toxicity, including teratogenicity, in multiple animal species at clinically relevant doses. When oral doses of 20 mg/kg, 100 mg/kg, or 500 mg/kg were administered to pregnant mice during the period of organogenesis, the incidence of fetal malformations (primarily craniofacial defects) was increased at all doses. The low dose is approximately 0.2 times the recommended human dose (RHD) 400mg per day on a mg/m2 basis. Fetal body weights and skeletal ossification were reduced at 500 mg/kg in conjunction with decreased maternal body weight gain.

In rat studies (oral doses of 20 mg/kg, 100 mg/kg, and 500 mg/kg or 0.2 mg/kg, 2.5 mg/kg, 30 mg/kg, and 400 mg/kg), the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased among the offspring of dams treated with 400 mg/kg (10 times the RHD on a mg/m2 basis) or greater during the organogenesis period of pregnancy. Embryotoxicity (reduced fetal body weights, increased incidence of structural variations) was observed at doses as low as 20 mg/kg (0.5 times the RHD on a mg/m2 basis). Clinical signs of maternal toxicity were seen at 400 mg/kg and above, and maternal body weight gain was reduced during treatment with 100 mg/kg or greater.

In rabbit studies (20 mg/kg, 60 mg/kg, and 180 mg/kg or 10 mg/kg, 35 mg/kg, and 120 mg/kg orally during organogenesis), embryo/fetal mortality was increased at 35 mg/kg (2 times the RHD on a mg/m2 basis) or greater, and teratogenic effects (primarily rib and vertebral malformations) were observed at 120 mg/kg (6 times the RHD on a mg/m2 basis). Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg and above.

When female rats were treated during the latter part of gestation and throughout lactation (0.2 mg/kg, 4 mg/kg, 20 mg/kg, and 100 mg/kg or 2, 20, and 200 mg/kg), offspring exhibited decreased viability and delayed physical development at 200 mg/kg (5 times the RHD on a mg/m2 basis) and reductions in pre-and/or postweaning body weight gain at 2mg/kg (0.05 times the RHD on a mg/m2 basis) and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg or greater.

In a rat embryo/fetal development study with a postnatal component (0.2 mg/kg, 2.5 mg/kg, 30 mg/kg, or 400mg/kg during organogenesis; noted above), pups exhibited delayed physical development at 400 mg/kg (10 times the RHD on a mg/m2 basis) and persistent reductions in body weight gain at 30 mg/kg (1 times the RHD on a mg/m2 basis) and higher.

8.2 Labor and Delivery

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

8.3 Nursing Mothers

Limited data on 5 breastfeeding infants exposed to topiramate showed infant plasma topiramate levels equal to 10-20% of the maternal plasma level. The effects of this exposure on infants are unknown. Caution should be exercised when topiramate ER is administered to a nursing woman.

8.4 Pediatric Use

Seizures in Pediatric Patients 6 Years of Age and Older

Because the capsule must be swallowed whole, and may not be sprinkled on food, crushed or chewed, topiramate ER is recommended only for children age 6 or older.

The safety and effectiveness of topiramate ER in pediatric patients is based on controlled trials with immediate-release topiramate.

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 (5.2]).

• dose-related increased incidence of metabolic acidosis [see Warnings and Precautions (5.3)].

• dose-related increased incidence of hyperammonemia [see Warnings and Precautions (5.9)].

Adjunctive Treatment for Partial Onset Epilepsy 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 per day) did not demonstrate efficacy compared with placebo in controlling seizures.

In general, the adverse reaction profile in this population was similar to that of older pediatric patients, although results from the above controlled study, and an open-label, long-term extension study in these infants/toddlers (1 to 24 months old) suggested some adverse reactions 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)].

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.

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 (5.3) and Adverse Reactions (6)].

In open-label, uncontrolled experience, increasing impairment of adaptive behavior was documented in behavioral testing over time in this population. There was a suggestion that this effect was dose-related. However, because of the absence of an appropriate control group, it is not known if this decrement in function was treatment related or reflects the patient’s underlying disease (e.g., patients who received higher doses may have more severe underlying disease) [see Warnings and Precautions (5.6)].

In this open-label, uncontrolled study, the mortality was 37 deaths/1000 patient years. It is not possible to know whether this mortality rate is related to immediate-release topiramate treatment, because the background mortality rate for a similar, significantly refractory, young pediatric population (1month to 24 months) with partial epilepsy is not known.

Other Pediatric Studies

Topiramate treatment produced a dose-related increased shift in serum creatinine from normal at baseline to an increased value at the end of 4 months treatment in adolescent patients (ages 12 years to 16 years) in a double-blind, placebo-controlled study [see Adverse Reactions (6.1)].

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.

8.5 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 GFR should be measured prior to dosing [see Dosage and Administration (2) and Clinical Pharmacology (12.3)].

8.6 Race and Gender Effects

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

8.7 Renal Impairment

The clearance of topiramate was reduced by 42% in moderately renally impaired (creatinine clearance 30 to 69 mL/min/1.73m2) 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 than70 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 (2.4)].

8.8 Patients Undergoing Hemodialysis

Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than a normal individual. Accordingly, a prolonged period of dialysis may cause topiramate concentration to fall below that required to maintain an anti-seizure effect. To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate may be required. The actual adjustment should take into account the duration of dialysis period, the clearance rate of the dialysis system being used, and the effective renal clearance of topiramate in the patient being dialyzed [see Dosage and Administration (2.5)].

8.9 Women of Childbearing Potential

Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or cleft palate (oral clefts) [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1)]. Consider the benefits and risks of topiramate when prescribing this drug to women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death. Because of the risk of oral clefts to the fetus, which occur in the first trimester of pregnancy before many women know they are pregnant, all women of childbearing potential should be apprised of the potential hazard to the fetus from exposure to topiramate. If the decision is made to use topiramate, women who are not planning a pregnancy would use effective contraception [see Drug Interactions (7.2)] Women who are planning a pregnancy would be counseled regarding the relative risks and benefits of topiramate use during pregnancy, and alternative therapeutic options should be considered for these patients.

9. OVERDOSAGE

Overdoses of topiramate resulted in signs and symptoms which included convulsions, drowsiness, speech disturbance, blurred vision, diplopia, mentation impaired, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness and depression. The clinical consequences were not severe in most cases, but deaths have been reported after polydrug overdoses involving topiramate.

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

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

Similar signs, symptoms, and clinical consequences are expected to occur with overdosage of topiramate ER. Therefore, in acute topiramate ER overdose, if the ingestion is recent, the stomach should be emptied immediately by lavage or by induction of emesis. Activated charcoal has been shown to adsorb topiramate in vitro. Treatment should be appropriately supportive. Hemodialysis is an effective means of removing topiramate from the body.

10. MECHANISM OF ACTION

The precise mechanisms by which topiramate exerts its anticonvulsant effects are unknown; however, preclinical studies have revealed four properties that may contribute to topiramate's efficacy for epilepsy. Electrophysiological and biochemical evidence suggests that topiramate, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV.

11. PHARMACODYNAMICS

Topiramate has anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests. Topiramate is only weakly effective in blocking clonic seizures induced by the GABAA receptor antagonist, pentylenetetrazole. Topiramate is also effective in rodent models of epilepsy, which include tonic and absence-like seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in rats by kindling of the amygdala or by global ischemia.

12. PHARMACOKINETICS

Absorption and Distribution

Linear pharmacokinetics of topiramate from topiramate ER were observed following a single oral dose over the range of 50 mg to 200 mg. At 25 mg, the pharmacokinetics of topiramate ER is nonlinear possibly due to the binding of topiramate to carbonic anhydrase in red blood cells.

The peak plasma concentrations (Cmax) of topiramate occurred at approximately 24 hours following a single 200 mg oral dose of topiramate ER. At steady-state, the (AUC0-24hr, Cmax, and Cmin) of topiramate from topiramate ER administered once-daily and the immediate-release tablet administered twice-daily were shown to be bioequivalent. Fluctuation of topiramate plasma concentrations at steady-state for topiramate ER administered once-daily was approximately 26% and 42% in healthy subjects and in epileptic patients, respectively, compared to approximately 40% and 51%, respectively, for immediate-release topiramate.

Compared to the fasted state, high-fat meal increased the Cmax of topiramate by 37% and shortened the Tmax to approximately 8 hour following a single dose of topiramate ER, while having no effect on the AUC. Modeling of the observed single dose fed data with simulation to steady state showed that the effect on Cmax is significantly reduced following repeat administrations. Topiramate ER can be taken without regard to meals.

Topiramate is 15% to 41% bound to human plasma proteins over the blood concentration range of 0.5 mcg/mL to 250 mcg/mL. The fraction bound decreased as blood concentration increased.

Carbamazepine and phenytoin do not alter the binding of immediate-release topiramate. Sodium valproate, at 500 mcg/mL (a concentration 5 to 10 times higher than considered therapeutic for valproate) decreased the protein binding of immediate-release topiramate from 23% to 13%. Immediate-release topiramate does not influence the binding of sodium valproate.

Metabolism and Excretion

Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption of topiramate. In rats, given probenecid to inhibit tubular reabsorption, along with topiramate, a significant increase in renal clearance of topiramate was observed. This interaction has not been evaluated in humans. Overall, oral plasma clearance (CL/F) is approximately 20 mL/min to 30 mL/min in adults following oral administration. The mean elimination half-life of topiramate was approximately 31 hours following repeat administration of topiramate ER.

Specific Populations

Renal Impairment

The clearance of topiramate was reduced by 42% in moderately renally impaired (creatinine clearance 30 to 69 mL/min/1.73m2) and by 54% in severely renally impaired subjects (creatinine clearance less than 30 mL/min/1.73m2) compared to normal renal function subjects (creatinine clearance greater than70 mL/min/1.73m2). Since topiramate is presumed to undergo significant tubular reabsorption, it is uncertain whether this experience can be generalized to all situations of renal impairment. It is conceivable that some forms of renal disease could differentially affect glomerular filtration rate and tubular reabsorption resulting in a clearance of topiramate not predicted by creatinine clearance. In general, however, use of one-half the usual starting and maintenance dose is recommended in patients with creatinine clearance less than 70 mL/min/1.73 m2 [see Dosage and Administration (2.3), (2.4)].

Hemodialysis

Topiramate is cleared by hemodialysis. Using a high-efficiency, counterflow, single pass-dialysate hemodialysis procedure, topiramate dialysis clearance was 120 mL/min with blood flow through the dialyzer at 400 mL/min. This high clearance (compared to 20 mL/min to 30 mL/min total oral clearance in healthy adults) will remove a clinically significant amount of topiramate from the patient over the hemodialysis treatment period. Therefore, a supplemental dose may be required [see Dosage and Administration (2.5)].

Hepatic Impairment

In hepatically impaired subjects, the clearance of topiramate may be decreased; the mechanism underlying the decrease is not well understood.

Age, Gender and Race

The pharmacokinetics of topiramate in elderly subjects (65 to 85 years of age, N=16) were evaluated in a controlled clinical study. The elderly subject population had reduced renal function (creatinine clearance [-20%]) compared to young adults. Following a single oral 100 mg dose, maximum plasma concentration for elderly and young adults was achieved at approximately 1 to 2 hours. Reflecting the primary renal elimination of topiramate, topiramate plasma and renal clearance were reduced 21% and 19%, respectively, in elderly subjects, compared to young adults. Similarly, topiramate half-life was longer (13%) in the elderly. Reduced topiramate clearance resulted in slightly higher maximum plasma concentration (23%) and AUC (25%) in elderly subjects than observed in young adults. Topiramate clearance is decreased in the elderly only to the extent that renal function is reduced.

In a study of 13 healthy elderly subjects and 18 healthy young adults who received topiramate ER, 30% higher mean Cmax and 44% higher AUC values were observed in elderly compared to young subjects. Elderly subjects exhibited shorter median Tmax at 16 hours versus 24 hours in young subjects. The apparent elimination half-life was similar across age groups. As recommended for all patients, dosage adjustment is indicated in elderly patients with a creatinine clearance rate less than 70 mL/min/1.73 m2) [see Dosage and Administration (2.4 )].

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

Pediatric Pharmacokinetics

Pharmacokinetics of immediate-release topiramate were evaluated in patients ages 2 years to less than 16 years. Patients received either no or a combination of other antiepileptic drugs. A population pharmacokinetic model was developed on the basis of pharmacokinetic data from relevant topiramate clinical studies. This dataset contained data from 1217 subjects including 258 pediatric patients aged 2 years to less than 16 years (95 pediatric patients less than 10 years of age). Pediatric patients on adjunctive treatment exhibited a higher oral clearance (L/h) of topiramate compared to patients on monotherapy, presumably because of increased clearance from concomitant enzyme-inducing antiepileptic drugs. In comparison, topiramate clearance per kg is greater in pediatric patients than in adults and in young pediatric patients (down to 2 years) than in older pediatric patients. Consequently, the plasma drug concentration for the same mg/kg/day dose would be lower in pediatric patients compared to adults and also in younger pediatric patients compared to older pediatric patients. Clearance was independent of dose.

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

13. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand names:

QUDEXY XR, by Upsher-Smith Labs.

TROKENDI XR, by Supernus Pharmaceuticals, Inc.

b) Generic drugs: None.

2) How Supplied:

QUDEXY XR Capsules

QUDEXY XR (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 0245-1071-30)

• Bottle of 90 count with desiccant (NDC 0245-1071-90)

• Bottle of 500 count with desiccant (NDC 0245-1071-15)

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 0245-1072-30)

• Bottle of 90 count with desiccant (NDC 0245-1072-90)

• Bottle of 500 count with desiccant (NDC 0245-1072-15)

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 0245-1074-30)

• Bottle of 90 count with desiccant (NDC 0245-1074-90)

• Bottle of 500 count with desiccant (NDC 0245-1074-15)

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 0245-1075-30)

• Bottle of 90 count with desiccant (NDC 0245-1075-90)

• Bottle of 500 count with desiccant (NDC 0245-1075-15)

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 0245-1073-30)

• Bottle of 90 count with desiccant (NDC 0245-1073-90)

• Bottle of 500 count with desiccant (NDC 0245-1073-15)

TROKENDI XR Capsules:

Trokendi XR™ (topiramate) extended-release capsules are available as extended-release capsules in the following strengths and colors:

Bottles

25 mg (light green opaque body/yellow opaque cap) topiramate extended-release capsules (black print “SPN” and “25”) -bottles of 100 count (NDC-17772-101-01)

50 mg (light green opaque body/orange opaque cap) topiramate extended-release capsules (black print “SPN” and “50”) -bottles of 100 count (NDC-17772-102-01)

100 mg (green opaque body/blue opaque cap) topiramate extended-release capsules (black print “SPN” and “100”) -bottles of 100 count (NDC-17772-103-01)

200 mg (pink opaque body/blue opaque cap) topiramate extended-release capsules (black print “SPN” and “200”) -bottles of 100 count (NDC-17772-104-01)

Blister package

25 mg (light green opaque body/yellow opaque cap) topiramate extended-release capsules (black print “SPN” and “25”) – blister packages of 30-count (NDC-17772-101-15)

50 mg (light green opaque body/orange opaque cap) topiramate extended-release capsules (black print “SPN” and “50”) – blister packages of 30-count (NDC-17772-102-15)

100 mg (green opaque body/blue opaque cap) topiramate extended-release capsules (black print “SPN” and “100”) – blister packages of 30-count (NDC-17772-103-15)

200 mg (pink opaque body/blue opaque cap) topiramate extended-release capsules (black print “SPN” and “200”) – blister packages of 30-count (NDC-17772-104-15)

3) Storage and Handling:

Store at 25°C (77°F); excursions 15°C-30°C (59°F-86°F)]. Protect from moisture and light.

Rx only

Rev 08/13