Trokendi XR

Supernus Pharmaceuticals, Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use TROKENDI XR safely and effectively. See full prescribing information for TROKENDI XR. Trokendi XR (topiramate) extended-release capsules for oral use Initial U.S. Approval: 1996INDICATIONS AND USAGETrokendi XR™ is an antiepileptic drug indicated for: Partial Onset Seizure and Primary Generalized Tonic-Clonic Seizures - 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 (1.1) Lennox-Gastaut Syndrome (LGS) - adjunctive therapy in patients 6 years of age and older with seizures associated with Lennox-Gastaut syndrome (1.2) DOSAGE AND ADMINISTRATION Initial Dose Titration Recommended Dose Monotherapy Therapy: Partial Onset or Primary Generalized Tonic-Clonic Seizures Adults and pediatric patients 10 years and older (2.1) 50 mg orally once daily Increase dose weekly by increments of 50 mg for first 4 weeks then 100 mg for weeks 5 to 6 400 mg once daily Adjunctive Therapy Adults with partial onset seizures or LGS (2.2) 25 mg to 50 mg orally once daily Increase dose weekly by increments of 25 mg to 50 mg to achieve an effective dose 200 mg to 400 mg once daily Adults with primary generalized tonic-clonic seizures (2.2) 25 mg to 50 mg orally once daily Increase dose weekly to an effective dose by increments of 25 mg to 50 mg 400 mg once daily Pediatric patients 6 years and older with partial onset seizures, primary generalized tonic-clonic seizures or LGS (2.2) 25 mg once at night-time (based on a range of 1 mg/kg to 3 mg/kg once daily) for first week Increase dosage at 1- or 2-week intervals by increments of 1 mg/kg to 3 mg/kg Dose titration should be guided by clinical outcome 5 mg/kg to 9 mg/kg once daily Swallow capsule whole and intact. Do not sprinkle on food, chew or crush (2.9)DOSAGE FORMS AND STRENGTHS Extended-release capsules: 25 mg, 50 mg, 100 mg, and 200 mg (3) CONTRAINDICATIONS With recent alcohol use (i.e., within 6 hours prior to and 6 hours after Trokendi XR use [(4), (5.4)] In patients with metabolic acidosis taking concomitant metformin [(4), (5.3)] WARNINGS AND PRECAUTIONS Acute myopia and secondary angle closure glaucoma: Untreated elevated intraocular pressure can lead to permanent visual loss. Discontinue Trokendi XR™ if it occurs (5.1) Oligohydrosis and hyperthermia: Monitor decreased sweating and increased body temperature, especially in pediatric patients (5.2) Metabolic acidosis: Measure baseline and periodic measurement of serum bicarbonate. Consider dose reduction or discontinuation of Trokendi XR™ if clinically appropriate (5.3) Suicidal behavior and ideation: Antiepileptic drugs increase the risk of suicidal behavior or ideation (5.5) Cognitive/neuropsychiatric: Trokendi XR™ may cause cognitive dysfunction. Use caution when operating machinery including automobiles. Depression and mood problems may occur (5.6) Fetal toxicity: Topiramate use during pregnancy can cause cleft lip and/or palate (5.7) Withdrawal of AEDs: Withdrawal of Trokendi XR™ should be done gradually (5.8) Hyperammonemia and encephalopathy: Patients with inborn errors of metabolism or reduced mitochondrial activity may have an increased risk of hyper-ammonemia. Measure ammonia if encephalopathic symptoms occur (5.9) Kidney stones: Avoid use with other carbonic anhydrase inhibitors, other drugs causing metabolic acidosis, or in patients on a ketogenic diet (5.10) Hypothermia: Reported with concomitant valproic acid use (5.11) Side EffectsThe most common (greater than 5% more frequent than placebo or low-dose topiramate in monotherapy) adverse reactions were paresthesia, anorexia, weight decrease, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, difficulty with memory, difficulty with concentration/attention, cognitive problem, confusion, mood problems, fever, infection, and flushing (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Supernus Pharmaceuticals at 1-866-398-0833- or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Oral contraceptives: Decreased contraceptive efficacy and increased breakthrough bleeding, especially at doses greater than 200 mg per day (7.2) Phenytoin or carbamazepine: Concomitant administration with topiramate decreased plasma concentrations of topiramate (7.3) Other carbonic anhydrase inhibitors: Monitor for the appearance or worsening of metabolic acidosis (7.5) Lithium: Monitor lithium levels when co-administered with high-dose topiramate (7.7) USE IN SPECIFIC POPULATIONS Renal Impairment: (creatinine clearance less than 70 mL/min/1.73m2), one-half of the adult dose is recommended (8.7) Patients undergoing hemodialysis: Topiramate is cleared by hemodialysis. Dosage adjustment is necessary to avoid rapid drops in topiramate plasma concentration during hemodialysis (8.8) Pregnancy: Increased risk of cleft lip and/or palate. Pregnancy registry available (8.1) Nursing mothers: Caution should be exercised when administered to a nursing mother (8.3) Pediatric Use: Because the capsule must be swallowed whole, and may not be sprinkled on food, crushed or chewed, Trokendi XR™ is recommended only for children ages 6 years and older (8.4)

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 TROKENDI XR INDICATIONS AND USAGE
  • 1.1 Partial Onset Seizure and Primary Generalized Tonic-Clonic Seizures
  • 1.2 Lennox-Gastaut Syndrome
• 2 TROKENDI XR DOSAGE AND ADMINISTRATION
  • 2.1 Monotherapy Use
  • 2.2 Adjunctive Therapy Use
  • 2.3 Administration with Alcohol
  • 2.4 Dose Modifications in Patients with Renal Impairment
  • 2.5 Dosage Modifications in Patients Undergoing Hemodialysis
  • 2.6 Laboratory Testing Prior to Treatment Initiation
  • 2.7 Dosing Modifications in Patients Taking Phenytoin and/or Carbamazepine
  • 2.8 Monitoring for Therapeutic Blood Levels
  • 2.9 Administration Instructions
• 3 DOSAGE FORMS AND STRENGTHS
• 4 TROKENDI XR CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Acute Myopia and Secondary Angle Closure Glaucoma
  • 5.2 Oligohydrosis and Hyperthermia
  • 5.3 Metabolic Acidosis
  • 5.4 Interaction with Alcohol
  • 5.5 Suicidal Behavior and Ideation
  • 5.6 Cognitive/Neuropsychiatric Adverse Reactions
  • 5.7 Fetal Toxicity
  • 5.8 Withdrawal of Antiepileptic Drugs
  • 5.9 Hyperammonemia and Encephalopathy
  • 5.10 Kidney Stones
  • 5.11 Hypothermia with Concomitant Valproic Acid Use
  • 5.12 Paresthesia
  • 5.13 Interaction with Other CNS Depressants
• 6 TROKENDI XR ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Postmarketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Alcohol
  • 7.2 Oral Contraceptives
  • 7.3 Antiepileptic Drugs
  • 7.4 CNS Depressants
  • 7.5 Other Carbonic Anhydrase Inhibitors
  • 7.6 Metformin
  • 7.7 Lithium
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.2 Labor and Delivery
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Race and Gender Effects
  • 8.7 Renal Impairment
  • 8.8 Patients Undergoing Hemodialysis
  • 8.9 Women of Childbearing Potential
• 9 DRUG ABUSE AND DEPENDENCE
  • 9.1 Controlled Substance
  • 9.2 Abuse
  • 9.3 Dependence
• 10 OVERDOSAGE
• 11 TROKENDI XR DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
  • 12.6 Relative Bioavailability of Trokendi XR™ Compared to Immediate-Release Topiramate
• 13 NON-CLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
• 14 CLINICAL STUDIES
  • 14.1 Bridging Study to Demonstrate Pharmacokinetic Equivalence between Extended-Release and Immediate-Release Topiramate Formulations
  • 14.2 Monotherapy Treatment in Patients with Partial Onset or Primary Generalized Tonic-Clonic Seizures
  • 14.3 Adjunctive Therapy in Patients with Partial Onset Seizures
  • 14.4 Adjunctive Therapy in Patients With Primary Generalized Tonic-Clonic Seizures
  • 14.5 Adjunctive Therapy in Patients With Lennox-Gastaut Syndrome
• 16 HOW SUPPLIED/STORAGE AND HANDLING
  • 16.1 Trokendi XR™ Capsules
  • 16.2 Storage and Handling
• 17 PATIENT COUNSELING INFORMATION
• MEDICATION GUIDE
• PRINCIPAL DISPLAY PANEL - 25 mg Capsule Bottle Label
• PRINCIPAL DISPLAY PANEL - 50 mg Capsule Bottle Label
• PRINCIPAL DISPLAY PANEL - 100 mg Capsule Bottle Label
• PRINCIPAL DISPLAY PANEL - 200 mg Capsule Bottle Label

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Partial Onset Seizure and Primary Generalized Tonic-Clonic Seizures

Trokendi XR™ (topiramate) extended-release 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 [see Clinical Studies (14.2, 14.3, 14.4) ]. Safety and effectiveness in patients who were converted to monotherapy from a previous regimen of other anticonvulsant drugs have not been established in controlled trials [see Clinical Studies (14.2) ].

1.2 Lennox-Gastaut Syndrome

Trokendi XR™ (topiramate) extended-release capsules are indicated as adjunctive therapy in patients 6 years of age and older with seizures associated with Lennox-Gastaut syndrome [see Clinical Studies (14.5) ].

2 DOSAGE AND ADMINISTRATION

2.1 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 Trokendi XR™ according to the following schedule:

2.2 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 Trokendi XR™ 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 [see Clinical Studies (14.4)].

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 Trokendi XR™ 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 (14.4) ].

2.3 Administration with Alcohol

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

2.4 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).

2.5 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.

2.6 Laboratory Testing Prior to Treatment Initiation

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

2.7 Dosing Modifications in Patients Taking Phenytoin and/or Carbamazepine

The co-administration of Trokendi XR™ 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 Trokendi XR™ may require adjustment of the dose of Trokendi XR™.

2.8 Monitoring for Therapeutic Blood Levels

It is not necessary to monitor topiramate plasma concentrations to optimize Trokendi XR™ therapy.

2.9 Administration Instructions

Trokendi XR™ can be taken without regard to meals.

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

3 DOSAGE FORMS AND STRENGTHS

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

25 mg: Size 2 capsules, light green opaque body/yellow opaque cap (printed "SPN" on the cap, "25" on the body)

50 mg: Size 0 capsules, light green opaque body/orange opaque cap (printed "SPN" on the cap, "50" on the body)

100 mg: Size 00 capsules, green opaque body/blue opaque cap (printed "SPN" on the cap, "100" on the body)

200 mg: Size 00 capsules, pink opaque body/blue opaque cap (printed "SPN" on the cap, "200" on the body)

4 CONTRAINDICATIONS

Trokendi XR™ is contraindicated in patients:

• With recent alcohol use (i.e., within 6 hours prior to and 6 hours after Trokendi XR™ 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 Trokendi XR™ as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of Trokendi XR™, may be helpful.

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

5.2 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 Trokendi XR™ should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when Trokendi XR™ 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.

5.3 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 Trokendi XR™. 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 Trokendi XR™ 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 Trokendi XR™ 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.

5.4 Interaction with Alcohol

In vitro data show that, in the presence of alcohol, the pattern of topiramate release from Trokendi XR™ capsules is significantly altered. As a result, plasma levels of topiramate with Trokendi XR™ may be markedly higher soon after dosing and subtherapeutic later in the day. Therefore, alcohol use should be completely avoided within 6 hours prior to and 6 hours after Trokendi XR™ administration.

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 Trokendi XR™ 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 1 shows absolute and relative risk by indication for all evaluated AEDs.

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

Anyone considering prescribing Trokendi XR™ 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 Side Effects

Adverse reactions most often associated with the use of topiramate, and therefore expected to be associated with the use of Trokendi XR™ 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 Trokendi XR™, 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 Trokendi XR™ should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency [see Clinical Studies (14) ]. In situations where rapid withdrawal of Trokendi XR™ 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). Trokendi XR™ 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 Trokendi XR™ 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 Trokendi XR™ 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. Trokendi XR™ is not approved for pediatric patients less than 6 years old [see Use in Specific Populations (8.4)].

Trokendi XR™ 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 Trokendi XR™ 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 Trokendi XR™ 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. Trokendi XR™ has not been studied in a randomized, placebo-controlled Phase III clinical study in the epilepsy patient population. However, it is expected that Trokendi XR™ 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 2) [see Clinical Studies (14.2) ].

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 3) [see Clinical Studies (14.2) ].

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.

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 4] [see Clinical Studies (14.3, 14.4, and 14.5)]. 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 6 ].

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 7 ].

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 4 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 7 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 4: Incidence of Adverse Reactions in Placebo-Controlled, Adjunctive Epilepsy Trials in Adults 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

	Topiramate Dosage (mg per day)
Body System/	Placebo	200-400	600-1,000
Adverse ReactionAdverse 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	(N=291)	(N=183)	(N=414)
Body as a Whole-General Disorders
Fatigue	13	15	30
Asthenia	1	6	3
Back pain	4	5	3
Chest pain	3	4	2
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
Hypoaesthesia	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 liability	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 incidence of adverse reactions (Table 5) 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 5: Incidence of Adverse Reactions in Study 7Patients 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

		Topiramate Dosage (mg per day)
Body System/	Placebo	200
Adverse ReactionAdverse reactions reported by at least 2% of patients in the topiramate 200 mg per day group and more common than in the placebo group	(N=92)	(N=171)
Body as a Whole-General Disorders
Fatigue	4	9
Chest pain	1	2
Cardiovasular 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 Disorder
Diplopia	0	2
Vision abnormal	0	2

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 Trokendi XR™.

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 Trokendi XR™ 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 Trokendi XR™. Patients taking estrogen-containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding [see Clinical Pharmacology (12.3) ].

7.3 Antiepileptic Drugs

Concomitant administration of phenytoin or carbamazepine with topiramate decreased plasma concentrations of topiramate [see Clinical Pharmacology (12.3) ].

Concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with and without encephalopathy. Concomitant administration of topiramate with valproic acid has also been associated with hypothermia (with and without hyperammonemia) in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.8), (5.10)and Clinical Pharmacology (12.3) ].

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 Trokendi XR™.

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 Trokendi XR™ is given concomitantly with another carbonic anhydrase inhibitor [see Clinical Pharmacology (12.3) ].

7.6 Metformin

Topiramate treatment can frequently cause metabolic acidosis, a condition for which the use of metformin is contraindicated. The concomitant use of Trokendi XR™ and metformin is contraindicated in patients with metabolic acidosis. [see Clinical Pharmacology (12.3) ].

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 Trokendi XR™ [see Clinical Pharmacology (12.3) ].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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

Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have 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 Trokendi XR™ 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, Trokendi XR™ is recommended only for children age 6 or older.

The safety and effectiveness of Trokendi XR™ in pediatric patients is based on controlled trials with immediate-release topiramate [see Clinical Studies (14)].

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) and Clinical Pharmacology (12.3) ].

8.8 Patients Undergoing Hemodialysis

Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than 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) and Clinical Pharmacology (12.3) ].

8.9 Women of Childbearing Potential

Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or cleft palate (oral clefts) [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1) ]. Consider the benefits and 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 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Trokendi XR™ (topiramate) extended-release capsule is not a controlled substance.

9.2 Abuse

The abuse and dependence potential of Trokendi XR™ has not been evaluated in human studies.

9.3 Dependence

Trokendi XR™ has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.

10 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 Trokendi XR™. Therefore, in acute Trokendi XR™ overdose, if the ingestion is recent, the stomach should be emptied immediately by lavage or by induction of emesis. Activated charcoal has been shown to adsorb topiramate in vitro. Treatment should be appropriately supportive. Hemodialysis is an effective means of removing topiramate from the body.

11 DESCRIPTION

Topiramate, USP, is a sulfamate-substituted monosaccharide. Trokendi XR™ (topiramate) extended-release capsules are available as 25 mg, 50 mg, 100 mg and 200 mg capsules for oral administration.

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 has the molecular formula C₁₂H₂₁NO₈S and a molecular weight of 339.4. Topiramate is designated chemically as 2,3:4,5-Di-O-isopropylidene-β-D-fructopyranose sulfamate and has the following structural formula:

Trokendi XR™ (topiramate) is an extended-release capsule. Trokendi XR™ capsules contain the following inactive ingredients:

Sugar Spheres, NF
Hypromellose (Type 2910), USP
Mannitol, USP
Docusate Sodium, USP
Sodium Benzoate, NF
Ethylcellulose, NF
Oleic Acid, NF
Medium Chain Triglycerides, NF
Polyethylene Glycol, NF
Polyvinyl Alcohol, USP
Titanium Dioxide, USP
Talc, USP
Lecithin, NF
Xanthan Gum, NF

The capsule shells contain gelatin, USP; Titanium Dioxide, USP; and Colorants.

The colorants are:

FD&C Blue #1 (all strength capsules)
Yellow Iron Oxide, USP (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, USP (25 mg capsules)

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

12 CLINICAL PHARMACOLOGY

12.1 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.

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

Absorption and Distribution

Linear pharmacokinetics of topiramate from Trokendi XR™ were observed following a single oral dose over the range of 50 mg to 200 mg. At 25 mg, the pharmacokinetics of Trokendi XR™ 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 Trokendi XR™. At steady-state, the (AUC_0-24hr, C_max, and C_min) of topiramate from Trokendi XR™ 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 Trokendi XR™ 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 [see Clinical Pharmacology (12.6)] .

Compared to the fasted state, high-fat meal increased the C_max of topiramate by 37% and shortened the T_max to approximately 8 hour following a single dose of Trokendi XR™, 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 C_max is significantly reduced following repeat administrations. Trokendi XR™ 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 Trokendi XR™.

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 Trokendi XR™, 30% higher mean C_max and 44% higher AUC values were observed in elderly compared to young subjects. Elderly subjects exhibited shorter median T_max 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.

Drug-Drug Interaction Studies

Antiepileptic Drugs

Potential interactions between immediate-release topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in Table 8. Interaction of Trokendi XR™ and standard AEDs is not expected to differ from the experience with immediate-release topiramate products.

In Table 8, the second column (AED concentration) describes what happened to the concentration of the AED listed in the first column when topiramate was added. The third column (topiramate concentration) describes how the co-administration of a drug listed in the first column modified the concentration of topiramate in experimental settings when topiramate was given alone.

In addition to the pharmacokinetic interaction described in the above table, concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with and without encephalopathy and hypothermia [see Warnings and Precautions (5.9), (5.11) and Drug Interactions (7.5)].

CNS Depressants or Alcohol

Concomitant administration of Trokendi XR™ and other CNS depressant drugs or alcohol has not been evaluated in clinical studies. [see Contraindications (4), Warnings and Precautions (5.4), (5.13), and Drug Interactions (7.1),(7.4) ].

Oral Contraceptives

In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), topiramate, given in the absence of other medications at doses of 50 to 200 mg per day, was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg per day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in patients taking valproic acid. In both studies, topiramate (50 mg per day to 800 mg per day) did not significantly affect exposure to NET. Although there was a dose-dependent decrease in EE exposure for doses between 200 to 800 mg per day, there was no significant dose-dependent change in EE exposure for doses of 50 to 200 mg per day. The clinical significance of the changes observed is not known. The possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking combination oral contraceptive products with Trokendi XR™. Patients taking estrogen-containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding [see Drug Interactions (7.2) ].

Digoxin

In a single-dose study, serum digoxin AUC was decreased by 12% with concomitant topiramate administration. The clinical relevance of this observation has not been established.

Hydrochlorothiazide

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg every 24 hours) and topiramate (96 mg every 12 hours) when administered alone and concomitantly. The results of this study indicate that topiramate C_max increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The addition of HCTZ to Trokendi XR™ therapy may require an adjustment of the Trokendi XR™ dose. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination.

Metformin

Topiramate treatment can frequently cause metabolic acidosis, a condition for which the use of metformin is contraindicated. Trokendi XR™ is expected to exhibit the same degree of metabolic acidosis as topiramate.

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin (500 mg every 12 hr) and topiramate in plasma when metformin was given alone and when metformin and topiramate (100 mg every 12 hr) were given simultaneously. The results of this study indicated that the mean metformin C_max and AUC_0-12h increased by 17% and 25%, respectively, when topiramate was added. Topiramate did not affect metformin tmax. The clinical significance of the effect of topiramate on metformin pharmacokinetics is not known. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect of metformin on topiramate or Trokendi XR™ pharmacokinetics is unclear. [see Drug Interactions (7.6) ].

Pioglitazone

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15% decrease in the AUC_τ,ss of pioglitazone with no alteration in C_max,ss was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in C_max,ss and AUC_τ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in C_max,ss and AUC_τ,ss of the active keto-metabolite. The clinical significance of these findings is not known.

When Trokendi XR™ is added to pioglitazone therapy or pioglitazone is added to Trokendi XR™ therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.

Glyburide

A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5mg per day) alone and concomitantly with topiramate (150 mg per day). There was a 22% decrease in C_max and 25% reduction in AUC₂₄ for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4-trans-hydroxy glyburide (M1) and 3-cis-hydroxyglyburide (M2), was also reduced by 13% and 15%, reduced C_max by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide.

Lithium

In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg per day; however, there was an observed increase in systemic exposure of lithium (27% for C_max and 26% for AUC) following topiramate doses up to 600 mg per day. Lithium levels should be monitored when co-administered with high-dose Trokendi XR™ [see Drug Interactions (7.7) ].

Haloperidol

The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hr) in 13 healthy adults (6 males, 7 females).

Amitriptyline

There was a 12% increase in AUC and C_max for amitriptyline (25 mg per day) in 18 normal subjects (9 males, 9 females) receiving 200 mg per day of topiramate. Some subjects may experience a large increase in amitriptyline concentration in the presence of Trokendi XR™ and any adjustments in amitriptyline dose should be made according to the patient's clinical response and not on the basis of plasma levels.

Sumatriptan

Multiple dosing of topiramate (100 mg every 12 hrs) in 24 healthy volunteers (14 males, 10 females) did not affect the pharmacokinetics of single-dose sumatriptan either orally (100 mg) or subcutaneously (6 mg).

Risperidone

When administered concomitantly with topiramate at escalating doses of 100, 250, and 400 mg per day, there was a reduction in risperidone systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg per day doses of topiramate). No alterations of 9-hydroxyrisperidone levels were observed. Coadministration of topiramate 400 mg per day with risperidone resulted in a 14% increase in C_max and a 12% increase in AUC₁₂ of topiramate. There were no clinically significant changes in the systemic exposure of risperidone plus 9-hydroxyrisperidone or of topiramate; therefore, this interaction is not likely to be of clinical significance.

Propranolol

Multiple dosing of topiramate (200 mg per day) in 34 healthy volunteers (17 males, 17 females) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg per day in 39 volunteers (27 males, 12 females) had no effect on the exposure to topiramate at a dose of 200 mg per day of topiramate.

Dihydroergotamine

Multiple dosing of topiramate (200 mg per day) in 24 healthy volunteers (12 males, 12 females) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg per day dose of topiramate in the same study.

Diltiazem

Co-administration of diltiazem (240 mg Cardizem CD^®) with topiramate (150 mg per day) resulted in a 10% decrease in C_max and 25% decrease in diltiazem AUC, 27% decrease in C_max and 18% decrease in des-acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem resulted in a 16% increase in C_max and a 19% increase in AUC₁₂ of topiramate.

Venlafaxine

Multiple dosing of topiramate (150 mg per day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg) did not affect the pharmacokinetics of topiramate.

Other Carbonic Anhydrase Inhibitors

Concomitant use of Trokendi XR™, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide, acetazolamide, or dichlorphenamide), may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, if Trokendi XR™ is given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis [see Drug Interactions (7.5) ].

Drug/Laboratory Tests Interactions

There are no known interactions of Trokendi XR™ with commonly used laboratory tests.

12.6 Relative Bioavailability of Trokendi XR™ Compared to Immediate-Release Topiramate

Study in Healthy Normal Volunteers

Trokendi XR™ taken once a day provides steady state plasma levels comparable to immediate-release topiramate taken every 12 hours, when administered at the same total 200 mg daily dose. In a crossover study, 33 healthy subjects were titrated to a 200mg dose of either Trokendi XR™ or immediate-release topiramate and were maintained at 200mg per day for 10 days.

The 90% CI for the ratios of AUC_0-24, C_max and C_min, as well as partial AUC (the area under the concentration-time curve from time 0 to time p (post dose) for multiple time points were within the 80 to 125% bioequivalence limits, indicating no clinically significant difference between the two formulations. In addition, the 90% CI for the ratios of topiramate plasma concentration at each of multiple time points over 24 hours for the two formulations were within the 80 to 125% bioequivalence limits, except for the initial time points before 1.5 hour post-dose.

Study in Patients with Epilepsy

In a study in epilepsy patients treated with immediate-release topiramate alone or in combination with either enzyme-inducing or neutral AEDs who were switched to an equivalent daily dose of Trokendi XR™, there was a 10% decrease in AUC_0-24, C_max, and C_min on the first day after the switch in all patients. At steady state, AUC_0-24 and C_max were comparable to immediate-release topiramate in all patients. While patients treated with Trokendi XR™ alone or in combination with neutral AEDs showed comparable C_min at steady state, patients treated with enzyme-inducers showed a 10% decrease in C_min. This difference is likely not clinically significant and probably due to the small number of patients on enzyme-inducers.

13 NON-CLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis

An increase in urinary bladder tumors was observed in mice given topiramate (20 mg/kg, 75 mg/kg, and 300 mg/kg) in the diet for 21 months. The elevated bladder tumor incidence, which was statistically significant in males and females receiving 300 mg/kg, was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. Plasma exposures in mice receiving 300 mg/kg were approximately 0.5 to 1 times steady-state exposures measured in patients receiving topiramate monotherapy at the recommended human dose (RHD) of 400 mg, and 1.5 to 2 times steady-state topiramate exposures in patients receiving 400 mg of topiramate plus phenytoin. The relevance of this finding to human carcinogenic risk is uncertain.

No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/kg (approximately 3 times the RHD on a mg/m² basis).

Mutagenesis

Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitro and in vivo assays. Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increase unscheduled DNA synthesis in rat hepatocytes in vitro; and it did not increase chromosomal aberrations in human lymphocytes in vitro or in rat bone marrow in vivo.

Impairment of Fertility

No adverse effects on male or female fertility were observed in rats at doses up to 100 mg/kg (2.5 times the RHD on a mg/m² basis).

14 CLINICAL STUDIES

14.1 Bridging Study to Demonstrate Pharmacokinetic Equivalence between Extended-Release and Immediate-Release Topiramate Formulations

The basis for approval of the extended-release formulation (Trokendi XR™) included the studies described below using an immediate-release formulation and the demonstration of the pharmacokinetic equivalence of Trokendi XR™ to immediate-release topiramate through the analysis of concentrations and cumulative AUCs at multiple time points [see Clinical Pharmacology (12.6) ].

The clinical studies described in the following sections were conducted using immediate-release topiramate.

14.2 Monotherapy Treatment in Patients with Partial Onset or Primary Generalized Tonic-Clonic Seizures

Adults and Pediatric Patients 10 Years of Age and Older

The effectiveness of topiramate as initial monotherapy in adults and children 10 years of age and older with partial onset or primary generalized tonic-clonic seizures was established in a multicenter, randomized, double-blind, dose-controlled, parallel-group trial (Study 1).

Study 1 was conducted in 487 patients diagnosed with epilepsy (6 to 83 years of age) who had 1 or 2 well-documented seizures during the 3-month retrospective baseline phase who then entered the study and received topiramate 25 mg per day for 7 days in an open-label fashion. Forty-nine percent of subjects had no prior AED treatment and 17% had a diagnosis of epilepsy for greater than 24 months. Any AED therapy used for temporary or emergency purposes was discontinued prior to randomization. In the double-blind phase, 470 patients were randomized to titrate up to 50 mg per day or 400 mg per day of topiramate. If the target dose could not be achieved, patients were maintained on the maximum tolerated dose. Fifty eight percent of patients achieved the maximal dose of 400 mg per day for greater than 2 weeks, and patients who did not tolerate 150 mg per day were discontinued.

The primary efficacy assessment was a between-group comparison of time to first seizure during the double-blind phase. Comparison of the Kaplan-Meier survival curves of time to first seizure favored the topiramate 400 mg per day group over the topiramate 50 mg per day group (p=0.0002, log rank test; Figure 1). The treatment effects with respect to time to first seizure were consistent across various patient subgroups defined by age, sex, geographic region, baseline body weight, baseline seizure type, time since diagnosis, and baseline AED use.

Figure 1: Kaplan-Meier Estimates of Cumulative Rates for Time to First Seizure in Study 1

14.3 Adjunctive Therapy in Patients with Partial Onset Seizures

Adult Patients with Partial Onset Seizures

The effectiveness of topiramate as an adjunctive treatment for adults with partial onset seizures was established in six multicenter, randomized, double-blind, placebo-controlled trials (Studies 2, 3, 4, 5, 6, and 7), two comparing several dosages of topiramate and placebo and four comparing a single dosage with placebo, in patients with a history of partial onset seizures, with or without secondarily generalized seizures.

Patients in these studies were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In each study, patients were stabilized on optimum dosages of their concomitant AEDs during baseline phase lasting between 4 and 12 weeks. Patients who experienced a prespecified minimum number of partial onset seizures, with or without secondary generalization, during the baseline phase (12 seizures for 12-week baseline, 8 for 8-week baseline or 3 for 4-week baseline) were randomly assigned to placebo or a specified dose of topiramate tablets in addition to their other AEDs.

Following randomization, patients began the double-blind phase of treatment. In five of the six studies, patients received active drug beginning at 100 mg per day; the dose was then increased by 100 mg or 200 mg per day increments weekly or every other week until the assigned dose was reached, unless intolerance prevented increases. In Study 7, the 25 or 50 mg per day initial doses of topiramate were followed by respective weekly increments of 25 or 50 mg per day until the target dose of 200 mg per day was reached. After titration, patients entered a 4, 8 or 12-week stabilization period. The numbers of patients randomized to each dose, and the actual mean and median doses in the stabilization period are shown in Table 9.

Pediatric Patients Ages 2 to 16 Years with Partial Onset Seizures

The effectiveness of topiramate as an adjunctive treatment for pediatric patients ages 2 to 16 years with partial onset seizures was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 8), comparing topiramate and placebo in patients with a history of partial onset seizures, with or without secondarily generalized seizures.

Patients in Study 8 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In Study 8, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least six partial onset seizures, with or without secondarily generalized seizures, during the baseline phase were randomly assigned to placebo or topiramate in addition to their other AEDs.

Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 25 or 50 mg per day; the dose was then increased by 25 mg to 150 mg per day increments every other week until the assigned dosage of 125, 175, 225 or 400 mg per day based on patients' weight to approximate a dosage of 6 mg/kg/day per day was reached, unless intolerance prevented increases. After titration, patients entered an 8-week stabilization period.

14.4 Adjunctive Therapy in Patients With Primary Generalized Tonic-Clonic Seizures

The effectiveness of topiramate as an adjunctive treatment for primary generalized tonic-clonic seizures in patients 2 years old and older was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 9), comparing a single dosage of topiramate and placebo.

Patients in Study 9 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least three primary generalized tonic-clonic seizures during the baseline phase were randomly assigned to placebo or topiramate in addition to their other AEDs.

Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 50 mg per day for four weeks; the dose was then increased by 50 mg to 150 mg per day increments every other week until the assigned dose of 175, 225 or 400 mg per day based on patients' body weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered a 12-week stabilization period.

14.5 Adjunctive Therapy in Patients With Lennox-Gastaut Syndrome

The effectiveness of topiramate as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome was established in a multicenter, randomized, double-blind, placebo-controlled trial comparing a single dosage of topiramate with placebo in patients 2 years of age and older (Study 10).

Patients in Study 10 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients who were experiencing at least 60 seizures per month before study entry were stabilized on optimum dosages of their concomitant AEDs during a 4 week baseline phase. Following baseline, patients were randomly assigned to placebo or topiramate in addition to their other AEDs. Active drug was titrated beginning at 1 mg/kg/day for a week; the dose was then increased to 3 mg/kg/day for one week then to 6 mg/kg/day. After titration, patients entered an 8-week stabilization period. The primary measures of effectiveness were the percent reduction in drop attacks and a parental global rating of seizure severity.

In all adjunctive topiramate trials, the reduction in seizure rate from baseline during the entire double-blind phase was measured. The median percent reductions in seizure rates and the responder rates (fraction of patients with at least a 50% reduction) by treatment group for each study are shown below in Table 10. As described above, a global improvement in seizure severity was also assessed in the Lennox-Gastaut trial.

Table 10: Efficacy Results in Double-Blind, Placebo-Controlled, Adjunctive Epilepsy Trials

Target Topiramate Dosage (mg per day)
Study #	#	Placebo	200	400	600	800	1,000	≈6mg/ kg/dayFor Studies 8 and 9, specified target dosages (less than 9.3 mg/kg/day) were assigned based on subject's weight to approximate a dosage of 6mg/kg per day; these dosages corresponded to mg per day dosages of 125 mg per day, 175 mg per day, 225 mg per day, and 400 mg per day
Partial Onset Seizures Studies in Adults
2	N	45	45	45	46	--	--	--
	Median % Reduction	11.6	27.2Comparisons with placebo: p=0.080;	47.5p ≤ 0.010;	44.7p ≤ 0.001;	--	--	--
	% Responders	18	24	44p ≤ 0.050;	46p ≤ 0.050;	--	--	--
3	N	47	--	--	48	48	47	--
	Median % Reduction	1.7	--	--	40.8p ≤ 0.001;	41.0p ≤ 0.001;	36.0p ≤ 0.001;
	% Responders	9	--	--	40p ≤ 0.001;	41p ≤ 0.001;	36p ≤ 0.050;
4	N	24	--	23	--	--	--	--
	Median % Reduction	1.1	--	40.7p=0.065;	--	--	--	--
	% Responders	8	--	35p ≤ 0.050;	--	--	--	--
5	N	30	--	--	30	--	--	--
	Median % Reduction	-12.2	--	--	46.4p ≤0.005;	--	--	--
	% Responders	10	--	--	47p ≤ 0.001;	--	--	--
6	N	28	--	--	--	28	--	--
	Median % Reduction	-20.6	--	--	--	24.3p ≤ 0.001;	--	--
	% Responders	0	--	--	--	43p ≤ 0.001;	--	--
7	N	91	168	--	--	--	--	--
	Median % Reduction	20.0	44.2p ≤ 0.001;	--	--	--	--	--
	% Responders	24	45p ≤ 0.001;
Studies in Pediatric Patients
8	N	45	--	--	--	--	--	41
	Median % Reduction	10.5	--	--	--	--	--	33.1p ≤ 0.050;
	% Responders	20	--	--	--	--	--	39
Primary Generalized Tonic-ClonicMedian % reduction and % responders are reported for PGTC seizures;
9	N	40	--	--	--	--	--	39
	Median % Reduction	9.0	--	--	--	--	--	56.7p ≤ 0.050;
	% Responders	20	--	--	--	--	--	56p ≤ 0.001;
Lennox-Gastaut SyndromeMedian % reduction and % responders for drop attacks, i.e., tonic or atonic seizures
10	N	49	--	--	--	--	--	46
	Median % Reduction	-5.1	--	--	--	--	--	14.8p ≤ 0.050;
	% Responders	14						28p=0.071;
	Improvement in Seizure SeverityPercent of subjects who were minimally, much, or very much improved from baseline.	28						52p ≤ 0.050;

Subset analyses of the antiepileptic efficacy of topiramate tablets in these studies showed no differences as a function of gender, race, age, baseline seizure rate, or concomitant AED.

In clinical trials for epilepsy, daily dosages were decreased in weekly intervals by 50 mg per day to 100 mg per day in adults and over a 2- to 8-week period in children; transition was permitted to a new antiepileptic regimen when clinically indicated.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 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)

16.2 Storage and Handling

Trokendi XR™ (topiramate) extended-release capsules should be stored in well closed containers at controlled room temperature [25°C (77°F); excursions 15°C-30°C (59°F-86°F)]. Protect from moisture and light.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Medication Guide)

Administration Instructions

Counsel patients to swallow Trokendi XR™ capsules whole and intact. Trokendi XR™ should not be sprinkled on food, chewed or crushed. [See Dosage and Administration (2.9)].

Consumption of Alcohol

Advise patients to completely avoid consumption of alcohol at least 6 hours prior to and 6 hours after taking Trokendi XR™[see Warnings and Precautions (5.4) ].

Acute Myopia and Secondary Angle Closure Glaucoma

Advise patients taking Trokendi XR™ to seek immediate medical attention if they experience blurred vision, visual disturbances or periorbital pain [see Warnings and Precautions (5.1) ].

Oligohydrosis and Hyperthermia

Counsel patients that Trokendi XR™, especially pediatric patients, can cause decreased sweating and increased body temperature, especially in hot weather, and they should seek medical attention if this is noticed [see Warnings and Precautions (5.2) ].

Metabolic Acidosis

Inform 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 (5.3)

Suicidal Behavior and Ideation

Counsel patients, their caregivers, and families that AEDs, including Trokendi XR™, 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. Behaviors of concern should be reported immediately to 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 them not to drive or operate machinery until they have gained sufficient experience on Trokendi XR™ to gauge whether it adversely affects their mental performance, motor performance, and/or vision. [see Warnings and Precautions (5.6) ].

Advise patients that even when taking Trokendi XR™ or other anticonvulsants, some patients with epilepsy will continue to have unpredictable seizures. Therefore, counsel all patients taking Trokendi XR™ 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. Physicians should 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. When appropriate, prescribers should counsel pregnant women and women of childbearing potential about alternative therapeutic options.

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 Warnings and Precautions (5.7) and Drug Interactions (7.2) ].

Encourage pregnant women using topiramate to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number, 1-888-233-2334. Information about the North American Drug Pregnancy Registry can be found at http://www.massgeneral.org/aed/ [see Use in Specific Populations (8.1) ].

Hyperammonemia and Encephalopathy

Warn patients about the possible development of hyperammonemia with or without encephalopathy. Although hyperammonemia may be asymptomatic, clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. This hyperammonemia and encephalopathy can develop with topiramate treatment alone or with topiramate treatment with concomitant valproic acid (VPA). Patients should be instructed to contact their physician if they develop unexplained lethargy, vomiting, or changes in mental status [see Warnings and Precautions (5.9) ].

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 Trokendi XR™ 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 by: Catalent Pharma Solutions, Winchester, Kentucky 40391

Manufactured for: Supernus Pharmaceuticals, Inc., Rockville, Maryland 20850

RA-TRO-V1
Revised: August 2013

MEDICATION GUIDE

Trokendi XR™ (tro-KEN-dee eks ahr)
(topiramate)
Extended-release Capsules

Read this Medication Guide before you start taking Trokendi XR™ and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about Trokendi XR™, talk to your healthcare provider or pharmacist.

What is the most important information I should know about Trokendi XR™?

Take Trokendi XR™ capsules whole. Do not sprinkle Trokendi XR™ on food, or break, crush, dissolve, or chew Trokendi XR™ capsules before swallowing. If you cannot swallow Trokendi XR™ capsules whole, tell your healthcare provider. You may need a different medicine.

Do not drink alcohol within 6 hours prior to and 6 hours after Trokendi XR™ administration.

Trokendi XR™ 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.

Trokendi XR™ 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.

Trokendi XR™ 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 Trokendi XR™. If you are pregnant, you should talk to your healthcare provider about whether you have metabolic acidosis.

Like other antiepileptic drugs, Trokendi XR™ 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 Trokendi XR™ without first talking to a healthcare provider.

• Stopping Trokendi XR™ 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.

Trokendi XR™ can harm your unborn baby.

• If you take Trokendi XR™ during pregnancy, your baby has a higher risk for birth defects called cleft lip and cleft palate. These defects can begin early in pregnancy, even before you know you are pregnant.
• Cleft lip and cleft palate may happen even in children born to women who are not taking any medicines and do not have other risk factors.
• There may be other medicines to treat your condition that have a lower chance of birth defects.
• All women of childbearing age should talk to their healthcare providers about using other possible treatments instead of Trokendi XR™. If the decision is made to use Trokendi XR™, you should use effective birth control (contraception) unless you are planning to become pregnant. You should talk to your doctor about the best kind of birth control to use while you are taking Trokendi XR™.
• Tell your healthcare provider right away if you become pregnant while taking Trokendi XR™. You and your healthcare provider should decide if you will continue to take Trokendi XR™ while you are pregnant.
• Metabolic acidosis may have harmful affects on your baby. Talk to your healthcare provider if Trokendi XR™ has caused metabolic acidosis during your pregnancy.
• Pregnancy Registry: If you become pregnant while taking Trokendi XR™, 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 Trokendi XR™ and other antiepileptic drugs during pregnancy.

What is Trokendi XR™?

Trokendi XR™ is a prescription medicine used:

• to treat certain types of seizures (partial onset seizures and primary generalized tonic-clonic seizures) in people 10 years and older,
• with other medicines to treat certain types of seizures (partial onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome) in adults and children 6 years and older.

What should I tell my healthcare provider before taking Trokendi XR™?

Before taking Trokendi XR™, tell your healthcare provider about all your medical conditions, including if you:

• have or have had depression, mood problems or suicidal thoughts or behavior
• have kidney problems, 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. Trokendi XR™ passes into your breast milk. It is not known if the Trokendi XR™ 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 Trokendi XR™.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Trokendi XR™ 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. Trokendi XR™ 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 Trokendi XR™.

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 Trokendi XR™?

• Take Trokendi XR™ exactly as prescribed.
• Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider.
• Take Trokendi XR™ capsules whole. Do not sprinkle Trokendi XR™ on food, or break, crush, dissolve, or chew Trokendi XR™ capsules before swallowing.
• Trokendi XR™ can be taken before, during, or after a meal. Drink plenty of fluids during the day. This may help prevent kidney stones while taking Trokendi XR™.
• If you take too much Trokendi XR™, call your healthcare provider or poison control center right away or go to the nearest emergency room.
• If you miss a single dose of Trokendi XR™, 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 professional for advice.
• Do not stop taking Trokendi XR™ without talking to your healthcare provider. Stopping Trokendi XR™ suddenly may cause serious problems. If you have epilepsy and you stop taking Trokendi XR™ suddenly, you may have seizures that do not stop. Your healthcare provider will tell you how to stop taking Trokendi XR™ slowly.
• Your healthcare provider may do blood tests while you take Trokendi XR™.

What should I avoid while taking Trokendi XR™?

• Do not drink alcohol within 6 hours before or 6 hours after taking Trokendi XR™ capsules. Trokendi XR 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 Trokendi XR™ affects you. Trokendi XR™ can slow your thinking and motor skills, and may affect vision.

What are the possible side effects of Trokendi XR™?

Trokendi XR™ may cause serious side effects including:

See "What is the most important information I should know about Trokendi XR™?"

• 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 Trokendi XR™ is taken with a medicine called valproic acid (DEPAKENE ® and DEPAKOTE®).
• Kidney stones. Drink plenty of fluids when taking Trokendi XR™ to decrease your chances of getting kidney stones.
• Low body temperature. Taking Trokendi XR™ when you are also taking valproic acid cause a drop in body temperature to less than 95ºF, feeling tired, confusion, or coma.
• Effects on thinking and alertness. Trokendi XR™ may affect how you think, and cause confusion, problems with concentration, attention, memory, or speech. Trokendi XR™ 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 Trokendi XR™ include:

• tingling of the arms and legs (paresthesia)
• not feeling hungry
• nausea
• a change in the way foods taste
• diarrhea
• weight loss
• nervousness
• upper respiratory tract infection

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all the possible side effects of Trokendi XR™. 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.

You may also report side effects to Supernus Pharmaceuticals, Inc. at 1-866-398-0833.

How should I store Trokendi XR™?

• Store Trokendi XR™ tablets at room temperature between 59°F to 86°F (15°C to 30°C).
• Keep Trokendi XR™ in a tightly closed container.
• Keep Trokendi XR™ dry and away from moisture and light.
• Keep Trokendi XR™ and all medicines out of the reach of children.

General information about Trokendi XR™

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Trokendi XR™ for a condition for which it was not prescribed. Do not give Trokendi XR™ to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Trokendi XR™. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Trokendi XR™ that is written for health professionals.

For more information, go to www.trokendixrcom or call1-866-398-0833.

What are the ingredients in Trokendi XR™?

Active ingredient: topiramate

Inactive ingredients:

Sugar Spheres, NF, Hypromellose (Type 2910), USP, mannitol, USP, docusate sodium, USP, sodium benzoate, NF,, ethylcellulose, NF, oleic acid, NF, medium chain triglycerides, NF, polyethylene glycol, NF, polyvinyl alcohol, USP titanium dioxide, USP, talc, USP, lecithin, NF, xanthan gum, NF

Capsule shells: Gelatin, USP; titanium Dioxide, USP, and Colorants.

Colorants:

FD&C Blue #1 (all strength capsules)

Yellow iron oxide, USP (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, USP (25 mg capsules)

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

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

Manufactured by: Catalent Pharma Solutions, Winchester, KY USA 40391

Manufactured for: Supernus Pharmaceuticals, Inc. Rockville, MD USA 20850

© Supernus Pharmaceuticals, June 2013

RA-TRO-MGV1

Issued: August 2013

PRINCIPAL DISPLAY PANEL - 25 mg Capsule Bottle Label

100 Capsules

NDC 17772-101-01

Trokendi XR_™
(topiramate) extended-release capsules

Once daily.

25 mg

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

ATTENTION PHARMACIST: Dispense
the Accompanying Medication Guide
to Each Patient

Supernus^®

Rx only

PRINCIPAL DISPLAY PANEL - 50 mg Capsule Bottle Label

100 Capsules

NDC 17772-102-01

Trokendi XR_™
(topiramate) extended-release capsules

Once daily.

50 mg

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

ATTENTION PHARMACIST: Dispense
the Accompanying Medication Guide
to Each Patient

Supernus^®

Rx only

PRINCIPAL DISPLAY PANEL - 100 mg Capsule Bottle Label

100 Capsules

NDC 17772-103-01

Trokendi XR_™
(topiramate) extended-release capsules

Once daily.

100 mg

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

ATTENTION PHARMACIST: Dispense
the Accompanying Medication Guide
to Each Patient

Supernus^®

Rx only

PRINCIPAL DISPLAY PANEL - 200 mg Capsule Bottle Label

100 Capsules

NDC 17772-104-01

Trokendi XR_™
(topiramate) extended-release capsules

Once daily.

200 mg

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

ATTENTION PHARMACIST: Dispense
the Accompanying Medication Guide
to Each Patient

Supernus^®

Rx only