FDA Approval Labeling Text dated August 18, 2013
`NDA 201635
`Page 1
`
`
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`-------------------WARNINGS AND PRECAUTIONS------------------­
`
`
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`• 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)
`
`
`
`
`--------------------------ADVERSE REACTIONS-------------------------­
`
`
`
`
`
`The 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)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`
`
`
`Medication Guide
`
`
`
`August 2013
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
`
` These 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 US Approval: 1996
`
`
`
`
`
`
`--------------------------------INDICATIONS AND USAGE----------------------------
`Trokendi 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)
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`
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`
` 400 mg once daily
`
` 200 mg to
`
`
`
` 400 mg once daily
`
`
`
`
`
`
`
` 400 mg once daily
`
`
`
`
` Increase dose weekly
`
` by increments of 50
`mg for first 4 weeks
`
` then
` 100 mg for weeks 5
`
` to 6
`
`
`
`
`
`
` Increase dose weekly
`
`
` by increments of 25
`
` mg to 50 mg to
`achieve an effective
`
` dose
` Increase dose weekly
`
`to an effective dose
`by increments of 25
`
`
`mg to
`
`
` 50 mg
`
`---------------------------DOSAGE AND ADMINISTRATION--------------------------­
`
` Recommended
`
`Initial Dose
`Titration
`
`
`
` Dose
` Monotherapy Therapy: Partial Onset or Primary Generalized Tonic-Clonic
`
`
`
`
`
`Seizures
`Adults and
`pediatric
`patients 10
`years and
`older (2.1)
`
`
`Adjunctive Therapy
`Adults with
`partial onset
`
`seizures or
`LGS (2.2)
`Adults with
`
` primary
`generalized
`
` tonic-clonic
` seizures (2.2)
`
`
`50 mg orally
`
`
`once daily
`
`
`
`
`
`25 mg to 50
`
`mg orally
`once daily
`
`
`
`
`
`
` 25 mg to 50
`mg orally
`once daily
`
`
`
`
`
`
`
`
`Pediatric
`patients 6
`years and
`older with
`
`partial onset
`
`seizures,
`
`primary
`generalized
`tonic-clonic
`seizures or
`
`LGS (2.2)
`Swallow capsule whole and intact. Do not sprinkle on food, chew or crush (2.9)
`
`
`
`
`
`
`
`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
`
`---------------------------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)]
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3357981
`
`
`
`00001
`
`ARGENTUM Exhibit 1223
`Argentum Pharmaceuticals LLC v. Research Corporation Technologies, Inc.
`IPR2016-00204
`
`

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`
` FDA Approval Labeling Text dated August 18, 2013
`NDA 201635
`Page 2
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` FULL PRESCRIBING INFORMATION: CONTENTS*
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`
` 1
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` 2
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`
`3
`
`4
`
`5
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`6
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`7
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` 8
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`9
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`10
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`11
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`12
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`13
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` 14
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`16
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`
`17
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`
`
` 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
`
`
`DRUG ABUSE AND DEPENDENCE
`
`
`9.1 Controlled Substance
`
`9.2 Abuse
`
`
`
`9.3 Dependence
`
`
`
`OVERDOSAGE
`
`DESCRIPTION
`
`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
`
`
`
`NONCLINICAL TOXICOLOGY
` 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
`
`
`
`
`
` 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
`
`
`
`
`Seizures
`
`
`14.5 Adjunctive Therapy in Patients with Lennox-Gastaut
`
`
`
`Syndrome
`
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`16.1 Trokendi XR™ Capsules
`
`
`
`
`16.2 Storage and Handling
`
`
`
`PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
`
`
` INDICATIONS AND USAGE
`
` 1.1Partial Onset Seizure and Primary Generalized Tonic-Clonic Seizures
`
`
` 1.2 Lennox-Gastaut Syndrome
`
` 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 Modification in Patients Taking Phenytoin and/or
`
`
`
`
`
`
`Carbamazapine
`
`
`
`
`
`2.8 Monitoring for Therapeutic Blood Levels
`
`
`
`2.9 Administration Instructions
`
`
`DOSAGE FORMS AND STRENGTHS
`
`CONTRAINDICATIONS
`
`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 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
`
`
`ADVERSE REACTIONS
`
`
`
`6.1 Clinical Trials Experience
`
`
`
`6.2 Postmarketing Experience
`
`
`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
`
`
` * Sections or subsections omitted from the full prescribing information are not listed
`
`
`
`
`
`
`
`__________________________________________________________________________________________
`
`
`Reference ID: 3357981
`
`00002
`
`

`
`
`
`
`
` FDA Approval Labeling Text dated August 18, 2013
`NDA 201635
`Page 3
`
`
`
` 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:
`
`
`
`
`
`
`
`
`
` Week 1
`
` Week 2
`
`Week 3
`
`Week 4
`
`Week 5
`
` Week 6
`
`
`
`
` 50 mg once daily
`
`
` 100 mg once daily
`
`
`
`
`150 mg once daily
`
`
`
`200 mg once daily
`
`
`
`300 mg once daily
`
`
` 400 mg once daily
`
`
`
` 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)].
`
`
`
`Reference ID: 3357981
`
`00003
`
`

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` FDA Approval Labeling Text dated August 18, 2013
`NDA 201635
`Page 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.
`
`
`
`
`
`
`
`
`
`Reference ID: 3357981
`
`00004
`
`

`
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`
` FDA Approval Labeling Text dated August 18, 2013
`NDA 201635
`Page 5
`
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` 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.
`
`
`
`
`
`
`
`
`Reference ID: 3357981
`
`00005
`
`

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` FDA Approval Labeling Text dated August 18, 2013
`NDA 201635
`Page 6
`
`
`
` 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%
`
`
`
`
`
`
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`for 50 mg per day and 25% for 400 mg per day. The incidence of a markedly abnormally low serum
`
`
`
`Reference ID: 3357981
`
`00006
`
`

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` FDA Approval Labeling Text dated August 18, 2013
`NDA 201635
`Page 7
`
` 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)].
`
`
`
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`
`
`
`
`
`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.
`
`
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`
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`
`
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`
`
` 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.
`
`
`
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`
`
`Reference ID: 3357981
`
`00007
`
`

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` FDA Approval Labeling Text dated August 18, 2013
`NDA 201635
`Page 8
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`
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` 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.
`
` Table 1: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
`
` Indication
`
`
`
`
`
` Placebo Patients
`
`with Events per
`1,000 Patients
`
`
`Drug Patients with
`Events per 1,000
`Patients
`
`
`
`
`
` Risk Difference:
` Additional Drug Patients
`
`with Events per 1,000
`patients
`
`
`
`
`
` 2.4
`
` 2.9
`
` 0.9
`
` 1.9
`
`Relative Risk: Incidence
`of Events in Drug
`Patients/
`
`Incidence in Placebo
`
`
` Patients
`
` 3.5
`
` 1.5
`
` 1.9
`
` 1.8
`
` Epilepsy
`
`
` Psychiatric
`
` Other
`
` Total
`
` 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.
`
`
`
` 1.0
`
` 5.7
`
` 1.0
`
` 2.4
`
`
` 3.4
`
` 8.5
`
` 1.8
`
` 4.3
`
`Reference ID: 3357981
`
`00008
`
`

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` FDA Approval Labeling Text dated August 18, 2013
`NDA 201635
`Page 9
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`
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` 5.6 Cognitive/Neuropsychiatric Adverse Reactions
` Adverse reactions most often associated with the use of topiramate, and therefore expected to be associated with
`
`
`
`
`
`
`
` the use of 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