QUDEXY XR – FDA Approval Labeling Text dated March 11, 2014
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` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` These highlights do not include all the information needed to use
` QUDEXY™ XR safely and effectively. See full prescribing information
`
`
` for QUDEXY XR.
`
`
`
`
`QUDEXY XR (topiramate) extended-release capsules, for oral use
`
`
`Initial U.S. Approval: 1996
`
`
`--------------------------INDICATIONS AND USAGE---------------------------­
`
`
`
`QUDEXY XR is an antiepileptic drug indicated for:
` Partial Onset Seizures 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 2 years of age and older with partial onset or primary generalized
`
`
`
`tonic-clonic seizures (1.1)
`
`
`
`
` Lennox-Gastaut Syndrome (LGS) - adjunctive therapy in patients 2 years
`
`of age and older with seizures associated with Lennox-Gastaut syndrome
`(1.2)
`
`
`
`
`
`
`
`----------------------DOSAGE AND ADMINISTRATION----------------------­
`
`
`
` Recommended
`Initial Dose
`Titration
`
`
`
`
` Dose
`
`
` Monotherapy: Partial Onset or Primary Generalized Tonic
`
` -Clonic Seizures
`
`
` 50 mg orally
`
` Adults and
`Increase dose
` 400 mg
`
` pediatric patients
`
` once daily
` once daily
`weekly by
`
`
` 10 years and
` increments of
`
`
` older (2.1)
`
` 50 mg for first 4
`
` weeks then 100 mg
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` for weeks 5 to 6
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`  Visual field defects: These have been reported independent of elevated
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` intraocular pressure. Consider discontinuation of QUDEXY XR (5.2)
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` Oligohydrosis and hyperthermia: Monitor decreased sweating and
` increased body temperature, especially in pediatric patients (5.3)
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`
`
`
`
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` Metabolic acidosis: Measure baseline and periodic measurement of serum
`
`bicarbonate. Consider dose reduction or discontinuation of QUDEXY XR
`
`if clinically appropriate (5.4)
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` Suicidal behavior and ideation: Antiepileptic drugs increase the risk of
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`
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`suicidal behavior or ideation (5.5)
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`
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` Cognitive/neuropsychiatric: QUDEXY XR may cause cognitive
`
`dysfunction. Use caution when operating machinery including
`
`
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`automobiles. Depression and mood problems may occur (5.6)
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` Fetal toxicity: Topiramate use during pregnancy can cause cleft lip and/or
`
`
`palate (5.7)
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`
`
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` Withdrawal of AEDs: Withdrawal of QUDEXY XR should be done
`
`
`gradually (5.8)
`
`
`
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` Hyperammonemia and encephalopathy: Patients with inborn errors of
`
`
`
`metabolism or reduced mitochondrial activity may have an increased risk
`
`of hyperammonemia. Measure ammonia if encephalopathic symptoms
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`
`occur (5.9)
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`
`
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` Kidney stones: Avoid use with other carbonic anhydrase inhibitors, other
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`drugs causing metabolic acidosis, or in patients on a ketogenic diet (5.10)
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`
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` Hypothermia: Reported with concomitant valproic acid use (5.11)
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`------------------------------ADVERSE REACTIONS-----------------------------­
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`
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`The most common (≥ 5% more frequent than placebo or low-dose topiramate
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`
`
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`in monotherapy) adverse reactions in a controlled, clinical trial of immediate
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`release topiramate were paresthesia, anorexia, weight decrease, fatigue,
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`dizziness, somnolence, nervousness, psychomotor slowing, difficulty with
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`memory, difficulty with concentration/attention, cognitive problem,
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`
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`confusion, mood problems, fever, infection, and flushing (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Upsher-Smith
`
`
`
`
`Laboratories, Inc. at 1-855-899-9180 or FDA at 1-800-FDA-1088 or
`
`www.fda.gov/medwatch
`
`
`------------------------------DRUG INTERACTIONS-----------------------------­
`
`
`
`
` Oral contraceptives: Decreased contraceptive efficacy and increased
`
`
`
`
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`breakthrough bleeding, especially at doses greater than 200 mg per day
`
`(7.1)
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` Phenytoin or carbamazepine: Concomitant administration with topiramate
`
`
`decreased plasma concentrations of topiramate (7.2)
`
`
`
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` Other carbonic anhydrase inhibitors: Monitor for the appearance or
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`worsening of metabolic acidosis (7.4)
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` Lithium: Monitor lithium levels when co-administered with high-dose
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`topiramate (7.6)
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`-----------------------USE IN SPECIFIC POPULATIONS---------------------­
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` Renal Impairment: (creatinine clearance less than 70 mL/min/1.73m2), one-
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`half of the adult dose is recommended (2.3) (8.7)
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` Patients undergoing hemodialysis: Topiramate is cleared by hemodialysis.
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`Dosage adjustment is necessary to avoid rapid drops in topiramate plasma
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`concentration during hemodialysis (2.4) (8.8)
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` Pregnancy: Increased risk of cleft lip and/or palate. Pregnancy registry
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`available (8.1)
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` Nursing mothers: Caution should be exercised when administered to a
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`nursing mother (8.3)
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` Geriatric use: Dosage adjustment may be necessary for elderly with
`
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`impaired renal function (8.5)
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`See 17 for PATIENT COUNSELING INFORMATION and Medication
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`
`
`Guide
`
`
`
`Revised: 3/2014
`
`
`
` 200 mg to
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`
` 400 mg
` once daily
`
`
` 400 mg
`
` once daily
`
`
`
` 5 mg/kg to
`
` 9 mg/kg
` once daily
`
`
`
`
`
`
` Adjunctive Therapy
`
`
` Adults with
`
` 25 mg to
`partial onset
`
` 50 mg orally
`seizures or LGS
`
` once daily
`
`
`(2.2)
`
`
` 25 mg to
`
`
` 50 mg orally
`
` once daily
`
`
`
`25 mg once
`at night-time
`(based on a
`range of
`
`1 mg/kg to
`
`3 mg/kg
`
`once daily)
`
`for first week
`
`
`
` Adults with
`
` primary
`generalized tonic­
`
` clonic seizures
`
` (2.2)
`Pediatric patients
`2 years and older
`with partial onset
`seizures, primary
`generalized tonic­
`clonic seizures or
`
` LGS (2.2)
`
`
`
`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
`
` 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
` Capsules may be swallowed whole or opened and sprinkled on a spoonful of
`
`
` soft food (2.8)
`
`---------------------DOSAGE FORMS AND STRENGTHS--------------------­
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`Extended-release capsules: 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg (3)
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`
`
`
`
`
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`-----------------------------CONTRAINDICATIONS-----------------------------­
`
`In patients with metabolic acidosis taking concomitant metformin (4) (5.4)
`
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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
`QUDEXY XR if it occurs (5.1)
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`
`Reference ID: 3469214
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` 1
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`ARGENTUM Exhibit 1203
`Argentum Pharmaceuticals LLC v. Research Corporation Technologies, inc.
`IPR2016-00204
`
`Page 00001
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`

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` INDICATIONS AND USAGE
`
`
` 1.1 Partial Onset Seizures and Primary Generalized Tonic-Clonic
`
`Seizures
`
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`1.2 Lennox-Gastaut Syndrome
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`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Monotherapy Use
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`2.2 Adjunctive Therapy Use
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`2.3 Dose Modifications in Patients with Renal Impairment
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`2.4 Dosage Modifications in Patients Undergoing Hemodialysis
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`2.5 Laboratory Testing Prior to Treatment Initiation
`
`
`
`
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`2.6 Dosing Modifications in Patients Taking Phenytoin and/or
`
`
`
`Carbamazapine
`
`
`
`
`
`
`2.7 Monitoring for Therapeutic Blood Levels
`
`
`
`2.8 Administration Instructions
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`3 DOSAGE FORMS AND STRENGTHS
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`4 CONTRAINDICATIONS
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`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Acute Myopia and Secondary Angle Closure Glaucoma
`
`
`
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`5.2 Visual Field Defects
`
`
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`5.3 Oligohydrosis and Hyperthermia
`
`
`
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`5.4 Metabolic Acidosis
`
`
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`5.5 Suicidal Behavior and Ideation
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`
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`5.6 Cognitive/Neuropsychiatric Adverse Reactions
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`5.7 Fetal Toxicity
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`5.8 Withdrawal of Antiepileptic Drugs
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`5.9 Hyperammonemia and Encephalopathy
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`5.10 Kidney Stones
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`5.11 Hypothermia with Concomitant Valproic Acid Use
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`5.12 Paresthesia
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`5.13 Interaction with Other CNS Depressants
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`6 ADVERSE REACTIONS
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`6.1 Clinical Trials Experience with Immediate-Release Topiramate
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`6.2 Clinical Trials Experience with QUDEXY XR
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`6.3 Postmarketing Experience
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`7 DRUG INTERACTIONS
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`7.1 Oral Contraceptives
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`7.2 Antiepileptic Drugs
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`7.3 CNS Depressants and Alcohol
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`7.4 Other Carbonic Anhydrase Inhibitors
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`7.5 Metformin
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`7.6 Lithium
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` QUDEXY XR – FDA Approval Labeling Text dated March 11, 2014
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`8 USE IN SPECIFIC POPULATIONS
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`8.1 Pregnancy
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`8.2 Labor and Delivery
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`8.3 Nursing Mothers
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`8.4 Pediatric Use
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`8.5 Geriatric Use
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`8.6 Race and Gender Effects
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`8.7 Renal Impairment
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`8.8 Patients Undergoing Hemodialysis
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`8.9 Women of Childbearing Potential
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`9 DRUG ABUSE AND DEPENDENCE
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`9.1 Controlled Substance
`
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`9.2 Abuse
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`9.3 Dependence
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`
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`10 OVERDOSAGE
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`11 DESCRIPTION
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`12 CLINICAL PHARMACOLOGY
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`12.1 Mechanism of Action
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`12.2 Pharmacodynamics
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`12.3 Pharmacokinetics
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`12.6 Relative Bioavailability of QUDEXY XR Compared to Immediate-
`
`
`
`
`Release Topiramate in Healthy Volunteers
`
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`13 NONCLINICAL TOXICOLOGY
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`
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`14 CLINICAL STUDIES
`
`
`14.1 Extended-Release: Bridging Study to Demonstrate Pharmacokinetic
`
`
`Equivalence between Extended-Release (QUDEXY XR) and
`
`
`
`Immediate-Release Topiramate Formulations
`
`
`14.2 Immediate-Release: Monotherapy Treatment in Patients with Partial
`
`
`
`Onset or Primary Generalized Tonic-Clonic Seizures
`
`
`14.3 Immediate-Release: Adjunctive Therapy in Patients with Partial
`
`
`
`
`Onset Seizures
`
`
`14.4 Immediate-Release: Adjunctive Therapy in Patients with Primary
`
`
`
`Generalized Tonic-Clonic Seizures
`
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`14.5 Immediate-Release: Adjunctive Therapy in Patients with Lennox-
`
`
`
`Gastaut Syndrome
`
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`14.6 Extended-Release: Adjunctive Therapy in Adult Patients with
`
`
`
`
`Partial Onset Seizures with QUDEXY XR (Study 11)
`
`
`
`
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`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`16.1 QUDEXY XR Capsules
`
`
`
`16.2 Storage and Handling
`
`
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`17 PATIENT COUNSELING INFORMATION
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`*Sections or subsections omitted from the full prescribing information are not
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`listed
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` FULL PRESCRIBING INFORMATION: CONTENTS*
`
` 1
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`Reference ID: 3469214
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` 2
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`Page 00002
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`FULL PRESCRIBING INFORMATION
`
`
`
`
`
`
`
`
` QUDEXY XR – FDA Approval Labeling Text dated March 11, 2014
`
`1
`
`
`
`INDICATIONS AND USAGE
`
`
`1.1
`
`
`
`
`Partial Onset Seizures and Primary Generalized Tonic-Clonic Seizures
`
`
`QUDEXY 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 2 years of age and older with partial onset or primary
`generalized tonic-clonic seizures [see Clinical Studies (14.2, 14.3 and 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
`
`
`QUDEXY XR (topiramate) extended-release capsules are indicated as adjunctive therapy in
`
`patients 2 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 QUDEXY 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
`
`
`
`Reference ID: 3469214
`
`
`
` 3
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`Page 00003
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` QUDEXY XR – FDA Approval Labeling Text dated March 11, 2014
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`
`
`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 QUDEXY XR as adjunctive therapy in adults with partial
`
`
`onset seizures or Lennox-Gastaut Syndrome is 200 mg to 400 mg orally once daily. The
`
`
`
`recommended total dose for adults with primary generalized tonic-clonic seizures is 400 mg
`
`
`
`
`orally once daily.
`
`
`Initiate therapy at 25 mg to 50 mg once daily followed by titration to an effective dose in
`
`
`increments of 25 mg to 50 mg every week. Daily topiramate doses above 1,600 mg have not
`
`
`been studied.
`
`
`In the study of primary generalized tonic-clonic seizures using topiramate, the assigned dose was
`
`
`reached at the end of 8 weeks [see Clinical Studies (14.4)].
`
`
`
`
`
`Pediatric Patients (Ages 2 Years to 16 Years) - Partial Onset Seizures, Primary Generalized
`Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome
`
`
`The recommended total daily dose of QUDEXY 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 (14.3, 14.4 and 14.5)].
`
`
`
`
`
`2.3
`Dose Modifications in Patients with Renal Impairment
`
`
`In patients with renal impairment (creatinine clearance less than 70 mL/min/1.73 m2), one-half of
`the usual adult dose is recommended. Such patients will require a longer time to reach steady-
`state at each dose [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
`
`
`
`
`
`
`Prior to dosing, obtain an estimated creatinine clearance (CrCl) in patients at high risk for renal
`
`
`insufficiency (e.g., older patients, or those with diabetes mellitus, hypertension, or autoimmune
`
`
`
`disease). CrCl can be estimated using the following equation (multiply by 0.85 for women):
`
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`
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`
` 4
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`Reference ID: 3469214
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`Page 00004
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`

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`QUDEXY XR – FDA Approval Labeling Text dated March 11, 2014
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` Dosage Modifications in Patients Undergoing Hemodialysis
`
`
` 2.4
`
`
`
` Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than in patients with
`
`
`
` normal renal function. Accordingly, a prolonged period of dialysis may cause topiramate
`concentration to fall below that required to maintain an anti-seizure effect. To avoid rapid drops
`in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate may
`
` be required. The actual adjustment should take into account the:
`
` duration of dialysis period
`
`
` clearance rate of the dialysis system being used
`
` effective renal clearance of topiramate in the patient being dialyzed [see Use in Specific
`
`
`
`Populations (8.8) and Clinical Pharmacology (12.3)].
`
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`2.5
`
`
`Laboratory Testing Prior to Treatment Initiation
`
`
`
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`Measurement of baseline and periodic serum bicarbonate during QUDEXY XR treatment is
`
`recommended [see Warnings and Precautions (5.4)].
`
`
`
`
`2.6
`
`
`Dosing Modifications in Patients Taking Phenytoin and/or Carbamazepine
`
`
`
`The co-administration of QUDEXY 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 QUDEXY XR may require adjustment of the dose
`
`
`
`of QUDEXY XR [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].
`
`
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`
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`2.7 Monitoring for Therapeutic Blood Levels
`
`
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`It is not necessary to monitor topiramate plasma concentrations to optimize QUDEXY XR
`
`therapy.
`
`
`2.8
`
`
`Administration Instructions
`
`
`
`QUDEXY XR capsules may be swallowed whole or may be administered by carefully opening
`
`
`the capsule and sprinkling the entire contents on a small amount (teaspoon) of soft food. This
`
`
`drug/food mixture should be swallowed immediately and not chewed or crushed. Do not store
`drug/food mixture for further use. QUDEXY XR can be taken without regard to meals [see
`
`
`
`
`Clinical Pharmacology (12.3)].
`
`
`Reference ID: 3469214
`
`
`
` 5
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`Page 00005
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`QUDEXY XR – FDA Approval Labeling Text dated March 11, 2014
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` DOSAGE FORMS AND STRENGTHS
`
`
`3
`
`
`
`
` QUDEXY XR (topiramate) extended-release capsules are available in the following strengths
` and colors:
`
` 25 mg: light pink and grey capsules, printed with "UPSHER-SMITH" on the cap in black ink
`
`
`
`and "25 mg" on the body in black ink
`
` 50 mg: golden yellow and grey capsules, printed with "UPSHER-SMITH" on the cap in black
`
`
`ink and "50 mg" on the body in black ink
`
` 100 mg: reddish brown and grey capsules, printed with "UPSHER-SMITH" on the cap in
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`black ink and "100 mg" on the body in black ink
`
`
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` 150 mg: pale yellow and grey capsules, printed with "UPSHER-SMITH" on the cap in black
`
`
`
`ink and "150 mg" on the body in black ink
`
`
` 200 mg: brown and grey capsules, printed with "UPSHER-SMITH" on the cap in white ink
`
`
`
`and "200 mg" on the body in black ink
`
`4
`
`
`
`CONTRAINDICATIONS
`
`QUDEXY XR is contraindicated in patients with metabolic acidosis who are taking concomitant
`metformin [see Warnings and Precautions (5.4), Drug Interactions (7.5) and Clinical
`
`
`
`
`
`Pharmacology (12.3)].
`
`
`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 QUDEXY XR as rapidly as possible,
`according to the judgment of the treating physician. Other measures, in conjunction with
`
`
`discontinuation of QUDEXY XR, may be helpful.
`
`Reference ID: 3469214
`
`
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`
`
`
` Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae
`
`
` including permanent vision loss.
`
`
`
`5.2
`
`
`Visual Field Defects
`
`
`Visual field defects have been reported in patients receiving topiramate independent of elevated
`
`
`intraocular pressure. In clinical trials, most of these events were reversible after topiramate
`
`discontinuation. If visual problems occur at any time during topiramate treatment, consideration
`
`
`
`should be given to discontinuing the drug.
`
`
`5.3 Oligohydrosis and Hyperthermia
`
`
`
`
`Oligohydrosis (decreased sweating), resulting in hospitalization in some cases, has been reported
`
`
`
`in association with topiramate use. Decreased sweating and an elevation in body temperature
`
`
`
`
`above normal characterized these cases. Some of the cases were reported after exposure to
`elevated environmental temperatures.
`
`
`
`
`The majority of the reports have been in pediatric patients. Patients, especially pediatric patients,
`treated with QUDEXY XR should be monitored closely for evidence of decreased sweating and
`
`increased body temperature, especially in hot weather. Caution should be used when QUDEXY
`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.
`
`
`
`
`5.4 Metabolic Acidosis
`
`
`Hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the
`
`
`normal reference range in the absence of chronic respiratory alkalosis) is associated with
`topiramate treatment. This metabolic acidosis is caused by renal bicarbonate loss due to the
`
`
`inhibitory effect of topiramate on carbonic anhydrase. Such electrolyte imbalance has been
`observed with the use of topiramate in placebo-controlled clinical trials and in the post-
`
`
`
`marketing period. Generally, topiramate-induced metabolic acidosis occurs early in treatment
`although cases can occur at any time during treatment. Bicarbonate decrements are usually mild-
`
`moderate (average decrease of 4 mEq/L at daily doses of 400 mg in adults and at approximately
`
`6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values
`
`
`below 10 mEq/L. Conditions or therapies that predispose patients to acidosis (such as renal
`
`disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet or specific drugs)
`
`
`
`may be additive to the bicarbonate lowering effects of topiramate.
`
`
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` 7
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`Reference ID: 3469214
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`Page 00007
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` QUDEXY XR – FDA Approval Labeling Text dated March 11, 2014
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` 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 a 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)
`
`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 than 17 mEq/L and greater than 5 mEq/L decrease from
`
`
`pretreatment) in these trials was 11% for topiramate and 0% for placebo. Cases of moderately
`
`
`
`severe metabolic acidosis have been reported in patients as young as 5 months old, especially at
`
`
`daily doses above 5 mg/kg/day.
`
`
`
`In pediatric patients (6 years to 15 years of age), the incidence of persistent 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 QUDEXY XR is not approved for use in patients less than 2 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)].
`
`
`Reference ID: 3469214
`
`
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`Page 00008
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`

`
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` Manifestations of Metabolic Acidosis
`
`
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` QUDEXY XR – FDA Approval Labeling Text dated March 11, 2014
`
`
`Some manifestations of acute or chronic metabolic acidosis may include hyperventilation,
`
`nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac
`arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for
`
`nephrolithiasis or nephrocalcinosis, and may also result in osteomalacia (referred to as rickets in
`
`
`pediatric patients) and/or osteoporosis with an increased risk for fractures. Chronic metabolic
`
`
`acidosis in pediatric patients may also reduce growth rates. A reduction in growth rate may
`
`eventually decrease the maximal height achieved. The effect of topiramate on growth and bone-
`related sequelae has not been systematically investigated in long-term, placebo-controlled trials.
`
`Long-term, open-label treatment of infants/toddlers, with intractable partial epilepsy, for up to 1
`
`year, showed reductions from baseline in Z SCORES for length, weight, and head circumference
`
`compared to age and sex-matched normative data, although these patients are likely to have
`
`different growth rates than normal infants. Reductions in Z SCORES for length and weight were
`correlated to the degree of acidosis [see Use in Specific Populations (8.4)]. Topiramate
`
`
`
`treatment that causes metabolic acidosis during pregnancy can possibly produce adverse effects
`
`on the fetus and might also cause metabolic acidosis in the neonate from possible transfer of
`
`
`topiramate to the fetus [see Warnings and Precautions (5.7) and Use in Specific Populations
`
`(8.1)].
`
`
`
`
`
`Risk Mitigation Strategies
`
`Measurement of baseline and periodic serum bicarbonate during topiramate treatment is
`
`recommended. If metabolic acidosis develops and persists, consideration should be given to
`
`reducing the dose or discontinuing topiramate (using dose tapering). If the decision is made to
`
`continue patients on topiramate in the face of persistent acidosis, alkali treatment should be
`
`considered.
`
`
`5.5
`
`
`
`Suicidal Behavior and Ideation
`
`
`
`Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in patients taking
`
`
`
`these drugs for any indication. Patients treated with any AED, including QUDEXY 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
`
`Reference ID: 3469214
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`
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` QUDEXY XR – FDA Approval Labeling Text dated March 11, 2014
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`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
`
`
`
`
` Relative Risk:
`
` Incidence of
`
` Events in
`
`Drug Patients/
`
`Incidence in
`
` Placebo Patients
`
` 3.5
`
` 1.5
`
` 1.9
`
` 1.8
`
`
`
`
`
`Risk Difference:
`Additional Drug
`
`Patients with
`Events per
` 1,000 Patients
`
`
` 2.4
`
` 2.9
`
` 0.9
`
` 1.9
`
`Placebo Patients
`
`with Events per
`
`
` 1,000 Patients
`
` 1.0
`
` 5.7
`
` 1.0
`
` 2.4
`
`Drug Patients with
`
`Events per 1,000
`
` Patients
`
` 3.4
`
` 8.5
`
` 1.8
`
` 4.3
`
`
` Indication
`
` 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 QUDEXY 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.
`
`Reference ID: 3469214
`
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` QUDEXY XR – FDA Approval Labeling Text dated March 11, 2014
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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 QUDEXY 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 we