TROKENDI XR™ (topiramate) extended-release capsules
`
`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 U.S. 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)
`--------------------------------DOSAGE AND ADMINISTRATION--------------------------------
`Recommended
`Titration
`
`Initial Dose
`
`
`
`Dose
` Monotherapy: Partial Onset or Primary Generalized Tonic-Clonic Seizures
` Adults and
`50 mg orally
`Increase dose weekly
` pediatric patients
`once daily
`by increments of 50 mg
` 10 years and
`
`for first 4 weeks then
` older (2.1)
`
`100 mg for weeks 5 to 6
` Adjunctive Therapy
` Adults with
` partial onset
` seizures or
` LGS (2.2)
` Adults with
` primary
` generalized
` tonic-clonic
` seizures (2.2)
` Pediatric patients
` 6 years and older
` with partial onset
` seizures, primary
` generalized tonic-
` clonic seizures,
` or LGS (2.2)
`
`400 mg
`once daily
`
`200 mg
`to 400 mg
`once daily
`
`400 mg
`once daily
`
`5 mg/kg
`to 9 mg/kg
`once daily
`
`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
`
`25 mg to
`50 mg orally
`once daily
`
`25 mg to
`50 mg orally
`once daily
`
`
`25 mg once at
`nighttime (based
`on a range of
`1 mg/kg to
`3 mg/kg once
`daily) for first
`week
`
`--------------------------------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 hyperammonemia. 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 problems, confusion, mood problems, fever, infection, and
`flushing (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Supernus Pharmaceuticals at 1-866-
`398-0833- or the 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
`Revised: August 2013
`
` 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 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 NONCLINICAL 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 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
`* Sections or subsections omitted from the full prescribing information are not listed
`
`
`
`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`
`3 DOSAGE FORMS AND STRENGTHS
`Trokendi XR™ (topiramate) extended-release capsules are available in the following strengths
`and colors:
`
`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)].
`
`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-Gastaut 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 50 mg every week. Daily topiramate doses above 1600 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
`(eg, 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 antiseizure 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.
`
`a Values represent the percentage of patients reporting a given adverse reaction. Patients may
`have reported more than one adverse reaction during the study and can be included in more than
`one adverse reaction category
`
`Table 3: Incidence of Treatment-Emergent Adverse Reactions in the Monotherapy Epilepsy Trial in
`Pediatric Patients (Ages 10 up to 16 Years)a Where Incidence Was at Least 5% in the 400 mg/day
`Immediate-Release Topiramate Group and Greater than the Rate in the 50 mg/day Immediate-
`Release Topiramate Group
`
`9
`
`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 (ie, 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 (ie, 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 postmarketing period. Generally, topiramate-induced metabolic acidosis
`occurs early in treatment although cases can occur at any time during treatment. Bicarbonate
`decrements are usually mild to 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 (ie, 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 (ie, 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 (ie, 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/
`
`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.
`Table 1: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
`Risk Difference:
`Indication
`Placebo Patients
`Drug Patients
`Relative Risk:
`Additional Drug
`
`with Events per
`with Events per
`Incidence of
`Patients with
`
`1,000 Patients
`1,000 Patients
`Events in Drug
`Events per
`
`
`
`Patients/Incidence
`1,000 Patients
`
`
`
`in Placebo Patients
`2.4
`3.4
`1.0
` Epilepsy
`3.5
`2.9
`8.5
`5.7
` Psychiatric
`1.5
`0.9
`1.8
`1.0
` Other
`1.9
`1.9
`4.3
`2.4
` Total
`1.8
`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 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 (eg, confusion, psychomotor slowing,
`difficulty with concentration/attention, difficulty with memory, speech or language problems,
`particularly word-finding difficulties), 2) Psychiatric/behavioral disturbances (eg, depression or
`mood problems), and 3) Somnolence or fatigue.
`
`30
`3
`3
`2
`4
`4
`1
`3
`1
`0
`<1
`
`a Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition
`to topiramate or placebo
`b Values represent the percentage of patients reporting a given reaction. Patient may have
`reported more than one adverse reaction during the study and can be included in more than one
`adverse reaction category
`c Adverse reactions reported by at least 1% of patients in the topiramate 200 mg to 400 mg per day
`group and more common than in the placebo group
`
`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.
`
`Adult Patients
`Cognitive Related Dysfunction
`The majority of cognitive-related adverse reactions were mild to moderate in severity, and they
`frequently occurred in isolation. Rapid titration rate and higher initial dose were associated with
`higher incidences of these reactions. Many of these reactions contributed to withdrawal from
`treatment [see Adverse Reactions (6.1)].
`
`In the adjunctive epilepsy controlled trials conducted with topiramate (using rapid titration
`such as 100 mg per day to 200 mg per day weekly increments), the proportion of patients who
`experienced one or more cognitive-related adverse reactions was 42% for 200 mg per day,
`41% for 400 mg per day, 52% for 600 mg per day, 56% for 800 and 1,000 mg per day, and
`14% for placebo. These dose-related adverse reactions began with a similar frequency in
`the titration or in the maintenance phase, although in some patients the events began during
`titration and persisted into the maintenance phase. Some patients who experienced one or more
`cognitive-related adverse reactions in the titration phase had a dose-related recurrence of these
`reactions in the maintenance phase.
`
`In the monotherapy epilepsy controlled trial conducted with topiramate, the proportion of patients
`who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg
`per day and 26% for 400 mg per day.
`
`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 d