Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 25 January 2018

Indication(s)

1 INDICATIONS AND USAGE TROKENDI XR® is indicated for: Epilepsy: initial monotherapy in patients 6 years of age and older with partial onset or primary generalized tonic-clonic seizures (1.1); adjunctive therapy in patients 6 years of age and older with partial onset, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome (LGS) (1.2) Prophylaxis of migraine in patients 12 years of age and older (1.3) 1.1 Monotherapy Epilepsy TROKENDI XR® is indicated in patients 6 years of age and older as initial monotherapy for partial onset or primary generalized tonic-clonic seizures [see Clinical Studies (14.2) ]. 1.2 Adjunctive Therapy Epilepsy TROKENDI XR® is indicated as adjunctive therapy in patients 6 years of age and older with partial onset or primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome [see Clinical Studies (14.3) ]. 1.3 Migraine TROKENDI XR® is indicated for patients 12 years and older for the prophylaxis of migraine headache [see Clinical Studies (14.4) ].

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Advisory information

contraindications
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 (5.5) ] With recent alcohol use, ie, within 6 hours prior to and 6 hours after TROKENDI XR® use (4), (5.5)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more detail in other sections of the labeling: Acute Myopia and Secondary Angle Closure Glaucoma [see Warnings and Precautions (5.1) ] Visual Field Defects [see Warnings and Precautions 5.2] Oligohydrosis and Hyperthermia [see Warnings and Precautions (5.3) ] Metabolic Acidosis [see Warnings and Precautions (5.4) ] Suicidal Behavior and Ideation [see Warnings and Precautions (5.6) ] Cognitive/Neuropsychiatric Adverse Reactions [see Warnings and Precautions (5.7) ] Withdrawal of Antiepileptic Drugs [see Warnings and Precautions (5.9) ] Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use) [see Warnings and Precautions (5.10) ] Kidney Stones [see Warnings and Precautions (5.11) ] Hypothermia with Concomitant Valproic Acid Use [see Warnings and Precautions (5.12) ] The data described in the following sections were obtained using immediate-release topiramate tablets. TROKENDI XR® has not been studied in a randomized, placebo-controlled Phase III clinical study; however, it is expected that TROKENDI XR® would produce a similar adverse reaction profile as immediate-release topiramate. Epilepsy: Most common (≥ 10% more frequent than placebo or low-dose topiramate in monotherapy and adjunctive therapy) adverse reactions in adult and pediatric patients were paresthesia, anorexia, weight loss, speech disorders/related speech problems, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, abnormal vision, and fever (6.1). Migraine: Most common (≥5% more frequent than placebo) adverse reactions in adult and pediatric patients were: paresthesia, anorexia, weight loss, difficulty with memory, taste perversion, upper respiratory tract infections, abdominal pain, diarrhea, hypoesthesia, and nausea (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. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates observed in practice. Monotherapy Epilepsy Adults 16 Years of Age and Older The most common adverse reactions in the controlled trial (Study 1) that occurred in adults in the 400 mg/day topiramate group and at an incidence higher (≥ 10%) than in the 50 mg per day group were: paresthesia, weight loss, and anorexia (see Table 3). Approximately 21% of the 159 adult patients in the 400 mg/day group who received topiramate as monotherapy in Study 1 discontinued therapy due to adverse reactions. The most common (≥ 2% more frequent than low-dose 50 mg/day topiramate) adverse reactions causing discontinuation were difficulty with memory, fatigue, asthenia, insomnia, somnolence and paresthesia. Pediatric Patients 6 Years to 15 Years of Age The most common adverse reactions in the controlled trial (Study 1) that occurred in pediatric patients in the 400 mg/day topiramate group and at an incidence higher (≥ 10%) than in the 50 mg/day group were fever and weight loss (see Table 4). Approximately 14% of the 77 pediatric patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. The most common (≥ 2% more frequent than in the 50 mg/day group) adverse reactions resulting in discontinuation in this trial were difficulty with concentration/attention, fever, flushing, and confusion. Tables 3 and 4 present the incidence of adverse reactions occurring in at least 3% of adult and pediatric patients treated with 400 mg/day immediate-release topiramate and occurring with greater incidence than 50 mg/day topiramate. Table 3: Incidence (%) of Adverse Reaction in the Monotherapy Epilepsy Trial in AdultsValues 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 Where Incidence Was at Least 3% in the 400 mg/day Immediate-Release Topiramate Group and Greater Than the Rate in the 50 mg/day Immediate-Release Topiramate Group Immediate-release topiramate Dosage (mg/day) Body System/ 50 400 Adverse Reaction (N=160) (N=159) Body as a Whole-General Disorders Asthenia 4 6 Leg pain 2 3 Central & Peripheral Nervous System Disorders Paresthesia 21 40 Dizziness 13 14 Hypoesthesia 4 5 Ataxia 3 4 Hypertonia 0 3 Gastro-intestinal System Disorders Constipation 1 4 Gastritis 0 3 Dry mouth 1 3 Liver and Biliary System Disorders Gamma-GT increased 1 3 Metabolic and Nutritional Disorders Weight Loss 6 17 Psychiatric Disorders Somnolence 10 15 Anorexia 4 14 Difficulty with Memory NOS 6 11 Insomnia 8 9 Depression 7 9 Difficulty with concentration/attention 7 8 Anxiety 4 6 Psychomotor slowing 3 5 Mood problems 2 5 Cognitive problem NOS 1 4 Decrease in libido 0 3 Reproductive Disorders, Female Vaginal hemorrhage 0 3 Resistance Mechanism Disorders Viral infection 6 8 Infection 2 3 Respiratory System Disorders Bronchitis 3 4 Rhinitis 2 4 Skin and Appendages Disorders Alopecia 3 4 Rash 1 4 Pruritus 1 4 Acne 2 3 Special Senses Other, Disorders Taste perversion 3 5 Urinary System Disorders Cystitis 1 3 Renal calculus 0 3 Table 4: Incidence (%) of Adverse Reactions in the Monotherapy Epilepsy Trial in Pediatric Patients (Ages 6 to 15 Years)Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category Where Incidence Was at Least 3% in the 400 mg/day Immediate-Release Topiramate Group and Greater than the Rate in the 50 mg/day Immediate-Release Topiramate Group Immediate-release topiramate Dosage (mg/day) Body System/ 50 400 Adverse Reaction (N=74) (N=77) Body as a Whole-General Disorders Fever 1 12 Asthenia 0 3 Central & Peripheral Nervous System Disorders Paresthesia 3 12 Involuntary muscle contractions 0 3 Vertigo 0 3 Gastro-Intestinal System Disorders Diarrhea 8 9 Metabolic and Nutritional Disorders Weight decrease 7 17 Platelet, Bleeding & Clotting Disorders Epistaxis 0 4 Psychiatric Disorders Difficulty with concentration/attention 7 10 Mood problems 1 8 Cognitive problems 1 6 Difficulty with memory 1 3 Confusion 0 3 Depression 0 3 Personality disorder (behavior problems) 0 3 Red Blood Cell Disorders Anemia 1 3 Reproductive Disorders, FemaleN with Reproductive Disorders, Female-Incidence calculated relative to the number of females; Pediatric TPM 50 mg n=40; Pediatric TPM 400 mg n=33 Intermenstrual bleeding 0 3 Resistance Mechanism Disorders Infection 3 8 Viral infection 3 6 Respiratory System Disorders Upper Respiratory Tract Infection 16 18 Rhinitis 5 6 Bronchitis 1 5 Sinusitis 1 4 Skin and Appendages Disorders Rash 3 4 Alopecia 1 4 Urinary System Disorders Urinary Incontinence 1 3 Micturition Frequency 0 3 Vascular (Extracardiac) Disorders Flushing 0 5 Adjunctive Therapy Epilepsy Adults 16 Years of Age and Older In pooled controlled clinical trials in adults with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, 183 patients received adjunctive therapy with immediate-release topiramate at dosages of 200 to 400 mg/day (recommended dosage range), and 291 patients received placebo. Patients in these trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to immediate-release topiramate or placebo. The most common adverse reactions in the controlled clinical trial that occurred in adult patients in the 200-400 mg/day topiramate group with an incidence higher (≥10%) than in the placebo group were: dizziness, speech disorders/ related speech problems, somnolence, nervousness, psychomotor slowing, and vision abnormal (see Table 5) [see Clinical Studies (14.3) ]. Table 5 presents the incidence of adverse reactions occurring in at least 3% of adult patients treated with 200 to 400 mg/day topiramate and was greater than placebo incidence. The incidence of some adverse reactions (e.g., fatigue, dizziness, paresthesia, language problems, psychomotor slowing, depression, difficulty with concentration/attention, mood problems) was dose-related and much greater at higher than recommended topiramate dosing (i.e., 600 to 1000 mg/day) compared to the incidence of these adverse reactions at the recommended dosing (200 to 400 mg/day) range. Table 5: Most Common Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trials in Adults Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo , Values represent the percentage of patients reporting a given reaction. Patient may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category. Body System/ Placebo Topiramate Dosage (mg/day) 200-400 Adverse Reaction (N=291) % (N=183) % Body as a Whole-General Disorders Fatigue 13 15 Asthenia 1 6 Back pain 4 5 Chest pain 3 4 Influenza-like symptoms 2 3 Central & Peripheral Nervous System Disorders Dizziness 15 25 Ataxia 7 16 Speech disorders/Related speech problems 2 13 Paresthesia 4 11 Nystagmus 7 10 Tremor 6 9 Language problems 1 6 Coordination abnormal 2 4 Gait abnormal 1 3 Gastro-Intestinal System Disorders Nausea 8 10 Dyspepsia 6 7 Abdominal pain 4 6 Constipation 2 4 Metabolic and Nutritional Disorders Weight loss 3 9 Psychiatric Disorders Somnolence 12 29 Nervousness 6 16 Psychomotor slowing 2 13 Difficulty with memory 3 12 Confusion 5 11 Anorexia 4 10 Difficulty with concentration/attention 2 6 Mood problems 2 4 Agitation 2 3 Aggressive reaction 2 3 Emotional liability 1 3 Cognitive problems 1 3 Reproductive Disorders, Female Breast pain 2 4 Respiratory System Disorders Pharyngitis 2 6 Rhinitis 6 7 Sinusitis 4 5 Vision Disorders Vision abnormal 2 13 Diplopia 5 10 In controlled clinical trials in adults, 11% of patients receiving immediate-release topiramate 200 to 400 mg per day as adjunctive therapy discontinued due to adverse reactions. This rate appeared to increase at dosages above 400 mg per day. Adverse reactions associated with discontinuing therapy included somnolence, dizziness, anxiety, difficulty with concentration or attention, fatigue, and paresthesia and increased at dosages above 400 mg per day. Pediatric Patients 2 to 15 Years of Age In pooled, controlled clinical trials in pediatric patients (2 to 15 years of age) with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, 98 patients received adjunctive therapy with immediate-release topiramate at dosages of 5 mg to 9 mg/kg/day (recommended dosage range) and 101 patients received placebo. The most common adverse reactions in the controlled clinical trial that occurred in pediatric patients in the 5 mg to 9 mg/kg/day immediate-release topiramate group with an incidence higher (≥10%) than in the placebo group were: fatigue and somnolence (see Table 6). Table 6 presents the incidence of adverse reactions that occurred in at least 3% of pediatric patients 2 to 15 years of age receiving 5 mg to 9 mg/kg/day (recommended dosage range) of immediate-release topiramate and was greater than placebo incidence. Table 6. Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trial in Pediatric Patients 2 to 15 Years of AgePatients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo , Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category Body System/ Adverse Reaction Placebo (N=101) % Topiramate (N=98) % Body as a Whole-General Disorders Fatigue 5 16 Injury 13 14 Central & Peripheral Nervous System Disorders Gait abnormal 5 8 Ataxia 2 6 Hyperkinesia 4 5 Dizziness 2 4 Speech disorders/Related speech problems 2 4 Gastro-Intestinal System Disorders Nausea 5 6 Saliva increased 4 6 Constipation 4 5 Gastroenteritis 2 3 Metabolic and Nutritional Disorders Weight loss 1 9 Platelet, Bleeding & Clotting Disorders Purpura 4 8 Epistaxis 1 4 Psychiatric Disorders Somnolence 16 26 Anorexia 15 24 Nervousness 7 14 Personality disorder (Behavior Problems) 9 11 Difficulty with concentration/attention 2 10 Aggressive reaction 4 9 Insomnia 7 8 Difficulty with memory 0 5 Confusion 3 4 Psychomotor slowing 2 3 Resistance Mechanism Disorders Infection viral 3 7 Respiratory System Disorders Pneumonia 1 5 Skin and Appendages Disorders Skin Disorder 2 3 Urinary System Disorders Urinary incontinence 2 4 None of the pediatric patients who received topiramate adjunctive therapy at 5 mg/kg/day to 9 mg/kg/day in controlled clinical trials discontinued due to adverse reactions. Migraine Adults In the four multicenter, randomized, double-blind, placebo-controlled, parallel group migraine prophylaxis clinical trials (which included 35 pediatric patients 12 to 15 years of age), most adverse reactions occurred more frequently during the titration period than during the maintenance period. The most common adverse reactions with immediate-release topiramate 100mg in migraine prophylaxis clinical trials of predominantly adults that were seen at an incidence higher (≥5%) than in the placebo group were: paresthesia, anorexia, weight loss, taste perversion, diarrhea, difficulty with memory, hypoesthesia, and nausea (see Table 7). Table 7 includes those adverse reactions that occurred in the placebo-controlled trials where the incidence in any immediate-release topiramate group was at least 3% and was greater than that for placebo patients. The incidence of some adverse reactions (e.g., fatigue, dizziness, somnolence, difficulty with memory, difficulty with concentration/attention) was dose-related and greater at higher than recommended topiramate dosing (200 mg/day) compared to the incidence of these adverse reactions at the recommended dosing (100 mg/day). Table 7: Adverse Reactions in Pooled, Placebo-Controlled, Migraine Trials in AdultsIncludes 35 adolescent patients age 12 to 15 years , Values represent the percentage of patients reporting a given reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category. , Blurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for more than 50% of reactions coded as vision abnormal, a preferred term Topiramate Dosage (mg/day) Body System/ Adverse Reaction Placebo (N=445) % 50 (N=235) % 100 (N=386) % Body as a Whole-General Disorders Fatigue 11 14 15 Injury 7 9 6 Central & Peripheral Nervous System Disorders Paresthesia 6 35 51 Dizziness 10 8 9 Hypoaesthesia 2 6 7 Language problems 2 7 6 Gastro-Intestinal System Disorders Nausea 8 9 13 Diarrhea 4 9 11 Abdominal pain 5 6 6 Dyspepsia 3 4 5 Dry mouth 2 2 3 Gastroenteritis 1 3 3 Metabolic and Nutritional Disorders Weight loss 1 6 9 Musculoskeletal System Disorders Arthralgia 2 7 3 Psychiatric Disorders Anorexia 6 9 15 Somnolence 5 8 7 Difficulty with memory 2 7 7 Insomnia 5 6 7 Difficulty with concentration/attention 2 3 6 Mood problems 2 3 6 Anxiety 3 4 5 Depression 4 3 4 Nervousness 2 4 4 Confusion 2 2 3 Psychomotor slowing 1 3 2 Reproductive Disorders, Female Menstrual disorder 2 3 2 Reproductive Disorders, Male Ejaculation premature 0 3 0 Resistance Mechanism Disorders Viral Infection 3 4 4 Respiratory System Disorders Upper respiratory tract infection 12 13 14 Sinusitis 6 10 6 Pharyngitis 4 5 6 Coughing 2 2 4 Bronchitis 2 3 3 Dyspnea 2 1 3 Skin and Appendages Disorders Pruritis 2 4 2 Special Sense Other, Disorders Taste perversion 1 15 8 Urinary System Disorders Urinary tract infection 2 4 2 Vision Disorders Blurred vision 2 4 2 Of the 1135 patients exposed to immediate-release topiramate in the adult placebo-controlled studies, 25% discontinued due to adverse reactions, compared to 10% of the 445 placebo patients. The adverse reactions associated with discontinuing therapy in the immediate-release topiramate-treated patients in these studies included paresthesia (7%), fatigue (4%), nausea (4%), difficulty with concentration/attention (3%), insomnia (3%), anorexia (2%), and dizziness (2%). Patients treated in these studies experienced mean percent reductions in body weight that were dose-dependent. This change was not seen in the placebo group. Mean changes of 0%, -2%, -3%, and -4% were seen for the placebo group, immediate-release topiramate 50 mg, 100 mg, and 200 mg groups, respectively. Pediatric Patients 12 to 17 Years of Age In five randomized, double-blind, placebo-controlled, parallel group migraine prophylaxis clinical trials, most of the adverse reactions occurred more frequently during the titration period than during the maintenance period. Among adverse reactions with onset during titration, approximately half persisted into the maintenance period. In four, fixed-dose, double-blind migraine prophylaxis clinical trials in immediate-release topiramate treated pediatric patients 12 to 17 years of age, the most common adverse reactions with immediate-release topiramate 100mg that were seen at an incidence higher (≥5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain (see Table 8). Table 8 shows adverse reactions from the pediatric trial (Study 3 [see Clinical Studies (14.4)]) in which 103 pediatric patients were treated with placebo or 50 mg or 100 mg of immediate-release topiramate, and three predominantly adult trials in which 49 pediatric patients (12 to 17 years) were treated with placebo or 50 mg, 100 mg or 200 mg of immediate-release topiramate [see Clinical Studies (14.4)]. Table 8 also shows adverse reactions in pediatric patients in controlled migraine trials when the incidence in an immediate-release topiramate dose group was at least 5% or higher and greater than the incidence of placebo. Many adverse reactions shown in Table 8 indicate a dose-dependent relationship. The incidence of some adverse reactions (e.g., allergy, fatigue, headache, anorexia, insomnia, somnolence, and viral infection) was dose-related and greater at higher than recommended immediate-release topiramate dosing (200 mg daily) compared to the incidence of these adverse reactions at the recommended dosing (100 mg daily). Table 8: Adverse Reactions in Pooled Double-Blind Migraine Prophylaxis Studies in Pediatric Patients 12 to 17 Years of Age)35 adolescent patients aged 12 to <16 years were also included in adverse reaction assessment for adults Incidence is based on the number of subjects experiencing at least 1 adverse event, not the number of events. Immediate-Release Topiramate Dosage Body System/ Adverse Reaction Placebo (N=45) % 50 mg/day (N=46) % 100 mg/day (N=48) % Body as a Whole – General Disorders Fatigue 7 7 8 Fever 2 4 6 Central & Peripheral Nervous System Disorders Paresthesia 7 20 19 Dizziness 4 4 6 Gastrointestinal System Disorders Abdominal pain 9 7 15 Nausea 4 4 8 Metabolic and Nutritional Disorders Weight loss 2 7 4 Psychiatric Disorders Anorexia 4 9 10 Somnolence 2 2 6 Insomnia 2 9 2 Resistance Mechanism Disorders Infection viral 4 4 8 Respiratory System Disorders Upper respiratory tract infection 11 26 23 Rhinitis 2 7 6 Sinusitis 2 9 4 Coughing 0 7 2 Special Senses Other, Disorders Taste perversion 2 2 6 Vision Disorders Conjunctivitis 4 7 4 In the double-blind placebo-controlled studies, adverse reactions led to discontinuation of treatment in 8% of placebo patients compared with 6% of immediate-release topiramate-treated patients. Adverse reactions associated with discontinuing therapy that occurred in more than one immediate-release topiramate-treated patient were fatigue (1%), headache (1%), and somnolence (1%). Increased Risk for Bleeding Topiramate is associated with an increased risk for bleeding. In a pooled analysis of placebo-controlled studies of approved and unapproved indications, bleeding was more frequently reported as an adverse reaction for topiramate than for placebo (4.5% versus 3.0% in adult patients, and 4.4% versus 2.3% in pediatric patients). In this analysis, the incidence of serious bleeding events for topiramate and placebo was 0.3% versus 0.2% for adult patients, and 0.4% versus 0% for pediatric patients. Adverse bleeding reactions reported with topiramate ranged from mild epistaxis, ecchymosis, and increased menstrual bleeding to life-threatening hemorrhages. In patients with serious bleeding events, conditions that increased the risk for bleeding were often present, or patients were often taking drugs that cause thrombocytopenia (other antiepileptic drugs) or affect platelet function or coagulation (e.g., aspirin, nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, or warfarin or other anticoagulants). Other Adverse Reactions Observed During Clinical Trials Other adverse reactions seen during clinical trials were: abnormal coordination, eosinophilia, gingival bleeding, hematuria, hypotension, myalgia, myopia, postural hypotension, scotoma, suicide attempt, syncope, and visual field defect. Laboratory Test Abnormalities Adult Patients In addition to changes in serum bicarbonate (i.e., metabolic acidosis), sodium chloride and ammonia, immediate-release topiramate was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies [see Warnings and Precautions (5.4, 5.10)]. Controlled trials of adjunctive topiramate treatment of adults for partial onset seizures showed an increased incidence of markedly decreased serum phosphorus (6% topiramate versus 2% placebo), markedly increased serum alkaline phosphatase (3% topiramate versus 1% placebo), and decreased serum potassium (0.4% topiramate versus 0.1% placebo). Pediatric Patients In pediatric patients (1-24 months) receiving adjunctive topiramate for partial onset seizures, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with immediate-release topiramate (vs placebo) for the following clinical laboratory analytes: creatinine, BUN, alkaline phosphatase, and total protein. The incidence was also increased for a decreased result for bicarbonate (i.e., metabolic acidosis), and potassium with immediate-release topiramate (vs. placebo) [see Use in Specific Populations (8.4)]. TROKENDI XR® is not indicated for partial onset seizures in pediatric patients less than 6 years of age. In pediatric patients (ranging from 6-17 years old) receiving immediate-release topiramate for migraine prophylaxis, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with immediate-release topiramate (vs placebo) for the following clinical laboratory analytes: creatinine, BUN, uric acid, chloride, ammonia, alkaline phosphatase, total protein, platelets, and eosinophils. The incidence was also increased for a decreased result for phosphorus, bicarbonate, total white blood count, and neutrophils [see Use in Specific Populations (8.4)]. TROKENDI XR® is not indicated for prophylaxis of migraine headache in pediatric patients less than 12 years of age. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of immediate-release topiramate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole-General Disorders: oligohydrosis and hyperthermia [see Warnings and Precautions (5.3)], hyperammonemia, hyperammonemic encephalopathy [see Warnings and Precautions (5.10)], hypothermia with concomitant valproic acid [see Warnings and Precautions 5.12)]. Gastrointestinal System Disorders: hepatic failure (including fatalities), hepatitis, pancreatitis Skin and Appendage Disorders: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), pemphigus Urinary System Disorders: kidney stones [see Warnings and Precautions (5.11)] Vision disorders: acute myopia, secondary angle closure glaucoma [see Warnings and Precautions (5.1)], maculopathy

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION TROKENDI XR® initial dose, titration, and recommended maintenance dose varies by indication and age group. See Full Prescribing Information for recommended dosage, and dosing considerations in patients with renal impairment, geriatric patients, and patients undergoing hemodialysis (2.1, 2.2, 2.3, 2.4, 2.5, 2.6) Swallow capsule whole and intact. Do not sprinkle on food, chew, or crush (2.7) 2.1 Dosing in Monotherapy Epilepsy Adults and Pediatric Patients 10 Years of Age and Older with Partial Onset or Primary Generalized Tonic-Clonic Seizures The recommended dose for topiramate monotherapy in adults and in pediatric patients 10 years of age and older is 400 mg orally once daily. Titrate TROKENDI XR® according to the following schedule: Week 1: 50 mg once daily Week 2: 100 mg once daily Week 3: 150 mg once daily Week 4: 200 mg once daily Week 5: 300 mg once daily Week 6: 400 mg once daily Pediatric Patients Ages 6 to 9 Years of Age Dosing in patients 6 to 9 years of age is based on weight. During the titration period, the initial dose of TROKENDI XR® is 25 mg/day nightly for the first week. Based upon tolerability, the dosage can be increased to 50 mg/day in the second week. Dosage can be increased by 25 mg to 50 mg/day each subsequent week as tolerated. Titration to the minimum maintenance dose should be attempted over 5-7 weeks of the total titration period. Based upon tolerability and clinical response, additional titration to a higher dose (up to the maximum maintenance dose) can be attempted at 25 mg to 50 mg/day weekly increments. The total daily dose should not exceed the maximum maintenance dose for each range of body weight (see Table 1). Table 1: Monotherapy Target Total Daily Maintenance Dosing for Patients 6 to 9 Years of Age Weight (kg) Total Daily Dose (mg/day) Minimum Maintenance Dose Total Daily Dose (mg/day) Maximum Maintenance Dose Up to 11 150 250 12 - 22 200 300 23 - 31 200 350 32 - 38 250 350 Greater than 38 250 400 2.2 Dosing in Adjunctive Therapy Epilepsy Adults (17 Years of Age and Over) 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 and 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. Titrating in increments of 25 mg/day every week may delay the time to reach an effective dose. Doses above 400 mg/day have not been shown to improve responses in adults with partial onset seizures. Pediatric Patients 6 to 16 Years of Age The recommended total daily dose of TROKENDI XR® as adjunctive therapy for patients 6 to 16 years of age 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 (or less, 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. The total daily dose should not exceed 400 mg/day. 2.3 Dosing in Migraine Prophylaxis The recommended total daily dose of TROKENDI XR® as treatment for prophylaxis of migraine headache in patients 12 years of age and older is 100 mg once daily. Titrate TROKENDI XR® for migraine prophylaxis according to the following schedule: Week 1: 25mg once daily Week 2: 50mg once daily Week 3: 75mg once daily Week 4: 100mg once daily Dose and titration rate should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used. 2.4 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 (5.5) ]. 2.5 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 of TROKENDI XR is recommended [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. 2.6 Dosage Modifications in Patients Undergoing Hemodialysis To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of TROKENDI XR may be required. The actual adjustment should take into account 1) the duration of dialysis period, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of topiramate in the patient being dialyzed [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. 2.7 Administration Instructions TROKENDI XR® can be taken without regard to meals. Swallow capsule whole and intact. Do not sprinkle on food, chew, or crush.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to topiramate during pregnancy. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334. Information about the North American Drug Pregnancy Registry can be found at http://www.aedpregnancyregistry.org/. Risk Summary Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have increased risk for cleft lip and/or cleft palate (oral clefts) and for being small for gestational age [see Human Data]. In multiple animal species, topiramate demonstrated developmental toxicity, including teratogenicity, in the absence of maternal toxicity at clinically relevant doses [see Animal Data]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse reactions Consider the benefits and risks of topiramate when prescribing this drug to women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death. Because of the risk of oral clefts to the fetus, which occur in the first trimester of pregnancy before many women know they are pregnant, all women of childbearing potential should be informed of the potential risk to the fetus from exposure to topiramate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of topiramate use during pregnancy, and alternative therapeutic options should be considered for these patients. Labor or Delivery Although the effect of topiramate on labor and delivery in humans has not been established, the development of topiramate-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus' ability to tolerate labor [see Use in Specific Populations (8.1) ]. TROKENDI XR treatment can cause metabolic acidosis [see Warnings and Precautions (5.4) ]. The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus' ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state [see Warnings and Precautions (5.4) ]. Newborns of mothers treated with TROKENDI XR should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic acidosis following birth. Data Human Data Data from pregnancy registries indicate an increased risk of oral clefts in infants exposed to topiramate during the first trimester of pregnancy. In the NAAED pregnancy registry, the prevalence of oral clefts among topiramate-exposed infants (1.1%) was higher than the prevalence of infants exposed to reference AEDs (0.36%) , or the prevalence in infants of mothers without epilepsy and without exposure to AEDs (0.12%). It was also higher than the background prevalence in United States (0.17%) as estimated by the Centers for Disease Control and Prevention (CDC). The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 9.6 (95% Confidence Interval=[CI] 4.0-23.0) as compared to the risk in a background population of untreated women. The UK Epilepsy and Pregnancy Register reported a prevalence of oral clefts among infants exposed to topiramate monotherapy (3.2%) that was 16 times higher than the background rate in the UK (0.2%). Data from the NAAED pregnancy registry and a population-based birth registry cohort indicate that exposure to topiramate in utero is associated with an increased risk of small for gestational age (SGA) newborns (birth weight <10th percentile). In the NAAED pregnancy registry, 18% of topiramate-exposed newborns were SGA compared to 7% of newborns exposed to a reference AED, and 5% of newborns of mothers without epilepsy and without AED exposure. In the Medical Birth Registry of Norway (MBRN), a population-based pregnancy registry, 25% of newborns in the topiramate monotherapy exposure group were SGA compared to 9 % in the comparison group who were unexposed to AEDs. The long-term consequences of the SGA findings are not known. Animal Data When topiramate (20, 100, and 500 mg/kg/day) was administered orally to pregnant mice during the period of organogenesis, the incidence of fetal malformations (primarily craniofacial defects) was increased at all doses. Fetal body weights and skeletal ossification were reduced at the highest dose tested in conjunction with decreased maternal body weight gain. A no-effect dose for embryofetal developmental toxicity in mice was not identified. The lowest dose tested, which was associated with teratogenic effects, is less than the maximum recommended human dose (MRHD) for epilepsy (400 mg/day) or migraine (100 mg/day) on a body surface area (mg/m2) basis. In pregnant rats administered topiramate (20, 100, and 500 mg/kg/day or 0.2, 2.5, 30, and 400 mg/kg/day) orally during the period of organogenesis, the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased in fetuses at 400 or 500 mg/kg/day. Embryotoxicity (reduced fetal body weights, increased incidences of structural variations) was observed at doses as low as 20 mg/kg/day. Clinical signs of maternal toxicity were seen at 400 mg/kg/day and above, and maternal body weight gain was reduced at doses of 100 mg/kg/day or greater. The no-effect dose for embryofetal developmental toxicity in rats is less than the MRHD for epilepsy or migraine on a mg/m2 basis. In pregnant rabbits administered topiramate (20, 60, and 180 mg/kg/day or 10, 35, and 120 mg/kg/day) orally during organogenesis, embryofetal mortality was increased at 35 mg/kg/day and teratogenic effects (primarily rib and vertebral malformations) were observed at 120 mg/kg/day. Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg/day and above. The no-effect dose (20 mg/kg/day) for embryofetal developmental toxicity in rabbits is equivalent to the MRHD for epilepsy and approximately 4 times the MRHD for migraine on a mg/m2 basis. When topiramate (0.2, 4, 20, and 100 mg/kg/day or 2, 20, and 200 mg/kg/day) was administered orally to female rats during the latter part of gestation and throughout lactation, offspring exhibited decreased viability and delayed physical development at 200 mg/kg/day and reductions in pre-and/or postweaning body weight gain at 2 mg/kg/day and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg/day or greater. In a rat embryo/fetal development study which included postnatal assessment of offspring, oral administration of topiramate (0.2, 2.5, 30, and 400 mg/kg/day) to pregnant animals during the period of organogenesis resulted in delayed physical development at 400 mg/kg/day and persistent reductions in body weight gain at 30 mg/kg/day and higher in the offspring. The no-effect dose (0.2 mg/kg/day) for pre- and postnatal developmental toxicity is less than the MRHD for epilepsy or migraine on a mg/m2 basis. 8.2 Lactation Risk Summary Topiramate is excreted in human milk [see Data]. The effects of topiramate exposure in breastfed infants or on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for TROKENDI XR and any potential adverse effects on the breastfed infant from TROKENDI XR or from the underlying maternal condition. Data Limited data from 5 women with epilepsy treated with topiramate during lactation showed drug levels in milk similar to those in maternal plasma. 8.3 Females and Males of Reproductive Potential Contraception Women of childbearing potential who are not planning a pregnancy should use effective contraception because of the risks to the fetus of oral clefts and of being small for gestational age [see Drug Interactions (7.5) and Use in Specific Populations (8.1) ]. 8.4 Pediatric Use Seizures in Pediatric Patients 6 Years of Age and Older The safety and effectiveness of TROKENDI XR® for treatment of partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndromes in pediatric patients at least 6 years of age is based on controlled trials with immediate-release topiramate [see Clinical Studies (14.2, 14.3) ]. The adverse reactions in pediatric patients treated for partial onset seizure, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome are similar to those seen in adults [see Warnings and Precautions (5) and Adverse Reactions (6) ]. These include, but are not limited to: oligohydrosis and hyperthermia [see Warnings and Precautions (5.3) ] dose-related increased incidence of metabolic acidosis [see Warnings and Precautions (5.4) ] dose-related increased incidence of hyperammonemia [see Warnings and Precautions (5.10) ] Not Recommended for Pediatric Patients Younger than 6 Years of Age The safety and effectiveness of TROKENDI XR for treatment of partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndromes in pediatric patients younger than 6 years of age has not been established. Because the capsule must be swallowed whole, and may not be sprinkled on food, crushed or chewed, TROKENDI XR® is recommended only for children age 6 or older. The following pediatric use information for adjunctive treatment for partial onset epilepsy in infants and toddlers (1 to 24 months) is based on studies conducted with immediate-release topiramate, which failed to demonstrate efficacy. Safety and effectiveness of immediate-release topiramate in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome. In a single randomized, double-blind, placebo-controlled investigational trial, the efficacy, safety, and tolerability of immediate-release topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in pediatric patients 1 to 24 months of age with refractory partial onset seizures, was assessed. After 20 days of double-blind treatment, immediate-release topiramate (at fixed doses of 5 mg/kg, 15 mg/kg, and 25 mg/kg per day) did not demonstrate efficacy compared with placebo in controlling seizures. In general, the adverse reaction profile for immediate-release topiramate in this population was similar to that of older pediatric patients, although results from the above controlled study, and an open-label, long-term extension study in these pediatric patients 1 to 24 months old suggested some adverse reactions not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions that occurred with a greater frequency and/or greater severity than had been recognized previously from studies in older pediatric patients or adults for various indications. These very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%). The following adverse reactions were observed in at least 3% of patients on immediate-release topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm. A generally similar profile was observed in older pediatric patients [see Adverse Reactions (6) ]. Immediate-release topiramate resulted in an increased incidence of patients with increased creatinine (any topiramate dose 5%, placebo 0%), BUN (any topiramate dose 3%, placebo 0%), and protein (any topiramate dose 34%, placebo 6%), and an increased incidence of decreased potassium (any topiramate dose 7%, placebo 0%). This increased frequency of abnormal values was not dose related. Creatinine was the only analyte showing a noteworthy increased incidence (topiramate 25 mg/kg/day 5%, placebo 0%) of a markedly abnormal increase [see Adverse Reactions (6.1) ]. The significance of these findings is uncertain. Immediate-release topiramate treatment also produced a dose-related increase in the percentage of patients who had a shift from normal at baseline to high/increased (above the normal reference range) in total eosinophil count at the end of treatment. The incidence of these abnormal shifts was 6 % for placebo, 10% for 5 mg/kg/day, 9% for 15 mg/kg/day, 14% for 25 mg/kg/day, and 11% for any topiramate dose [see Adverse Reactions (6.1) ]. There was a mean dose-related increase in alkaline phosphatase. The significance of these findings is uncertain. Topiramate produced a dose-related increased incidence of hyperammonemia [see Warnings and Precautions (5.10) ]. Treatment with immediate-release topiramate for up to 1 year was associated with reductions in Z SCORES for length, weight, and head circumference [see Warnings and Precautions (5.4) and Adverse Reactions (6) ]. In open-label, uncontrolled experience, increasing impairment of adaptive behavior was documented in behavioral testing over time in this population. There was a suggestion that this effect was dose-related. However, because of the absence of an appropriate control group, it is not known if this decrement in function was treatment related or reflects the patient's underlying disease (e.g., patients who received higher doses may have more severe underlying disease) [see Warnings and Precautions (5.7) ]. In this open-label, uncontrolled study, the mortality was 37 deaths/1000 patient years. It is not possible to know whether this mortality rate is related to immediate-release topiramate treatment, because the background mortality rate for a similar, significantly refractory, young pediatric population (1 month to 24 months) with partial epilepsy is not known. Other Pediatric Studies Topiramate treatment produced a dose-related increased shift in serum creatinine from normal at baseline to an increased value at the end of 4 months treatment in adolescent patients (ages 12 years to 16 years) in a double-blind, placebo-controlled study [see Adverse Reactions (6.1) ]. Migraine Prophylaxis in Pediatric Patients 12 to 17 Years of Age Safety and effectiveness of topiramate in the prophylaxis of migraine was studied in 5 double-blind, randomized, placebo-controlled, parallel-group trials in a total of 219 pediatric patients, at doses of 50 mg/day to 200 mg/day, or 2 to 3 mg/kg/day. These comprised a fixed dose study in 103 pediatric patients 12 to 17 years of age [see Clinical Studies (14.4)], a flexible dose (2 to 3 mg/kg/day), placebo-controlled study in 157 pediatric patients 6 to 16 years of age (including 67 pediatric patients 12 to 16 years of age), and a total of 49 pediatric patients 12 to 17 years of age in 3 studies of migraine prophylaxis primarily in adults. Open-label extension phases of 3 studies enabled evaluation of long-term safety for up to 6 months after the end of the double-blind phase. Efficacy of topiramate for migraine prophylaxis in pediatric patients 12 to 17 years of age is demonstrated for a 100 mg daily dose in Study 3 [see Clinical Studies (14.4)]. Efficacy of topiramate (2 to 3 mg/kg/day) for migraine prophylaxis was not demonstrated in a placebo-controlled trial of 157 pediatric patients (6 to 16 years of age) that included treatment of 67 pediatric patients 12 to 16 years of age) for 20 weeks. In the pediatric trials (12 to 17 years of age) in which patients were randomized to placebo or a fixed daily dose of immediate-release topiramate, the most common adverse reactions with immediate-release topiramate that were seen at an incidence higher (≥5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain [see Adverse Reactions (6.1)]. The most common cognitive adverse reaction in pooled double-blind studies in pediatric patients 12 to 17 years of age was difficulty with concentration/attention [see Warnings and Precautions (5.7)]. Markedly abnormally low serum bicarbonate values indicative of metabolic acidosis were reported in topiramate-treated pediatric migraine patients [see Warnings and Precautions (5.4)]. In topiramate-treated pediatric patients (12 to 17 years of age) compared to placebo-treated patients, abnormally increased results were more frequent for creatinine, BUN, uric acid, chloride, ammonia, total protein, and platelets. Abnormally decreased results were observed with topiramate vs placebo treatment for phosphorus and bicarbonate [see Warnings and Precautions(5.4) and Adverse Reactions (6.1))]. Notable changes (increases and decreases) from baseline in systolic blood pressure, diastolic blood pressure, and pulse that were observed occurred more commonly in pediatric patients treated with topiramate compared to pediatric patients treated with placebo [see Clinical Pharmacology (12.2)]. Migraine Prophylaxis in Pediatric Patients 6 to11 Years of Age Safety and effectiveness in pediatric patients below the age of 12 years have not been established for the prophylaxis treatment of migraine headache. In a double-blind study in 90 pediatric patients 6 to 11 years of age (including 59 topiramate-treated and 31 placebo patients), the adverse reaction profile was generally similar to that seen in pooled double-blind studies of pediatric patients 12 to 17 years of age. The most common adverse reactions that occurred in immediate-release topiramate-treated pediatric patients 6 to 11 years of age, and at least twice as frequently than placebo, were gastroenteritis (12% topiramate, 6% placebo), sinusitis (10% topiramate, 3% placebo), weight loss (8% topiramate, 3% placebo) and paresthesia (7% topiramate, 0% placebo). Difficulty with concentration/attention occurred in 3 topiramate-treated patients (5%) and 0 placebo-treated patients. The risk for cognitive adverse reactions was greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age) [see Warnings and Precautions (5.7)]. Juvenile Animal Studies When topiramate (30, 90, and 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose, which is approximately 5-8 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m2) basis. 8.5 Geriatric Use Clinical studies of immediate-release topiramate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Dosage adjustment may be necessary for elderly with creatinine clearance less than 70 mL/min/1.73 m2. Estimate GFR should be measured prior to dosing [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ]. 8.6 Renal Impairment The clearance of topiramate is reduced in patients with moderate (creatinine clearance 30 to 69 mL/min/1.73m2) and severe (creatinine clearance less than 30 mL/min/1.73m2) renal impairment. A dosage adjustment is recommended in patients with moderate or severe renal impairment [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ]. 8.7 Patients Undergoing Hemodialysis Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than in a normal individual. A dosage adjustment may be required [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3) ].

Interactions

7 DRUG INTERACTIONS Oral contraceptives: Decreased contraceptive efficacy and increased breakthrough bleeding, especially at doses greater than 200 mg per day (7.5) Monitor lithium levels if lithium is used with high-dose topiramate (7.8) 7.1 Alcohol Alcohol use is contraindicated within 6 hours prior to and 6 hours after TROKENDI XR® administration [see Contraindications (4) and Warnings and Precautions (5.5) ]. 7.2 Antiepileptic Drugs Concomitant administration of phenytoin or carbamazepine with topiramate resulted in a clinically significant decrease in plasma concentrations of topiramate when compared to topiramate given alone. A dosage adjustment may be needed [see Dosage and Administration (2.1), Clinical Pharmacology (12.3) ]. Concomitant administration of valproic acid and topiramate has been associated with hypothermia and hyperammonemia with and without encephalopathy. Examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.10, 5.12) and Clinical Pharmacology (12.3) ]. 7.3 Other Carbonic Anhydrase Inhibitors Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide, acetazolamide, or dichlorphenamide), may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Patients should be monitored for the appearance or worsening of metabolic acidosis when TROKENDI XR® is given concomitantly with another carbonic anhydrase inhibitor [see Clinical Pharmacology (12.3) ]. 7.4 CNS Depressants Concomitant administration of topiramate with other CNS depressant drugs or alcohol has not been evaluated in clinical studies. Because of the potential of topiramate to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse reactions, TROKENDI XR® should be used with extreme caution if used in combination with alcohol and other CNS depressants [see Warnings and Precautions (5.7) ]. 7.5 Oral Contraceptives The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking combination oral contraceptive products with TROKENDI XR®. Patients taking estrogen-containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding [see Clinical Pharmacology (12.3) ]. 7.6 Hydrochlorothiazide (HCTZ) Topiramate Cmax and AUC increased when HCTZ was added to immediate-release topiramate. The clinical significance of this change is unknown. The addition of HCTZ to TROKENDI XR® may require a decrease in the TROKENDI XR® dose [see Clinical Pharmacology (12.3)]. 7.7 Pioglitazone A decrease in the exposure of pioglitazone and its active metabolites were noted with the concurrent use of pioglitazone and immediate-release topiramate in a clinical trial. The clinical relevance of these observations is unknown; however, when TROKENDI XR® is added to pioglitazone therapy or pioglitazone is added to TROKENDI XR® therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state [see Clinical Pharmacology (12.3)]. 7.8 Lithium An increase in systemic exposure of lithium following topiramate doses of up to 600 mg/day can occur. Lithium levels should be monitored when co-administered with high-dose TROKENDI XR® [see Clinical Pharmacology (12.3) ]. 7.9 Amitriptyline Some patients may experience a large increase in amitriptyline concentration in the presence of TROKENDI XR® and any adjustments in amitriptyline dose should be made according to the patients' clinical response and not on the basis of plasma levels [see Clinical Pharmacology (12.3)].

More information

Category Value
Authorisation number NDA201635
Agency product number 0H73WJJ391
Orphan designation No
Product NDC 17772-104,17772-103,17772-102,17772-101
Date Last Revised 12-01-2018
Type HUMAN PRESCRIPTION DRUG
Storage and handling 16.2 Storage and Handling TROKENDI XR® (topiramate) extended-release capsules should be stored in well closed containers at controlled room temperature [25°C (77°F); excursions 15°C-30°C (59°F-86°F)]. Protect from moisture and light.
Marketing authorisation holder Supernus Pharmaceuticals