Trokendi Drug Information

Monotherapy Epilepsy

TROKENDI XR is indicated as initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 6 years of age and older .

Adjunctive Therapy Epilepsy

TROKENDI XR is indicated as adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome in patients 6 years of age and older .

Migraine

TROKENDI XR is indicated for the preventive treatment of migraine in patients 12 years of age and older .

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 3 ). 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. Table 3 represents 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: Adverse Reactions in the High Dose Group as Compared to the Low Dose Group, in Monotherapy Epilepsy Trial in Adult and Pediatric Patients Age Group Pediatric (6 to 15 Years) Adult (Age ≥16 Years) Immediate-release Topiramate Daily Dosage Group (mg/day) 50 400 50 400 Body System/ Adverse Reaction (N=74) % (N=77) % (N=160) % (N=159) % Body as a Whole-General Disorders Asthenia 0 3 4 6 Fever 1 12 Leg pain 2 3 Central & Peripheral Nervous System Disorders Paresthesia 3 12 21 40 Dizziness 13 14 Ataxia 3 4 Hypoesthesia 4 5 Hypertonia 0 3 Involuntary Muscle contraction 0 3 Vertigo 0 3 Gastro-intestinal System Disorders Constipation 1 4 Diarrhea 8 9 Gastritis 0 3 Dry mouth 1 3 Liver and Biliary System Disorders Increase in gamma-GT 1 3 Metabolic and Nutritional Disorders Weight loss 7 17 6 17 Platelet, Bleeding & Clotting Disorders Epistaxis 0 4 Psychiatric Disorders Anorexia 4 14 Anxiety 4 6 Cognitive problems 1 6 1 4 Confusion 0 3 Depression 0 3 7 9 Difficulty with concentration or attention 7 10 7 8 Difficulty with memory 1 3 6 11 Insomnia 8 9 Decrease in libido 0 3 Mood problems 1 8 2 5 Personality disorder (behavior problems) 0 3 Psychomotor slowing 3 5 Somnolence 10 15 Red Blood Cell Disorders Anemia 1 3 Reproductive Disorders, Female Intermenstrual bleeding 0 3 Vaginal hemorrhage 0 3 Resistance Mechanism Disorders Infection 3 8 2 3 Viral infection 3 6 6 8 Respiratory System Disorders Bronchitis 1 5 3 4 Upper respiratory tract infection 16 18 Rhinitis 5 6 2 4 Sinusitis 1 4 Skin and Appendages Disorders Alopecia 1 4 3 4 Pruritus 1 4 Rash 3 4 1 4 Acne 2 3 Special Senses Other, Disorders Taste perversion 3 5 Urinary System Disorders Cystitis 1 3 Micturition frequency 0 3 0 2 Renal calculus 0 3 Urinary incontinence 1 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 4 ) . Table 4 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 4: 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 Rhinitis 6 7 Pharyngitis 2 6 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.

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 5 ). Table 5 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 5: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trial in Pediatric Patients 2 to 15 Years of Age 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 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 clinical trials for the preventive treatment of migraine (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 100 mg in the clinical trials for the preventive treatment of migraine 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 6 ). Table 6 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 6: Adverse Reactions in Pooled, Placebo-Controlled, Migraine Trials in Adults Includes 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 Pruritus 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 clinical trials for the preventive treatment of migraine, 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 clinical trials for the preventive treatment of migraine in pediatric patients 12 to 17 years of age, the most common adverse reactions with immediate-release topiramate 100 mg 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 7 ). Table 7 shows adverse reactions from the pediatric trial (Study 13 ) 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 of age) were treated with placebo or 50 mg, 100 mg, or 200 mg of immediate-release topiramate. Table 7 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 7 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 7: Adverse Reactions in Pooled Double-Blind Studies for the Preventive Treatment of Migraine 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 . 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, blood urea nitrogen (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) . 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 of age) receiving immediate-release topiramate for the preventive treatment of migraine, 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. TROKENDI XR is not indicated for the preventive treatment of migraine in pediatric patients less than 12 years of age.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of topiramate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole-General Disorders : immediate hypersensitivity reactions (including anaphylaxis and angioedema ), delayed hypersensitivity reactions (including facial swelling, lip swelling, periorbital swelling, tongue swelling), oligohydrosis and hyperthermia , hyperammonemia, hyperammonemic encephalopathy , hypothermia with concomitant valproic acid . 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, urticaria Urinary System Disorders : kidney stones, nephrocalcinosis Vision Disorders : acute myopia, secondary angle closure glaucoma, maculopathy Hematological Disorders : decrease of the International Normalized Ratio (INR) or prothrombin time when given concomitantly with vitamin K antagonist anticoagulant medications such as warfarin.

Alcohol Alcohol use is contraindicated within 6 hours prior to and 6

hours after TROKENDI XR administration.

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. 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 .

Other Carbonic Anhydrase Inhibitors

Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide or acetazolamide) 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.

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.

Contraceptives

The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking contraceptive products with TROKENDI XR. Patients taking estrogen-containing or progestin-only contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding .

Hydrochlorothiazide (HCTZ) Topiramate C max 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 .

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 .

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.

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 .

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as TROKENDI XR, 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 TROKENDI XR 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 of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA) . SGA has been observed at all doses and appears to be dose-dependent. The prevalence of SGA is greater in infants of women who received higher doses of topiramate during pregnancy.

In addition, the prevalence of SGA in infants of women who continued topiramate use until later in pregnancy is higher compared to the prevalence in infants of women who stopped topiramate use before the third trimester. In multiple animal species, topiramate demonstrated developmental toxicity, including increased incidences of fetal malformations, in the absence of maternal toxicity at clinically relevant doses . All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 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. TROKENDI XR treatment can cause metabolic acidosis . 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 . 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. Based on limited information, topiramate has also been associated with pre-term labor and premature delivery. Data Human Data Data from pregnancy registries indicate an increased risk of major congenital malformations, including but not limited to oral clefts in infants exposed to topiramate during the first trimester of pregnancy.

Other than oral clefts, no specific pattern of major congenital malformations or grouping of major congenital malformation types were observed. In the NAAED pregnancy registry, when topiramate-exposed infants with only oral clefts were excluded, the prevalence of major congenital malformations (4.1%) was higher than that in infants exposed to a reference AED (1.8%) or in infants with mothers without epilepsy and without exposure to AEDs (1.1%). The prevalence of oral clefts among topiramate-exposed infants (1.4%) was higher than the prevalence in infants exposed to reference AEDs (0.3%), or the prevalence in infants with mothers without epilepsy and without exposure to AEDs (0.11%). 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 12.5 (95% Confidence Interval= 5.9-26.37) 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 SGA newborns (birth weight <10th percentile). In the NAAED pregnancy registry, 19.7% of topiramate-exposed newborns were SGA compared to 7.9% of newborns exposed to a reference AED, and 5.4% 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 (0, 20, 100, or 500 mg/kg/day) was administered orally to pregnant mice during the period of organogenesis, incidences of fetal malformations (primarily craniofacial defects) were 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 an increased incidence of malformations, 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/m 2 ) basis.

In pregnant rats administered topiramate (0, 20, 100, and 500 mg/kg/day or 0, 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 and 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 (2.5 mg/kg/day) for embryofetal developmental toxicity in rats is less than the MRHD for epilepsy or migraine on a mg/m 2 basis. In pregnant rabbits administered topiramate (0, 20, 60, and 180 mg/kg/day or 0, 10, 35, and 120 mg/kg/day) orally during organogenesis, embryofetal mortality was increased at 35 mg/kg/day and an increased incidence of fetal malformations (primarily rib and vertebral malformations) was 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/m 2 basis. When topiramate (0, 0.2, 4, 20, and 100 mg/kg/day or 0, 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 embryofetal development study which included postnatal assessment of offspring, oral administration of topiramate (0, 0.2, 2.5, 30, and 400 mg/kg/day) to pregnant animals during the period of organogenesis resulted in delayed physical development in offspring at 400 mg/kg/day and persistent reductions in body weight gain in offspring at 30 mg/kg/day and higher. 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/m 2 basis.

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 . 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 . These include, but are not limited to: oligohydrosis and hyperthermia dose-related increased incidence of metabolic acidosis dose-related increased incidence of hyperammonemia 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 have 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 were assessed. After 20 days of double-blind treatment, immediate-release topiramate (at fixed doses of 5, 15, 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.

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 . 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 . 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 . Treatment with immediate-release topiramate for up to 1 year was associated with reductions in Z SCORES for length, weight, and head circumference . 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) . 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 . A one-year, active-controlled, open-label study with blinded assessments of bone mineral density (BMD) and growth in pediatric patients 4 to 15 years of age, including 63 patients with recent or new onset of epilepsy, was conducted to assess effects of immediate-release topiramate (N=28, 6-15 years of age) versus levetiracetam (N=35, 4-15 years of age) monotherapy on bone mineralization and on height and weight, which reflect growth. Effects on bone mineralization were evaluated via dual-energy X-ray absorptiometry and blood markers. Table 8 summarizes effects of immediate-release topiramate at 12 months for key safety outcomes including BMD, height, height velocity, and weight.

All Least Square Mean values for immediate-release topiramate and the comparator were positive. Therefore, the Least Square Mean treatment differences shown reflect an immediate-release topiramate-induced attenuation of the key safety outcomes. Statistically significant effects were observed for decreases in BMD (and bone mineral content) in lumbar spine and total body less head and in weight.

Subgroup analyses according to age demonstrated similar negative effects for all key safety outcomes (i.e., BMD, height, weight). Table 8: Summary of Immediate-release Topiramate Treatment Difference Results at 12 Months for Key Safety Outcomes Safety Parameter Treatment Difference in Least Square Means (95 % Confidence Interval) Annual Change in BMD Lumbar Spine (g/cm 2 ) -0.036 (-0.058, -0.014) Annual Change in BMD TBLH TBLH=total body less head (g/cm 2 ) -0.026 (-0.039, -0.012) Annual Change in Height (cm) (4-9 years, Primary Analysis Population for Height) Whereas no patients were randomized to 2-5 year age subgroup for immediate-release topiramate, 5 patients (4-5 years) were randomized to the active control group. -0.84 (-2.67, 0.99) Annual Change in Height (cm) (4-15 years) -0.75 (-2.21, 0.71) Annual Change in Height (cm) (10-15 years) -1.01 (-3.64, 1.61) Height Velocity (cm/year) (4-9 years) -1.00 (-2.76, 0.76) Height Velocity (cm/year) (4-15 years) -0.98 (-2.33, 0.37) Height Velocity (cm/year) (10-15 years) -0.96 (-3.24, 1.32) Annual Change in Weight (kg) -2.05 (-3.66, -0.45) Metabolic acidosis (serum bicarbonate <20 mEq/L) was observed in all immediate-release topiramate-treated patients at some time in the study. Over the whole study, 76% more immediate-release topiramate-treated patients experienced persistent metabolic acidosis (i.e., 2 consecutive visits with or final serum bicarbonate <20 mEq/L) compared to levetiracetam-treated patients. Over the whole study, 35% more immediate-release topiramate-treated patients experienced a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and ≥5mEq/L decrease from pre-treatment), indicating the frequency of more severe metabolic acidosis, compared to levetiracetam-treated patients.

The decrease in BMD at 12 months was correlated with decreased serum bicarbonate, suggesting that metabolic acidosis was at least a partial factor contributing to this adverse effect on BMD. Immediate-release topiramate-treated patients exhibited an increased risk for developing an increased serum creatinine and an increased serum glucose above the normal reference range compared to control patients. Preventive Treatment of Migraine in Pediatric Patients 12 to 17 Years of Age Safety and effectiveness of topiramate for the preventive treatment 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, 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 for the preventive treatment of migraine 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 the preventive treatment of migraine in pediatric patients 12 to 17 years of age is demonstrated for a 100 mg daily dose in Study 3 . Efficacy of topiramate (2 to 3 mg/kg/day) for the preventive treatment of migraine 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 . 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 . Markedly abnormally low serum bicarbonate values indicative of metabolic acidosis were reported in topiramate-treated pediatric migraine patients . 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 . 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 . Preventive Treatment of Migraine in Pediatric Patients 6 to 11 Years of Age Safety and effectiveness in pediatric patients below the age of 12 years have not been established for the preventive treatment of migraine. 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) . 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/m 2 ) basis.

is contraindicated in patients with: recent alcohol use (i.e., within 6 hours prior to and 6 hours after TROKENDI XR use). a history of hypersensitivity reaction to topiramate, TROKENDI XR, or any of the inactive ingredients of TROKENDI XR. Anaphylaxis and angioedema have occurred. With recent alcohol use, i.e., within 6 hours prior to and 6 hours after TROKENDI XR use History of hypersensitivity reaction to topiramate. TROKENDI XR, or any of the inactive ingredients of TROKENDI XR

Overdoses of topiramate have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbance, blurred vision, diplopia, impaired mentation, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness, and depression. The clinical consequences were not severe in most cases, but deaths have been reported after overdoses involving topiramate.

Topiramate overdose has resulted in severe metabolic acidosis . A patient who ingested a dose of immediate-release topiramate between 96 g and 110 g was admitted to a hospital with a coma lasting 20 to 24 hours followed by full recovery after 3 to 4 days. Similar signs, symptoms, and clinical consequences are expected to occur with overdosage of TROKENDI XR. In the event of overdose, TROKENDI XR should be discontinued and general supportive treatment given until clinical toxicity has been diminished or resolved. Hemodialysis is an effective means of removing topiramate from the body.