TOPIRAMATE TABS 50 MG 500 TAB
Generic: topiramate
TOPIRAMATE TABS 50 MG 500 TAB
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Identification
topiramate
topiramate
Unichem Pharmaceuticals (USA), Inc.
HUMAN PRESCRIPTION DRUG
Administration
TABLET, FILM COATED
ORAL
ANDA090162
Active Ingredients
| Ingredient | Strength |
|---|---|
| TOPIRAMATE | 50 mg/1 |
Pharmacological Class
Data sourced from openFDA / DailyMed. For full prescribing information, consult the drug label.
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Clinical Drug Information
Indications & Usage
1 INDICATIONS AND USAGE Topiramate tablets are indicated for: Epilepsy: initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 2 years of age and older (1.1); adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome in patients 2 years of age and older ( 1.2 ) Preventive treatment of migraine in patients 12 years of age and older ( 1.3 ) 1.1 Monotherapy Epilepsy Topiramate tablets are indicated as initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 2 years of age and older. 1.2 Adjunctive Therapy Epilepsy Topiramate tablets are 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 2 years of age and older. 1.3 Migraine Topiramate tablets are indicated for the preventive treatment of migraine in patients 12 years of age and older.
Dosage & Administration
2 DOSAGE AND ADMINISTRATION Topiramate tablets 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 ) 2.1 Dosing in Monotherapy Epilepsy Adults and Pediatric Patients 10 Years of Age and Older The recommended dose for topiramate tablets monotherapy in adults and pediatric patients 10 years of age and older is 400 mg/day in two divided doses. The dose should be achieved by titration according to the following schedule (Table 1): Table 1: Monotherapy Titration Schedule for Adults and Pediatric Patients 10 years and older Morning Dose Evening Dose Week 1 25 mg 25 mg Week 2 50 mg 50 mg Week 3 75 mg 75 mg Week 4 100 mg 100 mg Week 5 150 mg 150 mg Week 6 200 mg 200 mg Pediatric Patients 2 to 9 Years of Age Dosing in patients 2 to 9 years of age is based on weight. During the titration period, the initial dose of topiramate tablets is 25 mg/day nightly for the first week. Based upon tolerability, the dosage can be increased to 50 mg/day (25 mg twice daily) in the second week. Dosage can be increased by 25 to 50 mg/day each subsequent week as tolerated. Titration to the minimum maintenance dose should be attempted over 5 to 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 to 50 mg/day weekly increments. The total daily dose should not exceed the maximum maintenance dose for each range of body weight (Table 2). Table 2: Monotherapy Target Total Daily Maintenance Dosing for Patients 2 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 to 22 200 300 23 to 31 200 350 32 to 38 250 350 Greater than 38 250 400 * Administered in two equally divided doses 2.2 Dosing in Adjunctive Therapy Epilepsy Adults (17 Years of Age and Older) The recommended total daily dose of topiramate tablets as adjunctive therapy in adults with partial onset seizures or Lennox-Gastaut Syndrome is 200 to 400 mg/day in two divided doses, and 400 mg/day in two divided doses as adjunctive treatment in adults with primary generalized tonic-clonic seizures. Topiramate tablets should be initiated at 25 to 50 mg/day, followed by titration to an effective dose in increments of 25 to 50 mg/day 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 2 to 16 Years of Age The recommended total daily dose of topiramate tablets as adjunctive therapy for pediatric patients 2 to 16 years of age with partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome is approximately 5 to 9 mg/kg/day in two divided doses. Titration should begin at 25 mg/day (or less, based on a range of 1 to 3 mg/kg/day) nightly for the first week. The dosage should then be increased at 1- or 2-week intervals by increments of 1 to 3 mg/kg/day (administered in two divided doses), 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 for the Preventive Treatment of Migraine The recommended total daily dose of topiramate tablets as treatment for patients 12 years of age and older for the preventive treatment of migraine is 100 mg/day administered in two divided doses (Table 3). The recommended titration rate for topiramate tablets for the preventive treatment of migraine is as follows: Table 3: Preventive Treatment of Migraine Titration Schedule for Patients 12 Years of Age and Older Morning Dose Evening Dose Week 1 None 25 mg Week 2 25 mg 25 mg Week 3 25 mg 50 mg Week 4 50 mg 50 mg Dose and titration rate should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used. 2.4 Administration Information Topiramate tablets can be taken without regard to meals. Topiramate Tablets Because of the bitter taste, tablets should not be broken. 2.5 Dosing in Patients with Renal Impairment In patients with renal impairment (creatinine clearance less than 70 mL/min/1.73 m 2 ), one-half of the usual adult dose of topiramate tablets is recommended [see Use in Specific Populations 8.5 8.6 ), Clinical Pharmacology ( 12.3 )] . 2.6 Dosing in Patients Undergoing Hemodialysis To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate tablets 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 )] .
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 )] Oligohidrosis and Hyperthermia [see Warnings and Precautions ( 5.3 )] Metabolic Acidosis [see Warnings and Precautions ( 5.4 )] Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.5 )] Cognitive/Neuropsychiatric Adverse Reactions [see Warnings and Precautions ( 5.6 )] Decrease of Bone Mineral Density [see Warnings and Precautions ( 5.9 )] Negative Effects on Growth (Height and Weight) [see Warnings and Precautions ( 5.10 )] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions [see Warnings and Precautions ( 5.11 )] Serious Skin Reactions [see Warnings and Precautions ( 5.12 )] Anaphylaxis and Angioedema [see Warnings and Precautions ( 5.13 )] Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid [VPA] Use) [see Warnings and Precautions ( 5.14 )] Kidney Stones [see Warnings and Precautions ( 5.15 )] Hypothermia with Concomitant Valproic Acid (VPA) Use [see Warnings and Precautions ( 5.16 )] The data described in the following sections were obtained using topiramate tablets. Epilepsy : Most common (≥10% more frequent than placebo or low-dose topiramate) 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, diarrhea, hypoesthesia, nausea, abdominal pain and upper respiratory tract infection ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Unichem Pharmaceuticals (USA), Inc., at 1-866-562-4616 or 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, the incidence of adverse reactions observed in the clinical trials of a drug cannot be directly compared to the incidence of adverse reactions in the clinical trials of another drug, and may not reflect the incidence of adverse reactions observed in practice. Monotherapy Epilepsy Adults 16 Years of Age and Older The most common adverse reactions in the controlled clinical 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/day group were: paresthesia, weight loss and anorexia (see Table 5 ). 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 to 15 Years of Age The most common adverse reactions in the controlled clinical 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 5 ). 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 low-dose 50 mg/day topiramate) adverse reactions resulting in discontinuation were difficulty with concentration/attention, fever, flushing, and confusion. Table 5 presents the incidence of adverse reactions occurring in at least 3% of adult and pediatric patients treated with 400 mg/day topiramate and occurring with greater incidence than 50 mg/day topiramate. Table 5: Adverse Reactions in the High Dose Group As Compared to the Low Dose Group, in Monotherapy Epilepsy Trial (Study 1) in Adult and Pediatric Patients Body System Adverse Reaction Age Group Pediatric (6 to 15 Years) Adult (Age ≥16 Years) Topiramate Daily Dosage Group (mg/day) 50 400 50 400 (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 contractions 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 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 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 topiramate or placebo. The most common adverse reactions in the controlled clinical trial that occurred in adult patients in the 200 to 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 (Table 6). Table 6 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 mg to 1000 mg daily) compared to the incidence of these adverse reactions at the recommended dosing (200 mg to 400 mg daily) range. Table 6: Most Common Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trials in Adults a Body System Adverse Reaction Placebo (N = 291) Topiramate Dosage (mg/day) 200-400 (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 lability 1 3 Cognitive problems 1 3 Reproductive Disorders 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 a Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo In controlled clinical trials in adults, 11% of patients receiving topiramate 200 to 400 mg/day as adjunctive therapy discontinued due to adverse reactions. This rate appeared to increase at dosages above 400 mg/day. Adverse reactions associated with discontinuing topiramate 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 topiramate at dosages of 5 to 9 mg/kg/day (recommended dose 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 topiramate group with an incidence higher (≥ 10%) than in the placebo group were: fatigue and somnolence (Table 7). Table 7 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 dose range) of topiramate and was greater than placebo incidence Table 7: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trials in Pediatric Patients 2 to 15 Years of Age a, b 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 a Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo. b Values represent the percentage of patients reporting a given 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. None of the pediatric patients who received topiramate adjunctive therapy at 5 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 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 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 8 ). Table 8 includes those adverse reactions that occurred in the placebo-controlled trials where the incidence in any topiramate treatment 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 daily) compared to the incidence of these adverse reactions at the recommended dosing (100 mg daily). Table 8: Adverse Reactions in Pooled, Placebo-Controlled, Migraine Trials in Adults a,b Body System / Adverse Reaction Placebo (N=445) % Topiramate Dosage (mg/day) 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 Hypoesthesia 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 c 2 4 2 a Includes 35 adolescent patients age 12 to 15 years. b 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. c Blurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for >50% of reactions coded as vision abnormal, a preferred term. Of the 1,135 patients exposed to topiramate in the adult placebo-controlled studies, 25% of topiramate-treated patients discontinued due to adverse reactions, compared to 10% of the 445 placebo-treated patients. The adverse reactions associated with discontinuing therapy in the topiramate -treated patients included paresthesia (7%), fatigue (4%), nausea (4%), difficulty with concentration/attention (3%), insomnia (3%), anorexia (2%), and dizziness (2%). Patients treated with topiramate 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, topiramate 50, 100, 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 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 topiramate-treated pediatric patients 12 to 17 years of age, the most common adverse reactions with 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 9 ). Table 9 shows adverse reactions from the pediatric trial (Study 13 [see Clinical Studies ( 14.3 )] ) in which 103 pediatric patients were treated with placebo or 50 mg or 100 mg of 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 topiramate. Table 9 also shows adverse reactions in pediatric patients in the controlled migraine trials when the incidence in a topiramate dose group was at least 5% or higher and greater than the incidence of placebo. Many adverse reactions shown in Table 9 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 topiramate dosing (200 mg daily) compared to the incidence of these adverse reactions at the recommended dosing (100 mg daily). Table 9: Adverse Reactions in Pooled Double-Blind Migraine Prophylaxis Studies for the Preventive Treatment of Migraine in Pediatric Patients 12 to 17 Years of Age a,b,c 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 a 35 adolescent patients aged 12 to <16 years were also included in adverse reaction assessment for adults (Tables 11 and 12) b Incidence is based on the number of subjects experiencing at least 1 adverse event, not the number of events. c Included studies MIG-3006, MIGR-001, MIGR-002 and MIGR-003 In the double-blind placebo-controlled studies, adverse reactions led to discontinuation of treatment in 8% of placebo patients compared with 6% of topiramate-treated patients. Adverse reactions associated with discontinuing therapy that occurred in more than one 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, topiramate was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies [see Warnings and Precautions ( 5.4 , 5.14 )] . 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 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 topiramate (vs placebo) [ see Use in Specific Populations ( 8.4 ) ]. Topiramate is not indicated for partial onset seizures in pediatric patients less than 2 years of age. In pediatric patients (ranging from 6-17 years of age) receiving topiramate for the preventive treatment of migraine, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with 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 ) ]. Topiramate is not indicated for the preventive treatment of migraine 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 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) [see Warnings and Precautions ( 5.13 )] , delayed hypersensitivity reactions (including facial swelling, lip swelling, periorbital swelling, tongue swelling), oligohydrosis and hyperthermia [see Warnings and Precautions ( 5.3 )] , hyperammonemia, hyperammonemic encephalopathy [see Warnings and Precautions ( 5.14 )] , hypothermia with concomitant valproic acid [see Warnings and Precautions ( 5.16 )] 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) [see Warnings and Precautions ( 5.12 )] , pemphigus, urticaria Urinary System Disorders : kidney stones, nephrocalcinosis [see Warnings and Precautions ( 5.4 , 5.15 )] Vision Disorders : acute myopia, secondary angle closure glaucoma [see Warnings and Precautions ( 5.1 )] , 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.
Information for Patients
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Eye Disorders Instruct patients taking topiramate to seek immediate medical attention if they experience blurred vision, visual disturbances, or periorbital pain [see Warnings and Precautions ( 5.1 , 5.2 )] . Oligohidrosis and Hyperthermia Closely monitor topiramate-treated patients, especially pediatric patients, for evidence of decreased sweating and increased body temperature, especially in hot weather. Counsel patients to contact their healthcare professionals immediately if they develop a high or persistent fever, or decreased sweating [see Warnings and Precautions ( 5.3 )] . Metabolic Acidosis Warn patients about the potential significant risk for metabolic acidosis that may be asymptomatic and may be associated with adverse effects on kidneys (e.g., kidney stones, nephrocalcinosis), bones (e.g., osteoporosis, osteomalacia, and/or rickets in children), and growth (e.g., growth delay/retardation) in pediatric patients, and on the fetus [see Warnings and Precautions ( 5.4 ), Use in Specific Populations ( 8.1 )] . Suicidal Behavior and Ideation Counsel patients, their caregivers, and families that AEDs, including topiramate, may increase the risk of suicidal thoughts and behavior, and advise of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior or the emergence of suicidal thoughts, or behavior or thoughts about self-harm. Instruct patients to immediately report behaviors of concern to their healthcare providers [see Warnings and Precautions ( 5.5 )] . Interference with Cognitive and Motor Performance Warn patients about the potential for somnolence, dizziness, confusion, difficulty concentrating, or visual effects, and advise patients not to drive or operate machinery until they have gained sufficient experience on topiramate to gauge whether it adversely affects their mental performance, motor performance, and/or vision [see Warnings and Precautions ( 5.6 )] . Even when taking topiramate or other anticonvulsants, some patients with epilepsy will continue to have unpredictable seizures. Therefore, advise all patients taking topiramate for epilepsy to exercise appropriate caution when engaging in any activities where loss of consciousness could result in serious danger to themselves or those around them (including swimming, driving a car, climbing in high places, etc.). Some patients with refractory epilepsy will need to avoid such activities altogether. Discuss the appropriate level of caution with patients, before patients with epilepsy engage in such activities. Fetal Toxicity Inform pregnant women and women of childbearing potential that use of topiramate during pregnancy can cause fetal harm. Topiramate increases the risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), which occur early in pregnancy before many women know they are pregnant. Also inform patients that infants exposed to topiramate monotherapy in utero may be SGA [see Use in Specific Populations ( 8.1 )] . There may also be risks to the fetus from chronic metabolic acidosis with use of topiramate during pregnancy [see Warnings and Precautions ( 5.7 ), Use in Specific Populations ( 8.1 )] . When appropriate, counsel pregnant women and women of childbearing potential about alternative therapeutic options. Advise women of childbearing potential who are not planning a pregnancy to use effective contraception while using topiramate, keeping in mind that there is a potential for decreased contraceptive efficacy when using estrogen-containing or progestin-only contraceptives with topiramate [see Drug Interactions ( 7.4 )] . Encourage pregnant women using topiramate, to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations ( 8.1 )] . Decrease in Bone Mineral Density Inform the patient or caregiver that long-term treatment with topiramate can decrease bone formation and increase bone resorption in children [see Warnings and Precautions ( 5.9 )] . Negative Effects on Growth (Height and Weight) Discuss with the patient or caregiver that long-term topiramate treatment may attenuate growth as reflected by slower height increase and weight gain in pediatric patients [see Warnings and Precautions ( 5.10 )] . Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions Instruct patients that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related. Advise patients to report such reactions to a healthcare provider immediately [see Warnings and Precautions ( 5.11 )] . Serious Skin Reactions Inform patients about the signs of serious skin reactions. Instruct patients to immediately inform their healthcare provider at the first appearance of skin rash [see Warnings and Precautions ( 5.12 )] . Anaphylaxis and Angioedema Inform patients about the signs and symptoms of hypersensitivity reactions such as anaphylaxis and angioedema, which can occur with topiramate. Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions [see Warnings and Precautions ( 5.13 )] . Hyperammonemia and Encephalopathy Warn patients about the possible development of hyperammonemia with or without encephalopathy. Although hyperammonemia may be asymptomatic, clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy and/or vomiting. This hyperammonemia and encephalopathy can develop with topiramate treatment alone or with topiramate treatment with concomitant valproic acid (VPA). Instruct patients to contact their physician if they develop unexplained lethargy, vomiting, or changes in mental status [see Warnings and Precautions ( 5.14 )] . Kidney Stones Instruct patients, particularly those with predisposing factors, to maintain an adequate fluid intake in order to minimize the risk of kidney stone formation [see Warnings and Precautions ( 5.15 )] . Instructions for a Missing Dose Instruct patients that if they miss a single dose of topiramate, it should be taken as soon as possible. However, if a patient is within 6 hours of taking the next scheduled dose, tell the patient to wait until then to take the usual dose of topiramate, and to skip the missed dose. Tell patients that they should not take a double dose in the event of a missed dose. Advise patients to contact their healthcare provider if they have missed more than one dose. 20-R-04/2026
Clinical data sourced from openFDA drug labeling. For complete prescribing information, consult the full drug label.