Kenyan Health Patient Information Leaflet
Therapeutic agent (verify pharmacological class)
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.
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 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 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 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 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 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 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. 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 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 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) ].
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 Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 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 to 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…
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Topiramate tablets, USP are available as debossed, film-coated, circular tablets in the following strengths and colors: 25 mg white (coded “S” on one side; “707” on the other) They are supplied as follows: 25 mg tablets Bottles of 30..............NDC 43063-998-30 Bottles of 60..............NDC 43063-998-60 16.2 Storage and Handling Store topiramate tablets at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Protect from moisture. Dispense in a tight container.