Topiramate capsules is 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 )
1.1Monotherapy Epilepsy
Topiramate capsules 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.
1.2Adjunctive Therapy Epilepsy
Topiramate capsules 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.
1.3Migraine
Topiramate capsules are indicated for the preventive treatment of migraine in patients 12 years of age and older.
Contraindications
Topiramate capsules are contraindicated in patients with a history of hypersensitivity reaction to topiramate, topiramate capsules, or any of the inactive ingredients of topiramate capsules. Anaphylaxis and angioedema have occurred [see Warnings and Precautions (5.13) ] . History of hypersensitivity reaction to topiramate, topiramate capsules, or any of the inactive ingredients of topiramate capsules ( 4 , 5.13 )
Warnings and precautions
Acute myopia and secondary angle closure glaucoma: can lead to permanent visual loss; discontinue topiramate as soon as possible ( 5.1 ) Visual field defects: consider discontinuation of topiramate ( 5.2 ) Oligohidrosis and hyperthermia: monitor decreased sweating and increased body temperature, especially in pediatric patients ( 5.3 ) Metabolic acidosis: baseline and periodic measurement of serum bicarbonate is recommended; consider dose reduction or discontinuation of topiramate if clinically appropriate ( 5.4 ) Suicidal behavior and ideation: antiepileptic drugs increase the risk of suicidal behavior or ideation ( 5.5 ) Cognitive/neuropsychiatric adverse reactions: use caution when operating machinery including cars; depression and mood problems may occur ( 5.6 ) Fetal Toxicity: use during pregnancy can cause major congenital malformations, including but not limited to cleft lip and/or palate, and being small for gestational age ( 5.7 ) Withdrawal of AEDs: withdraw topiramate gradually ( 5.8 ) Decrease in Bone Mineral Density: has been shown to decrease bone mineral density and bone mineral content in pediatric patients ( 5.9 ) Negative effects on growth (height and weight): may slow height increase and weight gain; carefully monitor children receiving prolonged therapy ( 5.10 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/ Multiorgan Hypersensitivity, serious skin reactions (SJS or TEN), anaphylaxis, and angioedema: Discontinue Topiramate if an alternative etiology cannot be established ( 5.11 , 5.12 , 5.13 ) Hyperammonemia/encephalopathy: measure ammonia if encephalopathic symptoms occur ( 5.14 ) Kidney stones: avoid use with other carbonic anhydrase inhibitors, drugs causing metabolic acidosis, or in patients on a ketogenic diet ( 5.15 ) Hypothermia has been reported with and without hyperammonemia during topiramate treatment with concomitant valproic acid use ( 5.16 )
5.1Acute Myopia and Secondary Angle Closure Glaucoma Syndrome
A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include some or all of the following: myopia, mydriasis, anterior chamber shallowing, ocular hyperemia (redness), choroidal detachments, retinal pigment epithelial detachments, macular striae, and increased intraocular pressure.
This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults.
The primary treatment to reverse symptoms is discontinuation of topiramate as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of topiramate, may be helpful. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss.
5.2Visual Field Defects
Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during topiramate treatment, consideration should be given to discontinuing the drug.
5.3Oligohidrosis and Hyperthermia Oligohidrosis
(decreased sweating), infrequently resulting in hospitalization, has been reported in association with topiramate use. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases were reported after exposure to elevated environmental temperatures. The majority of the reports have been in pediatric patients. Patients (especially pediatric patients) treated with topiramate should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather.
Caution should be used when topiramate is given with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity.
5.4Metabolic Acidosis
Topiramate can cause hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis). This metabolic acidosis is caused by renal bicarbonate loss due to carbonic anhydrase inhibition by topiramate. Topiramate-induced metabolic acidosis can occur at any time during treatment. Bicarbonate decrements are usually mild-moderate (average decrease of 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L.
Conditions or therapies that predispose patients to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet, or specific drugs) may be additive to the bicarbonate lowering effects of topiramate. Metabolic acidosis was commonly observed in adult and pediatric patients treated with topiramate in clinical trials. The incidence of decreased serum bicarbonate in pediatric trials, for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial-onset seizures was as high as 67% for topiramate (at approximately 6 mg/kg/day), and 10% for placebo.
The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value < 17 mEq/L and ≥5 mEq/L decrease from pretreatment) in these trials was up to 11%, compared to ≤ 2% for placebo. Manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis, and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures [see Warnings and Precautions ( 5.9 , 5.15 )] .
A one-year, active-controlled study of pediatric patients treated with topiramate demonstrated that topiramate decreased lumbar spine bone mineral density and that this lumbar spine bone mineral density decrease was correlated (using change from baseline for lumbar spine Z score at final visit versus lowest post-treatment serum bicarbonate) with decreased serum bicarbonate, a reflection of metabolic acidosis [see Warnings and Precautions (5.9) , Use in Specific Populations (8.4) ] .
Chronic metabolic acidosis in pediatric patients may also reduce growth rates, which may decrease the maximal height achieved. Long-term, open-label treatment of pediatric patients 1 to 24 months old with intractable partial epilepsy, for up to 1 year, showed reductions from baseline in length, weight, and head circumference compared to age and sex- matched normative data, although these patients with epilepsy are likely to have different growth rates than normal 1 to 24 month old pediatrics.
Reductions in length and weight were correlated to the degree of acidosis [see Use in Specific Populations (8.4) ] . Topiramate treatment that causes metabolic acidosis during pregnancy can possibly produce adverse effects on the fetus and might also cause metabolic acidosis in the neonate from possible transfer of topiramate to the fetus [see Warnings and Precautions (5.7) , Use in Specific Populations (8.1) ] . Measurement of Serum Bicarbonate in Epilepsy and Migraine Patients Measurement of baseline and periodic serum bicarbonate during
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Interactions
Contraceptives: decreased contraceptive efficacy and increased breakthrough bleeding, especially at doses greater than 200 mg/day ( 7.4 ) Monitor lithium levels if lithium is used with high-dose topiramate ( 7.7 )
7.1Antiepileptic Drugs
Concomitant administration of phenytoin or carbamazepine with topiramate resulted in a clinically significant decrease in plasma concentrations of topiramate when compared to topiramate given alone. A dosage adjustment may be needed [see Dosage and Administration (2.1) , Clinical Pharmacology (12.3) ]. Concomitant administration of valproic acid and topiramate has been associated with hypothermia and hyperammonemia with and without encephalopathy.
Examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions ( 5.14 , 5.16 ), Clinical Pharmacology (12.3) ] .
7.2Other 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. Therefore, patients given topiramate concomitantly with another carbonic anhydrase inhibitor should be monitored particularly closely for the appearance or worsening of metabolic acidosis [see Clinical Pharmacology (12.3) ] .
7.3CNS Depressants
Concomitant administration of topiramate and alcohol or other CNS depressant drugs 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, topiramate should be used with extreme caution if used in combination with alcohol and other CNS depressants.
7.4Contraceptives
The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking contraceptive products with topiramate. 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 [see Clinical Pharmacology (12.3) ].
7.5Hydrochlorothiazide (HCTZ) Topiramate
C max and AUC increased when HCTZ was added to topiramate. The clinical significance of this change is unknown. The addition of HCTZ to topiramate may require a decrease in the topiramate dose [see Clinical Pharmacology (12.3) ] .
7.6Pioglitazone
A decrease in the exposure of pioglitazone and its active metabolites were noted with the concurrent use of pioglitazone and topiramate in a clinical trial. The clinical relevance of these observations is unknown; however, when topiramate is added to pioglitazone therapy or pioglitazone is added to topiramate therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state [see Clinical Pharmacology (12.3) ] .
7.7Lithium
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 topiramate [see Clinical Pharmacology (12.3) ] .
7.8Amitriptyline
Some patients may experience a large increase in amitriptyline concentration in the presence of topiramate and any adjustments in amitriptyline dose should be made according to the patient's clinical response and not on the basis of plasma levels [see Clinical Pharmacology (12.3) ] .
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 TOPAMAX 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 Advagen Pharma Ltd,. at +1-866-488-0312 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical 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 Insomnia 1 3 6 8 11 9 Decrease in libido Mood problems 1 8 0 2 3 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 200-400 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 – 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
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Composition
Active ingredients
TOPIRAMATE 25MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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