Topamax Adverse Reactions

The following serious adverse reactions are discussed in more detail in Precautions: Acute Myopia and Secondary Angle Closure Glaucoma; Visual Field Defects; Oligohidrosis and Hyperthermia; Metabolic Acidosis; Suicidal Behavior and Ideation; Cognitive/Neuropsychiatric Adverse Reactions; Decrease of Bone Mineral Density; Negative Effects on Growth (Height and Weight); Serious Skin Reactions; Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid [VPA] Use); Kidney Stones; Hypothermia with Concomitant Valproic Acid (VPA) Use.
The data described in the following sections were obtained using TOPAMAX Tablets.
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 TOPAMAX group and at an incidence higher (≥10%) than in the 50 mg/day group were: paresthesia, weight loss and anorexia (see Table 9).
Approximately 21% of the 159 adult patients in the 400 mg/day group who received TOPAMAX as monotherapy in Study 1 discontinued therapy due to adverse reactions. The most common (≥2% more frequent than low-dose 50 mg/day TOPAMAX) 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 TOPAMAX group and at an incidence higher (≥10%) than in the 50 mg/day group were fever and weight loss (see Table 9).
Approximately 14% of the 77 pediatric patients in the 400 mg/day group who received TOPAMAX 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 TOPAMAX) adverse reactions resulting in discontinuation were difficulty with concentration/attention, fever, flushing, and confusion.
Table 9 presents the incidence of adverse reactions occurring in at least 3% of adult and pediatric patients treated with 400 mg/day TOPAMAX and occurring with greater incidence than 50 mg/day TOPAMAX. (See Table 9.)

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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 TOPAMAX 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 TOPAMAX or placebo.
The most common adverse reactions in the controlled clinical trial that occurred in adult patients in the 200-400 mg/day TOPAMAX 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 10).
Table 10 presents the incidence of adverse reactions occurring in at least 3% of adult patients treated with 200 to 400 mg/day TOPAMAX 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 TOPAMAX 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. (See Table 10.)

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In controlled clinical trials in adults, 11% of patients receiving TOPAMAX 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 TOPAMAX 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 TOPAMAX 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 TOPAMAX group with an incidence higher (≥10%) than in the placebo group were: fatigue and somnolence (Table 11).
Table 11 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 TOPAMAX and was greater than placebo incidence. (See Table 11.)

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None of the pediatric patients who received TOPAMAX 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 TOPAMAX 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 12).
Table 12 includes those adverse reactions that occurred in the placebo-controlled trials where the incidence in any TOPAMAX 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 TOPAMAX dosing (200 mg daily) compared to the incidence of these adverse reactions at the recommended dosing (100 mg daily). (See Table 12.)

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Of the 1,135 patients exposed to TOPAMAX in the adult placebo-controlled studies, 25% of TOPAMAX-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 TOPAMAX-treated patients included paresthesia (7%), fatigue (4%), nausea (4%), difficulty with concentration/attention (3%), insomnia (3%), anorexia (2%), and dizziness (2%).
Patients treated with TOPAMAX 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, TOPAMAX 50, 100, and 200 mg groups, respectively.
Increased Risk for Bleeding: TOPAMAX 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 TOPAMAX 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 TOPAMAX and placebo was 0.3% versus 0.2% for adult patients, and 0.4% versus 0% for pediatric patients.
Adverse bleeding reactions reported with TOPAMAX 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, TOPAMAX was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies [see Metabolic Acidosis, Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use) under Precautions]. Controlled trials of adjunctive TOPAMAX treatment of adults for partial-onset seizures showed an increased incidence of markedly decreased serum phosphorus (6% TOPAMAX versus 2% placebo), markedly increased serum alkaline phosphatase (3% TOPAMAX versus 1% placebo), and decreased serum potassium (0.4% TOPAMAX versus 0.1% placebo).
Pediatric Patients: In pediatric patients (1-24 months) receiving adjunctive TOPAMAX for partial-onset seizures, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with TOPAMAX (vs placebo) for the following clinical laboratory analytes: creatinine, BUN, alkaline phosphatase, and total protein, The incidence was also increased for a decreased result for bicarbonate (i.e., metabolic acidosis), and potassium with TOPAMAX (vs placebo) [see Use in Children under Precautions]. TOPAMAX is not indicated for partial-onset seizures in pediatric patients less than 2 years of age.
Postmarketing Experience: The following adverse reactions have been identified during post approval use of TOPAMAX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Body as a Whole - General Disorders: oligohydrosis and hyperthermia [see Oligohidrosis and Hyperthermia under Precautions], hyperammonemia, hyperammonemic encephalopathy [see Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use) under Precautions], hypothermia with concomitant valproic acid [see Hypothermia with Concomitant Valproic Acid Use under Precautions].
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 Serious Skin Reactions under Precautions], pemphigus.
Urinary System Disorders: kidney stones, nephrocalcinosis [see Metabolic Acidosis and Kidney Stones under Precautions].
Vision Disorders: acute myopia, secondary angle closure glaucoma [see Acute Myopia and Secondary Angle Closure Glaucoma Syndrome under Precautions], 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.