Side Effects of Topamax (topiramate)

Topamax (topiramate) is an anticonvulsant (antiepileptic drug) used alone or with other medications to prevent and control seizures (epilepsy). Topamax is also used to prevent migraine headaches and decrease how often they occur. Topamax will not treat a migraine headache once it occurs. 

Common side effects of Topamax include:

• tiredness,
• drowsiness,
• dizziness,
• loss of coordination,
• tingling of the hands/feet,
• loss of appetite,
• bad taste in the mouth,
• diarrhea,
• weight loss,
• confusion,
• slowed thinking,
• trouble concentrating or paying attention,
• nervousness,
• memory problems, and
• speech or language problems. 

Serious side effects of Topamax include:

• signs of kidney stones (such as severe back/side/abdominal/groin pain, fever, chills, painful or frequent urination, bloody/pink urine).

Anticonvulsants such as Topamax may rarely cause:

• depression,
• suicidal thoughts/attempts, or
• other mental/mood problems.

Drug interactions of Topamax include hormonal birth control products (such as pills, patch, ring); Topamax can decrease their effectiveness. 

Combining Topamax with other products that cause drowsiness can increase the sedative effects, including:

• alcohol,
• antihistamines,
• drugs for sleep or anxiety,
• muscle relaxants, and
• narcotic pain relievers. 

During pregnancy, Topamax should be used only when clearly needed. It may harm a fetus. If you are taking Topamax to treat seizures, note that untreated seizures are a serious condition that can harm both a pregnant woman and her unborn baby, so do not stop taking Topamax unless directed by your doctor. 

Topamax passes into breast milk and may have undesirable effects on a nursing infant. Consult your doctor before breastfeeding.

The most common side effects of topiramate are:

• tiredness,
• dizziness,
• coordination problems,
• nervousness,
• nausea,
• weight loss,
• confusion,
• speech problems,
• changes in vision or
• double vision,
• tingling or prickling sensation in hands and feet,
• difficulty with memory, and
• sensory distortion.

Other important side effects include:

• increased ammonia levels,
• metabolic acidosis,
• kidney stones,
• decreased sweating, and
• increased body temperature.

The following serious adverse reactions are discussed in more detail in other sections of the labeling:

• Acute Myopia and Secondary Angle Closure Glaucoma
• Visual Field Defects
• Oligohidrosis and Hyperthermia
• Metabolic Acidosis
• Suicidal Behavior and Ideation
• Cognitive/Neuropsychiatric Adverse 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 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 5).

Approximately 21% of the 159 adult 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 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 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 5).

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 5 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.

Table 5: Adverse Reactions in the High Dose Group As Compared to the Low Dose Group, in Monotherapy Epilepsy Trials in Adult and Pediatric Patients

Adjunctive Therapy Epilepsy

Adults 16 Years of Age and Older

In pooled controlled clinical trials in adults with partial onset seizures, primary generalized tonicclonic 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 6).

Table 6 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.

Table 6: Most Common Adverse Reactions in Pooled Placebo-Controlled, Add-On Epilepsy Trials in Adults^a

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 and increased at dosages above 400 mg/day.

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 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 Topamax and was greater than placebo incidence.

Table 7: Adverse Reactions in Pooled Placebo-Controlled, Add-On Epilepsy Trials in Pediatric Patients 2 to 15 Years of Age^a,b

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 prophylaxis clinical trials (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 migraine prophylaxis clinical trials 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 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).

Table 8: Adverse Reactions in Pooled, Placebo-Controlled, Migraine Trials in Adults^a,b

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.

Pediatric Patients 12 to 17 Years of Age

In five, randomized, double-blind, placebo-controlled, parallel group migraine prophylaxis clinical trials, 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 migraine prophylaxis clinical trials in Topamax-treated pediatric patients 12 to 17 years of age, the most common adverse reactions with Topamax 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 12) in which 103 pediatric patients were treated with placebo or 50 mg or 100 mg of Topamax, 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 Topamax. Table 9 also shows adverse reactions in pediatric patients in the controlled migraine trials when the incidence in a Topamax 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 Topamax 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 in Pediatric Patients 12 to 17 Years of Age^a,b,c

In the double-blind placebo-controlled studies, adverse reactions led to discontinuation of treatment in 8% of placebo patients compared with 6% of Topamax-treated patients. Adverse reactions associated with discontinuing therapy that occurred in more than one Topamax-treated patient were fatigue (1%), headache (1%), and somnolence (1%).

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.

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). Topamax is not indicated for partial onset seizures in pediatric patients less than 2 years of age.

In pediatric patients (ranging from 6-17 years old) receiving Topamax for migraine prophylaxis, 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, 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. Topamax is not indicated for prophylaxis of migraine headache in pediatric patients less than 12 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, 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

Urinary System Disorders: kidney stones

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.

Antiepileptic Drugs

Concomitant administration of phenytoin or carbamazepine with Topamax resulted in a clinically significant decrease in plasma concentrations of topiramate when compared to Topamax given alone. A dosage adjustment may be needed.

Concomitant administration of valproic acid and Topamax 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.

CNS Depressants

Concomitant administration of Topamax 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, Topamax should be used with extreme caution if used in combination with alcohol and other CNS depressants.

Oral Contraceptives

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

Lithium

An increase in systemic exposure of lithium following Topamax doses of up to 600 mg/day can occur. Lithium levels should be monitored when co-administered with high-dose Topamax.

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. Therefore, patients given Topamax concomitantly with another carbonic anhydrase inhibitor should be monitored particularly closely for the appearance or worsening of metabolic acidosis.

Hydrochlorothiazide (HCTZ)

Topiramate Cmax and AUC increased when HCTZ was added to Topamax. The clinical significance of this change is unknown. The addition of HCTZ to Topamax may require a decrease in the Topamax dose.

Pioglitazone

A decrease in the exposure of pioglitazone and its active metabolites were noted with the concurrent use of pioglitazone and Topamax in a clinical trial. The clinical relevance of these observations is unknown; however, when Topamax is added to pioglitazone therapy or pioglitazone is added to Topamax therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.

Amitriptyline

Some patients may experience a large increase in amitriptyline concentration in the presence of Topamax and any adjustments in amitriptyline dose should be made according to the patient's clinical response and not on the basis of plasma levels.