Topamax

[Topiramate]

Warnings & Precautions
WARNINGS

Metabolic Acidosis

Hyperchloremic, non-anion gap, metabolic acidosis (i. e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) is associated with topiramate treatment. This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of topiramate on carbonic anhydrase. Such electrolyte imbalance has been observed with the use of topiramate in placebo-controlled clinical trials and in the post-marketing period.

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Generally, topiramate-induced metabolic acidosis occurs early in treatment although cases 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 to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, surgery, ketogenic diet, or drugs) may be additive to the bicarbonate lowering effects of topiramate.

In adults, the incidence of persistent treatment-emergent decreases in serum bicarbonate (levels of <20 mEq/ L at two consecutive visits or at the final visit) in controlled clinical trials for adjunctive treatment of epilepsy was 32% for 400 mg/ day, and 1% for placebo. Metabolic acidosis has been observed at doses as low as 50 mg/ day. 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 3% for 400 mg/ day, and 0% for placebo.

Serum bicarbonate levels have not been systematically evaluated at daily doses greater than 400 mg/ day. In pediatric patients (< 16 years of age), the incidence of persistent treatment-emergent decreases in serum bicarbonate in placebo-controlled trials for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures was 67% for TOPAMAX (at approximately6 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 11% for TOPAMAX and 0% for placebo.

Cases of moderately severe metabolic acidosis have been reported in patients as young as 5 months old, especially at daily doses above 5 mg/ kg/ day. Although not approved for the prophylaxis of migraine, the incidence of persistent treatment-emergent decreases in serum bicarbonate in placebo-controlled trials for adults for prophylaxis of migraine was 44% for 200 mg/ day, 39% for 100 mg/ day, 23% for 50 mg/ day, and 7% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i. e., absolute value <17 mEq/ L and >5 mEq/ L decrease from pre-treatment) in these trials was 11% for 200 mg/ day, 9% for 100 mg/ day, 2% for 50 mg/ day, and <1% for placebo.

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