(topiramate) Tablets/Sprinkle Capsules
Drug Approval Classification: Supplemental New Drug Application (Approval Date: 12/18/03)
New Warnings: Topamax (topiramate) causes hyperchloremic, non-anion gap metabolic acidosis (decreased serum bicarbonate), the details of which are highlighted in a revised Warning section:
Hyperchloremic, non-anion gap, metabolic acidosis (ie, 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 postmarketing period. 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 2 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 (ie, 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 approximately 6 mg/kg/day) and 10% for placebo. The incidence of a markedly abnormally low serum bicarbonate (ie, 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 of age, 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 (ie, absolute value < 17 mEq/L and > 5 mEq/L decrease from pretreatment) in these trials was 11% for 200 mg/day, 9% for 100 mg/day, 2% for 50 mg/day, and < 1% for placebo.
Some 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. Chronic metabolic acidosis in pediatric patients may also reduce growth rates. A reduction in growth rate may eventually decrease the maximal height achieved. The effect of topiramate on growth and bone-related sequelae has not been systematically investigated.
Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering). If the decision is made to continue patients on topiramate in the face of persistent acidosis, alkali treatment should be considered.
Topamax (topiramate) Tablets/Sprinkle Capsules Labeling
Topamax (topiramate) Tablets/Sprinkle Capsules
Medscape Pharmacists. 2004;5(1) © 2004 Medscape
Cite this: January 2004 - Medscape - Jan 26, 2004.