Antiepileptic Drug Linked to Metabolic Acidosis
February 23, 2009 — The antiepileptic drug zonisamide (Zonegran, Eisai, Inc, and generic versions) has been linked to metabolic acidosis in some patients, the US Food and Drug Administration (FDA) announced today. The determination was made after a review of updated clinical data.
The FDA recommends that healthcare professionals measure serum bicarbonate before initiating therapy and during treatment with zonisamide, even when symptoms are absent. Changes in product labeling are underway to reflect this new safety information, according to an alert from MedWatch, the FDA's safety information and adverse event reporting program.
According to the FDA, in adult patients, zonisamide-related decreases in serum bicarbonate were typically mild to moderate, with an average decline of about 2 mEq/L. However, some patients experienced decreases of 10 mEq/L or more below baseline.
“The risk of development of zonisamide-induced metabolic acidosis appears to be greater at higher doses of zonisamide, but can occur with doses as low as 25 mg daily,” the FDA notes in a news release.
Signs and symptoms of persistent metabolic acidosis may include hyperventilation, fatigue, and anorexia. More severe symptoms may include cardiac arrhythmias and stupor.
Pivotal, placebo-controlled trials of zonisamide did not collect serum bicarbonate data. However, in placebo-controlled trials of zonisamide monotherapy in adults with epilepsy or as prophylaxis for migraine, the incidence of a persistent treatment-emergent decrease of less than 20 mEq/L in serum bicarbonate levels ranged from 21% in patients treated with a 25-mg daily dose to 43% in patients treated with a 300-mg daily dose.
Metabolic acidosis also appeared to be more frequent and more severe in younger patients. “The relatively high frequencies of varying severities of metabolic acidosis observed in pediatric patients (compared to the frequency and severity of metabolic acidosis observed in adults) suggest that pediatric patients may be more at risk than adults to developing metabolic acidosis,” the FDA warns.
Zonisamide is indicated as adjunctive therapy in the treatment of partial seizures in adults with epilepsy.
Adverse events related to use of zonisamide should be communicated to the FDA's MedWatch reporting program by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online athttp://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, Maryland 20852-9787.