FDA: Zonisamide MedWatch [Alerta]

Zonisamide (marketed as Zonegran, and generics)
Audience: Neurological healthcare professionals
[Posted 02/23/2009] FDA notified healthcare professionals that updated clinical data has determined that treatment with zonisamide, indicated as adjunctive therapy in the treatment of partial seizures in adults with epilepsy, can cause metabolic acidosis in some patients. Patients with predisposing conditions or therapies may be at greater risk for developing metabolic acidosis and the risk of zonisamide-induced metabolic acidosis appears to be more frequent and severe in younger patients. FDA recommends that healthcare professionals measure serum bicarbonate before starting treatment and periodically during treatment with zonisamide, even in the absence of symptoms and is working with the makers of zonisamide to revise the product labeling to reflect this new safety information. The notification includes recommendations for healthcare providers, information for patients, and a data summary.

[February 19, 2009 - Information for Healthcare Professionals: Zonisamide (marketed as Zonegran, and generics) - FDA]

Information for Healthcare Professionals
Zonisamide (marketed as Zonegran, and generics)
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FDA ALERT [February 23, 2009]: Following a review of updated clinical data, the FDA has determined that treatment with zonisamide can cause metabolic acidosis in some patients. Zonisamide is indicated as adjunctive therapy in the treatment of partial seizures in adults with epilepsy.

Metabolic acidosis is a disturbance in the body's acid-base balance that results in excessive acidity of the blood. Metabolic acidosis is diagnosed by laboratory tests measuring the serum bicarbonate level in the blood to determine the presence and severity of metabolic acidosis.

Metabolic acidosis can result in hyperventilation, and non-specific symptoms such as fatigue and anorexia, or more severe symptoms including cardiac arrhythmias or stupor. Chronic metabolic acidosis can have adverse effects on the kidneys and on bones, and can retard growth in children. Patients with predisposing conditions or therapies, including renal disease, severe respiratory disorders, diarrhea, surgery, ketogenic diet, or certain other drugs may be at greater risk for developing metabolic acidosis following treatment with zonisamide. The risk of zonisamide-induced metabolic acidosis appears to be more frequent and severe in younger patients.

The FDA recommends that healthcare professionals measure serum bicarbonate before starting treatment and periodically during treatment with zonisamide, even in the absence of symptoms. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing zonisamide (using dose tapering), and modifying the patient’s antiepileptic treatment as appropriate. If the decision is made to continue patients with metabolic acidosis on zonisamide, then alkali treatment should be considered.

The FDA is working with the makers of zonisamide to revise the product labeling to reflect this new safety information.

This information reflects FDA’s current analysis of data available to FDA concerning this drug. FDA intends to update this sheet when additional information or analyses become available.
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To report any unexpected adverse or serious events associated with the use of this drug, please contact the FDA MedWatch program and complete a form on line at http://www.fda.gov/medwatch/report/hcp.htm or report by fax to 1-800-FDA-0178, by mail using the postage-paid address form provided on line, or by telephone to 1-800-FDA-1088.

Recommendations and Information for Healthcare Providers to consider when prescribing zonisamide (marketed as Zonegran) and generics:

Zonisamide can cause metabolic acidosis, characterized by hyperchloremia and decreased serum bicarbonate. Metabolic acidosis is often asymptomatic.

Generally, zonisamide-induced metabolic acidosis occurs early in treatment, but may occur at any time during treatment.

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.

Conditions or therapies that may predispose patients to acidosis include renal disease, severe respiratory disorders, diarrhea, surgery, ketogenic diet, or other drugs (e.g. acetazolamide)

Younger patients may be at risk for zonisamide-induced metabolic acidosis. Data from one pediatric clinical trial shows a higher incidence of metabolic acidosis compared to data from trials of zonisamide in adults.

Signs and symptoms of persistent metabolic acidosis may include hyperventilation, fatigue and anorexia. More severe symptoms may include cardiac arrhythmias and stupor.

Chronic, untreated metabolic acidosis may increase the risk for kidney stones, nephrocalcinosis, and bone abnormalities (e.g., osteoporosis, osteomalacia, and rickets in pediatric patients) with an increased risk for fractures.

Chronic metabolic acidosis in pediatric patients can reduce growth rates, resulting in a reduction in the maximal height achieved. The specific effects of zonisamide on growth and bone have not been investigated.

Although the effects of metabolic acidosis from zonisamide on the fetus are not clearly known, metabolic acidosis in pregnancy (due to other causes) may affect fetal development (i.e., decreased fetal growth, decreased fetal oxygenation and fetal death) and the ability of the fetus to tolerate labor. In addition, significant amounts of zonisamide can appear in the breast milk of nursing women taking zonisamide, and the effects of this exposure on the infant from metabolic acidosis, or any other cause, are unknown.

A pre-treatment (baseline) and periodic measurements of serum bicarbonate are recommended during zonisamide treatment. In addition, if signs or symptoms of metabolic acidosis are observed, serum bicarbonate should be measured.

If metabolic acidosis develops and persists, consideration should be given to reducing the dose of zonisamide, or to discontinuing zonisamide using dose tapering and modifying the patient’s treatment as appropriate. If the decision is made to continue patients with persistent acidosis on zonisamide, then alkali treatment should be considered.

Information for Patients to consider if they are taking zonisamide (marketed as Zonegran) and generics:
Zonisamide may cause a condition known as metabolic acidosis. Metabolic acidosis is a decrease in serum bicarbonate, a blood chemical, to below the normal range. Serum bicarbonate is a chemical that helps the body keep acid and base in balance. Your doctor may order a blood test to measure serum bicarbonate levels in your blood.

Generally, zonisamide-induced metabolic acidosis occurs early in treatment, but it can develop at any time during treatment.

Some symptoms of metabolic acidosis are breathing fast (hyperventilation), fatigue, and loss of appetite. More severe symptoms include an irregular heart beat or unconsciousness.

Chronic, untreated, metabolic acidosis may increase the risk of kidney stones and the risk of different types of bone diseases which may increase the risk for a bone fracture. Metabolic acidosis in pregnancy may negatively affect fetal development. In addition, zonisamide can appear in the breast milk of nursing women taking zonisamide, and the effects of this exposure on the infant are unknown.

Talk to your doctor about any medical conditions you have or medicines you may be taking since these could make metabolic acidosis worse. These are conditions such as kidney disease, severe lung disorders, diarrhea, surgery, certain kinds of diets, or other drugs (e.g. acetazolamide). Tell you doctor if you are pregnant or nursing or if you are planning to become pregnant.

Although not approved by the FDA, zonisamide is sometimes used in children. Metabolic acidosis increases the risk for slowed growth in children and could reduce the overall height that they achieve.

Data Summary
Zonisamide is an antiepileptic drug that is approved as adjunctive therapy for the treatment of partial seizures in adults with epilepsy.

Following a review of updated clinical data, the FDA has determined that treatment with zonisamide can cause metabolic acidosis in some patients.

The development of metabolic acidosis generally appears to be dose-dependent and can occur at doses as low as 25 mg daily. The zonisamide-related decreases in serum bicarbonate are usually mild to-moderate (average decrease of about 2 mEq/L) in adult patients treated with various doses of zonisamide. However, some adult patients have experienced severe serum bicarbonate decreases as much as 10 mEq/L below their baseline. Conditions or therapies that predispose patients to developing acidosis (such as renal disease, severe respiratory disorders, diarrhea, surgery, ketogenic diet, or other medications) may worsen the bicarbonate-lowering effects of zonisamide.

The pivotal, placebo-controlled trials supporting the approval of zonisamide as adjunctive epilepsy treatment in adults did not collect serum bicarbonate data.

Zonisamide is not approved for the treatment of epilepsy in pediatric patients, as monotherapy treatment of epilepsy in adults, or for migraine prophylaxis in adults. However, serum bicarbonate data have been collected in various clinical development programs for these off-label indications. These data show that zonisamide treatment can cause metabolic acidosis in these patients.

The pediatric program consisted primarily of a large open-label, uncontrolled, adjunctive treatment trial of patients aged 3-16 years with partial epilepsy. In that trial, the incidence of a persistent decrease in serum bicarbonate to levels less than 20 mEq/L was up to 90% and generally increased with higher doses. The incidence of a persistent markedly abnormally low serum bicarbonate value (less than 17 mEq/L and more than 5 mEq/L decrease from a pretreatment value of at least 20 mEq/L) was as high as 18% and appeared to increase with higher doses.

In placebo-controlled studies of zonisamide monotherapy in adults with epilepsy or as prophylaxis for migraine in adults, the incidence of a persistent treatment-emergent decrease in serum bicarbonate (to <20 mEq/L) ranged from 21% in patients treated with a 25 mg daily dose to 43% in patients treated with a 300 mg daily dose. The incidence of persistent abnormally low serum bicarbonate was 2% or less across all doses evaluated.

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 urges both healthcare professionals and patients to report side effects from the use of zonisamide (marketed as Zonegran) and its generics to the FDA's MedWatch Adverse Event Reporting program available:
online at www.fda.gov/medwatch/report.htm
by returning the postage-paid FDA form 3500 available in PDF format at www.fda.gov/medwatch/getforms.htm to 5600 Fishers Lane, Rockville, MD 20852-9787
faxing the form to 1-800-FDA-0178
by phone at 1-800-332-1088
Date created: February 23, 2009