FDA Warns About CV Deaths, Risks With Obstetric Terbutaline Use

The Food and Drug Administration has issued a warning advising against the use of injectable terbutaline for preventing and for prolonged treatment of preterm labor and against any use of oral terbutaline in this setting, prompted by postmarketing reports of deaths and other serious cardiovascular events associated with the use of the drug in this setting.

"Death and serious adverse reactions, including increased heart rate, transient hyperglycemia, hypokalemia, cardiac arrhythmias, pulmonary edema, and myocardial ischemia have been reported after prolonged administration of oral or injectable terbutaline to pregnant women," according to an FDA statement issued on Feb. 17.

Based on these reports and a review of the medical literature, the agency "has concluded that the risk of serious adverse events outweighs any potential benefit to pregnant women receiving prolonged treatment with terbutaline injection (beyond 48-72 hours), or acute or prolonged treatment with oral terbutaline," the FDA said in the statement.

This is not the first FDA warning issued about the obstetrical-related risks of terbutaline, an FDA-approved treatment for bronchospasm that has been used off label to treat and prevent preterm labor and to treat uterine hyperstimulation. In 1997, the agency notified health care professionals in a letter about concerns over the safety of long-term administration of subcutaneous terbutaline and revised the drug’s labeling about the risk of serious cardiovascular adverse events associated with this use. But despite studies reporting a lack of safety and efficacy of terbutaline for the treatment of recurrent preterm labor and professional association recommendations, "prolonged use of terbutaline continues, with serious and sometimes fatal consequences," the FDA statement said.

Between 1976, when terbutaline was first marketed, and 2009, 16 maternal deaths associated with the obstetric use of terbutaline were reported to the FDA’s Adverse Event Reporting System (AERS), which included 3 in outpatients administered terbutaline via a subcutaneous pump. In 9 of the 16 cases, oral terbutaline was used alone or in combination with subcutaneous or intravenous terbutaline – including 2 cases that reported the outpatient use of oral terbutaline and 7 cases reporting inpatient use of oral terbutaline. The routes of administration for the remaining four cases were subcutaneous, intravenous, or unknown.

Between January 1998, soon after the FDA issued the warning letter, and July 2009, 12 maternal cases of serious cardiovascular events were reported to AERS, including cardiac arrhythmias, MI, pulmonary edema, hypertension, and tachycardia, associated with the use of terbutaline. Of these 12 cases, 3 were administered by a subcutaneous pump, and 5 involved oral terbutaline alone or in combination with subcutaneous terbutaline.

While there are "certain obstetrical conditions" in which health care professionals "may decide that the benefit of terbutaline injection for an individual patient in a hospital setting clearly outweighs the risk," the FDA statement said that terbutaline administered by injection or continuous infusion pump should not be used for more than 48 to 72 hours, and injectable terbutaline should not be used in outpatient settings.

These warnings are being added to a new boxed warning in terbutaline labels. The FDA says these label changes are consistent with statements from the American College of Obstetricians and Gynecologists.

Serious adverse events associated with terbutaline should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/medwatch.