November 13, 1997

Dear Colleague:

The Food and Drug Administration (FDA) would like to call to your attention concerns about subcutaneous administration, via infusion pump, of terbutaline sulfate for the treatment and prevention of preterm labor (tocolytic therapy).

Terbutaline sulfate, in various dosage forms, has been approved by FDA for the treatment of asthma. Adequate data establishing the safety and effectiveness of the use of terbutaline as a tocolytic agent have not been submitted to FDA. Thus, the use of terbutaline sulfate to treat preterm labor is an unapproved or "off-label" use. The only drug product currently approved for tocolytic therapy is ritodrine hydrochloride injection (Yutopar Intravenous Injection, manufactured by Astra), and it is approved for intravenous use only.

FDA is concerned about the promotion and increasingly widespread use of subcutaneous terbutaline delivered by infusion pump for the treatment/prevention of preterm labor. The approved labeling for terbutaline sulfate injection (Brethine, manufactured by CibaGeneva Pharmaceuticals, and Bricanyl, marketed by Hoechst Marion Roussel), states that the drug should not be used for the management of preterm labor. Infusion pumps are separately reviewed by FDA, and they are not labeled for subcutaneous administration of terbutaline.

Based on information available to the Agency, as well as a review of the published literature, it is clear that the demonstrated value of tocolytics in general is limited to an initial, brief period of treatment, probably no more than 48-72 hours. No benefit from prolonged treatment has been documented. In addition, the safety of long-term subcutaneous administration of terbutaline sulfate, especially on an outpatient basis, has not been adequately addressed.

Published reports on the safety of this use are seriously hampered by methodologic inadequacies. It appears that women receiving continuous subcutaneous terbutaline sulfate infusions experience side-effects and complications similar to those experienced by women receiving terbutaline and other beta-sympathomimetics intravenously. Complications include chest pain, tachycardia, dyspnea, and pulmonary edema. At least one maternal death occurred during outpatient use of a continuous infusion of terbutaline sulfate by subcutaneous pump. The impact of long-term use on maternal glucose metabolism and the risks of prolonged exposure of the fetus are largely unknown.

In June 1995, the American College of Obstetrics and Gynecology (ACOG) issued Technical Bulletin Number 206 which addresses preterm labor and, specifically, the use of tocolytic agents to manage uterine contractions. This bulletin notes that intermittent administration of subcutaneous terbutaline has been proposed as an alternative to oral maintenance therapy in certain patients. As stated in the Technical Bulletin, the ACOG found no clinical evidence to support the efficacy of this approach. Further, the bulletin states, "To date, no studies have convincingly demonstrated an improvement in survival or any index of long-term neonatal outcome with the use of tocolytic therapy. On the other hand, the potential damages of tocolytic therapy to the mother and neonate are well documented."

In the absence of data establishing the effectiveness and safety of the drug/device, FDA is alerting practitioners, home health care agencies, insurance carriers, and others that continuous subcutaneous administration of terbutaline sulfate has not been demonstrated to be effective and is potentially dangerous. FDA is investigating the promotional activities of companies providing tocolytic therapy services. We encourage health care professionals to report adverse events associated with the use of terbutaline sulfate as a tocolytic agent to the FDA's MedWatch program at 1-800-FDA-1088/FAX 1-800-FDA-0178. This is a voluntary system of reporting adverse events and product problems to FDA.

If you have comments and concerns about this issue, please contact the FDA Office of Health Affairs, Medicine Staff, telephone number (301) 443-5470.

Sincerely yours,

Stuart L. Nightingale, M.D.
Associate Commissioner
for Health Affairs

---