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ASTRA’s I.V. YUTOPAR (RITODRINE) USEFUL IN DEFINED PRETERM LABOR POPULATION -- ADVISORY CMTE.; AGENCY WOULD ACCEPT LITERATURE-BASED SNDA FOR TERBUTALINE

Executive Summary

The I.V. form of Astra's Yutopar (ritodrine) is useful in a defined subset of preterm labor patients, FDA's Fertility & Maternal Health Drugs Advisory Committee concluded unanimously at its Oct. 29 meeting. Defining the population most likely to benefit from Yutopar, the committee voted unanimously to endorse the proposed recommendation of Committee Chairman Ezra Davidson, MD, Charles R. Drew Post-graduate Medical School, Los Angeles, who said: "Considering the risks, the benefit [of I.V. Yutopar] is best realized in preterm labor in pregnancies 33 weeks or less in labors that are 4 cm or less of cervical dilation without premature rupture of the membrane." The committee's defined population for I.V. Yutopar treatment was similar to that outlined in a review of all clinical data on the drug by FDA's Phill Price, MD. He concluded that "ritodrine given I.V. inhibits preterm labor for at least 48 hours" and that "data only demonstrate improvement of birth weight beyond 2,500 gm, improvement of severe neonatal respiratory disorders and decreased perinatal mortality in patients treated before 33 weeks." The meeting was prompted by a study published in the July 30 issue of The New England Journal of Medicine by the Canadian Preterm Labor Investigator's Group and an accompanying editorial critical of ritodrine. The placebo-controlled study in 708 women in preterm labor found that while ritodrine delayed birth in a significant number of patients for at least 48 hours, there was no difference between placebo and treatment groups in perinatal mortality, the frequency of prolongation of pregnancy to term or birth weight ("The Pink Sheet" Aug. 3, T&G-6). The results of the study are similar to those of previous efficacy trials. The committee agreed with member Cassandra Henderson, MD, who said ritodrine "has been shown to be clearly beneficial for the first 24 to 48 hours and since a number of patients in preterm labor are at hospitals not equipped to handle babies in the 24 to 34 week range, it would certainly allow time for maternal transfer." She added that "it would also allow for the institution of glucocorticoid therapy." While I.V. ritodrine is efficacious, the usefulness of oral ritodrine once the labor is stabilized is in question. The committee voted unanimously that oral ritodrine "does not affect the course of preterm labor at current dose levels" and "does not have a place in obstetric practice" at its current dosage levels. FDA's Price concluded that the efficacy of oral ritodrine "has not been clearly established." Steve Caritis, MD, Magee Women's Hospital, Pittsburgh, noted that "the reason the oral preparation is so poor is not enough of it gets into the blood." The oral version would "probably be effective" if "we quintupled the dose." The committee suggested that further studies should be conducted on both I.V. and oral Yutopar to elucidate the appropriate dosage of the drug and the appropriate length of drug therapy, to compare ritodrine with other tocolytics, and to resolve the difficulty of designing a trial with appropriate statistical power to show a statistically significant difference in effect on perinatal mortality between ritodrine and placebo. Concerning the safety of ritodrine to the mother, the committee voted unanimously to recommend that FDA ask Astra to develop a patient package insert explaining the risks of the drug. Of particular concern to the committee and to the authors of the NEJM editorial was the possibility of pulmonary edema. While the committee appeared to agree with the concerns voiced in the editorial, Albert Reece, MD, Temple University, said that concern over the mother's health should be "qualified" with a statement that adverse events associated with ritodrine use "can be reduced or ameliorated by proper management" of the patient, particularly by avoiding excessive administration of I.V. fluids. Practitioners have taken note of the perceived shortcomings of ritodrine as currently dosed and moved toward more usage of alternative, off-label therapies. FDA Division of Epidemiology Technical Information Specialist Laurie Burke reviewed several drug use databases showing that "terbutaline [Ciba-Geigy's Brethine and Marion Merrell Dow's Bricanyl] is used for preterm labor to a much greater extent than is ritodrine." Magnesium sulfate is also used off-label for tocolysis. Data from the Hospital Diagnosis and Therapy Audit, taken from a panel of 50 U.S. hospitals, showed that of 7,090 women hospitalized for preterm labor, 2,454 (35%) were given oral or I.V. terbutaline or ritodrine. The 35% was composed of the 25% (1,738) who received oral terbutaline, 17% (1,221) who received injectable terbutaline, and 1% each receiving I.V. and oral ritodrine (83 and 75 patients, respectively). Some patients received more than one of the four drug/dosage forms, Burke said. FDA's Price said that "during the 1980s, several articles were published showing that terbutaline had comparable efficacy and safety to ritodrine. Two studies show that efficacy for terbutaline may be superior." Terbutaline has the "added advantage," Price said, "of being roughly six to 10 times less expensive than ritodrine." He added, however, that "no NDA has been filed in this agency for terbutaline for the treatment of preterm labor." Metabolism and Endocrine Drugs Division Director Solomon Sobel, MD, said the agency is "aware of wide and safe usage [of terbutaline] and we stand ready to evaluate an application for other indications." Alluding to FDA's stated intention of allowing the submission of supplemental NDAs based on literature reviews, Sobel said: "We have liberalized our stand. If the medical literature is greatly supportive, we can move very quickly in working on an additional indication." Sobel pointed out, however, that FDA "cannot unilaterally approve a drug -- the manufacturer must submit an application" and noted that "in the case of terbutaline there has not been great initiative" by manufacturers. "To be fair to the manufacturer," he said, "it is an area in which medical legal exposure is extremely hazardous...we can't fault the manufacturer." Ciba-Geigy's Brethine labeling includes a precaution stating that "terbutaline sulfate should not be used in tocolysis" due to "serious adverse reactions" that may occur in mother and child. Marion Merrell Dow's product labeling contains a similar warning. Ciba-Geigy said it has no plans to pursue a tocolysis indication for terbutaline. Another beta agonist for tocolysis, Altana's Delaprem (hexoprenaline), was unanimously recommended for approval by the advisory committee in February 1990 ("The Pink Sheet" Feb. 5, 1990, T&G-6). Altana's Savage Labs subsidiary said it is working on pharmacokinetic data requested by FDA and that those studies have been delayed by the difficulty of developing a reproducible assay for blood levels of hexoprenaline. That problem has been solved, the company said, and the data will be filed "very soon." The advisory committee found that the drug demonstrated a significantly better side-effect profile than ritodrine.

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