RITODRINE USE WILL BE DISCUSSED BY FDA ADVISORY COMMITTEE OCT. 20

RITODRINE USE WILL BE DISCUSSED BY FDA ADVISORY COMMITTEE OCT. 20: the agency's Fertility and Maternal Health Drugs Advisory Committee will assess the perinatal benefits and maternal risks associated with the use of the beta-adrenergic agonist for the management of preterm labor, FDA said July 30. A notice of the meeting will appear in an upcoming issue of the Federal Register. Astra markets ritodrine as Yutopar in the U.S. under a license from Solvay-Duphar of Holland. The decision to bring ritodrine before an advisory committee was prompted by a Canadian study of the drug published in the July 30 issue of The New England Journal of Medicine. Bristol-Myers Canada markets Yutopar in Canada. Conducted by the Canadian Preterm Labor Investigators Group in six centers in Canada, the randomized, double-blind, placebo- controlled study involved ritodrine use in 708 women undergoing preterm labor. The study showed a statistically significant benefit over placebo in lengthening the gestation period: 21.4% of ritodrine patients gave birth within 48 hours, compared with 35.4% of placebo patients. However, investigators also concluded that the use of the drug resulted in "no significant beneficial effect on perinatal mortality, the frequency of prolongation of pregnancy to term, or birth weight." The infant mortality rate was 6.1% in the ritodrine group and 6.4% in the placebo group. The incidence of infant respiratory distress, patent ductus arteriosus, intraventricular hemorrhage, infection, seizures, hypotension, and hypoglycemia "was similar in both groups," the study found. In the treatment arm, 55.9% of the babies weighed less than 1500 g, versus 61.8% of the children of placebo treated mothers. Aside from perinatal outcome measures, "maternal morbidity increased with the use of ritodrine in all gestational-age groups," the study states. Adverse events included chest pain, cardiac arrhythmias, palpitation, dyspnea, nausea, vomiting, tremor, and hyperglycemia. There was one case of pulmonary edema in the treatment group. Yutopar labeling contains a boxed warning that pulmonary edema is a possible side effect in the mother. Astra said that the NEJM study focused on outcomes different from those for which Yutopar efficacy is claimed; specifically, the firm said the drug does not claim to reduce infant mortality or bring pregnancies to term. Approved labeling states that Yutopar is indicated "for the management of preterm labor in suitable patients" and "will decrease uterine activity and thus prolong gestation in the majority of such patients." The "incidence of neonatal and respiratory distress syndrome increases when the normal gestation period is shortened," the labeling says. Ritodrine is the only tocolytic agent marketed in the U.S. Astra said that the extra time to delivery afforded by Yutopar therapy can be used to administer a full course of glucocorticoid injections, which could help prevent infant respiratory distress syndrome. In addition, the delay of delivery can allow the mother to be transferred to a facility equipped to treat premature infants. The Canadian researchers did not rule out Astra's assertions, but called for more studies. The article states: "It is probable that more liberal use of glucocorticoids, in conjunction with tocolytic treatment that is effective in delaying delivery for 48 hours, might have substantial benefit." Corticoid use was not part of the study protocol. Future trials might investigate the role of ritodrine "in facilitating the transfer of a woman who is in danger of delivering prematurely to a tertiary care center," the authors suggest. The authors conclude that it is "important that trials be conducted to determine the effects of other interventions that might effectively use the time gained [by ritodrine use] to improve perinatal outcome." In the same issue of NEJM, an editorial by Kenneth Leveno, MD, and Gary Cunningham, MD, states that in combination with previous data on the safety and efficacy of ritodrine, the Canadian study "compels us to ask that the FDA reappraise the vanishingly small neonatal benefits in the light of the substantial maternal risks of ritodrine." Based on an earlier study, Cunningham and Leveno estimated the annual ritodrine-treated patient population at approximately 100,000. Astra disputes that figure, saying the actual population is much lower, at approximately 17,000 to 20,000 patients treated annually in the U.S. Astra said its U.S. Yutopar sales are less than $5 mil. a year.

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