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Executive Summary

SANDOZ PARLODEL POSTPARTUM LACTATION INDICATION: FORMAL FDA ACTION will occur before the end of the year. Pursuant to a decision made in 1989, FDA said Sept. 3 that it plans to publish a Notice of Opportunity for Hearing proposing the withdrawal of the lactation prevention indication some time in the "next few months." FDA's decision to begin formal action to delete the lactation prevention indication for Parlodel (bromocriptine mesylate) was made at a meeting of Commissioner Keeler's staff held Sept. 2. The meeting followed the same-day receipt of a citizen's petition from Public Citizen's Health Research Group urging the agency to "complete the indication change process begun four years ago." The Center for Drug Evaluation & Research decided in 1989 to propose a hearing after informal efforts to have Sandoz delete the indication failed. In a Sept. 2 response to the HGR petition, Sandoz said: "For Sandoz the safety of patients taking any of its medications is paramount, and the company wholeheartedly rejects any allegations that it places business decisions above patients' lives." The company emphasized that it "strongly recommends that all women capable of breast-feeding do so, but we support the individual rights of women to consult with their physicians in selecting appropriate medical treatment." The company is also "committed to working with the FDA and all other interested parties to ensure the safe and effective use of our products." Parlodel is currently indicated "for the prevention of physiological lactation (secretion, congestion, and engorgement) occurring after parturition when the mother elects not to breast feed the infant, or when breast feeding is contraindicated, or... after stillbirth or abortion." Parlodel is also indicated, and is primarily sold, as a treatment for Parkinson's disease, acromegaly, and various hyperprolactinemia-associated dysfunctions. The use of Parlodel has been associated with strokes, myocardial infarction, seizures, hypertension and psychosis, and since the approval of the lactation suppression indication in 1980, the labeling has been changed twice, in 1983 and 1985, to strengthen statements about adverse reactions. FDA's Fertility & Maternal Health Drugs Advisory Committee met in June 1988 to consider the adverse reaction reports and review the validity of the lactation suppression indication. While expressing some doubt about the necessity of the drug, the committee agreed there was no reason to doubt the efficacy presumed in FDA's approval of the indication, but it postponed an in-depth discussion of safety considerations pending the results of Sandoz' ongoing FDA-requested epidemiology study ("The Pink Sheet" June 6, 1988, T&G-9). The panel met again in June 1989 and unanimously recommended that Parlodel not be used for the prevention of postpartum lactation, having decided that the risk-benefit profile did not warrant use of the drug for the temporary natural condition ("The Pink Sheet" June 5, 1989, T&G-11). The committee also agreed that the various sex hormone drugs approved for the prevention of postpartum breast engorgement should not be allowed for that indication. Following the 1989 advisory committee meeting, FDA informally requested that companies marketing drugs for the prevention of postpartum breast engorgement remove the indication from their labeling. The other manufacturers at the time -- Merrell Dow, Squibb, Brown Pharmaceutical, Schering, ICN Pharmaceuticals and Ciba -- complied with FDA's request, but Sandoz did not, and, following a meeting with Sandoz representatives in September 1989, FDA issued a formal request to Sandoz by letter. At that time, FDA determined that if Sandoz did not comply, the agency would issue a notice of opportunity for hearing on the proposal to withdraw the indication ("The Pink Sheet" Sept. 18, 1989, T&G-15). Sandoz turned down FDA's request, responding: "Because we believe that Parlodel continues to be safe and effective for its labeled indication and that there is no basis for withdrawal of the NDA [under the FD&C Act], we respectfully decline to withdraw the indication at this time." The company petitioned FDA in May 1990 against withdrawing the indication, arguing that by law, FDA's determination of an "unacceptable risk/benefit ratio must be based on new scientific evidence, or an objectively determined change in circumstance (e.g., a new safety of efficacy concern or a safer drug approved for the same indication)." Throughout its contact with FDA on this issue, Sandoz argued that additional labeling changes and educational programs can address the concerns of FDA and the advisory committee. The company proposed preparing a patient information booklet discussing the benefits of breastfeeding and modifying labeling to de-emphasize elective use of Parlodel postpartum. Current Parlodel labeling advises that "the physician should keep in mind that the incidence of significant painful engorgement is low and usually responsive to appropriate supportive therapy [i.e., breast-binders, ice packs and OTC NSAIDS or acetaminophen]." Labeling also notes that once Parlodel therapy is stopped, "18% to 40% of patients experience rebound of breast secretion, congestion or engorgement, which is usually mild to moderate in severity." HRG's petition charges that "FDA has failed to follow through with its own procedural outline" as set out in 1989 and "should immediately publish the NOOH...and notify all physicians of the indication change via the FDA Drug prevent any more women from being killed or otherwise harmed by this unnecessary medication." HRG estimates that there have been 220 bromocriptine-related adverse events reports filed since June 1989 for women under 50, including 13 deaths, 68 hospitalizations and "at least 14 disabling injuries." HRG calculates that about 300,000 women are prescribed bromocriptine each year for the prevention of postpartum breast engorgement, out of about 1.1 mil. total prescriptions for the drug. Revenues from the lactation indication are therefore about $12.5 mil. annually, HRG estimates. Athena Neurosciences markets a generic bromocriptine through its Athenaline, which is made by Sandoz subsidiary Creighton Products.

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