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ESTROGEN REPLACEMENT THERAPY SHOULD INCLUDE A PROGESTIN TO REDUCE RISK OF ENDOMETRIAL CANCER ADVISORY COMMITTEE SAYS; FDA TO CONSIDER COMBO NDAs

Executive Summary

Estrogen treatments for post-menopausal symptoms and osteoporosis prevention should be used in combination with progestins in women who have not had their uteri removed, FDA's Fertility & Maternal Health Drugs Advisory Committee recommended at its June 21 meeting. Although the committee lamented the lack of U.S. long-term data to support the use of progestins with estrogens, the panel agreed that the existing data were sufficient to suggest in labeling that adjuvant therapy with progestins be used on an individualized basis to reduce the risk of endometrial cancer associated with unopposed estrogen replacement therapy. For post-menopausal women who still have their uteri intact, "hormone replacement therapy is the therapy to use, not estrogen replacement therapy," FDA Endocrine & Metabolism Drug Products Division Director Solomon Sobel, MD, noted in a summary of the committee's opinion. Sobel said that labeling for estrogen products would be changed within the next six months to reflect the committee's recommendations. The committee also considered questions relating to the effects of unopposed estrogen therapy and estrogen/progestin combination therapy on endometrial cancer risk, osteoporosis, cardiovascular disease and breast cancer risk. Panel members agreed that unopposed estrogen use is associated with a significantly increased risk of endometrial cancer. However, the addition of 10 or more days of progestins to estrogen therapy leads to "almost total reversal" of the endometrial cancer risk, committee member Ann Wentz, MD, Northwestern University Medical School, noted. One of FDA's concerns is whether progestins alter the protective effect of estrogens against osteoporosis. Committee Chairman Barbara Hulka, MD, University of North Carolina, suggested that "the protective effect of ERT [estrogen replacement therapy] against osteoporosis is certainly not reduced by the addition of progestin and there could be additional protective effect." Despite the limited data currently available, the committee agreed that progestins may enhance the positive effect of estrogen therapy on bone mass. The committee also agreed that long-term, unopposed estrogen therapy is associated with a slightly increased incidence of breast cancer. "In the meta-analyses we have seen at 15 years, the [relative] risk goes to 1.3," committee member Subir Roy, MD, University of Southern California School of Medicine, pointed out. Although some studies presented at the meeting suggest a slightly increased breast cancer risk with the addition of progestins, the committee concluded that the question is "unanswerable by the data available." The committee concluded that it is unclear what effect the addition of progestins will have on the cardioprotective effect of estrogens. Data presented to the committee show that progestins tend to neutralize estrogen's effect of increasing HDL- cholesterol. Committee member Arthur Haney, MD, Duke Medical Center, however, pointed out that progestins may have a negative effect on lipids but long-term data has not been collected on whether progestins affect cardiovascular events such as stroke and myocardial infarction. Conjugated estrogens (Wyeth-Ayerst's Premarin) have been shown in studies to reduce cardiovascular mortality by up to 50%. The same advisory committee recommended in June 1990 that labeling reflect this benefit ("The Pink Sheet" June 18, 1990, p. 5). Wyeth-Ayerst is still negotiating with FDA to include data on Premarin's cardiovascular benefits in labeling. FDA also asked the committee to evaluate whether there is enough background data on estrogen plus progestin therapy to warrant consideration of NDAs for estrogen/progestin combination therapies. The committee agreed that there is enough information to consider such NDAs although they could not recommend what estrogen/progestin regimens would be acceptable. Fertility & Maternal Health Drugs Supervisory Medical Officer Philip Corfman, MD, assured the committee that "if [FDA] consider[s] an NDA, [the agency] will come to this committee."
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