FDA NEWS: U.S. Department of Healthand Human Services

FDA Approves New Labels for Estrogen and Estrogen with Progestin Therapies for Postmenopausal Women Following Review of Women's Health Initiative Data

The Food and Drug Administration (FDA) today is advising women and health care professionals about important new safety changes to labeling of all estrogen and estrogen with progestin products for use by postmenopausal women. These changes reflect FDA's analysis of data from the Women's Health Initiative study (WHI), a landmark study sponsored by the National Institutes of Health that raised concern about risks of using these products.

FDA's labeling revisions are part of a series of actions to provide risk management information to women and advice to health care providers who prescribe these estrogen and estrogen with progestin-containing drug products for postmenopausal women. FDA will also be issuing updated guidances for manufacturers of estrogen and estrogen with progestin products regarding labeling of those products and development of new products for use in postmenopausal women. FDA's new labeling changes include a new boxed warning that reflects new risk information and changes to the approved indications to emphasize individualized decisions that appropriately balance the benefits and the potential risks of these products.

FDA Commissioner Mark McClellan, M.D, Ph.D., said, "The Women's Health Initiative Study provided valuable information about the use of estrogen and progestin therapies for postmenopausal women. A woman who is using or considering estrogens or estrogen-progestin treatment should consult with her health care provider about the implications of the new information on risks and benefits in her case.

He added, "In many cases, women will still want to rely on these products to deal with the effects of menopause. In other cases, alternative treatments will be appropriate. FDA's actions today will help inform health care providers and their patients so that they can appropriately balance the benefits and risks to make the best possible decisions about use of these drugs."

The WHI study has several components, one of which was designed to assess the effects of Prempro, a combination of estrogens plus a progestin, on the risk of developing heart disease. The Prempro arm of the WHI was halted early in July 2002 because the overall health risks, particularly the risks of invasive breast cancer and cardiovascular disease, exceeded the benefits of the drug. Estrogen and progestin hormones have never been approved by FDA for prevention of heart disease, although physicians could prescribe them "off-label" for this use.

FDA's approval for new physician prescribing information and patient information leaflets for Prempro and Premphase (containing estrogens with a progestin) and Premarin (containing estrogens) highlight this important new safety information.

FDA has also requested that all other manufacturers of estrogen and estrogen with progestin drug products for use in postmenopausal women make similar changes to the labeling for their products.

It is estimated that about ten million postmenopausal women in the United States currently use estrogen and combination estrogen with progestin products for relief of menopausal symptoms and prevention of postmenopausal osteoporosis. Estrogen products are approved for use in relieving vasomotor symptoms of menopause such as "hot flashes" and night sweats; symptoms of vulvar and vaginal atrophy such as dryness, itching, and burning; and prevention of postmenopausal osteoporosis. Because there are few alternatives for the relief of severe vasomotor symptoms and severe symptoms of vulvar vaginal atrophy, estrogens and estrogens with progestins have an important role in women's health.

The revisions for the Premarin, Prempro, and Premphase labeling build on revisions to the labeling that Wyeth Pharmaceuticals (the products' manufacturer) made in August 2002, shortly after the release of the findings from WHI. Since August, FDA has carefully reviewed the data from the WHI study and has worked with Wyeth to develop the new labeling approved today for these products.

The new boxed warning, the highest level of warning information in labeling, highlights the increased risks for heart disease, heart attacks, strokes, and breast cancer. This warning also emphasizes that these products are not approved for heart disease prevention. FDA has also modified the approved indications for Premarin, Prempro, and Premphase to clarify that these drugs should only be used when the benefits clearly outweigh risks. Of the three indications, two have been revised to include consideration of other therapies:

• Treatment of moderate to severe vasomotor symptoms (such as "hot flashes") associated with the menopause. (This indication has not changed.)
• Treatment of moderate to severe symptoms of vulvar and vaginal atrophy (dryness and irritation) associated with the menopause. When these products are being prescribed solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.
• Prevention of postmenopausal osteoporosis (weak bones). When these products are being prescribed solely for the prevention of postmenopausal osteoporosis, approved non-estrogen treatments should be carefully considered, and estrogens and combined estrogen-progestin products should only be considered for women with significant risk of osteoporosis that outweighs the risks of the drug.

To minimize the potential risks and to accomplish the desired treatment goals, the new labeling also advises
health care providers to prescribe estrogen and combined estrogen with progestin drug products at the lowest dose and for the shortest duration for the individual woman. Women who choose to take estrogens or combined estrogen and progestin therapies after discussing their treatment with their doctor should have yearly breast exams by a health care provider, perform monthly breast self-examinations, and receive periodic mammography examinations scheduled based on their age and risk factors. Women should also talk to their health care provider about other ways to reduce their risk factors for heart disease (e.g., high blood pressure, poor diet, tobacco use) and osteoporosis (e.g., an appropriate diet, use of Vitamin D and Calcium supplements, weight-bearing exercise).

FDA will update guidances to provide advice on studies needed to demonstrate safety and effectiveness of new products for these indications and provide recommendations on labeling for estrogen and estrogen with progestin products used in postmenopausal women.

FDA's review of the WHI findings leads to some important research questions for the medical community. These questions include whether lower doses of estrogen and progestin will have lower risks, if other types of estrogens and progestins or other ways of administering these drugs, such as through patches, have different risks, and how best to stop taking estrogens and progestins. FDA intends to work with researchers, sponsors and product manufacturers to encourage this further research.

Wyeth Pharmaceuticals, a division of Wyeth of St. Davids, Pa., manufactures Premarin (conjugated estrogens), and Prempro and Premphase (conjugated estrogens/medroxyprogesterone).
Further information is available online at www.fda.gov/cder/drug/infopage/estrogens_progestins/default.htm.

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