Estrogen formulations get FDA "black-box" warning

Susan Jeffrey

January 08, 2003

Wed, 08 Jan 2003 21:45:00

Bethesda, MD - The US Food and Drug Administration has announced approval for proposed changes to the labels of estrogen and estrogen plus progestin products produced by Wyeth Pharmaceuticals (Philadelphia, PA): Premarin®, Prempro®, and Premphase®. The changes, incorporating a boxed warning that is the highest level of warning information in labeling, reflect the increased risks of heart disease, MI, stroke, and breast cancer in postmenopausal women using these products confirmed by results of the Women's Health Initiative, published July 9, 2002.

"In many cases, women will still want to rely on these products to deal with the effects of menopause," said FDA Commissioner Dr Mark McLellan in a statement from the FDA. "In other cases, alternative treatments will be appropriate. FDA's actions today will help inform healthcare 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 agency 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 of their products, the statement notes.

Never approved for CVD prevention

The statement from the FDA emphasizes that these drugs were never approved for heart disease prevention and notes that the agency has also modified the approved indications for these drugs to stress they should be used only when the benefits outweigh the risks. Of the 3 approved indications, the last 2 have been altered to include consideration of alternative therapies:

Treatment of moderate to severe vasomotor symptoms (eg, "hot flashes") associated with menopause.

Treatment of moderate to severe symptoms of vulvar and vaginal atrophy (dryness and irritation) associated with menopause. When these products are being prescribed solely for the treatment 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 nonestrogen treatments should be carefully considered, and estrogens and combined estrogen-progestin products should be considered only for women with significant risk of osteoporosis that outweighs the risks of the drugs.

A "Dear Doctor" letter was sent by Wyeth on January 6, 2003 to inform healthcare providers of the new boxed warning, which the company notes contains risk information that after August 2002 had already appeared in other sections of the labeling. The estrogen-only product contains the same warning, as well as the previously known risk of endometrial cancer when estrogen is used without a progestin.

The new labeling advises women who do choose to take these products to take them at the lowest dose and for the shortest duration possible. Such women should also have yearly breast exams by a healthcare provider, perform monthly breast self-exams, and receive periodic mammography based on their age and risk factors, the FDA statement notes. They should also discuss with their doctors other ways of reducing cardiovascular and osteoporotic risks.

The FDA plans to update guidances to provide advice on studies needed to demonstrate safety and effectiveness of new products for these indications and to support ongoing research into questions that remain about estrogen and estrogen-plus-progestin therapies, including whether lower doses or other modes of administration would have different risks, and how best to stop therapy.

Boxed warning language

Cardiovascular and other risks

Estrogens with or without progestins should not be used for the prevention of cardiovascular disease.

The Women's Health Initiative (WHI) reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women during 5 years of treatment with conjugated equine estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg) relative to placebo (see CLINICAL PHARMACOLOGY, Clinical Studies). Other doses of conjugated estrogens and medroxyprogesterone acetate and other combinations of estrogens and progestins were not studied in the WHI, and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

Related links


2. [Heartwire > News; Oct 29, 2002]

3. [Heartwire > News; Oct 17, 2002]

4. [Heartwire > News; Aug 16, 2002]

5. [Heartwire > News; Jul 12, 2002]

6. [Heartwire > News; Jul 9, 2002]


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