1. What is FDA announcing today?
The FDA is continuing to encourage all manufacturers of estrogen and estrogen with progestin drug products indicated for use by postmenopausal women to update the labeling for their products. The Women’s Health Initiative (WHI) trial about estrogens and progestins continues to have significant public health implications for postmenopausal women. As new study results from the WHI become available, FDA is strongly recommending that sponsors update the labeling for their estrogen- and progestin-containing drug products to include new information from these studies.
Access to the most current information available is important to health care providers and postmenopausal women who are prescribed estrogen- and progestin-containing drug products. This information will allow individuals to understand the risks of these products and make appropriate health care decisions.
2. What prompted FDA to request the changes in the physician prescribing information and patient information leaflet for all estrogen and estrogen with progestin drug products?
The Women's Health Initiative (WHI) conducted a large study sponsored by the National Institutes of Health (NIH) to determine the effects of estrogen with progestin on the prevention of heart disease. Results from this study have shown that postmenopausal women taking estrogen with progestin have an increased risk of heart attack, stroke, breast cancer, and blood clots.
An ancillary study of the Women’s Health Initiative (WHI) called the Women’s Health Initiative Memory Study (WHIMS) released more results in May 2003. WHIMS results showed that the combination of estrogen and progestin (Prempro) increased the risk of dementia in women 65 and older and failed to prevent memory loss.
FDA believes this information should be included in the physician prescribing information and patient information leaflet, also referred to as the labeling, for all estrogen and estrogen with progestin drug products.
3. What are estrogen drug products and what do they treat?
Estrogen is a hormone. It is given either alone to a woman without a uterus, or is given in combination with progestin to a woman with a uterus. Estrogen is used to:
- reduce hot flashes in menopause
- treat vaginal dryness, itching, and burning due to menopause
- help reduce chances of getting osteoporosis (thin weak bones) in menopause
- treat certain conditions in women before menopause if their ovaries do not make enough estrogen
- ease symptoms of certain cancers that have spread through the body, in men and women.
4. What are estrogen with progestin drug products?
Estrogen with progestin drug products contain two kinds of hormones: estrogens and a progestin. Adding progestin reduces the risk of endometrial cancer in a woman with a uterus.
Estrogen with progestin drug products are given to postmenopausal women with a uterus to:
- reduce hot flashes
- treat vaginal dryness, itching, and burning
- help reduce chances of getting osteoporosis (thin weak bones)
5. What is menopause?
The ovaries normally stop making estrogens when a woman is between 45 and 55 years old. This drop in body estrogen levels causes menopause (the end of monthly menstrual periods) or the "change of life."
6. What changes do women go through after menopause?
Every woman experiences menopause differently. Some may not experience any noticeable effects at all. As estrogen levels begin to drop, women may experience changes such as:
- Hot flashes ("hot flushes") - these symptoms can range from feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating.
- Vaginal changes/vaginal atrophy - the tissues lining the vagina may become drier, thinner and less elastic.
- Irregular menstruation - the menstrual cycle may become lighter or heavier and then stop.
- Sleep disturbances or night sweats
- Emotional changes - mood swings, irritability
7. What is the new, important information about all estrogen and estrogen with progestin drug products?
Estrogen and estrogen with progestin drug products remain the most effective products available to treat hot flashes and vaginal symptoms of menopause.
The major points arising from the WHI study and WHIMS are:
- Postmenopausal women should not take estrogen and progestin to protect the heart.
- Estrogens and progestins may increase the risk of heart attack, stroke, blood clots and breast cancer.
- Although other doses of Prempro and other estrogens and progestins were not studied, it is important to warn postmenopausal women who take estrogens and progestins about the potential risks, which must be presumed to be the same.
- When these drugs are being prescribed only to prevent osteoporosis, health care providers are encouraged to consider other treatments before prescribing estrogen or estrogen with progestin.
- Estrogens and estrogen with progestin should be used at the lowest dose for the shortest duration.
- The estrogen with progestin combination studied in WHIMS does not prevent dementia or slow progress toward dementia over time.
- Women treated with combination estrogen plus progestin have a greater risk of developing dementia.
- There is a higher incidence of mammography abnormalities requiring medical attention.
8. How great are the risks for women taking estrogen with progestin?
The study results show that of every 10,000 women per year taking estrogen with progestin, there would be:
- 8 more cases of breast cancer
- 7 more cases of heart attacks
- 8 more cases of stroke
- 18 more cases of blood clots in the lungs and legs
- 23 more cases of dementia in women over 65 years of age
9. Are there any risks that were found to be lowered in women taking estrogen with progestin?
The WHI study results show that of every 10,000 women per year taking estrogen with progestin drug products, there would be:
- 6 fewer cases of colon cancer
- 5 fewer cases of hip fracture
10. What are the major changes in the physician prescribing information and patient information leaflet for estrogens and estrogen with progestin drug products?
FDA is highlighting the important safety information from the WHI and the WHIMS study results. The FDA is encouraging all estrogen and progestin manufacturers to provide similar safety information for their products. In addition, FDA is asking that manufacturers of estrogen and progestin products state whether studies have been conducted to identify the lowest effective dose for their product.
11. What is FDA's advice to women?
- Estrogens and progestins should not be used to prevent memory loss, heart disease, heart attacks, or strokes.
- Estrogens provide valuable therapy for many women, but carry serious risks, and therefore postmenopausal women who use or are considering using estrogen or estrogen with progestin treatments should discuss with their physicians whether the benefits outweigh the risks.
- For hot flashes and significant symptoms of vulvar and vaginal atrophy, these products are the most effective approved therapies. These products are also options for women whose significant risk of osteoporosis outweighs the risks of treatment; other treatments for prevention of postmenopausal osteoporosis are available.
- Estrogens and progestins should be used at the lowest doses for the shortest duration to reach treatment goals, although it is not known at what dose there may be less risk of serious side effects. Women are encouraged to talk to their health care provider regularly about whether treatment is still needed.
- There is a higher incidence of abnormal mammograms which require medical attention.
- Each woman's individual medical situation needs to be carefully discussed with her health care provider to make the best decision for her.
12. Is it possible that FDA would think about taking estrogens and estrogen with progestin drug products off the market?
The FDA is not thinking of taking estrogens or estrogen with progestin drug products off the market at this time.
The FDA evaluates the ongoing safety and effectiveness of drugs both before and after their approval. The FDA monitors the safety of drugs through postmarketing surveillance and risk assessment programs to identify adverse events that appear during drug marketing. If changes are warranted, this information is used to update the physician prescribing information, to develop educational programs, and, on rare occasions, to reevaluate the original marketing approval decision.
Currently, the FDA seeks to minimize risks and maximize benefits of estrogen and estrogen with progestin drug products by ensuring that women and health care providers fully understand these risks and benefits.
13. Who should not take estrogens and progestins?
Women should not take estrogens and progestins if they:
- think they are pregnant
- have unusual vaginal bleeding
- have or had certain cancers
- have had a stroke or heart attack in the past year
- have or have had blood clots
- have liver problems or liver disease
14. Are estrogen and progestin containing drug products safer in lower doses?
The dose of Prempro used in the WHI study was 0.625 mg, which is the same as 0.625 mg Premarin (conjugated estrogens) plus 2.5 mg medroxyprogesterone acetate (progestin). It is not known whether Premarin and Prempro are safer in lower doses. Generally, medicines should be used at the lowest effective dose. The FDA approved a lower dose of Prempro in March 2003.
The FDA cannot make further recommendations until studies are performed using lower doses. That is why the FDA is asking that manufacturers update their labeling to let doctors and women know whether studies have been conducted to identify the lowest effective dose for their product.
15. Are other estrogen and progestin containing drug products safer than those used in the WHI study?
All estrogen and progestin containing drug products work in similar ways. Until there are data that show otherwise, postmenopausal women who take any type of estrogens or progestins should be similarly warned about risks.
16. How long should women take estrogen or estrogen with progestin drug products?
FDA recommends that women taking estrogen and estrogen with progestin drug products discuss regularly with their health care provider how they are doing with the treatment and if they need to continue. Estrogens and progestins should be taken for the shortest duration possible to achieve treatment goals.
17. What are some side effects of estrogens and progestins?
Less common but serious side effects include:
- Breast cancer
- Uterine cancer
- Heart attack
- Blood clots
- Gallbladder disease
- Ovarian cancer
Common side effects include:
- Breast pain
- Irregular vaginal bleeding or spotting
- Stomach cramps
- Nausea and vomiting
- Hair loss
These are not all the possible side effects of estrogen and estrogen with progestin drug products. For more information, women are encouraged to consult with a health care provider or pharmacist.
18. Should women stop taking estrogens and progestins for cardiovascular protection?
Estrogens and progestins have never been FDA-approved for heart attack prevention. The FDA has not allowed any claims about benefits for prevention of heart disease. Now, the WHI study findings clearly show an increased risk for heart attack and stroke in women.
Women should not take estrogens and progestins to prevent heart attacks or stroke. FDA recommends that women talk to their doctor about other medications or lifestyle measures (such as smoking cessation) to reduce the risk of heart attacks.
19. What does this mean for use of estrogen alone? (4/19/2004)
The estrogen alone substudy of the WHI was stopped by NIH on March 1, 2004 because estrogen alone does not appear to affect (either increase or decrease) heart disease in postmenopausal women without a uterus. At the same time, estrogen alone appears to increase the risk of stroke, decrease the risk of hip fracture, and it has not increased the risk of breast cancer after a mean of 6.8 years of follow-up. There are other side effects associated with the use of estrogen alone that women are encouraged to discuss with their health care providers.
20. Are there medicines other than estrogen hormones for prevention of osteoporosis?
Additional drugs that are FDA-approved for the prevention of postmenopausal osteoporosis include:
- Bisphosphonates - alendronate (Fosamax) and risedronate (Actonel)
- Selective Estrogen Receptor Modulators- raloxifene (Evista)
21. Are the estrogens and progestins in birth control pills (oral contraceptives) the same as those in the WHI study? Do they have the same risks?
Oral contraceptives also contain estrogens and progestins, but different types and doses. All estrogens have similar side effects. However, the risks of particular side effects may differ since oral contraceptives are used in younger women with different health status compared to postmenopausal women.
As with all estrogens, the use of oral contraceptives is also associated with increased risks of several serious conditions including heart attack, blood clots, stroke, liver tumors, and gallbladder disease. These risks are higher in women with underlying risk factors such as high blood pressure, high cholesterol, and diabetes, and in those who smoke cigarettes.
22. Will other estrogen and estrogen with progestin drug products carry the same warnings?
The FDA believes that the new findings regarding estrogens and progestins are very significant and have a major public health impact for postmenopausal women. We believe that all health care providers who prescribe estrogen and progestin drug products for postmenopausal women, and all postmenopausal women who use these drugs, need to know about the new risk information. Thus, the FDA is encouraging all manufacturers who have estrogen and progestin products approved for treatment of menopausal signs and symptoms to include the new information for their products. To help manufacturers include this new risk information, the FDA has reissued its guidance for labeling these products, including revised recommendations for patient information.
23. Are estrogens in patches or vaginal creams or vaginal rings safer than tablet forms?
We do not know if the other forms are safer than the tablets. Estrogens are available in a variety of forms including transdermal patches, estrogen gels, and vaginal creams and rings. Most of the data on the long-term health effects of estrogens come from studies involving estrogen and progestin oral tablets. Unless there are data to say otherwise, FDA recommends that postmenopausal women who take estrogen and progestin in other dosage forms be similarly warned about risks.
The amount of estrogen that enters the blood stream from estrogen-containing vaginal creams and rings can vary depending on the specific product; how it is used, and on factors that vary from woman to woman. FDA encourages manufacturers to provide drug blood level information in the physician prescribing information. However, it is important to realize that little is known about the relationship between blood levels of estrogens and potential health risks.
24. If a woman wants to stop taking estrogens, what should she do?
Women are advised to discuss this issue with their health care provider before stopping their medication.
25. If estrogens are stopped will that change a woman's sex drive? In what way?
Estrogen, and estrogen with progestin drug products have been shown to be effective in treating vaginal dryness, itching, and burning, which can cause discomfort with intercourse. By stopping estrogen and progestin, symptoms such as discomfort during sexual intercourse may return. Women are advised to discuss their symptoms off estrogens and options with their health care provider.
25. Will estrogen protect against aging, wrinkles, or other conditions?
Researchers are investigating the benefits of estrogen and estrogen with progestin in offering protection from a number of conditions and diseases such as macular degeneration, a serious condition that can lead to blindness. At this time there are no convincing studies to support these claims.
26. What can be done to lower the risks of side effects such as heart attack, stroke, blood clots or breast cancer while taking estrogen or estrogen with progestin?
Generally, the safety and effectiveness of medicines are increased when they are used as directed. Here are some points for women to consider:
- Talk with a health care provider periodically about whether estrogens should be continued and how to monitor for side effects.
- If unusual vaginal bleeding develops, see a health care provider right away.
- Do a self-breast examination regularly and have a breast exam by a health care provider and mammogram (breast X-ray) regularly.
- High blood pressure, high cholesterol (fat in the blood), diabetes, tobacco use, and being overweight increase the chances for getting heart disease. A health care provider can advise on how to lower the chances for getting heart disease.