Hormones Resource
Center
The
Estrogen and Progestin Dilemma: New Advice, Labeling
Guidelines
by Linda Bren
The Food and Drug Administration is giving important
new safety advice to postmenopausal women and their
health-care providers concerning drug products that
contain estrogen. The updated advice, which includes
product label revisions, reflects the agency's review
of data from the Women's Health Initiative (WHI) study,
sponsored by the National Institutes of Health.
The landmark WHI study has raised concern about the
risks associated with the use of estrogen and estrogen
with progestin products, including increased risks
for cardiovascular disease and breast cancer.
One arm of the WHI study found that after one year
of treatment with estrogen with progestin, for every
10,000 women, there may be seven more cases of heart
disease, eight more strokes, eight more instances of
blood clots in the lungs, 13 more cases of blood clots
in the limbs, and eight more cases of breast cancer.
This part of the study was stopped in July 2002 after
five years because the risks from taking the drug exceeded
the benefits of reduced instances of colon cancer and
bone fracture.
The WHI study included 16,000 postmenopausal women
who still had a uterus and were taking either a combination
estrogen-progestin drug or a placebo. The results are
published in the July 17, 2002, issue of the Journal
of the American Medical Association.
To help women and their health-care providers better
understand this new information and make appropriate
treatment decisions, the FDA has asked all manufacturers
of estrogen-containing products to revise their physician
prescribing information and patient information leaflets,
also referred to as the labeling. The new labeling
is one of several actions the agency has taken to help
clarify the risks, benefits, and appropriate indications
for using estrogen and estrogen-progestin products.
Other actions include issuing revised guidances to
manufacturers of these products and pursuing research
on questions involving the safety and effectiveness
of the products.
Labeling Changes
The WHI 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. Prempro's manufacturer, Wyeth Pharmaceuticals
of St. Davids, Pa., made labeling changes to Prempro
and two other estrogen-containing products, Premphase
and Premarin, shortly after the release of the WHI
findings. The FDA has worked with Wyeth to build on
these changes and develop the new labeling currently
approved for these products.
The
FDA is asking all manufacturers of estrogen and estrogen-progestin
products for postmenopausal use
to make similar changes to their product labeling because
it is believed these products have risks similar to
those of Prempro, the drug used in the WHI study. "We
don't want women to think these other products don't
have any risk or are less risky--we simply don't have
the data yet because we haven't studied them in the
manner Prempro was studied," says Florence Houn, M.D.,
director of the FDA office that reviews reproductive
drugs. "However, from what limited information we do
have, we know that blood clots, heart attacks, and
other side effects may also happen with other estrogen
and estrogen-progestin products." These products include
estrogen-containing tablets, gels, transdermal (skin)
patches, and vaginal creams and rings. About 10 million
postmenopausal women in the United States are taking
some form of estrogen, according to Wyeth.
The
FDA is requiring the physician's labeling to include
a boxed warning--the
highest level of warning information
in labeling--that highlights the increased risks found
in the WHI study and emphasizes that estrogen and estrogen-progestin
products are not approved for heart disease prevention. "For
over 20 years, many medical experts thought estrogens
protected women from heart disease," says Houn. "These
thoughts were based on less rigorous studies."
New Treatment Advice
Prior to the WHI study findings, the FDA had approved
three indications for the use of estrogen and estrogen-progestin
products in postmenopausal women. Two of the three
indications have now changed to include consideration
of alternative treatments:
-
Treatment of moderate to severe symptoms of vulvar
and vaginal atrophy (such as dryness, itching, and
burning) associated with 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. Estrogens and combined estrogen-progestin
products should only be considered for women with
significant risk of osteoporosis that outweighs the
risks of the drug.
-
Treatment of moderate to severe vasomotor symptoms
(such as hot flashes and night sweats) associated
with menopause. This indication has not changed.
Estrogen-containing products are the most effective
approved therapies for these symptoms.
If a woman and her
health-care provider decide that estrogen-containing
products are appropriate, they
should be used at the lowest doses for the shortest
duration to reach treatment goals. It is not yet known
what dose is less risky, says Houn. "We hope new studies
will tell us this, and as we learn more, we'll tell
the public." Women who are already taking these products
should talk to their physicians before stopping their
medication.
Women also should talk with a health-care provider
periodically about whether estrogens should be continued
and how to monitor for side effects. To minimize potential
risks, the new labeling advises that women do a monthly
breast self-examination and have a breast exam by a
health-care provider and mammogram (breast X-ray) regularly.
In addition, women should talk to a health-care provider
about other ways to lower their chances for getting
heart disease and osteoporosis.
More Study Needed
In addition to giving the industry advice on labeling,
FDA-issued guidances also will provide recommendations
on conducting studies to develop better information
on the lowest effective doses of estrogen-containing
drugs.
The FDA's review of the WHI study findings leads to
some important research questions for the medical community.
These questions include:
-
Will lower doses of estrogen and progestin have
lower risks?
-
Do other types of estrogens and progestins or other
ways of administering these drugs, such as through
patches, have different risks?
-
What is the best method to stop taking estrogens
and progestins?
The FDA plans to work with researchers, sponsors,
and product manufacturers to encourage this further
research.
Estrogen and Birth Control
The FDA's new advice and labeling changes on products
that contain estrogen or estrogen and progestin apply
to those prescribed for postmenopausal women. Oral
contraceptives also contain estrogen and progestin,
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 some 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.
--L.B.
article
syndicated from U.S.
Food and Drug Administration:
http://www.fda.gov/fdac/features/2003/203_estrogen.html
FDA Consumer Magazine, March-April 2003
