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