Included as part of the PRECAUTIONS section.
An increased risk of PE, DVT, stroke, and MI has been
reported with estrogen plus progestin therapy. An increased risk of stroke and
DVT has been reported with estrogen-alone therapy. Should any of these occur or
be suspected, estrogen with or without progestin therapy should be discontinued
Risk factors for arterial vascular disease (for example,
hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and
obesity) and/or venous thromboembolism (VTE) (for example, personal history or
family history of VTE, obesity, and systemic lupus erythematosus) should be
In the WHI estrogen plus progestin substudy, a
statistically significant increased risk of stroke was reported in women 50 to
79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to
women in the same age group receiving placebo (33 versus 25 per 10,000
women-years) [see Clinical Studies]. The increase in risk was
demonstrated after the first year and persisted.1 Should a stroke
occur or be suspected, estrogen plus progestin therapy should be discontinued
In the WHI estrogen-alone substudy, a statistically
significant increased risk of stroke was reported in women 50 to 79 years of
age receiving daily conjugated estrogens CE (0.625 mg)alone compared to women
in the same age group receiving placebo (45 versus 33 per 10,000 women-years).
The increase in risk was demonstrated in year 1 and persisted [see Clinical
Studies]. Should a stroke occur or be suspected, estrogen-alone therapy
should be discontinued immediately.
Subgroup analyses of women 50 to 59 years of age suggest
no increased risk of stroke for those women receiving CE (0.625 mg)-alone
versus those receiving placebo (18 versus 21 per 10,000 women-years).1
Coronary Heart Disease
In the WHI estrogen plus progestin substudy, there was a
statistically non-significant increased risk of coronary heart disease (CHD)
events (defined as nonfatal MI, silent MI, or CHD death) reported in women
receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving
placebo (41 versus 34 per 10,000 women-years).1 An increase in
relative risk was demonstrated in year 1, and a trend toward decreasing
relative risk was reported in years 2 through 5 [see Clinical Studies].
In the WHI estrogen-alone substudy, no overall effect on
CHD events was reported in women receiving estrogen-alone compared to placebo2
[see Clinical Studies].
Subgroup analyses of women 50 to 59 years of age suggest
a statistically non-significant reduction in CHD events (CE [0.625 mg]-alone
compared to placebo) in women with less than 10 years since menopause (8 versus
16 per 10,000 woman-years).1
In postmenopausal women with documented heart disease (n
= 2,763), average 66.7 years of age, in a controlled clinical trial of
secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin
Replacement Study [HERS]), treatment with daily CE (0.625 mg) plus MPA (2.5 mg)
demonstrated no cardiovascular benefit. During an average follow-up of 4.1
years, treatment with CE plus MPA did not reduce the overall rate of CHD events
in postmenopausal women with established CHD. There were more CHD events in the
CE plus MPA-treated group than in the placebo group in year 1, but not during
the subsequent years. Two thousand, three hundred and twenty-one (2,321) women
from the original HERS trial agreed to participate in an open label extension
of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for
a total of 6.8 years overall. Rates of CHD events were comparable among women
in the CE plus MPA group and the placebo group in HERS, HERS II, and overall.
In the WHI estrogen plus progestin substudy, a
statistically significant 2-fold greater rate of VTE (DVT and PE) was reported
in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women
receiving placebo (35 versus 17 per 10,000 women-years). Statistically
significant increases in risk for both DVT (26 versus 13 per 10,000
women-years) and PE (18 versus 8 per 10,000 women-years) were also
demonstrated. The increase in VTE risk was demonstrated during the first year
and persisted3 [see Clinical Studies]. Should a VTE occur or
be suspected, estrogen plus progestin therapy should be discontinued
In the WHI estrogen-alone substudy, the risk of VTE was
increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30
versus 22 per 10,000 women-years), although only the increased risk of DVT
reached statistical significance (23 versus 15 per 10,000 women-years). The
increase in VTE risk was demonstrated during the first 2 years4 [see
Clinical Studies]. Should a VTE occur or be suspected, estrogen-alone
therapy should be discontinued immediately.
If feasible, estrogens should be discontinued at least 4
to 6 weeks before surgery of the type associated with an increased risk of
thromboembolism or during periods of prolonged immobilization.
The most important randomized clinical trial providing
information about breast cancer in estrogen plus progestin users is the WHI
substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up of
5.6 years, the estrogen plus progestin substudy reported an increased risk of
invasive breast cancer in women who took daily CE plus MPA. In this substudy,
prior use of estrogen-alone or estrogen plus progestin therapy was reported by
26 percent of the women. The relative risk of invasive breast cancer was 1.24,
and the absolute risk was 41 versus 33 cases per 10,000 women-years for CE plus
MPA compared with placebo [see Clinical Studies]. Among women who
reported prior use of hormone therapy, the relative risk of invasive breast
cancer was 1.86 and the absolute risk was 46 versus 25 cases per 10,000
women-years for CE plus MPA compared with placebo. Among women who reported no
prior use of hormone therapy, the relative risk of invasive breast cancer was
1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for
CE plus MPA compared with placebo. In the same substudy, invasive breast
cancers were larger, were more likely to be node positive, and were diagnosed
at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared
with the placebo group. Metastatic disease was rare with no apparent difference
between the two groups. Other prognostic factors, such as histologic subtype,
grade and hormone receptor status did not differ between the groups5
[see Clinical Studies].
The most important randomized clinical trial providing
information about breast cancer in estrogen-alone users is the WHI substudy of
daily CE (0.625 mg)-alone. In the WHI estrogen-alone substudy, after an average
follow up of 7.1 years, daily CE-alone was not associated with an increased
risk of invasive breast cancer (relative risk [RR] 0.80 [see Clinical
Consistent with the WHI clinical trials, observational
studies have also reported an increased risk of breast cancer for estrogen plus
progestin therapy, and a smaller increased risk for estrogen-alone therapy,
after several years of use. The risk increased with duration of use, and
appeared to return to baseline over about 5 years after stopping treatment
(only the observational studies have substantial data on risk after stopping).
Observational studies also suggest that the risk of breast cancer was greater,
and became apparent earlier, with estrogen plus progestin therapy as compared
to estrogen-alone therapy. However, these studies have not found significant
variation in the risk of breast cancer among different estrogen plus progestin
combinations, doses, or routes of administration.
The use of estrogen-alone and estrogen plus progestin has
been reported to result in an increase in abnormal mammograms requiring further
All women should receive yearly breast examinations by a
healthcare provider and perform monthly breast self-examinations. In addition,
mammography examinations should be scheduled based on patient age, risk factors
and prior mammogram results.
Endometrial hyperplasia (a possible precursor of
endometrial cancer) has been reported to occur at a rate of approximately 1
percent or less with femhrt.
An increased risk of endometrial cancer has been reported
with the use of unopposed estrogen therapy in a woman with a uterus. The
reported endometrial cancer risk among unopposed estrogen users is about 2 to
12 times greater than in non-users, and appears dependent on duration of
treatment and on estrogen dose. Most studies show no significant increased risk
associated with use of estrogens for less than 1 year. The greatest risk
appears associated with prolonged use, with increased risks of 15-to 24-fold
for 5 to 10 years or more. This risk has been shown to persist for at least 8
to 15 years after estrogen therapy is discontinued.
Clinical surveillance of all women using estrogen-alone
or estrogen plus progestin therapy is important. Adequate diagnostic measures,
including directed or random endometrial sampling when indicated, should be
undertaken to rule out malignancy in postmenopausal women with undiagnosed
persistent or recurring abnormal genital bleeding.
There is no evidence that the use of natural estrogens
results in a different endometrial risk profile than synthetic estrogens of
equivalent estrogen dose. Adding a progestin to estrogen therapy in
postmenopausal women has been shown to reduce the risk of endometrial
hyperplasia, which may be a precursor to endometrial cancer.
The WHI estrogen plus progestin substudy reported a
statistically non-significant increased risk of ovarian cancer. After an
average follow-up of 5.6 years, the relative risk for ovarian cancer for CE
plus MPA versus placebo was 1.58 (95 percent CI, 0.77-3.24). The absolute risk
for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years.7
A meta-analysis of 17 prospective and 35 retrospective
epidemiology studies found that women who used hormonal therapy for menopausal
symptoms had an increased risk for ovarian cancer. The primary analysis, using
case-control comparisons, included 12,110 cancer cases from the 17 prospective
studies. The relative risks associated with current use of hormonal therapy was
1.41 (95% confidence interval [CI] 1.32 to 1.50); there was no difference in
the risk estimates by duration of the exposure (less than 5 years [median of 3
years] vs. greater than 5 years [median of 10 years] of use before the cancer
diagnosis). The relative risk associated with combined current and recent use
(discontinued use within 5 years before cancer diagnosis) was 1.37 (95% CI
1.27-1.48), and the elevated risk was significant for both estrogen-alone and
estrogen plus progestin products. The exact duration of hormone therapy use
associated with an increased risk of ovarian cancer, however, is unknown.
In the WHIMS estrogen plus progestin ancillary study of
WHI, a population of 4,532 postmenopausal women 65 to 79 years of age was
randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo.
After an average follow-up of 4 years, 40 women in the CE
plus MPA group and 21 women in the placebo group were diagnosed with probable
dementia. The relative risk of probable dementia for CE plus MPA versus placebo
was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for
CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years8
[see Use In Specific Populations, and Clinical Studies].
In the WHIMS estrogen-alone ancillary study of WHI, a
population of 2,947 hysterectomized women 65 to 79 years of age was randomized
to daily CE (0.625 mg)-alone or placebo.
After an average follow-up of 5.2 years, 28 women in the
estrogen-alone group and 19 women in the placebo group were diagnosed with
probable dementia. The relative risk of probable dementia for CE-alone versus
placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable
dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000
womenyears8 [see Use In Specific Populations, and Clinical
When data from the two populations in the WHIMS
estrogen-alone and estrogen plus progestin ancillary studies were pooled as
planned in the WHIMS protocol, the reported overall relative risk for probable
dementia was 1.76 (95 percent CI, 1.19-2.60). Since both ancillary substudies
were conducted in women 65 to 79 years of age, it is unknown whether these
findings apply to younger postmenopausal women8 [see Use In Specific
Populations, and Clinical Studies].
A 2-to 4-fold increase in the risk of gallbladder disease
requiring surgery in postmenopausal women receiving estrogens has been
Estrogen administration may lead to severe hypercalcemia
in women with breast cancer and bone metastases. If hypercalcemia occurs, use
of the drug should be stopped and appropriate measures taken to reduce the
serum calcium level.
Retinal vascular thrombosis has been reported in women
receiving estrogens. Discontinue medication pending examination if there is
sudden partial or complete loss of vision, or a sudden onset of proptosis,
diplopia, or migraine. If examination reveals papilledema or retinal vascular
lesions, estrogens should be permanently discontinued.
Addition Of A Progestin When A Woman Has Not Had A Hysterectomy
Studies of the addition of a progestin for 10 or more
days of a cycle of estrogen administration or daily with estrogen in a
continuous regimen, have reported a lowered incidence of endometrial
hyperplasia than would be induced by estrogen treatment alone. Endometrial
hyperplasia may be a precursor to endometrial cancer.
There are, however, possible risks that may be associated
with the use of progestins with estrogens compared to estrogen-alone regimens.
These include an increased risk of breast cancer.
Elevated Blood Pressure
In a small number of case reports, substantial increases
in blood pressure have been attributed to idiosyncratic reactions to estrogens.
In a large, randomized, placebo-controlled clinical trial, a generalized effect
of estrogen therapy on blood pressure was not seen.
In women with pre-existing hypertriglyceridemia, estrogen
therapy may be associated with elevations of plasma triglycerides leading to
pancreatitis. Consider discontinuation of treatment if pancreatitis occurs.
Hepatic Impairment And/Or A Past History Of Cholestatic
Estrogens may be poorly metabolized in women with
impaired liver function. For women with a history of cholestatic jaundice
associated with past estrogen use or with pregnancy, caution should be
exercised and in the case of recurrence, medication should be discontinued.
Estrogen administration leads to increased
thyroid-binding globulin (TBG) levels. Women with normal thyroid function can
compensate for the increased TBG by making more thyroid hormone, thus
maintaining free T4 and T3 serum concentrations in the normal range. Women
dependent on thyroid hormone replacement therapy who are also receiving
estrogen may require increased doses of their thyroid replacement therapy.
These women should have their thyroid function monitored in order to maintain
their free thyroid hormone levels in an acceptable range.
Estrogens plus progestins may cause some degree of fluid
retention. Women with conditions that might be influenced by this factor, such
as cardiac or renal impairment, warrant careful observation when estrogens plus
progestins are prescribed.
Estrogen therapy should be used with caution in women
with hypoparathyroidism as estrogen-induced hypocalcemia may occur.
Exacerbation Of Endometriosis
A few cases of malignant transformation of residual
endometrial implants have been reported in women treated post-hysterectomy with
estrogen-alone therapy. For women known to have residual endometriosis
post-hysterectomy, the addition of progestin should be considered.
Exogenous estrogens may exacerbate symptoms of angioedema
in women with hereditary angioedema.
Exacerbation Of Other Conditions
Estrogen therapy may cause an exacerbation of asthma,
diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus
and hepatic hemangiomas, and should be used with caution in women with these
Serum follicle stimulating hormone (FSH) and estradiol
levels have not been shown to be useful in the management of moderate to severe
Drug-Laboratory Test Interactions
Accelerated prothrombin time, partial thromboplastin time,
and platelet aggregation time; increased platelet count; increased factors II,
VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex,
II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa
and antithrombin III, decreased antithrombin III activity; increased levels of
fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
Increased TBG levels leading to increased circulating
total thyroid hormone levels as measured by protein-bound iodine (PBI), T4 levels
(by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin
uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations
are unaltered. Women on thyroid replacement therapy may require higher doses of
Other binding proteins may be elevated in serum, for
example, corticosteroid binding globulin (CBG), sex hormone-binding globulin
(SHBG), leading to increased total circulating corticosteroids and sex
steroids, respectively. femhrt 1/5 was associated with an SHBG
increase of 22 percent. Free hormone concentrations, such as testosterone and
estradiol, may be decreased. Other plasma proteins may be increased
(angiotensinogen/renin substrate, alpha-1antitrypsin, ceruloplasmin).
Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol
subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol
concentration, increased triglycerides levels.
Impaired glucose tolerance.
Patient Counseling Information
See FDA-approved patient labeling (PATIENT INFORMATION)
Abnormal Vaginal Bleeding
Inform postmenopausal women of the importance of reporting
abnormal vaginal bleeding to their healthcare provider as soon as possible [see
WARNINGS AND PRECAUTIONS].
Possible Serious Adverse Reactions With Estrogen Plus
Inform postmenopausal women of possible serious adverse
reactions of estrogen plus progestin therapy including Cardiovascular
Disorders, Malignant Neoplasms, and Probable Dementia [see WARNINGS AND
Possible Less Serious But Common Adverse Reactions With Estrogen
Plus Progestin Therapy
Inform postmenopausal women of possible less serious but
common adverse reactions of estrogen plus progestin therapy such as headache,
breast pain and tenderness, nausea and vomiting.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term continuous administration of natural and
synthetic estrogens in certain animal species increases the frequency of
carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
Use In Specific Populations
femhrt should not be used during pregnancy
[see CONTRAINDICATIONS]. There appears to be little or no increased risk
of birth defects in children born to women who have used estrogens and
progestins as an oral contraceptive inadvertently during early pregnancy.
femhrt should not be used during lactation.
Estrogen administration to nursing women has been shown to decrease the
quantity and quality of the breast milk. Detectable amounts of estrogen and
progestin have been identified in the breast milk of women receiving estrogen
plus progestin therapy. Caution should be exercised when femhrt is
administered to a nursing woman.
femhrt is not indicated in children.
Clinical studies have not been conducted in the pediatric population.
There have not been sufficient numbers of geriatric women
involved in clinical studies utilizing femhrt to determine
whether those over 65 years of age differ from younger subjects in their
response to femhrt.
The Women’s Health Initiative Studies
In the WHI estrogen plus progestin substudy (daily CE
[0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk
of nonfatal stroke and invasive breast cancer in women greater than 65 years of
age [see Clinical Studies].
In the WHI estrogen-alone substudy (daily CE [0.625
mg]-alone versus placebo), there was a higher relative risk of stroke in women
greater than 65 years of age [see Clinical Studies].
The Women’s Health Initiative Memory Study
In the WHIMS ancillary studies of postmenopausal women 65
to 79 years of age, there was an increased risk of developing probable dementia
in women receiving estrogen plus progestin or estrogen-alone when compared to
placebo [see WARNINGS AND PRECAUTIONS, and Clinical Studies].
Since both ancillary studies were conducted in women 65
to 79 years of age, it is unknown whether these findings apply to younger
postmenopausal women8 [see WARNINGS AND PRECAUTIONS, and Clinical
The effect of renal impairment on the pharmacokinetics of
femhrt has not been studied.
The effect of hepatic impairment on the pharmacokinetics
of femhrt has not been studied.
1. Rossouw JE, et al. Postmenopausal Hormone Therapy and
Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA.
2. Hsia J, et al. Conjugated Equine Estrogens and
Coronary Heart Disease. Arch Int Med. 2006;166:357-365.
3. Cushman M, et al. Estrogen Plus Progestin and Risk of
Venous Thrombosis. JAMA. 2004;292:1573-1580.
4. Curb JD, et al. Venous Thrombosis and Conjugated
Equine Estrogen in Women Without a Uterus. Arch Int Med. 2006;166:772-780.
5. Chlebowski RT, et al. Influence of Estrogen Plus
Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA.
6. Stefanick ML, et al. Effects of Conjugated Equine
Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women
With Hysterectomy. JAMA. 2006;295:1647-1657.
7. Anderson GL, et al. Effects of Estrogen Plus Progestin
on Gynecologic Cancers and Associated Diagnostic Procedures. JAMA.
8. Shumaker SA, et al. Conjugated Equine Estrogens and
Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal
Women. JAMA. 2004;291:2947-2958.