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 these occur or be
suspected, therapy should be discontinued immediately.
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 managed
In the Women's Health Initiative 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 immediately.
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 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 analysis of women 50 to 59 years of age suggests
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 women-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 coronary heart disease. 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 the original 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 immediately.
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% 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. 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 estrogenalone 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]6 [see
Consistent with the WHI clinical trial, observational
studies have also reported an increased risk of breast cancer for estrogen plus
progestin therapy, and a smaller increased risk for estrogenalone 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 generally 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
therapy has been reported to result in an increase in abnormal mammograms
requiring further evaluation.
In a one-year trial, among 1684 women who received a
combination of estradiol plus progesterone (1 mg estradiol plus 100 mg
progesterone or 0.5 mg estradiol plus 100 mg progesterone or 0.5 mg estradiol
plus 50 mg progesterone or 0.25 mg estradiol plus 50 mg progesterone) or
placebo (n=151), six new cases of breast cancer were diagnosed, two of which occurred
among the group of 415 women treated with BIJUVA (estradiol and progesterone) capsules,
1 mg/100 mg. No new cases of breast cancer were diagnosed in the group of 151
women treated with placebo.
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 BIJUVA (estradiol and progesterone) capsules, 1 mg/100 mg.
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-fold 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 an increased risk of 15- to 24-fold
for 5 to 10 years or more, and 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 progestogen 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 progestogen 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% confidence interval [CI], 0.77 to 3.24).
The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per
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% 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 to 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% CI, 1.21 to
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% CI, 0.83 to 2.66). The absolute risk of
probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000
women-years8 [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% CI, 1.19 to 2.60). 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 Use In Specific Populations, and Clinical
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 a
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 Progestogen 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 progestogen 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 estrogens 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 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 estrogens 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
Estrogens and progestins may cause some degree of fluid
retention. Women with conditions that might be influenced by this factor, such
as a cardiac or renal dysfunction, 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
Increased thyroid-binding globulin (TBG) levels leading
to increased circulating total thyroid hormone 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 thyroid hormone.
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. Free hormone concentrations, such as testosterone and
estradiol, may be decreased. Other plasma proteins may be increased
(angiotensinogen/rennin substrate, alpha-1-antitrypsin, ceruloplasmin).
Increased plasma high-density lipoprotein (HDL) and HDL2
cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL)
cholesterol concentrations, increased triglyceride levels.
Impaired glucose tolerance.
Patient Counseling Information
Advise the patient to read the 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 progesterone therapy including cardiovascular
disorders, malignant neoplasms, and probable dementia [see WARNINGS AND
Possible Less Serious But Common Adverse Reactions With Estrogen
Plus Progesterone Therapy
Inform postmenopausal women of possible less serious but
common adverse reactions of estrogen plus progesterone therapy such as breast
tenderness, headache, vaginal discharge, and pelvic pain [see ADVERSE
Missed Evening Dose Of BIJUVA
Advise the patient that if she misses her evening dose,
she should take the dose with food as soon as she can, unless it is within two
hours of the next evening dose.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Nonclinical toxicity studies to determine the potential
of BIJUVA (estradiol and progesterone) capsules, 1 mg/100 mg, to cause
carcinogenicity or mutagenicity have not been performed. The effect of BIJUVA
on fertility has not been evaluated in animals.
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.
Progesterone has not been tested for carcinogenicity in
animals by the oral route of administration. When implanted into female mice,
progesterone produced mammary carcinomas, ovarian granulosa cell tumors, and
endometrial stromal sarcomas. In dogs, long-term intramuscular injections
produced nodular hyperplasia and benign and malignant mammary tumors.
Subcutaneous or intramuscular injections of progesterone decreased the latency
period and increased the incidence of mammary tumors in rats previously treated
with a chemical carcinogen.
Progesterone did not show evidence of genotoxicity in in
vitro studies for point mutations or for chromosomal damage. In vivo studies
for chromosome damage have yielded positive results in mice at oral doses of
1000 mg/kg and 2000 mg/kg. Exogenously administered progesterone has been shown
to inhibit ovulation in a number of species and it is expected that high doses
given for an extended duration would impair fertility until the cessation of
Use In Specific Populations
BIJUVA (estradiol and progesterone) capsules, 1 mg/100
mg, are not indicated for use in pregnancy. There are no data with the use of
BIJUVA in pregnant women, however, epidemiologic studies and meta-analyses have
not found an increased risk of genital or non-genital birth defects (including
cardiac anomalies and limb reduction defects) following exposure to combined
hormonal contraceptives (estrogen and progestins) before conception or during
BIJUVA (estradiol and progesterone) capsules, 1 mg/100
mg, are not indicated for use in females of reproductive potential. Estrogens
are present in human milk and can reduce milk production in breast-feeding
females. This reduction can occur at any time but is less likely to occur once
breast-feeding is well-established.
BIJUVA (estradiol and progesterone) capsules, 1 mg/100
mg, are 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 BIJUVA (estradiol and progesterone)
capsules, 1 mg/100 mg, to determine whether those over 65 years of age differ
from younger women in their response to BIJUVA.
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 , 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
1. Rossouw JE, et al. Postmenopausal Hormone Therapy and
Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA. 2007;
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. 2003; 289:3243-3253.
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. 2003;
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.