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ESTRACE TABLETS
(estradiol tablets, USP)
ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER
Close clinical surveillance of all women taking estrogens is important. Adequate
diagnostic measures, including endometrial sampling when indicated, should be
undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring
abnormal vaginal bleeding. There is no evidence that the use of "natural" estrogens
results in a different endometrial risk profile than "synthetic" estrogens at equivalent
estrogen doses. (See WARNINGS, Malignant neoplasms, Endometrial cancer.)
CARDIOVASCULAR AND OTHER RISKS
Estrogens with or without progestins should not be used for the prevention of
cardiovascular disease. (See WARNINGS, Cardiovascular disorders.)
The Women’s Health Initiative (WHI) study reported increased risks of myocardial
infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in
postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral
conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA
2.5 mg) relative to placebo. (See CLINICAL PHARMACOLOGY, Clinical Studies.)
The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported
increased risk of developing probable dementia in postmenopausal women 65 years of
age or older during 4 years of treatment with oral conjugated estrogens plus
medroxyprogesterone acetate relative to placebo. It is unknown whether this finding
applies to younger postmenopausal women or to women taking estrogen alone therapy.
(See CLINICAL PHARMACOLOGY, Clinical Studies.)
Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other
combinations and dosage forms of estrogens and progestins were not studied in the WHI
clinical trials and, in the absence of comparable data, these risks should be assumed to be
similar. Because of these risks, estrogens with or without progestins should be prescribed
at the lowest effective doses and for the shortest duration consistent with treatment goals
and risks for the individual woman.
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DESCRIPTION
ESTRACE (estradiol tablets, USP) for oral administration contains 0.5, 1 or 2 mg of
micronized estradiol per tablet. Estradiol (17β-estradiol) is a white, crystalline solid,
chemically described as estra-1,3,5,(10)-triene-3, 17β-diol. It has an empirical formula of
C18H24O2 and molecular weight of 272.37. The structural formula is:
ESTRACE tablets, 0.5 mg, contain the following inactive ingredients: acacia, dibasic
calcium phosphate, lactose, magnesium stearate, colloidal silicon dioxide, starch (corn),
and talc.
ESTRACE tablets, 1 mg, contain the following inactive ingredients: acacia, D&C Red
No. 27 (aluminum lake), dibasic calcium phosphate, FD&C Blue No. 1 (aluminum lake),
lactose, magnesium stearate, colloidal silicon dioxide, starch (corn), and talc.
ESTRACE tablets, 2 mg, contain the following inactive ingredients: acacia, dibasic
calcium phosphate, FD&C Blue No. 1 (aluminum lake), FD&C Yellow No. 5 (tartrazine)
(aluminum lake), lactose, magnesium stearate, colloidal silicon dioxide, starch (corn),
and talc.
CLINICAL PHARMACOLOGY
Endogenous estrogens are largely responsible for the development and maintenance of
the female reproductive system and secondary sexual characteristics. Although
circulating estrogens exist in a dynamic equilibrium of metabolic interconversions,
estradiol is the principal intracellular human estrogen and is substantially more potent
than its metabolites, estrone and estriol at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian follicle,
which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual
cycle. After menopause, most endogenous estrogen is produced by conversion of
androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus,
estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating
estrogens in postmenopausal women.
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Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To
date, two estrogen receptors have been identified. These vary in proportion from tissue to
tissue.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing
hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback
mechanism. Estrogens act to reduce the elevated levels of these hormones seen in
postmenopausal women.
Pharmacokinetics
Distribution
The distribution of exogenous estrogens is similar to that of endogenous estrogens.
Estrogens are widely distributed in the body and are generally found in higher
concentrations in the sex hormone target organs. Estrogens circulate in the blood largely
bound to sex hormone binding globulin (SHBG) and albumin.
Metabolism
Exogenous estrogens are metabolized in the same manner as endogenous estrogens.
Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions.
These transformations take place mainly in the liver. Estradiol is converted reversibly to
estrone, and both can be converted to estriol, which is the major urinary metabolite.
Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide
conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis
in the gut followed by reabsorption. In postmenopausal women, a significant proportion
of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which
serves as a circulating reservoir for the formation of more active estrogens.
Excretion
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate
conjugates.
Special Populations
No pharmacokinetic studies were conducted in special populations, including patients
with renal or hepatic impairment.
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Drug Interactions
In vitro and in vivo studies have shown that estrogens are metabolized partially by
cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may
affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John’s Wort
preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may
reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic
effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as
erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice
may increase plasma concentrations of estrogens and may result in side effects.
Clinical Studies
Osteoporosis
Most prospective studies of efficacy for this indication have been carried out in white
menopausal women, without stratification by other risk factors, and tend to show a
universally salutary effect on bone.
The results of a two-year, randomized, placebo-controlled, double-blind, dose-ranging
study have shown that treatment with 0.5 mg estradiol daily for 23 days (of a 28 day
cycle) prevents vertebral bone mass loss in postmenopausal women. When estrogen
therapy is discontinued, bone mass declines at a rate comparable to the immediate
postmenopausal period. There is no evidence that estrogen replacement therapy restores
bone mass to premenopausal levels.
Women’s Health Initiative Studies
The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy
postmenopausal women to assess the risks and benefits of either the use of oral 0.625 mg
conjugated estrogens (CE) per day alone or the use of oral 0.625 mg conjugated estrogens
plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the
prevention of certain chronic diseases. The primary endpoint was the incidence of
coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with
invasive breast cancer as the primary adverse outcome studied. A “global index” included
the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism
(PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The
study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.
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The CE/MPA substudy was stopped early because, according to the predefined stopping
rule, the increased risk of breast cancer and cardiovascular events exceeded the specified
benefits included in the “global index.” Results of the CE/MPA substudy, which included
16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5%
Hispanic), after an average follow-up of 5.2 years are presented in Table 1 below:
Table 1 RELATIVE AND ABSOLUTE RISK SEEN IN THE CE/MPA
SUBSTUDY OF WHIa
Eventc Relative Risk
CE/MPA vs placebo
at 5.2 Years
(95% CI*)
Placebo
n = 8102
CE/MPA
n = 8506
Absolute Risk per 10,000 Women-Years
CHD events
Non-fatal MI
CHD death
1.29 (1.02-1.63)
1.32 (1.02-1.72)
1.18 (0.70-1.97)
30
23
6
37
30
7
Invasive breast cancerb 1.26 (1.00-1.59) 30 38
Stroke 1.41 (1.07-1.85) 21 29
Pulmonary embolism 2.13 (1.39-3.25) 8 16
Colorectal cancer 0.63 (0.43-0.92) 16 10
Endometrial cancer 0.83 (0.47-1.47) 6 5
Hip fracture 0.66 (0.45-0.98) 15 10
Death due to causes other than the
events above
0.92 (0.74-1.14) 40 37
Global Indexc 1.15 (1.03-1.28) 151 170
Deep vein thrombosisd 2.07 (1.49-2.87) 13 26
Vertebral fracturesd 0.66 (0.44-0.98) 15 9
Other osteoporotic fracturesd 0.77 (0.69-0.86) 170 131
a adapted from JAMA, 2002; 288:321-333
b includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer
a subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD
events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip
fracture, or death due to other causes
d not included in Global Index
* nominal confidence intervals unadjusted for multiple looks and multiple comparisons
For those outcomes included in the “global index,” the absolute excess risks per 10,000
women-years in the group treated with CE/MPA were 7 more CHD events, 8 more
strokes, 8 more PEs, and 8 more invasive breast cancers, while the absolute risk
reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip
fractures. The absolute excess risk of events included in the “global index” was 19 per
10,000 women-years. There was no difference between the groups in terms of all-cause
mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
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Women’s Health Initiative Memory Study
The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled
4,532 predominantly healthy postmenopausal women 65 years of age and older (47%
were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and
older) to evaluate the effects of CE/MPA (0.625 mg conjugated estrogens plus 2.5 mg
medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome)
compared with placebo.
After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per
10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were
diagnosed with probable dementia. The relative risk of probable dementia in the hormone
therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between
groups became apparent in the first year of treatment. It is unknown whether these
findings apply to younger postmenopausal women. (See BOXED WARNING and
WARNINGS, Dementia.)
INDICATIONS AND USAGE
ESTRACE (estradiol tablets, USP) is indicated in the:
1. Treatment of moderate to severe vasomotor symptoms associated with the
menopause.
2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy
associated with the menopause. When prescribing solely for the treatment of
symptoms of vulvar and vaginal atrophy, topical vaginal products should be
considered.
3. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian
failure.
4. Treatment of breast cancer (for palliation only) in appropriately selected women
and men with metastatic disease.
5. Treatment of advanced androgen-dependent carcinoma of the prostate (for
palliation only).
6. Prevention of osteoporosis. When prescribing solely for the prevention of
postmenopausal osteoporosis, therapy should only be considered for women at
significant risk of osteoporosis and for whom non-estrogen medications are not
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considered to be appropriate. (See CLINICAL PHARMACOLOGY, Clinical
Studies.)
The mainstays for decreasing the risk of postmenopausal osteoporosis are weight
bearing exercise, adequate calcium and vitamin D intake, and when indicated,
pharmacologic therapy. Postmenopausal women require an average of 1500 mg/day
of elemental calcium. Therefore, when not contraindicated, calcium
supplementation may be helpful for women with suboptimal dietary intake.
Vitamin D supplementation of 400-800 IU/day may also be required to ensure
adequate daily intake in postmenopausal women.
CONTRAINDICATIONS
Estrogens should not be used in individuals with any of the following conditions:
1. Undiagnosed abnormal genital bleeding.
2. Known, suspected or history of cancer of the breast except in appropriately selected
patients being treated for metastatic disease.
3. Known or suspected estrogen-dependent neoplasia.
4. Active deep vein thrombosis, pulmonary embolism or history of these conditions.
5. Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g.,
stroke, myocardial infarction).
6. Liver dysfunction or disease.
7. ESTRACE should not be used in patients with known hypersensitivity to its
ingredients. ESTRACE (estradiol tablets, USP), 2 mg, contain FD&C Yellow No. 5
(tartrazine) which may cause allergic-type reactions (including bronchial asthma) in
certain susceptible individuals. Although the overall incidence of FD&C Yellow
No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in
patients who also have aspirin hypersensitivity.
8. Known or suspected pregnancy. There is no indication for ESTRACE in pregnancy.
There appears to be little or no increased risk of birth defects in children born to
women who have used estrogens and progestins from oral contraceptives
inadvertently during early pregnancy. (See PRECAUTIONS.)
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WARNINGS
See BOXED WARNINGS.
1. Cardiovascular disorders
Estrogen and estrogen/progestin therapy has been associated with an increased risk
of cardiovascular events such as myocardial infarction and stroke, as well as venous
thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should
any of these occur or be suspected, estrogens should be discontinued immediately.
Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus,
tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism
(e.g., personal history or family history of VTE, obesity, and systemic lupus
erythematosus) should be managed appropriately.
a. Coronary heart disease and stroke
In the Women’s Health Initiative (WHI) study, an increase in the number of
myocardial infarctions and strokes has been observed in women receiving CE
compared to placebo. These observations are preliminary, and the study is
continuing. (See CLINICAL PHARMACOLOGY, Clinical Studies.)
In the CE/MPA substudy of WHI, an increased risk of coronary heart disease
(CHD) events (defined as nonfatal myocardial infarction and CHD death) was
observed in women receiving CE/MPA compared to women receiving placebo (37
vs 30 per 10,000 women-years). The increase in risk was observed in year one and
persisted.
In the same substudy of WHI, an increased risk of stroke was observed in women
receiving CE/MPA compared to women receiving placebo (29 vs 21 per 10,000
women-years). The increase in risk was observed after the first year and persisted.
In postmenopausal women with documented heart disease (n = 2,763, average age
66.7 years) a controlled clinical trial of secondary prevention of cardiovascular
disease (Heart and Estrogen/Progestin Replacement Study; HERS) treatment with
CE/MPA (0.625 mg/2.5 mg per day) demonstrated no cardiovascular benefit.
During an average follow-up of 4.1 years, treatment with CE/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/MPA-treated group than in
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the placebo group in year 1, but not during the subsequent years. Two thousand
three hundred and twenty one 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/MPA group and the placebo
group in HERS, HERS II, and overall.
Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those
used to treat cancer of the prostate and breast, have been shown in a large
prospective clinical trial in men to increase the risks of nonfatal myocardial
infarction, pulmonary embolism, and thrombophlebitis.
b. Venous thromboembolism (VTE)
In the Women’s Health Initiative (WHI) study, an increase in VTE has been
observed in women receiving CE compared to placebo. These observations are
preliminary, and the study is continuing. (See CLINICAL PHARMACOLOGY,
Clinical Studies.)
In the CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep
venous thrombosis and pulmonary embolism, was observed in women receiving
CE/MPA compared to women receiving placebo. The rate of VTE was 34 per
10,000 women-years in the CE/MPA group compared to 16 per 10,000
women-years in the placebo group. The increase in VTE risk was observed during
the first year and persisted.
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.
2. Malignant neoplasms
a. Endometrial cancer
The use of unopposed estrogens in women with intact uteri has been associated
with an increased risk of endometrial cancer. 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 one
year. The greatest risk appears associated with prolonged use—with increased risks
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of 15- to 24-fold for five to ten years or more—and this risk persists for 8 to over
15 years after estrogen therapy is discontinued.
Clinical surveillance of all women taking estrogen/progestin combinations is
important (see PRECAUTIONS). Adequate diagnostic measures, including
endometrial sampling when indi
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