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WARNINGSESTROGENS 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 result 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 and 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
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 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.
Estropipate (formerly piperazine estrone sulfate), is a natural estrogenic
substance prepared from purified crystalline estrone, solubilized as the sulfate
and stabilized with piperazine. It is appreciably soluble in water and has
almost no odor or taste — properties which are ideally suited for oral
administration. The amount of piperazine in estropipate is not sufficient to
exert a pharmacological action. Its addition ensures solubility, stability, and
uniform potency of the estrone sulfate. Chemically estropipate, molecular
weight: 436.56, is represented by estra-1,3,5(10)-trien-17-one,3-(sulfooxy)-,
compound with piperazine (1:1). The structural formula may be represented as
Estropipate is available as tablets for oral administration containing either
0.75 mg, 1.5 mg, 3 mg, or 6 mg estropipate (calculated as sodium estrone sulfate
0.625 mg, 1.25 mg, 2.5 mg and 5 mg, respectively).Inactive Ingredients
Each tablet contains: lactose NF, magnesium stearate NF,
piperazine USP, pregelatinized starch NF, talc USP, and coloring agents: 0.75
mg—D&C Yellow #10; 1.5 mg—FD&C Yellow #6; 3 mg—FD&C Blue #2; 6
mg—FD&C Blue #2 and D&C Yellow #10.
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
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.
Estrogens are well absorbed through the skin and gastrointestinal
tract. When applied for a local action, absorption is usually sufficient to
cause systemic effects.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
Estradiol, estrone, and estriol are excreted in the urine along
with glucuronide and sulfate conjugates.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
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 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.
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
|Event c||Relative Risk||Placebo||CE/MPA|
|CE/MPA vs. placebo||n=8102||N=8506|
|at 5.2 Years||Absolute Risk per
|CHD events||1.29 (1.02-1.63)||30||37|
|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||0.92 (0.74-1.14)||40||37|
|other than the events
|Global indexc||1.15 (1.03-1.28)||151||170|
|a adapted from JAMA, 2002; 288:321-333|
|b includes metastatic and non-metastatic breast cancer with the exception of in
situ breast cancer|
|c 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
|d not included in Global Index|
|* nominal confidence intervals unadjusted for multiple looks and multiple
For those outcomes included in the "global index," the absolute excess risks
per 10,000 person-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 absolute
risk reductions per 10,000 person-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
PRECAUTIONS.)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 (0.625mg 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
WARNINGS and WARNINGS,
The results of a double-blind, placebo-controlled two-year study
have shown that treatment with one tablet of estropipate 0.625 daily for 25 days
(of a 31-day cycle per month) prevents vertebral bone mass loss in
postmenopausal women. When estrogen therapy is discontinued, bone mass declines
at a rate comparable to that of the immediate postmenopausal period. There is no
evidence that estrogen replacement therapy restores to premenopausal levels.
Indications And Usage
Estropipate tablets are indicated in the:
Treatment of moderate to severe vasomotor symptoms associated
with the menopause.
Treatment of moderate to severe symptoms of vulval 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
Treatment of hypoestrogenism due to hypogonadism, castration or
primary ovarian failure.
Prevention of postmenopausal 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 considered to be appropriate.
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.
Estropipate tablets should not be used in women with any of the
Undiagnosed abnormal genital bleeding.
Known, suspected, or history of cancer of the breast.
Known or suspected estrogen-dependent neoplasia.
Active deep vein thrombosis, pulmonary embolism or history of
Active or recent (e.g., within the past year) arterial
thromboembolic disease (e.g., stroke, myocardial infarction).
Liver dysfunction or disease.
Estropipate tablets should not be used in patients with known
hypersensitivity to its ingredients.
Known or suspected pregnancy. There is no indication for
estropipate tablets 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
1. Cardiovascular Disorders
Estrogen and estrogen/progestin therapy have 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
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
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 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 study (WHI) an increase in
VTE has been observed in women receiving CE compared to placebo. These
observations are preliminary, and the study is continuing.
In the CE/MPA treatment substudy of WHI, a 2-fold greater rate of VTE,
including deep venous thrombosis and pulmonary embolism, was observed in women
receiving treatment with CE/MPA compared to women receiving placebo. The rate of
VTE was 34 per 10,000 woman-years in the CE/MPA group compared to 16 per 10,000
woman-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 nonusers, 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 of 15–to-24 fold for five to ten 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 taking estrogen/progestin combinations 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 of equivalent estrogen dose. Adding a
progestin to estrogen therapy has been shown to reduce the risk of endometrial
hyperplasia, which may be a precursor to endometrial cancer.b. Breast cancer
The use of estrogens and progestins by postmenopausal women has
been reported to increase the risk of breast cancer. The most important
randomized clinical trial providing information about this issue is the Women’s
Health Initiative (WHI) substudy of CE/MPA (see CLINICAL PHARMACOLOGY, Clinical Studies). The
results from observational studies are generally consistent with those of the
WHI clinical trial and report no significant variation in the risk of breast
cancer among different estrogens or progestins, doses, or routes of
The CE/MPA substudy of WHI reported an increased risk of breast cancer in
women who took CE/MPA for a mean follow-up of 5.6 years. Observational studies
have also reported an increased risk for estrogen/progestin combination therapy,
and a smaller increased risk for estrogen alone therapy, after several years of
use. In the WHI trial and from observational studies, the excess risk increased
with duration of use. From observational studies, the risk appeared to return to
baseline in about five years after stopping treatment. In addition,
observational studies suggest that the risk of breast cancer was greater, and
became apparent earlier, with estrogen/progestin combination therapy as compared
to estrogen alone therapy.
In the CE/MPA substudy, 26% of the women reported prior use of estrogen alone
and/or estrogen/progestin combination hormone therapy. After a mean follow-up of
5.6 years during the clinical trial, the overall relative risk of invasive
breast cancer was 1.24 (95% confidence interval 1.01-1.54), and the overall
absolute risk was 41 vs. 33 cases per 10,000 women-years, for CE/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
vs. 25 cases per 10,000 women-years, for CE/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 vs. 36 cases per
10,000 women-years for CE/MPA compared with placebo. In the same substudy,
invasive breast cancers were larger and diagnosed at a more advanced stage in
the CE/MPA 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
The use of estrogen plus progestin has been reported to result in an increase
in abnormal mammograms requiring further evaluation. All women should receive
yearly breast examinations by a health care provider and perform monthly breast
self-examinations. In addition, mammography examinations should be scheduled
based on patient age, risk factors, and prior mammogram results.
In the Women’s Health Initiative Memory Study (WHIMS), 4,532 generally healthy
postmenopausal women 65 years of age and older were studied, of whom 35% were 70
to 74 years of age and 18% were 75 or older. After an average follow-up of 4
years, 40 women being treated with CE/MPA (1.8%, n= 2,229) and 21 women in the
placebo group (0.9%, n= 2,303) received diagnoses of probable dementia. The
relative risk for CE/MPA versus placebo was 2.05 (95% confidence interval 1.21 –
3.48), and was similar for women with and without histories of menopausal
hormone use before WHIMS. The absolute risk of probable dementia for CE/MPA
versus placebo was 45 versus 22 cases per 10,000 women-years. It is unknown
whether these findings apply to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical
Studies and PRECAUTIONS,
4. Gallbladder Disease
A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in
postmenopausal women receiving estrogens has been reported.
Estrogen administration may lead to severe hypercalcemia in patients 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.
6. Visual Abnormalities
Retinal vascular thrombosis has been reported in patients 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.
Enter section text here
1. Addition of a progestin when a woman has not had a
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 a
possible increased risk of breast cancer, adverse effects on lipoprotein
metabolism (e.g., lowering HDL, raising LDL) and impairment of glucose
tolerance.2. 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. Blood pressure should be monitored at
regular intervals with estrogen use.3. Hypertriglyceridemia
In patients with pre-existing hypertriglyceridemia, estrogen
therapy may be associated with elevations of plasma triglycerides leading to
pancreatitis and other complications.4. Impaired liver function and past history of cholestatic
Estrogens may be poorly metabolized in patients with impaired
liver function. For patients 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.5. Hypothyroidism
Estrogen administration leads to increased thyroid-binding
globulin (TBG) levels. Patients 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. Patients dependent on thyroid hormone replacement therapy who are
also receiving estrogens may require increased doses of their thyroid
replacement therapy. These patients should have their thyroid function monitored
in order to maintain their free thyroid hormone levels in an acceptable
range.6. Fluid retention
Because estrogens may cause some degree of fluid retention,
patients with conditions that might be influenced by this factor, such as a
cardiac or renal dysfunction, warrant careful observation when estrogens are
Estrogens should be used with caution in individuals with severe
hypocalcemia.8. Ovarian cancer
The CE/MPA substudy of WHI reported that estrogen plus progestin
increased the risk of ovarian cancer. After an average follow-up of 5.6 years,
the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 (95%
confidence interval 0.77 – 3.24) but was not statistically significant. The
absolute risk for CE/MPA versus placebo was 4.2 versus 2.7 cases per 10,000
women-years. In some epidemiologic studies, the use of estrogen alone, in
particular for ten or more years, has been associated with an increased risk of
ovarian cancer. Other epidemiologic studies have not found these
associations.9. Exacerbation of endometriosis
Endometriosis may be exacerbated with administration of
estrogens. A few cases of malignant transformation of residual endometrial
implants have been reported in women treated post-hysterectomy with estrogen
alone therapy. For patients known to have residual endometriosis
post-hysterectomy, the addition of progestin should be considered.10. Exacerbation of other conditions
Estrogens may cause an exacerbation of asthma, diabetes mellitus,
epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic
hemangiomas and should be used with caution in women with these conditions.
B. Patient Information
Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients
for whom they prescribe estropipate tablets.
C. Laboratory Tests
Estrogen administration should be initiated at the lowest dose approved for the
indication and then guided by clinical response rather than by serum hormone
levels (e.g., estradiol, FSH).
D. 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 anti-factor 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, 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. Patients on thyroid
replacement therapy may require higher doses of thyroid hormone.
Other binding proteins may be elevated in serum, (i.e.,
corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG),
leading to increased circulating corticosteroids and sex steroids, respectively.
Free or biologically active hormone concentrations are unchanged. Other plasma
proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin,
Increased plasma HDL and HDL2 subfraction concentrations, reduced
LDL cholesterol concentration, increased triglycerides levels.
Impaired glucose tolerance.
Reduced response to metyrapone test.
Reduced serum folate concentration.
E. Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term continuous administration of estrogen, with and without
progestin, in women with and without a uterus, has shown an increased risk of
endometrial cancer, breast cancer, and ovarian cancer. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
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.
Estropipate tablets should not be used during pregnancy. (See CONTRAINDICATIONS.)
G. Nursing Mothers
Estrogen administration to nursing mothers has been shown to decrease the
quantity and quality of the milk. Detectable amounts of estrogens have been
identified in the milk of mothers receiving this drug. Caution should be
exercised when estropipate is administered to a nursing woman.
H. Geriatric Use
In the Women’s Health Initiative Memory Study, including 4,532 women 65 years of
age and older, followed for an average of 4 years, 82% (n= 3,729) were 65 to 74
while 18% (n= 803) were 75 and over. Most women (80%) had no prior hormone
therapy use. Women treated with conjugated estrogens plus medroxyprogesterone
acetate were reported to have a two-fold increase in the risk of developing
probable dementia. Alzheimer’s disease was the most common classification of
probable dementia in both the conjugated estrogens plus medroxyprogesterone
acetate group and the placebo group. Ninety percent of the cases of probable
dementia occurred in the 54% of women that were older than 70. (See WARNINGS, Dementia.)
The following additional adverse reactions have been reported with estrogens
and/or progestin therapy.
1. Genitourinary System
Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow;
breakthrough bleeding; spotting; dysmenorrhea; increase in size of uterine
leiomyomata; vaginitis; including vaginal candidiasis; change in amount of
cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial
hyperplasia; endometrial cancer.
Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic
breast changes; breast cancer.
Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis;
myocardial infarction; stroke; increase in blood pressure.
Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; increased
incidence of gallbladder disease; pancreatitis; enlargement of hepatic
Chloasma or melasma that may persist when drug is discontinued; erythema
multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair;
hirsutism; pruritus, rash.
Retinal vascular thrombosis; steepening of corneal curvature; intolerance to
7. Central Nervous System
Headache, migraine, dizziness; mental depression; chorea; nervousness; mood
disturbances; irritability; exacerbation of epilepsy; dementia.
Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of
porphyria; edema; arthralgias; leg cramps; urticaria; angioedema;
anaphylactoid/anaphylactic reactions; hypocalcemia; exacerbation of asthma;
changes in libido; triglycerides.
Serious ill effects have not been reported following acute ingestion of large
doses of estrogen-containing oral contraceptives by young children. Overdosage
of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in
Dosage And Administration
When estrogen is prescribed for a woman with a uterus, progestin
should also be initiated to reduce the risk of endometrial cancer. A woman
without a uterus does not need progestin. Use of estrogen, alone or in
combination with a progestin, should be with the lowest effective dose and for
the shortest duration consistent with treatment goals and risks for the
individual woman. Patients should be reevaluated periodically as clinically
appropriate (e.g., 3-month to 6-month intervals) to determine if treatment is
still necessary (See BOXED
WARNINGS.) For women who have a uterus, adequate diagnostic measures,
such as endometrial sampling, when indicated, should be undertaken to rule out
malignancy in cases of undiagnosed persistent or recurring abnormal vaginal
For treatment of moderate to severe vasomotor symptoms, vulval
and vaginal atrophy associated with the menopause, the lowest dose and regimen
that will control symptoms should be chosen and medication should be
discontinued as promptly as possible. Attempts to discontinue or taper
medication should be made at 3month to 6-month intervals. Usual dosage
Vasomotor symptoms—One estropipate 0.75
mg tablet to two estropipate 3 mg tablets per day. The lowest dose that will
control symptoms should be chosen. If the patient has not menstruated within the
last two months or more, cyclic administration is started arbitrarily. If the
patient is menstruating, cyclic administration is started on day 5 of
Vulval and vaginal atrophy—One
estropipate 0.75 mg tablet to two estropipate 3 mg tablets daily, depending upon
the tissue response of the individual patient. The lowest dose that will control
symptoms should be chosen. Administer cyclically.
For treatment of female hypoestrogenism due to hypogonadism,
castration, or primary ovarian failure. Usual dosage ranges:
Female hypogonadism—A daily dose of one estropipate 1.5 mg
tablet to three estropipate 3 mg tablets may be given for the first three weeks
of a theoretical cycle, followed by a rest period of eight to ten days. The
lowest dose that will control symptoms should be chosen. If bleeding does not
occur by the end of this period, the same dosage schedule is repeated. The
number of courses of estrogen therapy necessary to produce bleeding may vary
depending on the responsiveness of the endometrium. If satisfactory withdrawal
bleeding does not occur, an oral progestogen may be given in addition to
estrogen during the third week of the cycle.
castration or primary ovarian failure—A daily dose of one estropipate 1.5
mg tablet to three estropipate 3 mg tablets may be given for the first three
weeks of a theoretical cycle, followed by a rest period of eight to ten days.
Adjust dosage upward or downward according to severity of symptoms and response
of the patient. For maintenance, adjust dosage to lowest level that will provide
Treated patients with an intact uterus should be
monitored closely for signs of endometrial cancer and appropriate diagnostic
measures should be taken to rule out malignancy in the event of persistent or
recurring abnormal vaginal bleeding.
For prevention of osteoporosis. A daily dose of one estropipate
0.75 mg tablet for 25 days of a 31-day cycle per month.
Estropipate tablets USP are supplied as follows:
Store at 20° - 25°C (68° - 77°F). [See USP controlled room
- 0.75 mg Estropipate (calculated as sodium estrone sulfate 0.625 mg) as round,
scored, yellow tablets, in: bottles of 30 NDC 54868-3114-0
bottles of 100 NDC 54868-3114-1
- 1.5 mg Estropipate (calculated as sodium estrone sulfate 1.25 mg) as round,
scored, peach tablets, in: bottles of 30 NDC 54868-4149-0
bottles of 100 NDC 54868-4149-1
- 3 mg Estropipate (calculated as sodium estrone sulfate 2.5 mg) as round, scored,
blue tablets, in: bottles of 30 NDC 54868-4761-1
bottles of 60 NDC 54868-4761-2
Supplemental Patient Material
Estropipate Tablets USP
Read this PATIENT INFORMATION before you start taking estropipate tablets and
read what you get each time you refill estropipate tablets. There may be new
information. This information does not take the place of talking to your health
care provider about your medical condition or your treatment.
|WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT
ESTROPIPATE (AN ESTROGEN HORMONE)?|
|• Estrogens increase the chances of getting cancer of the uterus.|
Report any unusual vaginal bleeding right away while you are taking estrogens.
Vaginal bleeding after menopause may be a warning sign of cancer of the uterine
(womb). Your health care provider should check any unusual vaginal bleeding to
find out the cause.
|• Do not use estrogens with or without progestins to prevent heart disease,
heart attacks or strokes.|
Using estrogens with or without progestins may increase your chances of getting
heart attacks, strokes, breast cancer and blood clots. You and your health care
provider should talk regularly about whether you still need treatment with
What is estropipate?
Estropipate is a medicine that contains estrogen hormones.
What is estropipate used for?
Estropipate is used during and after menopause to:
reduce moderate or severe hot flashes.
Estrogens are hormones made by a woman’s ovaries. The ovaries normally stop
making estrogens when a woman is between 45 to 55 years old. This drop in body
estrogen levels causes the “change of life” or menopause (the end of monthly
menstrual periods). Sometimes, both ovaries are removed during an operation
before natural menopause takes place. The sudden drop in estrogen levels causes
When the estrogen levels begin dropping, some women develop very
uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest,
or sudden strong feelings of heat and sweating (“hot flashes” or “hot flushes”).
In some women, the symptoms are mild, and they do not need to use estrogens. In
other women, symptoms can be more severe. You and your health care provider
should talk regularly about whether you still need treatment with estropipate
treat moderate to severe dryness, itching, and
burning in and around the vagina.
You and your health care provider should talk regularly about whether you
still need treatment with estropipate tablets to control these problems. If you
use estropipate tablets only to treat your dryness, itching, and burning in and
around your vagina, talk with your health care provider about whether a topical
vaginal product would be better for you.
help reduce your chances of getting osteoporosis
(thin weak bones).
Osteoporosis from menopause is a thinning of the bones that makes them weaker
and easier to break. If you use estropipate tablets only to prevent osteoporosis
from menopause, talk with your health care provider about whether a different
treatment or medicine without estrogens might be better for you. You and your
health care provider should talk regularly about whether you should continue
with estropipate tablets.
Weight-bearing exercise, like walking or running, and taking calcium and
vitamin D supplements may also lower your chances of getting postmenopausal
osteoporosis. It is important to talk about exercise and supplements with your
health care provider before starting them.
Estropipate is also used to:
treat certain conditions in women before menopause if their ovaries do not
make enough estrogen naturally.
Who should not take estropipate tablets?
Do not start taking estropipate tablets if you:
have unusual vaginal bleeding.
currently have or have had certain
Estrogens may increase the chances of getting certain types of cancers,
including cancer of the breast or uterus. If you have or had cancer, talk with
your health care provider about whether you should take estropipate tablets.
had a stroke or heart attack in the past
currently have or have had blood clots.
currently have or have had liver
are allergic to estropipate tablets or any of
See the end of this leaflet for a list of ingredients in estropipate
think you may be pregnant.
Tell your health care provider:
if you are breastfeeding.
The hormone in estropipate tablets can pass into your milk.
about all of your medical problems.
Your health care provider may need to check you more carefully if you have
certain conditions, such as asthma (wheezing), epilepsy (seizures), migraine,
endometriosis, or problems with your heart, liver, thyroid, kidneys, or have
high calcium levels in your blood.
about all the medicines you take.
This includes prescription and nonprescription medicines, vitamins, and
herbal supplements. Some medicines may affect how estropipate works. Estropipate
may also affect how your other medicines work.
if you are going to have surgery or will be on
You may need to stop taking estrogens.
How should I take estropipate tablets?
Take estropipate tablets as directed by your health care provider.
Estropipate comes in four strengths. Check with your health care provider
periodically to make sure you are using the appropriate dose.
Estropipate Tablets USP
1. Start at the lowest dose and talk to your health care provider about how
well that dose is working for you.
2. Estrogens should be used at the lowest dose possible for your treatment
only as long as needed. The lowest effective dose of estropipate has not been
determined. You and your health care provider should talk regularly (for
example, every 3 to 6 months) about whether you still need treatment with
What are the possible side effects of estrogens?
Less common but serious side effects include:
Cancer of the uterus
These are some of the warning signs of serious side
Unusual vaginal bleeding
Dizziness and faintness
Changes in speech
Shortness of breath
Pains in your legs
Changes in vision
Call your health care provider right away if you get any of these warning
signs, or any other unusual symptom that concerns you.
Common side effects include:
Irregular vaginal bleeding or spotting
Stomach/abdominal cramps, bloating
Nausea and vomiting
Other side effects include:
High blood pressure
High blood sugar
Enlargement of benign tumors of the uterus (“fibroids”)
Vaginal yeast infections
These are not all the possible side effects of estropipate tablets. For more
information, ask your health care provider or pharmacist.
What can I do to lower my chances of getting a serious side
effect with estropipate tablets?
Talk with your health care provider regularly about whether you should
continue taking estropipate tablets. If you have a uterus, talk to your health
care provider about whether the addition of a progestin is right for you. See
your health care provider right away if you get vaginal bleeding while taking
estropipate tablets. Have a breast exam and mammogram (breast X-ray) every year
unless your health care provider tells you something else. If members of your
family have had breast cancer or if you have ever had breast lumps or an
abnormal mammogram, you may need to have breast examinations more often. If you
have high blood pressure, high cholesterol (fat in the blood), diabetes, are
overweight, or if you use tobacco, you may have higher chances for getting heart
disease. Ask your health care provider for ways to lower your chances for
getting heart disease.
General information about safe and effective use of
Medicines are sometimes prescribed for conditions that are not mentioned in
patient information leaflets. Do not take estropipate for conditions for which
it was not prescribed. Do not give estropipate tablets to other people, even if
they have the same symptoms you have. It may harm them. Keep
estropipate tablets out of the reach of children.
This leaflet provides a summary of the most important information about
estropipate tablets. If you would like more information, talk with your health
care provider or pharmacist. You can ask for information about estropipate
tablets that is written for health professionals. You can get more information
by calling the toll free number 1-800-272-5525.
What are the ingredients in estropipate tablets?
Estropipate tablets contain estropipate as the active ingredient. Estropipate
tablets also contain: lactose NF, magnesium stearate NF, piperazine USP,
pregelatinized starch NF, talc USP, and coloring agents: 0.75 mg—D&C Yellow
#10; 1.5 mg—FD&C Yellow #6; 3 mg— FD&C Blue #2; 6 mg—FD&C Blue #2
and D&C Yellow #10.
Watson Laboratories, Inc.
Corona, CA 92880 USA
Revised April 2006
Relabeling and Repackaging by:
Physicians Total Care, Inc.
Tulsa, OK 74146
Principal Display Panel
Estropipate Tablets USP
* Please review the disclaimer below.