CONTRAINDICATIONS
Estrogens Should Not be Used in Women (or Men) with any of the Following Conditions:
1. Known or suspected cancer of the breast, except in appropriately selected patients being
treated for metastatic disease.
2. Known or suspected estrogen-dependent neoplasia.
3. Known or suspected pregnancy. (See BOXED WARNING.)
4. Undiagnosed abnormal genital bleeding.
5. Active thrombophlebitis or thromboembolic disorders.
6. A past history of thrombophlebitis, thrombosis, or thromboembolic disorders associated
with previous estrogen use (except when used in treatment of breast malignancy).
Conjugated estrogens should not be used in patients hypersensitive to its ingredients.
WARNINGS
Tablets
1. Induction of Malignant Neoplasms: Some studies have suggested a possible increased
incidence of breast cancer in those women on estrogen therapy taking higher doses for
prolonged periods of time. The majority of studies, however, have not shown an association
with the usual doses used for estrogen replacement therapy. Women on this therapy should
have regular breast examinations and should be instructed in breast self-examination. The
reported endometrial cancer risk among estrogen users was about 4-fold or greater than in
nonusers and appears dependent on duration of treatment and on estrogen dose. There is no
significant increased risk associated with the use of estrogens for less than one year. The
greatest risk appears associated with prolonged use--five years or more. In one study,
persistence of risk was demonstrated for 10 years after cessation of estrogen treatment. In
another study, a significant decrease in the incidence of endometrial cancer occurred six
months after estrogen withdrawal. Estrogen therapy during pregnancy is associated with an
increased risk of fetal congenital reproductive-tract disorders. In females there is an
increased risk of vaginal adenosis, squamous cell dysplasia of the cervix, and cancer later in
life; in the male, urogenital abnormalities. Although some of these changes are benign, it is
not known whether they are precursors of malignancy.
2. Gallbladder Disease: A recent study has reported a 2.5-fold increase in the risk of
surgically confirmed gallbladder disease in women receiving postmenopausal estrogens.
3. Cardiovascular Disease: 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 risk of nonfatal myocardial infarction,
pulmonary embolism, and thrombophlebitis. It cannot necessarily be extrapolated from men
to women. However, to avoid the theoretical cardiovascular risk caused by high estrogen
doses, the doses for estrogen replacement therapy should not exceed the recommended
dose.
4. Elevated Blood Pressure: There is no evidence that this may occur with use of
estrogens in the menopause. However, blood pressure should be monitored with estrogen
use, especially if high doses are used.
5. Hypercalcemia: Administration of estrogens may lead to severe hypercalcemia in
patients with breast cancer and bone metastases. If this occurs, the drug should be stopped
and appropriate measures taken to reduce the serum calcium level.
Injection and Vaginal Cream
1. Induction of Malignant Neoplasms: Long-term, continuous administration of natural and
synthetic estrogens in certain animal species increases the frequency of carcinomas of the
breast, cervix, vagina, and liver. There are now reports that estrogens increase the risk of
carcinoma of the endometrium in humans (see BOXED WARNING.) At the present time
there is no satisfactory evidence that estrogens given to postmenopausal women increase the
risk of cancer of the breast,17 although a recent long-term follow-up of a single physician's
practice has raised this possibility.18 Because of the animal data, there is a need for caution
in prescribing estrogens for women with a strong family history of breast cancer, or who
have breast nodules, fibrocystic disease, or abnormal mammograms.
2. Gallbladder Disease: A recent study has reported a 2- to 3-fold increase in the risk of
surgically confirmed gallbladder disease in women receiving postmenopausal estrogens,17
similar to the 2-fold increase previously noted in users of oral contraceptives.19,24a
3. Effects Similar to Those Caused by Estrogen-Progestogen Oral
Contraceptives: There are several serious adverse effects of oral contraceptives, most of
which have not, up to now, been documented as consequences of postmenopausal estrogen
therapy. This may reflect the comparatively low doses of estrogen used in postmenopausal
women. It would be expected that the larger doses of estrogen used to treat prostatic or
breast cancer are more likely to result in these adverse effects, and, in fact, it has been
shown that there is an increased risk of thrombosis in men receiving estrogens for prostatic
cancer.20- 23
a. Thromboembolic Disease: It is now well established that users of oral contraceptives
have an increased risk of various thromboembolic and thrombotic vascular diseases, such as
thrombophlebitis, pulmonary embolism, stroke, and myocardial infarction.24-31 Cases of
retinal thrombosis, mesenteric thrombosis, and optic neuritis have been reported in
oral-contraceptive users. There is evidence that the risk of several of these adverse
reactions is related to the dose of the drug.32,33 An increased risk of postsurgery
thromboembolic complications has also been reported in users of oral contraceptives.34,35 If
feasible, estrogen should be discontinued at least 4 weeks before surgery of the type
associated with an increased risk of thromboembolism, or during periods of prolonged
immobilization. While an increased rate of thromboembolic and thrombotic disease in
postmenopausal users of estrogens has not been found,17-24,25-36 this does not rule out the
possibility that such an increase may be present, or that subgroups of women who have
underlying risk factors, or who are receiving relatively large doses of estrogens, may have
increased risk. Therefore, estrogens should not be used in persons with active
thrombophlebitis or thromboembolic disorders, and they should not be used (expect in
treatment of malignancy) in persons with a history of such disorders in association with
estrogen use. They should be used with caution in patients with cerebral vascular or
coronary artery disease and only for those in whom estrogens are clearly needed. 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
men37 to increase the risk of nonfatal myocardial infarction, pulmonary embolism, and
thrombophlebitis. When estrogen doses of this size are used, any of the thromboembolic and
thrombotic adverse effects associated with oral-contraceptive use should be considered a
clear risk.
b. Hepatic Adenoma: Benign hepatic adenomas appear to be associated with the use of
oral contraceptives.38-40 Although benign, and rare, these may rupture and may cause death
through intra-abdominal hemorrhage. Such lesions have not yet been reported in association
with other estrogen or progestogen preparations but should be considered in estrogen users
having abdominal pain and tenderness, abdominal mass, or hypovolemic shock.
Hepatocellular carcinoma has also been reported in women taking estrogen-containing oral
contraceptives.39 The relationship of this malignancy to these drugs is not known at this time.
c. Elevated Blood Pressure: Women using oral contraceptives sometimes experience
increased blood pressure which, in most cases, returns to normal on discontinuing the drug.
There is now a report that this may occur with use of estrogens in the menopause41 and
blood pressure should be monitored with estrogen use, especially if high doses are used.
d. Glucose Tolerance: A worsening of glucose tolerance has been observed in a significant
percentage of patients on estrogen-containing oral contraceptives. For this reason, diabetic
patients should be carefully observed while receiving estrogen.
4. Hypercalcemia: Administration of estrogens may lead to severe hypercalcemia in
patients with breast cancer and bone metastases. If this occurs, the drug should be stopped
and appropriate measures taken to reduce the serum calcium level.
PRECAUTIONS
Tablets
General
Addition of a Progestin: Studies of the addition of a progestin for seven or more days of a cycle of
estrogen administration have reported a lowered incidence of endometrial hyperplasia.
Morphological and biochemical studies of endometrium suggest that 10 to 13 days of progestin are
needed to provide maximal maturation of the endometrium and to eliminate any hyperplastic
changes. Whether this will provide protection from endometrial carcinoma has not been clearly
established. There are possible additional risks which may be associated with the inclusion of
progestin in estrogen replacement regimens. The potential risks include adverse effects on
carbohydrate and lipid metabolism. The choice of progestin and dosage may be important in
minimizing these adverse effects.
Physical Examination: A complete medical and family history should be taken prior to the
initiation of any estrogen therapy. The pretreatment and periodic physical examinations should
include special reference to blood pressure, breasts, abdomen, and pelvic organs, and should include
a Papanicolaou smear. As a general rule, estrogen should not be prescribed for longer than one
year without another physical examination being performed.
Familial Hyperlipoproteinemia: Estrogen therapy may be associated with massive elevations of
plasma triglycerides leading to pancreatitis and other complications in patients with familial defects
of lipoprotein metabolism.
Fluid Retention: Because estrogens may cause some degree of fluid retention, conditions which
might be influenced by this factor, such as asthma, epilepsy, migraine, and cardiac or renal
dysfunction, require careful observation.
Uterine Bleeding and Mastodynia: Certain patients may develop undesirable manifestations of
estrogenic stimulation, such as abnormal uterine bleeding and mastodynia.
Uterine Fibroids: Preexisting uterine leiomyomata may increase in size during prolonged high-dose
estrogen use.
Impaired Liver Function: Estrogens may be poorly metabolized in patients with impaired liver
function and should be administered with caution.
Hypercalcemia and Renal Insufficiency: Prolonged use of estrogens can alter the metabolism of
calcium and phosphorus. Estrogens should be used with caution in patients with metabolic bone
disease.
Information for the Patient
See PATIENT PACKAGE INSERT.
Laboratory Tests
Clinical response at the smallest dose should generally be the guide to estrogen administration for
relief of symptoms for those indications in which symptoms are observable. However, for
prevention and treatment of osteoporosis see DOSAGE AND ADMINISTRATION. Tests used to
measure adequacy of estrogen replacement therapy include serum estrone and estradiol levels and
suppression of serum gonadotrophin levels.
Drug/Laboratory Test Interactions
Some of These Drug/Laboratory Test Interactions Have Been Observed Only with
Estrogen-Progestin Combinations (Oral Contraceptives):
1. Increased prothrombin and factors VII, VIII, IX and X; decreased antithrombin 3;
increased norepinephrine-induced platelet aggregability, decreased fibrinolysis.
2. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid
hormone, as measured by T4 levels determined either by column or by radioimmunoassay.
Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is
unaltered.
3. Impaired glucose tolerance.
4. Reduced response to metyrapone test.
5. Reduced serum folate concentration.
Mutagenesis And Carcinogenesis
Long-term continuous administration of natural and synthetic estrogens in certain animal species
increases the frequency of carcinomas of the breast, cervix, vagina, and liver.
Pregnancy Category X
Estrogens should not be used during pregnancy. (See CONTRAINDICATIONS and BOXED
WARNING.)
Nursing Mothers
As a general principle, the administration of any drug to nursing mothers should be done only when
clearly necessary since many drugs are excreted in human milk.
Injection and Vaginal Cream
General
A complete medical and family history should be taken prior to the initiation of any estrogen
therapy. The pretreatment and periodic physical examinations should include special reference to
blood pressure, breasts, abdomen, and pelvic organs, and should include a Papanicolaou smear. As
a general rule, estrogens should not be prescribed for longer than one year without another physical
examination being performed.
Fluid Retention: Because estrogens may cause some degree of fluid retention, conditions which
might be influenced by this factor, such as asthma, epilepsy, migraine, and cardiac or renal
dysfunction, require careful observation.
Familial Hyperlipoprotenemia: Estrogen therapy may be associated with massive elevations of
plasma triglycerides leading to pancreatitis and other complications in patients with familial defects
of lipoprotein metabolism.
Certain patients may develop undesirable manifestations of excessive estrogenic stimulation, such
as abnormal or excessive uterine bleeding, mastodynia, etc.
Information for the Patient
See PATIENT PACKAGE INSERT.
Drug/Laboratory Tests Interactions
Certain endocrine and liver function tests may be affected by estrogen-containing oral
contraceptives. The following similar changes may be expected with larger doses of estrogen:
Increased sulfobromophthalein retention.
Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased
norepinephrine-induced platelet aggregability.
Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid
hormone, as measured by PBI, T4 by column, or T4 by radioimmunoassay. Free T3 resin
uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered.
Impaired glucose tolerance.
Decreased pregnanediol excretion.
Reduced response to metyrapone test.
Reduced serum folate concentration.
Increased serum triglyceride and phospholipid concentration.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
See WARNINGS for information on carcinogenesis.
Pregnancy Category X
(See CONTRAINDICATIONS and BOXED WARNING.)
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk and because of the potential for serious adverse reactions in nursing infants from
estrogens, a decision should be made whether to discontinue nursing or to discontinue the drug,
taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in children have not been established.
Additional Information for Vaginal Cream
Prolonged administration of unopposed estrogen therapy has been reported to increase the risk of
endometrial hyperplasia in some patients.
Oral contraceptives appear to be associated with an increased incidence of mental depression.24a
Although it is not clear whether this is due to the estrogenic or progestogenic component of the
contraceptive, patients with a history of depression should be carefully observed.
Preexisting uterine leiomyomata may increase in size during estrogen use.
The pathologist should be advised of estrogen therapy when relevant specimens are submitted.
Patients with a past history of jaundice during pregnancy have an increased risk of recurrence of
jaundice while receiving estrogen-containing oral-contraceptive therapy. If jaundice develops in any
patient receiving estrogen, the medication should be discontinued while the cause is investigated.
Estrogens may be poorly metabolized in patients with impaired liver function and should be
administered with caution in such patients.
Because estrogens influence the metabolism of calcium and phosphorus, they should be used with
caution in patients with metabolic bone diseases that are associated with hypercalcemia or in
patients with renal insufficiency.
Because of the effects of estrogens on epiphyseal closure, they should be used judiciously in young
patients in whom bone growth is not yet complete.
Concomitant Progestin Use: The lowest effective dose appropriate for the specific indication
should be utilized. Studies of the addition of a progestin for 7 or more days of a cycle of estrogen
administration have reported a lowered incidence of endometrial hyperplasia. Morphological and
biochemical studies of the endometrium suggest that 10-13 days of progestin are needed to provide
maximal maturation of the endometrium and to eliminate any hyperplastic changes. Whether this
will provide protection from endometrial carcinoma has not been clearly established. There are
possible additional risks which may be associated with the inclusion of a progestin in estrogen
replacement regimens. If concomitant progestin therapy is used, potential risks may include adverse
effects on carbohydrate and lipid metabolism. The choice of progestin and dosage may be important
in minimizing these adverse effects.
Additional Information for Injection
Certain endocrine and liver function tests may be affected by estrogen-containing oral
contraceptives. The following similar changes may be expected with larger doses of estrogen:
Increased sulfobromophthalein retention.
Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased
norepinephrine-induced platelet aggregability.
Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid
hormone, as measured by PBI, T4 by column, or T4 by radioimmunoassay. Free T3 resin
uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered.
Impaired glucose tolerance.
Decreased pregnanediol excretion.
Reduced response to metyrapone test.
Reduced serum folate concentration.
Increased serum triglyceride and phospholipid concentration.