CONTRAINDICATIONS
Estrogens Should not Be Used in Individuals with Any of the Following Conditions:
1. Known or suspected pregnancy (see BOXED WARNING). Estrogens may cause fetal
harm when administered to a pregnant woman.
2. Undiagnosed abnormal genital bleeding.
3. Known or suspected cancer of the breast except in appropriately selected patients being
treated for metastatic disease.
4. Known or suspected estrogen-dependent neoplasia.
5. Active thrombophlebitis or thromboembolic disorders.
WARNINGS
1. Induction of Malignant Neoplasms:
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 of 15- to 24-fold for 5 to 10 years or more. In three studies, persistence of risk was
demonstrated for 8 to over 15 years after cessation of estrogen treatment. In one study a significant
decrease in the incidence of endometrial cancer occurred 6 months after estrogen withdrawal.
Concurrent progestin therapy may offset this risk but the overall health impact in postmenopausal
women is not known (see PRECAUTIONS).
Breast Cancer: While the majority of studies have not shown an increased risk of breast cancer in
women who have ever used estrogen replacement therapy, some have reported a moderately
increased risk (relative risks of 1.3-2) in those taking higher doses or those taking lower doses for
prolonged periods of time, especially in excess of 10 years. Other studies have not shown this
relationship.
Congenital Lesions with Malignant Potential: Estrogen therapy during pregnancy is associated
with an increased risk of fetal congenital reproductive tract disorders, and possibly other birth
defects. Studies of women who received DES during pregnancy have shown that female offspring
have an increased risk of vaginal adenosis, squamous cell dysplasia of the uterine cervix, and clear
cell vaginal cancer later in life; male offspring have an increased risk of urogenital abnormalities and
possibly testicular cancer later in life. Although some of these changes are benign, others are
precursors of malignancy.
2. Gallbladder Disease: Two studies have reported a 2- to 4-fold increase in the risk of
gallbladder disease requiring surgery 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 risks of nonfatal myocardial infarction,
pulmonary embolism, and thrombophlebitis. These risks cannot necessarily be extrapolated
from men to women. However, to avoid the theoretical cardiovascular risk to women caused
by high estrogen doses, the dose for estrogen replacement therapy should not exceed the
lowest effective dose.
4. Elevated Blood Pressure: Occasional blood pressure increases during estrogen
replacement therapy have been attributed to idiosyncratic reactions to estrogens. More often,
blood pressure has remained the same or has dropped. One study showed that
postmenopausal estrogen users have higher blood pressure than nonusers. Two other studies
showed slightly lower blood pressure among estrogen users compared to nonusers.
Postmenopausal estrogen use does not increase the risk of stroke. Nonetheless, blood
pressure should be monitored at regular intervals with estrogen use.
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.
PRECAUTIONS
General
Addition of a Progestin: 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 which would
otherwise be induced by estrogen treatment. Morphological and biochemical studies of endometrium
suggest that 10-14 days of progestin are needed to provide maximal maturation of the endometrium
and to eliminate any hyperplastic changes. There are possible additional risks which may be
associated with the inclusion of progestins in estrogen replacement regimens. These include: (1.)
adverse effects on lipoprotein metabolism (lowering HDL and raising LDL) which may diminish the
possible cardioprotective effect of estrogen therapy (see Drug/Laboratory Test Interactions); (2.)
impairment of glucose tolerance; and (3.) possible enhancement of mitotic activity in breast
epithelial tissue (although few epidemiological data are available to address this point). The choice
of progestin, its dose, and its regimen may be important in minimizing these adverse effects, but
these issues will remain to be clarified.
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 reexamining the patient.
Hypercoagulability: Some studies have shown that women taking estrogen replacement therapy
have hypercoagulability, primarily related to decreased antithrombin activity. This effect appears
dose- and duration-dependent and is less pronounced than that associated with oral contraceptive
use. Also, postmenopausal women tend to have increased coagulation parameters at baseline
compared to premenopausal women. There is some suggestion that low dose postmenopausal
mestranol may increase the risk of thromboembolism, although the majority of studies (of primarily
conjugated estrogens users) report no such increase. There is insufficient information on
hypercoagulability in women who have had previous thromboembolic disease.
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 exacerbated 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.
Impaired Liver Function: Estrogens may be poorly metabolized in patients with impaired liver
function and should be administered with caution.
Estrace 2 mg tablets 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.
Laboratory Tests
Estrogen administration should generally be guided by clinical response at the smallest dose, rather
than laboratory monitoring, for relief of symptoms for those indications in which symptoms are
observable. For prevention of osteoporosis, however, see DOSAGE AND ADMINISTRATION.
Drug/Laboratory Test Interactions
1. 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 activity.
2. Increased thyroid-binding globulin (TBG) 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.
3. 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, ceruloplasmin).
4. Increased plasma HDL and HDL-2 subfraction concentrations, reduced LDL cholesterol
concentration, increased triglycerides levels.
5. Impaired glucose tolerance.
6. Reduced response to metyrapone test.
7. Reduced serum folate concentration.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long term continuous administration of natural and synthetic estrogens in certain animal species
increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver (see
CONTRAINDICATIONS and WARNINGS).
Pregnancy, Teratogenic Effects, 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. In addition, estrogen administration
to nursing mothers has been shown to decrease the quantity and quality of the milk.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established. Large and repeated doses
of estrogen over an extended period of time have been shown to accelerate epiphyseal closure,
resulting in short adult stature if treatment is initiated before the completion of physiologic puberty in
normally developing children. In patients in whom bone growth is not complete, periodic monitoring
of bone maturation and effects on epiphyseal centers is recommended.
Estrogen treatment of prepubertal children also induces premature breast development and vaginal
cornification, and may potentially induce vaginal bleeding in girls. In boys, estrogen treatment may
modify the normal pubertal process. All other physiological and adverse reactions shown to be
associated with estrogen treatment of adults could potentially occur in the pediatric population,
including thromboembolic disorders and growth stimulation of certain tumors. Therefore, estrogens
should only be administered to pediatric patients when clearly indicated and the lowest effective
dose should always be utilized.