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 wshow no significant increased risk
associated with use of estrogens for less than one year.
The greatest risk appears associated with prolonged use¾with
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 to 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.
Information for the Patient
See PATIENT PACKAGE INSERT, Vaginal Cream, Oral Tablets,
and Transdermal System.
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.
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