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 nonusers, 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 five to ten 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 six 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 1.3-2.0) in those taking higher doses
or those taking lower doses for prolonged periods of time,
especially in excess of 10 years.
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. Ethinyl estradiol and conjugated estrogens
have been shown to increase renin substrate. In contrast
to these oral estrogens, transdermally administered estradiol
has been reported not to affect renin substrate.
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.
Estraderm
Effects Similar to Those Caused by Estrogen-Progestogen
Oral Contraceptives: There are several serious
adverse effects of oral contraceptives and other high-dose
oral estrogen treatments, most of which have not, up to
now, been documented as consequences of postmenopausal
estrogen replacement therapy. This may reflect the comparatively
low doses of estrogen used in postmenopausal women.
Thromboembolic Disease: It
is now well established that users of oral contraceptives
have an increased risk of various thromboembolic and thrombotic
vascular disease, such as thrombophlebitis, pulmonary
embolism, stroke, and myocardial infarction. 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. An increased
risk of postsurgery thromboembolic complications has also
been reported in users of oral contraceptives. 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, 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 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 men 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.
Hepatic Adenoma: Benign hepatic
adenomas have been associated with the use of oral contraceptives.
Although benign and rare, these tumors may rupture and
cause death from intra-abdominal hemorrhage. Such lesions
have not yet been reported in association with other estrogen
or progestogen preparations, but they should be considered
if abdominal pain and tenderness, abdominal mass, or hypovolemic
shock occurs in patients receiving estrogen. Hepatocellular
carcinoma has also been reported in women taking estrogen-containing
oral contraceptives. The causal relationship of this malignancy
to these drugs is not known.
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.
PRECAUTIONS
General
Addition of a Progestin: Studies
of the addition of a progestin for 10 or more days of
a cycle of estrogen administration have reported a lowered
incidence of endometrial hyperplasia than would be induced
by estrogen treatment alone. Morphological and biochemical
studies of endometria suggest that 10 to 14 days of progestin
are needed to provide maximal maturation of the endometrium
and to reduce the likelihood of hyperplastic changes.
There are, however, possible risks which may be associated
with the use of progestins in estrogen replacement regimens.
These include: (1) adverse effects on lipoprotein metabolism
(lowering HDL and raising LDL) which could diminish the
purported 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 (see Drug/Laboratory Test Interactions). The choice
of progestin, its dose, and its regimen may be important
in minimizing these adverse effects, but these issues
will require further study before they are 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.
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.
Additional Information for Estraderm
Prolonged administration of unopposed estrogen therapy
has been reported to increase the risk of endometrial
hyperplasia in some patients. Estrogens should be used
with caution in patients who have or have had endometriosis.
Oral contraceptives, appear to be associated with an
increased incidence of mental depression. Although it
is not clear whether this is due to the ectogenic or progestogenic
component of the contraceptive, patients with a history
of depression should be carefully observed.
Preexisting uterine leiomyomata may increase in size
during prolonged estrogen use. If this occurs, estrogen
therapy should be discontinued while the cause is investigated.
In patients with a history of jaundice during pregnancy,
there is an increased risk that jaundice will recur with
the use of estrogen-containing oral contraceptives. If
jaundice develops in any patient receiving estrogen, the
medication should be discontinued while the cause is investigated.
Because the prolonged use of estrogens influences the
metabolism of calcium and phosphorus, estrogens should
be used with caution in patients with metabolic bone diseases
associated with hypercalcemia and in patients with renal
insufficiency.
Additional Information for Climara
Cardiovascular Risk: A causal
relationship between estrogen replacement therapy and
reduction of cardiovascular disease in postmenopausal
women has not been proven. Furthermore, the effect of
added progestins on this putative benefit is not yet known.
In recent years many published studies have suggested
that there may be a cause-effect relationship between
postmenopausal oral estrogen replacement therapy without
added progestins and a decrease in cardiovascular disease
in women. Although most of the observational studies that
assessed this statistical association have reported a
20% to 50% reduction in coronary heart disease risk and
associated mortality in estrogen takers, the following
should be considered when interpreting these reports:
(1) Because only one of these studies was randomized and
it was too small to yield statistically significant results,
all relevant studies were subject to selection bias. Thus,
the apparently reduced risk of coronary artery disease
cannot be attributed with certainty to estrogen replacement
therapy. It may instead have been caused by lifestyle
and medical characteristics of the women studied with
the result that healthier women were selected for estrogen
therapy. In general, treated women were of a higher socioeconomic
and educational status, more slender, more physically
active, more likely to have undergone surgical menopause,
and less likely to have diabetes than the untreated women.
Although some studies attempted to control for these selection
factors, it is common for properly designed randomized
trials to fail to confirm benefits suggested by less rigorous
study designs. (2) Current medical practice often includes
the use of concomitant progestin therapy with intact uteri
(see
WARNINGS
).
While the effects of added progestins on the risk of ischemic
heart disease are not known, all available progestins
reverse at least some of the favorable effects of estrogens
on HDL and LDL levels. (3) While the effects of added
progestins on the risk of breast cancer are also unknown,
available epidemiological evidence suggests that progestins
do not reduce, and may enhance, the moderately increased
breast cancer incidence that has been reported with prolonged
estrogen replacement therapy (see
WARNINGS
).
Because relatively long-term use of estrogens by a woman
with a uterus has been shown to induce endometrial cancer,
physicians often recommend that women who are deemed candidates
for hormone replacement should take progestins as well
as estrogens. When considering prescribing concomitant
estrogens and progestins for hormone replacement therapy,
physicians and patients are advised to carefully weigh
the potential benefits and risks of the added progestin.
Large-scale randomized, placebo-controlled, prospective
clinical trials are required to clarify these issues.
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.
Information for the Patient
See PATIENT PACKAGE INSERT; Vaginal Cream, Oral Tablets,
and Transdermal System.
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 betathromboglobulin; 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.
Laboratory Tests
Climara: 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.
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 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.
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