A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Ogen Warnings, Precautions, Pregnancy, Nursing, Abuse - Estropipate
Ogen Warnings, Precautions, Pregnancy, Nursing, Abuse - Estropipate
WARNINGS
Induction of Malignant Neoplasms
Endometrial Cancer: The reported endometrial
cancer risk among unopposed
estrogen users is about 2-
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- 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. 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.
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.
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.
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.
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 seven 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, #4.,
below); (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 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 estrogen
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: Estrogen may be poorly metabolized
in patients with impaired liver
function and should be administered with caution.
Information for the Patient. See PATIENT
INFORMATION.
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 and treatment
of osteoporosis, however.
see DOSAGE AND ADMINISTRATION section.
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-l- 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
sections.
Pregnancy Category X.
Estrogens should not be used during pregnancy. See CONTRAINDICATIONS
and DESCRIPTION: BOXED WARNINGS
.
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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