CONTRAINDICATIONS
Estrogens/Progestins Combined Should Not Be Used in Women under Any of the Following
Conditions or Circumstances:
1. Known or suspected pregnancy, including use for missed abortion or as a diagnostic test
for pregnancy. (See BOXED WARNING.) Estrogen or progestin may cause fetal harm
when administered to a pregnant woman.
2. Known or suspected cancer of the breast.
3. Known or suspected estrogen-dependent neoplasia.
4. Undiagnosed abnormal genital bleeding.
5. Active or past history of thrombophlebitis, thromboembolic disorders, or stroke.
6. Liver dysfunction or disease.
Estrogens, conjugated; medroxyprogesterone acetate therapy should not be used in patients
hypersensitive to these ingredients.
WARNINGS
ALL WARNINGS BELOW PERTAIN TO THE USE OF THIS COMBINATION PRODUCT.
These findings are based on experience with estrogens and/or progestins.
Induction of Malignant Neoplasms
Breast Cancer: Some studies have reported a moderately increased risk of breast cancer (relative
risk of 1.3-2.0) in those women of estrogen replacement therapy taking higher doses, or in those
taking lower doses for prolonged periods of time, especially in excess of 10 years. The majority of
studies, however, have not shown an association in women who have ever used estrogen
replacement therapy.
The effect of added progestin on the risk of breast cancer in unknown, although a moderately
increased risk in those taking combination estrogen/progestin therapy has been reported. Other
studies have not shown this relationship. In one year clinical trials of estrogens, conjugated;
medroxyprogesterone acetate and conjugated estrogen alone, 5 new cases of breast cancer were
detected among 1377 women who received the combination treatments, while no new cases were
detected among 347 women who received conjugated estrogen alone. The overall incidence of
breast cancer in this clinical trial does not exceed that expected in the general population.
Women on hormone replacement therapy should have regular breast examinations and should be
instructed in breast self-examination, and women over the age of 50 should have regular
mammograms.
Endometrial Cancer: The reported endometrial cancer risk among users unopposed estrogen was
about 2- to 12-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 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 years or more. In one study, a significant decrease in the incidence of endometrial
cancer occurred 6 months after estrogen withdrawal.
A large clinical trial has demonstrated that when MPA is administered with conjugated estrogen,
there is a markedly reduced incidence of endometrial hyperplasia, a possible precursor of
endometrial cancer. Endometrial hyperplasia has been reported in a large clinical trial to occur at a
rate of approximately 1% or less with estrogens, conjugated; medroxyprogesterone acetate. Studies
have also demonstrated a reduced risk of endometrial cancer when a progestin is administered with
estrogen replacement therapy. In the large clinical trial described above, only a single case of
endometrial cancer was reported to occur among women taking combination conjugated
estrogen/MPA therapy.
Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate
diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule
out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding.
Cardiovascular Disease
Large doses of estrogens (5 mg conjugated estrogens per day), comparable to those used to treat
cancer of the prostate and breast, have been shown in large prospective clinical trial in men to
increase the risk of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.
These risks cannot necessarily be extrapolated from men to women or from unopposed estrogen to
combination estrogen/progestin therapy. 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.
Effects During Pregnancy
Use in pregnancy is not recommended. (See BOXED WARNING.)
Gallbladder Disease
Two studies have reported a 2- to 4-fold increase in the risk of surgically confirmed gallbladder
disease in women receiving postmenopausal estrogens. In a large clinical trial, 5 of 1029 subjects
taking conjugated estrogen; medroxyprogesterone acetate at doses comparable to
Prempro/Premphase developed cholecystitis with cholelithiasis that required cholecystectomy.
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. In a large clinical trial, transient elevations from baseline of 40 mm Hg or more systolic
and 20 mm Hg or more diastolic were reported in less than 2% and 4% of postmenopausal subjects,
respectively. 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 drugs should be stopped and appropriate measures taken to
reduce the serum calcium level.
Thromboembolic Disorders
The physician should be alert to the earliest manifestations of thrombotic disorders
(thrombophlebitis, cerebrovascular disorders, pulmonary embolism, and retinal thrombosis). Should
any of these occur or be suspected, the drugs should be discontinued immediately.
Visual Abnormalities
Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a
sudden onset of proptosis, diplopia, or migraine. If examinations reveals papilledema or retinal
vascular lesions, medication should be withdrawn.
PRECAUTIONS
Based on Experience with Estrogens and/or Progestins
Cardiovascular Risk: A casual 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
which assessed this statistical association have reported a 20-50% reduction in coronary heart
disease risk and associated mortality in estrogen takers, the following should be considered when
interpreting these reports.
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 life-style and medical characteristics of the women studied
with the result that healthier women were selected for estrogen therapy. In general, treated women
were of 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. Thus, ongoing and future large-scale randomized trials may fail to confirm this apparent
benefit.
Current medical practice often includes the use of concomitant progestin therapy in women with
intact uteri. While the effects of added progestins on the risk of ischemic heart disease are not
known, medroxyprogesterone acetate at the dose in estrogens, conjugated; medroxyprogesterone
acetate attenuates much of the favorable effect of conjugated estrogens on LDL levels (see
CLINICAL PHARMACOLOGY).
While the effects of added progestins on the risk of breast cancer are also unknown, available
epidemiologic evidence suggests that progestins do not reduce, and may enhance, the moderately
increased breast cancer risk that had been reported with prolonged estrogen replacement therapy
(see WARNINGS).
The safety data regarding estrogens, conjugated; medroxyprogesterone acetate were
obtained from clinical trials and epidemiologic studies of postmenopausal Caucasian
women, who were at generally low risk for cardiovascular disease and higher than
average risk for osteoporosis. The safety profile of estrogens, conjugated;
medroxyprogesterone acetate derived from these study demographic composition. When
considering prescribing estrogens, conjugated; medroxyprogesterone acetate, physicians
are advised to weigh the potential benefits and risks of therapy as applicable to each
individual patient.
Use in Hysterectomized Women: Existing data do not support the use of the combination of
estrogen and progestin in postmenopausal women without a uterus. There are possible risks which
may be associated with the inclusion of progestin in estrogen, replacement regimens. The potential
risks include some deterioration in glucose tolerance, as reported in a large clinical trial of estrogens,
conjugated; medroxyprogesterone acetate, and adverse effects on lipid metabolism as compared to
the lipid effects of conjugated estrogen alone. (See CLINICAL PHARMACOLOGY.)
Physical Examination: A complete medical and family history should be taken prior to the
initiation of any estrogen/progestin 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.
Fluid Retention: Because estrogens/progestins 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: Certain patients may develop abnormal uterine bleeding. In cases of
undiagnosed abnormal bleeding, adequate diagnostic measures are indicated. (See WARNINGS.)
The pathologist should be advised of estrogen/progestin therapy when relevant specimens are
submitted.
Based on Experience with Estrogens
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.
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 changes in levels of coagulation parameters at
baseline compared to premenopausal women, 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. In a large clinical trial
of estrogens, conjugated; medroxyprogesterone acetate, factors VII and X concentrations and
plasminogen activity increased by 20%, 13%, and 14% over baseline, respectively, and antithrombin
III activity decreased approximately 5% from baseline.
Mastodynia: Certain patients may develop undesirable manifestations of estrogenic stimulation
such as mastodynia. In a large clinical trial of estrogens, conjugated; medroxyprogesterone acetate,
approximately one third of the subjects reported breast pain during treatment with estrogens,
conjugated; medroxyprogesterone acetate, versus 12% for conjugated estrogen alone.
Based On Experience With Progestins
Lipoprotein Metabolism: See CLINICAL PHARMACOLOGY.
Impaired Glucose Tolerance: See "Use in Hysterectomized Women".
Depression: Patients who have a history of depression should be observed and the drugs
discontinued if the depression recurs to a serious degree.
Information for the Patient
(See PATIENT PACKAGE INSERT.)
Drug/Laboratory Test Interactions
1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time;
increased platelet count; increased factors II, VII 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 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 substrated,
alpha-1- antitrypsin, ceruloplasmin).
4. Increased plasma HDL and HDL-2 subfraction concentrations, reduced LDL cholesterol
concentration, increased triglycerides levels.
5. Impaired glucose tolerance. For this reason, diabetic patients should be carefully observed
while receiving estrogen/progestin therapy.
6. Reduced response to metyrapone test.
7. Reduced serum folate concentration.
8. Aminoglutethimide administered concomitantly with MPA may significantly depress the
bioavailability of MPA.
Mutagenesis and Carcinogenesis
In a two-year oral study in which female rats were exposed to dosages of up to 5000 mg/kg/day in
their diets (50 times higher-based on AUC values-than the level observed experimentally in women
taking 10 mg of MPA), a dose-related increase in pancreatic islet cell tumors (adenomas and
carcinomas) occurred. Pancreatic tumor incidence increased at 1000 and 5000 mg/kg/day, but not at
200 mg/kg/day.
A decreased incidence of spontaneous mammary gland tumors was observed in all three
MPA-treated groups, compared to controls, in the two-year rat study. The mechanism for the
decreased incidence of mammary gland tumors observed in the MPA-treated rats may be linked to
the significant decrease in serum prolactin concentration observed in rats.
Beagle dogs treated with MPA developed mammary nodules, some of which were malignant.
Although nodules occasionally appeared in control animals, they are intermittent in nature, whereas
the nodules in the drug-treated animals were larger, more numerous, persistent, and there were
some breast malignancies with metastases. It is known that progestogens stimulate synthesis and
release growth hormone in dogs. The growth hormone, along progestogen, stimulates mammary
growth and tumors. In contrast, growth hormone in humans is not increased, nor does growth
hormone have any significant mammotrophic role. Therefore, the MPA-induced increase of
mammary tumors in dogs probably has no significance to humans. No pancreatic tumors occurred
in dogs.
Pregnancy Category X
Estrogens/progestins 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. Estrogen administration to nursing
mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of
progestin have been identified in the milk of mothers receiving the drug. The effect of this on the
nursing infant has not been determined.