Cardiovascular and Other Risks: Estrogens with progestins should not be used for the prevention of cardiovascular disease or dementia.
The Women's Health Initiative (WHI) estrogen plus progestin sub study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo.
The Women's Health Initiative Memory Study (WHIMS), a sub study of the WHI study, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE 0.625 mg combined with MPA 2.5 mg, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.
In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and other combinations and dosage forms of estrogens and progestins. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
The use of PROVERA during the first four months of pregnancy is not recommended.
The physician should be alert to the earliest manifestation of thrombotic disorders (thrombophlebitis, cerebrovascular disorders, pulmonary embolism, and retinal thrombosis).
Should any of these occur or be suspected, the drug should be discontinued immediately.
MPA has not been causally associated with the induction of thrombotic or thromboembolic disorders, however MPA is not recommended in any patient with a history of venous thromboembolism (VTE). Discontinuation of MPA is recommended in patients who develop VTE while undergoing therapy with MPA.
PROVERA, especially in the high doses used for cancer therapy, may cause weight gain and fluid retention. With this in mind, caution should be exercised in treating any patient with a pre-existing medical condition that might be adversely affected by weight gain or fluid retention.
Any patient who develops an acute impairment of vision, proptosis, diplopia, or migraine headache should be carefully evaluated ophthalmologically to exclude the presence of papillo-edema or retinal vascular lesions before continuing medication.
10 mg: Before using PROVERA Tablets, the status of the patient should be carefully evaluated.
This evaluation should exclude the presence of genital or breast neoplasia before considering the use of PROVERA.
Some patients receiving PROVERA Tablets may exhibit a decreased glucose tolerance.
The mechanism for this is not known. This fact should be borne in mind when treating all patients and especially known diabetics.
A negative pregnancy test should be demonstrated before starting therapy with PROVERA.
Detectable amounts of PROVERA have been identified in the milk of mothers receiving the drug. The effect of this on nursing infants has not been determined.
The age of the patient constitutes no absolute limiting factors although treatment with PROVERA may mask the onset of the climacteric.
100 mg: The high doses of PROVERA used in the treatment of cancer patients may, in some cases, produce Cushingoid symptoms, e.g., moon faces, fluid retention, glucose intolerance, and blood pressure elevation.
In the treatment of carcinoma of breast occasionally cases of hypercalcaemia have been reported.
Medroxyprogesterone acetate and/or its metabolites are secreted in breast milk but there is no evidence to suggest that this presents any hazards to the child.
The administration of large doses to pregnant women has resulted in the observation of some instances of female foetal masculinisation. Doctors should therefore check that patients are not pregnant before commencing treatment.
Additional Warnings and Precautions for Specific Use or Formulation: Breast Cancer: The use of combined estrogen/progestin by post-menopausal women has been reported to increase the risk of breast cancer. Results from a randomized placebo-controlled trial, the WHI trial, and epidemiological studies have reported an increased risk of breast cancer in women taking estrogen/progestin combinations for HT for several years. In the WHI conjugated equine estrogens (CEE) plus MPA trial and observational studies, the excess risk increased with duration of use (see Dosage & Administration). The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation.
In several epidemiologic studies no overall increased risk for breast cancer was found among users of injectable depot progestogens in comparison to non-users. However, an increased relative risk (e.g., 2.0 in one study) was found for women who currently used injectable depot progestogens or had used them only for a few years before. It is not possible to infer from these data whether this increased rate of breast cancer diagnosis among current users is due to increased surveillance among current users, the biological effects of injectable progestogens, or a combination of reason.
Cardiovascular Disorders: Estrogens with or without progestins should not be used for the prevention of cardiovascular disease. Several randomized, prospective trials on the long-term effects (see Dosage & Administration) of a combined estrogen/progestin regimen in postmenopausal women have reported an increased risk of cardiovascular events such as myocardial infarction, coronary heart disease, stroke, and venous thromboembolism.
Coronary Artery Disease: There is no evidence from randomized controlled trials of cardiovascular benefit with continuous combined conjugated estrogen and medroxyprogesterone acetate (MPA). Two large clinical trials [WHI CEE/MPA and Heart and Estrogen/progestin Replacement Study (HERS)] showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit.
In the CEE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving CEE/MPA compared to women receiving placebo (37 vs. 30 per 10,000 person years).
Stroke: In the same substudy of WHI, an increased risk of stroke was observed in women receiving CEE/MPA compared to women receiving placebo (29 vs. 21 per 10,000 person-years). The increase in risk was observed in year one and persisted over the observation period. (See Dosage & Administration.)
Venous thromboembolism/Pulmonary embolism: HT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e., deep vein thrombosis or pulmonary embolism. In the CEE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism was observed in women receiving CEE/MPA compared to women receiving placebo. The increase in VTE risk was observed in year one and persisted over the observation period.
Dementia: Pooling data from the Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, for CEE-alone and CEE/MPA reported an increased risk of developing probable dementia and mild cognitive impairment (MCI) in postmenopausal women 65 years of age or older. Use of HT to prevent dementia or MCI in women is not recommended.
Ovarian Cancer: Current use of estrogen only or estrogen plus progestin products in post-menopausal women for five or more years, has been associated with an increased risk of ovarian cancer in some epidemiological studies. Past users of estrogen only or estrogen plus progestin products were at no increased risk for ovarian cancer. Other studies did not show a significant association. The WHI CEE/MPA trial reported that estrogen plus progestin increased risk of ovarian cancer, but this risk was not statistically significant. In one study, women who use HRT are at increased risk of fatal ovarian cancer.
History and Physical Exam Recommendation: A complete medical and family history should be taken before the initiation of any hormone therapy. Pretreatment and periodic physical examinations should include special reference to blood pressure, breasts, abdomen, and pelvic organs, including cervical cytology.
Oncology: MPA may produce cushingoid symptoms.
Some patients receiving MPA may exhibit suppressed adrenal function. MPA may decrease ACTH and hydrocortisone blood levels.
The physician/laboratory should be informed that in addition to the endocrine biomarkers as previously mentioned, the use of MPA in oncology indications may also cause partial adrenal insufficiency (decrease in pituitary-adrenal axis response) during metyrapone testing. Thus the ability of adrenal cortex to respond to ACTH should be demonstrated before metyrapone is administered.
Oral Formulations and High Dose Parenteral Formulations (e.g., oncology use in pre-menopausal women): Decrease in Bone Mineral Density: There are no studies on the bone mineral density (BMD) effects of orally administered MPA or the high dose of parenteral MPA (e.g., for oncology use). An evaluation of BMD may be appropriated in some patients who use MPA long-term.