WARNINGS
1. ESTROGENS HAVE BEEN REPORTED TO INCREASE THE RISK OF ENDOMETRIAL CARCINOMA IN POSTMENOPAUSAL WOMEN.
Close clinical surveillance of all women taking estrogens 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. There is no evidence that "natural" estrogens are more or less hazardous than "synthetic" estrogens at equiestrogenic doses.
2. ESTROGEN SHOULD NOT BE USED DURING PREGNANCY.
There is no indication for estrogen therapy during pregnancy or during the immediate postpartum period. Estrogens are ineffective for the prevention or treatment of threatened or habitual abortion. Estrogens are not indicated for the prevention of postpartum breast engorgement.
Estrogen therapy during pregnancy is associated with an increased risk of congenital defects in the reproductive organs of the fetus, and possibly other birth defects. Studies of women who received diethylstilbestrol (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. The 1985 DES Task Force concluded that use of DES during pregnancy is associated with a subsequent increased risk of breast cancer in the mothers, although a causal relationship remains unproven and the observed level of excess risk is similar to that for a number of other breast cancer risk factors.
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INNOFEM SUMMARY
WARNINGS
Innofem™ (Estradiol Tablets, USP) for oral administration contains 0.5, 1 or 2 mg of micronized estradiol per tablet.
Innofem™ (Estradiol Tablets, USP) is indicated in the:
- Treatment of moderate to severe vasomotor symptoms associated with the menopause. There is no adequate evidence that estrogens are effective for nervous symptoms or depression which might occur during menopause and they should not be used to treat these conditions.
- Treatment of vulval and vaginal atrophy.
- Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
- Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease.
- Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).
- Prevention of osteoporosis.
Since estrogen administration is associated with risk, selection of patients should ideally be based on prospective identification of risk factors for developing osteoporosis. Unfortunately, there is no certain way to identify those women who will develop osteoporotic fractures. Most prospective studies of efficacy for this indication have been carried out in white menopausal women, without stratification by other risk factors, and tend to show a universally salutary effect on bone. Thus, patient selection must be individualized based on the balance of risks and benefits. A more favorable risk/benefit ratio exists in a hysterectomized woman because she has no risk of endometrial cancer (see BOXED WARNINGS).
Estrogen replacement therapy reduces bone resorption and retards or halts post menopausal bone loss. Case-control studies have shown an approximately 60 percent reduction in hip and wrist fractures in women whose estrogen replacement was begun within a few years of menopause. Studies also suggest that estrogen reduces the rate of vertebral fractures. Even when started as late as 6 years after menopause, estrogen prevents further loss of bone mass for as long as the treatment is continued. The results of a two-year, randomized, placebo-controlled, double-blind, dose-ranging study have shown that treatment with 0.5 mg estradiol daily for 23 days (of a 28 day cycle) prevents vertebral bone mass loss in postmenopausal women. When estrogen therapy is discontinued, bone mass declines at a rate comparable to the immediate postmenopausal period. There is no evidence that estrogen replacement therapy restores bone mass to premenopausal levels.
At skeletal maturity there are sex and race differences in both the total amount of bone present and its density, in favor of men and blacks. Thus, women are at higher risk than men because they start with less bone mass and, for several years following natural or induced menopause, the rate of bone mass decline is accelerated. White and Asian women are at higher risk than black women.
Early menopause is one of the strongest predictors for the development of osteoporosis. In addition, other factors affecting the skeleton which are associated with osteoporosis include genetic factors (small build, family history), and endocrine factors (nulliparity, thyrotoxicosis, hyperparathyroidism, Cushing's syndrome, hyperprolactinemia, Type 1 diabetes), lifestyle (cigarette smoking, alcohol abuse, sedentary exercise habits) and nutrition (below average body weight, dietary calcium intake).
The mainstays of prevention and management of osteoporosis are estrogen, an adequate lifetime calcium intake, and exercise. Postmenopausal women absorb dietary calcium less efficiently than premenopausal women and require an average of 1500 mg/day of elemental calcium to remain in neutral calcium balance. By comparison, premenopausal women require about 1000 mg/day and the average of calcium intake in the USA is 400-600 mg/day, therefore, when not contraindicated, calcium supplementation may be helpful.
Weight-bearing exercise and nutrition may be important adjuncts to the prevention and management of osteoporosis. Immobilization and prolonged bed rest produce rapid bone loss, while weight-bearing exercise has been shown both to reduce bone loss and to increase bone mass. The optimal type and amount of physical activity that would prevent osteoporosis have not been established, however in two studies an hour of walking and running exercise twice or three times weekly significantly increased lumbar spine bone mass.
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