Innofem

Innofem

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Questions & Answers

Side Effects & Adverse Reactions

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 non-users, 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 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 know (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.

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.

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.

Legal Issues

There is currently no legal information available for this drug.

FDA Safety Alerts

There are currently no FDA safety alerts available for this drug.

Manufacturer Warnings

There is currently no manufacturer warning information available for this drug.

FDA Labeling Changes

There are currently no FDA labeling changes available for this drug.

Uses

Innofem™ (Estradiol Tablets, USP) is indicated in the:

  1. 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.
  2. Treatment of vulval and vaginal atrophy.
  3. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
  4. Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease.
  5. Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).
  6. 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.

History

There is currently no drug history available for this drug.

Other Information

Innofem™ (Estradiol Tablets, USP) for oral administration contains 0.5, 1 or 2 mg of micronized estradiol per tablet. Estradiol (17β-estradiol) is a white, crystalline solid, chemically described as estra-1,3,5,(10)-triene-3, 17β-diol. It has a molecular formula of C18H2402 and molecular weight of 272.39. The structural formula is:

Image from Drug Label Content

Innofem™ , 0.5 mg, contains the following inactive ingredients: lactose monohydrate, starch (corn), gelatin, talc, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, yellow iron oxide and propylene glycol.

Innofem™ , 1 mg, contains the following inactive ingredients: lactose monohydrate, starch (corn), gelatin, talc, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, red iron oxide and propylene glycol.

Innofem™ , 2 mg, contains the following inactive ingredients: lactose monohydrate, starch (corn), gelatin, talc, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, indigo carmine and polyethylene glycol 400.

Innofem Manufacturers


  • Novo Nordisk Inc.
    Innofem (Estradiol) Tablet, Film Coated [Novo Nordisk Inc.]

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