VAGIFEM® is indicated for the treatment of atrophic vaginitis.

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ATROPHIC VAGINITIS --

Postmenopausal atrophic vaginitis --

The use of VAGIFEM is contraindicated in women who exhibit one or more of the following:1.

Known or suspected breast carcinoma.2.

Known or suspected estrogen- dependent neoplasia; e.g.

endometrial carcinoma.3.

Abnormal genital bleeding of unknown etiology.4.

Known or suspected pregnancy.

(See Precautions)5.

Porphyria.6.

Hypersensitivity to any VAGIFEM constituents.7.

Active thrombophlebitis or thromboembolic disorders.8.

A past history of thrombophlebitis, thrombosis, or thromboembolic disorders associated with previous estrogen use (except when used in treatment of breast malignancy).

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Breast Carcinoma -- (brest KAN-ser) Cancer that forms in tissues of the breast, usually the ducts (tubes that carry milk to the nipple) and lobules (glands that make milk). It occurs in both men and women, although male breast cancer is rare.

Endometrial Carcinoma -- A malignant tumor arising from the epithelium that lines the cavity of the uterine body. The vast majority of endometrial carcinomas are adenocarcinomas; squamous cell and adenosquamous carcinomas represent a minority of the cases. Endometrioid adenocarcinoma is the most frequently seen variant of endometrial adenocarcinoma. Uterine bleeding is an initial clinical sign. The prognosis depends on the stage of the tumor, the depth of myometrial wall invasion, and the degree of differentiation. -- 2004

Porphyria -- group of disorders characterized by the excessive production of porphyrins or their precursors that arises from abnormalities in the regulation of the porphyrin-heme pathway; acquired porphyrias, which are due to inhibition of enzymes in the metabolic pathway by a drug, toxin or abnormal metabolite, are more common than those which are inherited.

Hypersensitivity -- Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen.

Thrombophlebitis -- Inflammation of a vein associated with a blood clot (THROMBUS).

Thromboembolism -- Obstruction of a blood vessel (embolism) by a blood clot (THROMBUS) in the blood stream.

Thrombosis -- Formation and development of a thrombus or blood clot in the blood vessel.

Malignant Neoplasms -- A term for diseases in which abnormal cells divide without control. Cancer cells can invade nearby tissues and can spread through the bloodstream and lymphatic system to other parts of the body.

Primary malignant neoplasm --

1.

Induction of malignant neoplasms.

Long-term, continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, cervix, vagina, and liver.

There are now reports that estrogens increase risk of carcinoma of the endometrium in humans (See Boxed Warning).At the present time there is no satisfactory evidence that estrogens given to postmenopausal women increase the risk of cancer of the breast, although a recent long-term follow-up of a single physician’s practice has raised this possibility.

Because of the animal data, there is a need for caution in prescribing estrogens for women with a strong family history of breast cancer or who have breast nodules, fibrocystic disease, or abnormal mammograms.2.

Gallbladder disease.

A recent study has reported a 2- to 3-fold increase in the risk of surgically confirmed gallbladder disease in women receiving postmenopausal estrogens, similar to the 2-fold increase previously noted in users of oral contraceptives.3.

Effects similar to those caused by estrogen-progestogen oral contraceptives.

There are several serious adverse effects of oral contraceptives, most of which have not, up to now, been documented as consequences of postmenopausal estrogen therapy.

This may reflect the comparatively low doses of estrogens used in postmenopausal women.

It would be expected that the larger doses of estrogen used to treat prostatic or breast cancer are more likely to result in these adverse effects, and, in fact, it has been shown that there is an increased risk of thrombosis in men receiving estrogens for prostatic cancer.a.

Thromboembolic disease.

It is now well established that users of oral contraceptives have an increased risk of various thromboembolic and thrombotic vascular diseases, such as thrombophlebitis, pulmonary embolism, stroke, and myocardial infarction.

Cases of retinal thrombosis, mesenteric thrombosis, and optic neuritis have been reported in oral-contraceptive users.

There is evidence that the risk of several of these adverse reactions is related to the dose of the drug.

An increased risk of postsurgery thromboembolic complications has also been reported in users of oral contraceptives.

If feasible, estrogen should be discontinued at least 4 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.While an increased rate of thromboembolism and thrombotic disease in postmenopausal users of estrogens has not been found, this does not rule out the possibility that such an increase may be present, or that subgroups of women who have underlying risk factors, or who are receiving large doses of estrogens, may have increased risk.

Therefore, estrogens should not be used (except in treatment of malignancy) in a person with a history of such disorders in association with estrogen use.

They should be used with caution in patients with cerebral vascular or coronary artery disease and only for those in whom estrogens are clearly needed.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 a large prospective clinical trial in men, to increase the risk of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.

When estrogen doses of this size are used, any of the thromboembolic and thrombotic adverse effects associated with oral contraceptive use should be considered a clear risk.b.

Hepatic adenoma.

Benign hepatic adenomas appear to be associated with the oral contraceptives.

Although benign, and rare, these may rupture and may cause death through intra-abdominal hemorrhage.

Such lesions have not yet been reported in association with other estrogen or progestogen preparations but should be considered in estrogen users having abdominal pain and tenderness, abdominal mass, or hypovolemic shock.

Hepatocellular carcinoma has also been reported in women taking estrogen-containing oral contraceptives.

The relationship of this malignancy to these drugs is not known at this time.c.

Elevated blood pressure.

Women using oral contraceptives sometimes experience increased blood pressure which, in most cases, returns to normal on discontinuing the drug.

There is now a report that this may occur with the use of estrogens in the menopause and blood pressure should be monitored with estrogen use, especially if high doses are used.d.

Glucose tolerance.

A worsening of glucose tolerance has been observed in a significant percentage of patients on estrogen-containing oral contraceptives.

For this reason, diabetic patients should be carefully observed while using estrogens.4.

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.5.

Rare Event: Trauma induced by the VAGIFEM® applicator may occur, especially in patients with severely atrophic vaginal mucosa.