Covaryx

1.

Breast Cancer (See BOXED WARNINGS).

2.

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 is now evidence that estrogens increase the risk of carcinoma of the endometrium in humans (See BOXED WARNINGS). At the present time there is no satis- factory evidence that estrogens given to postmenopausal women increase the risk of cancer of the breast, 17 although a recent longterm follow-up of a single physician's practice has raised this possibility. 18 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.

3.

Cardiovascular Disorders: Estrogen with progestogen therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogen with progestogens should be discontinued immediately. Risk factors for cardiovascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) should be managed appropriately. If feasible, estrogens with progestins should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

4.

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, 17 similar to the 2-fold increase previously noted in users of oral contraceptives. 19-24
In the case of oral contraceptives the increased risk appeared after two years of use. 24

5.

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 estrogen used in postmenopausal women. It would be expected that the larger doses of estrogen used to treat prostatic or breast cancer or postpartum breast engorgement 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 and women for postpartum breast engorgement. 20-23

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.24-31 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.32,33 An increased risk of postsurgery thromboembolic complications has also been reported in users of oral contraceptives.34,35 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 thromboembolic and thrombotic disease in postmenopausal users of estrogens has not been found,18-36 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 relatively large doses of estrogens may have increased risk. Therefore estrogens should not be used in persons with active thrombophlebitis or thromboembolic disorders, and they should not be used (except in treatment of malignancy) in persons 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 estrogen (5 mg esterified 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 men37 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. Hepatic Adenoma: Benign hepatic adenomas appear to be associated with the use of oral contraceptives.38-40 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.30 The relationship of this malignancy to these drugs is not known at this time.

Elevated Blood Pressure: Increased blood pressure is not uncommon in women using oral contraceptives. There is now a report that this may occur with use of estrogens in the menopause41 and blood pressure should be monitored with estrogen use, especially if high doses are used.

Glucose Tolerance: A worsening of glucose tolerance has been observed in a significant percentage of patients of estrogen containing oral contraceptives. For this reason, diabetic patients should be carefully observed while receiving estrogens.

6.

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.

In patients with breast cancer, androgen therapy may cause hypercalcemia by stimulating osteolysis. In this case the drug should be discontinued. Prolonged use of high doses of androgens has been associated with the development of peliosis hepatis and hepatic neoplasms including hepatocellular carcinoma. (See PRECAUTIONS-Carcinogenesis). Peliosis hepatis can be a life-threatening or fatal complication. Cholestatic hepatitis and jaundice occur with 17-alpha-alkylandrogens at a relatively low dose. If cholestatic hepatitis with jaundice appears or if liver function tests become abnormal, the androgen should be discontinued and the etiology should be determined. Drug-induced jaundice is reversible when the medication is discontinued. Edema with or without heart failure may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease. In addition to discontinuation of the drug, diuretic therapy may be required.

Moderate to severe vasomotor symptoms associated with the menopause in those patients not improved by estrogens alone. (There is no evidence that estrogens are effective for nervous symptoms or depression without associated vasomotor symptoms, and they should not be used to treat such conditions.)

COVARYXT® and COVARYX® H.S. HAVE NOT BEEN SHOWN TO BE EFFECTIVE FOR ANY PURPOSE DURING PREGNANCY AND ITS USE MAY CAUSE SEVERE HARM TO THE FETUS (See BOXED WARNINGS).