FDA label 23265a22-20f1-a397-e063-6394a90a46f5

Warning 1. ESTROGENS HAVE BEEN REPORTED TO INCREASE THE RISK OF ENDOMETRIAL CARCINOMA. Three independent case control studies have shown an increased risk of endometrial cancer in postmenopausal women exposed to exogenous estrogens for prolonged periods. 1-3 The risk was independent of other known risk factors for endometrial cancer. These studies are further supported by the finding that incidence rates of endometrial cancer have increased sharply since 1969 in eight different areas of the United States with population-based cancer reporting systems, an increase which may be related to rapidly expanding use of estrogens during the last decade. 4 The three case control studies reported that the risk of endometrial cancer in estrogen users was about 4.5 to 13.9 times greater than in nonusers. The risk appears to depend on both duration of treatment 1 and on estrogen dose. 3 In view of these findings, when estrogens are used for the treatment of menopausal symptoms, the lowest dose that will control symptoms should be utilized and medication should be discontinued as soon as possible. When prolonged treatment is medically indicated, the patient should be reassessed on at least a semiannual basis to determine the need for continued therapy. Although the evidence must be considered preliminary, one study suggests that cyclic administration in low doses of estrogen may carry less risk than continuous administration, 3 it therefore appears prudent to utilize such a regimen. Close clinical surveillance of all women taking estrogens is important. In all cases of undiagnosed persistant or recurring abnormal vaginal bleeding, adequate diagnostic measures should be undertaken to rule out malignancy. There is no evidence at present that "natural" estrogens are more or less hazardous than "synthetic" estrogens at equiestrogenic doses. 2. ESTROGENS SHOULD NOT BE USED DURING PREGNANCY The use of female sex hormones, both estrogens and progestogens, during early pregnancy may seriously damage the offspring. It has been shown that females exposed in utero to diethylstilbestrol, a non-steroidal estrogen, have increased risk of developing in later life a form of vaginal or cervical cancer that is ordinarily extremely rare. 5,6 This risk has been estimated as not greater than 4 per 1000 exposures. 7 Furthermore, a high percentage of such exposed women (from 30 to 90 percent) have been found to have vaginal adenosis, 8-12 epithelial changes of the vagina and cervix. Although these changes are histologically benign, it is not known whether they are precursors of malignancy. Although similar data are not available with the use of other estrogens, it cannot be presumed they would not induce similar changes. Several reports suggest an association between intrauterine exposure to female sex hormones and congenital anomalies, including congenital heart defects and limb reduction defects. 13-16 One case control study 16 estimated a 4.7 fold increased risk of limb reduction defects in infants exposed in utero to sex hormones (oral contraceptives, hormones withdrawl tests for pregnancy, or attempted treatment for threatened abortion). Some of these exposures were very short and involved only a few days of treatment. The data suggest that the risk of limb reduction defects in exposed fetuses is somewhat less than 1 per 1000. In the past, female sex hormones have been used during pregnancy in an attempt to treat threatened or habitual abortion. There is no considerable evidence from well controlled studies that progestogens are effective for these uses. If Estrogen is used during pregnancy, or if the patient becomes pregnant while taking this drug, she should be apprised of the potential risks to the fetus, and the advisability of pregnancy continuation.

WARNINGS: 1. Induction of malignant neoplasma. Long term continuous administration of natural and synthetic estrogen in certain animal species increases the frequency of carcinomas of the breast, cervix, vagina, and liver. There is new evidence that estrogens increase the 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, 18 although a recent long-term followup of a single physician's practice has raised this possibility. 18a Because of the animal data there is a heed for caution, in prescribing estrogens for women with a strong 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 gall bladder disease in women receiving postmenopausal estrogens 18 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 3. Effects similar to those caused by estrogen-progestogen oral contraceptives. There are several serios adverse effects or 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. a. Thromboembolic disease. It is now we establish that users of oral contraceptives have an increased risk of various thromboembolic and thrombotic vascular disease, such as thrombophlebitis, pulminary 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 increase risk of post surgery thromboembolic complications has also been reported in users of oral contrceptives. 34,35 if feasable, 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 estrogen has not been found, 18,36 this does not rule out that such an increase may be present or that subgroups of women having underlying risk factors or who are receiving relatively large doses of estrogen may have an increased risk. Therefore estrogens should not be used in persons with active thrombophlebitis or thromboembolic disorders and they should not be used (except in treatent 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 estrogens (5mg 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 37 to increase the risk of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis. When estrogen doses of this size are used, any of the thromboembolicand 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 use of oral contraceptives. 38-40 Although benign, and rare, these may rupture and may cause death through intraabdominal 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. 39 The relationship of this malignancy to these drugs is not know at this time. c. Elevated blood pressure. Increased blood pressure is not uncommon in women using oral contraceptives. There is now a report that this may occur with the use of estrogens in menopause 41 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 receiving estrogen. 4. Hypercalcemia. Administration of estrogens may lead to severe hypercalceemia 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.

ADVERSE REACTIONS: (See Warnings regarding induction of neoplasia, adverse effects on the fetus, increased incidence of gall bladder disease, and adverse effects similar to those of oral contraceptives, including thromboembolism.) The following additional adverse reactions have been reported with estrogenic therapy, including oral cantraceptives: 1. Genitourinary System - breakthrough bleeding, spotting, change in menstrual flow; dysmenorrhea; premenstrual-like syndrome; amenorrhea during and after treatment; increase in size of uterine fibromyomata; vaginal candidas; change in cervical eversion and in degree of cervical secretion; cystitis-like syndrome. 2. Breasts - tenderness, enlargement, secretion 3. Gastrointestinal - nausea, vomiting,; abdominal cramps, bloating; cholestatic jaundice. 4. Skin - chloasma or melasma which may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism. 5. Eyes - steepening of corneal curvature; intolerance to contact lenses. 6. CNS - headache, migraine, dizziness, mental depression, chorea. 7. Miscellaneous - increase or decrease in weight;reduced carbohydrate tolerance; aggrevation of porphyria; edema, changes in libido.