" Citing a lack of cardiovascular benefit, the FDA is taking the unusual step of withdrawing approvals it had previously given for use of niacin and fenofibric acid with statins to treat high cholesterol.
The decision affects niac"...
(Generic versions may still be available.)
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 is now evidence that estrogens increase the risk of carcinoma of the endometrium in humans. (See DESCRIPTION: 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 need for caution in pre-scribing breast cancer or who have breast nodules, fibrocystic disease, estrogens for women with a strong family history of or abnormal mammograms.
2. Gall bladder disease. Arecent 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 tothe 2-fold increase previously noted in users of oral contracep-tives. 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 serious adverse effects of oral contraceptives, most ofwhich 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
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 myo-cardial 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 ofthese adverse reactions is related tothe dose ofthe drug. 32-33 An increased risk of postsurgery thromboembolic complica-tions 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 subgroupsof women who have underlying risk factors or who are receiving large doses of estrogens may have increased risk. Therefore estrogens should not be used in persons with activethrombophlebitis orthrombo-embolic 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 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 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. 39 The relationship of this malignancy to these drugs is not known 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 also occur with the use of estrogens during menopause. 41 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 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.
- A complete medical and family history should be taken prior to the initiation of any estrogen therapy. The pretreatment and periodic physical examinations should include special refer-ence to blood pressure, breasts, abdomen, and pelvic organs, and should include a Papanicolaou smear. As a general rule, estrogen should not be prescribed for longer than one year without another physical examination being performed.
- Fluid retention - Because estrogens may cause somedegree of fluid retention, conditions which might be influenced by this factor such as epilepsy, migraine, and cardiac or renal dys-function, require careful observation.
- Certain patients may develop undesirable manifestations of excessive estrogenic stimulation, such as abnormal or excessive uterine bleeding, mastodynia, etc.
- Oral contraceptives appearto be associated with an increased incidence of mental depression. 24Although it is notclear whether this is due tothe estrogenic or progestogenic component ofthe contraceptive, patients with a history of depression should be carefully observed.
- Preexisting uterine leiomyomata may increase in size during estrogen use.
- The pathologist should be advised of estrogen therapy when relevant specimens are submitted.
- Patients with a past history of jaundice during pregnancy have an increased risk of recurrence of jaundice while receiving estrogen-containing oral contraceptive therapy. If jaundice develops in any patient receiving estrogen, the medication should be discontinued while the cause is investigated.
- Estrogens may be poorly metabolized in patients with impaired liver function and they should be administered with caution in such patients.
- Because estrogens influence the metabolism of calcium and phosphorus, they should be used with caution in patients with metabolic bone diseases that are associated with hypercalcemia or in patients with renal insufficiency.
- Because of the effects ofestrogens on epiphyseal closure, theyshould be used judiciously in young patients in whom bone growth is not complete.
- The lowest effective dose appropriate for the specific indication should be utilized. Studies of the addition of a progestin for seven or more days of a cycle of estrogen administration have reported a lowered incidence of endo-metrial hyperplasia. Morphological and biochemical studies of endometrium suggest that 10 to 13 days of progestin are needed to provide maximal maturation of the endometrium and to eliminate any hyperplastic changes. Whether this will provide protection from endometrial carcinoma has not been clearly established. There are possible additional risks which may be associated with the inclusion of progestin in estrogen replacement regimens. The potential risks include adverse effects on carbohydrateand lipid metabolism. The choice of progestin and dosage may be important in minimizing these adverse effects.
Information for Patients
See text of Patient Package Information which is reproduced in PATIENT INFORMATION.
Carcinogenesis, Mutagenesis, Impairment of Fertility
It is not known whether this drug is excreted in human milk. Because many drugsare excreted in human milk, caution should be exercised when estrogens are administered to a nursing woman.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 1/29/2005
Additional Dienestrol Information
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