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Premarin Warnings, Precautions, Pregnancy, Nursing, Abuse - Estrogens Conjugated

WARNINGS

Tablets

1. Induction of Malignant Neoplasms: Some studies have suggested a possible increased incidence of breast cancer in those women on estrogen therapy taking higher doses for prolonged periods of time. The majority of studies, however, have not shown an association with the usual doses used for estrogen replacement therapy. Women on this therapy should have regular breast examinations and should be instructed in breast self-examination. The reported endometrial cancer risk among estrogen users was about 4-fold or greater than in nonusers and appears dependent on duration of treatment and on estrogen dose. There is no significant increased risk associated with the use of estrogens for less than one year. The greatest risk appears associated with prolonged use--five years or more. In one study, persistence of risk was demonstrated for 10 years after cessation of estrogen treatment. In another study, a significant decrease in the incidence of endometrial cancer occurred six months after estrogen withdrawal. Estrogen therapy during pregnancy is associated with an increased risk of fetal congenital reproductive-tract disorders. In females there is an increased risk of vaginal adenosis, squamous cell dysplasia of the cervix, and cancer later in life; in the male, urogenital abnormalities. Although some of these changes are benign, it is not known whether they are precursors of malignancy.

2. Gallbladder Disease: A recent study has reported a 2.5-fold increase in the risk of surgically confirmed gallbladder disease 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 risk of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis. It cannot necessarily be extrapolated from men to women. However, to avoid the theoretical cardiovascular risk caused by high estrogen doses, the doses for estrogen replacement therapy should not exceed the recommended dose.

4. Elevated Blood Pressure: There is no evidence that this may occur with use of estrogens in the menopause. However, blood pressure should be monitored with estrogen use, especially if high doses are used.

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.

Injection and Vaginal Cream

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 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,¹⁷ although a recent long-term 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.

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,¹⁷ similar to the 2-fold increase previously noted in users of oral contraceptives.^19,24a

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 estrogen 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.^{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 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,^17-24,25-36 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 (expect 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 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.

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: 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 use of estrogens in the menopause⁴¹ 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 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.

PRECAUTIONS

Tablets

General

Addition of a progestin: Studies of the addition of a progestin for seven or more days of a cycle of estrogen administration have reported a lowered incidence of endometrial 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 carbohydrate and lipid metabolism. The choice of progestin and dosage may be important in minimizing these adverse effects.

Physical Examination: 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 reference 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.

Familial Hyperlipoproteinemia: Estrogen therapy may be associated with massive elevations of plasma triglycerides leading to pancreatitis and other complications in patients with familial defects of lipoprotein metabolism.

Fluid Retention: Because estrogens may cause some degree of fluid retention, conditions which might be influenced by this factor, such as asthma, epilepsy, migraine, and cardiac or renal dysfunction, require careful observation.

Uterine Bleeding and Mastodynia: Certain patients may develop undesirable manifestations of estrogenic stimulation, such as abnormal uterine bleeding and mastodynia.

Uterine Fibroids: Preexisting uterine leiomyomata may increase in size during prolonged high-dose estrogen use.

Impaired Liver Function: Estrogens may be poorly metabolized in patients with impaired liver function and should be administered with caution.

Hypercalcemia and Renal Insufficiency: Prolonged use of estrogens can alter the metabolism of calcium and phosphorus. Estrogens should be used with caution in patients with metabolic bone disease.

Information for the Patient

See PATIENT PACKAGE INSERT.

Laboratory Tests

Clinical response at the smallest dose should generally be the guide to estrogen administration for relief of symptoms for those indications in which symptoms are observable. However, for prevention and treatment of osteoporosis see DOSAGE AND ADMINISTRATION. Tests used to measure adequacy of estrogen replacement therapy include serum estrone and estradiol levels and suppression of serum gonadotrophin levels.

Drug/Laboratory Test Interactions

Some of these drug/laboratory test interactions have been observed only with estrogen-progestin combinations (oral contraceptives):

1. Increased prothrombin and factors VII, VIII, IX and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability, decreased fibrinolysis.

2. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by T4 levels determined either by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered.

3. Impaired glucose tolerance.

4. Reduced response to metyrapone test.

5. Reduced serum folate concentration.

Mutagenesis And Carcinogenesis

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.

Pregnancy Category X

Estrogens should not be used during pregnancy. (See CONTRAINDICATIONS and BOXED WARNING.)

Nursing Mothers

As a general principle, the administration of any drug to nursing mothers should be done only when clearly necessary since many drugs are excreted in human milk.

Injection and Vaginal Cream

General: 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 reference to blood pressure, breasts, abdomen, and pelvic organs, and should include a Papanicolaou smear. As a general rule, estrogens should not be prescribed for longer than one year without another physical examination being performed.

Familial Hyperlipoprotenemia: Estrogen therapy may be associated with massive elevations of plasma triglycerides leading to pancreatitis and other complications in patients with familial defects of lipoprotein metabolism.

Certain patients may develop undesirable manifestations of excessive estrogenic stimulation, such as abnormal or excessive uterine bleeding, mastodynia, etc.

Information for the Patient: See PATIENT PACKAGE INSERT.

Drug/Laboratory Tests Interactions: Certain endocrine and liver function tests may be affected by estrogen-containing oral contraceptives. The following similar changes may be expected with larger doses of estrogen:

Increased sulfobromophthalein retention.
Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.
Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by PBI, T₄ by column, or T₄ by radioimmunoassay. Free T₃ resin uptake is decreased, reflecting the elevated TBG; free T₄ concentration is unaltered.
Impaired glucose tolerance.
Decreased pregnanediol excretion.
Reduced response to metyrapone test.
Reduced serum folate concentration.
Increased serum triglyceride and phospholipid concentration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility: See

WARNINGS

for information on carcinogenesis.

Pregnancy Category X (See CONTRAINDICATIONS and BOXED WARNING.)

Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from estrogens, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness in children have not been established.

Additional Information for Vaginal Cream

Prolonged administration of unopposed estrogen therapy has been reported to increase the risk of endometrial hyperplasia in some patients.

Oral contraceptives appear to be associated with an increased incidence of mental depression.^24a Although it is not clear whether this is due to the estrogenic or progestogenic component of the 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 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 of estrogens on epiphyseal closure, they should be used judiciously in young patients in whom bone growth is not yet complete.

Concomitant Progestin Use: The lowest effective dose appropriate for the specific indication should be utilized. Studies of the addition of a progestin for 7 or more days of a cycle of estrogen administration have reported a lowered incidence of endometrial hyperplasia. Morphological and biochemical studies of the 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 a progestin in estrogen replacement regimens. If concomitant progestin therapy is used, potential risks may include adverse effects on carbohydrate and lipid metabolism. The choice of progestin and dosage may be important in minimizing these adverse effects.

Additional Information for Injection

Certain endocrine and liver function tests may be affected by estrogen-containing oral contraceptives. The following similar changes may be expected with larger doses of estrogen:

Increased sulfobromophthalein retention.
Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.
Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by PBI, T4 by column, or T4 by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered.
Impaired glucose tolerance.
Decreased pregnanediol excretion.
Reduced response to metyrapone test.
Reduced serum folate concentration.
Increased serum triglyceride and phospholipid concentration.

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