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The estrogen-alone sub-study of the Women's Health Initiative Memory Study is currently ongoing. No data are available. It is unknown whether these findings apply to estrogen alone therapy. 4. Gallbladder Disease. A 2-to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported. 5. Hypercalcemia. Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level. Text Continues Below
6. Visual Abnormalities. Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be discontinued. PRECAUTIONS General 1. Addition of a progestin when a woman has not had a hysterectomy. Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared with estrogen-alone regimens. These include a possible increased risk of breast cancer, adverse effects on lipoprotein metabolism (e. g., lowering HDL, raising LDL) and impairment of glucose tolerance. 2. Elevated blood pressure. In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use. 3. Hypertriglyceridemia. In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications. In the HOPE study, the mean percent increase from baseline in serum triglycerides after one year of treatment with PREMPRO 0.625 mg/ 2.5 mg, 0.45 mg/ 1.5 mg, and 0.3 mg/ 1.5 mg compared with placebo were 32.8, 24.8, 23.3, and 10.7, respectively. After two years of treatment, the mean percent changes were 33.0, 17.1, 21.6, and 5.5, respectively. 4. Impaired liver function and past history of cholestatic jaundice. Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued. 5. Hypothyroidism. Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range. 6. Fluid retention. Because estrogens/ progestins may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed. 7. Hypocalcemia. Estrogens should be used with caution in individuals with severe hypocalcemia. 8. Ovarian cancer. Use of estrogen-only products, in particular for ten or more years, has been associated with an increased risk of ovarian cancer in some epidemiological studies. Other studies did not show a significant association. Data are insufficient to determine whether there is an increased risk with combined estrogen/ progestin therapy in postmenopausal women. 9. Exacerbation of endometriosis. Endometriosis may be exacerbated with administration of estrogens. 10. Exacerbation of other conditions. Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions. B. Patient Information Physicians are advised to discuss the contents of the PATIENT INFORMATION leaflet with patients for whom they prescribe PREMPRO or PREMPHASE. C. Laboratory Tests Estrogen administration should be initiated at the lowest dose approved for the indication and then guided by clinical response rather than by serum hormone levels (e. g., estradiol, FSH). D. Drug/ Laboratory Test Interactions 1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. 2. Increased thyroid binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay), or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone. 3. Other binding proteins may be elevated in serum, i. e., corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids, respectively. Free or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/ renin substrate,
alpha-1-antitrypsin, ceruloplasmin). 4. Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglyceride levels. 5. Impaired glucose tolerance. 6. Reduced response to metyrapone test. 7. Aminoglutethimide administered concomitantly with medroxyprogesterone acetate (MPA) may significantly depress the bioavailability of MPA. E. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breasts, uterus, cervix, vagina, testis, and liver. (See BOXED WARNING, CONTRAINDICATIONS and WARNINGS.) In a two-year oral study of medroxyprogesterone acetate (MPA) in which female rats were exposed to dosages of up to 5000 mcg/ kg/ day in their diets (50 times higher – based on AUC values – than the level observed experimentally in women taking 10 mg of MPA), a dose-related increase in pancreatic islet cell tumors (adenomas and carcinomas) occurred. Pancreatic tumor incidence was increased at 1000 and 5000 mcg/ kg/ day, but not at 200 mcg/ kg/ day. A decreased incidence of spontaneous mammary gland tumors was observed in all three MPA-treated groups, compared with controls, in the two-year rat study. The mechanism for the decreased incidence of mammary gland tumors observed in the MPA-treated rats may be linked to the significant decrease in serum prolactin concentration observed in rats. Beagle dogs treated with MPA developed mammary nodules, some of which were malignant. Although nodules occasionally appeared in control animals, they were intermittent in nature, whereas the nodules in the drug-treated animals were larger, more numerous, persistent, and there were some breast malignancies with metastases. It is known that progestogens stimulate synthesis and release of growth hormone in dogs. The growth hormone, along with the progestogen, stimulates mammary growth and tumors. In contrast, growth hormone in humans is not increased, nor does growth hormone have any significant mammotrophic role. No pancreatic tumors occurred in dogs. F. Pregnancy PREMPRO and PREMPHASE should not be used during pregnancy. (See CONTRAINDICATIONS.) G. Nursing Mothers Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogen and progestin have been identified in the milk of mothers receiving these drugs. Caution should be exercised when PREMPRO or PREMPHASE are administered to a nursing woman. H. Pediatric Use PREMPRO and PREMPHASE are not indicated in children. I. Geriatric Use Of the total number of subjects in the PREMPRO substudy of the Women's Health Initiative study, 44% (n = 7320) were 65 years and over, while 6.6% (n = 1,095) were 75 and over (see CLINICAL PHARMACOLOGY, Clinical Studies). No significant differences in safety were observed between subjects 65 years and over compared to younger subjects. There was a higher incidence of stroke and invasive breast cancer in women 75 and over compared to younger subjects. With respect to efficacy in the approved indications, there have not been sufficient numbers of geriatric patients involved in studies utilizing Premarin and medroxyprogesterone acetate to determine whether those over 65 years of age differ from younger subjects in their response to PREMPRO or PREMPHASE. Page: << Prev | 1 | 2 | 3 | 4 | 5
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