Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2631
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Estropipate (Tablet)
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PATIENT INFORMATION Estropipate Tablets USP Read this PATIENT INFORMATION before you start taking estropipate tablets and read what you get each time you refill estropipate tablets. There may be new information. This information does not take the place of talking to your health care provider about your medical condition or your treatment. What is estropipate? Estropipate is a medicine that contains estrogen hormones. What is estropipate used for? Estropipate is used during and after menopause to: Osteoporosis from menopause is a thinning of the bones that makes them weaker and easier to break. If you use estropipate tablets only to prevent osteoporosis from menopause, talk with your health care provider about whether a different treatment or medicine without estrogens might be better for you. You and your health care provider should talk regularly about whether youshould continue with estropipate tablets. Weight-bearing exercise, like walking or running, and taking calcium and vitamin D supplements may also lower your chances of getting postmenopausal osteoporosis. It is important to talk about exercise and supplements with your health care provider before starting them. Estropipate is also used to: treat certain conditions in women before menopause if their ovaries do not make enough estrogen naturally. Who should not take estropipate tablets? Do not start taking estropipate tablets if you: Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus. If you have or had cancer, talk with your health care provider about whether you should take estropipate tablets. See the end of this leaflet for a list of ingredients in estropipate tablets. These are some of the warning signs of serious side effects: Call your health care provider right away if you get any of these warning signs, or any other unusual symptom that concerns you. Common side effects include: These are not all the possible side effects of estropipate tablets. For more information, ask your health care provider or pharmacist. What can I do to lower my chances of getting a serious side effect with estropipate tablets? Talk with your health care provider regularly about whether you should continue taking estropipate tablets. If you have a uterus, talk to your health care provider about whether the addition of a progestin is right for you. See your health care provider right away if you get vaginal bleeding while taking estropipate tablets. Have a breast exam and mammogram (breast X-ray) every year unless your health care provider tells you something else. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast examinations more often.If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease. Ask your health care provider for ways to lower your chances for getting heart disease. General information about safe and effective use of estropipate Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take estropipate for conditions for which it was not prescribed. Do not give estropipate tablets to other people, even if they have the same symptoms you have. It may harm them. Keep estropipate tablets out of the reach of children. This leaflet provides a summary of the most important information about estropipate tablets. If you would like more information, talk with your health care provider or pharmacist. You can ask for information about estropipate tablets that is written for health professionals. You can get more information by calling the toll free number 1-800-272-5525. What are the ingredients in estropipate tablets? Estropipate tablets contain estropipate as the active ingredient. Estropipate tablets also contain: lactose NF, magnesium stearate NF, piperazine USP, pregelatinized starch NF, talc USP, and coloring agents: 0.75 mg���D&C Yellow #10; 1.5 mg���FD&C Yellow #6; 3 mg���FD&C Blue #2; 6 mg���FD&C Blue #2 and D&C Yellow #10. Watson Laboratories, Inc.Corona, CA 92880 USA 12270-4Revised April 2006
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When estrogen is prescribed for a woman with a uterus, progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be reevaluated periodically as clinically appropriate (e.g., 3-month to 6-month intervals) to determine if treatment is still necessary For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.
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Estropipate (formerly piperazine estrone sulfate), is a natural estrogenic substance prepared from purified crystalline estrone, solubilized as the sulfate and stabilized with piperazine. It is appreciably soluble in water and has almost no odor or taste���properties which are ideally suited for oral administration. The amount of piperazine in estropipate is not sufficient to exert a pharmacological action. Its addition ensures solubility, stability, and uniform potency of the estrone sulfate. Chemically estropipate, molecular weight: 436.56, is represented by estra-1,3,5(10)-trien-17-one,3-(sulfooxy)-, compound with piperazine (1:1). The structural formula may be represented as follows: Estropipate is available as tablets for oral administration containing either 0.75 mg, 1.5 mg, 3 mg, or 6 mg estropipate (calculated as sodium estrone sulfate 0.625 mg, 1.25 mg, 2.5 mg and 5 mg, respectively).<br/>Inactive Ingredients: Each tablet contains: lactose NF, magnesium stearate NF, piperazine USP, pregelatinized starch NF, talc USP, and coloring agents: 0.75 mg���D&C Yellow #10; 1.5 mg���FD&C Yellow #6; 3 mg���FD&C Blue #2; 6 mg���FD&C Blue #2 and D&C Yellow #10.
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Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.<br/>Pharmacokinetics:<br/>Absorption: Estrogens are well absorbed through the skin and gastrointestinal tract. When applied for a local action, absorption is usually sufficient to cause systemic effects.<br/>Distribution: The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.<br/>Metabolism: Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens existas sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.<br/>Excretion: Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.<br/>Drug Interactions: In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John's Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleedingprofile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.<br/>Clinical Studies:<br/>Women's Health Initiative Studies: The Women's Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of 0.625 mg conjugated estrogens (CE) per day alone or the use of oral 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms. The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the "global index." Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 1 below: For those outcomes included in the "global index," the absolute excess risks per 10,000 person-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the "global index" was 19 per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality.<br/>Women's Health Initiative Memory Study: The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CE/MPA (0.625mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo. After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women.<br/>Osteoporosis: The results of a double-blind, placebo-controlled two-year study have shown that treatment with one tablet of estropipate 0.625 daily for 25 days (of a 31-day cycle per month) prevents vertebral bone mass loss in postmenopausal women. When estrogen therapy is discontinued, bone mass declines at a rate comparable to that of the immediate postmenopausal period. There is no evidence that estrogen replacement therapy restores to premenopausal levels.
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Estropipate tablets should not be used in women with any of the following conditions: There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy.
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Estropipate tablets USP are supplied as follows: Store at 20��- 25��C (68��- 77��F). [See USP controlled room temperature.]
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WARNINGS:<br/>ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER: Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of���natural���estrogens result in a different endometrial risk profile than���synthetic���estrogens at equivalent estrogen doses. (SeeWARNINGS, Malignant neoplasms, Endometrial cancer.)<br/>CARDIOVASCULAR AND OTHER RISKS: Estrogens with and without progestins should not be used for the prevention of cardiovascular disease. The Women's Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo. The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate relative to placebo. It is unknown whether this finding applies to younger postmenopausal women or to women taking estrogen alone therapy.
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A. GENERAL:<br/>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 to 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.<br/>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 estrogens on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use.<br/>3. Hypertriglyceridemia: In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications.<br/>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.<br/>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 Tand Tserum 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.<br/>6. Fluid retention: Because estrogens may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.<br/>7. Hypocalcemia: Estrogens should be used with caution in individuals with severe hypocalcemia.<br/>8. Ovarian cancer: The CE/MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 (95% confidence interval 0.77���3.24) but was not statistically significant. The absolute risk for CE/MPA versus placebo was 4.2 versus 2.7 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen alone, in particular for ten or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations.<br/>9. Exacerbation of endometriosis: Endometriosis may be exacerbated with administration of estrogens. A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.<br/>10. Exacerbation of other conditions: Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.<br/>B. PATIENT INFORMATION: Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe estropipate tablets.<br/>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).<br/>D. DRUG/ LABORATORY TEST INTERACTIONS:<br/>E. CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: Long-term continuous administration of estrogen, with and without progestin, in women with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer. Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.<br/>F. PREGNANCY: Estropipate tablets should not be used during pregnancy.<br/>G. NURSING MOTHERS: Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when estropipate is administered to a nursing woman.<br/>H. GERIATRIC USE: In the Women's Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for an average of 4 years, 82% (n= 3,729) were 65 to 74 while 18% (n= 803) were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogens plus medroxyprogesterone acetate were reported to have a two-fold increase in the risk of developing probable dementia. Alzheimer's disease was the most common classification of probable dementia in both the conjugated estrogens plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of women that were older than 70.
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Serious ill effects have not been reported following acute ingestion of large doses of estrogen-containing oral contraceptives by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females.
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Estropipate
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Estropipate (Tablet)
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SeeBOXED WARNINGS,WARNINGS andPRECAUTIONS. The following additional adverse reactions have been reported with estrogens and/or progestin therapy.<br/>1. Genitourinary system: Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; dysmenorrhea; increase in size of uterine leiomyomata; vaginitis; including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer.<br/>2. Breasts: Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer.<br/>3. Cardiovascular: Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure.<br/>4. Gastrointestinal: Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; increased incidence of gallbladder disease; pancreatitis; enlargement of hepatic hemangiomas.<br/>5. Skin: Chloasma or melasma that may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; pruritus, rash.<br/>6. Eyes: Retinal vascular thrombosis; steepening of corneal curvature; intolerance to contact lenses.<br/>7. Central nervous system: Headache, migraine, dizziness; mental depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy; dementia.<br/>8. Miscellaneous: Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthralgias; leg cramps; urticaria; angioedema; anaphylactoid/anaphylactic reactions; hypocalcemia; exacerbation of asthma; changes in libido; triglycerides.
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ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER: Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of���natural���estrogens result in a different endometrial risk profile than���synthetic���estrogens at equivalent estrogen doses. (SeeWARNINGS, Malignant neoplasms, Endometrial cancer.)<br/>CARDIOVASCULAR AND OTHER RISKS: Estrogens with and without progestins should not be used for the prevention of cardiovascular disease. The Women's Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo. The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate relative to placebo. It is unknown whether this finding applies to younger postmenopausal women or to women taking estrogen alone therapy.
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Estropipate tablets are indicated in the: The mainstays for decreasing the risk of postmenopausal osteoporosis are weight-bearing exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400-800 IU/day may also be required to ensure adequate daily intake in postmenopausal women.
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Estropipate
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