Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/221
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Activella (Tablet, Film Coated)
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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 re-evaluated periodically as clinically appropriate (e.g., 3 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. Activella therapy consists of a single tablet to be taken once daily. 1. For the treatment of moderate to severe vasomotor symptoms associated with menopause, and the prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medications should be carefully considered. 2. For the treatment of moderate to severe symptoms of vulvar and vaginal atrophy. When used solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. Patients should be started at the lowest dose.
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Activella 1.0 mg/0.5 mg is a single tablet for oral administration containing 1 mg of estradiol and 0.5 mg of norethindrone acetate and the following excipients: lactose monohydrate, starch (corn), copovidone, talc, magnesium stearate, hypromellose and triacetin. Activella 0.5 mg/0.1 mg is a single tablet for oral administration containing 0.5 mg of estradiol and 0.1 mg of norethindrone acetate and the following excipients: lactose monohydrate, starch (corn), hydroxypropylcellulose, talc, magnesium stearate, hypromellose and triacetin. Estradiol (E) is a white or almost white crystalline powder. Its chemical name is estra-1, 3, 5 (10)-triene-3, 17��-diol hemihydrate with the empirical formula of CHO,��H2O and a molecular weight of 281.4. The structural formula of Eis as follows: Norethindrone acetate (NETA) is a white or yellowish-white crystalline powder. Its chemical name is 17��-acetoxy-19-nor-17��-pregn-4-en-20-yn-3-one with the empirical formula of CHOand molecular weight of 340.5. The structural formula of NETA is as follows:
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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. Progestin compounds enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes. Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, and central nervous system. Progestins produce similar endometrial changes to those of the naturally occurring hormone progesterone.
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Activella should not be used in women with any of the following conditions: 1. Undiagnosed abnormal genital bleeding. 2. Known, suspected, or history of cancer of the breast. 3. Known or suspected estrogen-dependent neoplasia. 4. Active deep vein thrombosis, pulmonary embolism, or history of these conditions. 5. Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction). 6. Liver dysfunction or disease. 7. Known hypersensitivity to the ingredients of Activella 1.0 mg/0.5 mg or Activella 0.5 mg/0.1 mg. 8. Known or suspected pregnancy. There is no indication for Activella in pregnancy. 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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Activella 1.0 mg/0.5 mg is a white, film-coated tablet, engraved with NOVO 288 on one side and the APIS bull on the other. It is round, 6mm in diameter and bi-convex. (NDC 0169-5174-02). It is supplied as 28 tablets in a calendar dial pack dispenser. Store in a dry place protected from light. Activella 0.5 mg/0.1 mg is a white, film-coated tablet, engraved with NOVO 291 on one side and the APIS bull on the other. It is round, 6mm in diameter and bi-convex. (NDC 0169-5175-10). It is supplied as 28 tablets in a calendar dial pack dispenser. Keep the container in the outer carton. Store at 25��C (77��F), excursions permitted to 15-30��C (59-86��F). [See USP Controlled Room Temperature.] ��2000-2006 Novo Nordisk Inc. Activella is a trademark owned by Novo Nordisk FemCare AG Revised December 2006 Version 7 Novo Nordisk Inc. Princeton, NJ 08540 1-866-668-6336 www.novonordisk-us.com Manufactured by Novo Nordisk A/S 2880 Bagsvaerd, Denmark
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CARDIOVASCULAR AND OTHER RISKS: Estrogens with or without progestins should not be used for the prevention of cardiovascular disease or dementia. The estrogen plus progestin substudy of the Women's Health Initiative (WHI) 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 5.6 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) per day, relative to placebo. The estrogen-alone substudy of the WHI reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 6.8 years and 7.1 years, respectively, of treatment with oral conjugated estrogens (CE 0.625 mg) per day, relative to placebo. The Women's Health Initiative Memory Study (WHIMS), a substudy of the WHI study, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with CE 0.625 mg combined with MPA 2.5 mg and during 5.2 years of treatment with CE 0.625 mg alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. Because of these trials, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
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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 treatment. These include a possible increased risk of breast cancer.<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 preexisting 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 estrogen may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored to maintain their free thyroid hormone levels in an acceptable range.<br/>6. Fluid retention: Estrogens may cause some degree of fluid retention. Because of this, patients who have 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 estrogen-plus-progestin substudy of WHI reported that after an average follow-up of 5.6 years, the relative risk for ovarian cancer for estrogen plus progestin vs. placebo was 1.58 (95% CI 0.77 - 3.24), but was not statistically significant. The absolute risk for estrogen plus progestin vs. placebo was 4.2 vs. 2.7 cases per 10,000 women-years. In some epidemiologicstudies, the use of estrogen-only products, in particular for 10 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. Malignant transformation of residual endometrial implants has 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 contents of the Patient Information leaflet with patients for whom they prescribe Activella 1.0 mg/0.5 mg or Activella 0.5 mg/0.1 mg.<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: 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, 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), Tlevels (by column or by radioimmunoassay), or Tlevels by radioimmunoassay. Tresin uptake is decreased, reflecting the elevated TBG. Free Tand free Tconcentrations 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), SHBG) leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/rennin substrate, alpha-1 antitrypsin, ceruloplasmin). 4. Increased plasma HDL and HDLcholesterol subfraction concentration, reduced LDL cholesterol concentration, increased triglyceride levels. 5. Impaired glucose tolerance. 6. Reduced response to metyrapone test.<br/>E. Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term continuous administration of estrogen, with or without progestin, in women with or 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: Activella 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 breast milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when Activella is administered to a nursing mother.<br/>H. Pediatric Use: Activella is not indicated in children.<br/>I. Geriatric Use: Clinical studies of Activella did not include sufficient number of subjects aged 65 and over to determine if they responded differently from younger subjects. Of the total number of subjects in the estrogen-plus-progestin substudy of the Women's Health Initiative (WHI) study, 44% (n=7,320) were 65-74 years of age, while 6.6% (n=1,095) were 75 years and over. There was a higher relative risk (CE/MPA vs. placebo) of non-fatal stroke and invasive breast cancer in women 75 and over compared to women less than 75 years of age. In women greater than 75, the increased risk of non-fatal stroke and invasive breast cancer observed in the estrogen-plus-progestin combination group compared to the placebo group was 75 vs. 24 per 10,000 women-years and 52 vs. 12 per 10,000 women-years, respectively. In the estrogen-plus-progestin Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 4,532 hysterectomized women, aged 65 to 79 years, was randomized to CE/MPA (0.625 mg/2.5 mg daily) or placebo. In the estrogen-plus-progestin group, after an average follow-up of four years, the relative risk (CE/MPA vs. placebo)of probable dementia was 2.05 (95% CI 1.21-3.48). The absolute risk of developing probable dementia with CE/MPA was 45 vs. 22 cases per 10,000 women-years with placebo. Of the total number of subjects in the estrogen-alone substudy of WHI, 46% (n=4,943) were 65 years and over, while 7.1% (n=767) were 75 years and over. There was a higher relative risk (CE vs. placebo) of stroke in women less than 75 years of age compared to women 75 years and over. In the estrogen-alone WHIMS substudy, a population of 2,947 hysterectomized women, aged 65 to 79 years, was randomized to CE (0.625 mg daily) or placebo. After an average follow-up of 5.2 years, the relative risk (CE vs. placebo) of probable dementia was 1.49 (95% CI 0.83-2.66). The absolute risk of developing probable dementia with estrogen alone was 37 vs. 25 cases per 10,000 women-years with placebo. Seventy-nine percent of the cases of probable dementia occurred in women that were older than 70 for the CE-alone group, and 82 percent of the cases of probable dementia occurred in women who were older than 70 in the CE/MPA group. The most common classification of probable dementia in both the treatment groups and placebo groups was Alzheimer's disease. When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95% CI 1.19-2.60). Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women.
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Serious ill effects have not been reported following acute ingestion of large doses of estrogen-containing drug products by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females.
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estradiol and norethindrone acetate
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Activella (Tablet, Film Coated)
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See BOXED WARNINGS, WARNINGS and PRECAUTIONS. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Adverse events reported with Activella 1.0 mg/0.5 mg by investigators in the Phase 3 studies regardless of causality assessment are shown in Table 6. Adverse events reported with Activella 0.5 mg/0.1 mg by investigators during the Phase 3 study regardless of causality assessment are shown in Table 7. The following adverse reactions have been reported with estrogen 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; pre-menstrual-like syndrome; cystitis-like syndrome; 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; changes in appetite; cholestatic jaundice; abdominal pain/cramps, flatulence, bloating; 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; seborrhea; hirsutism; itching; skin rash; pruritus.<br/>6. Eyes: Retinal vascular thrombosis, intolerance to contact lenses.<br/>7. Central nervous system: Headache; migraine; dizziness; mental depression; chorea; insomnia; nervousness; mood disturbances; irritability; exacerbation of epilepsy; probable dementia.<br/>8. Miscellaneous: Increase or decrease in weight; aggravation of porphyria; edema; leg cramps; changes in libido; fatigue; reduced carbohydrate tolerance; anaphylactoid/anaphylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides; back pain; arthralgia; myalgia.
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See BOXED WARNINGS.<br/>1. Cardiovascular disorders: Estrogen-plus-progestin therapy has been associated with an increased risk of myocardial infarction as well as stroke, venous thrombosis and pulmonary embolism. Estrogen-alone therapy has been associated with an increased risk of stroke and deep vein thrombosis (DVT). Should any of these events occur or be suspected, estrogens should be discontinued immediately. Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.<br/>a. stroke: In the estrogen plus progestin substudy of the Women's Health Initiative (WHI), a statistically significant increased risk of stroke was reported in women receiving CE/MPA 0.625 mg/2.5 mg daily compared to woman receiving placebo (31 vs. 24 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. . In the estrogen-alone substudy of the WHI, a statistically significant increased risk of stroke was reported in women receiving CE 0.625 mg daily compared to women receiving placebo (44 vs. 32 per 10,000 women-years). The increase in risk was demonstrated in year one and persisted.<br/>b. coronary heart disease: In the estrogen-plus progestin sub-study of WHI, no statistically significant increase in CHD events (defined as non-fatal, MI, silent MI, or death, due to CHD) was reported in women receiving CE/MPA compared to women receiving placebo (39 vs. 33 per 10,000 women-years). An increase in relative risk was demonstrated in year one, and a trend toward decreasing relative risk was reported in years 2 through 5. In the estrogen-alone substudy of WHI, no overall effect on coronary disease (CHD) events was reported in women receiving estrogen alone compared to placebo. In postmenopausal women with documented heart disease (n=2,763, average age 66.7 years), a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study (HERS)) treatment with CE/MPA (0.625mg/2.5mg per day) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Participation in an open-label extension ofthe original HERS trial (HERS II) was agreed to by 2,321 women. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and the placebo group in HERS, HERS II, and overall. 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.<br/>c. Venous thromboembolism: In the estrogen-plus-progestin substudy of the Women's Health Initiative (WHI), a statistically significant 2-fold greater rate of VTE (DVT and pulmonary embolism [PE]), was reported in women receiving CE/MPA compared to women receiving placebo (35 vs. 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 women-years) and PE (18 vs. 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted. In the estrogen-alone substudy of WHI, therisk of VTE was reported to be increased for women taking conjugated estrogens (30 vs. 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 vs. 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first two years. If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.<br/>2. Malignant neoplasms:<br/>a. Breast cancer: In some studies, the use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the CE/MPA substudy of the WHI study . The results from observational studies are generally consistent with those of the WHI clinical trial. Observational studies have also reported an increased risk of breast cancer for estrogen-plus-progestin combination therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. For both findings, the excess risk increased with duration of use, and appeared to return to baseline over about five years after stopping treatment (only the observational studies have substantial data on risk after stopping). In these studies, the risk of breast cancer was greater, and became apparent earlier, with estrogen-plus-progestin combination therapy as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogens or among different estrogen-plus-progestin combinations, doses, or routes of administration. In the estrogen-plus-progestin substudy, after a mean follow-up of 5.6 years, the WHI substudy reported an increased risk of breast cancer. In this substudy, prior use of estrogen alone or estrogen-plus-progestin combination hormone therapy was reported by 26% of the women. The relative risk of invasive breast cancer was 1.24 (95% nCI 1.01-1.54), and the absolute risk was 41 vs. 33 cases per 10,000 women-years, for estrogen plus progestin compared with placebo, respectively. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years, for estrogen plus progestin compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years of estrogen plus progestin compared with placebo. In the WHI trial, invasive breast cancers were larger and diagnosed at a more advanced stage in the estrogen-plus-progestin group compared with the placebo group. Metastatic disease wasrare, with no apparent difference between the two groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the groups. In the estrogen-alone substudy of WHI, after an average of 7.1 years of follow-up, CE (0.625 mg daily) was not associated with an increased risk of invasive breast cancer (RR 0.80, 95% nCI 0.62-1.04). In a one-year trial among 1,176 women who received either unopposed 1 mg estradiol or a combination of 1 mg estradiol plus one of three different doses of NETA (0.1, 0.25, and 0.5 mg), seven new cases of breast cancer were diagnosed, two of which occurred among the group of 295 women treated with Activella 1.0 mg/0.5 mg and two of which occurred among the group of 294 women treated with 1 mg estradiol/0.1 mg NETA. The use of estrogen alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a health care provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.<br/>b. Endometrial cancer: The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 fold greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than one year. The greatest risk appears associated with prolonged use, with an increased risk of 15- to 24-fold for five to ten years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. Clinical surveillance of all women taking estrogen/progestin combinations 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 results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Endometrial hyperplasia (a possible precursor of endometrial cancer) has been reported to occur in approximately 1% or less with Activella in one large clinical trial.<br/>3. Dementia: In the estrogen-plus-progestin Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 4,532 postmenopausal women aged 65 to 79 years was randomized to CE/MPA (0.625 mg/2.5 mg daily) or placebo. In the estrogen-alone WHIMS substudy, a population of 2,947 hysterectomized women, aged 65 to 79 years, was randomized to CE (0.625 mg daily) or placebo. In the estrogen-plus-progestin substudy, after an average follow-up of four years, 40 women in the estrogen-plus-progestin group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for estrogen plus progestin vs. placebo was 2.05 (95% CI 1.21-3.48). The absolute risk of probable dementia for CE/MPA vs. placebo was 45 vs. 22 cases per 10,000 women-years. In the estrogen-alone substudy, after an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE alone vs. placebo was 1.49 (95% CI 0.83-2.66). The absolute risk of probable dementia for CE alone vs. placebo was 37 vs. 25 cases per 10,000 women-years. When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk of probable dementia was 1.76 (95% CI 1.19-2.60). Since both substudies were conducted in women ages 65 to 79, it is unknown whether these findings apply to younger postmenopausal women.<br/>4. Gallbladder disease: A two-to four fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.<br/>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.<br/>6. Visual abnormalities: Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is a 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 permanently discontinued.
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Activella 1.0 mg/0.5 mg and 0.5 mg/0.1 mg are indicated in women who have a uterus for the: 1. Treatment of moderate to severe vasomotor symptoms associated with menopause. 2. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medications should be carefully considered. 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. Activella 1.0 mg/0.5 mg is also indicated in women who have a uterus for the: 3. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause. When used solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.
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Activella
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