PREMARIN (Tablet, Coated)

PREMARIN (Tablet, Coated)

PREMARIN (conjugated estrogens tablets, USP) for oral administration contains a mixture of conjugated estrogens obtained exclusively from natural sources, occurring as the sodium salts of water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mares' urine. It is a mixture of sodium estrone sulfate and sodium equilin sulfate. It contains as concomitant components, as sodium sulfate conjugates, 17��-dihydroequilin, 17��-estradiol, and 17��-dihydroequilin. Tablets for oral administration are available in 0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, and 1.25 mg strengths of conjugated estrogens. PREMARIN 0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, and 1.25 mg tablets also contain the following inactive ingredients: calcium phosphate tribasic, hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, sucrose, and titanium dioxide. ���0.3 mg tablets also contain: D&C Yellow No. 10 and FD&C Blue No. 2.���0.45 mg tablets also contain: FD&C Blue No. 2.���0.625 mg tablets also contain: FD&C Blue No. 2 and FD&C Red No. 40.���0.9 mg tablets also contain: D&C Red No. 30 and D&C Red No. 7.���1.25 mg tablets also contain: black iron oxide, D&C Yellow No. 10 and FD&C Yellow No. 6. PREMARIN tablets comply with USP Dissolution Test criteria as outlined below:

dailymed-ingredient:conjugated_estrogens

PREMARIN (conjugated estrogens tablets, USP) ���Each oval yellow tablet contains 1.25 mg, in bottles of 100 (NDC 0046-1104-81) and 1,000 (NDC 0046-1104-91). ���Each oval white tablet contains 0.9 mg, in bottles of 100 (NDC 0046-1103-81). ���Each oval maroon tablet contains 0.625 mg, in bottles of 100 (NDC 0046-1102-81) and 1,000 (NDC 0046-1102-91). ���Each oval blue tablet contains 0.45 mg, in bottles of 100 (NDC 0046-1101-81). ���Each oval green tablet contains 0.3 mg, in bottles of 100 (NDC 0046-1100-81) and 1,000 (NDC 0046-1100-91). The appearance of these tablets is a trademark of Wyeth Pharmaceuticals. Store at 20��-25��C (68��-77��F); excursions permitted to 15��-30��C (59��-86��F) [see USP Controlled Room Temperature]. Dispense in a well-closed container, as defined in the USP.

WARNINGSENDOMETRIAL CANCER: 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. (See WARNINGS, Malignant neoplasms, Endometrial cancer.)<br/>CARDIOVASCULAR AND OTHER RISKS: Estrogens with or without progestins should not be used for the prevention of cardiovascular disease or dementia. The estrogen alone substudy of the Women's Health Initiative (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 daily oral conjugated estrogens (CE 0.625 mg), relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders.) The estrogen plus progestin substudy of WHI reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and DVT in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily CE 0.625 mg combined with medroxyprogesterone acetate (MPA 2.5 mg), relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders and Malignant neoplasms, Breast cancer.) The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE 0.625 mg alone and during 4 years of treatment with daily CE 0.625 mg combined with MPA 2.5 mg, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL STUDIES and WARNINGS, Dementia and PRECAUTIONS, GeriatricUse.) In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and other combinations and dosage forms of estrogens and progestins. Because of these risks, 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.

dailymed-ingredient:D&C_Yellow_No._10, dailymed-ingredient:FD&C_Blue_No._2, dailymed-ingredient:calcium_phosphate_tribasic, dailymed-ingredient:hydroxypropyl_cellulose, dailymed-ingredient:hypromellose, dailymed-ingredient:lactose_monohydrate, dailymed-ingredient:magnesium_stearate, dailymed-ingredient:microcrystalline_cellulose, dailymed-ingredient:polyethylene_glycol, dailymed-ingredient:powdered_cellulose, dailymed-ingredient:sucrose, dailymed-ingredient:titanium_dioxide

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 (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 estrogen therapy on blood pressure was not seen. Blood pressure should be monitored at regular intervals during 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. Consider discontinuation of treatment if pancreatitis or other complications develop. In the HOPE study, the mean percent increase from baseline in serum triglycerides after one year of treatment with PREMARIN 0.625 mg, 0.45 mg, and 0.3 mg compared with placebo were 34.3, 30.2, 25.1, and 10.7, respectively. After two years of treatment, the mean percent changes were 47.6, 32.5, 19.0, and 5.5, respectively.<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: Estrogens 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.<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 a non-statistically significant increased 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 percent nCI 0.77���3.24). 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-only products, in particular for 5 or more years, has been associated with an increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association.<br/>9. Exacerbation of endometriosis: Endometriosis may be exacerbated with administration of estrogen therapy. 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: Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in patients 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 PREMARIN.<br/>C. Laboratory Tests: Serum follicle stimulating hormone and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar and vaginal atrophy. Laboratory parameters may be useful in guiding dosage for the treatment of hypoestrogenism due to hypogonadism, castration and primary ovarian failure.<br/>D. Drug/Laboratory Test Interactions:<br/>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 breast, uterus, cervix, vagina, testis, and liver.<br/>F. Pregnancy: PREMARIN should not be used during pregnancy.<br/>G. Nursing Mothers: PREMARIN should not be used during lactation. 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.<br/>H. Pediatric Use: Estrogen therapy has been used for the induction of puberty in adolescents with some forms of pubertal delay. Safety and effectiveness in pediatric patients have not otherwise been established. Large and repeated doses of estrogen over an extended time period have been shown to accelerate epiphyseal closure, which could result in short stature if treatment is initiated before the completion of physiologic puberty in normally developing children. If estrogen is administered to patients whose bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended during estrogen administration. Estrogen treatment of prepubertal girls also induces premature breast development and vaginal cornification, and may induce vaginal bleeding. In boys, estrogen treatment may modify the normal pubertal process and induce gynecomastia.<br/>I. Geriatric Use: With respect to efficacy in the approved indications, there have not been sufficient numbers of geriatric patients involved in studies utilizing PREMARIN to determine whether those over 65 years of age differ from younger subjects in their response to PREMARIN. In the estrogen alone substudy of the Women's Health Initiative (WHI) study, 46 percent (n=4,943) were 65 years of age and older, while 7.1 percent (n=767) were 75 years of age and older. There was a higher relative risk (daily conjugated estrogens [CE 0.625 mg] versus placebo) of stroke in women less than 75 years of age compared to women 75 years and older. In the estrogen alone Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 2,947 hysterectomized women, 65 to 79 years of age, was randomized to daily CE 0.625 mg or placebo. After an average follow-up of 5.2 years, the relative risk (CE versus placebo) of probable dementia was 1.49 (95 percent CI 0.83-2.66). The absolute risk of developing probable dementia with estrogen alone was 37 versus 25 cases per 10,000 women-years compared with placebo. Of the total number of subjects in the estrogen plus progestin substudy of the Women's Health Initiative study, 44 percent (n=7,320) were 65 years of age and older, while 6.6 percent (n=1,095) were 75 years and older. In women 75 years of age and older compared to women less than 74 years of age, there was a higher relative risk of nonfatal stroke and invasive breast cancer in the estrogen plus progestin group versus placebo. In women greater than 75, the increased risk of nonfatal stroke and invasive breast cancer observed in the estrogen plus progestin group compared to placebo was 75 versus 24 per 10,000 women-years and 52 versus 12 per 10,000 women years, respectively. In the estrogen plus progestin substudy of WHIMS, a population of 4,532 postmenopausal women, 65 to 79 years of age, was randomized to daily CE 0.625 mg/MPA 2.5 mg or placebo. In the estrogen plus progestin group, after an average follow-up of 4 years, the relative risk (CE/MPA versus placebo) of probable dementia was 2.05 (95 percent CI 1.21-3.48). The absolute risk of developing probable dementia with CE/MPA was 45 versus 22 cases per 10,000 women-years compared 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 percent CI 1.19-2.60). Since both substudies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women.

conjugated estrogens

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. During the first year of a 2-year clinical trial with 2,333 postmenopausal women between 40 and 65 years of age (88% Caucasian), 1,012 women were treated with conjugated estrogens and 332 were treated with placebo. Table 6 summarizes adverse events that occurred at a rate of���5%. The following additional adverse reactions have been reported with estrogen and/or progestin therapy:<br/>1. Genitourinary system: Abnormal uterine bleeding/spottingDysmenorrhea/pelvic painIncrease in size of uterine leiomyomataVaginitis, including vaginal candidiasisChange in amount of cervical secretionChange in cervical ectropionOvarian cancerEndometrial hyperplasiaEndometrial cancer<br/>2. Breasts: Tenderness, enlargement, pain, discharge, galactorrheaFibrocystic breast changesBreast cancer<br/>3. Cardiovascular: Deep and superficial venous thrombosisPulmonary embolismThrombophlebitisMyocardial infarctionStrokeIncrease in blood pressure<br/>4. Gastrointestinal: Nausea, vomitingAbdominal cramps, bloatingCholestatic jaundiceIncreased incidence of gallbladder diseasePancreatitisEnlargement of hepatic hemangiomasIschemic colitis<br/>5. Skin: Chloasma or melasma that may persist when drug is discontinuedErythema multiformeErythema nodosumHemorrhagic eruptionLoss of scalp hairHirsutismPruritus, rash<br/>6. Eyes: Retinal vascular thrombosisIntolerance to contact lenses<br/>7. Central Nervous System: HeadacheMigraineDizzinessMental depressionExacerbation of choreaNervousnessMood disturbancesIrritabilityExacerbation of epilepsyDementiaPossible growth potentiation of benign meningioma<br/>8. Miscellaneous: Increase or decrease in weightGlucose intoleranceAggravation of porphyriaEdemaArthralgiasLeg crampsChanges in libidoUrticaria, angioedema, anaphylactoid/anaphylactic reactionsHypocalcemia (preexisting condition)Exacerbation of asthmaIncreased triglycerides

PREMARIN therapy is indicated in the:

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