ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 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 summarizes adverse events that occurred at rate of >= 5%.TABLE 6. NUMBER (%) OF PATIENTS REPORTING >= 5% TREATMENT EMERGENT ADVERSE EVENTS --Conjugated Estrogens Treatment Group-- Body System0.625 mg0.45 mg0.3 mgPlacebo Adverse event(n 348)(n 338)(n 326)(n 332)Any adverse event323 (93%)305 (90%)292 (90%)281 (85%)Body as Whole Abdominal pain Accidental injury Asthenia Back pain Flu syndrome Headache Infection Pain56 (16%)21 (6%)25 (7%)49 (14%)37 (11%)90 (26%)61 (18%)58 (17%)50 (15%)41 (12%)23 (7%)43 (13%)38 (11%)109 (32%)75 (22%)61 (18%)54 (17%)20 (6%)25 (8%)43 (13%)33 (10%)96 (29%)74 (23%)66 (20%)37 (11%)29 (9%)16 (5%)39 (12%)35 (11%)93 (28%)74 (22%)61 (18%)Digestive System Diarrhea Dyspepsia Flatulence Nausea21 (6%)33 (9%)24 (7%)32 (9%)25 (7%)32 (9%)23 (7%)21 (6%)19 (6%)36 (11%)18 (6%)21 (6%)21 (6%)46 (14%)9 (3%)30 (9%)Musculoskeletal System Arthralgia Leg cramps Myalgia47 (14%)19 (5%)18 (5%)42 (12%)23 (7%)18 (5%)22 (7%)11 (3%)29 (9%)39 (12%)7 (2%)25 (8%)Nervous System Depression Dizziness Insomnia Nervousness25 (7%)19 (5%)21 (6%)12 (3%)27 (8%)20 (6%)25 (7%)17 (5%)17 (5%)12 (4%)24 (7%)6 (2%)22 (7%)17 (5%)33 (10%)7 (2%)Respiratory System Cough increased Pharyngitis Rhinitis Sinusitis Upper respiratory infection13 (4%)35 (10%)21 (6%)22 (6%)42 (12%)22 (7%)35 (10%)30 (9%)36 (11%)34 (10%)14 (4%)40 (12%)31 (10%)24 (7%)28 (9%)14 (4%)38 (11%)42 (13%)24 (7%)35 (11%)Skin and Appendages Pruritus14 (4%)17 (5%)16 (5%)7 (2%)Urogenital System Breast pain Leukorrhea Vaginal hemorrhage Vaginal moniliasis Vaginitis38 (11%)18 (5%)47 (14%)20 (6%)24 (7%)41 (12%)22 (7%)14 (4%)18 (5%)20 (6%)24 (7%)13 (4%)7 (2%)17 (5%)16 (5%)29 (9%)9 (3%)06 (2%)4 (1%)The following additional adverse reactions have been reported with estrogen and/or progestin therapy:1. Genitourinary systemAbnormal uterine bleeding/spotting Dysmenorrhea/pelvic pain Increase in size of uterine leiomyomata Vaginitis, including vaginal candidiasis Change in amount of cervical secretion Change in cervical ectropion Ovarian cancer Endometrial hyperplasia Endometrial cancer2. BreastsTenderness, enlargement, pain, discharge, galactorrhea Fibrocystic breast changes Breast cancer3. CardiovascularDeep and superficial venous thrombosis Pulmonary embolism Thrombophlebitis Myocardial infarction Stroke Increase in blood pressure4. GastrointestinalNausea, vomiting Abdominal cramps, bloating Cholestatic jaundice Increased incidence of gallbladder disease Pancreatitis Enlargement of hepatic hemangiomas Ischemic colitis5. SkinChloasma or melasma that may persist when drug is discontinued Erythema multiforme Erythema nodosum Hemorrhagic eruption Loss of scalp hair Hirsutism Pruritus, rash6. EyesRetinal vascular thrombosis Intolerance to contact lenses7. Central Nervous SystemHeadache Migraine Dizziness Mental depression Exacerbation of chorea Nervousness Mood disturbances Irritability Exacerbation of epilepsy Dementia Possible growth potentiation of benign meningioma8. MiscellaneousIncrease or decrease in weight Glucose intolerance Aggravation of porphyria Edema Arthralgias Leg cramps Changes in libido Urticaria, angioedema, anaphylactoid/anaphylactic reactions Hypocalcemia (preexisting condition) Exacerbation of asthma Increased triglycerides.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in 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 negative feedback mechanism. Estrogens act to reduce the elevated levels of these gonadotropins seen in postmenopausal women.PharmacokineticsA. AbsorptionConjugated estrogens are water-soluble and are well-absorbed from the gastrointestinal tract after release from the drug formulation. The PREMARIN tablet releases conjugated estrogens slowly over several hours. Table summarizes the mean pharmacokinetic parameters for unconjugated and conjugated estrogens following administration of x 0.625 mg and x 1.25 mg tablets to healthy postmenopausal women. The pharmacokinetics of PREMARIN 0.45 mg and 1.25 mg tablets were assessed following single dose with high-fat breakfast and with fasting administration. The Cmax and AUC of estrogens were altered approximately 3-13%. The changes to Cmax and AUC are not considered clinically meaningful. TABLE 1. PHARMACOKINETIC PARAMETERS FOR PREMARIN(R) Pharmacokinetic Profile of Unconjugated Estrogens Following Dose of x 0.625 mgPK ParameterArithmetic Mean (%CV)Cmax (pg/mL)tmax (h)t1/2 (h)AUC(pgoh/mL)Estrone87 (33)9.6 (33)50.7 (35)5557 (59)Baseline-adjusted estrone64 (42)9.6 (33)20.2 (40)1723 (52)Equilin31 (38)7.9 (32)12.9 (112)602 (54)Pharmacokinetic Profile of Conjugated Estrogens Following Dose of x 0.625 mgPK ParameterArithmetic Mean (%CV)Cmax (ng/mL)tmax (h)t1/2 (h)AUC(ngoh/mL)Total Estrone2.7 (43)6.9 (25)26.7 (33)75 (52)Baseline-adjusted total estrone2.5 (45)6.9 (25)14.8 (35)46 (48)Total Equilin1.8 (56)5.6 (45)11.4 (31)27 (56)Pharmacokinetic Profile of Unconjugated Estrogens Following Dose of x 1.25 mgPK ParameterArithmetic Mean (%CV)Cmax (pg/mL)tmax (h)t1/2 (h)AUC(pgoh/mL)Estrone124 (30)10.0 (32)38.1 (37)6332 (44)Baseline-adjusted estrone102 (35)10.0 (32)19.7 (48)3159 (53)Equilin59 (43)8.8 (36)10.9 (47)1182 (42)Pharmacokinetic Profile of Conjugated Estrogens Following Dose of x 1.25 mgPK ParameterArithmetic Mean (%CV)Cmax (ng/mL)tmax (h)t1/2 (h)AUC(ngoh/mL)Total Estrone4.5 (39)8.2 (58)26.5 (40)109 (46)Baseline-adjusted total estrone4.3 (41)8.2 (58)17.5 (41)87 (44)Total equilin2.9 (42)6.8 (49)12.5 (34)48 (51)B. DistributionThe distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentration in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.C. MetabolismExogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in 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 intestine followed by reabsorption. In postmenopausal women significant proportion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as circulating reservoir for the formation of more active estrogens.D. ExcretionEstradiol, estrone, and estriol are excreted in the urine, along with glucuronide and sulfate conjugates.E. Special PopulationsNo pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.F. Drug InteractionsData from single-dose drug-drug interaction study involving conjugated estrogens and medroxyprogesterone acetate indicate that the pharmacokinetic dispositions of both drugs are not altered when the drugs are coadministered. No other clinical drug-drug interaction studies have been conducted with conjugated estrogens.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. Johns Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin, may reduce plasma concentrations of estrogens, possibly resulting in decrease in therapeutic effects and/or changes in the uterine bleeding profile. 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.

CLINICAL STUDIES SECTION.

CLINICAL STUDIES. Effects on vasomotor symptomsIn the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, total of 2,805 postmenopausal women (average age 53.3 +- 4.9 years) were randomly assigned to one of eight treatment groups, receiving either placebo or conjugated estrogens, with or without medroxyprogesterone acetate. Efficacy for vasomotor symptoms was assessed during the first 12 weeks of treatment in subset of symptomatic women (n 241) who had at least seven moderate to severe hot flushes daily, or at least 50 moderate to severe hot flushes during the week before randomization. PREMARIN (0.3 mg, 0.45 mg, and 0.625 mg tablets) was shown to be statistically better than placebo at weeks and 12 for relief of both the frequency and severity of moderate to severe vasomotor symptoms. Table shows the adjusted mean number of hot flushes in the PREMARIN 0.3 mg, 0.45 mg, and 0.625 mg and placebo treatment groups over the initial 12-week period.TABLE 2. SUMMARY TABULATION OF THE NUMBER OF HOT FLUSHES PER DAY MEAN VALUES AND COMPARISONS BETWEEN THE ACTIVE TREATMENT GROUPS AND THE PLACEBO GROUP: PATIENTS WITH AT LEAST MODERATE TO SEVERE FLUSHES PER DAY OR AT LEAST 50 PER WEEK AT BASELINE, LAST OBSERVATION CARRIED FORWARD (LOCF)Treatment(No. of Patients) Time Period Baseline Observed Mean p-Values (week) Mean +- SDMean +- SDChange +- SDvs. Placeboa 0.625 mg CE(n 27) 412.29 +- 3.89 1.95 +- 2.77-10.34 +- 4.73less than 0.001 12 12.29 +- 3.890.75 +- 1.82-11.54 +- 4.62less than 0.001 0.45 mg CE(n 32) 12.25 +- 5.045.04 +- 5.31-7.21 +- 4.75less than 0.001 12 12.25 +- 5.042.32 +- 3.32-9.93 +- 4.64less than 0.001 0.3 mg CE(n 30) 13.77 +- 4.784.65 +- 3.71-9.12 +- 4.71less than 0.001 12 13.77 +- 4.782.52 +- 3.23-11.25 +- 4.60less than 0.001 Placebo(n 28) 11.69 +- 3.877.89 +- 5.28-3.80 +- 4.71- 12 11.69 +- 3.875.71 +- 5.22-5.98 +- 4.60- a: Based on analysis of covariance with treatment as factor and baseline as covariate. Effects on vulvar and vaginal atrophyResults of vaginal maturation indexes at cycles and 13 showed that the differences from placebo were statistically significant (p less than 0.001) for all treatment groups (conjugated estrogens alone and conjugated estrogens/medroxyprogesterone acetate treatment groups).Effects on bone mineral densityHealth and Osteoporosis, Progestin and Estrogen HOPE) StudyThe HOPE study was double-blind, randomized, placebo/active-drug-controlled, multicenter study of healthy postmenopausal women with an intact uterus. Subjects (mean age 53.3 +- 4.9 years) were 2.3 +- 0.9 years on average since menopause and took one 600-mg tablet of elemental calcium (Caltrate(TM)) daily. Subjects were not given Vitamin supplements. They were treated with PREMARIN 0.625 mg, 0.45 mg, 0.3 mg, or placebo. Prevention of bone loss was assessed by measurement of bone mineral density (BMD), primarily at the anteroposterior lumbar spine (L2 to L4). Secondarily, BMD measurements of the total body, femoral neck, and trochanter were also analyzed. Serum osteocalcin, urinary calcium, and N-telopeptide were used as bone turnover markers (BTM) at cycles 6, 13, 19, and 26.Intent-to-treat subjectsAll active treatment groups showed significant differences from placebo in each of the four BMD endpoints at cycles 6, 13, 19, and 26. The mean percent increases in the primary efficacy measure (L2 to L4 BMD) at the final on-therapy evaluation (cycle 26 for those who completed and the last available evaluation for those who discontinued early) were 2.46 percent with 0.625 mg, 2.26 percent with 0.45 mg, and 1.13 percent with 0.3 mg. The placebo group showed mean percent decrease from baseline at the final evaluation of 2.45 percent. These results show that the lower dosages of PREMARIN were effective in increasing L2 to L4 BMD compared with placebo, and therefore support the efficacy of the lower doses.The analysis for the other three BMD endpoints yielded mean percent changes from baseline in femoral trochanter that were generally larger than those seen for L2 to L4, and changes in femoral neck and total body that were generally smaller than those seen for L2 to L4. Significant differences between groups indicated that each of the PREMARIN treatments was more effective than placebo for all three of these additional BMD endpoints. With regard to femoral neck and total body, the active treatment groups all showed mean percent increases in BMD, while placebo treatment was accompanied by mean percent decreases. For femoral trochanter, each of the PREMARIN dose groups showed mean percent increase that was significantly greater than the small increase seen in the placebo group. The percent changes from baseline to final evaluation are shown in Table 3.TABLE 3. PERCENT CHANGE IN BONE MINERAL DENSITY: COMPARISON BETWEEN ACTIVE AND PLACEBO GROUPS IN THE INTENT-TO-TREAT POPULATION, LOCFRegion EvaluatedTreatment Groupa No. ofSubjects Baseline(g/cm2)Mean +- SDChange from Baseline(%)Adjusted Mean +- SEp-Value vs PlaceboL2 to L4 BMD 0.625 83 1.17 +- 0.152.46 +- 0.37less than 0.001 0.45 91 1.13 +- 0.152.26 +- 0.35less than 0.001 0.3 87 1.14 +- 0.151.13 +- 0.36less than 0.001 Placebo 85 1.14 +- 0.14-2.45 +- 0.36Total Body BMD 0.625 84 1.15 +- 0.080.68 +- 0.17less than 0.001 0.45 91 1.14 +- 0.080.74 +- 0.16less than 0.001 0.3 87 1.14 +- 0.070.40 +- 0.17less than 0.001 Placebo 85 1.13 +- 0.08-1.50 +- 0.17Femoral Neck BMD 0.625 84 0.91 +- 0.141.82 +- 0.45less than 0.001 0.45 91 0.89 +- 0.131.84 +- 0.44less than 0.001 0.3 87 0.86 +- 0.110.62 +- 0.45less than 0.001 Placebo 85 0.88 +- 0.14-1.72 +- 0.45Femoral TrochanterBMD 0.625 84 0.78 +- 0.133.82 +- 0.58less than 0.001 0.45 91 0.76 +- 0.123.16 +- 0.560.003 0.3 87 0.75 +- 0.103.05 +- 0.570.005 Placebo 85 0.75 +- 0.120.81 +- 0.58a: Identified by dosage (mg) of PREMARIN or placebo.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. When estrogen is prescribed for postmenopausal woman with uterus, progestin should also be initiated to reduce the risk of endometrial cancer. woman without uterus does not need progestin. Use of estrogen, alone or in combination with 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 (for example at 3-month to 6-month intervals) to determine if treatment is still necessary (see BOXED WARNINGS and WARNINGS). For women with 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.PREMARIN may be taken without regard to meals.For treatment of moderate to severe vasomotor symptoms and/or moderate to severe symptoms of vulvar and vaginal atrophy due to menopause:When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. Patients should be treated with the lowest effective dose. Generally, women should be started at 0.3 mg PREMARIN daily. Subsequent dosage adjustment may be made based upon the individual patient response. This dose should be periodically reassessed by the healthcare provider. PREMARIN therapy may be given continuously, with no interruption in therapy, or in cyclical regimens (regimens such as 25 days on drug followed by five days off drug), as is medically appropriate on an individualized basis. For prevention of postmenopausal osteoporosis:When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should be considered only for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate. Patients should be treated with the lowest effective dose. Generally, women should be started at 0.3 mg PREMARIN daily. Subsequent dosage adjustment may be made based upon the individual clinical and bone mineral density responses. This dose should be periodically reassessed by the healthcare provider. PREMARIN therapy may be given continuously, with no interruption in therapy, or in cyclical regimens (regimens such as 25 days on drug followed by five days off drug), as is medically appropriate on an individualized basis. For treatment of female hypoestrogenism due to hypogonadism, castration, or primary ovarian failure:Female hypogonadism -- 0.3 mg or 0.625 mg daily, administered cyclically (e.g., three weeks on and one week off). Doses are adjusted depending on the severity of symptoms and responsiveness of the endometrium. In clinical studies of delayed puberty due to female hypogonadism, breast development was induced by doses as low as 0.15 mg. The dosage may be gradually titrated upward at 6-to-12 month intervals as needed to achieve appropriate bone age advancement and eventual epiphyseal closure. Clinical studies suggest that doses of 0.15 mg, 0.3 mg, and 0.6 mg are associated with mean ratios of bone age advancement to chronological age progression (BA/CA) of 1.1, 1.5, and 2.1, respectively. (PREMARIN in the dose strength of 0.15 mg is not available commercially). Available data suggest that chronic dosing with 0.625 mg is sufficient to induce artificial cyclic menses with sequential progestin treatment and to maintain bone mineral density after skeletal maturity is achieved. Female castration or primary ovarian failure -- 1.25 mg daily, cyclically. Adjust dosage, upward or downward, according to severity of symptoms and response of the patient. For maintenance, adjust dosage to lowest level that will provide effective control. For treatment of breast cancer, for palliation only, in appropriately selected women and men with metastatic disease:Suggested dosage is 10 mg three times daily, for period of at least three months. For treatment of advanced androgen-dependent carcinoma of the prostate, for palliation only:1.25 mg to x 1.25 mg three times daily. The effectiveness of therapy can be judged by phosphatase determinations as well as by symptomatic improvement of the patient. For treatment of moderate to severe vasomotor symptoms and/or moderate to severe symptoms of vulvar and vaginal atrophy due to menopause:When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. Patients should be treated with the lowest effective dose. Generally, women should be started at 0.3 mg PREMARIN daily. Subsequent dosage adjustment may be made based upon the individual patient response. This dose should be periodically reassessed by the healthcare provider. PREMARIN therapy may be given continuously, with no interruption in therapy, or in cyclical regimens (regimens such as 25 days on drug followed by five days off drug), as is medically appropriate on an individualized basis. For prevention of postmenopausal osteoporosis:When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should be considered only for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate. Patients should be treated with the lowest effective dose. Generally, women should be started at 0.3 mg PREMARIN daily. Subsequent dosage adjustment may be made based upon the individual clinical and bone mineral density responses. This dose should be periodically reassessed by the healthcare provider. PREMARIN therapy may be given continuously, with no interruption in therapy, or in cyclical regimens (regimens such as 25 days on drug followed by five days off drug), as is medically appropriate on an individualized basis. For treatment of female hypoestrogenism due to hypogonadism, castration, or primary ovarian failure:Female hypogonadism -- 0.3 mg or 0.625 mg daily, administered cyclically (e.g., three weeks on and one week off). Doses are adjusted depending on the severity of symptoms and responsiveness of the endometrium. In clinical studies of delayed puberty due to female hypogonadism, breast development was induced by doses as low as 0.15 mg. The dosage may be gradually titrated upward at 6-to-12 month intervals as needed to achieve appropriate bone age advancement and eventual epiphyseal closure. Clinical studies suggest that doses of 0.15 mg, 0.3 mg, and 0.6 mg are associated with mean ratios of bone age advancement to chronological age progression (BA/CA) of 1.1, 1.5, and 2.1, respectively. (PREMARIN in the dose strength of 0.15 mg is not available commercially). Available data suggest that chronic dosing with 0.625 mg is sufficient to induce artificial cyclic menses with sequential progestin treatment and to maintain bone mineral density after skeletal maturity is achieved. Female castration or primary ovarian failure -- 1.25 mg daily, cyclically. Adjust dosage, upward or downward, according to severity of symptoms and response of the patient. For maintenance, adjust dosage to lowest level that will provide effective control. For treatment of breast cancer, for palliation only, in appropriately selected women and men with metastatic disease:Suggested dosage is 10 mg three times daily, for period of at least three months. For treatment of advanced androgen-dependent carcinoma of the prostate, for palliation only:1.25 mg to x 1.25 mg three times daily. The effectiveness of therapy can be judged by phosphatase determinations as well as by symptomatic improvement of the patient.

PRECAUTIONS SECTION.

PRECAUTIONS. A. General1. Addition of progestin when woman has not had hysterectomyStudies of the addition of progestin for 10 or more days of cycle of estrogen administration, or daily with estrogen in continuous regimen, have reported lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be 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: possible increased risk of breast cancer, adverse effects on lipoprotein metabolism (lowering HDL, raising LDL) and impairment of glucose tolerance.2. Elevated blood pressureIn small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In large, randomized, placebo-controlled clinical trial, generalized effect of estrogen therapy on blood pressure was not seen. Blood pressure should be monitored at regular intervals during estrogen use.3. HypertriglyceridemiaIn 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.4. Impaired liver function and past history of cholestatic jaundiceEstrogens may be poorly metabolized in patients with impaired liver function. For patients with 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. HypothyroidismEstrogen 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 retentionEstrogens 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. HypocalcemiaEstrogens should be used with caution in individuals with severe hypocalcemia.8. Ovarian cancerThe estrogen plus progestin substudy of WHI reported 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 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.9. Exacerbation of endometriosisEndometriosis 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.10. Exacerbation of other conditionsEstrogen 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.B. Patient InformationPhysicians are advised to discuss the contents of the PATIENT INFORMATION leaflet with patients for whom they prescribe PREMARIN.C. Laboratory TestsSerum 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.D. Drug/Laboratory Test InteractionsAccelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII 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. 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. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentrations, increased triglyceride levels. Impaired glucose tolerance. E. Carcinogenesis, Mutagenesis, Impairment of Fertility(See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)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.F. PregnancyPREMARIN should not be used during pregnancy. (See CONTRAINDICATIONS.)G. Nursing MothersPREMARIN 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. H. Pediatric UseEstrogen 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. (See INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION.)I. Geriatric UseWith 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 Womens 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 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 Womens Health Initiative Memory Study (WHIMS), substudy of WHI, 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 Womens 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 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, 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 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 Alzheimers 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. (See BOXED WARNINGS and WARNINGS, Dementia.). Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII 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. 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. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentrations, increased triglyceride levels. Impaired glucose tolerance.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION. PREMARIN(R)(conjugated estrogens tablets, USP)Read this PATIENT INFORMATION before you start taking PREMARIN and read what you get each time you refill your PREMARIN prescription. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.What is the most important information should know about PREMARIN (an estrogen mixture)Estrogens increase the chance of getting cancer of the uterus.Report any unusual vaginal bleeding right away while you are taking PREMARIN. Vaginal bleeding after menopause may be warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. Do not use estrogens with or without progestins to prevent heart disease, heart attacks, strokes, or dementia.Using estrogens, with or without progestins, may increase your chance of getting heart attacks, strokes, breast cancer, and blood clots. Using estrogens, with or without progestins, may increase your chance of getting dementia, based on study of women age 65 years or older. You and your healthcare provider should talk regularly about whether you still need treatment with PREMARIN. What is PREMARINPREMARIN is medicine that contains mixture of estrogen hormones.PREMARIN is used after menopause to:Reduce moderate to severe hot flashes. Estrogens are hormones made by womans ovaries. The ovaries normally stop making estrogens when woman is between 45 and 55 years old. This drop in body estrogen levels causes the change of life or menopause (the end of monthly menstrual periods). Sometimes both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes surgical menopause.When the estrogen levels begin dropping, some women get very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating (hot flashes or hot flushes). In some women the symptoms are mild, and they will not need to take estrogens. In other women, symptoms can be more severe. You and your healthcare provider should talk regularly about whether you still need treatment with PREMARIN. Treat moderate to severe dryness, itching, and burning, in and around the vagina. You and your healthcare provider should talk regularly about whether you still need treatment with PREMARIN to control these problems. If you use PREMARIN only to treat your dryness, itching, and burning in and around your vagina, talk with your healthcare provider about whether topical vaginal product would be better for you. Help reduce your chances of getting osteoporosis (thin weak bones). Osteoporosis from menopause is thinning of the bones that makes them weaker and easier to break. If you use PREMARIN only to prevent osteoporosis due to menopause, talk with your healthcare provider about whether different treatment or medicine without estrogens might be better for you. You and your healthcare provider should talk regularly about whether you should continue with PREMARIN.Weight-bearing exercise, like walking or running, and taking calcium and vitamin supplements may also lower your chances for getting postmenopausal osteoporosis. It is important to talk about exercise and supplements with your healthcare provider before starting them. PREMARIN is also used to:Treat certain conditions in women before menopause if their ovaries do not make enough estrogen naturally. Ease symptoms of certain cancers that have spread through the body, in men and women. Who should not take PREMARINDo not start taking PREMARIN if you:Have unusual vaginal bleeding. Currently have or have had certain cancers. Estrogens may increase the chance of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should take PREMARIN. Had stroke or heart attack in the past year.Currently have or have had blood clots.Currently have or have had liver problems. Are allergic to PREMARIN tablets or any of its ingredients. See the list of ingredients in PREMARIN at the end of this leaflet. Think you may be pregnant.Tell your healthcare provider:If you are breast feeding. The hormones in PREMARIN can pass into your milk. About all of your medical problems. Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), migraine, endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. About all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how PREMARIN works. PREMARIN may also affect how your other medicines work. If you are going to have surgery or will be on bedrest. You may need to stop taking estrogens. How should take PREMARINTake one PREMARIN tablet at the same time each day. If you miss dose, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your normal schedule. Do not take doses at the same time. Estrogens should be used at the lowest dose possible for your treatment only as long as needed. You and your healthcare provider should talk regularly (for example, every to months) about the dose you are taking and whether you still need treatment with PREMARIN. What are the possible side effects of PREMARINSide effects are grouped by how serious they are and how often they happen when you are treated.Serious but less common side effects include:Breast cancer Cancer of the uterus Stroke Heart attack Blood clots Dementia Gallbladder disease Ovarian cancer High blood pressure Liver problems High blood sugar Enlargement of benign tumors of the uterus (fibroids) Some of the warning signs of these serious side effects include:Breast lumps Unusual vaginal bleeding Dizziness and faintness Changes in speech Severe headaches Chest pain Shortness of breath Pains in your legs Changes in vision Vomiting Yellowing of the skin, eyes or nail beds Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptoms that concern you.Less serious but common side effects include:Headache Breast pain Irregular vaginal bleeding or spotting Stomach/abdominal cramps, bloating Nausea and vomiting Hair loss Fluid retention Vaginal yeast infection These are not all the possible side effects of PREMARIN. For more information, ask your healthcare provider or pharmacist.What can do to lower my chances of getting serious side effect with PREMARINTalk with your healthcare provider regularly about whether you should continue taking PREMARIN. If you have uterus, talk to your healthcare provider about whether the addition of progestin is right for you. The addition of progestin is generally recommended for women with uterus to reduce the chance of getting cancer of the uterus. See your healthcare provider right away if you get vaginal bleeding while taking PREMARIN. Have breast exam and mammogram (breast X-ray) every year unless your healthcare 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 exams 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 healthcare provider for ways to lower your chances for getting heart disease. General information about the safe and effective use of PREMARINMedicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take PREMARIN for conditions for which it was not prescribed. Do not give PREMARIN to other people, even if they have the same symptoms you have. It may harm them.Keep PREMARIN out of the reach of children. This leaflet provides summary of the most important information about PREMARIN. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about PREMARIN that is written for health professionals. You can get more information by calling the toll free number 800-934-5556.What are the ingredients in PREMARINPREMARIN contains mixture of conjugated estrogens, which are mixture of sodium estrone sulfate and sodium equilin sulfate and other components including sodium sulfate conjugates, 17 -dihydroequilin, 17 -estradiol, and 17 -dihydroequilin. 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. The tablets come in different strengths and each strength tablet is different color. The color ingredients are:-- 0.3 mg tablet (green color): D&C Yellow No. 10 and FD&C Blue No. 2. -- 0.45 mg tablet (blue color): FD&C Blue No. 2.-- 0.625 mg tablet (maroon color): FD&C Blue No. and FD&C Red No. 40.-- 0.9 mg tablet (white color): D&C Red No. 30 and D&C Red No. 7.-- 1.25 mg tablet (yellow color): black iron oxide, D&C Yellow No. 10, and FD&C Yellow No. 6.The appearance of these tablets is trademark of Wyeth Pharmaceuticals.Store at Controlled Room Temperature 20 25C (68 77F).Wyeth(R) Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101W10405C025ET01Rev 02/10. Estrogens increase the chance of getting cancer of the uterus.Report any unusual vaginal bleeding right away while you are taking PREMARIN. Vaginal bleeding after menopause may be warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. Do not use estrogens with or without progestins to prevent heart disease, heart attacks, strokes, or dementia.Using estrogens, with or without progestins, may increase your chance of getting heart attacks, strokes, breast cancer, and blood clots. Using estrogens, with or without progestins, may increase your chance of getting dementia, based on study of women age 65 years or older. You and your healthcare provider should talk regularly about whether you still need treatment with PREMARIN. Reduce moderate to severe hot flashes. Estrogens are hormones made by womans ovaries. The ovaries normally stop making estrogens when woman is between 45 and 55 years old. This drop in body estrogen levels causes the change of life or menopause (the end of monthly menstrual periods). Sometimes both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes surgical menopause.When the estrogen levels begin dropping, some women get very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating (hot flashes or hot flushes). In some women the symptoms are mild, and they will not need to take estrogens. In other women, symptoms can be more severe. You and your healthcare provider should talk regularly about whether you still need treatment with PREMARIN. Treat moderate to severe dryness, itching, and burning, in and around the vagina. You and your healthcare provider should talk regularly about whether you still need treatment with PREMARIN to control these problems. If you use PREMARIN only to treat your dryness, itching, and burning in and around your vagina, talk with your healthcare provider about whether topical vaginal product would be better for you. Help reduce your chances of getting osteoporosis (thin weak bones). Osteoporosis from menopause is thinning of the bones that makes them weaker and easier to break. If you use PREMARIN only to prevent osteoporosis due to menopause, talk with your healthcare provider about whether different treatment or medicine without estrogens might be better for you. You and your healthcare provider should talk regularly about whether you should continue with PREMARIN.Weight-bearing exercise, like walking or running, and taking calcium and vitamin supplements may also lower your chances for getting postmenopausal osteoporosis. It is important to talk about exercise and supplements with your healthcare provider before starting them. Treat certain conditions in women before menopause if their ovaries do not make enough estrogen naturally. Ease symptoms of certain cancers that have spread through the body, in men and women. Have unusual vaginal bleeding. Currently have or have had certain cancers. Estrogens may increase the chance of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should take PREMARIN. Had stroke or heart attack in the past year.. Currently have or have had blood clots.. Currently have or have had liver problems. Are allergic to PREMARIN tablets or any of its ingredients. See the list of ingredients in PREMARIN at the end of this leaflet. Think you may be pregnant.. If you are breast feeding. The hormones in PREMARIN can pass into your milk. About all of your medical problems. Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), migraine, endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. About all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how PREMARIN works. PREMARIN may also affect how your other medicines work. If you are going to have surgery or will be on bedrest. You may need to stop taking estrogens. Take one PREMARIN tablet at the same time each day. If you miss dose, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your normal schedule. Do not take doses at the same time. Estrogens should be used at the lowest dose possible for your treatment only as long as needed. You and your healthcare provider should talk regularly (for example, every to months) about the dose you are taking and whether you still need treatment with PREMARIN. Breast cancer Cancer of the uterus Stroke Heart attack Blood clots Dementia Gallbladder disease Ovarian cancer High blood pressure Liver problems High blood sugar Enlargement of benign tumors of the uterus (fibroids) Breast lumps Unusual vaginal bleeding Dizziness and faintness Changes in speech Severe headaches Chest pain Shortness of breath Pains in your legs Changes in vision Vomiting Yellowing of the skin, eyes or nail beds Headache Breast pain Irregular vaginal bleeding or spotting Stomach/abdominal cramps, bloating Nausea and vomiting Hair loss Fluid retention Vaginal yeast infection Talk with your healthcare provider regularly about whether you should continue taking PREMARIN. If you have uterus, talk to your healthcare provider about whether the addition of progestin is right for you. The addition of progestin is generally recommended for women with uterus to reduce the chance of getting cancer of the uterus. See your healthcare provider right away if you get vaginal bleeding while taking PREMARIN. Have breast exam and mammogram (breast X-ray) every year unless your healthcare 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 exams 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 healthcare provider for ways to lower your chances for getting heart disease.

WARNINGS SECTION.

WARNINGS. See BOXED WARNINGS.1. Cardiovascular disordersAn increased risk of stroke and deep vein thrombosis (DVT) has been reported with estrogen alone therapy. An increased risk of stroke, DVT, pulmonary embolism, and myocardial infarction has been reported with estrogen plus progestin therapy.Should any of these events occur or be suspected, estrogens with or without progestins should be discontinued immediately.Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.a. Stroke In the Womens Health Initiative (WHI) estrogen alone substudy, statistically significant increased risk of stroke was reported in women receiving daily conjugated estrogens (CE 0.625 mg) compared to placebo (44 versus 32 per 10,000 women-years). The increase in risk was demonstrated in year one and persisted. (See CLINICAL STUDIES.)In the estrogen plus progestin substudy of WHI, statistically significant increased risk of stroke was reported in women receiving daily CE 0.625 mg plus medroxyprogesterone acetate (MPA 2.5 mg) compared to placebo (31 versus 24 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. (See CLINICAL STUDIES.)b. Coronary heart diseaseIn the estrogen alone substudy of WHI, no overall effect on coronary heart disease (CHD) events (defined as nonfatal myocardial infarction [MI], silent MI, or CHD death) was reported in women receiving estrogen alone compared to placebo. (See CLINICAL STUDIES.)In the estrogen plus progestin substudy of WHI, no statistically significant increase of CHD events was reported in women receiving CE/MPA compared to placebo (39 versus 33 per 10,000 women years). An increase in relative risk was demonstrated in year 1, and trend toward decreasing relative risk was reported in years through 5.In postmenopausal women with documented heart disease (n 2,763, average age 66.7 years), in controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/progestin Replacement Study; HERS), treatment with daily CE 0.625 mg/MPA 2.5 mg 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 one, but not during the subsequent years. Two thousand three hundred and twenty one (2,321) women from the original HERS trial agreed to participate in an open-label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and the placebo group in the HERS, the HERS II, and overall.c. Venous thromboembolism (VTE)In the estrogen alone substudy of WHI, the risk of VTE (DVT and pulmonary embolism [PE]), was reported to be increased for women receiving daily CE compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women years). The increase in VTE risk was demonstrated during the first years. (See CLINICAL STUDIES.)In the estrogen plus progestin substudy of WHI, statistically significant 2-fold greater rate of VTE was reported in women receiving daily CE/MPA compared to placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus per 10,000 women years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted. (See CLINICAL STUDIES.)If feasible, estrogens should be discontinued at least to weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.2. Malignant neoplasmsa. Endometrial cancerAn increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in women with uterus. The reported endometrial cancer risk among unopposed estrogen users with an intact uterus is about to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for to 10 years or more, and this risk has been shown to persist for at least to 15 years after estrogen therapy is discontinued.Clinical surveillance of all women using estrogen plus progestin therapy 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 different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding progestin to postmenopausal estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be precursor to endometrial cancer.b. Breast cancerThe most important randomized clinical trial providing information about this issue in estrogen alone users is the Womens Health Initiative (WHI) substudy of daily conjugated estrogens (CE 0.625 mg). In the estrogen alone substudy of WHI, after an average 7.1 years of follow-up, daily CE 0.625 mg was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80, 95 percent nominal confidence interval [nCI] 0.62-1.04). (see CLINICAL STUDIES).The most important randomized clinical trial providing information about this issue in estrogen plus progestin users is the Womens Health Initiative (WHI) substudy of daily CE 0.625 mg plus medroxyprogesterone acetate (MPA 2.5 mg). In the estrogen plus progestin substudy, after mean follow-up of 5.6 years, the WHI substudy reported an increased risk of breast cancer in women who took daily CE/MPA. In this substudy, prior use of estrogen alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24 (95 percent nCI 1.01-1.54), and the absolute risk was 41 versus 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 versus 25 cases per 10,000 women-years, for CE/MPA 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 versus 36 cases per 10,000 women-years for estrogen plus progestin compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at more advanced stage in the CE/MPA group compared with the placebo group. Metastatic disease was rare, 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. (See CLINICAL STUDIES.)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 therapy, and smaller increased risk for estrogen alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.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 healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.3. DementiaIn the estrogen alone Womens Health Initiative Memory Study (WHIMS), substudy of WHI, population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily conjugated estrogens (CE 0.625 mg) or placebo. In the estrogen plus progestin WHIMS substudy, population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE 0.625 mg plus medroxyprogesterone acetate (MPA 2.5 mg) or placebo.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 versus placebo was 1.49 (95 percent CI 0.83-2.66). The absolute risk of probable dementia for CE alone versus placebo was 37 versus 25 cases per 10,000 women-years. (See CLINICAL STUDIES and PRECAUTIONS, Geriatric Use.)In the estrogen plus progestin substudy, after an average follow-up of years, 40 women in the CE/MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE/MPA versus placebo was 2.05 (95 percent CI 1.21-3.48). The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years. (See CLINICAL STUDIES and PRECAUTIONS, Geriatric Use.)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. (See BOXED WARNINGS and PRECAUTIONS, Geriatric Use.)4. Gallbladder DiseaseA 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.5. HypercalcemiaEstrogen 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.6. Visual abnormalitiesRetinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.7. AngioedemaExogenous estrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema.