OVERDOSAGE SECTION.

OVERDOSAGE. Overdosage of estrogen may cause nausea and vomiting, breast tenderness, abdominal pain, drowsiness/fatigue and withdrawal bleeding may occur in females. Treatment of overdose consists of discontinuation of PREMARIN together with institution of appropriate symptomatic care.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL PRINCIPAL DISPLAY PANEL 0.625 MG LABELNDC 53808-0770-1PREMARIN(R) (conjugated estrogens tablets, USP)0.625 mgSEALED FOR YOUR PROTECTIONRx only. Principal Display Panel 0.625 mg Label.

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 system. Abnormal 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 cancer. 2. Breasts. Tenderness, enlargement, pain, discharge, galactorrhea Fibrocystic breast changes Breast cancer. 3. Cardiovascular. Deep and superficial venous thrombosis Pulmonary embolism Thrombophlebitis Myocardial infarction Stroke Increase in blood pressure. 4. Gastrointestinal. Nausea, vomiting Abdominal cramps, bloating Cholestatic jaundice Increased incidence of gallbladder disease Pancreatitis Enlargement of hepatic hemangiomas Ischemic colitis. 5. Skin. Chloasma or melasma that may persist when drug is discontinued Erythema multiforme Erythema nodosum Hemorrhagic eruption Loss of scalp hair Hirsutism Pruritus, rash. 6. Eyes. Retinal vascular thrombosis Intolerance to contact lenses. 7. Central Nervous System. Headache Migraine Dizziness Mental depression Exacerbation of chorea Nervousness Mood disturbances Irritability Exacerbation of epilepsy Dementia Possible growth potentiation of benign meningioma. 8. Miscellaneous. Increase 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.

BOXED WARNING SECTION.

WARNINGS. ENDOMETRIAL CANCERAdequate 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.)CARDIOVASCULAR AND OTHER RISKSEstrogens with or without progestins should not be used for the prevention of cardiovascular disease or dementia. (See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders and Dementia.)The estrogen alone substudy of the Womens 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 Womens Health Initiative Memory Study (WHIMS), 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 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, Geriatric Use.)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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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.

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.. Pharmacokinetics. A. Absorption. Conjugated 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. Distribution. The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentration in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.. C. Metabolism. Exogenous 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. Excretion. Estradiol, estrone, and estriol are excreted in the urine, along with glucuronide and sulfate conjugates.. E. Special Populations. No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.. F. Drug Interactions. Data 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 symptoms. In 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)-------------------No. of Hot Flushes/Day------------------a: Based on analysis of covariance with treatment as factor and baseline as covariate.Time Period(week)BaselineMean +- SDObservedMean +- SDMeanChange +- SDp-Valuesvs. Placeboa 0.625 mg CE(n 27) 1212.29 +- 3.8912.29 +- 3.891.95 +- 2.770.75 +- 1.82-10.34 +- 4.73-11.54 +- 4.62<0.001<0.0010.45 mg CE(n 32) 1212.25 +- 5.0412.25 +- 5.045.04 +- 5.312.32 +- 3.32-7.21 +- 4.75-9.93 +- 4.64<0.001<0.0010.3 mg CE(n 30) 1213.77 +- 4.7813.77 +- 4.784.65 +- 3.712.52 +- 3.23-9.12 +- 4.71-11.25 +- 4.60<0.001<0.001Placebo(n 28) 1211.69 +- 3.8711.69 +- 3.877.89 +- 5.285.71 +- 5.22-3.80 +- 4.71-5.98 +- 4.60--. Effects on vulvar and vaginal atrophy. Results of vaginal maturation indexes at cycles and 13 showed that the differences from placebo were statistically significant (p 0.001) for all treatment groups (conjugated estrogens alone and conjugated estrogens/medroxyprogesterone acetate treatment groups).. Effects on bone mineral density. Health and Osteoporosis, Progestin and Estrogen (HOPE) Study. The 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 subjects. All 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. of SubjectsBaseline (g/cm2)Mean +- SDChange from Baseline (%)Adjusted Mean +- SEp-Value vs Placeboa: Identified by dosage (mg) of PREMARIN or placebo.L2 to L4 BMD 0.625 0.45 0.3 Placebo839187851.17 +- 0.151.13 +- 0.151.14 +- 0.151.14 +- 0.142.46 +- 0.372.26 +- 0.351.13 +- 0.36-2.45 +- 0.36<0.001<0.001<0.001 Total Body BMD 0.625 0.45 0.3 Placebo849187851.15 +- 0.081.14 +- 0.081.14 +- 0.071.13 +- 0.080.68 +- 0.170.74 +- 0.160.40 +- 0.17-1.50 +- 0.17<0.001<0.001<0.001 Femoral Neck BMD 0.625 0.45 0.3 Placebo849187850.91 +- 0.140.89 +- 0.130.86 +- 0.110.88 +- 0.141.82 +- 0.451.84 +- 0.440.62 +- 0.45-1.72 +- 0.45<0.001<0.001<0.001 Femoral Trochanter BMD 0.625 0.45 0.3 Placebo849187850.78 +- 0.130.76 +- 0.120.75 +- 0.100.75 +- 0.123.82 +- 0.583.16 +- 0.563.05 +- 0.570.81 +- 0.58<0.0010.0030.005 Figure shows the cumulative percentage of subjects with changes from baseline equal to or greater than the value shown on the x-axis.Figure 1. CUMULATIVE PERCENT OF SUBJECTS WITH CHANGES FROM BASELINE IN SPINE BMD OF GIVEN MAGNITUDE OR GREATER IN PREMARIN(R) AND PLACEBO GROUPSThe mean percent changes from baseline in L2 to L4 BMD for women who completed the bone density study are shown with standard error bars by treatment group in Figure 2. Significant differences between each of the PREMARIN dosage groups and placebo were found at cycles 6, 13, 19, and 26.Figure 2. ADJUSTED MEAN (SE) PERCENT CHANGE FROM BASELINE AT EACH CYCLE IN SPINE BMD: SUBJECTS COMPLETING IN PREMARIN(R) GROUPS AND PLACEBOThe bone turnover markers serum osteocalcin and urinary N-telopeptide significantly decreased (p 0.001) in all active-treatment groups at cycles 6, 13, 19, and 26 compared with the placebo group. Larger mean decreases from baseline were seen with the active groups than with the placebo group. Significant differences from placebo were seen less frequently in urine calcium.. Figure 1. Figure 2. Womens Health Initiative Studies. The Womens Health Initiative (WHI) enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of either the use of daily oral conjugated estrogens (CE 0.625 mg) alone or in combination with medroxyprogesterone acetate (MPA 2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease [CHD] (nonfatal myocardial infarction [MI], silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. global index included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer (only in CE/MPA substudy),colorectal cancer, hip fracture, or death due to other causes. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.The estrogen alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen alone in predetermined primary endpoints. Results of the estrogen alone substudy, which included 10,739 women (average age of 63 years, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other) after an average follow-up of 6.8 years, are presented in Table 4.TABLE 4. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN ALONE SUBSTUDY OF WHIEventRelative Risk CE vs. Placebo(95% nCIa)Placebon 5,429CEn 5,310Absolute Risk per 10,000Women-YearsaNominal confidence intervals unadjusted for multiple looks and multiple comparisons.bResults are based on centrally adjudicated data for an average follow-up of 7.1 years.cResults are based on an average follow-up of 6.8 years.dNot included in Global Index.eAll deaths, except from breast or colorectal cancer, definite/probable CHD, PE or cerebrovascular disease.fA subset of the events was combined in global index, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes.CHD eventsb 0.95 (0.79-1.16)5653 Non-fatal MI 0.91 (0.73-1.14)43 40 CHD death 1.01 (0.71-1.43)1616 Strokeb 1.37 (1.09-1.73)3345 Ischemicb1.55 (1.19-2.01)2538Deep vein thrombosisb,d 1.47 (1.06-2.06)1523Pulmonary embolismb 1.37 (0.90-2.07)1014Invasive breast cancerb 0.80 (0.62-1.04)3428Colorectal cancerc 1.08 (0.75-1.55)1617Hip fracturec 0.61 (0.41-0.91)1711Vertebral fracturesc,d 0.62 (0.42-0.93)1711Total fracturesc,d 0.70 (0.63-0.79)195139Death due to other causesc,e 1.08 (0.88-1.32)5053Overall mortalityc,d 1.04 (0.88-1.22)7881Global Indexc,f 1.01 (0.91-1.12)190192For those outcomes included in the WHI global index that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE alone were 12 more strokes while the absolute risk reduction per 10,000 women-years was fewer hip fractures. The absolute excess risk of events included in the global index was nonsignificant events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)Final centrally adjudicated results for CHD events and centrally adjudicated results for invasive breast cancer incidence from the estrogen alone substudy, after an average follow-up of 7.1 years, reported no overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE alone compared with placebo (see Table 4).Centrally adjudicated results for stroke events from the estrogen alone substudy, after an average follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE alone compared to placebo. Estrogen alone increased the risk of ischemic stroke, and this excess was present in all subgroups of women examined (see Table 4).The estrogen plus progestin substudy was also stopped early. According to the predefined stopping rule, after an average follow-up of 5.2 years of treatment, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the global index. The absolute excess risk of events included in the global index was 19 per 10,000 women-years (relative risk [RR] 1.15, 95 percent nCI 1.03-1.28).For those outcomes included in the WHI global index that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women years in the group treated with CE/MPA were more CHD events, more strokes, 10 more PEs, and more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were fewer colorectal cancers and fewer hip fractures. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.) Results of the estrogen plus progestin substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other), are presented in Table 5. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.TABLE 5. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS PROGESTIN SUBSTUDY OF WHI AT AN AVERAGE OF 5.6 YEARSa EventRelative RiskCE/MPA vs. Placebo(95% nCIb)Placebon 8,102CE/MPAn 8,506Absolute Risk per 10,000Women-yearsaResults are based on centrally adjudicated data. Mortality data was not part of the adjudicated data; however, data at 5.2 years of follow-up showed no difference between the groups in terms of all-cause mortality (RR 0.98, 95 percent nCI 0.82-1.18).bNominal confidence intervals unadjusted for multiple looks and multiple comparisons.cIncludes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer.CHD events1.24 (1.00-1.54)3339 Non-fatal MI 1.28 (1.00-1.63)25 31 CHD death 1.10 (0.70-1.75)8 All strokes1.31 (1.02-1.68)2431 Ischemic Stroke 1.44 (1.09-1.90) 18 26 Deep vein thrombosis1.95 (1.43-2.67)1326Pulmonary embolism2.13 (1.45-3.11)818Invasive breast cancerc 1.24 (1.01-1.54)3341Invasive colorectal cancer0.56 (0.38-0.81)169Endometrial cancer0.81 (0.48-1.36)76Cervical cancer1.44 (0.47-4.42)12Hip fracture0.67 (0.47-0.96)1611Vertebral fractures0.65 (0.46-0.92)1711Lower arm/wrist fractures0.71 (0.59-0.85)6244Total fractures0.76 (0.69-0.83)199152. Womens Health Initiative Memory Study. The estrogen alone Womens Health Initiative Memory Study (WHIMS), substudy of WHI, enrolled 2,947 predominantly healthy postmenopausal women 65 years of age and older (45 percent, age 65 to 69 years; 36 percent, 70 to 74 years; 19 percent, 75 years of age and older) to evaluate the effects of daily CE 0.625 mg on the incidence of probable dementia (primary outcome) compared with placebo.After an average follow-up of 5.2 years, 28 women in the estrogen alone group (37 per 10,000 women-years) and 19 in the placebo group (25 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the estrogen alone group was 1.49 (95 percent CI 0.83-2.66) compared to placebo. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.)The estrogen plus progestin WHIMS substudy enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent, age 65 to 69 years; 35 percent, 70 to 74 years; 18 percent, 75 years of age and older) to evaluate the effects of CE/MPA 0.625 mg conjugated estrogens/2.5 mg medroxyprogesterone acetate daily on the incidence of probable dementia (primary outcome) compared with placebo.After an average follow-up of years, 40 women in the estrogen plus progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95 percent CI 1.21-3.48) compared to placebo. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS, WARNINGS, Dementia 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). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.).

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. PREMARIN therapy should not be used in individuals with any of the following conditions:Undiagnosed abnormal genital bleeding.Known, suspected, or history of cancer of the breast except in appropriately selected patients being treated for metastatic disease.Known or suspected estrogen-dependent neoplasia.Active deep vein thrombosis, pulmonary embolism or history of these conditions.Active or recent (within the past year) arterial thromboembolic disease (for example, stroke, myocardial infarction).Liver dysfunction or disease.Known hypersensitivity to any of the ingredients in PREMARIN.Known or suspected pregnancy.. Undiagnosed abnormal genital bleeding.. Known, suspected, or history of cancer of the breast except in appropriately selected patients being treated for metastatic disease.. Known or suspected estrogen-dependent neoplasia.. Active deep vein thrombosis, pulmonary embolism or history of these conditions.. Active or recent (within the past year) arterial thromboembolic disease (for example, stroke, myocardial infarction).. Liver dysfunction or disease.. Known hypersensitivity to any of the ingredients in PREMARIN.. Known or suspected pregnancy.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. PREMARIN therapy is indicated in the:Treatment of moderate to severe vasomotor symptoms due to menopause.Treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease.Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).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 for whom non-estrogen medications are not considered to be appropriate. (See CLINICAL STUDIES.)The mainstays for decreasing the risk of postmenopausal osteoporosis are weight-bearing exercise, adequate calcium and vitamin 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 supplementation of 400-800 IU/day may also be required to ensure adequate daily intake in postmenopausal women. Treatment of moderate to severe vasomotor symptoms due to menopause.. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.. Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease.. Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).. 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 for whom non-estrogen medications are not considered to be appropriate. (See CLINICAL STUDIES.)The mainstays for decreasing the risk of postmenopausal osteoporosis are weight-bearing exercise, adequate calcium and vitamin 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 supplementation of 400-800 IU/day may also be required to ensure adequate daily intake in postmenopausal women.

INFORMATION FOR PATIENTS SECTION.

B. Patient Information. Physicians are advised to discuss the contents of the PATIENT INFORMATION leaflet with patients for whom they prescribe PREMARIN.

DESCRIPTION SECTION.

DESCRIPTION. PREMARIN(R) (conjugated estrogens tablets, USP) for oral administration contains 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 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, carnauba wax, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, powdered cellulose, 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. 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:PREMARIN 1.25 mg tabletsUSP Dissolution Test 4PREMARIN 0.3 mg, 0.45 mg and 0.625 mg tabletsUSP Dissolution Test 5PREMARIN 0.9 mg tabletsUSP Dissolution Test 6.

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.

DRUG & OR LABORATORY TEST INTERACTIONS SECTION.

D. Drug/Laboratory Test Interactions. 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.. 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.

DRUG INTERACTIONS SECTION.

F. Drug Interactions. Data 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.

GENERAL PRECAUTIONS SECTION.

A. General.

GERIATRIC USE SECTION.

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 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.).

HOW SUPPLIED SECTION.

HOW SUPPLIED. PREMARIN(R) (conjugated estrogens tablets, USP)-- Each oval green tablet contains 0.3 mg.-- Each oval blue tablet contains 0.45 mg.-- Each oval maroon tablet contains 0.625 mg.-- Each oval white tablet contains 0.9 mg.-- Each oval yellow tablet contains 1.25 mg.The appearance of these tablets is trademark of Wyeth Pharmaceuticals.They are supplied by State of Florida DOH Central Pharmacy as follows:NDCStrengthQuantity/FormColorSource Prod. Code53808-0770-10.625 mg30 Tablets in Blister PackMAROON0046-1102Store at 20-25C (68-77F); excursions permitted to 15-30C (59-86F) [see USP Controlled Room Temperature].Dispense in well-closed container, as defined in the USP.

LABORATORY TESTS SECTION.

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.

NURSING MOTHERS SECTION.

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.

PEDIATRIC USE SECTION.

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. (See INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION.).

PRECAUTIONS SECTION.

PRECAUTIONS. A. General. 1. Addition of progestin when woman has not had hysterectomy. Studies 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 pressure. In 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. 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.. 4. Impaired liver function and past history of cholestatic jaundice. Estrogens 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. Hypothyroidism. Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.. 6. Fluid retention. 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.. 7. Hypocalcemia. Estrogens should be used with caution in individuals with severe hypocalcemia.. 8. Ovarian cancer. The 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 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.. 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.. B. Patient Information. Physicians are advised to discuss the contents of the PATIENT INFORMATION leaflet with patients for whom they prescribe PREMARIN.. 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.. D. Drug/Laboratory Test Interactions. 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.. 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.. 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. Pregnancy. PREMARIN should not be used during pregnancy. (See CONTRAINDICATIONS.). 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. 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. (See INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION.). 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 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.).

PREGNANCY SECTION.

F. Pregnancy. PREMARIN should not be used during pregnancy. (See CONTRAINDICATIONS.).

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. 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 PREMARIN. PREMARIN 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. 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.. 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 PREMARIN. Do 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.. 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.. 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 PREMARIN. 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.. 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.. What are the possible side effects of PREMARIN. Side 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 cancerCancer of the uterusStrokeHeart attackBlood clotsDementiaGallbladder diseaseOvarian cancerHigh blood pressureLiver problemsHigh blood sugarEnlargement of benign tumors of the uterus (fibroids). 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 lumpsUnusual vaginal bleedingDizziness and faintnessChanges in speechSevere headachesChest painShortness of breathPains in your legsChanges in visionVomitingYellowing of the skin, eyes or nail bedsCall your healthcare provider right away if you get any of these warning signs, or any other unusual symptoms that concern you.. 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. Less serious but common side effects include:. HeadacheBreast painIrregular vaginal bleeding or spottingStomach/abdominal cramps, bloatingNausea and vomitingHair lossFluid retentionVaginal yeast infectionThese are not all the possible side effects of PREMARIN. For more information, ask your healthcare provider or pharmacist.. Headache. Breast pain. Irregular vaginal bleeding or spotting. Stomach/abdominal cramps, bloating. Nausea and vomiting. Hair loss. Fluid retention. Vaginal yeast infection. What can do to lower my chances of getting serious side effect with PREMARIN. 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.. 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.. General information about the safe and effective use of PREMARIN. Medicines 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 PREMARIN. PREMARIN 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, carnauba wax, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, powdered cellulose, 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).. This product was manufactured by:Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101This Product was Repackaged By:State of Florida DOH Central Pharmacy104-2 Hamilton Park DriveTallahassee, FL 32304United States.

SPL UNCLASSIFIED SECTION.

Rx only. WARNINGS. ENDOMETRIAL CANCERAdequate 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.)CARDIOVASCULAR AND OTHER RISKSEstrogens with or without progestins should not be used for the prevention of cardiovascular disease or dementia. (See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders and Dementia.)The estrogen alone substudy of the Womens 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 Womens Health Initiative Memory Study (WHIMS), 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 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, Geriatric Use.)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.

WARNINGS SECTION.

WARNINGS. See BOXED WARNINGS.. 1. Cardiovascular disorders. An 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 disease. In 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 neoplasms. a. Endometrial cancer. An 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 cancer. The 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. Dementia. 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 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 Disease. 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.. 5. Hypercalcemia. Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.. 6. Visual abnormalities. Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.. 7. Angioedema. Exogenous estrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema.