looking forward to [0.001:<0.001 0.45 mg/1.5 mg (n=29) 4 12.61 4.29 3.64 3.61 -8.98 4.74> <0.001 12 12.61 4.29 1.69 3.36 -10.92 4.63> <0.001 0.3 mg/1.5 mg (n=33) 4 11.30 3.13 3.70 3.29 -7.60 4.71> <0.001 12 11.30 3.13 1.31 2.82 -10.00 4.60> <0.001 Placebo (n=28) 4 11.69 3.87 7.89 5.28 -3.80 4.71 - 12 11.69 3.87 5.71 5.22 -5.98 4.60 - a:Identified by dosage (mg) of Premarin/MPA or placebo. b:There were no statistically significant differences between the 0.625 mg/2.5 mg, 0.45 mg/1.5 mg, and 0.3 mg/1.5 mg groups at any time period. Effects on vulvar and vaginal atrophy. Results of vaginal maturation indexes at cycles 6 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 the endometrium. In a 1-year clinical trial of 1376 women (average age 54.0 4.6 years) randomized to PREMPRO 0.625 mg/2.5 mg (n=340), PREMPRO 0.625 mg/5 mg (n=338), PREMPHASE 0.625 mg/5 mg (n=351), or Premarin 0.625 mg alone (n=347), results of evaluable biopsies at 12 months (n=279, 274, 277, and 283, respectively) showed a reduced risk of endometrial hyperplasia in the two PREMPRO treatment groups (less than 1%) and in the PREMPHASE treatment group (less than 1%; 1% when focal hyperplasia was included) compared to the Premarin group (8%; 20% when focal hyperplasia was included). See Table 4. TABLE 4. INCIDENCE OF ENDOMETRIAL HYPERPLASIA AFTER ONE YEAR OF TREATMENT ---------------------- Groups ------------------- PREMPRO 0.625 mg/2.5 mg PREMPRO 0.625 mg/5 mg PREMPHASE 0.625 mg/5 mg Premarin 0.625 mg Total number of patients 340 338 351 347 Number of patients with evaluable biopsies 279 274 277 283 No. (%) of patients with biopsies all focal and non-focal hyperplasia 2 ( <1) * 0 (0) * 3 (1) * 57 (20) excluding focal cystic hyperplasia 2 (> <1) * 0 (0) * 1 (> <1) * 25 (8) *Significant (p> <0.001) in comparison with Premarin (0.625 mg) alone. In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, 2001 women (average age 53.3 4.9 years) of whom 88% were Caucasian were treated with either Premarin 0.625 mg alone (n = 348), Premarin 0.45 mg alone (n = 338), Premarin 0.3 mg alone (n = 326) or PREMPRO 0.625 mg/2.5 mg (n = 331), PREMPRO 0.45 mg/1.5 mg (n = 331) or PREMPRO 0.3 mg/1.5 mg (n = 327). Results of evaluable endometrial biopsies at 12 months showed a reduced risk of endometrial hyperplasia or cancer in the PREMPRO treatment groups compared with the corresponding Premarin alone treatment groups, except for the PREMPRO 0.3 mg/1.5 mg and Premarin 0.3 mg alone groups, in each of which there was only 1 case. See Table 5. No endometrial hyperplasia or cancer was noted in those patients treated with the continuous combined regimens who continued for a second year in the osteoporosis and metabolic substudy of the HOPE study. See Table 6. TABLE 5. INCIDENCE OF ENDOMETRIAL HYPERPLASIA/CANCER a AFTER ONE YEAR OF TREATMENT b --------------------------- Groups --------------------------- Patient Prempro 0.625 mg/2.5 mg Premarin 0.625 mg Prempro 0.45 mg/1.5 mg Premarin 0.45 mg Prempro 0.3 mg/1.5 mg Premarin 0.3 mg Total number of patients 331 348 331 338 327 326 Number of patients with evaluable biopsies 278 249 272 279 271 269 No. (%) of patients with biopsies hyperplasia/cancer a (consensus c ) 0 (0) d 20 (8) 1 (> <1) a, d 9 (3) 1 (> <1) e 1 (> <1) a a: All cases of hyperplasia/cancer were endometrial hyperplasia except for 1 patient in the Premarin 0.3 mg group diagnosed with endometrial cancer based on endometrial biopsy and 1 patient in the Premarin/MPA 0.45 mg/1.5 mg group diagnosed with endometrial cancer based on endometrial biopsy. b: Two (2) primary pathologists evaluated each endometrial biopsy. Where there was lack of agreement on the presence or absence of hyperplasia/cancer between the two, a third pathologist adjudicated (consensus). c: For an endometrial biopsy to be counted as consensus endometrial hyperplasia or cancer, at least 2 pathologists had to agree on the diagnosis. d: Significant (p> <0.05) in comparison with corresponding dose of Premarin alone. e: Non-significant in comparison with corresponding dose of Premarin alone. TABLE 6. OSTEOPOROSIS AND METABOLIC SUBSTUDY, INCIDENCE OF ENDOMETRIAL HYPERPLASIA/CANCER a AFTER TWO YEARS OF TREATMENT b Patient -------------------------------------- Groups ------------------------------- Prempro 0.625 mg/2.5 mg Premarin 0.625 mg Prempro 0.45 mg/1.5 mg Premarin 0.45 mg Prempro 0.3 mg/1.5 mg Premarin 0.3 mg Total number of patients 75 65 75 74 79 73 Number of patients with evaluable biopsies 62 55 69 67 75 63 No. (%) of patients with biopsies hyperplasia/cancer a (consensus c ) 0 (0) d 15 (27) 0 (0) d 10 (15) 0 (0) d 2 (3) a: All cases of hyperplasia/cancer were endometrial hyperplasia in patients who continued for a second year in the osteoporosis and metabolic substudy of the HOPE study. b: Two (2) primary pathologists evaluated each endometrial biopsy. Where there was lack of agreement on the presence or absence of hyperplasia/cancer between the two, a third pathologist adjudicated (consensus). c: For an endometrial biopsy to be counted as consensus endometrial hyperplasia or cancer, at least 2 pathologists had to agree on the diagnosis. d: Significant (p> <0.05) in comparison with corresponding dose of Premarin alone. Effects on uterine bleeding or spotting. The effects of PREMPRO on uterine bleeding or spotting, as recorded on daily diary cards, were evaluated in 2 clinical trials. Results are shown in Figures 1 and 2. Note: The percentage of patients who were amenorrheic in a given cycle and through cycle 13 is shown. If data were missing, the bleeding value from the last reported day was carried forward (LOCF). Note: The percentage of patients who were amenorrheic in a given cycle and through cycle 13 is shown. If data were missing, the bleeding value from the last reported day was carried forward (LOCF). Effects on bone mineral density. Health and Osteoporosis, Progestin and Estrogen (HOPE) Study The HOPE study was a 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) daily. Subjects were not given vitamin D supplements. They were treated with PREMPRO 0.625 mg/2.5 mg, 0.45 mg/1.5 mg or 0.3 mg/1.5 mg, comparable doses of Premarin alone, or placebo. Prevention of bone loss was assessed by measurement of bone mineral density (BMD), primarily at the anteroposterior lumbar spine (L 2 to L 4 ). 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 4 BMD endpoints. These significant differences were seen at cycles 6, 13, 19, and 26. With PREMPRO, the mean percent increases in the primary efficacy measure (L 2 to L 4 BMD) at the final on-therapy evaluation (cycle 26 for those who completed and the last available evaluation for those who discontinued early) were 3.28% with 0.625 mg/2.5 mg, 2.18% with 0.45 mg/1.5 mg, and 1.71% with 0.3 mg/1.5 mg. The placebo group showed a mean percent decrease from baseline at the final evaluation of 2.45%. These results show that the lower dose regimens of PREMPRO were effective in increasing L 2 to L 4 BMD compared with placebo and, therefore, support the efficacy of lower doses of PREMPRO. The analysis for the other 3 BMD endpoints yielded mean percent changes from baseline in femoral trochanter that were generally larger than those seen for L 2 to L 4 and changes in femoral neck and total body that were generally smaller than those seen for L 2 to L 4 . Significant differences between groups indicated that each of the PREMPRO treatment groups was more effective than placebo for all 3 of these additional BMD endpoints. With regard to femoral neck and total body, the continuous combined treatment groups all showed mean percent increases in BMD while the placebo group showed mean percent decreases. For femoral trochanter, each of the PREMPRO groups showed a 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 7. TABLE 7. PERCENT CHANGE IN BONE MINERAL DENSITY: COMPARISON BETWEEN ACTIVE AND PLACEBO GROUPS IN THE INTENT-TO-TREAT POPULATION, LAST OBSERVATION CARRIED FORWARD Region Evaluated Treatment Group a No. of Subjects Baseline (g/cm 2 ) Mean SD Change from Baseline (%) Adjusted Mean SE p-Value vs Placebo L 2 to L 4 BMD 0.625/2.5 81 1.14 0.16 3.28 0.37> <0.001 0.45/1.5 89 1.16 0.14 2.18 0.35> <0.001 0.3/1.5 90 1.14 0.15 1.71 0.35> <0.001 Placebo 85 1.14 0.14 -2.45 0.36 Total body BMD 0.625/2.5 81 1.14 0.08 0.87 0.17> <0.001 0.45/1.5 89 1.14 0.07 0.59 0.17> <0.001 0.3/1.5 91 1.13 0.08 0.60 0.16> <0.001 Placebo 85 1.13 0.08 -1.50 0.17 Femoral neck BMD 0.625/2.5 81 0.89 0.14 1.62 0.46> <0.001 0.45/1.5 89 0.89 0.12 1.48 0.44> <0.001 0.3/1.5 91 0.86 0.11 1.31 0.43> <0.001 Placebo 85 0.88 0.14 -1.72 0.45 Femoral trochanter BMD 0.625/2.5 81 0.77 0.14 3.35 0.59 0.002 0.45/1.5 89 0.76 0.12 2.84 0.57 0.011 0.3/1.5 91 0.76 0.12 3.93 0.56> <0.001 Placebo 85 0.75 0.12 0.81 0.58 a: Identified by dosage (mg/mg) of Premarin/MPA or placebo. Figure 3 shows the cumulative percentage of subjects with percent changes from baseline in spine BMD equal to or greater than the percent change shown on the x-axis. The mean percent changes from baseline in L 2 to L 4 BMD for women who completed the bone density study are shown with standard error bars by treatment group in Figure 4. Significant differences between each of the PREMPRO dosage groups and placebo were found at cycles 6, 13, 19, and 26. The 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; only with PREMPRO 0.625 mg/2.5 mg and 0.45 mg/1.5 mg were there significantly larger mean decreases than with placebo at 3 or more of the 4 time points. Women's Health Initiative Studies. A substudy of the Women's Health Initiative (WHI) enrolled 16,608 predominantly healthy postmenopausal women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic) to assess the risks and benefits of the use of PREMPRO (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate per day) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of PREMPRO on menopausal symptoms. The estrogen plus progestin substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the "global index." Results are presented in Table 8 below: TABLE 8. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS PROGESTIN SUBSTUDY OF WHI a Event c Relative Risk PREMPRO vs Placebo at 5.2 Years (Nominal 95% CI * ) Placebo n=8102 PREMPRO n=8506 Absolute Risk per 10,000 Women-years CHD events 1.29 (1.02-1.63) 30 37 Non-fatal MI 1.32 (1.02-1.72) 23 30 CHD death 1.18 (0.70-1.97) 6 7 Invasive breast cancer b 1.26 (1.00-1.59) 30 38 Stroke 1.41 (1.07-1.85) 21 29 Pulmonary embolism 2.13 (1.39-3.25) 8 16 Colorectal cancer 0.63 (0.43-0.92) 16 10 Endometrial cancer 0.83 (0.47-1.47) 6 5 Hip fracture 0.66 (0.45-0.98) 15 10 Death due to causes other than the events above 0.92 (0.74-1.14) 40 37 Global Index c 1.15 (1.03-1.28) 151 170 Deep vein thrombosis d 2.07 (1.49-2.87) 13 26 Vertebral fractures d 0.66 (0.44-0.98) 15 9 Other osteoporotic fractures d 0.77 (0.69-0.86) 170 131 a: adapted from JAMA, 2002; 288:321-333 b: includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer c: a subset of the events was combined in a "global index," defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes d: not included in Global Index *:nominal confidence intervals unadjusted for multiple looks and multiple comparisons. Except for deep vein thrombosis and other osteoporotic fractures, based on adjusted confidence intervals, the relative risks were not statistically significant. For those outcomes included in the "global index", the absolute excess risks per 10,000 women-years in the group treated with PREMPRO were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the "global index" was 19 per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNING , WARNINGS , and PRECAUTIONS .) Women's Health Initiative Memory Study. The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of PREMPRO (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo. After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNING and WARNINGS , Dementia .) Indications and Usage PREMPRO or PREMPHASE therapy is indicated in women who have a uterus for the: Treatment of moderate to severe vasomotor symptoms associated with the menopause. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. 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 PHARMACOLOGY , Clinical Studies .) The mainstays for decreasing the risk of postmenopausal osteoporosis are weight-bearing exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400-800 IU/day may also be required to ensure adequate daily intake in postmenopausal women. Contraindications Estrogens/progestins combined should not be used in women with any of the following conditions: Undiagnosed abnormal genital bleeding. Known, suspected, or history of cancer of the breast. Known or suspected estrogen-dependent neoplasia. Active deep vein thrombosis, pulmonary embolism or a history of these conditions. Active or recent (e.g., within past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction). Liver dysfunction or disease. PREMPRO or PREMPHASE therapy should not be used in patients with known hypersensitivity to their ingredients. Known or suspected pregnancy. There is no indication for PREMPRO or PREMPHASE in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogen and progestins from oral contraceptives inadvertently during pregnancy. (See PRECAUTIONS .) Warnings See BOXED WARNING . 1. Cardiovascular disorders. Estrogen/progestin therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogen/progestin therapy should be discontinued immediately. Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. Coronary heart disease and stroke. In the estrogen plus progestin substudy of the Women's Health Initiative (WHI) study, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving PREMPRO (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) per day compared to women receiving placebo (37 vs 30 per 10,000 women-years). The increase in risk was observed in year one and persisted. (See CLINICAL PHARMACOLOGY , Clinical Studies .) In the same substudy of WHI, an increased risk of stroke was observed in women receiving PREMPRO compared to women receiving placebo (29 vs 21 per 10,000 women-years). The increase in risk was observed after the first year and persisted. In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/progestin Replacement Study; HERS) treatment with PREMPRO (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate per day) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with PREMPRO did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the PREMPRO-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one 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 a total of 6.8 years overall. Rates of CHD events were comparable among women in the PREMPRO group and the placebo group in HERS, HERS II, and overall. Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risk of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis. Venous thromboembolism (VTE). In the estrogen plus progestin substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving PREMPRO compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years in the PREMPRO group compared to 16 per 10,000 women-years in the placebo group. The increase in VTE risk was observed during the first year and persisted. (See CLINICAL PHARMACOLOGY , Clinical Studies .) If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. 2. Malignant neoplasms. Breast cancer. The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the Women's Health Initiative (WHI) trial of estrogen plus progestin (see CLINICAL PHARMACOLOGY , Clinical Studies .) The results from observational studies are generally consistent with those of the WHI clinical trial. After a mean follow-up of 5.6 years, the WHI trial reported an increased risk of breast cancer in women who took estrogen plus progestin. Observational studies have also reported an increased risk for estrogen/progestin combination therapy, and a smaller increased risk for estrogen alone therapy, after several years of use. For both findings, the excess risk increased with duration of use, and appeared to return to baseline over about five years after stopping treatment (only the observational studies have substantial data on risk after stopping). In these studies, the risk of breast cancer was greater, and became apparent earlier, with estrogen/progestin combination therapy as compared to estrogen alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogens or among different estrogen/progestin combinations, doses, or routes of administration. In the WHI trial of estrogen plus progestin, 26% of the women reported prior use of estrogen alone and/or estrogen/progestin combination hormone therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01-1.54), and the overall absolute risk was 41 vs. 33 cases per 10,000 women-years, for estrogen plus progestin compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years, for estrogen plus progestin compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years for estrogen plus progestin compared with placebo. In the WHI trial, invasive breast cancers were larger and diagnosed at a more advanced stage in the estrogen plus progestin group compared with the placebo group. Metastatic disease 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. The observational Million Women Study in Europe reported an increased risk of mortality due to breast cancer among current users of estrogens alone or estrogens plus progestins compared to never users, while the estrogen plus progestin sub-study of WHI showed no effect on breast cancer mortality with a mean follow-up of 5.6 years. The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a 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. Endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than one year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for five to ten years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Endometrial hyperplasia (a possible precursor of endometrial cancer) has been reported to occur at a rate of approximately 1% or less with PREMPRO or PREMPHASE in two large clinical trials. In the two large clinical trials described above, two cases of endometrial cancer were reported to occur among women taking combination Premarin/medroxyprogesterone acetate therapy. 3. Dementia. In the Women's Health Initiative Memory Study (WHIMS), an ancillary study of WHI, a population of 4,532 women aged 65 to 79 years was randomized to PREMPRO (0.625 mg/2.5 mg) or placebo. A population of 2,947 hysterectomized women, aged 65 to 79 years, was randomized to Premarin (0.625 mg) or placebo. In the planned analysis, pooling the events in women receiving Premarin or PREMPRO in comparison to those in women on placebo, the overall relative risk (RR) for probable dementia was 1.76 (95% CI 1.19-2.60). In the estrogen-alone group, after an average follow-up of 5.2 years a RR of 1.49 (95% CI 0.83-2.66) for probable dementia was observed compared to placebo. In the estrogen-plus-progestin group, after an average follow-up of 4 years, a RR of 2.05 (95% CI 1.21-3.48) for probable dementia was observed compared to placebo. Since this study was conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women. (See PRECAUTIONS , Geriatric Use .) 4. Gallbladder Disease. A 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 a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be discontinued. Precautions A. General Addition of a progestin when a woman has not had a hysterectomy. Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared with estrogen-alone regimens. These include a possible increased risk of breast cancer, adverse effects on lipoprotein metabolism (e.g., lowering HDL, raising LDL) and impairment of glucose tolerance. Elevated blood pressure. In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use. Hypertriglyceridemia. In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications. In the HOPE study, the mean percent increase from baseline in serum triglycerides after one year of treatment with PREMPRO 0.625 mg/2.5 mg, 0.45 mg/1.5 mg, and 0.3 mg/1.5 mg compared with placebo were 32.8, 24.8, 23.3, and 10.7, respectively. After two years of treatment, the mean percent changes were 33.0, 17.1, 21.6, and 5.5, respectively. Impaired liver function and past history of cholestatic jaundice. Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued. 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 T 4 and T 3 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. Fluid retention. Because estrogens/progestins 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. Hypocalcemia. Estrogens should be used with caution in individuals with severe hypocalcemia. Ovarian cancer. The estrogen plus progestin substudy of WHI reported that after an average follow-up of 5.6 years, the relative risk of ovarian cancer for estrogen plus progestin versus placebo was 1.58 (95% confidence interval 0.77-3.24) but was not statistically significant. The absolute risk for estrogen plus progestin 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 ten or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations. Exacerbation of endometriosis. Endometriosis may be exacerbated with administration of estrogen therapy. 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 women with these conditions. B. Patient Information Physicians are advised to discuss the contents of the PATIENT INFORMATION leaflet with patients for whom they prescribe PREMPRO or PREMPHASE. C. Laboratory Tests Estrogen administration should be initiated at the lowest dose approved for the indication and then guided by clinical response rather than by serum hormone levels (e.g., estradiol, FSH). D. Drug/Laboratory Test Interactions Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, 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), T 4 levels (by column or by radioimmunoassay), or T 3 levels by radioimmunoassay. T 3 resin uptake is decreased, reflecting the elevated TBG. Free T 4 and free T 3 concentrations ar many different types
study Estrogens, conjugated the sort of
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