CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 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 of 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. With PREMPRO 0.625 mg/2.5 mg, 0.45 mg/1.5 mg, and 0.3 mg/1.5 mg, the relief of both the frequency and severity of moderate to severe vasomotor symptoms was shown to be statistically improved compared to placebo at weeks and 12. Table shows the adjusted mean number of hot flushes in the PREMPRO 0.625 mg/2.5 mg, 0.45 mg/1.5 mg, 0.3 mg/1.5 mg, and placebo groups during the initial 12-week period.TABLE 5: 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)TreatmentIdentified by dosage (mg) of Premarin/MPA or placebo. (No. of Patients)-------------------No. of Hot Flushes/Day-----------------Time Period(week)BaselineMean +- SDObservedMean +- SDMeanChange +- SDp-Valuesvs. PlaceboThere 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. 0.625 mg/2.5 mg(n 34)411.98 +- 3.543.19 +- 3.74-8.78 +- 4.72<0.0011211.98 +- 3.541.16 +- 2.22-10.82 +- 4.61<0.0010.45 mg/1.5 mg(n 29)412.61 +- 4.293.64 +- 3.61-8.98 +- 4.74<0.0011212.61 +- 4.291.69 +- 3.36-10.92 +- 4.63<0.0010.3 mg/1.5 mg(n 33)411.30 +- 3.133.70 +- 3.29-7.60 +- 4.71<0.0011211.30 +- 3.131.31 +- 2.82-10.00 +- 4.60<0.001Placebo(n 28)411.69 +- 3.877.89 +- 5.28-3.80 +- 4.71-1211.69 +- 3.875.71 +- 5.22-5.98 +- 4.60-. 14.2 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.. 14.3 Effects on the Endometrium. In 1-year clinical trial of 1,376 women (average age 54 +- 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 reduced risk of endometrial hyperplasia in the two PREMPRO treatment groups (less than percent) and in the PREMPHASE treatment group (less than percent; percent when focal hyperplasia was included) compared to the Premarin group (8 percent; 20 percent when focal hyperplasia was included), see Table 6.TABLE 6: INCIDENCE OF ENDOMETRIAL HYPERPLASIA AFTER ONE YEAR OF TREATMENT--------------------------Groups-------------------------PREMPROPREMPROPREMPHASEPremarin0.625 mg/2.5 mg0.625 mg/5 mg0.625 mg/5 mg0.625 mgTotal number of patients340338351347Number of patients with evaluable biopsies279274277283No. (%) of patients with biopsies:o All focal and non-focal hyperplasia2 (<1)Significant (p 0.001) in comparison with Premarin (0.625 mg) alone. (0) (1) 57 (20)o Excluding focal cystic hyperplasia2 (<1) (0) (<1) 25 (8)In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, 2,001 women (average age 53.3 +- 4.9 years), of whom 88 percent 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 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 case, see Table 7.No endometrial hyperplasia or cancer was noted in those patients treated with the continuous combined regimens who continued for second year in the osteoporosis and metabolic substudy of the HOPE study, see Table 8.TABLE 7: INCIDENCE OF ENDOMETRIAL HYPERPLASIA/CANCERAll cases of hyperplasia/cancer were endometrial hyperplasia, except for patient in the Premarin 0.3 mg group diagnosed with endometrial cancer based on endometrial biopsy and patient in the Premarin/MPA 0.45 mg/1.5 mg group diagnosed with endometrial cancer based on endometrial biopsy. AFTER ONE YEAR OF TREATMENTTwo (2) primary pathologists evaluated each endometrial biopsy. Where there was lack of agreement on the presence or absence of hyperplasia/cancer between the two, third pathologist adjudicated (consensus). -----------------------------------Groups---------------------------------PatientPrempro0.625 mg/2.5 mgPremarin0.625 mgPrempro0.45 mg/1.5 mgPremarin0.45 mgPrempro0.3 mg/1.5 mgPremarin0.3 mgTotal number of patients331348331338327326Number of patients with evaluable biopsies278249272279271269No. (%) of patients with biopsies:o Hyperplasia/cancer (consensusFor an endometrial biopsy to be counted as consensus endometrial hyperplasia or cancer, at least pathologists had to agree on the diagnosis.)0 (0)Significant (p 0.05) in comparison with corresponding dose of Premarin alone. 20 (8)1 (<1) 9 (3)1 (<1)Non-significant in comparison with corresponding dose of Premarin alone. (<1) TABLE 8: OSTEOPOROSIS AND METABOLIC SUBSTUDY, INCIDENCE OF ENDOMETRIAL HYPERPLASIA/CANCERAll cases of hyperplasia/cancer were endometrial hyperplasia in patients who continued for second year in the osteoporosis and metabolic substudy of the HOPE study. AFTER TWO YEARS OF TREATMENTTwo (2) primary pathologists evaluated each endometrial biopsy. Where there was lack of agreement on the presence or absence of hyperplasia/cancer between the two, third pathologist adjudicated (consensus). -------------------------------Groups------------------------------PatientPrempro0.625 mg/2.5 mgPremarin0.625 mgPrempro0.45 mg/1.5 mgPremarin0.45 mgPrempro0.3 mg/1.5 mgPremarin 0.3 mgTotal number of patients756575747973Number of patients with evaluable biopsies625569677563No. (%) of patients with biopsies:o Hyperplasia/cancer (consensusFor an endometrial biopsy to be counted as consensus endometrial hyperplasia or cancer, at least pathologists had to agree on the diagnosis.)0 (0)Significant (p 0.05) in comparison with corresponding dose of Premarin alone. 15 (27)0 (0) 10 (15)0 (0) (3). 14.4 Effects on Uterine Bleeding or Spotting. The effects of PREMPRO on uterine bleeding or spotting, as recorded on daily diary cards, were evaluated in clinical trials. Results are shown in Figures and 2.FIGURE 1. PATIENTS WITH CUMULATIVE AMENORRHEA OVER TIME PERCENTAGES OF WOMEN WITH NO BLEEDING OR SPOTTING AT GIVEN CYCLE THROUGH CYCLE 13 INTENT-TO-TREAT POPULATION, LOCFNote: The percentage of patients who were amenorrheic in given cycle and through cycle 13 is shown. If data were missing, the bleeding value from the last reported day was carried forward (LOCF).FIGURE 2. PATIENTS WITH CUMULATIVE AMENORRHEA OVER TIME PERCENTAGES OF WOMEN WITH NO BLEEDING OR SPOTTING AT GIVEN CYCLE THROUGH CYCLE 13 INTENT-TO-TREAT POPULATION, LOCFNote: The percentage of patients who were amenorrheic in given cycle and through cycle 13 is shown. If data were missing, the bleeding value from the last reported day was carried forward (LOCF).. Figure 1. Figure 2. 14.5 Effects on Bone Mineral Density. Health and Osteoporosis, Progestin and Estrogen (HOPE) StudyThe HOPE study was double-blind, randomized, placebo/active-drug-controlled, multicenter study of healthy postmenopausal women with an intact uterus. Subjects (mean age 53.3 +- 4.9 years) were 2.3 +- 0.9 years on average since menopause and took one 600 mg tablet of elemental calcium (Caltrate(TM)) daily. Subjects were not given Vitamin supplements. They were treated with 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 (L2 to L4). Secondarily, BMD measurements of the total body, femoral neck, and trochanter were also analyzed. Serum osteocalcin, urinary calcium, and N-telopeptide were used as bone turnover markers (BTM) at cycles 6, 13, 19, and 26.. Intent-to-treat subjectsAll active treatment groups showed significant differences from placebo in each of the four BMD endpoints. These significant differences were seen at cycles 6, 13, 19, and 26.The percent changes from baseline to final evaluation are shown in Table 9.TABLE 9: PERCENT CHANGE IN BONE MINERAL DENSITY: COMPARISON BETWEEN ACTIVE AND PLACEBO GROUPS IN THE INTENT-TO-TREAT POPULATION, LOCFRegion Evaluated Treatment GroupIdentified by dosage (mg/mg) of Premarin/MPA or placebo. No. of SubjectsBaseline(g/cm2)Mean +- SDChange fromBaseline (%) AdjustedMean +- SEp-Valuevs.PlaceboL2 to L4 BMD 0.625/2.5811.14 +- 0.163.28 +- 0.37<0.001 0.45/1.5891.16 +- 0.142.18 +- 0.35<0.001 0.3/1.5901.14 +- 0.151.71 +- 0.35<0.001 Placebo851.14 +- 0.14-2.45 +- 0.36Total body BMD 0.625/2.5811.14 +- 0.080.87 +- 0.17<0.001 0.45/1.5891.14 +- 0.070.59 +- 0.17<0.001 0.3/1.5911.13 +- 0.080.60 +- 0.16<0.001 Placebo851.13 +- 0.08-1.50 +- 0.17Femoral neck BMD 0.625/2.5810.89 +- 0.141.62 +- 0.46<0.001 0.45/1.5890.89 +- 0.121.48 +- 0.44<0.001 0.3/1.5910.86 +- 0.111.31 +- 0.43<0.001 Placebo850.88 +- 0.14-1.72 +- 0.45Femoral trochanter BMD 0.625/2.5810.77 +- 0.143.35 +- 0.590.002 0.45/1.5890.76 +- 0.122.84 +- 0.570.011 0.3/1.5910.76 +- 0.123.93 +- 0.56<0.001 Placebo850.75 +- 0.120.81 +- 0.58Figure 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. FIGURE 3. CUMULATIVE PERCENT OF SUBJECTS WITH CHANGES FROM BASELINE IN SPINE BMD OF GIVEN MAGNITUDE OR GREATER IN PREMARIN/MPA 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 4. Significant differences between each of the PREMPRO dosage groups and placebo were found at cycles 6, 13, 19, and 26.FIGURE 4. ADJUSTED MEAN (SE) PERCENT CHANGE FROM BASELINE AT EACH CYCLE IN SPINE BMD: SUBJECTS COMPLETING IN PREMARIN/MPA 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; 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 or more of the time points.. Figure 3. Figure 4. 14.6 Womens Health Initiative Studies. The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal 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, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other causes. These substudies did not evaluate the effects of CE plus MPA or CE-alone on menopausal symptoms.. WHI Estrogen Plus Progestin SubstudyThe WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive 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.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 plus 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.Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 10. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.TABLE 10: Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 YearsAdapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. Results are based on centrally adjudicated data. Relative RiskCE/MPA vs. Placebo(95% nCINominal confidence intervals unadjusted for multiple looks and multiple comparisons.)CE/MPAn 8,506Placebon 8,102EventAbsolute Risk per 10,000Women-YearsCHD events1.23 (0.99-1.53)4134 Non-fatal MI 1.28 (1.00-1.63)3125 CHD death 1.10 (0.70-1.75)88All Strokes1.31 (1.03-1.68)3325 Ischemic stroke 1.44 (1.09-1.90)2618Deep vein thrombosisNot included in global index. 1.95 (1.43-2.67)2613Pulmonary embolism2.13 (1.45-3.11)188Invasive breast cancerIncludes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. 1.24 (1.01-1.54)4133Colorectal cancer0.61 (0.42-0.87)1016Endometrial cancer 0.81 (0.48-1.36)67Cervical cancer 1.44 (0.47-4.42)21Hip fracture0.67 (0.47-0.96)1116Vertebral fractures 0.65 (0.46-0.92)1117Lower arm/wrist fractures 0.71 (0.59-0.85)4462Total fractures 0.76 (0.69-0.83)152199Overall MortalityAll deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. 1.00 (0.83-1.19)5252Global IndexA 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. 1.13 (1.02-1.25)184165Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50 to 59 years of age, non-significant trend toward reduced risk for overall mortality [hazard ratio (HR) 0.69 (95 percent CI, 0.44-1.07)].. WHI Estrogen-Alone SubstudyThe WHI 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 63 years of age, 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 7.1 years, are presented in Table 11.Table 11: Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHIAdapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. Relative RiskCE vs. Placebo(95% nCINominal confidence intervals unadjusted for multiple looks and multiple comparisons.)CEn 5,310Placebon 5,429EventAbsolute Risk per 10,000Women-YearsCHD eventsResults are based on centrally adjudicated data for an average follow-up of 7.1 years. 0.95 (0.78-1.16)5457 Non-fatal MI 0.91 (0.73-1.14)4043 CHD death 1.01 (0.71-1.43)1616All Strokes 1.33 (1.05-1.68)4533 Ischemic stroke 1.55 (1.19-2.01)3825Deep vein thrombosis Not included in global index. 1.47 (1.06-2.06)2315Pulmonary embolism 1.37 (0.90-2.07)1410Invasive breast cancer 0.80 (0.62-1.04)2834Colorectal cancerResults are based on an average follow-up of 6.8 years. 1.08 (0.75-1.55)1716Hip fracture 0.65 (0.45-0.94)1219Vertebral fractures 0.64 (0.44-0.93)1118Lower arm/wrist fractures 0.58 (0.47-0.72)3559Total fractures 0.71 (0.64-0.80)144197Death due to other causes All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. 1.08 (0.88-1.32)5350Overall mortality 1.04 (0.88-1.22)7975Global IndexA 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. 1.02 (0.92-1.13)206201For 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 was 12 more strokes while the absolute risk reduction per 10,000 women-years was fewer hip fractures.9 The absolute excess risk of events included in the global index was non-significant events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality.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 was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow up of 7.1 years.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 for ischemic stroke, and this excess risk was present in all subgroups of women examined.10 Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy, stratified by age, showed in women 50 to 59 years of age non-significant trend toward reduced risk for CHD [HR 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46-1.11)].. 14.7 Womens Health Initiative Memory Study. The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age; 35 percent were 70 to 74 years of age; and 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo.After an average follow-up of years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimers disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.3), and Use in Specific Populations (8.5)].The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age and older (45 percent were 65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo.After an average follow-up of 5.2 years, 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. Probable dementia as defined in this study included AD, VaD and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.3), and Use in Specific Populations (8.5)].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 Warnings and Precautions (5.3), and Use in Specific Populations (8.5)].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are discussed elsewhere in the labeling:Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions (5.1)] Malignant Neoplasms [see Boxed Warning, Warnings and Precautions (5.2)] Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions (5.1)] Malignant Neoplasms [see Boxed Warning, Warnings and Precautions (5.2)] In two prospective, randomized clinical studies, the most common adverse reactions 5 percent are abdominal pain, asthenia, back pain, headache, flatulence, nausea, depression, pruritus, breast pain, dysmenorrhea, and leukorrhea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trial of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.In 1-year clinical trial that included 678 postmenopausal women treated with PREMPRO and 351 postmenopausal women treated with PREMPHASE, the following adverse reactions occurred at rate >= percent, see Table 1.TABLE 1: ALL TREATMENT RELATED ADVERSE REACTIONS AT FREQUENCY >= PERCENTBody SystemPREMPRO0.625 mg/2.5 mgcontinuousPREMPRO0.625 mg/5 mg continuousPREMPHASE0.625 mg/5 mg sequential Adverse event (n 340)(n 338)(n 351)Body As Whole Abdominal pain 35 (10%)51 (15%)58 (17%) Asthenia 13 (4%)18 (5%)21 (6%) Back pain 19 (6%)16 (5%)23 (7%) Chest pain (1%)4 (1%)4 (1%) Flu syndrome (<1%) (<1%) (1%) Generalized edema12 (4%) 12 (4%)8 (2%) Headache64 (19%)52 (15%) 66 (19%) Infection2 (<1%) (1)%0 Moniliasis4 (1%) (<1%)4 (1%) Pain12 (4%) 14 (4%)15 (4%) Pelvic pain11 (3%) 13 (4%)16 (5%)Cardiovascular System Hypertension7 (2%) (2%)6 (2%) Migraine (2%) (2%) (2%) Palpitation2 (<1%)3 (<1%)4 (1%) Vasodilatation2 (<1%)7 (2%)2 (<1%)Digestive System Diarrhea4 (1%) (<1%) (2%) Dyspepsia5 (1%)5 (1%)7 (2%) Eructation02 (<1%)4 (1%) Flatulence25 (7%)27 (8%)24 (7%) Increased appetite1 (<1%)5 (1%)5 (1%) Nausea26 (8%)19 (6%)26 (7%)Metabolic and Nutritional Edema5 (1%) (2%)3 (<1%) Glucose tolerance decreased2 (<1%)5 (1%)4 (1%) Peripheral edema 11 (3%)10 (3%) 11 (3%) Weight gain9 (3%)10 (3%)11 (3%)Musculoskeletal System Arthralgia (2%)2 (<1%)7 (2%) Leg cramps (2%)11 (3%)12 (3%)Nervous System Depression 14 (4%)26 (8%)29 (8%) Dizziness (3%)8 (2%)7 (2%) Emotional lability (1%) (1%) (2%) Hypertonia4 (1%)4 (1%)7 (2%) Insomnia7 (2%)6 (2%)4 (1%) Nervousness4 (1%) (3%) (2%) Skin and Appendages Acne1 (<1%) (1%)4 (1%) Alopecia3 (<1%)4 (1%)0 Dry skin2 (<1%)3 (<1%)4 (1%) Pruritus20 (6%)18 (5%)13 (4%) Rash8 (2%)6 (2%)7 (2%) Sweating (<1%)4 (1%)2 (<1%)Urogenital System Breast engorgement5 (1%)5 (1%)0 Breast enlargement14 (4%) 14 (4%) 14 (4%) Breast neoplasm2 (<1%)2 (<1%)4 (1%) Breast pain110 (32%)123 (36%)109 (31%) Cervix disorder10 (3%)6 (2%)10 (3%) Dysmenorrhea 26 (8%)18 (5%)44 (13%) Leukorrhea 19 (6%)13 (4%)29 (8%) Menstrual disorder (2%) (<1%)5 (1%) Menorrhagia01 (<1%)5 (1%) Metrorrhagia 13 (4%)5 (1%)7 (1%) Papanicolaou smear suspicious5 (1%) 08 (2%) Urinary incontinence4 (1%)2 (<1%)1 (<1%) Uterine spasm7 (2%)4 (1%)7 (2%) Vaginal hemorrhage5 (1%)3 (<1%)8 (2%) Vaginal moniliasis5 (1%)6 (2%)7 (2%) Vaginitis13 (4%)13 (4%)10 (3%)In addition, phargyngitis and sinusitis were reported as two of the more frequent adverse events (>5 percent) in the PREMPRO clinical study. For pharyngitis, of the 121 events, six events were considered by the investigator causally related to study drug. For sinusitis, of the 73 events, one event was considered as casually related to study drug.During the first year of 2-year clinical trial with postmenopausal women between 40 and 65 years of age (88 percent Caucasian), 989 postmenopausal women received continuous regimens of PREMPRO, and 332 received placebo tablets. Table summarizes adverse reactions that occurred at rate >= percent in at least treatment group.TABLE 2: ALL TREATMENT RELATED ADVERSE REACTIONS AT FREQUENCY OF >= PERCENTBody SystemAdverse eventPREMPRO0.625/2.5continuous(N=331)PREMPRO0.45/1.5continuous(N=331)PREMPRO0.3/1.5continuous(N=327)PLACEBOdaily(N=332)Any adverse event214 (65)208 (63)188 (57)164 (49)Body as Whole Abdominal pain38 (11)33 (10)24 (7)21 (6) Asthenia11 (3)11 (3)12 (4)3 (1) Back pain12 (4)12 (4)8 (2)4 (1) Chest pain4 (1)2 (1)1 (0)2 (1) Generalized edema7 (2)5 (2)6 (2)8 (2) Headache45 (14)45 (14)57 (17)46 (14) Moniliasis3 (1)6 (2)4 (1)1 (0) Pain9 (3)10 (3)17 (5)14 (4) Pelvic pain9 (3)7 (2)5 (2)4 (1)Cardiovascular System Hypertension2 (1)3 (1)1 (0)5 (2) Migraine11 (3)8 (2)5 (2)3 (1) Palpitation1 (0)1 (0)2 (1)4 (1) Vasodilatation03 (1)1 (0)5 (2)Digestive System Constipation5 (2)7 (2)6 (2)3 (1) Diarrhea5 (2)2 (1)6 (2)8 (2) Dyspepsia10 (3)9 (3)6 (2)14 (4) Flatulence16 (5)18 (5)13 (4)8 (2) Increased appetite6 (2)2 (1)02 (1) Nausea13 (4)13 (4)16 (5)16 (5)Metabolic and nutritional Peripheral edema7 (2)8 (2)4 (1)3 (1) Weight gain9 (3)8 (2)6 (2)14 (4)Musculoskeletal System Arthralgia2 (1)3 (1)3 (1)5 (2) Leg cramps13 (4)7 (2)10 (3)4 (1)Nervous System Anxiety5 (2)4 (1)1 (0)4 (1) Depression23 (7)11 (3)11 (3)17 (5) Dizziness3 (1)8 (2)6 (2)5 (2) Emotional lability10 (3)10 (3)9 (3)8 (2) Insomnia8 (2)7 (2)9 (3)14 (4) Nervousness6 (2)3 (1)4 (1)6 (2)Skin and Appendages Acne7 (2)3 (1)03 (1) Alopecia1 (0)6 (2)4 (1)2 (1) Pruritus8 (2)10 (3)9 (3)3 (1) Rash06 (2)4 (1)2 (1) Skin discoloration5 (2)1 (0)3 (1)1 (0) Sweating3 (1)1 (0)04 (1)Urogenital System Breast disorder7 (2)6 (2)5 (2)6 (2) Breast enlargement18 (5)9 (3)5 (2)3 (1) Breast neoplasm8 (2)7 (2)5 (2)7 (2) Breast pain87 (26)66 (20)41 (13)26 (8) Cervix disorder7 (2)2 (1)2 (1)0 Dysmenorrhea14 (4)18 (5)9 (3)2 (1) Hematuria4 (1)3 (1)1 (0)2 (1) Leukorrhea7 (2)14 (4)9 (3)6 (2) Metrorrhagia7 (2)14 (4)4 (1)1 (0) Urinary tract infection01 (0)1 (0)4 (1) Uterine spasm13 (4)11 (3)7 (2)2 (1) Vaginal dryness2 (1)1 (0)06 (2) Vaginal hemorrhage18 (5)14 (4)7 (2)0 Vaginal moniliasis13 (4)11 (3)8 (2)5 (2) Vaginitis6 (2)8 (2)7 (2)1 (0)In addition, the following events were considered as related to the study drug with an incidence less than percent, including accidental injury, infection, myalgia, cough increased, rhinitis, sinusitis, and upper respiratory infection.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of PREMPRO or PREMPHASE. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.. Genitourinary SystemAbnormal uterine bleeding, dysmenorrhea or pelvic pain, increase in size of uterine leiomyomata, vaginitis, vaginal candidiasis, amenorrhea, changes in cervical secretion, ovarian cancer, endometrial hyperplasia, endometrial cancer.. BreastsTenderness, enlargement, pain, nipple discharge, galactorrhea, fibrocystic breast changes, breast cancer.. CardiovascularDeep and superficial venous thrombosis, pulmonary embolism, superficial thrombophlebitis, myocardial infarction, stroke, increase in blood pressure.. GastrointestinalNausea, vomiting, abdominal pain, bloating, cholestatic jaundice, increased incidence of gallbladder disease, pancreatitis, changes in appetite, ischemic colitis.. SkinChloasma or melasma that may persist when drug is discontinued, erythema multiforme, erythema nodosum, loss of scalp hair, hirsutism, pruritus, urticaria, rash, acne.. EyesRetinal vascular thrombosis, intolerance of contact lenses.. Central Nervous System Headache, migraine, dizziness, mental depression, exacerbation of chorea, mood disturbances, anxiety, irritability, exacerbation of epilepsy, dementia, growth potentiation of benign meningioma.. MiscellaneousIncrease or decrease in weight, arthralgia, glucose intolerance, edema, changes in libido, exacerbation of asthma, increased triglycerides, hypersensitivity.Additional postmarketing adverse reactions have been reported in patients receiving other forms of hormone therapy.

BOXED WARNING SECTION.

WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER and PROBABLE DEMENTIA. Estrogen Plus Progestin TherapyCardiovascular Disorders and Probable DementiaEstrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.6, 14.7)].The Womens Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogen (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions (5.1), and Clinical Studies (14.6)].The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older 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 Warnings and Precautions (5.3), Use in Specific Populations (8.5), and Clinical Studies (14.7)].Breast CancerThe WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.2), and Clinical Studies (14.6)].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.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. Estrogen-Alone TherapyEndometrial CancerThere is an increased risk of endometrial cancer in woman with uterus who uses unopposed estrogens. Adding progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions (5.2)].Cardiovascular Disorders and Probable DementiaEstrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.6, 14.7)].The WHI estrogen-alone substudy reported increased risks of stroke and DVT in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral CE (0.625 mg)-alone, relative to placebo [see Warnings and Precautions (5.1), and Clinical Studies (14.6)].The WHIMS estrogen-alone ancillary study 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, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3), Use in Specific Populations (8.5), and Clinical Studies (14.7)].In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens.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.. WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER and PROBABLE DEMENTIASee full prescribing information for complete boxed warning.Estrogen Plus Progestin TherapyEstrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia (5.1, 5.3)The Womens Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of stroke, deep vein thrombosis (DVT), pulmonary embolism (PE), and myocardial infarction (MI) (5.1)The WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer (5.2)The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.3)Estrogen-Alone TherapyThere is an increased risk of endometrial cancer in woman with uterus who uses unopposed estrogens (5.2)Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia (5.1, 5.3)The WHI estrogen-alone substudy reported increased risks of stroke and DVT (5.1)The WHIMS estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.3). Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia (5.1, 5.3). The Womens Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of stroke, deep vein thrombosis (DVT), pulmonary embolism (PE), and myocardial infarction (MI) (5.1). The WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer (5.2). The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.3). There is an increased risk of endometrial cancer in woman with uterus who uses unopposed estrogens (5.2). Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia (5.1, 5.3). The WHI estrogen-alone substudy reported increased risks of stroke and DVT (5.1). The WHIMS estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.3).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action. 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, which is secreted by the adrenal cortex, to estrone in the 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 FSH, through negative feedback mechanism. Estrogens act to reduce the elevated levels of these gonadotropins seen in postmenopausal women.Parenterally administered medroxyprogesterone acetate (MPA) inhibits gonadotropin production, which in turn prevents follicular maturation and ovulation; although available data indicate that this does not occur when the usually recommended oral dosage is given as single daily doses. MPA may achieve its beneficial effect on the endometrium in part by decreasing nuclear estrogen receptors and suppression of epithelial DNA synthesis in endometrial tissue. Androgenic and anabolic effects of MPA have been noted, but the drug is apparently devoid of significant estrogenic activity.. 12.2 Pharmacodynamics. Currently, there are no pharmacodynamic data known for PREMPRO or PREMPHASE tablets.. 12.3 Pharmacokinetics. AbsorptionPREMPRO and PREMPHASE contain formulation of medroxyprogesterone acetate (MPA) that is immediately released and conjugated estrogens that are slowly released over several hours. Conjugated estrogens are water-soluble and are well-absorbed from the gastrointestinal tract after release from the drug formulation. MPA is well absorbed from the gastrointestinal tract. Table and Table summarize the mean pharmacokinetic parameters for select unconjugated and conjugated estrogens and medroxyprogesterone acetate following administration of PREMPRO to healthy, postmenopausal women.TABLE 3: PHARMACOKINETIC PARAMETERS FOR UNCONJUGATED AND CONJUGATED ESTROGENS (CE) AND MEDROXYPROGESTERONE ACETATE (MPA)DRUG2 0.625 mg CE/2.5 mg MPACombination Tablets(n 54)2 0.625 mg CE/5 mg MPACombination Tablets(n 51)BA Baseline adjusted max peak plasma concentration max time peak concentration occurs 1/2 apparent terminal-phase disposition half-life (0.693/z) AUC total area under the concentration-time curvePK ParameterArithmeticMean (%CV)Cmax(pg/mL)tmax(h)t1/2(h)AUC(pgh/mL)Cmax(pg/mL)tmax(h)t1/2(h)AUC(pgh/mL)Unconjugated EstrogensEstrone175(23)7.6(24)31.6(23)5358(34)124(43)10(35)62.2(137)6303(40)BA -Estrone159(26)7.6(24)16.9(34)3313(40)104(49)10(35)26.0(100)3136(51)Equilin71(31)5.8(34)9.9(35)951(43)54(43)8.9(34)15.5(53)1179(56)PK ParameterArithmeticMean (%CV)Cmax(ng/mL)tmax(h)t1/2(h)AUC(ngh/mL)Cmax(ng/mL)tmax(h)t1/2(h)AUC(ngh/mL)Conjugated EstrogensTotal Estrone6.6(38)6.1(28)20.7(34)116(59)6.3(48)9.1(29)23.6(36)151(42)BA -Total Estrone6.4(39)6.1(28)15.4(34)100(57)6.2(48)9.1(29)20.6(35)139(40)Total Equilin5.1(45)4.6(35)11.4(25)50(70)4.2(52)7.0(36)17.2(131)72(50)PK ParameterArithmetic Mean(%CV)Cmax(ng/mL)tmax(h)t1/2(h)AUC(ngh/mL)Cmax(ng/mL)tmax(h)t1/2(h)AUC(ngh/mL)Medroxyprogesterone AcetateMPA1.5(40)2.8(54)37.6(30)37(30)4.8(31)2.4(50)46.3(39)102(28)TABLE 4. PHARMACOKINETIC PARAMETERS FOR UNCONJUGATED AND CONJUGATED ESTROGENS (CE) AND MEDROXYPROGESTERONE ACETATE (MPA)DRUG4 0.45 mg CE/1.5 mg MPA Combination(n 65)BA Baseline adjusted max peak plasma concentration max time peak concentration occurs 1/2 apparent terminal-phase disposition half-life (0.693/z) AUC total area under the concentration-time curvePK ParameterArithmetic Mean (%CV)Cmax(pg/mL)tmax(h)t1/2(h)AUC(pgh/mL)Unconjugated EstrogensEstrone149(35)8.9(35)37.5(35)6641(39)BA -Estrone130(40)8.9(35)21.2(35)3799(47)Equilin83(38)8.3(48)15.9(44)1889(40)PK ParameterArithmetic Mean (%CV)Cmax(ng/mL)tmax(h)t1/2(h)AUC(ngh/mL)Conjugated EstrogensTotal Estrone5.4(49)7.9(48)22.4(53)119(48)BA -Total Estrone5.2(48)7.9(48)15.1(29)100(47)Total Equilin4.3(42)6.5(45)11.6(31)74(48)PK ParameterArithmetic Mean (%CV)Cmax(ng/mL)tmax(h)t1/2(h)AUC(ngh/mL)Medroxyprogesterone AcetateMPA0.7(66)2.0(52)26.2(35)5.0(61). Food-Effect: Single dose studies in healthy, postmenopausal women were conducted to investigate any potential drug interaction when PREMPRO or PREMPHASE is administered with high-fat breakfast. Administration with food decreased the Cmax of total estrone by 18 to 34 percent and increased total equilin Cmax by 38 percent compared to the fasting state, with no other effect on the rate or extent of absorption of other conjugated or unconjugated estrogens. Administration with food approximately doubles MPA Cmax and increases MPA AUC by approximately 20 to 30 percent.. Dose Proportionality: The Cmax and AUC values for MPA observed in two separate pharmacokinetic studies conducted with PREMPRO 0.625 mg/2.5 mg or PREMPRO or PREMPHASE 0.625 mg/5 mg tablets exhibited nonlinear dose proportionality; doubling the MPA dose from x 2.5 to x mg increased the mean Cmax and AUC by 3.2- and 2.8-fold, respectively.The dose proportionality of estrogens and medroxyprogesterone acetate was assessed by combining pharmacokinetic data across another two studies totaling 61 healthy, postmenopausal women. Single conjugated estrogens doses of x 0.3 mg, x 0.45 mg, or x 0.625 mg were administered either alone or in combination with medroxyprogesterone acetate doses of x 1.5 mg or x 2.5 mg. Most of the estrogen components demonstrated dose proportionality; however, several estrogen components did not. Medroxyprogesterone acetate pharmacokinetic parameters increased in dose-proportional manner.. DistributionThe distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to SHBG and albumin. MPA is approximately 90 percent bound to plasma proteins, but does not bind to SHBG.. MetabolismExogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is 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 portion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as circulating reservoir for the formation of more active estrogens. Metabolism and elimination of MPA occur primarily in the liver via hydroxylation, with subsequent conjugation and elimination in the urine.. ExcretionEstradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Most metabolites of MPA are excreted as glucuronide conjugates, with only minor amounts excreted as sulfates.. Use in Specific PopulationsNo pharmacokinetic studies were conducted in specific populations, including patients with renal or hepatic impairment.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionPREMPRO and PREMPHASE contain formulation of medroxyprogesterone acetate (MPA) that is immediately released and conjugated estrogens that are slowly released over several hours. Conjugated estrogens are water-soluble and are well-absorbed from the gastrointestinal tract after release from the drug formulation. MPA is well absorbed from the gastrointestinal tract. Table and Table summarize the mean pharmacokinetic parameters for select unconjugated and conjugated estrogens and medroxyprogesterone acetate following administration of PREMPRO to healthy, postmenopausal women.TABLE 3: PHARMACOKINETIC PARAMETERS FOR UNCONJUGATED AND CONJUGATED ESTROGENS (CE) AND MEDROXYPROGESTERONE ACETATE (MPA)DRUG2 0.625 mg CE/2.5 mg MPACombination Tablets(n 54)2 0.625 mg CE/5 mg MPACombination Tablets(n 51)BA Baseline adjusted max peak plasma concentration max time peak concentration occurs 1/2 apparent terminal-phase disposition half-life (0.693/z) AUC total area under the concentration-time curvePK ParameterArithmeticMean (%CV)Cmax(pg/mL)tmax(h)t1/2(h)AUC(pgh/mL)Cmax(pg/mL)tmax(h)t1/2(h)AUC(pgh/mL)Unconjugated EstrogensEstrone175(23)7.6(24)31.6(23)5358(34)124(43)10(35)62.2(137)6303(40)BA -Estrone159(26)7.6(24)16.9(34)3313(40)104(49)10(35)26.0(100)3136(51)Equilin71(31)5.8(34)9.9(35)951(43)54(43)8.9(34)15.5(53)1179(56)PK ParameterArithmeticMean (%CV)Cmax(ng/mL)tmax(h)t1/2(h)AUC(ngh/mL)Cmax(ng/mL)tmax(h)t1/2(h)AUC(ngh/mL)Conjugated EstrogensTotal Estrone6.6(38)6.1(28)20.7(34)116(59)6.3(48)9.1(29)23.6(36)151(42)BA -Total Estrone6.4(39)6.1(28)15.4(34)100(57)6.2(48)9.1(29)20.6(35)139(40)Total Equilin5.1(45)4.6(35)11.4(25)50(70)4.2(52)7.0(36)17.2(131)72(50)PK ParameterArithmetic Mean(%CV)Cmax(ng/mL)tmax(h)t1/2(h)AUC(ngh/mL)Cmax(ng/mL)tmax(h)t1/2(h)AUC(ngh/mL)Medroxyprogesterone AcetateMPA1.5(40)2.8(54)37.6(30)37(30)4.8(31)2.4(50)46.3(39)102(28)TABLE 4. PHARMACOKINETIC PARAMETERS FOR UNCONJUGATED AND CONJUGATED ESTROGENS (CE) AND MEDROXYPROGESTERONE ACETATE (MPA)DRUG4 0.45 mg CE/1.5 mg MPA Combination(n 65)BA Baseline adjusted max peak plasma concentration max time peak concentration occurs 1/2 apparent terminal-phase disposition half-life (0.693/z) AUC total area under the concentration-time curvePK ParameterArithmetic Mean (%CV)Cmax(pg/mL)tmax(h)t1/2(h)AUC(pgh/mL)Unconjugated EstrogensEstrone149(35)8.9(35)37.5(35)6641(39)BA -Estrone130(40)8.9(35)21.2(35)3799(47)Equilin83(38)8.3(48)15.9(44)1889(40)PK ParameterArithmetic Mean (%CV)Cmax(ng/mL)tmax(h)t1/2(h)AUC(ngh/mL)Conjugated EstrogensTotal Estrone5.4(49)7.9(48)22.4(53)119(48)BA -Total Estrone5.2(48)7.9(48)15.1(29)100(47)Total Equilin4.3(42)6.5(45)11.6(31)74(48)PK ParameterArithmetic Mean (%CV)Cmax(ng/mL)tmax(h)t1/2(h)AUC(ngh/mL)Medroxyprogesterone AcetateMPA0.7(66)2.0(52)26.2(35)5.0(61). Food-Effect: Single dose studies in healthy, postmenopausal women were conducted to investigate any potential drug interaction when PREMPRO or PREMPHASE is administered with high-fat breakfast. Administration with food decreased the Cmax of total estrone by 18 to 34 percent and increased total equilin Cmax by 38 percent compared to the fasting state, with no other effect on the rate or extent of absorption of other conjugated or unconjugated estrogens. Administration with food approximately doubles MPA Cmax and increases MPA AUC by approximately 20 to 30 percent.. Dose Proportionality: The Cmax and AUC values for MPA observed in two separate pharmacokinetic studies conducted with PREMPRO 0.625 mg/2.5 mg or PREMPRO or PREMPHASE 0.625 mg/5 mg tablets exhibited nonlinear dose proportionality; doubling the MPA dose from x 2.5 to x mg increased the mean Cmax and AUC by 3.2- and 2.8-fold, respectively.The dose proportionality of estrogens and medroxyprogesterone acetate was assessed by combining pharmacokinetic data across another two studies totaling 61 healthy, postmenopausal women. Single conjugated estrogens doses of x 0.3 mg, x 0.45 mg, or x 0.625 mg were administered either alone or in combination with medroxyprogesterone acetate doses of x 1.5 mg or x 2.5 mg. Most of the estrogen components demonstrated dose proportionality; however, several estrogen components did not. Medroxyprogesterone acetate pharmacokinetic parameters increased in dose-proportional manner.. DistributionThe distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to SHBG and albumin. MPA is approximately 90 percent bound to plasma proteins, but does not bind to SHBG.. MetabolismExogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is 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 portion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as circulating reservoir for the formation of more active estrogens. Metabolism and elimination of MPA occur primarily in the liver via hydroxylation, with subsequent conjugation and elimination in the urine.. ExcretionEstradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Most metabolites of MPA are excreted as glucuronide conjugates, with only minor amounts excreted as sulfates.. Use in Specific PopulationsNo pharmacokinetic studies were conducted in specific populations, including patients with renal or hepatic impairment.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION. PREMPRO(R) (Conjugated Estrogens/Medroxyprogesterone Acetate Tablets)PREMPHASE(R) (Conjugated Estrogens plus Medroxyprogesterone Acetate Tablets)Read this PATIENT INFORMATION before you start taking PREMPRO or PREMPHASE and read what you get each time you refill your PREMPRO or PREMPHASE 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 PREMPRO and PREMPHASE (combinations of estrogens and progestin)Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes, or dementia (decline of brain function)Using estrogens with progestins may increase your chances of getting heart attacks, strokes, breast cancer, or blood clotsUsing estrogens with progestins may increase your chance of getting dementia, based on study of women 65 years of age or olderDo not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementiaUsing estrogen-alone may increase your chance of getting cancer of the uterus (womb)Using estrogen-alone may increase your chances of getting strokes or blood clotsUsing estrogen-alone may increase your chance of getting dementia, based on study of women 65 years of age or olderYou and your healthcare provider should talk regularly about whether you still need treatment with PREMPRO or PREMPHASEWhat is PREMPRO or PREMPHASEPREMPRO or PREMPHASE are medicines that contain two kinds of hormones, estrogens and progestin.What is PREMPRO or PREMPHASE used forPREMPRO or PREMPHASE is used after menopause to:Reduce moderate to severe hot flashesEstrogens 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.Treat menopausal changes in and around the vaginaYou and your healthcare provider should talk regularly about whether you still need treatment with PREMPRO or PREMPHASE to control these problems. If you use PREMPRO or PREMPHASE only to treat your menopausal changes 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 PREMPRO or PREMPHASE 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. Weight-bearing exercise, like walking or running, and taking calcium (1500 mg per day of elemental calcium) and vitamin (400-800 IU per day) supplements may also lower your chances of getting postmenopausal osteoporosis. It is important to talk about exercise and supplements with your healthcare provider before starting them.You and your healthcare provider should talk regularly about whether you still need treatment with PREMPRO or PREMPHASE. Who should not take PREMPRO or PREMPHASEDo not take PREMPRO or PREMPHASE if you have had your uterus (womb) removed (hysterectomy).PREMPRO and PREMPHASE contain progestin to decrease the chance of getting cancer of the uterus. If you do not have uterus, you do not need progestin and you should not take PREMPRO or PREMPHASE.Do not take PREMPRO or PREMPHASE if you:Have unusual vaginal bleedingCurrently have or have had certain cancersEstrogens 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 use PREMPRO or PREMPHASE.Had stroke or heart attackCurrently have or have had blood clotsCurrently have or have had liver problemsHave been diagnosed with bleeding disorderAre allergic to PREMPRO or PREMPHASE or any of their ingredientsSee the list of ingredients in PREMPRO and PREMPHASE at the end of this leaflet.Think you may be pregnantTell your healthcare providerIf you have any unusual vaginal bleedingVaginal 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.About all of your medical problemsYour healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.About all the medicines you takeThis includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how PREMPRO or PREMPHASE works. PREMPRO or PREMPHASE may also affect how your other medicines work. If you are going to have surgery or will be on bedrestYou may need to stop taking PREMPRO or PREMPHASE.If you are breastfeedingThe hormones in PREMPRO and PREMPHASE can pass into your breast milk.How should take PREMPRO or PREMPHASETake one PREMPRO or PREMPHASE tablet at the same time each dayIf you miss dose, take it as soon as possibleIf 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 neededYou 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 PREMPRO or PREMPHASE.What are the possible side effects of PREMPRO or PREMPHASESide effects are grouped by how serious they are and how often they happen when you are treated.Serious, but less common side effects include:Heart attackStrokeBlood clotsDementiaBreast cancerCancer of the lining of the uterus (womb)Cancer of the ovaryHigh blood pressureHigh blood sugarGallbladder diseaseLiver problemsEnlargement of benign tumors of the uterus (fibroids)Mental depressionSevere allergic reactionCall your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:New breast lumpsUnusual vaginal bleeding Changes in vision or speechSudden new severe headachesSevere pains in your chest or legs with or without shortness of breath, weakness and fatigueSwollen lips, tongue and faceLess serious, but common side effects include:HeadacheBreast painIrregular vaginal bleeding or spotting Stomach or abdominal cramps, bloatingNausea and vomiting Hair lossFluid retentionVaginal yeast infectionThese are not all the possible side effects of PREMPRO or PREMPHASE. For more information, ask your healthcare provider or pharmacist for advice about side effects. You may report side effects to Pfizer Inc. at 1-800-438-1985 or to FDA at 1-800-FDA-1088. What can do to lower my chances of getting serious side effect with PREMPRO or PREMPHASETalk with your healthcare provider regularly about whether you should continue taking PREMPRO or PREMPHASESee your healthcare provider right away if you get vaginal bleeding while taking PREMPRO or PREMPHASEHave pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something elseIf 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 diseaseAsk your healthcare provider for ways to lower your chances of getting heart disease.General Information about the safe and effective use of PREMPRO and PREMPHASEMedicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take PREMPRO or PREMPHASE for conditions for which it was not prescribed. Do not give PREMPRO or PREMPHASE to other people, even if they have the same symptoms you have. It may harm them. Keep PREMPRO and PREMPHASE out of the reach of children.This leaflet provides summary of the most important information about PREMPRO and PREMPHASE. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about PREMPRO and PREMPHASE that is written for health professionals.What are the ingredients in PREMPRO and PREMPHASEPREMPRO contains the same conjugated estrogens found in Premarin, 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. PREMPRO also contains either 1.5, 2.5, or mg of medroxyprogesterone acetate.PREMPRO 0.3 mg/1.5 mg and 0.45 mg/1.5 mg tablets also contain calcium phosphate tribasic, microcrystalline cellulose, lactose monohydrate, carnauba wax, hypromellose, magnesium stearate, polyethylene glycol, sucrose, hydroxypropyl cellulose, Eudragit NE 30D, titanium dioxide, yellow iron oxide, propylene glycol and black iron oxide. PREMPRO 0.625 mg/2.5 mg tablets also contain calcium phosphate tribasic, microcrystalline cellulose, carnauba wax, lactose monohydrate, hypromellose, magnesium stearate, polyethylene glycol, sucrose, hydroxypropyl cellulose, Eudragit NE 30D, propylene glycol, titanium dioxide, red iron oxide, yellow iron oxide, and black iron oxide.PREMPRO 0.625 mg/5 mg tablets also contain calcium phosphate tribasic, carnauba wax, Eudragit NE 30D, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sucrose, titanium dioxide, triethyl citrate, FD&C Blue No. 2, black iron oxide, and propylene glycol.PREMPHASE is two separate tablets. One tablet (maroon color) is 0.625 mg of Premarin, which is mixture of sodium estrone sulfate and sodium equilin sulfate and other components, including sodium sulfate conjugates, 17 -dihydroequilin, 17 -estradiol and 17 -dihydroequilin. The maroon tablet also contains calcium phosphate tribasic, carnauba wax, hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, sucrose, titanium dioxide, propylene glycol, FD&C Blue No. 2, FD&C Red No. 40. The second tablet (light-blue color) contains 0.625 mg of the same ingredients as the maroon color tablet plus mg of medroxyprogesterone acetate. The light-blue tablet also contains calcium phosphate tribasic, carnauba wax, Eudragit NE 30D, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sucrose, titanium dioxide, triethyl citrate, FD&C Blue No. 2, black iron oxide, and propylene glycol.PREMPRO therapy consists of single tablet to be taken once daily.PREMPRO 0.3 mg/1.5 mgBlister Card Each carton includes blister card containing 28 oval, cream tablets. Each tablet contains 0.3 mg of the conjugated estrogens found in Premarin tablets and 1.5 mg of medroxyprogesterone acetate for oral administration. PREMPRO 0.45 mg/1.5 mgBlister Card Each carton includes blister card containing 28 oval, gold tablets. Each tablet contains 0.45 mg of the conjugated estrogens found in Premarin tablets and 1.5 mg of medroxyprogesterone acetate for oral administration.PREMPRO 0.625 mg/2.5 mgBlister Card Each carton includes blister card containing 28 oval, peach tablets. Each tablet contains 0.625 mg of the conjugated estrogens found in Premarin tablets and 2.5 mg of medroxyprogesterone acetate for oral administration.PREMPRO 0.625 mg/5 mgBlister Card Each carton includes blister card containing 28 oval, light-blue tablets. Each tablet contains 0.625 mg of the conjugated estrogens found in Premarin tablets and mg of medroxyprogesterone acetate for oral administration.PREMPHASE therapy consists of two separate tablets; one maroon Premarin tablet taken daily on days through 14 and one light-blue tablet taken on days 15 through 28.Each carton includes blister pack containing 28 tablets. One blister pack contains 14 oval, maroon Premarin tablets containing 0.625 mg of conjugated estrogens and 14 oval, light-blue tablets that contain 0.625 mg of the conjugated estrogens found in Premarin tablets and mg of medroxyprogesterone acetate for oral administration.The appearance of PREMPRO tablets is trademark of Pfizer Inc.The appearance of PREMARIN tablets is trademark of Pfizer Inc. The appearance of the conjugated estrogens/medroxyprogesterone acetate combination tablets is trademark.Store at 20 to 25C (68 to 77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature].This products label may have been updated. For current package insert and further product information, please visit www.pfizer.com.LAB-0504-9.0Revised May 2019. Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes, or dementia (decline of brain function). Using estrogens with progestins may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots. Using estrogens with progestins may increase your chance of getting dementia, based on study of women 65 years of age or older. Do not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia. Using estrogen-alone may increase your chance of getting cancer of the uterus (womb). Using estrogen-alone may increase your chances of getting strokes or blood clots. Using estrogen-alone may increase your chance of getting dementia, based on study of women 65 years of age or older. You and your healthcare provider should talk regularly about whether you still need treatment with PREMPRO or PREMPHASE. Reduce moderate to severe hot flashesEstrogens 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.. Treat menopausal changes in and around the vaginaYou and your healthcare provider should talk regularly about whether you still need treatment with PREMPRO or PREMPHASE to control these problems. If you use PREMPRO or PREMPHASE only to treat your menopausal changes 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 PREMPRO or PREMPHASE 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. Weight-bearing exercise, like walking or running, and taking calcium (1500 mg per day of elemental calcium) and vitamin (400-800 IU per day) supplements may also lower your chances of getting postmenopausal osteoporosis. It is important to talk about exercise and supplements with your healthcare provider before starting them.You and your healthcare provider should talk regularly about whether you still need treatment with PREMPRO or PREMPHASE. Have unusual vaginal bleeding. Currently have or have had certain cancersEstrogens 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 use PREMPRO or PREMPHASE.. Had stroke or heart attack. Currently have or have had blood clots. Currently have or have had liver problems. Have been diagnosed with bleeding disorder. Are allergic to PREMPRO or PREMPHASE or any of their ingredientsSee the list of ingredients in PREMPRO and PREMPHASE at the end of this leaflet.. Think you may be pregnant. If you have any unusual vaginal bleedingVaginal 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.. About all of your medical problemsYour healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.. About all the medicines you takeThis includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how PREMPRO or PREMPHASE works. PREMPRO or PREMPHASE may also affect how your other medicines work. If you are going to have surgery or will be on bedrestYou may need to stop taking PREMPRO or PREMPHASE.. If you are breastfeedingThe hormones in PREMPRO and PREMPHASE can pass into your breast milk.. Take one PREMPRO or PREMPHASE tablet at the same time each day. If you miss dose, take it as soon as possibleIf 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 neededYou 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 PREMPRO or PREMPHASE.. Heart attack. Stroke. Blood clots. Dementia. Breast cancer. Cancer of the lining of the uterus (womb). Cancer of the ovary. High blood pressure. High blood sugar. Gallbladder disease. Liver problems. Enlargement of benign tumors of the uterus (fibroids). Mental depression. Severe allergic reaction. New breast lumps. Unusual vaginal bleeding Changes in vision or speech. Sudden new severe headaches. Severe pains in your chest or legs with or without shortness of breath, weakness and fatigue. Swollen lips, tongue and face. Headache. Breast pain. Irregular vaginal bleeding or spotting Stomach or abdominal cramps, bloating. Nausea and vomiting Hair loss. Fluid retention. Vaginal yeast infection. Talk with your healthcare provider regularly about whether you should continue taking PREMPRO or PREMPHASE. See your healthcare provider right away if you get vaginal bleeding while taking PREMPRO or PREMPHASE. Have pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something elseIf 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 diseaseAsk your healthcare provider for ways to lower your chances of getting heart disease.. Logo.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Estrogens increase the risk of gallbladder disease (5.4)Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs (5.5, 5.6, 5.9, 5.10)Monitor thyroid function in women on thyroid replacement therapy (5.11, 5.19). Estrogens increase the risk of gallbladder disease (5.4). Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs (5.5, 5.6, 5.9, 5.10). Monitor thyroid function in women on thyroid replacement therapy (5.11, 5.19). 5.1 Cardiovascular Disorders. An increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin therapy. An increased risk of stroke and DVT has been reported with estrogen-alone therapy. Should any of these occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately.Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.. StrokeIn the WHI estrogen plus progestin substudy, statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years) [see Clinical Studies (14.6)]. The increase in risk was demonstrated after the first year and persisted.1 Should stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.In the WHI estrogen-alone substudy, statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year and persisted [see Clinical Studies (14.6)]. Should stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately.Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years).1 Coronary Heart DiseaseIn the WHI estrogen plus progestin substudy, there was statistically non-significant increased risk of coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years).1 An increase in relative risk was demonstrated in year 1, and trend toward decreasing relative risk was reported in years through [see Clinical Studies (14.6)].In the WHI estrogen-alone substudy, no overall effect on CHD events was reported in women receiving estrogen-alone compared to placebo2 [see Clinical Studies (14.6)].Subgroup analyses of women 50 to 59 years of age suggest statistically non-significant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years).1 In postmenopausal women with documented heart disease (n 2,763), average 66.7 years of age, in controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study [HERS]), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus 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 plus MPA-treated group than in the placebo group in year 1, but not during 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 plus MPA group and the placebo group in HERS, HERS II, and overall.. Venous Thromboembolism In the WHI estrogen plus progestin substudy, statistically significant 2-fold greater rate of VTE (DVT and PE) was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving 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 persisted3 [see Clinical Studies (14.6)]. Should VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.In the WHI estrogen-alone substudy, the risk of VTE was increased for women receiving daily CE (0.625 mg)-alone 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 years4 [see Clinical Studies (14.6)]. Should VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately.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.. 5.2 Malignant Neoplasms. Breast CancerThe most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus 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, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA 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 versus 25 cases per 10,000 women-years, for CE plus 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 CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) 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 groups5 [see Clinical Studies (14.6)].The most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the WHI substudy of daily CE (0.625 mg)-alone. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE (0.625 mg)-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80] [see Clinical Studies (14.6)].Consistent with the WHI clinical trials, 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.. Endometrial CancerEndometrial hyperplasia (a possible precursor of endometrial cancer) has been reported to occur at rate of approximately percent or less with PREMPRO or PREMPHASE.An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in woman with uterus. The reported endometrial cancer risk among unopposed estrogen users 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 use of estrogens for less than year. The greatest risk appears to be 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-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital 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 estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be precursor to endometrial cancer.. Ovarian CancerThe WHI estrogen plus progestin substudy reported statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77-3.24). The absolute risk for CE plus MPA versus placebo was versus cases per 10,000 women-years.7 meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risks associated with current use of hormonal therapy was 1.41 (95% confidence interval [CI] 1.32 to 1.50); there was no difference in the risk estimates by duration of the exposure (less than years [median of years] vs. greater than years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within years before cancer diagnosis) was 1.37 (95% CI 1.27-1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.. 5.3 Probable Dementia. In the WHIMS estrogen plus progestin ancillary study of WHI, population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo.After an average follow-up of years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years8 [see Use in Specific Populations (8.5), and Clinical Studies (14.7)].In the WHIMS estrogen-alone ancillary study of WHI, population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo.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-years8 [see Use in Specific Populations (8.5), and Clinical Studies (14.7)].When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies 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 ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 [see Use in Specific Populations (8.5), and Clinical Studies (14.7)].. 5.4 Gallbladder Disease. 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.. 5.5 Hypercalcemia. Estrogen administration may lead to severe hypercalcemia in women 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.. 5.6 Visual Abnormalities. Retinal vascular thrombosis has been reported in women 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.. 5.7 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 an increased risk of breast cancer.. 5.8 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.. 5.9 Hypertriglyceridemia. In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs.. 5.10 Hepatic Impairment and/or Past History of Cholestatic Jaundice. Estrogens may be poorly metabolized in women with impaired liver function. For women 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.. 5.11 Hypothyroidism. Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women 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. Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.. 5.12 Fluid Retention. Estrogens plus progestins may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogens plus progestins are prescribed.. 5.13 Hypocalcemia. Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.. 5.14 Exacerbation of Endometriosis. few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.. 5.15 Anaphylactic Reaction and Angioedema. Cases of anaphylaxis, which developed within minutes to hours after taking PREMPRO or PREMPHASE and require emergency medical management, have been reported in the postmarketing setting. Skin (hives, pruritis, swollen lips-tongue-face) and either respiratory tract (respiratory compromise) or gastrointestinal tract (abdominal pain, vomiting) involvement has been noted.Angioedema involving the tongue, larynx, face, hands, and feet requiring medical intervention has occurred postmarketing in patients taking PREMPRO or PREMPHASE. If angioedema involves the tongue, glottis, or larynx, airway obstruction may occur. Patients who develop an anaphylactic reaction with or without angioedema after treatment with PREMPRO or PREMPHASE should not receive PREMPRO or PREMPHASE again.. 5.16 Hereditary Angioedema. Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.. 5.17 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.. 5.18 Laboratory Tests Serum follicle stimulating hormone (FSH) 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.. 5.19 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 antifactor 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) leading to increased circulating total thyroid hormone, 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. Women on thyroid replacement therapy may require higher doses of thyroid hormone.Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentrations, increased triglyceride levels.Impaired glucose tolerance.