|
Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women a significant proportion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a 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. Text Continues Below
Excretion Estradiol, 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. Special Populations No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment. Drug Interactions Data from a single-dose drug-drug interaction study involving conjugated estrogens and medroxyprogesterone acetate indicate that the pharmacokinetic disposition of both drugs is not altered when the drugs are coadministered. No other clinical drug-drug interaction studies have been conducted with conjugated estrogens. In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John's Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/ or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects. Clinical Studies Effects on vasomotor symptoms.
In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, a total of 2805 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 a subset of symptomatic women (n = 241) who had at least 7 moderate to severe hot flushes daily or at least 50 moderate to severe hot flushes during the week before randomization. PREMPRO 0.625 mg/ 2.5 mg, 0.45 mg/ 1.5 mg, and 0.3 mg/ 1.5 mg were shown to be statistically better than placebo at weeks 4 and 12 for relief of both the frequency and severity of moderate to severe vasomotor symptoms. Table 3 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 3: 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 7 MODERATE TO SEVERE FLUSHES PER DAY OR AT LEAST 50 PER WEEK AT BASELINE, LOCF Treatment a
(No. of Patients)
---------------No. of Hot Flushes/ Day ------------------
Time Period
(week)
Baseline
Mean ± SD
Observed
Mean ± SD
Mean
Change ± SD
p-Values
vs. Placebo b
0.625 mg/ 2. 5 mg
(n = 34)
4 11.98 ± 3. 54 3.19 ± 3.74 -8. 78 ± 4.72 < 0.001
12 11.98 ± 3. 54 1.16 ± 2.22 -10.82 ± 4.61 < 0.001
0.45mg/ 1.5mg
(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 PREMPRO PREMPHASE Premarin
0. 625 mg/ 2. 5 mg 0.625 mg/ 5 mg 0.625 mg/ 5 mg 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
--------------------------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 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. FIGURE 1. PATIENTS WITH CUMULATIVE AMENORRHEA OVER TIME PERCENTAGES OF WOMEN WITH NO BLEEDING OR SPOTTING AT A GIVEN CYCLE THROUGH CYCLE 13 INTENT-TO-TREAT POPULATION, 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). FIGURE 2. PATIENTS WITH CUMULATIVE AMENORRHEA OVER TIME PERCENTAGES OF WOMEN WITH NO BLEEDING OR SPOTTING AT A GIVEN CYCLE THROUGH CYCLE 13 INTENT-TO-TREAT POPULATION, 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 (L2 to L4). Secondarily, BMD measurements of the total body, femoral neck, and trochanter were also analyzed. Serum osteocalcin, urinary calcium, and N-telopeptide were used as bone turnover markers (BTM) at cycles 6, 13, 19, and 26.
Intent-to-treat subjects All active treatment groups showed significant differences from placebo in each of the 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 (L2 to L4 BMD) at the final on-therapy evaluation (cycle 26 for those who completed and the last available evaluation for those who discontinued early) were 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 L2 to L4 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 L2 to L4 and changes in femoral neck and total body that were generally smaller than those seen for L2 to L4. Significant differences between groups indicated that each of the 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 L2 to L4 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. FIGURE 3. CUMULATIVE PERCENT OF SUBJECTS WITH CHANGES FROM BASELINE IN SPINE BMD OF GIVEN MAGNITUDE OR GREATER IN PREMARIN/ MPA AND PLACEBO GROUPS The 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 PLACEBO 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 equine 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 PREMPRO 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 PREMPRO SUBSTUDY OF WHI a
Placebo
n = 8102
PREMPRO
n = 8506
Event c Relative Risk
PREMPRO vs Placebo
at 5.2 Years
(95% CI*) Absolute Risk per 10,000 Person-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. For those outcomes included in the "global index", absolute excess risks per 10,000 person-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 absolute risk reductions per 10,000 person-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 person-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNING, WARNINGS and PRECAUTIONS.) Page: << Prev | 1 | 2 | 3 | 4 | 5
|
.gif)
