Support for treatment of vasomotor symptoms and vaginal and vulvar atrophy was shown through bioequivalence of the E2 component of the combination product with a currently marketed E2 product (Estrace®). The multiple-dose bioequivalence study evaluated the bioequivalence of E2 from a tablet containing DRSP (2 mg) and E2 (1 mg) relative to Estrace (1 mg) tablet. DRSP/E2 tablets met the criteria for bioequivalence to Estrace.
In a one year clinical trial of 1,142 postmenopausal subjects treated with E2 alone or E2 + 0.5, 1, 2, or 3 mg DRSP, endometrial biopsies were performed on 966 (84.6%) subjects during the treatment period. Eight subjects in the E2 monotherapy group developed endometrial hyperplasia (4 simple hyperplasia with no cytological atypia, 3 complex hyperplasia with no cytological atypia, and 1 complex hyperplasia with cytological atypia), and one subject in the 1 mg E2 + 2 mg DRSP group developed simple hyperplasia with no cytological atypia. Table 2 shows that there were no diagnoses of endometrial hyperplasia in the ANGELIQ group.
E2 1 mg
|Total No. Subjects||226||227|
Total No. ofOn-Treatment Biopsies
|Hyperplasia||8 (4.0%)||0 (0%)|
In a cumulative analysis performed over 12 months in a double blind trial, the proportions of women with amenorrhea increased and at one year, 73.5% of subjects on ANGELIQ had amenorrhea. Results are shown in Figure 2.
Figure 2: Cumulative proportion of subjects with amenorrhea at a given cycle through cycle 13, LOCF
The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of 0.625 mg conjugated equine estrogens (CE) per day alone or the use of 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) 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 CE or CE/MPA on menopausal symptoms.
The CE/MPA sub-study 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 of the CE/MPA sub-study, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 3 below:
|Eventc||Relative Risk CE/MPA vs placebo at 5.2 Years (95% CI)|
n = 8506
Absolute Risk per
|Invasive breast cancer||1.26 (1.00–1.59)||30||38|
|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||1.15 (1.03–1.28)||151||170|
|Deep vein thrombosis *||2.07 (1.49–2.87)||13||26|
|Vertebral fractures *||0.66 (0.44–0.98)||15||9|
|Other osteoporotic fractures *||0.77 (0.69–0.86)||170||131|
For those outcomes included in the “global index,” absolute excess risks per 10,000 person-years in the group treated with CE/MPA 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 Warnings , Warnings, and Precautions.)
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