Medroxyprogesterone Acetate (Page 2 of 6)

F. Drug Interactions

Medroxyprogesterone acetate (MPA) is metabolized in-vitro primarily by hydroxylation via the CYP3A4. Specific drug-drug interaction studies evaluating the clinical effects with CYP3A4 inducers or inhibitors on MPA have not been conducted. Inducers and/or inhibitors of CYP3A4 may affect the metabolism of MPA.

CLINICAL STUDIES

Effects on the Endometrium

In a 3-year, double-blind, placebo-controlled study of 356 nonhysterectomized, postmenopausal women between 45 and 64 years of age randomized to receive placebo (n=119), 0.625 mg conjugated estrogen only (n=119), or 0.625 mg conjugated estrogen plus cyclic MPA (n=118), results showed a reduced risk of endometrial hyperplasia in the treatment group receiving 10 mg MPA plus 0.625 mg conjugated estrogens compared to the group receiving 0.625 mg conjugated estrogens only. See Table 2.

Table 2. Number (%) of Endometrial Biopsy Changes Since Baseline After 3 Years of Treatment *
Histological Results Placebo(n=119) CEE (n=119) MPA + CEE(n=118)
*
Includes most extreme abnormal result
CEE = conjugated equine estrogens 0.625 mg/day
MPA = medroxyprogesterone acetate tablets 10 mg/day for 12 days
Normal/No hyperplasia (%) 116 (97) 45 (38) 112 (95)
Simple (cystic) hyperplasia (%) 1 (1) 33 (28) 4 (3)
Complex (adenomatous) hyperplasia (%) 1 (1) 27 (22) 2 (2)
Atypia (%) 0 14 (12) 0
Adenocarcinoma (%) 1 (1) 0 0

In a second 1-year study, 832 postmenopausal women between 45 and 65 years of age were treated with daily 0.625 mg conjugated estrogen (days 1–28), plus either 5 mg cyclic MPA or 10 mg cyclic MPA (days 15–28), or daily 0.625 mg conjugated estrogen only. The treatment groups receiving 5 or 10 mg cyclic MPA (days 15–28) plus daily conjugated estrogens showed a significantly lower rate of hyperplasia as compared to the conjugated estrogens only group. See Table 3.

Table 3. Number (%) of Women with Endometrial Hyperplasia at 1 Year
CEE * MPA + CEE *
(n=283) MPA 5 mg(n=277) MPA 10 mg(n=272)
*
CEE = conjugated equine estrogen 0.625 mg every day of a 28-day cycle.
Cyclic medroxyprogesterone acetate on days 15 to 28
Cystic hyperplasia (%) 55 (19) 3 (1) 0
Adenomatous hyperplasia without atypia 2 (1) 0 0

Women’s 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 coronary heart disease (CHD) (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A “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 cause. These substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms.

WHI Estrogen Plus Progestin Substudy

The 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 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reduction per 10,000 women-years were 6 fewer colorectal cancers and 5 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 4. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

Table 4 : RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS PROGESTIN SUBSTUDY OF WHI AT AN AVERAGE OF 5.6 YEARS *,
Event Relative RiskCE/MPA vs placebo(95%nCI ) CE/MPAn = 8,506 Placebon = 8,102
Absolute Risk per 10,000 Women-Years
*
Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi.
Results are based on centrally adjudicated data.
Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
§
Not included in “global index”.
Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer.
#
All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease.
Þ
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, colorectal cancer, hip fracture, or death due to other causes.
CHD events 1.23 (0.99–1.53) 41 34
Non-fatal MI 1.28 (1.00–1.63) 31 25
CHD death 1.10 (0.70–1.75) 8 8
All strokes 1.31 (1.03–1.68) 33 25
Ischemic stroke 1.44 (1.09–1.90) 26 18
Deep vein thrombosis § 1.95 (1.43–2.67) 26 13
Pulmonary embolism 2.13 (1.45–3.11) 18 8
Invasive breast cancer 1.24 (1.01–1.54) 41 33
Colorectal cancer 0.61 (0. 42–0.87) 10 16
Endometrial cancer § 0.81 (0.48–1.36) 6 7
Cervical cancer § 1.44 (0.47–4.42) 2 1
Hip fracture 0.67 (0.47–0.96) 11 16
Vertebral fractures § 0.65 (0.46–0.92) 11 17
Lower arm/wrist fractures § 0.71 (0.59–0.85) 44 62
Total fractures § 0.76 (0.69–0.83) 152 199
Overall mortality # 1.00 (0.83–1.19) 52 52
Global Index Þ 1.13 (1.02–1.25) 184 165

Timing 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 a nonsignificant trend toward reduced risk in overall mortality [hazard ration (HR) 0.69 (95 percent CI, 0.44–1.07)].

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