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Prometrium

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Prometrium

CLINICAL PHARMACOLOGY

PROMETRIUM Capsules are an oral dosage form of micronized progesterone which is chemically identical to progesterone of ovarian origin. The oral bioavailability of progesterone is increased through micronization.

Pharmacokinetics

Absorption

After oral administration of progesterone as a micronized soft-gelatin capsule formulation, maximum serum concentrations were attained within 3 hours. The absolute bioavailability of micronized progesterone is not known. Table 1 summarizes the mean pharmacokinetic parameters in postmenopausal women after five oral daily doses of PROMETRIUM Capsules 100 mg as a micronized soft-gelatin capsule formulation.

TABLE 1: Pharmacokinetic Parameters of PROMETRIUM Capsules

Parameter PROMETRIUM Capsules Daily Dose
100 mg 200 mg 300 mg
Cmax(ng/mL) 17.3 ± 21.9a 38.1 ± 37.8 60.6 ± 72.5
Tmax(hr) 1.5 ± 0.8 2.3 ± 1.4 1.7 ± 0.6
AUC(0-10) (ng hr/mL) 43.3 ± 30.8 101.2 ± 66.0 175.7 ± 170.3
aMean ± S.D.

Serum progesterone concentrations appeared linear and dose proportional following multiple dose administration of PROMETRIUM Capsules 100 mg over the dose range 100 mg per day to 300 mg per day in postmenopausal women. Although doses greater than 300 mg per day were not studied in females, serum concentrations from a study in male volunteers appeared linear and dose proportional between 100 mg per day and 400 mg per day. The pharmacokinetic parameters in male volunteers were generally consistent with those seen in postmenopausal women.

Distribution

Progesterone is approximately 96 percent to 99 percent bound to serum proteins, primarily to serum albumin (50 to 54 percent) and transcortin (43 to 48 percent).

Metabolism

Progesterone is metabolized primarily by the liver largely to pregnanediols and pregnanolones. Pregnanediols and pregnanolones are conjugated in the liver to glucuronide and sulfate metabolites. Progesterone metabolites which are excreted in the bile may be deconjugated and may be further metabolized in the intestine via reduction, dehydroxylation, and epimerization.

Excretion

The glucuronide and sulfate conjugates of pregnanediol and pregnanolone are excreted in the bile and urine. Progesterone metabolites are eliminated mainly by the kidneys. Progesterone metabolites which are excreted in the bile may undergo enterohepatic recycling or may be excreted in the feces.

Special Populations

The pharmacokinetics of PROMETRIUM Capsules have not been assessed in low body weight or obese patients.

Hepatic Insufficiency: The effect of hepatic impairment on the pharmacokinetics of PROMETRIUM Capsules has not been studied.

Renal Insufficiency: The effect of renal impairment on the pharmacokinetics of PROMETRIUM Capsules has not been studied.

Food–Drug Interaction

Concomitant food ingestion increased the bioavailability of PROMETRIUM Capsules relative to a fasting state when administered to postmenopausal women at a dose of 200 mg.

Drug Interactions

The metabolism of progesterone by human liver microsomes was inhibited by ketoconazole (IC50 < 0.1 μM). Ketoconazole is a known inhibitor of cytochrome P450 3A4, hence these data suggest that ketoconazole or other known inhibitors of this enzyme may increase the bioavailability of progesterone. The clinical relevance of the in vitro findings is unknown.

Co administration of conjugated estrogens and PROMETRIUM Capsules to 29 postmenopausal women over a 12-day period resulted in an increase in total estrone concentrations (Cmax 3.68 ng/mL to 4.93 ng/mL) and total equilin concentrations (Cmax 2.27 ng/mL to 3.22 ng/mL) and a decrease in circulating 17β estradiol concentrations (Cmax 0.037 ng/mL to 0.030 ng/mL). The half-life of the conjugated estrogens was similar with coadministration of PROMETRIUM Capsules. Table 2 summarizes the pharmacokinetic parameters.

TABLE 2: Mean (± S.D.) Pharmacokinetic Parameters for Estradiol, Estrone, and Equilin Following Coadministration of Conjugated Estrogens 0.625 mg and PROMETRIUM Capsules 200 mg for 12 Days to Postmenopausal Women

Drug Conjugated Estrogens Conjugated Estrogens plus PROMETRIUM Capsules
Cmax (ng/mL) Tmax (hr) AUC(0-24h) (ng h/mL) Cmax (ng/mL) Tmax (hr) AUC(0-24h) (ng h/mL)
Estradiol 0.037±0.048 12.7±9.1 0.676±0.737 0.030±0.032 17.32±1.21 0.561± 0.572
Estrone Totala 3.68±1.55 10.6±6.8 61.3±26.36 4.93±2.07 7.5±3.8 85.9± 41.2
Equilin Totala 2.27±0.95 6.0±4.0 28.8±13.0 3.22±1.13 5.3±2.6 38.1± 20.2
a Total estrogens is the sum of conjugated and unconjugated estrogen.

Clinical Studies

Effects on the endometrium

In a randomized, double-blind clinical trial, 358 postmenopausal women, each with an intact uterus, received treatment for up to 36 months. The treatment groups were: PROMETRIUM Capsules at the dose of 200 mg per day for 12 days per 28-day cycle in combination with conjugated estrogens 0.625 mg per day (n=120); conjugated estrogens 0.625 mg per day only (n=119); or placebo (n=119). The subjects in all three treatment groups were primarily Caucasian women (87 percent or more of each group). The results for the incidence of endometrial hyperplasia in women receiving up to 3 years of treatment are shown in Table 3. A comparison of the PROMETRIUM Capsules plus conjugated estrogens treatment group to the conjugated estrogens only group showed a significantly lower rate of hyperplasia (6 percent combination product versus 64 percent estrogen alone) in the PROMETRIUM Capsules plus conjugated estrogens treatment group throughout 36 months of treatment.

TABLE 3: Incidence of Endometrial Hyperplasia in Women Receiving 3 Years of Treatment

Endometrial Diagnosis Treatment Group
Conjugated Estrogens 0.625 mg + PROMETRIUM Capsules 200 mg (cyclical) Conjugated Estrogens 0.625 mg (alone) Placebo
Number of patients % of patients Number of patients % of patients Number of patients % of patients
n=117 n=115 n=116
HYPERPLASIAa 7 6 74 64 3 3
  Adenocarcinoma 0 0 0 0 1 1
  Atypical hyperplasia 1 1 14 12 0 0
  Complex hyperplasia 0 0 27 23 1 1
  Simple hyperplasia 6 5 33 29 1 1
a Most advanced result to least advanced result:
Adenocarcinoma > atypical hyperplasia > complex hyperplasia > simple hyperplasia

The times to diagnosis of endometrial hyperplasia over 36 months of treatment are shown in Figure 1. This figure illustrates graphically that the proportion of patients with hyperplasia was significantly greater for the conjugated estrogens group (64 percent) compared to the conjugated estrogens plus PROMETRIUM Capsules group (6 percent).

Figure 1: Time to Hyperplasia in Women Receiving up to 36 Months of Treatment

Time to Hyperplasia in Women - Illustration

The discontinuation rates due to hyperplasia over the 36 months of treatment are as shown in Table 4. For any degree of hyperplasia, the discontinuation rate for patients who received conjugated estrogens plus PROMETRIUM Capsules was similar to that of the placebo only group, while the discontinuation rate for patients who received conjugated estrogens alone was significantly higher. Women who permanently discontinued treatment due to hyperplasia were similar in demographics to the overall study population.

TABLE 4: Discontinuation Rate Due to Hyperplasia Over 36 Months of Treatment

Most Advanced Biopsy Result Through 36 Months of Treatment Treatment Group
Conjugated Estrogens + PROMETRIUM Capsules (cyclical) Conjugated Estrogens (alone) Placebo
n=120 n=119 n=119
Number of patients % of patients Number of patients % of patients Number of patients % of patients
Adenocarcinoma 0 0 0 0 1 1
Atypical hyperplasia 1 1 10 8 0 0
Complex hyperplasia 0 0 21 18 1 1
Simple hyperplasia 1 1 13 11 0 0

Effects on secondary amenorrhea

In a single-center, randomized, double-blind clinical study that included premenopausal women with secondary amenorrhea for at least 90 days, administration of 10 days of PROMETRIUM Capsules therapy resulted in 80 percent of women experiencing withdrawal bleeding within 7 days of the last dose of PROMETRIUM Capsules, 300 mg per day (n=20), compared to 10 percent of women experiencing withdrawal bleeding in the placebo group (n=21).

In a multicenter, parallel-group, open label, postmarketing dosing study that included premenopausal women with secondary amenorrhea for at least 90 days, administration of 10 days of PROMETRIUM Capsules during two 28-day treatment cycles, 300 mg per day (n=107) or 400 mg per day (n=99), resulted in 73.8 percent and 76.8 percent of women, respectively, experiencing withdrawal bleeding.

The rate of secretory transformation was evaluated in a multicenter, randomized, double-blind clinical study in estrogen-primed postmenopausal women. PROMETRIUM Capsules administered orally for 10 days at 400 mg per day (n=22) induced complete secretory changes in the endometrium in 45 percent of women compared to 0 percent in the placebo group (n=23).

A second multicenter, parallel-group, open label postmarketing dosing study in premenopausal women with secondary amenorrhea for at least 90 days also evaluated the rate of secretory transformation. All subjects received daily oral conjugated estrogens over 3 consecutive 28-day treatment cycles and PROMETRIUM Capsules, 300 mg per day (n=107) or 400 mg per day (n=99) for 10 days of each treatment cycle. The rate of complete secretory transformation was 21.5 percent and 28.3 percent, respectively.

Women's Health Initiative Studies

The Women's Health Initiative (WHI) enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral conjugated estrogens (CE) [0.625 mg]-alone or in combination with medroxyprogesterone acetate (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 myocardial infarction (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, pulmonary embolism (PE), endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. These sub studies 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 breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” The absolute excess risk of events 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 reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures.

Results of the estrogen plus progestin 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 5. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

TABLE 5: Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Yearsa, b

Event Relative Risk CE/MPA versus Placebo (95% nCIc) CE/MPA
n = 8,506
Placebo
n = 8,102
Absolute 10,000 Risk per Women-Years
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 stroke 1.31 (1.03-1.88) 33 25
  Ischemic stroke 1.44 (1.09-1.90) 26 18
Deep vein thrombosisd 1.95 (1.43-2.67) 26 13
Pulmonary embolism 2.13 (1.45-3.11) 18 8
Invasive breast cancere 1.24 (1.01-1.54) 41 33
Colorectal cancer 0.61 (0.42-0.87) 10 16
Endometrial cancerd 0.81 (0.48-1.36) 6 7
Cervical cancerd 1.44 (0.47-4.42) 2 1
Hip fracture 0.67 (0.47-0.96) 11 16
Vertebral fracturesd 0.65 (0.46-0.92) 11 17
Lower arm/wrist fracturesd 0.71 (0.59-0.85) 44 62
Total fracturesd 0.76 (0.69-0.83) 152 199
Overall mortalityf 1.00 (0.83-1.19) 52 52
Global Indexg 1.13 (1.02-1.25) 184 165
a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi.
b Results are based on centrally adjudicated data.
c Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
d Not included in Global Index.
e Includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer.
f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease.
g 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.

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 for age showed in women 50 to 59 years of age a non-significant trend toward reducing risk of overall mortality [hazard ratio (HR) 0.69 (95 percent CI, 0.44-1.07)].

Women's Health Initiative Memory Study

The estrogen plus progestin Women's Health Initiative Memory Study (WHIMS), an 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 4 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 per 10,000 women-years. Probable dementia as defined in this study included Alzheimer's disease (AD), vascular dementia (VaD) and mixed type (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, Probable dementia and PRECAUTIONS, Geriatric Use.)

Last reviewed on RxList: 1/19/2012
This monograph has been modified to include the generic and brand name in many instances.

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