PROGESTERONE — progesterone capsule
Aurobindo Pharma Limited
WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER and PROBABLE DEMENTIA FOR ESTROGEN PLUS PROGESTIN THERAPY
Cardiovascular Disorders and Probable Dementia
The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of deep vein thrombosis, pulmonary embolism, stroke and myocardial infarction in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders.)
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 4 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 CLINICAL STUDIES and WARNINGS, Probable dementia and PRECAUTIONS, Geriatric Use.)
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.
Progestins with estrogens should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
Progesterone capsules contain micronized progesterone for oral administration. Progesterone has a molecular weight of 314.47 and a molecular formula of C21 H30 O2 . Progesterone (pregn-4-ene-3, 20-dione) is a white or creamy white, crystalline powder or colorless crystals practically insoluble in water, soluble in alcohol, acetone and dioxane and sparingly soluble in vegetable oils, melting between 126º and 131ºC. The structural formula is:
Progesterone is synthesized from a starting material from a plant source and is chemically identical to progesterone of human ovarian origin. Progesterone capsules are available in multiple strengths to afford dosage flexibility for optimum management. Progesterone capsules contain 100 mg or 200 mg micronized progesterone USP. The inactive ingredients for progesterone capsules include: gelatin, glycerin, hypromellose, iron oxide black, lecithin, peanut oil, propylene glycol, titanium dioxide.
Progesterone 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.
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 progesterone capsules 100 mg as a micronized soft-gelatin capsule formulation.
|a Mean ± S.D.|
|Parameter||Progesterone 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|
Serum progesterone concentrations appeared linear and dose proportional following multiple dose administration of progesterone 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.
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).
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.
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.
E. Special Populations
The pharmacokinetics of progesterone capsules have not been assessed in low body weight or obese patients.
Hepatic Insufficiency: The effect of hepatic impairment on the pharmacokinetics of progesterone capsules has not been studied.
Renal Insufficiency: The effect of renal impairment on the pharmacokinetics of progesterone capsules has not been studied.
F. Food–Drug Interaction
Concomitant food ingestion increased the bioavailability of progesterone capsules relative to a fasting state when administered to postmenopausal women at a dose of 200 mg.
G. 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. Coadministration of conjugated estrogens and progesterone 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 progesterone capsules. Table 2 summarizes the pharmacokinetic parameters.
|a Total estrogens is the sum of conjugated and unconjugated estrogen.|
|Conjugated Estrogens||Conjugated Estrogens plus Progesterone Capsules|
|Drug||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 Total a||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 Total a||2.27 ± 0.95||6.0 ± 4.0||28.8 ± 13.0||3.22 ± 1.13||5.3 ± 2.6||38.1 ± 20.2|
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