Medroxyprogesterone acetate (MPA) administered orally or parenterally in the recommended doses to women with adequate endogenous estrogen, transforms proliferative into secretory endometrium. Androgenic and anabolic effects have been noted, but the drug is apparently devoid of significant estrogenic activity. While parenterally administered MPA inhibits gonadotropin production, which in turn prevents follicular maturation and ovulation, available data indicate that this does not occur when the usually recommended oral dosage is given as single daily doses.
The pharmacokinetics of MPA were determined in 20 postmenopausal women following a single-dose administration of eight PROVERA 2.5 mg tablets or a single administration of two PROVERA 10 mg tablets under fasting conditions. In another study, the steady-state pharmacokinetics of MPA were determined under fasting conditions in 30 postmenopausal women following daily administration of one PROVERA 10 mg tablet for 7 days. In both studies, MPA was quantified in serum using a validated gas chromatography-mass spectrometry (GC-MS) method. Estimates of the pharmacokinetic parameters of MPA after single and multiple doses of PROVERA tablets were highly variable and are summarized in Table 1.
| Tablet Strength | C max (ng/mL) | T max (h) | Auc 0–(∞) (ng∙h/mL) | t 1/2 (h) | Vd/f (L) | CL/f (mL/min) |
|---|---|---|---|---|---|---|
| ||||||
Single Dose | ||||||
2 × 10 mg | 1.01 (0.599) | 2.65 (1.41) | 6.95 (3.39) | 12.1 (3.49) | 78024 | 64110 |
8 × 2.5 mg | 0.805 (0.413) | 2.22 (1.39) | 5.62 (2.79) | 11.6 (2.81) | 62748 | 74123 |
Multiple Dose | ||||||
10 mg * | 0.71 (0.35) | 2.83 (1.83) | 6.01 (3.16) | 16.6 (15.0) | 40564 | 41963 |
No specific investigation on the absolute bioavailability of MPA in humans has been conducted. MPA is rapidly absorbed from the gastrointestinal tract, and maximum MPA concentrations are obtained between 2 to 4 hours after oral administration.
Administration of PROVERA with food increases the bioavailability of MPA. A 10 mg dose of PROVERA, taken immediately before or after a meal, increased MPA Cmax (50 to 70%) and AUC (18 to 33%). The half-life of MPA was not changed with food.
MPA is approximately 90% protein bound, primarily to albumin; no MPA binding occurs with sex hormone binding globulin.
Following oral dosing, MPA is extensively metabolized in the liver via hydroxylation, with subsequent conjugation and elimination in the urine.
Most MPA metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates.
MPA is almost exclusively eliminated via hepatic metabolism. In 14 patients with advanced liver disease, MPA disposition was significantly altered (reduced elimination). In patients with fatty liver, the mean percent dose excreted in the 24-hour urine as intact MPA after a 10 mg or 100 mg dose was 7.3% and 6.4%, respectively.
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.
Medroxyprogesterone acetate (MPA) administered orally or parenterally in the recommended doses to women with adequate endogenous estrogen, transforms proliferative into secretory endometrium. Androgenic and anabolic effects have been noted, but the drug is apparently devoid of significant estrogenic activity. While parenterally administered MPA inhibits gonadotropin production, which in turn prevents follicular maturation and ovulation, available data indicate that this does not occur when the usually recommended oral dosage is given as single daily doses.
The pharmacokinetics of MPA were determined in 20 postmenopausal women following a single-dose administration of eight PROVERA 2.5 mg tablets or a single administration of two PROVERA 10 mg tablets under fasting conditions. In another study, the steady-state pharmacokinetics of MPA were determined under fasting conditions in 30 postmenopausal women following daily administration of one PROVERA 10 mg tablet for 7 days. In both studies, MPA was quantified in serum using a validated gas chromatography-mass spectrometry (GC-MS) method. Estimates of the pharmacokinetic parameters of MPA after single and multiple doses of PROVERA tablets were highly variable and are summarized in Table 1.
| Tablet Strength | C max (ng/mL) | T max (h) | Auc 0–(∞) (ng∙h/mL) | t 1/2 (h) | Vd/f (L) | CL/f (mL/min) |
|---|---|---|---|---|---|---|
| ||||||
Single Dose | ||||||
2 × 10 mg | 1.01 (0.599) | 2.65 (1.41) | 6.95 (3.39) | 12.1 (3.49) | 78024 | 64110 |
8 × 2.5 mg | 0.805 (0.413) | 2.22 (1.39) | 5.62 (2.79) | 11.6 (2.81) | 62748 | 74123 |
Multiple Dose | ||||||
10 mg * | 0.71 (0.35) | 2.83 (1.83) | 6.01 (3.16) | 16.6 (15.0) | 40564 | 41963 |
No specific investigation on the absolute bioavailability of MPA in humans has been conducted. MPA is rapidly absorbed from the gastrointestinal tract, and maximum MPA concentrations are obtained between 2 to 4 hours after oral administration.
Administration of PROVERA with food increases the bioavailability of MPA. A 10 mg dose of PROVERA, taken immediately before or after a meal, increased MPA Cmax (50 to 70%) and AUC (18 to 33%). The half-life of MPA was not changed with food.
MPA is approximately 90% protein bound, primarily to albumin; no MPA binding occurs with sex hormone binding globulin.
Following oral dosing, MPA is extensively metabolized in the liver via hydroxylation, with subsequent conjugation and elimination in the urine.
Most MPA metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates.
MPA is almost exclusively eliminated via hepatic metabolism. In 14 patients with advanced liver disease, MPA disposition was significantly altered (reduced elimination). In patients with fatty liver, the mean percent dose excreted in the 24-hour urine as intact MPA after a 10 mg or 100 mg dose was 7.3% and 6.4%, respectively.
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.
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