DEPO-SUBQ PROVERA 104™ (medroxyprogesterone acetate injectable suspension) 104 mg/0.65
mL Clinical Pharmacology
depo-subQ provera 104™ (medroxyprogesterone acetate injectable
suspension), when administered at 104 mg/0.65 mL to women every 3 months (12 to
14 weeks), inhibits the secretion of gonadotropins, which prevents follicular maturation
and ovulation and causes endometrial thinning. These actions produce its contraceptive
effect.
Supression of serum estradiol concentrations and a possible direct action of depo-subQ
provera 104 on the lesions of endometriosis are likely to be responsible for the
therapeutic effect on endometriosis-associated pain.
Pharmacokinetics
The pharmacokinetic parameters of medroxyprogesterone acetate (MPA) following a
single SC injection of depo-subQ provera 104 are shown in Table 1 and Figure 1.
Table 1. Pharmacokinetic Parameters of MPA after a Single SC Injection of depo-subQ
provera 104 in Healthy Women (n = 42)
Absorption: Following a single SC injection of depo-subQ provera 104™,
serum MPA concentrations reach ≥ 0.2 ng/mL within 24 hours. The mean Tmax
is attained approximately 1 week after injection.
Figure 1. Mean (SD) Serum Concentration-Time Profile of MPA after a Single Injection
of depo-subQ provera 104 to Healthy Women
In a study to assess accumulation and the achievement of steady state following
multiple SC administrations, trough concentrations of MPA were determined after
6, 12, and 24 months, and in a subset of 8 subjects, bi-weekly concentrations were
determined within one dosing interval in the second year of administration. The
mean (SD) MPA trough concentrations were 0.67 (0.36) ng/mL (n=157), 0.79 (0.36)
ng/mL (n= 144), and 0.87 (0.33) ng/mL (n= 106) at 6, 12 and 24 months, respectively.
Effect of Injection Site: depo-subQ provera 104™
was administered into the anterior thigh or the abdomen to evaluate effects on the
MPA concentration-time profile. MPA trough concentrations (Cmin;
Day 91) were similar for the two injection locations.
Distribution: Plasma protein binding of MPA averages 86%. MPA binding
occurs primarily to serum albumin. No binding of MPA occurs with sex-hormone-binding
globulin (SHBG).
Metabolism: MPA is extensively metabolized in the liver by P450 enzymes.
Its metabolism primarily involves ring A and/or side-chain reduction, loss of the
acetyl group, hydroxylation in the 2-, 6-, and 21-positions or a combination of
these positions, resulting in more than 10 metabolites.
Excretion: Residual MPA concentrations at the end of the first dosing
interval (12 to 14 weeks) of depo-subQ provera 104 are generally below 0.5 ng/mL,
consistent with its apparent terminal half-life of ~40 days after SC administration.
Most MPA metabolites are excreted in the urine as glucuronide conjugates with only
small amounts excreted as sulfates.
Linearity/Non-Linearity: Following a single SC administration of doses
ranging from 50 to 150 mg, the AUC and Cmin (Day 91) increased
with higher doses of depo-subQ provera 104, but there was considerable overlap across
dose levels. Serum MPA concentrations at Day 91 increased in a dose proportional
manner but Cmax did not appear to increase proportionally
with increasing dose. The AUC data were suggestive of dose linearity.
Special Populations
Race: There were no significant differences in the pharmacokinetics
and/or pharmacodynamics of MPA after SC administration of depo-subQ provera 104
in African-American and Caucasian women. The pharmacokinetics/pharmacodynamics of
depo-subQ provera 104 were evaluated in Asian women in a separate study and also
found to be similar to African/American and Caucasian women.
Effect of Body Weight: Although total MPA exposure was lower in obese
women, no dosage adjustment of depo-subQ provera 104™
is necessary based on body weight. The effect of body weight on the pharmacokinetics
of MPA following a single dose was assessed in a subset of women (n = 42, body mass
index [BMI] ranged from 18.2 to 46.7 kg/m2). The AUC0-91
values for MPA were 71.6, 67.9, and 46.3 ng•day/mL in women with BMI categories
of ≤ 28 kg /m2, >28-38 kg/m2,
and >38 kg/m2, respectively. The mean MPA Cmax
was 1.74 ng/mL in women with BMI ≤ 28 kg/m2, 1.53 ng/mL
in women with BMI >28-38 kg/m2, and 1.02 ng/mL in women
with BMI > 38 kg/m2, respectively. The MPA trough (Cmin)
concentrations had a tendency to be lower in women with BMI >38 kg/m2.
Hepatic Insufficiency: No clinical studies have evaluated the effect
of hepatic disease on the disposition of depo-subQ provera 104™.
However, steroid hormones may be poorly metabolized in patients with severe liver
dysfunction (see CONTRAINDICATIONS).
Renal Insufficiency: No clinical studies have evaluated the effect
of renal disease on the pharmacokinetics of depo-subQ provera 104™.
Drug-Drug Interactions
See PRECAUTIONS, section 9.