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Depo-Provera (Medroxyprogesterone Acetate) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Depo-Provera CI contains medroxyprogesterone acetate, a derivative of progesterone, as its active ingredient. Medroxyprogesterone acetate is active by the parenteral and oral routes of administration. It is a white to off-white; odorless crystalline powder that is stable in air and that melts between 200°C and 210°C. It is freely soluble in chloroform, soluble in acetone and dioxane, sparingly soluble in alcohol and methanol, slightly soluble in ether, and insoluble in water.

The chemical name for medroxyprogesterone acetate is pregn-4-ene-3,20-dione, 17-(acetyloxy)-6-methyl-, (6α-).

The structural formula is as follows:

Depo-Provera CI for intramuscular (IM) injection is available in vials and prefilled syringes, each containing 1 mL of medroxyprogesterone acetate sterile aqueous suspension 150 mg/mL.

For Depo-Provera CI vials, each mL of sterile aqueous suspension contains:
Medroxyprogesterone acetate 150 mg
Polyethylene glycol 3350 28.9 mg
Polysorbate 80 2.41 mg
Sodium chloride 8.68 mg
Methylparaben 1.37 mg
Propylparaben 0.150 mg
Water for injection quantity sufficient
When necessary, pH is adjusted with sodium hydroxide or hydrochloric acid, or both.
For Depo-Provera CI prefilled syringes, each mL of sterile aqueous suspension contains:
Medroxyprogesterone acetate 150 mg
Polyethylene glycol 3350 28.5 mg
Polysorbate 80 2.37 mg
Sodium chloride 8.56 mg
Methylparaben 1.35 mg
Propylparaben 0.147 mg
Water for injection quantity sufficient
When necessary, pH is adjusted with sodium hydroxide or hydrochloric acid, or both.

CLINICAL PHARMACOLOGY

Mechanism of Action

Depo-Provera CI (medroxyprogesterone acetate [MPA]), when administered at the recommended dose to women every 3 months, inhibits the secretion of gonadotropins which, in turn, prevents follicular maturation and ovulation and results in endometrial thinning. These actions produce its contraceptive effect.

Pharmacodynamics

No specific pharmacodynamic studies were conducted with Depo-Provera CI.

Pharmacokinetics

Absorption

Following a single 150 mg IM dose of Depo-Provera CI in eight women between the ages of 28 and 36 years old, medroxyprogesterone acetate concentrations, measured by an extracted radioimmunoassay procedure, increase for approximately 3 weeks to reach peak plasma concentrations of 1 to 7 ng/mL.

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

The concentrations of medroxyprogesterone acetate decrease exponentially until they become undetectable (<100 pg/mL) between 120 to 200 days following injection. Using an unextracted radioimmunoassay procedure for the assay of medroxyprogesterone acetate in serum, the apparent half-life for medroxyprogesterone acetate following IM administration of Depo-Provera CI is approximately 50 days. Most medroxyprogesterone acetate metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates.

Specific Populations

The effect of hepatic and/or renal impairment on the pharmacokinetics of Depo-Provera CI is unknown.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

[See Warnings and Precautions, (5.3, 5.14, and 5.16).]

CLINICAL STUDIES

Contraception

In five clinical studies using Depo-Provera CI, the 12-month failure rate for the group of women treated with Depo-Provera CI was zero (no pregnancies reported) to 0.7 by Life-Table method. The effectiveness of Depo-Provera CI is dependent on the patient returning every 3 months (13 weeks) for reinjection.

Bone Mineral Density (BMD) Changes in Adult Women

In a controlled, clinical study, adult women using Depo-Provera CI for up to 5 years showed spine and hip BMD mean decreases of 5–6%, compared to no significant change in BMD in the control group. The decline in BMD was more pronounced during the first two years of use, with smaller declines in subsequent years. Mean changes in lumbar spine BMD of -2.86%, -4.11%, -4.89%, -4.93% and -5.38% after 1, 2, 3, 4, and 5 years, respectively, were observed. Mean decreases in BMD of the total hip and femoral neck were similar.

After stopping use of Depo-Provera CI (150 mg), there was partial recovery of BMD toward baseline values during the 2-year post-therapy period. Longer duration of treatment was associated with less complete recovery during this 2-year period following the last injection. Table 4 shows the change in BMD in women after 5 years of treatment with Depo-Provera CI and in women in a control group, as well as the extent of recovery of BMD for the subset of the women for whom 2-year post treatment data were available.

Table 4. Mean Percent Change from Baseline in BMD in Adults by Skeletal Site and Cohort (5 Years of Treatment and 2 Years of Follow-Up)
Time in Study Spine Total Hip Femoral Neck
Depo-Provera 1 Control 2 Depo-Provera Control Depo-Provera Control
5 years -5.38%
n=33
0.43%
n=105
-5.16%
n=21
0.19%
n=65
-6.12%
n=34
-0.27%
n=106
7 years -3.13%
n=12
0.53%
n=60
-1.34%
n=7
0.94%
n=39
-5.38%
n=13
-0.11%
n=63

1 The treatment group consisted of women who received Depo-Provera CI for 5 years and were then followed for 2 years post-use (total time in study of 7 years).
2 The control group consisted of women who did not use hormonal contraception and were followed for 7 years.

Bone Mineral Density Changes in Adolescent Females (12–18 years of age)

The impact of Depo-Provera CI (150 mg) use for up to 240 weeks (4.6 years) was evaluated in an open-label non-randomized clinical study in 389 adolescent females (12–18 years). Use of Depo-Provera CI was associated with a significant decline from baseline in BMD.

Partway through the trial, drug administration was stopped (at 120 weeks). The mean number of injections per Depo-Provera CI user was 9.3. The decline in BMD at total hip and femoral neck was greater with longer duration of use (see Table 5). The mean decrease in BMD at 240 weeks was more pronounced at total hip (-6.4%) and femoral neck (-5.4%) compared to lumbar spine (-2.1%).

In general, adolescents increase bone density during the period of growth following menarche, as seen in the untreated cohort. However, the two cohorts were not matched at baseline for age, gynecologic age, race, BMD and other factors that influence the rate of acquisition of bone mineral density.

Table 5. Mean Percent Change from Baseline in BMD in Adolescents Receiving ≥4 Injections per 60-week Period, by Skeletal Site and Cohort
Duration of Treatment Depo-Provera CI
(150 mg IM)
Unmatched, Untreated Cohort
N Mean % Change N Mean % Change
Total Hip BMD
Week 60 (1.2 years) 113 -2.75 166 1.22
Week 120 (2.3 years) 73 -5.40 109 2.19
Week 240 (4.6 years) 28 -6.40 84 1.71
Femoral Neck BMD
Week 60 113 -2.96 166 1.75
Week 120 73 -5.30 108 2.83
Week 240 28 -5.40 84 1.94
Lumbar Spine BMD
Week 60 114 -2.47 167 3.39
Week 120 73 -2.74 109 5.28
Week 240 27 -2.11 84 6.40

BMD recovery post-treatment in adolescent women

Longer duration of treatment and smoking were associated with less recovery of BMD following the last injection of Depo-Provera CI. Table 6 shows the extent of recovery of BMD up to 60 months post-treatment for adolescent women who received Depo-Provera CI for two years or less compared to more than two years. Post-treatment follow-up showed that, in women treated for more than two years, only lumbar spine BMD recovered to baseline levels after treatment was discontinued. Subjects treated with Depo-Provera for more than two years did not recover to their baseline BMD level at femoral neck and total hip even up to 60 months post-treatment. Adolescent women in the untreated cohort gained BMD throughout the trial period (data not shown).

Table 6: Extent of BMD Recovery (Months Post-Treatment) in Adolescents by Years of Depo Provera CI Use (2 Years or Less vs. More than 2 Years)
Duration of Treatment 2 years or less More than 2 years
N Mean % Change from baseline N Mean % Change from baseline
Total Hip BMD
End of Treatment 49 -1.5% 49 -6.2%
12 M post-treatment 33 -1.4% 24 -4.6%
24 M post-treatment 18 0.3% 17 -3.6%
36 M post-treatment 12 2.1% 11 -4.6%
48 M post-treatment 10 1.3% 9 -2.5%
60 M post-treatment 3 0.2% 2 -1.0%
Femoral Neck BMD
End of Treatment 49 -1.6% 49 -5.8%
12 M post-treatment 33 -1.4% 24 -4.3%
24 M post-treatment 18 0.5% 17 -3.8%
36 M post-treatment 12 1.2% 11 -3.8%
48 M post-treatment 10 2.0% 9 -1.7%
60 M post-treatment 3 1.0% 2 -1.9%
Lumbar Spine BMD
End of Treatment 49 -0.9% 49 -3.5%
12 M post-treatment 33 0.4% 23 -1.1%
24 M post-treatment 18 2.6% 17 1.9%
36 M post-treatment 12 2.4% 11 0.6%
48 M post-treatment 10 6.5% 9 3.5%
60 M post-treatment 3 6.2% 2 5.7%

Relationship of fracture incidence to use of DMPA 150 mg IM or non-use by women of reproductive age

A retrospective cohort study to assess the association between DMPA injection and the incidence of bone fractures was conducted in 312,395 female contraceptive users in the UK. The incidence rates of fracture were compared between DMPA users and contraceptive users who had no recorded use of DMPA. The Incident Rate Ratio (IRR) for any fracture during the follow-up period (mean = 5.5 years) was 1.41 (95% CI 1.35, 1.47). It is not known if this is due to DMPA use or to other related lifestyle factors that have a bearing on fracture rate.

In the study, when cumulative exposure to DMPA was calculated, the fracture rate in users who received fewer than 8 injections was higher than that in women who received 8 or more injections. However, it is not clear that cumulative exposure, which may include periods of intermittent use separated by periods of non-use, is a useful measure of risk, as compared to exposure measures based on continuous use.

There were very few osteoporotic fractures (fracture sites known to be related to low BMD) in the study overall, and the incidence of osteoporotic fractures was not found to be higher in DMPA users compared to non-users. Importantly, this study could not determine whether use of DMPA has an effect on fracture rate later in life.

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