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DEPO-PROVERA® CI Clinical Studies (medroxyprogesterone acetate injectable suspension, for intramuscular use)

14 CLINICAL STUDIES

14.1 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.

14.2 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 StudySpineTotal HipFemoral Neck
Depo-Provera*ControlDepo-Provera*ControlDepo-Provera*Control
*
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).
The control group consisted of women who did not use hormonal contraception and were followed for 7 years.
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

14.3 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 TreatmentDepo-Provera CI
(150 mg IM)
Unmatched, Untreated Cohort
NMean % ChangeNMean % Change
Total Hip BMD
Week 60 (1.2 years)113-2.751661.22
Week 120 (2.3 years)73-5.401092.19
Week 240 (4.6 years)28-6.40841.71
Femoral Neck BMD
  Week 60113-2.961661.75
  Week 12073-5.301082.83
  Week 24028-5.40841.94
Lumbar Spine BMD
  Week 60114-2.471673.39
  Week 12073-2.741095.28
  Week 24027-2.11846.40

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 Treatment2 years or lessMore than 2 years
NMean % Change from baselineNMean % Change from baseline
Total Hip BMD
End of Treatment49-1.5%49-6.2%
12 M post-treatment33-1.4%24-4.6%
24 M post-treatment180.3%17-3.6%
36 M post-treatment122.1%11-4.6%
48 M post-treatment101.3%9-2.5%
60 M post-treatment30.2%2-1.0%
Femoral Neck BMD
End of Treatment49-1.6%49-5.8%
12 M post-treatment33-1.4%24-4.3%
24 M post-treatment180.5%17-3.8%
36 M post-treatment121.2%11-3.8%
48 M post-treatment102.0%9-1.7%
60 M post-treatment31.0%2-1.9%
Lumbar Spine BMD
End of Treatment49-0.9%49-3.5%
12 M post-treatment330.4%23-1.1%
24 M post-treatment182.6%171.9%
36 M post-treatment122.4%110.6%
48 M post-treatment106.5%93.5%
60 M post-treatment36.2%25.7%

14.4 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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