Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1      Pharmacodynamic properties
Pharmacotherapeutic group: Progestogens, ATC code: G03AC06

Medroxyprogesterone acetate exerts anti-oestrogenic, anti-androgenic and antigonadotrophic effects.

Mechanism of action
DMPA, when administered parenterally at the recommended dose to women, inhibits the secretion of gonadotropins which, in turn, prevents follicular maturation and ovulation and causes thickening of cervical mucus which inhibits sperm entry into the uterus

BMD Changes in Adult Women

A study comparing changes in BMD in women using DMPA SC with women using DMPA- IM) showed similar BMD loss between the two groups after two years of treatment. Mean percent changes in BMD in the DMPA -SC group are listed in Table 1.

Table 1. Mean Percent Change (with 95% Confidence Intervals) from Baseline in BMD in Adult Women Using DMPA -SC by Skeletal Site
Lumbar Spine                   Total Hip                   Femoral Neck Time on          N        Mean % Change         N       Mean % Change       N       Mean % Change Treatment                 (95% CI)                      (95% CI)                    (95% CI) 1 year           166      -2.7                  166     -1.7                166 -1.9 (-3.1 to -2.3)                (-2.1 to -1.3)              (-2.5 to -1.4) 2 year           106      - 4.1                 106     -3.5                106 -3.5
(-4.6 to -3.5)                (-4.2 to -2.7)              (-4.3 to -2.6) CI = Confidence Interval
In another controlled, clinical study adult women using DMPA- IM for up to 5 years showed spine and hip mean BMD 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 –2.9%, -4. 1%, -4. 9%, -4.9% and –5.4% after 1, 2, 3, 4 and 5 years, respectively, were observed. Mean decreases in BMD of the total hip and femoral neck were similar. Please refer to Table 2 below for further details.

After stopping use of DMPA- IM, BMD increased towards baseline values during the post-therapy period. A longer duration of treatment was associated with a slower rate of BMD recovery.

In the same clinical study, a limited number of women who had used DMPA-IM for 5 years were followed-up for 2 years after stopping DMPA-IM use. BMD increased towards baseline values during the 2-year post-therapy period. Two years after stopping DMPA injections, mean BMD had increased at all 3 skeletal sites but deficits remained (see Table 2 below).

Table 2. Mean Percent Change (with 95% Confidence Intervals) from Baseline in BMD in Adults by Skeletal Site and Cohort after 5 Years of Therapy with DMPA- IM and after 2 Years Post- Therapy or 7 Years of Observation (Control)

Time in     Spine                           Total Hip                  Femoral Neck Study
DMPA             Control        DMPA             Control   DMPA           Control 
5 years*          33            105             21            65            34             106 n           -5.4%          0.4%           -5.2%         0.2%          -6.1%           -0.3% Mean          (3.57)         (3.27)         (3.60)        (3.18)        (4.68)          (5.22) (SD)       -6.65; -4.11   -0.20; 1.06    -6.80; -3.52     -0.60;     -7.75; -4.49    -1.27; 0.73 95% CI                                                      0.98
7 years**         12             60              7            39            13              63 n           -3.1%          0.5%           -1.3%         0.9%          -5.4%           -0.0% Mean          (3.15)         (3.65)         (4.95)        (3.81)        (2.73)          (5.88) (SD)       -5.13; -1.13   -0.39; 1.49    -5.92; 3.23      -0.29;     -7.03; -3.73    -1.51; 1.45 95% CI                                                      2.17


*The treatment group consisted of women who received DMPA- IM) for 5 years and the control group consisted of women who did not use hormonal contraception for this time period.
** The treatment group consisted of women who received DMPA- IM) for 5 years and were then followed up for 2 years post-use and the control group consisted of women who did not use hormonal contraceptive for 7 years.
SD = Standard Deviation
CI = Confidence Interval


BMD Changes in Adolescent Females (12-18 years)
Results from an open-label, non-randomised, clinical study of DMPA-IM (150 mg IM every 12 weeks for up to 240 weeks (4.6 years), followed by post–treatment measurements) in adolescent females (12- 18 years) also showed that medroxyprogesterone acetate IM use was associated with a significant decline in BMD from baseline. Among subjects who received ≥ 4 injections/60-week period, the mean decrease in lumbar spine BMD was - 2.1 % after 240 weeks (4.6 years); mean decreases for the total hip and femoral neck were -6.4 % and -5.4 %, respectively. Please refer to table 3. In contrast, a non- comparable cohort of unmatched, untreated subjects, with different baseline bone parameters from the DMPA users, showed mean BMD increases at 240 weeks of 6.4%, 1.7% and 1.9% for lumbar spine, total hip and femoral neck, respectively.
Table 3. Mean Percent Change (with 95% Confidence Intervals) from Baseline in BMD in Adolescents Receiving ≥4 Injections per 60-week Period, by Skeletal Site

Duration of                        DMPA-IM
Treatment
N       Mean % Change [95 % CI]
Total Hip BMD
Week 60 (1.2 years)       113            -2.7 [-3.27; -2.12]
Week 120 (2.3 years)       73            -5.4 [-6.16; -4.64]
Week 180 (3.5 years)       45            -6.4 [-7.38; -5.37]
Week 240 (4.6 years)       28            -6.4 [-8.56; -4.24]
Femoral Neck BMD
Week 60                   113            -2.9 [-3.72; -2.15]
Week 120                   73            -5.3 [-6.23; -4.37]
Week 180                   45            -6.0 [-7.31; -4.59]
Week 240                   28            -5.4 [-7.81; -3.00]
Lumbar Spine BMD
Week 60                   114            -2.5 [-2.95; -1.98]
Week 120                   73            -2.7 [-3.57; -1.91]
Week 180                   44            -2.7 [-3.99; -1.35]
Week 240                   27            -2.1 [-4.16; -0.07]
CI = Confidence Interval
Post-treatment follow-up of adolescent participants from the same study, who received at least 1 DMPA injection and provided at least 1 follow-up BMD measurement after stopping DMPA-IM use is shown in Table 4. The median number of injections received in this cohort during the treatment phase was 9. At the time of the final DMPA injection, BMD % changes from baseline in this cohort were -2.7%, -4.1% and -3.9% at the spine, total hip and femoral neck, respectively. Over time, these mean BMD deficits recovered to baseline after DMPA-IM was discontinued. Recovery to baseline required 1.2 years at the lumbar spine, 4.6 years at the total hip and 4.6 years at the femoral neck. However, it is important to note that a large number of subjects discontinued from the study, therefore these results are based on a small number of subjects and some subjects still had deficit in total hip BMD after 240 weeks. Longer duration of treatment and smoking were associated with slower recovery. Please refer to Table 4 below.

Table 4. Mean Percentage Changes (with 95% Confidence Intervals) from Baseline in BMD in Adolescents after Discontinuation of DMPA
Mean %                       Mean %
Median     change                    change (SE)
Week after
Number (SE) from                          from
DMPA              N                                95% CI                       95% CI of     baseline                     baseline discontinuation injections to end of                      to post- treatment                   DMPA visit
Total Hip BMD
0            98            9    -4.1 (0.43) [ -4.95; -3.25]      N/A
24            74            9    -4.1 (0.53) [ -5.15; -3.04]  -4.0 (0.61) [ -5.25; -2.80]
60            71            8    -3.6 (0.46) [ -4.48; -2.66]  -2.8 (0.56) [ -3.97; -1.72] 120            52           10    -4.3 (0.64) [ -5.56; -2.98]  -1.7 (0.72) [ -3.14; -0.26] 180            39            7    -4.1 (0.72) [ -5.55; -2.63]  -1.2 (0.85) [ -2.96; 0.46] 240            25            9    -3.4 (0.67) [ -4.73; -1.98]   0.1 (0.98) [ -1.95; 2.11]
Femoral Neck BMD
0             98            9    -3.9 (0.50) [ -4.92; -2.92]      N/A 24            74            9    -3.8 (0.60) [ -5.01; -2.62]  -4.0 (0.71) [ -5.40; -2.55]
60            71            8    -3.3 (0.56) [ -4.41; -2.18]  -3.6 (0.70) [ -4.99; -2.18] 120            52           10    -3.8 (0.74) [ -5.25; -2.28]  -1.8 (0.82) [ -3.43; -0.13] 180            39            7    -3.9 (0.85) [ -5.62; -2.17]  -1.0 (0.98) [ -3.00; 0.97] 240            25            9    -3.4 (0.80) [ -5.07; -1.78]  -0.7 (1.19) [ -3.20; 1.72]
Lumbar Spine BMD
0             98            9    -2.7 (0.39) [ -3.45; -1.91]      N/A 24            74            9    -2.6 (0.43) [ -3.42; -1.69]  -2.5 (0.51) [ -3.52; -1.48]
60            70            8    -2.8 (0.43) [ -3.66; -1.96]  -0.2 (0.60) [ -1.41; 1.01] 120            52           10    -2.7 (0.61) [ -3.96; -1.50]  2.2 (0.73)   [ 0.74; 3.67] 180            39            7    -3.0 (0.67) [ -4.35; -1.66]  2.8 (0.79)   [ 1.16; 4.35] 240            25            9    -2.6 (0.80) [ -4.28; -0.99]  4.5 (1.03)   [ 2.35; 6.61]


SE = Standard Error
CI = Confidence Interval
Relationship of Fracture Incidence to Use of DMPA-IM (150 mg) by Women of Reproductive Age 
A large retrospective cohort study using data from the General Practice Research Database (GPRD) included N=41,876 women who used DMPA for contraception and had data available for 6-24 months before their first use of DMPA and for mean 5.5 years after their first DMPA injection. Fracture risk was observed to be higher overall in the DMPA cohort when compared to non users both ‘before’ and ‘after’ DMPA use. Fracture risk was compared between the period ‘after’ first DMPA injection vs. the period ‘before’ first injection: Incident Risk Ratio=1.01 (95% CI: 0.92, 1.11), suggesting that DMPA did not increase risk for bone fracture.

Maximum follow-up in this study was 15 years, therefore, possible effects of DMPA that might extend beyond 15 years of follow-up cannot be determined. Importantly, this study could not determine whether use of DMPA has an effect on fracture rate later in life i.e. following the menopause.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties

Parenteral medroxyprogesterone acetate (MPA) is a long acting progestational steroid. The long duration of action results from its slow absorption from the injection site. Immediately after injection of 150 mg/ml MPA, plasma levels were 1.7 ± 0.3 nmol/l. Two weeks later, levels were 6.8 ± 0.8 nmol/l.
Concentrations fell to the initial levels by the end of 12 weeks. At lower doses, plasma levels of MPA appear directly related to the dose administered. Serum accumulation over time was not demonstrated.
MPA is eliminated via faecal and urinary excretion. Plasma half-life is about six weeks after a single intramuscular injection. At least 11 metabolites have been reported. All are excreted in the urine, some, but not all, conjugated.