Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

ATC Code: G03AC06
MPA is an analogue of 17-hydroxyprogesterone with anti-estrogenic, anti-androgenic and antigonadotrophic effects.

DMPA-SC 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. These actions produce its contraceptive effect.

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 years       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* n        33               105            21                 65        34             106 Mean       -5.4%            0.4%           -5.2%              0.2%      -6.1%          -0.3% 
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(SD)             (3.57)            (3.27)           (3.60)            (3.18)        (4.68)            (5.22) 95% CI        -6.65; -4.11       -0.20; 1.06     -6.80; -3.52        -0.60;      -7.75; -4.49       -1.27; 0.73 0.98
7 years** n          12                 60              7                   39          13                 63 Mean         -3.1%              0.5%            -1.3%               0.9%        -5.4%              -0.0% (SD)             (3.15)            (3.65)           (4.95)            (3.81)        (2.73)            (5.88) 95% CI        -5.13; -1.13       -0.39; 1.49     -5.92; 3.23         -0.29;      -7.03; -3.73       -1.51; 1.45 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 a 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 Treatment                             DMPA-IM
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; -4.65]
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 
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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 year 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 % change                         change (SE)
Week after                   Median
(SE) from                           from
DMPA              N      Number of                        95% CI                           95% CI baseline to                        baseline discontinuation               injections 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



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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

The pharmacokinetic parameters of MPA following a single SC injection of SAYANA® are shown in Table 5.

Table 5. Pharmacokinetic Parameters of MPA After a Single SC Injection of SAYANA® in Healthy Women (n=42)
Cmax         Tmax      C91 (min)    AUC0-91              AUC0-             t½ (ng/ml)      (day)      (ng/ml)     (ng·day/ml)          (ng·day/ml)        (day) Mean      1.56         8.8       0.402        66.98                92.84              43 Min       0.53         2.0       0.133        20.63                31.36              16 Max       3.08         80.0      0.733        139.79               162.29             114 Cmax = peak serum concentration; Tmax = time when Cmax is observed; AUC0-91 = area under the concentration-time curve over 91 days; t½ = terminal half-life; 1 nanogram = 10 3 picogram.

General Characteristics

Absorption
MPA absorption from the SC injection site to achieve therapeutic levels is relatively prompt. The mean Tmax attained approximately one week after injection. The peak MPA concentrations (C max) generally range from 0.5 to 3.0 ng/ml ,with a mean Cmax of 1.5 ng/ml after a single SC injection.

Effect of Injection Site
SAYANA ® was administered into the anterior thigh or the abdomen to evaluate effects on MPA concentration-time profile. MPA trough concentrations (Cmin; Day 91) were similar for the two injection locations, suggesting that injection site does not negatively affect the contraceptive efficacy.

Distribution
Plasma protein binding of MPA averages 86%. MPA binding occurs primarily to serum albumin; no binding of MPA occurs with SHBG.


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Biotransformation
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.

Elimination
Residual MPA concentrations at the end of the dosing interval (3 months) of SAYANA® 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
Based on single-dose data, there was no evidence of non-linearity over the dose range of 50 to 150 mg after SC administration. The relationship between the AUC or the Cmin and the SC dose of MPA appeared to be linear. The mean Cmax did not change substantially with increasing dose.

Special Populations

Race
There were no apparent differences in the pharmacokinetics and/or dynamics of MPA after SC administration of SAYANA® among women of all ethnic backgrounds studied. The pharmacokinetics/dynamics of MPA has been evaluated in Asian women in a separate study.

Effect of Body Weight
No dosage adjustment of SAYANA® is necessary based on body weight. The effect of body weight on the pharmacokinetics of MPA was assessed in a subset of women (n=42, body mass index [BMI] ranged from 18.2 to 46.0 kg/m2). The AUC0-91 values for MPA were 68.5, 74.8, and 61.8 ng-day/ml in women with BMI categories of 25 kg/m2, >25 to ≤30 kg/m2, and >30 kg/m2, respectively. The mean MPA Cmax was 1.65 ng/ml in women with BMI 25 kg/m2, 1.76 ng/ml in women with BMI >25 to ≤30 kg/m2, and 1.40 ng/ml in women with BMI >30 kg/m2, respectively. The range of MPA trough (Cmin) concentrations and the half-lives were comparable for the 3 BMI groups.

Pharmacokinetic/Pharmacodynamic Relationship(s)

From a pharmacodynamic perspective, the duration of ovulation suppression depends upon maintaining therapeutic MPA concentrations throughout the 13-week dosing interval.