Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Plastic IUD with progestogen, ATC code: G02BA03 

Pharmacodynamic effects
Janess has mainly local progestogenic effects in the uterine cavity.
The high levonorgestrel concentration in the endometrium down-regulates endometrial estrogen and progesterone receptors. The endometrium becomes relatively insensitive to the circulating estradiol and a strong antiproliferative effect is seen. Morphological changes of the endometrium and a weak local foreign body reaction are observed during use. Thickening of the cervical mucus prevents passage of the sperm through the cervical canal. The local milieu of the uterus and of the fallopian tubes inhibits sperm mobility and function, preventing fertilisation. In clinical trials with Janess ovulation was observed in the majority of the subjects studied. Evidence of ovulation was seen in 34 out of 35 women in the first year, in 26 out of 27 women in the second year, and in all 26 women in the third year.


Clinical efficacy and safety
The contraceptive efficacy of Janess has been evaluated in a clinical study with 1432 women aged 18-35 including 38.8% (556) nulliparous women of whom 83.6% (465) were nulligravid using Janess. The 1-year Pearl Index was 0.41 (95% confidence limits 0.13 – 0.96) and the 3-years Pearl Index was 0.33 (95% confidence limits 0.16 – 0.60). The failure rate was approximately 0.4% at 1 year and the cumulative failure rate was approximately 0.9% at 3 years. The failure rate also includes pregnancies occurring after undetected expulsions and perforations. Use of a levonorgestrel- releasing intrauterine system does not alter the course of future fertility. Based on 
data with a higher dosed LNG-IUS, about 80% of the women wishing to become pregnant conceived within 12 months after removal of the system.

The safety profile of Janess observed in a study of 304 adolescents was consistent with that in the adult population. Efficacy is expected to be the same for adolescents under the age of 18 as for users 18 years and older.

With Janess, the alterations in menstrual patterns are a result of the direct action of levonorgestrel on the endometrium and may not reflect the ovarian cycle. There is no clear difference in follicle development, ovulation or estradiol and progesterone production in women with different bleeding patterns. In the process of inhibition of the endometrial proliferation, there can be an initial increase of spotting during the first months of use. Thereafter, the strong suppression of the endometrium results in the reduction of the duration and volume of menstrual bleeding during use of Janess.
Scanty flow frequently develops into oligomenorrhea or amenorrhea. Ovarian function remains normal and estradiol levels are maintained, even when users of Janess are amenorrhoeic.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

Levonorgestrel is released locally into the uterine cavity. The in vivo release curve is characterized by an initial steep decline that slows down progressively resulting in little change after 1 year until the end of the intended 3-year period of use. Estimated in vivo delivery rates for different time points are provided in Table 3.

Table 3: Estimated in vivo release rates based on observed ex vivo residual content data
Time                    Estimated in vivo release rate
[micrograms/24 hours]
24 days af ter insertion                         14
60 days af ter insertion                          10
1 year af ter insertion                            6
3 years af ter insertion                           5
Average over 1st year                              8
Average over 3 years                               6


Absorption
Following insertion, levonorgestrel is released from the IUS into the uterine cavity without delay based on serum concentration measurements. More than 90% of the released levonorgestrel is systemically available. Maximum serum concentrations of levonorgestrel are reached within the first two weeks after insertion of Janess. Seven days after insertion, a mean levonorgestrel concentration of 162 pg/ml (5th percentile: 102pg/ml – 95th percentile: 249 pg/ml) was determined. Thereafter, serum concentrations of levonorgestrel decline over time to reach mean concentrations of 59 pg/ml (5th percentile: 36pg/ml – 95th percentile: 92 pg/ml) after 3 years. With the use of a levonorgestrel-releasing intrauterine system, the high local drug exposure in the uterine cavity leads to a strong concentration gradient from the endometrium to the myometrium (gradient endometrium to myometrium >100-fold), 

and to low concentrations of levonorgestrel in serum (gradient endometrium to serum >1000-fold).


Distribution
Levonorgestrel is bound non-specifically to serum albumin and specifically to SHBG.
Less than 2% of the circulating levonorgestrel is present as free steroid.
Levonorgestrel binds with high affinity to SHBG. Accordingly, changes in the concentration of SHBG in serum result in an increase (at higher SHBG concentrations) or in a decrease (at lower SHBG concentrations) of the total levonorgestrel concentration in serum. The concentration of SHBG declined on average by about 15% during the first month after insertion of Janess and remained stable over the 3 year period of use. The mean apparent volume of distribution of levonorgestrel is about 106 L.

Biotransformation
Levonorgestrel is extensively metabolized. The most important metabolic pathways are the reduction of the ∆4-3-oxo group and hydroxylations at positions 2α, 1β and 16β, followed by conjugation. CYP3A4 is the main enzyme involved in the oxidative metabolism of LNG. The available in vitro data suggest that CYP mediated biotransformation reactions may be of minor relevance for LNG compared to reduction and conjugation.
Elimination
The total clearance of levonorgestrel from plasma is approximately 1.0 ml/min/kg.
Only trace amounts of levonorgestrel are excreted in unchanged form. The metabolites are excreted in faeces and urine at an excretion ratio of about 1. The excretion half-life is about 1 day.

Linearity/non-linearity
The pharmacokinetics of levonorgestrel are dependent on the concentration of SHBG which itself is influenced by oestrogens and androgens. A decrease of SHBG concentration leads to a decrease of total levonorgestrel concentration in serum indicating non-linear pharmacokinetics of levonorgestrel with regard to time. Based on the mainly local action of Janess, no impact on the efficacy of Janess is expected.

Paediatric population
In a one-year phase III study in post-menarcheal female adolescents (mean age 16.2, range 12 to 18 years) pharmacokinetic analysis of 283 adolescents showed estimated LNG serum concentrations slightly higher (approximately 10%) in adolescents compared to adults. This correlates to the generally lower body weight in adolescents. The ranges estimated for adolescents lie, however, within the ranges estimated for adults, showing high similarity.
No differences in the pharmacokinetics of LNG are expected between adolescents and adults following insertion of Janess.

Ethnic differences
A three-year phase III study in the Asian-Pacific region (93 % Asian women, 7 % other ethnicities) using Janess has been performed. A comparison of pharmacokinetic characteristics of LNG of the Asian population in this study with that of the Caucasian population from another phase III study showed no clinically relevant difference in systemic exposure and other pharmacokinetic parameters. In addition, the daily release rate of Janess was the same in both populations.

No differences in the pharmacokinetics of LNG are expected between Caucasian and Asian women following insertion of Janess.