Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
ATC Code: G02BA03

Pharmacotherapeutic group: Plastic IUD with progestogen

Levonorgestrel is a progestogen used in gynaecology in various ways: as the progestogen component in oral contraceptives, in hormonal replacement therapy or alone f or contraception in minipills and subdermal implants. Levonorgestrel can also be administered directly into the uterine cavity as an intrauterine system. This allows a very low daily dosage, as the hormone is released directly into the target organ.

The contraceptive mechanism of action of Mirena is based on mainly hormonal effects producing the following changes:
- Prevention of proliferation of the endometrium
- Thickening of the cervical mucus thus inhibiting the passage of sperm - Suppression of ovulation in some women.

The physical presence of the system in the uterus would also be expected to make a minor contribution to its contraceptive effect.

The contraceptive efficacy of Mirena has been studied in 5 major clinical studies with 3330 women using Mirena. The f ailure rate (Pearl Index) was approximately 0.2% at 1 year and the cumulative failure rate was approximately 0.7% at 5 years. The f ailure rate also includes pregnancies due to undetected expulsions and perforation. Similar contraceptive efficacy has been observed in a large post-marketing study with more than 17000 women using Mirena. Because the use of Mirena does not require daily intake compliance by the users, the pregnancy rates in “typical use” are similar to those observed in controlled clinical trials (“perfect use”).

Mirena may be particularly useful for contraception in patients with excessive menstrual bleeding, and can be successfully used in the treatment of idiopathic menorrhagia.
Results f rom three comparative studies indicate that in menorrhagic women, menstrual blood loss decreased by 62-94% at the end of three months and by 71-95% at the end of six months of use. Mirena appears to have similar effects to endometrial ablation/resection in reducing the menstrual blood loss up to two years. Menorrhagia caused by submucosal fibroids may respond less favourably. Reduced bleeding promotes the increase of blood haemoglobin in patients with menorrhagia.

In idiopathic menorrhagia, prevention of proliferation of the endometrium is the probable mechanism of action of Mirena in reducing blood loss.

The ef f icacy of Mirena in preventing endometrial hyperplasia during continuous oestrogen treatment is the same when oestrogen is administered orally or transdermally.
The observed hyperplasia rate under oestrogen therapy alone is as high as 20%. In clinical studies with a total of 634 perimenopausal and postmenopausal users of Mirena, no cases of endometrial hyperplasia were reported up to four years.

Bleeding Patterns:

Dif ferent kinds of bleeding changes (frequent, prolonged or heavy bleeding, spotting, oligomenorrhoea, amenorrhoea) are experienced by all users of Mirena. In f ertile women the average number of spotting days/month decreases gradually from nine to four days during the f irst six months of use. The percentage of women with prolonged bleeding (more than eight days) decreases from 20% to 3% during the first three months of use. In clinical studies during the first year of use, 17% of women experienced amenorrhoea of at least three months duration.

When used in combination with oestrogen replacement therapy, perimenopausal users of Mirena may experience spotting and irregular bleeding during the first months of the treatment. The amount of bleeding becomes minimal during the first year, and 30-60% of users are totally free of bleedings.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
The active ingredient of Mirena is levonorgestrel. Levonorgestrel is delivered directly into the uterine cavity. Estimated in vivo release rates for different points in time are provided in table 3. Because of the low plasma concentrations, there are only minor effects on the metabolism.

Table 3: Estimated in vivo release rates for Mirena:

Time                        Estimated in vivo release rate
[micrograms per day]
Initial                                     20
1 year after insertion                      18
4 years after insertion                     12
5 years after insertion                     10
The pharmacokinetics of levonorgestrel itself have been extensively investigated and reported in the literature. In postmenopausal users of Mirena who were receiving non-oral concomitant oestrogen, plasma levonorgestrel concentrations have been 276 ±119 pg/ml, 196 ± 87pg/ml and 177 ± 70 pg/ml at 56 weeks, 24 months and 48 months respectively. A half life of 20 hours is considered the best estimate although some studies have reported values as short as 9 hours and others as long as 80 hours. Another important finding, although one in agreement with experience with other synthetic steroids, has been marked differences in metabolic clearance rates among individuals, even when administration was by the intravenous route. Levonorgestrel is extensively bound to proteins (mainly sex hormone binding globulin [SHBG]) and extensively metabolised to a large number of inactive metabolites.