Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1      Pharmacodynamic properties

Pharmacotherapeutic group: Sex hormones and modulators of the genital system, progestogens and estrogens, fixed combination; ATC-code: G03AA13.

Mechanism of action
EVRA acts through the mechanism of gonadotropin suppression by the estrogenic and progestational actions of ethinyl estradiol and norelgestromin. The primary mechanism of action is inhibition of the ovulation, but the alterations of the cervical mucus, and to the endometrium may also contribute to the efficacy of the product.

Clinical efficacy and safety
Pearl Indices (see table):

Study            CONT-002       CONT-003      CONT-003       CONT-004         CONT-004        All EVRA Group            EVRA           EVRA          COC*           EVRA             COC**           Subjects # of cycles 10,743         5,831        4,592       5,095         4,005          21,669 Overall      0.73          0.89         0.57        1.28          2.27           0.90 Pearl Index (0.15; 1.31) (0.02; 1.76) (0.0; 1.35)   (0.16; 2.39) (0.59; 3.96) (0.44; 1.35) (95% CI)
Method       0.61          0.67         0.28        1.02          1.30           0.72 Failure      (0.0; 1.14)   (0.0; 1.42)  (0.0; 0.84) (0.02; 2.02) (0.03; 2.57) (0.31; 1.13) Pearl Index
(95% CI)
* DSG 150 µg + 20 µg EE
**50 µg LNG + 30 µg for days 1 – 6, 75 µg LNG + 40 µg EE for days 7 – 11, 125 µg LNG + 30 µg EE for 12 – 21 days

Exploratory analyses were performed to determine whether in the Phase III studies (n=3,319) the population characteristics of age, race and weight were associated with pregnancy. The analyses indicated no association of age and race with pregnancy. With respect to weight, 5 of the15 pregnancies reported with EVRA were among women with baseline body weight equal or greater than 90 kg, which constituted < 3% of the study population. Below 90 kg there was no association between body weight and pregnancy. Although only 10-20% of the variability in pharmacokinetic data can be explained by weight (see section 5.2), the greater proportions of pregnancies among women at or above 90 kg was statistically significant and indicates the EVRA is less effective in these women.


With the use of higher dosed COCs (50 microgram ethinyl estradiol) the risk of endometrial and ovarian cancer is reduced. Whether this is also applies to the lower dosed combined hormonal contraceptives remains to be confirmed.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Following application of EVRA, norelgestromin and ethinyl estradiol levels in serum reach a plateau by approximately 48 hours. Steady state concentrations of norelgestromin and EE during one week of transdermal patch wear are approximately 0.8 ng/ml and 50 pg/ml, respectively. In multiple-dose studies, serum concentrations and AUC for norelgestromin and EE were found to increase only slightly over time when compared to week 1 cycle 1.

The absorption of norelgestromin and ethinyl estradiol following application of EVRA was studied under conditions encountered in a health club (sauna, whirlpool, treadmill and other aerobic exercise) and in a cold water bath. The results indicated that for norelgestromin there were no significant treatment effects on C ss or AUC when compared to normal wear. For EE, slight increases were observed due to treadmill and other aerobic exercise; however, the C ss values following these treatments were within the reference range. There was no significant effect of cool water on these parameters.

Results from an EVRA study of extended wear of single contraceptive transdermal patch for 7 days and 10 days indicated that target C ss of norelgestromin and ethinyl estradiol were maintained during a 3-day period of extended wear of EVRA (10 days). These findings suggest that clinical efficacy would be maintained even if a scheduled change is missed for as long as 2 full days.

Distribution
Norelgestromin and norgestrel (a serum metabolite of norelgestromin) are highly bound (> 97%) to serum proteins. Norelgestromin is bound to albumin and not to SHBG, while norgestrel is bound primarily to SHBG, which limits its biological activity. Ethinyl estradiol is extensively bound to serum albumin.


Biotransformation
Hepatic metabolism of norelgestromin occurs and metabolites include norgestrel, which is largely bound to SHBG, and various hydroxylated and conjugated metabolites. Ethinyl estradiol is also metabolised to various hydroxylated products and their glucuronide and sulfate conjugates.

Elimination
Following removal of a transdermal patch, the mean elimination half-lives of norelgestromin and ethinyl estradiol were approximately 28 hours and 17 hours, respectively. The metabolites of norelgestromin and ethinyl estradiol are eliminated by renal and fecal pathways.

Transdermal versus Oral Contraceptives
The pharmacokinetic profiles of transdermal and oral combined hormonal contraceptives are different and caution should be exercised when making a direct comparison of these PK parameters.

In a study comparing EVRA to an oral contraceptive containing norgestimate (parent drug of norelgestromin) 250 mcg /ethinyl estradiol 35 mcg, C max values were 2-fold higher for NGMN and EE in subjects administered the oral contraceptive compared to EVRA, while overall exposure (AUC and C ss ) was comparable in subjects treated with EVRA. Inter-subject variability (%CV) for the PK parameters following delivery from EVRA was higher relative to the variability determined from the oral contraceptive.
Effects of age, body weight, and body surface area
The effects of age, body weight, and body surface area on the pharmacokinetics of norelgestromin and ethinyl estradiol were evaluated in 230 healthy women from nine pharmacokinetic studies of single 7-day applications of EVRA. For both norelgestromin and EE, increasing age, body weight and body surface area each were associated with slight decreases in Css and AUC values.
However, only a small fraction (10 – 20%) of the overall variability in the pharmacokinetics of the norelgestromin and EE following application of EVRA may be associated with any or all of the above demographic parameters.