Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1. Pharmacodynamic Properties

ATC Code: G03AA11


Although the pharmacological actions of estrogens and progestogens which are present in all combined oral contraceptives are largely understood, the exact mechanism of their actions other than suppression of ovulation remains controversial.


TRADENAME 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 ovulation, but alterations to the cervical mucus, the fallopian tube motility and to the endometrium may also contribute to the efficacy of the product.


Receptor and sex hormone binding globulin (SHBG) binding studies, as well as studies in animals and humans, have shown that both norgestimate (NGM) and norelgestromin, the major serum metabolite of norgestimate following oral administration, exhibits high progestational activity with minimal intrinsic androgenicity, which illustrates the selective action of TRADENAME. Norgestimate, in combination with ethinyl estradiol, does not counteract the estrogen-induced increases in SHBG, resulting in lower levels of free testosterone in serum compared to baseline.

Pharmacokinetic Properties

5.2. Pharmacokinetic Properties

Absorption: Norgestimate and ethinyl estradiol are rapidly absorbed following oral administration. Following single or multiple (three cycles) administration of TRADENAME, serum concentrations of norgestimate remain below the quantitation limit of the assay (0.1 ng/mL) due to rapid metabolism (see Metabolism below). Its metabolites, norelgestromin and norgestrel, are found in measurable concentrations in circulation, reaching maximal serum levels approximately 1.5 hours post-dose.
Exposure to norelgestromin is proportional to dose following norgestimate doses of 0.180 to 0.250 mg. Ethinyl estradiol serum concentrations are measurable within 0.5 hours of dosing, reaching peak levels approximately 1.2 hours post-dose.


Distribution: Norelgestromin and norgestrel are highly bound (>97%) to serum proteins. norelgestromin is bound to albumin but not to SHBG, while norgestrel is bound primarily to SHBG and to a much lesser extent to albumin. Ethinyl estradiol is extensively bound to serum albumin.


Studies have shown that the lack of binding of norelgestromin to SHBG is unique when compared to other progestogens in oral contraceptives and plays a key role in enhancing its biological activity. In contrast, norgestrel formed from norgestimate is largely bound to SHBG, which limits its biologic activity. These findings together with the selectivity of norelgestromin for the progesterone receptor indicate that this metabolite may explain the unique clinical profile of norgestimate.


Metabolism: Norgestimate is rapidly metabolized by first-pass (intestinal and/or hepatic) mechanisms to norelgestromin (peak serum concentrations observed within 2 hours) and norgestrel, both of which are pharmacologically active progestogens.
Ethinyl estradiol is metabolized to various hydroxylated metabolites and their glucuronide and sulfate conjugates.


Elimination: Both norelgestromin and norgestrel, and ethinyl estradiol are subsequently metabolized and their metabolites are eliminated by renal and fecal pathways. Elimination half-life values at steady-state were 10 to 15 hours for ethinyl estradiol, 24.9 hours for norelgestromin and 45 hours for norgestrel. Following administration of 14C-norgestimate, 47% of the administered radioactivity was eliminated in the urine and 37% in the feces.


Steady-State Pharmacokinetics: Following administration of 0.250 mg /0.035 mg ethinyl estradiol, the daily exposure (mean AUC0-24h) at steady-state, based on non- SHBG bound serum levels, was 18.1 h ng/mL for norelgestromin and 3.64 h ng/mL for norgestrel. Following oral administration of 0.150 mg levonorgestrel/0.030 mg ethinyl estradiol, mean daily exposure at steady-state, based on non-SHBG bound serum levels, was 18.9 h ng/mL for norgestrel. The exposure to norgestrel following administration of 0.250 mg /0.035 mg ethinyl estradiol, corresponds to the exposure after a levonorgestrel dose of approximately 30 micrograms in combination with ethinyl estradiol.