Oral Contraception

Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).

In vitro and animal studies have shown that norethindrone combines high progestational activity with low intrinsic androgenicity. In humans, norethindrone acetate in combination with ethinyl estradiol does not counteract estrogen-induced increases in sex hormone binding globulin (SHBG). Following multiple-dose administration of ESTROSTEP, serum< SHBG concentrations increase two- to three-fold and free testosterone concentrations decrease by 47% to 64%, indicating minimal androgenic activity.

ACNE

Acne is a skin condition with a multifactorial etiology, including androgen stimulation of sebum production. While the combination of norethindrone acetate and ethinyl estradiol increases sex hormone binding globulin (SHBG) and decreases free testosterone, the relationship between these changes and a decrease in the severity of facial acne in otherwise healthy women with this skin condition has not been established.

Pharmacokinetics

Absorption

Norethindrone acetate appears to be completely and rapidly deacetylated to norethindrone after oral administration, since the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. Norethindrone acetate and ethinyl estradiol are rapidly absorbed, with maximum plasma concentrations of norethindrone and ethinyl estradiol occurring 1 to 2 hours postdose. Both are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64% for norethindrone and 43% for ethinyl estradiol.

Administration of norethindrone acetate/ethinyl estradiol with a high fat meal decreases rate, but not extent, of ethinyl estradiol absorption. The extent of norethindrone absorption is increased by 27% following administration with food.

Plasma concentrations of norethindrone and ethinyl estradiol following chronic administration of ESTROSTEP to 17 women are shown below (Figure 1). Mean steady- state concentrations of norethindrone for the 1/20, 1/30, and 1/35 tablet strengths increased as ethinyl estradiol dose increased over the 21-day dose regimen, due to dose- dependent effects of ethinyl estradiol on serum SHBG concentrations (Table 1). Mean steady-state plasma concentrations of ethinyl estradiol for the 1/20, 1/30, and 1/35 tablet strengths were proportional to ethinyl estradiol dose (Table 1).

Figure 1. Mean Steady-State Plasma Ethinyl Estradiol and Norethindrone Concentrations Following Chronic Administration of ESTROSTEP

Table 1. Mean (SD) Steady-State Pharmacokinetic Parameters Following Chronic Administration of ESTROSTEP^a

Bookmark this page: