Nuvaring (Etonogestrel / Ethinyl Estradiol Vaginal Ring) - Clinical Pharmacology

CLINICAL PHARMACOLOGY

Combination hormonal contraceptives act by suppression of gonadotropins. Although the primary effect 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).

Receptor binding studies, as well as studies in animals, have shown that etonogestrel, the biologically active metabolite of desogestrel, combines high progestational activity with low intrinsic androgenicity. The relevance of this later finding in humans is unknown.

PHARMACOKINETICS

ABSORPTION

Etonogestrel: Etonogestrel released by NuvaRing® is rapidly absorbed. Bioavailability of etonogestrel after vaginal administration is approximately 100%. The serum etonogestrel and ethinyl estradiol concentrations (pg/mL) observed during three weeks of NuvaRing® use are summarized in Table I.

Ethinyl estradiol: Ethinyl estradiol released by NuvaRing® is rapidly absorbed. Bioavailability of ethinyl estradiol after vaginal administration is approximately 55.6%, which is comparable to that with oral administration of ethinyl estradiol. The serum ethinyl estradiol concentrations observed during three weeks of NuvaRing® use are summarized in Table I.

The pharmacokinetic profile of etonogestrel and ethinyl estradiol during use of NuvaRing® is shown in Figure 1.

The pharmacokinetic parameters of etonogestrel and ethinyl estradiol were determined during one cycle of NuvaRing® use in 16 healthy female subjects and are summarized in Table II.

Distribution

Etonogestrel: Etonogestrel is approximately 32% bound to sex hormone binding globulin (SHBG) and approximately 66% bound to albumin in blood.

Ethinyl estradiol: Ethinyl estradiol is highly but not specifically bound to serum albumin (approximately 98.5%) and induces an increase in the serum concentrations of SHBG.

Metabolism

In vitro data shows that both etonogestrel and ethinyl estradiol are metabolized in liver microsomes by the cytochrome P450 3A4 isoenzyme. Ethinyl estradiol is primarily metabolized by aromatic hydroxylation, but a wide variety of hydroxylated and methylated metabolites are formed. These are present as free metabolites and as sulfate and glucuronide conjugates. The hydroxylated ethinyl estradiol metabolites have weak estrogenic activity. The biological activity of etonogestrel metabolites is unknown.

Excretion

Etonogestrel and ethinyl estradiol are primarily eliminated in urine, bile and feces.

SPECIAL POPULATIONS

Race

No formal studies were conducted to evaluate the effect of race on the pharmacokinetics of NuvaRing® (etonogestrel/ethinyl estradiol vaginal ring).

Hepatic Insufficiency

No formal studies were conducted to evaluate the effect of hepatic disease on the pharmacokinetics, safety, and efficacy of NuvaRing®. However, steroid hormones may be poorly metabolized in patients with impaired liver function (see PRECAUTIONS).

Renal Insufficiency

No formal studies were conducted to evaluate the effect of renal disease on the pharmacokinetics, safety, and efficacy of NuvaRing®.

DRUG. DRUG INTERACTIONS

Interactions between contraceptive steroids and other drugs have been reported in the literature (see PRECAUTIONS). The pharmacokinetics of NuvaRing® were evaluated in one cycle in 24 healthy female subjects randomized to a single-dose vaginal administration on Day 8 of 100 mg of a non-oxynol-9 spermicide gel or a 1200 mg miconazole nitrate antimycotic capsule. In this study, it was determined that the vaginally-administered, oil-based miconazole nitrate capsule increased the serum concentrations of etonogestrel and ethinyl estradiol by approximately 17% and 16%, respectively. The clinical significance of these findings is unknown; however, the contraceptive effectiveness of NuvaRing® is not expected to change. It was determined that the single dose of 100 mg vaginally-administered, water-based non-oxynol-9 gel did not affect the serum concentrations of etonogestrel or ethinyl estradiol. The effects of chronic administration of either of these products with NuvaRing® are unknown.