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 latter finding in humans is unknown.
Pharmacokinetics
Absorption
Etonogestrel: Etonogestrel released by NuvaRing® is rapidly absorbed. The bioavailability of etonogestrel after vaginal administration is approximately 100%. The serum etonogestrel and ethinyl estradiol concentrations observed during three weeks of NuvaRing® use are summarized in Table I.
Ethinyl estradiol: Ethinyl estradiol released by NuvaRing® is rapidly absorbed. The bioavailability of ethinyl estradiol after vaginal administration is approximately 56%, 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.
TABLE I: MEAN (SD) SERUM ETONOGESTREL AND ETHINYL ESTRADIOL CONCENTRATIONS (n=16). | 1 week | 2 weeks | 3 weeks |
| etonogestrel (pg/mL) | 1578 (408) | 1476 (362) | 1374 (328) |
| ethinyl estradiol (pg/mL) | 19.1 (4.5) | 18.3 (4.3) | 17.6 (4.3) |
The pharmacokinetic profile of etonogestrel and ethinyl estradiol during use of NuvaRing® is shown in Figure 1.
 Figure 1. Mean serum concentration-time profile of etonogestrel and ethinyl estradiol during three weeks of NuvaRing® use.
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.
TABLE II: MEAN (SD) PHARMACOKINETIC PARAMETERS OF NuvaRing® (n=16). | Hormone | Cmax
pg/mL | Tmax
hr | t½
hr | CL
L/hr |
Cmax - maximum serum drug concentration
Tmax - time at which maximum serum drug concentration occurs
t½ - elimination half-life, calculated by 0.693/Kelim
CL - apparent clearance |
| etonogestrel | 1716 (445) | 200.3 (69.6) | 29.3 (6.1) | 3.4 (0.8) |
| ethinyl estradiol | 34.7 (17.5) | 59.3 (67.5) | 44.7 (28.8) | 34.8 (11.6) |
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 (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®.
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 women 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 drug interactions of NuvaRing® were evaluated in several studies.
A single-dose vaginal administration of an oil-based 1200 mg miconazole nitrate capsule increased the serum concentrations of etonogestrel and ethinyl estradiol by approximately 17% and 16%, respectively. Following multiple doses of 200 mg miconazole nitrate by vaginal suppository or vaginal cream, the mean serum concentrations of etonogestrel and ethinyl estradiol increased by up to 40%.
A single-dose vaginal administration of 100 mg water-based nonoxynol-9 spermicide gel did not affect the serum concentrations of etonogestrel or ethinyl estradiol.
The serum concentrations of etonogestrel and ethinyl estradiol were not affected by concomitant administration of oral amoxicillin or doxycycline in standard dosages during 10 days of antibiotic treatment.
Tampon Use
The use of tampons had no effect on serum concentrations of etonogestrel and ethinyl estradiol during use of NuvaRing®.
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