NuvaRing

NUVARING- etonogestrel and ethinyl estradiol insert, extended release
Organon Pharmaceuticals USA

delivers 0.120 mg/0.015 mg per day

Women should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

FOR VAGINAL USE ONLY

DESCRIPTION

NuvaRing® (etonogestrel/ethinyl estradiol vaginal ring) is a non-biodegradable, flexible, transparent, colorless to almost colorless, combination contraceptive vaginal ring containing two active components, a progestin, etonogestrel (13-ethyl-17-hydroxy-11-methylene-18,19-dinor-17α -pregn-4-en-20-yn-3-one) and an estrogen, ethinyl estradiol (19-nor-17α -pregna-1,3,5(10)-trien-20-yne-3, 17-diol). When placed in the vagina, each ring releases on average 0.120 mg/day of etonogestrel and 0.015 mg/day of ethinyl estradiol over a three-week period of use. NuvaRing® is made of ethylene vinylacetate copolymers (28% and 9% vinylacetate) and magnesium stearate and contains 11.7 mg etonogestrel and 2.7 mg ethinyl estradiol. NuvaRing® is latex-free. NuvaRing® has an outer diameter of 54 mm and a cross-sectional diameter of 4 mm. The molecular weights for etonogestrel and ethinyl estradiol are 324.46 and 296.40, respectively.

The structural formulas are as follows:

Chemical Structure
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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 week2 weeks3 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
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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).
HormoneCmax pg/mLTmax hrt1/2 hrCLL/hr
Cmax — maximum serum drug concentrationTmax — time at which maximum serum drug concentration occurst1/2 — elimination half-life, calculated by 0.693/Kelim CL — apparent clearance
etonogestrel1716 (445)200.3 (69.6)29.3 (6.1)3.4 (0.8)
ethinyl estradiol34.7 (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.

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