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NuvaRing

NuvaRing

CLINICAL PHARMACOLOGY

Mechanism of Action

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).

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 2.

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 2.

Table 2: 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 2.

Figure 2: Mean Serum Concentration-Time Profile of Etonogestrel and Ethinyl Estradiol during Three Weeks of NuvaRing Use

Mean Serum Concentration-Time Profile - Illustration

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 3.

Table 3: Mean (SD) Pharmacokinetic Parameters of NuvaRing (n=16)

Hormone Cmax pg/mL Tmax hr t½ hr CL L/hr
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)
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

Prolonged use of NuvaRing: The mean serum etonogestrel concentration at the end of the fourth week of continuous use of NuvaRing was 1272 ± 311 pg/mL compared to a mean concentration range of 1578 ± 408 to 1374 ± 328 pg/mL at the end of weeks one to three. The mean serum ethinyl estradiol concentration at the end of the fourth week of continuous use of NuvaRing was 16.8 ± 4.6 pg/mL compared to a mean concentration range of 19.1 ± 4.5 to 17.6 ± 4.3 pg/mL at the end of weeks one to three.

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.

Drug Interactions

[See also DRUG INTERACTIONS]

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 [see DOSAGE AND ADMINISTRATION].

Clinical Studies

In three large one-year clinical trials enrolling 2,834 women aged 18-40 years, in North America, Europe, Brazil, and Chile, the racial distribution was 93% Caucasian, 5.0% Black, 0.8% Asian, and 1.2% Other. W omen with BMI ≥ 30 kg/m² were excluded from these studies.

Based on pooled data from the three trials, 2,356 women aged < 35 years completed 23,515 evaluable cycles of NuvaRing use (cycles in which no back-up contraception was used). The pooled pregnancy rate (Pearl Index) was 1.28 (95% CI [0.8, 1.9]) per 100 women-years of NuvaRing use. In the US study, the Pearl Index was 2.02 (95% CI [1.1, 3.4]) per 100 women-years of NuvaRing use.

REFERENCES

1. Dinger, J et. al., Cardiovascular risk associated with the use of an etonogestrel-containing vaginal ring. Obstetrics & Gynecology 2013; 122(4): 800-808.

2. Sidney, S. et. al., Recent combined hormonal contraceptives (CHCs) and the risk of thromboembolism and other cardiovascular events in new users. Contraception 2013; 87: 93– 100.

3. Combined hormonal contraceptives (CHCs) and the risk of cardiovascular endpoints. Sidney, S. (primary author) http://www.fda.gov/downloads/Drugs/DrugSafety/UCM277384.pdf, accessed 23Aug-2013.

Last reviewed on RxList: 10/18/2013
This monograph has been modified to include the generic and brand name in many instances.

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