Etonogestrel/Ethinyl Estradiol (Page 5 of 8)

7.4 Interference with Laboratory Tests

The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Etonogestrel/Ethinyl Estradiol Vaginal Ring is contraindicated during pregnancy because there is no need for pregnancy prevention in a woman who is already pregnant. Epidemiologic studies and meta-analyses have not shown an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following maternal exposure to low dose CHCs prior to conception or during early pregnancy. No adverse developmental outcomes were observed in pregnant rats and rabbits with the administration of etonogestrel during organogenesis at doses approximately 300 times the anticipated daily vaginal human dose (~0.002 mg/kg/day).

No adverse developmental outcomes were observed in pregnant rats and rabbits with the co-administration of the combination desogestrel/ethinyl estradiol during organogenesis at desogestrel/ethinyl estradiol doses at least 2/5 times, respectively, the anticipated daily vaginal human dose (~0.002 desogestrel/0.00025 ethinyl estradiol mg/kg/day).

Discontinue Etonogestrel/Ethinyl Estradiol Vaginal Ring use if pregnancy is confirmed.

Data

Animal Data

In rats and rabbits at dosages up to 300 times the anticipated dose, etonogestrel is neither embryotoxic nor teratogenic. Co-administration of a maternally toxic dose of desogestrel/ethinyl estradiol to pregnant rats was associated with embryolethality and wavy ribs at a desogestrel/ethinyl estradiol dose that was 40/130 times, respectively, the anticipated vaginal human dose (0.002 desogestrel/0.00025 ethinyl estradiol mg/kg/day). No adverse embryofetal effects were observed when the combination was administered to pregnant rats at a desogestrel/ethinyl estradiol dose that was 4/13 times, respectively, the anticipated vaginal human dose. When desogestrel/ethinyl estradiol was given to pregnant rabbits, pre-implantation loss was observed at a desogestrel/ethinyl estradiol dose that was 3/10 times, respectively, the anticipated vaginal human dose. No adverse embryofetal effects were observed when the combination was administered to pregnant rabbits at a desogestrel/ethinyl estradiol dose that was 2/5 times the anticipated vaginal human dose.

8.2 Lactation

Risk Summary

Small amounts of contraceptive steroids and/or metabolites, including etonogestrel and ethinyl estradiol are transferred to human milk. Harmful effects have not been observed in breastfed infants exposed to CHCs through breast milk. CHCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women.

When possible, advise the nursing mother to use non-estrogen-containing contraception until she has completely weaned her child. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Etonogestrel/Ethinyl Estradiol Vaginal Ring and any potential adverse effects on the breastfed child from Etonogestrel/Ethinyl Estradiol Vaginal Ring or from the underlying maternal condition.

8.4 Pediatric Use

Safety and efficacy of Etonogestrel/Ethinyl Estradiol Vaginal Ring have been established in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not indicated.

8.5 Geriatric Use

Etonogestrel/Ethinyl Estradiol Vaginal Ring has not been studied in postmenopausal women and is not indicated in this population.

8.6 Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of Etonogestrel/Ethinyl Estradiol Vaginal Ring has not been studied. Steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of CHC use until markers of liver function return to normal. [See Contraindications (4) and Warnings and Precautions (5.3).]

8.7 Renal Impairment

The effect of renal impairment on the pharmacokinetics of Etonogestrel/Ethinyl Estradiol Vaginal Ring has not been studied.

10 OVERDOSAGE

There have been no reports of serious ill effects from overdose of CHCs. Overdosage may cause withdrawal bleeding in females and nausea. If the ring breaks, it does not release a higher dose of hormones. In case of suspected overdose, all Etonogestrel/Ethinyl Estradiol Vaginal Ring rings should be removed and symptomatic treatment given.

11 DESCRIPTION

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. Etonogestrel/Ethinyl Estradiol Vaginal Ring 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. Etonogestrel/Ethinyl Estradiol Vaginal Ring is not made with natural rubber latex. Etonogestrel/Ethinyl Estradiol Vaginal Ring 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 StructureChemical Structure
C22 H28 O2 C20 H24 O2

12 CLINICAL PHARMACOLOGY

12.1 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).

12.3 Pharmacokinetics

Absorption

Etonogestrel: Etonogestrel released by Etonogestrel/Ethinyl Estradiol Vaginal Ring 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 Etonogestrel/Ethinyl Estradiol Vaginal Ring use are summarized in Table 2.

Ethinyl estradiol: Ethinyl estradiol released by Etonogestrel/Ethinyl Estradiol Vaginal Ring 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 Etonogestrel/Ethinyl Estradiol Vaginal Ring use are summarized in Table 2.

Table 2: 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 Etonogestrel/Ethinyl Estradiol Vaginal Ring is shown in Figure 2.

Figure 2: Mean Serum Concentration-Time Profile of Etonogestrel and Ethinyl Estradiol during Three Weeks of Etonogestrel/Ethinyl Estradiol Vaginal Ring Use
Figure 2
(click image for full-size original)

The pharmacokinetic parameters of etonogestrel and ethinyl estradiol were determined during one cycle of Etonogestrel/Ethinyl Estradiol Vaginal Ring use in 16 healthy female subjects and are summarized in Table 3.

Table 3: Mean (SD) Pharmacokinetic Parameters of Etonogestrel/Ethinyl Estradiol Vaginal Ring (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)

Prolonged use of Etonogestrel/Ethinyl Estradiol Vaginal Ring: The mean serum etonogestrel concentration at the end of the fourth week of continuous use of Etonogestrel/Ethinyl Estradiol Vaginal Ring 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 Etonogestrel/Ethinyl Estradiol Vaginal Ring 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 (7).]

The drug interactions of Etonogestrel/Ethinyl Estradiol Vaginal Ring 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 Etonogestrel/Ethinyl Estradiol Vaginal Ring [see Dosage and Administration (2.5)].

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