etonogestrel and ethinyl estradiol vaginal ring
NuvaRing

Available forms
Available by prescription only
Vaginal ring: Delivers 0.120 mg etonogestrel and 0.015 mg ethinyl estradiol daily

Indications and dosages
 Contraception. Women: One ring inserted into the vagina and left in place for 3 weeks. New ring inserted 1 week after previous ring has been removed.

Pharmacodynamics
Contraceptive action: Suppresses gonadotropins (inhibiting ovulation), increases the viscosity of cervical mucus (decreasing the ability of sperm to enter the uterus), and alters the endometrial lining (reducing potential for implantation).

Pharmacokinetics
Absorption: Both hormonal components are rapidly absorbed after release from the ring. Bioavailability of etonogestrel and ethinyl estradiol is 100% and 55.6%, respectively.
Distribution: Etonogestrel is 66% protein-bound and 32% bound to sex hormone-binding globulin. Ethinyl estradiol is about 98.5% protein-bound and increases serum levels of sex hormone-binding globulin.
Metabolism: Both components of drug are metabolized in the liver by cytochrome P-450 3A4. Many metabolites are present as free metabolites, sulfate, and glucuronide conjugates.
Excretion: Both components are eliminated mainly in urine, bile, and feces.

Contraindications and precautions
Contraindicated in patients hypersensitive to drugs or its components, in patients who are or may be pregnant or who are older than age 35 and smoke 15 or more cigarettes daily, in patients experiencing major surgery with prolonged immobilization, and in patients with thrombophlebitis, thromboembolic disorder, history of deep vein thrombophlebitis, cerebral vascular or coronary artery disease (current or previous), valvular heart disease with complications, severe hypertension, diabetes with vascular complications, headache with focal neurologic symptoms, known or suspected cancer of the endometrium or breast, estrogen-dependent neoplasia, abnormal undiagnosed genital bleeding, jaundice related to pregnancy or previous use of hormonal contraceptive, active liver disease, or benign or malignant hepatic tumors.
 Use cautiously in patients with hypertension, hyperlipidemias, obesity, or diabetes. Also use cautiously in patients with conditions that could be aggravated by fluid retention and in patients with a history of depression.

Interactions
Drug-drug. Acetaminophen: Decreases acetaminophen levels and increases ethinyl estradiol levels. Monitor patient for effects.
Ampicillin, barbiturates, carbamazepine, felbamate, griseofulvin, oxcarbazepine, phenylbutazone, phenytoin, rifampin, tetracyclines, topiramate: Decreases contraceptive efficacy and increases risk of pregnancy, breakthrough bleeding, or both. Tell patient to use an additional form of contraception while taking these drugs.
Ascorbic acid, atorvastatin, itraconazole: Increases ethinyl estradiol levels. Monitor patient for adverse effects.
Clofibric acid, morphine, salicylic acid, temazepam: Increases clearance of these drugs. Monitor patient for effectiveness.
Corticosteroids: Increases anti-inflammatory effect. Adjust dosage accordingly.
Cyclosporine, prednisolone, theophylline: Increases levels of these drugs. Monitor cyclosporine and theophylline levels and adjust dosages as needed.
Drug-herb. St. John’s wort: May reduce contraceptive effectiveness and increase risk of breakthrough bleeding and pregnancy. Advise patient to avoid use.
Drug-lifestyle. Smoking: Increases risk of serious CV adverse effects, especially in those older than age 35 who smoke 15 or more cigarettes daily. Discourage smoking.

Adverse reactions
CNS: headache, emotional lability, CVA.
CV: MI, thromboembolism.
EENT: sinusitis.
GI: nausea, hepatic neoplasia, gallbladder disease.
GU: vaginitis, leukorrhea, device-related events (such as foreign body sensation, coital difficulties, device expulsion), vaginal discomfort.
Metabolic: weight gain.
Respiratory: upper respiratory tract infection.

Effects on lab test results
• May increase levels of clotting factors VII, VIII, IX, and X; thyroid-binding globulin (leading to increased circulating total thyroid hormone levels); other binding proteins; sex hormone-binding globulins; and triglycerides. May decrease antithrombin III and serum folate levels.
• May increase PT and norepinephrine-induced platelet aggregability. May decrease T₃ resin uptake and glucose tolerance.

Overdose and treatment
Overdose may cause nausea, vomiting, vaginal bleeding, or other menstrual irregularities.
 Treatment is symptomatic.

Special considerations
• Stop drug at least 4 weeks before and for 2 weeks after procedures that may increase risk of thromboembolism and during and after prolonged immobilization.
• Stop drug if patient develops unexplained partial or complete loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions.
• Monitor blood pressure closely if patient has hypertension or renal disease. Stop drug if blood pressure rises.
• Stop drug if migraine begins or worsens or if patient has recurrent, persistent, or severe headaches.
• Stop drug if jaundice occurs. The hormones may be poorly metabolized in patients with liver disease.
• If patient has persistent or severe abnormal menstrual bleeding, look for cause. If amenorrhea occurs, rule out pregnancy.
• If depression occurs, stop drug to determine whether depression is drug-related.
• Ring should remain in place continuously for a full 3 weeks to maintain efficacy. It is then removed for 1 week. During this time, withdrawal bleeding occurs (usually starting on day 2 or 3 after removal). A new ring should be inserted 1 week after removal of the previous ring, regardless of whether menstrual bleeding is still present.
• If no hormonal contraceptive is used in the preceding month, insert ring on day 5 of the menstrual cycle (counting the first day of menstruation as day 1). For the first cycle of use, an additional form of birth control should be used until 7 days after the ring is inserted.
• When switching from other combination (estrogen plus progestin) hormonal contraceptives, insert the ring within 7 days after the last dose of combined hormonal contraceptive. This should be no later than the day that a new cycle of tablets would have begun. No backup method of contraception is needed.
• When switching from a progestin-only form of contraception, use a backup method of contraception for the first 7 days of using the ring in any of the following situations. If switching from progestin-only tablets, insert ring on any day of the month; don’t skip any days between the last oral dose and insertion of the ring. If switching from progestin-only implants (such as Norplant), insert the vaginal ring on the same day that the implants are removed. If switching from progestin-only intrauterine device (IUD), insert the vaginal ring on the same day that the IUD is removed. If switching from contraceptive injections (such as Depo-Provera), insert the vaginal ring on the same day that the next injection would be due. Begin use within the first 5 days after complete first-trimester abortion, 4 weeks postpartum in women who aren’t breast-feeding, or 4 weeks after a second-trimester abortion.
• If the ring is removed or expelled (for example, while patient is removing a tampon or moving the bowels), it should be washed with cool to lukewarm water and reinserted immediately. If the ring remains outside the body for longer than 3 hours, contraceptive efficacy may be compromised; patient should use a backup method of contraception until the newly reinserted ring has been used continuously for 7 days.
• Rule out pregnancy if patient hasn’t adhered to the prescribed regimen and a period is missed. Also rule out pregnancy even if prescribed regimen is adhered to but two periods are missed, or if patient has retained the ring for longer than 4 weeks.
Pregnant patients
• Rule out pregnancy before first use.
• Contraindicated during pregnancy. Device should be removed immediately if pregnancy is suspected.
• Don’t start drug earlier than 4 weeks after delivery in women who choose not to breast-feed.
Breast-feeding patients
• Drug isn’t recommended in breast-feeding women. Contraceptive steroids decrease the quantity and quality of breast milk.
Pediatric patients
• Safety and efficacy in postpubertal girls younger than age 16 are expected to be the same as for adults.
• Drug isn’t indicated before menarche.
Geriatric patients
• Don’t use in postmenopausal women.

Patient education
• Emphasize the importance of having regular annual physical examinations to check for adverse effects or developing contraindications.
• Tell patient that drug doesn’t protect against HIV and other sexually transmitted diseases.
• Advise patient not to smoke while using drug.
• Tell patient not to use a diaphragm or a sponge if a backup method of contraception is needed.
• Tell patient who wears contact lenses to contact an ophthalmologist if vision or lens tolerance changes.
• Tell patient to insert ring into the vagina (using fingers), to keep it in place continuously for 3 weeks to maintain efficacy, and then to remove it for 1 full week. Explain that, during this week, withdrawal bleeding occurs (usually starting on day 2 or 3 after removal). Tell patient to insert a new ring 1 week after removing the previous one, regardless of whether menstrual bleeding is still present.
• Instruct patient that the foil package is reclosable and should be used to dispose of the used ring. Tell her to reseal the ring in the package after removing the ring from the vagina.
• Advise patient that, if the ring is removed or expelled (for example, while she is removing a tampon, straining, or moving bowels), it should be washed with cool to lukewarm (not hot) water and reinserted immediately. Stress that contraceptive efficacy may be compromised if the ring stays outside the body for longer than 3 hours and that a backup method of contraception should be used until the newly reinserted ring has been used continuously for 7 days.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use