The most common adverse events reported by five to 14% of women using NuvaRing® in clinical trials (n=2501) were the following: vaginitis, headache, upper respiratory tract infection, vaginal secretion, sinusitis, weight gain, and nausea.

The most frequent system-organ class adverse events leading to discontinuation in one to 2.5% of women using NuvaRing® in the trials included the following: device-related events (foreign body sensation, coital problems, device expulsion), vaginal symptoms (discomfort/vaginitis/vaginal secretion), headache, emotional lability, and weight gain.

Listed below are adverse reactions that have been associated with the use of combination hormonal

contraceptives. These are also likely to apply to combination vaginal hormonal contraceptives, such as NuvaRing®.

An increased risk of the following serious adverse reactions has been associated with the use of combination hormonal contraceptives (see CONTRAINDICATIONS and WARNINGS):

There is evidence of an association between the following conditions and the use of combination hormonal contraceptives:

The following additional adverse reactions have been reported in users of combination hormonal contraceptives and are believed to be drug-related:

The following additional adverse reactions have been reported in users of combination hormonal contraceptives and a causal association has been neither confirmed nor refuted:

Changes in contraceptive effectiveness associated with co-administration of other drugs

Anti-infective agents and anticonvulsants

Contraceptive effectiveness may be reduced when hormonal contraceptives are co-administered with some antifungals, anticonvulsants, and other drugs that increase metabolism of contraceptive steroids. This could result in unintended pregnancy or breakthrough bleeding. Examples include barbiturates, griseofulvin, rifampin, phenylbutazone, phenytoin, carbamazepine, felbamate, oxcarbazepine, topiramate, and modafinil. Women may need to use an additional contraceptive method when taking such medications.

Anti-HIV protease inhibitors

Several of the anti-HIV protease inhibitors have been studied with co-administration of oral combination hormonal contraceptives; significant changes (increases and decreases) in the plasma levels of the estrogen and progestin have been noted in some cases. The efficacy and safety of hormonal contraceptive products may be affected with co-administration of anti-HIV protease inhibitors. Healthcare providers should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information.

Herbal products

Herbal products containing St. John's Wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding.

Increase in plasma hormone levels associated with co-administered drugs:

Co-administration of atorvastatin and certain oral contraceptives containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. CYP 3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels. Co-administration of vaginal miconazole nitrate and NuvaRing® increases the serum concentrations of etonogestrel and ethinyl estradiol by up to 40%.

Changes in plasma levels of co-administered drugs:

Combination hormonal contraceptives containing some synthetic estrogens (e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporine, prednisolone, and theophylline have been reported with concomitant administration of oral contraceptives. In addition, oral contraceptives may induce the conjugation of other compounds. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine and clofibric acid have been noted when these drugs were administered with oral contraceptives.

Interactions With Laboratory Tests

Certain endocrine and liver function tests and blood components may be affected by combined hormonal contraceptives:

a. Increased prothrombin and factors VII, VIII, IX and X; decreased antithrombin 3, increased norepinephrine-induced platelet aggregability.

b. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered.

c. Other binding proteins may be elevated in serum.

d. Sex hormone-binding globulins are increased and result in elevated levels of total circulating sex steroids; however, free or biologically active levels either decrease or remain unchanged.

e. Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected.

f. Glucose tolerance may be decreased.

g. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing NuvaRing®.

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