Etonogestrel/Ethinyl Estradiol (Page 4 of 8)

5.15 Effect on Binding Globulins

The estrogen component of CHCs may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin. The dose of replacement thyroid hormones or cortisol therapy may need to be increased.

5.16 Monitoring

A woman who is using Etonogestrel/Ethinyl Estradiol Vaginal Ring should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare.

5.17 Hereditary Angioedema

In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

5.18 Chloasma

Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while using Etonogestrel/Ethinyl Estradiol Vaginal Ring.

6 ADVERSE REACTIONS

The following serious adverse reactions with the use of CHCs are discussed elsewhere in the labeling.

Adverse reactions commonly reported by CHC users are:

  • Irregular uterine bleeding
  • Nausea
  • Breast tenderness
  • Headache

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Trials with a duration of 6 to 13 28-day cycles provided safety data. In total, 2,501 women, aged 18 to 41 contributed 24,520 cycles of exposure.

Common Adverse Reactions (≥ 2%): vaginitis (13.8%), headache (including migraine) (11.2%), mood changes (e.g., depression, mood swings, mood altered, depressed mood, affect lability) (6.4%), device-related events (e.g., expulsion/discomfort/foreign body sensation) (6.3%), nausea/vomiting (5.9%), vaginal discharge (5.7%), increased weight (4.9%), vaginal discomfort (4.0%), breast pain/discomfort/tenderness (3.8%), dysmenorrhea (3.5%), abdominal pain (3.2%), acne (2.4%), and decreased libido (2.0%).

Adverse Reactions (≥ 1%) Leading to Study Discontinuation: 13.0% of the women discontinued from the clinical trials due to an adverse reaction; the most common adverse reactions leading to discontinuation were device-related events (2.7%), mood changes (1.7%), headache (including migraine) (1.5%) and vaginal symptoms (1.2%).

Serious Adverse Reactions: deep vein thrombosis [see Warnings and Precautions (5.1)] , anxiety, cholelithiasis, and vomiting.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Etonogestrel/Ethinyl Estradiol Vaginal Ring. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders: hypersensitivity reactions, including anaphylaxis and angioedema

Nervous system disorders: stroke/cerebrovascular accident

Vascular disorders: arterial events (including arterial thromboembolism and myocardial infarction), aggravation of varicose veins

Skin and subcutaneous tissue disorders: urticaria, chloasma

Reproductive system and breast disorders: penile disorders, including local reactions on penis (in male partners of women using Etonogestrel/Ethinyl Estradiol Vaginal Ring), galactorrhea

General Disorders and Administration Site Conditions: device breakage (including with concomitant use of intravaginal antimycotic, antibiotic, and lubricant products)

Injury, poisoning and procedural complications: vaginal injury (including associated pain, discomfort, and bleeding) associated with ring breakage

7 DRUG INTERACTIONS

Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.

7.1 Effects of Other Drugs on CHCs

Substances decreasing the plasma concentrations of CHCs and potentially diminishing the effectiveness of CHCs

Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of CHCs and potentially diminish the effectiveness of CHCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include: phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St. John’s wort. Interactions between CHCs and other drugs may lead to breakthrough bleeding and/or contraceptive failure.

Counsel women to use an alternative non-hormonal method of contraception or a back-up method when enzyme inducers are used with Etonogestrel/Ethinyl Estradiol Vaginal Ring, and to continue back-up non-hormonal contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.

Note: Etonogestrel/Ethinyl Estradiol Vaginal Ring may interfere with the correct placement and position of certain female barrier methods such as a diaphragm or female condom. These methods are not recommended as back-up methods with Etonogestrel/Ethinyl Estradiol Vaginal Ring use [see Dosage and Administration (2.5)].

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. The effects of other antibiotics on etonogestrel or ethinyl estradiol concentrations have not been evaluated.

Substances increasing the plasma concentrations of CHCs

Co-administration of atorvastatin and certain CHCs containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20-25%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. Concomitant administration of strong or moderate CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma estrogen and/or progestin concentrations. Co-administration of vaginal miconazole nitrate and Etonogestrel/Ethinyl Estradiol Vaginal Ring increases the serum concentrations of etonogestrel and ethinyl estradiol by up to 40% [see Clinical Pharmacology (12.3)].

Human immunodeficiency virus (HIV) / Hepatitis C Virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors

Significant changes in the plasma concentrations of the estrogen and /or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir]) /HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., efavirenz, nevirapine] or increase [e.g., etravirine]). These changes may be clinically relevant in some cases.

7.2 Effects of CHCs on Other Drugs

CHCs containing ethinyl estradiol may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations. CHCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid and temazepam. A significant decrease in the plasma concentrations of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.

Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increase with use of CHCs.

7.3 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation

Do not co-administer Etonogestrel/Ethinyl Estradiol Vaginal Ring with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions (5.4)].

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