Ethinyl estradiol/Etonogestrel

Uses and Indications

Etonogestrel and ethinyl estradiol vaginal ring, also known as NuvaRing, EnilloRing, Haloette, and EluRyng, is an estrogen/progestin combination hormonal contraceptive (CHC) indicated for use by women to prevent pregnancy.

This product is intended solely for the prevention of pregnancy and does not provide protection against HIV infection (AIDS) or other sexually transmitted diseases.

No teratogenic or nonteratogenic effects are mentioned in the available data.

Dosage and Administration

One vaginal ring containing etonogestrel and ethinyl estradiol is to be inserted into the vagina. The ring must remain in place continuously for three weeks. Following this period, a one-week ring-free interval is required.

This administration schedule applies to all formulations of the vaginal ring, including NuvaRing, EnilloRing, Haloette, and EluRyng. It is essential that the ring is not removed during the three-week usage period to ensure effective contraceptive action. After the one-week interval, a new ring should be inserted to continue the regimen.

Contraindications

Use of this product is contraindicated in individuals with a high risk of arterial or venous thrombotic diseases, breast cancer, liver tumors or liver disease, undiagnosed abnormal uterine bleeding, and during pregnancy. Additionally, it is contraindicated in patients with hypersensitivity, including anaphylaxis and angioedema, to any of the components of the product. Co-administration with Hepatitis C drug combinations containing ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, is also contraindicated.

Warnings and Precautions

Women over 35 years old who smoke should not use Etonogestrel and Ethinyl Estradiol Vaginal Ring, NuvaRing, EnilloRing, Haloette, or any similar combination hormonal contraceptive (CHC). Cigarette smoking significantly increases the risk of serious cardiovascular events associated with the use of these products.

General Precautions

• Vascular Risks:

  • Discontinue use if a thrombotic event occurs.

  • Stop at least 4 weeks before and through 2 weeks after major surgery.

  • Initiate use no earlier than 4 weeks after delivery in women who are not breastfeeding.

• Toxic Shock Syndrome (TSS):

  • If signs or symptoms of TSS occur, consider this diagnosis and initiate appropriate medical evaluation and treatment.

• Liver Disease:

  • Discontinue use if jaundice develops.

• High Blood Pressure:

  • In women with well-controlled hypertension, monitor blood pressure and discontinue use if it rises significantly.

• Carbohydrate and Lipid Metabolic Effects:

  • Monitor prediabetic and diabetic women. Consider alternative contraceptive methods for those with uncontrolled dyslipidemia.

• Headache:

  • Evaluate significant changes in headaches and discontinue use if indicated.

• Uterine Bleeding:

  • Evaluate any irregular bleeding or amenorrhea.

Laboratory Tests

• Monitor blood pressure in women with well-controlled hypertension.

• Monitor prediabetic and diabetic women.

Emergency Medical Help Instructions

• If signs or symptoms of Toxic Shock Syndrome (TSS) are present, consider this diagnosis and initiate appropriate medical evaluation and treatment.

Stop Taking and Call Your Doctor Instructions

• Stop use if a thrombotic event occurs.

• Discontinue use if jaundice develops.

• Stop use if blood pressure rises significantly.

• Discontinue use if indicated due to significant changes in headaches.

Side Effects

Common adverse reactions (≥2%) associated with the use of Etonogestrel and Ethinyl Estradiol Vaginal Ring, NuvaRing, EnilloRing, Haloette, EluRyng, and Etonogestrel/Ethinyl Estradiol include:

• Vaginitis

• Headache (including migraine)

• Mood changes (e.g., depression, mood swings, mood altered, depressed mood, affect lability)

• Device-related events (e.g., expulsion/discomfort/foreign body sensation)

• Nausea/vomiting

• Vaginal discharge

• Increased weight

• Vaginal discomfort

• Breast pain/discomfort/tenderness

• Dysmenorrhea

• Abdominal pain

• Acne

• Decreased libido

Serious Adverse Reactions

Serious adverse reactions that may occur include:

• Deep vein thrombosis

• Stroke/cerebrovascular accident

• Arterial events (including arterial thromboembolism and myocardial infarction)

• Anxiety

• Cholelithiasis

• Vomiting

Warnings

• Cigarette Smoking and Serious Cardiovascular Events: Women over 35 years old who smoke should not use these products, as cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive (CHC) use.

• Toxic Shock Syndrome (TSS): If a patient exhibits signs or symptoms of TSS, the possibility of this diagnosis should be considered, and appropriate medical evaluation and treatment should be initiated.

• Liver Disease: Discontinue use if jaundice develops.

• High Blood Pressure: If used in women with well-controlled hypertension, blood pressure should be monitored, and use should be stopped if blood pressure rises significantly.

• Carbohydrate and Lipid Metabolic Effects: Monitor prediabetic and diabetic women. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia.

Additional Considerations

• Evaluate significant changes in headaches and discontinue use if indicated.

• Evaluate irregular bleeding or amenorrhea.

• Stop use if a thrombotic event occurs and discontinue at least 4 weeks before and through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery in women who are not breastfeeding.

Postmarketing Experience

Postmarketing experience has reported additional adverse reactions, including:

• Hypersensitivity reactions, including anaphylaxis and angioedema

• Urticaria

• Chloasma

• Device breakage (including with concomitant use of intravaginal antimycotic, antibiotic, and lubricant products)

• Vaginal injury (including associated pain, discomfort, and bleeding) associated with ring breakage

Contraindications

Contraindications for the use of these products include:

• A high risk of arterial or venous thrombotic diseases

• Breast cancer

• Liver tumors or liver disease

• Undiagnosed abnormal uterine bleeding

• Pregnancy

• Hypersensitivity, including anaphylaxis and angioedema, to any of the components

• Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir.

Drug Interactions

Drugs or herbal products that induce certain enzymes, particularly CYP3A4, may significantly decrease the effectiveness of combined hormonal contraceptives (CHCs) or lead to increased breakthrough bleeding. It is essential to counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used concurrently with CHCs.

This interaction is relevant across various formulations of CHCs, including:

• Etonogestrel and Ethinyl Estradiol Vaginal Ring

• Nuvaring

• Enilloring

• Haloette

• Etonogestrel and Ethinyl Estradiol

• Eluryng

• Etonogestrel/Ethinyl Estradiol

No specific drug and laboratory test interactions information is provided for some of these products, such as Haloette and Etonogestrel and Ethinyl Estradiol. However, the primary concern remains the impact of CYP3A4 inducers on the efficacy of these contraceptive methods.

Pediatric Use

The safety and efficacy of etonogestrel and ethinyl estradiol vaginal rings, including NuvaRing, Haloette, and Eluryng, have been established in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 as for users 18 years and older.

Use of these products is not indicated before menarche.

Geriatric Use

Elderly patients, particularly those who are postmenopausal, have not been studied in clinical trials involving NuvaRing, Haloette, Etonogestrel and Ethinyl Estradiol, and Eluryng. These products are not indicated for use in this population. Therefore, healthcare providers should exercise caution when considering these contraceptive options for geriatric patients, as the safety and efficacy in this demographic remain unestablished. Regular monitoring and alternative contraceptive methods should be considered for elderly patients, especially those who are postmenopausal.

Pregnancy

Etonogestrel and ethinyl estradiol vaginal ring is contraindicated during pregnancy, as there is no need for pregnancy prevention in women who are already pregnant. Epidemiologic studies and meta-analyses have not demonstrated an increased risk of genital or non-genital birth defects, including cardiac anomalies and limb-reduction defects, following maternal exposure to low-dose combined hormonal contraceptives (CHCs) prior to conception or during early pregnancy.

Animal studies have shown no adverse developmental outcomes in pregnant rats and rabbits when etonogestrel was administered during organogenesis at doses approximately 300 times the anticipated daily vaginal human dose (~0.002 mg/kg/day). Similarly, the co-administration of desogestrel and ethinyl estradiol during organogenesis did not result in adverse outcomes at doses at least 2/5 times, respectively, the anticipated daily vaginal human dose.

If pregnancy is confirmed, the use of the vaginal ring should be discontinued. In studies involving rats and rabbits at dosages up to 300 times the anticipated dose, etonogestrel was neither embryotoxic nor teratogenic. However, co-administration of a maternally toxic dose of desogestrel and ethinyl estradiol to pregnant rats was associated with embryolethality and skeletal abnormalities at doses significantly higher than the anticipated vaginal human dose. No adverse embryofetal effects were observed when the combination was administered at lower doses.

In summary, while the vaginal ring is contraindicated during pregnancy, available data suggest that exposure to etonogestrel and ethinyl estradiol prior to or during early pregnancy does not significantly increase the risk of major birth defects or adverse developmental outcomes.

Lactation

Small amounts of contraceptive steroids and/or metabolites, including etonogestrel and ethinyl estradiol, are transferred to human milk. However, harmful effects have not been observed in breastfed infants exposed to combined hormonal contraceptives (CHCs) through breast milk.

It is important to note that CHCs can reduce milk production in breastfeeding mothers. This reduction is less likely to occur once breastfeeding is well-established, but it can happen at any time in some women. Therefore, when possible, healthcare providers should advise nursing mothers to use non-estrogen-containing contraception until they have completely weaned their child.

The developmental and health benefits of breastfeeding should be carefully weighed against the mother's clinical need for CHCs, such as NuvaRing, Haloette, Eluryng, or other etonogestrel and ethinyl estradiol formulations, as well as any potential adverse effects on the breastfed child stemming from the use of these contraceptives or from the underlying maternal condition.

Renal Impairment

Patients with renal impairment have not been specifically studied in relation to the pharmacokinetics of Etonogestrel and Ethinyl Estradiol formulations, including the vaginal ring and other insertable forms. The available labels do not provide any information regarding dosage adjustments, special monitoring, or safety considerations for individuals with reduced kidney function. Consequently, healthcare providers should exercise caution when prescribing these products to patients with renal impairment, as the lack of data necessitates careful consideration of potential risks and benefits. Regular monitoring may be warranted in these patients, although specific guidelines are not outlined in the current labeling.

Hepatic Impairment

Patients with hepatic impairment should discontinue the use of etonogestrel and ethinyl estradiol vaginal ring, NuvaRing, EnilloRing, and Haloette if jaundice develops. The pharmacokinetics of Haloette have not been studied in this population, and steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of combined hormonal contraceptive (CHC) use until liver function markers return to normal. Monitoring for signs of jaundice is essential in these patients.

Overdosage

In cases of suspected overdose of combined hormonal contraceptives (CHCs) such as Etonogestrel and Ethinyl Estradiol, there have been no reports of serious ill effects. However, overdosage may lead to symptoms including withdrawal bleeding in females and nausea. It is important to note that if the vaginal ring breaks, it does not release a higher dose of hormones.

In the event of a suspected overdose, it is recommended that all vaginal rings, including Etonogestrel and Ethinyl Estradiol, NuvaRing, EnilloRing, Haloette, and EluRyng, be removed immediately. Symptomatic treatment should then be provided as necessary. Continuous monitoring of the patient may be warranted to address any symptoms that arise.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 24-month carcinogenicity study conducted in rats with subdermal implants releasing 10 and 20 mcg of etonogestrel per day, which corresponds to approximately 0.3 and 0.6 times the systemic steady-state exposure of women using the etonogestrel and ethinyl estradiol vaginal ring, no drug-related carcinogenic potential was observed.

Etonogestrel was evaluated for mutagenicity and was found to be non-genotoxic in several assays, including the in vitro Ames/Salmonella reverse mutation assay, the chromosomal aberration assay in Chinese hamster ovary cells, and the in vivo mouse micronucleus test.

A fertility study involving etonogestrel was performed in rats at a dose approximately 600 times the anticipated daily vaginal human dose (~0.002 mg/kg/day). The results indicated that treatment did not adversely affect litter parameters following cessation of treatment, thereby supporting the return to fertility after suppression with etonogestrel.

No information was provided regarding teratogenic or non-teratogenic effects, nor was there any specific data on animal pharmacology and toxicology.

Storage and Handling

Etonogestrel and Ethinyl Estradiol Vaginal Rings are supplied in individual packaging, typically within aluminum laminate sachets or reclosable pouches. Prior to dispensing to the user, these rings must be stored refrigerated at a temperature range of 2-8°C (36-46°F).

After dispensing, the rings can be stored for up to 4 months at room temperature, specifically at 25°C (77°F). Temperature excursions are permissible between 15-30°C (59-86°F). It is crucial to avoid exposure to direct sunlight and to ensure that the storage temperature does not exceed 30°C (86°F).

When the rings are dispensed, an expiration date must be placed on the label, which should not exceed either 4 months from the date of dispensing or the manufacturer's expiration date, whichever comes first.

After use, the rings should be returned to their original packaging and discarded in a waste receptacle that is out of reach of children and pets. It is important to note that the rings should not be flushed down the toilet.