Etonogestrel/Ethinyl estradiol

Description

Etonogestrel and ethinyl estradiol vaginal ring is a non-biodegradable, flexible, transparent, colorless to almost colorless combination contraceptive vaginal ring. The active components are etonogestrel (13-ethyl-17-hydroxy-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-3-one) and ethinyl estradiol (19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol). 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. The vaginal ring is composed of ethylene vinylacetate copolymers (28% and 9% vinylacetate) and magnesium stearate, containing 11.7 mg etonogestrel and 2.7 mg ethinyl estradiol. The ring is not made with natural rubber latex. It 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.

Uses and Indications

Etonogestrel and ethinyl estradiol vaginal ring is indicated for use by women for the prevention of pregnancy. This product is specifically designed to prevent pregnancy and does not provide protection against HIV infection (AIDS) or other sexually transmitted diseases.

Dosage and Administration

One etonogestrel and ethinyl estradiol vaginal ring should be inserted into the vagina. The ring must remain in place continuously for a duration of three weeks. Following this period, a one-week ring-free interval is required. It is essential for healthcare professionals to ensure that patients understand the importance of adhering to this schedule for optimal efficacy.

Contraindications

Use of this product is contraindicated in the following situations:

Patients with a high risk of arterial or venous thrombotic diseases due to the potential for exacerbating these conditions.

Individuals with breast cancer, as the product may promote tumor growth.

Patients with liver tumors or liver disease, given the risk of hepatic complications.

Those experiencing undiagnosed abnormal uterine bleeding, as this may mask underlying conditions.

Pregnant individuals, due to potential harm to the fetus.

Patients with hypersensitivity to any components of the etonogestrel and ethinyl estradiol vaginal ring, including a history of anaphylaxis or angioedema.

Coadministration with Hepatitis C drug combinations containing ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, is contraindicated due to the risk of significant drug interactions.

Warnings and Precautions

Women over 35 years of age who smoke are advised against the use of the etonogestrel and ethinyl estradiol vaginal ring due to an increased risk of serious cardiovascular events associated with cigarette smoking and combination hormonal contraceptive (CHC) use.

General Precautions

Vascular risks must be carefully considered. The etonogestrel and ethinyl estradiol vaginal ring should be discontinued immediately if a thrombotic event occurs. Additionally, it is recommended to stop using the ring at least 4 weeks prior to and for 2 weeks following any major surgical procedures. For women who are not breastfeeding, initiation of the ring should not occur earlier than 4 weeks postpartum.

Toxic Shock Syndrome (TSS) is a serious condition that requires immediate attention. If a patient presents with signs or symptoms suggestive of TSS, healthcare professionals should consider this diagnosis and initiate appropriate medical evaluation and treatment.

In patients with liver disease, the etonogestrel and ethinyl estradiol vaginal ring should be discontinued if jaundice develops. For women with well-controlled hypertension, it is essential to monitor blood pressure regularly. The use of the ring should be stopped if there is a significant rise in blood pressure.

Monitoring is also recommended for women with prediabetes or diabetes, as the etonogestrel and ethinyl estradiol vaginal ring may affect carbohydrate and lipid metabolism. An alternative contraceptive method should be considered for women with uncontrolled dyslipidemia.

Healthcare providers should evaluate any significant changes in headache patterns and discontinue the use of the ring if indicated. Irregular uterine bleeding or amenorrhea should also be assessed appropriately.

Laboratory Tests

Regular monitoring of blood pressure is advised for women with well-controlled hypertension. Additionally, prediabetic and diabetic women should be monitored closely to manage any potential metabolic effects.

Emergency Medical Help Instructions

In cases where a patient exhibits signs or symptoms of Toxic Shock Syndrome (TSS), immediate medical evaluation and treatment should be initiated.

Stop Taking and Call Your Doctor Instructions

Patients should discontinue the etonogestrel and ethinyl estradiol vaginal ring if any of the following occur: a thrombotic event, the development of jaundice, a significant rise in blood pressure, or significant changes in headache patterns.

Side Effects

Patients using the etonogestrel and ethinyl estradiol vaginal ring may experience a range of adverse reactions. Common adverse reactions occurring in clinical trials at a frequency of 2% or greater include vaginitis, headache (including migraine), mood changes (such as depression, mood swings, and affect lability), device-related events (including expulsion, discomfort, and foreign body sensation), nausea and vomiting, vaginal discharge, increased weight, vaginal discomfort, breast pain or tenderness, dysmenorrhea, abdominal pain, acne, and decreased libido.

Serious warnings are associated with the use of this contraceptive method, particularly regarding the risk of serious cardiovascular events in women over 35 years old who smoke. Cigarette smoking significantly increases this risk, and such patients should not use the etonogestrel and ethinyl estradiol vaginal ring.

Additional adverse reactions and important considerations include the need to discontinue use if a thrombotic event occurs, and to stop the ring at least 4 weeks before and through 2 weeks after major surgery. It is also advised to start no earlier than 4 weeks postpartum in women who are not breastfeeding. Patients should be monitored for signs of Toxic Shock Syndrome (TSS), and if symptoms arise, appropriate medical evaluation and treatment should be initiated. The use of the ring should be discontinued if jaundice develops, and blood pressure should be monitored in women with well-controlled hypertension, with discontinuation recommended if blood pressure rises significantly.

For women with prediabetes or diabetes, monitoring for carbohydrate and lipid metabolic effects is essential, and an alternate contraceptive method should be considered for those with uncontrolled dyslipidemia. Significant changes in headache patterns should prompt evaluation, and discontinuation of the ring may be necessary. Irregular bleeding or amenorrhea should also be evaluated.

Contraindications for the etonogestrel and ethinyl estradiol vaginal ring include a high risk of arterial or venous thrombotic diseases, breast cancer, liver tumors or liver disease, undiagnosed abnormal uterine bleeding, pregnancy, hypersensitivity to any components of the ring, and coadministration with Hepatitis C drug combinations containing ombitasvir, paritaprevir, ritonavir, with or without dasabuvir.

Drug Interactions

Drugs or herbal products that induce enzymes, particularly CYP3A4, may reduce the effectiveness of combined hormonal contraceptives (CHCs) and potentially lead to increased breakthrough bleeding. It is advisable for healthcare providers to counsel patients on the necessity of using a backup or alternative method of contraception when enzyme inducers are co-administered with CHCs to ensure continued contraceptive efficacy.

No specific drug and laboratory test interactions have been reported.

Packaging & NDC

The table below lists all NDC Code configurations of Etonogestrel and Ethinyl Estradiol, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The safety and efficacy of the etonogestrel and ethinyl estradiol vaginal ring have been established in women of reproductive age. Efficacy is anticipated to be comparable for postpubertal adolescents under the age of 18 and for users aged 18 years and older. However, the use of this product is not indicated for individuals prior to menarche.

Geriatric Use

Etonogestrel and ethinyl estradiol vaginal ring has not been studied in elderly patients, specifically those who are postmenopausal, and is not indicated for use in this population. Therefore, healthcare providers should exercise caution when considering this treatment for geriatric patients, particularly those aged 65 and older.

Due to the lack of clinical data in this demographic, it is essential to monitor for potential adverse effects and to consider alternative therapies that have been established as safe and effective for postmenopausal women.

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 that no adverse developmental outcomes were observed 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 coadministration of desogestrel and ethinyl estradiol during organogenesis at doses at least 2/5 times the anticipated daily vaginal human dose also did not result in adverse developmental outcomes.

However, caution is warranted as the coadministration of a maternally toxic dose of desogestrel and ethinyl estradiol to pregnant rats was associated with embryolethality and wavy ribs at doses that were 40/130 times the anticipated vaginal human dose. In contrast, no adverse embryofetal effects were observed when the combination was administered to pregnant rats at doses that were 4/13 times the anticipated vaginal human dose. In pregnant rabbits, preimplantation loss was noted at a desogestrel/ethinyl estradiol dose that was 3/10 times the anticipated vaginal human dose, while no adverse effects were observed at doses that were 2/5 times the anticipated vaginal human dose.

If pregnancy is confirmed, it is recommended to discontinue the use of the etonogestrel and ethinyl estradiol vaginal ring.

Lactation

Etonogestrel and ethinyl estradiol vaginal ring is contraindicated during pregnancy, as there is no need for pregnancy prevention in a woman who is already pregnant. Lactating mothers should discontinue the use of the etonogestrel and ethinyl estradiol vaginal ring if pregnancy is confirmed. There are no specific data provided regarding the excretion of etonogestrel and ethinyl estradiol in breast milk or the effects on breastfed infants. Therefore, healthcare professionals should exercise caution and consider the potential risks and benefits when advising lactating mothers regarding the use of this contraceptive method.

Renal Impairment

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

Hepatic Impairment

Patients with hepatic impairment should be closely monitored for any signs of liver dysfunction during treatment with the etonogestrel and ethinyl estradiol vaginal ring. In the event that jaundice develops, the use of the vaginal ring must be discontinued immediately. It is essential for healthcare providers to assess liver function regularly and to evaluate the necessity of continuing therapy in patients with compromised liver function.

Overdosage

In cases of overdosage with combined hormonal contraceptives (CHCs), there have been no documented instances of serious adverse effects. However, it is important to recognize that overdosage may lead to certain symptoms, including withdrawal bleeding in females and nausea.

In the event of a suspected overdose, it is recommended that all etonogestrel and ethinyl estradiol vaginal rings be removed promptly. Following the removal of the rings, healthcare professionals should provide symptomatic treatment as necessary to manage any adverse effects experienced by the patient. Monitoring and supportive care may be warranted based on the clinical presentation.

Nonclinical Toxicology

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 observed in women using the etonogestrel and ethinyl estradiol vaginal ring, no drug-related carcinogenic potential was identified.

Etonogestrel was evaluated for mutagenic potential 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 (approximately 0.002 mg/kg/day). The results indicated that treatment did not adversely affect litter parameters following the cessation of treatment, thereby supporting the conclusion that fertility was restored after suppression with etonogestrel.

Postmarketing Experience

In postmarketing surveillance, various adverse events have been reported voluntarily. Studies indicate that the risk of venous thromboembolism associated with the etonogestrel and ethinyl estradiol vaginal ring is comparable to that of women using combination birth control pills. However, some studies suggest a higher risk of blood clots in women using combination birth control pills containing desogestrel compared to those using pills without this progestin.

Serious complications related to blood clots, which may lead to severe outcomes such as heart attack or stroke, have been documented. Specific manifestations of serious blood clots include deep vein thrombosis, pulmonary embolism, loss of eyesight, heart attack, and stroke. Patients are advised to seek immediate medical attention if they experience symptoms such as persistent leg pain, sudden shortness of breath, sudden vision changes, severe chest pain, unusual headaches, weakness or numbness in limbs, or jaundice.

Additional serious risks reported include Toxic Shock Syndrome (TSS), characterized by symptoms similar to influenza that can escalate rapidly. Patients should contact their healthcare provider or seek emergency care if they experience sudden high fever, vomiting, a sunburn-like rash, diarrhea, muscle aches, or fainting.

Other adverse events include allergic reactions such as hives and angioedema, liver complications including tumors, hypertension, gallbladder issues, and accidental insertion of the device into the bladder. Symptoms of angioedema may occur, particularly in individuals with a family history of the condition.

Common side effects associated with the etonogestrel and ethinyl estradiol vaginal ring include tissue irritation in the vaginal or cervical area, headaches (including migraines), and mood changes, particularly in individuals with a history of depression. Patients are encouraged to contact their healthcare provider immediately if they experience thoughts of self-harm.

Other reported side effects encompass breast discharge, vaginal injury related to broken rings, and discomfort experienced by partners. Instances of the ring becoming adhered to vaginal tissue have also been noted, necessitating removal by a healthcare provider. Patients should inform their healthcare provider of any persistent or bothersome side effects.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling, which includes the Patient Information and Instructions for Use. It is essential to counsel patients about the increased risk of cardiovascular events associated with the use of etonogestrel and ethinyl estradiol vaginal ring. Specifically, patients should be informed that cigarette smoking significantly heightens the risk of serious cardiovascular events, particularly in women over 35 years of age, who should avoid using this contraceptive method.

Patients must be made aware that the risk of venous thromboembolism (VTE) is elevated compared to non-users of combined hormonal contraceptives (CHCs), especially during the initial use or after a break of four weeks or more from using the same or a different CHC.

In terms of use and administration, healthcare providers should inform patients that the etonogestrel and ethinyl estradiol vaginal ring does not offer protection against HIV infection (AIDS) or other sexually transmitted infections. Patients should receive guidance on the correct usage of the vaginal ring and the necessary steps to take if they do not adhere to the recommended timing for insertion and removal. It is also important for patients to regularly check for the presence of the ring in the vagina, particularly before and after intercourse.

Regarding pregnancy, patients should be informed that the etonogestrel and ethinyl estradiol vaginal ring is contraindicated during pregnancy. If a patient plans to become pregnant or discovers she is pregnant while using the ring, she should discontinue its use immediately.

Healthcare providers should also inform patients about the need for additional contraception. If the ring is removed for more than three continuous hours, a barrier method of contraception should be used until the ring has been in place continuously for at least seven days. Patients should be advised to use a backup or alternative method of contraception when taking enzyme inducers alongside the vaginal ring. For those starting the ring postpartum without having had a normal period, it is crucial to use a non-hormonal method of contraception for the first seven days.

In relation to lactation, patients should be informed that combined hormonal contraceptives may reduce breast milk production, although this is less likely if breastfeeding is well established.

Patients should also be made aware that amenorrhea may occur while using the ring. In cases of amenorrhea, pregnancy should be ruled out if the ring has been out of the vagina for more than three consecutive hours, if the ring-free interval has been extended beyond one week, if the patient has missed periods for two or more consecutive cycles, or if the ring has been retained for longer than four weeks.

Finally, healthcare providers should advise patients on the proper disposal methods for a used etonogestrel and ethinyl estradiol vaginal ring to ensure safe and responsible disposal.

Storage and Handling

The etonogestrel and ethinyl estradiol vaginal ring is supplied in a foil pouch, which should be resealed with the provided sticker after use. It is essential to store the ring refrigerated at a temperature range of 2° to 8°C (36° to 46°F) prior to dispensing to the user.

Once dispensed, the ring can be stored for up to 4 months at a controlled room temperature of 25°C (77°F), with permissible excursions between 15° to 30°C (59° to 86°F). Care should be taken to avoid exposure to direct sunlight and to ensure that the storage temperature does not exceed 30°C (86°F).

When labeling the dispensed ring, an expiration date must be indicated, which should not exceed 4 months from the date of dispensing or the product's original expiration date, whichever is earlier. After use, the ring should be placed back in its foil pouch, resealed, and disposed of in a waste receptacle that is out of reach of children and pets. It is important to note that the ring should not be flushed down the toilet.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Etonogestrel and Ethinyl Estradiol as submitted by Teva Pharmaceuticals USA, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)