Etonogestrel; Ethinyl Estradiol
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Mechanism of Action
US Drug Names
Insert 1 ring PV on or before Day 5 of cycle (count first day of menstruation as Day 1). Remove ring after 3 weeks, followed by a 1-week rest. Then insert new ring. During the first cycle use an additional method of contraception (e.g., male condoms or spermicide) for the first 7 days after insertion of ring. For altering ring change days, lost rings, or other special situations, see specific prescribing information.
Insert 1 ring PV anytime within 7 days after the last combined oral contraceptive tablet and no later than the day that a new cycle of pills would have been started. No back-up method is needed. Remove ring after 3 weeks, followed by a 1-week rest. Then insert new ring.
Insert 1 ring PV based on the progestin-only method as follows: 1) Any day of the month when switching from a progestin-only pill; do not skip any days between the last pill and the first day of the ring; 2) On the same day as contraceptive implant removal; 3) On the same day as removal of a progestin-only IUD; or 4) On the day when the next contraceptive injection would be due. In all cases, use an additional method of contraception (e.g., male condoms or spermicide) for the first 7 days after insertion of ring. Remove ring after 3 weeks, followed by a 1-week rest. Then insert new ring.
Insert 1 ring PV within 5 days following a complete first trimester abortion; no need to use an additional method of contraception. If use of ring is not started within 5 days, follow the instructions as if patient has not previously used hormonal contraception and advise patient use an additional method of contraception for the first 7 days after insertion of ring. Remove ring after 3 weeks, followed by a one-week rest. Then insert new ring.
Insert 1 ring PV 4 weeks postpartum in females who elect not to breast-feed or after a second-trimester abortion. Those who are breast-feeding should not use the ring and should choose other forms of contraception until the child is weaned. Consider the increased risk of thromboembolism. If the postpartum patient has not yet had a period, rule out pregnancy prior to initiation; instruct patient to use an additional method of contraception for the first 7 days after insertion of ring. Remove ring after 3 weeks, followed by a 1-week rest. Then insert new ring.
Follow dosage as for routine contraception. Improvement may not be noticeable for 2 to 4 months. Prolonged treatment may be needed to control condition.
Follow dosage as for routine contraception. Treatment for 6 to 12 months may be required; hormonal contraceptives have limited utility when the underlying cause is not related to a hypoestrogenic or hyperandrogenic state.  
Follow dosage as for routine contraception. Combined hormonal contraceptives can reduce endometriosis-associated dyspareunia, dysmenorrhea, and non-menstrual pelvic pain. Treatment for 6 to 9 months may be needed to induce endometrial atrophy and reduce symptoms.
1 ring/month PV.
Not indicated in prepubescent females.
Hormonal contraceptives are contraindicated for use in the presence of active liver disease or markedly impaired liver function.
Specific guidelines for dosage adjustments in renal impairment are not available; Nuvaring has not been studied in these patients.
Etonogestrel and ethinyl estradiol are used together in a combination hormonal contraceptive vaginal ring; the vaginal ring is left in place for 3 weeks, followed by a 1 week hiatus. Ethinyl estradiol is a potent, synthetic estrogen. Etonogestrel, also known as 3-keto-desogestrel, is the biologically active metabolite of desogestrel. Etonogestrel is a third-generation progestin with lowered androgenic effects and relatively no estrogenic action compared to older progestins. Thus, etonogestrel may have positive influences on acne, fluid retention, and lipid profiles. There are no epidemiologic data available to determine vaginal combination hormonal contraceptive safety profiles are different than combined oral contraceptives (COCs), and the standard risks and benefits of the combined hormonal contraceptives apply. Combined hormonal contraceptives can be used in female patients from menarche to over the age of 40 years up until the time of menopause with proper selection of products. The choice of a routine hormonal contraceptive for any given patient is based on the individual's contraceptive needs, underlying medical conditions or risk factors for adverse effects, and individual preferences for use. All combined hormonal contraceptives have risks related to venous and arterial thromboembolism, particularly in women who smoke and contain a boxed warning about tobacco smoking. The Centers for Disease Control's U.S. Medical Eligibility Criteria describe considerations for risk vs. benefits, including medical conditions or attributes that contraindicate use; these criteria can help prescribing practitioners in product selection for individual patients. Patients with a sensitivity for vaginal irritation, or those with conditions (e.g., vaginal stenosis, cervical prolapse, rectoceles, and cystoceles) that may make expulsion of the ring more likely to occur may not be the best candidates for this vaginal ring contraceptive.
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
Etonogestrel; ethinyl estradiol vaginal ring (NuvaRing):
Females who participated in clinical studies tolerated etonogestrel; ethinyl estradiol vaginal ring well. Genitourinary adverse reactions associated with the use of the vaginal ring that occurred in 5% to 14% of patients include vaginitis and vaginal secretions (leukorrhea). Some of these symptoms may also be due to vaginal candidiasis. The most frequent events leading to discontinuation in 1% to 2.5% of patients were device-related events (foreign body sensation, coital problems, device expulsion) and vaginal symptoms (discomfort, vaginitis, leukorrhea). Vaginal erosion, cervical erosion, vaginal ulceration, and cervical ulceration in women using etonogestrel; ethinyl estradiol has been rarely reported. In some cases, the ring adhered to vaginal tissue, necessitating removal by a healthcare provider. There have been reported cases of the ring disconnecting at the weld joint; this is not expected to affect the contraceptive effectiveness of the ring. In the event of a disconnected ring, vaginal discomfort or expulsion is more likely to occur. Vaginal injury (including associated vaginal pain, discomfort, and unusual bleeding) associated with ring breakage has been reported; these reports included patients concomitantly using intravaginal antimycotic, antibiotic, and lubricant products. Also, some women are aware of the ring at random times during the 21 days of use or intercourse. During intercourse, some sexual partners may feel the ring in the vagina. However, clinical studies revealed that 90% of couples did not find this to be a problem. There have been rare reports of inadvertent insertions of the etonogestrel; ethinyl estradiol vaginal ring into the urinary bladder, which has required cystoscopic removal. Patients who are unable to locate the vaginal ring who also present with urinary symptoms should be assessed for ring insertion into the urinary bladder.
During clinical trials of the etonogestrel; ethinyl estradiol vaginal ring, headache, nausea, upper respiratory tract infection, sinusitis, and weight gain were some of the most commonly reported adverse reactions occurring in 5% to 14% of patients. Additionally, headache, emotional lability, and weight gain lead to discontinuation of therapy in 1% to 2.5% of patients. The following adverse reactions are generally common during the initiation of a hormonal contraceptive regimen and often subside after the first few months of routine use. These require medical attention only if prolonged or bothersome: abdominal discomfort or cramps, appetite stimulation, mild vomiting, fluid retention or edema with weight gain, weight loss, azotemia, breast enlargement, and fatigue. In general, etonogestrel; ethinyl estradiol vaginal ring exhibits a low incidence of these side effects. If needed and appropriate for the patient, switching to an oral contraceptive combination with a different dose strength or estrogen to progestin ratio or combination can resolve troublesome effects that continue.
Cases of toxic-shock syndrome (TSS) have been associated with tampons and certain barrier contraceptives. Very rare cases of TSS have been reported by etonogestrel; ethinyl estradiol vaginal ring; in some of these cases, the women were also using tampons. Symptoms of TSS include chills, confusion, dizziness, fever, lightheadedness, myalgia, sunburn-like rash followed by peeling of the skin, hypotension, and unusual redness of the inside of the nose, mouth, throat, vagina, or conjunctivae. No causal relationship between the use of etonogestrel; ethinyl estradiol vaginal ring has been established. If a patient exhibits signs of TSS, the possibility of this diagnosis should be excluded and appropriate medical evaluation and treatment initiated.
The following additional adverse event information relates to the use of combination hormonal contraceptives as a class; in some cases the relation of listed side effects to etonogestrel; ethinyl estradiol vaginal ring use specifically is not known. Much of the adverse event information has been gathered from studies using oral contraceptives: Changes in menstrual bleeding patterns (e.g., menstrual irregularity) often occur after initiation of hormonal contraceptive therapy (e.g., the etonogestrel; ethinyl estradiol vaginal ring). Breakthrough bleeding and spotting are common during the first 3 months of administration of most hormonal contraceptives, especially in the first cycle of use. During 3 large clinical trials, 2% to 11.7% of patients during cycles 1 through 13 experienced breakthrough bleeding. These changes usually subside and are replaced by a more predictable menstrual bleeding pattern with the appropriate continuation of dosing. Amenorrhea, oligomenorrhea, and temporary infertility are occasionally reported in combination hormonal contraceptive users. If scheduled bleeding does not occur during the dose-free interval in a given monthly cycle, consider the possibility of pregnancy; in some patients, a pregnancy test may be indicated. If the patient has not adhered to the prescribed dosing schedule, consider the possibility of pregnancy at the time of the first missed period and perform a pregnancy test. If the patient has adhered to the prescribed dosing schedule and misses 2 consecutive periods, perform a pregnancy test to rule out pregnancy. Unusual or continued vaginal bleeding may prompt a need for examination.
Breast pain or tenderness (mastalgia) and galactorrhea (breast discharge) may occur during hormonal contraceptive use. Women using the etonogestrel; ethinyl estradiol vaginal ring should report any lumps or galactorrhea to their health care professionals.
When initiating therapy an individual's headache pattern should be observed and if headaches worsen or if focal neurologic findings are present, discontinue etonogestrel; ethinyl estradiol therapy and evaluate the cause. The relationship of migraine headache and the administration of hormonal contraceptives is not clearly defined. A number of changes can occur when a woman initiates hormonal contraceptive therapy and include 1) migraines can appear for the first time, 2) a change in frequency, severity and duration of headaches may be seen, or 3) an improvement or decrease in the occurrence of migraine or other headaches may occur.
Combined hormonal contraceptive use has traditionally been associated with various thromboembolic disorders. The risk for the development of deep venous thrombosis and/or pulmonary embolism is approximately 3 to 6 times greater in combined oral contraceptive (COC) users than in nonusers. In several studies, the risk of thromboembolism was reported to be higher in smokers compared with nonsmokers. Both hormone amount and hormone type may be important factors. Estrogens decrease levels of antithrombin-III and increase the production of blood clotting factors VII, VIII, IX, and X; risks increase with ethinyl estradiol doses greater than 50 mcg/day. The additional effects of progestin in combination with the estrogen may also influence embolic risk. Regarding stroke and COC use, the risk may be related to the amount of estrogen as well as the type of progestin, although this issue is controversial. Early epidemiological studies showed an increased risk for stroke; however, these studies assessed COCs containing more than 50 mcg of ethinyl estradiol. Recent literature has shown that the use of the lower dose (i.e., 35 mcg ethinyl estradiol or less) oral contraceptive combinations available today do not increase a healthy woman's risk of heart attack or stroke.  Smoking remains the most significant risk factor for embolic events while on hormonal contraceptives. An increased risk of mesenteric thrombosis and intracranial bleeding have also been associated with the use of oral contraceptives and may apply to etonogestrel; ethinyl estradiol use.
Hypertension may occur with hormonal contraceptives; the prevalence increases with duration of use and patient age, and possibly increasing progestin concentration. Close monitoring of blood pressures is recommended for patients at risk for hypertension; blood pressures usually return to normal after discontinuation of etonogestrel; ethinyl estradiol therapy.
Mood or personality changes occur commonly in women taking hormonal contraceptive agents like etonogestrel; ethinyl estradiol. These changes include emotional lability, mental depression, anxiety, libido decrease, frustration, anger, or other emotional outbursts. In some cases, women discontinue hormonal contraceptives due to mood changes or emotional lability. However, hormonal contraceptives have also been reported to improve PMS and other cyclic emotional changes in some patients.
Clinical case reports of retinal thrombosis associated with oral contraceptive use exist. Optic neuritis, which may lead to partial or complete loss of vision has been reported in users of oral contraceptives, however the association has been neither confirmed nor refuted. Likewise, cataracts have been reported during oral contraceptive use without evidence of causality. Exogenous estrogen use can cause a conical cornea to develop from steepening or increased curvature of the cornea, caused by thinning of the stroma. Patients with contact lenses may develop intolerance to their lenses. Any change in vision or visual acuity should be examined by an ophthalmologist. In the event of unexplained visual impairment, onset of proptosis or diplopia, papilledema, or retinal vascular lesions, discontinue etonogestrel; ethinyl estradiol. Immediately take appropriate diagnostic and therapeutic measures.
In a pooled-data analysis from 2 large United States sites, women between the ages of 18 to 44 years old who had no prior incidence of coronary heart disease (CHD) or cerebrovascular disease prior to their MI event were studied for relative risk related to low-dose oral contraceptives. After adjustment for ethnicity and major established risk factors for CHD, there was no evidence of increased risk of myocardial infarction associated with OC use. Most other recent studies have concurred. One major exception was the WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. This international multicenter case-control study found a 5-fold increased risk of MI associated with current OC use. The authors, however, concluded that the increased risk might reflect more frequent use of OCs internationally in populations at higher risk, such as smokers and those with pre-existing cardiovascular risk factors. No increased risk of MI was in women who were non-smokers and in whom blood pressure was screened prior to OC use. Smoking is a well known additive risk to hormonal contraceptive therapy, increasing the relative risk of MI by 5-fold. There is a 10 to 12-fold increase in risk of MI in patients who use hormonal contraceptive therapy and smoke compared to females who do not smoke or use OCs. Thus, one would expect a higher incidence of MI in any woman using hormonal contraceptives with known risk factors. In addition, data from a poster of an observational study presented during the European Society of Cardiology Congress in 2007 indicate that 10 years of OC use may increase the odds of atherosclerosis (as defined by the presence of femoral or carotid artery plaque). As compared to patients never taking OCs, the presence of plaque is increased after 10 years of OC use in a single carotid artery (OR 1.17, 95% CI 1 to 1.33), bilateral carotid arteries (OR 1.42, 95% CI 1.03 to 1.84), a single femoral artery (OR 1.28, 95% CI 1.1 to 1.47), or bilateral femoral arteries (OR 1.34, 95% CI 1.05 to 1.63). More data are needed to confirm these findings. This data would be expected to apply similarly to women who use etonogestrel; ethinyl estradiol vaginal ring.
Estrogens can cause a variety of dermatological reactions. Melasma, in the form of tan or brown patches, may develop on the forehead, cheeks, temples and upper lip. These patches may persist after etonogestrel; ethinyl estradiol is discontinued. Photosensitivity can be experienced with combined contraceptive use and protective clothing and sunscreens should be employed when exposed to sunlight or UV light. Other dermatologic reactions are infrequent and include maculopapular rash, urticaria, erythema nodosum, erythema multiforme, aggravation of varicose veins, hemorrhagic eruption, alopecia, or hirsutism. Other erythematous eruptions may occur. Although combined hormonal contraceptives have been used to treat acne vulgaris, in some cases they may induce or aggravate an existing acne vulgaris. Combined hormonal contraceptives have not been shown to increase the incidence of skin cancer of any type, including melanoma. Anaphylactoid reactions, including urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms have been reported during oral contraceptive use.
Some women taking combination hormonal contraceptives notice tenderness, swelling, or minor bleeding of their gums, which may lead to gingivitis. Proper attention to oral care and regular dental visits during etonogestrel; ethinyl estradiol therapy are recommended.
Abdominal pain or cramps, bloating, and cholestatic jaundice have been reported in patients receiving oral contraceptives and are believed to be drug-related. Abdominal pain can indicate cholelithiasis, cholecystitis, cholestasis, pancreatitis, or peliosis hepatis. An increased risk of gallbladder disease is associated with oral contraceptive use, but the risk may be minimal, especially with the use of oral contraceptive formulations that contain lower hormonal doses of estrogens and progestogens. In patients with familial defects of lipoprotein metabolism receiving estrogen-containing preparations, significant elevations of plasma triglycerides (hypertriglyceridemia) leading to pancreatitis have been reported. Numerous cases of bowel ischemia (ischemic colitis) have been reported during combined estrogen and progesterone use; mesenteric vein thrombus due to hypercoagulability is the proposed mechanism. Other adverse effects may include colitis, elevated hepatic enzymes, hepatitis, hyperlipidemia, diarrhea, dyspepsia, anorexia, weight loss, and Budd-Chiari syndrome or hepatic vein obstruction. Peliosis hepatis, a very rare consequence of taking estrogens and combined oral contraceptives, is characterized by the presence of blood-filled spaces. In rare cases, oral contraceptives can cause benign but dangerous liver tumors. Indirect calculations have estimated the attributable risk of hepatoma to be in the range of 3.3 cases per 100,000 for users, a risk that increases after 4 or more years of use. These benign liver tumors can rupture and cause fatal internal bleeding. Discontinue ethinyl estradiol; levonorgestrel if jaundice develops, as steroid hormones may be poorly metabolized in patients with impaired liver function. Cholestatic jaundice of pregnancy or jaundice with prior combined contraceptive use are contraindications for etonogestrel; ethinyl estradiol use.
The issue of hormonal influences on the development of cancers (new primary malignancy) has been widely researched for many decades. Most studies have been performed with combined oral contraceptives (COCs), and the risks related to combined hormonal contraceptives, regardless of route of administration, are thought to be similar. In general, the data suggest an increased risk of cervical cancer among COC users, with a decreased risk for endometrial and ovarian cancers. BREAST CANCER: Epidemiology studies have not found a consistent association between use of COCs and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (less than 6 months since last use) and current users with longer duration of COC use.  Several large, well-designed observational studies have provided data regarding the risk of breast cancer with COC use.   Breast cancers diagnosed in current or previous COC users tend to be less advanced clinically than in never-users. The risk of breast cancer is only slightly increased in current and recent COC users (i.e., within 10 years); however, 10 years after COC cessation, the risk of breast cancer appears to be similar to that in those patients that have never used COCs. From one large study published in 2017, the risk of breast cancer was higher among women who currently or recently used contemporary hormonal contraceptives than among women who had never used hormonal contraceptives, and this risk increased with longer durations of use; however, absolute increases in risk were small. The absolute risk of breast cancer associated with any hormonal contraceptive use was 13 per 100,000 women-years, which corresponds to 1 extra case of breast cancer for every 7,690 COC users in 1 year. Moreover, the same study data suggest that any increased risk of breast cancer usually disappears rapidly after an interruption in the use of COCs. There continues to be controversy regarding the risk of COC use in women with a family history of breast cancer (e.g., BRCA mutations). However, evidence does not suggest that the increased risk for breast cancer among women with either a family history of breast cancer or breast cancer susceptibility genes is modified by the use of COCs. Patients should be instructed to perform monthly self-breast examination and report any breast changes, lumps, or discharge to their health care professional. If breast cancer is suspected in a woman who is taking hormonal contraceptives, the contraceptive should be discontinued. CERVICAL CANCER: Some studies suggest that COC use has been associated with an increase in the risk of cervical cancer or intraepithelial neoplasia; however, such findings may be due to differences in sexual behavior, presence of the human papillomavirus (HPV) and other factors. HPV is thought to be the cause of more than 90% of all cervical cancers, although, hormonal factors may influence risk. The relative risk of invasive cervical cancer of 1.37 after 4 years of use; relative risk increased to 1.6 after 8 years of use. Because a potential for cervical dysplasia may exist, regularly evaluate patients taking COCs via cervical cytology screening as recommended per standards of care. OTHER CANCERS: A meta-analysis of 10 studies indicated significant trends for a reduced risk for endometrial and ovarian cancer with increased duration of COC use. Risk of endometrial or ovarian cancers may be reduced by up to 60% with 4 or more years of use. Data suggest COCs do not protect against hereditary forms of ovarian cancer (e.g., women who carry BRCA1 or BRCA2 gene alterations). Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (more than 8 years) COC users. However, these cancers are rare in the United States, and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than 1 per million users. 
Decreases in serum folate, porphyria, hyperlipidemia, and exacerbation of chorea and systemic lupus erythematosus have been reported in users of hormonal contraceptives. A cystitis-like syndrome, impaired renal function, and a hemolytic uremic syndrome have also been reported. There have been rare reports of inadvertent insertions of the etonogestrel; ethinyl estradiol vaginal ring into the urinary bladder, which has required cystoscopic removal. Patients who are unable to locate the vaginal ring who also present with urinary symptoms should be assessed for ring insertion into the urinary bladder. Lactation suppression has been reported in patients receiving combined hormonal contraceptives immediately postpartum. Additionally, impaired glucose tolerance has been reported in combined hormonal contraceptive users. In patients without diabetes, elevated blood glucose concentrations have not been reported.
Use of etonogestrel; ethinyl estradiol, as with other contraceptive steroids, may result in clinical changes that influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. Laboratory test interference has not been reported.
Etonogestrel; ethinyl estradiol vaginal ring is contraindicated in any patients with hypersensitivity to any of the product components. Hypersensitivity reactions reported include: throat constriction, facial edema, urticaria, hives, and wheezing. Ethinyl estradiol is generally contraindicated in patients who have a history of anaphylaxis or history of angioedema to estrogens. Hypersensitivity reactions, including both anaphylactic reactions and angioedema have been reported in patients taking estrogens. Events have developed in minutes and have required emergency medical treatment. In addition, exogenous estrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema, which may be hormonally sensitive.
Etonogestrel; ethinyl estradiol vaginal ring does not protect against human immunodeficiency virus (HIV) infection or other sexually transmitted disease. Conversely, patients with known HIV infection or acquired immunodeficiency syndrome (AIDS) should be aware that the use of the hormonal contraceptive vaginal ring will not prevent the transmission of HIV or other diseases to their partner(s).
Etonogestrel; ethinyl estradiol vaginal ring may not be a suitable contraceptive for some women. Vaginal stenosis, cervical prolapse, rectoceles, and cystoceles may make expulsion of the vaginal ring more likely to occur. Expulsion of the ring can occur during tampon removal. The ring device may not be suitable for females who are more susceptible to vaginal irritation or ulceration. Vaginal and cervical erosion and/or ulceration has been reported in females using other contraceptive vaginal devices. In some cases, the ring adhered to vaginal tissue, which necessitated removal by a health-care provider. Vaginal injury associated with ring breakage has also been reported. There have been rare reports of inadvertent insertion and removal complications of the other contraceptive vaginal rings into the urinary bladder, which has required cystoscopic removal. Patients who are unable to locate the vaginal ring that also present with urinary symptoms should be assessed for ring insertion into the urinary bladder. Some women are aware of the ring on occasion during the days of use or during intercourse, and sexual partners may feel the ring in the vagina. Intravaginal contraceptive devices, such as diaphragms, cervical caps, and female condoms are not recommended as non-hormonal contraception concurrently with this vaginal ring. The use of male condoms or spermicides are acceptable. Cases of toxic shock syndrome infection (TSS) have been reported by vaginal ring users. TSS has been associated with tampons and certain barrier contraceptive devices, and in some TSS cases vaginal ring users were also using tampons. Causal relationship between the use of a vaginal ring and TSS has not been established. If a patient exhibits signs or symptoms of TSS, consider the possibility of this diagnosis, remove the vaginal ring, and initiate appropriate medical evaluation and treatment. 
Combined hormonal contraceptives are contraindicated in patients with a current or past history of stroke, cerebrovascular disease, coronary artery disease, coronary thrombosis, myocardial infarction, thrombophlebitis, thromboembolism or thromboembolic disease, or valvular heart disease with complications. Hormonal combined contraceptive agents have been associated with thromboembolism such as deep venous thrombosis (DVT) and pulmonary embolism (PE). Such contraceptives are also generally contraindicated in women who have thrombogenic valvular disease or thrombogenic rhythm diseases of the heart (e.g., subacute bacterial endocarditis with valvular disease, or atrial fibrillation), or known inherited or acquired hypercoagulopathies (e.g., protein S deficiency, protein C deficiency, Factor V Leiden, prothrombin G20210A mutation, antithrombin deficiency, antiphospholipid antibodies). Because tobacco smoking increases the risk of thromboembolism, DVT, myocardial infarction, stroke and other thromboembolic disease, patients receiving combined hormonal contraceptives, including etonogestrel; ethinyl estradiol vaginal ring, are strongly advised not to smoke. Risk is especially high for female smokers more than 35 years of age or those who smoke 15 or more cigarettes per day. Therefore, combined hormonal contraceptives are generally considered contraindicated in women over the age of 35 years who are tobacco smokers. A positive relationship between estrogen dosage and thromboembolic disease has been demonstrated, and for example, oral products containing 50-mcg ethinyl estradiol should not be used unless medically indicated. In addition, certain progestins may increase thromboembolic risk. The overall risk of venous thromboembolism in women using combined hormonal contraceptives has been estimated to be 3 to 9 per 10,000 woman-years. Preliminary data from a large, prospective cohort safety study suggests that the risk is greatest during the first 6 months after initially starting combined hormonal contraceptives therapy or restarting (following a break from therapy 4 weeks or more) with the same or different combination product. The risk of arterial thromboses, such as stroke and myocardial infarction, is especially increased in women with other risk factors for these events. Pre-existing high blood pressure, kidney disease, hypercholesterolemia, hyperlipidemia, diabetes with vascular disease, and patients who are morbidly obese may also increase risk. After a combined hormonal contraceptive is discontinued, the risk of thromboembolic disease due to oral contraceptives gradually disappears. In 2 epidemiologic studies, which were required or sponsored by regulatory agencies, etonogestrel; ethinyl estradiol vaginal ring users had a risk of venous thromboembolism that was similar to combined oral contraceptive (COC) users. Because of their association with elevations in blood pressure, combined hormonal contraceptives should be used cautiously in patients with mild to moderate hypertension or kidney disease; use is contraindicated in patients with uncontrolled or severe hypertension or hypertension with vascular disease. An increase in blood pressure has been reported in women taking combined hormonal contraceptives, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin. Blood pressure should be monitored closely in individuals with high blood pressure; discontinue use of the etonogestrel; ethinyl estradiol vaginal ring if blood pressure rises significantly. Combined hormonal contraceptives may also cause fluid retention, and patients predisposed to complications from edema, such as those with renal disease or cardiac disease, should be closely monitored. 
Surgery can increase the risk for thromboembolism from combined hormonal contraceptives. If feasible, discontinue etonogestrel; ethinyl estradiol vaginal ring at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism, and during and following any prolonged immobilization.
Because of the increased potential for embolic risk, combined hormonal contraceptives (CHCs) containing etonogestrel; ethinyl estradiol are contraindicated in women who currently have diabetes mellitus and are over 35 years of age, diabetes mellitus with hypertension or with vascular disease or end-organ damage, or diabetes mellitus of greater than 20 years duration. Patients with diabetes mellitus should be observed for changes in glucose tolerance when initiating or discontinuing estrogen therapy, since estrogen therapy may exacerbate diabetes. Altered glucose tolerance secondary to decreased insulin sensitivity has been reported.
Consider the potential risks for venous thromboembolism (VTE) or cardiovascular risks in patients with dyslipidemia before initiating combined hormonal contraceptives such as etonogestrel; ethinyl estradiol in women, particularly a woman more than 35 years of age. Consider alternative contraception for females with uncontrolled hyperlipidemia. Combined hormonal contraceptives may cause adverse lipid changes. Females with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using combined hormonal contraceptives.
Etonogestrel; ethinyl estradiol vaginal ring is contraindicated in patients with migraine or other headache that is accompanied by focal neurological symptoms, such as aura, or women over age 35 with any migraine headaches. Combined hormonal contraceptives may cause an exacerbation of migraine or a change in headache patterns and should be used with caution in women with migraine. Patients who complain of migraine with focal neurologic visual changes should be medically evaluated, and in some patients, such changes may indicate cerebrovascular events.
Consistent with potential thrombotic effects of combined hormonal contraceptives, there have been clinical case reports of retinal thrombosis with combined hormonal contraceptive use. Etonogestrel; ethinyl estradiol vaginal ring should be discontinued if there is unexplained visual disturbance, partial or complete loss of vision, onset of proptosis or diplopia, papilledema, or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately. Estrogens can increase the curvature of the cornea; patients using contact lenses wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.
Given the increased prevalence of hypercoagulable states in patients with SLE (in particular antiphospholipid antibodies and lupus anticoagulant) and their risk factors for thromboembolism, consider risks vs. benefit of combined hormonal contraceptive use. Avoid use of these products in SLE patients with a history of venous or arterial thrombosis or the presence of a hypercoagulable state. If a combined hormonal contraceptive is initiated in SLE patients without hypercoagulable states, choose a low-dose estrogen contraceptive; consider the use of a progestin-only contraceptive. Combined hormonal oral contraceptive use has been reported to induce, unmask, or exacerbate systemic lupus erythematosus (SLE); more data are needed. 
Discontinue the etonogestrel; ethinyl estradiol vaginal ring if pregnancy is detected; there is no reason to continue combined hormonal contraceptives (CHCs) during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to CHCs before conception or during early pregnancy. If scheduled menstrual bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule, consider the possibility of pregnancy at the time of the first missed period and perform a pregnancy test. Perform a pregnancy test to rule out pregnancy if the patient has adhered to the prescribed dosing schedule but misses 2 consecutive periods.
Manufacturers recommend avoidance of combined hormonal contraceptives (CHCs) if possible until a mother has completely weaned her child. Small amounts of contraceptive steroids (estrogens and progestins) have been identified in the milk of nursing mothers and a few reports of effects on the infant exist, including jaundice and breast enlargement. Experts often recommend avoidance of estrogen-containing hormonal contraceptives, in the first 21 days postpartum due to maternal post-partum risks for thromboembolism following obstetric delivery, and th e potential for interference with the establishment of lactation. It is generally accepted that estrogen-containing CHCs may be used after this period in healthy women without other risk factors; general monitoring of the infant for effects such as appetite changes, breast changes and proper weight gain and growth should occur. Estrogens, including ethinyl estradiol, have been reported to interfere with milk production and duration of lactation in some women, particularly at doses of 30 mcg per day EE or more. One study found that lower dose oral combined contraceptives (e.g., 10 mcg per day EE) may not affect lactation. However, a systematic review concluded that the available evidence, even from randomized controlled trials, is limited and of poor quality; proper trials are needed. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. Alternate contraceptive agents for consideration for use during breast-feeding include non-hormonal contraceptive methods and also progestin-only contraceptives (e.g., medroxyprogesterone injection).
Combined hormonal contraceptives, such as the etonogestrel; ethinyl estradiol vaginal ring, are contraindicated in patients with hepatic disease. Because of the association with cholestasis and hepatic neoplasms, estrogens are contraindicated in the presence of hepatocellular cancer, hepatic adenoma, other liver tumors (benign or malignant), or markedly impaired liver function (e.g., uncompensated cirrhosis). Do not use hormonal contraceptives in patients with a history of cholestatic jaundice/pruritus of pregnancy or jaundice from prior hormonal contraceptives; these conditions can recur with subsequent combined hormonal contraceptive use. Discontinue use of ethinyl estradiol; etonogestrel if jaundice develops during combined oral contraceptive use. Steroid hormones may be poorly metabolized in patients with liver impairment. Acute or chronic disturbances of liver function may necessitate the discontinuation of combined hormonal contraceptive use until markers of liver function return to normal and combined hormonal contraceptive causation has been excluded. Patients with hepatitis C who are being treated with ombitasvir/paritaprevir/ritonavir, with or without dasabuvir are also contraindicated to receive combined hormonal contraceptives. During clinical trials with the hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications. Discontinue combined hormonal contraceptives prior to starting hepatitis C therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir; the combined hormonal contraceptive can be restarted approximately 2 weeks following completion of treatment with the hepatitis C combination drug regimen. Hepatic adenomas are associated with combined hormonal contraceptive use. An estimate of the attributable risk is 3.3 cases/100,000 combined hormonal contraceptive users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in long term (more than 8 years) combined hormonal contraceptive users. However, the attributable risk of liver cancers in combined hormonal contraceptive users is less than 1 case per million users. Combined hormonal contraceptives should be used cautiously in patients with pre-existing gallbladder disease. Studies suggest a small increased relative risk of developing gallbladder disease or worsening existing gallbladder disease among combined hormonal contraceptive users. 
Mood disorders, like depression, may be aggravated in women taking hormones or combined hormonal contraceptives (CHCs). Data regarding the association of CHCs with onset of depression or exacerbation of existing depression are limited. If significant depression occurs, etonogestrel; ethinyl estradiol vaginal ring should be discontinued.
Etonogestrel; ethinyl estradiol is contraindicated in patients with a history of, or known or suspected breast cancer, as breast cancer is a hormonally-sensitive tumor. All women taking combined hormonal contraceptives should receive clinical breast examinations and perform monthly self-examinations as recommended by their health care professional based on patient age, known risk factors, and current standards of care. Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (less than 6 months since last use) and current users with longer duration of COC use. The risks for etonogestrel; ethinyl estradiol vaginal ring contraceptive are expected to be similar to COCs. Several large, well-designed observational studies have provided data regarding the risk of breast cancer with combined oral contraceptive (COC) use.    From one large study published in 2017, the risk of breast cancer was higher among women who currently or recently used contemporary hormonal contraceptives than among women who had never used hormonal contraceptives, and this risk increased with longer durations of use; however, absolute increases in risk were small. The absolute risk of breast cancer associated with any hormonal contraceptive use was 13 per 100,000 women-years, which corresponds to 1 extra case of breast cancer for every 7,690 COC users in 1 year. Moreover, the same study data suggest that any increased risk of breast cancer usually disappears rapidly after an interruption in the use of COCs. There continues to be controversy regarding the risk of COC use in women with a family history of breast cancer (e.g., BRCA mutations). However, evidence does not suggest that the increased risk for breast cancer among women with either a family history of breast cancer or breast cancer susceptibility genes is modified by the use of COCs. Patients should be instructed to perform monthly self-breast examination and report any breast changes, lumps, or discharge to their health care professional. If breast cancer is suspected in a woman who is taking hormonal contraceptives, the contraceptive should be discontinued.
Etonogestrel; ethinyl estradiol vaginal ring combined contraceptive is contraindicated in the presence of cervical cancer or other estrogen-responsive tumors. Most cervical cancers are related to the presence of the human papillomavirus (HPV), but hormonal factors influence risk. In women taking combined oral hormonal contraceptives (COCs), studies have found a slightly increased risk of cervical cancer compared with never-users. The risk appears to increase with duration of use and appears to decline when COCs are discontinued. Clinical surveillance of all women using combined hormonal contraceptives (CHCs) is important; all women receiving CHC treatment should have a pelvic examination and other diagnostic or screening tests, such as cervical cytology, as clinically indicated or as generally recommended based on age, risk factors, and other individual needs. 
In those women with known endometrial cancer or other estrogen-dependent tumors (e.g., vaginal cancer, uterine cancer, ovarian cancer), combined hormonal contraceptives are contraindicated, as such tumors are hormonally sensitive. Hormonal contraceptives are contraindicated in women with undiagnosed vaginal bleeding; evaluate such patients before combined hormonal contraceptive use to determine if a contraindication to use exists. The use of combined oral contraceptives (COCs) appears to have a protective effect against some cancers. In women using COCs, a meta-analysis of 10 studies indicates a significant trend in decreasing endometrial and ovarian cancer risk with increasing duration of COC use. The beneficial effects of COCs in this regard may persist for 15 years or more after COC use ceases. Whether etonogestrel; ethinyl estradiol vaginal ring contraceptive use reduces the risk for endometrial or ovarian cancer is not known.   Use of the etonogestrel; ethinyl estradiol vaginal ring is not expected to cause growth in uterine leiomyomata (fibroids).
The estrogen component of combined hormonal contraceptives may raise the serum concentrations of thyroid-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin. Doses of thyroid hormone replacement for hypothyroidism may need to be increased, as indicated by clinical and laboratory monitoring for the individual. Cortisol replacement therapy (e.g., corticosteroid therapy) may also need adjusted for some patients.
Chloasma may occur with combined hormonal contraceptive (CHC) use, especially in women with a history of chloasma gravidarum (melasma). Advise females who tend to develop chloasma to avoid exposure to the sun or ultraviolet (UV) exposure while using etonogestrel; ethinyl estradiol vaginal ring.
Preexisting morbid obesity is one factor that may increase cardiovascular or thromboembolic risks associated with combination hormonal contraceptive use. Consider the presence of obesity and other underlying risk factors that may increase the risk of cardiovascular disease or thromboembolism, particularly for women over 35 years of age. In premarketing clinical trials of etonogestrel; ethinyl estradiol vaginal ring, females with obesity [body mass index (BMI) of 30 kg/m2 or more] were excluded. Limited literature suggests that the effectiveness of some hormonal contraceptive formulations might decrease with increasing body mass index (BMI). However, the evidence is conflicting; there are also data to suggest that the efficacy of most combined hormonal contraceptive products (with a few known exceptions) does not seem to be compromised in women who are overweight. 
The safety and efficacy of the etonogestrel; ethinyl estradiol vaginal rings have only been established in females of reproductive age. Safety and efficacy of hormonal birth control is expected to be the same for postpubertal children under the age of 18 and for users 18 years of age and older. Use of hormonal contraceptive products in female children before menarche is not indicated.
The primary action of the combination of an estrogen with a progestin is to suppress the hypothalamic-pituitary system, decreasing the secretion of gonadotropin-releasing hormone (GnRH). Progestins blunt luteinizing hormone (LH) release, and estrogens suppress follicle-stimulating hormone (FSH) from the anterior pituitary. Both estrogen and progestin ultimately inhibit maturation and release of the dominant ovule. In addition, viscosity of the cervical mucus increases with hormonal contraceptive use, which increases the difficulty of sperm entry into the uterus. Alteration in endometrial tissues also occurs, which reduces the likelihood of implantation of the fertilized ovum. The contraceptive effect is reversible. When traditional regimens of oral contraception are discontinued, ovulation usually returns within three menstrual cycles but can take up to 6 months in some women. Pituitary function and ovarian functions recover more quickly than endometrial activity, which can take up to 3 months to regain normal histology.
Both estrogens and progestins are responsible for a number of other metabolic changes. The summary of these changes is dependent on the net actions of the estrogen and progestin combinations. At the cellular level, estrogens and progestins diffuse into their target cells and interact with a protein receptor. Metabolic responses to estrogens and progestins require an interaction between DNA and the hormone-receptor complex. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins. Estrogens generally have a favorable effect on blood lipids, reducing LDL and increasing HDL cholesterol concentrations. Serum triglycerides increase with estrogen administration. Folate metabolism and excretion is increased by estrogens and may lead to slight serum folate deficiency. Estrogens also enhance sodium and fluid retention. Progestins are classified according to their progestational, estrogenic and androgenic properties. Progestins can alter hepatic carbohydrate metabolism, increase insulin resistance, and have either little to slightly favorable effects on serum lipoproteins. Less androgenic progestins, like etonogestrel, have only slight effects on carbohydrate metabolism. More androgenic progestins can aggravate acne. Serious adverse events, like thrombosis, are primarily associated with the estrogen component of hormonal contraceptives but may be the result of both estrogen and progestin components. The mechanism for thrombosis may be associated with increased clotting factor production and/or decreases in anti-thrombin III. Minor side effects can be addressed by choosing formulations that take advantage of relative estrogen, progestin, and androgenic potencies.
Etonogestrel; ethinyl estradiol is administered by the vaginal route. Etonogestrel; ethinyl estradiol does not undergo first-pass metabolism and steady-state blood levels of the hormones are reached within 3 days. Both hormones are widely distributed. Ethinyl estradiol is highly but non-specifically protein-bound to albumin. Ethinyl estradiol induces an increase in the serum concentrations of sex hormone-binding globulin (SHBG). Etonogestrel is roughly 32% bound to SHBG and 66% bound to albumin. Each vaginal ring slowly releases 0.120 mg/day of etonogestrel and 0.015 mg/day of ethinyl estradiol over a 3-week period of use. In vitro studies show that both etonogestrel and ethinyl estradiol are metabolized by the CYP450 3A4 isoenzyme. Ethinyl estradiol undergoes hydroxylation resulting in free, sulfated and glucuronide metabolites. The hydroxylated ethinyl estradiol metabolites have weak estrogenic activity; the biological activity of etonogestrel metabolites is not known. Excretion of the hormonal steroids occurs via the urine, bile and feces. Mean elimination half-life is roughly 29.3 hours for etonogestrel and 44.7 hours for ethinyl estradiol at steady state using the vaginal ring.
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A4, CYP2B6, CYP2C19, CYP2C9, P-glycoprotein (P-gp)
Oral desogestrel exhibits roughly 79% bioavailability. Ethinyl estradiol results in roughly 56% bioavailability.
Following vaginal administration of the hormonal ring, etonogestrel is rapidly absorbed with close to 100% bioavailability. Vaginal administration of ethinyl estradiol results in roughly 56% bioavailability.
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