Ethinyl Estradiol and Etonogestrel

• Tell all of your health care providers that you take ethinyl estradiol and etonogestrel. This includes your doctors, nurses, pharmacists, and dentists.
• Do not use a diaphragm or female condom while using this ring.
• If you have high blood sugar (diabetes), you will need to watch your blood sugar closely.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• High blood pressure has happened with drugs like this one. Have your blood pressure checked as you have been told by your doctor.
• This medicine may raise the chance of blood clots, a stroke, or a heart attack. Talk with the doctor.
• Talk with your doctor if you will need to be still for long periods of time like long trips, bedrest after surgery, or illness. Not moving for long periods may raise your chance of blood clots.
• Be sure to have regular breast exams and gynecology check-ups. Your doctor will tell you how often to have these. You will also need to do breast self-exams as your doctor has told you. Talk with your doctor.
• If you drink grapefruit juice or eat grapefruit often, talk with your doctor.
• This medicine may affect certain lab tests. Tell all of your health care providers and lab workers that you take this medicine.
• Certain drugs, herbal products, or health problems could cause ethinyl estradiol and etonogestrel to not work as well. Be sure your doctor knows about all of your drugs and health problems.
• This medicine does not stop the spread of diseases like HIV or hepatitis that are passed through blood or having sex. Do not have any kind of sex without using a latex or polyurethane condom. Do not share needles or other things like toothbrushes or razors. Talk with your doctor.
• Check to see if this medicine is in place as you have been told by your doctor or read the package insert.
• If the ring has come out and you do not know how long it has been, take a pregnancy test before putting in a new ring.
• Do not use in children who have not had their first menstrual period.
• If you have any signs of pregnancy or if you have a positive pregnancy test, call your doctor right away.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take ethinyl estradiol and etonogestrel or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to ethinyl estradiol and etonogestrel. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

• Etonogestrel and Ethinyl Estradiol

• Contraceptive
• Estrogen and Progestin Combination

Combination hormonal contraceptives inhibit ovulation via a negative feedback mechanism on the hypothalamus, which alters the normal pattern of gonadotropin secretion of a follicle-stimulating hormone (FSH) and luteinizing hormone by the anterior pituitary. The follicular phase FSH and midcycle surge of gonadotropins are inhibited. In addition, combination hormonal contraceptives produce alterations in the genital tract, including changes in the cervical mucus, rendering it unfavorable for sperm penetration even if ovulation occurs. Changes in the endometrium may also occur, producing an unfavorable environment for nidation. Combination hormonal contraceptive drugs may alter the tubal transport of the ova through the fallopian tubes. Progestational agents may also alter sperm fertility (Rivera 1999).

Absorption

Ethinyl estradiol and etonogestrel: Rapid

Tampons do not interfere with absorption.

Metabolism

Ethinyl estradiol: Hepatic via CYP3A4; forms metabolites (weak estrogenic activity)

Etonogestrel: Hepatic via CYP3A4; forms metabolites (activity not known)

Excretion

Ethinyl estradiol and etonogestrel: Urine, bile, and feces

Time to Peak

Vaginal: Ethinyl estradiol: 59 hours; Etonogestrel: 200 hours

Hypersensitivity to ethinyl estradiol, etonogestrel, or any component of the formulation; breast cancer or other estrogen- or progestin-sensitive cancer (current or a history of); hepatic tumors (benign or malignant) or hepatic disease; pregnancy; undiagnosed abnormal uterine bleeding.

Use is also contraindicated in women at high risk of arterial or venous thrombotic diseases including: Cerebrovascular disease; coronary artery disease; diabetes mellitus with vascular disease; DVT or PE (current or history of); headaches with focal neurological symptoms; migraine headaches with aura or migraine headaches if >35 years; hypertension (uncontrolled); thrombogenic valvular or rhythm diseases of the heart (eg, subacute bacterial endocarditis with valvular disease, atrial fibrillation); women >35 years who smoke; inherited or acquired hypercoagulopathies.

Canadian labeling: Additional contraindications (not in US labeling): Prodromi of a thrombosis (eg, angina pectoris or transient ischemic attack); severe dyslipoproteinemia; major surgery with prolonged immobilization, any ocular lesion from ophthalmic vascular disease such as partial or complete loss of vision or defect in visual fields; pancreatitis or history of pancreatitis with severe hypertriglyceridemia

Documentation of allergenic cross-reactivity for progestins and estrogens is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Prior to dispensing, store refrigerated at 2°C to 8°C (36°F to 46°F). After dispensing, can be stored for up to 4 months at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Avoid direct sunlight or temperatures above 30˚C (86˚F).

Concerns related to adverse effects:

• Breast cancer: In women at risk for breast cancer due to family history or susceptibility genes (BRCA1, BRCA2), the use of combination hormonal contraceptives has not been shown to modify the risk for breast cancer. However, breast cancer is a hormonal sensitive tumor and the prognosis for women with a current or recent history of breast cancer may be worse with combination hormonal contraceptive use (Curtis 2016b). Use is contraindicated in women with (or history of) breast cancer.

• Cervical cancer: The use of combination hormonal contraceptives has been associated with a slight increased risk of cervical cancer or intraepithelial neoplasia; however, studies are not consistent and may be related to additional risk factors (Gierisch 2013). Theoretically, use may affect prognosis of existing disease. Women awaiting treatment for cervical cancer may use combination hormonal contraceptives (Curtis 2016b).

• Chloasma: Combination hormonal contraceptives, as well as sun exposure and pregnancy, are triggers for chloasma. Women with a susceptibility to chloasma or additional risk factors should avoid exposure to sun or ultraviolet radiation during therapy (Handel 2014).

• Cholestasis: Risk of cholestasis may be increased with previous cholestasis of pregnancy or cholestasis with prior oral contraceptive use.

• Lipid effects: Combination hormonal contraceptives may adversely affect lipid levels, including serum triglycerides. Women with hypertriglyceridemia or a family history of hypertriglyceridemia may be at increased risk of pancreatitis when using combination hormonal contraceptives. Consider alternative contraception for women with uncontrolled dyslipidemia.

• Retinal vascular thrombosis: Discontinue if unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions occur and immediately evaluate for retinal vein thrombosis.

• Thromboembolic disorders: Discontinue use of combination hormonal contraceptives if an arterial or venous thrombotic event occurs. Oral contraceptives may increase the risk of venous thromboembolism (risk is greatest during first year of use and less than the risk associated with pregnancy); some studies suggest this risk may be higher in preparations with third- or fourth-generation progestins and/or high dose ethinyl estradiol. Women with inherited thrombophilias (eg, protein C or S deficiency, factor V Leiden mutation, prothrombin mutation, antithrombin deficiency) may have increased risk of venous thromboembolism. Age >35 years, hypertension, obesity, and tobacco use also increase the risk of thrombotic events in women taking combination hormonal contraceptives (ASRM 2017; Curtis 2016b; DeSancho 2010; van Vlijmen 2011). Combination hormonal contraceptives may also increase the risk of arterial thrombosis (eg, MI, stroke) and should not be used in women with a history of stroke or ischemic heart disease (Curtis 2016b). Use of combination hormonal contraceptives is contraindicated in women with a high risk of arterial or venous thrombotic disease.

• Toxic shock syndrome: Has been reported (causal relationship has not been established); increased risk with tampon use.

• Vaginal bleeding: Breakthrough or intracyclic bleeding and spotting may occur, especially during the first 3 months of therapy. In addition, occasional missed periods may occur. Presentation of irregular, unresolving vaginal bleeding warrants further evaluation to rule out malignancy or pregnancy. Amenorrhea or oligomenorrhea may occur after discontinuing combination hormonal contraceptives, especially when such a condition was preexistent.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with risk factors for cardiovascular disease (eg, hypertension, low HDL, high LDL, high triglycerides, older age, diabetes, women who smoke); use of combination hormonal contraceptives may increase the risk of cardiovascular disease (Curtis 2016b). Use is contraindicated in women at high risk of arterial or venous thrombotic diseases.

• Depression: Use with caution in patients with a history of depression; discontinue if serious depression recurs.

• Diabetes: May impair glucose tolerance; use caution in women with diabetes or prediabetes. In general, use of combination oral contraceptives has limited effects on daily insulin needs and no long term effects on diabetes control in women with nonvascular disease. However, use in women with concomitant nephropathy, neuropathy, retinopathy, other vascular disease, or diabetes >20 years duration should be evaluated for contraceptive use based on the severity of the condition (Curtis 2016b). Use is contraindicated in women with diabetes mellitus and vascular disease.

• Endometrial or ovarian cancer: The risk of endometrial or ovarian cancer is decreased in women using combination hormonal contraceptives; it is not known if use of the contraceptive ring also decreases this risk (Curtis 2016b; Walker 2015). Women awaiting treatment for endometrial or ovarian cancer may use combination hormonal contraceptives (Curtis 2016b).

• Gallbladder disease: Combination hormonal contraceptives may have a small increased risk of gallbladder disease or worsen existing gallbladder disease (Curtis 2016b).

• Hepatic adenomas or carcinomas: Use of combination hormonal contraceptives is associated with hepatic adenomas (rare); rupture may cause fatal intra-abdominal hemorrhage. Long term use may be associated with an increased risk of hepatocellular carcinoma (rare). Use is contraindicated in women with preexisting hepatic tumors.

• Hepatic impairment: Combination hormonal contraceptives may be poorly metabolized in women with hepatic impairment. Use is contraindicated in hepatic disease. Discontinue if jaundice develops during therapy or if liver function becomes abnormal. Use of combination hormonal contraceptives may be considered in women with mild (compensated) cirrhosis but should not be used in women with severe (decompensated) cirrhosis (Curtis 2016b).

• Hepatitis: Initiation of combination hormonal contraceptives is not recommended in women with acute viral hepatitis or during a flare. Continuation of use in women with chronic hepatitis has not been shown to increase the rate or severity of cirrhotic fibrosis or hepatocellular carcinoma. Continuation of use in women who are carriers has not been shown to trigger liver failure or severe hepatic dysfunction (Curtis 2016b).

• Hereditary angioedema: Estrogens may induce or exacerbate symptoms in women with hereditary angioedema (Geng 2013; Zuraw 2013).

• Hypertension: The risk of hypertension may be increased with age, dose, and duration of use. Combination hormonal contraceptives should not be used in women with hypertension and vascular disease, or persistent blood pressure values ≥160 mm Hg systolic or ≥100 mm Hg diastolic. The risks of use may not outweigh the benefits of treatment in women with less severe hypertension (140 to 159 mm Hg systolic or 90 to 99 mm Hg diastolic) or those with hypertension that is adequately controlled (Curtis 2016a). Other risk factors for cardiovascular disease (eg, older age, smoking, diabetes) should be considered when prescribing contraceptives (Curtis 2016b). The manufacturer contraindicates use in women with uncontrolled hypertension and recommends monitoring women with well-controlled hypertension; discontinue therapy if blood pressure rises significantly.

• Migraine: Evaluate new, recurrent, severe, or persistent headaches and consider discontinuing therapy if appropriate. Use of combination hormonal contraceptives may be considered in women who have migraines without aura (including menstrual migraines) (Curtis 2016b). Use in women with headaches with focal neurological symptoms, or migraine headaches with or without aura if >35 years is contraindicated.

• Solid organ transplant: Although data is limited, serious medical complications have been reported in women with complicated organ transplants (eg, graft failure, rejection, cardiac allograft vasculopathy); use of combination hormonal contraceptives is not recommended in women with complicated organ transplants (Curtis 2016b).

• Systemic lupus erythematosus: Women with systemic lupus erythematosus (SLE) are at an increased risk for heart disease, stroke, and VTE. Combination hormonal contraceptives should not be used in women with SLE who have positive (or unknown) antiphospholipid antibodies, due to an increased risk of arterial and venous thrombosis (Curtis 2016b).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Thyroid replacement therapy: Estrogens may increase thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels. Women on thyroid replacement therapy may require higher doses of thyroid hormone while receiving estrogens.

Special populations:

• Obese: In a study using the vaginal ring, ethinyl estradiol serum concentrations were decreased in obese women (BMI 30 to 39.9 kg/m2; n=19) in comparison to women of normal weight (BMI 19 to 24.9 kg/m2; n=18; p=0.004); etonogestrel concentrations did not differ significantly. Bleeding and spotting were more frequent in the obese women. The study was not powered to evaluate contraceptive effectiveness (Westhoff 2012).

• Pediatric: Not for use prior to menarche.

• Postmenopausal women: Use is not indicated in postmenopausal women.

• Smokers:[US Boxed Warning]: Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives use. This risk increases with age, particularly in women over 35 years, and with the number of cigarettes smoked. For this reason, combination oral contraceptives should not be used by women who are over 35 years and smoke.

• Surgical patients: Whenever possible, discontinue at least 4 weeks prior to and for 2 weeks following major surgery or other surgeries known to have an increased risk of thromboembolism or during periods of prolonged immobilization.

Dosage form specific issues:

• Vaginal preparation: Vaginally administered combination hormonal contraceptive agents may have a similar adverse effects associated with oral contraceptive products. In order to reduce some of the possible risks, the minimum dosage combination of estrogen/progestin that will effectively treat the individual patient should be used. May not be appropriate for use in women with conditions that make the vagina susceptible to irritation or ulceration; vaginal/cervical erosion and ulceration has been reported. The patients and their sexual partner may feel the ring in the vagina during intercourse. Ensure proper vaginal placement of the ring to avoid inadvertent urinary bladder insertion.

Other warnings/precautions:

• HIV infection protection: Combination hormonal contraceptives do not protect against HIV infection or other sexually transmitted diseases (Curtis 2016a; Curtis 2016b).

• Laboratory changes: The use of estrogens and/or progestins may change the results of some laboratory tests (eg, coagulation factors, lipids, glucose tolerance, binding proteins).