FOR VAGINAL USE ONLY Etonogestrel and ethinyl estradiol vaginal ring is indicated for use by females of reproductive age to prevent pregnancy. Etonogestrel and ethinyl estradiol vaginal ring is an estrogen/progestin combination hormonal contraceptive (CHC) indicated for use by women to prevent pregnancy. ( 1 )
Contraindications
Etonogestrel and ethinyl estradiol vaginal ring is contraindicated in females who are known to have or develop the following conditions: A high risk of arterial or venous thrombotic diseases. Examples include women who are known to: Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions ( 5.1 )] Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions ( 5.1 )] Have cerebrovascular disease [see Warnings and Precautions ( 5.1 )] Have coronary artery disease [see Warnings and Precautions ( 5.1 )] Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions ( 5.1 )] Have inherited or acquired hypercoagulopathies [see Warnings and Precautions ( 5.1 )] Have uncontrolled hypertension [see Warnings and Precautions ( 5.5 )] Have diabetes mellitus with vascular disease [see Warnings and Precautions ( 5.9 )] Have headaches with focal neurological symptoms or migraine headaches with aura [see Warnings and Precautions (5.10)] Women over age 35 with any migraine headaches [see Warnings and Precautions ( 5.10 )] Liver tumors, benign or malignant or liver disease [see Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.6 )] Undiagnosed abnormal uterine bleeding [see Warnings and Precautions ( 5.11 )] Pregnancy, because there is no reason to use CHCs during pregnancy [see Use in Specific Populations ( 8.1 )] Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive [see Warnings and Precautions ( 5.14 )] Hypersensitivity reactions, including anaphylaxis and angioedema, to any of the components of etonogestrel and ethinyl estradiol vaginal ring [see Warnings and Precautions ( 5.6 ) and Adverse Reactions ( 6 )] Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions ( 5.4 )] .
A high risk of arterial or venous thrombotic diseases ( 4 ) Breast cancer ( 4 ) Liver tumors or liver disease ( 4 ) Undiagnosed abnormal uterine bleeding ( 4 ) Pregnancy ( 4 ) Hypersensitivity, including anaphylaxis and angioedema, to any of the components of etonogestrel and ethinyl estradiol vaginal ring ( 4 ) Coadministration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir ( 4 )
Warnings and precautions
Vascular risks: Stop etonogestrel and ethinyl estradiol vaginal ring use if a thrombotic event occurs. Stop etonogestrel and ethinyl estradiol vaginal ring use at least 4 weeks before and through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery, in women who are not breastfeeding. ( 5.1 ) Toxic Shock Syndrome (TSS): If patient exhibits signs or symptoms of TSS, consider the possibility of this diagnosis and initiate appropriate medical evaluation and treatment.
( 5.2 ) Liver disease: Discontinue etonogestrel and ethinyl estradiol vaginal ring use if jaundice develops. ( 5.3 ) High blood pressure: If used in women with well-controlled hypertension, monitor blood pressure and stop etonogestrel and ethinyl estradiol vaginal ring use if blood pressure rises significantly. ( 5.5 ) Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia.
( 5.9 ) Headache: Evaluate significant change in headaches and discontinue etonogestrel and ethinyl estradiol vaginal ring use if indicated. ( 5.10 ) Uterine bleeding: Evaluate irregular bleeding or amenorrhea. ( 5.11 )
5.1Thromboembolic Disorders and Other Vascular Problems
Stop etonogestrel and ethinyl estradiol vaginal ring use if an arterial thrombotic or venous thromboembolic event (VTE) occurs. Stop etonogestrel and ethinyl estradiol vaginal ring use if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately [see Adverse Reactions ( 6 )]. If feasible, stop etonogestrel and ethinyl estradiol vaginal ring at least four weeks before and through two weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism, and during and following prolonged immobilization.
Start etonogestrel and ethinyl estradiol vaginal ring no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week. The use of CHCs increases the risk of VTE. Known risk factors for VTE include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of CHCs [see Contraindications ( 4 )] .
Two epidemiologic studies 1, 2, 3 that assessed the risk of VTE associated with the use of etonogestrel and ethinyl estradiol vaginal ring are described below. In these studies, which were required or sponsored by regulatory agencies, etonogestrel and ethinyl estradiol vaginal ring users had a risk of VTE similar to Combined Oral Contraceptives (COCs) users (see Table 1 for adjusted hazard ratios). A large prospective, observational study, the Transatlantic Active Surveillance on Cardiovascular Safety of etonogestrel and ethinyl estradiol vaginal ring (TASC), investigated the risk of VTE for new users, and women who were switching to or restarting etonogestrel and ethinyl estradiol vaginal ring or COCs in a population that is representative of routine clinical users.
The women were followed for 24 to 48 months. The results showed a similar risk of VTE among etonogestrel and ethinyl estradiol vaginal ring users (VTE incidence 8.3 per 10,000 WY) and women using COCs (VTE incidence 9.2 per 10,000 WY). For women using COCs that did not contain the progestins desogestrel (DSG) or gestodene (GSD), VTE incidence was 8.9 per 10,000 WY. A retrospective cohort study using data from 4 health plans in the US (FDA-funded Study in Kaiser Permanente and Medicaid databases) showed the VTE incidence for new users of etonogestrel and ethinyl estradiol vaginal ring to be 11.4 events per 10,000 WY, for new users of a levonorgestrel (LNG)-containing COC 9.2 events per 10,000 WY, and for users of other COCs available during the course of the study * 8.2 events per 10,000 WY. _____________________________________ * Includes low-dose COCs containing the following progestins: norgestimate, norethindrone, or levonorgestrel.
An increased risk of thromboembolic and thrombotic disease associated with the use of CHCs is well-established. Although the absolute VTE rates are increased for users of CHCs compared to nonusers, the rates associated with pregnancy are even greater, especially during the post-partum period (see Figure 1). The frequency of VTE in women using CHCs has been estimated to be 3 to 12 cases per 10,000 women-years. The risk of VTE is highest during the first year of CHC use and after restarting a CHC following a break of at least four weeks.
The risk of VTE due to CHCs gradually disappears after use is discontinued. Figure 1 shows the risk of developing a VTE for women who are not pregnant and do not use CHCs, for women who use CHCs, for pregnant women, and for women in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 women who are not pregnant and do not use CHCs are followed for one year, between 1 and 5 of these women will develop a VTE.
Table 1: Estimates (Hazard Ratios) of Venous Thromboembolism Risk in Users of Etonogestrel and Ethinyl Estradiol Vaginal Ring Compared to Users of Combined Oral Contraceptives (COCs) Epidemiologic Study (Author, Year of Publication) Population Studied Comparator Product(s) Hazard Ratios (HR) (95% CI) TASC (Dinger, 2012) Initiators, including new users, switchers and restarters All COCs available during the course of the study * HR † : 0.8 (0.5 to 1.5) COCs available excluding DSG- or GSD -containing OCs HR † : 0.8 (0.4 to 1.7) FDA-funded Study in Kaiser Permanente and Medicaid databases (Sidney, 2011) First use of a combined hormonal contraceptive (CHC) during the study period COCs available during the course of the study ‡ HR § : 1.1 (0.6 to 2.2) LNG/0.03 mg ethinyl estradiol HR § : 1.0 (0.5 to 2.0) * Includes low-dose COCs containing the following progestins: chlormadinone acetate, cyproterone acetate, desogestrel, dienogest, drospirenone, ethynodiol diacetate, gestodene, levonorgestrel, norethindrone, norgestimate, or norgestrel † Adjusted for age, BMI, duration of use, VTE history ‡ Includes low-dose COCs containing the following progestins: norgestimate, norethindrone, or levonorgestrel § Adjusted for age, site, year of entry into study Figure 1: Likelihood of Developing a VTE *CHC=combination hormonal contraception **Pregnancy data based on actual duration of pregnancy in the reference studies.
Based on a model assumption that pregnancy duration is nine months, the rate is 7 to 27 per 10,000 WY. Several epidemiology studies indicate that third generation oral contraceptives, including those containing desogestrel (etonogestrel, the progestin in etonogestrel and ethinyl estradiol vaginal ring, is the biologically active metabolite of desogestrel), may be associated with a higher risk of VTE than oral contraceptives containing other progestins.
Some of these studies indicate an approximate two-fold increased risk. However, data from other studies have not shown this two-fold increase in risk. Use of CHCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. CHCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes).
In general, the risk is greatest among older (>35 years of age), hypertensive women who also smoke. Use etonogestrel and ethinyl estradiol vaginal ring with caution in women with cardiovascular disease risk factors. fig1
5.2 Toxic Shock Syndrome (TSS) Cases of TSS have been reported by etonogestrel and ethinyl estradiol vaginal ring users. TSS has been associated with tampons and certain barrier contraceptives, and, in some cases the etonogestrel and ethinyl estradiol vaginal ring users were also using tampons. A causal relationship be
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Interactions
Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. Drugs or herbal products that induce certain enzymes, such as CYP3A4, may decrease the effectiveness of CHCs or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with CHCs.
( 7 )
7.1Effects of Other Drugs on CHCs
Substances decreasing the plasma concentrations of CHCs and potentially diminishing the effectiveness of CHCs Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of CHCs and potentially diminish the effectiveness of CHCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include: phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St.
John's wort. Interactions between CHCs and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative non-hormonal method of contraception or a back-up method when enzyme inducers are used with etonogestrel and ethinyl estradiol vaginal ring, and to continue back-up non-hormonal contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.
Note: Etonogestrel and ethinyl estradiol vaginal ring may interfere with the correct placement and position of certain female barrier methods such as a diaphragm or female condom. These methods are not recommended as back-up methods with etonogestrel and ethinyl estradiol vaginal ring use [see Dosage and Administration ( 2.5 )] . The serum concentrations of etonogestrel and ethinyl estradiol were not affected by concomitant administration of oral amoxicillin or doxycycline in standard dosages during 10 days of antibiotic treatment.
The effects of other antibiotics on etonogestrel or ethinyl estradiol concentrations have not been evaluated. Substances increasing the plasma concentrations of CHCs Coadministration of atorvastatin and certain CHCs containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20% to 25%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Concomitant administration of strong or moderate CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma estrogen and/or progestin concentrations. Coadministration of vaginal miconazole nitrate and etonogestrel and ethinyl estradiol vaginal ring increases the serum concentrations of etonogestrel and ethinyl estradiol by up to 40% [see Clinical Pharmacology ( 12.3 )] .
Human immunodeficiency virus (HIV) / Hepatitis C Virus (HCV) protease inhibitors and nonnucleoside reverse transcriptase inhibitors Significant changes in the plasma concentrations of the estrogen and /or progestin have been noted in some cases of coadministration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir]) /HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., efavirenz, nevirapine] or increase [e.g., etravirine]).
These changes may be clinically relevant in some cases.
7.2Effects of CHCs on Other Drugs
CHCs containing ethinyl estradiol may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations. CHCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid and temazepam. A significant decrease in the plasma concentrations of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation.
This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increase with use of CHCs.
7.3Concomitant Use with HCV Combination
Therapy – Liver Enzyme Elevation Do not coadminister etonogestrel and ethinyl estradiol vaginal ring with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions ( 5.4 )] .
7.4Interference with Laboratory Tests
The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary Etonogestrel
and ethinyl estradiol vaginal ring is contraindicated during pregnancy because there is no need for pregnancy prevention in a woman who is already pregnant. Epidemiologic studies and meta-analyses have not shown an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following maternal exposure to low dose CHCs prior to conception or during early pregnancy. No adverse developmental outcomes were observed in pregnant rats and rabbits with the administration of etonogestrel during organogenesis at doses approximately 300 times the anticipated daily vaginal human dose (~0.002 mg/kg/day).
No adverse developmental outcomes were observed in pregnant rats and rabbits with the coadministration of the combination desogestrel/ethinyl estradiol during organogenesis at desogestrel/ethinyl estradiol doses at least 2/5 times, respectively, the anticipated daily vaginal human dose (~0.002 desogestrel/0.00025 ethinyl estradiol mg/kg/day). Discontinue etonogestrel and ethinyl estradiol vaginal ring use if pregnancy is confirmed.
Data Animal Data In rats and rabbits at dosages up to 300 times the anticipated dose, etonogestrel is neither embryotoxic nor teratogenic. Coadministration of a maternally toxic dose of desogestrel/ethinyl estradiol to pregnant rats was associated with embryolethality and wavy ribs at a desogestrel/ethinyl estradiol dose that was 40/130 times, respectively, the anticipated vaginal human dose (0.002 desogestrel/0.00025 ethinyl estradiol mg/kg/day).
No adverse embryofetal effects were observed when the combination was administered to pregnant rats at a desogestrel/ethinyl estradiol dose that was 4/13 times, respectively, the anticipated vaginal human dose. When desogestrel/ethinyl estradiol was given to pregnant rabbits, preimplantation loss was observed at a desogestrel/ethinyl estradiol dose that was 3/10 times, respectively, the anticipated vaginal human dose.
No adverse embryofetal effects were observed when the combination was administered to pregnant rabbits at a desogestrel/ethinyl estradiol dose that was 2/5 times the anticipated vaginal human dose.
Adverse reactions
The following serious adverse reactions with the use of CHCs are discussed elsewhere in the labeling. Serious cardiovascular events and stroke [see Boxed Warning and Warnings and Precautions ( 5.1 )] Vascular events [see Warnings and Precautions ( 5.1 )] Liver disease [see Warnings and Precautions ( 5.3 )] Adverse reactions commonly reported by CHC users are: Irregular uterine bleeding Nausea Breast tenderness Headache The most common adverse reactions (≥2%) in clinical trials were: vaginitis, headache (including migraine), mood changes (e.g., depression, mood swings, mood altered, depressed mood, affect lability), device-related events (e.g., expulsion/discomfort/foreign body sensation), nausea/vomiting, vaginal discharge, increased weight, vaginal discomfort, breast pain/discomfort/tenderness, dysmenorrhea, abdominal pain, acne, and decreased libido.
( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Trials with a duration of 6 to 13 28-day cycles provided safety data. In total, 2,501 women, aged 18 to 41 contributed 24,520 cycles of exposure. Common Adverse Reactions (≥ 2%): vaginitis (13.8%), headache (including migraine) (11.2%), mood changes (e.g., depression, mood swings, mood altered, depressed mood, affect lability) (6.4%), device-related events (e.g., expulsion/discomfort/foreign body sensation) (6.3%), nausea/vomiting (5.9%), vaginal discharge (5.7%), increased weight (4.9%), vaginal discomfort (4.0%), breast pain/discomfort/tenderness (3.8%), dysmenorrhea (3.5%), abdominal pain (3.2%), acne (2.4%), and decreased libido (2.0%).
Adverse Reactions (≥1%) Leading to Study Discontinuation: 13.0% of the women discontinued from the clinical trials due to an adverse reaction; the most common adverse reactions leading to discontinuation were device-related events (2.7%), mood changes (1.7%), headache (including migraine) (1.5%) and vaginal symptoms (1.2%). Serious Adverse Reactions: deep vein thrombosis [see Warnings and Precautions ( 5.1 )] , anxiety, cholelithiasis, and vomiting.
6.2Postmarketing Experience
Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 to 1.12 (Figure 2). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 2). One of these studies reported no association between breast cancer risk and COC use.
The other two studies found an increased relative risk of 1.19 to 1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than 8 to 10 years of COC use. Figure 2: Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptives RR = relative risk; OR = odds ratio; HR = hazard ratio. “ever COC” are females with current or past COC use; “never COC use” are females that never used COCs.
The following adverse reactions have been identified during post-approval use of etonogestrel and ethinyl estradiol vaginal ring. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: hypersensitivity reactions, including anaphylaxis and angioedema Nervous system disorders: stroke/cerebrovascular accident Vascular disorders: arterial events (including arterial thromboembolism and myocardial infarction), aggravation of varicose veins Skin and subcutaneous tissue disorders: urticaria, chloasma Reproductive system and breast disorders: penile disorders, including local reactions on penis (in male partners of women using etonogestrel and ethinyl estradiol vaginal ring), galactorrhea General Disorders and Administration Site Conditions: device breakage (including with concomitant use of intravaginal antimycotic, antibiotic, and lubricant products) Injury, poisoning and procedural complications: vaginal injury (including associated pain, discomfort, and bleeding) associated with ring breakage image
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
