Etonogestrel and Ethinyl Estradiol Vaginal

5 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 changes in headaches and discontinue Etonogestrel and ethinyl estradiol vaginal ring use if indicated. ( 5.10 ) Uterine bleeding: Evaluate irregular bleeding or amenorrhea. ( 5.11 ) 5.1 Thromboembolic 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. 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 * COCs available excluding DSG-or GSD -containing OCs HR†: 0.8 (0.5-1.5) HR†: 0.8 (0.4-1.7) 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‡ LNG/0.03 mg ethinyl estradiol HR§: 1.1 (0.6-2.2) HR§: 1.0 (0.5-2.0) * 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 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 non-users, 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. 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. image description 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 between the use of Etonogestrel and ethinyl estradiol vaginal ring and TSS has not been established. If a patient exhibits signs or symptoms of TSS, consider the possibility of this diagnosis and initiate appropriate medical evaluation and treatment. 5.3 Liver Disease Impaired Liver Function Do not use Etonogestrel and ethinyl estradiol vaginal ring in women with liver disease such as acute viral hepatitis or severe (decompensated) cirrhosis of the liver [see Contraindications ( 4 )]. Acute or chronic disturbances of liver function may necessitate the discontinuation of CHC use until markers of liver function return to normal and CHC causation has been excluded [see Use in Specific Populations ( 8.6 )]. Discontinue Etonogestrel and ethinyl estradiol vaginal ring use if jaundice develops. Liver Tumors Etonogestrel and ethinyl estradiol vaginal ring is contraindicated in women with benign and malignant liver tumors [see Contraindications ( 4 )]. Hepatic adenomas are associated with CHC use. An estimate of the attributable risk is 3.3 cases per 100,000 CHC 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 (>8 years) CHC users. However, the attributable risk of liver cancers in CHC users is less than one case per million users. 5.4 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment CHCs, such as etonogestrel and ethinyl estradiol vaginal ring, are contraindicated for use with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir (with or without dasabuvir) [see Contraindications (4)]. Discontinue etonogestrel and ethinyl estradiol vaginal ring prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir (with or without dasabuvir). Etonogestrel and ethinyl estradiol vaginal ring can be restarted approximately 2 weeks following completion of treatment with this hepatitis C combination drug regimen. During clinical trials with some HCV combination drug regimens, ALT elevations were observed in women using ethinyl estradiol containing medications [see Drug Interactions (7)]. For example, 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, such as CHCs. 5.5 High Blood Pressure Etonogestrel and ethinyl estradiol vaginal ring is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see Contraindications ( 4 )] . For women with well-controlled hypertension, monitor blood pressure and stop Etonogestrel and ethinyl estradiol vaginal ring use if blood pressure rises significantly. An increase in blood pressure has been reported in women using CHCs and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentrations of progestin. 5.6 Hypersensitivity Reactions Hypersensitivity reactions of anaphylaxis and angioedema have been reported during use of Etonogestrel and ethinyl estradiol vaginal ring. If anaphylaxis and/or angioedema is suspected, Etonogestrel and ethinyl estradiol vaginal ring should be discontinued and appropriate treatment administered. [see Contraindications ( 4 ).] 5.7 Vaginal Use Etonogestrel and ethinyl estradiol vaginal ring may not be suitable for women with conditions that make the vagina more susceptible to vaginal irritation or ulceration. Vaginal/cervical erosion or ulceration in women using Etonogestrel and ethinyl estradiol vaginal ring has been reported. In some cases, the ring adhered to vaginal tissue, necessitating removal by a healthcare provider and in some instances (i.e., when the tissue had grown over the ring), removal was achieved by cutting the ring without incising the overlying vaginal tissue. Some women are aware of the ring on occasion during the 21 days of use or during intercourse, and sexual partners may feel Etonogestrel and ethinyl estradiol vaginal ring in the vagina. 5.8 Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder disease among CHC users. Use of CHCs may also worsen existing gallbladder disease. A past history of CHC-related cholestasis predicts an increased risk with subsequent CHC use. Women with a history of pregnancy-related cholestasis may be at an increased risk for CHC-related cholestasis. 5.9 Carbohydrate and Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who are using Etonogestrel and ethinyl estradiol vaginal ring. CHCs may decrease glucose tolerance. Consider alternative contraception for women with uncontrolled dyslipidemia. Some women will have adverse lipid changes while on CHCs. Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using CHCs. 5.10 Headache If a woman using Etonogestrel and ethinyl estradiol vaginal ring develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Etonogestrel and ethinyl estradiol vaginal ring if indicated. Consider discontinuation of Etonogestrel and ethinyl estradiol vaginal ring in the case of an increased frequency or severity of migraine during CHC use (which may be prodromal of a cerebrovascular event) [see Contraindications ( 4 )]. 5.11 Bleeding Irregularities and Amenorrhea Unscheduled Bleeding and Spotting Unscheduled bleeding (breakthrough or intracyclic) bleeding and spotting sometimes occur in women using CHCs, especially during the first three months of use. If bleeding persists or occurs after previously regular cycles, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different CHC. Bleeding patterns were evaluated in three large clinical studies. In the North American study (US and Canada, N=1,177), the percentages of subjects with breakthrough bleeding/spotting ranged from 7.2% to 11.7% during cycles 1-13. In the two non-US studies, the percentages of subjects with breakthrough bleeding/spotting ranged from 2.6% to 6.4% (Europe, N=1,145) and from 2.0% to 8.7% (Europe, Brazil, Chile, N=512). Amenorrhea and Oligomenorrhea If scheduled (withdrawal) 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 take appropriate diagnostic measures. Occasional missed periods may occur with the appropriate use of Etonogestrel and ethinyl estradiol vaginal ring. In the clinical studies, the percent of women who did not have withdrawal bleeding in a given cycle ranged from 0.3% to 3.8%. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. Some women may experience amenorrhea or oligomenorrhea after discontinuing CHC use, especially when such a condition was pre-existent. 5.12 Inadvertent Urinary Bladder Insertion There have been reports of inadvertent insertions of Etonogestrel and ethinyl estradiol vaginal ring into the urinary bladder, which required cystoscopic removal. Assess for ring insertion into the urinary bladder in Etonogestrel and ethinyl estradiol vaginal ring users who present with persistent urinary symptoms and are unable to locate the ring. 5.13 Depression Carefully observe women with a history of depression and discontinue Etonogestrel and ethinyl estradiol vaginal ring use if depression recurs to a serious degree. 5.14 Malignant Neoplasms Etonogestrel and ethinyl estradiol vaginal ring is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications ( 4 )]. 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 (<6 months since last use) and current users with longer duration of COC use [see Postmarketing Experience ( 6.2 )] . Cervical Cancer Some studies suggest that CHCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which these findings may be due to differences in sexual behavior and other factors. 5.15 Effect on Binding Globulins The estrogen component of CHCs may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin. The dose of replacement thyroid hormones or cortisol therapy may need to be increased. 5.16 Monitoring A woman who is using Etonogestrel and ethinyl estradiol vaginal ring should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare. 5.17 Hereditary Angioedema In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. 5.18 Chloasma Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while using Etonogestrel and ethinyl estradiol vaginal ring.