norelgestromin and ethinyl estradiol

5 WARNINGS AND PRECAUTIONS Vascular risks : Stop norelgestromin and ethinyl estradiol transdermal system if a thrombotic event occurs. Stop 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. Consider cardiovascular risk factors before initiating in all women, particularly those over 35 years. ( 5.1 ) Liver disease : Discontinue norelgestromin and ethinyl estradiol transdermal system if jaundice occurs. ( 5.3 ) High blood pressure : Do not prescribe norelgestromin and ethinyl estradiol transdermal system for women with uncontrolled hypertension or hypertension with vascular disease. ( 5.5 ) Carbohydrate and lipid metabolic effects : Monitor prediabetic and diabetic women taking norelgestromin and ethinyl estradiol transdermal system. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. ( 5.7 ) Headache : Evaluate significant change in headaches and discontinue norelgestromin and ethinyl estradiol transdermal system if indicated. ( 5.8 ) Uterine bleeding : Evaluate irregular bleeding or amenorrhea. ( 5.9 ) 5.1 Thromboembolic Disorders and Other Vascular Conditions Stop norelgestromin and ethinyl estradiol transdermal system if an arterial or venous thromboembolic event (VTE) occurs. Stop norelgestromin and ethinyl estradiol transdermal system if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. If feasible, stop norelgestromin and ethinyl estradiol transdermal system at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE. Discontinue use of norelgestromin and ethinyl estradiol transdermal system during prolonged immobilization and resume treatment based on clinical judgment. Start norelgestromin and ethinyl estradiol transdermal system no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum VTE decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week. Before starting norelgestromin and ethinyl estradiol transdermal system, evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy [see Contraindications ( 4 )]. Arterial Events The use of CHCs increases the risk of cardiovascular events and cerebrovascular events, such as myocardial infarction and stroke. The risk is greater among older women (> 35 years of age), smokers, and women with hypertension, dyslipidemia, diabetes, or obesity. Norelgestromin and ethinyl estradiol transdermal system is contraindicated in women over 35 years of age who smoke [see Contraindications ( 4 )]. Cigarette smoking increases the risk of serious cardiovascular events from CHC use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. Venous Events The use of CHCs increases the risk of venous thromboembolic events (VTEs), such as deep vein thrombosis and pulmonary embolism. Risk factors for VTEs include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of CHCs. The risk of VTE may be greater with norelgestromin and ethinyl estradiol transdermal system in women with a BMI ≥ 30 kg/m 2 compared to women with a lower BMI [see Contraindications ( 4 )]. While the increased risk of VTE associated with use of CHCs is well-established, the rates of VTE are even greater during pregnancy, and especially during the postpartum period (see Figure 1). The frequency of VTE in women using CHCs has been estimated to be 3 to 12 cases per 10,000 woman-years. The risk of VTE is highest during the first year of use of CHCs and when restarting hormonal contraception after a break of 4 weeks or longer. This initial higher risk declines during the first year, but users of CHCs remain at an increased risk of VTE compared to non-users of CHCs. Based on results from a few studies, there is some evidence that this is true for non-oral products as well. The risk of thromboembolic disease due to CHCs gradually disappears after CHC 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 with a range of doses and routes of administration, 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 Within One Year Among Pregnant and Non-Pregnant Women 5.2 Ethinyl Estradiol Exposure Higher estrogen exposure may increase the risk of adverse reactions, including venous thromboembolism (VTE). The Area Under the Curve (AUC) for ethinyl estradiol (EE) is approximately 60% higher in women using norelgestromin and ethinyl estradiol transdermal system compared to oral contraceptives containing EE 35 mcg. In contrast, the peak concentration (C max ) for EE is approximately 25% lower in women using norelgestromin and ethinyl estradiol transdermal system [see Clinical Pharmacology ( 12.3 )]. 5.3 Liver Disease Impaired Liver Function Do not use norelgestromin and ethinyl estradiol transdermal system in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of liver [see Contraindications ( 4 )]. Discontinue norelgestromin and ethinyl estradiol transdermal system if jaundice develops. 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. Liver Tumors Norelgestromin and ethinyl estradiol transdermal system 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/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 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 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, such as CHCs. Discontinue norelgestromin and ethinyl estradiol transdermal system prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications ( 4 )] . Norelgestromin and ethinyl estradiol transdermal system can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen. 5.5 High Blood Pressure Norelgestromin and ethinyl estradiol transdermal system 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 norelgestromin and ethinyl estradiol transdermal system if blood pressure rises significantly. An increase in blood pressure has been reported in women taking hormonal contraceptives, and this increase is more likely in older women with extended duration of use. The incidence of hypertension increases with increasing concentrations of progestin. 5.6 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. 5.7 Carbohydrate and Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who take norelgestromin and ethinyl estradiol transdermal system. CHCs may decrease glucose tolerance in a dose-related fashion. In a 6-cycle clinical trial with norelgestromin and ethinyl estradiol transdermal system there were no clinically significant changes in fasting blood glucose from baseline to end of treatment. Consider alternative contraception for women with uncontrolled dyslipidemia. A small proportion of women will have adverse lipid changes while on hormonal contraceptives. Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using hormonal contraceptives. 5.8 Headache If a woman taking norelgestromin and ethinyl estradiol transdermal system develops new headaches that are recurrent, persistent or severe, evaluate the cause and discontinue norelgestromin and ethinyl estradiol transdermal system if indicated. Consider discontinuation of norelgestromin and ethinyl estradiol transdermal system in the case of increased frequency or severity of migraine during hormonal contraceptive use (which may be prodromal of a cerebrovascular event). 5.9 Bleeding Irregularities Unscheduled Bleeding and Spotting Unscheduled (breakthrough) bleeding and spotting sometimes occur in women using norelgestromin and ethinyl estradiol transdermal system. Consider non-hormonal causes and take adequate diagnostic measures to rule out malignancy, other pathology, or pregnancy in the event of unscheduled bleeding, as in the case of any abnormal vaginal bleeding. If pathology and pregnancy have been excluded, time or a change to another contraceptive product may resolve the bleeding. In the clinical trials, most women started their scheduled (withdrawal) bleeding on the fourth day of the drug-free interval, and the median duration of withdrawal bleeding was 5 to 6 days. On average, 26% of women per cycle had 7 or more total days of bleeding and/or spotting (this includes both scheduled and unscheduled bleeding and/or spotting). Three clinical studies of the efficacy of norelgestromin and ethinyl estradiol transdermal system in preventing pregnancy assessed scheduled and unscheduled bleeding [see Clinical Studies ( 14 )] in 3,330 women who completed 22,155 cycles of exposure. A total of 36 (1.1%) of the women discontinued norelgestromin and ethinyl estradiol transdermal system at least in part, due to bleeding or spotting. Table 2 summarizes the proportion of subjects who experienced unscheduled (breakthrough) bleeding/spotting by treatment cycle. Table 2: Unscheduled (Breakthrough) Bleeding/Spotting (Subjects Evaluable for Efficacy) Treatment Cycle Pooled data from 3 studies N=3319 n % * Cycle 1 2994 18.2 Cycle 2 2743 11.9 Cycle 3 2699 11.6 Cycle 4 2541 10.1 Cycle 5 2532 9.2 Cycle 6 2494 8.3 Cycle 7 698 8.3 Cycle 8 692 8.7 Cycle 9 654 8.6 Cycle 10 621 8.7 Cycle 11 631 8.9 Cycle 12 617 6.3 Cycle 13 611 8.0 *Percentage of subjects with breakthrough bleeding/spotting events. Amenorrhea and Oligomenorrhea In the event of amenorrhea, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one patch or started the patch on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. Some women may encounter amenorrhea or oligomenorrhea after discontinuation of hormonal contraceptive use, especially when such a condition was pre-existent. 5.10 Hormonal Contraceptive Use Before or During Early Pregnancy Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned, when oral contraceptives are taken inadvertently during early pregnancy. Discontinue norelgestromin and ethinyl estradiol transdermal system use if pregnancy is confirmed. Administration of CHCs should not be used as a test for pregnancy [see Use in Specific Populations ( 8.1 )]. 5.11 Depression Carefully observe women with a history of depression and discontinue norelgestromin and ethinyl estradiol transdermal system if depression recurs to a serious degree. 5.12 Malignant Neoplasms Breast Cancer Norelgestromin and ethinyl estradiol transdermal system are 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 COC use has been associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. 5.13 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 hormone or cortisol therapy may need to be increased. 5.14 Monitoring A woman who is taking hormonal contraceptive should have routine visits with her healthcare provider for a blood pressure check and for other indicated healthcare. 5.15 Hereditary Angioedema In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. 5.16 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 norelgestromin and ethinyl estradiol transdermal system. figure2