LEVONORGESTREL AND ETHINYL ESTRADIOL

WARNINGS Breast Cancer Levonorgestrel and ethinyl estradiol tablet is contraindicated in women who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications]. 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]. Cervical Cancer Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. There is controversy about the extent to which these findings are due to differences in sexual behavior and other factors. 1. Thromboembolic Disorders and Other Vascular Conditions Stop levonorgestrel and ethinyl estradiol tablets if an arterial or venous thrombotic/thromboembolic event occurs. Stop levonorgestrel and ethinyl estradiol tablets if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately. Discontinue levonorgestrel and ethinyl estradiol tablets during prolonged immobilization. If feasible, stop Levonorgestrel and ethinyl estradiol tablets at least four weeks before and through two weeks after major surgery, or other surgeries known to have an elevated risk of thromboembolism. Start levonorgestrel and ethinyl estradiol tablets no earlier than four weeks after delivery in females who are not breast-feeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the likelihood of ovulation increases after the third postpartum week. Before starting levonorgestrel and ethinyl estradiol tablets evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. Levonorgestrel and ethinyl estradiol tablets are contraindicated in females with a high risk of arterial or venous thrombotic/thromboembolic diseases (see CONTRAINDICATIONS ). Arterial Events COCs increase 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 females with hypertension, dyslipidemia, diabetes, or obesity. Levonorgestrel and ethinyl estradiol tablets are contraindicated in women over 35 years of age who smoke (see CONTRAINDICATIONS ). Cigarette smoking increases the risk of serious cardiovascular events from COC use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. Venous Events Use of COCs 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 COCs (see CONTRAINDICATIONS ). While the increased risk of VTE associated with use of COCs is well-established, the rates of VTE are even greater during pregnancy, and especially during the postpartum period (see Figure 1). The rate of VTE in females using COCs has been estimated to be 3 to 9 cases per 10,000 woman-years. The risk of VTE is highest during the first year of use of a COC and when restarting hormonal contraception after a break of four weeks or longer. 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 COCs gradually disappears after COC use is discontinued. Figure 1 shows the risk of developing a VTE for females who are not pregnant and do not use oral contraceptives, for females who use oral contraceptives, for pregnant females, and for females in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 females who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these females will develop a VTE. Figure 1: Likelihood of Developing a VTE Figure 1 2. Liver Disease Elevated Liver Enzymes Levonorgestrel and ethinyl estradiol tablets are contraindicated in females with acute viral hepatitis or severe (decompensated) cirrhosis of liver (see CONTRAINDICATIONS ). Discontinue Levonorgestrel and ethinyl estradiol tablets if jaundice develops. Acute liver test abnormalities may necessitate the discontinuation of COC use until the liver tests return to normal and COC causation has been excluded. Liver Tumors Levonorgestrel and ethinyl estradiol tablets are contraindicated in females with benign or malignant liver tumors (see CONTRAINDICATIONS ). COCs increase the risk of hepatic adenomas. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death from abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) COC users. The attributable risk of liver cancers in COC users is less than one case per million users. 3. Malignant Neoplasms Breast Cancer Levonorgestrel and ethinyl estradiol tablet is contraindicated in women who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications]. 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]. Cervical Cancer Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. There is controversy about the extent to which these findings are due to differences in sexual behavior and other factors. 4. Hypertension Levonorgestrel and ethinyl estradiol tablets are contraindicated in females with uncontrolled hypertension or hypertension with vascular disease (see CONTRAINDICATIONS ). For all females, including those with well-controlled hypertension, monitor blood pressure at routine visits and stop levonorgestrel and ethinyl estradiol tablets if blood pressure rises significantly. An increase in blood pressure has been reported in females using COCs, and this increase is more likely in older women with extended duration of use. The effect of COCs on blood pressure may vary according to the progestin in the COC. 5. Age-related Considerations The risk for cardiovascular disease and prevalence of risk factors for cardiovascular disease increase with age. Certain conditions, such as smoking and migraine headache without aura, that do not contraindicate COC use in younger females, are contraindications to use in women over 35 years of age [see CONTRAINDICATIONS and WARNINGS (1) ]. Consider the presence of underlying risk factors that may increase the risk of cardiovascular disease or VTE, particularly before initiating a COC for women over 35 years, such as: Hypertension Diabetes Dyslipidemia Obesity 6. 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 COCs. Discontinue levonorgestrel and ethinyl estradiol tablets prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (see CONTRAINDICATIONS ). Levonorgestrel and ethinyl estradiol tablets can be restarted approximately 2 weeks following completion of treatment with the combination drug regimen. 7. Gallbladder Disease Studies suggest an increased risk of developing gallbladder disease among COC users. Use of COCs may also worsen existing gallbladder disease. A past history of COC-related cholestasis predicts an increased risk with subsequent COC use. Females with a history of pregnancy-related cholestasis may be at an increased risk for COC-related cholestasis. 8. Adverse Carbohydrate and Lipid Metabolic Effects Hyperglycemia Levonorgestrel and ethinyl estradiol tablets are contraindicated in diabetic women over age 35, or females who have diabetes with hypertension, nephropathy, retinopathy, neuropathy, other vascular disease, or females with diabetes of > 20 years duration (see CONTRAINDICATIONS ). Levonorgestrel and ethinyl estradiol tablets may decrease glucose tolerance. Carefully monitor prediabetic and diabetic females who are using levonorgestrel and ethinyl estradiol tablets. Dyslipidemia Consider alternative contraception for females with uncontrolled dyslipidemia. Levonorgestrel and ethinyl estradiol tablets may cause adverse lipid changes. Females with hypertriglyceridemia, or a family history thereof, may have an increase in serum triglyceride concentrations when using levonorgestrel and ethinyl estradiol tablets, which may increase the risk of pancreatitis. 9. Headache Levonorgestrel and ethinyl estradiol tablets are contraindicated in females who have headaches with focal neurological symptoms or have migraine headaches with aura, and in women over age 35 years who have migraine headaches with or without aura (see CONTRAINDICATIONS ). If a woman using levonorgestrel and ethinyl estradiol tablets develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue levonorgestrel and ethinyl estradiol tablets if indicated. Consider discontinuation of levonorgestrel and ethinyl estradiol tablets if there is an increased frequency or severity of migraines during COC use (which may be prodromal of a cerebrovascular event). 10. Bleeding Irregularities and Amenorrhea Unscheduled Bleeding and Spotting Females using levonorgestrel and ethinyl estradiol tablets may experience unscheduled (breakthrough or intracyclic) bleeding and spotting, especially during the first three months of use. Bleeding irregularities may resolve over time or by changing to a different contraceptive product. If bleeding persists or occurs after previously regular cycles, evaluate for causes such as pregnancy or malignancy. In two clinical trials of levonorgestrel and ethinyl estradiol (1084 subjects reporting for a total of 8186 treatment cycles and 238 subjects reporting for a total of 1102 treatment cycles), breakthrough bleeding occurred in 6.9% and 8.1% of reported cycles, and spotting occurred in 8.6% and 7.9% of reported cycles over the total study duration, respectively. In the two trials, intermenstrual bleeding (i.e., breakthrough bleeding and/or spotting) occurred in 13.1% and 12.9% of reported cycles over the total study duration, respectively. In one trial, 33 subjects out of 1084 (3.0%) discontinued due to bleeding irregularities (i.e., breakthrough bleeding and spotting); in the other trial, 6 subjects out of 238 (2.5%) discontinued due to bleeding irregularities. Amenorrhea and Oligomenorrhea Females who use levonorgestrel and ethinyl estradiol tablets may experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant. In two clinical trials of Levonorgestrel and ethinyl estradiol, one including 8186 reported treatment cycles, and the other including 1102 reported treatment cycles, amenorrhea occurred in 1.5% of treatment cycles in each trial. If scheduled bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or two active tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and perform appropriate diagnostic measures. If the patient has adhered to the prescribed dosing schedule and misses two consecutive periods, rule out pregnancy. After discontinuation of a COC, amenorrhea or oligomenorrhea may occur, especially if these conditions were pre-existent. 11. Depression Carefully observe females with a history of depression and discontinue levonorgestrel and ethinyl estradiol tablets if depression recurs to a serious degree. Data on the association of COCs with onset of depression or exacerbation of existing depression are limited. 12. Effect on Binding Globulins The estrogen component of levonorgestrel and ethinyl estradiol tablets 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. 13. Hereditary Angioedema In females with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. 14. Chloasma Chloasma may occur with levonorgestrel and ethinyl estradiol tablets use, especially in females with a history of chloasma gravidarum. Advise females with a history of chloasma to avoid exposure to the sun or ultraviolet radiation while using levonorgestrel and ethinyl estradiol tablets.