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warnings and cautions
5 WARNINGS AND PRECAUTIONS Vascular risks: Stop if a thrombotic or thromboembolic 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 females, particularly those over 35 years. ( 5.1 , 5.5 ) Liver disease: Discontinue if jaundice occurs. ( 5.2 ) Hypertension: If used in women with well-controlled hypertension, monitor blood pressure and stop if blood pressure rises significantly. ( 5.4 ) Gallbladder disease: May cause or worsen gallbladder disease. ( 5.6 ) Adverse carbohydrate and lipid effects: Monitor glucose in prediabetic and diabetic women taking SETLAKIN. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. ( 5.7 ) Headache: Evaluate significant change in headaches and discontinue if indicated. ( 5.8 ) Uterine bleeding: May cause irregular bleeding or amenorrhea. Evaluate for other causes if symptoms persist. ( 5.9 ) 5.1 Thromboembolic Disorders and Other Vascular Conditions Stop SETLAKIN if an arterial or venous thrombotic/thromboembolic event occurs. Stop SETLAKIN if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. Discontinue SETLAKIN during prolonged immobilization. If feasible, stop SETLAKIN at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism. Start SETLAKIN no earlier than 4 weeks after delivery in females who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the likelihood of ovulation increases after the third postpartum week. Before starting SETLAKIN evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. SETLAKIN is contraindicated in females with a high risk of arterial or venous thrombotic/thromboembolic diseases [see Contraindications ( 4 )]. 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. SETLAKIN is contraindicated in women over 35 years of age who smoke [ see Contraindications ( 4 ) ]. 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 ( 4 )] . 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. 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. Use of SETLAKIN provides women with more hormonal exposure on a yearly basis than conventional monthly COCs containing the same strength synthetic estrogens and progestins (an additional 9 weeks of exposure per year). In the clinical trial, one case of pulmonary embolism was reported. Postmarketing adverse reactions of VTE have been reported in women who used SETLAKIN. Figure 1 5.2 Liver Disease Elevated Liver Enzymes SETLAKIN is contraindicated in females with acute viral hepatitis or severe (decompensated) cirrhosis of the liver [see Contraindications ( 4 )] . Acute liver test abnormalities may necessitate the discontinuation of SETLAKIN until the liver tests return to normal and SETLAKIN causation has been excluded. Discontinue SETLAKIN if jaundice develops. Liver Tumors SETLAKIN is contraindicated in females with benign and malignant liver tumors [see Contraindications ( 4 )] . 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 through intra-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. 5.3 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 SETLAKIN. Discontinue SETLAKIN prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications ( 4 )] . SETLAKIN can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen. 5.4 Hypertension SETLAKIN is contraindicated in females with uncontrolled hypertension or hypertension with vascular disease [see Contraindications ( 4 )]. For all women, including those with well-controlled hypertension, monitor blood pressure at routine visits and stop SETLAKIN if blood pressure rises significantly. An increase in blood pressure has been reported in females taking COCs, and this increase is more likely in older women and with extended duration of use. The effect of COCs on blood pressure may vary according to the progestin in the COC. 5.5 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 ( 4 ) and Warnings and Precautions ( 5.1 ) ]. Consider the presence of underlying risk factors that may increase the risk of cardiovascular disease or VTE, particularly before initiating SETLAKIN for women over 35 years, such as: Hypertension Diabetes Dyslipidemia Obesity 5.6 Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs, including SETLAKIN, may 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. 5.7 Adverse Carbohydrate and Lipid Metabolic Effects Hyperglycemia SETLAKIN is 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 of duration [ see Contraindications (4) ]. SETLAKIN may decrease glucose tolerance. Carefully monitor prediabetic and diabetic females who are using SETLAKIN. Dyslipidemia Consider alternative contraception for females with uncontrolled dyslipidemia. SETLAKIN may cause adverse lipid changes. Females with hypertriglyceridemia, or a family history thereof, may have an increase in serum triglyceride concentrations when using SETLAKIN, which may increase the risk of pancreatitis. 5.8 Headache SETLAKIN is 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 (4)] . If a female taking SETLAKIN develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue SETLAKIN if indicated. Consider discontinuation of SETLAKIN if there is an increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) [see Contraindications (4)]. 5.9 Bleeding Irregularities and Amenorrhea Bleeding and/or spotting that occurs at any time while taking the first 84 tablets of each extended-cycle regimen is considered “unscheduled” bleeding/spotting. Bleeding that occurs during the time a woman takes the seven white inert tablets is considered “scheduled” bleeding. Unscheduled Bleeding and Spotting Females using SETLAKIN may experience unscheduled (breakthrough or intracyclic) bleeding and spotting especially during the first 3 months of use. Bleeding irregularities may resolve over time or by changing to a different contraceptive product. If unscheduled bleeding persists or occurs after previously regular cycles, evaluate for causes such as pregnancy or malignancy. Before prescribing SETLAKIN, advise the woman to weigh the occurrence of fewer scheduled menses (4 per year instead of 13 per year) against the occurrence of increased unscheduled bleeding and/or spotting. The clinical trial of the efficacy of levonorgestrel and ethinyl estradiol 0.15mg/0.03mg (91-day cycles) in preventing pregnancy also assessed scheduled and unscheduled bleeding. The participants in the study were composed primarily of women who had used oral contraceptives previously as opposed to new users. Women with a history of breakthrough bleeding/spotting ≥ 10 consecutive days on oral contraceptives were excluded from the study. More levonorgestrel and ethinyl estradiol 0.15mg/0.03mg (91-day cycles) subjects, compared to subjects on the comparator 28-day cycle regimen, discontinued prematurely for unacceptable bleeding (7.7% [levonorgestrel and ethinyl estradiol 0.15mg/0.03mg (91-day cycles)] vs. 1.8% [28-day cycle regimen]). Unscheduled bleeding and unscheduled spotting decreased over successive 91-day cycles. Table 3 below presents the number of days with unscheduled bleeding and/or spotting for each respective 91-day cycle. Table 3: Number of Unscheduled Bleeding and/or Spotting Days per 91-day Cycle Cycle (N) Days of Unscheduled Bleeding and/or Spotting per 84-Day Interval Median Days Per Subject-Month Mean Q1 Median Q3 1 (446) 15.1 3.0 12 23.0 3.0 2 (368) 11.6 2.0 6 17.5 1.5 3 (309) 10.6 1.0 6 15.0 1.5 4 (282) 8.8 1.0 4 14.0 1.0 Q1=Quartile 1: 25% of women had ≤ this number of days of unscheduled bleeding/spotting Median: 50% of women had ≤ this number of days of unscheduled bleeding/spotting Q3=Quartile 3: 75% of women had ≤ this number of days of unscheduled bleeding/spotting Table 4 shows the percentages of women with ≥7 days and ≥20 days of unscheduled spotting and/or bleeding in the levonorgestrel and ethinyl estradiol 0.15mg/0.03mg (91-day cycles) and the 28-day cycle treatment groups. Table 4: Percentage of Subjects with Unscheduled Bleeding and/or Spotting Days of unscheduled bleeding and/or spotting Percentage of Subjects a Levonorgestrel and ethinyl estradiol tablets (91-day regimen) Cycle 1 (N=385) Cycle 4 (N=261) ≥ 7 days 65% 42% ≥ 20 days 35% 15% 28-day regimen Cycles 1-4 (N=194) Cycles 10-13 (N=158) ≥ 7 days 38% 39% ≥ 20 days 6% 4% a Based on spotting and/or bleeding on days 1-84 of a 91 day cycle in the levonorgestrel and ethinyl estradiol tablets subjects and days 1-21 of a 28 day cycle over 4 cycles in the 28-day dosing regimen. Total days of bleeding and/or spotting (scheduled plus unscheduled) were similar over one year of treatment for levonorgestrel and ethinyl estradiol tablets subjects and subjects on the 28-day cycle regimen. Amenorrhea and Oligomenorrhea Females who use SETLAKIN may experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant. Based on data from the clinical trial of levonorgestrel and ethinyl estradiol tablets, amenorrhea occurred in approximately 0.8% of females during Cycle 1, 1.2% of females during Cycle 2, 3.7% of females during Cycle 3, and 3.4% of females during Cycle 4. Because females using SETLAKIN will likely have scheduled bleeding only 4 times per year, rule out pregnancy at the time of any missed menstrual period. After discontinuation of SETLAKIN, amenorrhea or oligomenorrhea may occur, especially if these conditions were pre-existent. 5.10 Depression Carefully observe females with a history of depression and discontinue SETLAKIN if depression recurs to a serious degree. Data on the association of COCs with onset of depression or exacerbation of existing depression are limited. 5.11 Malignant Neoplasms Breast Cancer SETLAKIN 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 COC are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. 5.12 Effect on Binding Globulins The estrogen component of SETLAKIN 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. 5.13 Hereditary Angioedema In females with hereditary angioedema, exogenous estrogens, including SETLAKIN, may induce or exacerbate symptoms of hereditary angioedema. 5.14 Chloasma Chloasma may occur with SETLAKIN 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 taking SETLAKIN.