warnings and cautions
5 WARNINGS AND PRECAUTIONS Hyperkalemia: Check serum potassium levels during the first treatment cycle in females receiving daily, long-term treatment for chronic conditions of diseases with medications that may increase serum potassium concentrations. ( 5.1 ) Thromboembolic disorders: Discontinue SLYND if a thromboembolic event occurs. ( 5.2 ) Bone loss: It is unknown if SLYND may cause a clinically relevant loss of bone mineral density. ( 5.3 ) Liver Disease: Discontinue use if jaundice or acute or chronic disturbances of liver function develop. ( 5.5 ) Ectopic pregnancy: Be alert to the possibility of ectopic pregnancy in females who become pregnant or complain of lower abdominal pain while on SLYND. ( 5.6 ) Risk of Hyperglycemia in Patients with Diabetes: Patients with diabetes may be at greater risk of hyperglycemia and may require additional medication adjustments or monitoring. ( 5.7 ) Bleeding Irregularities and Amenorrhea: May cause irregular bleeding or amenorrhea. Evaluate for other causes, such as pregnancy, if irregular bleeding or amenorrhea persists. ( 5.8 ) 5.1 Hyperkalemia SLYND contains drospirenone, a progestin, which has anti-mineralocorticoid activity, including the potential for hyperkalemia in high-risk females, comparable to a 25 mg dose of spironolactone. SLYND is contraindicated in females with conditions that predispose to hyperkalemia (e.g. renal impairment, hepatic impairment, and adrenal insufficiency). Females receiving daily, long-term treatment for chronic conditions or diseases with medications that may increase serum potassium concentration should have their serum potassium concentration checked prior to starting treatment and during the first treatment cycle. Consider monitoring serum potassium concentration in females at increased risk for hyperkalemia i.e., those females who take a strong CYP3A4 inhibitor long-term and concomitantly with SLYND. Strong CYP3A4 inhibitors include azole antifungals (e.g. ketoconazole, itraconazole, voriconazole), HIV/HCV protease inhibitors (e.g., indinavir, boceprevir), and clarithromycin [see Drug Interactions (7) ] . Monitor females taking SLYND who later develop medical conditions and/or begin medication that put them at an increased risk for hyperkalemia. Most females with hyperkalemia in the clinical development studies of SLYND had mild potassium elevations and/or isolated increases that returned to normal while still on study medication. No concurrent adverse reactions were attributed to hyperkalemia. In the pivotal trial, two females (0.2%) with persistent potassium elevations discontinued SLYND. 5.2 Thromboembolic Disorders Epidemiological studies have not indicated an association between progestin-only preparations and an increased risk of myocardial infarction, cerebral thromboembolism, or venous thromboembolism. Combined oral contraceptives containing drospirenone and ethinyl estradiol may be associated with a higher risk of venous thromboembolism (VTE) than those containing some other progestins in combination with ethinyl estradiol. It is unknown whether the risk of VTE is increased with drospirenone alone; however, if there is a risk, it is expected to be lower than that of drospirenone in combination with ethinyl estradiol. When prescribing SLYND, consider the increased risk of thromboembolism inherent in the postpartum period and in females with a history of thromboembolism. Discontinue SLYND if arterial or venous thromboembolic events occur. Consider discontinuing SLYND, if feasible, in case of prolonged immobilization due to surgery or illness. 5.3 Bone Loss Treatment with SLYND leads to decreased estradiol serum levels. It is unknown if this may cause a clinically relevant loss of bone mineral density. 5.4 Cervical Cancer Some studies suggest that use of combination hormonal contraceptives containing progestin and estradiol 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. 5.5 Liver Disease Discontinue SLYND if jaundice or acute or chronic disturbances of liver function develop. Do not resume use until markers of liver function return to normal and SLYND causation has been excluded. SLYND is contraindicated in females with liver tumors, benign or malignant, or hepatic impairment [see Use in Specific Populations (8.6) ]. 5.6 Ectopic Pregnancy Be alert to the possibility of ectopic pregnancy in females who become pregnant or complain of lower abdominal pain while on SLYND. 5.7 Risk of Hyperglycemia in Patients with Diabetes Some patients receiving progestins, including SLYND, may exhibit a decrease in insulin sensitivity. Therefore, patients with diabetes may be at greater risk of hyperglycemia and may require additional medication adjustments or monitoring. 5.8 Bleeding Irregularities and Amenorrhea Females using SLYND 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. Based on subject diaries from four clinical trials of SLYND, 64.4% of females experienced unscheduled bleeding at Cycle 1. This percentage decreased to 40.3% by Cycle 13. A total of 91 out of 2593 subjects (3.5%) discontinued SLYND due to menstrual bleeding disorders including metrorrhagia, menstrual irregular, vaginal hemorrhage, menorrhagia, uterine hemorrhage, and amenorrhea. 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. 5.9 Depression Carefully observe females for a history of depression and discontinue SLYND if depression recurs to a serious degree. Data on the association of progestin-only contraceptive products with onset of depression and exacerbation of depression are limited.