Drospirenone

SLYND is a progestin indicated for use by females of reproductive potential to prevent pregnancy. SLYND is a progestin indicated for use by females of reproductive potential to prevent pregnancy. ( 1 )

SLYND is supplied in blister cards, each containing 24 round, film-coated, unscored, white tablets and 4 round, film-coated, unscored green tablets. Each white tablet contains 4 mg of drospirenone. White tablets are debossed with an "E" on one side and a "D" on the other side Each green tablet is inert and does not contain drospirenone. Green tablets are debossed with an "E" on one side and a "4" on the other side. SLYND consists of 24 white tablets each containing 4 mg of drospirenone and 4 green inert tablets. ( 3 )

SLYND is contraindicated in females with the following conditions: Renal impairment [see Warnings and Precautions (5.1) and Use in Specific Populations (8.7) ] Adrenal insufficiency [see Warnings and Precautions (5.1) ] Presence or history of cervical cancer or progestin sensitive cancers [see Warnings and Precautions (5.4) ] Liver tumors, benign or malignant, or hepatic impairment [see Warnings and Precautions (5.5) and Use in Specific Populations (8.6) ] Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.8) ] Renal impairment ( 4 ) Adrenal insufficiency ( 4 ) Presence or history of progestin sensitive cancers ( 4 ) Liver tumors, benign or malignant, or hepatic impairment ( 4 ) Undiagnosed abnormal uterine bleeding ( 4 )

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.

The following clinically significant adverse reactions are described elsewhere in other sections of the labeling: Hyperkalemia [see Warnings and Precautions (5.1) ] Bleeding Irregularities and Amenorrhea [see Warnings and Precautions (5.8) ] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect the exposure of SLYND in females of reproductive potential desiring to prevent pregnancy based on four clinical studies including Study CF111/303 [see Clinical Studies (14) ] . The mean time of SLYND exposure ranged from 197 to 328 days. The demographic profile for the pooled study data was: mean age 28 years; mean BMI 25 kg/m 2 ; racial distribution was 83% White; 14% Black; 1% Asian and 2% Other. Table 3 Adverse Reactions Occurring in ≥ 1% of Females Receiving SLYND in Four Pooled Studies Adverse Reaction Total N = 2598 n (%) Any adverse reaction 627 (24.1) Acne 98 (3.8) Metrorrhagia 72 (2.8) Headache 71 (2.7) Breast pain 57 (2.2) Weight increased 50 (1.9) Dysmenorrhea 49 (1.9) Nausea 47 (1.8) Vaginal hemorrhage 45 (1.7) Libido decreased 33 (1.3) Breast tenderness 31 (1.2) Menstruation irregular 30 (1.2) Most common adverse reactions (>1%) are: acne, metrorrhagia, headache, breast pain, weight increased, dysmenorrhea, nausea, vaginal hemorrhage, libido decreased, breast tenderness, menstruation irregular ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Exeltis USA, Inc. at 1-877-324-9349 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. Drugs or herbal products that induce certain enzymes (for example, CYP3A4) may decrease the effectiveness of SLYND or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with SLYND. ( 7.1 )

7.1 Effects of other Drugs on Hormonal Contraceptives Substances decreasing the systemic concentrations of hormonal contraceptives (HCs) and potentially diminishing the efficacy of HCs: Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the systemic concentrations of HCs and potentially diminish the effectiveness of HCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of HCs include efavirenz, phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, rifabutin, rufinamide, aprepitant, and products containing St. John's wort. Interactions between HCs and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel females to use an alternative non-hormonal method of contraception or a back-up method when enzyme inducers are used with HCs, and to continue back-up non-hormonal contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability. Substances increasing the systemic concentrations of hormonal contraceptives (HCs): In a clinical drug-drug interaction study conducted in premenopausal females, once daily co-administration of drospirenone (DRSP) 3 mg/ethinyl estradiol (EE) 0.02 mg containing tablets with strong CYP3A4 inhibitor, ketoconazole 200 mg twice daily for 10 days, resulted in a moderate increase of DRSP systemic exposure.

7.2 Influence of SLYND on other Medicinal Products Based on in vitro studies and in vivo interaction studies in female volunteers using omeprazole, simvastatin and midazolam as marker substrate, an interaction of drospirenone with the metabolism of other active substances is unlikely. Potential to increase serum potassium concentration: There is a potential for an increase in serum potassium concentration in females taking SLYND with other drugs that may increase serum potassium concentration (for example, ACE inhibitors, angiotensin-II receptor antagonists, potassium-sparing diuretics, potassium supplementation, heparin, aldosterone antagonists, and NSAIDS [see Warnings and Precautions (5.1) ].

Pregnancy: Discontinue SLYND if pregnancy occurs ( 8.1 )

8.1 Pregnancy Risk Summary Based on epidemiologic studies and meta-analyses, there is little or no increased risk of birth defects in the children of females who inadvertently use oral progestins during early pregnancy ( See Data ). Discontinue SLYND if pregnancy occurs, because there is no reason to use hormonal contraceptives during pregnancy In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 percent and 15 to 20 percent, respectively. Data Human Data Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following maternal use of oral progestins before conception or during early pregnancy.

8.2 Lactation Risk Summary Negligible amounts of drospirenone are excreted in the breast milk (see Data ) . Thus, at therapeutic doses of SLYND, no effects on breastfed newborns/infants are anticipated. In general, no adverse effects have been found on milk production or on the health, growth, or development of the infant with use of progestin-only pills (POPs). Human Data After daily administration of 4 mg SLYND tablets, the average DRSP concentration in breast milk over a 24-hour period is 5.6 ng/mL. Based on this concentration, the estimated average infant daily dosages for an exclusively breastfed infant is 840 ng/kg/day (relative infant dose is 1.5%).

8.4 Pediatric Use Safety and efficacy of SLYND have been established in females of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and users 16 years and older. Study CF111/304 evaluated the bleeding associated with SLYND in females ≥12 years of age. Bleeding data were generally consistent with those from Study CF111/303 in adult females [see Clinical Studies (14) ] . Use of this product before menarche is not indicated.

8.5 Geriatric Use SLYND has not been studied in postmenopausal females and is not indicated in this population.

8.6 Hepatic Impairment SLYND is contraindicated in females with hepatic impairment [see Contraindications (4) , Warnings and Precautions (5.5) ]. The mean exposure to drospirenone in females with moderate liver impairment is approximately three times higher than the exposure in females with normal liver function. SLYND has not been studied in females with severe hepatic impairment [see Clinical Pharmacology (12.3) ] .

8.7 Renal Impairment SLYND is contraindicated in females with renal impairment [see Contraindications (4) , Warnings and Precautions (5.1) ]. In subjects with creatinine clearance (CLcr) of 50–79 mL/min, serum DRSP levels were comparable to those in a control group with CLcr ≥ 80 mL/min. In subjects with CLcr of 30–49 mL/min, serum DRSP concentrations were on average 37% higher than those in the control group. In addition, there is a potential to develop hyperkalemia in subjects with renal impairment whose serum potassium is in the upper reference range, and who are concomitantly using potassium sparing drugs [see Drug Interactions (7.2) and Clinical Pharmacology (12.3) ].

SLYND progestin-only oral contraceptive lowers the risk of becoming pregnant primarily by suppressing ovulation.