Drospirenone And Estradiol

⛔ FDA Black Box Warning

WARNING: CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, BREAST CANCER, and ENDOMETRIAL CANCER Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia The Women's Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of pulmonary embolism (PE), deep vein thrombosis (DVT), stroke, and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions (5.1) , and Clinical Studies (14.5) ]. The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.4) , Use in Specific Populations (8.5) , and Clinical Studies (14.5) ]. Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1 , 5.4) , Clinical Studies (14.4 , 14.5) ]. Breast Cancer The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.3) , and Clinical Studies (14.4) ] . Only daily oral 0.625 mg CE and 2.5 mg MPA were studied in the estrogen plus progestin substudy of WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events, dementia and breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestin products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen

Contraindications

4 CONTRAINDICATIONS Angeliq is contraindicated in women with any of the following conditions: Undiagnosed abnormal genital bleeding [see Warnings and Precautions (5.3) ] . Breast cancer or a history of breast cancer [see Warnings and Precautions (5.3) ]. Estrogen-dependent neoplasia [see Warnings and Precautions (5.3) ]. Active DVT, PE or history of these conditions [see Warnings and Precautions (5.1) ]. Active arterial thromboembolic disease (for example, stroke and MI) or history of these conditions [see Warnings and Precautions (5.1) ]. Renal Impairment [see Warnings and Precautions (5.2) , Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ]. Hepatic impairment or disease [see Warnings and Precautions (5.10) , Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . Adrenal insufficiency [see Warnings and Precautions (5.2) ]. Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders Known anaphylactic reaction, angioedema, or hypersensitivity to Angeliq or any of its ingredients [see Adverse Reactions (6.2) ] Undiagnosed abnormal genital bleeding ( 4 , 5.3 ) Breast cancer or a history of breast cancer ( 4 , 5.3 ) Estrogen-dependent neoplasia ( 4 , 5.3 ) Active DVT, PE, or a history of these conditions ( 4 , 5.1 ) Active arterial thromboembolic disease (for example, stroke and MI), or history of these conditions ( 4 , 5.1 ) Renal impairment ( 4 , 5.2 ) Hepatic impairment or disease ( 4 , 5.2 ) Adrenal insufficiency ( 4 , 5.2 ) Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders ( 4 ) Known anaphylactic reaction, angioedema, or hypersensitivity to Angeliq ( 4 , 5.16 )

Pregnancy & Breastfeeding

8.1 Pregnancy Risk Summary Angeliq is not indicated for use in pregnancy . There are no data with the use of Angeliq in pregnant women, however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies or limb-reduction defects) following exposure to combined hormonal contraceptives (estrogens and progestins) before conception or during early pregnancy. In reproduction studies in rats, rabbits and monkeys with oral administration of DRSP either as single compound or in combination with EE, no non-genital teratogenicity was observed. Adverse developmental outcomes like an increase in fetal mortality and a retardation of fetal maturation were seen in rats and rabbits at exposures to DRSP exceeding the human exposure by a factor of >15 (in rats) or >60 (rabbits). Related to the antiandrogenic activity of drospirenone, a feminization of male fetuses and an impairment of male fertility was observed in rats (>150 times the human exposure to drospirenone) but not in monkeys (at up to more than 300 times the human exposure to drospirenone). Due to the large safety margins observed in the animal studies only a low likelihood of an increased risk for human pregnancy was concluded ( see Data ). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryo-fetal toxicity study in pregnant rats, DRSP was given from day 6 to 15 of gestation orally at doses of 5, 15 and 45 mg/kg/day, more than 60 times the human exposure starting from the low dose based on AUC of DRSP. A slight increase in postimplantational loss and a slight increase in retardation of fetal development (e.g. delayed ossification of bones of the feet) was seen in the two higher doses. No teratogenicity was observed in rats. In an embryo-fetal study in rabbits, DRSP was given from day 6