Drospirenone and ethinyl estradiol: uses, appearance and warnings

Drospirenone and Ethinyl Estradiol Tablets USP is a combination of drospirenone, a progestin, and ethinyl estradiol, an estrogen, indicated for use by females of reproductive potential to prevent pregnancy. Drospirenone and Ethinyl Estradiol Tablets USP are indicated for use by females of reproductive potential to prevent pregnancy.

Drospirenone and Ethinyl Estradiol Tablets 3 mg/0.03 mg consists of 28 film coated, biconvex tablets in the following order ( 3 ): 21 yellow tablets, each containing 3 mg drospirenone (DRSP) and 0.03 mg ethinyl estradiol(EE) 7 inert white tablets Drospirenone and Ethinyl Estradiol Tablets 3 mg and 0.03 mg are available in blister packs. Each blister pack contains 28 film coated, round, bi-convex tablets in the following order: 21 yellow tablets each containing 3 mg drospirenone (DRSP) and 0.03 mg ethinyl estradiol (EE) debossed with a “EV1” on one side and plain on other side 7 inert white tablets debossed with a “EV2” on one side and plain on other side

16.1 How Supplied Drospirenone and Ethinyl Estradiol Tablets, USP 3 mg/0.03 mg are available in packages of three blister packs (NDC 60505-4897-8). Each blister pack contains 28 film coated tablets in the following order: • 21 Yellow, round, biconvex film coated tablets, debossed with ‘EV1’ on one side and plain on other side containing 3 mg drospirenone and 0.03 mg ethinyl estradiol • 7 White to off white, round, biconvex, film coated tablets, debossed with ‘EV2’ on one side and plain on other side. 16.2 Storage Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. 16.1 How Supplied Drospirenone and Ethinyl Estradiol Tablets, USP 3 mg/0.03 mg are available in packages of three blister packs (NDC 60505-4897-8). Each blister pack contains 28 film coated tablets in the following order: • 21 Yellow, round, biconvex film coated tablets, debossed with ‘EV1’ on one side and plain on other side containing 3 mg drospirenone and 0.03 mg ethinyl estradiol • 7 White to off white, round, biconvex, film coated tablets, debossed with ‘EV2’ on one side and plain on other side.

Renal impairment ( 4 ) Adrenal insufficiency ( 4 ) A high risk of arterial or venous thrombotic diseases ( 4 ) Undiagnosed abnormal uterine bleeding ( 4 ) Breast cancer ( 4 ) Liver tumors or liver disease ( 4 ) Co-administration with Hepatitis C drug combinations containing ombitasvir, paritaprevir/ritonavir, with or without dasabuvir ( 4 ) Drospirenone and Ethinyl Estradiol Tablets is contraindicated in females who are known to have or develop the following conditions: • Renal impairment • Adrenal insufficiency • A high risk of arterial or venous thrombotic diseases. Examples include women who are known to: ○ Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions ( 5.1 ) ] ○ Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions ( 5.1 ) ] ○ Have cerebrovascular disease [see Warnings and Precautions ( 5.1 ) ] ○ Have coronary artery disease [ see Warnings and Precautions ( 5.1 ) ] ○ Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions ( 5.1 ) ] ○ Have inherited or acquired hypercoagulopathies [see Warnings and Precautions ( 5.1 ) ] ○ Have uncontrolled hypertension [see Warnings and Precautions ( 5.6 ) ] ○ Have diabetes mellitus with vascular disease [see Warnings and Precautions ( 5.8 ) ] ○ Have headaches with focal neurological symptoms or have migraine headaches with or without aura if over age 35 [see Warnings And Precautions ( 5.9 ) ] Undiagnosed abnormal uterine bleeding [see Warnings and Precautions ( 5.10 ) ] Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive [see Warnings And Precautions ( 5.3 ) ] Liver tumor (benign or malignant) or liver disease [see Warnings And Precautions ( 5.4 ) and Use In Specific Populations ( 8.7 ) ] Use of Hepatitis C drug combinations containing ombitasvir, paritaprevir/ritonavir, with or without dasabuv …

Vascular risks: Stop Drospirenone and Ethinyl Estradiol Tablets if a thrombotic 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. ( 5.1 ) COCs containing DRSP may be associated with a higher risk of venous thromboembolism (VTE) than COCs containing levonorgestrel or some other progestins. Before initiating Drospirenone and Ethinyl Estradiol Tablets in a new COC user or a woman who is switching from a contraceptive that does not contain DRSP, consider the risks and benefits of a DRSP-containing COC in light of her risk of a VTE. ( 5.1 ) Hyperkalemia : DRSP has anti-mineralocorticoid activity. Do not use in patients predisposed to hyperkalemia. Check serum potassium concentration during the first treatment cycle in women on long-term treatment with medications that may increase serum potassium concentration. ( 5.2 , 7.1 , 7.2 ) Liver disease : Discontinue Drospirenone and Ethinyl Estradiol Tablets if jaundice occurs. ( 5.4 ) High blood pressure : Do not prescribe Drospirenone and Ethinyl Estradiol Tablets for women with uncontrolled hypertension or hypertension with vascular disease. ( 5.6 ) Carbohydrate and lipid metabolic effects : Monitor prediabetic and diabetic women taking Drospirenone and Ethinyl Estradiol Tablets. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. ( 5.8 ) Headache : Evaluate significant change in headaches and discontinue Drospirenone and Ethinyl Estradiol Tablets if indicated. ( 5.9 ) Uterine bleeding : Evaluate irregular bleeding or amenorrhea. ( 5.10 ) 5.1 Thromboembolic Disorders and Other Vascular Problems Stop Drospirenone and Ethinyl Estradiol Tablets if an arterial or venous thrombotic (VTE) event occurs. Based on presently available information on Drospirenone and Ethinyl Estradiol Tablets, DRSP-containing COCs may be associated with a higher risk of venous thromboembolism (VTE) than COCs containing the progestin levonorgestrel or some other progestins. Epidemiologic studies that compared the risk of VTE reported that the risk ranged from no increase to a three-fold increase. Before initiating use of Drospirenone and Ethinyl Estradiol Tablets in a new COC user or a woman who is switching from a contraceptive that does not contain DRSP, consider the risks and benefits of a DRSP-containing COC in light of her risk of a VTE. Known risk factors for VTE include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of COCs [see Contraindications ( 4 )]. A number of studies have compared the risk of VTE for users of Drospirenone and Ethinyl Estradiol Tablets to the risk for users of other COCs, including COCs containing levonorgestrel. Those that were required or sponsored by regulatory agencies are summarized in Table 2. Table 2: Estimates (Hazard Ratios) of Venous Thromboembolism Risk in Current Users of Drospirenone and Ethinyl Estradiol Tablets Compared to Users of Oral Contraceptives that Contain Other Progestins Epidemiologic Study (Author, Year of Publication) Population Studied Comparator Product (all are low-dose COCs; with < 0.04 mg of EE) Hazard Ratio (HR) (95% CI) i3 Ingenix (Seeger 2007) All COCs available in the US during the conduct of the study b HR: 0.9 (0.5 - 1.6) Initiators, including new users a EURAS (Dinger 2007) Initiators, including new users a All COCs available in Europe during the conduct of the study c Levonorgestrel/EE HR: 0.9 (0.6 - 1.4) HR: 1.0 (0.6 - 1.8) "FDA-funded study" (2011) New users a All users (i.e., initiation and continuing use of study combination hormonal contraception) Other COCs available during the course of the study d Levonorgestrel/0.03 mg EE Other COCs available during the course of the study d Levonorgestrel/0.03 mg EE HR: 1.8 (1.3 - 2.4) HR: 1.6 (1.1 - 2.2) HR: 1.7 (1.4 - 2.1) HR: 1.5 (1.2 - 1.8) a) "New users" - no use of combination hormonal contraception for at least the prior 6 months b) Includes low-dose COCs containing the following progestins: norgestimate, norethindrone, levonorgestrel, desogestrel,norgestrel, medroxyprogesterone, or ethynodiol diacetate c) Includes low-dose COCs containing the following progestins: levonorgestrel, desogestrel, dienogest, chlormadinone acetate, gestodene, cyproterone acetate, norgestimate, or norethindrone d) Includes low-dose COCs containing the following progestins: norgestimate, norethindrone, or levonorgestrel In addition to these "regulatory studies," other studies of various designs have been conducted. Overall, there are two prospective cohort studies (see Table 2): the US post-approval safety study Ingenix [Seeger 2007], the European post-approval safety study EURAS (European Active Surveillance Study) [Dinger 2007]. An extension of the EURAS study, the Long-Term Active Surveillance Study (LASS), did not enroll additional subjects, but continued to assess VTE risk. There are three retrospective cohort studies: one study in the US funded by the FDA (see Table 2), and two from Denmark [Lidegaard 2009, Lidegaard 2011]. There are two case-control studies: the Dutch MEGA study analysis [van Hylckama Vlieg 2009] and the German case-control study [Dinger 2010]. There are two nested case-control studies that evaluated the risk of non-fatal idiopathic VTE: the PharMetrics study [Jick 2011] and the GPRD study [Parkin 2011]. The results of all of these studies are presented in Figure 1. Figure 1: VTE Risk with Drospirenone and Ethinyl Estradiol Tablets Relative to LNG-Containing COCs (adjusted risk # ) Risk ratios displayed on logarithmic scale; risk ratio < 1 indicates a lower risk of VTE for DRSP, > 1 indicates an increased risk of VTE for DRSP. …

The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: • Serious cardiovascular events and stroke [see Boxed Warning and Warnings and Precautions ( 5.1 )] • Vascular events [see Warnings and Precautions ( 5.1 )] • Liver disease [see Warnings and Precautions ( 5.4 )] The most frequent adverse reactions (≥ 2%) are premenstrual syndrome (13.2%), headache /migraine (10.7%), breast pain/tenderness/discomfort (8.3%), nausea/vomiting (4.5%), abdominal pain/tenderness/discomfort (2.3%), mood changes (2.3%).( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. …

Drugs or herbal products that induce certain enzymes (for example, CYP3A4) may decrease the effectiveness of COCs or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs. ( 7.1 ) Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. 7.1 Effects of Other Drugs on Combined Oral Contraceptives Substances Diminishing the Efficacy of COCs: Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the effectiveness of COCs or increase breakthrough bleeding. …