Drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium

1 INDICATIONS AND USAGE Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium is a combination of drospirenone, a progestin and ethinyl estradiol, an estrogen containing a folate, indicated for use by females of reproductive potential to: • Prevent pregnancy. ( 1.1 ) • Raise folate levels in females of reproductive potential who choose to use an oral contraceptive for contraception. ( 1.2 ) 1.1 Oral Contraceptive Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium is indicated for use by females of reproductive potential to prevent pregnancy. 1.2 Folate Supplementation Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium is indicated in females of reproductive potential who choose to use an oral contraceptive as their method of contraception, to raise folate levels for the purpose of reducing the risk of a neural tube defect in a pregnancy conceived while taking the product or shortly after discontinuing the product.

2 DOSAGE AND ADMINISTRATION • Take one tablet daily by mouth at the same time every day. ( 2.1 ) • Tablets must be taken in the order directed on the blister pack. ( 2.1 ) 2.1 How to Take Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium Take one tablet by mouth at the same time every day. The failure rate may increase when pills are missed or taken incorrectly. To achieve maximum contraceptive effectiveness, Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium must be taken as directed, in the order directed on the blister pack. Single missed pills should be taken as soon as remembered. 2.2 How to Start Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium Instruct the patient to begin taking Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium either on the first day of her menstrual period (Day 1 Start) or on the first Sunday after the onset of her menstrual period (Sunday Start). Day 1 Start During the first cycle of Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium use, instruct the patient to take one orange Drospirenone/Ethinyl Estradiol/Levomefolate Calcium Tablet daily, beginning on Day 1 of her menstrual cycle. (The first day of menstruation is Day 1.) She should take one orange Drospirenone/Ethinyl Estradiol/Levomefolate Calcium Tablet daily for 21 consecutive days, followed by one light orange tablet, containing levomefolate calcium alone, daily on Days 22 through 28. Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium should be taken in the order directed on the package at the same time each day, preferably after the evening meal or at bedtime with some liquid, as needed. Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium can be taken without regard to meals. If Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium is first taken later than the first day of the menstrual cycle, Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium should not be considered effective as a contraceptive until after the first 7 consecutive days of product administration. Instruct the patient to use a non-hormonal contraceptive as back-up during the first 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered. Sunday Start During the first cycle of Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium use, instruct the patient to take one orange Drospirenone/Ethinyl Estradiol/Levomefolate Calcium Tablet daily, beginning on the first Sunday after the onset of her menstrual period. She should take one orange Drospirenone/Ethinyl Estradiol/Levomefolate Calcium Tablet daily for 21 consecutive days, followed by one light orange tablet, containing levomefolate calcium alone, daily on Days 22 through 28. Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium should be taken in the order directed on the package at the same time each day, preferably after the evening meal or at bedtime with some liquid, as needed. Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium can be taken without regard to meals. Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium should not be considered effective as a contraceptive until after the first 7 consecutive days of product administration. Instruct the patient to use a non-hormonal contraceptive as back-up during the first 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered. The patient should begin her next and all subsequent 28-day regimens of Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium on the same day of the week that she began her first regimen, following the same schedule. She should begin taking her orange tablets on the next day after ingestion of the last…

5 WARNINGS AND PRECAUTIONS • Vascular risks : Stop Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium 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/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium 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/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium if jaundice occurs. ( 5.4 ) • High blood pressure : Do not prescribe Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium for women with uncontrolled hypertension or hypertension with vascular disease. ( 5.6 ) • Carbohydrate and lipid metabolic effects : Monitor prediabetic and diabetic women taking Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. ( 5.8) • Headache : Evaluate significant change in headaches and discontinue Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium if indicated. ( 5.9 ) • Uterine bleeding : Evaluate irregular bleeding or amenorrhea. ( 5.10 ) 5.1 Thromboembolic Disorders and Other Vascular Problems Stop Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium if an arterial or venous thrombotic (VTE) event occurs. Based on presently available information on DRSP-containing COCs with 0.03 mg ethinyl estradiol (that is, Yasmin ® ), 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/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium 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 Yasmin (which contains 0.03 mg of EE and 3 mg of DRSP) 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 Yasmin 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) Initiators, including new users a All COCs available in the US during the conduct of the study b HR: 0.9 (0.5-1.6) 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 Other COCs available during the course of the study d Levonorgestrel/0.03 mg EE H…

4 CONTRAINDICATIONS Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium 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: o Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions ( 5.1 )] o Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions ( 5.1 )] o Have cerebrovascular disease [see Warnings and Precautions ( 5.1 )] o Have coronary artery disease [see Warnings and Precautions ( 5.1 )] o 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 )] o Have inherited or acquired hypercoagulopathies [see Warnings and Precautions ( 5.1 )] o Have uncontrolled hypertension [see Warnings and Precautions ( 5.6 )] o Have diabetes mellitus with vascular disease [see Warnings and Precautions ( 5.8 )] o 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 dasabuvir due to the potential for ALT elevations [see Warnings and Precautions ( 5.5 ) and Drug Interactions ( 7.3 )]. • 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 )

7 DRUG INTERACTIONS 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 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 ) 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. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampin, topiramate and products containing St. John’s wort. Interactions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability. Substances increasing the plasma concentrations of COCs: Co-administration of atorvastatin with certain COCs containing EE increase AUC values for EE by approximately 20%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. Concomitant administration of moderate or strong CYP3A4 inhibitors such as azole antifungals (e.g., ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g., clarithromycin, erythromycin), diltiazem, and grapefruit juice can increase the plasma concentrations of the estrogen or the progestin or both. In a clinical drug-drug interaction study conducted in premenopausal women, once daily co-administration of DRSP 3 mg/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. The exposure of EE was increased mildly [see Warnings and Precautions (5.2) and Clinical Pharmacology ( 12.3 )]. Human immunodeficiency virus (HIV)/Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors : Significant changes (increase or decrease) in the plasma concentrations of estrogen and progestin have been noted in some cases of co-administration with HIV/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors. Antibiotics : There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids. 7.2 Effects of Combined Oral Contraceptives on Other Drugs COCs containing EE may inhibit the metabolism of other compounds. COCs have been shown to significantly decrease plasma concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations. COCs Increasing the Plasma Concentrations of CYP450 Enzymes : In clinical studies, administration of a hormonal contraceptive containing EE did not lead to any increase or only to a weak increase in plasma concentrations of CYP3A4 substrates (e.g., midazolam) while plasma concentrations of CYP2C19 substrates (e.g., omeprazole and voriconazole) and CYP1A2 substrates (e.g., theophylline and tizanidine) can have a weak or moderate increase. Clinical studies did not indicate an inhibitory potential of DRSP towards …

8.1 Pregnancy Risk Summary There is no use for contraception in pregnancy; therefore, Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium should be discontinued during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to CHCs before conception or during early 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 A retrospective database study of women in Norway, that included 44,734 pregnancies of which 368 were women who inadvertently took drospirenone/ethinyl estradiol during the first trimester of a pregnancy, found there were no adverse effects on pre-term birth, small for gestational age, or birth weight Z-scores. Post-marketing adverse event data on the use of Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium in pregnant women suggest that frequencies of miscarriage and congenital anomalies were not higher than the estimated background risk in the general population.

6 ADVERSE REACTIONS 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%) in contraception and folate clinical trials are premenstrual syndrome (12.4%), headache/migraine (10.3%), breast pain/tenderness/discomfort (8.1%), nausea/vomiting (4.4%), mood changes (2.3%) and abdominal pain/tenderness/discomfort (2.2%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. Contraception and Folate Supplementation Clinical Trials The data provided reflect the experience with the use of Yasmin (3 mg DRSP/0.03 mg EE) in the adequate and well-controlled studies for contraception (N=2,837) and folate supplementation (N=172). For contraception, the US pivotal clinical study (N=326) for the oral contraception indication for Yasmin was a multicenter, open-label trial in healthy women aged 18 -35 who were treated with Yasmin for up to 13 cycles. The second contraceptive pivotal study (N=442) was a multicenter, randomized, open-label comparative European study of Yasmin vs. 0.150 mg desogestrel/0.03 mg EE conducted in healthy women aged 17-40 who were treated for up to 26 cycles. The primary efficacy study using Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium for folate supplementation was a randomized, single-center European trial in 172 healthy, female subjects aged 18-40 years comparing the pharmacodynamic effects of Yasmin + 0.451 mg levomefolate calcium to Yasmin co-administered with folic acid during 24 weeks of treatment followed by 20 weeks of open-label Yasmin. The adverse reactions seen across the 2 indications overlapped and are reported using the frequencies from the pooled dataset. The most common adverse reactions (≥ 2% of users) were: premenstrual syndrome (12.4%), headache/migraine (10.3%), breast pain/tenderness/discomfort (8.1%), nausea/vomiting (4.4%), mood changes (depression, depressed mood, irritability, mood swings, mood altered and affect lability (2.3%), and abdominal pain/discomfort/tenderness (2.2%). Adverse Reactions (≥ 1%) Leading to Study Discontinuation Contraception Clinical Trials Of 2,837 women, 6.7% discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reaction leading to discontinuation was headache/migraine (1.5%). Folate Clinical Trial There were no subjects who discontinued due to an adverse reaction. Serious Adverse Reactions : Contraception Clinical Trials : depression, pulmonary embolism, toxic skin eruption, and uterine leiomyoma. Folate Supplementation Clinical Trial: none reported in the clinical trial 6.2 Postmarketing Experience Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 - 1.12 (Figure 3). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 3). One of these studies reported no association between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19 - 1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than 8-10 years…