Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium

1 INDICATIONS AND USAGE Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium 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 ) • Treat symptoms of premenstrual dysphoric disorder (PMDD) for females of reproductive potential who choose to use an oral contraceptive for contraception. ( 1.2 ) • Treat moderate acne for females of reproductive potential at least 14 years old only if the patient desires an oral contraceptive for birth control. ( 1.3 ) • Raise folate levels in females of reproductive potential who choose to use an oral contraceptive for contraception. ( 1.4 ) 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 Premenstrual Dysphoric Disorder (PMDD) Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium is also indicated for the treatment of symptoms of premenstrual dysphoric disorder (PMDD) in females of reproductive potential who choose to use an oral contraceptive as their method of contraception. The effectiveness of Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium for PMDD when used for more than three menstrual cycles has not been evaluated. The essential features of PMDD according to the Diagnostic and Statistical Manual-4th edition (DSM-IV) include markedly depressed mood, anxiety or tension, affective lability, and persistent anger or irritability. Other features include decreased interest in usual activities, difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control. Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle pain, bloating and weight gain. In this disorder, these symptoms occur regularly during the luteal phase and remit within a few days following onset of menses; the disturbance markedly interferes with work or school, or with usual social activities and relationships with others. Diagnosis is made by healthcare providers according to DSM-IV criteria, with symptomatology assessed prospectively over at least two menstrual cycles. In making the diagnosis, care should be taken to rule out other cyclical mood disorders. Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium has not been evaluated for the treatment of premenstrual syndrome (PMS). 1.3 Acne Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium is indicated for the treatment of moderate acne vulgaris in females of reproductive potential at least 14 years of age, who have no known contraindications to oral contraceptive therapy and have achieved menarche. Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control. 1.4 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 and PMDD 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 pink 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 pink Drospirenone/Ethinyl Estradiol/Levomefolate Calcium Tablet daily for 24 consecutive days, followed by one light orange Levomefolate Calcium Tablet daily on Days 25 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 pink Drospirenone/Ethinyl Estradiol/Levomefolate Calcium Tablet daily, beginning on the first Sunday after the onset of her menstrual period. She should take one pink Drospirenone/Ethinyl Estradiol/Levomefolate Calcium Tablet daily for 24 consecutive days, followed by one light orange Levomefolate Calcium Tablet daily on Days 25 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 pink tablets on the next day after ingestion of the last light orange folate tablet, regardless of whether or not a menstrual period has occurred or is still in progress. Anytime a subsequent cycle of Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium is started later than the day following administration of the last light orange tablet, the patient should use another method of contraception until she has taken a pink Drospirenone/Ethinyl Estradiol/Levomefolate Calcium Tablet daily for seven consecutive days. When switching from a different birth control pill When switching from another birth control pill, Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium should be started on the same day that a new pack of the previous oral contraceptive would have been started. When switching from a method other than a birth control pill When switching from a transdermal patch or vaginal ring, Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium should be started when the next application would have been due. When switching from an injection, Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium should be started when the next dose would have been due. When switching from an intrauterine contraceptive or an implant, Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium should be started on the day of removal. Withdrawal bleeding usually occurs within 3 days following the last pink tablet. If spotting or breakthrough bleeding occurs while taking Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium, instruct the patient to continue taking Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium by the regimen described above. Counsel her that this type of bleeding is usually transient and without significance; however, advise her that if the bleeding is persistent or prolonged, she should consult her healthcare provider. Although the occurrence of pregnancy is low if Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium is taken according to directions, if withdrawal bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or more 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 take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. Discontinue Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium if pregnancy is confirmed. The risk of pregnancy increases with each active pink tablet missed. If breakthrough bleeding occurs following missed tablets, it will usually be transient and of no consequence. If the patient misses one or more light orange tablets, she should still be protected against pregnancy provided she begins taking a new cycle of pink tablets on the proper day. For postpartum women who do not breastfeed or after a second trimester abortion, start Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium no earlier than 4 weeks postpartum due to the increased risk of thromboembolism. If the patient starts on Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium postpartum and has not yet had a period, evaluate for possible pregnancy, and instruct her to use an additional method of contraception until she has taken Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium for 7 consecutive days. 2.3 Missed Doses Table 1: Instructions for Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium Missed Doses If one pink active tablet is missed Take it as soon as possible. Take the next tablet at the regular time. This means two tablets may be taken in one day. A back-up birth control method is not required if the patient has sex. If two pink active tablets in a row are missed in Week 1 or Week 2 Take two tablets as soon as possible and two tablets the next day. Then take one tablet a day until the pack is finished. Additional nonhormonal contraception (such as condoms and spermicide) should be used as back-up if the patient has sex within 7 days after missing tablets. If two pink active tablets in a row are missed in Week 3 or Week 4 Day 1 Start: Throw out the rest of the pack and start a new pack that same day. Sunday Start: Keep taking one tablet every day until Sunday. On Sunday, throw out the rest of the pack and start a new pack that same day. Additional nonhormonal contraception (such as condoms and spermicide) should be used as back-up if the patient has sex within 7 days after missing tablets. The patient may not have their period this month but this is expected. However, if they miss their period two months in a row, they should call their healthcare provider because they might be pregnant. If three or more pink active tablets in a row are missed during any week Day 1 Start: Throw out the rest of the pack and start a new pack that same day. Sunday Start: Keep taking one tablet every day until Sunday. On Sunday, throw out the rest of the pack and start a new pack that same day. Additional nonhormonal contraception (such as condoms and spermicide) should be used as back-up if the patient has sex within 7 days after missing tablets. The patient may not have their period this month but this is expected. However, if they miss their period two months in a row, they should call their healthcare provider because they might be pregnant. If any of the four light orange inactive tablets are missed in Week 4: Throw away the tablets that were missed. Keep taking one tablet each day until the pack is empty. They do not need a back-up method. Finally, if they are still not sure what to do about the tablets they have missed: Use nonhormonal contraception (such as condoms and spermicides) anytime they have sex. Contact their healthcare provider and continue taking one active pink tablet each day until otherwise directed. 2.4 Advice in Case of Gastrointestinal Disturbances In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken. If vomiting occurs within 3-4 hours after tablet-taking, this can be regarded as a missed tablet. 2.5 Folate Supplementation The U.S. Preventive Services Task Force recommends that women of childbearing age consume supplemental folic acid in a dose of at least 0.4 mg (400 mcg) daily. 1 Consider other folate supplementation that a woman may be taking before prescribing Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium. Ensure that folate supplementation is maintained if a woman discontinues Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium due to pregnancy.

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: • 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 tumors, 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 )

Not available.

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, acne and folate clinical trials are headache/migraine (5.9%), menstrual irregularities (4.1%), nausea/vomiting (3.5%) and breast pain/tenderness (3.2%). ( 6.1 ) • The most frequent adverse reactions (≥ 2%) in PMDD clinical trials are menstrual irregularities (24.9%), nausea (15.8%), headache (13.0%), breast tenderness (10.5%), fatigue (4.2%), irritability (2.8%), decreased libido (2.8%), increased weight (2.5%), and affect lability (2.1%). ( 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, Acne and Folate Supplementation Clinical Trials The data provided reflect the experience with the use of YAZ (3 mg DRSP/0.02 mg EE), in the adequate and well-controlled studies for contraception (N=1,056), for moderate acne vulgaris (N=536) and folate supplementation (N=379). For contraception, a Phase 3, multicenter, multinational, open-label study was conducted to evaluate safety and efficacy up to one year in 1,027 women aged 17-36 who took at least one dose of YAZ. A second Phase 3 study was a single center, open-label, active-controlled study to evaluate the effect of 7 28-day cycles of YAZ on carbohydrate metabolism, lipids and hemostasis in 29 women aged 18-35. For acne, two multicenter, double-blind, randomized, placebo-controlled studies, in 536 women aged 14–45 with moderate acne vulgaris who took at least one dose of YAZ, evaluated the safety and efficacy during up to 6 cycles. For folate supplementation, the primary efficacy study using Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium was a multicenter, double-blind, randomized, active-controlled US trial in 379 healthy women aged 18- 40 who were treated with Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium or YAZ for up to 24 weeks. The adverse reactions seen across the 3 indications overlapped, and are reported using the frequencies from the pooled dataset. The most common adverse reactions (≥ 2% of users) were: headache/migraine (5.9%), menstrual irregularities (including vaginal hemorrhage [primarily spotting], metrorrhagia and menorrhagia) (4.1%), nausea/vomiting (3.5%), and breast pain/tenderness (3.2%). PMDD Clinical Trials Safety data from trials for the indication of PMDD are reported separately due to differences in study design and setting in the OC, Acne and Folate Supplementation studies as compared to the PMDD clinical program. Two (one parallel and one crossover designed) multicenter, double-blind, randomized, placebo-controlled trials for the secondary indication of treating the symptoms of PMDD evaluated safety and efficacy of YAZ during up to 3 cycles among 285 women aged 18–42, diagnosed with PMDD and who took at least one dose of YAZ. Common adverse reactions (≥ 2% of users) were: menstrual irregularities (including vaginal hemorrhage [primarily spotting] and metrorrhagia) (24.9%), nausea (15.8%), headache (13.0%), breast tenderness (10.5%), fatigue (4.2%), irritability (2.8%), decreased libido (2.8%), increased weight (2.5%), and affect lability (2.1%). Adverse Reactions (≥1%) Leading to Study Discontinuation: Contraception Clinical Trials Of 1,056 women, 6.6% discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reactions leading to discontinuation were headache/migraine (1.6%) and nausea/vomiting (1.0%). Acne Clinical Trials Of 536 women, 5.4% discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reaction leading to discontinuation was menstrual irregularities (including menometrorrhagia, menorrhagia, metrorrhagia and vaginal hemorrhage) (2.2%). Folate Clinical Trial Of 285 women, 4.6% who used Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium or YAZ discontinued from the clinical trials due to an adverse reaction; no reaction leading to discontinuation occurred in ≥ 1% of women. PMDD Clinical Trials Of 285 women, 11.6% discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reactions leading to discontinuation were: nausea/vomiting (4.6%), menstrual irregularity (including vaginal hemorrhage, menorrhagia, menstrual disorder, menstruation irregular and metrorrhagia) (4.2%), fatigue (1.8%), breast tenderness (1.4%), depression (1.4%), headache (1.1%), and irritability (1.1%). Serious Adverse Reactions Contraception Clinical Trials : migraine and cervical dysplasia Acne Clinical Trials: none reported in the clinical trials Folate Supplementation Clinical Trial: cervix carcinoma stage 0 PMDD Clinical Trials: cervical dysplasia 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 of COC use. Figure 3 Relative Studies of Risk of Breast Cancer with Combined Oral Contraceptives RR = relative risk; OR = odds ratio; HR = hazard ratio. “ever COC” are females with current or past COC use; “never COC use” are females that never used COCs. The following adverse reactions have been identified during post approval use of YAZ. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions are grouped into System Organ Classes, and ordered by frequency. Vascular disorders: Venous and arterial thromboembolic events (including pulmonary emboli, deep vein thrombosis, cerebral thrombosis, retinal thrombosis, myocardial infarction and stroke), hypertension (including hypertensive crisis) Hepatobiliary disorders: Gallbladder disease, liver function disturbances, liver tumors Immune system disorders: Hypersensitivity (including anaphylactic reaction) Metabolism and nutrition disorders: Hyperkalemia, hypertriglyceridemia, changes in glucose tolerance or effect on peripheral insulin resistance (including diabetes mellitus) Skin and subcutaneous tissue disorders: Chloasma, angioedema, erythema nodosum, erythema multiforme Gastrointestinal disorders: Inflammatory bowel disease Musculoskeletal and connective tissue disorders: Systemic lupus erythematosus Figure 3: Relative Studies of Risk of Breast Cancer with Combined Oral Contraceptives