Zumandimine

1 INDICATIONS AND USAGE Zumandimine ® (drospirenone and ethinyl estradiol tablets) are indicated for use by females of reproductive potential to prevent pregnancy. Zumandimine (drospirenone and ethinyl estradiol tablets) is a combination of drospirenone, a progestin, and ethinyl estradiol, an estrogen, indicated for use by females of reproductive potential to prevent pregnancy. ( 1 )

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 Zumandimine 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, Zumandimine 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 Zumandimine Instruct the patient to begin taking Zumandimine 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 Zumandimine use, instruct the patient to take one light pink to pink Zumandimine daily, beginning on Day 1 of her menstrual cycle. (The first day of menstruation is Day 1.) She should take one light pink to pink Zumandimine daily for 21 consecutive days, followed by one green tablet daily on Days 22 through 28. Zumandimine 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. Zumandimine can be taken without regard to meals. If Zumandimine is first taken later than the first day of the menstrual cycle, Zumandimine 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 Zumandimine use, instruct the patient to take one light pink to pink Zumandimine daily, beginning on the first Sunday after the onset of her menstrual period. She should take one light pink to pink Zumandimine daily for 21 consecutive days, followed by one green tablet daily on Days 22 through 28. Zumandimine 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. Zumandimine can be taken without regard to meals. Zumandimine 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 Zumandimine on the same day of the week that she began her first regimen, following the same schedule. She should begin taking her light pink to pink tablets on the next day after ingestion of the last green tablet, regardless of whether or not a menstrual period has occurred or is still in progress. Anytime a subsequent cycle of Zumandimine is started later than the day following administration of the last green tablet, the patient should use another method of contraception until she has taken a light pink to pink Zumandimine daily for seven consecutive days. When switching from a different birth control pill When switching from another birth control pill, Zumandimine 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, Zumandimine should be started when the next application would have been due. When switching from an injection, Zumandimine should be started when the next dose would have been due. When switching from an intrauterine contraceptive or an implant, Zumandimine should be started on the day of removal. Withdrawal bleeding usually occurs within 3 days following the last light pink to pink tablet. If spotting or breakthrough bleeding occurs while taking Zumandimine, instruct the patient to continue taking Zumandimine 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 Zumandimine 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 Zumandimine if pregnancy is confirmed. The risk of pregnancy increases with each active light pink to 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 green tablets, she should still be protected against pregnancy provided she begins taking a new cycle of light pink to pink tablets on the proper day. For postpartum women who do not breastfeed or after a second trimester abortion, start Zumandimine no earlier than 4 weeks postpartum due to the increased risk of thromboembolism. If the patient starts Zumandimine 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 Zumandimine for 7 consecutive days. 2.3 Missed Doses Table 1: Instructions for Zumandimine Missed Doses If one pink to 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 to 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 to 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 to 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 seven green 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 to 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 to 4 hours after tablet-taking, this can be regarded as a missed tablet.

4 CONTRAINDICATIONS Zumandimine 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 dasabuvir due to the potential for ALT elevations [see Warnings and Precautions (5.5) and Drug Interactions (7.2) ]. 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%) 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 Aurobindo Pharma USA, Inc. at 1-866-850-2876 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. The data provided reflect the experience with the use of Zumandimine (3 mg DRSP/0.03 mg EE) in the adequate and well-controlled studies for contraception (N=2,837). The US pivotal clinical study (N=326) was a multicenter, open-label trial in healthy women aged 18 to 35 who were treated for up to 13 cycles. The second pivotal study (N=442)was a multicenter, randomized, open-label comparative European study of Zumandimine vs. 0.150 mg desogestrel/0.03 mg EE conducted in healthy women aged 17 to 40 who were treated for up to 26 cycles. The most common adverse reactions (≥ 2% of users) were: premenstrual syndrome (13.2%), headache/migraine (10.7%), breast pain/tenderness/discomfort (8.3%), nausea/vomiting (4.5%) abdominal pain/discomfort/tenderness (2.3%) and mood changes (depression, depressed mood, irritability, mood swings, mood altered and affect lability (2.3%). Adverse Reactions (≥ 1%) Leading to Study Discontinuation: 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%). Serious Adverse Reactions: Depression, pulmonary embolism, toxic skin eruption, and uterine leiomyoma. 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 to 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 to 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 to 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 Zumandimine. 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, including fatalities, are grouped into System Organ Classes and ordered by frequency. Vascular disorders: Venous and arterial thromboembolic events (including pulmonary emboli, deep vein thrombosis, intracardiac thrombosis, intracranial venous sinus thrombosis, sagittal sinus thrombosis, retinal vein occlusion, myocardial infarction and stroke), hypertension Hepatobiliary disorders: Gallbladder disease Immune system disorders: Hypersensitivity Metabolism and nutrition disorders: Hyperkalemia Skin and subcutaneous tissue disorders: Chloasma Figure 3: Relative Studies of Risk of Breast Cancer with Combined Oral Contraceptives