Lo Simpesse

1 INDICATIONS AND USAGE Lo Simpesse TM (Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets) is indicated for use by females of reproductive potential to prevent pregnancy. Lo Simpesse is a combination of levonorgestrel, 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 for 91 days in the order directed on the blister pack. ( 2 ) 2.1 How to Start and Take Lo Simpesse Begin Lo Simpesse on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, take the first light pink tablet that day. For each 91-day course, take in the following order: Take one light pink tablet daily for 84 consecutive days. Use a non-hormonal back-up method of contraception (such as condoms or spermicide) until a light pink tablet has been taken daily for 7 consecutive days. Then take one light blue tablet for 7 consecutive days. A scheduled period should occur during the 7 days that the light blue tablets are taken. Begin the next and all subsequent 91-day cycles without interruption on the same day of the week (Sunday) on which the patient began her first dose of Lo Simpesse, following the same schedule: 84 days taking a light pink tablet followed by 7 days taking a light blue tablet. If the patient does not immediately start her next pill pack, instruct her to protect herself from pregnancy by using a non-hormonal back-up method of contraception until she has taken a light pink tablet daily for 7 consecutive days. Switching to Lo Simpesse from another oral hormonal contraceptive or from another contraceptive method (transdermal patch, vaginal ring, injection, intrauterine contraceptive, implant) Start on the Sunday after the patient’s next period starts. Use additional non-hormonal contraceptive (such as condoms and spermicide) until the patient has taken a light pink tablet for 7 consecutive days. Starting Lo Simpesse after Abortion or Miscarriage First-trimester Lo Simpesse may be started on the Sunday after an abortion or miscarriage. The patient must use additional non-hormonal contraception (such as condoms and spermicide) until the patient has taken a light pink tablet for 7 consecutive days. Second-trimester Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start contraceptive therapy with Lo Simpesse following the instructions for women not currently using hormonal contraception. Use additional non-hormonal contraception (such as condoms and spermicide) until the patient has taken a light pink tablet for 7 consecutive days [see Contraindications (4) and Warnings and Precautions (5.1) ]. Starting Lo Simpesse after Childbirth Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with Lo Simpesse following the instructions for women not currently using hormonal contraception. Use additional non-hormonal contraception (such as condoms and spermicide) until the patient has taken a light pink tablet for 7 consecutive days [see Contraindications (4) and Warnings and Precautions (5.1) ]. If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of Lo Simpesse [see Warnings and Precautions (5.1) , Use in Specific Populations (8.1) ]. 2.2 Dosing Lo Simpesse Take one tablet by mouth at the same time every day. The dosage of Lo Simpesse is one light pink tablet daily for 84 consecutive days, followed by one light blue tablet daily for 7 days. To achieve maximum contraceptive effectiveness, Lo Simpesse must be taken exactly as directed, in the order directed, and at intervals not exceeding 24 hours. The failure rate may increase when pills are missed or taken incorrectly. 2.3 Missed Doses Table 1. Instructions for Missed Lo Simpesse Tablets If one light pink tablet is missed Take the missed tablet as soon as possible. Take the next tablet at the regular time. Continue taking one tablet a day until the pack is finished. A back-up birth control method is not required if the patient has sex. If two light pink tablets in a row are missed Take the two missed tablets as soon as possible, and the next two tablets the next day. Continue taking one tablet a day until the pack is finished. Use additional nonhormonal contraception (such as condoms and spermicide) until tablets have been taken for 7 days after missing tablets. If three or more light pink tablets in a row are missed Throw away the missed pills. Continue taking one tablet every day as indicated on the pack until the pack is finished. Bleeding may occur during the week following the missed tablets. Additional nonhormonal contraception (such as condoms and spermicide) until tablets have been taken for 7 days after missing tablets. If any of the seven light blue tablets are missed Throw away the missed tablets. Continue taking the remaining tablets until the pack is finished. A backup birth control method is not needed. 2.4 Advice in Case of Gastrointestinal Disturbances In case of prolonged vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken.

4 CONTRAINDICATIONS Lo Simpesse is contraindicated in females who are known to have or develop the following conditions: A high risk of arterial or venous thrombotic diseases. Examples include females who are known to: Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions (5.1) ] Have current or history of deep vein thrombosis or pulmonary embolism [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 or hypertension with vascular disease [see Warnings and Precautions (5.5) ] Have diabetes mellitus and are over age 35, diabetes mellitus with hypertension or with vascular disease or other end-organ damage, or diabetes mellitus of > 20 years duration [see Warnings and Precautions (5.7) ] Have headaches with focal neurological symptoms, migraine headaches with aura, or over age 35 with any migraine headaches [see Warnings and Precautions (5.8) ] Current diagnosis of, or history of, breast cancer, which may be hormone sensitive [see Warnings and Precautions (5.11) ] Liver tumors, acute viral hepatitis, or severe (decompensated) cirrhosis [see Warnings and Precautions (5.2) ] Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.8) ] 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 (5.4) ] . A high risk of arterial or venous thrombotic diseases ( 4 ) Undiagnosed abnormal uterine bleeding ( 4 ) Breast cancer ( 4 ) Liver tumors or liver disease, acute viral hepatitis or decompensated cirrhosis ( 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 (5.2) ] The most common adverse reactions in clinical trials for Lo Simpesse were headaches, irregular and/or heavy uterine bleeding, dysmenorrhea, nausea and/or vomiting and back pain. ( 6 ) 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 Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice. The clinical trial that evaluated the safety and efficacy of Lo Simpesse was a 12-month, multicenter, non-comparative open-label study, which enrolled women aged 18 to 41, of whom 2,185 took at least one dose of Lo Simpesse. Adverse Reactions Leading to Study Discontinuation: 11% of the women discontinued from the clinical trial due to an adverse reaction; the most common adverse reactions leading to discontinuation were irregular and/or heavy uterine bleeding, headache, mood changes, nausea, acne, and weight gain. Common Treatment-Emergent Adverse Reactions (≥5% of women): headaches (33%); irregular and/or heavy uterine bleeding (13%), dysmenorrhea (11%), nausea and/or vomiting (11%), back pain (8%). 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 2). 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: Relevant 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. Figure 3