LO SIMPESSE

Lo Simpesse (levonorgestrel and ethinyl estradiol tablets USP and ethinyl estradiol tablets USP) is an extended-cycle oral contraceptive regimen of 84 light pink tablets each containing 0.1 mg levonorgestrel USP and 0.02 mg ethinyl estradiol USP, followed by 7 light blue tablets each containing 0.01 mg ethinyl estradiol USP. The structural formulas for the active components are: Levonorgestrel is chemically 18,19-Dinorpregn-4-en-20-yn-3-one, 13­-ethyl-17-hydroxy-, (17α)-, (-)-. Ethinyl Estradiol is 19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-. Inactive ingredients for the light pink tablets include croscarmellose sodium, FD&C Red #40, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Inactive ingredients for the light blue tablets include colloidal silicon dioxide, FD&C Blue No. 1, lactose monohydrate, povidone, pregelatinized starch (maize), stearic acid, and vitamin E. Levonorgestrel Chemical Structure Ethinyl Estradiol Chemical Structure

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 )

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.

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 )

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

The sections below provide information on substances for which data on drug interactions with COCs are available. There is little information available about the clinical effect of most drug interactions that may affect COCs. However, based on the known pharmacokinetic effects of these drugs, clinical strategies to minimize any potential adverse effect on contraceptive effectiveness or safety are suggested. Consult the approved product labeling of all concurrently used drugs to obtain further information about interactions with COCs or the potential for metabolic enzyme or transporter system alterations. No formal drug-drug interaction studies were conducted with Lo Simpesse. Enzyme inducers (e.g., CYP3A4): May decrease the effectiveness of Lo Simpesse or increase breakthrough bleeding. Counsel patients to use a back-up method or alternative method of contraception when enzyme inducers are used with Lo Simpesse. ( 7.1 ) 7.1 Effects of Other Drugs on Combined Oral Contraceptives Substances Decreasing the Plasma Concentrations of COCs and Potentially Diminishing the Efficacy of COCs: Table 4 includes substances that demonstrated an important drug interaction with Lo Simpesse. Table 4: Significant Drug Interactions Involving Substances That Affect COCs Metabolic Enzyme Inducers Clinical effect Concomitant use of COCs with metabolic enzyme inducers may decrease the plasma concentrations of the estrogen and/or progestin component of COCs. Decreased exposure of the estrogen and/or progestin component of COCs may potentially diminish the effectiveness of COCs and may lead to contraceptive failure or an increase in breakthrough bleeding. Prevention or management Counsel females to use an alternative method of contraception or a backup method when enzyme inducers are used with COCs. Continue backup contraception for 28 days after discontinuing the enzyme inducer to maintain contraceptive reliability. Examples Aprepitant, barbiturates, bosentan, carbamazepine, efavirenz, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, rifabutin, rufinamide, topiramate, products containing St. John’s wort a , and certain protease inhibitors (see separate section on protease inhibitors below). Colesevelam Clinical effect Concomitant use of COCs with colesevelam significantly decreases systemic exposure of ethinyl estradiol. Decreased exposure of the estrogen component of COCs may potentially reduce contraceptive efficacy or result in an increase in breakthrough bleeding, depending on the strength of ethinyl estradiol in the COC. Prevention or management Administer 4 or more hours apart to attenuate this drug interaction. a Induction potency of St. John’s wort may vary widely based on preparation. Substances increasing the systemic exposure of COCs: Co-administration of atorvastatin or rosuvastatin and COCs containing ethinyl estradiol increase systemic exposure of ethinyl estradiol by approximately 20 to 25 percent. Ascorbic acid and acetaminophen may increase systemic exposure of ethinyl estradiol, possibly by inhibition of conjugation. CYP3A inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase systemic exposure of the estrogen and/or progestin component of COCs. Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant decreases in systemic exposure of the estrogen and/or progestin have been noted when COCs are co-administered with some HIV protease inhibitors (e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir), some HCV protease inhibitors (e.g., boceprevir and telaprevir), and some non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine). In contrast, significant increases in systemic exposure of the estrogen and/or progestin have been noted when COCs are co-administered with certain other HIV protease inhibitors (e.g., indinavir and atazanavir/ritonavir) and with other non-nucleoside reverse transcriptase inhibitors (e.g., etravirine). 7.2 Effects of Combined Oral Contraceptives on Other Drugs Table 5 provides significant drug interaction information for drugs co-administered with Lo Simpesse. Table 5: Significant Drug Interaction Information for Drugs Co-Administered With COCs Lamotrigine Clinical effect Concomitant use of COCs with lamotrigine may significantly decrease systemic exposure of lamotrigine due to induction of lamotrigine glucuronidation. Decreased systemic exposure of lamotrigine may reduce seizure control. Prevention or management Dose adjustment may be necessary. Consult the approved product labeling for lamotrigine. Thyroid Hormone Replacement Therapy or Corticosteroid Replacement Therapy Clinical effect Concomitant use of COCs with thyroid hormone replacement therapy or corticosteroid replacement therapy may increase systemic exposure of thyroid-binding and cortisol-binding globulin [see Warnings and Precautions (5.12) ] . Prevention or management The dose of replacement thyroid hormone or cortisol therapy may need to be increased. Consult the approved product labeling for the therapy in use [see Warnings and Precautions (5.12) ] . Other Drugs Clinical effect Concomitant use of COCs may decrease systemic exposure of acetaminophen, morphine, salicylic acid, and temazepam. Concomitant use with ethinyl estradiol-containing COCs may increase systemic exposure of other drugs (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole). Prevention or management The dosage of drugs that can be affected by this interaction may need to be increased. Consult the approved product labeling for the concomitantly used drug. 7.3 Concomitant Use with Hepatitis C Virus (HCV) Combination Therapy - Liver Enzyme Elevation Co-administration of Lo Simpesse with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir is contraindicated due to potential for ALT elevations [see Warning and Precautions (5.4) ] . Co-administration of Lo Simpesse and glecaprevir/pibrentasvir is not recommended due to potential for ALT elevations. 7.4 Effect on Laboratory Tests The use of COCs may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.