BALCOLTRA

Balcoltra (levonorgestrel and ethinyl estradiol tablets, USP, and ferrous bisglycinate tablets) provides an oral contraceptive regimen consisting of 21 orange active tablets and 7 blue inactive tablets. • 21 orange active tablets each containing 0.10 mg of levonorgestrel, d(-)-13β-ethyl-17α-ethinyl-17β-hydroxygon-4-en-3-one, a totally synthetic progestogen, and 0.02 mg of ethinyl estradiol, 17α-ethinyl-1,3,5(10)-estratriene-3, 17β-diol, an estrogenic compound. • 7 blue inactive tablets each containing 36.5 mg ferrous bisglycinate. The inactive ingredients present in orange active tablet are FD&C Yellow #5 Aluminum Lake, FD&C Yellow #6 Aluminum Lake, FD&C Red #40 Aluminum Lake, titanium dioxide, polyvinyl alcohol, talc, macrogol/polyethylene glycol 3350 NF, lecithin (soya), iron oxide black, lactose monohydrate, magnesium stearate and pregelatinized starch. Each inactive blue tablet contains the following inactive ingredients: ferrous bisglycinate, citric acid, glycine, water, maltodextrin , silica, microcrystalline cellulose NF, magnesium stearate NF, croscarmellose sodium NF, colloidal silicon dioxide NF, hypromellose type 2910, titanium dioxide, polyethylene glycol 400, FD&C Red #40 Aluminum Lake, FD&C Yellow #6 Aluminum Lake and FD&C Blue #1 Aluminum Lake. Levonorgestrel has the empirical formula of C 21 H 28 O 2 and the molecular weight of 312.4, and ethinyl estradiol has the empirical formula of C 20 H 24 O 2 and the molecular weight of 296.4. The molecular structures are provided below: Molecular Structures

Balcoltra is indicated for use by females of reproductive potential to prevent pregnancy. Balcoltra is a progestin/estrogen COC indicated for use by females of reproductive potential to prevent pregnancy. ( 1 )

• Take one tablet by mouth at the same time every day. ( 2.1 ) • Take tablets in the order directed on the blister pack. ( 2.1 ) 2.1 How to Start Balcoltra Balcoltra is dispensed in a blister card [see How Supplied/Storage and Handling ( 16 )] . Balcoltra may be started using either a Day 1 start or a Sunday start (see Table 1 ). For the first cycle of a Sunday Start regimen, an additional method of contraception should be used until after the first 7 consecutive days of administration. 2.2 How to Take Balcoltra Balcoltra (orange active tablets and blue placebo tablets) is swallowed whole once a day Table 1: Instructions for Administration of Balcoltra Complete instructions to facilitate patient counseling on proper tablet usage are located in the FDA-Approved Patient Labeling. Starting COCs in women not currently using hormonal contraception (Day 1 Start or Sunday Start) Important: Consider the possibility of ovulation and conception prior to initiation of this product. Tablet Color: •Balcoltra active tablets are orange (Day 1 to Day 21). •Balcoltra placebo tablets are blue (Day 22 to Day 28). Day 1 Start: •Take first orange active tablet on the first day of menses. •Take subsequent orange active tablets once daily at the same time each day for a total of 21 days. •Take one blue placebo tablet daily for 7 days and at the same time of day that active tablets were taken. •Begin each subsequent pack on the same day of the week as the first cycle pack (i.e. on the day after taking the last inactive tablet). Sunday Start: •Take first active tablet on the first Sunday after the onset of menses. Due to the potential risk of becoming pregnant, use additional non-hormonal contraception (such as condoms or spermicide) for the first seven days of the patient’s first cycle pack of Balcoltra. •Take subsequent orange tablets once daily at the same time each day for a total of 21 days. •Take one blue placebo tablet daily for the following 7 days and at the same time of day that active tablets were taken. •Begin each subsequent pack on the same day of the week as the first cycle pack (i.e., on the Sunday after taking the last inactive tablet) and additional non-hormonal contraceptive is not needed. Switching to Balcoltra from another hormonal contraceptive Start on the same day that a new pack of the previous hormonal contraceptive would have started. Switching from another contraceptive method to Balcoltra Start Balcoltra: • Transdermal patch •On the day when next application would have been scheduled • Vaginal ring •On the day when next insertion would have been scheduled • Injection •On the day when next injection would have been scheduled • Intrauterine contraceptive •On the day of removal •If the IUD is not removed on first day of the patient’s menstrual cycle, additional non-hormonal contraceptive (such as condoms or spermicide) is needed for the first seven days of the first cycle pack. • Implant •On the day of removal Starting Balcoltra after Abortion or Miscarriage First-trimester •After a first-trimester abortion or miscarriage, Balcoltra may be started immediately. An additional method of contraception is not needed if Balcoltra is started within 5 days after termination of the pregnancy. •If Balcoltra is not started within 5 days after termination of the pregnancy, the patient should use additional non-hormonal contraception (such as condoms or spermicide) for the first seven days of her first cycle pack of Balcoltra. Second-trimester •Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start Balcoltra, following the instructions in Table 1 for Day 1 or Sunday start, as desired. If using Sunday start, use additional non-hormonal contraception (such as condoms or spermicide) for the first seven days of the patient’s first cycle pack of Balcoltra. [See Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), and FDA-Approved Patient Labeling .] Starting Balcoltra after Childbirth •Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with Balcoltra following the instructions in Table 1 for women not currently using hormonal contraception. •If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of Balcoltra. [See Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.1 and 8.2 ), and FDA-Approved Patient Labeling ] . 2.3 Missed Tablets Table 2: Instructions for Missed Balcoltra Tablets •If one orange active tablet is missed in Weeks 1, 2, or 3 Take the tablet as soon as possible. Continue taking one tablet a day until the pack is finished. •If two orange active tablets are missed in Week 1 or Week 2 Take the two missed tablets as soon as possible and the next two active tablets the next day. Continue taking one tablet a day until the pack is finished. Additional non-hormonal contraception (such as condoms or spermicide) should be used as back-up if the patient has sex within 7 days after missing tablets. •If two orange tablets are missed in Week 3 or three or more orange active tablets are missed in a row in Weeks 1, 2, or 3 Day 1 start: Throw out the rest of the pack and start a new pack that same day. Sunday start: Continue taking one tablet a day until Sunday, then throw out the rest of the pack and start a new pack that same day. Additional non-hormonal contraception (such as condoms or spermicide) should be used as back-up if the patient has sex within 7 days after missing tablets. 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 or diarrhea occurs within 3 to 4 hours after taking an active tablet, handle this as a missed tablet [see FDA-Approved Patient Labeling ] .

Balcoltra is contraindicated in females who are known to have or develop the following conditions: •A high risk of arterial or venous thrombotic disease. 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 inherited or acquired hypercoagulopathies [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 uncontrolled hypertension [see Warnings and Precautions ( 5.4 )] . - Have diabetes mellitus with vascular disease [see Warnings and Precautions ( 5.6 )] . - Have headaches with focal neurological symptoms or have migraine headaches with aura [see Warnings and Precautions ( 5.7 )] . •Women over age 35 with any migraine headaches [see Warnings and Precautions ( 5.7 )] . •Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions ( 5.2 )] •Undiagnosed abnormal uterine bleeding [see Warnings and Precautions ( 5.8 )] . •Pregnancy, because there is no reason to use COCs during pregnancy [see Warnings and Precautions ( 5.10 ) and Use in Specific Populations ( 8.1 )] . •Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive [see Warnings and Precautions ( 5.11 )] . •Hypersensitivity to any of the components. •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 ( 5.3 )] •A high risk of arterial or venous thrombotic diseases ( 4 ) •Liver tumors or liver disease ( 4 ) •Undiagnosed abnormal uterine bleeding ( 4 ) •Pregnancy ( 4 ) •Breast cancer ( 4 ) •Hypersensitivity of any of the components ( 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 )] Adverse reactions commonly reported by COC users: • Irregular uterine bleeding • Nausea • Breast tenderness • Headache Common adverse reactions (≥2% of women): headache (14%), metrorrhagia (8%), dysmenorrhea and nausea (7% each), abdominal pain and breast pain (4% each), emotional lability and acne (3% each), and depression, amenorrhea, and vaginal moniliasis (2% each) ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Avion Pharmaceuticals, LLC at 1-888-612-8466 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, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In a clinical trial with levonorgestrel 0.1 mg and ethinyl estradiol 0.02 mg tablets, a total of 1477 healthy women of child-bearing potential were enrolled and had 7870 cycles of exposure. Of these, 792 subjects had completed 6 cycles of treatment. The women ranged in age from 17 to 49 years and 87% were Caucasian. Common Adverse Reactions (≥ 2% of women): • headache (14%) • metrorrhagia (8%) • dysmenorrhea (7%) • nausea (7%) • abdominal pain (4%) • breast pain (4%) • emotional lability (3%) • acne (3%) • depression (2%) • amenorrhea (2%) • vaginal moniliasis (2%) At the time of the report, 133 (9%) subjects had withdrawn from the study due to adverse events. The most frequent were due to headache and metrorrhagia (1% each). Other adverse events occurring in < 1% of those who discontinued included amenorrhea, depression, emotional lability, hypertension, acne, menorrhagia, nausea, hypercholesterolemia, weight gain, dysmenorrhea, and flatulence. All other reasons for discontinuation were reported by 3 or fewer subjects. 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 1). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 1). 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 1. 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. The following additional adverse drug reactions have been reported from worldwide postmarketing experience with levonorgestrel 0.1 mg and ethinyl estradiol 0.02 mg tablets. 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. Cardiac disorder : chest pain, dyspnea, palpitations Gastrointestinal disorders : abdominal pain, nausea, vomiting, diarrhea General disorders and administration site conditions : chest pain, fatigue, pain, malaise, injection site pain or erythema, feeling abnormal, pyrexia, condition aggravated, asthenia Immune system disorders : hypersensitivity reactions, including pruritus, rash, urticaria, erythema Injury, poisoning, and procedural complications : injury Investigations : weight decreased Musculoskeletal and connective tissue disorders : pain in extremity, arthralgia, back pain, muscle spasm Nervous system disorders : headache, migraine, dizziness, hypoesthesia, paresthesia Psychiatric disorders : depression, insomnia, anxiety Reproductive system and breast disorders : metrorrhagia, menorrhagia, hot flush, vaginal hemorrhage Respiratory, thoracic, and mediastinal disorders : nasopharyngitis, cough Sleep disorders and disturbances : somnolence Vascular disorders : deep vein thrombosis, pulmonary embolism image description

Consult the labeling of 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, including CYP3A4, may decrease the effectiveness of COCs or increase breakthrough bleeding. Counsel patients to use a back-up method 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 decreasing the plasma concentrations of COCs and potentially diminishing the efficacy of COCs: Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of COCs and potentially diminish 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, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St. John’s wort. Interactions between hormonal 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. Colesevelam: Colesevelam, a bile acid sequestrant, given together with a COC, has been shown to significantly decrease the AUC of ethinyl estradiol (EE). The drug interaction between the contraceptive and colesevelam was decreased when the two drug products were given 4 hours apart. Substances increasing the plasma concentrations of COCs: Co-administration of atorvastatin or rosuvastatin and certain COCs containing EE increase AUC values for EE by approximately 20-25%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors, such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma hormone concentrations. 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/or progestin have been noted in some cases of co-administration with HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, tipranavir/ritonavir, boceprevir, telaprevir, nevirapine and efavirenz] or increase [e.g., indinavir, atazanavir/ritonavir and etravirine]). 7.2 Effects of Combined Oral Contraceptives on Other Drugs Combined oral contraceptives containing EE may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations. Combined oral contraceptives have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, temazepam and lamotrigine. Significant decrease in plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because the serum concentration of thyroid-binding globulin increases with use of COCs [see Warnings and Precautions ( 5.12 )] . 7.3 Concomitant Use with HCV Combination Therapy - Liver Enzyme Elevation Do not co-administer Balcoltra with HCV drug combinations containing ombitasvir/ paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions ( 5.3 )] . 7.4 Interference with Laboratory Tests The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.