TRI-VYLIBRA LO

Tri-VyLibra Lo is a combination oral contraceptive containing the progestational compound norgestimate and the estrogenic compound ethinyl estradiol. Norgestimate is designated as (18,19-Dinor-17-pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl-, oxime, (17α)-(+)-) and ethinyl estradiol is designated as (19-nor-17α-pregna,1,3,5(10)-trien-20-yne-3,17-diol). Each active white to off white tablet contains 0.180 mg of norgestimate USP and 0.025 mg of ethinyl estradiol USP. Inactive ingredients include croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and titanium dioxide. Each active pale blue to bluish white tablet contains 0.215 mg of norgestimate USP and 0.025 mg of ethinyl estradiol USP. Inactive ingredients include croscarmellose sodium, FD&C Blue #2/Indigo carmine aluminum lake, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and titanium dioxide. Each active blue to light blue tablet contains 0.250 mg of norgestimate USP and 0.025 mg of ethinyl estradiol USP. Inactive ingredients include croscarmellose sodium, FD&C Blue #2/Indigo carmine aluminum lake, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and titanium dioxide. Each green placebo tablet contains only inert ingredients, as follows: anhydrous lactose, FD&C Blue No. 2 aluminum lake, ferric oxide yellow, magnesium stearate, microcrystalline cellulose, and povidone. Chemical Structure

Tri-VyLibra Lo (norgestimate and ethinyl estradiol tablets) is an estrogen/progestin COC, indicated for use by women to prevent pregnancy. ( 1.1 ) 1.1 Oral Contraception Tri-VyLibra Lo (norgestimate and ethinyl estradiol tablets) is indicated for use by females of reproductive potential to prevent pregnancy [see Clinical Studies (14) ] .

Take one tablet daily by mouth at the same time every day. ( 2.2 ) Take tablets in the order directed on the blister pack. ( 2.2 ) Do not skip or delay tablet intake. ( 2.2 ) 2.1 How to Start Tri-VyLibra Lo (Norgestimate and Ethinyl Estradiol Tablets) Tri-VyLibra Lo (norgestimate and ethinyl estradiol tablets) is dispensed in a blister pack [see How Supplied/Storage and Handling (16) ] . Tri-VyLibra Lo (norgestimate and ethinyl estradiol tablets) 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 Tri-VyLibra Lo (Norgestimate and Ethinyl Estradiol Tablets) Table 1: Instructions for Administration of Tri-VyLibra Lo (norgestimate and ethinyl estradiol tablets) 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: Tri-VyLibra Lo (norgestimate and ethinyl estradiol tablets) active tablets are white to off white (Day 1 to Day 7), pale blue to bluish white (Day 8 to Day 14) and blue to light blue (Day 15 to Day 21). Tri-VyLibra Lo inactive tablets are green (Day 22 to Day 28). Day 1 Start: Take first active tablet without regard to meals on the first day of menses. Take subsequent active tablets once daily at the same time each day for a total of 21 days. Take one green inactive 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 without regard to meals 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 and spermicide) for the first seven days of the patient’s first cycle pack of Tri-VyLibra Lo (norgestimate and ethinyl estradiol tablets). Take subsequent active tablets once daily at the same time each day for a total of 21 days. Take one green inactive 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 Tri-VyLibra Lo (norgestimate and ethinyl estradiol tablets) from another oral contraceptive Start on the same day that a new pack of the previous oral contraceptive would have started. Switching from another contraceptive method to Tri-VyLibra Lo (norgestimate and ethinyl estradiol tablets) Start Tri-VyLibra Lo (norgestimate and ethinyl estradiol tablets): 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 and spermicide) is needed for the first seven days of the first cycle pack. Implant On the day of removal Complete instructions to facilitate patient counseling on proper tablet usage are located in the FDA-Approved Patient Labeling. Starting Tri-VyLibra Lo (norgestimate and ethinyl estradiol tablets) after Abortion or Miscarriage First-trimester After a first-trimester abortion or miscarriage, Tri-VyLibra Lo (norgestimate and ethinyl estradiol tablets) may be started immediately. An additional method of contraception is not needed if Tri-VyLibra Lo (norgestimate and ethinyl estradiol tablets) is started immediately. If Tri-VyLibra Lo (norgestimate and ethinyl estradiol tablets) is not started within 5 days after termination of the pregnancy, the patient should use additional non-hormonal contraception (such as condoms and spermicide) for the first seven days of her first cycle pack of Tri-VyLibra Lo (norgestimate and ethinyl estradiol tablets). Second-trimester Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start Tri-VyLibra Lo (norgestimate and ethinyl estradiol tablets), 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 and spermicide) for the first seven days of the patient’s first cycle pack of Tri-VyLibra Lo (norgestimate and ethinyl estradiol tablets). [see Contraindications (4) , Warnings and Precautions (5.1) , and FDA-Approved Patient Labeling .] Starting Tri-VyLibra Lo (norgestimate and ethinyl estradiol tablets) after Childbirth Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with Tri-VyLibra Lo (norgestimate and ethinyl estradiol tablets) following the instructions in Table 1 for women not currently using hormonal contraception. Tri-VyLibra Lo (norgestimate and ethinyl estradiol tablets) is not recommended for use in lactating women [see Use in Specific Populations (8.3) ] . If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of Tri-VyLibra Lo (norgestimate and ethinyl estradiol tablets). [see Contraindications (4) , Warnings and Precautions (5.1) , Use in Specific Populations (8.1 and 8.3) , and FDA-Approved Patient Labeling ]. Blister Pack: 1. Decide what time of day you want to take your pill. It is important to take it at about the same time every day. 2. The 28-pill pack has 21 white to off white, pale blue to bluish white, and blue to light blue “active” pills (with hormones) to take for 3 weeks. This is followed by 1 week of green “reminder” pills (without hormones). 3. Also find: 1) where on the pack to start taking pills, 2) in what order to take the pills, and 3) the week numbers as shown in the picture below. 4. Be sure you have ready at all times: Another kind of birth control (such as condoms or spermicide) to use as a back-up method in case you miss pills. An extra, full pill pack. You have a choice of which day to start taking your first pack of pills. Tri-VyLibra Lo is available in a blister pack which is preset for a Sunday Start. Day 1 Start stickers are also provided. Decide with your healthcare professional which is the best day for you. Pick a time of day that will be easy to remember. Sunday Start: Take the first white to off white “active” pill of the first pack on the Sunday after your period starts , even if you are still bleeding. If your period begins on Sunday, start the pack that same day. Use another method of birth control (such as condoms or spermicide) as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). Day 1 Start: Take the first white to off white "active" pill of the first pack during the first 24 hours of your period . Pick the day label strip that starts with the first day of your period (this is the day you start bleeding or spotting, even if it is almost midnight when the bleeding begins). Place this day label strip in the cycle tablet over the area that has the days of the week (starting with Sunday) imprinted in the plastic. Note: If the first day of your period is a Sunday, you can skip steps #1 and #2. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period. Blister Pack Label Day Label Sticker 2.3 Missed Tablets Table 2: Instructions for Missed Tri-VyLibra Lo (norgestimate and ethinyl estradiol tablets) If one 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 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 and spermicide) should be used as back-up if the patient has sex within 7 days after missing tablets. If two active tablets are missed in the third week or three or more 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 and 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 ] .

Tri-VyLibra Lo (norgestimate and ethinyl estradiol tablets) 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 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 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 (5.9) 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) ] 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 ) Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive ( 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 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 are: Irregular uterine bleeding Nausea Breast tenderness Headache The most common adverse reactions reported during clinical trials (≥2%) were: headache/migraine, nausea/vomiting, breast issues, abdominal pain, menstrual disorders, mood disorders, acne, vulvovaginal infection, abdominal distension, weight increased, fatigue. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Afaxys Pharma, LLC at 1-855-888-2467 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 rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of Tri-VyLibra Lo was evaluated in 1,723 subjects who participated in a randomized, partially blinded, multicenter, active-controlled clinical trial of Tri-VyLibra Lo for contraception. This trial examined healthy, nonpregnant, volunteers aged 18 to 45 (nonsmoker if 35 to 45 years of age), who were sexually active with regular coitus. Subjects were followed for up to 13 28-day cycles. Common Adverse Reactions (≥ 2% of subjects) : The most common adverse reactions reported by at least 2% of the 1,723 women using the 28-day regimen were the following in order of decreasing incidence: headache/migraine (30.5%), nausea/vomiting (16.3%); breast issues (including tenderness, pain, enlargement, swelling, discharge, discomfort, cyst, and nipple pain) (10.3%), abdominal pain (9.2%), menstrual disorders (including dysmenorrhea, menstrual discomfort, menstrual disorder) (9.2%), mood disorders (including depression, mood altered, mood swings and depressed mood) (7.6%); acne (5.1%), vulvovaginal infection (3.5%), abdominal distension (2.8%), weight increased (2.4%), fatigue (2.1%). Adverse Reactions Leading to Study Discontinuation : In the clinical trial of Tri-VyLibra Lo 4% of subjects discontinued the trial due to an adverse reaction. The most common adverse reactions leading to discontinuation were headache/migraine (1.2%), nausea/vomiting (0.7%), cervical dysplasia (0.7%), abdominal pain (0.4%), ovarian cyst (0.3%), acne (0.2%), flatulence (0.2%) and depression (0.2%). Serious Adverse Reactions : carcinoma of the cervix in situ (1 subject) and cervical dysplasia (1 subject). 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 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 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 1: Risk of Breast Cancer with Combined Oral Contraceptive Use 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 norgestimate/ethinyl estradiol. 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. Infections and Infestations : Urinary tract infection Neoplasms Benign, Malignant and Unspecified (Including Cysts and Polyps) : Breast cancer, benign breast neoplasm, hepatic adenoma, focal nodular hyperplasia, breast cyst Immune System Disorders : Hypersensitivity Metabolism and Nutrition Disorders : Dyslipidemia Psychiatric Disorders : Anxiety, insomnia Nervous System Disorders : Syncope, convulsion, paresthesia, dizziness Eye Disorders : Visual impairment, dry eye, contact lens intolerance Ear and Labyrinth Disorders : Vertigo Cardiac Disorders : Tachycardia, palpitations Vascular Events : Deep vein thrombosis, pulmonary embolism, retinal vascular thrombosis, hot flush Arterial Events: Arterial thromboembolism, myocardial infarction, cerebrovascular accident Respiratory, Thoracic and Mediastinal Disorders : Dyspnea Gastrointestinal Disorders : Pancreatitis, abdominal distension, diarrhea, constipation Hepatobiliary Disorders: Hepatitis Skin and Subcutaneous Tissue Disorders : Angioedema, erythema nodosum, hirsutism, night sweats, hyperhidrosis, photosensitivity reaction, urticaria, pruritus, acne Musculoskeletal, Connective Tissue, and Bone Disorders : Muscle spasms, pain in extremity, myalgia, back pain Reproductive System and Breast Disorders : Ovarian cyst, suppressed lactation, vulvovaginal dryness General Disorders and Administration Site Conditions : Chest pain, asthenic conditions. norgestimate-fig3

Consult the labeling of concurrently used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. No drug-drug interaction studies were conducted with Tri-VyLibra Lo. 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 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 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 COCs include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant and products containing St. John’s wort. Interactions between COCs 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 to 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 protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]). 7.2 Effects of Combined Oral Contraceptives on Other Drugs COCs containing EE may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations. COCs 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. 7.3 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. 7.4 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer Tri-VyLibra Lo with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions (5.3) ] .