FEMLYV

FEMLYV (norethindrone acetate and ethinyl estradiol orally disintegrating tablets) is a combined oral contraceptive. FEMLYV consists of 24 green, round ODTs each containing 1 mg norethindrone acetate and 0.020 mg ethinyl estradiol and 4 white, round inert ODTs. Each green ODT also contains the following inactive ingredients: croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, mint green lake blend, pregelatinized starch, spearmint flavor, sucralose, vitamin E (DL-alpha-tocopherol). Each white ODT contains, croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, pregelatinized starch, spearmint flavor, sucralose. The empirical formula of norethindrone acetate is C 22 H 28 O 3 and the structural formula is: The chemical name of norethindrone acetate is [19-Norpregn-4-en-20-yn-3-one, 17-(acetyloxy)-, (17α)-]. The molecular weight of norethindrone acetate is 340.46. It is a neutral molecule and is practically insoluble in water. The empirical formula of ethinyl estradiol is C 20 H 24 O 2 and the structural formula is: The chemical name of ethinyl estradiol is [19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-]. The molecular weight of ethinyl estradiol is 296.40. It is a neutral molecule and is practically insoluble in water. Norethindrone acetate structural formula Ethinyl estradiol structural formula

FEMLYV is indicated for use by females of reproductive potential to prevent pregnancy [see Clinical Studies (14) ] . Limitations of Use The efficacy of FEMLYV in females with a body mass index (BMI) of more than 35 kg/m 2 has not been evaluated. FEMLYV is a combination of norethindrone acetate, a progestin, and ethinyl estradiol, an estrogen, indicated for use by females of reproductive potential to prevent pregnancy ( 1 ) Limitations of Use The efficacy in females of reproductive potential with a body mass index of more than 35 kg/m 2 has not been evaluated ( 1 , 8.8 )

• Place one FEMLYV orally disintegrating tablet (ODT) on the tongue, allow to disintegrate and then follow with 8 oz. (240 mL) of water. • The tablets can also be swallowed whole with 8 oz. (240 mL) of water. • Take at the same time daily without regards to meals ( 2.1 , 12.3 ) • Take ODTs in the order directed on the blister pack ( 2.1 ) 2.1 Dosing FEMLYV To achieve maximum contraceptive effectiveness, take one ODT every day at about the same time each day. Place one ODT on the tongue, allow to disintegrate and then follow with 8 oz. (240 mL) of water. The tablets can also be swallowed whole with 8 oz. (240 mL) of water. The recommended dosage of FEMLYV is one ODT daily for 28 consecutive days: one green active ODT daily during the first 24 days followed by one white inert ODT daily during the 4 following days (see Table 1 ). FEMLYV must be taken in the order directed on the blister pack. ODTs should not be skipped or taken at intervals exceeding 24 hours. FEMLYV may be administered without regard to meals [see 12.3 ] . Instruct the patient to begin taking FEMLYV 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). 2.2 Recommended Dosage and Administration Table 1 FEMLYV Administration Instructions Starting FEMLYV in females with no current use of hormonal contraception Important: • In females with irregular menstrual cycles, pregnancy testing may be necessary prior to initiation of this product Day 1 Start: • Take first green FEMLYV without regard to meals on the first day of menstruation • Take one green FEMLYV daily for 24 consecutive days, followed by one white FEMLYV daily on days 25 through to 28 • FEMLYV should be taken in the order directed on the package at the same time each day • Non-hormonal contraception (e.g. condoms and/or spermicide) should be used during the first 7 days if FEMLYV is started on a day other than the first day of menstruation Sunday Start: • Take one green FEMLYV daily, beginning on the first Sunday after the onset of menstruation • Take one green FEMLYV daily for 24 consecutive days, followed by one white FEMLYV daily on days 25 through to 28 • FEMLYV should be taken in the order directed on the package at the same time each day • Non-hormonal contraception should be used during the first 7 days if FEMLYV is started on a day other than the first day of menstruation • Begin next and all subsequent 28-day regimens of FEMLYV on the same day of the week as the first cycle pack (i.e., on the day after taking the last tablet) Switching to Femlyv from another contraceptive method: Start FEMLYV on the day: • Combined Oral Contraceptive (COC) Start FEMLYV on the day when the new pack of the previous COC would have been started • Transdermal System Start FEMLYV on the day when the next application would have been scheduled • Vaginal insert Start FEMLYV on the day when next insertion would have been scheduled • Injection Start FEMLYV on the day when next injection would have been scheduled • Intrauterine System (IUS) Start FEMLYV on the day of removal • Implant Start FEMLYV on the day of removal • Progestin-only pill Start FEMLYV after the last tablet was taken Starting FEMLYV after delivery (>20 weeks gestation) Must not start earlier than 4 weeks after delivery (due to the increased risk of thromboembolism [see Contraindications (4) and Warnings and Precautions (5.1 )] If menstrual cycles have returned, follow instructions for “Starting FEMLYV in females with no current use of hormonal contraception”. If menstrual cycles have not resumed, consider the possibility of ovulation and pregnancy. If not pregnant, use additional nonhormonal contraception for the first 7 days of FEMLYV use. Starting FEMLYV after Abortion or Miscarriage • ≤ 14 weeks gestation Within the first 7 days of complete first trimester abortion or miscarriage, use additional nonhormonal contraception for the next 7 days. After the first 7 days, follow instructions for “Starting FEMLYV in females with no current use of hormonal contraception”. • > 14 weeks but ≤ 20 weeks gestation After 4 weeks following second trimester abortion or miscarriage. Consider duration of pregnancy and increased risk of thromboembolism [see Warnings and Precautions (5.1) ] If menstrual cycles have returned, follow instructions for “Starting FEMLYV in females with no current use of hormonal contraception”. If menstrual cycles have not resumed, consider the possibility of ovulation and pregnancy. If not pregnant, use additional nonhormonal contraception for the first 7 days of FEMLYV use. 2.3 Missed Doses Table 2. Instructions for Missed FEMLYV ODTs If one green active ODT is missed Take the missed ODT as soon as possible. Take the next ODT at the regular time. Continue taking one ODT a day until the pack is finished. Additional nonhormonal contraception (such as condoms) is not needed. If two green active ODTs in a row are missed in Week 1 or Week 2 of the blister pack Take the two missed ODTs as soon as possible, and the next two ODTs the next day. Continue taking one ODT a day until the pack is finished. Use additional nonhormonal contraception (such as condoms) until green ODTs have been taken for 7 consecutive days. If two green active ODTs are missed in Week 3 or Week 4 of the blister pack Day 1 Starter: Discard the rest of the blister pack and start a new pack of ODTs that same day. Sunday Starter: Keep taking one ODT every day until Sunday. On Sunday, discard the rest of the blister pack and start a new pack of ODTs that same day. Use additional nonhormonal contraception (such as condoms) until green ODTs have been taken for 7 consecutive days. If three or more green active ODTs in a row are missed Day 1 Starter: Discard the rest of the blister pack and start a new pack that same day. Sunday Starter: Keep taking one ODT every day until Sunday. On Sunday, discard the rest of the blister pack and start a new blister pack of ODTs that same day. Bleeding may occur during the week following the missed ODTs. Use additional nonhormonal contraception (such as condoms) until green ODTs have been taken for 7 consecutive days. If any of the four white inert ODTs are missed Discard the missed ODTs. Continue taking the remaining ODTs until the blister pack is finished. Additional nonhormonal contraception (such as condoms) is not needed. 2.4 Advice in Case of Gastrointestinal Disturbances If vomiting or acute diarrhea occurs within 3 to 4 hours after taking an active ODT, take the new active ODT (scheduled for the next day) as soon as possible. If two or more active ODTs are missed, follow the advice concerning missed ODTs, including using backup non-hormonal contraception. For additional recommendations, refer to the table above [see Dosage and Administration (2.3) ] .

FEMLYV is contraindicated in females who are known to have or develop the following conditions: • A history of, increased risk for, or current arterial or venous thrombotic/thromboembolic diseases. Examples include women who are known to: • Smoke, if 35 years of age and older [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 (5.2) ] • Have diabetes mellitus with hypertension or end-organ damage; or diabetes mellitus of > 20 years duration [see Warnings and Precautions (5.7) ] • Have migraine headaches with aura o All women over age 35 with migraine headache [see Warnings and Precautions (5.3) ] • Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive [see Warnings and Precautions (5.4) ] • Liver tumors, benign or malignant, or hepatic impairment [see Warnings and Precautions (5.5) ] • 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 (5.6) ] • Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.9) ] • A high risk of arterial or venous thrombotic diseases ( 4 ) • Breast cancer or history of breast cancer ( 4 ) • Liver tumors, benign or malignant, or hepatic impairment ( 4 ) • Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir ( 4 ) • Undiagnosed abnormal uterine bleeding ( 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 (5.5) ] • The most common adverse reactions in clinical trials (≥2%) were: headache, vaginal candidiasis, nausea, menstrual cramps, breast tenderness, bacterial vaginitis, abnormal cervical smear, acne, mood swings, and weight gain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Millicent U.S. Inc. at 1-877-810-2101 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 safety of FEMLYV has been established from adequate and well-controlled studies of norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablets in adult females of reproductive potential for the prevention of pregnancy [see Clinical Studies (14) ] . The data described below reflect exposure to norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablets. Common Adverse Reactions (Greater Than or Equal to 2% of all Treated Subjects) : The most common adverse reactions reported by at least 2% of the 743 women using norethindrone acetate/ethinyl estradiol tablets were the following, in order of decreasing incidence: headache (6.3%), vaginal candidiasis (6.1%), nausea (4.6%), menstrual cramps (4.4%), breast tenderness (3.4%), bacterial vaginitis (3.1%), abnormal cervical smear (3.1%), acne (2.7%), mood swings (2.2%), and weight gain (2.0%). Adverse Reactions Leading to Study Discontinuation : Among the 743 women using norethindrone acetate/ethinyl estradiol tablets, 46 women (6.2%) withdrew because of an adverse event. Adverse events occurring in 3 or more subjects leading to discontinuation of treatment were, in decreasing order: abnormal or irregular bleeding (1.3%), nausea (0.8%), menstrual cramps (0.5%), and increased blood pressure (0.4%). 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 2 ). 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 2. 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 a 24-day regimen of norethindrone acetate 1 mg/ethinyl estradiol 0.020 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 evaluate a causal relationship to drug exposure. Adverse reactions are grouped into System Organ Classes. Vascular disorders: thrombosis/embolism (coronary artery, pulmonary, cerebral, deep vein). Hepatobiliary disorders: cholelithiasis, cholecystitis, hepatic adenoma, hemangioma of liver. Immune system disorders: hypersensitivity reaction. Skin and subcutaneous disorders: alopecia, rash (generalized and allergic), pruritus, skin discoloration. GI disorders: nausea, vomiting, abdominal pain. Musculoskeletal and connective tissue disorders: myalgia. Eye disorders: blurred vision, visual impairment, corneal thinning, change in corneal curvature (steepening). Infections and infestations: fungal infection, vaginal infection. Investigations: change in weight or appetite (increase or decrease), fatigue, malaise, peripheral edema, blood pressure increased. Nervous system disorders: headache, dizziness, migraine, loss of consciousness. Psychiatric disorders: mood swings, depression, insomnia, anxiety, suicidal ideation, panic attack, changes in libido. Renal and urinary disorders: cystitis-like syndrome. Reproductive system and breast disorders: breast changes (tenderness, pain, enlargement, and secretion), premenstrual syndrome, dysmenorrhea. Cardiovascular: chest pain, palpitations, tachycardia, myocardial infarction. Figure 2

• CYP3A Inducers: May lead to contraceptive failure and/or increase breakthrough bleeding. Avoid concomitant use. If concomitant use is unavoidable, use a back-up method or alternative method of contraception during co-administration and up to 28 days after discontinuation of the CYP3A inducer ( 7.1 ) • See Full Prescribing Information for additional clinically significant drug interactions ( 7 ) 7.1 Effects of Other Drugs on Combined Oral Contraceptives Substances diminishing the efficacy of COCs: Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease 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 and products containing St. John’s wort. Interactions between oral 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. Substances increasing the plasma concentrations of COCs: Co-administration of atorvastatin and certain COCs containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole 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 the estrogen and progestin have been noted in some cases of co-administration of HIV/HCV protease inhibitors or of non-nucleoside reverse transcriptase inhibitors. Antibiotics: There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids. 7.2 Effects of Combined Oral Contraceptives on Other Drugs COCs containing ethinyl estradiol may inhibit the metabolism of other compounds. COCs have been shown to significantly decrease plasma concentrations of lamotrigine, 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 serum concentration of thyroid-binding globulin increases with use of COCs. 7.3 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer FEMLYV with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions (5.6) ] . 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.