FEMLYV

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combined oral contraceptive (COC) use. This risk increases with age, particularly in females over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs, including FEMLYV, are contraindicated in females who are over 35 years of age and smoke [see Contraindications (4) and Warnings & Precautions (5) ]. WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS See full prescribing information for complete boxed warning. • Women over 35 years old who smoke should not use FEMLYV ( 4 ) • Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use ( 4 )

5 WARNINGS AND PRECAUTIONS • Thromboembolic Disorders and Other Vascular Problems: Discontinue FEMLYV if a thrombotic event occurs. Discontinue at least 4 weeks before through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery, in women who are not breastfeeding. Consider all cardiovascular risk factors before initiating in any female, particularly in the presence of multiple risk factors ( 5.1 ) • High blood pressure: Monitor blood pressure periodically and stop use if blood pressure rises significantly. Do not prescribe for women with uncontrolled hypertension or hypertension with vascular disease ( 5.2 ) • Migraine: Evaluate significant change in migraines and discontinue if new, recurrent, persistent, or severe migraines occur ( 5.3 ) • Hormonally-sensitive malignancy: Discontinue FEMLYV if a hormonally-sensitive malignancy is diagnosed ( 5.4 ). • Liver disease: Discontinue use if jaundice or acute or chronic disturbances of liver function occurs ( 5.5 ) • Glucose tolerance and hypertriglyceridemia: Monitor glucose in females with prediabetes and diabetes taking FEMLYV. Consider an alternative contraceptive method for women with uncontrolled dyslipidemia ( 5.7 ) • Gallbladder disease and cholestasis: Consider discontinuing FEMLYV in females with symptomatic gallbladder or cholestatic disease ( 5.8 ) • Uterine bleeding: Evaluate irregular bleeding or amenorrhea ( 5.9 ) 5.1 Thromboembolic Disorders and Other Vascular Problems Stop FEMLYV if an arterial or deep venous thrombotic event (VTE) occurs. Stop FEMLYV if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately. Discontinue FEMLYV during prolonged immobilization. If feasible, discontinue FEMLYV at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE. Start FEMLYV no earlier than 4 weeks after delivery in females who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the likelihood of ovulation increases after the third postpartum week. Before starting FEMLYV, evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. FEMLYV is contraindicated in females with a high risk of arterial or venous thrombotic/thromboembolic diseases [see Contraindications (4) ]. Cardiovascular and Cerebrovascular Events Use of CHCs increases the risk of cardiovascular events and cerebrovascular events, such as myocardial infarction and stroke. The risk is greater among females over age 40, smokers, and females with hypertension, dyslipidemia, diabetes, or obesity. The risk increases with age, particularly in females 35 years of age and older, and with the number of cigarettes smoked. In addition to cigarettes, use of other nicotine-containing products – including cigars, smokeless tobacco, hookah tobacco, e-cigarettes, and nicotine replacement therapy – may also increase the risk of serious cardiovascular events from CHC use. Venous Thromboembolism Use of CHCs also increases the risk of venous thromboembolic events (VTEs), such as deep vein thrombosis and pulmonary embolism. The rate of VTE in females using COCs has been estimated to be 3 to 9 cases per 10,000 woman-years and should be considered in the context of other female of reproductive potential subpopulations who are not taking CHCs [see Adverse Reactions (6.1) ] . Risk factors for VTEs include smoking, obesity, family history of VTE, and prolonged immobilization in addition to other factors that contraindicate use of CHCs [see Contraindications (4) ]. The presence of multiple risk factors for VTE may increase the risk synergistically. The risk of VTE is highest during the first year of CHC use and when restarting hormonal contraception after a break of four weeks or longer. The risk of VTE returns to baseline approximately 3 months after CHC use is discontinued. Postpartum Venous Thromboembolism The risk of VTE is increased during the first six weeks postpartum compared to the risk in nonpregnant, non-postpartum females. The risk is highest in the first three weeks postpartum but remains higher than baseline until at least six weeks postpartum. The presence of multiple risk factors for VTE may further increase the risk. Obstetric complications may extend the elevated risk up to 12 weeks postpartum. Figure 1 shows the risk of developing a VTE for females who are not pregnant and do not use COCs, for females who use COCs, for pregnant females, and for females in the postpartum period. To put the risk of developing a VTE into perspective: if 10,000 females who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these females will develop a VTE. Figure 1 Likelihood of Developing a VTE Figure 1 5.2 High Blood Pressure FEMLYV is contraindicated in females with uncontrolled hypertension or hypertension with vascular disease [see Contraindications (4) ] . For all females, including those with well-controlled hypertension, monitor blood pressure and stop FEMLYV if blood pressure rises significantly. An increase in blood pressure has been reported in females taking CHCs, and this increase is more likely in older women with extended duration of use. 5.3 Migraine FEMLYV is contraindicated in females who have migraines with aura [see Contraindications (4) ]. Discontinue FEMLYV in females using FEMLYV who develop new migraines that are recurrent, persistent, or severe. Discontinue FEMLYV if there is an increased frequency or severity of migraines during CHC use (which may be prodromal of a cerebrovascular event). Migraines with aura increase the risk for stroke. This stroke risk is further increased in females who have migraines with aura with use of CHCs. 5.4 Malignant Neoplasms Breast Cancer FEMLYV is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications (4) ] . Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use [see Postmarketing Experience (6.2) ] . Cervical Cancer A causal relationship between the use of CHCs and the development of cervical cancer and intraepithelial neoplasia has not been clearly established. In observational studies, the use of oral hormonal contraceptives in females for five years or more, compared to females who did not use oral hormonal contraceptives, was associated with an increased risk of cervical cancer and intraepithelial neoplasia. In these studies, the use of oral hormonal contraceptives in females for 10 years or more, compared to females who received oral hormonal contraceptives for 5-9 years, was associated with an increased risk of cervical cancer and intraepithelial neoplasia. Limitations in these epidemiologic studies include potential recall bias, differences in sexual behavior, and other factors such as establishing whether there were data on persistent high-risk Human Papilloma Virus (HPV) infection. 5.5 Liver Disease Elevated Liver Enzymes FEMLYV is contraindicated in females with acute hepatitis or severe (decompensated) cirrhosis of the liver [see Contraindications (4) ] . Withhold or permanently discontinue FEMLYV for persistent or significant elevation of liver enzymes. FEMLYV can cause elevated liver enzymes. Discontinue FEMLYV if jaundice develops. Liver Tumors FEMLYV is contraindicated in females with hepatic adenomas and malignant liver tumors [see Contraindications (4) ] . CHCs increase the risk of hepatic tumors, particularly, hepatic adenomas. Rupture of hepatic adenomas may cause death from abdominal hemorrhage. 5.6 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment CHCs, such as FEMLYV, are contraindicated for use with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir (with or without dasabuvir) [see Contraindications (4) ]. Discontinue FEMLYV prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir (with or without dasabuvir). FEMLYV can be restarted approximately 2 weeks following completion of treatment with this hepatitis C combination drug regimen. During clinical trials with the above-mentioned Hepatitis C combination drug regimen, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in females using ethinyl estradiol (EE)-containing drugs, such as CHCs. 5.7 Glucose Tolerance and Hypertriglyceridemia Glucose Tolerance Carefully monitor females with prediabetes and diabetes who are using FEMLYV. FEMLYV may decrease glucose tolerance. Hypertriglyceridemia Consider alternative contraception for females with hypertriglyceridemia. Females with hypertriglyceridemia, or a family history thereof, may have an increase in serum triglyceride concentrations when using FEMLYV, which may increase the risk of pancreatitis. 5.8 Gallbladder Disease and Cholestasis Consider discontinuing FEMLYV in females with symptomatic gallbladder disease or cholestatic disease. Studies suggest an increased risk of developing gallbladder disease among CHC users. Use of CHCs may also worsen existing gallbladder disease. A past history of CHC-related cholestasis predicts an increased risk with subsequent CHC use. Women with a history of pregnancy-related cholestasis may be at an increased risk for CHC-related cholestasis. 5.9 Bleeding Irregularities and Amenorrhea Unscheduled Bleeding and Spotting Females using FEMLYV may experience unscheduled (breakthrough or intracyclic) bleeding and spotting, especially during the first three months of use. Bleeding irregularities may resolve over time or by changing to a different contraceptive product. If bleeding persists or occurs after previously regular cycles, evaluate for causes such as pregnancy or malignancy. Based on patient diaries from a clinical trial evaluating the safety and efficacy of a 24-day regimen of norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablets, 24-35% of women experienced unscheduled bleeding per cycle. A total of 10 subjects out of 743 (1.3%) discontinued due to bleeding or spotting [see Adverse Reactions (6.1) ]. Amenorrhea and Oligomenorrhea If scheduled (withdrawal) bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. Females who use FEMLVY may experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant. In the clinical trial with a 24-day regimen of norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablets, 22 to 36% of the women using norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablets experienced amenorrhea in at least one of 6 cycles of use [see Adverse Reactions (6.1) ] . After discontinuation of FEMLYV, amenorrhea or oligomenorrhea may occur, especially if these conditions were pre-existent. 5.10 Depression Monitor females with a history of depression and discontinue FEMLYV if depression recurs to a serious degree. Data on the association of COCs with onset of depression or exacerbation of existing depression are limited. 5.11 Effect on Binding Globulins Increase the dosage of thyroid hormone replacement therapy as needed in females taking FEMLYV [see Clinical Pharmacology (12.2) ] . The estrogen component of FEMLYV may increase the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin. 5.12 Hereditary Angioedema Avoid FEMLYV in females with hereditary angioedema. Exogenous estrogens may induce or exacerbate symptoms of hereditary angioedema. 5.13 Chloasma Avoid FEMLYV in females with a history of chloasma gravidarum or increased sensitivity to sun and/or ultraviolet radiation exposure. Chloasma may occur with FEMLYV, especially in females with a history of chloasma gravidarum.

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 (5.5) ] • 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