Norethindrone Acetate/Ethinyl Estradiol

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 )

Orally disintegrating tablets:

• 1 mg norethindrone acetate and 0.02 mg ethinyl estradiol, green, round ODTs, imprinted with “M” on one side and “312” on the other side
• White, round, inert ODTs imprinted with “M” on one side and “313” on the other side Orally disintegrating tablets ( 3 ):
• 24 ODTs each containing 1 mg norethindrone acetate and 0.02 mg ethinyl estradiol
• 4 inert ODTs

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 )

• 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) ] . […]

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.

• Pregnancy: Discontinue if pregnancy occurs ( 8.1 )
• Lactation: Advise postpartum females that FEMLYV can decrease milk production ( 8.2 )

8.1 Pregnancy Risk Summary Discontinue FEMLYV if pregnancy occurs, because there is no reason to use hormonal contraceptives during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to COCs before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 percent and 15 to 20 percent, respectively.

8.2 Lactation Risk Summary Contraceptive hormones and/or metabolites are present in human milk. COCs can reduce milk production in breast-feeding females. This reduction can occur at any time but is less likely to occur once breast-feeding is well-established. When possible, advise the nursing female to use other methods of contraception until she discontinues breast-feeding [see Dosage and Administration (2.2) ]. The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for FEMLYV and any potential adverse effects on the breast-fed child from FEMLYV or from the underlying maternal condition.

8.4 Pediatric Use Safety and efficacy of FEMLYV have been established in females of reproductive potential. Efficacy is expected to be the same in postmenarcheal adolescents younger than 17 years as for users 17 years and older. FEMLYV is not indicated before menarche.

8.7 Hepatic Impairment FEMLYV is contraindicated in females with hepatic impairment [see Contraindications (4) , Warnings and Precautions (5.5 )]. Steroid hormones may be poorly metabolized in patients with hepatic impairment. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded [see Contraindications (4) and Warnings and Precautions (5.5) ].

8.8 Body Mass Index The safety and effectiveness of FEMLYV in females with a BMI greater than 35 kg/m 2 have not been fully evaluated [see Clinical Studies (14) ].

CHCs lower the risk of becoming pregnant primarily by suppressing ovulation.