FEMLYV Norethindrone Acetate/Ethinyl Estradiol Kit, 1 pouch — NDC 72495-601-28 (Billing 72495-0601-28)

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 )

5.1Thromboembolic 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.… [Excerpted — this section continues on DailyMed.]

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 .

6.1Clinical 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%).

6.2Postmarketing 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 al… [Excerpted — this section continues on DailyMed.]

7 DRUG INTERACTIONS • 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 )

7.1Effects 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.

7.2Effects 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.

7.3Concomitant 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) ] .

7.4Interference 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.