Norethindrone and ethinyl estradiol and ferrous fumarate

Warnings and Precautions ( 5.11 ) 11/2021

1. INDICATIONS AND USAGE Norethindrone and ethinyl estradiol tablets (chewable) 0.4 mg/0.035 mg and ferrous fumarate tablets are indicated for use by females of reproductive potential to prevent pregnancy. Norethindrone and ethinyl estradiol tablets (chewable) 0.4 mg/0.035 mg and ferrous fumarate tablets are progestin/estrogen COC indicated for use by females of reproductive potential to prevent pregnancy. ( 1 )

2. DOSAGE AND ADMINISTRATION Take one tablet by mouth at the same time every day. Norethindrone and ethinyl estradiol tablets (chewable) may be chewed or swallowed. ( 2.1 ) Take tablets in the order directed on the blister pack. ( 2.1 ) 2.1 How to Start Norethindrone and Ethinyl Estradiol Tablets (chewable) 0.4 mg/0.035 mg and Ferrous Fumarate Tablets Norethindrone and ethinyl estradiol tablets (chewable) 0.4 mg/0.035 mg and ferrous fumarate tablets are dispensed in a blister card [see How Supplied/Storage and Handling (16) ] . Norethindrone and ethinyl estradiol tablets (chewable) 0.4 mg/0.035 mg and ferrous fumarate 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 Norethindrone and Ethinyl Estradiol Tablets (chewable) 0.4 mg/0.035 mg and Ferrous Fumarate Tablets The Norethindrone and ethinyl estradiol tablets, USP may be swallowed whole or chewed. If Norethindrone and ethinyl estradiol tablets, USP are chewed, the patient should drink a full glass (8 ounces) of liquid immediately after swallowing. Table 1: Instructions for Administration of Norethindrone and Ethinyl Estradiol Tablets (chewable) 0.4 mg/0.035 mg and Ferrous Fumarate Tablets Starting CHCs 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: Norethindrone and ethinyl estradiol tablets (chewable) 0.4 mg/0.035 mg active tablets are white to off white (Day 1 to Day 21). Ferrous fumarate tablets placebo tablets are brown (Day 22 to Day 28). Day 1 Start: Take first white to off white active tablet on the first day of menses. Take subsequent white to off white active tablets once daily at the same time each day for a total of 21 days. Take one brown placebo 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 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 norethindrone and ethinyl estradiol tablets (chewable) 0.4 mg/0.035 mg and ferrous fumarate tablets. Take subsequent white to off white active tablets once daily at the same time each day for a total of 21 days. Take one brown placebo 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 norethindrone and ethinyl estradiol tablets (chewable) 0.4 mg/0.035 mg and ferrous fumarate tablets from another hormonal contraceptive Start on the same day that a new pack of the previous hormonal contraceptive would have started. Switching from another contraceptive method to norethindrone and ethinyl estradiol tablets (chewable) 0.4 mg/0.035 mg and ferrous fumarate tablets Start norethindrone and ethinyl estradiol tablets (chewable) 0.4 mg/0.035 mg and ferrous fumarate 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 …

3 DOSAGE FORMS AND STRENGTHS Norethindrone and Ethinyl Estradiol Tablets, USP (Chewable) and Ferrous Fumarate Tablets (Chewable) are available in cartons of 3 blister packs. Each blister pack contains 28 tablets in the following order: • 21 yellow, round, uncoated flat (active) tablets debossed with “226” on one side of the tablet and plain on the other side and each containing 0.4 mg norethindrone and 0.035 mg ethinyl estradiol. • 7 brown, round (non-hormonal placebo) tablets debossed with “291” on one side of the tablet and plain on the other side and each containing 75 mg ferrous fumarate. The ferrous fumarate tablets do not serve any therapeutic purpose. Norethindrone and ethinyl estradiol tablets, USP (chewable) and ferrous fumarate tablets (chewable) consist of 28 tablets in the following order ( 3 ): • 21 yellow tablets (active), each containing 0.4 mg norethindrone and 0.035 mg ethinyl estradiol • 7 brown tablets (non-hormonal placebo), each containing 75 mg ferrous fumarate. The ferrous fumarate tablets do not serve any therapeutic purpose.

4 CONTRAINDICATIONS Norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) are 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 have 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) ] • Hypersensitivity to any of the components. • 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 )

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 (5.2) ] The following adverse reactions are commonly reported by COC users. Because these reactions are voluntarily reported by from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: • Irregular uterine bleeding • Nausea • Breast tenderness • Headache The most common adverse reactions were: irregular uterine bleeding, nausea, breast tenderness, and headache. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.2 Post Marketing 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 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 - 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 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. Figure 1. Risk of Breast Cancer with Combined Oral Contraceptive Use

7 DRUG INTERACTIONS Consult the labeling of concurrently used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. • 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 method 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 and potentially diminishing the efficacy 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 hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St. John’s wort. Interactions between hormonal 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. Colesevelam: Colesevelam, a bile acid sequestrant, given together with a COC, has been shown to significantly decrease the AUC of 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, 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., 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 [see Warnings and Precautions (5.12) ]. 7.3 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) with HCV drug combinations containing ombitasvir/ paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions (5.3) ] …

8. USE IN SPECIFIC POPULATIONS Nursing mothers: Advise use of another contraceptive method. Norethindrone and ethinyl estradiol tablets (chewable) 0.4 mg/0.035 mg and ferrous fumarate tablets can decrease milk production. ( 8.3 ) 8.1 Pregnancy There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy. Do not use COCs to induce withdrawal bleeding as a test for pregnancy. Do not use COCs during pregnancy to treat threatened or habitual abortion. 8.3 Nursing Mothers Advise the nursing mother to use other forms of contraception, when possible, until she has weaned her child. COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk. 8.4 Pediatric Use Safety and efficacy of norethindrone and ethinyl estradiol tablets (chewable) 0.4 mg/0.035 mg and ferrous fumarate tablets have been established in women of reproductive age. Efficacy is expected to be the same in post-pubertal adolescents under the age of 18 years as for users 18 years and older. Use of this product before menarche is not indicated. 8.5 Geriatric Use Norethindrone and ethinyl estradiol tablets (chewable) 0.4 mg/0.035 mg and ferrous fumarate tablets have not been studied in postmenopausal women and is not indicated in this population. 8.6 Hepatic Impairment The pharmacokinetics of norethindrone and ethinyl estradiol tablets (chewable) 0.4 mg/0.035 mg and ferrous fumarate tablets have not been studied in women with hepatic impairment. However, 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 (5.2) ]. 8.7 Renal Impairment The pharmacokinetics of norethindrone and ethinyl estradiol tablets (chewable) 0.4 mg/0.035 mg and ferrous fumarate tablets have not been studied in women with renal impairment.

12.1 Mechanism of Action COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation.

11 DESCRIPTION Norethindrone and ethinyl estradiol tablets, USP (chewable) and ferrous fumarate tablets (chewable) are a combinational contraceptive containing the progestational compound norethindrone and the estrogenic compound ethinyl estradiol. The packaging includes 21 yellow tablets composed of norethindrone and ethinyl estradiol followed by 7 brown ferrous fumarate (placebo) tablets. The chemical name for norethindrone is 17-hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one and for ethinyl estradiol the chemical name is 19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol. The structural formulas are: The active yellow norethindrone and ethinyl estradiol tablets (chewable) contain 0.4 mg norethindrone and 0.035 mg ethinyl estradiol, and the following inactive ingredients: colloidal silicon dioxide, dibasic calcium phosphate, D & C Yellow No.10 Aluminium Lake, lactose anhydrous, lactose monohydrate, magnesium stearate, maltodextrin, povidone K-30, sodium starch glycolate, spearmint flavor and sucralose. The brown tablets contain ferrous fumarate, colloidal silicon dioxide, crosscarmellose sodium, lactose monohydrate, magnesium stereate, microcrystalline cellulose and povidone K-90.The ferrous fumarate tablets do not serve any therapeutic purpose. Ferrous fumarate tablets are not USP for dissolution and assay. USP Dissolution Test is pending. Norethindrone and Ethinyl Estradiol Structural Formulas

10. OVERDOSAGE There have been no reports of serious ill effects from overdosage of oral contraceptives, including ingestion by children. Overdosage may cause withdrawal bleeding in females and nausea.

16. HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Norethindrone and ethinyl estradiol tablets, USP (chewable) 0.4 mg/0.035 mg and ferrous fumarate tablets are available in a 28-day regimen of blister pack (NDC 79929-005-05) as follows: 21 active tablets: white to off-white, round, flat faced beveled edge, uncoated tablets debossed with "EJ1" on one side and plain on other side (0.4 mg norethindrone USP and 0.035 mg ethinyl estradiol USP). 7 inert tablets: brown, round, flat faced beveled edge, uncoated tablets debossed with 'EJ2' on one side and plain on other side; tablets may have mottled appearance on either of the surface. The blister packs are available in box of 3 . 16.2 Storage Conditions Store at 20 o C to 25o C (68 o F to 77o F); excursions permitted to 15 o C to 30o C (59 o F to 86o F) [see USP Controlled Room Temperature]. Protect from light. Keep out of the reach of children.

16.1 How Supplied Norethindrone and ethinyl estradiol tablets, USP (chewable) 0.4 mg/0.035 mg and ferrous fumarate tablets are available in a 28-day regimen of blister pack (NDC 79929-005-05) as follows: 21 active tablets: white to off-white, round, flat faced beveled edge, uncoated tablets debossed with "EJ1" on one side and plain on other side (0.4 mg norethindrone USP and 0.035 mg ethinyl estradiol USP). 7 inert tablets: brown, round, flat faced beveled edge, uncoated tablets debossed with 'EJ2' on one side and plain on other side; tablets may have mottled appearance on either of the surface. The blister packs are available in box of 3 .