norethindrone acetate and ethinyl estradiol

RECENT MAJOR CHANGES SECTION Warning and Precautions ( 5.11 ) 04/2022

INDICATIONS AND USAGE Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets are indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception. Oral contraceptives are highly effective. Table I lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates. TABLE I: LOWEST EXPECTED AND TYPICAL FAILURE RATES DURING THE FIRST YEAR OF CONTINUOUS USE OF A METHOD Adapted from RA Hatcher et al, Reference 7. % of Women Experiencing an Unintended Pregnancy in the First Year of Continuous Use Method Lowest Expected The authors’ best guess of the percentage of women expected to experience an accidental pregnancy among couples who initiate a method (not necessarily for the first time) and who use it consistently and correctly during the first year if they do not stop for any other reason. Typical This term represents “typical” couples who initiate use of a method (not necessarily for the first time), who experience an accidental pregnancy during the first year if they do not stop use for any other reason. (No contraception) (85) (85) Oral contraceptives 3 Combined 0.1 N/A N/A - Data not available. progestin only 0.5 N/A Diaphragm with spermicidal cream or jelly 6 20 Spermicides alone (foam, creams, gels, vaginal suppositories, and vaginal film) 6 26 Vaginal Sponge nulliparous 9 20 parous 20 40 Implant 0.05 0.05 Injection: depot medroxyprogesterone acetate 0.3 0.3 IUD progesterone T 1.5 2.0 copper T 380A 0.6 0.8 LNg 20 0.1 0.1 Condom without spermicides female 5 21 male 3 14 Cervical Cap with spermicidal cream or jelly nulliparous 9 20 parous 26 40 Periodic abstinence (all methods) 1- 9 25 Withdrawal 4 19 Female sterilization 0.5 0.5 Male sterilization 0.10 0.15

2 DOSAGE AND ADMINISTRATION One tablet daily chewed and swallowed taken at the same time of day. Follow with 8 ounces of water ( 2.1 ) Take one table by mouth at the same time every day for 28 days ( 2.1 ) Take tablets in the order directed on the blister pack (2.1 ) Tablets may be administered without regard to meals ( 12.3 ) 2.1 How to Take Norethindrone Acetate and Ethinyl Estradiol Tablets and Ferrous Fumarate Tablets To achieve maximum contraceptive effectiveness, norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets must be taken exactly as directed. Instruct patients to take one tablet by mouth at the same time every day. The Tablet may be chewed and swallowed or swallowed as whole. The patient should drink a full glass (8 ounces) of water immediately after the white tablets are chewed or swallowed whole. Tablets must be taken in the order directed on the blister pack. Tablets should not be skipped or taken at intervals exceeding 24 hours. For patient instructions for missed tablets, [see FDA-approved patient labeling] . Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets may be administered without regard to meals [see Clinical Pharmacology ( 12.3 )] . 2.2 How to Start Norethindrone Acetate and Ethinyl Estradiol Tablets and Ferrous Fumarate Tablets Instruct the patient to begin taking norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets 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). Day 1 Start During the first cycle of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets use, instruct the patient to take one white norethindrone acetate and ethinyl estradiol tablet daily, beginning on Day one (1 ) of her menstrual cycle (the first day of menstruation is Day one). She should take one white norethindrone acetate and ethinyl estradiol tablet daily for 24 consecutive days, followed by one brown ferrous fumarate tablet daily on days 25 through 28. Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets should be taken in the order directed on the package at the same time each day. Instruct the patient to use a non-hormonal contraceptive as back-up during the first 7 days if she starts taking norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets on a day other than the first day of her menstrual cycle. The possibility of ovulation and conception prior to initiation of medication should be considered. Sunday Start During the first cycle of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets use, instruct the patient to take one white norethindrone acetate and ethinyl estradiol tablet daily, beginning on the first Sunday after the onset of her menstrual period. She should take one white norethindrone acetate and ethinyl estradiol tablet daily for 24 consecutive days, followed by one brown ferrous fumarate tablet daily on days 25 through 28. Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets should be taken in the order directed on the package at the same time each day. Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets should not be considered effective as a contraceptive until after the first 7 consecutive days of product administration. Instruct the patient to use a non-hormonal contraceptive as back-up during the first 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered. The patient should begin her next and all subsequent 28-day regimens of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets on the same day of the week that she began her first regimen, following the same schedule. She should begin taking her white norethindrone acetate and ethinyl estradiol tablets on the next day after ingestion of …

3 DOSAGE FORMS AND STRENGTHS Norethindrone Acetate and Ethinyl Estradiol Tablets and Ferrous Fumarate Tablets, 1 mg/20 mcg is available in blister packs. Each blister pack contains 28 tablets in the following order: 24 white, round, (active) chewable tablets imprinted with “XI” on one side and “T4” on the other side, and each containing 1 mg norethindrone acetate and 20 mcg ethinyl estradiol. 4 brown, round (non-hormonal placebo) tablets imprinted with “XI” on one side and “12” on the other side, and each containing 75 mg ferrous fumarate. The ferrous fumarate tablets do not serve any therapeutic purpose. Norethindrone Acetate and Ethinyl Estradiol Tablets and Ferrous Fumarate Tablets, 1 mg/20 mcg consists of 28 tablets in the following order ( 3 ): 24 white chewable tablets (active), each containing 1 mg norethindrone acetate and 20 mcg ethinyl estradiol 4 brown tablets (non-hormonal placebo), each containing 75 mg ferrous fumarate, which do not serve any therapeutic purpose

4 CONTRAINDICATIONS Norethindrone Acetate and Ethinyl Estradiol Tablets and Ferrous Fumarate Tablets, 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 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 [see Warnings and Precautions ( 5.4 )] Have diabetes mellitus with vascular disease [see Warnings and Precautions ( 5.5 )] Have headaches with focal neurological symptoms or have migraine headaches with aura All women over age 35 with migraine headache [see Warnings and Precautions ( 5.6 )] Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions ( 5.2 )] Undiagnosed abnormal uterine bleeding [see Warnings and Precautions ( 5.7 )] Pregnancy, because there is no reason to use COCs during pregnancy [see Warnings and Precautions ( 5.8 ) 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 )] 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) Breast cancer or other estrogen- or progestin-sensitive cancer ( 4 ) Liver tumors or liver disease ( 4 ) Undiagnosed abnormal uterine bleeding ( 4 ) Pregnancy ( 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 )] Adverse reactions commonly reported by COC users are: Irregular uterine bleeding Nausea Breast Tenderness Headache The most common adverse reactions in clinical trials (greater than or equal to 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 Xiromed at 1-844-XIROMED (1-844-947-6633) 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 data presented in Section 6.1 are from a clinical trial conducted with a 24-day regimen of norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablets. Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets is bioequivalent to these norethindrone acetate/ethinyl estradiol 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 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. 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: hypersensi …

7 DRUG INTERACTIONS Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations. No drug-drug interaction studies were conducted with norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets. 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 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets with HCV drug combinations containing ombitasvir/ paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [ see Warnings and Precautions ( 5.3) ]. 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.

8 USE IN SPECIFIC POPULATIONS Nursing mothers: Not recommended; can decrease milk production ( 8.3 ) 8.1 Pregnancy Risk Summary There is no use for contraception in pregnancy; therefore, norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets should be discontinued 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 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets and any potential adverse effects on the breast-fed child from norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets or from the underlying maternal condition. 8.3 Nursing Mothers When possible, advise the nursing mother to use other forms of contraception 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 acetate and ethinyl estradiol tablets and ferrous fumarate tablets have been established in women of reproductive age. Efficacy is expected to be the same in postpubertal 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 acetate and ethinyl estradiol tablets and ferrous fumarate tablets has not been studied in postmenopausal women and is not indicated in this population. 8.6 Renal Impairment The pharmacokinetics of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets has not been studied in subjects with renal impairment. 8.7 Hepatic Impairment The pharmacokinetics of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets has not been studied in subjects 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 )] . 8.8 Body Mass Index The safety and efficacy of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets in women with a body mass index (BMI) greater than 35 kg/m 2 has not been evaluated [see Clinical Studies ( 14 )] .

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 Acetate and Ethinyl Estradiol Tablets and Ferrous Fumarate Tablets, 1 mg/20 mcg provides an oral contraceptive regimen consisting of 24 white active chewable tablets that contain the active ingredients, followed by 4 brown non-hormonal placebo tablets as specified below: 24 white, round tablets each containing 1 mg norethindrone acetate and 20 mcg ethinyl estradiol. 4 brown, round tablets each containing 75 mg ferrous fumarate Each white active chewable tablet also contains the following inactive ingredients: lactose monohydrate, mannitol, microcrystalline cellulose, povidone, sodium starch glycolate, peppermint flavor, magnesium stearate, alpha tocopherol, and sucralose. Each brown placebo tablet contains ferrous fumarate, lactose monohydrate, mannitol, povidone, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, sucralose and peppermint flavor. The ferrous fumarate tablets do not serve any therapeutic purpose. 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. 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.

OVERDOSAGE Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea, and withdrawal bleeding may occur in females. NON-CONTRACEPTIVE HEALTH BENEFITS The following non-contraceptive health benefits related to the use of oral contraceptives are supported by epidemiological studies which largely utilized oral contraceptive formulations containing estrogen doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg of mestranol (76-81). Effects on menses: • Increased menstrual cycle regularity • Decreased blood loss and decreased incidence of iron deficiency anemia • Decreased incidence of dysmenorrhea Effects related to inhibition of ovulation: • Decreased incidence of functional ovarian cysts • Decreased incidence of ectopic pregnancies Effects from long-term use: • Decreased incidence of fibroadenomas and fibrocystic disease of the breast • Decreased incidence of acute pelvic inflammatory disease • Decreased incidence of endometrial cancer • Decreased incidence of ovarian cancer

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Norethindrone Acetate and Ethinyl Estradiol Tablets and Ferrous Fumarate Tablets, 1 mg/20 mcg is available in blister cards (dispensers) containing 28 tablets: NDC 70700-101-85, Carton containing 3 blister cards. Each blister card contains 28 tablets in the following order: 24 white, round (active) tablets imprinted with “XI” on one side and “T4” on the other side, and each containing 1 mg norethindrone acetate and 20 mcg ethinyl estradiol. 4 brown, round (non-hormonal placebo) tablets imprinted with “XI” on one side and “12” on the other side, and each containing 75 mg ferrous fumarate. The ferrous fumarate tablets do not serve any therapeutic purpose. 16.2 Storage Conditions Store at 20o to 25o C (68o to 77oF); excursions permitted to 15o to 30oC (59 to 86o F) [see USP Controlled Room Temperature]. Keep this drug and all drugs out of the reach of children.