Norethindrone Acetate and Ethinyl Estradiol and Ferrous Fumarate

1 INDICATIONS AND USAGE Norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules are indicated for use by females of reproductive age to prevent pregnancy [see Clinical Studies ( 14 )] . The efficacy of norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules in women with a body mass index (BMI) of more than 35 kg/m 2 has not been evaluated. • Norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules are a combination of norethindrone acetate, a progestin, and ethinyl estradiol, an estrogen, indicated for use by females of reproductive potential to prevent pregnancy ( 1 ) • The efficacy of norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules in females of reproductive potential with a body mass index (BMI) of > 35 kg/m 2 has not been evaluated ( 1 , 8.8 )

2 DOSAGE AND ADMINISTRATION • Take one capsule by mouth at the same time every day ( 2.1 ) • Take capsules in the order directed on the blister pack ( 2.1 ) • Capsules may be administered without regard to meals ( 2.1 ) 2.1 How to Take Norethindrone Acetate and Ethinyl Estradiol Capsules and Ferrous Fumarate Capsules To achieve maximum contraceptive effectiveness, norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules must be taken exactly as directed. Instruct patients to take one capsule by mouth at the same time every day. Capsules must be taken in the order directed on the blister pack. Capsules should not be skipped or taken at intervals exceeding 24 hours. Norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules may be administered without regard to meals [see Clinical Pharmacology ( 12.3 )] . 2.2 How to Start Norethindrone Acetate and Ethinyl Estradiol Capsules and Ferrous Fumarate Capsules Instruct the patient to begin taking norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules 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 capsules and ferrous fumarate capsules use, instruct the patient to take one pink capsule daily, beginning on Day one (1) of her menstrual cycle (the first day of menstruation is Day one). She should take one pink capsule daily for 24 consecutive days, followed by one maroon capsule daily on days 25 through 28. Norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules 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 capsules and ferrous fumarate capsules 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 capsules and ferrous fumarate capsules use, instruct the patient to take one pink capsule daily, beginning on the first Sunday after the onset of her menstrual period. She should take one pink capsule daily for 24 consecutive days, followed by one maroon capsule daily on days 25 through 28. Norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules should be taken in the order directed on the package at the same time each day. Norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules 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 capsules and ferrous fumarate capsules on the same day of the week that she began her first regimen, following the same schedule. She should begin taking her pink capsules on the next day after ingestion of the last maroon capsule, regardless of whether or not a menstrual period has occurred or is still in progress. Anytime a subsequent cycle of norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules are started later than the day following administration of the last maroon capsule, the patient should use another method of contraception until she has taken a pink capsule daily for 7 consecutive days. For postpartum women who do not breastfeed or after a second trimester abortion, start norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules no ea…

5 WARNINGS AND PRECAUTIONS • Vascular risks: Stop norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules if a thrombotic event occurs. Stop 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 ( 5.1 ) • Liver disease: Discontinue if jaundice occurs ( 5.2 ) • High blood pressure: Do not prescribe norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules for women with uncontrolled hypertension or hypertension with vascular disease ( 5.4 ) • Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules. Consider an alternative contraceptive method for women with uncontrolled dyslipidemia ( 5.6 ) • Headache: Evaluate significant change in headaches and discontinue norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules if indicated ( 5.7 ) • Uterine bleeding: Evaluate irregular bleeding or amenorrhea ( 5.8 ) 5.1 Thromboembolic Disorders and Other Vascular Problems Stop norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules if an arterial or deep venous thrombotic event (VTE) occurs. Stop norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. If feasible, stop norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE. Start norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum VTE decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week. The use of COCs increases the risk of VTE. However, pregnancy increases the risk of VTE as much or more than the use of COCs. The risk of VTE in women using COCs is 3 to 9 per 10,000 woman-years. The risk of VTE is highest during the first year of use of a COC. The risk of thromboembolic disease due to oral contraceptives gradually disappears after COC use is discontinued. Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest in older (> 35 years of age), hypertensive women who also smoke. COCs also increase the risk for stroke in women with underlying risk factors. Use COCs with caution in women with cardiovascular disease risk factors. 5.2 Liver Disease Impaired Liver Function Do not use norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules in women with acute viral hepatitis or severe (decompensated) cirrhosis of liver [see Contraindications ( 4 )] . 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. Discontinue norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules if jaundice develops. Liver Tumors Norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules are contraindicated in women with benign and malignant liver tumors [see Contraindications ( 4 )]. Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases per 100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage. Studies have shown an increased risk of developi…

4 CONTRAINDICATIONS Norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules 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 ( 5.6 )] • Have headaches with focal neurological symptoms or have migraine headaches with aura • 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 )] • 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 ) • Liver tumors or liver disease ( 4 ) • Undiagnosed abnormal uterine bleeding ( 4 ) • Breast cancer ( 4 ) • Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir ( 4 )

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. • 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 estrogen and progestin have been noted in some cases of co-administration with HIV/HCV protease inhibitors or with 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 capsules and ferrous fumarate capsules 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.

8.1 Pregnancy Risk Summary There is no use for contraception in pregnancy; therefore, norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules 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.

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 (≥ 2%) are 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 Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 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 capsules and ferrous fumarate capsules are bioequivalent to these norethindrone acetate/ethinyl estradiol tablets. Common Adverse Reactions (≥ 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%). 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 to 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 to 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 to 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. 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 (general…