Norethindrone and Ethinyl Estradiol and Ferrous Fumarate

INDICATIONS AND USAGE Galbriela (norethindrone and ethinyl estradiol chewable tablet and ferrous fumarate chewable tablet) is indicated for use by women to prevent pregnancy. The efficacy of Galbriela in women with a body mass index (BMI) of > 35 kg/m 2 has not been evaluated. Galbriela is a combination of norethindrone, a progestin, and ethinyl estradiol, an estrogen, indicated for use by females of reproductive potential to prevent pregnancy. ( 1 ) The efficacy in females of reproductive potential with a body mass index (BMI) of > 35 kg/m 2 has not been evaluated. ( 1 , 8.8 )

DOSAGE AND ADMINISTRATION • Take one tablet by mouth at the same time every day. Tablets 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) and Ferrous Fumarate Tablets (chewable) Norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) are dispensed in a blister pack [see How Supplied/Storage and Handling (16) ] . Norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) 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) and Ferrous Fumarate Tablets (chewable) Norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) (yellow active tablets and brown placebo tablets) may be swallowed whole or chewed and swallowed. If the tablet is 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) and Ferrous Fumarate Tablets (chewable) 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 active tablets (chewable) are yellow (Day 1 to Day 21). • Ferrous fumarate (chewable) placebo tablets are brown (Day 22 to Day 28). Day 1 Start: • Take first yellow active tablet on the first day of menses. • Take subsequent yellow 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) and ferrous fumarate tablets (chewable). • Take subsequent yellow 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) and ferrous fumarate tablets (chewable) 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) and ferrous fumarate tablets (chewable) Start norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable): • 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 day of removal Complete instructions to facilitate patient counseling on proper tablet usage are located in the FDA-Approved Patient Labeling. Starting Norethindrone and Ethinyl Estradiol Tablets (chewable) and Ferrous Fumarate Tablets (chewable) after Abortion or Miscarriage First-trimester • After a first-trimester abortion or miscarriage, norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) may be started immediately. An additional method of contraception is not needed if norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) are started within 5 days after termination of the pregnancy. • If norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) are not started within 5 days after termination of the pregnancy, the patient should use additional non-hormonal contraception (such as condoms and spermicide) for the first seven days of her first cycle pack of norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable). Second-trimester • Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable), following the instructions in Table 1 for Day 1 or Sunday start, as desired. If using Sunday start, 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) and ferrous fumarate tablets (chewable). [See Contraindications (4) , Warnings and Precautions (5.1) , and FDA-Approved Patient Labeling .] Starting Norethindrone and Ethinyl Estradiol Tablets (chewable) and Ferrous Fumarate Tablets (chewable) after Childbirth • Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) following the instructions in Table 1 for women not currently using hormonal contraception. • If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable). [See Contraindications (4) , Warnings and Precautions (5.1) , Use in Specific Populations (8.1 and 8.3) , and FDA-Approved Patient Labeling ]. 2.3 Missed Tablets Table 2: Instructions for Missed Norethindrone and Ethinyl Estradiol Tablets (chewable) and Ferrous Fumarate Tablets (chewable) • If one yellow active tablet is missed in Weeks 1, 2, or 3 Take the tablet as soon as possible. Continue taking one tablet a day until the pack is finished. • If two yellow active tablets are missed in Week 1 or Week 2 Take the two missed tablets as soon as possible and the next two active tablets the next day. Continue taking one tablet a day until the pack is finished. Additional non-hormonal contraception (such as condoms and spermicide) should be used as back-up if the patient has sex within 7 days after missing tablets. • If two yellow active tablets are missed in Week 3 or three or more yellow active tablets are missed in a row in Weeks 1, 2, or 3 Day 1 start : Throw out the rest of the pack and start a new pack that same day. Sunday start : Continue taking one tablet a day until Sunday, then throw out the rest of the pack and start a new pack that same day. Additional non-hormonal contraception (such as condoms and spermicide) should be used as back-up if the patient has sex within 7 days after missing tablets. 2.4 Advice in Case of Gastrointestinal Disturbances In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken. If vomiting or diarrhea occurs within 3 to 4 hours after taking an active tablet, handle this as a missed tabl

WARNINGS AND PRECAUTIONS Vascular risks: Stop norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) if a thrombotic event occurs. Stop at least 4 weeks before and 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. ( 5.3 ) High blood pressure: Do not prescribe for women with uncontrolled hypertension or hypertension with vascular disease. ( 5.5 ) Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable). Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. ( 5.7 ) Headache: Evaluate significant change in headaches and discontinue if indicated. ( 5.8 ) Uterine bleeding: Evaluate irregular bleeding or amenorrhea. ( 5.9 ) 5.1 Thrombotic and Other Vascular Events Stop norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) if an arterial or deep venous thrombotic (VTE) event occurs. Although the use of COCs increases the risk of venous thromboembolism, pregnancy increases the risk of venous thromboembolism as much or more than the use of COCs. The risk of venous thromboembolism in women using COCs is 3 to 9 per 10,000 woman-years. The excess risk is highest during the first year of use of a COC. 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. The risk of thromboembolic disease due to oral contraceptives gradually disappears after COC use is discontinued. If feasible, stop norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism. Start norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week. 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 among older (>35 years of age), hypertensive women who also smoke. COCs also increase the risk for stroke in women with other underlying risk factors. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors. Stop norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. 5.2 Malignant Neoplasms Breast Cancer Norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) are 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 Adverse Reactions (6.2) ]. Cervical Cancer Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which these findings may be due to differences in sexual behavior and other factors. 5.3 Liver Disease Discontinue norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) if jaundice develops. Steroid hormones may be poorly metabolized in patients with impaired liver function. 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. Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users. Oral contraceptive-related cholestasis may occur in women with a history of pregnancy-related cholestasis. Women with a history of COC-related cholestasis may have the condition recur with subsequent COC use. 5.4 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment During clinical trials with Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications, such as COCs. Discontinue norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4) ]. Norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen. 5.5 High Blood Pressure For women with well-controlled hypertension, monitor blood pressure and stop norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) if blood pressure rises significantly. Women with uncontrolled hypertension or hypertension with vascular disease should not use COCs. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin. 5.6 Gallbladder Disease Studies suggest the relative risk of developing gallbladder disease may be increased among COC users. 5.7 Carbohydrate and Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who are taking norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable). COCs may decrease glucose tolerance in a dose-related fashion. Consider alternative contraception for women with uncontrolled dyslipidemia. A small proportion of women will have adverse lipid changes while on COCs. Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs. 5.8 Headache If a woman taking norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) if indicated. An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC. 5.9 Bleeding Irregularities Unscheduled (breakthrough or intracyclic) bleeding and spotting sometimes occur in patients on COCs, especially during the first three months of use. If bleeding persists or occurs after previously regular cycles, check for causes such as pregnancy or ma

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 )

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) ]. 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.

ADVERSE REACTIONS The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: Serious cardiovascular events and smoking [see Boxed Warning , and Warnings and Precautions (5.1) ] Vascular events [see Warnings and Precautions (5.1) ] Liver disease [see Warnings and Precautions (5.3) ] Adverse reactions commonly reported by COC users are: Irregular uterine bleeding Nausea Breast tenderness Headache The most common adverse reactions (≥ 2%) are nausea/vomiting (8.8%), headaches/migraine (7.5%), depression/mood complaints (4.1%), dysmenorrhea (3.9%), acne (3.2%), anxiety symptoms (2.4%), breast pain/tenderness (2.4%), and increased weight (2.3%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Xiromed, LLC at 844-XIROMED (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 rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. A phase 3 clinical trial evaluated the safety and efficacy of norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) for pregnancy prevention. The study was a multicenter, non-comparative, open-label study with a treatment duration of 12 months (thirteen 28-day cycles). A total of 1,677 women aged 18-46 were enrolled and took at least one dose of norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable). Adverse Reactions Leading to Study Discontinuation: 8.5% of the women discontinued from the clinical trial due to an adverse reaction. The most common adverse reactions leading to discontinuation were nausea (1.0%), weight increase (0.8%), acne (0.8%), metrorrhagia (0.7%), altered mood (0.4%), hypertension (0.4%), irritability (0.3%), migraine (0.3%), decreased libido (0.3%) and mood swings (0.3%). Common Adverse Reactions (≥ 2% of all treated subjects): nausea/vomiting (8.8%), headaches/migraine (7.5%), depression/mood complaints (4.1%), dysmenorrhea (3.9%), acne (3.2%), anxiety symptoms (2.4%), breast pain/tenderness (2.4%), and increased weight (2.3%). Serious Adverse Reactions: Hypertension, depression, cholecystitis, and deep vein thrombosis. 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: Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptives 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: Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptives

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.