Xelria Fe

1 INDICATIONS AND USAGE Xelria Fe is indicated for use by females of reproductive potential to prevent pregnancy. Xelria Fe is a 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. 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 Xelria Fe Xelria Fe is dispensed in a blister pack [see How Supplied/Storage and Handling (16) ] . Xelria Fe 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 Xelria Fe Xelria Fe (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 Xelria Fe 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 Xelria Fe after Abortion or Miscarriage First-trimester After a first-trimester abortion or miscarriage, Xelria Fe may be started immediately. An additional method of contraception is not needed if Xelria Fe is started within 5 days after termination of the pregnancy. If Xelria Fe is 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 Xelria Fe. Second-trimester Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start Xelria Fe, 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 Xelria Fe. [See Contraindications (4) , Warnings and Precautions (5.1) , and FDA-Approved Patient Labeling .] Starting Xelria Fe after Childbirth Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with Xelria Fe 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 Xelria Fe. [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 Xelria Fe 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 tablet [see FDA-Approved Patient Labeling ] .

4 CONTRAINDICATIONS Xelria Fe is 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: o Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions (5.1) ] o Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions (5.1) ] o Have inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1) ] o Have cerebrovascular disease [see Warnings and Precautions (5.1) ] o Have coronary artery disease [see Warnings and Precautions (5.1) ] o 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) ] o Have uncontrolled hypertension [see Warnings and Precautions (5.4) ] o Have diabetes mellitus with vascular disease [see Warnings and Precautions (5.6) ] o 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 )

5 WARNINGS AND PRECAUTIONS Thrombotic Disorders and Other Vascular Problems: Stop norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) 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 norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) if jaundice occurs ( 5.2 ) High blood pressure: If used in 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. ( 5.4 ) Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable). Consider an alternative contraceptive method for women with uncontrolled dyslipidemia ( 5.6 ) Headache: Evaluate significant change in headaches and discontinue norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) if indicated ( 5.7 ) Bleeding Irregularities and Amenorrhea: Evaluate irregular bleeding or amenorrhea ( 5.8 ) 5.1 Thrombotic Disorders and Other Vascular Problems Stop norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) if an arterial thrombotic event or venous thromboembolic (VTE) event occurs. 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. 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 VTE as well as during the following prolonged immobilization. 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 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 COCs and when restarting hormonal contraception after a break of 4 weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after 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). The risk increases with age, particularly in women over 35 years of age who smoke. Use COCs with caution in women with cardiovascular disease risk factors. 5.2 Liver Disease Impaired Liver Function Do not use norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) in women with liver disease, such as 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 and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) if jaundice develops. Liver Tumors Norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) 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/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 risk of liver cancers in COC users is less than one case per million users. 5.3 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment During clinical trials with the 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. 5.4 High Blood Pressure Norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) are contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see Contraindications (4) ]. 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. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women with extended duration of use. The incidence of hypertension increases with increasing concentrations of progestin. 5.5 Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs may worsen existing gallbladder disease. A past history of COC-related cholestasis predicts an increased risk with subsequent COC use. Women with a history of pregnancy-related cholestasis may be at an increased risk for COC related cholestasis. 5.6 Carbohydrate and Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who take norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable). COCs may decrease glucose tolerance. 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. 5.7 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. Consider discontinuation of norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event). 5.8 Bleeding Irregularities and Amenorrhea Unscheduled Bleeding and Spotting 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 malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different contraceptive product. Amenorrhea and Oligomenorrhea Women who use norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) may experience amenorrhea. Some women may experience amenorrhea or oligomenorrhea after discontinuation of COCs, especially when such a condition was preexistent. If scheduled (withdrawal) bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. 5.9 COC Use Before or During Early Pregnancy Extensive epidemiologic studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned, when oral contraceptives are taken inadvertently during early pregnancy. Discontinue norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) use if pregnancy is confirmed. Administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy [see Use in Specific Populations (8.1) ]. 5.10 Depression Carefully observe women with a history of depression and discontinue norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) if depression recurs to a serious degree. 5.11 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 Postmarketing Experience (6.2) ]. Cervical Cancer Some studies suggest that COC use has been associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. 5.12 Effect on Binding Globulins The estrogen component of COCs may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin. The dose of replacement thyroid hormone or cortisol therapy may need to be increased. 5.13 Monitoring A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare. 5.14 Hereditary Angioedema In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. 5.15 Chloasma Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable).

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) ]. 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.

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 Xiromed, LLC at 1-844-XIROMED (1-844-947-6633) 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

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.