Xelria Fe

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs are contraindicated in women who are over 35 years of age and smoke [see Contraindications (4) ] WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS See Full Prescribing Information for complete boxed warning. Xelria Fe is contraindicated in women over 35 years old who smoke. ( 4 ) Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (COC) use. ( 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).

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