0.3 ML methoxy polyethylene glycol-epoetin beta 0.667 MG/ML Prefilled Syringe [Mircera]

INDICATIONS AND USAGE Mircera is an erythropoiesis-stimulating agent (ESA) indicated for the treatment of anemia associated with chronic kidney disease (CKD) in: • adult patients on dialysis and adult patients not on dialysis ( 1.1 ). • pediatric patients 3 months to 17 years of age on dialysis or not on dialysis who are converting from another ESA after their hemoglobin level was stabilized with an ESA ( 1.1 ). Limitations of Use Mircera is not indicated and is not recommended for use: • In the treatment of anemia due to cancer chemotherapy ( 5.2 ). • As a substitute for RBC transfusions in patients who require immediate correction of anemia ( 12.2 ). Mircera has not been shown to improve quality of life, fatigue, or patient well-being. 1.1 Anemia Due to Chronic Kidney Disease Mircera is indicated for the treatment of anemia associated with chronic kidney disease (CKD) in: • adult patients on dialysis and adult patients not on dialysis. • pediatric patients 3 months to 17 years of age on dialysis or not on dialysis who are converting from another ESA after their hemoglobin level was stabilized with an ESA. Limitations of Use Mircera is not indicated and is not recommended: • In the treatment of anemia due to cancer chemotherapy [see Warnings and Precautions ( 5.2 )] . • As a substitute for RBC transfusions in patients who require immediate correction of anemia [see Clinical Pharmacology ( 12.2 )] . Mircera has not been shown to improve symptoms, physical functioning, or health-related quality of life.

DOSAGE AND ADMINISTRATION Mircera is administered by subcutaneous or intravenous injection ( 2.2 ). Adult Patients • Initial Treatment: (patients not currently treated with an ESA): • CKD patients on dialysis: 0.6 mcg/kg body weight administered once every two weeks ( 2.2 ). • CKD patients not on dialysis: 1.2 mcg/kg body weight administered once every month as a single subcutaneous injection. Alternatively, a starting dose of 0.6 mcg/kg body weight may be administered once every two weeks as a single intravenous or subcutaneous injection ( 2.2 ). • Conversion from Another ESA: • Dosed once monthly or once every two weeks based on total weekly epoetin alfa or darbepoetin alfa dose at time of conversion ( 2.2 ). Pediatric Patients • Conversion from another ESA: dosed once every 4 weeks based on total weekly epoetin alfa or darbepoetin alfa dose at time of conversion ( 2.2 ). • In patients less than 6 years of age, maintain the same route of administration as the previous ESA when switching from another ESA to Mircera. 2.1 Important Dosing Information Evaluation of Iron Stores and Nutritional Factors Evaluate the iron status in all patients before and during treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20%. The majority of patients with CKD will require supplemental iron during the course of ESA therapy. Monitoring of Response to Therapy Correct or exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding, etc.) before initiating Mircera [see Warnings and Precautions ( 5.9 )]. Following initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin level is stable and sufficient to minimize the need for RBC transfusion. Individualization of Dosing Individualize and use the lowest dose of Mircera sufficient to reduce the need for RBC transfusions [see Warnings and Precautions ( 5.1 )] . In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL for adult patients. No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks. Physicians and patients should weigh the possible benefits of decreasing transfusions against the increased risks of death and other serious cardiovascular adverse events [see Boxed Warning and Clinical Studies ( 14 )] . 2.2 For Adult Patients with CKD Prefilled syringes are not designed for administration of partial doses. Round doses to the closest dose achievable with the prefilled syringes. When initiating or adjusting therapy, monitor hemoglobin levels at least weekly until stable, then monitor at least monthly. When adjusting therapy consider hemoglobin rate of rise, rate of decline, ESA responsiveness and hemoglobin variability. A single hemoglobin excursion may not require a dosing change. • Do not increase the dose more frequently than once every 4 weeks. Decreases in dose can occur more frequently. Avoid frequent dose adjustments. • If the hemoglobin rises rapidly (e.g., more than 1 g/dL in any 2-week period), reduce the dose of Mircera by approximately 25% to the closest dose achievable with the prefilled syringes to reduce rapid responses. • If the hemoglobin continues to rise following a dose reduction, discontinue Mircera until the hemoglobin level begins to decrease, at which point therapy should be restarted with a dose that is approximately 25% below the previously administered dose. • For patients who do not respond adequately, if the hemoglobin has not increased by more than 1 g/dL after 4 weeks of therapy, increase the dose by approximately 25% to the closest dose achievable with the prefilled syringes. • For patients who do not respond adequately over a 12-week escalation period, increasing the Mircera dose further is unlikely to improve response and may increase risks. Use the lowest dose that will maintain a hemoglobin level sufficient to reduce the need for RBC transfusions. Evaluate other causes of anemia. Discontinue Mircera if responsiveness does not improve. Administer Mircera either intravenously or subcutaneously. When administered subcutaneously, Mircera should be injected in the abdomen, arm or thigh. For Adult Patients with CKD on dialysis : • Initiate Mircera treatment when the hemoglobin level is less than 10 g/dL. • If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the dose of Mircera. • The recommended starting dose of Mircera for the treatment of anemia in adult CKD patients who are not currently treated with an ESA is 0.6 mcg/kg body weight administered once every two weeks as a single intravenous or subcutaneous injection. The intravenous route is recommended for patients receiving hemodialysis because the intravenous route may be less immunogenic [see Adverse Reactions ( 6.2 )] . • Once the hemoglobin has been stabilized, Mircera may be administered once monthly using a dose that is twice that of the every-two-week dose and subsequently titrated as necessary. For Adult Patients with CKD not on dialysis : • Consider initiating Mircera treatment only when the hemoglobin level is less than 10 g/dL and the following considerations apply: o The rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion and , o Reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal. • If the hemoglobin level exceeds 10 g/dL, reduce or interrupt the dose of Mircera, and use the lowest dose of Mircera sufficient to reduce the need for RBC transfusions. • The recommended starting dose of Mircera for the treatment of anemia in adult CKD patients who are not currently treated with an ESA is 1.2 mcg/kg body weight administered once every month as a single subcutaneous injection. Alternatively, a starting dose of 0.6 mcg/kg body weight may be administered once every two weeks as a single intravenous or subcutaneous injection. • Once the hemoglobin has been stabilized, Mircera may be administered once monthly using a dose that is twice that of the every-two-week dose and subsequently titrated as necessary. Refer patients who self-administer Mircera to the Instructions for Use [see Patient Counseling Information ( 17 )] . Conversion from Epoetin alfa or Darbepoetin alfa to Mircera in Adult Patients with CKD Mircera can be administered once every two weeks or once monthly to patients whose hemoglobin has been stabilized by treatment with an ESA (see Table 1 ). The dose of Mircera, given as a single intravenous or subcutaneous injection, should be based on the total weekly ESA dose at the time of conversion. Table1: Mircera Starting Doses for Adult Patients Currently Receiving an ESA Previous Weekly Epoetin alfa Dose (units/week) Previous Weekly Darbepoetin alfa Dose (mcg/week) Mircera Dose Once Monthly (mcg/month) Once Every Two Weeks (mcg/every two weeks) Less than 8000 units Less than 40 mcg 120 mcg 60 mcg 8000 units to 16000 units 40 mcg to 80 mcg 200 mcg 100 mcg More than 16000 units More than 80 mcg 360 mcg 180 mcg 2.3 For Pediatric Patients with CKD Conversion from Epoetin alfa or Darbepoetin alfa to Mircera in Pediatric Patients with CKD Pre-filled syringes are not designed for administration of partial doses. Pediatric patients requiring a dose of less than 30 mcg of Mircera should not be treated with Mircera. In patients less than 6 years of age, maintain the same route of administration as the previous ESA when switching from another ESA to Mircera. Administer Mircera once every 4 weeks as an intravenous or subcutaneous injection to pediatric patients (ages 3 months to 17 years) whose hemoglobin level has been stabilized by treatment with an ESA. The starting dose of Mircera is calculated based on the total weekly ESA do

WARNINGS AND PRECAUTIONS • Hypertension: Control hypertension prior to initiating and during treatment with Mircera ( 5.3 ). • Seizures: Seizures have occurred in CKD patients participating in Mircera clinical studies. Increase monitoring of these patients for changes in seizure frequency or premonitory symptoms ( 5.4 ). • PRCA: If severe anemia and low reticulocyte count develop during Mircera treatment, withhold Mircera and evaluate for PRCA ( 5.6 ). • Serious Allergic Reactions: Discontinue Mircera and manage reactions ( 5.7 ). • Severe Cutaneous Reactions: Discontinue Mircera ( 5.8 ). 5.1 Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism • In controlled clinical trials of patients with CKD comparing higher hemoglobin targets (13 to 14 g/dL) to lower targets (9 to 11.3 g/dL), ESAs increased the risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events in the higher target groups. • Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit [see Clinical Studies ( 14 )] . Use caution in patients with coexistent cardiovascular disease and stroke [see Dosage and Administration ( 2.2 )] . Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality than other patients. A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may contribute to these risks. • In controlled clinical trials of patients with cancer, ESAs increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke. • In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and the risk of deep venous thrombosis (DVT) in patients undergoing orthopedic procedures. The design and overall results of the 3 large trials comparing higher and lower hemoglobin targets are shown in Table 4 (Normal Hematocrit Study (NHS), Correction of Hemoglobin Outcomes in Renal Insufficiency (CHOIR) and Trial to Reduce Cardiovascular Events with Aranesp ® Therapy (TREAT)). Table 4: Randomized Controlled Trials Showing Adverse Cardiovascular Outcomes in Patients With CKD NHS (N = 1265) CHOIR (N = 1432) TREAT (N = 4038) Time Period of Trial 1993 to 1996 2003 to 2006 2004 to 2009 Population CKD patients on hemodialysis with coexisting CHF or CAD, hematocrit 30 ± 3% on epoetin alfa CKD patients not on dialysis with hemoglobin less than 11 g/dL not previously administered epoetin alfa CKD patients not on dialysis with type II diabetes, hemoglobin ≤11 g/dL Hemoglobin Target; Higher vs. Lower (g/dL) 14.0 vs. 10.0 13.5 vs. 11.3 13.0 vs. ≥9.0 Median (Q1, Q3) Achieved Hemoglobin level (g/dL) 12.6 (11.6, 13.3) vs. 10.3 (10.0, 10.7) 13.0 (12.2, 13.4) vs. 11.4 (11.1, 11.6) 12.5 (12.0, 12.8) vs. 10.6 (9.9, 11.3) Primary Endpoint All-cause mortality or nonfatal MI All-cause mortality, MI, hospitalization for CHF, or stroke All-cause mortality, MI, myocardial ischemia, heart failure, and stroke Hazard Ratio or Relative Risk (95% CI) 1.28 (1.06 to 1.56) 1.34 (1.03 to 1.74) 1.05 (0.94 to 1.17) Adverse Outcome for Higher Target Group All-cause mortality All-cause mortality Stroke Hazard Ratio or Relative Risk (95% CI) 1.27 (1.04 to 1.54) 1.48 (0.97 to 2.27) 1.92 (1.38 to 2.68) Patients with Chronic Kidney Disease NHS: A prospective, randomized, open-label study of 1265 patients with chronic kidney disease on dialysis with documented evidence of congestive heart failure or ischemic heart disease was designed to test the hypothesis that a higher target hematocrit (Hct) would result in improved outcomes compared with a lower target Hct. In this study, patients were randomized to epoetin alfa treatment targeted to a maintenance hemoglobin of either 14 ± 1 g/dL or 10 ± 1 g/dL. The trial was terminated early with adverse safety findings of higher mortality in the high hematocrit target group. Higher mortality (35% vs. 29%) was observed for the patients randomized to a target hemoglobin of 14 g/dL than for the patients randomized to a target hemoglobin of 10 g/dL. For all-cause mortality, the HR=1.27; 95% CI (1.04, 1.54); p=0.018. The incidence of nonfatal myocardial infarction, vascular access thrombosis, and other thrombotic events was also higher in the group randomized to a target hemoglobin of 14 g/dL. CHOIR: In a randomized prospective trial, 1432 patients with anemia due to CKD who were not undergoing dialysis were assigned to epoetin alfa treatment targeting a maintenance hemoglobin concentration of 13.5 g/dL or 11.3 g/dL. The trial was terminated early with adverse safety findings. A major cardiovascular event (death, myocardial infarction, stroke, or hospitalization for congestive heart failure) occurred among 125 (18%) of the 715 patients in the higher hemoglobin group compared to 97 (14%) among the 717 patients in the lower hemoglobin group (HR 1.3, 95% CI: 1.0, 1.7 p=0.03). TREAT: A randomized, double-blind, placebo-controlled, prospective trial of 4038 patients with: CKD not on dialysis (eGFR of 20 – 60 mL/min), anemia (hemoglobin levels ≤ 11 g/dL), and type 2 diabetes mellitus, patients were randomized to receive either darbepoetin alfa treatment or a matching placebo. Placebo group patients also received darbepoetin alfa when their hemoglobin levels were below 9 g/dL. The trial objectives were to demonstrate the benefit of darbepoetin alfa treatment of the anemia to a target hemoglobin level of 13 g/dL, when compared to a “placebo” group, by reducing the occurrence of either of two primary endpoints: (1) a composite cardiovascular endpoint of all-cause mortality or a specified cardiovascular event (myocardial ischemia, CHF, MI, and CVA) or (2) a composite renal endpoint of all-cause mortality or progression to end stage renal disease. The overall risks for each of the two primary endpoints (the cardiovascular composite and the renal composite) were not reduced with darbepoetin alfa treatment (see Table 4 ), but the risk of stroke was increased nearly two-fold in the darbepoetin alfa-treated group vs. the placebo group: annualized stroke rate 2.1% vs. 1.1%, respectively, HR 1.92; 95% CI: 1.38, 2.68; p less than 0.001. The relative risk of stroke was particularly high in patients with a prior stroke: annualized stroke rate 5.2% in the darbepoetin alfa-treated group and 1.9% in the placebo group, HR 3.07; 95% CI: 1.44, 6.54. Also, among darbepoetin alfa-treated subjects with a past history of cancer, there were more deaths due to all causes and more deaths adjudicated as due to cancer, in comparison with the control group. Patients with Cancer An increased incidence of thromboembolic reactions, some serious and life-threatening, occurred in patients with cancer treated with ESAs. In a randomized, placebo-controlled study (Study 1 in Table 5 [see Warnings and Precautions ( 5.2 )] ) of 939 women with metastatic breast cancer receiving chemotherapy, patients received either weekly epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when epoetin alfa was administered to prevent anemia (maintain hemoglobin levels between 12 and 14 g/dL or hematocrit between 36% and 42%). This study was terminated prematurely when interim results demonstrated a higher mortality at 4 months (8.7% vs. 3.4%) and a higher rate of fatal thrombotic reactions (1.1% vs. 0.2%) in the first 4 months of the study among patients treated with epoetin alfa. Based on Kaplan-Meier estimates, at the time of study termination, the 12-month survival was lower in the epoetin alfa group than in the placebo group (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012). Patients Having Surgery Mircera is not approved for reduction of RBC transfusions in pat

CONTRAINDICATIONS Mircera is contraindicated in patients with: • Uncontrolled hypertension [see Warnings and Precautions ( 5.3 )] • Pure red cell aplasia (PRCA) that begins after treatment with Mircera or other erythropoietin protein drugs [see Warnings and Precautions ( 5.6 )] • History of serious or severe allergic reactions to Mircera (e.g., anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria) [see Warnings and Precautions ( 5.7 , 5.8 )] . • Uncontrolled hypertension ( 4 ). • Pure red cell aplasia (PRCA) that begins after treatment with Mircera or other erythropoietin protein drugs ( 4 ). • History of serious allergic reactions to Mircera, including anaphylaxis ( 4 ).

Mechanism of Action Mircera is an erythropoietin receptor activator with greater activity in vivo as well as increased half-life, in contrast to erythropoietin. A primary growth factor for erythroid development, erythropoietin is produced in the kidney and released into the bloodstream in response to hypoxia. In responding to hypoxia, erythropoietin interacts with erythroid progenitor cells to increase red cell production. Production of endogenous erythropoietin is impaired in patients with CKD and erythropoietin deficiency is the primary cause of their anemia.