Methoxy Polyethylene Glycol-Epoetin Beta

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.

Injection: 30 mcg, 50 mcg, 75 mcg, 100 mcg, 120 mcg, 150 mcg, 200 mcg, or 250 mcg in 0.3 mL clear, colorless to slightly yellowish solution in single-dose prefilled syringes Injection: 360 mcg in 0.6 mL clear, colorless to slightly yellowish solution in single-dose prefilled syringes

• Injection: 30 mcg, 50 mcg, 75 mcg, 100 mcg, 120 mcg, 150 mcg, 200 mcg, or 250 mcg in 0.3 mL solution in single-dose prefilled syringes ( 3 ).
• Injection: 360 mcg in 0.6 mL solution in single-dose prefilled syringes ( 3 ).

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 ).

• 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). […]

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

• Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism [see Warnings and Precautions ( 5.1 )]
• Increased Mortality and/or Tumor Progression in Patients with Cancer [see Warnings and Precautions ( 5.2 )]
• Hypertension [see Warnings and Precautions ( 5.3 )]
• Seizures [see Warnings and Precautions ( 5.4 )]
• Pure Red Cell Aplasia [see Warnings and Precautions ( 5.6 )]
• Serious Allergic Reactions [see Warnings and Precautions ( 5.7 )]
• Severe Cutaneous Reactions [see Warnings and Precautions ( 5.8 )] The most common adverse reactions (≥ 10%) are hypertension, diarrhea, nasopharyngitis ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Vifor (International) Inc. at 1-800-576-8295, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of Mircera cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. Adult Patients The data described below reflect exposure to Mircera in 2737 patients, including 1451 exposed for 6 months and 1144 exposed for greater than one year. Mircera was studied primarily in active-controlled studies (n=1789 received Mircera, and n=948 received another ESA) and in long-term follow up studies. The population was 18 to 92 years of age, 58% male, and the percentage of Caucasian, Black (including African Americans), Asian and Hispanic patients were 73%, 20%, 5%, and 9%, respectively. Approximately 85% of the patients were receiving dialysis. Most patients received Mircera using dosing regimens of once every two or four weeks, administered subcutaneously or intravenously. The most commonly reported adverse reactions in ≥10% of patients were hypertension [see Warnings and Precautions ( 5.3 )] , diarrhea, and nasopharyngitis. The most common adverse reactions that led to treatment discontinuation in the Mircera clinical studies were: hypertension, coronary artery disease, anemia, concomitant termination of other CKD therapy and septic shock. Some of the adverse reactions reported are typically associated with CKD, or recognized complications of dialysis, and may not necessarily be attributable to Mircera therapy. Adverse reaction rates did not importantly differ between patients receiving Mircera or another ESA. Table 6 summarizes the most frequent adverse reactions (≥5%) in patients treated with Mircera. Table 6: Adverse Reactions Occurring in ≥ 5% of CKD Patients BODY SYSTEM Adverse Reaction Patients Treated with Mircera (n=1789) VASCULAR Hypertension 13% Hypotension 5% GASTROINTESTINAL Diarrhea 11% Vomiting 6% Constipation 5% INFECTIONS AND INFESTATIONS Nasopharyngitis 11% Upper Respiratory Tract Infection 9% Urinary Tract Infection 5% NERVOUS SYSTEM Headache 9% MUSCULOSKELETAL AND CONNECTIVE TISSUE Muscle Spasms 8% Back Pain 6% Pain in Extremity 5% INJURY, POISONING AND PROCEDURAL COMPLICATIONS Procedural Hypotension 8% Arteriovenous Fistula Thrombosis 5% Arteriovenous Fistula Site Complication 5% METABOLISM AND NUTRITION Fluid Overload 7% RESPIRATORY, THORACIC AND MEDIASTINAL Cough 6% In the controlled trials, the rates of serious adverse reactions did not importantly differ between patients receiving Mircera and another ESA (38% vs. 42%) except for the occurrence of serious gastrointestinal hemorrhage (1.2% vs. 0.2%). Serious hemorrhagic adverse reactions of all types occurred among 5% and 4% of patients receiving Mircera or another ESA, respectively. Pediatric Patients In an open-label, multiple dose study, 64 pediatric patients (ages 5 to 17 years) with CKD who were on hemodialysis and who had stable hemoglobin levels while previously receiving another ESA (epoetin alfa/beta or darbepoetin alfa) were then converted to Mircera administered intravenously once every 4 weeks for 20 weeks (core study period). Patients who completed the core study period with hemoglobin within ± 1 g/dL of their baseline hemoglobin and within the target range of 10 to 12 g/dL were eligible to enter an optional 52-week safety extension period (total duration of treatment, up to 73 weeks). In the extension period, 25 (out of 37) patients were treated for at least an additional 5 months. During the whole study (core study and safety extension), 33 patients were exposed to Mircera for at least 6 months and 19 were exposed for greater than 15 months. All reported adverse reactions regardless of causality (more than 5% incidence) in the pediatric population included headache (22%), nasopharyngitis (22%), hypertension (19%), vomiting (11%), bronchitis (9%), abdominal pain (8%), arteriovenous fistula thrombosis (6%), cough (6%), device related infection (6%), hyperkalemia (6%), pharyngitis (6%), pyrexia (6%), thrombocytopenia (6%), and thrombosis in device (6%). A second open-label, single-arm, multicenter study was conducted to ascertain the optimal starting dose of Mircera given subcutaneously for the maintenance treatment of anemia in 40 pediatric patients (ages 3 months to 17 years) with CKD on dialysis or not on dialysis. Patients completing the 20 weeks of treatment (core period) with Hb within ±1 g/dL of their baseline Hb and within the target range of 10 to 12 g/dL, were eligible to enter an optional 24-week safety extension period. Mircera was administered subcutaneously once every 4 weeks for the duration of the study. Thirty-eight (38) patients were exposed to Mircera for 20 weeks, and 21 patients were exposed to Mircera for 44 weeks. Overall, the pattern of adverse events reported was similar to the established safety profile of Mircera in adult patients and the patients aged 5 to 17 years in the previous intravenous study.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Mircera. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity Stevens-Johnson syndrome/toxic epidermal necrolysis has been reported [see Warnings and Precautions ( 5.7 )] . Pure Red Cell Aplasia (PRCA) Cases of PRCA and of severe anemia, with or without other cytopenias that arise following the development of neutralizing antibodies to erythropoietin have been reported in patients treated with Mircera [see Warnings and Precautions ( 5.6 )] .

8.1 Pregnancy Risk Summary Available data from a small number of published case reports and postmarketing experience with Mircera use in pregnancy are insufficient to identify a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Chronic kidney disease is associated with maternal and embryo-fetal risks (see Clinical Considerations) . In animal reproduction studies, administration of methoxy polyethylene glycol-epoetin beta to rats and rabbits during pregnancy and lactation adversely affected offspring at doses 17-fold and greater than the recommended human dose (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease Associated Maternal and/or Embryo-Fetal Risk Pregnancy in women with chronic kidney disease has been associated with adverse outcomes including hypertension, pre-eclampsia, miscarriage, premature birth, low-birth-weight, polyhydramnios, and intrauterine growth restriction. Data When methoxy polyethylene glycol-epoetin beta was administered subcutaneously to rats and rabbits during gestation (including the period of organogenesis), bone malformation was observed in both species at 50 mcg/kg once every three days (corresponding to 500 mcg/kg/month or 417-fold the recommended human dose) in studies of embryo-fetal development. This effect was observed as missing caudal vertebrae resulting in a thread-like tail in one rat fetus, absent first digit metacarpal and phalanx on each forelimb resulting in absent pollex in one rabbit fetus, and fused fourth and fifth cervical vertebrae centra in another rabbit fetus. Dose-related reduction in fetal weights was observed in both rats and rabbits. At doses 5 mcg/kg once every three days and higher, corresponding to 50 mcg/kg/month or 42-fold the recommended human dose, methoxy polyethylene glycol-epoetin beta caused exaggerated pharmacodynamic effects in dams. Once-weekly doses of methoxy polyethylene glycol-epoetin beta up to 50 mcg/kg/dose (corresponding to 200 mcg/kg/month or 167-fold the recommended human dose) given to pregnant and lactating rats did not adversely affect pregnancy parameters, natural delivery or litter observations in a study of pre-and postnatal development. Increased deaths and significant reduction in the growth rate of the F1 generation were observed during lactation and early post weaning period at 20 and 50 mcg/kg/dose, corresponding to 80 and 200 mcg/kg/month or 67- and 167-fold the recommended human dose. A significant reduction in the growth rate of the F1 generation was evident already at 5 mcg/kg/dose, corresponding to 20 mcg/kg/month or 17-fold the recommended human dose. However, no remarkable effect on reflex, physical and cognitive development or reproductive performance was observed in F1 generation of any dose groups. The dose level not causing any adverse effect on dams or offspring was not determined.

8.2 Lactation Risk Summary There are no data on the presence of methoxy polyethylene glycol-epoetin beta in human milk, the effects on the breastfed child, or the effects on milk production. However, endogenous erythropoietin is present in human milk. In rats, methoxy polyethylene glycol-epoetin beta was present in maternal milk (see Data) . When a drug is present in animal milk, it is likely that the drug will be present in human milk. The lack of clinical data during lactation precludes a clear determination of the risk of Mircera to a child during lactation. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Mircera and any potential adverse effects on the breastfed child from Mircera or from the underlying maternal condition. Data A dose of methoxy polyethylene glycol-epoetin beta approximately 3-fold greater than the recommended human dose was administered to lactating rats. Methoxy polyethylene glycol-epoetin beta was detected in maternal milk 4 hours postdose and reached maximum concentration 48 hours postdose. The maximum amount of methoxy polyethylene glycol-epoetin beta in milk was about 10-fold lower than in serum. The concentration of drug in animal milk does not necessarily predict the concentration of drug in human milk.

8.4 Pediatric Use The safety and effectiveness of intravenous and subcutaneous Mircera for the treatment of anemia due to CKD have been established in pediatric patients 3 months to 17 years of age on dialysis and not on dialysis who are converting from another ESA after their hemoglobin level was stabilized with an ESA. The use of Mircera in this pediatric age group is supported by evidence from adequate and well-controlled studies of Mircera in adults, a dose-finding study in 64 pediatric patients 5 to 17 years of age with CKD on hemodialysis and a subcutaneous dose-finding study in 40 patients 3 months to 17 years of age with CKD on dialysis or not on dialysis. The adverse reaction profile observed in pediatric patients was consistent with the safety profile found in adults. The safety and effectiveness of Mircera have not been established in patients less than 3 months of age [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14.2 )] . The safety and effectiveness of Mircera have not been established for treatment of anemia in pediatric patients whose hemoglobin level has not been previously stabilized by treatment with an ESA.

8.5 Geriatric Use Clinical studies of Mircera did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

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.