Methoxy Polyethylene Glycol-Epoetin Beta

Q: What should I know before taking Methoxy Polyethylene Glycol-Epoetin Beta?

5 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

Q: Is Methoxy Polyethylene Glycol-Epoetin Beta available over the counter?

Methoxy Polyethylene Glycol-Epoetin Beta is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

Prescription

Handelsnamen: Mircera

Darreichungsform

Injection

Applikationsweg

INTRAVENOUS

Hersteller

Vifor (International), Inc.

About This Medication

11 DESCRIPTION Methoxy polyethylene glycol-epoetin beta, is an ESA which differs from erythropoietin through formation of a chemical bond between either the N-terminal amino group or the ε-amino group of any lysine present in erythropoietin, predominantly Lys 52 and Lys 45 , and methoxy polyethylene glycol (PEG) butanoic acid (approximately 30,000 daltons). This results in a total molecular weight of approximately 60,000 daltons. Methoxy polyethylene glycol-epoetin beta is produced in Chinese hamster ovary (CHO) cells using recombinant DNA technology. Mircera is formulated as a sterile, preservative-free protein solution for intravenous or subcutaneous administration. Mircera (methoxy polyethylene glycol-epoetin beta) injection is supplied in prefilled syringes (30 mcg, 50 mcg, 75 mcg, 100 mcg, 120 mcg, 150 mcg, 200 mcg, or 250 mcg in 0.3 mL) and formulated in an aqueous solution containing mannitol (9 mg), methionine (0.447 mg), poloxamer 188 (0.03 mg), sodium phosphate monobasic monohydrate (0.414 mg), and sodium sulfate (1.704 mg). Mircera 360 mcg in 0.6 mL is formulated in an aqueous solution containing mannitol (18 mg), methionine (0.894 mg), poloxamer 188 (0.06 mg), sodium phosphate monobasic monohydrate (0.828 mg), and sodium sulfate (3.408 mg). The solution is clear, colorless to slightly yellowish and the pH is 6.2 ± 0.2.

Wirkstoffe

Wirkstoff	Stärke
Methoxy Polyethylene Glycol-Epoetin Beta	-

Indikationen und Anwendung

1 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.

So funktioniert es

12.1 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.

Dosierung und Verabreichung

2 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 dose at the time of conversion. Refer to Table 2 for the dose of Mircera corresponding to the available commercial prefilled syringe strengths. Table 2: Mircera Starting Doses for Pediatric Patients Currently Receiving an ESA Previous Weekly Epoetin Alfa or Epoetin Beta Dose (Units/Week) Previous Weekly Darbepoetin Alfa Dose (mcg/week) Mircera Dose Once Every 4 Weeks (mcg) Less than 1300 units Less than 6 mcg 30 mcg 1300 units to less than 2000 units 6 mcg to less than 9 mcg 50 mcg 2000 units to less than 2700 units 9 mcg to less than 12 mcg 75 mcg 2700 units to less than 3500 units 12 mcg to less than 15 mcg 100 mcg 3500 units to less than 4200 units 15 mcg to less than 19 mcg 120 mcg 4200 units to less than 5500 units 19 mcg to less than 24 mcg 150 mcg 5500 units to less than 7000 units 24 mcg to less than 31 mcg 200 mcg 7000 units to less than 9500 units 31 mcg to less than 42 mcg 250 mcg greater than or equal to 9500 units greater than or equal to 42 mcg 360 mcg 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. If a dose adjustment is required to maintain the hemoglobin concentration above 10 g/dl and within the target range, refer to Table 3 for the Mircera dose adjustment based on hemoglobin response. Dose adjustments should not be made more often than once every 4 weeks. Table 3: Mircera Dose Adjustments for Pediatric Patients Hemoglobin Assessment Compared with the Previous Mircera Dose Hb decreases by more than 1.0 g/dL compared with baseline Hb Increase dose by approximately 25% to the closest dose achievable with the prefilled syringes Hb is less than 10 g/dL and greater than or equal to 9 g/dL (Hb<10.0 and ≥9.0 g/dL) Increase dose by approximately 25% to the closest dose achievable with the prefilled syringes Hb is less than 9 g/dL (Hb <9.0 g/dL) Increase dose by approximately 50% to the closest dose achievable with the prefilled syringes Hb increases by more than 1.0 g/dL compared with the baseline Hb Decrease dose by approximately 25% to the closest dose achievable with the prefilled syringes Hb is increasing and is approaching 12 g/dL or Hb is greater than or equal to 12 g/dL (Hb≥12 g/dL) Decrease dose by approximately 25% to the closest dose achievable with the prefilled syringes If Hb exceeds 12 g/dL and continues to increase following a dose reduction Stop doses until Hb is less than 12.0 g/dL. Resume dose at approximately 25% below previous dose to the closest dose achievable with the prefilled syringes at next scheduled dosing day. 2.4 Preparation and Administration of Mircera Mircera is packaged as single-dose prefilled syringes. Mircera contains no preservatives. Discard any unused portion. Do not pool unused portions from the prefilled syringes. Do not use the prefilled syringe more than once. Always store Mircera prefilled syringes in their original cartons. Vigorous shaking or prolonged exposure to light should be avoided. Do not mix Mircera with any parenteral solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use any prefilled syringes exhibiting particulate matter or a coloration other than colorless to slightly yellowish. For administration using the prefilled syringe, the plunger must be fully depressed during injection in order for the needle guard to activate. Following administration, remove the needle from the injection site and then release the plunger to allow the needle guard to move up until the entire needle is covered. Children and adolescents less than 17 years of age should not self-inject Mircera. Intravenous and subcutaneous administration should be performed by a healthcare professional or adult caregiver. See “Instructions for Use” for complete instructions on the preparation and administration of Mircera. Examine each prefilled syringe for the expiration date. Do not use Mircera after the expiration date.

Side Effects Overview

6 ADVERSE REACTIONS 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 )] .

Warnhinweise und Vorsichtsmaßnahmen

5 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 patients scheduled for surgical procedures. An increased incidence of deep vein thrombosis (DVT) in patients receiving epoetin alfa undergoing surgical orthopedic procedures has been observed. In a randomized controlled study (referred to as the “SPINE” study), 681 adult patients, not receiving prophylactic anticoagulation and undergoing spinal surgery, received epoetin alfa and standard of care (SOC) treatment, or SOC treatment alone. Preliminary analysis showed a higher incidence of DVT, determined by either Color Flow Duplex Imaging or by clinical symptoms, in the epoetin alfa group [16 patients (4.7%)] compared to the SOC group [7 patients (2.1%)]. In addition, 12 patients in the epoetin alfa group and 7 patients in the SOC group had other thrombotic vascular events. Increased mortality was observed in a randomized placebo-controlled study of epoetin alfa in adult patients who were undergoing coronary artery bypass surgery (7 deaths in 126 patients randomized to epoetin alfa vs. no deaths among 56 patients receiving placebo). Four of these deaths occurred during the period of study drug administration and all four deaths were associated with thrombotic events. 5.2 Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer Mircera is not indicated and is not recommended for use in the treatment of anemia due to cancer chemotherapy. A dose-ranging trial of Mircera in 153 patients who were undergoing chemotherapy for non-small cell lung cancer was terminated prematurely because more deaths occurred among patients receiving Mircera than another ESA. ESAs resulted in decreased locoregional control/progression-free survival and/or overall survival (see Table 5 ). These findings were observed in studies of patients with advanced head and neck cancer receiving radiation therapy (Studies 5 and 6), in patients receiving chemotherapy for metastatic breast cancer (Study 1) or lymphoid malignancy (Study 2), and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy (Studies 7 and 8). Table 5: Randomized, Controlled Trials with Decreased Survival and/or Decreased Locoregional Control *Q1= 25th percentile; Q3= 75th percentile Study/Tumor (n) Hemoglobin Target Achieved Hemoglobin (Median Q1,Q3*) Primary Endpoint Adverse Outcome for ESA-containing Arm Chemotherapy Cancer Study 1 Metastatic breast cancer (n=939) 12 to 14 g/dL 12.9 g/dL 12.2, 13.3 g/dL 12-month overall survival Decreased 12-month survival Cancer Study 2 Lymphoid malignancy (n=344) 13 to 15 g/dL (M) 13 to 14 g/dL (F) 11.0 g/dL 9.8, 12.1 g/dL Proportion of patients achieving a hemoglobin response Decreased overall survival Cancer Study 3 Early breast cancer (n=733) 12.5 to 13 g/dL 13.1 g/dL 12.5, 13.7 g/dL Relapse-free and overall survival Decreased 3-year relapse-free and overall survival Cancer Study 4 Cervical cancer (n=114) 12 to 14 g/dL 12.7 g/dL 12.1, 13.3 g/dL Progression-free and overall survival and locoregional control Decreased 3-year progression-free and overall survival and locoregional control Radiotherapy Alone Cancer Study 5 Head and neck cancer (n=351) more than 15 g/dL (M) more than 14 g/dL (F) Not available Locoregional progression-free survival (LRPFS) Decreased 5-year locoregional progression-free survival Decreased overall survival Cancer Study 6 Head and neck cancer (n=522) 14 to 15.5 g/dL Not available Locoregional disease control (LRC) Decreased locoregional disease control No Chemotherapy or Radiotherapy Cancer Study 7 Non-small cell lung cancer (n=70) 12 to 14 g/dL Not available Quality of life Decreased overall survival Cancer Study 8 Non-myeloid malignancy (n=989) 12 to 13 g/dL 10.6 g/dL 9.4, 11.8 g/dL RBC transfusions Decreased overall survival Decreased Overall Survival Cancer Study 1 (the “BEST” study) was previously described [see Warnings and Precautions ( 5.1 ) ]. Mortality at 4 months (8.7% vs. 3.4%) was significantly higher in the epoetin alfa arm. The most common investigator-attributed cause of death within the first 4 months was disease progression; 28 of 41 deaths in the epoetin alfa arm and 13 of 16 deaths in the placebo arm were attributed to disease progression. Investigator assessed time to tumor progression was not different between the two groups. Survival at 12 months was significantly lower in the epoetin alfa arm (70% vs. 76%, HR 1.37, 95% CI: 1.07, 1.75; p=0.012). Cancer Study 2 was a Phase 3, double-blind, randomized (darbepoetin alfa vs. placebo) study conducted in 344 anemic patients with lymphoid malignancy receiving chemotherapy. With a median follow-up of 29 months, overall mortality rates were significantly higher among patients randomized to darbepoetin alfa as compared to placebo (HR 1.36, 95% CI: 1.02, 1.82). Cancer Study 7 was a Phase 3, multicenter, randomized (epoetin alfa vs. placebo), double-blind study, in which patients with advanced non-small cell lung cancer receiving only palliative radiotherapy or no active therapy were treated with epoetin alfa to achieve and maintain hemoglobin levels between 12 and 14 g/dL. Following an interim analysis of 70 of 300 patients planned, a significant difference in survival in favor of the patients on the placebo arm of the trial was observed (median survival 63 vs. 129 days; HR 1.84; p=0.04). Cancer Study 8 was a Phase 3, double-blind, randomized (darbepoetin alfa vs. placebo), 16-week study in 989 anemic patients with active malignant disease, neither receiving nor planning to receive chemotherapy or radiation therapy. There was no evidence of a statistically significant reduction in proportion of patients receiving RBC transfusions. The median survival was shorter in the darbepoetin alfa treatment group (8 months) compared with the placebo group (10.8 months); HR 1.30, 95% CI: 1.07, 1.57. Decreased Progression-Free Survival and Overall Survival Cancer Study 3 (the “PREPARE” study) was a randomized controlled study in which darbepoetin alfa was administered to prevent anemia conducted in 733 women receiving neo-adjuvant breast cancer treatment. A final analysis was performed after a median follow-up of approximately 3 years at which time the survival rate was lower (86% vs. 90%, HR 1.42, 95% CI: 0.93, 2.18) and relapse-free survival rate was lower (72% vs. 78%, HR 1.33, 95% CI: 0.99, 1.79) in the darbepoetin alfa-treated arm compared to the control arm. Cancer Study 4 (protocol GOG 191) was a randomized controlled study that enrolled 114 of a planned 460 cervical cancer patients receiving chemotherapy and radiotherapy. Patients were randomized to receive epoetin alfa to maintain hemoglobin between 12 and 14 g/dL or to transfusion support as needed. The study was terminated prematurely due to an increase in thromboembolic events in epoetin alfa-treated patients compared to control (19% vs. 9%). Both local recurrence (21% vs. 20%) and distant recurrence (12% vs. 7%) were more frequent in epoetin alfa-treated patients compared to control. Progression-free survival at 3 years was lower in the epoetin alfa-treated group compared to control (59% vs. 62%, HR 1.06, 95% CI: 0.58, 1.91). Overall survival at 3 years was lower in the epoetin alfa-treated group compared to control (61% vs. 71%, HR 1.28, 95% CI: 0.68, 2.42). Cancer Study 5 (the “ENHANCE” study) was a randomized controlled study in 351 head and neck cancer patients where epoetin beta or placebo was administered to achieve target hemoglobins of 14 and 15 g/dL for women and men, respectively. Locoregional progression-free survival was significantly shorter in patients receiving epoetin beta (HR 1.62, 95% CI: 1.22, 2.14, p=0.0008) with a median of 406 days epoetin beta vs. 745 days placebo. Overall survival was significantly shorter in patients receiving epoetin beta (HR 1.39, 95% CI: 1.05, 1.84; p=0.02). Decreased Locoregional Control Cancer Study 6 (DAHANCA 10) was conducted in 522 patients with primary squamous cell carcinoma of the head and neck receiving radiation therapy randomized to darbepoetin alfa with radiotherapy or radiotherapy alone. An interim analysis on 484 patients demonstrated that locoregional control at 5 years was significantly shorter in patients receiving darbepoetin alfa (RR 1.44, 95% CI: 1.06, 1.96; p=0.02). Overall survival was shorter in patients receiving darbepoetin alfa (RR 1.28, 95% CI: 0.98, 1.68; p=0.08). 5.3 Hypertension Mircera is contraindicated in patients with uncontrolled hypertension. In Mircera clinical studies, approximately 27% of patients with CKD, including patients on dialysis and patients not on dialysis, required intensification of antihypertensive therapy. Hypertensive encephalopathy and/or seizures have been observed in patients with CKD treated with Mircera [see Warnings and Precautions ( 5.4 )] . Appropriately control hypertension prior to initiation of and during treatment with Mircera. Reduce or withhold Mircera if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions [see Patient Counseling Information ( 17 )] . 5.4 Seizures Seizures have occurred in patients participating in Mircera clinical studies. During the first several months following initiation of Mircera, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms, or change in seizure frequency. 5.5 Lack or Loss of Hemoglobin Response to Mircera For lack or loss of hemoglobin response to Mircera, initiate a search for causative factors (e.g., iron deficiency, infection, inflammation, bleeding). If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA [see Warnings and Precautions ( 5.6 )] . In the absence of PRCA, follow dosing recommendations for management of patients with an insufficient response to Mircera therapy [see Dosage and Administration ( 2.1 )]. 5.6 Pure Red Cell Aplasia 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 the postmarketing setting in patients treated with Mircera. This has been reported predominantly in patients with CKD receiving ESAs by subcutaneous administration. PRCA was not observed in clinical studies of Mircera. PRCA has also been reported in patients receiving ESAs for anemia related to hepatitis C treatment (an indication for which Mircera is not approved). If severe anemia and low reticulocyte count develop during treatment with Mircera, withhold Mircera and evaluate patients for neutralizing antibodies to erythropoietin [see Warnings and Precautions ( 5.5 )] . Serum samples should be obtained at least a month after the last Mircera administration to prevent interference of Mircera with the assay. Contact Vifor at 1-800-576-8295 to perform assays for binding and neutralizing antibodies. Permanently discontinue Mircera in patients who develop PRCA following treatment with Mircera or other erythropoietin protein drugs. Do not switch patients to other ESAs as antibodies may cross-react [see Adverse Reactions ( 6.2 )] . 5.7 Serious Allergic Reactions Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, tachycardia, pruritus skin rash and urticaria have been reported in patients treated with Mircera. If a serious allergic or anaphylactic reaction occurs due to Mircera, immediately and permanently discontinue Mircera and administer appropriate therapy. 5.8 Severe Cutaneous Reactions Blistering and skin exfoliation reactions including Erythema multiforme and Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with ESAs (including Mircera) in the postmarketing setting. Discontinue Mircera therapy immediately if a severe cutaneous reaction, such as SJS/TEN, is suspected. 5.9 Dialysis Management Patients may require adjustments in their dialysis prescription after initiation of Mircera. Patients receiving Mircera may require increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during hemodialysis.

Kontraindikationen

4 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 ).

Pharmakokinetik

12.3 Pharmacokinetics The pharmacokinetics of methoxy polyethylene glycol-epoetin beta were studied in adult anemic patients with CKD including patients on dialysis and those not on dialysis. Parameters are presented as the geometric mean [% coefficient of variation (%CV)] unless otherwise specified. Methoxy polyethylene glycol-epoetin beta did not accumulate following administration every four weeks. However, when Mircera was administered every 2 weeks, serum concentrations at steady state increased by 12%. Multiple dosing had no effect on clearance, volume of distribution or bioavailability of methoxy polyethylene glycol-epoetin beta. Absorption Following the subcutaneous administration of Mircera, the maximum serum concentrations of methoxy polyethylene glycol-epoetin beta were observed at a median [min, max] time of 72 [24, 192] hours. The absolute bioavailability of Mircera after the subcutaneous administration was 62%. Distribution The volume of distribution at steady state was 61 [46%] mL/kg. Elimination Following an intravenous administration of Mircera 0.4 mcg/kg body weight to patients with CKD receiving peritoneal dialysis, the observed terminal half-life was 119 [55%] hours, and the total systemic clearance was 0.47 [35%] mL/hr/kg. Following a subcutaneous administration of Mircera 0.8 mcg/kg to CKD patients receiving peritoneal dialysis, the terminal half-life was 124 [57%] hours. Specific Populations The pharmacokinetics of methoxy polyethylene glycol-epoetin beta were not altered by age (range: 6-89 years), gender, race, severe hepatic impairment (Child-Pugh Class C), site of subcutaneous injection (abdomen, arm or thigh), or the use of dialysis. Pediatric Patients A population pharmacokinetic analysis was performed with data from 103 pediatric patients ages 6 months to 17 years and 524 adult patients. Pediatric patients received Mircera intravenously (N=63, all on hemodialysis) or subcutaneously (total N=40, n=17 on pre-dialysis, n=18 on peritoneal dialysis and n=5 on hemodialysis). The covariate analysis showed a positive body weight effect on clearance (CL) and volume of distribution (V), and a positive age effect on V. Once those covariate effects were taken into account together with the addition of a pediatric subcutaneous bioavailability of 67%, compared to 31% in adults, no differences could be observed in the pharmacokinetic properties of Mircera in pediatric patients compared to adult patients.

Frequently Asked Questions

1 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 …

2 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 …

5 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 ( …

4 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 …

Methoxy Polyethylene Glycol-Epoetin Beta is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

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References & Data Sources

• DailyMed — Methoxy Polyethylene Glycol-Epoetin Beta drug label (National Library of Medicine)
• openFDA — Methoxy Polyethylene Glycol-Epoetin Beta label data (U.S. Food & Drug Administration)
• RxNorm — RXCUI 758159 (NLM Normalized Drug Names)
• NDC Directory — Methoxy Polyethylene Glycol-Epoetin Beta (FDA National Drug Code)

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