Introduction

Methoxy polyethylene glycol-epoetin beta is an erythropoiesis-stimulating agent (ESA).

Uses for Methoxy Polyethylene Glycol-epoetin Beta (Systemic)

Anemia of Chronic Kidney Disease (CKD)

Treatment of anemia in adults with CKD on dialysis or not on dialysis, and in pediatric patients 5–17 years of age with CKD on hemodialysis who are converting from another erythropoiesis-stimulating agent (ESA) after their hemoglobin level was stabilized with an ESA.

Guidelines generally support the consideration of ESAs for patients with anemia of CKD but do not specify a preferred ESA.

Not shown to improve quality of life, symptoms, or physical functioning.

Not recommended for treatment of anemia due to cancer chemotherapy or as a substitute for RBC transfusions in patients who require immediate correction of anemia.

Methoxy Polyethylene Glycol-epoetin Beta (Systemic) Dosage and Administration

General

Pretreatment Screening

• Assess iron status prior to treatment with methoxy polyethylene glycol-epoetin beta.

• Correct or exclude other causes of anemia (e.g., bleeding, vitamin deficiency, metabolic or chronic inflammatory conditions) prior to initiating methoxy polyethylene glycol-epoetin beta.

• Appropriately control hypertension prior to initiating therapy.

Patient Monitoring

• Assess iron status during treatment and administer supplemental iron therapy when serum ferritin is <100 mcg/L or serum transferrin saturation is <20%.

• Monitor hemoglobin weekly when initiating or adjusting therapy until hemoglobin level is stable and sufficient to minimize the need for RBC transfusion; monitor hemoglobin at least monthly thereafter.

• Appropriately control hypertension during treatment with methoxy polyethylene glycol-epoetin beta.

• Closely monitor patients for seizures and premonitory neurologic symptoms during the first few months of therapy.

Other General Considerations

• Adjustments to the dialysis prescription may be required after initiating methoxy polyethylene glycol-epoetin beta.

Administration

IV or Sub-Q Administration

Administer by IV or sub-Q injection in adults, and by IV injection only in pediatric patients. For sub-Q injection, inject in abdomen, arm, or thigh.

Available as single-dose prefilled syringes in various strengths for IV or sub-Q administration.

Contains no preservatives; discard any unused portions. Do not mix with any parenteral solution. Inspect visually for particulate matter and/or discoloration prior to administration; do not use if either observed. Avoid vigorous shaking or prolonged exposure of the prefilled syringes to light.

Dosage

Individualize dosing and use lowest dosage to reduce need for RBC transfusions. Targeting a hemoglobin level >11 g/dL has been shown to increase risk of death, serious adverse cardiovascular reactions, and stroke. No target hemoglobin level, erythropoiesis-stimulating agent (ESA) dose, or dosing strategy has been identified that decreases these risks. Weigh possible benefits of decreasing transfusions against increased risks of death and other serious cardiovascular adverse events.

When adjusting therapy, consider rate of increase or decrease in hemoglobin concentration, responsiveness to ESA, and hemoglobin concentration variability. A single hemoglobin excursion may not require a dosage change.

Avoid frequent dosage adjustments. Do not increase dosage more frequently than once every 4 weeks; decreases in dosage can occur more frequently. If hemoglobin concentration rises rapidly (e.g., >1 g/dL in any 2-week period), reduce dosage by ≥25% as needed to reduce rapid responses. If hemoglobin concentration has not increased by >1 g/dL after 4 weeks of therapy, increase dosage by 25%. If an adequate response is not obtained over a 12-week period of escalating dosages, evaluate patient for other causes of anemia; further dosage increases unlikely to improve patient response and may increase risks of therapy. Use lowest dosage that will maintain a hemoglobin concentration sufficient to reduce need for RBC transfusions. If responsiveness does not improve, discontinue drug.

Pediatric Patients

Anemia of CKD: Pediatric Patients ≥5 Years of Age Receiving Dialysis and Converting from Epoetin Alfa or Darbepoetin Alfa

IV

Administer once every 4 weeks in pediatric patients 5–17 years of age whose hemoglobin level has been stabilized by ESA treatment. Dosage of methoxy polyethylene glycol-epoetin beta is based on total weekly ESA dose at time of conversion (See Table 1).

Adults

Anemia of Chronic Kidney Disease (CKD): ESA-naïve Patients Receiving Dialysis

IV or Sub-Q

Initiate treatment when hemoglobin <10 g/dL. Recommended initial dosage in patients not currently treated with an ESA is 0.6 mcg/kg body weight administered as a single sub-Q or IV injection once every 2 weeks. In patients on hemodialysis, IV route is preferred because it may be less immunogenic. Reduce or interrupt dosage if hemoglobin level approaches or exceeds 11 g/dL. Once hemoglobin stabilizes, may administer once monthly at a dosage that is twice that of the every-2-week dosage and subsequently titrate as necessary.

Anemia of CKD: ESA-naïve Patients Not Receiving Dialysis

IV or Sub-Q

Consider initiating treatment when hemoglobin <10 g/dL and the following conditions apply: hemoglobin decline rate indicates likelihood of requiring RBC transfusion, and a goal of therapy is to reduce risk of alloimmunization and/or other RBC transfusion-related risks. Recommended initial dosage in patients not currently treated with an ESA is 1.2 mcg/kg body weight given once monthly as a single sub-Q injection. Alternatively, a starting dose of 0.6 mcg/kg body weight as a single IV or sub-Q injection once every 2 weeks may be administered. Reduce or interrupt dosage if hemoglobin level >10 g/dL; use lowest dosage sufficient to reduce need for RBC transfusions. Once hemoglobin stabilizes, may administer once monthly at a dosage that is twice that of the every-2-week dosage and subsequently titrate as necessary.

Patients Converting from Epoetin Alfa or Darbepoetin Alfa

IV or Sub-Q

Administer as a single sub-Q or IV injection once every 2 weeks or once monthly in patients whose hemoglobin has been stabilized by treatment with an ESA. Estimate the initial dosage of methoxy polyethylene glycol-epoetin beta based on the total weekly ESA dosage at the time of conversion (See Table 2).

Prescribing Limits

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Use

No specific dosage recommendations at this time. Select dosage with caution (usually starting at the low end of the dosing range).

Contraindications

• Uncontrolled hypertension.

• Pure red cell aplasia (PRCA) that begins after treatment with methoxy polyethylene glycol-epoetin beta or other erythropoietin protein drugs.

• History of serious allergic reactions (including anaphylaxis) to methoxy polyethylene glycol-epoetin beta.

Warnings/Precautions

Warnings

Increased Mortality, MI, Stroke, and Thromboembolism

Increased risk of death and serious cardiovascular events in patients with CKD receiving ESAs targeted to hemoglobin concentrations >11 g/dL. (See Boxed Warning.) In controlled clinical studies comparing higher (13–14 g/dL) to lower (9–11.3 g/dL) hemoglobin targets, an increased risk of death, MI, stroke, CHF, hemodialysis vascular access thrombosis, and other thromboembolic events was observed in the higher target hemoglobin groups. Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at greater risk for cardiovascular events and mortality. Increases in hemoglobin >1 g/dL during any 2-week period also may contribute to these risks.

Use the lowest methoxy polyethylene glycol-epoetin beta dose sufficient to reduce the need for RBC transfusions.

Increased incidence of thromboembolic events, some serious and life-threatening, in cancer patients receiving ESAs.

Increased risk of death observed in controlled clinical trials of ESAs in patients undergoing CABG surgery. Increased risk of DVT in patients undergoing orthopedic procedures also observed.

Methoxy polyethylene glycol-epoetin beta not approved for reduction of RBC transfusions in patients scheduled for surgical procedures.

Increased Mortality and/or Tumor Progression

Not indicated or recommended for treatment of anemia due to cancer chemotherapy. (See Boxed Warning.)

Increased mortality observed in patients with non-small-cell lung cancer receiving methoxy polyethylene glycol-epoetin beta compared with another ESA.

Several studies in patients with various cancers found decreased locoregional control, progression-free survival, and/or overall survival with ESA (epoetin alfa/beta or darbepoetin alfa) use.

Other Warnings and Precautions

Hypertension

Contraindicated in patients with uncontrolled hypertension.

Risk of worsening hypertension in both patients on dialysis and patients not on dialysis. Hypertensive encephalopathy and/or seizures observed in patients with CKD treated with methoxy polyethylene glycol-epoetin beta.

Appropriately control hypertension prior to initiation and during treatment. Reduce or withhold therapy if BP becomes difficult to control. Advise patients to maintain compliance with antihypertensive therapy and dietary restrictions.

Seizures

Seizures reported. Monitor closely for premonitory neurologic symptoms during first few months of therapy. Advise patients to contact clinician if new-onset seizures, premonitory symptoms, or change in seizure frequency occurs.

Lack or Loss of Hemoglobin Response

Evaluate patients who fail to respond or experience a loss of hemoglobin response for potential causative factors (e.g., iron deficiency, infection, inflammation, bleeding).

In the absence of another etiology, evaluate for evidence of PRCA. If PRCA is excluded, adjust dosage as recommended for management of patients with an insufficient response to the drug.

Pure Red Cell Aplasia

Pure red cell aplasia and severe anemia, with or without other cytopenias that arise following development of neutralizing antibodies to erythropoietin, reported in postmarketing setting. Cases predominantly reported in patients with CKD receiving ESAs by sub-Q administration. Pure red cell aplasia not observed in clinical studies of methoxy polyethylene glycol-epoetin beta.

Withhold therapy and evaluate patients for neutralizing antibodies to erythropoietin if severe anemia and low reticulocyte count develop. Obtain serum samples ≥1 month after the last administration to prevent interference of drug with assay. Contact manufacturer at 1-800-576-8295 to perform assays for binding and neutralizing antibodies. Permanently discontinue in patients who develop PRCA following treatment with methoxy polyethylene glycol-epoetin beta or other erythropoietin protein drugs; do not switch patients to other ESAs as antibodies may cross-react.

Serious Allergic Reactions

Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, tachycardia, pruritus, skin rash, and urticaria reported. Discontinue immediately and administer appropriate therapy if a serious allergic or anaphylactic reaction occurs; do not reinitiate drug.

Severe Skin Reactions

Blistering and skin exfoliation reactions including erythema multiforme, Stevens-Johnson Syndrome, and toxic epidermal necrolysis, reported with ESAs (including methoxy polyethylene glycol-epoetin beta) in postmarketing setting. Discontinue immediately if severe skin reaction suspected.

Dialysis Management

Adjustments to dialysis prescription may be required after initiation of therapy. Increased anticoagulation with heparin may be required to prevent clotting of extracorporeal circuit during hemodialysis.

Immunogenicity

Potential for immunogenicity.

Severe anemia or PRCA may result from neutralizing antibodies to methoxy polyethylene glycol-epoetin beta that cross-react with endogenous erythropoietin and other ESAs.

Compared to sub-Q administration, IV administration may decrease risk for development of antibodies. Antibody development not detected in any patients who received methoxy polyethylene glycol-epoetin beta in clinical studies.

Specific Populations

Pregnancy

Available data 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 (e.g., hypertension, pre-eclampsia, miscarriage, premature birth, low-birth-weight, polyhydramnios, intrauterine growth restriction).

In animal studies, adverse embryofetal effects observed at doses 17-fold greater than the recommended human dose.

Lactation

Not known if distributed into human milk; detected in maternal milk in rats. Endogenous erythropoietin is present in human milk. Effects on breast-fed infants or on milk production unknown.

Consider developmental and health benefits of breast-feeding along with mother’s clinical need for the drug and any potential adverse effects on breast-fed infant from the drug or underlying maternal condition.

Pediatric Use

Efficacy and safety established for treatment of anemia due to CKD in pediatric patients 5–17 years of age on hemodialysis who are converting from another ESA after their hemoglobin level was stabilized by ESA treatment.

Efficacy and safety not established for treatment of anemia due to CKD in pediatric patients <5 years of age; for sub-Q administration in pediatric patients of any age; for treatment of anemia in pediatric patients with CKD on peritoneal dialysis; for treatment of anemia in pediatric patients with CKD who are not yet on dialysis; and for pediatric patients whose hemoglobin level has not been previously stabilized by treatment with an ESA.

Geriatric Use

Clinical studies did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients. No differences in responses compared to younger patients identified in other reported clinical experience.

Hepatic Impairment

Pharmacokinetics not altered in severe hepatic impairment (Child-Pugh class C). No pharmacokinetic data available for patients with mild or moderate hepatic impairment.

Renal Impairment

Indicated for use in patients with anemia of CKD, including patients requiring hemodialysis. Pharmacokinetics not altered by use of dialysis.

Common Adverse Effects

Most common adverse reactions (≥10%): hypertension, diarrhea, nasopharyngitis.

General

Pretreatment Screening

• Assess iron status prior to treatment with methoxy polyethylene glycol-epoetin beta.

• Correct or exclude other causes of anemia (e.g., bleeding, vitamin deficiency, metabolic or chronic inflammatory conditions) prior to initiating methoxy polyethylene glycol-epoetin beta.

• Appropriately control hypertension prior to initiating therapy.

Patient Monitoring

• Assess iron status during treatment and administer supplemental iron therapy when serum ferritin is <100 mcg/L or serum transferrin saturation is <20%.

• Monitor hemoglobin weekly when initiating or adjusting therapy until hemoglobin level is stable and sufficient to minimize the need for RBC transfusion; monitor hemoglobin at least monthly thereafter.

• Appropriately control hypertension during treatment with methoxy polyethylene glycol-epoetin beta.

• Closely monitor patients for seizures and premonitory neurologic symptoms during the first few months of therapy.

Other General Considerations

• Adjustments to the dialysis prescription may be required after initiating methoxy polyethylene glycol-epoetin beta.

Administration

IV or Sub-Q Administration

Administer by IV or sub-Q injection in adults, and by IV injection only in pediatric patients. For sub-Q injection, inject in abdomen, arm, or thigh.

Available as single-dose prefilled syringes in various strengths for IV or sub-Q administration.

Contains no preservatives; discard any unused portions. Do not mix with any parenteral solution. Inspect visually for particulate matter and/or discoloration prior to administration; do not use if either observed. Avoid vigorous shaking or prolonged exposure of the prefilled syringes to light.

Dosage

Individualize dosing and use lowest dosage to reduce need for RBC transfusions. Targeting a hemoglobin level >11 g/dL has been shown to increase risk of death, serious adverse cardiovascular reactions, and stroke. No target hemoglobin level, erythropoiesis-stimulating agent (ESA) dose, or dosing strategy has been identified that decreases these risks. Weigh possible benefits of decreasing transfusions against increased risks of death and other serious cardiovascular adverse events.

When adjusting therapy, consider rate of increase or decrease in hemoglobin concentration, responsiveness to ESA, and hemoglobin concentration variability. A single hemoglobin excursion may not require a dosage change.

Avoid frequent dosage adjustments. Do not increase dosage more frequently than once every 4 weeks; decreases in dosage can occur more frequently. If hemoglobin concentration rises rapidly (e.g., >1 g/dL in any 2-week period), reduce dosage by ≥25% as needed to reduce rapid responses. If hemoglobin concentration has not increased by >1 g/dL after 4 weeks of therapy, increase dosage by 25%. If an adequate response is not obtained over a 12-week period of escalating dosages, evaluate patient for other causes of anemia; further dosage increases unlikely to improve patient response and may increase risks of therapy. Use lowest dosage that will maintain a hemoglobin concentration sufficient to reduce need for RBC transfusions. If responsiveness does not improve, discontinue drug.

Pediatric Patients

Anemia of CKD: Pediatric Patients ≥5 Years of Age Receiving Dialysis and Converting from Epoetin Alfa or Darbepoetin Alfa

IV

Administer once every 4 weeks in pediatric patients 5–17 years of age whose hemoglobin level has been stabilized by ESA treatment. Dosage of methoxy polyethylene glycol-epoetin beta is based on total weekly ESA dose at time of conversion (See Table 1).

Adults

Anemia of Chronic Kidney Disease (CKD): ESA-naïve Patients Receiving Dialysis

IV or Sub-Q

Initiate treatment when hemoglobin <10 g/dL. Recommended initial dosage in patients not currently treated with an ESA is 0.6 mcg/kg body weight administered as a single sub-Q or IV injection once every 2 weeks. In patients on hemodialysis, IV route is preferred because it may be less immunogenic. Reduce or interrupt dosage if hemoglobin level approaches or exceeds 11 g/dL. Once hemoglobin stabilizes, may administer once monthly at a dosage that is twice that of the every-2-week dosage and subsequently titrate as necessary.

Anemia of CKD: ESA-naïve Patients Not Receiving Dialysis

IV or Sub-Q

Consider initiating treatment when hemoglobin <10 g/dL and the following conditions apply: hemoglobin decline rate indicates likelihood of requiring RBC transfusion, and a goal of therapy is to reduce risk of alloimmunization and/or other RBC transfusion-related risks. Recommended initial dosage in patients not currently treated with an ESA is 1.2 mcg/kg body weight given once monthly as a single sub-Q injection. Alternatively, a starting dose of 0.6 mcg/kg body weight as a single IV or sub-Q injection once every 2 weeks may be administered. Reduce or interrupt dosage if hemoglobin level >10 g/dL; use lowest dosage sufficient to reduce need for RBC transfusions. Once hemoglobin stabilizes, may administer once monthly at a dosage that is twice that of the every-2-week dosage and subsequently titrate as necessary.

Patients Converting from Epoetin Alfa or Darbepoetin Alfa

IV or Sub-Q

Administer as a single sub-Q or IV injection once every 2 weeks or once monthly in patients whose hemoglobin has been stabilized by treatment with an ESA. Estimate the initial dosage of methoxy polyethylene glycol-epoetin beta based on the total weekly ESA dosage at the time of conversion (See Table 2).

Prescribing Limits

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Use

No specific dosage recommendations at this time. Select dosage with caution (usually starting at the low end of the dosing range).

No formal drug interaction studies conducted.