Methoxy Polyethylene Glycol-Epoetin Beta

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Prefilled Syringe, Injection [preservative free]:

Mircera: 30 mcg/0.3 mL (0.3 mL); 50 mcg/0.3 mL (0.3 mL); 75 mcg/0.3 mL (0.3 mL); 100 mcg/0.3 mL (0.3 mL); 150 mcg/0.3 mL (0.3 mL); 200 mcg/0.3 mL (0.3 mL)

Pharmacology

Mechanism of Action

Methoxy polyethylene glycol-epoetin beta is an erythropoietin receptor activator; erythropoietin is a primary growth factor for erythroid development and is produced in the kidney and released into the bloodstream in response to hypoxia. In response to hypoxia, erythropoietin interacts with erythroid progenitor cells to increase red blood cell production.

Pharmacokinetics/Pharmacodynamics

Distribution

V_dss: 61 mL/kg

Onset of Action

Hemoglobin increase (following a single initial dose): 7 to 15 days

Time to Peak

SubQ: 72 hours

Half-Life Elimination

IV: 119 hours

SubQ: 124 hours

Use: Labeled Indications

Anemia: Treatment of anemia associated with chronic kidney disease (CKD) in adult patients on dialysis, adult patients not on dialysis, and in pediatric patients 5 to 17 years of age on hemodialysis who are converting from another erythropoiesis-stimulating agent (ESA) after their hemoglobin level was stabilized with an ESA.

Limitations of use: Not indicated and is not recommended in the treatment of anemia due to cancer chemotherapy or as a substitute for RBC transfusions in patients who require immediate correction of anemia; has not been shown to improve symptoms, physical functioning or health-related quality of life.

Contraindications

Serious or severe hypersensitivity to methoxy polyethylene glycol-epoetin beta (eg, anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria); pure red cell aplasia (PRCA) that begins after treatment with methoxy polyethylene glycol-epoetin beta or other erythropoietin protein drugs; uncontrolled hypertension

Dosage and Administration

Dosing: Adult

Note: Evaluate iron status before and during treatment; administer supplemental iron therapy if serum ferritin is <100 ng/mL or when transferrin saturation (TSAT) is <20% (most patients will require iron supplementation during the course of erythropoiesis-stimulating agent [ESA] therapy).

Anemia associated with chronic kidney disease (CKD): Individualize dosing and use the lowest dose necessary to reduce the need for RBC transfusions:

Patients not currently taking an ESA:

Chronic kidney disease patients on dialysis (IV route is preferred for hemodialysis patients; initiate treatment when hemoglobin <10 g/dL): Initial: IV, SubQ: 0.6 mcg/kg once every 2 weeks. Reduce dose or interrupt treatment if hemoglobin approaches or exceeds 11 g/dL. After hemoglobin stabilizes, may administer once monthly with a dose that is double the dose administered every 2 weeks; titrate as necessary.

Chronic kidney disease patients NOT on dialysis (consider initiating treatment when hemoglobin <10 g/dL and the rate of hemoglobin decline would likely result in RBC transfusion and goal is to reduce risk of alloimmunization or other RBC transfusion-related risks): Initial: IV, SubQ: 0.6 mcg/kg once every 2 weeks. Reduce dose or interrupt treatment if hemoglobin exceeds 10 g/dL. After hemoglobin stabilizes, may administer once monthly with a dose that is double the dose administered every 2 weeks; titrate as necessary.

Patients converting from epoetin alfa or darbepoetin alfa: IV, SubQ: Based on total weekly ESA dose at the time of conversion (if hemoglobin is stabilized):

For epoetin alfa dose <8,000 units/week or darbepoetin alfa dose <40 mcg/week: Administer methoxy polyethylene glycol-epoetin beta 120 mcg once monthly or 60 mcg every 2 weeks.

For epoetin alfa dose 8,000 to 16,000 units/week or darbepoetin alfa dose 40 to 80 mcg/week: Administer methoxy polyethylene glycol-epoetin beta 200 mcg once monthly or 100 mcg every 2 weeks.

For epoetin alfa dose >16,000 units/week or darbepoetin alfa dose >80 mcg/week: Administer methoxy polyethylene glycol-epoetin beta 360 mcg once monthly or 180 mcg every 2 weeks.

Dosage adjustments for all CKD patients: Do not increase dose more frequently than every 4 weeks (dose decreases may occur more often); avoid frequent dosage adjustments.

If hemoglobin increases >1 g/dL in any 2-week period: Decrease dose by ≥25% as needed to reduce rapid responses.

If hemoglobin does not increase by >1 g/dL after 4 weeks of therapy: Increase dose by 25%.

Inadequate or lack of response over 12 weeks of therapy: If adequate response is not achieved after 12 weeks of therapy, further increases are unlikely to be of benefit and may increase the risk for adverse events; use the minimum effective dose that will maintain a hemoglobin level sufficient to avoid red blood cell transfusions and evaluate patient for other causes of anemia. Discontinue treatment if responsiveness does not improve.

Dosing: Geriatric

Refer to adult dosing; initiate at the lower end of dosing ranges.

Dosing: Pediatric

Note: Evaluate iron status before and during treatment; administer supplemental iron therapy if serum ferritin is <100 ng/mL or when transferrin saturation (TSAT) is <20% (most patients will require iron supplementation during the course of erythropoiesis-stimulating agent [ESA] therapy). Individualize dosing and use the lowest dose necessary to reduce the need for red blood cell transfusions.

Anemia associated with chronic kidney disease (CKD) on hemodialysis; conversion from either epoetin alfa or darbepoetin alfa: Note: Patients should already have hemoglobin stabilized on either current epoetin or darbepoetin therapy.

Children ≥5 years and Adolescents ≤17 years: IV: Methoxy polyethylene glycol-epoetin beta dose should be calculated on the following product-specific equations and administered IV every 4 weeks; begin therapy when next scheduled ESA dose would be due; discontinue other ESA agents.

Conversion from epoetin alfa:

Dose (mcg) = [4 x weekly epoetin alfa dose (units)]/125

For example, in a patient receiving epoetin alfa 1,500 units weekly: Methoxy PEG-epoetin beta dose (mcg) = [4 x 1,500 units epoetin alfa]/125 = 48 mcg every 4 weeks

Conversion from darbepoetin alfa:

Dose (mcg) = [4 x weekly darbepoetin alfa dose (mcg)]/0.55

For example, in a patient receiving darbepoetin 20 mcg weekly: Methoxy PEG-epoetin beta dose (mcg) = [4 x 20 mcg darbepoetin alfa]/0.55 = 145.5 mcg every 4 weeks

Dosage adjustments: Children ≥5 years and Adolescents ≤17 years: IV: Do not increase dose more frequently than every 4 weeks (dose decreases may occur more often); avoid frequent dosage adjustments.

If hemoglobin increases >1 g/dL in any 2-week period: Decrease dose by ≥25% as needed to reduce rapid responses.

If hemoglobin does not increase by >1 g/dL after 4 weeks of therapy: Increase dose by 25%.

Inadequate or lack of response over 12 weeks of therapy: If adequate response is not achieved after 12 weeks of therapy, further increases are unlikely to be of benefit and may increase the risk for adverse events; use the minimum effective dose that will maintain a hemoglobin level sufficient to avoid red blood cell transfusions and evaluate patient for other causes of anemia. Discontinue treatment if responsiveness does not improve.

Dosing adjustment for toxicity: Children ≥5 years and Adolescents ≤17 years:

Serious allergic/anaphylactic reactions: Discontinue immediately (and permanently).

Hypertension (difficult to control): Reduce dose or withhold treatment (use is contraindicated in uncontrolled hypertension).

Pure red cell aplasia (PRCA): Permanently discontinue treatment.

Dosing: Adjustment for Toxicity

Serious allergic/anaphylactic reactions: Discontinue immediately (and permanently).

Hypertension (difficult to control): Reduce dose or withhold treatment (use is contraindicated in uncontrolled hypertension).

Pure red cell aplasia (PRCA): Permanently discontinue treatment.

Reconstitution

Available in single-use, prefilled syringes: Discard any unused portion. Do not pool unused portions from the prefilled syringes. Do not use the prefilled syringe more than once. Avoid vigorous shaking or prolonged exposure to light. Do not mix with any parenteral solution.

Administration

Administer IV or SubQ.

For administration using the prefilled syringe, the plunger must be fully depressed during injection to activate the needle guard. Following administration, remove the needle from the injection site and release the plunger to allow the needle guard to move up until the entire needle is covered.

SubQ: Inject in the abdomen, arm, or thigh.

Storage

Store at 2°C to 8°C (36°F to 46°F); may store at temperatures up to 25°C (77°F) for no more than 30 days. Do not freeze. Protect from light. Keep in the original package until use. Do not shake.

Drug Interactions

Lenalidomide: Erythropoiesis-Stimulating Agents may enhance the thrombogenic effect of Lenalidomide. Monitor therapy

Nandrolone: May enhance the stimulatory effect of Erythropoiesis-Stimulating Agents. Specifically, nandrolone may enhance the erythropoiesis stimulatory effect of Erythropoiesis-Stimulating Agents. Monitor therapy

Pegloticase: May diminish the therapeutic effect of PEGylated Drug Products. Monitor therapy

Pegvaliase: PEGylated Drug Products may enhance the adverse/toxic effect of Pegvaliase. Specifically, the risk of anaphylaxis or hypersensitivity reactions may be increased. Monitor therapy

Pomalidomide: Erythropoiesis-Stimulating Agents may enhance the thrombogenic effect of Pomalidomide. Monitor therapy

Thalidomide: Erythropoiesis-Stimulating Agents may enhance the thrombogenic effect of Thalidomide. Monitor therapy

Test Interactions

Neutralizing antibody assay: Obtain serum samples at least a month after the last dose to prevent assay interference.

Adverse Reactions

>10%:

Cardiovascular: Exacerbation of hypertension (27%), hypertension (13% to 19%)

Central nervous system: Headache (children and adolescents: 22%; adults: 9%)

Gastrointestinal: Diarrhea (adults: 11%), vomiting (6% to 11%)

Respiratory: Nasopharyngitis (children and adolescents: 22%; adults: 11%)

1% to 10%:

Cardiovascular: Procedural hypotension (adults: 8%), thrombosis of arteriovenous shunt used for hemodialysis (5% to 6%; arteriovenous fistula), arteriovenous fistula site complication (adults: 5%), hypotension (adults: 5%), thrombosis (children and adolescents: 5%; in device)

Endocrine & metabolic: Hypervolemia (adults: 7%), hyperkalemia (children and adolescents: 6%)

Gastrointestinal: Abdominal pain (children and adolescents: 8%), constipation (adults: 5%), gastrointestinal hemorrhage (adults: 1%; serious)

Genitourinary: Urinary tract infection (adults: 5%)

Hematologic & oncologic: Thrombocytopenia (children and adolescents: 6%), hemorrhage (adults: 5%; serious)

Infection: Infection (children and adolescents: 6%; device-related)

Neuromuscular & skeletal: Muscle spasm (adults: 8%), back pain (adults: 6%), limb pain (adults: 5%)

Respiratory: Bronchitis (children and adolescents: 9%), upper respiratory tract infection (adults: 9%), cough (6%), pharyngitis (children and adolescents: 6%)

Miscellaneous: Fever (children and adolescents: 6%)

<1%, postmarketing, and/or case reports: Anaphylaxis, angioedema, bronchospasm, erythema multiforme, hypertensive encephalopathy, pruritus, pure red cell aplasia, seizure, severe anemia, skin rash, Stevens-Johnson syndrome, tachycardia, toxic epidermal necrolysis, urticaria

Warnings/Precautions

Concerns related to adverse effects:

• Cardiovascular events: [US Boxed Warning]: Erythropoiesis-stimulating agents (ESAs) increase the risk of death, myocardial infarction, stroke, venous thromboembolism, and thrombosis of vascular access. In controlled studies of patients with chronic kidney disease (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, MI, stroke, heart failure, hemodialysis vascular access thrombosis, and other thromboembolic events in the higher hemoglobin target groups. Using ESAs to target a hemoglobin >11 g/dL does not demonstrate additional benefit and may also contribute to these risks. Use with caution in patient with a current or a history of cardiovascular disease and stroke. A rate of hemoglobin rise of >1 g/dL over 2 weeks may also contribute to cardiovascular risks. In controlled studies of patients with cancer, ESAs increased the risk of death and cardiovascular reactions (including MI and stroke). Patients with cancer treated with ESAs have in increased incidence of thromboembolic events; may be serious or life-threatening. In controlled studies, ESAs increased the risk of death in patients undergoing CABG surgery and increased the risk of DVT in patients undergoing orthopedic procedures.
• Dermatologic toxicity: Severe cutaneous blistering and skin exfoliation reactions, including erythema multiforme, Stevens-Johnson syndrome (SJS), and/or toxic epidermal necrolysis (TEN) have been reported in patients treated with ESAs, including methoxy polyethylene glycol-epoetin beta. If a severe cutaneous reaction such as SJS or TEN is suspected, discontinue treatment immediately.
• Hypersensitivity: Serious allergic reactions (including anaphylactic reactions angioedema, bronchospasm, tachycardia, pruritus, rash, and urticaria) have been reported. Discontinue immediately (and permanently) in patients who experience serious allergic/anaphylactic reactions.
• Hypertension: In studies of methoxy polyethylene glycol-epoetin beta in patients with CKD, intensification of antihypertensive therapy was required in over one-fourth of patients. Hypertensive encephalopathy and/or seizures have been reported. Blood pressure should be controlled prior to treatment initiation and during therapy. Reduce or withhold treatment if blood pressure becomes difficult to control. Use is contraindicated in uncontrolled hypertension. Patients should comply with antihypertensive therapy and dietary restrictions.
• Pure red cell aplasia (PRCA): Although not observed in clinical studies, postmarketing cases of severe anemia and PRCA (with or without other cytopenias) have been reported with methoxy polyethylene glycol-epoetin beta, arising following the development of neutralizing antibodies to erythropoietin. PRCA reports associated with ESAs have been predominantly in patients with CKD receiving subQ administration. Cases have also been reported in patients with hepatitis C who were receiving ESAs for anemia. Withhold the dose and evaluate for neutralizing antibodies to erythropoietin in patients with severe anemia and a low reticulocyte count during treatment (obtain serum samples at least a month after the last dose to prevent assay interference). Discontinue treatment (permanently) in patients who develop PRCA (to any ESA); antibodies may cross-react; do not switch to another ESA.
• Seizures: Seizures have been observed in studies with methoxy polyethylene glycol-epoetin beta. Monitor closely for premonitory neurologic symptoms during the first several months after treatment initiation. Patients should be advised to contact health care provider if seizures occur (new -onset or change in frequency), orf for premonitory symptoms.

Disease-related concerns:

• Cancer: [US Boxed Warning]: Methoxy polyethylene glycol-epoetin beta is not indicated and is not recommended for the treatment of anemia due to cancer chemotherapy. A dose-ranging study was terminated early due to increased deaths among patients receiving methoxy polyethylene glycol-epoetin beta than another ESA. ESAs have demonstrated shortened overall survival and/or increased the risk of tumor progression or recurrence in studies in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers. Methoxy polyethylene glycol-epoetin beta is not approved and is not recommend for use in the treatment of anemia due to cancer chemotherapy. ESA use is associated with decreased locoregional control, progression free survival and/or overall survival.
• Chronic kidney disease: [US Boxed Warning]: 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 >11 g/dL. No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks. Use the lowest dose sufficient to reduce the need for red blood cell (RBC) transfusions. Evaluate the benefit of decreasing transfusions against the risk of death or other serious cardiovascular events. May reduce dialysis efficacy (due to increase in red blood cells and decrease in plasma volume); adjustments in dialysis parameters may be needed. Patients may require increased heparinization during dialysis to prevent clotting of the extracorporeal circuit.
• Perisurgical patients: Methoxy polyethylene glycol-epoetin beta is not approved for reduction in allogeneic red blood cell transfusions in patients scheduled for surgical procedures. An increased incidence of DVT has been observed in patients treated with epoetin alfa undergoing surgical orthopedic procedures. Increased mortality was observed in patients undergoing coronary artery bypass surgery who received epoetin alfa.

Other warnings/precautions:

• Appropriate use: Evaluate iron status (eg, transferrin saturation and serum ferritin) prior to and during treatment; administer supplemental iron therapy if serum ferritin is <100 ng/mL or when transferrin saturation (TSAT) is <20% (most patients will require iron supplementation during the course of ESA therapy). Correct (or exclude) other causes of anemia (eg, vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding) prior to treatment initiation. When adjusting therapy, consider rate of hemoglobin change, ESA responsiveness, and hemoglobin variability; a single hemoglobin level excursion may not require dosage alteration. For lack or loss of hemoglobin response, evaluate patient for causative factors (eg, iron deficiency, infection, inflammation, bleeding); if typical causes are excluded, evaluate for PRCA. If PRCA is excluded, follow dosing recommendation for insufficient response.

Monitoring Parameters

Hemoglobin levels (at least weekly following therapy initiation and dosage adjustments until stable, then at least monthly); iron stores (transferrin saturation and serum ferritin) at baseline and during therapy; monitor blood pressure; monitor for signs/symptoms of premonitory neurologic symptoms of seizures, hypersensitivity

Pregnancy

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. Information related to the use of methoxy polyethylene glycol-epoetin beta during pregnancy is limited.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience diarrhea, vomiting, constipation, common cold symptoms, muscle spasm, back pain, abdominal pain, stuffy nose, or sore throat. Have patient report immediately to prescriber signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of high potassium (abnormal heartbeat, confusion, dizziness, passing out, weakness, shortness of breath, or numbness or tingling feeling), signs of a urinary tract infection (blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain), severe dizziness, passing out, vision changes, shortness of breath, excessive weight gain, swelling of arms or legs, cold extremities, pale skin, severe headache, fast heartbeat, severe loss of strength and energy, seizures, abnormal gait, change in balance, bruising, bleeding, signs of blood clots (numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood), or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.