Version May 2024
Erythropoiesis-stimulating agents (ESAs) increase the risk of death, myocardial infarction, stroke, venous thromboembolism, and thrombosis of vascular access.
In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered 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.
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 because of more deaths among patients receiving methoxy polyethylene glycol-epoetin beta than another ESA. ESAs have shown shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers.
Note: Dose rounding: Doses are often rounded to the nearest unit dose (eg, a vial or combination of vials). Iron supplementation: Ensure adequate iron stores before initiating and throughout therapy; most patients with chronic kidney disease (CKD) will require iron supplementation. The manufacturer recommends supplemental iron be administered if serum ferritin is <100 ng/mL or serum transferrin saturation (TSAT) is <20%; however, the threshold for iron replacement should be individualized based on clinical considerations (eg, trends in Hb level, methoxy polyethylene glycol-epoetin beta dose, goals of therapy) (KDIGO 2012; manufacturer’s labeling).
Anemia due to chronic kidney disease:
Initial dose:
Patients not currently taking an erythropoiesis-stimulating agent: Note: Generally initiated when Hb is <10 g/dL; however, the decision to initiate therapy must be individualized based on patient-specific factors (eg, rate of Hb decline, risks of repeat RBC transfusion, symptom severity) (KDIGO 2012; manufacturer’s labeling).
Patients with chronic kidney disease ON dialysis: IV, SUBQ: 0.6 mcg/kg once every 2 weeks.
Patients with chronic kidney disease NOT on dialysis:
SUBQ: 0.6 mcg/kg once every 2 weeks or 1.2 mcg/kg once monthly.
IV: 0.6 mcg/kg once every 2 weeks.
Note: Some experts initiate at 0.6 mcg/kg once every 2 to 4 weeks based on patient-specific factors (eg, baseline Hb) (Fishbane 2018).
Patients converting from epoetin alfa or darbepoetin alfa: IV, SUBQ: Based on total weekly erythropoiesis-stimulating agent dose at the time of conversion, provided Hb has been 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 once 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 once 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 once every 2 weeks.
Dose adjustment: Use the lowest maintenance dose necessary to reduce the need for RBC transfusions and manage symptoms (KDIGO 2012; manufacturer’s labeling). Target Hb range suggested by Kidney Disease: Improving Global Outcomes (KDIGO) is 10 to 11.5 g/dL, while manufacturer’s labeling recommends a range of 10 to 11 g/dL for patients on dialysis and not exceeding 10 g/dL for patients not on dialysis. Target should be individualized for anticipated benefits and risks (KDIGO 2012; manufacturer’s labeling). An optimal dosage adjustment algorithm has not been identified. The following provides general guidance; refer also to institutional protocols.
If Hb does not increase by >1 g/dL after 4 weeks: Increase dose by 25%; do not increase dose more frequently than every 4 weeks.
Note: In patients who have no Hb response after adequate titration (generally over 4 to 12 weeks), or who have not met Hb targets despite high doses (eg, 2.4 mcg/kg every 2 weeks) in the presence of adequate iron stores, reassess for other underlying causes of anemia; further dose increases are unlikely to improve response and may increase cardiovascular risks and mortality (KDIGO 2012).
If Hb increases >1 g/dL in any 2-week period or >2 g/dL in any 4-week period: Reduce dose by 25% to 50% or hold therapy depending on Hb level and rate of Hb increase (Fishbane 2018; KDIGO 2012; manufacturer’s labeling).
If Hb is increasing and approaching the upper target threshold: Reduce dose by 25%; if Hb continues to increase, hold therapy until Hb begins to decrease and reinitiate at 75% of the previous dose (KDIGO 2012).
After Hb stabilizes, may administer once monthly with a dose that is double the dose administered every 2 weeks.
Loss of efficacy (ie, acquired hyporesponsiveness): If an acute Hb decrease occurs in a patient who previously achieved target Hb levels on a stable methoxy polyethylene glycol-epoetin beta dose, identify and treat underlying cause for acute Hb decrease prior to adjusting dose. If patient remains hyporesponsive, may cautiously use the minimum dose to avoid RBC transfusions; refer also to institutional protocols (KDIGO 2012; manufacturer’s labeling).
There are no dosage adjustments provided in the manufacturer’s labeling; however, methoxy polyethylene glycol-epoetin beta is indicated for use in patients with chronic kidney disease.
There are no dosage adjustments provided in the manufacturer's labeling; however, severe hepatic impairment does not appear to alter the pharmacokinetics.
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.
Refer to adult dosing; initiate at the lower end of dosing ranges.
(For additional information see "Methoxy polyethylene glycol-epoetin beta: Pediatric drug information")
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.
Children ≥5 years and Adolescents ≤17 years: There are no dosage adjustments provided in the manufacturer's labeling; however, methoxy polyethylene glycol-epoetin beta is indicated for use in pediatric patients with chronic kidney disease and on hemodialysis.
Children ≥5 years and Adolescents ≤17 years: There are no dosage adjustments provided in the manufacturer's labeling; however, severe hepatic impairment does not appear to alter the pharmacokinetics.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>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
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
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: Although not observed in clinical studies, postmarketing cases of severe anemia and pure red cell aplasia (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), or 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 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.
• Diabetes mellitus: ESAs may artificially lower HbA1c through increased circulation of immature erythrocytes in the peripheral blood stream (Kobayashi 2016; Rasche 2017).
• Perisurgical patients: Methoxy polyethylene glycol-epoetin beta is not approved for reduction in allogeneic RBC 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: Ensure adequate iron stores before initiating and throughout therapy; most patients with CKD will require iron supplementation (KDIGO 2012; manufacturer’s labeling). The manufacturer recommends supplemental iron be administered if serum ferritin is <100 ng/mL or serum transferrin saturation (TSAT) is <20%; however, the threshold for iron replacement should be individualized based on clinical considerations (eg, trends in Hb level, methoxy polyethylene glycol-epoetin beta dose, goals of 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.
A higher incidence of some adverse effects was reported in pediatric patients 5 to 17 years of age compared to adults: Headache (22% vs 9%), nasopharyngitis (22% vs 11%), hypertension (19% vs 13%).
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); 120 mcg/0.3 mL (0.3 mL); 150 mcg/0.3 mL (0.3 mL); 200 mcg/0.3 mL (0.3 mL)
No
Solution Prefilled Syringe (Mircera Injection)
30 mcg/0.3 ml (per 0.3 mL): $103.85
50 mcg/0.3 ml (per 0.3 mL): $173.09
75 mcg/0.3 ml (per 0.3 mL): $259.63
100 mcg/0.3 ml (per 0.3 mL): $346.18
120 mcg/0.3 ml (per 0.3 mL): $415.40
150 mcg/0.3 ml (per 0.3 mL): $519.25
200 mcg/0.3 ml (per 0.3 mL): $692.34
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Distribution is restricted to certain dialysis centers.
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.
IV: Administer IV only; do not administer SubQ in pediatric patients. Available in single-use, prefilled syringes. Discard any unused portion. Do not pool unused portions from the prefilled syringes and do not use the prefilled syringe more than once. Avoid vigorous shaking or prolonged exposure to light. Do not mix with any parenteral solution. After appropriate training, caregivers may also administer monthly doses.
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.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/125164s087lblcorretion.pdf#page=23
Anemia due to chronic kidney disease: 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.
Methoxy polyethylene glycol-epoetin beta may be confused with darbepoetin alfa, epoetin alfa
Mircera may be confused with Mirena
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Androgens: Hypertension-Associated Agents may enhance the hypertensive effect of Androgens. Risk C: Monitor therapy
Lenalidomide: Erythropoiesis-Stimulating Agents may enhance the thrombogenic effect of Lenalidomide. Risk C: Monitor therapy
Lovotibeglogene Autotemcel: Erythropoiesis-Stimulating Agents may diminish the therapeutic effect of Lovotibeglogene Autotemcel. Risk X: Avoid combination
Nandrolone: May enhance the stimulatory effect of Erythropoiesis-Stimulating Agents. Specifically, nandrolone may enhance the erythropoiesis stimulatory effect of Erythropoiesis-Stimulating Agents. Risk C: Monitor therapy
Pegloticase: May diminish the therapeutic effect of PEGylated Drug Products. Risk C: 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. Risk C: Monitor therapy
Pomalidomide: Erythropoiesis-Stimulating Agents may enhance the thrombogenic effect of Pomalidomide. Risk C: Monitor therapy
Roxadustat: May enhance the adverse/toxic effect of Erythropoiesis-Stimulating Agents. Risk X: Avoid combination
Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Risk C: Monitor therapy
Thalidomide: Erythropoiesis-Stimulating Agents may enhance the thrombogenic effect of Thalidomide. Risk C: Monitor therapy
Adverse events were observed in some animal reproduction studies. Information related to the use of methoxy polyethylene glycol-epoetin beta during pregnancy is limited.
It is not known if methoxy polyethylene glycol-epoetin beta is present in breast milk; however, endogenous erythropoietin is found in breast milk. According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should take into account the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
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 to ensure adequate iron stores; monitor BP; monitor for signs/symptoms of premonitory neurologic symptoms of seizures, hypersensitivity.
Diabetes: HbA1c is not useful as a glycemic indicator in patients treated with an erythropoiesis-stimulating agent. Other monitoring parameters may be more useful.
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.
Note: Age has not been shown to affect pharmacokinetics (range: 6 to 89 years).
Distribution: Vdss: 61 mL/kg.
Onset of action: Hemoglobin increase (following a single initial dose): 7 to 15 days.
Bioavailability: SUBQ: 62%.
Half-life elimination: IV: 119 hours; SUBQ: 124 hours.
Time to peak: SUBQ: 72 hours.
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