Erythropoiesis-stimulating agents (ESAs) increase the risk of death, MI, stroke, venous thromboembolism, 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 greater than 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 epoetin alfa dose sufficient to reduce the need for RBC transfusions.
ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers. To decrease these risks, as well as the risk of serious cardiovascular and thromboembolic reactions, use the lowest dose needed to avoid RBC transfusions. Use ESAs only for anemia from myelosuppressive chemotherapy. ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure. Discontinue following the completion of a chemotherapy course.
Due to increased risk of DVT, DVT prophylaxis is recommended.
Dosage guidance:
Dosing: Doses are often rounded to the nearest unit dose (eg, a vial or combination of vials) (Ref).
Dosage form information: Retacrit (epoetin alfa-epbx) is approved as a biosimilar to Epogen (epoetin alfa) and Procrit (epoetin alfa).
Clinical considerations: Ensure adequate iron stores before initiating and throughout therapy. The manufacturer recommends supplemental iron be administered if serum ferritin is <100 ng/mL or serum transferrin saturation is <20%; however, the threshold for iron replacement should be individualized based on clinical considerations (eg, trends in Hb level, epoetin alfa dose, goals of therapy) and may vary by indication. Most patients with chronic kidney disease (CKD) will require iron supplementation (Ref).
Anemia due to chemotherapy in patients with cancer: Initiate treatment only if Hb <10 g/dL and anticipated duration of myelosuppressive chemotherapy is at least 2 additional months. Titrate dosage to use the minimum effective dose that will maintain a Hb level sufficient to avoid RBC transfusions. Discontinue erythropoietin following completion of chemotherapy. SUBQ: Initial dose: 150 units/kg 3 times a week or 40,000 units once weekly until completion of chemotherapy.
Dosage adjustments:
If Hb does not increase by ≥1 g/dL and remains below 10 g/dL after initial 4 weeks: Increase to 300 units/kg 3 times a week or 60,000 units weekly; discontinue after 8 weeks of treatment if RBC transfusions are still required or there is no Hb response.
If Hb exceeds a level needed to avoid RBC transfusion: Withhold dose; resume treatment with a 25% dose reduction when Hb approaches a level where transfusions may be required.
If Hb increases >1 g/dL in any 2-week period or Hb reaches a level sufficient to avoid RBC transfusion: Reduce dose by 25%.
Anemia due to chronic kidney disease:
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) (Ref).
Initial dose: Individualize initial dose within ranges shown below according to baseline Hb concentration and risk of adverse effects (eg, cardiovascular) (Ref). An optimal initial dosing algorithm has not been established; refer to institutional protocols.
Patients with chronic kidney disease ON dialysis: IV, SUBQ: 20 to 50 units/kg 3 times per week (Ref); in some patients with lower initial Hb levels (eg, <8 g/dL), an initial dose of up to 100 units/kg 3 times per week may be considered (Ref).
Patients with chronic kidney disease NOT on dialysis: IV, SUBQ (preferred route): 50 to 100 units/kg every 1 to 2 weeks; typical initial regimens include 4,000 to 10,000 units once weekly or 10,000 to 20,000 units every other week (Ref).
Note: The initial doses recommended above are generally lower than those recommended in the manufacturer’s labeling. Due to safety concerns, lower doses are typically preferred according to clinical practice and guidelines (Ref).
Dosage adjustment: Use the lowest maintenance dose necessary to reduce the need for RBC transfusions and manage symptoms (Ref). Target Hb range suggested by 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 (Ref). 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 once 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, ≥450 units/kg per week IV or ≥300 units/kg per week SUBQ) 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 (Ref).
If Hb increases by >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 increase (Ref).
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 then reinitiate at 75% of the previous dose (Ref).
Loss of efficacy (ie, acquired hyporesponsiveness): If an acute Hb decrease occurs in a patient who previously achieved target Hb levels on a stable epoetin dose, identify and treat underlying cause for acute Hb decrease prior to adjusting epoetin dose. If patient remains hyporesponsive, may cautiously use the minimum epoetin dose to avoid RBC transfusions; refer also to institutional protocols (Ref).
Anemia due to zidovudine in HIV-infected patients: Titrate dosage to use the minimum effective dose that will maintain a Hb level sufficient to avoid RBC transfusions. Hb levels should not exceed 12 g/dL.
Serum erythropoietin levels ≤500 milliunits/mL and zidovudine doses ≤4,200 mg/week): IV, SUBQ: Initial: 100 units/kg 3 times a week; if Hb does not increase after 8 weeks, increase dose by ~50 to 100 units/kg at 4 to 8 week intervals until Hb reaches a level sufficient to avoid RBC transfusion; maximum dose: 300 units/kg. Withhold dose if Hb exceeds 12 g/dL, may resume treatment with a 25% dose reduction once Hb <11 g/dL. Discontinue if Hb increase is not achieved with 300 units/kg for 8 weeks.
Myelodysplastic syndromes, lower-risk, symptomatic anemia management (off-label use): SUBQ: 150 to 300 units/kg once daily (Ref) or 450 units/kg (up to 40,000 units/dose) once weekly; based on erythroid response after 8 weeks may increase to 1,050 units/kg (up to 80,000 units/dose) once weekly (Ref) or 450 to 1,000 units/kg/week in divided doses, 3 to 7 times a week (Ref) or 40,000 units once weekly (Ref) or 60,000 units once weekly (Ref).
Reduction of allogeneic RBC transfusion in patients undergoing elective, noncardiac, nonvascular surgery (perioperative Hb should be >10 g/dL and ≤13 g/dL; DVT prophylactic anticoagulation is recommended): SUBQ: Initial dose:
300 units/kg/day for 15 days total, beginning 10 days before surgery, on the day of surgery, and for 4 days after surgery or
600 units/kg once weekly for 4 doses, given 21-, 14-, and 7 days before surgery, and on the day of surgery.
RBC transfusion refusal (substitute) (off-label use): Note: Concomitantly administer iron (with or without vitamin B12 and folic acid supplementation) with epoetin alfa and use in conjunction with other blood conservation techniques.
Spinal (elective) surgery: SUBQ: 40,000 units weekly for 4 weeks prior to surgery (Ref).
Cardiac (elective) surgery:
One protocol based on timing of elective surgery and preoperative Hb used the following (Ref):
>21 days until surgery:
Hb <10 g/dL: Delay surgery; identify cause of anemia.
Hb 10 to 12 g/dL: SUBQ: 40,000 units (if <65 kg, use 600 units/kg/dose) weekly starting 21 days before surgery.
Hb >12 to <13 g/dL: SUBQ: 40,000 units (if <65 kg, use 600 units/kg/dose) weekly starting 10 days before surgery and repeat 3 days before surgery or on the morning of surgery.
<21 days until surgery:
Hb <10 g/dL: Delay surgery; identify cause of anemia.
Hb 10 to 12 g/dL: SUBQ: 20,000 units (if <65 kg, use 300 units/kg/dose) daily starting up to 10 days before surgery, on the day of surgery, and 4 days postoperatively if necessary.
Hb >12 to <13 g/dL: SUBQ: 20,000 units (if <65 kg, use 300 units/kg/dose) daily starting up to 10 days before surgery, on the day of surgery, and 4 days postoperatively if necessary.
Another protocol utilized weight-based dosing (Ref):
Preoperative:
IV: 200 units/kg every 24 hours.
SUBQ: 250 to 500 units/kg every 48 hours.
Note: Timing prior to surgery was not described; target Hb of 12 g/dL.
Postoperative:
IV: 200 to 300 units/kg every 24 hours.
SUBQ: 250 to 500 units/kg every 48 hours.
Note: Target Hb >10 g/dL.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function: No dosage adjustment necessary for any degree of kidney impairment (Ref).
Hemodialysis, intermittent (thrice weekly): Not significantly dialyzed (Ref): No supplemental dose or dosage adjustment necessary (Ref).
Peritoneal dialysis: Not significantly dialyzed (Ref): No dosage adjustment necessary (Ref).
CRRT: No dosage adjustment necessary (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (Ref).
There are no dosage adjustments provided in the manufacturer's labeling.
Refer to adult dosing.
(For additional information see "Epoetin alfa (including biosimilars): Pediatric drug information")
Dosage guidance:
Dosing: Dosing schedules need to be individualized and careful monitoring of patients receiving the drug is recommended.
Clinical considerations: Use has not been demonstrated in controlled clinical trials to improve symptoms of anemia, quality of life, fatigue, or patient well-being.
Anemia in chronic kidney disease, ON dialysis: Note: The IV route is preferred for hemodialysis patients; initiate treatment when hemoglobin is <10 g/dL; reduce dose or interrupt treatment if hemoglobin approaches or exceeds 12 g/dL (if age ≤16 years) or 11 g/dL (if age >16 years):
Initial dose:
Infants, Children, and Adolescents ≤16 years: IV, SubQ: 50 units/kg/dose 3 times weekly.
Adolescents >16 years: IV, SubQ: 50 to 100 units/kg/dose 3 times weekly.
Dosage adjustments: IV, SubQ:
If hemoglobin does not increase by >1 g/dL after 4 weeks: Increase dose by 25%; do not increase the dose more frequently than once every 4 weeks.
If hemoglobin increases >1 g/dL in any 2-week period: Reduce dose by ≥25%; dose reductions can occur more frequently than once every 4 weeks; avoid frequent dosage adjustments.
Inadequate or lack of response over a 12-week escalation period: Further increases are unlikely to improve response and may increase risks; use the minimum effective dose that will maintain an Hgb level sufficient to avoid RBC transfusions and evaluate patient for other causes of anemia. Discontinue therapy if responsiveness does not improve.
Anemia in chronic kidney disease, NO dialysis: Note: Consider initiating treatment when hemoglobin is <10 g/dL; use only if rate of hemoglobin decline would likely result in RBC transfusion and desire is to reduce risk of alloimmunization or other RBC transfusion-related risks; reduce dose or interrupt treatment if hemoglobin exceeds 12 g/dL (if age ≤16 years) or 10 g/dL (if age >16 years):
Initial dose:
Infants, Children, and Adolescents ≤16 years: IV, SubQ: 50 units/kg/dose 3 times weekly
Adolescents >16 years: IV, SubQ: 50 to 100 units/kg/dose 3 times weekly
Dosage adjustments: IV, SubQ:
If hemoglobin does not increase by >1 g/dL after 4 weeks: Increase dose by 25%; do not increase the dose more frequently than once every 4 weeks
If hemoglobin increases >1 g/dL in any 2-week period: Reduce dose by ≥25%; dose reductions can occur more frequently than once every 4 weeks; avoid frequent dosage adjustments
Inadequate or lack of response over a 12-week escalation period: Further increases are unlikely to improve response and may increase risks; use the minimum effective dose that will maintain a Hgb level sufficient to avoid RBC transfusions and evaluate patient for other causes of anemia. Discontinue therapy if responsiveness does not improve.
Anemia due to myelosuppressive chemotherapy in cancer patients: Note: Initiate treatment only if hemoglobin <10 g/dL and anticipated duration of myelosuppressive chemotherapy is ≥2 months.
Children ≥5 years and Adolescents:
Initial dose: IV: 600 units/kg/dose once weekly until completion of chemotherapy; titrate dosage to use the minimum effective dose that will maintain a hemoglobin level sufficient to avoid red blood cell transfusions.
Dosage adjustments: IV:
If hemoglobin does not increase by >1 g/dL and remains <10 g/dL after initial 4 weeks: Increase to 900 units/kg/dose (maximum dose: 60,000 units/dose); discontinue after 8 weeks of treatment if RBC transfusions are still required or there is no hemoglobin response
If hemoglobin exceeds a level needed to avoid red blood cell transfusion: Withhold dose; resume treatment with a 25% dose reduction when hemoglobin approaches a level where transfusions may be required
If hemoglobin increases >1 g/dL in any 2-week period or hemoglobin reaches a level sufficient to avoid red blood cell transfusion: Reduce dose by 25%
Anemia due to zidovudine in HIV-infected patients: Limited data available: Note: Epoetin alfa is not described as a therapeutic option for management of anemia in pediatric HIV patients on zidovudine therapy; experts suggest discontinuing zidovudine and switching to an anti-retroviral regimen that does not contain zidovudine (Ref):
Infants ≥3 months, Children, and Adolescents ≤17 years: IV, SubQ: Doses ranging from 50 to 400 units/kg/dose 2 to 3 times weekly have been reported; withhold dose if hemoglobin exceeds 12 g/dL, may resume treatment with a 25% dose reduction once hemoglobin <11 g/dL; titrate dosage to use the minimum effective dose that will maintain a hemoglobin level sufficient to avoid red blood cell transfusions (Ref).
Infants, Children, and Adolescents: No dosage adjustment necessary.
Infants, Children, and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Cardiovascular: Hypertension (6% to 28%)
Central nervous system: Headache (5% to 18%)
Dermatologic: Pruritus (16% to 21%), skin rash (2% to 19%)
Gastrointestinal: Nausea (35% to 56%), vomiting (19% to 28%)
Local: Injection site pain (9% to 13%)
Neuromuscular & skeletal: Arthralgia (10% to 16%)
Respiratory: Cough (4% to 26%)
Miscellaneous: Fever (10% to 42%)
1% to 10%:
Cardiovascular: Thrombosis of hemodialysis vascular access (8%), thrombosis (≤6%), deep vein thrombosis (5% to 6%), edema (3%)
Central nervous system: Dizziness (10%), chills (4% to 7%), insomnia (6%), depression (5%)
Dermatologic: Urticaria (3%)
Endocrine & metabolic: Weight loss (9%), hyperglycemia (6%), hypokalemia (5%)
Gastrointestinal: Stomatitis (10%), dysphagia (5%)
Hematologic & oncologic: Leukopenia (8%)
Local: Irritation at injection site (7%)
Neuromuscular & skeletal: Myalgia (10%), muscle spasm (7%), ostealgia (7%)
Respiratory: Upper respiratory tract infection (7%)
<1%, postmarketing, and/or case reports: Antibody development (neutralizing), cardiac failure, cerebrovascular accident, erythema, erythema multiforme, exfoliation of skin, hypertensive encephalopathy, myocardial infarction, porphyria, pure red cell aplasia, seizure, severe anemia, skin blister, Stevens-Johnson syndrome, toxic epidermal necrolysis
Serious allergic reactions to epoetin alfa products or any component of the formulations; uncontrolled hypertension; pure red cell aplasia (PRCA) that begins after treatment with epoetin alfa or other epoetin protein drugs; multidose vials contain benzyl alcohol and are contraindicated in neonates, infants, pregnant women, and breastfeeding women
Canadian labeling: Additional contraindications (not in the US labelings): Known hypersensitivity to mammalian cell-derived products or any component of the formulation; patients who for any reason cannot receive adequate antithrombotic treatment; use in patients with severe coronary, peripheral arterial, carotid, or cerebral vascular disease, including patients with recent MI or cerebral vascular accident scheduled for elective surgery and not participating in an autologous blood donation program.
Concerns related to adverse effects:
• Cardiovascular events: [US Boxed Warning]: Erythropoiesis-stimulating agents (ESAs) increased the risk of serious cardiovascular events, myocardial infarction (MI), stroke, venous thromboembolism (VTE), vascular access thrombosis, and mortality in clinical studies when administered to target Hb levels >11 g/dL (and provide no additional benefit); a rapid rise in Hb (>1 g/dL over 2 weeks) may also contribute to these risks.
• Cutaneous reactions: Erythema multiforme and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) have been reported with ESAs (including epoetin alfa products); discontinue immediately if a severe cutaneous reaction develops.
• Hypersensitivity: Potentially serious allergic reactions (including anaphylactic reactions, angioedema, bronchospasm, rash, and urticaria) have been reported rarely with epoetin alfa. Discontinue immediately (and permanently) in patients who experience serious allergic/anaphylactic reactions.
• Pure red cell aplasia (PRCA): Cases of severe anemia and PRCA have been reported, predominantly in patients with chronic kidney disease (CKD) receiving SUBQ epoetin alfa; cases have also been reported in patients with hepatitis C who were receiving ESAs, interferon, and ribavirin. Patients with a sudden loss of response (with severe anemia and a low reticulocyte count) should be evaluated for PRCA with associated neutralizing antibodies to erythropoietin; discontinue treatment (permanently) in patients with PRCA secondary to neutralizing antibodies to erythropoietin. Information on assays for binding and neutralizing antibodies may be obtained from the manufacturer of the specific epoetin alfa product used. Antibodies may cross-react; do not switch to another ESA in patients who develop antibody-mediated anemia.
Disease-related concerns:
• Cancer: [US Boxed Warning]: A shortened overall survival and/or increased risk of tumor progression or recurrence has been reported in studies with breast, cervical, head and neck, lymphoid, and non-small cell lung cancer patients. It is of note that in most of these studies, patients received ESAs to a target Hb of ≥12 g/dL; although risk has not been excluded when dosed to achieve a target Hb of <12 g/dL. [US Boxed Warnings]: To decrease these risks, and risk of cardio and thrombovascular events, use the lowest dose needed to avoid RBC transfusions. Use ESAs in cancer patients only for the treatment of anemia related to concurrent myelosuppressive chemotherapy; discontinue ESA following completion of the chemotherapy course. ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is curative. A dosage modification is appropriate if Hb levels rise >1 g/dL per 2-week time period during ESA treatment (ASCO/ASH [Bohlius 2019]). Use of ESAs has been associated with an increased risk of VTE without a reduction in transfusions in patients >65 years of age with cancer (Hershman 2009). Improved anemia symptoms, quality of life, fatigue, or well-being have not been demonstrated in controlled clinical trials.
• Chronic kidney disease: [US Boxed Warning]: An increased risk of death, serious cardiovascular events, and stroke was reported in CKD patients administered ESAs to target Hb levels >11 g/dL; use the lowest dose sufficient to reduce the need for RBC transfusions. An optimal target Hb level, dose or dosing strategy to reduce these risks has not been identified in clinical trials. Hb rising >1 g/dL in a 2-week period may contribute to the risk (dosage reduction recommended). CKD patients who exhibit an inadequate Hb response to ESA therapy may be at a higher risk for cardiovascular events and mortality compared to other patients. ESA therapy may reduce dialysis efficacy (due to increase in RBCs and decrease in plasma volume); adjustments in dialysis parameters may be needed. Patients treated with epoetin alfa 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).
• Heart failure: Avoid use; erythrocyte stimulating agents do not provide clinical benefit and may increase risk of thrombotic events, including stroke (AHA/ACC/HFSA [Heidenreich 2022]; Kang 2016; Swedberg 2013).
• Hypertension: Use with caution in patients with a history of hypertension (contraindicated in uncontrolled hypertension). An excessive rate of rise of Hb is associated with hypertension or exacerbation of hypertension; decrease the epoetin alfa dose if the Hb increase exceeds 1 g/dL in any 2-week period. BP should be controlled prior to start of therapy and monitored closely throughout treatment. Hypertensive encephalopathy has been reported with patients receiving erythropoietic therapy; monitor closely and control BP.
• Perisurgery: [US Boxed Warning]: Deep vein thrombosis (DVT) prophylaxis is recommended in perisurgery patients due to the increased risk of DVT. Increased mortality was also observed in patients undergoing coronary artery bypass surgery who received epoetin alfa; these deaths were associated with thrombotic events. Epoetin alfa is not approved for reduction of RBC transfusion in patients undergoing cardiac or vascular surgery and is not indicated for surgical patients willing to donate autologous blood.
• Seizures: The risk for seizures is increased with epoetin alfa product use in patients with CKD; use with caution in patients with a history of seizures. Monitor closely for neurologic symptoms during the first several months of therapy.
• Severe anemia or acute blood loss: Due to the delayed onset of erythropoiesis, epoetin alfa is not recommended for acute correction of severe anemia or as a substitute for emergency transfusion.
Dosage form specific issues:
• Albumin: Product may contain albumin, which confers a theoretical risk of transmission of viral disease or Creutzfeldt-Jakob disease.
• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggest that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.
• Phenylalanine: Some dosage forms may contain phenylalanine, which may be harmful in patients with phenylketonuria. Consider the combined daily phenylalanine amount from all sources prior to prescribing products containing phenylalanine (and aspartame).
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.
Other warnings/precautions:
• Appropriate use:
- Oncology: The American Society of Clinical Oncology and American Society of Hematology 2019 updates to the clinical practice guidelines for the use of ESAs in adult patients with cancer indicate that ESAs are appropriate when used according to the parameters identified within the FDA-approved labeling for epoetin alfa and darbepoetin alfa (ASCO/ASH [Bohlius 2019]). ESAs are an option for chemotherapy-associated anemia in patients whose cancer treatment is not of curative intent and when the Hb has fallen to <10 g/dL. ESAs should not be used when the intent of cancer chemotherapy is curative. ESAs should only be used in conjunction with concurrent myelosuppressive chemotherapy (except in the case of low-risk myelodysplastic syndromes). For patients with myeloma, non-Hodgkin lymphoma, or chronic lymphocytic leukemia, observe hematologic response to cancer treatment prior to considering an ESA. Consider risks versus benefits when there is an increased risk of thromboembolic complications. The recommended target Hb level is the lowest Hb concentration necessary to avoid or reduce the need for RBC transfusion. ESAs should be discontinued in patients who do not respond (eg, <1 to 2 g/dL increase in Hb or no reduction in RBC transfusions within 6 to 8 weeks [evaluate nonresponders for underlying tumor progression, iron deficiency, or other causes of anemia]). Iron replacement may be utilized to improve Hb response or reduce RBC transfusions in patients with and without iron deficiency receiving ESAs.
• Factors impairing erythropoiesis: Prior to treatment, correct or exclude deficiencies of iron, vitamin B12, and/or folate, as well as other factors that may impair erythropoiesis (inflammatory conditions, infections, bleeding). Poor response to therapy should prompt evaluation of potential factors impairing erythropoiesis, as well as possible malignant processes and hematologic disease (thalassemia, refractory anemia, myelodysplastic disorder), occult blood loss, hemolysis, osteitis fibrosa cystic, and/or bone marrow fibrosis.
May be associated with an increased risk of retinopathy of prematurity (ROP); an increase in ROP has been observed in neonates receiving epoetin alfa for anemia of prematurity, with a reported incidence of 15% to 17%; however, a direct association with the drug has not been established. A meta-analysis of early treatment with epoetin alfa showed that neonates treated within the first week of life did not have a significant increased incidence in stage ≥3 ROP; however, a post-ad hoc data analysis of all neonates (regardless of age at treatment) showed an increased risk (Ohlsson 2014); a meta-analysis of late treatment showed an overall trend toward increased incidence of ROP (all stages) and at stage ≥3 (Aher 2014). A phase 3 randomized, placebo-controlled trial of the use of high-dose erythropoietin in extremely preterm infants showed no significant difference between treatment and placebo groups for the incidence of ROP (Juul 2020). Risks and benefits should be assessed prior to initiation.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Injection:
Epogen: 10,000 units/mL (2 mL); 20,000 units/mL (1 mL) [contains albumin human, benzyl alcohol]
Procrit: 10,000 units/mL (2 mL); 20,000 units/mL (1 mL) [contains albumin human, benzyl alcohol]
Retacrit: Epoetin Alfa-epbx 10000 units/mL (2 mL); Epoetin Alfa-epbx 20000 units/mL (1 mL) [contains benzyl alcohol]
Solution, Injection [preservative free]:
Epogen: 2000 units/mL (1 mL); 3000 units/mL (1 mL); 4000 units/mL (1 mL); 10,000 units/mL (1 mL) [contains albumin human]
Procrit: 2000 units/mL (1 mL); 3000 units/mL (1 mL); 4000 units/mL (1 mL); 10,000 units/mL (1 mL); 40,000 units/mL (1 mL) [contains albumin human]
Retacrit: Epoetin Alfa-epbx 2000 units/mL (1 mL); Epoetin Alfa-epbx 3000 units/mL (1 mL); Epoetin Alfa-epbx 4000 units/mL (1 mL); Epoetin Alfa-epbx 10000 units/mL (1 mL); Epoetin Alfa-epbx 40000 units/mL (1 mL) [contains phenylalanine]
No
Solution (Epogen Injection)
2000 units/mL (per mL): $39.79
3000 units/mL (per mL): $59.69
4000 units/mL (per mL): $79.58
10000 units/mL (per mL): $198.96
20000 units/mL (per mL): $397.92
Solution (Procrit Injection)
2000 units/mL (per mL): $64.15
3000 units/mL (per mL): $96.22
4000 units/mL (per mL): $128.28
10000 units/mL (per mL): $320.70
20000 units/mL (per mL): $641.40
40000 units/mL (per mL): $1,282.80
Solution (Retacrit Injection)
2000 units/mL (per mL): $26.47
3000 units/mL (per mL): $39.71
4000 units/mL (per mL): $52.94
10000 units/mL (per mL): $132.36
20000 units/mL (per mL): $264.72
40000 units/mL (per mL): $529.44
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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Injection:
Eprex: 6000 units/0.6 mL (0.6 mL); 20,000 units/0.5 mL (0.5 mL); 40,000 units/mL (1 mL)
Solution Prefilled Syringe, Injection:
Eprex: 1000 units/0.5 mL (0.5 mL); 2000 units/0.5 mL (0.5 mL); 3000 units/0.3 mL (0.3 mL); 4000 units/0.4 mL (0.4 mL); 5000 units/0.5 mL (0.5 mL); 8000 units/0.8 mL (0.8 mL); 10,000 units/mL (1 mL); 30,000 units/0.75 mL (0.75 mL)
SUBQ: SUBQ is the preferred route of administration except in patients with chronic kidney disease (CKD) on hemodialysis. In patients with CKD on hemodialysis, the IV or SUBQ route can be used (Ref). Do not shake.
Epogen, Procrit: Usually administered undiluted, although preservative-free (single-dose vial) formulations may be diluted in a syringe prior to administration as a 1:1 dilution using bacteriostatic NS.
Retacrit: Do not dilute.
Parenteral: Do not shake as this may denature the glycoprotein rendering the drug biologically inactive; do not use if product has been shaken or frozen.
SubQ: Administer into the outer upper arm, abdomen (except within 2 inches of navel), front middle thigh, or the upper outer buttocks area. Rotate injection site; do not inject into areas that are tender, red, bruised, hardened, or scarred, or sites with stretch marks.
Neonates and Infants: Use single-dose vials only to provide doses; limits exposure to benzyl alcohol and potential toxicity. Do not mix with bacteriostatic NS.
Children and Adolescents:
Epogen, Procrit: Usually administered undiluted; preservative-free solutions may be mixed with bacteriostatic NS at time of administration to reduce pain at injection site. Multiple-dose vials already contain benzyl alcohol.
Retacrit: Do not dilute.
IV:
Neonates: Only use single-dose preservative-free formulations; limits exposure to benzyl alcohol and potential toxicity. Based on studies evaluating use in neonates for neuroprotection/hypoxic ischemia encephalopathy, administer peripherally or centrally as bolus injection over <2 minutes; may follow with NS flush through the most proximal port; flush volume ≥3 times the line volume (Ref).
Infants, Children, and Adolescents: Administer by IV bolus; usually administered undiluted; preservative-free solutions may be mixed with bacteriostatic NS at time of administration; may be administered into the hemodialysis line. Note: For infant doses, only use preservative-free single-use formulations; limits exposure to benzyl alcohol and potential toxicity.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Epogen: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/103234s5363s5366lbl.pdf#page=27
Procrit: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/103234s5360s5364lbl.pdf#page=58
Retacrit (epoetin alfa-epbx): https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125545s005lbl.pdf#page=31
Anemia due to chemotherapy in patients with cancer: Treatment of anemia in patients with nonmyeloid malignancies in which anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of 2 additional months of planned chemotherapy.
Anemia due to chronic kidney disease: Treatment of anemia due to chronic kidney disease, including patients on dialysis and not on dialysis, to decrease the need for RBC transfusion.
Anemia due to zidovudine in HIV-infected patients: Treatment of anemia due to zidovudine administered at ≤4.2 g/week in HIV-infected patients with endogenous serum erythropoietin levels of ≤500 milliunits/mL.
Reduction of allogeneic RBC transfusion in patients undergoing elective, noncardiac, nonvascular surgery: To reduce the need for allogeneic RBC transfusions among patients with perioperative hemoglobin >10 to ≤13 g/dL who are at high risk of perioperative blood loss from elective, noncardiac, nonvascular surgery. Epoetin alfa is not indicated for patients who are willing to donate autologous blood preoperatively.
Limitations of use: Epoetin alfa has not been shown to improve quality of life, fatigue, or patient well-being. Epoetin alfa is not indicated for use under the following conditions:
- Cancer patients receiving hormonal therapy, therapeutic biologic products, or radiation therapy unless also receiving concurrent myelosuppressive chemotherapy
- Cancer patients receiving myelosuppressive chemotherapy when the expected outcome is curative
- Cancer patients receiving myelosuppressive chemotherapy when anemia can be managed by transfusion
- Surgery patients who are willing to donate autologous blood
- Surgery patients undergoing cardiac or vascular surgery
- As a substitute for RBC transfusion in patients requiring immediate correction of anemia
Note: Retacrit (epoetin alfa-epbx) is approved as a biosimilar to Epogen (epoetin alfa) and Procrit (epoetin alfa).
Myelodysplastic syndromes, lower-risk (symptomatic anemia management); Red blood cell transfusion refusal (substitute)
Epoetin alfa may be confused with darbepoetin alfa, methoxy polyethylene glycol-epoetin beta
Epogen may be confused with Neupogen
Procrit may be confused with Retacrit
Epopen [Spain] may be confused with EpiPen brand name for epinephrine [US, Canada, and multiple international markets]
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
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
In vitro studies suggest that recombinant erythropoietin does not cross the human placenta (Reisenberger 1997). Polyhydramnios and intrauterine growth retardation have been reported with use in females with chronic kidney disease (CKD) (adverse effects also associated with maternal disease).
Recombinant erythropoietin alfa has been evaluated as adjunctive treatment for severe pregnancy associated iron deficiency anemia (Breymann 2001; Krafft 2009) and has been used in pregnant females with iron-deficiency anemia associated with CKD (Furaz-Czerpak 2012; Josephson 2007).
Multidose formulations containing benzyl alcohol are contraindicated for use in pregnant females; if treatment during pregnancy is needed, single-dose preparations should be used.
Endogenous erythropoietin is found in breast milk (Semba 2002). It is not known if recombinant erythropoietin alfa is present in breast milk. The manufacturer recommends caution be used if the single dose vial preparation is administered to breastfeeding women; use of the multiple dose vials containing benzyl alcohol is contraindicated in breastfeeding women. When administered enterally to neonates (mixed with human milk or infant formula), recombinant erythropoietin did not significantly increase serum EPO concentrations. If passage via breast milk does occur, risk to a breastfed infant appears low (Juul 2003).
Transferrin saturation and serum ferritin (prior to and during treatment) to ensure adequate stores before initiating and throughout therapy; Hb (weekly after initiation and following dose adjustments until stable and sufficient to minimize need for RBC transfusion, chronic kidney disease [CKD] patients should be also be monitored at least monthly following Hb stability); BP; monitor for signs of seizures (CKD patients following initiation for first few months, includes new-onset or change in seizure frequency or premonitory symptoms).
Cancer patients: Examinations recommended prior to treatment include: Appropriate history, physical, and diagnostic tests to identify/rule out other causes of anemia, including peripheral blood smear (in some situations a bone marrow exam may be necessary), assessment (if indicated) for iron, total iron-binding capacity, transferrin saturation, ferritin, folate, vitamin B12, or hemoglobinopathy screening, reticulocyte count, kidney function status, and occult blood loss; baseline erythropoietin level; in patients with chronic lymphocytic leukemia, non-Hodgkin lymphoma, or a history of autoimmune disease, direct antiglobulin testing (eg, Coombs test) may be necessary (ASCO/ASH [Bohlius 2019]). During erythropoiesis-stimulating agent (ESA) treatment, assess iron status with total iron-binding capacity, and transferrin saturation or ferritin levels.
Diabetes: HbA1c is not useful as a glycemic indicator in patients treated with an ESA. Other monitoring parameters may be more useful.
Myelodysplastic syndromes (off-label use): Patients with baseline erythropoietin levels >500 milliunits/mL are unlikely to respond to erythropoiesis-stimulating agents (ASCO/ASH [Bohlius 2019]).
Zidovudine-treated HIV patients: Available evidence indicates patients with endogenous serum erythropoietin levels >500 milliunits/mL are unlikely to respond.
Epoetin alfa induces erythropoiesis by stimulating the division and differentiation of committed erythroid progenitor cells; induces the release of reticulocytes from the bone marrow into the bloodstream, where they mature to erythrocytes. There is a dose response relationship with this effect. This results in an increase in reticulocyte counts followed by a rise in hematocrit and hemoglobin levels.
Note: While a much higher peak plasma concentration is achieved after IV bolus administration, it declines at a more rapid rate than after subcutaneous administration (McMahon 1990; Salmonson 1990)
Onset of action: Reticulocyte count increase: Within 10 days.
Peak effect: Hemoglobin level: 2 to 6 weeks
Absorption: SubQ: Slow (McMahon 1990; Salmonson 1990)
Distribution: Vd: 9 L; rapid in the plasma compartment; concentrated in liver, kidneys, and bone marrow; similar to extracellular plasma volume in adults (McMahon 1990; Salmonson 1990); reported to be higher in premature neonates on body weight basis (Brown 1993)
Metabolism: Some degradation does occur
Bioavailability: SubQ: Premature neonates: 42% (Brown 1993); Adults: 36% (Salmonson 1990); intraperitoneal epoetin alfa: 3% (Macdougall 1989)
Half-life elimination:
Neonates: With high doses, nonlinear kinetics have been observed (Wu 2012)
Anemia of prematurity:
Post menstrual age (PMA) <32 week (weight: 800 ± 206 grams): IV: 8.1 ± 2.7 hours; SubQ: 7.1 ± 4.1 hours (Brown 1993)
PMA ≥32 weeks (weight range: 1,330 to 1,740 g): SubQ: Median: 7.9 hours (range: 5.6 to 19.4 hours) (Krishnan 1996)
Neuroprotective/hypoxic ischemia encephalopathy (HIE) (Wu 2012): ≥36 weeks GA; IV:
250 units/kg: 7.6 ± 6.9 hours
500 units/kg: 7.2 ± 1.9 hours
1,000 units/kg: 15 ± 4.5 hours
2,500 units/kg: 18.7 ± 4.7 hours
Infants, Children, and Adolescents: Chronic kidney disease: IV: 4 to 13 hours
Adults: Cancer: SubQ: 16 to 67 hours; Chronic kidney disease: IV: 4 to 13 hours
Time to peak, serum: Pediatric patients >1 month and Adults: Chronic kidney disease: SubQ: 5 to 24 hours
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