Epoetin Alfa

Dosage Forms

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]

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: 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 phenylalanine]

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

Absorption

SubQ: Slow (McMahon 1990; Salmonson 1990)

Distribution

V_d: 9 L; rapid in the plasma compartment; concentrated in liver, kidneys, and bone marrow; similar to extracellular plasma volume in adults (McMahon 1990; Salmonson1990); reported to be higher in premature neonates on body weight basis (Brown 1993)

Metabolism

Some degradation does occur

Onset of Action

Reticulocyte count increase: Within 10 days; Peak effect: Hemoglobin level: 2 to 6 weeks

Time to Peak

Serum: Pediatric patients >1 month and Adults: Chronic kidney disease: SubQ: 5 to 24 hours

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

Use: Labeled Indications

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).

Use: Off Label

Myelodysplastic syndromes, lower-risk (symptomatic anemia management)ayes

Data from 4 studies, a meta-analysis, and a systematic review support the use of epoetin alfa (initially as a single agent and then in combination with growth-colony stimulating factor after single-agent failure) in the management of anemia in patients with lower-risk myelodysplastic syndromes Fenaux 2018, Greenberg 2009, Hellström-Lindberg 1995, Musto 2003, Park 2008, Park 2019.

Based on guidelines from the American Society of Clinical Oncology and the American Society of Hematology for management of cancer-associated anemia with erythropoiesis-stimulating agents (ESAs), ESAs may be an option for management of anemia in patients with lower-risk myelodysplastic syndromes who have an erythropoietin level ≤500 milliunits/mL.

Red blood cell transfusion refusal (substitute)cyes

Multiple case reports in patients (eg, Jehovah’s Witnesses) using epoetin alfa as a substitute in RBC transfusion refusal have been published in different clinical scenarios with varying dosing regimens Ball 2008, Brunetta 2015, Dallas 2015, Plunkett 2015, Rebel 2015. Additionally, data from 3 retrospective studies suggest that the use of high-dose epoetin alfa plus iron (with or without vitamin B₁₂ and folic acid supplementation) for perioperative hemoglobin optimization before and after major elective surgery (eg, cardiac, spinal surgery) in patients (eg, Jehovah’s Witnesses) refusing allogeneic blood transfusion is beneficial in this setting Joseph 2008, McCartney 2014, Tanaka 2015. Additional data may be necessary to further define the role of epoetin alfa for this situation.

Based on the 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines, it is reasonable to administer preoperative epoetin alfa plus iron several days before cardiac surgery to increase red cell mass in patients with preoperative anemia, in patients who refuse allogeneic blood transfusion (eg, Jehovah’s Witnesses), or in patients who are at high risk for postoperative anemia. Consider the association of epoetin alfa and thrombotic cardiovascular events in patients with renal failure.

Contraindications

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.

Dosage and Administration

Dosing: Adult

Note: Doses are usually rounded to the nearest vial size. Evaluate iron status in all patients before and during treatment. The manufacturer recommends supplemental iron be administered if serum ferritin is <100 ng/mL or serum transferrin saturation (TSAT) is <20%. Most patients with chronic kidney disease (CKD) will require iron supplementation. Retacrit (epoetin alfa-epbx) is approved as a biosimilar to Epogen (epoetin alfa) and Procrit (epoetin alfa).

Anemia due to CKD: Individualize dosing and use the lowest dose necessary to reduce the need for RBC transfusions.

CKD patients ON dialysis (IV route is preferred for hemodialysis patients; initiate treatment when Hb is <10 g/dL; reduce dose or interrupt treatment if Hb approaches or exceeds 11 g/dL): IV, SubQ: Initial dose: 50 to 100 units/kg 3 times a week.

CKD patients NOT on dialysis (consider initiating treatment when Hb is <10 g/dL; use only if rate of Hb decline would likely result in RBC transfusion and desire is to reduce risk of alloimmunization and/or other RBC transfusion-related risks; reduce dose or interrupt treatment if Hb exceeds 10 g/dL): IV, SubQ: Initial dose: 50 to 100 units/kg once weekly (Berns 2019; McGowan 2008; Provenzano 2004). May also consider administering 10,000 to 20,000 units every other week (Piccoli 2002; Provenzano 2005).

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

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

If Hb increases >1 g/dL in any 2-week period: Reduce dose by ≥25%.

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 Hb level sufficient to avoid RBC transfusions and evaluate patient for other causes of anemia. Discontinue therapy if responsiveness does not improve.

Anemia due to chemotherapy in cancer patients: 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 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 (Greenberg 2009) 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 (Fenaux 2018) or 450 to 1,000 units/kg/week in divided doses, 3 to 7 times a week (Hellström-Lindberg 1995) or 40,000 units once weekly (Musto 2003) or 60,000 units once weekly (Park 2008).

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 (Joseph 2008).

Cardiac (elective) surgery:

One protocol based on timing of elective surgery and preoperative Hb used the following (McCartney 2014):

>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 (Tanaka 2015):

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.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Dosing schedules need to be individualized and careful monitoring of patients receiving the drug is recommended. 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 (NOT on 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 (HHS [pediatric 2018]):

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 (Ferri 2002)

Reconstitution

Epogen, Procrit: Usually administered undiluted, although prior to administration, preservative-free solutions may be mixed with bacteriostatic NS containing benzyl alcohol 0.9% in a 1:1 ratio.

Retacrit: Do not dilute.

Administration

SubQ: SubQ is the preferred route of administration except in patients with chronic kidney diease (CKD) on hemodialysis. In patients with CKD on hemodialysis, the IV route is recommended. 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.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F). Do not freeze. Do not shake. Protect from light. Extended storage information for intact vials at room temperature may be available; contact product manufacturer to obtain current recommendations.

Single-dose 1 mL vial contains no preservative. Use one dose per vial. Do not re-enter vial; discard unused portions.

Multidose 1 mL or 2 mL vial contains preservative. Store at 2°C to 8°C (36°F to 46°F) after initial entry and between doses. Discard 21 days after initial entry.

Prefilled syringes containing the 20,000 units/mL formulation with preservative are stable for 6 weeks refrigerated (2°C to 8°C) (Naughton 2003).

Dilutions of 1:10 and 1:20 (1 part epoetin alfa:19 parts sodium chloride) are stable for 18 hours at room temperature (Ohls 1996).

Epogen, Procrit: Prior to SubQ administration, preservative free solutions may be mixed with bacteriostatic NS containing benzyl alcohol 0.9% in a 1:1 ratio (Corbo 1992).

Dilutions of 1:10 in D10W with human albumin 0.05% or 0.1% are stable for 24 hours.

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

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

Adverse Reactions

>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

Warnings/Precautions

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 (the IV route is preferred for hemodialysis patients); 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 patients: [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 patients: [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.
• 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 patients: [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.

- Cardiovascular disease: The American College of Physicians recommends against the use of ESAs in patients with mild to moderate anemia and heart failure or coronary heart disease (ACP [Qaseem 2013]). The American College of Cardiology Foundation/American Heart Association 2013 Heart Failure Guidelines do not provide a clear recommendation on the use of ESAs in anemic heart failure patients. The effects of ESAs on quality of life measures, morbidity, and mortality are potentially modest and still unclear. Additionally, the safety of epoetin alfa has not been well studied in this population. The authors declined to provide an official recommendation regarding the use of ESAs pending the completion of ongoing randomized trials (ACCF/AHA [Yancy 2013]).

• 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.

Monitoring Parameters

Transferrin saturation and serum ferritin (prior to and during treatment); Hb (weekly after initiation and following dose adjustments until stable and sufficient to minimize need for RBC transfusion, chronic kidney diease [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 ESA treatment, assess iron status with total iron-binding capacity, and transferrin saturation or ferritin levels.

Pregnancy

Pregnancy Considerations

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.

Patient Education

What is this drug used for?

• It is used to treat anemia.
• It is used to help avoid the need for blood transfusions.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Injection site irritation
• Nausea
• Vomiting
• Cough
• Bone pain
• Joint pain
• Muscle pain
• Muscle spasms
• Mouth irritation
• Mouth sores
• Weight loss
• Trouble sleeping
• Common cold symptoms

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Severe cerebrovascular disease like change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes
• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit
• Low potassium like muscle pain or weakness, muscle cramps, or an abnormal heartbeat
• Fast heartbeat
• Shortness of breath
• Excessive weight gain
• Swelling of arms or legs
• Severe dizziness
• Passing out
• Confusion
• Seizures
• Severe headache
• Vision changes
• Severe loss of strength and energy
• Pale skin
• Sweating a lot
• Depression
• Blood clots like 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
• Cool or pale arms or legs
• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes
• Abnormal gait
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.