VA Class:BL400

AHFS Class:

• Hematopoietic Agents 20:16

Generic Name(s):

• Epoetin AlfaEpoetin alfa-epbx

Chemical Name:

• 1-165-Erythropoietin (human clone λHEPOFL13 protein moiety)

Molecular Formula:

• C₈₀₉H₁₃₀₁N₂₂₉O₂₄₀S₅

Epoetin alfa, a biosynthetic form of the glycoprotein hormone erythropoietin, is a hematopoietic agent that principally affects erythropoiesis.1,2,3

Epoetin alfa-epbx is biosimilar to epoetin alfa (Epogen^®; Procrit^®).1,2,3,5 The FDA defines a biosimilar as a biological that is highly similar to an FDA-licensed reference biological with the exception of minor differences in clinically inactive components and for which there are no clinically meaningful differences in safety, purity, or potency.3,170,171,172 The claim of biosimilarity is based on a totality-of-evidence approach, which includes consideration of data from analytical, animal, and clinical studies.171,172 Therefore, biosimilarity of 2 drugs may be established even when there are formulation or minor structural differences or minor differences in rates of adverse effects between the drugs as long as these differences are not clinically meaningful.170,171,172 Biosimilars are approved through an abbreviated licensure pathway that establishes biosimilarity between the proposed biological and the reference biological but does not independently establish safety and effectiveness of the proposed biological.170,171

In order to be considered an interchangeable biosimilar, a biological product must meet additional requirements beyond demonstrating biosimilarity to its reference product; these requirements include demonstrating that the biological product can be expected to produce the same clinical results as the reference product in any given patient and, for a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is no greater than the risk of using the reference product without such alternation or switch.171 Biosimilar products that are interchangeable can be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product.171 The currently available epoetin alfa biosimilar does not have interchangeable data at this time.3

In this monograph, unless otherwise stated, the term “epoetin alfa products” refers to epoetin alfa (the reference drug), epoetin alfa-epbx (the biosimilar), or both drugs.

Epoetin alfa and epoetin alfa-epbx have not been shown to improve quality of life, fatigue, or patient well-being.1,2,3

Anemia of Chronic Kidney Disease

Epoetin alfa and epoetin alfa-epbx are used for the treatment of anemia associated with chronic kidney disease (CKD), including that in patients who are dialysis-dependent and in those who do not yet require maintenance dialysis (predialysis patients), to reduce the need for red blood cell (RBC) transfusions.1,2,3 Epoetin alfa has been designated an orphan drug by the US Food and Drug Administration (FDA) for anemia associated with end-stage renal disease (ESRD).4

Epoetin alfa is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia.1,2,3

Dialysis-dependent CKD

Adult Patients: Anemia in Dialysis-dependent CKD

The efficacy and safety of IV administration of epoetin alfa (50 to 150 units/kg 3 times weekly) in adults with anemia and dialysis-dependent CKD was evaluated across 13 studies (N=1,010); pooled data from these studies are summarized in the package labeling for epoetin alfa products.1,2,3 Epoetin alfa produced dose-dependent increases in hemoglobin concentration, and more than 90% of patients experienced improvement in hemoglobin concentration.1,2,3 In the 3 largest studies, the median dose necessary to maintain the hemoglobin between 10 to 12 g/dL was approximately 75 units/kg 3 times weekly; transfusions were avoided in more than 95% of patients.1,2,3 In the largest US multicenter study, approximately 65% of patients received doses of ≤100 units/kg 3 times weekly and were able to maintain a hemoglobin of approximately 11.7 g/dL; approximately 10% of patients each received a dose of ≤25 units/kg or >200 units/kg 3 times weekly to maintain a hemoglobin at this level.1,2,3

In the Normal Hematocrit Study (NHS), all hemodialysis patients received epoetin alfa.1,2,3,6 The yearly transfusion rate was 51.5% in the group targeting a lower hemoglobin concentration (10 g/dL) and 32.4% in the group targeting a higher hemoglobin concentration (14 g/dL).1,2,3 (See Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism under Cautions.)

In another 26-week, randomized, double-blind, placebo-controlled study (N=118), adults with dialysis-dependent CKD and an average hemoglobin concentration of 7 g/dL saw increases in hemoglobin concentration to approximately 11 g/dL with epoetin alfa therapy; hemoglobin concentration was unchanged in the placebo group.1,2,3,7 Starting at 2 months of therapy, patients treated with epoetin alfa experienced improvements in exercise tolerance and physical functioning.1,2,3,7

In patients receiving peritoneal dialysis who self-administered epoetin alfa subcutaneously (N=119), a multicenter unit-dose study found similar responses to those seen in patients receiving IV epoetin alfa therapy.1,2,3

A meta-analysis compared ESA originator products to biosimilars and epoetin alfa to darbepoetin alfa.8 A total of 30 randomized controlled trials (RCTs; N=7843) were included, of which 21 included patients receiving hemodialysis or peritoneal dialysis.8 The following outcomes were measured: hemoglobin concentration, transfusion requirements, fatigue, breathlessness, all-cause mortality, cardiovascular (CV) mortality, occurrence of myocardial infarction (MI), stroke, hypertension, vascular access thrombosis, or ESRD.8 In comparisons between epoetin alfa and biosimilar products, the results did not statistically differ for the risk of any outcome, and the quality of evidence rated from low to very low.8 In the comparisons between epoetin alfa and darbepoetin alfa, only blood transfusions reached statistical significance for increased risk with epoetin alfa versus darbepoetin alfa (relative risk, 2.18).8 The quality of evidence evaluating this outcome rated very low and for all other outcomes rated from low to very low.8 In another meta-analysis of 28 RCTs, optimal IV iron usage per a 2012 KDIGO guideline reduced ESA dose requirements by an average of 23% in dialysis-dependent patients with anemia, when compared to suboptimal iron usage.9

Pediatric Patients: Anemia in Dialysis-dependent CKD

The efficacy and safety of epoetin alfa in pediatric patients with anemia (hemoglobin ≤9 g/dL) undergoing peritoneal dialysis or hemodialysis were evaluated in a randomized, placebo-controlled study (N=113).1,2,3 Epoetin alfa was started at a dose of 50 units/kg 3 times weekly (IV or subcutaneously) and titrated to achieve either a hemoglobin concentration of 10 to 12 g/dL or an absolute increase in hemoglobin concentration of 2 g/dL.1,2,3 At 12 weeks, the rise in hemoglobin concentration was higher for patients treated with epoetin alfa (3.1 g/dL) versus placebo (0.3 g/dL).1,2,3 More patients in the epoetin alfa versus placebo group achieved a hemoglobin concentration of 10 g/dL or an increase in hemoglobin concentration of 2 g/dL over baseline (96% versus 58%).1,2,3 The majority of patients in the epoetin alfa group were transfusion independent within 12 weeks (92.3% versus 65.4% in those who received placebo).1,2,3 Among patients who received epoetin alfa therapy for 36 weeks, patients undergoing hemodialysis versus peritoneal dialysis received a higher median maintenance dose (167 units/kg/week [n=28] versus 76 units/kg/week [n=36]) and had a longer median time to achieve a hemoglobin of 10 to 12 g/dL (69 days versus 32 days).1,2,3

The pattern of adverse events in pediatric patients with anemia who are dialysis-dependent and receive epoetin alfa is similar to that observed in adults.1,2,3

Predialysis CKD

Adult Patients: Anemia in CKD Not Requiring Dialysis

The efficacy and safety of epoetin alfa in adults with anemia who are not receiving dialysis were evaluated in 4 studies (N=181); the observed response was similar to that seen in patients receiving dialysis.1,2,3 There was a dose-dependent and sustained increase in hemoglobin concentration when epoetin alfa was administered either IV or subcutaneously, with similar rates of rise in hemoglobin concentration when epoetin alfa was administered by either route.1,2,3

A post-hoc analysis of the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) demonstrated that RBC transfusions were less frequent in the group of patients administered another ESA, darbepoetin alfa, to target a hemoglobin concentration of 13 g/dL (15%), compared to the control group in which darbepoetin alfa was administered intermittently when hemoglobin concentration was <9 g/dL (25%).1,2,3 In the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial, neither administration of epoetin alfa to target a higher (13.5 g/dL) or lower (11.3 g/dL) hemoglobin concentrations reduced RBC transfusions.1,2,3,10 In each trial, the potential benefit of ESA therapy was offset by worse CV safety outcomes resulting in an unfavorable benefit-risk profile.1,2,3 (See Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism under Cautions.)

Pediatric Patients: Anemia in CKD Not Requiring Dialysis

The efficacy and safety of epoetin alfa in pediatric patients with anemia who are not receiving dialysis are supported by efficacy data in pediatric patients who are dialysis-dependent; the mechanism of action of epoetin alfa in these 2 populations is the same.1,2,3 In published literature, epoetin alfa therapy in this population has demonstrated dose-dependent increases in hemoglobin and hematocrit and reductions in transfusion requirements.1,2,3

The pattern of adverse events in pediatric patients who receive epoetin alfa is similar to that observed in adults.1,2,3 The manufacturer states that there does not appear to be differences in the safety profile of epoetin alfa in pediatric patients with CKD who are dialysis-dependent versus pediatric patients not requiring dialysis.1,2,3

Clinical Perspective

The Kidney Disease Improving Global Outcomes (KDIGO) guideline recommends addressing all correctable causes of anemia prior to starting erythropoietin stimulating agent (ESA) therapy and weighing the potential benefits and risks of ESAs for each patient where therapy is considered.48 Individualization of therapy when using ESAs is stressed, as individual patient responses to treatment may differ.48 ESAs are suggested for adults with CKD not receiving dialysis when hemoglobin concentration is <10 g/dL and for adults receiving dialysis when the hemoglobin concentration falls to 9 to 10 g/dL.48 In all pediatric patients with CKD, the guideline suggests that the hemoglobin threshold for initiating ESA therapy should be individualized based on the balance of risks and benefits of treatment.48 Concerning maintenance therapy, the guideline suggests that ESAs should not be used to maintain hemoglobin concentrations above 11.5 g/dL in adults with CKD; in pediatric patients with CKD, it is suggested that hemoglobin be maintained between 11 to 12 g/dL.48 Both IV and subcutaneous routes of administration are suggested for patients receiving dialysis, and the subcutaneous route is suggested for patients with CKD not receiving dialysis or receiving peritoneal dialysis.48 The guideline does not specify a preferred ESA and suggests that ‘copy' versions of ESAs should only be those which have been designated a true biosimilar.48 The Kidney Disease Outcomes Quality Initiative (KDOQI) US Commentary on the 2012 KDIGO guideline states that for maintenance therapy, KDOQI supports a lower limit of goal hemoglobin of 11 g/dL.48,49

Anemia in Patients with HIV infection Treated with Zidovudine

Epoetin alfa and epoetin alfa-epbx are used for the treatment of anemia associated with zidovudine therapy in patients with HIV infection.1,2,3 The drug is indicated in such patients with endogenous serum erythropoietin concentrations of ≤500 milliunits/mL who are receiving zidovudine therapy in dosages ≤4.2 g per week.1,2,3 Epoetin alfa products are not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia.1,2,3 Epoetin alfa has been designated an orphan drug by the FDA for anemia associated with HIV infection or HIV treatment.4

Adult Patients: Anemia in Patients with HIV infection Treated with Zidovudine

The efficacy and safety of epoetin alfa in patients with HIV infection treated with zidovudine were evaluated in 4 randomized, double-blind, placebo-controlled studies enrolling 297 patients with a hemoglobin <10 g/dL.1,2,3,11 Epoetin alfa was administered 3 times weekly for 12 weeks at a dose of 100 units/kg IV in 1 study and 100 to 200 units/kg IV or subcutaneously in 3 studies.11 In the subgroup of patients with pre-study endogenous serum erythropoietin levels ≤500 milliunits/mL (89/125 in the epoetin alfa group and 88/130 in the placebo group), epoetin alfa reduced the mean cumulative number of units of blood transfused per patient by approximately 40% versus the placebo group.1,2,3,11 During the second and third months of therapy, more patients treated with epoetin alfa (43%) versus placebo (18%) no longer required transfusions.1,2,3,11 Epoetin alfa also significantly increased hemoglobin concentration in comparison to placebo.1,2,3,11 Approximately 17% of the patients with endogenous serum erythropoietin levels ≤500 milliunits/mL achieved a hemoglobin of 12.7 g/dL without transfusion or significant reduction in zidovudine dose.1,2,3,11 In the subgroup of patients with a weekly zidovudine dose ≤4.2 grams during the 3 months of therapy, there was a statistically significant reduction in transfusion requirements for patients treated with epoetin alfa (n=51) versus placebo (n=54).1,2,3,11 Importantly, epoetin alfa did not reduce RBC transfusion requirements or increase hemoglobin concentration in the subgroup of patients whose pre-study endogenous serum erythropoietin levels were >500 milliunits/mL.1,2,3,11

Pediatric Patients: Anemia in Patients with HIV infection Treated with Zidovudine

The efficacy and safety of epoetin alfa in pediatric patients (ages 8 months to 17 years) with anemia and HIV infection treated with zidovudine have been evaluated (N=20); epoetin alfa was administered 2 to 3 times weekly at a dose of 50 to 400 units/kg IV or subcutaneously.1,2,3 Increases in hemoglobin concentration and reticulocyte count, and reduction in transfusion requirement, were observed in this population.1,2,3

Clinical Perspective

Older nucleoside reverse transcriptase inhibitors (NRTIs), including zidovudine, stavudine, and didanosine, are no longer recommended in routine clinical practice in the United States, and thus have reduced the need for epoetin alfa products in this setting.200 Zidovudine does still have a role in the prevention of perinatal transmission of HIV and is also recommended as an alternative agent in pediatric HIV infection.200,201,202

Anemia Due to Chemotherapy in Patients with Nonmyeloid Malignancies

Epoetin alfa and epoetin alfa-epbx are used for the treatment of chemotherapy-induced anemia in patients with nonmyeloid malignancies in whom chemotherapy is planned for at least 2 additional months.1,2,3 Therapy with epoetin alfa products or other ESAs should be initiated only when the hemoglobin concentration is <10 g/dL and should be discontinued after completion of a course of myelosuppressive chemotherapy.1,2,3

Epoetin alfa products are not indicated for use in patients with cancer receiving: hormonal agents, biologic products, or radiation therapy unless they are also receiving concomitant myelosuppressive chemotherapy; myelosuppressive chemotherapy when the anticipated outcome is cure; or myelosuppressive chemotherapy in whom the anemia can be managed by transfusion.1,2,3

Epoetin alfa products are not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia.1,2,3

Adult Patients: Anemia Due to Concomitantly Administered Cancer Chemotherapy

The efficacy and safety of epoetin alfa in adults with cancer and anemia due to concomitant myelosuppressive chemotherapy for nonmyeloid malignancy were evaluated in a single multicenter, randomized, placebo-controlled, double-blind trial and a pooled analysis of 6 additional randomized, multicenter, placebo-controlled, double-blind trials.1,2,3,13

In the randomized, placebo-controlled trial (N=344), 14% of patients receiving epoetin alfa (40,000 units by subcutaneous injection once weekly) required a RBC transfusion between weeks 5 and 16 or the last day on study, compared with 28% of those receiving placebo.1,2,3,13 Furthermore, transfusion requirements were reduced with epoetin alfa versus placebo in those who received a cisplatin-containing chemotherapy regimen (15% versus 39%) as well as in those who received a regimen without cisplatin (14% versus 26%).1,2,3,13

In the pooled analysis of placebo-controlled, double-blind studies in 131 patients with cancer and anemia who were receiving antineoplastic therapy (59 were receiving concomitant chemotherapy regimens containing cisplatin and 72 were receiving concomitant chemotherapy regimens not containing cisplatin), treatment with epoetin alfa (150 units/kg subcutaneously 3 times weekly for 12 weeks) resulted in a decrease in RBC transfusion requirements from week 5 through the end of the study.1,2,3 The combined proportion of patients transfused during this period (includes only those who remained on study beyond week 6) was 22% and 43% in those receiving epoetin alfa and placebo, respectively.1,2,3

A 2012 Cochrane review evaluated the use of ESAs to prevent or reduce anemia in patients with cancer when given alone or concomitantly with chemotherapy, radiotherapy, or combination therapy; a total of 91 studies (N=20,102) were included.14 Overall, ESAs significantly reduced the risk of transfusion by 35%, with an increased risk of thromboembolic complications and mortality in this population (relative risk, 1.52 and 1.17, respectively).14

Pediatric Patients: Anemia Due to Concomitantly Administered Cancer Chemotherapy

The efficacy and safety of epoetin alfa in pediatric patients with cancer and anemia due to concomitant myelosuppressive chemotherapy for nonmyeloid malignancy were evaluated in a single multicenter, randomized, placebo-controlled, double-blind trial.1,2,3,15 Epoetin alfa therapy was administered at a dose of 600 units/kg (maximum 40,000 units) IV weekly.1,2,3,15

In this trial involving children and young adults 5 to 18 years of age (N=222) with various malignancies (e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute lymphocytic leukemia, solid tumors), 51% of patients receiving epoetin alfa required RBC transfusions from week 5 through the end of the study, compared with 69% of those receiving placebo.1,2,3,15 A greater proportion of patients treated with epoetin alfa versus placebo were transfusion-free after 4 weeks (38.7% versus 22.5%), and epoetin alfa led to greater increases in hemoglobin overall.1,2,3,15 Epoetin alfa therapy did not result in improvements in health-related quality of life.15

Clinical Perspective

The American Society of Clinical Oncology (ASCO) and American Society of Hematology (ASH) published a joint guideline that provides recommendations for use of ESAs in patients with cancer.12 Per ASCO/ASH, ESAs and their biosimilars may be offered to patients with chemotherapy-induced anemia whose cancer treatment is not curative in intent and whose hemoglobin is <10 g/dL.12 The guideline's Expert Panel considers epoetin alfa and beta, darbepoetin, and biosimilar epoetin alfa to be equivalent with respect to effectiveness and safety.12 In patients with nonmyeloid hematologic malignancies who are receiving concurrent myelosuppressive chemotherapy, hematologic response to cancer treatment should be observed before considering therapy with ESAs.12 Particular caution should be exercised in the use of ESAs in patients with an increased risk of thromboembolic complications.12 Patients with nonchemotherapy-associated anemia should generally not be offered ESAs, with the exception of patients with lower risk myelodysplastic syndromes and a serum erythropoietin level ≤500 IU/L.12 Alternative causes of anemia aside from chemotherapy or an underlying hematopoietic malignancy should be evaluated for and addressed before considering therapy with ESAs.12 During ESA treatment, hemoglobin may be increased to the lowest concentration needed to avoid or reduce the need for transfusions.12 Discontinue ESAs in patients who do not respond within 6 to 8 weeks and reevaluate patients for other etiologies of anemia (tumor progression, iron deficiency, etc).12 Iron replacement may be used to improve hemoglobin response and reduce RBC transfusions in patients receiving ESAs with or without iron deficiency.12

Reduction of Red Blood Cell Transfusion Requirements in Anemic Surgery Patients

Epoetin alfa and epoetin alfa-epbx are used perioperatively to reduce the need for allogeneic RBC transfusions in adults with perioperative hemoglobin concentrations >10 to ≤13 g/dL who are at high risk for perioperative blood loss from elective, noncardiac, nonvascular surgery.1,2,3 Epoetin alfa products are not indicated in those who are willing to donate autologous blood prior to surgery or undergoing cardiac or vascular surgery.1,2,3 Epoetin alfa is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia.1,2,3

Adult Patients: Anemia Due to Surgery

The efficacy and safety of epoetin alfa for the reduction of allogeneic blood transfusion requirements have been evaluated in 2 RCTs that included orthopedic surgery patients.1,2,3,17,18

The first trial was placebo-controlled, double-blind, and involved 316 patients scheduled for major, elective hip or knee surgery who were expected to require 2 or more units of blood and who were unable or unwilling to participate in an autologous blood donation program.1,2,3,17 Patients were randomized to receive epoetin alfa 300 units/kg, epoetin alfa 100 units/kg, or placebo given by subcutaneous injection once daily for 10 days prior to surgery, on the day of surgery, and for 4 days after surgery; all patients received oral iron and a low-dose postoperative warfarin regimen.1,2,3,17 While patients with pretreatment hemoglobin concentrations ranging from 10 to ≤13 g/dL who received the 300 unit/kg dosage regimen of epoetin alfa had a reduced risk of allogeneic RBC transfusions, there was no evidence of benefit in those with higher pretreatment hemoglobin concentrations (>13 to ≤15 g/dL).1,2,3,17 Because there were too few patients enrolled with pretreatment hemoglobin concentrations of ≤10 g/dL, the effects of preoperative epoetin alfa treatment on transfusion requirements in these patients could not be determined.1,2,3,17 In the group of patients with pretreatment hemoglobin concentrations 10 to ≤13 g/dL, the mean number of units transfused was 0.45 in those who received the 300 unit/kg epoetin alfa regimen, 0.42 units in those who received the 100 unit/kg epoetin alfa regimen, and 1.14 units in those who received placebo.1,2,3,17 In addition, mean hemoglobin, hematocrit, and reticulocyte counts increased substantially during the presurgical period in those who received epoetin alfa.1,2,3,17

The second trial was open-label, parallel-group, and enrolled 145 patients with pretreatment hemoglobin concentrations ranging from 10 to ≤13 g/dL who were scheduled for orthopedic hip or knee surgery and who were not participating in an autologous blood donation program; all patients received oral iron and appropriate pharmacologic anticoagulation therapy.1,2,3,18 In this study, patients were randomized to receive epoetin alfa in a regimen of 600 units/kg once weekly for 3 weeks prior to surgery and on the day of surgery or a regimen of 300 units/kg once daily for 10 days prior to surgery, on the day of surgery, and for 4 days after surgery.1,2,3,18 The mean increase in hemoglobin from pretreatment to presurgery was greater and the mean increase in absolute reticulocyte count was less in patients receiving the once-weekly regimen than in those receiving the daily regimen; however, the mean number of units of blood transfused per patient was approximately 0.3 units in both treatment groups, and mean hemoglobin concentrations throughout the postsurgical period were similar in both groups.1,2,3,18

A meta-analysis compared the use of ESA plus iron versus iron alone in patients undergoing cardiac and noncardiac surgery, using data from 25 studies (N=4719).19 Results demonstrated that ESAs plus iron significantly reduced the risk of transfusion by 43% versus iron alone, without an increase in the risk of renal dysfunction, stroke, MI, or death.19 Similar results were demonstrated in a Cochrane review of 12 RCTs (N=1880) comparing ESA plus iron versus iron alone or placebo in patients undergoing non-cardiac surgery.20

Clinical Perspective

The American Society of Anesthesiologists Task Force on Perioperative Blood Management published a guideline on the use of perioperative blood transfusion and adjuvant therapies.16 Per the Task Force, erythropoietin with or without iron may be administered to reduce the need for transfusions in select patient populations (e.g., renal insufficiency, anemia of chronic disease, refusal of transfusion).16 The Task Force acknowledges that erythropoietin administration may be more expensive and requires a few weeks to induce a significant increase in hemoglobin concentration.16

Other Uses

Autologous Blood Donation

Therapy with ESAs may be beneficial prior to elective surgery to increase the volume of blood available for autologous donation†, particularly for procedures in which the potential for substantial blood loss exists (e.g., hip or knee replacement).21 In a meta-analysis including 18 studies (N=1914), erythropoietin therapy (exact products used not specified) via IV or subcutaneous route significantly increased the proportion of patients who were able to donate ≥4 units of blood and yield less of a reduction in hematocrit and hemoglobin concentration versus controls, when used for preoperative autologous blood donation in patients undergoing orthopedic surgery.21

The manufacturers state that epoetin alfa is not indicated in anemic patients who are willing to donate autologous blood prior to surgery.1,2,3

Anemia of Prematurity

Therapy with ESAs (epoetin alfa or darbepoetin alfa) has been evaluated in the treatment of anemia of prematurity†, a condition in premature neonates that is due to impaired production of erythropoietin after birth, which is more pronounced in preterm infants who are already born with lower hematocrit compared to term infants.22 Three Cochrane reviews have evaluated ESAs in this setting.24,25 A review of 34 studies (N=3643) evaluating early (<8 days of age) ESAs found small reductions in transfusion requirements in infants who received ESAs (only epoetin alfa studies identified) versus placebo or no intervention.24 A review of 31 studies (N=1651) evaluating late (≥8 days of age) ESAs concluded that any donor exposure is likely not avoided with ESA (epoetin alfa and darbepoetin alfa studies identified) use ≥8 days after birth, as most studies included infants who had received transfusions prior to trial entry.24 Lastly, a review of 2 RCTs (N=262) comparing early versus late use of ESAs did not demonstrate reduced transfusion requirements with early ESA use (only epoetin alfa studies identified).25

Sickle Cell Anemia

Therapy with ESAs may be useful for delayed hemolytic transfusion reaction (DHTR) in patients with sickle cell disease†.26,27 The 2020 ASH guidelines recommend ESAs with or without IV iron as supportive care for all patients with DHTR.26 A 2014 Expert Panel Report from the Department of Health and Human Services acknowledges data supporting ESAs for DHTR.27 Neither guideline gives preference to a specific ESA product.26,27

Myelodysplastic Syndrome

Therapy with ESAs may be useful for patients with myelodysplastic syndrome†.12 ASCO and ASH published a joint guideline that provides recommendations for use of ESAs in patients with cancer.12 Patients with nonchemotherapy-associated anemia should generally not be offered ESAs, with the exception of patients with lower risk myelodysplastic syndromes and a serum erythropoietin level ≤500 units/L.12 The guideline does not give preference to a specific ESA product for this use.12

Hypoxic-ischemic Encephalopathy

Therapy with ESAs (epoetin alfa or darbepoetin alfa) may be useful for infants with hypoxic-ischemic encephalopathy (HIE)†.28 A meta-analysis of 6 RCTs (N=454) compared ESAs (≤1000 units/kg/week) to placebo or no intervention for moderate to severe HIE.28 Results demonstrated that ESAs significantly reduced the risk of cerebral palsy and moderate to severe cognitive impairment in patients without hypothermia (relative risk, 0.47 and 0.49, respectively); ESAs also significantly reduced the risk of cerebral palsy in patients with or without hypothermia (relative risk, 0.70).28

Bloodless Medicine

Therapy with ESAs may be useful to improve the efficiency and production of RBCs and limit blood loss in patients who refuse or are unable to receive allogeneic blood or blood products†.29,30,31 The literature commonly refers to this practice as “bloodless medicine and surgery.”29,30

The use of ESAs has been described for Jehovah's Witness patients with severe anemia (hemoglobin concentration <7 g/dL).31 An IV or subcutaneous epoetin alfa at a dose of 40,000 units daily plus IV iron has been recommended until hemoglobin concentration is >7 g/dL; thereafter, 40,000 units weekly is recommended.31

General

• Give a copy of the medication guide and instruct patients to read the guide prior to initiating therapy with epoetin alfa products and each time the drug is dispensed.1,2,3
• Instruct patients who self-administer epoetin alfa products regarding proper, safe use of the drugs, including information on aseptic technique, on storage and disposal of the drugs and administration equipment, and on recognition and management of sensitivity reactions.1,2,3
• Discontinue therapy with epoetin alfa products when cancer chemotherapy is completed.1,2,3

Pretreatment Screening

• Assess iron status (i.e., transferrin saturation, serum ferritin concentration) prior to starting therapy.1,2,3
• Correct or exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding) prior to stating therapy.1,2,3
• Initiate supplemental iron therapy if serum ferritin concentration is <100 mcg/L or transferrin saturation is <20%.1 The manufacturer states that the majority of patients with CKD will require supplemental iron during the course of ESA therapy.1
• Control hypertension prior to starting therapy.1,2,3

Patient Monitoring

• Monitor iron status (i.e., transferrin saturation, serum ferritin concentration) throughout therapy.1,2,3
• Monitor hemoglobin weekly after initiation of therapy and following each dose adjustment until stable and sufficient to minimize the need for RBC transfusion; monitor hemoglobin at least monthly thereafter.1,2,3
• Monitor blood pressure throughout therapy and initiate antihypertensive medications as needed.1,2,3 Reduce or withhold epoetin alfa products if blood pressure becomes difficult to control.1Monitor patients for seizures and premonitory neurologic symptoms during the first several months of therapy.1,2,3 Epoetin alfa products increase the risk of seizure in patients with CKD.1
• Monitor for severe anemia and low reticulocyte count during treatment, which could indicate presence of neutralizing antibodies.1
• Monitor for serious blistering and skin exfoliation reactions as well as serious allergic reactions; discontinue therapy immediately if these reactions occur.1

Premedication and Prophylaxis

• Administer deep vein thrombosis prophylaxis to surgical patients receiving therapy for the reduction of allogeneic RBC transfusions.1,2,3

Other General Considerations

• Adjustments to concomitant dialysis medications may be required after initiating epoetin alfa products.1,2,3
• Only use single-dose vials (i.e., the benzyl-alcohol free formulation) in women who are pregnant or breastfeeding, neonates, and infants; do not admix epoetin alfa products from single-dose vials with bacteriostatic saline containing benzyl alcohol for these populations.1,2,3
• Because of the ergogenic effects of therapy with ESAs (i.e., increases in erythrocyte count, hematocrit and hemoglobin concentration, and oxygen-carrying capacity of blood), the potential exists for abuse of these drugs by athletes, especially those participating in high-aerobic demand, endurance-type events.32,33 Effects of ESAs would be expected to be similar to those of homologous or autologous RBC transfusions (“blood doping”), which have been used by athletes to increase cardiac output, oxygen uptake capacity of blood, and aerobic exercise endurance by increasing arterial blood oxygen content.32,33 These effects may be particularly evident in individuals with greater initial aerobic fitness.32,33 Erythropoietins and agents affecting erythropoiesis are included on the World Anti-Doping Code International Standard Prohibited List of substances in- and out-of-competition.32

Administration

Administer epoetin alfa products by IV or subcutaneous injection.1,2,3 In patients undergoing hemodialysis, the manufacturers recommend that epoetin alfa products be given IV rather than subcutaneously because of reports of pure red cell aplasia (PRCA) associated with the latter route of administration.1,2,3

Do not shake or freeze vials of epoetin alfa product, and discard if subjected to these conditions.1,2,3

Inspect visually the contents of vials of epoetin alfa product for discoloration and/or particulate matter prior to administration whenever solution and container permit; if either is present, discard the solution.1,2,3

For IV or subcutaneous use, withdraw the appropriate dose of the epoetin alfa product from the vial into the syringe for administration; once the dose has been withdrawn from the vial, administer promptly.1,2,3

Do not mix epoetin alfa products with other drug solutions in general.1,2,3 However, the manufacturers of Epogen^® and Procrit^® state that the preservative-free formulation from single-use vials may be admixed in equal parts (in a 1:1 ratio) in a syringe with bacteriostatic 0.9% sodium chloride injection (preserved with benzyl alcohol) at the time of administration.1,2

Discard unused portions of epoetin alfa product from single-dose preservative-free vials.1,2,3 Any unused portion of epoetin alfa product from multi-dose vials can be stored, protected from light, between 2-8°C for 21 days after initial entry.1,2,3 Because of the risks associated with benzyl alcohol, do not use epoetin alfa product that has been admixed with injection solutions containing benzyl alcohol in neonates, infants, and pregnant and nursing women.1,2,3

Dosage

Adult Dosage

Anemia of Chronic Kidney Disease

For the treatment of anemia associated with CKD in adults, the manufacturers of epoetin alfa products recommend an initial dosage of 50-100 units/kg IV (preferred for patients receiving hemodialysis) or subcutaneously 3 times weekly.1,2,3

Dosage should be individualized, and the lowest possible dosage sufficient to reduce the need for RBC transfusions should be used.1,2,3 For correction of anemia in hemodialysis, doses >300 units/kg 3 times weekly did not yield an additional response.1,2,3

When initiating or adjusting treatment with epoetin alfa in CKD patients, monitor hemoglobin at least weekly until stable, and then at least monthly.1,2,3 Factors including the rate of increase or decrease in hemoglobin concentration, responsiveness to the ESA, and hemoglobin concentration variability should be considered when determining whether a dosage adjustment is needed; a single hemoglobin excursion may not require a dosage change.1,2,3

Do not increase dosage more frequently than once every 4 weeks; decreases in dosage can occur more frequently.1,2,3

If the hemoglobin concentration increases rapidly (e.g., by more than 1 g/dL in any 2-week period), reduce dosage by 25% or more as necessary to decrease the risk of a rapid response.1,2,3 However, if the hemoglobin concentration has not increased by more than 1 g/dL after 4 weeks of therapy, increase the dosage by 25%.1,2,3 If an adequate response to epoetin alfa product is not obtained over a 12-week period of escalating dosages, evaluate the patient for other causes of anemia; further dosage increases are not likely to improve patient response and may increase the risks of therapy.1,2,3 Discontinue epoetin alfa products if responsiveness does not improve.1

The manufacturers state that patients with CKD on dialysis should initiate therapy when their hemoglobin concentration is less than 10 g/dL.1,2,3 If hemoglobin concentration approaches or exceeds 11 g/dL in such patients, reduce the dosage or interrupt therapy.1,2,3

The manufacturers also state that consideration should be given to initiating epoetin alfa products in patients with CKD not on dialysis only when their hemoglobin concentration is less than 10 g/dL and the following 2 conditions also apply: the rate of hemoglobin decline indicates the likelihood of requiring a transfusion, and a goal of therapy is to reduce the risk of alloimmunization and/or other risks associated with RBC transfusions.1,2,3 If hemoglobin concentration exceeds 10 g/dL in such patients, reduce the dosage or interrupt therapy.1,2,3

In clinical studies, patients with CKD on dialysis responded to epoetin alfa with clinically important increases in hemoglobin concentration, and over 95% of patients were RBC transfusion-independent after 3 months of therapy.1,2,3

Anemia in Patients with HIV Infection Treated with Zidovudine

For the treatment of anemia associated with zidovudine therapy in adults with HIV infection who have endogenous serum erythropoietin concentrations ≤500 milliunits/mL and who are receiving zidovudine dosages ≤4.2 g/week, the recommended initial dosage of epoetin alfa product is 100 units/kg IV or subcutaneously 3 times weekly.1,2,3 Patients with HIV infection with endogenous pretreatment (pretransfusion) serum erythropoietin concentrations ≤500 milliunits/mL who are receiving weekly cumulative zidovudine dosages ≤4.2 g are more likely to respond to epoetin alfa product therapy than patients with higher endogenous pretreatment erythropoietin concentrations (i.e., >500 milliunits/mL).1,11

If hemoglobin has not increased after 8 weeks of therapy, the dose given 3 times weekly may be increased by approximately 50-100 units/kg at 4- to 8-week intervals until an adequate hemoglobin concentration is obtained or a dose of 300 units/kg is reached.1,2,3 If hemoglobin concentration does not increase after 8 weeks of treatment with 300 units/kg 3 times weekly, discontinue the drug.1

If hemoglobin concentrations exceed 12 g/dL at any time during therapy, withhold treatment until the hemoglobin decreases to less than 11 g/dL; resume therapy at a dosage 25% less than the previous dosage.1,2,3

Anemia Due to Chemotherapy in Patients with Nonmyeloid Malignancies

For the treatment of chemotherapy-induced anemia in adults with nomyeloid malignancies, the recommended initial dosage of epoetin alfa products is 150 units/kg subcutaneously 3 times weekly or 40,000 units subcutaneously once weekly until completion of a chemotherapy course.1,2,3

Initiate therapy only in patients who have hemoglobin concentrations of less than 10 g/dL and in whom a minimum of 2 additional months of chemotherapy is planned upon initiation of epoetin alfa products.1,2,3 Use the lowest possible dosage sufficient to avoid RBC transfusions.1,2,3

If the hemoglobin concentration has increased by less than 1 g/dL after the initial 4 weeks of therapy and remains below 10 g/dL, increase dosage of the drug to 300 units/kg 3 times weekly or 60,000 units weekly.1,2,3 If response to epoetin alfa product is not satisfactory (i.e., continuing need for RBC transfusion, low hemoglobin concentrations) after 8 weeks of therapy, discontinue the drug.1,2,3

If the hemoglobin concentration reaches a level sufficient to avoid the need for RBC transfusion or increases by more than 1 g/dL in any 2-week period, decrease the dosage of the drug by 25%.1,2,3

If hemoglobin exceeds a concentration needed to avoid RBC transfusions, withhold doses of the epoetin alfa product.1 Reinitiate at a dose 25% below the previous dose when hemoglobin approaches a level where RBC transfusions may be required.1,2,3

Reduction of Allogeneic Blood Transfusion Requirements in Anemic Surgery Patients

When epoetin alfa products are used to reduce the need for allogeneic RBC transfusions in adults with hemoglobin concentration >10 but ≤13 g/dL who are at high risk for perioperative blood loss from elective, noncardiac, nonvascular surgery, the recommended dosage is 300 units/kg given by subcutaneous injection once daily for 10 days prior to surgery, on the day of surgery, and for 4 days after surgery.1,2,3 Alternatively, the drug can be given subcutaneously in a regimen of 600 units/kg once weekly for 3 weeks prior to surgery (i.e., days 21, 14, and 7 before surgery), with an additional dose given on the day of surgery.1,2,3

Prophylaxis for deep vein thrombosis is strongly recommended during therapy.1,2,3

Pediatric Dosage

Anemia of Chronic Kidney Disease

In pediatric patients 1 month of age or older, the recommended initial dosage of epoetin alfa is 50 units/kg 3 times weekly IV or subcutaneously.1,2,3

The manufacturers state that pediatric patients with CKD should initiate epoetin alfa products when their hemoglobin concentration is less than 10 g/dL.1,2,3 If hemoglobin concentration approaches or exceeds 12 g/dL, reduced the dosage or interrupt therapy.1,2,3

When initiating or adjusting treatment with epoetin alfa in CKD patients, monitor hemoglobin at least weekly until stable, and then at least monthly.1 Factors including the rate of increase or decrease in hemoglobin concentration, responsiveness to the ESA, and hemoglobin concentration variability should be considered when determining whether a dosage adjustment is needed; a single hemoglobin excursion may not require a dosage change.1

Do not increase the dosage more frequently than once every 4 weeks; decreases in dose can occur more frequently.1,2,3

If the hemoglobin concentration increases rapidly (e.g., by more than 1 g/dL in any 2-week period), reduce the dosage by 25% or more as necessary to reduce the risk of a rapid response.1,2,3 However, if the hemoglobin concentration has not increased by more than 1 g/dL after 4 weeks of therapy, increase the dosage by 25%.1,2,3 If an adequate response to epoetin alfa product is not obtained over a 12-week period of escalating dosages, evaluate the patient for other causes of anemia; further dosage increases are not likely to improve patient response and may increase the risks of therapy.1,2,3 Discontinue epoetin alfa products if responsiveness does not improve.1,2,3

Anemia in Patients with HIV-infection Treated with Zidovudine

Pediatric patients with HIV infection and zidovudine-induced anemia, 8 months to 17 years of age, have received epoetin alfa dosages of 50 to 400 units/kg subcutaneously or IV 2 or 3 times weekly.1,2,3

Anemia Due to Chemotherapy in Patients with Nonmyeloid Malignancies

For the treatment of chemotherapy-induced anemia in pediatric patients with nonmyeloid malignancies 5 to 18 years of age, the recommended initial dosage of epoetin alfa product is 600 units/kg IV once weekly until completion of chemotherapy course.1,2,3

If the hemoglobin has increased by less than 1 g/dL after 4 weeks and remains <10 g/dL, increase the weekly dosage to 900 units/kg IV (maximum 60,000 units weekly).1,2,3

If therapy produces a very rapid hemoglobin response (e.g., an increase exceeding 1 g/dL in any 2-week period) or if hemoglobin reaches a concentration sufficient to avoid the need for RBC transfusions, reduce the dosage by 25%.1,2,3

If hemoglobin exceeds a concentration needed to avoid RBC transfusions, temporarily withhold administration of the drug until the hemoglobin falls to a concentration at which transfusions may be required, then resume therapy at a dosage 25% below the previous dosage.1,2,3 If the response to epoetin alfa product is not satisfactory after 8 weeks of therapy, discontinue the drug.1,2,3

Special Populations

Hepatic Impairment

The manufacturers of epoetin alfa products do not make specific dosage recommendations for patients with hepatic impairment.1,2,3

Renal Impairment

The manufacturers of epoetin alfa products do not make specific dosage recommendations for patients with renal impairment.1,2,3

Geriatric Patients

In geriatric patients with anemia due to CKD, individualized dosing is recommended to maintain target hemoglobin concentrations.1,2,3

The manufacturers of epoetin alfa products do not make specific dosage recommendations for geriatric patients with anemia and HIV infection treated with zidovudine.1,2,3

In geriatric patients with chemotherapy-induced anemia and those undergoing elective surgery, dosage requirements appear to be similar to those in younger adults.1,2,3

Contraindications

• Uncontrolled hypertension.1,2,3
• Pure red cell aplasia (PRCA) following treatment with epoetin alfa products or other erythropoietin proteins.1,2,3
• History of a serious allergic reaction to epoetin alfa products.1,2,3
• Use of epoetin alfa products from multi-dose vials containing benzyl alcohol in women who are pregnant or breastfeeding, neonates, and infants.1,2,3

Warnings/Precautions

Warnings

Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism

A boxed warning about the risk of mortality and thromboembolic events is included in the prescribing information for epoetin alfa products.1

Therapy with epoetin alfa and other ESAs has been shown to increase the risk of death and serious and life-threatening cardiovascular (CV) events (e.g., myocardial infarction (MI), stroke, congestive heart failure, hemodialysis vascular access thrombosis) when targeted to achieve hemoglobin concentrations exceeding 11 g/dL in patients with CKD.1,2,3 Using ESAs to target a hemoglobin concentration exceeding 11 g/dL does not provide additional benefit.1,2,3 Use ESAs with caution in patients with concurrent CV disease and stroke.1,2,3

Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at greater risk for CV events and mortality than other patients; an increase in hemoglobin concentration exceeding 1 g/dL in a 2-week period may contribute to these risks.1,2,3

An increased risk of serious adverse CV events (MI and stroke) and/or death have been observed in controlled clinical trials of epoetin alfa in patients with cancer and in those undergoing coronary artery bypass graft surgery (CABG); an increased risk of deep vein thrombosis in patients undergoing orthopedic surgery has also been observed.1,2,3

Data from several controlled clinical studies in patients with CKD comparing higher ESA hemoglobin target concentrations (13-14 g/dL) to lower targets (9-11.3 g/dL) indicate that an increased risk of death, MI, stroke, congestive heart failure, hemodialysis vascular access thrombosis, and other thromboembolic events occurred in the higher target hemoglobin groups.1,2,3

In the randomized, open-label CHOIR trial of patients with CKD who were not receiving dialysis, therapy with epoetin alfa targeted to a hemoglobin concentration of 13.5 g/dL (high-hemoglobin group) was associated with an increased incidence of the primary composite end point of death, MI, hospitalization for congestive heart failure (without renal replacement therapy), or stroke (18%) compared with that in patients treated to a lower target hemoglobin of 11.3 g/dL (14%); the trial was terminated early as a result of these safety findings.1,2,3,10

In TREAT (a randomized, double-blind, placebo-controlled study), which included patients with type 2 diabetes mellitus, anemia, and non-dialysis-dependent CKD, treatment with another ESA, darbepoetin alfa, targeted to a hemoglobin concentration of 13 g/dL failed to reduce the overall rates of the primary CV and renal composite endpoints, but was associated with an increased risk of stroke compared with placebo (annualized stroke rate of 2.1% versus 1.1%, respectively).1,2,3 This increased risk was documented despite use of a conservative dosing strategy and measures designed to ensure gradual increases and avoidance of overshoots and oscillations in hemoglobin concentrations. The relative risk of stroke was particularly high in patients with a prior history of stroke compared with those who received placebo (annualized stroke rate of 5.2% versus 1.9%, respectively).1,2,3

In the Normal Hematocrit Study (NHS), hemodialysis patients with clinically evident cardiac disease (ischemic heart disease, congestive heart failure) who received epoetin alfa with a goal of achieving and maintaining a target hemoglobin concentration of 14 ± 1 g/dL had increased mortality (35%) compared with that in similar patients treated to a target hemoglobin concentration of 10 ± 1 g/dL (29%); the trial was terminated early as a result of these safety findings.1,2,3,6 The incidence of all-cause mortality, nonfatal MI, vascular access thrombosis, and other thromboembolic events was also higher in those treated to a target hemoglobin concentration of 14 g/dL.1,2,3

An increased incidence of thromboembolic events, some serious and life-threatening, has also been observed in patients with cancer receiving ESAs.1,2,3 In a randomized, controlled study in patients with metastatic breast cancer who were receiving cancer chemotherapy, mortality was higher in patients receiving weekly epoetin alfa therapy (targeted to a hemoglobin of 12-14 g/dL or a hematocrit of 36-42%) versus placebo.1,2,3 The study was terminated early when interim results showed a higher mortality with epoetin alfa versus placebo (8.7% and 3.4%, respectively) and a higher rate of fatal thrombotic events (1.1% and 0.2%, respectively) after 4 months.1,2,3,34 Based on Kaplan-Meier estimates, the proportion of these patients who survived 1 year after randomization was lower in the epoetin alfa group than in the placebo group (70% versus 76%, respectively).1,2,3,34

An increased incidence of deep vein thrombosis also has been observed in patients undergoing orthopedic surgical procedures and receiving epoetin alfa products to reduce allogeneic RBC transfusion requirements, and the manufacturers state that antithrombotic prophylaxis is strongly recommended when ESAs are used in such patients.1,2,3 In a randomized, open-label, controlled study in adults undergoing spinal surgery and not receiving prophylactic anticoagulation, deep vein thrombosis (as determined by color flow duplex imaging or clinical symptoms) occurred more frequently in patients who received epoetin alfa 600 units/kg (7, 14, and 21 days prior to surgery and on the day of surgery for a total of 4 doses) in addition to standard of care treatment (4.7%) than in patients who received standard of care treatment alone (2.1%).1,2,3 In addition, 12 patients in the epoetin alfa group had other thrombotic vascular events compared with 7 patients receiving only standard of care treatment.1,2,3

In a placebo-controlled study in patients undergoing CABG surgery, 7 deaths occurred in patients treated with perioperative epoetin alfa versus no deaths among those receiving placebo.1,2,3 Deaths that occurred during the time of epoetin alfa therapy (4 of 7 deaths) were associated with thromboembolic events.1,2,3 The manufacturers state that epoetin alfa products are not indicated in patients undergoing cardiac or vascular surgery.1,2,3

Increased Mortality and Tumor Progression

A boxed warning about the increased mortality and risk of tumor progression or recurrence in patients with cancer is included in the prescribing information for epoetin alfa products.1,2,3

Epoetin alfa therapy targeting a hemoglobin concentration of 12-14 g/dL resulted in shortened overall survival (OS) in patients with metastatic breast cancer receiving chemotherapy and patients with non-small cell lung cancer receiving palliative radiation therapy.1,2,3 Epoetin alfa therapy shortened OS and progression free survival (PFS) in patients with: metastatic breast cancer receiving chemotherapy and targeting a hemoglobin concentration of ≤12 g/dL; cervical cancer receiving chemotherapy and radiation therapy and targeting a hemoglobin concentration of 12-14 g/dL; and head and neck cancer receiving radiation and targeting a hemoglobin concentration of ≥15 in men and ≥14 in women.1,2,3,38,39

Shortened OS was observed in patients treated with another ESA, darbepoetin alfa, who had lymphoid malignancy and were receiving cancer chemotherapy (target hemoglobin concentration: 13-15 g/dL in men and 13-14 g/dL in women) or another malignant disease and not receiving chemotherapy or radiation therapy (target hemoglobin concentration: 12-13 g/dL).1,2,3 Shortened OS and PFS were observed in patients treated with darbepoetin alfa who had early breast cancer and were receiving neo-adjuvant breast cancer treatment (target hemoglobin concentration: 12.5-13 g/dL).1,2,3 Shortened locoregional control of disease was observed in patients treated with darbepoetin alfa or epoetin alfa who had primary squamous cell carcinoma of the head and neck and were receiving radiation therapy (target hemoglobin concentration: 14-15 g/dL).1,2,3,42

Epoetin alfa products should only be initiated in patients with cancer receiving chemotherapy if the hemoglobin is less than 10 g/dL, and if there is a minimum of 2 additional months of planned chemotherapy.1,2,3 Epoetin alfa products are not approved for use in patients with cancer who are: not receiving concomitant myelosuppressive chemotherapy; receiving myelosuppressive chemotherapy when the anticipated outcome is cure; or receiving myelosuppressive chemotherapy in whom the anemia can be managed by transfusion.1,2,3

Other Warnings and Precautions

Hypertension

Approximately 25% of patients on dialysis will either develop or experience an exacerbation of hypertension during therapy with epoetin alfa products, particularly during the early phase of therapy when hematocrit is rising.1,2,3 Hypertensive encephalopathy and seizures have been reported in patients with CKD receiving epoetin alfa products.1,2,3

Monitor blood pressure prior to initiation and throughout therapy with epoetin alfa products and initiate antihypertensive medications as needed.1,2,3

Management of persistently high blood pressure in patients receiving epoetin alfa products may require initiation or increased dosage of antihypertensive therapy.1,2,3 A decrease in the dosage of epoetin alfa product or temporary discontinuation of therapy may be necessary if blood pressure becomes too difficult to control.1,2,3

Advise patients to maintain compliance with concomitant antihypertensive therapy and dietary restrictions.1,2,3

Seizures

The risk of seizures is increased in patients with CKD administered epoetin alfa products.1,2,3

Monitor patients for seizures and premonitory neurologic symptoms during the first several months of therapy.1,2,3

Advise patients to contact their healthcare provider for new-onset seizures, premonitory symptoms, or change in seizure frequency.1,2,3

Lack or Loss of Hemoglobin Response

Patients who fail to respond or experience a loss of hemoglobin response to epoetin alfa products should be evaluated for causative factors.1,2,3 Conditions that may diminish or block the effects of epoetin alfa products include states of acute or chronic inflammation, infection, acute or chronic blood loss, and iron deficiency.1,2,3

Evaluate for PRCA if typical causes of lack or loss of hemoglobin response are excluded.1,2,3 If PRCA is excluded, dose adjustments may be necessary.1,2,3 (See Dosage under Dosage and Administration.)

Pure Red Cell Aplasia

Cases of PRCA and severe anemia, with or without other cytopenias, have been associated with neutralizing antibodies in patients receiving ESAs, including epoetin alfa products.1,2,3

These cases have been observed predominantly in patients treated with subcutaneous ESAs for CKD, but also have been reported in patients receiving ESAs for anemia related to treatment of hepatitis C virus (HCV) infection†.1,2,3 (See Immunogenicity under Cautions.)

Discontinue epoetin alfa products and evaluate patients for neutralizing antibodies to erythropoietin if severe anemia and low reticulocyte count develop during treatment.1,2,3 The manufacturer of the particular epoetin alfa product should be contacted to perform assays for binding and neutralizing antibodies (Procrit: Janssen Biotech at 800-526-7736; Epogen: Amgen at 800-772-6436; Retacrit: Hospira at 800-438-1985).1,2,3

Permanently discontinue epoetin alfa products in patients who develop PRCA following treatment with epoetin or other erythropoietin protein drugs; do not switch patients to other ESAs.1,2,3

Serious Allergic Reactions

Severe allergic reactions, including anaphylactic reactions, angioedema, respiratory symptoms, skin rash, and urticaria, may occur in patients receiving therapy with epoetin alfa products.1,2,3

Discontinue epoetin alfa products immediately and initiate appropriate therapy if a serious allergic or anaphylactic reaction occurs; the drug should not be reinitiated.1,2,3

Severe Cutaneous Reactions

Serious skin reactions, including blistering, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported in patients receiving ESA therapy.1,2,3

Discontinue epoetin alfa products immediately if a severe skin reaction is suspected.1,2,3

Adverse Reactions Due to Benzyl Alcohol Preservative

Commercially available multidose vials of epoetin alfa products contain benzyl alcohol as a preservative.1,2,3 Administration of injections preserved with benzyl alcohol has been associated with neurologic and other toxicity in neonates.1,2,3 Such toxicities include a potentially fatal “gasping syndrome” characterized by CNS depression, metabolic acidosis, gasping respirations, and high concentrations of benzyl alcohol and its metabolites in blood and urine.1,2,3 Other manifestations may include gradual neurologic deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hypotension, bradycardia, cardiovascular collapse, and hepatic or renal failure.1,2,3 Toxicity appears to have resulted from administration of large amounts (i.e., 99-234 mg/kg daily) of benzyl alcohol in these neonates.1,2,3 Premature or low-birthweight infants also appear to be at increased risk.1,2,3

Avoid the use of drugs preserved with benzyl alcohol in neonates and infants whenever possible.1,2,3 Only use single-dose vials (i.e., the benzyl-alcohol free formulation) in women who are pregnant or breastfeeding, neonates, and infants; do not admix epoetin alfa product from single-dose vials with bacteriostatic saline containing benzyl alcohol for these populations.1,2,3

Risk of Infection Due to Albumin

Because some forms of epoetin alfa contain albumin, a derivative of human blood, there is an extremely remote risk for transmission of human viruses.1,2 A theoretical risk for transmission of the causative agent of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote.1,2 No cases of transmission of viral diseases or CJD have ever been identified for albumin.1,2

Risk in Patients with Phenylketonuria

Each 1 mL single-dose vial of 2,000, 3,000, 4,000, 10,000, and 40,000 units of epoetin alfa-epbx contains 0.5 mg of phenylalanine, which may be harmful to patients with phenylketonuria (PKU).3 Consider the combined daily amount of phenylalanine from all sources before prescribing epoetin alfa-epbx to patients with PKU.3

Dialysis Management

Adjustments to concomitant dialysis medications may be required after initiating epoetin alfa products.1,2,3

Increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during dialysis may be required during epoetin therapy.1,2,3

Immunogenicity

As with all therapeutic proteins, there is the potential for immunogenicity with epoetin alfa product therapy.1,2,3 The observed incidence of antibody positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.1,2,3 For these reasons, comparison of the incidence of antibodies to epoetin alfa with the incidence of antibodies to other products may be misleading.1,2,3

Neutralizing antibodies to epoetin alfa that cross-react with endogenous erythropoietin and other ESAs can result in PRCA or severe anemia (with or without other cytopenias).1,2,3

Specific Populations

Pregnancy

Although there are no adequate and controlled studies to date of epoetin alfa product use during pregnancy, the drug has been used in a limited number of pregnant women with anemia alone or anemia associated with severe renal disease and hematologic disorders.1,2,3 Adverse pregnancy outcomes, including prenatal complications (i.e., polyhydramnios, intrauterine growth restriction) have been reported.1,2,3 The manufacturers state that due to the limited number of exposed pregnancies and the presence of multiple confounding factors (e.g., concomitant medications or other maternal conditions), such data cannot be used to reliably estimate the frequency or absence of adverse pregnancy outcomes.1,2,3 Epoetin alfa products should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1,2,3

Because of a potential risk of neurologic and other toxicity (e.g., gasping syndrome) in neonates exposed to benzyl alcohol, epoetin alfa product from multidose vials (with benzyl alcohol preservative) or from single-dose vials admixed with bacteriostatic saline containing benzyl alcohol should not be used in pregnant women.1,2,3 When therapy is needed during pregnancy or nursing, use of a benzyl alcohol-free formulation is recommended.1,2,3

Lactation

It is not known whether epoetin alfa is distributed into human milk.1,2,3 The effects of the drug on breast-fed infants or on the production of milk are unknown.1,2,3 Because of the potential for adverse reactions to epoetin alfa in breast-fed infants, caution is advised in women who breast-feed while receiving the drug.1,2,3

Because of a potential risk of neurologic and other toxicity in neonates exposed to benzyl alcohol, epoetin alfa from multidose vials (with benzyl alcohol preservative) or from single-dose vials admixed with bacteriostatic saline containing benzyl alcohol should not be used in nursing women.1,2,3 The manufacturer advises women not to breastfeed for at least 2 weeks after the last dose of epoetin alfa product from a multidose vial.1,2,3 When therapy is needed for women who are nursing, use of a benzyl alcohol-free formulation is recommended.1,2,3

Pediatric Use

The safety and efficacy of epoetin alfa products for the treatment of anemia associated with CKD, regardless of dialysis status, in pediatric patients younger than 1 month of age have not been established.1,2,3 In children at least 1 month of age with CKD, the pattern of most adverse events was similar to that found in adults.1,2,3 There does not appear to be a difference in safety profiles in pediatric patients with CKD requiring dialysis and not requiring dialysis.1,2,3

The safety and efficacy of epoetin alfa products have not been established in pediatric patients who are younger than 5 years of age with cancer and receiving chemotherapy.1,2,3 In pediatric patients with cancer who are at least 5 years of age, the pattern of most adverse events was similar to that found in adults.1,2,3

The safety and efficacy of epoetin alfa products have not been established in pediatric patients who are younger than 8 months of age with HIV infection receiving zidovudine.1,2,3

Because of a potential risk of neurologic and other toxicity in neonates and infants exposed to benzyl alcohol, epoetin alfa products from multidose vials (with benzyl alcohol preservative) or from single-dose vials admixed with bacteriostatic saline containing benzyl alcohol should not be used in these populations.1,2,3 When epoetin alfa products are needed for neonates or infants, use of a benzyl alcohol-free formulation is recommended.1,2,3

Geriatric Use

While safety and efficacy of epoetin alfa products have not been established specifically in geriatric patients, a large proportion of patients treated with the drug for anemia associated with CKD have been 65 years of age or older.1,2,3 In geriatric patients with anemia associated with CKD, no overall differences in safety and efficacy have been observed relative to younger adults.1,2,3

In geriatric patients with anemia due to concomitant chemotherapy or in those undergoing elective surgery, no overall differences in safety and efficacy of epoetin alfa products have been observed relative to younger adults; dosing requirements generally were similar between geriatric patients and younger adults for each indication.1,2,3

Data are insufficient in patients 65 years of age and older who have HIV infection and are treated with zidovudine to determine whether they respond differently than younger adults to epoetin alfa products.1,2,3

Hepatic Impairment

The manufacturer does not make recommendations regarding the use of epoetin alfa products in patients with hepatic impairment.1,2,3

Renal Impairment

The safety and efficacy of epoetin alfa products for the treatment of anemia associated with CKD, regardless of dialysis status, have been established in patients 1 month of age and older.1,2,3

Common Adverse Effects

Patients with CKD (≥5%): hypertension, arthralgia, muscle spasm, pyrexia, dizziness, medical device malfunction, vascular occlusion, and upper respiratory tract infection.1,2,3

Patients with HIV infection treated with zidovudine (≥5%): pyrexia, cough, rash, and injection site irritation.1,2,3

Patients with cancer receiving chemotherapy (≥5%): nausea, vomiting, myalgia, arthralgia, stomatitis, cough, weight decrease, leukopenia, bone pain, rash, hyperglycemia, insomnia, headache, depression, dysphagia, hypokalemia, and thrombosis.1,2,3

Surgical patients (≥5%): nausea, vomiting, pruritus, headache, injection site pain, chills, deep vein thrombosis, cough, and hypertension.1,2,3

Interactions between epoetin alfa and other drugs have not been fully evaluated.1,2,3

Description

Pharmacology

Epoetin alfa products are hematopoietic agents that principally influence erythropoiesis by acting as erythropoietin-stimulating agents (ESAs).1,2,3 Most studies of the pharmacology of epoetin alfa have been performed using the recombinant glycoprotein hormone.1,2,3 The amino acid sequence and biologic properties of epoetin alfa products are identical to those of endogenous human erythropoietin.1,2,3

Endogenous human erythropoietin, a growth factor, is a glycosylated protein hormone that appears to be secreted principally by renal peritubular interstitial cells of the kidney.43 Approximately 20% of the hormone is also produced in the liver and possibly in other extrarenal sites in adults, and fetal erythropoietin production occurs mainly in the liver.43 Secretion of erythropoietin occurs principally in response to reductions in tissue oxygenation in the kidney.43 Once released into the plasma, erythropoietin induces the production of erythrocytes mainly by stimulating the proliferation and differentiation of committed erythroid precursors, thereby leading to an increase in RBC production.43 Thereafter, the oxygen carrying capacity of the blood is enhanced and further erythropoietin production is inhibited via a negative feedback loop.43 Plasma iron and ferritin concentrations decrease with new erythrocyte formation as a result of iron incorporation into these cells and subsequent mobilization of tissue iron stores.43

The usual serum concentration of endogenous erythropoietin in healthy individuals with normal hematocrit is approximately 4-30 milliunits/mL; the erythropoietic response in patients with severe anemia may be associated with erythropoietin concentrations up to 1000 times greater than these concentrations.43

Epoetin alfa products increase reticulocyte count within 10 days of starting therapy; increases in hematocrit, hemoglobin, and RBC count follow within 2 to 6 weeks.1,2,3 The rise in hemoglobin following the administration of epoetin alfa products is dose dependent.1,2,3

Pharmacokinetics

A maximum serum concentration was achieved within 5-24 hours after subcutaneous administration of epoetin alfa.1,2,3 In adult and pediatric patients with CKD who received IV administration of epoetin alfa, the half-life ranged from 4-13 hours.1,2,3 The half-life of epoetin alfa is similar in adults older or younger than 65 years of age.1,2,3 In patients with impaired renal function, the elimination half-life does not appear to be affected by hemodialysis.1,2,3 Little, if any, accumulation of the drug appears to occur at dosages of 50-150 units/kg given IV or subcutaneously 3 times weekly or at dosages of 40,000 units weekly given subcutaneously in the setting of cancer chemotherapy administration.1,2,3

The pharmacokinetics of epoetin alfa in children and adolescents appear to be similar to that of adults.1,2,3 Limited data are available in neonates.1,2,3 Data from a study in preterm, very low birth-weight neonates receiving IV erythropoietin indicate that the volume of distribution and clearance of the drug were approximately 1.5-2 and 3 times higher, respectively, than in healthy adults.1,2,3 The pharmacokinetics of the drug in patients infected with HIV have not been determined.1,2,3

Advice to Patients

• Provide a copy of the manufacturer's patient information (medication guide) for epoetin alfa products to all patients before starting therapy and when new information about the drug becomes available.1,2,3 Patients who self-administer therapy should read the medication guide prior to initiation and each time the prescription is refilled.1,2,3
• If applicable, provide the patient or caregiver instructions regarding proper, safe use of the drug for self-administration, including information on aseptic techniques and on storage and disposal of the drug and administration equipment.1,2,3 Advise such patients and caregivers to follow the manufacturer's “Instructions for Use.”1,2,3
• Inform patients about the increased risks of death, serious cardiovascular effects, thromboembolic events, and tumor progression in certain populations.1,2,3
• Inform patients of possible adverse effects, including signs and symptoms of allergic drug reactions.1,2,3 Advise patients to inform their clinician immediately if serious allergic reaction occurs (e.g., whole body rash, shortness of breath, wheezing, decreases in blood pressure, swelling around mouth or eyes, fast pulse, sweating).1,2,3
• Advise patients to report signs or symptoms of chest pain, pain in the legs with or without swelling, stroke, irregular heartbeats, seizures, confusion, dizziness or loss of consciousness, extreme tiredness, blood clots in hemodialysis vascular access ports, or increases in blood pressure.1,2,3
• Advise patients to contact a clinician if any new-onset seizures, premonitory symptoms, or changes in seizure frequency occur.1,2,3
• Advise patients to inform their clinician of redness or pain at the injection site.1,2,3
• Advise patients to adhere to antihypertensive treatments and dietary restrictions.1,2,3
• Inform patients of the need to regularly monitor blood pressure and hemoglobin concentration.1,2,3
• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.1,2,3 Epoetin alfa products should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1,2,3 Inform patients of the risks associated with benzyl alcohol (preservative in some epoetin alfa product formulations) in neonates, infants, and pregnant and nursing women.1,2,3 When therapy is needed during pregnancy or nursing, use of a benzyl alcohol-free formulation is recommended.1,2,3 If an epoetin alfa product from a multidose vial is used in women who are nursing, the manufacturer advises women not to breastfeed for at least 2 weeks after the last dose.1,2,3
• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.1,2,3 Patients should inform clinicians of heart disease, high blood pressure, history of seizures or strokes, and blood disorders (e.g., sickle cell anemia, clotting disorders) prior to treatment initiation.1,2,3
• Advise patients to inform their clinician of other important precautionary information.1,2,3 (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Amgen, Inc. Epogen^® (epoetin alfa) prescribing information. Thousand Oaks, CA; 2018 Jul.

2. Janssen. Procrit^® (epoetin alfa) prescribing information. Horsham PA; 2018 Jul.

3. Pfizer, Inc. Retacrit^® (epoetin alfa-epbx) prescribing information. New York, NY; 2020 Aug.

4. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; 2006 Mar 21. From FDA website. Accessed 2021 Nov 3. [Web] [Web]

5. Anand S, Al-Mondhiry J, Fischer K, Glaspy J. Epoetin alfa-epbx: a new entrant into a crowded market. a historical review of the role of erythropoietin stimulating agents and the development of the first epoetin biosimilar in the United States. Expert Rev Clin Pharmacol . 2021;14:1-8. [PubMed 33307871]

6. Besarab A, Bolton WK, Browne JK et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med . 1998;339:584-90. [PubMed 9718377]

7. Keown PA, Churchill DN, Poulin-Costello M, et al. Dialysis patients treated with Epoetin alfa show improved anemia symptoms: A new analysis of the Canadian Erythropoietin Study Group trial. Hemodial Int . 2010;14:168-173.

8. Amato L, Addis A, Saulle R, Trotta F, Mitrova Z, Davoli M. Comparative efficacy and safety in ESA biosimilars vs. originators in adults with chronic kidney disease: a systematic review and meta-analysis. J Nephrol . 2018;31:321-332 [PubMed 28646375]

9. Roger SD, Tio M, Park HC, et al. Intravenous iron and erythropoiesis-stimulating agents in haemodialysis: A systematic review and meta-analysis. Nephrology (Carlton) . 2017;22:969-976. [PubMed 27699922]

10. Singh KA, Szczech L, Tang KL et al for the CHOIR Investigators. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med . 2006; 355:2085-98 [PubMed 17108343]

11. Henry DH, Beall GN, Benson CA, et al. Recombinant human erythropoietin in the treatment of anemia associated with human immunodeficiency virus (HIV) infection and zidovudine therapy. Overview of four clinical trials. Ann Intern Med . 1992;117:739-748. [PubMed 1416576]

12. Bohlius J, Bohlke K, Castelli R, et al. Management of cancer-associated anemia with erythropoiesis-stimulating agents: ASCO/ASH Clinical Practice Guideline Update. J Clin Oncol . 2019;37:1336-1351.[PubMed] [PubMed 30969847]

13. Witzig TE, Silberstein PT, Loprinzi CL, et al. Phase III, randomized, double-blind study of epoetin alfa compared with placebo in anemic patients receiving chemotherapy. J Clin Oncol . 2005;23:2606-2617. [PubMed 15452187]

14. Tonia T, Mettler A, Robert N, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev . 2012;12:CD003407.

15. Razzouk BI, Hord JD, Hockenberry M, et al. Double-blind, placebo-controlled study of quality of life, hematologic end points, and safety of weekly epoetin alfa in children with cancer receiving myelosuppressive chemotherapy. J Clin Oncol . 2006;24:3583-3589. [PubMed 16877725]

16. American Society of Anesthesiologists Task Force on Perioperative Blood Management. Practice guidelines for perioperative blood management: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Management*. Anesthesiology . 2015;122:241-275. [PubMed 25545654]

17. de Andrade JR, Jove M, Landon G, Frei D, Guilfoyle M, Young DC. Baseline hemoglobin as a predictor of risk of transfusion and response to Epoetin alfa in orthopedic surgery patients. Am J Orthop (Belle Mead NJ) . 1996;25:533-542. [PubMed 8871751]

18. Goldberg MA, McCutchen JW, Jove M, et al. A safety and efficacy comparison study of two dosing regimens of epoetin alfa in patients undergoing major orthopedic surgery. Am J Orthop (Belle Mead NJ) . 1996;25:544-552. [PubMed 8871751]

19. Kei T, Mistry N, Curley G, et al. Efficacy and safety of erythropoietin and iron therapy to reduce red blood cell transfusion in surgical patients: a systematic review and meta-analysis. Can J Anaesth . 2019;66:716-731. [PubMed 30924000]

20. Kaufner L, von Heymann C, Henkelmann A, et al. Erythropoietin plus iron versus control treatment including placebo or iron for preoperative anaemic adults undergoing non-cardiac surgery. Cochrane Database Syst Rev . 2020;8:CD012451 [PubMed 32790892]

21. Chang X, Li Q, Tang H. Use of preoperative erythropoietin therapy to facilitate autologous blood donation in orthopedic surgery: A meta-analysis. Medicine (Baltimore) . 2020;99:e18577 [PubMed 31914036]

22. Cibulskis CC, Maheshwari A, Rao R, Mathur AM. Anemia of prematurity: how low is too low?. J Perinatol . 2021;41:1244-1257. [PubMed 33664467]

23. Ohlsson A, Aher SM. Early erythropoiesis-stimulating agents in preterm or low birth weight infants. Cochrane Database Syst Rev . 2020;2:CD004863.

24. Aher SM, Ohlsson A. Late erythropoiesis-stimulating agents to prevent red blood cell transfusion in preterm or low birth weight infants. Cochrane Database Syst Rev . 2020;1:CD004868. [PubMed 31990982]

25. Aher SM, Ohlsson A. Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev . 2020;2:CD004865

26. Chou ST, Alsawas M, Fasano RM, et al. American Society of Hematology 2020 guidelines for sickle cell disease: transfusion support. Blood Adv . 2020;4:327-355. [PubMed 31985807]

27. US Department of Health and Human Services. Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014 [Web]

28. Razak A, Hussain A. Erythropoietin in perinatal hypoxic-ischemic encephalopathy: a systematic review and meta-analysis. J Perinat Med . 2019;47:478-489. [PubMed 30789826]

29. Resar LM, Wick EC, Almasri TN, Dackiw EA, Ness PM, Frank SM. Bloodless medicine: current strategies and emerging treatment paradigms. Transfusion . 2016;56:2637-2647. [PubMed 27473810]

30. Scharman CD, Burger D, Shatzel JJ, Kim E, DeLoughery TG. Treatment of individuals who cannot receive blood products for religious or other reasons. Am J Hematol . 2017;92(12):1370-1381 [PubMed 28815690]

31. Posluszny JA Jr, Napolitano LM. How do we treat life-threatening anemia in a Jehovah's Witness patient?. Transfusion . 2014;54:3026-3034 [PubMed 25330835]

32. Breenfeldt Andersen A, Jacobson GA, Bejder J, et al. An abductive inference approach to assess the performance-enhancing effects of drugs included on the World Anti-Doping Agency Prohibited List. Sports Med . 2021;51:1353-1376 [PubMed 33811295]

33. The World Anti-Doping Code International Standard Prohibited List. January 2020 [Web]

34. Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med . 2009;361:2019-2032 [PubMed 19880844]

35. Leyland-Jones B, Semiglazov V, Pawlicki M et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol . 2005;23:5960-72.

36. Stowell CP, Jones SC, Enny C, Langholff W, Leitz G. An open-label, randomized, parallel-group study of perioperative epoetin alfa versus standard of care for blood conservation in major elective spinal surgery: safety analysis. Spine (Phila Pa 1976) . 2009;34:2479-2485. [PubMed 19927096]

37. Wright JR, Ung YC, Julian JA, et al. Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol . 2007;25:1027-1032 [PubMed 17312332]

38. Leyland-Jones B, Bondarenko I, Nemsadze G, et al. A Randomized, Open-Label, Multicenter, Phase III Study of Epoetin Alfa Versus Best Standard of Care in Anemic Patients With Metastatic Breast Cancer Receiving Standard Chemotherapy. J Clin Oncol . 2016;34:1197-1207 [PubMed 26858335]

39. Thomas G, Ali S, Hoebers FJP et al. Phase III trial to evaluate the efficacy of maintaining hemoglobin levels above 12.0 g/dL with erythropoietin vs above 10.0 g/dL without erythropoietin in anemic patients receiving concurrent radiation and cisplatin for cervical cancer. Gynecol Oncol . 2008;108:317-25 [PubMed 18037478]

40. Henke M, Laszig R, Rube C et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet. 2003;362(Oct 18):1255-60. [PubMed 14575968]

41. Littlewood TJ, Kallich JD, San Miguel J, Hendricks L, Hedenus M. Efficacy of darbepoetin alfa in alleviating fatigue and the effect of fatigue on quality of life in anemic patients with lymphoproliferative malignancies. J Pain Symptom Manage . 2006;31:317-325 [PubMed 16632079/]

42. Overgaard J, Hoff CM, Hansen HS, et al. DAHANCA 10 - Effect of darbepoetin alfa and radiotherapy in the treatment of squamous cell carcinoma of the head and neck. A multicenter, open-label, randomized, phase 3 trial by the Danish head and neck cancer group. Radiother Oncol . 2018;127:12-19. [PubMed 29523409]

43. Bunn HF. Erythropoietin. Cold Spring Harb Perspect Med . 2013;3:a011619. [PubMed 23457296]

48. Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Int Suppl . 2012;2:279-335 [Web]

49. Kliger AS, Foley RN, Goldfarb DS, et al. KDOQI US commentary on the 2012 KDIGO Clinical Practice Guideline for Anemia in CKD. Am J Kidney Dis . 2013;62:849-859 [PubMed 23891356]

170. Food and Drug Administration. Healthcare provider materials (Biosimilars). Silver Spring, MD; 2021 July 28. From FDA web site. Accessed 2021 Nov 3. [Web]

171. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Scientific considerations in demonstrating biosimilarity to a reference product. Guidance for industry. From FDA website. Accessed 2021 Nov 3 [Web]

172. Griffith N, McBride A, Stevenson JG et al. Formulary Selection Criteria for Biosimilars: Considerations for US Health-System Pharmacists. Hosp Pharm . 2014;49:813-25. [PubMed 25477613]

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in adults and adolescents with HIV (August 16, 2021). Updates may be available at HHS AIDS Information (AIDSinfo) website. [Web]

201. Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (April 7, 2021). Updates may be available at HHS AIDS Information (AIDSinfo) website. [Web]

202. Panel on Treatment of Pregnant Women with HIV infection and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant women with HIV infection and interventions to reduce perinatal HIV transmission in the United States (February 10, 2021). Updates may be available at HHS AIDS Information (AIDSinfo) website. [Web]