Continuing Education Activity

Epoetin alfa is an erythropoiesis-stimulating agent used for the management of anemia. This activity examines the indications, actions, and contraindications associated with epoetin alfa, emphasizing its indispensability in treating anemia secondary to chronic kidney disease, myelosuppressive chemotherapy, and diverse etiologies. Ths activity discusses the mechanism of action, offers insights into the adverse event profile, and addresses pivotal factors such as off-label applications, dosing regimens, pharmacodynamics, pharmacokinetics, monitoring strategies, and relevant interactions.

Objectives:

• Evaluate the benefits of epoetin alfa in treating anemia secondary to chronic kidney disease and myelosuppressive chemotherapy.

• Determine the mechanism of action of epoetin alfa.

• Assess the adverse effects of epoetin alfa, including increased cardiovascular risk.

• Develop collaboration with other healthcare professionals to monitor patients undergoing epoetin alfa therapy effectively.

Indications

Erythropoietin is a 165-amino acid glycoprotein that stimulates red blood cell production in bone marrow.[1] Human erythropoietin was first isolated in 1977 from the urine of patients with aplastic anemia.[2] Epoetin alfa is a recombinant human erythropoietin (rhEPO) that was produced independently by 2 separate groups of scientists in 1985, including a group led by Dr. Fu-Kuen Lin, who produced the protein from hamster ovary cells.[3][4] 

RhEPO derived from eukaryotic cells is termed "epoetin," and Greek suffixes (eg, "epoetin alfa," "epoetin beta") are assigned to analogs of rhEPO with distinct patterns of glycosylation due to being produced in different cell hosts.[5] Changes in the amino acid sequence are indicated by a prefix (eg, "darbepoetin").

Epoetin alfa was first approved by the Food and Drug Administration (FDA) in 1989 for treating anemia in patients with chronic kidney disease (CKD), including patients requiring dialysis. In 1993, it was approved for treating anemia in patients undergoing myelosuppressive chemotherapy. Epoetin alfa offers an alternative therapy to red blood cell (RBC) transfusions, which can increase the risk of iron overload when administered chronically.

FDA-Approved Indications

• Anemia secondary to chronic kidney disease
  • In a 2004 meta-analysis of patients with CKD, 94% of whom were receiving hemodialysis, epoetin alfa increased mean hemoglobin by >3 g/dL from a baseline of 7.5 g/dL and hematocrit by >9% from a baseline of 24.3%. Epoetin alfa improved patients' quality of life, as indicated by a mean 8.5-point increase on the Karnofsky Performance Scale, which ranges from 10 (moribund) to 100 (normal and without limitations).[6]
  • In a 2023 Cochrane meta-analysis of patients with CKD, epoetin alfa was associated with preventing blood transfusions compared to placebo.[7] Current guidelines recommend an upper target hemoglobin of 11.5 g/dL in patients with CKD to avoid increased risk for cardiovascular events.
• Myelosuppressive effects of chemotherapy and at least 2 additional months of planned chemotherapy upon initiation of epoetin alfa
  • In a 2001 randomized controlled trial of patients with cancer receiving nonplatinum chemotherapy and baseline hemoglobin less than 12 g/dL, epoetin alfa increased mean hemoglobin levels by 2.2 g/dL over a 28-week study period, and fewer patients treated with epoetin alfa received transfusions compared to patients in the placebo group (24.7% versus 39.5%, respectively).[8]
  • In a 2004 meta-analysis of patients with cancer receiving chemotherapy, epoetin alfa significantly improved quality of life based on several clinical scales after adjusting for confounders.[9]
• Adverse effect of zidovudine in patients with HIV infection
  • In a combined analysis of 4 randomized controlled trials, epoetin alfa improved anemia in patients with HIV who were treated with zidovudine and had endogenous erythropoietin levels less than 500 IU/L. Epoetin alfa increased hematocrit by 4.6% from baseline and reduced the number of blood transfusions per patient compared to placebo (3.2 units versus 5.3 units, respectively).
  • Elevated quality of life was recorded but was not statistically significant.[10][11]
• Reducing the need for allogeneic red blood cell transfusions in patients pursuing elective, noncardiac, nonvascular surgery
  • Multiple studies have demonstrated reduced transfusion requirements in the perioperative period with epoetin alfa therapy.[12][13]
  • In an open randomized trial of patients undergoing elective major orthopedic surgery, patients treated with epoetin alfa had higher hemoglobin levels at the time of surgery and discharge, and they had a lower transfusion rate than patients receiving routine care (12% versus 46%, respectively).[14]

Off-Label Uses

• Low-risk myelodysplastic syndromes with symptomatic anemia
  • In a 2019 randomized controlled trial of patients with low-risk myelodysplastic syndrome and symptomatic anemia, epoetin alfa administration was associated with a significantly higher erythroid response than placebo based on the World Health Organization International Working Group 2006 criteria.
  • After 4 weeks of treatment, the median time to first blood transfusion was 20.3 weeks in patients treated with epoetin alfa and 7.1 weeks in the placebo group.[15][16]
• Substitute in patients who refuse red blood cell transfusions
  • Certain individuals refuse blood cell transfusions based on personal or religious preferences, including Jehovah's Witnesses.
  • A retrospective case series of hospitalized patients with anemia who refused blood transfusions demonstrated no significant difference in the rate of hemoglobin increase in patients who received high-dose epoetin alfa versus those who did not. Further, 3 of 19 patients in the case review experienced venous thromboembolic events. The decision to treat this population with epoetin alfa should be individualized based on the risks and benefits.[17]

Experimental Uses

• Anemia of prematurity: Blood transfusions are frequently used to treat preterm anemia. In a 2019 Cochrane meta-analysis of preterm infants, epoetin alfa had minimal effect on reducing the number of blood transfusions and did not reduce mortality.[18]
• Neuroprotection in preterm infants: Erythropoietin has been hypothesized to have a neuroprotective effect in preterm infants. In a 2020 randomized controlled trial of preterm infants, epoetin alfa was not associated with improved mortality or decreased severe neurodevelopmental impairment at the age of 2 years.[19]
• Anemia in critically ill and trauma patients: In a 2007 randomized controlled trial of critically ill patients, epoetin alfa did not reduce the number of blood transfusions compared to placebo but was associated with improved mortality in trauma patients.[20] A 2017 meta-analysis of critically ill trauma patients demonstrated a statistically significant 37% reduction in mortality in patients treated with epoetin alfa.[21]
• Anemia as an adverse effect of combined therapy for treating chronic hepatitis C virus infection: Combined therapy with interferon-alpha and ribavirin for hepatitis C virus infection can cause anemia, often prompting a dose reduction of ribavirin. A 2004 randomized controlled trial of patients in this population demonstrated that patients treated with epoetin alfa were more frequently able to maintain their initial dose of ribavirin and scored significantly higher on quality-of-life assessments.[22]
• Increase frataxin levels in Friedreich ataxia: Erythropoietin increases frataxin levels in peripheral blood mononuclear cells and has been studied as a therapeutic in Friedrich ataxia, characterized by low frataxin levels. In a 2016 randomized controlled trial of patients with Friedreich ataxia, epoetin alfa did not affect the primary endpoint of peak oxygen uptake and did not alter frataxin levels.[23]

Misuse

Epoetin alfa and other biosimilars have frequently been misused as performance-enhancing drugs in competitive athletes due to their ability to stimulate red blood cell production and enhance aerobic capacity.[24]

Mechanism of Action

Epoetin alfa is structurally identical to endogenous human erythropoietin and acts through the same mechanism of action. Erythropoietin is an endocrine hormone synthesized in peritubular interstitial fibroblasts in the kidneys. In tissue hypoxia, the transcription factor hypoxia-inducible factor 1 (HIF-1) stimulates the expression of erythropoietin. HIF-1 comprises 2 subunits, HIF-1 α and HIF-1 β, constitutively expressed in the cell. HIF-1 α is degraded in the presence of oxygen. Under hypoxic conditions, the prolyl hydroxylase domain of HIF-1 α is inactivated, allowing HIF-1 α to accumulate. HIF-1 then enters the cell nucleus and dimerizes with HIF-1 β. The heterodimer binds to the hypoxia response element region of DNA and upregulates the transcription of erythropoietin.

Erythropoietin is released into the circulation and binds to the erythropoietin receptor on erythrocytic progenitor cells in the bone marrow. Binding leads to a conformational change of the receptor and initiates a JAK2/STAT5 intracellular signaling cascade, resulting in erythropoietin’s principal action of preventing programmed cell death. Erythrogenic progenitors are then allowed to proliferate and differentiate into reticulocytes, which are released into the circulation and become mature red blood cells or erythrocytes.[25][26]

Reticulocyte count increases within 10 days of epoetin alfa administration and gradually declines as the cells mature into erythrocytes. This is followed by a rise in hemoglobin and hematocrit levels within 2 to 6 weeks. Epoetin alfa increases hemoglobin and hematocrit in a dose-dependent manner. [27][28]

Pharmacokinetics

Absorption: Epoetin alfa administered subcutaneously achieves a maximum serum concentration within 24 hours. The estimated bioavailability is 36%. In patients with chronic kidney disease, the elimination half-life is 4 to 13 hours after intravenous administration. In patients with anemia and cancer, the elimination half-life is 16 to 67 hours after subcutaneous administration.[29]

Distribution: The volume of distribution of epoetin alfa is approximately 3 to 7 L, similar to the total body plasma volume, which is attributable to its large molecular size confining it to the plasma.[29][30]

Metabolism: The primary site of epoetin alfa metabolism is unclear, but it has been hypothesized that erythropoietin receptor-mediated uptake and degradation account for most of its metabolism. Hepatic metabolism plays a minor role.[31]

Elimination: The kidney contributes to the elimination of epoetin alfa but is not the primary site of removal from circulation.[31]

Administration

Available Dosage Forms

Epoetin alfa is available in injection form for intravenous and subcutaneous administration. Subcutaneous administration is the preferred method, save for CKD patients receiving hemodialysis. Epoetin alfa is buffered in an isotonic sodium chloride/sodium citrate solution and stored in vials, appearing as a sterile, clear, colorless liquid. Formulations vary and can include human albumin, citric acid, sodium phosphate dibasic anhydrate, sodium phosphate monobasic monohydrate, and water. Vials contain single or multiple doses. Multiple-dose vials contain benzyl alcohol as a preservative.

Epoetin alfa can be stored in single-dose and multiple-dose vials. Single-dose vials contain 1 mL of solution and are available in various strengths, including 2,000, 3,000, 4,000, 10,000, or 40,000 units. Multiple-dose vials can contain 2 mL of solution with 10,000 units of epoetin alfa or 1 mL of solution with 20,000 units.

Adult Dosing

Patients with CKD receiving dialysis

• IV route is recommended for patients undergoing hemodialysis.
• Begin treatment when hemoglobin level is less than 10 g/dL.
• The starting dose on the manufacturer label is 50 to 100 units/kg 3 times weekly, intravenous or subcutaneous.
• Reduce or withhold dose when hemoglobin level approaches or exceeds 11 g/dL.

Patients with CKD not receiving dialysis

• Begin treatment when:
  • Hemoglobin level is less than 10 g/dL AND
  • The rate of hemoglobin decrease necessitates RBC transfusion AND
  • Reducing the number of RBC transfusions to avoid transfusion-related risk is a goal.
• The starting dose in the manufacturer label is 50 to 100 units/kg 3 times weekly, intravenous or subcutaneous.
• Reduce or withhold dose when hemoglobin level approaches or exceeds 10 g/dL.

Patients with HIV infection treated with zidovudine

• Starting dose: One hundred units/kg 3 times weekly, intravenous or subcutaneous.

Patients receiving cancer chemotherapy

• Begin treatment when hemoglobin level is less than 10 g/dL, and at least 2 additional months of chemotherapy are planned.
• One hundred fifty units/kg subcutaneously 3 times per week until completing a course of chemotherapy, or 40,000 units subcutaneously weekly until completing a course of chemotherapy.

Surgical patients

• Three hundred units/kg subcutaneously per day for 15 days total, administered 10 days before surgery, on the date of surgery, and 4 days after surgery OR
• Six hundred units/kg subcutaneously in 4 doses administered weekly for 3 weeks before and on the surgery date.
• Patients should receive deep venous thrombosis prophylaxis during treatment.

Specific Patient Populations

Pediatric patients

• CKD (1 month or older): The IV route is recommended for hemodialysis patients. Treatment should begin when the hemoglobin level is less than 12 g/dL. The starting dose is 50 units/kg 3 times weekly, intravenous or subcutaneous. The dose should be reduced or withheld when the hemoglobin level approaches or exceeds 12 g/dL.
• Receiving cancer chemotherapy (5 to 18 years of age): Treatment should begin when the hemoglobin level is less than 10 g/dL and at least 2 additional months of chemotherapy are planned. Six hundred units/kg intravenous weekly until completing a course of chemotherapy.

Hepatic impairment: There is no dosing adjustment.

Renal impairment: There is no dosing adjustment.

Adverse Effects

The most common adverse effects of epoetin alfa include hypertension, arthralgia, injection site pain, headache, nausea, vomiting, cough, and fever. More serious adverse effects are rare and include severe allergic reactions, anaphylaxis, and severe cutaneous reactions such as Stevens-Johnson Syndrome.

Epoetin alfa increases the risk of severe cardiovascular events. A 2006 open-label study of patients with CKD examined the effect of epoetin alfa on the primary composite end point of death, myocardial infarction, stroke, and hospitalization due to congestive heart failure. Patients assigned to a target hemoglobin level of 13.5 g/dL experienced the composite event 34% more often than patients with a target hemoglobin of 11.3 g/dL.[32]

Epoetin alfa increases mortality and the risk of tumor progression and recurrence in patients with cancer. A 2009 Cochrane meta-analysis of patients with cancer demonstrated a 17% increased mortality during the study period for patients treated with epoetin alfa or other erythropoietin-stimulating agents.[33]

Epoetin alfa has been reported to increase the risk of seizures in patients with CKD, but this relationship has not been examined well.[34] More recent data have not demonstrated this association.[35]

Pure red cell aplasia is rare after epoetin alfa administration due to the formation of neutralizing antibodies against epoetin alfa, which cross-react with endogenous erythropoietin. However, the incidence of this reaction has decreased after the implementation of appropriate storage and handling procedures, which reduce the immunogenicity of epoetin alfa.[36]

In patients with CKD receiving dialysis, epoetin alfa increases the risk of thrombosis at the vascular access site. Heparin is often used to mitigate this risk.[37]

Benzyl alcohol is a preservative used in multiple-dose vials of epoetin alfa and is toxic to neonates. This drug can cause a fatal “gasping syndrome” in pediatric patients, characterized by neurological and metabolic disturbances and gasping respirations.[38]

Formulations of epoetin alfa often contain human albumin, which poses a theoretical risk of infectious disease transmission.

Drug-Drug Interactions

Androgens may enhance the hypertensive effect of epoetin alfa and are not recommended for the adjuvant treatment of anemia. Vitamin C increases iron utilization in the body and may lead to a more significant hemoglobin level increase when combined with epoetin alfa. The safety of the combined use of epoetin alfa and vitamin C has not been well established, and simultaneous administration is not currently suggested.

Contraindications

Epoetin alfa is contraindicated in patients with:

• Uncontrolled hypertension
• Pure red cell aplasia that begins after treatment with epoetin alfa or other erythropoietin biosimilars
• Severe allergic reactions to epoetin alfa

Epoetin alfa in multiple-dose vials contains the preservative benzyl alcohol and is contraindicated in neonates, infants, and pregnant or breastfeeding women due to toxicity.

Box Warning and Precautions

According to product labeling, epoetin alfa is associated with the following:

• Increased mortality, myocardial infarction, stroke, and venous thromboembolism. Using epoetin alfa to raise the hemoglobin level above a target of 11 g/dL increases the risk of cardiovascular events with no additional benefit. Epoetin alfa should be used cautiously in patients with a history of cardiovascular disease.
• Increased mortality, risk of tumor progression, and recurrence risk in patients with cancer. Epoetin alfa should be used cautiously in patients with cancer.
• Hypertension. Blood pressure should be controlled before and during epoetin alfa treatment.
• Seizures in patients with CKD. Patients should be monitored for the development of neurological symptoms.
• Pure red cell aplasia. Epoetin alfa should be discontinued, and patients should be evaluated for the cause of acute anemia.
• Serious allergic reactions. Epoetin alfa should be discontinued, and supportive care should be provided.
• Serious cutaneous reactions. Epoetin alfa should be discontinued.

Monitoring

Iron status is evaluated before and during treatment with epoetin alfa. Iron supplementation is initiated when serum ferritin levels <100 μg/L or serum transferrin saturation <20%. Most patients with CKD require supplemental iron at some point during therapy with epoetin alfa.

Before initiating therapy with epoetin alfa, other causes of anemia should be corrected or ruled out, including vitamin deficiencies, bleeding, or chronic inflammatory conditions. After initiation of treatment and dose adjustments, hemoglobin is monitored weekly until it stabilizes at a level that indicates that blood transfusions are rarely needed. For patients with CKD, hemoglobin is monitored weekly until stabilization and then monthly. If hemoglobin rises at a rate >1 g/dL over 2 weeks, the dose of epoetin alfa should be reduced by ≥25%. In patients whose hemoglobin levels do not respond or decrease after initiation of therapy, bleeding or other causes of anemia should be ruled out. If other common causes of anemia are excluded, pure red cell aplasia should be considered.

Blood pressure should be regularly monitored while on epoetin alfa therapy to screen for developing or worsening hypertension. Epoetin alfa has also been reported to increase seizure risk in patients with CKD, so these individuals should be closely monitored for neurological symptoms in the first few months after initiation of therapy.

Toxicity

Management of Overdose and Recommendations

Epoetin alfa overdose can elevate hemoglobin levels to a dangerously high level, increasing blood viscosity and risk of thrombosis. This can be managed by discontinuing the agent, phlebotomy, and intravenous hydration.[39] The boxed warning recommends a hemoglobin goal of 11 g/dL to avoid the increased risk of cardiovascular events at higher hemoglobin levels. Severe hypertension has been reported following epoetin alfa overdose.[40] This can be managed by discontinuing the agent and administering antihypertensive medications.

Enhancing Healthcare Team Outcomes

Epoetin alfa is a medication helpful in managing symptomatic anemia secondary to chronic kidney disease, cancer chemotherapy, and other etiologies. Since anemia is associated with various diseases, specialists in different fields, particularly nephrologists and oncologists, should be trained to use epoetin alfa. Physicians trained in using epoetin alfa should recognize the appropriate indications, dosages, and target hemoglobin levels for this medication to minimize adverse effects.[32] Patients must be fully informed of the risks and benefits of starting this medication. Nurses should administer the medication using safe and standardized administration techniques. Pharmacists should review prescriptions to confirm the appropriate use of the medication and the absence of drug-drug interactions. Each member of the healthcare team must be vigilant of known adverse effects of epoetin alfa, including increased cardiovascular risk, as early intervention can be critical to reducing morbidity and mortality.