Continuing Education Activity

This educational activity focuses on epoetin alfa, an erythropoiesis-stimulating agent vital for managing anemia. Participants will learn about the indications for using epoetin alfa, which includes treating anemia associated with chronic kidney disease, myelosuppressive chemotherapy, and various other causes. The course covers the drug's mechanism of action and thoroughly examines its contraindications and adverse event profile. Emphasis is placed on understanding the pharmacodynamics and pharmacokinetics of epoetin alfa alongside discussions on dosing regimens, monitoring strategies, and pertinent drug interactions. This overview also addresses off-label uses, equipping healthcare professionals with the knowledge needed to implement this treatment in clinical practice effectively.

This session enhances healthcare providers' competency in prescribing and managing therapy with epoetin alfa. Attendees will be provided with insights into the operational aspects of epoetin alfa, ensuring its safe and effective application in patients with anemia. The offering aims to update practitioners on recent advances in the field, highlight critical considerations in the therapeutic use of epoetin alfa, and review essential monitoring and adjustment protocols to optimize patient outcomes.

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 (RBC) production in bone marrow.[1] Scientists first isolated human erythropoietin in 1977 from the urine of patients with aplastic anemia.[2] Epoetin alfa, a recombinant human erythropoietin (rhEPO), was independently produced in 1985 by 2 separate research teams, including one led by Dr. Fu-Kuen Lin using hamster ovary cells.[3][4]

The term "epoetin" refers to rhEPO derived from eukaryotic cells. Greek suffixes, such as "epoetin alfa" and "epoetin beta," denote rhEPO analogs with unique glycosylation patterns due to production in different cell hosts.[5] A prefix, as in "darbepoetin," indicates changes in the amino acid sequence.

The Food and Drug Administration (FDA) approved epoetin alfa in 1989 for treating anemia in patients with chronic kidney disease (CKD), including those requiring dialysis. In 1993, its use expanded to treat anemia in patients undergoing myelosuppressive chemotherapy. Epoetin alfa serves as an alternative to RBC transfusions, which can lead to chronic iron overload.

FDA-Approved Indications

Anemia secondary to CKD

• In a 2004 meta-analysis of patients with chronic kidney disease (CKD), 94% of whom were receiving hemodialysis, epoetin alfa increased mean hemoglobin by more than 3 g/dL from a baseline of 7.5 g/dL and hematocrit by more than 9% from a baseline of 24.3%. This treatment also improved patients' quality of life, as indicated by a mean 8.5-point increase on the Karnofsky Performance Scale, which ranges from 10 (dying) to 100 (normal and without limitations).[6]
• A 2023 Cochrane meta-analysis of patients with CKD found that epoetin alfa effectively prevented blood transfusions compared to placebo.[7] Current guidelines recommend an upper target hemoglobin of 11.5 g/dL in these patients to mitigate the increased risk for cardiovascular events.

Myelosuppressive effects of chemotherapy

• In a 2001 randomized controlled trial involving 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. Additionally, fewer patients treated with epoetin alfa required transfusions than those in the placebo group (24.7% versus 39.5%, respectively).[8]
• A 2004 meta-analysis of patients with cancer undergoing chemotherapy revealed that epoetin alfa significantly enhanced quality of life, as determined by several clinical scales after adjusting for confounders.[9]

Adverse effects of zidovudine

• In a combined analysis of 4 randomized controlled trials, epoetin alfa improved anemia in patients with HIV treated with zidovudine and 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).
• Although an elevated quality of life was recorded, it was not statistically significant.[10][11] 

Reducing allogeneic RBC transfusions in 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 involving patients undergoing elective major orthopedic surgery, those treated with epoetin alfa had higher hemoglobin levels at surgery and discharge. Additionally, these patients experienced a lower transfusion rate than those receiving routine care (12% versus 46%, respectively).[14]

Off-Label Uses

Low-risk myelodysplastic syndromes with symptomatic anemia

• In a 2019 randomized controlled trial involving patients with low-risk myelodysplastic syndrome and symptomatic anemia, epoetin alfa administration was associated with a significantly higher erythroid response than placebo, according to 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 for patients treated with epoetin alfa, compared to 7.1 weeks for those in the placebo group.[15][16]

Alternative for patients who refuse RBC transfusions

• Certain individuals, including Jehovah's Witnesses, refuse blood transfusions based on personal or religious preferences.
• A retrospective case series of hospitalized patients with anemia who refused blood transfusions showed no significant difference in the rate of hemoglobin increase between patients who received high-dose epoetin alfa and those who did not. Additionally, 3 of 19 patients in the case review experienced venous thromboembolic events. The decision to treat this population with epoetin alfa should be individualized, considering the risks and benefits.[17]

Experimental Uses

Anemia of prematurity: Blood transfusions commonly treat anemia in preterm infants. However, a 2019 Cochrane meta-analysis found that epoetin alfa had a minimal effect on reducing the number of blood transfusions and did not decrease mortality in preterm infants.[18]

Neuroprotection in preterm infants: Erythropoietin is hypothesized to have neuroprotective effects in preterm infants. A 2020 randomized controlled trial found that epoetin alfa was not associated with improved mortality or reduced severe neurodevelopmental impairment by the age of 2 years.[19]

Anemia in critically ill and trauma patients: In a 2007 randomized controlled trial involving critically ill patients, epoetin alfa did not decrease the number of blood transfusions compared to placebo. However, it was associated with improved mortality rates in trauma patients. Additionally, a 2017 meta-analysis of critically ill trauma patients showed a statistically significant 37% reduction in mortality among those treated with epoetin alfa.[20][21][20]

Anemia due to chronic Hepatitis C treatment: Combined therapy with interferon-α and ribavirin for hepatitis C virus infection often causes anemia, which may necessitate a dose reduction of ribavirin. A 2004 randomized controlled trial demonstrated that patients treated with epoetin alfa were more likely to maintain their initial ribavirin dose and reported significantly higher quality-of-life scores.[22]

Friedreich ataxia and frataxin levels: Erythropoietin increases frataxin levels in peripheral blood mononuclear cells, a key factor in Friedreich ataxia, characterized by low frataxin levels. In a 2016 randomized controlled trial of patients with Friedreich ataxia, epoetin alfa did not impact the primary endpoint of peak oxygen uptake or affect frataxin levels.[23]

Misuse

Epoetin alfa and other biosimilars have often been misused as performance-enhancing drugs by competitive athletes due to their capacity to stimulate RBC production and enhance aerobic performance.[24]

Mechanism of Action

Epoetin alfa is structurally identical to endogenous human erythropoietin and operates through the same mechanism of action. Erythropoietin, an endocrine hormone, is synthesized in the peritubular interstitial fibroblasts of the kidneys. During tissue hypoxia, the transcription factor hypoxia-inducible factor 1 (HIF-1), which consists of 2 subunits, HIF-1α and HIF-1β, stimulates erythropoietin expression. HIF-1α is degraded in the presence of oxygen but accumulates under hypoxic conditions when the prolyl hydroxylase domain of HIF-1α is inactivated. This accumulation allows HIF-1α to enter the cell nucleus, dimerize with HIF-1β, and bind to the hypoxia response element region of DNA to upregulate erythropoietin transcription.[25][26]

Erythropoietin is then released into the circulation and binds to receptors on erythrocytic progenitor cells in the bone marrow. This binding triggers a JAK2/STAT5 intracellular signaling cascade that primarily prevents programmed cell death. As a result, erythrogenic progenitors proliferate and differentiate into reticulocytes, which are released into the circulation and mature into erythrocytes.

Following the administration of epoetin alfa, reticulocyte count increases within 10 days and gradually declines as the cells mature into erythrocytes. This is followed by an increase in hemoglobin and hematocrit levels within 2 to 6 weeks, which is dose-dependent.[27][28]

Pharmacokinetics

Absorption: Epoetin alfa, when administered subcutaneously, reaches a maximum serum concentration within 24 hours, with an estimated bioavailability of 36%. In patients with chronic kidney disease (CKD), the elimination half-life ranges from 4 to 13 hours following intravenous administration. For patients with anemia and cancer, the elimination half-life extends from 16 to 67 hours after subcutaneous administration.[29]

Distribution: The volume of distribution for epoetin alfa is approximately 3 to 7 L, closely aligning with the total body plasma volume. This similarity is due to its large molecular size, which confines epoetin alfa primarily to the plasma.[29][30]

Metabolism: The primary site of epoetin alfa metabolism remains unclear; it is hypothesized that most of its metabolism occurs through erythropoietin receptor-mediated uptake and degradation. Hepatic metabolism contributes minimally to its breakdown.[31]

Elimination: The kidney plays a role in eliminating epoetin alfa but is not the primary site for its removal from circulation.[31]

Administration

Available Dosage Forms

Epoetin alfa is available in injectable form for intravenous (IV) and subcutaneous (SC) administration, with SC being the preferred method except for patients with CKD on hemodialysis. The medication is formulated in an isotonic sodium chloride/sodium citrate solution and presented as a sterile, clear, colorless liquid in vials. Formulations may include human albumin, citric acid, sodium phosphate dibasic anhydrate, sodium phosphate monobasic monohydrate, and water. Vials come in single or multiple doses, with multiple-dose vials containing benzyl alcohol as a preservative.

Epoetin alfa is packaged in both single-dose and multiple-dose vials. Single-dose vials contain 1 mL of solution and are available in various strengths: 2,000, 3,000, 4,000, 10,000, or 40,000 units. Multiple-dose vials are available in 2 mL containing 10,000 units or 1 mL containing 20,000 units of epoetin alfa.

Adult Dosing

Patients with CKD receiving dialysis

The IV route is recommended for patients undergoing hemodialysis. Treatment is indicated when the hemoglobin level is less than 10 g/dL. According to the manufacturer label, the starting dose is 50 to 100 units/kg 3 times weekly, IV or SC.

The dose should be reduced or withheld when the hemoglobin level approaches or exceeds 11 g/dL.

Patients with CKD not receiving dialysis

Begin treatment when:

• The hemoglobin level is less than 10 g/dL AND
• The rate of hemoglobin reduction necessitates RBC transfusion AND
• The number of RBC transfusions is being reduced to avoid transfusion-related risk.

The starting dose on the manufacturer's label is 50 to 100 units/kg 3 times weekly, IV or SC.

The dose should be reduced or withheld when the hemoglobin level approaches or exceeds 10 g/dL.

Patients treated with zidovudine

The starting dose is 100 units/kg 3 times weekly, IV or SC.

Patients receiving cancer chemotherapy

Treatment is indicated when the hemoglobin level is less than 10 g/dL and at least 2 more months of chemotherapy are planned. The dose is 150 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.

Surgery patients

For 10 days before surgery, on the date of surgery, and 4 days after surgery: 300 units/kg daily for 15 days, SC. 

OR

For 3 weeks before and on the surgery date: 600 units/kg in 4 doses per week, SC.

Patients should receive deep venous thrombosis prophylaxis during treatment.

Specific Patient Populations

Hepatic impairment: There is no dosing adjustment.

Renal impairment: There is no dosing adjustment.

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, IV or SC. The dose should be reduced or withheld when the hemoglobin level approaches or exceeds 12 g/dL.

Receiving cancer chemotherapy (5 to 18 years old): Treatment should begin when the hemoglobin level is less than 10 g/dL and at least 2 additional months of chemotherapy are planned. The dose is 600 units/kg weekly, IV, until completing a course of chemotherapy.

Adverse Effects

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

Epoetin alfa is associated with an increased risk of severe cardiovascular events. A 2006 open-label study of patients with chronic kidney disease (CKD) assessed the impact of epoetin alfa on a primary composite endpoint of death, myocardial infarction, stroke, and hospitalization due to congestive heart failure. Patients with a target hemoglobin level of 13.5 g/dL experienced the composite event 34% more frequently than those with a target of 11.3 g/dL.[32]

In patients with cancer, a 2009 Cochrane meta-analysis found that epoetin alfa or other erythropoietin-stimulating agents increased mortality by 17% during the study period.[33] Although epoetin alfa has been reported to increase the risk of seizures in patients with CKD, this association has not been thoroughly investigated, and more recent studies have not confirmed this link.[34][35][34]

Pure red cell aplasia, though rare, can occur after epoetin alfa administration due to the formation of neutralizing antibodies that also react with endogenous erythropoietin. However, the incidence of this reaction has decreased with improved storage and handling procedures that reduce the immunogenicity of epoetin alfa.[36]

In patients with CKD undergoing dialysis, epoetin alfa increases the risk of thrombosis at the vascular access site, often managed with heparin.[37]

Benzyl alcohol, used as a preservative in multiple-dose vials of epoetin alfa, is toxic to neonates, potentially causing a fatal "gasping syndrome" characterized by neurological and metabolic disturbances and gasping respirations.[38]

Epoetin alfa formulations often contain human albumin, posing a theoretical risk of transmitting infectious diseases.

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 and may lead to a more significant increase in hemoglobin levels when combined with epoetin alfa. However, the safety of simultaneous administration has not been established, and this combination is currently not recommended.

Contraindications

Epoetin alfa is contraindicated in patients with:

• Uncontrolled hypertension
• Pure red cell aplasia
• 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 risks:

• Increased cardiovascular risks: There is an elevated risk of mortality, myocardial infarction, stroke, and venous thromboembolism. Raising the hemoglobin level above a target of 11 g/dL with epoetin alfa increases the risk of cardiovascular events without additional benefit. Use caution in patients with a history of cardiovascular disease.
• Cancer-related risks: Increased mortality, tumor progression, and recurrence are observed in patients with cancer. Use epoetin alfa cautiously in this population.
• Hypertension: Blood pressure should be well-controlled before and during epoetin alfa treatment.
• Seizures in CKD: Monitor patients with chronic kidney disease (CKD) for the development of neurological symptoms indicative of seizures.
• Pure red cell aplasia: If suspected, discontinue epoetin alfa and evaluate the patient to determine the cause of acute anemia.
• Severe allergic reactions: Discontinue epoetin alfa and provide supportive care if severe allergic reactions occur.
• Severe cutaneous reactions: Discontinue epoetin alfa if severe skin reactions develop.

Monitoring

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

Before starting therapy with epoetin alfa, correcting or ruling out other causes of anemia, such as vitamin deficiencies, bleeding, or chronic inflammatory conditions, is crucial. After initiating treatment and adjusting doses, hemoglobin is monitored weekly until it stabilizes at a level indicating that blood transfusions are rarely needed. For patients with CKD, hemoglobin is initially monitored weekly until stabilization, then monthly after that. If hemoglobin increases by more than 1 g/dL over 2 weeks, the epoetin alfa dose should be reduced by at least 25%. If hemoglobin levels do not respond or decrease after starting therapy, investigate for bleeding or other causes of anemia. If these common causes are excluded, consider the possibility of pure red cell aplasia.

Blood pressure should be regularly monitored during epoetin alfa therapy to detect the onset or worsening of hypertension. Given the increased risk of seizures in patients with CKD, these individuals should also be closely monitored for neurological symptoms, especially in the first few months following the initiation of therapy.

Toxicity

Management of Overdose and Recommendations

An overdose of epoetin alfa can raise hemoglobin levels to dangerously high levels, increasing blood viscosity and the risk of thrombosis. Management strategies include discontinuing the agent, performing phlebotomy, and administering intravenous hydration.[39] The boxed warning advises maintaining a hemoglobin goal of 11 g/dL to avoid the increased risk of cardiovascular events associated with higher levels. Additionally, severe hypertension has been reported following an epoetin alfa overdose.[40] This condition can be managed by discontinuing the agent and administering antihypertensive medications.

Enhancing Healthcare Team Outcomes

Epoetin alfa is effective in managing symptomatic anemia related to chronic kidney disease, cancer chemotherapy, and other causes. Given anemia's association with various diseases, training is crucial for specialists in different fields, particularly nephrologists and oncologists, to properly utilize this medication. Trained physicians should recognize the correct indications, dosages and target hemoglobin levels for epoetin alfa to minimize adverse effects.[32] Patients must be fully informed about the risks and benefits of starting this treatment. Nurses are responsible for administering the medication using safe and standardized techniques, while pharmacists should review prescriptions to ensure appropriate use and check for potential drug-drug interactions. Each healthcare team member must remain vigilant about the known adverse effects of epoetin alfa, including increased cardiovascular risk, as early intervention can be crucial in reducing morbidity and mortality.