Continuing Education Activity

Epoetin alfa is a medication used in the management of anemia secondary to bone marrow failure. It is one of the erythropoiesis-stimulating classes of drugs. This activity outlines the indications, action, and contraindications of epoetin alfa. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional team in the management of patients with anemia due to bone marrow failure and related conditions.

Objectives:

• Describe the importance of epoetin alfa in patients with anemia due to chronic kidney disease and cancer therapy.
• Summarize the risks associated with initiating epoetin alfa along with key patient counseling points to prevent thromboembolism and other side effects.
• Explain the importance of monitoring in the patients who are on epoetin alfa.
• Review the importance of collaboration and coordination among interprofessional team members, which can enhance patient care.

Indications

Epoetin alfa is 165 amino acid glycoprotein manufactured by recombinant DNA technology, which has similar biological effects as endogenous erythropoietin. Erythropoietin stimulates red blood cell production in-situ. It is a hormone produced in the kidney and augments the differentiation of erythroid progenitors in the bone marrow. Indications of epoetin are as below. 

FDA Approved[1][2][3][4]

1. Chronic kidney disease patients who are on dialysis and not on dialysis 
2. The patient receiving myelosuppressive therapy for cancer
3. Anemia due to zidovudine in HIV-infected patient 
4. Reduction of allogeneic blood transfusion requirement in the patient who undergoes elective, noncardiac, nonvascular surgery

NON-FDA Approved[5][6][7][8][9][10]

1. Blood transfusion refusing patients like Jehovah’s Witnesses 
2. Anemia during therapy for chronic hepatitis C 
3. Myelodysplastic syndrome 
4. Symptomatic management for anemia
5. Preterm anemia  

Mechanism of Action

Epoetin alfa is recombinant human erythropoietin, which is nearly identical to the endogenous hormone erythropoietin (EPO). Erythropoietin occurs in the peritubular cells of the kidney. Anemia and hypoxia are sensed by these cells and lead to the rapid secretion of EPO, which acts on erythroid marrow. Hypoxia-inducible factor (HIF-1) is a (HIF-1 alpha and HIF-1 beta) transcription factor that boosts the expression of erythropoietin in the setting of hypoxia. During the state of hypoxia, the prolyl hydroxylase is inactive, allowing the accumulation of HIF-1 alpha and activating erythropoietin expression, which stimulates erythroid progenitors. 

Erythropoietin binds to specific receptors (JAK-STAT-binding receptor) on the surface of its target cells. It subsequently alters the phosphorylation of intracellular proteins and activates transcription factors to regulate gene expression. The magnitude of increase in red blood cell concentration after administration of epoetin alfa is primarily dependant on the length of time this medication is maintained, not by its concentration level.

It induces erythropoiesis in a dose-dependent manner but does not affect the RBC lifespan, which results in:

1. Stimulates the proliferation of colony-forming cells of the erythroid series
2. Induces hemoglobin formation and erythroblast maturation
3. Releases reticulocytes in circulation, followed by a rise in hematocrit and hemoglobin levels.[11]

A clinically significant increase in hemoglobin is usually not observed in less than two weeks because of the length required for the erythropoiesis process. The erythroid progenitors take several days to mature and undergo release into circulation.  

Administration

Epoetin alfa is available in single-dose, preservative-free, or multi-dose, preserved vials.

This medication can be administered via the intravenous or subcutaneous route. Subcutaneous is the preferred route for administration except in patients with end-stage kidney disease on maintenance hemodialysis. In dialysis patients and neonates, the IV route is recommended.[12] 

When injected intravenously, epoetin alfa clears from plasma with a half-life of 4 to 8 hours. However, the effect on bone marrow progenitors lasts much longer, and once-weekly dosing can be sufficient sometimes. Single vial dose is preservative-free, so, should be diluted in a syringe as a 1 to 1 dilution using normal saline in adults but do not dilute in neonates or infants.[13] Multiple-dose vials contain benzyl alcohol. Shaking of injection can denature the glycoprotein making the drug biologically inactive. This product should not be used if it is shaken or frozen.

Adverse Effects

Patients on erythropoietin therapy may develop absolute (decreased ferritin levels with low transferrin saturation) or functional iron deficiency (normal ferritin levels with low transferrin saturation). This deficiency results from an inability to move enough amount of iron rapidly from storage to support the enhanced erythropoiesis.

It increases the risk of serious cardiovascular events, vascular access thrombosis, stroke, myocardial infarction, venous thromboembolism in clinical studies when target Hb levels reach more than 11 g/dL or a rapid rise in hemoglobin over 1 g/dL over two weeks (U.S. Boxed Warning). Although epoetin alfa does not affect blood pressure directly, it may raise blood pressure in the early phase after administration when the hematocrit is increasing acutely. Therefore, clinicians should exercise care when using it in patients with uncontrolled hypertension. Additionally, patients may require dosage adjustments of antihypertensive therapy after initiating this medication. 

Pure red cell aplasia may occur in patients treated with specific epoetin alfa formulations. In chronic renal failure patients, chances of hypertensive encephalopathy and seizures have increased, particularly those with a previous history of seizures. Headache, nausea, shortness of breath, edema,  vomiting, tachycardia, diarrhea have also been noted. Injection site erythema and flu-like symptoms (like arthralgias and myalgias) can occur, which last for 2 to 4 hours.

Due to a sudden increase in hematocrit, blood viscosity, and peripheral vascular resistance, particularly dialysis patients, may require to adjust anticoagulation. Serious thromboembolic events like increased clot formation in atrioventricular (AV) shunts, migratory thrombophlebitis, microvascular thrombosis, thrombosis of major vessels like retinal, temporal, pulmonary, and renal vessels increases. The risk of thrombotic events is even higher in adults with ischemic heart disease or congestive heart failure. So, lower target hematocrit should be preferable in these patients. Some dosage forms may contain benzyl alcohol, which is associated with fatal toxicity “gasping syndrome” in neonates.[14]

Contraindications

Absolute contraindications:

• Multiple dosage vials contain benzyl alcohol, so this formulation is contraindicated in neonates, infants, pregnant women, and breastfeeding women. (Single dosage vial which is preservative-free should be used) 
• Uncontrolled hypertension
• Known hypersensitivity to mammalian cell-derived products
• Known hypersensitivity to albumin 
• Pure red cell aplasia that begins after treatment

Absolute contraindications:

• Due to the delayed onset of erythropoiesis, it is contraindicated for acute correction of severe anemia or emergency transfusion.
• It should be used cautiously with patients who have a history of seizures
• In patients with cancer receiving hormonal agents, biologic products, or radiotherapy
• In patients undergoing cardiac or vascular surgery
• In patients who receive myelosuppressive therapy when the anticipated outcome is curative

Monitoring

Serum ferritin and transferrin saturation require measurement before initiation of epoetin alfa. If the serum ferritin level is less than 100 ng/mL and/or serum transferrin saturation level is less than 20%, then supplemental iron should be started before the initiation of epoetin alfa treatment.

• If Hb does not increase by greater than 1 gram per deciliter after four weeks of the treatment, increase the dose by 25%. In any consecutive two weeks, hemoglobin increases greater than1 grams per deciliter, then cut down the dose by 25%. If there is inadequate or no response over three months of an escalation period, the clinician should stop treatment. 
• Serious cardiovascular events such as myocardial infarction, stroke, venous thromboembolism, and mortality increase when the Hb level increases more than 11 grams per deciliter. Signs and symptoms of these side effects also require monitoring. To decrease the risk of thromboembolism, encourage the patient to quit smoking and alcohol drinking, regular exercising, and diet modification. 
• Complete blood count, serum iron profile with ferritin should be monitored while the patient is receiving treatment.
• Consult with the cardiologist to monitor cardiac complications. 
• Consult with a nephrologist for further management with dialysis.
• Consult with the oncologist for coordinating myelosuppressive therapy if the patient is on chemotherapy. 
• Consult with the neurologist for a patient with a history of seizure. 

Toxicity

• Epoetin alfa increases the risk of serious cardiovascular events once the target hemoglobin level is greater than 11 g/dL or a rapid rise in hemoglobin (greater than 1 g/dL over two weeks of the period).
• Reports exist of erythema multiforme, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Immediately discontinuation of the treatment is needed.
• Overdose of this medication is very rare — no antidote available at present. 
• One case report describes an overdose of erythropoietin that caused essential erythrocytosis with the central nervous system and peripheral ischemia. The patient had successful treatment with emergent erythropheresis.[15]

Enhancing Healthcare Team Outcomes

Management of epoetin alfa requires an interprofessional team that includes a nurse, laboratory technologists, pharmacists, and several physicians involving different subspecialties. Without proper management, the rapid overcorrection of anemia can lead to various morbidity and mortality. The management of anemia secondary to multiple underlying causes such as kidney disease, zidovudine toxicity, cancer does not stop after starting epoetin alpha. Once the patient begins to respond, one has to determine treatment duration and when to decrease/stop treatment to prevent complications. Nursing can administer the drug, help explain therapy to the patient, answer questions, provide monitoring, and report any changes in status to the clinicians or pharmacist. The pharmacist can verify dosing and ensure there are no potential drug-drug interactions. Only by working as an interprofessional team, the proper management of anemia with this medication is possible. [Level 5] The long-term outcomes suggest that epoetin alfa is effective and safe for maintaining hemoglobin.[16]