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Epoetin Alfa


Epoetin Alfa

Article Author:
Saumil Patel
Article Editor:
Jayesh Patel
Updated:
5/23/2020 7:36:54 PM
For CME on this topic:
Epoetin Alfa CME
PubMed Link:
Epoetin Alfa

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][6][7][8][9][10][9][7][6]:

  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 a 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 erythropoiesis process. The erythroid progenitors take several days to mature and undergo release into the 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 who are 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

The patients who are 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. So, it should be used very carefully in patients with uncontrolled hypertension. Additionally, patients may require dosage adjustments of antihypertensive therapy after initiation of 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 who have 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 lasts 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 in 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 gram per deciliter. Signs and symptoms of these side effects also require monitoring. To decrease the risk of thromboembolism, encourage the patient for the cessation of smoking and alcohol drinking, regular exercising, and diet modification. 
  • Complete blood count, serum iron profile with ferritin should be monitored while the patient is on the 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 the 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]


References

[1] Fishbane S,Spinowitz BS,Wisemandle WA,Martin NE, Randomized Controlled Trial of Subcutaneous Epoetin Alfa-epbx Versus Epoetin Alfa in End-Stage Kidney Disease. Kidney international reports. 2019 Sep;     [PubMed PMID: 31517143]
[2] Ikunaiye NY,Denue BA,Aina BA,Aderemi-Williams R,Rawizza HE, INCIDENCE OF ANAEMIA AMONG HIV-INFECTED PATIENTS TREATED WITH ZIDOVUDINE-CONTAINING ANTIRETROVIRAL THERAPY IN NORTHEASTERN NIGERIA. Annals of Ibadan postgraduate medicine. 2018 Dec;     [PubMed PMID: 31217768]
[3] Ferri RS,Adinolfi A,Orsi AJ,Sterken DJ,Keruly JC,Davis S,MacIntyre RC, Treatment of anemia in patients with HIV Infection--Part 2: guidelines for management of anemia. The Journal of the Association of Nurses in AIDS Care : JANAC. 2002 Jan-Feb;     [PubMed PMID: 11828859]
[4] Bohlius J,Bohlke K,Castelli R,Djulbegovic B,Lustberg MB,Martino M,Mountzios G,Peswani N,Porter L,Tanaka TN,Trifirò G,Yang H,Lazo-Langner A, Management of Cancer-Associated Anemia With Erythropoiesis-Stimulating Agents: ASCO/ASH Clinical Practice Guideline Update. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2019 May 20;     [PubMed PMID: 30969847]
[5] Joseph SA Jr,Berekashvili K,Mariller MM,Rivlin M,Sharma K,Casden A,Bitan F,Kuflik P,Neuwirth M, Blood conservation techniques in spinal deformity surgery: a retrospective review of patients refusing blood transfusion. Spine. 2008 Oct 1;     [PubMed PMID: 18827697]
[6] Beliaev AM,Allen SJ,Milsom P,Nand P,Smith WM,Bergin CJ, Low-dose erythropoietin treatment is not associated with clinical benefits in severely anaemic Jehovah's Witnesses: a plea for a change. Blood transfusion = Trasfusione del sangue. 2018 Jan     [PubMed PMID: 27893353]
[7] Stickel F,Helbling B,Heim M,Geier A,Hirschi C,Terziroli B,Wehr K,De Gottardi A,Negro F,Gerlach T, Critical review of the use of erythropoietin in the treatment of anaemia during therapy for chronic hepatitis C. Journal of viral hepatitis. 2012 Feb     [PubMed PMID: 22239497]
[8] Gascón P,Krendyukov A,Mathieson N,Aapro M, Epoetin alfa for the treatment of myelodysplastic syndrome-related anemia: A review of clinical data, clinical guidelines, and treatment protocols. Leukemia research. 2019 Jun     [PubMed PMID: 31005849]
[9] Moura ATG,Duarte FB,Barbosa MC,Santos TEJD,Lemes RPG, Prolonged response to recombinant human erythropoietin treatment in patients with myelodysplastic syndrome at a single referral centre in Brazil. Clinics (Sao Paulo, Brazil). 2019     [PubMed PMID: 31508719]
[10] Saleh MI,Nalbant D,Widness JA,Veng-Pedersen P, Population pharmacodynamic analysis of erythropoiesis in preterm infants for determining the anemia treatment potential of erythropoietin. American journal of physiology. Regulatory, integrative and comparative physiology. 2013 May 1     [PubMed PMID: 23485870]
[11] Hematologic Growth Factors 2012;     [PubMed PMID: 31644052]
[12] Brown MS,Jones MA,Ohls RK,Christensen RD, Single-dose pharmacokinetics of recombinant human erythropoietin in preterm infants after intravenous and subcutaneous administration. The Journal of pediatrics. 1993 Apr;     [PubMed PMID: 8463922]
[13] Ohls RK,Christensen RD, Stability of human recombinant epoetin alfa in commonly used neonatal intravenous solutions. The Annals of pharmacotherapy. 1996 May     [PubMed PMID: 8740324]
[14] Neonatal deaths associated with use of benzyl alcohol--United States. MMWR. Morbidity and mortality weekly report. 1982 Jun 11;     [PubMed PMID: 6810084]
[15] Hoffman RS,Cobrin G,Nelson LS,Howland MA, Erythropoietin overdose treated with emergent erythropheresis. Veterinary and human toxicology. 2002 Jun     [PubMed PMID: 12046968]
[16] Provenzano R,Bhaduri S,Singh AK, Extended epoetin alfa dosing as maintenance treatment for the anemia of chronic kidney disease: the PROMPT study. Clinical nephrology. 2005 Aug     [PubMed PMID: 16114787]