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epoetin-alfa (Epogen, Procrit, Eprex)

Tradenames: Epogen, Procrit. Identical to the native erythropoietin. Indications: 1) anemia secondary to chronic renal failure a) indicated for blood hemoglobin < 11 g/dL [14] b) target: blood hemoglobin = 11-12 g/dL 2) anemia of HIV infection - zidovudine therapy in HIV+ patients 3) anemia of malignancy a) inhibition of erythropoiesis by IL-1 or TNF b) may negatively affect survival [7,12] 4) anemia caused by antineoplastic agents a) bone marrow insult from chemotherapy b) 3-6 week lag in response c) begin epoetin-alpha during 1st cycle of chemotherapy d) not for use with myelosuppressive agents when the expected outcome is cure [9] 5) surgery Contraindications: - uncontrolled hypertension - decreased survival in patients with non-small cell lung cancer [8] - hospitalized patients without symptoms of anemia or end organ damage [16] - not appropriate for acute renal failure - not appropriate for critically ill patients [16] Pregnancy category C Safety in lactation ? Dosage: 1) 50-100 units/kg 3X/week IV or SC 2) 40,000 units SC weekly 3) target hemoglobin 10-12 g/dL * check serum iron, TIBC, ferritin before initiating erythropoiesis-stimulating agent * maintain transferrin saturation > 30% & serum ferritin > 500 ng/mL * do not check serum erythropoietin [16] Injectable: 3000, 4000, *10,000, *20,000 units/mL * multidose vials tuberculin syringe 1 mL, 26G 3/8 inch Pharmacokinetics: 1) well absorbed after SC delivery 2) with IV administration, peak levels are less sustained 3) best absorption after SC administration in the thigh 4) elimination: 1st order, 1/2 life 4-16 hours 5) most likely metabolized by the kidneys 6) not removed by hemodialysis 7) onset of action: several days with peak effect in 2-3 weeks Adverse effects: 1) common (> 10%) a) hypertension b) headache c) arthralgia d) nausea 2) less common (1-10%) - edema, fatigue, diarrhea, vomiting, chest pain, asthenia, dizziness, seizures, thrombosis, fever 3) uncommon (< 1%) - myocardial infarction, stroke, transient ischemic attack (TIA), hypersensitivity reactions 4) other a) neutralizing antibodies against erythropoietin resulting in red cell aplasia with or without other cytopenias [5] b) increased mortality when hemoglobin targeted to 13.4 g/dL [6] c) increased mortality in stroke patients ? [10] d) increased risk of hemorrhagic stroke ? [11] Drug interactions: - desmopressin in combination increases bleeding time Mechanism of action: Epoetin alfa is a biosynthetic form of the glycoprotein erythropoietin, prepared commercially from cultures of genetically modified Chinese Hamster Ovary (CHO) cells. The cells have been transfected with plasmids containing the erythropoietin gene isolated from human fetal liver cells. Epoetin alfa & some other erythropoietin preparations including epoetin-beta & epoetin-gamma (neither of which is available commercially in the US) have amino acid sequences & pharmacologic activities identical to that of endogenous erythropoietin; however, differences in the nature & composition of the carbohydrate moieties exist. Production of erythropoietin in mammalian cell lines allows for glycosylation. Enzymatic removal of carbohydrate results in loss of pharmacologic activity. Apparently has neuroprotective effects in animal models of stroke, spinal cord compression, diabetic neuropathy, multiple sclerosis. Mechanism not established. Involves receptor different from erythropoietin receptor on erythrocyte precursors.

Interactions

drug adverse effects of erythropoiesis-stimulating agents monitor with erythropoietins

Related

darbepoetin-alfa (Aranesp)

General

erythropoiesis-stimulating agent recombinant protein; chimer erythropoietin (EPO)

References

  1. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  2. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  3. Journal Watch 24(16):129, 2004 - Leist M, Ghezzi P, Grasso G, Bianchi R, Villa P, Fratelli M, Savino C, Bianchi M, Nielsen J, Gerwien J, Kallunki P, Larsen AK, Helboe L, Christensen S, Pedersen LO, Nielsen M, Torup L, Sager T, Sfacteria A, Erbayraktar S, Erbayraktar Z, Gokmen N, Yilmaz O, Cerami-Hand C, Xie QW, Coleman T, Cerami A, Brines M. Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science. 2004 Jul 9;305(5681):239-42. PMID: 15247477 - Ehrenreich H. Medicine. A boost for translational neuroscience. Science. 2004 Jul 9;305(5681):184-5. No abstract available. PMID: 15247460
  4. West Los Angeles Veterans Administration Pharmacy, 2004
  5. FDA Medwatch http://www.fda.gov/medwatch/safety/2005/safety05.htm#epoetin http://www.fda.gov/medwatch/safety/2006/safety06.htm#erythropoiesis
  6. Prescriber's Letter 14(1): 2007 Erythropoiesis Stimulating Agents (Aranesp, Epogen, and Procrit): Caution not to Exceed Recommended Hemoglobin Targets Detail-Document#: 230105 (subscription needed) http://www.prescribersletter.com
  7. Wright JR et al, Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small cell lung cancer with disease- related anemia. J Clin Oncol 2007, 25:1021 PMID: 17312332
  8. Wright JR, Ung YC, Julian JA, Pritchard KI, Whelan TJ, Smith C, Szechtman B, Roa W, Mulroy L, Rudinskas L, Gagnon B, Okawara GS, Levine MN. Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol. 2007 Mar 20;25(9):1027-32. Epub 2007 Feb 20. PMID: 11742
  9. FDA MedWatch http://www.fda.gov/medwatch/safety/2008/safety08.htm#ESA2
  10. FDA: Center for Drug Evaluation and Research Early Communication about an Ongoing Safety Review Epoetin alfa http://www.fda.gov/cder/drug/early_comm/epoetin_alfa.htm
  11. FDA MedWatch http://www.fda.gov/medwatch/safety/2008/safety08.htm#ESA3
  12. Tonelli M et al. Benefits and harms of erythropoiesis-stimulating agents for anemia related to cancer: A meta-analysis. CMAJ 2009 May 26; 180:E62. http://dx.doi.org/10.1503/cmaj.090470 PMID: 19407261
  13. Prescriber's Letter 17(4): 2010 ESA APPRISE Oncology Program for Cancer Patients Using Procrit, Epogen, or Aranesp COMMENTARY: ESA APPRISE Oncology Program for Cancer Patients Using Procrit, Epogen, or Aranesp CHART: Drugs with Special Prescribing and Dispensing Requirements Detail-Document#: 260422 (subscription needed) http://www.prescribersletter.com
  14. Geriatric Review Syllabus, 7th edition Parada JT et al (eds) American Geriatrics Society, 2010
  15. Palmer SC, Navaneethan SD, Craig JC, et al. Meta-analysis: Erythropoiesis-stimulating agents in patients with chronic kidney disease. Ann Intern Med July 6, 2010; 153(1):23-33. PMID: 20439566 - Weiner DE and Miskulin DC Anemia management in chronic kidney disease: bursting the hemoglobin bubble. Ann Intern Med. 2010 Jul 6;153(1):53-5. Epub 2010 May 3. PMID: 20439567
  16. Medical Knowledge Self Assessment Program (MKSAP) 17, 18. American College of Physicians, Philadelphia 2015, 2018. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022