Epoetin alfa

Epoetin alfa
Clinical data
Pronunciation/ɛˈpoʊ.ɪtɪn/
Trade namesEpogen
Biosimilarsepoetin alfa-epbx, Abseamed,[1][2] Binocrit,[3] Epoetin Alfa Hexal,[4] Retacrit[5][6]
AHFS/Drugs.comMonograph
MedlinePlusa692034
License data
Routes of
administration		Intravenous, subcutaneous
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC815H1317N233O241S5
Molar mass18396.19 g·mol−1
 ☒NcheckY (what is this?)  (verify)

Epoetin alfa, sold under the brand name Epogen among others, is a human erythropoietin produced in cell culture using recombinant DNA technology.[8][9] Epoetin alfa is an erythropoiesis-stimulating agent.[8] It stimulates erythropoiesis (increasing red blood cell levels) and is used to treat anemia, commonly associated with chronic kidney failure and cancer chemotherapy. Epoetin alfa is developed by Amgen.[8]

It is on the World Health Organization's List of Essential Medicines.[10] It was approved for medical use in the European Union in August 2007,

Medical uses

Epoetin alfa is indicated for the treatment of anemia due to chronic kidney disease; zidovudine in people with human immunodeficiency virus; HIV infection; the effects of concomitant myelosuppressive chemotherapy; reduction of allogeneic red blood cell transfusions.

Anemia caused by kidney disease

For people who require dialysis or have chronic kidney disease, iron should be given with erythropoietin, depending on some laboratory parameters such as ferritin and transferrin saturation.[11]

Erythropoietin is also used to treat anemia in people, and cats and dogs, with chronic kidney disease who are not on dialysis (those in Stage 3 or 4 disease and those living with a kidney transplant). There are two types of erythropoietin for people, and cats and dogs, with anemia due to chronic kidney disease (not on dialysis).[12][13]

Anemia in critically ill people

Erythropoietin is used to treat people with anemia resulting from critical illness.

In a randomized controlled trial,[14] erythropoietin was shown to not change the number of blood transfusions required by critically ill patients. A surprising finding in this study was a small mortality reduction in patients receiving erythropoietin. This result was statistically significant after 29 days but not at 140 days. The mortality difference was most marked in patients admitted to the ICU for trauma. The authors provide several hypotheses for potential etiologies of this reduced mortality, but, given the known increase in thrombosis and increased benefit in trauma patients as well as marginal nonsignificant benefit (adjusted hazard ratio of 0.9) in surgery patients, it could be speculated that some of the benefit might be secondary to the procoagulant effect of erythropoietin. Regardless, this study suggests further research may be necessary to see which critical care patients, if any, might benefit from administration of erythropoietin.

Adverse effects

Epoetin alfa is generally well tolerated. Common side effects include high blood pressure, headache, disabling cluster migraine (resistant to remedies), joint pain, and clotting at the injection site. Rare cases of stinging at the injection site, skin rash, and flu-like symptoms (joint and muscle pain) have occurred within a few hours following administration. More serious side effects, including allergic reactions, seizures and thrombotic events (e.g., heart attacks, strokes, and pulmonary embolism) rarely occur. Chronic self-administration of the drug has been shown to cause increases in blood hemoglobin and hematocrit to abnormally high levels, resulting in dyspnea and abdominal pain.[15]

Erythropoietin is associated with an increased risk of adverse cardiovascular complications in patients with kidney disease if it is used to target an increase of hemoglobin levels above 13.0 g/dl.[16]

Early treatment (before an infant is 8 days old) with erythropoietin correlated with an increase in the risk of retinopathy of prematurity in premature and anemic infants, raising concern that the angiogenic actions of erythropoietin may exacerbate retinopathy.[17][18] Since anemia itself increases the risk of retinopathy, the correlation with erythropoietin treatment may be incidental.[19]

Safety advisories in anemic cancer patients

Amgen advised the U.S. Food and Drug Administration (FDA) regarding the results of the DAHANCA 10 clinical trial. The DAHANCA 10 data monitoring committee found that three-year loco-regional cancer control in subjects treated with Aranesp was significantly worse than for those not receiving Aranesp (p=0.01).[20]

In response to these advisories, the FDA released a Public Health Advisory[21] on 9 March 2007, and a clinical alert[22] for doctors in February 2007, about the use of erythropoiesis-stimulating agents (ESAs) such as epogen and darbepoetin. The advisory recommended caution in using these agents in cancer patients receiving chemotherapy or off chemotherapy, and indicated a lack of clinical evidence to support improvements in quality of life or transfusion requirements in these settings.

Several publications and FDA communications have increased the level of concern related to adverse effects of ESA therapy in selected groups. In a revised black box warning, the FDA notes significant risks, advising that ESAs should be used only in patients with cancer when treating anemia specifically caused by chemotherapy, and not for other causes of anemia. Further, the warning states that ESAs should be discontinued once the patient's chemotherapy course has been completed.[23][24][25][26]

Interactions

Drug interactions with erythropoietin include:

  • Major: lenalidomide—risk of thrombosis
  • Moderate: cyclosporine—risk of high blood pressure may be greater in combination with EPO. EPO may lead to variability in blood levels of cyclosporine.
  • Minor: ACE inhibitors and angiotensin receptor blockers may interfere with hematopoiesis, possibly by decreasing the synthesis of endogenous erythropoietin and decreasing bone marrow production of red blood cells.[27]

Society and culture

The publication of an editorial questioning the benefits of high-dose epoetin was canceled by the marketing branch of a journal after being accepted by the editorial branch highlighting concerns of conflict of interest in publishing.[28]

In 2011, author Kathleen Sharp published a book, Blood Feud: The Man Who Blew the Whistle on One of the Deadliest Prescription Drugs Ever,[29] alleging drug maker Johnson & Johnson encouraged doctors to prescribe epoetin in high doses, particularly for cancer patients, because this would increase sales by hundreds of millions of dollars. Former sales representatives Mark Duxbury and Dean McClennan, claimed that the bulk of their business selling epoetin to hospitals and clinics was Medicare fraud, totaling US$3 billion.[30]

Economics

The average cost per patient in the US was US$8,447 in 2009.[31]

Epoetin alfa has accounted for the single greatest drug expenditure paid by the US Medicare system; in 2010, the program paid US$2 billion for the medication.[32][33]

Biosimilars

See also: Biosimilars

In August 2007, Binocrit, Epoetin Alfa Hexal, and Abseamed were approved for use in the European Union.[3][4][1]

Research

Neurological diseases

Erythropoietin has been hypothesized to be beneficial in treating certain neurological diseases such as schizophrenia and stroke.[34] Some research has suggested that erythropoietin improves the survival rate in children with cerebral malaria, which is caused by the malaria parasite's blockage of blood vessels in the brain.[35][36][37] However, the possibility that erythropoietin may be neuroprotective is inconsistent with the poor transport of the chemical into the brain[38] and the low levels of erythropoietin receptors expressed on neuronal cells.

Psychiatric diseases

Randomized clinical control trials have shown promising results of EPO in improving cognition which is often intractable with the current treatment of mood disorders and schizophrenia.These domains include speed of complex cognitive processing across attention,memory and executive function.[39]

Preterm infants

Infants born early often require transfusions with red blood cells and have low levels of erythropoietin. Erythropoietin has been studied as a treatment option to reduce anemia in preterm infants. Treating infants less than 8 days old with erythropoietin may slightly reduce the need for red blood cell transfusions, but increases the risk of retinopathy. Due to the limited clinical benefit and increased risk of retinopathy, early or late erythropoietin treatment is not recommended for preterm infants.[17][18]

References

  1. ^ a b "Abseamed EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 2 April 2020.
  2. ^ "Abseamed". Union Register of medicinal products. Retrieved 14 January 2021.
  3. ^ a b "Binocrit EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 2 April 2020.
  4. ^ a b "Epoetin Alfa Hexal EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 2 April 2020.
  5. ^ "Retacrit- epoetin alfa-epbx injection, solution". DailyMed. 29 January 2020.
  6. ^ "Retacrit- epoetin alfa-epbx injection, solution". DailyMed. 26 June 2024. Retrieved 25 July 2024.
  7. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  8. ^ a b c d "Epogen- epoetin alfa solution". DailyMed. 25 July 2018.
  9. ^ Walsh G, Spada S (2005). "Epogen/Procrit". Directory of approved biopharmaceutical products. Boca Raton: CRC Press. pp. 39–41. ISBN 978-0-415-26368-9.
  10. ^ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl:10665/371090. WHO/MHP/HPS/EML/2023.02.
  11. ^ Macdougall IC, Tucker B, Thompson J, Tomson CR, Baker LR, Raine AE (November 1996). "A randomized controlled study of iron supplementation in patients treated with erythropoietin". Kidney International. 50 (5): 1694–9. doi:10.1038/ki.1996.487. PMID 8914038.
  12. ^ Fitzsimons H (14 November 2020). "Erythropoiesis Stimulating Agents (ESAs) for Severe Anaemia". Tanya's Feline CKD Website. Retrieved 17 September 2023.
  13. ^ Ruben D (6 August 2015). "Erythropoietin (Epogen®, Procrit®) for Dogs and Cats". PetPlace. Retrieved 17 September 2023.
  14. ^ Corwin HL, Gettinger A, Fabian TC, May A, Pearl RG, Heard S, et al. (September 2007). "Efficacy and safety of epoetin alfa in critically ill patients". The New England Journal of Medicine. 357 (10): 965–76. doi:10.1056/NEJMoa071533. PMID 17804841.
  15. ^ Baselt RC (2008). Disposition of Toxic Drugs and Chemicals in Man. Foster City, CA: Biomedical Publications. p. 547-549. ISBN 978-0-9626523-7-0.
  16. ^ Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, et al. (November 2006). "Normalization of hemoglobin level in patients with chronic kidney disease and anemia". The New England Journal of Medicine. 355 (20): 2071–84. doi:10.1056/NEJMoa062276. PMID 17108342.
  17. ^ a b Ohlsson A, Aher SM (February 2020). "Early erythropoiesis-stimulating agents in preterm or low birth weight infants". The Cochrane Database of Systematic Reviews. 2 (2): CD004863. doi:10.1002/14651858.CD004863.pub6. PMC 7014351. PMID 32048730.
  18. ^ a b Aher SM, Ohlsson A (February 2020). "Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants". The Cochrane Database of Systematic Reviews. 2020 (2): CD004865. doi:10.1002/14651858.CD004865.pub4. PMC 7014632. PMID 32048729.
  19. ^ Chou HH, Chung MY, Zhou XG, Lin HC (February 2017). "Early Erythropoietin Administration does not Increase the Risk of Retinopathy in Preterm Infants". Pediatrics and Neonatology. 58 (1): 48–56. doi:10.1016/j.pedneo.2016.03.006. PMID 27346390.
  20. ^ Wauters I, Pat K, Vansteenkiste J (June 2006). "Flexible dosing with Darbepoetin alfa for the treatment of chemotherapy-induced anemia". Therapeutics and Clinical Risk Management. 2 (2): 175–186. doi:10.2147/tcrm.2006.2.2.175. PMC 1661657. PMID 18360591.
  21. ^ "FDA Public Health Advisory: Erythropoiesis-Stimulating Agents (ESAs): Epoetin alfa (marketed as Procrit, Epogen), Darbepoetin alfa (marketed as Aranesp)". Food and Drug Administration. Archived from the original on 28 May 2007. Retrieved 5 June 2007.
  22. ^ "Information for Healthcare Professionals: Erythropoiesis Stimulating Agents (ESA)". Food and Drug Administration. Archived from the original on 15 May 2007. Retrieved 5 June 2007.
  23. ^ "Erythropoiesis Stimulating Agents: Aranesp (darbepoetin alfa), Epogen (epoetin alfa), and Procrit (epoetin alfa)". MedWatch - 2007 Safety Information Alerts. U.S. Food and Drug Administration. 3 January 2008. Archived from the original on 9 April 2009. Retrieved 9 April 2009.
  24. ^ "Procrit (Epoetin alfa) for injection" (PDF). U.S. Food and Drug Administration. 11 August 2007. Archived from the original (PDF) on 18 January 2009. Retrieved 9 April 2009.
  25. ^ "Aranesp (darbepoetin alfa) for Injection" (PDF). U.S. Food and Drug Administration. 8 November 2007. Archived from the original (PDF) on 18 January 2009. Retrieved 9 April 2009.
  26. ^ "Information on Erythropoiesis Stimulating Agents (ESA) (marketed as Procrit, Epogen, and Aranesp)". U.S. Food and Drug Administration. 26 January 2009. Retrieved 9 April 2009.
  27. ^ Cheungpasitporn W, Thongprayoon C, Chiasakul T, Korpaisarn S, Erickson SB (November 2015). "Renin-angiotensin system inhibitors linked to anemia: a systematic review and meta-analysis". QJM. 108 (11): 879–884. doi:10.1093/qjmed/hcv049. PMID 25697787. Open access icon
  28. ^ Hardell L, Walker MJ, Walhjalt B, Friedman LS, Richter ED (March 2007). "Secret ties to industry and conflicting interests in cancer research". American Journal of Industrial Medicine. 50 (3): 227–33. doi:10.1002/ajim.20357. PMID 17086516.
  29. ^ Napoli M (5 October 2011). "Whistleblower's story: New book reviewed". Center for Medical Consumers. Archived from the original on 5 January 2012. Retrieved 12 February 2012.
  30. ^ Edwards J (17 August 2009). "Drug Rep in $3B Procrit Case: "80% of My Sales Were Medicare Fraud"; Carried $400K in "Cash"". CBS news. Retrieved 12 February 2012.
  31. ^ Engelberg AB, Kesselheim AS, Avorn J (November 2009). "Balancing innovation, access, and profits--market exclusivity for biologics". The New England Journal of Medicine. 361 (20): 1917–9. doi:10.1056/NEJMp0908496. PMID 19828525.
  32. ^ "Testimony Before the Subcommittee on Health, Committee on Energy and Commerce, House of Representatives.] Medicare. Information on Highest-Expenditure Part B Drugs" (PDF). United States Government Accountability Office (GAO). 28 June 2013. Retrieved 29 June 2015.
  33. ^ Mitka M (14 August 2013), "Capitol Health Call: High-Cost Drugs Account for Most of Medicare Part B Spending", JAMA, 310 (6): 572, doi:10.1001/jama.2013.192555
  34. ^ Ehrenreich H, Degner D, Meller J, Brines M, Béhé M, Hasselblatt M, et al. (January 2004). "Erythropoietin: a candidate compound for neuroprotection in schizophrenia". Molecular Psychiatry. 9 (1): 42–54. doi:10.1038/sj.mp.4001442. PMID 14581931. S2CID 22595839.
  35. ^ Casals-Pascual C, Idro R, Picot S, Roberts DJ, Newton CR (January 2009). "Can erythropoietin be used to prevent brain damage in cerebral malaria?". Trends in Parasitology. 25 (1): 30–6. doi:10.1016/j.pt.2008.10.002. PMID 19008152.
  36. ^ Core A, Hempel C, Kurtzhals JA, Penkowa M (February 2011). "Plasmodium berghei ANKA: erythropoietin activates neural stem cells in an experimental cerebral malaria model". Experimental Parasitology. 127 (2): 500–5. doi:10.1016/j.exppara.2010.09.010. PMID 21044627.
  37. ^ McKie R (17 February 2008). "Kidney drug could save children from malaria brain damage". The Guardian. London.
  38. ^ Banks WA, Jumbe NL, Farrell CL, Niehoff ML, Heatherington AC (November 2004). "Passage of erythropoietic agents across the blood-brain barrier: a comparison of human and murine erythropoietin and the analog darbepoetin alfa". European Journal of Pharmacology. 505 (1–3): 93–101. doi:10.1016/j.ejphar.2004.10.035. PMID 15556141.
  39. ^ Ott CV, Vinberg M, Kessing LV, Miskowiak KW (August 2016). "The effect of erythropoietin on cognition in affective disorders - Associations with baseline deficits and change in subjective cognitive complaints". European Neuropsychopharmacology. 26 (8): 1264–1273. doi:10.1016/j.euroneuro.2016.05.009. PMID 27349944. S2CID 2335208.