Epoetin alfa

Epoetin alfa
Names
Pronunciation/ɛˈpoʊ.ɪtɪn/
Trade namesEpogen, Retacrit, Procrit, others
Other namesEpoetin alfa-epbx
Clinical data
Drug classErythropoiesis-stimulating agent[1]
Main usesLow red blood cells[2]
Side effectsJoint pain, fever, dizziness, high blood pressure[2]
Pregnancy
category
  • Unknown
Routes of
use		IV or subcutaneous
External links
AHFS/Drugs.comMonograph
US NLMEpoetin alfa
MedlinePlusa692034
Legal
License data
Legal status
Chemical and physical data
FormulaC815H1317N233O241S5
Molar mass18396.19 g·mol−1

Epoetin alfa, sold under the brand name Epogen among others, is a medication used to treat low red blood cells due to chronic kidney disease and chemotherapy.[2] It may also be used before surgery were moderate blood loss is expected.[1] It is given by injection under the skin or into a vein.[2]

Common side effects include joint pain, fever, dizziness, and high blood pressure.[2] Other side effects may include anaphylaxis, heart failure, blood clots, and worsening of a preexisting cancer.[2] It appears to be safe in pregnancy.[1] It is a erythropoiesis-stimulating agent made using recombinant DNA technology.[1][2] It works by stimulating red blood cell production.[2]

Epoetin alfa was approved for medical use in the United States in 1989.[2] It is on the World Health Organization's List of Essential Medicines.[5] In the United Kingdom 6,000 units costs the NHS about £33 as of 2021.[1] This amount in the United States costs about 105 USD.[6]

Medical uses

Erythropoietin is available as a therapeutic agent produced by recombinant DNA technology in mammalian cell culture. It is used in treating anemia resulting from chronic kidney disease and myelodysplasia, from the treatment of cancer (chemotherapy and radiation).

Kidney disease

For patients 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.[7] Dialysis patients in the U.S. are most often given Epogen; other brands of epoetin may be used in other countries.

Erythropoietin is also used to treat anemia in people 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 with anemia due to chronic kidney disease (not on dialysis).

Cancer

In March 2008, a panel of advisers for the U.S. Food and Drug Administration (FDA) supported keeping erythropoiesis-stimulating agents (ESAs) on the market for use in cancer patients. The FDA has focused its concern on study results from some clinical trials showing an increased risk of death and tumor growth in chemotherapy patients taking the anti-anemia drugs.

Critical illness

Erythropoietin is used to treat people with anemia resulting from critical illness. In a randomized controlled trial,[8] 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. Any benefit of erythropoietin use must be weighed against the increased likelihood of thrombosis, which has been demonstrated in numerous trials.

Neurological disease

Erythropoietin has been hypothesized to be beneficial in treating certain neurological diseases such as schizophrenia and stroke.[9] Some research has suggested that erythropoietin improves the survival rate in children suffering from cerebral malaria, which is caused by the malaria parasite's blockage of blood vessels in the brain.[10][11][12] However, the possibility that erythropoietin may be neuroprotective is inconsistent with the poor transport of the chemical into the brain[13] and the low levels of erythropoietin receptors expressed on neuronal cells.

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 with erythropoietin old 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.[14][15]

Dosage

For people with kidney failure it is started at 50 units per kg three times per week, which may be increased up to 300 units once per week.[1]

Side 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.[16]

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.[17]

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.[14][15] Since anemia itself increases the risk of retinopathy, the correlation with erythropoietin treatment may be incidental.

Cancer

Care should be take with use in people with cancer. The DAHANCA 10 data monitoring committee found that three-year loco-regional cancer control in subjects treated with epoetin alpha was worse than for those not receiving it.

In response to these advisories, the FDA released a Public Health Advisory[18] on March 9, 2007, and a clinical alert[19] for doctors on February 16, 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.

In addition, on March 9, 2007, drug manufacturers agreed to new black box warnings about the safety of these drugs.

On March 22, 2007, a congressional inquiry into the safety of erythropoietic growth factors was reported in the news media. Manufacturers were asked to suspend drug rebate programs for physicians and to also suspend marketing the drugs to patients.

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.[20][21][22][23]

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 may interfere with hematopoiesis by decreasing the synthesis of endogenous erythropoietin or decreasing bone marrow production of red blood cells.[24]

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.[25]

In 2011, author Kathleen Sharp published a book, Blood Feud: The Man Who Blew the Whistle on One of the Deadliest Prescription Drugs Ever,[26] 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.[27]

Cost

For several years, epoetin alfa has accounted for the single greatest drug expenditure paid by the U.S. Medicare system; in 2010, the program paid $2 billion for the drug.[28][29]

Similar medications

See also: Biosimilars

In August 2007, Binocrit, Epoetin Alfa Hexal, and Abseamed were approved for use in the European Union.[30][31][3]

Darbepoetin alfa (rINN) is a glycosylation analog of erythropoietin containing two additional N-linked carbohydrate chains.[32]

References

  1. 1 2 3 4 5 6 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 1060. ISBN 978-0857114105.
  2. 1 2 3 4 5 6 7 8 9 "Epoetin Alfa Monograph for Professionals". Drugs.com. Archived from the original on 27 December 2021. Retrieved 15 December 2021.
  3. 1 2 "Abseamed EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 23 March 2020. Retrieved 2 April 2020.
  4. ↑ "Abseamed". Union Register of medicinal products. Archived from the original on 21 January 2021. Retrieved 14 January 2021.
  5. ↑ World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
  6. ↑ "Epogen Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 27 December 2021. Retrieved 15 December 2021.
  7. ↑ 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.
  8. ↑ Corwin HL, Gettinger A, Fabian TC, May A, Pearl RG, Heard S, An R, Bowers PJ, Burton P, Klausner MA, Corwin MJ (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.
  9. ↑ Ehrenreich H, Degner D, Meller J, Brines M, Béhé M, Hasselblatt M, Woldt H, Falkai P, Knerlich F, Jacob S, von Ahsen N, Maier W, Brück W, Rüther E, Cerami A, Becker W, Sirén 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ McKie, Robin (2008-02-17). "Kidney drug could save children from malaria brain damage". The Guardian. London. Archived from the original on 2008-05-19. Retrieved 2021-10-05.
  13. ↑ 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.
  14. 1 2 Ohlsson, Arne; Aher, Sanjay M. (16 November 2017). "Early erythropoiesis-stimulating agents in preterm or low birth weight infants". The Cochrane Database of Systematic Reviews. 11: CD004863. doi:10.1002/14651858.CD004863.pub5. ISSN 1469-493X. PMC 6486170. PMID 29145693.
  15. 1 2 Aher, Sanjay M.; Ohlsson, Arne (11 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. 2: CD004865. doi:10.1002/14651858.CD004865.pub4. ISSN 1469-493X. PMC 7014632. PMID 32048729.
  16. ↑ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 547-549.
  17. ↑ Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger HU, Scherhag A (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.
  18. ↑ "FDA Public Health Advisory: Erythropoiesis-Stimulating Agents (ESAs): Epoetin alfa (marketed as Procrit, Epogen), Darbepoetin alfa (marketed as Aranesp)". Archived from the original on 2007-05-28. Retrieved 2007-06-05.
  19. ↑ "Information for Healthcare Professionals: Erythropoiesis Stimulating Agents (ESA)". Archived from the original on 2007-05-15. Retrieved 2007-06-05.
  20. ↑ "Erythropoiesis Stimulating Agents: Aranesp (darbepoetin alfa), Epogen (epoetin alfa), and Procrit (epoetin alfa)". MedWatch - 2007 Safety Information Alerts. U.S. Food and Drug Administration. 2008-01-03. Archived from the original on April 9, 2009. Retrieved 2009-04-09.
  21. ↑ "Procrit (Epoetin alfa) for injection" (PDF). U.S. Food and Drug Administration. 2007-08-11. Archived from the original (PDF) on January 18, 2009. Retrieved 2009-04-09.
  22. ↑ "Aranesp (darbepoetin alfa) for Injection" (PDF). U.S. Food and Drug Administration. 2007-11-08. Archived from the original (PDF) on January 18, 2009. Retrieved 2009-04-09.
  23. ↑ "Information on Erythropoiesis Stimulating Agents (ESA) (marketed as Procrit, Epogen, and Aranesp)". U.S. Food and Drug Administration. 2009-01-26. Archived from the original on 2009-05-09. Retrieved 2009-04-09.
  24. ↑ "Drug Interactions of Erythropoietin Alfa at Drugs.com". Archived from the original on 2016-05-29. Retrieved 2021-10-05.
  25. ↑ 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.
  26. ↑ Maryann Napoli (October 5, 2011), Whistleblower's story: New book reviewed, Center for Medical Consumers, archived from the original on January 5, 2012, retrieved 2012-02-12{{citation}}: CS1 maint: bot: original URL status unknown (link)| archive-url= | archive-date=January 5, 2012
  27. ↑ Edwards, Jim (August 17, 2009). "Drug Rep in $3B Procrit Case: "80% of My Sales Were Medicare Fraud"; Carried $400K in "Cash"". CBS news. Retrieved 2012-02-12.
  28. ↑ "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, archived (PDF) from the original on 24 September 2015, retrieved 29 June 2015
  29. ↑ Mitka, Mike (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
  30. ↑ "Binocrit EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 30 December 2019. Retrieved 2 April 2020.
  31. ↑ "Epoetin Alfa Hexal EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 30 December 2019. Retrieved 2 April 2020.
  32. ↑ Elliott S, Lorenzini T, Asher S, Aoki K, Brankow D, Buck L, et al. (April 2003). "Enhancement of therapeutic protein in vivo activities through glycoengineering". Nature Biotechnology. 21 (4): 414–21. doi:10.1038/nbt799. PMID 12612588. S2CID 7214868.
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