Epoetin alfa

Epoetin alfa is a human erythropoietin produced in cell culture using recombinant DNA technology.[1] Authorised by the European Medicines Agency on 28 August 2007, it stimulates erythropoiesis (increasing red blood cell levels) and is used to treat anemia, commonly associated with chronic renal failure and cancer chemotherapy.

Epoetin alfa
Clinical data
Pronunciation/ɛˈpoʊ.ɪtɪn/
AHFS/Drugs.comMonograph
MedlinePlusa692034
License data
Pregnancy
category
  • Unknown
Routes of
administration		IV or subcutaneous
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • US: ℞-only
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
ChEMBL
Chemical and physical data
FormulaC815H1317N233O241S5
Molar mass18396.1 g/mol g·mol−1
 NY (what is this?)  (verify)

Epoetin is manufactured and marketed by Amgen under the trade name Epogen. Johnson & Johnson subsidiary Janssen Biotech (formerly Ortho Biotech Products, LP), sells the same drug under the name Procrit, pursuant to a product license agreement. The average cost per patient in the U.S. was $8,447 in 2009.[2] Darbepoetin alfa (rINN) /dɑːrbəˈpɔɪtɪn/ is a glycosylation analog of erythropoietin containing two additional N-linked carbohydrate chains,[3] also manufactured and marketed by Amgen, with a trade name of Aranesp. The FDA warnings and safety precautions for Procrit, Epogen and Aranesp are identical.

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.[4][5] Raising hemoglobin levels has been found in some studies to be associated with higher risks of thrombotic events, strokes and death.[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).

Anemia caused by 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).

Anemia caused by cancer

In March 2008, a panel of advisers for the U.S. Food and Drug Administration (FDA) supported keeping erythropoiesis-stimulating agents (ESAs) produced by Amgen and Johnson & Johnson 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.

Anemia in critically ill people

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 erythropoetin. Regardless, this study suggests further research may be necessary to see which critical care patients, if any, might benefit from administration of erythropoeitin. Any benefit of erythropoetin use must be weighed against the increased likelihood of thrombosis, which has been demonstrated in numerous trials .

Neurological diseases

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]

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.[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.

Safety advisories in anemic cancer patients

Amgen sent a "dear doctor" letter in January 2007 that highlighted results from a recent anemia of cancer trial, and warned doctors to consider use in that off-label indication with caution.

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).

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 erythropoeisis-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 erythropoeitic 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, claim that the bulk of their business selling epoetin to hospitals and clinics was Medicare fraud, totaling $3 billion.[27] In a lawsuit, Duxbury alleged his employer wrongfully terminated him in 1998. He lived in Gig Harbor, Washington. He was born on March 23, 1960 and died on Tuesday, October 13, 2009, at age 49, while his case was still in litigation.

See also

References
  1. 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.
  2. 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.
  3. 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.
  4. "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
  5. 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
  6. Anemia drugs made billions, but at what cost? By Peter Whoriskey, Washington Post, July 19, 2012
  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" (PDF). Molecular Psychiatry. 9 (1): 42–54. doi:10.1038/sj.mp.4001442. PMID 14581931. Archived from the original (PDF) on 2012-03-05.
  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". London: The Guardian.
  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. Ohlsson A, Aher SM (April 2014). "Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants". The Cochrane Database of Systematic Reviews (4): CD004863. doi:10.1002/14651858.CD004863.pub4. PMID 24771408.
  15. Aher SM, Ohlsson A (October 2012). "Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants". The Cochrane Database of Systematic Reviews. 10: CD004865. doi:10.1002/14651858.CD004865.pub3. PMID 23076909.
  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. Retrieved 2009-04-09.
  24. Drug Interactions of Erythropoietin Alfa at Drugs.com
  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 2012-02-12CS1 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, event occurs at 4:58 PM, retrieved 2012-02-12
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