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Epoetin alfa (rINN) // is human erythropoietin produced in cell culture using recombinant DNA technology. Authorised by the European Medicines Agency on 28 August 2007, it stimulates erythropoiesis (increases red blood cell levels) and is used to treat anemia, commonly associated with chronic renal failure and cancer chemotherapy. Epoetin is manufactured by Amgen and is marketed Amgen under the trade names Epogen and by Johnson & Johnson's subsidiary, Janseen Biotech, formerly Ortho Biotech Products, LP, as Procrit, pursuant to a Product License Agreement. Epogen and Procrit are the same drug. Its annual cost to U.S. patients was $8,447 per patient per year in 2009. Darbepoetin alfa (rINN) /dɑrbəˈpɔɪtɨn/ is a synthetic form of erythropoietin, also manufactured by Amgen. Darbepoetin is marketed by Amgen under the trade name Aranesp. The FDA warnings and safety precautions for Procrit, Epogen and Aransep are identical.
For several years, epoetin alfa has been the single greatest drug expenditure paid for by U.S. Medicare. In 2010, Medicare paid $2 billion. Dosing is controversial, and higher doses, to raise hematocrit to normal levels, are associated with higher risks of hospitalization, strokes and death.
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). Current research suggests that, aminoacid R103 to E mutation in erythropoietin makes it neuroprotective and non-erythropoietic.
Anemia due to chronic kidney disease
In patients who require dialysis or chronic kidney disease(CKD)), iron should be given with erythropoietin depending some laboratory parameters such as Ferritin and Transferrin saturation. Dialysis patients in the US are most often given Epogen; outside of the US other brands of epoetin may be used.
Outside of people on dialysis, erythropoietin is used most commonly to treat anemia in people with chronic kidney disease who are not on dialysis (those in stage 3 or 4 CKD 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 due to treatment for cancer
|This section requires expansion. (November 2007)|
In March 2008, a panel of advisers for the U.S. Food and Drug Administration (FDA) supported keeping ESAs from Amgen and Johnson & Johnson on the market for use in cancer patients. The FDA has focused its concern on study results showing an increased risk of death and tumor growth in chemo patients taking the anti-anemia drugs. According to the FDA, evidence for increased rates of mortality exist in various cancers, including breast, lymphoid, cervical, head and neck, and non-small-cell lung cancer.
Anemia in critically ill patients
Erythropoietin is used to treat people with anemia, due to critical illness.
In a randomized controlled trial, 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. This mortality difference was most marked in patients admitted to the ICU for trauma. The authors speculate 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 must be weighed against the 50% increase in thrombosis, which has been demonstrated in numerous trials.
Erythropoietin has been shown to be beneficial in certain neurological diseases like schizophrenia. Research has suggested that EPO improves the survival rate in children suffering from cerebral malaria, caused by the malaria parasite's blocking of blood vessels in the brain.
Epoetin alfa is generally well tolerated. Common side effects include high blood pressure, headache, crippling 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 by two individuals caused increases in blood hemoglobin and hematocrit to abnormally high levels, resulting in dyspnea and abdominal pain.
Early treatment with erythropoietin correlated with an increase in the risk of Retinopathy of prematurity in premature infants who had anemia of prematurity, raising concern that the angiogenic actions of erythropoietin may exacerbate retinopathy. However, since anemia itself increases the risk of retinopathy, the correlation with erythropoietin treatment may be incidental, and merely reflect that anemia induces retinopathy.
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 3-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 on March 9, 2007, and a clinical alert 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 associated with ESA use. ESAs should be used only in patients with cancer when treating anemia specifically caused by chemotherapy, and not for other causes of anemia. Further, it states that ESAs should be discontinued once the patient's chemotherapy course has been completed.
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.
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.
In 2011, author Kathleen Sharp published a book, Blood Feud: The Man Who Blew the Whistle on One of the Deadliest Prescription Drugs Ever, 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. 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.
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