FDA Warned for Life Threatening Side Effects of Erythropoiesis Stimulating Agents (ESAS)
There are several medications available to treat certain types of anemia. These medications are known as erythropoietic agents because they stimulate erythropoiesis, the production of RBCs in the bone marrow. Several of these agents are forms of a natural growth factor known as erythropoietin, while another is closely related to erythropoietin.in fetuses and in some animals, erythropoeiesis also occurs outside the bone marrow, within the spleen, liver, or yolk sac. This is termed extramedullary erythropoiesis.
A feedback loop involving erythropoietin helps regulate the process of erythropoiesis so that, in non-disease states, the production of red blood cells is equal to the destruction of red blood cells and the red blood cell number is sufficient to sustain adequate tissue oxygen levels but not so high as to cause sludging, thrombosis, or stroke.
Erythropoietin molecules produced by means of gene technology (erythropoiesis-stimulating agents, ESA) have been the agents of choice to correct the anaemia of chronic kidney disease (CKD) since the first of these drugs was licensed in the late 1980s. The side effects seen in the early days may have been due to a too-rapid rise in haemoglobin concentration, along with possible direct effects on non-haematopoietic tissues, including the vascular endothelium. Recently, antibody-mediated pure red-cell aplasia (PRCA) associated with the administration of ESAs has been identified as a serious problem.
ESA-induced PRCA is caused by the development of neutralizing anti-erythropoietin antibodies in patients undergoing therapy with an ESA. These antibodies cross-react with the patient's endogenous erythropoietin and lead to an anaemia that is more severe than before the onset of erythropoietic therapy. Antibody-mediated PRCA is a serious, but fortunately rare, adverse event related to ESA therapy. The subject is still under intense investigation by the regulatory authorities, the manufacturers of ESAs and independent scientists of the nephrology community. More definitive results from these sources are needed before we can make specific, evidence-based treatment recommendations.
There are several commercially available erythropoietic agents, which are listed in the table below. Procrit, Epogen, and Eprex are the same substance (epoetin alfa) while NeoRecormon is slightly different (epoetin beta). All are man-made forms of natural erythropoietin. Aranesp® (darbepoetin alfa, Amgen, Inc.) has the same molecular make-up as natural erythropoietin and acts in the same way, but it has two additional carbohydrate chains to give it a longer half-life.
Recent reports of studies with erythropoiesis-stimulating agents (ESAs) have shown a higher chance of serious and life-threatening side effects and greater number of deaths in patients treated with these agents. ESAs stimulate the bone marrow to make more red blood cells and are FDA approved for use in reducing the need for blood transfusions in patients with chronic kidney failure, patients with cancer on chemotherapy, patients scheduled for major surgery (except heart surgery) and patients with HIV that are using AZT. Because all ESAs work the same way, the findings from these studies apply to all ESAs; the FDA is re-evaluating the safe use of this drug class.
Patients currently using or considering the use of an ESA should know the following:
- A higher chance of death and an increased rate of tumor growth were reported in patients with advanced head and neck cancer receiving radiation therapy and in patients with metastatic breast cancer receiving chemotherapy, when ESAs were given to maintain hemoglobin levels of more than 12 g/dL.
- A higher chance of death was reported and no fewer blood transfusions were received when ESAs were given to patients with cancer and anemia not receiving chemotherapy.
- A higher chance of death was reported and an increased number of blood clots, strokes, heart failure, and heart attacks was reported in patients with chronic kidney failure when ESAs were given to maintain hemoglobin levels of more than 12 g/dL.
- A higher chance of blood clots was reported in patients who were scheduled for major surgery and given ESAs.
- ESAs are not approved for treatment of the symptoms of anemia, such as fatigue in patients with cancer, surgical patients and patients with HIV.
- If you have any questions you should talk with your health care provider.
Important study results include the following:
- Patients with chronic kidney failure had an increased number of deaths and of non-fatal heart attacks, strokes, heart failure, and blood clots when ESAs were adjusted to maintain higher red blood cell levels (hemoglobin more than 12 g/dL).
- Patients with head and neck cancer receiving radiation therapy had faster tumor growth when ESAs were adjusted to maintain hemoglobin levels higher than 12 g/dL.
- Patients with cancer not receiving chemotherapy died sooner and had no fewer blood transfusions when ESAs were given according to the dosing recommendations for cancer patients receiving chemotherapy.
- Patients scheduled for orthopedic surgery who received ESAs to reduce blood transfusions during and after surgery had more blood clots than those not given an ESA.
- Physicians who prescribe ESAs should consider the important study results above and:
- Understand that ESAs are given to decrease the need for red blood cell transfusions;
- Consider both the risks of transfusions and those of ESAs when deciding to prescribe an ESA;
- Adjust the dose of ESA to maintain the lowest hemoglobin level necessary to avoid the need for transfusions.
- Monitor patients’ hemoglobin levels to ensure they do not exceed 12 g/dL;
- Understand that ESAs have not been shown to improve the outcomes of chemotherapy treatment (e.g., better tumor shrinkage, delay in tumor growth or longer time for survival); and
- Understand that in patients with cancer whose anemia is caused by chemotherapy and in patients with HIV whose anemia is caused by AZT (zidovudine), there are no data to support claims of improvement in health-related quality of life, including effects on fatigue, energy or strength.
Aranesp® and other erythropoiesis-stimulating agents (ESAs) increased the risk for death and for serious cardiovascular events in controlled clinical trials when administered to target a hemoglobin of greater than 12 g/dL. There was an increased risk of serious arterial and venous thromboembolic events, including myocardial infarction, stroke, congestive heart failure, and hemodialysis graft occlusion. A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may also contribute to these risks.
An increased incidence of thrombotic events has also been observed in patients with cancer treated with erythropoietic agents. In patients with cancer who received Aranesp®, pulmonary emboli, thrombophlebitis, and thrombosis occurred more frequently than in placebo controls .As with all therapeutic proteins, there is a potential for immunogenicity. Neutralizing antibodies to erythropoietin, in association with PRCA or severe anemia (with or without other cytopenias), have been reported in patients receiving Aranesp® during post-marketing experience.
FDA and Amgen, the manufacturer of these products, and Ortho Biotech Products, L.P, a Johnson & Johnson Pharmaceuticals Research and Development subsidiary, the distributor of Procrit, have agreed to change the labeling for Aranesp, Epogen, and Procrit to reflect the new safety information and to provide additional instructions for their use.
FDA-approved uses of ESAs are: for the treatment of anemia in chronic kidney failure patients, in patients with cancer whose anemia is caused by chemotherapy, in patients with HIV whose anemia is caused by AZT (zidovudine), and to reduce the number of transfusions in patients scheduled for major surgery (except heart surgery).