Erythropoietin adverse effects

The response to erythropoietin products must be monitored closely to prevent adverse effects associated with these agents. The common adverse effects experienced include hypertension and thrombosis. Concomitant drugs with the same adverse-effect profile may increase a patient s risk for these complications. Also, the patient s overall survival may be decreased if the hemoglobin level is titrated to above the recommended 11 to 12 g/dL (110-120 g/L or 6.82-7.44 mmol/L) value. Therefore, it is important to follow the dosing and titration scheme recommended by the NCCN and summarized in... 

Although EPO deficiency is the primary cause of CKD anemia, iron deficiency is often present, and it is essential to assess and monitor the CKD patient s iron status (NKF-K/DOQI guidelines). Iron stores in patients with CKD should be maintained so that transferrin saturation (TSAT) is greater than 20% and serum ferritin is greater than 100 ng/mL (100 mcg/L or 225 pmol/L). If iron stores are not maintained appropriately, epoetin or darbepoetin will not be effective, and most CKD patients will require iron supplementation. Oral iron therapy can be used, but it is often ineffective, particularly in CKD patients on dialysis. Therefore, intravenous iron therapy is used extensively in these patients. Details of the pharmacology, pharmacokinetics, adverse effects, interactions, dose, and administration of erythropoietin and iron products have been discussed previously. 

The most common adverse effects of erythropoietin are associated with a rapid increase in hematocrit and hemoglobin and include hypertension and thrombotic complications. These difficulties can be minimized by raising the hematocrit and hemoglobin slowly and by adequately monitoring and treating hypertension. Allergic reactions have been infrequent and mild. 

A 14-year-old child developed hypertensive encephalopathy, a known rare adverse effect of erythropoietin, after 2 months (69). 

Occasionally low-titer antibodies have been reported in patients treated with epoetin (38,108). Neutralizing antierythropoietin antibodies have been found in patients with chronic renal insufficiency who develop pure red cell aplasia after subcutaneous administration of epoetin alfa (especially Eprex). This adverse effect was probably restricted to patients with renal insufficiency because they had used subcutaneous erythropoietin for many years. The incidence was calculated as one in 10 000 patients after 1 year of use of erythropoietin (82-84). 

The adverse effects of erythropoietin in neonates are minimal compared with adults. There were no hypertensive effects reported and no effect on development and growth measured at 18-22 months (111). In a multicenter, randomized, double-blind trial in 21 anemic HIV-infected children, who were concomitantly treated with antiretroviral drugs, epoetin was effective and safe (112). 

Despite the use of recombinant erythropoietin, anemia remains a significant problem for patients with end-stage renal disease (8). Because oral iron formulations are relatively ineffective and poorly tolerated, intravenous iron dextran has been widely used, despite the risk of adverse effects. 

Large doses of intravenous iron dextran and iron saccha-rate have been compared in a retrospective study of 379 patients who had attended peritoneal dialysis clinics in the past 5 years (12). Of these, 62 were selected to receive intravenous iron based on ferrokinetic markers of iron deficiency, non-adherence to oral iron, ineffectiveness of oral iron, or increased erythropoietin requirements. Intravenous iron was given as two injections of 500 mg each 1 week apart in 61 patients, 33 of whom received iron dextran, 23 iron saccharate, and five both iron dextran and iron saccha-rate. One patient developed anaphylaxis to a test dose of iron dextran and was excluded from further therapy. Blood samples were collected before and 3 and 6 months after iron infusions. Five of the 34 patients who received iron dextran developed minor adverse effects and one had an anaphylactic reaction to the test dose. Of the 23 patients who received iron saccharate, one had an anaphylactic reaction and two had transient chest pain, which subsided without therapy. There were more adverse effects with iron dextran (7.4% of injections) compared with iron saccharate (4.3% of injections), but this difference was not statistically significant. The number of episodes of peritonitis also increased during the 6 months after intravenous iron infusion, especially with iron dextran, compared with the number of episodes during the 6 months before iron infusions, although the difference was not statistically significant. 

Iron deficiency is a common and important cause of poor response to erythropoietin in patients with severe chronic renal insufficiency, in whom oral iron supplements fail to correct iron deficiency (6). Ferric gluconate has a low adverse effects profile, but the recommended dose of 62.5-125 mg per treatment is not practical for patients... 

Anemia in hemodialysis (10) and mainly in renal transplant patients has been reported (11-13). The suggested mechanism is by an action on erythropoietin, similar to that of ACE inhibitors, which produce the same adverse effect. However, in a small uncontrolled but prospective study, losartan given for 3 months to 15 patients on chronic hemodialysis with anemia, neither altered plasma erythropoietin concentrations nor aggravated the anemia (14). In those taking losartan there was no need for higher doses of co-administered r-Hu Epo in order to correct anemia, in contrast to controls. 

Most patients who require dialysis have a normocytic normochronic anemia and a hypoproliferative bone marrow. As erythropoiesis decreases with advancing renal disease, iron shifts from circulating red cells to the reticuloendothelial system, leading to high serum ferritin levels. Repeated blood transfusion is also a common cause of iron overload and hyperferritinemia. Clearly the most important cause of the anemia of chronic renal failure is decreased erythropoietin production by the kidneys uremic patients have much lower plasma erythropoietin levels than comparably anemic patients with normal renal function (E8). Less important causes are shortened red cell survival, iron or folate deficiency, aluminum intoxication, and osteitis fibrosa cystica (E8). Uremic retention products such as methylguanidine (G10) and spermidine (R2) may also have an adverse effect on erythropoiesis. 

Erythropoietin derivatives are associated with an increased frequency of thrombo-vascular events in a variety of tumor types [97 ]. However, whether patients with susceptibility factors should receive prophylactic antithrombotic treatment has not been confirmed. The adverse effects of combination therapy with epoetin beta and all-trans retinoic acid (ATRA) in 59 patients with myelodysplastic syndromes were muscle pain, raised liver enzymes without hepatic failure, fatigue, headache, dry skin, and dry mucosa [98 ]. 

An even more complex situation has been observed with recombinant proteins (biotherapeutic drugs, biopharmaceuticals). ICFI S8 does not apply to these drugs, but increasingly adverse immune effects are being observed with biopharmaceuticals. Probably the best-known example involved recombinant erythropoietin (EPO), indicated for patients with anemia associated with cancer chemotherapy. For reasons that are not been completely understood, reformulated recombinant EPO, when administered to patients, was associated with pure red cell aplastic anemia. These patients developed neutralizing antibodies to EPO, resulting in ablation of both endogenous and recombinant molecule activity (Schellekens and Jiskoot, 2006). 

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