epoetin-alfa and Red-Cell-Aplasia--Pure

While prescribing biosimilars to patients naive to a biologic treatment is a well-accepted practice, switching clinically stable patients from an originator to a biosimilar is an issue for clinicians. Well-designed clinical trials and real-world data which study the consequences of switching from an originator biologic treatment to its biosimilar alternative are limited, especially for monoclonal antibodies. Areas covered: A systematic literature review was conducted on PubMed to identify evidence of the consequences of switching from original biologics to biosimilars. References of included papers were also scrutinized. After a title-, abstract- and full text screening, out of the 153 original hits and 77 additional ones from screening the references, 58 papers (12 empirical papers, 5 systematic reviews and 41 non-empirical papers) were included. Expert opinion: Preventing patients on biologic medicines from switching to biosimilars due to anticipated risks seems to be disproportional compared to the expected cost savings and/or improved patient access. Indeed, it is the opinion of the authors that the concern of switching to biosimilars is overhyped.

Topics: Anemia; Biosimilar Pharmaceuticals; Databases, Factual; Epoetin Alfa; Health Care Costs; Humans; Inflammatory Bowel Diseases; Kidney Failure, Chronic; Neoplasms; Red-Cell Aplasia, Pure; Rheumatic Diseases; Risk

Antibody-mediated pure red cell aplasia is a very rare but devastating condition affecting patients receiving treatment with erythropoiesis-stimulating agents. New cases continue to emerge, generally in clusters, consistent with an 'environmental' trigger to its pathogenesis. Defining the causes of antibody-mediated pure red cell aplasia is clearly of importance for patients with chronic kidney disease, but any developments in this area may also have relevance to other disease areas as therapeutic delivery of endogenous proteins rapidly increases. This review focuses on the current knowledge regarding the etiology of antibody-mediated pure red cell aplasia and the current approach to therapy.

Topics: Chemistry, Pharmaceutical; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Immune Tolerance; Protein Multimerization; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Insufficiency, Chronic; Time Factors

Pure red-cell aplasia (PRCA) is a serious, life threatening rare condition of multifactorial causes manifested as severe anemia with absence of erythroid precursors in the bone marrow. PRCA may be a consequence of antibody production against applied recombinant human erythropoietin (EPO). The first description of PRCA in the course of EPO therapy was performed in a patient receiving subcutaneously Eprex and in the next years after therapy with other erythropoiesis stimulating agents like erythropoietin beta, omega or darbepoetin. In the paper we describe epidemiology and diagnostic criteria of PRCA. The current treatment possibilities of this complication were described with special attention dedicated to different immunosuppressive agents and effectiveness of kidney transplantation with subsequent immunosuppression.

Topics: Antibodies; Epoetin Alfa; Erythropoietin; Humans; Immunosuppressive Agents; Kidney Transplantation; Recombinant Proteins; Red-Cell Aplasia, Pure

After almost 20 years, anemia in chronic kidney disease (CKD) and its treatment remain the focus of multiple questions for clinicians and investigators. The optimal hemoglobin (Hb) for patients with CKD is controversial and different targets are probably required for different populations. The current literature does not support an upper Hb target >12 g/dl and there is a clear demonstration of increased risk with Hb targets >13 g/dl. With this narrow target of 11-12 g/dl, fluctuations in Hb concentration are commonly observed in patients being treated with erythropoiesis-stimulating agents (ESAs). Studies to date provide a suggestion of an association between Hb cycling and mortality, but they have been primarily exploratory in nature and clinical trials comparing treatment strategies leading to different degrees of Hb variability are needed. The great majority of incidences of pure red cell aplasia (PRCA) was associated with ESA therapy and was first recognized several years ago after a change in the formulation in which human serum albumin was eliminated and replaced by polysorbate-80 in patients on epoetin alfa (Eprex). Years later, a registry (PRIMS) was established by the health authorities as part of a reapproval of the subcutaneous route to confirm that the cause of PRCA has been eliminated. The ongoing PRIMS study is a 3-year observation period prospective multicenter and international (Europe and Australia) registry that could serve as a model for assessment of the immunogenicity profiles of currently marketed and future ESAs. The association with a change in formulation makes PRCA of interest to the biotechnology industry as well as the medical community because it raises the broader question of the potential immunogenicity of biopharmaceuticals in general.

Topics: Anemia; Chronic Disease; Epoetin Alfa; Erythropoietin; Hemoglobins; Humans; Kidney Diseases; Recombinant Proteins; Red-Cell Aplasia, Pure

Since 1988, millions of patients have received epoetin products intravenously (IV) and subcutaneously. In 1998, epoetin-associated pure red cell aplasia (PRCA) was first reported and causation was attributed to formulations without human serum albumin (HSA), subcutaneous administration, and uncoated rubber stoppers.. Data on erythropoietin (EPO)-associated PRCA were obtained from the Food and Drug Administration (FDA), regulatory authorities in other countries, and the manufacturers of epoetin alfa, epoetin beta, and darbepoetin. The data included information on numbers of PRCA cases and estimated exposure-adjusted incidence rates by EPO product, anemia etiology, administration route, country of PRCA identification, and date reported.. In 1999, academicians in Paris identified 12 EPO-treated patients with antibody-mediated PRCA; 11 of these patients were on hemodialysis and had received subcutaneous Eprex (Johnson & Johnson). In 2002, authorities in Europe, Australia, Singapore, and Canada mandated Eprex by IV route to hemodialysis patients, and the relevant manufacturers added Teflon coating to prefilled syringes of Eprex; PRCA cases subsequently decreased by 90 percent. By 2003, 180 Eprex-associated PRCA cases were identified in Europe, Canada, Australia, and Asia, despite improvements in handling. Since 2002, FDA safety databases include information on 59 new cases of antibody-associated PRCA, primarily associated with subcutaneous epoetin alfa and darbepoetin that does not contain HSA.. Independent actions by regulatory authorities, manufacturers, and academic researchers identified significant numbers of PRCA cases between 1998 and 2003 and characterized the probable etiology. Today, antibody-mediated PRCA is an infrequent class toxicity occurring among some hemodialysis patients on EPOs.

Topics: Anemia; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Animals; Autoantibodies; Chemistry, Pharmaceutical; Epoetin Alfa; Erythropoietin; Humans; Learning; Recombinant Proteins; Red-Cell Aplasia, Pure

Antibody-mediated pure red cell aplasia is now recognized as a rare complication of erythropoiesis-stimulating agent therapy. The incidence of this adverse effect peaked in 2002, but new cases still appear sporadically. The aim of this review is to discuss the latest opinions regarding the detection and management of this condition.. The diagnosis of classical erythropoiesis-stimulating agent induced pure red cell aplasia is made by a constellation of clinical features, including severe transfusion-dependent anaemia, reticulocytopenia, low or absent erythroblasts in the bone marrow, and the presence of circulating antierythropoietin antibodies. Recently, some cases have been reported in which the bone marrow findings show red cell hypoplasia rather than aplasia; this may represent earlier presentations of the same condition.. Management of pure red cell aplasia as a complication of erythropoiesis-stimulating agent therapy consists of stopping the drug and implementing an immunosuppressive regimen to reduce or abolish erythropoietin antibody production. A recent animal study suggested that a possible alternative strategy may be to administer a novel peptide-based erythropoietin receptor agonist called Hematide that does not cross react with antierythropoietin antibodies, and will allow ongoing stimulation of erythropoiesis; this is the subject of a current clinical trial.

Topics: Epoetin Alfa; Erythropoietin; Humans; Immunosuppressive Agents; Peptides; Polyethylene Glycols; Recombinant Proteins; Red-Cell Aplasia, Pure

During the first 10 yr of therapy with recombinant human erythropoietin ([EPO]), only three cases of antibody-associated pure red cell aplasia have been described in patients who were treated with EPO, whereas several millions of patients have received this treatment. Thus, the possibility for epoetin to induce the formation of anti-EPO antibodies was considered extremely low. However, since 1998, a significant increase in the number of cases of EPO-induced pure red cell aplasia has been found in patients with chronic kidney disease with a peak in 2001 and 2002. The incidence rate seems now to be back to the baseline level. The change in formulation of epoetin a sold outside the United States seems to be the cause of these antibodies.

Topics: Autoimmune Diseases; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Humans; Incidence; Male; Prognosis; Recombinant Proteins; Red-Cell Aplasia, Pure; Risk Assessment

European and US guidelines for renal anaemia management recommend subcutaneous (s.c.) epoetin as the preferred route of administration in pre-dialysis, peritoneal dialysis and haemodialysis patients. However, the restriction of Eprex/Erypro to intravenous (i.v.) administration in Europe has increased the interest of health care professionals regarding the optimal route of administration for all epoetin formulations. There are five major considerations for the 'optimal' route of epoetin administration: efficacy; dosing frequency; convenience; safety and tolerability; and cost. Although epoetin bioavailability is lower after s.c. administration, its efficacy is higher, owing to its prolonged elimination half-life compared with i.v. epoetin. Several studies and clinical surveys comparing s.c. and i.v. administration have demonstrated that equivalent target haemoglobin levels can be maintained at much lower doses of epoetin when administered s.c. Furthermore, s.c. epoetin dosing frequency can be reduced in some patients to once every 2 weeks, without compromising efficacy. Devices such as the Reco-Pen have been specifically designed to facilitate self-administration of s.c. epoetin-beta. An upsurge in the incidence of pure red cell aplasia (PRCA) was linked to the epoetin-alpha product Eprex/Erypo in Europe, and an increase in PRCA cases of the same magnitude was not seen in patients taking other epoetin products s.c. Therefore, PRCA should not be used as an argument against s.c. administration. The reduced dose with s.c. administration of epoetin-beta provides significant cost benefits, without compromising either safety or efficacy, and may also increase patient satisfaction and compliance with treatment.

Topics: Anemia; Drug Administration Schedule; Drug Costs; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure; Treatment Outcome

Acquired pure red cell aplasia (PRCA) is a rare condition. Traditionally it has been described in association with various etiologies such as parvovirus B19 infection, auto-immune disorders and drugs. Immunologically mediated PRCA is by far the commonest cause in adults, particularly since 1998, when a marked increased incidence of PRCA was noted in chronic renal failure patients receiving subcutaneous (SC) recombinant erythropoietin (rEpo). Typically these patients had been given erythropoietin for correction of anemia of renal failure and subsequently present with severe transfusion dependent anemia. Most cases were associated with SC administration of human serum albumin (HSA) free erythropoieitin alfa product (Eprex). Early recognition and withdrawal of erythropoietin therapy is essential. Treatment with immunosuppressive therapy, particularly in conjunction with renal transplant results in good response with resolution in the majority of cases. The pathogenesis is related to interaction of multiple factors such as formulation change and improper storage leading to increased immunogenicity of the recombinant product. The incidence peaked in 2001 and 2002, subsequently dropping considerably from 2003. This can be explained by the institution of measures such as more stringent handling and storage conditions, improvements in formulation of HSA free Eprex and switch to intravenous (IV) administration for Eprex in dialysis patients. The evidence to date on this condition is summarized in this review.

Topics: Autoimmune Diseases; Epoetin Alfa; Erythropoietin; Humans; Incidence; Kidney Failure, Chronic; Parvoviridae Infections; Parvovirus; Recombinant Proteins; Red-Cell Aplasia, Pure

After 1998, the number of reported cases of pure red cell aplasia (PRCA) increased dramatically among patients with chronic renal failure treated with exogenous erythropoietin, although the incidence of this condition has now abated. Antibody-positive PRCA has been most commonly associated with use of the Eprex brand of epoetin-alpha. ESA (erythropoiesis-stimulating agent)-associated PRCA remains rare, and suspected cases should undergo a thorough diagnostic work-up before laboratory testing for anti-ESA antibody-positive status. This article provides an overview of the recent history and growing understanding of ESA-associated PRCA together with current approaches to the management of this rare side effect of an otherwise valuable therapy.

Topics: Epoetin Alfa; Erythropoietin; Humans; Incidence; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure

Pure red cell aplasia (PRCA) is a rare haematological condition that is characterized by severe aregenerative anaemia due to an almost complete cessation of red blood cell production. While antibody-mediated PRCA was extremely rare before 1998, the incidence of this disorder increased sharply after 1998 in patients receiving subcutaneous epoetin alfa produced by Ortho-Biotech and marketed outside the USA. The diagnosis of antibody-mediated PRCA relies mostly on the results of bone marrow biopsy or aspirate, which shows an absence of erythroid precursors and/or red cell maturation arrest while counts of white cell and platelet precursors are normal, and on the identification of circulating anti-erythropoietin antibodies. Retrospective analysis of PRCA cases has shown that immunosuppressive therapy can induce a disappearance of anti-erythropoietin antibodies in most patients. Eur J Clin Invest 2005; 35 (Suppl. 3): 95-99.

Topics: Antibodies; Blood Cell Count; Epoetin Alfa; Erythrocytes; Erythropoietin; Hematinics; Humans; Immunosuppressive Agents; Recombinant Proteins; Red-Cell Aplasia, Pure

To compare rates of pure red cell aplasia (PRCA) over time in patients with chronic renal failure treated with subcutaneous injections of two brands of epoetin alfa (either Eprex or Epogen) or epoetin beta (NeoRecormon).. Cases of antibody-mediated PRCA associated with epoetin alfa-treated patients were obtained from public databases and company websites and limited to time periods when exposure data also were available The subcutaneous exposure rates per 100 000 patient-years were calculated for the periods 1989-1998 and 1999-2002.. The event rate for antibody-mediated PRCA for Epogen and Eprex were similar from 1989 to 1998, but the number of cases of Eprex-associated PRCA has increased markedly since 1999, even after accounting for subcutaneous exposure. In contrast, rates have remained low for Epogen and NeoRecormon.. The recent increase in PRCA appears to be product specific and cannot be explained solely as a consequence of increased use of the subcutaneous route of administration.

Topics: Epoetin Alfa; Erythropoietin; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Antibody Specificity; Autoantibodies; Autoantigens; Autoimmune Diseases; Chemistry, Pharmaceutical; Drug Contamination; Epoetin Alfa; Erythropoietin; Europe; Humans; Immunosuppressive Agents; Injections, Subcutaneous; Prognosis; Recombinant Proteins; Red-Cell Aplasia, Pure; Risk Factors; Sorbitol; Treatment Outcome

The patents of the first generation of biopharmaceuticals derived from recombinant DNA such as interferons, growth hormone and epoietins are expiring, opening up the possibility for competitors to introduce biosimilar products. The concept of generics that applies to classical drugs and allows market admission on limited documentation cannot be extrapolated to these "off-patent biologics". Physicochemical characterization, bioassays and animals studies do not predict completely the efficacy and safety of therapeutic proteins. Clinical studies will nearly always be necessary to obtain marketing authorization for off-patent biologics. Immunogenicity is considered to be the main problem with therapeutic proteins. The recent upsurge of pure red cell aplasia (PRCA), a severe form of anemia associated with the use of epoietin-alpha, highlights both the unpredictability and the severe consequences of immunogenicity. A risk-based approach can be used to evaluate the potential induction of antibodies by off-patent biologics.

Topics: Animals; Antibodies; Biological Products; DNA, Recombinant; Epoetin Alfa; Erythropoietin; Humans; Patents as Topic; Proteins; Recombinant Proteins; Red-Cell Aplasia, Pure

Pure red cell aplasia (PRCA) is a rare condition characterised by an arrest in red blood cell production, which may be congenital or acquired. Recombinant human erythropoietin (epoetin) was introduced in 1989 for the treatment of anaemia of chronic kidney disease patients and has maintained an excellent therapeutic and safety record while treating hundreds of thousands of patients. A very rare, but serious adverse event associated with epoetin administration is a condition in which patients develop neutralising anti-erythropoietin antibodies and, consequently, PRCA. This condition is referred to as epoetin-induced PRCA (epo-PRCA). Since it is a rare condition, many haematologists and nephrologists around the world see the condition infrequently and may be uncertain about the diagnosis. For this reason, an ad hoc international working group of expert haematologists and nephrologists met together to derive new recommendations for the haematological diagnosis of epo-PRCA. These recommendations, which represent the consensus opinions of the working group, address haematological approaches to monitor and investigate suspected epo-PRCA and should help physicians differentiate between PRCA and other bone marrow diseases, as well as, between PRCA and epo-PRCA.

Topics: Autoantibodies; Blood Cell Count; Bone Marrow Examination; Epoetin Alfa; Erythropoietin; Hematopoietic Stem Cells; Hemoglobins; Humans; Practice Guidelines as Topic; Recombinant Proteins; Red-Cell Aplasia, Pure

Due to appearance in the world scientific literature of reports on occurrence of pure red cell aplasia (PRCA) as an adverse effect of treatment with recombinant human erythropoietin administered for anemia correction in the course of chronic renal failure, the paper presents rules of diagnosis and treatment of this complication. PRCA is more frequently observed during subcutaneous administration of erythropoietin a than erythropoietin beta. According to currently available analysis, prophylaxis of PRCA may include changing of the route of erythropoietin alpha administration from subcutaneous to intravenous one.

Topics: Epoetin Alfa; Erythropoietin; Humans; Injections, Intravenous; Injections, Subcutaneous; Recombinant Proteins; Red-Cell Aplasia, Pure

The problem of pure red cell aplasia (PRCA) prompted nephrologists to revert to a wider intravenous (i.v.) utilization of erythropoeitin (Epo). Once weekly i.v. Epo administration has been suggested to be as effective as the twice/thrice weekly i.v. dose. The aim of the present study was to test whether once weekly i.v. Epo administration is equally as cost-effective as once weekly subcutaneous (s.c.) and 2-3 times weekly i.v. administration.. We prospectively studied 41 patients (23 males, aged 28-82 years), on renal replacement therapy for 18-286 months, stabilized on twice or thrice weekly s.c. Epo-alpha (basal). The patients were treated for three consecutive 6 month periods with once weekly s.c. (OWSC), once weekly i.v. (OWIV) and twice/thrice weekly i.v. (TWIV) Epo-alpha. The initial dose for each period was equal to the final dose of the previous one; when necessary, the dose was adjusted according to DOQY guidelines. Iron, folic acid and vitamin B(12) supplementations were given throughout all the study periods. At the end of each of the four study periods, the following parameters were evaluated: haemoglobin, haematocrit, hypochromic red blood cells (RBCs), iron, serum ferritin, transferrin, folate, vitamin B(12), C-reactive protein (CRP), Kt/V, parathyroid hormone (PTH) and weekly dose of Epo-alpha.. Thirty-three out of 41 enrolled patients completed the study (there were five deaths, two renal transplants and one transfer). No significant changes were observed as regards iron, serum ferritin, transferrin, folate, vitamin B(12), CRP, Kt/V or PTH level. Haemoglobin levels were not different at the end of the basal (11.7+/-1.21), OWSC (11.8+/-0.86) and TWIV (12.1+/-1.04) periods, while significantly lower levels were observed after the OWIV period (11.0+/-0.97, P<0.01). Weekly Epo consumption (Epo U/week/kg body weight/g haemoglobin) was: basal 11.57+/-5.96; OWSC 10.22+/-4.53; OWIV 15.99+/-7.7*(a); and TWIV 11.89+/-6.3*(a) (*P<0.01 vs basal; (a)P<0.01 vs OWSC).. From our results, the OWIV schedule seems to have less efficacy in the control of anaemia of chronic renal failure patients on dialysis treatment than either OWSC or TWIV schedules.

Topics: Adult; Aged; Aged, 80 and over; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Injections, Intravenous; Injections, Subcutaneous; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis

Epoetin has been used to treat patients with renal anemia since 1988. -Anti-erythropoietin antibody-mediated pure red cell aplasia (PRCA) has been associated with epoetin usage, and a PRCA incidence of 4.5 per 10,000 patient-years was observed for epoetin-α (Eprex) in 2002. The PASCO II study (post-authorization safety cohort observation of Retacrit and Silapo (epoetin-ζ) administered subcutaneously for the treatment of renal anemia) followed 6,346 patients (4,501 Retacrit (group R); 1,845 Silapo (group S)) for up to 3 years of subcutaneous treatment with the biosimilar epoetin-ζ. One PRCA in 1 (0.02%) patient in group R who tested positive for neutralizing antibodies was reported. Overall, 527 adverse events of special interest (AESI) including PRCA occurred in 418 (6.60%) patients, lack of efficacy occurred in 34 (0.54%), and thromboembolic events in 389 (6.14%) patients. 41 adverse drug reactions other than AESIs were reported in 28 (0.44%) patients. The exposure-adjusted incident rate of PRCA was 0.84 per 10,000 patient-years. This real-world study showed that among patients with renal anemia receiving subcutaneous administration of the biosimilar product epoetin-ζ, the incidence rate of PRCA was substantially below the risk observed in 2002 for Eprex and that there was no immunogenicity concern or other new safety concern.

Topics: Anemia; Biosimilar Pharmaceuticals; Chronic Disease; Epoetin Alfa; Hematinics; Humans; Kidney Diseases; Recombinant Proteins; Red-Cell Aplasia, Pure

Pure red cell aplasia (PRCA) associated with erythropoiesis-stimulating agents (ESAs), which were first reported in 1998, usually occurs with subcutaneous administration of epoetin alfa (Eprex

Topics: Anemia; Antibodies; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Polyethylene Glycols; Prednisolone; Recombinant Proteins; Red-Cell Aplasia, Pure

Antibody-mediated pure red cell aplasia is a rare but serious complication in chronic kidney disease patients receiving recombinant human erythropoietin (r-HuEpo). Between April 2012 and May 2013, eight such cases were reported in our institution. Their clinical features were reviewed and their HLA alleles were compared with those of healthy controls. All patients were exposed to epoetin alfa (Eprex

Topics: Adult; Aged, 80 and over; Alleles; Asian People; Epoetin Alfa; Hematinics; HLA-DRB1 Chains; Humans; Immunosuppressive Agents; Male; Middle Aged; Red-Cell Aplasia, Pure; Renal Insufficiency, Chronic

Subcutaneous administration of Eprex(®) (epoetin alfa) in patients with chronic kidney disease (CKD) was contraindicated in the European Union between 2002 and 2006 after increased reports of anti-erythropoietin antibody-mediated pure red cell aplasia (PRCA). The Prospective Immunogenicity Surveillance Registry (PRIMS) was conducted to estimate the incidence of antibody-mediated PRCA with subcutaneous administration of a new coated-stopper syringe presentation of Eprex(®) and to compare this with the PRCA incidence with subcutaneous NeoRecormon(®) (epoetin beta) and Aranesp(®) (darbepoetin alfa).. PRIMS was a multicentre, multinational, non-interventional, parallel-group, immunogenicity surveillance registry. Adults with CKD receiving or about to initiate subcutaneous Eprex(®), NeoRecormon(®) or Aranesp(®) for anaemia were enrolled and followed for up to 3 years. Unexplained loss or lack of effect (LOE), including suspected PRCA, was reported, with antibody testing for confirmation of PRCA.. Of the 15 333 patients enrolled, 5948 received Eprex(®) (8377 patient-years) and 9356 received NeoRecormon(®)/Aranesp(®) (14 286 patient-years). No treatment data were available for 29 patients. Among 23 patients with LOE, five cases of PRCA were confirmed (Eprex(®), n = 3; NeoRecormon(®), n = 1; Aranesp(®), n = 1). Based on exposed time, PRCA incidence was 35.8/100 000 patient-years (95% CI 7.4-104.7) for Eprex(®) versus 14.0/100 000 patient-years (95% CI 1.7-50.6) for NeoRecormon(®)/Aranesp(®). The incidence of PRCA with Eprex(®) was not significantly different versus comparator ESAs (rate ratio: 2.56; 95% CI 0.43-15.31). An analysis based on observed time produced similar findings.. This large, prospective registry demonstrates that PRCA is rare with subcutaneous administration of either the new coated-stopper syringe presentation of Eprex(®), or NeoRecormon(®) or Aranesp(®).

Topics: Adult; Aged; Aged, 80 and over; Anemia; Autoantibodies; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Female; Humans; Incidence; Male; Middle Aged; Prognosis; Prospective Studies; Recombinant Proteins; Red-Cell Aplasia, Pure; Registries; Risk Assessment; Severity of Illness Index

Approximately 10% of patients receiving recombinant human erythropoietin (rHuEPO) do not respond to the treatment. We evaluated parvovirus B19 (B19) and cytomegalovirus (CMV) infections and antierythropoietin (anti-EPO) antibodies as potential causes of anemia in dialyzed patients, hyporesponsive to rHuEPO.. Data from 120 dialyzed patients, receiving rHuEPO alfa, were collected: demographic characteristics, rHuEPO dose, duration of rHuEPO treatment and time on dialysis, etiology of chronic kidney disease and transfusion history. Serology and PCR were performed to address B19 and CMV infection status. An ELISA was developed to detect anti-EPO antibodies.. rHuEPO resistance correlated with high ferritin levels (p = 0.001) and short time on dialysis (p = 0.012). B19 DNA was found in 10 (8.3%) dialyzed patients and CMV DNA was detected in 33 (27.5%). There was no significant correlation between B19 infection and anemia,while a tendency of correlation between active CMV infection and hemoglobin levels or hematocrit value (p= 0.069 and p= 0.070, respectively) has been observed. Anti-EPO antibodies were not detected in any patient.. B19 infection is a rare complication in dialyzed patients and should be investigated after exclusion of other common causes, while CMV infection is rather common. The role of CMV infection in the hyporesponsiveness in dialyzed patients should be further evaluated in other studies. Our data suggest that anti-EPO antibodies are not involved in rHuEPO resistance in this population.

Topics: Adult; Aged; Antibodies, Neutralizing; Antiviral Agents; Case-Control Studies; Cytomegalovirus Infections; Drug Resistance, Viral; Epoetin Alfa; Erythema Infectiosum; Erythropoietin; Female; Humans; Male; Middle Aged; Parvovirus B19, Human; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis

Antibody-mediated pure red cell aplasia (PRCA) is a rare complication of erythropoietin (EPO) therapy. Identification and demonstration of functional activity of EPO antibodies required to diagnose this condition is difficult and only performed in selected laboratories worldwide. In this article we report a recent cluster of three cases of antibody-mediated PRCA over a 16-month period in a single center associated with EPREX use. We also describe the use of a simple low-cost inhibitor assay that can be used to screen for PRCA in local laboratories.

Topics: Aged; Aged, 80 and over; Anemia; Antibodies, Neutralizing; Biomarkers; Calibration; Epoetin Alfa; Erythropoietin; Humans; Male; Predictive Value of Tests; Recombinant Proteins; Red-Cell Aplasia, Pure; Reference Standards; Serologic Tests

Topics: Epoetin Alfa; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Insufficiency, Chronic

Recombinant human erythropoietin (rhEPO) has been successfully used for correcting renal anemia. However, recent studies have raised some concerns about the safety of rhEPO treatment due to its immunogenic side effect - pure red cell aplasia (PRCA). We now report a case of development of anti-EPO neutralizing antibodies (Abs) implicated in thrombocytopenia as well as erythrocytopenia. A 35-year-old man had a history of administering rhEPO (epoetin alfa, epoetin beta and darbepoetin alfa) for 2years to treat renal anemia. The hematological parameters were collected. Anti-EPO, anti-platelet, and anti-thrombopoietin (TPO) Ab assays were performed to test the presence of autoreactive Abs. After performing antibody assays due to severe resistance to rhEPO treatment, a high titer of anti-EPO neutralizing Abs was detected. However, unexpectedly, this patient also showed thrombocytopenia rather than PRCA. We investigated the cause of the marked thrombocytopenia and found anti-TPO Abs in patient serum. To our best knowledge, this is the first report of the development of anti-TPO Abs during rhEPO treatment for anemia.

Topics: Adult; Antibodies, Neutralizing; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Humans; Male; Recombinant Proteins; Red-Cell Aplasia, Pure; Thrombocytopenia; Thrombopoietin; Treatment Outcome

We present a case of a young girl with end-stage renal disease secondary to anti-glomerular basement membrane disease who was receiving maintenance peritoneal dialysis and developed pure red cell aplasia secondary to anti-erythropoietin (EPO) antibodies. This occurred 13 months after the initiation of EPO alfa therapy for anemia. Initially, the patient required intermittent red blood cell transfusions. After immunosuppressive therapy had been initiated with corticosteroids and cyclosporine, the EPO antibody levels decreased precipitously, associated with an increased level of endogenous EPO production. For the following 6 months, the patient maintained adequate (>10 g/dL) hemoglobin levels and did not require red cell transfusions.

Topics: Anemia; Antibodies; Child, Preschool; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis; Time Factors; Treatment Outcome

An elderly patient with pure red cell aplasia (PRCA) with antierythropoietin (anti-EPO) antibodies is described. PRCA due to alloimmunization is a rare and severe complication of recombinant human erythropoietin (rHu-EPO) therapy. Most reported patients with PRCA were cured primarily by immunosuppressive drug therapy. The patient in this case, however, did not want to receive any immunosuppressive drugs. Therefore, rHu-EPO injection was simply discontinued, the severe anemia gradually improved, and the hemoglobin approached normal range. This case is very rare and significant in that there have been few such elderly patients with rHu-EPO-induced PRCA in whom PRCA remission was achieved, with decreasing antibody titers, after cessation of rHu-EPO alone. Further cases are needed to assess how PRCA should be treated in patients with anti-EPO antibodies.

Topics: Aged, 80 and over; Antibodies, Neutralizing; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure

Reports from the World Health Organization have suggested that counterfeit medicines pose a serious problem in developing countries. An investigation of anti-erythropoietin antibody-mediated pure red cell aplasia in Thailand found evidence of drug smuggling, which may have serious safety implications.. This study assessed the authenticity and quality of epoetin alfa samples in Thailand.. Samples of epoetin alfa-prefilled syringes were collected from the pharmacies at 2 major hospitals (62 samples), 8 retail pharmacies (41 samples), and Thai authorities (30 samples confiscated from smugglers at 2 airports, and 6 samples from a condominium used by smugglers). These samples were tested against the European Union Pharmacopeia specifications for aggregate content in epoetins of <2%. The integrity of epoetin alfa distribution channels, coldchain processes (maintenance at 2 degrees C-8 degrees C), primary and secondary packaging components (eg, batch number, expiration date, appearance, letter size), and company's confidential features (eg, nature of the ink, type and quality of the paper, other covered features) were also investigated. The main outcome measures were protein aggregate content, determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blotting; and isoform distribution, assessed by isoelectric focusing and Western blotting.. Epoetin alfa samples obtained from the company's cold-chain and authorized distribution channels met all quality standards, as did all epoetin alfa samples obtained from the hospital pharmacies. However, evidence showed that some samples were being smuggled or sold illegally through certain unauthorized retail pharmacies. The epoetin alfa samples obtained from both airports and the condominium were stored improperly at room temperature. Aggregate levels exceeded the specification of <2% in 11 samples from 2 of the retail pharmacies (range, 1.2%-3.1%), 15 samples from the Dongmuang Airport (range, 2.2%-17.0%), and all 6 samples from the condominium (range, 10.5%-19.8%). All samples from the 2 hospitals, 8 retail pharmacies, and Suvarnabhumi Airport had the authentic 6 isoform bands. Samples from Dongmuang Airport and the condominium appeared to have the 6 characteristic bands, but positive confirmation was difficult because of band smearing caused by a high level of aggregates. All features of primary and secondary packaging were found to be authentic.. This investigation found evidence that some epoetin alfa samples were smuggled into Thailand without proper cold chain, contained high levels of protein aggregates, and were sold illegally through certain retail pharmacies. The Thai authorities have intervened to stop such unauthorized products from reaching patients. Strenuous efforts must be made to prevent illegal cross-border smuggling of biopharmaceuticals without proper cold chain because of the serious safety implications for patients in developing countries.

Topics: Commerce; Crime; Drug and Narcotic Control; Drug Contamination; Drug Packaging; Drug Stability; Drug Storage; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Pharmacopoeias as Topic; Pharmacy; Quality Control; Recombinant Proteins; Red-Cell Aplasia, Pure; Syringes; Thailand

Topics: Anemia; Biopharmaceutics; Darbepoetin alfa; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Health Care Costs; Hematinics; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure; Risk Factors

Topics: Epoetin Alfa; Erythropoietin; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nephritis, Interstitial; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis

Topics: Aged; Aged, 80 and over; Anemia; Cyclosporine; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Recombinant Proteins; Red-Cell Aplasia, Pure

Biosimilars or follow-on biologics (FoB) are biopharmaceuticals that, unlike small molecule generic products, are copies of larger, much more complex proteins. As such, data generated from one biopharmaceutical cannot be extrapolated to another. Unlike small molecule generics, FoB require a full developmental programme, albeit smaller than for an originator product. This has been recognized by European regulatory authorities and it is becoming clear that accelerated processes for FoB marketing approval are not feasible.. To determine the balance between costs surrounding FoB (including relatively extensive developmental programmes and subsequent price to the market) and the necessity to ensure efficacy and safety.. It is important that FoB are sufficiently tested to ensure patient safety is not compromised. Conducting such a development programme followed by sound pharmacovigilance is very challenging and costly.. Cost-savings associated with FoB may be limited.

Topics: Biological Products; Cost Savings; Drug Approval; Drug Costs; Drugs, Generic; Epoetin Alfa; Erythropoietin; Humans; Product Surveillance, Postmarketing; Recombinant Proteins; Red-Cell Aplasia, Pure; Therapeutic Equivalency

Immunogenicity profiles of recombinant therapeutic proteins are important to understand because antibodies raised against these molecules may have important clinical sequelae. The purpose of the present study was to demonstrate that a flow cytometric bead array could be used to detect clinically relevant antibodies with specificity to such therapeutics. We chose to evaluate well-characterized specimens from persons treated with epoetin alfa that developed antibody-mediated pure red blood cell aplasia as a means to demonstrate the utility of this platform. Our data show that this assay is capable of detecting anti-epoetin alfa antibodies with a relative antibody concentration of 50 ng/ml, where 25 of 25 sera spiked with antibodies at this concentration scored positive. Moreover, the assay was designed to include positive and negative control beads for each specimen that is processed to ensure the specificity of the signal when detected. Measurement of interassay precision supports quantitative estimates of relative antibody concentrations in the range of 313 to 5,000 ng/ml, where the percent coefficient of variation did not exceed 20%. With respect to clinical specimens, antibodies with specificity for epoetin alfa could be easily detected in a set of specimens from persons with pure red blood cell aplasia that had prior exposure to the EPREX brand of recombinant epoetin alfa. Further development and validation of this approach may facilitate successful widespread application of the method for detection of anti-epoetin alfa antibodies, as well as antibodies directed against other recombinant therapeutic proteins.

Topics: Autoantibodies; Epoetin Alfa; Erythropoietin; Feasibility Studies; Flow Cytometry; Humans; Immunoassay; Microspheres; Recombinant Proteins; Red-Cell Aplasia, Pure

After liver transplantation, reinfection of the newly engrafted liver with hepatitis C virus is essentially universal in patients who are viremic at the time of transplantation. Treatment with interferon preparations with or without ribavirin is recommended in patients with marked histologic injury; however, hematologic toxicity associated with therapy has been reported, which is usually treated with growth factor support, including erythropoietin analogues. We present the first reported case of anti-erythropoietin antibody-mediated pure red cell aplasia arising in the setting of hepatitis C virus therapy in a patient who underwent living donor liver transplantation.

Topics: Anemia; Antibodies; Antiviral Agents; Epoetin Alfa; Erythropoietin; Graft Rejection; Hematinics; Hepatitis C; Humans; Immunocompromised Host; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Liver Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Polyethylene Glycols; Prednisone; Recombinant Proteins; Red-Cell Aplasia, Pure; Ribavirin; Secondary Prevention; Tacrolimus

Topics: Adverse Drug Reaction Reporting Systems; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure; Risk Assessment; Risk Factors

Topics: Animals; Epoetin Alfa; Erythropoietin; Humans; Incidence; Kidney Diseases; Mice; Ovalbumin; Recombinant Proteins; Red-Cell Aplasia, Pure; Structure-Activity Relationship

Anemia frequently complicates the treatment of chronic hepatitis C with interferon and ribavirin (RVN), requiring dose reduction and jeopardizing sustained virologic response. Increasingly, epoetin alfa is used to prevent anemia in this setting. Below, we report the first case of pure red cell aplasia (PRCA) in a patient with chronic hepatitis C who received epoetin alfa (Procrit) to manage anti-viral treatment-induced anemia. Red blood cell transfusion-dependence developed 16 wk after the patient was started on peginterferon alfa-2b and RVN for chronic hepatitis C despite the simultaneous administration of epoetin alfa and subsequent discontinuation of the antiviral medications. Bone marrow biopsy was consistent with PRCA. High-titer erythropoietin antibodies, assayed by two methods, appeared shortly after epoetin alfa was administered, and were associated with a decline in serum erythropoietin to undetectable levels. Erythropoietin antibodies directed toward epoetin alfa were shown to cross react with darbepoetin alfa (Aranesp), and a neutralization assay confirmed that they inhibited cell growth in the presence of erythropoietin. Transfusion-dependence resolved approximately 16 wk after discontinuing epoetin alfa, and 6 wk after starting danazol. PRCA caused by the development of erythropoietin antibodies is a potentially life-threatening complication of administering epoetin alfa to prevent the anemia associated with antiviral therapy in patients with chronic hepatitis C.

Topics: Antibodies; Danazol; Drug Hypersensitivity; Epoetin Alfa; Erythropoietin; Estrogen Antagonists; Follow-Up Studies; Hematinics; Hepatitis C, Chronic; Humans; Male; Middle Aged; Radioimmunoprecipitation Assay; Recombinant Proteins; Red-Cell Aplasia, Pure

Pure red cell aplasia (PRCA) is a rare, but important, complication of erythropoietin (EPO) replacement therapy in patients with renal disease. There is no consensus about the best way to treat this condition; however, recent reports indicated that immunosuppressive therapy is beneficial. We report a patient with EPO-induced PRCA treated with a regimen initially designed for antifactor VIII antibodies in patients with hemophilia. This regimen consists of immunoadsorption therapy using protein A columns, followed by oral prednisolone and single bolus infusions of intravenous immunoglobulin G and cyclophosphamide. Shortly after the course, a swift and rapid increase in reticulocyte count was evident; the patient became transfusion independent and has remained so during 2 years of follow-up. By means of this report, we wish to encourage others to consider this option when first-line treatments fail.

Topics: Anemia; Blood Transfusion; Cyclophosphamide; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Nephrosclerosis; Peritoneal Dialysis; Prednisolone; Recombinant Proteins; Red-Cell Aplasia, Pure; Remission Induction; Reticulocyte Count; Sorption Detoxification; Staphylococcal Protein A

The cause of antibody positive pure red cell aplasia associated with the subcutaneous administration of EPREX to patients with chronic kidney failure has been determined to be due to the leaching of weakly adjuvant compounds from the uncoated rubber stoppers that were formerly used in prefilled syringes. Other researchers have suggested that polysorbate 80 micelles containing erythropoietin may be a causative factor. The purpose of this work was to repeat previously published studies in a more controlled manner and to define the precise nature of the interactions between polysorbate 80 and erythropoietin.. The contents of EPREX prefilled syringes and laboratory-prepared, well-characterized formulations of EPREX were analyzed by size exclusion chromatography. Fractions were analyzed for the presence of erythropoietin by ELISA. EPREX formulations prepared with increasing amounts of polysorbate 80 were analyzed by light scattering.. Well-controlled chromatographic studies showed that when EPREX formulations containing no aggregate were analyzed by high-performance liquid chromatography, erythropoietin monomer could not be detected under the polysorbate 80 peak. Dimer and oligomers of erythropoietin coeluted under the polysorbate 80 peak as the molecular weights overlapped on the size exclusion chromatogram. Solution light scattering indicated that polysorbate 80 associates with erythropoietin in a defined stoichiometric ratio of 1:12.. Based on controlled studies, previous results suggesting that EPREX contains micelle-associated erythropoietin were incorrect. As with other surfactants and proteins, polysorbate 80 associates with erythropoietin in a defined stoichiometric ratio.

Topics: Chromatography, Gel; Chromatography, High Pressure Liquid; Drug Contamination; Enzyme-Linked Immunosorbent Assay; Epoetin Alfa; Erythropoietin; Excipients; Micelles; Molecular Weight; Polysorbates; Recombinant Proteins; Red-Cell Aplasia, Pure; Surface-Active Agents; Syringes

Since its introduction in 1988, recombinant human erythropoietin (epoetin) has been standard treatment for patients with anemia due to chronic kidney disease. From 1998 to 2004, nearly 200 epoetin-treated persons with chronic kidney disease developed antibodies to epoetin, resulting in pure red cell aplasia (PRCA). The majority of these patients received Eprex, an epoetin alfa product marketed exclusively outside the United States. Herein, we report on the long-term outcome of these individuals. For 170 chronic kidney disease patients who developed epoetin-associated PRCA and had 3 months or more follow-up information available, case reports from the Food and Drug Administration and epoetin manufacturers were reviewed for information on clinical characteristics of the patients, immunosuppressive treatments, epoetin responsiveness, and hematologic recovery. Overall, 64% of the PRCA patients received immunosuppressive therapy, including 19 who also underwent a renal transplantation. Thirty-seven percent experienced a hematologic recovery, with higher hematologic recovery rates among PRCA patients who received immunosuppressive therapy (57% vs 2%, P < .001). Among 34 patients who received epoetin after the onset of PRCA, 56% regained epoetin responsiveness. The highest rates of epoetin responsiveness were observed among persons whose antierythropoietin antibodies were undetectable when epoetin was administered (89%). Among chronic kidney disease patients with epoetin-associated PRCA, epoetin discontinuation and immunosuppressive therapy or renal transplantation is necessary for hematologic recovery. Reinitiation of epoetin therapy among individuals could be considered if antierythropoietin antibodies are undetectable.

Topics: Autoantibodies; Chronic Disease; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Hematinics; Humans; Immunosuppression Therapy; Kidney Diseases; Kidney Transplantation; Male; Recombinant Proteins; Red-Cell Aplasia, Pure; Retrospective Studies; Treatment Outcome; United States; United States Food and Drug Administration

There have been several recent reports of pure red-cell aplasia (PRCA) mediated by anti-erythropoietin antibodies (AEA) in patients with chronic renal failure treated with recombinant human erythropoietin (EPO). Among the factors thought to trigger this mechanism is the subcutaneous administration of EPO. Despite this being the normal route of administration in patients undergoing peritoneal dialysis (PD), to date there has only been 1 described case of PRCA due to AEA in PD. Herein, we report such a case involving a patient in whom a diagnosis of anemia due to PRCA was particularly difficult to make because of concomitant rectal bleeding.

Topics: Antibodies; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Red-Cell Aplasia, Pure

From May 1998 to November 2000, 13 European patients developed antibody-mediated pure red cell aplasia during treatment with recombinant human erythropoietin (rHuEPO), reinforcing the need for analytical testing for antibodies against erythropoietic agents. Specimens from 8 patients were provided for further antibody testing and characterization.. We evaluated 4 analytical methods with these sera: radioimmune precipitation (RIP), enzyme-linked immunosorbent assay (ELISA), biosensor immunoassay, and a bioassay for identification of neutralizing antibodies.. The RIP, biosensor immunoassay, and biological assay performed equally to detect and quantify anti-rHuEPO antibodies. The ELISA failed to detect antibodies in 2 patient samples. The biosensor immunoassay could determine antibody isotypes, subclasses, and dissociation rates and the bioassay could determine whether these antibodies were able to neutralize the biological effect of the drug; the other assays could not make this determination.. We recommend the use of the biosensor immunoassay followed by a bioassay to best identify and characterize anti-rHuEPO antibodies. The biosensor immunoassay allows for identification of all classes and subclasses of immunoglobulins and is a preferred method for the identification of lower-affinity antibodies. The bioassay is needed to determine if the antibodies identified have the capacity to neutralize a biological effect of the drug in a cell-based system.

Topics: Antibodies; Antibody Specificity; Biological Assay; Biosensing Techniques; Enzyme-Linked Immunosorbent Assay; Epoetin Alfa; Erythropoietin; Humans; Immunoassay; Radioimmunoprecipitation Assay; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Aged; Diabetic Nephropathies; Epoetin Alfa; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis

Topics: Aged; Aged, 80 and over; Antibodies; Cyclosporine; Darbepoetin alfa; Drug Resistance; Epoetin Alfa; Erythropoietin; Humans; Immunosuppressive Agents; Male; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis; Reticulocyte Count; Retreatment

Epoetin alfa (Eprex*; Johnson & Johnson, Manati, PR) has been used successfully to correct the anemia of chronic renal failure for more than 12 years. Anti-erythropoietin (anti-EPO) antibodies have been reported in a small number of patients, resulting in a blood disorder, pure red cell aplasia (PRCA). To evaluate the utility of a large-scale anti-EPO antibody screening program in patients with chronic kidney disease (CKD) administered epoetin alfa, a study involving 5 large renal centers in southern Ontario, Canada, was conducted.. More than 1,500 hemodialysis, peritoneal dialysis, and predialysis patients were screened for the prevalence of anti-EPO antibodies by means of a radioimmunoprecipitation (RIP) assay. Serum samples were drawn and shipped to PPD Development (Richmond, VA) for the immunoprecipitation assay. Serum EPO levels also were measured. All samples that tested positive or borderline for antibodies were sent to MDS Pharma Services (Montreal, Canada) for the neutralization assay.. Of 1,531 samples tested, 1 patient tested low-positive and 3 borderline results were detected by means of RIP. PRCA previously was diagnosed in the patient with the low-positive antibody level; the patient was treated with cyclosporine and currently is being administered epoetin alfa with good response. The 3 patients with borderline antibody results manifested no clinical signs of PRCA. Neutralization assays performed on all 4 serum samples were negative for anti-EPO antibodies.. Results from this surveillance study show that the prevalence of antibody to EPO in patients with CKD administered epoetin alfa in 5 Canadian renal centers is low, and the value of a large-scale antibody screening program for PRCA cannot be justified.

Topics: Aged; Aged, 80 and over; Anemia; Autoantibodies; Autoimmune Diseases; Cross-Sectional Studies; Cyclosporine; Epoetin Alfa; Erythropoietin; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Mass Screening; Middle Aged; Ontario; Peritoneal Dialysis; Population Surveillance; Radioimmunoprecipitation Assay; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis

Recombinant Human Erythropoietin (EPO) is extensively used for anemia in renal failure patients. It is normally safe and effective, improving symptoms of anemia. We report here a case of renal anemia in a patient undergoing peritoneal dialysis (PD) for end stage renal failure from renovascular disease. He initially responded well to Epoetin alpha (Eprex) but subsequently developed EPO antibodies and pure red cell aplasia (PRCA), becoming blood transfusion dependent. Subsequently, he responded to Darbepoetin alpha (Aranesp), without any complications in the presence of persisting EPO antibodies. This positive response, which restored hemoglobin values to normal, occurred despite general belief that any form of EPO will cross-react to EPO antibodies. This is the first case report where PRCA with EPO antibodies responded well to another EPO preparation without intervention from immunosuppression therapy.

Topics: Aged; Aged, 80 and over; Anemia; Antibodies; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Male; Peritoneal Dialysis; Recombinant Proteins; Red-Cell Aplasia, Pure

An 80-year-old man with chronic renal failure (CRF) had pure red cell aplasia (PRCA) 9 months after starting the subcutaneous administration of recombinant human erythropoietin alfa (rHuEPO-alpha). Owing to the advanced renal failure, conventional immunosuppressive therapies were not practicable. It was decided to administer rituximab (4 cycles of 375 mg/m2/wk). PRCA was treated successfully with rituximab. The administration of rHuEPO-alpha then was resumed via the intravenous route with a satisfactory correction of anemia (12 months after the EPO-alpha rechallenge the patient is still transfusion independent). To the authors' knowledge, this is the first report of (1) a successful treatment with rituximab with CD20 depletion in a CRF patient with PRCA and (2) a successful intravenous resumption of the same rHuEPO-alpha.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Male; Recombinant Proteins; Red-Cell Aplasia, Pure; Rituximab

Between 1988 and 1998, antibody-associated pure red-cell aplasia was reported in three patients who had undergone treatment with recombinant human erythropoietin (epoetin). Between 1998 and 2000, 13 such cases were reported from France--12 in patients who had received the Eprex formulation of epoetin alfa and 1 in a patient who had received Neorecormon (a formulation of epoetin beta); both are products that are marketed outside the United States.. We obtained reports of epoetin-associated pure red-cell aplasia from the Food and Drug Administration and from the manufacturers of Eprex, Epogen (another formulation of epoetin alfa), and Neorecormon. The numbers of case reports and estimates of exposure-adjusted incidence were analyzed according to the product, the cause of anemia, the route of administration, the country in which pure red-cell aplasia was identified, and the date on which pure red-cell aplasia was reported.. Between January 1998 and April 2004, 175 cases of epoetin-associated pure red-cell aplasia were reported for Eprex, 11 cases for Neorecormon, and 5 cases for Epogen. Over half these cases had occurred in France, Canada, the United Kingdom, and Spain. Between 2001 and 2003, the estimated exposure-adjusted incidence was 18 cases per 100,000 patient-years for the Eprex formulation without human serum albumin, 6 per 100,000 patient-years for the Eprex formulation with human serum albumin, 1 case per 100,000 patient-years for Neorecormon, and 0.2 case per 100,000 patient-years for Epogen. After procedures were adopted to ensure appropriate storage, handling, and administration of Eprex to patients with chronic kidney disease, the exposure-adjusted incidence decreased by 83 percent worldwide.. After the peak incidence of Eprex-associated pure red-cell aplasia was reached in 2001, interventions designed in response to drug-monitoring programs worldwide resulted in a reduction of more than 80 percent in the incidence of pure red-cell aplasia due to Eprex.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Epoetin Alfa; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure

Since 1998, there has been a marked increase in incidence of pure red cell aplasia secondary to development of anti-erythropoietin antibodies (Ab+ PRCA) in patients who have chronic kidney disease (CKD) and receive recombinant erythropoietin. The relationship between incidence of Ab+ PRCA and specific erythropoietin products has not been examined rigorously. Manufacturers provided data regarding exposure to erythropoietin products and incidence of Ab+ PRCA between January 1998 and March 2003 in patients with CKD. Assuming a Poisson distribution, a maximum likelihood estimate for the Poisson rate parameter was calculated for each product. A test for homogeneity of Poisson rates was conducted to compare likelihood estimates between products. Global incidence of Ab+ PRCA was relatively low. Likelihood estimates were not significantly different for Epogen, Procrit, and Aranesp, independent of their formulation or route of administration. Eprex lacking human serum albumin (HSA) and administered subcutaneously was associated with the greatest risk of Ab+ PRCA. HSA-containing Eprex administered subcutaneously was associated with a lower risk than HSA-free Eprex administered subcutaneously, but this risk exceeded that of intravenous Epogen and intravenous HSA-free Eprex. NeoRecormon administered subcutaneously was associated with less risk than subcutaneous HSA-free Eprex but more risk than intravenous Epogen. HSA-free Eprex should not be administered subcutaneously to patients with CKD due to increased risk of Ab+ PRCA. Although the subcutaneous administration of HSA-containing Eprex is riskier than intravenous Epogen and intravenous HSA-free Eprex, and the use of subcutaneous NeoRecormon is riskier than intravenous Epogen, there is currently no evidence that other products are safer.

Topics: Age Distribution; Autoantibodies; Cohort Studies; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Health Planning Guidelines; Humans; Kidney Failure, Chronic; Male; Prevalence; Primary Prevention; Recombinant Proteins; Red-Cell Aplasia, Pure; Risk Assessment; Severity of Illness Index; Sex Distribution

Topics: Aged; Antibodies; Antibodies, Monoclonal; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Recombinant Proteins; Red-Cell Aplasia, Pure; Reticulocyte Count; Retreatment

Topics: Antibody Formation; Epoetin Alfa; Erythropoietin; Humans; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure

Human recombinant erythropoietin is the main treatment for anemia in renal patients. Recently, there have been case reports of pure red blood cell aplasia (PRCA) developing in renal patients administered erythropoietin, probably because of neutralizing antibodies detected in all these patients. All reports were from the West, and most patients were treated with erythropoietin-alpha. Cyclosporine is an immunosuppressive agent used to treat a spectrum of autoimmune conditions. We report a series of Chinese renal patients who developed PRCA after treatment with erythropoietin-alpha, suggesting that this is a problem worldwide. They were treated successfully with cyclosporine and became transfusion independent.

Topics: Aged; Asian People; Cyclosporine; Epoetin Alfa; Erythropoietin; Humans; Kidney Failure, Chronic; Male; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Epoetin Alfa; Erythropoietin; Excipients; Hematinics; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure; Serum Albumin

In a patient with chronic renal failure due to diabetes mellitus pure red-cell aplasia developed during treatment with erythropoietin (epoetin alfa). The treatment with erythropoietin was stopped and immunosuppressive therapy resulted in normalisation of the bone marrow function and increase of the Hb level to normal values. Pure red cell aplasia which develops during treatment with erythropoietin has recently been reported in a few other patients with anaemia due to chronic renal failure. Hitherto our patient is the first case reported in Denmark.

Topics: Epoetin Alfa; Erythropoietin; Hematinics; Humans; Immunosuppressive Agents; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure; Remission, Spontaneous

We report the case of a woman with end-stage renal disease on maintenance hemodialysis and treated with recombinant human erythropoietin (epoetin alfa) administered subcutaneously, who developed a pure red cell aplasia secondary to the development of neutralizing antibodies anti-erythropoietin after 8 months of treatment. Despite epoetin withdrawal and immunosuppressive treatment with corticosteroids and gammaglobulins the patient still has high red blood cell transfusion requirements and undetectable plasma erythropoietin levels. Pure red cell aplasia secondary to the development of neutralizing antibodies anti-erythropoietin is a rare but severe complication associated with the use of recombinant human erythropoietin in uremic patients. In recent years, the incidence of this complication has sharply increased, specially associated with the use of epoetin alfa administered subcutaneously. For this reason, the Spanish Drug Agency has recently contraindicated treating uremic patients with epoetin alfa administered subcutaneously.

Topics: Adult; Autoantibodies; Epoetin Alfa; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure; Uremia

Topics: Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Aged; Anemia; Autoantibodies; Diagnosis, Differential; Epoetin Alfa; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Antibodies; Epoetin Alfa; Erythropoietin; Humans; Kidney Failure, Chronic; Receptors, Erythropoietin; Recombinant Proteins; Red-Cell Aplasia, Pure

Within a period of three years, we identified 13 patients in whom pure red-cell aplasia developed during treatment with recombinant human erythropoietin (epoetin). We investigated whether there was an immunologic basis for the anemia in these patients.. Serum samples from the 13 patients with pure red-cell aplasia were tested for neutralizing antibodies that could inhibit erythroid-colony formation by normal bone marrow cells in vitro. The presence of antierythropoietin antibodies was identified by means of binding assays with the use of radiolabeled intact, deglycosylated, or denatured epoetin.. Serum from all 13 patients blocked the formation of erythroid colonies by normal bone marrow cells. The inhibition was reversed by epoetin. Antibodies from 12 of the 13 patients bound only conformational epitopes in the protein moiety of epoetin; serum from the remaining patient bound to both conformational and linear epitopes in erythropoietin. In all the patients, the antibody titer slowly decreased after the discontinuation of treatment with epoetin.. Neutralizing antierythropoietin antibodies and pure red-cell aplasia can develop in patients with the anemia of chronic renal failure during treatment with epoetin.

Topics: Adult; Aged; Aged, 80 and over; Autoantibodies; Bone Marrow Cells; Cell Division; Epoetin Alfa; Erythroid Precursor Cells; Erythropoietin; Humans; Iodine Radioisotopes; Kidney Failure, Chronic; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Autoantibodies; Autoimmune Diseases; Epoetin Alfa; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Canada; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Product Surveillance, Postmarketing; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Adverse Drug Reaction Reporting Systems; Anemia; Epoetin Alfa; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure; United States