losartan-potassium and Drug-Hypersensitivity

A "biosimilar" or "similar biological medicinal product" is a biological agent that is similar in terms of quality, safety, and efficacy to an authorized reference biological medicine. Since the expiration of the epoetin alfa patent in Europe, three agents have received marketing authorization from the European Medicines Agency: Binocrit (epoetin alfa; aka Abseamed and Epoetin Alfa Hexal), Retacrit (epoetin zeta; aka Silapo), and Eporatio (epoetin theta; aka Biopoin and Ratioepo).. Using the EMA dossiers and journal publications, this article reviews clinical safety data for these products, with emphasis on serious/severe adverse events and a special consideration of immunogenicity, venous thromboembolism, and mortality.. A review of the available safety evidence shows that all three agents discussed have similar safety profiles. None were statistically higher on safety parameters to what is known about ESA as a class, when stratified by population. As with ESAs in general, immunogenicity, venous thromboembolism, and mortality are all concerns. What is known about ESAs regarding safety can be extended to biosimilar erythropoietins. Since biosimilars are unique, complex biological molecules, safety profiles may evolve from common to differentiated, once long-term product-specific safety data are available. Large-sample, long-term, observational studies of real-world practice will provide the heterogeneity and statistical power to demonstrate product-specific effectiveness and safety profiles. Statistically, out of the commercially available formulations of the three products reviewed, no single product is less or more safe.

Topics: Animals; Biosimilar Pharmaceuticals; Drug Hypersensitivity; Drug Monitoring; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Incidence; Pharmacovigilance; Recombinant Proteins; Venous Thromboembolism

The importance of iron in the manufacture of erythrocytes is self-evident. In recent years, the treatment of anaemia of end-stage renal disease with recombinant human erythropoietin (epoetin) has been optimized by adequate iron supply. Intravenous therapy with dextran-free iron compounds has become the ideal and necessary companion of epoetin therapy. Anxiety has been expressed by clinicians and researchers over the impact of excess levels of iron following i.v. administration. Their concerns have included the potential for short-term side effects such as anaphylactic reactions and response to 'free iron'. Long-term concerns have included the possibility of increased infection, oxidative stress and cardiovascular disease with higher levels of iron. The literature also implies that i.v. iron could be a 'two-edged sword', i.e. on the one hand, it optimizes epoetin therapy, while on the other, it puts the patient at greater risk of other complications. This review assesses the evidence for these concerns and concludes that i.v. therapy with dextran-free iron compounds, such as iron sucrose, optimizes epoetin therapy with no direct evidence of any short-term or long-term complications.

Topics: Anemia; Chemotherapy, Adjuvant; Drug Hypersensitivity; Erythropoietin; Ferritins; Heart Diseases; Hematinics; Humans; Infections; Infusions, Intravenous; Iron Compounds; Kidney Failure, Chronic; Oxidative Stress; Recombinant Proteins

Recombinant human erythropoietin (epoetin) was first used for the treatment of renal anaemia in 1986. During the first 10 years of its use, epoetin-induced antibodies were a rare complication and only three cases of patients with epoetin-induced antibodies associated with pure red cell aplasia (PRCA) were published. Since 1998, however, there has been a significant increase in the number of patients developing severe anaemia during the course of epoetin treatment due to neutralizing antibodies. Patients with PRCA present with an absolute resistance to epoetin therapy and then rapidly develop severe anaemia with a very low reticulocyte count (<10 000/mm(3)). Consequently, patients become dependent on blood transfusions to maintain an acceptable level of haemoglobin. By December 2002, approximately 142 patients worldwide had been diagnosed with antibody-positive PRCA after receiving epoetin. The vast majority of these patients had been treated with the Eprex/Erypo brand of epoetin alfa, but there were also some cases in which patients had been receiving epoetin beta (NeoRecormon). To date, there have been no cases of antibody-mediated PRCA reported with the sole use of darbepoetin alfa (Aranesp). All patients with epoetin-induced anti-erythropoietin antibodies had received the drug subcutaneously (s.c.), and almost all had chronic kidney disease-related anaemia. To our knowledge, no patient treated exclusively by intravenous (i.v.) administration has developed anti-erythropoietin antibodies. The increase in reported cases coincides with the removal of human serum albumin from the ex-US formulation of epoetin alfa, in order to comply with new regulations from the European regulatory authorities. It has been proposed that the new formulation is less stable, allowing aggregates of erythropoietin molecules to form, which increases the probability of antibody formation. Treatment with epoetin must be discontinued if PRCA is suspected. Patients do not respond to an increase in dose. Furthermore, patients must not be switched to another form of erythropoietic therapy as the antibodies cross-react with all erythropoietic therapies available. In around 70% of cases, immunosuppressive regimens are effective in eliminating the antibodies; cessation of epoetin therapy without concomitant immunosuppression is rarely effective. Kidney transplantation seems to provide an immediate and effective cure.

Topics: Antibodies; Drug Hypersensitivity; Erythropoietin; Hematinics; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure

This article, based on our own studies and those of others, presents evidence to show that the anemia of chronic renal failure in the predialysis period is, to a significant extent, caused by iron deficiency and can be improved in most cases by the administration of intravenous (i.v.) but not oral iron. We estimate that in approximately 30% of all predialysis patients with anemia, a target hematocrit (Hct) of 35% can be reached and maintained by giving i.v. iron alone without exceeding currently acceptable limits of serum ferritin (500 microg/liter) or the percentage of iron saturation (40%). If, in addition, subcutaneous erythropoietin (EPO-usually in only low doses-is added, the combination has an additive effect on the Hct response, and almost all anemic predialysis patients can reach and maintain the target Hct of 35% over a one-year period. Therefore, the advantage of maintaining adequate iron stores with i.v. iron is that if EPO is needed, lower doses will be required to achieve the target Hct than if EPO were used alone. This not only avoids the high cost of EPO therapy but also its associated side-effects, especially hypertension. Using Venofer, a ferric hydroxide sucrose complex, as our i.v. iron supplement, we have seen no anaphylactic reactions in over 20,000 infusions over a four-year period in 360 hemodialysis, 123 predialysis, and 58 peritoneal dialysis patients.

Topics: Administration, Oral; Anemia, Iron-Deficiency; Blood Pressure; Coronary Disease; Drug Hypersensitivity; Erythropoietin; Humans; Injections, Intravenous; Iron; Iron Deficiencies; Iron, Dietary; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Topics: Anemia; Anemia, Hypochromic; Animals; Drug Hypersensitivity; Erythropoietin; Humans; Hyperkalemia; Hypertension; Peritoneal Dialysis, Continuous Ambulatory; Phosphates; Recombinant Proteins; Renal Dialysis; Seizures; Thrombosis; Uremia

Sensitivity to iron dextran is a potent obstacle to maintaining optimum iron status in patients with dialysis-associated anemia. As part of the North American clinical trials for iron sucrose injection, we examined the effect of intravenous (IV) iron sucrose in 23 hemodialysis patients with documented sensitivity to iron dextran, ongoing epoetin alfa therapy, and below-target-range hemoglobin (Hgb) levels (<11.0 g/dL). We assigned patients to treatment groups according to whether reactions they had experienced to iron dextran were judged to be mild (n = 16; group A) or severe (n = 7; group B). We prospectively examined adverse events and vital signs after administering 100 mg of IV iron sucrose in each of 10 consecutive dialysis treatment sessions and compared results with those recorded in each of three consecutive dialysis sessions without iron treatment. We administered iron sucrose by IV push over 5 minutes to group A patients and by IV push over 5 minutes or IV infusion over 15 to 30 minutes to group B patients. We did not administer a test dose. Results showed no serious adverse drug reactions after a total of 223 doses of iron sucrose (184 doses by IV push, 39 doses by IV infusion). Intradialytic blood pressure changes after IV iron sucrose injection did not differ from those recorded during dialysis sessions without treatment. An increase in values for Hgb, hematocrit, transferrin saturation, and ferritin, coupled with no significant change in epoetin dose and a decrease in total iron-binding capacity, confirmed the efficacy of iron sucrose injection in managing anemia. We conclude that iron sucrose injection is safe and effective in the management of anemia in patients sensitive to iron dextran and can be administered without a test dose by IV push or infusion.

Topics: Anemia, Iron-Deficiency; Blood Pressure; Drug Hypersensitivity; Epoetin Alfa; Erythropoietin; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Hematinics; Humans; Infusions, Intravenous; Injections, Intravenous; Iron-Dextran Complex; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis

Ectopic pregnancy (EP) is an emergency condition in the gynecologic field. Methotrexate (MTX) is a drug of choice for the medical treatment of EP. Severe adverse events are rare among patients treated with MTX for this condition.. We describe a woman with severe multi-organ involvement experiencing about six days of instability after treatment with just a single-dose MTX for EP. This life-threatening condition is not common with a single dose of MTX. A 30-year-old healthy woman was treated medically with MTX for an EP. Three days later the patient was admitted to the emergency department of our hospital with generalized pustular rashes, alopecia, hyperpigmentation, nausea and vomiting, oral ulcers, and raised Creatinine level. Four days later due to pancytopenia, fever, and loss of consciousness, she was transferred to the intensive care unit and was intubated.. After 38 days of hospitalization, treatment was successful with leucovorin and supportive care and the patient's symptoms and clinical manifestations were regressed.

Topics: Abortifacient Agents, Nonsteroidal; Adult; Alopecia; Anti-Bacterial Agents; Drug Hypersensitivity; Erythropoietin; Female; Fever; Granulocyte Colony-Stimulating Factor; Humans; Hyperpigmentation; Meropenem; Methotrexate; Pancytopenia; Platelet Transfusion; Pregnancy; Pregnancy, Ectopic; Pseudomonas aeruginosa; Pseudomonas Infections; Unconsciousness

Peginesatide (Omontys(®); Affymax, Inc., Cupertino, CA) was voluntarily withdrawn from the market less than a year after the product launch. Although clinical trials had demonstrated the drug to be safe and efficacious, 49 cases of anaphylaxis, including 7 fatalities, were reported not long after market introduction. Commercialization was initiated with a multiuse vial presentation, which differs in formulation from the single-use vial presentation used in phase 3 studies. Standard physical and chemical testing did not indicate any deviation from product specifications in either formulation. However, an analysis of subvisible particulates using nanoparticle tracking analysis and flow imaging revealed a significantly higher concentration of subvisible particles in the multiuse vial presentation linked to the hypersensitivity cases. Although it is unknown whether the elevated particulate content is causally related to these serious adverse events, this report illustrates the utility of characterizing subvisible particulates not captured by conventional light obscuration.

Topics: Cells, Cultured; Chemistry, Pharmaceutical; Clinical Trials, Phase III as Topic; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Humans; Nanoparticles; Particulate Matter; Peptides; Product Surveillance, Postmarketing

Topics: Anaphylaxis; Drug Hypersensitivity; Erythropoietin; Hematinics; Humans; Hypersensitivity, Immediate; Injections, Intravenous; Male; Middle Aged; Polyethylene Glycols; Renal Dialysis; Time Factors; Treatment Outcome

Human recombinant erythropoietins (EPO) and darbepoetins are widely used for anemias associated with chronic kidney disease.  Allergic reactions to erythropoetins and darbepoetins have only occasionally been reported. These skin reactions include pruritus, wheals at the injection site, orofacial anaphylaxis and anjioedema. In this article, we report an 11 year-old female who experienced generalized   erithematous skin eruption and desquamation after both erythropoietin and darbepoetin treatments.  We successfully used darbepoetin with the support of premedication and desensitization.

Topics: Child; Darbepoetin alfa; Desensitization, Immunologic; Drug Hypersensitivity; Erythropoietin; Female; Hematinics; Humans

Topics: Anemia; Chronic Disease; Drug Hypersensitivity; Erythropoietin; Female; Humans; Hypersensitivity, Delayed; Injections, Subcutaneous; Kidney Diseases; Polyethylene Glycols; Recombinant Proteins

Anti-erythropoietin antibodies usually cross-react with all kinds of recombinant erythropoietins; therefore, erythropoiesis-stimulating agent (ESA)-induced pure red-cell aplasia (PRCA) is not rescued by different ESAs. Here, we present a case of ESA-induced PRCA in a 36-yr-old woman with chronic kidney disease, whose anemic condition improved following reintroduction of darbepoetin-α. The patient developed progressive, severe anemia after the use of erythropoietin-α. As the anemia did not improve after the administration of either other erythropoietin-α products or erythropoietin-β, all ESAs were discontinued. Oxymetholone therapy failed to improve the transfusion-dependent anemia and a rechallenge with ESAs continuously failed to obtain a sustained response. However, her anemia improved following reintroduction of darbepoetin-α at 3 yr after the initial diagnosis. Interestingly, anti-erythropoietin antibodies were still detectable, although their concentration was too low for titration. In conclusion, darbepoetin-α can improve ESA-induced PRCA when the anti-erythropoietin antibody titer declines and its neutralizing capacity is lost.

Topics: Adult; Anemia; Antibodies; Bone Marrow Cells; Darbepoetin alfa; Drug Hypersensitivity; Erythropoietin; Female; Glomerulonephritis, IGA; Hematinics; Humans; Kidney Failure, Chronic; Oxymetholone; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Drug Hypersensitivity; Erythropoietin; Hematinics; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure

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

The following case reports are of two patients who have developed hypersensitivity reactions to the red cell growth hormones, darbepoietin and erythropoietin. The subsequent skin testing and clinical course suggested that the cause of these reactions was due to the excipient polysorbate 80. This finding might have implications in the recent increase in the incidence of pure red cell aplasia.

Topics: Adult; Aged; Anemia; Darbepoetin alfa; Drug Hypersensitivity; Erythropoietin; Excipients; Female; Humans; Kidney Failure, Chronic; Polysorbates; Recombinant Proteins

Topics: Drug Hypersensitivity; Eosinophilia; Epoetin Alfa; Erythema Multiforme; Erythropoietin; Exanthema; Fever; Hematinics; Humans; Male; Middle Aged; Recombinant Proteins; Syndrome

A 73-year-old man, a 73-year-old woman, and a 57-year-old man with anaemia due to renal insufficiency were treated with epoetin. After 6-12 months, the haemoglobin level decreased despite dosage increases, after which the patients became dependent on regular transfusions of concentrated erythrocytes. The older man died from peritonitis following diagnostic examination because of the anaemia. The woman died from septic shock, even though epoetin had been replaced by darbepoetin. The haemoglobin level in the younger man returned to normal after the presence of antibodies against epoetin had been demonstrated, he had stopped using the drug, and he had started on immunosuppressive therapy following kidney transplantation. Since 1998, the number of patients with epoetin resistance due to the development of antibodies against the drug (epoetin-induced pure red-cell aplasia) has increased. This complication should be considered in every patient treated with epoetin who experiences unexplained transfusion-dependent anaemia.

Topics: Aged; Anemia; Antibodies; Drug Hypersensitivity; Erythrocyte Transfusion; Erythropoietin; Fatal Outcome; Female; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Insufficiency

Topics: Anemia, Iron-Deficiency; Ascorbic Acid; Bacteremia; Chronic Disease; Drug Hypersensitivity; Erythropoietin; Ferritins; Humans; Injections, Intravenous; Iron; Kidney Diseases; Predictive Value of Tests; Recombinant Proteins; Renal Dialysis

Topics: Aged; Anemia; Drug Hypersensitivity; Erythropoietin; Female; Humans; Red-Cell Aplasia, Pure