Human Erythropoietin

Erythropoiesis-stimulating agents (ESAs) increased the risk of serious cardiovascular events, MI, stroke, venous thromboembolism, vascular access thrombosis, and mortality in clinical studies when administered to target hemoglobin levels >11 g/dL (and provide no additional benefit); a rapid rise in hemoglobin (>1 g/dL over 2 weeks) may also contribute to these risks.

Erythema multiforme and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) have been reported with ESA use; discontinue immediately if a severe cutaneous reaction develops.

Potentially serious allergic reactions have been reported (rarely), including anaphylactic reactions, angioedema, bronchospasm, rash, and urticaria. Discontinue immediately (and permanently) in patients who experience serious allergic/anaphylactic reactions.

Cases of severe anemia and PRCA have been reported, predominantly in patients with chronic kidney disease receiving SubQ epoetin alfa (the IV route is preferred for hemodialysis patients); cases have also been reported in patients with hepatitis C who were receiving ESAs, interferon, and ribavirin. Patients with a sudden loss of response (with severe anemia and a low reticulocyte count) should be evaluated for PRCA with associated neutralizing antibodies to erythropoietin; discontinue treatment (permanently) in patients with PRCA secondary to neutralizing antibodies to erythropoietin. Antibodies may cross-react; do not switch to another ESA in patients who develop antibody-mediated anemia. Disease-related concerns:

A shortened overall survival and/or increased risk of tumor progression or recurrence has been reported in studies with breast, cervical, head and neck, lymphoid, and non-small cell lung cancer patients. It is of note that in most of in these studies, patients received ESAs to a target hemoglobin of ≥12 g/dL; although risk has not been excluded when dosed to achieve a target hemoglobin of [US Boxed Warnings]: To decrease these risks, and risk of cardio and thrombovascular events, use the lowest dose needed to avoid red blood cell transfusions. Use ESAs in cancer patients only for the treatment of anemia related to concurrent myelosuppressive chemotherapy; discontinue ESA following completion of the chemotherapy course. ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is curative. A dosage modification is appropriate if hemoglobin levels rise >1 g/dL per 2-week time period during treatment (ASCO/ASH [Rizzo 2010]). Use of ESAs has been associated with an increased risk of VTE without a reduction in transfusions in patients >65 years of age with cancer (Hershman 2009). Improved anemia symptoms, quality of life, fatigue, or well-being have not been demonstrated in controlled clinical trials.

An increased risk of death, serious cardiovascular events, and stroke was reported in chronic kidney disease (CKD) patients administered ESAs to target hemoglobin levels >11 g/dL; use the lowest dose sufficient to reduce the need for RBC transfusions. An optimal target hemoglobin level, dose or dosing strategy to reduce these risks has not been identified in clinical trials. Hemoglobin rising >1 g/dL in a 2-week period may contribute to the risk (dosage reduction recommended). CKD patients who exhibit an inadequate hemoglobin response to ESA therapy may be at a higher risk for cardiovascular events and mortality compared to other patients. ESA therapy may reduce dialysis efficacy (due to increase in red blood cells and decrease in plasma volume); adjustments in dialysis parameters may be needed. Patients treated with epoetin alfa may require increased heparinization during dialysis to prevent clotting of the extracorporeal circuit.

Use with caution in patients with a history of hypertension (contraindicated in uncontrolled hypertension). An excessive rate of rise of hemoglobin is associated with hypertension or exacerbation of hypertension; decrease the epoetin alfa dose if the hemoglobin increase exceeds 1 g/dL in any 2-week period. Blood pressure should be controlled prior to start of therapy and monitored closely throughout treatment. Hypertensive encephalopathy has been reported with patients receiving erythropoietic therapy; monitor closely and control blood pressure.

DVT prophylaxis is recommended in perisurgery patients due to the increased risk of DVT. Increased mortality was also observed in patients undergoing coronary artery bypass surgery who received epoetin alfa; these deaths were associated with thrombotic events. Epoetin alfa is not approved for reduction of red blood cell transfusion in patients undergoing cardiac or vascular surgery and is not indicated for surgical patients willing to donate autologous blood.

The risk for seizures is increased with epoetin alfa use in patients with CKD; use with caution in patients with a history of seizures. Monitor closely for neurologic symptoms during the first several months of therapy.

Due to the delayed onset of erythropoiesis, epoetin alfa is not recommended for acute correction of severe anemia or as a substitute for emergency transfusion. Dosage form specific issues:

Product may contain albumin, which confers a theoretical risk of transmission of viral disease or Creutzfeldt-Jakob disease.

Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.

Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling. Other warnings/precautions:

- Oncology: The American Society of Clinical Oncology (ASCO) and American Society of Hematology (ASH) 2010 updates to the clinical practice guidelines for the use of ESAs in patients with cancer indicate that ESAs are appropriate when used according to the parameters identified within the FDA approved labeling for epoetin and darbepoetin alfa (ASCO/ASH [Rizzo 2010]). ESAs are an option for chemotherapy associated anemia when the hemoglobin has fallen to - Cardiovascular disease: The American College of Physicians recommends against the use of ESAs in patients with mild to moderate anemia and heart failure or coronary heart disease (ACP [Qaseem 2013]). The ACCF/AHA 2013 Heart Failure Guidelines do not provide a clear recommendation on the use of ESAs in anemic heart failure patients. The effects of ESAs on quality of life measures, morbidity, and mortality are potentially modest and still unclear. Additionally, the safety of epoetin alfa has not been well studied in this population. The authors declined to provide an official recommendation regarding the use of ESAs pending the completion of ongoing randomized trials (ACCF/AHA [Yancy 2013]).

Prior to treatment, correct or exclude deficiencies of iron, vitamin B12, and/or folate, as well as other factors which may impair erythropoiesis (inflammatory conditions, infections, bleeding). Poor response to therapy should prompt evaluation of potential factors impairing erythropoiesis, as well as possible malignant processes and hematologic disease (thalassemia, refractory anemia, myelodysplastic disorder), occult blood loss, hemolysis, osteitis fibrosa cystic, and/or bone marrow fibrosis.