Darbepoetin Alfa

Erythropoiesis-stimulating agents (ESAs) increased the risk of serious cardiovascular events, myocardial infarction, 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 (with or without other cytopenias) have been reported, predominantly in patients with chronic kidney disease receiving SubQ darbepoetin alfa (the intravenous [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 to darbepoetin alfa (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 time to 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 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 (Rizzo 2010). Use of ESAs has been associated with an increased risk of venous thromboembolism (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 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). Chronic kidney disease 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. Chronic kidney disease patients not requiring dialysis may have a better response to darbepoetin alfa and may require lower doses. Patients treated with ESAs may require increased heparinization during dialysis to prevent clotting of the extracorporeal circuit.

Use with caution in patients with a history of hypertension; use is contraindicated in patients with uncontrolled hypertension. An excessive rate of rise of hemoglobin may be associated with exacerbation of hypertension; decrease the darbepoetin 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.

Increased mortality was observed in patients undergoing coronary artery bypass surgery who received epoetin; these deaths were associated with thrombotic events. An increased risk of deep vein thrombosis has been observed in patients treated with epoetin undergoing surgical orthopedic procedures. Darbepoetin alfa is not approved for reduction in allogeneic red blood cell transfusions in patients scheduled for surgical procedures.

The risk for seizures is increased with darbepoetin alfa use in patients with chronic kidney disease; 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, darbepoetin alfa is not recommended for acute correction of severe anemia or as a substitute for emergency transfusion. Dosage form specific issues:

The packaging of some formulations may contain latex.

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 (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 American College of Cardiology Foundation/American Heart Association (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. 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 that 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.