Darbepoetin alfa - Drug Monograph

Introduction

Darbepoetin alfa is a recombinant erythropoiesis-stimulating agent (ESA) used to treat anemia associated with chronic kidney disease and cancer chemotherapy. It is a hyperglycosylated analog of recombinant human erythropoietin with a longer half-life, allowing for less frequent dosing compared to conventional epoetin therapy.

Mechanism of Action

Darbepoetin alfa stimulates erythropoiesis by binding to the erythropoietin receptor on erythroid progenitor cells in the bone marrow. This binding activates intracellular signaling pathways that promote erythroid cell proliferation, differentiation, and survival. The additional sialic acid-containing carbohydrate chains in darbepoetin alfa compared to endogenous erythropoietin result in reduced receptor binding affinity but significantly prolonged serum half-life due to decreased metabolic clearance.

Indications

• Treatment of anemia associated with chronic kidney disease (CKD) in patients on dialysis and not on dialysis
• Treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant chemotherapy
• Reduction of allogeneic red blood cell transfusions in patients undergoing elective, non-cardiac, non-vascular surgery (off-label in some regions)

Dosage and Administration

• Initial dose: 0.45 mcg/kg IV or SC once weekly
• Alternative: 0.75 mcg/kg IV or SC once every 2 weeks
• Adjust dose to achieve and maintain hemoglobin levels between 10-12 g/dL

• Initial dose: 2.25 mcg/kg SC once weekly
• Alternative: 500 mcg SC once every 3 weeks

• Renal impairment: No additional dosage adjustment beyond CKD recommendations
• Hepatic impairment: No specific dosage recommendations
• Pediatrics: Safety and effectiveness established for CKD patients ≥1 year old

Pharmacokinetics

• Absorption: Bioavailability approximately 37% following SC administration
• Distribution: Volume of distribution approximately 0.21 L/kg; confined primarily to vascular space
• Metabolism: Primarily degraded by erythropoietin receptors in target tissues; hepatic metabolism minimal
• Elimination: Terminal half-life approximately 48.5 hours (IV) and 70.8 hours (SC) in CKD patients
• Excretion: Minimal renal excretion; primarily catabolized via cellular uptake and degradation

Contraindications

• Uncontrolled hypertension
• Pure red cell aplasia (PRCA) that begins after treatment with darbepoetin alfa or other erythropoietin protein drugs
• Known hypersensitivity to darbepoetin alfa or any component of the formulation
• Patients with hemoglobin >11 g/dL who are not receiving RBC transfusions (surgery patients)

Warnings and Precautions

• Increased mortality, myocardial infarction, stroke, venous thromboembolism, and thrombosis of vascular access: Observed in clinical trials using ESAs to target hemoglobin >11 g/dL
• Hypertension: May exacerbate or cause hypertension; monitor blood pressure closely
• Seizures: Increased risk in CKD patients
• Thrombotic events: Higher risk in surgical patients receiving ESAs
• Pure red cell aplasia: Monitor patients for loss of response to therapy
• Tumor progression: In cancer patients, ESAs may decrease survival and/or increase risk of tumor progression

Drug Interactions

• ACE inhibitors: May diminish therapeutic effect of ESAs
• Iron supplements: Required for optimal response; iron deficiency may impair response to therapy
• Corticosteroids: May potentiate erythropoietic response
• Cyclosporine: May enhance erythropoietic effect

Adverse Effects

• Hypertension
• Dyspnea
• Peripheral edema
• Cough
• Procedural hypotension
• Upper respiratory infection
• Diarrhea
• Nausea
• Arthralgia
• Back pain
• Fatigue

• Thrombotic events (DVT, PE, MI, stroke)
• Hypertension crisis
• Seizures
• Pure red cell aplasia
• Severe hypersensitivity reactions
• Cardiovascular mortality

Monitoring Parameters

• Hemoglobin levels: Weekly until stable, then periodically
• Iron stores: Transferrin saturation and ferritin before and during treatment
• Blood pressure: Before and during treatment
• CBC with differential: Regularly
• Signs of thrombosis: Especially in surgical patients
• Antibodies to erythropoietin: If suboptimal response occurs
• Renal function and electrolytes: Regularly in CKD patients

Patient Education

• Importance of adherence to prescribed dosing regimen
• Need for regular monitoring of hemoglobin and iron levels
• Recognition of thrombotic event symptoms (chest pain, shortness of breath, leg pain/swelling)
• Blood pressure monitoring at home if prescribed
• Report any signs of allergic reaction or loss of drug effect
• Do not adjust dose without consulting healthcare provider
• Understand risks and benefits of therapy
• Importance of adequate iron supplementation

References

1. FDA Prescribing Information: Aranesp® (darbepoetin alfa) 2. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease (2012) 3. NCCN Guidelines®: Cancer- and Chemotherapy-Induced Anemia (2023) 4. Macdougall IC. Novel erythropoiesis-stimulating agents: a new era in anemia management. Clin J Am Soc Nephrol. 2008;3(1):200-207. 5. Bohlius J, et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet. 2009;373(9674):1532-1542. 6. Singh AK, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355(20):2085-2098. 7. Rizzo JD, et al. American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. Blood. 2010;116(20):4045-4059.