Darbepoetin Alfa

Darbepoetin alfa is a hyperglycosylated erythropoietin analogue with a longer half-life, allowing weekly to monthly dosing. It is used for anaemia of chronic kidney disease and chemotherapy-induced anaemia.

Classification. Erythropoiesis-stimulating agent.

Mechanism. Binds the erythropoietin receptor, raising red cell production, with greater metabolic stability than epoetin alfa.

Pharmacokinetics. Half-life is about 21 hours intravenously and about 49 hours subcutaneously, roughly three times that of epoetin alfa. Subcutaneous bioavailability is about 37%.

Anaemia of chronic kidney disease (adults, haemoglobin under 10 g/dL after iron stores are replete).

• Dose: 0.45 µg/kg intravenously or subcutaneously once weekly, or 0.75 µg/kg subcutaneously every 2 weeks.
• Titration: raise the dose by about 25% if haemoglobin rises by less than 1 g/dL in 4 weeks. Reduce by 25% to 50% if it rises more than 2 g/dL in 4 weeks; interrupt if it exceeds 12 g/dL, then restart at 25% less.
• Maintenance: every 2 weeks, or monthly using double the fortnightly dose in non-dialysis patients. Target 10 to 12 g/dL. Doses above 4.5 µg/kg weekly are rarely effective and should prompt a search for resistance. Loading dose: none.
• Conversion from epoetin alfa: weekly darbepoetin in µg is about weekly epoetin in IU divided by 200.
• Children with chronic kidney disease (11 years and older): 0.45 µg/kg weekly.

Chemotherapy-induced anaemia (haemoglobin 10 g/dL or less, palliative intent).

• Dose: 500 µg subcutaneously every 3 weeks, or 2.25 µg/kg weekly. Stop if no response after 9 weeks, and 4 weeks after chemotherapy ends.

Adjustments. Kidney: dose by haemoglobin. Liver: none. Age: no adjustment.

Contraindications. Uncontrolled hypertension, pure red cell aplasia after any erythropoietin, hypersensitivity.

Boxed-warning-level risk. Increased risk of death, myocardial infarction, stroke, venous thromboembolism, vascular access thrombosis and tumour progression or recurrence; use the lowest effective dose.

Adverse effects. Hypertension, headache, arthralgia, injection-site pain, thrombosis, seizures. Rarely pure red cell aplasia.

Interactions. Response is blunted by iron deficiency, inflammation, hyperparathyroidism, aluminium toxicity and haemoglobinopathy.

Pregnancy and breastfeeding. Use only if benefit outweighs risk.

Regional points. Correct malaria, haemolysis, bleeding, hookworm and nutritional deficiencies first. Availability and cost vary.

Common errors. Switching agents without converting the dose; exceeding a haemoglobin of 12 g/dL; treating iron-deficient patients with erythropoietin alone.

Administration. Store at 2 to 8°C; do not shake. Subcutaneous or intravenous injection.

Baseline. Haemoglobin, ferritin (over 100 µg/L), transferrin saturation (over 20%), blood pressure.

Monitoring. Haemoglobin every 2 weeks during titration, then monthly. Blood pressure at every visit. Iron indices every 3 months.

Referral and escalation. Stop and refer for suspected pure red cell aplasia, thrombosis, or no response at high dose.