Darbepoetin Alfa

Darbepoetin alfa is a recombinant erythropoiesis-stimulating agent (ESA). Human erythropoietin, made mainly in the kidney in response to changes in tissue oxygen, is the main regulator of red blood cell production. In chronic renal failure its production is impaired, and this lack is the main cause of the anaemia. In patients with cancer receiving chemotherapy the cause is multifactorial: erythropoietin deficiency and a reduced response of red cell progenitors to the body’s own erythropoietin both contribute.

Mechanism of Action

• Receptor activation: darbepoetin alfa stimulates erythropoiesis by the same mechanism as the natural hormone. It binds the erythropoietin receptor on erythroid progenitor cells in the bone marrow, which dimerises the receptor and activates JAK–STAT signalling. STAT proteins then move to the nucleus and switch on genes that control cell division and differentiation.
• Extra carbohydrate: it has five N-linked carbohydrate chains, against three on the natural hormone and on recombinant human erythropoietin (r-HuEPO). The added sugar residues are molecularly indistinct from those of the natural hormone.
• Longer action: the greater carbohydrate content gives a longer terminal half-life and greater activity in the body than r-HuEPO, so it can be given less often, while the very narrow specificity for the erythropoietin receptor is retained.
• Effect: it supports a physiological circulating red cell mass and raises haemoglobin.

Pharmacokinetics

Figures are from patients with chronic renal failure.

• Absorption: bioavailability after subcutaneous injection is 37%.
• Distribution: the steady-state volume of distribution is about equal to plasma volume (50 mL/kg).
• Elimination: after intravenous injection the terminal half-life is 21 hours (SD 7.5) and clearance 1.9 mL/h/kg (SD 0.56). After monthly subcutaneous doses of 0.6 to 2.1 mcg/kg the terminal half-life is 73 hours (SD 24); the longer half-life reflects slow subcutaneous absorption. Accumulation is minimal by either route. Renal clearance is minimal (up to 2% of total clearance) and does not affect serum half-life; the liver is thought to be the main route of elimination.
• Dose by route: in 809 patients in European studies, the average weekly dose needed to maintain haemoglobin did not differ between the intravenous and subcutaneous routes.
• Special populations: in children aged 2 to 16 years with chronic renal failure, with or without dialysis, the pharmacokinetics were similar to those of adults. In a phase 1 study, exposure after an intravenous dose differed by about 25% between children and adults, less than the 2-fold range seen within the paediatric group.

• Chronic renal failure (CRF): treatment of symptomatic anaemia associated with chronic renal failure in adults and paediatric patients.
• Chemotherapy-induced anaemia: treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving chemotherapy.

• Hypersensitivity to the active substance or to any of the excipients.
• Poorly controlled hypertension.

The identified adverse reactions are hypertension, stroke, thromboembolic events, convulsions, allergic reactions, rash/erythema and pure red cell aplasia. Injection site pain was reported as treatment-related in studies with subcutaneous injection; it was generally mild and brief and occurred mostly after the first injection. The SmPC gives separate tables for patients with CRF (1,357 patients in controlled studies) and for cancer patients (4,630 patients in placebo-controlled studies).

Very common (≥1/10): hypersensitivity in both populations (a broad grouping that was also very common with placebo); hypertension in CRF patients.

Common (≥1/100 to <1/10): in CRF patients, stroke, rash/erythema and injection site pain; in cancer patients, hypertension, thromboembolic events (including pulmonary embolism), rash/erythema, oedema and injection site pain.

Uncommon (≥1/1,000 to <1/100): in CRF patients, thromboembolic events, convulsions, dialysis vascular access thrombosis, injection site bruising and injection site haemorrhage; in cancer patients, convulsions, injection site bruising and injection site haemorrhage. Convulsions, dialysis vascular access thrombosis and the injection site events were identified after marketing.

Not known: pure red cell aplasia (CRF patients); Stevens-Johnson syndrome and toxic epidermal necrolysis, erythema multiforme, blistering and skin exfoliation (both populations).

Serious hypersensitivity reactions (anaphylaxis, angioedema, allergic bronchospasm, skin rash, urticaria) have been reported after marketing. In children with CRF, no reactions beyond those seen in adults were identified.

The clinical results so far do not indicate any interaction of darbepoetin alfa with other medicines.

• Ciclosporin and tacrolimus: these are highly bound to red blood cells, so an interaction is possible. If they are given with Aranesp, their blood levels should be monitored and the dose adjusted as haemoglobin rises.
• Iron: iron stores are checked before and during treatment and supplementation is started if indicated; most patients with chronic kidney disease need iron while taking an ESA.
• Interferon and ribavirin: a paradoxical fall in haemoglobin with severe anaemia has been reported with epoetins in hepatitis C patients treated with interferon and ribavirin.

Treatment should be started by physicians experienced in the indications above. Aranesp can be injected subcutaneously by the patient or a carer after training by a doctor, nurse or pharmacist. It is supplied ready for use. The pre-filled syringe and the vial can be used subcutaneously or intravenously; the pre-filled pen is for subcutaneous use only. Injection sites are rotated, and injection from a syringe or vial is slow to avoid discomfort. Instructions for use, handling and disposal are in section 6.6 of the SmPC.

Renal Anaemia: Adults

The aim is a haemoglobin of no more than 12 g/dL (7.5 mmol/L), within a target range of 10 to 12 g/dL (6.2 to 7.5 mmol/L). The lowest dose that controls the symptoms of anaemia is used. A sustained level above 12 g/dL and a rise of more than 2 g/dL (1.25 mmol/L) over four weeks are avoided. In patients not on haemodialysis the subcutaneous route is preferred, to avoid puncturing peripheral veins.

• Correction phase: 0.45 mcg/kg once weekly as a single subcutaneous or intravenous injection. In patients not on dialysis, alternative subcutaneous starting doses are 0.75 mcg/kg once every two weeks or 1.5 mcg/kg once monthly.
• Raising the dose: if haemoglobin rises by less than 1 g/dL (0.6 mmol/L) in four weeks, increase the dose by about 25%, no more often than every four weeks.
• Lowering the dose: if haemoglobin rises by more than 2 g/dL in four weeks, reduce the dose by about 25%. If it exceeds 12 g/dL, consider a reduction; if it keeps rising, reduce by about 25%; if it still rises after a reduction, withhold the dose until haemoglobin starts to fall, then restart about 25% below the previous dose.
• Monitoring: haemoglobin every one or two weeks until stable, then at longer intervals; after any dose or schedule change, again every one or two weeks.
• Maintenance in dialysis patients: once weekly or once every two weeks. When converting from weekly to every other week, start at twice the previous weekly dose.
• Maintenance in patients not on dialysis: once weekly, once every two weeks or once monthly. Once at target on two-weekly dosing, a subcutaneous monthly dose of twice the previous two-weekly dose may be used. Adjust by about 25%, no more often than every two weeks.
• Changing route: keep the same dose and check haemoglobin every one or two weeks.
• Switching from epoetin: adults on r-HuEPO one to three times a week can move to Aranesp once weekly or every other week. The starting weekly dose in mcg is the total weekly r-HuEPO dose in IU divided by 200; the every-other-week dose is the total r-HuEPO dose over two weeks divided by 200. Titrate individually, monitor haemoglobin every one or two weeks and keep the same route.

Renal Anaemia: Children

Use under 1 year of age has not been studied in randomised clinical trials.

• Correction phase (1 year and older): 0.45 mcg/kg once weekly as a single subcutaneous or intravenous injection; in patients not on dialysis, 0.75 mcg/kg subcutaneously once every two weeks is an alternative. Dose increases and reductions follow the adult rules above. Correction with once-monthly dosing has not been studied.
• Maintenance: once weekly or once every two weeks. Children under 6 years may need higher maintenance doses. When converting dialysis patients from weekly to every other week, start at twice the previous weekly dose. In patients aged 11 years and older not on dialysis, once the target is reached on two-weekly dosing, a subcutaneous monthly dose of twice the previous two-weekly dose may be used.
• Switching from epoetin: the starting weekly dose in mcg is the total weekly r-HuEPO dose in IU divided by 240; the every-other-week dose is the two-week total divided by 240.
• Patients who start dialysis during treatment need close monitoring of haemoglobin.

Chemotherapy-induced Anaemia in Adults

Aranesp is given subcutaneously only, to patients with anaemia (for example a haemoglobin of 10 g/dL (6.2 mmol/L) or below), to raise haemoglobin to no more than 12 g/dL (7.5 mmol/L) within a target range of 10 to 12 g/dL.

• Starting dose: 500 mcg (6.75 mcg/kg) once every three weeks, or 2.25 mcg/kg once weekly.
• Response: if the response (fatigue, haemoglobin) is inadequate after nine weeks, further therapy may not be effective. Treatment stops about four weeks after the end of chemotherapy.
• Once the aim is reached: reduce the dose by 25 to 50% to keep the lowest approved dose that controls symptoms; titration between 500, 300 and 150 mcg should be considered.
• High haemoglobin: if it exceeds 12 g/dL, reduce the dose by about 25 to 50%. Stop temporarily if it exceeds 13 g/dL (8.1 mmol/L), and restart about 25% below the previous dose once it is back to 12 g/dL or below. If it rises by more than 2 g/dL in four weeks, reduce the dose by 25 to 50%.

Special Populations

• Liver disease: no data, because active liver disease was an exclusion criterion in all studies; use with caution.
• Children: authorised for renal anaemia only (see above); the cancer indication is for adults.
• Missed dose: the SmPC gives no rule; the patient or carer should ask the treating team.

Blood Pressure

Blood pressure is monitored in all patients, especially when treatment starts. Severe hypertension, including hypertensive crisis, hypertensive encephalopathy and seizures, has been seen in CRF patients. If blood pressure is hard to control, haemoglobin can be lowered by reducing or withholding the dose. Poorly controlled hypertension is a contraindication.

Iron and Lack of Response

Iron status is checked before and during treatment, and iron may be needed; in CRF it is recommended when serum ferritin is below 100 mcg/L or transferrin saturation is below 20%. Lack of response calls for a search for causes: iron, folic acid or vitamin B12 deficiency (to be corrected), infection, inflammation, trauma, occult blood loss, haemolysis, severe aluminium toxicity, an underlying blood disease or bone marrow fibrosis. A reticulocyte count helps. With reticulocytopenia a bone marrow examination is considered, and if it fits pure red cell aplasia, antibodies to erythropoietin are tested.

Pure Red Cell Aplasia

Neutralising anti-erythropoietin antibodies causing pure red cell aplasia have been reported with ESAs including Aranesp, mostly in CRF patients treated subcutaneously. The antibodies cross-react with all erythropoietic proteins, so patients with suspected or confirmed antibodies should not be switched to Aranesp. A paradoxical fall in haemoglobin with severe anaemia and low reticulocyte counts should lead to stopping the epoetin and testing for antibodies.

Severe Skin Reactions

Severe cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, which can be life-threatening or fatal, have been reported with epoetins, with more severe cases for long-acting ones. Patients are told the signs at the time of prescription and monitored closely. If such signs appear, Aranesp is withdrawn immediately. After Stevens-Johnson syndrome or toxic epidermal necrolysis due to Aranesp, it must never be restarted.

Haemoglobin Targets and Cardiovascular Risk

In CRF, haemoglobin must not be kept above the upper target limit. Targeting a haemoglobin above 12 g/dL (7.5 mmol/L) increased the risk of death, of serious cardiovascular or cerebrovascular events including stroke, and of vascular access thrombosis. High cumulative epoetin doses may carry a similar risk, so doses are escalated with caution. Controlled trials have shown no significant benefit from raising haemoglobin beyond what is needed to control symptoms and avoid transfusion. The risk of thrombotic vascular events is weighed against the benefit, particularly with risk factors such as obesity or a history of deep vein thrombosis, pulmonary embolism or stroke. Serum potassium is monitored regularly in CRF patients.

Cancer Patients: Tumour Growth and Survival

Erythropoietin receptors may be present on tumour cells, so epoetins might stimulate tumour growth; in several controlled studies they did not improve overall survival or reduce tumour progression in cancer-related anaemia. ESAs shortened the time to tumour progression in advanced head and neck cancer treated with radiotherapy when the target was above 14 g/dL, shortened survival in metastatic breast cancer on chemotherapy at a target of 12–14 g/dL, and increased the risk of death at a target of 12 g/dL in active cancer without chemotherapy or radiotherapy. ESAs are not indicated in those settings. In some situations a blood transfusion should be preferred. The decision to use an ESA rests on a benefit–risk assessment made with the patient, considering tumour type and stage, degree of anaemia, life expectancy, treatment setting and patient preference. In solid tumours or lymphoproliferative malignancies, the dose rules must be followed closely if haemoglobin exceeds 12 g/dL, to limit the thromboembolic risk, with regular platelet counts and haemoglobin checks.

Other Precautions

• Traceability: the trade name of the ESA given is recorded in the patient file.
• Liver disease, sickle cell anaemia and epilepsy: use with caution; convulsions have been reported.
• Misuse: use by healthy people may raise packed cell volume excessively, with life-threatening cardiovascular complications.
• Hepatitis C: epoetins are not approved for anaemia associated with hepatitis C.
• Latex: the needle cap of the pre-filled syringe and pen contains dry natural rubber (a latex derivative), which may cause allergic reactions.
• Sodium: less than 1 mmol (23 mg) per dose, essentially sodium-free.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no adequate, well-controlled studies in pregnant women. Animal studies show no direct harmful effects on pregnancy, embryonal or foetal development, birth or postnatal development, so caution is advised when prescribing.
• Breastfeeding: it is unknown whether darbepoetin alfa passes into human milk, and a risk to the infant cannot be excluded. A decision is made whether to stop breastfeeding or stop the treatment, weighing the benefit of each.
• Fertility: no change in fertility was found in animal studies.

Effect on Driving

Aranesp has no or negligible influence on the ability to drive and use machines.

Store in a refrigerator at 2–8 °C. Do not freeze. Keep the syringe, pen or vial in the outer carton to protect it from light. It is a cold-chain product: it stays refrigerated from dispatch until it is used.

For ambulatory use, Aranesp may be taken out of the refrigerator once, for a single period of up to seven days at room temperature (up to 25 °C). Once it has reached room temperature it must be used within 7 days or discarded.

3 years, unopened and stored in the refrigerator. After removal from the refrigerator for ambulatory use, use within 7 days at room temperature or discard.

Prescription only (Rx), subject to restricted medical prescription (Annex II B); treatment is started by physicians experienced in its indications. Because patients or carers can inject it subcutaneously after training by a doctor, nurse or pharmacist, it is supplied to the patient or to the treating clinic or hospital on prescription, with cold-chain delivery at 2–8 °C.