Darbepoetin alfa
- Drugs List
- Therapeutic Indications
- Dosage
- Administration
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Solution for injection containing 10 micrograms of darbepoetin alfa in 0.4ml (25 micrograms/ml)
Solution for injection containing 15 micrograms of darbepoetin alfa in 0.375ml (40 micrograms/ml)
Solution for injection containing 20 micrograms of darbepoetin alfa in 0.5ml (40 micrograms/ml)
Solution for injection containing 30 micrograms of darbepoetin alfa in 0.3ml (100 micrograms/ml)
Solution for injection containing 40 micrograms of darbepoetin alfa in 0.4ml (100 micrograms/ml)
Solution for injection containing 50 micrograms of darbepoetin alfa in 0.5ml (100 micrograms/ml)
Solution for injection containing 60 micrograms of darbepoetin alfa in 0.3ml (200 micrograms/ml)
Solution for injection containing 80 micrograms of darbepoetin alfa in 0.4ml (200 micrograms/ml)
Solution for injection containing 100 micrograms of darbepoetin alfa in 0.5ml (200 micrograms/ml)
Solution for injection containing 130 micrograms of darbepoetin alfa in 0.65ml (200 micrograms/ml)
Solution for injection containing 150 micrograms of darbepoetin alfa in 0.3ml (500 micrograms/ml)
Solution for injection containing 300 micrograms of darbepoetin alfa in 0.6ml (500 micrograms/ml)
Solution for injection containing 500 micrograms of darbepoetin alfa in 1ml (500 micrograms/ml)
Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1)
The solution is available in pre-filled syringes or pre-filled pens.
Drugs List
Therapeutic Indications
Uses
Treatment of symptomatic anaemia associated with chronic renal failure in adults and children.
Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving chemotherapy.
Dosage
Treatment should be initiated by a specialist experienced in the above mentioned indications.
The aim of treatment is to increase haemoglobin to not greater than 12g/dL (7.5mmol/L). Studies have shown variability in patient responses and the exact target haemoglobin concentration needs to be established for each patient. Avoid a rise in haemoglobin of greater than 2.0g/dL (1.25mmol/L) over a four week period or a sustained haemoglobin level greater than 12g/dL (7.5mmol/L).
Adults
Anaemia symptoms and sequelae may vary with age, gender, and overall burden of disease so assessment of individual patient's condition is required.
Treatment of symptomatic anaemia in chronic renal failure patients
Treatment is divided into the correction phase and the maintenance phase.
Correction phase
The recommended starting dose by subcutaneous or intravenous administration is 450nanograms/kg body weight as a single injection once weekly.
Alternatively, in patients not on dialysis, an initial dose of 750nanograms/kg may be administered subcutaneously as a single injection once every two weeks.
If the increase in haemoglobin is inadequate (less than 1g/dL (0.6 mmol/L) in four weeks) increase the dose by approximately 25%. Dose increases must not be made more frequently than once every four weeks.
If the rise in haemoglobin is greater than 2 g/dl (1.25 mmol/l) in four weeks reduce the dose by approximately 25%. If the haemoglobin exceeds 12 g/dl (7.5 mmol/l), a dose reduction should be considered. If the haemoglobin continues to increase, the dose should be reduced by approximately 25%. If after a dose reduction, haemoglobin continues to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which point therapy should be reinitiated at approximately 25% lower than the previous dose.
The haemoglobin should be measured every one or two weeks until it is stable. Thereafter the haemoglobin can be measured periodically.
Maintenance phase
In the maintenance phase, darbepoetin alfa may continue to be administered as a single injection once weekly or once every two weeks.
Patients receiving dialysis who convert from once weekly to once every fortnight dosing should initially receive a dose equivalent to twice the previous once weekly dose.
In patients not on dialysis, once the target haemoglobin has been achieved with once every two week dosing, darbepoetin alfa may be administered subcutaneously once monthly using an initial dose equal to twice the previous once every two week dose.
Thereafter, the dose should be titrated as necessary to maintain the haemoglobin target.
If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that the dose is adjusted by approximately 25%.
If the rise in haemoglobin is greater than 2 g/dl (1.25 mmol/l) in four weeks reduce the dose by approximately 25%, depending on the rate of increase. If the haemoglobin exceeds 12 g/dl (7.5 mmol/l), a dose reduction should be considered. If the haemoglobin continues to increase, the dose should be reduced by approximately 25%. If after a dose reduction, haemoglobin continues to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which point therapy should be reinitiated at approximately 25% lower than the previous dose.
Patients should be monitored closely to ensure that the lowest approved dose of darbepoetin alfa is used to adequately control the symptoms of anaemia.
After any dose or schedule adjustment the haemoglobin should be monitored every one or two weeks. Dose changes in the maintenance phase of treatment should not be made more frequently than every two weeks.
Treatment of symptomatic chemotherapy induced anaemia in cancer patients
Administer subcutaneously to patients with anaemia (e.g. haemoglobin concentration equal to or less than 10g/dL (6.2mmol/L)).
The recommended initial dose is 500micrograms (6.75micrograms/kg) given once every three weeks. Alternatively, 2.25micrograms/kg body weight as a single injection may be given once weekly. If the clinical response of the patient (fatigue, haemoglobin response) is inadequate after nine weeks, further therapy may not be effective. The therapy should be continued for approximately four weeks after the end of chemotherapy.
Haemoglobin levels should not exceed 12g/dL (7.5mmol/l).
Once the therapeutic objective has been achieved for the patient, the dose should be reduced by 25 - 50% in order to ensure that the lowest approved dose of darbepoetin alfa is used to maintain haemoglobin at that level. Appropriate dose titration between 500microgram, 300microgram, and 150microgram should be considered.
Patients should be monitored closely, if the haemoglobin exceeds 12 g/dl (7.5 mmol/l), the dose should be reduced by approximately 25 to 50%. Treatment with darbepoetin should be temporarily discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at approximately 25% lower than the previous dose after haemoglobin levels fall to 12 g/dl (7.5 mmol/l) or below.
The dose should be reduced by 25 to 50% if the rise in haemoglobin exceeds 2g/dL (1.25 mmol/l) in a four week period.
Children
Contraindicated in children under 1 year
Treatment of symptomatic anaemia in chronic renal failure patients
Correction phase
Children 11 years and over - See Adult dosage
There are no recommendations available for the correction of haemoglobin in children aged 1 to 10 years
Maintenance phase
Children 11 years and over - See Adult dosage
There are no recommendations available for the maintenance of haemoglobin in children aged 1 to 10 years
Patients with Hepatic Impairment
Active hepatic disease was an exclusion criteria in all studies of darbepoetin alfa, therefore no data are available from patients with hepatic impairment.
Since the liver is thought to be the principal route of elimination of darbepoetin alfa and recombinant human erythropoietins, darbepoetin alfa should be used with caution in patients with hepatic disease.
Additional Dosage Information
Changing from other treatments for anaemia in chronic renal failure
Adults
Clinical studies have shown that adult patients receiving recombinant human erythropoietin once, twice or three times weekly may change to once weekly or once every fortnight dosing of darbepoetin alfa. The initial weekly dose of darbepoetin alfa (micrograms/week) can be determined by dividing the total weekly dose of recombinant human erythropoietin (IU/week) by 200. The initial once every fortnight dose of darbepoetin alfa (micrograms/fortnight) can be determined by dividing the total cumulative dose of recombinant human erythropoietin administered over a 2 week period by 200. Titration of the optimal therapeutic dose is needed because of patient variability. When substituting darbepoetin alfa for recombinant human erythropoietin, the haemoglobin should be monitored every one or two weeks and the same route of administration should be used.
Children
Clinical studies have shown that paediatric patients aged 1-18 years receiving recombinant human erythropoietin two or three times weekly may change to once weekly darbepoetin alfa, and those receiving recombinant human erythropoietin once weekly may change to once every other week darbepoetin alfa. The initial weekly paediatric dose of darbepoetin alfa (micrograms/week) can be determined by dividing the total weekly dose of recombinant human erythropoietin (IU/week) by 240. The initial once every fortnight paediatric dose of darbepoetin alfa (micrograms/fortnight) can be determined by dividing the total cumulative dose of recombinant human erythropoietin administered over a 2 week period by 240. Titration of the optimal therapeutic dose is needed because of patient variability. When substituting darbepoetin alfa for recombinant human erythropoietin, the haemoglobin should be monitored every one or two weeks and the same route of administration should be used.
Administration
When changing the route of administration the same dose must be used and the haemoglobin monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the haemoglobin at the desired level.
Subcutaneous injection is preferable in patients who are not receiving haemodialysis to avoid the puncture of peripheral veins.
Rotate the injection site and inject slowly to avoid discomfort at the site of injection.
Pre-filled syringe
For subcutaneous or intravenous administration.
Pre-filled pen
For subcutaneous administration only.
Handling
The product is sterile but unpreserved. Do not administer more than one dose per pen/syringe, any solution remaining in the pen/syringe should be discarded.
The pre-filled pen delivers the complete dose and may only be used once.
Before administration the solution should be inspected for visible particles. Only solutions which are colourless, clear or slightly opalescent, should be injected. Do not shake. Allow the pre-filled pen/syringe to reach room temperature before injecting.
Dispose of any unused product or waste material in accordance with local requirements.
Incompatibilities
In the absence of incompatibility studies, darbepoetin alfa should not be mixed or administered as an infusion with other medicinal products.
Contraindications
Poorly controlled hypertension
Pure red cell aplasia following erythropoietin treatment
Suspected or confirmed neutralising antibodies to erythropoietin
Children under 1 year
Precautions and Warnings
Treatment should be initiated by a specialist experienced in the management of anaemia in chronic renal failure or non-myeloid malignancy.
Trade name of erythropoiesis-stimulating agents (ESA) should be clearly recorded in the patients file in order to improve traceability.
Not all indications are licensed for all age groups.
Pregnancy - see Pregnancy section
Breastfeeding - see Lactation section
Life threatening or fatal severe adverse skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in association with epoetin treatment. Advise the patient to monitor for signs and symptoms of skin reactions. Discontinue and do not restart treatment if severe skin reactions such as SJS or TEN occur.
Monitor iron status before and during treatment in all patients. Supplementary iron therapy may be necessary and is recommended for chronic renal failure patients with serum ferritin values below 100 microgram/L or whose transferrin saturation is below 20%.
All other causes of anaemia (iron deficiency, haemolysis, blood loss, vitamin B12 or folate deficiencies) should be excluded before instituting therapy with darbepoetin alfa.
Blood pressure should be monitored in all patients, particularly during the initiation of therapy. If blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be reduced by decreasing or withholding the dose of darbepoetin alfa.
Patients with no response to darbepoetin alfa should be investigated to establish the cause. Deficiencies of iron, folic acid or vitamin B12 reduce the effectiveness of the erythropoiesis stimulating agents and should therefore be corrected. Similarly, intercurrent infections, inflammatory or traumatic episodes, occult blood loss, haemolysis, underlying haematological diseases, bone marrow fibrosis or severe aluminium toxicity may also compromise an erythropoietic response.
Investigations should include a reticulocyte count. If typical causes of non-response are excluded and the patient has reticulocytopenia, bone marrow examination should be considered. Testing for anti-erythropoietin antibodies should be performed if the bone marrow is consistent with pure red cell aplasia.
Use with caution in thrombocytosis - monitor platelet count for first 8 weeks.
Erythropoietin therapy has been associated with pure red cell aplasia caused by neutralising anti-erythropoietin antibodies. These antibodies cross-react with all erythropoietic proteins and patients with these antibodies should not receive darbepoetin alfa - see also CSM Warnings.
Patients suspected or confirmed to have neutralising antibodies to erythropoietin should not be switched to darbepoetin alfa.
Risk of thrombosis may be increased if used before orthopaedic surgery. Avoid in cardiovascular disease including recent myocardial infarction or cerebrovascular event.
Risk of thrombosis may be increased when used for anaemia in adults receiving cancer chemotherapy.
Use with caution in patients with hepatic impairment - see Dosage; Hepatic Impairment
Use with caution in patients with sickle cell anaemia.
Use with caution in patients with epilepsy as convulsions have been reported during the treatment with darbepoetin alfa.
Misuse of darbepoetin alfa by healthy persons may lead to an excessive increase in packed cell volume. This may be associated with life threatening complications of the cardiovascular system.
Use is restricted in certain sports.
The needle cover of pre-filled pen/syringe contains dry natural rubber, a derivative of latex, which may cause allergic reactions.
Chronic renal failure patients
Supplementary iron therapy is recommended for chronic renal failure patients with serum ferritin values below 100 microgram/L or whose transferrin saturation is below 20%.
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed 12 g/dl (7.5 mmol/l). An increased risk of death, serious cardiovascular or cerebrovascular events including stroke, and vascular access thrombosis was observed when erythropoiesis-stimulating agents were administered to target a haemoglobin of greater than 12 g/dl (7.5 mmol/l).
Monitor serum potassium levels regularly during treatment since potassium elevation has been reported although causality has not been established. If an elevated or rising potassium level is observed then consideration should be given to ceasing darbepoetin alfa administration until the level has been corrected.
Cancer patients
If haemoglobin values exceed 12g/dL in patients with solid tumours or lymphoproliferative malignancies, recommended dosage adjustments should be closely adhered to in order to reduce the risk of developing thromboembolic events - see Dosage section. Platelet counts and haemoglobin level should be monitored regularly.
Darbepoetin alfa is a growth factor that stimulates red blood cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells. There is a concern that darbepoetin alfa could stimulate the growth of any type of malignancy.
Clinical studies have suggested, that when erythropoietins were administered to patients suffering from cancer there was a shortened time to tumour progression, shortened overall survival and increased deaths attributed to disease progression. Therefore, in some clinical situations blood transfusions should be the preferred treatment for the management of anaemia in patients with cancer. See CSM Warnings below.
The decision to administer erythropoietins to cancer patients should be made after an informed risk-benefit assessment which takes into account tumour type and its stage; degree of anaemia; life expectancy; the treatment environment and the patient's preference.
CSM Warnings
Pure red cell aplasia
There have been very rare reports of pure red cell aplasia in patients treated with erythropoietin therapy. The CSM (CHM) has advised that in patients developing erythropoietin failure with pure red cell aplasia, treatment with erythropoietins must be discontinued and testing for erythropoietin antibodies considered. Patients who develop pure red cell aplasia should not be switched to another erythropoietin.
Erythropoietins - haemoglobin concentrations
Overcorrection of haemoglobin concentration in patients with chronic kidney disease may increase the risk of death and serious cardiovascular events, and in patients with cancer may increase the risk of thrombosis and related complications:
- Patients may be treated with erythropoietins for the licensed indications in chronic kidney disease or cancer in patients receiving chemotherapy only if symptoms of anaemia are present;
- The target haemoglobin concentration range is 10-12g/100 ml;
- Haemoglobin concentrations higher than 12g/100ml should be avoided;
- The aim of treatment is to relieve symptoms of anaemia, and in patients with chronic renal disease to avoid the need for blood transfusion; the haemoglobin concentration should not be increased beyond that which provides adequate control of symptoms of anaemia (in some patients, this may be achieved at concentrations lower than the recommended range).
Erythropoietins - tumour progression and survival in patients with cancer( see also below)
Clinical trial data show an unexplained excess mortality and increased risk of tumour progression in patients with anaemia associated with cancer who have been treated with erythropoietins outside of the licensed indications (i.e. overcorrected haemoglobin concentration or patients who have not received chemotherapy):
- Erythropoietins licensed for the treatment of symptomatic anaemia associated with cancer, are licensed only for patients who are receiving chemotherapy;
- The decision to use erythropoietins should be based on an assessment of the benefits and risks for individual patients; blood transfusions may be the preferred treatment for anaemia associated with cancer chemotherapy, particularly in those with a good cancer prognosis.
Cancer patients who have a reasonable long life expectancy
The European Medicines Agency (EMEA) has stated that blood transfusions should be the preferred method for correcting anaemia in cancer patients who have a reasonably long life expectancy. Studies have shown an increased risk of tumour progression, venous thromboembolism and shorter survival times in those treated with erythropoietins. The decision to administer epoetin-containing medicines should be based on an informed assessment including: type and stage of tumour, degree of anaemia, life-expectancy, patient preference and treatment environment.
Pregnancy and Lactation
Pregnancy
Use with caution in pregnant women as no clinical data on exposed pregnancies is available.
Briggs suggests that the benefits from darbepoetin probably outweigh the known risks based on animal data and the experience with epoetin alfa.
It is not known whether darbepoetin alfa crosses the human placenta. The very high molecular weight (about 37,000) suggest that transfer across the placenta is unlikely.
Animal studies in rats and rabbits do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.
The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Lactation
Manufacturer advises not to administer to breastfeeding women as there is no clinical experience. When darbepoetin alfa is absolutely indicated women must stop breastfeeding during treatment.
Briggs suggests that as passage into milk is unexpected and if it did occur it would be digested by the infant therefore the risk to nursing infants appears to be non-existent.
Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1
Effects on Ability to Drive and Operate Machinery
No adverse effects on the ability to drive or operate machinery have been observed.
Counselling
Advise patient self-administering to rotate the injection site and inject slowly to avoid discomfort at the site of injection.
Side Effects
Allergic reaction
Anaphylactic reaction
Angioedema
Bronchospasm
Rash
Erythema
Urticaria
Local pain (injection site)
Hypertension
Convulsions
Red cell aplasia
Thromboembolic complications
Stroke
Pulmonary embolism
Oedema
Hypertensive crisis
Encephalopathy-like symptoms
Influenza-like symptoms
Hyperkalaemia
Injection site reactions
Headache
Peripheral oedema
Diarrhoea
Nausea
Vomiting
Tonic-clonic seizures (generalised)
Increase in haematocrit
Thrombocytosis
Increased platelet count
Stevens-Johnson syndrome
Toxic epidermal necrolysis
Blistering
Skin exfoliation
Overdosage
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Shelf Life and Storage
Store at 2 to 8 degrees C.
Do not freeze.
Keep the container in the outer carton to protect from light.
For the purpose of ambulatory use, darbepoetin may be removed from storage once for a maximum single period of seven days at room temperature (up to 25 degrees C).
Further Information
Last Full Review Date: July 2012
Reference Sources
Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.
Martindale: The Complete Drug Reference, 37th edition (2011) ed. Sweetman, S. Pharmaceutical Press, London.
Summary of Product Characteristics: Aranesp. Amgen Ltd. Revised December 2011.
Summary of Product Characteristics: Aranesp PFS SureClick Vial. Amgen Ltd. Revised September 2017.
NICE Evidence Services Available at: www.nice.org.uk Last accessed: 30 July 2012
Drug Safety Update: Volume 2, Issue 1 August 2008
Available at https://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON023078
Published 1st August 2008
Accessed July 16, 2012
EMEA public statement on safety of epoetins in patients with cancer and kidney disease
Available at https://www.ema.europa.eu/docs/en_GB/document_library/Public_statement/2009/11/WC500015604.pdf
Published 23rd October 2007
Accessed July 16, 2012
EMEA public statement recommending a new warning for epoetins for their use in cancer patients
Available at https://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2009/11/WC500015069.pdf
Published 26th June 2008
Accessed July 16, 2012
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