Epoetin zeta parenteral
- Drugs List
- Therapeutic Indications
- Dosage
- Administration
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Solution for injection containing epoetin zeta
Drugs List
Therapeutic Indications
Uses
Moderate anaemia before elective orthopaedic surgery (blood loss expected)
Symptomatic anaemia - due to chronic renal failure
Symptomatic anaemia - if severe in patients not yet undergoing dialysis
Symptomatic anaemia in adults with malignant lymphoma on chemotherapy
Symptomatic anaemia in adults with multiple myeloma receiving chemotherapy
Symptomatic anaemia in adults with solid tumours receiving chemotherapy
To increase yield of autologous blood in predonation programmes
Treatment of symptomatic anaemia associated with chronic renal failure in children and adults on haemodialysis and adults on peritoneal dialysis.
Treatment of severe symptomatic anaemia of renal origin in adult patients with renal impairment not yet undergoing dialysis.
Treatment of symptomatic anaemia and reduction of transfusion requirements in adult patients receiving chemotherapy for solid tumours, malignant lymphoma or multiple myeloma, and at risk of transfusion as assessed by the patient's general status (e.g. cardiovascular status, pre-existing anaemia at the start of chemotherapy).
To increase the yield of autologous blood from patients in a predonation programme. Treatment should only be given to patients with moderate anaemia (no iron deficiency), if blood conserving procedures are insufficient or unavailable when scheduled major elective surgery requires a large volume of blood (4 or more units for females, 5 or more units for males). The use of epoetin zeta in this indication must be balanced against the reported risk of thromboembolic events.
To reduce exposure to allogeneic blood transfusions in adult non-iron deficient patients at high risk of transfusion complications prior to major elective orthopaedic surgery. Use should be limited to patients with moderate anaemia (e.g. haemoglobin 10 to 13 g/dl) who do not have an autologous predonation programme available and with expected blood loss of 900 to 1800 ml.
Dosage
Treatment should be initiated under the supervision of a specialist experienced in management of patients with the above indications.
Patients should be monitored closely to ensure that the lowest approved dose of epoetin zeta is used to provide adequate control of the symptoms of anaemia. Anaemia symptoms and sequelae may vary with age, gender, and overall burden of disease: an evaluation of the patient's clinical course and condition is necessary. Due to intra-patient variability, occasional individual haemoglobin values for a patient above and below the desired haemoglobin levels may be observed.
Adults
Chronic renal failure patients
Should be administered either subcutaneously or intravenously in order to increase haemoglobin (Hb) to not greater than 12 g/dl (7.5 mmol/L). The Hb concentration aimed for is between 10 and 12 g/dl (6.2 to 7.5 mmol/l). In patients with chronic renal failure and clinically evident ischaemic heart disease or congestive heart failure, maintenance Hb concentration should not exceed the upper limit of the target Hb concentration.
The rate of increase of Hb should be approximately 1 g/dl (0.62 mmol/l) per month. The rate should not exceed 2 g/dl (1.25 mmol/l) per month to minimise the risk of exacerbation of hypertension. If a rise in Hb greater than 2 g/dl (1.25 mmol/l) per month occurs, the dose should be adjusted.
Haemodialysis patients
Correction phase: 50 units/kg three times per week. Dosage may be adjusted at 4 weekly intervals (in steps of 25 units/kg three times per week) until the desired response is achieved.
Maintenance phase: The recommended total weekly dose is between 75 and 300 units/kg. Dosage should be adjusted in order to maintain Hb levels between 10 and 12 g/dl (6.2 to 7.5 mmol/l).
The clinical data available suggest that those patients whose initial Hb is very low (Hb less than 6 g/dl or less than 3.75 mmol/l) may require higher maintenance doses than those whose initial anaemia is less severe (Hb greater than 8 g/dl or greater than 5mmol/l).
Patients with renal impairment not yet undergoing dialysis
Correction phase: 50 units/kg three times per week. Dosage may be adjusted at 4 weekly intervals (in steps of 25 units/kg three times per week) until the desired response is achieved.
Maintenance phase: Dosage should be adjusted in order to maintain Hb levels between 10 and 12 g/dl (6.2 to 7.5 mmol/l). Administer either 3 times per week, and in the case of subcutaneous administration, once weekly or once every 2 weeks. Extending dose intervals may require an increase in dose.
The maximum recommended dose should not exceed 150 units/kg three times per week, 240 units/kg (up to a maximum of 20,000 units) once weekly or 480 units/kg (up to a maximum of 40,000 units) once every 2 weeks.
Peritoneal dialysis patients
Correction phase: 50 units/kg twice a week.
Maintenance phase: 25 to 50 units/kg twice a week given in two equal injections. Dosage should be adjusted in order to maintain Hb levels between 10 and 12 g/dl (6.2 to 7.5 mmol/l).
Cancer patients receiving chemotherapy
The subcutaneous route should be used. Epoetin zeta therapy should be administered to patients with anaemia (e.g. haemoglobin less than or equal to 10 g/dl (6.2 mmol/l)). The haemoglobin (Hb) concentration aimed for is approximately 10 g/dl (6.2 mmol/l) to 12 g/dl (7.5 mmol/l). A sustained Hb level of greater than 12 g/dl (7.5 mmol/l) should be avoided.
Initial dose: 150 units/kg three times a week. Alternatively, an initial dose of 450 units/kg may be administered once weekly. Epoetin zeta therapy should continue until one month after the end of chemotherapy.
If the Hb has increased by at least 1 g/dl (0.62 mmol/l) or the reticulocyte count has increased to or above 40,000 cells/microlitre above baseline after 4 weeks of treatment, the dose should remain at 150 units/kg three times a week or 450 units/kg once weekly.
If the Hb increase is less than 1 g/dl (0.62 mmol/l) and the reticulocyte count increase is less than 40,000 cells/microlitre above baseline, the dosage should be increased to 300 units/kg three times per week.
If after an additional four weeks of treatment at 300 units/kg three times per week, the Hb has increased to or above 1 g/dl (0.62 mmol/l) or the reticulocyte count has increased to or above 40,000 cells/microlitre the dose should remain at 300 units/kg three times per week.
However, if the Hb has increased less than 1 g/dl (0.62 mmol/l) and reticulocyte count increase is less than 40,000 cells/microlitre above baseline, response is unlikely and treatment should be discontinued.
Once the therapeutic objective for an individual patient has been achieved, the dose should be reduced by 25 to 50% in order to maintain haemoglobin at that level. Appropriate dose titration should be considered.
Dose adjustment: If the Hb is rising by more than 2 g/dl (1.25 mmol/l) per month, reduce the epoetin zeta dose by about 25 to 50%. If the haemoglobin exceeds 12 g/dl (7.5 mmol/l), discontinue therapy until it falls to 12 g/dl (7.5 mmol/l) or lower and then reinstitute epoetin zeta at a dose 25% below the previous dose.
Autologous predonation programme
The intravenous route should be used.
At the time of donating blood, epoetin zeta should be administered after the completion of the blood donation procedure. Mildly anaemic patients (haematocrit of 33 to 39%) requiring predeposit of 4 or more units of blood should receive 600 units/kg twice weekly for 3 weeks prior to surgery.
Adequate oral iron supplementation should be given to all patients before and during treatment (e.g. 200 mg oral elemental iron daily). Iron supplementation should be started as soon as possible, even several weeks prior to initiating the autologous predeposit, in order to achieve high iron stores prior to initiating epoetin zeta therapy.
Patients scheduled for major elective orthopaedic surgery
The subcutaneous route should be used.
A dose of 600 units/kg should be administered once weekly for three weeks prior to the surgery and on the day of surgery. If the time prior to the surgery is less than 3 weeks then a dose of 300 units/kg should be administered daily for 10 consecutive days prior to surgery, on the day of surgery, and for 4 days after surgery.
If the haemoglobin level reaches 15 g/dl, or higher, during the preoperative period, epoetin zeta therapy should be discontinued.
Iron deficiencies should be treated before the start of therapy with epoetin zeta. Adequate oral iron supplementation (e.g. 200 mg oral elemental iron daily) should be given to all patients throughout the course of treatment with epoetin zeta and if possible started prior to the treatment.
Elderly
(See Dosage; Adults)
Children
Chronic renal failure patients
The intravenous route should be used.
The haemoglobin (Hb) concentration aimed for in paediatric patients is between 9.5 and 11 g/dl (5.9 to 6.8 mmol/l). The upper limit of the target Hb concentration should not be exceeded. In patients with chronic renal failure and clinically evident ischaemic heart disease or congestive heart failure, maintenance Hb concentration should not exceed the upper limit of the target Hb concentration.
The rate of increase of Hb should be approximately 1 g/dl (0.62 mmol/l) per month. The rate should not exceed 2 g/dl (1.25 mmol/l) per month to minimise the risk of exacerbation of hypertension. If a rise in Hb greater than 2 g/dl (1.25 mmol/l) per month occurs, the dose should be adjusted.
Haemodialysis patients
Correction phase: 50 units/kg three times per week. Dosage may be adjusted at 4 weekly intervals (in steps of 25 units/kg three times per week) until the desired response is achieved.
Maintenance phase: Dosage should be adjusted in order to maintain Hb levels between 9.5 and 11 g/dl (5.9 to 6.8 mmol/l).
Generally, children under 30 kg require proportionately higher maintenance doses than children over 30 kg and adults.
The following maintenance doses were observed in clinical trials after 6 months of treatment:
Weight less than 10 kg: Usual maintenance dose 75 to 150 units/kg three times a week (median dose 100 units/kg three times a week).
Weight between 10 and 30 kg: Usual maintenance dose 60 to 150 units/kg three times a week (median dose 75 units/kg three times a week).
Weight greater than 30 kg: Usual maintenance dose 30 to 100 units/kg three times a week (median dose 33 units/kg three times a week).
The clinical data available suggest that those patients whose initial Hb is very low (less than 6.8 g/dl or less than 4.25 mmol/l) may require higher maintenance doses than those whose initial Hb is higher (greater than 6.8 g/dl or greater than 4.25 mmol/l).
Administration
For administration by intravenous injection or subcutaneous injection (according to indication).
Intravenous injection
Administered by slow intravenous injection over at least one to five minutes, depending on the total dose. A slower injection is preferable in patients who react to treatment with 'flu-like' symptoms.
In patients receiving haemodialysis, a bolus injection may be administered through a suitable venous port in the dialysis line. Alternatively, the injection may be administered at the end of the dialysis session via fistula needle tubing. The tubing should then be flushed with 10ml of sodium chloride 0.9% injection.
Subcutaneous injection
Generally, the maximum volume per injection site should not exceed 1 ml. Where larger volumes are required, administer the dose at multiple injection sites. The required dose is administered via the subcutaneous route into the limbs or the anterior abdominal wall.
Contraindications
Inadequate antithrombotic prophylaxis
Pure red cell aplasia following previous erythropoietic therapy
Phenylketonuria
Uncontrolled hypertension
Precautions and Warnings
Predisposition to thromboembolic disease
Breastfeeding
Chronic hepatic impairment
Congestive cardiac failure
Epileptic disorder
Hepatitis C
History of seizures
Hypertension
Ischaemic heart disease
Pregnancy
Sickle cell disease
Thrombocythaemia
Blood transfusion is preferred treatment for anaemia in cancer patients
Consider early shunt revision/thrombosis prophylaxis in patients at risk
Exclude other causes of anaemia before treatment
Not all routes are licensed for all indications
Treatment to be initiated and supervised by a specialist
Contains phenylalanine
Record name and batch number of administered product
Monitor iron status before and during treatment
Avoid haemoglobin level >12g/dl
Consider discontinuing treatment until hyperkalaemia has been corrected
Increased risk of thrombotic events if haemoglobin >13g/dl
Investigate patients developing a sudden lack of response to treatment
Monitor blood pressure
Monitor haemoglobin levels
Monitor platelet counts for first 8 weeks of therapy
Monitor reticulocyte count at regular intervals
Monitor serum electrolytes in chronic renal failure
Monitor serum potassium regularly
Advise patient to contact their physician if worsening of anaemia symptoms
Iron supplements may be required if iron deficiency occurs
May act as growth factor for any tumour type
Discontinue and do not restart if severe cutaneous adverse reactions occur
Discontinue if blood pressure cannot be controlled
Discontinue if pure red cell aplasia is diagnosed
Maintain treatment at the lowest effective dose
Not licensed for all indications in all age groups
Optimise heparin dose in chronic renal failure patients on haemodialysis
Discontinue treatment with epoetin zeta if a paradoxical decrease in haemoglobin (Hb) and development of severe anaemia associated with low reticulocyte counts is seen. Anti-erythropoietin antibody testing should also be considered in this situation. Cases have been reported in patients with hepatitis C with interferon and ribavirin, when epoetins are used concomitantly. Epoetins are not approved in the management of anaemia associated with hepatitis C.
In all patients, typical causes of non-response should be investigated (such as iron, folate, or vitamin B12 deficiency; aluminium intoxication; intercurrent infections; inflammatory or traumatic episodes; occult blood loss; haemolysis, and bone marrow fibrosis of any origin). If no typical cause is identified, a bone marrow investigation and testing for antibodies should be considered. If antibody-mediated PRCA is suspected or if a sudden loss of efficacy is seen, therapy with epoetin zeta must be discontinued immediately. Patients must not be switched to other erythropoietin products. Other causes of PRCA should be excluded.
In cancer patients receiving chemotherapy, the 2 to 3 week delay between erythropoietin administration and the appearance of erythropoietin-induced red cells should be taken into account when assessing if epoetin zeta therapy is appropriate (patient at risk of being transfused). If the rate of increase in Hb exceeds 2 g/dl per month or the Hb level exceeds 12 g/dl, the dose adaptation detailed in 'Dosage' section should be thoroughly performed to minimise the potential risk of thrombotic events.
An increased incidence of thrombotic vascular events has been seen in cancer patients receiving erythropoietins. Before therapy is initiated, this risk should be carefully considered, especially in those with risk factors for thrombotic events such as obese patients and those with a history of thrombotic events (e.g. deep vein thrombosis or pulmonary embolism).
Erythropoietin receptors may be present on the surface of a variety of tumour cells. There is a possibility that erythropoietins may stimulate the growth of any type of malignancy. Clinical studies have suggested, that when erythropoietins were administered to patients with various cancers (including head and neck, lung and breast cancer) there was an associated reduction in overall survival and a negative effect on progression-free survival. The MHRA therefore suggests that blood transfusion should be the preferred treatment for anaemia in cancer patients. The decision to administer erythropoietins to cancer patients should be made after an informed risk benefit assessment which takes into account: tumour type and stage; degree of anaemia; life expectancy; the treatment environment and the patient's preference.
Pregnancy and Lactation
Pregnancy
Use epoetin zeta with caution in pregnancy.
There are no adequate and well controlled studies of epoetins in pregnant women. In animal studies, erythropoietin has been shown to decrease foetal body weight, delay ossification and increase foetal mortality when given in large doses. The manufacturer recommends that erythropoietin should generally be used during pregnancy only if the potential benefit outweighs the potential risk to the foetus.
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 to 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
Use epoetin zeta with caution in breastfeeding.
The manufacturer states that epoetin should be used during breastfeeding only if the potential benefit outweighs the potential risk to the foetus.
At the time of writing, no information relating to the use of epoetin zeta during breastfeeding was noted.
There is some information concerning the use of the related epoetin alfa. Epoetin alfa has a large molecular weight and passage into milk is not expected. Hale (2010) states that due to its protein nature, epoetin alfa is not likely to be absorbed orally to any degree by the infant. In small studies, epoetin alfa administration decreased serum prolactin in patients with amyotrophic lateral sclerosis, but had no effect in normal subjects or in patients with renal failure undergoing chronic ambulatory peritoneal dialysis (LactMed).
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
Side Effects
Aggravation of existing hypertension
Aneurysm
Angioedema
Antibody formation
Arterial thrombosis
Cerebral haemorrhage
Cerebral infarct
Cerebrovascular accident
Clotting of an artificial kidney
Confusion
Deep vein thrombosis (DVT)
Diarrhoea
Dizziness
Encephalopathy-like symptoms
Erythroblastopenia
Headache
Hyperkalaemia
Hypersensitivity reactions including anaphylaxis
Hypertension
Hypertensive crisis in some patients (with normal or low blood pressure)
Hypertensive encephalopathy
Increase in haematocrit
Increased blood pressure
Increased platelet count
Influenza-like symptoms
Injection site reactions
Joint pain
Migraine-like headache
Myocardial infarction
Myocardial ischaemia
Nausea
Peripheral oedema
Pruritus
Pulmonary embolism
Rash
Red cell aplasia
Respiratory congestion
Retinal vein thrombosis
Shunt thrombosis
Skin reactions
Stevens-Johnson syndrome
Thrombocytosis
Thromboembolic disorders
Tiredness
Tonic-clonic seizures (generalised)
Toxic epidermal necrolysis
Transient ischaemic attack
Vascular disorders
Vomiting
Weakness
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 ).
Further Information
Last Full Review Date: June 2014
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.
Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press https://www.medicinescomplete.com Accessed on 6 June, 2014.
Paediatric Formulary Committee. BNF for Children (online) London: BMJ Group, Pharmaceutical Press, and RCPCH Publications https://www.medicinescomplete.com Accessed on 6 June, 2014.
Martindale: The Complete Drug Reference, 37th edition (2011) ed. Sweetman, S. Pharmaceutical Press, London.
Medications and Mothers' Milk, 14th Edition (2010) Hale, T. Hale Publishing, Amarillo, Texas.
Summary of Product Characteristics: Retacrit solution for injection in pre-filled syringe. Hospira UK Ltd. Revised July 2014.
Drug Safety Update: Volume 2, Issue 1 August 2008
Available at https://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON023078
Published 1st August 2008.
Last accessed: June 6, 2014
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.
Last accessed: June 6, 2014
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.
Last accessed: June 6, 2014
US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Epoetin Alfa. Last revised: September 7, 2013.
Last accessed: June 6, 2014
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