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Drugs List
Therapeutic Indications
Dosage
Administration
Contraindications
Precautions and Warnings
Pregnancy and Lactation
Side Effects
Monograph

Dosage

Adults
Elderly
Children
Neonates

Symptomatic anaemia associated with chronic renal failure

The aim of treatment is to raise the haemoglobin level to within the target range of 10 g/dl (6.2 mmol/l) to 12 g/dl (7.5 mmol/l). Haemoglobin levels of greater than 12 g/dl (7.5 mmol/l) should be avoided.

For non-haemodialysed patients, subcutaneous administration is preferred to avoid puncturing the peripheral veins.
In the presence of hypertension or existing cardiovascular, cerebrovascular or peripheral vascular diseases, the weekly increase in the haemoglobin and target haemoglobin should be determined individually.

Correction phase

When given by subcutaneous injection:
20 units/kg three times weekly. May be increased in steps of 20 units/kg three times weekly at 4-week intervals if the increase in haemoglobin is not adequate (less than 0.25 g/dl per week). The total weekly dose can also be divided into daily doses.
The maximum correction dose should not exceed 720 units/kg weekly.

When given by intravenous injection:
40 units/kg three times a week for the first 4 weeks. May then be increased to 80 units/kg three times a week, and by further increments of 20 units/kg, three times a week, at monthly intervals.
The maximum correction dose should not exceed 720 units/kg weekly.

Maintenance phase

To maintain the haemoglobin between 10 g/dl (6.2 mmol/l) to 12 g/dl (7.5 mmol/l), reduce the dose to half the previously administered amount.
Adjust according to response at intervals of one or two weeks.
In the case of subcutaneous administration, the weekly dose can be given as one injection per week or in divided doses three or seven times per week. Patients who are stable on a once weekly dosing regimen may be switched to once every two weeks administration. In this case dose increases may be necessary.
Treatment with epoetin beta is normally a long term therapy. It can, however be interrupted at any time. Data on the once weekly dosage schedule are based on clinical studies with a treatment duration of 24 weeks.

Dose adjustment

Occasionally, haemoglobin values for a patient may be above or below those desired. This variability should be addressed through dose management, with consideration for the target range of 10 g/dl (6.2 mmol/l) to 12 g/dl (7.5 mmol/l). A rise in haemoglobin of greater than 2 g/dl (1.25 mmol/l) over a four week period or sustained haemoglobin levels of greater than 12 g/dl (7.5 mmol/l) should be avoided. If a rise of greater than 2 g/dl in one month occurs or if it is increasing and nearing the 12 g/dl preferred maximum, then the dose should be reduced by approximately 25%. If haemoglobin levels continue to rise treatment should be stopped until levels decrease. Treatment can then be restarted at a dose 25% lower than the previously administered dose.

Use the lowest dose necessary to provide adequate control of symptoms.

Treatment of symptomatic chemotherapy-induced anaemia in cancer patients

Treatment is indicated if the haemoglobin value is less than or equal to 10 g/dl (6.2 mmol/l).

The dose should be administered subcutaneously. The weekly dose may be given once weekly or divided into 3 to 7 doses.

The recommended initial dose is 450 units/kg per week (approximately 30,000 units per week for an average weight patient).

Dose adjustment

After 4 weeks of therapy, if the haemoglobin value has increased by at least 1 g/dl (0.62 mmol/l), the current dose should be continued. If the value has not increased by at least 1 g/dl after 4 weeks of therapy, doubling the weekly dose should be considered. If the value has not increased by at least 1 g/dl after 8 weeks of therapy, epoetin beta should be discontinued as a clinical response to treatment is unlikely.

Therapy should be continued for up to 4 weeks after the end of chemotherapy.

The maximum dose should not exceed 60,000 units per week.

Once the patient's goals have been achieved, the dose should be reduced by 25 to 50% in order to maintain that haemoglobin level. Further dose reductions may be made to maintain desired levels.

Ensure haemoglobin levels remain below 13 g/dl (8.1 mmol/l).

Occasionally, haemoglobin values for a patient may be above or below those desired. This variability should be addressed through dose management, with consideration for the target range of 10 g/dl (6.2 mmol/l) to 12 g/dl (7.5 mmol/l).
A rise in haemoglobin of greater than 2 g/dl (1.3 mmol/l) over a four week period should be avoided. If this occurs, the dose should be reduced by 25 to 50%.
Sustained haemoglobin levels of greater than 12 g/dl (7.5 mmol/l) should be avoided. If this occurs, the dose should be reduced by 25 to 50%.
If haemoglobin levels rise to or above 13 g/dl then treatment should be stopped until levels decrease to, or below, 12 g/dl. Treatment can then be restarted at a dose 25% lower than the previously administered dose.

Treatment for increasing the yield of autologous blood

The dose should be determined individually (see product information) and should be given by subcutaneous injection or by intravenous injection. The dose should be given twice weekly for 4 weeks.
During the entire treatment period, a packed cell volume (PCV) of 48% should not be exceeded.
When the patient has been able to donate blood, epoetin beta is given at the end of the blood donation.

The required amount of pre-donated blood depends on the anticipated blood loss, the use of blood conserving procedures, and the physical condition of the patient.

The amount should be the quantity that is expected to be sufficient so that homologous blood transfusions are not required. The required amount of pre-donated blood is expressed in units whereby one unit in the normogram is equivalent to 180 ml red cells.

Maximum dose should not exceed 1600 units/kg per week for intravenous or 1200 units/kg per week for subcutaneous administration.

Precautions and Warnings

Predisposition to thromboembolic disease
Premature infants
Breastfeeding
Chronic hepatic impairment
Epileptic disorder
Hepatitis C
Ischaemic heart disease
Malignant neoplasm
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
First dose should be given under medical supervision: Risk of anaphylaxis
Treatment to be prescribed under the supervision of a specialist
Contains phenylalanine
Record name and batch number of administered product
Monitor iron status before and during treatment
Avoid haemoglobin level >12g/dl
Investigate development of severe headaches or migraine
Monitor blood pressure
Monitor haemoglobin levels
Monitor platelet counts for first 8 weeks of therapy
Monitor premature infants for signs of retinopathy
Monitor reticulocyte count at regular intervals
Monitor serum electrolytes
Monitor serum phosphate levels periodically
Monitor serum potassium regularly
Iron supplements may be required if iron deficiency occurs
May act as growth factor for any tumour type
Nephrosclerosis without dialysis: Possible acceleration of renal failure
Discontinue and do not restart if severe cutaneous adverse reactions occur
Discontinue if pure red cell aplasia is diagnosed
Interrupt treatment if blood pressure cannot be controlled by drug therapy
Discontinue if a decrease in haemoglobin occurs
Discontinue if severe anaemia associated with low reticulocytes occurs
Maintain treatment at the lowest effective dose
Optimise heparin dose in chronic renal failure patients on haemodialysis

Increased risk of retinopathy in premature infants. The MHRA advises the following when using epoetin beta for preventing anaemia of prematurity:
- Consider the benefits and risks, including the possible risk of retinopathy
- Monitor the infant for features of retinopathy
- Advise patients or carers that their baby's eyes will be carefully monitored for any ill effects.

In patients with chronic renal failure caution should be exercised with escalation of epoetin beta doses since high cumulative epoetin doses may be associated with an increased risk of mortality, serious cardiovascular and cerebrovascular events. In patients with a poor haemoglobin response to epoetins, alternative explanations for the poor response should be considered.

In patients with chronic renal failure and clinically evident ischaemic heart disease, maintenance haemoglobin concentration should not exceed the upper limit of the target haemoglobin concentration as recommended under 'Dosage'.

No significant benefits have been attributable to the administration of epoetins to increase haemoglobin concentration beyond the level necessary to control symptoms of anaemia and to avoid blood transfusion.

Chronic renal failure and cancer patients on epoetin beta should have haemoglobin levels measured on a regular basis until a stable level is achieved, and periodically thereafter.

Severe aluminium overload in renal failure treatment may reduce the effectiveness of epoetin beta treatment.

In chronic renal failure patients there may be a moderate dose-dependent rise in the platelet count within the normal range during treatment with neorecormon, especially after intravenous administration. This regresses during the course of continued therapy. It is recommended that platelet count is monitored regularly during the first 8 weeks of therapy.

An increase in heparin dose during haemodialysis is frequently required during the course of therapy with epoetin beta as a result of the increased packed cell volume. Occlusion of the dialysis system is possible if heparinisation is not optimum.

If antibody-mediated pure red cell aplasia is suspected, therapy with the causative erythropoietin must be discontinued immediately.

In all patients receiving epoetin beta, blood pressure should be closely monitored and controlled as necessary. Epoetin beta should be used with caution in the presence of untreated, inadequately treated or poorly controllable hypertension. It may be necessary to add or increase antihypertensive treatment. If blood pressure cannot be controlled, epoetin beta treatment should be interrupted.

A sudden stabbing migraine-like pain is a possible warning sign of hypertensive crisis.

Shunt thrombosis may occur, particularly in patients who have a tendency to hypotension or whose arteriovenous fistula exhibit complications, such as aneurysms. Additional management may be required.

It is recommended that platelet count is regularly monitored during the first 8 weeks of therapy since there may be a moderate dose dependent rise in platelet count within the normal range during treatment with epoetin beta. This regresses during the course of continued therapy.

Use with caution in refractory anaemia with excess blasts in transformation.

Discontinue if a paradoxical decrease in haemoglobin and development of severe anaemia associated with low reticulocyte counts occurs. Perform anti-erythropoietin antibody tests. Epoetins are not approved in the management of anaemia associated with hepatitis C.

All other causes of anaemia (iron deficiency, haemolysis, blood loss, vitamin B12 or folate deficiencies) should be excluded before instituting therapy with epoetin beta. In most cases, the ferritin values in the serum fall simultaneously with the rise in packed cell volume. In order to ensure optimum response to epoetin beta, adequate iron stores should be assured.

The European Medicines Agency (EMA) has stated that blood transfusions should be the preferred method for correcting anaemia in cancer patients who have a reasonable 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.

In cancer patients receiving chemotherapy avoid haemoglobin levels above 12 g/dl. Should the rate of increase in haemoglobin exceed 2 g/dl per month or the haemoglobin level exceed 13g/dl, the dose adaptation detailed in 'Dosage' section should be thoroughly performed to minimise potential risk factors of thrombotic events.

It is recommended to monitor blood pressure, particularly in the initial treatment phase in cancer patients. Platelet counts and haemoglobin level should also be monitored at regular intervals in cancer patients.

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).
Epoetin beta is a growth factor that primarily stimulates red blood cell production. Erythropoietin receptors may be present on the surface of a variety of tumour cells. As with all growth factors, 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, cervical, neck and breast cancer) there was an associated reduction in overall survival and a negative effect on progression-free survival. The MHRA therefore suggest 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.

In autologous pre-donation therapy, if there is an increase in platelets of more than 150 x 10 to the power 9 per litre, or if platelets rise above the normal range, then treatment with epoetin beta should be discontinued.

All special warnings and special precautions associated with autologous predonation programmes should be respected in patients being supplemented with epoetin beta for autologous predonation.

A lower target haemoglobin concentration may be appropriate in patients with sickle-cell disease.

Premature infants who have already been transfused at the start of treatment with epoetin beta, will not benefit as much as those not having been transfused.

Misuse by healthy persons may lead to an excessive increase in packed cell volume. This may be associated with life-threatening cardiovascular complications.

Pregnancy and Lactation

Pregnancy

Use epoetin beta with caution in pregnancy. There are no adequate and well controlled studies in pregnant women.

Most available information concerns the related epoetin alfa.

The recombinant glycoprotein erythropoietin alfa does not appear to cross the human placenta.

There are a significant number of case reports describing the use of epoetin alfa during human pregnancy, mostly in pregnancies complicated by pre-existing renal disease.

No cases of thrombosis have been seen in the case reports in the literature, however the risk of this potentially serious complication should be considered

The events and outcomes experienced by the women, including hypertension or worsening renal disease, and offspring could not be specifically attributed to the original disease, concurrent treatments or the epoetin alfa therapy. Some successful outcomes to pregnancies have been described. Briggs concludes that because of the known risks associated with anaemia and blood transfusions, the benefits of epoetin alfa therapy are likely to outweigh the risks.

Studies in rats with epoetin alfa have shown reproductive toxicity. Foetal toxicity (decreased growth, delayed appearance of abdominal hair, delayed eye-lid opening, delayed ossification, decreased number of caudal vertebrae) was observed in the offspring of pregnant rats given 5 times the human dose. Increased foetal wastage was also seen. Similar effects were not seen in rabbits.
The manufacturer of epoetin beta states that animal studies do not indicate direct or indirect harmful effects on 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 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 beta with caution in breastfeeding. It is unknown whether epoetin beta is excreted in human milk.

Endogenous epoetin is a normal component of human milk and it has been hypothesized that this may help maintain the integrity of the lining of the mammary epithelium and the infant gastrointestinal tract.

Studies in which oral doses of the related epoetin alfa were given to preterm infants, found that epoetin is absorbed to a small extent, producing a small to negligible increase in the infants haematocrit.

The risks to a breastfed infant from ingestion of epoetin beta appears to be small.

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

Presentation

Solution for injection containing epoetin beta

Drugs List

epoetin beta 10000unit/0.6ml injection solution

epoetin beta 20000unit/0.6ml injection solution

epoetin beta 2000unit/0.3ml injection solution

epoetin beta 30000unit/0.6ml injection solution

epoetin beta 3000unit/0.3ml injection solution

epoetin beta 4000unit/0.3ml injection solution

epoetin beta 5000unit/0.3ml injection solution

epoetin beta 500unit/0.3ml injection solution

epoetin beta 6000unit/0.3ml injection solution

NEORECORMON 10000unit/0.6ml injection solution

NEORECORMON 20000unit/0.6ml injection solution

NEORECORMON 2000unit/0.3ml injection solution

NEORECORMON 30000unit/0.6ml injection solution

NEORECORMON 3000unit/0.3ml injection solution

NEORECORMON 4000unit/0.3ml injection solution

NEORECORMON 5000unit/0.3ml injection solution

NEORECORMON 500unit/0.3ml injection solution

NEORECORMON 6000unit/0.3ml injection solution

Therapeutic Indications

Uses

Prevention of anaemia in infants weighing 750-1500g and <34 weeks gestation
Symptomatic anaemia - due to chronic renal failure
Symptomatic anaemia in adults with solid tumours receiving chemotherapy
To increase yield of autologous blood in predonation programmes

Dosage

Adults

Symptomatic anaemia associated with chronic renal failure

Correction phase
When given by subcutaneous injection:
20 units/kg three times weekly. May be increased in steps of 20 units/kg three times weekly at 4-week intervals if the increase in haemoglobin is not adequate (less than 0.25 g/dl per week). The total weekly dose can also be divided into daily doses.
The maximum correction dose should not exceed 720 units/kg weekly.

Maintenance phase
To maintain the haemoglobin between 10 g/dl (6.2 mmol/l) to 12 g/dl (7.5 mmol/l), reduce the dose to half the previously administered amount.
Adjust according to response at intervals of one or two weeks.
In the case of subcutaneous administration, the weekly dose can be given as one injection per week or in divided doses three or seven times per week. Patients who are stable on a once weekly dosing regimen may be switched to once every two weeks administration. In this case dose increases may be necessary.
Treatment with epoetin beta is normally a long term therapy. It can, however be interrupted at any time. Data on the once weekly dosage schedule are based on clinical studies with a treatment duration of 24 weeks.

Dose adjustment
Occasionally, haemoglobin values for a patient may be above or below those desired. This variability should be addressed through dose management, with consideration for the target range of 10 g/dl (6.2 mmol/l) to 12 g/dl (7.5 mmol/l). A rise in haemoglobin of greater than 2 g/dl (1.25 mmol/l) over a four week period or sustained haemoglobin levels of greater than 12 g/dl (7.5 mmol/l) should be avoided. If a rise of greater than 2 g/dl in one month occurs or if it is increasing and nearing the 12 g/dl preferred maximum, then the dose should be reduced by approximately 25%. If haemoglobin levels continue to rise treatment should be stopped until levels decrease. Treatment can then be restarted at a dose 25% lower than the previously administered dose.

Use the lowest dose necessary to provide adequate control of symptoms.

Treatment of symptomatic chemotherapy-induced anaemia in cancer patients

Treatment is indicated if the haemoglobin value is less than or equal to 10 g/dl (6.2 mmol/l).

The dose should be administered subcutaneously. The weekly dose may be given once weekly or divided into 3 to 7 doses.

The recommended initial dose is 450 units/kg per week (approximately 30,000 units per week for an average weight patient).

Dose adjustment
After 4 weeks of therapy, if the haemoglobin value has increased by at least 1 g/dl (0.62 mmol/l), the current dose should be continued. If the value has not increased by at least 1 g/dl after 4 weeks of therapy, doubling the weekly dose should be considered. If the value has not increased by at least 1 g/dl after 8 weeks of therapy, epoetin beta should be discontinued as a clinical response to treatment is unlikely.

Therapy should be continued for up to 4 weeks after the end of chemotherapy.

The maximum dose should not exceed 60,000 units per week.

Once the patient's goals have been achieved, the dose should be reduced by 25 to 50% in order to maintain that haemoglobin level. Further dose reductions may be made to maintain desired levels.

Ensure haemoglobin levels remain below 13 g/dl (8.1 mmol/l).

Occasionally, haemoglobin values for a patient may be above or below those desired. This variability should be addressed through dose management, with consideration for the target range of 10 g/dl (6.2 mmol/l) to 12 g/dl (7.5 mmol/l).
A rise in haemoglobin of greater than 2 g/dl (1.3 mmol/l) over a four week period should be avoided. If this occurs, the dose should be reduced by 25 to 50%.
Sustained haemoglobin levels of greater than 12 g/dl (7.5 mmol/l) should be avoided. If this occurs, the dose should be reduced by 25 to 50%.
If haemoglobin levels rise to or above 13 g/dl then treatment should be stopped until levels decrease to, or below, 12 g/dl. Treatment can then be restarted at a dose 25% lower than the previously administered dose.

Treatment for increasing the yield of autologous blood

The required amount of pre-donated blood depends on the anticipated blood loss, the use of blood conserving procedures, and the physical condition of the patient.

Maximum dose should not exceed 1600 units/kg per week for intravenous or 1200 units/kg per week for subcutaneous administration.

Elderly

(See Dosage; Adult)

Children

Symptomatic anaemia associated with chronic renal failure

(See Dosage; Adult)

Results of clinical trials on children have shown that on average the younger the patient, the higher the dose required. The recommended dosage should be followed, adjusting to individual response.

Neonates

Prevention of anaemia of prematurity

250 units/kg by subcutaneous injection three times weekly and continuing for 6 weeks.

Premature infants who have already been transfused at the start of treatment with epoetin beta, will not benefit as much as those not having been transfused.

Symptomatic anaemia associated with chronic renal failure

(See Dosage; Adult)

Results of clinical trials on children have shown that on average the younger the patient, the higher the dose required. The recommended dosage should be followed, adjusting to individual response.

Administration

Pre-filled syringe presentations can be given by subcutaneous injection or by intravenous injection over 2 minutes.

When administered by intravenous injection, this should be given over not less than 2 minutes. Administration over 5 minutes may reduce the influenza-like symptoms sometimes reported.

Contraindications

Inadequate antithrombotic prophylaxis
Predisposition to venous thromboembolism - if for autologous blood yield
Pure red cell aplasia following previous erythropoietic therapy
Cerebrovascular accident in previous month - if for autologous blood yield
Myocardial infarction in previous month - if for autologous blood yield
Phenylketonuria
Uncontrolled hypertension
Unstable angina - if for autologous blood yield